High-Pressure-Mediated Asymmetric Organocatalytic Hydroxyalkylation of Indoles with Trifluoromethyl Ketones

Article abstract of DOI:10.1002/adsc.201600327

An enantioselective hydroxyalkylation of indoles and 7-azaindole with trifluoromethyl ketones was found to be effectively promoted under high-pressure conditions with a low loading of Cinchona alkaloids (e.g., 1–3 mol% of cinchonidine). Chiral tertiary alcohols containing a trifluoromethyl group were obtained at 9 kbar with good yield and enantioselectivity up to 89%, whereas usually merely traces of products were detected at atmospheric pressure. (Figure presented.).

Full text of DOI:10.1002/adsc.201600327

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DOI: 10.1002/adsc.201600327
High-Pressure-Mediated Asymmetric Organocatalytic
Hydroxyalkylation of Indoles with Trifluoromethyl Ketones
Adrian Kasztelan,a Michał Biedrzycki,a and Piotr Kwiatkowskia,*
a
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
E-mail: pkwiat@chem.uw.edu.pl
Received: March 25, 2016; Revised: July 4, 2016; Published online: && &&, 0000
Dedicated to Professor Janusz Jurczak on the occasion of his 75th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600327.
Abstract: An enantioselective hydroxyalkylation of selectivity up to 89%, whereas usually merely traces
indoles and 7-azaindole with trifluoromethyl ketones of products were detected at atmospheric pressure.
was found to be effectively promoted under high-
pressure conditions with a low loading of Cinchona
alkaloids (e.g., 1–3 mol% of cinchonidine). Chiral Keywords: asymmetric organocatalysis; Cinchona al-
tertiary alcohols containing a trifluoromethyl group kaloids; Friedel–Crafts reaction; high-pressure
were obtained at 9 kbar with good yield and enantio- effect; indoles; trifluoromethyl group
Introduction
with
AHCTUNGTRENNUNG
very
reactive
ethyl
3,3,3-trifluoropyru-
vate,[3a–d,6a,7d,8] only one asymmetric approach based on
The indole motif[1] as well as trifluoromethyl group[2] Brønsted acid catalysis has been developed in an
play an important role in the synthesis of biologically analogous reaction with simple and less reactive tri-
active compounds and in drug discovery. The pres- fluoromethyl ketones (Scheme 1).[7a] Ma and co-work-
ence of these two elements in one molecule seems to ers demonstrated that chiral phosphoric acids (e.g.,
be particularly interesting for medicinal chemistry.[3] TRIP, 5–1 mol%) are effective catalysts in this case.[7a]
One possible synthetic approach for achieving this
On the other hand, chiral tertiary amines were suc-
goal is functionalization of indoles at the 3-position cessfully applied as catalysts in reactions of indoles
with trifluoromethyl-containing electrophilic com- with 1,2-dicarbonyl compounds.[6a,11] Tçrçk et al.[6a]
pounds. Of special interest are enantioselective reac- found that Cinchona alkaloids (1a, 1b, 1d and 1e,
tions of indoles[4] with prochiral trifluoromethylated Figure 1) are efficient catalysts for the enantioselec-
substrates,[5] for example, trifluoromethyl ketones,[6,7,8] tive reaction of indoles with ethyl 3,3,3-trifluoropyru-
imines[9] or a,b-unsaturated compounds.[10]
vate. Deng[11] extended the scope of the reaction to
In our investigations we focused on the organocata- various 1,2-dicarbonyl compounds as well as aromatic
lytic asymmetric additions of indoles to aryl or alkyl aldehydes with 6’-OH Cinchona alkaloid derivatives
trifluoromethyl ketones (Scheme 1). We were inter- (e.g., 1i) as catalysts.
ested to explore the possibility of utilizing chiral
The aim of our study was to develop an amine-cata-
amines as catalysts in this reaction. Despite a number lyzed asymmetric synthesis of tertiary a-trifluorome-
of examples of enantioselective reactions of indoles thylated alcohols I (Scheme 1) bearing 3-indolyl and
aryl substituents, an alternative and complementary
approach to Brønsted acid catalysis.[7a] The literature
describes only one example of a base-catalyzed reac-
tion of indoles with trifluoroacetophenones utilizing
simple guanidines in the presence of water, and af-
forded racemic alcohols of type I.[12]
Scheme 1. Reaction of indoles with CF3-ketones.
