General and user-friendly protocol for the synthesis of functionalized aryl- and heteroaryl-cyclopropanes by Negishi cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2009.05.054

The introduction of an unsubstituted cyclopropyl moiety was efficiently accomplished via Negishi cross-coupling of cyclopropylzinc bromide with functionalized aryl halides in high yields and fast reaction rates. The stability and the efficient one-step sy

Full text of DOI:10.1016/j.tetlet.2009.05.054

Tetrahedron Letters 50 (2009) 4475–4477
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General and user-friendly protocol for the synthesis of functionalized
aryl- and heteroaryl-cyclopropanes by Negishi cross-coupling reactions
*
Brian M. Coleridge, Charles S. Bello, Andreas Leitner
BASF Corporation, 1424 Mars-Evans-City Road, Evans City, PA 16033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The introduction of an unsubstituted cyclopropyl moiety was efficiently accomplished via Negishi cross-
coupling of cyclopropylzinc bromide with functionalized aryl halides in high yields and fast reaction
rates. The stability and the efficient one-step synthesis of cyclopropylzinc bromide make this protocol
very valuable in particular for commercial applications.
Received 3 April 2009
Revised 12 May 2009
Accepted 18 May 2009
Available online 22 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Molecules bearing cyclopropyl groups as structural motifs have
emerged as important synthetic intermediates and pharmaceutical
active molecules.1 In particular, the higher metabolic stability of
the cyclopropyl group compared to aliphatic residues toward
microsomal oxidation enables applications of these derivatives in
structure–activity relationship studies.2,4
The introduction of a cyclopropyl group can be accomplished by
several methods such as radical substitution on arenes by cyclo-
propyl radicals,3 cyclopropanation of vinyl arenes with diazometh-
ane,4 the classical Simmons–Smith reaction,5 transformations with
sulfonium ylids,6 or reactions with ferrocenyl carbenes.7 Although
the cyclopropanation toolbox provides versatile methods, the re-
quired vinyl arenes for the transformations are usually obtained
from aryl halides.
To circumvent this reaction sequence, the direct introduction of
the cyclopropyl group by cross-coupling reactions of the corre-
sponding cyclopropyl nucleophile with organic halides has been
reported by several groups from academia and industry.8 Kumada
coupling reactions with cyclopropylmagnesium halides can be per-
formed with nickel and palladium catalysts, however, the high
reactivity of organomagnesium reagents limits this technology to
substrates without sensitive functional groups.9,10 Knochel pub-
lished the in situ generation of functionalized cyclopropylmagne-
sium halides via Br–Mg exchange reactions using i-PrMgClÁLiCl.11
Most impressively, an ester group adjacent to the Grignard center
was tolerated when conducting the reactions at low temperatures
of À50 °C. Organotin compounds like cyclopropyl(tri-n-
butyl)stannane have not been frequently applied because of low
reactivity and limited scope.12 Gagnon et al. recently reported tri-
cyclopropylbismuth, generated from cyclopropylmagnesium bro-
clopropylbismuth reagent is pyrophoric. This is a major drawback,
especially for applications at commercial scale.13
Wallace and Chen described the cross-coupling of cyclo-
propylboronic acid with aryl and vinyl halides employing an
in situ catalyst generated from Pd(OAc)2 and PCy3.14 Since cyclo-
propylboronic acid is prone to protodeboronation, which limits
its stability and shelf life, Molander and Gormisky developed a
cross-coupling protocol using the stable potassium cyclopropyltri-
fluoroborate as a nucleophile.15 Soderquist reported a method
which takes advantage of an in situ generation of a cyclopropylb-
orate complex from propargylic bromide and 9-borabicy-
clo[3.3.1]nonane.16,17 Although good to high yields and tolerance
to a broad variety of functional groups were observed under Suzuki
conditions,18 the multistep synthesis of cyclopropylboronic acid
derivatives often causes diminished yields of the nucleophile.
In 1996, Weichert et al. published a Negishi cross-coupling19
with cyclopropylzinc chloride, which was generated by cyclopro-
pylmagnesium chloride and zinc chloride by transmetallation,
and aryl bromides bearing functional groups such as methyl ester,
sulfone, or trifluoromethyl group. Reactions were conducted in the
presence of 5 mol % PdCl2dppf and the addition of 6–11 mol % of
CuI as co-catalyst was essential for high conversions and yields.20
Although the discussed protocols enable the direct introduction
of a cyclopropyl group by cross-coupling technology, to the best of
our knowledge there is no organometallic nucleophile which con-
solidates the following highly desirable properties: (1) synthesis of
the compound in high yield and few steps, (2) shelf life of several
months, (3) broad substrate scope and tolerance to sensitive func-
tional groups in cross-coupling reactions, and (4) convenient and
safe handling.
mide and bismuth chloride, as
Although the cross-coupling with this novel reagent has a broad
scope and tolerates a broad variety of functional groups, the tricy-
a
cyclopropanation reagent.
