Exploring the unique reactivities of heterobicyclic tetrazoles-access to functionally diverse and versatile heterocyclic scaffolds

Article abstract of DOI:10.1016/j.tet.2009.06.033

The benzylic hydrogen atom in oxabicyclic tetrazoles such as (6R,8R)-(8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazin-6-yl)-alkan ols (A, X=CH₂OH) is highly acidic, being alkylated in preference to a hydroxymethyl group with NaH and active

Full text of DOI:10.1016/j.tet.2009.06.033

Tetrahedron 65 (2009) 6656–6669
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploring the unique reactivities of heterobicyclic tetrazolesdaccess to
functionally diverse and versatile heterocyclic scaffolds
*
ˆ
ˆ
Stephen Hanessian , Benoıt Deschenes-Simard, Daniel Simard
Department of Chemistry, Universite´ de Montre´al, C. P. 6128, Succ. Centre-Ville, Montre´al, Que´bec, Canada H3C 3J7
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2009
Received in revised form 9 June 2009
Accepted 10 June 2009
Available online 16 June 2009
The benzylic hydrogen atom in oxabicyclic tetrazoles such as (6R,8R)-(8-phenyl-5,6-dihydro-8H-tetra-
zolo[5,1-c][1,4]oxazin-6-yl)-alkanols (A, X¼CH2OH) is highly acidic, being alkylated in preference to
a hydroxymethyl group with NaH and active alkyl halides. The enantioenriched products B now contain
a phenyl and alkyl group on a stereogenic benzylic carbon atom. The products are subject to b-elimi-
nation to give 1-{1-[3-propenyl]-1H-tetrazol-5-yl}-1-phenyl-alkanols. Cleavage of the propenyl chain
leads to chiral non-racemic 1-phenyl-1-(1H-tetrazol-5-yl)-alkanols C. Free-radical ‘anomeric’ azidation of
the oxabicyclic tetrazoles followed by reduction and ring closure with inversion of configuration pro-
duces azabicyclic tetrazoles D as constrained functionalized piperazines.
Dedicated to Professor Larry Overman,
friend, scholar, and chemist extraordinaire
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
these cycloaddition reactions compared to literature precedents,7 it
is clear that the proximity of the reacting azide and nitrile func-
The tetrazole nucleus has gained importance in recent years due
to its utility in wide-ranging areas of applications.1 In the field of
medicinal chemistry, the tetrazole nucleus is often used as a car-
boxyl group surrogate. Indeed several important drugs contain
a tetrazole moiety instead of a carboxyl group in their structures.2
Substituted tetrazoles are also useful as cis-amide isosteres,3 and as
conformationally rigid, flat, space-filling scaffolds.
We recently described a very mild and efficient Lewis acid-
mediated stereocontrolled synthesis of novel oxabicyclo tetrazoles
from arylidene acetals and alkylidene ketals4 of 1-azido-2,3-glyc-
erols in the presence of TMSCN (Scheme 1). The stereochemical
outcome of the reactions was rationalized on the basis of the ex-
istence of proximal 1a, and distal 1b, BF3-coordinated acetals in
solution.5 In the presence of TMSCN, the corresponding oxocarbe-
nium ion 2 and 3 would each give diastereomeric cyanohydrins 4, 5
and 6, 7 respectively.6 However, only the cyanohydrins arising from
oxocarbenium ion 3 could undergo a [2þ3]-cycloaddition to give
the cis- and trans-oxabicyclic tetrazoles 8 and 9 respectively. In
actual fact, preponderance of the cis-diastereomer 8 (>10:1 to
20:1) over the trans-isomer 9 is the result of a reversible equili-
bration of the cyanohydrins 6 and 7 to favor the diequatorial sub-
stitution pattern in the cis-isomer 8. Subjecting cyanohydrins 6 and
7 to BF3$Et2O led to 8 and 9 in the same ratio as in the original
reaction. Considering the extremely mild conditions required for
tionalities plays an important role. Fuzed tetrazoles were recently
obtained by the intramolecular iodocyclizations of
u-alkenyl
tetrazoles.8
2. Results and discussions
In this paper, we report on a series of site-selective reactions of
these oxabicyclic and azabicyclic tetrazoles.5 In the first of a series of
experiments, we studied the O-methylation and O-benzylation of the
oxabicyclic tetrazole 8, in the presence of silver oxide (Scheme 2).
Surprisingly, no reaction took place and starting material was re-
covered. We soon realized that oligomeric tetrazole–Ag complexes9
may have been formed, rendering the hydroxyl group ineffective as
a nucleophile. In the presence of benzyl bromide (1.5 equiv), sodium
hydride (2 equiv) and Bu4NI (0.1 equiv) at ꢀ15 ꢁC, compound 8, un-
derwent partial epimerization within 15 s to a mixture containing
25% of the trans isomer 9. This was followed by the formation of
epimeric C,O-dibenzyl oxabicyclic tetrazoles 10 and 11 in favor of the
trans isomer (5.3:1 with regard to the phenyl group, 46% yield), and
the C-benzylated products 12 and 13 in a trans/cis ratio of 4:1 (24%
yield). The hydroxyethyl analog 14 gave analogous products of C- and
O-alkylation, 15 and 16, albeit with higher ratios of the trans isomer
(1:7.5 cis/trans) in both cases. Treatment of the trans-hydroxymethyl
analogue 95 with NaH/THF and quenching with MeOH resulted in
anti-protonation to give 8 as the major isomer (4:1 cis/trans). Facile
formation of a benzylic carbanion in 8 in the presence of NaH at
ꢀ15 ꢁC was demonstrated by quenching with MeOD, and recovery
of the corresponding deuterated benzylic tetrazole (over 96%
* Corresponding author. Tel.: þ1 514 343 6738; fax: þ1 514 343 5728.
E-mail address: stephen.hanessian@umontreal.ca (S. Hanessian).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.033

S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
6657
Proximal
Distal
Coordination
Coordination
Ph
O
TMSCN
F3B
Ph
O
Ph
BF3•OEt2
O
O
O
N3
O
MeNO2
N3
N3
BF3
0 °C to rt
1a
1
1b
Ph
O
Ph
BF3O-
N3
O
N3
O-BF3
2
3
Ph
Ph
Ph
OR
N
N
BF3•OEt2
BF3•OEt2
53%
O
N3
O
O
CN
NC
N3
O
NR
N
N
OH
OH
OR
Ph
Ph
4
6
8
via
via
oxocarbenium
ions
oxocarbenium
ions
Ph
OR
N
N
BF3•OEt2
BF3•OEt2
6%
N3
CN
O
NC
N3
O
NR
N
N
OR
5
7
9
R = BF2, BF3
Scheme 1. Formation and reaction of isolated cyanohydrins.
Ph
Bn
N
Bn Ph
Ph
O
N
N
N
N
N
O
N
O
N
N
N
N
N
+
+
+
OBn
OH
OH
N
N
OH
OH
N
8
10
12
Ph
NaH (2 eq.)
BnBr (1.5 eq.)
N
N
O
N
TBAI (0.1 eq.)
THF, -15 °C
12h
N
OH
Ph
Bn Ph
Bn
N
Ph
O
N
N
N
N
N
N
O
N
O
8
N
+
OBn
13
11
9
(5.3:1 trans:cis)
(3.9:1 trans:cis)
46%
24%
Bn Ph
Ph Bn
Ph
NaH (2 eq.)
N
N
N
O
N
OR
N
N
O
OR
BnBr (1.5 eq.)
O
OH
N
N
+
N
N
N
N
TBAI (0.1 eq.)
THF, -15 °C
5h
14
15, R = H 58% (7.5:1, trans:cis)
16, R = Bn 17% (7.5:1, trans:cis)
Scheme 2. C-Alkylation and epimerization of oxabicyclic tetrazoles.
Table 1
incorporation). Similar results were obtained in the presence of
MeONa and quenching with MeOD.
C-Alkylation of oxabicyclic benzylic tetrazole anions
Ph
Ph R'
R' Ph
Base
R'X
Taking advantage of the reactivity of the benzylic anion in 8,
we treated the O-TBDPS ether 17a (R¼CH2OTBDPS, Table 1) with
benzyl bromide, methyl iodide, or allyl iodide which led to the
preponderant formation of the trans-products as major isomers.
With benzyl bromide and LiHMDS as a base, the ratio of trans/cis
alkylation products with respect to the phenyl group, was 95:5
as determined by HPLC and isolation of individual isomers 18a
and 19a (R¼CH2OTBDPS). That steric effects (or internal co-
ordination) were not responsible for the selectivity was ascer-
tained in the case of the methyl analog (17b, R¼Me, compare
entry 1 and 3 in Table 1). With the more reactive methyl and
allyl iodides, ratios were still in favor of the trans-isomers 18c,
d (R0¼Me, allyl, Table 1 entries 4, 5), although the nature of the
N
N
N
N
N
N
O
O
O
N
18
+
N
N
N
THF
T °C
N
N
R
R
R
19
cis
17
trans
Entry
R
R0X
Base
T (ꢁC) Ya (%) Products trans/cisb
1
2
3
4
5
CH2OTBDPS 17a BnBr
CH2OTBDPS 17a BnBr
NaH
ꢀ5 97
ꢀ78 87
ꢀ78 94
18a/19a 86:14
18a/19a 96:4
18b/19b 95:5
18c/19c
18d/19d 63:37
LiHMDS
LiHMDS
LiHMDS ꢀ100 94
Me
17b BnBr
CH2OTBDPS 17a Me–I
75:25
CH2OTBDPS 17a Allyl–I LiHMDS ꢀ100 95
Isolated yield.
a
b
HPLC ratio.

6658
S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
t-BuLi
THF
-78 °C
79%
Me Me
Me Me
N
N
N
N
O
OH
N
N
N
N
OH
N
OH
20
22
1) O3
2) H2O2
N
N
OH
99%
NH
25
t-BuLi
THF
N
N
N
OH
O
N
21
N
N
N
-78 °C
81%
N
OH
N
OH
23
Me Ph
Me Ph
1) O3
t-BuLi
Et2O
Me
Ph
O
2) H2O2
N
N
N
N
N
OH
OH
N
N
99%
-90 °C
94%
N
OTBDPS
NH
26
X-Ray
N
OTBDPS
N
24
X-Ray
18b
Scheme 3. Base-induced fragmentations of oxabicyclic tetrazoles.
electrophile and the base seem to be playing a role. Thus, unlike
the anti-selective protonation of Na dianions generated from 8 or
9 in the presence of NaH, alkylation of the benzylic anion (or its
delocalized variant on the tetrazole), of 17a and 17b occurred to
a major extent from the syn-side of the hydroxymethyl side-chain to
give trans-C-alkylated products as major isomers. The preponderance
of the trans-C-benzyl isomer 18a compared to the relatively lower
trans/cis ratios of the C-methyl 18c or C-allyl 18d analogs may be due
to steric factors associated with the size of the electrophile.
C-functionalized 1-H-tetrazoles 25, and 26, the latter harboring
a stereogenic center.10 Considering that the 1-H-tetrazoles are
isosteric with carboxylic acids,1 compound 26 can be regarded as
the tetrazole equivalent of a-methyl (R)-mandelic acid.
We next explored the reactivity of the benzylic carbon in the
oxabicyclic tetrazole 8 and 17 (R¼CH2OTBDPS) under free-radical
conditions (Scheme 4). Baruah and Bols11 had shown that O-ben-
zylidene acetals undergo an azido Hanessian ring-opening reaction
in the presence of IN3 in refluxing MeCN to give
u-azido benzoate
In the presence of t-BuLi at ꢀ78 ꢁC, the oxabicyclic tetrazoles 20,
esters. Guided by this result, we treated tetrazoles 17 and 8 with IN3
under the same conditions as described by the Danish group. The
benzylic azide 27 (58%, 15:1 cis/trans), and the rearranged N-phe-
nyloximino ether 28 (25%) were obtained as the major products
21, and 18b underwent smooth b-elimination to afford the corre-
sponding tertiary alcohols 22, 23, and 24 in excellent yields
(Scheme 3). Oxidative cleavage of the double bond led to
Ph
N
Ph N3
Ph
IN3
MeCN
36h
Δ
N
N
N
N
O
N
N
+
OR
O
N
O
N
N
N
N
OR
N
OR
28 25% R=TBDPS (X-Ray)
27 58% R=TBDPS
30 17% R=H
29 59% R=H
(X-Ray, R=p-bromobenzoate)
17 a R=TBDPS
8
R=H
MeO
OMe
MeO
MeO
OMe
OMe
MeO
OMe
N
N
IN3
N3
N
N
N
MeCN
24h
Δ
N
N
N
O
O
O
+
+
N
N
N
O
N
N
N
OTBDPS
N
OTBDPS
N
N
OTBDPS
OTBDPS
HO
31
55%
33
19%
34
8%
35
F
F
F
F
F
IN3 3 eq.
MeCN
96h
N
N
N
O
No Reaction
N
OTBDPS
Δ
32
Scheme 4. Radical azidation on tetrazoles.

S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
6659
ICl +
NaN3
MeCN
-10 °C
N3
O
N
N
N
N
IN3
O
N
N
N
OR
N
OR
MeCN
Δ
27 R=TBDPS
29 R=H
17a R=TBDPS
8
R=H
-
+ N3
via
Ph
Ph
I+, - I•
N
N
N
•N3, - HN3
O
O
N
N
N
OR
N
OR
H
N
H
N
N
N
N
N
N
N
N
N
O
O
O
N
N
N
N
OR
N
OR
N
OR
N
N
N
N
N
O
N
N
OR
28 R=TBDPS
30 R=H
Scheme 5. Suggested mechanism of the radical azidation.
(Scheme 4). The structure of the latter compound was ascertained
by a single crystal X-ray analysis. Similar results were obtained in
the radical azidation of the hydroxymethyl analogue 8, giving 29
(X-ray for p-bromobenzoate analogue), and 30 in 59% and 15%
yields respectively.
A plausible mechanism for this interesting distribution of prod-
ucts is shown in Scheme 5. Thus, abstraction of a benzylic hydrogen
radical leads to the corresponding oxocarbenium ion, which is
captured by azide ion to give the observed products. The imino-
lactone could result from participation of the phenyl group with the
loss of nitrogen, leading to a new aminophenyl oxocarbenium ion
which loses a proton. To shed some light on this proposal, we sub-
jected the 3,5-dimethoxy and 3,5-difluorophenyl tetrazoles 31 and
32 respectively to the same reaction conditions. Whereas 31 led to
the same distribution of azido and iminophenyl tetrazoles, 33and 34
respectively (with traces of the ketone 35), only starting material
was recovered in the case of 32. Thus, a phenonium ion participation
by the aryl group is not unlikely in this reaction.
The reduction of the azide group in 27 under a variety of condi-
tions led to entirely different products (Scheme 6). Treatment of 27
with magnesium powder12 in MeOH at 0 ꢁC led to the diastereomeric
amines 36 and 37 in a ratio of 2.2:1. The assigned stereochemistry to
Ph
Ph
N
N
N
N
Mg
NH2
NH2
N
N
N
N
MeOH
0 °C
80%
HO
HO
36
OTBDPS
OTBDPS
37
(dr = 2.2:1)
1) PMe3
Ph N3
Ph
THF
N
O
2) NH4OH 28%
N
O
N
N
N
N
OTBDPS
N
3) Ac2O, Pyr.
N
N
27
79%
O
AcO
38
OTBDPS
Ph NHAc
SH
N
N
2,6-lutidine
O
N
OTBDPS
CHCl3
Δ
39
78%
Scheme 6. Functionalized cyclic and acyclic tetrazoles.

