Anti-Markovnikov N-H and O-H additions to electron-deficient olefins catalyzed by well-defined Cu(I) anilido, ethoxide, and phenoxide systems

Article abstract of DOI:10.1021/ja057622a

The monomeric Cu(I) complexes (IPr)Cu(Z) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, Z = NHPh, OEt, or OPh) react with YH (Y = PhNH, PhCH₂NH, EtO, or PhO) to catalytically add Y-H bonds across the C=C bond of electron-deficient olefins to yield anti-Markovnikov organic products. Catalytic activity has been observed for olefins CH₂C(H)(X) with X = CN, C(O)Me, or CO₂Me as well as crotononitrile. Preliminary studies implicate an intermediate in which the C-Y bond forms through a nucleophilic addition pathway. Copyright

Full text of DOI:10.1021/ja057622a

Published on Web 01/12/2006
Anti-Markovnikov N-H and O-H Additions to Electron-Deficient Olefins
Catalyzed by Well-Defined Cu(I) Anilido, Ethoxide, and Phenoxide Systems
Colleen Munro-Leighton, Elizabeth D. Blue, and T. Brent Gunnoe*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
Received November 8, 2005; E-mail: brent_gunnoe@ncsu.edu
Scheme 1. Catalyst Precursors (IPr)Cu(NHPh) (1), (IPr)Cu(OEt)
(2), and (IPr)Cu(OPh) (3)
Conjugate addition reactions represent a class of versatile
reactions for the construction of small organic molecules.1 Di-
astereoselective and enantioselective variants are particularly at-
tractive for the formation of natural products and compounds of
biological interest, and the use of enantiopure transition metal
catalysts can obviate the need for stoichiometric incorporation of
chiral auxiliaries.1-3 Copper reagents have been widely incorporated
for conjugate addition reactions but have been primarily limited to
reactions that involve C-C bond formation.3-7 The addition of
N-H or O-H bonds to electron-deficient olefins provides a
pathway for N-C and O-C bond formation,8,9 respectively, and
can be catalyzed under acidic or basic conditions or using simple
Lewis acidic metal catalysts that likely coordinate and activate the
olefin toward nucleophilic addition;1,8,10-16 however, such conditions
are often incompatible with functionality and do not generally afford
opportunities to control selectivity (e.g., diastereo- or enantiose-
lectivity).
Table 1. Cu-Catalyzed Addition of Amine N-H Bonds and
Alcohol O-H Bonds Across Electron-Deficient CdC Bonds (C6D6,
% conversions determined by 1H NMR spectroscopy)
Recently, Kawatsura and Hartwig have reported screening of Pd
catalysts for the addition of amines to acrylic acid derivatives based
on the lead from Trogler on Pd-catalyzed addition of aniline to
acrylonitrile.17,18 Alkylphosphines have been demonstrated as
catalysts for the hydration and hydroalkoxylation of electron-
deficient olefins as well as addition of oxygen nucleophiles to
2-alkynoates.19,20 Ni(II) catalysts for the hydroamination of activated
olefins that likely coordinate the olefin and activate toward amine
nucleophilic addition have been reported.21 Herein, we report
catalytic addition of N-H and O-H bonds across CdC bonds of
electron-poor olefins using monomeric Cu(I) anilido, phenoxide,
or ethoxide complexes through a proposed mechanism that involves
initial nucleophilic addition of the nondative ligand to the electron-
deficient olefin.
The preparation of the catalyst precursors (IPr)Cu(NHPh) (1),
(IPr)Cu(OEt) (2), and (IPr)Cu(OPh) (3) (IPr ) 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) has recently been reported
(Scheme 1).22 Complexes 1-3 catalyze the addition of amine N-H
bonds or alcohol O-H bonds across the CdC bond of electron-
deficient olefins (Table 1). For all reactions that we have studied,
the transformations are selective for the anti-Markovnikov product.
For example, in the presence of 5 mol % of complex 1 in C6D6,
aniline and methyl vinyl ketone (MVK) are converted within 5 min
at room temperature to the anti-Markovnikov product 4-(phenyl-
amino)-2-butanone (entry 2). In the absence of catalyst, aniline and
MVK react only to 50% completion over the course of 10 days,
strongly implicating copper as an active catalyst. Similarly, in the
presence of 5 mol % of complex 1, the N-H bond of aniline is
added across the carbon-carbon double bonds of acrylonitrile
(>95% conversion, entry 1) and methyl acrylate (55% conversion,
entry 3), and benzylamine is added to acrylonitrile with 100%
conversion after 5 min at room temperature (entry 5). Reaction of
benzylamine with acrylonitrile in the absence of 1 proceeds at a
much slower rate and is not complete after 37 days at room
temperature (slower by a factor of ∼27,000 compared to the reaction
with 5 mol % of 1). In the absence of 1, neither acrylonitrile nor
methyl acrylate shows evidence of reaction with aniline at room
temperature after 3 and 14 days, respectively. Using only 1 mol %
of 1, the combination of acrylonitrile and aniline yields 95%
conversion to 3-(phenylamino)propionitrile after 145 h at room
temperature. Catalysis with disubstituted olefins to generate chiral
products is also possible. For example, a mixture of cis and trans
crotononitrile with 5 mol % of 1 proceeds to 54% conversion at
40 h at 80 °C (entry 4).
Control reactions were performed with (IPr)CuCl (precursor to
1), [Cu(OTf)]2‚C6H6 (OTf ) trifluoromethanesulfonate), and free
IPr ligand. None of these substrates catalyzes the addition of aniline
to acrylonitrile at room temperature (no reaction observed after 140
h for copper systems and no reaction after 113 h for the IPr ligand).
(IPr)Cu(OTf), however, affects approximately 52% conversion after
20 h. It is likely the (IPr)Cu(OTf) complex coordinates aniline,
and in the presence of base (i.e., excess aniline), a small amount
of (IPr)Cu(NHPh) can be produced and is responsible for the
observed catalytic reaction (see below). Indeed, the amine complex
[(IPr)Cu(NH2Ph)][OTf] has been independently synthesized, and
under catalytic conditions affects 46% conversion to 3-(phenylami-
no)propionitrile after 19 h.
The catalytic reactions can be extended to alcohols. For example,
in the presence of 2 (5 mol %), ethanol and acrylonitrile are
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C O M M U N I C A T I O N S
Scheme 2. Two Possible Pathways for Net Addition of N-H to
Acrylonitrile
while reaction with 1 equiv of HCl with 4 produces 3-(phenylami-
no)propionitrile and (IPr)CuCl (Scheme 3). During catalysis,
complex 4 is not present in sufficient concentration to be observed
1
by H NMR spectroscopy, and the amido complex 1 is the only
copper system observed.
Thus, we propose that the preliminary data support Pathway 1
(Scheme 2) as the most likely route for the catalytic transformations.
However, we cannot, at this point, definitively rule out the
possibility of olefin coordination, insertion followed by rapid
isomerization to complex 4, nor olefin coordination and intra-
molecular nucleophilic addition by the nondative ligand. These
results also indicate that a mechanism in which copper serves as a
simple Lewis acid to activate olefin toward nucleophilic attack from
free aniline without direct involvement of the amido ligand is an
unlikely pathway. Important from a synthetic perspective is the lack
of observation of products due to â-hydride elimination pathways.
We are presently working to delineate the full scope of these
transformations, extend our mechanistic understanding, and access
more active as well as enantioselective catalyst variants.
Scheme 3. Reactivity of 4 to Yield 3-(Phenylamino)propionitrile
Acknowledgment. We acknowledge the NSF (CAREER Award,
CHE 0238167) and Alfred P. Sloan Foundation for financial
support. E.D.B. acknowledges the NSF (Graduate Fellowship) and
the American Association of University Women Educational
Foundation for an American Fellowship.
Supporting Information Available: Details of synthesis and
characterization. This material is available free of charge via the Internet
at http://pubs.acs.org.
converted to 3-ethoxypropionitrile with 90% conversion after 20 h
(Table 1, entry 6). Similarly, 3 (5 mol %) catalyzes the conversion
of acrylonitrile and phenol to 3-phenoxypropionitrile at 80 °C with
64% conversion (Table 1, entry 7). In the absence of catalyst, no
reaction is observed between EtOH or PhOH and acrylonitrile.
We have considered two likely pathways for the catalytic
transformations (Scheme 2). In Pathway 1, initial nucleophilic
addition of the amido ligand to the olefin produces a zwitterionic
intermediate, which undergoes a proton transfer to yield the new
copper amido complex 4. Subsequent proton transfer from aniline
(presumably via coordination to Cu) to the amido ligand would
yield organic product and regenerate 1. The anti-Markovnikov
selectivity would be dictated by the nucleophilic N-C bond-forming
step. Alternatively, olefin coordination to 1 (Pathway 2) could
precede olefin insertion into the Cu-Namido bond and form a new
Cu-C bond. Direct observation of olefin insertions into metal-
amido bonds is rare.23 Subsequent proton transfer from aniline
would yield organic product and 1. We have previously demon-
strated that (IPr)Cu(R) (R ) Me or Et) systems react cleanly with
OH or NH bonds to yield RH and (IPr)Cu(X) (X ) amido, alkoxide,
or aryloxide).22 Thus, the product-forming step in Pathway 2 is
feasible.
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The stoichiometric reaction of 1 and acrylonitrile (in the absence
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with the product from olefin insertion depicted in Pathway 2.
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