Modular synthesis of naphthothiophenes by Pd-catalyzed tandem direct arylation/Suzuki coupling

Article abstract of DOI:10.1021/ol201585a

A short and highly modular three-step synthesis of a new class of substituted naphthothiophenes has been developed exploiting a Pd-catalyzed tandem direct arylation/Suzuki coupling transformation as the key step.

Full text of DOI:10.1021/ol201585a

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4236–4239
Modular Synthesis of Naphthothiophenes
by Pd-Catalyzed Tandem Direct Arylation/
Suzuki Coupling
Norman Nicolaus, Patrick T. Franke, and Mark Lautens*
Davenport Laboratories, Department of Chemistry, University of Toronto, Toronto,
Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received June 13, 2011
ABSTRACT
A short and highly modular three-step synthesis of a new class of substituted naphthothiophenes has been developed exploiting a Pd-catalyzed
tandem direct arylation/Suzuki coupling transformation as the key step.
Polyaromatic thiophenes have recently attracted con-
siderable attention in the field of material science as
organic electronics.1 Moreover, the thiophene core is an
important substructure present in numerous pharmaceu-
tically active compounds such as zileuton or raloxifene.2
The development of efficient and reliable protocols for
selective functionalization of thiophenes is an important
task. Particularly, the use of Pd-catalyzed direct arylation
strategies has become a powerful tool in this area,3 as it
provides an effective alternative that does not form reac-
tive intermediates prior to the coupling step.4,5 The devel-
opment of new methodologies combining this direct
arylation step with other transition-metal-catalyzed
CÀC-bond functionalization reactions in a tandem or
domino fashion would be even more attractive. Such an
approach would have several advantages since it signifi-
cantly improves the efficiency, atom economy, and
modularity of the synthesis.6
(1) (a) Roncali, J. Chem. Rev. 1992, 92, 711–738. (b) Katz, H. E.; Bao,
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(3) Schipper, D. J.; Fagnou, K. Chem. Mater. 2011, 23, 1594–1600.
(4) For selected reviews on direct arylations, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238. (b) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173–1193. (c)
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(6) Tietze, L.-F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006.
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(a) Gozzi, C.; Lavenot, L.; Ilg, K.; Penalva, V.; Lemaire, M. Tetrahedron
Lett. 1997, 38, 8867–8870. (b) Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.;
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Soc. 2002, 124, 5286–5287. (d) Yokooji, A.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron 2004, 60, 6757–6763. (e) Chiong, H. A.;
Daugulis, O. Org. Lett. 2007, 9, 1449–1451. (f) Yanagisawa, S.; Sudo,
T.; Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748–11749. (g)
(7) For selected examples of gem-dibromoolefines in synthesis, see:
(a) Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625–7628. (b) Fang,
Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549–3552. (c) Yuen, J.; Fang,
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ꢀ
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r
10.1021/ol201585a
Published on Web 07/27/2011
2011 American Chemical Society