6660
S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
Ph
Ph
1) Boc2O
10% Et3N in MeOH
30 °C, 99%
Ph
1) TFA, DCM
-15 °C to r.t.
2) (i-Pr)2EtN
N
N
N
N
NHBoc
NH2
N
N
NH
N
N
N
N
N
N
OTBDPS
2) Ms2O, DCM, 0 °C to rt
100%
MeOH, Δ, 71%
81:19, cis:trans
42
MsO
40
HO
36
OTBDPS
OTBDPS
[O]
Ph
Ph
N
N
N
N
N
MeOCOCl
NCO2Me
OTBDPS
N
OTBDPS
N
42
N
NaHCO3
Neat,60 °C
87%
N
Traces
44
45
[O]
Ph
Ph
1) Boc2O
10% Et3N in MeOH
30 °C, 98%
Ph
1) TFA, DCM
-15 °C to r.t.
2) (i-Pr)2EtN
N
N
N
NH2
NHBoc
N
N
NH
N
N
N
N
N
N
OTBDPS
2) Ms2O, DCM, 0 °C to rt
100%
N
MeOH, Δ, 77%
HO
MsO
41
10:90, cis:trans
OTBDPS
OTBDPS
43 (X-Ray)
37
Scheme 7. Access to functionalized azabicyclic tetrazoles.
37 was based on subsequent transformations. The imine resulting
from the treatment of 27 with Ph3P under Staudinger conditions13
was hydrolyzed in the workup process to the ketone which was
acetylated to give 38. Reduction of the azide group with thiolacetic
acid14 in the presence of 2,6-lutidine at reflux temperature in CHCl3
led to the oxabicyclic N-acetyl tetrazole 39 in 78% yield.
The aminotetrazole analog 36 was a suitable precursor to access
a novel azabicyclic tetrazole nucleus (Scheme 7). Thus, Boc pro-
tection and mesylation of 36 afforded 40 in quantitative yield.
Cleavage of the N-Boc group and treatment with Hu¨nig’s base
effected intramolecular displacement of the mesylate to give the
novel azabicyclic tetrazole 42 as an 81:19 cis/trans mixture. Alter-
natively, similar treatment of 37 gave 41 and 43 as a 10:90 mixture
of cis/trans isomers. The structure and stereochemistry of the major
trans-isomer 43 was determined by a single crystal X-ray analysis.
Application of a free-radical azidation reaction provides access
to benzylic anomeric azides which can be manipulated in a variety
of ways, including the formation of hitherto unknown azabicyclic
tetrazoles as constrained functionalized piperazines. The oxabicy-
clic tetrazoles are also amenable to classical chemical modification
at the hydroxymethyl (and aromatic group), to provide a host of
functionally diverse analogs.15
The novel tetrazole analogs described herein will be useful
scaffolds in a variety of contexts relative to medicinal chemistry,
molecular recognition, catalysis, and related applications.
4. Experimental
4.1. General information
Thus, it appears that the
a-aminobenzyl tetrazoles are prone to
Solvents were distilled under positive pressure of dry argon
before use and dried by standard methods; THF and ether, from Na/
benzophenone; and CH2Cl2, from CaCl2. All commercially available
reagents were used without further purification. NMR (1H, 13C)
spectra were recorded on AMX-300, ARX-400, AV-700, AV-500, AV-
400 and AV-300 spectrometers. Low- and high-resolution mass
spectra were recorded on AEI-MS 902, MS-50 or LC-MSD TOF
spectrometers using fast atom bombardment (FAB) or electrospray
techniques. IR spectra were recorded on a Perkin–Elmer Spectrum
One Version B Spectrometer. Analytical thin-layer chromatography
was performed on Merck 60F254 pre-coated silica gel plates. Visu-
alization was performed by ultraviolet light and/or by staining with
ceric ammonium molybdate or potassium permanganate. Flash
partial epimerization under the conditions of the base-catalyzed
azacycle formation. Curiously, the oily tetrazole 42 was slowly
transformed to the cyclic imine 44 when exposed to air. The same
product was also observed with the crystalline diastereomer 43,
albeit only after several weeks of standing. Protection of the amino
group in 42 as the methyl carbamate gave 45.
Finally, having easy access to the oxabicyclic scaffold 8, we ex-
plored a diversification protocol involving the hydroxymethyl
group as shown in Scheme 8. Oxidation of 8 under Jones conditions
followed by esterification gave the methyl esther 46 in high overall
yield. Tosylation to 47, displacement with azide to 48 and selective
catalytic reduction led to the aminomethyl analog 49 in excellent
yield. The easily obtained iodide 50 was transformed into the deoxy
17b, the endocyclic enol ether 51, and the exocyclic enol ether 52,
using standard methodology (Scheme 8). Treatment of 50 with Zn
dust led to the ring-opened benzylic alcohol tetrazole analog 53.
column chromatography was performed using (40–60
gel at increased pressure. Normal phase HPLC analyses were per-
formed on Phenomenex Luna 3 silica(2) (3 silica gel) column for
mm) silica
m
m
diastereomeric excess. All melting points are uncorrected. All
evaporations were carried out under reduced pressure at 40 ꢁC.
3. Conclusion
5. Experimental procedures
In conclusion, we have uncovered interesting reactivities asso-
ciated with the benzylic carbon of oxabicyclic tetrazoles exempli-
fied by 8. Remarkably facile C-alkylation led to the generation of
enantioenriched quaternary substituted analogs that undergo
5.1. General method for the formation of oxabicyclic
tetrazoles5
b-elimination to the corresponding tertiary alcohols. Oxidative
To a solution of pure azido acetal at 0 ꢁC in dry nitromethane
(0.12 M) (ꢂ99.0% from Aldrich) is added TMSCN (1.2 equiv) then
BF3$OEt2 dropwise over 2 min. The mixture is stirred at 0 ꢁC for
cleavage of the resulting allylic alcohols gives novel chiral, non-
racemic 5-substituted 1-H-tetrazoles.

S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
6661
Ph
Ph
N
N
1) Jones Oxidation
N
N
O
O
N
N
N
OH
N
OMe
2) MeOH
H2SO4 Cat.
MgSO4
O
8
46
84% For two steps
Ph
O
Ph
Ph
NaN3
N
N
N
N
N
Pyridine, TsCl
H2, Pd/C
Bu4NBr
N
O
O
N
N
DMF
OTs
MeOH
92%
N
N
N3
N
NH2
DCM, DMAP
92%
N
70 °C
95%
49
47
48
Ph
Ph
N
N
N
N
OH
O
Zn, NH4Cl
N
N
N
OH
EtOH (95%):THF
N
(2:1)
8
53
Δ
98%
Ph
Ph
PPh3, Imidazole,
I2
N
N
N
N
O
O
DBU
DME
Δ
N
N
N
N
I
N
N
THF
40 °C
98%
50
51
95%
Ph
Raney Nickel, H2
Et2NH, MeOH
100%
N
N
AgF
O
Pyridine
90%
52
Ph
N
O
N
N
N
17b
Scheme 8. Side-chain functionalized oxabicyclic tetrazoles.
30 min, then warmed up to room temperature. After 12 h, metha-
nol is added (30 equiv) and the mixture is stirred for 15 min.
Evaporation under reduced pressure of the solution yields an oil
which can be purified by flash chromatography (EtOAc/hexanes,
80:20). To remove the remaining traces of BF3 complexed to the
tetrazole, the solution is filtered on aluminum oxide (activated,
basic, Brockmann I) pad with ethyl acetate/MeOH mixture or it was
recrystallized from ethyl acetate/MeOH mixture.
cmꢀ1) 3390, 3064, 3013, 2934, 1729, 1668, 1598, 1495, 1478, 1448,
1382, 1329, 1274, 1218, 1188, 1150, 1063, 1002, 986, 922, 880, 850,
755, 716, 698; ESI/MS (m/z) [Mþ1]þ: 233.1; HRMS (FAB) for
C11H12N4O2: calcd [M]þ 232.0960; found 232.0971; [
a]
ꢀ90.4 (c
D
1.00, MeOH) (>99% ee).
5.1.2. (6S,8R)-2-(8-Phenyl-5,6-dihydro-8H-tetrazolo[5,1-
c][1,4]oxazin-6-yl)-ethanol (14)
This compound was obtained according to the general pro-
cedure for tetrazoles. From 4-azidomethyl-2-phenyl-[1,3]dioxane5
(150 mg, 0.684 mmol) was obtained tetrazole 14 as a white solid
(cis/trans, 3:1), (118 mg, 70%). Major cis-isomer: mp 98–100 ꢁC; 1H
5.1.1. (6R,8R)-(8-Phenyl-5,6-dihydro-8H-tetrazolo[5,1-
c][1,4]oxazin-6-yl)-methanol (8) and (6R,8S)-(8-phenyl-5,6-
dihydro-8H-tetrazolo[5,1-c][1,4]oxazin-6-yl)-methanol (9)
These compounds were obtained according to the general pro-
cedure for tetrazoles. From 15 (257 mg, 1.25 mmol) were obtained
tetrazoles 8 and 9 as a white solids (cis/trans, 19:1), (273 mg, 94%).
Major cis-isomer (8): mp 195–197 ꢁC; 1H NMR (400 MHz, CD3OD)
NMR (300 MHz, CD3OD)
d (ppm) 7.46–7.39 (m, 5H), 6.05 (s, 1H),
4.71 (dd, 1H, J¼0.99, 9.49 Hz), 4.40–4.33 (m, 1H), 4.35 (dd, 1H,
J¼10.7, 11.7 Hz), 3.81–3.76 (m, 2H), 2.02–1.96 (m, 2H); 13C NMR
(75 MHz, CD3OD) d (ppm) 153.2, 136.7, 129.4, 128.7,128.2, 75.3, 71.5,
d
(ppm) 7.48–7.39 (m, 5H), 6.06 (s, 1H), 4.69 (dd, 1H, J¼2.7, 12.6 Hz),
57.5, 50.2, 35.5; FTIR (KBr Disk, cmꢀ1) 3413, 3060, 3041, 2991, 2942,
1498, 1475, 1458, 1442, 1410, 1385, 1348, 1291, 1246, 1201, 1153,
1096, 1070, 1047, 1028, 997, 897, 747, 694, 679; ESI/MS (m/z)
[Mþ1]þ: 247.2; HRMS (ESI) for C11H12N4O2: calcd [M]þ 247.1189;
4.42 (t, 1H, J¼11.4 Hz), 4.34–4.28 (m, 1H), 3.87 (d, 2H, J¼4.7 Hz); 13C
NMR (100 MHz, CD3OD)
d (ppm) 153.1, 136.3, 129.5, 128.3, 128.2,
75.4, 74.8, 62.0, 47.3; FTIR (KBr Disk, cmꢀ1) 3348, 3066, 3032, 2993,
2929, 2897, 2872, 1524, 1497, 1477, 1457, 1445, 1429, 1374, 1345,
1280, 1265, 1247, 1153, 1075, 1048, 991, 926, 888, 769, 755; ESI/MS
(m/z) [Mþ1]þ: 233.1; HRMS (FAB) for C11H12N4O2: calcd [M]þ
found 247.11832; [
a]
D ꢀ65.5 (c 1.50, MeOH).
5.1.3. (trans- and cis-) 8-Benzyl-6-benzyloxymethyl-8-phenyl-5,6-
dihydro-8H-tetrazolo[5,1-c][1,4]oxazine (10, 11) and (trans- and
cis-) (8-benzyl-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-
c][1,4]oxazin-6-yl)-methanol (12, 13)
232.0960; found 232.0952; [
a
]
D
ꢀ27.3 (c 1.00, MeOH) (>99% ee).
Minor trans-isomer (9): mp 100–102 ꢁC; 1H NMR (300 MHz,
CD3OD)
(ppm) 7.40–7.32 (m, 5H), 6.45 (s, 1H), 4.62 (dd,1H, J¼3.64,
d
12.8 Hz), 4.33 (dd, 1H, J¼10.0, 12.8 Hz), 4.12–4.04 (m, 1H), 3.78 (d,
To a solution of tetrazole 8 (50 mg, 0.215 mmol) in THF (1.44 mL
2H, J¼4.75 Hz); 13C NMR (100 MHz, CD3OD)
d
(ppm) 151.3, 135.6,
(0.15 M)) at ꢀ15 ꢁC were added benzyl bromide (38.4
mL,
129.2, 129.1, 127.3, 72.3, 68.8, 62.2, 47.5; FTIR (thin film) (CHCl3,
0.323 mmol, 1.5 equiv) and TBAI (8 mg, 0.0215 mmol, 0.1 equiv),

