Highly efficient one-pot preparation of 1,2,4-oxadiazoles in the presence of diazabicycloundecene

Article abstract of DOI:10.1002/jhet.1689

New highly efficient method for the cyclization of acylamidoximes in the presence of diazabicycloundecene was developed and incorporated into a general and practical one-pot synthesis of 1,2,4-oxadiazoles (11 examples, 85-97% yields).

Full text of DOI:10.1002/jhet.1689

256
Highly Efficient One-Pot Preparation of 1,2,4-Oxadiazoles in the Presence
Vol 51
of Diazabicycloundecene
*
Kirill Lukin and Vimal Kishore
GPRD Process Chemistry, Abbott Laboratories, North Chicago, Illinois 60064
*
E-mail: kirill.lukin@abbott.com
Received November 11, 2011
DOI 10.1002/jhet.1689
Published online 31 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
R'
H2N
O
1. CDI
O
N
DBU
O
RCOOH
R'
N
R
2,
NH2
N
R
11 examples 85-97%
HON
R'
New highly efficient method for the cyclization of acylamidoximes in the presence of diazabicycloundecene
was developed and incorporated into a general and practical one-pot synthesis of 1,2,4-oxadiazoles
(11 examples, 85–97% yields).
J Heterocyclic Chem., 51, 256 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
1,2,4-Oxadiazoles have found numerous applications
in the design of biologically active compounds as
bioisosters for the amide or ester groups [1]. Scheme 1
outlines the most common synthesis of oxadiazoles 1,
which is based on the cyclocondensation reaction
between activated carboxylic acids and amidoximes 2
[2]. The starting amidoximes could be conveniently
prepared by treating nitriles with hydroxylamine [3].
Because of the importance of 1,2,4-oxadiazoles, a
number of optimized reaction conditions for Scheme 1
process has been reported [4]. However, these improve-
ments were still insufficient to establish a general method
for the preparation of compounds of type 1 in high
yields. For example, even relatively, structurally simple
oxadiazole 1a was obtained only in 50–60% yields while
utilizing the aforementioned conditions [4c–e].
It is important to note that the oxadiazole forma-
tion process consists of two separate chemical trans-
formations: the coupling of an activated carboxylic
acid with amidoxime 2 providing acylamidoxime inter-
mediate 3 and its subsequent cyclization into oxadiazole
1 (Scheme 2)[5].
Although intermediates 3 are typically stable and isola-
ble compounds [3,6], the majority of the oxadiazole
literature describes “one-pot” conditions where starting
amidoxime 2 is combined with a suitable carboxylic
acid derivative and the mixture was heated to directly
produce 1 [4]. We found that, although convenient
for synthetic purposes, such one-pot protocol was not
suitable for process optimization, as it made critical
parameters evaluation quite challenging. Instead, we
chose to separately evaluate and optimize the coupling
and the cyclization steps.
Evaluation of the coupling step. It has been reported
that amidoximes 2 could be acylated with a number
of carboxylic acid derivatives including acid chlorides
[4a], anhydrides [7a], or esters [7b] (eq. 1). More recently,
“active esters” such as imidazolides [4c], benzotriazolides
[4e], or uronium derivatives [4d] of carboxylic acids
have been frequently utilized in oxadiazole synthesis
because of their in situ preparation and milder reaction
conditions.
Although the literature suggest that the oxadiazole
yields could be effected by the reagent type used in the
acylation step, it is difficult to identify the preferred
one. Thus, it was reported that acid activation with
HOBT/EDAC or HATU resulted in higher yields of
oxadiazoles when compared with carbonyldiimidazole
(CDI) reagent [4d]. In another study, acid chlorides
were found (in some cases) superior to the corresponding
Achieving high reaction yields in oxadiazole prepara-
tions is particularly important for the syntheses of
complex biologically active compounds because this
transformation is often conducted in the final stage of
the process to provide a convergent assembly of target
molecules from two smaller building blocks (see
Scheme 1).
Through better understanding of the reaction para-
meters, we were able to develop a general, high-yielding
and convenient one-pot method for the preparation of
oxadiazoles in the presence of diazabicycloundecene
(DBU) base reported in this manuscript.
