Synthesis of trans-2-(trifluoromethyl)cyclopropanes via suzuki reactions with an N-methyliminodiacetic acid boronate

Article abstract of DOI:10.1021/ol401636d

trans-2-(Trifluoromethyl)cyclopropylboronic acid N-methyliminodiacetic acid (MIDA) ester 5 was synthesized as a pure diastereomer from vinylboronic acid MIDA ester and (trifluoromethyl)diazomethane in a single step. An X-ray study confirmed the trans-stereochemistry around the cyclopropyl ring. Use of 5 in Suzuki reactions, with a variety of aryl or heteroaryl coupling partners, provided trans-2-(trifluoromethyl)cyclopropyl products in moderate to excellent yields (17-90%).

Full text of DOI:10.1021/ol401636d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of trans-
2-(Trifluoromethyl)cyclopropanes
via Suzuki Reactions with an
N‑Methyliminodiacetic Acid Boronate
Matthew A. J. Duncton* and Rajinder Singh
Rigel, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080,
United States
mduncton@rigel.com; mattduncton@yahoo.com
Received June 11, 2013
ABSTRACT
trans-2-(Trifluoromethyl)cyclopropylboronic acid N-methyliminodiacetic acid (MIDA) ester 5 was synthesized as a pure diastereomer from
vinylboronic acid MIDA ester and (trifluoromethyl)diazomethane in a single step. An X-ray study confirmed the trans-stereochemistry around the
cyclopropyl ring. Use of 5 in Suzuki reactions, with a variety of aryl or heteroaryl coupling partners, provided trans-2-(trifluoromethyl)cyclopropyl
products in moderate to excellent yields (17ꢀ90%).
In recent years, medicinal chemists have described the
advantageous use of small groups for modulating multiple
properties in tandem, such as on-target potency, drug
metabolism, and pharmacokinetic properties (DMPK)
or toxicological (safety) profile. For instance, numerous
publications have described the beneficial effects of cyclo-
propyl,1 trifluomethyl,2 oxetan-3-yl,3 and other small motifs
on the above characteristics.4 One moiety that has been
under explored in this regard, is the 2-(trifluoromethyl)-
cyclopropyl group 1 (Figure 1). To date, only a small
number of publications have detailed the use of 2-(tri-
fluoromethyl)cyclopropanes within a medicinal chemistry
setting. For example, a small series of potent transient re-
ceptor potential vanilloid 1 (TRPV1) antagonists containing
a 2-(trifluoromethyl)cyclopropyl group have been disclosed
in the patent and primary literature.5,6 Other occurrences
tend to detail single compounds as part of a broader
grouping.7 The limited use of a 2-(trifluoromethyl)-
cyclopropyl fragment by medicinal chemists is unfortunate,
as its incorporation combines two substructures frequently
encountered in medicinal chemistry programs, the cyclo-
propyl and trifluoromethyl groups, in a three-dimensional,
chiral framework. This three-dimensional and chiral topology
may in itself be desirable, as these features have been noted to
result in a positive influence on DMPK and selectivity profiles
in some instances.8,9 Interestingly, recent experiences with
1-(trifluoromethyl)cyclopropanes, close structural cousins
to 2-(trifluoromethyl)cyclopropyl counterparts, demonstrate
a positive effect on metabolic stability when compared
with a tert-butyl congener.10 Beyond the realm of medicinal
chemistry, 2-(trifluoromethyl)cyclopropanes may be useful in
materials science, where the unique electronic properties
(1) Salaun, J. Topics Curr. Chem. 2000, 207, 1.
(2) (a) Yale, H. L. J. Med. Chem. 1959, 1, 121. (b) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem Soc. Rev. 2008, 37, 320. (c)
Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950.
(3) Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla,
I.; Schuler, F.; Rogers-Evans, M.; Muller, K. J. Med. Chem. 2010, 53,
3227.
(4) Kettle, J. G.; Ward, R. A.; Griffen, E. Med. Chem. Commun. 2010,
1, 331 and references cited therein.
(5) Kelly, M. G.; Kincaid, J.; Janagani, S.; Duncton, M. U.S. Patent
0205773, 2006; Chem. Abstr. 2006, 145, 336048.
(7) See the Supporting Information for a full discussion.
(8) (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752. (b) Lovering, F. Med. Chem. Commun. 2013, 4, 515.
(9) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson,
J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 18787.
(6) Duncton, M. A. J.; Ayala, L.; Kaub, C.; Janagani, S.; Edwards,
W. T.; Orike, N.; Ramamoorthy, K.; Kincaid, J.; Kelly, M. G. Tetra-
hedron Lett. 2010, 51, 1009.
