Stereoselective intermolecular carbolithiation of open-chain and cyclic 1-Aryl-1-alkenyl N,N-diisopropylcarbamates coupled with electrophilic substitution. Observation of p-carboxylation in a benzyllithium derivative

Article abstract of DOI:10.1055/s-2002-20040

1-Aryl-1-alkenyl N,N-diisopropylcarbamates (1) are obtained from alkyl aryl ketones and N,N-diisopropylcarbamoyl chloride (CbCl) by heating with excess pyridine. These undergo facile syn-carbolithiation by alkyllithium/diamine and produce configurationally stable lithiated benzyl carbamates, which have been trapped with different electrophiles. If the reaction is carried out in the presence of chiral diamines, such as (-)-sparteine or (-)-α-isosparteine, moderate enantiofacial differentiation is observed.

Full text of DOI:10.1055/s-2002-20040

PAPER
381
Stereoselective Intermolecular Carbolithiation of Open-Chain and Cyclic 1-
Aryl-1-alkenyl N,N-Diisopropylcarbamates Coupled with Electrophilic
Substitution. Observation of p-Carboxylation in a Benzyllithium Derivative
Observati
a
p
-Car
n
boxylation in
a
Ben
G
z
yllithium Deriva
e
tive org Peters, Michael Seppi, Roland Fröhlich,36a Birgit Wibbeling,36a Dieter Hoppe*
Institut für Organische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: dhoppe@uni-muenster.de
Received 8 November 2001
Ph
R1
Abstract: 1-Aryl-1-alkenyl N,N-diisopropylcarbamates (1) are ob-
tained from alkyl aryl ketones and N,N-diisopropylcarbamoyl chlo-
ride (CbCl) by heating with excess pyridine. These undergo facile
syn-carbolithiation by alkyllithium/diamine and produce configura-
tionally stable lithiated benzyl carbamates, which have been trapped
with different electrophiles. If the reaction is carried out in the pres-
ence of chiral diamines, such as ( )-sparteine or ( )- -isosparteine,
moderate enantiofacial differentiation is observed.
Li
Li
Ph
R1 Li
Ph
+
Ph
Ph
R1
A
B
Key words: 1-alkenyl carbamates, benzyl carbamates, chiral ben-
zyllithium compounds, carbolithiation, ( )-sparteine
R1 Li
Ph
X
+
X
Ph
R1
Li
The intermolecular nucleophilic addition of organolithi-
um to an alkene is the first step in anionic polymerisation
reactions of styrene.1 For synthetically useful carbolithia-
tion reactions,2 the formation of intermediate A must pro-
ceed much more rapidly than the next addition step. Thus,
special stabilization of A is required3 as was demonstrated
by Normant et al., utilizing cinnamyl derivatives C bear-
ing a Lewis-basic substituent X (X = OR, NR2) as sub-
strates in carbolithiation reactions.3,4 The complex-
induced proximity effect (CIPE),5 arising from the forma-
tion of the complex D, causes a rapid addition reaction to
form the stabilized adduct E, which can be trapped by
many different electrophilic reagents.6 In addition to two
carbon-carbon bond formations, up to two stereogenic
centers are established. Usually, high diastereoselectivity
is observed and, moreover, in the presence of chiral
ligands such as ( )-sparteine,7 high enantiofacial selectiv-
ity at the prostereogenic double bond is achieved
(Scheme 1).8
D
C
Li
X
El
ElX
Ph
Ph
X
R1
R1
F
E
= Li·(ligands)n
Li
Scheme 1
by proton acids with retention and by most other electro-
philes with inversion of the configuration. Thus a conve-
nient stereoselective approach for the preparation of more
complex chiral benzyl derivatives of type H seemed pos-
sible (Scheme 2).14
We expected that 1-aryl-1-alkenyl carbamates of type 1
could be ideal substrates for CIPE-driven stereoselec-
tive formation of secondary -carbamoyloxy-benzyllithi-
The vinyl carbamates 1a–f were prepared by heating the
appropriate ketones 3 with N,N-diisopropylcarbamoyl
chloride (4)15 and pyridine (1.9–3.0 equiv) for 2–9 days.16
Presumably, the reaction proceeds via the enol of 3
(Scheme 3, Table 1). The stilbene derivatives Z-1d/E-1d
were obtained in a ratio of 68:32 and could be separated
by chromatography on silica gel. The crystalline isomer
Z-1d was subjected to a X-ray structure analysis
(Figure 1).17 As expected, the torsion around the O C=O
bond in Z-1d is more restricted than that in E-1d; whereas
um compounds G by carbolithiation reactions.9,10–12
A
related study, concerning the carbolithiation of different
1-arylethenyl N,N-diethylcarbamates was published as a
short communication by Snieckus et al.13 when our work
was in progress. We had discovered that chiral com-
pounds G, prepared by deprotonation, are configuration-
ally stable at low temperatures and these are substituted
1
the H NMR-absorption in CDCl3 of the two isopropyl
protons in E-1d coincide at 3.97 ppm, two separate, sharp
signals (3.77 and 4.34 ppm) appear for Z-1d. The latter
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0381,0392,ftx,en;T10601SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

382
J. G. Peters et al.
PAPER
N(iPr)2
N(iPr)2
OCb
R1Li
Li·L2
R1
O
O
R
O
O
R
diamine (L2)
Ar
Ar
H
H
2
1
(iPr)2N
O
*
+ElX
CbO El
Li·L2
O
R1
H
R1
H
*
*
*
Ar
Ar
R
R
Figure 1 X-ray structure of Z-1d17
H
G
O
(4)
CNiPr2
Cl
OCb
OCb
O
a
2
b
c
pyridine, ∆
H
C6H5
H
R
Ar
R
α-Naphth 2-MeOC6H4
+
Ar
Ar
Ar
CH2R
H
H
38 - 73 %
R
H
Z-1
E-1
3
Scheme 2
a
1
b
c
d
e
f
undergo line broadening when warming the sample from
25 °C to 55 °C. Consequently, two enantiomeric atropoi-
somers are found in the crystal (Figure 1).17
C6H5
H
Ar
α-Naphth 2-MeOC6H4
C6H5 C6H5
C6H5 C(CH3)3
3-(CH2)2C6H4
R
H
H
For carbolithiation of the -non-prostereogenic vinyl car-
bamates, to a solution of the alkyllithium (1.4 equiv) 5a–
c and N,N,N’,N’-tetramethylethylenediamine (TMEDA,
1.4 equiv) in toluene–hexane at 78 °C, the appropriate
carbamate 1a–c was added dropwise and stirring contin-
ued for 5–15 hours. After formation of the lithium com-
Scheme 3
pound rac-6aa-cc,18 either methanol (for the preparation
of the secondary benzyl carbamates rac-7aa-cc) or anoth-
er electrophile such as CO2 (followed by methylation of
Table 1 Preparation of the 1-Alkenyl N,N-Diisopropylcarbamates 1a-c, E/Z-1d, E/Z-1e and 1f
Producta Ar
R
Reaction Time Equiv of 4
(d)/ Temperature
(°C)
Equiv of
Pyridine
Yield (%)
mp (°C)
Purificationb
1a
1b
1c
C6H5
H
H
H
6/95
1.5
1.5
1.5
3.0
3.0
3.0
73
64–65c
oil
E–PE; 1:20 1:4
E–PE; 1:10 1:1
-Naphthyl
9/reflux
9/reflux
38d
44
2-(MeO)C6H4
81–83e
triple recryst. from
PE at 20 °C
E/Z-1d
E/Z-1e
1f
C6H5
C6H5
C6H5
6/100
1.5
2.5
1.5
2.7
1.9
3.0
66
34
73
89f
E–PE; 1:20 1:5g
E–PE; 1:20 1:10i
C(CH3)3
2/reflux
9/reflux
53–54h
81–82e
3-C6H4(CH2)2
recryst. from PE
at 20 °C
a All compounds gave correct C,H-analyses (C 0.4, H 0.3) and showed infrared absorption at 1710–1695 cm–1 (C=ONR2).
b Column chromatography on silica gel; E = Et2O, PE = petroleum ether (bp 30–50 °C).
c From the melt.
d After additional kugelrohr distillation.
e From PE.
f Z-Isomer.
g Isomers were separated; E-Isomer: Yellow oil, 21%; Z-Isomer: Colourless crystals, 45%.
h Z-Isomer.
i Yielded an oil (E/Z, 10:90); Z-Isomer precipitated on standing.