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Table 1. Catalyst screening in the model reaction[a]
En- Catalyst
1 bar (20 h) 8 kbar (20 h)
try
(2 mol%)
Yield [%][b] Yield [%][b] er (R:S)[c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
0.3
0.2
0.5
0.3
0.1
1[d]
0
76
72
83
68
69
84
5
73
77
85
87
60
45
46
90
85
2
10:90
14:86
84:16
83:17
79:21
18:82
78:22
21:79
11:89
21:79
42.5:57.5
58:42
59:41
60:40
31:69
82:18
–
4[e]
0.5
<0.1
0.1
0.4
0.2
1.5
<0.1
0.5
<0.1
0.3
0.7
0
9
10
11
12
13
14
15
16
17
18
19
20
1q
1r
1s
49
95
5–6[f]
81:19
60:40
–
no catalyst
[a]
Reaction conditions: indole (0.5 mmol, c=0.5 mol/L), tri-
fluoroacetophenone (0.6 mmol, 1.2 equiv.), and catalyst
1 (0.01 mmol, 2 mol%) in toluene (ca. 0.75 mL), 20–
258C.
Determined by GC analysis using biphenyl as the inter-
nal standard.
Determined by HPLC analysis using Chiralpak IB
column.
14% after 7 days, er=23:77.
[b]
[c]
Figure 1. Organocatalysts examined in the model reaction.
[d]
[e]
Results and Discussion
25% after 7 days, er 21:79 (with 10 mol% of 1h: 26%
after 24 h; 90% after 7 days and er 20:80).
10% yield at 10 kbar.
[f]
Our preliminary experiments with various chiral
amines 1 (2 mol%, Figure 1) confirmed their very low
activity (Table 1) in the model reaction of indole (2a)
with trifluoroacetophenone (3a) under classical condi-
tions (1 bar, room temperature, 20 h). Among the hydroxyalkylation
reaction
presented
in
tested chiral amines cupreidine 9-O-benzyl ether (1h) Scheme 1.[17,18] However, this method of activation is
turned out to be the most active catalyst. After 7 days useful only for reactions characterized by a negative
the product 4a was obtained with 25% yield and 58% volume of activation.[19]
ee (Table 1, entry 8). With other amines (2 mol% of
Application of 2 mol% of various chiral amines
1a–f, 1h–o, 1q, 1r) only traces (<2%) of product 4a containing hydrogen-bonding donors (e.g., hydroxy
were observed at atmospheric pressure after 20 h. compounds, thioureas, squaramides) as catalysts
Further optimization with 10 mol% of catalyst 1h and under 8 kbar of pressure remarkably accelerated the
a higher concentration of reagents leads to 26% con- reaction rate (Table 1). The yield substantially in-
version after one day and 90% after 7 days with an creased to 45–95% at 8 kbar. In the control high-pres-
enantioselectivity of 60%.[13]
sure experiment without any catalysts we observed
Encouraged by our recent results in high-pressure formation of ca. 5% of the product (entry 20). The
organocatalytic conjugate additions,[14] we decided to presence of an amine moiety and hydrogen-bonding
investigate the influence of pressure[15,16] also in the donors in the catalyst structure is crucial for the activ-
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Table 2. Optimization of the model reaction[a]
ity. In contrast, the use of a chiral amine without hy-
drogen-bonding donors (e.g., O-protected quinidine,
1g, entry 7) or thiourea without an amine moiety (1q,
entry 17) resulted in very low conversion.
En-
try
mol%
of 1a
Pressure
2a conc.
[mol/L]
Yield
ee
[%][b,c]
[%][d]
1[e]
2
3
4
5
6
7
8
9
5
4
4
2
2
1
4
2
1 bar
1.0
1.0
1.0
0.5
1.0
1.0
0.5
0.5
0.5
1.0
0.5
0.5
12
53
83
76 (73)
93 (91)
81
85
87 (85)
74
58
75
78
81
77
76
80
80.5
80.5
75.5
78
Among various tested amines containing hydrogen-
bonding donors the most promising results in terms of
conversion (>68%) and enantioselectivity (58–80%
ee) were observed under high pressure conditions
with Cinchona alkaloids and their demethylated de-
rivatives, cupreine (1c) and cupreidine (1f) (entries 1–
6, 8–10).[20] The presence of the phenolic OH group at
C-6’ in catalysts 1c, 1f, 1h and 1i resulted in inversion
of the enantioselectivity, as compared to quinine and
quinidine, respectively. In contrast, with thiourea and
squaramide Cinchona derivatives (1k and 1l) a very
low enantiomeric excess was achieved (entries 11 and
12). We tested also thiourea derivatives based on
other chiral amines, for example, 1,2-diaminocyclo-
hexane (1o and 1p). An interesting level of enantiose-
lectivity was observed with primary amine-thiourea
1p (64% ee, entry 16). Surprisingly, use of the analo-
gous catalyst 1n (Takemotoꢁs catalyst) with a tertiary
amine instead of a primary one resulted in the oppo-
site enantioselectivity (38% ee, entry 15).