Table 2. Optimization of the Tandem Suzuki Coupling/Direct
Arylation Reaction Conditions
Scheme 1. Retrosynthesis
entry
catalyst
ligand
base
yielda (%)
1b,c
2b
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd-1
PtBu3 HBF4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
8
3
Table 1. Two-Step Synthesis of gem-Dibromoolefins of Type 2a
PtBu3 HBF4
30
3
PtBu3 HBF4
50
3
4
À
13
5
À
62 (45)f
17
6
Pd(OAc)2
Pd-1
S-Phos
À
7
36
8
Pd-1
À
K3PO4 H2O
26
3
9d
10
11
12
13
14e
15h
16i
Pd-1
À
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
54
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PPh3
TFP
PCy3
PCy3
PCy3
PCy3
PCy3
30
54
72
27
Pd2dba3
Pd(OAc)2
Pd(OAc)2
50
76 (66)f,g
65
a Yields were determined by NMR spectroscopy using mesitylene as
the internal standard. b Reaction was run in toluene. c Reaction was
performed without Bu4NBr. d Water (5 equiv) was added to the reaction
mixture. e 5 mol % Pd2dba3 were used. f Isolated yield. g On a 0.2 mmol
scale 66% of 23 could be isolated. h CsOPiv (50 mol %) was added.
i 5 mol % of Pd(OAc)2 were used.
approaches toward N-fused heterocycles.8 Encouraged by
these findings, we have realized a short and highly modular
three-step synthesis of a new class of naphthothiophenes of
general structure 1 (Scheme 1).
According to our retrosynthetic analysis we suggested
that the target structures should be accessible in a tandem
transformation from gem-dibromoolefins of type 2 and
boronic acids 3 utilizing a direct arylation/Suzuki coupling
approach. We proposed that the required gem-dibromoolefin
precursors 2 could be synthesized in a straightforward
manner starting from readily available 3-bromothiophenes
4 by Suzuki coupling with 2-formyl substituted phenylboro-
nic acids 5 followed by subsequent Ramirez olefination
(Scheme 1). In particular the use of two distinct Suzuki
couplings in this approach enables a high degree of mod-
ularity for the synthesis of 1.
We selected four 3-bromothiophene derivatives (7À10)
as building blocks for the synthesis of six functionalized
gem-diolefin intermediates (12, 14, 16, 18, 20, and 21) as
depicted in Table 1. For the initial Suzuki coupling step
toward aldehydes of type 6 we found that conditions
reported by Buchwald and co-workers employing
Pd2dba3/S-Phos and K3PO4 were well suited for our
a For further details see Supporting Information. b The crude
product of the Suzuki coupling was used for the olefination step due
to inseparability of the product from homo coupling byproducts of the
boronic acid.
In the course of our ongoing research in the field of Pd-
catalyzed tandem reactions utilizing gem-dibromoolefins7
as key intermediates, we have recently reported efficient
(8) (a) Bryan, C. S.; Lautens, M. Org. Lett. 2008, 10, 4633–4636.
(b) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054–3061.
Org. Lett., Vol. 13, No. 16, 2011
4237

Figure 1. Substrate scope of the direct arylation/Suzuki coupling approach.
system providing products 11, 13, 15, 17, and 19 in
excellent yields (Table 1).9 The subsequent conversion into
the desired gem-dibromoolefins could be achieved in good
to excellent yields by applying the standard Ramirez
olefination conditions using a combination of PPh3 and
CBr4.10 With these building blocks in hand, we next
focused on the optimization of the proposed tandem
transformation.
Interestingly, the yield dropped to 17% when the reaction
was carried out with Pd(OAc)2/S-Phos instead of complex
Pd-1 (entry 6), indicating that the Pd-source has a significant
impact on the outcome of the reaction.
Next, we investigated the effect of different bases includ-
ing K2CO3 and K3PO4, but no improvement could be
observed (entries 7 and 8) suggesting that Cs2CO3 is the
ideal base for this transformation. The addition of water
(entry 9) which is known to exhibit positive effects also
resulted in lower yields (compare entries 5 and 9).8b,12 We
turned our attention to ligand screening and identified
PCy3 as an appropriate candidate for this reaction (entries
10 to 12). It is important to note that Pd-sources other than
Pd(OAc)2 were detrimental to yields under these condi-
tions (entries 13 and 14). Finally, we observed that the
addition of 50 mol % CsOPiv,13 which might act as a
proton shuttle for a concerted metalationÀdeprotonation
mechanism, could further increase the yield of the tandem
reaction up to 76%.14 Attempts to lower the catalyst
We selected the reaction of the prototype gem-
dibromoolefin 12 and boronic acid 22 as our test system
(see Table 2). Reactions in toluene using a Pd(OAc)2/
PtBu3 HBF4 catalyst system and Cs2CO3 as the base led
3
to the formation of trace amounts of 23 (entry 1).5c
Fortunately, we observed that the addition of Bu4NBr
has a significant effect on the reaction resulting in the
exclusive formation of regioisomer 23 (entry 2).5a,b Moti-
vated by this observation, we screened different solvent
systems and identified 1,4-dioxane as our solvent of choice
(entry 3). Altering the Pd/L system to Pd(PPh3)4 dramati-
cally decreased the yield (entry 4), while the S-Phos-
complex Pd-1 was found to be beneficial (entry 5).11
(12) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett.
2008, 10, 3505–3508.
(13) No beneficial effect was observed, when only CsOPiv was used
as the base.
(14) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 10848–10849.
(15) While further studies are necessary to rationalize a possible
mechanism for the tandem process, we assume that the Suzuki coupling
occurs prior to direct arylation according to our recent observations on a
similar system (see ref 8b).
(9) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685–4696.
(10) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962,
84, 1745–1747. For a modification, see:Bryan, C.; Aurregi, V.; Lautens,
M. Org. Synth. 2009, 86, 36–46.
(11) (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686–6687. (b) Chai, D. I.; Hoffmeister, L.; Lautens, M. Org.
Lett. 2011, 13, 106–109.
4238
Org. Lett., Vol. 13, No. 16, 2011

