Metal-free intramolecular aziridination of alkenes using hypervalent iodine based sulfonyliminoiodanes

Article abstract of DOI:10.1021/ol9026655

(Figure presented) Intramolecular aziridination of alkenyl sulfonyliminoiodanes occurs thermally In the absence of conventional metal catalysts such as Rh(II) and Cu(II). In rigid molecular systems, conversions are near quantitative. The scope of the nonm

Full text of DOI:10.1021/ol9026655

ORGANIC
LETTERS
2010
Vol. 12, No. 2
364-366
Metal-Free Intramolecular Aziridination
of Alkenes Using Hypervalent Iodine
Based Sulfonyliminoiodanes
Robert M. Moriarty* and Sachin Tyagi
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
moriarty@uic.edu
Received November 23, 2009
ABSTRACT
Intramolecular aziridination of alkenyl sulfonyliminoiodanes occurs thermally in the absence of conventional metal catalysts such as Rh(II)
and Cu(II). In rigid molecular systems, conversions are near quantitative. The scope of the nonmetal process is related to the conformational
flexibility of the alkenyl sulfonyliminoiodane. A mechanism is proposed involving formal 2 + 2 cycloaddition of the RSO2NdIPh group to the
double bond followed by reductive elimination of PhI to yield the sulfonylaziridine. Green chemistry aspects of the process are highlighted.
Transition-metal-catalyzed cyclopropanation1 and aziridina-
tion2 of alkenes using hypervalent iodonium ylides and
iminoiodanes, respectively, have proven to be exceptionally
useful. Earlier we and others found that in the case of certain
intramolecular cyclopropanation processes, conventionally
effected using copper or rhodium catalysis, the reaction
occurred efficiently in the absence of these metals.1a,3
Originally treated as an undesirable complication in examples
using chirally modified copper catalysts for stereoselective
syntheses,1a but now viewed in a more current societal
context, the significance of this phenomenon requires re-
evaluation. Contemporary organic synthesis strives to be
metal free.4 General environmental awareness, i.e., green
chemistry, and more specifically concerns around the exigen-
cies of drug manufacture, i.e., pharmacovigilance, drive this
search for metal-free cognate reactions of synthetic processes
that are conventionally metal catalyzed.4a-d
(1) For reviews, see: (a) Mu¨ller, P Acc. Chem. Res. 2004, 37, 243. (b)
Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (c) Zhdankin, V. V.;
Stang, P. J. Chem. ReV. 2002, 102, 2523. (d) Stang, P. J.; Zhdankin, V. V.
Chem. ReV. 1996, 96, 1123. (e) Moriarty, R. M. J. Org. Chem. 2005, 70,
2893.
Transition-metal-catalyzed aziridination5 of alkenes has
been largely developed on the basis of ArSO2NdIPh, and
apparently the deletion of metal from this type of reactions
(2) (a) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (b) Guthikonda,
K.; When, P. M.; Caliando, B. J.; DuBois, J. Tetrahedron 2006, 62, 11331.
(c) Dauban, P.; Dodd, R. H. Syn. Lett. 2003, 11, 1571. (d) First example of
Cu(I) or Cu(II) catalysis: Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J.
Org. Chem. 1991, 56, 6744. (e) Evans, D. A.; Bilodeau, M. T.; Faul, M. M.
J. Am. Chem. Soc. 1994, 116, 2742. (f) Rovis, T.; Evans, D. A. Prog. Inorg.
Chem. 2001, 50, 1. (g) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem.
Lett. 1975, 361. (h) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem.
Soc. 1993, 115, 5326. Use of Rh(II): (i) Liang, J.-L.; Yuan, S.-X.; Chan,
P. W. H.; Che, C.-M. Org. Lett. 2002, 4, 4507.
(4) A recent example of this effort is the achievement of a copper-free
Sonogashira coupling: (a) Appukkuttan, P.; Dehaen, W.; Van der Eycken,
E. Eur. J. Org. Chem. 2003, 4713. (b) Leadbeater, N. E.; Marco, M.;
Tominack, B. J. Org. Lett. 2003, 5, 3919. (c) Luque, R.; Macquarrie, D. J.
Org. Bio. Chem. 2009, 7, 1627. For toxicity of copper, see: (d) Flemming,
C. A.; Trevors, J. T. Water Air Soil Poll. 1989, 44, 143. (e) Use of
organohypervalent iodine reagents as substitutes for Pb(IV), Tl(III), and
Hg(II) has been pursued (ref 1e). Use of the Dess-Martin reagent, IBX,
and PhIO as oxidants in place of Cr(VI) (ref 1c) and use of IBX as a
substitute for Se(IV) for conjugated carbonyl compound synthesis are
relevant advances. (f) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am.
Chem. Soc. 2000, 122, 75960. (g) A striking example of metal replacement
is the use of fullerene inplace of noble metals in catalytic hydrogenation:
Li, B.; Xu, Z. J. Am. Chem. Soc. 2009, 131, 16380.
(3) For the first example of this intramolecular thermal nonmetal process,
see: (a) Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J. Am. Chem.
Soc. 1989, 111, 6443. Erratum J. Am. Chem. Soc. 1990, 112, 1297. (b)
Gallos, J. K.; Koftis, T. V.; Massen, Z. S.; Dellios, C. C.; Mourtzinos, I. T.;
Coutouli-Argyropoulou, E.; Koumbis, A. E. Tetrahedron 2002, 58, 8043.
For a comparison of the intramolecular cyclopropanation using Cu(I), Rh(II),
and nonmetal, see: (c) Mu¨ller, P.; Bole˙a, C. Synlett 2000, 826. (d) Mu¨ller,
(5) (a) Evans, D. A.; Bilodeau, M. T.; Faul, M. M. J. Am. Chem. Soc.
1994, 116, 2742. (b) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem.
Soc. 1993, 115, 5326.
P.; Bole˙a, C. HelV. Chim. Acta 2001, 84, 1093
.
10.1021/ol9026655  2010 American Chemical Society
Published on Web 12/11/2009