With the purpose to design a reagent which addresses these
desirable requirements and is in addition scalable for manufactur-
ing of commercial quantities, we investigated cyclopropylzinc bro-
mide in more detail.21 The reagent is known in the literature but
applications are rare and often it is generated in situ by
transmetallation.2b
* Corresponding author. Tel.: +1 724 538 1334; fax: +1 724 538 1258.
E-mail address: Andreas.Leitner@basf.com (A. Leitner).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.054

4476
B. M. Coleridge et al. / Tetrahedron Letters 50 (2009) 4475–4477
As depicted in Scheme 1, cyclopropylzinc bromide was conve-
Zn*
Rieke Zn
niently prepared in one step by employing the Rieke active zinc
technology.22 We conducted the synthesis on multikilogram scale,
which provided the product as 1M solution in THF in excellent
yields of 80–90%.
Br
ZnBr
THF
80-90% yield
Scheme 1.
The excess of Zn* was filtered off and the organozinc compound
obtained as a solution in THF. In contrast to other nucleophiles, we
were able to demonstrate in ongoing room temperature shelf life
studies for the first time that cyclopropylzinc bromide is stable
over six months and can be stored under an inert atmosphere
without loss of reactivity.23 In addition we found that the organo-
zinc reagent is non-pyrophoric as a 1 M solution in THF.
In order to evaluate the full scope and limitations of cyclopro-
pylzinc bromide in the Negishi cross-coupling reaction, we started
Br
CF3
1% Pd(PPh3)4
+
BrZn
THF, RT
20h
CF3
quantitative (GC)
<5% homocoupling
Scheme 2.
Table 1
Palladium-catalyzed cross-coupling reactions of aryl halides with cyclopropylzinc bromidec
Pd catalyst
1-2.5 mol%
+
Ar-X
ZnBr
Ar
THF
RT or reflux
Entry
Substrate
Catalystb
Reaction time (h)/temperature
Product
Yielda
O
O
X
1
2
3
X@I
X@Br
X@Cl
Pd(PPh3)4, 2.5%
PEPPSI, 1%
PEPPSI, 1%
1/65 °C
1/65 °C
4/65 °C
99 (GC)
75
75
O
O
4
PEPPSI, 1%
1/rt
97 (GC)
Br
OMe
OMe
5
6
PEPPSI,1%
4/65 °C
92 (GC)
99 (GC)
OCH3
I
OCH3
CN
Pd(PPh3)4, 2.5%
18/65 °C
Br
CN
CN
NC
7
Pd(PPh3)4, 2.5%
18/65 °C
91
Br
CN
CN
Br
8
9
Pd(PPh3)4, 2.5%
PEPPSI, 1%
24/65 °C
8/65 °C
75
S
N
S
N
99 (GC)
Br
Br
10
11
Pd(PPh3)4, 2.5%
PEPPSI, 0.1%
24/65 °C
24/rt
56
99 (GC)
N
N
Br
12
Pd(PPh3)4, 2.5%
4/65 °C
62
N
N
13
14
Pd(PPh3)4, 2.5%
PEPPSI, 1%
1/rt
4/rt
77
5 (GC)
I
NO2
NO2
a
Isolated yields unless stated otherwise. Reactions conducted in THF on 10 mmol scale.
Catalyst loadings are not optimized.
Cyclopropylzinc bromide was prepared as 1 M solution in THF by BASF.
b
c

B. M. Coleridge et al. / Tetrahedron Letters 50 (2009) 4475–4477
4477
2. (a) Todo, Y.; Takagi, H.; Iino, F.; Fukuorka, Y.; Ikeda, Y.; Tanaka, K.; Saikawa, I.;
Narita, H. Chem. Pharm. Bull. 1994, 42, 2049; (b) Gagnon, A.; Amad, M.;
Bonneau, P.; Coulombe, R.; DeRoy, P. L.; Doyon, L.; Duan, L.; Garneau, M.; Guse,
I.; Jakalian, A.; Jolicoeur, E.; Landry, S.; Malenfant, E.; Simoneau, B.; Yoakim, C.
Bioorg. Med. Chem. Lett. 2007, 17, 4437–4441.
our studies with the conversion of 4-bromobenzotrifluoride in the
presence of 1% Pd(PPh3)4 in THF (Scheme 2). Very satisfyingly, we
observed a complete conversion of the aryl bromide to the desired
cross-coupling product after 20 h at room temperature. The reac-
tion proceeded cleanly and only a trace amount of the homocou-
pling by-product (<5%) of the electrophile was observed.
Interestingly, copper salts as co-catalyst, as reported by Weichert
et al., were not required to obtain high conversions.20
3. Shono, T.; Nishiguchi, I. Tetrahedron 1974, 30, 2183.
4. Turner, W. R.; Suto, M. J. Tetrahedron Lett. 1993, 34, 281.
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Commun. 1995, 1535.
We evaluated the substrate scope using Pd(PPh3)4 and PEPPSI,
which was developed by Organ and co-workers,24 as catalysts. As
depicted in Table 1, a broad variety of aryl halides bearing sensitive
functional groups such as ketone, methyl ester, ether, nitrile, and
nitro group can be tolerated under the described reaction condi-
tions.25 No side products by an uncatalyzed nucleophilic attack
of the organozinc reagent on these functionalities were observed.
In the case of 4-chloro-acetophenone, PEPPSI was applied as cata-
lyst to accomplish high conversions (Table 1, entry 3). In other
reactions, PEPPSI was employed due to its good stability to air
and moisture, making its handling under an inert atmosphere
unnecessary (Table 1, entries 2–5 and 9).26 In the case of 2-bromo
pyridine, the cross-coupling could be conducted efficiently with
0.1 mol % PEPPSI at room temperature. Interestingly, 1-iodo-4-
nitrobenzene showed low conversions with PEPPSI whereas
Pd(PPh3)4 gave complete conversion after 1 h and the final product
was isolated in 77% yield (Table 1, entries 13 and 14). The influence
of the substitution pattern of the aryl halide had no significant im-
pact on the reaction rate. For example, 2-, 3-, and 4-bromo benzo-
nitrile were converted with comparable high reaction rates
providing isolated yields up to 91% (Table 1, entries 6–8). The reac-
tion with heterocycles like 2-bromo-thiazole, 2-bromo-pyridine,
and 2-methyl-4-bromopyridine gave good yields (56–99%) of the
corresponding cross-coupling product (Table 1, entries 9–12).
In conclusion, we have developed a powerful protocol for the
Negishi cross-coupling of functionalized aryl halides with cyclo-
propylzinc bromide. The method outperforms competitive tech-
nologies because the organozinc reagent can be synthesized in
excellent yields in only one step on multikilogram scale, shows
high reactivity, is compatible to sensitive functional groups and
convenient to apply. To the best of our knowledge, we are report-
ing for the first time, thermal stability data of cyclopropylzinc bro-
mide. In ongoing stability studies, no significant loss of reactivity
or decomposition of this non-pyrophoric reagent was observed.
This is of particular interest for applications at commercial scale.
The cyclopropyl Negishi cross-coupling protocol is very user
friendly and no diligent optimization of catalysts, additives, or sol-
vents was required to obtain high yields of the final products.
7. Du, H.; Yang, F.; Hossain, M. M. Synth. Commun. 1996, 26, 1371.
8. (a) For general recent cross coupling reviews see: Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Meijere, A., Eds.; Wiley-VCH: Weinheim,
2004; (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev.
2002, 102, 1359–1469; (c) Top. Curr. Chem.; Miyaura, N., Ed.; Springer: New
York, 2002; Vol. 219, (d) Corbet, J.; Mignani, G. Chem. Rev. 2006, 106, 2651–
2710; (e) Leitner, A. Iron Catalyzed Cross Coupling Reactions. In Iron Catalysis in
Organic Chemistry; Plietker, B., Ed.; Wiley-VCH Verlag GmbH & Co. KgaA:
Weinheim, Germany, 2008; pp 147–176; (f) Sherry, D. B.; Fürstner, A. Acc.
Chem. Res. 2008, 41, 1500–1511; (g) Knochel, P.; Calaza, M. I.; Hupe, E. Carbon–
Carbon Bond-Forming Reactions Mediated by Organozinc Reagents, 2nd ed.. In
Metal-Catalyzed Cross-Coupling Reactions; De Meijere, A., Diederich, F., Eds.;
Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, Germany, 2004; Vol. 2, pp
619–670; (h) Knochel, P.; Leuser, H.; Gong, L.; Perrone, S.; Kneisel, F.
Functionalized Organozinc Compounds. In Chemistry of Organozinc
Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley & Sons Ltd: Chichester,
UK, 2006; Pt. 1, pp 287–393.
9. (a) Ng, D. K. P.; Luh, T. J. Am. Chem. Soc. 1989, 111, 9119–9121; (b) Ornstein, P.
L.; Bleisch, T. J.; Brian, M.; Kennedy, A. J. H.; Wright, R. A.; Johnson, B. G.;
Tizzano, J. P.; Helton, D. R.; Kallman, M. J.; Schoepp, D. D.; Hrin, M. J. Med. Chem.
1998, 41, 358–378.
10. For
a Kumada coupling of cyclopropylmagnesium bromide with aryl
tosylates see: Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem.
2005, 70, 9364.
11. (a) Rauhut, C. B.; Cervino, C.; Krasovskiy, A.; Knochel, P. Synlett 2009, 67–70; (b)
Vu, V. A.; Marek, I.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 351–
352.
12. (a) Schmitz, W. D.; Romo, D. Tetrahedron Lett. 1996, 37, 857; (b) Piers, E.; Jean,
M.; Marrs, P. S. Tetrahedron Lett. 1987, 28, 5075.
13. Gagnon, A.; Duplessis, M.; Alsabeh, P.; Barabe, F. J. Org. Chem. 2008, 73, 3604.
14. Wallace, D. J.; Chen, C.-Y. Tetrahedron Lett. 2002, 43, 6987.
15. Molander, G. A.; Gormisky, P. E. J. Org. Chem. 2008, 73, 7481–7485.
16. Soderquist, J. A.; Huertas, R.; Leon-Colon, G. Tetrahedron Lett. 2000, 41, 4251.
17. Fürstner, A.; Leitner, A. Synlett 2001, 73, 209.
18. Miyaura, N.; Suzuki, A. Chem. Rev. 1992, 95, 2457.
19. (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821–1823; (b)
Negishi, E. Bull. Chem. Soc. Jpn. 2007, 80, 233–257.
20. Weichert, A.; Bauer, M.; Wirsig, P. Synlett 1996, 473; See also Campbell, J. B., Jr.;
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21. For further information see: www.RZnX.basf.com.
22. Rieke, R. D. Science 1989, 246, 1260.
23. Cyclopropylzinc bromide is commercially available as 1 M solution from BASF.
The reagent was tested by iodometric titration as published by: Krasovskiy, A.;
Knochel, P. Synlett 2006, 890–891.
24. (a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough,
A.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2006, 12, 4743; (b) Organ, M. G.;
Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Valente, C. Eur.
J. Chem. 2006, 12, 4749.
25. Representative procedure: In a glove box under nitrogen, Pd(PPh3)4 (0.29 g,
0.25 mmol), 4-iodonitrobenzene (2.49 g, 10 mmol), and THF (3 ml) were added
to a 50 ml two necked round-bottomed flask with a magnetic stir bar. The
mixture was stirred for 0.5 h at room temperature. Cyclopropylzinc bromide
(15 ml, 1 M in THF, 15 mmol) was added and the reaction was stirred at 65 °C
for 1 h. After cooling down to room temperature, the reaction was quenched
with HCl (3 ml, 3 M). After addition of NaOH (3 ml, 22 wt %), the product was
extracted with diethyl ether (3 Â 30 ml). The combined organic phases were
washed with saturated aqueous KCl solution, dried over MgSO4, and
concentrated. Purification by flash column chromatography (hexanes/
ether = 10:1) delivered the final product 4-nitrophenylcyclopropane in 77%
isolated yield. 1H NMR (300 MHz, CDCl3): d 8.10 (2H, d), 7.2 (2H, d), 2.0 (1H, m),
1.1 (2H, m), 0.8 (2H, M). 13C NMR (75 MHz, CDCl3): d 152.8, 145.7, 125.9, 123.5,
15.8, 11.1. The analytical data are in accord to the literature: Lemhadri, M.;
Doucet, H.; Santelli, M. Synth. Commun. 2006, 36, 121.
Acknowledgments
The authors are grateful to BASF Corporation for releasing this
manuscript for publication. In particular we would like to thank
Dr. Karl Matos and Dr. Elizabeth R. Burkhardt for productive chem-
istry discussions.
References and notes
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Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107, 4493–4537; (c) Patai, S. In
The Chemistry of the Cyclopropyl Group, Part 2; John Wiley & Sons: New York,
1987; Vol. 1; (d) Salaün, J. Top. Curr. Chem. 2000, 207, 1; (e) Doucet, H. Eur. J.
Org. Chem. 2008, 2013.
26. Sase, S.; Jaric, M.; Metzger, A.; Malakhov, V.; Knochel, P. J. Org. Chem. 2008, 73,
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