Asymmetric cascade reaction sequences via chiral lithiated intermediates

Article abstract of DOI:10.1021/jo702290f

(Chemical Equation Presented) The (-)-sparteine-mediated enantioselective intermolecular carbolithiation of (E)-2-propenylarylamines allows for the generation of chiral lithiated intermediates which have broad synthetic potential. These intermediates have been exploited in a series of further in situ reactions with electrophiles to generate a collection of products each containing a common stereogenic center. The stereogenic center, formed in high enantiomeric ratio in the first carbolithiation step, is carried through the cascade reaction sequence to the final products and is independent of electrophile used. The methodology is demonstrated by the synthesis of structurally diverse chiral anilines, indoles, and indolones all with an er of 92:8 (±1). The heterocyclic syntheses involve an enantioselective alkene carbolithiation and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole or indolone rings.

Full text of DOI:10.1021/jo702290f

Asymmetric Cascade Reaction Sequences via Chiral Lithiated
Intermediates
Anne-Marie L. Hogan and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,
UniVersity College Dublin, Belfield, Dublin 4, Ireland
donal.f.oshea@ucd.ie
ReceiVed October 23, 2007
The (-)-sparteine-mediated enantioselective intermolecular carbolithiation of (E)-2-propenylarylamines
allows for the generation of chiral lithiated intermediates which have broad synthetic potential. These
intermediates have been exploited in a series of further in situ reactions with electrophiles to generate a
collection of products each containing a common stereogenic center. The stereogenic center, formed in
high enantiomeric ratio in the first carbolithiation step, is carried through the cascade reaction sequence
to the final products and is independent of electrophile used. The methodology is demonstrated by the
synthesis of structurally diverse chiral anilines, indoles, and indolones all with an er of 92:8 ((1). The
heterocyclic syntheses involve an enantioselective alkene carbolithiation and subsequent trapping of the
intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration
to generate the indole or indolone rings.
SCHEME 1. Product Independent Enantioselectivities
Introduction
The facile generation of chiral intermediates which could be
utilized in a range of further in situ transformations to produce
a diverse collection of chiral products is synthetically attractive.
For example, the reaction of substrate A with reagent B,
mediated by a chiral source, could generate a reactive chiral
intermediate [A-B]*, which could be in situ converted to chiral
products (P*1-n) by subsequent reaction with additional reagents
C1-n (Scheme 1). Advantageously, all products derived from
this intermediate would be generated with identical selectivity
provided the stereogenic center in [A-B]* is configurationally
stable. This approach could be anticipated to have application
to combinatorial library generation.
products can be readily obtained. Alkene carbolithiation provides
a practical methodology for this as it allows the construction
of a new C-C bond and organolithium center in a single
transformation.1 In addition, the carbolithiation of 1,2-disub-
(1) (a) Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem. Soc.
1969, 91, 6362. (b) Bartlett, P. D.; Friedman, S.; Stiles, M. J. Am. Chem.
Soc. 1953, 75, 1771. (c) Ziegler, K.; Gellert, H. G. Justus Liebigs Ann.
Chem. 1950, 567, 195. (d) Clayden. J. Organolithiums: SelectiVity for
Synthesis; Pergamon Press: Oxford, U.K., 2002; pp 273-335.
The key to a successful implementation of this approach is
the enantioselective generation of a reactive intermediate of
broad synthetic potential from which a collection of chiral
10.1021/jo702290f CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/01/2008
J. Org. Chem. 2008, 73, 2503-2509
2503

Hogan and O’Shea
SCHEME 3. Contrasting Approaches to Chiral C-3
SCHEME 2. Enantioselective Carbolithiation of
â-Methylstyrene
Substituted Indoles
stituted alkenes generates an organolithium intermediate with
two contiguous stereocenters.2 For example, the enantioselective
carbolithiation of the 1,2-disubstituted alkene â-methylstyrene
1 with n-BuLi has been previously reported utilizing (-)-
sparteine to induce asymmetry in the product.3 Following
protonation of the lithiated intermediate 2, 2-methylhexylben-
zene 3 was isolated in good yield and er (Scheme 2). In this
case, the chiral center created as a result of the C-C bond
formation is configurationally stable, but the benzylic C-Li
center has low configurational stability.4 Our goal was to exploit
a related carbolithiation reaction to provide one configurationally
stable stereogenic center which would be incorporated into all
products and utilize in situ reaction with electrophiles at the
C-Li center to allow access to a collection of products. It is
noteworthy that enantioselective substitution of configurationally
unstable benzylic lithium centers is achievable via kinetic or
thermodynamic resolution.5
To maximize synthetic potential of the intermediate, we chose
to investigate o-substituted â-methylstyrenes as our starting
substrates, therefore allowing the opportunity for the o-sub-
stituent to participate in further in situ steps. Specifically, one
application of this methodology to o-amino â-methylstyrenes
would provide a new route to the indole scaffold 4 with a chiral
substituent at C-3 (Scheme 3).6 Synthesis of this structural motif
is attractive as a demonstration of this concept due to its
prominence in many natural products and medicinal chemistry
targets.7 The known approach to such a structure entails a
Friedel-Crafts alkylation of a presynthesized indole ring with
an activated C-C double bond (disconnection (i), Scheme 3).
Recent examples include the Sc(OTf)3-pybox-controlled reaction
with acyl phosphonates,8 reaction of bis(oxazoline)-Cu(OTf)2
with R′-hydroxy enones,9 and the use of an imidazolidinone in
conjunction with R,â-unsaturated aldehydes.10 Both metal- and
organo-catalyzed methodologies have resulted in the successful
synthesis of this scaffold in high yields and enantioselectivities.
Our proposed methodology differs from the previous ap-
proaches in the order of bond formation. The first step involves
asymmetric carbolithiation of the prochiral substrate 5 to provide
lithiated intermediate 6 containing the key stereogenic center.
