Decarboxylative benzylation and arylation of nitriles

Article abstract of DOI:10.1039/c1cc16011g

Decarboxylative benzylation of nitriles is achieved via coupling of metallated nitriles with Pd-π-benzyl complexes that are generated in situ from cyanoacetic benzyl esters. In addition, decarboxylative couplings of α,α-disubstituted 2-methylfuranyl cyano

Full text of DOI:10.1039/c1cc16011g

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COMMUNICATION
Decarboxylative benzylation and arylation of nitrileswz
Antonio Recio, III, Jeffrey D. Heinzman and Jon A. Tunge*
Received 27th September 2011, Accepted 12th October 2011
DOI: 10.1039/c1cc16011g
Decarboxylative benzylation of nitriles is achieved via coupling
of metallated nitriles with Pd-p-benzyl complexes that are
generated in situ from cyanoacetic benzyl esters. In addition,
decarboxylative couplings of a,a-disubstituted 2-methylfuranyl
cyanoacetates can lead to either decarboxylative arylation or
benzylation depending on the reaction conditions.
Our initial studies began by determining competent catalytic
conditions for achieving decarboxylative benzylation (DcB) of
nitriles with ‘‘simple’’ aromatic and heteroaromatic benzyl esters.
Previous reports involving the DcB of alkynes and ketones
suggested that Pd-p-benzyl formation was difficult with benzyl
esters that lacked extended conjugation, so coupling of simple
benzene-derived esters was difficult.11a Interestingly, our initial
studies revealed that treatment of a benzyl cyanoacetate with
Pd(PPh3)4 resulted in oxidative addition of the benzyl ester, but
decarboxylation was followed by protonation to form
NCCH(Me)Ph rather than the desired C–C bond formation
(Table 1, entry 1). Gratifyingly, conditions developed by Hiyama
for cross-coupling of benzyl carbonates (cond. B)12a proved to be
excellent for formation of Pd-p-benzyl complexes, allowing for
efficient carbon–carbon bond formation with simple benzyl
alcohol derivatives (e.g. Table 1, entry 2).
Recently there has been much interest in developing catalytic
decarboxylative cross-coupling reactions as alternatives to
traditional cross-coupling reactions.1 In 2009, our group
reported that the decarboxylative allylation of cyanoacetic
esters (DMSO pKa B 22–33)2 proceeded by in situ generation
of
a metallated nitrile species under formally neutral
conditions.3,4 Traditionally, generation of metallated nitriles
takes place under highly basic conditions, requiring a metal
hydride, alkyl lithiate,5 or lithium amide base.6,7 Alternatively,
Flemming, Knochel and others8 have accessed metallated
nitriles via treatment of a-halo nitriles with Grignard
reagents.9 The resulting metallated nitriles are readily alkyl-
ated with a variety of electrophiles, including benzyl halides.6
In our efforts to develop methods for benzylation that
occur under mild conditions and avoid the use to toxic benzylic
halides,10 we hypothesized that decarboxylative benzyl-
ation11,12 would allow one to synthesize benzylated nitriles
from activated benzyl alcohol derivatives. Herein, we report
the decarboxylative benzylation of nitriles via the likely inter-
mediacy of Pd-p-benzyl complexes (eqn (1)).12 In addition, we
disclose that appropriate modification of the palladium
catalyst allows one to achieve either decarboxylative benzyl-
ation or decarboxylative arylation of nitriles with furans
derived from furylmethyl esters (eqn (2)).
To briefly probe the scope of benzyl electrophiles that
are compatible with decarboxylative benzylation, a variety
of a-methyl-a-phenyl cyanoacetates were synthesized and
subjected to the standard reaction conditions. Interestingly,
substrates with electron-donating substituents (Table 1,
entry 3) and electron-withdrawing functionalities (entries 4, 5)
both provided benzylated products in good yields. The DcB
reaction was not affected by ortho-substitution (entry 6)
providing excellent conversion to the benzylated product.
Furthermore, both the a-methyl- and b-methyl naphthyl cyano-
esters (entries 7, 8) were competent substrates for DcB coupling.
Given the pharmaceutical relevance of heterocyclic arenes,13
we investigated arylmethylations utilizing several hetero-
aromatic benzyl alcohol moieties. Indeed, treatment of a,a-
disubstituted 2-methyl thiophenyl, 3-methyl thiophenyl and
3-methyl furanyl benzyl esters (Table 1, entries 9–11) resulted
in smooth conversion to the arylmethylated products in
good yields. Other heteroaromatic benzyl cyanoesters were
subjected to the reaction conditions listed in Table 1: as
shown, 2-methyl benzofuran (entry 13), N-boc protected
3-methyl indole (entry 14), and 2-methyl pyridine (entry 15)
were all converted to the arylmethylated products, albeit with
dramatically reduced yields.
(1)
(2)
2010 Malott Hall, 1251 Wescoe Hall Dr, Lawrence, KS USA.
E-mail: tunge@ku.edu; Fax: 785-864-5396; Tel: 785-864-4136
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc16011g
(3)
c
142 Chem. Commun., 2012, 48, 142–144
This journal is The Royal Society of Chemistry 2012

