Base-promoted reaction of methyl 4,6-O-benzylidene-3-deoxy-hexopyranosid-2- ulose and various arylamines

Article abstract of DOI:10.1016/j.tetlet.2011.08.106

Reaction of methyl 4,6-O-benzylidene-3(2)-deoxy-hexopyranosid-2(3)-ulose (1) with various arylamines under Bargellini reaction conditions was investigated. A series of unique enaminoketones 3-12 was obtained unexpectedly under basic conditions in 52-72% y

Full text of DOI:10.1016/j.tetlet.2011.08.106

Tetrahedron Letters 52 (2011) 5693–5696
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Tetrahedron Letters
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Base-promoted reaction of methyl
4,6-O-benzylidene-3-deoxy-hexopyranosid-2-ulose and various arylamines
Jun Sun a, , Xuefeng Zhang b, , Fulong Li b, Chunyong Ding b, Wenjuan Wu a, , Ao Zhang b,
⇑
⇑
a School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
b Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences (CAS), Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of methyl 4,6-O-benzylidene-3(2)-deoxy-hexopyranosid-2(3)-ulose (1) with various arylamines
under Bargellini reaction conditions was investigated. A series of unique enaminoketones 3–12 was
obtained unexpectedly under basic conditions in 52–72% yield.
Received 20 July 2011
Revised 12 August 2011
Accepted 19 August 2011
Available online 25 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aminoglycosidation
Glycal
Arylamine
Base
Bargellini reaction
3-Amino-prop-2-en-1-ones are a class of unique compounds
bearing a double bond in Z-conformation due to the intramolecular
H-bonding between the carbonyl and the NH group. These com-
pounds are generally prepared by transition-metal-catalyzed trans-
formation of propargyl alcohol with an appropriate amine.1,2 During
our study on the glycosidation of glycals and arylamines,3,4 we pro-
H-3 (dH 7.36 ppm) and C-1 carbonyl, as well as H-3 and the quater-
nary C-5 in the aniline phenyl moiety (Fig. 2). The Z-conformation
of the double bond in 3 was ascertained by the coupling constant1
of 7.8 Hz between the two vinyl protons. The chemical shift of NH
moved to much downfield (dH 12.13 ppm) indicating the existence
of an intramolecular H-bonding with the carbonyl group. Finally,
single X-ray crystal of enaminoketone 3 was obtained after a care-
ful crystallization from CHCl3 that further secured the unique
structure of the product (Fig. 2).
To achieve a better yield, the reaction condition was optimized.
Originally, the reaction was conducted under typical Bargellini
reaction condition in which 1.0 equiv of 4-methoxyaniline was
reacted with 3.0 equiv of ketone 1, 5.0 equiv of CHCl3, and NaOH
in THF. Compound 3 was obtained in 52% isolated yield (entry 1,
Table 1). Reducing the amount of NaOH to 3.0 equiv improved
the work-up of the reaction and slightly improved the yield (entry
2). It is of note that compound 3 was obtained in identical yield
with or without the addition of CHCl3 confirming that the origi-
nally proposed Bargellini reaction process did not occur. Decreas-
ing NaOH to 1.0 equiv (entry 3) or reducing the amount of
ketone 1 (entry 4) significantly slowed down the reaction process.
Increasing the amount of ketone 1 to 5.0 equiv did not change the
yield significantly and compound 3 was isolated in 55% yield (entry
5). It was further found that LiOH was also able to promote the
reaction leading to product 3 in 56% yield (entry 6), compatible
to that using NaOH as the base. Weaker base Cs2CO3 initiated the
reaction as well but gave a much lower yield (entry 7). However,
the reaction did not occur using other organic or inorganic bases
posed to synthesize
zylidene-3(2)-deoxy-
a
a
–aminoacid 2 by treating methyl 4,6-O-ben-
-erythro-hexopyranosid-2(3)-ulose (1)
-D
with 4-methoxyaniline under Bargellini reaction conditions.5–8
The mechanism of this type of reactions includes deprotonation of
chloroform by NaOH followed by nucleophilic attack on the ketone
19 to yield dichloro epoxide intermediate I. Subsequent regioselec-
tive epoxide ring-opening by aniline followed by hydrolysis of the
resulting acid chloride II (Fig. 1) would yield the expected product 2.
To our surprise, the reaction of pyranose 1 with 4-methoxyan-
iline and NaOH in CHCl3 under standard Bargellini reaction condi-
tions went through smoothly, but the product we obtained was not
the expected compound 2, instead (Z)-1-(2-phenyl-6H-1,3
-dioxin-4-yl)-3-(4-methoxyphenylamino) prop-2-en-1-one (3)
was formed in 52% isolated yield.
Enaminoketone 3 was characterized by spectroscopic data (1H
and 13C NMR, MS, HRMS, HMQC, 1H–13C COSY). Such unusual
structure of 3 was also evidenced by the HMBC correlations
between H-50 (dH 5.84 ppm) and C-1 carbonyl (dC 183.8 ppm),
⇑
Corresponding authors.
E-mail address: aozhang@mail.shcnc.ac.cn (A. Zhang).
These two authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.106

