Proximity-assisted cycloaddition reactions - Facile Lewis acid-mediated synthesis of diversely functionalized bicyclic tetrazoles

Article abstract of DOI:10.1021/ol703071c

(Chemical Equation Presented) Aliphatic azidonitriles separated by three or four carbon atoms undergo facile Lewis acid-induced cycloadditions to give bicyclic tetrazoles, even at 0 °C. Extension to 3-azido-2-aryl-1,3- dioxolanes and the corresponding 1,3-dioxanes in the presence of TMSCN and BF₃·OEt₂ leads to a series of diversely functionalized novel oxabicyclic tetrazoles. The reactions represent new aspects of proximity-assisted dipolar cycloadditions that afford thermodynamically controlled enantiopure products proceeding through discrete oxocarbenium ion intermediates.

Full text of DOI:10.1021/ol703071c

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1381-1384
Proximity-Assisted Cycloaddition
Reactions Facile Lewis Acid-Mediated
s
Synthesis of Diversely Functionalized
Bicyclic Tetrazoles
Stephen Hanessian,* Daniel Simard, Benoˆıt Descheˆnes-Simard,
Caroline Chenel, and Edgar Haak
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre-Ville,
Montre´al, Que´bec H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received December 20, 2007
ABSTRACT
Aliphatic azidonitriles separated by three or four carbon atoms undergo facile Lewis acid-induced cycloadditions to give bicyclic tetrazoles,
even at 0 C. Extension to 3-azido-2-aryl-1,3-dioxolanes and the corresponding 1,3-dioxanes in the presence of TMSCN and BF3 OEt2 leads to
°
‚
a series of diversely functionalized novel oxabicyclic tetrazoles. The reactions represent new aspects of proximity-assisted dipolar cycloadditions
that afford thermodynamically controlled enantiopure products proceeding through discrete oxocarbenium ion intermediates.
Dipolar cycloaddition reactions have been the cornerstone
of heterocyclic chemistry for over 50 years.1 In this regard,
tetrazoles have gained prominence in medicinal chemistry
in recent years owing to their unique electronic and spacial
characteristics.2,3
The first reported synthesis of a tetrazole is attributed to
Bladin in 1885.4 Since then, a plethora of examples has been
published for the synthesis of tetrazoles by intermolecular
cycloadditions of an activated nitrile and an azide.5 Normally,
high temperatures and polar aprotic solvents are used. Other
methods are also known using oximes6 or amides.7 Von
Kereszty,8 Carpenter,9 and Smith10 provided early examples
of intramolecular cycloadditions to produce 5,5- or 5,6-
bicyclic 1,5-disubstituted tetrazoles. With a few exceptions,11
such reactions are conducted in solvents such as DMF or
DMSO at temperatures above 100 °C.12
(5) (a) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro, L.
J. Org. Chem. 2004, 69, 2896. (b) Shie, J.-J.; Fang, J.-M. J. Org. Chem.
2003, 68, 1158. (c) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2110.
(6) (a) Nishiyama, K.; Izumi, M. Bull. Chem. Soc. Jpn. 1985, 58, 2419.
(b) Singh, H.; Bhutani, K. K.; Malhotra, R. K.; Paul, D. J. Chem. Soc.,
Perkin Trans. 1 1979, 12, 3166.
(7) Duncia, J. V.; Pierce, M. E.; Santella, J. B., III. J. Org. Chem. 1991,
56, 2395.
(8) von Kereszty, W. German Patent 611,692, 1935.
(9) Carpenter, W. R. J. Org. Chem. 1962, 27, 2085.
(10) Smith, P. A. S.; Clegg, J. M.; Hall, J. H. J. Org. Chem. 1958, 23,
524.
(11) See for example (a) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001,
3, 4091. (b) Porter, T. C.; Smalley, R. K.; Teguiche, M.; Purwono, B.
Synthesis 1997, 773.
(12) (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.
(1) For reviews see : (a) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105,
2765. (b) Harju, K.; Yli-Kauhaluoma, J. Recent Res. DeVel. Org. Chem.
2004, 8, 111. (c) Jorgensen, K. A.; Gothelf, K. V. Chem. ReV. 1998, 98,
863. (d) Padwa, A. Angew. Chem., Int. Ed. 1976, 15, 123. (e) Huisgen, R.
Angew. Chem., Int. Ed. 1963, 2, 565.
(2) For pertinent references see: (a) Zabrocki, J.; Smith, D. G.; Dunbar,
Jr. J. B.; 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.
(3) (a) Butler, R. N. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, U.K. 1996;
Vol. 4. (b) Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26, 499. (c)
Koldobskii, G. I.; Ostrovskii, V. A.; Popavskii, V. S. Khim. Geterotsikl.
Soedin. 1981, 10, 1299. (d) Benson, F. R. Heterocycl. Compd. 1967, 8, 1.
(e) Benson, F. R. Chem. ReV. 1947, 40, 1.
(4) Bladin, J. A. Ber. 1885, 18, 2907.
10.1021/ol703071c CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/04/2008

