NMR study of the tautomeric behavior of N -(α-Aminoalkyl)tetrazoles

Article abstract of DOI:10.1021/jo101195z

N-(α-Aminoalkyl)tetrazoles exist in solution as equilibrium mixtures of N1 and N2 tautomers. The position of equilibrium depends significantly on the polarity of the solvent and the substituents in the tetrazole ring. Interconversion between individual tautomers is shown to proceed via tight ion-pair intermediates in which intramolecular recombination is faster than the intermolecular crossover since the latter probably requires solvent separation of ion-pair intermediates.

Full text of DOI:10.1021/jo101195z

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NMR Study of the Tautomeric Behavior of N-(r-Aminoalkyl)tetrazoles
Alan R. Katritzky,*,‡ Bahaa El-Dien M. El-Gendy,‡,§ Bogdan Draghici,‡ C. Dennis Hall,‡
and Peter J. Steel
‡Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville,
Florida 32611-7200, §Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt, and
Chemistry Department, University of Canterbury, Christchurch 8140, New Zealand
katritzky@chem.ufl.edu
Received June 18, 2010
N-(R-Aminoalkyl)tetrazoles exist in solution as equilibrium mixtures of N1 and N2 tautomers.
The position of equilibrium depends significantly on the polarity of the solvent and the substituents
in the tetrazole ring. Interconversion between individual tautomers is shown to proceed via tight
ion-pair intermediates in which intramolecular recombination is faster than the intermolecular
crossover since the latter probably requires solvent separation of ion-pair intermediates.
Introduction
Tetrazoles have wide application in chemistry:1 the ring
can serve as a metabolically stable analogue for the carboxyl
group2a-c and confer useful biological activity. Tetrazoles
bind anions tightly in polar solution when compared to the
corresponding carboxylic acids. Tetrazole-containing hosts
bind anions g50000 times stronger than the corresponding
acidic hosts. This remarkable difference in binding strength
is rationalized by considering the tautomeric equilibria in
tetrazoles and the conformational preferences in carboxylic
acids. The tetrazole 1H tautomer is energetically more
favored than the 2H tautomer by 3 kcal/mol, and it resembles
the anti conformation of carboxylic acid which is disfavored
energetically but is the preferred conformation for binding.2d
The tetrazole ring appears in some well-known drugs such
as diovan, benicar, avapro, atacand, and hyzaar, which are
generally used as cardiovascular or hypertension drugs. In
biological systems, free NH- tetrazoles usually exist mainly
in the anionic form.2e
FIGURE 1. Some examples of bioactive compounds containing
N-(R-aminoalkyl)tetrazole scaffolds.
N-(R-Aminoalkyl)tetrazoles 1-3 have recently provided
modified protein-formation inhibitors for the prevention
and treatment of diseases associated with AGEs (advanced
glycation end products) and ALEs (advanced lipoxidation
end products) (Figure 1).3a Benzodiazepine analogues (4 and
5) were found to be effective in treating cardiac arrhythmias3b,c
and Meniere’s disease3d,e in mammals by modulating the
slowly activating delayed rectifier potassium current (IKs)
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Published on Web 09/09/2010
DOI: 10.1021/jo101195z
r
2010 American Chemical Society

Katritzky et al.
JOCArticle
SCHEME 1. N1 to N2 Substituent Isomerization of (N,N-Disub-
stituted aminomethyl)benzotriazoles
SCHEME 2. (i) N1-, N2-, and N4-Substituted Isomers of
N-(R-Aminoalkyl)-1,2,4-triazoles and (ii) N1- and
N2-Substituted Isomers of N-(R-Aminoalkyl)-1,2,3-triazoles.
and the rapidly activating and deactivating relayed recti-
fier potassium current (IKr). All of these compounds are of
particular interest as therapeutic agents, and all of them are
reported without considering their tautomeric equilibria.
Individual tautomers may interact differently with a parti-
cular receptor.
Results and Discussion
Tautomerism of r-aminoalkylbenzotriazoles, -1,2,4-tria-
zoles, -1,2,3-triazoles, and -tetrazoles. N-(N,N-Disubstituted
aminomethyl)benzotriazoles exist in solution as equilibrium
mixtures of the corresponding 1-(N,N-disubstituted amino-
methyl)- and 2-(N,N-disubstituted aminomethyl)benzotria-
zoles4 with interconversion taking place via a dissociation-
recombination mechanism,5,6 involving an iminium cation
and a benzotriazole anion, the formation which is facilitated
by easy cleavage of the C-N bond. This type of tautomerism
is known as cationotropy since it is the cation which moves
from one position to another in a molecule. The equilibrium
position of such benzotriazoles depends on the polarity of
the solvent and on the substrate structure. Increasing solvent
polarity favors the 1-isomer as expected from dipole moment
measurements, which showed that 1-substituted benzotria-
zoles are more polar than their 2-substituted isomers.7,8
However, the N2 tautomer may predominate when the
dialkyaminoalkyl substituent is bulky.4,6 Crossover experi-
ments showed that this isomerization process is intermole-
cular and occurs by a dissociation-recombination mecha-
nism (Scheme 1 (i)) rather than an intramolecular concerted
mechanism (Scheme 1 (ii)).5
N-(R-Aminoalkyl)-1,2,4-triazoles also exist in solution as
mixtures of N1 [6(A)] and N2 [6(B)] isomers, and a previous
report9a demonstrated that a series of such compounds
convert easily between the N1- and N2- tautomers, but no
evidence for the N4 tautomer 6(C) was found [Scheme 2 (i)].
Recent work on the tautomerism of N-(R-aminoalkyl)-1,2,3-
triazoles9b showed that these compounds exist in nonpolar
CDCl3 predominantly as the 2-isomer 7(B), although in
polar DMSO (and D2O, when soluble) some of the 1-isomer
7(A) is present [Scheme 2 (ii)]. The present paper reports the
analogous intermediates of 1- and 2-tetrazoles.
1H-Tetrazole 8a and 5-phenyl-1H-tetrazole 8e are com-
mercially available. The other parent tetrazoles were synthe-
sized according to known methods A10 (8b), B11 (8d-f), and
C
12 (8c,g-i,k).
