Dearomative Indole Bisfunctionalization via a Diastereoselective Palladium-Catalyzed Arylcyanation

Article abstract of DOI:10.1021/acs.orglett.5b02403

The first Pd-catalyzed dearomative indole bisfunctionalization via a diastereoselective arylcyanation is reported. This method facilitates the formation of diverse indoline scaffolds bearing congested stereocenters with high levels of diastereoselectivity

Full text of DOI:10.1021/acs.orglett.5b02403

Letter
pubs.acs.org/OrgLett
Dearomative Indole Bisfunctionalization via a Diastereoselective
Palladium-Catalyzed Arylcyanation
David A. Petrone, Andy Yen, Nicolas Zeidan, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Canada, M5S 3H6
S
* Supporting Information
ABSTRACT: The first Pd-catalyzed dearomative indole bisfunctionalization via a diastereoselective arylcyanation is reported.
This method facilitates the formation of diverse indoline scaffolds bearing congested stereocenters with high levels of
diastereoselectivity. This also represents the first example of a cyanation mechanism involving a 2° benzylic Pd(II) intermediate.
ndolines represent privileged heterocyclic scaffolds, and due
Scheme 2. Approaches to Various Indoline Scaffolds via Pd-
I
to compounds containing this structural element exhibiting
Catalyzed Indole Dearomatizations
diverse biological activities, they have become highly sought after
for use as therapeutic agents.1 Thus, diverse methods that may
expediently access these frameworks have been the focus of
intense research effort.2 Specifically, indolines possessing one or
more fully substituted C-centers at C2 and C3 are of particular
interest, as these motifs are present in numerous complex natural
products (Scheme 1). Yet, general catalytic methods that easily
Scheme 1. Complex Indoline-Based Natural Products Bearing
Quaternary and Tetrasubstituted Tertiary C-Stereocenters
forge complex cores with this desirable substitution pattern
remain scarce in the literature.2o,q In light of this situation, we
envisioned simple 2-substituted indoles undergoing a highly
stereoselective, Pd-catalyzed dearomative bisfunctionalization
via a domino arylation/anion capture sequence3 to set the C2
and C3 stereocenters simultaneously. The transition-metal-
catalyzed dearomatization of (hetero)arenes has recently
become an attractive strategy that uses simple aromatic
substrates to yield products containing a high degree of
stereocomplexity.4 Elegant asymmetric dearomatizations have
been reported involving anilines5a and phenols,5b−d while others
have employed indoles6a−d and pyrroles6e as substrates.
Numerous metal-catalyzed (hetero)arene monofunctionaliza-
tions have also been reported that proceed via distinct
dearomatizations/rearomatization sequences (Scheme 2a, path
i).7,8 During these processes, catalytic intermediates (i.e., A) are
produced prior to the ultimate rearomatization step. Although
these intermediates possess a high level of stereochemical
information, there is still a paucity of methods that avoid the final
stereoablative rearomatization and retain this information via a
further functionalization step (Scheme 2a, path ii).
In 2012, Yao and Wu reported a Pd-catalyzed Heck-type
indole dearomatization involving carbopalladation of the C2−C3
moiety (Scheme 2b).9 This reaction facilitated the introduction
of a congested tetrasubstituted tertiary carbon center and gave
precedence for indole dearomatizations involving a carbopalla-
dation mechanism. More recently, Jia employed a simple
Pd(OAc)2/(R)-BINAP catalyst system to achieve the first
Received: August 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02403
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
asymmetric indole dearomatization, which proceeded via a
reductive Heck reaction (Scheme 2c).10 This method which is
rooted in previously reported reductive radical cyclizations of N-
(o-bromobenzoyl)indoles11 allows access to highly enantioen-
riched indolines bearing a similar tetrasubstituted tertiary carbon
center. However, despite the exquisite enantioselectivities
observed, the simple indoline products possess only a single
stereocenter and little functional group content. In line with
studies by our group12 and others,13 we envisioned that a
diastereoselective dearomative indole bisfunctionalization via an
arylcyanation would allow streamlined access to diverse indolines
bearing both a tetrasubstituted tertiary and a tertiary carbon
center at C2 and C3, respectively (Scheme 2d). To the best of
our knowledge, the reaction reported herein represents the first
example of a dearomative indole C2−C3 bisfunctionalization
proceeding via a carbopalladation mechanism.
in >20:1 dr. Increasing the concentration to 0.1 M in MeCN
showed no serious deleterious effects on yield (95%); yet, the dr
decreased to 19:1 (entry 2), which presumably results from
epimerization (cf. Table 2). Solvents such as DMF and dioxane
Table 2. Epimerization Studies for 2a
a
b
entry
solvent
additive (equiv)
dr
% yield (2a+2a′)
1
2
3
4
5
6
7
8
DMF
−
−
−
−
1.8:1
>20:1
>20:1
>20:1
>20:1
1:3
90
92
91
96
99
89
99
91
93
83
MeCN
1,2-DCE
PhMe
Our studies began by attempting the proposed dearomative
arylcyanation of 1a using previously established catalytic
conditions (eq 1).12 Examination of the crude reaction mixture
Dioxane
PhMe
−
HNBu2 (0.5)
c
DMF
−
>20:1
1.2:1
1:3
d
Dioxane
Dioxane
Dioxane
Zn(CN2) (0.55)
e
d
9
−
e
10
Pd(OAc)2 (0.05)
4.7:1
a
Determined by 1H NMR analysis of the crude reaction mixture.
b
c
d
Isolated yields. Reaction sparged with N2 for 18 h. Run in the
e
presence of Pd(OAc)2 (5 mol %) and DtBPF (5 mol %). Reaction
run for 4 h.
indicated full conversion of 1a to a mixture of two products. After
isolation, we assigned the structures as the desired indoline 2a
and the corresponding diastereomer 2a′. Single crystal X-ray
analysis later confirmed the relative stereochemistry of 2a, which
represents a syn-arylcyanation as anticipated. With this result in
hand, we proceeded to optimize the reaction to increase both the
yield and ratio of 2a:2a′.
were less effective and resulted in a higher level of epimerization
than MeCN (entries 3 and 4). PhMe was not an effective solvent
in this transformation and led to only 5% of the desired products,
albeit as a single stereoisomer (entry 5). Lowering the
temperature to 100 °C led to only partial conversion of 1a
(entry 6). Use of the Cl analog of 1a proved to be ineffective, and
2a was obtained in only 9% yield in 13:1 dr (entry 7). Other
After examining many parameters,14 Pd(OAc)2 (5 mol %) and
DtBPF (5 mol %) with Zn(CN)2 (55 mol %) in MeCN (0.067
M) at 110 °C for 18 h were found to be optimal (Table 1, entry
1). Under these conditions, 2a was obtained in 98% isolated yield
t
bulky phosphine ligands such as the DiPPF and BuXantphos
were not effective, and 1a was recovered quantitatively in both
instances (entries 8 and 9). The less toxic potassium hexacyano-
ferrate(II) was ineffective in this transformation, providing only
traces of 2a (entry 10). Finally, in the absence of Pd(OAc)2 or
DtBPF the reaction failed to provide 2a, and 1a was recovered
quantitatively (entries 11 and 12).
Table 1. Dearomative Indole Bisfunctionalization via Pd-
a
Catalyzed Arcylcyanation: Effect of Reaction Parameters
We sought to gain insight into the origin of 2a′ which was only
observed in reactions run in DMF and dioxane (Table 2).
Initially, when a sample of 2a (>20:1 dr) was resubjected to the
conditions from eq 1, epimerization occurred, producing a 1.6:1
mixture of 2a and 2a′ in 88% yield. However, in the absence of
catalyst, ligand, and Zn(CN)2, a 1.8:1 mixture of 2a and 2a′ was
still obtained in 90% yield (entry 1). Conversely, when 2a was
heated in neat MeCN, 1,2-DCE, PhMe, or dioxane, it was
recovered in high yield with no observable epimerization (entries
2−5), ruling out a strictly thermal process. Since DMF is known
to thermally decompose and hydrolyze in the presence of
moisture to products including HNMe2,15 we considered the
prospect of this byproduct facilitating epimerization. Accord-
a
a c
−
entry variation from the “standard” conditions
dr
yield 2a (%)
d
1
2
3
4
5
6
7
none
>20:1
19:1
1.6:1
3:1
99(98)
0.1 M instead of 0.067 M
DMF instead of MeCN
1,4-dioxane instead of MeCN
PhMe instead of MeCN
100 °C
95
90
92
5
>20:1
>20:1
13:1
−
37
9
ArCl instead of ArBr
DiPPF instead of DtBPF
tBuXantphos instead of DtBPF
K4Fe(CN)6 instead of Zn(CN)2
no Pd(OAc)2
e
8
9
<5
0
f
−
−
−
−
16
ingly, when 2a was heated in PhMe in the presence of HNBu2
e
e
10
11
12
<5
0
(0.5 equiv), indeed a 1:3 mixture of 2a and 2a′ was obtained in
89% yield (entry 6). In addition, epimerization was completely
suppressed when 2a was heated in DMF for 18 h with constant
nitrogen sparging (entry 7), providing further evidence for a base
mediated process. Since this argument could not be applied to
explain the observed epimerization in dioxane, we tested for the
ability of reaction components to mediate epimerization in
no DtBPF
0
a
Determined by 1H NMR analysis of the crude reaction mixture.
Combined yield of 2a and 2a′. Value in parentheses represents
isolated yields. Average value over three experiments. Quantitative
b
c
d
e
f
recovery of 1a. 0.22 equiv of K4Fe(CN)6 used.
B
DOI: 10.1021/acs.orglett.5b02403
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dioxane. Although neither Zn(CN)2 nor ZnBr2 (0.55 equiv)
caused epimerization, when 2a was reacted with Pd(OAc)2 and
DtBPF with or without Zn(CN)2 in dioxane, 1.2:1 and 1:3
mixtures of 2a and 2a′ were obtained in 91% and 93% yields,
respectively (entries 8 and 9). Even Pd(OAc)2 alone was found
to epimerize 2a in dioxane to some extent (dr = 4.7:1, entry 10).
To date, the exact origin for epimerization in dioxane remains
unclear. Another possibility may involve donation of the amide
nitrogen electron pair into the adjacent aryl group, causing
expulsion of −CN, which could then be reincorporated via a 1,4-
attack of the resulting N-benzoyl iminium species leading to the
observed stereochemical inversion.17
Scheme 3. Dearomative Indole Bisfunctionalization via Pd-
Catalyzed Arylcyanation: Reaction Scope
a c
−
Next, the conditions optimized for 1a were tested on a series of
indole substrates possessing sterically and electronically diverse
o-bromobenzoyl groups (Scheme 3). Indoline 2b could be
obtained in 51% yield as a single diastereomer, suggesting that
the reaction is sensitive to steric hindrance in close proximity to
the C−Br bond. F- and CF3-containing indolines 2c and 2e were
obtained in 94% and 96% yields with 20:1 and 12:1 dr.
Furthermore, Cl-containing 2d was obtained in 93% yield with
>20:1 dr. Electron-rich substrates were also well tolerated, and 2f
bearing an OMe moiety was afforded in 94% yield with >20:1 dr.
Ethyl groups (2g, 91%), benzylated alkyl alcohols (2h, 83%),
amines protected as phthalimides (2i, 98%), and alkyl chlorides
(2j, 64%) could be incorporated into the final products, which
were obtained with >20:1 dr. Various aromatic groups could
easily be incorporated at this position, and it was found that
electron-neutral, -rich, and -poor substrates were all converted to
the desired products 2k−2o with excellent yields and
selectivities. A methyl-indole-2-carboxylate substrate was also
reactive and was converted to the corresponding indoline 2p in
72% yield with 11:1 dr. To test the local electronic effects of the
indole component of 1, substrates 1q and 1r were synthesized
and subjected to the standard conditions. Electron-rich indoline
2q was obtained in 93% yield in >20:1 dr. Electron-deficient F-
containing 2r was obtained in 86% in >20:1 dr after only 5 h. In
an effort to incorporate heteroaromatic groups into the product
landscape, pyridine-containing 1s and thiophene-containing 1t
and 1u were tested. They were found to provide the desired
products 2s−2u in 40%, 78%, and 69% yield, respectively, all in
>20:1 dr. The initial substrates lacked a suitable β-H so C−CN
reductive elimination was the only option, but a substrate was
tested to determine the efficiency of C−CN bond formation vs
epimerization/β-H elimination or competing cyclization via C−
H functionalization.18 In practice, 2v can be obtained in 32%
yield in >20:1 dr, where the majority of the remaining mass
balance was recovered 1v. Substrate 1w possessing a 2,3-
dimethylindole motif was also tested, which would allow vicinal
tetrasubstituted C atoms to be forged in a single reaction.
Unfortunately, this reaction failed to produce any of the desired
indoline 2w, while only a catalytic amount of the product arising
from carbopalladation/β-H elimination was observed.9
a
b
Reactions were run on a 0.2 mmol scale unless otherwise stated. All
c
yields shown are combined isolated yields of the diastereomers. dr’s
1
were determined by H NMR analysis of the crude reaction mixture.
d
e
Reaction was run on a 1 g (3.17 mmol) scale. Reaction was run for 5
f
g
h. Pd(PtBu3)2 (10 mol %). Majority of the remaining mass balance
was 1v. Only Heck product was observed. Phth = Phthalimide.
h
yields, respectively. Indoline 2j was primed to undergo
intramolecular alkylation from the convex side to generate the
cis-angularly fused carbocycle-containing 6.
In summary, we have developed a Pd-catalyzed dearomative
bisfunctionalization of indoles that proceeds via an intra-
molecular arylcyanation mechanism. This also represents the
first cyanation reaction proceeding via a transmetalation to a 2°
benzylic Pd(II) intermediate. By using a Pd(OAc)2/DtBPF
catalyst system and Zn(CN)2, complex indolines bearing vicinal
tertiary and tetrasubstituted tertiary carbon stereocenters can be
obtained in excellent yields and dr from simple indoles. These
scalable conditions tolerate a broad variety of functional groups,
and by judiciously choosing MeCN, epimerization of the
products under the reaction conditions is largely inhibited.
Studies toward the application of this method and the
Finally, a series of derivitization experiments were carried out
to examine the synthetic utility of these indolines products
(Scheme 4). We reasoned that trapping of an α-cyano anion19
with the Davis oxaziridine20 would generate the cyanohydrin
alkoxide, which could spontaneously eliminate cyanide under the
reaction conditions to yield 3. This reaction proceeded using
NaHMDS as the base followed by the ( )-Davis oxaziridine to
generate ketone 3 in 74% yield. It was found that 2a could be
alkylated in >20:1 dr with NaH and either tert-butyl
bromoacetate or bromoacetaldehyde dimethyl acetal to generate
ester-containing 4 or aldehyde precursor 5 in 76% and 77%
C
DOI: 10.1021/acs.orglett.5b02403
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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development of an enantioselective variant are currently
underway in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02403.
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Industrial Chemistry; Wiley-VCH: Weinheim, 2010.
(16) HNBu2 was chosen due to its relatively high bp (159 °C).
(17) This pathway was suggested by a referee during the review
process. Attempts to trap the proposed intermediate with PhSH failed,
and only a mixture of 2a and 2a′ was obtained in 64% yield.
(18) Trace cyclized product resulting from C2−H functionalization
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All characterization data; 1H and 13C spectra (PDF)
Crystallographic data for 2a (CIF)
Crystallographic data for 4 (CIF)
Crystallographic data for 5 (CIF)
Crystallographic data for 6 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), the University of Toronto, and
Alphora Inc. for financial support. M.L. thanks the Canada
Council for the Arts for a Killam Fellowship. D.A.P. thanks
NSERC for a postgraduate scholarship (CGS-D). Dr. Alan
Lough (University of Toronto) is thanked for single-crystal X-ray
structural analysis of 2a, 4, 5, and 6.
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