A novel stereocontrolled synthesis of 1,2-trans cyclopropyl ketones via suzuki-type coupling of acid chlorides with cyclopropylboronic acids.

Article abstract of DOI:10.1021/ol000013h

[reaction: see text] The palladium-catalyzed cross-coupling reaction of cyclopropylboronic acids with acyl chlorides was achieved by the combination of Ag(2)O and K(2)CO(3) as the base. Highly enantiomerically enriched cyclopropyl ketones (ee >90%) were also obtained by the reaction of corresponding chiral cyclopropylboronic acids.

Full text of DOI:10.1021/ol000013h

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1649-1651
A Novel Stereocontrolled Synthesis of
1,2-trans Cyclopropyl Ketones via
Suzuki-Type Coupling of Acid Chlorides
with Cyclopropylboronic Acids
,†
Han Chen and Min-Zhi Deng*
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Academia Sinica, 354 Fenglin Lu, Shanghai 200032, China
dengmz@pub.sioc.ac.cn
Received January 19, 2000
ABSTRACT
The palladium-catalyzed cross-coupling reaction of cyclopropylboronic acids with acyl chlorides was achieved by the combination of Ag2O
and K2CO as the base. Highly enantiomerically enriched cyclopropyl ketones (ee >90%) were also obtained by the reaction of corresponding
3
chiral cyclopropylboronic acids.
The cyclopropyl ketone moiety is not only recognized to
exhibit important properties in mechanistic studies1 but it is
also found in a growing class of natural products isolated
from a wide spectrum of marine organisms with important
physiological properties.2 The general methods used for the
synthesis of cyclopropyl ketones are the cyclopropanation
of R,â-unsaturated ketones, or its derivatives by diverse
reagents,3 and the reaction of cyclopropane carboxylic acid
chlorides with organometallic reagents.4 The cross-coupling
of acid chlorides with cyclopropyltin and zinc reagents in
the presence or absence of a palladium catalyst also affords
cyclopropyl ketones.5 Despite the many existing strategies
for the construction of cyclopropyl ketones, new and effective
methods for stereocontrolled substituted cyclopropyl ketones
are still sought. Herein we wish to report a novel approach
to the synthesis of trans-2-substituted cyclopropyl ketones
by Suzuki-type coupling of acid chlorides with cyclopropyl-
boronic acids.
A wide range of aryl and 1-alkenylborane reagents undergo
the palladium-catalyzed cross-coupling reaction with alkyl,
allylic, alkenyl, aryl, and alkynyl substrates.6 However, there
are only limited reports about the couplings of arylboron
compounds with acid chlorides in the literature. In 1993
Uemura reported the Suzuki-type cross-coupling of acid
chlorides and sodium tetraphenylborate.7 More recently,
Bumagin and Haddach also reported the Suzuki-Miyaura-
type coupling of arylboronic acids with acid chlorides under
different conditions.8 However, the coupling of alkylboronic
acids with acid chlorides has not been described. Recently
the coupling reactions of cyclopropylboronic acids have
attracted increasing interest,9 because the cyclopropylboronic
acids are available by the stereodefined cyclopropanation of
†Fax: 86-21-64166128.
(1) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y. C.; Tanko, J.;
Hudlicky, T. Chem. ReV. 1989, 89, 165-198. (b) Ichiyanagi, T.; Kuniyama,
S.; Shimizu, M.; Fujisawa, T. Chem. Lett. 1997, 1149-1150. (c) Enholm,
E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 5248-5249. (d) Tanko, J. M.;
Phillips, J. P. J. Am. Chem. Soc. 1999, 121, 6078-6079.
(2) (a) Fukuyama, Y.; Hirono, M.; Kodama, M. Chem. Lett. 1992, 167-
170. (b) Nagle, D. G.; Gerwick, W. H. Tetrahedron Lett. 1990, 31, 2995-
2998. (c) White, J. D.; Jensen, M. S. J. Am. Soc. Chem. 1993, 115, 2970-
2971. (d) Rodr´ıguez, A. D.; Shi, J.-G. Org. Lett. 1999, 1, 337-340.
