Enantioselective synthesis of 3,3-disubstituted indolines via asymmetric intramolecular carbolithiation in the presence of (-)-sparteine 1

Article abstract of DOI:10.1055/s-2008-1072630

The functionalized N-benzyl-protected bromoanilines underwent an asymmetric intramolecular carbolithiation in the presence of t-BuLi and (-)-sparteine yielding 3,3-disubstituted indolines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072630

LETTER
1301
Enantioselective Synthesis of 3,3-Disubstituted Indolines via Asymmetric
Intramolecular Carbolithiation in the Presence of (–)-Sparteine1
Enantioselective
S
l
ynthesi
r
s
of 3, 3-
i
D
isubs
c
tituted Indo
h
lines Groth,* Peter Köttgen, Philipp Langenbach, Andreas Lindenmaier, Thorben Schütz, Matthias Wiegand
Fachbereich Chemie, Universität Konstanz, Postfach M-720, Universitätsstr. 10, 78457 Konstanz, Germany
Fax +49(7531)884155; E-mail: Ulrich.groth@uni-konstanz.de
Received 11 January 2008
lines using sterically demanding and highly functional-
ized disubstituted olefins as precursors.11,15
Abstract: The functionalized N-benzyl-protected bromoanilines
underwent an asymmetric intramolecular carbolithiation in the pres-
ence of t-BuLi and (–)-sparteine yielding 3,3-disubstituted indo-
lines.
The benzyl-protected N-methallyl-N-benzyl-2-bromo-
aniline (1a) was selected as the model for optimization of
Key words: asymmetric synthesis, indolines, lithiations, natural the reaction conditions (Scheme 1, R = Me).
products, sparteine
Br
Li
t-BuLi
R
R
3,3-Disubstituted indolines are incorporated in many bio-
logically active compounds and natural products such as
(–)-physostigmin,2 (–)-horsfilin3,4 (Figure 1) and the
spirotryprostatins.5 In the past few years these and other
alkaloids have been interesting and challenging targets for
chemical synthesis.6,7
(–)-sparteine
N
N
Bn
Bn
1a–c
2a–c
R
R
E
Li
E+
N
H
N
N
Bn
Bn
O
O
O
4a–c
3a–c
N
O
HN
Scheme 1
N
H
N
H
Figure 1 (–)-Physostigmin and (–)-horsfilin
Since it has been demonstrated that sparteine shows the
most pronounced effect in nonpolar solvents such as tolu-
ene, special attention was given to the reaction tempera-
ture and reaction time. The best results regarding
chemical yields were obtained, when after bromine–lithi-
um exchange at –80 °C the reaction mixture was allowed
to warm to room temperature. After standard aqueous
NH4Cl workup the N-benzyl-3,3-dimethylindoline (4a)
was obtained in 75% yield (Table 1, entry 1). As byprod-
uct (18%) the N-benzyl-N-methallylaniline was observed
presumably through competitive protonation by the sol-
vent or after workup. In order to determine the enantiose-
lectivity, the organolithium derivative 3a was allowed to
react with DMF. Under these reaction conditions the cor-
responding (1-benzyl-3-methylindolin-3-yl)acetaldehyde
was obtained in 70% chemical yield with 72% ee
(Table 1, entry 1). Next, the intramolecular carbolithia-
tion of N-benzyl-N-isopropylallyl-2-bromoaniline (1b)
was investigated. Under optimized reaction conditions the
indoline 4b was obtained in 69% yield with 80% ee
(Table 1, entry 2). The enantiomeric excess was signifi-
cantly higher, most probably due to the higher steric de-
mand of an isopropyl group compared to a methyl group.
The corresponding phenyl derivative 1c did not undergo
an intramolecular carbolithiation at all (Table 1, entry 3).
Fu et al. presented a new method for generating the qua-
ternary stereocenter in the 3-position of the heterocycle by
enantioselective rearrangement of O-acylated indoles.8 In
2004 Wood et al. used a SmI2-mediated reductive cou-
pling of acrylates with isocyanates to create the stereo-
center in the 3-position.9
Herein we wish to report the first direct and highly enan-
tioselective synthesis of 3,3-disubstituted indolines via a
(–)-sparteine-mediated asymmetric intramolecular carbo-
lithiation process. In the year 2000 we and others de-
scribed the enantioselective synthesis of 3-substituted
indolines via a (–)-sparteine-mediated asymmetric in-
tramolecular carbolithiation process.1,10,11 (–)-Sparteine is
a chiral bidentate ligand with broad applicability.12
Hoppe was the first to use a mixture of alkyllithium and
(–)-sparteine for very effective asymmetric deprotona-
tions.13 Beak examined enantioselective deprotona-
tions of N-Boc-pyrrolidines and N-Boc-allylamines.14
Consequently, we were interested if this strategy could be
employed for the construction of 3,3-disubstituted indo-
SYNLETT 2008, No. 9, pp 1301–1304
x
x.
x
x.
