Palladium-Catalyzed Carbamate-Directed Regioselective Halogenation: A Route to Halogenated Anilines

Article abstract of DOI:10.1021/acs.joc.6b00329

This study describes an efficient method for ortho-selective halogenation of N-arylcarbamates under mild conditions for the first time. Although being weakly coordinating, N-arylcarbamates act very well as a removable directing group for activation of C-H bonds. The developed procedure results in extremely valuable halogenated N-arylcarbmates that can further be hydrolyzed to halogenated anilines. The obtained reaction conditions showed broad scope and wide functional group tolerance. All the products were formed in good yields with extremely high selectivity.

Full text of DOI:10.1021/acs.joc.6b00329

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Article
Palladium-catalyzed carbamate-directed regioselective
halogenation: A route to halogenated anilines
Firouz Matloubi Moghaddam, Ghazal Tavakoli, Borna Saeednia, Peter Langer, and Behzad Jafari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00329 • Publication Date (Web): 13 Apr 2016
Downloaded from http://pubs.acs.org on April 14, 2016
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Palladium-catalyzed carbamate-directed regioselective
halogenation: A route to halogenated anilines
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Firouz Matloubi Moghaddam,*a Ghazal Tavakoli,a Borna Saeedniaa, Peter Langerb and
Behzad Jafarib
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aLaboratory of Organic Synthesis and Natural Products, Department of Chemistry,
Sharif University of Technology, Azadi Street, PO Box 111559516, Tehran, Iran.
bUniversität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
E-mail: matloubi@sharif.edu
Abstract: This study describes an efficient method for orthoꢀselective halogenation of Nꢀ
arylcarbamates under mild conditions for the first time. Although being weakly coordinating, Nꢀ
arylcarbamates act very well as a removable directing group for activation of CꢀH bonds. The
developed procedure results in extremely valuable halogenated Nꢀarylcarbmates that can further be
hydrolyzed to halogenated anilines. The obtained reaction conditions showed broad scope and wide
functional group tolerance. All the products were formed in good yields with extremely high
selectivity.
Introduction
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Apart from being abundant in natural products and pharmaceuticals,1,2 aryl halides have
always been extremely important synthetic intermediates for substitution reactions.3 On the
other hand, crossꢀcoupling reactions have become one of the most encountered organic
reactions that necessitate the use of prefunctionalized starting materials such as aryl halides
and pseudoꢀhalides;4ꢀ8 so, introducing halogens specially bromine and iodine, due to their
higher reactivity toward oxidative insertion relative to chlorine, on aromatic structures is
extremely valuable from the synthetic point of view.2, 4ꢀ8 Regarding this fact, finding efficient
methods for the synthesis of these structural motifs is of great importance. Traditional
methods for synthesis of halogenated aromatic compounds include direct electrophilic
halogenations,9 halogenꢀmetal exchange10 and diazotization/ halogenations.11 However, these
methods suffer from serious drawbacks such as harsh reaction conditions, poor
regioselectivity, necessity for use of hazardous chemicals, long reaction times, being limited
to electron rich structures and in some cases low yields.12
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One of the newest methodologies for Cꢀhalogen bond formation is via transition metalꢀ
catalyzed CꢀH activation. However, regioselective functionalization of a CꢀH bond is
possible only through employment of DGs activating a special CꢀH bond by forming
cyclometallates.13ꢀ18 These DGs generally contain electron donating atoms or piꢀdonating
functional groups capable of coordination to the employed transition metal catalyst.19ꢀ31
Transition metalꢀcatalyzed Cꢀhalogen bond formation through activating CꢀH bonds was
reported firstly by Shi et al. that showed the regioselective orthoꢀhalogenations of anilide
derivatives (scheme 1a).32ꢀ35 Then, Sanford introduced Nꢀhalosuccinimides as halogen source
in Pdꢀcatalyzed orthoꢀhalogenation of arenes to improve the former halogenation method
(Scheme 1b).36ꢀ39 However, the number of reports in this context is considerably less than that
of other Cꢀhetero atom bond formations.32ꢀ35 Previous researches have investigated the
catalytic activity of Cu,12,36,37,40 Pd,34,35,44ꢀ51 Rh,52ꢀ54 Ru,55,56 Au57,58 and Co58 in such reactions.
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Different types of halogen sources have been employed in the metalꢀcatalyzed halogenation
reactions such as LiX,36,37 CuX2,34 CaX2,60 DDQ35 and Nꢀhalosuccinimides.12,32,33,61
Generally, these kinds of reactions require the use of an oxidant along with the halogen
source. The dual role of Nꢀhalosuccinimides to act as both oxidant and halogen source
excludes the need for use of an external oxidant; so, in terms of atom economy, this type of
halogen source has a great privilege over the others. However, Cꢀhalogen bond formation has
remained a challenging task, probably due to the fact that formation of carbonꢀhalogen bond
through reductive elimination from the corresponding cyclometallate is disfavored relative to
oxidative insertion.62
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Scheme 1. Comparison of the presented halogenation conditions.
a) Shi et al.
NHAc
NHAc
X
Pd(OAc)2, Cu(OAc)2, CuCl2
DCE, 90 oC, 48 h, under N2
R
R
b) Sanford et al.
DG
DG
X
Pd(OAc)2, NXS
AcOH or MeCN
100 oC, 12 h
c) This work
O
O
HN
OMe
HN
OMe
X
Pd(OAc)2, NXS, PTSA
DCE, 50 oC, 3-4 h
R
R
R = H, 3-Cl, 4-Cl, 4-NO2, 4-OMe, 4-Me, 3-F, 2-Cl, 2-Me
Carbamates are important functional moieties frequently encountered in naturally
occurring compounds, herbicides, pesticides and polyurethanes.63,64 Oꢀarylcarbamates have
shown great capability as removable directing groups (DG).65 Some of the previously
investigated carbamateꢀdirected CꢀH functionalizations include alkenylation,66,67
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arylation,68,69,19 halogenations52,70,71 and oxygenation71 reactions. Although they are
structurally and electronically similar to Oꢀaryl carbamates, after being introduced by Li et
al.65 as an effective and removable DG, Nꢀarylcarbamates have not been investigated as CꢀH
activation DG. Contrary to many of the previously used DGs,28ꢀ30 this is also a removable
functionality that can be used as a versatile key intermediate in organic synthesis.
Furthermore, their ease of preparation, pronounced stability, and low reactivity toward Pd(0)
are among other advantages of these functionalities.73 So, Nꢀarylcarbamateꢀdirected CꢀH
activation reactions not only are suitable for preparation of functionilized derivatives of Nꢀ
protected amines, but also they can be used to access 2ꢀsubstituted anilines. 2ꢀHaloanilines
and orthoꢀhalogenated derivatives of Nꢀarylcarbamtes are found in various natural products
and pharmaceuticals;74,75 moreover, they are key intermediates in the synthesis of diverse
useful heterocyclic compounds such as indoles,76,77 carbazoles,78 phenazines,79 etc.; hence,
mild and efficient methods for their preparation is of great desire.
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To the best of our knowledge, this is the first report of application of Nꢀarylcarbamates as
DG in Cꢀhalogen bond formation. The importance of regioselective transition metalꢀ
catalyzed halogenation reactions in modern synthetic chemistry, along with the salient feature
of Nꢀarylcarbamate DGs tempted us to report a very efficient, general and operationally facile
methodology for regioselective formation of Cꢀhalogen bonds. This report explains orthoꢀ
selective halogenations of different Nꢀarylcarbamates bearing various functional groups on
the aromatic rings to afford the corresponding products in good yields that can be hydrolyzed
to orthoꢀhalogenated anilines.
Results and Discussion
Our exploration began by reacting NBS with methyl Nꢀ(pꢀtolyl)carbamate in the presence
of 5 mol% Pd(OAc)2 as catalyst and acetonitrile as solvent; after being heated at 100 oC for 2
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hours, the desired product, methyl Nꢀ(2ꢀbromoꢀ4ꢀmethylphenyl) carbamate, was formed in
62% yield (Table 1, entry 1). Being delighted by this result, various optimization experiments
were conducted to obtain the optimal reaction conditions using the aboveꢀmentioned reaction
as the model reaction.
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Table 1. Optimization of reaction conditions for C-H halogenation of Methyl N-arylcarbamates.a
O
O
HN
OMe
HN
OMe
Br
NBS, Catalyst, Additive
Solvent, 2 h
Entry
1
X Source
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
Temp. (oC)
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100
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100
100
Solvent
MeCN
MeCN
MeCN
MeCN
DCE
Catalyst (5mol%)
Pd(OAc)2
ꢀ
Additive(eq.)
ꢀ
Yield (%)b
62
2
ꢀ
15
3
Cu(OAc)2
PdCl2
ꢀ
33
4
ꢀ
54
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
Trace
Trace
15
6
1,4ꢀDioxane
PhCN
MeCN
MeCN
MeCN
MeCN
DCE
ꢀ
7
ꢀ
8
PTSA (0.5)
TFA (0.5)
AcOH (0.5)
Zn(OAc)2 (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (1)
PTSA (0.25)
Cu(OAc)2 (0.5)
AgOAc +PTSA
K2S2O8(2)+PTSA
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
78
9
70
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18
19
20c
21d
22e
40
37
93
1,4ꢀDioxane
DCE
59
24
DCE
92
DCE
74
DCE
35
DCE
25
DCE
50
DCE
43
DCE
92
DCE
91
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23f
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NBS
NBS
NBS
NBS
100
80
DCE
DCE
DCE
DCE
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
90
93
91
52
60
r.t.
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aReaction conditions: methyl Nꢀ(pꢀtolyl) carbamate (1 mmol), NBS (X mmol), Additive (X mmol), catalyst (X
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mol%), solvent (2 mL) and Temperature.
b Yield.
c2.5mol% of catalyst.
d10mol% of catalyst.
e1.5equiv. of NBS was used.
f3equiv. of NBS was used.
Firstly, dependence of the result on the presence of transition metal catalyst was checked
(entries 1ꢀ4). It was found that the presence of a palladium source is essential for the progress
of the reaction and copper could not act as an efficient catalyst under these conditions.
Among the palladium sources examined, palladium acetate proved to be the most effective
one (entry 1); so, it was chosen as the optimal catalyst.
Exploring the effect of solvents on halogenation reaction showed that the model reaction
did not proceed in DCE and 1,4ꢀdioxane (entries 5 and 6). Surprised by this result, we first
assumed that the coordinative nature of acetonitrile might be essential for this reaction; so,
benzonitrile was tested as another coordinative solvent; but the reaction also did not afford
the desired product in good yield (entry 7).
