Novel regioselective hydroxyl-alkylation of 4,5-diphenylimidazole-2-thione and a competitive intramolecular ring closure of the S-hydroxyalkyl-imidazoles to imidazo[2,1-b]thiazines and thiazoles. role of catalyst, microwave irradiation, and solid support

Article abstract of DOI:10.1080/15257770701426179

Under both conventional method (CM) and microwave (MW) irradiation (MWI) conditions, alkylation of 4,5-diphenylimidazole-2-thione (1) with halogeno-alkanols 2 or 5, chloroglycerol 11 and 2,3-O-isopropylidene-1-O-(p- tolylsulfonyl)-glycerol (8) in presence

Full text of DOI:10.1080/15257770701426179

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Novel Regioselective Hydroxyl-Alkylation
of 4,5-Diphenylimidazole-2-Thione and A
Competitive Intramolecular Ring Closure
of the S-Hydroxyalkyl-Imidazoles to
Imidazo[2,1-b]Thiazines and Thiazoles.
Role of Catalyst, Microwave Irradiation,
and Solid Support
E. S. H. El Ashry a , N. Rashed a , L. F. Awad a , E. Ramadan a , S. M.
Abdel-Maggeed a & N. Rezki a
a Chemistry Department , Faculty of Science, Alexandria University ,
Alexandria, Egypt
Published online: 19 Jun 2007.
To cite this article: E. S. H. El Ashry , N. Rashed , L. F. Awad , E. Ramadan , S. M. Abdel-Maggeed &
N. Rezki (2007) Novel Regioselective Hydroxyl-Alkylation of 4,5-Diphenylimidazole-2-Thione and A
Competitive Intramolecular Ring Closure of the S-Hydroxyalkyl-Imidazoles to Imidazo[2,1-b]Thiazines
and Thiazoles. Role of Catalyst, Microwave Irradiation, and Solid Support, Nucleosides, Nucleotides
and Nucleic Acids, 26:5, 423-435, DOI: 10.1080/15257770701426179
To link to this article: http://dx.doi.org/10.1080/15257770701426179
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Nucleosides, Nucleotides, and Nucleic Acids, 26:423–435, 2007
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701426179
NOVEL REGIOSELECTIVE HYDROXYL-ALKYLATION OF
4,5-DIPHENYLIMIDAZOLE-2-THIONE AND A COMPETITIVE
INTRAMOLECULAR RING CLOSURE OF THE
S-HYDROXYALKYL-IMIDAZOLES TO IMIDAZO[2,1-b]THIAZINES AND
THIAZOLES. ROLE OF CATALYST, MICROWAVE IRRADIATION, AND
SOLID SUPPORT
E. S. H. El Ashry, N. Rashed, L. F. Awad, E. Ramadan, S. M. Abdel-Maggeed,
and N. Rezki
Alexandria, Egypt
Chemistry Department, Faculty of Science, Alexandria University,
2
Under both conventional method (CM) and microwave (MW) irradiation (MWI) conditions,
2
alkylation of 4,5-diphenylimidazole-2-thione (1) with halogeno-alkanols 2 or 5, chloroglycerol 11
and 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (8) in presence of sodium ethoxide or sodium
acetate in alcohol afforded regioselectively the corresponding S-alkylated analogues 3, 6, 9, and 12;
they also were obtained using MW in absence and presence of bentonite as solid support with no
change in regioselectivity. In the presence of potassium carbonate in DMF, the bisalkylated analogues
4, 7, 10, and 13 were obtained except in case of compound 13 where it was accompanied with
the imidazothiazine 14. A convenient approach for imidazo-[2,1-b]thiazines and thiazoles 14–16
could be achieved by intramolecular dehydrative ring closure of the S-hydroxyalkylated imidazoles 3,
6, and 12 using potassium carbonate in DMF under both conventional and microwave methods.
Isopropylidenation of 12 and 13 and deprotection of 9 and 10 also were investigated.
Keywords Imidazole; imidazo[2,1-b][1,3]thiazine; Imidazo[2,1-b][1,3]thiazole; acy-
clonucleoside; alkylation; microwave irradiation; solid support
INTRODUCTION
Many acyclonucleoside analogues[1] such as acyclovir[2] (ACV),
ganciclovir[3] (GCV) and penciclovir[4] (PCV), and (S)-9-(2,3-dihydroxy-
propyl)adenine[5] posses potent antiviral activity. Extensive efforts have
Received 25 July 2006; accepted 5 March 2007.