© 2013 HeteroCorporation

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Highly Efficient Method for One-Pot Preparation of
257
1,2,4-Oxadiazoles in the Presence of DBUArticle
Scheme 1
typically went to completion within 15 min at ambient
temperature. The imidazolide formation from nitrobenzoic
acid 4a was the only exception, as it took ~ 4 h at ambient
temperature to completion.
O
N
O
NH2
+
R'
R
HON
R
R
X
R'
N
1
2
Table 1 also includes the isolated yields of compounds
7a–e which were conveniently precipitated from the
corresponding reaction mixtures by water addition.
As we determined that the acylation of amidoximes with
acid imidazolides provided a general and efficient method
for the preparation intermediate 7, the process optimization
effort was shifted to the subsequent cyclization step.
Activation
OH
NH2OH
N
O
R'
Scheme 2
Optimization of the cyclization reaction. As previously
mentioned, the majority of the reported 1,2,4-oxadiazoles
preparations were accomplished through a thermal cyclization
of the in situ formed intermediates 3 (Scheme 2) [4]. The
reaction times and the temperatures required to complete
the cyclization were found to vary significantly depending
on the acylamidoxime 3 structure. In particular, carboxylic
acid derivatives possessing electron-donating substituents
were found poorly reactive [4e]. Slower reactions requiring
prolonged heating and/or higher temperatures often resulted
in lower yields of oxadiazoles, which were attributed to the
degradation of intermediate 3 under forcing conditions. It
was suggested that one of the possible degradation
pathways involved a cleavage of acylamidoxime 3 with
water that was the cyclization reaction byproduct
(Scheme 4) [4e].
Consequently, improved yields in the thermal cycliza-
tion reactions were reported when the water was removed
from the mixture with molecular sieves [4e].
As an alternative to the thermal process, strong bases
such as sodium hydride were found to induce cyclization
of intermediate 3 into oxadiazole 1 even at ambient
temperature [2]. A different reaction mechanism which
included the formation of reactive anion 10 was proposed
to explain the accelerated heterocycle formation under the
basic conditions (Scheme 5).
H2N
R'
1. CDI
O
1
RCOOH
N
2.
NH2
- H2O
O
R
3
HON
R'
benzotriazole derivatives [4f]. Unfortunately, the afore-
mentioned conclusions were not derived from the actual
yields of intermediate 3 but extrapolated from the final
oxadiazole yields, which made the preferred acylating
agent selection even more complicated.
To address this uncertainty, we decided to re-evaluate CDI
(convenient and general reagent for the activation of carboxylic
acids) [8,9] in the oxadiazole synthesis by determining the
actual yields of intermediate 7 in a number of representative
coupling reactions (Scheme 3). Aromatic and aliphatic
carboxylic acids (4a, 4b, 5) and electron-rich and electron-
deficient arylamidoximes (6a, 6b) were selected for these
experiments to cover a typical reactivity range for these types
of compounds.
The results of the coupling experiments are combined in
Table 1 and demonstrate that the activation of carboxylic
acids with CDI enables a very efficient formation of the
corresponding acylamidoximes in nearly quantitative yields
with no noticeable substituent effect.
More recently, it was reported that even a milder base–
tetrabutylammonium fluoride (TBAF, as a THF solution)
could enable an efficient cyclization of intermediate 3 at
Although monitoring the rates of the imidazolide
formation and the subsequent coupling reactions (see
Experimental), we determined that both were fast and
Scheme 3
NOH
NH2
X'
X'
6a X'=NMe2
6b X'=F
O
O
CDI
X
X
COIm
X
COOH
NH2
N
7a-d
4a X=NO2
4b X=OMe
O(OC)H2CPh
N
CDI
6b
PhCH2(CO)Im
PhCH2COOH
F
H2N
5
7e
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258
K. Lukin and V. Kishore
Vol 51
Table 1
Preparation of acylamidoximes 7a–e via CDI activation.a
Entry
Carboxylic acid
Amidoxime
Acylamidoxime product
Reaction yield (%)b
1
2
3
4
5
4a
4b
4a
4b
5
6a
6a
6b
6b
6a
7a
7b
7c
7d
7e
98 (92)c
>99 (93)c
98 (89)c
>99 (81)c
>99 (90)c
a1.0 eq. acid, 1.05 eq. of CDI in acetonitrile at RT.
bDetermined by HPLC method.
cIsolated yield.
