Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry Reaction

Article abstract of DOI:10.1021/acs.joc.7b00079

We have developed a novel multifunctional C₂-symmetric biphenyl-based diamine-tethered bis(thiourea) organocatalyst, which was tested in the asymmetric Henry reaction. Under thoroughly optimized conditions, the catalyst provided exceptionally high yields and excellent enantioselectivities especially for electron-deficient aromatic and heterocyclic substrates. Due to a high affinity of the catalyst to silica gel, a simple chromatography-free nitroaldol isolation procedure was feasible. Preliminary kinetic and spectroscopic experiments were performed in order to complete the mechanistic picture of the organocatalyzed nitroaldolization process. Finally, the developed synthetic strategy was successfully applied to the catalytic enantioselective syntheses of enantiopure (S)-econazole and (R)-mirabegron a late-stage intermediate.

Full text of DOI:10.1021/acs.joc.7b00079

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Article
Diamine-Tethered Bis(thiourea) Organocatalyst
for Asymmetric Henry Reaction.
Jan Otevrel, and Pavel Bobal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00079 • Publication Date (Web): 17 Jul 2017
Downloaded from http://pubs.acs.org on July 18, 2017
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The Journal of Organic Chemistry
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Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric
Henry Reaction.
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Jan Otevrel, and Pavel Bobal.*
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences (UVPS) Brno,
Palackeho 1946/1, 612 42 Brno, Czech Republic.
Bis(thiourea); Asymmetric Henry reaction; Multifunctional Catalysts; Mirabegron; Econazole.
ABSTRACT: We have developed a novel multifunctional C2ꢀsymmetric biphenylꢀbased diamineꢀtethered bis(thiourea)
organocatalyst, which was tested in the asymmetric Henry reaction. Under thoroughly optimized conditions, the catalyst provided
exceptionally high yields and excellent enantioselectivities especially for electronꢀdeficient aromatic and heterocyclic substrates.
Due to a high affinity of the catalyst to silica gel, a simple chromatographyꢀfree nitroaldol isolation procedure was feasible.
Preliminary kinetic and spectroscopic experiments were performed in order to complete the mechanistic picture of the
organocatalyzed nitroaldolization process. Finally, the developed synthetic strategy was successfully applied to the catalytic enantiꢀ
oselective syntheses of enantiopure (S)ꢀeconazole and (R)ꢀmirabegron a lateꢀstage intermediate.
Introduction
OH
O
OH
N
H
The enantioenriched nitroaldol adducts have been recognized
as an almost unlimited source of valuable synthetic intermediꢀ
ates readily convertible into a variety of building blocks
(Scheme 1).
Br
N
O
O
Br
Cl
Cl
N
O
N
O
O
Br
furilazole
aplysamine 7
F
OE
OH
O
N
R2
NO2
R2
Cl
N
O
R1
R1
h
F3C
NO2
OH
R2
NO2
OH
O
R1
Cl
R2
g
R1
+
CF3
F3C
anacetrapib
Cl
lumefantrine
i
f
OH
OH
R2
O
NH2
R2
R2
a
R2
or
R1
R1
R1
O
OH
R1
NO2
H
N
NO2
NH2
O
NHOH
b
H2N
HO
B
e
OH
OH
O
OH
E
c
HO
O
d
R2
R2
R2
NO2
or
R1
R1
R2
NO2
R1
epetraborole
labetalol
O
O
Figure 1. Representative bioactive compounds of natural and
synthetic origin containing vicinal aryl amino alcohol structurꢀ
al unit.
Nu
O
R2
R1
R1
NO2
Although a number of literature reports describing chiral aryl
nitroaldols as starting materials is gradually rising, methods
employing their reduction to the corresponding aryl amino
alcohols are still one of the most abundant. The exceptional
interest of many pharmaceutical companies and research
groups in compounds possessing the vicinal aryl amino alcoꢀ
hol unit is likely caused by the ubiquitous occurrence of this
motif among bioactive substances of natural or synthetic
origin and hence its promising pharmacophoric properties
(Figure 1).17
Scheme 1. Overview of the functional group interconversion
related to nitroaldol intermediates. Notes: processes
comprising a loss of chirality are shown in gray; E =
electrophile, Nu = nucleophile.
Highly effective methods for their (a) reduction,1 (b) Nefꢀtype
transformation,2 (c) benzylic OH oxidation,3 (d) Ritter4 or
Mitsunobu reaction,5 benzylic arylation,6 aminosulfonylation,7
deoxyhalogenation,8 (e) Cꢀalkylation,9 αꢀhalogenation,8a,10 (f)
radical denitrations,11 (g) direct deoxygenations,12 (h)
Oꢀsilylation,13 Oꢀalkylation,9e,14 Oꢀacylation and related kinetic
resolution,14e,15 (i) dehydration16 etc. have been discovered.
All the vicinal aryl amino alcoholꢀbased compounds bear at
least one stereogenic center and both of their enantiomers usuꢀ
ally largely differ in their biological activities. The biological
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testing of pure enantiomers rather than their racemic samples tempts led us to the development of a novel type of multifuncꢀ
1
2
3
4
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8
is therefore highly justifiable and the development of proceꢀ
dures for their asymmetric syntheses has become a longꢀ
standing critical challenge.18
tional biphenylꢀbased diamineꢀtethered bis(thiourea) organoꢀ
catalyst (Ra)ꢀ1 (Scheme 2).
By taking advantage of its C2ꢀsymmetry, a highꢀyield and proꢀ
tectionꢀgroupꢀfree synthesis of the catalyst was performed
(Scheme S1). Under the optimized conditions, the exceptionalꢀ
ly good yields of all nitroaldol adducts were reached in the
reasonable reaction times. For electronꢀdeficient aromatic and
heteroaromatic nitroaldols, the excellent enantioselectivities
and good diastereoselectivities were achieved (85–96% ee).
Furthermore, due to a high affinity of the catalyst to silica gel,
a simple chromatographyꢀfree nitroaldol isolation procedure
was feasible. To shed light on the general reaction mechanism,
we have performed preliminary kinetic and spectroscopic exꢀ
periments. Finally, the developed synthetic strategy was sucꢀ
cessfully applied to larger scale catalytic enantioselective synꢀ
theses of enantiopure (S)ꢀeconazole and a lateꢀstage intermeꢀ
diate of (R)ꢀmirabegron.
The asymmetric nitroaldol (Henry) reaction can represent a
powerful method to synthesize the aforementioned compounds
in a substantially effective way. Although the reaction itself
has been discovered in 1895,19 its first metalꢀcatalyzed and
organocatalyzed asymmetric versions have been reported by
Shibasaki and Najera nearly hundred years later and the bioꢀ
catalyzed asymmetric Henry reaction was recognized by Purꢀ
kanhofer even in 2006.20
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An exhaustive research in the organocatalysis field over last
few years affected also the asymmetric Henry reaction,21 and
in 2006 has finally resulted in the methodology with synthetiꢀ
cally useful levels of enantioselectivities for aromatic and
branched aliphatic aldehydes reported by Hiemstra and Nagaꢀ
sawa.22 Nowadays, the most effective enantioselective nitroalꢀ
dolization organocatalysts (Figure 2) operate nearly exclusiveꢀ
ly through a chiral hydrogenꢀbonding activation of electroꢀ
phile (LUMOꢀlowering activation).22d,23 An external base for
αꢀproton removal is usually required to generate an active
nucleophile from the corresponding neutral nitroalkane. At
present, only several potent and highly enantioselective multiꢀ
functional organocatalysts being able to promote the asymmetꢀ
ric Henry reaction of aldehydes in the absence of an auxiliary
base have been documented.22a,24
Results and Discussion
Catalysts syntheses, reaction optimization and substrate
scope. Three different thiourea organocatalysts 1–3 built on
the biphenyl backbones were synthesized in both of their enꢀ
antiomeric forms. The corresponding enantiopure 6,6’ꢀ
dinitrobiphenic acid and 2,2’ꢀdimethylbiphenyldiamine were
chosen as relevant chiral educts in their syntheses (Schemes
S1–S3). The aforementioned catalysts differing in their symꢀ
metry and basicity properties were tested in the model asymꢀ
metric Henry addition of 4ꢀnitrobenzaldehyde (18m) and niꢀ
tromethane with and without the auxiliary base (Scheme 2).
Although the acidity of nitromethane (pKa 15.9 in DMSO) is
substantially low in order to be deprotonated by the respective
weakly basic aromatic dimethylamino groups of catalysts 2 or
3,26 the use of analogous 1,1’ꢀbinaphthylꢀbased bifunctional
thiourea as 3 (Wang’s catalyst) was documented in the asymꢀ
metric Michael addition between nitrostyrenes and correꢀ
sponding Cꢀacids of acidities comparable to MeNO2.27 Cataꢀ
lyst 2 with duplicated aromatic dimethylamino moieties was
designed to exhibit superior basicity relative to 3 due to the
Bn
C18H37
Cl
O
NH
H
H
N
H
H
N
N
N
N
Ar1
N
N
Ar1
Ar1
H
H
S
Bn
Bn
S
N
Nagasawa 2006
HN
HN
S
Cl
P
HN
Ar2
Ar2
H
H
S
HN
Ar1
Hiemstra 2006
N
N
Ar2
Ar2
N
H
N
H
NH
NH
Ooi 2007
Ar1
S
possible
proton
sponge
properties
of
2,2′ꢀ
HN
HN
S
Ar1
NH
bis(dimethylamino)biphenyl backbone, which was demonꢀ
strated to have dramatically stronger basicity than that of N,Nꢀ
dimethylaniline (pKa 2.5 vs. 7.9 in DMSO).28 In contrary to
our expectations, thiourea derivatives 2 and 3 showed no obꢀ
servable catalytic activity without an additional base, and their
use together with the Hünig’s base was lacking enantiodisꢀ
crimination completely (Scheme 2, Entries 6–9).
Ar1
S
Ito 2013
NH
O
O
N
H
OH
N
NH
NH
H
N
S
S
NH
Ar1
Kitagaki 2013
NH
Ar1
Otevrel, Bobal 2016
On the other hand, bis(thiourea) 1 provided promising results
(Scheme 2, Entry 1), which were considerably improved by
removal of the external base and by optimizations of the reꢀ
maining reaction parameters (Table S1).
Herrera 2016
Figure 2. Selected highly enantioselective nitroaldolization
organocatalysts. Multifunctional catalysts capable of acting
without the need for an auxiliary base are shown in red. Notes:
Ar1 = 3,5ꢀ(F3C)2C6H3, Ar2 = 4ꢀF3CC6H4.
It is noteworthy that under the optimized reaction conditions,
the clean and expectable reaction outcome was obtained withꢀ
out any detectable amount of byproducts, e.g. selfꢀaldolization
adducts of enolizable aliphatic aldehydes.
During the development of biphenylꢀbased organocatalyst for
the asymmetric Henry reaction of aromatic aldehydes in our
laboratory, we recognized 2,2’ꢀdimethylbiphenyldiamine as a
promising chiral scaffold for a design of the bis(thiourea) orꢀ
ganocatalyst.25 Under optimized reaction conditions, the cataꢀ
lyst together with the TMEDA base provided a very good steꢀ
reoselective outcome. Being encouraged by those results, we
wanted to design a catalyst, which combines both the
bis(thiourea) and dibasic moieties in its structure. These atꢀ
It is worth mentioning that the enantiomeric excess of (S)ꢀ19m
reached synthetically useful levels of enantioselectivity (81%
ee) even at ambient temperature and for −30 °C, an excellent
value (92% ee) was obtained (Scheme 2, Entries 2–5). The
stereoselection at ambient temperature was maintained with
the catalyst loading of 5 mol% only (Scheme 2, Entry 4) but
this decreased load was found inappropriate for the lowꢀ
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Scheme 2. Selection of the catalyst. Notes: a) carried out at –30 °C; ee values are based on chiral HPLC analyses of crude adducts,
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conversions are based on 1H NMR analyses of crude reaction mixtures; Ar = 3,5ꢀ(F3C)2C6H3. Please, see the SI for details.
temperature experiments because of the prolonged reaction
times. Furthermore, due to a high affinity of the catalyst to
silica gel, nitroaldol adducts can be isolated readily by filtraꢀ
tion through a pad of silica gel rather than by timeꢀ
consuming column chromatography.
βꢀnitroalcohol 19o provided by the Kitagaki catalyst was
68% ee,23a and for 19p, Hiemstra documented less than 20%
ee and incomplete conversion of the starting material only.22a
Compared to those preceding reports, our results with the
difficult substrates 18o and 18p do not represent a real failꢀ
ure.
It was found that the catalyst can be precipitated as the oxaꢀ
late salt by addition of an ethereal solution of anhydrous
oxalic acid, filtered out of the reaction mixture, and then
recovered by means of acid–base extraction. To test the posꢀ
sibility of the catalyst reuse, we have performed three subseꢀ
quent experiments with 18m under the abovementioned opꢀ
timized conditions (Scheme 2, Entry 5), in which (Ra)ꢀ1 was
regenerated after each run. Although the extent of this recyꢀ
cling study was considerably limited, about 60% of catalyst
was successfully regenerated after each run with negligible
changes in reactivity and selectivity of about 1% ee only.
Addition of the higher nitroparaffins to 18e, 18i, and 18l
leading to 19q–s required prolonged reaction times (168 h)
and slightly increased reaction temperatures (−20 °C) despite
their higher thermodynamic acidities.26,29 This quite surprisꢀ
ing behavior is probably caused by a soꢀcalled nitroalkane
anomaly.30 Anyway, adducts 19q–s were obtained in both
excellent yields and excellent enantioselectivities of the maꢀ
jor synꢀproducts (89–92% ee). The rather moderate diastereꢀ
oselective ratios differing slightly between the crude and
isolated products were comparable to the results of our preꢀ
vious study.25
With the optimized reaction conditions in hand, we have
investigated the substrate scope of the developed asymmetric
nitroaldolization process (Scheme 3). A variety of differently
substituted aromatic, several heterocyclic and aliphatic aldeꢀ
hydes were converted into appropriate enantioenriched niꢀ
troaldol adducts 19a–p. The diastereoselective outcome of
the Henry transformation was examined by addition of niꢀ
troethane and 1ꢀnitropropane to the three model aromatic
substrates 19q–s (Scheme 3). Adducts 19b–e, 19g–i, 19m,
and 19n possessing electronꢀpoorer aromatic or heterocyclic
systems were all formed in excellent yields and reasonable
reaction times (24–72 h) and with the exception of 19h (93%
ee) and 19m (92% ee), this represents the highest enantioꢀ
meric excesses reported for the organocatalyzed Henry reacꢀ
tion so far.22a,23,25 For the electronꢀricher aromatic substrates,
the longer reaction times (84 h) and slightly elevated reacꢀ
tion temperatures (–20 °C) were necessary. The correspondꢀ
ing βꢀnitroalcohols 19a, 19f, and 19j were furnished in conꢀ
sistently high yields albeit with partially decreased enantiꢀ
oselectivities (75–86% ee) apparently caused by retroꢀ
nitroaldol processes (see below).23a The suitability of the
reaction conditions was tested also for the aliphatic subꢀ
strates. Although the respective nitroaldols 19o and 19p
were isolated in excellent yields, the enantioselective outꢀ
come was found unsatisfactory (33–43% ee). In a wider perꢀ
spective of organocatalyzed asymmetric nitroaldol transforꢀ
mations, the highest enantiomeric excess of aliphatic
In summary, the catalyst (Ra)ꢀ1 was proven to work very
well for the asymmetric Henry reaction with the exceptionalꢀ
ly high performance for electronꢀdeficient aromatic and hetꢀ
erocyclic substrates. We have examined next the use of the
catalyst 1 in syntheses of several bioactive compounds.
