Dehydrative fragmentation of 5-hydroxyalkyl-1 h -tetrazoles: A mild route to alkylidenecarbenes

Article abstract of DOI:10.1021/ol300276p

The development of a mild, base-free method for the generation of alkylidenecarbenes is reported. Treatment of 5-hydroxyalkyl-1H-tetrazoles with carbodiimides generates products arising from the 1,2-rearrangement or [1,5]-C-H bond insertion of a putative alkylidenecarbene. Formation of this divalent intermediate is proposed to occur by way of a tetraazafulvene, which undergoes extrusion of 2 mol of dinitrogen. Details of this methodology, its application to the synthesis of combretastatin A-4, and an improved route to 5-hydroxyalkyl-1H-tetrazoles are described.

Full text of DOI:10.1021/ol300276p

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1548–1551
Dehydrative Fragmentation of
5-Hydroxyalkyl-1H-tetrazoles: A Mild
Route to Alkylidenecarbenes
Duncan J. Wardrop* and John P. Komenda
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061, United States
wardropd@uic.edu
Received February 3, 2012
ABSTRACT
The development of a mild, base-free method for the generation of alkylidenecarbenes is reported. Treatment of 5-hydroxyalkyl-1H-tetrazoles with
carbodiimides generates products arising from the 1,2-rearrangement or [1,5]-CÀH bond insertion of a putative alkylidenecarbene. Formation of
this divalent intermediate is proposed to occur by way of a tetraazafulvene, which undergoes extrusion of 2 mol of dinitrogen. Details of this
methodology, its application to the synthesis of combretastatin A-4, and an improved route to 5-hydroxyalkyl-1H-tetrazoles are described.
1H-Tetrazoles have long been recognized as metaboli-
cally stable bioisosteres of the carboxylate group for
which reason they have found widespread application
in medicinal chemistry.1 Our interest in these nitrogen-
rich heterocycles, however, stems from their chemical
instability2,3 and attendant potential as precursors of
alkylidenecarbenes: transient, electron-deficient spe-
cies, which undergo a number of synthetically valuable
reactions, including [1,2]-rearrangement, ylide forma-
tion, alkene cyclopropanation and [1,5]-CÀH bond
insertion.4 Over the past decade, we have studied
the latter transformation as a means to access O- and
N-heterocycles and natural products that encompass
these ring systems.5
Synthetic potential notwithstanding, the practical value
of alkylidenecarbenes remains limited by a deficiency of
methods for their generation under nonbasic conditions.6
Although a number of noteworthy solutions to this issue
have been reported, including the thermolysis of epoxya-
ziridinyl imines7 and addition of “soft” nucleophiles to
alkynyl(phenyl)iodonium salts,8 the continued develop-
ment of new methods appears to be warranted. In this
context, we were intrigued by a rarely cited report from
(5) (a) Wardrop, D. J.; Fritz, J. Org. Lett. 2006, 8, 3659. (b) Wardrop,
D. J.; Bowen, E. G. Chem. Commun. 2005, 5106. (c) Wardrop, D. J.;
Zhang, W.; Fritz, J. Org. Lett. 2002, 4, 489. (d) Wardrop, D. J.; Zhang,
W. Tetrahedron Lett. 2002, 43, 5389. (e) Wardrop, D. J.; Velter, A. I.;
Forslund, R. E. Org. Lett. 2001, 3, 2261.
(6) For representative examples of alkylidenecarbene generation
under strongly basic conditions, see: (a) Walsh, R. A.; Bottini, A. T.
J. Org. Chem. 1970, 35, 1086. (b) Stang, P. J.; Mangum, M., G.; Fox, D.,
P.; Haak, P. J. Am. Chem. Soc. 1974, 96, 4562. (c) Taber, D. F.; Christos,
T. E.; Neubert, T. D.; Batra, D. J. Org. Chem. 1999, 64, 9673. (d) Green,
M. P.; Prodger, J. C.; Sherlock, A. E.; Hayes, C. J. Org. Lett. 2001, 3,
3377. (e) Reference 5b.
