Regioselective 1,3-dipolar cycloaddition reaction of azides with alkoxy alkynyl fischer carbene complexes

Article abstract of DOI:10.1021/om1009523

Solvent-free conditions at moderate temperature promote regioselective 1,3-dipolar cycloaddition reactions between alkoxy alkynyl Fischer carbene complexes with a wide range of organic azides.

Full text of DOI:10.1021/om1009523

Organometallics 2010, 29, 6619–6622 6619
DOI: 10.1021/om1009523
Regioselective 1,3-Dipolar Cycloaddition Reaction of Azides with Alkoxy
Alkynyl Fischer Carbene Complexes
Amarnath Chakraborty, Surjendu Dey, Sudeshna Sawoo, N. N. Adarsh,† and
Amitabha Sarkar*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur,
Kolkata 700 032, India. †Crystal structure determination.
Received October 1, 2010
Summary: Solvent-free conditions at moderate temperature
promote regioselective 1,3-dipolar cycloaddition reactions be-
tween alkoxy alkynyl Fischer carbene complexes with a wide
range of organic azides.
cycloadditions.5 The pentacarbonylmetal fragment as a
powerful electron-withdrawing group makes the conjugated
alkyne considerably electron-deficient and polarized.6 The
reaction of 1,3-dipolar compounds, e.g., diazomethane,7
nitrones,8 and nitrilimines,9 with such Fischer carbene com-
plexes takes place readily to afford [3þ2] cycloadducts.
Chalcogenide-bridged iron clusters, despite their reluctance
to react with disubstituted alkynes, readily add to alkyne
carbene complexes.10 In comparison, literature reports on
reaction of azides with alkynyl Fischer carbene complexes
are scarce.
The versatility and utility of Fischer carbene complexes
have been widely demonstrated during the past two decades.1
The rich and diverse chemistry of these complexes has been
utilized as key steps in the synthesis of several natural
products.2 Especially rewarding has been their participation
in various cycloaddition reactions,3 the products of which
usually retain the metal carbene functionality that can be
utilized in further transformations.4
Sierra described11 Cu(I)-promoted “click” cycloaddition
to terminal acetylenes tethered to an alkynyl Fischer carbene
complex. The “click” product was derived from a terminal
alkyne in moderate yield, but it was not clear whether any
reaction occurred with the alkyne conjugated to the Fischer
carbene moiety. It was reported earlier12 that the reaction of
azides with an alkynyl Fischer carbene complex under
thermal activation afforded a β-amino alkenyl complex
instead of the expected cycloadduct.
Recently we have successfully used a [3þ2] cycloaddi-
tion between an alkynyl Fischer carbene complex and an
azido-terminated monolayer on glass and silicon surfaces
and achieved rapid, covalent immobilization of proteins.13
Grafting of protein was done by utilizing aminolysis of
Fischer carbene complexes by pendant lysine amino groups
on a protein surface. Since this reaction would not be
possible with β-amino alkenyl carbene complexes, we as-
sumed that the cycloaddition had indeed taken place. It was
not possible, however, to ascertain the extent of reaction
and regiochemistry of cycloaddition products on the solid
A triple bond conjugated with a Fischer carbene com-
plex is highly activated toward Diels-Alder and related
*To whom correspondence should be addressed. E-mail: ocas@iacs.
res.in.
€
(1) For reviews, see: (a) Dotz, K. H.; Stendel, J., Jr. Chem. Rev. 2009,
109, 3227. (b) de Meijere, A.; Schirmer, H.; Duetsch, M. Angew. Chem., Int.
Ed. 2000, 39, 3964. (c) Herndon, J. W. Coord. Chem. Rev. 2000, 206-207,
237. (d) Aumann, R. Eur. J. Org. Chem. 2000, 17. (e) Herndon, J. W.
Tetrahedron 2000, 56, 1257. (f) Aumann, R.; Nienaber, H. Adv. Organomet.
€
Chem. 1997, 41, 163. (g) Dotz, K. H. Angew. Chem., Int. Ed. 1984, 23, 587.
€
(h) Dotz, K. H.; Fischer, H.; Hofmann, P.; Kreissl, F. R.; Schubert, U.
Transition Metal Carbene Complexes; Verlag Chemie: Weinheim,
€
Germany, 1983. (i) Zaragoza Dorwald, F. Metal Carbenes in Organic
Synthesis; Wiley VCH: Weinheim, Germany, 1999.
ꢀ
´
(2) (a) Barluenga, J.; Santamarıa, J.; Tomas, M. Chem. Rev. 2004, 104,
2259. (b) Barluenga, J. Pure Appl. Chem. 2002, 74, 1317. (c) Barluenga, J.;
Martinez, S. Arkivoc 2006, vii, 129. (d) Bao, J.; Wulff, W. D.; Dragisich, V.;
Wenglowsky, S.; Ball, R. G. J. Am. Chem. Soc. 1994, 116, 7616.
(e) Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess, E.; Zask,
A. J. Am. Chem. Soc. 1982, 104, 5850. (f) Semmelhack, M. F.; Bozell, J. J.;
Keller, L.; Sato, T.; Spiess, E. J.; Wulff, W.; Zask, A. Tetrahedron 1985, 41,
5803. (g) Wulff, W. D.; Tang, P.-C. J. Am. Chem. Soc. 1984, 106, 434.
€
ꢀ
(6) Polarization of carbene complexes: (a) Segundo, A.; Moreto,
(h) Dotz, K. H.; Popall, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 1158.
€
~
(i) Dotz, K. H.; Popall, M.; M€uller, G. J. Organomet. Chem. 1987, 334, 57.
J. M.; Vinas, J. M.; Ricart, S.; Molins, E. Organometallics 1994, 13, 2467.
(j) Wulff, W. D.; Xu, Y.-C. J. Am. Chem. Soc. 1988, 110, 2312. (k) Boger,
D. L.; H€uter, O.; Mbiya, K.; Zhang, M. J. Am. Chem. Soc. 1995, 117,
11839.
(b) Wulff, W. D.; Yang, D. C. J. Am. Chem. Soc. 1984, 106, 7565.
(c) Mathur, P.; Ghosh, S.; Sarkar, A.; Satyanarayana, C. V. V.; Rheingold,
A. L.; Liable-Sands, L. M. Organometallics 1997, 16, 3536.
(7) (a) Chan, K. S.; Wulff, W. D. J. Am. Chem. Soc. 1986, 108, 5229.
(b) Kreissl, F. R.; Fischer, E. O.; Kreiter, C. G. J. Organomet. Chem. 1973,
57, C9.
€
(3) (a) Fruhauf, H.-W. Chem. Rev. 1997, 97, 523. (b) Harvey, D. F.;
Sigano, D. M. Chem. Rev. 1996, 96, 271. (c) Wulff, W. D. In Comprehensive
Organic Synthesis, Vol. 5; Trost, B. M., Fleming, I., Eds.; Pergamon
Press:: New York, 1991; p 1065. (d) Wulff, W. D. In Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, Eds.;
Pergamon Press: New York, 1995; p 469.
(8) (a) Chan, K. S.; Yeung, M. L.; Chan, W.-K.; Wang, R.-J.; Mak,
ꢀ
T. C. W. J. Org. Chem. 1995, 60, 1741. (b) Barluenga, J.; Fernandez-Marí,
ꢀ
~ ꢀ
F.; Gonzalez, R.; Aguilar, E.; Revelli, G. A.; Viado, A. L.; Fananas, F. J.;
(4) (a) Barluenga, J.; Aznar, F.; Palomero, M. A. Angew. Chem., Int.
Olano, B. Eur. J. Org. Chem. 2000, 1773.
ꢀ
ꢀ
´
Ed. 2000, 39, 4346. (b) Barluenga, J.; Andina, F.; Aznar, F.; Valdes, C. Org.
(9) Barluenga, J.; Fernandez-Marı, F.; Aguilar, E.; Viado, A. L.;
ꢁ
ꢀ
Lett. 2007, 9, 4143. (c) Barluenga, J.; Fananas-Mastral, M.; Andina, F.;
Olano, B. Tetrahedron Lett. 1998, 39, 4887.
ꢀ
Aznar, F.; Valdes, C. Organometallics 2008, 27, 3593. (d) Samanta, D.;
(10) Mathur, P.; Ghosh, S.; Sarkar, A.; Satyanarayana, C. V. V.;
Rheingold, A. L.; Liable-Sands, L. M. Organometallics 1997, 16, 3536.
Sawoo, S.; Sarkar, A. Chem. Commun. 2006, 3438–3440.
ꢀ ꢀ
(11) Baeza, B.; Casarrubios, L.; Ramırez-Lopez, P.; Gomez-Gallego,
´
(5) (a) Wulff, W. D.; Yang, D. C. J. Am. Chem. Soc. 1983, 105, 6726.
(b) Wulff, W. D.; Bauta, W. E.; Kaesler, R. W.; Lankford, P. J.; Miller, R. A.;
Murray, C. K.; Yang, D. C. J. Am. Chem. Soc. 1990, 112, 3642. (c) Wulff,
W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. C.; Gilbertson,
S. R. Tetrahedron 1985, 41, 5813.
M.; Sierra, M. A. Organometallics 2009, 28, 956.
(12) Zhang, H.; Chan, K. S. Synth. Commun. 1995, 25, 3329.
(13) Sawoo, S.; Dutta, P.; Chakraborty, A.; Mukhopadhyay, R.;
Bouloussa, O.; Sarkar, A. Chem. Commun. 2008, 5957.
r
2010 American Chemical Society
Published on Web 11/01/2010
pubs.acs.org/Organometallics

6620 Organometallics, Vol. 29, No. 23, 2010
Chakraborty et al.
Scheme 1. Reaction of Alkynyl Fischer Carbene Complex 1a
with Benzyl Azide
Table 2. Cycloaddition Reactions of Alkoxy Alkynyl Fischer
Carbene Complexes with Arylmethyl Azidesa
Table 1. Screening of Conditions for Azide-Alkyne
Cycloaddition Reactions (depicted in Scheme 1)
entry
solvent
temp (°C)
time (h)
yield (%)a
1
2
3
4
5
6
7
8
THF
THF
dichloromethane
toluene
toluene
dioxane
dioxane
no solvent (neat)
40
40
35
40
80
40
80
40
24
48
24
18
12
24
2
35 (42)
30 (54)
12 (30)
26 (34)
15 (58)
28 (40)
5 (60)
3
76 (5)
a Isolated yield of triazole complex 2a. Figures in parentheses are
isolated yields of complex 3a.
surface since usual solution spectroscopic techniques were
not applicable. We, therefore, investigated this methodology
in greater detail with reference to yield, modularity, and
regioselectivity. We report herein a practical protocol for
successful [3þ2] cycloaddition reaction of azides with alky-
nyl Fischer carbene complexes leading to triazolyl Fischer
carbene complexes regioselectively.
Initially, the Fischer carbene complex 1a was treated with
benzyl azide in dry THF and stirred for 24 h at 40 °C. We
obtained the triazolyl carbene complex 2a (35%) along with
β-aminoalkenyl carbene complex 3a (42%) (Scheme 1).
Screening of the reaction conditions revealed that longer
reaction times and elevated temperatures decrease the yield14
of the cycloaddition product (Table 1). Poor yield of the
desired product from the cycloaddition reaction in different
solvents prompted us to perform the reaction neat, i.e., with-
out any solvent. Gratifyingly, reaction of Fischer carbene
complex 1a with benzyl azide afforded a single regioisomer
of the triazole product 2a (76%) along with a very small
amount of the byproduct 3a (5%). Hence, reactions were
subsequently performed by heating the Fischer carbene
complexes and azides at 40 °C for 3-8 h without any solvent
under argon.
The major advantage of this protocol is fourfold: (a) no
solvent is required; (b) temperature of the reaction is mod-
erate (40 °C); (c) yield of 1,3-cycloadduct is consistently high;
and (d) only one regioisomer of the product was obtained
(Tables 2 and 3).
a Fischer carbene complex (1.0 equiv) and azide (1.5 equiv) heated at
40 °C under argon. b Yields of isolated products.
The entries of Table 2 comprise arylmethyl azides of a wide
structural variety, whereas Table 3 lists azides ranging from
alkyl to ketoaryl, aryl, and allyl. There was no significant
difference in yield when substituents in benzylic azides were
changed. Steric factors appear to influence the yield of this
cycloaddition reaction to some extent. For example, diphenyl
azidomethane, 2-chlorobenzyl azide, and 1-napthylmethyl
(14) We established that carrying out the reaction at higher tempera-
ture (65-90 °C) resulted in decomposition of the azide and formation of
product 3a predominantly. Although heating product 2a at elevated
temperature (∼90 °C) led to gradual decomposition, compound 3a was
not one of the decomposition products, as clearly seen by TLC.

Note
Organometallics, Vol. 29, No. 23, 2010 6621
Table 3. Reactions of Alkoxy Alkynyl Fischer Carbene Complexes
with Alkyl, Aryl, and Cinnamyl Azidesa
Figure 1. NOE analysis of compound 2r.
Figure 2. ORTEP diagram of 2a with thermal ellipsoids drawn
at the 50% probability level.
Scheme 2. Plausible Mechanism for Cycloaddition Reaction
Fischer carbenes 1a and 1b to give high yield of triazole
complexes 2r and 2u, respectively (Table 3, entries 6 and 9).
(2-Azidoethyl)benzene rapidly furnished the cycloadduct in
75% yield (Table 3, entry 8). Cinnamyl azide also afforded
the desired cycloadduct in good yield (Table 3, entry 4).
The assignment of regiochemistry of a representative 1,2,3-
triazolyl carbene complex (2r) was based on analysis of its
NMR spectral data (NOESY and NOE). Significant NOE en-
hancement was observed among the marked protons (Figure 1).
A single crystal of a representative triazolyl Fischer carbene
complex 2a was grown, and the crystal structure of the com-
plex was solved (see Supporting Information). The molecular
structure shown in Figure 2 corroborated the structural
assignment.
Theregioselectivityof the triazole complex can be explained
by considering the polarity of the triple bond conjugated
with the carbene moiety (partial positive charge is localized
on β-carbon) and the dipole of the azide15 as depicted in
Scheme 2.
In summary, we have reported a facile, regioselective [3þ2]
cycloaddition reaction of alkynyl Fischer carbene complexes
with different organic azides under mild conditions. The pre-
sent procedure is superior to earlier methods for cycloaddition
in that it does not require any organic solvent. The strongly
polarized triple bond of the carbene complex is responsible for
a Fischer carbene complex (1.0 equiv) and azide (1.5 equiv) heated at
40 °C under argon. b Yield of isolated products. c β-Aminoalkenylcar-
bene isolated: 14%, 11%, and 17% for entries 1, 2, and 3, respectively.
azide required more time for completion (Table 2, entries 3,
5, and 9). A heterocyclic azide such as 5-azidomethyl-2-
chloropyridine afforded an excellent yield of cycloaddition
product (Table 2, entry 11).
Aryl azides are less stable. As a result, the yields of the
cycloaddition products obtained from aryl azides were in-
ferior to those obtained from benzylic azides. The presence of
an electron-withdrawing group in aryl azide slowed the
reaction and decreased the yield of cycloaddition product,
whereas an electron-donating group in aryl azide (e.g.,
4-methoxyphenyl azide) improved the yield of the reaction
and shortened the reaction time (Table 3, entries 1, 2, and 3).
Alkyl azides proved to be good substrates for cycloaddi-
tion reaction with Fischer carbene complexes. Long-chain
alkyl azides responded well under similar reaction conditions
(Table 3, entries 5 and 7). Ethyl 2-azidoacetate reacted with
(15) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem.
Soc. 1973, 95, 7301.

6622 Organometallics, Vol. 29, No. 23, 2010
Chakraborty et al.
promoting this reaction without an additive, although the rate
may not be competitive with a Cu-promoted “click” reac-
tion.11 The method appears to be general and of a wide scope.
Diffractometer facility at the Department of Inorganic
Chemistry is gratefully acknowledged.
Supporting Information Available: Experimental details,
including copies of 1H and 13C NMR spectra of com-
plexes 2a-u, and X-ray crystal data of compound 2a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. Financialsupport from DST (SR/S1/
OC-29/2007), India, is gratefully acknowledged. A.C. and
S.S. thankCSIR, India, forSRF, andS.D.thanksIACSfor
a research fellowship. The National Single Crystal X-ray