Csp3-Csp2 palladium-catalyzed cross-coupling reaction of trialkylbismuth reagents with aryl, heteroaryl, and vinyl halides and triflates

Article abstract of DOI:10.1055/s-0030-1259023

The palladium-catalyzed cross-coupling reaction of trialkylbismuth reagents with aryl and heteroaryl halides and triflates is reported. Moderate to good yields were obtained for the transfer of primary alkyl groups. The reaction tolerates numerous functional groups on the electrophilic and nucleophilic partners. The cross-coupling of -bromostyrene with tris(1,3-dioxan-2-ylethyl) bismuth is also reported. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259023

2936
LETTER
Csp3–Csp2 Palladium-Catalyzed Cross-Coupling Reaction of Trialkylbismuth
Reagents with Aryl, Heteroaryl, and Vinyl Halides and Triflates
C
ross-Coupling Re
l
action
e
of Trialkyl
x
bismuth Rea
a
gents
w
ith
Aryl,
H
eteroa
d
ryl, and
V
in
r
yl
H
alides Gagnon,*1 Vincent Albert, Martin Duplessis*
Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Québec, H7S 2G5, Canada
Fax +1(450)6824189; E-mail: martin.duplessis@boehringer-ingelheim.com
Received 13 August 2010
of alkyl groups onto highly functionalized scaffolds
Abstract: The palladium-catalyzed cross-coupling reaction of tri-
alkylbismuth reagents with aryl and heteroaryl halides and triflates
is reported. Moderate to good yields were obtained for the transfer
of primary alkyl groups. The reaction tolerates numerous functional
through cross-coupling reactions involving trialkylbis-
muthanes. In order to have high synthetic value, we aimed
for a method that used commercially available ligands and
groups on the electrophilic and nucleophilic partners. The cross- catalysts, demonstrated excellent functional-group toler-
coupling of a-bromostyrene with tris(1,3-dioxan-2-ylethyl)bismuth
is also reported.
ance, and did not require isolation of the trialkylbismuth
reagent.
Key words: cross-coupling, organometallic reagents, palladium,
halides, catalysis
We recently reported the synthesis of tricyclopropylbis-
muth and its use in palladium-catalyzed cross-coupling
reactions with aryl and heteroaryl halides and triflates.14
As an extension to this methodology, the coupling of tri-
ethylbismuth with ethyl 4-bromobenzoate was shown to
provide the cross-coupling product in good yield, demon-
strating that the protocol is applicable to the transfer of
primary sp3 groups that are susceptible to b-hydride elim-
ination. Encouraged by this result, we initiated a program
to further study the scope of the cross-coupling reaction
involving trialkylbismuth reagents and we report herein
our results.
The introduction of alkyl groups onto aryl and heteroaryl
scaffolds is highly valuable in medicinal chemistry since
it facilitates the search for new interactions between a bio-
active compound and its receptor and the exploration of
new binding pockets.2 The transfer of alkyl groups via
cross-coupling reactions between alkyl-metal species and
aryl or heteroaryl halides and pseudo halides has emerged
as a powerful approach for the preparation of such com-
pounds.3 However, the coupling of alkyl groups possess-
ing hydrogen atoms in the b-position represents a
The required trialkylbismuth species 2 were prepared by
the slow addition of organomagnesium reagents15 1 over
a 0 °C THF suspension of bismuth chloride (Equation 1).
After stirring at 0 °C for 30 minutes, the reaction was
warmed to room temperature and heated at 65 °C for 30
minutes to ensure complete formation of the trialkylbis-
muth species. The trialkylbismuth reagents were used in
situ as a THF solution in the cross-coupling step.
significant challenge due to
a slower reductive
elimination4 and the propensity of such groups to undergo
b-hydride elimination.5 To overcome these issues, novel
ligands, catalysts, and additives have been developed for
the coupling of alkylboron,6 alkylzinc,7 and
alkylmagnesium8 species. These advances have also
found applications in the transfer of alkyl chains using or-
ganoaluminum, organogallium, and organoindium re-
agents.9 Nevertheless, some of these methods suffer from
poor functional-group tolerance or require excess organo-
metallic species, strictly anhydrous conditions, or com-
plex catalytic systems. Consequently, the development of
simple and general procedures for the coupling of sp3
groups is still highly desirable.
BiCl3 (0.3 equiv)
R
MgX
R3Bi
THF, 0 °C to r.t.
then 65 °C, 30 min
1
2
Equation 1
Using ethyl 4-bromobenzoate (3) as a test substrate, we
first optimized the reaction conditions for the cross-cou-
pling of tri-n-butylbismuth 2a (Table 1). By simply re-
fluxing a THF solution of 1.5 equivalents of the
trialkylbismuth reagent with the arylbromide 3, 2.0 equiv-
alents of potassium carbonate and 5 mol% of Pd(PPh3)4,
ethyl 4-n-butylbenzoate (4) was obtained in 14% isolated
yield (Table 1, entry 1). Unsatisfied with the efficiency of
the reaction, we hypothesized that superior yields of the
coupling product could be obtained by using a solvent that
would allow higher reaction temperatures and that would
destroy any residual Grignard reagent that could remain
after the preparation of the organobismuth reagent. In the
Organobismuth reagents have found applications in C–C,
C–O, and C–N bond-forming reactions, in part due to
their unique reactivity, the low toxicity, and low costs as-
sociated with bismuth salts.10 While the cross-coupling of
triarylbismuth reagents is well documented,11 to our
knowledge, the coupling of trialkylbismuth species is un-
precedented.12 As part of our research program dedicated
to studying the reactivity of organobismuth reagents,13 we
were interested in developing conditions for the transfer
SYNLETT 2010, No. 19, pp 2936–2940
x
x
.x
x
.2
0
1
0
Advanced online publication: 03.11.2010
DOI: 10.1055/s-0030-1259023; Art ID: S04910ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reaction of Trialkylbismuth Reagents with Aryl, Heteroaryl, and Vinyl Halides
2937
nylphosphine)palladium in DMF at 110 °C was found to
be ideal for this reaction (Table 1, entries 6 and 7). Re-
placing DMF with NMP gave a lower yield of product 4
(Table 1, entry 8). Attempts to use 0.33 or 0.66 equiva-
lents of reagent 2a also failed to deliver the desired prod-
uct under these conditions. The direct coupling of n-
BuMgCl with 3 under the conditions reported in entries 6
and 7 also failed, showing that the reactive species is the
bismuthane reagent.
Table 1 Optimization of the Conditions for the Palladium-Cata-
lyzed Cross-Coupling Reaction of Tri-n-butylbismuth (2a) with Ethyl
4-Bromobenzoate (3)
O
O
n-Bu3Bi (2a) (n equiv)
catalyst (5 mol%)
OEt
OEt
base (2.0 equiv)
solvent (0.1 M)
temp, 18 h
Br
3
4
Entry n
Catalyst
Base
Solvent Temp Yield
Using the optimized conditions identified in Table 1 (en-
tries 6 and 7),16 we next explored the scope of the reaction
through the cross-coupling of various trialkylbismuth re-
agents with highly functionalized aryl and heteroaryl
chlorides, bromides, iodides, and triflates. As illustrated
in Table 2, the method allows the transfer of simple alkyl
groups such as n-butyl (entry 1), methyl (entry 2), ethyl
(entry 3), and n-propyl (entry 4) in modest to good yields.