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0
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Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072630; Art ID: G00808ST
© Georg Thieme Verlag Stuttgart · New York

1302
U. Groth et al.
LETTER
Table 1 Carbon-Substituted Indolines
Table 2 Oxygen-Containing Derivatives
Entry 1, R
Temp
(°C)
Time
(h)
Yield of 4 ee of 4
Entry 5, R
Temp
(°C)
Time
(h)
Yield (%) ee (%)
(%)
75
69
0
(%)
72a
80
–
of 6
33
81
34
57
30
of 6
30
88
93
60
72
1
2
3
1a, Me
25
25
25
3
14
10
1
2
3
4
5
5a, OH
–80
–80
–80
25
20
14
8
1b, i-Pr
1c, Ph
5b, OMe
5c, OTHP
a Yield of the reaction when quenched with DMF.
5d, OTIPS
5e, (CH2)2OMe
3.5
6
25
Since a lithium organic compound (2) is formed after
halogen–metal exchange, this lithium organic compound
might be stabilized and put in a more rigid, sterically sta-
ble complex with the assistance of a chelating donor in the
side chain of the allylic moiety. Therefore, the N-allyl-N-
benzyl-2-bromoanilines 5a–e were prepared [R = OH,
OMe, OTHP, OTIPS, (CH2)2OMe; Scheme 2] and their
intramolecular carbolithiation was studied. Deprotonation
of N-allyl-N-benzyl-2-bromoaniline (5a) with two equiv-
alents of t-BuLi afforded the bisanion which after aqueous
workup gave the indoline 6a in 33% yield with 30% ee
(Table 2, entry 1).16,17 Once again the main product was
the debrominated starting material obtained by protona-
tion of the lithiated intermediate. Therefore we decided to
protect the hydroxyl group with various protecting groups
which were different in their steric demand. Good results
were obtained with the methyl-protected compound 5b af-
fording indoline 6b (Table 2, entry 2). The effect of the
chelating donor was significant since the enantioselectiv-
ity could be enhanced from 72% ee to 88% ee compared
with 4a whereas the yield was similar to that of 4a (81%
instead of 75%).
Table 3 Sulfur- and Nitrogen-Containing Derivatives
Entry 5, R
Temp
(°C)
Time Yield (%)
ee (%)
of 6
(h)
12
10
14
of 6
1
2
3
5f, SPh
–80
–80
–80
75
87
5g, SMe
81
91
5h, NMe2
83
85
Indolines 6f–h could be used as intermediates in natural
product synthesis.
The N-benzyl-N-methallyl-2-bromoanilines 1a–c and 5a–
h were also cyclized in the presence of TMEDA instead
of (–)-sparteine to afford racemic indolines 4a–c and 6a–
h. The yields were comparable or even higher and the re-
actions could be performed at lower temperatures.
The enantiomeric excesses were determined as follows:
Indoline 6b was demethylated with BBr3 to indoline 6a.
Indolines 6c,d were deprotected to compound 6a by treat-
ment with HCl in MeOH. Enantiomeric excesses of indo-
lines 6a,f,g,h were determined by NMR experiments
using (–)-binaphthylphosphoric acid as chiral solvating
agent.18 Indolines 4a,b, and 6e were debenzylated by
treatment with 1-chloroethyl chloroformate, sodium io-
dide, and acetone followed by methanol.19 Enantiomeric
excesses were determined by chiral GC–MS.20
When the side chain was extended by two CH2 groups
(Table 2, entry 5) the enantioselectivity was comparable
with that obtained for the unsubstituted methyl derivative
4a, while the chemical yield was low. In this case no
chelating effects was observed.
R
R
In order to determine the absolute configuration of the
generated quaternary stereocenter we synthesized a
known compound, which is the major intermediate to-
wards the synthesis of physostigmin, which was prepared
enantioselectively by Overman and co-workers.21 After
the synthesis of the cyclization precursor 8 from the readi-
ly available p-anisidine (7) the indoline core was generat-
ed by intramolecular carbolithiation by treatment with
t-BuLi in the presence of (–)-sparteine. The lithium inter-
mediate was trapped with DMF and the desired aldehyde
9 was isolated and subsequently protected as its acetal.
