First example of Lewis acid catalyzed 3-substituted 5-arylidene-1-methyl-2- thiohydantoin formation

Article abstract of DOI:10.1055/s-2006-950342

A survey of Lewis acids was conducted to facilitate the formation of arylidenethiohydantoins. The use of indium(III) triflate shows significant advantages in facilitating this reaction. In most examples, the Lewis acid promoted catalysis gave shorter reac

Full text of DOI:10.1055/s-2006-950342

4200
PAPER
First Example of Lewis Acid Catalyzed 3-Substituted 5-Arylidene-1-methyl-2-
thiohydantoin Formation
L
ewis AcidCatal
r
yzedFo
i
a
of
A
rylide
n
nethiohydantoins T. Gregg,* William G. Earley, Kathryn C. Golden, John F. Quinn, Dana A. Razzano, W. Martin Rennells
Albany Molecular Research, Inc., 21 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
Fax +1(518)8674381; E-mail: brian@albmolecular.com
Received 15 June 2006; revised 25 July 2006
groups. We herein report our findings for the protocol val-
Abstract: A survey of Lewis acids was conducted to facilitate the
formation of arylidenethiohydantoins. The use of indium(III) trif-
late shows significant advantages in facilitating this reaction. In
most examples, the Lewis acid promoted catalysis gave shorter re-
idation phase of our compound library synthesis. A num-
ber of potential Lewis acid catalysts were surveyed to
efficiently and reproducibly generate a library of previ-
action times, higher conversion, and better purity profiles as com- ously unreported 3-substituted 5-arylidene-1-methyl-2-
pared to the traditional uncatalyzed reactions.
thiohydantoins 3.
Key words: Lewis acids, catalysis, heterocycles, indium, conden-
sation
R'
O
N
O
N
O
a
b
H
N
N
R
N
OH
R
The 3-substituted 5-arylidene-1-methyl-2-thiohydantoin
moiety 3 is known to be a biologically active heterocycle
in areas of antimycobacterial,1 antiviral2 and potentially
anticonvulsant indications.3 As part of our efforts to gen-
erate libraries of medicinally relevant compounds, we set
out to prepare a focused library of approximately 400
compounds elaborating this interesting core. Most recent-
ly Nielsen4 reported the preparation of a small 28-member
library of 3-substituted 5-arylidene-1-methyl-2-thiohy-
dantoins 3 via microwave-mediated and traditional reflux
conditions with good results. Our initial approach for the
preparation of 3-substituted 5-arylidene-1-methyl-2-thio-
hydantoins involved the direct condensation of aldehydes
with 3-substituted 1-methyl-2-thiohydantoins 2 in the
presence of an organic base and a solvent such as toluene
or 1,4-dioxane (Scheme 1). Our observations showed
that, in general, uncatalyzed reactions give modest to
good yields of 40% to 80% with unhindered aldehydes
and that sterically hindered aldehydes typically gave very
poor results. Similar results (Scheme 2) are found in the
literature for other carbonyl compounds including 1,3-di-
hydroindol-2-one (4, oxindole),5 a,b-unsaturated ke-
tones,6,7 3-phenylisoxazol-5-one (5),8 benzofuran-2(3H)-
one (6),9 pyrazol-5-one (7),10 and 2-phenyl-3-thiazolin-5-
one (8).11 The use of catalysts (AlCl3, TsOH and KF/alu-
mina) has been reported for other similar substrates, in
particular oxindole, with good results for a limited num-
ber of examples. We envisaged using a large diversity of
the library ligand sets; however, the microwave-assisted
synthesis would not be viable for a two-dimensional li-
brary consisting of several hundred compounds. Hence
we sought to develop a reaction protocol which generated
the target 3-substituted 5-arylidene-1-methyl-2-thiohy-
dantoins 3 in good yield for a wide variety of R and R¢
S
S
1
2
3
a) RNCS, EtOH, reflux, 6 h
b) aldehyde, catalyst, pyrrolidine, 1,4-dioxane, 60 °C, 30 min
Scheme 1 General synthetic sequence for the preparation of 3-sub-
stituted 5-arylidene-1-methyl-2-thiohydantoins.
