1,3-Dipolar cycloaddition of benzyl azide to two highly functionalized alkynes

Article abstract of DOI:10.1007/s00706-011-0691-3

Benzyl azide undergoes [3 + 2] cycloaddition when reacted with 3,3,4,4-tetraethoxybut-1-yne, a ketal, and the corresponding ketone, 1,1-diethoxybut-3-yn-2-one, in the presence of a Cu(I) salt in various solvents. The outcome is sensitive to the structure

Full text of DOI:10.1007/s00706-011-0691-3

Monatsh Chem (2012) 143:505–512
DOI 10.1007/s00706-011-0691-3
ORIGINAL PAPER
1,3-Dipolar cycloaddition of benzyl azide to two highly
functionalized alkynes
•
Tahir Farooq Bengt Erik Haug Leiv K. Sydnes
•
•
¨
Karl W. Tornroos
Received: 25 September 2011 / Accepted: 14 November 2011 / Published online: 22 December 2011
Ó Springer-Verlag 2011
Abstract Benzyl azide undergoes [3 ? 2] cycloaddition
when reacted with 3,3,4,4-tetraethoxybut-1-yne, a ketal, and
the corresponding ketone, 1,1-diethoxybut-3-yn-2-one, in
the presence of a Cu(I) salt in various solvents. The outcome
is sensitive to the structure of the alkyne and the nature of the
metal salt. Both alkynes give the corresponding 1,4-disub-
stituted 1,2,3-triazoles in up to 70% yield, but the ketone also
affords a minor amount of the 1,5-disubstituted analogue.
When CuI is used as catalyst, the ketal in addition furnishes
some 1-benzyl-5-iodo-4-(1,1,2,2-tetraethoxyethyl)-1,2,3-
triazole. On the other hand, when the reaction was carried out
under Ru(II) catalysis, no 1,2,3-triazole formation was
observed for any of the substrates; the ketal did not react at
all, whereas the ketone underwent cyclotrimerization and
gave 1,3,5-tris(2,2-diethoxyacetyl)benzene in 60% yield. No
reaction occurred when the magnesium acetylide of 3,3,4,4-
tetraethoxybut-1-yne was reacted with benzyl azide.
Introduction
1,2,3-Triazoles exhibit noteworthy chemical properties and
biological activities, and such compounds have therefore
been used in organic synthesis and applied in a variety of
medicinal and industrial products for some time [1, 2].
Interestingly, the number of successful applications has
increased in recent years [3–8], a development that is
related to the flat structure of the triazole ring and its
reluctance to react under a range of conditions [9]. This
inspired us to incorporate disubstituted 1,2,3-triazole moi-
eties, preferably with at least one polar substituent, in
scaffolds to be applied in peptidomimetic studies.
Several fairly general methods are available for the
synthesis of 1,2,3-triazoles [10–15], but the most versatile
one is definitely the thermally induced addition of organic
azides to alkynes [16–23], one of several concerted 1,3-
dipolar cycloadditions studied extensively by Huisgen
et al. [24–27]. This reaction exhibits a high degree of
selectivity in the sense that when terminal alkynes and
organic azides are used, the 1,4-disubstituted adduct pre-
dominates completely or almost completely over the
corresponding 1,5-disubstituted analogue. However, sev-
eral notable exceptions to this rule are known [28–30].
Thus, when Sheehan and Robinson reacted 3-phenylprop-
2-ynal with phenyl azide, an approximately 5:2 mixture of
the 1,5- and 1,4-diphenyl-1,2,3-triazoles was obtained in
90% total yield [28]. Furthermore, Huisgen et al. found
that the reaction of methyl propynoate with the same azide
under similar conditions gave the expected 1,4- and 1,5-
disubstituted triazoles in a 7:1 ratio [31].
Keywords 1,2,3-Triazoles Á Selective cycloaddition Á
Terminal alkynes Á Trimerization
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0691-3) contains supplementary
material, which is available to authorized users.
¨
T. Farooq Á L. K. Sydnes (&) Á K. W. Tornroos
Department of Chemistry, University of Bergen,
´
Allegt. 41, 5007 Bergen, Norway
e-mail: leiv.sydnes@kj.uib.no
From these observations it is not straightforward to
predict what would happen when we set out to make tria-
zoles by reacting benzyl azide with two highly
functionalized polar terminal alkynes, the ketal 3,3,4,4-
B. E. Haug
Centre of Pharmacy, University of Bergen,
´
Allegt. 41, 5007 Bergen, Norway
e-mail: bengt-erik.haug@farm.uib.no
123

506
T. Farooq et al.
Scheme 1
tetraethoxybut-1-yne (1) [32–37] and the corresponding
ketone 1,1-diethoxybut-3-yn-2-one (2) [33–37]. However,
on the basis of discoveries of Meldal et al. [18–20] and
Sharpless et al. [21–23], and results subsequently published
by a large number of research groups [38–43], we expected
that the addition of benzyl azide to 1 and 2 in the presence of
a Cu(I) salt would result in a faster reaction, less by-product
formation, and regioselective formation of 1,4-disubstituted
1,2,3-triazoles, whereas reactions carried out in the pres-
ence of [Cp*RuCl]-based complexes should furnish the
corresponding 1,5-disubstituted analogues only [44–49]. As
the results presented here show, these expectations were not
really met.
lengths and angles were close to literature values for sim-
ilar compounds [50]. Irrespective of the conditions the
yield was moderate (Table 1; Fig. 2).
An alternative cuprous salt that is often used to facilitate
azide cycloaddition to alkynes is copper(I) iodide, which is
applied in the presence or absence of a base [51]. When this
salt was employed instead of CuSO4/sodium ascorbate, the
yield of 3 from 1 generally increased under most conditions,
although the best yield (71%, see Table 2) was only slightly
higher than the best yield obtained with the CuSO4-ascor-
bate catalyst (69%, see Table 1). A noteworthy feature is
the consistent formation of an additional product, 1-benzyl-
5-iodo-4-(1,1,2,2-tetraethoxyethyl)-1H-1,2,3-triazole (4,
Scheme 2). The yield of 4 was low when CuI was used in
the absence of base (\7%, see Table 2), but when per-
formed in the presence of diisopropylethylamine (DIPEA)
and either N-chlorosuccinimide (NCS) or N-bromosuccin-
imide (NBS) [52], triazole 3 was not formed, whereas
Results and discussion
Copper-catalyzed reactions
The addition of benzyl azide to ketal 1 was first studied.
Experiments were first carried out in acetonitrile, DMF,
and DMSO in the absence of Cu(I) at temperatures ranging
from 60 to 110°C, but cycloadducts were neither isolated
nor detected. To our surprise the result was the same when
reactions were performed in aqueous tert-butyl alcohol
containing Cu(I) generated in situ from copper(II) sulfate
and sodium ascorbate, reaction conditions commonly used
to obtain triazoles by azide addition [10–15, 21–23,
44–47]. The outcome was the same when the temperature
was elevated to 60°C and the solvent was changed to
aqueous DMF. However, when dry acetonitrile or mixtures
of water with chloroform, dichloromethane, or DMSO
were used as solvents and CuSO4/sodium ascorbate was
applied as catalyst, triazole formation took place. The only
product formed was 1-benzyl-4-(1,1,2,2-tetraethoxyethyl)-
1H-1,2,3-triazole (3) (Scheme 1) as substantiated by
spectroscopic data and an X-ray crystallography structure
determination (Fig. 1), which revealed that the bond
Table 1 Isolated yield of triazole 3, prepared by CuSO4/ascorbate-
catalyzed addition of benzyl azide to alkyne 1 for 48 h at two
temperatures
Solvent
Room temperature/%
60°C
CH3CN
44
41
61
55
58%
51%
H2O/CH3Cl (1:3)
H2O/DMSO (1:3)
H2O/CH2Cl2 (1:3)
a
69%
a
The reaction was not run since dichloromethane boils below 60°C
Fig. 2 Crystal structure of compound 3; anisotropic displacement
parameters are given at the 50% level
Fig. 1 The structures of the acetylenes investigated
123

1,3-Dipolar cycloaddition of benzyl azide
507
1-(1-benzyl-1H-1,2,3-triazol-4-yl)-2,2-diethoxyethanone
(5), which was also made in 90% yield by independent
synthesis (Scheme 3).
Table 2 Isolated yields of triazole 3 and 5-iodotriazole 4, prepared
by CuI-catalyzed addition of benzyl azide to alkyne 1
Solvent
Room temperature
60°C
When addition of benzyl azide to ketone 2 was carried
out under CuI catalysis, the outcome of the reaction
changed somewhat. 1,4-Disubstituted triazole 5 was still
the predominant product, but in addition the corresponding
1,5-disubstituted isomer, viz. 1-(1-benzyl-1H-1,2,3-triazol-
5-yl)-2,2-diethoxyethanone (6), was obtained (Scheme 4)
in up to 10% yield (Table 3, entry 8). Furthermore, unlike
ketal 1, the corresponding ketone 2 appeared not to furnish
any iodotriazole, and by analyzing the crude reaction
mixture with respect to the iodoketo corresponding to
iodoketal 4, viz. 1-(1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-
2,2-diethoxyethanone (7) prepared by deketalization of 4
(Scheme 5), it was proved that iodide 7 was not formed
under the conditions that furnished 4 from 1.
3
4
3
4
CH3CN
68%
69%
42%
6%
3%
5%
71%
61%
62%
5%
3%
7%
H2O/DMSO (1:3)
H2O/DMF (1:3)
iodide 4 was obtained in a respectable yield (72 and 62%
yield, respectively, Scheme 2).
Copper-catalyzed addition of benzyl azide to ketoalkyne
2 was then performed. On the basis of a paper published by
Girard et al. [53], we expected regiospecific formation of
the analogous 1,4-disubstituted triazole, and this was
observed when CuSO4/sodium ascorbate was used as
catalyst (Table 3). The only product obtained was
Scheme 2
Table 3 Isolated yields of
Entry
Catalyst
Solventa
Room temperature
60°C
triazoles 5 and 6, prepared by
Cu(I)-catalyzed addition of
benzyl azide to alkyne 2
5
6
5
6
1
2
CuSO4/ascorbate
CH3CN
59%
61%
51%
48%
70%
61%
54%
52%
58%
59%
61%
69%
60%
H2O/DMSO
H2O/DMF
H2O/CH3Cl
H2O/CH2Cl2
CH3CN
3
4
52%
b
5
6
CuI
3%
3%
10%
3%
0%
70%
61%
61%
3%
2%
4%
5%
a
7
H2O/DMSO
H2O/DMF
H2O/CH3Cl
H2O/CH2Cl2
The aqueous solvents contain
25% water by volume
8
b
The reaction was not run
since dichloromethane boils
9
54%
b
10
below 60°C
Scheme 3
123

508
T. Farooq et al.
Scheme 4
workup revealed that all of 2 had been consumed and been
converted to one product, which appeared not to be a tria-
zole, but 1,3,5-tris(2,2-diethoxyacetyl)benzene (9, Fig. 3),
which was obtained in 55 and 60% yield at 65 and 80°C,
respectively (Table 4, entries 3 and 4). This trimer of 2 has
previously been obtained by treating 2 with aqueous solu-
tions of sodium bicarbonate [54]. The formation of 9 is not
really surprising because ruthenium complexes have been
proved to facilitate cyclotrimerization of electron-deficient
alkynes [55, 56]. The mechanism for the reaction has not
been unraveled, but a suggestion is depicted in Fig. 4.
The different behavior of 1 and 2 toward Cp*RuCl(PPh3)2
is quite indicative of the importance of the polar moiety next
to the triple bond in the two alkynes. The inability of 1 to
react might be due to deactivation of the catalyst by some sort
of complexation involving some or all of the four oxygen
atoms in the tetraethoxyethyl moiety. Alkyne 2, on the other
hand, with its conjugated ynone structural motif, has been
rendered so much more prone to undergo Michael reactions
that azide addition to the triple bond cannot compete. It is
therefore not surprising that a thorough search of the litera-
ture reveals no publications describing 1,2,3-triazole
formation by azide addition to electron-deficient carbon-
carbon triple bonds similar to that found in 2.
