Multicomponent access to functionalized mesoionic structures based on TFAA activation of isocyanides: Novel domino reactions

Article abstract of DOI:10.1002/ejoc.200801084

The reactions of azines (isoquinolines, pyridine) with TFAA and isocyanides in a new domino process yield mesoionic acid fluorides with an imidazo[1,2-α]azine core. This multi-component reaction has a general character, tolerating a wide range of substitu

Full text of DOI:10.1002/ejoc.200801084

FULL PAPER
DOI: 10.1002/ejoc.200801084
Multicomponent Access to Functionalized Mesoionic Structures Based on
TFAA Activation of Isocyanides: Novel Domino Reactions
María José Arévalo,[a] Nicola Kielland,[a] Carme Masdeu,[a] Miriam Miguel,[a]
Nicolas Isambert,[a] and Rodolfo Lavilla*[a,b]
Keywords: Multicomponent reactions / Domino reactions / Isocyanides / Nitrogen heterocycles / Mesoionic compounds
The reactions of azines (isoquinolines, pyridine) with TFAA
and isocyanides in a new domino process yield mesoionic
acid fluorides with an imidazo[1,2-a]azine core. This multi-
component reaction has a general character, tolerating a
wide range of substitution patterns on each component, and
displays an unprecedented arrangement of reaction path-
ways. The protocol allows the incorporation of a fourth syn-
thetic input by the reaction of suitable nucleophile
(alcohols, thiols, amines) with the acid fluoride moiety.
a
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
tionalization of azines (pyridine, isoquinoline, etc.) with iso-
cyanides and acylating agents to form new mesoionic struc-
tures.[5] We previously disclosed an efficient Ugi–Reissert
reaction involving the interaction of isoquinolines, chloro-
formates and isocyanides in which the activated azine is car-
bamoylated at the α-position by the isocyanide to give dihy-
droazines such as 4a (Scheme 1).[4a] Arndtsen and Mironov
and their co-workers recently described related processes in-
volving, respectively, acid chlorides and isothiocyanates in
isocyanide MCRs.[6]
Introduction
Multicomponent reactions (MCRs, domino processes in
which three or more starting materials interact to form an
adduct) are specially attractive in organic synthesis because
they maximize complexity and convergency while using
structurally simple substrates in a single operation.[1] This
approach is particularly beneficial for the preparation of
libraries of compounds in which short synthetic sequences
are mandatory. In this context, the participation of hetero-
cyclic structures is critical as heterocycles are the most com-
mon motifs found in natural products and drugs, and are
often considered privileged substructures.[2] The rich and
intrinsic reactivity of heterocyclic systems brings fascinating
possibilities to the design and implementation of domino
reactions. However, the manifold evolutionary pathways of
such complex systems make reliable predictions difficult
and call for detailed mechanistic and synthetic experimenta-
tion. Therefore the development of new and efficient MCRs
involving the participation of important heterocycles re-
mains a challenging task in organic synthesis due to their
wide-ranging applications in medicinal chemistry.[3]
Scheme 1. Interaction of isoquinoline, acylating agents and isocya-
nides.
Several azines (pyridines for instance) are, however, inert
under these conditions. In our search for more potent acti-
vation reagents to overcome this limitation and also to in-
troduce a new point of diversity, we considered the use of
triflic anhydride (Tf2O), which was recently introduced by
Corey and Tian to activate pyridines in the presence of C-
nucleophiles.[7] However, its interaction with pyridine and
isocyanides led to a mixture of α- and γ-carbamoylated N-
triflyl-1,2- and 1,4-dihydropyridines and their oxidation
products (the corresponding pyridines) in low overall yields,
together with significant isocyanide polymerization. We
then investigated the reactivity of trifluoroacetic anhydride
(TFAA) in these systems. On mixing isoquinoline (1a) with
Results and Discussion
Reactivity Studies
Continuing our interest in the development of MCRs
based on heterocycles,[4] herein we report the direct func-
[a] Institute for Research in Biomedicine, Barcelona Science Park,
Baldiri Reixac 10–12, 08028 Barcelona, Spain
Fax: +34-93-403-71-04
E-mail: rlavilla@pcb.ub.es
[b] Laboratory of Organic Chemistry, Faculty of Pharmacy, Uni-
versity of Barcelona,
Av. Joan XXIII, s/n, 08028 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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cyclohexyl isocyanide (2a) and TFAA (3a) in dry THF, we
isolated the mesoionic acid fluoride 5a as a stable crystal-
line solid in 25% yield (Scheme 1).
Optimization of the process led us to perform the reac-
tion in anhydrous CH2Cl2 with isoquinoline, TFAA and the
isocyanide in a stoichiometric ratio of 1:2:3, which in-
creased the yield of 5a up to 85%. The structure of this
compound was unambiguously established by spectroscopic
methods and confirmed by X-ray diffraction (Figure 1).[8]
A related dipole has been prepared by Moody et al. through
a stepwise synthesis by the intramolecular reaction of a car-
benoid with the nitrogen atom of a pyridine.[9]
Scheme 2. Mechanistic proposal for the formation of acid fluoride
5a.
niscent of known processes.[11] The overall anionic domino
reaction consists of an orchestrated series of events in which
electrophilic and nucleophilic species are precisely engaged
to guarantee the formation of the C–C, C–N and C–O
bonds. Several features of this mechanism remain hypothet-
ical. However, the detection by MS of putative intermedi-
ates B and C (Scheme 2) together with species related to
intermediates A in modified experiments (lower tempera-
tures, short reaction times, exclusion of aqueous quenching)
supports this proposal. Interestingly, the order of addition
of the reactants does not substantially modify the synthetic
outcome or the yield of the process. In this way, we have
tested the addition of the isocyanide to a mixture of isoqui-
noline and TFAA (5a, 85%), the addition of TFAA to a
solution of isoquinoline and the isocyanide (5a, 72%) and,
finally, the addition of isoquinoline to a mixture of the iso-
cyanide and TFAA (5a, 65%). These results may be consis-
tent with a type II MCR[1c] in which a series of equilibria
are affected by a final irreversible step.
Figure 1. View of the X-ray crystal structure of 5a.
Mechanistic Proposal
Regarding the constitution of acid fluoride 5a, the con-
nectivity between the three components indicates the occur-
rence of a completely different process, overriding the
known pathway leading to the Ugi–Reissert products 4.
Note that the isocyanide moiety is linked to the isoquin-
oline ring through the N atom in the acid fluoride 5a,
whereas in the former process, which leads to 4a, the bond-
ing occurs through the C terminal atom. A plausible mech-
anistic explanation may involve the initial activation of the
isocyanide by the TFAA, previously described by El Kaïm
and co-workers,[10a,10b] to afford an adduct A. They have
To test the scope of the reaction, a systematic screening
of the three components was performed to fully exploit the
synthetic possibilities of the transformation and to deter-
mine its practical limits.
Reaction Scope – Isocyanide Range
A representative set of isocyanides 2 were treated under
successfully developed this chemistry to promote a variety the usual conditions with TFAA (3a) and isoquinoline (1a).
of useful transformations based on the reactivity of the tri- The results show that the MCR is quite general with alkyl
fluoropyruvamide intermediates.[10c,10d] In our system, this and benzyl isocyanides affording the expected dipoles 5 in
species undergoes nucleophilic attack by the isoquinoline to reasonable yields (Table 1, entries 1–3). Note that even
generate a reactive dipole B, which may evolve by intramo- moderate yields are synthetically useful reactions taking
lecular addition of the imine moiety to the α-position of the into account the multicomponent nature of the process and
azinium ion and by fluoride elimination promoted by the the number of bonds formed. Notable exceptions are tert-
oxyanion. The highly reactive amino epoxide intermediate butyl isocyanide (2d, entry 4, presumably because of the ste-
C (or related species) would then undergo a ring-opening/ ric hindrance linked to the N atom) and the less nucleo-
rearrangement sequence, presumably triggered by the now philic isocyanide TOSMIC (2e, entry 5). In this experiment,
nucleophilic heterocyclic nitrogen, to form the acyl fluoride the only new product was the hydrate of the N-tosylmethyl-
D, which affords the dipole 5a after proton loss (Scheme 2). trifluoropyruvamide. This compound has previously been
Alternatively, TFAA activation of the isoquinoline ring fol- obtained by hydrolysis of the TFAA-activated isocya-
lowed by isocyanide attack upon the carbonyl may also lead nide.[10b]
to the epoxide intermediate C.[10e]
Interestingly, methyl isocyanoacetate (2f, entry 6) dis-
To the best of our knowledge, there are no precedents plays the expected reactivity although in a lower yield (5d,
for the formation of an acid fluoride moiety from a trifluo- 21%). Remarkably, the formation of the Arndtsen-type di-
roacetoxy group, although some elementary steps are remi- pole 6a (14%; Figure 2)[6a] by TFAA activation of the iso-
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Multicomponent Access to Functionalized Mesoionic Structures
Table 1. Reaction scope of the isocyanides 2 in the MCR.
minished reactivity of the electron-rich intermediate A may
divert the cascade towards the Arndtsen route. However,
with less activated aromatic rings (2g and 2i, entries 7 and
9) the expected mesoionic compounds are successfully ob-
tained, albeit in lower yields. In these cases, the reduced
nucleophilicity of the aniline-type nitrogen atoms in inter-
mediates B (Scheme 2) may render the imidazole ring-clo-
sure less efficient than with aliphatic analogues and there-
fore account for the decrease in the overall yield. However,
we still lack conclusive evidence to fully explain the behav-
iour of aromatic isocyanides.
Entry[a]
R1
Adduct
Yield [%][b]
1
2
3
4
5
6
7
8
9
c-C6H11 (2a)
nBu (2b)
5a
5b
5c
–
85
80
65
Bn (2c)
tBu (2d)
–
–
pTolSO2CH2 (2e)
MeO2CCH2 (2f)
4-ClC6H4 (2g)
4-MeOC6H4 (2h)
2,6-Me2C6H3 (2i)
–
5d
5e
6b
5f
21[c,d]
20
23
Reaction Scope – Azine Range
Next, we examined the scope of reactive azines in the
MCR (Table 2). Differently substituted isoquinolines (1b–
1d, entries 1–3) gave the adduct 5 in good-to-moderate
26
[a] All reactions were performed following the standard procedure.
[b] Isolated yield. [c] Dipole 6a was also isolated. [d] Isoquinoline,
TFAA and the isocyanide were allowed to react in a 1:1:1 stoichio-
metric ratio.
Table 2. Reaction scope of the azines 1 in the MCR.
quinoline was also detected in this reaction, which suggests
that competing pathways are operating (Scheme 3). This
tendency is increased with 4-MeOC6H4NC (2h, entry 8) in
which the formation of 6b (Figure 2) predominates. The di-
Figure 2. Additional mesoionic compounds isolated in the MCRs.
Scheme 3. Competitive reaction pathways leading to dipoles 5d and
6a.
[a] All reactions were performed following the standard procedure.
[b] Isolated yield.
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R. Lavilla et al.
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yields, including the 4- and 5-bromo derivatives and the 4- Table 3. Reaction scope of the anhydrides 3 in the MCR.
boronate. Remarkably, pyridine (1e, entry 4), which is inert
in Ugi–Reissert conditions,[4a] gave the adduct 5j. Methyl
isonicotinate (1f, entry 5) and 4-methoxypyridine (1g, en-
try 6) did not afford the corresponding acid fluorides 5, the
former yielding the corresponding Arndtsen dipole (6c,
20%). The rationale for these results may relate to the nu-
cleophilic competition between the azine and the isocyanide
in their reaction with TFAA and the relative reactivity of
the resulting species: the intermediate azinium ion B and
the corresponding N-acylazinium salt. In this respect, a
somewhat restricted reaction window may appear as a con-
sequence of the balance between the nucleophilicity of the
azine and the electrophilicity of the azinium intermediate
B. Thermodynamic aspects and the relative rates of the ele-
mentary steps involved in this manifold process may also
determine the final outcome (Scheme 2 and Scheme 3).
Quinoline (1h, entry 7) did not react under the standard
conditions. Taking into account the similar reactivity of this
heterocycle with isoquinoline, this suggests a steric require-
ment that does not allow substitution at the α-positions of
the azine, presumably because of the structural and reactiv-
ity properties of the intermediate azinium ions
B
(Scheme 2). Pyridazine (1i, entry 8) showed different behav-
iour, forming the Arndtsen dipole 6d (54%), whereas
phthalazine (1j, entry 9) afforded a complex mixture in
which 5k was detected (MS evidence). In some cases, minor
amounts of dipoles arising from the incorporation of two
isocyanide units were generated.[12]
[a] All reactions were performed following the standard procedure.
[b] Isolated yield.
Reaction Scope – Anhydride Range
The third component in the reaction procedure was also
examined (Table 3). Aside from TFAA, which leads to acid
fluorides (Table 1 and Table 2), the results obtained show
that for doubly α-fluorinated anhydrides (3b–3e, entries 1–
4) the reaction is quite general and affords several different
patterns of substitution, such as fluorinated ketones (5l,
5m), aryl ketones (5n) or aldehydes (5o). Unfortunately the
use of mixed anhydrides (to integrate the moiety deriving
from the fluorinated acid precursor in a more efficient man-
ner) was not successful.[13] Trichloroacetic anhydride (3f,
entry 5)[10c] gives the amide 5p in a yield of 30% in a re-
markable process in which up to seven bonds are formed
(Figure 3).[14] This MCR does not stop at the correspond-
ing acid chloride (detected by MS), which, being more reac-
tive than its fluoride counterpart, keeps the domino process
alive, and by reacting with another equivalent of isoquin-
oline generates an N-acylisoquinolinium salt. This reactive
intermediate then undergoes nucleophilic addition of a tri-
chloromethyl anion (presumably generated in situ by decar-
boxylation of the trichloroacetate)[15] to finally yield 5p
Figure 3. View of the X-ray crystal structure of 5p.
Scheme 4. MCR with trichloroacetic anhydride leading to 5p.
Dipole Derivatization
Although remarkably stable (for instance, dipole 5a does
(Scheme 4). The less electrophilic dichloroacetic anhydride not react with acetylenedicarboxylate esters in [3+2] cyclo-
(3g, entry 6) did not show any reactivity under the standard addition reactions),[9] the acid fluoride function present in
conditions tested and probably sets the activation threshold dipoles 5 displays the expected reactivity and affords the
for the acylating component.
corresponding mesoionic derivatives 7a–7d on reaction with
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Multicomponent Access to Functionalized Mesoionic Structures
δ = 77.0 ppm. 19F NMR spectra are referenced to TFA as external
reference (–78.5 ppm). IR spectra were recorded with a Thermo
Nicolet Nexus spectrometer and are reported in frequency of ab-
sorption (cm–1).
nucleophiles (amines, alcohols and thiols). Interestingly, the
isoquinolinium moiety can be selectively reduced, as shown
by the formation of the dihydroisoquinoline derivative 7e
(Scheme 5).
General Procedure for the Multicomponent Reaction: The acid anhy-
dride (3 mmol, 3 equiv.) and isocyanide (2 mmol, 2 equiv.) were
added to a solution of the corresponding azine (1 mmol, 1 equiv.)
in anhydrous CH2Cl2 (5 mL) at –30 °C. Stirring was continued for
3 min at this temperature, then the cooling bath was removed and
the reaction mixture was stirred for 14 h at room temperature. A
saturated solution of Na2CO3 (10 mL) was added and the mixture
extracted with dichloromethane (2ϫ5 mL). The combined organic
extracts were washed with brine (10 mL) and then dried (Na2SO4)
and filtered. The solvent was removed under reduced pressure and
the residue was purified by column chromatography (SiO2, hex-
anes/ethyl acetate) to yield the pure mesoionic compound.
1-Cyclohexyl-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-imidazo[2,1-
a]isoquinolin-4-ium-3-ide (5a): Obtained as a white solid (85%),
m.p. 257 °C. 1H NMR (400 MHz, CDCl3): δ = 9.21 (d, J = 7.2 Hz,
1 H), 8.27 (d, J = 7.2 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.80–
7.72 (m, 2 H), 7.43 (d, J = 7.2 Hz, 1 H), 4.78 (m, 1 H), 2.89 (m, 2
H), 2.02–1.42 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
159.0, 153.2 (d, J = 312 Hz), 135.2, 133.6, 131.1, 129.2, 128.9,
123.9, 123.6, 116.3, 115.8, 90.9 (d, J = 81 Hz), 59.2, 29.8, 26.5,
25.1 ppm. 19F NMR (376 MHz, CDCl3): δ = 14.9 ppm. IR (NaCl):
Scheme 5. Reactivity of acid fluoride 5a. Reagents and conditions:
a) (S)-(–)-1-phenylethylamine, Et3N, DCM (99%); b) p-methoxy-
benzylamine, Et3N, DCM (75%); c) MeOH (excess), Et3N, DCM
(82%); d) EtSH (excess), DMAP, pyridine (62%); e) H2, Pd/C,
MeOH (85%).
ν = 2923, 1739, 1674, 1502, 1412, 1130 cm–1. UV (MeOH): λ
˜
max
Conclusions
(logε0) = 240 (4.44), 284 (4.47), 344 (4.13) nm. MS (EI): m/z (%) =
312 (9) [M]+, 292 (8), 264 (4), 252 (34), 230 (29), 210 (100), 154
We have described a new azine MCR based on the acti-
vation of isocyanides by anhydrides. This unique domino
transformation, which features elements of the Ugi–Reis-
sert, Chichibabin and organofluorine processes, yields me-
soionic imidazo[1,2-a]azine (isoquinoline, pyridine) cores
displaying a β-dicarbonyl moiety. These structures bear a
close resemblance to neutral imidazoazines, a privileged
scaffold of great importance in medicinal and combinato-
rial chemistry because of its broad spectrum of biological
activities.[16] Our approach nicely complements the Bien-
aymé–Blackburn–Groebke reaction[17] and, although with
some restrictions, allows the preparation of the heterocyclic
scaffold directly from the azine, ready to be functionalized
with a fourth component. Further studies are underway to
fully understand the mechanistic implications of this unique
transformation and to expand its synthetic outcome.
+
(36), 128 (13). HRMS: calcd. for C18H18FN2O2 313.1352; found
313.1349.
1-Butyl-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-imidazo[2,1-a]iso-
quinolin-4-ium-3-ide (5b): Obtained as a yellow solid (80%, purified
1
by crystallization from CH2Cl2/Et2O), m.p. 205–206 °C. H NMR
(400 MHz, CDCl3): δ = 9.23 (d, J = 7.2 Hz, 1 H), 8.37 (d, J =
7.6 Hz, 1 H), 7.92–7.97 (m, 1 H), 7.70–7.90 (m, 2 H), 7.50 (d, J =
7.2 Hz, 1 H), 4.52 (t, J = 7.6 Hz, 2 H), 1.89 (m, 2 H), 1.84–1.95
(m, 2 H), 1.03 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.9, 156.24 (d, J = 316 Hz), 134.8, 133.3, 131.4,
129.6, 128.8, 124.1, 123.2, 122.4, 115.8, 90.2 (d, J = 82 Hz), 41.7,
31.0, 20.2, 13.9 ppm. 19F NMR (376 MHz, CDCl3): δ = 11.8 ppm.
IR (NaCl): ν = 1747, 1683, 1639, 1518, 1412, 1044, 747 cm–1. UV
˜
(CH2Cl2): λmax (logε0) = 248 (4.24), 291 (4.38), 366 (3.82) nm. MS
(EI): m/z (%) = 286 (26) [M]+, 269 (38), 252 (16), 238 (17), 224
(26), 210 (100), 154 (51), 128 (27), 101 (14). HRMS: calcd. for
+
C16H16FN2O2 287.1190; found 287.1191.
1-Benzyl-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-imidazo[2,1-a]-
isoquinolin-4-ium-3-ide (5c): Obtained as a white solid (65%), m.p.
257–258 °C. 1H NMR (400 MHz, CDCl3): δ = 9.30 (d, J = 7.2 Hz,
1 H), 8.24 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.73 (t,
J = 7.6 Hz, 1 H), 7.57 (t, J = 8.0, 7.6 Hz, 1 H), 7.52 (d, J = 7.2 Hz,
1 H), 7.21–7.38 (m, 5 H), 5.74 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.2, 153.1 (d, J = 312 Hz), 135.0, 133.2, 131.5, 129.5,
128.5, 128.3, 126.4, 126.3, 124.1, 123.9, 123.1, 116.3, 116.1, 90.2 (d,
J = 83 Hz), 45.6 ppm. 19F NMR (376 MHz, CDCl3): δ = 12.2 ppm.
Experimental Section
General: Unless stated otherwise, all reactions were carried out un-
der argon in dried glassware. Commercially available reactants were
used without further purification. Reaction temperatures were con-
trolled by an IKA temperature modulator. Thin-layer chromatog-
raphy was conducted with Merck silica gel 60 F254 sheets and visu-
alized by UV and KMnO4 solution. Silica gel (particle size 35–
70 µm) was used for flash column chromatography. 1H, 13C and
19F NMR spectra were recorded with a Varian Mercury 400 spec-
trometer (at 400, 100 and 376 MHz, respectively). Unless otherwise
stated, NMR spectra were recorded in CDCl3 solution with TMS
as an internal reference. Data for 1H NMR spectra are reported as
follows: chemical shift (δ/ppm), multiplicity, integration and coup-
ling constant (Hz). Data for 13C NMR spectra are reported in
terms of chemical shift relative to the solvent peak of CDCl3 set at
IR (NaCl): ν = 3135, 2993, 1744, 1687, 1520, 1417, 1433, 1041,
˜
1026, 937, 742, 649 cm–1. UV (CH2Cl2): λmax (logε0) = 239 (3.99),
290 (4.05), 363 (3.50) nm. MS (EI): m/z (%) = 320 (27) [M]+, 300
(7), 231 (10), 170 (5), 153 (6), 128 (6), 91 (100), 65 (11). HRMS:
+
calcd. for C19H14FN2O2 321.1033; found 321.1045.
3-(Fluorocarbonyl)-1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-
imidazo[2,1-a]isoquinolin-4-ium-3-ide (5d): In this experiment the
stoichiometry of the reagents was modified: isoquinoline (360 mg,
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2.78 mmol, 1 equiv.), TFAA (0.393 mL, 2.78 mmol, 1 equiv.) and
6-Bromo-1-cyclohexyl-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-
isocyanide (0.253 mL, 2.78 mmol, 1 equiv.) were added in that or- imidazo[2,1a]isoquinolin-4-ium-3-ide (5h): Obtained as a purple so-
der. After the extractions silica and Na2SO4 were added to the or-
ganic extracts and left to stir for 1 h and then were filtered through
Celite. The precipitate was washed with AcOEt, and the collected
filtrates were combined. The solvent was removed under reduced
pressure and the residue was washed with Et2O (10 mL) to yield
lid (82%), m.p. 196–197 °C. 1H NMR (400 MHz, CDCl3): δ = 9.53
(s, 1 H), 8.34 (dd, J = 8.4, 0.8 Hz, 1 H), 8.30 (d, J = 8.3 Hz, 1 H),
7.92 (ddd, J = 8.3, 7.1, 1.0 Hz, 1 H), 7.84 (ddd, J = 8.4, 7.2, 1.3 Hz,
1 H), 4.77 (s, 1 H), 2.87 (m, 2 H), 2.09–1.91 (m, 4 H), 1.87–1.70
(m, 2 H), 1.52–1.36 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 157.6, 131.8, 129.8, 128.4, 124.5, 123.8, 120.2, 118.1, 116.3,
111.3, 59.3, 29.5, 26.2, 24.8 ppm (the signals of two quaternary
1
the dipole as a brown solid (176.9 mg, 21%), m.p. 194–195 °C. H
NMR (400 MHz, CDCl3): δ = 9.28 (d, J = 6.8 Hz, 1 H), 8.04 (d,
J = 8.4 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.83 (m, J = 7.2, 8.0 Hz, carbon atoms were not detected). 19F NMR (376 MHz, CDCl3): δ
1 H), 7.76 (m, J = 8.4, 7.2 Hz, 1 H), 7.56 (d, J = 7.2 Hz, 1 H), 5.31
(s, 2 H), 3.80 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
167.8, 157.1, 152.9 (d, J = 310.5 Hz), 135.0, 133.3, 131.6, 129.8,
128.9, 124.1, 122.3, 116.6, 116.4, 90.7 (d, J = 81 Hz), 53.5,
43.4 ppm. 19F NMR (376 MHz, CDCl3): δ = 13.3 ppm. IR (NaCl):
= 11.5 ppm. IR (NaCl): ν = 2925, 1706, 1505, 1417 cm–1. UV
˜
(MeOH): λmax (logε0) = 245 (4.09), 294 (4.36), 353 (3.78) nm. MS
(EI): m/z (%) = 392 (7) [M]+, 390 (7) [M]+, 372 (7), 370 (7), 310
(24), 308 (24), 290 (100), 288 (99), 234 (16), 232 (16). HRMS: calcd.
+
for C18H17BrFN2O2 391.0451; found 391.0452.
ν = 1746, 1699, 1522, 1441, 1419, 1364, 1224, 1042, 937, 748 cm–1.
˜
1-Cyclohexyl-3-(fluorocarbonyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-2,3-dihydro-1H-imidazo[2,1-a]isoquinolin-4-ium-
3-ide (5i): Obtained as an off-white solid (69%), m.p. 200–202 °C.
1H NMR (400 MHz, CDCl3): δ = 9.57 (s, 1 H), 8.87 (dd, J = 8.4,
0.8 Hz, 1 H), 8.24 (d, J = 8.2 Hz, 1 H), 7.82 (ddd, J = 8.3, 7.1,
1.0 Hz, 1 H), 7.73 (ddd, J = 8.4, 7.1, 1.2 Hz, 1 H), 4.79 (t, J =
11.6 Hz, 1 H), 2.90 (m, 2 H), 2.08–1.91 (m, 4 H), 1.50–1.36 (m, 2
H), 1.78 (m, 2 H), 1.42 (s, 12 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 159, 152 (d, J = 311 Hz), 137.8, 136.3, 131.6, 131.0,
129.6, 128.3, 123.6, 123.4, 115.7, 84.8, 59.3, 29.6, 26.2, 24.9 ppm
(one signal overlapped, the signal of one quaternary carbon atom
was not detected). 19F NMR (376 MHz, CDCl3): δ = 10.60 ppm.
UV (CH2Cl2): λmax (logε0) = 246 (4.35), 277 (4.24), 363 (4.23) nm.
MS (EI): m/z (%) = 302 (100) [M]+, 215 (25), 195 (16), 168 (11),
156 (19), 140 (11), 128 (18), 115 (7), 101 (7). HRMS: calcd. for
+
C15H12FN2O4 303.0775; found 303.0776.
1-(4-Chlorophenyl)-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-imid-
azo[2,1-a]isoquinolin-4-ium-3-ide (5e): Obtained as a yellow solid
(20%), m.p. 225–226 °C. 1H NMR (400 MHz, CDCl3): δ = 9.33 (d,
J = 6.8 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.74 (m, J = 7.2, 7.6 Hz,
1 H), 7.65 (d, J = 8.8 Hz, 2 H), 7.59 (d, J = 7.2 Hz, 1 H), 7.39–
7.50 (m, 3 H), 7.31 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.0, 153.1 (d, J = 314 Hz), 136.9, 134.3, 133.3, 132.5,
131.7, 131.0, 130.2, 129.3, 128.6, 124.1, 123.5, 116.7, 115.8, 90.1 (d,
J = 83 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = 12.4 ppm. IR
IR (NaCl): ν = 2977, 2931, 2851, 1738, 1692, 1389, 1365, 1317,
˜
1142 cm–1. UV (MeOH): λmax (logε0) = 248 (4.01), 287 (4.13), 341
(NaCl): ν = 1740, 1670, 1415, 1001, 805, 739 cm–1. UV (CH Cl ):
(3.74) nm. MS (EI): m/z (%) = 438 (7) [M]+, 418 (7), 390 (8), 356
˜
2
2
+
λmax (logε0) = 251 (4.03), 291 (4.06), 363 (3.67) nm. MS (EI): m/z
(17), 336 (100), 335 (24). HRMS: calcd. for C24H29BFN2O4
(%) = 340 (100) [M]+, 319 (46), 265 (31), 230 (16), 203 (8), 175 (5),
439.2199; found 439.2204.
+
111 (17), 75 (18). HRMS: calcd. for C18H11ClFN2O2 341.0487;
1-Cyclohexyl-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-imidazo[1,2-
a]pyridin-4-ium-3-ide (5j): Obtained as a white solid (40%), m.p.
190 °C. 1H NMR (400 MHz, CDCl3): δ = 9.35 (d, J = 6.4 Hz, 1
H), 7.65 (d, J = 7.6 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.19 (d, J
= 6.8 Hz, 1 H), 4.56 (m, 1 H), 1.97–1.48 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.4, 153.0 (d, J = 311 Hz), 137.6, 132.3,
129.6, 115.7, 107.8, 90.3 (d, J = 64 Hz), 52.2, 30.0, 26.1, 25.4 ppm.
found 341.0496.
1-(2,6-Dimethylphenyl)-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-imid-
azo[2,1-a]isoquinolin-4-ium-3-ide (5f): Obtained as a yellow solid
(26%), m.p. 214–216 °C. 1H NMR (400 MHz, CDCl3): δ = 9.35 (d,
J = 7.2 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.68–7.75 (m, 1 H),
7.58 (d, J = 7.2 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.35–7.40 (m,
1 H), 7.30–7.39 (m, 2 H), 7.09 (d, J = 8.8 Hz, 1 H), 2.09 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.0, 153.16 (d, J =
311 Hz), 137.1, 133.1, 132.3, 131.7, 130.8, 129.8, 129.6, 128.4,
19F NMR (376 MHz, CDCl ): δ = 9.5 ppm. IR (NaCl): ν = 2936,
˜
3
1737, 1688, 1513, 1440, 1132 cm–1. UV (MeOH): λmax (logε0) = 255
(4.22), 304 (3.86), 333 (3.82) nm. MS (EI): m/z (%) = 262 (10)
[M]+, 242 (9), 214 (13), 180 (34), 160 (100), 104 (29), 78 (32).
