Tandem multicomponent/click reactions: synthesis of functionalized oxazoles and tetrazoles from acyl cyanides

Article abstract of DOI:10.1016/j.tet.2007.03.127

The combination of multicomponent condensations with post-condensation dipolar cycloaddition reactions provides a useful route to densely functionalized oxazoles and tetrazoles in just two synthetic steps.

Full text of DOI:10.1016/j.tet.2007.03.127

Tetrahedron 63 (2007) 8665–8669
Tandem multicomponent/click reactions: synthesis of
functionalized oxazoles and tetrazoles from acyl cyanides
*
ꢀ
Isabelle F. Clemenc¸on and Bruce Ganem
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA
Received 6 January 2007; revised 20 March 2007; accepted 21 March 2007
Available online 27 March 2007
Abstract—The combination of multicomponent condensations with post-condensation dipolar cycloaddition reactions provides a useful
route to densely functionalized oxazoles and tetrazoles in just two synthetic steps.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
We recently reported that acyl cyanides undergo smooth
Passerini condensations with carboxylic acids and isocya-
nides to afford products 1 (Scheme 1) that can be directly
transformed into b-aminoacid diamide (b-peptide) struc-
tures.8
In the past decade, multicomponent reactions (MCRs), have
played an increasingly important role in the synthesis of
drug candidates,1 and especially heterocyclic compounds,2
by facilitating access to whole libraries of structurally
diverse compound family types for SAR studies. Several
strategies have been developed to enhance the structural
complexity that can be achieved using MCRs. For example,
uniting two known MCRs led to a seven-component Asin-
ger–Ugi coupling that produced pentasubstituted thiazoles.3
Post-condensation modifications of MCR products by both
intermolecular and intramolecular reactions have also been
widely used to build out molecular complexity.4
CN
H
N
R1
R3
R2
O
O
O
OCH3
1
N
N
CH3O2C
N
R4
N
O
N
H
N
R1
O
H
N
R3
R1
O
R3
R2
O
R2
O
The scope and versatility of click chemistry has recently
been mined to introduce additional structural modifications
to MCR products. For example, dihydropyrimidinones
(DHPMs) prepared by the three-component Biginelli reac-
tion have been subsequently functionalized with azide
groups, thus setting the stage for an azide–alkyne coupling
to create triazole-substituted DHPMs.5 In a complementary
strategy, several 2(1H)-pyrazinones prepared by multicom-
ponent condensation were subsequently derivatized with
alkyne groups in preparation for azide cycloadditions lead-
ing to triazolo-pyrazinones.6
O
2
3
O
Scheme 1.
By combining that modified Passerini protocol with post-
condensation dipolar cycloaddition reactions using either
diazomalonic esters or alkyl azides, we here demonstrate
that acyl cyanides may be transformed into functionally
complex 1,3-oxazoles 2 or tetrazoles 3, respectively. In the
case of tetrazoles, the transposed sequence of reactions
(click-then-MCR) provides an equally convenient route to
target structures 3.
We were interested in multicomponent reaction products
that might directly undergo click reactions without interven-
ing synthetic manipulations so as to streamline the overall
process. To our knowledge, only one example of this type
of two-step protocol has been described leading to a spiro-
cyclic triazole.7
Besides being active pharmacophores in their own right,9
oxazole rings are found in a number of natural products,
including virginiamycins,10 disorazoles,11 and ulapua-
lides.12 Tetrazoles function as peptide bond surrogates for
the cis amide bond,13 and have been incorporated into cis-
constrained hydroxyethylamine isosteres as a new class of
HIV-1 protease inhibitors.14
* Corresponding author. Tel.: +1 607 255 7360; fax: +1 607 255 6318;
e-mail: bg18@cornell.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.127

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I. F. Cleꢀmenc¸on, B. Ganem / Tetrahedron 63 (2007) 8665–8669
2. Results and discussion
(0.01 equiv–0.05 equiv) in CHCl3 at reflux over 8 h. Con-
centration and flash chromatography of the product afforded
the desired 2-methyl-4-carbomethoxy-5-methoxyacylox-
azole 4a (Scheme 3, 25%–40%) along with the diazoester-
derived dimer, tetramethyl ethene-1,1,2,2-tetracarboxylate,
which was co-eluted with 4a and could not be separated
using standard techniques. When reacted with acetic acid
and tert-butylisocyanide, impure acyloxazole 4a did afford
substituted oxazole 2a; however, the rate of Passerini
condensation of the acyloxazole was significantly slower
than that of the corresponding acyl cyanide. In view of that
finding, the alternative route to oxazoles 2 was not pursued
further.
