Selective functional group transformation using guanidine: The conversion of an ester group into an amide in vinylogous ester-aldehydes of imidazole

Article abstract of DOI:10.1016/j.tetlet.2005.07.024

An efficient and convenient method has been described for the selective conversion of an ester group into the corresponding carboxamide in vinylogous ester-aldehydes of imidazole. The method uses excess guanidine, which protects the aldehyde function as a diaminodihydro-s-triazine moiety. The carboxaldehyde group is regenerated by hydrolysis of the triazine moiety to provide vinylogous amide-aldehydes of imidazole as the final product.

Full text of DOI:10.1016/j.tetlet.2005.07.024

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6005–6009
Selective functional group transformation using guanidine:
the conversion of an ester group into an amide in vinylogous
ester–aldehydes of imidazole
Ravi K. Ujjinamatada and Ramachandra S. Hosmane*
Laboratory for Drug Design and Synthesis, Department of Chemistry & Biochemistry, University of Maryland,
Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA
Received 12 June 2005; revised 6 July 2005; accepted 7 July 2005
Abstract—An efficient and convenient method has been described for the selective conversion of an ester groupinto the correspond-
ing carboxamide in vinylogous ester–aldehydes of imidazole. The method uses excess guanidine, which protects the aldehyde func-
tion as a diaminodihydro-s-triazine moiety. The carboxaldehyde groupis regenerated by hydrolysis of the triazine moiety to provide
vinylogous amide–aldehydes of imidazole as the final product.
Ó 2005 Elsevier Ltd. All rights reserved.
Selective functional grouptransformation is of pivotal
interest in organic synthesis.1,2 While there are methods
available for the protection of an aldehyde group in the
presence of an ester functionality,3,4 not much is known
about procedures that allow, in a single-pot reaction, the
selective conversion of an ester groupinto an amide in a
vinylogous ester–aldehyde, while simultaneously pro-
tecting the aldehyde groupwith a labile moiety that
can be easily removed later (see Scheme 1). We report
herein an efficient and convenient method to accomplish
this goal.
Therefore, s-triazine is an excellent candidate for protec-
tion of any aldehyde provided that it can be built onto
an aldehyde in question using guanidine, and also can
be easily removed once the ester has been converted into
an amide. Since little is known in this regard, a pilot
experiment to try was to react a simple aldehyde such
as benzaldehyde with two equivalents of guanidine,
which would potentially yield a diaminodihydro-s-tri-
azine with concomitant elimination of a molecule of
ammonia. However, an extensive search through the lit-
erature for the reaction of an aromatic aldehyde with
guanidine to form a diaminodihydrotriazine surprisingly
revealed that no such product had ever been reported.
Instead, we came across a 1972 paper9 in which the
authors report the isolation of a fully aromatic product
s-triazine (2) in low yield from amongst a complex mix-
ture of products by the reaction of excess benzaldehyde
(used as a solvent) with guanidine carbonate (Scheme 2).
When the authors employed sodium methoxide in meth-
anol for the condensation reaction, they obtained yet
another product 3, which showed that two molecules
of aldehyde reacted with one molecule of guanidine.
Both 2 and 3 apparently involved an oxidation step that
followed the initial product formation. In either case,
the authors could not obtain the intended mono-
meric product, benzylideneguanidine (1). Obviously,
the authors always used excess benzaldehyde over gua-
nidine instead of vice versa as would be necessary to
form 1 or 2.
It is long known that s-triazine can be employed as a
masked formaldehyde,5 formimine6,7 or formamidine.8
O
O
O
NH2
O
NH2
OR
O
P
H
H
Scheme 1.
Keywords: Selective conversion; Vinylogous ester–aldehyde; Vinylo-
gous amide–aldehyde; Guanidine.
*
Corresponding author. Tel.: +1 410 455 2520; fax: +1 410 455
1148; e-mail: hosmane@umbc.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.024

6006
R. K. Ujjinamatada, R. S. Hosmane / Tetrahedron Letters 46 (2005) 6005–6009
NH
cleanly converted back to the starting aldehydes upon
heating in water at reflux for 6 h.