Following reaction with specific electrophiles, a subsequent
reaction sequence could occur between the reacted electrophile
and o-substituent, facilitating an in situ ring closure to generate
indole 4.11 This sequence of bond formation also allows for the
inclusion of further substituent diversity (R3) from the electro-
phile. Previous reports from our laboratory have shown that a
carbolithiation/electrophile reaction sequence can be employed
for the synthesis of achiral indoles, 7-azaindoles and quinolines
from o-substituted styrenes, vinylpyridines, and stilbenes,
respectively.12
Results and Discussion
The starting substrates 5a-d were screened to determine the
effect of o-substituents upon carbolithiation selectivity (see the
Supporting Information for preparation). To assist cross-
comparison of results, a uniform set of previously optimized
reaction conditions were employed as follows: 1 equiv of PhLi
to ensure complete NH deprotonation, followed by 2 equiv of
n-BuLi and 3 equiv of (-)-sparteine at -15 °C for 4 h.6 In
addition, the influence of two solvent conditions (non-coordinat-
ing and coordinating) was investigated by duplicating the
reactions in the hydrocarbon cumene and diethyl ether. Fol-
lowing carbolithiation of 5a-d with n-BuLi, the intermediate
(2) Normant, J. F. Top. Organomet. Chem. 2003, 5, 287.
(3) (a) Norsikian, S.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1997,
38, 7523. (b) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant,
J. F. Chem. Eur. J. 1999, 5, 2055.
(4) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6079.
(5) (a) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel,
D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715. (b) Wei, X.;
Taylor, R. J. K. Tetrahedron: Asymmetry 1997, 8, 665.
(6) For preliminary report, see: Hogan, A.-M. L.; O’Shea, D. F. J. Am.
Chem. Soc. 2006, 128, 10360.
(7) (a) Rawson, D. J.; Dack, K. N.; Dickinson, R. P.; James, K. Biorg.
Med. Chem. Lett. 2002, 12, 125. (b) Chang-Fong, J.; Rangisetty, J. B.; Dukat,
M.; Setola, V.; Raffay, T.; Roth, B.; Glennon, R. Biorg. Med. Chem. Lett.
2004, 14, 1961. (c) Christian, O. E.; Compton, J.; Christian, K. R.;
Mooberry, S. L.; Valeriote, F. A.; Crews, P. J. Nat. Prod. 2005, 68, 1592.
(8) (a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu,
J. J. Am. Chem. Soc. 2003, 125, 10780. (b) Evans, D. A.; Fandrick, K. R.;
Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942.
(11) For examples of heterocycle synthesis via asymmetric intramolecular
carbolithiation, see: (a) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am.
Chem. Soc. 1996, 118, 5322. (b) Hoppe, D.; Hense, T. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2282. (c) Bailey, W. F.; Mealy, M. J. J. Am. Chem.
Soc. 2000, 122, 6787. (d) Sanz Gil, G.; Groth, U. M. J. Am. Chem. Soc.
2000, 122, 6789. (e) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem.
2002, 646, 59 (review). (f) Barluenga, J.; Fan˜ana´s, F. J.; Sanz, R.; Marcos,
C. Chem. Eur. J. 2005, 11, 5397.
(12) (a) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125,
4054. (b) Kessler, A.; Coleman, C. M.; Charoenying, P.; O’Shea, D. F. J.
Org. Chem. 2004, 69, 7836. (c) Cottineau, B.; O’Shea, D. F. Tetrahedron
Lett. 2005, 46, 1935. (d) Hogan, A.-M. L.; O’Shea, D. F. Org. Lett. 2006,
8, 3769. (e) McKinley, N. F.; O’Shea, D. F. J. Org. Chem. 2006, 71, 9552.
(f) Cotter, J.; Hogan, A.-M. L.; O’Shea, D. F. Org. Lett. 2007, 9, 1493. (g)
Cottineau, B.; O’Shea, D. F. Tetrahedron 2007, 63, 10354. (h) Hogan,
A.-M. L.; O’Shea, D. F. J. Org. Chem. 2007, 72, 9557.
(9) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A.
J. Am. Chem. Soc. 2005, 127, 4154.
(10) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172.
2504 J. Org. Chem., Vol. 73, No. 7, 2008

Applications of EnantioselectiVe Carbolithiations
TABLE 1. Carbolithiation of 5a-d
SCHEME 4. Carbolithiation of 8
entry
sm
R1
solvent
product
yield,a %
erb (S/R)
good (Bn) selectivity group within the same molecule (Scheme
4, Supporting Information). Carbolithiation of 8 with n-BuLi/
(-)-sparteine, followed by treatment of the lithiated intermediate
with MeOH gave compound 9 in unoptimized yields of 51%
and 30% from reaction in cumene and diethyl ether respectively.
Hydrogenation of the benzyl group provided 7b for er deter-
mination (Scheme 4). In both solvents, 9 was obtained with an
identical er of 86:14 (S/R), only marginally inferior to that of
N-benzyl derivative 7d. Therefore, it could be concluded that
the N-benzyl group is optimal for achieving high enantioselec-
tivity, yet the presence of the lithium amide does not appear to
be essential.
1
2
3
4
5
6
7
8
5a
5a
5b
5b
5c
5c
5d
5d
Boc
Boc
Me
Me
Et
Et
Bn
Bn
cumene
Et2O
cumene
Et2O
cumene
Et2O
cumene
Et2O
7a
7a
7b
7b
7c
7c
7d
7d
57
53:47
57:43
62:38
63:37
50:50
52:48
92:8
39c
60
40d
47e
30f
89
65
92:8
a Isolated purified yield. b Determined by chiral HPLC and compared to
the racemic product generated with TMEDA as additive. c Starting material
recovered in 36% yield. d Starting material recovered in 53% yield. e Starting
material recovered in 21% yield. f Starting material recovered in 53% yield.