Synthesis of (S)-(+)-econazole. Econazole is an azoleꢀclass
antimycotic drug highly effective against dermatophytes,
yeasts, actinomycetes, molds, and other fungi. Furthermore,
it also affects the growth of some Gramꢀpositive bacteria. Its
mechanism of action is likely complex in nature and inꢀ
volves interference with ergosterol biosynthesis as well as
inhibition of several membraneꢀbound fungal enzymes.
Econazole, administered mainly for treatment of topical and
vaginal infections, is commonly used as the nitrate salt of the
racemic form.31 While both econazole enantiomers differ in
their ability to suppress the growth of several microbial
strains, (S)ꢀenantiomer shows a higher potency against Crypꢀ
tococcus neoformans, Penicillium chrysogenum, and Asperꢀ
gillus niger.32
We have tested the developed enantioselective nitroaldolizaꢀ
tion in the catalytic asymmetric synthesis of (S)ꢀeconazole
(Scheme 4). The corresponding nitroaldol adduct (S)ꢀ19g
obtained by a simple filtration of the crude reaction mass
through a small pad of silica was reached in both the excelꢀ
lent yield and enantiopurity (98%, 96% ee). The reduction
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1) (Ra)-1 (10 µmol)
Et2O (0.1 mL)
–30 or –20 °C, 24–168 h
NO2
Cl
NH2
O
H
OH
1
2
3
4
5
6
7
8
HO
HO
O
NO2
R2
+
Cl
R1
a
b
2) NH4Cl
R1
H
R2
Cl
NO2
y. 98%
96% ee
y. 67%
isol. as HCl
18a–p
(0.1 mmol)
(S) or (1S,2S)-19a–s
(2 mmol)
OH
Cl
18g
Cl
Cl
(S)-19g
OH
OH
(S)-20
NO2
NO2
NO2
N
Cl
N
N
Boc
19c
19a
19b
9
y. 95%, 75% ee (S)
N
y. 91%, 93% ee (S)
y. 97%, 96% ee (S)
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OH
OH
OH
HO
c
y. 76%
d
NO2
NO2
NO2
y. 65%
> 99% ee
isol. as H2C2O4
Cl
N
O
NO2
19d
y. 97%, 96% ee (S)
Cl
19e
Me
19f
N
y. 97%, 96% ee (S)
y. 96%, 76% ee (S)
OH
Cl
(S)-21
OH
OH
Cl
Cl
(S)-22
NO2
O2N
NO2
F
NO2
Scheme 4. Catalytic enantioselective synthesis of (S)ꢀ
econazole. Conditions: a) MeNO2, (Ra)ꢀ1, 60 h, –30 °C; b)
H2 (60 psi), Ra–Ni, MeOH, 10 h, rt (isol. as HCl salt); c)
H2CO, glyoxal, NH4OAc, MeOH, 12 h, 80 °C (sealed tube);
d) NaH, 4ꢀchlorobenzyl chloride, nꢀBu4NI, DMF/THF
(10:1), 12 h, 0–25 °C (isol. as H2C2O4 salt).
Cl
Cl
19g
y. 98%, 96% ee (S)
19h
y. 97%, 93% ee (S)
OH
19i
y. 96%, 90% ee (S)
OH
OH
NO2
NO2
F3CO
NO2
Cl
Br
19j
y. 96%, 86% ee (S)
OH
19k
19l
The total synthesis of (S)ꢀeconazole was successfully acꢀ
complished in the 4ꢀstep longest linear sequence and providꢀ
ed the final product in a satisfactory overall yield (32%) and
an excellent enantiopurity (> 99% ee, [α]20D: +86.8 (c 1.0;
CH2Cl2), lit.32 > 99% ee, [α]20D: +87.1 (c 1.0; CH2Cl2)).
y. 94%, 87% ee (S)
y. 87%, 88% ee (S)
OH
NO2
NO2
O2N
F3C
19m
19n
y. 95%, 92% ee (S)
y. 95%, 85% ee (S)
Synthesis of (R)-mirabegron a direct precursor. Overacꢀ
tive bladder syndrome (OAB) is a common impairing condiꢀ
tion characterized by a group of urinary symptoms such as
urinary urgency, increased urination frequency, and nocturia.
The identification of a predominant expression of β3ꢀ
adrenoreceptor in human urinary bladder and the understandꢀ
ing of its role in detrusor muscle relaxation and the increase
in urine storage led to the development of mirabegron, the
firstꢀinꢀclass orally available β3ꢀadrenergic receptor agonist.
Mirabegron, developed as a single (R)ꢀenantiomer, is used
for the symptomatic treatment of OAB and exhibits signifiꢀ
cantly less extent of sideꢀeffects compared to standardly
administered antimuscarinic drugs.37
OH
OH
NO2
NO2
19o
19p
y. 97%, 43% ee (S)
y. 96%, 33% ee (S)
OH
OH
OH
F
NO2
NO2
NO2
Cl
19q
y. 92%, dr 62:38
92% ee (1S,2S)*
Br
19r
19s
y. 94%, dr 63:37
86% ee (1S,2S)*
y. 89%,dr 69:31
90% ee (1S,2S)*
Scheme 3. Substrate scope of the asymmetric Henry addition
catalyzed by (Ra)ꢀ1 catalyst. Notes: yields of isolated prodꢀ
ucts, ee values are based on chiral HPLC analyses of crude
adducts, dr values are based on 1H NMR analyses of purified
adducts; *in all cases, ee values of antiꢀadducts were low
(23–37% ee).
We have decided to apply our catalytic enantioselective Henꢀ
ry reaction for the synthesis of mirabegron the lateꢀstage
intermediate (Scheme 5). The nitroaldol adduct (R)ꢀ19a was
isolated in an excellent yield (96%) and a good enantiopurity
(75% ee) by a simple purification step as in the case above.
The hydrogenation of (R)ꢀ19a over 10% Pd/C afforded the
corresponding enantioenriched βꢀamino alcohol, which was
step was found unexpectedly challenging, 10% Pd/C cataꢀ
lyzed hydrogenation carried out under 60 psi of H2 led to
traces of the desired product only,33 and the previously reꢀ
ported Zn/HCl reduction resulted in the product of insuffiꢀ
cient purity.34 The hydrogenation over a freshly prepared
Ra–Ni catalyst followed by an HCl isolation workꢀup gave
finally the product (S)ꢀ20 in a reasonable yield (67%) with a
slightly increased enantiopurity ([α]25D: +73.8 (c 0.5;
CHCl3), lit.34 98% ee [α]25D: +73.5 (c 0.51; CHCl3)). The
cyclocondensation step was realized according to the literaꢀ
ture.34ꢀ35 The imidazole product (S)ꢀ21 was obtained in a
isolated as the HCl salt (97%, 75% ee, [α]25 −46.0 (c 0.5;
D
MeOH)). The single recrystallization step from methanol and
diethyl ether afforded the desired vicinal amino alcohol hyꢀ
drochloride (R)ꢀ23ꢁHCl as a pure (R)ꢀenantiomer (67%,
> 99% ee, [α]25D: −62.0 (c 0.5; MeOH)). The acylation of its
freeꢀbase by 4ꢀnitrophenylacetic acid was found messy beꢀ
cause a considerable amount of diacylated sideꢀproduct was
obtained. Modified Steglich reaction conditions (EDCl,
HOBt, Et3N) led to the sole monoacylated product (R)ꢀ24 in
a good yield (67%, [α]20D: +12.0 (c 0.5; MeOH)). The hyꢀ
drogenation of (R)ꢀ24 over 10% Pd/C in methanol quantitaꢀ
tively provided (R)ꢀ25 (98%, [α]20D: −44.0 (c 0.5; CHCl3)).
The subsequent reduction of the amide group of (R)ꢀ25 to
amine by sodium bis(2ꢀmethoxyethoxy)aluminiumhydride
good yield (76%) with the retention of configuration ([α]25
:
D
+82.8 (c 0.5; CHCl3), lit.36 > 99% ee [α]25D: +83.0 (c 0.5;
CHCl3)). An in situ Finkelstein reaction–alkylation protocol
yielded the crude enantioenriched econazole (S)ꢀ22, purified
as the oxalate salt (65%).
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NO2
NH2
stereomeric (dr = syn/anti) or enantiomeric ratio (er = S/R)
O
H
against the reciprocal reaction temperature.41ꢀ43
HO
1
HO
a
b
c
2
3
4
5
6
7
8
9
The temperature vs. stereoselectivity profile of nitroaldol
19q (Figure 3A) exhibited a linear trend intersecting at a
value of the reciprocal inversion temperature (Tinv = –5 °C).43
The synꢀdiastereomers prevailed only at reaction temperaꢀ
tures lower than Tinv. At temperatures higher than Tinv, a
weak temperature control of selectivity was observed and the
diastereomeric reaction outcome showed the flattened trend
with a slightly predominating occurrence of antiꢀadducts
similar to the racemic standard (please, see p. S51 for deꢀ
tails).
y. 95%
75% ee
y. 67%
> 99% ee
isol. as HCl
y. 98%
after 1 x recryst.
18a
(R)-19a
(R)-23
NH2
NH2
NO2
d
e
O
O
10
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19
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y. 98%
y. 95%
HN
HO
HN
HO
HN
HO
The break in the plot might suggest a change in the reaction
mechanism caused either by a reversibility of the above proꢀ
cess at higher temperatures or by an epimerization pathꢀ
way.42ꢀ43
(R)-25
(R)-26
(R)-24
First, we have evaluated the extent of the competing racemic
background reactions in the absence of the catalyst. As deꢀ
picted in Scheme 6, these pathways were sufficiently supꢀ
pressed under the standard reaction conditions even at ambiꢀ
ent temperature.
OH
H
N
S
O
NH2
N
N
H
(R)-mirabegron
Scheme 5. Catalytic enantioselective synthesis of the miraꢀ
begron precursor. Conditions: a) MeNO2, (Sa)ꢀ1, 84 h,
−20 °C; b) H2 (60 psi), 10% Pd/C, MeOH, 3 h, rt (isol. as
HCl salt); c) 4ꢀnitrobenzoic acid, EDCl, HOBtꢁH2O, Et3N,
THF, 1 h, rt; d) H2 (60 psi), 10% Pd/C, MeOH, 3 h, rt; e)
SMEAH, MePh, 48 h, rt.
(SMEAH) in toluene gave the mirabegron precursor (R)ꢀ(–)ꢀ
26 in an excellent yield (98%, [α]20D: −32.0 (c 0.5; CHCl3)).
In summary, we have accomplished successfully the syntheꢀ
sis of the enantiopure (R)ꢀmirabegron precursor in a good
overall yield (58%) in the 5ꢀstep longest linear sequence
excluding any chromatographic purification.
Although the early example of the mirabegron synthesis
described the final acylation step of (R)ꢀ26 with the NꢀBoc
protected secondary aliphatic amine,38 it has been revealed
later that the reactivity of the primary aromatic amino and
secondary aliphatic amino groups of (R)ꢀ26 can be distinꢀ
guished fundamentally under specific reaction conditions.
The Steglichꢀtype acylation of (R)ꢀ26 with 2ꢀaminoꢀ
4ꢀthiazoleacetic acid using the EDCl reagent in acidic aqueꢀ
ous environment acylates selectively the incompletely protoꢀ
nated and hence more nucleophilic primary aromatic nitroꢀ
gen of (R)ꢀ26. This implies that the use of a protecting group
is therefore nonꢀessential.39
Scheme 6. Control experiments for investigations of the
competing background reaction pathways in the absence of
the catalyst.
These findings indicate that the changes in the stereochemiꢀ
cal outcome of 19q observed upon varying the reaction temꢀ
perature are rather catalystꢀmediated and may involve retroꢀ
nitroaldol cleavage and/or epimerization of the labile nitroꢀ
substituted stereocenter throughout the reaction course
(Scheme 7).13e,44
Therefore, we have investigated the extent of these two posꢀ
sible catalystꢀdriven racemization processes. Accordingly,
the stereoenriched or racemic adduct 19q was subjected to
the normal reaction conditions (Table 1). We have presumed
that if the α deprotonation–reprotonation takes place solely,
the stereochemistry of the hydroxyꢀsubstituted stereocenter
of 19q will be preserved over time. It implies that the
amount of the newly formed (1S,2S)ꢀ19q should be equal to
the amount of the consumed (1S,2R)ꢀ19q and the same is
true for another pair of diastereomers (1R,2S)ꢀ19q and
(1R,2R)ꢀ19q. On the contrary, if the stereochemistry of both
stereocenters is altered at the same time, the retroꢀHenry
process will be likely involved.
Solvent and temperature effects. The influence of the solꢀ
vent type on the enantiomeric excess of (S)ꢀ19m was deterꢀ
mined during the optimization study (see pp. S8–S9 for deꢀ
tails) and an excellent efficiency of etheric solvents was conꢀ
firmed, which was in accordance with numerous preceding
reports.22a,22b,23a,25,40 When compared to our former catalyst
(Figure 2), the enantioselective outcome of (Ra)ꢀ1 catalyzed
nitroaldolization exhibited more consistent ee values regardꢀ
less of the solvent type (± 20% ee), with an exception of
MeOH, which likely disrupted the hydrogenꢀbonding
framework of the catalyst.
Next, we have surveyed the reaction stereoselectivity upon
varying the temperature. We have chosen two model derivaꢀ
tives 19q and 19m and plotted the natural logarithm of diaꢀ
The obtained data summarized in Table 1 show that the conꢀ
figuration change on both stereocenters of 19q is mutually
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A
B
C
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Figure 3. (A) Nonlinear Eyring plots of the temperatureꢀdependent enantiomeric and diastereomeric ratios of 19q. (B) Eyring plot
of the temperatureꢀdependent enantiomeric ratios of 19m. (C) Investigation of a nonlinear effect of (S)ꢀ19d with (Ra)ꢀ1 catalyst.
Table 1. Control experiments for investigations of the
reaction mechanism.
EtNO2 (1 mmol)
(Ra)-1 (5 µmol)
19q
(50 µmol)
(initial ee and dr)
19q
(recovered ee and dr)
Et2O (50 µL)
OH
OH
OH OH
NO2
Cl
NO2
Cl
NO2
NO2
Cl
Cl
(1R,2S)-19q
(1S,2R)-19q
(1R,2R)-19q
(1S,2S)-19q
A
B
C
D
Entry Adduct
initial ratio
(A:B/C:D)
recovered ratio
(A:B/C:D)
1a)
2b)
3a)
4b)
5b)
racꢀ19q
racꢀ19q
30:30/20:20
30:30/20:20
18:11/3:68
18:11/3:68
31:29/15:25
29:29/20:22
28:28/21:23
18:11/3:68
32:29/14:25
31:29/15:25
Scheme 7. Working hypothesis of a selection model of the
(Ra)ꢀ1 catalyzed stereoselective Henry reaction between 18e
and EtNO2. Note: dashed line – epimerization by deprotonaꢀ
tion and diastereoselective reprotonation on the nitroꢀ
substituted stereocenter, plain line – epimerization by retroꢀ
nitroaldol and asymmetric nitroaldol processes.