6662
S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
followed by 60% NaH in mineral oil (17 mg, 0.413 mmol, 2 equiv).
The mixture was stirred for 12 h, then quenched with few drops of
aqueous NaHCO3. Silica and MeOH were added and the mixture
was evaporated under reduced pressure to make a dry solid that
was purified by flash chromatography (EtOAc/hexanes, 20:80 to
90:10). For 10, 11 C- and O-benzylated products obtained as a col-
orless gum (40.5 mg, 46%) and as a mixture of diastereomeres
1093, 1069, 1030, 750, 700; ESI/MS (m/z) [Mþ1]þ: 427.3; HRMS
(ESI) for C26H26N4O2: calcd [Mþ1]þ 427.21285; found 427.21314.
Major trans-isomer (15): 1H NMR (300 MHz, CDCl3)
d (ppm) 7.61–
7.57 (m, 2H), 7.43–7.32 (m, 3H), 7.21–7.12 (m, 3H), 7.06–7.02 (m,
2H), 4.37 (dd, 1H, J¼3.10, 12.6 Hz), 4.14–4.05 (m, 1H), 3.96–3.92 (m,
2H), 3.89–3.84 (m, 1H), 3.55 (d, 1H, J¼13.9 Hz), 3.47 (d, 1H,
J¼13.9 Hz), 2.11–1.93 (m, 2H), 1.81 (br s, 1H); 13C NMR (75 MHz,
(5.3:1): 1H NMR (400 MHz, CDCl3)
d
(ppm) 7.84–7.81 (m, 8/25H),
CDCl3) d (ppm) 153.5, 139.5, 134.7, 131.4, 130.8, 129.2, 129.1, 128.8,
7.69–7.67 (m, 42/25H), 7.44–7.30 (m, 8H), 7.19–7.10 (m, 3H), 7.08–
7.06 (m, 42/25H), 6.99–6.97 (m, 8/25), 4.66 (d, 21/25H, J¼12.1 Hz),
4.64 (d, 21/25H, J¼12.2 Hz), 4.61 (d, 4/25H, J¼12.0 Hz), 4.56 (d, 4/
25H, J¼12.1 Hz), 4.73 (dd, 4/25H, J¼2.98, 12.9 Hz), 4.37 (dd, 21/25,
J¼3.16, 12.6 Hz), 4.18–4.11 (m, 1H), 3.97–3.91 (m, 1H), 3.88 (dd, 21/
25H, J¼5.23, 10.4 Hz), 3.81–3.74 (m, 1H), 3.69 (dd, 4/25H, J¼5.96,
128.7, 128.2, 127.5, 126.3, 126.2, 81.3, 67.7, 59.2, 50.17, 50.13, 35.4;
ESI/MS (m/z) [Mþ1]þ: 337.2.
5.1.5. cis-6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-phenyl-5,6-
dihydro-8H-tetrazolo[5,1-c][1,4]oxazine (17a)
To a solution of tetrazole 8 (1 g, 4.13 mmol) in DMF (14.4 mL
(0.3 M)) at room temperature was added imidazole (813 mg,
12.9 mmol, 3 equiv) then, TBDPS-Cl (1.65 mL, 6.46 mmol, 1.5 equiv).
The mixture was stirred for 5 h, then quenched with water. The so-
lution was extracted with ether 5 times and extracts were dried on
Na2SO4. Evaporation under reduced pressure yielded an oil which
was purified by flash chromatography (EtOAc/hexanes, 25:75 to
35:65) to give 17a as a white solid (1.80 g, 89%): 1H NMR (400 MHz,
10.1 Hz), 3.56–3.41 (m, 2H); 13C NMR (100 MHz, CDCl3)
d (ppm)
152.8, 138.7, 137.1, 134.0, 130.7, 128.4, 128.2, 128.1, 127.6, 127.3, 127.2,
126.5, 125.5, 80.6, 73.3, 69.2, 67.9, 49.5, 47.1; ESI/MS (m/z) [Mþ1]þ:
413.2, [MþNa]þ: 435.1; HRMS (ESI) for C25H25N4O2: calcd [Mþ1]þ
413.1972; found 413.19776; for C25H24N4NaO2: calcd [MþNa]þ
435.17915; found 435.17983. For 12, 13 C-benzylated products
obtained as a colorless gum (16.5 mg, 24%) and as a mixture of
diastereomeres (3.9:1): 1H NMR (400 MHz, CDCl3)
d
(ppm) 7.81–
CDCl3)
d
(ppm) 7.69 (d, 4H, J¼7.54 Hz), 7.50–7.37 (m,11H), 5.96 (s,1H),
7.80 (m, 4/10H), 7.66–7.61 (m, 16/10H), 7.42–7.30 (m, 32/10H), 7.22–
7.13 (m, 28/10H), 7.06–7.03 (m, 16/10H), 6.97–6.95 (m, 4/10H), 4.48
(dd, 2/10H, J¼2.74, 12.9 Hz), 4.32 (d, 8/10H, J¼9.44 Hz), 4.23 (dd, 2/
10H, J¼9.44, 12.9 Hz), 4.08–3.99 (m, 24/10H), 3.95 (dd, 2/10H,
J¼5.74, 10.5 Hz), 3.88–3.84 (m, 12/10H), 3.79 (d, 2/10H, J¼14.1 Hz),
3.59 (d, 8/10H, J¼14.0 Hz), 3.54–3.45 (m, 1H), 2.10 (br s, 1H); 13C
4.78 (dd, 1H, J¼2.64, 12.8 Hz), 4.45 (t, 1H, J¼11.6 Hz), 4.32–4.25 (m,
1H), 4.09 (dd, 1H, J¼4.67, 10.9 Hz), 3.96 (dd, 1H, J¼5.99, 10.9 Hz), 1.11
(s, 9H); 13C NMR (75 MHz, CDCl3)
d (ppm) 152.6,136.1,136.04,135.96,
133.3, 133.1, 130.5, 129.8, 129.2, 128.40, 128.36, 128.1, 75.5, 74.4, 64.4,
48.1, 27.3, 20.0; FTIR (thin film) (CHCl3, cmꢀ1) 3070, 2931, 2857, 1472,
1428, 1391, 1362, 1133, 1113, 1056, 991, 823, 804, 741, 701; ESI/MS
(m/z) [Mþ1]þ: 471.3; HRMS (ESI) for C27H30N4O2Si: calcd [Mþ1]þ
471.22108; found 471.22025.
NMR (100 MHz, CDCl3)
d (ppm) 152.6, 138.6, 134.0, 130.5, 128.4,
128.3, 127.4, 126.7, 125.4, 80.4, 68.6, 62.2, 49.5, 46.0; ESI/MS (m/z)
[Mþ1]þ: 323.1, [MþNa]þ: 345.1; HRMS (ESI) for C18H19N4O2: calcd
[Mþ1]þ 323.15025; found 323.15178; for C18H18N4NaO2: calcd
[MþNa]þ 345.1322; found 345.13361.
5.1.6. trans-8-Benzyl-6-(tert-butyl-diphenyl-silanyloxymethyl)-8-
phenyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazine (18a)
To a solution of tetrazole 17a (100 mg, 0.212 mmol) in THF
(1.4 mL (0.15 M)) at ꢀ78 ꢁC was added benzyl bromide (0.028 mL,
0.234 mmol, 1.1 equiv), followed by LiHMDS 1 M in THF (0.256 mL,
0.255 mmol, 1.2 equiv) dropwise. The mixture was stirred for 4 h,
then quenched with aqueous NaHCO3. The solution was extracted
with ether and extracts were dried on Na2SO4. Evaporation under
reduced pressure yielded an oil which was purified by flash chro-
matography (EtOAc/hexanes, 15:85 to 30:70) to give 18a as a col-
orless gum (103 mg, 87%). Major trans-isomer (18a): 1H NMR
5.1.4. (trans- and cis-) 8-Benzyl-6-(2-benzyloxy-ethyl)-8-phenyl-
5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazine (16) and (trans- and
cis-) 2-(8-benzyl-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-
c][1,4]oxazin-6-yl)-ethanol (15)
To a solution of tetrazole 14 (50 mg, 0.203 mmol) in THF
(1.40 mL (0.15 M)) at ꢀ15 ꢁC were added benzyl bromide (36
mL,
0.305 mmol, 1.5 equiv) and TBAI (7.5 mg, 0.0203 mmol, 0.1 equiv),
followed by 60% NaH in mineral oil (16.0 mg, 0.406 mmol, 2 equiv).
The mixture was stirred for 12 h, then quenched with few drops of
aqueous NaHCO3. Silica and MeOH were added and the mixture
was evaporated under reduced pressure to make a dry solid that
was purified by flash chromatography (EtOAc/hexanes, 20:80 to
90:10) to give 15 and 16 as colorless gums. Major trans-isomer (16):
(300 MHz, CDCl3)
d (ppm) 7.79–7.72 (m, 6H), 7.57–7.45 (m, 6H),
7.43–7.35 (m, 3H), 7.19–7.09 (m, 5H), 4.36 (dd, 1H, J¼2.99, 12.4 Hz),
4.16–4.08 (m, 1H), 4.04–3.89 (m, 3H), 3.57 (d, 1H, J¼14.0 Hz), 3.48
(d, 1H, J¼14.0 Hz), 1.15 (s, 9H); 13C NMR (75 MHz, CDCl3)
d (ppm)
154.2, 140.0, 136.5, 136.4, 135.3, 133.4, 131.9, 131.0, 129.6, 129.3,
128.8, 128.5, 127.7, 126.8, 81.8, 70.7, 64.7, 50.8, 48.1, 27.6, 20.1; FTIR
(thin film) (CHCl3, cmꢀ1) 3068, 3032, 2958, 2930, 2893, 2858, 1495,
1471, 1454, 1445, 1428, 1129, 1113, 1087, 1065, 1021, 824, 771, 743,
701; ESI/MS (m/z) [Mþ1]þ: 561.3; HRMS (ESI) for C34H36N4O2Si:
calcd [Mþ1]þ 561.26803; found 561.26858.
1H NMR (400 MHz, CDCl3)
d (ppm) 7.64–7.61 (m, 2H), 7.37–7.22 (m,
8H), 7.16–7.10 (m, 3H), 7.07–7.04 (m, 2H), 4.51 (d, 1H, J¼11.7 Hz),
4.46 (d, 1H, J¼11.7 Hz), 4.29 (dd, 1H, J¼3.16, 12.7 Hz), 4.09–4.03 (m,
1H), 3.80 (dd, 1H, J¼10.8, 12.7 Hz), 3.75–3.71 (m, 2H), 3.53 (d, 1H,
J¼13.9 Hz), 3.45–3.42 (d, 1H, J¼13.9 Hz), 2.13–1.98 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d (ppm) 153.0, 139.3, 137.6, 134.4, 131.0,
128.5, 128.3, 127.7, 127.5, 127.5, 126.7, 125.7, 80.5, 73.1, 66.6, 65.4,
49.8, 49.6, 32.9; FTIR (thin film) (CHCl3, cmꢀ1) 3063, 3031, 2925,
2863, 1719, 1495, 1453, 1445, 1366, 1273, 1153, 1132, 1092, 1075,
1028, 768, 748, 699; ESI/MS (m/z) [Mþ1]þ: 427.3; HRMS (ESI) for
C26H26N4O2: calcd [Mþ1]þ 427.21285; found 427.21314. Minor cis-
5.1.7. trans-8-Benzyl-6-methyl-8-phenyl-5,6-dihydro-8H-
tetrazolo[5,1-c][1,4]oxazine (18b)
To a solution of tetrazole 17b (108 mg, 0.499 mmol) in THF
(3.33 mL (0.15 M)) at ꢀ78 ꢁC was added benzyl bromide (65
mL,
5.49 mmol, 1.1 equiv), followed by LiHMDS 1 M in THF (0.60 mL,
0.60 mmol, 1.2 equiv) dropwise. The mixture was stirred for 4 h,
then quenched with aqueous NaHCO3. The solution was extracted
with ether and extracts were dried on Na2SO4. Evaporation under
reduced pressure yielded an oil which was purified by flash chro-
matography (EtOAc/hexanes, 15:85 to 30:70) to give 18b as a col-
orless gum (144 mg, 94%) Major trans-isomer (18b): 1H NMR
isomer (16): 1H NMR (400 MHz, CDCl3)
d (ppm) 7.80–7.77 (m, 2H),
7.39–7.26 (m, 8H), 7.17–7.07 (m, 3H), 6.92–7.90 (m, 2H), 4.58–4.47
(m, 3H), 4.03 (dd, 1H, J¼10.2, 12.7 Hz), 3.95–3.90 (m, 1H), 3.73 (d,
1H, J¼14.1 Hz), 3.68–3.62 (m, 2H), 3.46 (d, 1H, J¼14.1 Hz), 2.14–1.99
(m, 2H); 13C NMR (100 MHz, CDCl3)
d (ppm) 154.2, 140.4, 137.6,
134.5, 130.3, 128.4, 128.0, 127.8, 127.7, 127.5, 126.9, 125.7, 78.7, 73.1,
68.2, 65.4, 49.9, 47.5, 32.8; FTIR (thin film) (CHCl3, cmꢀ1) 3063,
3031, 2925, 2864, 1719, 1496, 1454, 1446, 1365, 1274, 1241, 1146,
(300 MHz, CDCl3)
d (ppm) 7.70–7.63 (m, 2H), 7.44–7.33 (m, 3H),
7.19–7.07 (m, 5H), 4.29 (dd, 1H, J¼3.04, 12.5 Hz), 4.06–3.96 (m, 1H),