(7) (a) Kim, S.; Cho, C. M. Tetrahedron Lett. 1994, 35, 8405. (b)
Kirmse, W. Eur. J. Org. Chem. 1998, 201.
(8) (a) Ochiai, M.; Kunishima, M.; Tani, S.; Nagao, Y. J. Am. Chem.
Soc. 1991, 113, 3135. (b) Williamson, B. L.; Tykwinski, R. R.; Stang,
P. J. J. Am. Chem. Soc. 1994, 116, 93. (c) Feldman, K. S. In Strategies and
Tactics in Organic Synthesis; Harmata, M., Ed.; Elsevier Academic Press:
London, 2004; Vol. 4, p 133. (d) Reference 5c.
(1) For reviews of the medicinal chemistry of 1H-tetrazoles, see: (a)
Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem. Heterocycl.
Compd. 2007, 43, 1. (b) Herr, J. R. Bioorg. Med. Chem. 2002, 10, 3379.
(2) In this context, tetrazoles play a key role in many modern high-
€
energy density materials (HEDM): Klapotke, T. M., Structure and
Bonding (Berlin); Springer: Berlin/Heidelberg, Germany, 2007; Vol. 125,
p 85.
(3) For a review of the thermal decomposition of tetrazoles, see:
Lesnikovich, A. I.; Levchik, S. V.; Balabanovich, A. I.; Ivashkevich,
O. A.; Gaponik, P. N. Thermochim. Acta 1992, 200, 427.
(4) For reviews of alkylidenecarbene chemistry and the FritschÀ
ButtenbergÀWiechell (FBW) rearrangement, see: (a) Jahnke, E.; Tyk-
winski, R. R. Chem. Commun. 2010, 3235. (b) Knorr, R. Chem. Rev.
2004, 104, 3795. (c) Kirmse, W. Angew. Chem., Int. Ed. Engl. 1997, 36 (6),
1164. (d) Taber, D. F. In Methods of Organic Chemistry, 4th ed.;
Helmchen, G., Ed.; Georg Thieme Verlag: New York, 1995; Vol. E21,
p 1127. (e) Stang, P. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 274. (f)
Stang, P. J. Chem. Rev. 1978, 78, 383.
r
10.1021/ol300276p
Published on Web 02/28/2012
2012 American Chemical Society

Behringer regarding the thermolysis and rearrangement of
5-hydroxy(diarylmethyl)-1H-tetrazoles and related deriv-
atives 1 to form diarylalkynes 4 (Scheme 1).9 In this case,
dehydration of 1 (X = OH) was proposed to generate
unstable tetraazafulvene intermediate 2 which undergoes
conversion to the observed products through extrusion of
2 mol of dinitrogen and rearrangement of the resulting
alkylidenecarbene 3.10,11
Table 1. Preparation of 5-Hydroxyalkyl-1H-tetrazoles 8
Scheme 1
Here we report on our investigation of this unusual
tetrazole reactivity manifold and the development of con-
ditions that trigger the dehydration and fragmentation of
5-hydroxyalkyl-1H-tetrazoles to form alkylidenecarbenes
under exceptionally mild conditions. In addition to em-
ploying this methodology in the preparation of alkynes,
diynes, triynes, and five-membered hetero/carbocycles, its
application to the stereoselective total synthesis of com-
bretastatin A4 (18) is also described.
Our study commenced with the development of a gen-
eral method for the preparation of 5-hydroxyalkyl-1H-
tetrazoles 7 (Table 1). While potentially available from
cyanohydrins via cycloaddition with azide,12 we sought to
establish a more flexible route to these substrates that
avoided the direct use of cyanide and azide-based
reagents.13 In this regard, we opted to adapt a two-step
protocol reported by Satoh involving the addition of
1-benzyl-5-tetrazoyllithium to carbonyl electrophiles and
subsequent de-N-benzylation.14,15 Thus, treatment of ke-
tones, ynones, and an aldehyde 6 with 1-allyl-5-tetrazoyl-
lithium (5)16 in THF at low temperature provided the
desired alcohols 7 in excellent yield (Table 1).
a Unless otherwise noted, isolated yield, after purification by flash
chromatography on silica gel. b Unless otherwise noted, yield after
aqueous workup; no further purification required. c Isolated yield, after
purification by back extraction.
