Selectively substituted thiophenes and indoles by a tandem palladium-catalyzed multicomponent reaction

Article abstract of DOI:10.1021/ol061373t

A variety of di- and trisubstituted thiophenes were synthesized by a one-pot palladium-catalyzed ortho-alkylation sequence terminated by either Heck or C-H coupling. Initial results toward the functionalization of indoles are also presented.

Full text of DOI:10.1021/ol061373t

ORGANIC
LETTERS
2
006
Vol. 8, No. 18
939-3942
Selectively Substituted Thiophenes and
Indoles by a Tandem
3
Palladium-Catalyzed Multicomponent
Reaction
Koichi Mitsudo, Praew Thansandote, Thorsten Wilhelm, Brian Mariampillai, and
Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received June 5, 2006
ABSTRACT
A variety of di- and trisubstituted thiophenes were synthesized by a one-pot palladium-catalyzed ortho-alkylation sequence terminated by
either Heck or C−H coupling. Initial results toward the functionalization of indoles are also presented.
5
Polysubstituted thiophenes are useful compounds for both
thiophenes. We are interested in the sequential substitution
of aromatic compounds and recently reported a method for
1
2
pharmaceutical and material sciences. While a number of
methods have been reported for their preparation, selective
substitution remains as a challenging goal.1 Various se-
quential substitution reactions have been reported for aro-
6
the formation of fused aromatic rings based on the work of
Catellani and co-workers.
We have extended the ortho-alkylation procedure to
include heteroaryl halides and now report a route to
selectively functionalized thiophenes.
,5
7
3,4
matic compounds, most notably using palladium catalysis;
however, there are few reports in this area pertaining to
Initial studies found that 2-iodothiophene is a poor
substrate for the tandem ortho-alkylation/Heck coupling
reaction. Thus, we examined commercially available 3-iodo-
thiophene (1) as a substrate (Table 1). Among several
(
1) (a) Press: J. B. In The Chemistry of Heterocyclic Compounds:
Thiophene and Its DeriVatiVes; Gronowitz, S., Ed.; John Wiley & Sons:
New York, 1991; Vol. 44, Part 4, pp 397-502. (b) Pillai, A. D.; Rathod,
P. D.; Xavier, F. P.; Vasu, K. K.; Padh, H.; Sudarsanam, V. Bioorg. Med.
Chem. 2004, 12, 4667-4671. (c) Sall, D. J.; Bastian, J. A.; Briggs, S. L.;
Buben, J. A.; Chirgadze, N. Y.; Clawson, D. K.; Denney, M. L.; Giera, D.
D.; Gifford-Moore, D. S.; Harper, R. W.; Hauser, K. L.; Klimkowski, V.
J.; Kohn, T. J.; Lin, H.-S.; McCowan, J. R.; Palkowitz, A. D.; Smith, G.
F.; Takeuchi, K.; Thrasher, K. J.; Tinsley, J. M.; Utterback, B. G.; Yan,
S.-C. B.; Zhang, M. J. Med. Chem. 1997, 40, 3489-3493.
2
parameters tested, Pd(OAc) and tri-2-furylphosphine (TFP)
in CH CN gave the best yield of the desired product 2a
3
8
,9
compared to the direct Heck product 3. The amount of
norbornene greatly affects the yield of 2a, improving with
(
2) (a) Inganaes, O.; Berggren, M.; Andersson, M. R.; Gustafsson, G.;
Hjertberg, T.; Wennerstroem, O.; Dyreklev, P.; Granstroem, M. Synth. Met.
995, 71, 2121-2124. (b) Wolf, M. O. AdV. Mater. 2001, 13, 545-553.
3) (a) Hegedus, L. S. In Transition Metals in the Synthesis of Complex
Organic Molecules, 2nd ed.; University Science Books: Sausalito, CA,
999. (b) Tsuji, J. Palladium Reagents and Catalysts; John Wiley:
Chichester, 2004.
4) (a) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56,
959-5989. (b) Negishi, E.; Cop e´ ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem.
ReV. 1996, 96, 365-394.
5) Hassan, J.; Gozzi, C.; Schulz, E.; Lemaire, M. J. Organomet. Chem.
003, 687, 280-283 and references therein.
(6) (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045-
1046. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem.
2001, 66, 8127-8134. (c) Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org.
Chem. 2002, 67, 3972-3974. (d) Pache, S.; Lautens, M. Org. Lett. 2003,
5, 4827-4830. (e) Alberico, D.; Paquin, J.-F.; Lautens, M. Tetrahedron
2005, 61, 6283-6297. (f) Bressy, C.; Alberico, D.; Lautens, M. J. Am.
Chem. Soc. 2005, 127, 13148-13149.
(7) (a) Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994,
33, 2421-2422. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 119-122. (c) Faccini, F.; Motti, E.; Catellani, M.
J. Am. Chem. Soc. 2004, 126, 78-79.
1
(
1
(
5
(
2
1
0.1021/ol061373t CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/03/2006

