Palladium-catalyzed carbonylation of aryl bromides using microwave heating and bis[CP-Fe(II)-(CO)2] as a carbon monoxide source

Article abstract of DOI:10.1016/j.tetlet.2018.02.035

A palladium-catalyzed, microwave assisted carbonylative reaction is described for the synthesis of benzamides from aryl bromides and primary or secondary amines. The developed method uses bis(cyclopentadienyldicarbonyliron) as a solid source of carbon monoxide to produce a diverse set of secondary and tertiary amides in 42–82% yield.

Full text of DOI:10.1016/j.tetlet.2018.02.035

Accepted Manuscript
Palladium-catalyzed carbonylation of aryl bromides using microwave heating
and bis[CP-Fe(II)-(CO)2] as a carbon monoxide source
Tamal Roy, Jonas Rydfjord, Jonas Sävmarker, Patrik Nordeman
PII:
S0040-4039(18)30223-5
https://doi.org/10.1016/j.tetlet.2018.02.035
TETL 49720
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 December 2017
31 January 2018
14 February 2018
Please cite this article as: Roy, T., Rydfjord, J., Sävmarker, J., Nordeman, P., Palladium-catalyzed carbonylation of
aryl bromides using microwave heating and bis[CP-Fe(II)-(CO)2] as a carbon monoxide source, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.035
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
Palladium-catalyzed carbonylation of aryl bromides using microwave heating and
bis[CP-Fe(II)-(CO)2] as a carbon monoxide source
Tamal Roy, Jonas Rydfjord, Jonas Sävmarker and Patrik Nordeman*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, PO Box 574, SE-751 23 Uppsala,
Sweden. *Corresponding Author. E-mail address: patrik.nordeman@akademiska.se (P. Nordeman)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A palladium-catalyzed, microwave assisted carbonylative reaction is described for the synthesis
of benzamides from aryl bromides and primary or secondary amines. The developed method
uses bis(cyclopentadienyldicarbonyliron) as a solid source of carbon monoxide to produce a
diverse set of secondary and tertiary amides in 42-82% yield.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Carbon monoxide
Carbonylation
CORM
Microwaves
Introduction
We envisioned that using microwave (µ-wave) irradiation,
aryl bromides could be used as substrates in the rapid
Carbonylation reactions, including the carbamoylation of aryl
halides using catalytic palladium, has undoubtedly become an
integral part of modern organic synthetic chemistry.1 These three
component reactions provide access to a range of products
including carboxylic acids, esters and amides, ketones and
aldehydes and also serves as intermediates for further
transformations of the carbonylative product.1 In recent years,
safer methods for using carbon monoxide (CO) in the form of
CO surrogates or CO releasing molecules (CORMs) has been
developed.2,3 By utilizing such methodologies, stoichiometric
amounts of the CO source can be accessed in millimolar scale
reactions without the potential harm and danger of using gaseous
CO.
carbonylative synthesis of amides (Scheme 1, B). Herein, we
describe the use of bis[CP-Fe(II)-(CO)2] as the CO source in the
palladium-catalyzed carbonylation of aryl bromides using µ-
wave irradiation.
Results and Discussion
We initiated our survey by evaluating different ligands using a
model reaction with 2-bromotoluene and n-hexylamine as
reagents (Table 1). Initially, Xphos was employed together with
palladium acetate and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)
using µ-wave irradiation in 1,4-dioxane at 130 °C for 20 min.
This reaction resulted in the formation of 2a in 17% yield (Table
1, entry 1).6,7
Oshima and co-workers have previously reported the
carbonylative coupling of aryl iodides into various products using
bis(cyclopentadienyldicarbonyliron) as the source of CO
(Scheme 1, A).4 This solid CO source is comparatively
inexpensive as well as easy to handle.5
Table 1. Impact of the ligand in the Pd-catalyzed
carbonylation.6
Entry
Ligand
Yield 2a (%)a
1
2
3
4
5
6
Xphos
17
Sphos
35
P(t-Bu)3HBF4
dppf
95 (82b)
44
CataXium A
Xantphos
26
Scheme 1. Carbonylation reactions using bis[CP-Fe(II)-
(CO)2] as the CO source. (A) Literature procedure with Ar-I.
(B) Current method with µ-wave irradiation and Ar-Br.
45

aReagents and conditions: o-Tol-Br (0.5 mmol), n-hexylamine (1.0 mmol), 1
(0.5 mmol), Pd(OAc)2 (5 mol%), ligand (monodentate 10 mol%, bidentate 5
mol%), µ-wave irradiation (130 °C, 20 min), 1,4-dioxane (2 mL).
aDetermined by GC-MS using a standard curve of 2a. bIsolated yield.
8
0
Changing the ligand to Sphos slightly increased the yield to
35% (Table 1, entry 2).8 When the ligand was changed to tri-tert-
butylphosphonium tetrafluoroborate an almost quantitative yield
(95% from GC-MS and 82% isolated) was obtained (Table 1,
entry 3). Changing to the bidentate ligands dppf, CataXium A or
Xantphos gave 2a in 44%, 26% and 45% yield, respectively
(Table 1, entries 4-6).
aReagents and conditions: ArBr (0.5 mmol), n-hexylamine (1.0 mmol), 1 (0.5
mmol), Pd(OAc)2 (5 mol%), P(t-Bu)3HBF4 (10 mol-%), µ-wave irradiation
(130 °C, 20 min), 1,4-dioxane (2 mL). bIsolated yield.
Next, the effect of the amine was evaluated (Table 3). Primary
amines generally provided the corresponding product in higher
yield than secondary amines or aniline. 2-Methylpropan-1-amine
provided amide 2i in 60% yield, whereas when benzylamine was
used, a yield of 68% (2j) was obtained (Table 3, entries 1-2). The
secondary amines 4-phenylpiperidine and morpholine gave
amides 2k and 2l in 52% and 65% yield, respectively (Table 3,
entries 3-4). Changing the amine to aniline provided the
corresponding amide 2m in 42% yield (Table 3, entry 5). Lastly,
when diisobutylamine was used no amide 2n could be identified
in the crude mixture (Table 3, entry 6). The flexible and bulky
nature of this amine may cause the reaction to be hampered.
Using the optimized reaction conditions for the palladium-
catalyzed carbonylation we sought to evaluate the scope and
limitations of the developed method. Initially the impact of the
aryl bromide was evaluated (Table 2). In general, the electronic
properties had little effect on the yield of the products. Aryl
bromides containing electron-withdrawing or donating groups
gave the corresponding amides (2a-2f) in 70-82% isolated yield
(Table 2, entries 1-6). Functional groups such as methoxy (2b
and 2e) or cyano (2d) did not significantly change the yield. One
exception was the 2-phenyl substituted product 2f (Table 2, entry
7). In this case the steric bulk of the phenyl group in close
vicinity to the bromide most likely causes the decreased yield
(52%). When 1-bromo-4-nitrobenzene was used no amide 2h
was formed (Table 2, entry 8). The iron-containing 1 may cause a
reduction of the nitro functional group to an amine which could
compete with n-hexylamine in the carbonylative reaction.
Table 3. Influence of the amine in the carbonylative reaction.
Entry
1
Producta
Yield (%)b
60
Table 2. Influence of the aryl bromide in the µ-wave assisted
carbonylative reaction.
2
3
68
52
Entry
1
Producta
Yield (%)b
82
2
3
74
71
4
5
65
42
4
72
6
0
aReagents and conditions: p-Tol-Br (0.5 mmol), amine (1.0 mmol), 1 (0.5
mmol), Pd(OAc)2 (5 mol%), P(t-Bu)3HBF4 (10 mol%), µ-wave irradiation
(130 °C, 20 min), 1,4-dioxane (2 mL). bIsolated yield.
5
6
7
74
70
52
Conclusion
In conclusion a palladium-catalyzed method was developed
for the carbonylation of aryl bromides into amides using µ-wave
irradiation at 130 °C for 30 min. After optimization of the
reaction condition it was shown that tri-tert-butylphosphonium
tetrafluoroborate (P(t-Bu)3HBF4) was a superior ligand that
provided the desired products in up to 82% isolated yield.

References and notes
1. Representative carbonylative reviews: (a) Brennfuhrer A,
Neumann H, Beller M. Angew Chem Int Ed. 2009;48:4114-4133. (b)
Wu XF, Neumann H, Beller M. Chem Soc Rev. 2011;40:4886-5009.
(c) Gautam P, Bhanage BM. Catal Sci Technol. 2015;5:4663-4702.
(d) Liu Q, Zhang H, Lei A. Angew Chem Int Ed. 2011;50:10788-
10799.
2. For selected literature on CORMs, see: (a) Friis SD, Lindhardt
AT, Skrydstrup T. Acc Chem Res. 2016;49:594-605. (b) Odell LR,
Russo F, Larhed M. Synlett 2012;5:685-698.
3. For selected literature on CO surrogates see: (a) Cao J, Zheng Z,
Xu Z, Xu LW. Coordin Chem Rev. 2017;336:43-53 (b) Ueda T,
Konishi H, Manabe K. Org Lett. 2012;14:5370-5373. (c) Wu FP,
Peng JB, Qi X,Wu XF. J Org Chem. 2017;82;9710 (d) Fu-Wu P,
Peng JB, Meng LS, Qi X., Wu XF. ChemCatChem. 2017;9:3121 (e)
Jiang LB, Qi X, Wu XF, Tetrahedron Lett. 2016;57:3368-3370.
4. Nakaya R, Yorimitsu H, Oshima K. Chem Lett. 2011;40:904-906.
5. Compared to other CORMS such as Mo(CO)6. For 1: CAS:
12154-95-9. Saftey classification: GHS07, exlamation mark. Signal
word: warning. Hazard statements: H302 + H332. Use dustmask,
eyeshields and gloves.
6. Yield determined by GC-MS using a calibration curve of 2a.
7. General procedure for the µ-wave assisted carbonylative reaction:
In a 5 mL microwave vial, palladium acetate (0.025 mmol) and tri-
tert-butylphosphonium tetrafluoroborate (0.05 mmol) were taken
together in 1,4-dioxane (2 mL) and the resulting mixture was stirred
for 10 min at room temperature. To this solution, aryl bromide (0.5
mmol), amine (1 mmol), bis[CP-Fe(II)-(CO)2] (0.5 mmol) and DBU
(1 mmol) were added. The reaction vial was subsequently sealed and
heated under µ-wave irradiation at 130 °C for 20 min. After cooling
to room temperature, the reaction mixture was purified using silica
gel column chromatography (10-50% ethyl acetate in isohexane) to
obtain the amide products.
8. Surry DS, Buchwald SL. Angew Chem Int Ed. 2008;47:6338-
6361.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at XYZ.




A palladium-catalyzed carbonylative reaction to
yield benzamides is described.
Bis(cyclopentadienyldicarbonyliron) is used as
solid source of CO.
The reaction is enabled by microwave heating
at 130 °C for 20 min.

Graphical Abstract
To create your abstract, type over the instructions in the template box
below.
Palladium-catalyzed carbonylation of aryl
bromides using microwave heating and
bis[CP-Fe(II)-(CO)2] as a carbon monoxide
source
Leave this area blank for abstract info.
Tamal Roy, Jonas Rydfjord, Jonas Sävmarker and Patrik Nordeman*
Fonts or abstract dimensions should not be changed or altered.