Asymmetric Deprotonations: Lithiation of N-(tert-Butoxycarbonyl)indoline with sec-Butyllithium/ (-)-Sparteine

Article abstract of DOI:10.1021/jo9708856

The asymmetric lithiation of N-Boc indoline (1) with s-BuLi/(-)-sparteine and subsequent substitution provides the 2-substituted N-Boc indolines 3 and 5-11 with excellent enantiomeric ratios and in variable yields. The asymmetric lithiation-substitution sequence with N-Boc-7-chloroindoline (12) provides products 13-19 with good enantiomeric ratios. Mechanistic investigation establishes that the enantioselectivities arise from an initial asymmetric deprotonation to provide the enantioenriched and configurationally stable organolithium intermediates (S)-28 and (S)-29, which react stereoselectively with electrophiles.

Full text of DOI:10.1021/jo9708856

J . Org. Chem. 1997, 62, 7679-7689
7679
Asym m etr ic Dep r oton a tion s: Lith ia tion of
N-(ter t-Bu toxyca r bon yl)in d olin e w ith sec-Bu tyllith iu m /
(-)-Sp a r tein e
Kathleen M. Bertini Gross, Young M. J un, and Peter Beak*
Department of Chemistry, Roger Adams Laboratory, University of Illinois at UrbanasChampaign,
Urbana, Illinois 61801
Received May 19, 1997X
The asymmetric lithiation of N-Boc indoline (1) with s-BuLi/(-)-sparteine and subsequent
substitution provides the 2-substituted N-Boc indolines 3 and 5-11 with excellent enantiomeric
ratios and in variable yields. The asymmetric lithiation-substitution sequence with N-Boc-7-
chloroindoline (12) provides products 13-19 with good enantiomeric ratios. Mechanistic investiga-
tion establishes that the enantioselectivities arise from an initial asymmetric deprotonation to
provide the enantioenriched and configurationally stable organolithium intermediates (S)-28 and
(S)-29, which react stereoselectively with electrophiles.
In tr od u ction
lithiocarbamates and dithiolithiocarbamates have re-
cently been reported to undergo lithiation at the 3-posi-
tion.12 We now report that N-Boc indoline (1) and N-Boc-
7-chloroindoline (12) can be metalated selectively in the
2-position with sec-butyllithium(s-BuLi)/(-)-sparteine (2),
and the resulting enantioenriched and configurationally
stable organolithium intermediates (S)-28 and (S)-29
react readily with electrophiles to provide 2-substituted
N-Boc indolines with high enantiomeric ratios (er’s).
Chiral indoline structures are important in chiral
auxiliaries and chiral catalysts as well as in a number
of biologically active compounds.1-4 Syntheses of enan-
tioenriched 2-substituted indolines have included elabo-
rations of the commerically available (S)-indoline-2-
carboxylic acid2-4 and chiral auxiliary-mediated cycli-
zations5 or reductions.6 We wish to report asymmetric
syntheses of 2-substituted indolines by asymmetric re-
placement of a prochiral hydrogen in a chiral ligand-
mediated asymmetric lithiation-substitution sequence.7-9
Lithiation-substitution reactions of N-substituted in-
dolines have been reported previously. The tert-butyl
formamidine functionality has been used as a directing
group for the lithiation-substitution of indolines to
provide 2-substituted indolines.10 In contrast, the lithia-
tion of N-Boc indoline in the presence of TMEDA occurs
regioselectively at the 7-position.10b,11 However, Meyers
and Milot have reported that N-Boc-7-deuteroindoline is
lithiated to a limited extent at the 2-position.10b Indoline
Resu lts a n d Discu ssion
En a n tioselective Syn th eses w ith (-)-Sp a r tein e.
The reaction of 1 with s-BuLi/(-)-sparteine (2) followed
by trimethyltin chloride (Me3SnCl)13 provides predomi-
nantly the enantioenriched 2-substituted indoline (S)-3
in addition to a small amount of N-Boc-7-(trimethylstan-
nyl)indoline (4). The lithiation reaction was carried out
under the conditions summarized in Table 1. The
enantioselectivity of the lithiation-substitution was very
high; (S)-3 was formed with a 99:1 er in each reaction
carried out at -78 °C.
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) Bird, C. W.; Cheeseman, G. W. H. Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York,
1984; Vol. 4, p 89-153.
(2) (a) Kim, Y. H.; Kim, S. H.; Park, D. H. Tetrahedron Lett. 1993,
34, 6063-6066. Byun, I. S.; Kim, Y. H. (b) Kim, Y. H.; Kim, S. H.
Tetrahedron Lett. 1995, 36, 6895-6898. (c) Choi, J . Y.; Kim, Y. H.
Tetrahedron Lett. 1996, 37, 7795-7796. (d) Corey, E. J .; Harbans, S.
S.; Gougoutas, J . Z.; Saenger, W. J . Am. Chem. Soc. 1970, 92, 2488-
2500. (e) Corey, E. J .; McCaully, R. J .; Sachdev, H. S. J . Am. Chem.
Soc. 1970, 92, 2476-2587.
(3) Martens, J .; Dauelsberg, Ch.; Behnen, W.; Wallbaum, S. Tetra-
hedron: Asymmetry 1992, 3, 347-350.
(4) (a) Somei, M.; Kawasaki, T. Chem. Pharm. Bull. 1989, 37, 3426-
3428. (b) De Lombaert, S.; Blanchard, L.; Stamford, L. B.; Sperbeck,
D. M.; Grim, M. D.; J enson, T. M.; Rodriguez, H. R. Tetrahedron Lett.
1994, 35, 7513-7516.
(5) (a) Scholl, v B.; Hansen, H-J . Helv. Chim. Acta 1980, 63, 1823-
1832. (b) Meyers, A. I.; Sielecki, T. M. J . Org. Chem. 1992, 57, 3673-
3676. (c) Marino, J . P.; Bogdan, S.; Kimura, K. J . Am. Chem. Soc. 1992,
114, 5566-5572.
(6) Karchava, A. V.; Yurovskaya, M. A.; Wagner, T. R.; Zybailov,
L.; Bundel, Y. G. Tetrahedron: Asymmetry 1995, 6, 2895-2898.
(7) Nozaki, H.; Arantani, T.; Toraya, T.; Noyori, R. Tetrahedron
1971, 27, 905-913.
(8) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens, H.;
Schwerdtfeger, J .; Sommerfield, P.; Haller, J .; Guarnieri, W.; Kolcze-
wski, S.; Hense, T.; Hoppe, I. Pure Appl. Chem. 1994, 66, 1479-1486.
(9) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J . J . Am. Chem. Soc. 1994,
116, 3231-3239.
(10) (a) Meyers, A. I.; Hellring, S. Tetrahedron Lett. 1981, 22, 5119-
5122. (b) Meyers, A. I.; Milot, G. J . Org. Chem. 1993, 58, 6538-6540.
The data in Table 1 show that the regioselectivity of
the asymmetric lithiation-substitution and the extent
of reaction are dependent on the solvent. When tert-butyl
(11) (a) Iwao, M.; Kuraishi, T. Heterocycles 1992, 34, 1031-1038.
(b) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109-1117.
(12) Ahlbrecht, H.; Kornetzky, D.; Purder, T.; Katritzky, A. R.;
Ghiviriga, I.; Levell, J . Synthesis 1997, 172-173.
(13) Me3SnCl is a highly toxic compound and should be handled with
appropriate caution. Sax, N. I.; Lewis, R. J . Dangerous Properties of
Industrial Materials, 7th ed.; Van Nostrand Reinhold: New York, 1988;
p 899.
S0022-3263(97)00885-2 CCC: $14.00 © 1997 American Chemical Society

7680 J . Org. Chem., Vol. 62, No. 22, 1997
Gross et al.
Ta ble 1. Su r vey of Con d ition s for th e
Ta ble 2. Asym m etr ic Lith ia tion -Su bstitu tion of 1 To
P r ovid e 3, 5-11
Lith ia tion -Su bstitu tion of 1 To P r ovid e (S)-3 a n d 4a
yield
yield
yield
product
(S)-3
(R)-5
electrophile
E
(%)a
erb
99:1
>99:1
98:2, 91:9
98.5:1.5
97.5:2.5
92.5:7.5
68:32
T (°C) time (h) solvent (S)-3 (%) er (S)-3b 4 (%) 1 (%)
Me3SnCl
CO2
SnMe3
70
65
61, 13
52
57
-78
-78
-78
-78
-40
-40
5.5
3
3
3
1
cumene
cumene
MTBE
toluene
cumene
MTBE
70
61
58
42
29
23
99:1
99:1
99:1
99:1
97:3
97:3
3
3
17
3
2
20
15
25
9
48
36
16
CO2Mec
CH(OH)Ph
Me
(R)-6, (R)-7d PhCHO
(S)-8e
(S)-9
(R)-10
(S)-11
(S)-11
(S)-11
Me2SO4
TMSCl
Ph2CO
C3H5Br
C3H5Cl
SiMe3
C(OH)Ph2
11
0.75
CH2CHdCH2 28
CH2CHdCH2 18
C3H5Cl/DMPU CH2CHdCH2 15
a
b
Isolated yields of pure materials are reported. The enantio-
meric ratios were determined by chiral stationary phase (CSP)
HPLC.
65:35
99:1
a
b
Isolated yields of pure materials are reported. The er’s were
determined by CSP HPLC. c The crude product mixture was
treated with diazomethane to afford the ester, and the yield of
methyl ether (MTBE) was used, the products (S)-3 and
4 were formed in a 3:1 ratio. A 20:1 ratio of (S)-3 to 4
was obtained when cumene was used as the solvent. The
reaction was nearly complete after 3 h in MTBE, and only
9% of the starting material was recovered. When the
reaction was carried out in cumene for the same amount
of time, 25% of the starting material was recovered. A
5.5-h lithiation in cumene followed by electrophilic
substitution provided a 70% yield of (S)-3 as well as 15%
of the starting material. Although a highly regioselective
lithiation-substitution took place in toluene, 48% of the
starting material was recovered after a 3-h lithiation.
As indicated in Table 1, the reaction could also be
carried out at -40 °C to provide (S)-3 with a 97:3 er. At
this temperature the regioselectivity of the reaction was
also much higher in cumene than in MTBE. Nearly a
1:1 ratio of regioisomers was obtained in MTBE, but the
reaction in cumene provided (S)-3 and 4 in a 15:1 ratio.
The yields for the reactions carried out at -40 °C were
unoptimized, but the high enantioselectivity and regi-
oselectivity of the reaction in cumene demonstrate its
utility.
d
the ester is reported. Two diastereomers of the 2-substituted
indoline were obtained. e A 3-h lithiation time was used.
Ta ble 3. Asym m etr ic Lith ia tion a n d Su bstitu tion of
In d olin e 12 To Give En a n tioen r ich ed 13-17
yield
product
electrophile
E
(%)a
erb
(R)-13
(R)-14
(S)-15
(S)-16
rac-17
CO2
COOH
90
77
75
69
32e
89:11c
86:14d
87:13
86.5:13.5
55:45
Ph2CO
Me3SnCl
Bu3SnCl
C3H5Br
C(OH)Ph2
SnMe3
SnBu3
CH2dCHCH2
a
b
Isolated yields of pure materials are reported. The er’s were
determined by CSP HPLC. c The er was determined by conversion
of the carboxylic acid to 2-carbethoxy-7-chloroindoline and analysis
by CSP HPLC.16 After recrystallization, the product was obtained
d
with a 96:4 er. e Boc-7-chloroindole was isolated in 20% yield.