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Observation of p-Carboxylation in a Benzyllithium Derivative
383
the crude product with diazomethane), chlorotrimethylsi-
lane, or chlorotrimethylstannane was added (rac-8aa-ca,
Scheme 4). Aqueous workup at room temperature and
chromatographic separation afforded the expected prod-
ucts rac-7aa-cc or rac-8aa-ca, respectively, in good
yields (Table 2).
O
(iPr)2N
Li
R1
CbO
O
+
R1Li / TMEDA
Ar
Ar
1a-c
rac-6aa-6cd
5a-d
+ MeOH
H
+ ElX
El
Figure 2 X-ray structure of rac-9a19
R1
R1
CbO
CbO
Ar
Ar
O
(iPr)2N
R
Li
R
CbO
rac-7aa-7cd
rac-8aa-8ca
O
n-BuLi / TMEDA
+
H
H
Ar
Ph
a
5
R1
b
c
d
n-Bu
i-Pr
t-Bu
Ph
rac-6da
+ElX
Retention
Inversion
Scheme 4
Similarly, the reaction of stilbene carbamate Z-1d was
carried out. Using toluene as solvent, stirring for 1 hour at
–78 °C and warming the reaction mixture for 45 minutes
to 15 °C for completion of the addition reaction provid-
ed the best yields (Scheme 5, Table 2). Here, two diaste-
reomeric products rac-9 and rac-10 are possible
(Scheme 5, Table 2). Protonation of the reaction mixture
with methanol afforded the pure secondary carbamate
rac-9a with (1R*,2R*) configuration; the latter one was
confirmed by an X-ray crystal structure analysis19
(Figure 2). Since the protonation of this type of benzyl-
lithium compounds proceeds with retention of the config-
uration,20 clear evidence for a syn-stereochemistry of the
addition step is presented. The reaction of methyl iodide
yielded a diastereomeric mixture of rac-9c/rac-10c in a
ratio of 13:87 with 61% yield. Although the configura-
tions have not been established rigorously, the high pref-
erence of methyl iodide for stereoinversion substitution
reactions with benzyllithium compounds, as it had been
found previously,10b,c leads to the assignment of the
(1S*,2R*) configuration for the major product 10c.
El
OCb
R
R
CbO
El
H
H
Ph
Ph
rac-10e
rac-9a-e
a
9, 10
b
c
d
e
C6H5
H
R
C6H5
D
C6H5
CH3
C6H5
C(CH3)3
H
El
CO2CH3
Scheme 5
H
n-BuLi / TMEDA
CbO
+
LiOCb
Ph
C C Ph
Ph
Ph
E-1d
11
Scheme 6
Surprisingly, the diastereomer E-1d did not undergo addi-
tion of n-butyllithium/TMEDA; elimination of lithium Starting from the tert-butyl derivative 1e (Z/E, 90:10) the
carbamate led to the formation of diphenylethyne (11) in
reaction with n-butyllithium (3 h at 40 °C) and quench-
high yield (Scheme 6). The -proton of E-1d is in an ideal
ing with methanol leads to diastereomerically pure 9e
position for being removed by the base, being complexed (Table 2).
by the carbamate group.
The reaction of the cyclic enol carbamate 1f with n-butyl-
lithium and tert-butyllithium, respectively, after protonol-
ysis gave rise to the formation of the trans alkyl-
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

384
J. G. Peters et al.
PAPER
Table 2 Compounds Prepared by Carbolithiation of 1a–1c, Z-1d, Z-1e, 1f, 18, and Reaction with Electrophiles
Entry Sub-
Meth- Organolithi- Electrophile Reaction Product Ar
R1
El
Yield
(%)
mp (°C)
strate od
um Reagentk
n-BuLi
PhLi
Time (h)
0.5
0.5
0.5
0.5
0.5
15
1
2
1a
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
C
D
D
E
MeOHg
MeOHg
7aa
7ad
8aa
8ab
8ac
8ba
8ca
7ba
7bb
7bc
7ca
7cb
7cc
9a
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
(CH2)3CH3
C6H5
H
85
54
72
71
75
49
62
54
91
90
25
53
91
87
89
61
29
51
58
84
78
24
79
51f
95
88
43
oil
H
oil
a,h
3
n-BuLi
i-PrLi
CO2
(CH2)3CH3
CH(CH3)2
C(CH3)3
CO2Me
oil
a,h
4
CO2
CO2Me
oil
5
t-BuLi
n-BuLi
n-BuLi
n-BuLi
i-PrLi
CO2
CO2Me
89–90b
oil
a,h
6
Me3SiCli
Me3SnClj
MeOHg
MeOHg
MeOHg
MeOHg
MeOHg
MeOHg
MeOH
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
CH(CH3)2
C(CH3)3
SiMe3
7
15
SnMe3
oil
8
1b
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.25
0.25
0
-Naphthyl
H
oil
9
-Naphthyl
H
oil
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
t-BuLi
n-BuLi
i-PrLi
-Naphthyl
H
104–105c
oil
1c
2-(MeO)C6H4
(CH2)3CH3
CH(CH3)2
C(CH3)3
H
2-(MeO)C6H4
H
oil
t-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
2-(MeO)C6H4
H
oil
100c
100c
n.b.d
oile
100c
100c
oil
n
Z-1d
–
–
–
–
–
–
–
–
–
–
–
–
–
–
C6H5
H
MeODl
MeIm
9b
C6H5
D
n
n
9c/10c
9d/10d
9a
C6H5
Me
a,h
n
CO2
C6H5
CO2Me
Me3SiCli
Me3SnClj
MeOHg
1
C6H5
H
n
n
0.5
0
9a
C6H5
H
n
Z-1e
9e
C(CH3)3
H
1f
MeOHg
0
12a
–
–
–
–
–
–
–
H
oil
a,h
CO2
0
13a
17
CO2Me
oil
a,h
CO2
0
–
123–124c
oil
E
MeOHg
MeODl
MeOHg
Me3SnClj
0
15a
15b
21a
21b
H
E
0
D
oil
18
F
0.5
24
H
oil
F
SnMe3
oil
a Subsequent methylation with diazomethane.
b From the melt.
c From Et2O–petroleum ether.
d Mixture of diastereomers; l:u 87:13.
e Mixture of diastereomers; l:u 79:21.
f 49 % of the starting material were recovered.
g Method A: 0.2 mL, 6 mmol, Method B: 0.1 mL, 2.5 mmol, Method C, E: 1 mL, Method D, F: 0.5 mL.
h Method A: stream of dry CO2 for 30 min, Method B: stream of dry CO2 for 45 min, Method D, E: stream of dry CO2 for 1 h.
i 270 mg, 2.5 mmol.
j 1.0 M solution in hexanes, Method A: 2.0 mL, 2.0 mmol, Method B: 2.5 ml. 2.5mmol, Method F: 1.2 mmol.
k Method A, B: 1.05 mmol added; Method C 1.4 mmol added; Method D: 1.2 mmol; Method E: 1 mmol; Method F: 1.10 mmol; the reagents
have the following concentrations: n-BuLi (1.6 M in hexanes), i-PrLi (0.22 M in pentane), t-BuLi (1.5 M in pentane), PhLi (2 M in cyclohex-
ane–Et2O).
l Method B: 0.15 mL, 2.5 mmol, Method E: 0.5 mL, 12.3 mmol.
m Method B: 360 mg, 2.5 mmol.
n See residue R in Scheme 5.
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Observation of p-Carboxylation in a Benzyllithium Derivative
385
substituted 2-alkyl tetrahydronaphthalenes rac-12a/rac-
12b (Scheme 7); the 1H NMR coupling constants between
CbO
H
1
4
MeOH
2
3
1
1H-1 and H-2 are 6.2 Hz (12a) and 5.1 Hz (12b). The
trans-configuration of compounds 12a, 15a, and 15b is in
accordance with that expected; the syn-addition of alkyl-
lithium onto the double bond of 1f, followed by protona-
tion with retention of configuration leads to the observed
relative configuration. Carboxylation of the intermediate
9fa to form the carboxylic acid, isolated in the form of the
methyl ester 13d, took place in surprisingly low yield. The
shown stereochemistry of the carboxylate rac-13a had to
be deduced indirectly: We had demonstrated that the car-
boxylation of lithiated secondary benzyl carbamates pro-
ceeds with inversion of configuration,10b,c although in
cyclic cases some erosion of stereospecificity might oc-
cur.10d In the case of rac-6fa, the butyl residue, cis to lith-
ium, should reinforce the tendency for antarafacial attack
of the electrophile.
rac-12a
Li TMEDA
OCb
.
