Palladium-catalyzed cross-coupling of cyclopropylmagnesium bromide with aryl bromides mediated by zinc halide additives

Article abstract of DOI:10.1021/jo100983c

The key Pd-catalyzed cross-coupling of aryl bromides or triflates and cyclopropylmagnesium bromide in the presence of substoichiometric amounts of zinc bromide produces cyclopropyl arenes in good to excellent yields. The cross-coupling of other alkyl, cyc

Full text of DOI:10.1021/jo100983c

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reactivity (in cross-coupling reactions) due to the “hardness”
Palladium-Catalyzed Cross-Coupling of
Cyclopropylmagnesium Bromide with Aryl Bromides
Mediated by Zinc Halide Additives
of the magnesium species.5 Even though these issues can
be partially addressed by premixing Grignard reagents with
stoichiometric amounts of zinc halides to form the zinc re-
agents prior to the coupling reaction6 and a new protocol for
the synthesis of cyclopropylarenes by cross-coupling of
cyclopropylzinc bromide with aryl halide,7 an improved
coupling of cyclopropylmagnesium halides using a catalytic
amount of zinc reagents would be a useful addition to the
current available methodologies. A successful catalytic process
would also be applicable for the coupling of other Grignard
reagents. Reported herein is our finding that the addition of
a substoichiometric amount of zinc bromide, even as low as
0.15 equiv, can effectively “soften” the Grignard reagent8
and significantly improve the Pd-catalyzed coupling reaction
of aryl and heteroaryl halides/triflates with 1.
Chutian Shu, Kanwar Sidhu, Li Zhang, Xiao-jun Wang,*
Dhileepkumar Krishnamurthy, and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim
Pharmaceuticals Inc., Ridgefield, Connecticut 06877
xiao-jun.wang@boehringer-ingelheim.com
Received May 19, 2010
We began our study with p-bromobenzonitrile (2a) as a
model substrate for coupling with 1 in THF at room tem-
perature (Table 1). The initial screening revealed that the
selection of appropriate catalysts and ligands is important
for the success of this reaction (entries 1-4). Among the
catalyst systems that we examined, the combination of palla-
dium acetate and tri-tert-butylphosphine9 gave the best reac-
tion. The Pd/phosphine ratio also had no significant impact
on the reaction (entries 4-6). We next examined the effect of
in situ formation of the zinc reagent with substoichiometric
amounts of zinc halide additives (entries 7-10). In these
experiments, 1 was added slowly to a premixed solution of
2a, zinc halide, and catalyst. We were pleased to find that the
use of 0.3-0.6 equiv of zinc bromide provided better yield
than the premixing approach (entries 7, 8). Here the use of
P(tBu)3, an electron-rich and bulky phosphine ligand, is
important, as it greatly accelerates the coupling reaction.10
Reducing the amount of additive further to 0.15 equiv (entry 9)
caused a slight decrease in yield, although the result is still
comparable to that obtained with the premixing approach.
Use of zinc chloride gave decreased conversion to product,
demonstrating again the importance of halide counterion
(entry 10). Finally the control experiment with no additive
gave significantly lower yield (entry 11). In all experiments,
the use of excess 1 (1.8 equiv) was necessary to achieve a
complete coupling by consuming all the starting material 2a.
After establishing the optimum conditions for this reac-
tion, we turned our attention to exploring the reaction scope.
As shown in Table 2, a wide range of aryl and heteroaryl
bromides were suitable substrates. Electron-rich substrates
2b and 2c gave the desired products 3b and 3c in excellent
yields (entries 1, 2). Reactions with the substrates 2d-f,
The key Pd-catalyzed cross-coupling of aryl bromides or
triflates and cyclopropylmagnesium bromide in the pres-
ence of substoichiometric amounts of zinc bromide
produces cyclopropyl arenes in good to excellent yields.
The cross-coupling of other alkyl, cycloalkyl, and aryl
Grignard reagents with aryl bromides under the same
conditions gives the corresponding substituted arenes in
good yields.