loading to 5 mol % resulted in slightly lower yields and
formation of impurities (entry 16).15
connected to an indole moiety to form substituted carba-
zoles. Since carbazoles are well-known to exhibit impor-
tant biological activities, this modification would open a
practical entry to a broad variety of related derivatives.16
We were pleased to find that gem-dibromoolefin 42
reacts smoothly with 3-methoxyphenyl boronic acid 22
to form carbazole 43 under our previously optimized
tandem conditions (Scheme 2). An extension of this meth-
odology toward other heterocycles is currently under
investigation in our group and will be reported separately.
With our optimized conditions in hand (Figure 1), we
next investigated the scope of the reaction regarding the
electronic nature of the boronic acid coupling partner. It
was found that electron-rich (23), electron-neutral (24),
and electron-poor (29 and 30) boronic acids can be toler-
atedtoformthedesiredproductsingood toexcellent yields
(Figure 1). Furthermore, sterically more demanding (33
and 38), heteroaromatic (32, 35, and 37), and halogen
substituted boronic acids (26 and 27) can be used without
any problems (Figure 1). Under our conditions, various
substitution patterns on the thiophene moiety at the 3- and
4-position (for instance 37 or 39) or the use of a more
electron-rich benzothiophene substrate (40 and 41) were
also tolerated. Additional substituents at the aromatic ring
next to the gem-dibromoolefin moiety were also accepted
(34 and 35). The only limitation of our protocol was
observed for precursor 21, as only trace amounts of the
expected products could be identified. This suggests that
the presence of an additional thiophene made the reaction
more sluggish.
Scheme 2. Synthesis of Carbazol 43a
a For the synthesis of 42, see Supporting Information.
We were able to obtain an X-ray crystal structure for 40
to confirm the expected polyaromatic structure of this new
compound class also indicating these molecules are twisted
along their biaryl axis (Figure 2).
In conclusion, we have developed a short, highly mod-
ular and reliable synthesis of a new class of naphthothio-
phenes employing a tandem direct arylation/Suzuki
coupling transformation as the key step. A remarkable
number of boronic acids bearing different electronic and
steric properties could be successfully used to access the
target structures in good to excellent yields. Due to the
simplicity and high overall yield of our approach, it is
suited for the generation of novel polyaromatic thiophenes
relevant to applications in biology and material science. In
addition its potential to synthesize carbazoles opens an
attractive entrance toward this important compound class.
Acknowledgment. N.N. and P.T.F. thank the DAAD
(Deutscher Akademischer Austauschdienst) for support in
the form of postdoctoral fellowships. We also thank the
Merck Frosst Centre for Therapeutic Research, the Nat-
ural Science and Engineering Research Council of Canada
(NSERC) and the University of Toronto. We also thank
Dr. Alan Lough of the University of Toronto for X-ray
analysis.
Figure 2. Structure of 40 in the crystalline state (gray, carbon;
white, hydrogen; red, oxygen; yellow, sulfur).
Due to the broad generality of our direct arylation/
Suzuki coupling strategy for the synthesis of naphthothio-
phenes, we questioned if these conditions could also be
applied for the functionalization of gem-dibromoolefins
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.
€
(16) (a) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–
€
4427. (b) Choi, T. A.; Czerwonka, R.; Frohner, W.; Krahl, M. P.;
€
Reddy, K. R.; Franzblu, S. G.; Knolker, H.-J. ChemMedChem 2006, 1,
812–815.
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