Facile and versatile annulation of the imidazole ring: Single and sequential cyclization reactions of fischer carbene complexes with 1,4-diazafulvenes

Article abstract of DOI:10.1002/chem.200501402

We examined the reactivity of dimethylaminodiazafulvene 1 toward Fischer alkenylcarbene 2 and alkynylcarbene 3 complexes. Diazafulvene 1 reacts with alkenylcarbenes 2 through a formal [6+3] heterocyclization in a regio- and stereoselective manner to affor

Full text of DOI:10.1002/chem.200501402

FULL PAPER
Chem. Eur. J. 2006, 12, 3201 – 3210
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3201

DOI: 10.1002/chem.200501402
Facile and Versatile Annulation of the Imidazole Ring: Single and Sequential
Cyclization Reactions of Fischer Carbene Complexes with 1,4-Diazafulvenes
JosØ Barluenga,* Jaime García-Rodríguez, Silvia Martínez, Angel L. Suµrez-Sobrino, and
Miguel Tomµs[a]
Abstract: We examined the reactivity
of dimethylaminodiazafulvene
vene 1 and alkynyl carbenes 3 undergo
a [6+2] cyclization to afford pyrrolo-
[1,2-a]imidazole carbene complex 6
to the corresponding imidazole-based
polyfused systems 10, 11, and 13 re-
spectively. Finally, enynylcarbenes 3d,f
undergo consecutive [6+2]/[5+1] cycli-
zation reactions with diazafulvene 1
and tBuNC, respectively, to yield tetra-
cyclic adducts 14 and 15. All these
processes resultin high yields and pro-
vide a route to the preparation of imi-
dazopyridines and pyrroloimidazoles as
well as other polycyclic molecules that
contain imidazole groups, which are in-
teresting from a pharmacological and
biological pointof view.
1
toward Fischer alkenylcarbene 2 and
alkynylcarbene 3 complexes. Diazaful-
vene 1 reacts with alkenylcarbenes 2
through a formal [6+3] heterocycliza-
tion in a regio- and stereoselective
manner to afford dihydroimidazo[1,2-
a]pyridines 4. Acid-promoted dimethyl-
amine elimination in compound 4c
gives rise to the aromatic imidazo pyri-
dine 5. A likely mechanism for this re-
action is a 1,2-nucleophilic addition/
[1,2]-shift metal-promoted cyclization
sequence. On the other hand, diazaful-
that can be readily oxidized to the cor-
responding esters 7. When enynylcar-
benes 3e–i are treated with diazaful-
vene 1, consecutive and diastereoselec-
tive [6+2]/cyclopentannulation cycliza-
tion reactions take place affording new
polycyclic complex systems 8, 9, and 12
that can be appropriately demetallated
Keywords: azafulvenes · carbenes ·
chromium · cyclization · imidazole
Introduction
[2+2+1+1],[12d,17] and [2+2+2+1],[14a] carbocyclization reac-
tions have been reported in the recent past.
Stabilized Fischer carbene complexes have been shown to
be useful reagents in a number of cyclization reactions, al-
lowing the preparation of a plethora of three- to eight-mem-
bered carbocyclic rings and acyclic compounds.[1] Despite
the fact that the activated carbon–carbon double and triple
bonds of a,b-unsaturated carbene complexes efficiently par-
ticipate in a number of [2+2][2] and [4+2][3] cycloaddition re-
actions, the most characteristic and valuable reactions are
those in which the metal–carbon bond is involved. Thus, a
number of two-component, such as [2+1],[4] [3+1],[5]
[3+2],[6] [3+3],[5,7] [4+1],[8] [4+3],[6c,8c,9] [5+1],[10] and
[5+2][11] as well as multicomponent, such as [2+2+1],[12]
Despite the intensive work on carbocyclization reactions,
the reactivity of metal–carbene complexes toward substrates
containing heteroatoms has been much less studied. Apart
from the known heterocycloaddition reactions, that is, the
[4+2], [2+2], and 1,3-dipolar reactions, through the activat-
ed carbon–carbon bond of unsaturated carbene com-
plexes,[18] the attention on heterocyclization reactions involv-
ing metal–carbene functionality has largely focused on the
use of imines and unsaturated imine derivatives as sub-
strates in both photochemical and thermal processes.[19] We
have searched for new nitrogen-containing substrates and
thought that diazafulvene derivatives might be appropriate
candidates because we were convinced of the potential of
these metal–carbene complexes as reagents in heterocyclic
synthesis[20]. First, the polyvalent nature of the pentafulvene
system has permitted us to selectively access different poly-
carbocyclic structures through [2+1], [4+3], and [6+3] cycli-
zation reactions of Fischer carbene complexes.[21] Secondly,
surprisingly few reports exist on the use of azafulvenes in
heterocyclic synthesis.[22] Specifically, we thought of the 1,4-
diazafulvene structure as a reactive imidazole building block
[3+2+1],[13]
[3+2+2],[14]
[4+2+1],[15]
[5+2+1],[16]
[a] Prof. Dr. J. Barluenga, J. García-Rodríguez, Dr. S. Martínez,
Dr. A. L. Suµrez-Sobrino, Prof. Dr. M. Tomµs
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al CSIC Universidad de Oviedo
Juliµn Clavería 8, 33006 Oviedo (Spain)
Fax : (+34)985-103-450
E-mail: barluenga@uniovi.es
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Chem. Eur. J. 2006, 12, 3201 – 3210

Cyclization Reactions
FULL PAPER
for an annulation-based strategy to rapidly prepare fused
imidazole heterocycles.
Thus, we report on the reaction of the readily available 6-
dimethylamino-1,4-diazafulvene (1)[22] with alkenyl and al-
kynyl Fischer carbene complexes 2 and 3 to produce simple
and complex imidazo[1,2-a]pyridine and pyrrolo[1,2-a]imi-
dazole structures, respectively.
Results and Discussion
[6+3] Cycloaddition of 6-dimethylamino-1,4-diazafulvene
(1) with alkenylcarbene complexes (2): First, we examined
the reactivity of alkenylcarbenes toward dimethylaminodi-
azafulvene (Scheme 1). Thus, chromium–alkenylcarbene
complexes 2a–d (M=Cr) were found to smoothly react with
diazafulvene 1 in acetonitrile at room temperature. After
stirring for one hour, the reaction mixture was subjected to
demetallation (air, sunlight) and was filtered through a pad
of Celite to produce nearly pure [6+3] cycloadducts 4a–d
with complete regio- and diastereoselectivity (Table 1, en-
tries 1–4). Further column chromatography purification gave
pure dihydroimidazo[1,2-a]pyridines 4a–d in excellentyields
(82–90%). Similarly, the dienylcarbene complex 2e under-
went cycloaddition to compound 1 in a chemoselective
manner giving rise to the more-functionalized phenylethenyl
À
derivative 4e (R=trans-Ph CH=CH) in excellentyield
(Table 1, entry 5). Heterocyclic carbene complexes also
work well allowing the synthesis of more complex polyheter-
ocyclic systems. For instance, the tricyclic imidazole 4 f was
obtained in 84% yield from diazafulvene 1 and chromium–
carbene 2 f under the same reaction conditions (Table 1,
entry 6). The tungsten–alkenylcarbene 2g (M=W) reacted
in the same way, though the resulting cycloadduct 4a was
isolated in significantly lower yield than in the case of the
chromium–carbene 2a (45 versus 82% yield; Table 1, en-
tries 1 and 7). The trans relationship between the dimethyl-
amino group and the R substituent was determined by nu-
clear Overhauser enhancementexperimenst performed on
compound 4e. The treatment of cycloadduct 4c with con-
centrated HCl in dichloromethane resulted in the elimina-
Abstract in Spanish: Se ha investigado la reactividad de di-
metilaminodiazafulveno 1 frente a los complejos alquenilcar-
beno y alquinilcarbeno de Fischer 2 y 3. El diazafulveno 1
reacciona con los alquenilcarbenos 2 mediante una heteroci-
clación [6+3] dando lugar a dihidroimidazo[1,2-a]piridinas
4 de forma regio- y diastereoselectiva; la eliminación de di-
metilamina en medio µcido en 4c da lugar a la imidazopiridi-
na aromµtica 5. Un mecanismo plausible para esta reacción
implica una secuencia adición nucleófila-1,2/ciclación induci-
da por la migración-[1,2] del fragmento metµlico. Por otra
parte, el diazafulveno 1 y los alquinilcarbenos 3 dan lugar a
una ciclación [6+2] generando los complejos carbeno con es-
tructura de pirrolo[1,2-a]imidazol 6, los cuales pueden oxi-
darse fµcilmente a los correspondientes Østeres 7. Cuando los
eninilcarbenos 3e–i reaccionan con 1 se obtienen, a travØs de
la secuencia diastereoselectiva ciclación [6+2]/ciclopentanu-
lación, los complejos metµlicos policíclicos 8, 9, y 12, cuya
desmetalación en condiciones adecuadas permite acceder a
los correspondientes imidazoles polifusionados 10, 11, y 13,
respectivamente. Finalmente, el tratamiento secuencial de los
eninilcarbenos 3d,f con diazafulveno 1 y con tBuNC da
lugar a los aductos tetracíclicos 14,15 en un proceso multi-
componente de doble ciclación [6+2] y [5+1]. Todos estos
procesos tienen lugar con altos rendimientos y representan
una vía de entrada a imidazopiridinas y pirroloimidazoles,
así como a otras molØculas policíclicas que contienen el
anillo de imidazol con interØs desde el punto de vista biológi-
co y farmacológico.
Scheme 1. [6+3] Cycloaddition of 1,4-diazafulvene 1 and alkenylcarbenes 2.
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J. Barluenga etal.
Table 1. Dihydroimidazopyridines 4 from diazafulvene 1 and carbenes 2.
[6+2] Cycloaddition of 6-dimethylamino-1,4-diazafulvene 1
with alkynylcarbenes 3a–d: We also explored the reactivity
of Fischer alkynylcarbene complexes toward 6-dimethylami-
no-1,4-diazafulvene (Scheme 2). Thus, it was found that the
Carbene
R
ProductYield
[%][a]
1
2
3
4
2a
2b
2c
2d
Ph
4a
4b
4c
4d
82
88
90
83
pOMe-C6H4
2-furyl
2-thienyl
5
2e
4e
90
6
7
2 f
2g
4 f
4a
84
45
Ph
[a] Yields after column chromatography purification (silica gel, hexanes/
EtOAc/Et3N 8:1:1).
Scheme 2. [6+2] Cyclization of diazafulvene 1 with alkynyl Fischer car-
bene complexes 3a–d.
tion of dimethylamine and the formation of the aromatic
imidazopyridine structure 5 in 70% yield. Looking athte
overall process 6-dimethylamino-1,4-diazafulvene behaves
as a synthon of the elusive 1,4-diazafulvene species.
A likely mechanistic rationale for this [6+3] cycloaddition
reaction of alkenylcarbenes and fulvenes is based on the ac-
cepted sequence of nucleophilic addition and metal-migra-
tion-promoted cyclization (Figure 1).[23] Thus, the 1,2-addi-
reaction of the chromium–alkynylcarbene 3a with diazaful-
vene 1 went to completion after stirring in THF for one
hour at room temperature. Simple column-chromatography
purification of the reaction crude on silica gel yielded the
new pyrrolo[1,2-a]imidazole–carbene complex 6a (M=Cr;
R=tBu, 78%) resulting from the [6+2] cycloaddition reac-
tion (Table 2, entry 1). The tungsten–carbene complex 3b
Table 2. Cycloadducts 6,7 from diazafulvene 1 and carbenes 3a–d.
Carbene
M
R
ProductYield
[%][a]
1
2
3
4
5
6
3a
3b
3c
Cr
W
Cr
tBu
Ph
6a
7a
6b
78
88
61
90
–
Figure 1. Feasible mechanism of the [6+3] cycloaddition of diazafulvene
1 and alkenylcarbenes 2.
7b
Ph
6c[b]
7b[c]
70
tion of the ring nitrogen atom of the diazafulvene to the car-
bene complex would form the intermediate I, which would
then undergo a [1,2]-M(CO)5-shift and stereoselective cycli-
zation through the more favorable conformation to give the
intermediate II. The last step involves metal elimination to
generate the enolether functionality.
7
3d
6d[b]
–
8
7d[c]
74
[a] Yields after column chromatography purification (silica gel, hexanes/
EtOAc/Et3N 8:1:1). [b] Carbene cycloadducts not isolated. [c] Overall
yield from diazafulvene 1 and carbenes 3c,d.
Therefore, a facile access to the imidazo[1,2-a]pyridine
ring is accomplished by a procedure that involves annulation
of the pyridine unit onto the existing imidazole ring.[24] In-
terestingly, most strategies leading to this heterocyclic struc-
ture are based on the construction of the imidazole ring
from the pyridine nucleus and provide imidazo[1,2-a]pyri-
dines substituted at the imidazole moiety.[25] Moreover, com-
pounds of type 4 are of particular interest because many
imidazo[1,2-a]pyridines display a broad range of pharmaco-
logical (antiinflammatory, antiviral, antibacterial, antiproto-
zoal, hypnotic, and anxiolytic) and biological activity (glyco-
(M=W; R =Ph) also works well affording 6b in 61% yield
(Table 2, entry 3). Chromium–alkynyl complexes with
phenyl and cyclopentenyl substituents 3c and 3d, respective-
ly, undergo cycloaddition to diazafulvene 1 in the same way,
though the corresponding cycloadducts 6c,d could notbe
purified; however, they underwent oxidation to the corre-
sponding esters 7b,d in high overall yield when subjected to
column chromatography (Table 2, entries 6,8). The carbene
cycloadducts 6a,b were in turn oxidatively demetallated to
the corresponding esters 7a,b (Table 2, entries 2,4). The pro-
posed structures 6 and 7 are in good agreement with their
sidase, cyclin-dependentkinase, and
H
+/K+ ATPase
enzyme inhibitors).[26,27]
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Cyclization Reactions
FULL PAPER
spectroscopic data. Looking at the pyrrole ring, it should be
noted that the initially formed tautomer III isomerizes
under the reaction conditions to the more stable, fully con-
jugated carbene system 6. This structural feature is con-
firmed by HMBC (heteronuclear multiple bond correlation)
and NOESY experiments on compound 7d. The reaction
can be readily understood by
Therefore, we turned our attention to the acyclic and cy-
clohexenyl analogues 3e–i as the starting carbene com-
plexes, for which the consecutive cyclization process would
be presumably more favorable. We firstexplored the behav-
ior of dihydropyranyl- and cyclohexenylethynyl carbenes 3e
and 3 f,g, respectively, in this process (Scheme 3). When
the conjugate nucleophilic addi-
tion of the ring nitrogen atom
of diazafulvene 1 to the electro-
philic alkynyl ligand 3 forming
the zwitterion species IV,[28]
which spontaneously undergoes
cyclization into tautomer III
and then isomerization into the
pyrrolo[1,2-a]imidazole deriva-
tives 6.
It must be mentioned that
[6+2] cycloaddition reactions of
the diazafulvene system are
rarely found in the literature. In
an isolated case, the reaction of
diazafulvene 1 with dimethyl
acetylenedicarboxylate
has
Scheme 3. Synthesis of tetracycles 8–11 from carbenes 3e–g and diazafulvenes 1.
been reported by Muchowski to
occur in refluxing toluene.[22b]
This facthighlighst one of hte
these carbene complexes were treated with diazafulvene 1
in THF at room temperature for 1–12 h, the corresponding
[6+2] cycloadducts 6e–g were not isolated, but the tetracy-
clic complexes 8 and 9a,b resulting from the cyclopentannu-
lation reaction of the primary isomers V and the coordina-
tion of M(CO)5 to the sp2-nitrogen were obtained (82–88%
yield) with complete diastereoselectivity (Scheme 3). The
relative stereochemistry of complexes 8 and 9 was deter-
advantages of carbene complexes as activated alkynes over
classical metal-free electrophilic alkynes.
The occurrence of the pyrrolo[1,2-a]imidazole unitin sev-
eral biologically active compounds, for example, several
classes of pyrrolo[1,2-a]benzimidazole-based antitumor
agents[29] increases the interest in this [6+2] cyclization reac-
tion.
1
mined from H NMR nuclear Overhauser experiments and
Consecutive cyclization reactions of 6-dimethylamino-1,4-di-
azafulvene (1) with enynylcarbene complexes 3d–i: It is
known that the cyclization of conjugated cis-dienylcar-
bene(1-metalla-1,3,5-hexatriene) complexes can be promot-
ed either thermally (pentannulation reaction)[30] or in the
presence of carbon monoxide/isonitriles (benzannulation re-
action).[10] In this way, one can realize that the potential of
the implemented [6+2] cyclization might be significantly ex-
tended beyond a single cyclization. For instance, starting
with enynylcarbenes would produce alkenyl-substituted car-
bene cycloadducts 6 (see Scheme 2; R=alkenyl), which
seem to be appropriate candidates to produce imidazole-
based polyfused systems. Unexpectedly, the dienylcarbene
structure III (R=1-cyclopentenyl), which is presumed to be
generated upon reaction of diazafulvene 1 and carbene 3d
at room temperature (see above), does not undergo cycliza-
tion after prolonged heating at 808C in THF. We argued
that this disappointing result might be due to stereoelectron-
ic factors, because of the particular nature of the cyclopen-
tenyl moiety that would slow down the cyclization and thus
make the isomerization from tautomer III into 6d the pre-
ferred reaction pathway (see Scheme 2).
the structure of the cycloadduct 9b was unambiguously con-
firmed by an X-ray analysis (Figure 2). Finally, the demetal-
lation of complexes 8 and 9b to give compounds 10 and 11
readily occurred by ligand displacementwiht tBuNC/THF
(258C; 75% yield) and pyridine (808C; 79% yield), respec-
À
tively. Importantly, the resulting tBuNC Cr(CO)5 and
Figure 2. X-ray crystal structure of compound 9b.
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J. Barluenga etal.
À
pyridine W(CO)5 complexes could be quantitatively recov-
ered.
Conclusion
The acyclic enynylcarbene complexes 3h,i were found to
behave similarly toward the diazafulvene 1. Thus, the con-
secutive [6+2] cyclization/pentannulation reaction takes
place in THF at room temperature to produce the tricyclic
adducts 12a,b in 80–85% yield (Scheme 4) regio- and ste-
reoselectively. The structure and the relative stereochemis-
try of adducts 12 was confirmed by HMBC and NOESY ex-
periments conducted on compound 12b. The metal decoor-
dination to the metal-free cycloadduct 13 was accomplished
in 86% yield by bubbling CO gas into a solution of com-
pound 12a in THF.
A new set of heterocyclization reactions of Group 6 Fischer
carbene complexes toward 6-dimethylamino-1,4-diazaful-
vene have been performed. Alkenylcarbene complexes pro-
vide high yields of imidazo[1,2-a]pyridines with complete
regio- and stereoselectivity through a [6+3] heterocycliza-
tion. On the other hand, the first [6+2] cyclization of al-
kynylcarbene complexes was found to occur upon reaction
with the diazafulvene system affording pyrrolo[1,2-a]imida-
zole derivatives. The presence of the metal–carbene func-
tionality for the latter allows cascade heteropolycyclization
reactions to occur, for example, [6+2] cyclization/pentannu-
lation and [6+2] cyclization/[5+1] cyclization. From a syn-
thesis point of view, a new strategy based on Fischer carbene
complexes has been implemented for the rapid preparation
of simple bicyclic imidazole systems, like imidazopyridines
and pyrroloimidazoles, as well as rarer complex derivatives,
such as tricyclic and tetracyclic imidazole-containing mole-
cules. It is also worth noting the ready availability of the
starting materials on the multigram scale as well as the ease
with which the experimental synthesis is executed. Finally,
an additional point of interest is that the biological activity
of fused imidazoles, or molecules containing that unit, is cur-
rently well-documented.
Scheme 4. Tricycles 12 and 13 from reaction of diazafulvene 1 and car-
benes 3h,i.
The usefulness of the cyclization process to synthesize
complex heteropolycyclic targets could be further enhanced
by using the one-pot [6+2] cyclization/[5+1] cyclization se-
quence, as outlined in Scheme 5. Thus, cyclopentenyl- and
Experimental Section
General: All reactions involving air-sensitive compounds were carried
out under nitrogen atmosphere (99.99%). All glassware was oven-dried
(1208C), evacuated, and purged with nitrogen. All common reagents and
solvents were obtained from commercial suppliers and used without any
further purification unless otherwise indicated. Fischer carbene com-
plexes 2,3[2i,3f,32] and the diazafulvene 1[22] were prepared by following the
described procedures. Solvents were dried by standard methods and dis-
tilled prior to use. Flash column chromatography was carried out on
silica gel 60, 230–240 mesh. NMR measurements were recorded on
Bruker AC-200, AC-300, or DPX-300 spectrometers. 1H NMR spectra
were recorded in CDCl3 (unless otherwise noted) at 300.08 MHz at 208C
with tetramethylsilane (d=0.0 ppm) as the internal standard. 13C NMR
spectra were recorded in CDCl3 (unless otherwise noted) at 75.46 MHz
at20 8C. 1H NMR splitting pattern abbreviations are: s, singlet; d, dou-
blet; m, multiplet. 13C NMR multiplicities were determined by DEPT, ab-
Scheme 5. [6+2] Cyclization/isocyanide insertion of Fischer carbenes
3d,f.
cyclohexenylethenylcarbene complexes of chromium 3d and
3 f were stirred with diazafulvene 1 at room temperature in
THF for one hour with the expectation that the correspond-
ing [6+2] cycloadducts of type V had been formed. Then,
tBuNC (2 equiv) was added and the mixture stirred for one
additional hour to give, after column chromatography purifi-
cation (SiO2, hexanes/ethyl acetate 5:1), the cycloadducts 14
(n=1) and 15 (n=2) in high yields (85–93%). In these
cases, the primary [6+2] cycloadducts would undergo isocya-
nide insertion to produce the nonisolated metal heterocu-
mulene species VI[31] followed by metal-promoted electrocy-
clic ring-closure and isomerization to the aromatic ring.
breviations are: q, CH3; t , CH; d, CH; s, quaternary carbon atoms, some
2
13C NMR signals overlap. COSY, HMSQC, HMBC, and NOESY experi-
ments were carried out on a Bruker AMX-400 spectrometer. Standard
pulse sequences were employed for the DEPT experiments. High-resolu-
tion mass spectra (HRMS) were obtained with a Finnigan Mat 95 mass
spectrometer and electron impact techniques (70 eV) were employed. El-
emental analyses were carried out with a Perkin–Elmer 240 B microana-
lyzer.
General procedure for synthesis of dihydroimidazo[1,2-a]pyridines (4): A
solution of diazafulvene 1 (0.75 mmol) and carbenes 2 (0.5 mmol) in
MeCN (3 mL) was stirred under nitrogen at room temperature for 1 h.
Then, the solvent was removed in vacuo and the crude product dissolved
in a mixture of EtOAc/hexane (1:1) and oxidized by air in an open flask
in sunlight (10–12 h). The solution was then filtered through Celite, and
the filtrate was concentrated under vacuum. The resulting crude product
was purified by column chromatography (silica gel, hexanes/EtOAc/Et3N
8:1:1).
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Cyclization Reactions
FULL PAPER
[(7S,8S)/(7R,8R)-5-Methoxy-7-phenyl-7,8-dihydroimidazo[1,2-a]pyridin-
8-yl]dimethylamine (4a): Yield=82%; 1H NMR: d=7.2 (s, 1H), 7.1–7.2
(m, 3H), 7.0 (s, 1H), 6.9 (m, 2H), 4.5 (d, J=5.9 Hz, 1H), 3.9 (d, J=
5.9 Hz, 1H), 3.8 (s, 1H), 3.7 (s, 3H), 2.3 ppm (s, 6H); 13C NMR: d=145.6
(s), 142.4 (s), 141.0 (s), 128.1 (d), 127.3 (d), 126.2 (d), 112.4 (d), 82.0 (d),
63.1 (q), 54.8 (d), 42.7 (d), 41.5 ppm (q); HRMS: m/z: calcd for
C16H19N3O: 269.1522; found: 269.1512 [M]+; elemental analysis calcd
(%) for C16H19N3O: C 71.35, H 7.11, N 15.60; found: C 71.18, H 7.22, N
15.52.
Adducts 6a and 6b were oxidized to the corresponding esters 7a and 7b
by treatment in THF with 3 equiv of pyridine oxide followed by extrac-
tion, workup, and purification as above.
Chromium–carbene 6a: Yield=78%; 1H NMR: d=7.1 (s, 1H), 7.0 (s,
1H), 5.1 (s, 1H), 4.8 (s, 3H), 2.2 (s, 6H), 1.3 ppm (s, 9H); 13C NMR: d=
351.7 (s), 222.6 (s), 215.6 (s), 151.3 (s), 140.7 (s), 140.4 (s), 135.8 (d), 114.1
(d), 67.7 (d), 66.9 (q), 40.0 (q), 33.6 (s), 29.0 ppm (q); HRMS: m/z: calcd
for C19H21CrN3O6: 439.0830; found: 439.0839 [M]+; elemental analysis
calcd (%) for C19H21CrN3O6: C 51.94, H 4.82, N 9.56; found: C 51.74, H
4.80, N 9.70.
[(7S,8S)/(7R,8R)-5-Methoxy-7-(4-methoxyphenyl)-7,8-dihydroimidazo-
[1,2-a]pyridin-8-yl]dimethylamine (4b): Yield=88%; 1H NMR: d=7.2
(s, 1H), 7.0 (s, 1H), 6.9 (d, J=8.5 Hz, 2H), 6.7 (d, J=8.5 Hz, 2H), 4.5 (d,
J=5.8 Hz, 1H), 3.9 (d, J=5.8 Hz, 1H), 3.85 (s, 1H), 3.7 (s, 3H), 3.6 (s,
3H), 2.3 ppm (s, 6H); 13C NMR: d=158.0 (s), 145.7 (s), 141.4 (s), 134.7
(s), 127.7 (d), 127.5 (d), 113.6 (d), 112.5 (d), 82.5 (d), 63.6 (d), 55.0 (q),
54.7 (q), 42.1 (d), 41.8 ppm (q); HRMS: m/z: calcd for C17H21N3O2:
299.1628; found: 299.1633 [M]+.
1
Tungsten–carbene 6b: Yield=61%; H NMR: d=7.3–7.4 (m, 5H), 7.3 (s,
1H), 7.1 (s, 1H), 6.5 (s, 1H), 4.4 (s, 3H), 3.6 ppm (s, 6H); 13C NMR: d=
264.4 (s), 202.0 (s), 199.4 (s), 150.3 (s), 147.2 (s), 140.2 (s), 136.8 (d), 130.1
(s), 129.8 (d), 129.5 (d), 127.8 (d), 117.7 (d), 67.7 (d), 65.8 (q), 46.1 ppm
(q); HRMS: m/z: calcd for C21H17N3O6W: 591.0621; found: 591.0629
[M]+; elemental analysis calcd (%) for C21H17N3O6W: C 42.66, H 2.90, N
7.11; found: C 42.85, H 2.99, N 7.29.
1
[(7S,8S)/(7R,8R)-7-(Furan-2-yl)-5-methoxy-7,8-dihydroimidazo[1,2-a]pyr-
idin-8-yl]dimethylamine (4c): Yield=90%; 1H NMR: d=7.3 (s, 1H), 7.2
(s, 1H), 7.0 (m, 1H), 6.2 (m, 1H), 5.9 (m, 1H), 4.5 (d, J=6.7 Hz, 1H),
4.0 (s, 1H), 3.95 (d, J=6.7 Hz, 1H), 3.8 (s, 3H), 2.3 ppm (s, 6H);
13C NMR: d=154.8 (s), 146.6 (s), 142.0 (s), 141.6 (d), 127.8 (d), 112.9 (d),
109.9 (d), 105.2 (d), 79.2 (d), 60.8 (d), 55.3 (q), 42.1 (q, 2C), 36.5 ppm (d);
HRMS: m/z: calcd for C14H17N3O2: 259.1315; found: 259.1315 [M]+; ele-
mental analysis calcd (%) for C14H17N3O2: C 64.85, H 6.61, N 16.20;
found: C 64.92, H 6.80, N 16.29.
Compound 7a: Yield=88%; H NMR: d=7.2 (s, 1H), 7.1 (s, 1H), 4.7 (s,
1H), 3.7 (s, 3H), 3.5 (s, 6H), 0.8 ppm (s, 9H); 13C NMR: d=164.3 (s),
151.7 (s), 151.2 (s), 133.1 (d), 118.1 (d), 98.4 (s), 69.5 (d), 50.1 (q), 44.1
(q), 29.6 (s), 26.30 ppm (q); HRMS: m/z: calcd for C14H21N3O2: 263.1634;
found: 263.1627 [M]+.
Compound 7b: Yield=70%; 1H NMR: d=7.3 (m, 4H), 7.1 (m, 2H), 6.8
(s, 1H), 5.7 (s, 1H), 3.55 (s, 3H), 3.5 ppm (s, 6H); 13C NMR: d=163.8
(s), 150.5 (s), 148.3 (s), 139.9 (s), 134.2 (d), 128.5 (d), 128.0 (d), 127.0 (d),
115.8 (d), 101.7(s), 63.1 (d), 50.3 (q), 43.5 ppm (q); HRMS: m/z: calcd for
C16H17N3O2 283.1321; found: 283.1329 [M]+; elemental analysis calcd
(%) for C16H17N3O2: C 67.83, H 6.05, N 14.83; found: C 67.97, H 5.89, N
14.98.
[(7S,8S)/(7R,8R)-5-Methoxy-7-(thiophen-2-yl)-7,8-dihydroimidazo[1,2-
a]pyridin-8-yl]dimethylamine (4d): Yield=83%; 1H NMR: d=7.2 (s,
1H), 7.0–7.1 (m, 2H), 6.8 (m, 1H), 6.7 (m, 1H), 4.6 (d, J=6.1 Hz, 1H),
4.2 (d, J=6.1 Hz, 1H), 3.9 (s, 1H), 3.8 (s, 3H), 2.3 ppm (s, 6H);
13C NMR: d=147.6 (s), 147.1 (s), 142.5 (s), 129.0 (d), 127.6 (d), 124.6 (d),
124.4 (d), 113.8 (d), 83.4 (d), 65.4 (d), 56.3 (q), 43.2 (q), 39.1 ppm (d);
HRMS: m/z: calcd for C14H17N3OS: 275.1086; found: 275.1087 [M]+.
1
Compound 7d: Yield=74%; H NMR: d=7.2 (s, 1H), 6.9 (s, 1H), 5.7 (s,
1H), 5.3 (s, 1H), 3.6 (s, 3H), 3.3 (s, 6H), 2.3 (m, 2H), 1.9 (m, 1H), 1.7
(m, 2H), 1.5 ppm (m, 1H); 13C NMR: d=164.6 (s), 151.0 (s), 148.9 (s),
142.0 (s), 134.0 (d), 130.7 (d), 116.4 (d), 99.8 (s), 60.4 (d), 50.9 (q), 44.0
(q), 32.9 (t), 29.6 (t), 23.3 ppm (t); HRMS: m/z: calcd for C15H19N3O2:
273.1477; found: 273.1473 [M]+; elemental analysis calcd (%) for
C15H19N3O2: C 65.91, H 7.01, N 15.37; found: C 65.78, H 7.08, N 15.23.
[(7S,8S)/(7R,8R)-5-Methoxy-7-styryl-7,8-dihydroimidazo[1,2-a]pyridin-8-
yl]dimethylamine (4e): Yield=90%; 1H NMR: d=7.2–7.3 (m, 6H), 7.0
(s, 1H), 6.4 (d, J=15.6 Hz, 1H), 5.9 (dd, J=15.6, 7.9 Hz, 1H), 4.5 (d, J=
6.2 Hz 1H), 3.8 (s, 3H), 3.7 (s, 1H), 3.5 (dd, J=7.9, 6.2 Hz, 1H), 2.3 ppm
(s, 6H); 13C NMR: d=145.9 (s), 142.0 (s), 136.8 (s), 129.8 (d), 128.4 (d),
127.8 (d), 127.3 (d), 126.2 (d), 113.1 (d), 81.0 (d), 61.8 (d), 55.4 (q), 42.3
(q), 40.7 ppm (d); HRMS: m/z: calcd for C18H21N3O: 295.1679; found:
295.1673 [M]+; elemental analysis calcd (%) for C18H21N3O: C 73.19, H
7.17, N 14.23; found: C 73.03, H 7.21, N 14.01.
Preparation of polycyclic complexes 8, 9, and 12: Carbenes 3e–i
(0.5 mmol) and diazafulvene 1 (0.5 mmol) were dissolved in THF (3 mL)
and the solution stirred for 12 h (1 h for compound 3e). After solvent re-
moval the crude was purified by column chromatography (silica gel, hex-
anes/EtOAc 5:1).
Chromium complex 8: Yield=88%; 1H NMR: d=7.2 (s, 1H), 7.0 (s,
1H), 4.9 (s, 1H), 4.3 (m, 1H), 3.8 (s, 3H), 3.7 (m, 1H), 3.4 (dd, J=12.5,
6.2 Hz, 1H), 2.5 (m, 1H), 2.2 (s, 6H), 1.8–2.0 (m, 2H), 1.6 ppm (m, 1H);
13C NMR: d=221.1 (s), 214.9 (s), 158.8 (s), 153.8 (s), 138.0 (d), 127.2 (s),
114.1 (s), 113.3 (d), 111.9 (s), 72.1 (t), 60.4 (d), 58.9 (q), 47.5 (d), 40.9 (q),
26.8 (t), 24.8 ppm (t); HRMS: m/z: calcd for C20H19CrN3O7: 465.0628;
found: 465.0633 [M]+; elemental analysis calcd (%) for C20H19CrN3O7: C
51.62, H 4.12, N 9.03; found: C 51.83, H 4.23, N 8.94.
Chromium complex 9a: Yield=82%; 1H NMR: d=7.1 (s, 1H), 7.0 (s,
1H), 4.9 (s, 1H), 3.9 (s, 3H), 3.4 (m, 1H), 2.7 (m 1H), 2.5 (m, 1H), 2.4 (s,
6H), 1.9 (m, 2H), 1.4 (m, 1H), 1.2 (m, 2H), 0.9 ppm (m, 1H); 13C NMR:
d=221.2 (s), 214.9 (s), 161.4 (s), 160.1 (s), 138.2 (d), 129.6 (s), 112.6 (d),
112.1 (s), 109.9 (s), 60.3 (d), 58.9 (q), 52.8 (d), 41.0 (q), 31.2 (t), 27.6 (t),
25.1 (t), 24.8 ppm (t); HRMS: m/z: calcd for C21H21CrN3O6: 463.0830;
found: 463.0830 [M]+.
[(9aS,10S)/(9aR,10R)-5-Methoxy-7,8,9,9a-tetrahydro-10H-pyrano[3’,2’-
d]imidazo[1,2-a]pyridin-10-yl]dimethylamine
(4 f):
Yield=84%;
1H NMR (C6D6): d=7.3 (d, J=1.2 Hz, 1H), 7.1 (d, J=1.2 Hz, 1H), 3.9
(m, 1H), 3.7 (s, 3H), 3.5 (d, J=10.6 Hz, 1H), 3.2 (m, 1H), 2.7 (s, 6H),
2.6 (m, 1H), 2.2 (m, 1H), 1.5 (m, 1H), 1.2 (m, 1H), 1.0 ppm (m, 1H);
13C NMR (C6D6): d=141.8 (s), 134.0 (s), 129.3 (d), 113.2 (d), 70.0 (t),
65.1 (q), 61.3 (d), 42.3 (q), 38.2 (d), 30.1 (t), 26.1 ppm (t); HRMS: m/z:
calcd for C13H19N3O2: 249.1471; found: 249.1468 [M]+; elemental analysis
calcd (%) for C13H19N3O2: C 62.63, H 7.68, N 16.85; found: C 62.45, H
7.75, N 16.72.
Synthesis of imidazo[1,2-a]pyridine 5:
A solution of compound 4c
(130 mg, 0.5 mmol) in CH2Cl2 (3 mL) was treated with HCl (12n, 1 mL)
and the mixture stirred for 3 h. After extraction, workup, and solvent re-
moval, the resulting crude was purified by column chromatography
(silica gel, hexanes/EtOAc/Et3N 8:1:1) to afford pure compound
5
Tungsten complex 9b: Yield=85%; 1H NMR: d=7.2 (s, 1H), 7.1 (s,
1H), 4.8 (s, 1H), 4.1 (s, 3H), 3.1 (dd, J=12.3, 5.7 Hz, 1H), 2.7 (m 1H),
2.35 (m, 1H), 2.3 (s, 6H), 2.1 (m, 1H), 1.7–1.9 (m, 2H), 1.4 (m, 1H), 1.0–
1.3 ppm (m, 2H); 13C NMR: d=203.9 (s), 199.6 (s), 162.7 (s), 161.0 (s),
140.5 (d), 130.5 (s), 114.2 (d), 112.7 (s), 111.6 (s), 61.7 (d), 60.0 (q), 53.9
(d), 42.1 (q), 32.2 (t), 28.7 (t), 26.2 (t), 25.8 ppm (t); HRMS: m/z: calcd
for C21H21N3O6W: 595.0934; found: 595.0918 [M]+; elemental analysis
calcd (%) for C21H21N3O6W: C 42.37, H 3.56, N 7.06; found: C 42.20, H
3.71, N 6.92.
(75.0 mg, 70%); 1H NMR: d=7.65 (m, 2H), 7.6 (s, 1H), 7.5 (s, 1H), 6.7
(m, 1H), 6.5 (m, 1H), 6.4 (s, 1H), 4.1 ppm (s, 3H); 13C NMR: d=152.3
(s), 149.5 (s), 142.7 (d), 135.6 (d), 128.4 (s), 111.9 (d), 108.0 (d), 106.7 (d),
103.7 (d), 84.5 (d), 56.3 ppm (q); HRMS: m/z: calcd for C12H10N2O2:
214.0736; found: 214.0730 [M]+; elemental analysis calcd (%) for
C12H10N2O2: C 67.28, H 4.71, N 13.08; found: C 67.21, H 4.78, N 12.94.
Synthesis of pyrrolo[1,2-a]imidazole compounds 6 and 7: A solution of
carbene complexes 3 (0.5 mmol) and diazafulvene 1 (0.5 mmol) in THF
(5 mL) was stirred at room temperature for 1 h. Then, the solvent was re-
moved and the resulting crude was purified by column chromatography
(silica gel, hexanes/EtOAc/Et3N 8:1:1).
1
Chromium complex 12a: Yield=80%; H NMR: d=7.5–7.2 (m, 5H), 7.1
(s, 1H), 7.0 (s, 1H), 5.0 (s, 1H), 4.6 (s, 1H), 3.6 (s, 3H), 2.3 (s, 6H),
Chem. Eur. J. 2006, 12, 3201 – 3210
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3207

J. Barluenga etal.
1.7 ppm (s, 3H); 13C NMR: d=221.2 (s), 214.9 (s), 160.1 (s), 160.0 (s),
138.6 (d), 135.9 (s), 133.8 (s), 129.1 (d), 127.8 (d), 127.5 (d), 113.2 (s),
112,6 (d), 107.9 (s), 62.2 (d), 60.6 (d), 58.7 (q), 41.1 (q), 10.8 ppm (q);
HRMS: m/z: calcd for C24H21CrN3O6: 499.0835; found: 499.0839 [M]+.
22.8 ppm (t); HRMS: m/z: calcd for C21H30N4O: 354.2414; found:
354.2418 [M]+; elemental analysis calcd (%) for C21H30N4O: C 71.15, H
8.53, N 15.80; found: C 71.23, H 8.76, N 15.87.
X-ray crystal structure determination: The mostrelevantcrysatl and re-
Tungsten complex 12b: Yield=86%; 1H NMR (C6D6): d=7.3–7.1 (m,
3H), 7.0 (d, J=6.6 Hz, 2H), 6.9 (s, 1H), 6.4 (s, 1H), 4.9 (s, 1H), 4.1 (s,
1H), 3.1 (s, 3H), 2.2 (s, 6H), 1.5 ppm (s, 3H); 13C NMR (C6D6): d=202.5
(s), 199.1 (s), 160.2 (s), 159.5 (s), 139.7 (d), 136.7 (s), 133.6 (s), 129.1 (d),
127.9 (d), 127.7 (d), 112.9 (d), 112.5 (s), 108.0 (s), 62.0 (d), 61.1 (d), 58.1
(q), 40.9 (q), 10.2 ppm (q); HRMS: m/z: calcd for C24H21N3O6W:
631.0940; found: 631.0953 [M]+; elemental analysis calcd (%) for
C24H21N3O6W: C 45.66, H 3.35, N 6.66; found: C 45.70, H 3.38, N 6.79.
finementdaat for
9b are as follows: empirical formula C21H21N3O6W,
Mr =595.26, T=100(2) K, l=1.54178 Š, crystal system, space group:
monoclinic, P21/c,unitcell dimensions: a=10.0012(1), b=18.0404(1), c=
12.7948 (1) Š, b=110.50 (0)8, V=2162.37(3) Š3, Z=4, 1calcd
=
1.828 MgmÀ3, m=10.275 mmÀ1, F(000)=1160, crystal size: 0.18”0.12”
0.06 mm3, q range for data collection: 4.43–70.378, index ranges: À11ꢀ
hꢀ12, À20ꢀkꢀ20, À15ꢀlꢀ14, reflections collected/unique=13686/
3955 [Rint =0.0273], completeness to 2q=70.37 (96.0%), absortion cor-
rection: empirical, refinement method: full-matrix least-squares on F2,
Demetallation of complex 8 to give compound 10: tBuNC (1.5 mmol)
was added to a solution containing complex 8 (140 mg, 0.3 mmol) in THF
(3 mL) and the mixture was stirred for 12 h. After solvent removal the
crude was purified by column chromatography (silica gel, hexanes/
EtOAc/Et3N 8:1:1) to afford of compound 10 (62 mg, 75%); 1H NMR
(C6D6): d=7.3 (s, 1H), 7.2 (s, 1H), 4.8 (s, 1H), 3.9 (s, 3H), 3.4 (m, 2H),
3.1 (m, 1H), 2.4 (s, 6H), 2.2 (m, 1H), 1.5–1.4 (m, 2H), 1.2 ppm (s, 1H);
13C NMR (C6D6): d=156.5 (s), 154.5 (s), 133.6 (d), 124.8 (s), 115.8 (s),
112.8 (d), 110.7 (s), 71.9 (t), 60.4 (d), 58.3 (q), 48.8 (d), 40.9 (q), 27.1 (t),
25.3 ppm (t); HRMS: m/z: calcd for C15H19N3O2: 273.1477; found:
273.1468 [M]+; elemental analysis calcd (%) for C15H19N3O2: C 65.91, H
7.01, N 15.37; found: C 66.10, H 7.09, N 15.49.
data/restraints/parameters=3955/0/365, goodness-of-fiton
F2 =1.053,
final R indices [I>2s(I)]: R1 =0.0191, wR2 =0.0488, R indices (all data):
R1 =0.0205, wR2 =0.0496; extinction coefficient=0.00028(2), largestdif-
ference peak and hole=0.568 and À1.256 eŠÀ3. CCDC 289214 contains
the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Demetallation of complex 9b to give compound 11: Compound 9b
(180 mg, 0.3 mmol) was dissolved in pyridine (3 mL) and the solution
heated at 808C for 3 h. Then the solvent was removed and the crude pu-
rified by column chromatography (silica gel, hexanes/EtOAc/Et3N 8:1:1)
to yield of compound 11 (64 mg, 79%); 1H NMR: d=7.1 (d, J=1.4 Hz,
1H), 7.15 (d, J=1.4 Hz, 1H), 4.8 (s, 1H), 4.0 (s, 3H), 3.1 (dd, J=12.2,
5.4 Hz, 1H), 2.7–2.6(m, 2H), 2.3 (s, 6H), 2.2 (m, 1H), 2.0–1.9 (m, 2H),
1.4 (m, 1H), 1.2–1.1 ppm (m, 2H); 13C NMR: d=161.6 (s), 157.3 (s),
132.7 (d), 130.9 (s), 112.0 (d), 110.8 (s), 106.4 (s), 59.9 (d), 58.8 (q), 53.8
(d), 40.7 (q), 30.9 (t), 29.6 (t), 27.9 (t), 24.9 ppm (t); HRMS: m/z: calcd
for C16H21N3O: 271.1679; found: 271.1681 [M]+; elemental analysis calcd
(%) for C16H21N3O: C 70.82, H 7.80, N 15.49; found: C 70.75, H 7.92, N
15.37.
This research was partially supported by the Spanish and Principado de
Asturias Governments (BQU-2001-3853 and GE-EXP01–11), MEC, and
ESF (Juan de la Cierva contract to S.M.).
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Demetallation of complex 12a to give compound 13: Compound 12a
(150 mg, 0.3 mmol) was dissolved in THF (2 mL) and CO gas was bub-
bled through the solution for 1 h. The mixture was filtered through Celite
and the filtrate was concentrated in vacuo. The resulting crude was puri-
fied by column chromatography (silica gel, hexanes/EtOAc/Et3N 8:1:1)
to yield compound 13 (80 mg, 86%); 1H NMR: d=7.3 (m, 3H), 7.25 (s,
1H), 7.2 (s, 1H), 7.1 (d, J=6.6 Hz, 2H), 5.0 (s, 1H), 4.4 (s, 1H), 4.0 (s,
3H), 2.4 (s, 6H), 1.7 ppm (s, 3H); 13C NMR: d=160.7 (s), 157.1 (s), 137.8
(s), 133.5 (d), 130.9 (s), 129.2 (d), 128.6 (d), 127.6 (d), 112.5 (d), 112.3 (s),
104.6 (s), 63.8 (d), 60.6 (d), 59.5 (q), 41.2 (q), 11.2 ppm (q); HRMS: m/z:
calcd for C19H21N3O: 307.1685; found: 307.1681 [M]+; elemental analysis
calcd (%) for C19H21N3O: C 74.24, H 6.89, N 13.67; found: C 74.13, H
6.77, N 13.60.
Synthesis of tetracycles 14 and 15:
A solution of carbenes 3d,f
(0.5 mmol) and diazafulvene 1 (0.5 mmol) in THF (3 mL) was stirred for
1 h, then tBuNC (1 mmol) was added and the mixture stirred further for
1 h. After solvent removal the resulting crude was purified by column
chromatography (silica gel, hexanes/EtOAc 5:1).
1
Compound 14: Yield=85%; H NMR: d=7.2 (s, 1H), 7.1 (s, 1H), 5.0 (s,
1H), 3.8 (s, 3H), 3.1 (m, 2H), 2.9 (m, 2H), 2.3 (s, 6H), 2.2 (m, 2H),
1.2 ppm (s, 9H); 13C NMR: d=152.7 (s), 151.8 (s), 143.6 (s), 132.5 (d),
132.3 (s), 130.4 (s), 121.4 (s), 121.2 (s), 111.7 (d), 62.5 (d), 58.7 (q), 55.3
(s), 40.7 (q), 33.1 (t), 30.5 (q), 29.9 (t), 26.3 ppm (t); HRMS: m/z: calcd
for C20H28N4O: 340.2258; found: 340.2259 [M]+; elemental analysis calcd
(%) for C20H28N4O: C 70.56, H 8.29, N 16.46; found: C 70.44, H 8.27, N
16.59.
1
Compound 15: Yield=93%; H NMR: d=7.4 (d, J=1.3 Hz, 1H), 7.1 (d,
J=1.3 Hz, 1H), 4.9 (s, 1H), 4.0 (s, 3H), 2.9 (m, 2H), 2.7 (m, 2H), 2.3 (s,
6H), 1.9–1.7 (m, 4H), 1.2 ppm (s, 9H); 13C NMR: d=153.4 (s), 151.8(s),
137.0 (s), 135.3 (s), 134.0 (s), 132.7 (d), 121.4 (s), 116.7 (s), 114.2 (d), 62.5
(d), 59.0 (q), 55.3 (s), 41.2 (q), 31.3 (q), 28.4 (t), 25.7 (t), 23.1 (t),
3208
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Chem. Eur. J. 2006, 12, 3201 – 3210

Cyclization Reactions
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J. Barluenga etal.
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Received: November 10, 2005
Published online: February 28, 2006
3210
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