S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
6663
3.72 (dd, 1H, J¼10.7, 12.5 Hz), 3.52 (d, 1H, J¼13.9 Hz), 3.43 (d, 1H,
J¼13.9 Hz), 1.50 (d, 3H, J¼6.20 Hz); 13C NMR (75 MHz, CDCl3)
12.0 Hz), 4.09 (dd, 1H, J¼4.36, 10.8 Hz), 4.01 (dd, 1H, J¼5.75,
10.8 Hz), 3.12 (dd, 1H, J¼6.69, 14.6 Hz), 3.05 (dd, 1H, J¼7.02,
d
(ppm) 154.0, 140.0, 135.4, 131.9, 129.6, 129.3, 128.5, 127.7, 126.6,
14.7 Hz),1.15 (s, 9H); 13C NMR (75 MHz, CDCl3)
d (ppm) 155.5, 140.4,
81.6, 66.2, 51.7, 50.8, 18.8; FTIR (thin film) (CHCl3, cmꢀ1) 3036, 3032,
2980, 2930, 1495, 1442, 1388, 1373, 1150, 1076, 1018, 959, 771, 748,
700; ESI/MS (m/z) [Mþ1]þ: 307.1; HRMS (ESI) for C18H18N4O: calcd
[Mþ1]þ 307.15534; found 307.15655.
136.44, 136.41, 133.5, 133.4, 131.5, 131.0, 129.1, 129.0, 128.8, 126.8,
120.8, 79.1, 70.6, 64.7, 48.9, 45.2, 27.6, 20.1; FTIR (thin film) (CHCl3,
cmꢀ1) 3071, 2956, 2930, 2892, 2857, 1641, 1598, 1494, 1471, 1446,
1428, 1155, 1112, 1073, 1064, 993, 921, 823, 808, 741, 702; ESI/MS
(m/z) [Mþ1]þ: 511.3; HRMS (ESI) for C30H34N4O2Si: calcd [Mþ1]þ
511.25238; found 511.25367.
5.1.8. (trans- and cis-) 6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-
methyl-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazine
(18c, 19c)
5.1.10. (8,8-Dimethyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazin-
6-yl)methanol (20)
To a solution of tetrazole 17a (350 mg, 0.744 mmol) inTHF (7.4 mL
(0.1 M)) at ꢀ100 ꢁC was added methyl iodide (51
mL, 0.818 mmol,
This compound was obtained according to the general procedure
for tetrazoles. From 4-azidomethyl-2,2-dimethyl-[1,3]dioxo-
lane5 (2.16 g, 13.7 mmol) was obtained tetrazole 20 as a white
1.1 equiv), followed by LiHMDS 1 M in THF (0.892 mL, 0.892 mmol,
1.2 equiv) dropwise. The mixture was stirred for 4 h, then quenched
with aqueous NaHCO3. The solution was extracted with ether and
extracts were dried on Na2SO4. Evaporation under reduced pressure
yielded an oil which was purified by flash chromatography (EtOAc/
hexanes, 15:85 to 30:70) to give 18c and 19c as colorless gums
(338 mg, 94%). Major trans-isomer (18c): 1H NMR (400 MHz, CDCl3)
solid (1.90 g, 75%): 1H NMR (400 MHz, CD3OD)
d (ppm) 4.62
(dd, 1H, J¼2.82, 12.2 Hz), 4.32–4.28 (m, 1H), 4.22 (dd, 1H, J¼10.7,
12.2 Hz), 3.83–3.82 (m, 2H), 1.68 (s, 3H), 1.66 (s, 3H); 13C NMR
(100 MHz, CD3OD)
d (ppm) 157.8, 74.3, 70.3, 63.1, 48.3, 28.8,
25.9; FTIR (KBr Disk, cmꢀ1) 3497, 2995, 2968, 2926, 2886, 1478,
1439, 1411, 1385, 1363, 1343, 1276, 1253, 1237, 1189, 1162, 1142,
1070, 1033, 995, 976, 898, 825, 771; ESI/MS (m/z) [Mþ1]þ:
185.1; HRMS (ESI) for C7H12N4O2: calcd [Mþ1]þ 185.10330;
found 185.10410.
d
(ppm) 7.73–7.69 (m, 4H), 7.54–7.39 (m, 8H), 7.38–7.35 (m, 3H), 4.50
(dd,1H, J¼3.42, 12.7 Hz), 4.28 (dd, 1H, J¼10.8,12.6 Hz), 4.09–4.05 (m,
1H), 4.02 (dd, 1H, J¼5.33, 10.7 Hz), 3.89 (dd, 1H, J¼5.02, 10.8 Hz), 1.94
(s, 3H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 154.2, 140.0,
135.3,135.1,132.3,132.2,129.71,129.66,128.5,128.0,127.5,125.0, 77.8,
68.9, 63.6, 47.2, 30.7, 26.4, 18.9; FTIR (thin film) (CHCl3, cmꢀ1) 3071,
2932, 2859, 1494, 1472, 1447, 1428, 1371, 1221, 1166, 1114, 1049, 997,
967, 911, 824, 808, 770, 738, 702; ESI/MS (m/z) [Mþ1]þ: 485.3; HRMS
(ESI) for C28H32N4O2Si: calcd [Mþ1]þ 485.2367; found 485.23625.
5.1.11. 3-[5-(1-Hydroxy-1-methylethyl)-tetrazol-1-yl]propenol (22)
To a solution of 20 (147 mg, 0.80 mmol) in THF (8.0 mL (0.1 M))
at ꢀ78 ꢁC was added dropwise t-BuLi 1.7 M in pentane (1.17 mL,
2.00 mmol, 2.5 equiv). The reaction mixture was stirred 30 min,
then quenched slowly with few drops of aqueous NH4Cl. Silica and
MeOH were added and the mixture was evaporated under reduced
pressure to a dry solid that purified by flash chromatography
(EtOAc/hexanes1:1) to give 22 as a white solid (116 mg, 79%): 1H
Minor cis-isomer (19c): 1H NMR (400 MHz, CDCl3)
d (ppm) 7.78–7.71
(m, 6H), 7.51–7.31 (m, 9H), 4.75 (d, 1H), 4.33–4.25 (m, 2H), 4.10 (dd,
1H, J¼4.14,10.7 Hz), 3.99 (dd,1H, J¼5.52, 10.7 Hz), 1.96 (s, 3H),1.13 (s,
9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 154.9, 141.1, 135.2, 132.3,
132.2, 129.7, 128.0, 127.9, 127.6, 125.1, 69.0, 63.7, 47.8, 26.9, 26.4, 18.9;
FTIR (thin film) (CHCl3, cmꢀ1) 3072, 2932, 2859, 1496, 1472, 1446,
1428,1377,1232,1114,1068, 944, 910, 824, 767, 741, 701; ESI/MS (m/z)
[Mþ1]þ: 485.5; HRMS (ESI) for C28H32N4O2Si: calcd [Mþ1]þ
485.2367; found 485.23619.
NMR (400 MHz, CD3OD)
d
(ppm) 7.81 (dt, 1H, J¼2.01, 14.0 Hz), 6.75
(dt, 1H, J¼4.85, 14.0 Hz), 4.33 (dd, 2H, J¼1.99, 4.85 Hz), 1.70 (s, 6H);
13C NMR (100 MHz, CD3OD)
d
(ppm) 157.8, 125.8, 121.3, 67.4, 58.7,
27.9; FTIR (thin film) (CHCl3, cmꢀ1) 3306, 2991, 2901, 1675, 1459,
1414, 1372, 1260, 1183, 1148, 1105, 1007, 968, 944, 923, 865; ESI/MS
(m/z) [Mþ1]þ: 185.1.
5.1.9. (trans- and cis-) 8-Allyl-6-(tert-butyl-diphenyl-
silanyloxymethyl)-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-c]-
[1,4]oxazine (18d and 19d)
5.1.12. 2-(50,60-Dihydrospiro[cyclohexane-1,80-tetrazolo[5,1-c]-
[1,4]oxazine]-60-yl)ethanol (21)
To a solution of tetrazole 17a (50.0 mg, 0.106 mmol) in THF
This compound was obtained according to the general pro-
cedure for tetrazoles. From 2-(azidomethyl)-1,5-dioxaspir-
o[5.5]undecane5 (150 mg, 0.71 mmol) was obtained tetrazole 21 as
(1.1 mL (0.1 M)) at ꢀ100 ꢁC was added allyl iodide (10.7
m
m
L,
L,
0.117 mmol, 1.1 equiv), followed by LiHMDS 1 M in THF (138
0.138 mmol, 1.2 equiv) dropwise. The mixture was stirred for 4 h,
then quenched with aqueous NaHCO3. The solution was extracted
with ether and extracts were dried on Na2SO4. Evaporation under
reduced pressure yielded an oil which was purified by flash chro-
matography (EtOAc/hexanes, 15:85 to 30:70) to give 18d and 19d as
colorless gums (51.5 mg, 95%). Major trans-isomer (18d): 1H NMR
a colorless gum (67 mg, 40%): 1H NMR (300 MHz, CD3OD)
d (ppm)
4.62 (dd, 1H, J¼3.05, 12.6 Hz), 4.34–4.28 (m, 1H), 4.11 (dd, 1H,
J¼10.6, 12.6 Hz), 3.86–3.83 (m, 2H), 2.21–2.19 (m, 1H), 2.11–2.03 (m,
1H), 1.99–1.94 (m, 2H), 1.87–1.67 (m, 7H), 1.49–1.46 (m, 1H); 13C
NMR (75 MHz, CD3OD)
d (ppm) 156.8, 74.2, 65.1, 58.9, 50.3, 36.8,
35.4, 32.5, 25.0, 21.0, 20.8; ESI/MS (m/z) [Mþ1]þ: 239.2.
(300 MHz, CDCl3) d (ppm) 7.78–7.73 (m, 4H), 7.67–7.64 (m, 2H), 7.55–
7.35 (m, 9H), 5.67 (ddt, 1H, J¼7.08, 10.2, 17.2 Hz), 5.07 (dd, 1H, J¼1.57,
17.4 Hz), 5.03 (d, 1H, J¼9.05 Hz), 4.50 (dd, 1H, J¼3.25, 12.5 Hz), 4.30
(dd, 1H, J¼10.8, 12.5 Hz), 4.17–4.09 (m, 1H), 4.04 (dd, 1H, J¼5.18,
10.9 Hz), 3.95 (dd, 1H, J¼4.72, 10.9 Hz), 3.04 (dd, 1H, J¼7.64, 14.3 Hz),
2.95 (dd, 1H, J¼6.57, 14.3 Hz), 1.14 (s, 9H); 13C NMR (75 MHz, CDCl3)
5.1.13. 1-[1-(4-Hydroxy-but-1-enyl)-1H-tetrazol-5-yl]-
cyclohexanol (23)
To a solution of 21 (40.0 mg, 0.168 mmol) in THF (1.7 mL (0.1 M))
at ꢀ78 ꢁC was added dropwise t-BuLi 1.7 M in pentane (0.247 mL,
0.420 mmol, 2.5 equiv). The reaction mixture was stirred 30 min,
then quenched slowly with few drops of aqueous NH4Cl. Silica and
MeOH were added and the mixture is evaporated under reduced
pressure to a dry solid that was purified by flash chromatography
(EtOAc/hexanes 1:1) to give 23 as a colorless gum (32.2 mg, 81%):
d
(ppm) 154.4, 139.9, 136.5, 136.4, 133.5, 133.4, 131.7, 130.99, 130.91,
129.6, 129.3, 128.8, 126.6, 121.0, 81.4, 70.3, 64.7, 49.0, 48.2, 27.6, 20.1;
FTIR (thin film) (CHCl3, cmꢀ1) 3071, 2999, 2957, 2931, 2894, 2858,
1642, 1589, 1493, 1472, 1441, 1428, 1159, 1113, 1069, 998, 923, 824, 743,
702; ESI/MS (m/z) [Mþ1]þ: 511.3; HRMS (ESI) for C30H34N4O2Si:
calcd [Mþ1]þ 511.25238; found 511.25319. Minor cis-isomer (19d):
1H NMR (400 MHz, CD3OD)
d
(ppm) 7.65 (d, 1H, J¼12.0 Hz), 6.61 (dt,
1H, J¼6.2, 12.0 Hz), 3.74 (t, 2H, J¼6.2 Hz), 2.51–2.43 (m, 2H), 2.03–
1H NMR (300 MHz, CDCl3)
d
(ppm) 7.87–7.84 (m, 2H), 7.77–7.73 (m,
1.92 (m, 4H), 1.87–1.72 (m, 2H), 1.55–1.72 (m, 3H), 1.45–1.22 (m,
4H), 7.55–7.31 (m, 9H), 5.63–5.49 (m, 1H), 5.04–4.98 (m, 2H), 4.76
(dd, 1H, J¼2.20, 12.1 Hz), 4.41–4.34 (m, 1H), 4.29 (dd, 1H, J¼10.3,
3H); 13C NMR (100 MHz, CD3OD)
d
(ppm) 159.5, 125.6, 124.4, 70.4,
61.8, 37.7, 34.1, 26.2, 22.2; FTIR (thin film) (CHCl3, cmꢀ1) 3339, 3108,