Herein, we report on an exceptionally facile formation
of bicyclic tetrazoles containing functionally useful groups
at room temperature or lower. Our work was instigated
by an unexpectedly mild formation of a tetracyclic tetrazole
in conjunction with a synthetic approach to malayamycin13
and N-malayamycin.14 Thus, treatment of the triacetate 1
with TMSCN in nitromethane in the presence of BF3‚OEt2
(2 equiv) led to the crystalline tetrazole 3 via the intermed-
iate acetal 2 (Scheme 1). Model cyclization of ω-azido-
Table 1. Formation of Oxabicyclic Tetrazoles from Azido
2-aryl-1,3-dioxolanesa
cis(15)/
trans(16)c
entry
Ra
yield (%)b
Scheme 1. Formation of Tetrazoles from Different Acetals
a
b
c
d
e
f
g
h
i
Phd
o-Cl-Ph
m-Cl-Ph
p-Cl-Ph
m-NO2-Ph
p-NO2-Ph
m-MeO-Ph
m-Br-Ph
m-CF3-Ph
m-CN-Ph
94
74
74
78
48
29
97
73
43
46
>19:1
10:1
>19:1
>19:1
10:1
10:1
>19:1
10:1
and Azido-nitriles
>19:1
>19:1
j
a Racemic series. b Isolated yield. c NMR ratio. d From enantiopure 14a,
81%, >19:1.
Extension to ketals 17-20 was equally successful leading
to spiro oxabicyclic and related disubstituted oxabicyclic
tetrazoles 21-24 (Scheme 2). The scope of the reaction was
Scheme 2. Formation of Diverse Oxabicyclic Tetrazoles from
2,2′-Substituted 1,3-Dioxolanes and from â-Azido Ethyl Esters
nitriles 4 and 5 at 0 °C gave the corresponding bicyclic
tetrazoles 6 and 7, respectively, in over 90% yield. Related
compounds had been previously obtained in the presence of
concentrated H2SO4 in chloroform.8,9 ω-Azido dimethyl
acetals 8 and 9 gave the bicyclic methoxy tetrazoles 10 and
11 respectively (Scheme 1).
Extension to 5,7-systems could not be achieved in agree-
ment with previous observations.8-10 Finally, a bis-ω-azido
acetal 12 gave the C-benzyl oxabicyclic tetrazole 13 in 95%
yield. These preliminary results paved the way to a study of
ω-azido cyclic acetals as versatile precursors to hitherto
unknown functionalized oxabicyclic tetrazoles. Thus, treat-
ment of the readily available 1-azido-2,3-O-arylidene-2,3-
propane diols 14a-j prepared from the corresponding
racemic diols with TMSCN in MeNO2 in the presence of
BF3‚OEt2 (0 °C to rt), afforded the corresponding cis-oriented
bicyclic tetrazoles 15a-j as major isomers in good to
excellent yields depending on the aromatic substituent (Table
1). The reaction was equally successful on an enantiopure
diol.15
a NMR ratio.
expanded by starting with a â-azido ester 25. Reduction with
Dibal-H, acetylation of the intermediate hemiacetal16 to 26,
and treatment with TMSCN led to a monosubstituted
oxabicyclic tetrazole 27. In principle, this nonoptimized
(13) (a) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G. Org.
Lett. 2003, 5, 4277. (b) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang,
G.; Pierron, J.; Loiseleur, O. Tetrahedron 2006, 62, 5201.
(14) Hanessian, S.; Huang, G.; Chenel, C.; Machaalani, R.; Loiseleur,
O. J. Org. Chem. 2005, 70, 6721.
(16) Rychnovsky, S. D.; Vitale, J.; Jasti, R. J. Am. Chem. Soc. 2004,
126, 9904.
(15) See Supporting Information.
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Org. Lett., Vol. 10, No. 7, 2008

approach can be extended to other 2-azido ethyl esters of
other carboxylic acids.
cyanohydrins 28-31 during the course of the reaction favors
the thermodynamically more stable cis-isomer 15a. In fact,
treatment of isolated cyanohydrins 28 and 29 with BF3‚OEt2
led to no reaction and eventual hydrolysis. On the other hand,
both cyanohydrins 30 and 31 cyclized to give the cis-isomer
15a in preponderance although much slower in the case of
31.19 The dioxane analogue 32 gave a 3:1 mixture of the
cis- and trans-oxabicyclic tetrazoles 35 and 36, while the
dioxepane 33 gave 37 and 38 as a 1:1.2 separable mixture.
The isomeric dioxepan 34 also gave a separable 1:1 mixture
of 39 and 40 (Scheme 4).
The Lewis acid-catalyzed ring opening of cyclic acetals
has been the subject of numerous studies.17 In the case of
the 2- and 2,2′-substituted 1,3-dioxolanes exemplified by 14a,
proximal and distal coordination of BF3‚OEt2 could lead to
two oxocarbenium ions A and B, respectively (Scheme 3).
Scheme 3. Formation and Reaction of Isolated Cyanohydrinsa
Scheme 4. Reaction of 2-Phenyl-1,3-dioxane and
1,3-Dioxepane Analoguesa
a NMR ratios.
a R ) BF2 or BF3.
Although the exact nature of coordinated species is still
under investigation, it is possible that pseudocyclic alkoxy-
borinate intermediates20,21 are present (Scheme 5). Activation
These can each lead to two pairs of diastereoisomeric cyano-
hydrins 28, 29 and 30, 31, respectively.18 Only the latter pair
can engage in cycloaddition to give 15a and 16a, respec-
tively.
The formation of 15a (and related analogues) as the major
product, denotes a preference for transition states that lead
to the cis-diequatorially disposed isomer over the trans
(minor), arising from 30 and 31, respectively. The alternative
oxepan analogues coming from the other cyanohydrin pair
(28, 29) were not observed. Thus equilibration of the
Scheme 5. Possible Alkoxydifluoroborinate Intermediates15
(17) 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.
(18) (a) Brunel, J.-M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43,
2752. (b) Gregory, R. H. J. Chem. ReV. 1999, 99, 3649.
(19) It should be noted that re-enactment of the cycloaddition reaction
starting with the individually isolated cyanohydrins does not accurately
represent the same oxygen-coordinated intermediates found in the acetal-
opening reaction. The O-TMS ether of 30 cyclized with an 83% yield to
15a exclusively.
(20) (a) Hayashi, Y.; Rohde, J. J.; Corey, E. J. J. Am. Chem. Soc. 1996,
118, 5502. (b) Gerrard, W.; Mooney, E. F.; Peterson, W. G. J. Inorg. Nucl.
Chem. 1967, 29, 943.
(21) A negative ion mass spectrum of the reaction mixture containing
uncyclized cyanohydrins showed ion masses corresponding to [M + BF3]
and [M + BF2OH]. See Supporting Information.
of the nitrile by a second equivalent of BF3‚OEt2 results in
the observed facile cycloaddition.
A slower rate of cycloaddition of 31 to the trans-isomer
16a allows for equilibration to the pro-cis-precursor 30 which
Org. Lett., Vol. 10, No. 7, 2008
1383

undergoes faster ring closure to the thermodynamically more
stable cis-adduct 15a. Presumably, in the case of the dioxane
and dioxepane analogues (Schemes 4, 5), the respective
boron-coordinated dioxacyanohydrins are each relatively
stable and do not equilibrate as readily as in the dioxolane
analogues.
Scheme 6. Aube´-type Reaction Leading to the Formation of
Dihydro-oxazinea
We next studied the nature of the Lewis acid, the solvent
polarity, and the source of cyanide. Nitromethane and
BF3•OEt2 were found to be the most effective combination
leading to the highest yields. Me2AlCl, Me3Al or BF3‚OEt2
in hexanes (2-phase system) was surprisingly good although
the diastereoselectivity was slightly diminished.15 Other
Lewis acids were either ineffective or did not lead to
product.15 Two equivalents of BF3‚OEt2 were required to
achieve maximum conversion. As observed by Sharpless and
co-workers,22 zinc bromide (but not chloride) gave acceptable
results (77% yield, 81:19 cis:trans). Using TBSCN, KCN,
Bu4NCN, etc. resulted in recovery of starting acetal or
eventual hydrolysis. The least effective solvents were THF,
ether, CH2Cl2, toluene, CHCl3, and CH3CN.15
a R ) BF2 or BF3.
Finally we comment on the influence of substituent effects
on the aromatic ring. Selectivities ranging from cis:trans 10:1
to over 20:1 were observed for selected o-, m-, and
p-substituents which were not highly stabilizing to the
incipient oxocarbenium ions 42 and 43 that could arise from
the p-methoxyphenyl acetal 41 (Scheme 6). Surprinsingly,
the p-methoxyphenyl acetal led instead to the dihydrooxazine
45 in 91% yield. A plausible explanation is illustrated in
Scheme 6. The highly stabilized proximal oxocarbenium ion
42 can undergo reversible attack by cyanide to give the
tetrazole. However, another pathway is via the distal oxo-
carbenium ion 43 which undergoes an Aube´-type23 reaction
by internal azide attack leading to the observed product 45.
Interestingly, the corresponding dihydro-oxazoline 44 is not
formed most probably because of an unfavorable endo-trig
closure.24 Dihydrooxazines such as 45 were also the major
products when traces of water (e.g., undistilled nitromethane)
were present.15
The facile synthesis of diversely functionalized bicyclic
tetrazole scaffolds should find ample utility in a variety of
applications related to medicinal chemistry, agrochemistry,
and material science.
Acknowledgment. We thank the National Science and
Engineering Council of Canada (NSERC), and Le Fonds
Que´becois de la Recherche sur la Nature et les Technologies
(FQRNT) for financial assistance. We thank Dr. Michel
Simard (Universite´ de Montre´al) for X-ray structures. We
also thank Alexandra Furtos and Karine Venne (Universite´
de Montre´al) for high-resolution mass spectrometric analysis.
Supporting Information Available: General experimen-
tal procedures, characterization of main compounds, and
X-ray ORTEP structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) Himo, F.; Demko, A. P.; Noodleman, L.; Sharpless, K. B. J. Am.
Chem. Soc. 2003, 125, 9983.
(23) (a) Aube´, J.; Badiang, J. G. J. Org. Chem. 1996, 61, 2484. (b)
Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B. T.; Reddy, C. E.;
Aube´, J. J. Am. Chem. Soc. 2003, 125, 7914.
(24) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
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