Ar
O
O
O
N
N
H
H
4
Ar
O
O
O
N
N
Ar
5
6
O
O
O
O
O
O
Ar
N
N
N
N
7
Ar
N
N
O
O
S
S
8
Scheme 2 Examples of literature substrates and subsequent aldehy-
de condensation products.
SYNTHESIS 2006, No. 24, pp 4200–4204
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950342; Art ID: M03906SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Lewis Acid Catalyzed Formation of Arylidenethiohydantoins
4201
After reviewing the literature for Lewis acid catalyzed re-
actions, we chose to investigate three primary catalysts
(10 mol% concentration): aluminum trichloride, boron tri-
fluoride diethyl etherate and indium(III) triflate. Starting
thiohydantoin cores 2 were prepared as previously de-
scribed in the literature12 by the reaction of N-methylgly-
cine (sarcosine, 1) with isothiocyanates in ethanol at
reflux for 6 hours. Figures 1 and 2, respectively, show the
four thiohydantoins and five aldehydes that were used in
this study for the generation of a validation library of 20
compounds. Also included are our results for the aldehyde
condensation reaction with oxindole to demonstrate the
versatility of this methodology.
Figure 3 Extent of product formation for the condensation reaction
of aldehydes A–E with oxindole (4, peak area percent from analytical
RP-HPLC/MS monitored via UV absorbance at 220 nm and 254 nm)
with and without the addition of catalysts.
O
O
N
N
N
H
OMe
S
4
11
12
O
O
N
N
N
N
S
S
9
O
O
N
N
N
S
10
Figure 1 Core 3-substituted 1-methyl-2-thiohydantoins 9–12 and
oxindole 4 utilized in this study.
Figure 4 Extent of product formation for the condensation reaction
of aldehydes A–E with 3-isopropyl-1-methyl-2-thiohydantoin (9,
peak area percent from analytical RP-HPLC/MS monitored via UV
absorbance at 220 nm and 254 nm) with and without the addition of
catalysts.
O
O
S
N
H
H
A
D
O
O
OMe
H
N
H
OH
B
E
O
O
O
H
C
Figure 2 Aldehydes A–E used in condensation reaction of 3-substi-
tuted 1-methyl-2-thiohydantoins to generate 3-substituted 5-aryli-
dene-1-methyl-2-thiohydantoins.
Figure 5 Extent of product formation for the condensation reaction
of aldehydes A–E with 3-(3-morpholin-4-yl-propyl)-1-methyl-2-
thiohydantoin (10, peak area percent from analytical RP-HPLC/MS
monitored via UV absorbance at 220 nm and 254 nm) with and with-
out the addition of catalysts.
Figures 3 through 7 show the percentage conversion (RP-
HPLC/MS analysis at t = 30 min) for the catalyzed and
uncatalyzed condensation reaction of aldehydes A–E with
the four thiohydantoin cores 9–12 and oxindole 4.
Our observations indicate that reactions which proceed in
less than 40% overall yield after 30 minutes typically
show little additional conversion to desired product with
Synthesis 2006, No. 24, 4200–4204 © Thieme Stuttgart · New York

4202
B. T. Gregg et al.
PAPER
sion. Similar results are found in Figure 6 whereby the
condensation of aldehyde E with 3-(4-methoxyphenyl)-1-
methyl-2-thiohydantoin (11) resulted in >90% conversion
to the desired product with indium(III) triflate, yet shows
only a modest % conversion with the other catalysts.
