Tert-Butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as a green and chemoselective N-tert-butoxycarbonylation reagent

Article abstract of DOI:10.1039/c9nj00885c

The use of tert-butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as a chemoselective tert-butoxycarbonylation reagent for aromatic and aliphatic amines has been demonstrated. To gain insight into this reaction, in situ React IR technology was used to confirm the effectivity and chemoselectivity of this novel Boc reagent. The reaction was carried out chemoselectively in high yield under mild, environment-friendly conditions and was completed quickly within 1 hour. Simultaneously, the Boc carrier was easily recyclable, and has great application prospects for industrial production.

Full text of DOI:10.1039/c9nj00885c

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The role of atropisomers on the photo-reactivity and fatigue of
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tert-Butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as a green
and chemoselective N-tert-butoxycarbonylation reagent
Fangyu Du 1, Qifan Zhou 1, Yang Fu, Hanqi Zhao, Yuanguang Chen, Guoliang Chen †
Received 00th January
20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The use of tert-butyl(3-cyano-4,6-dimethylpyridin-2-yl)carbonate as chemoselective tert-butoxycarbonylation reagent for
aromatic and aliphatic amines has been demonstrated. To get insight into this reaction, in situ React IR technology was
performed to confirm the affectivity and chemoselectivity of this novel Boc reagent. The reaction carried chemoselectively
out in high yield under mild, environment-friendly conditions and was completed quickly within 1 hour. Simultaneously, the
Boc carrier was easily recyclable which has great application prospects for industrial production.
suitable for industrial application, especially from the
15
Introduction
perspective of green chemistry
. However, the most
unfavorable shortcoming of (Boc)2O is the lack of selectivity for
amino and phenolic hydroxyl groups. In 2001, Ouchi et al.
disclosed that aromatic and aliphatic amine hydrochlorides and
phenols were tert-butoxycarbonylation using 1-tert-butoxy-2-
tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) as reagent
in the absence of a base 16. However, lower atom economy is
the main disadvantage of this method as waste of the
isoquinoline, which is inconvenient to recycle, leading to the
solvent waste and pollution, Simultaneously, the reaction was
carried out in dichloroethane and benzene, which were
The (Boc)2O, along with benzyl chloroformate (Cbz-Cl) and 9-
fluorenylmethyl chloroformate (Fmoc-Cl), etc. are widespread
reagents in organic synthesis and play significant roles in
pharmaceutical and chemical industries 1. They are widely used
as N-protecting reagents in the syntheses of peptides, amino
acids and other natural products because of different stability
and availability 2.
Among various amine protecting groups, the tert-
butoxycarbonyl (Boc) group has been employed extensively to
decrease the nucleophilicity of the amino group, such as in both
organic and peptide synthesis owing to the exceptional stability
toward catalytic hydrogenation and resistance toward basic
conditions and other nucleophilic reagents 3-8. Removal of the
Boc protecting group is easily performed by acid-catalyzed
hydrolysis. Various reagents and methodologies developed for
the preparation of N-tert-butyl carbamates using di-tert-butyl
dicarbonate (Boc)2O have been carried out either in the
undesirable solvents 17
.
The goal of this study was to create a general atom
economical method for the synthesis and selective protection
of amines. Herein, we disclosed the use of tert-butyl(3-cyano-
4,6-dimethylpyridin-2-yl)carbonate (BCMP) as a novel tert-
butoxycarbonylation reagent for amines. By employing BCMP
with different amines with hydroxyl moiety under mild
temperature (78 °C), the desired N-Boc amines were obtained
in high yields, especially the Boc carrier (3-cyano-4,6-dimethyl-
presence of a base (DMAP, NaHMDS, K2CO3, NaOH, Et3N) or
9-11
more recently acid catalysts and miscellaneous reagents
.
2-hydroxypyridine, CDP,
1) was insoluble in most solvents,
However, these methodologies have various drawbacks such as
long reaction time, the use of many additives, the preparation
of complex catalyst and lack of selectivity for amino and
hydroxyl groups. Furthermore, some undesirable byproducts,
for example, isocyanate, urea, and N,N-di-Boc derivatives, were
simultaneously formed under the base catalyzed condition
leading to lower reaction efficiency 12-14. In addition, those
protocols, featured by the high toxicity, unpleasant smell, non-
recoverable and requirement of excess amount catalyst, aren’t
which lead to safer processes and more easily available reactive
reagents. Importantly, this reagent is general with respect to
the amines, including the aromatic primary amines, aliphatic
primary and secondary amines. This generality and
chemoselectivity of the reagent allow preparation of many N-
Boc amino acid esters and peptide. In considering the effect of
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of
Education, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenhe
District, Shenyang 110016, P. R. of China
†Corresponding author: spucgl@163.com
1 Authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Fig. 1 Novel tert-butoxycarbonylation reagents and CDP.
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pyridine ring, cyano and methyl groups, we were drawn to use
the tert-butyl pyridin-2-yl carbonate (BPC-1) and tert-butyl
phenyl carbonate (BPC-2) as compared Boc reagents (Fig. 1 and
Table 1), which displayed weaker acylation reactivity and took
longer time to give target compound than BCMP.
View Article Online
DOI: 10.1039/C9NJ00885C
Table 1. Optimization of reaction conditions a
8
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Results and Discussion
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Boc
reagent
BCMP
BCMP
BCMP
BCMP
BCMP
BCMP
BCMP
BPC-1
BPC-2
Temp
Time
(h)
24
24
10
2
2
4
2
10
10
Yield
(%) b
--c
Identification of Reaction Conditions
Entry
Solvent
(oC)
The chemoselectivity of tert-butoxycarbonylation for amino
and hydroxyl groups on an aryl ring was investigated using 4-
aminophenol as a model substrate (Table 1). Preliminary
experiments were carried out on 4-aminophenol with BCMP in
1
2
3
4
5
6
7 e
8
toluene
THF
acetonitrile
ethanol
methanol
H2O
ethanol
ethanol
ethanol
reflux
reflux
reflux
reflux
reflux
50
reflux
reflux
reflux
--c
60 d
97
97
90
96
54 d
35 d
toluene (entry
hydroxyphenyl)carbamate wasn’t observed. Attempts to
employ THF as solvent led to the similar result (entry ).
1
). The desired product tert-butyl (4-
2
However, a poorly soluble byproduct was obtained in the two
entries. It was proved that the byproduct was Boc carrier of 4,6-
dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1, Fig. 1) by
heating only BCMP in corresponding reaction conditions. The N-
Boc product in 60% yield, along with unreacted starting material
9
a Unless otherwise noted, 1 equiv of BCMP was used. b Isolated yield. c Almost
no reactions were observed by TLC. Isolated yield, along with unreacted
starting material. e Conditions: 2 equiv of BCMP.
d
(entry 3) was obtained by replacing THF with acetonitrile. It was
shown that the solvent played an important role in the reaction
according to the results of entries 1-3. Therefore, attempts to
optimize the reaction through modification of the solvent
proved successful. With the use of more environmentally
friendly ethanol and methanol as solvents respectively, a target
hydroxyphenyl)carbamate 3a was isolated in 97% yield. The
ability of 4-aminophenol to participate in the reaction opens the
possibility for tert-butoxycarbonylation.
Identification of Conversion by React IR
In situ React IR technology was employed to monitor the
conversion of 4-aminophenol to the corresponding tert-butyl(4-
hydroxyphenyl)carbamate (3a). As seen in Fig. 2 (A, 3D surface
and B, 2D trends), less than 5 min after addition of BCMP to the
4-aminophenol in methanol start heating, a new, sharp peak
appears at 1723 cm-1. The intensity of this peak gradually
increased as the reaction temperature was raised to reflux.
Importantly, the disappearance of the 1770 and 1667 cm-1 band
were marked by the appearance of three bands at 1723, 1622
and 1611 cm-1 corresponding to tert-butyl (4-
compound was obtained in the yield of 97% (entry
4, 5),
suggesting that the O−H bond of solvent might be integral to its
success. We postulated that hydrogen bond between ethanol
and the carbonyl oxygen atoms of BCMP causes “electrophilic
activation” making the carbonyl group more susceptible to
nucleophilic attack since polar protic solvents could effectively
selectively catalyze the tert-butoxycarbonylation of aromatic
amines. Surprisingly, water, a strong polar solvent, was also
favored (entry 6). When the amount of BCMP was increased to
2 equiv, the desired compound 3a was obtained in 96% yield
and the phenolic hydroxyl couldn’t be tert-butoxycarbonylated
hydroxyphenyl)carbamate (Fig. 2, A). We believed that the new
IR absorption at 1723 cm-1 was attributable to the existence of
carbamate carbonyl 3a. The appearance of peaks at 1622 cm-1
1611 cm-1 were responsible for amide N-H and benzene ring C-
C, respectively. IR data of similar N-Boc compounds revealed
that a stretch of 1723 cm-1 was highly characteristic of this type
(entry
7). Given the propensity of poor water solubility of
compound, the tert-butoxycarbonylation was carried out in
ethanol at reflux temperature. Certainly, for water-soluble
amino acids, we preferred water as the solvent. Under these
optimized
conditions,
the
desired
tert-butyl(4-
Fig.2 3D surface and 2D trends of ReactIR experiment.