In order to confirm (-)-sparteine as the optimal agent for
promoting enantioselective carbolithiation of 5d, we screened
a selection of known chiral amines and amino alcohols as
potential ligands for the reaction. The ligands tested included
lithium alkoxides 10, 11, and 12,14 lithium amides 13 and 14,15
binaphthal 15,16 and bisoxazoline 16,17 all of which have
previously been successfully employed in organolithium trans-
formations (Figure 1).
organolithium species 6a-d were treated with methanol,
generating the substituted 2-(methylhexyl)phenylamines 7a-d
and providing a convenient method of determining the selectivity
of the reaction (Table 1). As expected, the o-substituent had a
significant impact as the selectivities ranged from very poor
for the N-Boc and N-alkyl analogues 7a-c (Table 1, entries
1-6) to a high er of 92:8 for the N-benzyl substituted 7d.
Encouragingly, an identical er of 92:8 was obtained for
carbolithiation of 5d using either cumene or diethyl ether as
the reaction solvent with 7d isolated in yields of 89 and 65%
respectively (entries 7 and 8). This solvent independent selectiv-
ity contrasts with other studies of enantioselective intermolecular
carbolithiation reactions in which a hydrocarbon solvent is
essential to achieve optimal er.3 The absolute configuration of
the stereocenter was determined by conversion of 7d to
3-methylheptanoic acid, via NaIO4/RuCl3 mediated oxidation
and comparison of the optical rotation with that reported for
the enantiopure compound (Supporting Information).13
The results in Table 1 indicate the influence of a combination
of factors on the enantioselectivity of the reaction, including a
steric effect and the coordinating ability of the o-substituent.
Use of the stronger coordinating N-Boc group as the o-sub-
stituent had a detrimental effect on the reaction selectivity, as
did the N-alkyl substituted derivatives 5b,c. Interestingly, the
highest selectivity was recorded from the reaction with the
N-benzyl derivative 5d, which is more sterically demanding than
the other alkyl substituents tested. As the lithium amide formed
from the deprotonation of 5d (prior to carbolithiation) could
exist in solution as a monomer or dimer, a further study was
carried out to investigate if this amide was essential to obtaining
a high er. The tertiary amine 8 provided a suitable substrate for
this investigation as it eliminates the lithium amide from the
reaction sequence and combines the effects of a poor (Me) and
FIGURE 1. Chiral Ligand Screening.
Under our standard set of reaction conditions, the only
alternative ligand which resulted in product formation was
lithium amide 14 derived from [S-(R,R)]-(-)-bis(R-methylben-
zyl)amine, which facilitated the generation of 7d in a low 9%
yield with respectable enantioselectivity of 13:87 (S/R) er. For
(14) (a) Fort, Y.; Gros, P.; Rodriguez, A. L. Tetrahedron: Asymmetry
2001, 12, 2631. (b) Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002, 3375. (c)
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124,
773. (d) Coldham, I.; Dufour, S.; Haxell, T. F. N.; Patel, J.; Sanchez-Jimenez,
G. J. Am. Chem. Soc. 2006, 128, 10943.
(15) (a) Mun˜oz-Mun˜iz, O.; Juaristi, E. Tetrahedron 2003, 59, 4223. (b)
Burton, A. J.; Graham, J. P.; Simpkins, N. S. Synlett 2000, 1640.
(16) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111,
8266.
(17) Hodgson, D. M.; Lee, G. P.; Marriott, R. E.; Thompson, A. J.;
Wisedale, R.; Witherington, J. J. Chem. Soc., Perkin Trans. 1 1998, 2151.
(13) Meyers, A. I.; Kamata, K. J. Org. Chem. 1974, 39, 1603.
J. Org. Chem, Vol. 73, No. 7, 2008 2505

Hogan and O’Shea
TABLE 2. Carbolithiation of Aryl Substituted Derivatives
SCHEME 5. Diverse Product Set from 6d
entry
sm
R1
R2
Et
n-Hex
n-Bu
n-Bu
n-Hex
product
yield,a %
erb
1
2
3
4
5
5d
5d
5e
5f
H
H
OCH3
7e
7f
7g
7h
7i
52
76
60
63
61
93:7
92:8
ndc
92:8
93:7
F
F
5f
a Isolated purified yield. b Determined by HPLC and compared to the
racemic product generated with TMEDA as additive. c Chiral HPLC
separation not achieved.
all other ligands tested starting material was recovered following
reaction workup. Thus, the results of the ligand screen highlight
the exceptional complementary relationship of carbolithiation
reactions with (-)-sparteine and justifies its selection.18
In order to further explore the scope of the carbolithiation
reaction we investigated the consequence of variation in
alkyllithium and aryl substituents on the starting substrates 5d-f
upon reaction outcome. Application of both EtLi and n-HexLi
to the carbolithiation of 5d resulted in the formation of products
7e and 7f with the same high er as the n-Bu example (entries
1 and 2, Table 2). The carbolithiation reaction was also
successful for both electron donating and electron withdrawing
substituents in the aromatic ring of the substrates 5e,f (entries
3-5, Table 2). Introduction of a methoxy group at the para
position led to the isolation of 7g in 60% yield and although
chiral HPLC separation was not achieved for this example, a
comparable er to that of 7d was observed when an alternative
electrophile was employed (see entries 9 and 10, Table 3).
Carbolithiation of the 4-fluoro derivative 5f with both n-Bu and
n-HexLi yielded the expected products 7h and 7i in respectable
yields and high er’s of 92:8 and 93:7, respectively (entries 4
and 5).
dehydration and protonation of the alkoxide generating an alkyl
alcohol at C-2. The use of CO2 as the electrophile allows
synthetic access to the indolone ring 18a following acid induced
ring closure and dehydration. The one-pot production of this
diverse product set of chiral anilines, indoles and indolones from
a common starting material and chiral mediator highlights the
advantage of this approach.
