Development of a palladium-catalyzed α-arylation of cyclopropyl nitriles

Article abstract of DOI:10.1021/ol5030426

1,1-Disubstituted aryl cyclopropyl nitriles are useful moieties in biologically active compounds and provide access to a range of cyclopropyl derivatives. Herein, we describe the development of a palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl, and cyclopentyl nitriles that affords these functional groups in one step from a variety of aryl bromides in good to excellent yields. Furthermore, we demonstrate the transformation of aryl cyclopropyl nitriles into aryl trifluoromethyl cyclopropanes.

Full text of DOI:10.1021/ol5030426

Letter
pubs.acs.org/OrgLett
Development of a Palladium-Catalyzed α‑Arylation of Cyclopropyl
Nitriles
Jamie M. McCabe Dunn,* Jeffrey T. Kuethe, Robert K. Orr, Matthew Tudge,†
and Louis-Charles Campeau†
Department of Process Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033,
United States
S
* Supporting Information
ABSTRACT: 1,1-Disubstituted aryl cyclopropyl nitriles are useful
moieties in biologically active compounds and provide access to a range
of cyclopropyl derivatives. Herein, we describe the development of a
palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl, and cyclo-
pentyl nitriles that affords these functional groups in one step from a
variety of aryl bromides in good to excellent yields. Furthermore, we
demonstrate the transformation of aryl cyclopropyl nitriles into aryl trifluoromethyl cyclopropanes.
yclopropanes are structural motifs found in many natural
products and biologically active molecules.1 The unique
relationships in medicinal chemistry because fragment coupling
of this useful synthon would speed drug discovery efforts.3a
Inspired by the recent advances in palladium-catalyzed α-arylation
of esters9 and nitriles,10 we investigated the direct α-arylation of
cyclopropyl nitrile (2a) and cyclopropyl ester (2b) for the
preparation of 1,1-disubstituted aryl cyclopropanes.11 Herein, we
report the development of an effective protocol for the direct
α-arylation of cyclopropyl nitriles with aryl bromides to afford
1,1-aryl cyclopropyl nitriles and their subsequent conversion to
1,1-aryl trifluoromethyl cyclopropanes.
C
steric, electronic and conformational properties of cyclopropanes
render them attractive and privileged pharmacophores for
medicinal chemistry.2 The appeal of 1,1-disubstituted cyclo-
propanes is the enhanced ability to lock two geminal or vicinal
substituents conformationally into a bioactive conformation,
often providing increased potency (Figure 1).3 Another potential
benefit, especially in the case of arylcyclopropanes,
is the ability to block/divert metabolism at metabolically labile
benzylic positions.4
Our investigations began by probing the cross-coupling
between cyclopropyl nitrile 2a and ester 2b with aryl bromide
1.12 Attempts to apply Verkade’s10 conditions for the α-arylation
of nitriles [NaHMDS, Pd(OAc)2, and P(i-BuNCH2CH2)3N] or
Hartwig’s13 conditions for the α-arylation of esters [Cy2NLi
and {[P(t-Bu)3]PdBr}2] or [base, Zn*, Pd source and Q-Phos/
{[P(t-Bu)3]PdBr}2] to form quaternary centers were unsuccess-
ful. To identify a desirable starting point for reaction develop-
ment, we employed high-throughput experimentation (HTE)14
to interrogate a large array of reaction parameters simultaneously.
Our initial screen employing 1-(benzyloxy)-4-bromobenzene
(1a) yielded no product formation with ester 2b;15 however,
when Josiphos catalyst SL-J009-1 was used, a low yield (<5%) of
aryl nitrile 3a was observed. Using these conditions as a starting
point, we were able to improve the efficiency of the catalytic
system by optimizing the base, solvent, and reaction temperature.
Lithium hexamethyldisilazide (LiHMDS) and cyclopentyl
methyl ether (CPME) at 80 °C provided the cleanest conversion
of bromide 1a to 3a as assessed by HPLC analysis; however, only
15% yields were obtained upon scale-up. Finally, rescreening of
palladium source and ligands, employing the optimal base,
solvent, and temperature, revealed BINAP as the ideal ligand for
this reaction (section C, Scheme 1), which are similar conditions
Figure 1. Bioactive 1,1-disubstituted cyclopropanes.
