N-indolyltriethylborate: A useful reagent for synthesis of C3-quaternary indolenines

Article abstract of DOI:10.1021/ol4005992

N-Indolyltriethylborate was found to be a useful reagent for dearomatizing C3-alkylation of 3-substituted indoles with both activated and nonactivated alkyl halides to give C3-quaternary indolenines, pyrroloindolines, furoindoline, and hexahydropyridoindoline under mild reaction conditions. The utility of these reagents was demonstrated in the syntheses of a pyrroloindoline-4- cholestene hybrid and debromoflustramine B.

Full text of DOI:10.1021/ol4005992

ORGANIC
LETTERS
2013
Vol. 15, No. 8
1950–1953
N‑Indolyltriethylborate: A Useful Reagent
for Synthesis of C3-Quaternary Indolenines
Aijun Lin, Jiong Yang,* and Mohamed Hashim
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255,
United States
yang@mail.chem.tamu.edu
Received March 5, 2013
ABSTRACT
N-Indolyltriethylborate was found to be a useful reagent for dearomatizing C3-alkylation of 3-substituted indoles with both activated and
nonactivated alkyl halides to give C3-quaternary indolenines, pyrroloindolines, furoindoline, and hexahydropyridoindoline under mild reaction
conditions. The utility of these reagents was demonstrated in the syntheses of a pyrroloindoline-4-cholestene hybrid and debromoflustramine B.
Indole alkaloids are widely distributed in both terrestrial
and marine organisms and often show interesting biological
and pharmacological properties.1 Whereas Nature em-
ploys biosynthetic machineries to enzymatically synthesize
indole alkaloids from tryptophan and other biosynthetic
precursors,2 dearomatization of simple indoles provides a
convenient connection between the readily available aro-
matic heterobicycle and complex indole-containing struc-
tural motifs through chemical synthesis.3 In particular,
dearomatizing C3-alkylation/arylation of 3-substituted in-
doles leads to the formation of C3-quaternary indolenines,
which are versatile building blocks for the synthesis of the
alicyclic molecular frameworks found in complex indole
alkaloids and related compounds.4 A number of approaches
have been developed for the synthesis of these compounds
from electron-rich indoles and activated electrophiles, such as
carbonyl, imine, Michael acceptors, transition metal com-
plexes, etc., by FriedelÀCrafts or similar transformations.5
In order to overcome the thermodynamic cost associated
with dearomatization of indoles and the relatively low
π-nucleophilicity of 3-substituted indoles for formation of
the quaternary center, these transformations are often exe-
cuted intramolecularly to give spiro- or other polycyclic
indolenines6 or coupled with intramolecular N- or C-cycliza-
tion of the initial indolenine products to give pyrroloindolines,
(5) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (b) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A.
Synlett 2005, 1199. (c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev.
2009, 38, 2190. (d) Zeng, M.; You, S.-L. Synlett 2010, 1289. (e) Loh,
C. C. J.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 46.
(6) (a) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012,
51, 1680. (b) Cai, Q.; Zheng, C.; Zhang, J.-W.; You, S.-L. Angew. Chem.,
Int. Ed. 2011, 50, 8665. (c) Wu, Q. F.; He, H.; Liu, W.-B.; You, S.-L.
J. Am. Chem. Soc. 2010, 132, 11418. (d) Wu, K.-J.; Dai, L.-X.; You, S.-L.
Org. Lett. 2012, 14, 3772. (e) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Chem.
Sci. 2013, 4, 97.
(7) (a) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134,
10815. (b) Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. Chem. Sci.
2012, 3, 3170. (c) Cai, Q.; You, S.-L. Org. Lett. 2012, 14, 3040. (d) Cai,
Q.; Liu, C.; Liang, X.-W.; You, S.-L. Org. Lett. 2012, 14, 4588.
(e) Lucarini, S.; Bartoccini, F.; Battistoni, F.; Diamantini, G.; Piersanti,
G.; Righi, M.; Spadoni, G. Org. Lett. 2010, 12, 3844. (f) Repka, L. M.;
Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132, 14418. (g) Austin,
J. F.; Kim, S.-G.; Sinz, G. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5482. (h) Lozano, O.; Blessley, G.;
Martinez del Campo, T.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.;
Walker, M.; Borman, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011,
50, 8105. (i) Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 13606. (j) Liu, Y.; Xu, W.; Wang, X. Org. Lett.
