Synthesis of acyl carbamates via four component Pd-catalyzed carbonylative coupling of aryl halides, potassium cyanate, and alcohols

Article abstract of DOI:10.1021/acs.orglett.5b00221

A simple and mild method is demonstrated for assembling acyl carbamates through a base-free four-component Pd-catalyzed carbonylation of aryl halides in the presence of potassium cyanate and alcohols in a two-chamber system. This approach produces a wide range of aryl acyl carbamates in good to excellent yields from the corresponding aryl bromides or iodides with near-stoichiometric carbon monoxide. In addition, the method can be extended to the synthesis of primary amides thereby expanding the usefulness of cyanate as an ammonia equivalent.

Full text of DOI:10.1021/acs.orglett.5b00221

Letter
pubs.acs.org/OrgLett
Synthesis of Acyl Carbamates via Four Component Pd-Catalyzed
Carbonylative Coupling of Aryl Halides, Potassium Cyanate, and
Alcohols
Hongfei Yin,† Angelina M. de Almeida,†,§ Mauro V. de Almeida,§ Anders T. Lindhardt,*,‡
and Troels Skrydstrup*,†
†Center for Insoluble Protein Structures (inSPIN), Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry,
Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark
‡Interdisciplinary Nanoscience Center (iNANO), Department of Engineering, Aarhus University, Finlandsgade 22, 8200 Aarhus N,
Denmark
§Department of Chemistry, Federal University of Juiz de Fora, Campus Martelos, Juiz de Fora, MG 36036-330, Brazil
S
* Supporting Information
ABSTRACT: A simple and mild method is demonstrated for
assembling acyl carbamates through a base-free four-
component Pd-catalyzed carbonylation of aryl halides in the
presence of potassium cyanate and alcohols in a two-chamber
system. This approach produces a wide range of aryl acyl
carbamates in good to excellent yields from the corresponding
aryl bromides or iodides with near-stoichiometric carbon
monoxide. In addition, the method can be extended to the
synthesis of primary amides thereby expanding the usefulness of cyanate as an ammonia equivalent.
N-Acyl carbamates represent a widely common functional
group found in bioactive compounds such as antimalassezia
agents,1a antibiotics,1b O-acyl-transferase inhibitors,1c pro-
drugs,1d and insecticides.1e Furthermore, acylated carbamates
are used as linkers for phototriggers due to their unique
cleavage properties upon photolysis, or even as directing groups
in nucleoside synthesis.2,3
letter, we report on the identification of such conditions for the
coupling of aryl and heteroaryl bromides in the presence of
KOCN and an alcohol. Furthermore, by introduction of water
as the nucleophile, an alternative route to primary amides was
secured.
For our optimization studies, 4-bromoanisole was chosen.
CO (1.1−1.5 equiv) was delivered using the previously
described COware/COgen setup.16 Isopropyl alcohol was
used as both the solvent and nucleophile, and the reactions
were run at 80 °C for 18 h. Applying Pd(cod)Cl2 in
combination with BINAP as the ligand, 22% conversion into
isopropyl (4-methoxybenzoyl)carbamate (1) was detected by
1H NMR analysis of the crude reaction mixture (Table 1, entry
1). After a short ligand screening, Xantphos proved efficient
affording 1 in an 86% isolated yield (Table 1, entries 2−4).
Other Pd-sources were tested for their activity without
improving the isolated yield (Table 1, entries 5−7). Lowering
the reaction temperature to 70 °C provided 1 in a near-
quantitative yield (Table 1, entry 8). Further reduction of the
reaction temperature led to incomplete conversion, and the use
of KOCN proved important (Table 1, entries 9 and 10). The
reaction was complete in 8 h, whereas shorter reaction times
led to incomplete transformation (Table 1, entries 11 and 12).
