C-H functionalization of cyclopropanes: A practical approach employing a picolinamide auxiliary

Article abstract of DOI:10.1021/ol401931s

A Pd-catalyzed, picolinamide-enabled, and efficient C-H arylation of cyclopropanes is described. The reaction can be promoted by either a silver additive or catalytic pivalic acid in the presence of a carbonate base. Various aryl iodides can be employed as coupling partners, providing exclusively cis-substituted cyclopropylpicolinamides.

Full text of DOI:10.1021/ol401931s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
CꢀH Functionalization of Cyclopropanes:
A Practical Approach Employing
a Picolinamide Auxiliary
ꢀ
Daniela Sustac Roman and Andre B. Charette*
ꢀ
Centre in Green Chemistry and Catalysis, Department of Chemistry, Universite de
Montreal, P.O. Box 6128 Station Downtown, Montreal, Quebec H3C 3J7, Canada
ꢀ
ꢀ
ꢀ
andre.charette@umontreal.ca
Received July 9, 2013
ABSTRACT
A Pd-catalyzed, picolinamide-enabled, and efficient CꢀH arylation of cyclopropanes is described. The reaction can be promoted by either a silver
additive or catalytic pivalic acid in the presence of a carbonate base. Various aryl iodides can be employed as coupling partners, providing
exclusively cis-substituted cyclopropylpicolinamides.
The catalytic transformation of C(sp3)ꢀH bonds is
a continuously growing field in organic synthesis due to
the ubiquity of CꢀH bonds in nature. As such, a plethora
of powerful methods have already been developed, most
of them employing a transition-metal catalyst.1 One sig-
nificant challenge is the regioselectivity of the reaction, and
that has been overcome by the use of directing groups or
auxiliaries.2 Most notably, the picoline and aminoquino-
line carboxamide auxiliaries introduced by Daugulis have
proven to be valuable tools for the synthesis of CꢀC bonds
at the γ-position of the amide nitrogen (Scheme 1).3 These
auxiliaries have also been exploited in the formation of
CꢀN, CꢀO, and CꢀF bonds through the employment of
different metal catalysts.4
Our group has had a long-standing interest in both
the synthesis and functionalization of cyclopropanes5
due to their versatility in medicinal chemistry, in natural
product synthesis, and as scaffolds for other chemical
transformations.6 The rigidity of the cyclopropyl ring
and orbital hybridization leads to a more sp2-like character
(4) For recent examples, please see: (a) Feng, Y.; Wang, Y.;
Landgraf, B.; Liu, S.; Chen, G. Org. Lett. 2010, 12, 3414. (b) Zhao,
Y.; Chen, G. Org. Lett. 2011, 13, 4850. (c) He, G.; Chen, G. Angew.
Chem., Int. Ed. 2011, 50, 5192. (d) He, G.; Zhao, Y.; Zhang, S.; Lu, C.;
Chen, G. J. Am. Chem. Soc. 2011, 134, 3. (e) He, G.; Lu, C.; Zhao, Y.;
Nack, W. A.; Chen, G. Org. Lett. 2012, 14, 2944. (f) Zhao, Y.; He, G.;
Nack, W. A.; Chen, G. Org. Lett. 2012, 14, 2948. (g) Zhang, S.-Y.; He,
G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135,
2124. (h) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133,
12984. (i) Aihara, Y.; Chatani, N. Chem. Sci 2013, 4, 664. (j) Rouquet,
G.; Chatani, N. Chem. Sci. 2013, 4, 2201. (k) Hasegawa, N.; Shibata, K.;
Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. Tetrahedron 2013, 69,
4466. (l) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am.
Chem. Soc. 2013, 135, 6030. (m) Truong, T.; Klimovica, K.; Daugulis, O.
J. Am. Chem. Soc. 2013, 135, 9342.
(5) (a) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am.