2010, 12, 1448. (k) Liu, C.; Zhang, W.; Dai, L.-X.; You, S.-L. Org. Lett.
2012, 14, 4525. (l) Ref 8c.
(1) (a) Pearce, H. L. In The Alkaloids; Brossi, A., Suffness, M., Eds;
Academic: San Diego, CA, 1990; Vol. 37, p 145. (b) Anthoni, U.;
Christophersen, C.; Nielsen, P. H. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1999; Vol. 13, p 163.
(2) Dewick, P. M. Medicinal Natural Products; 3rd ed.; John Wiley &
Sons: West Sussex, U.K., 2009; p 366.
(3) Reviews of dearomatization reactions: (a) Roche, S. P.; Porco,
J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068. (b) Zhuo, C.-X.; Zhang,
W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662.
(4) Examples of indolenines as intermediates in syntheses: (a)
Robinson, R.; Suginome, H. J. Chem. Soc. 1932, 298. (b) Woodward,
R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker,
K. J. Am. Chem. Soc. 1954, 76, 4749. (c) Stork, G.; Dolfini, J. E. J. Am.
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Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628.
r
10.1021/ol4005992
Published on Web 04/08/2013
2013 American Chemical Society

furoindoline, or hexahydrocarbazoles as the products.7 Thus,
it is not surprising that only a few examples exist for dear-
omatizing allylation/benzylation of 3-substituted indoles to
give C3-quaternary indolenines,8 and the corresponding alky-
lation reactions with nonactivated electrophiles have been
rare.9 The development of new approaches for the dearoma-
tizing alkylation will significantly expand the scope of this
process and could provide new synthetic strategies to complex
indole alkaloids. Herein we report that N-indolytriethylbo-
rates are excellent reagents for synthesis of C3-quaternary
indolenines through dearomatizing alkylation of indoles with,
not only activated alkyl groups (such as allyl, benzyl, etc.) but
also nonactivated primary and secondary alkyl halides.
of indoles because of the electron-rich nature of the aro-
matic system and the tight NÀB association which would
prevent not only the competing N-alkylation but also the
C2-alkylation pathway, as well (Scheme 1).
We tested this hypothesis using benzylation of 3-methy-
lindole. Indeed, in the presence of Et3B, benzylation of
lithium 3-methylindolide, prepared by N-deprotonation
of the indole with n-BuLi, led to formation of indolenine
2a (Table 1, entry 1). Encouraged by this result, other
Table 1. Screening of Reaction Conditionsa
Scheme 1. C3-Alkylation of N-Indolyltrialkylborates
entry
additive
Et3B
base
solvent
THF
2a (%)
1
2
n-BuLi
n-BuLi
n-BuLi
n-BuLi
NaH
74
62
<10
NR
78
75
81
20
<10
23
68
94
70
82
80
78
53
17
hexyl-9-BBN
Ph3B
(F5C6)3B
Et3B
THF
3
THF
4
THF
5
THF
The N-deprotonation of indoles leads to the build up of
electron density. However, this does not necessarily trans-
late into increased π-nucleophilicity, as N1- and C2-alky-
lation may compete with the desired C3-alkylation of
indolides.10 Whereas magnesium, zinc, and some other
metal indolides have been employed in C3-nucleophilic
reactions to give 3-substituted indoles,11 presumably be-
cause the relatively stable covalent metalÀN bonds pre-
vent the N-alkylation pathway, these metal indolides
are only moderately nucleophilic, and low reactivity was
observed when 3-substituted indolides were employed
as the nucleophile. Our recent study of decarboxylative
allylic alkylation of allyl indolenin-3-carboxylates suggests
that N-indolyltrialkylborates are formed as reactive inter-
mediates.12 We envisioned that these species would be
useful π-nucleophiles for the dearomatizing C3-alkylation
6
Et3B
KH
THF
7
Et3B
t-BuOK
NaOMe
K2CO3
Et3N
THF
8
Et3B
THF
9
Et3B
THF
10
11
12
13
14
15
16
17
18
Et3B
THF
Et3B
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Et2O
Et3B
1,4-dioxane
DMF
Et3B
Et3B
toluene
CH2Cl2
1,4-dioxane
1,4-dioxane
1,4-dioxane
Et3B
Et3Bb
Et3Bc
a Reactions carried out with 0.50 mmol of 1a, 1.1 equiv of the base,
1.1 equiv of the borane additive, and 1.1 equiv of benzyl bromide at room
temperature. b 0.55 equiv of Et3B. c 0.30 equiv of Et3B.
