The synthesis of 1,2,3-triazoles from nitroalkenes - Revisited

Article abstract of DOI:10.1055/s-2005-918463

Nitroalkenes or vicinal acetoxy nitro derivatives undergo a clean reaction with sodium azide in hot dimethyl sulfoxide to give the corresponding 1,2,3-triazoles in good yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918463

PAPER
3319
The Synthesis of 1,2,3-Triazoles from Nitroalkenes – Revisited
S
ynthesis of 1,2,3
é
-Triazoles
a
from Nitro
t
a
lkenesrice Quiclet-Sire,* Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS Ecole Polytechnique, 91128 Palaiseau, France
Fax +33(1)69333851; E-mail: zard@poly.polytechnique.fr
Received 27 September 2005
This paper is dedicated with respect and affection to Professor Steven V. Ley on the occasion of his 60th birthday.
small amount of triazole 2a was isolated and no triphenyl-
benzene 3a was formed, as indicated by comparison (TLC
and HPLC) with an authentic sample. The major product
turned out to be compound 9a (determined by NMR and
mass spectrometric analysis), logically derived by addi-
tion of azide to a molecule of nitrostyrene, followed by
conjugate addition of the resulting nitronate 4a to another
molecule of nitrostyrene to give 7a as outlined in
Scheme 2. Equilibration with 8a and ring closure involv-
ing elimination of nitrite, as shown for the transformation
of 4a into 2a via 5a and 6a, finally provides the observed
triazole 9a. Various experimental modifications in terms
of concentration and ratios of reactants, whilst keeping the
medium at room temperature, did not significantly alter
the results.
Abstract: Nitroalkenes or vicinal acetoxy nitro derivatives undergo
a clean reaction with sodium azide in hot dimethyl sulfoxide to give
the corresponding 1,2,3-triazoles in good yield.
Key words: azides, cyclisations, heterocycles, nitroalkenes, 1,2,3-
triazoles
In 1971, Zefirov et al.1 reported that the reaction of sodi-
um azide with nitrostyrenes 1a–c led to the formation of
the corresponding triazoles 2a–c in about 60% yield as
well as to ‘considerable quantities’ of 1,3,5-triarylben-
zenes 3a–c (Scheme 1).2 The reactions were performed in
dimethyl sulfoxide at room temperature and no other
products were apparently isolated. Although a reasonable
mechanism can be written for these transformations, we
were intrigued by the fact that the action of an azide on a
nitrostyrene could lead to a 1:1 ratio of both triazole 2 and
trimer 3, resulting from the ultimate interaction of three
molecules of the nitrostyrene without the formation of
major side products from the reaction of one or more of
the intermediates with the azide anion. It seemed, there-
fore, worthwhile re-examining this intriguing transforma-
tion, more than thirty years after its discovery.
The NMR spectrum of the crude reaction mixture indicat-
ed the presence of other compounds, some of which could
be obtained semi-pure by chromatography and whose
spectra indicated structures of type 10a and 11a. These
derivatives, which arise by addition of the triazoles to the
starting nitrostyrene, were not thermally stable. Attempt-
ed recrystallisation caused partial decomposition via a ret-
ro-Michael reaction. Their exact structure could not,
therefore, be determined unambiguously.
N
N
When we carried out the reaction at 80 °C, the outcome
was very different. Both phenyltriazole 2a and 1,3,5-
triphenylbenzene (3a) were obtained in 24 and 13% yield,
respectively, but triazole 9a was nevertheless still pro-
duced, in approximately 40% yield. Heating resulted in a
much cleaner reaction because side products such as 10a
and 11a were automatically decomposed to release the ni-
trostyrene, which could then react with the azide anion.
How Zefirov and his co-workers obtained phenyltriazole
2a and triphenylbenzene 3a by operating at room temper-
ature and at the same time did not observe any significant
amount of triazole 9a, nor compounds of type 10a and
11a, remains an inexplicable mystery. This is all the more
surprising because the formation of both 3a and 9a pro-
ceeds by way of intermediate 7a and possibly also via 8a,
depending on whether the addition of the third nitrosty-
rene molecule precedes or follows the elimination of the
azide anion. Moreover, the formation of triphenylbenzene
is a more complex process that is slower than the one lead-
ing to triazole 9a, which occurs readily even at room tem-
perature. It must be said that the manifold reaction
displayed in Scheme 2 only highlights what we feel are
the main pathways, but remains nevertheless incomplete
NH
NO2
2a–c
R
NaN3
+
R
R
DMSO
R
1a–c
a, R = H
b, R = Cl
c, R = Br
3a–c
R
Scheme 1
Relying on the scant experimental information given in
the communication, we exposed nitrostyrene 1a to sodium
azide (2 equiv) in dimethyl sulfoxide (1 mmol, 2 mL). The
starting material disappeared within an hour, but only a
SYNTHESIS 2005, No. 19, pp 3319–3326
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918463; Art ID: C09005SS
x
x.
x
x
.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

3320
B. Quiclet-Sire, S. Z. Zard
PAPER
the greater electrophilicity of 1d compared to nitrostyrene
(Scheme 3). Furthermore, the pyridine series proved easi-
er to analyse because of the greater spread of the signals
in the NMR spectra. Thus, reaction at room temperature
produced mostly triazole 9d, but this time triazole 2d and
trimer 3d could also be observed; at 80 °C, a separable
mixture of 2d, 3d, and 9d was obtained (25, 15, and 17%
yield, respectively).
N
N
N3
N
N
N
NO2
N
NO2
Ph
Ph
Ph
1a
4a
NO2
5a
1a
– NO2
N
N
N
N
N
Nitroalkene 1
Triazole 2
N
NH
NH
N
N
N
N
Ph
N
NO2
NH
NO2
6a
Ph
Ph
NO2
Me
Ph
Ph
7a
Me
R
R
NO2
NO2
8a
N
2e, R = OMe 96%
2f, R = OBn 95%
1e, R = OMe
1f, R = OBn
Ph
N
N
2a
1a
1a
– N3
– NO2
NH
MeO
MeO
MeO
NO2
Me
Me
MeO
NO2
NO2
N
O2N
Ph
OMe
N
Ph
OMe
N
2g 98%
NH
1g
N
N
N
N
Ph
Ph
NO2
N
N
NO2
NH
N
Ph
F3CS
F3CS
NO2
Ph
9a
12a
NO2
NO2
Ph
Me
Ph
Me
1h
11a
2h 95%
1a
Ph
1a
N
N
– 3 HNO2
NH
O2N
Ph
MeO
MeO
MeO
MeO
NO2
– N3
– 3 HNO2
Ph
N
N
N
OMe
OMe
1i
Ph
NO2
Ph
Ph
2i 90%
10a
3a
Ph
N
N
NH
Scheme 2
NO2
Et
Et
1j
N
N
despite its complexity. Various alternative routes and pos-
sible side reactions have been omitted for clarity.
2j 96%
N
N
We performed an analogous series of experiments starting
from 3-(2-nitrovinyl)pyridine (1d). The qualitative out-
come was similar, even if the reactions were faster due to
NH
NO2
Me
Me
1k
N
N
2k 90%
NO2
N
N
NH
NO2
1d
N
N
N
Ph3C
Ph3C
Me
NaN3
DMSO
N
Me
1l
N
2l 75%
Figure 1 Formation of 1,2,3-triazoles from nitroalkenes
N
N
NH
N
N
N
N
NO2
The above experiments provided us with a better mecha-
nistic picture and gave us a feel for the rates of the various
steps. In particular, it became apparent that ring closure
leading to the tetrazole of a primary nitronate, such as 4a,
is in fact a sluggish process at room temperature and the
intermolecular Michael addition to a nitroalkene molecule
is preferred. This suggested a simple modification of the
NH
+
+
N
N
N
N
3d
2d
9d
Scheme 3
Synthesis 2005, No. 19, 3319–3326 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,2,3-Triazoles from Nitroalkenes
3321
Et
experimental procedure that would suppress the unwanted
side reactions. Because the ring closure is by definition
unimolecular and, therefore, insensitive to concentration,
slow addition of the nitroalkene to a hot solution of sodi-
um azide in dimethyl sulfide should favour the formation
of the desired triazole 2 relative to the other products,
which all derive from further bimolecular reactions with
the nitroalkene. Indeed, under these conditions, the yields
of triazoles 2a and 2d increased to 78 and 80%, respec-
tively, and only very small amounts of the other products
were observed in the NMR spectra of the crude reaction
mixtures.
N
NO2
N
N
a or b
NH
Et
N
+
N
NO2
Et
Et
1m
2m
13m
a: 40%
b: 90%
a: 33%
b: —
N
N
NH
b
a
NO2
SO2Ph
SO2Ph
1n
2n 80%
N
The reaction now becomes a synthetically useful route to
1,2,3-triazoles. Furthermore, the ease of formation of
compound 9a (or 9d), even at room temperature, indicated
that ring closure of a secondary nitronate is, contrastingly,
a quite facile process. In fact, with nitroalkenes possessing
a substituent geminal to the nitro group, there was no need
for slow addition. Mixing all the ingredients [nitroalkene
1 (1 mmol), NaN3 (2 mmol), DMSO (2 mL)] and heating
at 80–90 °C for a few hours brought about the desired
transformation in generally high yield, as indicated by the
results compiled in Figure 1. In most cases, triazole 2
could be recovered by simple filtration after dilution of
the reaction mixture with water, and purified by recrystal-
lisation. The starting nitroalkenes are readily obtained by
condensation of the appropriate nitroalkane with the de-
sired aromatic or heteroaromatic aldehyde.3
OAc
N
NH
Et
2o 54%
Et
Me
Me
NO2
1o
N
OAc
N
NH
a
Ph
Me
Me
Ph
NO2
1p
2p 55%
Scheme 4 Reagents and conditions: (a) nitroalkene (1 mmol), NaN3
(2 mmol), DMSO (1.2 mL), 80–90 °C; (b) nitroalkene (1 mmol),
NaN3 (4 mmol), DMSO (4 mL), 80–90 °C.
Finally, we examined the possibility of constructing the
triazoles through a multicomponent process as outlined in
Scheme 5. The concept hinges on the possibility of cap-
turing the initial azide adduct 4a with formaldehyde be-
fore ring closure to the triazole occurs. Indeed, heating
nitrostyrene 1a with sodium azide and aqueous formalde-
hyde produced the expected hydroxymethyl-substituted
triazole 17a, albeit in modest yield (34%). However, pre-
mature closure to the simple triazole 2a (13%) and, more
importantly, to N-hydroxymethylated derivatives 14a
(8%) and 18a (17%) could not be avoided. Heating the
crude residue in refluxing methanolic sodium hydroxide
caused the elimination of formaldehyde from compounds
14a and 18a and resulted in an increase in the yield of 17a
to 47%. The structure of 17a was confirmed by an alterna-
tive synthesis from preformed 2-nitro-3-phenylprop-2-
enol (19). Despite its lack of efficiency at this stage, this
approach provides, nevertheless, an expedient entry into
hydroxymethyl-substituted triazoles. These are rare
compounds4 and may prove to be useful starting materials
for the synthesis of more complex triazoles by substitution
or modification of the alcohol function.
When we examined the reaction of nitroalkene 1m, de-
rived from cyclopropanecarbaldehyde, with sodium
azide, we were surprised to find that under otherwise iden-
tical conditions of temperature and dilution to those
above, compound 13m was formed in 33% yield, in addi-
tion to the expected triazole 2m (40% yield; Scheme 4).
Compound 13m arises from the Michael addition of tri-
azole 2m to the starting nitroalkene 1m, a transformation
that appears to be especially facile in this case. The forma-
tion of this unwanted side product could be suppressed by
doubling the volume of dimethyl sulfoxide and the quan-
tity of sodium azide. Under these modified conditions, the
yield of triazole 2m increased to 90%. With the more hin-
dered nitroalkene 1n, no complications from subsequent
conjugate addition of the product were observed and the
reaction proceeded normally to furnish triazole 2n in 80%
yield.
In the case of purely aliphatic derivatives, it was more
convenient to start directly from the vicinal acetoxy nitro
precursors, which are easily prepared by the Henry addi-
tion of a nitroalkane to an aldehyde, followed by acetyla-
tion of the nitro alcohol.3 The mild basic character of the
sodium azide is sufficient to induce the b-elimination of
the acetoxy group and produce the nitroalkene in situ.
Thus, the vicinal acetoxy nitro derivative acts as a conve-
nient surrogate for the somewhat delicate nitroalkene. In
this manner, 2-acetoxy-3-nitropentane 1o and 2-acetoxy-
3-nitro-5-phenylpentane 1p could be converted into tri-
azoles 2o and 2p in 54 and 55% yield, respectively, as de-
picted in Scheme 4.
In summary, while attempting to understand the observa-
tions of Zefirov and co-workers, we developed a practical
and efficient access to 1,2,3-triazoles. This family of com-
pounds has been recently popularised by Sharpless
through what is now called ‘click’ chemistry5 and several
members of it are reported to have interesting pharmaco-
logical properties.6 It is noteworthy that simple 4-aryl-
1,2,3-triazoles (e.g., 2a, 2d) were very recently found to
be potent, nanomolar inhibitors of angiogenesis in vivo.7
Synthesis 2005, No. 19, 3319–3326 © Thieme Stuttgart · New York

3322
B. Quiclet-Sire, S. Z. Zard
PAPER
MS (CI, NH3): m/z = 179 [M + H+].
N
N
3-[(E)-2-Nitropropenyl]quinoline (1k)
N
This compound was prepared from quinoline-3-carbaldehyde (1 g,
6.37 mmol) and nitroethane (1 mL), and was isolated as crystals af-
ter chromatography (silica gel, toluene–EtOAc 95:5).
NO2
NO2
NaN3 / CH2O
DMSO
r.t. to 80 °C
4a
1a
Yield: 0.81 g (60%)
CH2O
N
NaN3/CH2O
DMSO, 80 °C
Mp 96–97 °C (EtOAc–PE).
IR (CCl4): 1656, 1614, 1567, 1518, 1503 cm–1.
N
N
OH
N
N
N
N
1H NMR (400 MHz, CDCl3): d = 8.96 (s, 1 H, N=CH), 8.23 (s, 2 H,
CH), 8.14 (d, 1 H, J = 8.3 Hz, CH), 7.89 (d, 1 H, J = 8.2 Hz, CH),
7.82 (t, 1 H, J = 7.8 Hz, CH), 7.64 (t, 1 H, J = 8.0 Hz, CH), 2.56 (s,
3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 150.6 (CH), 149.1, 148.0 (Cq),
137.2, 131.2, 130.1, 129.5, 128.3, 127.8 (CH), 127.3, 125.7 (Cq),
14.3 (CH3).
NH
N
NO2
O
CH2O
15a
14a 8%
2a 13%
N
MS (CI, NH3): m/z = 215 [M + H+].
OH
N
N
N
N
N
N
NH
N
Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71. Found: C, 67.08; H,
4.59.
NO2
OH
CH2O
HO
17a 34%
HO
18a 17%
[(E)-2-Nitrobut-1-enyl]cyclopropane (1m)
16a
This compound was prepared from cyclopropanecarbaldehyde and
1-nitropropane, and was isolated as a yellow oil after chromatogra-
phy (silica gel, PE–Et2O, 95:5).
NaN3
DMSO, 80 °C
~ 50%
NO2
Yield: 2.06 g (73%).
Ph
IR (CCl4): 1661, 1522 cm–1
19
OH
1H NMR (400 MHz, CDCl3): d = 6.52 (d, 1 H, J = 11.1 Hz, CH=C),
2.70 (q, 2 H, J = 7.4 Hz, CH2CH3), 1.57 (m, 1 H, CH), 1.17 (t, 3 H,
J = 7.4 Hz, CH2CH3), 1.11 (m, 2 H, CH2), 0.77 (m, 2 H, CH2).
Scheme 5 A three-component synthesis of hydroxymethyl triazoles
13C NMR (100 MHz, CDCl3): d = 151.1 (Cq), 142.1 (CH=C), 20.1
(CH3), 12.6 (CH2), 11.0 (2 CH2), 9.2 (CH).
MS (CI, NH3): m/z = 159 [M + H+ + NH3].
Solvents were used as received. Merck Geduran SI 60 Å silica gel
(35–70 mm) was used for column chromatography. Petroleum ether
used had the boiling range 40–60 °C. IR spectra were recorded on a
Perkin-Elmer 1420 spectrometer. 1H and 13C NMR spectra were re-
corded using 400 MHz ARX 400 Brucker spectrometers. Chemical
shifts are given in ppm, referenced to the residual proton resonances
of the solvents. Nitrostyrene is commercially available; nitroalk-
enes 1d,8 1e,9 1f,10 1g,11 1i,12 and 1l13 and nitroacetates 1o14 and 1p15
were prepared according to literature procedures. Compound 1h
was a gift from Synthelabo (now Sanofi-Aventis).
{[(E)-4-Cyclopropyl-3-nitrobut-3-enyl]sulfonyl}benzene (1n)
A mixture of 3-(phenylsulfonyl)-1-nitropropane17 (0.16 g, 0.69
mmol) and cyclopropanecarbaldehyde (0.073 g, 1.04 mmol) was
stirred at r.t. overnight in the presence of DMAP (10 mg, 0.08
mmol). The mixture was diluted with THF (0.5 mL) and treated
with Ac2O (0.2 mL). The reaction was quenched with MeOH and
the solvent was evaporated off under reduced pressure. The residue
was purified by chromatography (silica gel, toluene–EtOAc 95:5) to
yield 1n as crystals.
Nitroalkenes 1j, 1k, and 1m; General Procedure
A solution of the aldehyde (20 mmol) in the requisite nitroalkane
(20 mL) was heated at 100 °C in the presence of ethylenediamine
(0.44 mL).16 The mixture was cooled and the precipitate filtered and
dried in the case of solid nitroalkenes. Otherwise, the solvent was
evaporated and the residue was purified by flash column chroma-
tography (silica gel).
Yield: 0.1 g (50%).
Mp 106–107 °C (Et2O–PE).
IR (CCl4): 1659, 1521, 1327, 1156, 1142 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.94 (d, 2 H, J = 7.2 Hz, CHAr),
7.69 (t, 1 H, J = 7.4 Hz, CHAr), 7.60 (t, 2 H, J = 7.6 Hz, CHAr),
6.64 (d, 1 H, J = 11.3 Hz, CH=C), 3.39 (dd, 2 H, J = 6.4, 8.9 Hz,
CH2), 3.14 (dd, 2 H, J = 6.4, 9.0 Hz, CH2), 1.60 (m, 1 H, CH), 1.20
(m, 2 H, CH2), 0.83 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 146.3 (CH), 145.0, 138.6 (Cq),
134.0, 129.4, 127.9 (CH), 53.5 (CH2SO2), 20.6 (CH2), 11.6 (CH),
10.1 (2 CH2).
3-[(E)-2-Nitrobut-1-enyl]pyridine (1j)
This compound was prepared from pyridine-3-carbaldehyde and 1-
nitropropane, and was isolated as a yellow oil after chromatography
(silica gel, PE–EtOAc 7:3).
Yield: 1.2 g (34%).
IR (CCl4): 1659, 1559, 1531 cm–1.
MS (CI, NH3): m/z = 282 [M + H+], 299 [M + H+ + NH3].
1H NMR (400 MHz, CDCl3): d = 8.67 (d, 1 H, J = 2.1 Hz, CHAr),
8.64 (dd, 1 H, J = 1.4, 4.8 Hz, CHAr), 7.94 (s, 1 H, CH), 7.72 (dt, 1
H, J = 1.6, 7.9 Hz), 7.40 (dd, 1 H, J = 4.8, 7.9 Hz), 2.84 (q, 2 H, J =
7.4 Hz), 1.27 (t, 3 H, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): d = 154.9 (Cq), 150.7, 150.3, 136.4,
129.3 (CH), 128.6 (Cq), 123.7 (CH), 20.9 (CH2), 12.6 (CH3).
1,2,3-Triazoles 2; General Procedure
To a solution of the nitroalkene (1 mmol) in DMSO (2 mL) was
added NaN3 (2 mmol). The mixture was then heated at 80–90 °C un-
til the starting material was totally consumed as indicated by TLC
(30 min to 8 h). After cooling, H2O was added and the resulting pre-
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Synthesis of 1,2,3-Triazoles from Nitroalkenes
3323
cipitate was filtered, washed with H2O, and dried to give the desired
triazole, which was recrystallised. When no precipitate was ob-
served, the triazole was isolated after extraction with EtOAc or
Et2O.
Anal. Calcd for C10H8F3N3S: C, 46.33; H, 3.11. Found: C, 46.61; H,
3.02.
5-Cyclohex-1-enyl-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-tri-
azole (2i)
4-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole (2e)
This compound was isolated as white crystals.
This compound was isolated as a yellow oil after chromatography
(silica gel, EtOAc–PE 1:1).
Yield: 0.364 g (96%).
Yield: 0.285 g (90%).
Mp 169–170 °C (EtOAc–PE).
IR (CCl4): 3454, 3149 cm–1 (NH).
1H NMR (400 MHz, CDCl3–CD3OD): d = 7.61 (d, 2 H, J = 8 Hz,
CHAr), 6.98 (d, 2 H, J = 8 Hz, CHAr), 3.84 (s, 3 H, OCH3), 2.49 (s,
3 H, CH3).
1H NMR (400 MHz, CDCl3): d = 6.96 (s, 2 H, CHAr), 6.10 (m, 1 H,
C=CH), 3.89 (s, 3 H, OCH3), 3.85 (s, 6 H, 2 OCH3), 2.32 (m, 2 H),
2.13 (m, 2 H, CH2), 1.73 (m, 2 H, CH2), 1.65 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3–CD3OD): d = 159.4 (Cq, COMe),
128.4 (2 CHAr), 123.3 (Cq), 114.3 (2 CHAr), 55.3 (OCH3), 10.9
(CH3).
13C NMR (100 MHz, CDCl3): d = 153.1 (Cq, 3 COCH3), 137.6
(Cq), 130.5 (CH=C), 127.5, 126.5 (Cq,), 104.7 (2 CHAr), 60.9
(OCH3), 55.9 (2 OCH3), 27.5, 25.5, 22.6, 21.7 (CH2).
MS (CI, NH3): m/z = 190 [M + H+].
MS (CI, NH3): m/z = 316 [M + H+].
HMRS (EI): m/z [M+] calcd for C10H11N3O: 189.0902; found:
HRMS (EI): m/z [M+] calcd for C17H21N3O3: 315.1583; found:
189.0901.
315.1584.
4-(4-Benzyloxyphenyl)-5-methyl-1H-1,2,3-triazole (2f)
This compound was isolated as white crystals.
3-(5-Ethyl-1H-1,2,3-triazol-4-yl)pyridine (2j)
After extraction with Et2O, the compound was isolated as white
crystals.
Yield: 0.505 g (95%).
Yield: 0.334 g (96%).
Mp 166–169 °C (EtOAc–PE).
Mp 115–116 °C (Et2O–PE).
1H NMR (400 MHz, CDCl3): d = 7.61 (d, 2 H, J = 8.7 Hz), 7.46–
7.30 (m, 5 H, CHAr), 7.06 (d, 2 H, J = 8.8 Hz, CHAr), 5.10 (s, 2 H,
OCH2Ph), 2.48 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3–CD3OD): d = 158.4, 136.5 (Cq, Ar),
128.4, 128.2, 127.9, 127.3 (CHAr), 123.0 (Cq), 114.9 (CHAr), 69.9
(CH2Ph), 10.5 (CH3).
1H NMR (400 MHz, CDCl3–CD3OD): d = 8.95 (d, 1 H, J = 1.5 Hz,
CHAr), 8.60 (dd, 1 H, J = 1.6, 4.9 Hz, CHAr), 8.06 (dt, 1 H, J = 8.0,
1.6 Hz, CHAr), 7.41 (ddd, 1 H, J = 0.8, 4.9, 7.9 Hz, CHAr), 2.92 (q,
2 H, J = 7.6 Hz, CH2CH3), 1.33 (t, 3 H, J = 7.6 Hz, CH2CH3).
13C NMR (100 MHz, CDCl3–CD3OD): d = 148.3, 147.6 (CHAr),
140.1 (m, Cq), 135.1 (CHAr), 127.8 (Cq), 123.8 (CHAr), 18.5
(CH2), 13.2 (CH3).
MS (CI, NH3): m/z = 266 [M + H+].
Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70. Found: C, 72.51; H,
5.54.
MS (CI, NH3): m/z = 175 [M + H+].
Anal. Calcd for C9H10N4: C, 62.05; H, 5.79. Found: C, 61.91; H,
5.84.
5-Methyl-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (2g)
This compound was isolated as white crystals.
3-(5-Methyl-1H-1,2,3-triazol-4-yl)quinoline (2k)
This compound was isolated as a solid.
Yield: 0.43 g (98%).
Mp 124–125 °C (EtOAc–PE).
1H NMR (400 MHz, CDCl3): d = 6.94 (s, 2 H, CH), 3.92 (s, 6 H, 2
OCH3), 3.90 (s, 3 H, OCH3), 2.55 (s, 3 H, CH3).
Yield: 0.376 g (90%).
Mp 229–230 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.36 (s, 1 H, CH=N), 8.67 (s,
1 H, CHAr), 8.12 (d, 1 H, J = 7.6 Hz, CHAr), 8.09 (d, 1 H, J = 8.4
Hz, CHAr), 7.81 (t, 1 H, J = 7.6 Hz, CHAr), 7.68 (t, 1 H, J = 7.6
Hz), 2.62 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 148.9 (CH=N), 146.6 (Cq),
132.3, 129.6, 128.7, 128.3, 127.1 (CHAr), 127.4, 124.5 (Cq).
13C NMR (100 MHz, CDCl3): d = 153.3 (Cq, 3 COMe), 137.7,
126.3 (Cq), 104.3 (2 CHAr), 60.9 (OCH3), 56.1 (2 OCH3), 10.9
(CH3).
MS (CI, NH3): m/z = 250 [M + H+], 267 [M + H+ + NH3].
Anal. Calcd for C12H15N3O3: C, 57.82; H, 6.07. Found: C, 57.92, H,
6.09.
MS (CI, NH3): m/z = 211 [M + H+].
5-Methyl-4-{3-[(trifluoromethyl)sulfanyl]phenyl}-1H-1,2,3-tri-
azole (2h)
HMRS (EI): m/z [M+] calcd for C12H10N4: 210.0905; found:
210.0910.
This compound was isolated as white crystals.
5-Methyl-4-(1-trityl-1H-imidazol-4-yl)-1H-1,2,3-triazole (2l)
This compound was isolated as a solid after chromatography (silica
gel, EtOAc–PE 3:7).
Yield: 0.492 g (95%).
Mp 116–117 °C (CH2Cl2–PE).
1H NMR (400 MHz, CDCl3): d = 8.02 (s, 1 H, CH), 7.86 (d, 1 H, J =
8 Hz, CH), 7.67 (d, 1 H, J = 8 Hz, CH), 7.52 (t, 1 H, J = 8 Hz, CH),
2.57 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 135.6, 134.6 (CH), 129.5 (q, J =
306 Hz, SCF3), 132.2 (Cq), 129.9, 129.4 (CHAr), 125.0 (Cq), 10.8
(CH3).
Yield: 0.22 g (75%).
Mp 211–212 °C (DMSO).
1H NMR (400 MHz, CDCl3): d = 7.71 (br s, 1 H, NH), 7.36 (m, 10
H, CH), 7.19 (m, 7 H, CH), 2.40 (br s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 142.0 (Cq), 138.7 (m, Cq),
129.1, 128.3, 128.0 (CH), 74.8 (Cq).
MS (CI, NH3): m/z = 260 [M + H+].
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Anal. Calcd for C25H21N5: C, 76.70; H, 5.41. Found: C, 76.52; H,
5.44.
1H NMR (400 MHz, CDCl3): d = 7.94 (d, 2 H, J = 8.1 Hz, CHAr),
7.67 (t, 1 H, J = 7.4 Hz, CHAr), 7.57 (t, 2 H, J = 7.7 Hz, CHAr),
3.55 (m, 2 H, CH2), 3.16 (m, 2 H, CH2), 1.7 (m, 1 H, CH), 0.95 (m,
2 H, CH2CH), 0.80 (m, 2 H, CH2CH).
4-Cyclopropyl-5-ethyl-1H-1,2,3-triazole (2m)
This compound was isolated in 40% yield using the general proce-
dure described above, or using the modified procedure as follows:
Nitroalkene 1m (0.282 g, 2 mmol) was dissolved in DMSO (8 mL)
and NaN3 (0.52 g, 8 mmol) was added. After heating for 8 h at 80–
90 °C, the mixture was cooled and extracted (Et2O, 3×) to afford tri-
azole 2m as white crystals.
13C NMR (100 MHz, CDCl3): d = 145.4, 140.8, 138.6 (Cq), 133.8,
129.3, 128.0 (CH), 54.5, 18.2 (CH2), 7.8 (2 CH2), 5.5 (CH).
MS (CI, NH3): m/z = 278 [M + H+].
HMRS (EI): m/z [M+] calcd for C13H15N3O2S: 277.0885; found:
277.0886.
Yield: 0.247 g (90%).
5-Ethyl-4-methyl-1H-1,2,3-triazole (2o)
Mp 110–111 °C (Et2O–PE).
IR (CCl4): 3466, 3170 cm–1 (NH).
This known compound18 was prepared from nitro acetate derivative
1o (0.50 g, 2.85 mmol) in DMSO (3 mL) and obtained as an oil.
1H NMR (400 MHz, CDCl3): d = 13.6 (br s, 1 H, NH), 2.77 (q, 2 H,
J = 7.6 Hz, CH2CH3), 1.80 (m, 1 H, CH), 1.30 (t, 3 H, J = 7.6 Hz,
CH2CH3), 0.94 (m, 2 H, CH2), 0.88 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 145.8–145.2 (m, Cq), 17.8 (CH3),
13.4 (CH2), 7.0 (2 CH2), 5.3 (CH).
Yield: 0.17 g (54%).
1H NMR (400 MHz, CDCl3): d = 2.68 (q, 2 H, J = 7.6 Hz, CH2), 2.29
(s, 3 H, CH3), 1.27 (t, 3 H, J = 7.6 Hz, CH3).
MS (CI, NH3): m/z = 112 [M + H+].
MS (CI, NH3): m/z = 138 [M + H+], 155 [M + H+ + NH3].
4-Methyl-5-(2-phenylethyl)-1H-1,2,3-triazole (2p)
This compound was prepared according to the general procedure
from nitro acetate 1p and was isolated as crystals after extraction
with Et2O and chromatography (silica gel, PE–EtOAc 9:1 → 7:3).
Anal. Calcd for C7H11N3: C, 61.29; H, 8.08. Found: C, 61.44; H,
8.09.
4-Cyclopropyl-1-(1-cyclopropyl-2-nitrobutyl)-5-ethyl-1H-
1,2,3-triazole (13m)
This compound was isolated as a solid as mixture of two diaste-
reomers in a 2:1 ratio.
Yield: 0.207 g (55%).
Mp 104–105 °C (Et2O–PE).
1H NMR (400 MHz, CDCl3): d = 7.27–7.14 (m, 5 H, Ph), 2.97 (s, 4
H, 2 CH2), 2.11 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 143.3, 141.0, 139.5 (Cq), 128.4,
128.3, 126.1 (CHAr), 35.4 (ArCH2), 26.4 (CH2), 9.1 (CH3).
MS (CI, NH3): m/z = 188 [M + H+].
Yield: 0.093 g (33%).
Major isomer
IR (CCl4): 1556 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.20 (dt, 1 H, J = 3.4, 10.4 Hz,
CHNO2), 4.22 (t, 1 H, J = 9.8 Hz, CHCHNO2), 2.66 (q, 2 H, J = 7.6
Hz, CH2CH3), 2.26 (dqd, 1 H, J = 3.5, 7.5, 14.9 Hz, CHHCH3), 2.05
(qdd, 1 H, J = 7.2, 10.9, 14.4 Hz, CHHCH3), 1.71 (qd, 1 H, J = 5.0,
8.4 Hz, CH), 1.35–1.26 (m, 1 H, CH), 1.24 (t, 3 H, J = 7.6 Hz,
CH2CH3), 1.02 (t, 3 H, J = 7.4 Hz, CH2CH3), 0.90–0.73 (m, 5 H,
CHH, 2 CH2), 0.52–0.37 (m, 3 H, CHH, CH2).
13C NMR (100 MHz, CDCl3): d = 147.8, 147.2 (Cq), 92.6, 70.3
(CH), 24.3, 18.2 (CH2), 13.5, 13.2 (CH3), 10.3 (CH), 7.5, 7.3, 6.1
(CH2), 5.7 (CH), 2.5 (CH2).
Anal. Calcd for C11H13N3: C, 70.56; H, 7.00. Found: C, 70.53; H,
7.11.
1,2,3-Triazoles 14a, 17a, and 18a; Typical Procedure
To a solution of nitrostyrene (1a) (0.3 g, 2 mmol) in DMSO (5 mL)
and aq CH2O (20 mmol) was added portionwise NaN3 (0.65 g, 10
mmol). The mixture was stirred for 1 h at r.t. and then heated at 80–
90 °C for another 1 h. The solvent was removed by flushing with N2
and the residue was taken up in a mixture of EtOAc and MeOH. Af-
ter filtration and evaporation under reduced pressure, the residue
was purified by chromatography (silica gel, PE–EtOAc gradient)
and crystallisation to yield 14a (0.029 g, 8%), 17a (0.119 g, 34%),
18a (0.069 g, 17%), and 2a (0.038 g, 13%). When the crude mixture
was refluxed in MeOH (5 mL) in the presence of NaOH (3 equiv)
for 2 h, 17a was obtained in 47% yield.
MS (CI, NH3): m/z = 279 [M + H+], 296 [M + H+ + NH3].
Minor isomer
IR (CCl4): 1556 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.01 (dt, 1 H, J = 3.1, 10.4 Hz,
CHNO2), 4.02 (t, 1 H, J = 9.8 Hz, CHCHNO2), 2.70 (q, 2 H, J = 7.6
Hz, CH2CH3), 1.89–1.79 (m, 1 H, CHHCH3), 1.78–1.71 (m, 1 H,
CHHCH3), 1.48–1.40 (m, 1 H, CH), 1.27 (t, 3 H, J = 7.6 Hz,
CH2CH3), 1.20–1.10 (m, 1 H, CH), 0.96–0.91 (m, 2 H, CH2), 0.84
(t, 3 H, J = 7.6 Hz, CH2CH3), 0.84–0.79 (m, 2 H, CH2), 0.71–0.65
(m, 1 H, CHH), 0.46–0.41 (m, 1 H, CHH), 0.36–0.27 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): d = 148.1, 147.5 (Cq), 92.6, 70.2
(CH), 24.3, 18.3 (CH2), 13.7, 13.6 (CH3), 10.0 (CH), 7.5 (CH2), 5.7
(CH), 5.6, 2.1 (CH2).
(4-Phenyl-1H-1,2,3-triazol-1-yl)methanol (14a)
This compound was isolated as a white solid.
Mp 100–101 °C (CH2Cl2–PE).
1H NMR (400 MHz, CDCl3–D2O): d = 7.91 (s, 1 H, CH=C), 7.77
(d, 2 H, J = 7.2 Hz, CHAr), 7.43 (t, 2 H, J = 7.5 Hz, CHAr), 7.37 (t,
1 H, J = 7.5 Hz, CHAr), 5.81 (s, 2 H, CH2OH).
13C NMR (100 MHz, CDCl3–D2O): d = 148.8 (Cq), 132.2, 132.1,
129.8, 129.0, 128.9, 126.2, 126.1 (Cq, CH), 76.3 (CH2OH).
MS (CI, NH3): m/z = 279 [M + H+], 296 [M + H+ + NH3].
MS (CI, NH3): m/z = 146 [MH – CH2O+], 176 [M + H+].
Anal. Calcd for C9H9N3O: C, 61.70; H, 5.18. Found: C, 61.65; H,
5.14.
5-[2-(Phenylsulfonyl)ethyl]-4-cyclopropyl-1H-1,2,3-triazole
(2n)
This compound was prepared according to the modified procedure
described for 2m and was isolated as a foam after extraction with
Et2O.
(5-Phenyl-3H-1,2,3-triazol-4-yl)methanol (17a)
This compound was isolated as a white solid.
Mp 130–131 °C (CH2Cl2–MeOH).
Yield: 0.054 g (80%).
Synthesis 2005, No. 19, 3319–3326 © Thieme Stuttgart · New York

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Synthesis of 1,2,3-Triazoles from Nitroalkenes
3325
1H NMR (400 MHz, DMSO-d6): d = 15.2 (br s, 1 H, NH), 8.01 (d,
2 H, J = 6.7 Hz), 7.66 (t, 2 H, J = 6.5 Hz), 7.56 (t, 1 H, J = 6.9 Hz),
5.65 (br s, 1 H, OH), 4.83 (s, 2 H, CH2OH).
MS (CI, NH3): m/z = 295 [M + H+], 312 [M + H+ + NH3].
HMRS (EI): [M+] calcd for C16H14N4O2: 294.1116; found:
294.1128.
MS (CI, NH3): m/z = 176 [M + H+], 193 [M + H+ + NH3].
HMRS (EI): m/z [M+] calcd for C9H9N3O: 175.0745; found:
175.0744.
References
(1) Zefirov, N. S.; Chapovskaya, N. K.; Kolesnikov, V. V. J.
Chem. Soc. D 1971, 1001.
[5-(Hydroxymethyl)-4-phenyl-1H-1,2,3-triazol-1-yl]methanol
(18a)
This compound was isolated as a white solid.
(2) For the synthesis of 1,2,3-triazoles by cycloaddition of
organic azides to nitroalkenes, see: (a) Piet, J.-C.; Le Hetet,
G.; Cailleux, P.; Benhaoua, H.; Carrié, R. Bull. Soc. Chim.
Belg. 1996, 105, 33. (b) Cailleux, P.; Piet, J.-C.; Benhaoua,
H.; Carrié, R. Bull. Soc. Chim. Belg. 1996, 105, 45. Very
recently, the cycloaddition of trimethylsilyl azide with
aromatic nitroacrylates and nitroacrylonitriles has been
reported, see: (c) Amantini, D.; Fringuelli, F.; Piermatti, O.;
Pizzo, F.; Zunino, E.; Vaccaro, L. J. Org. Chem. 2005, 70,
6526. The reaction of sodium azide with vinyl sulfones was
found to give 1,2,3-triazoles, see: (d) Beck, G.; Günther, D.
Chem. Ber. 1973, 106, 2758.
(3) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001. (b) Ballini, R.; Bosica, G.; Fiorini,
D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933.
(c) Rosini, G.; Ballini, R. Synthesis 1988, 833. (d) Seebach,
D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 33, 1.
(4) Surprisingly, a search of Beilstein revealed only one
example of a 1,2,3-triazole with a hydroxymethyl side chain
on the carbon: Vereshchagin L. I.; Tikhonova L. G.,
Maksikova A. V., Gavrilov L. D., Gareev G. A.; Zh. Org.
Khim.; 1979, 15: 612.
Mp 83–85 °C (CH2Cl2–PE).
1H NMR (400 MHz, CDCl3–D2O): d = 7.66 (d, 2 H, J = 7.3 Hz,
CHAr), 7.36 (m, 3 H, CHAr), 5.71 (s, 2 H, NCH2), 4.77 (s, 2 H,
CH2).
13C NMR (100 MHz, DMSO-d6): d = 145.3, 144.9, 130.4 (Cq),
128.7, 128.2, 127.1 (CHAr), 75.9 (CH2OH), 54.3 (CH2OH).
MS (CI, NH3): m/z = 176 [MH – CHO+].
Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40. Found: C, 58.42; H,
5.41.
Improved Synthesis of 1,2,3-Triazoles 2a and 2d
A solution of nitrostyrene (1a) (0.15 g, 1 mmol) in DMSO (7 mL)
was added dropwise over 4 h to a hot (80–90 °C) solution of NaN3
(0.13 g, 2 mmol) in DMSO (2 mL). The mixture was cooled and
partitioned between H2O and EtOAc, and the organic layer further
washed with H2O and dried (Na2SO4). Concentration under reduced
pressure and purification of the residue by chromatography (silica
gel, toluene–EtOAc 8:2) gave phenyltriazole 2a; yield: 0.113 g
(78%).
(5) (a) Rostovstev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornøe, C.
W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (c) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem. Int. Ed. 2001, 40, 2004. (d) Kolb, H. C.; Sharpless,
K. B. Drug Discov. Today 2003, 8, 1128.
It was identical to an authentic sample.
The preparation of 2d was carried out on a larger scale: Nitroalkene
1d (1.00 g, 6.66 mmol) in DMSO (50 mL) was added dropwise over
4 h to a hot (80–90 °C) solution of NaN3 (0.866 g, 13.5 mmol) in
DMSO (13 mL). The mixture was worked up as for 2a, but chro-
matographic purification was not necessary in this case.
(6) 1,2,3-Triazoles have been found to possess muscarinic
anticonvulsant anti-HIV and b-lactamase inhibitory
activities. Some act as anticoccidiostats, see: (a) Bochis, R.
J.; Chabala, J. C.; Harris, E.; Peterson, L. H.; Barash, L.;
Beattie, T.; Brown, J. E.; Graham, D. W.; Waksmunski, F.