CbO
n-BuLi /
TMEDA
rac-6fa
1f
MeO2C
OCb
t-BuLi /
TMEDA
1
4
2
3
CO2/CH2N2
rac-13a
.
TMEDA
Li
OCb
CbO
CO2
LiO2C
The characterization of the methyl carboxylate, prepared
via nucleophilic tert-butylation and carboxylation, gave a
surprising result. The X-ray analysis21 (Figure 3) revealed
the p-position of the carboxylic group and the cis-config-
uration (JH-1,H-2 = 1.9 Hz) of the ester 17.
H
rac-14
base / H+
rac-6fc
ElX
CbO El
OCb
H
1
2
1
4
2
3
H
3
4
R2O2C
CH2N2
rac-16 (R2 = H)
rac-15a (El = H)
rac-15b (El = D)
rac-17 (R2 = CH3)
Scheme 7
The intramolecular version of the carbolithiation reaction
proceeds with great ease (Scheme 8). Iodide25 18 under-
goes smooth iodine-lithium exchange26 and the intermedi-
ate 19 cyclizes to form the cyclopentyl-substituted
benzyllithium rac-20, which is trapped by protonation
(rac-21a, 88%) or by stannylation (rac-21b, 43%).
Figure 3 X-ray structure of rac-1721
Obviously, the benzylic position in intermediate rac-6fc is
sterically hindered to such an extent, that carbon dioxide
attacks the p-position of the phenyl ring, although the
electron density there is comparably low. The (alkyl-
idenecyclohexadiene)carboxylate 14 formed will rapidly
undergo rearomatization, combined with a kinetically
controlled protonation in the benzylic position from the
less shielded -face, leading to the thermodynamically
unfavourable cis-diastereomer 16.
(iPr)2N
O
.
OCb
O
TMEDA
Li
toluene,
-78 °C
1
2
3
5
4
6
X
rac-20
X = I
18
t-BuLi/TMEDA,
2.2 eq., -78 °C
ElX
.
X = Li TMEDA 19
In contrast to competing p-substitution reactions of ben-
zylic radicals,22 reports on corresponding carbanionic re-
actions are rare. Attack at the para position was first
observed by Wittig et al.23 during the benzoylation of so-
dium triphenyl-(triphenylmethyl)aluminate. Fraenkel et
al. found p-substitution occuring during the carbolithia-
tion of -methylstyrene with tert-butyllithium and subse-
quent bis-trimethylsilylation.24
CbO El
1
rac-21 a El = H
(88%)
b El = Me3SnCl (43%)
Scheme 8
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

386
J. G. Peters et al.
PAPER
The complexed conformers P/M-2, formed by the coordi- 7aa–ac; after purification, the enantiomeric excess was
*
nation of R1Li (5a–d) and a chiral ligand L2 (22–27), will determined.
react with the C=C bond in an intramolecular syn-addition
The absolute configuration was assessed by independent
*
to form the benzyllithium derivatives (R)-6 L2 and (S)-
asymmetric synthesis28 of (+)-7aa and comparison of the
*
6 L2 , which are configurationally stable and can be
trapped (Scheme 9). Overall, the sequence provides enan-
tiofacial attack at the styrene double bond. Note, that the
1
sense of optical rotation and H NMR shift experiments
with that of ( )-7aa produced via the carbolithiation se-
quence.
carbanionic centre in the reagent is not stereogenic; any
*
The data are collected in Table 3. Best results were ob-
tained with n-BuLi/( )- -isosparteine29 (23) (58% ee, en-
try 2) and i-PrLi/( )-sparteine (22) (44% ee, entry 8).
With diamines 24–2630 and 27,31 less than 22% ee were
achieved. This demonstrates, that (as in many cases) ( )-
sparteine32 and ( )- -isosparteine16 lithium complexes
have superior efficiency. The substituted carbamates 1b–
1f provided even lower enantioselectivities.33
differentiation is due to the chiral ligand L2 . Only a few
efficient examples for such a strategy are known.7,8,27
-Styryl carbamate 1a was allowed to react with each
*
1.4 equivalents of R1Li and L2 in toluene for 5 hours at
78 °C and then the benzyllithium compound was
trapped to yield the chain-extended benzyl carbamate
N(iPr)2
N(iPr)2
N(iPr)2
As a consequence, we assume that the problem of enantio-
selective additions onto vinyl carbamates is due to the in-
terconversion of the conformers M-2 and P-2 being too
slow, and the energetic barrier is in the magnitude of the
activation energies of the competing diastereomorphic ad-
dition step.
*
*
O
O
H
Li·L2
R1
O
O
H
Li·L2
R1
O
O
H
R1Li · L2
*
Ar
Ar
Ar
H
1a
H
H
P-2
M-2
Si
Re
All reactions which are sensitive to moisture or air were carried out
under argon. All solvents were purified by distillation and dried, if
necessary, prior to use. 1H and 13C NMR spectra were recorded on
a Bruker AM 300 spectrometer. Optical rotations were recorded on
a Perkin-Elmer polarimeter 241. Melting points were obtained on a
Gallenkamp melting point apparatus MFB-595 and are uncorrected.
Products were purified by flash column chromatography on silica
gel (40–63 m) using Et2O and petroleum ether, PE (30–50 °C) as
solvents.
(iPr)2N
(iPr)2N
O
O
*
*
O
O
Li·L2
Li·L2
R1
R1
Ar
Ar
(S)-6·L2
*
*
(R)-6·L2
HOMe
R1
HOMe
Preparation of Enol Carbamates 1a–c, E/Z-1d, E/Z-1e, 1f;
General Procedure
CbO
Ar
(R)-7aa-ac
H
CbO
Ar
(S)-7aa-ac
H
The ketone (25 mmol), carbamoyl chloride 4 (37.5–75 mmol, see
Table 1) and anhyd pyridine (48–75 mmol, see Table 1) were heat-
ed to 95 °C or reflux and stirred for 2–9 d (see Table 1). The cooled
reaction mixture was poured onto crushed ice (50 g) and 2 N aq HCl
(120 mL), extracted with Et2O (3 50 mL) and the collected ex-
tracts were neutralized with sat. NaHCO3 solution (50 mL). After
drying (MgSO4 or Na2SO4), the solvents were evaporated and the
crude product was purified by flash column chromatography on sil-
ica gel or recrystallisation to yield enol carbamates 1a–c, E/Z-1d, E/
Z-1e and 1f (see Table 1).
R1
*
L2
=
N
N
N
N
N
N
24
23
22
(Z)-6-Iodo-1-phenyl-1-hexenyl N,N-Diisopropylcarbamate (18)
1-Phenyl-prop-2-enyl N,N-Diisopropylcarbamate:
To a solution of 1-phenylprop-2-enol34 (3.95 g, 29.4 mmol) in an-
hyd THF (20 mL), NaH (1.77 g, 44.1 mmol) was added slowly and
the mixture was stirred for 1.2 h. After cooling (ice bath) solid car-
bamoyl chloride 4 (7.46 g, 45.6 mmol) was added in small portions.
The mixture was stirred for 16 h at r.t. Sat. NH4Cl solution (15 mL)
was added to destroy the excess of NaH and the THF was evaporat-
ed subsequently. After extraction with Et2O (3 20 mL) the com-
bined ethereal solutions were dried (Na2SO4) and the solvent
evaporated in vacuo. The crude product was purified by flash chro-
matography (Et2O–PE, 1:6) and yielded 1-phenyl-prop-2-enyl N,N-
diisopropylcarbamate (6.40 g, 24.5 mmol, 84%) as a colourless oil;
Rf 0.57 (Et2O–PE, 1:4).
N
N
N
N
CH2OCH3
CH3OCH2
26
25
N(CH3)2
N(CH3)2
27
IR (film): 1720 (C=ONR2), 770, 760 (C6H5).