The cyclopropyl group is a common structural motif in
natural products and pharmaceutical molecules,1 and its in-
corporation via Pd-catalyzed coupling has been extensively
studied mainly using boron-,2 zinc-,3 and bismuth-based4
reagents. These soft organometallic reagents offer wide
functional group compatibility, but their high cost severely
limits their attractiveness for large-scale synthesis. The less
expensive cyclopropylmagnesium bromide (1), on the other
hand, suffers from poor functional group tolerance and low
(1) (a) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. Rev. 2003,
103, 1625–1648. (b) The Chemistry of the Cyclopropyl Group; Patai, S.,
Rappoport, Z., Eds.; John Wiley & Sons: New York, 1987.
(2) (a) Wallace, D.; Chen, C. Tetrahedron Lett. 2002, 43, 6987–6990.
(b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634–
12635. (c) Molander, G. A.; Gormisky, P. E. J. Org. Chem. 2008, 73, 7481–
7485.
(6) Coleridge, B. M.; Bello, C. S.; Leitner, A. Tetrahedron Lett. 2009, 50,
4475–4477.
(3) (a) Campbell, J. B., Jr.; Firor, J. W.; Davenport, T. W. Synth.
Commun. 1989, 19, 2265–2272. (b) Weichert, A.; Bauer, M.; Wirsig, P.
Synlett 1996, 473–474.
(4) (a) Gagnon, A.; Duplessis, M.; Alsabeh, P.; Barabe, F. J. Org. Chem.
2008, 73, 3604–3607. (b) Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.;
Barabe, F. J. Am. Chem. Soc. 2007, 129, 44–45.
(5) (a) Ogle, C. A.; Black, K. C.; Sims, P. F. J. Org. Chem. 1992, 57, 3499–
3503. (b) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70,
9364–9370. (c) Miller, J. A.; Dankwardt, J. W. Tetrahedron Lett. 2003, 44,
1907–1910.
(7) Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
pp 1-48.
(8) For a related example of using Grignard nucleophiles together with
substoichiometric amount of zinc halide, see: Hatano, M.; Suzuki, S.;
Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998–9999.
(9) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–1564.
(10) (a) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158–163. (b) Dai, C.; Fu, G. C.
J. Am. Chem. Soc. 2001, 123, 2719–2724.
DOI: 10.1021/jo100983c
r
Published on Web 09/03/2010
J. Org. Chem. 2010, 75, 6677–6680 6677
2010 American Chemical Society

Shu et al.
JOCNote
TABLE 1. Screening of Cross-Coupling between 1 and 2a
entry
Pd/ligand (mol ratio)
additive (equiv)a
zinc reagent
yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3 (1/1.2)
Pd(OAc)2/PCy3 (1/1.2)
Pd(dppf)Cl2
ZnBr2 (1.2)
ZnBr2 (1.2)
ZnBr2 (1.2)
ZnBr2 (1.2)
ZnBr2 (1.2)
ZnBr2 (1.2)
ZnBr2 (0.6)
ZnBr2 (0.3)
ZnBr2 (0.15)
ZnCl2 (0.3)
none
preformed
preformed
preformed
preformed
preformed
preformed
in situ
in situ
in situ
in situ
in situ
72
19
73
89
90
89
95
Pd(OAc)2/P(tBu)3 (1/1.2)
Pd(OAc)2/P(tBu)3 (1/2.4)
Pd(OAc)2/P(tBu)3 (1/3.6)
Pd(OAc)2/P(tBu)3 (1/1.2)
Pd(OAc)2/P(tBu)3 (1/1.2)
Pd(OAc)2/P(tBu)3 (1/1.2)
Pd(OAc)2/P(tBu)3 (1/1.2)
Pd(OAc)2/P(tBu)3 (1/1.2)
95 (92 c)
88
82
9
10
11
71
aStoichiometry relative to Grignard 1. bWt % assay yield based on HPLC quantification. cIsolated yield.
bearing sensitive ester and lactone groups, afforded the
products in moderate yields (entries 3, 4). The cross-coupling
of thioether 2g gave a satisfactory result with 70% yield of 3g
(entry 6). Pyridyl and quinolinyl substrates 2i and 2j under-
went cross-coupling reactions to give 3i and 3j in excellent
yields, respectively (entries 8, 9). The study also showed that
the coupling reaction was highly dependent on the choice of
halide. It is noteworthy to mention that a slow addition of 1
to the mixture of aryl halides (especially for those substrates
bearing sensitive functional groups) and ZnBr2 (typically
30 min for 5-10 mmol scale) is necessary to ensure no accu-
mulation of 1 occurs during the reaction; that is, the rate of
addition of the reagent is lower than that of transmetalation
and cross-coupling. In the absence of ZnBr2, the yields for
3d,e and 3j fell to 40-50% due to side reactions such as
addition of Grignard reagent to sensitive functional groups.
