A one-pot double C-H activation palladium catalyzed route to a unique class of highly functionalized thienoisoquinolines

Article abstract of DOI:10.1021/ol3009655

The synthesis of a unique class of highly functionalized 3,4-thienoisoquinolines via an efficient palladium-catalyzed one-pot, regioselective double C-H activation is presented. This class of biologically relevant compounds has been prepared in five steps from commercially available starting materials with overall yields ranging from 27 to 62%. A masked carboxylic acid was used to direct C-H activation to the typically less reactive C4 position. Additionally, the carboxylic acid provides a synthetically useful handle for further functionalization.

Full text of DOI:10.1021/ol3009655

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2738–2741
A One-Pot Double CÀH Activation
Palladium Catalyzed Route to a Unique
Class of Highly Functionalized
Thienoisoquinolines
Nicholas W. Y. Wong and Pat Forgione*
Department of Chemistry & Biochemistry, Concordia University, 7141 rue Sherbrooke
ꢀ
O. H4B 1R6, Montreal, QC, Canada and Centre for Green Chemistry & Catalysis,
Montreal, QC, Canada
ꢀ
pat.forgione@concordia.ca
Received April 13, 2012
ABSTRACT
The synthesis of a unique class of highly functionalized 3,4-thienoisoquinolines via an efficient palladium-catalyzed one-pot, regioselective
double CÀH activation is presented. This class of biologically relevant compounds has been prepared in five steps from commercially available
starting materials with overall yields ranging from 27 to 62%. A masked carboxylic acid was used to direct CÀH activation to the typically less
reactive C4 position. Additionally, the carboxylic acid provides a synthetically useful handle for further functionalization.
Heteroaromatics continue to play an important role in
the discovery of new drugs against a range of diseases.1,2
However, a key criterion in drug discovery remains the
need to prepare inhibitors that are orally bioavailable.
Toward this aim, guidelines have been established to
evaluate which lead structures are most likely to achieve
this important property.3 A key criterion is the need to
prepare compounds that have a relatively low molecular
weight while maintaining high structural diversity. There-
fore, the ability to prepare densely functionalized hetero-
aromatics in a facile and modular manner is important
since it allows the exploration of a diverse region of
chemical space without significantly increasing the molec-
ular weight of potential lead structures. Toward this
end, palladium catalyzed cross-coupling reactions4 have
emerged as an important tool for the preparation of aryl-
substituted heteroaromatics in drug discovery.5 However,
ꢀ
(4) For selected references: (a) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Martin, R.;
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S. P. Acc. Chem. Res. 2008, 41, 1440.
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Wang, L.; Liu, G.; Geng, M.; Zhang, A. J. Med. Chem. 2011, 54, 2127.
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(6) For selected examples employing Pd: (a) Campeau, L.-C.;
Fagnou, K. Chem. Commun. 2006, 1253. (b) Campeau, L.-C.; Schipper,
D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266. (c) Campeau,
L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.; Gorelsky, S.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276. (d) Satoh, T.; Kametani,
Y.; Terao, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997, 36,
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Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337.
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J. Org. Chem. 2009, 74, 1826. (g) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu,
J.-H.; Luo, D.-F.; Xu, J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250. (h)
Karthikeyan, J.; Cheng, C.-H. 2011, 50, 9880. (i) Derridj, F.; Roger, J.;
Djebbar, S.; Doucet, H. Org. Lett. 2010, 12, 4320. (j) Chen, L.; Bruneau,
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r
10.1021/ol3009655
Published on Web 05/11/2012
2012 American Chemical Society