TABLE 3. Synthesis of 1,3-, 1,2,3-, 1,3,5-, and 1,2,3,5-Substituted
Indoles
entry
R1
R2
R3
product yield,a %
erb
Having established optimized conditions for chiral organo-
lithium intermediate formation, the next goal was to exploit these
compounds by reaction with a series of electrophiles thereby
generating a diverse product set with a common er (Scheme
5). For example, starting from intermediate 6d, the synthesis
of aniline 7d, 1,3- and 1,2,3-substituted indoles 17a-f, or
indolone 18a was achieved by reaction with the electrophiles
methanol, DMF, N-methoxy-N-methylacetamide, 2,2-dimeth-
ylpropionitrile, benzonitrile, 2,2-diethoxypropionitrile, γ-buty-
rolactone, and CO2, respectively (Scheme 5). Since all products
are generated from a common chiral intermediate 6d, all have
an identical er of 92:8 ((1), within experimental error (Table
1, entry 7; Table 3, entries 1-6; Table 4, entry 1). For indole
synthesis, the substituent at C-2 on the ring is determined by
the choice of electrophile. Thus, DMF generates an indole which
is unsubstituted at C-2, while alkyl or aryl substituents can be
introduced at this position using a Weinreb base or a nitrile as
the electrophile. When 2,2-diethoxypropionitrile was used as
electrophile, acidification resulted in cyclization, dehydration
and deprotection of the acetal to provide a ketone at C-2. The
organolithium intermediate causes ring opening of γ-butyro-
lactone, which following acidification undergoes cyclization,
1
2
3
4
5
6
7
8
9
6d
6d
6d
6d
6d
6d
6e
6f
H
H
H
H
H
H
H
H
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Et
H
17a
17b
17c
17d
17e
17f
17g
17h
17i
60
30c
50
38
51
45
40
58
43
31
15f
92:8
93:7d
91:9
93:7
92:8
92:8
nde
92:8
93:7
92:8
92:8
CH3
t-Bu
Ph
COCH3
(CH2)3OH
H
n-Hex
H
H
6g OCH3 n-Bu
6g OCH3 n-Bu
6h
10
11
(CH2)3OH
(CH2)2CH-
(CH3)OH
17j
17k
F
n-Bu
12
6i
F
n-Hex COCH3
17l
37
91:9
a Isolated purified yield. b Determined by HPLC and compared with
racemic sample generated with TMEDA as additive. c Compound 7d was
also isolated in 62% yield. d An increased er of 99:1 was obtained after
one recrystallization from pentane. e Chiral HPLC separation not achieved.
f Compound 7h was also isolated in 77% yield.
The carbolithiation initiated cascade reaction sequence is also
tolerant to variations in alkyllithium, with both Et and n-HexLi
successfully employed (Table 3, entries 7, 8, and 12). In
addition, methoxy and fluoro substituents have been included
in the aryl ring without affecting the er of the indole products
17i-l (Table 3, entries 9-12). Introduction of an alkyl alcohol
at C-2, by employing γ-butyrolactone as the electrophile, gave
indole 17j in 31% yield and 92:8 er. Carbolithiation of fluoro-
(18) Mealy, M. J.; Ludered, M. R.; Bailey, W. F.; Sommer, M. B. J.
Org. Chem. 2004, 69, 6042.
2506 J. Org. Chem., Vol. 73, No. 7, 2008

Applications of EnantioselectiVe Carbolithiations
TABLE 4. Indolone Synthesis
o-substituted â-methylstyrenes is currently underway and will
be reported in due course.
Experimental Section
Representative Synthesis of Anilines 7.
Benzyl-[4-fluoro-2-(2-methylhexyl)phenyl]amine, 7h. PhLi
(0.30 mL, 0.51 mmol) was added to a solution of 5f (121.9 mg,
0.51 mmol) in cumene (2 mL) and stirred at room temperature for
15 min. This solution was added dropwise, over 15 min, to a
premixed solution of n-BuLi (0.47 mL, 1.03 mmol) and (-)-
sparteine (0.35 mL, 1.52 mmol) in cumene (2 mL) at -15 °C. The
mixture was stirred at -15 °C for a further 4 h and treated with
methanol (1 mL). The reaction mixture was washed with HCl (aq)
(1 M, 10 mL) and the aqueous layer extracted with diethyl ether
(2 × 10 mL). The combined organic layers were dried over sodium
sulfate and concentrated to dryness. Silica gel chromatography
(eluent: 99/1 pentane/diethyl ether) gave the purified product as
colorless oil (96.0 mg, 63%). 1H NMR (CDCl3, 400 MHz) δ: 7.36-
7.35 (m, 4H), 7.31-7.27 (m, 1H), 6.80-6.75 (m, 2H), 6.54-6.50
(m, 1H), 4.32 (s, 2H), 3.77 (bs, 1H), 2.51 (dd, 1H, J ) 14.2, 5.8
Hz), 2.21 (dd, 1H, J ) 14.2, 8.5 Hz), 1.82-1.71 (m, 1H), 1.40-
1.15 (m, 6H), 0.89 (d, 3H, J ) 6.4 Hz), 0.88-0.84 (m, 3H). 13C
NMR (CDCl3, 100 MHz) δ: 155.7 (d, 1JCF ) 236.3 Hz), 142.3 (d,
entry
R1
R2
product
yield,a %
erb
1
2
3
6d
6f
6h
H
H
F
n-Bu
n-Hex
n-Bu
18a
18b
18c
64
55
32
92:8
92:8
ndc
a Isolated purified yield. b Determined by HPLC and compared with
racemic sample generated with TMEDA as additive. c Chiral HPLC
separation not achieved.
substituted 5f with both n-Bu and n-HexLi, followed by
electrophile reaction (γ-valerolactone and 2,2-diethoxypropi-
onitrile), resulted in isolation of indoles 17k and 17l with
comparable selectivity (entries 11 and 12).