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of carbamate carbonyl system. The conversion of BCMP before the case. BCMP had high chemoselectively in aromatic amine to
reflux reached 50% after only 15 min, and 100% after 30 min afford moderate to high yield.
View Article Online
DOI: 10.1039/C9NJ00885C
(
Fig. 2
aminophenol
hydroxyphenyl)carbamate underwent quickly nucleophilic 18% yield respectively. When the aromatic amine substituted
,
B
). Thus, it was concluded that the conversion of 4-
The aromatic amine substituted with electron withdrawing
to the corresponding tert-butyl(4- group led to the lower yields, for example, 3l and 3o in 36% and
substitution to afford target compound.
tert-Butoxycarbonylation of Amines by BCMP
with a stronger electron withdrawing group such as a nitro
group in para-position 2v the tert-butoxycarbonylation
,
couldn’t occur. When the strong electron-withdrawing nitro
group was in the meta-position of the amino group, producing
a weaker electronic-withdrawing effect and a small amount of
product could be obtained with 18% yield, such as 3o. To our
delight, ester compounds with weaker electron-withdrawing
effect delivered the Boc product in moderate yield. Moreover,
compared with the para-substitution, the electron-withdrawing
substituent is in the meta position, leading to accelerating the
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The scope of the reaction with respect to aromatic primary
amines, aliphatic primary and secondary amines is broad (Table
), but alcohol, phenol, mercaptan, thiophenol and amide
couldn’t be tert-butoxycarbonylated by BCMP. Meanwhile, a
more sterically encumbered compound such as 2,6-
diisopropylaniline couldn’t react in the case. A wide range of
functional groups are tolerated, including hydroxy, methoxy,
thiol, methyl, cyano, carbonyl and nitro groups. Both electron-
rich and some electron-poor aniline participated equally well in
2
reaction (e.g. 3t, 3u). In contrast, the aromatic amines
Table 2 Scope with Respect to amines a
Entry
1
Substrate
Product
Yield (%) b
97
Entry
9
Substrate
Product
Yield (%) b
91
2
3
4
94
99
97
10
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12
95
85
36
5
6
98
13
14
96
95
100
7
8
97
89
15
16
18
88
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Substrate
Product
Yield (%) b
92
Entry
21
Substrate
Product
Yield (%)
DOI: 10.1039/C9NJ00885C
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a Unless otherwise noted, the products were obtained by method A. Method A：A mixture of BCMP (2.02 mmol) and substituted amine (2.02 mmol) in ethanol (10
mL) was heated under reflux for 1 h; Isolated yield. b Almost no reactions were observed by TLC.
substituted with electron-donating group could increase the
yield (3f). The methoxyl promoting the reaction resulted in 100% product under the general reaction conditions over 97% yields,
yield. Different results were observed for aromatic secondary such as 3c 3e and 3g. Further, aliphatic secondary amines also
amines. The N-methylaniline couldn’t be protected with Boc in can be used in the reaction to afford N-Boc product in over 95%
the general condition, which displayed the selectivity to yields, such as 3m 3n and 3r. However, under this condition
aromatic primary amines. tert-butoxycarbonylation of phenol and 4-nitrophenol did not
1,2-Diaminobenzene, which has been used in this reaction occur, resulting in the recovery of Boc carrier in 95% recovery
with the use of 2 equiv BCMP, led to a more promising result. rate. With these results in hand, we concluded that functional
The mono-Boc product was isolated in 85% yield (3k), and groups with weaker nucleophilicity than oxygen atom were
importantly, the di-Boc product wasn’t observed. This abnormal failed to be tert-butoxycarbonylaed with Boc using BCMP as Boc
result led us to examine 1,3-diaminobenzene substrate. reagent under the general condition.
Interestingly, two amino groups were in the meta-position to
Moreover, aliphatic primary amines also provided the N-Boc
,
,
give the di-Boc product in 88% yield, such as 3p. We speculated
that mono-Boc product of 1,2-diaminobenzene formed
hydrogen bond with the ortho-amino group, which led to a
decrease the nucleophilicity of the amino group, di-Boc product
Scheme 1. Synthetic method of Lenvatinib.
of 1,2-diaminobenzene couldn’t been obtained.
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Table 3 Scope with Respect to Amino acids A a
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Entry
1
Substrate
Product
Yield (%)b Entry
Substrate
Product
Yield (%)b
96
91
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a Unless otherwise noted, the products were obtained by method B. Method B: A mixture of BCMP (2.02 mmol), potassium carbonate (2.02 mmol), amino acids ester
hydrochlorides (2.02 mmol) in water (10 mL) was heated under reflux for 1 h. b Isolated yield.
There is clear relevance of 3s from 4-amino-3-chlorophenol
and the BCMP to the preparation of bioactive molecule. ester hydrochlorides was undertaken. Screening experiments
Lenvatinib
Simultaneously, the tert-butoxycarbonylation of amino acids
18
(Scheme 1) is an important medicinal agent used were made with L-Trp-OMe•HCl as a model compound using
in the treatment of progressive radioiodine-refractory the equal amount of BCMP in ethanol. It was found the target
differentiated thyroid cancer. This compound can be readily compound was not observed, whereas additive of potassium
prepared from tert-butyl (2-chloro-4-hydroxyphenyl)carbamate. carbonate (1 equiv) resulted in 80% yield (Method B). Use of
As an illustration of the utility of our tert-butoxycarbonylation water as a solvent provided a better result (91%) with reflux. On
process, simple tert-butoxycarbonylation of 4-amino-3- the basis of these results, the standard condition for the tert-
chlorophenol provided in high yield the tert-butyl(2-chloro-4- butoxycarbonylation of several amino acid ester hydrochlorides
hydroxyphenyl) carbamate. This result suggests that our new with BCMP (1 equiv) and potassium carbonate (1 equiv) was in
chemoselectivity tert-butoxycarbonylation method can be an water under reflux. Thus, the tert-butoxycarbonylation of
alternative method for synthesis of Lenvatinib.
tert-Butoxycarbonylation of Amino Acids by BCMP
various amino acids in this study was normally performed, and
the corresponding N-Boc-L-amino acid esters were obtained in
high yields as shown in Table 3
Possible Mechanistic Pathway
.
19
The role of ethanol may be explained by Scheme 2
.
Hydrogen bond formation between ethanol and the carbonyl
oxygen atoms of BCMP causes “electrophilic activation” making
the carbonyl group more susceptible to nucleophilic attack
(transition state 1, TS1). In turn, the oxygen atom of ethanol
forms a hydrogen bond with the hydrogen atom of the amine
and increases the electron density at the nitrogen atom creating
nucleophilic activation (transition state 2, TS2). Then,
intramolecular nucleophilic attack by the nitrogen atom on the
carbonyl carbon followed by elimination of 4,6-dimethyl-2-oxo-
1,2-dihydropyridine-3-carbonitrile forms the carbamate.
Conclusions
Scheme 2. Plausible mechanism for N-Boc protection of amines
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R. K. Dieter, J. W. Dieter, C. W. Alexander and N. S.
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16 H. Ouchi, Y. Saito, Y. Yamamoto and H. Takahata, Org. Lett.,
In summary, we have developed a cyclic system for the
selective tert-butoxycarbonylation of amines that utilizes
readily available Boc reagent (BCMP) and related aromatic
primary amines, aliphatic primary and secondary amines. This
protocol proposes a highly chemoselective Boc reagent in C-N
bond construction and provides the examples of tert-
butoxycarbonylation of amines using readily available starting
materials under mild reaction conditions and simple workup,
which is a useful Boc reagent in the preparation of bioactive
molecules such as peptide. The key to this discovery was the
identification of a highly chemoselective Boc reagent and
recyclable Boc carrier. The Boc carrier of 4,6-dimethyl-2-oxo-
1,2-dihydropyridine-3-carbonitrile has poor solubility in most
solvents which can be recycled just by filtration to achieve
recycling in 95% recovery rate (Scheme 3) and has broad
prospects for industrial application.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the project 201602707 (Natural
Science Foundation of Liaoning Province.
Notes and references
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