Copper-promoted N-cyclopropylation of anilines and amines by cyclopropylboronic acid

Article abstract of DOI:10.1039/b925499d

Reaction of anilines, primary and secondary aliphatic amines with cyclopropylboronic acid in dichloroethane in the presence of Cu(OAc)₂ (1 equiv.), 2,2′-bipyridine (1 equiv.) and sodium carbonate or sodium bicarbonate (2 equiv.) under air atmos

Full text of DOI:10.1039/b925499d

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Copper-promoted N-cyclopropylation of anilines and amines
by cyclopropylboronic acidw
´ ´
Sebastien Benard, Luc Neuville* and Jieping Zhu*
Received (in Cambridge, UK) 3rd December 2009, Accepted 4th March 2010
First published as an Advance Article on the web 1st April 2010
DOI: 10.1039/b925499d
Reaction of anilines, primary and secondary aliphatic amines
with cyclopropylboronic acid in dichloroethane in the presence of
Cu(OAc)2 (1 equiv.), 2,20-bipyridine (1 equiv.) and sodium
carbonate or sodium bicarbonate (2 equiv.) under air atmosphere
afforded the corresponding N-cyclopropyl derivatives in good to
Scheme 1 N-Cyclopropylation of anilines and aliphatic amines.
excellent yields.
widely used as probes for bio-mechanism investigations.10
Consequently, we became interested in this transformation
and we report herein that the N-cyclopropylation of anilines
and aliphatic amines can be realized under mild oxidative
conditions in the presence of a stoichiometric amount of
Cu(OAc)2/2,20-bipyridine under air atmosphere (Scheme 1).
Wallace and Chen were the first to examine the Cu(OAc)2-
promoted reaction of aniline with cyclopropylboronic acid.
However, it was concluded that the cross-coupling did not
take place under the Chan–Lam reaction conditions.11 Indeed,
oxidative homocoupling of the anilines to azobenzenes under
similar conditions were known and could be competitive to the
desired process.12 Despite this discouraging report, we set out
to re-investigate this transformation as, in other circumstances,
anilines have been successfully engaged in coupling reactions
with other organoboronic acids.3a The cross-coupling of
4-methoxy-N-methylaniline (2a) with 1 was investigated as a
model reaction. Pleasingly, the expected N-cyclopropyl-4-
methoxy-N-methylaniline (3a, R1 = Me, R2 = 4-MeOC6H4)
was isolated in nearly quantitative yield under our previously
established conditions [cyclopropyl boronic acid (2.0 equiv.),
Cu(OAc)2 (1.0 equiv.), Bipy (1.0 equiv.), Na2CO3, (2 equiv.),
in dichloroethane at 70 1C, air atmosphere, 2 h). Similar
results were obtained when NaHCO3 was used as base instead
of Na2CO3. On the other hand, cyclopropyl trifluoroborate
was found to be far less effective than boronic acid 1 for this
transformation. We have also briefly examined the catalytic
version using 0.1 equiv. each of Cu(OAc)2 and bipyridine
under otherwise identical conditions. Although the reaction
did occur, the conversion was low and the desired product was
isolated in only 19% yield.13
The unique electronic and steric properties in conjunction with
high metabolic stability have made the cyclopropyl group a
privileged structural unit in medicinal chemistry.1 Indeed, it is
increasingly found in drugs and drug candidates. On the other
hand, anilines and amines are ubiquitous functions found in
numerous natural, pharmaceutical and agrochemical products.
With the advent of combinatorial chemistry, a large number of
compound libraries containing aniline and amine functions
have been constructed and screened. To fully exploit the
biological potential of these compound collections, the ability
to perform the N-cyclopropylation of amino function would
be of great interest,2 as it allows fine-tuning the bioactivity of a
given set of end-products without the need to re-synthesize
each individual compound.