Table 1 Decarboxylative benzylation of nitriles
Table 2 Catalyst screening
Cond./
yield Entry Product
Cond./
yield
Entry Pd source Ligand
Solvent benzyl. : aryl. : prot.
Entry Product
1
2
3
4
5
Pd(PPh3)4 None
CpPd(allyl) dppe
CpPd(allyl) dppf
CpPd(allyl) BINAP
THF 14 : 85 : 1
1
2
A/0%
THF o5 : o5 : 490
THF 45 : o10 : 45
THF 85 : o5 : 10
9
A/88%
B/87%
CpPd(allyl) (S) DTBMSEGPHOS THF 89a : 11 : trace
a
3
4
5
6
B/86% 10
B/75% 11
B/75% 12
B/93% 13
A/87%
A/86%
Ba/65%
A/50%
Chiral stationary phase chromatography: 11% ee.
the screening was conducted with enantioenriched (S)-DTBM
SEGPHOS, the product was analyzed by chiral stationary
phase HPLC. Unfortunately, the arylmethylated product was
formed in low ee (11%).
With the newly found reaction conditions, Pd(PPh3)4 to
facilitate arylation and CpPd(allyl)/(S)-DTBM SEGPHOS for
generation of the arylmethylated products, we then investi-
gated a number of a,a-disubstituted 2-methyl furanyl cyanoester
substrates for selectivity (Table 3). Our forays began with
examining the electronics of the nitrile anion via synthesis of
benzyl esters derivatized at the para-position on the a-phenyl
substituent. The results shown in Table 3 suggest that there is
no obvious correlation of selectivity with the electronics of the
nitrile (entries 1–7). Similarly, a substrate with a b-naphthyl
substituent provides the arylated product with Pd(PPh3)4, and
arylmethylation product when using the bidentate SEGPHOS
derivative. In addition, only small changes in selectivities were
observed when exchanging the a-methyl group for more
sterically demanding a-benzyl or isopropyl substituents
(Table 3, entries 10–16). Lastly, substituents with functional
groups that are capable of coordinating to the catalyst (alkene,
pyridine) reduced the selectivity for arylation (entries 14, 17).
Moreover, these substrates did not undergo C–C bond for-
mation under conditions that were expected to afford aryl-
methylated product (cond. B).
7
8
B/80% 14
B/83% 15
B/31%c
Bb/35%
Ligands substituted for dppf:a (S)-DTBM-SEGPHOS in THF.
b
c
rac-BINAP. Includes 3% protonation byproduct.
Surprisingly, subjecting the a,a-disubstituted 2-methyl furanyl
cyanoacetic esters to similar reaction conditions resulted in
formation of a mixture of arylmethylation and arylation
products, with the latter being the major product (eqn (3)). This
result was quite interesting given that there are no reports for
the inter-molecular decarboxylative arylation of nitriles or any
other nucleophiles via Pd-p-benzyl complexes, nor is there any
precedent for the a-arylation of non-stabilized nitriles under
formally neutral conditions.14 Earlier this year, Kwong reported
the decarboxylative arylation of nitriles, however did so via the
more conventional base mediated coupling of aryl halides.15,16
Intrigued by this result, we turned our attention to developing
conditions for both the decarboxylative arylmethylation and
arylation of the a,a-disubstituted 2-methyl furanyl cyanoesters.
While Pd(PPh3)4 catalyst favored the arylation products
(Table 2, entry 1), combining CpPd(allyl) precatalyst with
(diphenylphosphino)ethane heavily favored formation of the
protonation product (entry 2). Unfortunately, the conditions
reported by Hiyama for Pd-p-benzyl couplings also formed
significant amounts of the unwanted protonation product
(entry 3).12a Having previously shown that BINAP ligand can
partially circumvent protonation3 in allylations of sulfones,17
the (rac)-BINAP modified catalyst was investigated and shown
to greatly increase the amount of the observed benzylated
products.11b Lastly, use of the bulky bidentate phosphine
(S)-DTBM SEGPHOS favored formation of the arylmethylation
products, with minimal protonation (entry 5, Table 2). Since
In simplest terms, the results in Table 3 represent a distinct
switch in selectivity when changing from the monodentate
PPh3 ligand to the bidentate DTBM-SEGPHOS ligand. We
postulate that both products originate from formation of an
Z3-Pd-p-furfuryl intermediate.18 To explain the ligand-dependant
selectivity, we suggest that monodentate ligand (PPh3) allows
access to an open coordination site on the metal center, allowing
for inner-sphere attack of the nucleophile as suggested in
Scheme 1, I. Hartwig has crystallographically characterized an
analogous palladium ketiminate complex,16c and mechanistic
studies of an allylative dearomatization reaction by Lin19 suggest
that our proposed Z3-p-benzyl, Z1-N-bound ketenimine3,20
transition state is feasible.21,22 Moreover, dearomatization of
benzyl electrophiles with allenyl stannanes likely proceeds by
intermediates similar to I.21b Lack of an available coordination
site with the bidentate ligated system forces outer-sphere attack
of the nitrile-stabilized anion (Scheme 2, II), delivering the
arylmethylated product 8.
In conclusion, we have developed catalytic decarboxylative
benzylations and arylations of nitriles. These methods allow
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 142–144 143

Table 3 Decarboxylative arylmethylation vs. arylation
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Chem., 1976, 41, 1885; (b) W. S. Matthews, J. E. Bares,
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%
Yieldb
Entry
Substrate
X = H
Conditions C : Da
1
2
3
4
5
6
7
A
B
A
B
A
B
A
84 : 14
11 : 89
86 (71)
83 (65)
X = OMe
495 : o5 75 (75)
o5 : 495 69 (69)c
X = Cl
80 : 20
10 : 90
84 (69)
— (65)
X = CN
495 : o5 70 (70)
8
9
A
B
495 : o5 89 (89)
16 : 84
70 (53)
10
11
12
13
14
R = Ph
A
B
A
B
A
90 : 10
9 : 91
90 : 10
— (75)
86 (77)c
84 (70)
R =
4-OMePh
R =
2-Cl-5-pyridyl
o5 : 495 76 (76)d
75 : 25
65 (51)
15
16
A
B
85 : 15
90 (63)
o5 : 495 71 (71)
75 : 25 — (60)
R=
i-propyl
17
R = Allyl
A
a
b
Calculated from crude HNMR. Combined yield (isolated yield
c
d
major isomer). Contains 5% protonation byproduct. Contains
8% protonation byproduct.
13 (a) A. D. Mills, M. Z. Nazer, M. Haddadin and M. Kurth,
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Scheme 1 Mechanistic rationale for arylation v. benzylation.
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M. Bao; J. Org. Chem., 2010, 75, 2619.
for the coupling of aromatic- and heteroaromatic benzyl
alcohol derivatives opposed to traditional alkylations that
utilize benzyl halides.
This work has been supported financially the National Institute
of General Medical Sciences (NIGMS 1R01GM079644).
Notes and references
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c
144 Chem. Commun., 2012, 48, 142–144
This journal is The Royal Society of Chemistry 2012