Table 1. Optimization of Domino Alkylation/Heck Reaction
Scheme 2. Proposed Mechanism
a
yield (%)
tert-butyl
Cs2CO3
entry solvent ligand acrylate (equiv) (equiv)
2a
3
b
1
2
3
4
5
6
7
8
9
DME
DME
Dioxane TFP
CH3CN
CH3CN
DME
DME
CH3CN
CH3CN
PPh3
TFP
5
5
5
5
5
2
2
2
2
2
2
2
2
2
5
5
5
5
<1
<1
<1
<1
37
75
69
80
56
46
43
59
56
26
0
0
0
0
b
b
b
TFP
TFP
PPh3
TFP
TFP
PPh3
a
Isolated yields. b With 2 equiv of norbornene.
increasing equivalents of norbornene and reaching a maxi-
mum at 6 equivalents.
The optimal conditions of 1 (1.0 equiv), 1-iodobutane (10
equiv), and tert-butyl acrylate (2.0 equiv) at 80 °C in CH
in the presence of Pd(OAc) (10 mol %), TFP (20 mol %),
norbornene (6.0 equiv), and Cs CO (5.0 equiv) gave the
trisubstituted product 2a in 91% yield (Scheme 1). The use
of 3-bromothiophene under the same reaction conditions gave
3
CN
2
Alternatively, C-H activation of the 4-position could take
place in the first step; however, at this time we do not know
which C-H activation occurs first. Heck reaction with 4e
yields product 2a. We believe an excess of norbornene is
needed to compete with the direct Heck pathway.
The scope of this reaction is presented in Table 2. In all
cases, trisubstituted products were obtained in moderate to
high yields. In addition to tert-butyl acrylate, ethyl and
2
3
2a in 33% yield.
11
Scheme 1. Optimal Conditions for the Domino
Ortho-Alkylation/Heck Coupling Reaction
Table 2. Scope of the Ortho-Alkylation/Heck Coupling
The proposed mechanism is presented in Scheme 2.7,10
Pd(0) inserts into the C-I bond of 3-iodothiophene,
entry
R1
R2
2 (yield, %)a
followed by carbopalladation of norbornene to give 4a. C-H
activation of the 2-position forms 4b. Oxidative addition of
the alkyl iodide leads to the Pd(IV) species 4c and reductive
elimination generates 4d. This process then occurs for the
-position C-H bond, and extrusion of norbornene gives
the 2,4-dialkylated 3-(thienyl)palladium(II) complex 4e.
1
2
3
4
5
6
7
8
9
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
CO2-t-Bu
CO Et
CO2Me
C(O)NMe2
C(O)NH-t-Bu
C(O)Et
CO2Et
CO2Et
2a (91)
2b (96)
2
b
2c (65)
c
2d (70)
4
b
2e (54)
2f (52)
2g (74)
2h (82)
2i (55)c
TBSO(CH2)3
Ph(CH2)3
Cl(CH2)3
(8) The use of Pd(OAc)2 as a palladium source gave the best selectivity.
b
The reaction using Pd2(dba)3‚CHCl3 or PdCl2(CH3CN)2 as a catalyst
precursor gave the direct Heck product as the major product together with
trace amounts of the desired compound.
CO2-t-Bu
a
Isolated yields. b With 4 equiv of norbornene. c With 10 equiv of
(
9) The use of PPh3 also gives 2a in comparable but lower yields.
(10) This mechanism is based on mechanistic studies of Catellani,
norbornene.
Pregosin, and co-workers (ref 6c,d) and on our own preliminary studies.
3940
Org. Lett., Vol. 8, No. 18, 2006