Several years ago Helquist et al. developed a useful route to
4-carbomethoxy-5-methoxy-1,3-oxazoles by the transition
metal-catalyzed dipolar cycloaddition of dimethyl diazo-
malonate with nitriles.15 After investigating several catalysts
for activity, the authors concluded that Rh2(OAc)4 afforded
1,3-oxazoles in the best yield. Because of possible side reac-
tions involving the additional functionality in more complex
nitriles like 1 we elected to screen a representative group
of copper and rhodium complexes in cycloadditions of
dimethyl diazomalonate using 1a, prepared from pyruvo-
nitrile, acetic acid and tert-butylisocyanide, as a test case
(Scheme 2).
OCH3
CH3O2C
OCH3
N2C(CO2CH3)2
CN
CH3O2C
O
2a
N
Rh2(OAc)4
CHCl3
CH3
O
CN
O
N
N2C(CO2CH3)2
CH3
NH-t-Bu
O
CH3
AcO
catalyst
(0.01 equiv)
CHCl3
NH-t-Bu
4a
CH3
AcO
O
O
Scheme 3.
8 h
1a
2a
We next explored the cycloaddition of Passerini-derived
nitriles 1 with alkyl azides as a route to multiply-functional-
ized tetrazoles. Sharpless et al. have shown that such ‘click
chemistry’ processes can be successfully applied to a wide
range of nitriles,16 including acyl cyanides.17 However,
attempted cycloaddition of either benzyl azide or cyclohexyl
azide with nitrile 1a in the presence of the standard zinc
catalysts18 led to recovered starting material in near-quanti-
tative yield in all cases. We reasoned that the low reactivity
of the nitrile group in 1a was likely due to its sterically
congested environment. Consequently, we decided to re-
verse the order of steps and first perform the click reaction
on the acyl cyanide component.
Scheme 2.
As the data in Table 1 indicate, Rh2(OAc)4 proved to be the
catalyst of choice. The yield of oxazole 2a was further
improved to 52% using a catalyst loading of 0.05 equiv
(instead of the 0.01 equiv used by Helquist) and 1.5 equiv
of dimethyl diazomalonate added over 8 h.
Table 1. Catalyzed cycloadditions of N2C(CO2CH3)2 with 1a
Catalyst
Temp (ꢀC)
2a (% Yield)
Cu(tfacac)2
Cu(hfacac)2
Cu(acac)2
45
70
70
70
0
20
25
42
Sharpless reported that acyl cyanides formed 1-substituted-
5-acyltetrazoles by regioselective [2+3] cycloaddition
when heated in slight excess (1.5 equiv) with azides neat
at 120 ꢀC. Benzoyl cyanide 6 (Scheme 4) cyclized cleanly
with benzyl azide 5a (R2¼Bn) to afford 1-benzyl-5-benzoyl-
tetrazole 8a (R2¼Bn).
Rh2(OAc)4
The scope of this cycloaddition was surveyed using repre-
sentative examples of the Passerini-derived nitriles 1. As
data summarized in Table 2 indicate, the cycloaddition of
dimethyl diazomalonate appears to accommodate a variety
of substitution patterns in 1.
R2
O
R2N3
5
O
N
R1
R1 CN
N
ZnBr2
N
N
Table 2. MCR/cycloaddition route to substituted oxazoles 2
6 R1 = Ph
8 R1 = Ph
7 R1 = CH3
9 R1 = CH3
R1
R2
R3
Product (% yield)
Scheme 4.
