Synthesis of fused and bridged bicyclic diazenium salts by intramolecular cycloaddition

Article abstract of DOI:10.1021/ol900502s

Bicyclic diazenium salts were efficiently prepared by a Lewis acid mediated intramolecular cycloaddition. Terminal olefins provided mixtures of fused and bridged bicyclic diazenium salts. The α-chloroazo cycloaddition precursors were conveniently prepared

Full text of DOI:10.1021/ol900502s

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2189-2192
Synthesis of Fused and Bridged
Bicyclic Diazenium Salts by
Intramolecular Cycloaddition
Muhammad I. Javed, Jodi M. Wyman, and Matthias Brewer*
Department of Chemistry, The UniVersity of Vermont, 82 UniVersity Place,
Burlington, Vermont 05405
matthias.brewer@uVm.edu
Received March 10, 2009
ABSTRACT
Bicyclic diazenium salts were efficiently prepared by a Lewis acid mediated intramolecular cycloaddition. Terminal olefins provided mixtures
of fused and bridged bicyclic diazenium salts. The r-chloroazo cycloaddition precursors were conveniently prepared from the corresponding
phenyl hydrazones by treatment with chlorodimethylsulfonium chloride.
Structurally complex nitrogen-containing heterocycles are
ubiquitous in biologically active compounds,1,2 and synthetic
chemists continually look for efficient ways to prepare these
beneficial scaffolds.3 Cyclic trisubstituted diazenium salts
(e.g., 5, Table 2) are more reactive than their nonionic
diazene analogs4 and can serve as azomethinimine 1,3-dipole
precursors5 or can be reduced to the corresponding trisub-
stituted hydrazines.6 However, these cationic species have
received less attention from the synthetic community than
most classes of nitrogen-containing heterocycles, and few
methods exist for their preparation.7
Nelsen and co-workers8-11 have prepared bridged bicyclic
diazenium salts by alkylation of the corresponding diazene
and have thoroughly studied the redox properties, structure,
and charge distribution of these salts. In related work, Nelsen
has also studied the [4 + 2] cycloaddition of bicyclic
diazenium cations with dienes.12,13 More recently, Jochims
and colleagues14,15 reported that R-chloroazo compounds
react with halophilic Lewis acids to provide 1-aza-2-
azoniaallene cation intermediates that in turn can undergo
intermolecular [3 + 2] cycloadditions with alkenes to provide
diazenium salts by a process reminiscent of the reactivity of
Huisgen-type 1,3-dipolar compounds.16 Despite this pioneer-
(1) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem.
1999, 1, 55
.
(7) Kuznetsov, M. A. Russ. Chem. ReV. 1979, 48, 1054.
(2) (a) Annual Reports in Medicinal Chemistry; Macor, J. E., Ed.;
Academic Press: New York, 2008; Vol. 43. (b) Annual Reports in Medicinal
Chemistry; Macor, J. E., Ed.; Academic Press: New York, 2007; Vol. 42.
(c) Landquist, J. K. Application as Pharmaceuticals. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: New York, 1984; Vol. 1, pp 143-183.
(8) Nelsen, S. F.; Landis, R. T. J. Am. Chem. Soc. 1974, 96, 1788
(9) Nelsen, S. F.; Landis, R. T. J. Am. Chem. Soc. 1973, 95, 2719
.
.
(10) Nelsen, S. F.; Blackstock, S. C. J. Org. Chem. 1984, 49, 1134
.
(11) Nelsen, S. F.; Chang, H.; Wolff, J. J.; Powell, D. R. J. Org. Chem.
1994, 59, 6558
(12) Nelsen, S. F.; Blackstock, S. C.; Frigo, T. B. J. Am. Chem. Soc.
1984, 106, 3366
.
(3) Bur, S. K.; Padwa, A. Chem. ReV. 2004, 104, 2401.
.
(4) For a recent example of bicyclic diazene preparation by intramo-
lecular cycloaddition of diazo compounds, see: Taber, D. F.; Guo, P. J.
Org. Chem. 2008, 73, 9479.
(13) Nelsen, S. F.; Blackstock, S. C.; Frigo, T. B. Tetrahedron 1986,
42, 1769
.
(14) Wirschun, W. G.; Al-Soud, Y. A.; Nusser, K. A.; Orama, O.; Maier,
(5) (a) Cauquis, G.; Chabaud, B. Tetrahedron 1978, 34, 903. (b) Snyder,
J. P.; Heyman, M.; Gundestrup, M. J. Org. Chem. 1978, 43, 2224.
(6) Nelsen, S. F.; Parmelee, W. P.; Goebl, M.; Hiller, K.-O.; Veltwisch,
D.; Asmus, K.-D. J. Am. Chem. Soc. 1980, 102, 5606.
G. M.; Jochims, J. C. J. Chem. Soc., Perkin Trans. 1 2000, 4356
(15) Wang, Q. R.; Amer, A.; Mohr, S.; Ertel, E.; Jochims, J. C.
Tetrahedron 1993, 49, 9973
(16) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
.
.
10.1021/ol900502s CCC: $40.75
Published on Web 04/16/2009
 2009 American Chemical Society

