One-pot tandem palladium-catalyzed decarboxylative cross-coupling and C-H activation route to thienoisoquinolines

Article abstract of DOI:10.1002/adsc.201300924

Two experimental approaches to the synthesis of a scarcely reported biologically active thienoisoquinoline system are demonstrated. A 5-step linear synthesis employing a palladium-catalyzed decarboxylative cross-coupling and functionalization sequence allowed for the preparation of a diverse range of substituted thienoisoquinoline systems. Alternatively the palladium-catalyzed decarboxylative cross-coupling and C-H activation steps can be telescoped to produce a one-pot reaction sequence that provides efficient access to aryl-substituted thienoisoquinolines.

Full text of DOI:10.1002/adsc.201300924

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DOI: 10.1002/adsc.201300924
One-Pot Tandem Palladium-Catalyzed Decarboxylative Cross-
À
Coupling and C H Activation Route to Thienoisoquinolines
Fei Chen,a Nicholas W. Y. Wong,a and Pat Forgionea,*
a
Department of Chemistry & Biochemistry, Concordia University, 7141 rue Sherbrooke O., and Centre for Green
Chemistry and Catalysis, H4B 1R6, Montrꢀal, QC, Canada
E-mail: pat.forgione@concordia.ca
Received: October 16, 2013; Revised: January 27, 2014; Published online: April 15, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300924.
Abstract: Two experimental approaches to the syn-
thesis of a scarcely reported biologically active thi-
ACHTUNGTRENNUNGenoisoquinoline system are demonstrated. A 5-step
linear synthesis employing a palladium-catalyzed
decarboxylative cross-coupling and functionaliza-
tion sequence allowed for the preparation of a di-
verse range of substituted thienoisoquinoline sys-
tems. Alternatively the palladium-catalyzed decar-
À
boxylative cross-coupling and C H activation steps
can be telescoped to produce a one-pot reaction se-
quence that provides efficient access to aryl-substi-
tuted thienoisoquinolines.
Keywords: catalysis; cross-coupling; decarboxyla-
tion; heteroaromatics; palladium
Heteroaromatics play an important role in the discov-
Scheme 1. Wyethꢁs synthetic pathway towards biologically
ery of new drugs for a wide range of diseases.[1,2] For active thienoisoquinolines.
example, Wyeth have disclosed compounds, based on
a functionalized thienoisoquinoline scaffold, that are
estrogen receptor-mediated nuclear factor kB (ER- by-products and waste. To this end, catalysis has
NFkB) inhibitors and potential therapeutics for proven to be an instrumental synthetic tool allowing
cancer.[3] Despite the potential interest in thienoiso- for the use of sub-stoichiometric reagent quantities.
quiolines as drug candidates, there have been only However, classical palladium-catalyzed cross-coupling
a few reported syntheses of this class of important reactions typically employ high molecular weight or-
compounds.[4] Furthermore, these syntheses are ganometallic coupling partners, reducing the environ-
lengthy[5] and are not ideal for late-stage functionali- mental benefits achieved through catalysis. Decarbox-
[9]
zation[6,7] that is often important for drug discovery. In ylative cross-coupling[8] and C H activation have re-
À
their initial report, Wyeth accesses these biologically cently been developed as alternative methods to cir-
active molecules in 8 steps (Scheme 1). Their synthet- cumvent the requirement of prefunctionalization with
ic pathway involved the initial formation of the three- cumbersome organometallic components.[10] As such,
ring scaffold followed by both bromination and reduc- we developed a synthesis of the biologically important
tion steps that are essential for further functionaliza- thienoisoquinoline scaffold (Scheme 2) employing
tion but result in limited functional group tolerance. more environmentally benign cross-coupling reac-
An emerging understanding of the human footprint tions.
and its impact on the environment has discouraged
From advanced intermediate 2, previously reported
the use of lengthy inflexible syntheses that produce by our group,[4c] an intramolecular palladium-cata-
Adv. Synth. Catal. 2014, 356, 1725 – 1730
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Fei Chen et al.
ic sulfonamide (entry 7) was also well tolerated in the
reaction resulting in good yields. Importantly, no in-
À
termolecular C H arylation of the thiophenes was ob-
served in entries 1–5 or in entry 6 where two poten-
À
tially reactive C H groups were present.
