A rapid and simple amine-catalyzed microwave-assisted isomerization of maleamides into fumaramides

Article abstract of DOI:10.1016/j.tetlet.2011.04.066

An improved, efficient, and simple method for the synthesis of nonsymmetrical diamides of fumaric acid is reported. Starting from commercially available substrates, maleic diamides are formed in two steps, and then isomerized in a focused microwave reactor in acetonitrile as the solvent in the presence of a catalytic amount of piperidine, giving the corresponding fumaramides in high yields and purity.

Full text of DOI:10.1016/j.tetlet.2011.04.066

Tetrahedron Letters 52 (2011) 3287–3290
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A rapid and simple amine-catalyzed microwave-assisted isomerization
of maleamides into fumaramides
⇑
ˇ
Vita Majce, Marijan Kocevar, Slovenko Polanc
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerceva 5, SI-1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved, efficient, and simple method for the synthesis of nonsymmetrical diamides of fumaric acid
is reported. Starting from commercially available substrates, maleic diamides are formed in two steps,
and then isomerized in a focused microwave reactor in acetonitrile as the solvent in the presence of a
catalytic amount of piperidine, giving the corresponding fumaramides in high yields and purity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 March 2011
Revised 16 March 2011
Accepted 15 April 2011
Available online 23 April 2011
Dedicated to Professor Miha Tišler on the
occasion of his 85th birthday.
Keywords:
Amine catalysis
Microwave irradiation
Isomerization
Fumaramides
The isomerization of maleamic derivatives (Z-form) to their fu-
maric counterparts (E-form) has been known for some time. Re-
With these results in mind, we turned our attention to their
C@C analogues that retain the main scaffold of the diazenedicar
boxamide structure (Fig. 2).
It is well known that these derivatives, fumaramides (E-iso-
mers), as well as their Z-isomers (maleamides), possess interesting
search has been conducted mostly on maleamic acids and esters
1
and isomerizations are known to be catalyzed by P4O10
,
NBS/
AIBN,2 thiourea and other thio reagents,3 PPh3,4 heating in the
presence of an acid,5 and with various organic amines.6 The isom-
erization of maleamides has been described to a much lesser ex-
tent: reactions leading to fumaramides being catalyzed in these
cases by UV irradiation in combination with bromine (in the for-
mation of gels),7 and in combination with rotaxanes entwined
around the maleamide core.8 The isomerization of simple mono-
substituted maleamides was achieved by the addition of almost
equimolar or even excess amounts of morpholine, thiophenol, or
aniline and refluxing in alcohol solutions.9 Structurally similar,
but electronically quite different, amidic hydroxamic acid deriva-
tives of maleic acid are known to isomerize in the presence of ben-
biological activities. Both, the maleamide and fumaramide of L-
DOPA methyl ester, were studied as anti-Parkinson’s prodrugs in
a liposomal formulation.13 It should be noted that macrocyles hav-
ing either a fumaramide or maleamide fragment in the ring suc-
cessfully modulate kinase activity.14 In the case of diamides with
an incorporated phenylalanine moiety, maleamide displays good
inhibition of rhodesain as well as good antitrypanosomal activity,
while the fumaramide only exhibits inhibition of rhodesain.15 Sev-
eral heptapeptides with fumaramide in their structure were de-
scribed as cysteine protease inhibitors active against falcipain
and rhodesain.16 Some fumaramides were found to be effective
irreversible inhibitors of epidermal growth factor receptors.17 Fur-
thermore, a fumaramide having the phenyl group on one nitrogen
and a thieno[2,3-d]oxazine functionality on the other is active
against HSV-2 and VZV proteases.18
zylamine, possibly via
a reversible Michael addition of the
benzylamine to the double bond.10
We have long been interested in the synthesis and transforma-
tions of various diazenes.11 Among them, several diazenedicarbox-
amides (Fig. 1) were found to be good inhibitors of an essential
bacterial enzyme
D-alanine:D-alanine ligase, having lower IC50
values than therapeutically used D
-cycloserine.12
O
H
N
N
R2
R1
N
N
H
O
⇑
Corresponding author. Tel.: +386 1 24 19 236; fax: +386 1 24 19 271.
E-mail address: slovenko.polanc@fkkt.uni-lj.si (S. Polanc).
Figure 1. General structure of diazenecarboxamides.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.066

3288
V. Majce et al. / Tetrahedron Letters 52 (2011) 3287–3290
Table 1
H
H
N
H
O
Optimization of the isomerization reaction under microwave conditions on model
H
substrate 2aa
H
N
R1
R2
R1
N
H
H
O
R2
O
N
H
N
O
N
H
O
H
MW
N
H
O
O
N
H
a
b
O
3a
2a
Figure 2. (a) Maleamides; (b) fumaramides.
Entry Solvent Catalyst
T
(°C)
t
Conversionb
(%)
Yieldc
(%)
(min)
In the light of the above-mentioned properties there is a need
for new and simple approaches toward maleamides and fumara-
mides. The shortest and cheapest route to both types of com-
pounds seemed to be synthesis of the Z-isomer, followed by its
isomerization into the E-isomer. The synthesis of the Z-isomer is
depicted in Scheme 1. First, monoamides of maleic acid 1a–k were
formed by reacting maleic anhydride with various primary and
secondary amines. The reactions proceeded quickly (within 1–
4 h) with good to excellent yields obtained. The isolation was sim-
ple; mostly the products precipitated from the reaction mixture
and were filtered, washed, and dried thoroughly, requiring no fur-
ther purification.19
Various procedures were investigated to carry out the second
step. Although many methods exist for the formation of the amide
bond only a few of them work on substrates such as 1a–k. Several
attempts via acid chlorides or mixed anhydrides, as well as activa-
tion of the acid with carbonyldiimidazole (CDI) failed, while cou-
pling with cyanuric chloride in the presence of NaOH or N,N0-
dicyclohexylcarbodiimide (DCC) gave very low yields (only up to
34%), especially for reactions where the monoamide had to be cou-
pled with an amine possessing a pyridine nitrogen in the structure
(e.g., 3-picolylamine). Finally, 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide (EDC) was found to work better for compounds
1a–k, giving moderate yields of up to 50%. If EDC was used as its
hydrochloride salt, with N-methylmorpholine (NMM) acting as a
base, the yield increased up to 97%. The improvements seem to
be connected with the choice of solvent (CH2Cl2 turned out to work
best) and shortening of the activation period with EDCꢀHCl to only
10 min.20
The third step, preparation of the fumaric diamides 3a–k, was
optimized on a model substrate N1-benzyl-N4-(m-tolyl)maleamide
(2a) and is summarized in Table 1. All the experiments were per-
formed in a focused microwave reactor, where the temperature,
pressure, and heating/cooling time could be monitored during
the reaction.21 Due to the lower solubility of 3a compared to 2a,
most of the product could be isolated directly from the reaction
mixture by filtering off the resulting solid.
The formation of the product 3a was observed after 30 min at
120 °C (entry 1), but the conversion and yield were low. By heating
at a higher temperature (150 °C) and for a longer time (2 h), a high-
er conversion was obtained (entry 2), but the isolated yield was
still low. Hence, we tried to optimize the reaction by varying the
solvent, the reaction temperature, and time and also used different
organocatalysts in very small amounts (8 mol %), in order to make
the reaction proceed even faster and with better conversion and
yields. Iodine (entry 3) did not work as a catalyst, while thiophenol
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
—
–
–
I2
120
150
120
30
120
35
30
10
10
10
10
10
10
10
5
20
30
120
10
10
10
10
10
23
86
4
15
49
2
Thiophenol 120
99
44
63
98
100
99
67
96
70
99
100
100
86
99
14
22
18
68
40
51
80
63
49
23
46
58
80
78
70
74
89
6
Aniline
n-BuNH2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
120
120
120
120
120
80
160
120
120
120
120
EtOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Morpholine 120
Piperidine
DABCO
Et3N
120
120
120
120
20
2
Pyridine
a
General procedure:
a mixture of 2a (0.5 mmol), solvent (0.5 mL), with or
without a catalyst (if present, then 8 mol %) was placed into a sealed glass vessel
together with a Teflon-coated magnetic stirring bar and heated in a microwave
reactor for the time and at the temperature specified in Table 1.