(9) Behringer, H.; Matner, M. Tetrahedron Lett. 1966, 24, 1663.
(10) Tetraazafulvene intermediates have also been implicated in the
Pb(IV)-mediated oxidation of 2-(tetrazol-5-yl)alkanoic acids: Fetter, J.;
Efficient, direct de-N-allylation of the addition products
7 was now accomplished under Yamamoto’s conditions,17
by treatment with a combination of catalytic NiCl2(dppe)
and tert-BuMgCl inCH2Cl2 (Table 1). The easewithwhich
the N-allyl groups are removed from 7 is notable, as
cleavage of N-benzyl protecting groups from this type of
substrate has previously proved problematic.14a
Turning our attention to the generation of alkylidene-
carbenes 9, we now opted to examine carbodiimide dehy-
drating agents as a means to access the putative
tetraazafulvene intermediate since Behringer noteda single
example of the use of DCC in mediating the decomposition
of 1. Gratifyingly, treatment of 8a with a range of
ꢀ
Nagy, I.; Giang, L. T.; Kajtar-Peredy, M.; Rockenbauer, A.; Korecz, L.;
Czira, G. J. Chem. Soc., Perkin Trans. 1 2001, 1131. See also (b) Scott,
F. L.; Donovan, J.; O’Halloran, J. K. Tetrahedron Lett. 1970, 28, 4079.
(11) The mechanism by which nitrogen loss occurs in this case is, as
yet, unknown.
(12) For an overview of this transformation, see: Wittenberger, S. J.
Org. Prep. Proced. Int. 1994, 26, 499.
(13) For a complementary approach to alkylidenecarbenes from
R-cyanomesylates, see: Cordonnier, R.; Van Nhien, A. N.; Soriano,
E.; Marco-Contelles, J.; Postel, D. Tetrahedron 2010, 66, 736.
(14) (a) Satoh, Y.; Marcopulos, N. Tetrahedron Lett. 1995, 36, 1759.
(b) Raap, R. Can. J. Chem. 1971, 49, 2139.
(15) For a review of the organometallic chemistry of tetrazoles, see:
Voitekhovich, S. V.; Gaponik, P. N.; Koldobskii, G. I. Russ. J. Org.
Chem. 2005, 41, 1599.
(16) Generated by n-BuLi-mediated deprotonation of 1-allyltetra-
zole, which is available in one step through the condensation of
allylamine, sodium azide, and ethyl orthoformate: Gaponik, P. N.;
Karavai, V. P.; Grigor’ev, Y. V. Chem. Heterocycl. Compd. 1985, 11,
1255.
(17) Kamijo, S.; Jin, T.; Yamamoto, Y. J. Org. Chem. 2002, 67, 7413.
Org. Lett., Vol. 14, No. 6, 2012
1549

carbodiimides, including DCC, EDC, and, most conveni-
ently, diisopropylcarbodiimide (DIC), smoothly provided
diphenylacetylene (10a) in excellent yield (Figure 1). In all
cases but 8f and 8l, decomposition occurred at room
temperature over the course of 24 h.
carbene 9c through competitive oxonium ylide formation
and de-O-alkylation at the o-MeO substituent.19 That
pyridines are known to undergo ring opening in the
presence of carbodiimides may account for the inefficiency
observed during the formation of product 10g.20
Given the success of the [1,2]-rearrangement process, we
next sought to expand our methodology to include the
[1,5]-CÀH insertion manifold. In this case, substrates were
purposely chosen with substituents known to have low
migratory aptitude.21 The requisite tetrazoles 12 (Figure 2)
were prepared from the corresponding methyl ketones
through the two-step sequence previously described. In
all cases, the overall yield of these substrates compared
favorably with those noted in Table 1.
