Oxidative dearomatic cyclization of N-substituted benzanilide derivatives: Conformational effect of amide groups on the reaction

Article abstract of DOI:10.3987/COM-16-13515

The synthesis of spirooxindoles with a hypervalent iodine reagent depended on N-substituted benzanilide derivatives as starting materials. Reaction yields of benzanilides containing various N-substituents were discovered to relate to the cis and trans con

Full text of DOI:10.3987/COM-16-13515

HETEROCYCLES, Vol. 92, No. 10, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 8th June, 2016, Accepted, 4h Agust, 2016, Published online, 18th August, 2016
DOI: 10.3987/COM-16-13515
OXIDATIVE DEAROMATIC CYCLIZATION OF N-SUBSTITUTED
BENZANILIDE DERIVATIVES: CONFORMATIONAL EFFECT OF
AMIDE GROUPS ON THE REACTION
Kousuke Hayashi,a Jun Takayama,a,* Yousuke Shimano,a Meiyan Xuan,a
Misaki Suda,b Hiroyuki Teramae,b and Takeshi Sakamotoa,*
a
Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado,
Saitama 350-0295, Japan. b Department of Chemistry, Faculty of Science, Josai
University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
takayama@josai.ac.jp
e-mail:
Abstract – The synthesis of spirooxindoles with a hypervalent iodine reagent
depended on N-substituted benzanilide derivatives as starting materials. Reaction
yields of benzanilides containing various N-substituents were discovered to relate
to the cis and trans conformations of the amide bond by ab initio molecular
orbital calculations at the B3LYP/6-31G(d,p) and MP2/6-31G(d,p) levels,
including full geometry optimizations. The relationship between the reaction and
conformation of the starting material by quantum chemical calculations was
applied to the formal synthesis of SR121463.
In recent years, many new biologically active spirooxindoles have been discovered.1 The unique core
structure and bioactive nature of these compounds have long been a focus of pharmaceutical development.
One of these, named SR121463 1,2 is manufactured by Sanofi and is a V2 receptor antagonist (Figure 1).
N
O
O
EtO
O
O
N
EtO
S O
O
O
H
N
R1
N
OMe
R1: protecting group
O
synthetic intermediate 2
SR121463 1
Figure 1. Structures of SR121463 and synthetic intermediate

The synthesis of a SR121463 intermediate 2 with N-methyl and benzyl protecting groups, has also been
published using oxidative dearomatic reaction with hypervalent iodine reagent by Yu and co-workers in
2011.3 This intermediate is useful in the synthesis of bioactive natural products such as phenanthridinone
derivatives4 using the dienone-phenol rearrangement,5 and synthesis of a hydrocarbazole skeleton6 by ring
opening reaction of a lactam followed by aza-Michael addition (Figure 2). However, commercial
applications utilizing intermediate 2 are inherently difficult due to issues with scaling up of the synthesis.
For example, deprotection of the nitrogen when R is benzyl requires severe conditions such as in the
Birch reduction.7 Removal of protecting groups in total syntheses of bioactive natural products should
proceed under mild conditions, otherwise the constructed structures will decompose. Therefore, the initial
focus of this paper was to explore better protecting groups for intermediate 2. Also, in the course of the
screening, we employed computational methods to optimize our synthesis.
Figure 2. Syntheses of phenanthridinone and hydrocarbazole derivatives from spirooxindole derivative
Scheme 1 shows the synthesis of spirooxindole derivatives 4 from benzanilide derivatives 3 with
hypervalent iodine reagent. Cyclization reaction by phenol oxidation with hypervalent iodine reagent has
been proposed via two synthetic pathways, path A and path B.8 However, neither route has been
confirmed despite numerous studies.9 In path A, cyclization, dearomatization and elimination reactions
take place in order. In path B, on the other hand, phenoxenium cation is generated prior to the
electrophilic aromatic substitution reaction. Compound 3 is generated from 4-hydroxybenzoic acid and
aniline derivatives. The synthesis is designed and performed as described below.