The conditions that were selected for the investigation
of the scope of the lithiation-substitution were lithiation
for 6 h in cumene at -78 °C followed by the addition of
the electrophile. Carbonyl compounds, silyl and stannyl
chlorides, and dimethyl sulfate (Me2SO4) were used as
electrophiles to provide products 5-9 with excellent er’s
and useful yields as summarized in Table 2. In these
reactions up to 25% of the starting material was recov-
ered, and the 7-substituted Boc indoline was obtained in
<5% yield. A diastereoselectivity of 5:1 was obtained
when benzaldehyde was used as the electrophile. The
major diastereomer was formed with an er of 98:2, and
the minor diastereomer had an er of 91:9.
Low yields of 2-substituted products 10 and 11 were
obtained when benzophenone, allyl bromide, and allyl
chloride were used as electrophiles. N-Boc indole was
isolated in 52% yield as the major product from the
reaction with benzophenone, and (R)-10 was formed in
11% yield with a 92.5:7.5 er. N-Boc indole was also
obtained in 23% yield from the reaction with allyl
bromide.14 Indoline (S)-11 was obtained in low yield with
an approximate er of 65:35 when allyl chloride and allyl
bromide were used as electrophiles. The low enantiose-
lectivity may be explained by low stereoselectivity in the
substitution step (vide infra). When N,N′-dimethylpro-
pyleneurea (DMPU) was added to the reaction mixture
immediately before the addition of allyl chloride, (S)-11
was obtained in 15% yield with an er of 99:1. Enolizable
ketones were unsuccessful as electrophiles in this se-
quence; the use of cyclohexanone as an electrophile
resulted in the recovery of starting material.
When the 7-position of Boc indoline is blocked by a
chloro substituent, a lithiation-substitution can be car-
ried out at the 2-position to provide 2-substituted N-Boc-
7-chloroindolines with good enantioselectivities and in
good yields. N-Boc-7-chloroindoline (12) was prepared
by lithiation of N-Boc indoline followed by reaction with
hexachloroethane as described by Iwao.11a The treatment
of indoline 12 with a premixed solution of s-BuLi/(-)-
sparteine in MTBE and subsequent addition of carbonyl
electrophiles or trialkyltin chlorides provided products
13-17 in good yields with er’s of approximately 87:13 as
shown in Table 3. Careful recrystallization of enriched
indoline (R)-14 enhanced its enantioenrichment to 96:4
er. Although the enantioselectivity for the asymmetric
lithiation-substitution of 12 is lower than that of 1, the
deprotonation is actually more facile. A competition
(14) The indole may arise from oxidation of the 2-lithioindoline with
benzophenone or allyl bromide.

Asymmetric Deprotonations
J . Org. Chem., Vol. 62, No. 22, 1997 7681
Ta ble 4. Lith ia tion s a n d Su bstitu tion s of 12 To Give
experiment between 1 and 12 with s-BuLi/(-)-sparteine
in cumene established that 12 was lithiated eight times
faster than 1. The presence of the 7-chloro substituent
may change the orientation of the Boc group with respect
to the R-protons during the lithiation-substitution se-
quence and thereby alter the rate and enantioselectivity
of the reaction.15
Ra cem ic 13-19
Under optimal conditions the metalation of 12 was
carried out in MTBE for 3-4 h at -78 °C, and after the
addition of the electrophile, the solution was stirred at
-78 °C for an additional 4 h before the addition of
aqueous NH4Cl. The enantioselectivity of the asym-
metric lithiation-substitution of 12 was generally not
affected by the reaction time or the choice of solvent
except for the case of THF. The use of toluene, pentane,
or diethyl ether as solvents with Bu3SnCl as the electro-
phile provided (S)-16 with an 85:15 er, but racemic 16
was obtained from the reaction carried out in THF.17
Lower yields were obtained with shorter reaction times
and when pentane or toluene was used as a solvent.
product
electrophile
E
yield (%)a
b
13
14
15
16
17
18
19
CO2
COOH
C(OH)Ph2
SnMe3
SnBu3
CH2CHdCH2
TMS
85
79
83
89
25e
88
55
Ph2CO
Me3SnClc
Bu3SnCl
C3H5Brd
TMSCl
MeI
Me
a
Isolated yields of pure material are reported. The remainder
b
of the mass balance is starting material. The metalation time
was 3.5 h, and the reaction was carried out in MTBE. The reaction
was quenched at room temperature. c The metalation conditions
d
were 2 h in MTBE followed by a room temperature quench. The
metalation was for 3 h followed by room temperature quench. e N-
The yields of products 13-16 from the lithiation-
substitution were satisfactory for carbonyl and alkyltin
chloride electrophiles as shown in Table 3, and products
arising from lithium-chlorine exchange were produced
in less than 3% yield when s-BuLi and (-)-sparteine were
premixed before metalation.18 When s-BuLi was added
to a solution of 12 and (-)-sparteine, significantly more
lithium-chlorine exchange took place, and the 2- and
7-substituted products were formed in approximately a
3:1 ratio. Lithium-chlorine exchange was the major
reaction pathway when 12 was treated with s-BuLi in
the absence of diamine; therefore, the premixing of
s-BuLi and (-)-sparteine to complex the free s-BuLi is
required for high chemoselectivity in the asymmetric
lithiation-substitution. In contrast, premixing s-BuLi
and (-)-sparteine did not have a significant effect on the
regiochemical outcome of the lithiation of 1 in MTBE.
The scope of the asymmetric lithiation-substitution
of indoline 12 is not as general as for 1. Methyl iodide
(MeI), Me2SO4, TMSCl, and allyl chloride were unsuc-
cessful electrophiles. Lithiated 12 appears to be less
easily oxidized than 1 since no indole product was
isolated during the preparation of (R)-14. However, a
significant amount of N-Boc-7-chloroindole14 was isolated
from the reaction mixture when allyl bromide was used
as the electrophile, along with a 32% yield of nearly
racemic indoline 17.
Boc-7-chloroindole was isolated in 19% yield.
stationary phase (CSP) HPLC. When 7-chloroindoline
12 was treated with s-BuLi/TMEDA at -78 °C for 1-3
h followed by the addition of electrophiles, the 2-substi-
tuted N-Boc-7-chloroindolines 13-17 were obtained as
shown in Table 4. As in the asymmetric sequence, the
reaction with carbonyl electrophiles or trialkyltin chlo-
rides provides products 13-16 in useful yields, and a low
yield of 17 was obtained when allyl bromide was the
electrophile. TMSCl and MeI were also used successfully
as electrophiles in this sequence to provide indolines 18
and 19, respectively.
Racemic indolines 3, 5-11 cannot be prepared by a
lithiation and substitution of indoline 1 in the presence
of TMEDA because 7-lithiation is dominant under those
conditions.10b,11 Similarly, the treatment of indoline 1
with s-BuLi in the absence of diamine and subsequent
reaction with Me3SnCl afforded only N-Boc-7-(trimeth-
ylstannyl)indoline in low yield. Racemic indolines 5 and
10 were synthesized from commercially available racemic
indoline-2-carboxlic acid in the same way that (S)-5 and
(S)-10 were obtained from (S)-indoline-2-carboxylic acid
(vide infra). The achiral ligand 20, which is structurally
similar to (-)-sparteine, was used in the lithiation
reaction to provide racemic 3, 6-9, and 11 along with
7-substituted products 4 and 21-24. As the data in
Table 5 indicate, the regioselectivities observed for the
lithiations in the presence of bispidine 20 are similar to
those observed in the presence of (-)-sparteine in MTBE;
therefore, 20 is a better (-)-sparteine mimic than TME-
DA.
Syn t h eses of R a cem ic P r od u ct s w it h Ach ir a l
Dia m in es. Syntheses of racemic indolines 3, 5-11, and
13-17 were necessary for the verification of the enan-
tiomeric ratios of the enantioenriched products by chiral
Deter m in a tion of Absolu te Con figu r a tion . The
absolute configurations of the lithiation-substitution
products were determined by CSP HPLC and optical
rotation data comparisons to compounds of known con-
figuration. Ester (R)-5 was prepared by lithiation of 1
and substitution with CO2 followed by treatment of the
crude product mixture with diazomethane (CH2N2). The
CSP HPLC profile and the optical rotation for (R)-5 were
compared to (S)-5, which was synthesized from (S)-
indoline-2-carboxylic acid (25). Reaction of (S)-25 with
thionyl chloride and methanol followed by Et3N and Boc-
O-Boc provided (S)-5 in 76% overall yield. Treatment of
(S)-5 with PhMgBr afforded (S)-10, whose CSP HPLC
profile and optical rotation were compared to (R)-10
prepared by asymmetric lithiation-substitution. In
(15) Gross, K. M. B.; Beak, P. Unpublished work. The effect of
directing group orientation on benzamide and benzylic alkoxide
directed ortho lithiation reactions has been reported. Beak, P.; Kerrick,
S. T.; Gallagher, D. J . J . Am. Chem. Soc. 1993, 115, 10628-10636.
(16) Pirkle, W. H.; Pochapsky, T. C.; Mahler, G. S.; Field, R. E. J .
Chromatog. 1985, 348, 89-96.
(17) Lowered enantioselectivities in the presence of THF have been
reported for other (-)-sparteine-mediated reactions of organolithium
reagents. (a) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2158-2160. (b) Wu, S.; Lee,
S.; Beak, P. J . Am. Chem. Soc. 1996, 118, 715-721. (c) Park, Y. S.;
Boys, M. L.; Beak, P. J . Am. Chem. Soc. 1996, 118, 3757-3758.
(18) These minor products can be removed readily from the enan-
tiomerically enriched products by chromatographic purification.
Lithium-halogen exchange of aryl chlorides is not a common reaction
and may be facilitated in this case by complexation of the lithiating
reagent with the Boc group.28a When tert-butyllithium/(-)-sparteine
was used as a chiral base for the lithiation-substitution of 12, only
the product from lithium-chlorine exchange was isolated.

7682 J . Org. Chem., Vol. 62, No. 22, 1997
Gross et al.
Ta ble 5. Rea ction of 1 w ith s-Bu Li/20 To P r ovid e
Regioisom er ic P r od u ctsa
yield
yield
electrophile
E
2-product (%) 7-product (%)
Me3SnClb SnMe3
3
6, 7
8
9
11
46
28, 5
43
11
26
4
21
22
23
24
21
38
19
19
8
The absolute configuration of 2-trialkyltin indolines
was assigned as S since the treatment of optically
enriched indoline (S)-3 with n-butyllithium (n-BuLi)
followed by CO2 or Me2SO4 afforded predominantly (R)-5
or (S)-8, respectively (vide infra). Similarly, treatment
of 7-chloroindoline (S)-15 with n-BuLi followed by ben-
zophenone provided (R)-14. These assignments involve
the assumption that the tin-lithium exchange and
reaction with electrophiles proceed with retention of
configuration.20,21 The absolute configurations of (R)-6,
(R)-7, (S)-9, and (S)-11 were assigned by analogy to
products of known configuration.
Rea ction P a th w a y. Two limiting pathways are
available for the enantioselective lithiation-substitution
of prochiral substrates with a chiral base: asymmetric
deprotonation and asymmetric substitution.22 In an
asymmetric deprotonation a s-BuLi and (-)-sparteine
complex selectively removes a prochiral proton to give a
configurationally stable organolithium intermediate,9,21
which reacts with electrophiles stereoselectively to give
enantioenriched products. In an asymmetric substitution
the enantioselectivity is determined during a post-depro-
tonation step.23 The series of tin-lithium exchange
experiments shown in Table 6 have been carried out with
3 and 15 to distinguish between these alternative path-
ways.