The conversion was determined by 1H NMR spectroscopy.
b
c
Isolated yields are given.
was the first to drive the conversion to practically 100%, giving a
moderate isolated yield, although only after a prolonged time of
0.5 h, and with the formation of side products (entry 4). Aniline
and n-butylamine gave moderate conversions and yields (entries
5–6). The benzylamine-catalyzed reaction (entry 7) gave a nearly
quantitative conversion and a very good yield, so we continued
with this catalyst and changed the solvent (entries 8 and 9).
Although the conversions either without solvent or in ethanol were
almost the same, the yields decreased and the isolation became
more complicated. Also, lowering the reaction temperature to
80 °C (entry 10) was not sufficient to achieve a quantitative con-
version, and the yield dropped to only 23%. On the other hand,
heating the reaction mixture to 160 °C (entry 11) did not seem to
change drastically the conversion, but did decrease the yield
significantly due to the formation of side products (presumably
addition of benzylamine to the double bond after the isomeriza-
tion). We also tried to enhance the yield by changing the reaction
time (entries 12–15); 5 min was insufficient for quantitative con-
version, while longer reaction times gave more side products
and lower yields, showing that the conversion is achieved
quantitatively in the first 10 min of the benzylamine-catalyzed
reaction. Furthermore, we decided to use various secondary and
R1
R1
N
O
N
a
b
O
O
R2
R2
O
R3
O
O
N
H
O
OH
1a− k
2a−k
Scheme 1. Synthesis of maleic acid mono (1a–k) and diamides (2a–k). Reagents and conditions: (a) R1R2NH (1 equiv), Et2O or Et2O/CH3CN or acetone, rt, 1–4 h (62–97%); (b)
R3NH2, EDCꢀHCl (1.1 equiv), NMM (2.1 equiv), CH2Cl2, 0 °C, 16–24 h (54–97%).

V. Majce et al. / Tetrahedron Letters 52 (2011) 3287–3290
3289
Table 2
Synthesis of fumaramides 3a–k
R1
N
uncatalyzed
R1
O
or piperidine (8 mol%)
R2
N
R3
R2
N
H
O
R3
CH3CN, 10 min,
O
2
N
H
O
120 °C, MW
3
Product
R1
R2
R3
Conversiona (%)
ic
Yieldb (%)
i
ii
ii
3a
3b
3c
3d
3-Me–C6H4–
4-Me–C6H4–
4-i-Pr-C6H4–
4-F–C6H4–
H
H
H
H
Benzyl
Benzyl
3-Picolyl
3-Picolyl
23d
45
8
99
15d
38
0
89
79
80
80
100
100
100
35
33
3e
H
3-Picolyl
12
97
12
88
3f
H
H
3-Picolyl
Benzyl
54
12
100
100
53
8
84
73
O
3g
O
3h
3i
3j
–(CH2)2O(CH2)2–
–(CH2)2NMe(CH2)2–
3,5-Cl–C6H3–
3-Cl–C6H4–
Benzyl
m-Tolyl
Phenyl
Phenyl
1
85
7
96
94
92
94
0
85
0
72
94
65
81
H
H
3k
8
0
a
b
c
The conversion was determined by 1H NMR spectroscopy.
Isolated yields are given.
(i) Uncatalyzed, (ii) piperidine-catalyzed (8 mol %).
Prolonged time of 30 min.
d
tertiary amines (entries 16–20). Morpholine gave a good conver-
sion and yield of the desired product (entry 16), but piperidine (en-
try 17) was even better, driving the reaction to quantitative
conversion and gave the highest isolated yield of 3a after 10 min
(89%). In addition, 1H NMR spectroscopic analysis of the remaining
filtrate showed that most of the product could be filtered directly
from the reaction mixture. The amines DABCO, triethylamine,
and pyridine (entries 18–20) did not work well for this reaction.
Thus the optimal conditions for the synthesis of fumaramides
3a–k using piperidine as a catalyst were: 10 min, 120 °C, 200 W,
8 mol % of catalyst. The results are summarized in Table 2.22
Overall, piperidine was shown to work well as a catalyst, as it
increased the conversion and yields in all cases. For reactions that
barely proceeded when uncatalyzed (3c,e,g,h,j,k, 1–12%), it
enhanced the conversion by almost 100-fold (92–100%) with
good-to-excellent isolated yields (65–88%). The reactions that
proceeded uncatalyzed with only moderate conversions (3a,b,d,f,
23–54%) and low yields (15–53%), were driven to quantitative con-
versions and excellent yields of 79–89%. Interestingly, piperidine
also improved the result in the case of 3i. In this case, the conver-
sion and yield of the uncatalyzed reaction were already 85%, but
the addition of 8 mol % of piperidine increased the conversion to
94%.
Ljubljana, Slovenia) for recording mass spectra. This work was also
partially supported with infrastructure of the EN-FIST Centre of
Excellence, Ljubljana, Slovenia.
Supplementary data
Supplementary data (experimental procedures and compound
characterization) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2011.04.066.
References and notes
1. Balasubramaniyan, V.; Bhatia, V. G.; Wagh, S. B. Tetrahedron 1983, 39, 1475–
1485.
2. Baag, M. M.; Kar, A.; Argade, N. P. Tetrahedron 2003, 59, 6489–6492.
3. (a) Spatz, S. M.; Stone, H. J. Org. Chem. 1958, 23, 1559–1560; (b)
Balasubramaniyan, V.; Argade, N. P. Ind. J. Chem. B 1987, 26B, 476–477.
4. Hands, A. R. J. Chem. Soc. 1964, 1181–1182.
5. (a) Callahan, R.; Prip, R.; Shariff, N.; Sklyut, O.; Rothchild, R.; Bynum, K. Appl.
Spectrosc. 2005, 59, 354–365; (b) Jumina; Zulkarnain, A. K.; Mulyono, P.
Indonesian J. Pharm. 2005, 16, 116–123.
6. (a) Nozaki, K. J. Am. Chem. Soc. 1941, 2681–2683; (b) Junek, H.; Jacobson, N. M.;
Wiedner, P.; Nordberg, K.; Rauch-Puntigam, H. Monatsh. Chem. 1978, 109, 395–
404; (c) Griehl, C.; Strohl, D.; Jeschkeiet, H.; Kleinpeter, E. Monatsh. Chem. 1992,
123, 647–654; (d) Kolbe, A.; Griehl, C.; Biehler, S. J. Mol. Struct. 2003, 661–662,
239–246; (e) Gupta, G.; Wagh, S. B. Ind. J. Chem. B 2006, 45B, 697–702; (f) Tao,
C.; Wang, Q.; Trieu, V.; Desai, N.; Soon-Shiong, P. PCT Int. Appl., 2008064060;
Chem. Abstr. 2008, 149, 9382.; (g) Sanchez, A.; Pedroso, E.; Grandas, A. Eur. J.
Org. Chem. 2010, 2600–2606.
In conclusion, we have developed a simple and straightforward
approach to disubstituted nonsymmetrical maleamides and
fumaramides. Piperidine was shown to be the best catalyst for
achieving nearly quantitative isomerization under microwave-as-
sisted conditions, giving the desired products of high purity, in
good-to-excellent yields, and in short reaction times.
´
´
´
7. Frkanec, L.; Jokic, M.; Makarevic, J.; Wolsperger, K.; Zinic, M. J. Am. Chem. Soc.
2002, 124, 9716–9717.
8. (a) Bottari, G.; Leigh, D. A.; Perez, E. J. Am. Chem. Soc. 2003, 125, 13360–13361;
(b) Bottari, G.; Dehez, F.; Leigh, D. A.; Nash, P. J.; Perez, E. M.; Wong, J. K. Y.;
Zerbetto, F. Angew. Chem., Int. Ed. 2003, 42, 5886–5889; (c) Li, Y.; Li, H.; Li, Y.;
Liu, H.; Wang, S.; He, X.; Wang, N.; Zhu, D. Org. Lett. 2005, 7, 4835–4838; (d) Ji,
F.-Y.; Zhu, L.-L.; Ma, X.; Wang, Q.-C.; Tian, H. Tetrahedron Lett. 2009, 50, 597–
600.
Acknowledgments
9. Augustin, M.; Kohler, M. Tetrahedron 1976, 32, 2141–2145.
10. Hearn, M. T. W.; Ward, A. D. Aust. J. Chem. 1977, 30, 2031–2043.
This work was supported by the Ministry of Higher Education,
Science and Technology, Republic of Slovenia and the Slovenian
Research Agency (P1-0230). We thank Dr. Bogdan Kralj and Dr.
ˇ
11. Košmrlj, J.; Kocevar, M.; Polanc, S. Synlett 2009, 2217–2235.
ˇ
ˇ
12. Kovac, A.; Majce, V.; Lenaršic, R.; Bombek, S.; Bostock, J. M.; Chopra, I.; Polanc,
ˇ
ˇ
Dušan Zigon (Mass Spectrometry Centre, Jozef Stefan Institute,
S.; Gobec, S. Bioorg. Med. Chem. Lett. 2007, 17, 2047–2054.

3290
V. Majce et al. / Tetrahedron Letters 52 (2011) 3287–3290
13. Di Stefano, A.; Sozio, P.; Iannitelli, A.; Marianecci, C.; Santucci, E.; Carafa, M. J.
Drug Targeting 2006, 14, 652–661.
14. Kleiner, R. E.; Dumelin, C. E.; Tiu, G. C.; Sakurai, K.; Liu, D. R. J. Am. Chem. Soc.
2010, 132, 11779–11791.
15. Breuning, A.; Degel, B.; Schulz, F.; Buchold, C.; Stempka, M.; Machon, U.;
Heppner, S.; Gelhaus, C.; Leippe, M.; Leyh, M.; Kisker, C.; Rath, J.; Stich, A.; Gut,
J.; Rosenthal, P. J.; Schmuck, C.; Schirmeister, T. J. Med. Chem. 2010, 53, 1951–
1963.
16. Machon, U.; Buchold, C.; Stempka, M.; Schirmeister, T.; Gelhaus, C.; Leippe, M.;
Gut, J.; Rosenthal, P. J.; Kisker, C.; Leyh, M.; Schmuck, C. J. Med. Chem. 2009, 52,
5662–5672.
overnight (16 h). The reaction mixture was washed with water (3 ꢂ 15 mL),
dried over Na2SO4, and the solvent evaporated, giving 0.838 g (97%) of the
crude product, which was purified by triturating with 10 mL of Et2O, and
filtering the resulting yellow powder, which required no further purification.
Analysis: pale yellow powder, yield 0.838 g (97%), mp 114–116.5 °C (Et2O); IR
(KBr)
m ;
3282, 2803, 1606, 1562, 1511, 1255, 841 cmꢁ1 1H NMR (300 MHz,
DMSO-d6) d (ppm) 2.26 (s, 3H); 4.38 (d, J = 5.7 Hz, 2H), 6.30 (s, 2H), 7.12 and
7.50 (AA0XX0, J = 8.3 Hz, 4H), 7.28 (m, 5H), 9.16 (t, J = 5.7 Hz, 1H); 11.08 (s, 1H);
13C NMR (75.5 MHz, DMSO-d6) d (ppm) 21.4, 43.2, 120.2, 127.8, 128.3, 129.2,
130.0, 131.8, 133.4, 133.8, 137.2, 139.6, 163.8, 165.8; MS-ES m/z 293 ([MꢁH]ꢁ,
53%). Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.20; H,
6.17; N, 9.39.
17. Smaill, J. B.; Hollis Showalter, H. D.; Zhou, H.; Bridges, A. J.; McNamara, D. J.;
Fry, D. W.; Nelson, J. M.; Sherwood, V.; Vincent, P. W.; Roberts, B. J.; Elliott, W.
L.; Denny, W. A. J. Med. Chem. 2001, 44, 429–440.
