Copper-mediated N-cyclopropylation of azoles, amides, and sulfonamides by cyclopropylboronic acid

Article abstract of DOI:10.1021/jo801033y

(Chemical Equation Presented) Reaction of azoles, amides, and sulfonamides in dichloroethane with readily available cyclopropylboronic acid in the presence of copper acetate and sodium carbonate afforded the N-cyclopropyl derivatives in good to excellent

Full text of DOI:10.1021/jo801033y

scope is rather limited. Very recently, Gagnon and co-workers6
reported an elegant copper-mediated direct N-cyclopropylation
of azoles and amides using tricyclopropylbismuth as a donor
of cyclopropyl group.7 Although the reaction proceeded in good
to excellent yields with a broad substrate scope, the limited
availability and stability of the bismuth reagent leave neverthe-
less room for improvement.
Copper-Mediated N-Cyclopropylation of Azoles,
Amides, and Sulfonamides by Cyclopropylboronic
Acid
Se´bastien Be´nard, Luc Neuville, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
Transition-metal-catalyzed cross-coupling reactions for the for-
mation of carbon-heteroatom bonds have been a subject of
intensive research during the past few years.8 Among them, the
copper-promoted coupling of amines with organoboronic acids has
emerged as a powerful tool since the initial report of Chan and
Lam9 and has found wide applications because of the mildness of
the reaction conditions.10 Cyclopropylboronic acids are easily
available and are relatively stable to air and water. Although they
have been used in palladium-catalyzed reaction to create C-C
bonds,11 cyclopropylboronic acids have not been employed for the
formation of C-N bond at the outset of this work.
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr; neuVille@icsn.cnrs-gif.fr
ReceiVed May 14, 2008
Despite a reported unsuccessful attempt at coupling of cyclo-
propylboronc acid and aniline under Chan-Lam conditions,12 we
decided to evaluate in detail the reaction of cyclopropylboronic
acid with azoles and amides, reasoning that the increased acidity
of NH in these compounds could facilitate the desired transforma-
tion. A recent report by Tsuritani13 on the copper-mediated coupling
of cyclopropylboronic acid with indoles and cyclic amides prompted
us to report our own results in this Note.
Reaction of azoles, amides, and sulfonamides in dichloro-
ethane with readily available cyclopropylboronic acid in the
presence of copper acetate and sodium carbonate afforded
the N-cyclopropyl derivatives in good to excellent yields.
(5) (a) Kang, J.; Kim, K. S. J. Chem. Soc., Chem. Commun. 1987, 897–898.
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Yokoyama, Y. Tetrahedron 2006, 62, 4253–4261. (e) Liu, J.; An, Y.; Jiang,
H.-Y.; Chen, Z. Tetrahedron Lett. 2008, 49, 490–494.
The cyclopropyl unit is found in a number of natural products
and occupies a central position in pharmaceutical and agro-
chemical science. Indeed, the unique electronic and geometrical
properties1 associated with its metabolic stability2 make the
cyclopropyl a major structural element in fine-tuning the
biological potency of a drug candidate.3 Since nitrogen-
containing molecules are highly represented in bioactive
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direct introduction of a N-cyclopropyl group is of great
importance in medicinal chemistry.4
Mainly two strategies have previously been developed for
the synthesis of N-cyclopropylated molecules: condensation of
amines/anilines with cyclopropanone equivalents and function-
alization of cyclopropylamines.5 However, both routes gave
generally low yields of desired products and the application
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and C-O Bond Formation. In Topics in Current Chemistry; Miyaura, N., Ed.;
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10.1021/jo801033y CCC: $40.75
Published on Web 07/09/2008
2008 American Chemical Society
2008, 73, 6441–6444 6441