an emerging understanding ofthe human footprint and the
impact on the environment has led to the development of
alternatives to classical palladium mediated cross-coupling
reactions. CÀH activation has emerged as a method to
circumvent the requirement of prefunctionalization of the
organometallic components.6,7 Therefore, the ability to
perform multiple CÀH activation reactions on a substrate
using a single set of reaction conditions to prepare densely
functionalized heteroaromatics would greatly facilitate
library synthesis that is important for drug discovery.
Despite the many advantages of CÀH activation, lim-
itations arise when more than one activated hydrogen is
available, which leads to selectivity issues. As an example,
when 3-methyl thiophene undergoes CÀH activation under
palladium catalysis conditions (Scheme 1, conditions a)
with an aryl-bromide, a mixture of C2-arylation (2, R =
Me) and C5-arylation (3, R = Me) in a 3.3 to 1 ratio is
obtained.8 Doucet provided a solution to this issue by
manipulating the C3-susbstituent to favor either C2- or
C5-arylation. He demonstrated that employing an alde-
hyde at the C3-position (1, R = CHO) improves the
selectivity for C2-arylation (Scheme 1, conditions b, ratio
of 2:3 = 81:19, R = CHO). The selectivity could be
reversed by increasing the steric bulk at C3 and converting
the aldehydes to the corresponding acetal (R = CH(OEt2)
to obtain C5ÀH activation as the major product (ratio of
3:2 = 24:76, R = CH(OEt)2) (Scheme 1, conditions b).9
Although an improvement in selectivity was achieved, a
mixture of products was obtained in all cases and isolated
yields of the desired isomer were modest.
simultaneously. The masked carboxylic acid group would
direct intramolecular C4ÀH activation while also allowing
exclusive intermolecular arylation at C5. The Itami group
has demonstrated elegant conditions to selectively arylate
the C4-position of thiophenes;11 however our route re-
quired conditions that would allow both C4 and C5
arylation to occur simultaneously. The carboxylic acid
could then be unmasked providing a synthetic handle for
further functionalization.8,12,13 To our knowledge, only
one synthesis of these biologically important compounds
has been reported by the group of Bogza, which required
the heating of an advanced intermediate under harsh
acidic conditions at elevated temperatures for an extended
period of time.14
Scheme 2. Proposed Route towards Thienoisoquinolines
Our modular synthesis begins with a commercially
available thiophene (8) which was functionalized with a
variety of sulfonyl chlorides resulting in the corresponding
sulfonamides. These sulfonamides were subsequently ben-
zylated in good to excellent yields over two steps giving rise
to the functionalized key intermediates (4) (Table 1).
Benzyl-sulfonamides (4aÀg) were then subjected to
double CÀH activation conditions with a variety of
aryl-bromides (Table 2). Rewardingly, this double
Scheme 1. C2- vs C5-Arylation
During our efforts to prepare thienoisoquinoline inhi-
bitors of estrogen receptor NFκB,10 we proposed a double
arylation (Scheme 2) of an advanced intermediate (4) to
streamline the synthesis of these densely functionalized
heteroaromatics. To prepare these highly functionalized
thienoisoquinolines and circumvent the limitation of CÀH
activation selectivity, we envisioned employing a car-
boxylic acid derivative at the C2-position that allows
for a single set of conditions to undertake both C4-
intramolecular arylation and C5-intermolecular arylation
(11) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew.
Chem., Int. Ed. 2010, 49, 8946.
(12) For a recent review, see: Cornella, J.; Larrosa, I. Synthesis 2012,
44, 653.
(13) For selected examples: (a) Gooßen, L. J.; Zimmermann, B.;
Knauber, T. Angew. Chem., Int. Ed. 2008, 47, 7103. (b) Goossen, L. J.;
Rodrıguez, N.; Lange, P. P.; Linder, C. Angew. Chem., Int. Ed. 2010, 49,
1111. (c) Lange, P. P.; Goossen, L. J.; Podmore, P.; Underwood, T.;
Sciammetta, N. Chem. Commun. 2011, 47, 3628. (d) Goossen, L. J.;
Linder, C.; Rodrıguez, N.; Lange, P. P. Chem.;Eur. J. 2009, 15, 9336.
(e) Goossen, L. J.; Lange, P. P.; Rodrıguez, N.; Linder, C. Chem.;Eur.
J. 2010, 16, 3906. (f) Goossen, L. J.; Rodrıguez, N.; Melzer, B.; Linder,
C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (g)
Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662. (h)
Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005,
127, 10323. (i) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem.
Soc. 2002, 124, 11250. (j) Becht, J.-M.; Le Drian, C. Org. Lett. 2008, 10,
3161. (k) Bilodeau, F.; Brochu, M.-C.; Guimond, N.; Thesen, K. H.;
Forgione, P. J. Org. Chem. 2010, 75, 1550. (l) Mitchell, D.; Coppert,
D. M.; Moynihan, H. A.; Lorenz, K. T.; Kissane, M.; McNamara, O. A.;
Maguire, A. R. Org. Process Res. Dev. 2011, 15, 981.
(7) For selected reviews: (a) Newhouse, T.; Baran, P. S. Angew.
Chem., Int. Ed. 2011, 50, 3362. (b) Ackermann, L.; Vincente, R.; Kapdi,
A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (c) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(8) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey,
M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11351.
(9) Dong, J. J.; Doucet, H. Eur. J. Org. Chem. 2010, 611.
(10) Coghlan, R. D.; Fobare, W. F.; Trybulski, E. J. Thienoisoquino-
line-Phenylsulfonamides and Their Use as ER-NFkappaB Inhibitors,
U.S. 2006/0154875, Wyeth (2006).
(14) Zinchenko, S. Y.; Efimenko, R. A.; Suikov, S. Y.; Kobrakov,
K. I.; Bogza, S. L. Chem. Heterocycl. Compd. 2009, 45, 365.
Org. Lett., Vol. 14, No. 11, 2012
2739

Preparation of our model substrate (Table 2, entry 2)
demonstrates the potential of this sequence on an indus-
trial scale. The three-step, four-reaction process was per-
formed on a gram scale converting 8 to 5b in a 75% overall
yield using only recrystallization and trituration as purifi-
cation techniques, circumventing the need for large quan-
tities of silica gel for purification.
Table 1. Synthesis of Key Intermediate
The methyl ester present at C2 was employed to direct
the intramolecular arylation at C4 and allow C5-intermo-
lecular arylation to occur exclusively and in high yields.
Subsequently, the ester was hydrolyzed in quantitative
yields and the resulting acid was subjected to proto-
decarboxylation (Table 3). The corresponding product
was obtained over two steps in yields ranging from mod-
erate to excellent and tolerates a variety of substituents.
The products 7aÀi can be further arylated at C2 via CÀH
activation.
entry
Ar
product
yielda (%)
1
2
3
4
5
6
7
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
4-O2N-C6H4
4-F-C6H4
4a
4b
4c
4d
4e
4f
76
69
87
79
41
61
63
2-thiophene
4g
a Yields over two steps, isolated and characterized after each step. (1)
Aryl sulfonyl chloride (1.5 equiv) was added to a solution of 8 (1 equiv) in
pyridine (0.8 M) and was heated to 50 °C for 1 h. (2) Bromobenzyl-
bromide (1.2 equiv) was added to a solution of K2CO3 (2 equiv), and
sulfonamide (1 equiv) in DMF (0.3 M) and heated to 50 °C for 16 h.
Table 3. Proto-decarboxylationa
C4/C5-arylation protocol yielded a wide range of desired
products in high yields. Although coupling with bromo-
benzene (entry 1) proceeded in modest yield, all other
couplings proceeded in very good to excellent yields,
including both electron rich (entries 2, 3, and 6À9) and
electron poor (entries 4, 5) aryl-bromides. Importantly, the
efficiency of the reaction is demonstrated by only requiring
1 equiv of aryl-bromide. Lastly, without the addition of an
external aryl-bromide, C4-arylation is obtained exclusively
in excellent yield (entry 10).
entry
Ar
Ar2
product
yield (%)
1
2
3
4
5
6
7
8
9
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
4-F-C6H4
C6H5
7a
7b
7c
7d
7e
7f
55
65
78
84
70
69
70
68
78
3-MeO-C6H4
4-MeO-C6H4
3-HOOC-C6H4
4-HOOC-C6H4
3-MeO-C6H4
3-MeO-C6H4
3-MeO-C6H4
3-MeO-C6H4
7g
7h
7i
Table 2. Double CÀH Activation Scopea
a 5 was dissolved in a 1:2:1 mixture of 2 M NaOH/THF/MeOH and
brought to reflux for 1 h. The resulting acid (6) was isolated and then
dissolved in DMF. 6 in DMF was then added to a microwave vial
containing PdCl2 (0.05 equiv), PtBu3 HBF4 (0.05 equiv), and Cs2CO3
3
(1.5 equiv) purged with argon, sealed, and irradiated at 170 °C for 8 min.
Additionally, preliminary results demonstrate that
the carboxylic acid can be used as a synthetic handle
for direct arylation via decarboxylative cross-coupling
(Scheme 3); current efforts are focused on optimizing this
transformation.
entry
Ar
R
product
yield (%)
1
2
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
4-F-C6H4
C6H5
5a
5b
5c
5d
5e
5f
64
99
90
97
81
80
81
79
90
96
3-MeO-C6H4
4-MeO-C6H4
3-EtOOC-C6H4
4-EtOOC-C6H4
3-MeO-C6H4
3-MeO-C6H4
3-MeO-C6H4
3-MeO-C6H4
H
3
4
5
6
Scheme 3. Decarboxylative Cross-Coupling
7
5g
5h
5i
8
9
10
4-Me-C6H4
5j
a Ar2ÀBr (1 equiv) was added to a solution of 4 (1 equiv), Pd(OAc)2
(0.05 equiv), PCy3 HBF4 (0.1 equiv), PivOH (0.3 equiv), K2CO3 (1.5
3
equiv) in DMF (0.1 M) and heated to 100 °C for 6 h.
2740
Org. Lett., Vol. 14, No. 11, 2012

ꢀ
In conclusion, we have reported an efficient, modular
synthesis of highly substituted 3,4-thienoisoquinoline sys-
tems, featuring a one step palladium-catalyzed regioselec-
tive double CÀH activation, from a commercially available
thiophene. The use of a masked carboxylic acid promotes
intramolecular C4-arylation and intermolecular C5-aryla-
tion in a single pot in excellent yields. This method provides
facile access to a densely functionalized biologically impor-
tant set of heteroaromatics. Current research is aimed
toward the further functionalization of the thiophene core
employing the carboxylic acid as a synthetic handle.
Canada and Le Fonds de Recherche du Quebec, Nature
et Technologies (FQRNT). Support was also kindly
provided by Boehringer Ingelheim, Wyeth, Merck Frosst,
and Concordia University. Special thanks to Anne-
ꢀ
Catherine Bedard (Universite de Montreal) and Professor
Shawn Collins (Universite de Montreal) for their assis-
ꢀ
ꢀ
ꢀ
ꢀ
tance in preparing this manuscript.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Thisworkwas fundedbythe Natural
Sciences and Engineering Research Council (NSERC) of
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2741