Chiral bronsted base-promoted nitroalkane alkylation: Enantioselective synthesis of sec -Alkyl-3-substituted indoles

Article abstract of DOI:10.1021/ol1025712

A Bronsted base-catalyzed reaction of nitroalkanes with alkyl electrophiles provides indole heterocycles substituted at C3 bearing a sec-alkyl group with good enantioselectivity (up to 90% ee). Denitration by hydrogenolysis provides a product with equally high ee. An indolenine intermediate is implicated in the addition step, and surprisingly, water cosolvent was found to have a beneficial effect in this step, leading to a one-pot protocol for elimination/enantioselective addition using PBAM, a bis(amidine) chiral nonracemic base.

Full text of DOI:10.1021/ol1025712

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5744-5747
Chiral Brønsted Base-Promoted Nitroalkane
Alkylation: Enantioselective Synthesis of
sec-Alkyl-3-Substituted Indoles
Mark C. Dobish and Jeffrey N. Johnston*
Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt
UniVersity, NashVille, Tennessee 37235-1822, United States
jeffrey.n.johnston@Vanderbilt.edu
Received October 22, 2010
ABSTRACT
A Brønsted base-catalyzed reaction of nitroalkanes with alkyl electrophiles provides indole heterocycles substituted at C3 bearing a sec-alkyl
group with good enantioselectivity (up to 90% ee). Denitration by hydrogenolysis provides a product with equally high ee. An indolenine
intermediate is implicated in the addition step, and surprisingly, water cosolvent was found to have a beneficial effect in this step, leading to
a one-pot protocol for elimination/enantioselective addition using PBAM, a bis(amidine) chiral nonracemic base.
Indole and pyrrole-derived small molecules bearing an
n-alkyl substituent at C3 are very common, but the emer-
gence of small molecules exhibiting a sec-alkyl substituent
at C3 is more recent. Compelling biological activity can be
associated with these congeners (Figure 1): the gonadotropin
releasing hormone antagonist developed by Merck (1),1 the
antibiotic roseophilin (2),2 and inhibitors of MDM2 in the
spirotryprostatin class (3).3
Synthetic methods that provide for functionalization of the
C3 indole carbon do not often translate to the production of
chiral nonracemic products, though an exception to this is
the Friedel-Craft alkylation4 of indole where asymmetric
Figure 1. Examples of biologically active indole- and pyrrole-
derived heterocycles bearing a chiral C3-sec-alkyl substituent.
versions have been reported.5 While both metal-based chiral
(1) Farr, R. N.; Alabaster, R. J.; Chung, J. Y. L.; Craig, B.; Edwards,
J. S.; Gibson, A. W.; Ho, G.-J.; Humphrey, G. R.; Johnson, S. A.;
Grabowski, E. J. J. Tetrahedron: Asymmetry 2003, 14, 3503–3515.
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Tetrahedron Lett. 1992, 33, 2701–2704. rac-2 syntheses: Fuerstner, A.;
Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817–2825. Harrington, P. E.;
Tius, M. A. Org. Lett. 1999, 1, 649–651. Robertson, J.; Hatley, R. J. D.
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Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801–3810. Boger, D. L.;
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Fuerstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582–3603.
complexes and organocatalysts have been used to catalyze
the addition of indoles to nitroalkenes,6 there are currently
no asymmetric additions to nonactivated R,ꢀ-substituted
nitroalkenes, which would deliver highly substituted sec-
alkyl substituents at the indole 3-position.7,8
In 2006, Petrini described an innovative solution to this
structural motif using 3-(1-arylsulfonylalkyl) indole pre-
cursors to indolenine reactive intermediates.9 They have
10.1021/ol1025712  2010 American Chemical Society
Published on Web 11/19/2010

since reported a range of bases and nucleophiles to effect
the elimination and subsequent addition.10 A variety of
indolenine precursors have also been reported to be
generated using both acidic11 and basic12 reaction condi-
tions. Though a broad scope of additions has already been
demonstrated (Grignard, nitroalkane, malonate, malono-
nitriles), there have been very few asymmetric variations
reported.13-16 More recently, a Brønsted-base catalyzed
asymmetric addition of malononitrile using a cinchona based
thiourea catalyst was reported with high selectivity.17 This
has prompted us to report our findings on the catalytic,
enantioselective Michael addition of arylnitromethanes to
indolenine intermediates. In the context of BAM (Bis(AMi-
dine)) catalysis,18 this is the first report of their use as chiral
Brønsted bases.19
To gauge the reactivity of nitroalkanes with sulfone 5a using
a BAM catalyst, the Petrini protocol was utilized for direct
comparison. In this experiment using dichloromethane, conver-
sion to the desired nitroalkane alkylation product (6a) was
observed, but with low enantioselectivity (20% ee, Table 1,
(3) Isolation and biological activity: Cui, C.-B.; Kakeya, H.; Osada, H.
