Microwave-assisted synthesis of pyrrolidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.06.062

Microwave-assisted bismesylate amination is an efficient method of synthesizing pyrrolidine ring derivatives and provides a good to excellent product yield.

Full text of DOI:10.1016/j.tetlet.2009.06.062

Tetrahedron Letters 50 (2009) 4925–4929
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Tetrahedron Letters
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Microwave-assisted synthesis of pyrrolidine derivatives
Yuan-Chun Chang a, Jiun-Ly Chir b, Shuan-Yi Tsai a, Wei-Fu Juang a, An-Tai Wu a,
*
a Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
b Biotechnology Center in Southern Taiwan, Academia Sinica, Tainan County 744, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave-assisted bismesylate amination is an efficient method of synthesizing pyrrolidine ring deriv-
atives and provides a good to excellent product yield.
Received 13 April 2009
Revised 2 June 2009
Accepted 12 June 2009
Available online 16 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Bismesylate
Pyrrolidine
Microwave irradiation
Polyhydroxylated pyrrolidines,1 a sub-class of iminosugars that
naturally occurs in plants and microorganisms, have attracted
attention due to their significant biological activities. Many of
them are potent glycosidase and glycosyltransferase inhibitors2
because their structures mimic the transition states of an en-
zyme-catalyzed reaction. The hydroxylated pyrrolidine analogues,
ciency of this approach, this study explores the use of microwave
irradiation to develop an efficient and rapid procedure for prepar-
ing N-substituted pyrrolidine analogues. These compounds may
lead to precursors of potent glycosidase inhibitors.
HO
H
N
H
N
HO
OH
such as 1,4-dideoxy-1,4-imino-
inhibitory potential and a broad inhibitory spectrum toward mam-
malian glucosidases, including -glucosidase II, -mannosidases I
and II, intestinal isomaltase, and trehalase.3 In addition, 1,4-dide-
oxy-1,4-imino- -arabinitol (LAB1) 2, the isomer of 1, shows po-
tent inhibition toward the -arabinofuranosidase III of Monilinia
D-arabinitol (DAB1) 1, show potent
HO
HO
OH
a
a
1
2
L
L
N-Substituted pyrrolidine analogues were synthesized by the
amination of dimesylate 3a with various alkylamines (Scheme 1).
Heating dimesylate 3a with various alkylamines under reflux con-
ditions in the absence of solvent produced some of the desired
products (4a–e), but only at a low yield (Table 1, entries 1, 3, 5,
7, and 9). However, when 2-aminoethanol was applied under con-
ventional conditions, the amination reaction could not produce the
desired product 4f even with an extended reaction time (entry 11).
The conversion was markedly improved when the reaction was
performed under microwave conditions in a microwave oven
a
-L
fructigena.4 Therefore, many synthetic approaches have focused
on the preparation of analogues of polyhydroxylated pyrrolidines
1 derived from carbohydrates5 and non-carbohydrates.6 However,
the preparations of pyrrolidine analogues7 are multistep proce-
dures and provide low yield and/or poor stereoselectivity. Among
these, construction of the pyrroline ring through amination of ben-
zylamine with dimesylate analogues to afford N-benzyl pyrrolidine
derivatives has been reported.8 However, under conventional con-
ditions, this kind of transformation often requires a long reaction
time and high temperature to allow the substitution to take place
and, at best, the product yield is low. Therefore, finding a practical
method to synthesize pyrrolodine analogues is necessary. Micro-
wave-assisted reaction conditions9 are well known and greatly in-
crease yields, but their application in the field of carbohydrate
research has not been yet widespread. To demonstrate the effi-
R
N
BnO
OMs
RNH2
4
OMs
1
5
2
3
BnO
BnO
OBn
BnO
R
3a R = OBn down
3b R = OBn up
4 R = OBn down
5 R = OBn up
* Corresponding author. Fax: +886 4 7211 190.
E-mail address: antai@cc.ncue.edu.tw (A.-T. Wu).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.062