has not been investigated.6,7 Because of the obvious similarity
between the cyclopropanation and the aziridination reaction,
we decided to study the metal-free reaction. Apart from
environmental reasons, synthetically the aziridine group
serves as a synthon for a wide range of functional groups,2c
and a noncatalytic route would obviously be valuable.
Table 1. Metal-Free Intramolecular Aziridination of Unsaturated
Sulfonamides with I(III)a
Reference to Table 1 reveals the realization of the
nonmetal route for intramolecular sulfonylaziridination.
Bridged bicyclic systems 1a and 1b proceeded with quantita-
tive conversions affording aziridines 4a and 4b (entries 1
and 2). Cyclohexenyl systems 1c-e provided 4c-e in very
high yields (entries 3-5). Entry 6 (1f) is instructive in that
a degree of conformational flexibility of the alkenyl group
is present relative to the cycloalkenyl examples; nonetheless,
efficient aziridination occurs. Also, a comparison with the
CuOTf-catalyzed reaction8a reveals that the nonmetal reaction
proceeds in higher yield, 83% vs 61%, while the Rh2(OAc)48b
reaction is slightly inferior, 95% vs 100% conversion. Entry
7 (1g), 0% conversion, illustrates the effect of the intramo-
lecular proximity of the reacting groups and presages the
synthetic scope and limitations of the nonmetal intramolecu-
lar aziridination relative to the metal-catalyzed process.
Together with example 1g, control experiments of 1h-1j
provide an insight into the mechanism of the process.
The results shown in Table 1 can be discussed on the basis
of Scheme 1, and these data enable formulation of a tentative
competitive metal-catalyzed process. The relevant processes
are: reversible formation of iminoiodanes9 (1f2), intramo-
lecular reaction of iminoiodanes (2f4) with adjacent double
bond, Cu(I) or Rh(II) exchange (2f3), aziridination forma-
tion of metal nitrenoids (3f4), initial double bond hyperi-
odination followed by intramolecular cyclization (1f4 via
5f6),10 and consumption of PhIO by disproportionation.11
Entries 1-6 of Table 1 correspond to capture of the
equilibrium concentration of the iminoiodanes by the adjacent
double bond to yield aziridine.
a Reactions were done under thermal conditions, unless catalyst is
mentioned in parentheses. b Conversion on the basis of crude 1H NMR.
c Isolated yield after column chromatography. d Almost 100% of starting
material was retrieved.
The fact that the N-ethylsulfonamide (1h) is recovered
unreacted proves that initial reaction at the double bond is
not the route to the aziridination. It can be implied that 1h,
1i, and 1j form the iminoiodanes because of the obtention
of PhI and PhIO2. Finally, entry 6 instantiates the importance
of equilibrium 1f2; 1-pentenylsulfonamide (1g) forms the
iminoiodane, but the rate of intramolecular addition to the
double bond is slower than the rate of reversion to the starting
alkene.
Scheme 1
.
Pathways for the Intramolecular Aziridination of
Alkenylsulfonamides with I(III)
(6) An example of the Rh(II) and nonmetal intramolecular cyclization
of a cycloalkenyl carbamate with I(III) has been reported: Padwa, A.;
Stengel, T. Org. Lett. 2002, 4, 2137
.
(7) The focus of the present metal-free reactions of alkenes is on
organohypervalent iodine and transition metals. Of course, metal-free
aziridination7 can be accomplished via thermal or photochemical generation
of nitrenes from azides just as cyclopropanation can be effected by thermal
or photochemical decomposition of diazocompounds. For other metal-free
intermolecular alkene aziridination processes, see: (a) Li, J.; Liang, J.-L.;
Chan, P. W. H.; Che, C.-M. Tetrahedron Lett. 2004, 45, 2685. (b) Li, J.;
Chan, P. W. H.; Che, C.-M. Org. Lett. 2005, 7, 5801. (c) Jeong, J. U.; Tao,
B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J. Am. Chem. Soc. 1998,
120, 6844. (d) Minakata, S.; Morino, Y.; Oderaotoshi, Y.; Komatsu, M.
J. Chem. Soc., Chem. Commun. 2006, 3337. (e) Minakata, S. Acc. Chem.
Res. 2009, 42, 1172
.
(8) (a) Dauban, P.; Dodd, R. H. Org. Lett. 2000, 2, 2327. (b) Liang,
J.-L.; Yuan, S.-X.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2002, 4, 4507.
(9) White, R. E. Inorg. Chem. 1987, 26, 3916.
(10) For an example of (1f5f6f4), see: Cochran, B. M.; Michael,
F. E. Org. Lett. 2008, 10, 5039.
By contrast, the capture of the iminoiodane by Cu(I) or
Rh(II) is assumed to be faster (2f3) than reversion, and
(11) Bressan, M.; Morvillo, A. Inorg. Chem. 1989, 28, 950.
Org. Lett., Vol. 12, No. 2, 2010
365