E. S. H. El-Ashry is on leave to International Center for Chemical and Biological Sciences, HEJ
Research Institute, University of Karachi, Karachi, Pakistan.
N. Rezki is on leave from the Ministry of High Education and Scientific Research, Algeria.
Address correspondence to E. S. H. El Ashry, Chemistry Department, Faculty of Science, Alexandria
University, Alexandria, Egypt. E-mail: eelashry60@hotmail.com
423

424
E. S. H. El Ashry et al.
been directed to synthesize acyclonucleoside analogues of the natural
ones by modification of the heterocyclic base and/or the acyclic side
chain.[1,6–11]
Valuable medicinal applications such as antiinflammatory,[12]
antiasthmatic,[13] antiulcerative[14] and antithrombotic[15] activities have
been associated with 2-thiosubstituted imidazoles and diaryl imidazoles.
Microwave technology has opened up new horizons for chemists and
increasingly used to accelerate organic reactions.[16–20] The solvent free
conditions also have been adopted to organic synthesis as a tool for green
chemistry[21–24] particularly when coupled to microwave irradiation.
On the basis of these findings, it was of interest to report on the
regioselectivity encountered and the intramolecular anellation to form
imidazothiazine and imidazothiazole during the synthesis of acyclonucle-
oside analogues from the 4,5-diphenylimidazole-2-thione[25] under both
conventional method (CM) and microwave (MW) as a continuation of a
program directed to use microwave technology in our laboratory.[16,17,26–36]
The competitive intramolecular cyclization with the N-hydroxylalkylation
can be explained by the semiemperical AM1 theoritical calculations.
RESULTS AND DISCUSSION
This work describes the regioselective alkylation of 4,5-
diphenylimidazole-2-thione (1) by reaction with one and two equivalents
of different hydroxyl-alkylating agents including halogeno-ethanol 2,
propanol 5, 2,3-dihydroxychloropropanol 11 and 2,3-O-isopropylidene-1-
O-(p-tolylsulfonyl)-glycerol (8) under both conventional and microwave
methods. Reaction of 1 with 1.1 equivalents of 2, 3, 8, and 11 in a boiling
solution of sodium ethoxide in ethanol for 2–6 hours or in boiling
methanol in the presence of NaOAc for 4-14 hours afforded only the
S-alkyl derivatives 3, 6, 9, and 12, respectively in 62–74%. Deprotection
of 9 with 70% acetic acid at reflux temperature gave the corresponding
2-(2,3-dihydroxyprop-1-ylthio)-4,5-diphenylimidazole (12) whose reaction
with acetone in sulfuric acid gave back compound 9 (Schemes 1 and
2). When the above reactions were carried out under MW, 1–5 minutes
were required to give the same products in higher yields (Table 1), and
no change in regioselectivity was noticed. A higher yield (79–88%) was
achieved under MW irradiation for 1–3 minutes of a mixture of 1 with the
alkylating agent adsorbed on the surface of the bentonite in a closed Teflon
vessel.
The structures of the S-alkylated compounds have been established on
the basis of their elemental analyses and spectral data. The IR spectra of
3, 6, and 12 showed characteristic absorption band at 3314—3413 cm−1
1
due to OH of the acyclic side chains. Their H NMR spectra indicated the

Novel Regioselective Hydroxyl-Alkylation
425
SCHEME 1 Reaction of imidazole thione with halogeno-ethanol and propanol.
TABLE 1 Comparative results from conventional method (CM) and microwave (MW) method
Microwave
method
(MW)
Conventional
method (CM)
Conditions
Base
Compd.
No.