TABLE 1. Survey of Reaction Conditionsa
(entry 9-13). Although both dichloroethane (DCE) and toluene
were effective solvents, we found that the reaction performed
in the former gave better reproducibility. Finally, we briefly
screened other copper sources such as CuCl2 and CuI and found
they were less efficient than Cu(OAc)2. Solvent played also an
important role and other solvents such as DMSO, methanol,
and THF-H2O were less effective than DCE and toluene.
Overall, the best conditions were established as follows:
Cu(OAc)2 (0.2 equiv), Bipy (0.2 equiv), Na2CO3 (2 equiv), air,
in dichloroethane at 70 °C, 6 h (entry 14); or Cu(OAc)2 (1.0
equiv), Bipy (1.0 equiv), Na2CO3 (2 equiv), air, in dichloroet-
hane at 70 °C, 3 h (entry 15).
With these optimized conditions in hand, the scope and limitation
of this reaction were examined using a stoichiometric amount of
copper acetate.17 Various N-heterocycles (imidazole, benzimida-
zole, 2-acetylpyrrole, benzotriazole, carbazole and oxazolidinone)
were successfully transformed to the corresponding cyclopropyl
derivatives under standard conditions (Table 2, entry 1-6). It is
interesting to note that imidazole failed to undergo N-cyclopropy-
lation under Gagnon’s conditions. Reaction of thymine with 2
afforded the double N-cyclopropylated adduct 5k in 53% (entry
10). However, when 6-methyluracil was subjected to the established
reaction conditions, mono N-alkylation occurred predominantly to
provide the 3-N-cyclopropyl-6-methyl uracil 5i18 and the 1,3-
dicyclopropyl-6-methyl uracil 5j in 72% and 7% yields, respec-
tively (entry 9). The observed regioselectivity can be accounted
for on the steric ground.
The N-cyclopropylation of indoles with different electronic
properties was also realized (entry 11-16). The reaction
tolerated a variety of functional groups, such as halogen atoms
(entries 12 and 18), ester and carbamate (entry 16), ether (entry
14), ketone (entry 15), and nitro (entry 13) groups. Whereas
electron-deficient indoles gave excellent results, the electron-
rich 5-methoxyindole furnished only 36% yield of 5o. Interest-
ingly, the yield could be improved to 55% yield when the
reaction was carried out under argon atmosphere.
The N-cyclopropylation of amides was next investigated.
Whereas diflurobenzamide afforded the corresponding 5g in
59% yield (entry 7), 2-naphthalenacetamide furnished the
compound 5h in a lower yield (36%, entry 8). Sulfonamide can
be similarly alkylated to afford the mono- and dicyclopropylated
compounds 5t and 5u in yields of 66% and 10%, respectively
(entry 19). Resubmitting the monocyclopropylated compound
5t to the reaction conditions afforded the bis-cyclopropylated
product 5u in 61% yield (78% based on conversion). 4-Meth-
oxy-acetanilide was however unreactive under the present
reaction conditions (entry 20).19
Cu(OAc)2
temp yield
entry
(equiv)
solvent
base/ligand (equiv)
Et3N (2.0)
Et3N (2.0)
(°C) (%)b
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1.0
DCE
DCE
toluene Py (2.0)
rt 16
50 30
70 70c
70 >95c
70 75c
70 <10c
toluene Py (2.0)
toluene Na2CO3 (2.0) Py (0.4)
toluene Na2CO3 (2.0) Et3N (0.4)
toluene Na2CO3 (2.0) TMEDA (0.2) 70 60c
toluene Na2CO3 (2.0) Phen (0.2)
toluene Na2CO3 (2.0) BiPy (0.2)
toluene NaHCO3 (2.0) BiPy (0.2)
toluene K3PO4 (2.0) BiPy (0.2)
toluene K2CO3 (2.0) BiPy (0.2)
toluene Cs2CO3 (2.0) BiPy (0.2)
70 50c
70 80c
70 80c
70 15c
70 28c
70 0c
9
10
11
12
13
14
15
DCE
DCE
Na2CO3 (2.0) BiPy (0.2)
Na2CO3 (2.0) BiPy (1.0)
70 80c
70 100
a All reactions were carried out under air atmosphere using 2 equiv of
2, 0.1 M. b Yield after flash column chromatography. c Yield estimated
by 1H NMR analysis of the crude product. Abbreviations: Py
)
)
pyridine; TMEDA
1,10-phenanthridine, BiPy ) 2,2-bipyridine.
) N,N,N′,N′-tetramethylethylenediamine; Phen
Phthalimide 1 was chosen as a model substrate to begin our
study because it showed a good behavior in related copper-
mediated reactions.14 We were pleased to find that reaction of
1 with cyclopropylboronic acid (2, 2 equiv) furnished the desired
N-cyclopropylphthalimide 3 in 16% yield under the following
conditions: Cu(OAc)2 (1.0 equiv), Et3N (2.0 equiv), air, in
dichloroethane (DCE), room temperature, 24 h (Table 1, entry
1). Upon heating the reaction mixture to 50 °C, the yield of 3
increased to 30% (entry 2). Encouraged by these results, we
set out to optimize the reaction conditions by varying the ligand,
the base, the reaction temperature, and the solvent. These results
are summarized in Table 1.
Carrying out the reaction at 70 °C in toluene in the presence
of pyridine afforded compound 3 in 70% yield according to 1H
NMR analysis of the crude product (entry 3). The reaction was
very clean since about 30% of the phthalimide (1) was recovered
under these conditions. Increasing the reaction time or introduc-
ing an additional amount of cyclopropylboronic acid failed to
increase the conversion. However, we were able to drive the
reaction to completion by simply adding 2.0 equiv of Na2CO3
under otherwise identical conditions (entry 4).15
Conversion of the arylboronic acid in the presence of copper
catalyst and oxygen to the corresponding phenol has been
Interestingly, the coupling reaction worked even under
catalytic conditions to afford 3 in about 75% yield (entry 5).16
Using a catalytic amount of copper acetate (0.2 equiv), the effect
of ligand structures and bases was next examined (entries 5-9).
From these experimental results, the bipyridine stood out as the
ligand of choice in terms of product yield and reaction time,
whereas Na2CO3 or NaHCO3 was found to produce superior
results as a base compared to Et3N, K3PO4, K2CO3 and Cs2CO3
(16) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236. (b) Lam,
P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett.
2001, 42, 3415–3418. (c) Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J.
Org. Chem. 2001, 66, 1528–1531. (d) Antilla, J. C.; Buchwald, S. L. Org. Lett.
2001, 3, 2077–2079. (e) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397–
4400. (f) van Berkel, S. S.; Van den Hoogenband, A.; Terpstra, J. W.; Tromp,
M.; Van Leeuwen, P. W. N. M; Van Strijdonck, G. P. F Tetrahedron Lett. 2004,
45, 7659–7662. (g) Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R.-G. Chem.
Commun. 2004, 188–189.
(12) Wallace, D. J.; Chen, C.-Y. Tetrahedron Lett. 2002, 43, 6987–6990.
(13) Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki, M.; Yasuda,
N.; Mase, T. Org. Lett. 2008, 10, 1653–1655.
(17) Most of the transformations reported in Table 2 worked in the presence
of catalytic amount of copper salt. However, longer reaction time was required
with reduced yields of coupling product.
(14) (a) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron
Lett. 2003, 44, 4927–4931. (b) Bolshan, Y.; Batey, R. A. Angew. Chem., Int.
Ed. 2008, 47, 2109–2112.
(18) The structure of 5i was confirmed by NOE experiment.
(19) Preliminary experiments indicate that anilines could be cyclopropylated
under established conditions. However, no cyclopropylated product was isolated
when N-methyl benzylamine was submitted to the identical reaction conditions.
We are working towards the optimization of these reactions and the results will
be reported in due course.
(15) Such reaction conditions have been used recently in copper-catalyzed
aerobic oxidative amination: Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 833–834.
6442 Vol. 73, No. 16, 2008