PhCHOb
MeIc
CH(OH)Ph
Me
SiMe3
CH2CHdCH2
TMSClc
C3H5Brd
a
Isolated yields of pure materials are reported. b 18-h lithiation.
c 3-h lithiation. 7-h lithation.
d
order to determine whether the presence of the chloro
substituent changes the sense of enantioselectivity for
the asymmetric lithiation-substitution, (S)-10 was al-
lowed to react with s-BuLi/TMEDA followed by hexachlo-
roethane to provide (S)-14 in 11% yield along with 70%
of the starting material. Each of the products (S)-5, (S)-
10, and (S)-14 prepared from (S)-25 were found to have
a configuration at C-2 that is opposite to the configuration
of the products obtained from asymmetric lithiation-
substitution.19
A tin-lithium exchange experiment with enriched
indoline (S)-3 (99:1 er) and n-BuLi in cumene followed
by addition of CO2 and subsequent treatment with CH2N2
gave the ester (R)-5 in 25% isolated yield with a 99:1 er
as shown in Table 6. Similarly, when an enriched sample
of (S)-3 of 99:1 er was treated with n-BuLi in MTBE in
the presence of bispidine 20 followed by the addition of
Me2SO4 or CO2/CH2N2, (S)-8 and (R)-5 were obtained in
55% and 59% isolated yields, respectively, with er’s of
98:2. These experiments established the configurational
stability of organolithium intermediate (S)-28 under the
reaction conditions both in the absence and in the
presence of 20. The transmetalation in MTBE of en-
The absolute configuration of (S)-8 was determined in
order to establish the facial selectivity of the reaction of
alkylating agents with lithiated 1. Indoline (S)-25 was
reduced to the alcohol with BH3‚THF, and the amine was
treated with Boc-O-Boc to provide (S)-26 in 80% yield
over two steps. The alcohol was converted to the tosylate
(S)-27 in 85% yield, and the tosylate was reduced to (R)-8
with NaBH4 in 87% yield. Indoline (R)-8 was found to
have the opposite CSP HPLC profile and optical rotation
to (S)-8 formed from the asymmetric lithiation-substitu-
tion sequence. Therefore, both carbonyl and alkylating
electrophiles were found to give products arising from
the same facial selectivity.
(20) Still, W. C.; Sreekumar, C. J . Am. Chem. Soc. 1980, 102, 1201.
Recently a nonstereospecific tin-lithium exchange was reported:
Clayden, J .; Pink, J . H. Tetrahedron Lett. 1997, 38, 2565-2568.
(21) For studies on configurational stability of dipole-stabilized
carbanions, see (a) Pearson, W. H.; Lindbeck, A. C. J . Am. Chem. Soc.
1991, 113, 8546-8548. (b) Chong, J . M.; Park, S. B. J . Org. Chem.
1992, 57, 2220-2222. (c) Gawley, R. E.; Zhang, Q. Tetrahedron 1994,
50, 6077-6088. (d) Elworthy, T. R.; Meyers, A. I. Tetrahedron 1994,
50, 6089-6096. (e) Aggarwal, V. K. Angew. Chem., Int. Ed. Engl. 1994,
33, 175.
(22) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552-560.
(23) (a) Beak, P.; Du, H. J . Am. Chem. Soc. 1993, 115, 2516. (b)
Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J . Am. Chem. Soc. 1994,
116, 9755. (c) Basu, A.; Beak, P. J . Am. Chem. Soc. 1996, 118, 1575-
1576.
(19) We found that (R)-14 is the more retained enantiomer on the
(S,S)-Whelk-O 1 column while (S)-5 is more retained than (R)-5 on
the same column. The presence of the 7-chloro may change the
conformation of the Boc group, thereby changing the interaction of the
substrate with the chiral stationary phase. In contrast, the 7-chloro
substituent does not affect the elution order of the 2-carbethoxyindo-
lines.16

Asymmetric Deprotonations
J . Org. Chem., Vol. 62, No. 22, 1997 7683
Ta ble 6. Tin -Lith iu m Exch a n ge Exp er im en ts w ith 3
lithium 28 was allowed to react with Me2SO4 in the
presence of (-)-sparteine to provide racemic 8 in 28%
yield. Racemic 14 was obtained in 63% after racemic 29
was allowed to react with benzophenone in the presence
of (-)-sparteine. In these experiments (-)-sparteine did
not induce asymmetry in the electrophilic substitution
of racemic organolithium intermediates 28 and 29.
Therefore, an asymmetric substitution mechanism can
be discounted.
a n d 15 To Affor d 5, 8, 11, a n d 14
T,
yield
substrate(er) diamine °C electrophile product (er)a (%)
(S)-3 (99:1)b
none
-78
-78
-78
CO2
CO2
(R)-5 (99:1)
(R)-5 (98.5:1.5) 59
25
(S)-3 (98.5:1.5)c 20
(S)-3 (99:1)c
(S)-3 (99:1)c
(S)-3 (99:1)c
3 (50:50)c
20
20
2
2
20
Me2SO4 (S)-8 (98:2)
55d
71d
47d
28d
-40e Me2SO4 (S)-8 (97:3)
-78
-78
-78
-78
Me2SO4 (S)-8 (95:5)
Me2SO4 8 (55:45)
(S)-3 (99:1)c
C3H5Br
Ph2CO
Ph2CO
Ph2CO
(S)-11 (67:33) 27d,f
(R)-14 (87:13) 38d
(R)-14 (88:12) 46d
(S)-15 (88:12)g none
The evidence from the mechanistic studies supports
an asymmetric deprotonation pathway for the reaction
of 1 and 12 with s-BuLi/(-)-sparteine. The generated
intermediates (S)-28 and (S)-29 are configurationally
stable and react stereoselectively with electrophiles to
give enantiomerically enriched products. The facial
selectivity of the deprotonation step is lower in the
presence of the chloro substituent. The asymmetric
deprotonation pathway is also operative in the enantio-
selective lithiation-substitution of N-Boc pyrrolidine,
and the sense of enantioselectivity is the same for the
two cyclic, five-membered Boc amines.9 The fact that the
carbonyl and alkylating electrophiles give the same sense
of chirality in the products is taken to indicate retentive
substitutions. The configurational assignments of (S)-
28 and (S)-29 are in agreement with the configuration
of structurally related (S)-N-Boc-R-lithiopyrrolidine, which
was established previously.25
(S)-15 (87:13)c TMEDA -78
15 (50:50)c
2
-78
14 (50:50)
63d
a
b
The er’s were determined by CSP HPLC. The reaction was
carried out in cumene. c The reaction was carried out in MTBE.
d
A substantial amount of destannylated material was recovered
from the reactions. e The transmetalation was carried out at -78
°C, and 28 was allowed to warm to -40 °C over 1 h. The reaction
was maintained at -40 °C for 1.25 h and was cooled to -78 °C
before reaction with the electrophile. f Boc indole was recovered
g
from the reaction. The reaction was carried out in diethyl ether.
riched (S)-3 in the presence of (-)-sparteine followed by
substitution with Me2SO4 provided enantioenriched (S)-8
with the same absolute configuration obtained for the
lithiation-substitution sequence.24 The organolithium
(S)-28 was also determined to be configurationally stable
at -40 °C in MTBE in the presence of 20. The trans-
metalation of enriched (S)-3 at -78 °C followed by
warming to -40 °C for 1.5 h, cooling to -78 °C, and
treating with Me2SO4 provided (S)-8 in 71% yield and a
97:3 er. The choice of the bispidine ligand 20 was
important for these experiments because tin-lithium
exchange experiments with (S)-3 in the presence of
TMEDA provided very little of the desired substitution
product.
The organolithium (S)-29 was also determined to be
configurationally stable by transmetalation experiments.
A tin-lithium exchange was carried out with enriched
indoline (S)-15 (88:12 er) and n-BuLi in diethyl ether,
and subsequent reaction with benzophenone provided the
alcohol (R)-14 in 38% yield and with an 87:13 er as shown
in Table 6. Similarly, when (S)-15 with an 87:13 er was
treated with n-BuLi in the presence of TMEDA in MTBE,
(R)-14 was isolated in 46% yield with an 88:12 er.
A configurationally stable organolithium intermediate
is required if an asymmetric deprotonation is the enan-
tiodetermining step for the reaction. The results from
the two series of transmetalation experiments indicate
that the organolithium intermediates (S)-28 and (S)-29
are configurationally stable under the conditions tested.
In order to test for an asymmetric substitution path-
way for the reaction of 1 and 12, the racemic tin-
substituted indolines 3 and 15 were treated with n-BuLi
in the presence of (-)-sparteine in MTBE to generate
racemic 28 and racemic 29, respectively. The organo-
The low enantioselectivity observed for the lithiation
of 1 and substitution with allyl bromide or allyl chloride
is probably explained by low facial selectivity in the
substitution step. The undesired oxidation reaction that
occurred in the presence of allyl bromide is not respon-
sible for the erosion of enantioselectivity since this side
reaction is minimal in the presence of allyl chloride, and
the two electrophiles provide products with the same er.
As shown in Table 6, the transmetalation of (S)-3 with a
99:1 er and subsequent reaction with allyl bromide
provided indoline (S)-11 with a 67:33 er. It has been
demonstrated that the organolithium (S)-28 is configu-
rationally stable under these reaction conditions. It can
be concluded that the electrophilic substitution with allyl
bromide occurs with 66% retention and 34% inversion of
configuration.
Regioselectivity of th e Lith ia tion . The ligands
TMEDA and (-)-sparteine exhibit different regioselec-
tivities in the lithiation of 1, and differences between
(24) Inversions of configuration have been observed in transmeta-
lation substitutions of enantioenriched tin-substituted amine deriva-
tives in the presence of (-)-sparteine.17c (a) Weisenburger, G. A.; Beak,
P. J . Am. Chem. Soc. 1996, 118, 12218-12219. (b) Park, Y. S.; Beak,
P. J . Org. Chem. 1997, 62, 1574-1575.
(25) Studies of the deprotonation of (S,S)-N-Boc-dideuteropyrrolidine
with s-BuLi/(-)-sparteine indicated that the removal of the pro-S
proton occurs with 94% enantioselectivity. Kerrick, S. T., Ph.D. Thesis,
University of Illinois at UrbanasChampaign, 1992.

7684 J . Org. Chem., Vol. 62, No. 22, 1997
Gross et al.
these two ligands have been observed previously.26 The
present work establishes that dibutyl bispidine 20 is a
better analog of (-)-sparteine than is TMEDA.
The regioselectivity of the lithiation of 1 is not deter-
mined by a thermodynamic equilibration. The genera-
tion of N-Boc-7-lithioindoline from 4 in the presence of
(-)-sparteine in cumene followed by the addition of 1
resulted in the isolation of only 22 and recovered 1 in
67% and 75% yields, respectively, after preparative
HPLC.
in the direction of the proton removed in the lithiation
of 1.28,15 It is possible that the 1/s-BuLi/(-)-sparteine
complex that would lead to the transition state for
lithiation at C-7 is more sterically conjested than the
complex leading to removal of H-2, and consequently a
regioselective lithiation at C-2 takes place. Complexes
1/s-BuLi and 1/s-BuLi/TMEDA leading to 7-lithiation
may be sterically less encumbered and therefore give rise
to a different regiochemical outcome for the reaction.