5694
J. Sun et al. / Tetrahedron Letters 52 (2011) 5693–5696
O
OCH3
O
O
OCH3
O
O
NaOH,CHCl3
THF, rt, 52%
H2N
OMe
Ph
O
Ph
O
HOOC
N
H
OCH3
1
2
NH2
O
OCH3
O
O
OCH3
O
O
OCH3
O
O
O
OMe
-HCl
-Cl-
-CCl3
Ph
O
Cl
Cl
Cl
O
Ph
O
Ph
HN
OCH3
O
I
II
Figure 1. Proposed reaction of pyranose 1 with 4-methoxyaniline under Bargellini reaction condition.
H
5'
O
6'
O
4
5
1'
HN
O
O
1
4'
2
2' 3'
3
Ph
H
3
(HMBC)
Figure 2. HMBC and X-ray crystal analyses of 3.
Table 1
Optimization of reaction conditionsa
O
O
OCH3
O
O
HN
O
O
OMe
H2N
O
Ph
O
Ph
1
3
Entry
Base/acid
Equiv
Ratio (ketone 1:4-methoxyaniline)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
NaOH
NaOH
NaOH
NaOH
NaOH
LiOH
5
3
1
3
3
3
3
3
3
3
3
3
3
3
3:1
3:1
3:1
1:1
5:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
52
58
Trace
<20
55
56
23
Cs2CO3
Na2CO3
DBU
Trace
NRc
NRc
NRc
NRc
NRc
NRc
EtN(iPr)2
NEt3
BF3ꢀEt2O
FeCl3
TiCl4
a
The reaction was conducted with 1.0 equiv of 4-methoxyaniline, appropriate amount of ketone 1, 5.0 equiv of chloroform, and appropriate amount of NaOH in 10 mL of
anhydrous THF at rt overnight.
b
Isolated yield.
NR = no reaction.
c
(Na2CO3, DBU, NEt3, EtN(iPr)2 (entries 8–11). In addition, several
Lewis acids were also used and no reaction was observed at all
(entries 12–14).
arylamines bearing larger substituent (entry 8), or ortho-substitu-
ent (entry 6) also led to good yields. Arylamines with an elec-
tron-withdrawing substituent (entry 10) participated in this
reaction as well and the corresponding product 12 was obtained
in 52% yield. However, reaction using N-methyl substituted aryl-
amine did not go through apparently due to the steric effect of
the N-methyl group (entry 11). Further, using alkyl amines also
did not afford the expected products.
Based on the results obtained above, the optimal reaction
condition is to use 3.0 equiv of ketone 1, 1.0 equiv of aniline, and
3.0 equiv of NaOH in THF leading to product 3 in 58%. To explore
the practicality of this reaction in the preparation of enaminoke-
tones, various arylamines were used to react with ketone 1, and
the results were summarized in Table 2.10 Most arylamines partic-
ipated in this reaction and the corresponding enaminoketones
3–12 were obtained in 52–72% yields. Both mono- and di-substi-
tuted arylamines gave compatible yields. Reactions using
To rationale this reaction, a tentative base-initiated mechanism
was proposed. As described in Figure 3, ketone 1 would easily lose
a proton (a to the carbonyl) upon a base-attacking to form an anion
intermediate I. Ring-opening would then occur to form