Figure 2. Dehydrative fragmentation of 5-hydroxyalkyl-1H-
a
tetrazoles: alkylidenecarbene [1,5]ÀC-H bond insertion. For
Figure 1. Dehydrative fragmentation of 5-hydroxyalkyl-1H-
tetrazoles: alkylidenecarbene 1,2-rearrangement. aUnless other-
wise noted, isolated yield, after purification by flash chromato-
graphy on silica gel. bReaction conducted in 1,2-dichloroethane
at reflux: 10f (5 min); 10l (1 h). cEDC used in place of DIC for
ease of purification.
details of the preparation of substrates 12aÀf, see Supporting
b
Information. Isolated yields, after purification by flash chro-
matography on silica gel. cDCC used in place of DIC. dIsolated
as an inseparable 5:4 mixture of [1,5]-CÀH insertion and 1,2-
rearrangement products.
That the onset of these reactions is accompanied by the
generation ofnitrogen gasappearsto beconsistent with the
proposed mechanism. Encouragingly, this processdisplays
considerable scope and offers access to symmetrical and
nonsymmetrical alkynes (10aÀj) as well as diynes (10k)
and triynes (10l) in yields which compare favorably with
the 1,2-rearrangement of other precursors, including 1,1-
dihaloalkenes.18 In addition to product 10c, dehydration
of o-anisole derivative 8c also yielded traces (3%) of
3-phenylbenzofuran (11), which is believed to arise from
While attempts to effect the decomposition of 12 at
room temperature in the presence of DIC or DCC failed,
conducting this reaction in 1,2-dichloroethane at reflux
(84 °C) rapidly generated the desired insertion products 13
in reasonable yield. Significantly, the efficiency of these
cyclizations compare favorably with that of other intra-
molecular alkylidenecarbene CÀH insertion reactions.22
While the low yield of cyclopentene 13a arises, in part,
from the volatility of this product, it may also reflect the
increased bond dissociation energy of the target CÀH
(20) Wilchek, M.; Miron, T.; Kohn, J. Anal. Biochem. 1981, 114, 419.
(21) Wolinsky, J.; Clark, G. W.; Thorstenson, P. C. J. Org. Chem.
1976, 41, 745.
(22) For the preparation of 13b (28À48%) via the CÀH insertion of
an alkylidenecarbene generated from 1,1-dihaloalkenes, see: Kunishi-
ma, M.; Hioki, K.; Tani, S.; Kato, A. Tetrahedron Lett. 1994, 35, 7253.
(23) Malatesta, V.; Ingold, K. U. J. Am. Chem. Soc. 1981, 103, 609–
614.
(18) For selected examples of alkyne formation through the 1,2-
rearrangement of alkylidenecarbenes or their carbenoids, see: (a) Re-
ference 6b. (b) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1
1977, 869. (c) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44,
4997. (d) Eisler, S.; Tykwinski, R. R. J. Am. Chem. Soc. 2000, 122, 10736.
(e) Reference 4b. (f) Reference 8a.
(19) Hari, Y; Kondo, R.; Date, K.; Aoyama, T. Tetrahedron 2009, 65,
8708.
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Org. Lett., Vol. 14, No. 6, 2012

bond in this system relative to the other substrates in which
the presence of an adjoining heteroatom favors CÀH
insertion.23 Unexpectedly, the formation of 4-azaspiro-
[2.4]heptane 13f was accompanied by a significant amount
of [1,2]-rearrangement.