Further examples were provided by the treatment of the
lithiated species 6d,f,h with CO2 generating the corresponding
carboxylic acids which were effectively cyclized with 1 M HCl
(aq) to form the indolones 18a-c in a one-pot operation (Table
4). Indolones 18a-c were isolated as a mixture of diastereo-
isomers due to the presence of the second stereogenic center in
the 5-membered ring, however the asymmetric generation of
quaternary centers on indolone rings has been the subject of
several recent reports.19
Use of the N-benzyl group is a requirement for high
enantioselectivity, however debenzylation of the final products
can be achieved by treatment with lithium and ammonia, as
illustrated for indoles 17a and 17h (Scheme 6). Following
reduction, the deprotected indoles 19a,b were isolated in yields
of 92% and 57%, respectively.
JCF ) 1.7 Hz), 139.6, 128.9, 127.6, 127.5, 127.4, 117.2 (d, 2JCF
)
2
3
22.0 Hz), 113.0 (d, JCF ) 21.6 Hz), 111.5 (d, JCF ) 7.5 Hz),
49.2, 39.4, 37.1, 32.5, 29.6, 23.1, 20.1, 14.3. IR (neat): 1509, 2857,
2926, 2956, 3031, 3454 cm-1. ES-MS: m/z 300.2 [M + H]+.
HRMS [M + H]+: 300.2125, C20H27NF requires 300.2128. Anal.
Calcd for C20H26FN: C, 80.22; H, 8.75; N, 4.68; F, 6.34. Found:
C, 80.20; H, 8.66; N, 4.70; F, 6.52. [R]D ) +3.1 (c ) 1.6, CH2Cl2,
20 °C). The enantiomeric ratio was determined using a Chiracel
OD column (95/5 pentane/2-propanol, 0.3 mL/min), retention times
of isomers: 21.0 min (7%) and 22.0 min (93%). A racemic mixture
generated with TMEDA gave a 1:1 ratio.
Benzyl-[4-fluoro-2-(2-methyloctyl)phenyl]amine, 7i. PhLi (0.29
mL, 0.50 mmol) was added to a solution of 5f (119.9 mg, 0.50
mmol) in cumene (2 mL) and stirred at room temperature for 15
min. This solution was added dropwise, over 15 min, to a premixed
solution of n-HexLi (0.43 mL, 1.00 mmol) and (-)-sparteine (0.35
mL, 1.52 mmol) in cumene (2 mL) at -15 °C. The mixture was
stirred at -15 °C for a further 4 h and treated with methanol (1
mL). The reaction mixture was washed with HCl (aq) (1 M, 10
mL) and the aqueous layer extracted with diethyl ether (2 × 10
mL). The combined organic layers were dried over sodium sulfate
and concentrated to dryness. Chromatography on alumina (eluent:
99/1 pentane/diethyl ether) gave the purified product as colorless
SCHEME 6. Deprotection of Indoles 17a,h
1
oil (99.0 mg, 61%). H NMR (CDCl3, 400 MHz) δ: 7.36-7.33
(m, 4H), 7.30-7.27 (m, 1H), 6.80-6.75 (m, 2H), 6.54-6.50 (m,
1H), 4.32 (s, 2H), 3.76 (bs, 1H), 2.51 (dd, 1H, J ) 14.3, 5.8 Hz),
2.21 (dd, 1H, J ) 14.3, 8.5 Hz), 1.78-1.74 (m, 1H), 1.33-1.20
(m, 10H), 0.90-0.85 (m, 6H). 13C NMR (CDCl3, 125 MHz) δ:
155.7 (d, 1JCF ) 230.5 Hz), 142.3 (d, JCF ) 1.7 Hz), 139.6, 128.9,
In summary, enantioselective cascade reaction sequences are
very powerful synthetic protocols for the efficient assembly of
complex architectures. We have shown that by exploiting an
asymmetric carbolithiation of (E)-2-propenylarylamines, chiral
lithiated intermediates of broad synthetic potential can be readily
generated with the asymmetric induction being governed by the
organic natural product (-)-sparteine. Application of these
intermediates to further in situ transformations provides access
to a diverse product set with all final products having a common
stereogenic center and identical selectivity. The methodology
is exemplified by the synthesis of chiral substituted anilines,
indoles and indolones. Utilization of this synthetic methodol-
ogy for the generation of other heterocycles from alternatively
2
2
127.6, 127.5, 127.4, 117.2 (d, JCF ) 21.7 Hz), 113.0 (d, JCF
)
3
21.7 Hz), 111.5 (d, JCF ) 7.5 Hz), 49.2, 39.4, 37.4, 32.6, 32.1,
29.7, 27.4, 22.9, 20.1, 14.3. IR (neat): 1509, 2854, 2925, 3031,
3454 cm-1. ES-MS: m/z 328.2 [M + H]+. HRMS [M + H]+:
328.2445, C22H31NF requires 328.2441. Anal. Calcd for C22H30-
FN: C, 80.69; H, 9.23; N, 4.28. Found: C, 80.34; H, 9.16; N,
4.10. [R]D ) -2.1 (c ) 1.6, CH2Cl2, 20 °C). The enantiomeric
ratio was determined using a Chiracel OD column (95/5 pentane/
2-propanol, 0.3 mL/min), retention times of isomers: 22.2 min (7%)
and 23.1 min (93%). A racemic mixture generated with TMEDA
gave a 1:1 ratio.
Representative Synthesis of Indoles 17.