The copper promoted coupling of amines with organo-
boronic acids has emerged as a powerful tool since the initial
reports of Chan and Lam3 and has found wide applications in
organic synthesis because of the mildness of the reaction
conditions.4 Whereas aryl, heteroaryl and vinyl boronic acid
derivatives have been extensively studied as coupling partners,
the use of cyclopropylboronic acid (1) in the Chan–Lam
reaction was reported only very recently. Thus, Tsuritani
and co-workers described Cu-promoted N-cyclopropylation
of indoles and cyclic amides by 1 using NaHDMS as a base.5,6
Concurrent to this work, we independently reported the use of
the coupled system Cu(OAc)2/bipyridine as a promoter and
sodium carbonate (Na2CO3) as a milder inorganic base
for performing the same transformation. The protocol was
applied to amides, oxindoles, sulfonamides and a variety
of azoles including indoles, imidazoles, benzoimidazoles,
benzotriazoles, pyrroles, carbazoles etc.7 However, direct
N-cyclopropylation of anilines/amines remained unexploited.
This is unfortunate since N-alkyl-N-cyclopropylamines are
known to be potent suicide inhibitors of cytochrome
P4508 and monoamine oxidase.9 In addition, they have been
With these results in hand, the generality of this copper-
promoted coupling reaction was examined. As shown
in Table 1, anilines having electron-donating (entry 1) and
withdrawing groups in the para position (entries 2, 3) participated
in this reaction to afford the corresponding coupled products
in good to excellent yields. Primary anilines furnished the
mono-cyclopropylated product (entries 3–5).14 The reaction
is insensitive to steric hindrance as 2,6-dimethylaniline (2d)
was converted to product 3d in 98% yield (entry 4). The
2-iodo-4-nitroaniline (2e) was N-cyclopropylated to afford 3e
in 99% yield without affecting the aryliodide function. The
presence of iodo substituent in 3e provided a handle for
Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS, 91198 Gif-sur-Yvette, France.
E-mail: zhu@icsn.cnrs-gif.fr, neuville@icsn.cnrs-gif.fr;
Fax: 33(0)1-69-07-72-47; Tel: 33 (0)1-69-82-45-77
w Electronic supplementary information (ESI) available: Spectral
characterisation and analytical data of reported compounds. See
DOI: 10.1039/b925499d
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Table 1 Copper-mediated cyclopropylation of anilines
Table 2 Copper-mediated cyclopropylation of aliphatic amines
Entry
1
Aniline
Product
Yielda (%)
99
Entry Amine
Product
Yielda (%)
97
1
55
93
98
2
3
2
3
75
92
4
5
99
83
4
5
71
56
6
6
7
8
40
a
Isolated yield.
60b
55b
47c
further structural diversifications using metal-catalyzed cross-
coupling reactions. It is interesting to note that N,N-dicyclo-
propylated derivatives were not isolated when anilines 2c–2e
were employed as substrates. As a matter of fact, when
N-cyclopropylaniline 3c was re-submitted to the reaction
conditions, the N,N-dicyclopropylated derivative was isolated
in 14% yield, along with recovered 3c (73%). Finally, indoline
2f participated in the reaction to afford the cross-coupled
product 3f in 83% yield (entry 6). N-acetanilide exemplified
by N-(4-methoxyphenyl)acetamide was found to be unreactive
under present conditions.
9
a
b
c
Isolated yield. 4 equiv. of 1 was used. NaHCO3 was used as base,
er = 93/7.
Copper-mediated/catalyzed functionalization of aliphatic
amines by aryl and vinyl boronic acids have been reported.3,13,15
However, these reactions are generally less efficient due to the
competitive N-dealkylation under oxidative conditions.16 We
thus set out to examine the cyclopropylation of aliphatic
amines and the results are summarized in Table 2. Gratefully,
cyclic secondary amines including N-monoacylated/arylated
piperazines (2g, 2h), piperidine (2i), isoindoline (2j), and
N-Boc-1,4-diazepine (2k) were cleanly converted to their
N-cyclopropyl analogues (entries 1–5). It is interesting to note
that N-arylpiperazine 2h, a potential chelating ligand for
copper acetate, was successfully converted to the coupled
product 3h in 75% yield (entry 2). Piperidine 2i having an
enolisable ketone side chain was also converted to the cyclopropyl
derivative in excellent yield (entry 3).17 Whereas no cyclo-
propylated product was isolated when N-methylbenzylamine
was submitted to the reaction conditions, N-isopropylbenzyl-
amine (2l) was successfully converted to compound 3l in 40%
yield. Although yield remained moderate, the result was
particularly noteworthy as benzylic amines are known to be
very sensitive to N-dealkylation via an imine intermediate
under oxidative conditions.