Oxidation to the 2-oxoindole 10 by Hg(OAc)2–EDTA22
and deprotection yielded the desired product 11 with an
enantiomeric excess of 60%, the negative sign of the opti-
cal rotary power revealed R-configuration of the starting
indoline 9 (Scheme 3).
Br
a, b
N
N
Bn
Bn
5a–h
6a–h
Scheme 2 Reagents and conditions: (a) t-BuLi, (–)-sparteine, tolu-
ene; (b) MeOH.
The sulfur- and nitrogen-substituted anilines 5f–h
(Scheme 2, R = CH2SPh, CH2SMe, CH2NMe2) also
showed significant chelating effects which were compara-
ble to the methoxy or OTHP group (Table 3).
The dimethylamino derivative 6h was obtained in 83%
yield with 85% ee (Table 3, entry 3) whereas the yield for
the benzylmethylamino derivative was very low (22%).
In summary, we have developed the first method for direct
and highly enantioselective synthesis of 3,3-disubstituted
indolines via a (–)-sparteine-mediated asymmetric in-
Synlett 2008, No. 9, 1301–1304 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of 3,3-Disubstituted Indolines
1303
O
MeO
MeO
MeO
Br
a–c
d
N
NH2
N
7
9
8
e, f
O
O
O
MeO
MeO
g
O
O
N
N
11
10
Scheme 3 Reagents and conditions: (a) Br2, AcOH, 3 h, 35%; (b) n-BuLi, MeI, 3 h, 60%; (c) methallyl chloride, K2CO3, 90%; (d) (–)-spar-
teine, t-BuLi, 20 h, then DMF, 31%, 60% ee; (e) MeOH, p-TsOH, 82%; (f) Hg(OAc)2, EDTA, 48%; (g) amberlyst-15, acetone, 24 h, 68%.
(9) Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss, M. M.;
Tamaki, K.; Ovaska, T. V.; Wood, J. L. Angew. Chem. Int.
Ed. 2004, 43, 1270; Angew. Chem. 2004, 116, 1290.
(10) (a) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122,
6787. (b) Sanz Gil, G.; Groth, U. M. J. Am. Chem. Soc.
2000, 122, 6789.
tramolecular carbolithiation process. As substituents at
the aromatic system do not effect the cyclization and it is
possible to trap the lithium organic species 3 with other
electrophiles, significant utility and broad application of
the present methodology may be anticipated.
(11) For recent articles on (intramolecular) carbolithiations, see:
(a) Oestreich, M.; Hoppe, D. Tetrahedron Lett. 1999, 40,
1881. (b) Marek, I. J. Chem. Soc., Perkin Trans. 1 1999,
535. (c) Laqua, H.; Frohlich, R.; Wibbeling, B.; Hoppe, D.
J. Organomet. Chem. 2001, 624, 96. (d) Rychnovsky, S. D.;
Hata, T.; Kim, A. I.; Buckmelter, A. J. Org. Lett. 2001, 3,
807. (e) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem.
2002, 646, 59. (f) Bailey, W. F.; Luderer, M. R.; Mealy, M.
J. Tetrahedron Lett. 2003, 44, 5303. (g) Barluenga, J.;
Fananas, F. J.; Sanz, R.; Marcos, C. Chem. Eur. J. 2005, 11,
5397.
Acknowledgment
The authors are thankful to the Merck KGaA and the Wacker AG
for generous gifts of reagents. T.S. thanks the Konrad-Adenauer-
Stiftung for a PhD fellowship.
References and Notes
(1) Asymmetric Carbolithiations, Part II; for part I, see
reference 10b.
(2) Yu, Q. S.; Atack, J. R.; Rapoport, S. I.; Brossi, A. J. Med.
Chem. 1988, 31, 2297.
(3) Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B.
J. Org. Chem. 1991, 56, 6527.
(4) Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.;
Flower, K.; Vit, I.; Willing, R. I. Phytochemistry 1998, 48,
437.
(5) Cui, C.-B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52,
12651.
(6) For an overview, see: (a) Somei, M.; Yamada, F. Nat. Prod.
Rep. 2005, 22, 73. (b) Kawasaki, T.; Higuchi, K. Nat. Prod.