Inspired by the work of DeVries and van Leeuwen's,80 the effect of the presence of
different additives was later examined and to this end, pꢀtoluenesulphonic acid (PTSA) was
tested as an additive. Application of 0.5 equivalent of PTSA proved to enhance the yield by a
considerable amount; therefore, a wide variety of acidic additives, both Lewis acid and protic
acids, were tested in acetonitrile as solvent (entries 8 to 11); the best results were obtained
using PTSA as additive in the model reaction. Thereafter, the combination of PTSA and
different solvents was investigated as the reaction medium (entries 12 and 13) and to our
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pleasure, the reaction proceeded with higher yield in DCE compared to entry 1 while an
acidic additive was added; so, DCE was chosen as the optimal solvent in the presence of
PTSA as optimal additive. An experiment was also conducted in the absence of palladium
acetate and using PTSA and DCE as the optimal medium (entry 14); it was demonstrated that
the desired product could not produce in good yield without transition metal catalyst.
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In order to optimize the loading of the acidic additive, the model reaction was treated also
with 1 and 0.25 equivalent of PTSA (entries 15 and 16); no significant change was observed
in the presence of 1 equiv. of additive; however, reaction afforded to lower yield when the
amount of PTSA was reduced to 0.25 equivalent.
On the other hand, the effect of addition of different types of coꢀoxidants was examined
and experiments showed that none of them had any obvious influence on the reaction
progress (entries 17 to 19).
The amount of catalyst required for such transformation was optimized in the next step. It
was shown that reducing the amount of catalyst to 2.5 mol% resulted in a decrease in the
yield while increasing that to 10 mol% had no significant influence on the rate and yield of
the reaction (entries 20ꢀ21).
In addition, the reaction yield did not show any improvement upon increasing the amount
of NBS to 1.5 equivalents. Further increasing the amount of NBS to 3 equiv. also did not
result in the formation of the dihalogenated product indicating the monoselectivity of the
reaction (entries 22ꢀ23).
Finally, conducting the model reaction at room temperature resulted in the formation of
o
the desired product with moderate yield. Increasing the temperature to 60 C caused better
formation of the halogenated product. However, when the temperature was raised to 80 or
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100 C, the formation of the desired product was not affected seriously; so, 60 C was
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selected as the optimal temperature for this reaction (entries 24ꢀ26).
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Having obtained the optimal reaction conditions, the scope of the reaction of different
methyl Nꢀarylcarbamates was explored. The results are listed in Table 2. As can be seen, the
optimal conditions can also be applied to chlorination and iodination as well as bromination
of methyl Nꢀarylcarbamates. Furthermore, the halogenated products were accessible
regardless of the electronic nature of the methyl Nꢀarylcarbamates.
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The effect of the presence of both electronꢀdonating and electronꢀwithdrawing groups on
the aromatic ring was considered. The results proved that the electronic characteristics of
substituents on the aromatic ring have no considerable influence on the reaction yields. Also,
different types of ortho-, meta- and para-substituted methyl Nꢀarylcarbamates were
investigated under optimized reaction conditions. Results showed that paraꢀsubstituted
carbamates afford the corresponding monoꢀhalogenated products with very good
regioselectivity (12, 20, 22 and 29). The reaction was also chemoselective in the case of
methylꢀsubstituted arylcarbamates; as it is demonstrated, NXSs are superior reagents for
halogenations of benzylic positions; however, in this case, methyl Nꢀ(2ꢀhaloꢀ4ꢀ
methylphenyl)carbamate was obtained in a chemospecific manner. The halogenation of more
electronꢀrich derivative, i.e. methyl 4ꢀmethoxyphenylcarbamate also proceeds
regioselectively (13 and 21).
Table 2. Halogenation of methyl N-arylcarbamate derivatives.a
O
O
NH
OR
NH
OR
NXS (1.1eq)
Pd(OAc)2 (5 mol%)
X
PTSA (0.5 eq.), DCE
R'
R'
12-33
1-11
NCS
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O
O
O
O
NH
Cl
OMe
NH
OMe
Cl NH
OMe
NH
OMe
Cl
NH
OMe
Cl
Cl
Cl
Cl
OMe
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13
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16
12
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4h; 84%b,c
3.5h; 80%
5h; 82%
8h; 0%
3.5h; 87%
O
O
O
O
O
NH
OMe
Cl
NH
OMe
F
NH
OMe
NH
OMe
Cl
NH
OMe
Cl
Cl
Cl
Me
Cl
:
:
F
Cl
17
19: 19'; 2.6:1
18: 18'; 3.8:1
8h; 0%
3.5h; 88%
4h; 84%
NBS
O
O
O
O
O
NH
OMe
NH
Cl
OMe
Cl
NH
OMe
NH
OMe
Br
NH
OMe
Br
Br
Br
Br
NO2
OMe
21
24
20
23
2h; 90%
22
2.5 h; 86%
8h; 0%
3h; 88%
4h; 77%
O
O
O
O
O
NH
Br
OMe
NH
OMe
NH
OMe
NH
OMe
NH
OMe
Br
Br
Br
Me
Br
:
:
Cl
F
F
Cl
25
27: 27'; 3.4:1
26: 26'; 4.4: 1
8h; 0%
3h; 84%
2.5h; 90%
O
Br NH
OMe
28
4h; 87%
NIS
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O
O
O
O
O
NH
OMe
NH
OMe
I
NH
OMe
I
NH
OMe
Cl
NH
OMe
F
I
Me
Cl
I
I
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30
3h; 86%
31
3h; 91%
32
8h; 0%
33
8h; 0%
29
3h; 89%
aRection conditions: Nꢀarylcarbamate (1 mmol), NXS (1.1 mmol), PTSA (0.5 mmol), Pd(OAc)2 (5 mol%) in
DCE (2 cc) at 60 oC.
b,c Reaction times and yields, respectively.
in fact, from the two available positions, only the one ortho to the DG is halogenated. Using
methyl N-(2ꢀchlorophenyl)carbamate, application of the optimized reaction conditions failed
to produce the desired product even under much longer reaction times (16, 24 and 33). This
result is in accord with the observation that the dihalogenated products were not also
produced using other mꢀ or pꢀsubstituted Nꢀarylcarbamates. The same results were obtained
using methyl Nꢀ(2ꢀmethylphenyl)carbamate (17, 25 and 32). However, application of 3ꢀ
substituted carbamates could theoretically result in two different products from substitution
on two possible ortho positions. Fortunately, our optimized conditions proceeded with very
good regioselectivity for substitution on the ortho position farther from the subtituent on meta
position that could be attributed to the steric hindrance (18, 19, 26, 27). However, in both
metaꢀsubstituted substrates, using NIS as the halogenating source, only one product is
produced maybe due to more steric demand of iodine compared to bromine and chlorine (30
and 31). Using methyl Nꢀ(1ꢀnaphthyl)carbamate as substrate, chlorination and bromination
reactions only occurred on the 8ꢀposition (14, 28).
In order to investigate the effect of alkoxyl group in carbamates on the reaction, isoꢀ
propylꢀ and tꢀbutyl Nꢀ(4ꢀmethylphenyl)carbamate derivatives were reacted with NBS under
optimized conditions (Scheme 2).
Scheme 2. Effect of alkoxyl group on the halogenation reaction
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O
O
4
5
6
Pd(OAc)2 (5mol%)
NBS (1.1 eq.)
PTSA (0.5 eq.)
NH
O
NH
O
Br
7
8
DCE, 60 oC, 16h
9
34, 65%
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O
O
NH
O
Pd(OAc)2 (5mol%)
NBS (1.1 eq.)
PTSA (0.5 eq.)
NH
O
Br
DCE, 60 oC, 16h
35, 51%
Our investigation revealed that both the reactions resulted in the formation of the
predicted brominated products; however, increasing the size of alkoxyl group increases the
steric hindrance around the ortho positions and thereby, decreases the yield of reaction even
after much longer reaction time.
To indicate the scalability of the procedure, bromination of methyl Nꢀ(4ꢀ
methylphenyl)carbamate was explored under optimized reaction conditions in 10 mmole
scale (Scheme 3). Results shows that the proposed procedure has the potential to be
employed for large scale synthesis of halogenated carbamates.
Scheme 3. Examining scalability of the reaction
O
O
Pd(OAc)2 (5mol%)
NBS (1.1 eq.)
PTSA (0.5 eq.)
NH
O
NH
O
Br
DCE (10 cc), 60 oC, 6 h
6 mmol, 1.00 g
1.12 g, 76%
Also, as it is mentioned above, deprotection of these halogenated carbamates can produce the
corresponding halogenated anilines. To this end, the procedure reported by Coudert et al.81
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was employed to deprotect compound 20 (Scheme 4) resulted in the formation of 2ꢀbromoꢀ4ꢀ
methylaniline (36) in 83% yield.
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9
Scheme 4. Deprotection of compound 20; a route to halogenated anilines.
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O
NH
O
NH2
Br
Br
5 equiv. TBAF
THF, Reflux, 3 h
36, 83%
20
In order to account for the observations, a possible mechanism is proposed (Scheme 5). A
PdII/PdIV catalytic system seems to be responsible for this transformation. The reaction starts
with chelationꢀassisted CꢀH activation step in which the corresponding cyclopalladate A is
formed. This step is followed by oxidative insertion of Nꢀhalosuccinimide to cyclopalladate
A to form intermediate B. Subsequently, reductive elimination of intermediate B affords the
halogenated product and regenerates PdII. PTSA assumed to have a dual role in this
mechanism; first it activates Nꢀhalosuccinimed by protonating one of the two carbonyl groups
rendering it a more efficient source of X+ and second it forms a more electrophilic palladium
catalyst.
According to the proposed mechanism, the unreactivity of the orthoꢀsubstituted alkyl Nꢀ
arylcarbamates could be attributed to the steric hindrance around the orthoꢀCꢀH bond; in fact,
the presence of a substituent on one of the two ortho positions of the carbamate directing
group causes the formation of the expected palladacycle to be more difficult due to the steric
repulsion between alkoxy group of carbamate and the orthoꢀsubstituent.
Scheme 5. Plausible mechanism for ortho-halogenation of alkyl N-arylcarbamates.
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OAc
Pd
O
O
O
HN OMe
N
OMe
5
6
7
H
HOAc
O
ox. add.
A
O
8
9
HN
OMe
PdII
AcOPd
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red. el.
O
O
O
insertion
HN OMe
H
X
Pd
AcO
HN
OMe
O
N
O
O
X
N
PTSA
O
X
N
X
O
B
In Summary, this report introduces a mild and practical method for preparation of orthoꢀ
halogenated Nꢀarylcarbamates through Pdꢀcatalyzed CꢀH bond activation. The optimized
reaction conditions can conduct the halogenation reaction with excellent regioselectvity for
ortho position of DG. Different Nꢀhalosuccinimides including NIS, NBS and NCS serve both
as oxidant and halogen source at the same time excluding the need for an external oxidant.
This report depicts one of the few reports of application of alkyl Nꢀarylcarbamates as
removable DGs paving the way for synthesis of both orthoꢀhalogenated derivatives of alkyl
Nꢀarylcarbamates and anilines. The reaction showed wide functional group tolerances and
resulted in the desired products with very good yields.
The proposed mechanism for this reaction encounters a PdII/PdIV catalytic cycle in which
PTSA is assumed to have a dual role of activating Nꢀhalosuccinimide through protonation
and forming a more electrophilic Pd catalyst.
Experimental section
General information
Unless otherwise stated, all experiments were conducted in ovenꢀdried glassware under air.
All chemicals were purchased from commercial sources and were used without any further
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purification. Palladium acetate was purchased from SigmaꢀAldrich with 98% purity. All H
and 13C NMR spectra were recorded in CDCl3 as solvent at RT on a 500 MHz NMR
spectrometer. All chemical shifts (δ) were reported in ppm relative to TMS. Melting point
data are uncorrected. Highꢀresolution mass spectra (HRMS) were recorded by ESI on an
iFunnel QꢀTOF (timeꢀofꢀflight) mass spectrometer.
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Column chromatographic purification of compounds was performed by using silica gel (mesh
100−200) and a hexane−ethyl acetate mixture as eluent. Thin layer chromatography was done
on 20 cm*20 cm silica gel plates. All the alkyl Nꢀarylcarbamate derivatives and also NIS
were prepared according to the procedures reported in the following.
Procedure A for the synthesis of N-arylcarbamates 1 to 7:
The Nꢀarylcarbamates 1 to 7 were prepared according to the procedure reported by Keillor et
al. with some modifications.74 To a roundꢀbottomed equipped with a magnetic stirring bar
and condenser was added the corresponding benzamide (1 mmol) and NBS (1 mmol, 178
mg) followed by the addition of methanol (7 mL). Then, potassium tꢀbutoxide (1.5 mmol,
o
168 mg) was added to the mixture and stirred at 80 C for ca. 40 min (in the case of 4ꢀ
nitrobenzamide the reaction mixture should be stirred overnight to be completed). The
reaction mixture was further concentrated under reduced pressure after completion. The
residue was diluted with dichloromethane (20 mL) and washed with HCl (20 mL, 15% aq.
solution) followed by NaHCO3 (20 mL, saturated aq. solution). The organic layer was
concentrated under vacuum and purified using gradient elution column chromatography on
silica gel (nꢀHexane: Ethyl Acetate). Using this procedure, the desired Nꢀarylcarbamates were
prepared in 75ꢀ85% yields.
Methyl N-(4-methylphenyl)carbamate (1)
Yield: 151.8 mg (92%).83
Methyl N-(4-methoxyphenyl)carbamate (2)
Yield: 162.9 mg (90%).85
Methyl N-(4-nitrophenyl)carbamate (3)
Yield: 186.2 mg (95%).83
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Methyl N-(4-chlorophenyl)carbamate (4)
Yield: 172.5 mg (93%).83
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8
9
Methyl N-(2-chlorophenyl)carbamate (5)
Yield: 155.8 mg (84%).86
Methyl N-(2-methylphenyl)carbamate (6)
Yield: 141.9 mg (86%).83
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Methyl N-(3-fluorophenyl)carbamate (7)
Yield: 148.7 mg (88%).83
Procedure B for the synthesis of N-arylcarbamates 8-11:
The Nꢀarylcarbamates 8 to 11 were prepared according to the previous reported method.75
Methyl N-(1-naphthyl)carbamate (8)
o
1
Yield: 186.9 mg (93%), light pink powder; Mp. 154ꢀ157 C. H NMR (500 MHz, CDCl3,
ppm): δ 7.69ꢀ7.65 (m, 2H), 7.45 (d, 1H, J = 7.7), 7.33ꢀ7.29 (m, 3H), 7.21 (d, 1H, J = 7.6),
6.84 (brs, 1H), 3.87 (s, 3H); HRMS (ESIꢀTOF) (m/z): calcd for C12H11NO2 [M]+ 201.0790;
found 201.0790.
Methyl N-(3-chlorophenyl)carbamate (9)
Yield: 170.0 mg (90%).83
Iso-propyl N-(4-methylphenyl)carbamate (10)
Yield: 178.5 mg (93%).83
t-butyl N-(4-methylphenyl)carbamate (11)
Yield: 188.4 mg (91%), Cream crystals; Mp. 59ꢀ62 C; 1H NMR (500 MHz, CDCl3, ppm): δ
o
7.36 (d, 2H, J = 8.0), 7.19 (d, 2H, J = 8.0), 6.87 (brs, 1H), 2.35 (s, 3H), 1.46 (s, 9H); HRMS
(ESIꢀTOF) (m/z): calcd for C12H17NO2 [M + H]+ 207.1260; found 207.1260.
Procedure for the preparation of N-iodosuccinimide
Nꢀiodosucinimide was prepared according to the procedure reported by Vankar et al.
with some modifications.84 NaI (10 mmol, 2.25 g) and NCS (10 mmol, 1.34 g) were
individually dissolved in acetone (25 mL). The two solutions were mixed in a 100 mL roundꢀ
bottomed flask equipped with a magnetic stirring bar. After stirring for 15 min, the NaCl
formed during the course of reaction was filtered; the filtrate was concentrated under reduced
pressure. In order to remove iodine from the crude product, the solid was washed several
times with 15 mL portions of diethyl ether until a bright yellowꢀcolored powder was
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obtained. The NIS produced using this procedure was used without further purification.
Bright yellowꢀcolored powder; yield; 2.115 g (94%), M.p. = 196ꢀ198 oC [lit.84 200ꢀ201 oC].
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General procedure for preparation of o-halogenated alkyl N-arylcarabamtes
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Methyl N-arylcarbamate (1 mmol), NXS (1.1 mmol), PTSA.2H2O (0.5 mmol, 90 mg)
and Pd(OAc)2 (0.05 mmol, 10 mg) were added to a sealed tube equipped with a magnetic
stirring bar followed by the addition of DCE (2 mL). The reaction mixture was stirred at 60
oC and the completion of the reaction was monitored using TLC (nꢀHexane: Ethyl Acetate:
Methanol; 20:5:2). After being completed, the reaction mixture was cooled to room
temperature and diluted with dichloromethane (2*10 mL). The organic layer was further
washed with HCl (20 mL, 10% aq. solution) followed by NaHCO3 (20 mL, saturated aq.
solution). Afterwards, the organic layer was separated and dried over anhydrous MgSO4 and
concentrated under reduced pressure using a rotary evaporator. Purification was
accomplished using thin layer chromatography on 20 cm*20 cm silica gel plates (nꢀHexane:
Ethyl Acetate: Methanol; 25:5:2).
Methyl N-(2-chloro-4-methylphenyl)carbamate (12)
o
Yield: 167.5 mg (84%), orange powder; Mp. 60ꢀ62 C. 1H NMR (500 MHz, CDCl3, ppm): δ
8.03 (d, 1H, J = 6.8), 7.19 (brs, 1H), 7.10ꢀ7.08 (m, 2H), 3.83 (s, 3H), 2.23 (s, 3H); 13C {1H}
NMR (125 MHz, CDCl3, ppm): δ 153.9, 139.0, 136.3, 132.6, 128.1, 121.7, 120.1, 53.4, 22.9;
HRMS (ESIꢀTOF) (m/z): calcd for C9H10NO2Cl [M]+ 199.0395; found 199.0392.
Methyl N-(2-chloro-4-methoxyphenyl)carbamate (13)
o
1
Yield: 172.5 mg (80%), white crystals; Mp. 54ꢀ58 C. H NMR (500 MHz, CDCl3, ppm): δ
7.99 (s, 1H), 6.95 (d, 1H, J = 2.6), 6.92 (brs, 1H), 6.86 (dd, 1H, J = 2.5, J = 9.0), 3.82 (s, 3H),
13
3.81 (s, 3H); C{1H} NMR (125 MHz, CDCl3, ppm): δ 158.2, 153.9, 135.5, 134.8, 131.9,
121.5, 116.1, 55.1, 53.1; HRMS (ESIꢀTOF) (m/z): calcd for C9H10NO3Cl [M]+ 215.0349;
found 215.0349.
Methyl N-(8-chloro-1-naphthyl)carbamate (14)
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o
1
Yield: 207.2 mg (88%), light yellow powder; Mp.182ꢀ184 C. H NMR (500 MHz, CDCl3,
ppm): δ 7.90 (d, 1H, J = 8.6), 7.74ꢀ7.64 (m, 2H), 7.46ꢀ7.40 (m, 2H), 7.22 (d, 1H, J = 8.8),
6.87 (brs, 1H), 3.86 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3, ppm): δ 153.9, 139.4, 139.0,
135.6, 132.7, 128.8, 126.9, 124.4, 122.1, 121.9, 112.3, 53.2; HRMS (ESIꢀTOF) (m/z): calcd
for C12H10NO2Cl [M]+ 235.0400; found 235.0394.
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Methyl N-(2,4-dichlorophenyl)carbamate (15)
Yield: 191.5 mg (87%), yellow crystals; Mp. 52ꢀ55 oC. 1H NMR (500 MHz, CDCl3, ppm): δ
8.16 (d, 1H, J = 8.5), 7.40 (d, 1H, J = 2.5), 7.28 (dd, 1H, J = 8.9, J = 2.2), 7.13 (brs, 1H), 3.80
13
(s, 3H); C{1H} NMR (125 MHz, CDCl3, ppm): δ 153.9, 138.1, 135.6, 129.9, 128.6, 123.5,
115.8, 53.2; HRMS (ESIꢀTOF) (m/z): calcd for C8H7NO2Cl2 [M + H]+ 219.9927; found
219.9928.
Methyl N-(2,5-dichlorophenyl)carbamate (18)
o
1
Yield: 185.1 mg (84%), cream solid; Mp. 63ꢀ68 C. H NMR (500 MHz, CDCl3, ppm): δ
8.30 (s, 1 H), 7.30 (d, 1H, J = 3.0), 7.19 (brs, 1H), 7.01 (dd, 1H, J = 2.4, J = 6.1), 3.86 (s,
3H); 13C {1H} NMR (125 MHz, CDCl3, ppm): δ 153.7, 136.0, 134.1, 130.1, 124.0, 120.4,
120.1, 53.2; HRMS (ESIꢀTOF) (m/z): calcd for C8H7NO2Cl2 [M + H]+ 219.9927; found
219.9928.
Methyl N-(2-chloro-5-fluorophenyl)carbamate (19)
Yield: 168.5 mg, (83%), yellow powder; Mp. 91ꢀ93 oC. 1H NMR (500 MHz, CDCl3, ppm): δ
8.06 (d, 1H, J = 9.6), 7.32 (dd, 1H, J = 9.0, J = 6.0), 7.23 (brs, 1H), 6.75 (dd, 1H, J = 8.0, J =
3.0), 3.86 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3, ppm): δ 164.8 (d, J = 246), 153.4, 139.9
(d, J = 9.4), 135.4 (d, J = 3.3), 128.7 (d, J = 23.3), 118.7 (d, J = 9), 116.3 (d, J = 23), 53.2;
HRMS (ESIꢀTOF) (m/z): calcd for C8H7NO2ClF [M]+ 203.0149; found 203.0150.
Methyl N-(2-bromo-4-methylphenyl)carbamate (20)
o
1
Yield: 215 mg (88%), yellow solid; Mp. 121ꢀ124 C. H NMR (500 MHz, CDCl3, ppm): δ
8.01 (d, 1H, J = 7.5), 7.36 (d, 1H, J = 1.2), 7.13 (dd, 1H, J = 8.0, J = 1.2), 7.07 (brs, 1H), 3.84
13
(s, 3H), 2.32 (s, 3H); C {1H} NMR (125 MHz, CDCl3, ppm): δ 153.9, 134.6, 132.9, 130.4,
129.0, 122.9, 122.0, 53.3, 21.2. HRMS (ESIꢀTOF) (m/z): calcd for C9H10BrNO2 [M + H]+
243.9968; found 243.9970.
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Methyl N-(2-bromo-4-methoxyphenyl)carbamate (21)
Yield: 224 mg (86%), light orange powder; Mp. 63ꢀ67 oC. 1H NMR (500 MHz, CDCl3, ppm):
δ 7.92 (brs, 1H), 7.07 (d, 1H, J = 2.8), 6.86 (dd, 1H, J = 9.0, J = 2.8), 3.78 (s, 3H), 3.77 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 154.5, 152.9, 139.6, 138.2, 129.6, 118.0,
114.5, 56.1, 52.9; HRMS (ESIꢀTOF) (m/z): calcd for C9H10NO3Br [M]+ 258.9839; found
258.9834.
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Methyl N-(2-bromo-4-nitrophenyl)carbamate (22)
o
Yield: 212 mg (77%), yellow crystals; Mp.193ꢀ195 C. 1H NMR (500 MHz, CDCl3, ppm): δ
8.49 (d, 1H, J = 2.8), 8.47 (d, 1H, J = 9.4), 8.25 (dd, 1H, J = 9.3, J = 2.5), 7.52 (brs, 1H), 3.91
13
(s, 3H); C{1H} NMR (125 MHz, CDCl3, ppm): δ 154.0, 142.8, 140.3, 134.7, 133.3, 130.4,
125.5, 53.3; HRMS (ESIꢀTOF) (m/z): calcd for C8H7N2O4Br [M]+ 273.9584; found
273.9584.
Methyl N-(2-bromo-4-chlorophenyl)carbamate (23)
o
1
Yield: 238 mg (90%), cream crystals; Mp. 86ꢀ89 C. H NMR (500 MHz, CDCl3, ppm): δ
8.10 (d, 1H, J = 9.0), 7.70 (d, 1H, J = 2.0), 7.46 (dd, 1H, J = 9.0, J = 2.0), 7.14 (brs, 1H), 3.85
13
(s, 3H); C{1H} NMR (125 MHz, CDCl3, ppm): δ 153.9, 135.1, 132.1, 129.0, 128.9, 121.2,
113.0, 53.1; HRMS (ESIꢀTOF) (m/z): calcd for C8H7NO2BrCl [M + H]+ 262.9343; found
262.9340.
Methyl N-(2-bromo-5-chlorophenyl)carbamate (26)
o
1
Yield: 238 mg (90%), yellow powder. Mp. 97ꢀ99 C. H NMR (500 MHz, CDCl3, ppm): δ
8.27 (s, 1H), 7.45 (d, 1H, J = 8.5), 7.18 (brs, 1H), 6.95 (dd, 1H, J = 8.5, J = 1.6), 3.86 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3, ppm): δ 153.8, 137.2, 134.8, 133.3, 124.6, 120.4, 110.4,
53.2; HRMS (ESIꢀTOF) (m/z): calcd for C8H7NO2BrCl [M]+ 262.9343; found 262.9343.
Methyl N-(2-bromo-5-fluorophenyl)carbamate (27)
o
1
Yield: 208 mg (84%), cream powder. Mp. 108ꢀ111 C H NMR (500 MHz, CDCl3, ppm): δ
8.04 (dd, 1H, J = 11.0, J = 2.0), 7.49 (dd, 1H, J = 5.8, J = 3.1), 7.23 (brs, 1H), 6.70 (ddt, 1H,
J = 9.5, J = 3.0, J = 1.1), 3.85 (s, 3H); 13C{1H} NMR (400 MHz, CDCl3, ppm): δ 163.8 (d, J
= 245), 153.9, 138.6 (d, J = 8.1), 131.0 (d, J = 20.7), 118.7 (d, J = 2.6), 112.0 (d, J = 20.5),
108.7 (d, J = 8.4), 53.2; HRMS (ESIꢀTOF) (m/z): calcd for C8H7NO2BrF [M]+ 246.9644;
found 246.9645.
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Methyl N-(8-bromo-1-naphthyl)carbamate (28)
o
Yield: 223 mg (87%), cream powder; Mp. 199ꢀ202 C. 1H NMR (500 MHz, CDCl3, ppm): δ
6
7
8
9
7.81 (d, 1H, J = 8.0), 7.60ꢀ7.56 (m, 2H), 7.40ꢀ7.33 (m, 2H), 7.18 (d, 1H, J = 7.1), 6.88 (brs,
1H), 3.85 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 153.9, 136.1, 133.5, 128.0,
127.3, 124.6, 121.1, 119.2, 118.9, 117.0, 111.7, 53.3; HRMS (ESIꢀTOF) (m/z): calcd for
C12H10NO2Br [M]+ 278.9895; found 278.9894.
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Methyl N-(2-iodo-4-methylphenyl)carbamate (29)
o
1
Yield: 259 mg, (89%), yellow crystals; Mp. 83ꢀ85 C. H NMR (500 MHz, CDCl3, ppm): δ
7.90 (s, 1H), 7.62 (d, 1H, J = 7.0), 7.16 (d, 1H, J = 8.5), 6.90 (brs, 1H), 3.82 (s, 3H), 2.29 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 154.4, 139.5, 136.3, 135.6, 130.4, 120.9,
120.8, 52.9, 20.7; HRMS (ESIꢀTOF) (m/z): calcd for C9H10NO2I [M]+ 290.9751; found
290.9756.
Methyl N-(5-fluoro-2-iodophenyl)carbamate (30)
Yield: 254 mg (86%), orange oil. 1H NMR (500 MHz, CDCl3, ppm): δ 7.98 (dd, 1H, J = 11, J
= 9.0), 7.72 (dd, 1H, J = 9.0, J = 6.0), 7.07 (brs, 1H), 6.62 (ddt, 1H, J = 9.0, J = 3.0, J = 1.0),
3.86 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 163.9 (d, J = 243), 153.9, 139.7 (d, J
= 9.0), 128.9 (d, J = 7.1), 127.5, 112.6 (d, J = 22.4), 107.9 (d, J = 29.0), 53.2; HRMS (ESIꢀ
TOF) (m/z): calcd for C8H7NO2FI [M]+ 294.9500; found 294.9494.
Methyl N-(5-chloro-2-iodophenyl)carbamate (31)
Yield: 283.5 mg (91%), yellow crystals; Mp. 109ꢀ113 oC. 1H NMR (500 MHz, CDCl3, ppm):
δ 8.20 (s, 1H), 7.69 (d, 1H, J = 8.4), 7.02 (brs, 1H), 6.85 (dd, 1H, J = 2.4, J = 6.0), 3.86 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 153.9, 139.8, 136.0, 125.5, 115.6, 107.2,
107.0, 53.2; HRMS (ESIꢀTOF) (m/z): calcd for C8H7NO2ClI [M]+ 310.9204; found
310.9202.
Iso-propyl N-(2-bromo-4-methylphenyl)carbamate (34)
o
Yield: 242 mg (89%), cream powder; Mp. 129ꢀ131 C. 1H NMR (500 MHz, CDCl3, ppm): δ
7.73 (d, 1H, J = 8.0), 7.42ꢀ7.39 (m, 1H), 7.32 (d, 1H, J = 8.0), 6.89 (brs, 1H), 4.28 (hep, 1H, J
= 9.1), 2.33 (s, 3H), 1.44 (d, 6H, J = 9.1); 13C{1H} NMR (125 MHz, CDCl3, ppm): δ 153.9,
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139.9, 136.8, 133.3, 128.3, 127.4, 121.0, 62.8, 27.8, 26.2; HRMS (ESIꢀTOF) (m/z): calcd for
C11H14NO2Br [M]+ 271.0208; found 271.0207.
6
7
8
9
t-Butyl N-(2-bromo-4-methylphenyl)carbamate (35)
Yield: 248.5 mg (87%), white powder; Mp. 122ꢀ125 oC.1H NMR (500 MHz, CDCl3, ppm): δ
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7.68 (s, 1H), 7.42 (d, 1H, J = 8.0), 7.19 (dd, 1H, J = 7.7, J = 2.0), 6.90 (brs, 1H), 2.31 (s, 3H),
13
1.40 (s, 9H); C{1H} NMR (125 MHz, CDCl3, ppm): δ 153.7, 138.8, 134.3, 131.5, 128.6,
125.7, 118.5, 61.8, 28.4, 25.8; HRMS (ESIꢀTOF) (m/z): calcd for C12H16NO2Br [M]+
285.0364; found 285.0366.
2-Bromo-4-methylaniline (36)
Yield: 154.4 mg (83%).87
Procedure for gram-scale reaction
Methyl N-(4ꢀmethyl phenyl)carbamate (6 mmol, 1.00 g), NBS (1.1 mmol, 1.17 g), PTSA
(0.5 mmol, 0.5 g) and Pd(OAc)2 (0.05 mmol, 60 mg) were added to a sealed tube equipped
with a magnetic stirring bar followed by the addition of DCE (10 mL). The reaction mixture
was stirred at 60 oC and the completion of the reaction was monitored using TLC (nꢀHexane:
Ethyl Acetate: Methanol; 20:5:2). After being completed, the reaction mixture was cooled to
room temperature and the reaction mixture was diluted with dichloromethane (3*30 mL). The
organic layer was further washed with HCl (100 mL, 10% aq. solution) followed by NaHCO3
(100 mL, saturated aq. solution). Afterwards, the organic layer was separated and dried over
anhydrous MgSO4 and concentrated under reduced pressure using a rotary evaporator.
Purification was accomplished using column chromatography using silica gel as the
stationary phase (nꢀHexane: Ethyl Acetate; 4:1).
Supporting Information
1H and 13C NMR spectra of the synthesized starting materials and products.
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