Functionalized alkyl groups such as homoallyl (entry 5),
phenethyl (entries 6–10), trimethylsilylmethylene (entry
11), 1,3-dioxan-2-ylethyl (entries 12–14), and 3,7-dime-
thyloctyl (entry 15) were also efficiently transferred under
these conditions. Gratifyingly, the reaction proceeded
equally well with bromides, iodides, and triflates. Addi-
tionally, as an indication of the excellent substrate scope,
the reaction was successfully performed on bromobenzo-
(°C)
(%)a
14
85
70
80
50
83
84
67
1
2
3
4
5
6
7
8
1.5 Pd(PPh3)4
1.5 Pd(PPh3)4
1.0 Pd(PPh3)4
1.0 Pd(PPh3)4
K2CO3 THF
65
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
90
90
130
130
110
110
110
1.0 PdCl2(dppf)·CH2Cl2 K2CO3 DMF
1.1 Pd(PPh3)4
1.1 Pd(PPh3)4
1.1 Pd(PPh3)4
K2CO3 DMF
Cs2CO3 DMF
K2CO3 NMP
a Yields of isolated pure compound 4.
event, dilution of the trialkybismuth solution with DMF furan (5a, entry 1), bromobenzimidazole (5b, entry 2),
prior to the addition of the base and the catalyst, followed bromo N-phenylsulfonylindole (5d, entry 4), iodoben-
by stirring at 90 °C led to the cross-coupling product 4 in zonitrile (5h, entry 8), 2-chloropyridine (5j, entry 10),
a gratifying 85% yield (Table 1, entry 2). Using 1.0 equiv-
alent of reagent 2a led to a substantial drop in the yield of
4 (Table 1, entry 3), but performing the reaction at 130 °C
instead of 90 °C solved that issue (Table 1, entry 4). Other
catalysts such as PdCl2(dppf)·CH2Cl2 were found to be
less efficient for this transformation (Table 1, entry 5).
The use of 1.1 equivalents of tri-n-butylbismuth (2a) in
conjunction with 2.0 equivalents of potassium carbonate
or cesium carbonate and 5 mol% of tetrakis(triphe-
bromoquinoline (5n, entry 14), and iodothiophene (5o,
entry 15). Finally, N-Boc protecting groups (entry 3), ni-
tro groups (entry 5), esters (entry 6), aldehydes (entry 7),
nitriles (entries 8 and 10), b-ketoesters (entry 9), cinnamic
esters (entry 11), and acetals (entry 13) were tolerated,
demonstrating the mildness of the reaction conditions.
Table 2 Palladium-Catalyzed Cross-Coupling Reaction of Trialkylbismuth Reagents 2a–i with Aryl and Heteroaryl Halides and Triflates
R3Bi (2a–i) (1.1 equiv)
Pd(PPh3)4 (5 mol%)
Ar(Het)
R
Ar(Het)
X
K2CO3 or Cs2CO3 (2.0 equiv)
DMF (0.1 M), 110 °C, 18 h
5
6
Entry
1
ArX or HetX
R3Bia
ArR or HetR
Yield (%)b Methodc
Br
n-Bu3Bi 2a
65
A
O
O
5a
6a
Br
Me
N
N
N
N
N
N
2
Me3Bi 2b
63
A
5b
6b
Synlett 2010, No. 19, 2936–2940 © Thieme Stuttgart · New York

2938
A. Gagnon et al.
LETTER
Table 2 Palladium-Catalyzed Cross-Coupling Reaction of Trialkylbismuth Reagents 2a–i with Aryl and Heteroaryl Halides and Triflates
(continued)
R3Bi (2a–i) (1.1 equiv)
Pd(PPh3)4 (5 mol%)
Ar(Het)
R
Ar(Het)
X
K2CO3 or Cs2CO3 (2.0 equiv)
DMF (0.1 M), 110 °C, 18 h
5
6
Entry
ArX or HetX
R3Bia
ArR or HetR
Yield (%)b Methodc
Br
CN
CN
3
Et3Bi 2c
64
B
N
N
Boc
Boc
5c
6c
Br
4
5
n-Pr3Bi 2d
77
85
B
B
N
N
SO2Ph
SO2Ph
6d
5d
O2N
O2N
(CH2=CHCH2CH2)3Bi 2e
(PhCH2CH2)3Bi 2f
Br
6e
5e
Br
Ph
6
7
8
64
70
42
A
A
A
CO2Et
CO2Et
CHO
3
I
6f
Ph
CHO
5g
I
6g
Ph
CN
F
CN
F
5h
6h
O
O
O
O
I
Ph
9
OEt
OEt
68
73
A
A
5i
6i
CN
Cl
CN
10
N
N
Ph
5j
6j
O
O
OEt
OEt
11
12
(Me3SiCH2)3Bi 2g
65
63
A
A
Me3Si
Br
6k
5k
O
Br
O
O
O
Bi
CO2Et
3
CO2Et
3
2h
6l
Synlett 2010, No. 19, 2936–2940 © Thieme Stuttgart · New York

LETTER
Cross-Coupling Reaction of Trialkylbismuth Reagents with Aryl, Heteroaryl, and Vinyl Halides
2939
Table 2 Palladium-Catalyzed Cross-Coupling Reaction of Trialkylbismuth Reagents 2a–i with Aryl and Heteroaryl Halides and Triflates
(continued)
R3Bi (2a–i) (1.1 equiv)
Pd(PPh3)4 (5 mol%)
Ar(Het)
R
Ar(Het)
X
K2CO3 or Cs2CO3 (2.0 equiv)
DMF (0.1 M), 110 °C, 18 h
5
6
Entry
13
ArX or HetX
R3Bia
ArR or HetR
Yield (%)b Methodc
O
O
O
46
A
O
O
OTf
O
5m
5n
6m
O
Br
14
15
62
37
A
A
O
N
N
6n
Bi
I
S
S
3
O
O
5o
6o
2i
a Trialkylbismuth reagents 2a–i were prepared in THF according to Equation 1 and used without further purification.
b Unoptimized yields of isolated pure compounds 6a–o.
c Method A: R3Bi (1.1 equiv), Pd(PPh3)4 (5 mol%), K2CO3 (2.0 equiv), DMF (0.1 M), 110 °C, 18 h. Method B: R3Bi (1.1 equiv), Pd(PPh3)4 (5
mol%), Cs2CO3 (2.0 equiv), DMF (0.1 M), 110 °C, 18 h.
related to this work. This manuscript was prepared by AG. Due to
his affiliation with Boehringer-Ingelheim, MD should be contacted
for any question related to this work.
To further increase the scope of the reaction, we next in-
vestigated the cross-coupling of trialkylbismuth 2h with
a-bromostyrene 7 (Equation 2). In the event, alkene 8 was
obtained in 43% isolated yield.
References
O
(1) Current address: Constellation Pharmaceuticals, Cambridge,
MA, USA; alex.gagnon@constellationpharma.com.
(2) For an excellent review on molecular interactions in
medicinal chemistry, see: (a) Bissantz, C.; Kuhn, B. K.;
Stahl, M. J. Med. Chem. 2010, 53, 5061. (b) See also:
Gagnon, A.; Duplessis, M.; Fader, L. Org. Prep. Proced. Int.
2010, 42, 1.
O
Bi
3
O
2h (1.1 equiv)
Br
Pd(PPh3)4 (5 mol%)
K2CO3 (2.0 equiv)
DMF, 110 °C
O
7
8 43%
overnight
(3) See: Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131,
7532; and references cited therein.
Equation 2
(4) (a) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.; Zhang,
T.; Lei, A. Org. Lett. 2007, 9, 4571. (b) Zhang, H.; Lu, X.;
Wongkhan, K.; Duan, H.; Li, Q.; Zhu, L.; Wang, J.;
Batsanov, A. S.; Howard, J. A. K.; Marder, T. B.; Lei, A.
Chem. Eur. J. 2009, 15, 3823.
(5) (a) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. Rev.
2000, 100, 3187. (b) Frisch, A. C.; Beller, M. Angew. Chem.
Int. Ed. 2005, 44, 674.