Table 4 Outcome of syntheses performed to obtain the 1,5-disub-
stituted analogues of triazoles 3 and 5
Entry Alkyne Reaction conditions Isolated compounds
(yield)
1
2
3
4
1
2
Cp*RuCl(PPh3)2,
THF 65°C, 24 h
Cp*RuCl(PPh3)2,
C6H6 80°C, 24 h
Cp*RuCl(PPh3)2,
1 (95%) and BnN3 (96%)
1 (94%) and BnN3 (93%)
9 (55%) and BnN3 (91%)
9 (60%) and BnN3 (88%)
THF 65°C, 4 h
Cp*RuCl(PPh3)2,
C6H6 80°C, 3 h
Scheme 5
Ruthenium-catalyzed cycloadditions
Regioselective synthesis of 1,5-disubstituted 1,2,3-tria-
zoles from terminal alkynes has also been achieved by
reacting bromomagnesium acetylides with organic azides
[57, 58]. After having carried out the reaction between
benzyl azide and the acetylide from phenylacetylene sev-
eral times and isolated 1-benzyl-5-phenyl-1,2,3-triazole
(8) as the only product in 93% yield the acetylide from
ketal 1 was reacted with benzyl azide in exactly the same
way. To our disappointment the reaction failed to give any
1,2,3-triazole; instead, both benzyl azide and ketal 1 were
recovered in almost quantitative yield.
The formation of 1,5-disubstituted triazole 6 as a by-product
when alkyne 2 was reacted in the presence of CuI indicates
that6 mightbeformedinhigheryieldsifthe reactioniscarried
out under conditions that are known to favor 1,5-disubstituted
1,2,3-triazoles over 1,4-disubstituted 1,2,3-triazole. In order
to achieve this the literature suggests that Cu(I) salts should be
replaced by a ruthenium complex, preferably bis(triphenyl-
phosphine)pentamethylcyclopentadienylruthenium(II) chlo-
ride (Cp*RuCl(PPh3)2) in an adequate solvent [48, 49]. After
having reproduced the reaction between benzyl azide and
phenylacetylene under Cp*RuCl(PPh3)2 catalysis several
timesand obtained 1-benzyl-5-phenyl-1,2,3-triazole(8) asthe
only product in consistently better than 85% yield, ketal 1 was
reacted with benzyl azide under the same conditions. To our
surprisenoreactionoccurred asjudgedfromchromatographic
and spectroscopic analyses, and when the reaction mixture
wasworkedupintheusualway,bothreactantswererecovered
in high yield (Table 4).
However, when the substrate was changed to ketone 2,
TLC analysis showed that a reaction took place. Subsequent
Fig. 3 The product from ruthenium-induced trimerization of
ketone 2
123

1,3-Dipolar cycloaddition of benzyl azide
509
Fig. 4 A proposed mechanism
for the formation of 9; Nu-
denotes an unknown
nucleophilic species derived
from Cp*RuCl(PPh3)2
Conclusion
recorded on a Bruker Spectrospin DPX 400 MHz spec-
trometer; the chemical shifts are reported in ppm relative to
Me4Si, the coupling constants (J) in Hz, and the multi-
plicity as singlet (s), doublet (d), triplet (t), and multiplet
(m). TLC analyses were carried out using silica gel (60
The highly functionalized terminal alkynes 3,3,4,4-tetra-
ethoxybut-1-yne (1) and 1,1-diethoxybut-3-yn-2-one (2)
undergo [3 ? 2] cycloaddition with benzyl azide in the
presence of a Cu(I) salt and produce the expected 1,4-
disubstituted 1,2,3-triazoles. However, both alkynes failed
to give the isomeric 1,5-disubstituted 1,2,3-triazole when
reacted with the same azide in the presence of ruthenium; 1
gave no product whatsoever, whereas 2 suffered trimer-
ization and gave a benzene derivative as the only product.
This clearly indicates that the ruthenium-catalyzed azide
addition to alkynes is more sensitive to substituent influ-
ence than so far acknowledged in the literature.
F254) on aluminium sheets as stationary phase, and a
mixture of hexanes and ethyl acetate as the mobile phase.