Having explored the effects of different sulfona-
mides, efforts were then focused on C-5 functionaliza-
tion to obtain analogs of the reported ER-NFkB in-
hibitors. Thienoisoquinolines were functionalized with
À
a variety of aryl bromides employing a C H activa-
tion reaction (Table 2). An electron-neutral aryl bro-
mide (entry 1) provided the desired product in good
yields. Electron-poor aryl bromides proved to be fav-
oured in the reaction giving good to excellent yields
(entries 2 and 3). Electron-rich aryl bromides were
also tolerated in the reaction although yields were
Scheme 2. Synthesis of functionalized thienoisoquinolines.
lyzed decarboxylative cross-coupling reaction would slightly diminished (entries 4 and 5). The position of
provide the unfunctionalized thienoisoquinoline substituents on the aryl bromide also had an influence
system (3). This compound can then be further func- on the reactions, with meta-substituted aryl bromides
À
tionalized through a palladium-catalyzed C H activa- (entries 2 and 4) resulting in higher yields than the
tion reaction to the desired biologically active thienoi- para-substituted one (entries 3 and 5). Furthermore,
soquinoline scaffold (4).
Thienoisoquinolines were successfully synthesized ed bromothienoisoquinoline analogs in good yields
employing palladium-catalyzed decarboxylative (entries 6 and 7) providing a handle for further elabo-
cross-coupling reaction of carboxylic acid (2) ration of the thienoisoquinoline core.
C-5 bromination was also demonstrated that generat-
a
(Table 1). The scope of the reaction was examined,
Although the desired inhibitors could be obtained
starting with the effect of the electronic nature of the in a 5-step linear sequence, the route utilized two se-
aromatic sulfonamide on the reaction. Both weak (en- quential palladium-catalyzed cross-coupling reactions.
tries 1–3) and strong (entry 4) electron-donating To improve the efficiency of the overall synthesis,
groups on the aromatic ring of the sulfonamide were a tandem one-pot decarboxylative cross-coupling and
À
well tolerated, giving the desired thienoisoquinolines C H activation reaction sequence was envisioned.
in good to excellent yields. Electron-withdrawing Employing a single set of conditions to achieve both
À
groups on the aromatic ring of the sulfonamide decarboxylative cross-coupling and C H activation
proved to be detrimental to the reaction, resulting in would reduce reagent and solvent consumption. As
lowered yields with a 4-fluoro substituent (entry 5) a practical benefit, the one-pot sequence reduces the
and a complete shutdown of the reaction with a 4-
nitro analog (entry 6). An electron-rich heteroaromat-
Table 2. C-5 functionalization.
Table 1. Synthesis of thienoisoquinolines via decarboxylative
cross-coupling.
Entry
Ar
Yield [%]
Entry
Ar
R
Yield [%]
1
2
3
4
5
6
7
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
4-CH3OC6H4
4-FC6H4
68
76
84
99
56
0
1
2
3
4
5
6
7
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
C6H5
67
86
54
47
25
60
59
3-EtO2CC6H4
4-EtO2CC6H4
3-CH3OC6H4
4-CH3OC6H4
Br
4-NO2C6H4
2-thiophene
83
Br
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One-Pot Tandem Palladium-Catalyzed Decarboxylative Cross-Coupling
À
Table 3. Optimizations of a one-pot decarboxylative cross-coupling C H activation reaction.
Entry
Pd source
Pd(OAc)2
Ligand
Base
6 Yield[e] [%]
3 Yield[e] [%]
4 Yield[e] [%]
1[a]
G
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
Et3N
24
–
–
14
–
15
–
–
–
11
–
–
13
28
67
12
20
16
14
–
50
8.4
23
38
26
48
1
16
13
–
<5
<5
<5
<5
<5
<5
14
–
–
<5
<5
52
2[a]
Pd(acac)2
Pd(dba)2
PdCl2
Pd(OAc)2
Pd(OAc)2
R
3[a]
E
4[a]
5[a]
R
T
PACHTUNGTRENNUNG
6[a]
7[a]
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PACHTUNGTRENNUNG
8[a]
Davephos
dppf
PPh3
9[a]
10[a]
11[a]
12[a]
13[a]
14[b]
15[c]
16[d]
P
P
P
P
P
P
N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
–
–
–
1
80
[a]
Reaction mixture was heated at 1008C for 16 h.
Reaction mixture was heated at 1208C for 6 h.
Reaction mixture was heated at 1408C for 6 h.
Reaction mixture was heated at 1408C for 16 h.
[b]
[c]
[d]
[e]
GC yields normalized to an isolated yield of product (4) at 1408C for 16 h.
required purification steps allowing for a further re- Fagnou and co-workers.[9] Using these conditions re-
duction in solvent usage and silica gel consumption. sulted in a low yield and incomplete conversion as
Although both reactions were catalyzed by palladium, starting materials were observed (entry 1); therefore,
different reaction conditions were required for each various palladium sources, ligands and bases were ex-
transformation. Reaction conditions were therefore amined (entries 2–13). The more sterically encum-
optimized once again for the one-pot reaction to bered ligand, PACTHNUGTRNEUNG(t-Bu)3·HBF4, was found to decrease
ensure that the reaction would proceed as efficiently the undesired protodecarboxylation side product (6)
as possible. Compound (2) was employed as a model formed compared to PCy3·HBF4 (entry 1 vs. entry 5).
substrate in these reactions, and different palladium Although the combination of PdCl2, dppf and K2CO3
sources, ligands and bases were examined to deter- appears to produce the highest yield of intermediate
mine the optimal reagents to employ (Table 3).
Optimization of the one-pot reaction sequence was conversion of the starting material. In contrast, the
attempted while monitoring the reaction for the 3 combination of PdCl2, P(t-Bu)3·HBF4 and Cs2CO3 re-
(3) in Table 3 (entry 9), this yield results from full
AHCTUNGTRENNUNG
major products generated. From the starting material sulted in good yields of (3) and (4) in spite of incom-
(2), protodecarboxylation can occur resulting in unde- plete conversion of starting material (entry 13), so
sired side product (6). The desired decarboxylative these conditions were chosen for further optimization
cross-coupling reaction would result in an unsubstitut- since they appeared to have the greatest potential for
À
ed thienoisoquinoline system (3) that upon C H acti- improvement. As the starting material (2) was still
vation would react further to generate the desired observed in the reaction carried out at 1008C for
product (4). Full conversion of the unfunctionalized 16 h, optimizations of the reaction temperature were
thienoisoquinoline (3) to the desired product (4) performed. Increasing the reaction temperature to
while minimizing protodecarboxylation is essential to 1208C resulted in an increased yield of the intermedi-
maximize yields and simplify purification.
ate unfunctionalized thienoisoquinoline (3), but still
Initial conditions employed were obtained from the produced a low yield of the desired final product (4)
À
optimized C H activation reaction reported by from the tandem reaction. Increasing the reaction
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À
Scheme 3. Double C H activation reaction: PdCl2 (5 mol%), PACHTUNRGTENUNG(t-Bu)3·HBF4 (10 mol%), PivOH (30 mol%), Cs2CO3
(3 equiv.) in DMA at 1408C for 16 h. ArBr is bromobenzene.