1-Benzyl-2-tert-butyl-3-(1-methylpentyl)-1H-indole, 17c. PhLi
(0.39 mL, 0.49 mmol) was added to a solution of 5d (109.5 mg,
0.49 mmol) in cumene (2 mL) and stirred at room temperature for
15 min. This solution was added dropwise, over 15 min, to a
(19) For examples, see: (a) Trost, B. M.; Frederiksen, M. U. Angew.
Chem., Int. Ed. 2005, 44, 308. (b) Hamashima, Y.; Suzuki, T.; Takano, H.;
Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164. (c) Huang,
A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043.
J. Org. Chem, Vol. 73, No. 7, 2008 2507

Hogan and O’Shea
premixed solution of n-BuLi (0.46 mL, 0.98 mmol) and (-)-
sparteine (0.34 mL, 1.48 mmol) in cumene (2 mL) at -15 °C. The
mixture was stirred at -15 °C for a further 4 h and treated with
2,2-dimethylpropionitrile (0.81 mL, 7.34 mmol) in THF (4 mL).
Stirring was continued for 3 h, during which time the temperature
was gradually increased to room temperature. HCl (aq) (2 M, 10
mL) was added and stirring continued at room temperature for 10
min. The organic layer was separated and the aqueous layer
extracted with diethyl ether (2 × 10 mL). The combined organic
layers were dried over sodium sulfate and concentrated to dryness.
Chromatography on alumina (eluent: 99/1 pentane/diethyl ether)
gave the purified product as colorless oil (85.1 mg, 50%). 1H NMR
(CDCl3, 300 MHz) δ: 7.81-7.77 (m, 1H), 7.26-7.16 (m, 3H),
7.02-7.00 (m, 3H), 6.84-6.81 (m, 2H), 5.60 (s, 2H), 3.67-3.55
(m, 1H), 2.07-1.95 (m, 1H), 1.93-1.81 (m, 1H), 1.53-1.47 (m,
2H), 1.49 (s, 9H), 1.38-1.17 (m, 5H), 0.86 (t, 3H, J ) 7.2 Hz).
13C NMR (CDCl3, 75 MHz) δ: 141.7, 139.1, 138.4, 128.5, 127.1,
126.7, 125.6, 121.2, 120.9, 118.4, 118.3, 110.0, 49.3, 36.5, 34.8,
32.6, 31.8, 31.1, 23.0, 21.1, 14.2. IR (neat): 2870, 2926, 2957,
3028 cm-1. ES-MS: m/z 348.2 [M + H]+. HRMS [M + H]+:
348.2695, C25H34N requires 348.2691. [R]D ) -5 (c ) 0.1, CH2-
Cl2, 20 °C). The enantiomeric ratio was determined using a Chiracel
OD column (99.75/0.25 pentane/2-propanol, 0.6 mL/min), retention
times of isomers: 17.1 min (91%) and 18.5 min (9%). A racemic
mixture generated with TMEDA gave a 1:1 ratio.
temperature for 2 h. The organic layer was separated and the
aqueous layer extracted with diethyl ether (2 × 10 mL). The
combined organic layers were dried over sodium sulfate and
concentrated to dryness. Silica gel chromatography (eluent: 3/2
pentane/diethyl ether) gave the purified product as colorless oil (90.3
mg, 64%) [NMR data for product as an equal mixture of
diastereoisomers]. 1H NMR (CDCl3, 400 MHz) δ: 7.30-7.28 (m,
4H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 1H), 7.01-6.99 (m, 1H),
6.72-6.70 (m, 1H), 5.02 (dd, 1H, J ) 15.5, 3.3 Hz), 4.78 (dd, 1H,
J ) 15.5, 6.7 Hz), 3.53 (dd, 1H, J ) 13.3, 3.4 Hz), 2.45-2.38 (m,
0.5H, isomer 1), 2.37-2.30 (m, 0.5H, isomer 2), 1.59-1.43 (m,
2H), 1.41-1.26 (m, 4H), 0.99 (d, 1.5H, J ) 6.9 Hz, isomer 2),
0.94-0.85 (m, 3H), 0.78 (d, 1.5H, J ) 6.8 Hz, isomer 1). 13C NMR
(CDCl3, 100 MHz) δ: 178.2, 177.6, 144.3, 144.2, 136.5, 136.4,
129.0, 128.8, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.7, 124.9,
124.4, 122.5, 122.4, 109.3, 109.2, 51.0, 50.6, 44.1, 44.0, 36.4, 35.9,
34.5, 33.0, 31.3, 30.2, 23.1, 23.1, 17.3, 15.9, 14.4, 14.4. IR (neat):
1358, 1466, 1488, 1613, 1713, 2858, 2928, 2958, 3032, 3060 cm-1
.
ES-MS: m/z 308.2 [M + H]+. HRMS [M + H]+: 308.2005,
C21H26NO requires 308.2014. [R]D ) +12.1 (c ) 1.4, CH2Cl2, 20
°C). The enantiomeric ratio was determined using a Chiracel OD
column (99.8/0.2 pentane/2-propanol + 0.1% TFA, 0.6 mL/min),
retention times of isomers: 26.2 min (4%), 27.2 min (4%), 28.4
min (44%) and 29.4 min (48%). A racemic mixture generated with
TMEDA gave retention times 26.2 min (27%), 27.2 min (23%),
28.4 min (22%) and 29.4 min (28%). 92:8 er.