Purification by flash column chromatography was per-
formed using silica gel (230–400 mesh) as the stationary
phase and a mixture of hexanes and ethyl acetate as the
mobile phase. The mass spectra were obtained on a JEOL
AccuTOF T100GC, operated in the DART mode, and MS-
ESI spectra were obtained on a Thermo electron LTQ
Orbitrap XL with an electrospray ion source (ION-MAX).
Chemicals
Experimental
CuI was purchased from EMD, and all other reagents and
organic solvents were purchased from Sigma-AldrichÒ and
used without further purification. Benzyl azide was pre-
pared as described in the literature [59], and so were
The IR spectra were run on a Nicolet Impact 410 infrared
spectrophotometer, and the intensities are given as weak
(w), medium (m), and strong (s). The NMR spectra were
123

510
T. Farooq et al.
ꢀm = 2,979 (s), 2,931 (m), 2,899 (w), 2,358 (s), 2,340 (m),
1,653 (m), 1,557 (m), 1,440 (m), 1,241 (m), 1,209 (m),
1,173 (w), 1,121 (s), 1,077 (s), 973 (s), 929 (m), 724
3,3,4,4-tetraethoxybutyne (1), following a previously pub-
lished procedure [34, 35], and 1,1-diethoxy-3-butyn-2-one
(2), obtained by deketalization of 1 in moist acetone con-
taining Dowex 50 W as described in the literature [35].
(s) cm-1
;
1H NMR (methanol-d4): d = 1.12 (6H, t,
J = 7.0 Hz, 2 CH3), 1.24 (6H, t, J = 7.0 Hz, 2 CH3),
3.51–3.71 (8H, m, 4 OCH2), 4.73 (1H, s, (EtO)2CH), 5.68
(2H, s, PhCH2), 7.19–7.32 (5H, m, Ph) ppm; 13C NMR
(methanol-d4): d = 15.6 (2 CH3), 15.8 (2 CH3), 54.9
(PhCH2), 58.9 (2 OCH2), 66.5 (2 OCH2), 100.9 (C(OEt)2),
106.7 (HC(OEt)2), 126.5 (C), 129.1 (2 CH), 129.7 (CH),
130.1 (2 CH), 137.1 (C), 148.4 (C) ppm; HRMS (ESI):
m/z calcd. for [M ? H]? ([C19H29IN3O4]?) 490.11973,
found 490.11950.
Cu-catalyzed addition of benzyl azide, general
procedure
Terminal alkyne 1 (230 mg, 1.00 mmol) or 156 mg 2
(1.00 mmol), 146 mg benzyl azide (1.10 mmol), and either
9.3 mg CuSO4Á5H2O (0.040 mmol)/22 mg sodium ascor-
bate (0.11 mmol) or 19 mg CuI (0.010 mmol) were
suspended in 4 cm3 solvent (for solvents, see Tables 1, 2,
3). The mixture was stirred vigorously at room temperature
or 60°C for 48 h. For extraction one of the solvents,
CH2Cl2, CHCl3, EtOAc, or Et2O (3 9 10–15 cm3), was
used. The combined organic fractions were dried (MgSO4)
and concentrated under vacuum on a rotary evaporator to
give a crude product, from which pure triazoles were iso-
lated by flash column chromatography using a 7:3 mixture
of hexanes and ethyl acetate as eluent.
Alternative synthesis of triazole 4
Ketal 1 (230 mg, 1.00 mmol), 146 mg benzyl azide
(1.10 mmol), 209 mg CuI (1.10 mmol), 129 mg diisopro-
pylethylamine (DIPEA, 1.00 mmol), and 160 mg N-chloro-
succinimide (NCS, 1.20 mmol) were added to 5 cm3 THF,
and the resulting mixture was stirred vigorously at room
temperature for 4 h. Extraction was carried out with EtOAc
(3 9 10 cm3). The combined organic fractions were washed
with brine, dried (MgSO4), and concentrated under vacuum
on a rotary evaporator to give a crude product. Analyses gave
no indications whatsoever that triazole 3 had been formed.
Isolation by flash column chromatography using a 7:3 mix-
ture of hexanes and ethyl acetate as eluent furnished 352 mg
(72%) of triazole 4 as a yellowish solid. When the reaction
was repeated using 213.6 mg N-bromosuccinimide (NBS,
1.20 mmol) instead of NCS, the yield of 4 dropped to
302 mg (62%). In both cases the physical properties of 4
were identical to those reported above.
Cu-catalyzed addition to 1
1-Benzyl-4-(1,1,2,2-tetraethoxyethyl)-1H-1,2,3-triazole
(3, C19H29N3O4)
Ketal 1 was reacted at room temperature under CuSO4/
ascorbate catalysis in water/DMSO (1:3) following the
general procedure (see above) and gave 220 mg (61%) of 3
as a white solid. M.p.: 74–75.5°C; Rf = 0.35 (Hex/EtOAc,
ꢀ
7:3); IR (KBr): m = 3,154 (s), 2,986 (s), 2,940 (m), 2,886
(m), 2,366 (m), 2,334 (w), 1,613 (w), 1,499 (w), 1,458 (m),
1,371 (m), 1,188 (s), 1,125 (s), 1,084 (s), 979 (m), 928 (m),
1
842 (m), 728 (s), 687 (m) cm-1; H NMR (methanol-d4):
d = 1.08 (6H, t, J = 7.0 Hz, 2 CH3), 1.16 (6H, t,
J = 7.0 Hz, 2 CH3), 3.41–3.71 (8H, m, 4 OCH2), 4.72
(1H, s, (EtO)2CH), 5.57 (2H, s, PhCH2), 7.29–7.36 (5H, m,
Ph), 7.82 (1H, s, triazole H) ppm; 13C NMR (methanol-d4):
d = 14.6 (2 CH3), 14.7 (2 CH3), 53.9 (PhCH2), 57.9 (2
OCH2), 65.5 (2 OCH2), 99.9 (C(OEt)2), 104.7 (HC(OEt)2),
125.5 (C), 128.1 (2 CH), 128.6 (CH), 129.1 (2 CH), 136.0
(CH), 147.3 (C) ppm; HRMS (DART): m/z calcd. for
[M ? H]? ([C19H30N3O4]?) 364.22363, found 364.22338.
When ketal 1 was reacted at 60°C under CuI catalysis in
acetonitrile following the general procedure (see above),
240 mg (71%) of 3 and 25 mg (5%) of triazole 4 were
obtained. The physical data for 3 are as described above.
Cu-catalyzed addition to 2
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2,2-diethoxyethanone
(5, C15H19N3O3)
When ketone 2 was reacted at room temperature under
CuSO4/ascorbate catalysis in water/CH2Cl2 (1:3) following
the general procedure (see above) isolation furnished
190 mg (70%) of 5 as a yellowish oil. Rf = 0.27 (Hex/
ꢀ
EtOAc, 7:3); IR (film): m = 3,127 (m), 3,027 (w), 2,975 (s),
2,923 (m), 2,891 (m), 1,701 (s), 1,529 (s), 1,490 (m), 1,457
(m), 1,369 (m), 1,321 (w), 1,241 (s), 1,113 (m), 1,065 (m),
917 (w), 828 (m), 716 (s), 700 (w) cm-1 1H NMR
;
(CDCl3): d = 1.22 (6H, t, J = 7.0 Hz, 2 CH3), 3.65–3.81
(4H, m, 2 OCH2), 5.45 (1H, s, (EtO)2CH), 5.57 (2H, s,
PhCH2), 7.29–7.40 (5H, m, Ph), 8.12 (1H, s, triazole H)
ppm; 13C NMR (CDCl3): d = 15.7 (2 CH3), 54.9 (PhCH2),
64.0 (2 OCH2), 100.9 (HC(OEt)2), 128.6 (CH), 128.9 (2
1-Benzyl-5-iodo-4-(1,1,2,2-tetraethoxyethyl)-1H-1,2,3-
triazole (4, C19H28IN3O4)
Triazole 4 was isolated as a yellowish crystalline solid.