While it was not within the scope of this work to deter-
mine the E vs Z isomer formation and ratio of the resulting
3-substituted 5-arylidene-1-methyl-2-thiohydantoins, in
some cases both isomers were detected by HPLC/MS
1
analysis and were further characterized by H and 13C
NMR analysis that was in agreement with previously re-
ported data for similar compounds.11
In conclusion, indium(III) triflate, aluminum chloride and
boron trifluoride diethyl etherate were all found to be ef-
ficient catalysts for the formation of 3-substituted 5-
arylidene-1-methyl-2-thiohydantoins. Indium(III) triflate
was chosen as the catalyst for the subsequent library syn-
thesis due to the scope of application, easy of handling, air
stability, reproducible results, low toxicity and cost. Iso-
lated yields were in excess of 80% for all catalyzed reac-
tions and reaction times were typically less than 30
minutes.
Figure 6 Extent of product formation for the condensation reaction
of aldehydes A–E with 3-(4-methoxyphenyl)-1-methyl-2-thiohydan-
toin (11, peak area percent from analytical RP-HPLC/MS monitored
via UV absorbance at 220 nm and 254 nm) with and without the ad-
dition of catalysts.
Thiohydantoins 9–12; General Procedure12
To a 250 mL single-neck round-bottomed flask fitted with a mag-
netic stir bar was charged sarcosine (1; 1.5 g, 16.8 mmol) and anhyd
EtOH (100 mL). To the resulting solution was added the appropriate
isothiocyanate (1.0 equiv, 16.8 mmol) and the mixture was refluxed
for 6 h after which time the reaction was allowed to cool to r.t. The
EtOH was removed under reduced pressure and the resulting crude
material was dissolved into a minimum of CH2Cl2 and purified by
silica gel chromatography (50 g) with EtOAc–hexanes (1:4) to give
the title compound.
Figure 7 Extent of product formation for the condensation reaction
of aldehydes A–E with 3-(indan-5-yl)-1-methyl-2-thiohydantoin (12,
peak area percent from analytical RP-HPLC/MS monitored via UV
absorbance at 220 and 254 nm) with and without the addition of cata-
lysts.
Catalyst Survey for the Preparation of Arylidene Thiohydanto-
ins 4A–E, 9A–E, 10A–E, 11A–E and 12A–E; General Procedure
To a 2 dram vial fitted with a magnetic stir bar was added the appro-
priate thiohydantoin 4, 9–12 (0.75 mmol), aldehyde A–E (1.2
equiv, 0.90 mmol), pyrrolidine (1.5 equiv, 1.13 mmol) and 1,4-di-
oxane (1.5 mL). To the mixture was added the desired catalyst (0.1
equiv, 0.075 mmol) and the mixture was heated to 60 °C using a J-
Chem heater block. Aliquots were removed and the samples ana-
lyzed after 30 min, 90 min, 5 h and 24 h by HPLC at 210 and 254
nm. For all reactions with In(OTf)3 as the catalyst, the reaction mix-
tures were concentrated to dryness under reduced pressure and the
crude residue was chromatographed on silica gel (10 g) with
increased reaction time, and in some cases additional
byproduct formation was observed that would have made
the sample intractable to purification in a parallel format.
All three catalysts [AlCl3, BF3·Et2O, In(OTf)3] showed an
increase in % conversion for the formation of 3-substitut-
ed 5-arylidene-1-methyl-2-thiohydantoins compared to
the uncatalyzed reactions. Indium(III) triflate was gener- CH2Cl2–MeOH (95:5) to give the title compound.
ally superior to the other catalysts both in terms of % con-
version and ease of experimental and work-up procedures.
4A
1H NMR (300 MHz, CDCl3): d = 3.08 [6 H, s, N(CH3)2], 6.72–6.76
(4 H, m, Ar), 6.81–6.92 [2 H, m, CH=CHN(CH3)2], 7.77 (1 H,
s, =CH), 7.82 [2 H, d, J = 7.73 Hz, CH=CHN(CH3)2], 8.39 (1 H, d,
J = 8.94 Hz, Ar).
