One-pot regio- and chemo-selective synthesis of thiaazatricyclododecane

Article abstract of DOI:10.1016/j.tet.2016.09.049

A highly regio- and chemo-selective heteroannulation protocol for the synthesis of unreported polysubstituted thiaazatricyclododecanes has been developed by a sequential four-component reaction of isoquinoline, 2-bromoacetophenones, aryl isothiocyanates,

Full text of DOI:10.1016/j.tet.2016.09.049

Accepted Manuscript
One-pot regio- and chemoselective synthesis of thiaazatricyclododecane
Abdolali Alizadeh, Akram Bagherinejad, Fahimeh Bayat, Long-Guan Zhu
PII:
S0040-4020(16)30965-6
10.1016/j.tet.2016.09.049
TET 28120
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 June 2016
Revised Date: 6 September 2016
Accepted Date: 20 September 2016
Please cite this article as: Alizadeh A, Bagherinejad A, Bayat F, Zhu L-G, One-pot regio-
and chemoselective synthesis of thiaazatricyclododecane, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.09.049.
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Leave this area blank for abstract info.
One-Pot Regio- and Chemoselective Synthesis of
Thiaazatricyclododecane
Abdolali Alizadeh,a,* Akram Bagherinejad,a
Fahimeh Bayat,a Long-Guan Zhub
aDepartment of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
bDepartment of Chemistry, Zhejiang University, Hangzhou 310027 P.R. of China.

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One-Pot Regio- and Chemoselective Synthesis of
Thiaazatricyclododecane
Abdolali Alizadeha,*, Akram Bagherinejad,a Fahimeh Bayat,a Long-Guan Zhub
aDepartment of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
bDepartment of Chemistry, Zhejiang University, Hangzhou 310027 P.R. of China.
Abstract— A highly regio- and chemoselective heteroannulation protocol for the synthesis of
unreported polysubstituted thiaazatricyclododecanes has been developed by a sequential four-
component reaction of isoquinoline, 2-bromoacetophenones, aryl isothiocyanates, and methyl 4-
chloro-3-oxobutanoate under mild conditions in CH3CN. To the best of our knowledge there are
no previous reports for the synthesis of these classes of thiaazatricyclododecanes. The method
features formation of various C−N, C−S, and C−C bonds, low-cost and readily available
substrates, as well as simple one-pot operation, which makes this process highly profitable. This
synthesis serves as a nice addition to chemistry in which purification via chromatography and
recrystallization can be avoided, and the pure products were obtained simply by washing the
crude products with hexane-ethyl acetate (10:1).
Keywords: isoquinoline, 2-bromoacetophenones, aryl isothiocyanates, methyl 4-chloro-3-
oxobutanoate, thiaazatricyclododecane, multicomponent reaction
* Corresponding author, Tel.: +98 21 8800663; fax: +98 21 88006544; e-mail: aalizadeh@modares.ac.ir

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1. Introduction
Bridged tricyclic
N-heterocycles are interesting because they occur in many natural
products. Several alkaloids like the C20-diterpenoid alkaloid racemulsonine,
calyciphylline A, and daphniglaucins D are known to possess an azatricyclic core as part
of their structures.1
Most of these frameworks have interesting biological properties. For example, FR901483
isolated from the fermentation broth of Cladobotryum, is a new immunosuppressant containing a
novel azatricyclododecane ring system.2 Thiourea derivatives of 4-azatricyclo[5.2.2.02,6]undec-8-
ene-3,5-dione inhibitors malarial aspartic protease plasmepsin II.3 From the another point of
view tricyclo[6.4.0.04,9]dodecane structure demonstrates a fascinating ring structure that features
an 1,5-ethano-bridged cis decalin. Therefore, they have drawn some attention from both
theoretical and synthetic points of view.4 Despite the advances described above; there is a lack of
convenient synthetic access to bridged tricyclic N-heterocycles. Kibayashi and co-workers
developed a route to azatricyclic core skeleton based on vinylation at the bridgehead position of
2-azabicyclo[3.3.1]nonane via an anti-Bredt iminium ion using vinylaluminum reagents.5 Coates
synthesized bridgehead aza-tricyclic frameworks by starting from ent-beyeran-16-one.6 Most of
the reported methods suffer from disadvantageous like low yields, require longer reaction times,
limited substrate scopes, expensive catalysts, and many tedious isolation steps.
The construction of architecturally complex molecules by a short pathway from inexpensive and
available starting materials is of much attention to organic chemists due to the benefits such as
generation of multiple bonds in a single transformation, avoiding the isolation of intermediates,
and saving in cost and time. So the methods which involve domino, tandem and cascade
processes are more important.7 Pyridinium, quinolinium, and isoquinolinium ylides have
emerged as interesting synthetic intermediates in the construction of numerous nitrogen
heterocycles, most of which include 1,3-cycloaddition reactions of ylides with electron-deficient

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alkenes and alkynes.8 [3+2] Annulation of isoquinolinium ylides with allenoates or enals yields
pyrroloisoquinolines.9 Ley et al. reported the sequential condensation of an isoquinolinium salt
with isothiocyanates and isocyanides to yield the pyrrole structures.10 Recently, we established a
sequential four-component domino reaction of isoquinoline, 2-bromoacetophenones, aryl
isothiocyanates, and dimethyl acetylenedicarboxylate for the formation of thiazepino[5,4-
a]isoquinolines.11
2. Results and Discussion
In continuation of our interest in innovative one-pot reactions that offer easy access to
some nitrogen tricyclic skeletons,12 in this study, we developed a novel one-pot
construction of bridged tricyclic
bromoacetophenones , aryl isothiocyanates
based on the factors that the sequential addition of isoquinoline to 2-bromoacetophenones
and aryl isothiocyanates could generate in situ betaines, which may react with methyl
4-chloro-3-oxobutanoate.
N-heterocycle from readily available isoquinoline, 2-
1
2, and methyl 4-chloro-3-oxobutanoate
1
2
For this purpose, we investigated the reaction of isoquinoline, 2-bromoacetophenone 1a, phenyl
isothiocyanate 2a, and methyl 4-chloro-3-oxobutanoate in CH3CN at room temperature in the
presence of Et3N. Quite surprisingly, instead of the anticipated [1,4]thiazino[3,4-a]isoquinoline
5a (Scheme 1), we observed an unexpected process leading to thiaazatricyclododecane 4a
(thiazinoisoquinoline having an ethano bridge) in excellent yields. Then we investigated the
reaction of isoquinoline, 2-bromoacetophenone 1a, phenyl isothiocyanate 2a, and methyl 4-
chloro-3-oxobutanoate in different solvents like CH2Cl2, CHCl3, THF, CH3CN, and DMF in the
presence of Et3N and K2CO3. The best result was obtained using Et3N in CH3CN.

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Scheme 1. The reaction of betaine, resulted from isoquinoline, 2-bromoacetophenone 1a, and
phenyl isothiocyanate 2a, and methyl 4-chloro-3-oxobutanoate
With the established optimal conditions, the scope of this sequential four-component
reaction was examined by applying a variety of 2-bromoacetophenones
isothiocyanates (Table 1).
Table 1: Scope of regio- and chemoselective synthesis of thiaazatricyclododecane 4a-k
1 and aryl
2
Entry
R1
H
R2
H
H
H
H
H
Cl
H
H
H
H
Cl
R3
H
R4
H
H
H
H
H
Cl
F
Compound 4
Yield (%)
1
2
95
87
66
85
87
53
77
76
75
82
70
4a
4b
4c
4d
4e
4f
Br
Cl
OMe
H
H
3
H
4
H
5
Br
H
6
H
7
H
H
4g
4h
4i
8
Br
Br
Cl
Cl
Br
H
H
F
9
10
11
Br
H
H
Cl
4j
4k

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Applying pyridine instead of isoquinoline and phenyl isocyanate as a replacement for
phenyl isothiocyanate produced the betain intermediate but unfortunately did not yield the
final product.
The structures of the resultant products
4
have been confirmed by mass spectrometric
analyses and by IR, H NMR, and C NMR spectral analysis. In addition, one of them
4b) has been unambiguously determined by X-ray diffraction analysis (Figure 1).
1
13
(
Figure 1. The Ortep Diagram of Compound 4b

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The mass spectrum of 4a displayed the molecular ion peak at m/z = 496. In the IR
spectrum of 4a absorption bands at 3465 (NH and OH), 1653 (C=O), and 1620 (C=C) cm-
1 are the most significant stretching frequencies. In 1H NMR spectrum of 4a a doublet and
a doublet of doublet at
CH2 group. Three CH groups appeared at
= 3.62 ppm is related to the methoxy group. The NH and OH were assigned at
δ
= 2.34 and 2.49 ppm are ascribed to diastereotopic protons of
= 3.38, 4.03, and 4.52 ppm. A singlet signal at
= 11.52
δ
δ
δ
and 12.6 ppm, respectively. The fourteen aromatic hydrogen atoms gave rise to
characteristic resonances in the aromatic region of the spectrum. Observation of 26
1
13
distinct signals in the H- decoupled C NMR spectrum of 4a is in agreement with the
proposed structure.
On the basis of our results, we propose the mechanism shown in Scheme 2 (exemplified for 4a).
The reaction of isoquinoline with 2-bromoacetophenone 1a led to the isoquinolinium salt 6a.
Subsequent addition of phenyl isothiocyanate 2a and triethylamine gave the corresponding
betaine 3a. Then nucleophilic addition of betaine 3a to methyl 4-chloro-3-oxobutanoate
happened to produce the S-alkylated intermediate 7a. Then Enolic form of 7a (8a) underwent an
intramolecular cyclization to produce [1,4]thiazino[3,4-a]isoquinoline 5a followed by
transformation to iminium salt 9a. Enolic form of 9a (10a) was altered to 11a through the second
chemoselective intramolecular cyclization. Finally by keto-enol tautomerization the product 4a is
produced.13-15
3. Conclusion
In conclusion, we have synthesized thiaazatricyclododecanes through the reaction of methyl 4-
chloro-3-oxobutanoate with betaine generated in situ from reaction of isoquinoline, 2-
bromoacetophenones, and aryl isothiocyanates. The mild reaction conditions and formation of
multiple bonds make this strategy highly viable.

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Scheme 2. Mechanistic rationalization for the formation of 4a
4. Experimental
Melting points measured on an Electrothermal 9100 apparatus. IR spectra were recorded as KBr
1
13
pellets on a NICOLET FT-IR 100 spectrometer. H NMR (400 and 300 MHz) and C NMR
(100 and 75 MHz) spectra were obtained using Bruker DRX-400 AVANCE and Bruker DRX-
500 AVANCE spectrometers. All NMR spectra at room temperature were recorded in CDCl3 or
DMSO-d6. Chemical shifts are reported in parts per million (δ) downfield from an internal
tetramethylsilane reference. Coupling constants (J values) are reported in hertz (Hz), and spin
multiplicities are indicated by the following symbols: bs (broad singlet), s (singlet), d (doublet), t
(triplet), td (triplet of doublets), dd (doublet of doublets), m (multiplet). Elemental analyses for
C, H and N performed using a Heraeus CHN–O–Rapid analyzer. Mass spectra were recorded on
a FINNIGAN-MATT 8430 mass spectrometer operating at an ionization potential of 20 or 70
eV. All chemicals were purchased from Merck or Aldrich and were used without further
purification.

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4.1. General procedure for the preparation of compounds 4a-k.
A solution of 2-bromoacetophenone 1 (1 mmol) and isoquinoline (1 mmol) in CH3CN was
magnetically stirred for 3 h and then aryl isothiocyanate 2 (1 mmol) was added followed by the
drop wise addition of a solution of triethylamine (1.1 mmol) in CH3CN at r.t over 10 min. The
mixture was stirred for 20 min and subsequently methyl 4-chloro-3-oxobutanoate was added to
the reaction mixture. After completion of reaction, the solvent was removed under reduced
pressure, and the residue was washed with hexane-ethyl acetate (10:1) to afford the pure product
4a-k.
4.1.1. Methyl
15-anilino-16-benzoyl-12-hydroxy-14-thia-1-
azatetracyclo[8.6.0.02,13.03,8]hexadeca-3,5,7,11,15-pentaene-11-carboxylate (4a). Yellow
powder, mp = 145-147 °C, 0.5 g, yield: 95%. IR (KBr) (νmax, cm-1): 3465 (OH and NH), 1653
(C=O), 1620 (CO2Me), 1527 and 1442 (Ar), 1288, 1244 and 1192 (C-O). Anal. Calcd. for
C29H24N2O4S (496.58): C, 70.14; H, 4.87; N, 5.64%. Found: C, 70.10; H, 4.86; N, 5.48%. MS
(EI, 70 eV): m/z (%) = 496 (11), 464 (13), 439 (60), 405 (4), 361 (9), 333 (5), 308 (8), 279 (7),
1
2
129 (48), 105 (100), 77 (94), 51 (16). H NMR (400.13 MHz, CDCl3): δH 2.34 (1H, d, JHH
=
16.0 Hz, CH2), 2.49 (1H, dd, 2JHH = 16.0 Hz, 3JHH = 4.8 Hz, CH2), 3.38 (1H, s, CH13), 3.62 (3H,
s, OMe), 4.03 (1H, d, 3JHH = 5.2 Hz, CH10), 4.52 (1H, s, CH2), 6.96 (1H, d, 3JHH = 6.8 Hz, CH of
Ar), 7.14-7.58 (11H, m, 11CH of Ph and Ar), 7.78 (2H, d, 3JHH = 7.2 Hz, 2CHortho of Ph), 11.52
(1H, s, NH), 12.6 (1H, s, OH). 13C NMR (100.00 MHz, CDCl3): δC 33.7 (CH2), 40.6 (CH13), 52.5
(OMe), 55.4 (CH10), 56.4 (CH2), 98.4 (C11), 120.2 (C16), 124.6 (2CHortho of Ph), 126.5 (CH6),
127.7 (CH4), 127.8 (2CHmeta of Ph), 128.2 (CHpara of Ph), 129.1 (2CHmeta of Ph), 129.7 (2CHortho
of Ph), 130.5 (CH7), 130.5 (CHpara of Ph), 132.7 (CH5), 133.6 (C3), 135.4 (C8), 135.8 (Cipso–CO),
138.6 (Cipso-NH), 140.7 (C15), 167.4 (C-OH), 170.7 (CO2Me), 190.8 (C=O).
4.1.2. Methyl
15-anilino-16-(4-bromobenzoyl)-12-hydroxy-14-thia-1-azatetracyclo
[8.6.0.02,13.03,8]hexadeca-3(8),4,6,11,15-pentaene-11-carboxylate (4b). Yellow powder, mp =

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210-213 °C, 0.5 g, yield: 87%. IR (KBr) (νmax, cm-1): 3436 (OH and NH), 1739 (C=O), 1653
(CO2Me), 1583, 1513 and 1444 (Ar), 1286, 1246 and 1196 (C-O). Anal. Calcd. for
C29H23BrN2O4S (575.47): C, 60.53; H, 4.03; N, 4.87%. Found: C, 60.48; H, 4.06; N, 4.84%. MS
(EI, 70 eV): m/z (%) = 516 (3), 333 (2), 255 (6), 230 (8), 202 (3), 183 (73), 155 (45), 129 (100),
1
2
102 (29), 77 (91), 51 (42). H NMR (400.13 MHz, CDCl3): δH 2.40 (1H, d, JHH = 16.0 Hz,
CH2), 2.61 (1H, dd, 2JHH = 16.0 Hz, 3JHH = 4.8 Hz, CH2), 3.54 (1H, s, CH13), 3.72 (1H, d, 3JHH
=
4.0 Hz, CH10), 3.75 (3H, s, OMe), 4.49 (1H, s, CH2),7.02 (1H, t, 3JHH = 4.8 Hz, CH of Ar), 7.22-
7.42 (8H, m, 8CH of Ar and Ph), 7.50 (2H, d, 3JHH = 8.4 Hz, 2CH of Ar), 7.76 (2H, d, 3JHH = 8.4
Hz, 2CH of Ar), 11.86 (1H, s, NH), 13.06 (1H, s, OH). 13C NMR (100.00 MHz, CDCl3): δC 33.9
(CH2), 40.1 (CH13), 51.9 (OMe), 56.2 (CH10), 56.3 (CH2), 98.5 (C11), 118.5 (C16), 124.4 (Cipso
-
Br), 125.6 (2CHorthoof Ph), 126.3 (CH6), 126.5 (CH4), 126.6 (CHpara of Ph), 128.0 (CH7), 129.1
(2CHmeta of Ph), 129.8 (CH5), 130.7 (2CH of Ar), 130.9 (2CH of Ar), 132.8 (C3), 135.1 (C8),
137.9 (Cipso-CO), 139.3 (Cipso–NH), 153.8 (C15), 167.5 (C-OH), 171.3 (CO2Me), 189.1(C=O).
Crystal data for 3b C33H33BrN2O5S (CCDC 1425334): MW = 649.57,monoclinic, P21/n,a =
12.170(5) Å, b = 10.609(5) Å, c = 23.592(5) Å, α = 90.00,
β = 94.030(5), γ = 90.00, V = 3039(2)
Å3, Z = 4, Dc = 1.420 mg/m3, F (000) = 1344, crystal dimension 0.48×0.42×0.38 mm radiation,
Mo Kα (λ = 0.71073Å), 2.99 ≤ 2
θ
≤ 25.10, intensity data were collected at 293(2) K with a
/2 scanning technique, in the range
Bruker APEX area-detector diffractometer, and employing
ω
θ
of -14 ≤ h ≤ 14, -10 ≤ k ≤ 12, -28 ≤ l ≤ 22; the structure was solved by a direct method, all non-
hydrogen atoms were positioned and anisotropic thermal parameters refined from 4062 observed
reflections with R (into) = 0.0743 by a full-matrix least-squares technique converged to R =
0.0504 and Raw = 0.1192 [I>2sigma(I)].
4.1.3.
Methyl
15-anilino-16-(4-chlorobenzoyl)-12-hydroxy-14-thia-1-
azatetracyclo[8.6.0.02,13.03,8]hexadeca-3(8),4,6,11,15-pentaene-11-carboxylate (4c). Orange

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powder, mp = 164-166 °C, 0.35 g, yield: 66%. IR (KBr) (νmax, cm-1): 3430 (OH and NH), 1657
(C=O), 1586 (CO2Me), 1531 and 1443 (Ar), 1247, 1197 and 1127 (C-O). Anal. Calcd for
1
C29H23ClN2O4S (531.02): C, 65.59; H, 4.37; N, 5.28%. Found: C, 65.40; H, 4.26; N, 5.20%. H
NMR (300.13 MHz, CDCl3): δH 2.39 (1H, d, 2JHH = 15.9 Hz, CH2), 2.61 (1H, dd, 2JHH = 15.9 Hz,
3
3JHH = 5.1 Hz, CH2), 3.53 (1H, s, CH13), 3.71 (1H, d, JHH = 4.2 Hz, CH10), 3.74 (3H, s, OMe),
3
4.49 (1H, s, CH2), 7.01 (1H, d, JHH = 4.5 Hz, CH of Ar), 7.23-7.42 (10H, m, 10CH of Ar and
Ph), 7.82 (2H, d, 3JHH = 8.1 Hz, 2CH of Ar), 11.76 (1H, s, NH), 12.81 (1H, s, OH). 13C NMR (75
MHz, CDCl3): δC 33.9 (CH2), 40.1 (CH13), 51.9 (OMe), 56.2 (CH10), 56.3 (CH2), 98.5 (C11),
111.5 (C16), 125.6 (2CHortho of Ph), 126.2 (CH6), 126.5 (CH4), 126.6 (CHpara of Ph), 127.7 (2CH
of Ar), 128.0 (CH5), 129.1 (2CHmeta of Ph), 129.8 (CH7), 130.7 (2CH of Ar), 132.8 (C3), 135.1
(C8), 135.9 (Cipso–Cl), 137.9 (Cipso–CO), 138.8 (Cipso-NH), 153.7 (C15), 167.5 (C-OH), 171.3
(CO2Me), 187.6 (C=O).
4.1.4.
Methyl
15-anilino-12-hydroxy-16-(4-methoxybenzoyl)-14-thia-1-azatetracyclo
[8.6.0.02,13.03,8]hexadeca-3(8),4,6,11,15-pentaene-11-carboxylate (4d). Cream powder, mp =
167-170 °C, 0.45 g, yield: 85%. IR (KBr) (νmax, cm-1): 3430 (OH and NH), 1630 (C=O), 1604
(CO2Me), 1538 and 1445 (Ar), 1248, 1170 and 1113 (C-O). Anal. Calcd. for C30H26N2O5S
(526.60): C, 68.43; H, 4.98; N, 5.32%. Found: C, 68.40; H, 4.96; N, 5.30%. MS (EI, 70 eV): m/z
(%) = 523 (M+, 2), 494 (2), 368 (2), 281 (4), 236 (6), 203 (5), 183 (13), 135 (100), 115 (4), 97
1
2
(18), 77 (53), 57 (38). H NMR (400.13 MHz, CDCl3): δH 2.31 (1H, d, JHH = 16.4 Hz, CH2),
2
2.05 (1H, dd, JHH = 16.4 Hz, 3JHH = 5.2 Hz, CH2), 3.45 (1H, s, CH13), 3.64 (3H, s, OMe), 3.68
3
3
(1H, d, JHH = 4.0 Hz, CH10), 3.77 (3H, s,OMe),4.42 (1H, s, CH2), 6.78 (2H, d, JHH = 8.8 Hz,
3
2CH of Ar), 6.92 (1H, t, JHH = 4.8 Hz, CH of Ar), 7.12-7.31 (8H, m, 8CH of Ar and Ph), 7.84
3
13
(2H, d, JHH = 8.8 Hz, 2CH of Ar), 11.76 (1H, s, NH), 12.81 (1H, s, OH). C NMR (100.00
MHz, CDCl3): δC 33.9 (CH2), 40.0 (CH13), 51.8 (OMe), 55.3 (CH10), 56.1 (OMe), 56.2 (CH2),
98.7 (C11), 112.7 (2CH of Ar), 119.1 (C16), 125.3 (2CHortho of Ph), 125.9 (CH6), 126.2 (CH4),

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126.7 (CHpara of Ph), 127.9 (CH7), 129.0 (2CHmetaof Ph), 129.8 (CH5), 131.4 (2CH of Ar), 132.8
(C3), 133.0 (C8), 135.4 (Cipso–CO), 138.4 (Cipso–NH), 151.6 (C15), 161.2 (Cipso–OMe), 167.6 (C-
OH), 171.4 (CO2Me), 189.7 (C=O).
4.1.5.
Methyl
16-benzoyl-15-(3-bromoanilino)-12-hydroxy-14-thia-1-azatetracyclo
[8.6.0.02,13.03,8]hexadeca-3(8),4,6,11,15-pentaene-11-carboxylate (4e). Yellow powder, mp =
135-139 °C, 0.50 g, yield: 87%. IR (KBr) (νmax, cm-1): 3435 (OH and NH), 1657 (C=O), 1622
(CO2Me), 1531 and 1441 (Ar), 1244, 1198 and 1069 (C-O). Anal. Calcd. for C29H23BrN2O4S
1
(574.47): C, 60.53; H, 4.03; N, 4.87%. Found: C, 60.31; H, 3.96; N, 4.80%. H NMR (300.13
2
2
3
MHz, CDCl3): δH 2.34 (1H, d, JHH = 15.9 Hz, CH2), 2.52 (1H, dd, JHH = 16.2 Hz, JHH = 4.9
Hz, CH2), 3.58 (1H, s, CH13), 3.73 (3H, s, OMe), 3.81 (1H, d, 3JHH = 4.5 Hz, CH10), 4.49 (1H, s,
CH2), 6.98 (1H, d, 3JHH = 5.1 Hz, CH of Ar), 7.24-7.28 (6H, m, 6CH of Ar), 7.36 (2H, t, 3JHH
=
3
7.2 Hz, 2CHmeta of Ph), 7.42 (1H, t, JHH = 7.2 Hz, CHpara of Ph), 7.53 (1H, s, CH of Ar), 7.83
3
13
(2H, d, JHH = 7.2 Hz, 2CHortho of Ph), 11.86 (1H, s, NH), 12.93 (1H, s, OH). C NMR (75
MHz, CDCl3): δC 33.7 (CH2), 40.1 (CH13), 51.9 (OMe), 56.1 (CH10), 56.2 (CH2), 98.6 (C11),
119.7 (C16), 122.5 (Cipso-Br), 123.5 (CH of Ar), 126.2 (CH of Ar), 126.7 (CH6), 127.5 (2CHortho
of Ph), 127.8 (CH4), 127.9 (CH of Ar), 128.7 (CH of Ar), 129.1 (2CHmeta of Ph), 129.7 (CH5),
130.1 (CHpara of Ph), 130.3 (CH7), 132.9 (C3), 135.0 (C8), 139.7 (Cipso–CO), 140.1 (Cipso–NH),
151.3 (C15), 167.3 (C–OH), 171.3 (CO2Me), 191.4 (C=O).
4.1.6.
Methyl
16-benzoyl-15-(2,4-dichloroanilino)-12-hydroxy-14-thia-1-
azatetracyclo[8.6.0.02,13.03,8]hexadeca-3(8),4,6,11,15-pentaene-11-carboxylate (4f). Yellow
powder, mp = 165-167 °C, 0.30 g, yield: 53%. IR (KBr) (νmax, cm-1): 3438 (OH and NH), 1670
(C=O), 1642 (CO2Me), 1529 and 1477 (Ar), 1251, 1174 and 1083 (C-O). Anal. Calcd. for
C29H22Cl2N2O4S (565.47): C, 61.60; H, 3.92; N, 4.95%. Found: C, 61.31; H, 3.66; N, 4.70%. 1H
NMR (300.13 MHz, CDCl3): δH 2.36 (1H, d, 2JHH = 16.2 Hz, CH2), 2.53 (1H, dd, 2JHH = 16.5 Hz,
3
3JHH = 4.9 Hz, CH2), 3.61 (1H, s, CH13), 3.74 (3H, s, OMe), 3.87 (1H, d, JHH = 5.1 Hz, CH10),

ACCEPTED MANUSCRIPT
13
3
4.48 (1H, s, CH2), 6.98 (1H, d, JHH = 5.1 Hz, CH of Ar), 7.24-7.28 (4H, m, 4CH of Ar), 7.36
3
(2H, t, 3JHH = 7.2 Hz, 2CHmeta of Ph), 7.43 (1H, d, JHH = 7.5 Hz, CH of Ar), 7.45 (1H, s, CH of
3
3
Ar), 7.52 (1H, d, JHH = 8.4 Hz, CH of Ar), 7.87 (2H, d, JHH = 8.4 Hz, 2CHortho of Ph), 11.88
13
(1H, s, NH), 12.58 (1H, s, OH). C NMR (75 MHz, CDCl3): δC 33.6 (CH2), 40.2 (CH13), 51.9
(OMe), 55.9 (CH10), 56.1 (CH2), 98.7 (C11), 104.9 (C16), 126.1 (CH6), 126.3 (CH4), 126.7 (CH of
Ar), 127.1 (CH of Ar), 127.5 (2CHmeta of Ph), 128.0 (CH of Ar), 129.4 (2CHortho of Ph), 129.7
(CH5),129.8 (Cipso-Cl), 129.9 (CH7), 130.5 (CHpara of Ph), 130.9 (Cipso-Cl), 132.9 (C3), 134.9
(C8), 139.8 (Cipso–CO), 144.5 (Cipso–NH), 154.2 (C15), 167.4 (C-OH), 176.8 (CO2Me), 194.4
(C=O).
4.1.7.
Methyl
16-benzoyl-15-(4-fluoroanilino)-12-hydroxy-14-thia-1-
azatetracyclo[8.6.0.02,13.03,8]hexadeca-3(8),4,6,11,15-pentaene-11-carboxylate (4g). Yellow
powder, mp = 166-169 °C, 0.4 g, yield: 77%. IR (KBr) (νmax, cm-1): 3438 (OH and NH), 1655
(C=O), 1620 (CO2Me), 1516 and 1442 (Ar), 1289, 1236 and 1190 (C-O). Anal. Calcd. for
C29H23FN2O4S (514.57): C, 67.69; H, 4.51; N, 5.44%. Found: C, 67.58; H, 4.49; N, 5.42%. MS
(EI, 70 eV): m/z (%) = 514 (9), 482 (9), 456 (62), 423 (3), 390 (3), 367 (12), 346 (6), 326 (12),
1
297 (9), 269 (6), 235 (10), 211 (6), 185 (6), 153 (11), 130 (60), 105 (100), 77 (99), 51 (21). H
NMR (400.13 MHz, CDCl3): δH 2.31 (1H, d, 2JHH = 16.4 Hz, CH2), 2.53 (1H, dd, 2JHH = 16.4 Hz,
3
3JHH = 4.8 Hz, CH2), 3.54 (1H, s, CH13), 3.73 (1H, d, JHH = 3.2 Hz, CH10), 3.74 (3H, s, OMe),
4.48 (1H, s, CH2), 6.98 (1H, t, 3JHH = 4.8 Hz, CH of Ar), 7.09 (2H, t, 3JHH = 8.8 Hz, 2CH of Ar),
7.23-7.43 (8H, m, 8CH of Ph and Ar), 7.84 (2H, d, 3JHH = 8.0 Hz, 2CHortho of Ph), 11.87 (1H, s,
NH), 12.87 (1H, s, OH). 13C NMR (100.00 MHz, CDCl3): δC 33.8 (CH2), 40.2 (CH13), 51.9
2
(OMe), 56.2 (CH10), 56.2 (CH2), 98.6 (C11), 115.9 (d, JCF = 22.5 Hz, 2CH of Ar), 118.6 (C16),
3
126.2(CH6), 126.6 (CH4), 127.5 (2CHmeta of Ph), 127.8 (d, JCF = 8.5 Hz, 2CH of Ar), 127.9
(CH7), 129.0 (2CHortho of Ph), 129.7 (CH5), 129.9 (CHpara of Ph), 133.0 (C3), 134.1 (C8), 135.2

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14
1
(Cipso–CO), 140.4 (Cipso–NH), 153.5 (C15), 161.1 (d, JCF = 245.3 Hz, Cipso–F), 167.5 (C-OH),
171.4 (CO2Me), 190.9 (C=O).
4.1.8.
Methyl
15-(3-bromoanilino)-16-(4-bromobenzoyl)-12-hydroxy-14-thia-1-
azatetracyclo [8.6.0.02,13.03,8]hexadeca-3,5,7,11,15-pentaene-11-carboxylate (4h). Orange
powder, mp = 197-199 °C, 0.50 g, yield: 76%. IR (KBr) (νmax, cm-1): 3427 (OH and NH), 1658
(C=O), 1622 (CO2Me), 1578 and 1442 (Ar), 1241, 1194 and 1113 (C-O). Anal. Calcd. for
C29H22Br2N2O4S (654.37): C, 53.23; H, 3.39; N, 4.28%. Found: C, 53.15; H, 3.26; N, 4.20%. 1H
NMR (300.13 MHz, CDCl3): δH 2.40 (1H, d, 2JHH = 16.2 Hz, CH2), 2.60 (1H, dd, 2JHH = 16.2 Hz,
3
3JHH = 4.8 Hz, CH2), 3.78 (1H, s, CH13), 3.70 (1H, d, JHH = 4.0 Hz, CH10), 3.74 (3H, s, OMe),
3
4.48 (1H, s, CH2), 7.02 (1H, d, JHH = 5.1 Hz, CH of Ar), 7.24-7.38 (6H, m, 6CH of Ar), 7.50
3
3
(2H, d, JHH = 8.4 Hz, 2CH of Ar), 7.52 (1H, s, CH of Ar), 7.75 (2H, d, JHH = 8.4 Hz, 2CH of
13
Ar), 11.85 (1H, s, NH), 12.98 (1H, s, OH). C NMR (75 MHz, CDCl3): δC 33.8 (CH2), 40.1
(CH13), 51.9 (OMe), 56.1 (CH10), 56.3 (CH2), 98.5 (C11), 119.3 (C16), 122.5 (Cipso-Br), 123.7
(CH of Ar), 124.7 (Cipso-Br), 126.3 (CH of Ar), 126.7 (CH6), 128.0 (CH of Ar), 128.1 (CH4),
129.0 (CH of Ar), 129.8 (CH5), 130.3 (CH7), 130.7 (2CH of Ar), 130.9 (2CH of Ar), 132.7 (C3),
134.9 (C8), 138.9 (Cipso–CO), 139.5 (Cipso–NH), 152.3 (C15), 167.3 (C-OH), 171.3 (CO2Me),
189.6 (C=O).
4.1.9.
Methyl
16-(4-Bromobenzoyl)-15-(4-fluoroanilino)-12-hydroxy-14-thia-1-
azatetracyclo [8.6.0.02,13.03,8]hexadeca-3,5,7,11,15-pentaene-11-carboxylate (4i). Yellow
powder, mp = 184-188 °C, 0.45 g, yield: 75%. IR (KBr) (νmax, cm-1): 3422 (OH and NH), 1657
(C=O), 1619 (CO2Me), 1512 and 1441 (Ar), 1232, 1190 and 1131 (C-O). Anal. Calcd. for
C29H22BrFN2O4S (593.46): C, 58.69; H, 3.74; N, 4.72%. Found: C, 58.60; H, 3.96; N, 4.65%.
MS (EI, 70 eV): m/z (%) = 592 (26), 562 (28), 536 (19), 445 (5), 406 (3), 377 (9), 349 (5), 312
(9), 221 (19), 183 (100), 155 (56), 129 (85), 95 (32), 69 (27). 1H NMR (400.13 MHz, CDCl3): δH
2.40 (1H, d, 2JHH = 16.4 Hz, CH2), 2.61 (1H, dd, 2JHH = 16.4 Hz, 3JHH = 5.2 Hz, CH2), 3.53 (1H,

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15
3
s, CH13), 3.71 (1H, d, JHH = 4.0 Hz, CH10), 3.75 (3H, s, OMe), 4.47 (1H, s, CH2), 7.02 (1H, t,
3JHH = 4.8 Hz, CH of Ar), 7.09 (2H, t, 3JHH = 8.4 Hz, 2CH of Ar), 7.22-7.33 (5H, m, 5CH of Ph
and Ar), 7.50 (2H, d, 3JHH = 8.4 Hz, 2CH of Ar), 7.76 (2H, d, 3JHH = 8.4 Hz, 2CH of Ar), 11.86
13
(1H, s, NH), 12.91 (1H, s, OH). C NMR (100.00 MHz, CDCl3): δC 33.9 (CH2), 40.2 (CH13),
2
51.9 (OMe), 56.2 (CH10), 56.3 (CH2), 98.5 (C11), 116.0 (d, JCF = 21.5 Hz, 2CH of Ar) 118.4
3
(C16), 124.4 (Cipso-Br), 126.3 (CH6), 126.6 (CH4), 127.9 (CH7), 128.0 (d, JCF = 8.8 Hz, 2CH of
Ar), 129.9 (CH5), 130.7 (2CH of Ar), 130.9 (2CH of Ar), 132.8 (C3), 133.85 (C8), 135.0 (Cipso
–
1
CO), 139.2 (Cipso-NH), 154.3 (C15), 161.2 (d, JCF = 245.6 Hz, Cipso–F), 167.4 (C-OH), 171.3
(CO2Me), 189.2 (C=O).
4.1.10. Methyl
15-(3-bromoanilino)-16-(4-chlorobenzoyl)-12-hydroxy-14-thia-1-
azatetracyclo [8.6.0.02,13.03,8]hexadeca-3,5,7,11,15-pentaene-11-carboxylate (4j). Orange
powder, mp = 207-213 °C, 0.50 g, yield: 82%. IR (KBr) (νmax, cm-1): 3431 (OH and NH), 1659
(C=O), 1621 (CO2Me), 1546 and 1438 (Ar), 1245, 1193 and 1087 (C-O). Anal. Calcd. for
C29H22BrClN2O4S (609.92): C, 57.11; H, 3.64; N, 4.59%. Found: C, 56.95; H, 3.26; N, 4.50%.
1H NMR (300.13 MHz, CDCl3): δH 2.40 (1H, d, 2JHH = 16.2 Hz, CH2), 2.60 (1H, dd, 2JHH = 16.2
3
3
Hz, JHH = 5.1 Hz, CH2), 3.58 (1H, s, CH13), 3.69 (1H, d, JHH = 4.8 Hz, CH10), 3.74 (3H, s,
OMe), 4.48 (1H, s, CH2), 7.02 (1H, d, 3JHH = 4.2 Hz, CH of Ar), 7.24-7.28 (6H, m, 6CH of Ar),
7.34 (2H, d, 3JHH = 7.2 Hz, 2CH of Ar), 7.52 (1H, s, CH of Ar), 7.82 (2H, d, 3JHH = 7.2 Hz, 2CH
13
of Ar), 11.85 (1H, s, NH), 12.97 (1H, s, OH). C NMR (75 MHz, CDCl3): δC 33.8 (CH2), 40.0
(CH13), 51.9 (OMe), 56.1 (CH10), 56.3 (CH2), 98.5 (C11), 119.3 (C16), 122.5 (Cipso-Br), 123.7
(CH of Ar), 126.3 (CH of Ar), 126.7 (CH6), 127.8 (2CHof Ar), 127.9 (CH4), 128.0 (CH of Ar),
128.9 (CH of Ar), 129.8 (CH5), 130.3 (CH7), 130.7 (2CH of Ar), 132.7 (C3), 135.0 (C8), 136.2
(Cipso–Cl), 138.5 (Cipso–CO), 139.5 (Cipso-NH), 152.2 (C15), 167.3 (C-OH), 171.3 (CO2Me), 189.5
(C=O).

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16
4.1.11. Methyl
16-(4-chlorobenzoyl)-15-(2,4-dichloroanilino)-12-hydroxy-14-thia-1-
azatetracyclo[8.6.0.02,13.03,8]hexadeca-3,5,7,11,15-pentaene-11-carboxylate (4k). Yellow
powder, mp = 213-217 °C, 0.45 g, yield: 79%. IR (KBr) (νmax, cm-1): 3437 (OH and NH), 1670
(C=O), 1624 (CO2Me), 1532 and 1477 (Ar), 1247, 1197 and 1084 (C-O). Anal. Calcd. for
C29H21Cl3N2O4S (599.91): C, 58.06; H, 3.53; N, 4.67%. Found: C, 58.01; H, 3.46; N, 4.50%. 1H
NMR (300.13 MHz, CDCl3): δH 2.42 (1H, d, 2JHH = 16.2 Hz, CH2), 2.62 (1H, dd, 2JHH = 16.2 Hz,
3
3JHH = 5.1 Hz, CH2), 3.60 (1H, s, CH13), 3.72 (1H, d, JHH = 4.5 Hz, CH10), 3.75 (3H, s, OMe),
3
4.47 (1H, s, CH2), 7.02 (1H, d, JHH = 5.1 Hz, CH of Ar), 7.25-7.28 (4H, m, 4CH of Ar), 7.34
(2H, d, 3JHH = 8.4 Hz, 2CH of Ar), 7.47 (1H, d, 4JHH = 1.8 Hz, CH of Ar), 7.51 (1H, d, 3JHH = 8.4
3
Hz, CH of Ar), 7.86 (2H, d, JHH = 8.4 Hz, 2CH of Ar), 11.87 (1H, s, NH), 12.98 (1H, s, OH).
13C NMR (75 MHz, CDCl3): δC 33.7 (CH2), 40.1 (CH13), 51.9 (OMe), 56.1 (CH10), 56.2 (CH2),
98.6 (C11), 120.6 (C16), 126.3 (CH6), 126.4 (CH4), 126.7 (CH of Ar), 127.2 (CH of Ar), 127.8
(2CH of Ar), 128.1 (CH of Ar), 129.78 (Cipso-Cl), 129.8 (CH5), 129.9 (CH7), 130.9 (2CH of Ar),
131.2 (Cipso-Cl), 132.7 (C3), 134.6 (C8), 134.7 (Cipso–Cl), 136.5 (Cipso–CO), 138.1 (Cipso-NH),
150.5 (C15), 167.1 (C-OH), 171.2 (CO2Me), 189.9 (C=O).
Acknowledgements
Financial support of this research from Tarbiat Modares University, Iran is gratefully
acknowledged.
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