Chem. Soc. 1998, 120, 11943. (b) Charette, A. B.; Gagnon, A.; Fournier,
J.-F. J. Am. Chem. Soc. 2001, 124, 386. (c) Lindsay, V. N. G.; Fiset, D.;
Gritsch, P. J.; Azzi, S.; Charette, A. B. J. Am. Chem. Soc. 2013, 135,
1463. (d) Beaulieu, L.-P. B.; Schneider, J. F.; Charette, A. B. J. Am.
Chem. Soc. 2013, 135, 7819.
(1) (a) Ackermann, L. Chem. Commun. 2011, 46, 4866. (b) Li, H.; Li,
B.-J.; Shi, Z.-J. Catal. Sci. Technol 2011, 1, 191. (c) Baudoin, O. Chem.
Soc. Rev. 2011, 40, 4902. (d) Mousseau, J. J.; Charette, A. B. Acc. Chem.
Res. 2013, 46, 412.
(2) For selected examples and reviews: (a) Dick, A. R.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (b) Giri, R.; Chen, X.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112. (c) Kalyani, D.;
Sanford, M. S. Org. Lett. 2005, 7, 4149. (d) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (e) Engle, K. M.; Mei, T.-S.; Wasa,
M.; Yu, J.-Q. Acc. Chem. Res. 2011, 45, 788. (f) Ackermann, L.;
Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875. (g) Rousseau, G.;
Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450. (h) Zhang, X.-G.; Dai,
H.-X.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 11948. (i) Li,
G.; Leow, D.; Wan, L.; Yu, J.-Q. Angew. Chem., Int. Ed. 2013, 52, 1245.
(j) Chan, L. Y.; Kim, S.; Ryu, T.; Lee, P. H. Chem. Commun. 2013, 49,
4682.
(6) (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977. (b) Rubin, M.; Rubina, M.; Gevorgyan, V.
Chem. Rev. 2007, 107, 3117. (c) Gagnon, A.; Duplessis, M.; Fader, L.
Org. Prep. Proced. Int. 2010, 42, 1.
(3) (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.
r
10.1021/ol401931s
XXXX American Chemical Society

for its carbon atoms, which should facilitate CꢀH func-
tionalization processes. To this end, our group has recently
disclosed an intramolecular palladium-catalyzed direct
CꢀH arylation reaction of cyclopropanes leading to the
synthesis of biologically relevant spirooxindole scaffolds
(Scheme 1).7 We further expanded this methodology to the
synthesis of seven-membered benzazepine rings through
cyclopropyl CꢀH activation followed by ring-opening.8
We next sought to develop a corresponding intermolecular
process, as reports for these transformations are scarce in
the literature.9 The group of Yu has recently disclosed an
enantioselective arylation of cyclopropanes employing
boronic esters as coupling partners and an electron-poor,
highly substituted arylamide as the auxiliary.10 We were
interested in developing a complementary methodology
that would be robust, efficient and scalable. Further-
more, we sought to use an inexpensive and easy to cleave
auxiliary. We were also encouraged by the fact that many
of the resulting cyclopropyl carboxylic acids or amines
possess interesting pharmacological properties.11 To ad-
dress these issues, we developed herein, a Pd-catalyzed,
picolinamide-enabled CꢀH activation of cyclopropanes
employing aryl iodides as coupling partners. Preliminary
investigations into the reaction mechanism are also
disclosed.
We initiated our screen by looking at different picolina-
mide (PA) and aminoquinoline derived auxiliaries (1aꢀc).