6664
S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
2935, 2858,1721,1669,1448,1419,1350,1261,1251,1160, 1140,1041,
984, 953, 909, 850, 755; ESI/MS (m/z) [Mþ1]þ: 239.1; HRMS (ESI)
for C11H12N4O2: calcd [M]þ 239.1502; found 239.14972.
added. The mixture was heated for an additional 12 h, and the
solution was cooled down to room temperature, prior to the
addition of a 5% Na2S2O3 solution. The aqueous phase was
extracted with EtOAc (3 times), the combined organic phases
were dried with Na2SO4, and evaporated under reduced pressure.
The residue was purified by flash chromatography (EtOAc/hex-
anes, 10:90 to 20:80). For (27), a colorless gum (1.26 g, 58%): 1H
5.1.14. 1-{1-[3-(tert-Butyl-diphenyl-silanyloxy)-propenyl]-1H-
tetrazol-5-yl}-1-phenyl-ethanol (24)
To a solution of 20 (245 mg, 5.06 mmol) in ether (10.1 mL
(0.05 M)) at ꢀ90 ꢁC was added dropwise t-BuLi 1.7 M in pentane
(0.446 mL 0.758 mmol, 1.5 equiv). The reaction mixture was stirred
30 min, then quenched slowly with aqueous NH4Cl. The mixture was
extracted with ether, then dried on Na2SO4. After evaporation under
reduced pressure, the crude residue was purified by flash chroma-
tography (EtOAc/hexanes 15:85 to 30:70) to give 24 as a white solid
NMR (300 MHz, CD2Cl2)
d (ppm) 8.00–7.98 (m, 2H), 7.80–7.78 (m,
4H), 7.54–7.47 (m, 9H), 4.87–4.80 (m, 1H), 4.78 (dd, 1H, J¼3.23,
15.6 Hz), 4.51 (dd, 1H, J¼11.1, 12.8 Hz), 4.17 (d, 2H, J¼4.36 Hz), 1.16
(s, 9H); 13C NMR (75 MHz, CD2Cl2)
d (ppm) 151.5, 136.0, 133.0,
130.7, 130.5, 129.2, 128.37, 128.35, 127.0, 90.8, 70.7, 63.8, 47.6, 27.0,
19.5; FTIR (thin film) (DCM, cmꢀ1) 3071, 2931, 2858, 2113, 1449,
1211, 1134, 1113, 1051; ESI/MS (m/z) [Mþ1]þ: 512.2; HRMS (ESI)
for C27H29N7O2Si: calcd [Mþ1]þ 512.22248; found 512.22291. For
(28), a white solid (0.512 g, 25%): 1H NMR (300 MHz, CD2Cl2)
(230 mg, 94%): 1H NMR (400 MHz, CDCl3)
d (ppm) 7.64–7.62 (m, 2H),
7.60–7.57 (m, 2H), 7.48–7.43 (m, 2H), 7.40–7.27 (m,10H), 6.55 (dt,1H,
J¼3.53, 13.7 Hz), 4.30 (ddd, 1H, J¼2.43, 3.49, 16.4 Hz), 4.22 (ddd, 1H,
J¼2.42, 3.52, 16.4 Hz), 3.64 (br s, 1H), 2.18 (s, 3H), 1.08 (s, 9H); 13C
d
(ppm) 7.70–7.61 (m, 4H), 7.57–7.36 (m, 10H), 7.29–7.23 (m, 1H),
NMR (100 MHz, CDCl3)
d
(ppm) 156.4,142.2,135.1,135.0,132.5,132.4,
5.00–4.92 (m, 1H), 4.86–4.78 (m, 2H), 4.05 (dd, 1H, J¼3.54,
129.53,129.48, 128.4, 127.6, 127.5, 127.4, 124.9,124.1, 120.2, 71.6, 60.8,
31.5, 26.4, 18.8; FTIR (thin film) (CHCl3, cmꢀ1) 3325, 3071, 2959,
2932, 2857, 1472, 1448, 1428, 1377, 1134, 1113, 1073, 966, 939, 823,
768, 741, 701; ESI/MS (m/z) [Mþ1]þ: 485.3; HRMS (ESI) for
C28H33N4O2Si: calcd [Mþ1]þ 485.23673; found 485.23626; for
C28H32N4NaO2Si: calcd [MþNa]þ 507.21867; found 507.21818.
11.7 Hz), 3.99 (dd, 1H, J¼3.36, 11.7 Hz), 1.06 (s, 9H); 13C NMR
(75 MHz, CD2Cl2)
d (ppm) 146.9, 144.4, 140.8, 136.4, 136.3, 132.9,
132.7, 131.0, 130.9, 129.6, 128.81, 128.79, 126.8, 124.8, 77.1, 64.1,
47.0, 27.2, 19.8; FTIR (thin film) (CHCl3, cmꢀ1) 3071, 3052, 2957,
2931, 2892, 2858, 1682, 1590, 1531, 1485, 1472, 1428, 1268, 1220,
1166, 1114, 1047, 1025, 978, 823, 770, 740, 702; ESI/MS (m/z)
[Mþ1]þ: 484.2; HRMS (ESI) for C27H29N5O2Si: calcd [Mþ1]þ
484.2163; found 484.21492.
5.1.15. 2-(1H-Tetrazol-5-yl)propan-2-ol (25)
Into a solution of 22 (116 mg, 0.63 mmol) in MeOH (2 mL
(0.3 M)), was bubbled ozone for 30 min. Then, H2O2 30% (300
m
L,
5.1.18. cis-(8-Azido-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-c]-
[1,4]oxazin-6-yl)-methanol (29) and (8-phenylimino-5,6-dihydro-
8H-tetrazolo[5,1-c][1,4]oxazin-6-yl)-methanol (30)
2.8 mmol, 4.5 equiv) was added and the solution was stirred for
30 min. Afterevaporation under reduced pressure, the crude residue
was dissolved in water and washed 3 times with DCM. The water
solution was lyophilized to give 25 as a white solid (79 mg, 99%): 1H
To a solution of ICl (5.24 g, 32.2 mmol, 2.5 equiv), in MeCN
(43 mL (0.3 M)) at ꢀ10 ꢁC was added a solution of NaN3 (4.95 g,
76.2 mmol, 5.9 equiv) in MeCN (26 mL (0.5 M)). After 15 min, the
cooling bath was removed and the tetrazole 31 (3.0 g, 12.9 mmol)
was added. The mixture was heated to reflux for 36 h, and the so-
lution was cooled down to room temperature, prior to the addition
of a 5% Na2S2O3 solution. The aqueous phase was then extracted
with EtOAc (5 times), the combined organic phases were dried with
Na2SO4 and evaporated under reduced pressure. The residue was
purified by flash chromatography (EtOAc/hexanes, 50:50 to 75:25).
For (29), a colorless gum (2.10 g, 59%): 1H NMR (300 MHz, CD2Cl2)
NMR (400 MHz, CD3OD)
d
(ppm) 1.65 (s, 6H); 13C NMR (100 MHz,
CD3OD)
d
(ppm) 164.7, 68.7, 30.1; ESI/MS (m/z) [Mþ1]þ: 129.1.
5.1.16. 1-Phenyl-1-(1H-tetrazol-5-yl)-ethanol (26)
Into a solution of 24 (36.4 mg, 0.0751 mmol) in formic acid/
DCM (4:1) (2.5 mL (0.03 M)), was bubbled ozone for 30 min.
Then, H2O2 30% (510
was refluxed for 30 min. H2O2 30% (510
m
L, 60 equiv) was added and the solution
L, 60 equiv) was again
m
added and the solution was refluxed for an extra 30 min. After
evaporation under reduced pressure, the crude solid was purified
by flash chromatography (MeOH/EtOAc 10:90 to 30:70).
Remaining silica in the final product was precipitated in EtOAc/
DCM (1:1) solution and filtered on cotton pad to give 26 as
d
(ppm) 7.97–7.94 (m, 2H), 7.54–7.49 (m, 3H), 4.82–4.69 (m, 2H),
4.50 (dd, 1H, J¼11.1, 13.0 Hz), 4.15 (dd, 1H, J¼3.87, 12.3 Hz), 4.07 (dd,
1H, J¼4.49, 12.3 Hz), 2.63 (br s, 1H); 13C NMR (100 MHz, CD2Cl2)
d
(ppm) 151.4, 135.9, 130.7, 129.2, 126.9, 90.7, 70.8, 62.3, 47.1; FTIR
a white solid (14.1 mg, 99%): 1H NMR (400 MHz, CD3OD)
d
(ppm)
7.52 (d, 2H, J¼7.32 Hz), 7.35 (t, 2H, J¼7.52 Hz), 7.29–7.26 (m, 1H),
2.03 (s, 3H); 13C NMR (100 MHz, CD3OD)
(ppm) 163.2, 145.0,
(thin film) (DCM, cmꢀ1) 3401, 2929, 2115, 1449, 1213, 1153, 1056,
1030; ESI/MS (m/z) [Mþ1]þ: 274.0; HRMS (ESI) for C11H11N7O2:
calcd [Mþ1]þ 274.10470; found 274.10497. For (30), a white solid
(0.526 g, 17%): ESI/MS (m/z) [Mþ1]þ: 246.1; HRMS (ESI) for
C11H11N5O2: calcd [Mþ1]þ 246.0986; found 246.09839.
d
128.4, 127.7, 125.0, 71.2, 29.1; FTIR (thin film) (CHCl3, cmꢀ1) 3350,
2986, 2929, 2855, 1548, 1494, 1447, 1373, 1216, 1146, 1073, 1029,
914, 746, 697, 666; ESI/MS (m/z) [Mþ1]þ: 191.1, [MþNa]þ: 213.1;
HRMS (ESI) for C9H11N4O: calcd [Mþ1]þ 191.09274; found
191.09309; for C9H10N4NaO: calcd [MþNa]þ 213.07468; found
213.07411.
5.1.19. cis-[8-(3,5-Dimethoxy-phenyl)-5,6-dihydro-8H-
tetrazolo[5,1-c][1,4]oxazin-6-yl]-methanol
This compound was obtained according to the general procedure
for tetrazoles. From 4-azidomethyl-2-(3,5-dimethoxy-phenyl)-
[1,3]dioxolane corresponding to 15 (3.21 g,12.1 mmol) was obtained
tetrazole as a white solid (cis/trans, 19:1), (3.00 g, 85%). Major cis-
5.1.17. cis-8-Azido-6-(tert-butyl-diphenyl-silanyloxymethyl)-8-
phenyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazine (27) and
[6-(tert-butyl-diphenyl-silanyloxymethyl)-5,6-dihydro-tetrazolo-
[5,1-c][1,4]oxazin-8-ylidene]-phenyl-amine (28)
To a solution of ICl (1.38 g, 8.50 mmol, 2 equiv), in MeCN
(14.2 mL (0.3 M)) at ꢀ10 ꢁC was added a solution of NaN3 (1.30 g,
20.0 mmol, 4.7 equiv), in MeCN (8.50 mL (0.5 M)). After 15 min,
the cooling bath was removed and the tetrazole 8a (2.17 g,
4.25 mmol) was added. The mixture was heated to reflux for 24 h
and a pre-mixed solution of ICl (1 equiv, 0.3 M) and NaN3
(2.4 equiv, 0.5 M) in MeCN, obtained as previously described, was
isomer: 1H NMR (400 MHz, CD3OD)
d
(ppm) 6.68 (d, 1H, J¼2.24 Hz),
6.53(t,1H, J¼2.24 Hz), 6.03 (s,1H), 4.71 (dd,1H, J¼3.24,12.6 Hz), 4.46
(dd, 1H, J¼11.1, 11.7 Hz), 4.35–4.30 (m, 1H), 3.90 (d, 2H, J¼5.08 Hz),
3.79 (s, 6H); 13C NMR (100 MHz, CD3OD)
d (ppm) 160.7, 152.2, 137.6,
105.3, 100.4, 74.5, 74.1, 61.1, 54.1, 46.4; FTIR (thin film) (CHCl3, cmꢀ1
)
3402, 2937, 2842,1598,1463,1432,1345,1297,1205,1156,1062, 832;
ESI/MS (m/z) [Mþ1]þ: 293.1, [MþNa]þ: 315.1; HRMS (ESI) for
C13H17N4O4: calcd [Mþ1]þ 293.12443; found 293.12389; for
C13H16N4NaO4: calcd [MþNa]þ 315.10638; found 315.10593.