TABLE 2. Scope of the N-Cyclopropylationa,b,c
a Yield after flash column chromatography. b Under argon atmosphere. c Racemic tryptophane derivative was used. N-Cyclopropylation of the
carbamate nitrogen was not observed.
Vol. 73, No. 16, 2008 6443

observed previously20 and has been developed for the synthesis
of symmetric biaryl ethers.21 This in part could explain the need
of using an excess of cyclopropylboronic acid in the present
reaction. It is thus of interest to observe that N-cyclopropylation
can take place in the argon atmosphere in the presence of
stoichiometric amount of copper catalyst.22
In conclusion, we have documented a direct copper acetate-
mediated N-cyclopropylation of nitrogen containing compounds
with cyclopropylboronic acid. The method is applicable to a
wide range of azoles including imidazole, benzoimidazole,
pyrrole, carbazole, oxazolidinone, indole, pyrazole, and cyclic
ureas. Primary amides and sulfonamides can be similarly
N-cyclopropylated.
Na2CO3(63.6 mg, 0.6 mmol) in dichloroethane (1.0 mL) was
added a suspension of Cu(OAc)2 (54.5 mg, 0.3 mmol) and
bipyridine (46.8 mg, 0.3 mmol) in hot dichloroethane (2.0 mL).
The mixture was warmed to 70 °C and stirred for 2 h under air.
The resulting mixture was cooled to room temperature, and a
saturated aqueous NH4Cl solution was added, followed by water.
The organic layer was separated, and the aqueous layer was
extracted three times with CH2Cl2. The combined organic layers
were washed with brine, dried, and concentrated under reduced
pressure. Purification by flash column chromatography (SiO2,
dichloromethane) afforded the N-cyclopropyl phthalimide 3 as
a white solid (56.0 mg, quantitative). Rf ) 0.43 (3:1 heptane/
EtOAc). Mp 136 °C. IR (neat, cm-1) ν 3026, 1765, 1710, 1697,
1
1610, 1462, 1396, 1139, 946, 710. H NMR (CDCl3, 500 MHz)
δ 7.82 (m, 2H), 7.69 (m, 2H), 2.71 (m, 1H), 1.01 (m, 4H). 13C
NMR (CDCl3, 75,5 MHz) δ 168.9, 134.0, 131.8, 123.1, 20.9,
5.2. HRMS (m/z) found 242.0798, requires 242.0793 (M + Na
+ MeOH).
Experimental Section
General Procedure. To a suspension of cyclopropylboronic acid
(51.6 mg, 0.6 mmol), phthalimide (44.0 mg, 0.3 mmol), and
Acknowledgment. Financial support from the CNRS and this
institute is gratefully acknowledged.
(20) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G; Combs, A. P.
Tetrahedron Lett. 2003, 44, 1691–1694.
(21) (a) Sagar, A. D.; Tale, R. H.; Adude, R. N. Tetrahedron Lett. 2003, 44,
7061–7063. (b) For an initial report on copper-mediated C-O bond formation
between phenol and arylboronic acid, see: Evans, D. A.; Katz, J. L.; West, T. R
Tetrahedron Lett. 1998, 39, 2937–2940.
Supporting Information Available: Physical and spectro-
1
scopic data and copies of H NMR and 13C NMR spectra for
(22) One referee pointed out that the presence of a tiny amount of oxygen
in the reaction media might serve to oxidize the copper salt. We are working to
understand this coupling process. However, we note that the reactions performed
under argon atmosphere provided indeed the reproducible results with several
different substrates.
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801033Y
6444 Vol. 73, No. 16, 2008