O
NH2
NH2
NH2
N
H
1/2 H2CO3
H2N
+
The above encouraging results led us to our original
objective of one-stepconversion of an ester to amide
in a vinylogous ester–aldehyde. We were especially inter-
ested in exploring this with heterocycles, imidazole in
particular, as the stated synthetic goal actually origi-
nated while working with two vinylogous ester–alde-
hydes of imidazole. The necessary starting materials,
4-ethoxycarbonyl-1-benzylimidazole-5-carbaldehyde (7)12
and 4-ethoxycarbonyl-1-benzyloxymethylimidazole-5-
carbaldehyde (8),12 along with their respective regio-
isomers, 9 and 10, were prepared by alkylation of
4 (5)-ethoxycarbonylimidazole-5(4)-carbaldehyde (6)12
with benzyl- and benzyloxymethyl chlorides, respec-
tively, catalyzed by potassium carbonate in dimethyl-
formamide (Scheme 4). The two regioisomers obtained
in each case could be easily separated by flash chromato-
1
1. NaOMe/MeOH
2. HCl
Complex mixture of products
including:
NH2
O
NH
N
N
(30% yield)
N
N
H
H
Ph
NH2
N
3
2
Scheme 2.
NH2
NH
O
R
R
N
NH2
H
+
MeOH / Reflux
12 h
N
NH2
H2N
NH2
R
1
R
(Excess)
graphy, and distinguished from each other by H NMR
R= H or OMe
4; R=H
5; R=OMe
NOESY, which indicated the presence of NOE between
the CHO groupand the benzyl CH 2 in 7 and 8 but not in
9 and 10. Compounds 7 and 8 were separately reacted
with excess guanidine in anhydrous ethanol at reflux
for 15 h, which gave the amide–triazines, 1112 (or 15,
see below) and 1212 (or 16), respectively. Upon heating
in water at reflux for 8 h, 11 and 12 yielded the respec-
tive amide–aldehydes 1312 and 14.12 The structures of
H2O / Reflux / 6 h
Scheme 3.
Indeed, when benzaldehyde was reacted with two or
more equivalents of guanidine, freshly liberated from
the corresponding hydrochloride salt by treatment with
sodium methoxide in methanol, 2,6-diamino-3,6-di-
hydro-6-phenyl-1,3,5-triazine (4)12 was obtained in
61% yield (Scheme 3). The analogous reaction with
2,4-dimethoxybenzaldehyde also gave the corresponding
product 512 in 67% yield. Both 4 and 5 exhibited the
characteristic triazine methine proton in their respective
1H and 13C NMR spectra at ꢀ5.7 and 60 d, respectively.
Both compounds are stable, colourless, crystalline solids
and were fully characterized by spectroscopic (1H and
13C NMR, HMBC and HMQC) and microanalytical
(HRMS) data. Both compounds could be readily and
1
all products were confirmed by H and 13C NMR spec-
tra as well as mass spectral and microanalytical data.12
Finally, a reasonable mechanistic rationalization (see
Scheme 5) for the formation of the amide–triazines 11
and 12 from the respective ester–aldehydes 7 and 8,
could not rule out the alternative 5:7-fused ring struc-
tures 15 and 16 for 11 and 12, based on spectral and
analytical data alone. The respective pairs of com-
pounds have the same molecular formula, the same
characteristic methine signal of either the dihydrotri-
azine or the dihydrodiazepine ring, and with proper
O
O
O
O
N
N
H
N
OEt
H
OEt
H
K2CO3/DMF
R-CH2Cl
+
OEt
N
N
H
N
(R = Ph or PhCH2-O)
O
CH2R
O
CH2R
9; R = Ph
10; R = OCH2Ph
6
7; R = Ph
8; R = OCH2Ph
NH
Anhy. EtOH
H2N
NH2
Reflux
15 h
(Excess)
O
O
N
O
O
NH
N
N
N
NH2
N
H2O/Reflux
N
NH2 OR
NH2
H
NH2
N
N
8 h
N
CH2R
NH
CH2R
N
NH2
H
CH2R
NH2
11; R = Ph
12; R = OCH2Ph
NH
13; R = Ph
14; R = OCH2Ph
15; R = Ph
16; R = OCH2Ph
Scheme 4.

