Auxiliary-enabled Pd-catalyzed direct arylation of methylene C(sp 3)-H bond of cyclopropanes: Highly diastereoselective assembling of Di- and trisubstituted cyclopropanecarboxamides

Article abstract of DOI:10.1021/ol4012212

An auxiliary-enabled and Pd(OAc)₂-catalyzed direct arylation of C(sp³)-H bonds of cyclopropanes and production of di- and trisubstituted cyclopropanecarboxamides having contiguous stereocenters are reported. The installation of aryl groups on cyclopropanecarboxamides led to the assembling of novel mono- and di- aryl-N-(quinolin-8-yl)cyclopropanecarboxamide scaffolds and mono- and di- aryl-N-(2-(methylthio)phenyl) cyclopropanecarboxamides. The stereochemistry of products was unequivocally assigned from the X-ray structures of key compounds.

Full text of DOI:10.1021/ol4012212

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Auxiliary-Enabled Pd-Catalyzed Direct
Arylation of Methylene C(sp3)ÀH Bond of
Cyclopropanes: Highly Diastereoselective
Assembling of Di- and Trisubstituted
Cyclopropanecarboxamides
Ramarao Parella, Bojan Gopalakrishnan, and Srinivasarao Arulananda Babu*
Department of Chemical Sciences, Indian Institute of Science Education and
Research (IISER) Mohali, Knowledge City, Mohali, Punjab, India
sababu@iisermohali.ac.in
Received May 1, 2013
ABSTRACT
An auxiliary-enabled and Pd(OAc)2-catalyzed direct arylation of C(sp3)ÀH bonds of cyclopropanes and production of di- and trisubstituted
cyclopropanecarboxamides having contiguous stereocenters are reported. The installation of aryl groups on cyclopropanecarboxamides led to
the assembling of novel mono- and di- aryl-N-(quinolin-8-yl)cyclopropanecarboxamide scaffolds and mono- and di- aryl-N-(2-(methylthio)-
phenyl)cyclopropanecarboxamides. The stereochemistry of products was unequivocally assigned from the X-ray structures of key compounds.
Cyclopropane, the smallest carbocyclic ring, is one of
the privileged structural motifs, present as a core unit
in numerous natural products, biologically active and
prospective drug molecules, and synthetic intermediates.1,2
Incorporation of cyclopropane rings in the molecular frame-
works is considered an important molecular tool to constrain
the conformation and study the reaction pathways.3
Along this line, various arylcyclopropane-carboxylic acid
derivatives have been reported to exhibit promising bio-
logical activities and used as molecular tools in the field
of chemical biology.3,4 Among the available methods,1,2,5
cyclopropanation of olefins is one of the cornerstone
protocols for producing cyclopropanes. Generally, the
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Dwyer, M. P.; Hartmann, B.; Knight, K. S. J. Org. Chem. 2000, 65, 1305.
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Wei, Y.; Shao, L. X. Acc. Chem. Res. 2012, 45, 641. (g) de Meijere, A.
Angew. Chem., Int. Ed. Engl. 1979, 18, 809. (h) Dıaz-Requejo, M. M.;
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123, 3167. (i) Sydnes, L. K. Chem. Rev. 2003, 103, 1133. (j) Danishefsky,
S. Acc. Chem. Res. 1979, 12, 66. (k) Lindsay, V. N. G.; Nicolas, C.;
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3061. (b) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051. (c)
Reisman, S. E.; Nani, R. R.; Levin, S. Synlett 2011, 2437. (d) Tang, P.;
Qin, Y. Synthesis 2012, 2969. (e) Zhang, D.; Song, H.; Qin, Y. Acc.
Chem. Res. 2011, 44, 447. (f) Simone, F. D.; Waser, J. Synthesis 2009,
3353. (g) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (h) Sathishkannan,
G.; Srinivasan, K. Org. Lett. 2011, 13, 6002.
(4) (a) Delong, M. A.; Royalty, S. M.; Sturdivant, J. M.; Heintzelman,
G. R. 6-Aminoisoquinoline Compounds. WO2008086269 A2 20080717,
2008. (b) Quinoline-Derived Amide Modulators of Vanilloid VR1 Receptor.
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Lindsay, V. N. G.; Charette, A. B. Cyclopropanation Reactions. In
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r
10.1021/ol4012212
XXXX American Chemical Society

production of substituted cyclopropanes with the trans
stereochemistry is a popular protocol. For example, the
metal-catalyzed reaction ofa diazocompound withstyrene
results in the cyclopropane Ia with trans stereochemistry
as the major isomer (Scheme 1).1b,c The cis/trans substi-
tuted cyclopropanes Ic/Id can also be obtained under
SimmonsÀSmith reaction conditions.5aÀc Noticeably,
the production of substituted cyclopropanes with cis
stereochemistry is a challenging task.1h,k For example,
the cyclopropane Ia can be obtained only by employing
special efforts.1h When compared to the field dealing with
the construction of cyclopropanes,1À5 the direct func-
tionalization of cyclopropanes is an underexplored research
area. This is because the cyclopropane ring is known to
have a strained structure and unique reactivity patterns
due to the steric and electronic factors.1,2
cyclopropanecarboxylic acid using an arylboronic acid as
the coupling partner, which resulted in the corresponding
arylated product in 20% yield. Then, in 2011, the same
group reported the ligand-enabled Pd-catalyzed stereo-
selective arylation of N-aryl cyclopropanecarboxamide (IIa)
using a boronic acid derivative (Scheme 1). While we were
engaged in investigating the ‘auxiliary-enabled Pd(OAc)2-
catalyzed CÀH arylation of cyclopropanecarboxamides’,
in late 2012, Yu’s group revealed an example related to
the arylation of N-aryl cyclopropanecarboxamide (IIb)
via ‘the ligand-enabled Pd(TFA)2-catalyzed CÀH activa-
tion in the presence of K2HPO4’. Successively, Cramer,8b
Rousseaux,8d and Charette8e have reported the Pd-
catalyzed intramolecular arylation of cyclopropane-
carboxamides using an appropriate ligand and additive
and the synthesis of tetrahydroquinoline- and spiro-
oxindole scaffolds, possessing a cyclopropyl unit.
Scheme 1. Assembling of Substituted Cyclopropanes
Scheme 2. Theme of This Work
A simple and an alternative route for the production
of the cis substituted cyclopropanes especially is the
direct metal-catalyzed functionalization of the C(sp3)ÀH
bond of cyclopropanes. However, only a few exceptional
reports6À8 exist in this regard, while the activation of the
methylene C(sp3)ÀH bond still remains a challenging
and potential topic of current and future research.9
In a primary work, Yu’s group showed an example related
to the arylation of the C(sp3)ÀH bond of 1-methyl
Taking impetus from the recent progress in CÀH activa-
tion reactions, particularly, the directing group enabled
Pd-catalyzed C(sp3)ÀH bond activation reactions
reported by the Daugulis, Chen, and Baran groups,9aÀf
we envisaged examining the construction of mono- and
diaryl-N-(quinolin-8-yl)cyclopropanecarboxamide scaffolds.
Nevertheless, it is important to mention that the 2-aryl
N-(isoquinolinyl)cyclopropanecarboxamide scaffolds (IIIa
and IIIb, Scheme 2), which are analogous to the present
investigation, are known to exhibit kinase and vanilloid
VR1 receptor inhibition activities.4 Herein, we report an
efficient, auxiliary-enabled, andPd(OAc)2-catalyzeddirect
functionalization of methylene bonds of cyclopropane-
carboxamides (1) and diastereoselective production of
novel mono- and diaryl-N-(quinolin-8-yl)cyclopropane-
carboxamides and mono- and diaryl-N-(2-(methylthio)-
phenyl)cyclopropanecarboxamides.
(6) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510.
(7) (a) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q.
