Two-step cyanomethylation protocol: Convenient access to functionalized aryl- and heteroarylacetonitriles

Article abstract of DOI:10.1021/ol503479g

A two-step protocol has been developed for the introduction of cyanomethylene groups to metalated aromatics through the intermediacy of substituted isoxazoles. A palladium-mediated cross-coupling reaction was used to introduce the isoxazole unit, followed by release of the cyanomethylene function under thermal or microwave-assisted conditions. The intermediate isoxazoles were shown to be amenable to further functionalization prior to deprotection of the sensitive cyanomethylene motif, allowing access to a wide range of aryl- and heteroaryl-substituted acetonitrile building blocks.

Full text of DOI:10.1021/ol503479g

Letter
pubs.acs.org/OrgLett
Two-Step Cyanomethylation Protocol: Convenient Access to
Functionalized Aryl- and Heteroarylacetonitriles
Peter J. Lindsay-Scott,* Aimee Clarke, and Jeffery Richardson
Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom
S
* Supporting Information
ABSTRACT: A two-step protocol has been developed for the
introduction of cyanomethylene groups to metalated aromatics
through the intermediacy of substituted isoxazoles. A
palladium-mediated cross-coupling reaction was used to
introduce the isoxazole unit, followed by release of the
cyanomethylene function under thermal or microwave-assisted
conditions. The intermediate isoxazoles were shown to be amenable to further functionalization prior to deprotection of the
sensitive cyanomethylene motif, allowing access to a wide range of aryl- and heteroaryl-substituted acetonitrile building blocks.
rylacetonitriles serve as versatile intermediates in organic
synthesis due to their ability to undergo a broad range of
but Velcicky and Schmalz successfully harnessed this feature to
access a range of α-aryl nitriles, including a single heterocyclic
example (2-pyridylacetonitrile).
A
functional group transformations. The methylene protons are
reactive toward electrophiles by virtue of their acidity,1 while the
cyano group can be readily transformed into various other
functionalities, including amides, amines, ketones, and acids.2
The arylacetonitrile motif itself can also be used as a building
block in the construction of heterocycles.3 In addition to their
popularity as synthetic intermediates, substituted arylacetoni-
triles have appeared in several pharmaceutically active molecules
recently.4
We were intrigued by the possibility of introducing acetonitrile
units into aromatic molecules through the intermediacy of 3,5-
disubstituted isoxazoles. This additional substitution might allow
us to more readily intercept the cross-coupled intermediates
bearing an intact isoxazole group 3, which could then undergo
further functionalization, prior to isoxazole deprotection. We
postulated that functionalized aryl reagents 1 could be coupled to
bromoisoxazole 2,15 bearing an ester group in the 3-position, and
then deprotected in a separate step via intermediates 4 and 5 to
reveal the target arylacetontriles 6 (Scheme 1). The ester
Classically, the α-aryl nitrile motif has been installed by (i)
nucleophilic substitution reactions involving cyanide and benzyl
halides,5 (ii) photolytic reactions,6 (iii) dehydrations,7 and (iv)
nucleophilic aromatic substitution reactions followed by
decarboxylation.8 More recently, several methods have emerged
that employ the coupling of functionalized acetonitriles with aryl
halides under the action of palladium catalysis. Since Migita and
co-workers demonstrated the coupling of cyanomethyltributyltin
with aryl bromides in 1984,9 this methodology has been
extended to include the coupling of aryl metal reagents with
bromoacetonitrile,10 the coupling of trimethylsilylacetonitrile
Scheme 1. Proposed Route to Arylacetonitriles 6
11
with aryl bromides in the presence of ZnF2 and the
decarboxylative coupling of cyanoacetate salts with aryl halides
and triflates.12 These methods have the potential to suffer from
overarylation, where the initially formed arylacetonitriles might
undergo further arylation. However, judicious choice of reaction
conditions enabled the selective formation of monoarylated
products, including a single heterocyclic example (3-thiophe-
neacetonitrile).12 A deaminative metal-free approach was also
recently reported.13
In 2011, a conceptually different approach was realized by the
group of Velcicky and Schmalz,14 where they showed that
isoxazole 4-boronic acid pinacol ester could undergo efficient
cross-coupling with aryl halides to furnish arylacetonitriles
directly. Because of the acidic nature of the 3- and 5-positions
of 4-substituted isoxazoles, their cross-couplings are often
complicated by side reactions and decomposition pathways,
function would serve to both (i) protect the molecule toward
mildly basic conditions (typically employed in cross-coupling
reactions) and (ii) trigger a hydrolysis/decarboxylation cascade
sequence under more forcing conditions.16 We anticipated that
loss of carbon dioxide would result in spontaneous N−O bond
cleavage, leading to arylcyanoacetates 5 after tautomerization.
