Palladium-catalyzed cross-coupling reaction of tricyclopropylbismuth with aryl halides and triflates

Article abstract of DOI:10.1021/jo702377h

(Chemical Equation Presented) The palladium-catalyzed cross-coupling reaction of tricyclopropylbismuth with aryl and heterocyclic halides and triflates is reported. The reaction tolerates numerous functional groups and does not require anhydrous conditions. The method was successfully extended to the cross-coupling of triethylbismuth.

Full text of DOI:10.1021/jo702377h

In the course of our ongoing medicinal chemistry programs,
we required a simple, general, and expedient method to
introduce unsubstituted cyclopropyl groups onto highly func-
tionalized aryl and heteroaryl scaffolds. Historically, function-
alized arylcyclopropanes were prepared by radical substitution
on arenes using cyclopropyl radicals5 or by halogenation of
arylcyclopropanes followed by further derivatization.6 More
recently, arylcyclopropanes have been accessed via cyclopro-
panation of the corresponding vinylarenes under Simmons-Smith
conditions4b,7 or through the use of diazomethane,4a,c sulfonium
ylides,8 or ferrocenyl carbenes.9 However, this approach neces-
sitates the preparation of a styrenyl intermediate which is usually
obtained from an aryl halide. For this reason, arylcyclopropanes
are more commonly prepared directly from the corresponding
halides via cross-coupling reactions with a cyclopropyl metal.
However, cross-coupling of cyclopropylzinc halides under
Negishi conditions2,10 requires strict exclusion of water, whereas
the use of cyclopropylmagnesium bromide in a Kumada-type
coupling4e,11 precludes the presence of numerous functional
groups. Further, due to the lack of reactivity, the Stille coupling
of cyclopropyltin reagents has been utilized only in limited
cases.12 Recently, the transfer of unsubstituted cyclopropyl units
has been efficiently achieved through Suzuki coupling employ-
ing cyclopropylboronic acid,13 but no reaction was observed
with aryl triflates. Finally, the cross-coupling of tricyclopropyl-
indium has also allowed the transfer of unsubstituted cyclopropyl
fragments on arenes, but the reagent has to be prepared in situ
and used as a stock solution.14
Palladium-Catalyzed Cross-Coupling Reaction of
Tricyclopropylbismuth with Aryl Halides and
Triflates
Alexandre Gagnon,* Martin Duplessis, Pamela Alsabeh, and
Francis Barabé
Boehringer Ingelheim Canada Ltd., Research and
DeVelopment, 2100 Cunard Street, LaVal,
Québec, Canada H7S 2G5
agagnon@laV.boehringer-ingelheim.com
ReceiVed NoVember 2, 2007
The palladium-catalyzed cross-coupling reaction of tricy-
clopropylbismuth with aryl and heterocyclic halides and
triflates is reported. The reaction tolerates numerous func-
tional groups and does not require anhydrous conditions. The
method was successfully extended to the cross-coupling of
triethylbismuth.
The chemistry of organobismuth reagents has found wide
application in numerous C-C, C-O, and C-N bond-forming
reactions, in part due to the low toxicity of bismuth salts.15
Although the palladium-catalyzed cross-coupling reaction of
triarylbismuth reagents has been extensively documented,16
Cyclopropanes are commonly found in pharmaceutically
active compounds since they provide unique structural and
electronic properties.1 In addition, cyclopropyl fragments are
generally metabolically more stable toward microsomal oxida-
tion than other aliphatic groups.2,3 Consequently, cyclopropanes
(5) Shono, T.; Nishiguchi, I. Tetrahedron 1974, 30, 2183.
(6) Applequist, D. E.; McKenzie, L. F. J. Org. Chem. 1976, 41, 2262.
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2676. (b) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621. (c)
Lorenz, J. C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. J. Org. Chem. 2004,
69, 327.
are often part of structure–activity relationship studies2,4
.
(1) For a review on biological activities of cyclopropane derivatives, see:
Salaün, J. Top. Curr. Chem. 2000, 207, 1. For a general review on cyclopropanes,
see: Patai, S. The Chemistry of the Cyclopropyl Group, Part 2; John Wiley &
Sons: New York, 1987; Vol. 1.
