Copper(I)-catalyzed [3+1] cycloaddition of alkenyldiazoacetates and iminoiodinanes: Easy access to substituted 2-azetines

Article abstract of DOI:10.1002/chem.201200998

The copper(I)-catalyzed reaction of alkenyldiazoacetates and iminoiodinanes affords functionalized azetine derivatives. This process is consistent with the formation of an aziridinyldiazoacetate intermediate, which gives rise to the four-membered heterocycles by metal-catalyzed ring expansion. The resulting azetine structure is a direct precursor of azeditine-2-carboxylic acid derivatives (EWG=electron-withdrawing group). Copyright

Full text of DOI:10.1002/chem.201200998

COMMUNICATION
DOI: 10.1002/chem.201200998
Copper(I)-Catalyzed [3+1] Cycloaddition of Alkenyldiazoacetates and
Iminoiodinanes: Easy Access to Substituted 2-Azetines
Josꢀ Barluenga,*[a] Lorena Riesgo,[b] Giacomo Lonzi,[a] Miguel Tomꢁs,[a] and
Luis A. Lꢂpez*[a]
Dedicated to Prof. Julio Delgado Martꢀn on the occasion of his 70th birthday
Four-membered nitrogen het-
erocycles are an important class
of
compounds,
exhibiting
a wide range of biological activ-
ities. In contrast to the well-
studied chemistry of 2-azetidi-
nones (b-lactmas) and azeti-
dines,[1] 2-azetines represent
a virtually unexplored class of
azaheterocycles. Both stability
considerations and the absence
of efficient routes to the prepa-
ration of this heterocyclic core
have led to a lack of studies in-
volving azetine derivatives. The
[2+2] cycloaddition of imines
Scheme 1. Vinyldiazo compounds as precursors for the synthesis of four-membered carbo- and heterocycles.
and electron-rich alkynes (e.g., ynamines, alkynyl selenides/
sulfides) could be considered a convenient method to gener-
ate this heterocyclic framework, however, the resulting aze-
tine ring is not isolated and rapidly undergoes electrocyclic
ring opening to the corresponding azadiene derivatives.[2,3]
In fact, only one report on the preparation of azetine deriva-
tives by [2+2] cycloaddition of imines to electron-poor al-
kynes has been published to date.[4] On the other hand, we
recently found that vinyldiazo acetates readily undergo cop-
per(I)-catalyzed cyclopropanation and ring expansion to cy-
clobutenes.[5] Based on the ability of iminoiodinanes to
transfer a nitrene function to olefins,[6] we now report
a direct and regioselective route to substituted 2-azetines 3
from stabilized alkenyldiazo derivatives 1[7] and (N-arylimi-
no)phenyliodinanes
(Scheme 1).[8]
In accordance with our previous research, [Cu
AHCTUNTGREG[NUNN BF4] in dichloromethane was initially selected as the cata-
lytic system. Stirring a solution of vinyldiazoacetate 1a
(R1 =R2 =H), (N-(p-toluenesulfonyl)imino)phenyliodinane
2
using
a
copper(I) catalyst
ACHTUNGTNER(NUNG MeCN)4]-
(PhI=NTs) 2a, and [CuACHTNUTRGENN(UG MeCN)4]ACHTUNTGREN[NUGN BF4] (5 mol%) in di-
chloromethane at room temperature for 4 h resulted in the
formation of 2-azetine 3aa in 33% yield after chromato-
graphic purification. While other copper(I)-based catalysts
did not improve the efficiency of the process, replacing di-
chloromethane with acetonitrile as the solvent increased the
yield to 56% (Table 1). Importantly, this formal [3+1] heter-
ocyclization reaction takes place with complete regioselec-
tivity. The structure of azetine 3aa was elucidated by NMR
spectroscopy (1H/13C and 1D/2D experiments) and high-res-
olution mass spectrometry (HRMS) data.
Further studies performed to determine the scope of the
process are given in Table 1. In relation to the structure of
the diazo substrate 1, some points should be noted: 1) the
reaction works well for substrates with alkyl/aryl substitu-
tion at C-a (1b,c) and C-b (1d), while diazo compound 1e
bearing a b-alkoxycarbonyl substituent does not react under
these conditions; 2) using tert-butyl vinyldiazoacetate (1 f)
does not appreciably decrease the yield; 3) keto-stabilized
diazo compounds, for example, 1g where the electon-with-
drawing group (EWG) is an acetyl, are also amenable to
[a] Prof. J. Barluenga, G. Lonzi, Prof. M. Tomꢀs, Dr. L. A. Lꢁpez
Instituto Universitario de Quꢂmica Organometꢀlica “Enrique Moles”
Universidad de Oviedo
Juliꢀn Claverꢂa 8, 33006 Oviedo (Spain)
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
lalg@uniovi.es
[b] Dr. L. Riesgo
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢃsos Catalans 16, 43007 Tarragona (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200998.