Primary amines were next examined. Reaction of methyl
6-aminohexanoate 2m with 1 under standard conditions furn-
ished the bis-N-cyclopropylated product 3m as only isolable
adduct in a modest 37% yield. The yield was improved to 60%
by using 4 equivalents of 1 (2 equivalents of 1 per cyclo-
propylation). Geranyl amine (2n) was similarly N-biscyclo-
propylated to afford 3n (entry 8). Interestingly, L-methyl
phenylalanate 2o was mono-N-cyclopropylated to afford 3o
in 47% yield. We hypothesized that steric factors as well as the
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Y. Hamada, N. Atsumi and F. Tabuchi, Synlett, 2003, 2139–2142;
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4 (a) D. M. T. Chan and P. Y. S. Lam, Recent Advances in Copper-
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Scheme 2 Chemoselective N-cyclopropylation of aliphatic amines vs.
secondary amides.
6 For
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7 S. Benard, L. Neuville and J. Zhu, J. Org. Chem., 2008, 73,
a related coupling involving tricyclopropylbismuth, see:
´
,
chelating ability of a-aminoester could hamper the second
N-cyclopropylation. Using Na2CO3 as base caused a significant
degree of racemization (ee 65%). However, racemization was
minimized using NaHCO3 as a base, leading to 3o with an ee
of 85%.
´
6441–6444.
8 R. P. Hanzilk, V. Kishore and R. Tullman, J. Med. Chem., 1979,
22, 760–761.
9 R. B. Silverman and S. J. Hoffman, J. Am. Chem. Soc., 1980, 102,
884–886.
Finally, it was possible to chemoselectively N-cyclopropylate
the aliphatic amines in the presence of amides (Scheme 2).
Thus reaction of N-isobutylpiperidine-3-carboxamide (2p)
with 2 equivalents of 1 under standard conditions afforded
the 1-cyclopropyl-N-isobutylpiperidine-3-carboxamide (3p) in
95% yield. Similarly, N-(4-aminobutyl)acetamide (2q) was
converted to N-[4-(dicyclopropylamino)butyl]acetamide (3q)
in 62% yield.
10 M. A. Cerny and M. R. P. Hanzlik, J. Am. Chem. Soc., 2006, 128,
3346–3354, and references therein.
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(b) K. Kinoshita, Bull. Chem. Soc. Jpn., 1959, 32, 780–783;
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F. Barbot and C. Len, Tetrahedron, 2009, 65, 10105–10123.
13 Catalytic Chan–Lam reaction, see: (a) J. P. Collman and
M. Zhong, Org. Lett., 2000, 2, 1233–1236; (b) P. Y. S. Lam,
G. Vincent, C. G. Clark, S. Deudon and P. K. Jadhav, Tetrahedron
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We also synthesized compound 3c by other literature
procedures (see ESIw) that indicated clearly the effectiveness
of the present methodology.18
In conclusion, we have developed a copper-promoted
coupling of anilines, secondary and primary amines with
cylcopropylboronic acid (1) to afford the corresponding
N-cyclopropylated derivatives in good to excellent yields.
Amide, ester, ketone, carbamate (N-Boc), and double bond
were tolerated under these reaction conditions. We believe that
such a protocol could find application in medicinal chemistry
for fine-tuning the bioactivities of in-house compound
collections.
14 A selective copper promoted monomethylation of anilines with
MeB(OH)2 has appeared recently: I. Gonza
C. Guerrero, R. Rodrıguez and J. Cruces, Org. Lett., 2009, 11,
1677–1680.
´
lez, J. Mosquera,
´
15 Catalytic conditions that are particularly suitable to aliphatic
amines have been developed, see ref. 13e.
Notes and references
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Chem. Soc., 1996, 118, 11555–11574; (b) S. Mahapatra,
J. A. Halfen and W. B. Tolman, J. Am. Chem. Soc., 1996, 118,
11575–11586.
17 No cyclopropylated compound was isolated when the reaction was
performed under Tsuritani’s condition (KHMDS), see ref. 5. Such
conditions also failed to provide cyclopropylated aniline 3d.
18 We thank one of the reviewers for suggesting these experiments.
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Chem. Commun., 2010, 46, 3393–3395 | 3395