(6) (a) Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron 2004,
60, 3813. (b) Wang, B.; Sun, H.-X.; Sun, Z.-H.; Lin, G.-Q.
Adv. Synth. Catal. 2009, 351, 415. (c) Wang, B.; Sun, H.-
X.; Sun, Z.-H. Eur. J. Org. Chem. 2009, 3688. (d)Chemler,
S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed.
2001, 40, 4544.
In summary, we have developed a general and simple pro-
cedure for the cross-coupling of trialkylbismuth reagents
with highly functionalized aryl and heteroaryl halides and
pseudo halides. This reaction does not require isolation of
the trialkylbismuth species and allows the transfer of pri-
mary alkyl groups having hydrogen atoms in the b-posi-
tion. Numerous sensitive functional groups are tolerated
under these reaction conditions. Vinylhalides can also be
cross-coupled using this protocol.
Acknowledgment
(7) (a) Manolikakes, G.; Muñoz Hernandez, C.; Schade, M. A.;
Metzger, A.; Knochel, P. J. Org. Chem. 2008, 73, 8422.
(b) Liu, J.; Deng, Y.; Wang, H.; Zhang, H.; Yu, G.; Wu, B.;
Zhang, H.; Li, Q.; Marder, T. B.; Yang, Z.; Lei, A. Org. Lett.
The authors would like to thank the Université de Montréal for in-
valuable support during manuscript preparation. Sébastien Gou-
dreau is gratefully acknowledged for helpful scientific discussions
Synlett 2010, No. 19, 2936–2940 © Thieme Stuttgart · New York

2940
A. Gagnon et al.
LETTER
2008, 10, 2661. (c) Liu, Q.; Duan, H.; Luo, X.; Tang, Y.; Li,
G.; Huang, R.; Lei, A. Adv. Synth. Catal. 2008, 350, 1349.
(d) Wang, H.; Liu, J.; Deng, Y.; Min, T.; Yu, G.; Wu, X.;
Yang, Z.; Lei, A. Chem. Eur. J. 2009, 15, 1499.
(14) Gagnon, A.; Duplessis, M.; Alsabeh, P.; Barabé, F. J. Org.
Chem. 2008, 73, 3604.
(15) The organomagnesium reagents were titrated before use
using diphenylditelluride: Aso, Y.; Yamashita, H.; Otsubo,
T.; Ogura, F. J. Org. Chem. 1989, 54, 5627.
(8) (a) Kondolff, I.; Feuerstein, M.; Doucet, H.; Santellli, M.
Tetrahedron 2007, 63, 9514. (b) Hamaguchi, H.; Uemura,
M.; Yasui, H.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2008,
37, 1178.
(9) (a) Shenglof, M.; Gelman, D.; Heymer, B.; Schumann, H.;
Molander, G. A.; Blum, J. Synthesis 2003, 302. (b) Pena,
M. A.; Pérez Sestelo, J.; Sarandeses, L. A. Synthesis 2005,
485. (c) Chupak, L. S.; Wolkowski, J. P.; Chantigny, Y. A.
J. Org. Chem. 2009, 74, 1388.
(16) General Procedure for the Preparation of 4, 6a-o, and 8
In a round-bottom flask equiped with a condenser and
sparged with argon, BiCl3 (173 mg, 0.55 mmol) was
suspended in anhydrous THF (3 mL) and cooled to 0 °C. The
organomagnesium reagent (1.705 mmol, THF or Et2O
solution) was slowly added dropwise, and the solution was
stirred at 0 °C for 30 min, warmed to r.t., and then heated at
65 °C for an additional 30 min. The reaction mixture was
cooled to r.t. and diluted with DMF (1 mL). A DMF solution
of the aryl or heteroaryl halide or pseudo halide (0.500 mmol
in 4 mL) was then added, followed by K2CO3 or Cs2CO3
(1.00 mmol) and Pd(PPh3)4 (28 mg, 0.025 mmol). The
solution was degassed by bubbling argon during 15 min, and
then stirred at 110 °C for 18 h. The reaction mixture was
cooled to r.t., diluted with sat. aq NaHCO3 (10 mL) and
extracted with EtOAc (2 × 10 mL). The combined organic
phases were washed with brine (3 × 10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (1% to
15% EtOAc–hexanes or Et2O–hexanes) to afford the desired
products 4, 6a–o, and 8.
(10) For reviews on bismuth chemistry, see: (a) Finet, J.-P.
Chem. Rev. 1989, 89, 1487. (b) Suzuki, H.; Ikegami, T.;
Matano, Y. Synthesis 1997, 249.
(11) (a) Barton, D. H. R.; Ozbalik, N.; Ramesh, M. Tetrahedron
1988, 44, 5661. (b) Rao, M. L. N.; Yamazaki, O.; Shimada,
S.; Tanaka, T.; Suzuki, Y.; Tanaka, M. Org. Lett. 2001, 3,
4103. (c) Shimada, S.; Yamazaki, O.; Tanaka, T.; Rao, M. L.
N.; Suzuki, Y.; Tanaka, M. Angew. Chem. Int. Ed. 2003, 42,
1845. (d) Kang, S.-K.; Ryu, H.-C.; Kim, J. W. Synth.
Commun. 2001, 31, 1021. (e) Kang, S.-K.; Ryu, H.-C.;
Hong, Y.-T.; Kim, M.-S.; Lee, S.-W.; Jung, J.-H. Synth.
Commun. 2001, 31, 2365. (f) Moiseev, D. V.; Malysheva,
Y. B.; Shavyrin, A. S.; Kurskii, Y. A.; Gushchin, A. V.
J. Organomet. Chem. 2005, 690, 3652. (g) Rao, M. L. N.;
Banerjee, D.; Jadhav, D. N. Tetrahedron Lett. 2007, 48,
2707. (h) Rao, M. L. N.; Banerjee, D.; Jadhav, D. N.
Tetrahedron Lett. 2007, 48, 6644.
Spectral Data for 6n
Rf = 0.41 (20% EtOAc–hexanes). 1H NMR (400 MHz,
CDCl3): d = 8.81 (d, J = 1.8 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1
H), 7.94 (s, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.66 (t, J = 8.2
Hz, 1 H), 7.53 (t, J = 7.0 Hz, 1 H), 4.56 (t, J = 5.1 Hz, 1 H),
4.12 (dd, J = 10.0, 5.0 Hz, 2 H), 3.76 (dt, J = 12.5, 2.4 Hz, 2
H), 2.93 (t, J = 7.8 Hz, 2 H), 2.13–2.04 (m, 1 H), 2.02–1.99
(m, 2 H), 1.35 (d, J = 13 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 152.5, 147.2, 134.8, 134.7, 129.6, 129.0, 128.6,
127.8, 127.0, 101.4, 67.3, 36.6, 27.7, 26.2. IR (neat): 2959,
2850, 1494, 1378, 1240, 1138, 1082, 1043, 1002 cm–1.
HRMS (EI): m/z calcd for C15H17NO2 [M]: 243.1259; found:
244.1328 [M + H].
(12) For the coupling of methyl groups using
dialkoxymethylbismuth and diarylmethylbismuth species,
see: (a) Rao, M. L. N.; Shimada, S.; Tanaka, M. Org. Lett.
1999, 1, 1271. (b) Rao, M. L. N.; Shimada, S.; Yamazaki,
O.; Tanaka, M. J. Organomet. Chem. 2002, 659, 117.
(c) Yamazaki, O.; Tanaka, T.; Shimada, S.; Suzuki, Y.;
Tanaka, M. Synlett 2004, 1921.
(13) Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabé,
F. J. Am. Chem. Soc. 2007, 129, 44.
Synlett 2010, No. 19, 2936–2940 © Thieme Stuttgart · New York