4 kbar
6 kbar
8 kbar
8 kbar
8 kbar
8 kbar
9 kbar
9 kbar
9 kbar
9 kbar
9 kbar
1
0.5
4
10
11[f]
12[g]
75
62
87
4
80.5
[a]
General reaction conditions: indole (0.5 mmol), trifluor-
oacetophenone (0.6 mmol, 1.2 equiv.), and catalyst 1a in
toluene, 20–258C, 20 h.
Determined by GC analysis using biphenyl as the inter-
nal standard.
Isolated yield in parentheses; 2 mmol reaction scale.
Determined by HPLC analysis using Chiralpak IB
column.
[b]
[c]
[d]
[e]
[f]
Reaction at 508C for 5 d.
Reaction time: 4 h.
Reaction time: 8 h.
Finally, cinchonidine (1a) turned out to be the best
catalyst in terms of enantioselectivity (80% ee) as
well as availability and this natural product was used
[g]
in further optimization studies. A subsequent solvent carried out under atmospheric pressure at 508C the
screening (e.g., CH2Cl2, CHCl3, acetonitrile, THF, yield was very low even after 5 days (12%, Table 2,
MeOH)[21] revealed that toluene was the best entry 1). We observed that a high yield (83%) can be
choice.[22]
obtained by using the same reaction mixture with
The influence of pressure in the range of 4–10 kbar 4 mol% of 1a under 6 kbar at room temperature after
on the model reaction catalyzed by 2 mol% of cincho- 20 h (Table 2, entry 3). The reaction with a higher
nidine is shown in Figure 2. A pressure increase has concentration of reactants is effective even with 1–
a significant effect on the reaction rate and very good 0.5 mol% of cinchonidine under a pressure of 8–
results in terms of yield were obtained at 9–10 kbar. 9 kbar (74–81%, entries 6 and 10) with ee up to 76%.
However, the best enantioselectivity (80–82% ee) was Experiments with a lower concentration of reagents
observed at the 6–9 kbar pressure range.
(0.5 mol/L of 2a) improved the enantioselectivity up
The reaction was also investigated with higher load- to 81% (entry 4), but the yield decreased, for exam-
ings of cinchonidine (up to 5 mol%) and concentra- ple, with 2 mol% of 1a at 8 kbar from 93% to 76%
tions of reagents (1 mol/L of 2a). In the experiment (entries 4 and 5). Application of 9 kbar pressure,
2 mol% of 1a and 0.5 mol/L concentration of 2a
offers the best compromise in terms of yield (87%)
and enantioselectivity (up to 80.5% ee; entry 8). The
reaction time can be significantly reduced (e.g., from
20 h to 8 h) by increasing the catalyst concentration
(e.g., to 4 mol%; entry 12).
To demonstrate the scope of the reaction of tri-
fluoroacetophenone with various indoles we applied
9 kbar of pressure and 2–3 mol% of cinchonidine
(Scheme 2). Products 4b–f having in the structure var-
ious 5-substitued indoles were isolated in good yield
(79–89%) and enantioselctivity in the range of 71–
82% ee. The most problematic was the addition of the
less reactive 5-cyanoindole; the product 4g was ob-
tained at 10 kbar with 5 mol% of 1a in 60% yield and
moderate enantioselectivity. We also tested indoles
Figure 2. Effect of pressure on the model reaction.
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Scheme 3. Reaction of 7-azaindole with trifluoromethyl ke-
tones.
In the reaction of 7-azaindole with 3a we also
tested the possibility of an alternative approach with
Brønsted acid catalysis.[7a] Application of 1 mol% of
BINOL-derived phosphoric acids with 3,3’-di(2,4,6-
triisopropylphenyl) groups (TRIP) failed in this reac-
tion under atmospheric pressure as well as at high
pressure.
