Palladium-catalyzed carbonylative cross-coupling with imines: A multicomponent synthesis of imidazolones

Article abstract of DOI:10.1021/jo701875b

(Chemical Equation Presented) The palladium-catalyzed coupling of imines, chloroformates, organotin reagents, and carbon monoxide leads to the one-pot formation of ketocarbamates in good yields. These products can further be converted to highly substituted imidazolones via a cyclocondensation reaction. Overall, this methodology provides an alternative approach to imidazolones from five simple and readily available building blocks via a one-pot, multicomponent process.

Full text of DOI:10.1021/jo701875b

SCHEME 1. Carbonylative Cross Coupling with Imines
Palladium-Catalyzed Carbonylative
Cross-Coupling with Imines: A Multicomponent
Synthesis of Imidazolones
Ali R. Siamaki, Daniel A. Black, and Bruce A. Arndtsen*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke
Street West, Montreal, Quebec, H3A 2K6, Canada
bruce.arndtsen@mcgill.ca
ReceiVed August 27, 2007
substrates for imidazole synthesis.2 A variety of methods have
been developed to generate and functionalize these heterocycles.
These include the condensation of substituted ureas with
carbonyl compounds,3 the coupling of â-amino carbonyl
reagents with isocyanates,4 intramolecular iminium salt cycliza-
tions,5 as well as more recent metal-catalyzed methods,6-8 such
the rhodium catalyzed N-H insertion of primary ureas with
diazo carbonyl compounds,2a,6 or the ruthenium-catalyzed
reaction of substituted ureas with vicinal diols.7,8
In principle, an attractive approach to imidazolones would
be to assemble their core structure directly from multiple,
available building blocks. Transition metal catalysis can be a
powerful tool in developing such transformations, by activating
what are often unreactive substrates toward coupling via metal-
based reactions.9 Toward this end, we have recently reported
that imines can undergo a palladium-catalyzed cross-coupling-
type reaction with organostannanes by the addition of acid
chlorides or chloroformates, to generate R-substituted amides
(or carbamates).10 In addition, preliminary studies showed this
reaction could proceed in concert with carbon monoxide
insertion, allowing the synthesis of one example of a ketocar-
bamate (Scheme 1). Considering that ketoamides are known to
behave as precursors to imidazoles,11 we became intrigued with
The palladium-catalyzed coupling of imines, chloroformates,
organotin reagents, and carbon monoxide leads to the one-
pot formation of ketocarbamates in good yields. These
products can further be converted to highly substituted
imidazolones via a cyclocondensation reaction. Overall, this
methodology provides an alternative approach to imidazo-
lones from five simple and readily available building blocks
via a one-pot, multicomponent process.
Imidazolones are found in a range of biologically active
compounds, including anti-inflammatory,1a, anticancer,1b and
cardioactive agents,1c angiotensin II receptor antagonists,1d and
others.1e-h In addition, 2-imidazolones can serve as potential
(1) (a) Sheppeck, J. E., II; Glimore, J. L.; Tebben, A.; Xue, C.-B.;
Liu, R.-Q.; Decicco, C. P.; Duan, J. J. W. Bioorg. Med. Chem. Lett.
2007, 17, 2769-2774. (b) Lai, Z.; Yang. T.; Kim, Y. B.; Sielecki,
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P. A.; Auger, K. R.; Copleland, R. A. PNAS 2002, 99, 14734-14739.
(c) Schnettler, R. A.; Dage, R. C.; Grisar, J. M. J. Med. Chem. 1982,
25, 1477-1481. (d) Bernhart, C. A.; Perreaut, P. M.; Ferrari, B. P.;
Muneaux, Y. A.; Assens, J.-L. A.; Clement, J.; Haudricourt, F.;
Muneaux, C. F.; Taillades, J. E.; Vignal, M.-A.; Gougat, J.; Guiraudou, P.
R.; Lacour, C. A.; Roccon, A.; Cazaubon, C. F.; Breliere, J.-C.;
Le Fur, G.; Nisato, D. J. Med. Chem. 1993, 36, 3371-3380. (e)
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Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Strader, C.
D.; Tota, L.; Wang, P.-R.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E.
Bioorg. Med. Chem. Lett. 1999, 9, 755-758. (f) Reitz, D. B.; Garland, D.
J.; Norton, M. B.; Collins, J. T.; Reinhard, E. J.; Manning, R. E.; Olins, G.
M.; Chen, S. T.; Palomo, M. A.; McMahon, E. G. Bioorg. Med. Chem.
Lett. 1993, 3, 1055-1060. (g) Adres, J. I.; et al. Bioorg. Med. Chem. Lett.
2002, 12, 653-658. (h) Carling, R. W.; Moore, K. W.; Moyes, C. R.; Jones,
E. A.; Bonner, K.; Emms, F.; Marwood, R.; Patel, S.; Patel, S.; Fletcher,
A. E.; Beer, M.; Sohal, B.; Pike, A.; Leeson, P. D. J. Med. Chem. 1999,
42, 2706-2715.
(3) For example: (a) Butler, A. R.; Hussain, I. J. Chem. Soc., Perkin 2
1981, 310-316. (b) Patek, M.; Weichsel, A. S.; Drake, B.; Smrcina, M.
Synlett 2005, 8, 1322-1324.
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10.1021/jo701875b CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/29/2007
J. Org. Chem. 2008, 73, 1135-1138
1135

TABLE 1. Palladium-Catalyzed Carbonylative Coupling of Imines,
Chloroformates, CO, and Organostannanesa
FIGURE 1. A multicomponent approach to imidazolones.
the potential use of this ketocarbamate synthesis in an analogous
fashion, to achieve the overall construction of imidazolones.
As described below, this can provide a modular route to
construct imidazolones from five separate and available building
blocks, as shown in Figure 1.
Our initial efforts focused upon the palladium-catalyzed
carbonylative cross-coupling reaction with imines. While we
have shown that acid chlorides can activate imines toward cross
coupling with organostannanes,10 their use under carbonylative
conditions leads instead to the formation of imidazolines 2
(eq 1, Tol ) p-tolyl; Bn ) benzyl). The latter presumably occurs
via a mechanism involving the cyclization of the carbonylated
palladium intermediate 3 to form 1,3-oxazolium-5-olate 4 (path
B), followed by 1,3-dipolar cycloaddition of an imine (Scheme
1), a reaction we have previously reported.12 In considering
approaches to limit this pathway, we postulated that lowering
the basicity of the carbonyl oxygen in intermediate 3 might
disfavor cyclization to form 4, and allow for competitive cross
coupling to occur (path A). As shown in Table 1, replacement
of the acid chloride with a chloroformate leads to the carbo-
nylative cross-coupling product 1a in nearly quantitative yield
at ambient temperature.13
This palladium-catalyzed carbonylative coupling is compat-
ible with a number of chloroformates (entries 1-3). Both
aromatic and heteroaromatic organostannanes can participate
in the reaction, each providing ketocarbamates in good yields.
An even greater variety of imines can participate in this reaction,
including those of functionalized aryl-aldehydes (entries 2-4),
and N-alkyl or N-aryl imines (entries 4 and 5). There are certain
limitations to this methodology. For example, more reactive
transmetalating agents, such as vinylstannanes, appear to
transmetalate more rapidly than carbonylation, leading instead
to the formation of simple R-substituted carbamate (entry 6).
Similarly, alkyl-substituted organostannanes are not sufficiently
reactive to participate in this coupling, and enolizable imines
lead to side reactions.
a 0.48 mmol of imine, 1.90 mmol of chloroformate, 0.52 mmol of
organotin reagent, Pd2dba3‚CHCl3 (5%), 0.57 mmol of Bu4NBr, and CO
(1 atm) in CH3CN/CH2Cl2 (2:1) at rt for 24-48 h; p-An ) 4-CH3OC6H4.
b 50 atm of CO.
to our knowledge ketocarbamates such as 1 have not been
employed in similar cyclization reactions. As shown in eq 2,
the addition of ammonium acetate to 1a results in the clean
cyclization, along with spontaneous removal of the former
chloroformate substituent, leading to the synthesis of imida-
zolone 5a in 86% yield.14
Considering the high yield cyclization of 1a, and the ability
to access these substrates via carbonylative cross-coupling, we
became interested in the potential coupling of these steps in a
one-pot format. As shown in Table 2, this can provide an
efficient and high-yield synthesis of imidazolones, where the
products are assembled overall from five separate and readily
available building blocks (imines, chloroformates, organostan-
nanes, carbon monoxide, and ammonium acetate). Notably,
much of the same diversity noted in cross-coupling chemistry
can be incorporated into these imidazolone products, including
the use of variously substituted and functionalized imines, as
well as aryl- or heteroaryl-tin reagents. Overall, this allows
access to a range of di- and triaryl-substituted imidazolones with
independent control over three substituents about the ring.
Ketoamides are well established to undergo ammonium
acetate mediated cyclization to generate imidazoles.11 However,
(11) (a) Lee, H. B.; Balasubramanian, B. Org. Lett. 2000, 2, 323-326.
(b) Bleicher, K. H.; Gerber, F.; Wu¨thrich, Y.; Alanine, A.; Capretta, A.
Tetrahedron Lett. 2002, 43, 7687-7690. (c) Claiborne, C. F.; Liverton, N.
J.; Nguyen, K. T. Tetrahedron. Lett. 1998, 39, 8939-8942. (d) Frantz, D.
E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski, E. J. J.; Tillyer, R.
D. Org. Lett. 2004, 6, 843-846.
(12) Dghaym, R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int.
Ed. 2001, 40, 3228-3230.
(13) Bu4NBr is added in order to keep the ligandless palladium catalyst
in solution (see ref 10).
(14) The structure of 5a was distinguished from its 1H-imidazol-2-ol
tautomer by means of NOE, and HSQC NMR experiments, as well as IR
spectral data; see the Supporting Information for details.
1136 J. Org. Chem., Vol. 73, No. 3, 2008