CH3
CH3
n-C6H11
CH3
CH3
CH3
PhCH2CH2
CH3
t-Bu
n-Bu
n-C6H11
EtO2CCH2
2a (52)
2b (50)
2c (42)
2d (31)
However, Sharpless noted that acyl cyanides like pyruvo-
nitrile 7 having a hydrogen at the a position were unstable
during the prolonged heating required for tetrazole formation.
We therefore developed an improved protocol for the forma-
tion of 5-acetyltetrazoles. The use of ZnBr2 (1 equiv) made it
possible to run the cycloaddition of 7 with benzyl azide
(10 equiv) at rt, which improved the yield of 1-benzyl-5-ace-
tyltetrazole 9a (R2¼Bn, 65%) and increased the purity of the
product.
It was also of interest to determine whether the yield of
products 2a–d obtained by the two-step reaction sequence
shown above might be improved by inverting the order of
steps. Although dipolar cycloaddition reactions of diazomal-
onate with nitriles have been well-studied, comparable re-
actions with acyl cyanides have not been reported. To test
this sequence, dimethyl diazomalonate (1 equiv–3 equiv)
was added to a solution of pyruvonitrile and Rh2(OAc)4
This modified cycloaddition protocol for 7 was successful
with several different azides and afforded 5-acetyltetrazoles

I. F. Cleꢀmenc¸on, B. Ganem / Tetrahedron 63 (2007) 8665–8669
8667
9 as summarized in Table 3. Reactions were run neat in
a tightly capped vial for 48 h at rt. Stirring of the crude reac-
tion mixture with aqueous potassium carbonate, extraction
with ethyl acetate, and flash chromatography afforded the
pure 5-acetyltetrazoles.
reflux under argon. A solution of dimethyl diazomalonate
(83 mg, 0.52 mmol) in CHCl3 (0.3 mL) was gradually added
to the reaction mixture over 8 h. After addition, the solution
was cooled to rt and concentrated in vacuo. The remaining
oil was purified by silica gel flash column chromatography
(1:1 petroleum ether/ethyl acetate and 1:2 petroleum ether/
1
ethyl acetate) to give a yellow oil (63 mg, 52%): H NMR
Table 3. Formation of 1-substituted-5-acetyltetrazoles 9
(500 MHz, CDCl3) d 7.30 (s, 1H), 4.16 (s, 3H), 3.85 (s,
3H), 2.17 (s, 3H), 1.93 (s, 3H), 1.39 (s, 9H); 13C NMR
(400 MHz, CDCl3) d 169.02, 166.29, 161.67, 161.52,
151.05, 106.75, 60.09, 51.94, 51.89, 28.55, 23.04, 21.40;
IR (neat) 2957 (w), 2361 (w), 2255 (m), 1753 (m), 1719
(m), 1634 (m), 1522 (w), 1456 (w), 1398 (w), 1370 (w),
1221 (m), 1096 (m), 909 (s), 735 (s), 650 (m), 424
(w) cmꢁ1; CIMS (methane) m/z: 343 (M+H), 283.
5 (R2¼)
Bn
C8H17
C6H11
PhCH]CHCH2
9 (% Yield)
9a R2¼Bn (65)
9b R2¼C8H17 (73)
9c R2¼C6H11 (49)
9d R2¼PhCH]CHCH2 (11)
The 5-acetyltetrazoles 9a–d functioned as reactive carbonyl
components in Passerini reactions using various carboxylic
acids and isocyanides. The expected MCR products 3a–g
(Fig. 1) were obtained in moderate to good yields.
3.1.2. Oxazole 2b. The product was purified by silica gel
flash column chromatography (1:2 hexanes/ethyl acetate)
to give a brown oil (35 mg, 50%): H NMR (400 MHz,
1
CDCl3) d 7.54 (m, 1H), 4.17 (s, 3H), 3.86 (s, 3H), 3.33 (m,
2H), 2.18 (s, 3H), 1.92 (s, 3H), 1.56 (m, 2H), 1.38 (m,
2H), 0.94 (t, 3H, J¼7 Hz); 13C NMR (500 MHz, CDCl3)
d 169.17, 167.30, 161.67, 161.61, 151.02, 106.85, 60.20,
52.00, 39.82, 31.53, 23.27, 21.36, 20.20, 13.92; IR (neat)
3435 (br), 2957 (m), 2874 (w), 1751 (w), 1721 (m), 1676
(m), 1630 (s), 1534 (m), 1456 (m), 1398 (m), 1233 (s), 1119
(m), 1078 (s) cmꢁ1; CIMS (methane) m/z: 343 (M+H), 283.