(10) Barnes-Seeman, D.; Jain, M.; Bell, L.; Ferreira, S.; Cohen, S.;
Chen, X. H.; Amin, J.; Snodgrass, B.; Hatsis, P. ACS Med. Chem. Lett.
2013, 4, 514.
r
10.1021/ol401636d
XXXX American Chemical Society

of fluorine and cyclopropane may offer an ability to fine-tune
individual properties.
generated in solid form and as a single geometrical isomer.
In this paper, we disclose a method for preparing a wide
variety of racemic trans-2-(trifluoromethyl)cyclopropane
products by synthesizing trans-2-(trifluoromethyl)-
cyclopropylboronic acid MIDA ester, which functions as
a readily handled and air-stable, solid donor of a trans-
2-(trifluoromethyl)cyclopropyl group in Suzuki reac-
tions.16,17 In particular, we have focused on introducing
the trans-2-(trifluoromethyl)cyclopropyl group into
templates frequently encountered within drug discovery
laboratories, such as functionalized aromatics or hetero-
aromatic rings.
The limited use of 2-(trifluoromethyl)cyclopropanes
by chemists may, in part, be due to a small number of
techniques for synthesizing such compounds (Figure 1).11
For instance, the vast majority of methods for pre-
paring 2-(trifluoromethyl)cyclopropyl products rely on
a metal-catalyzed cyclopropanation of an alkene with
(trifluoromethyl)diazomethane 2, with the diazo species
generated in a step prior to cyclopropanation or in situ
during the cyclopropanation process.11ꢀ13 Uses of this
approach include studies by Morandi and Carreira on
ruthenium-catalyzed cyclopropanation of styrene starting
materials with (trifluoromethyl)diazomethane 2, gener-
ated in situ.13 However, only seven examples with styrenes
were detailed, and no examples with heteroaromatic
substrates were reported. A complementary technique
for preparing 2-(trifluoromethyl)cyclopropanes utilizes
a Suzuki reaction with dibutyl 2-(trifluoromethyl)-
cyclopropylboronate 3, which is itself also derived from
(trifluoromethyl)diazomethane 2.5,6 The disadvantage
with this approach is that the boronate coupling partner
3 is a liquid, and it is used as a mixture of cis- and trans-
isomers (ca. 2:3 ratio), giving rise to a mixture of geome-
trical isomers in the coupled products. Recently, another
method for synthesizing 2-(trifluoromethyl)cyclopropanes
has been reported. This approach uses a ruthenium-
catalyzed Kharasch reaction of alkenes with halothane
(F3CCHBrCl), followed by dehalogenation/cyclization.14
However, a large excess of halothane and magnesium
reagents are required, and mixtures of cis- and trans-
isomers are obtained in some cases. Again, no examples
withheteroaromaticsubstrates were reported. Othermeth-
ods for preparing 2-(trifluoromethyl)cyclopropanes have
included additions to β-(trifluoromethyl)vinyl sulfonium
salts with active methylene compounds.15 However, no
examples to provide 1-heteroaryl-2-(trifluoromethyl)-
cyclopropanes have been disclosed.
Figure 1. Synthesis of 2-(trifluoromethyl)cyclopropanes.
Our synthesis of trans-2-(trifluoromethyl)cyclopro-
pylboronic acid MIDA ester 5 began by examining
the addition of (trifluoromethyl)diazomethane 2 to vinyl-
boronic acid MIDA ester 418 under palladium-catalysis.5,6
Gratifyingly, this reaction proceeded uneventfully to give
a 61ꢀ87% yield of the cyclopropanated product after
column chromatography on silica gel (Scheme 1). To our
delight, the reaction provided only the trans-isomer as a
free-flowing solid. The trans-stereochemistry was con-
firmed from an X-ray crystallographic study after recrys-
tallization from 1,2-dichloroethane. In contrast, a similar
cyclopropanation reaction undertaken with vinylboronic
acid dibutyl ester provided dibutyl 2-(trifluoromethyl-
)cyclopropylboronate 3 as a liquid and a 2:3 mixture of
cis- and trans-isomers.5,6 The increase in stereoselectivity
observed for cyclopropanation of 4 may be attributed to
reaction of a bulky and conformationally rigid MIDA
ester, promoting reaction from only one face of the alkene.19
Importantly, the cyclopropanation reaction to provide
MIDA boronate 5 could be undertaken on a multigram
scale without any reduction in yield or stereochemical
integrity of the product. Similar to other MIDA esters,18ꢀ21
compound 5 requires no special handling and is stable to
Regardless of the limitations described above for dibutyl
2-(trifluoromethyl)cyclopropylboronate 3, the use of a
cross-coupling strategy to prepare 2-(trifluoromethyl)-
cyclopropanes is an attractive concept, as the method
can be applied to a diverse array of aryl and heteroaryl
substrates. Additionally, (trifluoromethyl)diazomethane 2
is used only once, in the preparation of a suitable boronate
coupling partner, which can then be utilized for multiple
Suzuki reactions. Such a coupling strategy would be even
more valuable if a suitable coupling partner could be
(11) For a review on the synthesis of (trifluoromethyl)cyclopropanes,
see: Grygorenko, O. O.; Artamonov, O. S.; Komarov, I. V.; Mykhailiuk,
P. K. Tetrahedron 2011, 67, 803.
(12) (a) Le Maux, P.; Juillard, S.; Simonneaux, G. Synthesis 2006,
1701. (b) Mykhailiuk, P. K.; Afonin, S.; Ulrich, A. S.; Komarov, I. V.