À
À
temperature to 1408C was sufficient to drive the C H coupling/C H activation route proved superior to
activation step further, resulting in an increase in the access this class of thienoisquinolines.
yield of the desired final product (4) with only a trace
With optimized conditions established, the scope of
À
amount of the intermediate (3) remaining. Extending the one-pot decarboxylative cross-coupling C H acti-
the reaction time while maintaining the 1408C reac- vation reaction was explored employing various aryl
tion temperature provided the best result, providing bromides as cross-coupling partners (Table 4). A wide
the desired product (4) in an isolated yield of 80% range of aryl bromide substrates give modest to good
(entry 16).
yields of the desired products (Table 4), with the ex-
In the synthetic route presented, the carboxylic ception of ortho- substituted aryl bromides. Likely
acid group governs the position where decarboxyla- due to steric hindrance, only trace amounts of prod-
tive cross-coupling occurs and thus acts to control the ucts are observed with ortho-substituted electron-rich
regioselectivity of the intramolecular cyclization reac- (entry 6) and electron-deficient (entry 12) aryl bro-
tion (Scheme 3). We also investigated the feasibility mides. As observed before with the stepwise route,
À
of a one-pot heteroatom directed double C H activa- electron-rich meta-methoxy substituted aryl bromides
tion strategy on thiophene 6 for the synthesis of thie- provided better yields than the corresponding para-
noisoquinolines. Employing the optimized conditions, substituted substrates (entries 4 and 5). However,
three products were obtained. While the desired thie- with electron-deficient substrates such as the ethyl
noisoquinoline 4 was the major product, one of the benzoates, the difference in yields for the meta- and
side products is the C-4 cyclized product 9. For intra- para-substituted aryl bromides is not significant in the
À
molecular C H activation reactions that can cyclize one-pot reaction (entries 7 and 8), which differs from
onto C-2 or C-4 of thiophenes, the C-2 cyclized prod- the results obtained with the stepwise reaction
uct generally predominates. Our previous studies (Table 2, entries 2 and 3). The products produced
have shown, however, that when the C-2 position is from the reactions with 4-bromobenzonitrile
blocked, C-4 cyclization will occur.[4c] These previous (entry 10) and 3-bromopyridine (entry 13) appear to
À
studies suggest that compound 9 arises from C H ary- be acid sensitive and the diminished yields may be
lation at C-2 prior to cyclization at C-4. Regardless, a consequence of decomposition during purification,
À
because the double C H activation strategy produces despite the use of base-treated silica. Importantly, in
a mixture of products that could not be separated by most cases a higher overall yield was obtained in the
chromatography, the one-pot decarboxylative cross- tandem one-pot decarboxylative cross-coupling and
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One-Pot Tandem Palladium-Catalyzed Decarboxylative Cross-Coupling
Table 4. Substrate scope.
over sodium sulfate and filtered. Solvent was then removed
under reduced pressure. The resulting crude mixtures were
purified by column chromatography using 20% EtOAc in
hexanes.
General Procedure for Bromination
NBS (1 equiv.) was added to a mixture of thienoisoquino-
line-phenylsulfonamide (1 equiv.) in a 1:1 mixture of acetic
acid and chloroform (0.2M) at À58C. The mixture was
slowly warmed to 238C before subsequent heating to 608C,
and was stirred for 16 h at this temperature. The reaction
mixture was cooled to 238C and basified to pH 9 with
sodium bicarbonate. The resulting biphasic mixture was par-
titioned between EtOAc and water. The water phase was
extracted with EtOAc, and the combined organic phases
were washed three times with water. The combined organic
phases were then dried using sodium sulfate, filtered and
solvent was removed under reduced pressure. Samples were
purified by recrystallization using EtOAc and hexanes.
