Synthesis of spirocyclic indolines by interruption of the Bischler-Napieralski reaction

Article abstract of DOI:10.1021/ol401465y

The development of a versatile method for the synthesis of spirocyclic pyrrolidinoindolines is discussed. Treatment of N-acyltryptamines with trifluoromethanesulfonic anhydride-2-chloropyridine reagent combination affords highly persistent spiroindoleninium ions that are subject to intra- and intermolecular addition at C2 by nucleophiles.

Full text of DOI:10.1021/ol401465y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Spirocyclic Indolines by
Interruption of the BischlerÀNapieralski
Reaction
Jonathan William Medley and Mohammad Movassaghi*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts
Avenue, Cambridge, Massachusetts 02139, United States
movassag@mit.edu
Received May 23, 2013
ABSTRACT
The development of a versatile method for the synthesis of spirocyclic pyrrolidinoindolines is discussed. Treatment of N-acyltryptamines with
trifluoromethanesulfonic anhydrideÀ2-chloropyridine reagent combination affords highly persistent spiroindoleninium ions that are subject to
intra- and intermolecular addition at C2 by nucleophiles.
Spirocyclic pyrrolidinoindolines are a ubiquitous sub-
structure in nature, representing the core of the aspi-
dosperma, strychnos, and kopsia alkaloid families, and are
prevalent also in pharmaceutically active compounds
and other fine chemicals (Figure 1).1 The importance of
this structural motif has motivated the development of a
number of elegant synthetic strategies in the context of
complex alkaloid synthesis.2 A direct route to the spiro-
pyrrolidinoindoline substructure would involve intramo-
lecular electrophilic trapping of an appropriate tryptamine
derivative at C3; however, the inherent tendency of
2H-indole systems to undergo rapid WagnerÀMeerwein
rearrangement (Scheme 1) makes such an approach diffi-
cult. Previously reported methods2c,g,3 for such transfor-
mations overcome this problem by employing strongly
nucleophilic intramolecular traps or electron-withdrawing
groups on the indole and aliphatic nitrogen to minimize such
rearrangements, which can still occur. We have recently
reported the use of an interrupted BischlerÀNapieralski
(1) (a) Brown, R. T. Indoles, The Monoterpenoid Indole Alkaloids.
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Saxton, J. E. In The Alkaloids, Chemistry and Biology; Cordell, G. A., Ed.;
Academic Press: San Diego, 1998; Vol. 51, p 1. (c) Dewick, P. M. In
Medicinal Natural Products: A Biosynthetic Approach, 2nd ed.; Wiley:
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McCoy, E. Recent Adv. Phytochem. 2006, 40, 1. (f) O’Connor, S. E. In
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r
10.1021/ol401465y
XXXX American Chemical Society

reaction as a highly stereoselective and general strategy for
the synthesis and arylative dimerization of aspidosperma
alkaloids.4 Herein, we report a method for the efficient
synthesis of spiropyrrolidinoindolines by interruption of
the BischlerÀNapieralski reaction of 2H-N-acyltrypta-
mines via persistent spiroindoleninium intermediates with
high resilience to WagnerÀMeerwein rearrangements.
Scheme 1. Plausible Mechanism for Spirocycle Formation
conditions, the spirocycle (()-3a-d6 was isolated in 29%
yield with complete deuterium retention on the alkenyl
methyl groups and no deuterium enrichment at C2 (eq 1).
Furthermore, when amide 1a was exposed to the reaction
conditions with lithium aluminum deuteride used in place
of triethylamine (after warming to 23 °C for 1 h), mono-
deuterated spirocycle (()-3a-d1 was isolated in 60% yield
with incorporation of exactly one deuterium atom at
C2 (eq 2, 6:1 dr at C2).9 This showed unequivocally that
(()-5a persists until an exogenous hydride source is intro-
duced to afford reduction at C2. We posited that triethyl-
amine might be acting as a hydride source,10,11 and
conjectured that the modest mass balance might be the
resultof spiroindoleninium (()-5aundergoing competitive
decomposition upon warming. Importantly, when lithium
aluminum hydride (eq 1) or lithium aluminum deuteride
(eq 2, without warming to 23 °C) were introduced 5 min
after warming the respective reactions to 0 °C, products
(()-3a-d6 and (()-3a-d1 were isolated in95and 96% yields,
respectively.
