New [4+2] heterocycloaddition of alkynyl Fischer carbene complexes. A facile access to pyrimidyl carbene complexes

Article abstract of DOI:10.1055/s-1999-2573

Pyrimidyl carbene complexes 4 have been obtained by [4+2] cycloaddition of 1,3-diazadiene derivative 1 and alkynyl carbene complexes 2, 3. Compounds 4 are precursors of some indeno[1,2-d]pyrimidine and quinazoline derivatives.

Full text of DOI:10.1055/s-1999-2573

LETTER
219
New [4+2] Heterocycloaddition of Alkynyl Fischer Carbene Complexes.
A Facile Access to Pyrimidyl Carbene Complexes
José Barluenga,* Luis A. López, Silvia Martínez and Miguel Tomás
Instituto Universitario de Química Organometálica "Enrique Moles", Unidad Asociada al CSIC, Universidad de Oviedo, Julian Clavería 8,
3071-Oviedo, Spain
3
Fax (34) 98 510 34 50; E-mail: barluenga@sauron.quimica.uniovi.es
Received 2 November 1998
compounds 4a-d to ester derivatives 6a-d was further
brought about with pyridine oxide in THF at room tem-
perature (Scheme 1, Table 1).
Abstract: Pyrimidyl carbene complexes 4 have been obtained by
[4+2] cycloaddition of 1,3-diazadiene derivative 1 and alkynyl car-
bene complexes 2, 3. Compounds 4 are precursors of some inde-
no[1,2-d]pyrimidine and quinazoline derivatives.
Key words: 1,3-diazadiene, Fischer carbene complexes, [4+2] cy-
cloaddition, pyrimidine, fused pyrimidine
In recent years Fischer carbene complexes have been de-
veloped into useful reagents for selective organic synthe-
1
sis. For instance, the relevance that various types of
cyclization reactions (e.g. Dötz benzannulation and Diels-
Alder cycloaddition) and aldolic and Michael additions
have acquired in the area of carbon-carbon bond forma-
2
tion is widely recognized. In recent years great attention
has been devoted in our laboratory to finding new appli-
cations of Fischer carbene complexes in heterocyclic
chemistry. In particular, we have reported that alkynyl
carbene complexes smoothly undergo the [4+2] cycload-
3
4
dition towards 1- and 2-azadiene derivatives leading se-
lectively to new 1,4-dihydro-2-pyridyl carbene
complexes. Continuing our work on the usefulness of het-
erodienes towards Fischer alkynyl carbene complexes we
decided to test 1,3-diazadienes, specifically 4-dimethy-
lamino-2-trichloromethyl-1,3-diazabutadiene 1, because
of, i) no reports concerning the cycloaddition of unsatur-
ated carbene complexes with dienes containing two het-
Scheme 1
5
eroatoms are known, and ii) the hypothetical [4+2]
cycloadducts would aromatize to produce 6-membered
heteroaryl carbene complexes, a type of Fischer complex
that seems to be elusive in sharp contrast to the 5-mem-
6
bered analogs. Herein we report the [4+2] cycloaddition
of tungsten and chromium alkynyl carbene complexes 2
and 3 with diazadiene 1 leading to pyrimidine complexes
4
and their transformation into various metal-free pyrimi-
7
dine derivatives.
8
Thus, 1,3-diazadiene 1 reacted with tungsten and chromi-
um carbene complexes 2 and 3, respectively, in THF (mo-
lar ratio 1:1.5) at room temperature to produce after 3-12
h (TLC monitoring) the metal carbene-containing cy-
cloadducts 4 in fair yields along with b-dimethylamino
alkenyl carbenes 5 resulting from Michael addition of
dimethylamine to the starting carbene (Scheme 1, Table
The preliminary results on synthetic applications of cy-
cloadducts 4 in metal carbene complexes-mediated het-
erocyclic chemistry are outlined in Scheme 2. First,
heating of compound 4e in THF at 80°C in a sealed tube
resulted in the formation of the 5H-indeno[1,2-d]pyrimi-
dine 7 in 70% yield (eq 1).9
,10,12
This process represents a
9,10,11
well-known transformation in alkenyl carbene complexes
1
).
The molar ratio of reagents (1:1.5 for 1/2,3) has
13
having an aromatic group at C-3. The same type of cy-
clization but with incorporation of an additional carbon
atom into the ring can be effected sometimes by isocya-
been optimized by balancing the chemical yield and the
ease of isolation of pure products 4. Clean oxidation of
Synlett 1999, No. 2, 219–221 ISSN 0936-5214 © Thieme Stuttgart · New York

2
20
J. Barluenga et al.
LETTER
nides. In line with the observation by Merlic et al.14 we References and Notes
found that the open-chain amide 8 was exclusively formed
(
1) Recent representative reviews: (a) Wulff, W. D. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds; Per-
gamon: New York, 1991, Vol. 5, p 1065. (b) Wulff, W. D. In
Comprehensive Organometallic Chemistry II; Abel, E. W.,
Stone, F. G. A., Wilkinson, G. Eds.; Pergamon: New York,
when either complex 4a (M=W) or 4e (M=Cr) was heated
60°C, THF) in the presence of 2 equivalents of tert-butyl-
isocyanide followed by chromatographic purification (eq
). Breaking the aromaticity of two rings very likely caus-
(
2
1995; Vol 12, p 469. (c) Doyle, M. P. In Comprehensive Or-
es failure of the cyclization. Therefore, the cyclopentenyl
substituted carbene complex 4d was selected and found to
undergo efficient isocyanide insertion/electrocyclic ring
ganometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G. Eds.; Pergamon: New York, 1995; Vol 12, p
387. (d) Harvey, D. F.; Sigano, D. M. Chem. Rev. 1996, 96,
271. (e) Aumann, R., Nienaber, H. Adv. Organomet. Chem.
1997, 41, 163.
t
closure (60°C, THF, 2 eq BuNC) furnishing the fused py-
rimidine 9, a type of quinazoline with a non trivial substi-
7
b,9,10
tution pattern.
(2) For a recent review covering the most important features on
the application of Fischer carbene complexes in asymmetric
synthesis, see: Wulff, W.D. Organometallics 1998, 17, 3116.
(
(
(
3) Barluenga, J.; Tomás, M.; López-Pelegrín, J.A.; Rubio, E. Te-
trahedron Lett. 1997, 38, 3981.
4) Barluenga, J.; Tomás, M.; Ballesteros, A.; Santamaría, J.;
Suárez-Sobrino. A. J. Org. Chem. 1997, 62, 9229.
5) The [4+1] cyclization of acylimine derivatives with aryl car-
bene complexes is known. See: Fischer, E.O.; Hollfelder, H.;
Kreissl, F.R.; Uedelhoven, W. J. Organomet. Chem. 1976,
113, C31.
(
6) (a) Recently, the failure of synthesizing pyridyl carbene com-
plexes by the standard Fischer method was reported: Peterson,
G.A.; Wulff, W.D. Tetrahedron Lett. 1997, 38, 5587. (b) The
preparation of pyridyl amino carbene complexes has been pro-
posed: Wu, F.; Merlic, C.A. Abstracts of Papers, 216th Natio-
nal Meeting of the American Chemical Society (Boston, MA),
Washington D.C., 1998; ORGN 236.
(7) For the interest of the pyrimidine nucleus, see: (a) Polo, R.;
Moretó, J.M.; Schick, U.; Ricart, S. Organometallics 1998,
17, 2135 (b) Undheim, K.; Benneche, T. in Comprehensive
Heterocyclic Chemistry II; Katrizky, A.R., Ed; Pergamon:
New York, 1996; Vol. 6, p 93. (c) For the synthetic utility of
2-(trichloromethyl)pyrimidines, see reference 8.
(
(
8) Guzman, A.; Romero, M.; Talamás, F.X.; Villena, R.; Green-
house, R.; Muchowsky, J.M. J. Org. Chem. 1996, 61, 2470.
9) Typical experimental procedure for the synthesis of com-
plexes 4. To a stirred solution of 1 (0.32 g, 1.5 mmol) in THF
(20 mL) at 0 °C was added dropwise a solution of the alkynyl
carbene complex 2,3 (2.25 mmol) in THF. The mixture was
stirred at rt until disappearance of the starting complex (TLC
monitoring). The solvent was removed and the resulting crude
(a mixture of compounds 4 and 5) was subjected to flash chro-
matography (silica gel; hexane/ethyl acetate, 3:1). Com-
pounds 4 were isolated as red solids (54-72%) which were
crystallized (hexane/chloroform) for analytical purposes.
Yields of compounds 4 are given in Table 1.
Experimental procedure for the synthesis of compound 7.
A solution of complex 4e (253 mg, 0.5 mmol) in THF (10 mL)
was heated at 80 °C in a sealed tube until disappearance of the
starting complex (2 hours, TLC monitoring). The solvent was
removed and the resulting crude was subjected to flash chro-
matography (silica gel; hexane/ethyl acetate, 3:1) to give pure
compound 7 (98 mg, 70%) as a brown oil.
In conclusion, choosing heterodiene 1 as a model we have
shown that 1,3-diazadienes cycloadd to readily available
alkynyl Fischer carbene complexes under very mild reac-
tion conditions to furnish the [4+2] cycloadducts 4. Com-
parison of the reaction conditions of the [4+2]
cycloaddition for alkynyl carbenes and for alkynyl esters
reveals that the former react much faster in accordance
with the superior activation power of the pentacarbonyl-
metal carbene over the carbonyl group. Taking advan-
tage of the presence of the metal carbene functionality
further useful transformations of 4 into polycyclic pyrim-
idines 7 and 9 are demonstrated. Further work to explore
the usefulness of these Fischer pyrimidyl carbene com-
plexes 4, particularly their ability for the Dötz benzannu-
lation, are in progress.
1
5
Experimental procedure for the synthesis of compound 9.
tert-Butylisocyanide (50 mL, 0.4 mmol) was added to a soluti-
on of complex 4d (99 mg, 0.2 mmol) in THF (10mL) at 0°C.
After consumption of the carbene complex (1 hour), as evi-
denced by TLC and colour change, the mixture was heated for
1
2 hours at 60°C. The resulting mixture was purified by flash
Acknowledgement
chromatography (silica gel; hexane/ethyl acetate, 10:1) to
yield pure compound 9 (47 mg, 60%) as a yellow oil.
This work was supported by DGICYT (Grant PB97-1271) and Uni-
versity of Oviedo (Fellowship to S.M.).
(
10) All compounds gave satisfactory spectroscopic and analytical
1
data. Selected spectroscopic data: (4e): H NMR (300 MHz,
1
3
CDCl ): d 4.9 (s, 3H), 7.5-7.7 (m, 5H), 8.4 (s, 1H); C NMR
3
Synlett 1999, No. 2, 219–221 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New [4+2] Heterocycloaddition of Alkynyl Fischer Carbene Complexes
221
(
(
(
75 MHz, CDCl ): d 67.6 (CH ), 96.1 (C), 128.9 (CH), 129.9 (12) A single reduction of CCl in 4e to CHCl in 7 took place that
3
3
3
2
CH), 131.4 (CH), 135.8 (C), 144.3 (C), 149.9 (CH), 157.1
was probably promoted by undetermined chromium species.
For conventional reduction of this group see reference 8.
(13) Barluenga, J.; Aznar, F.; Barluenga, S.; Fernández, M.; Mar-
tín, A.; García-Granda, S.; Piñera-Nicolás, A. Chem. Eur. J.
1998, 4, 2273.
1
C), 163.9 (C), 214.4 (C), 222.7 (C), 347.7 (C); (7): H NMR:
d 3.2 (s, 3H), 5.7 (s, 1H), 6.9 (s, 1H), 7.5-7.8 (m, 3H), 8.2 (m,
1
1
3
H), 9.0 (s, 1H); C NMR: d 54.1 (CH ), 71.0 (CH), 78.4
3
(CH), 122.9 (CH), 125.8 (CH), 130.0 (CH), 132.4 (CH), 133.3
(
C), 137.3 (C), 144.9 (C), 153.1 (CH), 166.2 (C), 168.9 (C);
(14) Merlic, C.A.; Burns, E.E.; Xu, D.; Chen, S.Y. J. Am. Chem.
Soc. 1992, 114, 8722.
(15) For instance, the cycloadduct 6a was previously obtained in
51% by heating at 101°C (toluene, 30 h) a 1:2 mixture of 1 and
methyl phenylpropynoate. See reference 8.
1
(
2
9) H NMR: d 1.4 (s, 9H), 2.3 (m, 2H), 3.1 (m, 2H), 3.4 (m,
1
3
H), 4.0 (s, 3H), 9.6 (s, 1H); C NMR: d 24.5 (CH ), 30.5
2
(CH ), 30.6 (CH ), 33.6 (CH ), 56.0 (C), 60.6 (CH ), 97.5 (C),
2 3 2 3
1
04.3 (C), 105.4 (C), 118.7 (C), 137.0 (C), 138.3 (C), 145.0
(C), 149.0 (C), 156.4 (CH).
(
11) No [4+3] cycloaddition products were detected in the case of
chromium carbene complexes 3 unlike what was found for 1-
azadienes. See, Barluenga, J.; Tomás, M.; López-Pelegrín,
J.A.; Rubio, E.; García-Granda, S.; Pertierra, P. J. Am. Chem.
Soc. 1996, 118, 695.
Synlett 1999, No. 2, 219–221 ISSN 0936-5214 © Thieme Stuttgart · New York