(1S,2S)ꢀ19q
(1S,2S)ꢀ19q
(1R,2S)ꢀ19q
a) Conditions: –20 °C, 168 h; b) 20 °C, 12 h.
In contrast with the above somewhat complicated scenario,
the (S)ꢀ19m adduct exhibited rather simple enthalpically
manifested stereoselectivity (please, see p. S52). An Eyring
plot of the logarithmic er of (S)ꢀ19m against the reciprocal
reaction temperature showed a linear correlation with a modꢀ
erate slope only (Figure 3B). This nearꢀideal Arrhenius beꢀ
havior together with the similar sense and magnitude of the
enantiomeric excesses, relatively independent of the solvent
type, indicates that the reaction mechanism of this organoꢀ
catalyzed process remained the same in the tested solvents
and temperature range.42
concomitant. This supports that the configuration change is
caused by the microscopic reverse of the catalytic reaction,
rather than by some entirely new epimerization event. Thereꢀ
fore the epimerization of the nitroꢀsubstituted stereocenter
caused by αꢀdeprotonation–reprotonation during the reaction
course is a presumably less important consideration in this
case. Instead of it, the retroꢀaldol cleavage and the subseꢀ
quent Henry reaction are plausibly responsible for the
change in stereochemistry of the 19q adduct.45
Although it is too early to present any kinetic model of the
selection process, the presence of the Tinv might suggest a
temperatureꢀdependent balance between two reverse cataꢀ
lystꢀmediated reactions – Henry and retroꢀHenry, which can
form two distinct levels of stereoselection in the abovemenꢀ
tioned process (Scheme 7). The formation of synꢀ
diastereomers, especially (1S,2S)ꢀ19q, is apparently kinetꢀ
ically favored. Their prevalence over antiꢀdiastereomers at
lowꢀtemperature region is dictated mostly by the lower barriꢀ
er of formation because the retroꢀaldol cleavage is sufficientꢀ
ly suppressed. On the contrary, the barriers of formation
leading to antiꢀdiastereomers are easily surmountable at
higher temperatures and the products are allowed to interꢀ
convert mutually by the retroꢀnitroaldol reaction. Hence, the
thermodynamic mixture slightly enriched in antiꢀadducts is
obtained.
Nonlinear effect. In comparison with the adduct 19m, the
nitroaldol 19d provided superior enantioselective outcome
while maintaining excellent reactivity. Therefore it was choꢀ
sen as a probe derivative for investigations of a possible nonꢀ
linear effect (NLE). The reaction mixtures of 18d and cataꢀ
lyst (Ra)ꢀ1 present in the gradually increasing enantiomeric
ratios were visually inspected for homogeneity in order to
reduce errors of a falsely positive NLE caused by a precipitaꢀ
tion of the racemic catalyst from the reaction mixture. Thus,
a linear relationship with a strong correlation coefficient was
obtained demonstrating that a monomeric form of the cataꢀ
lyst is involved in the studied organocatalytic process (Figꢀ
ure 3C).46
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Figure 4. (A) Kinetic experiments using different initial loadings of 18d. (B) Determination of the kinetic order in (Ra)ꢀ1 (10–
25 mol%). (C) Plot illustrating differences in the reaction progress by using CD3NO3 (20 equiv.) instead of CH3NO2 (20 equiv.).
(Figure 4C). This indicates that the reaction is no longer
dependent on the aldehyde concentration and a slow deuterꢀ
on abstraction from MeNO2ꢀd3 assisted by the catalyst probꢀ
ably limits the overall rate of the asymmetric Henry addiꢀ
tion.50 It is noteworthy that under the reaction conditions,
only a negligible deuterium exchange between the N–H
groups of the catalyst (Ra)ꢀ1 and MeNO2ꢀd3 was noticed
(please, compare the integrals of N–H signals on p. S63).
The ee values of the isolated adducts 19d or 19dꢀd3 were
virtually the same (91% vs. 90% ee).
Similarly as in the above case, the higher nitroalkanes,
whose kinetic acidities are appreciably lower when comꢀ
pared to nitromethane, presumably reflect the rateꢀ
controlling αꢀdeprotonation step in a retarded overall reacꢀ
Scheme 8. Isotopic substitution experiment. Note: R–NO2
was used as both the coꢀsolvent and the reactant.
tion rate and exhibit more or less similar saturation behavior
Kinetic studies. In order to gain better insight into the
mechanistic picture of the above transformation, we have
performed some preliminary kinetic studies with 18d. The
standard reaction conditions used “flooding” in nitromethane
natively due to its role as a reaction coꢀsolvent (pseudoꢀzeroꢀ
order conditions). Moreover, a large excess of MeNO2
(20 equiv.) had also a beneficial effect on conversion rate
and stereoselectivity (please, see pp. S8–S9). Under these
conditions, an exponential decay of [18d] was noticed,
which implies the first order kinetics with respect to 18d
(please, see pp. S57–S58).
to that of MeNO2ꢀd3.30,50
NMR studies. Hydrogenꢀbonding properties of the newly
developed catalyst were further studied by means of NMR
spectroscopy.51 A small upfield shift of both N–H signals
was observed during the fourfold dilution of the (Ra)ꢀ1 soluꢀ
tion (Figure 5A). Moreover, protonation of a dibasic site of
the catalyst using trifluoroacetic acid (TFA) in C6D6 also
resulted in noticeable upfield shifts of both thiourea hydroꢀ
gens (Figure 5B). These findings suggest that a possible selfꢀ
assembly of the catalyst under the synthetically relevant conꢀ
centrations may generate e.g. offꢀloop species not directly
involved in the productive catalytic cycle.52
Two additional kinetic experiments using different initial
loadings of [18d]0 (0.39 M and 0.29 M) were done in order
to test the catalyst robustness. Accordingly, the rate vs. conꢀ
centration profiles indicates a wellꢀbehaved kinetics with no
appreciable catalyst deactivation or product inhibition
throughout the reaction (Figure 4A).47
Although the reaction mechanism is not completely elucidatꢀ
ed at this moment, we believe that the stereoselection proꢀ
cess of the above transformation is mainly governed by the
bis(thiourea) units of the catalysts.
This hypothesis was supported by the 1H NMR complexation
experiments that established the presence of interactions of
the catalyst with the reaction components in 1:1 mixtures in
C6D6 (Figure 6). The thiourea N–H proton signals experiꢀ
enced relatively small downfield shifts, which were accomꢀ
panied by their broadening and weakening. This indicates a
formation of rather weak Hꢀbonded complexes and a possiꢀ
ble participation of chemical exchange processes.53 The apꢀ
From a set of four kinetic experiments with catalyst loadings
varied within the synthetically relevant range (10–25 mol%),
the firstꢀorder kinetics with respect to the catalyst 1 is asꢀ
sessed by excellent overlay of the concentration vs. normalꢀ
ized time scale [1]1ꢁt curves (Figure 4B).48
The investigations of the reaction order in nitromethane
could not be possible due to the solubility issues and its sigꢀ
nificant volatility.49
1
propriate association constants (Ka) were determined by H
However, the role of nitromethane was surveyed by its isoꢀ
topic substitution with MeNO2ꢀd3 used in the same excess
(Scheme 8). Although the twofold load of (Ra)ꢀ1 catalyst was
employed in this run (20 mol%), a shift from the firstꢀorder
kinetics to the zeroꢀorder kinetics in aldehyde was observed
NMR titration experiments in C6D6. The most obvious
changes in chemical shifts were observed for the proton sigꢀ
1
nal shown in red in Figures 5–6. The obtained H NMR
shifts were plotted as a titration isotherm and fitted to a 1:1
binding model using a Pythonꢀbased global fitting program
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Figure 5. (A) Changes in 1H NMR spectrum of (Ra)ꢀ1 upon fourfold dilution from 0.04 M to 0.01 M (700 MHz, 25 °C, CDCl3). (B)
Changes in 1H NMR spectrum of (Ra)ꢀ1 upon addition of trifluoroacetic acid (400 MHz, 25 °C, C6D6).
Bindfit developed by Thordarson and coꢀworkers.54 To verify
the expected 1:1 complexation equilibria of host and guest,
the titration data were also fitted to another physically acꢀ
ceptable 1:2 host–guest binding model (with respect to the
C2ꢀsymmetry of the catalyst). In both the abovementioned
models, the residual data points were dispersed randomly
around the horizontal axis, however, the 1:2 binding model
was associated with larger uncertainties and in some cases
provided thermodynamically nonꢀsensible negative binding
constants. Based on this evidence, the binding stoichiꢀ
ometries in the above cases were best represented by simple
1:1 complexes (please, see pp. S64–S76).54ꢀ55
Preliminary catalytic cycle proposal. According to the
aforementioned mechanistic and spectroscopic experiments
and the previously published computational studies on the
reaction mechanism,22b,24,56 we have proposed a working
hypothesis of the catalytic cycle (Scheme 9).
Based on the lack of an NLE, a monomer of the organocataꢀ
lyst seems to be involved in the catalytic cycle. According to
our hypothesis, a large excess of nitromethane prevents the
(1) nonꢀproductive association of the catalyst, which can
explain the abovementioned beneficial effect of the excess
on both the conversion rate and the stereoselectivity. The
observed kinetic isotope effect supports that the (2) deprotoꢀ
nation of the nitroalkane is a rateꢀlimiting (or a partially rateꢀ
limiting) step in the overall reaction that precedes the forꢀ
mation of the ternary complex (nitronate–catalyst–aldehyde).
Although the binding constant of the catalyst towards nitroꢀ
methane (Ka = 12.5 M−1) is lower than the association conꢀ
stants determined for the model aromatic aldehydes (Ka =
68.2 M–1 and 79.8 M–1), we believe that the concentration of
nitromethane in the reaction medium being 20 times higher
enables the successful competition thereof for the active sites
of the catalyst. Additionally, we should also take into acꢀ
count the different binding affinities of the catalyst towards
the neutral nitroalkane and its anion – nitronate. The latter
species, apparently formed throughout the reaction in small
equilibrium concentration only, is likely immediately conꢀ
sumed in the presence of the appropriate electrophile. As
shown by Kelly and Hamilton, the negatively charged nitroꢀ
nate is essential for strong association with the hydrogenꢀ
bonding network, while the charge neutral nitro group does
The analysis of the obtained association constants revealed
that the binding affinity of the catalyst 1 towards electronꢀ
rich (18f, 19f) and electronꢀpoor (18d, 19d) reaction compoꢀ
nents followed a decreasing order of 18f > 18d > 19f > 19d
> CH3NO2 (Figure 6).
The binding arrangement between (Ra)ꢀ1 and other reaction
components was further studied by 2DꢀROESY experiments
in CDCl3.51b,c The adducts (S)ꢀ19c and (S)ꢀ19f were chosen
1
due to their easily identifiable alkyl groups on H NMR
spectrum, which were expected to give rise to considerable
NOE interactions. This study implied that in CDCl3 at room
temperature, the (Z,Z)ꢀconformer of bis(thiourea) 1 is inꢀ
volved in the Hꢀbonded complex between (Ra)ꢀ1 and OH
groups of the adducts (S)ꢀ19c or (S)ꢀ19d (please, see pp.
S77–S78). Although our primary intent was also to study the
spatial arrangement of (Ra)ꢀ1 with 18c, 18f and
1ꢀnitropropane, no significant intermolecular NOE interacꢀ
tions were detected in those cases.
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Figure 6. Changes in chemical shifts of N–H signals of (Ra)ꢀ1 upon addition of different reaction components (400 MHz, C6D6, 1:1
mixtures). Notes: association constants (Ka) with standard errors and binding free energies (ꢂG0) for 1:1 complexes were deterꢀ
mined by 1H NMR titrations (400 MHz, 25 °C, C6D6); Ar = 3,5ꢀ(F3C)2C6H3.
not show any significant complexation.57 The association of
the catalyst–nitronate preꢀcomplex with the aldehyde comꢀ
poses the (3) ternary complex resulting in the (4) 1,2ꢀ
addition step. Next, the catalyst (5) reprotonates the intermeꢀ
diary alkoxide and the product is subsequently (6) liberated
from the weak catalyst–nitroladol complex (Ka = 17.3 M–1
and 23.6 M–1).
kanes and a variety of aldehydes with a special focus on
benzaldehyde derivatives. One of the tested catalysts (1)
exhibited a promising potential and provided consistently
high yields, good to excellent enantioselectivities, and modꢀ
erate synꢀdiastereoselectivities of the corresponding nitroꢀ
aldol adducts. For electronꢀdeficient aromatic and heterocyꢀ
clic aldehydes, an exceptionally good catalytic performance
was reached. The catalyst 1, offering operationally simple
isolation of the respective βꢀnitroalcohols, was applied to the
syntheses of enantiopure (S)ꢀeconazole and (R)ꢀmirabegron
the lateꢀstage intermediate. Preliminary kinetic and spectroꢀ
scopic experiments conducted in order to shed better light on
the mechanistic picture of the above process revealed:
Summary
We have demonstrated that the atropisomeric biphenyl skeleꢀ
ton represents a tunable framework for a design of organoꢀ
catalysts. The three novel biphenylꢀbased multifunctional
catalysts were introduced, which were screened in the
asymmetric Henry addition between several linear nitroalꢀ
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(1) An unusual temperature effect on ee and dr values of 19q Solvents and reagents. Purchased from commercial suppliꢀ
1
2
3
4
5
6
7
8
likely caused by a catalystꢀmediated reversibility of the reacꢀ
tion at T > Tinv. On the other hand, such behavior was much
less pronounced in the temperature profile of 19m, which
exhibited a simple temperature effect.
ers and used as received, if not stated otherwise. Anhydrous
solvents and reagents were absolutized as usual and distilled
prior to use. All aldehydes for smallꢀscale experiments were
purified in order to be acidꢀfree. Raney nickel (Ra–Ni), hyꢀ
drocinnamaldehyde (18o), 2,2'ꢀdimethylꢀ6,6'ꢀdinitroꢀ1,1'ꢀbiꢀ
phenyl (4), racemic adducts 19a–s, 6,6'ꢀdimethylꢀ1,1'ꢀ
biphenylꢀ2,2'ꢀdiamine (14) and both of its enantiomers were
prepared according to the literature.13e,58
(2) The absence of a nonlinear effect suggesting that the
active form of 1 is a monomeric species.
(3) The wellꢀbehaved first order kinetics with respect to the
model aldehyde (18d) and the catalyst (1) at 0 °C.
Analytical data. The specific rotation was determined by an
automatic polarimeter AAꢀ10 (Optical Activity). Melting
points were measured by a Böetius apparatus (Franz Küstner
Nachf.) and are uncorrected. HPLC data were recorded on a
Dionex UltiMate 3000 LC System (Thermo Fisher Scienꢀ
tific) and edited with Chromeleon Dionex software ver.
7.2.0.3765 (Thermo Fisher Scientific). IR spectra were colꢀ
lected on a SmartMIRacle ATR Zn/Se for Nicolet Impact
410 FTꢀIR (Thermo Scientific) and edited with Omnic softꢀ
ware ver. 7.4 (Thermo Scientific). NMR spectra were obꢀ
tained from a Varian Inova VXRꢀ300 MHz (Agilent Techꢀ
nologies), a JEOL ECZRꢀ400 MHz (Jeol Corp.), a 500 MHz
spectrometer Bruker Avance III (Bruker Corp.), a 600 MHz
spectrometer Varian Unity Inova VNMRS (Agilent Techꢀ
nologies), a 700 MHz NMR spectrometer Bruker Avance III
HD (Bruker Corp.), and an 850 MHz NMR spectrometer
Bruker Avance III HD (Bruker Corp.). Experiments were
standardly carried out at 25 °C, chemical shifts are reported
in δ parts per million (ppm) and J values in Hz, the signal of
TMS or the residual solvent signals of CDCl3, C6D6 or
DMSOꢀd6 were used as a reference. Spectra were edited with
ACD/NMR processor software ver. 12.01 (Advanced Chemꢀ
istry Development). HRMS measurements were performed
using a LTQ Orbitrap XL highꢀresolution mass spectrometer
(Thermo Fisher Scientific) equipped with a HESI II (Heated
electrospray ionization) source operated in full scan with
resolution 60 000. Spectra were acquired over a mass range
50–1000 in a positive mode and 65–1000 in a negative mode
(m/z).
9
(4) The proton abstraction of the nitroalkane as a rateꢀ
limiting (or a partially rateꢀlimiting) step in the overall reacꢀ
tion.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) A tendency of the catalyst 1 for selfꢀassociation under the
synthetically relevant conditions.
(6) A complexation ability of the catalyst 1 towards all the
reaction components and different binding affinities of 1
towards electronꢀrich (18f, 19f) and electronꢀpoor (18d, 19d)
reaction components, which followed a decreasing order of
18f > 18d > 19f > 19d > CH3NO2.
(7) The (Z,Z)ꢀconformer of bis(thiourea) 1 involved in the Hꢀ
bonded complex between 1 and OH groups of the adducts
19c or 19d.
N
N
S
N
S
N
5
H
N
H
N
H
N
N
Ar
Ar
O
S
N
S
N
H
H
HO
H
R1 R2
elucidated by
2D-ROESY
N
O
N
H
N
H
H
Ar
Ar
OH
O
H
H
R2
6
2
O
H
N
O
R1
H
R1 R2
NO2
1
off-loop
species
4
(Ra)-1
NO2
R2
H
N
N
N
S
N
S
N
H
N
H
N
N
H
Ar
Ar
S
S
N
Diffraction data. Collected on a Rigaku Saturn724+ fourꢀ
circle CCD Xꢀray diffractometer at 120 K using monochroꢀ
mated MoꢀKα radiation from MicroMaxꢀ007HF DW 1.2 kW
rotating anode (Rigaku Corp.). CrystalClear–SM Expert ver.
2.1 b32 software package was used for data collection and
data reduction (Rigaku Corp.). The structure was solved and
refined (full matrix leastꢀsquares refinement on F2) using a
SHELXL program.59 All nonꢀhydrogen atoms were refined
anisotropically.
6,6'-dinitro-[1,1'-biphenyl]-2,2'-dicarboxylic acid (5):60
The compound 5 was obtained from 2,2'ꢀdimethylꢀ6,6'ꢀ
dinitroꢀ1,1'ꢀbiphenyl (15 g, 55.1 mmol) according to the
literature. The crude 5 obtained as pale yellow solid (13 g,
yield: 71%) was used directly in the following step. The
analytic racemic sample was recrystallized from glacial aceꢀ
tic acid. The related enantiopure samples were obtained by
resolution of the corresponding diastereomeric salts of 5 with
(R)ꢀ(+) and (S)ꢀ(–)ꢀ1ꢀphenylethylamine in absolute Me2CO
as reported in the literature.56b Racꢀ5: mp 262–263 °C; (Sa)ꢀ
5: mp 230–232 °C; > 99% ee (Astec Chirobiotic R column
(5 ꢃm, 100 × 4.6 mm), MeOH–AcOH–Et3N 99.7:0.2:0.1,
5 °C, 0.2 mL/min, λ = 230 nm): tS = 2.81 min; [α]25D: −170.0
(c 1.0, MeOH); (Ra)ꢀ5: mp 230–232 °C; > 99% ee; tR = 3.26
min; [α]25D: +170.0 (c 1.0, MeOH); 1H NMR (DMSOꢀd6, 300
H
O
N
O
H
N
H
N
H
O
H
H N
Ar
3
H
H
Ar
R1 R2
O
O
N
R1
O
H
R2
Scheme 9. Working hypothesis of the catalytic pathway.
Notes: 1 = catalyst selfꢀassociation, 2 = nitroalkane
deprotonation, 3 = formation of the ternary complex, 4 =
asymmetric 1,2ꢀaddition, 5 = alkoxide protonation, 6 =
liberation of the resulting nitroaldol.
Experimental Section
Special equipment and operating procedures. Moisture
and airꢀsensitive reactions were done in ovenꢀdried glassꢀ
ware (140 °C) under Ar atmosphere in anhydrous solvents.
Smallꢀscale lowꢀtemperature experiments were carried out in
an aluminum heatꢀtransfer block with a centrally placed stirꢀ
ring rotor and the temperature of the block was controlled by
an external thermostat. Preparative separations were perꢀ
formed with a Büchi Sepacore flash system X10 (BÜCHI
Labortechnik). Catalytic hydrogenations over Pd/C and Ra–
Ni were conducted with a Parr 3910 Shaker Hydrogenation
Apparatus (Parr Instrument Co.).
10
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The Journal of Organic Chemistry
left stirring 48 h at rt under Ar. Then the reaction was
MHz) δ/ppm: 7.78 (t, JHH = 9.0, 2H), 8.25 (dd, JHH = 7.8, 1.2,
2H), 8.35 (dd, JHH = 9.0, 1.3, 2H), 13.27 (br. s, 2H); 13C
NMR (DMSOꢀd6, 75 MHz) δ/ppm: 127.2, 129.4, 131.7,
132.4, 134.7, 148.9, 166.0; IR (neat) ṽ/cm−1: 2991br, 1688s,
1603w, 1568m, 1528s, 1456m, 1404w, 1347s, 1263m,
1142m, 1159w, 1108w, 902m, 839m, 775m, 747m, 713s;
HRMS (ESIꢀOrbitrap) m/z: [M–H]– calcd for C14H7N2O8
331.0202; Found 331.0208.
quenched by dropwise addition of water, diluted with water
and the organic phase was separated. The aqueous phase was
basified with 2.5 M NaOH to pH 10 and backꢀextracted with
several portions of fresh MePh. Combined organic extracts
were washed with brine, dried with Na2SO4 and evaporated
in vacuo to reach 9 as beige solid (0.87 g, yield: 95%). The
crude product was used directly in the next step. The analytic
sample was recrystallized from EtOAc–nꢀheptane. Racꢀ9:
mp 73–74 °C; (Sa)ꢀ9: 64–66 °C; [α]23D: −125.0 (c 1.0,
CH2Cl2); (Ra)ꢀ9: mp 65–66 °C; [α]23D: +126.0 (c 1.0,
1
2
3
4
5
6
7
N,N,N',N'-tetramethyl-6,6'-dinitro-[1,1'-biphenyl]-2,2'-
dicarboxamide (7):61a A suspension of 5 (1.5 g, 4.5 mmol),
DMAP (55 mg, 10 mol%) and SOCl2 (3.3 mL, 10 equiv.)
was heated to reflux for 2 h under Ar. The excess of SOCl2
was evaporated in vacuo to provide the crude acyl chloride
6. Meanwhile, a suspension of Me2NHꢁHCl (1.10 g, 3
equiv.) in dry CH2Cl2 (15 mL) was cooled to 0 °C and anhyꢀ
drous Et3N (3.80 mL, 6 equiv.) was added dropwise. The
resulting solution was stirred for further 10 min under Ar.
The crude acyl chloride 6 was dissolved in 10 mL of dry
CH2Cl2 and added dropwise to the solution of the free base
of Me2NH at 0 °C. The reaction mixture was left to rise to rt
and to stir overnight under Ar. Then the reaction mixture
was washed with 1 M HCl, saturated solution of NaHCO3
and brine. The organic layer was dried with Na2SO4 and
evaporated in vacuo to furnish 7 as white solid (1.8 g, yield:
98%). The crude amide was used directly in the following
step. The analytic sample was recrystallized from CH2Cl2–nꢀ
heptane. Racꢀ7: mp 214–216 °C; (Sa)ꢀ7: mp 274–276 °C;
[α]25D: −133.0 (c 1.0, CH2Cl2); (Ra)ꢀ7: mp 276–278 °C;
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
CH2Cl2); H NMR (DMSOꢀd6, 300 MHz) δ/ppm: 2.01 (s,
12H), 2.89 (ABq, ꢂνAB = 14.1, JAB = 13.5, 4H), 4.13 (s, 4H),
6.66 (dd, JHH = 7.9, 0.9, 2H), 6.81 (d, JHH = 6.7, 2H), 7.05 (t,
J
HH = 9.0, 2H); 13C NMR (DMSOꢀd6, 75 MHz) δ/ppm: 45.5,
60.6, 112.9, 116.4, 120.3, 127.8, 138.5, 145.3. IR (neat)
ṽ/cm−1: 3646w, 3396w, 3290w, 3170w, 2980w, 2930w,
2940w, 2811w, 2755w, 2354w, 1622w, 1616w, 1580w,
1454s, 1439m, 1361m, 1294m, 1262m, 1247w, 1169m,
1150m, 1122w, 1068w, 1043m, 1028m, 983w, 948m, 855s,
768s, 755m; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for
C18H27N4 299.2236; Found 299.2235.
1,1'-(6,6'-bis((dimethylamino)methyl)-[1,1'-biphenyl]-
2,2'-diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea)
(1): To a solution of 9 (100 mg, 350 ꢃmol) in dry THF
(2 mL), 3,5ꢀbistrifluoromethylphenylisothiocyanate (131 ꢃL,
2.05 equiv.) was added dropwise at rt. The reaction mixture
was stirred overnight at rt under Ar and then evaporated in
vacuo. The resulting glassy residue was triturated with nꢀ
heptane and sonicated. The white fluffy solid was filtered,
washed with fresh nꢀheptane, and subjected to flash chromaꢀ
tography (SiO2) EtOAc–Et3N, 99:1 to furnish 1 as white
solid (250 mg, yield: 89%). Racꢀ1: mp 149–151 °C; (Sa)ꢀ1:
mp 91–93 °C; [α]25D: −311.0 (c 0.5; CH2Cl2); (Ra)ꢀ1: mp 91–
[α]25D: +134.0 (c 1.0, CH2Cl2); H NMR (DMSOꢀd6, 300
1
MHz) δ/ppm: 2.74 (d, JHH = 6.0, 12H), 7.70 (t, JHH = 7.5,
2H), 7.78 (dd, JHH = 6.0, 1.4, 2H), 8.27 (dd, JHH = 8.1, 1.3,
2H); 13C NMR (DMSOꢀd6, 75 MHz) δ/ppm: 34.4, 38.6,
124.8, 128.9, 129.6, 132.1, 135.5, 149.0, 166.1; IR (neat)
ṽ/cm−1: 2980w, 1638s, 1520s, 1458w, 1408w, 1397m, 1348s,
1266m, 1106m, 1060m, 950w, 866m, 825s, 773m, 758m,
749s, 739s, 730m; HRMS (ESIꢀOrbitrap) m/z: [M–H]– calcd
for C18H17N4O6 385.1148; found 385.1155.
1
93 °C; [α]25D: +310.0 (c 0.5; CH2Cl2); H NMR (CDCl3,
700 MHz) δ/ppm: 2.22 (s, 12H), 2.99 (d, JHH = 11.6, 2H),
3.15 (d, JHH = 11.9, 2H), 7.36–7.37 (m, 4H), 7.42–7.43 (m,
4H), 7.54 (t, JHH = 7.8, 2H), 8.08 (s, 4H), 11.04 (br. s, 2H);
13C NMR (CDCl3, 176 MHz) δ/ppm: 44.4, 62.3, 118.1, 122.8
6,6'-diamino-N,N,N',N'-tetramethyl-[1,1'-biphenyl]-2,2'-
dicarboxamide (8): To a solution of 7 (1.5 g, 3.9 mmol) in
MeOH (50 ml), 10% Pd/C (0.5 g) was added and the resultꢀ
ing mixture was shaken vigorously for 3 h under H2 (60 psi).
Then the reaction mass was filtered and the filtrate was
evaporated in vacuo to afford 8 as white solid (1.2 g, yield:
95%). The crude product was used directly in the next step.
The analytic sample was purified by trituration with cold
(q, 1JFC = 272.2), 124.0, 126.6, 129.8, 130.7, 131.0 (q, 2JFC
=
34.1), 135.5, 136.2, 138.4, 139.4, 178.3; 19F NMR (DMSOꢀ
d6, 564 MHz) δ/ppm: −61.89 (s); IR (neat) ṽ/cm−1: 3361w,
1623w, 1545m, 1472m, 1382m, 1344w, 1319w, 1270s,
1249m, 1169s, 1125s, 1104m, 1093m, 1019w, 1001w, 987m,
911w, 884s, 846m, 780m, 759w, 729w, 700s; HRMS (ESIꢀ
Orbitrap) m/z: [M−H]− calcd for C36H31F12N6S2 839.1860;
Found 839.1859.
MeOH. Racꢀ8: mp 270–271 °C; (Sa)ꢀ8: mp 92–94 °C; [α]25
D
−132.0 (c 1.0, CH2Cl2); (Ra)ꢀ8: mp 93–95 °C; [α]25D: +132.0
(c 1.0, CH2Cl2); 1H NMR (DMSOꢀd6, 300 MHz) δ/ppm: 2.77
(d, JHH = 6.0, 12H), 4.38 (s, 4H), 6.48 (dd, JHH = 7.5, 1.0,
6,6'-dinitro-[1,1'-biphenyl]-2,2'-dicarboxamide (10):62 To
a vigorously stirred solution of concentrated aqueous ammoꢀ
nia (30 mL) in dioxane (30 mL), the crude acyl chloride 6
(1.7 g, 4.5 mmol) in anhydrous dioxane (20 mL) was added
dropwise at rt. The resulting mixture was left stirring overꢀ
night and evaporated in vacuo. The crude product was susꢀ
pended in distilled water, filtered off and washed sequentialꢀ
ly with 1 M HCl, saturated solution of NaHCO3 and distilled
water and then dried in vacuo to furnish 10 as white solid
(1.4 g, yield: 94%). The crude 10 was used directly in the
following step. The analytic sample was recrystallized from
MeOH. Racꢀ10: mp 270–271 °C; (Ra)ꢀ10: mp 217–218 °C;
2H), 6.74 (dd, JHH = 8.1, 1.0, 2H), 7.06 (t, JHH = 7.5, 2H); 13
C
NMR (DMSOꢀd6, 75 MHz) δ/ppm: 34.1, 38.9, 114.8, 115.3,
119.6, 127.6, 147.6, 169.5, 185.5; IR (neat) ṽ/cm−1: 3674w,
3442w, 3346m, 1621s, 1579m, 1559w, 1505m, 1451m,
1436m, 1405m, 1391m, 1310m, 1301m, 1267m, 1176w,
1061m, 999m, 866w, 803m, 755m, 745m, 728w; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C18H23N4O2 327.1821;
Found 327.1814.
6,6'-bis((dimethylamino)methyl)[1,1'-biphenyl]-2,2'-
diamine (9): To a solution of 8 (1.0 g, 3.1 mmol) in dry
MePh (30 mL), 60% solution of SMEAH in MePh (15.0 mL,
46.1 mmol) was added dropwise in order to maintain the
reaction temperature below 20 °C. The resulting mixture was
[α]25D +250.0 (c 1.0; MeOH); (Sa)ꢀ10: mp 216–217 °C; [α]25
D
1
–249.0 (c 1.0; MeOH); H NMR (DMSOꢀd6, 300 MHz)
δ/ppm: 7.39 (br. s, 2H), 7.72 (t, JHH = 9.0, 2H), 7.84 (dd, JHH
= 7.5, 1.2, 2H), 8.00 (br. s, 2H), 8.25 (dd, JHH = 8.1, 1.2,
11
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The Journal of Organic Chemistry
Page 12 of 20
2H); 13C NMR (DMSOꢀd6, 75 MHz) δ/ppm: 125.3, 129.2,
equiv.) was added dropwise at rt under Ar. The reaction
129.3, 132.2, 137.7, 148.2, 168.2; IR (neat) ṽ/cm−1: 3473w,
3258br, 2350w, 1679m, 1646m, 1613m, 1530s, 1462w,
1385w, 1350s, 1283w, 1259w, 1149w, 1098w, 1061w,
1005w, 904w, 823m, 791w, 773w, 747m, 733w; HRMS (ESIꢀ
Orbitrap) m/z: [M–H]– calcd for C14H9N4O6 329.0522;
Found 329.0528.
course was stirred for 2 h at the same temperature and then
evaporated in vacuo. The resulting glassy residue was trituꢀ
rated with nꢀheptane and sonicated. The white fluffy solid
was filtered, washed with fresh nꢀheptane, and subjected to
flash chromatography (SiO2) nꢀheptane–EtOAc, 75:25 to
furnish 2 as white solid (260 mg, yield: 86%). Racꢀ2: mp
178–180 °C; (Ra)ꢀ2: [α]25D +306.0 (c 0.5; CH2Cl2); mp 151–
1
2
3
4
5
6
7
8
6,6'-dinitro-[1,1'-biphenyl]-2,2'-diamine (11):63 The comꢀ
pound 11 was obtained from 10 (1.1 g, 3.3 mmol) according
to the literature. The crude 11 obtained as orange solid (450
mg, yield: 45%) was used directly in the following step. The
analytic sample was recrystallized from MeOH–H2O. Mp
239–240 °C; 1H NMR (DMSOꢀd6, 300 MHz) δ/ppm: 5.09 (s,
4H), 7.09 (d, JHH = 6.6, 2H), 7.23–7.33 (m, 4H); 13C NMR
(DMSOꢀd6, 75 MHz) δ/ppm: 111.3, 111.7, 119.6, 129.2,
147.9, 149.6; IR (neat) ṽ/cm−1: 3478w, 3378m, 1621m,
1520s, 1456w, 1346s, 1314s, 999w, 825m, 815m, 801m,
726s, 719m, 708w; HRMS (ESIꢀOrbitrap) m/z: [M–H]– calcd
for C12H9N4O4 273.0624; Found 273.0632.
153 °C; (Sa)ꢀ2: mp 151–153 °C; [α]25 –305.0 (c 0.5;
D
1
CH2Cl2); H NMR (CDCl3, 700 MHz) δ/ppm: 2.67 (s, 12H),
9
7.11 (d, JHH = 7.7, 2H), 7.19 (d, JHH = 7.7, 2H), 7.42 (s, 2H),
7.52–7.54 (m, 4H), 7.87 (s, 4H), 9.25 (br. s, 2H); 13C NMR
(CDCl3, 176 MHz) δ/ppm: 42.9, 118.4, 118.8, 120.9, 122.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
(q, JFC = 272.2), 122.9, 126.4, 130.9, 131.6 (q, JCF = 34.1),
135.4, 139.3, 151.6, 179.2; 19F NMR (DMSOꢀd6, 564 MHz)
δ/ppm: –61.89 (s); IR (neat) ṽ/cm−1: 2958w, 2836w, 1592w,
1531w, 1454w, 1434w, 1384m, 1351w, 1308w, 1275s,
1182m, 1133m, 1115m, 1104w, 1042w, 1001w, 984m, 963w,
902w, 888m, 848w, 830w, 807w, 701w, 755w, 721m, 704m;
HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd for C34H29F12N6S2
813.1703; Found 813.1719.
N,N,N',N'-tetramethyl-6,6'-dinitro-[1,1'-biphenyl]-2,2'-
diamine (12):61b,64 A solution of 11 (0.4 g, 1.5 mmol) in
THF (15 mL) and solid NaBH4 (0.8 g, 21.1 mmol) were
simultaneously portionwise added to a mixture of 37% aqueꢀ
ous formaldehyde (1.8 mL, 24.2 mmol), 20% H2SO4 (3 mL)
and THF (7.5 mL) at temperature below 20 °C. After 1 h, the
reaction mixture was poured into saturated solution of
K2CO3 and the resulting suspension was extracted with Et2O.
The combined organic extracts were washed with brine,
dried with Na2SO4 and evaporated in vacuo to furnish 12 as
orange crystalline solid (420 mg, yield: 85%). The crude 12
was used directly in the following step. The analytic sample
N-(2'-amino-6,6'-dimethyl-[1,1'-biphenyl]-2-yl)acetamide
(15):65 Ac2O (1.1 mmol, 104 ꢃL) was added dropwise to a
solution of 6,6'ꢀdimethylꢀ1,1'ꢀbiphenylꢀ2,2'ꢀdiamine (1.0
mmol, 212 mg) in AcOH (600 ꢃL) and anhydrous CH2Cl2
(10 mL) at 0 °C under Ar. The resulting solution was left to
rise to rt gradually and to stir overnight. Then the reaction
mixture was extracted with CH2Cl2, washed with saturated
solution of NaHCO3, brine, dried with Na2SO4 and evapoꢀ
rated in vacuo. The crude mixture was subjected to flash
chromatography (SiO2) nꢀheptane–EtOAc, 75:25 to furnish
1
1
15 as colorless oil (180 mg, yield: 71%). H NMR (DMSOꢀ
was recrystallized from MeOH–H2O. Mp 160–162 °C; H
d6, 400 MHz) δ/ppm: 1.77 (s, 3H), 1.81 (s, 3H), 1.91 (s, 3H),
4.18 (br. s, 2H), 6.57 (d, JHH = 7.3, 1H), 6.64 (d, JHH = 7.8,
1H), 7.00 (t, JHH = 7.8, 1H), 7.14 (d, JHH = 7.3, 1H), 7.25 (t,
JHH = 7.8, 1H), 7.62 (d, JHH = 7.3, 1H), 8.11 (br. s, 1H); 13C
NMR (DMSOꢀd6, 100 MHz) δ/ppm: 19.3, 19.6, 23.5, 112.6,
118.4, 120.8, 122.1, 126.7, 127.4, 128.1, 130.7, 136.2, 137.2,
145.4, 168.5; IR (neat) ṽ/cm−1: 3868w, 3463w, 3337w,
2917w, 1928w, 1682s, 1605m, 1579m, 1516s, 1462s, 1411m,
1365m, 1296m, 1245w, 1228w, 1165w, 1078w, 1037w,
1002m, 971w, 945w, 780s, 741m; HRMS (ESIꢀOrbitrap)
m/z: [M−H]– calcd for C16H17N2O 253.1341; Found
253.1347.
NMR (DMSOꢀd6, 300 MHz) δ/ppm: 2.30 (s, 12H), 7.50 (dd,
JHH = 7.5, 1.5, 2H), 7.70 (dd, JHH = 7.9, 1.5, 2H); 13C NMR
(DMSOꢀd6, 75 MHz) δ/ppm: 42.2, 118.6, 123.8, 125.4,
129.7, 149.0, 151.6; IR (neat) ṽ/cm−1: 2950w, 2859w,
2838w, 2787w, 1520s, 1481m, 1464w, 1452w, 1433w,
1357s, 1321m, 1278w, 1230w, 1209w, 1186w, 1159w,
1142m, 1056m, 1002m, 991m, 975m, 901w, 882m, 873s,
810s, 772m, 755m, 728s, 717s; HRMS (ESIꢀOrbitrap) m/z:
[M+H]+ calcd for C16H19N4O4 331.1406; Found 331.1401.
N,N,N',N'-tetramethyl-[1,1'-biphenyl]-2,2',6,6'-tetra-
amine (13):64 A solution of 12 (0.4 g, 1.2 mmol) in MeOH
(30 mL) was hydrogenated over 10% Pd/C (0.2 g) and treatꢀ
ed analogously to compound 8. The crude oily product was
triturated with a small amount of nꢀheptane and sonicated.
The resulting suspension was evaporated to dryness in vacuo
to provide 13 as redꢀbrown solid (260 mg, yield: 80%),
which was used directly in the next step. Mp 109–110 °C; 1H
NMR (DMSOꢀd6, 300 MHz) δ/ppm: 2.41 (s, 12H), 4.25 (br.
s, 4H), 6.36 (d, JHH = 8.1, 2H), 6.41 (d, JHH = 6.0, 2H), 6.96
(t, JHH = 9.0, 2H); 13C NMR (DMSOꢀd6, 75 MHz) δ/ppm:
43.2, 107.7, 108.9, 115.6, 128.0, 146.4, 153.0; IR (neat)
ṽ/cm−1: 3453m, 3344m, 2935w, 2817w, 2773m, 1620m,
1604m, 1570s, 1457s, 1424m, 1326w, 1285m, 1220w,
1183m, 1142m, 1111w, 1090w, 1064w, 1045m, 999s, 955w,
890w, 792s, 749s, 734s; HRMS (ESIꢀOrbitrap) m/z: [M+H]+
calcd for C16H23N4 271.1923; Found 271.1924.
N-(2'-(dimethylamino)-6,6'-dimethyl-[1,1'-biphenyl]-2-
yl)acetamide (16): A solution of 15 (710 ꢃmol, 180 mg) in
THF (10 mL) and 37% aqueous formaldehyde (10.1 mmol,
750 ꢃL) was stirred at rt for 15 min. Then NaBH3CN (3.2
mmol, 200 mg) was added at once the reaction mass was
stirred for additional 15 min. After this period, AcOH (1 mL)
was added dropwise and the resulting mixture was left to stir
at rt for 1 h. Then the reaction mixture was poured into satuꢀ
rated solution of NaHCO3 and extracted with Et2O. The
combined organic extracts were washed with brine, dried
with Na2SO4 and evaporated in vacuo. The crude product
was subjected to flash chromatography (SiO2) nꢀheptane–
EtOAc, 75:25 to provide 16 as yellowish oil (180 mg, yield:
1
90%). H NMR (DMSOꢀd6, 400 MHz) δ/ppm: 1.81 (s, 3H),
1.83 (s, 3H), 1.88 (s, 3H), 2.41 (s, 6H), 6.97 (t, JHH = 8.0,
2H), 7.07 (d, JHH = 7.3, 1H), 7.23 (dt, JHH = 15.7, 7.9, 2H),
7.72 (d, JHH = 6.4, 1H), 7.84 (s, 1H); 13C NMR (DMSOꢀd6,
100 MHz) δ/ppm: 19.7, 23.7, 43.3, 47.6, 116.2, 120.9, 123.9,
125.9, 126.9, 128.4, 129.4, 131.4, 135.7, 136.4, 137.3, 151.9,
1,1'-(6,6'-bis(dimethylamino)-[1,1'-biphenyl]-2,2'-
diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea) (2):
To a solution of 13 (100 mg, 370 ꢃmol) in dry THF (2 mL),
3,5ꢀbistrifluoromethylphenylisothiocyanate (138 ꢃL, 2.05
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The Journal of Organic Chemistry
168.0; IR (neat) ṽ/cm−1: 3628w, 3399w, 2943w, 2828w,
umn (SiO2) EtOAc, 100%. The eluate was evaporated in
1
2
3
4
2777w, 1694s, 1604m, 1575m, 1517s, 1456s, 1407w, 1366m,
1297m, 1242m, 1228m, 1197w, 1183w, 1165w, 1096w,
1041m, 967m, 886w, 864w, 782s, 758m, 739m; HRMS (ESIꢀ
Orbitrap) m/z: [M+H]+ calcd for C18H23N2O 283.1810;
Found 283.1804.
vacuo and the residue was dissolved in the mobile phase
(1 mL) and directly subjected to HPLC analysis (Hypersil
silica precolumn (3 ꢃm, 100 × 4.6 mm) connected via a blue
PEEK capillary (L 200 mm, ID 0.01”, OD 1/16”) to the Pheꢀ
nomenex Lux Celluloseꢀ1 column (3 ꢃm, 250 × 4.6 mm)).
5
2-nitro-1-phenylethanol (19a):66 According to GP, the adꢀ
duct (S)ꢀ19a was prepared with (Ra)ꢀ1 and after 84 h at
−20 °C obtained as colorless oil (15.9 mg, HPLC conv.:
> 99%, yield: 95%). [α]25D: +26.3 (c 0.8; CH2Cl2); 75% ee
(iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm):
tR = 26.44 min (minor R), tS = 32.05 min (major S). The adꢀ
duct (R)ꢀ19a was prepared with (Sa)ꢀ1 analogously (16.0 mg,
HPLC conv.: > 99%, yield: 96%). [α]25D: −26.5 (c 0.8;
CH2Cl2); 75% ee; tR = 26.78 min (major R), tS = 33.01 min
(minor S); analytical data were identical to those reported in
the literature.25
2-nitro-1-(pyridin-3-yl)ethan-1-ol (19b):23a According to
GP, the adduct (S)ꢀ19b was prepared with (Ra)ꢀ1 and after
48 h at −20 °C obtained as yellowish oil (15.3 mg, HPLC
conv.: 96%, yield: 91%). [α]25D: +31.0 (c 0.8; CH2Cl2); 93%
ee (iꢀPrOH–nꢀheptane, 25:75, 0.6 mL/min, 5 °C, λ = 205
nm): tR = 26.44 min (minor R), tS = 32.05 min (major S);
analytical data were identical to those reported in the literaꢀ
ture.25
6
7
8
9
N,N,6,6'-tetramethyl-[1,1'-biphenyl]-2,2'-diamine (17): A
mixture of 16 (640 ꢃmol, 180 mg), 96% EtOH (15 mL) and
4 M HCl (6 mL) was refluxed for 5 h. Then the solution was
basified to pH 10 with 5 M NaOH and EtOH was evaporated
in vacuo. The aqueous phase was extracted with CH2Cl2,
washed with brine, dried with Na2SO4 and evaporated in
vacuo. The crude product was subjected to flash chromatogꢀ
raphy (SiO2) nꢀheptane–EtOAc, 75:25 to provide 16 as yelꢀ
lowish oil, which solidifies upon standing (140 mg, yield:
91%). Mp 69–70°C; 1H NMR (DMSOꢀd6, 400 MHz) δ/ppm:
1.76 (s, 3H), 1.87 (s, 3H), 2.46 (s, 6H), 4.22 (br. s, 2H), 6.52
(d, JHH = 7.3, 1H), 6.59 (d, JHH = 7.8, 1H), 6.91–6.94 (m,
3H), 7.18 (t, JHH = 7.8, 1H); 13C NMR (DMSOꢀd6, 100 MHz)
δ/ppm: 19.4, 19.8, 43.4, 112.3, 116.0, 118.4, 123.7, 124.5,
127.2, 127.8, 130.7, 135.7, 137.3, 144.9, 152.5; IR (neat)
ṽ/cm−1: 3730w, 3436m, 3352m, 3053w, 2954w, 2916w,
2857w, 2823w, 2771w, 1921w, 1608s, 1574s, 1464s, 1455s,
1372w, 1308s, 1293s, 1197m, 1180m, 1168m, 1149m, 1016s,
1002m, 965m, 864w, 793s, 775s, 753s, 737s; HRMS (ESIꢀ
Orbitrap) m/z: [M+H]+ calcd for C16H21N2 241.1705; Found
241.1697.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tert-butyl
2-(1-hydroxy-2-nitroethyl)-1H-pyrrole-1-
carboxylate (19c):22a According to GP, the adduct (S)ꢀ19c
was prepared with (Ra)ꢀ1 and after 48 h at −20 °C obtained
as yellow oil (24.8 mg, HPLC conv.: 99%, yield: 97%).
[α]25D: +6.0 (c 1.2; CH2Cl2); 96% ee (iꢀPrOH–nꢀheptane,
20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 14.57 min (miꢀ
1-(3,5-bis(trifluoromethyl)phenyl)-3-(2'-(dimethylamino)-
6,6'-dimethyl-[1,1'-biphenyl]-2-yl)thiourea (3): A solution
of 17 (140 mg, 582 ꢃmol) in dry THF (2 mL), was treated
with 3,5ꢀbistrifluoromethylphenylisothiocyanate (112 ꢃL,
1.05 equiv.) analogously to compound 1. The crude yellowꢀ
ish fluffy solid was subjected to flash chromatography (SiO2)
nꢀheptane–EtOAc to furnish 3 as white solid (260 mg, yield:
1
nor R), tS = 15.92 min (major S); H NMR (DMSOꢀd6, 400
MHz) δ/ppm: 1.57 (s, 9H), 4.46 (dd, JHH = 12.3, 9.6, 1H),
4.92 (dd, JHH = 12.6, 3.0, 1H), 5.77 (ddd, JHH = 9.3, 5.6, 3.0,
1H), 5.98 (d, JHH = 5.5, 1H), 6.19 (t, JHH = 3.4, 1H); 6.37–
6.39 (m, 1H), 7.29 (dd, JHH = 3.2, 1.8, 1H); 13C NMR
(DMSOꢀd6, 100 MHz) δ/ppm: 27.5, 64.3, 80.8, 84.6, 110.5,
112.5, 122.0, 133.8, 148.6; IR (neat) ṽ/cm−1: 3434br, 2979w,
2924w, 1732s, 1553s, 1478w, 1459w, 1417w, 1396w,
1372m, 1332s, 1249w, 1161w, 1126s, 1083w, 1060w,
1009w, 885w, 844m, 773w, 729m; HRMS (ESIꢀOrbitrap)
m/z: [M–H]– calcd for C11H15N2O5 255.0981; Found
255.0992.
2-nitro-1-(2-nitrophenyl)ethanol (19d):66 According to
GP, the adduct (S)ꢀ19d was prepared with (Ra)ꢀ1 and after
36 h at −30 °C obtained as yellow oil (20.6 mg, HPLC conv.:
> 99%, yield: 97%). [α]25D: –159.0 (c 1.0; CH2Cl2); 96% ee
(iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm):
tR = 27.27 min (minor R), tS = 30.38 min (major S); analytiꢀ
cal data were identical to those reported in the literature.25
1-(2-chlorophenyl)-2-nitroethanol (19e):66 According to
GP, the adduct (S)ꢀ19e was prepared with (Ra)ꢀ1 and after
36 h at −30 °C obtained as colorless oil (19.6 mg, HPLC
conv.: > 99%, yield: 97%). [α]25D: +43.0 (c 1.0; CH2Cl2);
96% ee (iꢀPrOH–nꢀheptane, 5:95, 0.5 mL/min, 5 °C, λ = 230
nm): tR = 53.11 min (minor R), tS = 56.52 min (major S);
analytical data were identical to those reported in the literaꢀ
ture.25
2-nitro-1-(o-tolyl)ethan-1-ol (19f):66 According to GP, the
adduct (S)ꢀ19d was prepared with (Ra)ꢀ1 and after 84 h at
−20 °C obtained as yellowish oil (17.3 mg, HPLC conv.:
> 99%, yield: 96%). [α]25D: +33.1 (c 0.9; CH2Cl2); 76% ee
86%). Racꢀ3: mp 133–134 °C; (Ra)ꢀ3: mp 51–52 °C; [α]20
D
+80.0 (c 0.5; DCM); (Sa)ꢀ3: 50–52 °C; [α]20 –80.0 (c 0.5;
D
1
DCM); H NMR (CDCl3, 700 MHz) δ/ppm: 1.95 (s, 3H),
2.16 (s, 3H), 2.43 (s, 6H), 6.98 (d, JHH = 7.5, 2H), 7.27 (t,
JHH = 7.8, 1H), 7.33–7.34 (m, 1H), 7.39–7.41 (m, 2H), 7.65
(s, 1H), 7.80 (br. s, 1H), 7.85 (s, 2H), 8.15 (br. s, 1H); 13C
NMR (CDCl3, 176 MHz) δ/ppm: 19.9, 20.0, 43.9, 116.5,
118.9 (q, 3JCF = 3.2), 122.9 (q, 1JCF = 271.1), 123.9 (q, 3JCF
=
2
3.2), 124.1, 125.3, 128.3, 129.0, 129.9, 130.2, 132.1 (q, JCF
= 35.3), 134.5, 136.3, 137.3, 139.5, 139.8, 151.3, 179.7; 19F
NMR (CDCl3, 800 MHz) δ/ppm: –62.97 (s); IR (neat)
ṽ/cm−1: 3738w, 3178w, 2358w, 1539w, 1506w, 1457w,
1377m, 1276s, 1174m, 1160m, 1134s, 1107w, 1018w,
1042w, 903w, 892w, 798w, 791m, 750m, 762w, 736w, 703m;
HRMS (ESI) m/z: [M–H]– calcd for C25H22F6N3S 510.1439;
Found 510.1449.
General procedure for synthesis of enantio- and diastere-
oenriched nitroaldols 19a–s (GP): A solution of (Ra)ꢀ1 or
(Sa)ꢀ1 (8.4 mg, 10 ꢃmol) and an appropriate aldehyde 18a–p
(100 ꢃmol) in dry Et2O (100 ꢃL) was treated dropwise at
−20 °C (or −30 °C) with the corresponding nitroalkane (2
mmol). After the complete addition, the reaction mixture was
left under stirring at the above temperature for 24–168 h
under Ar. When TLC revealed full consumption of the startꢀ
ing material, the reaction was quenched by saturated solution
of NH4Cl (or brine) and the mixture was extracted with sevꢀ
eral portions of EtOAc. Combined organic extracts were
dried with Na2SO4 and passed through a Pasteur pipette colꢀ
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(iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm):
tR = 24.21 min (minor R), tS = 39.13 min (major S); 1H NMR
(DMSOꢀd6, 400 MHz) δ/ppm: 2.36 (s, 3H), 4.47 (dd, JHH
87% ee (iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ =
1
2
3
4
5
6
7
8
230 nm): tR = 23.71 min (minor R), tS = 29.94 min (major S);
analytical data were identical to those reported in the literaꢀ
ture.25
=
12.8, 10.1, 1H), 4.81 (ddd, JHH = 12.6, 3.0, 1.4, 1H), 5.45–
5.48 (m, 1H), 5.99 (d, JHH = 4.6, 1H), 7.17–7.26 (m, 3H),
7.50 (d, JHH = 7.8, 1H); 13C NMR (DMSOꢀd6, 100 MHz)
δ/ppm: 18.4, 67.1, 81.1, 126.1, 126.2, 127.8, 130.3, 134.4,
138.5; IR (neat) ṽ/cm−1: 3440br, 2919w, 1548s, 1487w,
1461w, 1417w, 1376m, 1282w, 1180w, 1120w, 1067m,
893w, 761m, 728m, 701w; HRMS (ESIꢀOrbitrap) m/z:
[M−H]– calcd for C9H10NO3 180.0661; Found 180.0669.
1-(4-bromophenyl)-2-nitroethan-1-ol (19l):66b According
to GP, the adduct (S)ꢀ19l was prepared with (Ra)ꢀ1 at −30 °C
within 60 h. The crude product was purified by column
chromatography in a Pasteur pipette (SiO2) nꢀheptane–
EtOAc, 90:10 and obtained as colorless waxy solid (21.4 mg,
HPLC conv.: 92%, yield: 87%). [α]25D: +29.0 (c 1.0;
CH2Cl2); 88% ee (iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min,
5 °C, λ = 230 nm): tR = 26.74 min (minor R), tS = 35.52 min
(major S); analytical data were identical to those reported in
the literature.25
2-nitro-1-(4-nitrophenyl)ethanol (19m):66 According to
GP, the adduct (S)ꢀ19m was prepared with (Ra)ꢀ1 and after
36 h at −30 °C obtained as orange oil (20.1 mg, HPLC conv.:
> 99%, yield: 95%). [α]25D: +37.8 (c 0.8; CH2Cl2); 92% ee
(iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm):
tR = 40.54 min (minor R), tS = 50.24 min (major S); analytiꢀ
cal data were identical to those reported in the literature.25
2-nitro-1-(4-(trifluoromethyl)phenyl)ethan-1-ol (19n):67
According to GP, the adduct (S)ꢀ19n was prepared with (Ra)ꢀ
1 and after 60 h at −30 °C obtained as colorless oil (22.3 mg,
HPLC conv.: > 99%, yield: 95%). [α]25D: +28.0 (c 1.1;
CH2Cl2); 85% ee (iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min,
5 °C, λ = 230 nm): tR = 19.89 min (minor R), tS = 25.02 min
(major S); analytical data were identical to those reported in
the literature.25
1-nitro-4-phenylbutan-2-ol (19o):66a According to GP, the
adduct (S)ꢀ19o was prepared with (Ra)ꢀ1 and after 24 h at
−20 °C obtained as colorless oil (18.9 mg, HPLC conv.:
> 99%, yield: 97%). [α]25D: –4.1 (c 1.0; CH2Cl2); 43% ee
(iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ = 205 nm):
tS = 45.63 min (major S), tR = 48.34 min (minor R); analytiꢀ
cal data were identical to those reported in the literature.25
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(2,4-dichlorophenyl)-2-nitroethan-1-ol (19g):34 Acꢀ
cording to GP, the adduct (S)ꢀ19g was prepared with (Ra)ꢀ1
and after 60 h at −30 °C obtained as colorless waxy solid
(23.1 mg, HPLC conv.: > 99%, yield: 98%). [α]25D: +36.7 (c
1.2; CH2Cl2); 96% ee (iꢀPrOH–nꢀheptane, 5:95, 0.5 mL/min,
5 °C, λ = 230 nm): tR = 26.44 min (minor R), tS = 32.05 min
1
(major S); H NMR (DMSOꢀd6, 400 MHz) δ/ppm: 4.51 (dd,
JHH = 12.8, 9.6, 1H), 4.82 (ddd, JHH = 12.8, 2.6, 1.0, 1H),
5.56 (ddd, JHH = 9.6, 5.0, 3.2, 1H), 6.41 (dd, JHH = 5.0, 0.9,
1H), 7.50 (dd, JHH = 8.5, 2.1, 1H), 7.64–7.67 (m, 2H); 13C
NMR (DMSOꢀd6, 100 MHz) δ/ppm: 66.8, 80.1, 127.8,
128.7, 129.8, 131.8, 133.4, 136.8; IR (neat) ṽ/cm−1: 3494br,
3056w, 1588w, 1547s, 1471w, 1418m, 1378m, 1327m,
1298w, 1214m, 1148w, 1084w, 1046m, 921w, 874m, 859w,
810m, 786s, 717w; HRMS (ESIꢀOrbitrap) m/z: [M−H]–
calcd for C8H6Cl2NO3 233.9725, Found 233.9735.
2-nitro-1-(3-nitrophenyl)ethan-1-ol (19h):66b According to
GP, the adduct (S)ꢀ19h was prepared with (Ra)ꢀ1 and after
36 h at −30 °C obtained as yellow oil (20.6 mg, HPLC conv.:
> 99%, yield: 97%). [α]25D: +22.0 (c 1.0; CH2Cl2); 93% ee
(iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm):
tR = 40.84 min (minor R), tS = 46.18 min (major S); analytiꢀ
cal data were identical to those reported in the literature.25
1-(3-fluorophenyl)-2-nitroethanol (19i):66b According to
GP, the adduct (S)ꢀ19i was prepared with (Ra)ꢀ1 and after
60 h at −30 °C obtained as colorless oil (17.8 mg, HPLC
conv.: > 99%, yield: 96%). [α]25D: +31.1 (c 0.9; CH2Cl2);
90% ee (iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min, 5 °C, λ =
230 nm): tR = 23.23 min (minor R), tS = 27.10 min (major S);
analytical data were identical to those reported in the literaꢀ
ture.25
4-methyl-1-nitropentan-2-ol (19p):66 According to GP, the
adduct (S)ꢀ19p was prepared with (Ra)ꢀ1 and after 48 h at
−20 °C obtained as colorless oil (14.1 mg, HPLC conv.:
> 99%, yield: 96%). [α]25D: –2.9 (c 0.7; CH2Cl2); 33% ee
(iꢀPrOH–nꢀheptane, 5:95, 0.5 mL/min, 5 °C, λ = 230 nm): tR
1
= 32.26 min (minor R), tS = 34.39 min (major S). H NMR
2-nitro-1-(3-(trifluoromethoxy)phenyl)ethan-1-ol (19j):
According to GP, the adduct (S)ꢀ19j was prepared with (Ra)ꢀ
1 and after 72 h at −20 °C obtained as colorless oil (23.9 mg,
HPLC conv.: > 99%, yield: 96%). [α]25D: +22.0 (c 1.2;
CH2Cl2); 86% ee (iꢀPrOH–nꢀheptane, 20:80, 0.5 mL/min,
5 °C, λ = 230 nm): tR = 17.55 min (minor R), tS = 19.13 min
(DMSOꢀd6, 400 MHz) δ/ppm: 0.88 (t, JHH = 6.6, 6H), 1.16
(ddd, JHH = 13.4, 9.0, 4.1, 1H), 1.33 (ddd, JHH = 13.4, 9.4,
4.4, 1H), 1.69–1.79 (m, 1H), 4.10–4.18 (m, 1H), 4.30 (dd,
JHH = 12.1, 9.4, 1H), 4.64 (dd, JHH = 11.9, 3.2, 1H), 5.28 (d,
J = 6.9, 1H); 13C NMR (DMSOꢀd6, 100 MHz) δ/ppm: 21.6,
23.3, 23.7, 42.6, 66.4, 82.0; IR (neat) ṽ/cm−1: 3411br,
2907m, 2871w, 1548s, 1469w, 1418w, 1383m, 1368m,
1292w, 1203w, 1144w, 1088w, 1041w, 919w, 886w, 847w,
820w, 734w; HRMS (ESIꢀOrbitrap) m/z: [M–H]– calcd for
C6H12NO3 146.0817; Found 146.0826.