J. Am. Chem. Soc. 2011, 133, 19598. (b) Wasa, M.; Chan, K. S. L.; Zhang,
X.-G.; He, J.; Miura, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 18570.
(8) (a) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135,
3375 and references therein. (b) Saget, T.; Cramer, N. Angew. Chem., Int.
Ed. 2012, 51, 12842. (c) Kubota, A.; Sanford, M. S. Synthesis 2011, 2579.
ꢀ
(d) Rousseaux, S.; Liegault, B.; Fagnou, K. Chem. Sci. 2012, 3, 244. (e)
Ladd, C. L.; Roman, D. S.; Charette, A. B. Org. Lett. 2013, 15, 1350.
(9) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2010, 132, 3965. (c) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50,
5192. (d) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133,
19076. (e) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew.
Chem., Int. Ed. 2012, 51, 7507. (f) He, G.; Zhao, Y.; Zhang, S.; Lu, C.;
Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (g) Gutekunst, W. R.; Baran,
P. S. Chem. Soc. Rev. 2011, 40, 1976. (h) Li, H.; Li, B.-J.; Shi, Z.-J. Catal.
Sci. Technol. 2011, 1, 191. (i) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-
Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (j) Santos,
A. D.; Kaım, L. E.; Grimaud, L.; Ramozzi, R. Synlett 2012, 438. (k)
Ladd, C. L.; Roman, D. S.; Charette, A. B. Tetrahedron 2013, 69, 4479.
At the outset, several reactions were carried out to find
the best reaction conditions and solvents. Table 1 shows the
reaction scheme, which comprises the Pd-catalyzed arylation
of N-(quinolin-8-yl)cyclopropane-carboxamide (1a), pre-
pared from cyclopropanecarbonyl chloride and an auxiliary,
e.g. 8-aminoquinoline, with 1-iodo-4-methoxybenzene (2a).
The CÀH functionalization reaction of N-(quinolin-8-yl)-
cyclopropanecarboxamide (1a) with 1-iodo-4-methoxyben-
zene (2a) in the absence of a Pd catalyst did not afford any
B
Org. Lett., Vol. XX, No. XX, XXXX

bond of cyclopropanecarboxamides was tested using a
variety of electron-withdrawing and -donating groups
containing aryl iodides (Scheme 3). The arylation of the
methylene CÀH bond of 1a with various substituted aryl
iodides proceeded smoothly and gave the corresponding
products 3aÀ3fin 28À78% yields. The arylation of1awith
1-iodonaphthalene and 1-iodo-3-methylbenzene gave 3g
and 3h in only 40 and 33% yields, respectively. The
arylation of 1a with 1-iodo-3-nitrobenzene gave 3i in
62% yield. All these reactions were highly stereoselective
and gave cyclopropanes with cis stereochemistry.10a
Table 1. Optimization of CÀH Activation Reaction Conditions
Scheme 3. Diastereoselective CÀH Arylation of 1a
a All the reactions were done using 1-iodo-4-methoxybenzene (2a)
under a nitrogen atmosphere. Isolated yields are given. b 1.2 mmol of 2a
was used. c In this case, 0.5 mmol of 2a was used. d In this case, 0.75 mmol
of 2a was used. e The reaction was done under an open atmosphere.
f In this case, 1-bromo-4-methoxybenzene (2b) was used instead of 2a.
g In this case, 1-chlorobenzene (2c) was used instead of 2a. h In this case,
0.26 mmol of 2a was used.
a In this case, 1 mmol of aryl iodide was used. b In this case, 0.5 mmol
of aryl iodide was used. The reaction was done using 1a (1.06 g,
5 mmol), 2a (1.02 g, 10 mmol), AgOAc (1.83 g, 11 mmol), and toluene
(15 mL).
c
Subsequently, we extended the scope of this protocol by
producing a wide range of novel trisubstituted cyclopro-
panes via the Pd-catalyzed direct arylation of the CÀH
bond of (1S*,2S*)-2-phenyl-N-(quinolin-8-yl)cyclopro-
panecarboxamide (1b) (Scheme 4).10b The arylation of
cyclopropanecarboxamide (1b) with phenyl iodide and
other aryl iodides having electron-donating or -withdraw-
ing groups at the para-position gave the corresponding
trisubstituted cyclopropanes (3jÀ3n) as single diastereo-
mers in 55À80% yields. Similarly, the trisubstituted cyclo-
propanes 3o (77%), 3p (74%), and 3q (64%) were obtained
using various aryl iodides having different substituents
(e.g., NO2, acetyl, and CF3) on the aromatic ring. Further,
product under neat conditions (entry 1, Table 1). The arylated
product 3 was obtained in 28% yield in the presence of a
Pd(OAc)2 catalyst without any oxidant under neat conditions
(entry 2). The arylation of 1a with 2a in the presence of a
Pd(OAc)2 catalyst and AgOAc under neat conditions gave 3
in only 35% yield (entry 3). Usage of different solvents such as
1,2-DCE, 1,4-dioxane, MeCN, DMF, and AcOH for the
arylation of 1a did not improve the yield of 3 (entries 4À8).
The arylation of 1a in the presence of Pd(OAc)2 and AgOAc
proceeded smoothly in toluene at 110 °C and furnished 3
having cis stereochemistry in 71% yield as a single diaster-
eomer (entry 9). Employing other Pd- and Ni-based catalysts
failed to furnish 3 with improved yields (entries 10À15). The
arylation of 1a with 2a in the presence of Pd(OAc)2 and
AgOAc under an open or nitrogen atmosphere and further
trials using a variety of oxidants did not significantly improve
the yield of 3 (entries 16À21). The Pd-catalyzed arylation of
1a with 2a without AgOAc under an open atmosphere gave 3
in 10% yield (entry 22). This reaction indicates that perhaps
AgOAc helps in the catalyst regeneration via a ligand ex-
change process, producing AgI and Pd(OAc)2.9 The arylation
of 1a with 2a in the presence of K2CO3 instead of AgOAc was
not effective (entry 23). Employing 1-bromo-4-methoxyben-
zene (2b) or chlorobenzene (2c) instead of 2a was not effective
(entries 24, 25). Using just 0.26 mmol of 2a instead of 1 mmol
gave 3 only in 37% yield (entry 26).
(10) (a) The stereochemistry of the products 3aÀi was assigned based
on the X-ray structure of 3 and the similarity in the 1H NMR spectral
pattern of 3 and 3aÀi. (b) The stereochemistry of the products 3jÀt was
assigned based on the X-ray structure of 3o and the similarity in the 1H
NMR spectral pattern of 3jÀt. (c) The stereochemistry of the products
4aÀc was assigned based on the X-ray structure of 4b and the similarity
in the 1H NMR spectral pattern of 4aÀc. (d) The stereochemistry of the
products 4dÀj was assigned based on the X-ray structure of 4d and the
similarity in the 1H NMR spectral pattern of 4dÀj. (e) The stereochem-
istry of the products 5aÀd was assigned based on the X-ray structure of
5a and the similarity in the 1H NMR spectral pattern of 5aÀd. (f)
Crystallographic data of X-ray structures (3: CCDC 936504; 3o: CCDC
936506; 4b: CCDC 936505; 4d: CCDC 936623; and 5a: CCDC 936503)
of this work have been deposited at the Cambridge Crystallographic
Data Centre. (g) All the reactions gave only a single diastereomer under
the present experimental conditions (if the aryl iodide is used in <4
equiv), and along with products the corresponding unreacted starting
materials 1aÀd were recovered. In some cases, we also obtained a
mixture of mono- and diarylated compounds when we used the aryl
iodide in excess (6À8 equiv). We are unable to represent the results at this
stage, as the optimization work and establishment of the stereochemistry
of the mono- and diarylated compounds is incomplete.
The scope of this auxiliary-enabled Pd-catalyzed inter-
molecular direct arylation of the methylene C(sp3)ÀH
Org. Lett., Vol. XX, No. XX, XXXX
C

the arylated products 3r (84%) and 3s (66%) were
obtained by using the respective disubstituted aryl iodides
(Scheme 4). Heterocyclic substitution on the cyclopropane
1b via the CÀH functionalization using 2-iodothiophene
successfully gave 3t (86%). The Pd-catalyzed arylation of
1b led to the stereoselective installation of various second
aryl groups at the methylene group of 1b and the synthesis
of novel trisubstituted cyclopropane-carboxamides 3jÀ3t
having contiguous stereocenters.
Scheme 5. Diastereoselective CÀH Activation of 1c,1d
Scheme 4. Stereoselective CÀH Functionalization of 1b
a In this case, 0.5 mmol of aryl iodide was used.
Scheme 6. Scope of This Work
Furthermore, we were focused on establishing the aryla-
tion scope by using the cyclopropanecarboxamides pre-
pared by using other auxiliaries. Toward this end, the
Pd-catalyzed arylation of N-(2 (methylthio)phenyl)cyclo-
propanecarboxamides (1c,1d) with a variety of aryl iodides
was studied (Scheme 5).10c,d The arylation of 1c gave the
products 4aÀc in 64, 55, and 40% yields as single diaste-
reomers, respectively (Scheme 5). Next, the Pd-catalyzed
CÀH functionalization of (1S*,2S*)-N-(2-(methylthio)-
phenyl)-2-phenylcyclopropanecarboxamide (1d) with dif-
ferent aryl iodides was explored for the production of
trisubstituted cyclopropanecarboxamides. Along this line,
various (1R*,2S*,3S*)-2-(aryl)-N-(2-(methylthio)phenyl)-
3-phenylcyclopropanecarboxamides (4dÀ4j) were obtained
as single diastereomers from the installation of various
second aryl groups at the methylene CÀH bond of the
cyclopropane 1d (Scheme 5).
and a facile access to novel mono- and diaryl-N-(quinolin-8-yl)-
cyclopropanecarboxamide scaffolds and mono- and
diaryl-N-(2-(methylthio)phenyl)cyclopropanecarboxamide
scaffolds, having contiguous stereocenters. Further work is
in progress to reveal the applications of these molecules.
Additionally, the Pd-catalyzed arylation of 1a,1b with
excess iodobenzene or 1-iodo-4-methylbenzene furnished
the respective diarylated cyclopropanes 5aÀc having the
1,2-cis/2,3-cis/1,3-cis stereochemistry10e (Scheme 6). Like-
wise, the Pd-catalyzed arylation of 4a having the 1,2-cis
stereochemistry with 1-iodo-4-ethylbenzene furnished the
cyclopropanecarboxamide 5c with the 1,2-cis/2,3-cis/1,3-
cis stereochemistry. Then, to reveal the utility of this
protocol, we performed the amide hydrolysis of 3j,3t,
which gave the corresponding substituted cyclopropane-
carboxylic acids 6a,6b. The reduction of the amide group
of the representative compound 3b afforded N-(((1S*,2R*)-
2-phenylcyclopropyl)methyl)quinolin-8-amine (7).
Acknowledgment. This research was funded by
IISER-Mohali. We thank the NMR and X-ray facilities
of IISER-Mohali. R.P. and B.G. are grateful to CSIR-
and DST, New Delhi, for JRF and INSPIRE fellow-
ships, respectively. We thank NIPER-Mohali, CDRI-
Lucknow, and IICT-Hyderabad for providing the mass
spectral data.
Supporting Information Available. Experimental pro-
cedures, X-ray structures, characterization data, and
copy of 1H, 13C NMR charts of all the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have reported an auxiliary-enabled and
Pd(OAc)2-catalyzed highly diastereoselective direct aryla-
tion of the methylene C(sp3)ÀH bond of cyclopropanes
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX