Synthesis of 2-alkoxy-substituted thiophenes, 1,3-thiazoles, and related S-heterocycles via Lawesson's reagent-mediated cyclization under microwave irradiation: Applications for liquid crystal synthesis

Full text of DOI:10.1021/jo016063x

J . Org. Chem. 2001, 66, 7925-7929
7925
products. The synthesis of short-chain 5-alkoxy-1,3-
Syn th esis of 2-Alk oxy-Su bstitu ted
Th iop h en es, 1,3-Th ia zoles, a n d Rela ted
S-Heter ocycles via La w esson ’s
thiazoles from the corresponding alkyl â-acylaminoetha-
noate proceeds in moderate to good yield using P2S5.10
A
single high-yielding example was also reported using
Lawesson’s reagent,7c although full details of the scope
and limitations of this chemistry were never published.
In recent studies, we have shown that Lawesson’s
reagent can be used for the synthesis of alkoxythiophenes
from γ-keto esters;11 however, while the yields for longer-
chain alkoxythiophenes were excellent, the yields for
shorter-chain analogues were more modest (47-62%).
Rea gen t-Med ia ted Cycliza tion u n d er
Micr ow a ve Ir r a d ia tion : Ap p lica tion s for
Liqu id Cr ysta l Syn th esis
Andre A. Kiryanov, Paul Sampson,* and
Alexander J . Seed*
Department of Chemistry, Kent State University,
Kent, Ohio 44242
psampson@kent.edu
The above approaches for S-heterocycle synthesis typi-
cally suffer from one or more of the following draw-
backs: moderate to low yields, extensive formation of
byproducts, use of anhydrous hydrocarbon solvent, long
reaction times at elevated temperatures, and/or use of a
large excess of the sulfurization reagent. In this paper,
we show that these drawbacks can be overcome by
performing such cyclization reactions using Lawesson’s
reagent in the absence of solvent under microwave
irradiation. Solvent-free reactions have many advantages
(reduced pollution, low costs, and simplicity in processing
and handling), which can make them attractive for large-
scale (industrial) applications.12 The use of microwave
irradiation as a nonconventional source of energy has
proven to be very beneficial in this area.13
Received August 28, 2001
In tr od u ction
Five-membered sulfur-containing heterocycles are im-
portant synthetic intermediates and have found a variety
of applications in medicinal, agricultural, and materials
chemistry.1 We are interested in liquid crystals contain-
ing these heterocycles in order to obtain potential can-
didates for ferroelectric display applications.2 S-Hetero-
cycle-containing liquid crystals have been shown to have
several beneficial physical characteristics when compared
to their phenyl counterparts such as lower viscosity and
fast switching times.3 An additional feature of these
heterocyclic ferroelectric materials is the high birefrin-
gence conferred by the heterocyclic core, which has been
identified as being crucial for use in the latest comple-
mentary metal oxide semiconductor (CMOS)-based pix-
els. These are employed, for example, in optical-phase
modulation devices, including holograms and telecom-
munication interconnects.4
Herein, we report that when the Lawesson’s reagent-
mediated cyclization of various 1,4-dicarbonyl compounds
is performed under microwave irradiation conditions in
a conventional microwave oven, high yields of the desired
S-heterocycles are obtained, little or no byproduct is
formed, reaction times are extremely short (3-13 min),
and no solvent is needed for the reaction.
Simple thiophenes,5 1,3-thiazoles,6 and 1,3,4-thiadia-
zoles7 have previously been prepared via sulfuration of
the corresponding 1,4-dicarbonyl precursors using re-
agents such as H2S/HCl, P2S5, and Lawesson’s reagent.
In contrast, the synthesis of 2-alkoxythiophenes and
related alkoxy-substituted S-heterocycles is much less
well developed. Treatment of a series of ethyl γ-aryl-γ-
oxopropanoates with H2S/HCl afforded the corresponding
5-aryl-2-ethoxythiophenes in very poor (10-20%) yield,8
while analogous reactions of γ-alkyl-γ-oxo esters with
(5) (a) Campaigne, E. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol.
4, pp 884-888. (b) Nakayama, J . In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier: New York, 1996; Vol. 2, pp 641-643. (c) Shridar, D. R.;
J ogibhukta, M.; Rao, P. S.; Handa, V. K. Synthesis 1982, 1061-1062.
(6) (a) Metzger, J . V. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol.
6, p 302. (b) Dondoni, A.; Merino, P. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier: New York, 1996; Vol. 3, p 436.
H2S/HCl8 or P2S5 did not afford any alkoxythiophene
9
(7) (a) Potts, K. T. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: New
York, 1996; Vol. 5, p 115. (b) El-Barbary, A. A.; Scheibye, S.; Lawesson.
S.-O.; Fritz, H. Acta Chem. Scand. Ser. B 1980, 34, 597-602. (c)
Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T.
P.; Lawesson, S.-O. Chem. Lett. 1983, 809-810. (d) Rasmussen, P. B.;
Pedersen, U.; Thomsen, I.; Yde, B.; Lawesson, S.-O. Bull. Soc. Chim.
Fr. 1985, 62-65.
* Corresponding authors. E-mail address for A.J.S.: aseed@kent.edu.
(1) (a) Press, J . B. In The Chemistry of Heterocyclic Derivatives.
Thiophene and its Derivatives; Gronowitz, S., Ed.; Wiley: New York,
1984; Vol. 44 (Part 1), pp 353-456. (b) Press, J . B. In Heterocyclic
Chemistry. Thiophene and its Derivatives; Gronowitz, S., Ed.; Wiley:
New York, 1990; Vol. 44 (Part 4), pp 397-502. (c) Russel, R. K.; Press,
J . B. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: New York, 1996; Vol. 2,
pp 679-729. (d) Dondoni, A.; Merino, P. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier: New York, 1996; Vol. 3, pp 465-474. (e) Kornis, G. I. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Elsevier: New York, 1996; Vol. 4, pp 407-
408.
(2) (a) J ones, J . C.; Raynes, E. P.; Towler, M. J .; Sambles, J . R. Mol.
Cryst. Liq. Cryst., Lett. Sect. 1990, 7, 91-99. (b) J ones, J . C.; Towler,
M. J .; Hughes, J . R. Displays 1993, 14, 86-93. (c) Markscheffel, S.;
J a´kli, A.; Saupe, A. Ferroelectrics 1996, 180, 59-70.
(3) (a) Mills, J .; Gleeson, H.; Seed, A.; Hird, M.; Styring, P. Mol.
Cryst. Liq. Cryst. 1997, 303, 145-152. (b) Mills, J . T.; Gleeson, H. F.;
Goodby, J . W.; Hird, M.; Seed, A.; Styring, P. J . Mater. Chem. 1998, 8,
2385-2390.
(4) Wilkinson, T. D.; Crossland, W. A.; Davey, A. B. Oral Presenta-
tion I-21, 8th International Conference on Ferroelectric Liquid Crys-
tals, Washington, DC, August 2001.
(8) Brunet, J .; Puquer, D.; Rioult, P. Phosphorus Sulfur Relat. Elem.
1977, 3, 377.
(9) Sedavkina, V. A.; Morozova, N. A.; Egorova, A. Yu.; Ostroumov,
I. G. Chem. Heterocycl. Compd. 1987, 377-380.
(10) (a) Tarbell, D. S.; Hirschler, H. P.; Carlin, R. B. J . Am. Chem.
Soc. 1950, 72, 3138-3140. (b) Kurkjy, R. P.; Brown, E. V. J . Am. Chem.
Soc. 1952, 74, 6260-6262. (c) Urbansky, M.; Draser, P. Synth.
Commun. 1993, 23, 829-845.
(11) Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J . J .
Org. Chem. 2001, 66, 7283-7286.
(12) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025-1074.
(13) See, for example: (a) de la Hoz, A.; Diaz-Ortis, A.; Moreno, A.;
Langa, F. Eur. J . Org. Chem. 2000, 22, 3659-3673 and references
therein. (b) Varma, R. S. Green Chem. 1999, 1, 43-55. (c) One report
outlining the conversion of monocarbonyl compounds into the corre-
sponding thiocarbonyl derivatives using Lawesson’s reagent under
microwave irradiation has recently appeared: Varma, R. S.; Kumar,
D. Org. Lett. 1999, 1, 697-700.
10.1021/jo016063x CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

7926 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Ta ble 1. Syn th esis of Va r iou s S-Heter ocycles via La w esson ’s Rea gen t-Med ia ted Cycliza tion of 1,4-Dica r bon yl
Com p ou n d s u n d er Micr ow a ve Ir r a d ia tion Con d ition s in th e Absen ce of Solven t
a
b
Isolated yield of product after chromatographic purification. In addition, 11% of 2-(4-methoxyphenyl)thiophene was isolated as a
byproduct. c A variety of irradiation times were explored (3-10 min).
Resu lts a n d Discu ssion
are more comparable for longer-chain ester substrates,
although the much shorter reaction times and the avoid-
ance of the need for an anhydrous solvent still confer a
significant advantage on the microwave method. It was
important to control the irradiation time precisely: to
obtain optimal yields, the irradiation had to be stopped
when the reaction mixture turned into an orange or red
liquid. Prolonged irradiation of the reaction mixture gave
a dark-brown tarry mixture, and product decomposition
was observed. For example, when γ-keto ester 1 was
allowed to react for 6 min, loss of the alkoxy chain
occurred, resulting in the formation of monosubstituted
thiophene 2 in 55% yield (eq 1).14
Our initial studies were focused on the synthesis of
alkoxythiophenes as intermediates for liquid crystal
synthesis, which we envisaged would be prepared from
the corresponding γ-keto esters.11 When these γ-keto
ester derivatives were mixed with 1.2 equiv of solid
Lawesson’s reagent and subjected to microwave irradia-
tion conditions, alkoxythiophenes were obtained in high
yield (see Table 1, entries 1-7). Short-chain [ethyl (entry
1), n-butyl (entry 2)] esters as well as longer-chain
[n-hexyl, n-octyl, n-decyl, and n-dodecyl (entries 3, 4, 6,
and 7, respectively)] and branched-chain [1-methylheptyl
(entry 5)] esters were used with equal success. The yields
of alkoxythiophene products obtained from these micro-
wave-mediated cyclization reactions are dramatically
superior to those from the analogous solvent-based
reactions for short-chain ester substrates. For example,
89-90% yields of the desired alkoxythiophene products
along with only traces of byproduct were formed when
ethyl and n-butyl ester substrates were employed in the
present study (Table 1, entries 1 and 2). In contrast, the
analogous solution-phase reactions provided the same
products in only 47-62% yields, and formation of complex
mixtures of byproducts was also observed.11 It should be
noted, however, that the yields from the two processes
Interestingly, the use of smaller amounts of Lawesson’s
reagent (0.6 equiv) resulted in only a modest reduction
(14) An apparently related process was previously observed with
γ-keto acid substrates: Noe, C. N.; Knolmuller, M.; Wagner, E.
Monatsh. Chem. 1986, 117, 621-629.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7927
Sch em e 1
in yield and avoided byproduct formation even at these
longer reaction times. Thus, prolonged irradiation (6 min)
of a mixture of decyl 4-(4-bromophenyl)-4-oxobutanoate
with 0.6 equiv of Lawesson’s reagent afforded a dark-
brown mixture that yielded ca. 70-75% of the desired
alkoxythiophene product with little or no byproduct
formation.
Application of the same microwave-mediated reaction
conditions for the synthesis of aryloxythiophenes pro-
ceeded in somewhat lower yields (65%, entry 8), and
formation of the monosubstituted thiophene byproduct
3 through loss of the aryloxy substituent competed with
product formation even at short reaction times (eq 2).15
1,4-diphenylbutane-1,4-dione could be cyclized to 2,5-
diphenylthiophene in 92% yield (entry 9). No product de-
composition was observed even upon prolonged irradia-
tion. Similarly high yields were obtained when this pro-
cedure was applied for the synthesis of 5-alkoxy-1,3-
thiazoles (entries 10-12). When these conditions were
employed in the attempted synthesis of 2-alkoxy-1,3,4-
thiadiazoles, however, no product formation was observed
and several byproducts were formed instead that were
not characterized (entry 13). This result is in accordance
with the original Lawesson’s report for the analogous
solution-phase reaction.7d However, alkylthiadiazoles
could be obtained using this procedure in high yield from
the corresponding N,N′-diacylhydrazine precursor (en-
tries 14 and 15).
It is noteworthy that a number of the reactions
described above were scaled up to several grams without
a significant reduction in yield (entries 11, 12, and 15).
This newly developed microwave-mediated closure of
various 1,4-dicarbonyl compounds was successfully ap-
plied in the synthesis of several S-heterocycle-containing
liquid crystalline targets. The thiazole-containing me-
sogen 4 was prepared as outlined in Scheme 1. Esteri-
fication of glycine with dodecanol16 followed by N-acyla-
tion with 4-bromobenzoyl chloride17 afforded the 1,4-
dicarbonyl cyclization precursor 5. Application of the
aforementioned microwave-mediated cyclization using
Lawesson’s reagent afforded 5-alkoxy-1,3-thiazole 6 in
83% yield. Attempts to obtain the desired carboxylic acid
8 via lithiation with n-BuLi followed by quenching with
excess CO2 failed due to competing deprotonation of the
thiazole ring next to nitrogen. To avoid this problem,
bromide 6 was converted into the nitrile 7 using copper
cyanide,18 which was then hydrolyzed under basic condi-
tions.19 DCC-DMAP esterification20 of the resulting
carboxylic acid 8 with readily available phenol 921
provided the target liquid crystal 4 in good yield.
The thiadiazole-containing liquid crystalline target 10
was prepared starting from commercially available 4-bro-
mobenzohydrazide (Scheme 2). N-Acylation with myris-
toyl chloride17 afforded the unsymmetrical N,N′-diacyl-
hydrazine 11, which was cyclized into the corresponding
We next examined the use of these reaction conditions
for the synthesis of 2,5-diarylthiophenes and found that
(15) The loss of the alkoxy (aryloxy) side chain during the synthesis
of 2-alkoxy- and 2-aryloxythiophenes has previously been noted by one
of us under conventional solution-phase Lawesson’s cyclization condi-
tions, although no byproducts were characterized due to the complexity
of the mixtures obtained.11 The reduction byproducts 2 and 3 described
above only form after a substantial amount of the desired alkoxy- or
aryloxythiophene has accumulated and usually when almost no
starting material remains. Therefore, it is very likely that the initially
formed alkoxy- or aryloxythiophene products, and not the original
γ-keto ester substrates, undergo reduction to these byproducts. Control
experiments have shown that this reduction is not achieved by
Lawesson’s reagent alone.11 Similarly, bubbling H2S through a toluene
solution of 2-(4-bromophenyl)-5-dodecyloxythiophene at reflux in the
presence of 1.2 equiv of Lawesson’s reagent also failed to effect this
cleavage. Thus, it appears that the presence of some (presumably
oxodesulfurized) Lawesson’s reagent byproduct is a prerequisite for
this reduction. The minimization of byproduct formation that occurs
when the microwave procedure is used might then be explained by
the rapid evolution of H2S from the solvent-free reaction mixture (the
amount of H2S gas evolved during the microwave reaction was
measured to be approximately 1 mmol for a 1 mmol scale reaction),
effectively lowering the concentration of available reducing agent. The
ease of the loss of the RO-substituent during our S-heterocycle ring-
closure reactions seems to be in accordance with leaving group ability
(4-bromophenoxy > ethoxy > butoxy). The fact that there is no
byproduct generated during thiazole ring formation (Table 1, entry
10) might suggest that at least some carbocation character develops
at C-2 during the loss of the RO-group. The electron-withdrawing
nitrogen would then destabilize the positive charge at C-2 and account
for the observed result. It is known that polar mechanisms tend to be
favored under microwave irradiation.13a Hence, it is feasible that a
protonated or Lewis acid-coordinated alkoxy or aryloxy group leaves
to form a carbocation that is then reduced by some hydride source to
form the byproduct 2 or 3. Concomitant oxidation of some S-H-
containing intermediate could conceivably facilitate such a hydride
transfer mechanism.
(16) (a) Penney, C. L.; Shah, P.; Landi, S. J . Org. Chem. 1985, 50,
1457-1459. (b) Ohtani, N.; Inoue, Y.; Inagaki, Y.; Fukuda, K.;
Nishiyama, T. Bull. Chem. Soc. J pn. 1995, 68, 1669-1675.
(17) (a) Sandler, S. R.; Karo, W. In Organic Functional Group
Preparations; Wasserman, H. H., Ed.; Academic Press: New York,
1983; Vol. 12, pp 434-465. (b) Parra, M.; Villouta, S.; Vera, V.; Belmar,
J .; Zuniga, C.; Zunza, H. Z. Naturforsch., B: Chem. Sci. 1997, 52,
1533-1538. (c) Parra, M.; Belmar, J .; Zunza, H.; Zuniga, C.; Villouta,
S.; Martinez, R. Bol. Soc. Chil. Quim. 1993, 38, 325-330.
(18) Newman, M. S.; Boden, H. J . Org. Chem. 1961, 26, 2525.
(19) (a) Fray, M. J .; Cooper, K.; Parry, M. J .; Richardson, K.; Steele,
J . J . Med. Chem. 1995, 38, 3514-3523. (b) Tius, M. A.; Gu, X.-q.;
Truesdell, J . W.; Savariar, S.; Crooker, P. P. Synthesis 1988, 36-40.
(20) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475-4478.
(21) Robinson, W. K.; Gleeson, H. F.; Hird, M.; Seed, A. J .; Styring,
P. Ferroelectrics 1996, 178, 249-266.

7928 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Sch em e 2
precipitate was filtered, washed well with hexanes, and sus-
pended in ethyl ether (300 mL). It was then filtered again and
air-dried to afford dodecyl 2-aminoethanoate hydromethane-
sulfonate as a white solid (13.33 g, 79%): 1H NMR δ 7.91 (br s,
3H), 3.91 (m, 2H), 2.76 (s, 3H), 1.64 (quint, J ) 6.8 Hz, 2H),
1.20-1.35 (m, 18H), 0.88 (t, J ) 6.7 Hz, 3H); 13C NMR δ 168.1,
66.5, 40.7, 39.2, 32.1, 29.8 (2), 29.7, 29.5, 29.4, 28.6, 25.9, 22.8,
14.3. Anal. Calcd for C14H31NO5S: C, 51.66; H, 9.60; N, 4.30.
Found: C, 51.32; H, 9.40; N, 4.57.
Sch em e 3
A solution of 4-bromobenzoyl chloride (4.39 g, 20.0 mmol) in
CHCl3 (15 mL) was added dropwise over a period of 3 min to a
stirred, cooled (0 °C) solution of dodecyl 2-aminoethanoate
hydromethanesulfonate (6.74 g, 20.0 mmol) and NEt3 (6.10 mL,
44.0 mmol) in CHCl3 (35 mL). The reaction mixture was stirred
at 0 °C for 1 h, and the solvent was evaporated in vacuo. The
residue was triturated with CH2Cl2 (100 mL), and the extract
was passed through a short silica column (8 cm long, 4 cm in
diameter). The solvent was evaporated to afford the title
compound 5 as an off-white solid (6.85 g, 80%): 1H NMR δ 7.67
(d, J ) 8.5 Hz, 2H), 7.54 (d, J ) 8.5 Hz, 2H), 6.92 (t, J ) 4.7 Hz,
1H), 4.19 (d, J ) 5.1 Hz, 2H), 4.17 (t, J ) 6.7 Hz, 2H), 1.65 (quint,
J ) 6.9 Hz, 2H), 1.18-1.42 (m, 18H), 0.87 (t, J ) 6.7 Hz, 3H);
13C NMR δ 170.3, 166.7, 132.6, 132.0, 128.9, 126.7, 66.1, 42.0,
32.1, 29.8, 29.7 (2), 29.5, 29.4, 28.7, 26.0, 22.8, 14.3. Anal. Calcd
for C21H32BrNO3: C, 59.15; H, 7.56; N, 3.28. Found: C, 58.88;
H, 7.58; N, 3.22.
2-(4-Br om oph en yl)-5-dodecyloxy-1,3-th iazole (6). The title
compound was prepared according to the general Lawesson’s
reagent-mediated cyclization procedure outlined above using
3.98 g (9.34 mmol) of compound 5 and 4.46 g (11.0 mmol) of
Lawesson’s reagent. An 8 min reaction time was employed. The
cooled reaction mixture was dissolved in CH2Cl2 (250 mL) and
evaporated onto silica gel (50 g). This was then placed on top of
a silica column and chromatographed (140 g SiO2, 4:1 hexanes-
ethyl acetate). The product was then recrystallized from metha-
nol (220 mL) and dried under reduced pressure (1.1 mmHg,
P2O5, 20 h) to afford the title compound 6 as a white solid (3.30
g, 83%): 1H NMR δ 7.67 (d, J ) 8.5 Hz, 2H), 7.52 (d, J ) 8.5
Hz, 2H), 7.12 (s, 1H), 4.09 (t, J ) 6.5 Hz, 2H), 1.81 (quint, J )
6.9 Hz, 2H), 1.52-1.20 (m, 18H), 0.89 (t, J ) 6.6 Hz, 3H); 13C
NMR δ 162.6, 154.1, 133.3, 132.1, 127.1, 123.4, 123.1, 75.6, 32.1,
29.8, 29.7 (2), 29.5, 29.4, 29.3, 25.9, 22.9, 14.3. Anal. Calcd for
C21H30BrNOS: C, 59.43; H, 7.12; N, 3.30; S, 7.55. Found: C,
59.52; H, 7.20; N, 3.33; S, 7.95.
2-(4-Cyan oph en yl)-5-dodecyloxy-1,3-th iazole (7). A stirred
solution of compound 6 (2.12 g, 5.00 mmol) and CuCN (0.586 g,
6.54 mmol) in anhydrous NMP (12 mL) was heated at 160 °C
for 5 h. The cooled reaction mixture was poured into cooled (0
°C) 10% aq HCl (20 mL) and stirred for 0.5 h before it was
extracted with ethyl ether (3 × 100 mL). The combined organic
extracts were dried (MgSO4) and evaporated in vacuo. The
residual dark-brown oil was purified by flash column chroma-
tography (100 g of SiO2, 10:1 hexanes-ethyl acetate) to afford
the title compound 7 as a white solid (1.70 g, 92%): 1H NMR δ
7.89 (d, J ) 8.8 Hz, 2H), 7.67 (d, J ) 8.8 Hz, 2H), 7.19 (s, 1H),
4.11 (t, J ) 6.5 Hz, 2H), 1.82 (quint, J ) 6.9 Hz, 2H), 1.23-1.51
(m, 18H), 0.88 (t, J ) 6.7 Hz, 3H); 13C NMR δ 163.9, 152.5, 138.2,
132.8, 125.9, 123.7, 118.8, 112.3, 75.8, 32.1, 29.8, 29.7, 29.6, 29.5,
29.4, 25.9, 22.8, 14.3. Anal. Calcd for C22H30N2OS: C, 71.31; H,
8.16; N, 7.56; S, 8.65. Found: C, 70.96; H, 8.28; N, 7.43; S, 8.89.
1,3,4-thiadiazole derivative 12 in 91% yield. The target
liquid crystal 10 was then obtained via cyanation and
basic hydrolysis to obtain the corresponding carboxylic
acid 13 followed by DCC-DMAP esterification.
The new ring-closure methodology was also helpful in
improving the yield of a previously synthesized liquid
crystal 1422 as depicted in Scheme 3.
Each of the synthesized target materials 4, 10, and 14
possesses liquid crystalline properties. Of particular
importance to us are compounds 4 and 10, which have
the desired ferroelectric and antiferroelectric phases.
Materials exhibiting these phases may be useful in
surface-stabilized ferroelectric and antiferroelectric liquid
crystal displays.23 A detailed study of the physical
properties of these compounds is now in progress.
Exp er im en ta l Section
Gen er a l P r oced u r e for La w esson ’s Rea gen t-Med ia ted
Cycliza tion Rea ction s. The 1,4-dicarbonyl compound (1.0
mmol) and Lawesson’s reagent (0.486 g, 1.20 mmol) were mixed
thoroughly in a glass reaction tube. The tube was placed in a
beaker with a cover glass and irradiated using a commercial
conventional microwave oven with a rotating tray (Samsung,
MW6940W, 1000W) for 3-6 min until the evolution of gas ceased
and the reaction mixture became an orange or yellow transpar-
ent liquid. It was then allowed to cool, and the resulting viscous
mixture was dissolved in CH2Cl2 and evaporated on silica gel.
Flash column chromatography on activated basic alumina (50-
200 µm) or silica (200-425 mesh) provided the corresponding
five-membered ring S-heterocycle, which was dried under vacuum
(1.1 mmHg, P2O5, 24 h). Caution: these reactions must be
performed in an efficient fume hood due to the generation of
toxic H2S gas.24
Syn th esis of Liqu id Cr ysta ls 4 a n d 10.
Dod ecyl (4-Br om oben zoyla m in o)eth a n oa te (5). Glycine
(3.80 g, 50.7 mmol) and dodecan-1-ol (23.25 g, 125.0 mmol) were
stirred at 130 °C for 3 min. To this mixture was added
methanesulfonic acid (3.56 mL, 55.0 mmol) over a period of 1
min. The reaction mixture was stirred vigorously at 130 °C for
2.5 h. The brown mixture was then cooled to room temperature,
diluted with hexanes (250 mL), and cooled to 0 °C. The
(22) Kiryanov, A. A.; Sampson, P.; Seed, A. J . J . Mater. Chem. In
press.
(23) Lagerwall, S. T. Ferroelectric and Antiferroelectric Liquid
Crystals; Wiley-VCH: Weinheim, 1999.
(24) For appropriate precautions when handling H2S, see: Prudent
Practices in the Laboratory: Handling and Disposal of Chemicals;
National Research Council, National Academy Press: Washington, DC,
1995; pp 342-343.
2-(4-Ca r boxyp h en yl)-5-d od ecyloxy-1,3-th ia zole (8). A so-
lution of compound 7 (1.46 g, 3.95 mmol) and NaOH (2.00 g,
50.0 mmol) in 1:1 ethanol-H2O (20 mL) was heated under reflux
for 4 h. The solvent was removed in vacuo (20 mmHg, 80 °C),

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7929
and the residue was triturated with water (100 mL). The
suspension was acidified with 10% aq HCl to pH 1 and stirred
for 2 h at room temperature. The precipitate was filtered off,
washed with water (200 mL), and dried under reduced pressure
(1 mmHg, P2O5, 24 h) to afford the title compound 8 as a white
solid (1.30 g, 85%): 1H NMR (DMSO-d6) δ 0.84 (t, J ) 6.7 Hz,
3H), 1.17-1.46 (m, 18H), 1.74 (quint, J ) 6.8 Hz, 2H), 4.16 (t, J
) 6.5 Hz, 2H), 7.38 (s, 1H), 7.89 (d, J ) 8.5 Hz, 2H), 8.00 (d, J
) 8.5 Hz, 2H), the carboxylic acid signal was not observed; 13C
NMR (DMSO-d6) δ 14.0, 22.1, 25.2, 28.4, 28.6, 28.7, 28.9 (2), 29.0,
31.3, 75.1, 123.6, 125.1, 130.1, 131.3, 137.1, 152.4, 162.7, 166.8.
Anal. Calcd for C22H31NO3S: C, 67.83; H, 8.02; N, 3.60; S, 8.23.
Found: C, 67.80; H, 8.24; N, 3.56; S, 8.60.
The resulting mixture was extracted with CH2Cl2 (3 × 100 mL),
and the combined organic extracts were washed with brine (100
mL), dried (MgSO4), and passed through a short silica plug (10
cm long, 4 cm wide). The filtrate was concentrated in vacuo; the
residue was suspended in water (200 mL), and the resulting
precipitate was filtered and air-dried. This solid was then
triturated twice with boiling methanol (250 mL, 100 mL). The
combined solutions were cooled and filtered to obtain 2-(4-
cyanophenyl)-5-tridecyl-1,3,4-thiadiazole as a yellowish solid,
which was dried under reduced pressure (1.1 mmHg, P2O5, 10
h) (4.13 g, 81%): 1H NMR δ 8.07 (d, J ) 8.6 Hz, 2H), 7.77 (d, J
) 8.6 Hz, 2H), 3.17 (t, J ) 7.6 Hz, 2H), 1.85 (quint, J ) 7.5 Hz,
2H), 1.49-1.23 (m, 20H), 0.88 (t, J ) 6.6 Hz, 3H); 13C NMR δ
171.9, 166.4, 134.5, 133.0, 128.4, 118.2, 114.4, 32.0, 30.4, 30.2,
29.7 (2), 29.5 (2), 29.3, 29.1, 22.8, 14.2. Anal. Calcd for
C22H31N3S: C, 71.50; H, 8.45; N, 11.37; S, 8.68. Found: C, 71.38;
H, 8.50; N, 11.15; S, 8.97.
(S)-1-Met h ylh ep t yl 4-[4-(5-Dod ecyloxy-1,3-t h ia zolyl-2-
yl)p h en ylca r bon yloxy]ben zoa te (4). To a suspension of
compound 8 (0.622 g, 1.60 mmol), DMAP (0.0490 g, 0.402 mmol),
and phenol 9 (0.375 g, 1.50 mmol) in anhydrous CH2Cl2 (200
mL) was added DCC (0.340 g, 1.65 mmol) in one portion. The
reaction mixture was stirred at room temperature for 30 h,
diluted with hexane (50 mL), and filtered. The filtrate was
washed with 10% aq HOAc (100 mL) and brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (100 g of SiO2, 12:1 petroleum
ether-ethyl acetate (500 mL), followed by 9:1 petroleum ether-
ethyl acetate) to afford the title compound 4 as a white solid
(0.650 g, 70%): 1H NMR δ 8.23 (d, J ) 8.8 Hz, 2H), 8.14 (d, J )
8.8 Hz, 2H), 7.95 (d, J ) 8.5 Hz, 2H), 7.32 (d, J ) 8.5 Hz, 2H),
7.22 (s, 1H), 5.17 (app sext, J ) 6.3 Hz, 1H), 4.13 (t, J ) 6.6 Hz,
2H), 1.84 (quint, J ) 7.0 Hz, 2H), 1.68-1.78 (m, 1H), 1.55-1.68
(m, 1H), 1.35 (d, J ) 6.3 Hz, 3H), 1.24-1.53 (m, 26H), 0.89 (t, J
) 6.7 Hz, 6H); 13C NMR δ 165.6, 164.4, 163.7, 154.5, 153.4, 139.1,
131.3, 131.0, 129.3, 128.8, 125.6, 123.7, 121.8, 75.6, 72.1, 36.0,
32.1, 31.9, 29.8, 29.7 (2), 29.5, 29.4, 29.3, 29.2, 25.9, 25.6, 22.8,
22.7, 20.2, 14.3, 14.2. Anal. Calcd for C37H51NO5S: C, 71.46; H,
8.27. Found: C, 71.47; H, 8.33. Transition temperatures: Cryst.
81.5 SC*ANTI 89.0 SC*FERRI 90.6 SC*FERRO 94.9 SA 99.6 Iso. Liq.
N-(4-Br om oben zoyl)-N′-tetr adecan oh ydr azide (11). Myris-
toyl chloride (11.5 g, 46.7 mmol) was added dropwise to a
solution of 4-bromobenzohydrazide (10.0 g, 46.5 mmol) in
anhydrous pyridine (200 mL) at 10 °C under argon. The reaction
mixture was heated at 60 °C for 3 h and then concentrated in
vacuo at 70 °C. The crude residue was suspended in boiling
water (600 mL) and heated at reflux for 0.5 h. Once all of the
solid was finely suspended, the precipitate was filtered, air-dried,
and suspended in hot petroleum ether (300 mL). The cooled
suspension was filtered, and the precipitate was dried under
reduced pressure (1.1 mmHg, P2O5, 24 h) to afford the title
compound 11 as a white solid (16.4 g, 83%): 1H NMR δ 8.92 (br
s, 1H), 8.43 (br s, 1H), 7.69 (d, J ) 8.4 Hz, 2H), 7.61 (d, J ) 8.4
Hz, 2H), 2.32 (t, J ) 7.5 Hz, 2H), 1.70 (quint, J ) 7.4 Hz, 2H),
1.49-1.23 (m, 20H), 0.88 (t, J ) 6.7 Hz, 3H); 13C NMR δ 170.8,
167.3, 132.5, 129.5, 129.3, 125.4, 32.0, 30.4, 30.2, 29.8, 29.7, 29.6,
29.5, 29.3, 29.1, 22.8, 14.2. Anal. Calcd for C21H33BrN2O2: C,
59.29; H, 7.82; N, 6.59. Found: C, 59.28; H, 7.88; N, 6.52.
2-(4-Br om op h en yl)-5-tr id ecyl-1,3,4-th ia d ia zole (12). The
title compound was prepared according to the general Lawes-
son’s reagent-mediated cyclization procedure outlined above
using 8.50 g (20.0 mmol) of compound 11 and 8.91 g (22.0 mmol)
of Lawesson’s reagent. A 13 min reaction time was employed.
The cooled reaction mixture was dissolved in CH2Cl2 (250 mL)
and evaporated onto silica gel (50 g). This was then placed on
top of a short silica plug (10 cm long, 6 cm wide) and chromato-
graphed using 3:1 petroleum ether-ethyl acetate as an eluent.
The filtrate was concentrated in vacuo, and the resulting solid
was recrystallized from methanol (450 mL) to afford the title
compound 12 as fine white needles (7.67 g, 91%): 1H NMR δ
7.81 (d, J ) 8.5 Hz, 2H), 7.59 (d, J ) 8.5 Hz, 2H), 3.13 (t, J )
7.6 Hz, 2H), 1.83 (quint, J ) 7.5 Hz, 2H), 1.50-1.23 (m, 20H),
0.88 (t, J ) 6.6 Hz, 3H); 13C NMR δ 170.8, 167.3, 132.5, 129.5,
129.3, 125.4, 32.0, 30.4, 30.2, 29.8, 29.7, 29.6, 29.5, 29.3, 29.1,
22.8, 14.2. Anal. Calcd for C21H31BrN2S: C, 59.56; H, 7.38; N,
6.62; S, 7.57. Found: C, 59.53; H, 7.47; N, 6.51; S, 7.75.
2-(4-Cyanophenyl)-5-tridecyl-1,3,4-thiadiazole (3.00 g, 8.13
mmol) was heated under reflux in a solution of sodium hydroxide
(10.0 g, 0.250 mol) in ethanol (175 mL) and water (50 mL) for 3
h. A portion of the solvent (100 mL) was then distilled off at
atmospheric pressure. The remaining solvent was evaporated
in vacuo, and the beige mixture was suspended in water (350
mL). To this suspension was added 10% aq HCl (250 mL), and
the resulting white mixture was stirred for 1 h. The precipitate
was filtered off and dissolved in boiling acetic acid (100 mL).
The resulting solution was cooled by addition of ice (100 g), and
the precipitate was filtered and dried under reduced pressure
(1.1 mmHg, P2O5, 14 h) to afford the title compound 13 as a
white solid (2.94 g, 93%): 1H NMR (DMSO-d6) δ 8.07 (app s,
4H), 3.14 (t, J ) 7.6 Hz, 2H), 1.76 (quint, J ) 7.3 Hz, 2H), 1.42-
1.19 (m, 20H), 0.84 (t, J ) 6.7 Hz, 3H), the carboxylic acid signal
was not observed; 13C NMR (DMSO-d6) δ 170.9, 166.5, 166.3,
133.3, 132.7, 130.0, 127.5, 31.0, 29.1 (2), 28.8, 28.7 (2), 28.6, 28.4,
28.3, 28.0, 21.8, 13.6. Anal. Calcd for C22H31NO3S: C, 68.00; H,
8.30; N, 7.21; S, 8.25. Found: C, 67.86; H, 8.43; N, 7.09; S, 8.34.
(S)-1-Meth ylh ep tyl 4-[4-(5-Tr id ecyl-1,3,4-th ia d ia zolyl-2-
yl)p h en ylca r bon yloxy]ben zoa te (10). To a suspension of
compound 13 (0.776 g, 2.00 mmol), DMAP (0.0976 g, 0.800
mmol), and phenol 9 (0.391 g, 1.56 mmol) in anhydrous CH2Cl2
(150 mL) was added DCC (0.433 g, 2.10 mmol) in one portion.
The reaction mixture was stirred at room temperature for 1 h
and heated at reflux for 7 h. The reaction mixture was diluted
with petroleum ether (100 mL) and cooled (0 °C). The precipitate
was filtered off and washed with petroleum ether (50 mL) and
CH2Cl2 (50 mL). The combined washings and the filtrate were
evaporated in vacuo. The residue was recrystallized from 5:1
methanol-ethyl acetate (300 mL) to afford the title compound
10 as a white solid (0.530 g, 55%): 1H NMR δ 8.30 (d, J ) 8.5
Hz, 2H), 8.14 (d, J ) 8.8 Hz, 2H), 8.10 (d, J ) 8.5 Hz, 2H), 7.32
(d, J ) 8.8 Hz, 2H), 5.17 (app sext, J ) 6.2 Hz, 1H), 3.17 (t, J )
7.6 Hz, 2H), 1.86 (quint, J ) 7.4 Hz, 2H), 1.80-1.68 (m, 1H),
1.68-1.54 (m, 1H), 1.35 (d, J ) 6.1 Hz, 3H), 1.52-1.23 (m, 28H),
0.88 (t, J ) 6.6 Hz, 6H); 13C NMR δ 171.6, 167.1, 165.5, 164.0,
154.4, 135.3, 131.3, 131.1, 129.0, 128.1, 121.7, 72.1, 36.2, 32.0,
31.9, 30.4, 30.2, 29.7 (2), 29.6, 29.5, 29.3 (2), 29.1, 25.5, 22.8,
22.7, 20.2, 14.2, 14.1. Anal. Calcd for C37H51NO5S: C, 71.57; H,
8.44; N, 4.51; S, 5.16. Found: C, 71.65; H, 8.46; N, 4.51; S, 5.22.
Transition temperatures: Cryst. 93.5 SC*ANTI 101.2 SC*FERRI
102.0 SC*FERRO 104.9 SA 115.7 Iso. Liq.
Ack n ow led gm en t. We thank Dr. Mahinda Gangoda
for his help with obtaining NMR spectra and elemental
analyses.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures, procedures (or literature references) for the
synthesis of 1,4-dicarbonyl compounds employed in Lawesson’s
reagent-mediated cyclization studies, and details of purifica-
tion procedures and characterization data for all S-heterocycles
produced during these cyclization reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
2-(4-Ca r boxyp h en yl)-5-tr id ecyl-1,3,4-th ia d ia zole (13). A
stirred solution of compound 12 (6.35 g, 15.00 mmol) and CuCN
(1.75 g, 19.5 mmol) in anhydrous NMP (36 mL) was heated at
160 °C for 21 h. The cooled reaction mixture was poured into
cooled (0 °C) 10% aq HCl (20 mL) and stirred for a short time.
J O016063X