S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
6665
5.1.20. cis-6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-(3,5-
5.1.22. cis-(8-Pentafluorophenyl-5,6-dihydro-8H-tetrazolo[5,1-
c][1,4]oxazin-6-yl)-methanol
dimethoxy-phenyl)-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]-
oxazine (31)
This compound was obtained according to the general pro-
cedure for tetrazoles. From 4-azidomethyl-2-pentafluorophenyl-
[1,3]dioxolane corresponding to 15 (0.5 g, 1.69 mmol) was obtained
tetrazole as a white solid (cis/trans, 3:1), (266 mg, 49%). Major cis-
See procedure for (17a): 1H NMR (400 MHz, CDCl3)
d (ppm)
7.71–7.68 (m, 4H), 7.50–7.45 (m, 2H), 7.44–7.38 (m, 4H), 6.63 (d,
J¼2.20 Hz), 6.50 (t, J¼4.52 Hz), 5.89 (s, 1H), 4.77 (dd, 1H, J¼2.50,
12.8 Hz), 4.45 (dd, J¼10.8, 11.9 Hz), 4.29–4.23 (m, 1H), 4.09 (dd, 1H,
J¼4.60, 10.9 Hz), 3.97 (dd, 1H, J¼6.00, 10.9 Hz), 3.78 (s, 6H), 1.11 (s,
isomer: 1H NMR (700 MHz, CDCl3)
d (ppm) 6.39 (s,1H), 4.72 (dd,1H,
J¼3.77, 13.2 Hz), 4.58 (dd, 1H, J¼9.56, 13.2 Hz), 4.25–4.22 (m, 1H),
9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 160.6, 151.6, 136.8, 135.24,
3.99 (dd, 1H, J¼3.48, 12.2 Hz), 3.91–3.88 (m, 1H), 2.56 (br s, 1H); 13C
135.15, 132.2, 132.0, 129.7, 127.6, 127.5, 105.1, 101.1, 74.8, 73.6, 63.5,
55.1, 47.5, 26.4, 18.9; FTIR (thin film) (CHCl3, cmꢀ1) 3071, 3049,
3000, 2932, 2890, 2857, 1599, 1462, 1428, 1359, 1295, 1205, 1157,
1134, 1113, 1062, 911, 823, 806, 737, 703; ESI/MS (m/z) [Mþ1]þ:
531.3, [MþNa]þ: 553.2; HRMS (ESI) for C29H35N4O4Si: calcd [Mþ1]þ
531.24221; found 531.24315; for C29H34N4NaO4Si: calcd [MþNa]þ
553.22415; found 553.22449.
NMR (233 MHz, CDCl3)
d
(ppm) 150.0, 145.6 (d, J¼337 Hz), 142.7 (d,
J¼343 Hz), 137.8 (d, J¼337 Hz), 109.6, 74.8, 65.0, 62.1, 46.7; FTIR
(thin film) (CHCl3, cmꢀ1) 3409, 3062, 2932, 1659, 1505, 1435, 1373,
1307, 1268, 1133, 1070, 972, 877, 853, 777, 739; ESI/MS (m/z)
[Mþ1]þ: 323.0, [MþNa]þ: 355.1; HRMS (ESI) for C11H8F5N4O2: calcd
[Mþ1]þ 323.05619; found 323.05627; for C11H7F5N4NaO2: calcd
[MþNa]þ 345.03814; found 345.03785.
5.1.21. cis-8-Azido-6-(tert-butyl-diphenyl-silanyloxymethyl)-8-
(3,5-dimethoxy-phenyl)-5,6-dihydro-8H-tetrazolo[5,1-
5.1.23. cis-6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-
pentafluorophenyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazine (32)
c][1,4]oxazine (33), [6-(tert-butyl-diphenyl-silanyloxymethyl)-5,6-
dihydro-tetrazolo[5,1-c][1,4]oxazin-8-ylidene]-(3,5-dimethoxy-
phenyl)-amine (34) and {1-[3-(tert-butyl-diphenyl-silanyloxy)-2-
hydroxy-propyl]-1H-tetrazol-5-yl}-(3,5-dimethoxy-phenyl)-
methanone (35)
See procedure for (17a): 1H NMR (400 MHz, CDCl3)
d (ppm)
7.67–7.65 (m, 4H), 7.51–7.45 (m, 2H), 7.44–7.37 (m, 4H), 6.31 (s, 1H),
4.78 (dd, 1H, J¼2.32, 12.9 Hz), 4.46 (ddd, 1H, J¼0.78, 11.5, 12.9 Hz),
4.30–4.25 (m, 1H), 4.06 (dd, 1H, J¼4.58, 11.1 Hz), 3.94 (dd, 1H, J¼5.8,
11.1 Hz), 1.10 (s, 9H). 13C NMR (100 MHz, CDCl3)
d (ppm) 149.7,
To a solution of ICl (180 mg, 1.11 mmol, 3 equiv) in MeCN
(1.23 mL (0.3 M)) at ꢀ10 ꢁC was added a solution of NaN3 (171 mg,
2.62 mmol, 7.1 equiv) in MeCN (0.74 mL (0.5 M)). After 15 min, the
cooling bath was removed and the tetrazole 31 (196 mg,
0.369 mmol) was added. The mixture was heated to reflux for 24 h,
and the solution was cooled down to room temperature, prior to
the addition of a 5% Na2S2O3 solution. The aqueous phase was then
extracted with EtOAc (3 times), the combined organic phases were
dried with Na2SO4 and evaporated under reduced pressure. The
residue was purified by flash chromatography (EtOAc/hexanes,
10:90 to 20:80). For (33), a colorless gum (116 mg, 55%): 1H NMR
135.2, 135.1, 132.1, 132.0, 129.8, 127.6, 127.5, 74.2, 64.6, 63.1, 47.3,
26.4, 18.9 (Carbons bearing fluorides have not been observed, see
233 MHz carbon NMR for the starting material to see them); FTIR
(thin film) (CHCl3, cmꢀ1) 3073, 2933, 2860, 1657, 1524, 1512, 1473,
1428, 1362, 1307, 1134, 1113, 1061, 1005, 990, 972, 823, 740, 702; ESI/
MS (m/z) [Mþ1]þ: 561.2, [MþNa]þ: 583.2; HRMS (ESI) for
C27H26F5N4O2Si: calcd [Mþ1]þ 561.17397; found 561.17473; for
C27H25F5N4NaO2Si: calcd [MþNa]þ 583.15591; found 583.15671.
5.1.24. 1-[5-(Amino-phenyl-methyl)-tetrazol-1-yl]-3-(tert-butyl-
diphenyl-silanyloxy)-propan-2-ol (36 and 37)
(400 MHz, CDCl3)
d
(ppm) 7.76–7.72 (m, 4H), 7.53–7.42 (m, 6H), 7.15
To a solution of 27 (720 mg, 1.41 mmol) at 0 ꢁC in MeOH (9.4 mL
(0.5 M)) was added Mg powder (171 mg, 7.04 mmol, 5 equiv). The
mixturewasstirredfor12 h, then filteredona Celite pad. Evaporation
under reduced pressure gave an oil which was purified by flash
chromatography (EtOAc/hexanes/NH3 7 M in MeOH, 55:40:5) to give
36 and 37 as colorless gums (547 mg, 80%). Major isomer (36): 1H
(d, 2H, J¼2.28 Hz), 6.55 (t, 1H, J¼2.26 Hz), 4.77–4.71 (m, 2H), 4.43
(dd, 1H, J¼11.6, 13.5 Hz), 4.16–4.07 (m, 2H), 3.84 (s, 6H), 1.14 (s, 9H);
13C NMR (100 MHz, CDCl3)
d (ppm) 160.7, 150.7, 137.0, 135.2, 132.0,
129.9, 129.8, 127.69, 127.67, 104.3, 101.8, 89.9, 69.8, 63.0, 55.2, 47.0,
26.4, 18.9; FTIR (thin film) (CHCl3, cmꢀ1) 3072, 3001, 2933, 2858,
2116,1598, 1462, 1427, 1350,1327,1298,1206,1158, 1134, 1112,1064,
1043, 1007, 936, 842, 824, 740, 703; ESI/MS (m/z) [Mþ1]þ: 572.3,
[MþNa]þ: 594.3, [MꢀN3]þ: 529.3; HRMS (ESI) for C29H34N7O4Si:
calcd [Mþ1]þ 572.24361; found 572.24374; for C29H33N7NaO4Si:
calcd [MþNa]þ 594.22555; found 594.22586. For (34), a colorless
NMR (300 MHz, CDCl3) d (ppm) 7.66–7.60 (m, 4H), 7.44–7.33 (m, 7H),
7.30–7.18 (m, 5H), 5.54 (s, 1H), 4.42 (d, 1H, J¼11.6 Hz), 4.08–3.98 (m,
2H), 3.71–3.68 (m, 1H), 3.65 (dd, 1H, J¼5.26, 10.5 Hz), 3.35 (br s, 3H),
1.06 (s, 9H); 13C NMR (75 MHz, CDCl3)
d (ppm) 157.9, 139.3, 135.5,
135.4, 132.7, 132.6, 129.9, 129.1, 128.5, 127.8, 127.0, 126.8, 70.6, 65.4,
50.9, 51.6, 26.8, 19.1; FTIR (thin film) (DCM, cmꢀ1) 3355, 3296, 3071,
2958, 2931, 2892, 2858, 1589, 1472, 1457, 1428, 1113, 824, 742, 702;
ESI/MS (m/z) [Mþ1]þ: 488.2; HRMS (ESI) for C27H33N5O2Si: calcd
[Mþ1]þ 488.24763; found 488.24821. Minor isomer (37): 1H NMR
gum (39 mg, 19%): 1H NMR (400 MHz, CD2Cl2)
d (ppm) 7.65–7.59
(m, 4H), 7.52–7.35 (m, 6H), 6.49 (d, 2H, J¼2.28 Hz), 6.38 (t, 1H,
J¼2.26 Hz), 4.94 (dd, 1H, J¼3.26, 12.9 Hz), 4.86–4.74 (m, 2H), 4.02
(dd, 1H, J¼4.20, 12.8 Hz), 3.96 (dd, 1H, J¼3.40, 11.6 Hz), 3.77 (s, 6H),
1.03 (s, 9H); 13C NMR (100 MHz, CD2Cl2)
d
(ppm) 160.5, 145.0, 139.8,
(400 MHz, CDCl3) d (ppm) 7.68–7.64 (m, 4H), 7.48–7.39 (m, 6H), 7.34–
137.3, 135.11, 135.06, 131.7, 131.4, 129.7, 129.6, 127.5, 127.4, 101.2,
97.6, 75.8, 62.8, 55.0, 45.8, 26.0, 18.5; ESI/MS (m/z) [Mþ1]þ: 544.3,
[MþNa]þ: 566.3; HRMS (ESI) for C29H34N5O4Si: calcd [Mþ1]þ
544.23746; found 544.23764; for C29H33N5NaO4Si: calcd [MþNa]þ
566.2194; found 566.21934. For (35), a colorless gum (16 mg, 8%):
7.28 (m, 5H), 5.69 (s, 1H), 4.38–4.30 (m, 2H), 4.14–4.08 (m, 1H), 4.72
(d, 2H, J¼5.42 Hz), 3.24 (br s, 3H), 1.10 (s, 9H); 13C NMR (100 MHz,
CDCl3)
d (ppm) 157.3, 138.6, 135.4, 135.4, 132.7, 132.6, 129.9, 129.1,
128.5, 127.7, 126.6, 70.0, 64.9, 50.4, 50.2, 26.7, 19.1; FTIR (thin film)
(CHCl3, cmꢀ1) 3352, 3293, 3071, 2957, 2931, 2858, 1589, 1494, 1471,
1456, 1428, 1113, 824, 741, 702; ESI/MS (m/z) [Mþ1]þ: 488.2; HRMS
(ESI) for C27H33N5O2Si: calcd [Mþ1]þ 488.24763; found 488.24801.
1H NMR (400 MHz, CDCl3)
d (ppm) 7.69–6.65 (m, 4H), 7.55 (d, 2H,
2.32 Hz), 7.49–7.34 (m, 6H), 6.82 (t, 1H, J¼2.30 Hz), 4.98 (dd, 1H,
J¼8.64, 13.8 Hz), 4.84 (dd, 1H, J¼3.54, 13.8 Hz), 4.17–4.07 (m, 1H),
3.89 (s, 6H), 3.81 (dd, 1H, J¼4.60, 6.04 Hz), 3.71 (dd, 1H, J¼4.80,
5.1.25. Acetic acid 2-(5-benzoyl-tetrazol-1-yl)-1-(tert-butyl-
diphenyl-silanyloxymethyl)-ethyl ester (38)
10.6 Hz), 1.11 (s, 9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 181.8,
160.8, 150.5, 136.4, 135.4, 134.6, 134.2, 132.3, 132.3, 130.0, 127.80,
127.73, 108.5, 180.1, 70.4, 64.6, 55.6, 51.4, 26.7, 19.1; ESI/MS (m/z)
[Mþ1]þ: 547.3, [MþNa]þ: 569.3; HRMS (ESI) for C29H35N4O5Si:
calcd [Mþ1]þ 547.23712; found 547.23661; for C29H34N4NaO5Si:
calcd [MþNa]þ 569.21907; found 569.21894.
To a solution of 27 (90 mg, 0.176 mmol) in THF (0.88 mL (0.2 M))
was added PMe3 (1 M in THF) (193 mL, 0.193 mmol, 1.1 equiv), the
mixture was heated at 50 ꢁC for 30 min. The solution was cooled
down to room temperature, prior to the addition of a 28% aqueous
NH4OH. The mixture was heated and stirred at 35 ꢁC for 2 h, then

6666
S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
extracted with ether and extracts were dried on Na2SO4. Evapora-
tion under reduced pressure gave an oil which was dissolved in
pyridine (0.50 mL (0.5 M)). The solution was cooled at 0 ꢁC and
J¼8.20 Hz), 5.96 (d, 1H, J¼8.09 Hz), 4.48–4.36 (m, 2H), 4.12 (br s,
1H), 3.72 (dd, 1H, J¼5.12, 10.5 Hz), 3.69–3.66 (m, 1H), 2.48 (br s, 1H),
1.43 (s, 9H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 156.9,
acetic anhydride (33
m
L, 2 equiv) was added. After 8 h at room
155.9, 137.7, 136.4, 136.4, 133.4, 130.9, 130.0, 129.7, 128.8, 128.4, 81.6,
temperature, a solution of HCl 10% was added, and the mixture was
extracted with EtOAc. The extracts were washed with a solution of
aqueous NaHCO3 and with brine. Processing the organic layer gave
an oil which was purified by flash chromatography (EtOAc/hexanes,
15:85) to give 38 as a colorless gum (72.3 mg, 79%): 1H NMR
71.3, 65.7, 50.9, 50.0, 29.1, 27.7, 20.1; FTIR (thin film) (CHCl3, cmꢀ1
)
3307, 3071, 3051, 2961, 2932, 2893, 2859, 1713, 1699, 1496, 1472,
1456, 1428, 1368,1249, 1166,1113,1049, 824, 739, 702; ESI/MS (m/z)
[Mþ1]þ: 588.3; HRMS (ESI) for C32H41N5O4Si: calcd [Mþ1]þ
588.30006; found 588.30083.
(400 MHz, CD2Cl2)
d
(ppm) 8.42 (d, 2H, J¼7.72 Hz), 7.79 (t, 1H,
J¼7.44 Hz), 7.74–7.70 (m, 4H), 7.63 (t, 2H, J¼7.79 Hz), 7.51–7.43 (m,
6H), 5.40–5.35 (m, 1H), 5.21 (dd, 1H, J¼3.35, 14.25 Hz), 5.14 (dd, 1H,
J¼7.96, 14.25 Hz), 3.90 (dd, 1H, J¼4.58, 11.19 Hz), 3.84 (dd, 1H,
J¼5.07, 11.17 Hz), 1.75 (s, 3H), 1.14 (s, 9H); 13C NMR (100 MHz,
5.1.29. Methanesulfonic acid 2-[5-(tert-butoxycarbonylamino-
phenyl-methyl)-tetrazol-1-yl]-1-(tert-butyl-diphenyl-
silanyloxymethyl)-ethyl ester (40)
To a solution of the preceding product (1.08 g, 1.83 mmol) in
DCM (18.3 mL (0.1 M)) was added Et3N (0.766 mL, 5.50 mmol,
3 equiv) and the mixture was cooled at 0 ꢁC in an ice bath. Ms2O
(511 mg, 2.93 mmol, 1.6 equiv) was added and the reaction mixture
was stirred at room temperature for 24 h. The solution was evap-
orated under reduced pressure. The crude residue was purified by
flash chromatography (EtOAc/hexanes 25:75) to give 40 as a color-
CD2Cl2)
d (ppm) 182.3, 170.1, 150.5, 136.0, 135.9, 135.6, 135.4, 133.2,
133.1, 131.4, 130.3, 129.3, 128.22, 128.20, 72.0, 63.2, 50.2, 26.9, 20.6,
19.5; FTIR (thin film) (DCM, cmꢀ1) 3072, 2959, 2932, 2859, 1747,
1668, 1598, 1428, 1276, 1229, 1114, 921; ESI/MS (m/z) [Mþ1]þ:
528.2; HRMS (ESI) for C29H32N4O4Si: calcd [Mþ1]þ 529.2265;
found 529.22714.
less gum (1.22 g, 100%): 1H NMR (400 MHz, CDCl3)
d (ppm) 7.68–
5.1.26. cis-N-[6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-phenyl-
5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazin-8-yl]-acetamide (39)
7.63 (m, 1H), 7.50–7.32 (m, 11H), 6.26 (d, 1H, J¼7.58 Hz), 5.86 (d, 1H,
J¼7.54 Hz), 5.00 (m, 1H), 4.57 (dd, 1H, J¼4.89, 15.4 Hz), 4.52 (dd, 1H,
J¼7.97, 15.0 Hz), 3.93 (dd, 1H, J¼4.13, 11.8 Hz), 3.85 (dd, 1H, J¼4.22,
11.8 Hz), 2.83 (s, 3H), 1.44 (s, 9H), 1.09 (s, 9H); 13C NMR (100 MHz,
To a solution of 27 (25.0 mg, 0.0489 mmol) in chloroform (325
(0.15 M)) was added 2,6-lutidine (102 L, 0.879 mmol, 18 equiv),
then thioacetic acid (65 L, 0.909 mmol, 18.6 equiv). The solution
mL
m
m
CDCl3) d (ppm) 155.9, 154.5, 135.5, 135.2, 135.1, 131.9, 131.5, 129.8,
was refluxed for 36 h, and the solvent removed under reduced
pressure to give an oil which was purified by flash chromatography
(EtOAc/hexanes, 45:55). A second flash may be required to remove
all the sulfur derivatives. Compound 39 was obtained as a colorless
129.2, 129.1, 129.0, 127.7, 127.5, 80.5, 78.0, 63.1, 49.5, 47.2, 37.2, 27.9,
26.4, 18.9; FTIR (thin film) (CHCl3, cmꢀ1) 3307, 2931, 2859, 1709,
1467, 1472, 1458, 1428, 1367, 1248, 1178, 1114, 926, 702; ESI/MS (m/z)
[Mþ1]þ: 666.3; HRMS (ESI) for C32H43N5O6SSi: calcd [Mþ1]þ
666.27761; found 666.27728.
gum (20.1 mg, 78%): 1H NMR (400 MHz, CDCl3)
d (ppm) 7.97–7.95
(m, 2H), 7.75–7.69 (m, 4H), 7.51–7.41 (m, 9H), 6.57 (s, 1H), 5.01–4.99
(m, 1H), 4.74 (dd, 1H, J¼3.36, 12.9 Hz), 4.42 (dd, 1H, J¼10.8, 12.9 Hz),
4.08–4.00 (m, 2H), 2.03 (s, 3H), 1.12 (s, 9H); 13C NMR (100 MHz,
5.1.30. Methanesulfonic acid 2-[5-(tert-butoxycarbonylamino-
phenyl-methyl)-tetrazol-1-yl]-1-(tert-butyl-diphenyl-
silanyloxymethyl)-ethyl ester (41)
CD2Cl2)
d (ppm) 170.2, 151.7, 138.7, 135.2, 135.1, 132.4, 129.6, 129.2,
128.8,128.2,127.5,126.2,126.0, 81.0, 70.9, 63.5, 46.6, 26.2, 23.2,18.7;
FTIR (thin film) (DCM, cmꢀ1) 3279, 3071, 3050, 2959, 2932, 2858,
1694,1673,1538,1512,1491,1472,1448,1428,1282,1113,1042,1029,
741, 702; ESI/MS (m/z) [Mþ1]þ: 528.3; HRMS (ESI) for C29H33N5O3Si:
calcd [Mþ1]þ 528.2425; found 528.24287.
See procedure for (40): 1H NMR (400 MHz, CDCl3)
d (ppm) 7.70–
7.63 (m, 4H), 7.50–7.33 (m, 11H), 6.17 (d, 1H, J¼7.72 Hz), 5.73 (d, 1H,
J¼7.72 Hz), 4.84 (dd, 1H, J¼7.75, 14.8 Hz), 4.60 (dd, 1H, J¼2.97,
14.9 Hz), 3.95 (dd,1H, J¼3.85,11.2 Hz), 3.90 (dd,1H, J¼5.50,11.3 Hz),
2.53 (s, 3H), 1.43 (s, 9H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
(ppm) 155.8, 154.4, 135.2, 135.1, 131.9, 131.8, 129.8, 129.1, 129.0,
5.1.27. ({1-[3-(tert-Butyl-diphenyl-silanyloxy)-2-hydroxy-propyl]-
1H-tetrazol-5-yl}-phenyl-methyl)-carbamic acid tert-butyl ester
(N-Boc 36)
To a mixture of 36 (921 mg, 1.89 mmol) in a solution of 10:90
Et3N/MeOH (19 mL (0.1 M)) was added Boc2O (618 mg, 2.83 mmol,
2 equiv). The reaction mixture was stirred at 30 ꢁC for 2 h, then
evaporated under reduced pressure. The crude residue was purified
by flash chromatography (EtOAc/hexanes 30:70) to give the title
compound as a colorless gum (1.10 mg, 99%): 1H NMR (400 MHz,
127.7, 127.6, 127.5, 80.6, 62.8, 49.0, 47.1, 37.0, 27.9, 26.5, 18.9; FTIR
(thin film) (CHCl3, cmꢀ1) 3306, 2931, 2858, 1705, 1496, 1472, 1457,
1428, 1367, 1247, 1178, 1114, 924, 739, 702, ESI/MS (m/z) [Mþ1]þ:
666.3; HRMS (ESI) for C32H43N5O6SSi: calcd [Mþ1]þ 666.27761;
found 666.27736.
5.1.31. cis-6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-phenyl-
5,6,7,8-tetrahydro-tetrazolo[1,5-a]pyrazine (42)
To a solution of 40 (1.00 g, 1.51 mmol) in DCM (30 mL (0.05 M))
at ꢀ15 ꢁC was added TFA (2.33 mL, 30.2 mmol, 20 equiv). The re-
action mixture was stirred 3 h at room temperature, then quenched
CDCl3)
d (ppm) 7.67–7.64 (m, 4H), 7.49–7.36 (m, 11H), 6.39 (d, 1H,
J¼7.88 Hz), 5.81 (d,1H, J¼7.76 Hz), 5.58 (d,1H, J¼12.2 Hz), 4.18–4.09
(m, 2H), 3.75 (dd,1H, J¼4.88, 10.6 Hz), 3.70 (dd,1H, J¼4.39, 10.8 Hz),
3.63 (br s, 1H), 1.43 (s, 9H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3)
with
a minimum of saturated NaHCO3. When effervescence
stopped, few drops of (i-Pr)2EtN were added, and mixture was
dried with Na2SO4 and filtered on Celite. After evaporation, meth-
anol (150 mL (0.01 M)) and (i-Pr)2EtN (0.526 mL, 3.02 mmol,
2 equiv) were added, the reaction mixture was refluxed for 60 h,
then evaporated under reduced pressure. The crude residue was
purified by flash chromatography (EtOAc/hexanes 20:80 to 30:70)
to give 42 as a colorless gum (0.501 g, 71%): 1H NMR (400 MHz,
d
(ppm) 157.1, 156.1, 137.0, 136.42, 136.38, 133.6, 133.5, 130.9, 130.2,
129.9, 128.8, 128.7, 128.4, 81.8, 72.0, 66.0, 51.9, 50.6, 29.1, 27.7, 20.1;
FTIR (thin film) (CHCl3, cmꢀ1) 3306, 3072, 2961, 2932, 2859, 1694,
1496, 1472, 1457, 1428, 1393, 1368, 1249, 1167, 1113, 1050, 739, 702;
ESI/MS (m/z) [Mþ1]þ: 588.2; HRMS (ESI) for C32H41N5O4Si: calcd
[Mþ1]þ 588.30006; found 588.30004.
CDCl3)
d
(ppm) 7.67 (d, 4H, J¼7.35 Hz), 7.50–7.40 (m, 1H), 5.33 (s,
5.1.28. ({1-[3-(tert-Butyl-diphenyl-silanyloxy)-2-hydroxy-propyl]-
1H-tetrazol-5-yl}-phenyl-methyl)-carbamic acid tert-butyl ester
(N-Boc 37)
1H), 4.59 (dd, 1H, J¼3.81, 12.4 Hz), 4.14 (t, 1H, J¼11.6 Hz), 3.93–3.87
(m, 2H), 3.58–3.54 (m, 1H), 2.40 (br s, 1H), 1.10 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d (ppm) 153.0, 137.1, 135.18, 135.17, 132.2, 132.1,
See procedure for (N-Boc 36): 1H NMR (400 MHz, CDCl3)
129.8, 128.62, 128.59, 127.7, 127.6, 64.2, 56.5, 54.1, 48.1, 26.5, 18.9;
d
(ppm) 7.67–7.65 (m, 4H), 7.50–7.34 (m, 11H), 6.38 (d, 1H,
FTIR (thin film) (CHCl3, cmꢀ1) 3306, 3070, 2930, 2857, 1496, 1471,