Tetrahedron 1996, 52, 12651–12666. Kondoh, M.; Usui, T.; Mayumi, T.;
Osada, H. J. Antibiot. 1998, 51, 801–804. Syntheses of 3: Edmondson, S. D.;
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Sulfonylmethyl Indolesa
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M
ee (%)b
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D. J. Am. Chem. Soc. 2008, 130, 16464–16465. Itoh, J.; Fuchibe, K.;
Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016–4018. Liu, H.; Lu,
S.-F.; Xu, J.; Du, D.-M. Chem. sAsian J. 2008, 3, 1111–1121. Yuan, Z.-
L.; Lei, Z.-Y.; Shi, M. Tetrahedron: Asymmetry 2008, 19, 1339–1346.
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1c
2
3
4
5
6
7
8
4c
4c
4c
4c
4c
4c
4c
4a
4b
4c
4c
KF/Alumina
KF/Alumina
KF/Alumina
KF/Alumina
KF
Na2CO3
K2CO3
K2CO3
rt
rt
-20
-78
rt
rt
rt
rt
rt
0.2
0.2
0.2
0.2
0.1
0.1
0.2
0.2
0.2
0.1
0.1
20
60
57
49
68
61
70
56
73
78
81
9d
10
11d
K2CO3
K2CO3
K2CO3
rt
rt
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Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Synthesis 2002, 1110–1114.
Ballini, R.; Clemente, R. R.; Palmieri, A.; Petrini, M. AdV. Synth. Catal.
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Laha, S.; Yadav, J.; Srinivas, P. Synth. Commun. 2009, 39, 4100–4108.
Ye, M.-C.; Yang, Y.-Y.; Tang, Y.; Sun, X.-L.; Ma, Z.; Qin, W.-M. Synlett
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a All reactions were performed using 2 equivalents of phenylni-
tromethane on a 0.1 mmol scale and resulted in less than 1.5:1 dr material
and between 30-80% yield. Absolute stereochemistry assigned by cor-
relation. See Supporting Information for details. b Enantiomeric ratios were
measured using chiral stationary phase HPLC and are reported for the major
diastereomer. c Dichloromethane was used instead of toluene. d One equiv-
alent of phenylnitromethane was used.
(8) Enantioselective additions have been reported using nitroalkenes
bearing an additional activating group (-CO2R): Sui, Y.; Liu, L.; Zhao, J.-
L.; Wang, D.; Chen, Y.-J. Tetrahedron 2007, 63, 5173–5183.
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entry 1). Use of toluene improved selectivity to 60% ee (Table
1, entry 2). Attempts to improve enantioselection by lowering
the temperature provided lower conversion and enantioselection
(Table 1, entries 3-4), likely due to the heterogeneity of the
reaction mixture and the sluggish elimination step. There was
no change in diastereoselection throughout the reaction opti-
mization process.20 Considering the possibility that the sto-
(10) For a review: Palmieri, A.; Petrini, M.; Shaikh, R. R. Org. Biomol.
Chem. 2010, 8, 1259–1270. For other works Palmieri, A.; Petrini, M. J.
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M.; Shaikh, R. R. Synlett 2008, 2008, 1845–1851. Ballini, R.; Gabrielli,
S.; Palmieri, A.; Petrini, M. AdV. Synth. Catal. 2010, 352, 2459–2462.
