5132
D. Chen et al. / Tetrahedron Letters 51 (2010) 5131–5133
transformation, and (o-tol)3P also showed less activity, which
therefore led to 3a only in 21% yield (entries 4 and 10, Table 1).
In contrast, the combined usage of 5 mol % of Pd(dba)2 and
10 mol % of diphenylphosphinoethane (dppe) dramatically in-
creased the yield of 3a to 87% (entry 10, Table 1). More impor-
tantly, only single cis-isomer was detected, which could be
deduced by NOE analysis, and further confirmed by X-ray diffrac-
tion study of cis-3a. Other bisphosphine ligands, such as dppb,
dppf, and DPEphos, produced similar yields, accompanying with
a relative low diastereoselectivity (entries 6–9, Table 1). Of the sol-
vents we screened, including toluene, tetrahydrofuran (THF), dim-
ethylforamide (DMF), and dioxane, THF turned out to be the best
solvent, while other solvents resulted in relative lower stereoselec-
tivity (entries 11–13, Table 1). Slightly slower reaction was
observed employing 1b (X = OAc) as a substrate and no reaction
occurred when using 1c (X = Cl) as a substrate. The reaction of
E-1a, an E-2-butene-1,4-diol derivative, afforded 3a in 84% yield
and excellent diastereoselectivity (entry 14, Table 1). Finally, we
chose 5 mol % of Pd(dba)2, 10 mol % of dppe, THF as the solvent,
and 50 °C for the optimized reaction conditions.
Bs
N
Bs
N
Pd/C, H2
92%
PdLn
75%
Et
Bu
Ph
Ph
HO
Et
AcO
1d
O
O
3n
3o
Scheme 1.
producing the cis-isomer with >97:3 selectivity. For example,
imine 2f and 2g, two electron-rich aromatic ring containing imines,
gave 1,3-oxazolidine 3f and 3g in 87% and 88% yields, respectively
(entries 6 and 7, Table 2). The aromatic imine 2k, substituted by
electron-withdrawing group such as fluoride atom, led to 1,3-oxa-
zolidine 3k in 80% yield as a single isomer (entry 11, Table 2). In
addition, the furyl possessing imine 2m also reacted smoothly with
1a to afford 1,3-oxazolidine 3m in 85% yield and in a highly diaste-
reoselective fashion (dr >97:3, entry 13, Table 2). Moreover, the
halides in the aromatic ring were intact under the reaction condi-
tions, which may permit further chemical transformations such as
transition-metal-catalyzed coupling reactions for the introduction
of other functional groups.
Then, we further checked the scope and limits of the reaction,
and found that 1d, another 2-butene-1,4-diol derivatives, also
underwent the Pd-catalyzed cyclization to give the 1,3-oxazolidine
3n in 75% yield (E/Z = 9:1). The excellent diastereoselectivity was
confirmed by the NMR analysis of the hydrogenated product 3o
(Scheme 1).
1,2-Amino alcohols and their derivatives have attracted numer-
ous attentions because of the potential biological activity and
building blocks for the synthesis of nitrogen-containing natural
products.10 Thus, we extended this protocol to synthesize certain
of 1,2-amino alcohols or their derivatives. For example, N-tosyl-
2-amino-3-butenol 4a was prepared in 71% yield via TFA-mediated
ring opening of 1,3-oxazolidines 3a. As we known, C@C bond is a
good potential functional group in organic synthesis, therefore
functionalized amino alcohol derivatives may be synthesized
through further chemical transformations from the C@C bond pos-
sessing 1,3-oxazolidines.
The synthetic application of this protocol was well illustrated in
the efficient synthesis of aminobutanol, a key building block for the
synthesis of ethambutol.11 Palladium-catalyzed cyclization of 1a
with N-Boc imine 2n gave 1,3-oxazolidine 3p in 86% yield. Pd/C
catalyzed hydrogenation not only reduced the C@C bond, but also
cleaved the ring of 1,3-oxazolidines to give N-Boc-aminobutanol in
95% yield. Then, deprotection of Boc in the presence of TFA yielded
aminobutanol in 82% yield. Thus, aminobutanol could be prepared
in 67% overall yield over three steps (Scheme 2).
With the optimal reaction conditions in hand, we then explored
the scope and limits of the cyclization reaction using a variety of
imine substrates. The results were summarized in Table 2.
As shown in Table 2, although the reaction of the imine 2b was
sluggish somehow, the reaction could be successfully extended to
other activated imines especially the N-sulfonylimines. 1,3-Oxaz-
olidines 3b and 3c were obtained from 2b and 2c in 59% and 90%
yield, respectively, while no desired 1,3-oxazolidine product was
observed employing tert-butylphenylsulfinimine 2d as a substrate
(entries 2–4, Table 2). The more activated imine 2e was subjected
to the standard reaction conditions to give the 1,3-oxazolidine 3e
in moderate yield, however, an obvious decrease in diastereoselec-
tivity was detected (entry 5, Table 2). Attempts to the extension of
the reaction to other imines, such as ketimines and N-arylimines,
did not give any of the desired 1,3-oxazolidines.
Thus, the N-sulfonyl imines appeared to be the most suitable
substrates for the cyclization reaction. Both aromatic N-benze-
nesulfonylimine and aliphatic N-benzenesulfonylimine are good
reaction partners, although the aliphatic N-benzenesulfonylimine
2l led to a decrease of yield to 51% (entry 12, Table 2). All the
aromatic N-benzenesulfonylimines resulted in 1,3-oxazolidine
products with good yields and excellent diastereoselectivity,
Table 2
Pd-catalyzed cyclization of 1a with various iminesa
R2
N
R2
On the other hand, Pd-catalyzed asymmetric allylation reac-
tions12 have made great breakthrough in recent years, and number
of chiral ligands could produce excellent asymmetric induction.
The reaction presented herein is thought to be a typical Pd-cata-
lyzed reaction involving allylpalladium intermediates, therefore,
it is highly possible to generate chiral amino alcohols learning from
the Pd-catalyzed asymmetric allylation reactions. What is more,
the tuning of chiral ligands may result in the enantioselective syn-
PdLn
R1
+
N
HO
OCO2Et
THF, 50 o
C
R1
1a
2
O
3
Entry
2
R1
R2
3
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
Ts
Ms
Bs
3a
3b
3c
3d
3e
3f
3g
3h
3i
87
59
90
NR
57
87
88
80
85
86
80
51
85
>98/2
>98/2
>98/2
—
53/47
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>97/3
thesis of
ditional methods.
D-amino alcohol, which is quite difficult to obtain by tra-
S(O)But
Piv
Bs
p-OMe-C6H4
p-Me-C6H4
p-Br-C6H4
p-OMe-C6H4
p-Cl-C6H4
p-F-C6H4
Pent
Bs
Bs
Ts
Bs
Bs
Bs
Bs
Boc
N
Pd(dba)2
dppe
Ph
1a
+
PhCH=NBoc
2n
86%
2j
2k
2l
3j
3k
3l
(
)
O
3p
NHBoc
NH2
Pd/C H
,
2
TFA
82%
2m
Furyl
3m
HO
HO
95%
a
b
c
All the reactions were run under optimal reaction conditions.
Isolated yields.
4b
4c
Determined by 1H NMR. Piv = COBut.
Scheme 2.