(2) For an example, see: Gagnon, A.; Amad, M. H.; Bonneau, P. R.;
Coulombe, R.; DeRoy, P. L.; Doyon, L.; Duan, J.; Garneau, M.; Guse, I.; Jakalian,
A.; Jolicoeur, E.; Landry, S.; Malenfant, E.; Simoneau, B.; Yoakim, C. Bioorg.
Med. Chem. Lett. 2007, 17, 4437.
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B.; Julia, M. Synlett 1991, 271. (c) Gibson, S. E.; Jefferson, G. R.; Prechtl, F.
J. Chem. Soc., Chem. Commun. 1995, 1535.
(9) Du, H.; Yang, F.; Hossain, M. M. Synth. Commun. 1996, 26, 1371.
(10) (a) Campbell, J. B., Jr.; Wawerchak Firor, J.; Davenport, T. W. Synth. Commun.
1989, 19, 2265. (b) Weichert, A.; Bauer, M.; Wirsig, P. Synlett 1996, 473.
(11) (a) Ogle, C. A.; Black, K. C.; Sims, P. F. J. Org. Chem. 1992, 57, 3499.
(b) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364.
(c) Miller, J. A.; Dankwardt, J. W. Tetrahedron Lett. 2003, 44, 1907.
(12) Schmitz, W. D.; Romo, D. Tetrahedron Lett. 1996, 37, 4857.
(13) Wallace, D. J.; Chen, C.-Y. Tetrahedron Lett. 2002, 43, 6987.
(14) Pérez, I.; Pérez Sestelo, J.; Sarandeses, L. A. J. Am. Chem. Soc. 2001,
123, 4155.
(3) For reports on oxidation of cyclopropanes by cytochromes P-450, see:
(a) Suckling, C. J.; Nonhebel, D. C.; Brown, L.; Suckling, K. E.; Seilman, S.;
Wolf, C. R. Biochem. J. 1985, 232, 199. (b) Riley, P.; Hanzlik, R. P. Tetrahedron
Lett. 1989, 30, 3015. (c) Riley, P.; Hanzlik, R. P. Xenobiotica 1994, 24, 1.
(4) For representative examples, see: (a) Turner, W. R.; Suto, M. J.
Tetrahedron Lett. 1993, 34, 281. (b) Cuisiat, S.; Bourdiol, N.; Lacharme, V.;
Newman-Tancredi, A.; Colpaert, F.; Vacher, B. J. Med. Chem. 2007, 50, 865.
(c) Haning, H.; Woltering, M.; Mueller, U.; Schmidt, G.; Schmeck, C.;
Voehringer, V.; Kretschmer, A.; Pernerstorfer, J. Bioorg. Med. Chem. Lett. 2005,
15, 1835. (d) Li, Z.; Chen, W.; Hale, J. J.; Lynch, C. L.; Mills, S. G.; Hajdu, R.;
Keohane, C. A.; Rosenbach, M. J.; Milligan, J. A.; Shei, G.-J.; Chrebet, G.;
Parent, S. A.; Bergstrom, J.; Card, D.; Forrest, M.; Quackenbush, E. J.; Wickham,
L. A.; Vargas, H.; Evans, R. M.; Rosen, H.; Mandala, S. J. Med. Chem. 2005,
48, 6169. (e) Durley, R. C.; Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.;
Wang, J. L.; Spangler, D. P.; Mischke, D. A.; Parnas, B. L.; Fobian, Y. M.;
Rath, N. P.; Honda, D. D.; Zeng, M.; Connolly, D. T.; Heuvelman, D. M.;
Witherbee, B. J.; Melton, M. A.; Glenn, K. C.; Krul, E. S.; Smith, M. E.; Sikorski,
J. A. J. Med. Chem. 2002, 45, 3891.
(15) For reviews on bismuth chemistry, see: (a) Finet, J.-P. Chem. ReV. 1989,
89, 1487. (b) Freedman, L. D.; Doak, G. O. Chem. ReV. 1982, 82, 15.
(16) (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,
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48, 6644.