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1313–1316. Campetella, S.; Palmieri, A.; Petrini, M. Eur. J. Org. Chem.
2009, 2009, 3184–3188. Boas, U.; Brask, J.; Jensen, K. J. Chem. ReV. 2009,
109, 2092–2118.
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Petrini, M.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47,
8707–8710.
(14) Preliminary results using NHC: Li, Y.; Shi, F. Q.; He, Q. L.; You,
S. L. Org. Lett. 2009, 11, 3182–3185.
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J.-I.; Tanaki, Y.; Ishibashi, H. Tetrahedron 2008, 64, 5262–5267.
(15) Enantioselective addition of N-Bz enamines to indolyl alcohols
using a chiral phosphoric acid: Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.;
Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett. 2009, 11, 4620–4623.
Org. Lett., Vol. 12, No. 24, 2010
5745

ichiometric base might intervene during the addition as an
achiral base, we examined several alternatives (Table 1, entries
5-7). Potassium fluoride (without alumina) provided a slight
improvement while sodium and potassium carbonate provided
similar enantioselection.
(Table 2, entry 5) and heterocyclic (Table 2, entry 6)
substituents were tolerated, but a lowering of ee was
observed. We were encouraged to see that selectivity
remained relatively constant for the aliphatic analog tested
(Table 2, entry 7). Though ester substituents gave slightly
lower ee (Table 2, entries 8-9) we were encouraged by an
improvement in diastereoselection to 3:1. Variations at the
2-position of the indole were also tolerated (Table 2, entries
10-11), but the lower enantioselection suggests the need
for a steric influence at the indole C2. These observations
translated to a pyrrole electrophile, as 5l (Table 2, entry 12)
furnished 6l with good enantioselection. Electronic modifica-
tions of the nitroalkane pronucleophile (Table 2, entries
13-14) demonstrated that electron rich arylnitroalkanes
result in improved enantioselection, whereas electron defi-
cient aryl nitroalkanes provide substitution products with
lower enantioselection. The use of nitroethane was also less
selective (Table 2, entry 15), but gave encouraging results.
Experiments directed at probing the influence of base
solubility revealed a beneficial water effect. We hypothesized
that water might solubilize the inorganic base in a biphasic
mixture, and in so doing, further limit the possible contribu-
tion of direct K2CO3-mediated substitution that would lead
to racemic product formation. Furthermore, toluene sulfinate
would also be solubilized by water. In a control experiment
where water is used as solvent (no toluene), the product forms
in high yield but as the racemate (Table 3, entry 1). However,
when water was used as a cosolvent (2:1, toluene:water),
dramatic increases in yield and enantioselection (Table 3,
entry 2) were observed.
In a second line of optimization, we hypothesized that the
reactive indolenine intermediate might be formed fully in situ
prior to the addition of pronucleophile (Table 3, Method B).
This also provided the desired substitution products with similar
enantioselection in most cases. Together, these methods suggest
that similar indolenine intermediates are formed, leading to
enantioselective product-forming pathways. Attenuations in
enantioselection can be attributed, at least in part, to achiral
base-promoted product formation. Table 3 compares these two
methods across a range of substrates.
Both methods A and B gave high enantioselection for the
various aryl analogs tested (Table 3, entries 4-9). Use of
para-methoxy phenylnitromethane leads to an increase in
ee for method A and B, but a significant difference in the
major and minor diastereomers is observed in the latter
(Table 3, entry 11). The furan analog saw a sharp increase
in ee from the original method (53% ee/44% ee) to the new
methods, as both gave 90% ee for the major diastereomer
(Table 3, entries 12-13). The aliphatic analog (Table 3,
entries 14-15) saw a small drop in ee from the original
method, as well as in yield. The ester derivative (Table 3,
entry 16) provided a small increase in ee while 3:1 dr was
We briefly investigated BAM catalyst alternatives.18 The
less Brønsted basic catalyst 4a (Table 1, entry 8) gave lower
enantioselection while increasing the catalyst Brønsted
basicity (4b) increased enantioselection (Table 1, entry 9).21
Our most Brønsted basic catalyst H,4PyrrolidineQuin-BAM
(4c, PBAM) provided the highest enantioselection under the
given conditions. Decreasing the concentration (Table 1,
entry 10) and the equivalents of nucleophile (Table 1, entry
11) further improved enantioselection, thereby defining the
optimal conditions.
