Regioselective sulfonylation and N- to O-sulfonyl migration of quinazolin-4(3H)-ones and analogous thienopyrimidin-4(3H)-ones

Article abstract of DOI:10.1021/jo4010876

The sulfonylation of quinazolin-4(3H)-ones and related tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones with mesyl, tosyl, and p-cyanobenzenesulfonyl chloride was studied. A hydrogen substituent at 2-position directed the sulfonyl group to the N-3 position, while alkylsulfanyl or amino substituents led to sulfonylation of the carbonyl oxygen. The latter effect was attributed to steric influence and the positive mesomeric effect of the 2-substituent. An access to N-sulfonylated 2-substituted regioisomers was established. An unexpected 1,3-sulfonyl migration was observed and further analyzed. This process occurred as an intramolecular N- to O-shift as verified by kinetic and crossover experiments.

Full text of DOI:10.1021/jo4010876

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Regioselective Sulfonylation and N- to O‑Sulfonyl Migration of
Quinazolin-4(3H)‑ones and Analogous Thienopyrimidin-4(3H)‑ones
Matthias D. Mertens,† Markus Pietsch,†,§ Gregor Schnakenburg,‡ and Michael Gutschow*,†
̈
†Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
‡Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany
S
* Supporting Information
ABSTRACT: The sulfonylation of quinazolin-4(3H)-ones
and related tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-
ones with mesyl, tosyl, and p-cyanobenzenesulfonyl chloride
was studied. A hydrogen substituent at 2-position directed the
sulfonyl group to the N-3 position, while alkylsulfanyl or
amino substituents led to sulfonylation of the carbonyl oxygen.
The latter effect was attributed to steric influence and the
positive mesomeric effect of the 2-substituent. An access to N-
sulfonylated 2-substituted regioisomers was established. An
unexpected 1,3-sulfonyl migration was observed and further analyzed. This process occurred as an intramolecular N- to O-shift as
verified by kinetic and crossover experiments.
the SO2 center by S−O bond scission,3,4 and a competing C−O
INTRODUCTION
■
bond cleavage occurs to release the sulfonate anion from a
Nucleophilic displacement reactions of sulfonamides and
Meisenheimer-type intermediate.1
sulfonates are characterized by competitive reaction pathways
N-Unsubstituted O-sulfonyl hydroxamic acids are substrates
and have been the subject of numerous mechanistic studies and
for the Lossen rearrangement, whereas N-substituted derivates
synthetic applications. The underlying mechanistic variations
behave differently in the presence of nucleophiles. By
are known to depend on the nucleophile, the solvent, and
concomitant loss of the sulfonyl group, amides or lactams
explicitly, the substrate, i.e., the structure of the parent sulfonic
with the newly introduced substituent in α-position are
acid and the amine or alcohol/phenol portion, respectively.1
formed.5 In N-(sulfonyloxy)imides (Chart 1, C), the typical
Sulfonamides composed of basic amines are notably stable to
reaction is initiated by the nucleophilic attack at the carbonyl
alkaline hydrolysis and other conditions, whereas sulfonamides
carbon followed by the expulsion of the sulfonate,6,7 but a
of less basic amines are easier to cleave due to their improved
nucleophilic displacement at the sulfonate sulfur is also
possible.8 Moreover, α-sulfonyl carbanions of alkanesulfonates
nucleofugality. Alternatively, arenesulfonamides can undergo a
nucleophilic aromatic substitution at the ipso-carbon of the
or -sulfonamides can attack electrophilic sites to undergo
intramolecular or intermolecular coupling reactions.9 Thus, in
electron-poor aromatic ring (Chart 1, A; nucleophilic attacks
are indicated by arrows) as utilized in nosyl protecting groups.2
heterocyclic chemistry, different sulfonyl transfer reactions may
have to be considered, for example, for the targeted preparation
of N- or O-sulfonylated lactams and their utilization for
subsequent chemical transformations.
In common nucleophilic substitutions of alkyl sulfonates, the
sulfonate anion serves as leaving group. In aryl sulfonates
(Chart 1, B), nucleophilic displacement reactions take place at
In this study, we examined sulfonylation reactions of
Chart 1. Possible Sites for Nucleophilic Attack at
Arenesulfonamides, Aryl Sulfonates, N-(Sulfonyloxy)imides,
and Fused 3-(Arylsulfonyl)pyrimidin-4(3H)-ones
quinazolin-4(3H)-ones and related thieno[2,3-d]pyrimidin-
4(3H)-ones. While the regioselectivity of alkylation of such
systems has been investigated,10,11 corresponding reports on
sulfonylation of fused pyrimidinones are lacking. The products,
i.e., N- or O-sulfonylated heterocycles, possess biological
activities and represent attractive intermediates for diverse
transformations. Fused pyrimidin-4(3H)-ones, e.g., unsubsti-
tuted in the 2-position and bearing an arylsulfonyl substituent
at N-3, are susceptible to nucleophilic attack at four positions
(Chart 1, D).12
Received: July 2, 2013
© XXXX American Chemical Society
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Table 1. Preparation of N- and O-Sulfonylated Fused Pyrimidines 11−14
Quinazoline-2,4-diones with aromatic sulfonyl groups at
position N-3 were identified as inhibitors of the serine protease
chymase. Their interaction with the target enzyme was assumed
to involve a nucleophilic attack of the active-site serine at the
C‑4 carbonyl followed by ring-opening.13 In addition, related
compounds are useful in heterocyclic syntheses. For example,
N-3 tosyl-substituted quinazolin-4(3H)-one undergoes a ring-
opening−recyclization reaction with primary alkylamines to
afford 3-alkylquinazolin-4(3H)-ones upon loss of tosyl amide.14
Inosines bearing aromatic sulfonyl groups at position N-1
(corresponding to N-3 in pyrimidin-4(3H)-ones) have been
studied in detail with respect to their reactivity toward primary
aliphatic amines. An initial attack at C-2 and alternate ring
closure reactions of the ring-open intermediates yield various
types of products.15
O-Sulfonylated fused pyrimidin-4(3H)-ones have attracted
attention as versatile electrophilic intermediates. For example,
activation of quinazolin-4(3H)-ones with tosyl chloride
generates a sulfonate structure, which is subsequently replaced
with thiols or amines.16 Arylsulfonyloxy groups were
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introduced at C-6 of purines (corresponding to position C-4 in
pyrimidines) and successfully used for the preparation of
corresponding amines, O-alkyl or O-aryl ethers.17,18 Further-
more, 6-arylsulfonyloxy purines are valuable building blocks for
Pd-catalyzed cross-couplings. Such derivatives of 2′-deoxygua-
nosine or guanosine were shown to undergo Suzuki-Miyaura
reactions with arylboronic acids,19 and were employed as
halogen surrogates in Stille-type reactions with vinyltributyl-
stannane.20 Similarly, 4-arylsulfonyloxy derivatives of uridines
and thymidines were successfully utilized in C−C coupling
reactions.21,22
With the exception of 2,4,6-triisopropylbenzenesulfonyl
chloride, the nature of the reagent, i.e., aliphatic (mesyl),
electron-rich aromatic (tosyl), or electron-deficient aromatic
(p-cyanobenzenesulfonyl chloride), did not influence the
regioselectivity of the reaction.
The structures of the two types of products were elucidated
1
on the basis of H and 13C NMR spectra and confirmed by X-
ray diffraction analyses, both for two representative N-
sulfonylated derivatives (11d and 12b; see the Supporting
Information, Figures S1 and S2) and for seven O-sulfonylated
derivatives 14d, 13e, 14e, 14f, 14g, 14k, and 14o (see the
Supporting Information, Figures S3−9). Comparison of the 13C
NMR resonances of the N- and O-isomers revealed diagnostic
differences (see below).
Our results are in accordance with the reported N-
sulfonylation of quinazolin-4(3H)-one 1.14,26 Analogously,
reaction of inosine derivatives with 2,4-dinitrobenzenesulfonyl
chloride or ortho-nosyl chloride only gave N-sulfonylated
products.12,15 Mixtures of N- and O-sulfonylated products
were formed in reactions of hypoxanthine nucleosides with
2,4,6-triisopropylbenzenesulfonyl chloride,18 whereas 2-isobu-
tyrylamino and 2-(dimethylamino)methyleneamino hypoxan-
thines and as well as 2-amino, 2-tritylamino, acetylamino and 2-
benzoylamino guanosines furnished O-sulfonylated compounds
when reacted with aromatic sulfonyl chlorides.4,23 Reactions of
thymidines and uridines with aromatic sulfonyl chlorides
resulted in 4-sulfonyloxy products.21,22,24
RESULTS AND DISCUSSION
■
As initial part of this study, we investigated the regioselectivity
of the sulfonylation of a series of representative fused
pyrimidin-4-ones (1−10). Three sulfonyl chlorides, i.e.,
mesyl, tosyl, and p-cyanobenzenesulfonyl chloride, were reacted
with 1−10 in dichloromethane in the presence of DIPEA (N,N-
diisopropylethylamine) and DMAP (4-dimethylaminopyridine)
at room temperature (Table 1, all entries except of entries 4
and 8), and the main products of these transformations were
isolated. On the one hand, N-sulfonylated compounds (11a−c
and 12a−c) were obtained in good yields from quinazoline 1
and thienopyrimidine 2, bearing no substitutent at position 2
(R1 = H). On the other hand, starting materials 3−10 with
various substituents R1 in position 2 gave exclusively the
corresponding O-sulfonylated products.
For the exemplary preparation of the 2-substituted N-
sulfonyl compounds, which were not accessible via direct
sulfonylation of pyrimidinones 3−10, we followed another
synthetic strategy. It includes, similar to the preparation of 3-
arylsulfonylquinazoline-2,4-diones,13 the attachment of the
sulfonyl group to the terminal nitrogen of an isothiourea
moiety prior to cyclization (Scheme 1). Starting from 2-
nitrobenzoic acid (15), the corresponding tert-butyl ester was
A steric influence of the sulfonylating reagent was studied by
treating 1 and 2 with the sterically demanding 2,4,6-
triisopropylbenzenesulfonyl chloride (Table 1, entries 4 and
8). This reagent has frequently been used for O-sulfonylations
of related lactams.4,22−24 The reaction of the quinazolinone 1
afforded the N-sulfonylated product 11d, whereas the
thienopyrimidinone 2 gave the O-sulfonylated product 14d.
A strong impact of the substituent at position 2 on the
outcome of the sulfonylation was observed. A hydrogen
substituent with the lowest steric hindrance for an electrophilic
attack at the adjacent N-3 position allowed for the sulfonylation
of the lactam nitrogen. The only exception (entry 8) was the
formation of 14d from 2,4,6-triisopropylbenzenesulfonyl
chloride and the thienopyrimidinone 2. The quinazolinone 1
gave exclusively 3-sulfonylated products, even with 2,4,6-
triisopropylbenzenesulfonyl chloride (entry 4). The different
behavior of 1 and 2 might be attributed to an increased electron
density of the carbonyl oxygen in 2 due to the anellated
thiophene ring.25 The larger 2-substituents (i.e., methylsulfanyl,
benzylsulfanyl, morpholino, N-benzyl-N-methylamino) directed
the sulfonyl group to the carbonyl oxygen. In addition to the
steric influence, the positive mesomeric effect of these
substituents, connected to carbon C-2 via S or N atoms, is
expected to contribute to O-sulfonylation. Such substituents
can donate their lone pair for resonance, which leads to an
increased electron density at the oxygen (Chart 2).10
a
Scheme 1. Synthesis of the N-Sulfonylated Quinazoline 11e
Chart 2. Mesomeric Effect of the 2-Substituent (X = N-Alk,
S) in Fused Pyrimidin-4(3H)-ones
a
Reagents and conditions: (a) (i) (COCl)2, cat. DMF, CH2Cl2, 2 h;
(ii) t-BuOH, cat. ZnCl2, pyridine, 12 h; (b) H2, Pd/C (10%), EtOH, 3
days; (c) CSCl2, Et3N, EtOAc, −78 °C to rt, 12 h; (d) TsNH2, K2CO3,
acetone, reflux, 20 h; (e) MeI, EtOH, NaOH(aq), 2 h; (f) TFA, 2 h; (g)
CDI, THF, 1 h.
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prepared with oxalyl chloride and a catalytic amount of DMF,
followed by the treatment with tert-butyl alcohol in the
presence of pyridine and ZnCl2. The resulting ester 16 was
hydrogenated using Pd/C to give the tert-butyl ester of
anthranilic acid (17). Upon treatment with thiophosgene, 17
was converted to the isothiocyanate 18. Reaction with p-
toluenesulfonamide in the presence of potassium carbonate
yielded the corresponding sulfonylthiourea 19, which was S-
methylated to give 20. Cleavage of the ester group with
trifluoroacetic acid produced the benzoic acid derivative 21.
While 2-thioureidobenzoic acids are readily accessible in their
open-chain structure, in particular if an electron withdrawing
group is placed at the terminal nitrogen,27 benzoic acids with an
adjacent isothioureido group have not been described so far.
Compound 21 was cyclized by activating the carboxylic acid
with CDI to yield the desired N-tosylated product 11e.
Oxalyl chloride was not applicable for the cyclization of the
benzoic acid derivative 21 (Scheme 1) as, instead of 11e, the
corresponding desulfonylated quinazolinone 3 (for structure,
see Table 1) and tosyl chloride were isolated. These products
originate from the nucleophilic attack of chloride at the sulfur
atom of 11e. The different behavior reflects the decreased
electron density of the quinazolinone in comparison to the
thienopyrimidinone scaffold. This finding indicates the ability
of N-3 sulfonylated fused pyrimidines to act as sulfonyl donors.
In their 13C NMR spectra, the three downfield signals were
found to be indicative to distinguish between the substrates of
the sulfonylation reaction, the N-sulfonylated products 11 and
12 and the isomeric O-sulfonylated products 13 and 14. For
example, in the case of the N-sulfonyl quinazoline 11e, the
three downfield carbon shifts (146.1, 154.2, 161.2 ppm for C-2,
C-4 and C-8a) appeared at higher field than in 3 (149.2, 155.2,
163.1 ppm for C-2, C-4 and C-8a). On the contrary, the signals
for the O-sulfonylated quinazoline 13e were shifted downfield
(153.3, 160.9, 166.9 ppm for C-2, C-4 and C-8a) in comparison
to the substrate 3. For the thienopyrimidine series, similar shift
differences were noticed. The N-sulfonylated thienopyrimidines
12e, 12f, 12g, 12h, and 12j showed resonances (∼155, ∼157,
∼160 ppm for C-2, C-4, C-9a) similar to or at higher field than
the unsulfonylated compounds 4 and 6 (∼155, ∼158, ∼163
ppm for C-2, C-4, C-9a). A notable downfield shift occurred for
two of the three downfield carbon signals as a result of the O-
sulfonylation of 4 and 6 to 14e, 14f, 14g, 14h, and 14j (∼156,
∼165, ∼171 ppm for C-2, C-4, and C-9a). The corresponding
signals for 2-unsubstituted, O-sulfonylated 14d appeared at
151.2, 157.8, and 170.1 ppm.
In order to receive further pairs of isomeric N- and O-
sulfonated compounds, in addition to the quinazolines 11e and
13e, a subseries of N-sulfonylated tetrahydrobenzothienopyr-
imidines was prepared. For this purpose, the established
synthetic route was transferred to the thiophene scaffold
(Scheme 2). Isothiocyanate 22 was synthesized28 and
Scheme 2. Synthesis of N-Sulfonylated Thieno[2,3-
a
d]pyrimidines 12e−h,j
When inspecting different cyclization conditions, 27e
(Scheme 2) was also treated with boiling acetic anhydride.
Instead of 12e, we obtained the isomeric O-sulfonylated
product 14e (for structure, see Table 1) suggesting that an
unexpected migration of the sulfonyl group from the nitrogen
atom to the carbonyl oxygen might have occurred.33 To proof
this hypothesis, compound 12e was heated in acetonitrile and
the course of the reaction was monitored by HPLC (Figure 1,
see also the Supporting Information, Figure S11). The
separation of both regioisomers was accomplished using an
isocratic elution. Indeed, 12e was completely converted to 14e
and side products were only formed to minor extent. The
reaction followed a first-order kinetics and the analysis of the
migration process by nonlinear regression using the equation
for exponential decay gave a first-order rate constant of 0.0041
0.0001 min−1. These data confirm the postulated sulfonyl
transfer to the thermodynamically more stable O-sulfonylated
isomer and are also in agreement with the results of the direct
sulfonylation as outlined in Table 1. However, the educts which
are unsubstituted at 2-position, i.e., 1 and 2, behaved differently
and were predominately sulfonylated at the nitrogen N-3.
When 12a was heated in acetonitrile over 24 h, it remained
unchanged. Thus, an N- to O-transfer did not occur, which
indicates that in this case the N-sulfonylated products represent
the thermodynamically favored isomers.
a
Reagents and conditions: (a) R2SO2NH2, K2CO3, acetone, reflux, 20
h (R2 = C6H4-4-Me or C6H4-4-CN) or NaH, DMF, 60 °C, 1 h (R2 =
Me); (b) R1I/Br, EtOH, NaOH(aq), 2 h; (c) TFA, 2 h; (d) (COCl)2,
cat. DMF, CH2Cl2, 1 h.
subsequently reacted with different sulfonamides. In the case
of the less acidic methanesulfonamide, sodium hydride was
applied as base according to a literature report.29 S-Alkylation
yielded compounds 26, whose tert-butyl esters were cleaved.30
The resulting 2-isothioureidothiophene-3-carboxylic acids 27
underwent cyclocondensation with oxalyl chloride to give the
final N-sulfonyl compounds 12e, 12f, 12g, 12h, and 12j. The
molecular structure of 12e is shown in the Supporting
Information (Figure S10).
Further kinetic experiments were performed to shed light on
the observed N- to O-sulfonyl migration. We repeated the
experiment in the presence of 0.2 equiv of the unsulfonylated
thienopyrimidine 4. Under the assumption of an intermolecular
sulfonyl shift,34 4 might act as sulfonyl acceptor and 12e as
donor. The additive 4 would then lead to an accelerated
sulfonyl transfer. However, we obtained the same first-order
rate constant as before (see the Supporting Information, Figure
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Figure 1. (A) N- to O-sulfonyl migration to convert 12e into 14e.
Compound 12e (1 mM) was heated in acetonitrile at 81 °C, and the
reaction mixture was subjected to HPLC analysis. (B) Chromatograms
after 0 min (bottom), 175 min (middle), and 630 min (top).
Retention times of 12e and 14e were 22.7 and 25.4 min, respectively.
(C) Relative concentrations of 12e, determined as the ratio of the
AUC of the substrate to the sum of the AUCs of substrate and
product, were plotted versus reaction time. Nonlinear regression using
the equation for exponential decay gave a first-order rate constant of
0.0041 0.0001 min−1.
Figure 2. (A) Sulfonyl migration in the presence of a potential sulfonyl
acceptor. Compounds 12e (1 mM) and 3 (0.2 mM) were heated in
acetonitrile at 81 °C and the reaction mixture was subjected to HPLC
analysis. The O-sulfonylated product 14e was exclusively formed. An
intermolecular sulfonyl migration, i.e., the conversion of 3 into 13e,
did not occur. (B) Chromatograms of the reaction mixture after 0 min
(bottom) and 495 min (middle), chromatogram of 13e (top).
Retention times were as follows: 20.6 min (12e), 2.07 min (3), 22.3
min (14e), and 8.22 min (13e). (C) Relative concentrations of 12e
were plotted versus reaction time and the first-order rate constant of
0.0045 0.0001 min−1 was obtained as described in Figure 1.
S12). The kinetic analysis of the crossover migration reaction in
the presence of 0.2 equiv of the unsulfonylated quinazoline 3 as
additive is illustrated in Figure 2. This time, a sulfonyl transfer
from the thienopyrimidine 12e to 3 would lead to the
formation of the crossover product, i.e., the O-sulfonylated
quinazoline 13e. This possible product, available by direct
sulfonylation (Table 1), was employed as reference for the
HPLC analysis. However, no additional product peak was
observed and 13e was not formed. Again, the depletion of 12e
was only accompanied by the formation of 14e and the rate
constant was similar to the previous experiments. It could be
concluded from these findings that the unsulfonylated hetero-
cycles do not function as intermediates in the sulfonyl transfer.
We therefore postulate an intramolecular 1,3-sulfonyl migration
as the underlying mechanism.
There are several literature reports on sulfonyl shifts.35,36 For
example, similar N- to O-sulfonyl shifts in pyridinones have
been observed (Chart 3, A).37 In addition to such 1,3-
migrations, the aromatization of 6-hydroxy-1-tosyl-1,6-dihydro-
2H-pyrid-3-ones and a subsequent tosyl transfer gave 3-pyridyl
tosylates (Chart 3, B). This 1,4-sulfonyl migration was assumed
to proceed as intramolecular reaction.38
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Elution was performed with an isocratic mixture of H2O and
acetonitrile (45:55). A flow rate of 2.0 mL/min was applied.
Compounds 1,45 2,46 3,47 4,31 and 547 were prepared as described.
Quinazolin-4(3H)-one (1). A mixture of 2-aminobenzoic acid (10.0
g, 73 mmol) and formamide (15 mL) was refluxed for 4 h. After the
mixture was cooled to room temperature, water (200 mL) was added
and the precipitate was filtered off. The crude product was
recrystallized from acetonitrile (100 mL) to yield 1 as a white solid
Chart 3. 1,3- and 1,4-Sulfonyl Migrations in Pyridinones
(8.44 g, 79%): mp 213−214 °C (lit.45 mp 215 °C); H NMR (500
1
3
3
4
MHz, DMSO-d6) δ 7.51 (ddd, 1H, J = 7.6 Hz, J = 7.6 Hz, J = 1.3
Hz), 7.65 (d, 1H, 3J = 7.9 Hz), 7.80 (ddd, 1H, 3J = 7.1 Hz, 3J = 8.4 Hz,
4J = 1.6 Hz), 8.08 (s, 1H), 8.11 (dd, 1H, J = 7.9 Hz, J = 1.3 Hz),
12.20 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 122.8, 126.0, 126.9,
127.3, 134.4, 145.5, 148.9, 160.9. The material’s identity was confirmed
3
4
Further 1,3-sulfonyl shifts have been described which occur
as N- to C-migrations. 3-Tosyl-4-vinylidene-2-oxazolidinones
undergo an intramolecular migration of the sulfonyl group from
N to Cα that can be promoted by enol ethers or silanes. The
reactions are proposed to pass through intermediate four-
membered sulfurane oxides.39 Such cyclic intermediates
resemble the 1,2-oxathietan-4-one-type transition states in the
intramolecular carboxyl-catalyzed hydrolysis of sulfonamides.40
An aza-Claisen-1,3-sulfonyl shift was reported when N-allyl-N-
sulfonyl ynamides were heated in toluene for several hours and
α-sulfonyl carbonitriles were formed.41 N-Alkynyl-N-sulfonyl
hydroxylamines are precursors for 3-pyrrolidinones whereby
the AuI-catalyzed cyclization is accompanied by a N- to C-
transfer.42 AuBr3-catalyzed syntheses of 3- and 6-sulfonylin-
doles were reported, with the former reactions being intra-
molecular 1,3-sulfonyl migrations.43 However, recently pub-
lished AlCl3-assisted transformations of N-sulfonyl to 7-sulfonyl
indoles were found to be nonconcerted processes involving N−
S cleavage and subsequent C-7 sulfonylation as could be
demonstrated by a crossover experiment.44
In summary, the regioselectivity of sulfonylation reactions of
quinazolin-4(3H)-ones and tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-ones was found to depend on the respective
2-substituent. 2-Unsubstituted substrates afforded predom-
inately N-sulfonylated products, whereas methylsulfanyl,
benzylsulfanyl, morpholino and N-benzyl-N-methylamino
substituents directed the sulfonyl group to the carbonyl oxygen.
A synthetic access to the corresponding N-sulfonylated isomers
was demonstrated, which relies on the attachment of the
sulfonyl group to the nitrogen atom prior to the ring closure.
We observed an N- to O-sulfonyl migration which was,
although unexpected to occur, in agreement with the
regioselectivity of the direct sulfonylations. Most likely, this
sulfonyl shift proceeded as an intramolecular event.
48
by comparison with H NMR and 13C NMR literature data.
1
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one
(2). A mixture of ethyl 2-amino-5,6,7,8-tetrahydrobenzo[b]thiophene-
3-carboxylate (2.25 g, 10 mmol) and formamide (60 mL) was refluxed
for 2 h, then left to cool to room temperature overnight. The
precipitated solid was filtered off, washed with water (50 mL), dried,
and recrystallized from EtOH (60 mL) to yield 2 as brown crystals
(1.32 g, 64%): mp 269−270 °C (lit.46 mp 259 °C); H NMR (500
1
MHz, DMSO-d6) δ 1.71−1.81 (m, 4H), 2.71−2.73 (m, 2H), 2.84−
2.87 (m, 2H), 7.97 (s, 1H), 12.23 (br s, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 21.9, 22.6, 24.6, 25.5, 122.8, 131.0, 132.2, 145.0, 157.8,
162.6. Anal. Calcd for C10H10N2OS: C, 58.23; H, 4.89; N, 13.58.
Found: C, 58.23; H, 4.86; N, 13.72.
2-(Methylsulfanyl)quinazolin-4(3H)-one (3). 2-Thioxo-2,3-dihy-
droquinazolin-4(1H)-one (2.23 g, 12.5 mmol) and NaOH (0.55 g,
13.75 mmol) were dissolved in water (62.5 mL). Methyl iodide (0.86
mL, 13.75 mmol) was added dropwise, and the solution was stirred for
3 h at room temperature. The resulting precipitate was filtered off and
washed with water (20 mL) to yield 3 as a pale brown solid (1.66 g,
69%): mp 209−210 °C (lit.47 mp 210−211 °C); 1H NMR (500 MHz,
3
3
4
CDCl3) δ 2.68 (s, 3H), 7.38 (ddd, 1H, J = 7.4 Hz, J = 7.5 Hz, J =
0.9 Hz), 7.60 (d, 1H, 3J = 7.9 Hz), 7.70 (ddd, 1H, 3J = 7.1 Hz, 3J = 8.4
Hz, 4J = 1.6 Hz), 8.24 (dd, 1H, 3J = 8.0 Hz, 4J = 1.3 Hz), 11.05 (br s,
1H); 13C NMR (125 MHz, CDCl3) δ 13.4, 119.8, 125.8, 126.4, 126.7,
134.9, 149.2, 155.2, 163.1. Anal. Calcd for C9H8N2OS·0.2H2O C,
55.20; H, 4.32; N, 14.30. Found: C, 55.17, H, 4.07; N, 14.28.
2-(Methylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (4). Ethyl 2-(3-benzoylthioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (18.0 g, 46.2 mmol) was
heated under reflux for 2 h in a mixture of EtOH (230 mL) and 1 N
NaOH (115 mL). After being cooled to room temperature, the
solution was filtered and diluted with EtOH (30 mL) and 1 N NaOH
(230 mL). Methyl iodide (4.8 mL, 77 mmol) was added dropwise, and
the mixture was stirred for an additional 2 h. A solid was obtained,
filtered off, and washed with water (80 mL) to yield 3-methyl-2-
(methylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
4(3H)-one (0.64 g, 5%). The filtrate was acidified with 2 N HCl to
precipitate 4 as a white solid (10.9 g, 90%): mp 255−257 °C (lit.31 mp
1
EXPERIMENTAL SECTION
251−255 °C); H NMR (500 MHz, DMSO-d6) δ 1.67−1.82 (br m,
■
4H), 2.49 (s, 3H), 2.66−2.68 (m, 2H), 2.79−2.81 (m, 2H), 12.50 (s,
1H); 13C NMR (125 MHz, DMSO-d6) δ 13.0, 21.9, 22.6, 24.4, 25.3,
119.0, 130.2, 130.7, 156.5, 158.2, 162.8. The material’s identity was
General Experimental Methods. Thin-layer chromatography
was carried out on aluminum sheets, silica gel 60 F254. Detection was
performed with UV light at 254 nm. Preparative column
chromatography was performed on silica gel 60 (70−230 mesh).
Petroleum ether used was a mixture of alkanes boiling between 40 and
60 °C, according to the supplier’s declaration. Melting points are
49
1
confirmed by comparison with H NMR literature data.
2-(Benzylsulfanyl)quinazolin-4(3H)-one (5). 2-Thioxo-2,3-dihydro-
quinazolin-4(1H)-one (1.78 g, 10 mmol) was dissolved in EtOH (75
mL) and 1 N NaOH (20 mL). Benzyl bromide (1.31 mL, 11 mmol)
was added dropwise, and the solution was stirred for 3 h at room
temperature. The mixture was diluted with water (70 mL) and
acidified with 2 N HCl to pH ∼3. The resulting precipitate was filtered
off and washed with water (20 mL) to yield 5 as a white solid (2.14 g,
1
uncorrected. H NMR and 13C NMR spectra were recorded at 500
and 125 MHz, unless stated otherwise. NMR spectra were recorded in
CDCl3 or DMSO-d6, and chemical shifts δ are given in ppm referring
to the signal center using the solvent peaks for reference: CDCl3 7.26/
77.0 ppm and DMSO-d6 2.49/39.7 ppm. In addition, HSQC and
HMBC spectra of representative compounds were measured. HRMS
(EI or ESI) spectra were recorded on a micrOTOF-Q spectrometer.
LC-DAD chromatograms and ESI-MS spectra were recorded on an
HPLC system with mass spectrometer. Elemental analyses were
performed for C, H, and N. HPLC was carried out with a UV detector
(λ = 220 nm) on a 5 μ C18 column, 110A, 250 × 4.60 mm, 5 μm.
80%): mp 213-215 °C (lit.47 mp 212−213 °C); H NMR (500 MHz,
1
3
CDCl3) δ 4.54 (s, 2H), 7.25−7.32 (m, 3H), 7.39 (ddd, 1H, J = 7.4
Hz, 3J = 7.6 Hz, 4J = 1.0 Hz), 7.44 (m, 2H), 7.62 (d, 1H, 3J = 8.2 Hz),
7.72 (ddd, 1H, 3J = 7.7 Hz, 3J = 7.8 Hz, 4J = 1.6 Hz), 8.20 (dd, 1H, 3J =
4
7.9 Hz, J = 1.6 Hz), 9.95 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
35.0, 120.0, 125.9, 126.4, 126.8, 127.7, 128.6, 129.2, 134.9, 136.5,
F
dx.doi.org/10.1021/jo4010876 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
149.0, 154.1, 162.9. Anal. Calcd for C15H12N2OS: C, 67.14; H, 4.51;
N, 10.44. Found: C, 67.12; H, 4.46; N, 10.22.
250−253 °C; 1H NMR (500 MHz, DMSO-d6) δ 1.68−1.79 (m, 4H),
2.58−2.60 (m, 2H), 2.75−2.78 (m, 2H), 3.01 (s, 3H), 4.77 (s, 2H),
7.19−7.34 (m, 5H), 10.93 (br s, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 22.17, 22.9, 24.3, 25.5, 35.8, 52.2, 113.4, 125.1, 127.2, 127.3,
128.7, 130.1, 137.5, 152.0, 159.2, 166.4; HRMS-EI m/z [M]+ calcd for
C18H19N3OS 325.1243, found 325.1245.
2-(Benzylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (6). Ethyl 2-(3-benzoylthioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (2.33 g, 6.0 mmol) was
heated under reflux for 2 h in EtOH (30 mL) and 1 N NaOH (15
mL). After being cooled to room temperature, the solution was filtered
and diluted with EtOH (10 mL) and 1 N NaOH (30 mL). Benzyl
bromide (1.2 mL, 10 mmol) was added dropwise, and the mixture was
stirred for 2 h. The solution was filtered off, and the filtrate was
acidified with 2 N HCl to precipitate 6 as a white solid (2.33 g, 93%):
2-(Methylsulfonyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (28). Method A: 2-(Methylsulfanyl)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (4) (0.51 g,
2.0 mmol) was stirred for 5 h at 45 °C in AcOH/H2O2 (10 mL/8 mL,
30%). The precipitate was filtered off and washed with water (60 mL)
to yield the product as a white solid (0.20 g, 35%). Method B: 2-
(Methylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
4(3H)-one (4) (1.26 g, 5.0 mmol) was suspended in acetone (50 mL)
and cooled to 0 °C. m-CPBA (70%, 2.70 g, 11 mmol) was added over
30 min. The mixture was stirred for 24 h at room temperature. After
evaporation in vacuo, the residue was dissolved in H2O (70 mL) and 2
N NaOH (15 mL). The solution was acidified with 2 N HCl to pH
∼5. The precipitate was filtered off and washed with water (25 mL) to
1
mp 225−228 °C; H NMR (500 MHz, DMSO-d6) δ 1.70−1.81 (m,
4H), 2.68−2.82 (m, 4H), 4.41 (s, 2H), 7.23−7.26 (m, 1H), 7.28−7.41
(m, 4H), 12.53 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 21.9, 22.6,
24.5, 25.3, 33.9, 119.3, 127.5, 128.6, 129.2, 130.5, 130.8, 137.0, 155.3,
158.2, 162.6. Anal. Calcd for C17H16N2OS2: C, 62.16; H, 4,91; N, 8.53.
Found: C, 61.97; H, 5.07; N, 8.34.
2-(Morpholin-4-yl)quinazolin-4(3H)-one (7). 2-(Methylsulfanyl)-
quinazolin-4(3H)-one (3) (0.96 g, 5.0 mmol) was heated in
morpholine (20 g, 20 mL, 230 mmol) in a sealed glass reactor at
160 °C overnight. After being cooled to room temperature, the
solution was diluted with water (80 mL) and acidified with 2 N HCl to
pH ∼2. The aqueous layer was extracted with EtOAc (3 × 100 mL).
The combined organic layers were washed with brine (50 mL) and
dried with anhydrous Na2SO4. After evaporation, the residue was
recrystallized from EtOH/EtOAc (50 mL, 1:1) to yield 7 as white
needles (0.61 g, 53%): mp 247−250 °C (lit.50 mp 245−248.5 °C); 1H
NMR (500 MHz, DMSO-d6) δ 3.59 (m, 4H), 3.65−3.67 (m, 4H),
7.14−7.17 (m, 1H), 7.28−7.29 (m, 1H), 7.57−7.60 (m, 1H), 7.90−
7.91 (m, 1H), 11.34 (br s, 1H); 13C NMR (125 MHz, DMSO-d6) δ
45.4, 65.8, 117.4, 122.5, 125.1, 126.0, 134.5, 150.4, 151.1, 163.1. Anal.
Calcd for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C, 62.31;
H, 5.56; N, 18.18.
1
yield 28 as a white solid (0.45 g, 32%): mp 246−249 °C; H NMR
(500 MHz, CDCl3) δ 1.82−1.91 (m, 4H), 2.80−2.83 (m, 2H), 3.01−
3.04 (m, 2H), 3.32 (s, 3H), 10.38 (br s, 1H); 13C NMR (125 MHz,
CDCl3) δ 22.0, 22.7, 25.3, 25.5, 40.4, 124.7, 132.5, 138.8, 149.0, 156.7,
160.1. Anal. Calcd for C11H12N2O3S2 × 0.2 H2O: C, 45.88; H, 4.34; N,
9.73. Found: C, 45.92; H, 4.42; N, 9.81.
General Prodecure for Sulfonylation. DIPEA (N,N-diisopro-
pylethylamine, 1.2 equiv) and the sulfonyl chloride (1.2 equiv, unless
stated otherwise) were added to a suspension of the appropriate
substrate (1−10) and a catalytic amount of DMAP (4-dimethylami-
nopyridine) in CH2Cl2. The mixture was stirred at room temperature,
and a solution was obtained. After evaporation in vacuo, the residue
was recrystallized from MeOH or purified by column chromatography
to yield compounds 11−14. The compounds are listed in the order of
their appearance in Table 1.
2-(Morpholin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (8). 2-(Methylsulfonyl)-5,6,7,8-tetrahydrobenzo-
[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (28) (0.20 g, 0.7 mmol) was
heated in morpholine (5.0 g, 5 mL, 57 mmol) in a sealed glass reactor
at 160 °C for 18.5 h. After the mixture was cooled to room
temperature, the resulting precipitate was filtered off and washed with
water (10 mL) to yield 8 as a pale gray solid (0.14 g, 69%): mp >350
3-(4-Methylbenzenesulfonyl)quinazolin-4(3H)-one (11a). Com-
pound 1 (0.29 g, 2.0 mmol), DMAP (20 mg), DIPEA (0.31 g, 2.4
mmol), and 4-methylbenzenesulfonyl chloride (0.46 g, 2.4 mmol)
were reacted in CH2Cl2 (10 mL) for 2 h. The crude product was
recrystallized from MeOH to yield 11a as white crystals (0.51 g, 73%):
mp 184−187° (lit.26 mp 185−188 °C); 1H NMR (500 MHz, CDCl3)
δ 2.43 (s, 3H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.46 (ddd, 1H, 3J = 7.1 Hz, 3J
= 8.0 Hz, 4J = 1.3 Hz), 7.70 (dd, 1H, 3J = 8.2 Hz, 4J = 0.6 Hz), 7.74−
°C (lit.51 mp 330 °C); H NMR (500 MHz, DMSO-d6) δ 1.68−1.80
1
(m, 4H), 2.59−2.62 (m, 2H), 2.75−2.78 (m, 2H), 3.51−3.53 (m, 4H),
3.61−3.64 (m, 4H), 10.95 (br s, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 22.0, 22.9, 24.4, 25.4, 45.4, 65.7, 114.2, 126.1, 130.1, 152.0, 159.3,
165.8. Anal. Calcd for C14H17N3O2S·0.5H2O: C, 55.98; H, 6.04; N,
13.99. Found: C, 56.03; H, 5.76; N, 13.89.
7.77 (m, 1H), 8.04−8.06 (d, 2H, 3J = 8.5 Hz), 8.15−8.17 (m, 1H); 13
C
NMR (125 MHz, CDCl3) δ 21.8, 122.0, 127.2, 128.0, 128.3, 129.8,
133.4, 135.6, 140.4, 146.7, 146.7, 158.6. Anal. Calcd for C15H12N2O3S
C, 59.99; H, 4.03; N, 9.33. Found: C, 59.97; H, 4.14; N, 9.15.
4-((4-Oxoquinazolin-3(4H)-yl)sulfonyl)benzonitrile (11b). Com-
pound 1 (0.15 g, 1.0 mmol), DMAP (10 mg), DIPEA (0.16 g, 1.2
mmol), and 4-cyanobenzenesulfonyl chloride (0.24 g, 1.2 mmol) were
reacted in CH2Cl2 (10 mL) for 1 h. The crude product was
recrystallized from MeOH to yield 11b as a white solid (0.17 g, 55%):
mp 200−202 °C; 1H NMR (500 MHz, CDCl3) δ 7.50 (ddd, 1H, 3J =
7.6 Hz, 3J = 7.6 Hz, 4J = 1.3 Hz), 7.72 (d, 1H, 3J = 7.6 Hz), 7.80 (ddd,
2-(N-Benzyl-N-methylamino)quinazolin-4(3H)-one (9). 2-
(Methylsulfanyl)quinazolin-4(3H)-one (3) (0.96 g, 5.0 mmol) was
heated in N-benzyl-N-methylamine (18.8 g, 20 mL, 155 mmol) in a
sealed glass reactor at 180 °C overnight. After the mixture was cooled
to room temperature, the precipitated solid was filtered off and
recrystallized from EtOH (60 mL) to yield 9 as white needles (0.53 g,
1
40%): mp 199−200 °C; H NMR (500 MHz, DMSO-d6) δ 3.20 (s,
3
1H, J = 8.0 Hz, 3J = 7.6 Hz, 4J = 1.3 Hz), 7.86−7.88 (d, 2H, 3J = 8.8
3H), 4.91 (s, 2H), 7.07−7.10 (m, 1H), 7.24−7.31 (m, 5H), 7.38 (d,
1H, 3J = 8.2 Hz), 7.54−7.57 (m, 1H), 7.95 (d, 1H, 3J = 7.0 Hz), 10.83
(br s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 35.3, 52.9, 116.4,
122.1, 124.9, 126.3, 127.46, 127.52, 128.7, 134.8, 137.0, 150.6, 151.2,
165.0; HRMS-ESI m/z [M + Na]+ calcd for C16H15N3ONa 288.1107,
found 288.1106.
Hz), 8.13−8.15 (dd, 1H, 3J = 8.0 Hz, 4J = 1.3 Hz), 8.29−8.31 (d, 2H,
3J = 8.8 Hz), 8.72 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 116.7,
118.8, 121.6, 127.2, 128.2, 128.8, 130.4, 132.8, 136.1, 139.5, 140.5,
146.5, 158.5. Anal. Calcd for C15H9N3O3S: C, 57.87; H, 2.91; N,
13.50. Found: C, 57.90; H, 2.96; N, 13.16.
3-(Methylsulfonyl)quinazolin-4(3H)-one (11c). Compound 1 (0.73
g, 5.0 mmol), DMAP (40 mg), DIPEA (0.78 g, 6.0 mmol), and
methanesulfonyl chloride (0.69 g, 6.0 mmol) were reacted in CH2Cl2
(30 mL) for 7 h. The product was purified by column chromatography
using petroleum ether/EtOAc (1:1) to yield 11c as a white powder
(0.65 g, 58%): mp 146−149 °C; 1H NMR (500 MHz, CDCl3) δ 3.65
(s, 3H), 7.54−7.58 (m, 1H), 7.73−7.75 (m, 1H), 7.81−7.85 (m, 1H),
8.29−8.31 (m, 1H), 8.55 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
42.6, 121.7, 127.3, 128.2, 128.6, 136.0, 139.7, 146.8, 159.7. Anal. Calcd
for C9H8N2O3S: C, 48.21; H, 3.60; N, 12.49. Found: C, 48.33; H,
3.73; N, 12.28.
2-(N-Benzyl-N-methylamino)-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4(3H)-one (10). 2-(Methylsulfonyl)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (28) (0.20 g,
0.7 mmol) was heated in N-benzyl-N-methylamine (6.6 g, 7 mL, 54
mmol) in a sealed glass reactor at 200 °C for 52 h. After being cooled
to room temperature, the mixture was poured on ice−water (150 mL)
and neutralized with 8 N HCl. The aqueous layer was extracted with
CH2Cl2 (2 × 100 mL). The organic layer was washed with 2 N
CH3COOH (50 mL) and brine (100 mL) and dried with anhydrous
Na2SO4. After evaporation, the residue was suspended in MeOH (30
mL) and filtered off to yield 5a as white needles (0.12 g, 53%): mp
G
dx.doi.org/10.1021/jo4010876 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
3-(2,4,6-Triisopropylbenzenesulfonyl)quinazolin-4(3H)-one (11d).
Compound 1 (0.15 g, 1.0 mmol), DMAP (10 mg), DIPEA (0.16 g, 1.2
mmol), and 2,4,6-triisopropylbenzenesulfonyl chloride (0.36 g, 1.2
mmol) were reacted in CH2Cl2 (10 mL) for 1 h. The crude product
was recrystallized from MeOH to yield 11d as colorless crystals (0.22
21.8, 113.6, 123.5, 126.6, 129.57, 129.59, 133.5, 135.0, 146.0, 153.3,
160.9, 166.9, one signal was not detected; HRMS-ESI m/z [M + Na]+
calcd for C16H14N2O3S2Na 369.0338, found 369.0330.
2-(Methylsulfanyl)quinazolin-4-yl 4-Cyanobenzenesulfonate
(13f). Compound 3 (0.19 g, 1.0 mmol), DMAP (10 mg), DIPEA
(0.16 g, 1.2 mmol), and 4-cyanobenzenesulfonyl chloride (0.24 g, 1.2
mmol) were reacted in CH2Cl2 (5 mL) for 1 h. The product was
purified by column chromatography using petroleum ether/EtOAc
(4:3) to yield 13f as a white solid (0.25 g, 71%): mp 122−124 °C, 1H
NMR (500 MHz, CDCl3) δ 2.55 (s, 3H), 7.50−7.53 (m, 1H), 7.80−
1
g, 52%): mp 157−159 °C; H NMR (500 MHz, CDCl3) δ 1.12 (d,
3
3
12H, J = 6.7 Hz), 1.20 (d, 6H, J = 6.9 Hz), 2.95 (sept, 1H), 4.03
(sept, 2H), 7.34 (s, 2H), 7.58−7.62 (m, 1H), 7.78−7.80 (m, 1H),
7.91−7.95 (m, 1H), 8.08−8.09 (m, 1H), 8.92 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 23.3, 24.1, 29.0, 33.6, 121.2, 124.5, 126.8, 128.0,
129.0, 130.1, 136.5, 140.3, 146.3, 151.2, 155.5, 158.6; HRMS-ESI m/z
[M + Na]+ calcd for C23H28N2NaO3S 435.1713, found 435.1715.
3-(4-Methylbenzenesulfonyl)-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4(3H)-one (12a). Compound 2 (0.21 g, 1.0
mmol), DMAP (10 mg), DIPEA (0.16 g, 1.2 mmol), and 4-
methylbenzenesulfonyl chloride (0.23 g, 1.2 mmol) were reacted in
CH2Cl2 (7.5 mL) for 3 h. The crude product was recrystallized from
MeOH to yield 12a as white crystals (0.27 g, 74%): mp 166−167 °C;
1H NMR (500 MHz, DMSO-d6) δ 1.66−1.76 (m, 4H), 2.41 (s, 3H),
3
7.86 (m, 2H), 7.88−7.90 (d, 2H, J = 8.9 Hz), 8.04−8.06 (m, 1H),
8.33 (d, 2H, 3J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) δ 14.1, 113.3,
117.0, 118.3, 123.3, 126.8, 126.9, 130.3, 132.6, 135.4, 140.8, 153.5,
160.5, 166.6; HRMS-ESI m/z [M + Na]+ calcd for C16H11N3O3S2Na
380.0134, found 380.0136.
2-(Methylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl 4-Methylbenzenesulfonate (14e). Compound 4 (0.25
g, 1.0 mmol), DMAP (10 mg), DIPEA (0.16 g, 1.2 mmol), and 4-
methylbenzenesulfonyl chloride (0.23 g, 1.2 mmol) were reacted in
CH2Cl2 (5 mL) for 1.5 h. The crude product was recrystallized from
EtOH to yield 14e as yellow crystals (0.28 g, 69%): mp 123−124 °C;
1H NMR (500 MHz, CDCl3) δ 1.83−1.91 (m, 4H), 2.40 (s, 3H), 2.45
3
3
2.70−2.73 (m, 4H), 7.49 (d, 2H, J = 7.9 Hz), 8.03 (d, 2H, J = 8.5
Hz), 8.75 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 21.4, 21.6, 22.3,
24.6, 25.2, 122.0, 129.5, 130.0, 131.7, 133.3, 135.5, 141.6, 146.7, 154.3,
160.9. Anal. Calcd for C17H16N2O3S2: C, 56.65; H, 4.47; N, 7.77.
Found: C,56.44; H, 4.57; N, 7.72.
(s, 3H), 2.75−2.79 (m, 2H), 2.91−2.94 (m, 2H) 7.36 (d, 2H, 3J = 7.85
Hz), 7.99 (d, 2H, 3J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 14.1,
21.7, 22.1, 22.7, 25.2, 25.5, 116.9, 126.1, 129.1, 129.6, 134.2, 135.7,
145.6, 156.5, 165.2, 171.4. Anal. Calcd for C18H18N2O3S3: C, 53.18; H,
4.46; N, 6.89. Found: C, 53.02; H, 4.35; N, 6.83.
4-((4-Oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
3(4H)-yl)sulfonyl)benzonitrile (12b). Compound 2 (0.41 g, 2.0
mmol), DMAP (20 mg), DIPEA (0.31 g, 2.4 mmol), and 4-
cyanobenzenesulfonyl chloride (0.48 g, 2.4 mmol) were reacted in
CH2Cl2 (7.5 mL) for 30 min. A solid precipitated, which was filtered
off and washed with CH2Cl2 (5 mL). The filtrate was evaporated in
vacuo, and the combined material was recrystallized from MeOH/
CH2Cl2 (9:1) to yield 12b as pale yellow crystals (0.53 g, 72%): mp
206−211 °C; 1H NMR (500 MHz, DMSO-d6) δ 1.66−1.77 (m, 4H),
2-(Methylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl 4-Cyanobenzenesulfonate (14f). Compound 4 (0.51
g, 2.0 mmol), DMAP (20 mg), DIPEA (0.31 g, 2.4 mmol), and 4-
cyanobenzenesulfonyl chloride (0.48 g, 2.4 mmol) were reacted in
CH2Cl2 (10 mL) for 30 min. The crude product was recrystallized
from MeOH to yield 14f as yellow crystals (0.64 g, 76%): mp 162−
3
3
1
2.69−2.75 (m, 4H), 8.18 (d, 2H, J = 8.8 Hz), 8.34 (d, 2H, J = 8.8
Hz), 8.73 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 21.6, 22.3, 24.6,
25.2, 117.4, 117.6, 121.9, 130.1, 131.7, 133.6, 135.7, 140.3, 141.5,
154.3, 161.0. Anal. Calcd for C17H13N3O3S2: C, 54.97; H, 3.53; N,
11.31. Found: C, 54.71; H, 3.70; N, 11.20.
165 °C; H NMR (500 MHz, DMSO-d6) δ 1.81−1.86 (m, 4H), 2.31
(s, 3H), 2.81−2.85 (m, 4H), 8.22 (d, 2H, 3J = 8.9 Hz), 8.30 (d, 2H, 3J
= 8.9 Hz); 13C NMR (125 MHz, DMSO-d6) δ 13.6, 21.6, 22.3, 24.8,
25.1, 116.5, 117.4, 117.5, 125.6, 129.4, 133.9, 136.7, 140.5, 155.8,
164.9, 171.2. Anal. Calcd for C18H15N3O3S3: C, 51.78; H, 3.62; N,
10.06. Found: C, 51.61; H, 3.75; N, 9.91.
3-(Methylsulfonyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4(3H)-one (12c). Compound 2 (0.21 g, 1.0 mmol), DMAP
(10 mg), DIPEA (0.31 g, 2.4 mmol), and methanesulfonyl chloride
(0.27 g, 2.4 mmol) were reacted in CH2Cl2 (7.5 mL) for 1 h. The
crude product was recrystallized from MeOH to yield 12c as a brown
2-(Methylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl Methanesulfonate (14g). Compound 4 (0.25 g, 1.0
mmol), DMAP (10 mg), DIPEA (0.16 g, 1.2 mmol), and
methanesulfonyl chloride (0.14 g, 1.2 mmol) were reacted in
CH2Cl2 (5 mL) for 1.5 h. The crude product was recrystallized
from MeOH to yield 14g as brown crystals (0.11 g, 56%): mp 152−
1
solid (0.11 g, 40%): mp 152−155 °C; H NMR (500 MHz, DMSO-
d6) δ 1.75−1.83 (m, 4H), 2.77−2.79 (m, 2H), 2.86−2.89 (m, 2H),
3.80 (s, 3H), 8.44 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 21.8,
22.4, 24.7, 25.3, 42.1, 122.1, 131.8, 135.3, 141.6, 155.5, 161.2; HRMS-
EI m/z [M]+ calcd for C11H12N2O3S2 284.0284, found 284.0290.
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl 2,4,6-
Triisopropylbenzenesulfonate (14d). Compound 2 (0.21 g, 1.0
mmol), DMAP (10 mg), DIPEA (0.16 g, 1.2 mmol), and 2,4,6-
triisopropylbenzenesulfonyl chloride (0.36 g, 1.2 mmol) were reacted
in CH2Cl2 (10 mL) for 1 h. The crude product was recrystallized from
MeOH to yield 14d as colorless crystals (0.29 g, 61%): mp 135−137
°C; 1H NMR (600 MHz, CDCl3) δ 1.24 (d, 18H, 3J = 5.7 Hz), 1.89−
1.92 (m, 4H), 2.84−2.86 (m, 2H), 2.92 (sept, 1H, 3J = 7.0 Hz), 3.00−
3.01 (m, 2H), 4.28 (sept, 2H, 3J = 6.8 Hz), 7.19 (s, 2H), 8.43 (s, 1H);
13C NMR (150 MHz, CDCl3) δ 22.1, 22.7, 23.5, 24.5, 25.4, 25.7,
1
155 °C; H NMR (500 MHz, DMSO-d6) δ 1.83−1.84 (m, 4H), 2.59
(s, 3H), 2.81−2.84 (m, 4H), 3.79 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 14.1, 21.6, 22.3, 24.9, 25.1, 41.8, 116.6, 125.8, 136.2,
156.4, 165.1, 171.0. Anal. Calcd for C12H14N2O3S3: C, 43.63; H, 4.27;
N, 8.48. Found: C, 43.37; H, 4.41; N, 8.38.
2-(Benzylsulfanyl)quinazolin-4-yl 4-Methylbenzenesulfonate
(13h). Compound 5 (0.40 g, 1.5 mmol), DMAP (15 mg), DIPEA
(0.23 g, 1.8 mmol), and 4-methylbenzenesulfonyl chloride (0.34 g, 1.8
mmol) were reacted in CH2Cl2 (7.5 mL) for 2 h. The product was
purified by column chromatography using petroleum ether/EtOAc
(6:1) to yield 13h as a white solid (0.41 g, 64%): mp 105−107 °C; 1H
NMR (500 MHz, CDCl3) δ 2.41 (s, 3H), 4.39 (s, 2H), 7.22−7.34 (m,
5H), 7.40−7.42 (m, 2H), 7.47−7.50 (m, 1H), 7.78−7.82 (m, 2H),
8.04−8.06 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 21.7, 35.4, 113.8,
123.6, 126.6, 126.7, 127.3, 128.5, 129.1, 129.5, 129.6, 133.5, 135.1,
137.2, 146.0, 153.2, 161.0, 166.0. Anal. Calcd for C22H18N2O3S2: C,
62.54; H, 4.29; N, 6.63. Found: C, 62.58; H, 4.16; N, 6.41.
120.3, 123.9, 126.3, 131.5, 138.4, 150.8, 151.2, 154.3, 157.8, 170.1;
HRMS-ESI m/z [M + Na]+ calcd for C25H32N2NaO3S2 473.1927,
found 473.1932.
2-(Methylsulfanyl)quinazolin-4-yl 4-Methylbenzenesulfonate
(13e). Compound 3 (0.19 g, 1.0 mmol), DMAP (10 mg), DIPEA
(0.16 g, 1.2 mmol), and 4-methylbenzenesulfonyl chloride (0.23 g, 1.2
mmol) were reacted in CH2Cl2 (5 mL) for 30 min. The crude product
was recrystallized from EtOH to yield 13e as pale yellow crystals (0.28
2-(Benzylsulfanyl)quinazolin-4-yl 4-Cyanobenzenesulfonate
(13i). Compound 5 (0.27 g, 1.0 mmol), DMAP (10 mg), DIPEA
(0.16 g, 1.2 mmol), and 4-cyanobenzenesulfonyl chloride (0.24 g, 1.2
mmol) were reacted in CH2Cl2 (16 mL) for 1 h. The crude product
was recrystallized from MeOH to yield 13i as a light green solid (0.15
1
g, 83%): mp 146−148 °C; H NMR (500 MHz, CDCl3) δ 2.45 (s,
3
3
1
3H), 2.54 (s, 3H), 7.37 (d, 2H, J = 7.9 Hz), 7.47 (ddd, 1H, J = 6.6
Hz, 3J = 8.4 Hz, 4J = 1.3 Hz), 7.76−7.78 (m, 2H), 8.03−8.05 (m, 1H),
8.06−8.08 (d, 2H, 3J = 8.2 Hz); 13C NMR (125 MHz, CDCl3) δ 14.2,
g, 34%): mp 145−148 °C; H NMR (500 MHz, CDCl3) δ 4.41 (s,
2H), 7.24−7.25 (m, 1H), 7.29−7.32 (m, 2H), 7.41−7.42 (m, 2H),
7.51−7.54 (m, 1H), 7.83−7.86 (m, 4H), 8.05−8.06 (m, 1H), 8.29 (d,
H
dx.doi.org/10.1021/jo4010876 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Featured Article
3
2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ 35.3, 113.4, 116.9,
methylbenzenesulfonyl chloride (0.12 g, 0.6 mmol) were reacted in
CH2Cl2 (5 mL) for 3 h. The crude product was recrystallized from
MeOH to yield 14k as white crystals (0.15 g, 66%): mp 207−211 °C;
1H NMR (500 MHz, DMSO-d6) δ 1.77−1.83 (m, 4H), 2.43 (s, 3H),
2.68−2.71 (m, 2H), 2.75−2.79 (m, 2H), 3.41 (m, 4H), 3.53−3.55 (m,
118.2, 123.3, 126.8, 127.0, 127.4, 128.6, 129.1, 130.2, 132.6, 135.5,
136.9, 140.7, 153.3, 160.7, 165.6. Anal. Calcd for C22H15N3O3S2: C,
60.95; H, 3.49; N, 9.69. Found: C, 60.87; H, 3.56; N, 9.61.
2-(Benzylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl 4-Methylbenzenesulfonate (14h). Compound 6 (0.22
g, 0.7 mmol), DMAP (10 mg), DIPEA (0.12 g, 0.9 mmol), and 4-
methylbenzenesulfonyl chloride (0.17 g, 0.9 mmol) were reacted in
CH2Cl2 (5 mL) for 2 h. The crude product was recrystallized from
MeOH to yield 14h as pale yellow crystals (0.10 g, 30%): mp 149−
3
3
4H), 7.50 (d, 2H, J = 8.2 Hz), 7.92 (d, 2H, J = 8.6 Hz); 13C NMR
(125 MHz, DMSO-d6) δ 21.3, 21.8, 22.6, 24.8, 24.9, 44.4, 65.8, 111.4,
125.3, 128.4, 130.2, 130.9, 134.0, 145.9, 157.0, 157.2, 172.7. Anal.
Calcd for C21H23N3O4S2: C, 56.61; H, 5.20; N, 9.43. Found: C, 56.44;
H, 5.38; N, 9.34.
1
153 °C; H NMR (500 MHz, CDCl3) δ 1.85−1.91 (m, 4H), 2.37 (s,
2-(Morpholin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl 4-Cyanobenzenesulfonate (14l). Compound 8 (0.15
g, 0.5 mmol), DMAP (5 mg), DIPEA (0.08 g, 0.6 mmol), and 4-
cyanobenzenesulfonyl chloride (0.12 g, 0.6 mmol) were reacted in
CH2Cl2 (6 mL) for 1 h. The crude product was recrystallized from
MeOH to yield 14l as white crystals (0.18 g, 79%): mp 231−232 °C;
1H NMR (500 MHz, CDCl3) δ 1.80−1.92 (m, 4H), 2.69−2.71 (m,
3H), 2.77−2.79 (m, 2H), 2.93−2.95 (m, 2H), 4.19 (s, 2H), 7.21−7.32
(m, 7H), 7.97 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) δ
3
21.7, 22.1, 22.8, 25.3, 25.6, 35.4, 117.3, 126.2, 127.3, 128.5, 129.06,
129.09, 129.64, 134.3, 136.0, 137.0, 145.7, 156.6, 164.3, 171.5. Anal.
Calcd for C24H22N2O3S3: C, 59.73; H, 4.59; N, 5.80. Found: C, 60.00;
H, 4.59; N, 5.79.
2-(Benzylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl 4-Cyanobenzenesulfonate (14i). Compound 6 (0.31
g, 1.0 mmol), DMAP (10 mg), DIPEA (0.16 g, 1.2 mmol), and 4-
cyanobenzenesulfonyl chloride (0.24 g, 1.2 mmol) were reacted in
CH2Cl2 (5 mL) for 30 min. The crude product was recrystallized from
MeOH to yield 14i as pale yellow crystals (0.15 g, 31%): mp 174−177
2H), 2.81−2.83 (m, 2H), 3.50 (m, 4H), 3.63−3.65 (m, 4H), 7.86 (d,
3
3
2H, J = 8.6 Hz), 8.15 (d, 2H, J = 8.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 22.2, 22.9, 25.2, 25.3, 44.6, 66.5, 112.1, 116.8, 117.7, 125.4,
129.0, 132.0, 132.7, 142.1, 157.0, 157.1, 173.4. Anal. Calcd for
C21H20N4O4S2: C, 55.25; H, 4.42; N, 12.27. Found: C, 55.15; H, 4.42;
N, 12.31.
1
°C; H NMR (500 MHz, CDCl3) δ 1.88−1.91 (m, 4H), 2.79−2.81
2-(Morpholin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl Methanesulfonate (14m). Compound 8 (0.15 g, 0.5
mmol), DMAP (5 mg), DIPEA (0.16 g, 1.2 mmol), and
methanesulfonyl chloride (0.14 g, 1.2 mmol) were reacted in
CH2Cl2 (5 mL) for 4 h. The crude product was recrystallized from
MeOH to yield 14m as white solid (0.16 g, 68%): mp 178−180 °C;
1H NMR (500 MHz, DMSO-d6) δ 1.77−1.83 (m, 4H), 2.69−2.75 (m,
(m, 2H), 2.92−2.94 (m, 2H), 4.25 (s, 2H), 7.23−7.34 (m, 5H), 7.78−
7.80 (m, 2H), 8.19−8.22 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
22.1, 22.7, 25.2, 25.6, 35.3, 117.0, 118.0, 126.0, 127.5, 128.6, 129.0,
129.8, 132.6, 136.7, 136.8, 141.4, 156.2, 164.2, 171.8. Anal. Calcd for
C24H19N3O3S3: C, 58.40; H, 3.88; N, 8.51. Found: C, 58.23; H, 3.94;
N, 8.20.
4H), 3.68 (s, 8H), 3.74 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ
21.8, 22.6, 24.8, 24.9, 41.6, 44.6, 65.9, 111.5, 125.4, 130.9, 157.3, 157.6,
172.6; HRMS-EI m/z [M]+ calcd for C15H19N3O4S2 369.0812, found
369.0818.
2-(Benzylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl Methanesulfonate (14j). Compound 6 (0.63 g, 2.0
mmol), DMAP (20 mg), DIPEA (0.31 g, 2.4 mmol), and
methanesulfonyl chloride (0.27 g, 2.4 mmol) were reacted in
CH2Cl2 (10 mL) for 1 h. The product was purified by column
chromatography using CH2Cl2 to yield 14j as a pale brown solid (0.38
g, 47%): mp 184−186 °C; 1H NMR (500 MHz, CDCl3) δ 1.84−1.91
(m, 4H), 2.79−2.81 (m, 2H), 2.90−2.93 (m, 2H), 3.50 (s, 3H), 4.45
(s, 2H), 7.22−7.31 (m, 4H), 7.41−7.43 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 22.1, 22.7, 25.2, 25.6, 35.7, 41.9, 117.6, 126.2, 127.4,
128.6, 128.9, 136.5, 136.8, 156.6, 164.3, 171.9; HRMS-EI m/z [M]+
calcd for C18H18N2O3S3 406.0475, found 406.0480.
2-(N-Benzyl-N-methylamino)quinazolin-4-yl 4-Methylbenzene-
sulfonate (13n). Compound 9 (0.27 g, 1.0 mmol), DMAP (10 mg),
DIPEA (0.16 g, 1.2 mmol), and 4-methylbenzenesulfonyl chloride
(0.23 g, 1.2 mmol) were reacted in CH2Cl2 (10 mL) for 2 h. The
crude product was recrystallized from MeOH to yield 13n as pale
1
green crystals (0.28 g, 67%): mp 80−82 °C, H NMR (500 MHz,
CDCl3) δ 2.29 (br s, 3H), 3.06 (br s, 3H), 4.76 (br s, 2H), 7.12−7.20
(m, 5H), 7.25−7.30 (m, 3H), 7.52 (d, 1H, 3J = 8.2 Hz), 7.64 (ddd, 1H,
3
4
2-(Morpholin-4-yl)quinazolin-4-yl 4-Methylbenzenesulfonate
(13k). Compound 7 (0.23 g, 1.0 mmol), DMAP (10 mg), DIPEA
(0.16 g, 1.2 mmol), and 4-methylbenzenesulfonyl chloride (0.23 g, 1.2
mmol) were reacted in CH2Cl2 (5 mL) for 2 h. The crude product was
recrystallized from n-hexane/EtOAc (2:1) to yield 13k as pale green
crystals (0.16 g, 41%): mp 133−136 °C; 1H NMR (500 MHz, CDCl3)
δ 2.44 (s, 3H), 3.68−3.71 (m, 8H), 7.17−7.20 (m, 1H), 7.35 (d, 2H, 3J
= 8.5 Hz), 7.50 (br d, 1H, 3J = 8.5 Hz), 7.62−7.66 (m, 1H), 7.86 (dd,
3J = 8.4 Hz, J = 7.1 Hz, J = 1.3 Hz), 7.85−7.93 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 21.6, 34.8, 52.5, 110.5, 122.6, 123.6, 125.3,
127.1, 127.4, 128.3, 128.5, 129.6, 134.3, 134.8, 138.0, 145.2, 155.1,
157.9, 162.3; HRMS-ESI m/z [M + H]+ calcd for C23H22N3O3S
420.1376, found 420.1370.
2-(N-Benzyl-N-methylamino)quinazolin-4-yl 4-Cyanobenzene-
sulfonate (13o). Compound 9 (0.27 g, 1.0 mmol), DMAP (10 mg),
DIPEA (0.16 g, 1.2 mmol), and 4-cyanobenzenesulfonyl chloride (0.24
g, 1.2 mmol) were reacted in CH2Cl2 (10 mL) for 1 h. The crude
product was recrystallized from MeOH to yield 13o as light green
crystals (0.22 g, 51%): mp 122−127 °C, 1H NMR (500 MHz, CDCl3)
δ 3.09 (br s, 3H), 4.64 (br s, 2H), 7.03 (m, 2H), 7.21−7.49 (m, 6H),
7.56 (d, 1H, 3J = 8.6 Hz), 7.68 (ddd, 1H, 3J = 7.7 Hz, 3J = 7.9 Hz, 4J =
1.3 Hz), 7.91−7.99 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 35.0,
52.5, 110.2, 116.8, 117.5, 123.0, 123.3, 125.5, 126.7, 127.6, 128.6,
128.8, 132.7, 135.3, 137.6, 141.5, 155.4, 157.7, 162.2. Anal. Calcd for
C23H18N4O3S: C, 64.17; H, 4.21; N, 13.01. Found: C, 63.85; H, 4.27;
12.92.
3
4
3
1H, J = 8.2 Hz, J = 1.3 Hz), 7.95 (d, 2H, J = 8.2 Hz); 13C NMR
(125 MHz, CDCl3) δ 21.7, 44.5, 66.7, 110.7, 123.1, 123.5, 125.3,
128.5, 129.7, 134.3, 135.0, 145.6, 154.9, 157.1, 162.3. Anal. Calcd for
C19H19N3O4S: C, 59.21; H, 4.97; N, 10.90. Found: C, 59.15; H, 4.82;
N, 10.82.
2-(Morpholin-4-yl)quinazolin-4-yl 4-Cyanobenzenesulfonate
(13l). Compound 7 (0.23 g, 1.0 mmol), DMAP (10 mg), DIPEA
(0.16 g, 1.2 mmol), and 4-cyanobenzenesulfonyl chloride (0.24 g, 1.2
mmol) were reacted in CH2Cl2 (10 mL) for 2 h. The crude product
was recrystallized from MeOH (60 mL) to yield 13l as green crystals
1
(0.20 g, 50%): mp 143−146 °C; H NMR (500 MHz, CDCl3) δ
2-(N-Benzyl-N-methylamino)-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4-yl 4-Methylbenzenesulfonate (14n). Com-
pound 10 (0.16 g, 0.5 mmol), DMAP (5 mg), DIPEA (0.08 g, 0.6
mmol), and 4-methylbenzenesulfonyl chloride (0.12 g, 0.6 mmol)
were reacted in CH2Cl2 (5 mL) for 3 h. The crude product was
recrystallized from MeOH to yield 14n as white crystals (0.17 g, 68%):
3
3.68−3.69 (m, 8H), 7.21−7.24 (m, 1H), 7.52 (d, 1H, J = 8.6 Hz),
3
7.66−7.69 (m, 1H), 7.82−7.84 (m, 1H), 7.88 (d, 2H, J = 8.5 Hz),
8.20 (d, 2H, 3J = 8.6 Hz); 13C NMR (125 MHz, CDCl3) δ 44.5, 66.6,
110.4, 116.7, 118.0, 123.2, 123.5, 125.6, 129.0, 132.9, 135.4, 141.5,
155.2, 157.0, 162.1; HRMS-EI m/z [M]+ calcd for C19H16N4O4S
396.0887, found 396.0892.
1
mp 87−90 °C; H NMR (500 MHz, CDCl3) δ 1.83−1.88 (m, 4H),
2.28 (s, 3H), 2.68−2.71 (m, 2H), 2.88−2.90 (m, 2H), 2.94 (s, 3H),
4.61 (br s, 2H), 7.07−7.08 (m, 4H), 7.23−7.27 (m, 3H), 7.80−7.82
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 21.6, 22.3, 23.0, 25.3, 25.4,
2-(Morpholin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-
pyrimidin-4-yl 4-Methylbenzenesulfonate (14k). Compound 8 (0.15
g, 0.5 mmol), DMAP (5 mg), DIPEA (0.08 g, 0.6 mmol), and 4-
I
dx.doi.org/10.1021/jo4010876 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
34.8, 52.6, 111.5, 125.8, 127.1, 127.3, 128.3, 128.5, 129.5, 130.3, 135.1,
138.0, 144.9, 157.5, 158.3, 173.3. Anal. Calcd for C25H25N3O3S2: C,
62.61; H, 5.25; 8.76. Found: C, 62.30; H, 5.47; N, 8.61.
tert-Butyl 2-(3-(4-Methylbenzenesulfonyl)thioureido)benzoate
(19). 4-Methylbenzenesulfonamide (1.71 g, 10 mmol) and potassium
carbonate (1.80 g, 10 mmol) were added to a solution of tert-butyl 2-
isothiocyanatobenzoate (18) (2.35 g, 10 mmol) in anhydrous acetone
(100 mL), and the mixture was refluxed for 20 h. After evaporation,
the residue was dissolved in a mixture of water (70 mL) and EtOH (35
mL) and acidified with 2 N HCl. A precipitate was filtered off and
washed with water (20 mL) to afford 19 (0.90 g, 24%) as a pale brown
solid: mp 134−136 °C; 1H NMR (500 MHz, CDCl3) δ 1.61 (s, 9H),
2.42 (s, 3H), 7.19−7.22 (m, 1H), 7.31 (d, 2H, 3J = 8.2 Hz), 7.42−7.45
(m, 1H), 7.88 (d, 2H, 3J = 8.5 Hz), 7.92−7.94 (m, 1H), 8.14−8.16 (m,
1H), 11.60 (br s, 1H), one signal (NH) was not detected; 13C NMR
(125 MHz, CDCl3) δ 21.7, 28.2, 82.9, 122.8, 124.9, 125.5, 127.6,
130.0, 130.8, 132.2, 135.6, 139.1, 145.3, 166.0, 177.1. Anal. Calcd for
C19H22N2O4S2: C, 56.14; H, 5.45; N, 6.89. Found: C, 55.75; H, 5.46;
N, 6.50.
2-(N-Benzyl-N-methylamino)-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4-yl 4-Cyanobenzenesulfonate (14o). Com-
pound 10 (0.16 g, 0.5 mmol), DMAP (5 mg), DIPEA (0.08 g, 0.6
mmol), and 4-cyanobenzenesulfonyl chloride (0.12 g, 0.6 mmol) were
reacted in CH2Cl2 (7 mL) for 1 h. The crude product was
recrystallized from MeOH to yield 14o as white crystals (0.17 g,
74%): mp 167−170 °C; 1H NMR (500 MHz, DMSO-d6) δ 1.83−1.91
(m, 4H), 2.71−2.73 (m, 2H), 2.88−2.89 (m, 2H), 2.99 (br s, 3H),
4.52 (br s, 2H), 7.01 (m, 2H), 7.30−7.45 (m, 5H), 7.96 (m, 2H); 13C
NMR (125 MHz, DMSO-d6) δ 22.3, 23.0, 25.3, 25.3, 35.1, 52.6, 111.6,
116.9, 117.3, 125.5, 126.7, 127.5, 128.6, 128.8, 131.4, 132.6, 137.4,
142.0, 157.2, 157.8, 173.4. Anal. Calcd for C25H22N4O3S2: C, 61.20; H,
4.52; N, 11.42. Found: C, 60.86; H, 4.58; N, 11.11.
(Z)-tert-Butyl 2-((4-Methylbenzenesulfonamido)(methylsulfanyl)-
methyleneamino)benzoate (20). tert-Butyl 2-(3-(4-
methylbenzenesulfonyl)thioureido)benzoate (19) (1.27 g, 3.15
mmol) was dissolved in EtOH (30 mL), and 1 N NaOH (6 mL)
and methyl iodide (0.64 mL, 4.5 mmol) were added dropwise. The
mixture was stirred for 2 h at room temperature. After acidification
with 2 N HCl to pH ∼3, the mixture was stored at −20 °C for 2 h to
2-(N-Benzyl-N-methylamino)-5,6,7,8-tetrahydrobenzo[4,5]-
thieno[2,3-d]pyrimidin-4-yl Methanesulfonate (14p). Compound 10
(0.16 g, 0.5 mmol), DMAP (5 mg), DIPEA (0.16 g, 1.2 mmol), and
methanesulfonyl chloride (0.14 g, 1.2 mmol) were reacted in CH2Cl2
(5 mL) for 3 h. The crude product was recrystallized from MeOH to
1
yield 14p as white crystals (0.12 g, 56%): mp 149−150 °C; H NMR
(500 MHz, DMSO-d6) δ 1.76−1.83 (m, 4H), 2.69−2.75 (m, 4H), 3.12
(s, 3H), 3.62 (br s, 3H), 4.86 (s, 2H), 7.24−7.33 (m, 5H); 13C NMR
(125 MHz, DMSO-d6) δ 21.8, 22.6, 24.8, 25.0, 35.4, 41.5, 52.3, 110.9,
125.4, 127.2, 127.2, 128.7, 130.3, 137.9, 157.3, 158.0, 172.8; HRMS-EI
m/z [M]+ calcd for C19H21N3O3S2 403.1019, found 403.1020.
1
obtain 20 as white needles (0.83 g, 55%): mp 85−87 °C, H NMR
(500 MHz, CDCl3) δ 1.58 (s, 9H), 2.39 (s, 3H), 2.51 (s, 3H), 7.17−
7.20 (m, 1H), 7.26 (d, 2H, 3J = 7.9 Hz), 7.43−7.47 (m, 1H), 7.89 (d,
2H, 3J = 8.2 Hz), 7.91−7.92 (m, 1H), 8.09−8.10 (m, 1H), 11.06 (br s,
1H); 13C NMR (125 MHz, CDCl3) δ 15.1, 21.5, 28.1, 83.1, 121.8,
124.4, 125.2, 126.8, 129.2, 131.1, 133.2, 138.8, 139.4, 142.7, 165.1,
166.8. Anal. Calcd for C20H24N2O4S2·0.2H2O: C, 56.63; H, 5.80; N,
6.60. Found: C, 56.52; H, 5.78; N, 6.72..
tert-Butyl 2-Nitrobenzoate (16). 2-Nitrobenzoic acid (15) (11.7 g,
70 mmol) was suspended in CH2Cl2 (105 mL) and oxalyl chloride
(7.0 mL, 70 mmol), and four drops of DMF were added. The
suspension was stirred until a solution was obtained, and after
evaporation, tert-butyl alcohol (52.5 mL), pyridine (52.5 mL), and a
catalytic amount of ZnCl2 (50 mg) were added to the residue. The
mixture was stirred for 12 h and cold 1N HCl solution (250 mL) was
added. The product was extracted with EtOAc (3 × 200 mL), and the
organic layer was dried with anhydrous Na2SO4 and evaporated to
(Z)-2-((4-Methylbenzenesulfonamido)(methylsulfanyl)-
methyleneamino)benzoic Acid (21). (Z)-tert-Butyl 2-((4-
methylbenzenesulfonamido)(methylsulfanyl)methyleneamino)-
benzoate (20) (0.50 g, 1.2 mmol) was dissolved in a mixture of
CH2Cl2 (14 mL) and trifluoroacetic acid (7 mL), and the solution was
stirred for 2 h at room temperature. After evaporation in vacuo, the
residue was suspended in EtOAc (10 mL) and the insoluble material
was filtered off to yield 21 (0.42 g, 96%) as a white solid: mp 174−176
°C; 1H NMR (500 MHz, DMSO-d6) δ 2.37 (s, 3H), 2.56 (s, 3H), 7.31
(ddd, 1H, 3J = 7.9 Hz, 3J = 7.5 Hz, 3J = 1.3 Hz), 7.37 (d, 2H, 3J = 7.9
Hz), 7.61 (ddd, 1H, 3J = 8.5 Hz, 3J = 7.1 Hz, 4J = 1.6 Hz), 7.76 (d, 2H,
3J = 8.2 Hz), 8.00 (dd, 1H, 3J = 7.9 Hz, 4J = 1.6 Hz), 8.10 (d, 1H, 3J =
obtain 1652 as a pale green oil (13.8 g, 88%): H NMR (500 MHz,
1
3
3
4
CDCl3) δ 1.54 (s, 9H), 7.56 (ddd, 1H, J = 7.9 Hz, J = 7.6 Hz, J =
1.6 Hz), 7.61 (ddd, 1H, 3J = 7.2 Hz, 3J = 7.6 Hz, 4J = 1.3 Hz), 7.70 (dd,
1H, 3J = 7.7 Hz, 4J = 1.6 Hz), 7.81 (dd, 1H, 3J = 8.0 Hz, 4J = 1.3 Hz);
13C NMR (125 MHz, CDCl3) δ 27.7, 83.7, 123.5, 128.9, 129.8, 131.2,
132.6, 148.4, 164.2. The material’s identity was confirmed by
53
1
comparison with H NMR and 13C NMR literature data.
8.2 Hz), 11.09 (s, 1H), 13.79 (br s, 1H); 13C NMR: (125 MHz,
DMSO-d6) δ 14.7, 21.1, 120.9, 123.9, 125.5, 126.5, 129.5, 131.3, 133.7,
138.9, 139.5, 142.7, 164.8, 168.9. Anal. Calcd for C16H16N2O4S2: C,
52.73; H, 4.43; N, 7.69. Found: C, 52.52; H, 4.40; N, 7.60.
tert-Butyl 2-Aminobenzoate (17). A suspension of tert-butyl 2-
nitrobenzoate (16) (12.4 g, 55.5 mmol) and Pd/C (1.2 g) in EtOH
(100 mL) was hydrogenated using hydrogen gas at approximately 2
atm. Upon completion, the catalyst was filtered off and the filtrate
evaporated in vacuo. Compound 1754 was obtained as a colorless oil
(9.05 g, 84%): 1H NMR (500 MHz, CDCl3) δ 1.57 (s, 9H), 5.67 (br s,
2H), 6.59−6.62 (m, 2H), 7.20−7.23 (m, 1H), 7.79−7.80 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 28.3, 80.5, 112.5, 116.1, 116.6, 131.4,
133.5, 150.3, 167.6. (C11H15NO2); LC-MS (ESI) (90% H2O to 100%
MeOH in 10 min, then 100% MeOH to 20 min, DAD 220−400 nm),
100% purity, m/z = 194.26 ([M + H]+).
tert-Butyl 2-Isothiocyanatobenzoate (18). Thiophosgene (2.7 g,
23.0 mmol) was dissolved in EtOAc (90 mL) and cooled to −78 °C.
Triethylamine (4.6 g, 46.0 mmol) dissolved in EtOAc (60 mL) was
added dropwise over 30 min. The resulting suspension was stirred
vigorously for 15 min, and tert-butyl 2-aminobenzoate (17) (4.0 g, 21
mmol) in EtOAc (70 mL) was added over 30 min. The obtained
solution was stirred for 20 h at room temperature, subsequently
diluted with EtOAc (200 mL), and washed sequentially with water (2
× 200 mL) and brine (200 mL). The organic layer was dried with
anhydrous Na2SO4 and evaporated in vacuo to yield 18 as a brown oil,
which solidified upon cooling to −20 °C (4.47 g, 83%): 1H NMR (500
MHz, CDCl3) δ 1.61 (s, 9H) 7.27−7.30 (m, 2H) 7.43−7.46 (m, 1H),
7.86−7.88 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 28.2, 82.5, 126.8,
128.0, 128.4, 129.7, 131.4, 132.5, 134.2, 163.2; HRMS-EI m/z [M]+
calcd for C12H13NO2S 235.0662, found 235.0668. (C12H13NO2S).
3-(4-Methylbenzenesulfonyl)-2-(methylsulfanyl)quinazolin-
4(3H)-one (11e). (Z)-2-((4-Methylbenzenesulfonamido)-
(methylsulfanyl)methyleneamino)benzoic acid (21) (0.18 g, 0.5
mmol) was dissolved in THF (10 mL) and 1,1′-carbonyldiimidazole
(0.1 g, 0.6 mmol) was added. The mixture was stirred for 1 h at room
temperature. After evaporation in vacuo, the residue was purified by
flash column chromatography using petroleum ether/EtOAc (2:1) to
1
yield 11e as a white solid (0.13 g, 78%): mp 122−127 °C; H NMR
3
(500 MHz, CDCl3) δ 2.43 (s, 3H), 2.57 (s, 3H), 7.30 (ddd, 1H, J =
3
4
3
7.7 Hz, J = 7.6 Hz, J = 1.0 Hz), 7.35 (d, 2H, J = 8.5 Hz), 7.48 (d,
1H, 3J = 8.2 Hz), 7.66 (ddd, 1H, 3J = 7.6 Hz, 3J = 7.4 Hz, 4J = 1.6 Hz),
8.02 (dd, 1H, 3J = 8.0 Hz, 4J = 1.6 Hz), 8.16 (d, 2H, 3J = 8.5 Hz); 13
C
NMR (125 MHz, CDCl3) δ 16.8, 21.8, 119.6, 126,2, 126.5, 127.2,
129.3, 129.5, 135.5, 135.6, 145.4, 146.1, 154.2, 161.2; HRMS-ESI m/z
[M + Na]+ calcd for C16H14N2O3S2Na 369.0338, found 369.0336.
tert-Butyl 2-Isothiocyanato-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate (22). A mixture prepared from thiophos-
gene (8.0 g, 70 mmol), CaCO3 (7.0 g, 70 mmol), CH2Cl2 (35 mL),
and H2O (70 mL) was stirred at 0 °C, and a solution of tert-butyl 2-
amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate27 (17.7 g,
70 mmol) in CH2Cl2 (120 mL) was added dropwise over a period
of 40 min. The mixture was stirred overnight at room temperature.
The organic layer was washed with water, dried using anhydrous
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Na2SO4, and evaporated in vacuo. The residue was purified by column
chromatography using petroleum ether/EtOAc (9:1) to obtain 22 as a
yellow solid (15.6 g, 75%): mp 89 °C (lit.28 mp 79−80 °C); 1H NMR
(500 MHz, DMSO-d6) δ 1.52 (s, 9H), 1.67−1.76 (m, 4H), 2.62−2.66
(m, 4H). Anal. Calcd for C14H17NO2S2: C, 56.92; H, 5.80; N, 4.74.
Found: C, 56.64; H, 5.58; N; 4.71.
(Z)-tert-Butyl 2-((4-Cyanobenzenesulfonamido)(methylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxy-
late (26f). tert-Butyl 2-(3-(4-cyanobenzenesulfonyl)thioureido)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (24) (1.05 g, 2.2
mmol) was dissolved in a mixture of EtOH (20 mL) and 2 N NaOH
(2.2 mL). Methyl iodide (0.47 g, 3.3 mmol) was added dropwise, and
the mixture was stirred for 2 h at room temperature. After acidification
with 2 N HCl to pH ∼3, a precipitate was filtered off to obtain 26f as a
tert-Butyl 2-(3-(4-Methylbenzenesulfonyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (23). 4-Methylbenzene-
sulfonamide (1.71 g, 10 mmol) and potassium carbonate (1.80 g, 10
mmol) were added to a solution of tert-butyl 2-isothiocyanato-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (22) (2.95 g, 10 mmol) in
anhydrous acetone (140 mL), and the reaction mixture was refluxed
for 20 h. After evaporation, the residue was dissolved in a mixture of
water (140 mL) and EtOH (100 mL) and acidified with 2 N HCl. A
precipitate was filtered off and washed with water (20 mL) to yield 23
(4.42 g, 95%) as a pale yellow solid: mp 176−180 °C; 1H NMR (500
MHz, CDCl3) δ 1.62 (s, 9H), 1.73−1.77 (m, 4H), 2.39 (s, 3H), 2.59−
2.61 (m, 2H), 2.73−2.75 (m, 2H), 7.26−7.28 (m, 2H), 7.91−7.93 (m,
2H), 8.10 (s, 1H), 13.15 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
21.7, 22.8, 22.9, 24.3, 26.5, 28.4, 82.5, 117.3, 127.8, 128.2, 130.0, 131.4,
135.2, 145.4, 146.9, 165.6, 171.8. Anal. Calcd for C21H26N2O4S3: C,
54.05; H, 5.62; N, 6.00. Found: C, 54.37; H, 5.56; N, 6.12.
tert-Butyl 2-(3-(4-Cyanobenzenesulfonyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (24). 4-Cyanobenzene-
sulfonamide (0.64 g, 3.5 mmol) and potassium carbonate (0.46 g, 3.5
mmol) were added to a solution of tert-butyl 2-isothiocyanato-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (22) (1.03 g, 3.5 mmol)
in anhydrous acetone (40 mL), and the mixture was refluxed for 20 h.
After evaporation, the residue was dissolved in a mixture of water (60
mL) and EtOH (90 mL) and acidified with 2 N HCl. A precipitate was
filtered off and washed with water (20 mL) to provide 24 (1.27 g,
76%) as a yellow solid: mp 164−167 °C; 1H NMR (500 MHz,
CDCl3) δ 1.61 (s, 9H), 1.74−1.77 (m, 4H), 2.60−2.62 (m, 2H),
2.72−2.74 (m, 2H), 7.78−7.80 (m, 2H), 8.17−8.19 (m, 2H), 8.31 (br
s, 1H), 13.18 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.79, 22.79,
24.4, 26.5, 28.4, 82.8, 116.9, 117.3, 117.8, 128.5, 128.6, 131.6, 133.1,
142.3, 146.6, 165.9, 170.7. Anal. Calcd for C21H23N3O4S3: C, 52.81; H,
4.85; N, 8.80. Found: C, 52.45; H, 4.87; N, 8.57.
1
pale yellow solid (1.00 g, 92%): mp 194−196 °C; H NMR (500
MHz, CDCl3) δ 1.54 (s, 9H), 1.73−1.77 (m, 4H), 2.58−2.60 (m, 2H),
2.65 (s, 3H), 2.68−2.71 (m, 2H), 7.75−7.76 (m, 2H), 8.10−8.12 (m,
2H), 12.26 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 15.1, 22.73,
22.77, 24.4, 26.5, 28.3, 82.9, 114.9, 115.7, 117.7, 127.8, 129.6, 131.3,
132.4, 145.8, 146.0, 160.7, 166.8. Anal. Calcd for C22H25N3O4S3: C,
53.74; H, 5.13; N, 8.55. Found: C, 53.59; H, 5.15; N, 8.43.
(Z)-tert-Butyl 2-((Methylsulfonyl)(methylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxy-
late (26g). tert-Butyl 2-(3-(methylsulfonyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (25) (1.56 g, 4.0 mmol)
was dissolved in a mixture of EtOH (30 mL) and 2 N NaOH (4 mL).
Methyl iodide (0.85 g, 6 mmol) was added dropwise, and the mixture
was stirred for 2 h at room temperature. After acidification with 2 N
HCl to pH ∼3, a precipitate was filtered off to obtain 26g as a white
solid (1.27 g, 78%): mp 135−138 °C; 1H NMR (500 MHz, CDCl3) δ
1.56 (s, 9H), 1.73−1.79 (m, 4H), 2.61−2.63 (m, 2H), 2.67 (s, 3H),
2.71−2.73 (m, 2H), 3.14 (s, 3H), 12.07 (br s, 1H); 13C NMR (125
MHz, CDCl3) δ 15.1, 22.79, 22.84, 24.4, 26.5, 28.3, 42.4, 82.6, 114.3,
128.7, 131.1, 146.3, 159.2, 166.8; HRMS-EI m/z [M]+ calcd for
C16H24N2O4S3: 404.0893, found: 404.0898.
(Z)-tert-Butyl 2-((4-Methylbenzenesulfonamido)(benzylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxy-
late (26h). tert-Butyl 2-(3-(4-methylbenzenesulfonyl)thioureido)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (23) (0.7 g, 1.5
mmol) was dissolved in a mixture of EtOH (20 mL) and 1 N NaOH
(3 mL). Benzyl bromide (0.38 g, 2.25 mmol) was added dropwise, and
the mixture was stirred for 2 h at room temperature. After acidification
with 2 N HCl to pH ∼ 3, a precipitate was filtered off to obtain 26h as
1
a white solid (0.58 g, 70%): mp 152−155 °C; H NMR (500 MHz,
CDCl3) δ 1.53 (s, 9H), 1.71−1.77 (m, 4H), 2.40 (s, 3H), 2.58−2.60
(m, 2H), 2.68−2.70 (m, 2H), 4.34 (s, 2H), 7.23−7.32 (m, 7H), 7.87
(d, 2H, 3J = 8.2 Hz), 12.08 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
21.5, 22.79, 22.82, 24.4, 26.5, 28.3, 36.6, 82.5, 127.3, 128.1, 128.8,
129.1, 129.3, 131.1, 133.2, 138.9, 142.7, 146.2, 158.6, 158.8, 166.5.
Anal. Calcd for C28H32N2O4S3 × 1.0 H2O: C, 58.51; H, 5.96; N, 4.87.
Found: C, 58.69; H, 5.63; N, 4.90.
tert-Butyl 2-(3-(Methylsulfonyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (25). Methanesulfona-
mide (0.52 g, 5.5 mmol) and sodium hydride (0.22 g, 5.5 mmol, 70%
oil dispersion) were dissolved in anhydrous DMF (15 mL) and stirred
for 15 min. tert-Butyl 2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate (22) (1.47 g, 5.0 mmol) was added, and the
mixture was stirred at 60 °C for 1 h. After evaporation in vacuo, the
residue was dissolved in water (20 mL) and EtOH (10 mL) and
acidified with 6 N HCl to provide a precipitate that was collected by
suction filtration to yield 25 (1.93 g, 99%) as a white solid: mp 159−
(Z)-tert-Butyl 2-((Methylsulfonamido(benzylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxy-
late (26j). tert-Butyl 2-(3-(methylsulfonyl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (25) (0.39 g, 1 mmol)
was dissolved in a mixture of EtOH (10 mL) and 1 N NaOH (2 mL).
Benzyl bromide (0.26 g, 1.5 mmol) was added dropwise, and the
mixture was stirred for 2 h at room temperature. After acidification
with 2 N HCl to pH ∼3, a precipitate was filtered off to afford 26j as a
1
162 °C; H NMR (500 MHz, CDCl3) δ 1.56 (s, 9H), 1.73−1.79(m,
4H), 2.63−2.65 (m, 2H), 2.72−2.75 (m, 2H), 3.33 (s, 3H), 8.09 (s,
1H), 13.02 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.84, 22.84,
24.4, 26.5, 28.3, 41.5, 82.7, 117.3, 128.3, 131.5, 146.7, 166.0, 171.8.
Anal. Calcd for C15H22N2O4S3: C, 46.13; H, 5.68; N, 7.17. Found: C,
46.22; H, 5.97; N, 6.96.
1
white solid (0.38 g, 80%): mp 178−181 °C; H NMR (500 MHz,
CDCl3) δ 1.55 (s, 9H, 1.73−1.79 (m, 4H), 2.61−2.63 (m, 2H), 2.70−
2.73 (m, 2H), 3.12 (s, 3H), 4.42 (s, 2H), 7.26−7.33 (m, 3H), 7.42−
7.44 (m, 2H), 12.09 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.78,
22.83, 24.4, 26.5, 28.3, 36.8, 42.4, 82.6, 128.3, 128.9, 129.0, 129.4,
131.3, 133.0, 146.1, 158.1, 166.6, one carbon signal was not observed;
HRMS-EI m/z [M]+ calcd for C22H28N2O4S3 480.1206, found
480.1215.
(Z)-tert-Butyl 2-((4-Methylbenzenesulfonamido)(methylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxy-
late (26e). tert-Butyl 2-(3-(4-methylbenzenesulfonyl)thioureido)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (23) (1.45 g, 3.0
mmol) was dissolved in a mixture of EtOH (30 mL) and 1 N NaOH
(6 mL). Methyl iodide (0.64 g, 4.5 mmol) was added dropwise, and
the mixture was stirred for 2 h at room temperature. After acidification
with 2 N HCl to pH ∼3, a precipitate was filtered off to obtain 26e as a
(Z)-2-((4-Methylbenzenesulfonamido)(methylsulfanyl)-
methyleneamino)-4,5,6,7-tetra-hydrobenzo[b]thiophene-3-carbox-
ylic Acid (27e). (Z)-tert-Butyl 2-((4-methylbenzene-sulfonamido)-
(methylsulfanyl)methyleneamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate (26e) (0.30 g, 0.62 mmol) was dissolved in
CH2Cl2 (7 mL) and trifluoroacetic acid (3.5 mL), and the mixture was
stirred for 2 h at room temperature. After evaporation in vacuo, the
residue was suspended in EtOAc (10 mL) and filtered off to yield 27e
as a light-brown solid (0.22 g, 84%): mp 225−226 °C; 1H NMR (500
MHz, DMSO-d6) δ 1.67−1.73 (m, 4H), 2.36 (s, 3H), 2.58−2.61 (m,
1
white solid (1.31 g, 91%): mp 209−213 °C; H NMR (500 MHz,
CDCl3) δ 1.53 (s, 9H), 1.71−1.77 (m, 4H), 2.38 (s, 3H), 2.59−2.61
(m, 5H), 2.68−2.70 (m, 2H), 7.24−7.25 (m, 2H), 7.88−7.89 (m, 2H),
12.05 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 15.0, 21.5, 22.81,
22.84, 24.4, 26.5, 28.3, 82.5, 114.3, 127.2, 129.1, 129.1, 131.0, 139.0,
142.7, 146.5, 159.8, 166.8. Anal. Calcd for C22H28N2O4S3 × 0.1 H2O:
C, 54.77; H, 5.89; N, 5.81. Found: C, 54.42; H, 5.92; N, 5.76.
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2H), 2.65 (s, 3H), 2.69−2.71 (m, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.75
in 10 min, then 100% MeOH to 20 min, DAD 220−400 nm), 97%
purity, m/z = 425.17 ([M + H]+).
3
(d, 2H, J = 8.2 Hz), 12.12 (s, 1H), one signal (CO2H) was not
detected; 13C NMR: (125 MHz, DMSO-d6) δ 14.4, 21.1, 22.3, 22.6,
23.8, 25.8, 113.9, 126.7, 128.4, 129.5, 131.4, 139.0, 142.9, 145.7, 160.5,
167.9; LC-MS (ESI) (90% H2O to 100% MeOH in 10 min, then
100% MeOH to 20 min, DAD 220−400 nm), 98% purity, m/z =
425.18 ([M + H]+). Anal. Calcd for C18H20N2O4S3·0.3H2O: C, 50.28;
H, 4.83; N, 6.52. Found: C, 50.08; H, 4.88; N, 6.23.
3-(4-Methylbenzenesulfonyl)-2-(methylsulfanyl)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (12e). To a
suspension of (Z)-2-((4-methylbenzenesulfonamido)-
(methylsulfanyl)methyleneamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylic acid (27e) (0.21 g, 0.5 mmol) in CH2Cl2 (5
mL) were added three drops of DMF and oxalyl chloride (0.05 mL,
0.5 mmol). The mixture was stirred for 45 min at room temperature.
After evaporation in vacuo, the residue was purified by flash column
chromatography using petroleum ether/EtOAc (2:1) to yield 12e as a
(Z)-2-((4-Cyanobenzenesulfonamido)(methylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
ylic Acid (27f). (Z)-tert-Butyl 2-((4-cyanobenzene-sulfonamido)-
(methylsulfanyl)methyleneamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate (26f) (0.73 g, 1.5 mmol) was dissolved in
CH2Cl2 (15 mL) and trifluoroacetic acid (7.5 mL), and the mixture
was stirred for 2 h at room temperature. After evaporation in vacuo,
the residue was suspended in EtOAc (10 mL) and filtered off to yield
1
white solid (0.15 g, 74%): mp 195−197 °C; H NMR (500 MHz,
CDCl3) δ 1.70−1.75 (m, 2H), 1.77−1.82 (m, 2H), 2.43 (s, 3H), 2.51
(s, 3H), 2.65−2.68 (m, 2H), 2.78−2.80 (m, 2H), 7.32−7.34 (m, 2H),
8.11−8.12 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 17.1, 21.8, 22.0,
22.8, 25.0, 25.3, 118.9, 129.2, 129.4, 131.9, 132.9, 135.8, 145.9, 155.3,
157.4, 160.5; HRMS-EI m/z [M]+ calcd for C18H18N2O3S3 406.0475,
found 406.0482.
1
27f as a light-brown solid (0.56 g, 85%): mp 211−214 °C; H NMR
(500 MHz, DMSO-d6) δ 1.65−1.73 (m, 4H), 2.58−2.61 (m, 2H), 2.67
(s, 3H) 2.69−2.71 (m, 2H), 8.01−8.03 (m, 2H), 8.05−8.06 (m, 2H),
12.31 (s, 1H), one signal (CO2H) was not detected; 13C NMR (125
MHz, DMSO-d6) δ 14.5, 22.2, 22.5, 23.8, 25.8, 114.4, 115.0, 117.9,
127.4, 128.8, 131.6, 133.3, 145.4, 145.8, 161.6, 167.8; HRMS-ESI m/z
[M − H]− calcd for C18H16N3O4S3 434.0308, found 434.0314.
(Z)-2-(Methylsulfonamido(methylsulfanyl)methyleneamino)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic Acid (27g). (Z)-
tert-Butyl 2-((methylsulfonyl)(methylsulfanyl)methyleneamino)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (26g) (0.81 g, 2.0
mmol) was dissolved in CH2Cl2 (20 mL) and trifluoroacetic acid (10
mL), and the mixture was stirred for 2 h at room temperature. After
evaporation in vacuo, the residue was suspended in EtOAc (10 mL)
and filtered off to obtain 27g as a white solid (0.67 g, 96%): mp 213-
215 °C; 1H NMR (500 MHz, DMSO-d6) δ 1.68−1.75 (m, 4H), 2.61−
2.63 (m, 2H), 2.70 (s, 3H), 2.71−2.73 (m, 2H), 3.08 (s, 3H), 12.03 (s,
1H), one signal (CO2H) was not detected; 13C NMR: (125 MHz,
DMSO-d6) δ 14.4, 22.3, 22.6, 23.8, 25.9, 42.2, 113.5, 128.1, 131.4,
146.0, 159.5, 168.0. Anal. Calcd for C12H16N2O4S3: C, 41.36; H, 4.63;
N, 8.04. Found: C, 41.61; H, 4.80; N, 7.72.
4-((2-(Methylsulfanyl)-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno-
[2,3-d]pyrimidin-3(4H)-yl)sulfonyl)benzonitrile (12f). To a suspen-
sion of (Z)-2-((4-cyanobenzenesulfonamido)(methylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic
acid (27f) (0.22 g, 0.5 mmol) in CH2Cl2 (5 mL) were added three
drops of DMF and oxalyl chloride (0.05 mL, 0.5 mmol). A solution
was obtained and the mixture was stirred for 45 min at room
temperature. After evaporation in vacuo, the residue was purified by
flash column chromatography using petroleum ether/EtOAc (9:1) to
1
yield 12f as a white solid (0.12 g, 56%): mp 136−143 °C; H NMR
(500 MHz, CDCl3) δ 1.71−1.75 (m, 2H), 1.78−1.83 (m, 2H), 2.54 (s,
3
3H), 2.66−2.69 (m, 2H), 2.74−2.76 (m, 2H), 7.83 (d, 2H, J = 8.9
Hz), 8.32 (d, 2H, 3J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) δ 17.0,
21.9, 22.7, 25.0, 25.3, 117.0, 118.0, 118.6, 129.6, 131.9, 132.5, 133.7,
142.9, 154.9, 157.1, 160.6; HRMS-EI m/z [M]+ calcd for
C18H15N3O3S3: 417.0271, found: 417.0277.
3-(Methylsulfonyl)-2-(methylsulfanyl)-5,6,7,8-tetrahydrobenzo-
[4,5]thieno[2,3-d]-pyrimidin-4(3H)-one (12g). To a suspension of
(Z)-2-((methylsulfonamido)(methylsulfanyl)methyleneamino)-
4,5,6,7-tetrahydrobenzo[b]-thiophene-3-carboxylic acid (27g) (0.21 g,
0.5 mmol) in CH2Cl2 (5 mL) were added three drops of DMF and
oxalyl chloride (0.05 mL, 0.5 mmol). The mixture was stirred for 45
min at room temperature. After evaporation in vacuo, the residue was
purified by flash column chromatography using petroleum ether/
EtOAc (9:1) to yield 12g as a white solid (0.13 g, 78%): mp 147−150
°C; 1H NMR (500 MHz, CDCl3) δ 1.77−1.87 (m, 4H), 2.48 (s, 3H),
2.70−2.73 (m, 2H), 2.87−2.90 (m, 2H), 3.65 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 16.9, 22.0, 22.8, 25.0, 25.3, 44.5, 118.7, 131.95, 133.4,
155.0, 158.5, 160.8. Anal. Calcd for C12H14N2O3S3: C, 43.62; H, 4.27;
N, 8.48. Found: C, 43.68; H, 4.86; N, 7.91.
(Z)-2-((4-Methylbenzenesulfonamido)(benzylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
ylic Acid (27h). (Z)-tert-Butyl 2-((4-methylbenzenesulfonamido)-
(benzylsulfanyl)methyleneamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate (26h) (0.45 g, 0.8 mmol) was dissolved in
CH2Cl2 (8 mL) and trifluoroacetic acid (4 mL), and the mixture was
stirred for 2 h at room temperature. After evaporation in vacuo, the
residue was suspended in EtOAc (10 mL) and filtered off to yield 27h
as a white solid (0.29 g, 59%): mp 204−207 °C; 1H NMR (500 MHz,
DMSO-d6) δ 1.69−1.72 (m, 4H), 2.38 (s, 3H), 2.58−2.59 (m, 2H),
2.70−2.71 (m, 2H), 4.50 (s, 2H), 7.28−7.30 (m, 5H), 7.37 (d, 2H, 3J
3-(4-Methylbenzenesulfonyl)-2-(benzylsulfanyl)-5,6,7,8-
tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-4(3H)-one (12h). To a
suspension of (Z)-2-((4-methylbenzenesulfonamido)(benzylsulfanyl)-
methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic
acid (27h) (0.21 g, 0.5 mmol) in CH2Cl2 (5 mL) were added three
drops of DMF and oxalyl chloride (0.05 mL, 0.5 mmol). The mixture
was stirred for 45 min at room temperature. After evaporation in
vacuo, the residue was purified by flash column chromatography using
petroleum ether/EtOAc (2:1) to yield 12h as a white solid (0.14 g,
3
= 7.9 Hz), 7.73 (d, 2H, J = 8.2 Hz), 12.26 (br s, 1H), one signal
(CO2H) was not detected; 13C NMR (125 MHz, DMSO-d6) δ 21.1,
22.3, 22.6, 23.8, 25.8, 35.6, 114.1, 126.8, 128.1, 128.7, 128.9, 129.2,
129.5, 131.6, 133.9, 138.8, 142.9, 145.5, 158.8, 167.9. Anal. Calcd for
C24H24N2O4S3: C, 57.58; H, 4.83; N, 5.60. Found: C, 57.42; H, 4.61;
N, 5.39.
(Z)-2-((Methylsulfonamido)(benzylsulfanyl)methyleneamino)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic Acid (27j). (Z)-
tert-Butyl 2-((methylsulfonamido)(benzyl-sulfanyl)methyleneamino)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (26j) (0.3 g, 0.63
mmol) was dissolved in CH2Cl2 (6 mL) and trifluoroacetic acid (3
mL), and the mixture was stirred for 2 h at room temperature. After
evaporation in vacuo, the residue was recrystallized from EtOAc (30
mL) to obtain 27j as white crystals (0.24 g, 90%): mp 202−204 °C;
1H NMR (500 MHz, DMSO-d6) δ 1.69−1.75 (m, 4H), 2.62−2.64 (m,
2H), 2.72−2.74 (m, 2H), 3.08 (s, 3H), 4.56 (s, 2H), 7.30−7.39 (m,
3H), 7.47−7.48 (m, 2H), 12.17 (br s, 1H), one signal (CO2H) was
not detected; 13C NMR (125 MHz, DMSO-d6) δ 22.3, 22.6, 23.9,
25.9, 35.7, 42.2, 113.9, 128.2, 128.4, 129.0, 129.4, 131.6, 133.9, 145.8,
157.9, 167.9; HRMS-EI m/z [M − H2O]+ calcd for C18H18N2O3S3
406.0474, found 406.0483; LC-MS (ESI) (90% H2O to 100% MeOH
1
59%): mp 195−197 °C, H NMR (500 MHz, CDCl3) δ 1.70−1.75
(m, 2H), 1.77−1.82 (m, 2H), 2.42 (s, 3H), 2.66−2.69 (m, 2H), 2.77−
2.79 (m, 2H), 4.33 (s, 2H), 7.22−7.35 (m, 5H), 7.41 (d, 2H, 3J = 8,5
Hz), 8.08 (d, 2H, 3J = 8,5 Hz); 13C NMR (125 MHz, CDCl3) δ 21.8,
22.0, 22.8, 25.0, 25.3, 38.5, 119.1, 127.48, 127.48, 128.5, 129.2, 129.4,
129.6, 132.0, 133.1, 135.6, 145.9, 154.0, 157.3, 160.2; HRMS-ESI m/z
[M + Na]+ calcd for C24H22N2O3S3Na 505.0685, found 505.0678.
2-(Benzylsulfanyl)-3-(methylsulfonyl)-5,6,7,8-tetrahydrobenzo-
[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (12j). To a suspension of (Z)-
2-((methylsulfonamido)(benzylsulfanyl)methyleneamino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylic acid (27j) (0.20 g, 0.47
mmol) in CH2Cl2 (5 mL) were added three drops of DMF and oxalyl
chloride (0.05 mL, 0.5 mmol). The mixture was stirred for 30 min at
L
dx.doi.org/10.1021/jo4010876 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
room temperature. After evaporation in vacuo, the residue was purified
by flash column chromatography using petroleum ether/EtOAc (4:1
to 2:1) to yield 12j as a white solid (0.15 g, 78%): mp 148−151 °C;
1H NMR (500 MHz, CDCl3) δ 1.77−1.88 (m, 4H), 2.71−2.74 (m,
2H), 2.87−2.90 (m, 2H), 3.62 (s, 3H), 4.30 (s, 2H), 7.23−7.25 (m,
1H), 7.27−7.30 (m, 2H), 7.37−7.38 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 22.1, 22.8, 25.1, 25.3, 38.3, 44.5, 119.0, 127.6, 128.5, 129.7,
132.0, 133.6, 135.7, 153.6, 158.4, 160.5. Anal. Calcd for
C18H18N2O3S3: C, 53.18; H, 4.46; N, 6.89. Found: C, 52.78; H,
4.80; N, 6.52.
HPLC Analysis of the Sulfonyl Migration. A mixture of
compound 12e (13.2 mg, 0.032 mmol) and anhydrous acetonitrile
(32 mL) was refluxed under argon atmosphere. Without interrupting
the heating, aliquots of 200 μL were collected via a syringe through a
rubber septum. After 2 min, these aliquots were directly subjected to
the HPLC. The chromatograms were analyzed to determine relative
concentrations under the assumption of equal extinction coefficients
for 12e and 14e at 220 nm. The first-order rate constant of the
exponential decay was determined by nonlinear regression using the
program GraFit v5.0 (Erithacus Software, Horley, U.K.). Similarly, the
reaction of compound 12e (13.2 mg, 0.032 mmol) in acetonitrile (32
mL) in the presence of compound 3 (1.23 mg, 0.0064 mmol) and the
reaction of 12e (13.2 mg, 0.032 mmol) in acetonitrile (32 mL) in the
presence of compound 4 (1.64 mg, 0.0064 mmol) were analyzed.
(7) The subsequent Lossen rearrangement to isocyanates gives rise to
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J.; Pour, M.
ASSOCIATED CONTENT
* Supporting Information
Tetrahedron 2013, 69, 1705−1711.
(15) Terrazas, M.; Ariza, X.; Farras
2005, 3968−3970.
■
̀
, J.; Vilarrasa, J. Chem. Commun.
S
X-ray crystal structures (CIF), additional analytical data to
sulfonyl migration, and 1H NMR, 13C NMR, HSQC, and
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AUTHOR INFORMATION
Corresponding Author
*E-mail: guetschow@uni-bonn.de.
■
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Present Address
§Department of Pharmacology, University of Cologne, Gleueler
Strasse 24, D-50931 Cologne, Germany.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
G.S. thanks Prof. A. C. Filippou for support. We thank Marion
Schneider for performing LC/MS analyses and Sabine Terhart-
Krabbe and Annette Reiner for recording NMR spectra.
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