Organic Letters
Letter
the Kukhtin−Ramirez adduct outcompetes the otherwise
anticipated P-alkylation of P(NMe2)3. Once formed, subse-
quent dissolution of 5 in water (0.05 M) at 60 °C for 2 h
resulted in hydrolysis to complete a Barbier-like synthesis of
alcohol 6 in 75% isolated yield (Scheme 1). The formation of
alkene 7 as a minor product via elimination from 5 (vide infra)
accounts for the balance of mass under these conditions.
The two-step, one-pot method is amenable to benzylic,
allylic, and methyl electrophiles, generally providing isolable
intermediate alkoxyphosphonium salts10 that furnish alcohols
9−26 upon hydrolysis (Figure 2). The sequence is largely
disubstituted acrylates12 as the major product (Scheme 2). In
this event, a one-pot olefination of methyl benzoylformate with
Scheme 2. Screening of Benzylating Reagents in the
Olefination Reaction of Methyl Benzoylformate with
P(NMe2)3
benzyl bromide can be achieved in wet acetonitrile giving 7 in
84% isolated yield (Scheme 2).13 Benzyl bromide gives better
overall yields than either benzyl chloride or tosylate electro-
philes, although a marginally higher Z/E ratio was observed in
the reaction using benzyl tosylate rather than benzyl halides
(Scheme 2). Control reactions between independently
synthesized benzylphosphonium 8 and methyl benzoylformate
under the reaction conditions outlined in Scheme 2 are
negative, eliminating the possible intervention of transient P-
ylides in these olefination reactions. Similarly, the possible
intervention of benzyl carbanionic intermediates through
halophilic displacement14 is inconsistent with the observation
of product formation using benzyl triflate as an electrophile.
Additional examples of this nonylidic P-mediated olefination
reaction are depicted in Figure 3. As in the P(NMe2)3-mediated
Barbier-like reductive alkylation reaction (vide supra), Z-α,β-
diaryl acrylates bearing diverse functionalities including bromo
(29 and 30), acetoxyalkyl (33), bromoalkyl (34), cyano (36),
acetyl (37), and iodo (38) on either α- or β-aromatic rings are
accessible by this method in good yield and with excellent
configurational selectivity. Furthermore, tetrasubstituted alkene
32 was obtained in 58% isolated yield from the reaction of (1-
bromoethyl)benzene with methyl benzoylformate. The ob-
served compatibility of a free hydroxy group (35) and an acidic
terminal alkyne (39) reveals the quasi-neutral reaction
conditions. Substituted benzoylformate derivatives are similarly
olefinated (42−44).
The success of the above P-mediated C−C bond forming
methods, which necessitates fast umpolung C-alkylation of an
α-keto ester substrate in preference to a potential direct P-
alkylation of P(NMe2)3, warrants additional mechanistic
comment. Burgada has shown that the Kukhtin−Ramirez
reaction of methyl aroylformates (45) with P(NMe2)3 is rapid
at temperatures below −40 °C15 and that the resulting 1:1
adduct 46 reversibly adds to an additional equivalent of 45 in
aldol-like fashion to form a 2:1 adduct (47/48, Figure 4).16
Burgada’s findings suggest that the dynamic equilibrium 46 ⇌
47/48 is stable in the absence of exogeneous reagents, only
undergoing expulsion of hexamethylphosphoramide (HMPA)
to generate epoxide 49 upon warming above −40 °C. However,
in the presence of an alkylating agent as in this current study,
the oxyphosphonium enolate intermediate 46 may be removed
from the equilibrium via C-alkylation by reactive benzyl/allyl
bromides to give the observed alkoxyphosphonium salt 50. At
such low temperatures, direct quaternization of P(NMe2)3 with
benzyl bromide to give (Me2N)3PBn+Br− (8)17 evidently is not
kinetically competitive.
Figure 2. P(NMe2)3-mediated Barbier-coupling of methyl aroylfor-
mates with benzyl/allyl bromides.a a Reaction conditions: methyl
aroylformate (2.2 mmol, 1.1 equiv), benzyl/allyl bromide (2.0 mmol,
1.0 equiv), and P(NMe2)3 (2.2 mmol, 1.1 equiv) in toluene (20 mL),
−78 °C to rt, 2−3 h; decantation, then dissolution of alkoxyphos-
phonium salt in H2O (40 mL), 60 °C for 2 h. Isolated yield based on
benzyl/allyl bromide was reported. Yield of the elimination product
was not determined. b Methyl benzoylformate (1.3 equiv) and
c
P(NMe2)3 (1.3 equiv) were employed. Methyl iodide was employed.
insensitive to electronic variation within the series of benzyl
bromide electrophiles investigated, although lower yields are
observed with sterically encumbered ortho-substituted benzyl
bromides (15 and 16). As intimated above in the introduction,
the fidelity of the Kukhtin−Ramirez redox reaction between the
tricoordinate phosphorus reagent and α-dicarbonyl compound
permits the use of electrophiles containing a variety of reactive
functional groups, allowing straightforward access to alcohols
bearing cyano (13), iodo (17), acetoxy (18), and ethynyl (22)
moieties. In fact, the specificity of the Kukhtin−Ramirez trigger
allows for selective reductive C−C alkylation even in the
presence of pendant carbonyl (14) and alkyl bromide (19)11
groups, illustrating the chemoselectivity of the mild closed-shell
conditions. Substituted benzoylformate derivatives are similarly
benzylated (24−26).
Once formed, alkoxyphosphonium salt 50 evolves via either
solvolysis or elimination as a function of the reaction medium.
In view of the significant steric congestion at the reacting 3°
By modifying conditions in Scheme 1, the decomposition of
alkoxyphosphonium salt 5 can be diverted to form Z-α,β-
B
Org. Lett. XXXX, XXX, XXX−XXX