Loss of acetic acid would then deliver the α-aryl nitriles 6.
Received: December 2, 2014
© XXXX American Chemical Society
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To test this hypothesis, bromoisoxazole 2 was coupled with a
range of substituted aryl boron and tin compounds 1. We were
pleased to find that this cross-coupling could be readily
accomplished under palladium-catalyzed conditions with a
range of commercially available potassium aryltrifluoroborate
salts 7 in yields of 45−78% (with concomitant transesterifica-
tion)17 using conditions similar to those developed by Molander
and co-workers for the coupling of 3,5-dimethylsubstituted
isoxazoles (Scheme 2).18,19
biphenyl 10 (at this stage the ratio of products could not be
quantified accurately, but a 12:1 ratio of 12b:13 was observed
after deprotection of the isoxazole; see Scheme 3 below).
Scheme 3. Deprotection of Cross-Coupled Isoxazoles 8 To
Give Arylacetonitriles 12
Scheme 2. Cross-Coupling of Potassium Aryltrifluoroborates
a
7 with Isoxazole Bromide 2
a
b
Starting material contained compound 9 as an impurity. Material
contained compound 13 as an impurity after flash column
c
chromatography. Material contained 4,4′-diacetylbiphenyl 11 as an
d
impurity after flash column chromatography. Reaction performed in
NMP/H2O (0.5 M) at 175 °C for 20 min under microwave
e
irradiation. Reaction performed in NMP/H2O (0.5 M) at 200 °C for
20 min under microwave irradiation (see the Supporting Information).
A range of other functional groups were also found to be
tolerated under the reaction conditions (see 8c−r). It was
necessary to utilize a boronic acid to synthesize 4-cyano-
substituted compound 8n (74% yield), as the corresponding
potassium 4-cyanophenyltrifluoroborate salt failed to generate
the desired product under the standard reaction conditions.
With a broad range of cross-coupled compounds 8 bearing the
substituted isoxazole unit in hand, we set out to investigate the
deprotection step to reveal the target arylacetonitriles 12
(Scheme 3). A range of bases and solvents were screened to
accomplish this transformation, and gratifyingly, we found that
the desired compounds could be formed by heating the cross-
coupled intermediates in a mixture of DMF and water in the
presence of potassium fluoride.14 Cross-coupled compounds
that were carried into this isoxazole deprotection step containing
minor amounts of debrominated material 9 (see Scheme 2) gave
clean arylacetonitriles after purification by flash column
chromatography, presumably because 9 decomposed to volatile
components under the reaction conditions.17
a
b
Reactions performed in sealed vials. Material contained compound 9
c
as an impurity after flash column chromatography. Material contained
compound 10 as an impurity after flash column chromatography.
d
e
XPhos-Pd G2 (5 mol %) utilized in place of SPhos-Pd G2. Material
contained 4,4′-diacetylbiphenyl 11 as an impurity after flash column
chromatography (see the Supporting Information).