1-[1-Benzyl-5-fluoro-3-(1-methylheptyl)-1H-indol-2-yl]etha-
none, 17l. PhLi (0.31 mL, 0.53 mmol) was added to a solution of
5f (127.6 mg, 0.53 mmol) in cumene (2 mL) and stirred at room
temperature for 15 min. This solution was added dropwise, over
15 min, to a premixed solution of n-HexLi (0.46 mL, 1.06 mmol)
and (-)-sparteine (0.37 mL, 1.61 mmol) in cumene (2 mL) at -15
°C. The mixture was stirred at -15 °C for a further 4 h and treated
with 2,2-diethoxypropionitrile (0.83 mL, 5.32 mmol). Stirring
continued for 3 h, during which time the temperature was gradually
increased to room temperature. Saturated ammonium chloride
solution (10 mL) was added and stirring continued at room
temperature for 10 min. The aqueous layer was removed; HCl (aq)
(5 M, 10 mL) was added to the organic layer and the mixture stirred
at room temperature for 30 min. The organic layer was separated
and the aqueous layer extracted with diethyl ether (2 × 10 mL).
The combined organic layers were dried over sodium sulfate and
concentrated to dryness. Chromatography on alumina (eluent: 9/1
to 1/1 pentane/diethyl ether) gave the purified product as pale yellow
1-Benzyl-5-fluoro-3-(1-methylpentyl)-1,3-dihydroindol-2-
one, 18c. PhLi (0.31 mL, 0.47 mmol) was added to a solution of
5f (112.8 mg, 0.47 mmol) in cumene (2 mL) and the mixture stirred
at room temperature for 15 min. This solution was added dropwise,
over 15 min, to a premixed solution of n-BuLi (0.43 mL, 0.93
mmol) and (-)-sparteine (0.32 mL, 1.39 mmol) in cumene (2 mL)
at -15 °C. The mixture was stirred at -15 °C for a further 4 h
and treated with solid carbon dioxide. The cooling bath was
removed, HCl (aq) (1 M, 10 mL) was added, and stirring was
continued at room temperature for 2 h. The organic layer was
separated and the aqueous layer extracted with diethyl ether (2 ×
10 mL). The combined organic layers were dried over sodium
sulfate and concentrated to dryness. Silica gel chromatography
(eluent: 3/2 pentane/diethyl ether) gave the purified product as a
colorless oil (48.8 mg, 32%) [NMR data of product as an equal
mixture of diastereoisomers]. 1H NMR (CDCl3, 400 MHz) δ:
7.33-7.24 (m, 5H), 7.01-6.98 (m, 1H), 6.88-6.82 (m, 1H), 6.62-
6.58 (m, 1H), 5.01 (dd, 1H, J ) 15.7, 3.2 Hz), 4.77 (dd, 1H, J )
15.7, 6.7 Hz), 3.53 (dd, 1H, J ) 11.5, 3.0 Hz), 2.42-2.38 (m, 0.5H,
isomer 1), 2.35-2.28 (m, 0.5H, isomer 2), 1.55-1.41 (m, 2H),
1.40-1.25 (m, 4H), 0.99 (d, 1.5H, J ) 7.0 Hz, isomer 2), 0.94-
0.86 (m, 3H), 0.79 (d, 1.5H, J ) 6.7 Hz, isomer 1). 13C NMR
1
oil (74.0 mg, 37%). H NMR (CDCl3, 400 MHz) δ: 7.50-7.47
(m, 1H), 7.25-7.19 (m, 4H), 7.05-7.00 (m, 1H), 6.94-6.92 (m,
2H), 5.51 (s, 2H), 3.42-3.31 (m, 1H), 2.50 (s, 3H), 1.96-1.87
(m, 1H), 1.85-1.78 (m, 1H), 1.48 (d, 3H, J ) 7.1 Hz), 1.28-1.19
(m, 8H), 0.88-0.82 (m, 3H). 13C NMR (CDCl3, 100 MHz) δ:
194.9, 157.4 (d, 1JCF ) 238.8 Hz), 138.5, 136.0, 135.7, 128.8, 127.5,
127.4, 126.4, 125.3 (d, 3JCF ) 10.8 Hz), 114.2 (d, 2JCF ) 26.5 Hz),
1
(CDCl3, 100 MHz) δ: 177.7, 177.0, 159.2 (d, JCF ) 238.8 Hz),
159.1 (d, 1JCF ) 238.8 Hz), 140.1, 139.9, 136.1, 136.0, 129.3, 129.2,
3
2
2
112.1 (d, JCF ) 9.5 Hz), 107.6 (d, JCF ) 23.6 Hz), 48.4, 37.1,
32.6, 32.0, 31.9, 29.5, 28.6, 22.8, 21.4, 14.3. 19F NMR (CDCl3,
376 MHz) δ: -123.7-123.8 (m). IR (neat): 1452, 1661, 2855,
2927, 2959, 3031 cm-1. ES-MS: m/z 378.2 [M - H]-. HRMS [M
- H]-: 378.2248, C25H29NOF requires 378.2233. [R]D ) +2.6 (c
) 0.6, CH2Cl2, 20 °C). The enantiomeric ratio was determined using
a Chiracel OD column (95/5 pentane/2-propanol, 0.4 mL/min),
retention times of isomers: 14.3 min (9%) and 15.1 (91%). A
racemic mixture generated with TMEDA gave a 1:1 ratio.
Representative Synthesis of Indolones 18.
129.0, 127.8, 127.6, 127.5, 114.1 (d, JCF ) 23.2 Hz), 114.0 (d,
2JCF ) 26.5 Hz), 112.9 (d, 2JCF ) 26.5 Hz), 112.4 (d, 2JCF ) 23.2
Hz), 109.4 (d, 3JCF ) 8.3 Hz), 109.3 (d, 3JCF ) 9.1 Hz), 51.2, 50.8,
44.1, 44.0, 36.2, 35.8, 34.2, 32.8, 30.0, 30.0, 23.0, 22.9, 17.0, 15.8,
14.3, 14.3. IR (neat): 1489, 1712, 2859, 2929, 2959, 3033, 3065
cm-1. ES-MS: m/z 326.2 [M + H]+. HRMS [M + H]+: 326.1927,
C21H25NOF requires 326.1920. Anal. Calcd for C21H24FNO: C,
77.51; H, 7.43; N, 4.30; F, 5.84. Found: C, 77.46; H, 7.51; N,
4.30; F, 5.35. [R]D ) +15.9 (c ) 0.5, CH2Cl2, 20 °C). Chiral HPLC
separation not achieved.