The substrate scope was investigated next (Table 2). Aryl
rings bearing electron donating as well as electron withdraw-
Table 2. Chiral Base-Catalyzed Enantioselective Nitroalkane
Alkylationsa
ee yield (%)c
entry
R1
R2
R3
(%)b
(conv)
1
Me
Ph
pBrC6H4
pMeOC6H4
pF3CC6H4
oMePh
2Furyl
nBu
Ph
Ph
a
b
c
d
e
f
81/81
82/75
81/81
84/74
76/70
53/44
76/74
66/47
65/66
40/0
74/72
72/69
89/85
37/43
66/67
78(85)
74(76)
68(88)
71(78)
76(95)
69(99)
51(56)
47(52)
55(70)
65(68)
49(52)
69(79)
52(77)
63(86)
65(87)
2
Me
3
Me
Ph
4
Me
Ph
5e
Me
Ph
6
Me
Ph
7
Me
Ph
g
h
i
8d
9d,e
10
11e
12e
13
14
15e,f
Me
CO2tMe
CO2 Bu
Ph
Ph
Me
Ph
H
Ph
j
k
l
m
n
o
Ph
Ph
Ph
2,5-Me-Pyrrole
Ph
Ph
Me
Me
Me
Ph
pMeOC6H4
pO2NC6H4
Me
Ph
Ph
a All reactions were performed on a 0.1 mmol scale using a standard
22 h reaction time and 7 equivalents of K2CO3. Diastereomeric ratios
observed for crude reaction mixtures were measured by 1H NMR spec-
troscopy and ranged from 1:1 to 1.5:1 dr. See Supporting Information for
complete details. b Enantiomeric ratios were measured using chiral stationary
phase HPLC. c Isolated yields with conversions in parentheses. d Three to
one dr observed. e Seventy-two hour reaction time. f One and a half
equivalents of nitroethane used.
ing groups were tolerated (Table 2, entries 2-4), yielding
the product with good enantioselection. Sterically hindered
(16) Silver catalyzed diastereo- and enantioselective synthesis of tryp-
tophans: Zheng, B.-H.; Ding, C.-H.; Hou, X.-L.; Dai, L.-X. Org. Lett. 2010,
12, 1688–1691.
(17) Jing, L.; Wei, J.; Zhou, L.; Huang, Z.; Li, Z.; Wu, D.; Xiang, H.;
Zhou, X. Chem.sEur. J. 2010, 16, 10955–10958.
(18) BAM catalysis: Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am.
Chem. Soc. 2004, 126, 3418–3419. Singh, A.; Yoder, R. A.; Shen, B.;
Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466–3467. Shen, B.; Johnston,
J. N. Org. Lett. 2008, 10, 4397–4400. Singh, A.; Johnston, J. N. J. Am.
Chem. Soc. 2008, 130, 5866–5867. Davis, T. A.; Wilt, J. C.; Johnston, J. N.
J. Am. Chem. Soc. 2010, 132, 2880–2882. Shen, B.; Makley, D. M.;
Johnston, J. N. Nature 2010, 465, 1027–1032.
(19) For a recent review: Ting, A.; Goss, J.; McDougal, N.; Schaus, S.
In Asymmetric Organocatalysis; Springer: Berlin/Heidelberg, 2009; Vol.
291, pp 145-200.
(20) Material enriched in one diastereomer by column chromatography
(4:1) was resubmitted to the reaction conditions to give material with the
same diastereoselection (4:1).
(21) Hess, A. S.; Yoder, R. A.; Johnston, J. N. Synlett 2006; 0147-0149.