Scheme 9
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Observation of p-Carboxylation in a Benzyllithium Derivative
387
*
Table 3 Carbolithiation of 1a in the Presence of Optically Active Ligands L2
*
20
Entry
Reagent R1Lif
n-BuLi (5a)
n-BuLi (5a)
n-BuLi (5a)
n-BuLi (5a)
n-BuLi (5a)
n-BuLi (5a)
n-BuLi (5a)
i-PrLi (5b)
Ligand L2
Producta
( )-7aa
( )-7aa
( )-7aa
( )-7aa
( )-7aa
( )-7aa
( )-8aa
(+)-8ab
(+)-8ac
Yield (%)
er [ee(%)] S/R-7/8 [ ]D
1
2
3
4
5
6
7
8
9
22
23
24
25
26
27
22
22
22
86
63
83
73
81
47
83
80
77
65:35 (30)b
79:21 (58)b
51:49 (2)b
1.9 (c = 1.01, CH2Cl2)
58:42 (16)b
40:60 (20)b
61:39 (22)b
65:35 (30)c,d
28:72 (44)c,d
38:62 (24)d,e
0.8 (c = 0.97, MeOH)
+4.3 (c = 1.00, MeOH)
+1.4 (c = 1.15, MeOH)
t-BuLi (5c)
a Prepared by Method A (see experimental section) and Table 2.
b Determined by 1H NMR shift experiments with 7.5 mol% (+)-Eu(hfc)3 in C6D6.
c Determined by 1H NMR shift experiments with 45 mol% (+)-Eu(hfc)3 in C6D6.
d Assignment of the absolute configuration tentatively by comparison of the sense of optical rotation with known compounds.
e Determined by 1H NMR shift experiments with 51 mol% (+)-Eu(hfc)3 in C6D6.
f Method A: 1.05 mmol added; the reagents have the following concentrations: n-BuLi (1.6 M in hexanes), i-PrLi (0.22 M in pentane), t-BuLi.
(1.5 M in pentane), PhLi (2 M in cyclohexane–Et2O).
Table 4 Selected NMR-Data of 1-Alkenyl N,N-Diisopropylcarbamates 1a–c, E/Z-1d, E/Z-1e and 1f (see Scheme 3)a
Product 1H NMR (300 MHz, CDCl3), , J (Hz)
13C NMR (75 MHz, CDCl3),
H-2
R
–
Ar
C-1
C-2
R
–
Ar
1a
1b
4.98 (H , d), 5.40
7.20–7.60
153.26
101.19
124.90, 128.32, 128.48,
135.43
(H , d, 2J2,2 = 1.9)
5.14 (H , d), 5.48
–
–
3.84 (s, OCH3),
6.87–6.96,
7.22–7.29, 7.36
153.84
153.36
106.05
105.07
–
–
55.78 (OCH3), 111.52,
120.75, 125.20, 129.04,
129.89
(H , d, 2J2,2 = 1.0)
1c
5.15 (H , d), 5.35
7.41–7.55, 7.60,
7.80–7.85
125.06, 125.74, 126.18,
128.22, 128.93, 130.95,
133.64, 134.53
(H , d, 2J2,2 = 1.4)
E-1d
Z-1d
E-1e
Z-1e
1f
6.47
6.66
5.50
5.62
7.07–7.40
(Ar-H)
7.07-7.40
7.18–7.56
147.97
146.95
145.17
145.17
145.98
119.22
116.78
124.58
124.58
114.87
126.71–135.33
(Ar-C)
126.71–135.33
7.18–7.56
(Ar-H)
124.77–136.84
(Ar-C)
124.77–136.84
0.97 [s, C(CH3)3] 7.17–7.44
1.20 [s, C(CH3)3] 7.17–7.44
31.22 [C(CH3)3], 127.23, 127.41, 128.22,
32.27 [C(CH3)3] 137.75
30.32 [C(CH3)3], 127.23, 127.41, 128.22,
32.27 [C(CH3)3]
137.75
5.68 (t, 3J2,3 = 4.8) 2.43 (dt, 3J3,4 = 8.4, 7.05–7.25
CH2CH2-Ar), 2.87
22.09 (CH2CH2-
Ar), 27.60
120.76, 126.29, 127.38,
127.51, 131.53, 136.41
(t, CH2CH2-Ar)
(CH2CH2-Ar)
a NMR-data of the Cb group is omitted.
1H NMR (CDCl3, 300 MHz): = 1.23 [m, 12 H, CH(CH3)2], 3.95
13C NMR (CDCl3, 75 MHz): = 21.49 [CH(CH3)2], 46.37
[CH(CH3)2], 77.85 (C-1), 116.50 (C-3), 127.52, 128.10, 128.79,
140.30 (C6H5), 137.87 (C-2), 155.05 (C=ONR2).
[m, 2 H, CH(CH3)2], 5.21 (dd, 1 H, 2J3 = 1.6 Hz, 3J2,3 = 10.7 Hz,
,3
3
3-H ), 5.34 (dd, 1 H, J2,3 = 17.2 Hz, 3-H ), 6.05 (ddd, 1 H,
3J1,2 = 5.6 Hz, 2-H), 6.24 (d, 1 H, 1-H), 7.21–7.43 (m, 5 H, C6H5).
Anal. Calcd for C16H21NO2 (261.36): C, 73.53; H, 8.87. Found: C,
73.37; H, 9.05.
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

388
J. G. Peters et al.
PAPER
Table 5 Selected NMR-Data of Carbamates 7aa–cc, 8aa–ac, 9a–e, 10c–d (see Scheme 4 and Scheme 5)a,b
Product 1H NMR (300 MHz, CDCl3), , J (Hz) 13C NMR (75 MHz, CDCl3),
H-2
R/R1
1.70–2.00 (m, H , H ) 0.87 (m, CH3), 1.10– 5.69 (dd, 3J1,2
El
C-1
C-2
R/R1
El
–
7aa
7ad
=
76.66
25.18
13.88 (CH3), 22.41,
31.55, 36.77 [(CH2)3]
1.45 [m, (CH2)3]
5.0, 3J1,2 = 8.8)
3.09 (dd, 2J2 ,2
=
7.03–7.34 (m, C6H5) 5.96 (dd, 3J1,2
=
77.63
43.94
126.69–130.02
(C6H5)
–
13.6, 3J1,2 = 6.7), 3.22
(dd, 3J1,2 = 7.1)
6.7, 3J1,2 = 7.1)
7ba
7bb
1.92–2.11 (m, H , H ) 0.85 (m, CH3), 1.22– 6.52 (t, 3J1,2 = 6.2) 75.53
38.65
25.77
16.00 (CH3), 24.56,
27.69, 33.70 [(CH2)3]
–
–
1.29 [m, (CH2)3]
1.75–1.80 and1.98–
2.04 (m, H , H )
0.96 and 1.04 (d,
6.60 (dd, 3J1,2
4.3, 3J1,2 = 6.9)
=
72.33
71.51
22.27 (CH3), 23.61
(CH),
3JCH ,CH = 6.4, CH3),
1.753–1.80 (m, CH)
7bc
1.76 (dd, 2J2 ,2
=
1.03 [s, C(CH3)3]
6.68 (dd, 3J1,2
=
50.86
30.38 and 31.32
[C(CH3)3]
–
14.9, 3J1,2 = 2.8), 2.06
(dd, 3J1,2 = 9.2)
2.8, 3J1,2 = 9.2)
7ca
7cb
1.70–1.90 (m, H , H ) 0.85 (m, CH3), 1.22– 6.12 (t, 3J1,2 = 6.2) 71.67
36.27
27.62
14.33 (CH3), 22.88,
25.53, 32.01 [(CH2)3]
–
–
1.29 [m, (CH2)3]
1.52–1.71 (m, H , H ) 0.92–0.98 (d, 3JCH ,CH 6.19 (dd, 3J1,2
=
69.89
69.42
85.64
22.34 and 22.49
(CH3), 25.04 (CH),
3
= 6.2, CH3), 1.72–1.84 4.5, 3J1,2 = 8.1)
(m, CH)
7cc
8aa
1.58 (dd, 2J2 ,2
=
0.96 [s, C(CH3)3]
6.25 (dd, 3J1,2
2.9, 3J1,2 = 8.3)
=
50.29
24.00
30.25 and 31.01
[C(CH3)3]
–
14.6, 3J1,2 = 2.9), 1.80
(dd, 3J1,2 = 8.3)
2.20–2.35 and 2.65– 0.75–0.85 (m, CH3), 3.65 (s, OCH3)
15.45 (CH3), 24.00, 53.86 (COOCH3),
33.17, 37.79 [(CH2)3] 174.15 (COOCH3)
2.80 (ddd, 2J2
=
0.90–1.45 [m, (CH2)3]
,2
14.5, 3J2
11.9, 3J2
11.2)
= 4.5/
= 4.8,
,3
,3
8ab
2.35 and 2.65 (dd,
0.67 and 0.86 (d,
3.65 (s, OCH3)
3.59 (s, OCH3)
84.10
83.79
44.05
23.27 and 24.47
(CH3), 23.60 (CH),
52.27 (COOCH3),
172.64 (COOCH3)
2J2 = 15.0, 3J2
=
3JCH ,CH = 6.7, CH3),
,2
/ ,3
4.5, 7.4)
1.393–1.53 (m, CH)
8ac
8ba
8ca
9a
2.45 and 2.89 (d,
0.77 [s, C(CH3)3]
46.51
23.52
25.08
52.02
51.90
58.47
51.25
51.69
52.99
30.09 and 31.11
[C(CH3)3]
52.14 (COOCH3),
172.81 (COOCH3)
2J2 = 15.0)
,2
2.03 / 2.26 (m, H , H ) 0.82 (t, CH3), 1.10-
1.61 [m, (CH2)3]
0.10 [Si(CH3)3] 81.91
0.02 [Sn(CH3)3] 84.61
13.95 (CH3), 22.50,
32.27, 36.53 [(CH2)3] 0.34 [Si(CH3)3]
1.05, 0.68,
1.95–2.30 (m, H , H ) 0.82 (t, CH3), 1.10–
1.60 [m, (CH2)3]
14.00 (CH3), 22.52,
32.19, 39.77 [(CH2)3]
6.00 [Sn(CH3)3]
3.03 (ddd, 3J1,2 = 8.8, 7.13–7.34 (m, C6H5) 5.90 (d, 3J1,2
=
79.56
79.56
85.77
85.36
85.93
77.65
13.78 (CH3), 22.44,
29.24, 31.60 [(CH2)3]
–
–
3J2,3 = 4.1, 9.1)
8.8)
9b
3.03 (dd, 3J2,3 = 5.1, 7.08–7.36 (m, C6H5)
9.7)
–
13.76 (CH3), 22.43,
29.23, 31.58 [(CH2)3]
9c/ 10c 3.00 and 3.16 (dd,
3J2,3 = 2.9, 11.9)
6.80
–7.73 (m, C6H5)
1.90 and 1.93
(CH3)
13.79 (CH3), 22.52, 10.92 (CH3)
29.86, 30.36 [(CH2)3]
9d
3.96 (dd, 3J2,3 / = 2.9, 6.83–7.35 (m, C6H5) 3.67 (s, OCH3)
12.1)
13.81 (CH3), 22.38, 52.00 (COOCH3),
29.79, 30.83 [(CH2)3] 172.33 (COOCH3)
10d
9e
3.55 (dd, 3J2,3 = 3.1, 6.82–7.30 (m, C6H5) 3.67 (s, OCH3)
12.2)
13.78 (CH3), 22.34, 54.62 (COOCH3),
29.01, 29.59 [(CH2)3] 171.15 (COOCH3)
1.65–1.73 (m, H , H ) 0.93 [s, C(CH3)3]
5.88 (d, 3J1,2
=
28.86 and 32.77
[C(CH3)3]
–
6.4)
a NMR data of the aryl group (7aa–7cc, 8aa–ac) and the Cb group is omitted; infrared absorptions at 1710–1690 cm–1 (C=ONR2).
b All compounds gave correct C,H-analyses (C 0.4, H 0.3) or correct exact mass analyses.
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Observation of p-Carboxylation in a Benzyllithium Derivative
389
(Z)-[1-Phenyl-6-(tetrahydropyran-2-yloxy)-hex-1-enyl] N,N-Diiso-
1H NMR (CDCl3, 300 MHz): = 1.12–1.49 [m, 12 H, CH(CH3)2],
propylcarbamate:
1.49–1.70 (m, 4 H, 4-H2,), 1.81 (m, 2 H, 5-H2), 2.21 (dt, 1 H,
3
3J2,3 = 7.5 Hz, 3-H), 3.18 (t, 1 H, J5,6 = 8.1 Hz, 6-H2), 4.03 [sept,
To a solution of ( )-sparteine (305 mg, 1.30 mmol) in a n-BuLi so-
lution (1.6 M, 0.72 mL, 1.15 mmol) in hexane, 1-phenyl-prop-2-
enyl N,N-diisopropylcarbamate (261 mg, 1.00 mmol), dissolved in
toluene (1.0 mL), was added at 78 °C and stirred for 30 min. A so-
lution of 1-iodo-3-(tetrahydropyran-2-yloxy)-propane35 (297 mg,
1.10 mmol) in toluene (1.0 mL) was added slowly. After stirring for
another 4 h at 78 °C, the mixture was warmed to r.t. and sat.
NH4Cl solution (5 mL) was added. The organic layer was separated
and the aq phase extracted with CH2Cl2 (3 10 mL). The collected
extracts were dried (Na2SO4) and the solvent was evaporated in vac-
uo. Purification by flash column chromatography (Et2O–PE, 1:3)
afforded the enol carbamate (208 mg, 52%) as a colourless oil;
Rf 0.16 (Et2O–PE, 1:2). The (Z)-configuration was confirmed by a
1H NMR–NOE experiment.
2 H, CH(CH3)2], 5.76 (t, 1 H, 2-H), 7.16–7.45 (m, 5 H, C6H5).
13C NMR (CDCl3, 75 MHz): = 6.96 (C-6), 20.92, 22.09
[CH(CH3)2], 25.49, 28.99 (C-3, C-4), 33.54 (C-5), 47.01
[CH(CH3)2], 117.38 (C-2), 124.90, 128.17, 128.74, 136.52 (C6H5),
147.47 (C-1), 153.17 (C=O).
Anal. Calcd for C19H28NO2I (429.34): C, 53.15; H, 6.57. Found: C,
53.55; H, 6.87.
Preparation of 7aa–cc, 8aa–ca, 9a–e, 10c,d, 12a, 13a, 17, 21a,b;
General Procedures
Carbolithiation Procedures
Method A: To a stirred solution of the chiral diamine [1.05 mmol
(Table 3, entry 1–9)], or TMEDA (122 mg, 1.05 mmol) in toluene
(1.0 mL) at 78 °C the appropriate organolithium reagent (1.05
mmol) was added, directly followed by the enol carbamate (0.75
mmol), dissolved in toluene (1.0 mL). After stirring for 5 h at
78 °C, the electrophile (Table 2), was introduced. The reaction
mixture was stirred at 78 °C for the time given in Table 2 before
the workup.
IR (film): 1720 (C=ONR2), 770, 760 (C6H5).
1H NMR (CDCl3, 300 MHz): = 1.23 [m, 12 H, CH(CH3)2], 1.45–
3
1.90 [m, 10 H, 4-H2, 5H2, O2CH(CH2)3], 2.20 (dt, 1 H, J2,3 = 7.4
Hz, 3-H), 3.35–3.54, 3.70–3.91 (2 m, 4 H, 6-H2, OCHROCH2),
3.94–4.12 [m, 2 H, CH(CH3)2], 4.54–4.60 (m, 1 H, OCHRO), 5.79
(t, 1 H, 2-H), 7.19–7.43 (m, 5 H, C6H5).
13C NMR (CDCl3, 75 MHz): = 20.04 (C-4-THP), 20.93, 22.08
[CH(CH3)2], 25.09, 26.21, 26.47 (C-3, C-4, C-3-THP), 29.98 (C-5-
THP), 31.18 (C-5), 46.66, 46.99 [CH(CH3)2], 62.66 (C-6-THP),
67.73 (C-6), 99.22 (C-2-THP), 118.09 (C-2), 124.86, 128.41,
129.21, 136.68 (C6H5), 147.04 (C-1), 153.27 (C=O).