Synthesis 2008, 1757.
(16) Duncton, M.; Singh, R. Patent WO 075316, 2012; Chem. Abstr.
2012, 157, 76933.
(13) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49,
938.
(17) For a review on the benefits of boronic acid MIDA esters, see:
Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 42, 17.
(18) (a) Uno, B. C.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009, 65,
3130. (b) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.
(19) (a) Mancilla, T.; Contreras, R.; Wrackmeyer, B. J. Organomet.
Chem. 1986, 307, 1. (b) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2008, 130, 14084.
ꢀ
(14) Risse, J.; Fernandez-Zumel, M. A.; Cudre, Y.; Severin, K. Org.
ꢀ
ꢀ
Lett. 2012, 14, 3060.
(15) (a) Lin, H.; Shen, Q.; Lu, L. J. Org. Chem. 2011, 76, 7359. (b)
Kasai, N.; Maeda, R.; Furuno, H.; Hanamoto, T. Synthesis 2012, 44,
3489.
B
Org. Lett., Vol. XX, No. XX, XXXX

prolonged storage under benchtop conditions (ambient
temperature and air). Thus, the results above also provide
another illustration as to the advantages of MIDA boronate
chemistry, when compared to experiences with alterna-
tive boronic esters or the parent boronic acid. Importantly,
the synthesis of compound 5 adds another valuable building
block to the MIDA family of reagents, which are rapidly
emerging as a versatile toolbox of stable boronic acid surro-
gates, for drug discovery and natural product synthesis.20,21
Of special note were Suzuki reactions with a wide variety of
heteroaromatic coupling partners (entries 9ꢀ15). These were
particularly significant since a large percentage of marketed
drugs contain a heterocyclic core.24 Thus, Suzuki reactions
with MIDA boronate 5 may present a particularly useful
method for introducing a trans-(trifluoromethyl)cyclopropyl
group into a heterocyclic substrate. This is noteworthy since
previous studies to prepare (trifluoromethyl)cycloropyl pro-
ducts, using a 2 þ 1 cycloaddition between an alkene and
(trifluoromethyl)diazomethane, have detailed few examples
employing a heterocyclic starting material.11ꢀ13
Scheme 1. Synthesis and X-ray Structure of 5a
Table 1. Coupling with Halides or Pseudohalides
entry
X
yield of 7 (%)
1
2
3
4
I (6a)
78
78
65
54
OTf (6b)
Br (6c)
Cl (6d)
a Crystalimage simplified for clarity(see theSupportingInformation).
Next, we examined the use of (trifluoromethyl)cyclopropyl
MIDA boronate 5 in palladium(0)-catalyzed Suzuki reac-
tions (Tables 1 and 2).22 It was found that 5 could readily
participate in such cross-couplings.23 For example, Suzuki
reactions could be undertaken with aryl iodide, triflate,
bromide, or chloride starting materials, using a model
naphthyl example (Table 1). As expected, the yield of the
trans-2-(trifluoromethyl)cyclopropyl coupled product 7 was
greatest when starting from an aryl iodide or aryl triflate
(both giving a 78% yield; entries 1 and 2), as opposed to
starting from an aryl bromide or aryl chloride (65% and 54%
yield respectively; entries 3 and 4). Further reactions, pre-
dominately using bromo-containing starting materials due to
their commercial availability, demonstrate that a multitude
of functional groups commonly encountered in medicinal or
synthetic organic chemistry were tolerated in the coupling
partners (Table 2). For instance, compounds containing
fluoro, nitro, anilino, tetrazolone, alkyl, ketone, pentafluor-
osulfur, ether, ester, acetal, and lactam groups were not
affected under the reaction conditions, giving rise to the
expected trans-2-(trifluoromethyl)cyclopropyl coupled pro-
ducts in moderate to excellent yields (entries 1ꢀ15).
Taken together, the results presented above provide
a broad illustration of the utility of MIDA boronate 5
in Suzuki cross-couplings. Presumably, these reactions
occur in a similar fashion to couplings with other MIDA
boronates, via in situ release of the corresponding boronic
acid from the MIDA ester starting material under the
basic conditions encountered in the reaction media.25
Significantly, many of the 2-(trifluoromethyl)cyclopropyl
products described above are relatively low in mole-
cular weight and are compliant with “rule-of-three”
criteria26 describing attractive fragments for medicinal
chemists.27
In summary, this paper describes the synthesis of trans-
2-(trifluoromethyl)cyclopropylboronic acid MIDA ester 5
and its use in Suzuki cross-coupling reactions with aryl or
heteroaryl substrates. By virtue of its unique structure and
three-dimensional chiral framework, the introduction of a
trans-2-(trifluoromethyl)cyclopropyl group may present
a particularly useful fragment for chemists engaged in drug
discovery or materials science. Furthermore, our studies
provide another illustration as to the benefits of MIDA
boronate chemistry for solving a challenging synthetic
(20) For select examples of MIDA boronates in natural products
synthesis, see: (a) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am.
Chem. Soc. 2008, 130, 466. (b) Woerly, E. M.; Cherney, A. H.; Davis,
E. K.; Burke, M. D. J. Am. Chem. Soc. 2010, 132, 6941. (c) Lee, S. J.;
Anderson, T. M.; Burke, M. D. Angew. Chem., Int. Ed. 2010, 49, 8860.
(d) Brak, K.; Ellman, J. A. Org. Lett. 2010, 12, 2004. (e) Fujii, S.; Chang,
S. Y.; Burke, M. D. Angew. Chem., Int. Ed. 2011, 50, 7862. (f) Gray,
K. C.; Palacios, D. S.; Dailey, I.; Endo, M. M.; Uno, B. E.; Wilcock,
B. C.; Burke, M. D. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 2234.
(21) Grob, J. E.; Nunez, J.; Dechantsreiter, M. A.; Hamann, L. G.
J. Org. Chem. 2011, 76, 10241.
(24) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887.
(25) (a) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2009, 131, 6961. (b) Lennox, A. J. J.; Lloyd-Jones, G. C. Israel J. Chem.
2010, 50, 664.
(26) Congreve, M.; Carr, R.; Murray, C.; Jhoti, H. Drug Discovery
Today 2003, 8, 876.
(27) See the Supporting Information for full details.
(28) For asymmetric syntheses of 2-(trifluoromethyl)cyclopropanes,
see ref 12a and Morandi, B.; Mariampillai, B.; Carreira, E. M. Angew.
Chem., Int. Ed. 2011, 50, 1101.
(22) (a) Wallace, D. J.; Chen, C. Tetrahedron Lett. 2002, 43, 6987.
(b) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(23) For a review, see: Gagnon, A.; Duplessis, M.; Fader, L. Org.
Prep. Proced. Int. 2010, 42, 1 and references cited therein.
(29) We have undertaken
a
chiral synthesis of
a trans-
2-(trifluoromethyl)cyclopropylboronic acid equivalent. Results will be
reported in due course.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Suzuki Couplings with Boronate Ester 5*
* Conditions A: Pd(OAc)2, Cy3P, Cs2CO3 or K2CO3, toluene, H2O, heat. Conditions B: Pd(OAc), RuPhos, K2CO3, toluene, H2O, heat. a Conditions
A with Cs2CO3 at 80 °C. b Conditions B at 100 °C. c Conditions A with Cs2CO3 at reflux. d Conditions B at 115 °C. e Conditions B at 80 °C. f Conditions A
with K2CO3 at reflux. g Conditions A with K2CO3 at 115 °C (see the Supporting Information for individual reaction conditions).
problem. Future work will focus on a homochiral synthesis
of trans-2-(trifluoromethyl)cyclopropyl products28,29 and
a further examination of the medicinal chemistry qualities
associated with the trans-2-(trifluoromethyl)cyclopropyl
group.
Rigel, Inc. analytical chemistry for high-resolution mass
spectrometry.
Supporting Information Available. Details of known
2-(trifluoromethyl)cyclopropanes. Discussion of log P for
2-(trifluoromethyl)cyclopropanes, experimental details,
and analytical data for compounds 5, 7, and 9aꢀo. X-ray
data for compound 5 (CIF; see also CCDC 955803). This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We thank Dr. Peter S. White
(University of North Carolina at Chapel Hill) for perform-
ing the X-ray analysis with compound 5. We also
thank Prof. Martin D. Burke (University of Illinois at
UrbanaꢀChampaign) for insightful discussions regard-
ing the synthesis and use of MIDA boronates and
Mark Irving, Van Ybarra, and Duayne Tokushige of
The authors declare the following competing financialinterest(s): The
authors are employees of Rigel, Inc. and receive compensation, includ-
ing stock-based awards.
D
Org. Lett., Vol. XX, No. XX, XXXX