Synthesis of Indoles 19.
1-Benzyl-3-(1-methylpentyl)-1,3-dihydroindol-2-one, 18a. PhLi
(0.31 mL, 0.47 mmol) was added to a solution of 5d (101.8 mg,
0.46 mmol) in cumene (2 mL) and stirred at room temperature for
15 min. This solution was added dropwise, over 15 min, to a
premixed solution of n-BuLi (0.42 mL, 0.91 mmol) and (-)-
sparteine (0.32 mL, 1.39 mmol) in cumene (2 mL) at -15 °C. The
mixture was stirred at -15 °C for a further 4 h and treated with
solid carbon dioxide. The cooling bath was removed, HCl (aq) (1
M, 10 mL) was added, and stirring was continued at room
3-(1-Methylpentyl)-1H-indole, 19a. Lithium wire (17.3 mg, 2.49
mmol) was added to liquid ammonia (75 mL) at -78 °C and stirred
for 30 min. A solution of 17a (24.1 mg, 0.08 mmol) in THF (1
mL) was added and stirring continued at -78 °C for 2 h. Solid
ammonium chloride was added, the bath removed, and the ammonia
allowed evaporate. Water (15 mL) was added and the aqueous layer
extracted with diethyl ether (2 × 25 mL). The combined organic
layers were dried over sodium sulfate and concentrated to dryness.
2508 J. Org. Chem., Vol. 73, No. 7, 2008

Applications of EnantioselectiVe Carbolithiations
Silica gel chromatography (eluent: 9/1 pentane/diethyl ether) gave
the product as a colorless oil (14.8 mg, 92%). H NMR (CDCl3,
MHz) δ: 7.85 (bs, 1H), 7.64 (d, 1H, J ) 8.0 Hz), 7.33 (d, 1H, J
) 8.0 Hz), 7.18-7.15 (m, 1H), 7.11-7.07 (m, 1H), 6.94 (s, 1H),
3.07-2.98 (m, 1H), 1.81-1.75 (m, 1H), 1.64-1.57 (m, 1H), 1.34
(d, 3H, J ) 6.9 Hz), 1.31-1.19 (m, 8H), 0.90-0.84 (m, 3H). 13C
NMR (CDCl3, 125 MHz) δ: 136.8, 127.2, 123.2, 122.0, 120.0,
119.7, 119.2, 111.3, 37.9, 32.1, 31.1, 29.7, 27.9, 22.9, 21.6, 14.3.
IR (neat): 1457, 1619, 2855, 2926, 2957, 3057, 3418 cm-1. ES-
MS: m/z 230.2 [M + H]+. HRMS [M + H]+: 230.1900, C16H24N
requires 230.1909. The enantiomeric ratio was determined using a
Chiracel OD column (99/1 pentane/2-propanol, 0.6 mL/min),
retention times of isomers: 38.9 min (7%) and 40.2 min (93%).
1
400 MHz) δ: 7.87 (bs, 1H), 7.64 (d, 1H, J ) 7.9 Hz), 7.34 (d, 1H,
J ) 8.1 Hz), 7.19-7.15 (m, 1H), 7.11-7.07 (m, 1H), 6.94 (s, 1H),
3.07-2.98 (m, 1H), 1.83-1.75 (m, 1H), 1.65-1.57 (m, 1H), 1.34
(d, 3H, J ) 7.0 Hz), 1.33-1.27 (m, 4H), 0.90-0.85 (m, 3H). 13C
NMR (CDCl3, 100 MHz) δ: 136.7, 127.2, 123.2, 122.0, 120.0,
119.7, 119.1, 111.3, 37.6, 31.0, 30.2, 23.1, 21.7, 14.4. IR (neat):
1457, 1619, 2857, 2927, 2957, 3057, 3418 cm-1. ES-MS: m/z 202.2
[M + H]+. HRMS [M + H]+: 202.1596, C14H20N requires
202.1596. The enantiomeric ratio was determined using a Chiracel
OD column (99/1 pentane/2-propanol, 0.4 mL/min), retention times
of isomers: 63.8 min (7%) and 66.1 min (93%).
Acknowledgment. A-M.L.H. thanks the Irish Research
Council for Science, Engineering and Technology for a stu-
dentship. Funding support from the Program for Research in
Third-Level Institutions administered by the HEA and Science
Foundation Ireland. Thanks to Dr. D. Rai of the CSCB Mass
Spectrometry Centre.
3-(1-Methylheptyl)-1H-indole,20 19b. Lithium wire (17.3 mg,
2.49 mmol) was added to liquid ammonia (75 mL) at -78 °C and
stirred for 30 min. A solution of 17h (38.6 mg, 0.12 mmol) in THF
(1 mL) was added and stirring continued at -78 °C for 2 h. Solid
ammonium chloride was added, the bath removed, and the ammonia
allowed evaporate. Water (15 mL) was added and the aqueous layer
extracted with diethyl ether (2 × 25 mL). The combined organic
layers were dried over sodium sulfate and concentrated to dryness.
Silica gel chromatography (eluent: 9/1 pentane/diethyl ether) gave
the product as colorless oil (15.6 mg, 57%). 1H NMR (CDCl3, 500
Supporting Information Available: Analysis and experimental
procedures for starting materials 7a-g, 8, 9, 17a,b,d-k, and 18b.
1H and 13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Pratt, E. F.; Botimer, L. W. J. Am. Chem. Soc. 1957, 79, 5248.
JO702290F
J. Org. Chem, Vol. 73, No. 7, 2008 2509