1-(2-chlorophenyl)-2-nitropropan-1-ol (19q):68 According
to GP, the adduct (S)ꢀ19q was prepared using (Ra)ꢀ1 within
168 h at −20 °C. The crude product was purified by column
chromatography in a Pasteur pipette (SiO2) nꢀheptane–
EtOAc, 90:10 and obtained as colorless oil (19.8 mg, HPLC
conv.: 96%, yield: 92%). [α]25D: +22.7 (c 1.1; CH2Cl2);
92:23% ee (1S,2S)/(1R,2S); dr 71:29 (syn/anti) determined
by chiral HPLC from the crude product (iꢀPrOH–nꢀheptane,
5:95, 0.5 mL/min, 5 °C, λ = 230 nm): tRS = 28.47 min (major
diastereomer 1R,2S), tSR = 34.51 min (minor diastereomer
1
(major S); H NMR (DMSOꢀd6, 400 MHz) δ/ppm: 4.61 (dd,
JHH = 12.6, 9.8, 1H), 4.92 (dd, JHH = 12.3, 3.2, 1H), 5.33–
5.37 (m, 1H), 6.30 (d, JHH = 5.0, 1H), 7.31 (d, JHH = 7.3, 1H),
7.46–7.54 (m, 3H); 13C NMR (DMSOꢀd6, 100 MHz) δ/ppm:
1
69.1, 81.5, 118.8, 120.1 (q, JCF = 256.1), 120.4, 125.4,
130.4, 143.4, 148.5; 19F NMR (DMSOꢀd6, 376 MHz) δ/ppm:
–56.60 (s); IR (neat) ṽ/cm−1: 3454br, 1592w, 1553s, 1490w,
1450w, 1421w, 1378w, 1251s, 1208s, 1154s, 1072m, 1003w,
893w, 789w, 699m; HRMS (ESIꢀOrbitrap) m/z: [M–H]–
calcd for C9H7F3NO4 250.0327; Found 250.0332.
1-(4-chlorophenyl-2-nitroethan-1-ol (19k):66 According to
GP, the adduct (S)ꢀ19k was prepared with (Ra)ꢀ1 and after
60 h at −30 °C obtained as yellowish oil (18.9 mg, HPLC
conv.: > 99%, yield: 94%). [α]25D: +29.0 (c 1.0; CH2Cl2);
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The Journal of Organic Chemistry
(syn/anti) determined by 1H NMR from the purified product;
1S,2R), tRR = 45.63 min (minor diastereomer 1R,2R), tSS
=
49.04 min (major diastereomer 1S,2S); dr 62:38 (syn/anti)
1H NMR (500 MHz, CDCl3) δ/ppm: 0.89 (t, JHH = 7.3,
3.00H) (syn), 0.94 (t, JHH = 7.5, 1.32H) (anti), 1.45 (dqd, JHH
= 14.7, 7.4, 3.6, 1.00H) (syn), 1.81–1.92 (m, 1.44H)
(syn+anti); 2.10–2.21 (m, 0.44H) (anti), 2.57 (d, JHH = 4.4,
1.00H) (syn), 2.75 (d, JHH = 3.1, 0.44H) (anti), 4.51–4.59 (m,
1.44H) (syn+anti), 5.02 (dd, JHH = 8.7, 4.3, 1.00H) (syn),
5.16 (dd, JHH = 4.3, 3.1, 0.44H) (anti), 7.24–7.26 (m, 2.88H)
(syn+anti), 7.50–7.52 (m, 0.88H) (anti), 7.53–7.56 (m,
2.00H) (syn); 13C NMR (126 MHz, CDCl3) δ/ppm: 10.0
(syn), 10.3 (anti), 21.3 (anti), 23.9 (syn), 73.6 (anti), 74.8
(syn), 94.4 (anti), 94.9 (syn), 122.8 (anti), 123.2 (syn), 127.9
(anti), 128.5 (syn), 131.9 (anti), 132.2 (syn), 137.5 (anti),
137.6 (syn); IR (neat) ṽ/cm−1: 3487br, 2974w, 1909w,
1593w, 1545s, 1486w, 1457w, 1372w, 1298w, 1096w,
1070m, 1010m, 927w, 891w, 824m, 803m, 721w; HRMS
(ESIꢀOrbitrap) m/z: [M–H]– calcd for C10H11BrNO3
271.9922; Found 271.9936.
1
2
determined by 1H NMR from the purified product; H NMR
1
3
4
5
6
7
8
9
(500 MHz, CDCl3) δ/ppm: 1.45–1.47 (m, 4.86H) (syn+anti),
2.81 (d, JHH = 5.0, 1.00H) (syn), 2.88 (d, JHH = 3.8, 0.62H)
(anti), 4.85–4.92 (m, 1.62H) (syn+anti), 5.61 (dd, JHH = 8.1,
4.9, 1.00H) (syn), 5.85 (t, JHH = 2.7, 0.62H) (anti), 7.28–7.42
(m, 4.86H) (syn+anti), 7.49 (dd, JHH = 7.6, 1.8, 1.00H) (syn),
7.63 (dd, JHH = 7.6, 1.5, 0.62H) (anti); 13C NMR (126 MHz,
CDCl3) δ/ppm: 11.2 (anti), 16.0 (syn), 70.5 (anti), 71.9 (syn),
84.0 (anti), 88.0 (syn), 127.3 (anti), 127.7 (syn), 128.1 (anti),
128.2 (syn), 129.62 (syn), 129.65 (anti), 129.9 (syn), 130.1
(syn), 131.5 (anti), 132.8 (syn), 135.8 (anti), 136.1 (syn); IR
(neat) ṽ/cm−1: 3473br, 3086w, 2992w, 2973w, 2962w,
1680w, 1594w, 1547s, 1475w, 1440w, 1388m, 1360m,
1193w, 1139w, 1099w, 1046m, 990m, 871w, 757s, 732m,
703m; HRMS (ESIꢀOrbitrap) m/z: [M–H]– calcd for
C9H9ClNO3 214.0271, Found 214.0280.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(3-fluorophenyl)-2-nitropropan-1-ol (19r):68 According
to GP, the adduct (S)ꢀ19r was prepared using (Ra)ꢀ1 within
168 h at −20 °C. The crude product was purified by column
chromatography in a Pasteur pipette (SiO2) nꢀheptane–
EtOAc, 90:10 and obtained as colorless oil (18.7 mg, HPLC
conv.: 97%, yield: 94%). [α]25D: +20.0 (c 1.0; CH2Cl2);
86:28% ee (1S,2S)/(1S,2R); dr 58:42 (syn/anti) determined
by chiral HPLC from the crude product (iꢀPrOH–nꢀheptane,
20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tRS = 16.39 min (miꢀ
nor diastereomer 1R,2S), tSR = 20.35 min (major diastereꢀ
omer 1S,2R), tRR = 17.59 min (minor diastereomer 1R,2R),
tSS = 21.09 min (major diastereomer 1S,2S); dr 63:37
(syn/anti) determined by 1H NMR from the purified product;
1H NMR (500 MHz, CDCl3) δ/ppm: 1.36 (d, JHH = 6.9,
3.00H) (syn), 1.50 (d, JHH = 6.9, 1.77H) (anti), 2.74 (br. s,
1.00H) (syn), 2.82 (d, JHH = 2.4, 0.59H) (anti), 4.66–4.70 (m,
0.59H) (anti), 4.71–4.77 (m, 1.00H) (syn), 5.05 (d, JHH = 8.7,
1.00H) (syn), 5.43 (br. s, 0.59H) (anti), 7.01–7.17 (m, 4.77H)
2-amino-1-(2,4-dichlorophenyl)ethan-1-ol (20):34 To
a
solution of (S)ꢀ19g (170 mg, 720 ꢃmol) in MeOH (15 mL),
the freshly prepared Ra–Ni catalyst (200 mg) was added and
the resulting reaction mixture was shaken vigorously for
10 h under H2 (60 psi). Then the reaction mass was filtered
and the filtrate was evaporated in vacuo. The crude waxy
product was dissolved in a small amount of MePh, filtered
and treated with excess of a saturated ethereal HCl solution.
The resulting suspension was left undisturbed overnight in a
refrigerator. The precipitate was filtered off, washed several
times with anhydrous Et2O and dried in vacuo to furnish (S)ꢀ
20ꢁHCl salt as white solid (150 mg, yield: 86%). Mp 186–
1
188 °C; H NMR (DMSOꢀd6, 400 MHz) δ/ppm: 2.70–2.77
(m, 1H), 2.97–3.00 (m, 1H), 5.15 (dd, JHH = 9.4, 2.5, 1H),
6.42 (br. s, 1H), 7.49 (dd, JHH = 8.5, 2.1, 1H), 7.60–7.65 (m,
2H), 8.32 (br. s, 3H); 13C NMR (DMSOꢀd6, 100 MHz)
δ/ppm: 43.8, 65.8, 127.7, 128.6, 129.5, 131.7, 133.1, 138.3;
IR (neat) ṽ/cm−1: 3332br, 2974br, 2895br, 1591m, 1562m,
1505s, 1474m, 1453w, 1381w, 1299w, 1202w, 1187m,
1118w, 1100s, 1043s, 1052s, 1001s, 995w, 868s, 833s, 825s,
759m; HRMS (ESIꢀOrbitrap) m/z: [M−HCl+H]+ calcd for
C8H10Cl2NO 206.0139; Found 206.0136. The free base of
(S)ꢀ20ꢁHCl was released with 2.5 M NaOH and extracted
with CH2Cl2. Organic phase was washed with brine, dried
with Na2SO4, and evaporated in vacuo to afford (S)ꢀ20 as
(syn+anti), 7.34–7.41 (m, 1.59H) (syn+anti); 13C NMR (126
MHz, CDCl3) δ/ppm: 11.9 (anti), 16.4 (syn), 73.1 (d, JCF
1.8) (anti), 75.6 (d, JCF = 1.8) (syn), 87.2 (anti), 88.1 (syn),
113.2 (d, JCF = 22.5) (anti), 113.9 (d, JCF = 22.5) (syn),
4
=
4
2
2
2
2
115.4 (d, JCF = 21.8) (anti), 116.2 (d, JCF = 21.8) (syn),
121.5 (d, JCF = 2.7) (anti), 122.6 (d, 4JCF = 2.7) (syn), 130.4
4
3
3
(d, JCF = 8.2) (anti), 130.6 (d, JCF = 8.2) (syn), 140.8 (d,
3JCF = 6.4) (syn), 141.0 (d, 3JCF = 6.4) (anti), 163.0 (d, 1JCF
=
yellow waxy solid (100 mg, overall yield: 67%). [α]25
:
D
247.9) (syn+anti); 19F NMR (471 MHz, CDCl3) δ/ppm:
−111.77 (s, 0.78F) (anti), –111.43 (s, 1.00F) (syn); IR (neat)
ṽ/cm−1: 3471br, 3005w, 2874w, 1615w, 1591m, 1545s,
1488m, 1449m, 1389m, 1360m, 1237m, 1140m, 1050m,
1026w, 993w, 875m, 786m, 700m; HRMS (ESIꢀOrbitrap)
m/z: [M–H]– calcd for C9H9FNO3 198.0566; Found
198.0574.
+73.8 (c 0.5; CHCl3).
1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol
(21):34 A solution of (S)ꢀ20 (100 mg, 485 ꢃmol), 40% aqueꢀ
ous glyoxal (111 ꢃL, 97 ꢃmol), 35% aqueous formaldehyde
(76 ꢃL, 97 ꢃmol), and NH4OAc (75 mg, 97 ꢃmol) in methaꢀ
nol (1 mL) was stirred overnight at 80 °C in the pressure vial
under Ar. After cooling to rt, MeOH was evaporated in vacꢀ
uo and the oily residue was treated with 2 M NaOH and exꢀ
tracted with CH2Cl2. Organic extract was washed with brine,
dried with Na2SO4, filtered and evaporated in vacuo. The
crude oily product purified by flash column chromatography
(SiO2) EtOAc, 100% afforded (S)ꢀ21 as yellow oil, which
solidifies upon standing (95 mg, yield: 76%). [α]25D: +82.8 (c
1-(4-bromophenyl)-2-nitrobutan-1-ol (19s):69 According to
GP, the adduct (S)ꢀ19r was prepared using (Ra)ꢀ1 within
168 h at −20 °C. The crude product was purified by column
chromatography in a Pasteur pipette (SiO2) nꢀheptane–
EtOAc, 90:10 and obtained as milky oil (24.4 mg, HPLC
conv.: 95%, yield: 89%). [α]25D: +14.3 (c 1.3; CH2Cl2);
90:37% ee (1S,2S)/(1S,2R); dr 82:18 (syn/anti) determined
by chiral HPLC from the crude product (iꢀPrOH–nꢀheptane,
20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tRS = 15.65 min (miꢀ
nor diastereomer 1R,2S), tSR = 17.13 min (major diastereꢀ
omer 1S,2R), tRR = 18.86 min (minor diastereomer 1R,2R),
tSS = 20.37 min (major diastereomer 1S,2S); dr 69:31
1
0.5; CHCl3); H NMR (CDCl3, 400 MHz) δ/ppm: 3.85 (dd,
JHH = 14.2, 8.2, 1H), 4.20 (dd, JHH = 14.2, 2.7, 1H), 5.23
(JHH = 8.2, 2.3, 1H), 6.82 (s, 1H), 6.89 (s, 1H), 7.29 (dd, JHH
= 8.2, 2.3, 1H), 7.37 (br. s, 1H), 7.39 (d, JHH = 2.3, 1H), 7.58
(d, JHH = 8.2, 1H); 13C NMR (CDCl3, 100 MHz) δ/ppm:
53.4, 69.6, 119.7, 127.7, 128.3, 128.6, 129.0, 131.9, 134.1,
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137.3, 137.4; IR (neat) ṽ/cm−1: 3742w, 3648w, 3108w, 127.8, 128.4, 142.0; IR (neat) ṽ/cm−1: 3205br, 3031br,
1
2
3
4
5
6
7
2960w, 2922w, 2851w, 1732w, 1652w, 1587w, 1559w,
1512m, 1464m, 1432w, 1378w, 1334w, 1282w, 1259m,
1234m, 1207w, 1181w, 1104m, 1088m, 1079s, 1047m,
1022s, 956w, 922s, 868s, 826s, 787s, 751m, 734m; HRMS
(ESIꢀOrbitrap) m/z: [M+H]+ calcd for C11H11Cl2N2O
257.0248; Found 257.0245.
1615w, 1568w, 1490m, 1460w, 1451w, 1344w, 1138w,
1124w, 1055m, 999s, 954m, 912m, 802w, 747s; HRMS (ESIꢀ
Orbitrap) m/z: [M–HCl+H]+ calcd for C8H12NO 138.0919;
Found 138.0911. The free base of 23ꢁHCl was released with
2.5 M NaOH and extracted with CH2Cl2. Organic phase was
washed with brine, dried with Na2SO4, and evaporated in
vacuo to afford 23 as colorless oil.