The most dramatic example of the catalyst effectiveness is
illustrated in Figures 4 and 5 where aldehydes A, C and E
are nearly unreactive towards the condensation reaction in
the absence of a catalyst yet show significant conversion
to the desired products with the addition of a catalyst. Spe-
cifically, the versatility of indium(III) triflate can be seen
in Figure 7 with aldehyde E, 4-(1-pyrrolidino)benzalde-
hyde, and 1-methyl-5-indan-2-thiohydantoin (12) where
the % conversion increased from <30% to 72% while the
HRMS-EI: m/z calcd for C17H16N2O: 265.1341; found: 265.1333.
4B
1H NMR (300 MHz, CDCl3): d = 3.82 (3 H, s, OCH3), 5.85 (1 H, s,
OH), 6.80–6.98 (4 H, m, Ar), 7.11–7.36 (3 H, m, Ar), 7.70 (1 H,
s, =CH), 7.74 (1 H, d, J = 7.70 Hz, Ar).
other catalysts surveyed only resulted in <20% conver- HRMS-EI: m/z calcd for C16H13NO3: 268.0973; found: 268.0966.
Synthesis 2006, No. 24, 4200–4204 © Thieme Stuttgart · New York

PAPER
Lewis Acid Catalyzed Formation of Arylidenethiohydantoins
4203
4C
NCH2CH2CH2), 6.36 (1 H, s, =CH), 6.60 (2 H, d, J = 8.96 Hz, Ar),
7.18 (1 H, d, J = 9.38 Hz, Ar), 8.02 (1 H, d, J = 8.99 Hz, Ar).
1H NMR (300 MHz, CDCl3): d = 4.32 (4 H, m, OCH2), 6.83–7.02
(4 H, m, Ar), 7.18–7.43 (2 H, m, Ar), 7.78 (1 H, s, =CH), 7.90 (1 H,
d, J = 7.71 Hz, Ar), 8.10 (1 H, d, J = 8.15 Hz, Ar).
HRMS-EI: m/z calcd for C20H28N4O2S: 389.2011; found: 389.2005.
HRMS-EI: m/z calcd for C17H13NO3: 280.0973; found: 280.0966.
10B
1H NMR (300 MHz, CDCl3): d = 1.92 (2 H, pent, J = 6.95 Hz,
NCH2CH2CH2), 2.45 (6 H, m), 3.59 (3 H, s, NCH3), 3.67 (4 H, m,
NCH2CH2O), 3.96 (3 H, s, OCH3), 4.02 (2 H, m NCH2CH2CH2),
6.40 (1 H, s, =CH), 6.88 (2 H, d, J = 8.26 Hz, Ar), 7.27 (1 H, d,
J = 8.96 Hz, Ar), 8.37 (1 H, d, J = 1.88 Hz, Ar).
4D
1H NMR (300 MHz, CDCl3): d = 6.86–6.95 (1 H, m, Ar), 7.01–7.10
(1 H, m, Ar), 7.15–7.24 (2 H, m, Ar), 7.53 (1 H, m, Ar), 7.65 (1 H,
m, Ar), 7.73 (1 H, s, =CH), 7.85 (1 H, d, J = 3.68 Hz, Ar).
HRMS-EI: m/z calcd for C13H9NOS: 228.0483; found: 228.0480.
HRMS-EI: m/z calcd for C19H25N3O4S: 392.1644; found: 392.1638.
4E
10C
1H NMR (300 MHz, CDCl3): d = 2.04 (4 H, m, NCH2CH2), 3.40 (4
H, m, NCH2CH2), 6.58–6.61 (3 H, m, Ar), 6.80–7.00 (2 H, m, Ar),
7.14–7.49 (1 H, m, Ar), 7.67 (2 H, m, Ar), 7.91 (1 H, s, =CH), 8.41
(1 H, d, J = 8.79 Hz, Ar).
1H NMR (300 MHz, CDCl3): d = 1.87 (2 H, pent, J = 7.13 Hz,
NCH2CH2CH2), 2.41 (6 H, m), 3.58 (3 H, s, NCH3), 3.67 (4 H, m,
NCH2CH2O), 4.00 (2 H, m NCH2CH2CH2), 4.29 (4 H, m, OCH2),
6.36 (1 H, s, =CH), 6.86 (1 H, d, J = 8.53 Hz, Ar), 7.49 (1 H, d,
J = 8.52 Hz, Ar), 7.82 (1 H, d, J = 2.09 Hz, Ar).
HRMS-EI: m/z calcd for C19H18N2O: 291.1497; found: 291.1487.
HRMS-EI: m/z calcd for C20H25N3O4S: 404.1644, found: 404.1643.
9A
1H NMR (300 MHz, CDCl3): d = 0.94 [6 H, d, J = 6.70 Hz,
CH(CH3)2], 2.32 [1 H, sept, J = 6.70 Hz, CH(CH3)2], 3.05 [6 H, s,
N(CH3)2], 3.62 (3 H, s, NCH3), 3.77 [2 H, d, J = 7.39 Hz,
CH2CH(CH3)2], 6.46 (1 H, s, =CH), 6.69 (2 H, d, J = 8.96 Hz, Ar),
8.10 (2 H, d, J = 8.95 Hz, Ar).
10D
1H NMR (300 MHz, CDCl3): d = 1.92 (2 H, pent, J = 7.15 Hz,
NCH2CH2CH2), 2.44 (6 H, m), 3.60 (3 H, s, NCH3), 3.66 (4 H, m,
NCH2CH2O), 4.03 (2 H, m NCH2CH2CH2), 6.71 (1 H, s, =CH),
7.11 (1 H, m, Ar), 7.52 (1 H, d, J = 5.15 Hz, Ar), 7.71 (1 H, d,
J = 3.65 Hz, Ar).
HRMS-EI: m/z calcd for C17H23N3OS: 318.1640; found: 318.1635.
HRMS-EI: m/z calcd for C16H21N3O2S2 requires 352.1153; found:
9B
352.1161.
1H NMR (300 MHz, CDCl3): d = 0.95 [6 H, d, J = 6.73 Hz,
CH(CH3)2], 2.31 [1 H, sept, J = 6.73 Hz, CH(CH3)2], 3.62 (3 H, s,
NCH3), 3.77 [2 H, d, J = 7.61 Hz, CH2CH(CH3)2], 4.00 (3 H, s,
OCH3), 5.95 (1 H, s, OH), 6.44 (1 H, s, =CH), 6.92 (1 H, d, J = 8.21
Hz, Ar), 7.28 (1 H, d, J = 8.21 Hz, Ar), 8.41 (1 H, d, J = 1.75 Hz,
Ar).
10E
1H NMR (300 MHz, CDCl3): d = 1.93 (2 H, m, NCH2CH2CH2),
2.01 (4 H, m, NCH2CH2), 2.46 (6 H, m), 3.38 (4 H, m, NCH2CH2),
3.62 (3 H, s, NCH3), 3.69 (4 H, m, NCH2CH2O), 4.04 (2 H, m
NCH2CH2CH2), 6.46 (1 H, s, =CH), 6.56 (2 H, d, J = 8.71 Hz, Ar),
8.12 (2 H, d, J = 8.73 Hz, Ar).
HRMS-EI: m/z calcd for C16H20N2O3S: 321.1273; found: 321.1278.
HRMS-EI: m/z calcd for C22H30N4O2S: 415.2167; found: 415.2171.
9C
1H NMR (300 MHz, CDCl3): d = 0.95 [6 H, d, J = 6.71 Hz,
CH(CH3)2], 2.30 [1 H, sept, J = 6.72 Hz, CH(CH3)2], 3.60 (3 H, s,
NCH3), 3.74 [2 H, d, J = 7.59 Hz, CH2CH(CH3)2], 4.29 (4 H, m,
OCH2), 6.38 (1 H, s, =CH), 6.86 (1 H, d, J = 8.56 Hz, Ar), 7.52 (1
H, d, J = 8.54 Hz, Ar), 7.81 (1 H, d, J = 1.94 Hz, Ar).
11A
1H NMR (300 MHz, CDCl3): d = 3.03 [6 H, s, N(CH3)2], 3.66 (3 H,
s, NCH3), 3.82 (3 H, s, OCH3), 6.51 (1 H, s, =CH), 6.64 (2 H, d,
J = 9.10 Hz, Ar), 7.00 (2 H, d, J = 8.90 Hz, Ar), 7.28 (2 H, d,
J = 8.90 Hz, Ar), 8.13 (2 H, d, J = 9.04 Hz, Ar).
HRMS-EI: m/z calcd for C17H20N2O3S: 333.1273; found: 333.1286.
HRMS-EI: m/z calcd for C20H21N3O2S: 368.1432; found: 368.1435.
9D
11B
1H NMR (300 MHz, CDCl3): d = 0.94 [6 H, d, J = 6.84 Hz,
CH(CH3)2], 2.32 [1 H, sept, J = 7.04 Hz, CH(CH3)2], 3.60 (3 H, s,
NCH3), 3.77 [2 H, d, J = 7.50 Hz, CH2CH(CH3)2], 6.71 (1 H,
s, =CH), 7.11 (1 H, m, Ar), 7.52 (1 H, d, J = 4.89 Hz, Ar), 7.72 (1
H, d, J = 3.67 Hz, Ar).
1H NMR (300 MHz, CDCl3): d = 3.72 (3 H, s, NCH3), 3.84 (3 H, s,
OCH3), 3.97 (3 H, s, OCH3), 5.31 (1 H, s, OH), 6.53 (1 H, s, =CH),
6.87–7.04 (3 H, m, Ar), 7.24–7.29 (3 H, m, Ar), 8.50 (1 H, d,
J = 1.86 Hz, Ar).
HRMS-EI: m/z calcd for C19H18N2O4S: 371.1065; found: 371.1075.
HRMS-EI: m/z calcd for C13H16N2OS2: 281.0782; found: 281.0782.
11C
9E
1H NMR (300 MHz, CDCl3): d = 3.70 (3 H, s, NCH3), 3.84 (3 H, s,
OCH3), 4.28 (4 H, m, OCH2), 6.46 (1 H, s, =CH), 6.85 (1 H, d,
J = 8.55 Hz, Ar), 6.99 (2 H, d, J = 8.95 Hz, Ar), 7.26 (2 H, d,
J = 8.94 Hz, Ar), 7.56 (1 H, d, J = 8.62 Hz, Ar), 7.81 (1 H, d,
J = 2.09 Hz, Ar).
1H NMR (300 MHz, CDCl3): d = 0.94 [6 H, d, J = 6.74 Hz,
CH(CH3)2], 2.01 (4 H, m, NCH2CH2), 2.33 [1 H, sept, J = 6.71 Hz,
CH(CH3)2], 3.35 (4 H, m, NCH2CH2), 3.63 (3 H, s, NCH3), 3.77 [2
H, d, J = 7.52 Hz, CH2CH(CH3)2], 6.47 (1 H, s, =CH), 6.56 (2 H, d,
J = 8.98 Hz, Ar), 8.12 (2 H, d, J = 8.91 Hz, Ar).
HRMS-EI: m/z calcd for C20H18N2O4S: 383.1065; found: 383.1077.
HRMS-EI: m/z calcd for C19H25N3OS: 344.1796, found: 344.1812.
11D
10A
1H NMR (300 MHz, CDCl3): d = 3.70 (3 H, s, NCH3), 3.84 (3 H, s,
OCH3), 6.81 (1 H, s, =CH), 7.01 (2 H, d, J = 8.97 Hz, Ar), 7.14 (1
H, m, Ar), 7.26 (2 H, m, Ar), 7.54 (1 H, d, J = 4.90 Hz, Ar), 7.75 (1
H, d, J = 3.62 Hz, Ar).
1H NMR (300 MHz, CDCl3): d = 1.84 (2 H, pent, J = 7.17 Hz,
NCH2CH2CH2), 2.38 (6 H, m), 2.96 [6 H, d, J = 5.39 Hz, N(CH3)2],
3.45 (3 H, s, NCH3), 3.60 (4 H, m, NCH2CH2O), 3.94 (2 H, m
Synthesis 2006, No. 24, 4200–4204 © Thieme Stuttgart · New York

4204
B. T. Gregg et al.
PAPER
HRMS-EI: m/z calcd for C16H14N2O2S2: 331.0575; found:
331.0584.
6.58 (2 H, m, Ar), 7.12 (1 H, d, J = 7.89 Hz, Ar), 7.18 (1 H, s, Ar),
7.32 (1 H, d, J = 7.92 Hz, Ar), 8.15 (2 H, d, J = 8.92 Hz, Ar).
HRMS-EI: m/z calcd for C22H23N3O2S: 404.1796; found: 404.1796.
11E
1H NMR (300 MHz, CDCl3): d = 2.00 (4 H, m, NCH2CH2), 3.32 (4
H, m, NCH2CH2), 3.63 (3 H, s, NCH3), 3.82 (3 H, s, OCH3), 6.48 (1
H, s, =CH), 6.52 (2 H, m, Ar), 7.00 (2 H, d, J = 8.87 Hz, Ar), 7.27
(2 H, d, J = 8.89 Hz, Ar), 8.12 (2 H, d, J = 8.87 Hz, Ar).
Acknowledgment
The authors wish to thank and acknowledge Drs. Michael P. Trova,
Douglas B. Kitchen, Dmytro O. Tymoshenko and Mr. James E.
Schermerhorn for their input and helpful discussions.
HRMS-EI: m/z calcd for C22H23N3O2S: 394.1589; found: 394.1594.
12A
1H NMR (300 MHz, CDCl3): d = 2.12 (2 H, sept, J = 7.45 Hz,
CH2CH2CH2), 2.94 (4 H, m, CH2CH2CH2), 3.03 [6 H, s, N(CH3)2],
3.67 (3 H, s, NCH3), 6.51 (1 H, s, =CH), 6.64 (2 H, d, J = 9.11 Hz,
Ar), 7.11 (1 H, d, J = 7.89 Hz, Ar), 7.17 (1 H, s, Ar), 7.32 (1 H, d,
J = 7.87 Hz, Ar), 8.16 (2 H, d, J = 9.06 Hz, Ar).
References
(1) Kiec-Kononowicz, K.; Szymanska, E. Farmaco 2002, 57,
909.
(2) Khodair, A. I.; El-Barbary, A. A.; Abbas, Y. A.; Imam, D. R.
Phosphorous, Sulfur Silicon Relat. Elem. 2001, 170, 261.
(3) Mehta, N.; Risiger, C. A.; Soroko, F. E. J. Med. Chem. 1981,
24, 465.
HRMS-EI: m/z calcd for C22H23N3OS: 378.1640; found: 378.1651.
12B
(4) Khodair, A. I.; Nielsen, J. Heterocycles 2002, 57, 1017.
(5) (a) Villemin, D.; Martin, M. Synth. Commun. 1998, 28,
3201. (b) Bramson, H. N.; Corona, J.; Davis, S. T.;
Dickerson, S. H.; Edelstein, M.; Frye, S. V.; Gampe, R. T.
Jr.; Harris, P. A.; Hassell, A.; Holmes, W. D.; Hunter, R. N.;
Lackey, K. E.; Lovejoy, B.; Luzzio, M. J.; Montana, V.;
Roque, W. J.; Rusnak, D.; Shewchuk, L.; Veal, J. M.;
Walker, D. H.; Kuyper, L. F. J. Med. Chem. 2001, 44, 4339.
(c) Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.;
Cui, J.; Fukuda, J. Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.;
Chen, H.; Sistla, A.; Luu, T. C.; Tang, F.; Wei, J.; Tang, C.
J. Med. Chem. 2003, 46, 1116. (d) Thompson, A. M.;
Delaney, A. M.; Hamby, J. M.; Schroeder, M. C.; Spoon, T.
A.; Crean, S. M.; Showalter, H. D. H.; Denny, W. A. J. Med.
Chem. 2005, 48, 4628.
(6) Deng, G.; Tiegan, R. Synth. Commun. 2003, 33, 2995.
(7) Zheng, X.; Zhang, Y. Synth. Commun. 2003, 33, 161.
(8) Villemin, D.; Martin, B.; Garrigues, B. Synth. Commun.
1993, 23, 2251.
(9) Msaddek, M.; Rammah, M.; Ciamala, K.; Vebrel, J.; Laude,
B. Synthesis 1997, 1495.
1H NMR (300 MHz, CDCl3): d = 2.13 (2 H, sept, J = 7.40 Hz,
CH2CH2CH2), 2.95 (4 H, m, CH2CH2CH2), 3.70 (3 H, s, NCH3),
3.93 (3 H, s, OCH3), 6.01 (1 H, s, OH), 6.52 (1 H, s, =CH), 6.93 (1
H, d, J = 9.11 Hz, Ar), 7.08 (1 H, d, J = 7.86 Hz, Ar), 7.16 (1 H, s,
Ar), 7.26 (1 H, d, J = 8.28 Hz, Ar), 7.34 (1 H, d, J = 7.89 Hz, Ar),
8.51 (1 H, d, J = 1.94 Hz, Ar).
HRMS-EI: m/z calcd for C22H23N3O2S: 381.1273; found: 381.1273.
12C
1H NMR (300 MHz, CDCl3): d = 2.11 (2 H, sept, J = 7.48 Hz,
CH2CH2CH2), 2.93 (4 H, m, CH2CH2CH2), 3.66 (3 H, s, NCH3),
4.26 (4 H, m, OCH2), 6.44 (1 H, s, =CH), 6.83 (1 H, d, J = 8.54 Hz,
Ar), 7.07 (1 H, d, J = 7.89 Hz, Ar), 7.15 (1 H, s, Ar), 7.32 (1 H, d,
J = 7.91 Hz, Ar), 7.56 (1 H, dd, J = 8.56, 2.09 Hz, Ar), 7.82 (1 H, d,
J = 2.12 Hz, Ar).
HRMS-EI: m/z calcd for C22H23N3O2S: 393.1273; found: 393.1276.
12D
1H NMR (300 MHz, CDCl3): d = 2.11 (2 H, sept, J = 7.32 Hz,
CH2CH2CH2), 2.95 (4 H, m, CH2CH2CH2), 3.68 (3 H, s, NCH3),
6.79 (1 H, s, =CH), 7.10 (1 H, m, Ar), 7.17 (1 H, s, Ar), 7.33 (1 H,
d, J = 7.90 Hz, Ar), 7.52 (1 H, d, J = 4.98 Hz, Ar), 7.73–7.76 (2 H,
m, Ar).
(10) Sun, J.; Chao-Guo, Y.; Han, Y. Synth. Commun. 2001, 31,
151.
(11) Muxfeldt, H.; Behling, J.; Grethe, G.; Rogalski, W. J. Am.
Chem. Soc. 1967, 89, 4991.
HRMS-EI: m/z calcd for C22H23N3O2S: 341.0782; found: 341.0791.
(12) (a) Cook, A. H.; Cox, S. F. J. Chem. Soc. 1949, 2342.
(b) Hassan, E.; Sulkowski, T. S.; Abou-Gharbia, M.; Butera,
J. A.; Chai, S.-Y.; McFarlane, G. R.; McKean, M.-L.;
Babiak, J. L.; Adelman, S. J.; Quinet, E. M. J. Med. Chem.
2004, 47, 681.
12E
1H NMR (300 MHz, CDCl3): d = 1.98 (4 H, m, NCH2CH2), 2.10 (2
H, sept, J = 7.44 Hz, CH2CH2CH2), 2.94 (4 H, m, CH2CH2CH2),
3.35 (4 H, m, NCH2CH2), 3.67 (3 H, s, NCH3), 6.49 (1 H, s, = CH),
Synthesis 2006, No. 24, 4200–4204 © Thieme Stuttgart · New York