We identified1aasa promising leadand performedfurther
optimization studies (Table 1). Employing our previously
reported conditions7a,8a with Ag3PO4, K2CO3, Pd(OAc)2
and P(t-Bu)3 HBF4 as the ligand, 59% of monoarylated
3
product 2a was observed, along with 10% diarylation 3a
(entry 1). It should be noted that 2a was determined to be
one diastereomer with a cis substitution pattern, while
diaryl 3a was a mixture of cis and trans.12 Replacing the
base with Na2CO3 improved the yield of 2a (entry 2, 75%),
while removing the carbonate base and increasing the
amount of silver additive had a detrimental effect on the
yield (entries 3 and 4). We soon realized that the reaction did
not require the addition of a phosphine ligand (entry 5) and
that the amounts of catalyst and base could be decreased to
5 mol % and 0.3 equiv to give >90% conversion (entry 5,
conditions A).13 Cognizant of the use of pivalic acid in CꢀH
activation chemistry,14,8b we also tested this additive and
observed comparable yields to the silver conditions (entry 7,
conditions B).15 Changing the base from K2CO3 to Na2CO3
(entry 8) provided little conversion and no product forma-
tion. Applying both optimized conditions to other picoline
and aminoquinoline auxiliaries 1b and 1c, we observed little
or no product formation.
Table 1. Reaction Optimization
Scheme 1. Cyclopropane Functionalization
yielda (%)
entry
Pd (x)
base (y), additive (z)
1a 2a 3a
1b
2b
3b
4b
5c
6
Pd(OAc)2 (10) K2CO3 (2), Ag3PO4 (0.33)
Pd(OAc)2 (10) Na2CO3 (2), Ag3PO4 (0.33)
Pd(OAc)2 (10) ꢀ, Ag3PO4 (0.5)
13 59 10
15 75 10
54 20
16 51
1
9
5
1
Pd(OAc)2 (10) ꢀ, Ag2CO3 (1.25)
Pd(OAc)2 (5) Na2CO3 (0.3), Ag3PO4 (0.5)
Pd(OAc)2 (5) K2CO3(2), ꢀ
8
78
78 <5
7d Pd(OAc)2 (5) K2CO3 (2), PivOH (0.3)
6
76 15
8
9
Pd(OAc)2 (5) Na2CO3 (2), PivOH (0.3)
Pd(OAc)2 (5) K2CO3 (2), PivOH (0.5)
82
1
ꢀ
74 20
1
(7) (a) Ladd, C. L.; Sustac Roman, D.; Charette, A. B. Org. Lett.
2013, 15, 1350. For examples from other groups, see: (b) Saget, T.;
Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 12842. (c) Saget, T.; Perez,
D.; Cramer, N. Org. Lett. 2013, 15, 1354.
a 1H NMR yield using trimethoxybenzene as internal standard.
b P-t-Bu3 HBF4 (10 mol %) was used in the reaction. c Conditions A.
3
d Conditions B.
(8) (a) Ladd, C. L.; Roman, D. S.; Charette, A. B. Tetrahedron 2013,
69, 4479. For a related example, see: (b) Rousseaux, S.; Liegault, B.;
Fagnou, K. Chem. Sci. 2012, 3, 244.
(9) Kubota, A.; Sanford, M. S. Synthesis 2011, 2011, 2579.
(10) (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.
(11) (a) Cheng, K.; Lee, Y. S.; Rothman, R. B.; Dersch, C. M.;
Bittman, R. W.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2011, 54,
957. (b) Lim, J.; Taoka, B.; Otte, R. D.; Spencer, K.; Dinsmore, C. J.;
Altman, M. D.; Chan, G.; Rosenstein, C.; Sharma, S.; Su, H.-P.;
Szewczak, A. A.; Xu, L.; Yin, H.; Zugay-Murphy, J.; Marshall, C. G.;
Young, J. R. J. Med. Chem. 2011, 54, 7334. (c) Yamaguchi, K.; Kazuta,
Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 9255.
(12) See the Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

products were better under conditions A. In all cases, the
monoarylated product 2 was exclusively the cis diastereo-
mer, thus providing a robust method for the synthesis of
aryl and heteroaryl cis-substituted cyclopropanes.16 The di-
arylation product 3 had a predominant cis stereochemistry,
with the exception of 3a, 3j, and 3l which provided trans,
while 3f and 3g gave a mixture of both.17
Scheme 2. Aryl Iodide Scopea
To further demonstrate the applicability of the reaction,
a picolinamide derivative 4 containing a methyl R to the
cyclopropane was synthesized via Ellman’s chiral auxiliary18
and submitted to conditions A (Scheme 3).19 For p-OMe and
p-CF3, two diastereomers were obtained in 81% and 69%
yield, respectively, with good dr (7:1 and 8:1, respectively).20
Scheme 3. Diastereoselective CꢀH Activation
of Cyclopropanesa
a Conditions A: 1a (0.2 mmol, 1 equiv), Pd(OAc)2 (5 mol %), Na2CO3
(0.3 equiv), Ag3PO4 (0.5 equiv), aryl iodide (1.5 equiv), PhMe (0.2 M),
130 °C, 15 h. b Traces of diarylation <3% also observed.
To prove the practicality and robustness of the method-
ology, the reaction was carried out on a 5 mmol scale to
provide 1.05 g (74%) of desired product 2a employing only
2 mol % of Pd(OAc)2 (Scheme 4). Moreover, the auxiliary
could be removed in good yield to provide the Boc-
protected amine 2a0 (Scheme 4).
a Conditions A: 1a (0.5 mmol, 1 equiv), Pd(OAc)2 (5 mol %), Na2CO3
(0.3 equiv), Ag3PO4 (0.5 equiv), aryl iodide (1.5 equiv), PhMe (0.2 M),
130 °C, 15 h. b Conditions B: 1a (0.5 mmol, 1 equiv), Pd(OAc)2 (5 mol %),
K2CO3 (2 equiv), PivOH (0.3 equiv), aryl iodide (1.5 equiv), PhMe (0.2 M),
130 °C, 15 h. c The reaction was run for 45 h. d 0.4 equiv Ag3PO4. e Reported
as 1H NMR yield using an internal standard. f 10 mol % of Pd(OAc)2.
With the optimized conditions in hand, the scope of
the reaction was explored (Scheme 2). Substitution at the
para position was well-tolerated, with electron-donating
(2a) and electron-neutral (2b, 2c) aryl iodides giving great
yields. A variety of electron-withdrawing groups were also
well tolerated in the reaction, including trifluoromethyl
(2d), ester (2f), and ketone (2g). Bromo- (2e) and chloro-
substituted (2h) aryl iodides were also great coupling
partners (80% and 77%, respectively), thus allowing for
further functionalization of the products through cross-
coupling methods. The reaction also tolerated hetero-
cycles, with a protected indole reacting in 83% yield under
conditions A (2j). 2-Iodothiophene was also reactive, with
60% yield (2k). The reaction proved to be slightly sensitive
to sterics, as only a modest yield of 44% was isolated for
1-iodonaphthalene (2l:3l, 5:1) under conditions A, while
conditions B resulted in poor conversion. In general, the
yields and ratios between the monoarylated and diarylated
Scheme 4. Large Scale and Auxiliary Cleavage
(16) Cyclopropanation methods often provide a hard-to-separate
mixture of cis and trans diastereomers; for example, Cu-catalyzed
addition of diazo compounds to styrenes: Evans, D. A.; Woerpel,
K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113,
726. See also ref 11c.
(17) See the Supporting Information for characterization details.
Attempts at performing a mixed diarylation to a cis substrate 2 resulted
in low yields (<30%), even after longer reaction times.
(18) (a) Lim, J.; Taoka, B.; Otte, R. D.; Spencer, K.; Dinsmore, C. J.;
Altman, M. D.; Chan, G.; Rosenstein, C.; Sharma, S.; Su, H.-P.;
Szewczak, A. A.; Xu, L.; Yin, H.; Zugay-Murphy, J.; Marshall, C. G.;
Young, J. R. J. Med. Chem. 2011, 54, 7334. (b) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(13) Unreacted aryl iodide is still present at the end of the reaction, as
determined by GCꢀMS analysis. No significant biaryl formation was
observed.
(14) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496. (b) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2007, 129, 14570.
(19) Conditions B led to lower yields (45%).
(20) The stereochemistry of the major diastereomer was determined
via 1D NOE analysis.
(15) Aryl bromides were unreactive under both reaction conditions.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Screen of Pd Sources and Additives
Scheme 5. Proposed Mechanism
yielda (%)
2a/3a
entry
Pd (x)
additive (y)
1a
1
2
3
4
Pd2dba3 (2.5)
Pd2dba3 (2.5)
PdBr2 (5)
none
53
8
43/ꢀ
76/14
28/ꢀ
63/3
KOAc (10)
none
56
5
PdBr2 (5)
KOAc (10)
a 1H NMR yield using trimethoxybenzene as internal standard.
The mechanism proposed by Daugulis3b for the picoli-
namide auxiliary involves a Pd(II)/Pd(IV)21 catalytic
cycle.22 In our case, it is hypothesized that an initial five-
membered metallocycle species A is formed, where Pd is
stabilized through coordination to the pyridine nitrogen
as well as the highly acidic secondary amide moiety
(Scheme 5). CꢀH palladation mediated by acetate pro-
vides intermediate B,23 followed by oxidative addition of
the aryl iodide to give C. Reductive elimination provides the
final product and the palladium amide A is regenerated.
When our reaction was performed in presence of a Pd(0)
source, Pd2dba3, 43% desired product 2a was observed
(Table 2, entry 1), while a different Pd(II) source, PdBr2,
provided 28% 2a (entry 3). Interestingly, upon addition
of a catalytic amount of acetate in the reaction, the
reactivity is restored (entries 2 and 4), clearly demonstrat-
ing the necessity of acetate in the concerted metalation
deprotonation step as a ligand for Pd.24 Also, the cis CꢀH
bonds of the cyclopropane of 1a could be deuterated
in 75% upon stirring the starting material and Pd(OAc)2
in AcOD, suggesting that activation of the CꢀH bond
occurs in absence of the aryl iodide. No deuteration
was observed when Pd2dba3 was employed as the
catalyst.25
In conclusion, a highly diastereoselective CꢀH arylation
of cyclopropanes employing a practical and versatile picoli-
namide auxiliary was developed.26 The transformation
tolerates a variety of aryl iodides as coupling partners, it is
scalable, and the auxiliary can be easily removed. Both Pd(0)
and Pd(II) sources catalyze the reaction, but the presence of
catalytic acetate is required for high conversions. More
detailed mechanistic studies are underway in our laboratory.
Acknowledgment. This work was supported by the
ꢀ
ꢀ
Universite de Montreal, the Natural Science and Engineer-
ing Council of Canada (NSERC), the Canada Research
Chair Program, and the Canada Foundation for Innova-
tion. D.S.R. thanks NSERC for a CGS-D scholarship.
Supporting Information Available. Experimental pro-
cedures, characterization data, and spectral data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) (a) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 14047. (b) Racowski, J. M.; Sanford, M. S. Top. Organomet.
Chem. 2011, 35, 61.
(22) A Pd(II)/Pd(III) mechanism cannot be excluded: Powers, D. C.;
Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009,
131, 17050.
(23) Attempts to isolate the putative palladacycle in our case have
been unsuccessful thus far.
(24) A similar effect has been previously reported: Mousseau, J. J.;
(25) This suggests that in the presence of ArꢀI, Pd(0) will form
Pd(II)I2 and ArꢀAr. We observed traces amount of biaryl by GCꢀMS.
Alternatively, Agþ may be involved in oxidizing Pd(0) to Pd(II).
(26) During the preparation of this manuscript, a related report
appeared: Parella, R.; Gopalakrishnan, B.; Babu, S. A. Org. Lett.
2013, 15, 3238.
ꢀ
Vallee, F.; Lorion, M. M.; Charette, A. B. J. Am. Chem. Soc. 2010, 132,
14412. See also ref 8a.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX