2 H-azirines from a concerted addition of alkylcarbenes to nitrile groups

Article abstract of DOI:10.1021/ol100703r

Photolysis of aziadamantanes in the presence of fumaronitrile (FN) unexpectedly afforded conjugated 2H-azirines resulting from addition of the carbene to the CN triple bond. This represents the first example of a direct azirine formation starting from an alkylcarbene for which a concerted pathway is postulated. The novel outcome of the reaction is favored by the prior formation of a carbene-alkene complex, a type of adduct that only recently has been described.

Full text of DOI:10.1021/ol100703r

ORGANIC
LETTERS
2
010
Vol. 12, No. 10
366-2369
2H-Azirines from a Concerted Addition
of Alkylcarbenes to Nitrile Groups
†
2
‡
‡
§
‡
Wolfgang Knoll, Jean-Luc Mieusset, Vladimir B. Arion, Lothar Brecker, and
Udo H. Brinker*
,‡
Chair of Physical Organic and Structural Chemistry, Institute of Organic Chemistry,
UniVersity of Vienna, W a¨ hringer Strasse 38, A-1090 Vienna, Austria, and Institute of
Inorganic Chemistry, UniVersity of Vienna, W a¨ hringer Strasse 42, A-1090 Vienna, Austria
udo.brinker@uniVie.ac.at
Received March 25, 2010
ABSTRACT
Photolysis of aziadamantanes in the presence of fumaronitrile (FN) unexpectedly afforded conjugated 2H-azirines resulting from addition of
the carbene to the CN triple bond. This represents the first example of a direct azirine formation starting from an alkylcarbene for which a
concerted pathway is postulated. The novel outcome of the reaction is favored by the prior formation of a carbene-alkene complex, a type
of adduct that only recently has been described.
6
2
H-Azirines are important synthetic intermediates in organic
aziridines. Intermolecular reactions are far less successful. In
particular, the addition of nitrenes to alkynes afforded minimal
chemistry. They occur, foremost, during the well-known Neber
rearrangement. And whereas intramolecular routes to azirines
dominate, syntheses via intermolecular pathways are rare.
Usually, 2H-azirines are formed from nitrene intermediates
generated by pyrolysis or photolysis of vinyl azides. Other
approaches include ring contraction of azete derivatives and
isoxazoles at high temperatures, as well as oxidation of
1
7
yields. Correspondingly, in the reaction between carbenes and
nitriles, the carbene tends to react as an electrophile and generate
nitrile ylides. These transient species can be very efficiently
trapped as pyrrolines by using dipolarophiles; this was de-
monstrated in the case of the addition of 1-naphthylcarbene to
2
8
3
4
5
8,9
acetonitrile. In an extreme case, a stable crystalline ylide
formed by tetrakis(trifluoromethyl)cyclopentadiene and 1-ad-
†
Carbene Rearrangements 79. For Part 78 see: Wagner, G.; Knoll, W.;
10
amantyl nitrile could even be synthesized. To date, the sole
example of a cycloaddition of a carbene to a nitrile to yield
an azirine is the direct azirination of benzonitrile by a highly
Bobek, M. M.; Brecker, L.; van Herwijnen, H.W.G.; Brinker, U. H. Org.
Lett. 2010, 12, 332.
‡
Institute of Organic Chemistry, University of Vienna.
Institute of Inorganic Chemistry, University of Vienna.
§
1
1
(
1) (a) Neber, P. W.; Burgard, A. Justus Liebigs Ann. Chem. 1932, 493,
nucleophilic phosphinosilylcarbene.
2
4
81. (b) Neber, P. W.; v. Friedolsheim, A. Justus Liebigs Ann. Chem 1926,
49, 109.
(2) For a review, see: (a) Palacios, F.; Ochoa de Retana, A. M.; Mart ´ı nez
(6) Gentilucci, L.; Grijzen, Y.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1995, 36, 4665.
de Marigorta, E.; De los Santos, J. M. Eur. J. Org. Chem. 2001, 2401. (b)
Rai, K. M. L.; Hassner, A. In AdVances in Strained and Interesting Organic
Molecules; Halton, B., Ed.; JAI: Stamford, CT, 2000; Vol. 8, pp 187-257.
(7) Huisgen, R.; Blaschke, H. Chem. Ber. 1965, 98, 2985.
(8) (a) Escolano, C.; Duque, M. D.; Vazquez, S. Curr. Org. Chem. 2007,
11, 741. (b) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263.
(9) Barcus, R. L.; Hadel, L. M.; Johnston, L. J.; Platz, M. S.; Savino,
T. G.; Scaiano, J. C. J. Am. Chem. Soc. 1986, 108, 3928.
(10) Janulis, E. P., Jr.; Wilson, S. R.; Arduengo, A. J., III Tetrahedron
Lett. 1984, 405.
(
c) Backes, J. In Houben-Weyl; Klamann, D., Ed.; Thieme: Stuttgart,
Germany, 1992; Vol. E16c, pp 321-369.
(
(
3) Smolinsky, G. J. Org. Chem. 1962, 27, 3557.
4) Vogelbacher, U. J.; Lederman, M.; Schach, T.; Michels, G.; Hess,
U.; Regitz, M. Angew. Chem., Int. Ed. Engl. 1988, 27, 272.
(
5) (a) Sauers, R. R.; Hadel, L. M.; Scimone, A. A.; Stevenson, T. A.
(11) (a) Alcaraz, G.; Wecker, U.; Baceiredo, A.; Dahan, F.; Bertrand,
G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1246. (b) Piquet, V.; Baceiredo,
A.; Gornitzka, H.; Dahan, F.; Bertrand, G. Chem.sEur. J. 1997, 3, 1757.
J. Org. Chem. 1990, 55, 4011. (b) Himbert, G.; Kuhn, H.; Barz, M. Liebigs
Ann. Chem. 1990, 403.
10.1021/ol100703r  2010 American Chemical Society
Published on Web 04/16/2010

Our discovery that a dialkylcarbene is able to form a 2H-
azirine was quite serendipitous. During the investigation of
the products resulting from substituted adamantanylidenes
adamantanes 5 effectively but also adamantanylidenes 2!
Under these conditions, formation of pyrazolines 7 and
cyclopropanes 3 was anticipated. Due to its singlet ground
state with a small S-T (singlet-triplet) gap of 2.8 kcal/
mol, the relatively long-lived adamantanylidene should react
2
1
generated by photolysis of the corresponding 3H-diazirines
12,13
,
it was necessary to add fumaronitrile (FN) to scavenge
1
4,15
16
the intermediate diazo compounds 5 (Scheme 1).
It has
by a singlet pathway.
Thus, exclusive formation of trans-substituted 3 was
expected. Indeed, trans-cyclopropanes 3h and 3f were
obtained in 22% and 6% yield, respectively (Table 1); no
cis-cyclopropanes were observed. The cis-isomer could have
been formed by the decomposition of the corresponding
Scheme 1
.
Diazo vs Carbene Chemistry and Tautomerization of
to 7
6
1
intermediate ∆ -pyrazoline 6.
The main products remaining are pyrazolines 7 (50% for
7
h and 51% for 7f). This agrees well with previous results
obtained from the photolyses of aziadamantane 1h, wherein
0% of the diazirine reacts through the intermediacy of diazo
compound 5 and only 40% decomposes directly to adaman-
6
1
5
tanylidene 2. Since carbene 2f is diastereotopic, two
diastereomers of pyrazoline 7f are formed in a ratio of about
1
:1, which is characteristic for a product evolving from
diazoadamantane 5f. The formation of pyrazoline 7 can be
prevented if adamantanylidene 2 is generated thermally. Then
1
7
diazirine 1 decomposes preferably to the carbene. Almost
no diazo compound 5 is formed and hence no trapping
products 7 are observed.
Surprisingly, however, a third compound was isolated. It
shows an intense UV band at 263 nm, which fits well within
the range of substituted azirines. Although the analytical data,
HRMS, IR, and NMR were in accordance with this inter-
pretation, the NMR analysis was insufficient, because the
anticipated azirine ring bears no proton. Thus, X-ray data
are essential and crystallization was successful in the case
of 1-fluoro-4-aziadamantane (1f) with FN (Figure 1). In
summary, azirines 4h and 4f were synthesized in 17% and
1
6% yield, respectively. In stark contrast to pyrazolines 7f
already been demonstrated that diazo protonation has a
falsifying effect on the ratios observed from intermolecular
(1:1), azirine 4f was nearly exclusively present in its anti
form (anti:syn ratio ) 9:1). Such high selectivity results from
the intermediacy of carbene 2f, in which the reacting carbon
atom is unequally stabilized by its neighboring bonds
depending on the electronic properties of the substituent.
This is one of the major arguments against formation of the
azirine via cyclization of a nitrile ylide intermediate.
A second argument stems from the experimental condi-
tions. Nitrile ylides are known to be very reactive toward
1
2-14
carbene insertions into the O-H bond of CH
3
OH.
In
these reactions, the scavenging product is not the initially
1
2
formed ∆ -pyrazoline 6 but the rearranged ∆ -pyrazoline 7,
which is more stable and not prone to eliminate nitrogen.
To investigate the reactive behavior of aziadamantanes 1
1
3
1
8
(λmax ca. 330 nm) with FN in aprotic solvents, photolyses
were performed in both benzene and ether with excess FN.
Unexpectedly, this dipolarophile not only scavenges diazo-
8
a
1
,3-dipolar cycloadditions and an excess of the electron-
deficient fumaronitrile dipolarophile was present in the
reaction mixture. So, formation of pyrrolines should be
(
(
12) Bobek, M. M.; Brinker, U. H. J. Am. Chem. Soc. 2000, 122, 7430
.
13) (a) Knoll, W.; Bobek, M. M.; Giester, G.; Brinker, U. H.
Tetrahedron Lett. 2001, 42, 9161. (b) Knoll, W.; Bobek, M. M.; Kalch-
hauser, H.; Rosenberg, M. G.; Brinker, U. H. Org. Lett. 2003, 5, 2943. (c)
Tomoda, S.; Kaneno, D. Org. Lett. 2003, 5, 2947
14) (a) Holm, K. H.; Skattebøl, L. J. Am. Chem. Soc. 1977, 99, 5480.
b) Warner, P. W.; Chu, I.-S. J. Am. Chem. Soc. 1984, 106, 5366. (c) Kirmse,
W.; Meinert, T.; Modarelli, D. A.; Platz, M. J. Am. Chem. Soc. 1993, 115,
.
(16) (a) Shustov, G. V.; Liu, M. T. H.; Houk, K. N. Can. J. Chem.
1999, 77, 540. (b) Bonneau, R.; Liu, M. T. H. J. Phys. Chem. A 2000, 104,
4115. (c) Liu, M. T. H.; Ramakrishnan, K. Tetrahedron Lett. 1977, 36,
3139.
(
(
8
918. (d) Kirmse, W. In AdVances in Carbene Chemistry; Brinker, U. H.,
(17) Liu, M. T. H.; Choe, Y.-K.; Kimura, M.; Kobayashi, K.; Nagase,
S.; Wakahara, T.; Niino, Y.; Ishitsuka, M. O.; Maeda, Y.; Akasaka, T. J.
Org. Chem. 2003, 68, 7471.
Ed.; JAI: Greenwich, CT, 1994; Vol. 1, pp 1-57. (e) Kirmse, W. In
AdVances in Carbene Chemistry; Brinker, U. H., Ed.; Elsevier: Amsterdam,
The Netherlands, 2001; Vol. 3, pp 1-52.
(18) In fact, only a few publications can be found in which a nitrile
8
b,11
(
15) (a) Niino, Y.; Wakahara, T.; Akasaka, T.; Liu, M. T. H. ITE Lett.
ylide cyclization is postulated.
For instance, it concerns the formation
Batteries, New Technol. Med. 2002, 3, 82. (b) Bonneau, R.; Liu, M. T. H.
J. Am. Chem. Soc. 1996, 118, 7229. (c) Akasaka, T.; Liu, M. T. H.; Niino,
Y.; Maeda, Y.; Wakahara, T.; Okamura, M.; Kobayashi, K.; Nagase, S.
J. Am. Chem. Soc. 2000, 122, 7134. (d) Pezacki, J. P.; Shukla, D.; Lusztyk,
of an azirine after the generation of fluorenylidene in acetonitrile: (a) Grasse,
P. B.; Brauer, B. E.; Zupancic, J. J.; Kaufmann, K. J.; Schuster, G. B. J. Am.
Chem. Soc. 1983, 105, 6833. (b) Griller, D.; Hadel, L.; Nazran, A. S.; Platz,
M. S.; Wong, P. C.; Savino, T. G.; Scaiano, J. C. J. Am. Chem. Soc. 1984,
106, 2227.
J.; Warkentin, J. J. Am. Chem. Soc. 1999, 121, 6589
.
Org. Lett., Vol. 12, No. 10, 2010
2367

6 6
Table 1. Photolysis of Substituted Aziadamantanes 1 in 1,3,5-Trimethoxybenzene/C D
aziadamantane 1
a
1s, SiMe
3
1h, H
1m, Me
1n, NH
2
1o, OH
1f, F
1h, H, ∆
carbene products
diazo product
azirine 4
13
24
61
17
22
51
8
12
42
23
85
16
12
45
11
5
24
7
16
6
50
17
64
cyclopropane 3
pyrazoline 7
starting material
b
obsd yield
98
90
73
47
72
81
a
b
Thermolysis at 140 °C in molten fumaronitrile. The remaining material consists of insoluble material and of products formed in less than 1% yield.
azirines 4f differ by less than 1 kJ/mol. This difference is
too small to account for the large excess obtained experi-
mentally for one diastereomer (9:1).
The most probable pathway for the azirination of fuma-
22
ronitrile is a concerted addition of the reactive-nucleophilic
carbene 2f to the triple bond of the nitrile group (Figure 2,
Figure 1. X-ray diffraction structure of 4f.
expected. However, none was observed and therefore the
presence of nitrile ylides during the photolyses of 1 can be
excluded, because they would have been trapped by FN. The
absence of nitrile ylides was further ensured by laser-flash
photolysis experiments: no ylidic band arose from the
decomposition of 1h at 351 nm. In contrast, azirine 4h could
be decomposed by excitation at 248 and 308 nm, but not at
3
51 nm. The generated signal at 400 nm decays rapidly for
Figure 2. Structure A: carbene-alkene complex between 2f and
about 0.5-0.7 ms. Azirines are known to generate nitrile
ylides upon irradiation.
be reversible, the transient nature of the obtained nitrile
ylide probably does not allow a photochemical activation.
Moreover, azirine 4h was also obtained thermally.
FN. Structure B: transition state between adamantanylidene 2f and
8a,19
Although this photoreaction may
fumaronitrile. Distances in pm.
2
0
structure B; this transition state is only 4.5 kJ/mol higher in
energy than complex A). In the special case of fumaronitrile,
this reaction is highly favored by the prior formation of a
carbene-alkene complex (CAC, structure A). This CAC is
strongly stabilized by 37 kJ/mol. As revealed by the NBO
analysis, the stabilization of this structure results from
electron donation from the carbenic lone pair to the C-H
antibond of FN assisted by electrostatic dipole-dipole
21
Finally, DFT calculations were performed at the B3LYP/
-31G(d) level of theory in order to find the most realistic
6
pathway. For the reaction between adamantanylidene 2f and
FN, the formation of azirine 4f and the ylide is strongly
exothermic (256 and 235 kJ/mol, respectively). A transition
state connecting the ylide and the azirine could be located,
but it was highly energetic (+163 kJ/mol from the ylide),
and the ground state reaction is forbidden. Considering the
fact that usually nitrile ylides are nonisolable reactive species,
this high energetic barrier would speak against a thermally
driven ring closure reaction. Furthermore, the energies of
the two transition states between the nitrile ylide and both
23
interactions. For a C-H bond-based interaction this is an
impressively high value. Its strength is correlated with the
presence of electron-withdrawing groups at the double
23
bond. Because of this hydrogen bridge, the two reactants
(
22) Mieusset, J.-L.; Brinker, U. H. J. Org. Chem. 2008, 73, 1553.
(
19) The UV spectra of several nitrile ylides have been recorded with
max ranging from 280 to 410 nm. See ref 8a.
20) Photolyses of azirines are widely used to generate nitrile ylides,
(23) (a) Mieusset, J.-L.; Abraham, M.; Brinker, U. H. J. Am. Chem.
Soc. 2008, 130, 14634. This type of complex resulting from interactions
with the vinylic proton should be differentiated from the proposed
carbene-olefin complexes (COC) based on interactions with the olefinic π
orbitals which have been discussed in the past: (b) Nigam, M.; Platz, M. S.;
Showalter, B. M.; Toscano, J. P.; Johnson, R.; Abbot, S. C.; Kirchhoff,
M. M. J. Am. Chem. Soc. 1998, 120, 8055.
λ
(
since the reaction pathways are barrierless. However, little is known about
the feasibility of the reverse reaction, which involves a barrier of ca. 45
kJ/mol: Bornemann, C.; Klessinger, M. Chem. Phys. 2000, 259, 263.
(
21) The energetic values given represent E+ZPVE.
2368
Org. Lett., Vol. 12, No. 10, 2010

2
4
are oriented in such a way that the nitrile moiety is placed
in immediate proximity to the carbenic center, thus favoring
the azirine formation. For the ylide formation and for the
cyclopropanation reaction, no transition structures could be
located, in accordance with the fact that no energetic barrier
exists during these reactions as long as the reactants and their
orbitals are properly oriented. The only barrier to be
overcome is of entropic nature.
Analysis of the data obtained with other substituents
reactivity of alkylcarbenes have been observed previously,
which can be explained in terms of carbene complexation
by the solvent.
2
5,26
In conclusion, azirines have been synthesized which
comprise a double bond in conjugation with the azirine CdN
2
7
bond, a rather rare feature. We provide strong evidence
that during the synthesis of azirines generated by the reaction
of reactive-nucleophilic carbenes with nitriles, a concerted
addition of the carbene to the triple bond is preferred over
the two-step pathway (formation of a nitrile ylide and its
subsequent cyclization) previously postulated. With this
background knowledge, the carbene route to azirines will
become more practicable and will expand the repertoire of
methods available to prepare 2H-azirines.
2
3
(
3 2
SiMe , Me, NH , OH) revealed a strong dependence of the
azirine:cyclopropane ratio upon the substituent, which can
be correlated with their electronegativity. The electron-
withdrawing -F, -OH, and -NH
formation whereas the electron-releasing SiMe
2
groups favor azirine
even more
3
strongly favors cyclopropanation. Indeed, azirination of
fumaronitrile by adamantanylidenes depends on a delicate
Acknowledgment. The authors thank Prof. J. Wirz
(University of Basel) for laser-flash photolysis experiments
and fruitful discussions and Prof. S. Tomoda (University of
Tokyo) for calculations on substituted adamantanylidenes.
8b,9
balance of the ambiphilicity of the carbene. As mentioned,
many carbenes are too electrophilic and preferably form
2
2
nitrile ylides whereas the more nucleophilic carbenes can
very efficiently cyclopropanate the electron-deficient double
Supporting Information Available: Experimental pro-
cedures, spectral and crystallographic data (CIFs) for 1f and
4f, and computational data. This material is available free
of charge via the Internet at http://pubs.acs.org.
2
3
bond of fumaronitrile. Moreover, azirine formation could
be obtained with maleonitrile.
A second observation can be made from this series of
experiments: the azirine:cyclopropane ratio is strongly de-
pendent on the solvent. Undoubtedly, ether strongly favors
azirine formation. Indeed, major solvent effects on the
OL100703R
(25) For a review about carbene complexes, see: Kirmse, W. Eur. J.
Org. Chem. 2005, 237
(26) Mieusset, J.-L.; Brinker, U. H. Eur. J. Org. Chem. 2008, 3363
(27) Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103.
.
(
24) (a) Ruck, R. T.; Jones, M., Jr. Tetrahedron Lett. 1998, 39, 2277.
.
(
b) Tomioka, H.; Ozaki, Y.; Izawa, Y. Tetrahedron 1985, 41, 4987.
Org. Lett., Vol. 12, No. 10, 2010
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