Bio-based synthesis of secondary arylamines from (-)-shikimic acid

Article abstract of DOI:10.1039/c1gc16162h

A specific family of secondary arylamines, including diarylamines and arylalkylamines have been synthesized in good yields starting from the renewable and biomass-based feedstock (-)-shikimic acid (1). The tandem cross-coupling and aromatization reactions

Full text of DOI:10.1039/c1gc16162h

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PAPER
Bio-based synthesis of secondary arylamines from (-)-shikimic acid†
Wei Wu,a,b Yong Zou,*a Yu Chen,a,b Jun Li,c Zeliang Lv,a,b Wen Wei,a Tongkun Huanga and Xianke Liua,b
Received 19th September 2011, Accepted 27th October 2011
DOI: 10.1039/c1gc16162h
A specific family of secondary arylamines, including diarylamines and arylalkylamines have been
synthesized in good yields starting from the renewable and biomass-based feedstock (-)-shikimic
acid (1). The tandem cross-coupling and aromatization reactions between primary amines and the
intermediate (-)-methyl-3-dehydroshikimate (3) are crucial for realizing this strategy. The
application of arylamines and alkylamines provided 3-arylamino-4-hydroxybenzoates (5) and
3,4-dihydroxy-5-alkylaminobenzoates (7) respectively via a selective dehydration or
dehydrogenation process.
as a microbial catalyst.6 Considering the increased availability of
Introduction
1, it is obvious that this biofeedstock deserves further research
Owing to the limited supply and non-renewability of fossil
and application as a renewable and reliable resource in place of
oil, the conversion of biomass feedstocks to useful chemicals,
fossil oil for modern chemical and pharmaceutical industries.
especially complex molecules with diverse properties or inter-
Secondary arylamines, either diarylamines or arylalky-
mediates with a desired scaffold is becoming an increasingly
lamines, have constantly drawn much attention from synthetic
important research area in organic chemistry.1 From a modern
chemists because of their ubiquity in pharmaceuticals and
green chemistry perspective, plant biomass, especially those
fine chemicals. Typically, the secondary arylamines are mainly
with non-grain or non-corn origin are of great advantage for
application as alternatives to fossil oil.2
obtained by cross-coupling reactions between aryl halides and
amines in the presence of transition metal catalysts such as
(-)-Shikimic acid (1) is a renewable biomass feedstock that
palladium, copper, nickel, and iridium complexes.7,8 Although
great efforts have been made, many limitations still exist con-
cerning the efficiency, applicability and expense of the catalytic
systems.9,10 Moreover, the general strategy for the preparation of
secondary arylamines from renewable biomass-based starting
materials has never been established. Accordingly, a green and
novel procedure for the preparation of these compounds based
on renewable biomass resources under mild reaction conditions
would be genuinely attractive.
is widely distributed in plants, microbes and parasites.3 It
R
is used as the key precursor for the synthesis of Tamifluꢀ
and can also be converted to a series of fine chemicals such
as phenol, benzoic acid, protocatechuic acid, and gallic acid
through aromatization.4 Presently, 1 can be obtained in large
amounts through extraction from fruits, branches, and leaves
of Chinese star anise (Illicium verum Hook. f.). In the fruit of
some superior strains of the plant, the content of 1 could be as
high as 12% or more.5 It is worth mentioning that the plant of
Illicium verum belongs to the category of non-grain biomass and
that 1 is not obtained from barks, stems, and roots of the plant.
Therefore, the acquisition of 1 from this plant brings no ethical
problems caused by competition with food and results in no
damage to the plant itself. More encouragingly, recent advances
in metabolic engineering have enabled high-yielding and cost-
effective fermentative production of 1 from glucose using E. coli
As a part of our ongoing endeavour to develop biomass-based
processes for access to natural products and fine chemicals,11
we herein describe a novel procedure for the synthesis of
various secondary arylamines under mild conditions via aro-
matic or aliphatic amine-involved aromatization of (-)-methyl-
3-dehydroshikimiate (3), a key intermediate readily obtained
from 1.
Results and discussion
aGuangzhou Institute of Chemistry, Chinese Academy of Sciences,
Guangzhou, 510650, P. R. of China. E-mail: zou_jinan@163.com;
Fax: +86(20)85231119; Tel: +86(20)85231309
Starting from the commercially available (-)-shikimic acid (1),
the methyl (-)-shikimate (2) was readily obtained through
esterification with methanol in presence of SOCl2. Compound 3
could then be achieved in 72% yield by highly selective oxidation
of 3R-hydroxyl group in THF with 2-iodoxybenzoic acid (IBX).
It is noteworthy that, although 2 has three unprotected hydroxyl
groups in its cyclohexene framework, the oxidizing reaction
bGraduate School of Chinese Academy of Sciences, Beijing, 100039, P. R.
of China
cSecond Affiliated Hospital, College of Medicine, Zhejiang University,
Zhejiang, 310009, P. R. of China
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c1gc16162h
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caused by IBX selectively took place at 3R-hydroxyl position,
whereas the 4S and 5R hydroxyl groups remained intact even in
large excess of IBX (3 equiv), thus affording 3 as the sole product
(Scheme 1).12
to afford 5a in excellent yields (Table 1, entries 1 and 8). Other
acidic catalysts such as HCOOH, AcOH, H2SO4, ZnCl2, and
AlCl3 gave relatively lower yields, indicating that the p-TsOH
was optimal for this transformation (Table 1, entries 9–13). No
desired product was detected in the absence of acidic catalyst
(Table 1, entry 2), which gave an explanation for the failure of
similar reactions conducted by M. Baltas et al. Investigation
on the reaction medium revealed that CH3OH seemed to be
the optimal solvent for this reaction. When other solvents (t-
BuOH, DMF, DMSO, CH3CN, THF) were utilized, relatively
lower yields were obtained (Table 1, entries 3–7). Running the
reaction at ambient temperature can also furnish the product
with relatively lower yield (88%, Table 1, entry 14). Additionally,
the catalyst loading could be successfully reduced to 1 mol%
in a gram-scale reaction to give 5a, albeit in lower yield and
prolonged time (Table 1, entry 15).
Scheme 1 Aromatization of (-)-shikimic acid promoted by primary
amines.
To illustrate the scope of the present method, the reactions
of a range of primary arylamines bearing different functional
groups were examined and the results are listed in Table 2. Gen-
erally, electron-rich primary arylamines were more reactive and
afforded better yields than electron-deficient arylamines (entries
2–4 vs. 8–10). The electron-donating groups are expected to
increase the nucleophilic activity of arylamines and to accelerate
the reactions. Moreover, steric hindrance of arylamines exerts a
significant influence on the reactions. The less sterically hindered
o-aminotoluene (4m) reacted with 3 to give 5m in a good isolated
yield of 84% (Table 2, entry 13), while the more sterically
hindered 2,4,6-trimethylaniline (4s) and 2,6-diethylaniline (4t)
resulted in a moderate yields of 65% and 62%, respectively
(Table 2, entries 19–20). Besides, 4t required a longer time to
complete the reaction. In addition, we have also studied the
reaction of 3 with p-phenylenediamine and o-phenylenediamine.
The results indicated that the cross-coupling and aromatization
reaction of p-phenylenediamine (4l) with 3 was accomplished in
excellent yield to give the disubstituted product 5l (87%, Table 2,
entry 12), while the same reaction between o-phenylenediamine
and 3 afforded 4-hydroxyphenazine-2-carboxylic acid methyl
ester (5v) in 72% yield (Table 2, entry 22). This cyclic prod-
uct was obviously formed through a successive dehydration-
cyclization and dehydrogenation-aromatization process. It is
worth noting that the natural phenazine-containing compounds,
such as phenazine-1-carboxylic derivatives (PCAs) represent the
secondary metabolic pathway of (-)-shikimic acid and possess
broad-spectrum antimicrobial effects.14 To the best of our
knowledge, the above-mentioned reaction is the first example
documented for access to phenazine derivative via a (-)-shikimic
acid-based method. The o- or m-substitued anilines were
also workable in our protocol, furnishing the corresponding
products with moderate to high yields (Table 2, entries 13–17).
Also worthy of mention is that when secondary and tertiary
arylamines, such as N-methylaniline, N-phenylanthranilic acid
and N,N-dimethylaniline were employed, no desired product
was observed in the reaction mixture, with only trace amount
of protocatechuic acid obtained (Table 2, entries 23–25). A
control experiment in absence of primary arylamines also
produced protocatechuic acid, indicating that it is the reactant 3
itself undergoes the dehydration reaction in acidic conditions.
Furthermore, we examined the reactivity of benzophenone
hydrazone (4u) with 3, moderate yield (70%) was obtained after
In 1993, M. Baltas et al. reported very few examples of pri-
mary alkylamine-involved aromatization of 3, affording methyl
3-alkylamino-4-hydroxybenzoates in low to moderate yields.
However, they failed to give any examples of primary arylamine-
involved aromatization regarding 3.13 We reasoned that, under
proper conditions, the aromatization of 3 would theoretically
be accomplished both by reaction with primary arylamines and
alkylamines, thus implying a great potential for application in
the alternative synthesis of diarylamines and arylalkylamines.
Unfortunately, to the best of our knowledge, no further study
along this road has been conducted.
We proceeded with our investigation using aniline (4a) as the
model substrate on reaction with 3. The results are summarized
in Table 1. To our delight, the tandem cross-coupling and
aromatization reaction proceeded smoothly in refluxing CH3OH
and CH2Cl2 in the presence of p-toluenesulfonic acid (p-TsOH)
Table 1 Screening of conditions for reaction of (-)-methyl-3-
dehydroshikimate with anilinea
Entry
Solvent
t(h)
T/◦C
Cat. (5 mol%)
Yield (%)b
1
2
3
4
5
6
7
8
CH3OH
CH3OH
t-BuOH
DMSO
DMF
CH3CN
THF
CH2Cl2
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
12.0
12.0
65 ◦
65 ◦
80 ◦
C
C
C
p-TsOH
—
98
0
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
HCOOH
AcOH
H2SO4
ZnCl2
AlCl3
p-TsOH
p-TsOH
85
87
86
90
76
95
70
69
71
65
62
88
81
80 ◦C
80 ◦C
80 ◦
C
65 ◦C
35 ◦
65 ◦
65 ◦
65 ◦
65 ◦
65 ◦
rt
C
C
C
C
C
C
9
10
11
12
13
14
15c
65 ◦
C
a Reaction conditions: 3 (5.0 mmol), aniline (5.0 mmol), acidic catalyst
(0.25 mmol), and solvent (20.0 mL) at indicated temperature. b Isolated
yield. c 1 mol% p-TsOH was used.
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Table 2 Reaction of (-)-methyl-3-dehydroshikimate with arylaminesa
Entry
1
Amine
t(h)
Product
Yield(%)b
85
8.0
2
3
4
5
6
7
5.0
5.0
6.0
6.0
8.0
8.0
94
98
90
88
66
70
8
9
8.0
73
67
10.0
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Table 2 (Contd.)
Entry
10
Amine
t(h)
Product
Yield(%)b
76
10.0
11
10.0
80
12c
12.0
8.0
87
84
13
14
15
16
8.0
8.0
8.0
87
87
83
17
10.0
81
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Table 2 (Contd.)
Entry
18
Amine
t(h)
Product
Yield(%)b
68
10.0
19
12.0
65
20
24.0
62
21
20.0
70
22d
18.0
72
23e
24e
36.0
36.0
—
—
—
—
25e
36.0
—
—
a Reaction conditions: 3 (5.0 mmol), arylamines (5.0 mmol), p-TsOH (0.25 mmol), and CH3OH (20.0 mL) at refluxing temperature. b Isolated yield.
c The reaction was carried out with 3 (4.0 mmol) and p-phenylenediamine (2.0 mmol). d 4-Hydroxyphenazine-2-carboxylic acid (5v) was obtained via
a successive dehydration-cyclization and dehydrogenation-aromatization process. e Trace amount of protocatechuic acid was obtained, the control
experiment carried out with 3 (5.0 mmol) and p-TsOH (0.25 mmol) in refluxing CH3OH (20.0 ml) also furnished protocatechuic acid.
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Table 3 Reaction of (-)-methyl-3-dehydroshikimate with alkylaminesa
Entry
1
Amine
t(h)
Product
Yield(%)b
59
CH3NH2 6a
2.0
2
3
4
5
6
7
CH3CH2NH2 6b
2.0
2.0
2.0
2.0
3.0
3.0
65
70
75
68
61
71
CH3(CH2)2NH2 6c
(CH3)2CHNH2 6d
CH3(CH2)3NH2 6e
(CH3)2CHCH2NH2 6f
CH3(CH2)5NH2 6g
8
3.0
54
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Table 3 (Contd.)
Entry
9
Amine
t(h)
Product
Yield(%)b
65
PhCH2NH2 6i
4.0
10
11
12
(CH3)2 NH 6j
(CH3CH2)2NH 6k
(CH3CH2)3N 6l
8.0
8.0
8.0
—
—
—
—
—
—
a Reaction conditions: 3 (5.0 mmol), aliphatic amines (5.0 mmol), p-TsOH (0.25 mmol), and CH2Cl2 (20.0 mL) at ambient temperature. b Isolated
yield.
prolonged reaction time (Table 2, entry 21). Overall, the present
protocol proved to be compatible with a wide range of primary
arylamines bearing various functional groups.
The scope and generality of our protocol were further
investigated by coupling of 3 with primary alkylamines in
another set of experiments. The results are listed in Table 3.
Interestingly, the condensation of primary alkylamines with
Scheme 2 Reaction of aniline (4a) and 3 in the presence of Cu(OAc)2
3 gave 3,4-dihydroxy-5-alkylamine analogues in moderate to
good yields, probably due to a dehydrogenation (or oxidation)
reaction took place in this process (Table 3, entries 1–9). It is
noteworthy that primary alkylamines showed higher efficiency
in accelerating the aromatization of 3 than arylamines did, for
these reactions were performed at ambient temperature and
completed in much shorter times. In addition, the yields of the
products obtained in CH2Cl2 were higher than those of obtained
in CH3OH. Similarly to the results mentioned above, when the
reactions were tried with secondary or tertiary alkylamines such
as dimethylamine, diethylamine and triethylamine, no desired
products were obtained (Table 3, entries 10–12), indicating that
the primary amine moieties are essential for the aromatization
process.
In order to get a better understanding of the different
behavior displayed by arylamines and alkylamines which lead
to the formation of 3-arylamino-4-hydroxybenzoates (5) and
3,4-dihydroxy-5-alkylaminobenzoates (7) respectively. A control
experiment has been conducted and an interesting result has
been obtained, the reaction between aniline (4a) and (-)-
methyl-3-dehydroshikimate (3) in CH3OH in the presence of
Cu(OAc)2 which act as an oxidant afforded 3, 4-dihydroxy-
5-anilinebenzoates (12), indicating that the presence of an
oxidant (including oxygen distributed in reaction mixture) is
probably responsible for the different behaviour of arylamines
and alkylamines (Scheme 2). Further investigation to expand the
substrate scope for reaction conditions including or excluding
an oxidant is ongoing in our laboratory.
as an external oxidant.
Scheme 3 A plausible mechanism for the reaction between (-)-methyl-
3-dehydroshikimiate (3) and primary amines.
conjugated a,b-unsaturated carboxylic ester scaffold was ex-
pected to facilitate the aromatization process.
Conclusions
In conclusion, we have developed a novel and efficient method
for the synthesis of substituted secondary arylamines starting
from the biofeedstock (-)-shikimic acid (1). The tandem cross-
coupling and aromatization reaction between primary amines
and (-)-methyl-3-dehydroshikimiate (3) are considered to be
involved in the transformation. Arylamines on reaction with
3 gave 3-arylamino-4-hydroxybenzoates (5) via a dehydration-
aromatization process, while alkylamines on reaction with
3 afforded 3,4-dihydroxy-5-alkylaminobenzoates (7) via an
oxidation-aromatization process, both under mild reaction con-
ditions. Our findings provided a conceptually green, simple, and
practical methodology for CAr–N formation based on renewable
resources, representing an interesting complement to the existing
strategy using aryl halides and transition metal catalysts. Further
applications of the protocol using chiral amines as reactants
are currently under investigation in our laboratory and will be
reported in due course.
According to the above results, a plausible mechanism for
this reaction is illustrated in Scheme 3. Primary amines, either
arylamines or alkylamines, coupled with 3 in acidic conditions
forming a Schiff base 8 or 10, which rapidly enolized to
form a enamine 9 or 11, subsequent dehydration of 9 or
dehydrogenation (oxidation) of 11 would then occur, affording
the aromatization product 5 or 7 respectively. The pre-existing
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Acknowledgements
This work was financially supported by Guangxi Wanshan Spice
Co. Ltd., the Science and Technology Program of Guangdong
Province, Strategic Cooperation Program between Guangdong
Province and Chinese Academy of Sciences and National
Key Technology R&D Program, PR China (2003B31603,
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