The utility of cyclopropane motifs has prompted intense
research directed at discovering efficient and high-yielding
methods for their preparation.3,5 In the context of a drug
discovery effort, we became interested in the preparation of
1,1-disubstituted aryl cyclopropanes of general Type 1 (section A,
Scheme 1). Traditional synthetic methods to access compounds
of Type 1 require construction of the cyclopropane ring, often via
double alkylation of 1,2-dihaloethanes6 or the Corey−Chaykovsky
reaction.7 Direct access via a single step transformation8 would
be enormously valuable when studying structure−activity
Received: October 16, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Scheme 1. Development of the Direct Palladium-Catalyzed α-Arylation of Cyclopropyl Nitrile 2a
Table 1. Scope of the Direct α-Arylation of Cyclopropyl Nitrile
a
b
c
Percent isolated yields reported. Single diastereomer isolated. Product co-eluted with ligand during chromatography, leading to material loss.
d
Complete TBS group cleavage was observed via HPLC yielding 1p.
B
dx.doi.org/10.1021/ol5030426 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
previously developed by Hartwig and Culkin for the coupling
acyclic nitriles with aryl bromides.16 In the final optimized
protocol, a mixture of bromide 1a and cyclopropyl nitrile 2a in
CPME was first treated with a preactivated mixture of Pd2dba3
and BINAP in THF17 followed by LiHMDS. This solution was
then heated to 80 °C until complete consumption of starting
material was observed. This robust protocol was performed on
10 g scale to produce adduct 3a in 75% yield.
Table 2. Scope of Direct α-Arylation of Cyclobutyl- and
Cyclopentyl Nitrile
Having successfully demonstrated the application of our
protocol to 4-(benzyloxy)bromobenzene (1a), the scope of the
aryl bromide component was evaluated. Many substrates showed
good reactivity under the standard reaction conditions (Table 1).
As seen with the benzyloxy case (entry 1, Table 1), a THP-
protected phenol was well-tolerated under the reaction con-
ditions (entry 2). Conversely, base-labile silyl-protected phenols
were cleaved to the corresponding 4-bromophenol with no
reaction (entry 17). Reaction of 4-bromophenol failed
to provide any of the desired product, and the starting material
was recovered intact (entry 16). However, silyl-protected benzyl
alcohols were tolerated18 (entries 5 and 6) along with ortho-
substitution on the aromatic ring (entries 6 and 7). Aryl bromides
containing electron-donating groups and electron-withdrawing
groups underwent α-arylation, providing moderate to high
yields (59−79%) of coupled products (entries 1−4, 8, and 10).
The products obtained by reacting bromochloroarenes 1f or 1h
afforded selective coupling at the bromide, leaving the chloride
intact as a useful handle for further functionalization (entries 6
and 8). Reaction of 1,4-dibromobenzene (1i) in the presence of
an excess of base and nitrile 2a provided the bis-aryl cyclopropyl
product 3i, thus demonstrating the feasibility of dicyclopropana-
tions. Heterocyclic aryl bromides provided substituted pyridines,
imidazoles, and indoles (entries 13, 14, and 15). Lastly, reaction of
2-phenylcyclopropanecarbonitrile with 2-bromonaphthalene
(1l) provided the desired product 3l as a single diastereomer
(entry 12).
Cyclohexyl nitrile is the smallest reported monocyclic nitrile
reported to undergo successful direct Pd-catalyzed α-arylation.10a,c
Given our success with cyclopropyl nitrile 2a, we postulated
that other smaller ring nitriles would also be reactive under
our conditions. We were gratified to find that this was the case,
and both aryl and heteroaryl bromides coupled with cyclobutyl
nitrile 4a and cyclopentyl nitrile 4b in high yields (Table 2).
With a method in hand to generate 1,1-disubstituted aryl
cyclopropyl nitriles, we elected to demonstrate their synthetic
utility in the synthesis of trifluoromethylcyclopropanes.10a,b
While the nitrile functional group of 1,1-disubstituted aryl
cyclopropyl nitriles had been transformed to an aldehyde, acid,
alcohol, difluoromethyl, and an amide,19 the conversion of
1,1-disubstituted aryl cyclopropyl nitriles to a 1,1-disubstituted
aryl trifluoromethyl cyclopropane had not been demonstrated.