N
N
N
N
N
N
N
Bn
N
CH2CH=CHPh
H
N
H
N
R3
CH3
CH3
CH3
R2
O
O
O
O
O
O
3a R2 = CH3, R3 = t-Bu
3e
3b R2 = CH3, R3 = n-Bu
3.1.3. Oxazole 2c. The product was purified by silica gel
flash column chromatography (3:1 hexanes/ethyl acetate
and 1:1 hexanes/ethyl acetate) to give a yellow oil (22 mg,
3c R2 = Ph, R3 = cyclohexyl
3d R2 = PhCH=CH-, R3 = n-Bu
1
N
N
N
N
N
42%): H NMR (400 MHz, CDCl3) d 8.64 (m, 1H), 7.19–
N
N
N
C6H11
C8H17
7.30 (m, 5H), 3.86 (m, 7H), 3.00 (m, 2H), 2.83 (m, 2H),
0.78–2.09 (m, 21H); 13C NMR (400 MHz, CDCl3)
d 172.17, 164.54, 161.61, 161.28, 150.84, 140.62, 128.67,
128.55, 126.45, 106.18, 81.90, 60.02, 51.99, 48.62, 46.88,
35.45, 32.66, 32.34, 30.62, 27.61, 26.92, 26.19, 26.08,
26.04, 25.81, 24.44; IR (neat) 3428 (br), 2930 (m), 2855
(w), 1748 (m), 1686 (m), 1634 (s), 1551 (w), 1452 (w), 1397
H
N
H
N
CH3
CH3
CH3
t-Bu
t-Bu
O
O
O
O
O
O
3f
3g
Figure 1.
(w), 1250 (w), 1142 (w), 1090 (w), 980 (w), 637 (br) cmꢁ1
;
CIMS (methane) m/z: 527 (M+H), 377.
In summary, we have shown that merging multicomponent
condensations with dipolar cycloadditions can broaden the
diversity of complex heterocycle-containing scaffolds that
are readily accessible in two steps. Click chemistry reactions
are easy to perform using readily available reagents that are
insensitive to air and moisture, and thus are ideally suited
partners for MCRs. The densely functionalized oxazole
and tetrazole products described here represent just a few
of the readily conceived examples of complexity-generating
MCR-based strategies. Our findings suggest that there may
be numerous opportunities to apply this approach to diver-
sity-based chemical synthesis.
3.1.4. Oxazole 2d. The product was purified by silica gel
flash column chromatography (1:3 hexanes/ethyl acetate
and 1:5 hexanes/ethyl acetate) to give a green oil (16 mg,
1
31%): H NMR (400 MHz, CDCl3) d 7.95 (m, 1H), 4.24
(q, 2H, J¼7 Hz), 4.18 (s, 3H), 4.09 (t, 2H, J¼5 Hz), 3.87
(s, 3H), 2.19 (s, 3H), 2.00 (s, 3H), 1.30 (t, 3H, J¼8 Hz);
13C NMR (500 MHz, CDCl3) d 169.37, 169.02, 167.75,
161.70, 161.64, 150.46, 106.99, 61.85, 60.25, 52.00,
41.89, 22.91, 21.32, 14.30; IR (neat) 3424 (br), 1719 (br),
1630 (s), 1541 (w), 1456 (w), 1398 (w), 1217 (m), 1078
(w), 1018 (w) cmꢁ1; CIMS (methane) m/z: 373 (M+H), 313.
3.2. Representative procedure for the synthesis
of 5-acetyltetrazoles 9a–d
3. Experimental section
3.1. Representative procedure for the synthesis
of substituted oxazoles 2a–d
3.2.1. Synthesis of 9a. A one-dram vial was charged with
benzyl azide (174 mg, 1.3 mmol), ZnBr2 (304 mg,
1.3 mmol), pyruvonitrile (0.9 mL, 13 mmol), and a stirbar
and tightly capped. The reagents were stirred vigorously
for 48 h at rt. The reaction mixture was then poured in
a round bottom flask containing 15 mL aqueous NaHCO3.
3.1.1. Synthesis of 2a. A heterogeneous mixture of
Rh2(OAc)4 (7.9 mg, 0.02 mmol), a-acyloxy-a-cyanoamide
1a (76 mg, 0.36 mmol), and CHCl3 (0.5 mL) was heated to

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The vial was rinsed with ethyl acetate (3ꢂ2 mL) and the
rinses were added to the round bottom flask. The two-phase
mixture was stirred overnight at rt. The organic layer was
then isolated and the aqueous layer was extracted with ethyl
acetate (2ꢂ10 mL). The combined organic layers were dried
over MgSO4. After filtration and concentration, the brown
oil was purified by silica gel flash column chromatography
(3:1 hexanes/ethyl acetate) to afford the known19 9a as a
yellow oil (171 mg, 65%).
3H), 1.79 (s, 3H), 1.55 (m, 2H), 1.36 (m, 2H), 0.93 (t, 3H,
J¼8 Hz); 13C NMR (500 MHz, CDCl3) d 169.11, 167.35,
154.51, 133.91, 129.26, 128.79, 127.05, 52.38, 40.11,
31.46, 24.31, 20.71, 20.20, 13.90; IR (neat) 3351 (br), 2959
(m), 2874 (w), 1757 (s), 1682 (s), 1532 (m), 1456 (m), 1371
(m), 1219 (s), 1138 (m), 1015 (w), 947 (w), 878 (w), 729
(m), 604 (w) cmꢁ1; CIMS (methane) m/z: 346 (M+H), 304.
3.3.3. Tetrazole 3c. The product was purified by silica gel
flash column chromatography (2:1 hexanes/ethyl acetate)
to give a yellow oil (50 mg, 58%): H NMR (400 MHz,
1
3.2.2. Acetyltetrazole 9b. The product was purified by silica
gel flash column chromatography (6:1 hexanes/ethyl ace-
tate) to give 9b as a colorless oil (73%): 1H NMR
(400 MHz, CDCl3) d 4.70 (t, 2H, J¼8 Hz), 2.86 (s, 3H),
1.89 (m, 2H), 1.29 (m, 10H), 0.88 (t, 3H, J¼7 Hz); 13C
NMR (500 MHz, CDCl3) d 188.51, 149.27, 50.00, 31.81,
29.93, 29.14, 29.08, 29.00, 26.37, 22.73, 14.21; IR (neat)
3449 (br), 2928 (s), 2857 (m), 1713 (s), 1636 (br), 1491
(w), 1449 (m), 1362 (m), 1262 (w), 1128 (m), 963 (w),
637 (m) cmꢁ1; CIMS (methane) m/z: 225 (M+H).
CDCl3) d 8.02 (m, 1H), 7.84 (m, 2H), 7.58 (m, 1H), 7.39
(m, 2H), 7.19 (m, 3H), 7.02 (m, 2H), 5.64 (dd, 2H, J¼
16 Hz, 61 Hz), 3.80 (m, 1H), 1.97 (s, 3H), 1.90 (m, 1H), 1.74
(m, 2H), 1.61 (1H), 1.23–1.42 (m, 6H); 13C NMR (500 MHz,
CDCl3) d 166.38, 164.98, 154.68, 134.11, 133.49, 131.42,
130.15, 129.23, 129.19, 129.02, 128.73, 128.70, 128.46,
127.33, 127.00, 52.52, 49.34, 32.74, 32.66, 29.04, 25.64,
24.81, 24.75; IR (neat) 3437 (w), 3308 (m), 2936 (s), 2857
(m), 2253 (m), 1732 (s), 1682 (s), 1520 (m), 1452 (m),
1273 (s), 1103 (m), 1026 (w), 910 (s), 729 (s), 648
(m) cmꢁ1; CIMS (methane) m/z: 434 (M+H).