Method B: To a stirred solution of TMEDA (160mg, 1.4 mmol)
(Table 2) and Z-1d (323 mg, 1.00 mmol) in toluene (3.0 mL) at
78 °C the n-BuLi solution was added. After stirring (Table 2, en-
try 14: 5 h; entry 15: 50 min at 78 °C, 30 min at 15 °C, then
78 °C; entry 16: 1.5 h; entry 17: 1 h; entry 18, 19: 5 h), the elec-
trophile was introduced. The reaction mixture was stirred at 78 °C
for the time given in Table 2 before the workup.
(Z)-(6-Hydroxy-1-phenylhex-1-enyl) N,N-diisopropylcarbamate:
(Z)-[1-Phenyl-6-(tetrahydropyran-2-yloxy)-hex-1-enyl] N,N-diiso-
propylcarbamate (202 mg, 0.50 mmol) and Amberlyst 15 (200 mg)
in MeOH (3 mL) were stirred for 6 h. After filtration, the Amberlyst
was intensively eluted with Et2O (5 2 mL, sonification bath) and
the combined organic phases were evaporated in vacuo. A second
filtration (silica gel, Et2O–PE, 1:3) yielded the alcohol (159 mg,
100%) as a colourless oil; Rf 0.37 (Et2O).
Method C: To a stirred solution of TMEDA (163 mg, 1.4 mmol) and
n-BuLi (1.6 M in hexane, 0.89 mL, 1.4 mmol) in toluene (1.5 mL)
at 78 °C, 1e (303 mg, 1.00 mmol), dissolved in toluene (1.0 mL),
was added. After stirring for 3 h at 40 °C MeOH (1 mL, 25 mmol)
was injected. The workup followed directly.
Method D: To a stirred solution of TMEDA (130 mg, 1.20 mmol)
and n-BuLi (1.6 M in hexane, 0.75 mL, 1.20 mmol) in toluene
(2.0 mL) at 78 °C, 1f (273 mg, 1.00 mmol), dissolved in toluene
(1.0 mL), was added. After stirring for 4 h at 78 °C, the electro-
phile was injected. The workup followed directly.
IR (film): 3350 (OH), 1710 (C=ONR2), 770, 760 (C6H5).
1H NMR (CDCl3, 300 MHz): = 1.12–1.49 [m, 12 H, CH(CH3)2],
3
1.49–1.73 (m, 4 H, 4-H2, 5H2), 2.21 (dt, 1 H, J2,3 = 7.5 Hz, 3-H),
3.64 (t, 1 H, 3J5,6 = 8.2 Hz, 6-H2); 4.03 [sept, 2 H, CH(CH3)2], 5.79
Method E: To a stirred solution of TMEDA (163 mg, 1.40 mmol)
and t-BuLi (1.5 M in pentane, 0.93 mL, 1.40 mmol) in toluene
(2.0 mL) at 78 °C, 1f (273 mg, 1.00 mmol), dissolved in toluene
(1.0 mL), was added, directly following the injection of t-BuLi. Af-
ter stirring for 4 h at 78 °C, the electrophile was injected. The
workup followed directly.
(t, 1 H, 2-H), 7.16–7.45 (m, 5 H, C6H5).
13C NMR (CDCl3, 75 MHz): = 20.92, 22.09 [CH(CH3)2], 25.53,
26.23, (C-3, C-4), 32.73 (C-5), 46.65, 47.11 [CH(CH3)2], 63.03
(C-6), 118.01 (C-2), 124.86, 128.10, 128.74, 136.59 (C6H5), 147.17
(C-1), 153.44 (C=O).
Anal. Calcd for C19H29NO3 (319.45): C, 71.44; H, 9.15. Found: C,
71.54; H, 9.41.
Method F: To a stirred solution of TMEDA (209 mg, 1.80 mmol)
and Iodide 17 (322 mg, 0.75 mmol) in toluene (5.0 mL) at 78 °C
t-BuLi (1.5 M in pentane; 1.10 mL, 1.65 mmol) was added. After
stirring for 6.5 h at 78 °C, the electrophile was injected. The reac-
tion mixture was stirred at 78 °C [Table 2, entry 26: 0.5 h; entry
27: 24 h] before the workup.
(Z)-(6-Iodo-1-phenyl-1-hexenyl) N,N-diisopropylcarbamate (18):
To a stirred solution of (Z)-(6-hydroxy-1-phenylhex-1-enyl) N,N-
diisopropylcarbamate (2.07 g, 6.48 mmol), triphenylphosphine
(2.21 g, 8.42 mmol), and imidazole (575 mg, 8.42 mmol) in Et2O–
MeCN (3:1, 40 mL), I2 (1.73 g, 6.80 mmol) was added slowly in
small portions until the solution remained pale yellow. After stirring
for 1.5 h, Na2S2O3 (1 g) was added and the mixture was stirred for
a further 5 min. After filtration, Et2O (50 mL) was added and the
solvent was evaporated. The procedure was repeated three times to
remove MeCN completely. The residue was purified by flash col-
umn chromatography (Et2O–PE, 1:6) to afford iodide 18 (2.33 g,
84%) as colourless crystals; Rf 0.53 (Et2O–PE, 1:4), mp 80–81 °C
(Et2O–PE). The (Z)-configuration of the double bond was con-
firmed by a 1H NMR–NOE experiment.
General Workup
After Carboxylation: MeOH (0.5 mL) and then aq HCl (2 N, 10 mL)
were injected into the reaction mixture. After warming to r.t., the
layers were separated, the aq phase was extracted with Et2O (3 10
mL), the combined etheral phases were dried (Na2SO4 or MgSO4)
and the Et2O was evaporated in vacuo. The remaining solution in
toluene was treated with etheral CH2N2 until a pale yellow colour
persisted. After stirring for 1 h, silica gel (100 mg) was added and
the suspension was stirred for 30 min in order to destroy excessive
CH2N2. The crude product was purified by flash column chromatog-
raphy (Et2O–PE, 1:20 1:6).
IR (KBr): 1710 (s, C=ONR2), 770, 760 (C6H5).
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

390
J. G. Peters et al.
PAPER
rac-trans-2-tert-Butyl-1,2,3,4-tetrahydronaphth-1-yl N,N-
Diisopropylcarbamate (15a)
Method E, yield: 167 mg (51%), colourless oil; Rf 0.43 (Et2O–PE,
1:5).
Other electrophiles: MeOH (0.5 mL) and then aq HCl (2 N, 10 mL)
were injected into the reaction mixture. After warming to r.t., the
layers were separated, the aq phase was extracted with Et2O (3 10
mL) and the combined organic phases were dried and neutralized
(solid Na2SO4 or MgSO4; with a little NaHCO3). The solvent was
evaporated and the crude product purified by flash column chroma-
tography (Et2O–PE, 1:20 1:1).
IR (film): 1695 (C=ONR2), 770, 740 (C6H4).
1H NMR (CDCl3, 300 MHz): = 0.98 [s, 9 H, C(CH3)3], 0.98–1.24
[m, 12 H, CH(CH3)2], 1.49 (ddt, 1 H, 2J3 = 13.1 Hz, 3J2,3 = 10.5
,3
3
Hz, 3J3
= 4.8 Hz, 3-H ), 1.89 (ddd, 1 H, J1,2 = 5.1 Hz,
,4
/
rac-trans-2-Butyl-1,2,3,4-tetrahydronaphth-1-yl N,N-Diiso-
propylcarbamate (rac-12a)
Method D, yield: 256 mg (78%); colourless oil; Rf 0.33 (Et2O–PE
1:9).
3J2,3 = 5.2 Hz, 2-H), 2.06 (ddd, 1 H, 3-H ), 2.66–2.88 (m, 2 H, 4-
H2), 3.50–4.10 [m, 2 H, CH(CH3)2], 6.11 (d, 1 H, 1-H), 7.02–7.42
(m, 4 H, C6H4).
13C NMR (CDCl3, 75 MHz): = 21.41 [CH(CH3)2], 24.91 (C-4),
28.45 [C(CH3)3], 28.88 (C-3), 29.52 [C(CH3)3], 46.14 [CH(CH3)2],
50.36 (C-2), 72.80 (C-1), 126.53, 127.72, 127.97, 130.06 (C-5, C-6,
C-7, C-8), 137.55, 139.95 (C-4a, C-8a), 155.78 (C=ONR2).
IR (film): 1695 (C=ONR2), 770, 740 (C6H4).