While the amount of CO required for the reaction could be
lowered to 1.1 equiv, the initial 5 mol % of both Xantphos and
Pd(cod)Cl2 was necessary (Table 1, entries 13−15). Finally,
Traditionally, N-acyl carbamates are obtained through the
reaction of acyl halides with carbamates or from the treatment
of amides with chloroformates.4 These structures have also
been obtained through the ozonolysis of substituted phenyl-
oxazoles, oxidation of alkylated carbamates, and others.5−7
Alternatively, the condensation of acyl isocyanates with alcohols
has been shown to provide the desired N-acyl carbamates.8
Despite these different approaches, all of them lack a broad
functional group compatibility or require the synthesis of labile
compounds, such as the acyl chlorides or acyl isocyanates.9−11
With our interest in Pd-catalyzed carbonylation reac-
tions,12,13 and recent reports by the laboratories of Buchwald,
Baghersad, and Ma on the Pd- and Cu-catalyzed couplings of
aryl halides with sodium or potassium cyanates (NaOCN or
KOCN, respectively), we examined an alternative approach for
the formation of acyl isocyanates.14,15 As the moisture sensitive
nature of acyl isocyanates limits their purification, possibly their
in situ formation by the three-component coupling of aryl
halides, CO, and a suitable metal cyanate would be a unique
approach to these reactive intermediates. Finally, in the
presence of alcohols, the acyl isocyanates would generate the
desired N-acyl carbamates in a single reaction setup. In this
Received: January 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00221
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Organic Letters
Letter
Table 1. Optimization Studies for the Synthesis of N-Acyl
Carbamate 1
Scheme 1. Scope of the Pd-Catalyzed Synthesis of Acyl
a
a
,b
Carbamates
b
entry
catalyst (mol %)
ligand (mol %)
conversion (%)
1
2
3
4
5
6
7
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
[Pd(cinnamyl)Cl]2 (2.5)
Pd(OAc)2 (5.0)
Pd(dba)2 (5.0)
BINAP (5.0)
PPh3 (10.0)
22
0
PPF-tBu (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (2.5)
Xantphos (1.0)
−
>95 (43)
>95 (86)
>95 (83)
>95 (80)
50
c
8
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (5.0)
Pd(cod)Cl2 (2.5)
Pd(cod)Cl2 (1.0)
Precatalyst (2.0)
>95 (99)
20
d
9
e
10
56
f
11
>95 (96)
60
g
12
fh
13 ,
>95 (90)
>95 (72)
70
fh
14 ,
fh
15 ,
d
16
>95 (87)
a
Chamber A: COgen (0.75 mmol), HBF4(tBu)3P (1.0 mol %),
Pd(cod)Cl2 (1.0 mol %), Cy2NMe (1.5 mmol) in dioxane (3.0 mL).
Chamber B: 4-bromoanisole (0.50 mmol), KOCN (0.75 mmol), Pd
source (x mol %), ligand (y mol %) in iPrOH (2.0 mL) at 80 °C for 18
a
Chamber A: COgen (0.55 mmol), HBF4(tBu)3P (1.0 mol %),
Pd(cod)Cl2 (1.0 mol %), Cy2NMe (1.1 mmol) in dioxane (3.0 mL).
Chamber B: aryl bromide (0.50 mmol), KOCN (0.75 mmol),
Pd(cod)Cl2 (5.0 mol %), Xantphos (5.0 mol %) in iPrOH (2.0 mL)
b
h. Determined by 1H NMR, isolated yields shown in brackets.
c
d
e
Reaction performed at 70 °C. Reaction performed at 50 °C. 0.75
f
g
h
b
c
mmol of NaOCN. Reaction time 8 h. Reaction time 5 h. 1.1 equiv
of COgen.
at 70 °C. Isolated yields. Catalyst 1a (2.0 mol %) was used.
the Xantphos-precatalyst developed by Buchwald et al. proved
highly reactive, even at 50 °C affording a good 87% isolated
yield of 1 (Table 1, entry 16).17
ing of the Pd(cod)Cl2/Xantphos combination, CO (1.5 equiv),
and the alcohol (2 equiv) in dioxane at 70 °C for 24 h proved
effective (Scheme 2; see Supporting Information for
optimization). Pentanol afforded 24 in a 91% isolated yield.
Other aliphatic alcohols carrying terminal functionalities such as
an alkene, chloride, trifluoromethyl group, O-methyl glycol, or a
tetrahydrofuran moiety all proved reactive with isolated yields
ranging from 62% to 92% (compounds 25−29). Cyclopentanol
afforded the desired N-acyl carbamate 30 in an excellent 97%
yield. 4-Methoxybenzyl alcohol provided 31 in an 84% isolated
yield.
Applying 2-iodophenol and 4-amino-3-iodobenzonitrile as
the substrates yielded the heterocyclic structures 32 and 33 in
84% and 86% isolated yields, respectively, by intramolecular
attack of the phenol or amine on the acyl isocyanate
intermediates. Finally, with cholesterol, 34 was isolated in a
good 75% yield. Substituting the alcohol for other nucleophiles,
such as thiols or amines, provided either no conversion or the
direct aminocarbonylated product, respectively.
As seen in Scheme 1, compound 22, representing a Boc-
protected amide, was obtained in high yield. Deprotection
would lead to the primary amide, and two sets of acid
promoted conditions for its deprotection were tested, namely,
HCl in dioxane and TFA in CH2Cl2 (Scheme 3).18 The latter
provided primary amide 35 in a quantitative yield. Next, by the
direct treatment of the crude carbonylation reaction mixture
with TFA, 35 could be prepared in a one-pot fashion in an
excellent 97% yield. By switching to iodoanisole as the
electrophile, this same reaction sequence was repeated on a
With the identified optimal reaction conditions in hand,
several substituted aromatic and heteroaromatic bromides were
tested, the results of which are depicted in Scheme 1. Initially,
4-substituted aryl bromides were tested; substitutions including
fluorine, Boc-protected anilines, nitriles, and others, and all
products 2−9 were isolated in yields ranging from 75−99%.
3-Trifluoromethylphenyl bromide along with the xylyl- and
the di-O-methyl catechol bromide afforded the desired N-
acylated carbamates in high yields (compounds 10−12, 89%,
82%, and 95%, respectively). Substituents placed ortho to the
bromide, as with 2-bromoanisole, led to a reduction in isolated
yield (13). Next, 1-bromo-, 2-bromo-, and 2-bromo-6-
methoxynaphthalenes were tested with isolated yields ranging
from 89% to 99% (compounds 14−16). Heteroaromatic
bromides such as thiophene, pyridines, and quinolines, all but
one, provided the desired products in almost identical 90%
isolated yields (compounds 17−21). Only 2-bromopyridine
provided a somewhat lower yield of 51% of 19. Finally, EtOH
and t-BuOH were tested as the solvent and nucleophile. The
more bulky tert-butanol provided an almost quantitative yield of
22 whereas ethanol gave a 57% yield of 23. The lower yield of
23 was related to the competing formation of the
corresponding ethyl ester.
Next, the possibility of applying other alcohols as
nucleophiles, though only in stoichiometric amounts, was
examined. Applying the near-identical catalytic system consist-
B
DOI: 10.1021/acs.orglett.5b00221
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the Pd-Catalyzed Synthesis of Acyl
a
,b
Carbamates with Different Alcohols in Dioxane
Figure 1. Proposed catalytic cycle.
been shown to reluctantly undergo reductive elimination.14b
Additionally, complex D carries two electron-withdrawing
groups, thereby retarding the reductive elimination step even
further.21 Addition of an alcohol to the cyanate ligand forms the
carbamate ligated complex E, thereby setting the stage for an
efficient reductive elimination of ligands of opposed electronic
nature.
In conclusion, a four-component, base-free, Pd-catalyzed
carbonylative coupling of aromatic and heteroaromatic
bromides with potassium cyanate in the presence of alcohols
has been developed. Several alcohols proved reactive as
nucleophiles, and further optimization eliminated their role as
solvent. This mild and practical approach to acylated
carbamates was extended to include the direct formation of
primary amides, and isotope labeling thereof, in a one-pot
setup.
a
Chamber A: COgen (0.75 mmol), HBF4(tBu)3P (1 mol %),
Pd(cod)Cl2 (1 mol %), Cy2NMe (1.5 mmol) in dioxane (1.0 mL).
Chamber B: aryl bromides (0.50 mmol), KOCN (0.75 mmol),
Pd(cod)Cl2 (5.0 mol %), Xantphos (5.0 mol %), alcohol (1 mmol) in
dioxane (1 mL) at 70 °C. bIsolated yields. Aryl iodides used as
coupling partners. Reaction time 48 h.
c
d
a
,b
Scheme 3. Primary Amide Synthesis
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lindhardt@eng.au.dk.
a
Isolated yields. bSee Supporting Information for reaction details.
*E-mail: ts@chem.au.dk.
cReaction run at rt. Reaction run at 70 °C.
d
Notes
The authors declare no competing financial interest.
0.5 and 2.5 mmol scale without a decrease in yield of the
desired primary amide 36.
ACKNOWLEDGMENTS
■
Applying 13CO resulted in the isolation of the 13C-isotope-
labeled primary amide 37 in a 94% yield. Finally, it was
envisioned that the implementation of water as the nucleophile,
instead of t-BuOH, could provide the primary amide directly,
by decarboxylation of the intermediately formed acylated
carbamate. Indeed this proved possible and both 4-iodo- and
4-bromoanisole were transformed into 36, however, in a
slightly lower isolated yield of 72% and 55%, respectively.19
A mechanistic suggestion for the carbonylative trans-
formation is depicted in Figure 1. Classical steps of oxidative
addition (A to B), CO-insertion (B to C), and ligand exchange
with KOCN forms complex D. Omitting the alcohol did not
provide any aroyl cyanate, indicating that complex D does not
undergo reductive elimination.20 ArPd−NCO complexes have
We are appreciative of generous financial support of this work
from the Danish National Research Foundation (Grant No.
DNRF59), the Villum Foundation, the Carlsberg Foundation,
and the Lundbeck Foundation. Furthermore, we thank the
Chinese Scholarship Council for a grant to H.Y. and the
́
Coordenaca̧ o de Aperfeico̧ amento de Pessoal de Nivel Superior
̃
(CAPES) for a grant to A.M.d.A. (No. BEX 6280/13-7) and
FAPEMIG.
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D
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