Alkylating
agent
Solid
support
Time
(hr)
Yield
(%)
Time
Yield
(%)
Entry∗
Solvent
(min)
3
3
3
4
6
6
6
7
2
2
2
2
3
3
3
3
5
5
5
5
4
4
4
4
a, b
c, d
e
f, g
a, b
c, d
e
f, g
a, b
c, d
e
f, g
a, b
c, d
e
NaOEt
NaOAc
—
K2CO3
NaOEt
NaOAc
—
K2CO3
NaOEt
NaOAc
—
K2CO3
NaOEt
NaOAc
—
EtOH
MeOH
—
DMF
EtOH
MeOH
—
DMF
EtOH
MeOH
—
DMF
EtOH
MeOH
—
—
—
2.0
4.0
—
8.0
3.0
74
70
—
66
72
69
—
65
67
62
—
62
69
65
—
68
60
65
55
1.0
2.0
1.0
4.0
2.0
2.5
1.5
4.5
3.0
5.0
3.0
5.0
3.0
4.0
3.0
6.0
4.0
6.0
4.0
89
84
88
81
88
82
86
76
82
76
79
75
81
76
79
79
70
78
65
Bentonite
—
—
—
6.0
—
Bentonite
—
—
—
10.0
06.0
14.0
—
20.0
05.0
10.0
—
14.0
48.0
96.0
72.0
9
9
9
Bentonite
10
12
12
12
13, 14
14
15
16
—
—
—
Bentonite
f, g
f, g
f, g
f, g
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
—
—
—
—
—
—
—
∗See Scheme.

426
E. S. H. El Ashry et al.
SCHEME 2 Reaction of imidazolethione with glycerol derivatives.
formation of the S-alkylated products by the assignment of one exchange-
able proton at δH 12.54–12.61 due to a one NH proton of the imidazole
ring. Moreover, the OH protons of 3 and 6 were assigned to the singlets at
δH 5.13 and 4.72, respectively. The spectrum of 12 showed two doublet of
doublets of the SCH2 at δH 3.14 and 3.31 ppm, which were correlated with
the multiplet at δH 3.7–3.7 ppm of CHO whereas their respective carbons
were assigned at δc 37.2 and 71.8, respectively. The multiplet at δH 3.35–3.43
ppm for CH2O was correlated with its corresponding carbon at δc 64.5. The
spectrum of 12 also showed a triplet at δH 4.98 and a singlet at δH 5.45, which
were assigned to the OH groups.

Novel Regioselective Hydroxyl-Alkylation
427
1
The H NMR spectrum of compound 9 has two doublet of doublets at
δH 3.20 and 3.27 ppm corresponding to the SCH2 protons, whereas the
two doublet of doublets at δH 3.80 and 4.16 were assigned to the CH2O
protons. Its 13C NMR spectrum showed signals at δc 36.8, 68.4, 77.1, and
110.1 corresponding to SCH2, CHO, -CH2O, and Me2C, respectively.
Attempted preparation of the acyclonucleosides 4, 7, 10, and 13 from
1 by using 2.2 equivalents of the alkylating agents 2, 5, and 8 in presence
of NaOEt or NaOAc in alcoholic solvent was unsuccessful. On the other
hand, in the presence of K2CO3 in boiling DMF as base for 8–20 hours the
corresponding acyclonucleosides analogues 4, 7, and 12 were successfully
obtained in 62–66% yield. The use of 1.1 equivalent of the alkylating
agent in presence of K2CO3 in boiling DMF gave a mixture of the S-
alkylated and S,N-bis(alkylated) derivatives as well as some starting material.
Isopropylidenation of 13 gave 10 whose deprotection gave 13.
Unexpectedly, reaction of 1 with 11 under the same condition did
not only afford the S,N-bis(dihydroxypropyl) 13, but an additional prod-
uct was obtained and identified as imidazothiazine 14 (Scheme 2). The
identity of such cyclized product indicated that its precursor would be the
respective monoalkylated derivative 12. The formation of the two products
has reflected that a competitive reaction, following the preliminary common
S-alkylation, between the intramolecular dehydrative cyclization reaction
and the further alkylation on the nitrogen-imidazole atom has taken place.
Such tendency of intramolecular ring closure has prompted us to apply
these conditions, K2CO3 in DMF, to the S-alkylated analogue 12 whereby
the cyclized product was formed as a sole product. Moreover, the cyclization
of 3 or 6 gave 15 and 16, respectively, under similar conditions, indicating
the generality of these conditions to achieve such intramolecular cyclization
and it is favorable that the S-alkylated derivatives were the intermediates.
Although, the cyclizations required heating for long periods of times, much
shorter times were only needed under the MW to give even better yields
(Table 1). Mitsunobu reaction condition[37,38] was used to achieve the
cyclization of 6-amino-9-(3-hydroxypropyl)-7H-purine-8(9H)-thione to the
anhydro analogue.
The structures of the fused heterocyles were deduced from the analysis
of their spectra. The IR and the 1H NMR spectra showed the disappearance
of NH proton of the imidazole ring. The 1H NMR spectrum of 14 indicated
that the terminal OH of its precursor 12 disappeared upon the cyclization
and the multiplet of the terminal methylene protons of 12 was shifted to the
downfield region as two doublets of doublets at δH 3.55 and 3.76 ppm.
In order to explain the observed difference in the mode of reaction of
1 with the different alkylating agents and the competitive intramolecular
cyclization with the formation of acyclonucleoside analogues, the semiem-
perical AM1 theoretical methods, carried out with MOPAC7 program pack-

428
E. S. H. El Ashry et al.
EQUATION 1 Synthesis of imadazo-thiazones and thaizoles.
age has been used. Thus, the heat of formation for the mono S-alkylated
derivatives 3, 4, and 12 and the S,N-bis(alkylated) products 4, 7, and 13 as
well as the respective fused rings 14–16 have been calculated. The higher
stability of the S-alkylated product 12 (ꢀH = −2.95 Kcal·mol−1) compared
to other analogues 3 and 6 (ꢀH = 48.06 and 41.38 Kcal·mol−1, respectively)
allowed a more chance of intramolecular dehydrative cyclization to take
place to give 14 in addition to the alkylation to give 13. Moreover, the lower
heat of formation of imidazo-thiazine 14 (ꢀH = 59.69 Kcal·mol−1) than that
of the other fused imidazo derivative 15 and 16 (ꢀH = 119.15 and 106.26
Kcal·mol−1, respectively) facilitated its formation (Table 2). The imidazo-
thiazines 14 and 16 were found to be more stable than the imidazo-thiazole
which is reflected in the higher yields of 14 and 16 compared to 15 which
was accompanied with a recovered starting material.
The energy difference (ꢀE1 −71.09 and ꢀE3 −64.88 Kcal·mol−1)
between the mono-S-alkylated products 3 and 6 and their corresponding
fused rings were higher than that between the mono alkylated derivatives
and the bis-alkylated analogues (ꢀE2 = 46.67 and ꢀE4 = 51.54 Kcal·mol−1,
TABLE 2 Heat of formation of products
Compd.
No.
Heat of formation
Energy difference
ꢀE (Kcal. mol−1
ꢀH (Kcal. mol−1
)
)
3
4
15
48.06
1.39
119.15
ꢀE1 = ꢀH(3) − ꢀH(4) = 46.67
ꢀE2 = ꢀH(3) − ꢀH(15) =
−71.09
6
7
16
41.38
−10.16
106.26
ꢀE3 = ꢀH(6) − ꢀH(7) = 51.54
ꢀE4 = ꢀH(6) − ꢀH(16) =
−64.88
12
13
−2.95
−98.02
ꢀE5 = ꢀH(12) − ꢀH(13) =
95.07
14
59.69
ꢀE6 = ꢀH(12) − ꢀH(14) =
−62.64

Novel Regioselective Hydroxyl-Alkylation
429
respectively). These results explain the formation of the bis-alkylated 4 and
7 as sole products from the reaction of 1 or 3 and 6 with bromoethanol
(2) or chloropropanol (5) in presence of potassium carbonate in boiling
DMF.
In contrast, the energy difference between the mono-alkylated 12 and its
corresponding imidazo-thiazine (ꢀE6 = −62.64 Kcal.mol−1) is lower than
that between 12 and the bis-alkylated 13 (ꢀE5 = 95.07 Kcal.mol−1). On the
basis of these results, one could predict that the imidazo-thiazine 14 was
favored to be formed rather than the bis-alkylated product but the higher
stability of 12 has altered the energetic behavior of this reaction where both
of the bis-alkylated analogue 13 and the imidazo-thiazine 14 were formed.
These conclusions were in agreement with the experimental results.
CONCLUSIONS
A regioselective alkylation of 4,5-diphenylimidazole-2-thiol (1) with
hydroxyl-alkylating agents in the presence of NaOEt or NaOAc has been
achieved successfully to give only the respective S-alkylated derivatives, via
the formation of the sodium salt of the thiolate anion generated by proton
abstraction from the thiol group. Further alkylation of the S-alkylated
analogues in boiling DMF and in the presence of potassium carbonate
afforded the acyclonucleoside analogues. This could presumably be due
to the ability of K2CO3 to abstract the proton from NH group which
is not the case with NaOEt or NaOAc. These conditions were used to
develop a general method for the synthesis of the fused imidazo-thiazines
or thiazolines via the cyclization of 4, 6, and 12 with K2CO3 /DMF.
A comparison of the results from using MWI with that under conven-
tional method revealed that higher yields were obtained in shorter times.
Better results were obtained when bentonite was used as solid support. Thus,
economical and environmental impacts can be achieved when the MW
irradiation was combined with the solid support. The results were supported
by the semiemoerical AM1 theoritical calculations.
EXPERIMENTAL
General Procedures
Melting points were determined with a Melt-Temp apparatus and are
uncorrected. TLC was performed on Baker-Flex silica gel (Merck) using
ethyl acetate-hexane as developing solvents, and the spot were detected
by UV light absorption. Irradiation was done in a domestic microwave
oven EM-230M (1200 watt output power). IR spectra were recorded with
Perkin-Elmer 1430 spectrometer. The NMR spectra were recorded on Jeol
spectrometer (500 MHz). Chemical shifts δ are given in ppm relative to

430
E. S. H. El Ashry et al.
the signal for TMS as internal standard. The double quatum filtered-
correlation spectroscopy DQF-COSY and heteronuclear multiple quantum
correlation HMQC experiments were used to confirm the spectral analysis.
The elemental analyses were performed by the microanalysis unit at the
Faculty of Science, Cairo University.
General Procedure for the Alkylation 4,5-Diphenylimidazole-
2-thione (1)
Conventional Method (CM). To a solution of compound 1, 3, 6, 9, or 12
(1 mmol) in a solvent (15 mL) and base (1.1 or 2.2 mmol), the appropriate
hologeno-ethanols 2 or 3, chloroglycerol 11, and 2,3-O-isopropylidene-1-
O-(p-tolylsulfonyl)-glycerol (8) (1.1 mmol or 2.2 mmol) were added with
stirring. The conditions of the reaction are shown in Table 1. The reaction
mixture was poured onto crushed ice. The products were washed with water,
dried, and recrystallized from ethanol.
Microwave Method (MW). A mixture of compound 1, 3, 6, 9, or 12
(0.36 mmol), solvent (3 mL), base (0.36 or 0.73 mmol), and the appropriate
alkylating agents (0.33 mmol or 0.73 mmol) were placed in a closed Teflon
vessel and then irradiated by MW. The reaction mixture was processed as
described above (Table 1).
Microwave and Solid Support Method. A mixture of 1, 3, 6, 9, or
12 (0.36 mmol) and an appropriate alkylating agent (0.36 mmol or 0.73
mmol) and bentonite (0.3 g) were mixed uniformly. The mixture was placed
in a closed Teflon vessel and then irradiated by MW for 1–3 minutes.
After cooling the products were extracted by boiled ethanol and were
recrystallized from ethanol.
2-[(2-Hydroxyeth-1-yl)thio]-4,5-diphenyl-1H-imidazole (3). This com-
pound was obtained as colorless crystals, m.p: 168–170◦C, IR (KBr): 3087
(CH-Ar), 3413 (OH). 1H NMR (DMSO-d6) δ: 3.17 (dd, 2H, J = 6.1 Hz, J =
6.9 Hz, SCH2), 3.67 (ddd, 2H, J = 6.1 Hz, J = 6.9 Hz, J = 11.9 Hz, CH2O),
5.13 (br, 1H, D2O exchangeable, OH), 7.15–7.43 (m, 10H, Ar-H), 12.54
(s, 1H, D2O exchangeable, NH). Anal. Calcd. for C17H16N2OS (296.10): C,
68.89; H, 5.44; N, 9.45. Found: C, 68.79; H, 5.65; N, 9.25.
1-(2-Hydroxyeth-1-yl)-2-[(2-hydroxyeth-1-yl)thio]-4,5-diphenylimidazole
(4). This compound was obtained as colorless crystals; m.p: 119–120◦C, IR
(KBr): 3410 (OH). 1H NMR (DMSO-d6) δ: 3.12 (br, 1H, D2O exchangeable,
OH), 3.24 (t, 2H, J = 4.6 Hz, SCH2), 3.65 (dd, 2H, J = 5.3 Hz, J = 6.1 Hz,
NCH2), 3.97 (dd, 2H, J = 5.3 Hz, J = 6.1 Hz, CH2O), 4.05 (t, 2H, J = 4.6
Hz, CH2O), 4.42 (br, 1H, D2O exchangeable, OH), 7.15–7.43 (m, 10H,
Ar-H). Anal. Calcd. for C19H20N2O2S (340.12): C, 67.03; H, 5.92; N, 8.23.
Found: C, 66.97; H, 5.61; N, 8.03.
2-[(3-Hydroxyprop-1-yl)thio]-4,5-diphenyl-1H-imidazole (6). This com-
pound was obtained as colorless crystals; m.p: 158–160◦C, IR (KBr): 1585

Novel Regioselective Hydroxyl-Alkylation
431
(C = C), 3059 (CH-Ar), 3390 cm−1 (OH). 1H NMR (DMSO-d6) δ: 1.74–1.79
(m, 2H, CH2CH2CH2), 3.12 (t, 2H, J = 6.9 Hz, SCH2), 3.49 (t, 2H, J =
6.1 Hz, CH2O), 4.72 (br, 1H, D2O exchangeable, OH), 7.20–7.32 (m, 10H,
Ar-H), 12.55 (s, 1H, D2O exchangeable, NH). Anal. Calcd. for C18H18N2OS
(310.11): C, 69.65; H, 5.84; N, 9.02. Found: C, 69.76; H, 6.03; N, 8.67.
1-(3-Hydroxyprop-1-yl)-2-[(3-hydroxyprop-1-yl)thio]-4,5-diphenylimida-
zole (7). This compound was obtained as yellow crystals, m.p: 145◦C;
IR (KBr): 3438 (OH). 1H NMR (DMSO-d6) δ: 1.54–1.59 (m, 2H,
SCH2CH2CH2) 1.82–1.85 (m, 2H, NCH2CH2CH2), 3.19–3.22 (m, 4H, SCH2,
NCH2), 3.50–3.52 (m, 2H, CH2O), 3.76–3.79 (m, 2H, CH2O), 4.46–4.49
(br, 1H, D2O exchangeable, OH), 4.68–4.71 (br, 1H, D2O exchangeable,
OH), 7.05–7.47 (m, 10H, Ar-H). Anal. Calcd. for C21H24N2O2S (368.16): C,
68.45; H, 6.56; N, 7.60. Found: C, 68.32; H, 6.43; N, 7.89.
2-[(2,3-O-Isopropylidene-2,3-dihydroxyprop-1-yl)thio]-4,5-diphenyl-1H-
imidazole (9). This compound was obtained as colorless crystals; m.p:
1
159–160◦C, IR (KBr): 3022 cm−1 (C-H Ar). H NMR (CDCl3) δ: 1.40, 1.44
(2 s, 6H, 2 × CH3), 3.20 (dd, 1H, J = 6.9 Hz, J = 14.5 Hz, SCH2), 3.27 (dd,
1H, J = 4.6 Hz, J = 14.5 Hz, SCH2), 3.80 (dd, 1H, J = 7.7 Hz, J = 8.4 Hz,
CH2O), 4.16 (dd, 1H, J = 6.1 Hz, J = 8.4 Hz, CH2O), 4.48–4.50 (m, 1H,
CHO), 7.26–7.48 (m, 10H, Ar-H) 12.60 (s, 1H, D2O exchangeable, NH).
13C NMR (CDCl3) δ: 25.7 (CH3), 26.8 (CH3), 36.8 (SCH2), 68.4 (CH2O),
77.1 (CHO), 110.1 (C(CH3)2), 127.6, 128.7, 140.14 (Ar-C). Anal. Calcd. for
C21H22N2O2S (366.14): C, 68.82; H, 6.05; N, 7.64. Found: C, 68.50; H, 6.22;
N, 7.98.
1-(2,3-O-Isopropylidene-2,3-dihydroxyprop-1-yl)-2-[(2,3-O-isopropylide-
ne-2,3-dihydroxyprop-1-yl)thio]-4,5-diphenylimidazole (10). This compound
1
was obtained as colorless crystals, m.p: 180–182◦C; H NMR (DMSO-d6) δ:
1.19, 1.20, 1.21, 1.27 (4 s, 12H, 4 × CH3), 3.39 (dd, 2H, J = 3.1 Hz, J = 9.2
Hz, SCH2), 3.73 (dd, 1H, J = 2.3 Hz, J = 5.3 Hz, J = 9.2, CH2O(a)), 3.90
(dd, 1H, J = 5.3Hz, J = 9.2, CH2O(b)), 3.99–4.09 (m, 2H, 2 × CH2O(a),
CH2O(b)), 4.21 (dd, 1H, J = 5.3 Hz, J = 14.5 Hz, NCH2), 4.28–4.32 (m,
1H, NCH2), 4.33–4.46 (m, 2H, 2 x CHO), 7.18–7.41 (m, 10H, Ar-H). Anal.
Calcd. for C27H32N2O4S (480.21): C, 67.47; H, 6.71; N, 5.83. Found: C,
67.68; H, 6.91; N, 5.90.
2-[(2,3-Dihydroxyprop-1-yl)thio]-4,5-diphenyl-1H-imidazole (12). This
compound was obtained as colorless crystals; m.p: 148◦C, IR (KBr): 3096
(C-H Ar), 3314 (br OH). 1H NMR (DMSO-d6) δ: 3.14 (dd, 1H, J = 6.1 Hz, J
= 13.7 Hz, SCH2), 3.31 (dd, 1H, J = 6.1 Hz, J = 13.7 Hz, SCH2), 3.35–3.43
(m, 2H, CH2O), 3.72–3.75 (m, 1H, CHO), 4.98 (t, 1H, J = 5.3 Hz, D2O
exchangeable, OH), 5.45 (br, 1H, D2O exchangeable, OH), 7.15–7.43 (m,
10H, Ar-H), 12.61 (s, 1H, D2O exchangeable, NH). 13C NMR (DMSO-d6) δ:
37.2 (SCH2), 64.5 (CH2O), 71.8 (CHO), 127.2, 127.4, 128.2, 128.8, 129.2,

432
E. S. H. El Ashry et al.
131.1, 135.1, 137.2 (Ar-C). Anal. Calcd. for C18H18N2O2S (326.11): C, 66.23;
H, 5.56; N, 8.58. Found: C, 65.98; H, 5.86; N, 8.41.
1-(2,3-Dihydroxyprop-1-yl)-2-[(2,3-dihydroxyprop-1-yl)thio-4,5-diphenyl-
imidazole (13). This compound was obtained as colorless needless after
purification by column chromatography using EtOAc-Hexane (40–60) as
eluant; m.p: 125–126◦C; IR (KBr): 1565 (C = C), 1610 (C = N), 3463 (OH).
1H NMR (DMSO-d6) δ: 3.20 (ddd, 1H, J = 5.4 Hz, J = 7.7 Hz, J = 10.7
Hz, SCH2), 3.33–3.43 (m, 5H, SCH2, 2 × CH2O), 3.68–3.75 (m, 1H, CHO),
3.84–3.90 (m, 1H, CHO), 4.05 (dd, 1H, J = 8.4 Hz, J = 14.5 Hz, NCH2),
4.24 (dd, 1H, J = 3.8 Hz, J = 14.5 Hz, NCH2), 4.80 (t, 1H, J = 6.1 Hz, D2O
exchangeable, OH), 4.90 (t, 1H, J = 6.2 Hz, D2O exchangeable, OH), 5.17
(d, 1H, J = 4.5 Hz, D2O exchangeable, OH), 5.21 (dd, 1H, J = 3.1 Hz, J =
5.3 Hz, D2O exchangeable, OH), 7.16–7.45 (m, 10H, Ar-H). Anal. Calcd.
for C21H24N2O4S (400.15): C, 62.98; H, 6.04; N, 6.99. Found: C, 63.19; H,
5.95; N, 6.68.
Deisopropylidenation of 9 and 10. General procedure. The isopropyli-
denes 9 and 10 (5 mmol) were dissolved in 70% AcOH (5 mL). The mixture
was heated under reflux for 2 hours. The solvent was evaporated under
reduced pressure and the resulting products were collected and crystallized
from ethanol to give 12 and 13, respectively. The products were identical
with those prepared by the above method.
Isopropylidenation of 12 and 13. General procedure. Compound 12
and 13 (0.25 mmol) were stirred vigorously with dry acetone (10 mL) and
96% H2SO4 (3 drops) for 2 hours, and then kept for overnight at room
temperature. The resulting mixture was neutralized by Na2CO3, filtered,
and the inorganic salts were well washed with dry acetone. The filtrate was
evaporated under reduced pressure and the resulting products 9 and 10
were crystallized from ethanol or purified by column chromatography to
give identical products with those obtained by the above alkylation method.
General Procedure for the Synthesis of Imidazothiazines and
Thiazole
Conventional method (CM). A mixture of 3, 7, or 12 (1 mmol) and
potassium carbonate (1.5 mmol) in DMF (15 mL) was heated under reflux.
The reaction mixture was then poured onto crushed ice (10 mL). The
product was filtered out and recrystallized from ethanol.
Microwave Method (MW). A mixture of 6, 7, or 12 (0.33 mmol) and
potassium carbonate (0.5 mmol) in DMF (3 mL) in a closed Teflon vessel
was irradiated by MWI. The obtained reaction mixture was treated as
described above (Table 1).
6,7-Diphenyl-2H,3H,4H-3-hydroxy-tetrahydroimidazo[2,1-b][1,3]thiazi-
ne (14). This compound was obtained as colorless crystals, m.p: 210–212◦C;
1
IR (KBr): 3269 cm−1 (OH). H NMR (DMSO-d6) δ: 3.11 (dd, 1H, J = 2.3

Novel Regioselective Hydroxyl-Alkylation
433
Hz, J = 12.6 Hz, SCH2), 3.26 (dd, 1H, J = 6.3 Hz, J = 13.0 Hz, SCH2), 3.55
(dd, 1H, J = 6.5 Hz, J = 12.6 Hz, NCH2), 3.76 (dd, 1H, J = 3.4 Hz, J =
12.6 Hz, NCH2), 4.26–4.30 (m, 1H, CHO), 5.61 (br, 1H, D2O exchangeable
OH), 7.18–7.41 (m, 10H, Ar-H). Anal. Calcd. for C18H16N2S (308.40): C,
70.10; H, 5.23; N, 9.08. Found: C, 69.92; H, 5.39; N, 9.36.
5,6-Diphenyl-2,3-dihydroimidazo[2,1-b][1,3]thiazole (15). This com-
1
pound was obtained as colorless plates, m.p: 232–234◦C; H NMR (DMSO-
d6) δ: 3.82 (t, 2H, J = 8.4, SCH2), 4.10 (t, 2H, J = 8.4, NCH2), 7.15–7.23 (m,
2H, Ar-H), 7.34–7.40 (m, 5H, Ar-H), 7.49–7.54 (m, 3H, Ar-H). Anal. Calcd.
for C17H14N2S (278.37): C, 73.35; H, 5.07; N, 10.06. Found: C, 73.21; H,
4.93; N, 10.19.
6,7-Diphenyl-2H,3H,4H-tetrahydroimidazo[2,1-b][1,3]thiazine (16). This
1
compound was obtained as colorless plates, m.p: 272◦C; H NMR (DMSO-
d6) δ: 1.92–1.95 (m, 2H, CH2CH2CH2), 3.46 (t, 2H, J = 6.1, SCH2), 3.83
(t, 2H, J = 5.3, NCH2), 7.15–7.23 (m, 2H, Ar-H), 7.34–7.40 (m, 5H, Ar-H),
7.49–7.54 (m, 3H, Ar-H). Anal. Calcd. for C18H16N2S (292.40): C, 73.94; H,
5.52; N, 9.58. Found: C, 74.07; H, 5.83; N, 9.39.
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