S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
6667
1427, 1391, 1362, 1113, 823, 739, 701; ESI/MS (m/z) [Mþ1]þ: 470.3;
HRMS (ESI) for C27H31N5OSi: calcd [Mþ1]þ 470.23706; found
470.23741.
crude residue was purified by flash chromatography (EtOAc/hex-
anes 30:70) to give 46 as a colorless gum (189 mg, 84%): 1H NMR
(300 MHz, CD3OD) d (ppm) 7.47–7.39 (m, 5H), 6.13 (s, 1H), 4.97 (dd,
1H, J¼3.81, 11.0 Hz), 4.89 (dd, 1H, J¼3.11, 12.9 Hz), 4.62 (t, 1H,
5.1.32. trans-6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-phenyl-
J¼11.9 Hz), 3.78 (s, 3H); 13C NMR (75 MHz, CD3OD)
d (ppm) 167.7,
5,6,7,8-tetrahydro-tetrazolo[1,5-a]pyrazine (43)
152.6, 135.7, 129.8, 128.9, 128.5, 75.7, 72.0, 52.5, 47.1; ESI/MS (m/z)
[Mþ1]þ: 261.1; HRMS (ESI) for C12H12N4O3: calcd [Mþ1]þ
261.09822; found 261.09735.
See procedure for (42): 1H NMR (400 MHz, CDCl3)
d (ppm) 7.67–
7.63 (m, 4H), 7.51–7.32 (m, 11H), 5.73 (s, 1H), 4.46 (dd, 1H, J¼4.46,
12.3 Hz), 4.21 (dd, 1H, J¼10.0, 12.6 Hz), 3.89 (dd, 1H, J¼4.53,
10.4 Hz), 3.80 (dd,1H, J¼5.64,10.4 Hz), 4.43–3.39 (m,1H), 2.68 (br s,
5.1.36. cis-Toluene-4-sulfonic acid 8-phenyl-5,6-dihydro-8H-
tetrazolo[5,1-c][1,4]oxazin-6-ylmethyl ester (47)
1H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3)
d (ppm) 151.9, 137.2,
135.2, 135.1, 132.0, 129.8, 129.77, 128.5, 127.9, 127.63, 127.59, 126.7,
63.6, 52.3, 48.7, 47.5, 26.4, 18.9; FTIR (thin film) (CHCl3, cmꢀ1) 3324,
3070, 2931, 2893, 2858, 1494, 1471, 1449, 1428, 1113, 1090, 823, 736,
701; ESI/MS (m/z) [Mþ1]þ: 470.3; HRMS (ESI) for C27H31N5OSi:
calcd [Mþ1]þ 470.23706; found 470.23645.
To a solution of 8 (1.00 g, 4.31 mmol) in DCM (5.7 mL (0.75 M))
and pyridine (0.90 mL (4.8 M)) was added a catalytic amount of
DMAP (42 mg, 0.34 mmol, 0.08 equiv) and TsCl (1.50 g, 6.46 mmol,
1.5 equiv). The solution was stirred 12 h, DCM was added, the or-
ganic phase was extracted 3 times with 1 N HCl, washed once with
saturated NaHCO3 and once with brine. The organic phase was
dried on Na2SO4 and evaporated under reduced pressure. The crude
residue was purified by flash chromatography (EtOAc/hexanes
20:80 to 70:30) to give 47 as a white solid (1.54 g, 92%): 1H NMR
5.1.33. 6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-phenyl-5,6-
dihydro-tetrazolo[1,5-a]pyrazine (44)
1H NMR (300 MHz, CDCl3)
d (ppm) 8.42–8.38 (m, 2H), 7.68–7.60
(m, 4H), 7.59–7.34 (m, 9H), 4.90 (dd, 1H, J¼6.45, 13.4 Hz), 4.60 (dd,
1H, J¼9.24, 13.4 Hz), 4.49–4.40 (m, 1H), 4.20 (dd, 1H, J¼4.23,
10.5 Hz), 3.98 (dd, 1H, J¼7.37, 10.5 Hz), 1.02 (s, 9H); 13C NMR
(300 MHz, CDCl3)
d
(ppm) 7.80 (d, 2H, J¼8.21 Hz), 7.45–7.40 (m,
5H), 7.32 (dd, 2H, J¼0.51, 8.58 Hz), 5.95 (s, 1H), 4.67 (d, 1H,
J¼12.3 Hz), 4.48–4.29 (m, 4H), 2.45 (s, 3H); 13C NMR (75 MHz,
(75 MHz, CDCl3)
d
(ppm) 154.4, 145.3, 136.41, 136.37, 134.5, 133.5,
CDCl3) d (ppm) 152.6, 146.6, 135.5, 132.8, 130.9, 130.5, 129.7, 128.9,
133.2, 132.8, 130.93, 130.89, 129.5, 128.8, 128.7, 65.7, 60.1, 45.6, 27.6,
20.0; FTIR (thin film) (CHCl3, cmꢀ1) 3070, 2955, 2930, 2857, 1599,
1571, 1471, 1461, 1437, 1428, 1330, 1151, 1113, 1024, 974, 956, 823,
786, 743, 702, 691; ESI/MS (m/z) [Mþ1]þ: 468.2; HRMS (ESI) for
C27H30N5OSi: calcd [Mþ1]þ 468.22141; found 468.22279; for
C27H29N5NaOSi: calcd [MþNa]þ 490.20336; found 490.20441.
128.5, 76.2, 71.9, 68.8, 47.7, 22.6; FTIR (thin film) (CHCl3, cmꢀ1
)
3066, 3036, 2956, 2924, 1598, 1496, 1473, 1455, 1400, 1360, 945,
907, 816, 755, 698, 666; ESI/MS (m/z) [Mþ1]þ: 387.1; HRMS (ESI) for
C18H18N4O4S: calcd [Mþ1]þ 387.11215; found 387.11407.
5.1.37. cis-6-Azidomethyl-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-
c][1,4]oxazine (48)
5.1.34. cis-6-(tert-Butyl-diphenyl-silanyloxymethyl)-8-phenyl-5,6-
dihydro-8H-tetrazolo[1,5-a]pyrazine-7-carboxylic acid methyl
ester (45)
To a solution of 41 (66 mg, 0.141 mmol) in methyl chloroformate
(2.81 mL (0.05 M)) is added NaHCO3 (59 mg, 0.703 mmol, 5 equiv).
The solution is stirred at 60 ꢁC and monitored by TLC. Additional
reagent was added to complete the reaction. After 24 h, the mixture
is filtered and evaporated under reduced pressure. The crude res-
idue was purified by flash chromatography (EtOAc/hexanes 20:80)
to give 45 as a colorless gum (64 mg, 87%): 1H NMR (400 MHz,
To a solution of 47 (472 mg, 1.22 mmol) in DMF (12 mL (0.1 M))
was added NaN3 (254 mg, 3.91 mmol, 3.2 equiv) and a catalytic
amount of n-Bu4NBr (38 mg, 0.12 mmol, 0.1 equiv). The reaction
mixture was then stirred 5 h at 70 ꢁC. After, standing at room
temperature, the solution was filtered on a small pad of silica,
evaporated under reduced pressure, and the crude residue was
dissolved in EtOAc and filtered again. After evaporation, the crude
residue was purified by flash chromatography (EtOAc/hexanes
30:70) to give 48 as a colorless gum (298 mg, 95%): 1H NMR
(400 MHz, CDCl3) d (ppm) 7.53–7.50 (m, 2H), 7.47–7.41 (m, 3H), 6.04
CDCl3)
d
(ppm) 7.46–7.39 (m, 4H), 7.36–7.28 (m, 6H), 7.26–7.17 (m,
(s, 1H), 4.62 (d, 1H, J¼10.2 Hz), 4.45–4.34 (m, 2H), 3.73 (dd, 1H,
5H), 6.82 (br s,1H), 5.11 (br s,1H), 4.96 (dd,1H, J¼0.98,13.3 Hz), 4.41
(dd, 1H, J¼5.62, 13.3 Hz), 3.84 (s, 3H), 3.35 (dd, 1H, J¼5.62, 10.4 Hz),
3.15 (t, 1H, J¼10.2 Hz), 1.01 (s, 9H); 13C NMR (100 MHz, CDCl3)
J¼3.50, 13.1 Hz), 3.65 (dd, 1H, J¼4.39, 13.2 Hz); 13C NMR (100 MHz,
CDCl3) d (ppm) 151.5, 134.5, 129.2, 128.5, 127.1, 74.8, 72.3, 51.2, 46.9;
FTIR (thin film) (CHCl3, cmꢀ1) 3036, 2925, 2105, 1498, 1473, 1443,
1285, 1246, 1149, 1082, 1058, 1027, 980, 908, 889, 752, 698; ESI/MS
(m/z) [Mþ1]þ: 258.1; HRMS (ESI) for C11H11N7O: calcd [Mþ1]þ
258.1097; found 258.10917.
d
(ppm) 155.5, 149.4, 134.9, 134.85, 131.9, 131.6, 129.7, 129.6, 128.2,
128.0,127.49,127.47,126.1, 61.1, 53.6, 51.9, 44.5, 26.3,18.6; FTIR (thin
film) (CHCl3, cmꢀ1) 3070, 2955, 2930, 2857, 1711, 1445, 1428, 1391,
1341, 1307, 1262, 1112, 1076, 739, 701; ESI/MS (m/z) [Mþ1]þ: 528.3;
HRMS (ESI) for C29H35N5O3Si: calcd [Mþ1]þ 528.24254; found
528.24289; for C29H33N5NaO3Si: calcd [MþNa]þ 550.22449; found
550.22499.
5.1.38. cis-(8-Phenyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazin-6-
yl)-methylamine (49)
To a solution of 48 (262 mg, 1.02 mmol) in ethanol (14.5 mL
(0.07 M)) was added (79 mg (30 mol %)) of 5% Pd/C and hydroge-
nated under 1 atm of H2. The suspension was then stirred 3 h at
room temperature, filtered on Celite and, the resulting solution was
evaporated under reduce pressure. The crude residue was filtered
on silica by eluting first with EtOAc and then with 30:70 EtOAc/
MeOH to give 49 as a slightly yellow gum (218 mg, 92%): 1H NMR
5.1.35. cis-8-Phenyl-5,6-dihydro-8H-tetrazolo[5,1-c][1,4]oxazine-6-
carboxylic acid methyl ester (46)
To a solution of 8 (200 mg, 0.861 mmol) in acetone (1.7 mL
(0.5 M)) was added an excess of Jones reagent and the mixture was
stirred for 30 min. An additional amount of Jones reagent was
added and the mixture was stirred again for 30 min. The reaction
was quenched with a minimum amount of isopropyl alcohol, then
filtered on Florisil and eluted with 1:1 MeOH/acetone eluant. The
resulting solution was evaporated under reduced pressure and co-
evaporated with dry MeOH. The crude residue was diluted with dry
MeOH (29 mL (0.03 M)) and a catalytic amount of conc. H2SO4 was
added with an excess of Na2SO4 as a drying agent. The mixture was
refluxed for 12 h, then evaporated under reduced pressure. The
(400 MHz, CD3OD)
6.10 (s, 1H), 4.72 (dd, 1H, J¼2.26, 12.4 Hz), 4.40–4.35 (m, 1H), 3.11–
2.99 (m, 2H); 13C NMR (100 MHz, CD3OD)
(ppm) 152.4, 135.7,
d (ppm) 7.50–7.47 (m, 2H), 7.44–7.42 (m, 3H),
d
128.7, 128.0, 127.5, 74.7, 74.3, 47.2, 42.2; FTIR (thin film) (CHCl3,
cmꢀ1) 3584, 3378, 3308, 3065, 3035, 3010, 2924, 2876, 1601, 1524,
1498, 1471, 1455, 1444, 1376, 1352, 1287, 1245, 1201, 1148, 1061,
1029, 928, 905, 753, 699; ESI/MS (m/z) [Mþ1]þ: 273.1; HRMS (ESI)
for C11H13N5O: calcd [Mþ1]þ 232.1192; found 232.11963.