(3) (a) Mende, U.; Radu¨chel, B.; Skuballa, W.; Vorbru¨ggen, H.;
Tetrahedron Lett. 1975, 9, 629-632. (b) Mori, A.; Arai, I.; Yamamoto,
H.; Tetrahedron 1986, 42, 6447-6458. (c) Rodriques, K. E. Tetrahedron
Lett. 1991, 32, 1275-1278. (d) Aggarwal, V. K.; Smith, H. W.; Jones, R.
V. H.; Fieldhouse, R. Chem. Commun. 1997, 1785-1786. (e) Lautens, M.;
Delanghe, P. H. M. J. Org. Chem. 1995, 60, 2474-2487. (f) Mash, E. A.;
Gregg, T. M.; Kaczynski, M. A.; J. Org. Chem. 1996, 61, 2743-2752.
(4) For a recent review, see: Matveeva, E. D.; Kvasha, M. P.; Kurts, A.
L. Zh. Org. Khim. 1996, 32, 29-32.
(5) (a) Pohmakotr, M.; Khosavanna, S. Tetrahedron 1993, 49, 6483-
6488. (b) Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. J. Org. Chem.
1993, 58, 2958-2965.
(6) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(7) Cho, C. S.; Itotani, K.; Uemura, S. J. Organomet. Chem. 1993, 433,
253-259.
10.1021/ol000013h CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

the corresponding alkenylboronic acids (esters).10 They are
highly stable in air and are easily purified by recrystallization
from water. In addition, enantiomerically enriched cyclo-
propylboronic acids can readily be obtained by the cyclo-
propanation of the corresponding alkenylboronic acid esters
with the appropriate chiral auxiliaries.11 Our group has
investigated the cross-coupling of cyclopropylboronic acids
with aryl halides9b and bromoacrylates.9d We now report a
new synthesis of stereodefined cyclopropyl ketones (Scheme
1).
coupling reactions12 encouraged us to use it to active the
reaction. As expected, the coupling reaction of cyclopropy-
lboronic acid with benzoyl chloride occurred when Ag2O
was employed as the base, albeit in lower yield (Table 1,
entry 3).
When the reaction was carried out with Ag2O and other
bases (Cs2CO3 or KOH), the reaction yields were improved
(entries 4 and 5). After further screening, it was found that
the combination of Ag2O and K2CO3 in a nonpolar solvent
led to a facile cross-coupling reaction (entry 6), but in a polar
solvent (dioxane) the reaction was sluggish (entry 7). We
believe that Ag2O may play an important role in accelerating
the transmetalation between cyclopropylboronic acids and
the RCOPdCl species.
Scheme 1
The reactions of various acid chlorides with cyclopropy-
lboronic acids were explored under the optimized reaction
conditions; the results are collected in Table 2.
Table 2. Ag2O-Assisted, Palladium-Catalyzed Cross-Coupling
Reactions of Cyclopropylboronic Acid with Various Acid
Chloridesa
We first studied the coupling of trans-1,2-butylcyclopro-
pylboronic acid with benzoyl chloride under Bumagin’s
conditions, using 3% PdCl2 as the catalyst in acetone-water
(3:1) and Na2CO3 as the base.8a Unfortunately, the desired
product was not detected (Table 1, entry 1). This is probably
entry
1, R1
)
2, R2
)
yield, % (3)b