trialkylboranes were briefly surveyed. The sterically bulky
n-hexyl-9-BBN gave a reasonable reaction yield (entry 2),
while only less than 10% of 2a was formed in the presence
of Ph3B (entry 3). The reaction did not proceed at all when
the more Lewis acidic (F5C6)3B was used as the additive
and 3-methylindole was recovered (entry 4). Various bases
were also tested for the reaction. While NaH (entry 5) and
KH (entry 6) gave results similar to that of n-BuLi, improved
reaction efficiency was obtained when t-BuOK was used
(entry 7). On the other hand, NaOMe was found to be
significantly less effective for the reaction (entry 8). Also
ineffective were K2CO3 and Et3N (entries 9 and 10), which
gave 2a in low yields only. A number of solvents were
screened, and 1,4-dioxane was found to give the highest yield
of 2a (entries11À15). In order to evaluate if the reaction could
be executed under catalytic conditions, the benzylation was
also tested using substoichiometric amount of Et3B. While
only C3-benzylation was observed under these conditions,
this was accompanied by reduced reaction efficiency under
otherwise identical reaction conditions (entries 16 and 17).
(8) For synthesis of C3-quaternary indolenines by transition metal-
catalyzed dearomatizing allylation and benzylation, see: (a) Zhu, Y.;
Rawal, V. H. J. Am. Chem. Soc. 2011, 134, 111. (b) Kagawa, N.;
Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381. (c) Trost,
B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314. (d) Eastman,
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740. (f) Chen, J.; Cook, M. J. Org. Lett. 2013, 15, 1088. (g) Montgomery,
T. D.; Zhu, Y.; Kagawa, N.; Rawal, V. H. Org. Lett. 2013, 15, 1140.
(9) (a) Fishwick, C. W. G.; Jones, A. D.; Mitchell, M. B. Heterocycles
1991, 32, 685. For synthesis of C3-quaternary indolenines by dearoma-
tizing alkylation with activated alkyl groups (allyl and benzyl), see: (b)
Tan, G. H.; Ganesan, A. Org. Lett. 2003, 5, 1801. (c) Solovjova, J.;
Martynaitis, V.; Magnelinckx, S.; Holzer, W.; De Kimpe, N.; Sackus, A.
Synlett 2009, 3119.
(10) (a) Espejo, V. R.; Rainier, J. D. J. Am. Chem. Soc. 2008,
130, 12894. (b) Heaney, H.; Ley, S. V. Org. Synth. 1974, 54, 58 and
those cited in ref 11.
(11) (a) Sharma, R.; Chouhan, M.; Sood, D.; Nair, V. A. Appl.
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2002, 67, 2705. (c) Powers, J. C.; Meyer, W. P.; Parsons, T. G. J. Am.
Chem. Soc. 1967, 89, 5812. (d) Nunomoto, S.; Kawakami, Y.; Yamashita,
Y.; Takeuchi, H.; Eguchi, S. J. Chem. Soc., Perkin Trans. 1 1990, 111.
(e) Wenkert, E.; Angell, E. C.; Ferreira, V. F.; Michelotti, E. L.; Piettre,
S. R.; Sheu, J.-H.; Swindell, C. S. J. Org. Chem. 1986, 51, 2343.
(12) Kaiser, T. M.; Yang, J. Submitted.
Org. Lett., Vol. 15, No. 8, 2013
1951

conditions to give the corresponding allylation and benzyla-
tion products in good yields. Benzylation of unsubstituted
indole under the optimized reaction conditions gave a mixture
of 3-benzyl indole (not shown) and 3,3-dibenzyl indolenine 2t
(1:1, 37%). The latter was exclusively formed when unsub-
stituted indole reacted with excess of t-BuOK and Et3B.