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Y.-C. Chang et al. / Tetrahedron Letters 50 (2009) 4925–4929
Table 1
Comparative amination of dimesylate 3 under microwave irradiation and under conventional conditions10
Entry
Reactant
Product
Temp (°C)
Microwave
Time (min)
Conventional
Time (min)
Yield (%)
Yield (%)
Bn
N
1a
BnNH2
120
20
20
99
120
58
BnO
BnO
OBn
4a
Bn
OBn
N
N
N
2a
BnNH2
120
120
97
99
BnO
BnO
5a
O
3a
10
90
75
O
NH2
BnO
BnO
BnO
OBn
OBn
4b
5b
O
4a
120
10
93
O
H2N
H2N
NH2
BnO
NH2
5a
116
116
10
10
99
96
600
67
NH2
N
BnO
BnO
BnO OBn
NH2
4c
5c
6a
NH2
OBn
N
BnO
NH2
NH
H
N
7a
120
10
99
60
85
H2N
NH2
N
BnO
BnO OBn
NH2
4d
NH
H
N
8a
120
10
99
H2N
NH2
OBn
N
BnO
BnO
BnO
5d
4e
9a
N
84
60
76
1110
36
NH2
BnO
OBn

Y.-C. Chang et al. / Tetrahedron Letters 50 (2009) 4925–4929
4927
Table 1 (continued)
Entry
Reactant
Product
Temp (°C)
Microwave
Time (min)
Conventional
Yield (%)
Time (min)
Yield (%)
10a
84
60
10
10
70
OBn
N
N
NH2
BnO
BnO
HO
5e
11a
120
120
97
95
4320
—
NH2
HO
HO
BnO
BnO
BnO OBn
HO
4f
12a
NH2
OBn
N
BnO
5f
NH2
BnO
BnO
BnO
N
N
OBn
OBn
13a
120
120
120
30
20
30
—
4320
4320
4320
—
—
—
N
BnO
BnO OBn
4g
4c
OBn
BnO
BnO
BnO
H
N
N
OBn
OBn
14b
78
N
H2N
NH2
OBn
NH2
4g
4g
BnO
NH
BnO
BnO
N
OBn
OBn
15b
64
N
N
BnO
BnO OBn
OBn
4d
a
This reaction was performed under solvent-free conditions. (—) = no reaction.
This reaction was performed in toluene. (—) = no reaction.
b
(300 W) for 10 min, producing the corresponding N-alkylated pyr-
rolidine derivative (4a–f, entries 1, 3, 5, 7, 9, and 11).10 The amina-
tion of dimesylate 3b with various alkylamines was also performed
under microwave conditions, producing an excellent yield of prod-
ucts (5a–f, entries 2, 4, 6, 8, 10, and 12). In both the synthesized N-
alkylated pyrrolidine derivatives 4 and 5, the synthetic processes
did not change the absolute configurations at C(2) or C(3). How-
ever, the configuration at C(4) was inverted to that of the starting
sired product 4g (Table 1, entry 13). Surprisingly, amination of 4d
or diethylenetriamine with dimesylate 3a (3.0 equiv) in toluene for
20–30 min under microwave irradiation produced a Hoffman elim-
ination product 4g as the major product,11 and none of the desired
compound 6 (entries 14 and 15). In contrast, we could not obtain
the Hoffman elimination product 4g or 6 under conventional heat-
ing conditions. The proposed mechanism for this transformation is
shown in Scheme 2. These results demonstrate that the micro-
wave-assisted approach overcame steric problems and produced
intermediate 7, which underwent further elimination to produce
4g.
material, which resulted from
process.
a stereocontrolled cyclization
Based on these results, we attempted to extend this methodol-
ogy to the synthesis of dimeric pyrrolidine derivatives using simi-
lar conditions, except for variations in the solvent (Table 1).
Amination of 4c with dimesylate 3a in toluene under both types
of heating conditions was not successful and did not yield the de-
Compound 6 can be obtained using the N-alkylated derivative
4f as the starting material. When 4f underwent standard mesyla-
tion in the presence of triethylamine or pyridine, it produced an
unexpected chloride derivative 8 (62%) instead of the mesyl deriv-