Table 1. Effect of the Bases and Solvents on the Coupling
Reaction of trans-Butylcyclopropylboronic Acid with Benzoyl
Chloridea
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
21
n-C4H9 (1a )
n-C6H13 (1b)
2a
78 (3a a )
75 (3bb)
77 (3a c)
76 (3a d )
70 (3be)
64 (3bf)
60 (3bg)
64 (3bp )
74 (3bq)
75 (3bh )
59 (3a i)
69 (3a j)
70 (3a k )
59 (3bk )
c
4-MeC6H4 (2b)
2-MeOC6H4 (2c)
3-MeOC6H4 (2d )
4-MeOC6H4 (2e)
2-FC6H4 (2f)
2,4-2FC6H3 (2g)
3-CF3C6H4 (2p )
4-BuOC6H4 (2q)
4-EtOC6H4 (2h )
3-CNC6H4 (2i)
4-PhC6H4 (2j)
2-naphthyl (2k )
2-naphthyl (2k )
2,6-2ClC6H3 (2l)
2,4,6-3MeOC6H2 (2m )
2-thiophene-yl (2n )
2-furyl (2o)
1a
1a
1b
1b
1b
1b
1b
1b
1a
1a
1a
1b
1b
1b
entry
conditions
yield, %b
1
2
3
4
5
6
7
acetone-water (3:1), Na2CO3, 3%PdCl2
toluene, Cs2CO3, 3% Pd(PPh3)4
toluene, Ag2O, 3% PdCl2(dppf)
toluene, Ag2O, Cs2CO3, 3% PdCl2(dppf)
toluene, Ag2O, KOH, 3%PdCl2 (dppf)
toluene, Ag2O, K2CO3, 3% PdCl2(dppf)
dioxane, Ag2O, K2CO3, 3% PdCl2(dppf)
c
c
15
35
40
78
30
a All reactions were carried out using a mixture of trans-2-butylcyclo-
popylboronic acid (1.0 mmol), benzoyl chloride (2.0 mmol), 3% catalyst,
and base (2 equiv) in 4 mL of solvent, for 16 h, at 80 °C (except for entry
1) under a nitrogen atmosphere. b Yields of isolated product based on the
amount of trans-2-butylcyclopopylboronic acid used. c Unreacted trans-2-
butylcyclopopylboronic acid was obtained in these cases.
c
n-C5H11 (1c)
49 (3cn )d
45 (3co)d
44 (3a o)d
51 (3a n )d
1c
1a
1a
2o
2n
due to the slow transmetalation between the cyclopropylbo-
ronic acids and RCOPdCl species, because of the low
nucleophilicity of the cyclopropyl group on the boron. The
use of Cs2CO3 as the base (Haddach’s condition8b) also did
not make the coupling reaction take place (Table 1, entry
2). The fact that Ag2O dramatically enhances the rate of some
a All the reactions were carried out using a mixture of cyclopropylboronic
acids (1.0 mmol) and acid chlorides (2 mmol), 2 equiv of Ag2O, 2 equiv of
K2CO3 (based on boronic acids), and 3% PdCl2(dppf) in 4 mL of toluene
at 80 °C under a nitrogen atmosphere for 12-16 h. All the products were
identified by 1H NMR, IR, and mass spectral and elemental analysis or
HRMS and 13C NMR. b On the basis of the amount of cyclopopylboronic
acids used. c Unreacted cyclopopylboronic acid was recovered in these cases.
d Reactions were carried out for 24 h.
(8) (a) Bumagin, N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40,
3057-3060. (b) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999,
40, 3109-3122.
(9) (a) Hildebrand, J. P.; Marsden, S. P. Synlett 1996, 893-894. (b)
Wang, X.-Z.; Deng, M.-Z.; J. Chem. Soc., Perkin Trans. 1 1996, 2663-
2664. (c) Charette, A. B.; De Freitas-Gil, R. P. Tetrahedron Lett. 1997, 38,
2809-2812. (d) Zhou, S.-M.; Yan, Y.-L.; Deng, M.-Z. Synlett 1998, 198-
200. (e) Ma, H.-R.; Wang, X.-H.; Deng, M.-Z. Synth. Commun. 1999, 29,
2477-2485.