This is particularly relevant since the cyclopropyltrifluoromethyl
group has recently been identified as an attractive tert-butyl
replacement in medicinal chemistry owing to its increased
metabolic stability.20 The conventional method to synthesize
1,1-disubstituted aryl trifluoromethyl cyclopropanes employs
diazomethane, which raises safety concerns, especially on a large
scale.20,21
a
Isolated yields reported.
Scheme 2. Synthesis of Cyclopropyltrifluoromethyl
Compounds
(3 equiv) at 60 °C provided the desired 1,1-disubstituted aryl
trifluoromethyl cyclopropanes 6 and 8 in 92% and 87% yields,
respectively.22 To our knowledge, this is the first example of the
synthesis of a 1,1-disubstituted aryl trifluoromethyl cyclo-
propane starting from a cyclopropyl nitrile (via a cyclopropyl
acid) and provides a general method to cyclopropyltrifluor-
omethyl arenes. Further scope and limitations of this trans-
formation are being explored and will be the subject of a separate
publication.
In conclusion, we discovered conditions for a single-step route
to 1,1-disubstituted aryl cyclopropyl nitriles via high-throughput
experimentation. Under optimized conditions, the reaction
was effective on a variety of aryl and heteroaryl bromides to
afford adducts in high yield. Furthermore, cyclobutyl nitrile
4a and cyclopentyl nitrile 4b were also effective substrates in
the coupling reaction. Lastly, we expanded the utility of aryl
cyclopropyl nitriles by transforming them into cyclopropyl
trifluoromethyl arenes.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental data and characterization of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
We chose to demonstrate the conversion of the nitrile group
on substrates 1h and 7 to a cyclopropyltrifluoromethyl group,
since these substrates provide handles for further functionaliza-
tion. Hydrolysis of cyclopropyl nitrile 1h and 7 with LiOH
in MeOH provided the desired cyclopropyl acid (Scheme 2).
Treatment of the crude cyclopropyl carboxylic acids with Fluolead
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jamie.mccabe.dunn@merck.com.
C
dx.doi.org/10.1021/ol5030426 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Present Address
†Department of Process Chemistry, Merck Research Laboratories,
126 E Lincoln Ave, Rahway, NJ 07065.
Letter
1690. (e) Uno, M.; Seto, K.; Takahashi, S. J. Chem. Soc., Chem. Commun.
1984, 932.
(11) Cyclopropyl nitrile is found to have lower acidity and a unique
carbanion structure and reactivity when compared to acyclic and larger
ring cyclic nitriles. See: Juchnovski, I. N.; Tsenov, J. A.; Binev, I. G.
Spectrochim. Acta Part A 1996, 52, 1145.
(12) To our knowledge, the direct Pd-catalyzed α-arylation of
cyclopropyl-derived nitriles or cyclopropyl esters has not been reported.
For a report on deprotonation kinetics of cyclopropanes, see: Van
Wunen, W. Th.; Steinberg, H.; De Boer, TH. J. Tetrahedron 1972, 28,
5423.
(13) (a) Hama, T.; Ge, S.; Hartwig, J. F. J. Org. Chem. 2013, 78, 8250.
(b) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545.
(14) (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A.
J. Am. Chem. Soc. 2008, 130, 9257. (b) Schultz, S. C.; Krska, S. W. Acc.
Chem. Res. 2007, 40, 1320. (c) Schmink, J. R.; Bellomo, A.; Berritt, S.
Aldrichimica Acta 2013, 46, 71.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Junling Gao (Merck Research Laboratories,
Kenilworth) for high-resolution mass spectroscopy work, Peter
Dormer (Merck Research Laboratories, Kenilworth) for help
with the carbon−fluorine coupling interpretations, and Rebecca
Ruck (Merck Research Laboratories, Kenilworth) and Cameron
Cowden (Merck Research Laboratories, Rahway) for helpful
advice and guidance during the preparation of this manuscript.
(15) Unsuccessful reactions employing 2b may be due to the instability
of the deprotonated ester at elevated temperatures; see: Haner, R.;
Maetzke, T.; Seebach, D. Helv. Chim. Acta 1986, 69, 1655.
̈
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