Whereas the coupling of triflates 2k,n produced 3k,b in
reasonable yields (entries 10, 13), both chloride 2l and iodide
2m afforded very poor product yields (entries 11, 12). In the
former case, the low reactivity of aryl chloride resulted in
clean but low conversion (<20%) to 3a even after extended
reaction time, whereas in the latter case, the high reactivity of
iodide resulted in a significant amount of deiodinated by-
product (>30%).
Besides cyclopropylmagnesium bromide (1), alkyl, cyclo-
alkyl, and aryl Grignard reagents 4 were also studied (Table 3).
Primary n-propyl Grignard reagents 4a and 4b were sub-
jected to coupling with 2b (entries 1, 2). Interestingly, the
counterion (Br vs Cl) had a significant effect on the reaction
yield. On the other hand, the isopropyl and tert-butyl
Grignard reagents 4cand 4d did not afford the desired product
(entries 3, 4). Instead n-propyl- and isobutyl-(p-methoxy)-
benzenes 5a and 5d were isolated as the major products, pre-
sumably from the competing Pd-H scrambling pathway.5
The coupling reaction of cyclohexyl Grignard reagents 4e
and 4f with bromide afforded the desired product with ex-
cellent yield and purity. In this case, the counterion (Br vs Cl)
had a slight impact on the reaction yield. Aryl Grignard
reagent 4g reacted similarly to afford the desired product in
excellent yield under the same conditions (entry 7).
substoichiometric zinc bromide additive. The scope of
nucleophiles was further extended to other alkyl, cycloalkyl,
and aryl Grignard reagents with good results.
Experimental Section
General Procedure of Pd-Catalyzed Cross-Coupling. To a
suspension of aryl halide/triflate (2.3 mmol, 1.0 equiv) and tri-
tert-butylphosphonium tetrafluoroborate (0.14 mmol, 41 mg,
0.06 equiv) in THF (2.5 mL) under N2 were added Pd(OAc)2
(0.11 mmol, 25 mg, 0.05 equiv) and zinc bromide solution (27.6
wt % solution in THF, 0.57 g, 0.7 mmol, 0.3 equiv). Cyclopro-
pylmagnesium bromide (0.50 M in THF, 7.36 mL, 3.68 mmol,
1.6 equiv) was added slowly over 30 min while maintaining the
temperature at 20-25 °C. The reaction mixture was stirred at
room temperature for an additional 2 h and monitored by
HPLC. Upon completion (>99% conversion), the reaction
was cooled to 0 °C, and water (8.0 mL) was added slowly while
maintaining the temperature below 15 °C. Ethyl acetate (10 mL)
was added, and the aqueous layer was extracted with ethyl
acetate (2 ꢀ 10 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated. The crude mix-
ture was purified by chromatography (silica gel, ethyl acetate/
hexanes) to afford the purified product.
4-Cyclopropylbenzonitrile (3a). Following the general proce-
dure, the title compound was obtained in 92% yield (303 mg)
from 2a or 81% yield (267 mg) from 2j as a yellow oil.2c 1H NMR
(400 MHz, CDCl3): δ 7.52 (ABq, J = 8.4 Hz, 2H), 7.12 (ABq,
J = 8.4 Hz, 2H), 1.96-1.90 (m, 1H), 1.11-1.06 (m, 2H),
0.78-0.74 (m, 2H). 13C NMR (400 MHz, CDCl3): δ 150.4,
132.3, 126.3, 119.4, 109.0, 16.0, 10.8.
1-Cyclopropyl-4-methoxybenzene (3b). Following the general
procedure, the title compound was obtained in 88% yield (300
mg) as a yellow oil.2c 1H NMR (400 MHz, CDCl3): δ 7.03 (ABq,
J = 8.8 Hz, 2H), 6.83 (ABq, J = 8.8 Hz, 2H), 3.79 (s, 3H),
1.89-1.85 (m, 1H), 0.93-0.88 (m, 2H), 0.65-0.61 (m, 2H). 13
C
NMR (400 MHz, CDCl3): δ 157.9, 136.1, 127.0, 114.0, 55.5,
14.8, 8.7.