127.0, 124.2, 122.1, 116.3, 116.2, 90.6 (d, J = 83 Hz), 18.1 ppm. 19
NMR (376 MHz, CDCl ): δ = 12.0 ppm. IR (NaCl): ν = 2918,
F
˜
+
3
HRMS: calcd. for C14H16FN2O2 263.1190; found 263.1197.
2850, 1747, 1743, 1703, 1514, 1413, 997, 748, 665 cm–1. UV
(CH2Cl2): λmax (logε0) = 263 (3.96), 292 (3.91), 363 (3.82) nm. MS
(EI): m/z (%) = 334 (50) [M]+, 314 (100), 299 (11), 285 (24), 271
(12), 258 (89), 245 (20), 232 (30), 217 (16), 103 (17), 77 (31).
1-Cyclohexyl-2-oxo-3-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-imid-
azo[2,1-a]isoquinolin-4-ium-3-ide (5l): Obtained as a white solid
(38%), m.p. 228 °C. 1H NMR (400 MHz, CDCl3): δ = 9.79 (d, J =
7.2 Hz, 1 H), 8.26 (d, J = 7.6 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H),
7.78 (t, J = 7.2 Hz, 1 H), 7.74 (m, J = 7.6, 1.6 Hz, 1 H), 7.42 (q, J
= 7.2 Hz, 1 H), 4.76 (m, 1 H), 2.85 (m, 2 H), 2.02–1.38 (m, 8
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.3 (m), 158.6, 136.4,
134.2, 131.4, 128.9, 128.6, 124.9, 118.9, 116.0, 115.5, 58.9, 29.5,
26.2, 24.9 ppm (the signals of two quaternary carbon atoms were
not detected). 19F NMR (376 MHz, CDCl3): δ = –79.1 ppm. IR
+
HRMS: calcd. for C20H16FN2O2 335.1190; found 335.1198.
7-Bromo-1-cyclohexyl-3-(fluorocarbonyl)-2-oxo-2,3-dihydro-1H-imid-
azo[2,1-a]isoquinolin-4-ium-3-ide (5g): Obtained as a white waxy so-
lid (35%), m.p. 275 °C. H NMR (400 MHz, CDCl3): δ = 9.30 (d,
1
J = 7.6 Hz, 1 H), 8.24 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1
H), 7.93 (d, J = 7.2 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 4.74 (m, 1
H), 2.88 (m, 2 H), 2.02–1.42 (m, 8 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.5, 152.8 (d, J = 313 Hz), 134.7, 132.1, 129.1, 124.7,
123.6, 122.9, 120.9, 117.2, 114.6, 90.8 (d, J = 81 Hz), 59.3, 29.5,
26.2, 24.8 ppm. 19F NMR (376 MHz, CDCl3): δ = 15.9 ppm. IR
(NaCl): ν = 2923, 1700, 1610, 1508, 1456, 1251, 1143 cm–1. UV
˜
(MeOH): λmax (log ε0) = 262 (4.24), 279 (4.28), 294 (4.32), 359
(4.22) nm. MS (EI): m/z (%) = 362 (15) [M]+, 280 (58), 211 (100),
+
155 (23), 128 (13). HRMS: calcd. for C19H18F3N2O2 363.1320;
(NaCl): ν = 2930, 1739, 1706, 1502, 1405, 1155 cm–1. UV (MeOH):
˜
found 363.1313.
λmax (logε0) = 247 (4.66), 294 (4.79), 348 (4.31) nm. MS (EI): m/z
(%) = 390 (7) [M]+, 370 (10), 344 (4), 308 (28), 288 (100), 234 (11), 1-Cyclohexyl-2-oxo-3-(2,2,3,3,3-pentafluoropropanoyl)-2,3-dihydro-
+
209 (7), 153 (41), 127 (21). HRMS: calcd. for C18H17BrFN2O2
391.0457; found 391.0453.
1H-imidazo[2,1-a]isoquinolin-4-ium-3-ide (5m): Obtained as a white
solid (45%), m.p. 235 °C. 1H NMR (400 MHz, CDCl3): δ = 9.83
622
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 617–625

Multicomponent Access to Functionalized Mesoionic Structures
+
(d, J = 7.6 Hz, 1 H), 8.27 (d, J = 8.0 Hz, 1 H), 7.90 (d, J = 8.0 Hz,
1 H), 7.80 (t, J = 7.2 Hz, 1 H), 7.74 (t, J = 7.2 Hz, 1 H), 7.41 (d,
J = 7.2 Hz, 1 H), 4.76 (m, 1 H), 2.86 (m, 2 H), 2.00–1.39 (m, 8
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.9 (m), 158.4, 136.7,
134.2, 131.5, 128.9, 128.6, 124.9, 118.9 (m), 115.6, 115.4, 108.8,
103.3, 59.0, 29.5, 26.2, 24.8 ppm (the signal of one quaternary car-
bon atom was not detected). 19F NMR (376 MHz, CDCl3): δ =
184 (46), 155 (23), 128 (16). HRMS: calcd. for C18H19N2O2
295.1447; found 295.1446.
1-Cyclohexyl-2-oxo-3-[1-(trichloromethyl)-1,2-dihydroisoquinolin-2-
ylcarbonyl]-2,3-dihydro-1H-imidazo[2,1-a]isoquinolin-4-ium-3-ide
(5p): Obtained as a white solid (30%), m.p. 141.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.40 (d, J = 7.2 Hz, 1 H), 8.75 (m, 1 H),
8.39 (m, 1 H), 8.20–7.90 (m, 5 H), 7.82–7.60 (m, 4 H), 6.45 (br. d,
J = 7.2 Hz, 1 H), 4.84 (br. s, 1 H), 2.84 (br. s, 2 H), 2.02–1.41 (m,
8 H) ppm. 13C NMR (100 MHz, CDCl3, mixture of rotamers): δ =
171.3, 162.2, 158.6, 133.5, 132.4, 131.6, 129.9, 129.0, 128.8, 128.5,
128.3, 126.4, 124.9, 124.6, 124.2, 122.4, 122.3, 116.5, 114.9, 113.9,
–85.6, –124.4 ppm. IR (NaCl): ν = 2930, 1693, 1597, 1514, 1450,
˜
1213, 1123 cm–1. UV (MeOH): λmax (logε0) = 280 (4.29), 361 (4.24),
371 (4.21) nm. MS (EI): m/z (%) = 412 (13) [M]+, 330 (36), 211
+
(100), 155 (21), 128 (12). HRMS: calcd. for C20H18F5N2O2
413.1282; found 413.1280.
96.3, 58.7, 41.8, 29.8, 26.2, 24.9 ppm. IR (NaCl): ν = 3430, 2923,
˜
1643, 1617, 1508, 1454, 1245 cm–1. UV (MeOH): λmax (logε0) = 271
(4.67), 349 (4.99), 362 (4.95) nm. MS (EI): m/z (%) = 422, 328 (7),
293 (25), 246 (16), 211 (100), 176 (38), 155 (25), 128 (17). HRMS:
3-Benzoyl-1-cyclohexyl-2-oxo-2,3-dihydro-1H-imidazo[2,1-a]isoquin-
olin-4-ium-3-ide (5n): Oxalyl chloride (0.136 mL, 1.6 mmol,
3 equiv.) was slowly added to a suspension of potassium difluo-
ro(phenyl)acetate (677.2 mg, 3.2 mmol, 6 equiv.)[18] in toluene
(1.5 mL) at 0 °C. The reaction was left to stir under nitrogen at
room temp. for 2 h and then heated at reflux for 2 h to yield difluo-
ro(phenyl)acetic anhydride, which was used without purification.
The mixture containing the anhydride was then cooled to –78 °C.
At this temperature, CH2Cl2 (4 mL), cyclohexyl isocyanide
(0.131 mL, 1.1 mmol, 2 equiv.) and isoquinoline (70.5 mg,
0.533 mmol, 1 equiv.) were added in that order. After 3 min, the
dry ice bath was removed and the reaction mixture was left to stir
for 24 h. An aqueous saturated solution of Na2CO3 (10 mL) was
added and the mixture was extracted with dichloromethane
(2ϫ5 mL). The combined organic extracts were washed with brine
(10 mL) and then dried (Na2SO4) and filtered. The solvent was
removed under reduced pressure and the residue was washed with
Et2O (6 mL) to yield 5n (81.1 mg, 41%) as a yellow solid, m.p. 128–
129 °C. 1H NMR (400 MHz, CDCl3): δ = 9.99 (d, J = 7.6 Hz, 1
H), 8.28 (br., 1 H), 7.86–7.95 (m, 1 H), 7.82 (m, 2 H), 7.73 (m, 2
H), 7.39–7.49 (m, 4 H), 4.80 (br., 1 H), 2.85 (m, 2 H), 1.90–2.10
(m, 4 H), 1.70–1.80 (m, 1 H), 1.30–1.50 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 183.9, 159.7, 140.0, 134.2, 131.0, 130.4,
128.9, 128.7, 128.6, 128.5, 127.8, 125.4, 123.8, 116.2, 115.1, 104.73,
+
calcd. for C28H25Cl3N3O2 540.1012; found 540.0987.
(2-Methoxy-2-oxoethylimino)-3-(trifluoromethyl)-1,3-dihydroox-
azolo[4,3-a]isoquinolin-4-ium-3-ide (6a): In this experiment the or-
der of addition was modified. The isocyanide (0.281 mL,
3.10 mmol, 2 equiv.), TFAA (0.658 mL, 4.64 mmol, 3 equiv.) and
isoquinoline (200 mg, 1.55 mmol, 1 equiv.) were added in that order
to yield under the standard conditions the dipole 6a as a white solid
1
(70.5 mg, 14%), m.p. 194–195 °C. H NMR (400 MHz, CDCl3): δ
= 8.07 (d, J = 7.2 Hz, 1 H), 7.95–8.05 (m, 1 H), 7.85–7.92 (m, 1
H), 7.68–7.76 (m, 2 H), 7.46 (d, J = 7.2 Hz, 1 H), 5.36 (s, 2 H),
3.79 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.0, 153.2,
131.1, 130.1, 129.8, 128.8, 121.9, 121.8, 121.7, 121.6, 119 (q, J =
264 Hz), 116.5, 53.4, 43.3 ppm (the signal of one quaternary carbon
atom was not detected). 19F NMR (376 MHz, CDCl3): δ =
–59.4 ppm. IR (NaCl): ν = 3138, 2955, 2926, 1751, 1676, 1639,
˜
1523, 1477, 1449, 1220, 1126, 1064, 647 cm–1. UV (CH2Cl2): λmax
(logε0) = 236 (4.17), 286 (4.25), 357 (4.17) nm. MS (EI): m/z (%) =
324 (100) [M]+, 305 (10), 266 (12), 237 (20), 217 (18), 197 (10), 168
(11), 142 (9), 128 (13). HRMS: calcd. for C15H12F3N2O3+ 325.0794;
found 325.0802. The acid fluoride product 5d (23.5 mg, 5%) was
also obtained in this experiment.
59.0, 29.8, 26.5, 25.1 ppm. IR (NaCl): ν = 3128, 2926, 2854, 1675,
˜
(4-Methoxyphenylimino)-3-(trifluoromethyl)-1,3-dihydrooxazolo-
[4,3-a]isoquinolin-4-ium-3-ide (6b): In this experiment the typical
stoichiometry was modified: isocyanide (1 equiv., TFAA 1 equiv.),
isoquinoline (1 equiv.) The product 6b was obtained as a white so-
lid (23%), m.p. 196–197 °C. 1H NMR (400 MHz, CDCl3): δ = 8.09
(d, J = 7.2 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.59 (m, J = 7.6,
7.2 Hz, 1 H), 7.43 (d, J = 7.2 Hz, 1 H), 7.37 (m, J = 9.2 Hz, 2 H),
7.34 (m, J = 7.2 Hz, 1 H), 7.28 (m, J = 9.2 Hz, 1 H), 7.14 (m, J =
8.8 Hz, 2 H), 3.94 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 161.2, 154.7, 151.6, 133.3, 131.5, 130.0, 129.1, 128.4, 126.2, 124.0,
123.8, 116.4, 116.1, 116.0, 55.92 ppm (the signals of two quaternary
carbon atoms were not detected). 19F NMR (376 MHz, CDCl3): δ
1587, 1557, 1509, 1447, 1410, 1366, 1345, 1321, 1227, 1140, 1026,
977, 809, 740, 650 cm–1. UV (CH2Cl2): λmax(logε0) = 241 (3.32),
292 (3.25), 392 (3.22) nm. MS (EI): m/z (%) = 370 (34) [M]+, 288
(100), 211 (15), 155 (12), 128 (9), 105 (24), 77 (18). HRMS: calcd.
+
for C24H23N2O2 371.1754; found 371.1763.
1-Cyclohexyl-3-formyl-2-oxo-2,3-dihydro-1H-imidazo[2,1-a]isoquin-
olin-4-ium-3-ide (5o): Difluoroacetic anhydride (0.500 mL, 5 mmol,
5 equiv.) and cyclohexyl isocyanide (0.096 mL, 1 mmol, 1 equiv.)
were added to a solution of the corresponding azine (100 mg,
0.78 mmol, 1 equiv.) in anhydrous CH2Cl2 (5 mL) at –30 °C. After
stirring for 3 min at this temperature, the dry ice bath was removed
and the reaction mixture was stirred for 14 h at room temperature.
A saturated solution of Na2CO3 (10 mL) was added and the mix-
ture was extracted with dichloromethane (2ϫ5 mL). The combined
organic extracts were washed with brine (10 mL), dried (Na2SO4)
and filtered. The solvent was removed under reduced pressure and
the residue was purified by column chromatography [SiO2, hexanes/
= –76.9 ppm. IR (NaCl): ν = 2957, 2924, 1753, 1672, 1607, 1469,
˜
1443, 1252, 1122, 666 cm–1. UV (CH2Cl2): λmax (log ε0) = 265
(3.72), 295 (3.70), 334 (3.36), 371 (3.52) nm. MS (EI): m/z (%) =
358 (100) [M]+, 337 (40), 261 (20), 218 (25), 191 (8), 128 (8), 92
+
(9), 77 (10). HRMS: calcd. for C19H14F3N2O2 359.1002, found
359.1008.
ethyl acetate (1:5)] to yield 5o (73.7 mg, 32%) as a white solid, m.p.
1
242 °C. H NMR (400 MHz, CDCl3): δ = 9.70 (s, 1 H), 9.64 (d, J 1-(Cyclohexylimino)-7-(methoxycarbonyl)-3-(trifluoromethyl)-1,3-di-
= 7.2 Hz, 1 H), 8.28 (m, 1 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.74 (m, hydrooxazolo[3,4-a]pyridin-4-ium-3-ide (6c): Obtained as a white so-
1
2 H), 7.40 (d, J = 7.2 Hz, 1 H), 4.79 (m, 1 H), 2.86 (m, 2 H), 2.00–
lid (20%). H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 4.0 Hz,
1.42 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.3, 161.9, 1 H), 7.87 (s, 1 H), 7.58 (dd, J = 6.8, 1.7 Hz, 1 H), 4.53 (m, 1 H),
133.3, 130.4, 128.8, 128.7, 124.2, 123.5, 122.3, 116.1, 115.5, 104.5,
3.96 (s, 3 H), 2.08–2.25 (m, 2 H), 1.65–2.00 (m, 5 H), 1.20–1.50 (m,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.3, 154.1, 131.7,
126.9, 123.6, 122.2 (q, J = 270 Hz), 114.8, 108.0, 53.04, 52.6, 30.2,
58.6, 29.7, 26.2, 24.9 ppm. IR (NaCl): ν = 2923, 1668, 1617, 1514,
˜
1450, 1354, 1149 cm–1. UV (MeOH): λmax (logε0) = 265 (4.44), 294
(4.42), 354 (4.36) nm. MS (EI): m/z (%) = 294 (27) [M]+, 212 (100), 25.8, 25.0 ppm (the signal of one quaternary carbon atom was not
Eur. J. Org. Chem. 2009, 617–625
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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623

R. Lavilla et al.
detected). 19F NMR (376 MHz, CDCl3): δ = –61.0 ppm. IR CH2Cl2 (5 mL). The mixture was extracted with brine (4ϫ5 mL)
FULL PAPER
(NaCl): ν = 2956, 2867, 1718, 1510, 1301, 1198, 1112, 970, and the combined organic extracts were dried (Na2SO4) and fil-
˜
760 cm–1. MS (EI): m/z (%) = 342 (98) [M]+, 301 (38), 260 (100), tered. The solvent was removed under reduced pressure and the
240 (12), 81 (10). MS (ESI): m/z = 343 [M + H], 342 [M]+.
residue was purified by column chromatography [SiO2, hexanes/
ethyl acetate (1:1)] to yield 7c (88.0 mg, 82%) as a white glassy
solid. H NMR (400 MHz, CDCl3): δ = 9.58 (d, J = 7.6 Hz, 1 H),
8.24 (m, 1 H), 7.86 (d, J = 8.6 Hz, 1 H), 7.70 (m, 2 H), 7.37 (d, J
= 7.6 Hz, 1 H), 4.80 (m, 1 H), 3.93 (m, 3 H), 2.96 (m, 2 H), 2.02–
1.41 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.6, 158.0,
132.3, 129.8, 128.6, 128.5, 123.9, 123.0, 122.9, 116.2, 115.1, 95.0,
5-(Cyclohexylimino)-7-(trifluoromethyl)-5,7-dihydrooxazolo[3,4-b]-
pyridazin-8-ium-7-ide (6d): Obtained as a yellowish oil (54%). 1H
NMR (400 MHz, CDCl3): δ = 8.41 (d, J = 5.2 Hz, 1 H), 7.59 (d,
J = 8.8 Hz, 1 H), 7.15 (dd, J = 8.8, 5.2 Hz, 1 H), 4.63 (m, 1 H),
2.04–1.25 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.9,
142.5, 128.3, 121.5 (q, J = 264 Hz), 120.2, 115.2, 51.9, 30.7, 25.8,
25.2 ppm (the signal of one quaternary carbon atom was not de-
tected). 19F NMR (376 MHz, CDCl3): δ = –65.8 ppm. MS (EI):
m/z (%) = 285 (11) [M]+, 203 (67), 177 (41), 120 (32), 95 (100), 69
(49), 55 (58).
1
59.0, 51.1, 29.6, 26.3, 24.9 ppm. IR (NaCl): ν = 2930, 1783, 1655,
˜
1597, 1463, 1200, 1072 cm–1. UV (MeOH): λmax (log ε0) = 262
(4.42), 287 (4.52), 344 (4.18) nm. MS (EI): m/z (%) = 324 (21)
[M]+, 242 (78), 210 (100), 184 (22), 154 (33), 128 (16). HRMS:
+
calcd. for C19H21N2O3 325.1552; found 325.1547.
(S)-1-Cyclohexyl-2-oxo-3-(1-phenylethylcarbamoyl)-2,3-dihydro-1H-
imidazo[2,1-a]isoquinolin-4-ium-3-ide (7a): Triethylamine 1-Benzyl-3-(ethylthiocarbonyl)-2-oxo-2,3-dihydro-1H-imidazo[2,1-a]-
(0.053 mL, 0.38 mmol, 2 equiv.) was added to a solution of 5a
(50 mg, 0.19 mmol, 1 equiv.) in anhydrous CH2Cl2 (2 mL) under
nitrogen. After stirring for 2 min (S)-(–)-α-methylbenzylamine
(0.029 mL, 0.23 mmol, 1.2 equiv.) was added dropwise and the re-
action mixture was stirred at room temperature overnight. A satu-
rated solution of brine (7 mL) was added and the mixture was ex-
tracted with dichloromethane (2ϫ5 mL). The combined organic
extracts were dried (Na2SO4) and filtered. The solvent was removed
under reduced pressure and the residue was purified by column
chromatography [SiO2, hexanes/ethyl acetate (1:3)] to yield 7a
(77.9 mg, 99%) as a gum. [α]2D0 = +56.35 (c = 2.7, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 9.88 (d, J = 7.2 Hz, 1 H), 8.94 (d,
J = 7.6 Hz, 1 H), 8.22 (br. s, 1 H), 7.85 (m, 1 H), 7.60–7.80 (m, 2
H), 7.47 (m, 2 H), 7.35 (m, 3 H), 7.20 (m, 1 H), 5.30 (m, 1 H), 4.9
(br. s, 1 H), 2.95 (br. s, 2 H) 2.00–2.1 (m, 4 H), 1.75–1.85 (br., 1
isoquinolin-4-ium-3-ide (7d): DMAP (10 mg, 81.8 µmol, 0.5 equiv.)
and ethanethiol (0.5 mL, 9.6 mmol, 61.4 equiv.) were added to a
solution of 5c (50.0 mg, 0.156 mmol, 1 equiv.) in pyridine (2 mL).
The reaction mixture was left to stir for 40 h under an inert atmo-
sphere at room temp. A saturated solution of Na2CO3 (6 mL) was
added and the mixture was extracted with dichloromethane
(2ϫ3 mL). The combined organic extracts were washed with brine
(6 mL) and then dried (Na2SO4) and filtered. The solvent was re-
moved under reduced pressure and the residue was washed with
Et2O (6 mL) to yield 7d (35.1 mg, 62%) as a yellow solid M.p. 224–
225 °C. 1H NMR (400 MHz, CDCl3): δ = 9.83 (d, J = 7.3 Hz, 1
H), 8.21 (d, J = 8.6 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.65 (t, J
= 7.5 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.42 (d, J = 7.3 Hz, 1 H),
7.23–7.37 (m, 5 H), 5.75 (s, 2 H), 3.08 (m, J = 7.4 Hz, 2 H), 1.39
(t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.5,
H), 1.59 (d, J = 7.2 Hz, 3 H) 1.45–1.55 (m, 3 H) ppm. 13C NMR 158.2, 153.3, 132.6, 132.2, 130.5, 129.4, 129.0, 128.3, 128.1, 126.4,
(100 MHz, CDCl3): δ = 161.8, 158.9, 145.2, 131.9, 129.1, 129.0, 124.7, 123.7, 116.2, 115.7, 102.2, 45.52, 21.96, 15.31 ppm. IR
128.9, 128.7, 128.6, 128.5, 127.0, 126.3, 124.5, 122.7, 116.7, 115.1,
(NaCl): ν = 2923, 1747, 1673, 1593, 1520, 1455, 1406, 1347,
˜
59.14, 48.4, 30.1, 26.5, 25.3, 23.5 ppm. IR (NaCl): ν = 2929, 2854,
917 cm–1. UV (CH2Cl2): λmax (logε0) = 241 (3.88), 271 (3.92), 298
(3.96), 380 (3.86) nm. MS (EI): m/z (%) = 362 (29) [M]+, 301 (92),
˜
1653, 1624, 1534, 1506, 1452, 1415, 1369, 1214, 742, 699 cm–1. UV
(CH2Cl2): λmax (logε0) = 249 (3.96), 270 (3.99), 2.96 (4.00), 371 273 (18), 91 (100). HRMS: calcd. for C21H19N2O2S+ 363.1161,
(3.88) nm. MS (EI): m/z (%) = 413 (49) [M]+, 396 (23), 294 (41),
found 363.1169.
266 (38), 227 (82), 211 (100), 184 (92), 155 (55), 120 (62), 105 (70).
HRMS: calcd. for C26H28N3O2 414.2176; found 414.2180.
+
1-Cyclohexyl-3-(methoxycarbonyl)-2-oxo-2,3,5,6-tetrahydro-1H-imid-
azo[2,1-a]isoquinolin-4-ium-3-ide (7e): Pd/C (10%, 15 mg) was
added to a stirring suspension of 7c (35.8 mg, 0.110 mmol) in
MeOH (3 mL) under hydrogen at atmospheric pressure. After 48 h
the hydrogen atmosphere was removed, CH2Cl2 (1 mL) was added
and the solution was filtered through Celite. A saturated solution
of Na2CO3 (6 mL) was added and the mixture was extracted with
dichloromethane (2ϫ3 mL). The combined organic extracts were
washed with brine (6 mL) and then dried (Na2SO4) and filtered.
The solvent was removed under reduced pressure and the residue
was purified by column chromatography (SiO2, hexanes/ethyl ace-
tate) to yield the pure reduced mesoionic ester as a white solid
1-Cyclohexyl-3-(4-methoxybenzylcarbamoyl)-2-oxo-2,3-dihydro-1H-
imidazo[2,1-a]isoquinolin-4-ium-3-ide (7b): By using the same pro-
cedure as above with p-methoxybenzylamine, 7b (75%) was ob-
1
tained as a white solid. H NMR (400 MHz, CDCl3): δ = 9.90 (d,
J = 7.2 Hz, 1 H), 8.85 (m, 1 H), 8.19 (m, 1 H), 7.82 (d, J = 8.0 Hz,
1 H), 7.64 (m, 2 H), 7.31 (m, 3 H), 6.83 (m, 2 H), 4.84 (m, 1 H),
4.55 (d, J = 6.0 Hz, 2 H), 3.76 (s, 3 H), 2.84 (m, 2 H), 2.02–1.39
(m, 8 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.2, 158.6,
131.6, 129.0, 128.8, 128.5, 128.3, 124.2, 122.4, 122.3, 122.2, 116.5,
114.9, 113.9, 96.3, 58.7, 55.2, 41.8, 29.8, 26.2, 24.9 ppm (the signal
of one quaternary carbon atom was not detected). IR (NaCl): ν =
˜
1
(30.6 mg, 85%), m.p. 123–124 °C. H NMR (400 MHz, CDCl3): δ
3429, 2923, 1645, 11617, 1508, 1412, 1245, 1028 cm–1. UV
(MeOH): λmax (logε0) = 262 (4.45), 288 (4.33), 348 (4.24) nm. MS
(EI): m/z (%) = 429 (56) [M]+, 294 (17), 266 (23), 211 (40), 184
(43), 155 (22), 121 (100). HRMS: calcd. for C26H28N3O3+ 430.2131;
found 430.2124.
= 7.44–7.49 (m, 3 H), 7.35–7.40 (m, 1 H), 4.60 (m, J = 6.8, 6.6 Hz,
2 H), 4.26 (m, 1 H), 3.84 (s, 3 H), 3.07 (m, J = 6.9, 6.6 Hz, 2 H),
2.80–3.00 (m, 1 H), 1.90–2.00 (m, 2 H), 1.80–1.88 (m, 2 H), 1.60–
1.70 (m, 1 H), 1.20–1.40 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 162.54, 158.25, 153.86, 133.08, 130.60, 128.77, 127.84,
1-Cyclohexyl-3-(methoxycarbonyl)-2-oxo-2,3-dihydro-1H-imidazo- 124.76, 120.89, 97.49, 57.76, 50.79, 42.07, 29.37, 28.34, 26.09,
[2,1-a]isoquinoline-4-ium-3-ide (7c): Triethylamine (0.4 mL,
3.2 mmol, 10 equiv.) was added to a solution of 5a (100 mg,
0.3 mmol, 1 equiv.) in MeOH (5 mL) under nitrogen and the reac-
tion mixture was heated at reflux overnight. Then the solvent was
removed under reduced pressure and the residue was dissolved in
24.89 ppm. IR (NaCl): ν = 2932, 2855, 1743, 1646, 1456, 1384,
˜
1339, 1201, 1166 cm–1. UV (CH2Cl2): λmax (logε0) = 251 (3.70), 297
(4.00), 384 (3.90) nm. MS (EI): m/z (%) = 326 (23) [M]+, 244 (100),
212 (53), 186 (15), 156 (23), 130 (22), 116 (15), 103 (9). HRMS:
+
calcd. for C19H23N2O3 327.1703; found 327.1705.
624
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 617–625

Multicomponent Access to Functionalized Mesoionic Structures
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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1
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Acknowledgments
We thank the Spanish Dirección General de Investigación Ciencia
y Técnica (DGICYT) (project BQU 2006-03794) and Laboratorios
Almirall (Barcelona) for financial support.
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[14] Crystallographic data for 5p: C28H24Cl3N3O2, Mr = 540.85,
monoclinic, space group P21/n, a = 9.8728(2), b = 24.8023(5),
c = 10.1993(2) Å, V = 2420.67(8) Å3, T = 100(2) K, d =
1.484 Mgm–3, 0.412 mm–1, 58646 reflections measured, 7086
unique reflections (Rint = 0.064), R1 = 0.0405, wR2 = 0.0866.
CCDC-684677 contains the supplementary crystallographic
data for 5p. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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[8] Crystallographic data for 5a: C18H17FN2O2, Mr = 312.34, mo-
noclinic, space group P21/n, a = 5.08900(10), b = 17.8638(3),
c = 15.6258(3) Å, V = 1411.56(5) Å3, T = 100(2) K, d =
1.470 Mgm–3, 0.106 mm–1, 33721 reflections measured, 3512
unique reflections (Rint = 0.0413), R1 = 0.0394, wR2 = 0.0906.
CCDC-684676 contains the supplementary crystallographic
data for 5a. These data can be obtained free of charge from
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Received: November 4, 2008
Published Online: December 19, 2008
Eur. J. Org. Chem. 2009, 617–625
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
625