Table 2
Cyclization of acylamidoximes 7a–e.
Scheme 4
H2N
R'
N
O
O
Starting
Material
Reaction
time
Product
(yield %)d
R'
N
R
Entry
Base
N
- H2O
O
R
a
1
1
2
3
4
5
6
7
8
7c
7a
7d
7a
7b
7d
7d
7d
7d
7d
7a
7b
7c
–
–
–
2
4
9c (96)
9a (66)
1a (86)
3
a
a
10
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
TBAFb
TBAFb
TBAFb
TEAc
9a > 99 (87)e
9b > 99 (88)e
1a > 99 (93)e
1a (0)
Scheme 5
O
DEIAc
TMGc
DBUc
DBUc
DBUc
DBUb
1a (0)
1a (51)
NH2
NH
Base
9
7
X
9
O
10
11
11
12
1a > 99 (94)e
9a > 99 (91)e
9b > 99 (89)b
9c > 99 (92)b
10
X'
0.5
TBAF, tetrabutylammonium fluoride; TMG, tetramethylguanidine; DBU,
1,8-diazabicyclo[5.4.0]jundec-7-ene.
aMolecular sieves, 120 ꢀC.
bRoom temperature.
c50 ꢀC.
room temperature (RT) [10]. Nevertheless, the applications
of the base-induced oxadiazole preparation have been very
limited [11]. In order to find out which cyclization method
provided the highest synthetic utility, we compared their
efficiency in the conversion of acylamidoximes 7a–d into
the corresponding oxadiazoles 1a and 9a–c (Scheme 6).
The results are summarized in Table 2 and demonstrate
that the efficiency of the thermal cyclization varied signifi-
cantly depending on the substrate. Thus, only compound 7c
possessing electron-withdrawing groups in both aryl frag-
ments underwent smooth thermal cyclization (entry 1). The
reaction of electron-rich amidoxime (7a) was accompanied
dReaction yield by assay.
eIsolated yield.
by substantial degradation even in the presence of molecular
sieves (entry 2), whereas the cyclization of compound (7d)
derived from electron-rich carboxylic acid did not go to
completion even after prolonged heating (entry 3).
At the same time, all reactions in the presence of TBAF
went to completion within minutes at ambient temperature
and provided the corresponding oxadiazoles in high yields
(entries 4–6).
Highly efficient cyclization observed in the presence of
TBAF encouraged us to search for other basic reaction
promoters more amendable for a one-pot process [12].
Although evaluating amines for this purpose, we found that
a relatively high basicity was required to induce the cycli-
zation reaction. For example, no formation of oxadiazole
1a was observed at 50 ꢀC in the presence of triethylamine
or diisopropylethylamine (pKa = 8–9) [13] (entries 7, 8).
However, addition of stronger bases–DBU and tetramethyl-
guanidine (pKa = 12–13) [13] provided a remarkable reaction
Scheme 6
N
O
7a-d
N
X'
X
9a X=NO2 X'= NMe2
9b X=OMe X'= NMe2
9c X=NO2 X'=F
1a X=OMe X'= F
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Highly Efficient Method for One-Pot Preparation of
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1,2,4-Oxadiazoles in the Presence of DBU
acceleration (entries 9, 10). DBU was found the most efficient
reaction promoter. Thus, in the presence of 1 eq. of this base,
the cyclization of a more reactive substrate 7c went to com-
pletion within 30 min at RT (entry 12). Even the least reactive
compound 7b was converted into oxadiazole 9b within 2 h at
50 ꢀC in nearly quantitative yield using 2 eq of DBU [14].
Importantly, under the DBU-induced cyclization conditions,
we did not observe the formation of degradation related
side-products which enabled the isolation of high purity
oxadizoles via a simple precipitation with water (see Table 2).
One-pot synthesis of 1,2,4-oxadiazoles. After identifying
the optimal reaction conditions for each step of the
oxadiazole synthesis, their combination into an efficient
“one-pot” process was further explored. We were pleased
to find that the cyclization reaction in the presence of
DBU was compatible with CDI-induced coupling
because imidazole–the only by-product of the coupling
reaction had no effect on the cyclization step [15]. After
some additional optimization, a general protocol for the
one-pot synthesis of 1,2,4-oxadiazoles was developed (see
Experimental). High purity products (>95% by HPLC and
NMR) were isolated by simple water precipitation from
the corresponding reaction mixtures, whereas the process
by-products–imidazole and DBU were conveniently
rejected into the liquors.