M.p.: 83–84°C; Rf = 0.60 (Hex/EtOAc, 7:3); IR (KBr):
123

1,3-Dipolar cycloaddition of benzyl azide
511
CH), 129.7 (CH), 129.8 (2 CH), 134.1 (C), 145.1 (C), 187.7
(CO) ppm; HRMS (DART): m/z calcd. for [M ? H]?
([C15H20N3O3]?) 290.15047, found 290.15251.
(EtO)2CH), 7.31–7.38 (5H, m, Ph) ppm; 13C NMR
(CDCl3): d = 16.8 (2 CH3), 55.6 (PhCH2), 64.8 (2
OCH2), 99.6 (HC(OEt)2), 129.6 (2 CH), 130.3 (CH),
130.5 (2 CH), 130.7 (C), 135.0 (C), 147.2 (C), 188.4 (CO)
ppm; HRMS (ESI): m/z calcd for [M ? H]? ([C15H19
IN3O3]?) 416.04656; found 416.04661.
When ketone 2 was reacted at 60°C under CuI catalysis
in acetonitrile following the general procedure (see above),
isolation afforded 240 mg (70%) of 5 and 25 mg (3%) of 6.
The physical data for 5 are as described above.
1-(1-Benzyl-1H-1,2,3-triazol-5-yl)-2,2-diethoxyethanone
(6, C15H19N3O3)
Triazole 6 was isolated as a greenish oil. Rf = 0.51 (Hex/
Ru-catalyzed addition of benzyl azide to 1 and 2
Alkyne 1 (139 mg, 0.60 mmol) or 94 mg 2 (0.60 mmol),
44 mg benzyl azide (0.33 mmol), and 4 mg Cp*RuCl(PPh3)2
(0.005 mmol, 1 mol%) were dissolved in 5 cm3 of either dry
THF at 65°C or anhydrous benzene at 80°C. The mixture was
stirred vigorously for 3–4 h or 24 h (Table 4). The solvent
was removed under vacuum and left a residue that was ana-
lyzed by TLC. Flash-column chromatography with hexanes/
EtOAc (9:1) as eluent afforded only the reactants benzyl azide
and 1 in 93% yield or better in the reactions involving 1
(Table 4, entries 1 and 2), whereas reactions with 2 furnished
unreacted benzyl azide in 88–91% yield and 1,3,5-tris(2,2-
diethoxy-1-oxoethyl)benzene (9, Table 4, entries 5 and 6).
When 2 was reacted an intractable mixture of colored com-
pounds with unknown structures was also formed, but the
compounds attached strongly to the column and could neither
be isolated nor separated. Compound 9 was isolated as a
colorless oil, 52 mg (55%) in THF at reflux (65°C) and 55 mg
(60%) in benzene at reflux (80°C), and the spectroscopic and
spectrometric data were in accordance with those of an
authentic sample of the compound [23].
ꢀ
EtOAc, 7:3); IR (film): m = 3,047 (w), 2,987 (s), 2,943 (w),
2,891 (w), 1,709 (s), 1,505 (w), 1,449 (m), 1,333 (m), 1,245
(w), 1,125 (m), 1,073 (s), 921 (w), 724 (s), 700 (m) cm-1
;
1H NMR (CDCl3): d = 1.19 (6H, t, J = 7.0 Hz, 2 CH3),
3.51–3.69 (4H, m, 2 OCH2), 4.93 (1H, s, (EtO)2CH), 5.92
(2H, s, PhCH2), 7.30–7.32 (5H, m, Ph), 8.47 (1H, s, triazole
H) ppm; 13C NMR (CDCl3): d = 15.6 (2 CH3), 54.4
(PhCH2), 64.0 (2 OCH2), 103.0 (HC(OEt)2), 128.6 (2 CH),
128.8 (CH), 129.2 (2 CH), 130.4 (C), 135.4 (C), 140.6
(CH), 186.0 (CO) ppm; HRMS (DART): m/z calcd. for
[M ? H]? ([C15H20N3O3]?) 290.15047, found 290.15017.
Alternative synthesis of 5
The synthesis was based on a procedure used to convert
ketal 1 to ketone 2 [15]. Triazole 3 (363 mg, 1.00 mmol)
was dissolved in a mixture of 18 cm3 acetone and 0.5 cm3
water, and 260 mg Dowex 50 W was subsequently added.