Rep. 2005, 22, 761. (c) Borschberg, H.-J. Curr. Org. Chem.
2005, 9, 1465.
(7) Some recent examples. Horsfiline: (a) Trost, B. M.;
Brennan, M. K. Org. Lett. 2006, 8, 2027. (b) Murphy, J. A.;
Tripoli, R.; Khan, T. A.; Mali, U. W. Org. Lett. 2005, 7,
3287. (c) Chang, M.-Y.; Pai, C.-L.; Kung, Y.-H.
Tetrahedron Lett. 2005, 46, 8463. Physostigmin: (d) Trost,
B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
(e) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani, A. Org.
Lett. 2006, 8, 83. (f) Santos, P. F.; Srinivasan, N.; Almeida,
P. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005, 61,
9147. Spirotryprostatins: (g) Marti, C.; Carreira, E. M.
J. Am. Chem. Soc. 2005, 127, 11505. (h) Miyake, F. Y.;
Yakushijin, K.; Horne, D. A. Angew. Chem. Int. Ed. 2004,
43, 5357. (i) Onishi, T.; Sebahar, P. R.; Williams, R. M.
Org. Lett. 2003, 5, 3135.
(12) Schütz, T. Synlett 2003, 901.
(13) (a) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl.
1989, 28, 69; Angew. Chem. 1989, 101, 67. (b) Hoppe, D.;
Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl. 1990,
29, 1422; Angew. Chem. 1990, 102, 1457. (c) Hoppe, D. In
Encyclopedia of Reagents for Organic Synthesis, Vol. 7;
Paquette, L. A., Ed.; Wiley: Chichester, 1995, 4662–4664.
(d) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 2282; Angew. Chem. 1997, 109, 2376. (e) Özlügedik,
M.; Kristensen, J.; Wibbeling, B.; Fröhlich, R.; Hoppe, D.
Eur. J. Org. Chem. 2002, 414. (f) Hoppe, D. In Topics in
Organometallic Chemistry, Vol. 5; Hodgson, D. M., Ed.;
Springer: Heidelberg, 2003, 61–138.
(14) (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113,
9708. (b) Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc.
1996, 118, 12218. (c) Beak, P.; Basu, A.; Gallagher, D. J.;
Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29,
552. (d) Basu, A.; Thayumanavan, S. Angew. Chem. Int. Ed.
2002, 41, 716; Angew. Chem. 2002, 114, 740.
(15) (a) Normant, J. F. Top. Organomet. Chem. 2003, 5, 287.
(b) Najera, C.; Sansano, J. M.; Yus, M. Tetrahedron 2003,
59, 9255. (c) Sotomayor, N.; Lete, E. Curr. Org. Chem.
2003, 7, 275.
(16) General Procedure for the Carbolithiation: All
experiments were carried out under an argon atmosphere
using Schlenk techniques. A solution of substrate 5 (0.83
mmol) and (–)-sparteine (1.5 equiv) in toluene (10 mL) was
cooled to –78 °C and t-BuLi (2.2 equiv, 1.5 M in pentane)
was added. The reaction mixture was stirred for 16 h at this
temperature. MeOH (5 mL) was added to quench the lithium
(8) Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 3921;
Angew. Chem. 2003, 115, 4051.
Synlett 2008, No. 9, 1301–1304 © Thieme Stuttgart · New York

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U. Groth et al.
LETTER
intermediate. After addition of sat. NH4Cl solution (10 mL)
and H2O (10 mL) the aqueous layer was extracted using
EtOAc (3 × 30 mL). The combined organic phases were
dried (MgSO4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography
to give the desired indoline 6.
CDCl3): d = 25.1, 25.9, 37.2, 43.3, 53.1, 58.5, 65.7, 73.2,
106.9, 117.6, 122.5, 127.1, 127.6, 127.8, 128.5, 137.4,
138.6, 151.5. MS (EI, 70 eV): m/z = 295 [M+], 222 [M +
+
CH2CH2CH2OMe], 91 [C7H7 ].