S.; Tischler, M.; Joshua, H.; Smith, J.; Colwell, L. F.;
Wyvratt, M. J. Jr.; Fisher, M. H.; Tamas, T.; Nicolich, S.;
Schleim, K. D.; Wilks, G.; Olson, G. J. Med. Chem. 1991,
34, 2843. (b) Willner, D.; Jelenevsky, A. M.; Cheney, L. C.
J. Med. Chem. 1972, 15, 948. (c) Micetich, R. G.; Maiti, S.
N.; Spevak, P.; Hall, T. W.; Yamabe, S.; Ishida, N.; Tanaka,
M.; Yamazaki, T.; Nakai, A.; Ogawa, K. J. Med. Chem.
1987, 30, 1469. (d) Hlasta, D. J.; Ackerman, J. H. J. Org.
Chem. 1994, 59, 6184. (e) Alvarez, R.; Velazquez, S.; San-
Felix, A.; Aquaro, S.; De Clercq, E.; Perno, C.-F.; Karlsson,
A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem. 1994, 37,
4185. (f) Kelley, J. L.; Koble, C. S.; Davis, R. G.; McLean,
E. W.; Soroko, F. E.; Cooper, B. R. J. Med. Chem. 1995, 38,
4131. (g) Moltzen, E. K.; Pedersen, H.; Boegesoe, K. P.;
Meier, E.; Frederiksen, K.; Sanchez, C.; Lemboel, H. L. J.
Med. Chem. 1994, 37, 4085.
(7) Kallander, L. S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang, G.;
Tew, D.; Meek, T. D.; Hofmann, G. A.; Schulz-Pritchard, C.
K.; Smith, W. W.; Janson, C. C.; Ryan, M. D.; Zhang, G.-F.;
Johanson, K. O.; Kirkpatrick, R. B.; Ho, T. F.; Fisher, P. W.;
Mattern, M. R.; Johnson, R. K.; Hansbury, M. J.; Winkler, J.
D.; Ward, K. W.; Veber, D. F.; Thompson, S. K. J. Med.
Chem. 2005, 48, 5644.
(8) Bourguignon, J.; Le Nard, G.; Quéguiner, G. Can. J. Chem.
1985, 63, 2354.
(9) Wessling, M.; Schaefer, H. J. Chem. Ber. 1991, 124, 2303.
3-(1H-1,2,3-triazol-4-yl)pyridine (2d)
This compound was isolated as a solid.
Yield: 0.78 g (80%).
Mp 196–197 °C (sublimed) (Lit. 197 °C,19a 187–192 °C19b).
1H NMR (400 MHz, CDCl3): d = 9.00 (s, 1 H), 8.55 (dd, 1 H, J =
1.3, 4.9 Hz), 8.15 (d, 1 H, J = 7.9 Hz), 7.99 (s, 1 H), 7.40 (dd, 1 H,
J = 4.7, 7.6 Hz).
MS (CI, NH3): m/z = 147 [M + H+].
5-(2-Nitro-1-phenylethyl)-4-phenyl-1H-1,2,3-triazole (9a)
If, instead of adding the nitrostyrene slowly to the NaN3, as above,
the components were simply dissolved in DMSO and heated ac-
cording to the typical procedure used for the triazoles in Figure 1,
the reaction led not only to triazole 2a, but also to 1,3,5-triphenyl-
benzene (3a) and triazole 9a. The latter compound was isolated as
a solid after chromatography (silica gel, toluene–EtOAc 8:2).
Yield: 0.118 g (40%).
Mp 138–140 °C (Et2O–PE).
IR (CCl4): 3450, 3162 (NH), 1557 cm–1 (NO2).
1H NMR (400 MHz, CDCl3): d = 7.46 (m, 10 H, CHAr), 5.26 (dd,
1 H, J = 8.9, 13.2 Hz), 5.13 (dd, 1 H, J = 6.7, 8.9 Hz), 4.90 (dd, 1 H,
J = 6.6, 13.4 Hz).
13C NMR (100 MHz, CDCl3): d = 142.6, 137.4 (Cq), 129.3, 129.0,
128.9, 128.2, 128.0 (CH), 79.0 (CH2), 40.5 (CH).
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B. Quiclet-Sire, S. Z. Zard
PAPER
(10) Barton, D. H. R.; Motherwell, W. B.; Simon, E. S.; Zard, S.
Z. J. Chem. Soc., Perkin Trans. 1 1986, 2243.
(11) Frost, D. A.; Morrison, G. A. J. Chem. Soc., Perkin Trans. 1
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(12) Ouvry, G.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2003, 5,
2907.
(16) (a) Barton, D. H. R.; Motherwell, W. B.; Zard, S. Z. J. Chem.
Soc., Chem. Commun. 1982, 551. (b) Barton, D. H. R.;
Motherwell, W. B.; Zard, S. Z. Bull. Soc. Chim. Fr. 1983, II,
61.
(17) Bordwell, F. G.; Bartmess, J. E. J. Org. Chem. 1978, 43,
3101.
(13) Shih, N. Y.; Lupo, A. T.; Aslanian, R.; Orlando, S.;
Piwinski, J. J.; Green, M. J.; Ganguly, A. K.; Clark, M. A.;
Tozzi, S.; Kreutner, W.; Hey, J. A. J. Med. Chem. 1995, 38,
1593.
(14) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron
1990, 46, 7587.
(18) Fusco, R.; Bianchetti, G.; Pocar, D. Gazz. Chim. Ital. 1961,
91, 933.
(19) (a) Buckler, R. T.; Hartzler, H. E.; Kurchacova, E.; Nichols,
G.; Phillips, B. M. J. Med. Chem. 1978, 21, 1254.
(b) Moltzen, E. K.; Pedersen, H.; Boegesoe, K. P.; Meier, E.;
Frederiksen, K.; Sanchez, C.; Lembol, H. L. J. Med. Chem.
1994, 37, 4085.
(15) Tokunaga, Y.; Ihara, M.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1997, 207.
Synthesis 2005, No. 19, 3319–3326 © Thieme Stuttgart · New York