Organic Letters
Letter
yield of 3aa and the formation of a measurable amount of
ketone 4 remained a cause of concern.
Table 2. Scope Asymmetric Allylic Alkylation of Vinyl
a
Azides
We reasoned that the use of a more electron-rich aryl
substituent on the vinyl azide might favor the Schmidt
rearrangement pathway over the undesired hydrolysis of the
iminodiazonium intermediate (B in Scheme 2). Although the
ketone formation was completely suppressed when the
reaction was carried out with 1-(p-methoxyphenyl) vinyl
azide 1b in THF at 50 °C, the undesired alkyl migration was
found to compete with aryl migration. The resulting products
3
ba and 5 were isolated as almost a 1:1 mixture with an
excellent er of both 3ba and 5 (entry 6). As previously
discussed, the formation of the (E)-iminodiazonium inter-
mediate was deemed to be the key for a productive aryl
migration. With the anticipation of increasing the steric bulk
on the aryl ring to favor (E)-B over (Z)-B (see Scheme 2)
while maintaining its electron-rich nature, we sought to apply
1
-(o-methoxyphenyl) vinyl azide 1c as the amide enolate
surrogate. We were pleased to note that the use of 1c
eliminated both of these undesired pathways and resulted in α-
allyl amide 3ca as the sole product, albeit with only 89:11 er
(
entry 7). Carrying out the reaction at 25 °C restored the
enantioselectivity to 99:1 er, and 3ca was isolated in 63% yield
entry 8). It must be noted that even though 2.0 equiv of
(
racemic allylic alcohol (2a) was used in this reaction with
respect to vinyl azide, no kinetic resolution was observed, and
the recovered 2a remained racemic.
With the optimum reaction conditions (Table 1, entry 8) at
hand, we tested the compatibility of this protocol with other
branched allylic alcohols. As shown in Table 2A, allylic
alcohols having electronically diverse aryl substituents were
found to react smoothly with 1-(o-methoxyphenyl) vinyl azide
1
c and furnished the corresponding α-allyl N-arylacetamide
derivatives in moderate to good yield with exquisite regio- (b
vs l) as well as chemoselectivity. Whereas the products derived
from allylic alcohols containing electron-rich aryl substituents
were formed with moderate to good enantioselectivity (entries
2
−4), allylic alcohols with aryl groups bearing electron-
withdrawing substituents at various positions fared extremely
well, and in most cases, the products were isolated with an
outstanding level of enantioselectivity. Only in the case of m-
bromophenyl-substituted allylic alcohol 2m was the product
a
Unless noted otherwise, the reaction conditions indicated above
were followed. Yields refer to the isolated product after chromato-
graphic purification. Enantiomeric ratios (ers) were determined by
b
HPLC analysis on a chiral stationary phase. Reaction with 50 mol %
c
d
(
3cm) obtained with surprisingly modest er (entry 13). Allylic
Sc(OTf) . Reaction with 25 mol % Sc(OTf) . Reaction at 50 °C.
3 3
e
Values in parentheses indicates the er of 3ah after a single
recrystallization.
alcohols bearing heterocyclic substituents such as dioxolane
and thienyl (2t,u) also afforded the products with good to
excellent enantioselectivity, albeit in somewhat lower yield
(
entries 20 and 21). Note that neither α-allyl acetophenone
Table 2B). The configurations of the other products were
tentatively assigned to be the same by analogy.
nor N-homoallylbenzamide derivatives (E and D′, respectively,
in Scheme 2) were detected in any of these reactions.
Unfortunately, no reaction was observed in the case of alkyl- or
alkenyl-substituted allylic alcohols, which marks a limitation
of this protocol.
The scope of vinyl azide was also found to be very limited.
Reactions with a number of 1-aryl vinyl azides apart from 1a−c
were tested, and no desired product was obtained in any of
these cases. However, 1-phenyl vinyl azide 1a could be used
with other branched allylic alcohols, as shown for p-
bromophenyl derivative 2h: Although the product 3ah was
isolated in only 54% yield, it was formed with 98:2 er (Table
To verify the scalability of this protocol, the allylic alkylation
reaction between vinyl azide 1c and allylic alcohol 2l was
carried out on a 1.0 mmol scale under our standard reaction
conditions (Scheme 3). The corresponding α-allyl N-
arylacetamide 3cl was isolated in 66% yield with >99.5:0.5
er. The synthetic potential of the product was demonstrated
through the conversion of the newly built functionalities. The
amide of 3cl was converted to the corresponding thioamide 6
by refluxing with Lawesson’s reagent in toluene. The
protection of the secondary amide in 3cl as the Boc carbamate
enabled further functionalizations. For example, hydroboration
of the terminal double bond of 7 with pinacolborane could be
17
1
7
2
B). It was possible to improve the enantioselectivity through a
20
single recrystallization, which afforded diffraction-quality
revealed its absolute configuration to be (S) (CCDC 2020776,
accomplished under Ir catalysis and furnished the alkyl
boronate 8 in 85% yield. Olefin cross-metathesis of 7 with
methyl acrylate in the presence of Grubbs second-generation
C
Org. Lett. XXXX, XXX, XXX−XXX
Chakrabarty, Aditya