Compound 6g: [a]D20 +21.3° (c = 0.92, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d = 1.37 (s, 3 H, CMe), 2.02 (s, 3 H,
SMe), 2.73, 2.78 (2 × d, J = 12.8 Hz, 2 × 1 H, CH2SMe),
3.02, 3.38 [2 × d, J = 9.0 Hz, 2 × 1 H, N(Bn)CH2], 4.18, 4.33
(2 × d, J = 14.8 Hz, 2 × 1 H, NCH2Ph), 6.50 (d, J = 7.8 Hz,
1 H, ArH), 6.70 (t, J = 7.4 Hz, 1 H, ArH), 7.06–7.09 (m, 2 H,
ArH), 7.24–7.37 (m, 5 H, ArH). 13C NMR (100.6 MHz,
CDCl3): d = 17.9 (CMe), 24.3 (SMe), 45.0 (CMe), 45.7
(CH2SMe), 52.9 (CH2Ph), 64.9 [N(Bn)CH2], 107.2, 117.7,
122.6, 127.1, 127.8, 128.1, 128.5 (7 × CHArH), 136.3
(Cq,ArH), 138.3, 151.2 (CqN). GC–MS (EI, 70 eV): m/z = 283
(17) All products have been fully characterized by 1H NMR and
13C NMR. The analyses of known compounds are in
agreement with the published data. The characteristics of
selected compounds are as follows:
Compound 6b: [a]D20 +32.4° (c = 1.15, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d = 1.34 (s, 3 H, CMe), 3.01, 3.39 [2 ×
d, J = 8.2 Hz, 2 × 1 H, N(Bn)CH2], 3.33 (s, 3 H, OMe), 3.35,
3.59 (2 × d, JAB = 10 Hz, 2 H, CH2OMe), 4.24, 4.31 (2 × d,
J = 15.0 Hz, 2 × 1 H, NCH2Ph), 6.49 (d, J = 7.8 Hz, 1 H,
ArH), 6.68 (t, J = 7.4 Hz, 1 H, ArH), 7.03–7.10 (m, 2 H,
ArH), 7.24–7.35 (m, 5 H, ArH). 13C NMR (100.6 MHz,
CDCl3): d = 22.8 (CMe), 44.9 (CMe), 52.7 (CH2Ph), 59.3
(OMe), 63.1 [N(Bn)CH2], 79.0 (CH2O), 106.9, 117.5, 122.9,
127.0, 127.7, 128.0, 128.4 (7 × CHAr), 135.0 (CMeCAr),
138.4 (Cq,Ph), 151.5 (NCAr). MS (EI, 70 eV): m/z = 267 [M+],
+
[M+], 222 [M+ – CH2 – SMe], 91 [C7H7 ]. Anal. Calcd for
C18H21NS: C, 76.28; H, 7.47; N, 4.94. Found: C, 76.20; H,
7.47; N, 5.29.
(18) Shapiro, M. J.; Archinal, A. E.; Jarema, M. A. J. Org. Chem.
1989, 54, 5826.
(19) (a) Olofson, R. A.; Abbott, D. E. J. Org. Chem. 1984, 49,
2795. (b) Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau,
M.; Malfroot, T. J. Org. Chem. 1984, 49, 2081.
(c) Olofson, R. A. Pure Appl. Chem. 1988, 60, 1715.
(20) Enantiomeric excess was determined using a HP 6890 Series
GC System with a chiral column CycloSil-B (J&W
Scientific).
(21) (a) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J.
J. Org. Chem. 1993, 58, 6949. (b) Matsuura, T.; Overman,
L. E.; Poom, D. J. J. Am. Chem. Soc. 1998, 120, 6500.
(22) Wenkert, E.; Angell, E. C. Synth. Commun. 1988, 18, 1331.
+
222 [M+ – CH2 – OMe], 91 [C7H7 ]. IR (film): 3026, 2922,
2869, 2823, 1605, 1494, 1453, 1118 cm–1. Anal. Calcd for
C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.60; H,
7.82; N, 5.20.
Compound 6e: [a]D20 +19.6° (c = 0.52, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d = 1.28 (s, 3 H, CMe), 1.42–1.78 (m,
2 × 2 H, CH2CH2CH2OMe), 3.00, 3.18 (2 × d, J = 8.6 Hz,
2 × 1 H, NCH2CMe), 3.27 (s, 3 H, OMe), 3.30 (t, J = 7.8 Hz,
2 H, CH2OMe), 4.17, 4.29 (2 × d, J = 15.2 Hz, 2 × 1 H,
NCH2Ph), 6.47 (d, J = 7.8 Hz, 1 H, ArH), 6.64–6.69 (m, 2 H,
ArH), 6.98–7.34 (m, 6 H, ArH). 13C NMR (100.6 MHz,
Synlett 2008, No. 9, 1301–1304 © Thieme Stuttgart · New York

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