Microwave-assisted, Mo(CO)6-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up

Article abstract of DOI:10.1016/j.tetlet.2008.07.053

Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)₆ as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in promoting the conversions in a mere 10-20 min with various (hetero)aryl iodides, bromides and chlorides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed successfully.

Full text of DOI:10.1016/j.tetlet.2008.07.053

Tetrahedron Letters 49 (2008) 5625–5628
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted, Mo(CO)6-mediated, palladium-catalyzed
amino-carbonylation of aryl halides using allylamine:
from exploration to scale-up
Prasad Appukkuttan a, Linda Axelsson a, Erik Van der Eycken b, Mats Larhed a,
*
a Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
b Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)6
as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in
promoting the conversions in a mere 10–20 min with various (hetero)aryl iodides, bromides and chlo-
rides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed
successfully.
Received 26 May 2008
Revised 26 June 2008
Accepted 9 July 2008
Available online 12 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Carbonylation
Microwave
Palladium
Aryl chloride
Scale-up
Transition metal-mediated carbonylation protocols are a rela-
tively under-explored area of research for the functionalization of
aryl halides, in comparison with other transition metal-mediated
protocols such as cross-couplings and Heck and Sonogashira reac-
tions.1–6 The traditional drawbacks of using gaseous reagents and
high-pressure reaction conditions have limited the scope of these
valuable reactions to a considerable extent. However, gas-free car-
O
ArX
ArX, Pd(0)
Mo(CO)6
Ar
H2N
H2N
N
H
Ar
Pd(0)
Carbonylation product
Heck product
Scheme 1. Aminocarbonylation versus Heck reaction.
bonylative protocols7 using solid CO-sources such as Mo(CO)6
8–11
tion19,20 and aminocarbonylation under Pd(0)-catalyzed conditions
(Scheme 1).
have paved swift and straightforward routes to small-scale car-
bonylations under conventional conditions or under high-density
microwave irradiation.
Depending on the competing reactions, the arylpalladium(II)
intermediate can thus lead to an N-allylbenzamide via a 1,1-inser-
tion process with CO, or a styrene derivative as a consequence of a
1,2-insertion-b-elimination sequence. In this contribution, we
disclose the development of a completely chemoselective micro-
wave-enhanced protocol for the in situ aminocarbonylation of
(hetero)aryl halides using allylamine as the nucleophile. The
We have previously explored Mo(CO)6-based carbonylative
transformations for the functionalization of various aryl- and het-
eroaryl halides using a variety of nucleophiles under microwave-
enhanced conditions.12–14 As a part of our research towards the
development of new HIV-protease inhibitors,10,15,16 we were inter-
ested in carrying out aminocarbonylations of various P1 and P3
aryl halide side chains using allylamine as the nucleophile,17 aimed
at the generation of viable handles for macrocyclizations using
Ring-Closing Metathesis (RCM).18 However, we envisaged that
the presence of a terminal double bond together with a free amino
group could lead potentially to competition between Heck reac-
method was applied successfully to
a number of diversely
functionalized aryl iodides, bromides and chlorides. Furthermore,
we report the first successful scale-up of a Mo(CO)6-mediated,
microwave-enhanced aminocarbonylation reaction.
We began our investigations by choosing 2-iodotoluene (1a) as
the model aryl iodide for reactions with allylamine (2), using a
modified version of a microwave protocol reported by Wannberg
and Larhed.21 Due to the high reactivity of aryl iodides in palla-
dium(0)-catalyzed transformations, we explored a completely
phosphine-free strategy. A number of experiments were conducted
* Corresponding author. Tel.: +46 18 471 46 67; fax: +46 18 471 44 74.
E-mail address: Mats.Larhed@orgfarm.uu.se (M. Larhed).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.053

5626
P. Appukkuttan et al. / Tetrahedron Letters 49 (2008) 5625–5628
altering the temperature and irradiation time, using a slight excess
of 2 (1.5 equiv). It quickly became apparent that the aminocarb-
onylations clearly dominated over the competing Heck reactions.
This strong chemoselectivity can be explained in terms of a rapid
CO-insertion followed by a subsequent attack of the nucleophile,
compared to the much slower 1,2-alkene insertion in the Heck
reaction.22 Appropriate conditions were found to be Pd(OAc)2 as
precatalyst and DBU as base in 1,4-dioxane with microwave-heat-
ing at 125 °C for 10 min. The use of an inert atmosphere was found
to be unnecessary. In fact, the applied conditions were not ideal for
Heck reactions, as an experiment run under these conditions, but
without Mo(CO)6, furnished essentially no Heck product. Based
on the success of initial explorations, we decided to investigate
the aminocarbonylation of a variety of aryl iodides 1a–f with allyl-
amine 2 (see Table 1) under microwave conditions.
As can be seen from Table 1, all the reactions proceeded
smoothly under microwave irradiation using a standard single-
mode reactor, providing moderate to good isolated yields (72–
81%) of the corresponding N-allyl benzamides 3.23 The electronic
nature of the aryl ring did not influence the course of the reaction
in any substantial manner, with electron-donating (Table 1, entries
1 and 4) and electron-withdrawing substituents on the aryl ring
(entry 3) providing comparable yields. Heterocyclic iodides 1e, f
were carbonylated smoothly, generating the 2-thienyl- (entry 5)
and 3-furoyl derivatives (entry 6) in good yields. None of the aryl
iodides generated the corresponding Heck reaction or dehalogen-
ation products in more than trace amounts as was indicated by
LC–MS and NMR.
Encouraged by the good results with aryl iodides, we decided to
extend the scope of our investigation by incorporating a diverse
array of (hetero)aryl bromides as the carbonylation substrates.
Based on our previous experience with the aminocarbonylation
of aryl bromides,24 we envisaged the need for a more reactive
catalytic system to conduct the transformation efficiently. Thus,
the pre-ligand [(t-Bu)3PH]BF425,26 in combination with Herrmann’s
palladacycle27 was chosen as the catalytic combination to promote
the reactions reliably.
Carbonylations of selected aryl bromides are summarized in
Table 2. The dibromoaryls 1g–i furnished the corresponding
di-N-allyl benzamides 3g–i in good yields only after 15 min (Table
2, entries 1–3), and the presence of side products arising from
mono-carbonylation or dehalogenation was negligible. Benzo-
phenone 3j was obtained in a disappointing 43% yield. The ester
functionality of 1k remained intact in product 3k.
Heterocyclic bromides 1l–n were found to react promptly, gen-
erating the corresponding furoyl- (3l and 3f, entries 6 and 7) and
thienyl- (3e, entry 8) derivatives in good yields of 66–76%. In all
cases, only >5% of the Heck arylation products were detected.
At this stage, we decided to investigate aryl- and heteroaryl
chlorides as the arylpalladium precursors with 2. From previous
experiences with other nucleophiles, we knew that the aminocarb-
onylation of aryl chlorides would benefit from elevated reaction
temperatures, and thus conditions of 160 °C for 20 min were
employed.28–34
As can be seen from Table 2, good yields of amide products 3
were obtained quickly. Aryl chloride 1o reacted in a straightfor-
Table 1
Aminocarbonylation of aryl iodides 1a–f with allylamine 2
O
H2N
R
R
I
2
N
H
Mo(CO)6, Pd(OAc)2
DBU, dioxane
MW, 125 ºC, 10 min
3a-f
1a-f
No.
1
Ar–I
Product
Yield (%)
76
O
O
I
I
1a
3a
N
H
2
3
1b
1c
3b
3c
73
76
N
H
O
I
N
H
H
N
I
O
O
I
4
1d
3d
81
N
H
78a
MeO
S
MeO
O
O
5
6
1e
1f
3e
3f
76
72
N
H
I
S
I
N
H
O
O
All reactions were performed in a sealed-vial on a 0.4 mmol scale with 1.5 equiv of 2, 1.0 equiv of Mo(CO)6, 3.0 equiv of DBU and 7.0 mol % of Pd(OAc)2 in 3.0 mL of 1,4-
dioxane at 125 °C for 10 min under microwave irradiation. All yields are isolated yields.
a
Reaction was performed at 130 °C on a 2.0 mmol scale.

P. Appukkuttan et al. / Tetrahedron Letters 49 (2008) 5625–5628
5627
Table 2
O
Aminocarbonylation of aryl bromides and chlorides 1 with 2
H2N
I
2
N
H
dimer
Pd
O
Mo(CO)6, Pd(OAc)2
DBU, dioxane
MW, 125 ºC, 10 min
MeO
MeO
O
P
Ac
R
R
o
-tol
X
1d
3d
80% yield
o
-tol
N
H
2, [(t-Bu)3PH]BF4, Mo(CO)6
DBU, dioxane, MW, 140 oC, 15 min
Scheme 2. Aminocarbonylation on a 25 mmol scale.
X = Br
1g-n
X = Cl
1o-q
3g-l
Due to potential problems in handling the CO-gas released dur-
ing the process, no in situ carbonylation reaction has been reported
previously in a large-scale (>20 mL) microwave reactor. The reac-
tion between 1d and 2 was chosen as the model reaction. In order
to validate the microwave methodology step-wise, the reaction
was first scaled-up to a 2.0 mmol scale in 10 mL of 1,4-dioxane
in a 20 mL sealed Pyrex vial at 130 °C for 15 min. The reaction
was found to proceed smoothly, furnishing 3d in a good 78% yield
(Table 1, entry 4). Encouraged by this result, we further increased
the scale of the reaction to 25.0 mmol in 125 mL of 1,4-dioxane,
keeping the reaction stoichiometry intact. The reaction was carried
out for 15 min at 125 °C in the cavity of a Biotage Advancer batch
reactor,38 equipped with a reaction vessel designed to handle 50–
350 mL volumes, a powerful mechanical stirrer, as well as an effi-
cient ‘instant’ adiabatic cooling system. Once again, the reaction
was found to proceed as expected, providing 3d in a good 80% iso-
lated yield (Scheme 2). The maximum observed pressure during
the reaction was 3.0 bar, which was found to decrease to 1.0 bar
as the reaction proceeded, indicating the gradual consumption of
the liberated CO-gas during the amidation step.
No.
1
Ar–Br/Ar–Cl
Product
Yield (%)
OMe
OMe
O
N
H
H
N
1ga
3g
73
O
O
N
1ha
3h
3i
76
81
H
N
2
3
H
O
O
O
N
H
N
H
1ia
O
In conclusion, we have successfully demonstrated a microwave-
enhanced aminocarbonylation of various (hetero)aryl iodides,
bromides and chlorides using allylamine as the nucleophile. The
reactions proceeded with complete selectivity, generating no com-
peting Heck-reaction products. The produced benzamides were
isolated in good yields and purity. Furthermore, a scale-up of a
microwave-enhanced aminocarbonylation reaction was success-
fully performed. Further scope of the protocol as well as its use
in generating valuable allyl handles for macrocyclizations reac-
tions is under current investigation.
N
H
4
5
6
1ja
1ka
1la
3j
43
56
76
O
O
O
N
H
3k
3l
O
O
N
H
Acknowledgement
O
7
8
9
10
11
1ma
1na
1ob
1pa
1qa
3f
66
72
67
69
73
We acknowledge the support from the Swedish Research Coun-
cil, the Knut and Alice Wallenberg’s Foundation and Biotage.
3e
3b
3e
3f
Supplementary data
All reactions were performed in a sealed-vial on a 0.4 mmol scale with 1.5 equiv of
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.053.
2, 1.0 equiv of Mo(CO)6, 3.0 equiv of DBU.
a
2.5 mol % of palladacycle and 7.0 mol % of [(t-Bu)3PH]BF4 in 3.0 mL of 1,4-
dioxane at 140 °C for 15 min.
b
3.5 mol % of palladacycle and 9.0 mol % of [(t-Bu)3PH]BF4 in 3.0 mL of 1,4-
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(6.3 mg, 7.0 mol %) and 1,4-dioxane (3.0 mL). DBU (183 mg, 1.20 mmol,
3.0 equiv) was added and the vial was immediately sealed. The reaction
mixture was then exposed to microwave heating for 10 min at a pre-selected
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through
a
small plug of CeliteÒ and the plug was washed with EtOAc
(5 mL Â 3). The combined fractions were evaporated under reduced pressure
and the crude product was purified by column chromatography (silica gel) to
furnish the corresponding benzamide 3d in 81% yield.