Molybdenum-mediated carbonylation of aryl halides with nucleophiles using microwave irradiation

Article abstract of DOI:10.1021/ol1016965

Figure Presented. A new, efficient, and practical molybdenum-mediated carbonylation of aryl and heteroaryl halides with a variety of nucleophiles is described using microwave irradiation. A range of reactions illustrating the wide scope of this chemistry were carried out and proceeded in good to excellent yields.

Full text of DOI:10.1021/ol1016965

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4280-4283
Molybdenum-Mediated Carbonylation of
Aryl Halides with Nucleophiles Using
Microwave Irradiation
Bryan Roberts,* David Liptrot, Lilian Alcaraz, Tim Luker, and Michael J. Stocks
Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road,
Loughborough, Leics LE11 5RH, United Kingdom
bryan.roberts@astrazeneca.com
Received July 21, 2010
ABSTRACT
A new, efficient, and practical molybdenum-mediated carbonylation of aryl and heteroaryl halides with a variety of nucleophiles is described
using microwave irradiation. A range of reactions illustrating the wide scope of this chemistry were carried out and proceeded in good to
excellent yields.
Heck and co-workers first reported the palladium-catalyzed
reaction of carbon monoxide, aryl halides, and alcohols or
amines to give the respective benzoate and benzamide
products.1 Since then, the scope of this reaction has been
developed such that a wide range of nucleophiles can be
used, enabling the efficient synthesis of numerous carbonyl
compounds.2 In recent years, a number of CO gas-free
palladium-catalyzed carbonylative conditions have been
reported using formamides or solid metal carbonyls as CO
sources.3 The palladium-catalyzed carbonylative coupling of
aryl and heteroaryl halides with a variety of nucleophiles
using Mo(CO)6 as the CO source is also well established.4
It is also known that some metal carbonyls such as Ni(CO)4
can be used stoichiometrically to carbonylate aryl iodides
and alkenyl halides in the presence of alcohols, metal
alkoxides, or amines to give carboxylic acids, esters, and
amides.5 Here, we report molybdenum-mediated carbonyl-
ation of aryl halides with a variety of nucleophiles in the
absence of palladium using microwave irradiation in sealed
vials.6
We began by examining the reaction shown in Table 1;
using iodobenzene and benzylamine with 1,4-dioxane as
solvent, we screened a range of group VI metal carbonyl
complexes. Reactions were carried out with a 1:1:2 ratio of
metal carbonyl complex, iodobenzene, and benzylamine and
(4) For selected examples, see: (a) Lagerlund, O.; Larhed, M. J. Comb.
Chem. 2006, 8, 4. (b) Wu, X.; Wannberg, J.; Larhed, M. Tetrahedron 2006,
62, 4665, and references cited within.
(1) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(2) (a) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder,
T. E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102, and references cited
within. For a general review on carbonylation reactions, see: Barnard, C. F. J.
Organometallics 2008, 5402.
(5) (a) Bauld, N. L. Tetrahedron Lett. 1963, 1841. (b) Nakayama, M.;
Mizoroki, T. Bull. Chem. Soc. Jpn. 1971, 44, 508. (c) Corey, E. J.; Hegedus,
L. S. J. Am. Chem. Soc. 1969, 91, 1233.
(6) All reactions were performed in a CEM Discover single-mode
microwave reactor equipped with a 300 W source set to 50 W. Each of the
reactions were performed in a CEM 10 mL microwave reaction vial. All
temperature measurements were performed with an infrared probe. Caution:
Mo(CO)6 and its derivatives are toxic, and these pressurized reactions should
only be carried out using specialized microwave equipment.
(3) (a) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43,
5580. (b) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6232. (c) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A.
J. Comb. Chem. 2003, 5, 82.
10.1021/ol1016965  2010 American Chemical Society
Published on Web 08/26/2010

Table 1. Reaction of Metal Carbonyl Complexes [M] with
Table 2. Mo(CO)6-Mediated Carbamoylation of Aryl Halides
Iodobenzene and Benzylaminea
with Benzylaminea
entry
aryl halide
C6H5I
C6H5Br
2-MeC6H4I
2-MeC6H4Br
3-ClC6H4I
3-ClC6H4Br
4-MeOC6H4I
4-MeOC6H4Br
4-Et2NC(O)C6H4I
4-Me2NC(O)C6H4Br
2-naphthyl-Br
C6H5CHdCHBr
3-thienyl-I
yieldb (%)
entry
[M]
Cr(CO)6
Cr(CO)5Cl.NEt4
Mo(CO)6
Mo(CO)5Cl.NEt4
W(CO)6
W(CO)5Cl.NEt4
time (h)
temp (°C)
yieldb (%)
1
2
3
4
5
6
7
8
84
1
2
3
4
5
6
3
4
3
4
3
4
160
130
160
130
160
130
trace
trace
84
95
10
92 (87)c
93
98
99
92
84
87
72
77
97
89
98
95
84
29
a Iodobenzene (1 mmol), benzylamine (2 mmol), and metal carbonyl
complex (1 mmol) mixed in 1,4-dioxane (1 mL) and microwave heated in
a sealed vial. b Isolated and purified.
9
10
11
12
13
14
15
16
optimized in the microwave with respect to time and
temperature. The molybdenum carbonyl complexes gave the
best conversions and excellent isolated yields (Table 1,
entries 3 and 4). Interestingly, entry 4 provided a slightly
higher isolated yield of product at a lower temperature. At
first, we suspected palladium contamination. These two
exciting results were repeated using sublimed and reagent-
grade molybdenum hexacarbonyl7 and new magnetic stirrer
bars,8 and the reaction mixtures were subjected to palladium
analysis before and after reaction. Identical results were
obtained, and gratifyingly, no detectable levels of palladium
(limit of quantification <2 ppm) were found.9
Further examination of the Mo(CO)6-mediated carbam-
oylation using benzylamine was then performed with a range
of aryl and heteroaryl halides. The reactions were carried
out with a 1:1:2 ratio of Mo(CO)6, aryl halide, and benzyl-
amine. Aryl iodides required a temperature of 160 °C and a
time of 3 h, whereas aryl bromides required a temperature
of 200 °C and a time of 5 h for complete conversion (Table
2). A wide range of ortho-, meta-, and para-electron-
deficient and -electron-rich aryl halides all gave excellent
yields (Table 2, entries 3-10). Alkenyl bromide and
heteroaryl halides also performed well in the reaction
(Table 2, entries 12-16). It is worth noting that a
subsequent optimization of brombenzene with benzyl-
amine was repeated, and a temperature of 150 °C for 5 h
gave 87% yield of benzamide (Table 2, entry 2), indicating
that our initial optimization temperatures for aryl bromides
are higher than required for complete conversion. While
amines performed well in this reaction, other nucleophiles
gave poor results using these conditions.
3-thienyl-Br
3-pyridyl-I
3-pyridyl-Br
92
a Aryl halide (1 mmol), benzylamine (2 mmol), and molybdenum
hexacarbonyl (1 mmol) mixed in 1,4-dioxane (1 mL) and microwave heated
in a sealed vial. Aryl iodides 160 °C for 3 h. Aryl bromides 200 °C for 5 h.
b Isolated and purified. c 150 °C for 5 h.
While this work was in progress, we noted a related
recent publication by Ren and Yamane10 where they
reported palladium-free carbamoylation of aryl halides
using molybdenum and tungsten amine pentacarbonyl
complexes. This method is efficient but is limited to amide
formation and requires the synthesis and isolation of the
individual amine complexes to obtain products with amide
variation. Inspired by this report and our previous result
of using Mo(CO)5Cl·NEt4 (Table 1, entry 4), we envisaged
a one-pot procedure where Mo(CO)5Cl·NEt4 could be formed
in situ from Mo(CO)6 in the presence of a nucleophile (Nu)
to give a complex of type Mo(CO)5·Nu, which would then
react with aryl halides to give a range of carbonylated
products. Initial attempts combining iodobenzene, Mo(CO)6,
tetraethylammonium chloride, and benzylamine in 1,4-
dioxane with microwave heating at 130 °C for 4 h gave the
required benzamide product in an encouraging 62% yield.
However, microwave heating Mo(CO)6 and tetraethylam-
monium chloride in 1,4-dioxane at 140 °C for 2 min
(formation of Mo(CO)5Cl·NEt4 was confirmed by comparison
1
with an authentic isolated sample by H NMR) and then
adding iodobenzene and benzylamine, followed by further
microwave heating for 4 h at 130 °C, gave the required
benzamide in 95% yield (Table 3, entry 1).
Application of this one-pot method using benzylamine was
then performed with a range of aryl and heteroaryl halides.
Aryl iodides required a temperature of 130 °C and a reaction
time of 4 h, whereas aryl bromides required a temperature
(7) Sublimed Mo(CO)6 (purity 99+%) and reagent grade Mo(CO)6
(purity 98%) were purchased from Adrich Chemicals, and ClMo(CO)5·NEt4
was synthesized from sublimed and reagent-grade Mo(CO)6 by the method
of: Abel, E. W.; Butler, I. S.; Reid, J. G. J. Chem. Soc. 1963, 2068.
(8) Rare earth Teflon-coated magnetic stirrer bars.
(9) ICP analysis of all independent reagents and reaction mixtures before
and after the reaction were analyzed, and at a limit of detection of 2 ppm,
no palladium was observed. Full information, ICP, and corroborating XRF
spectra for a pre-reaction mixture are provided in the Supporting Informa-
tion.
(10) Ren, W.; Yamane, M. J. Org. Chem. 2010, 75, 3017.
Org. Lett., Vol. 12, No. 19, 2010
4281

Table 3. In Situ Mo(CO)5Cl·NEt4-Mediated Carbonylation of
Table 4. In Situ Mo(CO)5Cl·NEt4-Mediated Carbonylation of
Aryl Halides with Benzylaminea
Iodobenzene with a Range of Nucleophilesa
entry
aryl halide
C6H5I
C6H5Br
2-MeC6H4I
2-MeC6H4Br
3-ClC6H4I
3-ClC6H4Br
4-MeOC6H4I
4-MeOC6H4Br
4-Et2NC(O)C6H4I
4-Me2NC(O)C6H4Br
2-naphthyl-Br
C6H5CHdCHBr
3-thienyl-I
yieldb (%)
1
2
3
4
5
6
7
8
95
91
98
79
98
96
90
81
99
80
75
85
97
91
95
87
9
10
11
12
13
14
15
16
3-thienyl-Br
3-pyridyl-I
3-pyridyl-Br
a Mo(CO)6 (1 mmol) and NEt4·Cl (1 mmol) in 1,4-dioxane (1 mL) were
microwave heated in a sealed vial to 140 °C for 2 min and then allowed to
cool, aryl halide (1 mmol); benzylamine (2 mmol) added; mixture
microwave heated in a sealed vial. Aryl iodides 130 °C for 4 h. Aryl
bromides 150 °C for 5 h. b Isolated and purified.
of 150 °C and a reaction time of 5 h for complete conversion
(Table 3). Gratifyingly, all the previous halide classes
described in Table 2 performed equally well in the reaction
under these conditions.
Having established a good scope with this one-step
protocol using benzylamine, we investigated other nucleo-
philes (Table 4). Aqueous ammonia, cyclic secondary
amines, and the less nucleophilic aniline all performed well
in the reaction (Table 4, entries 1-4). Using tert-butyl
carbamate and tert-butyl alcohol, the corresponding primary
amide and carboxylic acid were formed, presumably by
thermolytic cleavage of the tert-butyl groups11 (Table 4,
entries 5 and 6). Methanol and water gave the corresponding
carboxylic ester and acid (Table 4, entries 7 and 8). Aryl
and alkyl sulfonamides also performed well in the reaction
(Table 4, entries 9 and 10). This easy variation in the
nucleophile and broad scope represents a significant advan-
tage over previously reported work.
a Mo(CO)6 (1 mmol) and NEt4·Cl (1 mmol) in 1,4-dioxane (0.8 mL)
microwave heated in a sealed vial to 140 °C for 2 min and then allowed to
cool; iodobenzene (1 mmol); nucleophile (2 mmol) added and mixture
microwave heated to 130 °C for 4 h. b Nucleophile (0.2 mL) was used.
c Isolated and purified.
Ren and Yamane10 suggested two possibile pathways: (i)
Formation of acyl metal intermediate (E). This would be
generated by oxidative addition of aryl halide to molyb-
denum complex (C) followed by CO insertion to the
phenyl-molybdenum bond. (ii) Formation of carbamoyl
metal intermediate (G). This would be generated from aryl
metal halide (D) or from carbamoyl intermediate (F) by
oxidative addition of aryl halide. To gain some insight to
the Mo(CO)6-mediated carbamoylation, benzylamine, Mo-
(CO)6, and 1,4-dioxane were heated in a 1:1 ratio in the
microwave at 160 °C for 30 min; formation of Mo(CO)5-
The mechanism for these reactions is unclear at present,
but one can speculate on possible pathways (Scheme 1).12
In their work with amine molybdenum complexes (B),
(11) Choy, J.; Jaime-Figueroa, S.; Lara-Jaime, T. Tetrahedron Lett. 2010,
51, 2244, and references cited within.
(12) For related mechanisms and oxidative addition of aryl halides to
group VI metal(0) complexes, see: (a) Sangu, K.; Watanabe, T.; Takaya,
J.; Iwasawa, N. Synlett 2007, 6, 929. (b) Sangu, K.; Takaya, J.; Iwasawa,
N. Angew. Chem., Int. Ed. 2009, 48, 7090. (c) Pan, Y. H.; Ridge, D. P.
J. Am. Chem. Soc. 1992, 114, 2773. (d) Looman, S. D.; Richmond, T. G.
Inorg. Chim. Acta 1995, 240, 479. (e) McCusker, J. E.; Main, A. D.;
Johnson, K. S.; Grasso, C. A.; McElwee-White, L. J. Org. Chem. 2000,
65, 5216.
1
NH2Bn (B) was confirmed by H NMR comparison with
an authentic sample synthesized from Mo(CO)5Cl·NEt4 and
benzylamine.13 For the in situ Mo(CO)5Cl·NEt4-mediated
4282
Org. Lett., Vol. 12, No. 19, 2010

Scheme 1
.
Speculative Mechanisms for the Mo(CO)6 and the in Situ Mo(CO)5Cl·NEt4-Mediated Carbonylation of Aryl Halides with
Amines (R1 ) Benzyl)
carbonylation we have confirmed formation of Mo(CO)5Cl·
NEt4 from Mo(CO)6, and we know this readily reacts with
amines to give the amine-molybdenum complex. Thus,
we suggest that the Mo(CO)6-mediated carbamoylation and
the in situ Mo(CO)5Cl·NEt4-mediated carbonylation both
proceed through amine-molybdenum complexes (C) via
one of the suggested pathways. More work to clarify
further steps in the mechanism is underway.
in modern drug discovery. Further development of nonsto-
ichiometric and catalytic versions of the reactions are in
progress.
Acknowledgment. We are grateful to Hema Pancholi and
Richard Evans, both of AstraZeneca Charnwood Chemistry
Department, for their expert assistance with MS studies and
microwave equipment, respectively. We also thank Andrew
Paterson of AstraZeneca Charnwood PARD Department for
palladium analyses.
In summary, we have developed a Mo(CO)6-mediated
carbamoylative coupling and an in situ Mo(CO)5Cl·NEt4-
mediated carbonylation with a range of nucleophiles from
Mo(CO)6. These methods allow access to a wide range of
carbonyl compounds in excellent yield without the need for
gaseous CO and palladium catalysts. The methods are ideally
suited for parallel synthesis and automation often required
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra and HRMS analysis
for all compounds. Characterization (1H and 13C NMR data)
for all new compounds. ICP palladium analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Schenk, W. A. J. Organomet. Chem. 1979, 179, 253.
OL1016965
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