1-(2-((4-chlorobenzyl)oxy)-2-(2,4-dichlorophenyl)ethyl)-
1H-imidazole (22):34,70 To a solution of (S)ꢀ21 (95 mg,
365 ꢃmol) in THF/DMF (2.5 mL, 10:1 v/v), NaH (60%,
21.9 mg, 1.5 equiv.) was added in portions at 0 °C. After 15
min, 4ꢀchlorobenzyl chloride (47 ꢃL, 1 equiv.) was added
dropwise followed by a oneꢀtime addition of nꢀBu4NI
(13.5 mg, 10 mol%) and the resulting reaction mass was left
stirring at rt overnight under Ar. Then the reaction mixture
was evaporated in vacuo, diluted with water and extracted
with CH2Cl2. Organic layer was washed with brine, dried
with Na2SO4, and evaporated in vacuo. The crude oily prodꢀ
uct was treated with excess of an ethereal oxalic acid soluꢀ
tion and the resulting white precipitate was washed with
fresh anhydrous Et2O and dried in vacuo to reach
(S)-2ꢁH2C2O4 salt as white solid (148 mg, yield: 85%). Mp
146–147 °C; IR (neat) ṽ/cm−1): 3843w, 3650w, 3130w,
2572w, 1733s, 1633s, 1577m, 1541w, 1488m, 1470w,
1447w, 1409w, 1390w, 1349w, 1285w, 1226s, 1091s,
1077m, 1046m, 1014s, 895w, 868m, 852m, 828s, 797s, 786s,
762s, 722s; HRMS (ESIꢀOrbitrap) m/z: [M−H2C2O4+H]+
calcd for C18H16Cl3N2O 381.0328; Found 381.0329. The free
base of (S)ꢀ22ꢁH2C2O4 was released with 2.5 M NaOH and
extracted with CH2Cl2. Organic phase was washed with
brine, dried with Na2SO4, and evaporated in vacuo to afford
N-(2-hydroxy-2-phenylethyl)-2-(4-nitrophenyl)acetamide
(24): To a solution of 23 (0.73 mmol, 100 mg), EDCl (1.1
equiv., 154 mg), HOBtꢁH2O (1.1 equiv., 110 mg), and Et3N
(2.1 equiv., 215 ꢃL) in anhydrous THF (5 mL), 4ꢀ
nitrophenylacetic acid (1.0 equiv., 132 mg) was added porꢀ
tionwise and the reaction mass was left stirring for 1 h at rt
under Ar. Then the reaction mixture was diluted with water
and extracted with EtOAc. The organic phase was washed
with 1 M HCl, saturated solution of NaHCO3 and brine,
dried with Na2SO4 and evaporated in vacuo to provide 24 as
white solid (140 mg, yield: 64%), which was used directly in
the next step. Racꢀ24: mp 128–129 °C; (R)ꢀ24: mp 143–
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
144 °C; [α]20D: +12.0 (c 0.5; MeOH); H NMR (DMSOꢀd6,
400 MHz) δ/ppm: 3.15–3.18 (m, 1H), 3.29–3.32 (m, 1H),
3.59 (s, 2H), 4.61 (br. s, 1H), 5.52 (d, JHH = 3.7, 1H), 7.23–
7.30 (m, 5H), 7.48 (d, JHH = 7.8, 2H), 8.15 (d, JHH = 7.8, 2H),
8.27 (br. s, 1H); 13C NMR (DMSOꢀd6, 100 MHz) δ/ppm:
41.9, 46.9, 71.3, 123.3, 126.1, 127.1, 128.1, 130.4, 143.6,
144.7, 146.3, 169.2; IR (neat) ṽ/cm−1: 3295br, 3095br,
2965w, 1651m, 1604w, 1553w, 1515m, 1494w, 1417w,
1347s, 1252w, 1203w, 1109w, 1058m, 1029w, 852m, 828w,
812w, 754w, 701s; HRMS (ESIꢀOrbitrap) m/z: [M+H]+ calcd
for C16H17N2O4 301.1188; Found 301.1177.
(S)ꢀ22 as colorless oil (90 mg, overall yield: 65%). [α]20
:
D
2-(4-aminophenyl)-N-(2-hydroxy-2-phenylethyl)acet-
amide (25): To a solution of 24 (140 mg, 0.5 mmol) in
MeOH (15 mL), 10% Pd/C (100 mg) was added and the
resulting reaction mixture was shaken vigorously for 3 h
under H2 (60 psi). Then the reaction mass was filtered and
the filtrate was evaporated in vacuo to furnish 25 as white
solid (130 mg, yield: 98%), which was used directly in the
1
+86.8 (c 1.0; CH2Cl2); > 99% ee; H NMR (CDCl3, 400
MHz) δ/ppm: 4.03 (dd, JHH = 14.6, 7.8, 1H), 4.16–4.21 (m,
2H), 4.43 (d, JHH = 11.9, 1H), 4.95 (dd, JHH = 7.8, 2.7, 1H);
6.89 (t, JHH = 1.3, 1H), 7.05 (t, JHH = 8.0, 3H), 7.27–7.34 (m,
4H), 7.44–7.46 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ/ppm: 51.3, 70.7, 76.8, 119.7, 127.9, 128.4, 128.7, 129.0,
129.2, 129.6, 133.3, 133.8, 133.9, 134.9, 135.3, 137.8.
next step. Racꢀ25: mp 128–129 °C; (R)ꢀ25: mp 113–115 °C;
2-amino-1-phenylethan-1-ol (23):71 To a solution of 19a
(250 mg, 1.5 mmol) in MeOH (50 mL), 10% Pd/C (100 mg)
was added and the resulting reaction mixture was shaken
vigorously for 3 h under H2 (60 psi). Then the reaction mass
was filtered and the filtrate was evaporated in vacuo to furꢀ
nish 23 as colorless oil, which solidifies upon standing
(200 mg, yield: 97%). The crude product was treated with
excess of ethereal HCl solution and the resulting precipitate
was filtered and washed with anhydrous Et2O, CH2Cl2 and
dried in vacuo to produce 23ꢁHCl as white solid (245 mg,
overall yield: 97%). Racꢀ23ꢁHCl: mp 134–135 °C; (R)ꢀ
[α]25 +3.0 (c 1.0; MeOH); −44.0 (c 0.5; CHCl3); H NMR
1
D
(DMSOꢀd6, 400 MHz) δ/ppm: 3.11 (ddd, JHH = 13.2, 7.9,
5.0, 1H), 3.21 (s, 2H), 3.23–3.29 (m, 1H), 3.38 (s, 1H), 4.58
(dd, JHH = 7.3, 5.0, 1H), 4.91 (br. s, 2H), 5.53 (br. s, 1H),
6.48 (d, JHH = 8.7, 2H), 6.87 (d, JHH = 8.2, 2H), 7.21–7.33
(m, 5H), 7.89 (t, JHH = 5.5, 1H); 13C NMR (DMSOꢀd6, 100
MHz) δ/ppm: 41.6, 47.0, 71.3, 113.8, 123.3, 126.0, 127.0,
128.0, 129.5, 143.8, 147.1, 171.2; IR (neat) ṽ/cm−1: 3734w,
3340br, 2960w, 1652w, 1626s, 1557m, 1516s, 1494w,
1455w, 1436w, 1411w, 1253w, 1212w, 1170w, 1065m,
1028w, 918w, 838w, 814w, 785w, 761m, 703s; HRMS (ESIꢀ
Orbitrap) m/z: [M+H]+ calcd for C16H19N2O2 271.1447;
Found 271.1437.
2-((4-aminophenethyl)amino)-1-phenylethan-1-ol (26):72
To a solution of 25 (130 mg, 0.5 mmol) in anhydrous MePh
(5 mL), 60% solution of SMEAH in MePh (2.5 mL,
7.5 mmol) was added dropwise in order to maintain the reacꢀ
tion temperature below 20 °C. The resulting mixture was left
stirring 48 h at rt under Ar. Then the reaction was quenched
by dropwise addition of water, diluted with water and the
organic phase was separated. The aqueous phase was basiꢀ
fied with 2.5 M NaOH to pH 10 and backꢀextracted with
several portions of fresh MePh. Combined organic extracts
23ꢁHCl: mp 138–140 °C; [α]25 −46.0 (c 0.5; MeOH); 75%
D
ee. The enantioenriched (R)ꢀ23ꢁHCl salt was dissolved in a
small amount of MeOH and Et2O was added dropwise until
precipitation occurred. The resulting mixture was left undisꢀ
turbed for 2 h in the refrigerator. The white microcrystalline
precipitate was filtered, washed with fresh anhydrous Et2O
and dried in vacuo to afford enantiopure (R)ꢀ23ꢁHCl as white
powder (170 mg, overall yield: 67%). Mp 149–150 °C;
1
[α]25D: −62.0 (c 0.5; MeOH); > 99% ee; H NMR (DMSOꢀ
d6, 400 MHz) δ/ppm: 2.81 (dd, JHH = 12.6, 9.8, 1H), 2.99
(dd, JHH = 12.8, 2.7, 1H), 4.84 (dt, JHH = 9.9, 3.7, 1H), 6.11
(d, JHH = 3.7, 1H), 7.27–7.40 (m, 5H), 8.17 (br. s, 3H); 13C
NMR (DMSOꢀd6, 100 MHz) δ/ppm: 45.9, 69.1, 126.0,
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The Journal of Organic Chemistry
Någren, K.; Bottlaender, M.; Maziére, B.; Crouzel, C. Bioorg. Med.
Chem. 2001, 9, 677–694.
were washed with brine, dried with Na2SO4 and evaporated
1
2
3
4
5
6
7
8
in vacuo to provide 26 as yellowish solid (117 mg, yield:
95%). Racꢀ26: mp 87–88 °C; (R)ꢀ26: mp 76–77 °C; [α]25
−32.0 (c 0.5; CHCl3); H NMR (CDCl3, 400 MHz) δ/ppm:
(2) (a) Burés, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 49, 441–
444. (b) Buchanan, D. J.; Dixon, D. J.; HernandezꢀJuan, F. A. Org.
Biomol. Chem. 2004, 2, 2932–2934. (c) Nikalje, M. D.; Sayyed Ali,
I.; Dewkar, G. K.; Sudalai, A. Tetrahedron Lett. 2000, 41, 959–961.
(d) Vichare, P.; Chattopadhyay, A. Tetrahedron: Asymmetry 2010,
21, 1983–1987. (e) Ballini, R.; Petrini, M. Tetrahedron 2004, 60,
1017–1047.
(3) (a) Adams, L. L.; Luzzio, F. A. J. Org. Chem. 1989, 54,
5387–5390. (b) Mei, Z.ꢀW.; Omote, T.; Mansour, M.; Kawafuchi,
H.; Takaguchi, Y.; Jutand, A.; Tsuboi, S.; Inokuchi, T. Tetrahedron
2008, 64, 10761–10766. (c) Elmaaty, T. A.; Castle, L. W. Org. Lett.
2005, 7, 5529–5530. (d) Biftu, T.; SinhaꢀRoy, R.; Chen, P.; Qian,
X.; Feng, D.; Kuethe, J. T.; Scapin, G.; Gao, Y. D.; Yan, Y.; Krueꢀ
ger, D.; Bak, A.; Eiermann, G.; He, J.; Cox, J.; Hicks, J.; Lyons, K.;
He, H.; Salituro, G.; Tong, S.; Patel, S.; Doss, G.; Petrov, A.; Wu,
J.; Xu, S. S.; Sewall, C.; Zhang, X.; Zhang, B.; Thornberry, N. A.;
Weber, A. E. J. Med. Chem. 2014, 57, 3205–3212. (e) Rosini, G.;
Ballini, R.; Sorrenti, P.; Petrini, M. Synthesis 1984, 1984, 607–608.
(f) Ballini, R.; Petrini, M.; Rosini, G. Synthesis 1986, 1986, 849–
852.
D
1
1.27 (br. s, 1H), 2.67–2.94 (m, 6H), 3.66 (br. s, 2H), 4.69
(dd, JHH = 9.1, 3.3, 1H), 5.31 (br. s, 1H), 6.64 (d, JHH = 8.1,
2H), 6.99 (d, JHH = 8.0, 2H), 7.29–7.36 (m, 5H); 13C NMR
(CDCl3, 100 MHz) δ/ppm: 35.4, 50.8, 56.9, 71.6, 115.3,
125.8, 127.4, 128.3, 129.5, 129.6, 142.6, 144.6; IR (neat)
ṽ/cm−1: 3324w, 2920w, 2826br, 1612m, 1515s, 1451m,
1424m, 1335w, 1261m, 1179w, 1115m, 1070m, 1041m,
983w, 908m, 884w, 856w, 812m, 755m, 700s; HRMS (ESIꢀ
Orbitrap) m/z: [M+H]+ calcd for C16H21N2O 257.1654;
Found 257.1642.
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ASSOCIATED CONTENT
Supporting Information
SI is available free of charge on the ACS Publications website.
SI contains synthetic schemes, optimization, kinetic and specꢀ
troscopic experiments, HPLC, NMR, HRMS and crystalloꢀ
graphic data for compounds 1–17, 19a–s, and 20–26. (PDF)
Crystallographic data for racꢀ7. (CIF)
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2132.
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Crystallographic data for racꢀ12. (CIF)
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2671. (b) Stadler, D.; Mühlthau, F.; Rubenbauer, P.; Herdtweck, E.;
Bach, T. Synlett 2006, 2573–2576.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: bobalp@vfu.cz
(7) Hanessian, S. (2016, September). The Enterprise of Drug
Discovery from an Academic Perspective: A Personal Odyssey.
PowerPoint presentation at 8th Central European Conference: Chemꢀ
istry toward Biology, UVPS Brno, Brno, Czech Republic.
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4905–4909. (b) Grob, C. A.; Von Sprecher, H. Helv. Chim. Acta
1952, 35, 902–909. (c) Fukazawa, Y.; Aoki, Y.; Mita, H.; Komatsu,
H. (Mitsui Chemicals Agro) Patent US 20100267963, 2010; Chem.
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Y. J. Org. Chem. 2015, 80, 1446–1456. (b) Chung, J. Y. L.; Peng,
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Author Contributions
All authors have given approval to the final version of the manꢀ
uscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support of the work was provided by the project
308/2017/FaF and 327/2016/FaF (IGA UVPS Brno). NMR part
of the work was realized in Central European Institute of Techꢀ
nology (CEITEC) under open access project LM2011020 fundꢀ
ed by the Ministry of Education, Youth and Sports of the Czech
Republic (MEYS CR) under the activity “Projects of major
infrastructures for research, development and innovations.”
CIISB research infrastructure project LM2015043 funded by
MEYS CR is gratefully acknowledged for the financial support
of the measurements at the CF XꢀRay Diffraction and Bioꢀ
SAXS. We wish to thank Radovan Fiala (CEITEC) and Otakar
Humpa (CEITEC) for NMR measurements, Jaromir Marek
(CEITEC) for Xꢀray part of the manuscript and Radim Hrdina
(JLU Giessen) for fruitful discussions.
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The Journal of Organic Chemistry
Page 20 of 20
CF3
1
2
3
4
5
6
S
N
N
S
F3C
N
N
H
H
H
H
N
N
CF3
O
OH
7
8
9
R1
R2
H
CF3
(10 mol%)
Et2O
R2
R1
NO2
– 30 or –20 °C
10
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NO2
up to 96% ee
up to 69:31 syn/anti
87–98% yield
19 examples
R1 = Ar, Het, Alk
R2 = H, Me, Et
20
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