While both fluoro- (8a, 61% yield) and chloro-substitution
(8b, 83% yield) were tolerated in the 4-position, the
corresponding coupling with potassium 4-bromophenyltrifluor-
oborate did not yield any of the desired product under the
reaction conditions. In fact, the chloro product 8b underwent
further cross-coupling to a small extent with the starting
trifluoroborate salt under the reaction conditions to give
Interestingly, the Weinreb amide 8p and 3-nitro substrate 8q
did not give good conversion to the intended products 12p and
12q under the standard deprotection conditions. Further
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Letter
investigation of these problematic substrates revealed that
microwave-assisted reaction conditions at higher temperatures
were required to facilitate the smooth deprotection of 8p to 12p
in 51% yield and of 8q to 12q in 62% yield.
Scheme 5. Deprotection of Cross-Coupled Isoxazoles 15 To
Give Heteroarylacetonitriles 17
Having shown that both potassium aryltrifluoroborates and
arylboronic acids were competent coupling partners for isoxazole
bromide 2, we turned our attention to the cross-coupling of
heteroaryl compounds (Scheme 4). Although we were unable to
Scheme 4. Cross-Coupling of Heteroarylstannanes 14 with
a
Isoxazole Bromide 2
a
Reaction performed in NMP/H2O (0.5 M) at 200 °C for 20 min
b
under microwave irradiation. Starting material contained compound
16 as an impurity (see the Supporting Information).
Scheme 6. Functionalization of Cross-Coupled Isoxazole 8f
a
b
Reactions performed in sealed vials. Material contained compound
16 as an impurity after flash column chromatography (see the
Supporting Information).
effect the cross-coupling of potassium heteroaryltrifluoroborates
or heteroarylboronic acids efficiently with isoxazole bromide 2,
we were able to successfully carry out the analogous cross-
couplings with stannanes under the action of palladium catalysis
using conditions inspired by those of Fu and co-workers.20 Thus,
pyridines 15a and 15b, thiazole 15c, benzothiophene 15d, and
indole 15e were formed in yields of 63−86% from the
corresponding stannane reagents.
Next, we investigated the conversion of these heteroaryl cross-
coupled compounds 15a−e to the corresponding heteroaryla-
cetonitriles 17a−e under similar reaction conditions as before
(Scheme 5). We observed that acetontriles 17a, 17b, and 17c
formed in good yields under thermal conditions, while the
benzothiophene 17d and indole 17e required microwave-
assisted reaction conditions at higher temperatures to generate
the requisite products in 68% and 81% yields, respectively.
Having explored the scope and limitations of this two-step
cyanomethylation protocol, we examined the possibility of
functionalizing the intermediate cross-coupled isoxazole 8f prior
to the deprotection step. We hoped to differentiate two
cyanomethylene groups in the same molecule by utilizing the
protected nature of the substituted isoxazole unit, which would
allow functionalization of the remaining unprotected group. To
this end, cross-coupled isoxazole 8f was converted to the ester 18
in 91% yield (Scheme 6). Subjection of ester 18 to our standard
thermal deprotection conditions furnished the corresponding α-
aryl nitrile 19 in 74% yield (with concomitant hydrolysis of the
ester function to the acid).21
a
Standard conditions: KF (3 equiv), 1:1 DMF/H2O (0.5 M), 125 °C,
16 h.
alkylation of 8f with 1,5-dibromopentane led to functionalized
product 20 in 50% yield, which was deprotected to give
arylacetonitrile 21 (75% yield). Likewise, α-arylation of 8f led to
the formation of diphenylacetonitrile 22, which was observed to
be prone to oxidation to the corresponding benzophenone.22
With this in mind, the diphenylacetonitrile 22 was oxidized under
basic conditions and subsequently subjected to the standard
deprotection protocol to generate α-aryl nitrile 23 in 32% yield
over three steps from 8f. In contrast, the alkylation and α-
arylation of 1,3-phenylenediacetonitrile under reaction con-
ditions similar to those shown in Scheme 6 led to mixtures of
compounds that were challenging to purify.
Finally, we examined whether our two-step cyanomethylation
protocol could be carried out in a one-pot manner (Scheme 7).