Su m m a r y. The present work demonstrates that N-
Boc indoline 1 can be deprotonated regioselectively in the
2-position with s-BuLi/(-)-sparteine and allowed to react
with electrophiles to afford 2-substituted N-Boc indolines
in variable yields and excellent er’s. The regioselectivity
of this lithiation-substitution is dependent upon the
choice of ligand and solvent, with a 20:1 regioselectivity
observed with (-)-sparteine in cumene. In addition,
N-Boc-7-chloroindoline 12 can be deprotonated in the
2-position with s-BuLi/(-)-sparteine and allowed to react
with electrophiles to provide 2,7-disubstituted indolines
with satisfactory yields and er’s. The enantiomerically
enriched products obtained from these sequences comple-
ment the series of indoline ligands and auxiliaries2,3 that
are available from the commercially available (S)-indo-
line-2-carboxylic acid. The source of enantioselectivity
is an asymmetric deprotonation. The organolithium
intermediates (S)-28 and (S)-29 formed in these reactions
are configurationally stable and react stereoselectively
with a variety of electrophiles.
We also observed a large kinetic isotope effect for the
lithiation of N-Boc-7-deuteroindoline in the presence of
(-)-sparteine in MTBE. When indoline 1 was treated
with s-BuLi/(-)-sparteine in MTBE and subsequently
allowed to react with Me2SO4, (S)-8 and 22 were isolated
in 43% yield and 15% yield, respectively. In addition 8%
of 1 was recovered. A sample of 1-d1 of 99% d1 was
prepared by reaction of 1 with s-BuLi/TMEDA followed
by MeOD. The product 1-d1 was formed as an 81:19 ratio
of 1a -d1 and 1b-d1 as indicated by 2H NMR.27 When 1-d1
was treated with s-BuLi/(-)-sparteine in MTBE followed
by Me2SO4, the products (S)-8d1 and 22-d1 were isolated
in 37% yield and 3% yield, respectively, along with 19%
of the starting material. The 86% deuterium incorpora-
tion for 22-d1 was established by GC/MS and is consistent
with the 2H NMR data. From these results, a kinetic
isotope effect of approximately 30 can be calculated for
the deprotonation of 1a -d1. These results show that the
regioselectivity in the lithiation of 1 is kinetically deter-
mined.
Exp er im en ta l Section
Gen er a l. Organolithium reagents were handled under dry
nitrogen. All reagents were obtained from commercial sources
and were used without further purification unless otherwise
noted. (-)-Sparteine was obtained from (-)-sparteine sulfate
pentahydrate and distilled under vacuum from calcium hy-
dride as reported previously.9 TMEDA, toluene, and TMSCl
were distilled from calcium hydride under a nitrogen atmo-
sphere. Benzaldehyde, Me2SO4, DMPU, and DMSO were
distilled from calcium hydride under vacuum. Diethyl ether
(Et2O), MTBE, THF, and pentane were distilled from sodium
and benzophenone under nitrogen. Cumene was distilled from
sodium metal. Allyl bromide and allyl chloride were passed
through a plug of neutral alumina prior to use. Solutions of
s-BuLi in cyclohexane and n-BuLi in hexanes were titrated
using the method of Suffert.29 Either the Regis Rexchrom
Pirkle Concept D-phenylglycine column, the (R,R)-Beta-Gem
1 column or the Regis (S,S)-Whelk-O 1 column was used for
the separation of enantiomers. Retention times (rt) are given
in minutes.
Gen er a l P r oced u r e for th e Asym m etr ic Dep r oton a -
tion of 1-(ter t-Bu toxyca r bon yl)in d olin e. To a 0.1 M
solution of 1 (1 equiv) under a N2 atmosphere was added (-)-
sparteine (2) (1.3 equiv), and the solution was cooled to -78
°C. A 1.3 M solution of s-BuLi (1.3 equiv) in cyclohexane was
added, and the yellow solution was allowed to stir at -78 °C
for several hours. An excess of the electrophile (1.5 equiv) was
added, and the solution was allowed to come to room temper-
ature slowly and stirred overnight. The reaction was quenched
with H2O, and the aqueous layer was extracted with Et2O. The
organic extracts were washed with 5% H3PO4 solution, dried
over MgSO4, filtered, and concentrated in vacuo. Crude
product mixtures were purified by flash chromatography and
preparative HPLC.
It is reasonable that a prelithiation complex is formed
between 1 and s-BuLi/(-)-sparteine prior to reaction and
that in this complex the Boc carbonyl group should point
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-1-(ter t-
Bu toxyca r bon yl)-2-(tr im eth ylsta n n yl)in d olin e (3). To a
solution of 1 (91.4 mg, 0.417 mmol) and 2 (125 µL, 0.542 mmol)
(26) Other reports indicate that TMEDA and (-)-sparteine do not
effect the same configurational stability in intermediate organo-
lithiums.23c,24
(27) This result is dependent upon experimental conditions. When
a bottle of s-BuLi that was not filtered through Celite was used for
the reaction, a 96:4 ratio of 7-substituted to 2-substituted products was
obtained as determined by 2H NMR.
(28) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-363.
(b) Gallagher, D. J .; Beak, P. J . Org. Chem. 1995, 60, 7092-7093.
(29) Suffert, J . J . Org. Chem. 1989, 54, 509-510.

Asymmetric Deprotonations
J . Org. Chem., Vol. 62, No. 22, 1997 7685
in cumene was added s-BuLi (0.42 mL, 1.3 M, 0.54 mmol) at
-78 °C. After 5.5 h a solution of Me3SnCl13 (0.63 mL, 1.0 M,
0.63 mmol) in hexanes was added, and the solution was
allowed to come to room temperature and stirred overnight.
Following flash chromatography on basic alumina with 100%
hexane and preparative HPLC with 0.5% EtOAc/hexane, 110.8
(br, 1H), 3.11-2.99 (br m, 2H), 1.60 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 140.2, 130.9, 128.3, 127.4, 127.1, 125.9, 124.4,
122.7, 115.1, 81.7, 74.4, 65.0, 28.4, 28.0; HRMS calcd for C20H23
-
NO3 (M+) 325.1677, found 325.1678 (0.0 mDa). The enanti-
omers were separated on the (S,S)-Whelk-O 1 column (2.5%
IPA/hex, 1.25 mL/min): rt ) 14.6 (9%), 18.7 (91%). The
resonances of the carbonyl carbon and one aromatic carbon
are quite broad and are not listed in the 13C data.
mg (70%) of 3 was isolated as a colorless oil: [R]25 +95° (c
D
1
0.0203, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.9 (br, 0.3H),
7.50 (br, 0.7H), 7.15 (d, J ) 7.1 Hz, 2H), 6.94 (t, J ) 7.35 Hz,
1H), 4.25 (br, 0.3H), 4.08 (br, 0.7H), 3.46-3.34 (br, 1H), 3.15-
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-1-(ter t-
Bu toxyca r bon yl)-2-m eth ylin d olin e (8). To a solution of 1
(131 mg, 0.596) and 2 (180 µL, 0.78) in cumene was added
s-BuLi (0.60 mL, 1.3M, 0.78 mmol) at -78 °C. After 3 h Me2-
SO4 (85 µL, 0.89 mmol) was added, and the solution was
allowed to come to room temperature and stirred overnight.
Following purification by preparative HPLC with 1% EtOAc/
3.04 (br, 1H), 1.58 (s, 9H), 0.09 (s, J (Sn-C) ) 52 Hz, 9H); 13
C
NMR (CDCl3, 75 MHz) δ 152.6, 142.2, 133.0, 127.1, 124.7,
122.0, 114.9, 81.1, 49.1, 31.8, 28.5, -9.1 (J (Sn-H) ) 335 Hz,
330 Hz). Anal. Calcd for C16H25NO2Sn: C, 50.30; H, 6.59; N,
3.67. Found: C, 50.29; H, 6.66; N, 3.71. The enantiomers of
3 were separated by CSP HPLC using the (S,S)-Whelk-O 1
column (100% hexane, 0.5 mL/min): rt ) 11.7 min (1%), 12.7
min (99%).
In addition 1-(tert-butoxycarbonyl)-7-(trimethylstannyl)in-
doline (4) (4.7 mg, 3%) was produced as a white solid, and
starting material 1 (13.3 mg, 15%) was recovered from this
reaction.
hexane, 8 (71.7 mg, 52%) was isolated as a colorless oil: [R]25
D
+39° (c 0.0101, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.74 (br,
1H), 7.15 (m, 2H), 6.93 (td, J ) 1.0, 7.4 Hz, 1H), 4.51 (br, 1H),
3.34 (dd, J ) 9.8, 15.9 Hz, 1H), 2.61 (d, J ) 15.9 Hz, 2H), 1.58
(s, 9H), 1.29 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 152.2, 141.7, 129.9, 127.2, 124.9, 122.2, 115.2, 80.5, 55.1, 35.6,
28.4, 21.1. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N,
6.00. Found: C, 71.89; H, 8.43; N, 6.02. The enantiomers
were separated on the (S,S)-Whelk-O 1 column (0.5% IPA/
hexane, 1.25 mL/min): rt ) 10.0 (1.5%), 11.3 (98.5%).
P r ep a r a tion of En a n tiom er ica lly En r ich ed (R)-1-(ter t-
Bu toxyca r bon yl)-2-ca r bom eth oxyin d olin e (5). To a solu-
tion of 1 (132 mg, 0.601 mmol) and 2 (180 µL, 0.78 mmol) in
cumene was added s-BuLi (0.60 mL, 1.3 M, 0.78 mmol) at -78
°C. After 6 h CO2 was bubbled through the flask for 5 h, and
the reaction was allowed to come to room temperature slowly
and stirred overnight under a positive pressure of CO2. After
the reaction was quenched with water, the layers were
separated, and 5% HCl was added to bring the aqueous
solution to pH 2. The aqueous layer was extracted with Et2O
(3 × 15 mL), and the combined organic extracts were treated
In addition, 1 (30.0 mg, 23%) was recovered from the
1
reaction as well as 22 (3.6 mg, 3%). The H NMR data of 22
matched the previously reported data.11a
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-1-(ter t-
Bu toxyca r bon yl)-2-(tr im eth ylsilyl)in d olin e (9). To a so-
lution of 1 (173 mg, 0.788 mmol) and 2 (234 µL, 1.02 mmol) in
cumene was added s-BuLi (0.66 mL, 1.55 M, 1.02 mmol) at
-78 °C. After 6 h TMSCl (150 µL, 1.2 mmol) was added, and
the solution was allowed to come to room temperature and
stirred overnight. Following chromatography on basic alumina
30
with CH2N2 in Et2O at 0 °C until a yellow color persisted.
The solution was allowed to stand at room temperature
overnight and was concentrated in vacuo. The crude material
was purified by flash chromatography with 5% EtOAc/hexane,
with hexane, 9 (130 mg, 57%) was isolated as a colorless oil:
1
[R]25 +96° (c 0.0145, CHCl3); H NMR (CDCl3, 400 MHz) δ
D
and 5 (108.0 mg, 65%) was obtained as a colorless oil: [R]25
7.4 (br, 1H), 7.15-7.09 (m, 2H), 6.90 (td, J ) 0.98, 7.6 Hz,
1H), 4.03 (dd, J ) 2.9, 11.7 Hz, 1H), 3.43 (br m, 1H), 2.87 (dd,
J ) 3.0, 15.7 Hz, 1H), 1.56 (s, 9H), -0.02 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 152.7, 142.9, 132.4, 127.1, 124.3, 122.3,
115.8, 80.6, 50.2, 30.2, 28.4, -3.1; HRMS calcd for C16H25NO2-
Si (M+) 291.1650, found 291.1655 (0.5 mDa). The enantiomers
were separated on the (S,S)-Whelk-O 1 column (1% IPA/hex,
1.25 mL/min): rt ) 5.4 (2.3%), 6.5 (97.7%).