The examples shown in Table 3 demonstrate a general
utility and efficiency of this new method. The process
could be applied to the synthesis of oxadiazoles possessing
a variety of aromatic (1a, 9, 10), aliphatic (11, 13), and
heterocyclic (12) substituents which could contain either
electron withdrawing or donating functional groups.
The natural limitation of the method relates to the prep-
aration of oxadiazoles from the starting materials or inter-
mediates that could react with DBU. In particular, this
applies to the compounds with base sensitive stereo-
centers. At this point, we have found that stereo-centers
at the a-position to the carboxylic group are generally
stable under the process conditions (e.g., compound 13).
On the other hand, the application of the method to more
sensitive a-amino acid derivatives could be accompanied
by racemization, as we observed during the preparation
of oxadiazole 14 from t-butoxycarbonyl-L-phenylalanine.
CONCLUSIONS
In summary, we have developed a general and highly
efficient one-pot synthesis of 1,2,4-oxadiazoles, which
incorporates the acylation of amidoximes with imidazo-
lides of carboxylic acids and the cyclization of the resulting
Table 3
Examples of one-pot synthesis of 1,2,4-oxadiazoles.
Journal of Heterocyclic Chemistry
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260
K. Lukin and V. Kishore
Vol 51
General procedure for the synthesis of acylamidoximes
acylamidoximes in the presence of DBU. Under these new
conditions, many previously challenging compounds could
be obtained in high yields. As an added convenience, the
method eliminates a necessity to conduct the reactions at
high temperatures, in microwave ovens, or in the presence
of molecular sieves. In a typical example, the overall time
required for the preparation and isolation of oxadiazole
products is reduced to 1.5–2 h.
7a–e.
Carboxylic acid 4a,b, 5 (1.05 mmol) is added to a
solution of CDI (0.17 g, 1.05 mmol) in acetonitrile (3.0 mL).
Upon the completion of carbon dioxide evolution, amidoxime 6
(1.0 mmol) is added to the reaction mixture and the agitation is
continued for 30 min at RT. The mixture is then diluted with
water (3.0 mL), and the product is filtered, washed with 1:1
ACN-water (1.5 mL) and dried under vacuum at 40 ꢀC to give
compounds 7a–e.
4-Fluoro-N’-(4-nitrobenzoyloxy)benzimidamide (7c). was
isolated in 89% yield; 1H nmr (d, DMSO-d6): 7.14 (broad
s, 2H), 7.32 (m, 2H), 7.82 (m, 2H), 8.32 (d, 2H), 8.42 (d, 2H);
13C NMR (d, DMSO-d6): 115.0 (d, 2C), 123.1 (2C), 127.4,
128.8 (d, 2C), 130.5 (2C), 134.1, 149.5, 156.0, 161.5. 162.8 (d).
Anal. Calcd. For C14H10FN3O4: C, 55.45; H, 3.32; N, 13.86.
Found: C, 55.25; H, 3.10; N, 14.13.
EXPERIMENTAL
General.
The reactions were monitored by HPLC method
utilizing Zorbax Eclipse XDB-C18 (Agilent Technologies)
column with detection at 205 nm. Reaction yields were
determined by HPLC method using standard solutions of the
corresponding isolated purified compounds as a reference.
General procedure for one-pot preparation of oxadiazoles 1,
4-Fluoro-N’-(2-phenylacetoxy)benzimidamide (5). was
1
isolated in 90% yield. H NMR (d, DMSO-d6): 3.81 (s, 2H), 6.89
(broad s, 2H), 7.21–7.31 (m, 3H), 7.31–7.36 (m, 4H), 7.75 (m, 2H).
13C NMR (d, DMSO-d6): 39.3; 114.8 (d, 2C), 126.3, 127.4, 127.8
(2C), 128.6 (d, 2C), 128.9 (2C), 134.1, 155.4, 162.7 (d), 168.2. Anal.
