Iodine(III)-mediated bicyclic diazenium salt formation

Article abstract of DOI:10.1016/j.tetlet.2012.07.116

The hypervalent iodine(III) reagent PhI(OTf)₂ has been shown to be an effective oxidant for the conversion of linear aryl-hydrazones bearing a pendant alkene into bicyclic diazenium salts. This oxidative cyclization presumably occurs by the iodine(III) mediated formation of a 1-aza-2-azoniaallene salt intermediate that undergoes a subsequent intramolecular 1,3-dipolar cycloaddition with the pendant alkene.

Full text of DOI:10.1016/j.tetlet.2012.07.116

Tetrahedron Letters 53 (2012) 5411–5413
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Tetrahedron Letters
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Iodine(III)-mediated bicyclic diazenium salt formation
⇑
Nezar Q. Al-Bataineh, Matthias Brewer
The University of Vermont, Department of Chemistry, 82 University Place, Burlington, VT 05405, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The hypervalent iodine(III) reagent PhI(OTf)2 has been shown to be an effective oxidant for the conver-
sion of linear aryl-hydrazones bearing a pendant alkene into bicyclic diazenium salts. This oxidative cycli-
Received 12 July 2012
Accepted 26 July 2012
Available online 2 August 2012
zation presumably occurs by the iodine(III) mediated formation of
a 1-aza-2-azoniaallene salt
intermediate that undergoes a subsequent intramolecular 1,3-dipolar cycloaddition with the pendant
alkene.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Diazenium salt
1-Aza-2-azoniaallene salt
1,3-Dipolar cycloaddition
Iodine(III) reagent
PhI(OTf)2
The development of new methods to prepare N heterocycles is
important because of the prevalence of these structures in biologi-
cally active compounds.1,2 Recent work in our group has focused
on investigating highly reactive 1-aza-2-azoniaallene salts (e.g. 2,
Scheme 1) as precursors to nitrogen heterocycles.3–5 1-Aza-2-azon-
iaallene salts are a class of hetero-cumulene that can participate in a
diverse set of reactions. For example, we have recently shown that
these species can participate in intramolecular amination reactions
to provide pyrazoline products5 Gladstone et al.6,7 have shown that
1-aza-2-azoniaallene salts derived from aryl ketones undergo
electrophilic aromatic substitution to provide indazole products,
and Jochims etal.8–10 have shownthat these hetero-cumulenes react
readily via 1,3-dipolar cycloaddition with a variety of different
Hypervalent iodine(III) reagents are versatile oxidants11–13 that
can mediate a variety of transformations including the oxidation of
alcohols to carbonyl compounds,14,15 the
a-hydroxylation of ke-
tones,16,17 and the oxidative dearomatization of phenols.18,19 In
addition, iodine(III) reagents can dehydrogenate hydrazodicarbo-
nyls to azodicarbonyls20 and Lutz and Thomson21 recently reported
that allyl hydrazones react with hypervalent iodine reagents to
give products derived from the 3,3-sigmatropic rearrangement of
a presumed 1-aza-2-azoniaallene salt intermediate. With this in
mind, we became interested in the prospect of using iodine(III)
reagents as oxidants for the conversion of hydrazones to bicyclic
p
-systems. In this latter regard, we rendered the 1,3-dipolar
Ar
cycloaddition reaction of 1-aza-2-azoniaallene salts with alkenes
intramolecular as a way to form bicyclic diazenium salts.3 In each
of the above cases, the heteroallene intermediate was generated
by the Lewis acid-mediated deoxygenation or dehalogenation of
Ar
HN
TfO Ar
N
N
N
Ar
N
Me2S(OTf)2
TfO
N
N
TfO
N
+
DTBMP
CH2Cl2
-78 °C to rt
1
2
3
4
an
a-functionalized azo precursor. More recently, we discovered
67% combined yield
Ar = 4-Cl-Ph
that bicyclic diazenium salts could also be formed directly from aryl
hydrazones bearing a pendant alkene by reaction with dimethyl sul-
fide ditriflate (Me2S(OTf)2; Scheme 1).4 This latter transformation
presumably occurs via sulfonium salt-mediated oxidation of the
hydrazone to a 1-aza-2-azoniaallene salt intermediate that under-
goes a subsequent intramolecular cycloaddition and we became
interested in the prospect of identifying other oxidants that could
mediate this same transformation.
Scheme 1.
Ph
Ph
TfO Ph
N
N
Ph
PhI(OTf)
2
TfO
N
HN
N
N
TfO
N
N
+
DTBMP
CH Cl
2
2
-78 °C to rt
~50% yield
5a
6a
7a
8a
⇑
Corresponding author. Tel.: +1 802 656 1042; fax: +1 802 656 8705.
E-mail address: matthias.brewer@uvm.edu (M. Brewer).
Scheme 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.116