The parent tetrazoles were used to prepare the desired
N-(R-aminoalkyl)tetrazoles by the procedure of Bechmann
and Heisey13 for compounds 9a,e-o (Table 1). This failed
for compounds 9b-d (Table 1), which were prepared by
another synthetic route.14
Preliminary work on the tautomeric composition of
N-(R-aminoalkyl)tetrazoles reported that 4-(1H-tetrazol-1-
ylmethyl)morpholine (9a) exists predominately as the N2-
isomer 9a(B) in CDBr3 with ΔG° = -1.03 kcal/mol and
ΔGq =17.6 kcal/mol.9a The N2-isomer of 9a(B) was also
predominant in toluene-d8, but substantial amounts of
the N1-isomer [9a(A)] appeared in CD3NO2. Similarly, for
4-((5-methyl-1H-tetrazol-1-yl)methyl)morpholine (9e), the
N2-isomer 9e(B) was the dominant isomer in CDBr3 with
ΔGq = 20.0 kcal/mol for the interconversion of tautomers.9a
N1-Substituted tetrazoles have dipole moments higher
than those of N2-substituted tetrazoles17a-c (e.g., 1-methyl-
5-phenyltetrazole, μ = 5.88 D, and its 2-methyl-isomer, μ =
2.52 D); this higher polarity is consistent with the N1-isomer
predominating in polar solvents.17a
(9) (a) Katritzky, A. R.; Jozwiac, A.; Lue, P.; Yannakopoulou, K.;
Palenik, G. J.; Zhang, Z.-Y. Tetrahedron 1990, 46, 633–640. (b) Katritzky,
A. R.; Buciumas, A.-M.; Todadze, E.; Munawar, A. M.; Khelashvili, L.
Heterocycles 2010, in press.
(10) Ogilvie, W.; Rank, W. Can. J. Chem. 1987, 65, 166–169.
(11) Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem. Soc. 1958,
80, 3908–3911.
(12) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945–7950.
(13) Bechmann, G. B.; Heisey, L. V. J. Am. Chem. Soc. 1946, 68, 2496–
2499.
(4) Lindsay Smith, J. R.; Sadd, J. S. J. Chem. Soc., Perkin Trans. 1 1975,
1181–1184.
(14) Getz, J. J.; Prankerd, R. J.; Sloan, K. B. J. Org. Chem. 1993, 58,
4913–4918.
ꢀ
(5) Katritzky, A. R.; Yannakopoulou, K.; Kuzmierkiewicz, W.;
Aurrecoechea, J. M.; Palenik, G. J.; Koziol, A. E.; Szczesniac, M.; Skarjune,
R. J. Chem. Soc., Perkin Trans. 1 1987, 2673–2679.
(6) Katritzky, A. R.; Yannakopoulou, K. Heterocycles 1989, 28, 1121–
1134.
(7) Boyer, J. H. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley:
New York, 1961; Vol. 7, pp 384-461.
(8) Katritzky, A. R.; Yannakopoulou, K.; Anders, E.; Stevens, J.;
Szafran, M. J. Org. Chem. 1990, 55, 5683–5687.
(15) Binda, M.; Dziklinska, A.; Hachiam, A. F. H.; Plenkiewicz, J. Pol. J.
Chem. 1992, 66, 1257–1261.
(16) Rusinov, G. L.; Ishmetova, R. I.; Chupakhin, O. N. Russ. J. Org.
Chem. 1997, 33, 524–531.
(17) (a) Ostrovskii, V. A.; Serebryakova, N. M.; Koldobskii, G. I.;
Odokienko, S. S. Zh. Org. Khim. 1984, 20, 2464–2468. (Engl. Transl. 1984,
2244). (b) Kaufman, M. H.; Ernsberger, F. M.; McEwan, W. S. J. Am.
Chem. Soc. 1956, 78, 4197–4201. (c) Kaufman, M. H.; Woodman, A. L.
J. Phys. Chem. 1958, 62, 508–509.
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TABLE 1. Synthesis of N-(R-Aminoalkyl)tetrazoles 9a-o
N-(R-aminoalkyl)tetrazoles
compd
R1
R2
R3
yield (%)
mp °C (lit. mp °C)
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
H
H
H
H
CH3
(CH3)2CH
PhCH2
PhCH2
Ph
Ph
(CH2)2O(CH2)2
75
64
74
60
60
80
70
60
75
74
70
86
80
70
55
81.0-82.0 (80.0-82.0)9
146.0-147.0
139.0-145.0
177.0-179.0
75.0-77.0 (75.0)9
oil
CO(CH2)2CO
CO-o-C6H4CO
CO-o-C6H4SO2
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)5
59.0-61.0
oil
(CH2)2O(CH2)2
(CH2)5
57.0-59.0 (60.0-61.0)15
67.0-69.0 (65.0-66.0)16
50.0-51.0
Ph
CH3
CH3
p-NO2C6H4
p-ClC6H4
p-(CH3)2NC6H4
p-MeOC6H4
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)2O(CH2)2
133.0-135.0
111.0-112.0
146.0-148.0
146.0-147.0
SCHEME 3. N1 to N2 Substituent Isomerization of 9a (R = H)
and 9e (R = Me)
shielded and the -NCHdN protons are more deshielded
relative to the B isomer. Also, as previously reported,19 the
tetrazole carbon is more deshielded in the B isomer than in
the A isomer.
The 15N chemical shifts were assigned on the basis of the
following correlations seen in the 1H-15N CIGAR-gHMBC
experiment: In 9b(A), the methylene protons H-10(6.02 ppm)
showed two-bond correlation with N1(239.4 ppm) and pyr-
rolidine nitrogen N100 (180.4 ppm) and three-bond correlation
with N2 (370.0 ppm). H-5 (9.42 ppm) showed two-bond
correlation to both N1 (239.4 ppm) and N4 (395.0 ppm). In
9b(B), the methylene protons H-10 (6.20 ppm) showed two-
bond correlations to N2 (307.9 ppm) and pyrrolidine nitro-
gen N100 (180.0 ppm) and three-bond correlations to both
N1 (383.5 ppm) and N3 (284.1 ppm). Moreover, N1 and N2
showed correlations to H-5 (9.01 ppm) by large coupling to
N1 and small coupling to N2 (Table 5).
N-((1H-Tetrazol-1-yl)methyl)-1,2-benzisothiazole-3(2H)-
one 1,1-dioxide (9d) exists in benzene-d6 mainly as a 2-sub-
stituted tetrazole, but in all other solvents the 1-isomer
predominates (Table 2). The 1H, 13C, and four 15N chemical
shifts were assigned in both isomers using 2D NMR techni-
ques (Tables 3-5).
Nonempirical quantum mechanical calculations (MP2/
6-31G* and MP2/6-31G*//HF/6-31G*) concluded that
N2-substituted tetrazoles are more stable than the N1-iso-
mers in the gas phase and in nonpolar solvents and also
suggested that the equilibrium would be displaced toward
the N1-tautomer by increasing solvent polarity.18
Tautomeric Equilibria of 1- and 2-Substituted Tetrazoles.
We now show that both 9a and 9e exist mainly as the N2-
isomeric form [9a,e(B) in Scheme 3] in nonpolar solvents but
as the N1-isomers 9a,e(A) in polar solvents (Table 2). At
ambient temperatures, the 1H NMR spectra of 9a,e showed
broad signals throughout the range, indicating that the N1
and N2-isomers were exchanging rapidly as reported pre-
viously (Scheme 3).9a
The assignments for 9d(A) were based on the correla-
tion seen in gHMBC between the methylene protons and
C-5 of the tetrazole ring; such a correlation was not seen in
the case of 9d(B). The 1H and 13C chemical shifts of NCHdN
The chemical shifts for both 9b and 9c were fully as-
signed by 2D NMR experiments carried out in DMSO-d6
(Tables 3-5). In both cases, the N2-isomer was predomi-
nant, and both compounds have the following characteristic
patterns: in the A isomer, the -N(CH2)N- protons are more
(19) Begtrup, M.; Elguero, J.; Faure, R.; Camps, P.; Estopa, C.; Ilavsky,
D.; Fruchier, A.; Marzin, C.; De Mendoza, J. Magn. Reson. Chem. 1988, 26,
134–151.
(18) Ivashkevich, O. A.; Gaponik, P. N.; Matulis, Vit. E.; Matulis, Vad.
E. Russ. J. Gen. Chem. 2003, 73, 275–282.
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Katritzky et al.
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TABLE 2. Percentage of N1 Isomer Observed in Different Solvents
compd
D2O (62.8)a
(CD3)2SO (45.1)a
CD3CN (45.6)a
CD3OD (55.4)a
(CD3)2CO (42.2)a
CDCl3 (39.1)a
C6D6 (34.3)a
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
85
>99
40
15
80
71
67
40
15
79
64
26
33
<1
<1
<1
<1
<1
<1
<1
<1
81
40
59
40
15
83
55
20
30
17
NSb
15
57
18
17
20
15
24
20
<1
10
40
NSb
58
reactsc
62
63
reactsc
86
NSb
92
29
44
5
11
20
NMd
<1
<1
<1
<1
<1
<1
<1
<1
<1
N M d
<1
NMd
<1
<1
<1
<1
<1
<1
<1
<1
<1
N M d
<1
N M d
N M d
<1
<1
<1
<1
NMd
NMd
<1
N M d
N M d
56/44
reactsc
<1
NMd
NMd
reactsc
<1
NSb
NSb
NSb
<1
reactsc
reactsc
aDimroth-Reichardt polarity index ET(30). bInsoluble. cReacts with the solvent. dNot measured.
TABLE 3. Numbering and 1H Chemical Shift Assignments in 9b,c,d,f (DMSO-d6)
compd
H-5
H-10
H-200
H-300
other
9b
9c
9d
9f
9b(A)
9b(B)
9c(A)
9c(B)
9d(A)
9d(B)
9f(A)
9.42
9.01
9.54
9.02
9.59
9.02
6.02
6.20
6.27
6.46
6.57
6.72
5.51
2.69
2.74
H-400 (7.91), H-500 (7.95), H-600 (7.95), H-700 (7.91)
H-400 (7.97), H-500 (7.88), H-600 (7.88), H-700 (7.99)
H-400 (8.36), H-500 (8.10), H-600 (8.03), H-700 (8.18)
H-400 (8.36), H-500 (8.10), H-600 (8.03), H-700 (8.18)
H-50 (3.23), H-500 (1.33)
2.53
3.57
TABLE 4. 13C Chemical Shift Assignments in 9b,c,d,f (DMSO-d6)
compd
C-5
C-10
C-200
C-300
other
9b
9c
9d
9f
9b(A)
146.4
155.3
145.1
154.2
145.4
154.2
161.0
48.9
53.4
48.9
53.3
49.2
53.7
73.9
178.4
178.0
30.0
29.9
9b(B)
9c(A)
9c(B)
9d(A)
9d(B)
9f(A)
167.1
166.8
158.6
158.6
66.6
C-100 (167.1), C-4a00 (131.7), C-400 (135.9), C-500 (124.5),C-600 (124.5),C-700 (135.9), C-7a00 (131.7)
C-100 (166.8), C-4a00 (131.9), C-400 (124.3), C-500 (135.7),C-600 (135.7),C-700 (124.3), C-7a00 (131.9)
C-4a00 (137.7), C-400 (122.7), C-500 (137.3),C-600 (136.3),C-700 (126.5)
C-4a00 (137.7), C-400 (122.7), C-500 (137.3),C-600 (136.3),C-700 (126.5)
C-50 (26.0), C-500 (50.0)
50.0
TABLE 5. 15N Chemical Shift Assignments in 9b,c,d,f (DMSO-d6)
(H-5 and C-5) and NCH2N- (H-10 and C-10) follow the usual
trend. We recorded the 15N chemical shifts of all four nitro-
gens in both isomers. In 9d(A), the methylene protons H-10
(6.57 ppm) showed two-bond correlation to N1 (239.0 ppm)
and to saccharine nitrogen N200 (160.9 ppm) and three-bond
correlation to N2 (370.2 ppm). The tetrazole proton H-5
(9.59 ppm) showed two-bond correlations to N1 (239.0 ppm)
and to N4 (396.4 ppm) and a three-bond correlation to
N2 (370.2 ppm). In the case of 9d(B), N1 (384.4 ppm) was
compd
N1
N2
N3
N4
other
9b
9c
9d
9b(A)
239.3
383.5
240.7
382.5
239.0
384.4
370.0
307.9
369.2
307.1
370.2
308.2
NMa
284.1
NMa
287.8
NMa
285.1
395.0
NMa
395.7
NMa
396.4
NMa
N100 (180.4)
N100 (180.0)
N200 (162.4)
N200 (161.7)
N200 (160.9)
N200 (160.9)
9b(B)
9c(A)
9c(B)
9d(A)
9d(B)
aNot measured.
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TABLE 6. Coalescence Temperatures (Tc), Equilibrium Constants (K), Chemical Shift Differences (Δν), Free Energy Barriers (ΔGq), and Natural
Logarithm of Exchange Rate Constant (kr) from the 1H and 13C NMR Spectra of 9g (Acetonitrile-d3 as Solvent)
Tc (K)
Kc
Δν (Hz)
ΔGqAfB(Tc) (kcal mol-1
)
ln kr AfB
ΔGqBfA(Tc) (kcal mol-1
)
ln kr BfA
-N(CH2)N-a
PhCH2-a
338
325
343
318
323
318
308
1
0.54
0.55
0.55d
0.58
0.58d
0.55
0.55d
b
195.0
40.7
271
30.3
45
17.5
17.2
17.4
17.1
17.2
17.3
17.4
c
3.5
2.9
4.1
2.4
2.7
2.1
1.0
15.8
15.8
15.8
16
16.2
15.8
16
6.0
5.1
6.4
4.2
4.3
4.5
3.3
PhCH2-b
-N(CH2)2-a
-N(CH2)2-b
-O(CH2)2-a
-O(CH2)2-b
38.7
13.8
aTc calculated from H NMR. Tc calculated from 13C NMR. Calculated at 273 K, K = PA/PB where PA and PB are the population of 1- and
2-isomers (A and B). dAssumed to be the same as in 1H NMR.
identified through a two-bond correlation to H-5 (9.09 ppm)
and three-bond correlations to the methylene protons H-10
(6.72 ppm). The methylene protons correlate to N2 (308.2
ppm), N3 (285.1 ppm), and to saccharine nitrogen N200
(160.9 ppm) (Table 5).
4-((5-Isopropyl-1H-tetrazol-1-yl)methyl)morpholine (9f)
exists exclusively as the N2-isomer 9f(B) in C6D6 and CDCl3
(nonpolar solvents) as is clear from the 13C chemical shift
FIGURE 2. X-ray structure of 9i.
of tetrazole C-5 (171.5 ppm) (Table 4). On increasing the
polarity of the solvent, the N1 isomer 9f(A) appears in the 1H
NMR spectra. The highest ratio of N1-isomer (1 to 2) was
obtained in DMSO-d6, which is the most polar in the series of
solvents used (Table 2). We were able to assign completely
the 1H and 13C chemical shifts for 9f(A) (cf. Tables 3-5) but
were unable to assign chemical shifts for 9f(B) due to broad
peaks of low intensity in DMSO-d6.
4-((5-Benzyl-1H-tetrazol-1-yl)methyl)morpholine (9g) ex-
ists in C6D6 and in CDCl3 as a mixture of N2/N1 isomers
with a ratio of 9:1. The proportion of the N1 isomer increases
with increasing solvent polarity so the N1 isomer is dominant
in D2O with a ratio of 9:1 (Table 2).
1-((5-Benzyl-2H-tetrazol-2-yl)methyl)piperidine (9h) exists
in CDCl3, CD3CN, DMSO-d6, and toluene-d8 at -60 °C as
the N2-isomer with no evidence for N1-isomer in any of these
FIGURE 3. Plot of ln kr vs 1/Tc in case of interconversion of A f B
and B f A.
solvents (Table 2).
For N-(R-aminoalkyl)tetrazoles 9i-o only the N2-isomers
9i-o(B) were observed in solution (cf. Table 2), probably be-
cause of the steric bulk of the C-5 substituent. The 13C
chemical shifts of C-5 in 9i-o range from 152.8 to 179.0,
which is in agreement with literature values for the N2-isomer
reported by Begtrup et al.19 It was also shown by Binda et al.15
that the aminomethylation of 5-substituted tetrazoles bearing
aromatic substituents at C-5 occur regioselectively at the N2
of the tetrazole ring. Finally, an X-ray crystal structure for 9i
(Figure 2) showed clearly that this compound exists exclu-
sively in the solid state as the N2-isomer thus avoiding steric
interaction between the substituents at N1 and C-5.
groups on nitrogen destabilizing the iminium ion and there-
fore slowing down the isomerization process.
Variable-temperature 1H and 13C NMR were carried out
for 9g in CD3CN; seven different sites within the molecule
showed coalescence at six different temperatures (see Figure
S1, Supporting Information, for VT 1H NMR).
Free energy barriers (ΔGq), calculated using the method of
Shanan-Atidi and Bar-Eli20 for the case of unequal populations
(PA ¼ PB) (Table 6), showed that the 2-substituted isomer
9g(B) is less stable than the 1-substituted isomer 9g(A) in
CD3CN by on average 0.56 kcalmol-1
.
Thermodynamic and Kinetic Parameters. Free energies of
activation for the isomerization of 9a and 9e were measured
previously.9a A variable-temperature 1H NMR study of
compounds 9c and 9d failed to detect coalescence even at
150 °C in DMSO-d6, probably due to the electron-withdrawing
For interconversion of A f B, a plot of ln kr vs 1/Tc gave
a straight line (Figure 3) from which values of Ea (16.5 kcal
mol-1), ΔHq (15.9 kcal mol-1), and ΔSq (-4.5 eu) were derived.
(20) Shanan-Atidi, H.; Bar-Eli, K. H. J. Phys. Chem. 1970, 74, 961–963.
6472 J. Org. Chem. Vol. 75, No. 19, 2010

Katritzky et al.
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TABLE 7. Signal Assignments and Molar Percentage Ratios of Com-
pounds 9a, 9g, 9h, and 9p in Crossover Experiment
compd
δH (ppm)a 4.14
molar % 5.2
δH (ppm)b 7.50
9a(A) 9a(B) 9 g(A) 9 g(B) 9 h(A) 9 h(B) 9p(A) 9p(B)
4.70 3.98 4.66 4.15 4.80 4.29 4.84
17.6
8.04
24.8
7.99 3.77
2.6
26.1
4.05 3.82
1.7
17.4
4.08 7.49
4.5
aProtons in the methylene group carrying a piperidine or a morpho-
line moiety. bBenzyl protons or H5.
mixture are given in Table 7. It is worth mentioning here
that the molar percentage of the 2-isomers is higher than the
1-isomer because the 2-isomer predominates in nonpolar
solvents. The size of the exchange peaks in the NOESY
spectrum demonstrates that piperidine isomerizes faster than
morpholine and that exchange between positions 1 and 2 is
faster than the intermolecular crossover process (Figure 5).
The crossover experiment was initially carried out in
polar solvent (acetonitrile-d3), and it gave almost the same
crossover products with different molar ratios, but the
-NCH2N- protons of the eight isomers were not well sepa-
rated in this solvent.
FIGURE 4. Different isomers expected from crossover experiment
between 9a and 9h.
For interconversion of B f A, a similar plot (Figure 3) gave
values of Ea (18.5 kcalmol-1), ΔHq (17.9 kcal mol-1), and
ΔSq (-6.0 eu).
The low entropies of activation in both directions suggest
that the isomerization process occurs via a unimolecular
dissociation-recombination mechanism involving a tight ion
pair (Scheme 3). This is entirely consistent with a polar sol-
vent (e.g., CD3CN) facilitating the isomerization. By con-
trast, in the less polar solvent CDCl3 solution no coalescence
was observed up to 55 °C.
Conclusions
Crossover Experiment. An equimolar mixture of 9a with
In conclusion, we have shown that the equilibrium bet-
ween the N1 and N2 tautomers of N-(R-aminoalkyl)tetra-
zoles favors the N2 tautomer in nonpolar solvents but that
the equilibrium shifts to favor the N1 tautomer with increas-
ing solvent polarity. Bulky substituents in the 5-position of
the tetrazole ring favor the N2 tautomer; this is analogous
to C-substituted 1,2,4-triazoles.9a Because of symmetry, the
equilibrium constant in the case of unsubstituted 1,2,4-
triazoles is equal to 1, but since there is no such symmetry
in the unsubstituted tetrazoles, their tautomeric ratios de-
pend mainly on the polarity of the solvent.
The N2 isomer of N-(R-aminoalkyl)-1,2,3-triazoles is
usually favored in all solvents, but the N1 isomer predomi-
nates when electron-withdrawing groups are attached to the
exocyclic amino group.9b N-(R-Aminoalkyl)tetrazoles be-
have similarly with the N1 isomer predominating in polar
solvents, but with substituents at C-5 the N2 was the major
isomer in nonpolar solvents.
The N1 isomer for N,N-(disubstitutedaminomethyl)-
benzotriazoles dominates in the solid phase. However, in
solution and in the vapor phase a mixture of N1 and N2
isomers is observed with the N1 isomer dominant due to the
greater aromaticity of N1 substituted benzotriazoles.5
The detailed mechanism of interconversion between the
N1 and N2 isomers is shown to involve tight ion pairs,
which can (i) relax to give isomerism without crossover or
(ii) become solvent-separated and thus lead to crossover bet-
ween different components in a mixture of two tetrazoles in
which both the tetrazole ring and the amino substituents
differ.
1
9h in toluene-d8 was prepared at 20 °C and its H NMR
recorded at -10 °C, displayed twelve signals in the region
4.9-3.7 ppm, corresponding to the eight possible isomers
resulting from the cross-reaction (Figure 4).
The four signals for the methylene protons in the benzyl
moiety in 9 g(A), 9 g(B), 9 h(A), and 9 h(B), were identified by
their cross-peaks in the gHMBC spectrum with three sp2
carbons, namely Cipso and Cortho on the phenyl ring and C-5
on the tetrazole moiety. Two of these methylene protons, at
3.77 9 g(A) and 3.82 9 h(A) ppm, coupled with C-5 signal at
153.7 ppm, while the other two at 4.05 9 g(B) and 4.08 9 h(B)
ppm coupled with C-5 signals at 165.4 and 165.1 ppm,
indicating that the first pair are 1-substituted tetrazole and
the second pair the 2-substituted isomers.
The signals for the H-5 proton in tetrazoles 9a and 9p were
assigned in a similar manner as 7.50 [9a(A)] and 7.49 [9p(A)]
on carbons at 142.4 assigned to 1-substituted compounds
and 7.99 [9a(B)] and 8.04 [9p(B)] on the carbons at 152.3 and
152.5 corresponding to 2-substituted compounds.
The triplets at 3.30, 3.29, 3.26, and 3.18 have the distinct
chemical shifts of the methylene hydrogens R to the oxygen in
morpholine. They display cross-peaks in the NOESY spec-
trum with triplets at 2.18, 2.12, 1.78, and 1.82, which are the
methylene protons R to nitrogen. These protons display
NOE peaks with protons at 4.66 [9 g(B)], 4.70 [9a(B)], 4.14
[9a(A)], and 3.98 [9 g(A)], which are the methylene protons
attached to the morpholine moiety. The other four signals at
4.84 [9p(B)], 4.80 [9 h(B)], 4.29 [9p(A)], and 4.15 [9 h(A)] are
for the methylene protons attached to the piperidine group
and show NOEs with the two protons at 2.33 and 2.28.
A NOE between the benzyl protons at 3.77 ppm and the
morpholine protons at 3.98 ppm identified these signals as
from the 9 g(A) compound, as confirmed by their equal
integrals. The other signals of the methylene groups bearing
piperidine or morpholine moieties were assigned by match-
ing their integrals to the integrals of H-5 or to the integrals of
the benzyl protons. The assignment of the significant proton
signals and the molar percentage of compounds in the
Experimental Section
General Procedures. Melting points were determined on a
capillary point apparatus equipped with a digital thermometer
and are uncorrected.
The 1H and 13C NMR spectra for starting materials were
recorded on a Varian Gemini instrument, operating at 300 MHz
1
for H and 75 MHz for 13C. The NMR spectra for final pro-
ducts were recorded on a Varian Inova instrument, operating
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Katritzky et al.
JOCArticle
FIGURE 5. NOESY spectrum of crossover experiment between 9a and 9h in toluene-d8 at -10 °C.
1
at 500 MHz for H, 125 MHz for 13C and 50 MHz for 15N,
equipped with a three-channel, 5 mm, indirect detection probe,
400 ppm, and the corresponding FID was zero-filled twice prior
to Fourier transform. The accordion delay was optimized for
1
with z-axis gradients. The H NMR spectra were recorded in
1
a value of H-15N coupling constants between 3 and 10 Hz.
deuterium oxide, dimethyl sulfoxide-d6, acetonitrile-d3, metha-
nol-d, acetone-d6, chloroform-d, and benzene-d6 with TMS for
1H (500 MHz) and 13C (125 MHz) as an internal reference. The
chemical shifts for 15N were referenced to Ξ = 10.1328898,
corresponding to 0 for neat ammonia. On the Ξ scale the fre-
quency of protons in tetramethylsilane is 100.0000000 MHz. For
conversion to the neat nitromethane scale, subtract 381.7 ppm.
1H spectra were acquired in one transient, with a 90° pulse, no
relaxation delay, and an acquisition time of 5 s over a spectral
window from þ16 to -2 ppm. The FID was zero-filled to 131072
points prior to Fourier transform.
The number of transients per increment was between 4 and 64,
depending on the concentration of the sample.
General Procedures for Synthesis of Compounds 8b-d,f-i.
Method A:10 Preparation of 5-Methyltetrazole (8b). Sodium
azide (4.88 g, 75 mmol) was added to a solution of acetonitrile
(1.03 g, 25 mmol) in dry tetrahydrofuran (5 mL). A solution
of aluminum chloride (3.5 g, 26 mmol) in dry tetrahydrofuran
(20 mL) was added to the previous suspension. The reaction
mixture was heated under reflux for 40 h and then allowed to
cool to room temperature. Hydrochloric acid (5 mL, 10%) was
added, and the mixture was allowed to stir for 8 h. The solvent
was removed under reduced pressure, and the residue was
extracted with 25 mL of hot acetone to give oil that crystallized
under vacuum. The solid formed was recrystallized from chloro-
form to give compound 8b in 10% yield (0.25 g): mp 145.0-
147.0 °C (lit.2 mp 143.0 °C); 1H NMR (300 MHz, acetone-d6) δ
2.57 (s, 3H). 13C NMR (75 MHz, Acetone-d6) δ 153.5, 8.83.
Method B:11 Preparation of Compounds 8d and 8f. A mixture
of benzyl nitrile (0.12 g, 1 mmol) or 4-nitrobenzonitrile (0.148 g,
1 mmol), sodium azide (0.195 g, 3 mmol), ammonium chloride
(0.214 g, 4 mmol), and dimethylformamide (5 mL) was heated
under reflux for 12 h. After the reaction was allowed to cool to
room temperature, water (20 mL) was added with continuous
stirring. The mixture was then acidified with HCl (6 N) to pH 2.
Typically, H-13C gHMBC spectra were acquired in 4096
1
points in f2, on a spectral window from 1.5 to 11 ppm, and 1 s re-
laxation delay. 512 increments were acquired in 1 transient over
a spectral window from 170 to 10 ppm, and then the correspond-
ing FIDs were zero-filled twice prior to the second Fourier
transform.
1H-15N CIGAR-gHMBC spectra were acquired with a pulse
sequence optimized for 15N, as described in ref 21. A total of
2048 points were acquired in f2, over a spectral window typically
from 1.5 to 11 ppm, with 1 s relaxation delay. A total of 1024
increments were acquired in f1, on a spectral window from 0 to
(21) Kline, M.; Cheatham, S. Magn. Reson. Chem. 2003, 41, 307–314.
6474 J. Org. Chem. Vol. 75, No. 19, 2010

Katritzky et al.
JOCArticle
The reaction mixture was extracted with ethyl acetate (3 ꢀ
50 mL) and dried over MgSO4, and the solvent was removed
under reduced pressure. The resultant solid was recrystallized to
give compounds 8d and 8f, respectively.
5-Benzyl-1H-tetrazole (8d). The product was crystallized from
DCM/hexanes to give gray needles (81%): mp 118.0-120.0 °C
(lit.22 mp 120.0-121.0 °C); 1H NMR (300 MHz, CDCl3) δ
7.32-7 0.23 (m, 5H), 4.34 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 156.2, 134.4, 129.2, 128.9, 127.8, 30.0. Anal. Calcd for C8H8N4
(160.18): C, 59.99; H, 5.03; N, 34.98. Found: C, 60.13; H, 5.11; N,
35.10.
128.0, 116.3, 114.6, 55.2. Anal. Calcd for C8H8N4 (176.18): C,
54.54; H, 4.58; N, 31.80. Found: C, 54.56; H, 4.42; N, 31.73.
General Procedure for Synthesis of Compounds 9a,e-o13.
Tetrazoles 8a-i were dissolved in methanol (5 mL) unless
otherwise specified, and the solutions were cooled in an ice bath.
Morpholine (1.1 mmol, 0.086 mL) was added, and the mix-
ture was allowed to stir for 15 min. Formalin 37% (1.2 mmol,
0.096 mL) was added dropwise and the mixture stirred for 1 h.
The ice bath was then removed, and the reaction was stirred for
additional 12 h. The solvent was evaporated, and the residue was
recrystallized to give 9a,e-o.
5-(4-Nitrophenyl)-1H-tetrazole (8f). The product was crys-
tallized from EtOH to give brown microcrystals (94%): mp
218.0-220.0 °C (lit.23 mp 219.0-220.0 °C); 1H NMR (300 MHz,
DMSO-d6) δ 8.44 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 8.8 Hz, 2H);
13C NMR (75 MHz, DMSO-d6) δ 155.5, 148.7, 130.7, 128.2,
124.6. Anal. Calcd for C7H5N5O2 (191.15): C, 43.98; H, 2.64; N,
36.64. Found: C, 44.35; H, 2.17; N, 36.25.
4-(1H-Tetrazol-1-ylmethyl)morpholine (9a). The product
was obtained as colorless prisms after recrystallization from
DCM/hexanes (75%): mp 81.0-82.0 °C (lit.9a mp 80.0-82.0 °C).
Two tautomers: 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 0.3H from
A), 8.53 (s, 0.7H from B), 5.50 (s, 1.6 H from B), 5.29 (s, 0.4 H from
A), 3.69 (t, J = 4.7 Hz, 4H), 2.63 (t, J = 4.7 Hz, 3.3H from B), 2.58
(t, J = 4.5 Hz, 0.7 H from A). Two tautomers: 13C NMR (75 MHz,
CDCl3) δ 152.8 (B), 142.8 (A), 74.1 (B), 70.0 (A), 66.8 (B), 66.6 (A),
49.9. Anal. Calcd for C6H11N5O (169.19): C, 42.59; H, 6.55; N,
41.39. Found: C, 42.92; H, 6.67; N, 41.41.
4-((5-Methyl-1H-tetrazol-1-yl)methyl)morpholine (9e). The
product was obtained as colorless prisms after recrystallization
from chloroform/hexanes (60%): mp 75.0-77.0 °C (lit.9a mp
75.0 °C). Two tautomers: 1H NMR (300 MHz, CDCl3) δ 5.37 (s,
1.6H from B), 5.05 (s, 0.4H from A), 3.67 (t, J = 4.4 Hz, 4H),
2.62 (t, J = 4.6 Hz, 4H), 2.62 (t, J = 4.6 Hz, 4H), 2.53 (s, 3H).
Two tautomers: 13C NMR (75 MHz, CDCl3) δ 162.9, 73.8, 68.6,
66.8, 66.6, 50.4, 50.0, 31.0, 11.0, 9.26. Anal. Calcd for C6H11N5O
(169.19): C, 45.89; H, 7.15; N, 38.23. Found: C, 46.33; H, 6.78;
N, 37.75.
Method C:12 Preparation of Compounds 8c,g,h,i. A mixture
of the corresponding nitrile (10 mmol), sodium azide (0.72 g,
11 mmol), zinc bromide (2.25 g, 10 mmol), and water (20 mL) was
heated under reflux for 24 h. The reaction mixture was allowed to
cool and acidified with HCl (6 N) to pH 1. The product was
extracted with ethyl acetate (3 ꢀ 50 mL). Ethyl acetate was then
evaporated, and 100 mL of 0.25 N NaOH was added. The
mixture was stirred for 30 min until the solid dissolved, and a
suspension of zinc hydroxide was formed. The suspension was
filtered, and the solid was washed with 10 mL of 1 N NaOH. The
filtrate was acidified again with HCl (6 N) and stirred vigorously
until the tetrazole precipitated. In some cases, the tetrazole did
not precipitate from water and was extracted from water with
ethyl acetate (3 ꢀ 50 mL). The combined ethyl acetate extracts
were dried over MgSO4 and then distilled under reduced pressure
to give the desired product.
5-Isopropyl-1H-tetrazole (8c). The product was crystallized
from DCM/hexanes to give white sharp needles (32%): mp
98.0-100.0 °C (lit.24 mp 113.0-114.0 °C); 1H NMR (300
MHz, CDCl3) δ 12.42 (br s, 1H), 3.60-3.46 (septet, J = 7.0
Hz, 1H), 1.50 (d, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
161.9, 24.8, 21.3. Anal. Calcd for C4H8N4 (112.14): C, 42.84; H,
7.19; N, 49.96. Found: C, 43.07; H, 7.32; N, 49.88.
4-((5-Isopropyl-1H-tetrazol-1-yl)methyl)morpholine (9f). The
reaction was carried out in water, and the product was obtained
as a colorless oil (80%): 1H NMR (300 MHz, CDCl3) δ 5.53 (s,
2H), 3.64 (t, J = 4.7 Hz, 4H), 3.22 (septet, J = 7.0 Hz, 1H), 2.59
(t, J = 4.7 Hz, 4H), 1.35 (d, J = 7.0 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 171.5, 77.6, 73.6, 66.7, 49.9, 26.1, 21.5. Anal.
Calcd for C9H17N5O (211.27): C, 51.17; H, 8.11; N, 33.15.
Found: C, 50.99; H, 8.32; N, 32.96.
4-((5-Benzyl-1H-tetrazol-1-yl)methyl)morpholine (9g). The pro-
duct was obtained as colorless needles after recrystallization
from DCM/hexanes (70%): mp 59.0-61.0 °C. Two tautomers:
1H NMR (300 MHz, CDCl3) δ 7.27-7.15 (m, 5H), 5.36 (s, 1.8H
from B), 4.77 (s, 0.2H from A), 4.33 (s, 0.2H from A), 4.22 (s, 1.8H
from B), 3.64 (t, J = 4.7 Hz, 3.5H from B), 3.57 (t, J = 4.5 Hz,
0.5H from A), 2.59 (t, J = 4.7 Hz, 3.5H from B), 2.43 (t, J = 4.5
Hz, 0.5H from A). 13C NMR (75 MHz, CDCl3) Two tautomers: δ
165.6 (B), 136.8 (A), 129.3 (A), 128.9 (B), 128.8 (B), 128.7 (A),
127.9 (A), 127.0 (B), 73.9 (B), 68.8 (A), 66.8 (B), 66.6 (A), 50.5 (A),
50.0 (B), 32.0 (B), 29.9 (A). Anal. Calcd for C13H17N5O (259.13):
C, 60.12; H, 6.61; N, 27.01. Found: C, 60.59; H, 6.74; N, 27.12.
1-((5-Benzyl-2H-tetrazol-2-yl)methyl)piperidine (9h). The re-
action was carried out in water and the product was obtained as
a sticky yellow oil (60%). 1H NMR (500 MHz, acetonitrile-d3) δ
7.34-7.24 (m, 5H), 5.27 (br s, 2H), 4.26 (s, 2H), 2.51 (t, J = 5.1
Hz, 4H), 1.54-1.49 (m, 4H), 1.34-1.29 (m, 2H); 13C NMR (125
MHz, acetonitrile-d3) δ 129.8, 129.7, 128.0, 51.8, 26.6, 24.4.
Anal. Calcd for C14H19N5 (257.34): C, 65.34; H, 7.44; N, 27.21.
Found: C, 65.13; H, 7.46; N, 27.50.
5-(4-Chlorophenyl)-1H-tetrazole (8g). The product was ob-
tained in analytically pure form as white crystals (75%): mp
246.0-255.0 °C (lit.25 mp 252.0-253.0 °C); 1H NMR (300 MHz,
DMSO-d6) δ 8.02 (d, J = 6.0 Hz, 2H), 7.56 (d, J = 6.0 Hz, 2H),
5.50-6.50 (br s, 1H); 13C NMR (75 MHz, DMSO -d6) δ 154.9,
135.9, 129.2, 128.4, 123.2. Anal. Calcd for C8H8N4 (176.18): C,
46.55; H, 2.79; N, 31.02. Found: C, 46.94; H, 2.80; N, 30.88.
N,N-Dimethyl-4-(1H-tetrazol-5-yl)aniline (8h). The product
was obtained as yellow microcrystals (63%), mp 78.0-80.0 °C
1
(lit.26 mp 81.0-83.0 °C); H NMR (300 MHz, Acetone-d6) δ
7.94 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 3.05 (s, 6H);
13C NMR (75 MHz, acetone-d6) δ 153.2, 129.1, 128.7, 112.9,
40.2.
5-(4-Methoxyphenyl)-1H-tetrazole (8i). The product was ob-
tained in analytically pure form as white needles (68%): mp
234.0-239.0 °C (lit.27 mp 233.0-235.0 °C); 1H NMR (300 MHz,
DMSO-d6) δ 7.99 (d, J = 8.65 Hz, 2H), 7.17 (d, J = 8.65 Hz,
2H), 3.83 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.3, 128.4,
4-((5-Phenyl-2H-tetrazol-2-yl)methyl)morpholine (9i). The re-
action was carried out in water, and the product was obtained
as colorless sheets (75%): mp 57.0-59.0 °C (lit.15 mp 60.0-
(22) Satoh, Y.; Marcopulos, N. Tetrahedron Lett. 1995, 36, 1759–1762.
(23) Koyama, M.; Ohtani, N.; Kai, F.; Moriguchi, I.; Inouye, S. J. Med.
Chem. 1987, 30, 552–562.
(24) Mihina, J. S.; Herbst, R. M. J. Org. Chem. 1950, 15, 1082–1092.
(25) Butler, R. N.; Garvin, V. C. J. Chem. Soc., Perkin Trans. 1 1981, 2,
390–393.
(26) Mochizuki, H.; Hasui, T.; Kawamoto, M.; Ikeda, T.; Adachi, C.;
Taniguchi, Y.; Shirota, Y. Macromolecules 2003, 36, 3457–3464.
(27) Shie, J.-J.; Fang, J.-M. J. Org. Chem. 2007, 72, 3141–3144.
1
61.0 °C); H NMR (300 MHz, CDCl3) δ 8.18-8.15 (m, 2H),
7.51-7.48 (m, 3H), 5.50 (s, 2H), 3.71 (t, J = 4.7 Hz, 4H), 2.71 (t,
J = 4.7 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 165.1, 130.5,
129.0, 127.5, 127.1, 74.2, 66.8, 50.0. Anal. Calcd for C12H15N5O
(245.29): C, 58.76; H, 6.16; N, 28.55. Found: C, 58.91; H, 6.24;
N, 28.63.
J. Org. Chem. Vol. 75, No. 19, 2010 6475

Katritzky et al.
JOCArticle
1-((5-Phenyl-2H-tetrazol-2-yl)methyl)piperidine (9j). The pro-
duct was obtained as white prisms after recrystallization from
DCM/hexanes (74%): mp 67.0-69.0 °C (lit.16 mp 65.0-
46.7. Anal. Calcd for C13H17N5O2 (275.31): C, 56.72; H, 6.22; N,
25.44. Found: C, 56.34; H, 6.19; N, 25.04.
General Procedure for Synthesis of Compounds 9b-d. Equi-
molar amounts (1 mmol) of N-chloromethyl derivatives of the
corresponding amide, potassium carbonate, sodium iodide, and
1H-tetrazole 8a were added to dry acetone (5 mL) and stirred for
12 h. The mixture was diluted with methylene chloride (50 mL)
and filtered. The filtrate was extracted with 10 mL of 0.5%
NaOH solution. The organic phase was collected, dried over an-
hydrous MgSO4, filtered and the solvent evaporated to give the
desired product.