D
+63° (c 0.0073, CHCl3). The 1H NMR data matched that of
(S)-5 (vide infra). The enantiomers were separated on the
(S,S)-Whelk-O 1 column (0.75% IPA/hexane, 1.5 mL/min): rt
) 14.6 (0.5%), 15.5 (99.5%).
In addition 21% (27.3 mg) of the starting material was
recovered, and a material tentatively identifed as N-(tert-
butoxycarbonyl)-7-carbomethoxyindoline (4.8 mg, 3%) was
isolated as an off-white solid.
In addition, 1 (43.8 mg, 25%) was recovered from this
reaction as well as 23 (13 mg, 3%). The 1H NMR data of 23
agreed with the previously reported data.11a
Chromatography on silica gel causes decomposition of (S)-
9.
P r ep a r a tion of En a n tiom er ica lly En r ich ed (R)-1-(ter t-
Bu toxyca r bon yl)-r-p h en yl-2-in d olin e Meth a n ol (6 a n d
7). To a solution of 1 (95.4 mg, 0.435 mmol) and 2 (130 µL,
0.566 mmol) in cumene was added s-BuLi (0.44 mL, 1.3 M,
0.57 mmol) at -78 °C. After 6 h benzaldehyde (66 µL, 0.66
mmol) was added, and the solution was allowed to come to
room temperature and stirred overnight. Following flash
chromatography and preparative HPLC with 10% EtOAc/
hexane, the major diastereomer, 6 (86.5 mg, 61%), was isolated
P r ep a r a tion of En a n tiom er ica lly En r ich ed (R)-1-(ter t-
Bu t oxyca r b on yl)-2-(d ip h en ylh yd r oxym et h yl)in d olin e
(10). To a solution of 1 (117 mg, 0.534 mmol) and 2 (160 µL,
0.70 mmol) in cumene was added s-BuLi (0.53 mL, 1.3 M, 0.70
mmol) at -78 °C. After 7 h a solution of benzophenone (146
mg, 0.801 mmol) in cumene was added, and the solution was
allowed to come to room temperature and stirred overnight.
Following flash chromatography (5-10% EtOAc/hexane), (R)-
10 (22.9 mg, 11%) was isolated as a white solid: mp 88-92
°C. The spectral data for enriched (R)-10 agreed with that
reported for (S)-10 (vide infra). The enantiomers were sepa-
rated on the (S,S)-Whelk-O 1 column (2.5% IPA/hexane, 1.25
mL/min): rt ) 9.5 (92%) and 20.6 (8%).
as a colorless oil: [R]25 +37° (c 0.0127, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ 7.49 (br, 1H), 7.36-7.26 (m, 5H), 7.17 (t,
J ) 7.7 Hz, 1H), 7.06 (d, J ) 7.3 Hz, 1H), 6.95 (t, J ) 7.3 Hz,
1H), 4.81 (m, 1H), 4.65 (d, J ) 8.8 Hz, 1H), 3.07 (dd, J ) 9.8,
16.6 Hz, 1H), 2.63 (d, J ) 16.6 Hz, 1H), 1.65 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 155.3, 145.4, 141.2, 130.4, 128.4, 128.0,
127.4, 127.3, 124.7, 123.0, 116.2, 82.6, 77.4, 64.9, 30.8, 28.4.
Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30.
Found: C, 73.93; H, 7.09; N, 4.52. The enantiomers were
separated on the (S,S)-Whelk-O 1 column (2.5% IPA/hex, 1.25
mL/min): rt ) 15.0 (2%), 28.8 (98%). The 13C NMR and
elemental analysis data were obtained for the racemic com-
pound.
The major product from this reaction was 1-(tert-butoxy-
carbonyl)indole (60.2 mg, 52%), which was identified by
1
comparison of its H NMR data to previously reported data.31
Starting material (23.7 mg, 20%) was also recovered.
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-1-(ter t-
Bu toxyca r bon yl)-2-a llylin d olin e (11). To a solution of 1
(112 mg, 0.511 mmol) and 2 (150 µL, 0.67 mmol) in cumene
was added s-BuLi (0.51 mL, 1.3 M, 0.67 mmol) at -78 °C. After
6 h allyl bromide (66 µL, 0.77 mmol) was added, and the
solution was allowed to come to room temperature and stirred
overnight. Following purification by preparative HPLC with
The minor diastereomer 7 (18.7 mg, 13%) was isolated as a
white solid, difficult to purify: mp 109-112 °C; [R]25 +38° (c
D
0.0090, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.5 (br, 1H), 7.41
(d, J ) 7.5, 2H), 7.34 (br, 2H), 7.27 (br, 1H), 7.15-7.08 (m,
2H), 6.92 (t, J ) 7.3 Hz, 1H), 5.31 (d, J ) 2.2 Hz, 1H), 4.71
1% EtOAc/hexane, (S)-11 (37.6 mg, 28%) was isolated as a
1
(30) Black, T. H. Aldrichim. Acta 1983, 16, 3-10.
colorless oil: [R]25 +29° (c 0.0099, CHCl3); H NMR (CDCl3,
D

7686 J . Org. Chem., Vol. 62, No. 22, 1997
Gross et al.
400 MHz) δ 7.75 (br, 1H), 7.18-7.12 (m, 2H), 6.93 (td, J )
0.98, 7.6 Hz, 1H), 5.79-5.68 (m, 1H), 5.11-5.05 (m, 2H), 4.46
(br, 1H), 3.24 (dd, J ) 9.8, 16.1 Hz, 1H), 2.79 (dd, J ) 2.0,
16.1 Hz, 1H), 2.52 (br, 1H) 2.32-2.25 (m, 1H), 1.58 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 152.2, 140, 133.7, 130, 127.3,
124.8, 122.3, 117.9, 118.1, 82.5, 58.5, 39.0, 32.7, 28.4. Anal.
Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C,
73.69; H, 8.08; N, 5.41. The enantiomers were separated on
the (S,S)-Whelk-O 1 column (0.5% IPA/hexane, 1.00 mL/
min): rt ) 10.1 (32%), 11.2 (68%).
mmol) was added a 0.10 M solution of 2 (110 µL, 0.48 mmol)
and s-BuLi (0.43 mL, 1.1 M, 0.48 mmol). After the addition
of Me3SnCl13 (1.0 M, 0.60 mL, 0.60 mmol), the solution was
stirred at -78 °C for 5 h. Following chromatographic purifica-
tion (2.5-5% EtOAc/hexane), 15.4 mg of starting material was
recovered, and (S)-15 (131.4 mg, 78%) was obtained as a
1
colorless oil: [R]25 +51° (c 0.0094, CHCl3); H NMR (CDCl3,
D
300 MHz) δ 7.14 (d, J ) 7.9 Hz, 1H), 7.07 (d, J ) 7.1 Hz, 1H),
6.94 (t, J ) 7.5 Hz, 1H), 4.22 (dd, J ) 7.0, 8.7 Hz, 1H), 3.34
(dd, J ) 8.9, 15.5 Hz, 1H), 2.89 (dd, J ) 6.8, 15.5 Hz, 1H),
1.52 (s, 9H), 0.07 (s, J (Sn-H) ) 53.1 Hz, 9H); 13
In addition, 1-(tert-butoxycarbonyl)indole31 (25.2 mg, 23%)
and 1 (28.6, 26%) were isolated from this reaction.
C NMR (CDCl3,
75 MHz) δ 153.6, 140.9, 138.5, 128.7, 124.9, 123.8, 122.4, 81.2,
53.4 (J (Sn-C) ) 388.9 Hz), 34.6, 28.1, -9.4 (J (Sn-C) ) 339.5
Hz, 324.3 Hz); HRMS calcd for C16H24ClNO2Sn (M+) 413.0513,
found 413.0513 (0.0 mDa). The enantiomers were separated
on the (R,R)-Beta-Gem column (100% hexane, 0.5 mL/min):
rt ) 7.5 (12%), 8.4 (88%).
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-1-(ter t-
Bu toxyca r bon yl)-2-(tr im eth ylsta n n yl)in d olin e (3) a t -40
°C. To a solution of 1 (116 mg, 0.527 mmol) and 2 (160 µL,
0.69 mmol) in 5.5 mL of cumene at -40 °C was added s-BuLi
(0.53 mL, 1.3 M, 0.69 mmol). The solution stirred at -40 °C
for 1 h, and a solution of Me3SnCl13 (0.79 mL, 1.00 M, 0.79
mmol) in hexanes was added. The solution was maintained
at -40 °C for 1 h, and then the reaction was quenched with
water. The workup was as described above. Following flash
chromatography with 2% EtOAc/hexane and preparative
HPLC with 0.5% EtOAc/hexane, (S)-3 (59.3 mg, 29%) was
isolated as a colorless oil. The enantiomers were separated
by CSP HPLC using the (R,R)-Beta-Gem column (100%
hexane, 0.25 mL/min): rt ) 18.4 min (3%), 20.2 min (97%).
In addition 1 (41.9 mg, 36%) was recovered from the reaction
as well as 4 (4.4 mg, 2.2%).
Gen er a l P r oced u r e for th e Asym m etr ic Dep r oton a -
tion of 1-(ter t-Bu toxyca r bon yl)-7-ch lor oin d olin e (12). To
a solution of (-)-sparteine (2) (1.2 equiv) in MTBE was added
a solution of s-BuLi (1.2 equiv) in cyclohexane at -78 °C. The
solution was stirred for 10 min, and a precooled solution of 12
(1 equiv) in MTBE was added to the s-BuLi/(-)-sparteine. The
solution was stirred for 3.5 h, and then an excess of electrophile
(1.5 equiv) was added. After 3 h, the reaction was quenched
at -78 °C with 5 mL of 15% NH4Cl solution. The mixture
was allowed to come to room temperature slowly and stirred
overnight. The aqueous solution was then extracted with
ether (3 × 10 mL). The combined organic layers were washed
with 5 mL of brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The crude products were purified by flash
chromatography. The er’s were determined by analytical CSP
HPLC.
In addition 4 (2 mg, 1%) was isolated as a white solid.
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-1-(ter t-
Bu toxycar bon yl)-7-ch lor o-2-(tr ibu tylstan n yl)in dolin e (16).
To a 0.07 M solution of 2 (85 µL, 0.37 mmol) and s-BuLi (0.29
mL, 1.3 M, 0.37 mmol) was added a 0.03 M solution of 12 (77.9
mg, 0.307 mmol). Bu3SnCl was added, and following the
workup and chromatographic purification (2.5% EtOAc/hex-
ane), indoline (S)-16 (116 mg, 69%) was isolated as a colorless
oil: 1H NMR (CDCl3, 300 MHz) δ 7.14 (d, J ) 7.8 Hz, 1H),
7.06 (d, J ) 7.0 Hz, 1H), 6.93 (t, J ) 7.6 Hz, 1H), 4.46 (dd, J
) 4.1, 9.3 Hz, 1H), 3.51 (dd, J ) 9.4, 15.3 Hz, 1H), 2.89 (dd, J
) 4.0, 15.4 Hz, 1H), 1.53 (s, 9H), 1.40 (m, 6H), 1.25 (sextet, J
) 7.0 Hz, 6H), 0.85 (t, J ) 7.1 Hz, 9H), 0.8-0.9 (m, 6H); 13C
NMR (CDCl3, 75 MHz) δ 153.1, 140.8, 138.6, 128.7, 125.0,
124.2, 122.5, 81.0, 53.4, 35.0, 29.0, 28.2, 27.4, 13.6, 9.4. Anal.