3.2.3. Acetyltetrazole 9c. The product was purified by silica
gel flash column chromatography (3:1 hexanes/ethyl ace-
tate) to afford the known19 9c as a white solid (49%).
3.3.4. Tetrazole 3d. The product was purified by silica gel
flash column chromatography (3:1 hexanes/ethyl acetate)
1
3.2.4. Acetyltetrazole 9d. The product was purified by silica
gel flash column chromatography (3:1 hexanes/ethyl ace-
tate) to afford 9d as a yellow oil (11%): 1H NMR
(400 MHz, CDCl3) d 7.26–7.38 (m, 5H), 6.74 (d, 1H, J¼
16 Hz), 6.31 (m, 1H), 5.47 (dd, 2H, J¼1 Hz, 6 Hz), 2.86
(s, 3H); 13C NMR (500 MHz, CDCl3) d 188.52, 149.15,
136.76, 135.48, 128.91, 128.90, 126.99, 120.61, 51.81,
29.05; IR (neat) 3455 (br), 3059 (w), 2928 (w), 1713 (s),
1647 (br), 1495 (m), 1441 (m), 1362 (m), 1252 (w), 1125
(m), 966 (m), 762 (m), 691 (m), 637 (m) cmꢁ1; CIMS
(methane) m/z: 229.1 (M+H), 157, 117.
to give a white solid (28 mg, 50%): mp¼171–172 ꢀC; H
NMR (400 MHz, CDCl3) d 7.92 (s, 1H), 7.53 (d, 1H,
J¼16 Hz), 7.41 (m, 5H), 7.20–7.31 (m, 3H), 7.12 (d, 2H, J¼
7 Hz), 6.14 (d, 1H, J¼16 Hz), 5.72 (dd, 2H, J¼16 Hz,
24 Hz), 3.34 (m, 2H), 1.97 (s, 3H), 1.57 (m, 2H), 1.38 (m,
2H), 0.94 (t, 3H, J¼7 Hz); 13C NMR (400 MHz, CDCl3) d
167.34, 165.05, 154.67, 147.63, 133.90, 133.88, 131.19,
129.14, 128.79, 128.58, 127.29, 115.62, 52.57, 40.17, 31.48,
24.59, 20.25, 13.93; IR (neat) 3410 (br), 3102 (w), 2926 (m),
2857 (m), 2368 (br), 1730 (s), 1682 (s), 1634 (s), 1530 (m),
1452 (m), 1422 (w), 1370 (w), 1331 (m), 1281 (w), 1204 (w),
1130 (s), 982 (w), 864 (w), 768 (m), 727 (s), 685 (w) cmꢁ1
;
3.3. Representative procedure for the synthesis
of substituted oxazoles 3a–g
CIMS (methane) m/z: 434 (M+H), 288.
3.3.5. Tetrazole 3e. The product was purified by silica gel
flash column chromatography (1:1 hexanes/ethyl acetate)
to give an off-white solid (12 mg, 40%): mp¼149 ꢀC–
152 ꢀC; 1H NMR (400 MHz, CDCl3) d 7.48 (m, 1H),
7.26–7.37 (m, 5H), 6.53 (m, 1H), 6.31 (m, 1H), 5.30 (dd,
2H, J¼1 Hz, 5 Hz), 3.76 (m, 1H), 2.13 (s, 3H), 2.10 (s,
3H), 1.85–1.96 (m, 2H), 1.68–1.75 (m, 2H), 1.19–1.40 (m,
6H); 13C NMR (500 MHz, CDCl3) d 169.36, 166.66,
154.50, 135.74, 135.26, 129.24, 129.07, 127.11, 121.55,
51.40, 49.66, 33.03, 32.92, 25.89, 25.08, 25.03, 24.65,
21.70; IR (neat) 3117 (br), 2934 (m), 2857 (w), 1755 (m),
1678 (s), 1526 (m), 1451 (w), 1406 (s), 1371 (w), 1219
(m), 1152 (w), 968 (w), 731 (w), 692 (w) cmꢁ1; CIMS
(methane) m/z: 398 (M+H), 117.
3.3.1. Synthesis of tetrazole 3a. A vial was charged with 9a
(81 mg, 0.4 mmol), acetic acid (20 mL, 0.4 mmol), and a stir-
bar and tightly capped. The reagents were stirred for 10 min
at 0 ꢀC whereupon tert-butyl isocyanide (50 mL, 0.4 mmol)
was added. After stirring for 10 min at 0 ꢀC, the reaction
mixture was warmed to rt and stirred for 24 h. After evapo-
ration, the crude oil was purified by silica gel flash column
chromatography (1:1 hexanes/ethyl acetate) to give a color-
less oil (80 mg, 58%): 1H NMR (400 MHz, CDCl3) d 7.45 (s,
1H), 7.35 (m, 3H), 7.10 (m, 2H), 5.71 (dd, 2H, J¼16 Hz,
33 Hz), 1.97 (s, 3H), 1.75 (s, 3H), 1.39 (s, 9H); 13C NMR
(500 MHz, CDCl3) d 168.87, 166.28, 154.55, 133.96,
129.20, 128.69, 126.96, 52.31, 52.20, 28.55, 24.08, 20.69;
IR (neat) 3370 (br), 2972 (m), 2251 (w), 1757 (s), 1690
(s), 1526 (s), 1456 (s), 1370 (s), 1217 (s), 1138 (m), 1096
(m), 1014 (w), 907 (w), 729 (s) cmꢁ1; CIMS (methane)
m/z: 346 (M+H).
3.3.6. Tetrazole 3f. The product was purified by silica gel
flash column chromatography (3:1 hexanes/ethyl acetate
and 1:1 hexanes/ethyl acetate) to give a white solid (9 mg,
1
28%): mp¼138 ꢀC–141 ꢀC; H NMR (400 MHz, CDCl3)
3.3.2. Tetrazole 3b. The product was purified by silica gel
flash column chromatography (1:1 hexanes/ethyl acetate)
d 7.33 (s, 1H), 4.63 (m, 1H), 2.18 (s, 3H), 2.09 (s, 3H),
1.89–2.07 (m, 6H), 1.77 (m, 1H), 1.26–1.43 (m, 12H); 13C
NMR (400 MHz, CDCl3) d 168.66, 166.23, 153.28, 59.74,
52.38, 33.60, 33.14, 28.57, 25.82, 25.71, 25.03, 24.38,
21.33; IR (neat) 3422 (br), 2938 (m), 2861 (w), 1753 (m),
1
to give a colorless oil (16 mg, 31%): H NMR (400 MHz,
CDCl3) d 7.76 (s, 1H), 7.35 (m, 3H), 7.12 (m, 2H), 5.72
(dd, 2H, J¼16 Hz, 22 Hz), 3.32 (q, 2H, J¼6 Hz), 1.97 (s,

I. F. Cleꢀmenc¸on, B. Ganem / Tetrahedron 63 (2007) 8665–8669
8669
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1686 (s), 1638 (w), 1524 (m), 1456 (m), 1370 (m), 1215 (s),
1138 (m), 1094 (m), 1011 (w) cmꢁ1; CIMS (methane) m/z:
338 (M+H), 256.
3.3.7. Tetrazole 3g. The product was purified by silica gel
flash column chromatography (6:1 hexanes/ethyl acetate)
to give a colorless oil (13 mg, 28%): H NMR (400 MHz,
1
CDCl3) d 7.26 (s, 1H), 4.40 (m, 2H), 2.41 (m, 1H), 2.07 (s,
3H), 1.98 (m, 4H), 1.81 (m, 2H), 1.67 (m, 2H), 1.22–1.49
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31.91, 29.97, 29.29, 29.28, 29.14, 28.91, 28.58, 26.89,
25.75, 25.49, 25.43, 24.32, 22.80, 14.28; IR (neat) 3412
(br), 2930 (s), 2857 (s), 1761 (s), 1692 (s), 1518 (m), 1456
(m), 1368 (m), 1223 (m), 1121 (s), 1020 (w), 619
(w) cmꢁ1; CIMS (methane) m/z: 436 (M+H), 225.
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