J. Sun et al. / Tetrahedron Letters 52 (2011) 5693–5696
5695
Table 2
Reactions of ketone 1 with various arylaminesa
6
7
O
5
8
R
HN
O
Entry
Arylamine
Yieldb (%)
O
Ph
1
2
3
4
5
6
7
8
9
4-MeO-PhNH2
Aniline
p-Toluidine
3 (R = 8-MeO)
4 (R = H)
5 (R = 8-Me)
6 (R = 8-Et)
7 (R = 8-EtO)
8 (R = 6-MeO)
9 (R = 7-Me)
10 (R = 8-Morc)
11 (R = 7,8-di-MeO)
12 (R = 8-Br)
—
58
54
69
71
63
55
63
65
72
52
4-Et-PhNH2
4-EtO-PhNH2
2-MeO-PhNH2
m-Toluidine
4-Mor-PhNH2
3,4-Di-MeO-PhNH2
4-Br-PhNH2
N-Me-PhNH2
10
11
d
—
a
b
c
The reaction was conducted on 1.0 mmol scale of arylamine using the optimized conditions.
Isolated yield.
Mor = morpholin-4-yl.
No reaction.
d
O
OCH3
O
5
Ph
Ph
O
O
2
1
O
O
4
Ph
Ph
OH
O
O
O
3
OCH3
O
OCH3
O
O
I
II
NH2-Ar
O
O
O
OCH3
O
O
O
-CH3OH
-OH
O
H
O
HN Ar
N
O
Ar
OCH3
Ph
O
1
Ph
O
3-12
III
Figure 3. Possible base-initiated mechanism.
4. Ding, C.; Tu, S.; Li, F.; Wang, Y.; Yao, Q.; Hu, W.; Xie, H.; Meng, L.; Zhang, A. J.
Org. Chem. 2009, 74, 6111–6119.
5. Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329–332.
6. Butcher, K. J.; Hurst, J. Tetrahedron Lett. 2009, 50, 2497–2500.
7. Cvetovich, R. J.; Chung, J. Y. L.; Kress, M. H.; Amato, J. S.; Matty, L.; Weingarten,
M. D.; Tsay, F.-R.; Li, Z.; Zhou, G. J. Org. Chem. 2005, 70, 8560–8563.
8. Rychnovsky, S. D.; Beauchamp, T.; Vaidyanathan, R.; Kwan, T. J. Org. Chem.
1998, 63, 6363–6374.
enolate-like II. Subsequent Michael addition of arylamine gener-
ated species III that then underwent elimination of MeOH and
OHꢁ under basic condition to yield products 3–12. Theoretically,
this reaction also likely went through by a Lewis acid, however,
replacing NaOH with Lewis acids such as BF3, TiCl4, or FeCl3 did
not promote this reaction at all (Table 1, entries 12–14).11
In summary, reaction of methyl 4,6-O-benzylidene-3(2)-deoxy-
hexopyranosid-2(3)-ulose (1) with various arylamines under
Bargellini reaction conditions was investigated. A series of unique
enaminoketones 3–12 was obtained in 52–72% yield, and a base-
promoted mechanism was proposed.
9. Peseke, K.; Feist, H.; Cuny, E. Carbohydr. Res. 1992, 230, 319–325.
10. General experimental procedure: To a solution of methyl 4,6-O–benzylidene-
2-deoxy-a-D-erythro-hexopyran-osid-3-ulose (129 mg, 0.49 mmol) and
arylamines (0.16 mmol) in THF (10 mL) NaOH (20 mg, 0.48 mmol) were
added. The mixture was stirred at 0 °C for 0.5 h and then at room
temperature for 12 h. The solution was extracted with EtOAc, washed with
water, brine, dried over anhydrous Na2SO4 and filtered. The solvent was
removed under reduced pressure to give a residue which was then purified by
chromatography on silica gel to afford products 3–12 as yellow solid.
Acknowledgments
For (Z)-3-(4-methoxyphenylamino)-1-(2-phenyl- 4H-1,3-dioxin-6-yl) prop-2-en-
1-one (3): 1H NMR (400 MHz, CDCl3) d 12.13 (d, J = 12.4 Hz, 1H, NH), 7.59 (m,