5412
N. Q. Al-Bataineh, M. Brewer / Tetrahedron Letters 53 (2012) 5411–5413
Table 1
PhI(OTf)2 mediated bicyclic diazenium salt formation
TfO
R2
R4
R3
R5
TfO
R2
Ph
N
Ph
N
Ph
HN N
N
R4
R5
PhI(OTf)2
N
R2
R3
R4
R2
+
DTBMP
CH2Cl2
-40 to 40 °C
R2
R1
8a-h
R1
R1
7a-h
R3
R2
R5
5a-h
Entry
1
Hydrazone
Product
Yielda (%)
Ratio 7:8b
Ph
Ph
TfO
N
Ph
TfO
N
HN
N
N
N
78
1:0.4
5a
7a
8a
Ph
Ph
Ph
TfO
N
TfO
HN
N
N
N
N
N
N
2
70
1:0.10
7b
5b
8b
Ph
TfO
N
Ph
TfO
Ph
Ph
HN
N
N
3
4
5
79
22
0
1:0.10
Trace:1
—
5c
7c
8c
TfO
N
Ph
Ph
TfO
N
N
HN
N
N
7d
5d
8d
Ph
TfO
N
Ph
Ph
TfO
N
N
N
N
5e
7e
8e
Ph
HN
Ar
TfO
N
N
N
N
6
7
8
68
26
0
—
—
—
5f
7f
Ph
HN
Ph
TfO
N
N
5g
7g
CO2Me
Ph
Ph
HN
TfO
N
N
N
CO2Me
7h
5h
a
Yield determined by NMR vs. an internal standard.
Diazenium salts 7a–d and 8a–d were formed as mixtures.
b
diazenium salts and here we report that PhI(OTf)2 can effectively
facilitate this transformation.
et al. have reported that PhI(OAc)2 reacts with phenyl hydrazones
to give
-acetoxy azo products.23 Changing the oxidant to PhI(OT-
a
Iodosobenzene diacetate (PhI(OAc)2) and iodosylbenzene are
stable, storable compounds that can be easily modified to other
iodine(III) reagents11 and we focused our studies on these oxidants.
Unfortunately, treating hydrazone 5a (Scheme 2) with PhI(OAc)2 in
the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) did
not provide any of the desired diazenium salt product. Barton
FA)2 led to a complex mixture of products that did not contain
any of the expected fused diazenium salt (7a). However, a small
amount of the bridged diazenium salt (8a) was observed in the
NMR spectrum of the crude reaction mixture and it is possible that
the more labile fused salt 7a was also formed but subsequently de-
graded under the reaction conditions. In our earlier studies using

N. Q. Al-Bataineh, M. Brewer / Tetrahedron Letters 53 (2012) 5411–5413
5413
sulfonium salts as oxidants for these intramolecular cycloadditions
Acknowledgments
we observed that a highly non-nucleophilic counterion was neces-
sary for success. With this in mind we turned our attention to
PhI(OTf)2 as a potential oxidant and we were pleased to observe
that treating hydrazone 5a with freshly generated PhI(OTf)2 in the
presence of DTBMP at À78 °C for 2 h and then warming the mixture
to room temperature provided the expected 5,5-fused (7a) and 6,5-
bridged (8a) bicyclic diazenium salts in ꢀ50% combined yield. Using
a large excess of oxidant (2.5 equiv) reduced the yield of the desired
products, as did changing the base from DTBMP to Et3N. Extending
the reaction time at low temperature also resulted in decreased
yield of the diazenium salt products, whereas allowing the reaction
to warm soon after mixing appeared to improve the reaction out-
come. After some experimentation we discovered that consistently
good results were obtained when the hydrazone and DTBMP were
added to the oxidant at À40 °C and the reaction was then immedi-
ately transferred to a 40 °C bath and concentrated in vacuo.22 Under
these conditions bicyclic diazenium salts 7a and 8a were formed in
a 2.5:1 ratio in 78% combined yield (Table 1).
This material is based upon work supported by the National Sci-
ence Foundation under CHE-0748058 and instrumentation grant
CHE-0821501. This work was facilitated by use of a facility sup-
ported by the Vermont Genetics Network through Grant Number
8P20GM103449 from the INBRE Program of the National Institute
of General Medical Sciences (NIGMS), a component of the National
Institutes of Health (NIH).
References and notes
1. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Combi. Chem. 1999, 1, 55.
2. Lesney, M. S. Today’s Chemist at Work 2004, 26.
3. Javed, M. I.; Wyman, J. M.; Brewer, M. Org. Lett. 2009, 11, 2189.
4. Wyman, J.; Javed, M. I.; Al-Bataineh, N.; Brewer, M. J. Org. Chem. 2010, 75, 8078.
5. Bercovici, D. A.; Brewer, M. J. Am. Chem. Soc. 2012, 134, 9890.
6. Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc. (Resumed) 1965, 3048.
7. Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc., C: Organic 1966, 1527.
8. Wang, Q. R.; Jochims, J. C.; Kohlbrandt, S.; Dahlenburg, L.; Altalib, M.; Hamed,
A.; Ismail, A. E. H. Synthesis 1992, 710.
9. Wang, Q. R.; Amer, A.; Mohr, S.; Ertel, E.; Jochims, J. C. Tetrahedron 1993, 49,
9973.
To test the generality of this transformation we subjected a ser-
ies of hydrazones bearing pendent alkenes to the optimized cycli-
zation conditions and the results of these studies are presented in
Table 1. Mono-substituted terminal olefins reacted easily to pro-
vide mixtures of fused and bridged bicyclic products in good yield
(entries 1–3). Extending by one carbon the tether length joining
the reacting centers resulted in a significant decrease in product
yield; hydrazone 5d (entry 4) provided predominantly bridged salt
8d in only 22% yield. In our prior work, we observed that di-substi-
tuted terminal olefin 5e failed to provide any of the desired diaze-
nium salts, which is the case here as well (entry 5). Conversely,
hydrazone 5f, which contains a 1,2-disubstituted olefin, reacted
smoothly to yield 5,5-fused diazenium salt 7f as a single diastereo-
mer in 68% yield. Hydrazone 5g (entry 7), which contains a trisub-
stituted olefin, provided the desired diazenium salt product in low
yield (26%), whereas the hydrazone 5h (entry 8), which contains an
electron deficient olefin, failed to provide any desired product.
In summary, PhI(OTf)2 is an effective oxidant for the direct for-
mation of bicyclic diazenium salts from a variety of linear hydra-
zone precursors. This oxidative cyclization presumably occurs by
the iodine(III) mediated formation of a 1-aza-2-azoniaallene salt
intermediate that undergoes a subsequent intramolecular 1,3-dipo-
lar cycloaddition with the pendent alkene. These studies provide
further evidence that iodine(III) reagents react with hydrazones to
yield synthetically versatile heteroallene salt intermediates.
10. Wirschun, W. G.; Al-Soud, Y. A.; Nusser, K. A.; Orama, O.; Maier, G. M.; Jochims,
J. C. J. Chem. Soc., Perkin Trans. 2000, 1, 4356.
11. Zhdankin, V. V. ARKIVOC 2009, 2009, 1.
12. Yusubov, M. S.; Zhdankin, V. V. Curr. Org. Synth. 2012, 9, 247.
13. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
14. Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J. H.; Abrams, J. N.; Forsyth, C.
J. Tetrahedron Lett. 2003, 44, 57.
15. Tohma, H.; Takizawa, S.; Maegawa, T.; Kita, Y. Angew. Chem., Int. Ed. 2000, 39,
1306.
16. Koser, G. F.; Rebrovic, L.; Wettach, R. H. J. Org. Chem. 1981, 46, 4324.
17. Moriarty, R. M.; Hou, K.-C.; Prakash, I.; Arora, S. K. Org. Synth. 1986, 64, 138.
18. Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D. Synthesis
2007, 2007, 3759.
19. Quideau, S.; Pouységu, L.; Deffieux, D. Synlett 2008, 2008, 467.
20. Moriarty, R. M.; Prakash, I.; Penmasta, R. Synth. Commun. 1987, 17, 409.
21. Lutz, K. E.; Thomson, R. J. Angew. Chem., Int. Ed. 2011, 50, 4437.
22. Representative experimental procedure: Trimethylsilyl triflate (0.353 g,
1.59 mmol) was added dropwise to a stirred 0 °C solution of iodosobenzene
(0.175 g, 0.79 mmol) in CH2Cl2 (2 mL). After 5 min the reaction was cooled to
À40 °C and
a solution of hydrazone 5a (0.107 g, 0.53 mmol) and DTBMP
(0.130 g, 0.64 mmol) in CH2Cl2 (1 mL) was added in one portion. The reaction
vessel was transferred to a 40 °C water bath and solvents were removed in
vacuo. The residue was dissolved in CH2Cl2 (2 mL) and a 1 M solution of 3,5-
dinitrobenzonitrile in CH2Cl2 (0.53 mL, 0.53 mmol) was added as an internal
standard to determine yield by NMR spectroscopy. The mixture was carefully
concentrated under moderately reduced pressure and analyzed by 1H NMR
spectroscopy which showed the formation of 7a and 8a in 57% and 21% yield,
respectively.
23. Barton, D. H. R.; Jaszberenyi, J. Cs.; Liu, W.; Shinada, T. Tetrahedron 1996, 52,
1467.