18 were found to be in complete agreement with those
reported by Pettit for the natural product.31
Scheme 2
Having established the viability of our methodology in
[1,5]-CÀH insertions, we turned our attention to its appli-
cation to natural product synthesis. The dried stem wood
of the South African bush willow tree Combretum caffrum
harbors several biologically active stilbenoid phenols now
commonly known as combretastatins. First isolated by
Pettit in 1989,24 combretastatin A4 (18) competitively binds
the colchicine site of tubulin and is an exceptionally potent
inhibitor of microtubule assembly and cellular mitosis. Its
selectivity for proliferating endothelial cells and suppression
of tumor angiogenesis places 18 and its numerous synthetic
analogs25 in an emerging class of anticancer drugs referred
to as vascular disrupting agents.26
Our route to combretastatin A4 (18) commenced from
isovanillin derivative 14,27 which underwent addition of
3,4,5-trimethoxyphenyllithium28 to generate the corre-
sponding benzhydryl alcohol in excellent yield (93%)
(Scheme 2). Treatment of this compound with 2-iodox-
ybenzoic acid (IBX) in DMSO then provided ketone 15.
After tetrazole addition and de-N-allylation, treatment of
16 with DIC led to the formation of 17 in good overall
yield. Low temperature treatment of this alkyne with
Bu2Ti(Oi-Pr)2, generated in situ by treatment of Ti(Oi-
Pr)4 with n-BuLi (2 equiv), and protolytic workup, exclu-
sively provided the Z-stilbene.29 Diastereoselectivity in this
case arises through stereospecific diprotonation of the
three-membered titanacyle formed by epimetalation of
alkyne 17.30 Finally, acid hydrolysis of the MEM ether
afforded combretastatin A4 (18) with an overall yield of
38% from isovanillin. Spectral data collected for synthetic
In summary, we have developed a new method for the
generation of alkylidenecarbenes involving the dehydration
and fragmentation of 5-hydroxyalkyl-1H-tetrazoles under
exceptionally mild conditions. This methodology displays
wide substrate scope and can be utilized for the synthesis of
alkynes, diynes, and triynes through the 1,2-rearrangement of
the intermediate carbene, or five-membered carbocycles and
heterocycles via [1,5]-CÀH bond insertion. This chemistry
was also successfully utilized in a highly stereoselective total
synthesis of combretastatin A4 (18), which was accomplished
in eight steps from isovanillin with an overall yield of 38%.
(24) Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts, D. S.;
Garcia-Kendal, D. Cell. Mol. Life Sci. 1989, 45, 209.
(25) For reviews, see: (a) Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai,
F.; Busacca, S.; Genazzani, A. A. J. Med. Chem. 2006, 49, 3033. (b)
Singh, R.; Kaur, H. Synthesis 2009, 2471.
(26) For reviews, see: (a) Daenen, L. G.; Roodhart, J. M.; Shaked,
Y.; Voest, E. E. Curr. Clin. Pharmacol. 2010, 3, 178. (b) Lippert, J. W.,
III. Bioorg. Med. Chem. 2007, 15, 605. (c) Tozer, G. M.; Kanthou, C.;
Baguley, B. C. Nat. Rev. Cancer 2005, 5, 423.
(27) Crombie, L.; Jamieson, S. V. J. Chem. Soc., PerkinTrans. 1 1982,
1467.
Acknowledgment. We thank the National Institutes of
Health (GM-59157) for partial support of this work. J.P.K.
thanks both the UIC Honors College for a Sarah Madonna
Kabbes Fellowship and the Herbert E. Paaren Endowment
for Chemical Sciences for generous support in the form of
a Paaren Fellowship.
(28) Generation by metalation of 3,4,5-trimethoxyiodobenzene with
tert-BuLi: Hoye, T. R.; Kaese, P. A. Synth. Commun. 1982, 12, 49.
(29) While this work was in progress, related approaches to 18 were
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
reported: (a) Lara-Ochoa, F.; Espinosa-Perez, G. Tetrahedron Lett.
2007, 48, 7007. (b) Petrov, O. I.; Gerova, M. S.; Chanev, C. D.; Petrova,
K. V. Synthesis 2011, 3711.
(30) Eisch, J. J.; Gitua, J. N. Organometallics 2003, 22, 24.
(31) Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.;
Schmidt, J. M.; Hogan, F. J. Med. Chem. 1995, 38, 1666.
The authors declare no competing financial interest.
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