1H NMR (CDCl3, 300 MHz): = 0.88 [m, 3 H, (CH2)3CH3], 1.21
[m, 12 H, CH(CH3)2], 1.10–1.55 [m, 5 H, (CH2)3CH3], 1.63 (m, 1
H, 3-H ), 1.95–2.12 (m, 2 H, H-2, 3-H ), 2.78 (m, 2 H, 4-H2); 3.50–
3
Anal. Calcd for C21H33NO2 (331.49): C, 76.09; H, 10.03. Found: C,
76.23; H, 10.26.
4.40 [m, 2 H, CH(CH3)2], 5.76 (d,1 H, J1,2 = 6.2 Hz, 1-H), 7.05-
7.31 (m, 4 H, C6H4).
13C NMR (CDCl3, 75 MHz): = 14.05 [(CH2)3CH3], 21.02
[CH(CH3)2], 22.95, 26.76, 29.25 [(CH2)3CH3], 24.40 (C-4), 30.46
(C-3), 38.98 (C-2), 45.80 [CH(CH3)2], 74.61 (C-1), 125.89, 127.34,
128.56, 129.53, 135.66, 137.35 (C6H4), 156.01 (C=ONR2).
rac-(1R*,2R*)-2-tert-Butyl-1-deutero-1,2,3,4-tetrahydronaphth-
1-yl N,N-Diisopropylcarbamate (15b)
Method E, yield: 315 mg (95%); colourless oil; Rf 0.45 (Et2O–PE,
1:5).
Anal. Calcd for C21H33NO2 (331.49): C, 76.09; H, 10.03. Found: C,
76.03; H, 9.74.
IR (film): 1695 (C=ONR2), 770, 740 (C6H4).
1H NMR (CDCl3, 300 MHz): = 0.95 [s, 9 H, C(CH3)3], 0.98–1.24
[m, 12 H, CH(CH3)2], 1.49 (ddt, 1 H, 2J3 = 13.1 Hz, 3J2,3 = 10.5
rac-(1R*,2R*)-2-Butyl-1-methoxycarbonyl-1,2,3,4-tetrahydro-
naphth-1-yl N,N-Diisopropylcarbamate (rac-13a)
Method D, yield: 70 mg (24%); colourless oil; Rf 0.45 (Et2O–PE,
1:5).
,3
3
3
Hz, J3
= 4.8 Hz, 3-H ), 1.89 (dd, 1 H, J2,3 = 5.2 Hz, 2-H),
,4
/
2.06 (ddd, 1 H, 3-H ), 2.66–2.88 (m, 2 H, 4-H2), 3.50–4.10 [m, 2 H,
CH(CH3)2], 7.02–7.42 (m, 4 H, C6H4).
13C NMR (CDCl3, 75 MHz): = 21.41 [CH(CH3)2], 24.91 (C-4),
28.45 [C(CH3)3], 28.88 (C-3), 29.52 [C(CH3)3], 46.14 [CH(CH3)2],
50.36 (C-2), 72.80 (C-1), 126.53, 127.72, 127.97, 130.06 (C-5, C-6,
C-7, C-8), 137.55, 139.95 (C-4a, C-8a), 155.78 (C=ONR2).
IR (film): 1750 (C=OOMe), 1700 (C=ONR2), 775, 750 (C6H4).
1H NMR (CDCl3, 300 MHz): = 0.87 [m, 3 H, (CH2)3CH3], 1.10–
1.48 [m, 6 H, (CH2)3CH3], 1.21 [m, 12 H, CH(CH3)2], 1.88–1.99 (m,
1 H, 2-H), 2.44–2.72 (m, 2 H, 3-H2), 2.75–3.05 (m, 2 H, 4-H2), 3.68
(s, 3 H, OCH3), 3.70–4.15 [m, 2 H, CH(CH3)2], 7.05–7.24, 7.74–
7.79 (m, C6H4).
The degree of deuteration (96%) was determined from the 1-H-sig-
nal in the 1H NMR spectrum.
13C NMR (CDCl3, 75 MHz): = 13.91 [(CH2)3CH3], 20.96, 21.72
[CH(CH3)2], 22.37, 26.52, 29.15 [(CH2)3CH3], 22.77 (C-3), 24.39
(C-4), 37.62 (C-2), 45.99, 46.44 [CH(CH3)2], 52.09 (OCH3), 82.29
(C-1), 125.26, 127.91, 128.76, 129.60, 133.39, 138.32 (C6H4),
153.86 (C=ONR2), 172.29 (C=O).
rac-(1-Cyclopentyl-1-phenyl-methyl) N,N-Diisopropylcarba-
mate (21a)
Method F, yield: 199 mg (88%); colourless oil; Rf 0.35 (Et2O–PE,
1:4).
IR (film): 1700 (C=ONR2), 770 (C6H5).
Anal. Calcd for C23H35NO4 (389.53): C, 70.09; H, 9.06. Found: C,
69.99; H, 9.25.
1H NMR (CDCl3, 300 MHz): = 1.07–1.25 [m, 20 H, CH(CH2)4,
CH(CH3)2], 2.37 (sext, 1 H, 3J1,2 = 7.5 Hz, 2-H), 3.75–4.10 [m, 2 H,
CH(CH3)2], 5.52 (d, 1 H, 1-H), 7.18–7.30 (m, 5 H, C6H5).
13C NMR (CDCl3, 75 MHz): = 21.09 [CH(CH3)2], 25.24, 29.21,
29.57 [CH(CH2)4], 45.84 [CH(CH3)2], 80.21 (C-1), 126.93, 127.19,
128.00, 128.19 (C6H5), 155.09 (C=ONR2).
rac-cis-2-tert-Butyl-6-methoxycarbonyl-1,2,3,4-tetrahydro-
naphth-1-yl N,N-Diisopropylcarbamate (17)
Method E, yield: 230 mg (79%); colourless crystals; Rf 0.47 (Et2O–
PE, 1:4); mp 123–124 °C (Et2O–PE).
IR (KBr): 1735 (C=OOMe), 1700 (C=ONR2), 780, 750 (C6H4).
Anal. Calcd for C19H29NO2 (303.44): C, 75.21; H, 9.63. Found: C,
75.25; H, 9.63.
1H NMR (CDCl3, 300 MHz): = 1.06 [s, 9 H, C(CH3)3], 1.10–1.33
[m, 12 H, CH(CH3)2], 1.45–1.59 (m, 1 H, 2-H), 1.87–2.03 (m, 2 H,
4-H2), 2.75–2.90, 3.02–3.14 (m, 2 H, 3-H2), 3.55–4.05 [m, 2 H,
CH(CH3)2], 3.89 (s, 3 H, OCH3), 6.34 (d, 1 H, 3J1,2 = 1.9 Hz, 1-H),
7.48, 7.77, 7.80 (d, d, s, 3 H, 3J7,8 = 8.1 Hz, C6H3).
13C NMR (CDCl3, 75 MHz): = 19.96 (C-3), 21.08, 21.60
[CH(CH3)2], 22.17 [C(CH3)3], 28.86 (C-2), 30.44 (C-4), 32.87
[C(CH3)3], 45.90, 46.74 [CH(CH3)2], 52.34 (OCH3), 70.64 (C-1),
127.23, 130.29, 130.46 (C-5, C-7, C-8), 129.95 (C-6), 137.33 (C-
4a), 142.51 (C-8a), 155.10 (C=ONR2), 167.49 (C=O).
rac-(1-Cyclopentyl-1-phenyl-1-trimethylstannyl)-methyl N,N-
Diisopropylcarbamate (21b)
Method F, yield: 150 mg (43%); colourless oil; Rf 0.61 (Et2O–PE,
1:9).
IR (film): 1690 (C=ONR2), 770 (C6H5).
1H NMR (CDCl3, 300 MHz):
=
0.02 [s, 9 H, 2JSn-C-H = 25.2 Hz,
Sn(CH3)3], 1.20–1.83 [m, 20 H, CH(CH2)4, CH(CH3)2], 2.81 (quin,
3
1 H, 2-H), 3.90–4.16 [sept, 2 H, JCH,CH = 6.7 Hz, CH(CH3)2],
3
6.92–7.34 (m, 5 H, C6H5).
13C NMR (CDCl3, 75 MHz):
Anal. Calcd for C23H35NO4 (405.57): C, 70.09; H, 9.06. Found: C,
70.16; H, 8.86.
