Catalytic α-monoallylation of aryl acetonitriles

Article abstract of DOI:10.1021/ol5024294

α-Cyano aldehydes undergo selective transition-metal-catalyzed monoallylation to provide α-allylated nitriles. The transformation leads to linear substitution products with palladium catalysts or branched allylated nitriles using an iridium catalyst. Faci

Full text of DOI:10.1021/ol5024294

Letter
pubs.acs.org/OrgLett
Catalytic α‑Monoallylation of Aryl Acetonitriles
Tapan Maji and Jon A. Tunge*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
S
* Supporting Information
ABSTRACT: α-Cyano aldehydes undergo selective transition-metal-catalyzed monoallylation to provide α-allylated nitriles. The
transformation leads to linear substitution products with palladium catalysts or branched allylated nitriles using an iridium
catalyst. Facile TBD-catalyzed retro-Claisen cleavage is leveraged to attain selective monoallylation.
Table 1. Amine Screening
ransition-metal-catalyzed Tsuji−Trost-type allylation of
Tstabilized nucleophiles is a powerful method for carbon−
carbon bond formation.1 While the allylation of stabilized
malonate nucleophiles has received significant attention,
somewhat less attention has been paid to nitrogen-containing
carbon nucleophiles. Given the preponderance of nitrogen-
containing biologically active molecules, we are interested in
developing methods that allow facile incorporation of nitrogen
via transition-metal-catalyzed allylation reactions.
The versatility of nitriles, which can be rapidly transformed
to amides and amines,2 has motivated development of α-
allylation of nitriles by decarboxylative allylation.3,4 These
reactions often lead to quaternary carbon centers, thus
obviating problems with overallylation.3a In contrast, the α-
monoallylation of nitriles to form tertiary carbon centers is
challenging due to competing overallylation and protonation
reactions.5,6
To achieve selective α-monoallylation of nitriles, we
envisioned that a carbonyl functional group α to a nitrile
group would (A) activate the substrate toward Tsuji−Trost
allylation and (B) act as a blocking group to prohibit
overallylation (Scheme 1). Moreover, it was anticipated that
the carbonyl group could be removed in situ via retro-Claisen
condensation.
Our preliminary studies focused on the treatment of α-cyano
aldehyde 1a with cinnamyl carbonate 2a in the presence of
catalytic Pd(PPh3)4 and amine (Table 1). In each case, selective
a
Isolated yield after purification by column chromatography on SiO2.
monoallylation was achieved. However, triazabicyclodecene
(TBD) proved to be the best catalyst, smoothly giving rise to
the corresponding allylated product 3a within 30 min (Table 1,
entry 5).
Scheme 1. Retro-Claisen Allylation Concept
Using 1a and 2a as representative substrates, a series of
control experiments were performed. Exclusion of Pd(PPh3)4
catalyst did not yield any product, whereas exclusion of TBD
Received: August 15, 2014
Published: September 19, 2014
© 2014 American Chemical Society
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a
yielded 3a (15%) and the allylated aldehyde 4a (22%) after
extended reaction time (16 h). Thus, TBD is necessary for
rapid allylation and retro-Claisen cleavage of the aldehyde.
The choice of allyl methyl carbonate as allylating agent was
also crucial to promote the retro-Claisen condensation to form
3. Employment of allylic acetates as allylating agents yielded the
aldehyde product 4a as the major product (Table 2, entry 1),
Table 3. Palladium-Catalyzed Allylation
Table 2. Allylating Agents
a
entry
allylating reagent, 2
time (h)
yield (%) 3a/4a
1
2
3
R = CH3
R = OtBu
R = OCH3
14
14
22:58
63:18
95:0
0.5
a
Isolated yield after purification by column chromatography on SiO2.
whereas use of allyl tert-butyl carbonate provided a mixture of
3a and 4a. Only use of allyl methyl carbonate exclusively
yielded the product of retro-Claisen cleavage (3a) in high yield
in a short reaction time.
Mechanistically, we propose that the allylation reaction
involves two synergistic catalytic cycles (Scheme 2). The TBD
Scheme 2. Potential Mechanism
catalyst likely acts as a general base to generate the stabilized
carbanion nucleophile.7 This nucleophile undergoes catalytic
allylation. Finally, to explain why rapid retro-Claisen cleavage
requires both methyl carbonate and TBD, we propose that
TBD catalyzes the cleavage of the aldehyde with methanol.8
Such a proposal is consistent with the proposed mechanism for
TBD-catalyzed transesterifications.9
A representative range of allylic carbonates participated in the
deformylative allylation (Table 3, entries 1−7 and 14).
Substitution of the aromatic ring of cinnamyl carbonate showed
that electron-deficient carbonates react more slowly than
electron-rich allyl carbonates, although the magnitude of the
effect is relatively small (entries 2 and 3). Alkyl carbonates also
underwent efficient coupling, with both primary and secondary
alkyl carbonates providing the linear allylation product (97:3,
entries 5 and 6). Substitution of the aromatic ring α to the
a
Reaction conditions: cyano aldehyde (1.0 equiv), reagent (1.1 equiv),
b
Pd(PPh3)4 (2.5 mol %), TBD (20 mol %), THF, rt. Isolated yield
after purification by column chromatography on SiO2. Linear/
branched = 97:3. Linear/branched = 96:4. Diastereomeric ratio (dr
= 1:1) was determined by 1H NMR spectroscopy of the crude reaction
mixture.
c
d
e
nitrile was also tolerated (entries 8−13 and 15). Importantly,
allylic alkylation is faster than the oxidative addition to a
brominated arene (entry 13). Unfortunately, under the same
reaction conditions, α-aliphatic nitrile substrates gave the
allylated aldehyde, which did not undergo in situ retro-Claisen
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cleavage to give the protonated product even after elongated
reaction time (entry 16).
Scheme 4. Asymmetric Allylation and Dynamic
Crystallization
To extend this protocol further, we envisioned that the
method would yield branched allylated product by tuning the
transition metal catalyst. While nucleophilic addition to the less
hindered position of allylic electrophiles is typically favored by
palladium catalysts,1 branched substituted products are often
favored by Mo, Ru, Rh, and Ir catalysts.10
Thus, we also examined the analogous reaction of nitriles in
the presence of an Ir catalyst, which forms the branched
product regioselectively with a range of allylic electrophiles. For
example, in the presence of 4 mol % of [Ir(COD)Cl]2, 8 mol %
of ligand L,11,12 and 40 mol % of DABCO, cyano aldehydes
1a,b smoothly underwent the allylation in THF at room
temperature to afford moderate to high regioselectivity in favor
of branched products (Scheme 3). The reaction proceeded well
allylation, a facile in situ retro-Claisen cleavage of the
activating/blocking group provides the monoallylated nitriles.
The regiochemistry of allylation can be controlled by the choice
of catalyst, with Pd providing the linear allylation products and
an Ir catalyst giving the branched products. Lastly, use of an
enantiopure Ir-phosphoramidite catalyst leads to enantioselec-
tive allylation.
Scheme 3. Iridium-Catalyzed Allylation
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds and a CIF file for compound 5f. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
at room temperature, albeit with longer reaction times (15−26
h) as compared to the palladium-catalyzed reactions. Higher
temperatures resulted in complicated reaction mixtures.
Interestingly, the reaction without DABCO did not provide
any product, which might be due to the improper in situ
formation of the active Ir catalyst.12 Varying the substitution on
the aromatic moiety of the pro-nucleophile does not have a
remarkable effect on regioselectivity (cf. Scheme 3, 5b and 5e),
whereas the branched to linear selectivity changes significantly
with changes to the substituent on the allyl carbonate
electrophile. In identical reaction conditions, aromatic allyl
carbonates provided good to excellent branched selectivities
(Scheme 3, 5b, 5c, and 5e) in comparison to aliphatic allyl
carbonates which provided much lower selectivities (Scheme 3,
5a and 5d). Using the optically active (S,S,Sa) phosphoramidite
ligand allowed the synthesis of 5c in 62% ee (major
diastereomer) and 5e in 58% ee. The low dr coupled with
the modest enantioselectivities was somewhat discouraging.
However, in our pursuit of a synthesis of an estrogen receptor
inhibitor (FEDPN),13 it was noted that the presence of an
electron-donating methoxy group on both the pro-electrophile
and pro-nucleophile produced more highly enantioenriched
product (89% ee). However, the product was formed as a 2:1
mixture of diastereomers (Scheme 4). Gratifyingly, epimeriza-
tion with TBD in EtOAc/hexane solvent allowed selective
dynamic crystallization to form a single diastereomer of 5f in
acceptable yield and good ee (52%, 89% ee).14 The anti
stereochemistry was confirmed by X-ray crystallographic
analysis.15
*E-mail: tunge@ku.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1058855)
and the Kansas Bioscience Authority Rising Star program for
financial support. We thank Dr. Victor Day (University of
Kansas) for X-ray crystallographic analysis using a diffrac-
tometer purchased with NSF-MRI Grant CHE-0923449.
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