Scheme 1. Synthetic pathways of cyclization reaction by phenol oxidation with hypervalent iodine
reagent
First, possible candidates for the starting material, 3a-3f (Table 1), with various N-substituents were
selected. N-Methyl and benzyl compounds, 3a-3d, were prepared following published procedures.3
Reported compounds 3a-3d were synthesized to identify correlations between yield of cyclization
reaction and amide conformation. The remaining two starting materials, N-methoxybenzanilide derivative
3e10 and N-phthaloylbenzanilide derivative 3f,10 were generated from 4-acetoxybenzoic acid11 in 3 steps
including arylation via nitrenium ion12 with hypervalent iodine reagent. We also included two
N-protecting groups reported in the literature: N-methoxy and N-phthaloyl groups. It was reported that
N-methoxy group was easily deprotected under mild conditions such as hydrogenation,13 and N-phthaloyl
group was removed in two steps, hydrolysis with hydrazine followed by reduction.14
Second, the oxidative dearomatization reaction of the benzanilides was screened using 3a-3c, 3e and 3f in
4 different solvents, (CF3)2CHOH, CF3CH2OH, MeOH, and CH2Cl2. Compound 3d was also investigated
in MeCN as a solvent. The yield of products 4a-4d in Table 1 shows that phenol oxidation with 3a-3d
afforded the desired spiro compounds 4a-4d with excellent yields (entries 1-16), whereas the yield of the
cyclization reaction with N-methoxy compound 3e was much lower (entries 17-20). The amide 3f
produced spirooxindole 4f10 in moderate yield (entries 21-24). PhI(OAc)2 (PIDA) was evaluated but it
was found to be less effective than PhI(OCOCF3)2 (PIFA) (entry 15, 16). The result of the cyclization
reactions showed that the differences between the yields of spirooxindole 4a-4f depended on the various
N-substituents in the starting materials. N-Methyl and benzyl compounds (3a-3d) afforded the best yields.
However, it was not possible to predict which N-substituent would work better for the cyclization
reactions.

Table 1. Syntheses of spirooxindoles with various N-substituents
hypervalent
starting
material
time temp. yield of
entry
R1
R2
iodine reagent
(eq.)
solvent
(min.) (°C)
4 (%)
1
2
3
4
5
6
7
8
(CF3)2CHOH
CF3CH2OH
MeOH
1
3
10
15
1
1
5
20
1
5
0
rt
rt
rt
81
99
80
83
83
90
82
85
91
91
85
89
83
85
31
91
75
52
25
25
31
14
55
43
14
40
-Me
-H
PIFA (1.1)
PIFA (1.1)
PIFA (1.1)
3a
CH2Cl2
(CF3)2CHOH
CF3CH2OH
MeOH
-CH2Ph
-Me
-H
rt
rt
3b
3c
CH2Cl2
9
(CF3)2CHOH
CF3CH2OH
MeOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-OEt
5
10
1
CH2Cl2
(CF3)2CHOH
CF3CH2OH
MeOH
PIFA (1.1)
PIDA (2.0)
5
>120
15
15
15
30
60
60
30
5
-CH2Ph
-OEt
rt
3d
MeOH
CH2Cl2
MeCN
PIFA (1.1)
PIFA (1.1)
PIFA (1.5)
PIFA (1.1)
PIFA (1.5)
(CF3)2CHOH
CF3CH2OH
MeOH
0
rt
rt
0
-OMe
-OEt
-OEt
3e
3f
CH2Cl2
(CF3)2CHOH
CF3CH2OH
MeOH
5
5
5
-NPhth
PIFA (1.1)
rt
CH2Cl2
In order to build a better predictive model, the impact of amide conformations (Figure 3) in the
cyclization reactions was investigated. It was reported that cis N-methylbenzanilide is the predominant
conformer according to NMR analysis.15
The cis-trans conformations of each candidate material (3a-3f) were determined by employing
computational methods, specifically quantum chemical calculations. Both ab initio DFT molecular orbital
calculations at the B3LYP/6-31G(d,p) level and ab initio molecular orbital calculations at the
MP2/6-31G(d,p) level using the Gaussian09 program package16 can estimate the energetics of each
conformation to determine the most stable form, and both tools were used to identify the cis-trans

conformations of all starting materials (3a-3f). Note that the complete analysis for all conformations,
including methoxy groups, were not performed at this time. One of the optimized structures of cis and
trans conformers for each compound were calculated. The energetics would vary a little if complete
calculations were performed on the most stable cis and trans conformers. Such calculations using
Hamiltonian algorithm17 is in progress and will be published elsewhere. The trans-cis ratio was estimated
by the Boltzmann distribution law at 300 K (kT product is 0.596 kcal/mol at 300 K). The calculated
results were compared to the yields of synthetic products 4a-4f (Table 2).
Figure 3. cis-trans Conformations of amide bond of benzanilide 3
Table 2. Comparison of reaction yield and B3LYP/6-31G(d,p) and MP2/6-31G(d,p) total energies of cis
and trans conformations of amide bonds of benzanilides 3
OH
R2
O
R2
N
: reaction point
R1
N
R1
O
OH
trans-benzanilide 3
cis-benzanilide 3
energy [a.u.]
trans
∆E
(trans-cis)
[kcal/mol]
yield
of 4
starting
material
ratio at 300 K
(cis : trans)
entry
cis
(%)*
B3LYP/6-31G(d,p)
1
2
3
4
5
6
-746.544453 -746.539481
-977.602999 -977.595583
-900.389066 -900.384022
-1131.447946 -1131.438950
-975.544321 -975.547944
-1372.939529 -1372.937754
3.12
4.65
3.17
5.65
-2.27
1.11
1 : 0.00533
1 : 0.000410
1 : 0.00490
1 : 0.0000765
0.0222 : 1
81
83
91
83
25
55
3a
3b
3c
3d
3e
3f
1 : 0.155
MP2/6-31G(d,p)
1
2
3
4
5
6
-744.305375 -744.298414
-974.645940 -974.637055
-897.695408 -897.688375
-1128.036452 -1128.027030
-972.661310 -972.661707
-1368.695258 -1368.694586
4.36
5.57
4.41
5.91
-0.24
0.42
1 : 0.000665
1 : 0.0000873
1 : 0.000612
1 : 0.0000494
0.669 : 1
81
83
91
83
25
55
3a
3b
3c
3d
3e
3f
1 : 0.494
*: 1,1,1,3,3,3-hexafluoroisopropanol as a solvent

The result of the calculations correlates very closely with the yields of the cyclization reaction. According
to the data, amides 3a-d, which are predominantly cis compounds, gave high yields of the products 4a-d.
On the other hand, benzamide 3e with the N-methoxy group provided a low yield of 4e. The dipole
moments of the carbonyl and methoxy groups are one of the possible factors contributing to the
trans-conformation of N-methoxyamide 3e (Figure 4). In addition, steric hindrance of the methoxy group
is smaller than the methyl group allowing easier cis to trans conformational change. The calculated
results for N-phthaloylamide 3f show that the trans-conformation is predominant, probably due to both
dipole moments and steric hindrance.
Figure 4. Dipole moments of carbonyl and methoxy groups
These calculations provide a practical way to identify cis-trans conformations of compounds to find
better starting materials to generate products with high yields, however no one has yet reported utilizing
quantum chemical calculations for cis-trans conformations of amide bonds. Such calculations are useful,
since the reaction points in the cis form of benzanilide derivatives are closer than those in the trans form,
hence the higher yields.
Table 3. Calculations of cis and trans conformations of N-methoxymethylbenzanilide derivatives 3g, h
with B3LYP/6-31G(d,p) and MP2/6-31G(d,p)
energy [a.u.]
trans
∆E
(trans-cis)
[kcal/mol]
starting
material
ratio at 300 K
(cis : trans)
entry
cis
B3LYP/6-31G(d,p)
1
2
-861.068100 -861.064440
-1014.914950 -1014.911500
2.29
2.18
1 : 0.02135
1 : 0.02553
3g
3h
MP2/6-31G(d,p)
1
2
-858.512474 -858.506150
-1011.904137 -1011.897700
3.96
4.05
1 : 0.00130
1 : 0.00112
3g
3h

Although the starting materials that showed high yields of the products so far were 3a-3d, they are not
actually ideal compounds since it is known that the N-methyl group cannot be removed and deprotecting
the N-benzyl group requires severe conditions. Therefore, more effective N-protecting groups were
investigated as the next step. Synthesis of a spirooxindole with the N-methoxymethyl (MOM) group,
which can be deprotected using acid hydrolysis, was evaluated. Initial screening was performed using ab
initio DFT molecular orbital calculations on N-methoxymethylbenzanilide derivatives to find possible
compounds with the cis form, and two candidates, 3g and 3h, were selected (Table 3).
N-Methoxymethyl compounds (3g, 3h) were obtained from 4-benzyloxybenzanilide derivatives in 2 steps
following literature procedures.18 After the oxidative dearomatization reaction of compounds 3g, 3h,
spirooxindole derivatives 4g, 4h were obtained in excellent yields (Table 4).
Table 4. Syntheses of spirooxindoles with N-methoxymethyl substituent
starting
material
PIFA
(eq.)
time
(min.) (°C)
temp. yield of 4
entry
R
solvent
(%)
1
2
1.1
(CF3)2CHOH
CF3CH2OH
10
46
20
0
64
-H
3g
3h
1.2
3
4
5
6
MeOH
CH2Cl2
(CF3)2CHOH
CF3CH2OH
60
85
61
97
94
22
3
5
0
0
-OEt
1.2
7
8
MeOH
CH2Cl2
30
60
rt
rt
93
69
The oxidative dearomatization reaction of N-methoxymethylbenzanilide 3h was applied to the synthesis
of SR121463 intermediate 6 (Scheme 2). Catalytic hydrogenation of spirodienone 4h in ethyl acetate at
room temperature produced spirocyclohexanone 5 in >99% yield. The deprotection of the methoxymethyl
group was carried out by treating 5 with trimethylsilyl iodide in acetonitrile at ambient temperature and
triethylamine in methanol at 55 °C to give intermediate 6.19 The structure of 620 was confirmed by
spectroscopic data, which was identical to reported data by Curran and co-workers.21 Therefore, the
synthesis afforded 6 under mild conditions.

Scheme 2. Concise synthesis of SR121463 intermediate 6
In summary, we presented a concise synthesis of a SR121463 intermediate under mild conditions by
oxidative dearomatization cyclization with hypervalent iodine reagent as a key step. It is proposed that
N-MOM will be a better protecting group, not only for synthesis of the intermediate 2, but perhaps also
for other bioactive compounds since the deprotection can be performed under mild conditions.
Hypervalent iodine reagent could also react with the nitrogen of the amide, however, we believe N-Me,
Bn and MOM substituted amides were sufficiently protected, allowing the reaction to occur on the
hydroxy group in the spirooxindole synthesis. In addition, we established a practical way to identify
cis-trans conformations of amides to screen for better reactive compounds to give higher yields. We
identified a correlation between experimental data and ab initio DFT molecular orbital calculations, and
successfully identified better benzamide derivatives for the target compound. This correlation suggests
more applicability of these calculations to screen compounds for improved reactivity. This is also the first
report to demonstrate that the cis-trans conformations of amide bonds can have an effect on the yield of
oxidative dearomatization cyclizations.
ACKNOWLEDGEMENTS
We would like to thank Dr. Jeffrey Stewart and Dr. Aeri Park for assistance with preparation of the
manuscript.
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1
10. 3e: mp 166-168 ºC; H NMR (400 MHz, CD3OD) δ 7.40 (d, 2H, J = 8.8 Hz), 7.22 (d, 2H, J = 8.8
Hz), 6.90 (d, 2H, J = 8.8 Hz), 6.68 (d, 2H, J = 8.8 Hz), 4.02 (q, 2H, J = 7.0 Hz), 3.70 (s, 3H), 1.37 (t,
13
3H, J = 7.0 Hz); C NMR (100 MHz, CD3OD) δ 170.0, 161.5, 160.2, 133.7, 132.1, 129.5, 125.9,
115.9, 115.7, 64.8, 61.4, 15.0; IR (KBr) 3224, 2939, 1635, 1597, 1512, 1442, 1350, 1257, 1226,

1165 cm-1; HRMS (EI) Calcd for C16H17NO4 287.1158, Found 287.1157; Anal. Calcd for
1
C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.87; H, 5.94; N, 4.85. 3f: mp 139-142 ºC; H
NMR (400 MHz, CDCl3) δ 7.86 (d, 2H, J = 3.2 Hz), 7.77-7.74 (m, 2H), 7.44-7.40 (m, 2H), 7.36 (d,
2H, J = 8.6 Hz), 6.89-6.77 (m, 3H), 6.59 (d, 2H, J = 8.6 Hz), 3.97 (q, 2H, J = 7.0 Hz), 1.37 (t, 3H, J
13
= 7.0 Hz); C NMR (100 MHz, CDCl3) δ 165.1, 158.9, 158.6, 134.8, 131.7, 129.9, 129.7, 129.2,
124.0, 123.8, 120.6, 115.0, 113.0, 63.7, 14.6; IR (KBr) 3317, 2985, 1735, 1651, 1604, 1512, 1327,
1280, 1242, 1172, 1111 cm-1; HRMS (EI) Calcd for C23H18N2O5 402.1216, Found 402.1199; Anal.
Calcd for C23H18N2O5: C, 68.65; H, 4.51; N, 6.96. Found: C, 68.36; H, 4.79; N, 6.68. 4e: mp 99-102
1
ºC; H NMR (400 MHz, CD3OD) δ 7.11 (d, 1H, J = 8.4 Hz), 7.00 (dd, 1H, J = 8.8 Hz and 2.4 Hz),
6.79 (d, 2H, J = 9.8 Hz), 6.69 (d, 1H, J = 2.4 Hz), 6.53 (d, 2H, J = 9.8 Hz), 4.04 (s, 3H), 3.97 (q, 2H,
13
J = 7.0 Hz), 1.34 (t, 3H, J = 7.0 Hz); C NMR (100 MHz, CD3OD) δ 187.1, 167.8, 158.2, 145.4,
134.3, 132.3, 125.4, 116.7, 113.3, 110.5, 65.3, 64.4, 56.2, 15.1; IR (KBr) 3070, 2985, 2939, 2877,
1743, 1666, 1604, 1473, 1404, 1280, 1211, 1072 cm-1; HRMS (EI) Calcd for C16H15NO4 285.1001,
Found 285.1029; Anal. Calcd for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.23; H, 5.31;
1
N, 4.86. 4f: mp 219-220 ºC; H NMR (400 MHz, CDCl3) δ 8.02-7.99 (m, 2H), 7.90-7.88 (m, 2H),
6.87 (dd, 1H, J = 8.4 Hz and 2.4 Hz), 6.84 (d, 2H, J = 10.0 Hz), 6.77 (d, 1H, J = 8.4 Hz), 6.69 (d, 1H,
J = 2.4 Hz), 6.61 (d, 2H, J = 10.0 Hz), 3.97 (q, 2H, J = 7.0 Hz), 1.39 (t, 3H, J = 7.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 184.7, 168.9, 163.2, 156.9, 142.5, 135.3, 133.8, 131.6, 129.6, 124.7, 124.4,
115.6, 112.0, 109.6, 64.1, 54.3, 14.6; IR (KBr) 2978, 1797, 1743, 1666, 1496, 1458, 1273, 1165
cm-1; HRMS (EI) Calcd for C23H16N2O5 400.1059, Found 400.1039; Anal. Calcd for C23H16N2O5 C,
69.00; H, 4.03; N, 7.00. Found: C, 68.72; H, 4.19; N, 6.83.
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20. 4h: mp 110-112 °C; H NMR (400 MHz, CDCl3) δ 7.04 (d, 1H, J = 8.8 Hz), 6.89 (dd, 1H, J = 8.8
Hz and 2.8 Hz), 6.62 (d, 1H, J = 2.8 Hz), 6.62 (d, 2H, J = 10.2 Hz), 6.53 (d, 2H, J = 10.2 Hz), 5.15
(s, 2H), 3.96 (q, 2H, J = 6.9 Hz), 3.35 (s, 3H), 1.37 (t, 3H, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3)
δ 185.1, 171.6, 156.3, 143.3, 135.1, 131.4, 126.8, 115.6, 111.8, 111.2, 72.2, 64.2, 56.5, 56.4, 14.7; IR
(KBr) 2939, 1728, 1666, 1496, 1327, 1273, 1188, 1087 cm-1; HRMS (EI) Calcd for C17H17NO4
299.1158, Found 299.1176; Anal. Calcd for C17H17NO4: C, 68.22; H, 5.72; N, 4.68. Found: C, 68.28;
H, 5.62; N, 4.73. 5: mp 115-116 °C; 1H NMR (400 MHz, CDCl3) δ 6.98 (d, 1H, J = 8.6 Hz), 6.85 (d,
1H, J = 2.4 Hz), 6.82 (dd, 1H, J = 8.6 Hz and 2.4 Hz), 5.13 (s, 2H), 4.00 (q, 2H, J = 7.2 Hz), 3.34 (s,
3H), 3.19-3.11 (m, 2H), 2.49 (dt, 2H, J = 15.2 Hz and 5.4 Hz), 2.19-2.14 (m, 4H), 1.41 (t, 3H, J =
7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 210.4, 179.6, 155.7, 134.2, 133.9, 113.0, 111.0, 110.1, 71.2,
64.1, 56.2, 46.1, 36.8, 33.8, 14.9; IR (KBr) 2939, 1705, 1597, 1489, 1450, 1342, 1327, 1188, 1095
cm-1; HRMS (EI) Calcd for C17H21NO4 303.1471, Found 303.1474; Anal. Calcd for C17H21NO4: C,
67.31; H, 6.98; N, 4.62. Found: C, 67.19; H, 6.97; N, 4.65. 6: mp 192-194 °C; 1H NMR (400 MHz,
CDCl3) δ 8.36 (s, 1H), 6.86 (d, 1H, J = 8.4 Hz), 6.83 (d, 1H, J = 2.4 Hz), 6.77 (dd, 1H, J = 8.4 Hz
and 2.4 Hz), 4.00 (q, 2H, J = 7.0 Hz), 3.20-3.12 (m, 2H), 2.50 (dt, 2H, J = 15.2 Hz and 5.5 Hz),
2.25-2.11 (m, 4H), 1.41 (t, 3H, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 210.7, 181.8, 155.2,
135.0, 133.2, 112.9, 111.1, 110.3, 64.1, 46.3, 36.8, 33.5, 14.8; IR (KBr) 3163, 3047, 2901, 1712,
1697, 1604, 1489, 1465, 1303, 1203, 1049; HRMS (EI) Calcd for C15H17NO3 259.1208, Found
259.1212; Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.32; H, 6.46; N, 5.38.
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