21. For the equipment applied here and the methodology in general, see, for
ˇ
example: (a) Maraš, N.; Polanc, S.; Kocevar, M. Tetrahedron 2008, 64, 11618–
ˇ ˇ ˇ
11624; (b) Hren, J.; Pozgan, F.; Bunic, A.; Parvulescu, V. I.; Polanc, S.; Kocevar,
18. Pinto, I. L.; Jarvest, R. L.; Clarke, B.; Dabrowski, C. E.; Fenwick, A.; Gorczyca, M.
M.; Jennings, L. J.; Lavery, P.; Sternberg, E. J.; Tew, D. G.; West, A. Bioorg. Med.
Chem. Lett. 1999, 9, 449–452.
ˇ
M. Tetrahedron 2009, 65, 8216–8221; (c) Kranjc, K.; Kocevar, M. Curr. Org. Chem.
2010, 14, 1050–1074.
19. Preparation of 1b: p-Toluidine (3.30 mL, 30 mmol) was added to a stirred
solution of maleic anhydride (2.94 g, 30 mmol) in Et2O (180 mL). The reaction
mixture was stirred for 2 h at rt, and the resulting precipitate was filtered and
washed with Et2O. Analysis: Yellow powder, yield 6.00 g (98%), mp 183–185 °C
22. Typical procedure: To a thick-wall borosilicate glass vial (10 mL) were added 2b
(147 mg, 0.5 mmol), piperidine (4.0 lL, 0.04 mmol), CH3CN (0.5 mL), and a
magnetic stir bar. The vial was sealed, the reaction mixture pre-stirred for
1 min and then irradiated in a CEMÒ Discover focused microwave reactor for
10 min at 120 °C at 200 W. The reaction mixture was allowed to cool to room
temperature, and the resulting precipitate was filtered, washed with a small
amount of CH3CN, and dried to give 3b. Analysis: white powder, yield 0.116 g
(Et2O); IR (KBr)
m ;
3286, 3096, 1703, 1634, 1536, 1404, 850 cm–1 1H NMR
(300 MHz, DMSO-d6) d (ppm) 2.26 (s, 3H), 6.29 (d, J = 12.1 Hz, 1H), 6.46 (d,
J = 12.1 Hz, 1H), 7.14 and 7.50 (AA0XX0, J = 8.3 Hz, 4H), 10.36 (s, 1H), 13.26 (s,
1H); 13C NMR (75.5 MHz, DMSO-d6) d (ppm) 20.5, 119.7, 129.2, 130.8, 131.7,
133.1, 135.9, 163.1, 166.7; MS–ES m/z 204 ([MꢁH]ꢁ, 48%). Anal. Calcd for
(79%), mp 287–288 °C (EtOAc/Et2O); IR (KBr)
m 3289, 1638, 1557, 1536, 1337,
993, 696 cmꢁ1 1H NMR (300 MHz, DMSO-d6) d (ppm) 2.26 (s, 3H), 4.40 (d,
;
C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.41; H, 5.14; N, 6.79.
J = 5.8 Hz, 2H), 7.01 (d, J = 15.1 Hz, 1H), 7.08 (d, J = 15.1 Hz, 1H), 7.13 and 7.56
(AA0XX0, J = 8.4 Hz, 4H), 7.30 (m, 5H), 8.95 (t, J = 5.8 Hz, 1H), 10.34 (s, 1H); 13C
NMR (75.5 MHz, DMSO-d6) d (ppm) 21.4, 43.3, 120.2, 127.8, 128.2, 129.3,
130.1, 133.7, 134.2, 134.3, 137.2, 139.8, 162.9, 164.5; MS-ES m/z 293 ([M–H]–,
62%). Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.34; H,
5.98; N, 9.51.
20. Preparation of 2b: N-Methylmorpholine (0.679 mL, 6.17 mmol) was added to a
stirred suspension of 1b (0.604 g, 2.94 mmol) in CH2Cl2 (30 mL). The resulting
solution was cooled to 0 °C on an ice bath and then EDCꢀHCl (0.620 g,
3.2 mmol) was added. After 10 min, benzylamine (0.321 mL, 2.94 mmol) was
added and the reaction mixture was left to warm slowly to rt and stirred