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Chemistry Letters Vol.38, No.6 (2009)
Gallium(III) Chloride-catalyzed Sakurai Reaction of ꢀ-Amido Sulfones with Allyltrimethylsilane:
Access to Synthesis of 2,6-Disubstituted Piperidine Alkaloid Derivatives
R. Sateesh Chandra Kumar, G. Venkateswar Reddy, K. Suresh Babu, and J. Madhusudana Raoꢀ
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 607, India
(Received February 19, 2009; CL-090173; E-mail: janaswamy@iict.res.in)
NHCbz
The Sakurai reaction of N-alkoxycarbonylamino sulfones (ꢀ-
amido sulfones) with allyltrimethylsilane in the presence of galli-
um(III) chloride (5 mol %) proceeded smoothly to afford the corre-
sponding protected homoallylamines in high yields (82–96%). As
an application of this methodology, two-step synthesis of biologi-
cally active natural products, 2,6-disubstituted piperidine alkaloid
derivatives was carried out.
NHCbz
GaCl3 (5 mol %)
CH2Cl2, rt, 3 h
+
Me3Si
R
R
SO2Tol
1
2
3
Scheme 2.
Table 1.
Entry
Catalyst loading (x mol %)
Time/h
Yield/%a,b
Over the past few decades, Lewis acid catalyzed allylation
has become an important carbon–carbon bond-forming reaction
in organic synthesis.1 Allylation of aldimines provides a useful
synthetic method for homoallylamines, which are versatile
building blocks for the synthesis of ꢁ-amino acids, ꢁ-lactams,
ꢂ-lactams, aziridines, amines, HIV-protease inhibitors, and bio-
logically active nitrogen-containing natural products.2,3 In gen-
eral, homoallylamines are prepared either by the addition of or-
ganometallic reagents to imines or by the nucleophilic addition
of allylsilane, allylstannane, allylborane, or allylgermane re-
agents to imines in the presence of acid catalysts.4 Consequently,
several methods have been reported for the allylation of aldi-
mines in the presence of Lewis acids, such as TiCl4, Sc(OTf)3,
BF3ꢁOEt2, PdCl2(PPh3)2, PtCl2(PPh3)2, Selectfluor, Bi(OTf)3,
and iodine.5 However, imines in general tend to unstable during
purification and methods involving in situ formation of imines
are preferable. It is well known that N-acyliminiums are attrac-
tive alternatives, which are prepared6 from stable precursors.
As shown in Scheme 1, N-alkoxycarbonylamino sulfones
(generally referred as ꢀ-amido sulfones) have been prepared7
from aldehydes, sodium p-toluenesulfinate or benzenesulfinate,
and a suitable carbamate. They are converted to N-alkoxycar-
bonyl imine derivatives through treatment with Lewis acid
(Scheme 1).8 Thus, Lewis acid catalyzed Sakurai reaction of
these sulfones with the allyltrimethylsilane constitutes an impor-
tant method for the synthesis of homoallylamines.
In continuation of our efforts to develop useful synthetic
methodologies,9 herein we wish to report gallium(III) chloride-
catalyzed Sakurai reaction of ꢀ-amido sulfones with allyltri-
methylsilane, which produces homoallylamines in high yields
at room temperature (Scheme 2). In addition, two-step synthesis
of 2,6-disubstituted piperidine derivatives is also reported as an
application of this methodology.
To define the optimal reaction conditions, we have studied
the Sakurai reaction of ꢀ-amido sulfone 1a (R = C7H15) and
allyltrimethylsilane (2) as model substrates to afford the homo-
allylamine. Optimization experiments with respect to the cata-
1
2
3
4
5
1
2
5
5
10
3
3
3
9
3
35
50
94
96
95
aYields of pure isolated compounds after column chromatography.
bReaction conditions: ꢀ-amido sulfone (1 mmol), allyltrimethyl silane
(1.3 mmol), GaCl3 x mol %, and the reaction was carried out at rt.
lyst revealed that 5 mol % of the GaCl3 was found to be the most
effective (Table 1) as observed by the TLC monitoring, which
indicated the total disappearance of the starting material after
3 h. Moreover, a decreased quantity of GaCl3 (1% vs. 5%) led
to the low yield of the homoallylamines. However, higher
amounts of the catalyst (10 mol %) did not improve the yields
even after prolonged reaction times. We have also examined
several Lewis acids such as Bi(OTf)3, InCl3, ZrCl4, and CuBr2
for this transformation (Table 2). Among these, GaCl3 was found
to be an efficient catalyst for the formation of the corresponding
Cbz-protected homoallylamines in excellent yield after extrac-
tive work up and purification. Encouraged by the results, we
studied the scope of this reaction with respect to the ꢀ-amido
sulfones employed in the process (results are summarized in
Table 3). Interestingly, a wide range of substrates including ar-
omatic, aliphatic, heteroaromatic, and alicyclic sulfones reacted
efficiently under similar conditions to give the corresponding ho-
moallylamines in excellent yields. To the best of our knowledge,
to date only two catalytic Sakurai reactions of ꢀ-amido sulfones
with allyltrimethylsilane have been reported using bismuth tri-
flate and indium chloride.8,10 These protocols suffer from longer
reaction times (generally 9–44 h) and low yields (generally 50–
75%). For comparison, in preparation of 3l with Bi(OTf)3 and
InCl3 the reaction times are 26 and 10 h, yields are 74 and
78% respectively,8,10 whereas the present method requires only
3 h and yield is 90%. Moreover, sulfones derived from the ali-
phatic aldehyde 1a requires much longer times (Table 2). There
are advantages with gallium(III) chloride for this conversion,
which require neither harsh conditions nor long reaction times.
In addition, the present method is equally effective for ꢀ-amido
sulfones derived from aliphatic aldehydes (open chain and cy-
clic), aromatic aldehydes (bearing electron-donating and elec-
tron-withdrawing substituents), sterically hindered aldehyde
(2-naphthaldehyde, Table 3, Entry j), and acid-sensitive alde-
hyde (furfuraldehyde, Table 3, Entry k) to afford excellent yields
in a short period (Table 3). The present method is mild to toler-
NHCOOR'
NHCOOR'
R'OC(O)NH2
ArSO2Na
Lewis acid
RCHO
R
SO2Ar
aq HCOOH
R
R, R' = Alkyl, Aryl
Scheme 1.
Copyright Ó 2009 The Chemical Society of Japan
Kumar, R. Sateesh Chandra