1-((1H-Tetrazol-1-yl)methyl)pyrrolidine-2,5-dione (9b). The
reaction was carried out in acetonitrile, and the product
was crystallized from toluene/ethanol (5:1) to give white crystals
(64%): mp 146.0-147.0 °C. Two tautomers: 1H NMR (500
MHz, acetone-d6) δ 9.12 (s, 0.4H from A), 8.74 (s, 0.6H from B),
6.26 (s, 1.2H from B), 6.13 (s, 0.8H from A), 2.84 (s, 2.4H from
B), 2.80 (s, 1.6H from A). Two tautomers: 13C NMR (125 MHz,
acetone-d6) δ 177.0 (B), 176.5 (A), 154.0 (B), 145.1 (A), 53.6 (B),
49.1(A), 28.9 (B), 28.9 (A). Anal. Calcd for C6H7N5O2 (181.5):
C, 39.78; H, 3.89; N, 38.66. Found: C, 39.52; H, 4.23; N, 37.90.
2-((2H-Tetrazol-2-yl)methyl)isoindoline-1,3-dione (9c). The
reaction was carried out in acetonitrile, and the product
was crystallized from toluene to give white crystals (60%): mp
139.0-145.0 °C. Two tautomers: 1H NMR (500 MHz, acetone-
d6) δ 9.29(s, 0.2H from A), 8.76 (s, 0.8H from B), 7.99-7.92
(m, 6H), 6.54 (s, 2H from B), 6.41 (s, 0.5H from A). Two tauto-
mers: 13C NMR (125 MHz, acetone-d6) δ 167.4 (A), 167.0 (B),
154.2 (B), 145.0 (A), 136.0 (B), 135.8 (A), 132.7 (A), 123.6 (B),
124.7 (B), 124.6 (A), 53.5 (B), 49.0 (A). Anal. Calcd for
C10H7N5O2 (229.2): C, 52.40; H, 3.08; N, 30.56. Found: C,
52.65; H, 3.30; N, 30.02.
1
66.0 °C); H NMR (500 MHz, CDCl3) δ 8.18-8.16 (m, 2H),
7.51-7.46 (m, 3H), 5.50 (s, 2H), 2.65 (t, J = 5.4 Hz, 4H),
1.62-1.57 (m, 4H), 1.36-1.33 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 164.7, 130.3, 129.0, 127.7, 127.0, 126.9, 75.2, 51.0,
25.9, 23.5. Anal. Calcd for C13H17N5 (243.31): C, 64.17; H, 7.04;
N, 28.78. Found: C, 64.08; H, 7.15; N, 28.70.
N,N-Dimethyl-1-(5-phenyl-2H-tetrazol-2-yl)methanamine (9k).
The product was obtained as white prisms (70%): mp 50.0-
51.0 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.10-8.06 (m, 2H),
7.59-7.53 (m, 3H), 5.58 (s, 2H), 2.35 (s, 6H); 13C NMR (125
MHz, DMSO-d6) δ 162.9, 130.4, 129.2, 127.0, 126.4, 75.1, 41.3.
Anal. Calcd for C10H13N5 (203.25): C, 59.09; H, 6.45; N, 34.46.
Found: C, 58.94; H, 6.34; N, 34.60.
4-((5-(4-Nitrophenyl)-2H-tetrazol-2-yl)methyl)morpholine (9l).
The product was crystallized from DCM/hexanes to give yellow
microcrystals (86%): mp 133.0-135.0 °C; 1H NMR (300 MHz,
CDCl3) δ 8.36 (s, 4H), 5.55 (s, 2H), 3.72 (t, J = 4.7 Hz, 4H), 2.72
(t, J = 4.7 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 163.3, 149.1,
133.5, 127.9, 124.4, 74.7, 66.8, 50.0. Anal. Calcd for C12H14N6O3
(290.28): C, 49.65; H, 4.86; N, 28.95. Found: C, 49.87; H, 4.48; N,
28.91.
4-((5-(4-Chlorophenyl)-2H-tetrazol-2-yl)methyl)morpholine (9m).
The product was crystallized from toluene to give white prisms
(80%): mp 111.0-112.0 °C; 1H NMR (300 MHz, CDCl3) δ8.10 (d,
J = 8.7 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 5.51 (s, 2H), 3.72 (t, J =
4.6Hz, 4H), 2.71(t,J= 4.5 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ
179.0, 164.2, 136.4, 129.2, 128.2, 125.9, 74.2, 66.6, 49.8. Anal. Calcd
for C12H14N5OCl (279.73): C, 51.53; H, 5.04; N, 25.04. Found C,
51.93; H, 5.07; N, 24.64.
N,N-Dimethyl-4-(2-(morpholinomethyl)-2H-tetrazol-5-yl)-
aniline (9n). The product was crystallized from toluene to give
white prisms (70%): mp 146.0-148.0 °C; 1H NMR (500 MHz,
acetone-d6) δ 7.96 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H),
5.54 (s, 2H), 3.63 (t, J = 4.5 Hz, 4H), 2.67 (t, J = 4.5 Hz, 4H);
13C NMR (125 MHz, acetone-d6) δ 153.1, 128.7, 113.0, 74.7,
67.4, 51.0, 40.4, 30.6, 30.3. Anal. Calcd for C14H20N6O
(288.36): C, 58.31; H, 6.99; N, 29.14. Found C, 57.97; H, 6.70;
N, 28.97.
4-((5-(4-Methoxyphenyl)-2H-tetrazol-2-yl)methyl)morpholine
(9o). The reaction was carried out in ethanol, and the product
was crystallized from toluene to give white crystals (55%): mp
146.0-147.0 °C; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J = 8.6
Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 5.48 (s, 2H), 3.88 (s, 3H), 3.72
(t, J = 4.6 Hz, 4H), 2.72 (t, J = 4.7 Hz, 4H); 13C NMR (75 MHz,
CDCl3) δ 165.1, 161.5, 128.6, 120.2, 114.5, 74.1, 66.9, 55.6, 50.1,
N-((1H-Tetrazol-1-yl)methyl)-1,2-benzisothiazole-3(2H)-one
1,1-Dioxide (9d). The product was obtained as yellow crys-
tals that turned white upon washing with methylene chloride
(60%): mp 177.0-179.0 °C. Two tautomers: 1H NMR (500
MHz, DMSO-d6) δ 9.59 (s, 0.5H from B), 9.09 (s, 0.1H from A),
8.39-8.37 (m, 1H), 8.22-8.18 (m, 1H), 8.12-8.09 (m, 1H),
8.07-8.03 (m, 1H), 6.71 (s, 0.5H from A), 6.56 (s, 2H from B).
Two tautomers: 13C NMR (75 MHz, DMSO-d6) δ 158.0, 153.9,
144.7, 136.6, 135.6, 125.7, 125.6, 121.9, 48.4. Anal. Calcd for
C9H7N5O3S 1/2H2O (283.27): C, 39.41; H, 2.94; N, 25.54.
3
Found: C, 39.37; H, 2.80; N, 24.60.
1
Supporting Information Available: H and 13C spectra for all
reported compounds, 2D NMR spectra for 9b,c,d,f and full
details of the X-ray crystal structure of 9i. This material is
available free of charge via the Internet at http://pubs.acs.org.
6476 J. Org. Chem. Vol. 75, No. 19, 2010