Thus, reaction of trifluoroborate salt 24 and bromide 2 was
followed by the addition of potassium fluoride, DMF, and water
and further heating to give arylacetonitrile 12l in 63% overall
yield.
Next, we attempted further differentiation through the
alkylation and arylation of cross-coupled isoxazole 8f. Thus,
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Letter
a
(8) Stazi, F.; Maton, W.; Castoldi, D.; Westerduin, P.; Curcuruto, O.;
Bacchi, S. Synthesis 2010, 3332.
Scheme 7. One-Pot Formation of Arylacetonitrile 12l
(9) Kosugi, M.; Ishiguro, M.; Negishi, Y.; Sano, H.; Migita, T. Chem.
Lett. 1984, 1511.
(10) (a) Frejd, T.; Klingstedt, T. Synthesis 1987, 40. (b) Yang, Y.; Tang,
S.; Liu, C.; Zhang, H.; Suna, Z.; Lei, A. Org. Biomol. Chem. 2011, 9, 5343.
(11) (a) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
(b) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330.
(12) Shang, R.; Ji, D.-S.; Chu, L.; Fu, Y.; Liu, L. Angew. Chem., Int. Ed.
2011, 50, 4470. For a related intramolecular decarboxylative α-allylation
reaction of nitriles, see: Recio, A., III; Tunge, J. A. Org. Lett. 2009, 11,
5630.
a
Reactions performed in sealed vials.
(13) Wu, G.; Deng, Y.; Wu, C.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2014, 53, 10510.
(14) Velcicky, J.; Soicke, A.; Steiner, R.; Schmalz, H.-G. J. Am. Chem.
Soc. 2011, 133, 6948.
(15) For the preparation of methyl 4-bromo-5-methylisoxazole-3-
carboxylate (2), see: Imanshi, Y.; Awai, N.; Hirai, M.; Hosaka, T.; Kono,
R. Patent Appl. 037271, 2005.
(16) For examples of the decarboxylative opening of isoxazoles, see:
(a) Zhoua, P.; Natalea, N. R. Synth. Commun. 1998, 28, 3317. (b) Perez,
C.; Janin, Y. L.; Grierson, D. S. Tetrahedron 1996, 52, 987. (c) Ciller, J.
A.; Seoane, C.; Soto, J. L. Heterocycles 1984, 22, 1989.
(17) In some cases, compound 9 was observed in the crude reaction
mixtures and it was not always possible to separate this from the
products. The amount of 9 was quantified by analysis of the 1H NMR
spectra, and the mixture of compounds was taken through into the
isoxazole deprotection step.
In summary, we have developed a two-step cyanomethylation
protocol whereby bromoisoxazole 2 was shown to couple
effectively with potassium aryltrifluoroborate salts to give aryl
isoxazoles that were deprotected to give the target α-aryl nitriles.
Notably, five heteroarylacetonitriles were also accessed via their
corresponding heteroarylstannanes, offering considerable ad-
vantage over existing cyanomethylation methodologies. The
cross-coupled isoxazole intermediates were also shown to be
amenable to functionalization prior to deprotection, allowing
facile access to challenging molecular scaffolds bearing two
differently substituted cyanomethylene units.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(18) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009,
74, 973.
(19) SPhos-Pd G2 = chloro(2-dicyclohexylphosphino-2′,6′-dime-
thoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) and
XPhos-Pd G2 = chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-
1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).
(20) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
6343.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lindsay-scott_peter@lilly.com.
(21) The enzymatic hydrolysis of 1,3-phenylenediacetonitrile has
previously been reported: Cohen, M. A.; Sawden, J.; Turner, N. J.
Tetrahedron Lett. 1990, 31, 7223.
Notes
The authors declare no competing financial interest.
(22) For the oxidative decyanation of diphenylacetonitriles, see: Kulp,
S. S.; McGee, M. J. J. Org. Chem. 1983, 48, 4097.
ACKNOWLEDGMENTS
We thank Christopher Reutter (Eli Lilly) for his assistance with
high resolution mass spectrometry samples.
■
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