Application of primary allylamines from morita-baylis-hillman adducts: Cyanogen azide mediated synthesis of substituted 5-aminotetrazoles and their attempted transformation into tetrazolo[1,5-a]pyrimidinones

Article abstract of DOI:10.1002/ejoc.201000586

A general protocol for the synthesis of substituted 5-aminotetrazoles by treating cyanogen azide with primary allylamines afforded either by S _N2 or S_N2′ reactions of Morita- Baylis-Hillman acetates of acrylate has been developed. Th

Full text of DOI:10.1002/ejoc.201000586

FULL PAPER
DOI: 10.1002/ejoc.201000586
Application of Primary Allylamines from Morita–Baylis–Hillman Adducts:
Cyanogen Azide Mediated Synthesis of Substituted 5-Aminotetrazoles and
Their Attempted Transformation into Tetrazolo[1,5-a]pyrimidinones[‡]
Somnath Nag,[a] Subhendu Bhowmik,[a] Harsh M. Gauniyal,[b] and Sanjay Batra*[a]
Keywords: Allylic compounds / Amines / Azides / Tautomerism / Nitrogen heterocycles
A general protocol for the synthesis of substituted 5-amino- that substituted tetrazolo[1,5-a]pyrimidin-7(4H)-ones could
tetrazoles by treating cyanogen azide with primary allyl-
amines afforded either by SN2 or SN2Ј reactions of Morita–
Baylis–Hillman acetates of acrylate has been developed. The
base-promoted intramolecular cyclizations of these tetrazoles
afford highly substituted 2-azidopyrimidin-4(3H)-ones in-
stead of the expected tetrazolopyrimidinone due to azide–
tetrazole tautomerism. Nevertheless it has been discovered
be isolated in pure form from a methanolic solution of the
respective 2-azidopyrimidin-4(3H)-ones through crystalli-
zation. The structure of tetrazolo[1,5-a]pyrimidin-7(4H)-one
was unambiguously assigned by X-ray crystallography. The
existence of azide–tetrazole tautomerism in this class of com-
pounds has been supported through NMR spectroscopic
studies.
Owing to the propensity to deliver densely functionalized
products amenable to a variety of manipulations, the MBH
reaction has become very popular in synthetic organic
chemistry.[10] The synthetic intermediates afforded from ad-
ducts provide a versatile platform for developing novel ap-
proaches to a variety of heterocyclic frameworks.[10b,11] One
such derivative is the primary allylamine, which is an effec-
tive precursor to different azaheterocycles.[12] Although
MBH-acetate, in principle, has the potential to afford two
variants of primary allylamines as depicted in Figure 1, a
general route to primary allylamines of only type II has
been developed.[13] To the best of our knowledge, a general
and practical method for synthesizing primary allylamines
of type I is not know, and henceforth, their synthetic poten-
tial remains unexplored. Although Xu et al. reported the
isolation of such amines as hydrochloride salts through de-
protection of aza-MBH adducts prepared from N-dithio-
phosphoryl imine and activated alkenes, the scope of the
methodology was not investigated.[14]
Introduction
Tetrazoles are structural cores of many compounds with
wide-ranging applications. In coordination chemistry[1] they
serve as ligands, whereas in material chemistry they serve
as structural elements of high energy-density materials.[2]
Besides, the therapeutic potential of tetrazole derivatives is
of major interest, as they serve as metabolically stable sur-
rogates for carboxylic acids[3] and have shown to display
antiallergic, antiasthmatic,[4] antiviral, antibiotic,[5] anti-
inflammatory,[6] antineoplastic,[7] and cognition enhancing
activities.[8] In our program focused at the construction of
tetrazole-fused frameworks from intermediates derived
from Morita–Baylis–Hillman chemistry (MBH),[9] we re-
port herein the synthesis of substituted 5-aminotetrazoles
from primary allylamines by using cyanogen azide and
a base-promoted intramolecular cyclization leading to
2-azido-pyrimidin-4(3H)-ones instead of the expected
tetrazolo[1,5-a]pyrimidin-5(4H)-ones. Nevertheless the
azido derivatives display azide–tetrazole tautomerism in
solution to furnish the corresponding tetrazolo[1,5-a]pyr-
imidin-7(4H)-ones, which were isolated by crystallization
from methanol.
[‡] CDRI Communication No. 7942
[a] Medicinal and Process Chemistry Division, Central Drug
Research Institute, CSIR,
PO Box 173, Lucknow 226001, UP, India
Fax: +91-522-2623405
Figure 1. MBH acetate as viable precursors to primary allylamines
(I and II).
E-mail: batra_san@yahoo.co.uk
s_batra@cdri.res.in
[b] Sophisticated Analytical Instrument Facility, Central Drug
Research Institute, CSIR,
It occurred to us that like any other SN2Ј–SN2Ј displace-
ment reaction, treatment of the DABCO salt of MBH acet-
ate with ammonia under aqueous conditions would furnish
amine I. On the basis of literature precedence we envisaged
PO Box 173, Lucknow 226001, UP, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000586.
Eur. J. Org. Chem. 2010, 4705–4712
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4705

S. Nag, S. Bhowmik, H. M. Gauniyal, S. Batra
FULL PAPER
that treatment of this amine with cyanogen bromide will
lead to cyanamide.[15] Reaction of cyanamide with sodium
azide would result in the substituted 5-aminotetrazole,
which may undergo concomitant intramolecular cyclization
with the ester group to afford the annulated tetrazole. Our
reasoning was supported by the retrosynthetic evaluation as
presented in Scheme 1.
Scheme 1. Retrosynthetic scheme for the synthesis of annulated
tetrazole from amine I.