Calcd for C25H42NO2ClSn: C, 55.32; H, 7.80; N, 2.58. Found:
C, 55.37; H, 7.88; N, 2.53. The enantiomers were separated
on the (R,R)-Beta-Gem column (100% hexane, 1.0 mL/min):
rt ) 2.9 (13.5%), 3.2 (86.5%). The elemental analysis data
were obtained for the racemic compound.
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-2-Allyl-
1-(ter t-bu toxyca r bon yl)-7-ch lor oin d olin e (17). To a 0.03
M solution of indoline 12 (71.0 mg, 0.280 mmol) were added 2
(77 µL, 0.34 mmol, 0.07 M) and s-BuLi (0.26 mL, 1.3 M, 0.34
mmol) at -78 °C. Allyl bromide (36 µL, 0.42 mmol) was added,
and following chromatographic purification with 2.5-5%
EtOAc/hexane and preparative HPLC with 1% EtOAc/hexane,
17 (26 mg, 32%) was isolated as colorless oil: 1H NMR (CDCl3,
300 MHz) δ 7.18 (d, J ) 7.9 Hz, 1H), 7.07 (d, J ) 7.5 Hz, 1H),
6.95 (t, J ) 7.7 Hz, 1H), 5.85-5.64 (m, 1H), 5.07-5.02 (m, 2H),
4.61 (q, J ) 7.3 Hz, 1H), 3.35 (dd, J ) 8.5, 15.9 Hz, 1H), 2.59
(d, J ) 15.9 Hz, 1H), 2.39 (m, 1H), 2.21 (m, 1H), 1.53 (s, 9H);
13C NMR (CDCl3, 75 MHz) δ 153.1, 139.5, 135.7, 133.9, 128.9,
125.0, 124.2, 123.7, 117.6, 81.4, 62.0, 39.4, 34.2, 28.2. Anal.
Calcd for C16H20NO2Cl: C, 65.41; H, 6.86; N, 4.77. Found: C,
65.44; H, 6.76; N, 4.86. The enantiomers were separated on
the (S,S)-Whelk-O 1 column (2% IPA/hexane, 1.00 mL/min):
rt ) 6.1 (55%), 6.6 (45%).
P r ep a r a tion of En a n tiom er ica lly En r ich ed (R)-1-(ter t-
Bu toxycar bon yl)-7-ch lor o-2-(diph en ylh ydr oxym eth yl)in -
d olin e (14). To a 0.28 M solution of 2 (330 µL, 1.4 mmol)
and s-BuLi (1.07 mL, 1.35 M, 1.44 mmol) at -78 °C was added
a 0.06 M solution of 12 (304 mg, 1.20 mmol). A 0.36 M solution
of benzophenone in MTBE was added. Following the workup
and chromatographic purification with 5% EtOAc/hexane as
the eluent, indoline (R)-14 (403 mg, 77%) was isolated as a
white solid: mp 138-141 °C; [R]26 +78° (c 0.0046, CHCl3);
D
1H NMR (CDCl3, 300 MHz) δ 7.45-7.32 (m, 7H), 7.14-7.11
(m, 3H), 6.97 (t, J ) 4.5 Hz, 1H), 6.75 (d, J ) 4.9 Hz, 2H),
5.44 (dd, J ) 1.1, 9.4 Hz, 1H), 4.46 (br, 1H), 3.64 (dd, J )9.5,
16.6 Hz, 1H), 2.92 (d, J ) 16.8 Hz, 1H), 1.51 (s, 9H); 13C NMR
(CDCl3, 75 MHz) δ 155.0, 144.5, 141.7, 140.4, 135.5, 128.3,
127.9, 127.6, 127.3, 127.0, 124.9, 123.7, 121.9, 82.7, 80.7, 69.0,
33.4, 27.9. Anal. Calcd for C26H26NO3Cl: C, 71.63; H, 6.01;
N, 3.22. Found: C, 71.60; H, 6.02; N, 3.25. The enantiomers
were separated on the (S,S)-Whelk-O 1 column (5% IPA/
hexane, 1.25 mL/min): rt ) 6.7 (14%), 7.6 (86%). The
elemental analysis data were obtained for racemic material.
Recrystallization of 273 mg of (R)-14 from Et2O/pentane
yielded 177 mg (65%) of crystals: mp 145-147 °C. The er of
the product was determined to be 96:4 by HPLC. The crystals
of enriched (R)-14 were optically pure but were accompanied
by a small amount of racemic powder, which also crystallized
from the mother liquor.
Also isolated from this reaction were a colorless oil tenta-
tively identified as N-Boc-7-chloroindole (7.7 mg, 11%) and 12
(12.2 mg, 17%).
P r ep a r a tion of En a n tiom er ica lly En r ich ed (R)-1-(ter t-
Bu toxycar bon yl)-7-ch lor oin dolin e-2-car boxylic Acid (13).
To a 0.08 M solution of indoline 12 (95.4 mg, 0.376 mmol) at
-78 °C was added a 0.09 M precooled solution of 2 (104 µL,
0.451 mmol) and s-BuLi (0.34 mL, 1.3 M, 0.45 mmol). After
3.5 h, a stream of CO2 was passed through the flask for 0.5 h.
The solution was stirred at -78 °C for 3 h under a positive
pressure of CO2. The reaction was quenched with water, and
the aqueous solution was acidified to pH 2 with 10% HCl and
extracted with Et2O. Following chromatographic purification
with 10-50% MeOH/EtOAc, N-Boc-indoline-7-carboxylic acid
(3.1 mg, 3%) was obtained as a white solid,11a and (R)-13 (100.5
mg, 90%) was obtained as a white solid.
To indoline (R)-13 (76.9 mg, 0.258 mmol) in ethanol (10 mL)
was slowly added thionyl chloride (23 µL, 0.31 mmol) at -10
°C. The solution was allowed to stir at room temperature for
45 min and was then heated at 65 °C for 2 h. The thionyl
chloride was removed by successive additions of ethanol (3 ×
P r ep a r a tion of En a n tiom er ica lly En r ich ed (S)-1-(ter t-
Bu t oxyca r b on yl)-7-ch lor o-2-(t r im e t h ylst a n n yl)in d o-
lin e (15). To a 0.04 M solution of indoline 12 (102.1 mg, 0.402
(31) Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy,
A. B. J . Org. Chem. 1981, 46, 157-164.

Asymmetric Deprotonations
J . Org. Chem., Vol. 62, No. 22, 1997 7687
15 mL) followed by concentration in vacuo: The crude oil was
chromatographed on silica gel with 5% EtOAc/hexane contain-
ing 0.5% Et3N to give 2-carbethoxy-7-chloroindoline (30.8 mg,
(br, 0.33H), 7.19 (t, J ) 7.5 Hz, 1H), 7.10 (d, J ) 7.4 Hz, 1H),
6.94 (t, J ) 7.2 Hz, 1H), 4.9 (br, 1H), 3.75 (s, 3H), 3.4 (m, 1H),
3.11 (dd, J ) 4.4, 17 Hz, 1H), 1.50 (br s, 9H); 13C NMR (CDCl3,
125 MHz) δ 172.3, 151.4, 142.4, 128.7, 127.7, 124.2, 122.4,
114.4, 81.1, 60.2, 52.1, 32.4, 28.0. Anal. Calcd for C15H19NO4:
C, 64.97; H, 6.91; N, 5.05. Found: C, 65.01; H, 7.06; N, 5.12.
The enantiomeric purity of the product was verified using the
(S,S)-Whelk-O 1 column (0.75% IPA/hexane, 1.5 mL/min): rt
) 14.6 (100%).
53%) as a colorless oil: [R]23 +36.5° (c 0.0139, methanol); 1H
D
NMR (CDCl3, 300 MHz) δ 7.03 (d, J ) 8.0 Hz, 1H), 6.96 (d, J
) 7.2 Hz, 1H), 6.66 (t, J ) 7.7 Hz, 1H), 4.55 (br, 1H), 4.42 (dd,
J )6.1, 9.7 Hz, 1H), 4.21 (q, J ) 7.1 Hz), 3.4 (AB-X q’s, C+ )
1027.7 Hz, C- ) 1020.6 Hz, J (A-B) ) 15.9 Hz, 2H), 1.29 (t,
J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 173.2, 147.1,
128.1, 127.3, 122.5, 120.0, 115.2, 61.4, 59.5, 34.2, 14.0. Anal.
Calcd for C11H12NO2Cl: C, 58.54; H, 5.36; N, 6.21. Found: C,
58.94; H, 5.37; N, 6.39. The enantiomers were separated on
the D-phenylglycine column (5% IPA/hexane, 2.00 mL/min):
rt ) 5.4 (11%), 7.2 (89%).
P r ep a r a tion of (S)-1-(ter t-Bu toxyca r bon yl)-2-(d ip h en -
ylh yd r oxym eth yl)in d olin e (10). A solution of (S)-5 (1.17
g, 4.24 mmol) in 25 mL of THF was cooled to 0 °C. A solution
of PhMgBr (3.0 M, 2.96 mL, 8.89 mmol) in Et2O was added to
the solution slowly. After stirring for 7 h at 0 °C to room
temperature, the solution was quenched with 10% aqueous
H2SO4 (3 mL). The aqueous solution was extracted with Et2O
(3 × 20 mL), and the combined organic layers were dried over
MgSO4, filtered, and concentrated. Following flash chromato-
graphic purification with 5-20% EtOAc/hexane, pure indoline
(S)-10 (418 mg, 25%) was obtained as a white solid: mp 88-
In addition the indole ethyl ester (9.8 mg, 19%) was obtained
as a white solid: mp 105-106 °C (lit.32 113.5-114 °C).
Gen er a l P r oced u r e for th e Dep r oton a tion of 1-(ter t-
Bu toxyca r bon yl)-7-ch lor oin d olin e (12) in th e P r esen ce
of TMEDA. To a 0.03 M solution of 12 in Et2O or MTBE was
added TMEDA (1.2 equiv), and the solution was cooled to -78
°C. A solution of s-BuLi in cyclohexane (1.2 equiv) was added,
and the solution was allowed to stir for 1-4 h. An excess of
the electrophile (1.5 equiv) was added, and the solution was
either allowed to stir for 0.5 h at -78 °C or allowed to come to
ambient temperature slowly and stirred overnight. A 15%
solution of NH4Cl in water was added to quench the reaction.
The aqueous solution was extracted with Et2O (3 × 10 mL),
and the combined organic extracts were washed with brine (5
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude materials were purified by flash chromatography.
P r ep a r a tion of Ra cem ic 1-(ter t-Bu toxyca r bon yl)-7-
ch lor o-2-(tr im eth ylsilyl)in d olin e (18). TMSCl was used as
the electrophile to provide after chromatographic purification
170 mg (88%) of indoline 18, which was obtained as a colorless
oil: 1H NMR (CDCl3, 300 MHz) δ 7.13 (d, J ) 7.9 Hz, 1H),
7.03 (d, J ) 7.3 Hz, 1H), 6.92 (t, J ) 7.6 Hz, 1H), 4.14 (dd, J
) 1.4, 10.5 Hz, 1H), 3.53 (dd, J ) 10.6, 15.5 Hz, 1H), 2.71 (d,
J ) 15.5 Hz, 1H), 1.52 (s, 9H), -0.09 (s, 9H); 13C NMR (CDCl3,
75 MHz) δ 153.7, 140.9, 137.8, 128.6, 125.1, 124.4, 122.4, 81.0,
54.0, 31.3, 28.2, -3.9. Anal. Calcd for C16H24NO2ClSi: C,
58.97; H, 7.42; N, 4.30. Found: C, 58.99; H, 7.22; N, 4.13.
P r ep a r a tion of Ra cem ic 1-(ter t-Bu toxyca r bon yl)-7-
ch lor o-2-m eth ylin d olin e (19). MeI was used as the elec-
trophile to provide after chromatographic purification 110 mg
(55%) of indoline 19, which was obtained as an off-white
92 °C; [R]26 -110° (c 0.0052, CHCl3); 1H NMR (CDCl3, 300
D
MHz) δ 7.4-7.26 (m, 8H), 7.11 (d, J ) 4.4, 3H), 7.02 (t, J )
7.7, 1H), 6.87-6.78 (m, 2H), 5.46 (dd, J ) 2.5, 10.3 Hz, 1H),
4.9 (br, 1H), 3.43 (dd, J ) 16.2, 16.8 Hz, 1H), 2.94 (dd, J )
2.0, 16.7 Hz, 1H), 1.43 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
154.8, 145.0, 142.2, 131.0, 127.9, 127.5, 127.4, 127.2, 127.1,
126.9, 126.8, 123.8, 122.7, 115.9, 82.3, 82.1, 66.8, 33.0, 28.1.
Anal. Calcd for C26H27NO3: C, 77.78; H, 6.78; N, 3.49.
Found: C, 77.53; H, 7.21; N, 3.27. The enantiomeric purity
was verified using the (S,S)-Whelk-O 1 column (2.5% IPA/
hexane, 1.25 mL/min): rt ) 20.5 (100%).
P r ep a r a tion of (S)-1-(ter t-Bu toxyca r bon yl)-7-ch lor o-
2-(d ip h en ylh yd r oxym eth yl)in d olin e (14) fr om (S)-1-(ter t-
Bu t oxyca r b on yl)-2-(d ip h en ylh yd r oxym et h yl)in d olin e
(10). To a solution of (S)-10 (325.9 mg, 0.812 mmol) and
TMEDA (0.37 mL, 2.4 mmol) in MTBE (30 mL) at -78 °C was
added s-BuLi (1.7 mL, 1.4 M, 2.4 mmol). After 7 h at -78 °C,
a solution of hexachloroethane (636.6 mg, 2.69 mmol) in MTBE
(15 mL) was added to the red anion. The solution was allowed
to come to room temperature slowly and stirred overnight. The
reaction was quenched with water (5 mL), and the aqueous
layer was extracted with Et2
O (3 × 10 mL). The organic
extracts were washed with 5% H3PO4 (5 mL), dried over
MgSO4, filtered, and concentrated. Following flash chroma-
tography with 5% EtOAc/hexane and preparative HPLC using
5% EtOAc/hexane, (S)-14 (37.5 mg, 11%) was isolated as an
1
solid: mp 74-76 °C; H NMR (CDCl3, 300 MHz) δ 7.18 (d, J
) 7.9 Hz, 1H), 7.10 (d, J ) 7.3 Hz, 1H), 6.95 (t, J ) 7.8 Hz,
1H), 4.70 (m, 1H), 3.42 (dd, J )7.9, 15.6 Hz, 1H), 2.45 (d, J )
15.6 Hz, 1H), 1.55 (s, 9H), 1.25 (d, J ) 6.7 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 153.0, 139.0, 135.6, 129.0, 124.9, 124.2,
123.2, 81.2, 58.7, 36.8, 28.2, 21.3. Anal. Calcd for
C14H18NO2Cl: C, 62.80; H, 6.78; N, 5.23. Found: C, 62.71; H,
6.79; N, 5.22.
oil: [R]26 -116° (c 0.0203, CHCl3). The enantiomeric purity
D
of the product was verified by analysis on the (S,S)-Whelk-O
1 column (2.5% IPA/hexane, 1.25 mL/min): rt ) 7.3 (100%).
The remainder of the material isolated from this reaction was
identified as starting material (S)-10 (224 mg, 69%).
P r ep a r a tion of (R)-1-(ter t-Bu toxyca r bon yl)-2-m eth yl-
in d olin e (8) fr om (S)-2-in d olin eca r boxylic Acid (25). To
a solution of (S)-25 (979 mg, 6.00 mmol) in 12 mL of THF at
0 °C was added BH3‚THF (15.0 mL, 15.0 mmol), and the
solution was allowed to come to room temperature and stirred
for 24 h. Water was added to quench the reaction, and the
aqueous solution was extracted with Et2O (3 × 20 mL). The
organic solution was washed with saturated NaHCO3 (2 × 5
mL) and brine (10 mL) and dried over Na2SO4, filtered, and
concentrated in vacuo to provide 2-(hydroxymethyl)indoline
(752 mg, 84%) as an off-white solid: mp 60-62 °C (lit. 68-69
°C2e). To a solution of 2-(hydroxymethyl)indoline in CH2Cl2
(5 mL) at 0 °C was added Boc-O-Boc (1.10 g, 5.03 mmol) in
CH2Cl2 (2 mL), and the solution was allowed to stir for 16 h.
Following concentration in vacuo and Kugelrohr distillation
(125-135 °C @ 0.05 mmHg), (S)-26 (1.17 g, 94%) was obtained
as a viscous oil: 1H NMR (CDCl3, 400 MHz) δ 7.52 (br, 1H),
7.18-7.11 (m, 2H), 6.96 (td, J ) 0.98, 7.6 Hz, 1H), 4.61 (br,
1H), 3.79-3.69 (m, 2H), 3.35 (dd, J ) 10.3, 16.4 Hz, 1H), 2.87-
2.49 (br, 2H), 1.59 (s, 9H). The material was converted to the
tosylate without further purification.
P r ep a r a tion of (S)-1-(ter t-Bu toxyca r bon yl)-2-ca r bo-
m eth oxyin d olin e (5). To (S)-indoline-2-carboxylic acid 25
(259.8 g, 1.59 mmol) in methanol (20 mL) was added thionyl
chloride (140 µL, 1.9 mmol) at -10 °C. The solution was
allowed to stir at -10 °C for 0.5 h and then was heated at
reflux for 3 h. The thionyl chloride was removed by successive
additions of methanol (3 × 15 mL) followed by concentration
in vacuo, and the resulting yellow amine hydrochloride salt
was carried on without purification. To the salt was added
CH2Cl2, and the solution was cooled to 0 °C followed by the
addition of Et3N (550 µL, 4.0 mmol) and di-tert-butyldicar-
bonate (Boc-O-Boc) (462 mg, 2.11 mmol). The solution was
stirred at room temperature for 24 h. The reaction was
quenched with water (10 mL), and the aqueous solution was
extracted with Et2O (3 × 25 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
Following chromatographic purification with 5% EtOAC/
hexane as the eluent, methyl ester (S)-5 (335.4 mg, 76%) was
obtained as a white solid: mp 51-53 °C; [R]22D -73° (c 0.0088,
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 7.85 (br, 0.66 H), 7.43
To a solution of (S)-26 (1.17 g, 4.69 mmol) in 11 mL of
pyridine and 5 mL of CH2Cl2 at 0 °C was added tosyl chloride
(1.79 g, 9.38 mmol), and the solution was allowed to stir for
18 h. Water was added, and the mixture was allowed to stir
(32) Ishii, H.; Murakami, Y.; Furuse, T.; Hosoya, K.; Ikeda, N. Chem.
Pharm. Bull. 1973, 21, 1495-1505.

7688 J . Org. Chem., Vol. 62, No. 22, 1997
Gross et al.
for 1 h before separating the layers. The aqueous layer was
extracted with Et2O (3 × 30 mL). The extracts were washed
with 6 M HCl, saturated NaHCO3, water, and brine, dried over
MgSO4, filtered, and concentrated in vacuo to provide 1.71 g
of a mixture of starting material (0.44 mmol, 9%) and (S)-27
(3.97 mmol, 85%) as an off-white solid: mp 78-81 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.68 (d, J ) 8.2 Hz, 2H), 7.30 (d, J ) 8.2
Hz, 2H), 7.14 (t, J ) 7.8 Hz, 1H), 7.10 (d, J ) 7.3 Hz, 1H),
6.94 (t, J ) 7.4 Hz, 1H), 4.60 (br, 1H), 4.20 (dd, J ) 3.7, 9.7
Hz, 1H), 3.99 (br, 1H), 3.76-3.71 (m, 0.2 H), 3.28 (dd, J )
10.1, 16.4 Hz, 1H), 2.95 (dd, J ) 1.6, 16.7 Hz, 1H), 2.43 (s,
3H), 1.59 (s, 1H), 1.49 (s, 9H). The product mixture was used
in the reduction without purification.
(m, 8H), 0.90 (t, J ) 7.0 Hz, 6H); 13C NMR (CDCl3, 75 MHz)
δ 59.3, 58.4, 21.1, 30.2, 29.6, 21.2, 14.3. These data are
consistent with data previously reported for this compound.36
Gen er a l P r oced u r e for th e Dep r oton a tion of N-Boc
In d olin e w ith s-Bu Li/20. To a 0.1 M solution 1 in MTBE
and 20 (1.3 equiv) at -78 °C under a N2 atmosphere was added
a 1.3 M solution of s-BuLi (1.3 equiv) in cyclohexane. The
yellow solution was stirred at -78 °C for 18 h, and then an
excess of the electrophile (1.5 equiv) was added. The solution
was allowed to come to room temperature slowly and stirred
overnight. The reaction was quenched with water, and the
aqueous solution was extracted with Et2O. The combined
organic layers were washed with 5% H3PO4, dried over MgSO4,
filtered, and concentrated in vacuo. The crude product
mixtures were purified by flash chromatography or preparative
HPLC.
Gen er a l P r oced u r e for Tin -Lith iu m Exch a n ge Ex-
p er im en ts w ith (S)-1-(ter t-Bu toxyca r bon yl)-2-(tr im eth -
ylsta n n yl)in d olin e (3) a n d (S)-1-(ter t-Bu toxyca r bon yl)-
7-ch lor o-2-(tr im eth ylsta n n yl)in d olin e (15). To a 0.02-0.1
M solution of (S)-3 or (S)-15 and diamine (1.3 equiv) was added
a solution of n-BuLi (1.3 equiv) in hexanes at -78 °C, and
exchange was allowed to take place for several hours. An
excess of electrophile (1.5 equiv) was added at -78 °C, and
the reaction was allowed to warm to room temperature slowly
and stirred overnight before the aqueous quench in the case
of (S)-3. For the reactions with (S)-15, following the addition
of the electrophile the reaction temperature was maintained
at -78 °C for 2-3 h before quenching with a 15% NH4Cl
solution (5 mL). The aqueous solution was extracted with Et2O
(3 × 10 mL), and the organic layers were washed with brine
(5 mL) or 5% H3PO4 (5 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the crude product
mixtures was carried out using flash chromatography.
Tin -Lith iu m Exch a n ge Exp er im en t w ith (S)-1-(ter t-
Bu toxyca r bon yl)-2-(tr im eth ylsta n n yl)in d olin e (3) a t -40
°C. To a solution of (S)-3 (165 mg, 0.432 mmol) and 20 (142
mg, 0.598 mmol) at -78 °C in MTBE was added n-BuLi (0.39
mL, 1.5 M, 0.598 mmol). The yellow solution was maintained
at -78 °C for 20 min and then allowed to warm to -40 °C
over 45 min. The solution was maintained at -40 °C for 1.25
h and recooled to -78 °C over 20 min. Me2SO4 (82 µL, 0.86
mmol) was added, and the solution was allowed to come to
room temperature slowly and stirred overnight. The reaction
was quenched with water, and the aqueous solution was
extracted with Et2O (3 × 20 mL). The organic extracts were
washed with 5% H3PO4 (5 mL), dried over MgSO4, filtered,
and concentrated in vacuo. Following purification by prepara-
tive HPLC (1% EtOAc/hexane), (S)-8 (78.5 mg, 78%) was
isolated as a colorless oil. The enantiomers were separated
on the (S,S)-Whelk-O 1 column (0.5% IPA/hexane, 1.25 mL/
min): rt ) 10.0 (1.5%), 11.3 (98.5%).
P r ep a r a tion of (S)-1-(ter t-Bu toxyca r bon yl)-2-a llylin -
d olin e (11) via Tin -Lith iu m Exch a n ge. To a solution of
(S)-3 (99:1 er, 118 mg, 0.307 mmol) and 20 (86.5 mg, 0.363
mmol) in 4 mL of MTBE at -78 °C was added n-BuLi (0.25
mL, 1.5 M, 0.36 mmol). After 2.5 h at -78 °C, allyl bromide
(40 µL, 0.46 mmol) was added, and the solution was allowed
to come to room temperature slowly and stirred overnight.
Following preparative HPLC with 1% EtOAc/hexane, (S)-11
(21.5 mg, 27%) was isolated as a colorless oil along with 1 (8.7
mg, 13%) and N-Boc indole (16.3 mg, 24%). The enantiomers
of 11 were separated on the (S,S)-Whelk-O 1 column (0.5%
IPA/hexane, 1.00 mL/min): rt ) 9.9 (33%), 11.1 (67%).
Gen er a l P r oced u r e for Tin -Lith iu m Exch a n ge Ex-
p er im en ts w ith Ra cem ic 1-(ter t-Bu toxyca r bon yl)-2-(tr i-
m eth ylsta n n yl)in d olin e (3) a n d 1-(ter t-Bu toxyca r bon yl)-
7-ch lor o-2-(tr im eth ylstan n yl)in dolin e (15) in th e P r esen ce
of (-)-Sp a r tein e. To a 0.02-0.1 M solution of 3 or 15 and 2
(1.3 equiv) was added a solution of n-BuLi (1.3 equiv) in
hexanes at -78 °C, and exchange was allowed to take place
for several hours. An excess of electrophile (1.5 equiv) was
added at -78 °C, and the reaction was allowed to warm to
room temperature slowly and stirred overnight before the
aqueous quench in the case of 3. For the reaction with 15,
following the addition of the electrophile the reaction temper-
To a mixture of (S)-27 (3.80 mmol) and NaBH4 (374 mg,
9.89 mmol) was added freshly distilled DMSO.33 The reaction
was heated to 100 °C and stirred for 12 h. The solution was
diluted with water, and the aqueous solution was extracted
with Et2O (3 × 40 mL). The organic layers were washed with
water (3 × 5 mL), dried over MgSO4, filtered, and concentrated
in vacuo. Following purification by flash chromatography
using 5% EtOAc/hexane, (R)-8 (769 mg, 87%) was isolated as
a colorless oil: [R]26 -41.7° (c 0.0247, CHCl3). The product
D
1
was identified by comparison of its H NMR data to (S)-8. The
enantiomeric purity of (R)-8 was established by analysis on
the (S,S)-Whelk-O 1 column (0.5% IPA/hexane, 1.25 mL/
min): rt ) 9.1 (100%).
P r ep a r a t ion of 3,7-Dib u t yl-3,7-d ia za b icyclo[3.3.1]-
n on a n e (20). To a solution of butylamine (6.00 g, 82.0 mmol),
K2CO3 (23.0 g, 172 mmol), ethanol (250 mL), and water (125
mL) heated at reflux was added dropwise a solution of
4-methylpiperidone methiodide (29.5 g, 0.115 mol), which was
prepared by the published method.34 The reaction was heated
at reflux for 1.5 h and cooled to room temperature, and the
ethanol was removed in vacuo. The water layer was extracted
with Et2O (3 × 50 mL), and the combined Et2O layers (red
color) were dried over K2CO3. Filtration, concentration in
vacuo, and Kugelrohr distillation (70-85 °C, 0.8 mmHg)
provided 4-butyl-1-piperidone as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ 2.63 (t, J ) 5.8 Hz, 4H), 2.35 (t overlapping
with m, 6H), 1.41 (m, 2H), 1.27 (m, 2H), 0.83 (t, J ) 7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ 209.2, 57.2, 53.1, 41.2, 29.5,
20.6, 14.0. The 13C data are consistent with previously
reported data.35
The conversion of 4-butyl-1-piperidone to 20 was carried out
using a modification of the approach of Smissman and Ruen-
itz.36 To a solution of 4-butyl-1-piperidone (7.36 g, 47.5 mmol)
in ethanol (100 mL) were added butylamine (3.47 g, 47.5 mmol)
and acetic acid (2.70 mL, 47.5 mmol), and the solution was
heated at reflux for 7 h. The ethanol was removed in vacuo
to provide a thick red oil that was treated with 50% KOH (100
mL) and extracted with Et2O (3 × 100 mL). The combined
Et2O layers were dried over Na2SO4, filtered, and concentrated
to provide a red oil that was carried on to the next step without
purification.
The red oil was rinsed into a steel bomb with butanol (100
mL), and anhydrous hydrazine (5.20 mL, 166 mmol) and
potassium tert-butoxide (10.7 g, 95.0 mmol) were added. The
bomb was sealed and heated at 180 °C for 12 h. The reaction
vessel was cooled and the contents poured into a separatory
funnel. The bomb was rinsed with Et2O (200 mL), and the
mixture was separated. The organic layer was washed with
brine (200 mL), and the brine was extracted with Et2O (2 ×
200 mL). The combined organic layers were dried over K2CO3,
filtered, and concentrated to provide a brown oil, which was
distilled (97-100 °C, 0.4 mmHg) to afford 20 (4.87 g, 43% from
4-butyl-1-piperidone) as a colorless oil: 1H NMR (CDCl3, 300
MHz) δ 2.72 (m, 4H), 2.20 (m, 8H), 1.86 (m, 2H), 1.26-1.50
(33) Hutchins, R. O.; Kandasamy, D.; Dux, F.; Maryanoff, C. A.;
Rotstein, D.; Goldsmith, B.; Burgoyne, W.; Cistone, F.; Dalessandro,
J .; Puglis, J . J . Org. Chem. 1978, 43, 2259-2267.
(34) Thompson, M. D.; Holt, E. M.; Berlin, K. D. J . Org. Chem. 1985,
50, 2580-2581.
(35) von Luppen, J .; Lepoivre, J .; Lemie`re, G.; Alderweireldt, F.
Heterocycles 1984, 22, 749-761.
(36) Smissman, E. E.; Ruenitz, P. C. J . Org. Chem. 1976, 41, 1593-
1597.

Asymmetric Deprotonations
J . Org. Chem., Vol. 62, No. 22, 1997 7689
ature was maintained at -78 °C for 2-3 h before quenching
with a 15% NH4Cl solution (5 mL). The aqueous solution was
extracted with Et2O (3 × 10 mL), and the organic layers were
washed with brine (5 mL) or 5% H3PO4 (5 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification of
the crude product mixtures was carried out using flash
chromatography.
Evalu ation of th e Kin etic Isotope Effect for th e Depr o-
ton a tion of 1-(ter t-Bu toxyca r bon yl)in d olin e (1). To a
solution of 1 (126.7 mg, 0.578 mmol) and 2 (173 µL, 0.751
mmol) in MTBE (6 mL) at -78 °C was added s-BuLi (0.58 mL,
1.3 M, 0.75 mmol). The yellow solution was stirred for 3 h,
and then Me2SO4 (82 µL, 0.87 mmol) was added. The solution
was allowed to come to room temperature slowly and stirred
overnight, and the standard workup procedure was used (vide
supra). Following purification by preparative HPLC (1%
EtOAc/hexane), (S)-8 (58.1 mg, 43%) was isolated as a colorless
oil. The enantiomers of (S)-8 were separated on the (S,S)-
Whelk-O 1 column (0.5% IPA/hexane, 1.25 mL/min): rt ) 10.0
(5%), 11.3 (95%). Indoline 22 (20.2 mg, 15%) was isolated as
a colorless oil, and its characterization data matched the
previously reported data. In addition, 8% (10.0 mg) of 1 was
recovered from the reaction.
To a solution of 1a -d1 and 1b-d1 (120.5 mg, 0.550 mmol, 81:
19 ratio determined by 2H NMR, 99% d1) and 2 (164 µL, 0.714
mmol) in MTBE (6 mL) at -78 °C was added s-BuLi (0.55 mL,
1.3 M, 0.71 mmol). The yellow solution was stirred for 3 h,
and then Me2SO4 (78 µL, 0.82 mmol) was added. The solution
was allowed to come to room temperature slowly and stirred
overnight, and the standard workup procedure was used (vide
supra). Following purification by preparative HPLC (1%
EtOAc/hexane), (S)-8-d1 (47.1 mg, 37%) was isolated as a
colorless oil. The enantiomers of (S)-8-d1 were separated on
the (S,S)-Whelk-O 1 column (0.5% IPA/hexane, 1.25 mL/
min): rt ) 10.0 (7%), 11.3 (93%). Indoline 22-d1 (4.0 mg, 3%)
was isolated as a colorless oil, and its deuterium incorporation
was determined to be 86.1% by GC/MS analysis. In addition,
19% (22.6 mg) of 1 was recovered from the reaction.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health GM 18874 and the Na-
tional Science Foundation NSF CHE-95-26355. We are
grateful to Dr. Don Gallagher for the synthesis of achiral
bispidine 20. We are grateful to Professor William
Pirkle for helpful discussions regarding the CSP HPLC
separations of several compounds. We would like to
2
thank Dr. Vera Mainz for help obtaining the H NMR
data.
Su p p or tin g In for m a tion Ava ila ble: The experimental
details for the synthesis of racemic products 3, 5-11, and 13-
17 are available. The characterization data for 7-substituted
products 4, 21-24, and N-Boc-7-carbomethoxyindoline, N-Boc
indole, N-Boc-7-chloroindole, and 2-carbethoxy-7-chloroindole.
The experimental details for the formation of (S)-3 and 4 in
various solvents are reported as well as the details of the tin-
lithium exchange experiments in Table 6. The competition
experiment between 1 and 12 and the transmetalation of 4 in
the presence of 1 are described. The calculation of the kinetic
isotope effect is provided. The 13C and 1H NMR spectra are
provided for those compounds for which no elemental analysis
data were reported (23 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9708856