3604 J. Org. Chem. 2008, 73, 3604–3607
10.1021/jo702377h CCC: $40.75 2008 American Chemical Society
Published on Web 03/26/2008

TABLE 1. Optimization of the Palladium-Catalyzed
Cross-Coupling Reaction Conditions Using Tricyclopropylbismuth
2a
TABLE 2. Impact of the Nature of the Halogen on the Outcome
of the Cross-Coupling Reaction with Tricyclopropylbismuth 2a
entry
X
isolated yield of 6 (%)
entry
change from “standard conditions”
no changeb
toluene instead of DMF, 100 °C
Na2CO3 instead of K2CO3
K3PO4 instead of K2CO3
No K2CO3
isolated yield of 4 (%)
1
2
3
5a, OTf
5b, Br
5c, I
66
73
79
1
2
3
4
5
6
7
8
9
80
63
83
80
39
65
77
82
89
70
dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) re-
sulted in a considerable decrease in the yield of the reaction
(entry 6), whereas reducing the catalyst loading to 5 mol %
had no impact on the efficiency of the transformation (entry 7).
The presence of ca. 5.0 equiv of water had no consequence on
the outcome of the reaction (entry 8), showing that strict
exclusion of moisture is unnecessary. Although we chose to
pursue our studies with isolated crude tricyclopropylbismuth,
we demonstrated that the use of 1.0 equiv of reagent 2a
generated in situ leads to excellent yield of coupling product 4
(entry 9).20 In order to address the ability of the second
cyclopropyl group to transfer, 0.50 equivalent of reagent was
used (entry 10). The result indicates that more than one
cyclopropyl group is transferred in the course of the reaction
but also suggests that the reactivity of the second cyclopropyl
group is slightly lower than the first one.
Aryl triflates are an important class of electrophiles in
palladium-catalyzed cross-coupling reactions due to their ease
of preparation from phenols. Therefore, we compared the
reactivity of 4-trifluoromethanesulfonyl benzophenone 5a to that
of the corresponding bromide 5b and iodide 5c. In the event,
the reaction proceeded smoothly in all cases, giving 4-cyclo-
propylbenzophenone 6 in similar yields (Table 2). This is in
contrast with the Suzuki reaction involving cyclopropylboronic
acid where no reaction was observed with aryl triflates.13
We then embarked on establishing the scope of the method
using various aryl bromides, iodides, and triflates (Table 3). As
a general observation, the reaction proceeded smoothly with
ortho- (entry 2), meta- (entry 3), and para-substituted (entry 4)
aryl halides. Again, iodides, bromides, and triflates gave
comparable yields of the corresponding coupling products (7a
vs 3 and 7d vs 7e). The presence of an electron-donating group
such as a phenoxy (entry 7), an amine (entry 9), an alkyl thiolate
(entry 10), or a dioxolane (entry 11) had little impact on the
outcome of the reaction. Moreover, functional groups such as
nitriles (entry 6), acetals (entry 12), indanones (entry 13), and
phthalides (entry 14) were unaffected during the transformation.
Due to the ubiquity of heterocycles in medicinal chemistry,
we expanded our studies to heterocyclic halides (Table 4). In
the event, 3-, 4-, and 5-bromothiophenes 9a, 9b, and 9c gave
good yields of the corresponding coupling products (entries 1,
2, and 3, respectively). 5-Iodothiophene 9d gave slightly higher
yield of 10c than the corresponding bromide 9c (entry 4 vs 3).
Further, modest to good yields of coupling products were
observed for thiophene 9e, furan 9f, thiazole 9g, pyrrole 9h,
indole 9i, and bromopyridine 9j. Interestingly, 2-chloropyridine
9k was found to react smoothly under the current conditions to
give the desired cross-coupling compound 10k (entry 11) in
moderate yield.
PdCl2(dppf) instead of Pd(PPh3)4
Pd(PPh3)4 0.05 equiv instead of 0.1 equiv
H2O (5.0 equiv) added
reagent 2a generated in situ (1.0 equiv)21
10 reagent 2a generated in situ (0.50 equiv)
a Standard conditions: ethyl 4-bromobenzoate 3 (0.30 mmol), reagent
2a (1.5 equiv), Pd(PPh3)4 (0.1 equiv), K2CO3 (2.0 equiv), DMF (3 mL,
0.1 M), degassed solution, 90 °C (oil bath temperature), 18 h. b The
number of equivalents for 2a was calculated assuming that pure reagent
is used.
surprisingly, no report could be found for the corresponding
coupling of trialkylbismuth reagents.17 Based on the fact that
cyclopropyl carbons have a partial sp2 character,18 we hypoth-
esized that tricyclopropylbismuth could undergo palladium-
catalyzed cross-coupling reaction with aryl halides, similarly
to triarylbismuth reagents, allowing access to arylcyclopropanes.
We recently reported the synthesis of tricyclopropylbismuth
and its use in the direct N-cyclopropylation of azoles and cyclic
amides.19 Tricyclopropylbismuth 2a is easily prepared by the
addition of commercially available cyclopropyl magnesium
bromide 1 to bismuth chloride (eq 1). The presence of chloro
derivative 2b was suspected based on elemental analysis and
neutronic activation of the crude reagent. We report herein our
studies in the palladium-catalyzed cross-coupling reaction of
tricyclopropylbismuth with aryl and heteroaryl halides and
triflates.
Utilizing ethyl 4-bromobenzoate 3 as a test substrate, we
explored the reactivity of reagent 2a in the context of palladium-
catalyzed cross-coupling reaction (Table 1). In the event, the
desired product 4 was obtained in 80% isolated yield using
standard conditions for cross-coupling reactions (entry 1).
Optimization of the reaction protocol showed that other solvents
such as toluene gave lower yields of the desired product (entry
2) and that the base could be replaced by sodium carbonate
(entry 3) or potassium phosphate (entry 4). Interestingly, the
reaction proceeded even in the absence of base (entry 5),
although at much lower efficiency. Changing the catalyst for
(17) Dialkoxymethylbismuth and diarylmethylbismuth were reported for the
transfer of a methyl group only. (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.
(18) De Meijere, A. Angew. Chem., Int. Ed. 1979, 18, 809.
(19) Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabé, F. J. Am.
Chem. Soc. 2007, 129, 44.
(20) A control experiment using only cyclopropylmagnesium bromide (no
bismuth chloride) gave recovered aryl bromide 3.
J. Org. Chem. Vol. 73, No. 9, 2008 3605

TABLE 3. Cross-Coupling Reaction of Tricyclopropylbismuth 2a
with Aryl Bromides, Iodides, and Triflates
TABLE 4. Cross-Coupling Reaction of Tricyclopropylbismuth 2a
with Heterocyclic Halides
4-ethylbenzoate 12 in excellent isolated yield (eq 2).21 Gratify-
ingly, the transfer of one ethyl group proceeded smoothly under
simple conditions and did not require additiVes or complex
ligands.22 A full account of our work involving the cross-
coupling of other aliphatic groups will be reported in due course.
In summary, we have reported the palladium-catalyzed cross-
coupling reaction of tricyclopropylbismuth 2a with aryl and
heterocyclic halides and triflates. The reaction tolerates numer-
ous functional groups and proceeds efficiently under standard
conditions for cross-coupling reactions, without requiring strict
anhydrous conditions. The reaction can be performed with
a Contains 5% of dehalogenated product.
Having demonstrated the scope of the cross-coupling reaction
using reagent 2a, we wondered if other trialkylbismuth reagents
could be used for the transfer of acyclic aliphatic groups.
Keeping in mind the propensity of linear aliphatic groups to
undergo ꢀ-hydride elimination during palladium-catalyzed cross-
coupling reaction and being aware of the absence of examples
involving trialkylbismuth reagents, we elected to test the reaction
conditions with triethylbismuth. When generated and used in
situ, triethylbismuth 11 smoothly underwent cross-coupling with
ethyl 4-bromobenzoate 3 under standard conditions to give ethyl
(21) See the Supporting Information for experimental details.