As shown in Table 2, the cross-coupling reaction of trans-
2-alkylcyclopropylboronic acids with various acid chlorides
proceeded readily (except for entries 15 and 16) with
satisfactory yields. It is important to note that substituents
on the acid chlorides did not significantly affect the coupling
1650
Org. Lett., Vol. 2, No. 12, 2000

Table 3. Synthesis of Enantiomerically Enriched Cyclopropyl Ketones by the Coupling Reaction of the Chiral Cyclopropylboronic
Acids with Acid Chloridesa
a Coupling reactions were carried out using a mixture of chiral cyclopropylboronic acids (1.0 mmol) and acid chlorides (2 mmol), 2 equiv of Ag2O, 2
equiv of K2CO3 (based on boronic acids), and 3% PdCl2(dppf) in 4 mL of toluene at 80 °C under a nitrogen atmosphere for 12-16 h. b The enantiomeric
purities were established on the basis of the ee values of the corresponding carbinols generated by the alkali oxidation of the cyclopropylboronic acids.
c Yields of isolated products based on the cyclopropylboronic acids. d Determined by HPLC (Chiralcel AD). e Determined by HPLC (Chiralcel OJ).
reaction; the yields of reaction with acid chlorides bearing
donating groups were only slightly better than those of acid
chlorides bearing withdrawing functions. However, the bulky
2,6-di- or 2,4,6-trisubstituted acid chlorides did not give the
desired products (entries 15 and 16). Apparently, the reaction
rate is greatly influenced by steric hindrance. Moderate yields
of cyclopropyl ketones were obtained with heteroaryl acid
enantiomerically enriched cyclopropylboronic acids also
successfully gave the corresponding cyclopropyl ketones with
high ee (Table 3).
Table 3 outlined that the ee values of the coupling products
were similar to those of the corresponding cyclopropyl-
boronic acids used. In addition, the reaction of the cyclo-
propylboronic acid of the same optical purity with different
acid chlorides gave the corresponding cross-coupling prod-
ucts with similar optical purities (entries 1 and 3; 2 and 4).
All these results suggest that the chirality is retained in the
coupling process.
In summary, the first palladium-catalyzed cross-coupling
reaction of cyclopropylboronic acids with acid chlorides has
been achieved. The addition of Ag2O and K2CO3 as base
was found to be essential. As the stereodefined cyclopro-
pylboronic acids and the enantiomerically enriched cyclo-
propylboronic acids were readily available, the present
method provided a new and effective approach to the
synthesis of stereodefined cyclopropyl ketones from acid
chlorides and cyclopropylboronic acids. Further study on the
scope of the reaction is currently underway in our laboratory.
1
chlorides as well (entries 17-21). The H NMR spectra of
the products and 2D 1H-1H NOESY NMR of products (3aa,
3bb, 3ad, 3bf) showed that the configurations of the
cyclopropyl groups of their organoboron partner were
retained.
The enantiomerically enriched (1R,2R)-cyclopropylboronic
acids can be readily obtained by the asymmetric cyclopro-
panation of the corresponding (E)-alkenylboronic ester with
the enantiomerically pure (+)-N,N,N′,N′-tetramethyltartaric
acid diamide, (+)-TMTA, as the chiral auxiliary, followed
by the hydrolysis. Similarly, the corresponding (1S,2S)-
isomer was obtained by using (-)-TMTA as the auxiliary.
The cross-coupling reaction of acid chlorides with the
(10) (a) Fontani, P.; Carboni, B.; Vaultier, M.; Mass, G. Synthesis 1991,
605-609.
(11) (a) Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem. 1990, 55, 4986-
4988. (b) Pietruszka, J.; Widenmeyer, M. Synlett 1997, 977-979. (c) Zhou,
S.-M.; Deng, M.-Z.; Xia, L.-J.; Tang, M.-H. Angew. Chem., Int. Ed. 1998,
37, 2845-2847. (d) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 1999,
64, 8287-8297.
Acknowledgment. We thank the NNSF of China and
Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, for
financial support.
(12) (a) Uenishi, J.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756-4758. (b) de Lera, A. R.; Torrado, A.; Iglesias,
B.; Lo´pez, S. Tetrahedron Lett. 1992, 33, 6205-6208. (c) Gillmann, T.;
Weeber, T. Synlett 1994, 649-650. (d) Anderson, J. C.; Namli, H.; Roberts,
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washima, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Org. Lett. 1999, 1, 299-
301.
Supporting Information Available: Experimental details
and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL000013H
Org. Lett., Vol. 2, No. 12, 2000
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