methyl acrylate can be used as Heck acceptors (entries 1-3),
as well as acrylamides (entries 4-5) and ethylvinyl ketone
Table 3. Scope of Ortho-Alkylation/C-H Coupling
(
entry 6). A variety of iodides with remote reactive functional
groups were also tolerated under the reaction conditions
entries 7-9). The ortho-alkylation/Heck coupling reaction
(
was further extended to 3-iodobenzo[b]thiophene (5) to give
the adduct 6 in 56% yield. Using a bis-acceptor produced
tricyclic compound 7 in 55% yield (Scheme 3). To the best
of our knowledge, these are the first examples of Heck
reactions using 3-iodobenzo[b]thiophenes.
a
entry
R
yield (%)
1
2
3
4
5
CO2Et
1-oxirane
2-(1,3)-dioxolane
N-phthalimide
CN
10a (42)
10b (54)
10c (36)
10d (24)
10e (26)
Scheme 3. Ortho-Alkylation/Heck Couplings Using 5
a
Isolated yields. b Slow addition.
ing step from 4e is a C-H coupling using isopropylboronic
acid. Though the yields are moderate to low, a variety of
functional groups are tolerated, and afford products which
are difficult to synthesize using classical methods. The
functionalized alkyl chains can also be useful synthetic
handles for further modification.
To create tri- and tetrasubstituted thiophenes, the 5-position
was functionalized using direct thiophene arylation16 to
generate a 2,4,5-trisubstituted thiophene (11a) and tetra-
substituted thiophenes (11b and 11c) (Scheme 5) in good
yields from the parent compounds.
To create an unsymmetrically substituted thiophene at the
2
- and 4-positions, regioselective halogen-magnesium ex-
1
2
change of 2,3-diiodothiophene with EtMgCl (1.1 equiv)
13
produced the 2-substituted Grignard reagent, which under-
14
went Kumada-Tamao-Corriu coupling with iodobenzene
(1.2 equiv) and Pd(PPh
3 4
) (10 mol %) to give 8 in 80% yield
(
Scheme 4). Subjecting 8 to our optimized conditions gave
Scheme 5. Direct Thiophene Arylation of Selectively
unsymmetrically substituted thiophene 9 in 82% yield.
Scheme 4. Use of 2,3-Diiodothiophene
Substituted Thiophenes
Our next goal was to extend the methodology to the
functionalization of indoles, a structural motif that is very
common in a number of natural products and medicinally
important compounds. After careful screening of the reaction
parameters, we were able to achieve 81% yield of the desired
(
11) Typical procedure for sequential alkylation/alkenylation reaction of
3
0
-iodothiophene (Table 2, entry 1): A mixture of 3-iodothiophene (42 mg,
.2 mmol), 1-iodobutane (368 mg, 2.0 mmol), tert-butyl acrylate (53 mg
To generate 2,4-disubstituted thiophenes, an ortho-alkyl-
ation/C-H coupling previously developed in our group for
0.4 mmol), Pd(OAc)2 (4.5 mg, 10 mol %), TFP (9.3 mg, 20 mol %),
norbornene (113 mg, 1.2 mmol), and Cs2CO3 (326 mg, 1.0 mmol) in dry
CH3CN (2.0 mL) was stirred at 80 °C for 20 h under nitrogen. After being
cooled to room temperature, the resulting mixture was treated with water
and extracted with Et2O. The combined organic phase was dried over
MgSO4 and concentrated under reduced pressure. The residue was chro-
matographed on silica gel (hexane/AcOEt ) 20/1-10/1) to afford 2a (59
mg, 91%) as a pale yellow oil.
iodoarenes15 was applied to 3-iodothiophene to produce 10
(Table 3). Compared to arenes, lower temperatures and
longer reaction times were needed to inhibit thiophene
polymerization and decomposition. The mechanism for this
transformation is similar to Scheme 2, although the terminat-
Org. Lett., Vol. 8, No. 18, 2006
3941

addition, 3-iodobenzo[b]thiophene and 2-substituted 3-iodo-
thiophene can be used. Application of our ortho-alkylation/
C-H coupling produces 2,4-disubstituted thiophenes, and
direct arylation of di- and trisubstituted thiophenes produces
Scheme 6. Optimized Coupling for 2,3 Coupling of
-Iodoindole
3
2,4,5-trisubstituted and tetrasubstituted thiophene derivatives.
Finally, this methodology has also been extended to include
indoles, the scope of which is currently under investigation
and will be reported in due course.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the University of Toronto, the Natural
Sciences and Engineering Research Council of Canada
product 13 (Scheme 6). Fortuitously, it could be crystallized
which provided a method to unquivocally prove the structure
of 13. During the course of optimization, it was found that
the nature of the nitrogen protecting group was crucial to
the efficiency of the reaction. Use of a methyl protecting
group yielded only the direct Heck product.
In summary, we have established a palladium-catalyzed
tandem alkylation/alkenylation reaction of 3-iodothiophene
to construct trisubstituted thiophenes in good yields. In
(NSERC), and Merck Frosst Canada for an IRC. We also
thank Dr. Alan Lough (University of Toronto) for X-ray
structure determination. P.T. thanks NSERC for Canada
Graduate Scholarships (CGSM and CGSD). B.M. thanks Dr.
Dino Alberico (University of Toronto) for helpful discus-
sions.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Knochel and co-workers reported that polyfunctional arylmagnesium
and alkenylmagnesium reagents can be prepared by iodine-magnesium
exchange reaction: Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel,
F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
2
003, 36, 4302-4320 and references therein.
OL061373T
(
13) Regioselective halogen-magnesium exchange reaction of 2,3-
dibromothiophene was reported; see: Christophersen, C.; Begtrup, M.;
Ebdrup, S.; Petersen, H.; Vedsø, P. J. Org. Chem. 2003, 68, 9513-9516.
(16) (a) Gozzi, C.; Lavenot, L.; Ilg, K.; Penalva, V.; Lemaire, M.
Tetrahedron Lett. 1997, 51, 8867-8870. (b) Okazawa, T.; Satoh, T.; Miura,
M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286-5287. (c) Lavenot,
L.; Gozzi, C.; Ilg, K.; Orlova, I.; Penalva, V.; Lemaire, M. J. Organomet.
Chem. 1998, 567, 49-55. (d) Glover, B.; Harvey, K. A.; Liu, B.; Sharp,
M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301-304.
(
14) For reviews on Kumada-Tamao coupling, see: (a) Tamao, K. J.
Organomet. Chem. 2002, 653, 27-33. (b) Hayashi, T. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John
&
Wiley & Sons: Hoboken, NJ; 2002; Vol. 1, pp 791-806.
15) Wilhelm, T.; Lautens, M. Org. Lett. 2005, 7, 4053-4056.
(
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