R. K. Ujjinamatada, R. S. Hosmane / Tetrahedron Letters 46 (2005) 6005–6009
6007
O
tautomerization, the same number of amino/imino
groups that are exchangeable with D2O. In order to
resolve this structural ambiguity, we resorted to an
unequivocal synthesis of one of the two amide–triazine
products (12).
O
NH
NH2
OEt
NH2
NH
N
N
OEt
H
H2N
N
R
N
R
N
O
7 or 8
The structural ambiguity of 12 lay with compound 16.
In this regard, compound 12 being a simple imidazole
derivative seemed easier to synthesize than the 5:7-fused
imidazodiazepine ring system 16. Therefore, compound
12 was chosen over 16 for the purpose of unequivocal
synthesis. The synthesis of 12 commenced with the
known imidazole derivative, 4-ethoxycarbonylimidaz-
ole-5-carbaldehyde diethyl acetal10,11 (17) (Scheme 6).
Imidazole ring nitrogen atom of 17 was substituted with
the benzyloxymethyl (BOM) groupas before by reaction
with benzyloxymethyl chloride in dimethylformamide,
catalyzed by potassium carbonate, to obtain the two
regioisomers 1812 and 19. The isomers were separated
by flash chromatography, and distinguished by NOESY
NMR as before. The isomer 18 was further reacted with
methanolic ammonia in a stainless steel vessel at 150 °C
for 48 h to obtain the acetal–amide 20.12 The acetal
groupof 20 was hydrolyzed with 80% acetic acid to
obtain the amide–aldehyde 14. The latter upon reaction
with excess guanidine in methanol at reflux provided 12,
which was found to be identical in all respects with the
compound obtained by the reaction of 8 with excess
guanidine shown in Scheme 4.
(R = CH2Ph or CH2OCH2Ph)
NH
NH2
O
O
H2N
NH
N
NH
N
N
N
NH
NH
Path a
N
R
N
R
H2N
H2N
NH
NH2
NH
Path b
H2N
O
O
NH
N
N
NH
N
N
NH
NH2
N
R
N
R
HN
H2N
NH
H2N
H2N
NH
15 or 16
(R = CH2Ph or CH2OCH2Ph)
The above results, however, raise another mechanistic
possibility for the formation of 11 or 12 from 7 or 8,
in which the carboxaldehyde groupof the latter would
react with excess guanidine to form the triazine ring
first. A molecule of ammonia released during the forma-
tion of triazine would subsequently react with the ester
group to produce the amide product. While this reaction
pathway could not be completely ruled out, it appears
less likely, however, in view of (a) the harsh reaction
conditions that were necessary to convert the ester 18
to amide 20, and (b) the lack of formation of equally
plausible other products such as the ones formed by the
O
O
N
NH2
N
NH2
N
NH2
N
R
N
R
C
NH
N
N
NH
NH2
HN
HN
NH2
11 or 12
(R = CH2Ph or CH2OCH2Ph)
Scheme 5.
O
OEt
O
Cl
N
N
N
N
N
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Ph
O
+
N
H
K2CO3/DMF
O
O
O
Ph
OEt
18
Ph
17
19
NH3
MeOH
150 0
C
NH
O
O
O
O
H2N
NH2
N
N
NH2
N
N
NH2
OEt
(Excess)
N
N
NH2
H
80% aq. AcOH
Ph
NH2
N
O
N
NH
NH2
O
Ph
OEt
O
Ph
14
20
12
Scheme 6.