Finally, the scope of trifluoromethyl ketones in the
reaction with indole was investigated under 9 kbar
(Scheme 4). The reaction works well in terms of yield
and enantioselectivity with variously para-, meta- and
Scheme 2. Reaction of indoles with trifluoroacetophenone.
substituted in positions 2, 4 and 7 (see products 4h, 4i some ortho- substituted trifluoroacetophenones (4k–
and 4j). The best enantioselectivity (89%) was found 4s) with 86–70% enantioselectivity. Moreover the hy-
with 4-methoxyindole.
droxyalkylation catalyzed by cinchonidine tolerates
The presence of a free NH in the indole ring is es- the trifluoromethyl ketone with a 3-pyridyl group
sential for this reaction in terms of reactivity and (product 4t) and 2-chloro-2,2-difluoroacetophenone
enantioselectivity. The use of N-methylindole instead (product 6). Unfortunately, the reaction with less re-
of indole resulted in very low yield and loss of enan- active aliphatic trifluoromethyl ketones resulted in
1
tioselectivity. This observation and H NMR spectra the formation of nearly racemic alcohol 4u. Under at-
of 1a with 2a support the importance of catalyst inter- mospheric pressure usually traces (yield <2%) of
action with the NH of indole (via hydrogen bonding products were observed after one day, up to 8% yield
with the quinuclidine part).[23] Addition of cinchoni- for addition to more active 3-trifluoroacetylpyridine
dine shifts the indole NH signal to lower field. On the (see 4t).
other side, the hydroxy group in cinchonidine partici-
The absolute configurations of 4a and 4n, obtained
pates in hydrogen bonding activation of the carbonyl in the presence of cinchonidine, was determined by
in the trifluoromethyl ketone. After addition of comparison of their optical rotations[7a] and were as-
2 equiv. of trifluoroacetophenone to cinchonidine, the signed to be (S). In some cases the ee of the alcohols
signal from the OH group at C-9 disappeared in the 4 can be improved to >98.0% after a single crystalli-
1H NMR spectra.[23]
zation (e.g., for products 4a, 4f, 4n).
In addition, we have found that cinchonidine can
also effectively catalyze the reaction of trifluoroaceto-
phenones with 7-azaindole at 9 kbar, however the Conclusions
enantioselectivity is slightly lower (Scheme 3, 58–63%
ee), as compared to indole. To the best of our knowl- An alternative and complementary approach to the
edge, this is the first example of the use of 7-azain- Brønsted acid-catalyzed asymmetric hydroxyalkyla-
doles in the enantioselective 1,2-addition to carbonyl tion of indoles with trifluoromethyl ketones is demon-
compounds.[24]
strated. We have found that high pressure remarkably
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Experimental Section
Results of Solvent Screening
For the model reaction (conditions: 4 mol% of 1a, c(2a) =0.5
mol/L, 1.2 equiv. of 3a, 8 kbar, 20–258C, 20 h): CH2Cl2
(70%, 72% ee), CHCl3 (86%, 67% ee), fluorobenzene (50%,
54% ee), chlorobenzene (72%, 70% ee), ethylbenzene
(86%, 78% ee), m-xylene (63%, 64% ee), acetonitrile (71%,
63% ee), THF (5%), methanol (<2%).
General Procedure for Asymmetric High-Pressure-
Mediated Addition of Indoles to Trifluoromethyl
Ketones
A 3-mL Teflon ampoule was charged with 2–3 mol% of cin-
chonidine (9.0–13.5 mg), 1.5 mmol of indole and 1.65–
1.8 mmol of trifluoromethyl ketone (1.1–1.2 equiv.). The
Teflon ampoule was filled up with toluene and after com-
plete dissolution of all reactants was closed. Then the Teflon
ampoule with the homogeneous reaction mixture was placed
in a high-pressure chamber filled with the inert liquid
(hexane or petroleum ether) and the pressure was slowly in-
creased to 9 kbar at ambient temperature (20–258C) by
hexane compression. After the pressure was stabilized, the
reaction mixture was kept under these conditions for 20 h.
After decompression, the reaction mixture was directly
chromatographed on silica gel to afford the tertiary a-tri-
fluoromethylated alcohols 4.
High-pressure reactions for isolation were carried out on
a 1.0–1.5 mmol scale in 2 mL or 3 mL Teflon ampoules.[23]
Analytical Data for New Compounds
(S)-2,2,2-Trifluoro-1-(5-methyl-1H-indol-3-yl)-1-phenyl-
AHCTUNGTRENNUNG
ethanol (4c): white solid; 81% yield; 82% ee; 1H NMR
(400 MHz, CDCl3): d=8.11 (bs, 1H, NH), 7.61–7.55 (m,
2H), 7.39–7.36 (m, 1H), 7.35–7.31 (m, 3H), 7.24 (d, J=
8.3 Hz, 1H), 6.98 (dd, J=8.3, 1.6 Hz, 1H), 6.95–6.93 (m,
1H), 2.86 (s, 1H, OH), 2.25 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d=137.6 (C), 134.6 (C), 129.6 (C), 128.5
(CH), 127.9 (2CH), 127.6 (2CH), 125.4 (q, J=286.1 Hz,
CF3), 125.3 (C), 124.4 (CH), 123.3 (q, J=3.1 Hz, CH), 120.5
(CH), 113.5 (C), 110.9 (CH), 77.1 (q, J=29.6 Hz, C-CF3),
21.4 (CH3); 19F NMR (376 MHz, CDCl3): d=À77.3 (s, 3F);
IR (film): n=3411, 3033, 2921, 1486, 1450, 1271, 1164, 1040,
886, 798, 765, 719 cmÀ1; LR-MS (ESI): m/z=306.1, mass cal-
culated for [M+H]+ (C17H15F3NO): 306.11; the enantiomer-
ic excess was determined by HPLC analysis using a Chiral-
pakꢂ IB column (hexane/i-PrOH: 95/5, flow rate
1.0 mLminÀ1, l=225 nm): ent-minor tr =18.2 min and ent-
Scheme 4. Reaction of indole with trifluoromethyl ketones.
accelerates the reaction of indoles and 7-azaindole
with trifluoroacetophenones in the presence of low
loadings of Cinchona alkaloids and their simple deriv- major tr =24.8 min.
(S)-2,2,2-Trifluoro-1-(4-methoxy-1H-indol-3-yl)-1-phenyl-
atives. The reaction is very slow with typical amine-
based catalysts under conventional conditions. A com-
bination of easily available cinchonidine (typically 2–
3 mol%) and high pressure activation (8–9 kbar)
allows an asymmetric synthesis of tertiary a-trifluoro-
methylated alcohols with indole and 7-azaindole het-
erocycles in good yields and enantioselectivities of up
to 89% ee.
AHCTUNGTRENNUNG
(400 MHz, CDCl3): d=8.34 (bs, 1H, NH), 7.55–7.49 (m,
2H), 7.34–7.26 (m, 3H), 7.19–7.16 (m, 1H), 7.11 (dd, J=8.2,
7.8 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.49 (d, J=7.8 Hz,
1H), 6.07 (s, 1H, OH), 3.62 (s, 3H, OCH3); 13C NMR
(100 MHz, CDCl3): d=151.3 (C), 140.5 (C), 138.1 (C), 128.1
(CH), 127.7 (2CH), 127.6 (q, J=1.0 Hz, 2CH), 125.4 (q, J=
285.2 Hz, CF3), 123.5 (CH), 122.4 (q, J=3.1 Hz, CH), 115.6
(C), 114.7 (C), 105.7 (CH), 101.5 (CH), ~77.1 (q overlaps
with CDCl3 peaks, C-CF3), 55.7 (CH3); 19F NMR (376 MHz,
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CDCl3): d=À76.1 (s, 3F); IR (film): n=3456, 3402, 3132,
2844, 1582, 1508, 1443, 1330, 1267, 1242, 1165, 1092, 1051,
883, 834, 739, 723 cmÀ1; LR-MS (ESI): m/z=322.1, mass cal-
culated for [M+H]+ (C17H15F3NO2): 322.11; the enantiomer-
ic excess was determined by HPLC analysis using a Chiral-
pakꢂ IA column (hexane/i-PrOH: 83/13, flow rate
1.0 mLminÀ1, l=225 nm): ent-minor tr =7.1 min and ent-
major tr =10.6 min.
(S)-2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-(naphthalen-2-yl)-
AHCTUNGTRENNUNG
(R)-2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-(2-methoxyphen-
1
N
(400 MHz, CDCl3): d=8.20 (s, 1H, NH), 7.36–7.27 (m, 2H),
7.23–7.19 (m, 2H), 7.11 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.03
(dm, J=7.8, 1H), 7.02 (dd, J=8.3, 1.0 Hz, 1H), 6.94 (ddd,
J=8.0, 7.0, 1.0 Hz, 1H), 6.84–6.78 (m, 1H), 6.55 (s, 1H,
OH), 3.92 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3): d=
158.2 (C), 136.3 (C), 131.3 (q, J=1.3 Hz, CH), 130.2 (CH),
125.6 (C), 125.4 (C), 125.7 (q, J=287.4 Hz, CF3), 123.6 (q,
J=3.0 Hz, CH), 122.2 (CH), 121.3 (CH), 121.3 (CH), 119.8
(CH), 113.9 (C), 112.5 (CH), 111.1 (CH), 79.5 (q, J=
30.1 Hz, C-CF3), 56.4 (CH3); 19F NMR (376 MHz, CDCl3):
d=À77.2 (s, 3F); IR (film): n=3321, 1584, 1459, 1412, 1286,
1235, 1173, 1160, 1113, 1036, 927, 743 cmÀ1; LR-MS (ESI):
m/z=320.1, mass calculated for [MÀH]À (C17H13F3NO2):
320.09; the enantiomeric excess was determined by HPLC
analysis using a Chiralpakꢂ IA column (hexane/i-PrOH: 88/
12, flow rate 1.0 mLminÀ1, l=225 nm): ent-major tr =
10.9 min and ent-minor tr =12.7 min.
(S)-2,2,2-Trifluoro-1-(1H-indol-3-yl)-1-(pyridin-3-yl)etha-
nol (4t): white solid; 71% yield; 68% ee; 1H NMR
[400 MHz, (CD3)2SO]: d=11.36 (s, 1H, NH), 8.64 (d, J=
1.8 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 7.87 (d, J=
8.1 Hz, 1H), 7.50 (s, 1H), 7.45–7.36 (m, 2H), 7.31 (s, 1H,
OH), 7.09–7.04 (m, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.86–6.81
(m, 1H); 13C NMR [100 MHz, (CD3)2SO]: d=149.2 (CH),
148.5 (CH), 136.5 (C), 135.2 (C), 135.1 (CH), 125.1 (C),
125.6 (q, J=287.5 Hz, CF3), 123.7 (q, J=2.5 Hz, CH), 123.0
(CH), 121.5 (CH), 120.3 (CH), 119.0 (CH), 112.0 (C), 111.8
(CH), 74.9 (q, J=29.1 Hz, C-CF3); 19F NMR [376 MHz,
(CD3)2SO]: d=À76.1 (s, 3F); IR (film): n=3277, 1424, 1264,
1247, 1166, 1041, 1028, 889, 734, 708 cmÀ1; LR-MS (ESI): m/
z=293.1, mass calculated for [M+H]+ (C15H12F3N2O):
293.09; the enantiomeric excess was determined by HPLC
analysis using a Chiralpakꢂ IC column (hexane/i-PrOH: 88/
12, flow rate 1.0 mLminÀ1, l=225 nm): ent-major tr =
8.8 min and ent-minor tr =11.2 min.
1,1,1-Trifluoro-2-(1H-indol-3-yl)-5-phenylpentan-2-ol (4u):
40% yield (conv. >80%); ee <2%; 1H NMR (400 MHz,
CDCl3): d=8.13 (bs, 1H, NH), 7.73 (d, J=8.1 Hz, 1H), 7.34
(dm, J=8.2 Hz, 1H), 7.25–7.03 (m, 8H), 2.72–2.50 (m, 2H),
2.42 (bs, 1H, OH), 2.36 (ddd, J=14.0, 12.5, 4.6 Hz, 1H),
2.08 (ddd, J=14.1, 12.1, 4.6 Hz, 1H), 1.80–1.67 (m, 1H),
1.62–1.47 (m, 1H); 13C NMR (100 MHz, CDCl3): d=141.6
(C), 136.5 (C), 128.4 (2CH), 128.3 (2CH), 126.1 (q, J=
285.8 Hz, CF3), 125.9 (CH), 125.1 (C), 123.6 (d, J=1.3 Hz,
CH), 122.3 (CH), 120.8 (q, J=1.6 Hz, CH), 120.3 (CH),
112.4 (C), 111.4 (CH), 76.7 (q, J=29.6 Hz, C-CF3), 35.6
(CH2), 34.1 (CH2), 24.4 (CH2); 19F NMR (376 MHz, CDCl3):
d=À80.9 (s, 3F); the enantiomeric excess was determined
by HPLC analysis using a Chiralpakꢂ IA column (hexane/i-
PrOH: 80/20, flow rate 1.0 mLminÀ1, l=225 nm): ent-1 tr =
5.9 min and ent-2 tr =7.7 min.
(R)-1-(2-Chlorophenyl)-2,2,2-trifluoro-1-(1H-indol-3-yl)-
ACHTUNGTRENNUNG
ethanol (4p): white solid; 68% yield; 86% ee; 1H NMR
(400 MHz, CDCl3): d=8.23 (s, 1H, NH), 7.92 (dm, J=
7.5 Hz, 1H), 7.38–7.30 (m, 4H), 7.27–7.25 (m, 1H), 7.17
(ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.96
(ddd, J=8.1, 7.0, 1.0 Hz, 1H), 3.75 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3): d=136.1 (C), 134.8 (C), 133.6 (C), 131.9
(CH), 130.1 (q, J=2.3 Hz, CH), 130.0 (CH), 126.7 (CH),
125.3 (C), 125.2 (q, J=286.6 Hz, CF3), 124.1 (q, J=2.3 Hz,
CH), 122.5 (CH), 120.2 (2CH), 113.5 (C), 111.3 (CH), 77.6
(q, J=30.3 Hz, C-CF3); 19F NMR (376 MHz, CDCl3): d=
À75.5 (s, 3F); IR (film): n=3411, 3061, 1547, 1459, 1431,
1339, 1270, 1171, 1015, 929, 889, 741 cmÀ1; LR-MS (ESI): m/
z=324.0, mass calculated for [MÀH]À (C16H10ClF3NO): m/
z=324.04; the enantiomeric excess was determined by
HPLC analysis using a Chiralpakꢂ ID column (hexane/i-
PrOH: 90/10, flow rate 1.0 mLminÀ1, l=225 nm): ent-minor
tr =6.0 min and ent-major tr =7.1 min.
(S)-1-(3-Bromophenyl)-2,2,2-trifluoro-1-(1H-indol-3-yl)-
ACHTUNGTRENNUNG
ethanol (4q): white solid; 95% yield; 75% ee; 1H NMR
(400 MHz, CDCl3): d=8.26 (s, 1H, NH), 7.81 (s, 1H), 7.48–
7.42 (m, 3H), 7.37 (dm, J=8.2 Hz, 1H), 7.21–7.13 (m, 3H),
6.97 (ddd, J=8.1, 7.0, 1.0 Hz, 1H), 2.90 (s, 1H, OH);
13C NMR (100 MHz, CDCl3): d=139.9 (C), 136.2 (C), 131.7
(CH), 130.6 (q, J=1.1 Hz, CH), 129.5 (CH), 126.5 (q, J=
1.0 Hz, CH), 125.0 (q, J=286.4 Hz, CF3), 124.8 (C), 123.1
(q, J=3.1 Hz, CH), 122.9 (CH), 122.2 (C), 120.7 (CH), 120.5
(CH), 113.3 (C), 111.3 (CH), 76.6 (q, J=29.9 Hz, C-CF3);
19F NMR (376 MHz, CDCl3): d=À77.3 (s, 3F); IR (film):
n=3448, 3411, 3066, 1459, 1421, 1338, 1273, 1164, 1040, 944,
739 cmÀ1; LR-MS (ESI): m/z=367.9, mass calculated for
[MÀH]À (C16H10BrF3NO): 367.99; the enantiomeric excess
was determined by HPLC analysis using a Chiralpakꢂ IA
column (hexane/i-PrOH: 95/5, flow rate 2.0 mLminÀ1, l=
225 nm): ent-major tr =13.0 min and ent-minor tr =14.7 min.
1-(4-Chlorophenyl)-2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]-
pyridin-3-yl)ethanol (5b): white solid; 82% yield; 62% ee;
1H NMR [400 MHz, (CD3)2SO]: d=11.89 (s, 1H, NH), 8.19
(d, J=4.5 Hz, 1H), 7.56–7.49 (m, 3H), 7.43 (d, J=8.3 Hz,
2H), 7.38 (d, J=7.9 Hz, 1H), 7.29 (s, 1H, OH), 6.93 (dd, J=
7.9, 4.7 Hz, 1H); 13C NMR [100 MHz, (CD3)2SO]: d=148.6
(C), 143.2 (CH), 138.2 (C), 133.1 (C), 129.2 (CH), 128.6
(CH), 125.6 (q, J=287.5 Hz, CF3), 128.0 (2CH), 126.9, 124.0
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(q, J=2.2 Hz, CH), 117.6 (C), 115.6 (CH), 111.8 (C), 75.4
(q, J=29.0 Hz, C-CF3); 19F NMR [376 MHz, (CD3)2SO]: d=
À75.4 (s, 3F); LR-MS (ESI): m/z=327.1, mass calculated
for [M+H]+ (C15H11ClF3N2O): m/z=327.05; the enantio-
meric excess was determined by HPLC analysis using a Chir-
alpakꢂ ID column (hexane/i-PrOH: 90/10, flow rate
2.0 mLminÀ1, l=225 nm): ent-minor tr =2.8 min and ent-
major tr =3.9 min.
2,2,2-Trifluoro-1-(naphthalen-2-yl)-1-(1H-pyrrolo[2,3-b]-
pyridin-3-yl)ethanol (5c): white solid; 70% yield; 58% ee;
1H NMR [400 MHz, (CD3)2SO]: d=11.90 (s, 1H, NH), 8.19
(bs, 1H), 8.17 (dd, J=4.7, 1.6 Hz, 1H), 8.00–7.88 (m, 1H),
7.87 (d, J=8.8 Hz, 1H), 7.63–7.49 (m, 4H), 7.37 (dd, J=8.0,
1.6 Hz, 1H), 6.85 (dd, J=8.0, 4.7 Hz, 1H), 7.32 (s, 1H, OH);
13C NMR [100 MHz, (CD3)2SO] d=148,6 (C), 143.0 (CH),
136.7 (C), 132.5 (C), 132.3 (C), 128.6 (CH), 128.4 (CH),
127.4 (2CH), 126.6 (CH), 126.3 (CH), 126.2 (CH), 125.8 (q,
J=287.3 Hz, CF3), 125.2 (CH), 124.1 (q, J=2.3 Hz, CH),
117.8 (C), 115.5 (CH), 112.2 (C), 75.8 (q, J=28.8 Hz, C-
CF3); 19F NMR [376 MHz, (CD3)2SO]: d=À74.9 (s, 3F);
LR-MS (ESI): m/z=343.1, mass calculated for [M+H]+
(C19H14F3N2O): 343.11; the enantiomeric excess was deter-
mined by HPLC analysis using a Chiralpakꢂ ID column
(hexane/i-PrOH: 80/20, flow rate 1.0 mLminÀ1, l=225 nm):
ent-minor tr =5.7 min and ent-major tr =6.5 min.
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(S)-2-Chloro-2,2-difluoro-1-(1H-indol-3-yl)-1-phenyletha-
nol (6): white solid; 76% yield; 74% ee; 1H NMR
(400 MHz, CDCl3): d=8.21 (bs, 1H, NH), 7.63–7.57 (m,
2H), 7.49 (dd, J=4.6, 2.2 Hz, 1H), 7.35 (dm, J=8.2 Hz,
1H), 7.33–7.29 (m, 3H), 7.21 (d, J=8.1 Hz, 1H), 7.15 (ddd,
J=8.2, 7.1, 1.1 Hz, 1H), 6.94 (ddd, J=8.1, 7.1, 0.9 Hz, 1H),
3.04 (bs, 1H, OH); 13C NMR (100 MHz, CDCl3): d=138.1
(C), 136.0 (C), 131.4 (t, J=302.5 Hz, CF2Cl), 128.4 (CH),
128.0 (t, J=1.3 Hz, 2CH), 127.7 (2CH), 125.5 (C), 123.3 (t,
J=3.7 Hz, CH), 122.7 (CH), 121.1 (CH), 120.2 (CH), 114.5
(C), 111.1 (CH), 80.6 (t, J=25.4 Hz, C-CF2Cl); 19F NMR
(376 MHz, CDCl3): d=À61.1 (s, 2F); IR (film): n=3558,
3414, 3060, 1456, 1418, 1338, 1172, 1120, 1046, 998, 807, 743,
699 cmÀ1; LR-MS (ESI): m/z=308.1, mass calculated for
[M+H]+ (C16H13ClF2NO): 308.07; the enantiomeric excess
was determined by HPLC analysis using a Chiralpakꢂ IC
column (hexane/i-PrOH: 97/3, flow rate 1.0 mLminÀ1, l=
225 nm): ent-minor tr =10.2 min and ent-major tr =11.4 min.
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Acknowledgements
This work was financially supported by the Polish Ministry
of Science and Higher Education through Iuventus Plus Pro-
gramme (Grant No. IP2011 028671).
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oacetophenone (0.62 mmol, 1.25 equiv.) were added
and the reaction mixture was left at room temperature
under atmospheric presssure. The reaction progress
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days = 90% and 60% ee.
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[22] Dry toluene is not necessary. When the reaction was
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Hydroxyalkylation of Indoles with Trifluoromethyl Ketones
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Adrian Kasztelan, Michał Biedrzycki, Piotr Kwiatkowski*
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