Palladium-catalyzed synthesis of 2-cyanoindoles from 2-gem-dihalovinylanilines

Article abstract of DOI:10.1021/acs.orglett.7b02244

An efficient Pd(0)-catalyzed synthesis of 2-cyanoindoles from 2-gem-dihalovinylanilines is reported. Few methods have aimed to synthesize these scaffolds which are found in many natural products and have high bioactivity. This protocol features a robust c

Full text of DOI:10.1021/acs.orglett.7b02244

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Synthesis of 2‑Cyanoindoles from 2-gem-
Dihalovinylanilines
Nicolas Zeidan, Sabine Bognar, Sophia Lee, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: An efficient Pd(0)-catalyzed synthesis of 2-
cyanoindoles from 2-gem-dihalovinylanilines is reported. Few
methods have aimed to synthesize these scaffolds, which are
found in many natural products and have high bioactivity. This
protocol features a robust catalyst system utilizing Zn(TFA)2 to
prolong the catalytic activity. Additionally, the amount of cyanide
in the reaction phase is minimized by taking advantage of the
solubility of Zn(CN)2 in a two-solvent mixture.
Scheme 2. Metal-Catalyzed Syntheses of 2-Substituted
Indoles
etal-catalyzed cyanation of aromatic and heteroaromatic
Mcompounds has been an important research objective, as
nitriles serve as versatile synthetic handles for functional group
manipulation.1−3 Derivatives of 2-cyanoindoles exhibit high
bioactivity and can be identified in many natural products and
pharmaceutical agents (Scheme 1).4,5
Scheme 1. Examples of Biologically Relevant Compounds
Featuring 2-Cyanoindole-Derived Cores
Recent protocols have utilized Rh,6,7 Pd,8 Cu,9 Co,10 or Mn/
Zn11 as catalysts to activate the C−H bond at the 2-position of
indoles for cyanation (Scheme 2a). These methods allow
functionalization of indoles without prefunctionalization of the
starting material. However, the use of specific directing groups,
which are removed under harsh conditions, limits the scope of
the free indole products. Our group12−17 and others18−20 have
developed protocols for the synthesis of functionalized
heterocycles from vinylic gem-dihalide substrates (Scheme
2b). The reaction involves two orthogonal coupling reactions:
a Buchwald−Hartwig-type coupling to form the core hetero-
cycle and a second coupling reaction such as a Suzuki, Heck, or
Sonogashira coupling. Seminal reports by Hartwig21−23 of the
reversibility of oxidative addition with a bulky palladium
catalyst into aryl−halogen bonds led our group to develop a
catalytic synthesis of 2-bromoindoles in the absence of a
coupling partner.24 Herein we report a protocol for the
palladium-catalyzed synthesis of 2-cyanoindoles from 2-gem-
dihalovinylanilines and an external source of cyanide to
terminate the coupling sequence (Scheme 2c).
We began our studies with conditions similar to those
previously reported24 and the use of Zn(CN)2 as the cyanide
source. After screening reaction parameters, we found Pd(t-
Bu3P)2 (5 mol %), Zn(CN)2 (0.55 equiv), Zn(TFA)2 (10 mol
%), and K3PO4 (2 equiv) in PhMe−DMA (3:1) at 110 °C for
18 h on a 0.5 mmol scale to be our optimal conditions for 2a in
74% yield (Table 1, entry 1). The reaction was run on a 1
mmol scale with no change in yield (Table 1, entry 2). The use
of the gem-dichloride is possible, delivering the product in
comparable yield (Table 1, entry 3).
When no additive was used, the reaction was irreproducible
and failed to fully consume all of the starting material (Table 1,
Received: July 21, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b02244
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Table 1. Optimized Conditions
Scheme 3. Scope of the Pd(0)-Catalyzed Synthesis of 2-
a
Cyanoindoles from gem-Dibromides
entry
change to standard conditions
none
conv. (%) 2a (%) 2a′ (%)
1
2
3
4
5
full
full
full
92
74
73
78
−
−
−
5
double the scale (1 mmol)
dichloride instead of dibromide
no additive
55
a
a
Zn dust instead of Zn(TFA)2
Zn(OAC)2 instead of Zn(TFA)2
no DMA
85
58
−
−
70
−
b
c
6
full
full
46
42
15
11
b
7
b
8
PhMe−DMA (1:1)
a
b
Average of three runs. Yield determined by 1H NMR analysis of the
crude mixture using 1,3,5-trimethoxybenzene as an internal standard.
c
Large amounts of 3 were isolated (42%).
entry 4). Grushin and Macgregor have recently described the
modes of Pd catalyst deactivation during cyanations by the
presence of air, water, amines, and excess cyanide.25 Limited
reports on the use of Zn(0) and Zn(OAc)2 to improve catalytic
turnover are available.26,27 When Zn(0) was used, improved
conversion was observed, but the reaction remained irreprodu-
cible with variance in the yield of up to 30% in parallel studies
(Table 1, entry 5). The use of Zn(OAc)2 was detrimental to the
reaction, and large amounts of bromoalkyne 3 were produced
(Table 1, entry 6). The trifluoro variant was used to reduce the
basicity of the acetate counterion in order to prevent the
elimination from occurring. Zn(TFA)2 led to full consumption
of the starting material and the highest yield consistently.
Although the role of the additive is unclear, it may facilitate
transmetalation.
The solvent ratio was carefully selected to accommodate the
opposing polarity requirements for cyclization12−17,24 and
cyanation,3 as they necessitate the use of nonpolar and polar
conditions, respectively. In the absence of DMA as a cosolvent,
full consumption of the starting material, is achieved and 2a′ is
the major product (Table 1, entry 7). The bromoindole is a
likely intermediate in the reaction (vide infra), suggesting that
the cyanation is slower. We reasoned that the lower reactivity
was the result of the poor solubility of Zn(CN)2 in PhMe.25 In
contrast, poor conversions were observed in a 1:1 solvent ratio
(Table 1, entry 8). Only 2a was observed, suggesting that
cyanation of 2a′ occurred rapidly but with poor catalytic
turnover. A 3:1 solvent ratio was found to be ideal for a
consecutive cyclization/cyanation. We believe that this may also
moderate the amount of Zn(CN)2 present in solution
throughout the reaction, hence slowing the formation of
catalytically inert, coordinatively saturated palladium com-
plexes. DMA proved to be better than other polar solvents
such as THF and MeCN because of its high boiling point.
Reactions with DMF yielded greater amounts of 3 as a
byproduct, presumably by solvent decomposition at high
temperatures.28
a
b
Reactions were run on a 0.5 mmol scale. Pd(t-Bu3P)2 (7.5 mol %),
c
Zn(TFA)2 (15 mol %), 120 °C. From 4-bromo-2-(2,2-dibromovinyl)-
aniline using Zn(CN)2 (2.2 equiv).
synthesis of 1a−q was realized from the nitroaldehydes by
olefination using CBr4 and reduction as we previously reported
(see the Supporting Information). Extending the aromatic
system to the naphthyl ring delivered product 2b with no loss
in yield (74%). Alkyl substitution adjacent to the aniline or the
vinyl dibromide delivered products 2c and 2d in 71% and 69%
yield, respectively. Alkyl and benzyl groups on the aniline
nitrogen provided the N-capped indoles with no loss in yield
(2e−g, 72%, 72%, 77%), even when a sterically demanding
isopropyl group was used. Placing an electron-donating OMe at
the para position relative to the aniline gave an improved yield
(2h, 77%), presumably by increasing the nucleophilicity of the
nitrogen. In contrast, an electron-withdrawing substituent para
to the aniline, as in 2i and 2j bearing CO2Me and F,
necessitated slightly higher catalyst loading and higher
temperature to achieve full consumption (48%, 67%). A Cl-
containing aniline was well-tolerated and delivered product 2k
with minimal loss in yield (70%). An opposite trend was found
for the electronic effect of the position para to the olefin. While
the methoxy substitution required forcing conditions to deliver
product 2l in 68% yield, the methyl ester-containing scaffold
reacted smoothly to afford product 2m in 75% yield. Fluorine
substitution led to product 2n, albeit in reduced yield (61%).
Having similar electronic properties to 1h, 1o reacted smoothly
to afford 2o in slightly improved yield (77%). Interestingly, the
highly electron-rich nature of the scaffold bearing the dioxolane
ring was more challenging, providing 2p in reduced yield
(53%). Upon treatment under the standard conditions, Br-
containing scaffold 1q led to a complex mixture, possibly
because of competing cyanation of the aryl ring. Increasing the
With our optimized conditions in hand, we proceeded to
investigate the scope of the transformation (Scheme 3). The
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Zn(CN)2 loading to 2.2 equiv afforded 2q in satisfactory yield
(61%).
To further evaluate the mechanism of the transformation and
gain insight into the roles of the observed species, 2a′ and 3
were synthesized. Subjecting 2a′ to the standard conditions
delivered the desired product in 93% yield (eq 1):This result
To show the synthetic versatility of these products, a one-pot
derivatization was perfomed (Scheme 5). Upon completion of
the Pd step, NaN3 and NH4Cl were added to the vial, and upon
heating for 14 h, 4 was isolated in 65% yield.
Scheme 5. One-Pot Derivatization To Afford the
Corresponding Tetrazole
supports the proposal that the reaction proceeds via the
formation of 2a′. In contrast, when 3 was subjected to the same
conditions, 60% of the material was recovered unreacted with
no other compounds identified (eq 2):This result suggests that
3 is part of a nonproductive decomposition pathway leading to
loss in mass balance under these conditions.
In conclusion, we have developed a convenient method for
the synthesis of 2-cyanoindoles from easily accessible aniline
precursors. This reaction utilizes an additive that maintains the
catalytic activity and a solvent mixture that limits the cyanide
concentration in the reaction phase to prevent catalyst
poisoning. Finally, the versatility of the products was
demonstrated by extending the protocol to a one-pot
transformation of the nitrile to the tetrazole.
We sought to investigate the order of events, i.e., the
possibility that cyanation occurs prior to cyclization. Although
we have never observed these products in reactions carried out
to partial conversions, this sequence remains a plausible
pathway since oxidative addition of a catalyst across the C−
(E)-Br bond would give the kinetically favored product.
Selective coupling of the C−(E)-Br with boronic acids is
known,14 but any attempts29 to cyanate by selective cross-
coupling led to full recovery of unreacted starting material. The
difficulty of this cyanation by metal-catalyzed methods raises
doubt about cyanation occurring prior to cyclization.
A plausible mechanism for the reaction is shown in Scheme
4. Oxidative addition into the C−Br bond of 1a provides the
stabilized palladacycle. Deprotonation of the aniline and
reductive elimination provides 2a′. Oxidative addition into
the C2−Br bond occurs reversibly. Transmetalation from a zinc
species and reductive elimination delivers 2a and regenerates
the catalyst.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02244.
■
S
Procedures, characterization data, and 1H/13C NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
ORCID
Nicolas Zeidan: 0000-0002-7959-5005
Notes
The authors declare no competing financial interest.
Scheme 4. Proposed Mechanism
ACKNOWLEDGMENTS
■
We thank the Natural Science and Engineering Research
Council (NSERC), the University of Toronto, and Alphora Inc.
for financial support. N.Z. thanks the Province of Ontario for a
graduate scholarship (OGS). S.B. thanks the German Academic
Exchange Service (DAAD) for a scholarship. S.L. thanks
NSERC for a summer scholarship. We thank Dr. D. A. Petrone
(Eidgenossische Technische Hochschule Zurich) and Dr. I.
̈
̈
Franzoni (University of Toronto) for helpful discussions
throughout the project.
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DOI: 10.1021/acs.orglett.7b02244
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