Calcd. For C15H13FN2O2: C, 66.17; H, 4.81; N, 10.29. Found: C,
66.05; H, 4.85; N, 10.33.
Previously reported in the literature amidoximes 7a, 7b, and
7d were isolated in 92, 93, and 81% yields, respectively, and
had matching spectral data.
9–13.
All of these reactions were conducted under nitrogen
atmosphere. Carboxylic acid (10.5 mmol) was added to a solution
of CDI (1.7 g, 10.5mmol) in acetonitrile (30 ml). Upon the
completion of carbon dioxide evolution, amidoxime 2 (10mmol)
was added to the reaction mixture and the agitation is continued
for 30 min at RT. DBU (3.0 g, 20mmol) was then added, and the
reaction mixture was heated to 60 ꢀC. After 1 h, the mixture was
cooled to RT and diluted with water (30mL). The product was
filtered, washed with 1:1 ACN-water (20 mL) and dried under
vacuum at 50 ꢀC to give oxadiazoles 1, 9–13.
3-(4-Dimethylaminophenyl)-5-(4’-nitrophenyl)-1,2,4-oxadiazole
(9a). 1H NMR (d, Pyridine-d5): 2.82 (s, 6H), 6.84 (d, 2H), 8.26–
8.40 (m, 6H). Anal. Calcd. For C16H14N4O3: C, 61.93; H, 4.55; N,
18.06. Found: C, 62.27; H, 4.16; N, 18.05.
3-(4-Dimethylaminophenyl)-5-(4’-methoxyphenyl)-1,2,4-oxadiazole
(9b). 1H NMR (d, CDCl3): 3.03 (s, 6H), 3.88 (s, 3H), 6.75 (d, 2H),
7.01 (d, 2H), 8.00 (d, 2H), 8.13 (d, 2H). 13C NMR (d, CDCl3): 40.4
(2C), 55.6, 111.4 (2C), 114.1 (2C), 116.9, 128.3 (2C), 129.6 (2C),
151.7 (d), 162.4 (d), 168.3 (d), 174.3. Anal. Calcd. For C17H17N3O2:
C, 69.14; H, 5.80; N, 14.23. Found: C, 69.35; H, 5.51; N, 14.28.
General procedure for the cyclization of acylamidoximes 7a-d
into oxadiazoles 1a, 9a–c.
A solution of acylimidazole 7
(1.0mmol) and DBU (0.30 g, 2.0 mmol) in acetonitrile (3.0 mL) is
heated to 60ꢀC. After 1 h, the mixture is cooled at RT and diluted
with water (3.0mL). The product is filtered, washed with 1:1
ACN-water (1.5 mL) and dried under vacuum at 50 ꢀC to give
oxadiazoles 1a, 9a–c in 94, 91, 89, 92% yields, respectively
(see the aforementioned one-pot procedure for characterization of
these compounds).
REFERENCES AND NOTES
5-(2-Chloro-4-fluorophenyl)-3-(4’-fluorophenyl)-1,2,4-oxadiazole
(10). 1H NMR (d, CDCl3): 7.11–7.23 (m, 3H), 7.32 (m, 1H),
8.10–8.21 (m, 3H). 13C NMR (d, CDCl3): 114.6 (d), 115.8 (d, 2C),
118.7 (d), 119.8, 122.6 (d), 129.3 (d, 2C), 133.3 (d), 135.1 (d),
163.9 (d), 164.1 (d), 167.3, 173.0. Anal. Calcd. For C14H7ClF2
N2O: C, 57.45; H, 2.41; N, 9.57. Found: C, 57.81; H, 2.04; N, 9.48.
[1] a) Luthman, K.; Borg, S.; Hacksell, U. Methods Mol Med
1999, 23, 1; b) For more recent examples see: Farooqui, M.; Bora, R.;
Patil, C. R. European J. Med. Chem. 2009, 44, 794; Wu, Z.; Hartnett,
J. C. PCT Int. Appl. 2009 WO 2009051705; Hobson, A.D.; Fix-Stenzel,
S. R.; Cusack, K. P.; Breinlinger, E. C.; Ansell, G. K.; Stoffel, R. H., Woller,
K. R., Grongsaard, P. US Patent 7,834,039, 2010.
[2] Jochims, J. C. In Comprehensive Heterocyclic Chemistry
II; Stor, R. C., Ed.; Pergamon Press: Oxford, 1996; Vol. 4,
pp 179–228.