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Table 1. Copper (I)-catalyzed synthesis of azetine derivatives 3 from vi-
nyldiazo compounds 1 and iminoiodinanes 2.
Substrate 1
Ar (2)
Product 3
Yield[a]
[%]
p-MeC6H4
(2a)
p-NO2C6H4
(2d)
3aa
3ad
56
54
1a
p-MeC6H4
(2a)
3ba
62
C6H5 (2b)
1b p-MeOC6H4
(2c)
3bb
3bc
66
53
Scheme 2. Proposed mechanism for the copper(I)-catalyzed synthesis of
azetine derivatives 3 from vinyldiazo compounds 1 and iminoiodinanes 2.
p-NO2C6H4
(2d)
3bd
57
p-MeC6H4
C=C functionality of 1 by metal-bound nitrene intermediate
I to form key aziridinyldiazoacetate intermediate II.[10] For-
mation of the 2-azetine structure (3) would imply the
copper-catalyzed decomposition of II to copper–aziridinyl-
carbene III followed by selective [1,2]-amino rearrange-
ment.[11,12]
Further studies were directed toward finding evidence for
the presence of key intermediates II/III (Scheme 3). The re-
action of silyloxy-substituted vinyl diazoacetate 1h (R1 =
OSiMe2tBu) with iodinane 2c (Ar=p-MeOC6H4) did not
lead to the expected 2-azetine derivative. Instead, a novel
functionalized diazocompound (4) was obtained in 75%
yield by ring opening of the corresponding silyloxy-substitut-
ed aziridine II [Eq. (1), Scheme 3].[13] Moreover, the ring
opening of this hypothetical aziridine II could be selectively
1c
3ca
58
(2a)
p-MeC6H4
1d
3da
–
44
–
(2a)
p-MeC6H4
1e
no reaction
(2a)
p-MeC6H4
1 f
3 fa
52
(2a)
p-MeC6H4
1g
3ga
46
(2a)
[a] Yield of isolated product after column chromatography.
this cyclization. On the other
hand, the nature of substituents
on the aromatic ring (Ar) in the
iminoiodane 2 (p-Me, 2a; H,
2b; p-OMe, 2c; p-NO2, 2e)
appear to exert little influence
on the reaction. With the ex-
ception of 4-substituted azetine
3da, all of the compounds pre-
pared are stable and can be
stored in pure form or in solu-
tion without noticeable decom-
position for a number of days
at 0–208C.[9]
In accordance with our previ-
ous work,[5] the mechanism out-
lined in Scheme 2 is proposed
for the formation of compounds
3. The process would be initiat-
ed by the aziridination of the MeOC6H4).
Scheme 3. Experimental evidence for the participation of aziridinyl intermediates II and III (Ar=p-
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Substituted 2-Azetines
COMMUNICATION
effected by an external nucleophile such as methanol. Thus,
diazo compound 1h led directly to stabilized b-methoxydia-
zo derivative 5 (73% yield) when the reaction was carried
out in methanol [Eq. (2), Scheme 3]. Finally, support for the
participation of metal carbene intermediate III arose from
the reaction of vinyldiazoacetate 1a with 2c in methanol in
the presence of copper(I) [Eq. (3), Scheme 3]. In this case,
ethyl 2-methoxy-4-aminoalkenoate 6 was produced, proba-
Acknowledgements
We are grateful to the Ministerio de Ciencia e Innovaciꢁn of Spain
(MICINN) (CTQ2010–20517-C02–01) for financial support. L. R. and G.
L. thank the MICINN and the European Union (European Social Fund)
for predoctoralfellowships.
Keywords: 2-azetines
· carbenes · copper catalysts ·
À
bly by MeO H insertion into the metal carbene of III fol-
cycloaddition · diazo compounds · iminoiodinanes
lowed by ring opening of the resulting aziridine intermedi-
ate.[14,15]
Finally, we have undertaken preliminary studies focused
on the synthetic potential of the new azetine framework (3).