5-Cyclopropylbenzo[d][1,3]dioxole (3c). Following the general
procedure, the title compound was obtained in 82% yield (266
mg) as a colorless oil.4a 1H NMR (400 MHz, CDCl3): δ 6.71 (d,
J = 8.0 Hz, 1H), 6.58 (d, J = 8.0, 1H), 6.55 (s, 1H), 5.91 (s, 2H),
1.89-1.81 (m, 1H), 0.91-0.88 (m, 2H), 0.63-0.60 (m, 2H). 13
C
NMR (400 MHz, CDCl3): δ 147.9, 145.6, 138.0, 119.2, 108.2,
106.5, 101.0, 15.46, 8.9.
In summary, we have developed a general and mild Pd-
catalyzed cross-coupling reaction between aryl bromides/
triflates and cyclopropylmagnesium bromide using a
Methyl 3-Cyclopropyl-4-methylbenzoate (3d). Following the
general procedure, the title compound was obtained in 68%
6678 J. Org. Chem. Vol. 75, No. 19, 2010

Shu et al.
JOCNote
TABLE 2. Coupling of Aryl Halides with Cyclopropylmagnesium
Bromide (1)
TABLE 3. Coupling of Aryl Bromides with Grignard Reagents 4
δ 7.18 (ABq, J = 8.0 Hz, 2H), 7.04 (ABq, J = 8.0 Hz, 2H), 4.15
(q, J = 7.2 Hz, 2H), 3.57 (s, 2H), 1.91-1.87 (m, 1H), 1.26 (t, J =
7.2 Hz, 3H), 0.98-0.94 (m, 2H), 0.71 (m, 2H). 13C NMR (400
MHz, CDCl3): δ 171.8, 142.8, 121.1, 129.1, 125.9, 60.8, 41.0,
15.1, 14.2, 9.2.
(3-Cyclopropylphenyl)(methyl)sulfide (3g). Following the gen-
eral procedure, the title compound was obtained in 70% yield
(172 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.17
(m, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J =
8.0 Hz, 1H), 2.49 (s, 2H), 1.91-1.85 (m, 1H), 0.99-0.95 (m, 2H),
0.73-0.69 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 144.7,
138.2, 128.7, 124.3, 123.7, 122.5, 15.9, 15.3, 9.1.
2-Cyclopropylbenzonitrile (3h). Following the general proce-
dure, the title compound was obtained in 68% yield (224 mg)
as a colorless oil.13 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J =
7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H),
6.93 (d, J = 8.0, 1H), 2.31-2.24 (m, 1H), 1.16-1.11 (m, 2H),
0.80-0.77 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 148.0,
133.0, 132.7, 126.0, 124.5, 118.5, 113.2, 14.3, 9.7.
b
aIsolated yield by flash chromatography on silica gel. Wt % assay
yield by GC.
3-Cyclopropylquinoline (3j). Following the general procedure,
the title compound was obtained in 83% yield (280 mg) as a
colorless oil.2a 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.07
(t, J = 8.0 Hz, 1H), 7.71 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H),
7.62-7.60 (m, 1H), 7.51-7.45 (m, 1H), 2.09-2.03 (m, 1H),
1.12-1.07 (m, 2H), 0.86-0.82 (m, 2H). 13C NMR (400 MHz,
CDCl3): δ 150.6, 146.6, 136.7, 130.9, 129.1, 128.4, 128.1, 127.2,
126.6, 13.4, 9.2.
1-Methoxy-4-propylbenzene (5a). Following the general pro-
cedure, the title compound was obtained in 88% yield (264 mg)
from nPrMgBr, 63% yield (189 mg) from nPrMgCl, and 72%
yield (216 mg) from iPrMgCl as a colorless oil.14 1H NMR
yield (298 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
7.75 (d, J = 7.6 Hz, 1H), 7.65 (s, 1H), 7.19 (d, J = 7.6 Hz, 1H),
3.88 (s, 3H), 2.47 (s, 3H), 1.89-1.86 (m, 1H), 0.98-0.94 (m, 2H),
0.70-0.66 (m, 2H). 13C NMR (400 MHz, CDCl3): δ 167.6,
143.8, 141.8, 129.8, 127.9, 127.1, 126.9, 52.1, 20.1, 13.6, 7.1.
