Palladium-catalyzed hydrofunctionalization of vinyl phenol derivatives with heteroaromatics

Article abstract of DOI:10.1021/ol200913r

A hydroheteroarylation reaction of vinyl phenols using an alkyl chloride as the sacrificial hydride source is reported. The method tolerates a wide range of heterocycles as the exogenous nucleophile including indoles and pyrroles. The resulting products are easily processed to biologically relevant scaffolds.

Full text of DOI:10.1021/ol200913r

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2774–2777
Palladium-Catalyzed
Hydrofunctionalization of Vinyl Phenol
Derivatives with Heteroaromatics
Tejas P. Pathak and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States
sigman@chem.utah.edu
Received April 7, 2011
ABSTRACT
A hydroheteroarylation reaction of vinyl phenols using an alkyl chloride as the sacrificial hydride source is reported. The method tolerates a wide
range of heterocycles as the exogenous nucleophile including indoles and pyrroles. The resulting products are easily processed to biologically
relevant scaffolds.
In recent years, substantial attention has been given to
metal-catalyzed hydrofunctionalization reactions, in par-
ticular to hydroheteroarylation reactions.1 When using
vinyl arenes as substrates, these reactions rapidly generate
molecular complexity while also accessing 1,1-diaryl sub-
structures commonly found in biologically active com-
pounds.2 Various methods have been reported to access
such compounds including Au-3 and Ni-catalyzed4 hydro-
heteroarylation reactions. In this regard, our laboratory
has reported the use of styrenes5 and dienes6 as substrates
in oxidative Pd(II)-catalyzed hydrofunctionalization reac-
tions with organometallic reagents and either an alcohol5À7
or alkylzinc reagents8 as the hydride source. These reac-
tions have generally been limited to the introduction of
simple arenes and alkyl groups as the organometallic
reaction partner. Considering this limitation and our
recent discovery of lead compounds 1 and 2, which illicit
activity in breast cancer assays and arrest cells in different
phases of the cell cycle,9 we became interested in develop-
ing new alkene hydrofunctionalization reactions, which
allow for the facile incorporation of broad classes of
heteroaromatic compounds (Figure 1a). Herein we present
the design and development of such a reaction of vinyl
phenol derivatives, to access diverse analogues of 1 and 2,
(1) (a) Mitchell, D.; Yu, H. Curr. Opin. Drug Discovery Dev. 2003, 6,
876. (b) Goj, L. A.; Gunnoe, T. B. Curr. Org. Chem. 2005, 9, 671.
(c) Shen, H. C. Tetrahedron 2008, 64, 3885. (d) Foley, N. A.; Lee, J. P.;
Ke, Z.; Gunnoe, T. B.; Cundari, T. R. Acc. Chem. Res. 2009, 42, 585.
(e) de Mendoza, P.; Echavarren, A. M. Pure Appl. Chem. 2010, 82, 801.
(2) Howard, H. R., Jr.; Sarges, R. Preparation and formulation of
indolinone derivatives useful in treatment of diabetes-associated chronic
complications. EP 252713, 1988. (b) Howard, H. R.; Sarges, R.; Siegel,
T. W.; Beyer, T. A. Eur. J. Med. Chem. 1992, 27, 779. (c) Parenti, M. D.;
Pacchioni, S.; Ferrari, A. M.; Rastelli, G. J. Med. Chem. 2004, 47, 4258.
(d) Beaulieu, C.; Guay, D.; Wang, Z.; Leblanc, Y.; Roy, P.; Dufresne, C.;
Zamboni, R.; Berthelette, C.; Day, S.; Tsou, N.; Denis, D.; Greig, G.;
Mathieu, M.-C.; O’Neill, G. Bioorg. Med. Chem. Lett. 2008, 18, 2696.
(e) See Supporting Information for complete list.
(5) (a) Gligorich, K. M.; Cummings, S. A.; Sigman, M. S. J. Am.
Chem. Soc. 2007, 129, 14193. (b) Iwai, Y.; Gligorich, K. M.; Sigman,
M. S. Angew. Chem., Int. Ed. 2008, 47, 3219. (c) Gligorich, K. M.; Iwai,
Y.; Cummings, S. A.; Sigman, M. S. Tetrahedron 2009, 65, 5074.
(6) Liao, L.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 10209.
(7) (a) Zhang, Y.; Sigman, M. S. Org. Lett. 2006, 8, 5557.
(b) Gligorich, K. M.; Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc.
2006, 128, 2794.
(3) (a) Wang, M.-Z.; Wong, M.-K.; Che, C.-M. Chem.;Eur. J. 2008,
14, 8353. (b) Xiao, Y.-P.; Liu, X.-Y.; Che, C.-M. J. Organomet. Chem.
2009, 694, 494 and references therein..
(8) Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc. 2009, 131,
18042.
(9) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.; Sigman, M. S. J.
Am. Chem. Soc. 2010, 132, 7870.
(4) (a) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem.
Soc. 2006, 128, 8146. (b) Kanyiva, K. S.; Nakao, Y.; Hiyama, T.
Heterocycles 2007, 72, 677. (c) Nakao, Y.; Kashihara, N.; Kanyiva,
K. S.; Hiyama, T. Angew. Chem., Int. Ed. 2010, 49, 4451.
r
10.1021/ol200913r
Published on Web 04/21/2011
2011 American Chemical Society

which is proposed to be initiated by a Pd(0)-catalyzed
oxidative addition of an alkyl chloride to ultimately gen-
erate a Pd-hydride.
forms a quinone methide intermediate of type D to provide
a potent latent electrophile for nucleophilic addition.10
Initial investigation of this proposed process began with
the selection of Pd2(dba)3, P(Cy)3, and an alkyl bromide as
the potential hydride source based on Fu’s reported Pd-
catalyzed alkylÀalkylcross-couplings.11 Itshouldbenoted
that Fu’s conditions are generally utilized to slow β-
hydride elimination of the Pd-alkyl generated from oxida-
tive addition of an alkyl electrophile. However, when the
reactionisperformed above 50°C, β-hydrideelimination is
observed.11c Using vinyl phenol 3 and 1,2-dimethylindole
as the exogenous nucleophile, a 33% yield of the desired
product was observedat80°C. Unfortunately, a 26% yield
of the alkylated phenol was alsodetected (Table 1, entry 1).
Table 1. Optimization of Reaction Conditions
Figure 1. (a) Structure of proposed framework. (b) Addition
of N-methylindole to a vinyl phenol under previously reported
conditions.
We previously reported a hydroalkoxylation reaction of
vinyl phenols utilizing a coupled alcohol oxidation to form
a Pd-hydride followed by addition of the alcohol to a
proposed o-quinone methide intermediate.7a Under these
conditions, poor yields was observed when employing N-
methylindole as the exogenous nucleophile (Figure 1b).
Furthermore, indole derivatives lacking a protecting group
on nitrogen are not tolerated under our reported Pd(II)
oxidative catalytic conditions severely limiting the scope of
the process.9 On the basis of these observations, alternative
methods to generate the requisite Pd-hydride were con-
sidered. Specifically, oxidative addition of an alkyl electro-
phile to form A followed by β-hydride elimination to
generate a Pd-hydride B is proposed (Scheme 1). Of note,
β-hydride elimination is generally considereddeleterious in
cross-coupling of alkyl electrophiles. Using a vinyl phenol
as a substrate, addition of the Pd-hydride to yield C and
subsequent electron transfer from the substrate to Pd
entry
X
ligand
RX
t(h) % conva % 6b % 7b
1
20 P(Cy)3 2 equiv C12H25Br 48
87
71
68
44
76
65
81
98
98
96
33
35
35
20
42
63
76
82c
26
24
30
18
26
<2
<2
<2
2
10 dcpe
10 dppf
2 equiv C12H25Br 48
2 equiv C12H25Br 48
3
4
10 BINAP 2 equiv C12H25Br 48
17 P(Cy)3 2 equiv C12H25Br 48
5
6
17 P(Cy)3 4 equiv CyBr
17 P(Cy)3 4 equiv C4H9CI
60
60
7
8
9
17 P(Cy)3 6 equiv C4H9CI 72
17 P(Cy)3
À
72
72
40c NA
31c,d NA
10
_
_
_
a The conversion was measured by GC with an internal standard.
b The yield was determined by GC with an internal standard. c Isolated
yield. d No Pd catalyst and base added. Concentration of the reaction
mixture (with respect to 3): 0.1 M.
Use of bidentate ligands did not improve the reaction
outcome (Table 1, entries 2À4). Modest improvement
was observed by changing the ligand loading (Table 1,
compare entries 1 and 5). Considering that the phenol
alkylation process most likely is the result of an SN2
reaction, other less reactive electrophiles were evaluated.
Using either a secondary bromide or an alkyl chloride, a
significant reduction of the phenol alkylation product was
observed with concomitant slowing of the desired hydro-
functionalization reaction (Table 1, entries 6 and 7). The
use of butyl chloride was preferred due to the low cost
(∼$ 0.03/g) and simplicity. Upon further optimization,
excellent yield and selectivity is achieved (Table 1, entry 8).
Scheme 1. Proposed Mechanism
(10) Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc.
2010, 132, 17471.
€
(11) (a) Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 10099. (b) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 13178. (c) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu,
G. C. J. Am. Chem. Soc. 2002, 124, 13662.
Org. Lett., Vol. 13, No. 10, 2011
2775

When, a control experiment in the absence of alkyl chloride
was performed (Table 1, entry 9), to our surprise, product
formation was observed presumably via a 1,5-sigmatropic
rearrangement albeit in lower yield.12a Additionally, a reaction
of the vinyl phenol with 1,2-dimethyl indole in the absence of
any catalyst was performed to achieve a similar yield (Table 1,
entry 10). It should be noted that such 1,5-sigmatropic
rearrangements are not commonly used for o-QM formation
and functionalization and often require more forcing condi-
tions.12 While these control experiments suggest that alter-
native mechanistic pathways are operational for product
formation (vide infra), the presence of the Pd catalyst and
the alkyl chloride significantly improves the reaction outcome.
Having optimized the reaction conditions, the reaction
scope was evaluated. Unprotected 1H-indole gave the
product in 80% isolated yield with >90% recovery
of the remaining nucleophile (Table 2, entry 2a).2e,13
Unprotected indoles/heteroaromatics as nucleophiles
are beneficial because they not only avoid an undesired
protectionÀdeprotection sequence but also provide flexi-
bility for further synthetic modifications. N-alkyl substi-
tuted indoles perform well giving products in good yields
(entries 2b and 2c). Indoles with different steric and
electronic parameters are well tolerated under the reaction
conditions including various substitution at the 2-position
(entry 2dÀ2i). Additionally, a 3-substituted indole under-
goes addition from the 2-position allowing entry into this
important compound class (entry 2j). The reaction is not
limited to the use of indoles as the nucleophilic heterocycle
as demonstrated by the successful use of pyrroles, an
indolizine, and a furan (entry 2kÀ2o). Additionally, the
nature of the phenol was evaluated with both electron
withdrawing and electron rich vinyl phenols giving good
yields of the desired products (entry 2pÀ2s). Furthermore,
p-vinylphenol also reacts under the optimized conditions,
albeit a low yield of the product was observed (entry 2t).
Table 2. Substrate Scope of Hydrofunctionalization of Vinyl
Phenols
Figure 2. Rapid access to various biologically relevant scaffolds.
The phenol, which is a mechanistic requirement for
o-QM formation, provides a handle for further functiona-
lization of the products into biologically relevant scaffolds
as demonstrated in Figure 2.2e Conversion of phenol 2a to
the corresponding aryl triflate followed by intramolecular
Heck reaction gives a known antioxidant 8 in 87% yield
(Figure 2a).14 Related tetracyclic indanoindole scaffolds
are also found in various biologically active compounds
(12) (a) Hansen, H.-J. Helv. Chim. Acta 1977, 60, 2007. (b) Hug, R.;
Hansen, H.-J.; Schmid, H. Helv. Chim. Acta 1972, 55, 1828.
(13) For other examples see: El Kaim, L.; Grimaud, L.; Oble, J. Org.
Biomol. Chem. 2006, 4, 3410.
(14) (a) Talaz, O.; Gulcin, I.; Goksu, S.; Saracoglu, N. Bioorg. Med.
Chem. 2009, 17, 6583. (b) Brown, D. W.; Graupner, P. R.; Sainsbury,
M.; Shertzer, H. G. Tetrahedron 1991, 47, 4383.
a Yields are average of at least two runs at 0.3 mmol scale. b Reactions
performed at 100 °C. c 1 mL of nucleophile was used. d Performed on
1.5 mmol scale. e Ratio of C2/C3 alkylatlon = 4:1.
2776
Org. Lett., Vol. 13, No. 10, 2011

showcasing diverse biological activity.14a,15 Compound 2a
can also be converted to compound 9 in excellent yield via
reduction of the corresponding aryl triflate (Figure 2b),
which leads to a styrene hydroheteroarylation product and
is a common pharmacological framework.2 Additionally,
the treatment of compound 2a with NBS gives the tetra-
cyclic compound 10 in excellent yield (Scheme 3c).
To further explore the utility of this method, an inverse
electron-demand DielsÀAlder reaction with an electron-
rich cyclic enamine was conducted (Scheme 2). The reac-
tion proceeds smoothly to give chromane derivative 11 in
63% yield as a single diastereomer. This showcases the
utility of the developed method to generate relatively
complex frameworks from a simple substrate in a single
step.
reaction conditions results in <5% deuterium incorpora-
tion into the product (Scheme 3a). In contrast, excellent
incorporation of deuterium (>95%) is observed when using
a deuterated alkyl bromide (Scheme 3b).16 These experi-
ments suggest that a mechanism involving a Pd-hydride is
directly involved in product formation but does not rule out
multiple reaction pathways, including a 1,5-sigmatropic
rearrangement, for any specific substrate evaluated.17
Scheme 3. Deuterium-Labeling Experiments
Scheme 2. Inverse Electron Demand Diels-Alder Reaction
In conclusion, we have successfully utilized a simple
and inexpensive alkyl chloride to generate a proposed Pd-
hydride, which is used to initiate an alkene hydrofunctiona-
lization reaction. This approach offers a distinct mechanistic
alternative to most reported hydrofunctionalization reac-
tions including previous work from our laboratory that has
focused on oxidative palladium catalysis. The reaction dis-
plays a broad scope in reaction partners, and the products
formed through this reaction can be rapidly processed to
biologically relevant scaffolds. Future work is focused on the
evaluation and comparison of the compounds produced
using this method to compounds 1 and 2 in breast cancer
assays as well as exploiting the use of alkyl halides to generate
a Pd-hydride for new reaction development.
While the control experiments performed in the optimi-
zation suggest that the catalyst and the alkyl chloride are
not required to observe product, the enhancement of yield
advocates for a role of both. Therefore, the origin of the
hydrogen atom in product 2a was explored through two
isotopic labeling experiments. First, treating deuterated
phenol 12 with an alkyl bromide under otherwise standard
(15) (a) Alper, P.; Marsilje, T.; Chatterjee, A.; Lu, W.; Mutnick, D.;
Roberts, M. J.; He, Y. Preparation of benzo[a]carbazole and indeno-
[1,2-b]indole derivatives as TPO mimetics. WO 2007009120, 2007.
(b) Marsilje, T. H.; Alper, P. B.; Lu, W.; Mutnick, D.; Michellys, P.-Y.; He,
Y.; Karanewsky, D. S.; Chow, D.; Gerken, A.; Lao, J.; Kim, M.-J.; Seidel,
H. M.; Tian, S.-S. Bioorg. Med. Chem. Lett. 2008, 18, 5259. (c) Wierzbicki,
M.; Boussard, M.-F.; Rousseau, A.; Atassi, G.; Hickman, J.; Pierre, A.;
Leonce, S.; Guilbaud, N.; Kraus-Berthier, L. Indenoindoline deriva-
tives, process for their preparation, and pharmaceutical compositions
containing them, for use in the treatment of cancer. EP 2002291463,
2002.
Acknowledgment. This research was supported by
the National Institutes of Health (RO1GM3540 and
R01CA140296).
(16) The major side product in both of these cases was alkylated
phenol.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) While Brønsted acid catalysis is unlikely under the basic reaction
conditions, it should be noted that the use of TsOH (20 mol %) at 80 °C
does promote this reaction to give 72% yield of compound 2a. However,
acid-sensitive nucleophiles such as furans and enamines are not compa-
tible under these acidic conditions.
Org. Lett., Vol. 13, No. 10, 2011
2777