Figure 1. Representative spirocyclic pyrrolidinoindolines.
Earlier, we reported the use of the reagent combination
trifluoromethanesulfonic anhydride (Tf2O)-2-chloropyridine
(2-ClPyr)5 to induce the BischlerÀNapieralski reaction of
secondary amides.6 Interestingly, exposure of amide 1a to
Tf2O (1.1 equiv) in the presence of 2-ClPyr (1.2 equiv)
followed by warming and addition of excess triethylamine7
provided the expected BischlerÀNapieralski product 2a
(76%) along with the unexpected spirocyclic side product
(()-3a in low yield (∼5%, Scheme 1). The sulfonylation
of the amide nitrogen of spirocycle (()-3a was rationalized
by interception of a putative spirocyclic indoleninium
intermediate (()-4a with the slight excess of Tf2O to afford
spiroindoleninium (()-5a. Consistent with this hypothesis,
the use of excess Tf2O (2.1 equiv) and 2-ClPyr (3.2 equiv)
increased the yield of (()-3a to 30% together with a
complex mixture of side products and none of the BischlerÀ
Napieralski product 2a. Given the propensity of
spiropyrrolidino-indoleninium intermediates to undergo
WagnerÀMeerwein rearrangement unless a strongly nucleo-
philic trap is present during spirocyclization,2c,g,3aÀf,hÀk we
hypothesized that the reduction at C2 may have been the
result of a rapid hydride transfer reaction between two
intermediates along the reaction pathway (Scheme 1).8
However, such a disproportionation reaction was ruled
out with a concise set of deuterium labeling studies. When
hexadeuterated amide 1a-d6 was subjected to the reaction
These results suggested that spirocyclic N-trifluoro-
methanesulfonyl indoleninium (()-5a was electrophilic at
C2 but recalcitrant to undergo a WagnerÀMeerwein
rearrangement due to deactivation of the trifluoromethane-
sulfonamide nitrogen lone pair. Electrophilic activation
of 1a followed by reduction with lithium aluminum hy-
dride afforded spirocycle (()-3a in excellent yield (Table 1,
entry 1, 98% yield). When a less potent hydride source,
triethylsilane, was introduced after activation and the
(4) Medley, J. W.; Movassaghi, M. Angew. Chem., Int. Ed. 2012, 51,
4572.
(5) (a) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc.
2007, 129, 10096. (b) Medley, J. W.; Movassaghi, M. J. Org. Chem. 2009,
74, 1341. (c) Ahmad, O. K.; Medley, J. W.; Coste, A.; Movassaghi, M.
Org. Synth. 2012, 89, 549.
(6) Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10, 3485.
(7) The addition of triethylamine at the end of the reaction was
carried out with the intention of neutralizing the trifluoromethanesul-
fonate salts prior to workup.
(9) See Supporting Information for details.
(10) Product (()-3a was not detected when potassium carbonate or
1,4-diazabicyclo[2.2.2]octane was used for neutralization prior to
workup.
ꢀ
(11) Coquerel, Y.; Bremond, P.; Rodriguez, J. J. Organomet. Chem.
2007, 692, 4805.