Results and Discussion
The first objective of the present study was to develop a
general synthesis for primary allylamine I from the DABCO
salt of the MBH acetate of acrylate. Accordingly, we syn-
thesized acetate 2a from 1a and utilized it as model sub-
strate to optimize the synthesis of the amine. Treating 2a
with DABCO in THF/water at room temperature gave the
DABCO salt, which was treated with aqueous ammonia un-
der different conditions with respect to time and tempera-
ture. Notably, the aqueous medium essential for the forma-
tion of the DABCO salt influenced our decision to explore
aqueous ammonia for introducing the amino functionality.
It was pleasing to note that treatment of the DABCO salt
of 2a with aqueous ammonia (30%) for 30 min at 15 °C
followed by workup with dichloromethane resulted in re-
Scheme 2. Reagents and conditions: (i) AcCl (1.5 equiv.), pyridine
(1.3 equiv.), CH2Cl2, 0 °C to room temp., 2 h; (ii) a) DABCO
(1.0 equiv.), THF/H2O, room temp., 15 min; b) aq. NH3 (30%), 10–
20 °C, 30 min; (iii) N3CN (2.0 equiv.), MeCN, 0–10 °C, 8 h;
(iv) a) NaH (2.5 equiv., 60% in oil), THF, room temp., 15 min;
b) aq. HCl (2 , to pH 2); (v) equilibration in solution of MeOH,
CD3OD, [D6]acetone, [D5]pyridine, or [D6]DMSO; (vi) crystalli-
zation from a solution of MeOH; (vii) Zn (3.0 equiv.), AcOH,
80 °C, 2 h; (viii) POCl3, PCl5 (catalytic), 110 °C, 1 h.
quired amine 3a (Scheme 2). Attempts to purify 3a by col- advantage of using this reagent was that no anhydrous con-
umn chromatography or even leaving it unattended at room ditions were required to perform the reaction. As a conse-
temperature for a couple of hours, however, resulted in po- quence, crude 3a was treated with cyanogen azide in aceto-
lymerization. As a consequence, freshly prepared 3a was im- nitrile at low temperature, which in turn was freshly pre-
mediately treated with cyanogen bromide and NaHCO3 in pared by treating cyanogen bromide with sodium azide in
ethanol at a temperature below 10 °C for 1 h followed by dry acetonitrile at 0 °C. Workup and purification of the re-
addition of sodium azide. The reaction mixture was then action mixture gave a product in 46% yield. On the basis
acidified by the slow addition of dilute HCl (1:1) at 0 °C. of spectral analysis, this product was established to be 1-
The reaction was continued for 2 h at the same temperature substituted 5-aminotetrazole 4a. Perhaps the lower stability
and then heated at 90 °C for another 3 h, following a litera- of 3a could be one of the reasons for the low yield. Unex-
ture procedure.[14] Contrary to the reported method, the re- pectedly, no intramolecular cyclization was observed during
action in our hands was not clean, and TLC analysis dis- this reaction.
played a mixture of several nonpolar spots. This led us to
seek an alternate route for the synthesis of the 5-amino- examined base-mediated intramolecular cyclization of 4a to
tetrazole from amine 3a. achieve the synthesis of tetrazolopyrimidinone. Accord-
With substituted the 5-aminotetrazole in hand, we then
Recently, Shreeve and co-workers demonstrated that cy- ingly, 4a was treated with NaH in THF at room tempera-
anogen azide is an excellent reagent for generating tetra- ture for 15 min to furnish a product that could be isolated
zoles directly from hydrazines and primary and secondary only after acidifying the reaction mixture to pH 2.0 with
amines at low temperature, though safety methods for 2  HCl. The isolated crude product upon triturating with
handling this reagent are necessary for a successful out- diethyl ether furnished the pure product as a solid, which
come.[16] Nevertheless the low stability and short shelf life appeared as a black spot under UV light (254 nm) in TLC
of 3a prompted us to examine cyanogen azide for achieving analysis. The IR spectrum of the product displayed peaks
the synthesis of the desired 5-aminotetrazole. An additional for the azide and amide groups, whereas the 1H NMR spec-
4706
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4705–4712

5-Aminotetrazoles and Their Transformation into Tetrazolo[1,5-a]pyrimidinones
trum recorded in [D6]DMSO indicated the product to be a the isolated product unambiguously, colorless crystals suit-
mixture of two compounds with similar proton disposition. able for X-ray studies were obtained by slow evaporation of
1
There were two signals for methyl groups in the H NMR its saturated methanolic solution. To our surprise, analysis
spectrum at δ = 1.89 and 1.92 ppm in a ratio of 2:1, whereas revealed the structure to be 6-methyl-5-phenyltetrazolo[1,5-
in the 13C NMR spectrum the corresponding peaks were a]pyrimidin-7(4H)-one (7a) instead of envisaged product 5a
observed at δ = 12.4 and 12.9 ppm. The origin of the methyl (Figure 2).[19] The spot for the crystalline product on TLC
group in the product was attributed to the isomerization of corresponded to the fluorescent violet spot. Moreover, the
the exocyclic double bond to the endocyclic position in the IR spectrum of the crystalline compound recorded as KBr
presence of base.[17] This result invoked us to perform TLC disc displayed a peak for the amide group, but the charac-
analysis with the recovered NMR sample, which revealed teristic peak for the azide group was absent. Subjecting a
the presence of two spots. One of the spots corresponded freshly prepared sample of 7a to NMR spectroscopic analy-
to the initial black spot, whereas the second was observed sis showed the signal of the methyl group at δ = 1.92 ppm
1
to be a more polar fluorescent violet spot that had appeared in the H NMR spectrum and at δ = 12.4 ppm in the 13C
after the solution was prepared. Thus, we considered TLC NMR spectrum. These signals matched the new signals ap-
analysis of the product at different time intervals. It was pearing over time in the NMR spectra of 6a (Figure 3).
observed that when spotted immediately after preparation However, repeated NMR spectroscopic analysis of the same
of the solution, the product appears as a single black spot, sample of 7a after 24 h showed it too tautomerizes to co-
but after a short interval, a new violet spot starts to appear. exist with 6a. Thus, we concluded that the compound iso-
Essentially, to provide additional support, the NMR spec- lated as a solid from the reaction mixture is azidopyrimid-
trum of a freshly prepared solution of the isolated product inone 6a, which tautomerizes to tetrazolopyrimidinone 7a
in [D6]DMSO was recorded. Notably, this time we could in solution to reach an equilibrium in approximately 24 h.
observe the presence of a single compound, wherein a signal Importantly, however, 7a can be isolated in pure form by
for the methyl group was present at δ = 1.89 ppm and crystallization from methanol. To chemically ascertain the
1
12.9 ppm in the H and 13C NMR spectrum, respectively. presence of the azido form, 6a was subjected to reduction
However, after a time gap of 1.0 h, a new peak at δ = in the presence of Zn in AcOH to furnish a single product
1
1.92 ppm in the H NMR spectrum started to appear. As in 91% yield that was delineated to be 2-amino-5-methyl-6-
monitored by 1H NMR spectroscopy, the percentage of this phenylpyrimidin-4(3H)-one (8). On the other hand, even
peak increased with time, and after 24 h, the ratio of the pure 7a upon treatment with Zn in AcOH resulted in 8 in
two products stabilized to 2:1; this ratio did not change
even after 48 h (see Supporting Information). In the 13C
NMR spectrum, the appearance of a peak at δ = 12.4 ppm
corresponded to this new compound. These results inferred
that in solution the product generated through reaction of
4a with NaH equilibrated with a compound having similar
disposition of protons.
It is widely reported that annulated tetrazoles display
ring-chain tautomerism to exist in the azido form in solu-
tion, but this process is reversible.[18] Hence, it was assumed
that the isolated product is 2-azido-5-methyl-6-phenyl-
pyrimidin-4(3H)-one (6a), which tautomerized in solution
to coexist as 6-methyl-7-phenyltetrazolo[1,5-a]pyrimidin-
5(4H)-one (5a). Nevertheless, to arrive at the structure of Figure 2. ORTEP diagram of 7a at 35% probability level.
1
Figure 3. H NMR spectra ([D6]DMSO) of (a) an equilibrated mixture of 6a and 7a, (b) pure 6a, and (c) pure 7a.
Eur. J. Org. Chem. 2010, 4705–4712
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4707

S. Nag, S. Bhowmik, H. M. Gauniyal, S. Batra
FULL PAPER
93% yield.[20] The formation of 8 from 7a was rationalized
on the basis of the conversion of 7a into 6a under acidic
conditions followed by reduction. Additional support for
this assumption came from the reaction of 7a with POCl3
in the presence of a catalytic amount of PCl5, which re-
sulted in the formation of chloride 9. The IR spectrum of
9 displayed the characteristic peak for the azido group,
thereby confirming the opening of the tetrazole subunit un-
der acidic conditions.
In view of the results achieved by Zn/AcOH reduction of
6a and 7a, we considered it worthwhile to study the effect
of acidic and basic conditions on 6a and 7a independently
by NMR spectroscopic experiments. As a consequence,
samples for both compounds were prepared in [D]TFA and
[D5]pyridine. The 1H NMR spectra of 6a and 7a in [D]TFA
were found to be identical whether recorded immediately or
after 24 h. The chemical shifts of these spectra corre-
sponded to the one observed for the azido form. This obser-
vation was in agreement with the literature, which docu-
ments the existence of the azido form in acidic medium,
and in particular TFA.[21] On the other hand, the 1H NMR
spectra of 6a and 7a in [D5]pyridine recorded immediately
displayed the azido and tetrazolyl forms, respectively, but
repetition of the 1H NMR spectroscopic experiments of the
same samples after 24 h showed both forms equilibrating,
wherein the azido and tetrazolyl forms were present in a 3:2
ratio.
To assess the generality of the protocol, we examined
MBH acetates 2b–h for similar series of reactions, and the
results have been illustrated in Table 1. In all cases primary
allylamines 3b–h were formed, which were subsequently
transformed into 5-aminotetrazoles 4b–h in moderate
yields. Gratifyingly, reactions of 4b–h with NaH yielded the
respective substituted 2-azido-pyrimidin-4(3H)-ones 6b–h
in good yields. Crystallization of 6c from MeOH resulted
in isolation of corresponding tetrazole form 7c.
Figure 4. Plausible mechanism for the isolation of azide derivative
6 through acidic workup during NaH-promoted intramolecular cy-
clization.
Encouraged by the success of the protocol with primary
allylamine I, we decided to extend its application to primary
allylamine II, which is rather easily accessible from the
MBH acetate.[12] Accordingly, we selected allylamine 10a
for initial optimization studies, which was readily obtained
from acetate 2a by following a reported procedure. Treating
10a with freshly prepared cyanogen azide for 8 h afforded
required substituted 5-aminotetrazole 11a in 61% yield
(Scheme 3). Intramolecular cyclization in the presence of
NaH in THF was complete in 15 min to afford a product
after acidic workup. Similar to the preceding section, TLC
analysis of the product carried out immediately displayed a
single nonpolar spot, whereas analysis of the same solution
after different time intervals showed the appearance of a
violet spot in addition to the original black spot, which in-
creased in intensity with time. The IR spectrum of the iso-
lated product displayed the presence of a peak for the azido
and amide groups, whereas the 1H NMR spectrum re-
corded immediately after preparing the sample in [D6]-
DMSO showed the presence of one compound with a char-
Table 1. Isolated yields of substituted 5-aminotetrazoles 4 and azi-
dopyrimidinones 6.
Compd. no.
Ar
% Yield of 4
% Yield of 6
a
b
c
d
e
f
Ph
46
50
39
53
48
51
55
45
96
93
95
90
92
95
92
82
2-ClC6H4
2-FC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
2,4-Cl2C6H3
2-thienyl
g
h
On the basis of the findings it is speculated that the NaH-
mediated intramolecular cyclization proceeds by the path-
way delineated in Figure 4. Initially, intramolecular cycliza-
tion involving the free amino and the ester moiety takes
place in tetrazole A to furnish intermediate B, which imme-
diately stabilizes as C. Acid workup of the reaction mixture
yields azido derivative D, which in solvent equilibrates with
tetrazole form E.
Scheme 3. Reagents and conditions: (i) NH3/MeOH, room temp.
1 h; (ii) N3CN (2.0 equiv.), MeCN, 0–10 °C, 8 h; (iii) a) NaH
(2.5 equiv., 60% in oil), THF, room temp., 15 min; b) aq. HCl (2 ,
to pH 2); (iv) equilibration in solution of MeOH, CD3OD, [D6]ace-
tone, [D5]pyridine, or [D6]DMSO; (v) crystallization from MeOH;
(vi) Zn (3.0 equiv.), AcOH, 80 °C, 2 h; (vii) POCl3, PCl5 (catalytic),
110 °C, 1 h; (viii) benzyl bromide (1.2 equiv.), NaH (2.5 equiv.,
60% in oil), DMF, room temp., 6 h.
4708
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4705–4712

5-Aminotetrazoles and Their Transformation into Tetrazolo[1,5-a]pyrimidinones
1
Figure 5. H NMR spectra ([D6]DMSO) of (a) an equilibrated mixture of 12a and 13a, (b) pure 12a, and (c) pure 13a.
acteristic peak for the =CH proton appearing at δ = Table 2. Isolated yields of substituted 5-aminotetrazoles 11 and azi-
dopyrimidinones 12.
8.96 ppm. Therefore, the structure of the product was as-
signed as 2-azido-5-(phenylmethyl)pyrimidin-4(3H)-one
(12a). In line with earlier observations, recording of the
NMR spectrum of the sample after 24 h displayed it to be
a mixture of two products, but the ratio was observed to be
5:6. Moreover, TLC analysis of the recovered sample
showed the presence of a new violet spot besides the origi-
nal one. Fortunately, we were able to crystallize the more
polar compound corresponding to the fluorescent violet
spot from a saturated methanolic solution as tetrazolyl
form 13a. In the 1H NMR spectrum of pure 13a the chemi-
cal shift of the =CH proton was observed to be δ =
8.21 ppm. This chemical shift was identical with the chemi-
cal shift of the peak that had appeared in the NMR spec-
trum of 12a recorded after a gap of 24 h. For the sake of
Compd. no.
Ar
% Yield of 11 % Yield of 12
a
b
c
d
e
f
Ph
61
65
66
70
59
71
69
51
93
87
91
94
92
91
90
89
2-ClC6H4
2-FC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
2,4-Cl2C6H3
2-thienyl
g
h
Having utilized the primary allylamines from the MBH
acetate of acrylates we decided to investigate the scope of
the strategy with the corresponding amines generated from
the MBH acetate of acrylonitrile. Accordingly, allylamine
19 was first generated from adduct 17 and was then sub-
jected to reaction with cyanogen azide as outlined above.
This resulted in the formation of substituted 5-amino-
tetrazole 20 (Scheme 4). However, attempts to carry out in-
tramolecular cyclization by using different bases failed to
1
clarity, a comparison of the H NMR spectra of 12a and
13a has been provided in Figure 5. Chemically, the re-
duction of either 12a or 13a in the presence of Zn/AcOH
resulted in the formation of 14. Furthermore, reaction of
13a with POCl3 in the presence of a catalytic amount of
PCl5 led to the isolation of azido derivative 15 in 86% yield.
With the desire to understand the general trend of our
methodology for these substrates, allylamines 10b–h were
examined, and the results are presented in Table 2. Amines
10b–h successfully furnished the respective 5-aminotetra-
zoles 11b–h. Subsequent treatment of 11b–h with NaH fol-
lowed by acidic workup provided azido compounds 12b–h
in good yields. Further crystallization of 12b,d,e,g,h from
methanol successfully led to isolation of a crystalline com-
pound in each case, and the structures of each was delin-
eated to be corresponding tetrazoles 13b,d,e,g,h. Unfortu-
nately, crystals of none of the compounds were found to be
suitable for X-ray analysis. Thus, to ascertain the structure
of 13a unambiguously, we embarked on a detailed NOESY
experiment of 16, which was realized through benzylation
of 13a. The NOE of the =CH proton of the pyrimidinone
ring with protons of both of the benzylic group confirmed
the assigned structure.
Scheme 4. Reagents and conditions: (i) AcCl (1.5 equiv.), pyridine
(1.3 equiv.), dry CH2Cl2, 0 °C to room temp.; (ii) a) DABCO
(1.0 equiv.), THF/H2O, room temp., 15 min; b) aq. NH3, 10–20 °C,
30 min; (iii) N3CN, MeCN, 0–10 °C, 8 h; (iv) NH3/MeOH, room
temp., 1 h.
Eur. J. Org. Chem. 2010, 4705–4712
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4709

S. Nag, S. Bhowmik, H. M. Gauniyal, S. Batra
FULL PAPER
diluted with acetonitrile (40 mL), and the volume of the solution
was evaporated under reduced pressure at low temperature (below
10 °C). The concentrated solution containing allylamine 3a was in-
stantly used for further reaction without any purification.
yield the desired annulated tetrazole. Simultaneously, amine
21 was also prepared and subjected to reaction with cyano-
gen azide to yield required 5-aminotetrazole 22 in good
yield. Unfortunately, 22 also failed to undergo intramolecu-
lar cyclization to furnish the annulated tetrazole derivative.
General Procedure for the Synthesis of 4a–h, 11a–h, 20, and 22 as
Exemplified for 4a: At 0 °C, cyanogen bromide (1.45 g,
13.68 mmol) was dissolved in dry acetonitrile (25 mL) to which so-
dium azide (2.67 g, 41.04 mmol) was added. The reaction mixture
was stirred at 0–10 °C for 4 h. The inorganic salt was filtered off
(Caution! After filtering, the salt must be dissolved in cold water
quickly). The solution of amine 3a in acetonitrile was diluted with
water (6 mL) and stirred at 0 °C. To this solution was added the
filtrate containing cyanogen azide at the same temperature. After
stirring for 8 h at 10 °C, reaction mixture was concentrated under
reduced pressure, and the residue was diluted with water (20 mL).
The mixture was extracted with ethyl acetate (3ϫ20 mL). The or-
ganic layers were pooled, dried with anhydrous Na2SO4, and con-
centrated under reduced pressure. Purification of the crude product
by column chromatography over silica gel (ethyl acetate/hexanes,
1:1) furnished pure product 4a as a white solid (0.81 g, 46%).
Conclusions
In summary, we have developed a benign and general
protocol for the synthesis of primary allylamines through
SN2Ј–SN2Ј displacement reactions of MBH acetates. We
demonstrated the utility of primary allylamines generated
from the MBH acetates of acrylates for the synthesis of
substituted 5-aminotetrazoles by reaction with cyanogen
azide. The base-promoted intramolecular cyclization of
these tetrazoles resulted in isolation of highly substituted
azidopyrimidinones instead of the expected tetrazolo[1,5-a]-
pyrimidin-5(4H)-ones. Nevertheless, we could successfully
isolate the tetrazolo[1,5-a]pyrimidin-7(4H)-one form in
pure state through crystallization of the azido derivative
from methanolic solution. We have further studied the
scope of the strategy and found that the primary allyl-
amines from the MBH acetate of acrylonitrile furnished the
5-aminotetrazoles but failed to undergo intramolecular cy-
clization to furnish the fused tetrazole system. This work
signifies the usefulness of MBH chemistry for achieving the
synthesis of important heterocyclic motifs.
Methyl 2-[(5-Amino-1H-1,2,3,4-tetraazol-1-yl)(phenyl)methyl]acryl-
ate (4a): Rf = 0.43 (ethyl acetate/hexanes, 4:1). M.p. 170–171 °C.
1
IR (KBr): ν = 1648 (C=N), 1724 (CO Me), 3324 (NH ) cm–1. H
˜
2
2
NMR (200 MHz, [D6]DMSO): δ = 3.64 (s, 3 H, OCH3), 5.26 (d, J
= 1.3 Hz, 1 H, CH), 6.45 (s, 1 H, =CH2), 6.56 (s, 1 H, =CH2), 6.90
(s, 2 H, exchangeable with D2O, NH2), 7.21–7.25 (m, 2 H, ArH),
7.35–7.44 (m, 3 H, ArH) ppm. 13C NMR (50 MHz, [D6]DMSO):
δ = 53.1, 59.0, 129.0, 129.4, 129.6, 130.0, 136.5, 139.0, 156.1,
165.8 ppm. MS (ESI+): m/z (%) = 259.9 (100) [M + 1]+, 175.1 (12)
[M – 84]+. C12H13N5O2 (259.1069): calcd. C 55.59, H 5.05, N 27.01;
found C 55.73, H 4.85, N 27.25.
General Procedure for the Synthesis of 6a–h and 12a–h as Exem-
plified for 6a: To a solution of 4a (0.25 g, 0.97 mmol) in anhydrous
THF (15 mL) was added NaH (60% in mineral oil, 0.05 g,
2.00 mmol) at 0 °C, and the reaction mixture was stirred at ambient
temperature for 15 min. Thereafter, the reaction mixture was
quenched with MeOH and concentrated under reduced pressure.
The residue was acidified with 2  HCl to pH 2, and the resulting
solution was extracted with Et2O (3ϫ15 mL). The combined or-
ganic layer was dried with anhydrous Na2SO4 and concentrated
under reduced pressure to obtain a residue, which upon trituration
with Et2O yielded product 6a as a white solid (0.21 g, 96%).
Experimental Section
General: Melting points were determined in capillary tubes with a
Precision melting point apparatus containing silicon oil. IR spectra
were recorded by using a Perkin–Elmer RX I FTIR spectropho-
tometer. 1H and 13C NMR spectra were recorded with either a
Bruker DPX-200 FT or a Bruker Avance DRX-300 spectrometer
by using TMS as an internal standard. Mass spectra (ESI) were
recorded with a MICROMASS Quadro-II LC–MS system. HRMS
(EI) spectra were recorded with a JEOL system and DART-HRMS
(recorded as ESI+) were recorded with a JEOL-AccuTOF JMS-
T100LC mass spectrometer having a DART (direct analysis in real
time) source. Elemental analyses were performed with a Carlo Erba
108 or an Elementar Vario EL III microanalyzer. Room tempera-
ture varied between 20 and 35 °C. The 13C NMR spectra of fluoro-
substituted derivatives display extra peaks due to C–F couplings.
For all final compounds where the azido and tetrazolyl forms were
isolated, individual spectroscopic data for the pure state along with
the data of solution containing both forms have been provided. For
all azide derivatives where the corresponding tetrazoles were not
isolated, spectroscopic data for the azide and the mixture contain-
ing both tautomeric forms have been provided.
2-Azido-5-methyl-6-phenylpyrimidin-4(3H)-one (6a): Rf
= 0.34
(ethyl acetate/hexanes, 4:1). M.p. 207–209 °C. IR (KBr): ν = 1679
˜
1
(C=N and CO), 2148 (N3), 3447 (NH) cm–1. H NMR (400 MHz,
1
[D6]DMSO): δ = 1.89 (s, 3 H, CH3), 7.61 (s, 5 H, ArH) ppm. H
NMR (300 MHz, [D]TFA): δ = 2.32 (s, 3 H, CH3), 7.54 (d, J =
7.0 Hz, 2 H, ArH), 7.62–7.75 (m, 3 H, ArH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 12.9, 117.5, 129.1, 130.1, 131.0, 141.2,
149.8, 162.0 ppm. 13C NMR (300 MHz, [D]TFA): δ = 9.8, 113.8,
128.1, 128.5, 129.4, 132.6, 155.9, 157.3 ppm. MS (ESI+): m/z (%)
= 228.1 (100) [M + 1]+. HRMS (EI): calcd. for C11H9N5O
227.0807; found 227.0876.
General Procedure for the Synthesis of 3a–h and 19 as Exemplified
for 3a: To a solution of acetate 2a (1.60 g, 6.84 mmol) in THF/
H2O (1:1, 20 mL) was added DABCO (0.77 g, 6.84 mmol), and the
reaction mixture was stirred for 15 min at room temperature. After
the reaction mixture became clear, aqueous ammonia (30%,
10 mL) was added at 15 °C, and the reaction was continued at the
same temperature. After 30 min, CH2Cl2 (10 mL) was added, and
the organic phase was separated. The aqueous phase was further
extracted with CH2Cl2 (10 mL). The combined organic layer was
General Procedure for Isolation of 7a,c and 13a,b,d,e,g,h: Tetrazolo-
pyrimidinones 7a,c and 13a,b,d,e,g,h were obtained by crystallizing
the corresponding azidopyrimidinones 6a,c and 12a,b,d,e,g,h from
methanol.
6-Methyl-5-phenyl[1,2,3,4]tetraazolo[1,5-a]pyrimidin-7(4H)-one
(7a): Obtained as a white solid by crystallizing 7c from methanol.
Rf = 0.14 (ethyl acetate/hexanes, 4:1). M.p. 210–212 °C. IR (KBr):
1
ν = 1679 (C=N and CO), 3446 (NH) cm–1. H NMR (200 MHz,
˜
4710
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4705–4712

5-Aminotetrazoles and Their Transformation into Tetrazolo[1,5-a]pyrimidinones
1
[6]
[7]
V. M. Girijavallabhan, P. A. Pinto, A. K. Ganguly, R. W. Ver-
sace, Eur. Patent EP 274867, 1988 [Chem. Abstr. 1989, 110,
23890].
a) H. Akimoto, K. Ootsu, F. Itoh, Eur. Patent EP 530537, 1993
[Chem. Abstr. 1993, 119, 226417]; b) A. G. Taveras, A. K. Mal-
lams, A. Afonso, Int. Patent WO 9811093, 1998 [Chem. Abstr.
1998, 128, 230253].
[D6]DMSO): δ = 1.92 (s, 3 H, CH3), 7.58 (s, 5 H, ArH) ppm. H
NMR (300 MHz, [D5]pyridine): δ = 2.11 (s, 3 H, CH3), 7.55 (s, 3
H, ArH), 7.67–7.70 (s, 2 H, ArH) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 12.5, 106.4, 129.4, 129.6, 130.3, 131.1, 131.3, 133.2,
150.8, 156.2 ppm. MS (ESI+): m/z (%) = 228.1 (100) [M + 1]+.
HRMS (EI): calcd. for C11H9N5O 227.0807; found 227.0796.
[8]
[9]
C. H. Mitch, S. J. Quimby, Int. Patent WO 9851312, 1998
Supporting Information (see footnote on the first page of this arti-
[Chem. Abstr. 1998, 130, 13997].
cle): Additional experimental details and spectroscopic data and
a) M. Nayak, S. Batra, Tetrahedron Lett. 2010, 51, 510–516; b)
A. Mishra, S. Hutait, S. Bhowmik, N. Rastogi, R. Roy, S. Batra
Synthesis, DOI: 10.1055/s-0029-1218847.
1
stacked H NMR spectra showing the tautomeric equilibration.
[10]
a) V. Declerck, J. Martinez, F. Lamaty, Chem. Rev. 2009, 109,
1–48; b) V. Singh, S. Batra, Tetrahedron 2008, 64, 4511–4574
and references cited therein; c) D. Basavaiah, J. R. Rao, T. Sa-
tyanarayana, Chem. Rev. 2003, 103, 811–892; d) S. Gowrisan-
kar, H. S. Lee, S. H. Kim, K. Y. Lee, J. N. Kim, Tetrahedron
2009, 65, 8769–8780.
Acknowledgments
S.N. and S.B. gratefully acknowledge financial support from the
University Grants Commission, New Delhi and the Council of Sci-
entific and Industrial Research, New Delhi in the form of fellow-
ships. This work was supported generously by a grant from Depart-
ment of Science and Technology, New Delhi. Authors acknowledge
the help extended by Prof. Sandeep Verma, Chemistry Department,
IIT, Kanpur, and one of his graduate students Mr. Jitendra Kumar
for solving the crystal structure of compound 7a. Authors also
acknowledge the SAIF division of CDRI for recording the spectro-
scopic data. The help extended by Mr. A. Pandey and Mr. S. Seng-
upta for recording the NMR spectra is gratefully acknowledged.
[11]
A few recent citations: a) D. Basavaiah, K. Aravindu, K. S.
Kumar, K. R. Reddy, Eur. J. Org. Chem. 2010, 1843–1848; b)
D. Basavaiah, B. Devendar, K. Aravindu, A. Veerendhar,
Chem. Eur. J. 2010, 16, 2031–2035; c) S. Ishikawa, F. Noguchi,
H. Uno, A. Kamimura, Tetrahedron Lett. 2010, 51, 2329–2331;
d) S. P. Park, S.-H. Ahn, K.-J. Lee, Tetrahedron 2010, 66, 3490–
3498; e) D. Basavaiah, K. R. Reddy, Tetrahedron 2010, 66,
1215–1219; f) H. Kurasaki, I. Okamoto, N. Morita, O. Tamura,
Chem. Eur. J. 2009, 15, 12754–12763; g) V. Singh, S. Hutait, S.
Batra, Eur. J. Org. Chem. 2010, 531–539; h) V. Singh, S. Hutait,
S. Batra, Eur. J. Org. Chem. 2009, 6211–6216; i) V. Singh, S.
Hutait, S. Batra, Eur. J. Org. Chem. 2009, 3454–3466.
a) S. Nag, R. Pathak, M. Kumar, P. K. Shukla, S. Batra, Bi-
oorg. Med. Chem. Lett. 2006, 16, 3824–3828; b) R. Pathak, S.
Batra, Tetrahedron 2007, 63, 9448–9455; c) S. Nag, S. Madapa,
S. Batra, Synthesis 2008, 101–109; d) S. Nag, A. Mishra, S.
Batra, Tetrahedron 2008, 64, 10162–10171.
R. Pathak, V. Singh, S. Nag, S. Kanojiya, S. Batra, Synthesis
2006, 813–816.
X. Xu, C. Wang, Z. Zhou, X. Tang, Z. He, C. Tang, Eur. J.
Org. Chem. 2007, 4487–4491.
R. M. Herbst, C. F. Froberger, J. Org. Chem. 1957, 22, 1050–
1053.
a) Y.-H. Joo, J. M. Shreeve, Org. Lett. 2008, 10, 4665–4667; b)
Y.-H. Joo, B. Twamley, S. Garg, J. M. Shreeve, Angew. Chem.
Int. Ed. 2008, 47, 6236–6239; c) Y.-H. Joo, J. M. Shreeve, Eur.
J. Org. Chem. 2009, 3573–3578.
A few citation only a) R. Pathak, S. Madapa, S. Batra, Tetrahe-
dron 2007, 63, 451–460; b) S. Nag, A. Mishra, S. Batra, Eur. J.
Org. Chem. 2008, 4334–4343.
A few citations only: a) J. H. Boyer, E. J. Miller, J. Am. Chem.
Soc. 1959, 81, 4671–4673; b) Ch. K. Lowe-Ma, R. A. Nissan,
W. S. Wilson, J. Org. Chem. 1990, 55, 3755–3761; c) R. A. Ev-
ans, C. Wentrup, J. Chem. Soc., Chem. Commun. 1992, 1062–
1064; d) T. Kappe, P. Roschger, J. Heterocycl. Chem. 1993, 30,
1267–1271; e) T. Sasaki, K. Kanematsu, M. Murata, J. Org.
Chem. 1971, 36, 446–478; f) C. J. Shishoo, C. S. Jain, J. Hetero-
cycl. Chem. 1992, 29, 883–893; g) A. A. Hamed, I. F. Zeid,
H. H. El-Ganzory, M. T. A. Aal, Monatsh. Chem. 2008, 139,
809–820; h) P. Cmoch, H. Korczak, L. Stefaniak, G. A. Webb,
J. Phys. Org. Chem. 1999, 12, 470–478; i) M. H. V. Huynh,
M. A. Hiskey, D. E. Chavez, D. L. Naud, R. D. Gilardi, J. Am.
Chem. Soc. 2005, 127, 12537–12543; j) E. Cubero, M. Orozco,
F. J. Luque, J. Am. Chem. Soc. 1998, 120, 4723–4731; k) B.
Chattopadhyay, C. I. Rivera-Vera, S. Chuprakov, V. Gevor-
gyan, Org. Lett. 2010, 12, 2166–2169; l) M. K. Lakshman,
M. K. Singh, D. Parrish, R. Balachandran, B. W. Day, J. Org.
Chem. 2010, 75, 2461–2473; m) R. N. Butler, Adv. Heterocycl.
Chem. 1977, 21, 323–435; n) M. Tisler, Synthesis 1973, 123–
136.
[1] a) V. A. Ostrovskii, G. I. Koldobskii, R. E. Trifonov in Compre-
hensive Heterocyclic Chemistry (Eds.: A. R. Katritzky, C. A.
Ramsden, E. F. V. Scriven, R. J. K. Taylor), Pergamon, Oxford,
U. K., 2008, vol. 6, pp. 257–423; b) R. N. Butler in Comprehen-
sive Heterocyclic Chemistry (Eds.: A. R. Katritzky, C. W. Rees,
E. F. V. Scriven), Pergamon, New York, 1996, vol. 4, pp. 621–
678; c) B. C. Tappan, M. H. Huynh, M. A. Hiskey, D. E.
Chavez, E. P. Luther, J. T. Mang, S. F. Son, J. Am. Chem. Soc.
2006, 128, 6589–6594; d) M. H. Huynh, M. A. Hiskey, T. J.
Meyer, M. Wetzler, Proc. Natl. Acad. Sci. USA 2006, 103,
5409–5412; e) M. Friedrich, J. C. Galvez-Ruiz, T. M. Klapotke,
P. Mayer, B. Weber, J. Weigand, Inorg. Chem. 2005, 44, 8044–
8052; f) A. Hammerl, G. Holl, M. Kaiser, T. M. Klapotke, P.
Mayer, H. Noth, H. Piotrowski, M. Warchhold, Eur. J. Inorg.
Chem. 2002, 834–845; g) M. A. Hiskey, D. E. Chavez, D. L.
Naud, US 6214139, 2001 [Chem. Abstr. 2001, 134, 282929].
[2] a) R. P. Singh, R. D. Verma, D. T. Meshri, J. M. Shreeve, An-
gew. Chem. Int. Ed. 2006, 45, 3584–3601; b) G. Steinhauser,
T. M. Klapotke, Angew. Chem. Int. Ed. 2008, 47, 3330–3347; c)
R. P. Singh, H. Gao, D. T. Meshri, J. M. Shreeve in High En-
ergy Density Materials (Eds.: T. M. Klapotke), Springer, Berlin,
2007, pp. 35–83; d) T. M. Klapotke in High Energy Density
Materials (Eds.: T. M. Klapotke), Springer, Berlin, 2007, pp.
85–122.
[3] R. J. Herr, Bioorg. Med. Chem. 2002, 10, 3379–3393.
[4] a) J. Yoshinaga, T. Shogaki, T. Kakita, H. Ozeki, N. Sugimoto,
Y. Kato, Eur. Patent EP 262873, 1988 [Chem. Abstr. 1988, 109,
54782]; b) W. A. Cetenko, D. T. Connor, M. D. Mullican, R. J.
Sorenson, Eur. Patent EP 249236, 1987 [Chem. Abstr. 1988,
108, 150482]; c) D. T. Connor, P. C. Unangst, R. J. Weikert,
Eur. Patent EP 279466, 1988 [Chem. Abstr. 1988, 109, 231035];
d) R. E. Ford, P. Knowles, E. Lunt, S. M. Marshall, A. J. Pen-
rose, C. A. Ramsden, A. J. H. Summers, J. L. Walker, D. E.
Wright, J. Med. Chem. 1986, 29, 538–549; e) N. P. Peet, L. E.
Baugh, S. Sundler, J. E. Lewis, E. H. Matthews, E. L. Olberd-
ing, D. N. Shah, J. Med. Chem. 1986, 29, 2403–2409.
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[5] a) A. Andrus, B. Partridge, J. V. Heck, B. G. Christensen, Tetra-
hedron Lett. 1984, 25, 911–914; b) S. Bondock, W. Fadaly,
M. A. Metwally, Eur. J. Med. Chem. 2009, 44, 4813–4818; c)
H. Singh, A. S. Chawla, V. K. Kapoor, D. Paul, R. K. Malho-
tra, Prog. Med. Chem. 1980, 17, 151–183.
[19]
Crystal data of compound 7a (crystallized from MeOH):
¯
C11H9N5O, M = 227.23, monoclinic, P1, a = 7.378(3) Å, b =
Eur. J. Org. Chem. 2010, 4705–4712
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4711

S. Nag, S. Bhowmik, H. M. Gauniyal, S. Batra
FULL PAPER
12.501(2) Å, c = 10.971(2) Å, α = 90.00, β = 103.934(2)°, γ =
nation, refinements, and molecular graphics. CCDC-773490
contains the supplementary crystallographic data for this pa-
per. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
A.-R. B. A. El-Gazzar, M. M. El-Enanyb, M. N. Mahmoud,
Bioorg. Med. Chem. 2008, 16, 3261–3273.
90°, V = 982.1(5) Å3, Z = 4, Dcalcd. = 1.537 gcm–3, µ(Mo-Kα)
=
0.107 mm–1,
F
(000)
= 472 yellow block, dimension
0.20ϫ0.20ϫ0.20 mm, 5244 reflections measured (Rint
=
0.0607), 1916 unique, wR2 = 0.1249, conventional R = 0.0494
on F2 values of 1916 reflections with IϾ2σ(I), (∆/σ) max = 000),
S = 1.108 for all data and 156 parameters. Unit cell determi-
nation and intensity data collection (2θ = 50°) were performed
with a Bruker P4 diffractometer at 293(2) K. Structure solu-
tions by direct methods and refinements by full-matrix least-
squares methods on F2. Programs: XSCANS (Siemens Analyti-
cal X-ray Instrument Inc., Madison, WI, USA, 1996) for data
collection and data processing; SHELXTL-NT (Bruker AXS
Inc., Madison, Wisconsin, USA, 1997) for structure determi-
[20]
[21] a) C. Temple Jr., M. C. Thorpe, W. C. Coburn Jr., J. A. Mont-
gomery, J. Org. Chem. 1966, 31, 935–938; b) C. Temple Jr.,
C. L. Kussner, J. A. Montgomery, J. Org. Chem. 1966, 31,
2210–2215.
Received: April 27, 2010
Published Online: July 7, 2010
4712
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4705–4712