Successive formation of two amide linkages between two benzene rings

Article abstract of DOI:10.1246/cl.130143

To successively construct two amide bonds between two benzene rings, the reaction of methyl N-alkylanthranilate and N-alkylisatoic anhydride in the presence of a base was studied. When the reaction was carried out with lithium hexamethyldisilazide and N,N,N,N-tetramethylethylenediamine in THF at 70 °C under reduced pressure, a cyclic diamide was obtained in high yield.

Full text of DOI:10.1246/cl.130143

doi:10.1246/cl.130143
Published on the web May 18, 2013
641
Successive Formation of Two Amide Linkages between Two Benzene Rings
Akihiro Yokoyama,*1 Makoto Karasawa,2 Masahisa Taniguchi,2 and Tsutomu Yokozawa*2
1Department of Materials and Life Science, Faculty of Science and Technology,
Seikei University, 3-3-1 Kichijoji-kitamachi, Musashino, Tokyo 180-8633
2Department of Material and Life Chemistry, Kanagawa University,
Rokkakubashi, Kanagawa-ku, Yokohama, Kanagawa 221-8686
(Received February 20, 2013; CL-130143; E-mail: ayokoyama@st.seikei.ac.jp)
To successively construct two amide bonds between two
benzene rings, the reaction of methyl N-alkylanthranilate and
N-alkylisatoic anhydride in the presence of a base was studied.
When the reaction was carried out with lithium hexamethyldi-
silazide and N,N,N¤,N¤-tetramethylethylenediamine in THF at
70 °C under reduced pressure, a cyclic diamide was obtained in
high yield.
donation of the oxygen and nitrogen atoms reduces the electro-
philicity of the carbonyl carbon between these atoms. The
decarbonation of the carbamic anion 3 would then provide the
amide anion 4, and subsequent intramolecular nucleophilic
attack by the amide anion on the ester carbonyl carbon would
result in formation of the second amide linkage, yielding the
cyclic diamide 5. We plan to apply this reaction to the synthesis
of defect-free ladder polymers, which are difficult to obtain,
except by Diels-Alder reaction under high pressure7 or acid-
induced ring-closing reaction between two imino-bridged
benzene rings.8 In this letter, we report the results of our
investigation of the reaction of 1 and 2 and demonstrate that the
successive formation of two amide linkages can be achieved
under appropriate conditions.
The reaction of methyl N-methylanthranilate (6) and
N-methylisatoic anhydride (7) was first carried out in THF at
0 °C in the presence of one equivalent of lithium hexamethyldi-
silazide (LiHMDS) as a base,9 and the starting materials were
consumed after 1 h (Scheme 2).10 However, the main product
was not the desired cyclic diamide, but the monoamide 8, which
was obtained in 89% yield. Under these conditions, the second
amide bond formed neither intermolecularly nor intramolecu-
larly. Further, it is worthy to note that the polymerization of 6
did not occur at all and deprotonated 6 reacted selectively with
7, because N-alkylated para- and meta-aminobenzoic acid esters
polymerized under similar conditions.6 The treatment of isolated
8 with one equivalent of LiHMDS at room temperature afforded
the cyclic diamide 9 in 93% yield and the hemiacetal precursor
The amide linkage is one of the most important chemical
bonds and plays a critical role in constructing and functionaliz-
ing many materials, such as drugs, proteins, and polymers.1
There are many ways to construct amide linkages. Typically, the
condensation of an amine and a carboxylic acid is carried out in
the presence of a dehydration-condensation agent,2 such as
N,N¤-dicyclohexylcarbodiimide,3 1H-benzotriazol-1-yloxytris-
(dimethylamino)phosphonium hexafluorophosphate,4 or 4-(4,6-
dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride.5
Reactions of amines with acid chlorides or acid anhydrides are
also conducted. The condensation of an amine and ester is
sometimes used for the synthesis of polyamides.
In the course of our study on chain-growth condensation
polymerization, we synthesized N-substituted polybenzamides
with a controlled molecular weight and narrow polydispersity.6
In these polymerizations, the amide linkage was constructed by
the nucleophilic substitution of an ester with an amide anion. We
thought that, if such an amide-forming reaction was applied to
the reaction of deprotonated N-alkylanthranilic acid ester 1 and
N-alkylisatoic anhydride 2, we could successively construct
two amide linkages between two benzene rings, as shown in
Scheme 1. That is, the amide anion of 1 would attack the
carbonyl carbon between the benzene ring and the oxygen atom
in 2 to form an amide linkage. The nucleophilic attack by the
amide anion would occur at this position because the electron-
CH3
O
N
H
O
LiHMDS
THF, 0 °C
OCH3
C
O
O
N
CH3
6
7
1
1
H3C
O
C
R
O
R
O
C
N
N
N
LiHMDS
THF, rt
O
2
2
OCH3
OR
OR
O
1
C
O
H N
CH3
N
N
C
C
O
O
1
C
O
3
3
R
O R
8 (89%)
1
2
3
H3C
O
H3C HO
R
O
R
O
C
OCH3
N
C
C
N
C
N
C
N
2
CO
OR
2
2
OR
N
C
N
C
O
N
R
C
N
3
3
O
CH3
O
CH3
O
R
4
5
9 (93%)
10 (2%)
Scheme 1.
Scheme 2.
Chem. Lett. 2013, 42, 641-642
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

642
C8H17
N
H
O
N
Table 1. Effect of additives and pressure on the reaction of 6
and 7a
LiHMDS
TMEDA, THF
O
Yieldb/%
reduced pressure
OCH3
THF
/mL
Time
/h
C
O
O
O
Entry Additive/mL
Temp
70 °C, 6 h
9
10
8
C8H17
1
2
3
4
5
6
7c
8c
9c
HMPA (0.1)
HMPA (2.0)
HMPA (1.0)
HMPA (1.0)
2.1
2.1
1.1
0
rt
rt
rt
rt
rt
22
24
24
24
24
9
6
2
2
20
50
53
53
70
82
84
84
85
6
0
0
0
0
0
0
0
0
43
24
2
0
24
3
3
2
2
11
12
C8H17
N
C8H17
N
O
C
C
OCH3
TMEDA (0.85) 2.1
C
O
N
C
O
H
N
TMEDA (0.82) 2.0 50 °C
TMEDA (0.82) 2.0 50 °C
TMEDA (0.82) 2.0 70 °C
TMEDA (0.82) 2.0 90 °C
C8H17
C8H17
13 (79%)
14 (5%)
Scheme 3.
aReaction of 6 (1 mmol) and 7 (1 mmol) was carried out in the
presence of LiHMDS (1 equiv) in THF. bIsolated yield.
cReaction was carried out under reduced pressure.
85%). Therefore, it was determined that the optimized reaction
conditions were those for Entry 8.
If this reaction is applied to the synthesis of ladder-type
aromatic polyamides, the alkyl group used as the N-substituent
must be larger than a methyl group to increase the solubility of
the polymer.12 Thus, the reaction of N-octyl compounds 11 and
12 were examined under the optimized conditions (Scheme 3).10
The reaction needed a longer time (6 h) to reach completion than
that required for N-methyl compounds (2 h), but the reaction
afforded the target cyclic diamide 13 in high yield (79%) with
the generation of only a small amount of the monoamide 14
(5%).
In conclusion, we designed a reaction to successively form
two amide linkages between two benzene rings using methyl
N-alkylanthranilate and N-alkylisatoic anhydride with LiHMDS
and TMEDA in THF. This reaction can be used to synthesize
defect-free ladder-type aromatic polyamides. The synthesis of
monomers and the investigation of their polymerization are in
progress. We are also conducting structural analysis of the cyclic
diamides by means of X-ray crystallography and NMR spec-
troscopy, and the results will be published elsewhere.
10 in 2% yield. These results indicated that the reaction of
deprotonated 6 with 7 halted at the decarbonation step of the
carbamic anion 3, not at the cyclization of the amide anion 4.11
Therefore, to obtain the cyclized product 9 directly from the
reaction of 6 and 7, the rate of the decarbonation step had to be
enhanced. It was thought that an increase in the polarity of the
reaction medium would increase the decarbonation rate, and
thus, the effects of additives were investigated (Table 1). When
the reaction of 6 and 7 was carried out with one equivalent of
LiHMDS at room temperature in the presence of a small amount
of hexamethylphosphoric triamide (HMPA) as an additive, the
target cyclic diamide 9 was obtained in 20% yield. However, the
main product remained the monoamide 8 (43%), and 10 was
obtained in 6% yield (Entry 1). The material balance of this
reaction was poor due to the formation of many by-products,
which was confirmed by thin-layer chromatography analysis of
the reaction mixture. Excess of HMPA improved the yield of 9,
and the use of the same volume of HMPA as that of THF formed
9 in 50% yield (Entry 2). However, running the reaction under
concentrated conditions (Entry 3) or in HMPA alone (Entry 4)
did not further increase the yield of the desired product. Thus,
N,N,N¤,N¤-tetramethylethylenediamine (TMEDA) was used in-
stead of HMPA, and both the yield of 9 and the material balance
of the products was significantly improved; the reaction with
TMEDA at room temperature for 24 h gave 9 and 8 in 70% and
24% yield, respectively (Entry 5). An increase in the temper-
ature accelerated the reaction, and 9 was obtained in 82% yield
after 9 h at 50 °C (Entry 6). Under these conditions, use of other
bases such as sodium and potassium hexamethyldisilazide did
not afford 9 at all.
This study was partly supported by JSPS KAKENHI Grant
Number 20550114.
References and Notes
1
The Amide Linkage: Structural Significance in Chemistry, Biochem-
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2
3
4
5
6
M. Kunishima, C. Kawachi, K. Hioki, K. Terao, S. Tani, Tetrahedron
2001, 57, 1551.
a) A. Yokoyama, T. Yokozawa, Macromolecules 2007, 40, 4093. b) T.
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K. Miyatake, A. S. Hay, F. Mitsuhashi, E. Tsuchida, Macromolecules
2001, 34, 2385.
Next, we examined the effect of the reaction pressure,
because the reduction of pressure was expected to enhance the
decarbonation of 3. A reaction mixture containing the same
amount of reagents as described in Entry 6 was prepared at 0 °C
in a reaction tube, and the reaction tube was degassed and then
cooled using liquid nitrogen. The pressure inside the reaction
tube was reduced using a vacuum pump, and the reaction tube
was sealed and heated to 50 °C. The reaction was complete in
6 h, and the yield of 9 increased slightly to 84% (Entry 7).
Reaction at 70 (Entry 8) and 90 °C (Entry 9) further shortened
the reaction time while providing nearly the same yield of 9 (84-
7
8
9
T. Yokozawa, D. Muroya, R. Sugi, A. Yokoyama, Macromol. Rapid
Commun. 2005, 26, 979.
10 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
11 Considering that the carbamic acid tends to decompose rapidly under
acidic conditions, the compound 8 formed during the work-up after the
reaction of 6 and 7.
12 T. Ohishi, R. Sugi, A. Yokoyama, T. Yokozawa, J. Polym. Sci., Part A:
Polym. Chem. 2006, 44, 4990.
Chem. Lett. 2013, 42, 641-642
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/