TABLE 2. A One-Pot Synthesis of Imidazolones
SCHEME 2. Synthesis of Triarylimidazoles
palladium-catalyzed cross coupling provides access the triaryl-
substituted imidazole core in good yield. Notably, the four
substituents in 6 arise overall from two separate cross-coupling
reactions (e.g., positions 2- and 4-) and from the imine building
block (positions 1- and 5-).
In conclusion, the palladium-catalyzed four-component cross-
coupling of imines, chloroformates, organostannane reagents,
and carbon monoxide can be utilized to generate ketocarbamates,
which are amenable to cyclization to generate imidazolones.
Considering the mild conditions (1 atm of carbon monoxide,
room temperature) and simple building blocks employed, this
provides straightforward access to these heterocycles. Experi-
ments directed toward the use of this multicomponent reaction
to generate other targets are underway.
Experimental Section
General Procedure for the Synthesis of Ketocarbamates 1.
In a drybox, imine (0.48 mmol) and chloroformate (1.91 mmol)
were dissolved in acetonitrile (10 mL) then the solution was stirred
for 15 min in a 50 mL reaction bomb. To this solution was added
Pd2dba3‚CHCl3 (25 mg, 0.024 mmol) and the mixture was stirred
for 30 min until the Pd2dba3‚CHCl3 was dissolved. Tetrabutylam-
monium bromide (186 mg, 0.576 mmol) in methylene chloride (5
mL) and the organostannane (0.53 mmol) in methylene chloride
(5 mL) were added to the reaction mixture. The solution was frozen
in liquid nitrogen then degassed, and carbon monoxide (15 psi)
was added. The mixture was stirred at room temperature for 24 h.
After the reaction period was completed, solvents were removed
in vacuo. The product was dissolved in 50 mL of ethyl acetate,
then 25 mL of saturated KF solution was added and the mixture
was stirred for 5 h. This solution was filtered over celite and
extracted with ethyl acetate (3 × 50 mL). The organic layers were
combined and dried over MgSO4 then solvent was evaporated under
reduced pressure and the product was purified by silica gel
chromatography with hexane:ethylacetate as eluent.
Synthesis of 1a. The above procedure was followed, yielding
1
1a as a yellow oil (93%). H NMR (400 MHz, CDCl3, 60 °C): δ
7.8 (s, br, 2H), 7.47-7.43 (t, 1H), 7.34-7.27 (t, 2H), 7.27-7.25
(m, 3H), 7.18-7.15 (m, 4H), 7.13-7.11 (m, 4H), 7.04-7.02 (d,
2H), 6.92 (s, br, 2H), 5.25-5.16 (dd, 2H), 4.95-4.91 (d, 1H), 4.33-
4.29 (d, 1H), 2.27 (s, 3H). 13C NMR (125 MHz, CDCl3, 60 °C):
δ 197.6, 157.6, 139.4, 138.9, 136.5, 135.8, 133.3, 131.1, 130.7,
129.9, 129.0, 128.7, 128.6, 128.4, 128.1, 128.0, 127.3, 126.6, 67.9,
65.9, 49.0, 21.3. IR (KBr): νCO 1703, 1698 cm-1. HRMS: calcd
+
for C30H28NO3 450.2069, found 450. 2063.
General Procedure for the Synthesis of Imidazolones 5. In a
drybox, imine (0.48 mmol) and chloroformate (1.91 mmol) were
dissolved in acetonitrile (10 mL) and stirred for 15 min in a 50
mL reaction bomb. To this solution was added Pd2dba3‚CHCl3 (25
mg, 0.024 mmol) and the mixture was stirred for 30 min until the
Pd2dba3‚CHCl3 was dissolved. Tetrabutylammonium bromide (186
mg, 0.576 mmol) in methylene chloride (5 mL) and the organostan-
nane (0.53 mmol) in methylene chloride (5 mL) were added to the
reaction mixture. The solution was frozen in liquid nitrogen and
degassed, then carbon monoxide (15 psi) was added. The mixture
was stirred at room temperature for 24 h. After the reaction period
was completed, solvents were removed in vacuo. To this was added
25 mL of acetic acid and 15 equiv of ammonium acetate, and the
mixture was refluxed for 16 h. The resulting deep yellow solution
a Procedure of Table 1, followed by removal of solvent and addition of
15-20 equiv of NH4OAc in AcOH, reflux 12-16 h. b Ketocarbamate was
isolated and refluxed in NH4OAc/AcOH solution for 5 h.
Finally, this synthesis of imidazolones can also be used to
access imidazoles. Triaryl-substituted imidazoles have been
found to display potent biological activity, including as selective
P38 MAP kinase inhibitors.15 As illustrated in Scheme 2, the
coupling of the catalytic formation of imidazolones with the
protocol developed by Janda for their bromination and use in
(15) For review: Jackson, P. F.; Bullington, J. L. Curr. Top. Med. Chem.
2002, 2, 1011-1020.
J. Org. Chem, Vol. 73, No. 3, 2008 1137

was quenched with saturated Na2CO3 solution, the pH was adjusted
to 7-8, and the product was extracted with methylene chloride (3
× 50 mL). The organic layers were combined, dried over MgSO4,
and filtered. The yellow residue was further purified by silica gel
chromatography with hexane:ethylacetate as eluent.
(KBr): νNH 3435 cm-1; νCO 1684 cm-1. HRMS: calcd for
C23H21N2O+ 341.1648, found 341.1648.
Acknowledgment. We thank NSERC, FQRNT, and CFI for
financial support of this research.
Synthesis of 5a. The above procedure was followed, yielding
5a as a white solid (86%). H NMR (400 MHz, CDCl3): δ 10.24
(s, 1H), 7.26 (s, 2H), 7.21-7.17 (m, 5H), 7.15-7.13 (m, 3H), 7.08-
7.04 (m, 4H), 4.77 (s, 2H), 2.39 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 154.3, 138.8, 137.7, 130.9, 129.7, 129.5, 128.5, 128.3,
127.4, 127.1, 126.6, 126.4, 125.4, 121.9, 118.3, 44.7, 21.4. IR
Supporting Information Available: Synthetic details and
characterization of the compounds in eq 1and Tables 1 and 2. This
material is available free of charge via the Internet at http://pubs.acs
.org.
1
JO701875B
1138 J. Org. Chem., Vol. 73, No. 3, 2008