= 4.29 (SnCH3), 21.45, 22.31
[CH(CH3)2], 24.58, 24.79, 27.99, 31.68 [CH(CH2)4], 46.74, 47.00
[CH(CH3)2], 50.24 [CH(CH2)4], 86.50 (C-1), 123.83, 125.05,
128.68, 128.96, 129.76, 127.54 (C6H5), 157.33 (C=ONR2).
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Observation of p-Carboxylation in a Benzyllithium Derivative
391
HRMS (EI, 70 eV): m/z calcd for C22H37NO2Sn–CH3: 452.16116;
(17) X-ray crystal structure analysis of 1d: formula C21H25NO2,
found: 452.16199.
M = 323.42, colourless crystal 0.40 0.40 0.20 mm,
a = 12.118(2), b = 13.509(2), c = 23.090(4) Å,
= 92.32(1)°, V = 3776.8(11) Å3, calc = 1.138 g cm–3,
Anal. Calcd for C22H37NO2Sn (466.24): C, 56.67; H, 8.00. Found:
C, 57.15; H, 8.16.
= 0.72 cm–1, no absorption correction (0.994
C 0.999),
Z = 8, monoclinic, space group P21/c (No. 14), = 0.71073
Å, T = 293 K, /2 scans, 6700 reflections collected (+h,+k,
l), [(sin )/ ] = 0.59 Å–1, 6374 independent (Rint = 0.028)
and 3227 observed reflections [I 2 (I)], 441 refined
parameters, R = 0.048, wR2 = 0.114, max. residual electron
density 0.45 (–0.23) e Å–3, hydrogens calculated and refined
as riding atoms, two almost identical molecules in the
asymmetric unit, differences in the torsion angles C1–C2–
O2–C3 and C31–C32–O32–C33.36
Acknowledgement
Generous support by the Fonds der Chemischen Industrie and Deut-
sche Forschungsgemeinschaft (SFB 424) is gratefully acknowled-
ged.
References
(18) If not denoted otherwise in Tables: the first letter
corresponds to the substrate and the second letter
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(2) Review: Marek, I. J. Chem. Soc., Perkin Trans 1 1999, 535.
(3) Review on early work: Klumpp, G. W. Recl. Trev. Chim.
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corresponds to the carbolithiation reagent.
(19) X-ray crystal structure analysis of 9a: formula C25H35NO2,
M = 381.54, colourless crystal 0.70 0.50 0.30 mm,
a = 29.416(5), c = 11.006(2) Å, V = 9524(3) Å3,
calc = 1.064 g cm–3, = 0.66 cm–1, empirical absorption
correction via scan data (0.928
C
0.999), Z = 16,
tetragonal, space group I41/a (No. 88), = 0.71073 Å,
T = 293 K, /2 scans, 8176 reflections collected (+h,
k,+l), [(sin )/ ] = 0.59 Å–1, 4011 independent
(Rint = 0.099) and 1859 observed reflections [I 2 (I)], 258
refined parameters, R = 0.062, wR2 = 0.161, max. residual
electron density 0.18 (–0.17) e Å–3, hydrogens calculated
and refined as riding atoms.36
(6) The sense of diastereoselectivity, by which F is formed,
depends on the configuration of intermediate E and the
stereochemistry of the substitution step.
(7) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J. F. J. Am.
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cation by (–)-sparteine, see: (a) Bailey, W. F.; Mearly, M. J.
J. Am. Chem. Soc. 2000, 122, 6787. (b) Sanz Gil, G.; Groth,
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(9) Racemates: Hoppe, D.; Brönneke, A. Synthesis 1982, 1045.
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D.; Carstens, A.; Krämer, T. Angew. Chem. Int. Ed. Engl.
1990, 29, 1424. (b) Carstens, A.; Hoppe, D. Tetrahedron
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149. (d) Derwing, C.; Frank, H.; Hoppe, D. Eur. J. Org.
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Peric Simov, B.; Völlenkle, H.; Werner, A. Eur. J. Org.
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(11) For further configurationally stable benzyllithiums:
(a) Hoppe, D.; Kaiser, B.; Stratmann, O.; Fröhlich, R.
Angew. Chem. Int. Ed. Engl. 1997, 36, 2784. (b)Stratmann,
O.; Kaiser, B.; Fröhlich, R.; Meyer, O.; Hoppe, D. Eur. J.
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(12) Reviews: (a) Hoppe, D.; Hense, T. Angew. Chem. Int. Ed.
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552.
(20) See Ref.10 For a further example: Laqua, H.; Fröhlich, R.;
Wibbeling, B.; Hoppe, D. J. Organomet. Chem. 2001, 624,
96.
(21) X-ray crystal structure analysis of 17: formula C23H35NO4,
M = 389.52, colourless crystal 0.30 0.25 0.15 mm,
a = 10.689(1), b = 10.717(1), c = 10.953(1) Å,
= 101.53(1), = 96.47(1), = 108.18(1)°, V = 1147.2(2)
Å3, calc = 1.128 g cm–3, = 0.76 cm–1, no absorption
correction (0.978
T
0.989), Z = 2, triclinic, space group
P1bar (No. 2), = 0.71073 Å, T = 293 K, and scans,
8217 reflections collected ( h, k, l), [(sin )/ ] = 0.65 Å–1,
5220 independent (Rint = 0.020) and 4004 observed
reflections [I 2 (I)], 261 refined parameters, R = 0.052,
wR2 = 0.138, max. residual electron density 0.17 (–0.16) e
Å–3, hydrogens calculated and refined as riding atoms.36
(22) Tolbert, L. M.; Martone, D. P. J. Org. Chem. 1983, 38, 1185.
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carbamoylation, a deprotonation- -alkylation sequence with
a
-oxy-2-(tetrahydropyranyloxy)propyl iodide,
deprotection of the hydroxy group and conversion to the
iodide; see experimental section.
(26) (a) Winkler, H. J. S.; Winkler, H. J. Am. Chem. Soc. 1966,
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(13) Superchi, S.; Sotomayor, N.; Miao, G.; Joseph, B.;
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(14) High simple diastereoselectivity may result from the syn-
addition process.
(15) Hoppe, D.; Hanko, R.; Brönneke, A.; Lichtenberg, F.; van
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(16) Heinl, T.; Retzow, S.; Hoppe, D.; Fraenkel, G. Chem.– Eur.
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(28) Pentyl phenyl ketone was submitted to an asymmetric
reduction by (+)-diisopinocampheylchloroborane and the
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York

392
J. G. Peters et al.
PAPER
resulting alcohol was subsequently carbamoylated by N,N-
diisopropylcarbamoyl chloride (4) in pyridine: (a) Brown,
H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539. (b) See Ref.15
diffractometers, the later one equipped with a rotating anode
generator Nonius FR591. Programs used: data collection
EXPRESS (Nonius B.V., 1994) and COLLECT (Nonius
B.V., 1998), data reduction MolEN (K. Fair, Enraf-Nonius
B.V., 1990) and Denzo-SMN: Otwinowski, Z.; Minor, W.
Methods in Enzymology 1997, 276, 307. (c) Absorption
correction for CCD data SORTAV: Blessing, R. H. Acta
Crystallogr. 1995, A51, 33. (d) Blessing, R. H. J. Appl.
Crystallogr. 1997, 30, 421. (e) Structure solution
SHELXS-86 and SHELXS-97: Sheldrick, G. M. Acta
Crystallogr. 1990, A46, 467. (f) Sheldrick, G. M. Structure
refinement SHELXL-93 and SHELXL-97; Universität
Göttingen: Germany, 1997. (g) Graphics: Keller, E.
SCHAKAL; Universität Freiburg: Germany, 1997.
(h) Crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposited with
Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC-156957–156959. Copies of the data
can be obtained free of charge on application to The
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: int. code+44(1223)336-033; e-mail:
(29) Galinousky, F.; Knoth, P.; Fischer, W. Monatsh. Chem.
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(35) Cox, G. G.; Moody, C. J.; Austin, D. J.; Padwa, A.
Tetrahedron 1993, 49, 5109.
(36) (a) X-ray analysis. (b) X-ray data sets were collected with
Enraf-Nonius CAD4 and Nonius Kappa CCD
deposit@ccdc.cam.ac.uk).
Synthesis 2002, No. 3, 381–392 ISSN 0039-7881 © Thieme Stuttgart · New York