4928
Y.-C. Chang et al. / Tetrahedron Letters 50 (2009) 4925–4929
NH2
BnO
NH
BnO
BnO
H
3a
N
N
or
N
H2N
NH2
NH
OBn
OBn
toluene
MW 20-30 min
N
BnO
BnO OBn
3a, toluene
MW 20-30 min
6
4d
OBn
BnO
B:
BnO
OBn
OBn
OBn
BnO
BnO
N
OBn
OBn
BnO
N
BnO
H
Hoffman elimination
N
N
N
OBn
4g
BnO
OBn
OBn
7
Scheme 2.
BnO
OH
Cl
BnO
BnO
N
N
N
(a)
(b)
NH
OBn
OBn
BnO
BnO
BnO
OBn
N
BnO OBn
4f
8
6
OBn
Scheme 3. Reagents and conditions: (a) MsCl, TEA; CH2Cl2; (b) 4c, TEA, CH3CN.
BnO
OH
N3
BnO
BnO
N
N
N
(b)
(a)
BnO
BnO
N
N
OBn
OBn
BnO OBn
BnO
OBn
N
N
4f
9
10
OBn
Scheme 4. Reagents and conditions: (a) HN3, THF; (b) Cu(0), 4e, MeOH.
ative. Compound 6 can be successfully obtained by treatment of 8
with 4c and TEA in CH3CN under conventional refluxing for 19 h,
but the yield of 6 is low (36%). However, when this reaction was
performed under microwave conditions at 80 °C for 20 min in
CH3CN, the yield improved to 57% (Scheme 3).
times from 1.5–72 h to 10–30 min and the yields are also im-
proved. Following subsequent deprotection, these compounds
may lead to more potent glycosidase inhibitors and such work is
currently underway.
With compounds 4e and 4f in hand, we then attempted to syn-
thesize the dimeric pyrrolidine derivative 10 using a triazole as a
linker (Scheme 4). Treating 4f with hydrazoic acid (HN3) in THF
produced the azido derivative 9. Compound 9 was treated with
4e and copper(I) catalyst in ethanol under reflux12 for 12 h, pro-
ducing the sugar triazole 10 (44%) with 1,4-regioselectivity. When
this reaction was conducted under microwave conditions with
20 min irradiation, the yield improved to 65%.
Acknowledgment
This work was supported by the National Science Council of
Taiwan.
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a
yellow syrup. 1H NMR (CDCl3,
300 MHz): d 7.39–7.19 (m, 15H, Ph), 4.74, 4.63 (AB, J = 12.0 Hz, 2H, PhCH2),
4.58 (s, 2H, PhCH2), 4.49 (s, 2H, PhCH2), 4.05 (dd, J = 8.4, 4.5 Hz, 1H, H-3), 3.99
(dd, J = 9.9, 5.1 Hz, 1H, H-4), 3.84 (dd, J = 9.0, 6.6 Hz, 1H, H-1a), 3.63 (dd, J = 9.3,
5.7 Hz, 1H, H-1b), 3.20 (dd, J = 10.5, 5.1 Hz, 1H, H-5a), 3.04 (dd, J = 12.3, 6.6 Hz,
1H, H-2), 3.01–2.88 (m, 1H, H-6a), 2.67 (dd, J = 10.5, 6.3 Hz, 1H, H-5b), 2.65–
2.51 (m, 1H, H-6b); 13C NMR (CDCl3, 75 MHz): d 138.6 (Ph), 138.5 (Ph), 138.4
(Ph), 128.2 (Ph), 128.2 (Ph), 128.1 (Ph), 127.6 (Ph), 127.6 (Ph), 127.4 (Ph), 127.4
(Ph), 127.3 (Ph), 78.3 (C-3), 77.3 (C-4), 73.2 (PhCH2), 72.8 (PhCH2), 71.6
(PhCH2), 70.0 (C-1), 64.8 (C-2), 55.7 (C-5), 54.5 (C-6); HRMS (FAB): calcd for
C54H61N2O6 (M+H), m/z 833.4530; found m/z 833.4527.
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