Solvent-free synthesis of monoacylaminals from the reaction of amides and aminals as precursors in carbinolamide synthesis

Article abstract of DOI:10.1016/j.tetlet.2010.09.043

A solvent-free method of generating monoacylaminals by heating the amide and aminal starting materials in the presence of one another has been developed. Yields were generally between 45% and 65% with the monoacylaminal being isolated, needing no further purification after drying under high vacuum.

Full text of DOI:10.1016/j.tetlet.2010.09.043

Tetrahedron Letters 51 (2010) 6031–6033
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-free synthesis of monoacylaminals from the reaction of amides
and aminals as precursors in carbinolamide synthesis
⇑
Matthew F. Sansone, Takaoki Koyanagi, David E. Przybyla, Richard W. Nagorski
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A solvent-free method of generating monoacylaminals by heating the amide and aminal starting materi-
als in the presence of one another has been developed. Yields were generally between 45% and 65% with
the monoacylaminal being isolated, needing no further purification after drying under high vacuum.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 August 2010
Revised 6 September 2010
Accepted 13 September 2010
Available online 17 September 2010
Keywords:
Solvent-free
Monoacylaminal
Carbinolamides are a functional group generated by the nucle-
ophilic attack by an amide on an aldehyde followed by a proton
shift.1 Under neutral aqueous conditions, the compounds are very
stable with their breakdown being catalyzed by both acids and
hydroxide.2,3 The compounds themselves have a long history, with
reports appearing in the literature as early as the 1870’s.4 More re-
cently, carbinolamides have been found to be involved in biological
processes that have both postive5,6 and negative7 outcomes for the
host. In addition, their synthesis has been the focus of increasing
attention with the discovery of a growing number of compounds
with interesting biological properties that possess either a carbi-
nolamide moiety or the O-alkylated derivative.8–10 Examples such
as azaspirene (1)9a,10 and psymberin (2)11 are shown in Figure 1.
Given the growing number of compounds being discovered that
incorporate carbinolamides or its derivatives, there are surpris-
ingly few routes leading to their generation (see below). One meth-
od, that we have found to be particularly versatile for the synthesis
of carbinolamides, involves the generation of a monoacylaminal
precursors which are subsequently hydrolyzed to the carbinolam-
ide target.12 Reported here are the details of the development of a
solvent-free method of generating monoacylaminals from the
amide and aminal precursors.
proved to be useful with highly electrophilic aldehydes such as
formaldehyde and chloral but produced complex mixtures with
less electrophilic aldehydes.1
More recently, Williams and co-workers developed a method of
synthesizing carbinolamides from a broader range of amide and
aldehyde starting materials utilizing dicyclohexylboron chloride
and triethylamine in diethyl ether/hexane solution (see Scheme 1:
method B).13 This method has proved to be very useful in the direct
synthesis of carbinolamides incorporating alkyl aldehydes.13 In
addition, a process for the direct synthesis of the N-(meth-
oxyalkyl)amides has been developed by Lokensgard et al. utilizing
acyl chlorides and imidates.14
The primary means we have utilized, in the synthesis of carbin-
olamides, has been to first generate the monoacylaminal precursor
which was then solvolyzed to yield the target compound.12 The lit-
erature process involved mixing equimolar amounts of the amine,
amide, and aldehyde in methanol followed by addition of water
and cooling (see Scheme 2).2d This procedure worked very well
OCH3
O
OCH3
O
OH
N
H
Our long standing interest in probing the reactivity of carbinola-
mides in aqueous solution3 has led to the investigation of many
methods of synthesizing this functionality. The traditional method
involved simply mixing the amide and aldehyde, in solution, with
the product precipitating out of solution or being isolated from the
reaction mixture (see Scheme 1: method A).1 This method has
OH
O
O
HO
NH
O
HO
O
OH
HO
OH
O
azaspirene (1)
Psymberin (2)
⇑
Corresponding author. Tel.: +1 309 438 8978; fax: +1 309 438 5538.
E-mail address: rnagor@ilstu.edu (R.W. Nagorski).
Figure 1. Carbinolamide and derivative containing compounds.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.043

6032
M. F. Sansone et al. / Tetrahedron Letters 51 (2010) 6031–6033
Table 1
O
Method A:
K2CO3/CH3OH
O
Yields and melting points for the synthesis of monoacylaminals from morpholine
aminals of benzaldehyde derivatives and acetamide
OH
O
+
H2N
R
H
R
N
H
Method B:
Cy2BCl/NEt3
Et2O
Amide
Aminal
Yielda (%)
Melting pointb (°C)
Lit. Mpt. (°C)
151–2c
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
CH3CONH2
H
4-CH3
4-Cl
56
64
50
71
56
53
41
66
51
51
151–2
150–1
181–3
157–8
144–7
181–3
143–4
188–9
129–30
130–1
—
—
—
—
—
—
—
—
—
Scheme 1. Two methods of carbinolamide synthesis.
4-CN
4-N(CH3)2
4-NO2
4-OCH3
4-CF3
3-Cl
O
O
O
3-NO2
H
H2N
+
+
N
H
a
Based upon 1–3 independent determinations.
All melting points were determined using a commercial apparatus and are
b
uncorrected.
CH3OH
37 ºC for
48 hours
c
Refs. 16a and 16b.
O
N
The resulting mixture was cooled and the crystalline product col-
lected by vacuum filtration.
O
H2O +
N
H
In the case of the acetamide derivatives, the solvent-free reac-
tions were performed with a 2:1 molar ratio of the amide to aminal
(see details in Supplementary data). This procedure resulted in the
crude monoacylaminal product being contaminated with excess
acetamide. However, the acetamide could easily be removed by
washing the crude product with water during vacuum filtration.
While the total yield of the monoacylaminal product (yields were
between 40% and 70%) was diminished using this method, it was
found that the monoacylaminal obtained needed no further purifi-
cation (see Table 1; yields are based upon 1–3 independent
experiments).
Scheme 2. Direct monoacylaminal synthesis.
for the production of the monoacylaminal generated from benzam-
ide, benzaldehyde, and morpholine.2d,15 However, as substituents
were added to the amide/aldehyde or acetamide was used as the
starting amide, the major product isolated via this procedure be-
came the aminal.
Attempts to find other methods of synthesizing monoacylami-
nals yielded a paper by Sakai and Sekiya.16a In this paper, a method
was mentioned wherein the pyrrolidine aminal of benzaldehyde
was heated at 85–90 °C in the presence of an amide for several
hours, yielding the monoacylaminal.16a Attempts to repeat this
work, using the conditions described, with the morpholine aminal
of benzaldehyde and acetamide, yielded limited quantities of the
desired monoacylaminal. However, modifications to the procedure
were developed that consistently produced the target monoacyla-
minals incorporating a variety of amides (see Scheme 3, Tables 1
and 2).
The general procedure used for all the monoacylaminal synthe-
ses reported involved first mixing the aminal and amide in an
Erlenmeyer flask (in all cases described here, both were solids).
Using a Bunsen burner, the flask containing these materials was
gently heated until the materials had melted, thus ensuring a
homogenous mixture.17 After the solids had melted, heating was
continued with the solution reaching temperatures of ꢀ185–
220 °C. The period of heating was variable; however, in general,
heating was continued for 5–10 min. Following cessation of heat-
ing, the flask was allowed to cool until it was hot to the touch
but could be safely handled (ꢀ30–40 °C). At this point a small
amount of ether was added to the reaction mixture, which com-
pleted the cooling and initiated crystallization upon agitation.
For the benzamide derivatives (see Table 2), the solvent-free
reactions were performed using a 0.99:1 molar ratio of the amide
to aminal (see details in Supplementary data). When larger than
equimolar amounts of amide were used, it became difficult to sep-
arate the monoacylaminal product from the excess amide. The
most efficient means to overcome this problem was to use a slight
excess of the aminal which would therefore limit the amount of
benzamide starting material remaining in the reaction mixture.
Any residual amide could be removed by washing the crystals iso-
lated by vacuum filtration with ice cold ether and/or 95% ethanol.
As with the acetamide derivatives, these compounds were pure
upon drying under vacuum.
Shown in Scheme 4 is the proposed mechanism for the forma-
tion of the monoacylaminal under the solvent-free conditions of
the reactions. In the proposed mechanism, the first stage involves
the generation of an iminium ion and the anion of morpholine.
The morpholine anion then deprotonates the amide, to generate
morpholine and an amidate. This thermodynamically favored
acid/base reaction18 was further assisted by the morpholine boiling
from the reaction solution as generated, leaving the amidate and
iminium ion remaining in the reaction vessel. Condensate at the
neck of the Erlenmeyer flask that formed during heating was col-
lected and 1H NMR showed it to be morpholine. Nucleophilic at-
tack by the amidate on the carbon of the iminium ion resulted in
the formation of the monoacylaminal.
Presented here is a method for the production of monoacylami-
nals via thermal initiation of a reaction between an aminal and an
amide in the absence of solvent. The method provides good to
modest yields of the target compounds having a variety of substit-
uents on both the amide and aminal starting materials. Using the
methods described herein, the products can be obtained directly
from the reaction in a pure form. In our hands, the monoacylami-
nals have proved to be versatile intermediates that can be solvo-
O
O
O
N
1) Δ
O
N
+
H2N
R
N
2) Et2O
N
H
R
O
R = CH3
Ar-X
lyzed, under acidic conditions, to produce
a
variety of
carbinolamides and their O-alkylated derivatives.12
Scheme 3. Solvent-free synthesis of monoacylaminals.

M. F. Sansone et al. / Tetrahedron Letters 51 (2010) 6031–6033
6033
Table 2
Yields and melting points for the synthesis of monoacylaminals from morpholine aminals of benzaldehyde derivatives and benzamide derivatives
Benzamide
Aminal
Yielda (%)
Melting pointb (°C)
Lit Mpt. (°C)
Benzamide
Aminal
Yielda (%)
Melting pointb (°C)
Lit. Mpt. (°C)
H
4-NO2
4-Cl
3-NO2
4-SCH3
4-SCH3
4-SCH3
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
H
64
89
61
56
69
37
50
97
47
47
69
24
49
50
33
62
43
49
34
54
165–6
158–60
235–8
152–3
132–6
176–9
158–9
159–61
148–52
132–4
114–20
161–2
165–6
150–1
171–3
161–4
113–5
140–3
134–6
166–8
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
4-NO2
4-Cl
3-Cl
H
4-CH3
3-CH3
4-NO2
3-NO2
4-Cl
H
3-CH3
4-NO2
4-Cl
3-Cl
H
4-CH3
3-CH3
4-Cl
H
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
3-OCH3
3-OCH3
H
59
57
35
78
27
49
66
36
41
32
40
67
65
25
44
32
43
51
60
67
116–8
154–6
148–9
158–60
140–2
143–6
105–8
139–42
98–100
136–8
161–3
135–8
140–2
140–2
132–4
145–6
125–8
171–3
151–2
160–2
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
H
4-NO2
3-NO2
4-Cl
H
4-CH3
3-CH3
4-NO2
4-CF3
4-Cl
H
3-CH3
4-NO2
3-NO2
4-Cl
4-CH3
3-CH3
H
H
H
H
—
—
—
H
166–7c
a
b
c
Based upon 1–3 independent determinations.
All melting points were determined using a commercial apparatus and are uncorrected.
Ref. 16a.
4. (a) Jacobson Ann. Chim. 1871, 157, 245; (b) Pinner Ann. Chim. 1875, 179, 40.
5. (a) Young, S. D.; Tamburini, P. P. J. Am. Chem. Soc. 1989, 111, 1933–1934; (b)
Eipper, B. A.; Mains, R. E.; Glembotski, C. C. Proc. Natl. Acad. Sci. U.S.A. 1983, 80,
5144–5148; (c) Bradbury, A. F.; Finnie, M. D. A.; Smyth, D. G. Nature 1982, 298,
686–688.
O
O
O
N
N
+
6. (a) McIninch, J. K.; McIninch, J. D.; May, S. W. J. Biol. Chem. 2003, 278, 50091–
50100; (b) Takada, Y.; Noguchi, T. Biochem. J. 1986, 235, 391–397.
N
N
O
O
H
7. (a) Chung, F. L.; Nath, R. G.; Nagao, M.; Nishikawa, A.; Zhou, G. D.; Randerath, K.
Mutat. Res. 1999, 424, 71–81; (b) Marnett, L. J. Mutat. Res. 1999, 424, 83–95; (c)
Nair, J.; Barbin, A.; Velic, I.; Bartsch, H. Mutat. Res. 1999, 424, 59–69.
8. (a) Vela, M.; Kohn, H. J. Org. Chem. 1992, 57, 5223–5231; (b) Miyoshi, T.; Miyari,
N.; Aoki, H.; Kohsaka, M.; Sakai, H.; Imanaka, H. J. Antibiot. 1972, 25, 569–575;
(c) Miyamura, S.; Ogasawara, N.; Otsuka, H.; Niwayama, S.; Takana, H.; Take, T.;
Uchiyama, T.; Ochiai, H.; Abe, K.; Koizumi, K.; Asao, K.; Matuski, K.; Hoshino, T.
J. Antibiot. 1972, 25, 610–612.
9. (a) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.; Osada, H. Org.
Lett. 2002, 4, 2845–2848; (b) Nakai, R.; Ogawa, H.; Asai, A.; Ando, K.; Agatsuma,
T.; Matsumiya, S.; Akinaga, S.; Yamashita, Y.; Mizukami, T. J. Antibiot. 2000, 53,
294–296; (c) Suzuki, S.; Hosoe, T.; Nozawa, K.; Kawai, K.; Yaguchi, T.; Udagawa,
S. J. Nat. Prod. 2000, 63, 768–772; (d) Singh, S. B.; Goetz, M. A.; Jones, E. T.; Bills,
G. F.; Giacobbe, R. A.; Herranz, L.; Stevensmiles, S.; Williams, D. L. J. Org. Chem.
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N
H
R
O
N
O
O
O
O
N
+
+
N
H
R
N
H
N
R
H
Scheme 4. Proposed mechanism of the solvent-free monoacylaminal formation.
10. (a) An angiogenesis inhibitor.; (b) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.;
Yamaguchi, S.; Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am.
Chem. Soc. 2002, 124, 12078–12079.
Acknowledgments
This work was supported by the National Science Foundation
under CHE-051830 and also a MRI grant under CHE-0722385.
11. (a) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951–1954; (b)
Pettit, G. R.; Xu, J.-P.; Chapuis, J.-C.; Pettit, R. K.; Tackett, L. P.; Doubek, D. L.;
Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47, 1149–1152.
12. (a) Unpublished work. (b) The reactions producing the carbinolamides were
performed at room temperature with the monoacylaminals being hydrolyzed
in a weakly acidic solution (pH maintained between 4 and 5 using 0.1 M HCl).
Reaction progress was followed by monitoring the pH of the solution with the
solvolysis being deemed complete when no further changes in pH occurred.
The product precipitated during formation but the reaction solution was
cooled, in an ice bath, prior to collection of the product by vacuum filtration.
13. Kiren, S.; Shangguan, N.; Williams, L. J. Tetrahedron Lett. 2007, 48, 7456–7459.
14. Lokensgard, J. P.; Fischer, J. W.; Bartz, W. J. J. Org. Chem. 1985, 50, 5609–5611.
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K. Chem. Pharm. Bull. 1963, 11, 888.
Supplementary data
Supplementary data (synthetic methods and characterization of
all monoacylaminals) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.043.
References and notes
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