(22) Less than 4% of dehalogenated product was observed by 1H NMR. For
other methods allowing the transfer of an ethyl group, see: (a) Bumagin, N. A.;
Luzikova, E. V. J. Organomet. Chem. 1997, 532, 271. (b) Shenglof, M.; Gelman,
D.; Molander, G. A.; Blum, J. Tetrahedron Lett. 2003, 44, 8593. (c) Fardis, M.;
Mertzman, M.; Thomas, W.; Kirschberg, T.; Collins, N.; Polniaszek, R.; Watkins,
W. J. J. Org. Chem. 2006, 71, 4835. (d) Takami, K.; Yorimitsu, H.; Shinokubo,
H.; Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 1997. (e) Kondolff, I.; Doucet,
H.; Santelli, M. Organometallics 2006, 25, 5219.
3606 J. Org. Chem. Vol. 73, No. 9, 2008

than a few minutes. The solid should be placed immediately under
argon in the freezer after use. The reactiVity will remain essentially
the same for a few weeks if stored appropriately. CAUTION: On
a larger scale, a pyrophoric material is sometimes obtained.
isolated reagent 2a or with less than 1.0 equivalent of reagent
2a generated in situ. The protocol was extended to the coupling
of triethylbismuth 11, allowing the transfer of a linear aliphatic
group with hydrogens in ꢀ-position. To the best of our
knowledge, this work constitutes the first report of cross-
coupling reactions involving trialkylbismuth reagents.
General Procedure for Palladium-Catalyzed Cross-Coupl-
ing Reaction with Reagent 2a. In a sealed tube, the starting iodide,
bromide, chloride, or triflate (0.30 mmol) was dissolved in N,N-
dimethylformamide (3 mL). Potassium carbonate (83 mg, 0.60
mmol) was added, followed by tetrakis(triphenylphosphine) pal-
ladium (35 mg, 0.030 mmol) and cyclopropylbismuth reagent 2a
(150 mg, 0.45 mmol). Argon was bubbled in the reaction mixture
for 15 min. The tube was sealed and heated at 90 °C for 18 h. The
reaction mixture was cooled to rt, diluted with saturated aqueous
sodium bicarbonate (50 mL), and extracted with ether (2 × 50 mL).
The combined organic phases were washed with saturated aqueous
sodium bicarbonate (2 × 50 mL) and brine (2 × 50 mL), dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy using 10% ether in hexanes to afford the desired pure aryl
or heteroaryl cyclopropane.
Experimental Section
Preparation of Tricyclopropylbismuth (2a). Bismuth chloride
(2.50 g, 7.93 mmol) was dissolved in anhydrous THF (100 mL)
and cooled to -10 °C (ice-acetone bath). The bismuth chloride is
not entirely soluble at this temperature, and a white solid may be
observed. Cyclopropylmagnesium bromide (77.1 mL, 26.2 mmol,
0.34 M in THF) was slowly added dropwise under argon via syringe
pump over 1 h. The reaction mixture was stirred at room
temperature for 1 h and heated at 70 °C for 30 min, at which time
a black precipitate was observed. After being cooled to room
temperature, the solution was cannulated under argon over a
degassed biphasic solution of brine (200 mL) and ether (200 mL).
The heterogeneous solution was stirred for 5 min, transferred in a
separatory funnel, and diluted with ether (100 mL). The organic
phase was collected, dried over sodium sulfate, filtered, and
concentrated under reduced pressure to afford a yellow oily solid.
Ether (50 mL) was added, followed by hexanes (50 mL). The
mixture was sonicated, cooled to 0 °C, and filtered over a Buchner
Acknowledgment. We thank our colleagues at Boehringer
Ingelheim (Canada) Ltd. for valuable help during manuscript
preparation and Sylvain Bordeleau for his help with compound
characterization.
1
funnel to afford 2a as a white solid (1.75 g, 72%): H NMR (400
Supporting Information Available: Experimental procedures
and characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
MHz, DMSO-d6) δ 1.91 (s (br), 3H), 1.57 (s (br), 6H), 1.22 (s (br)
6H); HRMS (EI) calcd for C9H15Bi (M) 332.0978, found 332.0973
(M), 291.0584 (M - c-Pr), 250.0191 (M - 2(c-Pr)), 208.9808 (Bi).
The reagent should not be pumped under high Vacuum for more
JO702377H
J. Org. Chem. Vol. 73, No. 9, 2008 3607