2H, Ar), 7.41 (m, 3H, Ar), 7.40 (m, 1H, H-30), 7.02 (d, J = 9.2 Hz, 2H, ArOMe), 6.88
(d, J = 9.2 Hz, 2H, ArOMe), 6.12 (d, J = 1.6 Hz, 1H, H-20), 5.84 (d, J = 7.6 Hz, 1H,
H-2), 5.83 (s, 1H, H-50), 4.70 (dd, J = 17.2, 2.4 Hz, 1H), 4.57 (dd, J = 17.2, 3.6 Hz,
1H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) d 183.8, 156.6, 151.0, 146.8, 136.9,
133.4, 129.3, 128.4 (2C), 126.4 (2C), 118.1 (2C), 114.9 (2C), 105.5, 98.3, 91.50,
65.1, 55.6; MS (EI-LR) 337 (M+); HRMS (EI) calcd for C20H19NO4 (M+) 337.1314;
found 337.1295. For (Z)-1-(2-phenyl-4H-1,3-dioxin-6-yl)-3-(phenylamino) prop-
2-en-1-one (4): 54%; yellow solid; 1H NMR (300 MHz, CDCl3) d 12.04 (d,
J = 11.7 Hz, 1H), 7.58 (dd, J = 6.6, 2.7 Hz, 2H), 7.44 (m, 4H), 7.33 (t, J = 7.8 Hz,
2H), 7.08 (t, J = 7.8 Hz, 3H), 6.13 (m, 1H), 5.88 (d, J = 7.8 Hz, 1H), 5.82 (s, 1H),
4.69 (dd, J = 17.5, 2.1 Hz, 1H), 4.56 (dd, J = 17.4, 3.6 Hz, 1H); 13C NMR (75 MHz,
The authors are grateful to the Chinese National Science Foun-
dation (81072528), Shanghai Commission of Science and Technol-
ogy (10410702600, 10JC1417100, 10dz1910104), National Science
& Technology Major Project on ‘Key New Drug Creation and Man-
ufacturing Program’ (2009ZX09301-001, 2009ZX09103-062).
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.106.
CDCl3)
d 184.3, 150.9, 145.9, 139.8, 136.9, 129.7(2C), 129.3, 128.4(2C),
126.4(2C), 124.0, 116.4(2C), 105.8, 98.3, 92.3, 65.0; MS (EI-LR) 307 (M+);
HRMS (EI) calcd for C19H17NO3 (M+) 307.1208; found 307.1190. For (Z)-1-(2-
phenyl-4H-1,3-dioxin-6 yl)-3-(p-tolyl amino)prop-2-en-1-one (5): 69%; yellow
solid; 1H NMR (300 MHz, CDCl3) d 12.06 (d, J = 12.9 Hz, 1H), 7.58 (dd, J = 7.5,
2.1 Hz, 2H), 7.45 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.12
(dd, J = 3.6, 2.4 Hz, 1H), 5.87 (d, J = 7.8 Hz, 1H), 5.82 (s, 1H), 4.69 (dd, J = 17.4,
2.2 Hz, 1H), 4.56 (dd, J = 17.4, 3.6 Hz, 1H), 2.32 (s, 3H); 13C NMR (75 MHz,
References and notes
1. Haak, E. Eur. J. Org. Chem. 2007, 2815–2824.
2. Haak, E. Synlett 2006, 1847–1848.
3. Li, F.; Ding, C.; Wang, M.; Yao, Q.; Zhang, A. J. Org. Chem. 2011, 76, 2820–2827.

5696
CDCl3)
J. Sun et al. / Tetrahedron Letters 52 (2011) 5693–5696
d
184.0, 150.9, 146.3, 137.5, 133.8, 130.2(2C), 129.3, 128.4(2C),
126.4(2C), 116.5(2C), 105.6, 98.3, 96.6, 91.8, 60.5, 20.8; MS (EI-LR) 321 (M+);
HRMS (EI) calcd for C20H19NO3 (M+) 321.1365; found 321.1366.
11. In the course of submission of this Letter, one reviewer suggested an
alternative mechanism (showing below), where base-attack and
deprotonation occur at the C-4, instead of C-2. Although C-2 is generally
more active than the C-4 in substrate 1 due to the effect of the C-1 acetal, this
mechanism can not be excluded.
OH
H
O
O
Ph
Ph
O
2
O
O
4
O
Ph
Ar
NaOH
-H2O
O
H
O
-CH3O
O
O
OCH3
O
OCH3
1
O
O
II
I
H
O
O
NH2-Ar
N
-H2O
HN
O
Ar
O
Ph
O
3-12
H
H
H
Ph
OH
III