.
Angewandte
Communications
Table 3: Optimization of the 3-methylenepyrrolidine formation.[a]
lithium salts for the NEt3-promoted a-vinyl enolization. The
different aptitudes of a-vinyl enolization between stereo-
defined b-chlorovinyl ketones are believed to be due to the
planar s-cis conformation for (Z)-1a and the nonplanar s-cis
conformation for (E)-1a. In addition, the preferential for-
mation of the unconjugated propargyl ketone 5a rather than
its conjugated counterpart, alkynyl ketone, provides strong
evidence for the a-vinyl enolization pathway of (E)-1.[12]
Next, the formation of 3a from 4a and 5a was examined.
While the stereoselective formation of 3a was observed upon
subjecting a 2:1 mixture of 4a and 5a under our optimized
reaction conditions, the inefficient formation of 3a persisted
under varied reaction conditions such as longer reaction time,
higher reaction temperature, and varied amounts of LiClO4
and NEt3. Taken together, these observations lead us to
conclude that while the direct a-vinyl enolization pathway of
allenyl ketones to lithium cumulenolates is feasible, the
process is not efficient under our reaction conditions.[15] Thus,
the major pathway to vinyl allenones from (E)-1a should
involve the lithium cumulenolates derived from the direct a-
vinyl enolization pathway of (E)-1a. Based on our data, we
propose a possible mechanism for the lithium-promoted vinyl
allenone formation from (E)-b-chlorovinyl ketones which
involves a vinylogous conjugate addition reaction of the
[3]cumulenolates with subsequent alkyne–allene isomeriza-
tion (6!3). The high stereoselectivity of a pendant alkene
moiety in vinyl allenones suggests a closed transition state
rather than an open transition state.[16]
Entry
LiX (mol%)
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
LiClO4 (100)
LiOTf (100)
LiBr (100)
LiBr (100)
LiBr (100)
LiBr (100)
LiBr (100)
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Et2O
0
12
15
95
50
94
36
95
0
THF
PhCH3
CH3CN
CH3CN
CH3CN
LiBr (10)
9[c]
10[d]
–
LiBr (10)
n.r.
[a] Reaction conditions: (E)-1a (1.5 mmol), 7 (1.0 mmol), NEt3
(1.1 mmol), LiX in solvents (0.10m) at 238C. [b] Yield of 8a isolated after
column chromatography. [c] Reaction without lithium salt. [d] Reaction
without NEt3.
Table 4: Scope of the 3-methylenepyrrolidine formation.[a]
Entry
R1
R2
Yield [%][b]
The electrophilic behavior of lithium cumulenolates in our
vinyl allenone formation is remarkable considering the fact
that the titanium cumulenolates[13] and lithium cumuleno-
lates[17] previously behaved as nucleophilic species. This
unique reactivity of lithium cumulenolates can be favorably
compared to the electrophilic behavior of allenyl ketones
under Lewis acid catalysis.[18] Motivated by the observed
electrophilic reactivity mode of lithium cumulenolates, we
1
2
3
4
5
6
nBu
nBu
nBu
nBu
nBu
nBu
nBu
nBu
C6H4
8a: 95
8b: 95
8c: 95
8d: 95
8e: 95
8 f: 97[c]
8g: 93
8h: 95
8i: 87
8j: 99
8k: 95
2-naphthyl
4-MeC6H4
4-OMeC6H4
4-BrC6H4
4-NO2C6H4
Me
Et
C6H4
C6H4
C6H4
7[d]
8[d]
9
10
11
ꢀ
(CH2)3Cl
(CH2)2CO2Me
phthalyl
investigated intermolecular C C bond formations between
(E)-b-chlorovinyl ketones and nucleophilic species. Thus,
upon subjecting a mixture of (E)-1a and the ketimine ester
7[19] under stoichiometric amounts of both NEt3 and lithium
salts at ambient temperature, the stereoselective formation of
the 3-methylenepyrrolidine 8a was observed (Table 3). Our
optimization efforts resulted in the single diastereomeric form
of 8a in greater than 95% yield in the presence of a catalytic
amount of LiBr using CH3CN as an optimal solvent (entry 8).
Additional control experiments of the reaction also showed
that the formation of 8a could not be effected in the absence
of either LiBr or NEt3 (entries 9 and 10).
[a] Reaction conditions: (E)-1a (1.5 mmol), 7 (1.0 mmol), NEt3
(1.1 mmol), LiBr (0.1 mmol) in CH3CN (0.10m) at 238C. [b] Yield of 8
isolated after column chromatography. [c] No purification. [d] Reaction
using 20 mol% of LiBr in 36 h.
stepwise [3+2] cycloaddition pathways,[20] we were pleased to
observe several conjugate addition products 9 which could be
converted into 8 under the reaction conditions (Scheme 4).[21]
Thus, it is likely that the formation of 8 is a stepwise process
by the conjugate addition reaction of the ketimine ester 7 with
lithium cumulenolates and susbsequent intramolecular Man-
nich-type cyclization.[22] In addition, the g,g-disubstituted-b-
chlorovinyl ketone (E)-1l was also transformed into a formal
[3+2] addition product in a one-pot fashion to give 8l in 78%
yield.[23] Our preliminary study also revealed the synthetic
potential of the vinyl allenones 3 in the intermolecular Diels–
Alder reaction, where highly functionalized cyclohexene
derivatives 11 with a stereodefined exocyclic double bond
had been stereoselectively constructed under mild reaction
conditions.[24]
The scope of the 3-methylenepyrrolidine formation from
the reaction of (E)-b-chlorovinyl ketones and a ketimine ester
in the presence of lithium salts is illustrated in Table 4. The
reaction was readily applicable to a range of aryl and alkyl
ketones with excellent yields (87–99%). The electronic and
steric nature of (E)-1 showed little effect on the reaction
(entries 1–8), and the reaction tolerated functional groups
such as halide (entry 9), ester (entry 10), and phthalimide
(entry 11).
While the stereoselective formation of 8 raises an
interesting mechanistic issue between the concerted and the
4
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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