ing work, only simple diazenium salts have been prepared
by Jochims’ method, and no intramolecular cycloadditions
of this type have been reported.
Table 1. Formation of R-Chloroazos Bearing a Pendent Alkene
Intramolecular reactions are a particularly efficient way
to increase structural complexity.17 Tethering reactive species
together can enforce conformational constraints that result
in high levels of stereoselectivity or regioselectivity, and
because of the proximity of the reacting groups, it is
sometimes possible to effect intramolecular reactions that
normally do not occur intermolecularly. In this Letter we
report our preliminary results on the preparation of fused
and bridged bicyclic diazenium salts by Lewis acid mediated
intramolecular cycloaddition reactions.
During studies on the reactivity of hydrazones with
sulfonium salts18-20 we discovered that treating phenyl
hydrazones with chlorodimethylsulfonium chloride provided
phenyl-R-chloroazo products21 (e.g., 2, Scheme 1) in high
Scheme 1. Sulfonium Salt Mediated R-Chloroazo Formation
yield. This route to R-chloroazo compounds is more mild
and functional-group-compatible than previous routes to these
species, which involve treating hydrazones with chlorine gas
or tert-butyl hypochlorite.22,23
The sulfonium salt mediated formation of R-chloroazo
compounds is completely tolerant of alkenes, and by this
method we prepared R-chloroazo 4a (Table 1), one of the
first examples of an R-chloroazo compound containing a
pendent alkene, in 94% yield.24 In view of the functional
group combination present in R-chloroazo 4a, we considered
the possibility that this compound might serve as a precursor
to a bicyclic diazenium salt. In fact, treating R-chloroazo 4a
with antimony pentachloride resulted in an intramolecular
cycloaddition in which a new carbocyclic and a new
heterocyclic ring were formed to provide fused bicyclic
diazenium salt 5a as a single diastereomer in 71% isolated
yield (entry 1, Table 2).
To assess the scope of this intramolecular cycloaddition
reaction and to probe for differences between the inter-
molecular and intramolecular variants of this reaction, we
prepared a preliminary set of R-chloroazo compounds with
(17) Evans, D. A.; Scheerer, J. R. Angew. Chem., Int. Ed. 2005, 44,
6038.
(18) Brewer, M. Tetrahedron Lett. 2006, 47, 7731
.
(19) Javed, M. I.; Brewer, M. Org. Lett. 2007, 9, 1789
(20) Javed, M. I.; Brewer, M. Org. Synth. 2008, 85, 189
(21) Wyman, J. M.; Jochum, S.; Brewer, M. Synth. Commun. 2008, 38,
.
varying steric and electronic properties (Table 1) and
subjected these to Lewis acid mediated intramolecular
cyclization (Table 2). In each case, the requisite R-chlo-
roazo was isolated in good yield with no apparent
degradation of the alkene by treating the corresponding
phenyl hydrazone with chlorodimethylsulfonium chloride.
.
3623.
(22) Moon, M. W. J. Org. Chem. 1972, 37, 386
(23) Moon, M. W. J. Org. Chem. 1972, 37, 383
(24) An R-chloroazo containing a pendant alkene was described in the
following patent: Unsymmetrical tert-aliphatic azoalkanes. MacLeay, R. E.;
Sheppard, C. S. 74-453444, 4007165, 1977.
.
.
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Org. Lett., Vol. 11, No. 10, 2009