(8) For a review on a classical redox disproportionation reaction, see
Geissman, T. A. Org. React. 1944, 2, 94.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Spirocyclization and Reduction
entry amide
R1
R2
temp (°C) time (min) yielda (%)
1
2
3
4
5
6
7
1a
1a
1b
1b
1b
1c
1d
Me Me
Me Me
0
23
0
5
30
30
5
98b
55
Motivated by a desire to extend the range of diastereo-
selective trappings of spiroindoleninium intermediates and
based on our prior synthetic work,4 we hypothesized that
nonenolizable tertiary amides would, upon activation with
Tf2OÀ2-ClPyr, undergo rapid spirocyclization to afford a
putative persistent diiminium dication resilient to WagnerÀ
Meerwein rearrangement. To our delight, treatment of
tertiary pivalamide 1f with Tf2OÀ2-ClPyr at 0 °C in
acetonitrile13 and warming to 23 °C, followed by sequen-
tial trapping with triethylsilane and lithium aluminum
hydride, afforded spirocyclic indoline (()-7f as a single
diastereomer9 in 91% yield (eq 5), suggesting the in situ
formation of a persistent diiminium ion intermediate. The
diastereoselectivity is likely a result of the steric bulk of the
arene, which blocks approach of lithium aluminum hy-
dride. Use of lithium aluminum deuteride in place of
lithium aluminum hydride afforded monodeuterated spir-
ocyclic indoline (()-7f-d1, demonstrating the regioselective
trapping at C2 with triethylsilane.9 Similarly, activation of
lactam 1g followed by tandem reduction with triethylsilaneÀ
lithium aluminum hydride afforded tetracyclic indoline
(()-7g in quantitative yield as a single diastereomer9 (eq 6).
Me
Me
Me
Bn
Ts
H
H
H
H
H
97
0
92b
72c
100
94
23
0
60
30
30
23
a Isolated yield. b LiAlH4 (3.0 equiv) used as reducing agent at 0 °C.
c Et3N (5.0 equiv) used as reducing agent.
resulting mixture warmed to ambient temperature, spiro-
cycle (()-3a was afforded in just 55% yield (Table 1,
entry 2). On the other hand, 1-methyl-N-acetyltryptamine
(1b), which bears no β-hydrogens, underwent highly effi-
cient spirocyclization and reduction to afford spirocycle
(()-3b using either triethylsilane (Table 1, entry 3, 97%
yield), lithium aluminum hydride (Table 1, entry 4, 92%
yield), or triethylamine (Table 1, entry 5, 72% yield) as
reducing agent. Spirocyclization followed by reduction
with triethylsilane proceeded smoothly with 1-benzyl-N-
acetyltryptamine (1c) and even with electron-deficient
1-p-toluenesulfonyl-N-acetyltryptamine (1d), providing
the corresponding spirocycles (()-3c (Table 1, entry 6,
100% yield) and (()-3d (Table 1, entry 7, 94% yield),
respectively.
Furthermore, trapping the spiroindoleninium of amide
1b at C2 with a carbon nucleophile, 1-methylindole,
afforded the spirocyclic indole adduct (()-6b in excellent
isolated yield (eq 3, 76%) as a single diastereomer.9 The
stereochemical outcome of the reaction is consistent with
approach of the 1-methylindole nucleophile opposite the
bulky and highly electronegative12 trifluoromethanesulfon-
amide moiety.
Additionally, we hypothesized that a rapid, reversible
nucleophilic trap at C2 with an oxygen nucleophile might
give a persistent intermediate that could be further deriva-
tized. Thus, treatment of tryptamineÀoxazolidinone urea
1e with Tf2O (1.1 equiv) and 2-ClPyr (2.2 equiv) followed
by sequential addition of 1-methyltryptamine, titanium
tetrachloride, and heating to 45 °C afforded 1-methyltrypt-
amine adduct (()-6e in 83% yield as a single diastereomer9
(eq 4) that was consistent with a nucleophile approach from
the same face of the spiroindoleninium as seen with amide
1b (eq 3). The use of titanium tetrachloride was found to be
essential to achieve CÀC bond formation, consistent with
competitive nucleophilic inibition at C2 by the oxazolidi-
none oxygen atom.
Encouraged by the efficiency of the spirocyclization/
intermolecular nucleophilic trapping protocol, we envisaged
a double-cyclization cascade making use of enolizable sec-
ondary amides with pendant nucleophiles. To explore and
optimize this transformation, tryptamineÀphenylacetamide
1h wasselectedassubstrate. ActivationwithTf2O(2.1equiv)
in the presence of 2-ClPyr (3.2 equiv) in CH2Cl2 followed
by warming to 23 °C provided pentacycle (()-8h in 40%
yield (Scheme 2) accompanied with monocyclized side
products and no recovered starting material or BischlerÀ
Napieralski derived products. Heating the reaction to
45 °C in an oil bath afforded (()-8h in excellent yield14
(Scheme 2, 91% yield), while brief heating in a microwave15
(13) Acetonitrile was used as solvent due to the poor solubility of the
activated intermediates in dichloromethane.