C3-Alkylation of 3-substituted indoles with less reactive
electrophiles is challenging and rarely reported.9 Thus, even
though an elevated reaction temperature (60À65 °C) was
necessary, we were pleased to observe that 2,3-dimethylin-
dole combined with nPrBr to give 2u in 65% yield under
otherwise identical reaction conditions. This alkylation
reaction could also be extended to secondary alkyl halides
such as (1-bromoethyl)benzene to give 2v as a mixture of
diastereomers (1.5:1). Cyclohexylbromide, a nonactivated
secondary alkyl halide, also smoothly combined with 2,3-
dimethylindole to give 2w in 45% yield. Unsurprisingly, the
reaction of 2,3-dimethylindole and t-butyl bromide did not
proceed under the reaction conditions (not shown).
Scheme 2. Scope of the Reactiona
This reaction protocol was also effective for dearomatiz-
ing alkylation of tryptamine derivatives, and the initial C3-
quaternary indolenine products underwent spontaneous
cyclization to give pyrroloindolines (Scheme 3). Thus, the
reaction of tryptamine derivatives (N-tosyl, N-CO2Me,
and N-Boc) and benzyl or allyl bromides led to formation
of the corresponding pyrroloindolines (4aÀ4h) in high
yields. N-Alkylation of the starting tryptamine derivatives
or the pyrroloindoline products was not observed. Inter-
estingly, furoindoline 4i was obtained as the sole product
when 1H-indole-3-ethanol was used, indicating that free
a Unless noted otherwise, the reaction was carried out with 0.50 mmol
of 1, 1.1 equiv of t-BuOK, 1.1 equiv of Et3B, and 1.1 equiv of alkyl halides
at room temperature for 12 h. b 60À65 °C. c 3.0 equiv of benzyl
bromide, 2.5 equiv of t-BuOK, and 1.5 equiv of Et3B. d 2.0 equiv of alkyl
halide, 60À65 °C, 36 h. e 3.0 equiv of cyclohexyl bromide, 90À95 °C, 36 h.
Unsurprisingly, in the absence of Et3B, N-benzylindole (not
shown) was generated as the major product (40%) while 2a
was formed in 17% yield only (entry 18).
We examined the scope of the reaction using various
substituted indoles and alkyl halides (Scheme 2). C2,C3-
Disubstitution was found to be compatible with the reaction
as 2b was formed in 85% yield upon reaction of 2,3-
dimethylindole and benzyl bromide. Benzyl bromides sub-
stituted with π-donating methoxyl, electron-withdrawing
chloride, or simple methyl groups all reacted with 2,3-
dimethylindole to give the corresponding C3-benzylation
products 2cÀ2f in high yields. Reactions of 2,3-dimethylin-
dole and various substituted allyl bromides proceeded
smoothly as well under the optimized reaction conditions
to give the C3-allylation products in unanimously good yields
(2gÀ2k). Hexahydrocarbazole readily reacted with benzyl
and allyl bromides to give the corresponding C3-quaternary
indolenines (2lÀ2p) with good efficiency. Indoles with var-
ious C3-substitutions were also compatible with the reaction
Scheme 3. Reaction of Tryptamine Derivativesa
(13) (a) Numata, A.; Takahashi, C.; Ito, Y.; Takaka, T.; Kawai, K.;
Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Terahe-
dron Lett. 1993, 34, 2355. (b) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg,
A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod.
2004, 67, 78. (c) Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci.
Biotechnol. Biochem. 2004, 68, 753. (d) Dalsgaard, P. W.; Blunt, J. W.;
Munro, M. H. G.; Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005,
68, 258. (e) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion,
G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124.
(14) Trialkylboranes may also participate through coordination with
the bromide and increase its activity as a leaving group; see: Jiang, Y.;
Hess, J.; Fox, T.; Berke, H. J. Am. Chem. Soc. 2010, 132, 18233.
(15) Recent reviews: (a) Li, S.-M. Nat. Prod. Rep. 2010, 27, 57.
(b) Ishikura, M.; Yamada, K.; Abe, T. Nat. Prod. Rep. 2010, 27, 1630.
a Unless noted otherwise, the reaction was carried out with 0.50 mmol
of 3, 1.1 equiv of t-BuOK, 1.1 equiv of Et3B, and 1.1 equiv of alkyl halide
at room temperature for 12 h. b 2.0 equiv of alkyl halides, 60À65 °C, 36 h.
c 3.0 equiv of cyclohexyl bromide, 90À95 °C, 36 h.
hydroxyl groups are also compatible with the reaction
conditions. The excellent π-nucleophilicity of indoles
1952
Org. Lett., Vol. 15, No. 8, 2013

Scheme 4. Synthesis of Hexahydropyridoindoline 6
Scheme 6. Synthesis of Pyrroloindoline-4-cholestene Hybrid
under this protocol was also demonstrated in reaction of
N-tosyltryptamine with nonactivated primary and second-
ary alkyl halides to give the corresponding pyrroloindolines
(4jÀ4l) that could not be synthesized by other means.
Hexahydropyridoindole, a structure motif found in
complex indole alkaloids such as communesins and
perophoramidine,13 is also accessible through this method.
Thus, reaction of 3-methylindole and 5 gave hexahydropyr-
idoindoline 6 in 75% yield under the reaction conditions
(Scheme 4).
Scheme 7. Synthesis of (()-Debromoflustramine B
We attribute the excellent indole π-nucleophilicity in the
dearomatizing alkylation process to formation of the electron-
rich N-indolyltriethylborates. These reagents are unlikely to
form between 7-substituted indoles and trialkylboranes be-
cause of the resulting severe 1,3-interactions. Indeed, reaction
of N-tosyl-7-methyltryptamine and benzyl bromide led to
exclusive formation of 7 (Scheme 5), indicating that forma-
tion of N-indolyltriethylborate is necessary for enhanced
π-nucleophilicity.14 Formation of N-indolytriethylborate
also serves to temporarily block the N1 and C2 positions
so that regioselective C3-alkylation occurs exclusively.
of N-Boc-tryptamine and prenyl bromide under the opti-
mized reaction conditions led to the formation of 10
(Scheme 7), which was subjected to further prenylation
and reduction with LiAlH4 to give debromoflustramine B
in 76% yield over three steps at 5.0 mmol scale.
Scheme 5. Benzylation of N-Tosyl-7-methyltryptamine
In summary, N-indolyltriethylborate was found to be an
excellent reagent for synthesis of C3-quaternary indole-
nines through dearomatizing alkylation of indoles with
not only activated alkyl groups but also nonactivated pri-
mary and secondary alkyl halides. These reactions proceed
under mild conditions with a broad range of substrates to give
C3-quaternary indolenines, pyrroloindolines, furoindoline,
and hexahydropyridoindoline in high yields. N1- or
C2-alkylation products were not formed. The utility of
these reagents was demonstrated in the synthesis of pyrro-
loindoline-4-cholestene hybrids and in the total synthesis
of debromoflustramine B.
Prenylated indole alkaloids are hybrids of indole and
isoprenoid units.15 These natural products are found in a
wide range of natural sources and often show interesting
biological and pharmacological properties. In order to
demonstrate the utility of this synthetic method, pyrro-
loindoline-4-cholestene hybrid 8 was synthesized as shown
in Scheme 6 through alkylation of 3 with known 4-choles-
ten-3-bromide.11b Even though the hybrid was formed as
a mixture of diasteromers, this method provides conveni-
ent access to these unique unnatural indoleÀisoprenoid
hybrids which might be of potential biomedical value.
The utility of this synthetic method was further demon-
strated in the total synthesis of debromoflustramine B,
a prenylated indole alkaloid isolated from the marine
briozoan Flustra foliacea, and the closely related pseudo-
phyrnamines, such as pseudophrynaminol.16 Thus, reaction
Acknowledgment. Financial support provided by the
Robert A. Welch Foundation (A-1700) and the National
Science Foundation (CHE-1150606).
Supporting Information Available. Experimental proce-
1
dures and characterization data, including H, 13C NMR,
and HRMS for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) Holst, P. B.; Anthoni, U.; Christophersen, C.; Nielsen, P. H.
J. Nat. Prod. 1994, 57, 997.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
1953