6008
R. K. Ujjinamatada, R. S. Hosmane / Tetrahedron Letters 46 (2005) 6005–6009
Rf = 0.11 (2:1:0.25 chloroform/methanol/ammonium
hydroxide); 1H NMR (400 MHz, DMSO-d6): d 7.40 (m,
6H), 5.77 (s, 1H), 3.47 (s, 4H); 13C NMR (100 MHz,
DMSO-d6): d 158.5, 141.2, 129.5, 129.3, 126.5, 62.4;
HRMS (FAB) calculated for C9H12N5, 190.1096 m/z
(MH+); observed 190.1093. Compound 5: Yield 67%; mp
170–172 °C; Rf = 0.23 (2:1:0.25 chloroform/methanol:
NH4OH); 1H NMR (400 MHz, DMSO-d6): d 7.09 (d,
J = 8.2 Hz, 1H), 6.57 (s, 1H), 6.45 (d, J = 8.2 Hz, 1H),
6.05 (br s, 4H), 5.74 (br s, 1H), 5.73 (s, 1H), 3.72 (s, 3H),
3.70 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 161.1,
159.1, 157.8, 127.5, 122.9, 104.8, 98.9, 59.7, 56.0, 55.7;
HRMS (FAB) calculated for C11H15N5O2, 250.1304 m/z
(MH+); observed 250.1289. Compound 6: Yield 91%; mp
reaction of the ester groupwith guanidine. This is espe-
cially true as there is a large molar excess of guanidine in
the reaction mixture as compared to the transiently
formed ammonia, whose concentration is expected to
be further diminished at the reflux temperature of
ethanol.
In conclusion, we have discovered a novel functional
grouptransformation involving a selective conversion of
an ester groupof a vinylogous ester–aldehyde attached
to an imidazole ring into the corresponding amide, while
simultaneously protecting the aldehyde group as an
s-triazine. The aldehyde group is deprotected upon sim-
ply heating in water at reflux without any acid or base
catalysis. The method has distinct advantages over the
conventional methods such as the one employed in
Scheme 6, in that no prior protection of the aldehyde
groupwould be necessary before conversion of the ester
into amide. Furthermore, the aldehyde protecting group
can be removed under much milder as well as neutral
conditions than would be normally necessary, for exam-
ple, removal of an acetal group. We are currently
exploring the generality of this transformation to other
heterocyclic and aromatic systems.
1
212 °C; Rf = 0.41 (10:1 chloroform/methanol); H NMR
(DMSO-d6, 300 MHz): d 13.74 (s, 1H), 10.16 (s, 1H), 8.01
(s, 1H), 4.28 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H);
MS (FAB) m/z 169 (MH+); C7H8N2O3 requires C, 50.00;
H, 4.80; N, 16.66. Found: C, 49.88, H, 4.76, N, 16.61.
Compound 7: Yield 64%; mp69–71 °C; Rf = 0.24 (1:1
ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3): d
10.42 (s, 1H), 7.63 (s, 1H), 7.19 (m, 5H), 5.48 (s, 2H), 4.36
(q, J = 6.8 Hz, 2H), 1.35 (t, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 183.2, 162.1, 142.0, 135.2, 132.1,
129.3, 128.8, 127.8, 61.9, 51.2, 14.5; MS (FAB) m/z 259
(MH+); C14H14N2O3 requires C, 65.11; H, 5.42; N, 10.85.
Found: C, 64.88, H, 5.48, N, 10.81. Compound 8: Yield
1
70%; oil; Rf = 0.27 (1:1 ethyl acetate/hexanes); H NMR
(300 MHz, CDCl3): d 10.50 (s, 1H), 7.82 (s, 1H), 7.35 (m,
5H), 5.81 (s, 2H), 4.55 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H),
1.41 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
182.4, 161.2, 141.1, 135.5, 131.3, 128.1, 128.0, 127.8, 127.3,
75.5, 71.1, 61.2, 13.7; MS (FAB) 289 (MH+); C15H16N2O4
requires C, 62.49; H, 5.59; N, 9.72. Found: C, 62.57, H,
5.52, N, 9.79. Compound 11: Yield 66%; mp184–186 °C;
Rf = 0.24 (chloroform/methanol/ammonium hydroxide,
2:1:0.25); 1H NMR (400 MHz, DMSO-d6): d 7.54 (s,
1H), 7.24 (m, 5H), 6.72 (s, 1H), 5.44 (br s, 4H), 3.32 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d 165.6, 159.4,
138.1, 138.0, 132.2, 129.0, 128.4, 128.1, 61.3, 49.2, 40.6;
HRMS (FAB) calculated for C14H16N8O, 313.1525 m/z
(MH+); observed 313.1536. Compound 12: Yield 61%; mp
195–197 °C; Rf = 0.28 (chloroform/methanol/ammonium
hydroxide, 2:1:0.25); 1H NMR (400 MHz, DMSO-d6): d
7.8 (s, 1H), 7.5 (s, 1H), 7.25 (m, 6H), 6.7 (s, 1H), 5.7 (s,
2H), 4.5 (s, 2H); 13C NMR (100 MHz, DMSO-d6): d
165.4, 159.1, 139.1, 137.8, 133.6, 128.8, 128.8, 128.2, 128.1,
75.5, 70.6, 59.5; C15H18N8O2Æ0.5CH3OH requires C,
51.93, H, 5.58, N, 31.27. Found: C, 52.03, H, 5.31, N,
31.35; HRMS (FAB) calculated for C15H18N8O2, 343.1631
m/z (MH+); observed 343.1583. Compound 13: Yield 81%;
mp223–225 °C; Rf = 0.37 (20:1 chloroform/methanol); 1H
NMR (400 MHz, DMSO-d6): d 10.38 (s, 1H), 8.23 (s, 1H),
7.82 (s, 1H), 7.63 (s, 1H), 7.21 (m, 5H), 5.50 (s, 2H); 13C
NMR (100 MHz, DMSO-d6): d 182.9, 163.0, 143.9, 141.6,
136.1, 129.3, 128.2, 127.4, 126.8, 49.6; C12H11N3O2
requires C, 62.87; H, 4.84; N, 18.33. Found: C, 63.12, H,
4.93, N, 18.35; HRMS (FAB) calculated for C12H11N3O2,
230.0929 m/z (MH+); observed 230.0903. Compound 14:
Yield 88%; mp137–138 °C; Rf = 0.4 (20:1 chloroform/
methanol); 1H NMR (400 MHz, DMSO-d6): d 10.48 (s,
1H), 8.28 (s, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.29 (m, 5H),
5.75 (s, 2H), 4.54 (s, 1H); 13C NMR (100 MHz, DMSO-
d6): d 183.7, 163.7, 145.1, 143.1, 137.7, 130.1, 128.8, 128.3,
76.2, 70.9; C13H13N3O3 requires C, 60.10, H, 5.13, N,
15.99. Found, C, 60.22, H, 5.05, N, 16.21; HRMS (FAB)
calculated for C13H13N3O3, 260.1035 m/z (MH+);
observed 260.1061. Compound 18: Yield 33%;
oil; Rf = 0.23 (2:1 hexanes/ethyl acetate); 1H NMR
Acknowledgements
This paper is dedicated to Professor Nelson J. Leonard
on the occasion of his 89th birthday. The research was
supported in part by a grant (#9RO1 AI55452) from
the National Institute of Allergy and Infectious Diseases
(NIAID) of the National Institutes of Health, Bethesda,
MD, and an unrestricted grant from Nabi Biopharma-
ceuticals, Rockville, MD.
References and notes
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12. Physicochemical data for the key compounds reported are
as follows: Compound 4: Yield 61%; mp173–175 °C;

R. K. Ujjinamatada, R. S. Hosmane / Tetrahedron Letters 46 (2005) 6005–6009
6009
(300 MHz, CDCl3): d 7.72 (s, 1H) 7.28 (m, 5H), 6.36 (s,
1H), 5.67 (s, 2H), 4.54 (s, 2H), 4.38 (q, J = 6.9 Hz, 2H),
3.81 (q, J = 7.2 Hz, 2H), 3.53 (q, J = 7.2 Hz, 2H), 1.40 (t,
J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 6H); MS (FAB) 363
(MH+). Compound 20: Yield 92%; oil; Rf = 0.29 (20:1
chloroform/methanol); 1H NMR (300 MHz, DMSO-d6): d
7.63 (s, 1H), 7.31 (m, 5H), 7.15 (s, 2H), 6.53 (s, 1H), 5.68
(s, 2H), 4.57 (s, 2H), 3.86 (q, J = 7.2 Hz, 2H), 3.56 (q,
J = 6.9 Hz, 2H), 1.20 (t, J = 6.9 Hz, 6H); 13C NMR
(75 MHz, DMSO-d6): d 164.9, 136.4, 132.4, 131.8, 128.0,
127.5, 127.2, 127.2, 95.2, 75.4, 70.7, 63.4, 14.6; MS (FAB)
334 (MH+).