Entry
Ar2
Yield [%]
1
2
3
4
5
6
C6H5
80
70
51
60
82
trace
78
80
70
45
61
trace
68
4-CH3C6H4
naphthyl (C10H7)
4-CH3OC6H4
3-CH3OC6H4
2-CH3OC6H4
4-EtO2CC6H4
3-EtO2CC6H4
4-FC6H4
4-CNC6H4
4-CF3C6H4
2-CF3C6H4
3-pyridyl (C5H4N)
7[a]
8[a]
9
10[a]
11[a]
12
13[a]
À
General Procedure for C H Activation
The unfunctionalized thienoisoquinoline (1 equiv.) and aryl
bromide (1 equiv.) in DMA (0.1M) were added to a flame-
dried round-bottom flask containing PCy3·HBF4 (0.1 equiv.),
[a]
Reaction with 10 mol% Pd and 20 mol% PACTHNUTGRNEUNG(t-Bu)3·HBF4.
K2CO3 (3 equiv.), PivOH (0.3 equiv.) and PdACHTUNGTRENNUNG(OAc)2
(0.05 equiv.). The mixture was then heated to 1008C and
stirred for 16 h. The resulting mixture was filtered over
a pad of celite, the filtrate was washed once with water, and
the aqueous phase was extracted with EtOAc. The com-
bined organic phases were then washed three times with
brine solution, dried over sodium sulfate and filtered. Sol-
vent was then removed under reduced pressure. The result-
ing crude mixtures were purified by column chromatography
using 30% hexanes in DCM.
À
C H activation reaction sequence compared to the
stepwise process with two discrete reactions.
In summary, we have developed a synthetic route
to access the scaffold of reported biologically active
anti-cancer agents. The step-wise route employing
two palladium cross-coupling reactions allowed for
late stage functionalization through either bromina-
tion or arylation reactions. This point of diversifica-
tion provides additional flexibility for this route as
a result of the additional reactions available to the
brominated intermediate. Alternatively, in cases
where the arylated product is required, a more effi-
cient and green one-pot decarboxylative cross-cou-
General Procedure for One-Pot Reaction
The carboxylic acid (1 equiv.) and aryl bromide (1.1 equiv.)
in DMA (0.1M) were added to a flame-dried round-bottom
flask containing
PACHTUNGTERN(NUG t-Bu)3·HBF4 (0.1 equiv.), Cs2CO3
(3 equiv.), PivOH (0.3 equiv.) and PdCl2 (0.05 equiv.). The
mixture was then heated to 1408C and stirred for 16 h. The
resulting mixture was filtered over a pad of celite, the fil-
trate was washed once with water, and the aqueous phase
was extracted with EtOAc. The combined organic phases
were then washed three times with brine solution, dried
over sodium sulfate and filtered. Solvent was then removed
under reduced pressure. The resulting crude mixtures were
purified by column chromatography using 30% hexanes in
DCM.
À
pling and C H activation reaction sequence is possi-
ble. In the examples for which there is a direct com-
parison, yields from the one-pot reaction were up to
50% higher than those obtained from the step-wise
route.
Experimental Section
General Procedure for Decarboxylative Cross-
Coupling
Acknowledgements
The carboxylic acid (1 equiv.) in DMA (0.1M) was added to
a flame-dried round-bottom flask containing PACHTUNTRGNEUNG(t-Bu)3·HBF4
(0.1 equiv.), Cs2CO3 (3 equiv.) and PdCl2 (0.05 equiv.). The
mixture was then heated to 1708C and stirred for 1 h. The
resulting mixture was filtered over a pad of celite, the fil-
trate was washed once with water, and the aqueous phase
was extracted with EtOAc. The combined organic phases
were then washed three times with brine solution, dried
This work was funded by the Natural Sciences and Engineer-
ing Research Council (NSERC) of Canada and Le Fonds de
recherche du Quꢀbec, nature et technologies (FQRNT). Sup-
port was also kindly provided by Boehringer Ingelheim,
Wyeth, Centre for Green Chemistry and Catalysis (CGCC),
Merck Frosst and Concordia University. Special thanks to
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Dr. Simon Woo and Professor Shawn Collins (Universitꢀ de
Montrꢀal) for their assistance in preparing this manuscript.
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