The mixture was heated at reflux for 6 h and was then
filtered, dried (MgSO4), and concentrated. Flash-column
chromatography using a 7:3 mixture of hexanes and ethyl
acetate as eluent was then carried out, and 260 mg (90%)
of 5 was obtained. The physical and spectroscopic data of
the product are identical to those reported above.
Mg-catalyzed addition of benzyl azide, general
procedure
To the dried flask containing a solution of 0.36 cm3 of
2.0 M EtMgBr and 5 cm3 dry THF under nitrogen atmo-
sphere, 183 mg 1 (0.79 mmol) was added dropwise at
room temperature. The solution was heated to 50°C for
15 min and cooled to room temperature, and 96 mg benzyl
azide (0.72 mmol) was added dropwise. The reaction was
run at 50°C for 24 h. After quenching with 4 cm3 aqueous
NH4Cl, extraction was carried out with EtOAc (3 9 10
cm3). The combined organic extracts were dried (MgSO4),
filtered, concentrated to a colorless residue, and finally
worked up by flash-column chromatography with hexanes/
EtOAc (9:1) as eluent. This furnished 179 mg (98%) of
ketal 1 and 93 mg (97%) of benzyl azide.
1-(1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl)-
2,2-diethoxyethanone (7, C15H18IN3O3)
The synthesis was based on a procedure used to convert
ketal 1 to ketone 2 [15]. Iodotriazole 4 (489 mg,
1.00 mmol) was dissolved in a mixture of 18 cm3 acetone
and 0.5 cm3 water, and 260 mg Dowex 50 W was subse-
quently added. The mixture was heated at reflux for 6 h
and was then filtered, dried (MgSO4), and concentrated.
Flash-column chromatography using a 7:3 mixture of
hexanes and ethyl acetate as eluent was then carried out,
and 353 mg (85%) of the title compound was obtained as a
brownish oil. Rf = 0.50 (Hex/EtOAc, 7:3); IR (film):
ꢀ
m = 3,600 (m), 2,975 (m), 2,931 (w), 2,891 (w), 1,713
(s), 1,497 (s), 1,461 (w), 1,445 (m), 1,421(m), 1,097 (w),
X-ray structure determination
1,065 (s), 980 (m), 920 (m), 710 (m) cm-1 1H NMR
;
Analysis was performed using a Bruker AXS APEXII TXS
Ultra rotating anode diffractometer. A thin colorless plate
(CDCl3): d = 1.28 (6H, t, J = 7.0 Hz, 2 CH3), 3.80–3.84
(4H, m, 2 OCH2), 5.66 (2H, s, PhCH2), 5.90 (1H, s,
123

512
T. Farooq et al.
23. Wang Q, Chan RC, Hilgraf R, Fokin VV, Sharpless KB, Finn MG
(2003) J Am Chem Soc 125:3192
24. Huisgen R (1963) Angew Chem 75:604
was mounted under a nitrogen stream at 123 K. Data were
collected in 0.3° frames over 182° in x at four orthogonal
u-positions. The crystal diffracted rather poorly and showed
broad Bragg profiles. The raw data were processed, and the
structure solved and refined using the programs contained in
the Bruker AXS APEX2 software package [60].
¨
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Chem 77:119
34. Kvernenes OH, Sydnes LK (2005) Org Synth 83:184
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Complete crystallographic data (excluding structure fac-
tors) for the structure have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 811697. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: ?44(0)1223336033
or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgments Financial support from the Higher Education
Commission (HEC) of Pakistan (to TF), administered by The Nor-
wegian Centre for International Cooperation in Higher Education
(SIU), is acknowledged with considerable appreciation. Thanks are
also due to Terje Lygre and Egil Nodland at the University of Bergen
and Jostein Johansen at the University of Tromsø for recording the
mass spectra.
38. Genin MJ, Allwine DA, Anderson DJ, Barbachyn MR, Emmert
DE, Garmon SA, Graber DR, Grega KC, Hester JB, Hutchinson
DK, Morris J, Reischer RD, Stper D, Yagi BH (2004) J Med
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