6668
S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
5.1.39. cis-6-Iodomethyl-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-c]-
[1,4]oxazine (50)
101.2, 75.6, 18.2; FTIR (thin film) (CHCl3, cmꢀ1) 3132, 3065, 3036,
2960, 2923, 1672, 1496, 1474, 1456, 1429, 1384, 1342, 1261, 1199,
1110, 1073, 1029, 992, 967, 756, 724, 697; ESI/MS (m/z) [Mþ1]þ:
215.1; HRMS (ESI) for C11H10N4O: calcd [Mþ1]þ 215.09274; found
215.09269.
To a solution of 8 (750 mg, 3.23 mmol) in THF (65 mL (0.05 M))
was added PPh3 (1.86 g, 7.10 mmol, 2.2 equiv), imidazole (703 mg,
1.03 mmol, 3.2 equiv) and I2 (2.05 g, 8.07 mmol, 2.5 equiv). The
reaction mixture was stirred 12 h at 35 ꢁC, EtOAc was added and
a saturated sodium thiosulfate solution was added to quench the
excess of I2. The resulting organic phase was extracted two more
times with saturated sodium thiosulfate solution, then, succes-
sively washed with 10% HCl, saturated NaHCO3, and finally with
brine. The organic phase was then dried on Na2SO4 and evaporated
under reduced pressure. The crude residue was purified by flash
chromatography (EtOAc/hexanes 40:60 to 60:40) to give 50 as
5.1.43. 6-Methylene-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-c]-
[1,4]oxazine (52)
To a solution of 50 (116 mg, 0.339 mmol) in dry pyridine (3.4 mL
(0.1 M)) was added AgF (86 mg, 0.678 mmol, 2 equiv). The solution
was stirred in the dark (covered with aluminum foil) for 24 h. The
reaction mixture was then filtered on silica with ether and then
evaporated under reduced pressure. The crude residue was purified
by flash chromatography (EtOAc/hexanes 15:85 to 25:75) to give 52
as a colorless gum (65.7 mg, 90%): 1H NMR (300 MHz, CDCl3)
a colorless gum (1.09 g, 98%): 1H NMR (300 MHz, CDCl3)
d (ppm)
7.55–7.48 (m, 2H), 7.47–7.40 (m, 3H), 6.03 (s, 1H), 4.86 (ddd, 1H,
J¼0.93, 2.64, 12.1 Hz), 4.32–4.24 (m, 1H), 4.23–4.15 (m, 2H); 13C
d
(ppm) 7.48–7.37 (m, 5H), 6.36 (s, 1H), 5.18 (dd, 1H, J¼0.68,
NMR (75 MHz, CDCl3)
d
(ppm) 152.6, 135.8, 130.5, 129.8, 128.5, 76.0,
15.0 Hz), 5.11 (d, 1H, J¼15.0 Hz), 5.03 (s, 1H), 4.88 (s, 1H); 13C NMR
73.5, 51.2, 2.7; FTIR (thin film) (CHCl3, cmꢀ1) 3034, 2958, 2877,1497,
1472, 1455, 1440, 1368, 1287, 1246, 1201, 1146, 1094, 1074, 1050,
1028, 1005, 903, 749, 698; ESI/MS (m/z) [Mþ1]þ: 342.9; HRMS (ESI)
for C11H11IN4O: calcd [Mþ1]þ 343.0050; found 343.00581.
(75 MHz, CDCl3) d (ppm) 151.9, 147.6, 135.6, 130.6, 129.8, 128.2,
102.2, 76.2, 48.1; FTIR (thin film) (CHCl3, cmꢀ1) 3066, 3035, 3012,
2924, 1667, 1496, 1473, 1455, 1332, 1249, 1079, 1026, 898, 742, 697;
ESI/MS (m/z) [Mþ1]þ: 215.0; HRMS (ESI) for C11H10N4O: calcd
[Mþ1]þ 215.09274; found 215.09309.
5.1.40. cis-6-Methyl-8-phenyl-5,6-dihydro-8H-tetrazolo[5,1-c]-
[1,4]oxazine (17b)
Acknowledgements
To a solution of 50 (830 mg, 2.43 mmol) in MeOH (24.3 mL
(0.1 M)) was added Et2NH (359 mg, 4.85 mmol, 2 equiv) and
Raney nickel (208 mg (25% w/w)). The reaction mixture was
stirred 2 h under H2 (1 atm), filtered on Celite and evaporated
under reduced pressure. The crude residue was filtered on silica
and eluted with EtOAc/hexanes 1:1 to give 17b as a colorless gum
We thank the National Science and Engineering Consil of Canada
´
(NSERC), and Le Fonds Quebecois de la Recherche sur la Nature et
les Technologies (FQRNT) for financial assistance. We also thank
Dr. Michel Simard for X-ray structures and Stefano Rizzo for some
preparation of some intermediates in the project.
(0.524 mg, 100%): 1H NMR (300 MHz, CDCl3)
d (ppm) 7.41–7.26
(m, 5H), 5.87 (s, 1H), 4.45 (ddd, 1H, J¼0.98, 2.94, 12.5 Hz), 4.25–
Supplementary data
4.12 (m, 1H), 4.03 (ddd, 1H, J¼1.08, 10.7, 12.4 Hz), 1.42 (d, 3H,
J¼6.10 Hz); 13C NMR (75 MHz, CDCl3)
d (ppm) 152.0, 135.5, 129.3,
128.7, 127.6, 74.9, 70.0, 66.5, 18.2; FTIR (thin film) (CHCl3, cmꢀ1
)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.06.033.
3066, 3036, 2984, 2937, 2880, 1497, 1471, 1455, 1445, 1372, 1229,
1154, 1088, 1067, 1045, 1028, 934, 916, 754, 698; ESI/MS (m/z)
[Mþ1]þ: 217.1; HRMS (ESI) for C11H12N4O: calcd [Mþ1]þ 217.1083;
found 217.10884.
References and notes
1. (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, NY, 1996; Vol. 4; (b) Witten-
berger, S. J. Org. Prep. Proced. Int. 1994, 26, 499 and references cited herein.
2. (a) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.;
Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.;
Timmermans, P. B. M. W. M. J. Med. Chem. 1991, 34, 2525; (b) Carini, D. J.; Duncia,
J. V. Eur. Patent 253,310 A2, 1988; See also: (c) Brunner, H. R.; Nussberger, J.;
Burnier, M.; Waeber, B. Clin. Exp. Hypertens. 1993, 15, 1221; (d) Brunner, H. R.;
Nussberger, J.; Waeber, B. J. Hypertens. 1993, 11, S53; (e) Otsuka Pharmaceutical
Co., Ltd., Japan, Belg. Patent 878,548, 1979; (f) Hiatt, W. R. Vasc. Med. 1997, 2, 257;
(g) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, K. R. Prog. Med.
Chem. 1980, 17, 151 and references cited therein.
3. For pertinent references, see: (a) Zabrocki, J.; Smith, D. G.; Dunbar, J. B., Jr.;
Iijima, H.; Marshall, G. R. J. Am. Chem. Soc. 1988, 110, 5875; (b) Zabrocki, J.;
Dunbar, J. B., Jr.; Marshall, K. W.; Toth, M. V.; Marshall, G. R. J. Org. Chem. 1992,
57, 202.
4. For pertinent recent references, see: (a) Sammakia, T.; Smith, R. S. J. Am. Chem.
Soc. 1994, 116, 7915; (b) Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1991,
113, 8089; (c) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.; Yamamoto, H.;
Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107; (d) Corcoran, R. C.
Tetrahedron Lett. 1990, 31, 2101.
5.1.41. (1-Allyl-1H-tetrazol-5-yl)-phenyl-methanol (53)
To a solution of 50 (1.45 g, 4.25 mmol) in EtOH/THF (2:1)
(159 mL, 0.027 M) was added Zn (2.33 g, 35.7 mmol, 8.4 equiv)
and NH4Cl (0.568 g, 10.6 mmol, 2.5 equiv). The reaction mixture
was refluxed 1 h, then filtered on Florisil, and the resulting solu-
tion was evaporated under reduced pressure. The crude residue
was purified by flash chromatography (EtOAc/hexanes 35:70) to
give 53 as a colorless oil (0.90 g, 98%): 1H NMR (300 MHz, CDCl3)
d
(ppm) 7.42–7.37 (m, 5H), 6.37 (s, 1H), 5.72 (ddt, 1H, J¼6.20, 10.3,
17.0 Hz), 5.19 (dd, 1H, J¼0.74, 10.2 Hz), 5.06 (dd, 1H, J¼0.70,
17.0 Hz), 4.88 (m, 2H); 13C NMR (75 MHz, CDCl3)
(ppm) 156.8,
d
138.7, 130.6, 129.8, 129.6, 126.9, 121.1, 67.3, 51.2; FTIR (thin film)
(CHCl3, cmꢀ1) 3307, 3091, 3066, 3033, 2921, 1647, 1495, 1452, 1419,
1251, 1093, 1053, 1028, 989, 938, 725, 699; ESI/MS (m/z) [Mþ1]þ:
217.0; HRMS (ESI) for C11H12N4O: calcd [Mþ1]þ 217.10839; found
217.10906.
ˆ
5. Hanessian, S.; Simard, D.; Deschenes–Simard, B.; Chenel, C.; Haak, E. Org. Lett.
2008, 10, 1381.
6. The four cyanohydrins isomers can be separated by flash column chromatog-
raphy; see also: (a) Brunel, J.-M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43,
2752; (b) Gregory, R. H. J. Chem. Rev. 1999, 99, 3649.
7. (a) Davis, B.; Brandstetter, T.; Smith, C.; Hackett, L.; Winchester, B. G.; Fleet, G. K.
Tetrahedron Lett. 1995, 36, 7507; (b) Davis, B.; Nash, R. J.; Watson, A. A.; Smith,
C.; Fleet, G. W. J. Tetrahedron 1999, 55, 4501; (c) Sharpless, K. B.; Demko, Z. P.
Angew. Chem., Int. Ed. 2002, 41, 2113.
8. Ek, F.; Wistrand, L.-G.; Frejd, T. Tetrahedron 2003, 59, 6759.
9. (a) Popov, A. I.; Bodner, R. L. Inorg. Chem.1972,11,1410; (b) Popov, A. I. Coord. Chem.
Rev. 1969, 4, 463; (c) Robinson, S. D.; Moore, D. S. Adv. Inorg. Chem. 1988, 32, 205.
10. For the related racemic 5-substituted tetrazoles, see: (a) Satoh, Y.; Marcopulos,
N. Tetrahedron Lett. 1995, 36, 1759; (b) Satoh, Y.; Moliterni, J. Synlett 1998, 528.
5.1.42. 6-Methyl-8-phenyl-8H-tetrazolo[5,1-c][1,4]oxazine (51)
To a solution of 50 (23 mg, 0.0672 mmol) in DME (0.84 mL
(0.08 M)) was added DBU (21 mg, 0.134 mmol, 2 equiv). The re-
action mixture was refluxed 1 h, then evaporated under reduced
pressure. The crude residue was purified by flash chromatography
(EtOAc/hexanes 30:70) to give 51 as a colorless gum (13.7 mg,
95%): 1H NMR (300 MHz, CDCl3)
d (ppm) 7.48–7.45 (m, 1H), 6.98
(q, 1H, J¼1.22 Hz), 6.73 (s, 1H), 2.08 (d, 3H, J¼1.23 Hz); 13C NMR
(75 MHz, CDCl3)
d (ppm) 147.6, 146.3, 135.4, 130.7, 129.9, 127.6,

S. Hanessian et al. / Tetrahedron 65 (2009) 6656–6669
6669
11. (a) Baruah, M.; Bols, M. Synlett 2002, 1111; (b) Viuf, C.; Bols, M. Angew. Chem.,
Int. Ed. 2001, 40, 623.
12. Maiti, S. N.; Spevak, P.; Narender Reddy, A. V. Synth. Commun. 1988, 18, 1201.
13. (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635; (b) Vautier, M.;
Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983, 24, 763.
14. (a) Shangguan, N.; Katukojvala, S.; Grenberg, R.; Williams, L. J. J. Am. Chem. Soc.
2003, 125, 7754; (b) Rosen, T.; Lico, I. M.; Chu, D. T. W. J. Org. Chem. 1998, 53,
1580; (c) Fazio, F.; Wong, C.-H. Tetrahedron Lett. 2003, 44, 9083.
15. For X-ray crystallographic data of compounds 8, 9, 14, 22, 24, 26, 28, 29
(p-bromobenzoate), 43, see Supplementary data.