(14) 2-Chloropyridine was found to be the optimal base additive for
this reaction; the use of 2-fluoropyridine or 2,6-lutidine gave yields of 90
and 66%, respectively, of (()-8h under 45 °C conditions.
ꢀ
(12) Cherest, M.; Felkin, H.; Prudent, M. Tetrahedron Lett. 1968, 18,
2199.
Org. Lett., Vol. XX, No. XX, XXXX
C

amides is removed under reductive or eliminative condi-
tions: desulfonylation of pentacycle (()-8i with sodium
and ammonia in the presence of methanol provided pen-
tacyclic diamine (()-9i in excellent yield (95%) as a single
diastereomer (eq 7), while dehydrosulfinylation of tricycle
(()-3a is affected upon treatment with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) in acetonitrile under microwave
heating conditions (eq 8) to afford the unsaturated imine
(()-10a in 71% yield.
Scheme 2. Double-cyclization Cascadesa
a Isolated yields of single diastereomers. bTf2O (2.1 equiv), 2-ClPyr
(3.2 equiv), 130 °C (microwave), 5 min. c45 °C, 3 h. d23 °C, 3 h. eTf2O
We have presented a method for the efficient generation
of distinctively persistent spiroindoleninium intermediates
from secondary and tertiary N-acyl tryptamines. The ex-
ceptional resilience of the intermediates, accessed under
the described reaction conditions, to WagnerÀMeerwein
rearrangement allows for efficient intra- and intermolecu-
lar trapping with nucleophiles, including weak nucleo-
philes such as deactivated arenes, even after activation
and spirocyclization. The use of urea and tertiary amides
under our conditions allows for the direct and highly
diastereoselective synthesis of spiropyrrolidinoindolines
without competitive rearrangement2c,3a,3cÀ3e,3h,3k or the
need for an electron-withdrawing group2c,3a,3c,3d,3g,3j on
the aliphatic or indole nitrogen atoms.
f
(2.1 equiv), 2-ClPyr (3.2 equiv), 45 °C, 3 h. Tf2O (3.1 equiv), 2-ClPyr
(4.2 equiv), 130 °C (microwave), 10 min. gTf2O (3.1 equiv), 2-ClPyr
(4.2 equiv), 45 °C, 3 h.
to 130 °C provided (()-8h in quantitative yield. While
similar cascades have been reported previously, the lack of
any requirement of large excesses of activating agents3a,c,d
and the ability to completely avoid WagnerÀMeerwein
rearrangement3d are specific advantages to the chemistry
described here, and highlight the importance of nitrogen
lone pair deactivation by the highly electronegative trifluoro-
methanesulfonyl group. Not surprisingly, electron-rich
3,4-dimethoxyphenylacetamide 1i provided pentacycle (()-8i
in 98% yield as a single regio- and diastereomer9 under 45 °C
conditions on half-gram scale (Scheme 2). Even highly
electron-deficient 4-nitrophenylacetamide 1j afforded pen-
tacycle (()-8j in moderate yield (53%) under microwave
heatingconditions(130°C, 10min), and vinylacetamide 1k
afforded tetracyclic spiroindoline (()-8kin 56% yield after
heating at 45 °C. The trifluoromethanesulfonyl group
present in the spirocyclic indolines derived from secondary
Acknowledgment. We are grateful for financial sup-
port by NIHÀNIGMS (GM074825). M.M. is a CamilleÀ
Dreyfus TeacherÀScholar. J.W.M. acknowledges a National
Defense Science and Engineering Graduate Fellowship.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) (a) Hill, M. D.; Movassaghi, M. Tetrahedron Lett. 2008, 49, 4286.
For related reviews, see: (b) Caddick, S. Tetrahedron 1995, 51, 10403. (c)
Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57,
9225. (d) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX