Communication
tion conditions was performed with respect to solvent (Table 1,
entries 4–7), temperature (entry 8), and catalyst loading
(entry 9), which determined the use of 1 mol% of [Rh2(oct)4]
under heating in 1,2-dichloroethane (DCE) at 808C (Table 1,
entry 3) to be optimum.
The mechanism of this reaction should involve the insertion
of the in situ-generated Rh–carbenoid into the benzylic CÀH
bond. In fact, when bis-deuterated benzylamine [D2]1 was sub-
mitted to the reaction [Eq. (1)], the two deuterium atoms were
Moreover, the nature of the N-protecting group of the ben-
zylamines was also found to be crucial (Scheme 2). It should
be emphasized that the N-sulfonyl protecting group adopted
in 1 is key to the success in obtaining pyrrolidine 2, as other
amine derivatives, such as N-alkyl- or N-acyl-protected sub-
strates 3–5, did not give the desired products 6–8 at all.
As can be seen from Table 1 and Scheme 2, another impor-
tant feature of this transformation is the high stereoselectivity
imparted to the product. Under the optimum conditions, rep-
resentative starting material 1 gave crude sulfonylimine 2 in
quantitative yield and with an isomeric ratio of 97:3 (judged by
1H NMR spectroscopy). As sulfonylimines are unstable to mois-
ture and could not be purified by routine flash chromatogra-
phy, this crude product was immediately reduced with LiAlH4
to give, after chromatography on silica gel, bis-sulfonylamine 9
in 74% overall yield from 1 and with the same isomeric com-
position as above (Scheme 3, method a). The cis and trans
structures were unambiguously assigned to the major and
minor isomers of 9, respectively, in comparison with authentic
samples of both isomers of 9,[11] which in turn determined that
the stereochemistry of the major isomer of parent sulfonyli-
mine 2 was cis, as depicted. In certain cases where recrystalliza-
tion of the products was operative, pure samples of sulfonyli-
mines were available (Scheme 3, method b).[12] For example,
crude 2 was successfully recrystallized from hexane/ethyl ace-
tate to give chemically and isomerically pure 2 in 54% overall
yield from 1. When this pure sample of 2 was treated with
LiAlH4, as in the method a, pure 9 was produced in 98% yield,
confirming that no cis/trans isomerization took place during
the reduction. Therefore, when sulfonylimines such as 2 are re-
quired for the subsequent transformations, either their crude
samples of high isomeric purities or isomerically pure samples
after recrystallization could be used.
preserved at the specified positions of product [D2]9, consis-
tent with the above process. Based on this mechanism, the
high cis-stereoselectivity of the product could be rationalized
as in Scheme 4. In the six-membered transition state 31 follow-
ing the generation of 30, the sterically demanding [Rh] portion
occupies the equatorial position, while the Ph group is located
at the axial position to minimize the steric repulsion against
the neighboring bulky N-sulfonyl group shown in another tran-
sition state 32. From preferred structure 31, observed [D2]2
was produced, releasing the Rh catalyst to make the catalytic
cycle continue.
Other pyrrolidines prepared by this method are shown in
Table 2. The products were isolated in one or both of the fol-
lowing two ways (Scheme 3): method a) When the crude prod-
ucts are reduced to sulfonylamines, the cis/trans ratios of the
sulfonylamines most likely reflect those of the parent sulfonyli-
mines; method b) when the products solidify, recrystallization
to pure sulfonylimines can be undertaken, even though the
yields are somewhat decreased. A variety of aryl groups in the
benzylamine moiety, including electron-rich or -deficient ones,
participated in the reaction to give pure cis-2-aryl-3-[(arenesul-
fonylimino)methyl]pyrrolidines 2 and 26 or their amine deriva-
tives 9 and 18–22 with high cis-selectivities (Table 2, entries 1–
6). Although several N-(arenesulfonyl) protecting groups were
acceptable in this reaction, the naphthalenesulfonyl group, as
in 16, could enhance the crystallization of products (Table 2,
entry 8). Another sulfonyl group on the imino group could also
be changed (Table 2, entry 9). The stereodefined pyrrolidines
obtained by this method are useful for subsequent stereose-
lective transformations.
Scheme 4. Proposed stereochemical course of the reaction.
The above cyclization is also applicable to benzyl ethers
(Scheme 5), with the reaction conditions given in Table 2.
Benzyl ether 33 afforded crude tetrahydrofuran 34 with a 1:1
1
isomeric ratio in quantitative yield by H NMR analysis. As 34
was an oil and a mixture of isomers, it was reduced to sulfonyl-
amine 35, the structure of which was unambiguously deter-
mined to be a 52:48 mixture of the trans and cis isomers by
comparison with authentic samples of 35. If necessary, crude
sulfonylimines could be converted into the corresponding al-
dehydes by basic hydrolysis. For example, crude 34 (trans/cis=
47:53) afforded aldehyde 36 of a higher trans purity (trans/
cis=89:11) in excellent yield, apparently through concomitant
Chem. Eur. J. 2016, 22, 890 – 895
892
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Senoo, Masato