5-Benzyl-3-(4-fluorophenyl)-1,2,4-oxadiazole (11). 1H NMR
(d, CDCl3): d 4.27 (s, 2H), 7.14 (t, 2H), 7.26–7.40 (m, 5H), 8.05
(m, 2H). 13C NMR (d, CDCl3): 33.2; 115.7 (d, 2C), 122.7, 127.3,
128.6 (4C), 129.2 (d, 2C), 133.1, 164.0 (d), 167.1, 177.5. Anal.
Calcd. For C15H11F N2O: C, 70.86; H, 4.36; N, 11.02. Found: C,
71.05; H, 4.10; N, 11.03.
[3] Eloy, F.; Lenaers, R. Chem Rev 1962, 62, 155.
[4] a) Chiou S.; Shine, H. J. J Heterocycl Chem 1989, 27, 125; b)
Liang, G.-B.; Feng, D. D. Tetrahedron Lett 1996, 37, 6627; c) Deegan, T.
L.; Nitz, T. J.; Cebzanov, D.; Pufko, D. E.; Porco J. A. Bioorg Med Chem
Lett 1999, 9, 209; d) Poulain, R. F.; Tartar, A. L.; Deprez, B. P. Tetrahe-
dron Lett 2001, 42, 1495; e) Pipik, B.; Ho, G.-J.; Williams, J. M.; Conlon,
D. A. Synth Commun 2004, 34, 1863; f) Wang, Y.; Miller, R. L.; Sauer,
D. R.; Djuric, S. W. Org Lett 2005, 7, 925.
[5] For additional detailes on the oxadiazole formation mechanism
see: Ooi, N. S.; Wilson, D. S. J Chem Soc Perkin Trans 2 1980, 12, 1792.
[6] Lasovsky, J.; Grambal, F. Coll Czech Chem Commun 1985,
50, 2722.
5-(trans-2-Phenylcyclopropyl)-3-(4’-fluorophenyl)-1,2,4-
oxadiazole (13).
1H NMR (d, CDCl3): 1.71 (m, 1H), 1.90
(m, 1H), 2.48 (m, 1H), 2.79 (m, 1H), 7.09–7.19 (m, 4H), 7.19–7.26
(m, 1H), 7.31 (m, 2H), 8.04 (m, 2H). 13C NMR (d, CDCl3): 18. 66
(CH2), 18.78, 28.51, 115.7 (d, 2C), 122.9, 125.9 (2C), 119.8, 126.6,
128.3 (2C), 129.2 (d, 2C), 138.7, 162.7, 165.2, 166.9, 179.7. Anal.
Calcd. For C17H13F N2O: C, 72.85; H, 4.67; N, 9.99. Found: C,
73.25; H, 4.36; N, 9.98.
Previously reported in the literature oxadiazoles 1a, 9c–f, and
12 were isolated in the yields provided in Table 3 and had
matching spectral data.
[7] a) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csoregh, I.;
Hesselink, W.; Hacksell, U. J Org Chem 1995, 60, 3112; b) Amarasinghe, K.
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Highly Efficient Method for One-Pot Preparation of
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1,2,4-Oxadiazoles in the Presence of DBU
[9] HOBT and HATU reagents appear less practical as the former
requires a co-activator (e.g. EDAC), and the latter produces tetramethy-
lurea side product.
[12] Polymer supported diazophosphorine (BEMP) base has been
also utilized in parallel synthesis of oxadiazoles (see ref. [4f]).
[13] pKa values calculated for DMSO solutions.
[10] Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.;
Wang, V. R.; Rice, K. D. Tetrahedron Lett 2001, 42, 1441.
[11] Commonly utilized cyclization in refluxing pyridine (ref. 4a)
cannot be considered a base induced reaction, as the basicity of pyridine
is not sufficient to deprotonate 3.
[14] Observation that only strong amine bases promote the cycliza-
tion indicates that this reaction could proceed via deprotonated amidoxime
10 as shown in Scheme 5.
[15] Under one-pot conditions cyclization with TBAF required
3 eq. of the base to achieve the reaction completion.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet