Stereodivergent synthesis of arylcyclopropylamines by sequential C-H borylation and Suzuki-Miyaura coupling

Article abstract of DOI:10.1002/anie.201409186

A step-economical and stereodivergent synthesis of privileged 2-arylcyclopropylamines (ACPAs) through a C-(sp³)-H borylation and Suzuki-Miyaura coupling sequence has been developed. The iridium-catalyzed C-H borylation of N-cyclopropylpivalamide proceeds with cis selectivity. The subsequent B-cyclopropyl Suzuki-Miyaura coupling catalyzed by [PdCl₂(dppf)]/Ag₂O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen-bound carbon atoms of both the starting materials and products is observed under the reaction conditions. This epimerization is, however, suppressed in the presence of O₂. The present new ACPA synthesis results in not only a significant reduction in the steps required for making ACPA derivatives, but also the ability to access either isomer (cis or trans) by simply changing the atmosphere (N₂ or O₂) in the coupling stage.

Full text of DOI:10.1002/anie.201409186

Angewandte
Chemie
DOI: 10.1002/anie.201409186
Small Ring Systems
Stereodivergent Synthesis of Arylcyclopropylamines by Sequential
À
C H Borylation and Suzuki–Miyaura Coupling**
Shin Miyamura, Misaho Araki, Takayoshi Suzuki, Junichiro Yamaguchi,* and Kenichiro Itami*
Abstract: A step-economical and stereodivergent synthesis of
privileged 2-arylcyclopropylamines (ACPAs) through a C-
3
À
(sp ) H borylation and Suzuki–Miyaura coupling sequence
À
has been developed. The iridium-catalyzed C H borylation of
N-cyclopropylpivalamide proceeds with cis selectivity. The
subsequent B-cyclopropyl Suzuki–Miyaura coupling catalyzed
by [PdCl2(dppf)]/Ag2O proceeds with retention of configura-
tion at the carbon center bearing the Bpin group, while
epimerization at the nitrogen-bound carbon atoms of both the
starting materials and products is observed under the reaction
conditions. This epimerization is, however, suppressed in the
presence of O2. The present new ACPA synthesis results in not
only a significant reduction in the steps required for making
ACPA derivatives, but also the ability to access either isomer
(cis or trans) by simply changing the atmosphere (N2 or O2) in
the coupling stage.
2-Arylcyclopropylamines (ACPAs) have received much
attention from the organic and medicinal community because
of their unique biological activity (Figure 1a).[1,2] However,
there is significant room for improvement in the synthesis of
ACPAs, particularly when rapid structural diversification is
desired for biological testing. Conventionally, ACPAs are
synthesized in multistep sequences consisting of Wittig
[*] S. Miyamura, M. Araki, Prof. Dr. J. Yamaguchi, Prof. Dr. K. Itami
Department of Chemistry, Graduate School of Science
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
E-mail: junichiro@chem.nagoya-u.ac.jp
itami@chem.nagoya-u.ac.jp
Prof. Dr. T. Suzuki
Graduate School of Medical Science, Kyoto Prefectural University
of Medicine, Kita-ku, Kyoto 603-8334 (Japan)
and
Figure 1. a) Arylcyclopropylamine (ACPA)-containing drugs and drug
candidates. b) Conventional synthetic route for ACPAs. c) A new
À
stereodivergent route for ACPAs through C H activation.
JST, PRESTO
4-1-8 Honcho Kawaguchi, Saitama 332-0012 (Japan)
Prof. Dr. K. Itami
reactions on aldehydes, cyclopropanation of the resulting
Institute of Transformative Bio-Molecules (WPI-ITbM)
alkenes, hydrolysis of esters, and subsequent Curtius rear-
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
and
rangement (Figure 1b).[3,4] Following this conventional route,
to make n ACPA derivatives with different aryl groups, as
many as 4n steps are required. During our studies directed
towards developing inhibitors of lysine-specific demethy-
lase 1 (LSD1),[2c,d] the difficulty posed by the lack of a concise
JST, ERATO, Itami Molecular Nanocarbon Project
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
[**] We thank Dr. Yasutomo Segawa for assistance with X-ray crystal
structure analysis. This work was supported by the Funding
Program for Next Generation World-Leading Researchers from JSPS
(K.I.), and a Grant-in-Aid for Scientific Research on Innovative Areas
“Molecular Activation Directed toward Straightforward Synthesis”
(25105720 to J.Y.), KAKENHI (25708005 to J.Y.) from MEXT. ITbM is
supported by the World Premier International Research Center
(WPI) Initiative (Japan).
synthesis became immediately evident. We envisaged that
[5]
À
applying emerging C H functionalization logic would
provide a new step-economical, stereodivergent route for
ACPAs. In planning ACPA synthesis through diversity-
À
oriented C H functionalization, we decided to explore the
3
[6,7]
À
stereoselective C(sp ) H borylation
of readily available
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409186.
cyclopropylamine ($3.87 per gram from Sigma–Aldrich) or its
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À
derivatives (Figure 1c). Furthermore, with recent advances in
stereoretentive or stereoinvertive B-alkyl Suzuki–Miyaura
cross-coupling[8] and the precedent of stereospecific coupling
of cyclopropylboronic acids (or esters),[9] we expected chiral
aminocyclopropylboronic esters to be valuable substrates for
conversion into various ACPAs through coupling chemistry.
Thus herein we report a new ACPA synthesis which permits
not only a significant reduction in the number of steps
required for making ACPA derivatives (n + 1 steps for
n derivatives), but also the production of either isomer (cis
or trans) by slightly changing the atmosphere in the coupling
stage (Figure 1c).
propane C H borylation (steric-controlled, trans-selec-
tive).[11] This outcome clearly indicates that the pivaloylamide
À
group on 1 functions as a directing group during the C H
activation step.[12] It should be noted that the group of
Sawamura recently reported a heteroatom-directed cis-selec-
À
tive C H borylation of cyclopropanes by silica-supported
monophosphine iridium catalysts.[13]
Possible modes of action for the pivaloylamide directing
effect might be worth mentioning. Given that most ortho-
À
directed C H borylations require an iridium (or rhodium)
center to have two accessible coordination sites and that
phenanthroline ligands are unsuitable for providing them, we
assume that the pivaloylamide group was interacting with
a boryl ligand on iridium either by coordination of Lewis basic
Our first goal was to find appropriate conditions for the
3
À
stereoselective C(sp ) H borylation of cyclopropylamines.
À
Although cyclopropanes have been rarely investigated in C
atom (O or N) to boron[14] or by hydrogen bonding of the
H borylation chemistry,[10] Hartwig recently reported a trans-
acidic proton (N H) to the pinacolboryl oxygen atom.
[15]
À
À
selective C H borylation of cyclopropanes catalyzed by
Based on this auspicious result, we optimized the reaction
conditions using 1a as a substrate (Table 1). When 4,4’-di-tert-
butylpyridine (4,4’-dibpy) was used as the ligand instead of
2,9-Me2phen, the yield of 2a increased slightly (entry 2).
Changing the ligand to 3,4,7,8-tetramethylphenanthroline
(3,4,7,8-Me4phen)[11,16] provided the best result, thus giving
2a in 31% yield (entry 3). Interestingly, when the amount of
both iridium and ligand were decreased from 2.5 mol% to
0.5 mol%, the yield of 2a increased to 43% (entry 4). The use
of HBpin instead of B2pin2 resulted in a similar yield of 2a
(entry 5). We also found that the amount of iridium and
ligand are critically important for the reaction efficiency.
Thus, with 0.5 mol% of [{Ir(OMe)(cod)}2]/3,4,7,8-Me4phen
catalyst, 1a (7.1 mmol) reacted with HBpin (1.5 equiv) to give
2a in 85% yield as determined by NMR spectroscopy (62%
yield upon isolation).[17,18] Interestingly, under these reaction
[{Ir(OMe)(cod)}2] and 2,9-dimethylphenanthroline (2,9-
Me2phen).[11] However, in early experiments, we found that
simple application of this catalyst system to the reaction of
unprotected cyclopropylamine and bis(pinacolato)diboron
À
(B2pin2) did not lead to the C H borylation product at all.
After extensive screening of N substituents on the cyclo-
propylamine unit, we determined that N-cyclopropylpivala-
mide (1a) was a viable substrate. For example, the treatment
of 1a (1.0 equiv) and B2pin2 (0.5 equiv) in the presence of
[{Ir(OMe)(cod)}2] (2.5 mol%) and 2,9-Me2phen (10 mol%)
À
in cyclohexane at 708C furnished the C H borylation product
2a in 6% yield with most of starting material remaining intact
À
(Table 1, entry 1). Very interestingly, we found that the C H
borylation proceeded in a cis-selective manner, which is
opposite to the finding of Liskey and Hartwig for cyclo-
À
conditions employing excess amounts of HBpin, a double C
H borylation product was observed only in a trace amounts.
À
We also conducted C H borylation of the cyclopropyl-
À
Table 1: Iridium-catalyzed cis-selective C H borylation of the cyclopro-
pylamine 1a.[a]
amines 1b–j with various substituents (see the Supporting
Information for details). The pivaloyl group is by far the best
N substituent in this particular reaction. Although there exist
À
other protecting groups providing C H borylation products
to some extent [e.g., N-cyclopropylisobutyramide (1b) and N-
cyclopropyl-2,2,2-trifluoroacetamide (1e)], careful optimiza-
tion will be needed to achieve a synthetically useful level of
Entry
Boron reagent
(equiv)
x (mol%)
Ligand
Yield [%][b]
À
efficiency. We also found that the C H borylation of the n-
1
2
3
4
5
6
B2pin2 (0.5)
B2pin2 (0.5)
B2pin2 (0.5)
B2pin2 (0.5)
HBpin (1.0)
HBpin (1.5)
HBpin (1.5)
HBpin (1.5)
HBpin (1.5)
2.5
2.5
2.5
0.5
0.5
0.5
0.5
0.5
0.5
2,9-Me2phen
4,4’-dibpy
6
15
31
43
49
61
67
propyl-substituted cyclopropylamide 1j proceeded in a regio-
and stereoselective manner, albeit with low reaction effi-
ciency [23% yield upon isolation; Eq. (1)]. Judging from
3,4,7,8-Me4phen
3,4,7,8-Me4phen
3,4,7,8-Me4phen
3,4,7,8-Me4phen
3,4,7,8-Me4phen
3,4,7,8-Me4phen
3,4,7,8-Me4phen
7[c]
8[d]
9[c,e]
19
85 (62)[f]
[a] Reaction conditions: 1a (1.6 mmol, 1.0 equiv), boron reagent, [{Ir-
(OMe)(cod)}2] (x mol%), ligand (2x mol%), cyclohexane, 708C, 18 h.
[b] Yield of 2a based on 1a, as determined by NMR analysis. [c] The
reaction was conducted at 808C. [d] THF was used as solvent. [e] 1a
(7.1 mmol) was used. [f] Yield of isolated product.
B2pin2 =bis(pinacolato)diboron, cod=1,5-cyclooctadiene, HBpin=pi-
nacolborane, 2,9-Me2phen=2,9-dimethylphenanthroline, 4,4’-
dibpy=4,4’-di-tert-butylpyridine, 3,4,7,8-Me4phen=3,4,7,8-tetramethyl-
phenanthroline.
NOE experiments, the boryl group was introduced cis to the
amide group and trans to the n-propyl group. As the present
study is directed towards the development of LSD1 inhibitors
having cyclopropylamine moiety with one aryl substituent on
the cyclopropyl ring,[2c,d] substituted cyclopropanes are
beyond the scope of this paper.
2
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With stereoselective C H borylation conditions estab-
lished, we next examined the B-alkyl Suzuki–Miyaura cross-
coupling of 2a with haloarenes to provide ACPAs.[9] We were
initially expecting that stereoretentive and/or stereoinvertive
B-alkyl coupling conditions established by the groups of
Crudden[8a] and Suginome[8b] would transform 2a into the
corresponding cis and trans isomers of ACPAs. However, the
outcome was very surprising, even though the stereodivergent
production of both isomers was possible (Table 2). The first
Scheme 1. Suzuki–Miyaura coupling of enantioenriched (1S,2R)-2a
with 3b.
Table 2: Palladium-catalyzed Suzuki–Miyaura coupling of 2a and 3a.[a]
(1R,2S)-4b (28% yield) and (1S,2S)-4b (26% yield). This
result clearly shows that the coupling proceeds with complete
retention of configuration at the carbon center bearing the
Bpin group and that epimerization occurs at the nitrogen-
bound carbon atom.
This somewhat unexpected epimerization at the nitrogen-
bound carbon under palladium catalysis could possibly occur
before and/or after the cross-coupling reaction. Thus, to shed
light on this epimerization reaction, we monitored the
isomerization of the coupling products 4a as well as the
starting 2a under coupling conditions. Firstly, the purified
products, trans-4a and cis-4a, were individually treated with
the standard reaction conditions (but without iodoarene)
under N2 or O2 atmosphere as outlined in Figure 2a. Both
trans-4a and cis-4a isomerized under N2. The compound cis-
4a underwent significant isomerization under N2 after
48 hours to give a mixture of isomers favoring the trans
isomer (trans/cis = 63:37), and trans-4a also isomerized, but to
a lesser extent as both isomers appeared to trend towards an
equilibrium point slightly enriched in trans (Figure 2a). In
contrast, exposing either the cis or the trans to the reaction
conditions in the presence of O2 resulted in virtually no
Entry
Atmosphere
Yield [%][b]
trans-4a/cis-4a
1
2
N2
O2
87
67
77:23
16:84
[a] Reaction conditions: 2a (1.0 equiv), 3a (1.5 equiv), [PdCl2-
(dppf)]·CH2Cl2 (8 mol%), Ag2O (1.5 equiv), Cs2CO3 (2.0 equiv), H2O
(2.0 equiv), 708C, 6 h, under N2 or O2. [b] Combined yield of isolated
trans-4a and cis-4a. In the ORTEP drawings of trans-4a and cis-4a,
hydrogen atoms are omitted for clarity and the thermal ellipsoids are
drawn at 50% probability.[21] dppf=bis(diphenylphosphino)ferrocene,
THF=tetrahydrofuran.
optimal reaction conditions[19] were established by modifying
the Crudden protocol.[8a,20] Thus cross-coupling of 2a
(1.0 equiv) and 4-iodotoluene (3a; 1.5 equiv) was carried
out in the presence of [PdCl2(dppf)] (8 mol%), Ag2O
(1.5 equiv), Cs2CO3 (2.0 equiv), and H2O (2.0 equiv) in THF
at 708C for 6 hours under an N2 atmosphere to afford the
coupling products, trans-4a and cis-4a, in 87% combined
yield (trans/cis = 77:23, entry 1). These cis and trans isomers
were readily separated by silica-gel column chromatography
and their structures were unambiguously confirmed by X-ray
crystal structure analysis. The key features found during
reaction optimization were: 1) Ag2O is crucial for reactivity;
2) dppf is the most effective ligand; and 3) rate acceleration is
observed by the addition of Cs2CO3 and H2O. Surprisingly, the
trans product (trans-4a) was preferentially formed from the
cis-configured starting material (cis-2a) under what is
expected to be stereoretentive conditions. While trying to
identify the controlling factors in this coupling, we found that
the preferential production of cis-4a could be achieved by
simply performing the reaction under O2 atmosphere
(entry 2; 67% combined yield, trans/cis = 16:84).
To understand how these cis and trans products are
formed, we investigated the Suzuki–Miyaura cross-coupling
reaction using the enantioenriched 2a (Scheme 1). Thus
(1S,2R)-2a (93% ee), which was prepared according to the
literature,[9e] was coupled with iodobenzene (3b) under our
standard reaction conditions (N2 atmosphere), thus giving
Figure 2. a) Isomerization experiments of trans-4a and cis-4a. b) Iso-
merization experiments of cis-2a.
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isomerization. These results strongly suggest that O2 helps
prevent the isomerization of both isomers.
products 4j and 4k in moderate yields. Aryl iodides with
a functional group on the benzene ring at the C4 position such
as trifluoromethyl (3l), trifluoromethoxy (3m), methoxy
(3n), and methoxycarbonyl (3o) were coupled with 2 to
furnish the expected products 4l–o in moderate yields.
Heteroaryl iodides bearing pyridine (3p), thiophene (3q),
and indole (3r) also gave the corresponding coupling
products 4p–r, albeit in lower yields. With some exception
(4d, 4l, 4p, and 4r), the trans APCAs were preferentially
obtained under N2, and the cis isomers were obtained as
major products under O2.
Next, cis-2a was subjected to the standard reaction
conditions without iodoarene to examine the isomerization
reaction (Figure 2b). The isomerization of cis-2a also oc-
curred to give a mixture of cis-2a and trans-2a, and it was
found that the isomerization was faster under N2 (cis/trans =
54:46 after 1.5 h) than that under O2 (cis/trans = 78:22 after
À
1.5 h). These results clearly show that isomerization at the C
N bond occurred from 2a as well.
We found that when the coupling reaction of cis-2a and 3a
was performed with 10 mol% of BHT (dibutylhydroxyto-
luene) under N2, the isomerization was suppressed (cis-4a
55%, trans-4a 6%). We initially assumed that this BHTeffect
is a testimony to the occurrence of radical-based isomer-
ization under the standard reaction conditions. However,
other radical scavengers such as DHA (dihydroanthracene)
and TEMPO (10 mol% employed) had almost no effect in
suppressing the cis–trans isomerization. Although the precise
mechanism of epimerization at the nitrogen-bound carbon
atom and the inhibiting action of O2 and BHTremain unclear,
the atmosphere-controlled stereodivergent production of
ACPAs is of great importance from synthetic point of view.
With reaction conditions in hand to preferentially produce
either stereoisomer, we examined the substrate scope of the
Suzuki–Miyaura cross-coupling reaction of cis-2a with vari-
ous aryl iodides under N2 and O2 (Scheme 2). A broad range
of aryl iodides containing groups such as phenyl (3b), meta-
tolyl (3c), ortho-tolyl (3d), para-phenyl (3e), ortho-phenyl
(3 f), ortho-fluoro (3g), meta-fluoro (3h), and difluoro (3i),
can be coupled with 2a under N2 and O2 to afford the
corresponding coupling products 4a–h in good to moderate
yields. When meta-chloro- (3j) and para-bromo-substituted
(3k) aryl iodides were used, the reaction proceeded selec-
tively at the iodine atom to afford the corresponding coupling
Finally, we demonstrated a one-pot borylation/arylation
resulting in a gram-scale synthesis of ACPA (Scheme 3). The
compound 1a (14 mmol) was borylated with HBpin under the
optimized reaction conditions, followed by a Suzuki–Miyaura
cross-coupling reaction with 3k to afford 1.4 grams of the
Scheme 3. One-pot borylation/arylation and gram-scale synthesis of
ACPA 5. Reaction conditions: a) 1a (14.2 mmol, 1.0 equiv), HBpin
(1.5 equiv), [{Ir(OMe)(cod)}2] (0.5 mol%), 3,4,7,8-Me4phen
(1.0 mol%), cyclohexane, 808C, 18 h; removal of the solvent; 2a, 3a
(1.5 equiv), [PdCl2(dppf)]·CH2Cl2 (8 mol%), Ag2O (1.5 equiv), Cs2CO3
(2.0 equiv), H2O (2.0 equiv), 708C, 6 h, under N2, 35% yield (one pot).
b) 4k (5.3 mmol, 1.0 equiv), conc. HCl (1.0 mL), 1-propanol (2.0 mL),
1008C, 60 h, 73% yield.
Scheme 2. Substrate scope. Yield is that of the two isolated product isomers. Ratios represent the trans/cis products.
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8047; e) H. Sekizawa, K. Amaike, Y. Itoh, T. Suzuki, K. Itami, J.
coupling product 4k in one pot (35% yield). Thereafter,
treatment of 4k with HCl in 1-propanol gave 2-arylcyclopro-
pylamine 5 in 73% yield.
Yamaguchi, ACS Med. Chem. Lett. 2014, 5, 582; f) T. Kang, Y.
Kim, D. Lee, Z. Wang, S. Chang, J. Am. Chem. Soc. 2014, 136,
4141.
In summary, we have developed a step-economical and
À
[6] For recent reviews on C H borylation, see: a) I. A. I. Mkhalid,
stereodivergent synthesis of privileged 2-arylcyclopropyla-
J. H. Barnard, T. B. Marder, J. M. Murphy, J. F. Hartwig, Chem.
Rev. 2010, 110, 890; b) J. F. Hartwig, Acc. Chem. Res. 2012, 45,
3
À
mines through a sequence of C(sp ) H borylation and
À
Suzuki–Miyaura coupling. The iridium-catalyzed C H bor-
864.
3
À
ylation of N-cyclopropylpivalamide proceeds with cis selec-
tivity. The subsequent B-cyclopropyl Suzuki–Miyaura cou-
pling catalyzed by [PdCl2(dppf)]/Ag2O proceeds with reten-
tion of configuration at the carbon atom bearing the Bpin
group, while epimerization at the nitrogen-bound carbon
centers of both starting materials and products is observed
under the reaction conditions, epimerization which is sup-
pressed in the presence of O2. This unprecedented atmos-
phere-controlled epimerization process allowed access to
both the cis and trans isomers of ACPAs in a rapid and
operationally simple manner. Further mechanistic investiga-
[7] For selected examples of iridium- or rhodium-catalyzed C(sp )
H borylation, see: a) C. W. Liskey, J. F. Hartwig, J. Am. Chem.
Soc. 2012, 134, 12422; b) S. Kawamorita, T. Miyazaki, T. Iwai, H.
Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2012, 134, 12924; c) T.
Ohmura, T. Torigoe, M. Suginome, J. Am. Chem. Soc. 2012, 134,
17416; d) S. Kawamorita, R. Murakami, T. Iwai, M. Sawamura, J.
Am. Chem. Soc. 2013, 135, 2947; e) S. H. Cho, J. F. Hartwig, J.
Am. Chem. Soc. 2013, 135, 8157; f) T. Mita, Y. Ikeda, K.
Michigami, Y. Sato, Chem. Commun. 2013, 49, 5601; g) T. Iwai,
T. Harada, K. Hara, M. Sawamura, Angew. Chem. Int. Ed. 2013,
52, 12322; h) T. Ohmura, T. Torigoe, M. Suginome, Chem.
Commun. 2014, 50, 6333.
[8] For stereoretentive or stereoinvertive B-alkyl Suzuki–Miyaura
coupling, see: a) D. Imao, B. W. Glasspoole, V. S. Laberge, C. M.
Crudden, J. Am. Chem. Soc. 2009, 131, 5024; b) T. Ohmura, T.
Awano, M. Suginome, J. Am. Chem. Soc. 2010, 132, 13191;
c) D. L. Sandrock, L. Jean-Gerard, C.-Y. Chen, S. D. Dreher,
G. A. Molander, J. Am. Chem. Soc. 2010, 132, 17108; d) J. C. H.
Lee, R. McDonald, D. G. Hall, Nat. Chem. 2011, 3, 894; e) J. Li,
M. D. Burke, J. Am. Chem. Soc. 2011, 133, 13774; f) T. Awano, T.
Ohmura, M. Suginome, J. Am. Chem. Soc. 2011, 133, 20738;
g) G. A. Molander, S. R. Wisniewski, J. Am. Chem. Soc. 2012,
134, 16856; h) B. M. Partridge, L. Chausset-Boissarie, M. Burns,
A. P. Pulis, V. K. Aggarwal, Angew. Chem. Int. Ed. 2012, 51,
11795; i) S. C. Matthew, B. W. Glasspoole, P. Eisenberger, C. M.
Crudden, J. Am. Chem. Soc. 2014, 136, 5828.
À
tions of pivaloyl-directed C H borylation and epimerization
of cyclopropylamines as well as the development of ACPA-
based LSD1 inhibitors are now ongoing.
Received: September 17, 2014
Published online: && &&, &&&&
À
Keywords: C H activation · cross-coupling · boron · iridium ·
.
small ring systems
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À
this paper, the authors demonstrated trans-selective C H
borylation of cyclopropanes with substituents such as alkyl,
ether, bromo, ester, ketone, amide, and cyano groups.
À
[12] For a review on functional-group-directed C H borylation, see:
A. Ros, R. Fernandez, J. M. Lassaletta, Chem. Soc. Rev. 2014, 43,
3
À
3229. See ref. [7] for the examples of directed C(sp ) H
borylation.
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[17] The yield of isolated 2a was somewhat lower than that of the
yield determined by NMR spectroscopy (before isolation). This
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Angew. Chem. Int. Ed. 2014, 53, 1 – 7
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Angewandte
Communications
difference is due to the difficulty in separating 2a from a starting
material 1a by simple silica-gel column chromatography.
[18] For the effect of other reaction parameters, see the Supporting
Information for details.
[19] For details of optimization, see the Supporting Information.
[20] The reaction conditions reported by Suginome et al. (Ref [8b])
did not work in our case.
[21] CCDC 1030537 (trans-4a), CCDC 1030536 (cis-4a), and
CCDC 1030538 (cis-8a) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Communications
Small Ring Systems
S. Miyamura, M. Araki, T. Suzuki,
J. Yamaguchi,* K. Itami*
&&&& — &&&&
Stereodivergent Synthesis of
À
Arylcyclopropylamines by Sequential C
H Borylation and Suzuki–Miyaura
Coupling
All about atmosphere: A step-economical
synthesis of 2-arylcyclopropylamines
through the title sequence has been
figuration at the carbon center bearing
the Bpin group, and epimerization at the
nitrogen-bound carbon atoms. Either
isomer (cis or trans) can be accessed by
simply changing the atmosphere (N2 or
O2).
À
developed. The iridium-catalyzed C H
borylation proceeds with cis selectivity,
and the subsequent Suzuki–Miyaura
coupling proceeds with retention of con-
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!