subsequent intramolecular reaction with the double bond
yields the aziridine (3f4). One salient feature of the
nonmetal intramolecular aziridination is that conformationally
rigid systems are most favored candidates for successful
aziridination. Thus, the alkenyl group in 1f (83%) is
comparatively conformationally fixed relative to the more
conformationally flexible linear alkenyl system of 1g (0%).
Ochiai12 has shown that the more reactive alkyl iminobro-
manes undergo intermolecular aziridination with alkene via
a nitrenoid mechanism. This pathway is unlikely in the
present system because 1g, 1i, and 1f all should react if a
nitrenoid intermediate occurred.
addition of R2CdCuLn to alkenes2e to form a metallocy-
clobutane (2f8). In the instant case, the resulting incipient
azaiodoniocyclobutane13 (7) yields the aziridine by reductive
elimination of PhI (7f4).
In conclusion, a search for nonmetal variants of classically
metal-catalyzed reactions was productively pursued guided
by mechanistic insight. In the present case, the stability of
the iminoiodane is the key.14 The scope of the nonmetal
aziridination can be broadened by variations in the stability
of the iminoiodane. More reactive Cl(III)15 and Br(III)12
iminohalogans are also potentially useful in this regard.
Finally, we envision the most interesting applications will
be in total synthesis of complex molecules. In such cases,
critical intramolecular distances between RSO2NdIPh and
the double bond will be fixed in favorable orientations for
aziridination because of the rigid molecular framework. A
very clever example of the use of intramolecular aziridination
followed by ring opening is found in the recent total synthesis
of (-)-Agelastatin A.16
Scheme 2
.
Aziridination via a Formal [2 + 2] Cycloaddition
Step
Acknowledgment. We thank KYTHERA Biopharmaceu-
ticals, Inc., Calabasas, California, for the support of this work.
We also thank Professor Daesung Lee of the Department of
Chemistry, University of Illinois at Chicago, for insightful
discussions.
Supporting Information Available: Experimental pro-
cedures, structural proofs, and spectral data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
The pathway from the iminoiodane 2f4 may involve an
electrophilic addition of the tethered double bond to the PhI+
center with concomitant neutralization of the thus formed
carbocation by the anionic nitrogen center (2f7) (Scheme
2). Within the limits of synchronicity, this devolves into a
[2 + 2] cycloaddition, and the observed rather strict
geometric requirements for the reaction agree with this
pathway. A similar process has been discussed for the
OL9026655
(13) For an example of stable four-membered tricoordinated iodine(III)
heterocycle, see: Kawashima, T.; Hoshiba, K.; Kano, N. J. Am. Chem. Soc.
2001, 123, 1507.
(14) Sodergren, M. J.; Alonso, D. A.; Andersson, P. G. Tetrahedron:
Asymmetry 1997, 8, 3563.
(15) Moriarty, R. M.; Tyagi, S.; Ivanov, D.; Constantinescu, M. J. Am.
Chem. Soc. 2008, 130, 7564.
(12) Ochiai, M.; Kaneaki, T.; Tada, N.; Miyamoto, K.; Chuman, H.;
Shiro, M.; Hayashi, S.; Nakanishi, W. J. Am. Chem. Soc. 2007, 129, 12938.
(16) Wehn, P. M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 3802.
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Org. Lett., Vol. 12, No. 2, 2010