tivity of this process further supports the notion that the
cycloaddition occurs by a concerted process.14
Table 2. Bicyclic Diazenium Salt Formation
Of particular note, electron-deficient alkene 4c reacted with
SbCl5 to provide diazenium salt 5c in 83% yield (entry 3,
Table 2). This result is important because electron-deficient
alkenes do not participate in intermolecular cyclizations of
this type,14 and this result broadens the useful substrate range
of this transformation. On handling, diazenium salt 5c readily
tautomerized to hydrazonium salt 7.
A limitation to the intramolecular cyclization became
apparent on treating disubstituted terminal alkene 4d with
SbCl5 (entry 4, Table 2). In this case, NMR analysis of the
crude reaction mixture showed a complex mixture of
products and no resonances characteristic for diazenium salts
were observed. The expected diazenium salt product (5d)
would contain adjacent quaternary centers, and steric en-
cumbrance likely inhibits cyclization.
We were surprised to observe that treating terminal alkene
4e with SbCl5 provided a mixture of ring-fused diazenium
salt 5e and bridged diazenium salt 6e in a 1:0.2 ratio (entry
5, Table 2). The corresponding intermolecular cyclizations
consistently provided products having the more substituted
carbon adjacent to the nitrogen bearing the positive charge,14
which can be attributed to a preferred electronic arrangement
in the transition state. On the basis of this electronic
preference, the major product would be expected to be
bridged bicyclic diazenium salt 6e, which would form via
transition state 8 (Figure 1). However, it appears that the
Figure 1. Possible transition sates leading to the formation of
diazenium salts 5e and 6e.
underlying electronic bias for transition state 8 is overcome
by the fact that the tether provides a more facile alignment
of the reactive partners in transition state 9 leading to fused
diazenium 5e as the major product. It is not clear to us at
this point why the bridged diazenium salt did not form from
disubstituted terminal alkene 4d.
Other terminal alkenes also provided a mixture of fused
and bridged diazenium salts (entries 6 and 7, Table 2), and
the ratio of these products appears to be affected by steric
factors. For example, Lewis acid induced cyclization of
isopropyl derivative 4f provided a 1:0.05 ratio of fused (5f)
to bridged (6f) products, and incorporation of a gem-dimethyl
a Diazenium salts 5 and 6 were isolated as mixtures. b Diazenium salts
5b and 5c were formed as single diastereomers. The relative configurations
of 5b and 5c were assigned by NOE experiments.
Upon treatment with SbCl5, cis-disubstituted alkene 4b
(entry 2, Table 2) was transformed into diazenium salt 5b
as a single diastereomer in 88% yield. The diastereoselec-
Org. Lett., Vol. 11, No. 10, 2009
2191

group within the chain (4g) provided the fused (5g) and
bridged (6g) products in a 1:0.09 ratio. In each case, steric
interactions imparted by the additional substituents likely
destabilize the transition state leading to the bridged diaz-
enium salt.
Of final note, extending the length of the tether by one
carbon had a dramatic effect on the outcome of the
cyclization reaction. The Lewis acid mediated cyclization
of R-chloroazo 4h (Scheme 2) favored formation of the
cloadditions in which a new carbocyclic and a new hetero-
cyclic ring are formed. Overall, this two-step sequence is
an efficient way to make structurally complex bicyclic
heterocycles from simple linear hydrazone starting materials.
Tethering the cycloaddition partners together allows electron-
deficient alkenes to participate in the reaction, which is not
the case in intermolecular processes. Terminal alkenes
provide mixtures of fused and bridged bicyclic diazenium
salt products, and the ratio of these products depends
primarily on the length of the tether. Further studies on the
scope of this intramolecular cycloaddition and synthetic
applications of the diazenium salt products are underway.
Scheme 2. Preferential Formation of Bridged Bicyclic
7-Membered-Ring-Containing Diazenium Salt
Acknowledgment. We thank Dr. John Greaves (Univer-
sity of California, Irvine) for obtaining mass spectral data
and Dr. Bruce Deker (University of Vermont) for assistance
with NMR characterization. This material is based upon work
supported by the National Science Foundation under CHE-
0748058 and instrumentation grant CHE-0821501. Financial
support from the University of Vermont is gratefully
acknowledged. M.B. thanks Amgen for financial support in
the form of a new faculty award.
bridged bicycle 6h in which a new seven-membered ring
has been formed; only small quantities of the 5,6-fused
bicyclic product 5h were observed in this reaction (1:0.2
ratio).
In conclusion, the mildness and simplicity of the sulfonium
salt mediated formation of phenyl R-chloroazo species
provides ready access to tethered R-chloroazo alkenes, which
in turn undergo Lewis acid catalyzed intramolecular cy-
Supporting Information Available: Experimental details
1
and characterization data including copies of H and 13C
NMR spectra for compounds 4a-h, 5a-c, 5e-h, and 6e-h.
This information is free of charge via the Internet at
http://pubs.acs.org.
OL900502S
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