5746
Org. Lett., Vol. 12, No. 24, 2010

potassium carbonate is used the reaction is much slower (50%
conversion after 22 h), leading to the conclusion that the
organocatalyst is a more effective promoter of indolenine
formation. If potassium carbonate regenerates PBAM from its
sulfinic acid salt, the catalyst can then deprotonate the nitroal-
kane to form the nucleophilic nitronate. Alternatively, the
PBAM-HTs-indolenine complex (7) could react with the
potassium nitronate, PBAM-nitronic acid salt, or the simple
nitronic acid enantioselectively. Based on the observations
outlined above, we favor the first of these possibilities wherein
the PBAM-nitronate salt reacts with the indolenine selectively.
Table 3. Chiral Base-Catalyzed Enantioselective Nitroalkane
Alkylations Improved by a Semiaqueous, One-Pot Protocola
entry
R1
R2
method
ee (%)b yieldc
1d
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16e
17e
18
19
Ph
Ph
water
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
a
a
a
b
b
c
0/0
83
96
85
84
94
92
66
83
83
72
82
87
72
42
48
89
71
0
86/86
88/89
87/86
88/86
85/85
87/88
84/76
88/78
87/87
90/75
90/79
90/81
71/70
73/59
76/65
50/38
-
pBrC6H4
pMeOC6H4
pF3CC6H4
Ph
Ph
Ph
Scheme 2. Convergence of Diastereomeric Nitroalkanes to a
sec-Alkyl 3-Substituted Indole with High Enantioselection
c
Ph
d
d
m
m
f
pMeOC6H4
Ph
2Furyl
nBu
f
Ph
g
g
h
h
o
o
CO2Me
Ph
Ph
Nitroalkanes offer many opportunities for functionalization
through reduction (tryptamine analogs), oxidation (Nef) and
removal (denitration).22 Using modified conditions for the
cleavage of benzylic nitro bonds by Carreira23 we were able
to denitrate in high yield while enantioenrichment was
conserved (Scheme 2). Denitration gives products (9) that
would result from the enantioselective Friedel-Crafts reac-
tion between indole and stilbene, a reaction not yet devel-
oped.
Me
A
B
10/10
68
a All reactions were performed on a 0.1 mmol scale using a standard
22 h reaction time and 7 equivalents of K2CO3. Diastereomeric ratios
observed for crude reaction mixtures were measured by 1H NMR spec-
troscopy and ranged from 1:1 to 1.5:1 dr. See Supporting Information for
complete details. b Enantiomeric ratios were measured using chiral stationary
phase HPLC. c Isolated yields. d Reaction run in water for 5 days. e Three
to one dr observed.
maintained. Unfortunately, the nitroethane addition product
was produced with significantly lower ee for method B and
did not produce any product for method A (Table 3, entries
18-19). The increased solubility of the nitroethane in water
may have contributed to the low yield of the reaction.
Using the data from all three methods and control experi-
ments, a working mechanism is proposed in Scheme 1. We
In conclusion, an enantioselective Brønsted base-catalyzed
alkylation of nitroalkanes has been developed using indo-
lenine electrophiles. The final protocol provides ꢀ-substituted
tryptamine analogs and illustrates how these enantioselective
reactions at room temperature can be improved by the
addition of water.24
Acknowledgment. We are grateful to the NIH (GM
084333) and Amgen for financial support of this work, and
the VICB for fellowship support (MCD).
Scheme 1. Proposed Cycle for Chiral Base Catalysis of
Nitroalkane Alkylations by an in situ-formed Indolenine
Supporting Information Available: Complete experi-
mental details and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1025712
(22) Ono, N. In The Nitro Group in Organic Synthesis; Feuer, H., Ed.;
Wiley-VCH: New York, 2001; p 1.
(23) Fessard, T.; Motoyoshi, H.; Carreira, E. Angew. Chem., Int. Ed.
2007, 46, 2078–2081.
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Med. Chem. Lett. 2009, 19, 4971–4973. Hong, K. B.; Donahue, M. G.;
Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 2323.
hypothesize that both PBAM and potassium carbonate can effect
the elimination of toluene sulfinate. However, when only
Org. Lett., Vol. 12, No. 24, 2010
5747