HRMS: calcd for [C12H14O2 þ H]þ 191.1077, found 191.1086.
5-Cyclopropylisobenzofuran-1(3H)-one (3e). Following the
general procedure, the title compound was obtained in 75%
yield (301 mg) as a beige powder.4a 1H NMR (400 MHz,
CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H),
7.13 (s, 1H), 5.25 (s, 2H), 2.03-1.99 (m, 1H), 1.14-1.09 (m, 2H),
0.83-0.79 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 171.3,
152.2, 147.4, 126.9, 125.8, 123.2, 118.8, 69.6, 16.3, 10.9.
(11) Kusuyama, Y.; Ikeda, Y. Bull. Chem. Soc. Jpn. 1973, 46, 204–207.
(12) Lazzaroni, S.; Dondi, D.; Fagnoni, M.; Albini, A. Eur. J. Org. Chem.
2007, 26, 4360–4365.
Ethyl (4-Cyclopropylphenyl)acetate (3f). Following the gen-
eral procedure, the title compound was obtained in 78% yield
(318 mg) as a beige powder.11 1H NMR (400 MHz, CDCl3):
(13) Shono, T.; Nishiguchi, I. Tetrahedron 1974, 30, 2183–2190.
J. Org. Chem. Vol. 75, No. 19, 2010 6679

Shu et al.
JOCNote
(400 MHz, CDCl3): δ 7.01 (ABq, J = 8.8 Hz, 2H), 6.74 (ABq,
J = 8.8 Hz, 2H), 3.73 (s, 3H), 2.45 (t, J = 7.4 Hz, 2H), 1.52 (m,
2H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (400 MHz, CDCl3):
δ 157.8, 135.0, 129.5, 113.83, 55.5, 37.4, 25.0, 14.0.
1-Isobutyl-4-methoxybenzene (5d). Following the general pro-
cedure, the title compound was obtained in 86% yield (282 mg)
as a yellow oil.5b 1H NMR (400 MHz, CDCl3): δ 7.06 (ABq, J =
8.8 Hz, 2H), 6.83 (ABq, J = 8.8 Hz, 2H), 3.79 (s, 3H), 2.42 (d,
J = 7.2 Hz, 2H), 1.82 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). 13C
NMR (400 MHz, CDCl3): δ 157.9, 134.0, 130.2, 113.7, 55.4,
44.74, 30.6, 22.5.
(ABq, J = 8.7 Hz, 2H), 3.79 (s, 3H), 2.45 (m, 1H), 1.84 (m, 4H),
1.73 (m, 1H), 1.39 (m, 4H), 1.26 (m, 1H). 13C NMR (400 MHz,
CDCl3): δ 157.9, 140.6, 127.8, 113.9, 55.4, 43.9, 34.9, 27.17,
26.4.
40-Ethylbiphenyl-4-carbonitrile (5g). Following the general
procedure, the title compound was obtained in 84% yield (435
mg) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.71-7.65
(m, 4H), 7.51 (ABq, J = 8.2 Hz, 2H), 7.31 (ABq, J = 8.2 Hz,
2H), 2.70 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR
(400 MHz, CDCl3): δ 145.80, 145.26, 136.67, 132.74, 128.84,
127.67, 127.34, 119.23, 110.71, 28.75, 15.77. HRMS: calcd for
[C15H13N þ H]þ 208.1126, found 208.1138.
1-Cyclohexyl-4-methoxybenzene (5e). Following the general
procedure, the title compound was obtained in 77% yield (293
mg) from 4e and 80% yield (304 mg) from 4f as a white foam.15
1H NMR (400 MHz, CDCl3): δ 7.13 (ABq, J = 8.7 Hz, 2H), 6.84
Acknowledgment. We thank Dr. John Proudfoot and
Dr. Jonathan Reeves for discussions.
(14) Maras, N.; Polanc, S.; Kocevar, M. Tetrahedron 2008, 64, 11618–
Supporting Information Available: Copies of 1H/13C NMR
spectra for compounds 3a-j, 5a, and 5d-f. This material is
available free of charge via the Internet at http://pubs.acs.org.
11624.
(15) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew. Chem., Int.
Ed. 2007, 46, 4364–4366.
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