This core structure can be seen as a precursor for the azeti-
dine-2-carboxylic acid scaffold, an important moiety due to
its presence in conformationally restricted a-amino acids.[16]
In this context, cis-hydrogenation was accomplished by
simply subjecting compounds 3aa and 3ba in ethyl acetate
to hydrogen gas (1 atm) in the presence of palladium on
carbon to afford azetidines 7a,b in near quantitative yield
(Scheme 4).
[1] For a recent Review on the synthesis of azetidinones and azetidines,
see: A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2008, 108, 3988.
[2] 2-Azetine derivatives are known to undergo spontaneous electrocy-
clic ring opening to afford the 1-azadiene isomers. For a recent ex-
ample, see: N. Shindoh, K. Kitaura, Y. Takemoto, K. Takasu, J. Am.
Chem. Soc. 2011, 133, 8470.
[3] For specific syntheses of stable 2-azetine derivatives, see: a) S. Man-
gelinckx, V. Van Speybroeck, P. Vansteenkiste, M. Waroquier, N. De
Kimpe, J. Org. Chem. 2008, 73, 5481; b) P. L. Coe, I. L. Owen, S. J.
Till, J. Chem. Soc. Perkin Trans. 1 2000, 1529; c) Y. Dejaegher, S.
Mangelincks, N. De Kimpe, J. Org. Chem. 2002, 67, 2075; d) M. E.
Jung, Y. M. Choi, J. Org. Chem. 1991, 56, 6729; e) A. P. Marchand,
D. Rajagopal, S. G. Bott, J. Org. Chem. 1994, 59, 1608.
[4] J. Barluenga, A. Gꢁmez, J. Santamarꢂa, M. Tomꢀs, Angew. Chem.
2010, 122, 1328; Angew. Chem. Int. Ed. 2010, 49, 1306.
[5] J. Barluenga, L. Riesgo, L. A. Lꢁpez, E. Rubio, M. Tomꢀs, Angew.
Chem. 2009, 121, 7705; Angew. Chem. Int. Ed. 2009, 48, 7569.
[6] For seminal contributions to the field of copper-catalyzed aziridina-
tion of alkenes, see: a) H. Kwart, A. A. Kahn, J. Am. Chem. Soc.
1967, 89, 1951; b) D. A. Evans, M. M. Faul, M. Bilodeau, J. Org.
Chem. 1991, 56, 6744.
[7] For select studies on the applications of vinyldiazoacetates in the
synthesis of five- to seven-membered nitrogen heterocycles, see:
a) M. P. Doyle, M. Yan, W. Hu, L. S. Gronenberg, J. Am. Chem. Soc.
2003, 125, 4692; b) J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lꢁpez,
M. Tomꢀs, J. Am. Chem. Soc. 2010, 132, 13200; c) J. R. Manning,
H. M. L. Davies, J. Am. Chem. Soc. 2008, 130, 8602; d) M. P. Doyle,
W. Hu, D. J. Timmons, Org. Lett. 2001, 3, 3741.
[8] We recently reported that a copper(II)-catalyzed reaction of vinyl
diazo derivatives and iodosylbenzene (O=I-Ph) does not lead to
oxygen heterocycles, but rather b-oxodiazo compounds resulting
from a novel oxidative rearrangement were formed: J. Barluenga,
G. Lonzi, L. Riesgo, M. Tomꢀs, L. A. Lꢁpez, J. Am. Chem. Soc.
2011, 133, 18138.
[9] Azetine 3da was found to undergo facile isomerization to ethyl 2-
(tosylimino)hex-3-enoate 8 (CDCl3, RT, 12 h). This process takes
place with total stereoselectivity affording exclusively the (E)-aza-
diene.
Scheme 4. Synthesis of azetidine derivatives 7a,b from azetines 3aa and
3ba.
In conclusion, we have developed a simple and regioselec-
tive copper(I)-catalyzed synthesis of functionalized 2-azetine
derivatives by the formal [3+1] cycloaddition of vinyldiazo
derivatives and iminoiodinanes. Such a process is explained
by a copper(I)-catalyzed aziridination of the alkenyl func-
tionality followed by a regioselective copper(I)-catalyzed
ring expansion of the resulting aziridinyldiazo intermediate.
It is noteworthy that the implications of the copper catalyst
are multiple, sequentially producing aziridination through
metal nitrene species and 1,2-amino migration through
metal carbene species. The resulting azetine structure (a-de-
hydro amino acid) is a direct precursor of a relevant type of
conformationally restricted a-amino acid.
[10] Although it is generally accepted that metal-bound nitrenes are in-
volved in the copper/(N-(p-toluenesulfonyl)imino)phenyliodinane
(PhI=NTs) aziridination reaction of alkenes, the nature of the reac-
tive intermediate is still a controversial subject. For a theoretical
study, see: P. Brandt, M. J. Sçdergren, P. G. Andersson, P.-O. Norrby,
J. Am. Chem. Soc. 2000, 122, 8013.
[11] For a theoretical study on the aziridinylcarbene–azetine rearrange-
Experimental Section
ment, see: C. Mꢅck-Lichtenfeld, J. Org. Chem. 2000, 65, 1366.
À
À
[12] For a Review of aziridine ring-opening reactions via C C and C N
bond breaking, see: P. Dauban, G. Malik, Angew. Chem. 2009, 121,
9188; Angew. Chem. Int. Ed. 2009, 48, 9026.
[CuACHTUNGTRENNUNG(MeCN)4]ACHTUNGTRENNUNG[BF4] (7.9 mg, 0.025 mmol) was added to a solution of vinyl-
diazo 1 (0.5 mmol) and iminoiodane 2 (0.5 mmol) in CH3CN (5 mL). The
mixture was stirred at RT until consumption of 1 (monitored by TLC; 2–
3 h). The solvent was removed in vacuo, and the residue was purified by
flash chromatography (SiO2; hexane/EtOAc, 5:1) to give 2-azetine deriv-
ative 3.
[13] A similar ring opening of aziridine intermediates was proposed in
the metal-catalyzed reaction of silyl enol ethers with iminoiodi-
nanes: a) M. Anada, M. Tanaka, T. Washio, M. Yamawaki, T. Abe,
S. Hashimoto, Org. Lett. 2007, 9, 4559; b) M. Nakanishi, A.-F. Salit,
C. Bolm, Adv. Synth. Catal. 2008, 350, 1835; c) see also Referen-
ce [6b].
Full synthetic protocols, characterization data, and NMR spectra for
products 3–7 are given in the Supporting Information.
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J. Barluenga, L. A. Lꢁpez et al.
[14] The copper(I)-catalyzed insertion of a carbene fragment into the
M. A. Bonache, M. T. Garcꢂa-Lꢁpez, R. Gonzꢀlez-MuÇiz, M.
Martꢂn-Martꢂnez, Amino Acids 2010, 39, 1299; b) Z. Sajjadi, W. D.
Lubell, J. Pept. Res. 2008, 65, 298; c) F. Couty, G. Evano, N. Rabasso,
Tetrahedron: Asymmetry 2003, 14, 2407; d) L. Kovꢀcs, M. Hornyꢀk,
N. M. Howarth, Nucleosides Nucleotides Nucleic Acids 2003, 22,
1363; e) C. Toniolo, M. Crisma, F. Formaggio, E. Benedetti, A. San-
tini, R. Iacovino, M. Saviano, B. Di Blasio, C. Pedone, J. Kamphuis,
Biopolymers 1996, 40, 519.
À
O H bond of alcohols is a well-documented process. For an exam-
ple, see: M. E. Morilla, M. J. Molina, M. M. Dꢂaz-Requejo, T. R.
Belderrain, M. C. Nicasio, S. Trofimenko, P. J. Pꢆrez, Organometal-
lics 2003, 22, 2914.
[15] An alternative mechanism for the formation of compound 6 could
involve nucleophilic attack of methanol at the carbenoid carbon of
intermediate III, followed by metal elimination and ring opening of
the aziridine.
Received: March 23, 2012
[16] For select examples of the use of azetidine-2-carboxylic acids to pre-
pare conformationally constrained peptides, see: a) J. L. Baeza,
Revised: April 16, 2012
Published online: && &&, 0000
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Substituted 2-Azetines
COMMUNICATION
Synthetic Methods
J. Barluenga,* L. Riesgo, G. Lonzi,
M. Tomꢁs, L. A. Lꢂpez* .... &&&& — &&&&
Copper(I)-Catalyzed [3+1] Cycloaddi-
tion of Alkenyldiazoacetates and
Iminoiodinanes: Easy Access to
Substituted 2-Azetines
The copper(I)-catalyzed reaction of
alkenyldiazoacetates and iminoiodi-
nanes affords functionalized azetine
derivatives. This process is consistent
with the formation of an aziridinyldia-
zoacetate intermediate, which gives
rise to the four-membered heterocycles
by metal-catalyzed ring expansion. The
resulting azetine structure is a direct
precursor of azeditine-2-carboxylic
acid derivatives.
Chem. Eur. J. 2012, 00, 0 – 0
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