The synthesis of symmetrical bis-1,2,5-thiadiazole ligands

Article abstract of DOI:10.1016/j.tetlet.2004.05.045

We have been engaged in a search for coordination catalysts for the copolymerization of polar monomers (such as vinyl chloride and vinyl acetate) with ethylene. We have been investigating complexes of late transition metals with heterocyclic ligands. In this report we describe the synthesis of a symmetrical bis-thiadiazole. We have characterized one of the intermediates using single crystal X-ray diffraction. Several unsuccessful approaches toward 1 are also described, which shed light on some of the unique chemistry of thiadiazoles.

Full text of DOI:10.1016/j.tetlet.2004.05.045

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5441–5444
The synthesis of symmetrical bis-1,2,5-thiadiazole ligandsq
Dean M. Philipp,a Rick Muller,a William A. Goddard,a Khalil A. Abboud,b
Michael J. Mullins,c R. Vernon Snelgrovec and Phillip S. Atheyc,*
aMaterials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA
bDepartment of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
cThe Dow Chemical Company, Chemical Sciences, Corporate Research, 2301 N. Brazosport Blvd., Freeport, TX 77541, USA
Received 9 February 2004; revised 11 May 2004; accepted 11 May 2004
Abstract—We have been engaged in a search for coordination catalysts for the copolymerization of polar monomers (such as vinyl
chloride and vinyl acetate) with ethylene. We have been investigating complexes of late transition metals with heterocyclic ligands.
In this report we describe the synthesis of a symmetrical bis-thiadiazole. We have characterized one of the intermediates using single
crystal X-ray diffraction. Several unsuccessful approaches toward 1 are also described, which shed lighton some of ht e unique
chemistry of thiadiazoles.
Ó 2004 Elsevier Ltd. All rights reserved.
The ability to homopolymerize (or copolymerize with
ethylene) commercially available polar vinyl monomers
in a controlled fashion (i.e., producing tacticity) has
been a goal of polymer scientists since the advent of
Ziegler–Natta catalysts. Although there has been some
success for acrylate copolymerizations,1 there have been
no reliable reports of the coordination polymerization of
vinyl acetate or vinyl chloride, two of the least expensive
polar monomers.
However, late metals also form relatively strong olefin–
metal p-complexes, which increases the insertion barrier
and therefore slows the insertion rates. The key is to de-
velop new complexes using late metals, which have a
favorable balance of slow elimination chemistry and
acceptable insertion rates for chain propagation.3 The
complexes that our models suggest may be useable cata-
lysts have some common features: hard, anionic hetero-
atoms at 180°, delocalized charge in a conjugated ligand,
and a soft p-interaction directly behind the active site.4
Jordan and our group have shown conclusively in sev-
eral cases that known catalysts fail due to an elimination
process, which occurs after insertion of the polar
monomer.2;3 The driving force for this elimination pro-
cess is the strength of metal–oxygen (or metal–chlorine)
bonds relative to metal–carbon bonds, particularly for
early metals. This difference in energy is less for the late
metals, and this has been the focus of the search for
polar monomer catalysts.
Two of the proposed ligand complexes, which fit this
criteria are the bis-1,2,5-thiadiazole ligands 1 and 2. In
this report we describe the synthesis of a symmetrical
bis-thiadiazole. Several unsuccessful approaches toward
1 are also described, which shed lighton some of hte
unique chemistry of thiadiazoles.
S
N
N
N
S
N
N
S
N
N
N
S
OH
HO
OH
OH
2
1
Keywords: Thiadiazole; Polar monomer catalysis; Bis-hydroxy thia-
diazole; Vinyl chloride.
q Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tetlet.2004.05.045
* Corresponding author. Tel.: +1-9792389973; fax: +1-9792380414;
e-mail: pathey@dow.com
In our efforts to prepare such bis-thiadiazoles (1 or 2),
numerous synthetic routes were investigated, which fall
into two categories. Our first strategy was to form the
thiadiazole rings after the carbon framework was
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.045

5442
D. M. Philipp et al. / Tetrahedron Letters 45 (2004) 5441–5444
assembled. The second strategy, which ultimately
proved to be successful, was to join two functionalized
thiadiazoles. The former approach will be discussed
first.
R
N
N
Cl
R
N
N
X
R'
S
S
ð2Þ
R
10a R = Cl
10b R = OH
11a R = Cl
11b R = OH
Our initial plan was to start with a symmetrical six-
carbon backbone, and build the thiadiazole rings on the
ends. One common synthetic method for 1,2,5-thia-
diazoles is to treat an a-aminocarboxamide (3) with an
electrophilic sulfur species such as S2Cl2 or PhNSO
(Eq. 1).5 Accordingly, we attempted to synthesize bis-a-
aminocarboxamide (5), and expected to produce 6, a
saturated version of 1. These methods were thwarted by
a strong propensity for these molecules to cyclize. For
example, in Scheme 1 the commercially available di-
bromide 7 was converted to diamine diester 8 via a bis-
azide intermediate.6 Attempts to convert diamine diester
8 to the bis-a-aminocarboxamide 5 using either aqueous
or liquid ammonia under pressure led to the formation
of piperidone 9, and none of the desired product (6).7
We used single crystal X-ray diffraction to conclusively
identify piperidone 9, which is shown in Figure 1. The
structure is unexceptional.8
We investigated the reaction of a variety of acetylene
nucleophiles (Na–CBC–Na, Li–CBC–SiMe3, Li–CBC–
SnMe3) with 3,4-dichlorothiadiazole (10a) and 3-chloro-
4-hydroxythiadiazole (10b). Throughouthtis series of
reactions, the starting material was consumed quickly,
with no significant higher molecular weight products
being formed. It has been reported in the literature that
the reaction of Na–CC–SiMe3 with 3,4-dichloro thi-
adiazole results in the formation of S(CBC–SiMe3)2 and
Me3SiCBC–CN.9 We also investigated the use of
HCBCCMe2OH under phase-transfer conditions,
which has been used successfully with 3-chlorothiophene
and 2-chloropyridine.10;11 However, the use of this pro-
cedure with 3,4-dichloro thiadiazole or 3-chloro-4-
hydroxy-1,2,5-thiadiazole again formed
reaction mixture.
a complex
An alternative to this procedure was the implementation
of an olefin metathesis methodology (Eq. 3). Specific-
ally, we reasoned that the desired bis-thiadiazole 1 might
be produced from olefin metathesis on vinyl-substituted
thiadiazole 12.
O
N
S2Cl2 or PhNSO
S
H2N
ð1Þ
N
4
HO
NH2
3
We turned our attention to approaches, which started
with functionalized 1,2,5-thiadiazoles (10a,b). We rea-
soned that if a chlorinated thiadiazole would behave in a
fashion similar to that of pyridine, we might be able to
add an acetylenic nucleophile as shown in Eq. 2.
NH3+Cl-
NH2
S
N
N
N
N
i, ii, iii
iv
S
+ 1
S
S
olefin metathesis
HO
HO
O
13
14
12
i) Hexane, 68
°
°
C ii) Pyridine, 90
°
C, distill off hexane
iii) Cool to 34 C, add PHNSO heat to 90 C for 16 h
°
iv) CH3CO3H, KOtBu, CHCl3
ð3Þ
The precursor (12) was prepared starting with the con-
version of methionine amide 13 to the thiadiazole 14
using PhNSO. The published12 procedure for conversion
of 14 to the vinyl derivative 12 gave uneven results in
our hands. We developed a one-potprocedure for pre-
paring the vinyl derivative 12 from the thioether via
oxidation, followed by treatment with base.13 The
crystalline olefin was isolated in good yield. Attempts to
perform the olefin metathesis step with several different
catalysts gave no reaction. Finally, attempted coupling
of 14 with 3,4-dichloro-1,2,5-thiadiazole (10a) under
Figure 1. X-ray structure of lactam 9.
O
H
N
O
H2N
NH3+Cl-
O
Br
O
NH2
O
O
NH2
O
9
OEt
i, ii
OEt
iii
NH2
EtO
EtO
H2N
X
Br
O
NH2
NH2
7
8
5
S
N
N
N
S
OH
N
HO
6
Scheme 1. Reagents and conditions: (i) NaN3 EtOH, 76 °C, 17 h; (ii) EtOH, HCl, PtO, H2; (iii) NH3.

D. M. Philipp et al. / Tetrahedron Letters 45 (2004) 5441–5444
5443
O
CF3
NH3+Cl-
N
N
N
HO
HO
HO
BzlO
iv
i, ii, iii
H2N
TMS
S
S
+
N
O
N
OH
15
16
18
1
17
Cl-
Ph3P
+
N
N
vii
S
v
S
N
OBzl
BzlO
N
19
ix
18
N
S
N
OBzl
viii
N
O
vi
S
21
N
BzlO
20
Scheme 2. Reagents and conditions: (i) MeCN, 1 h ambient temp; (ii) 0 °C, Et3N; (iii) SO2 in MeCN is added, warm to ambient temp; (iv) dioxane,
HMPA, BzlCl, K2CO3, reflux for 3.5 h; (v) CHCl3, SOCl2, reflux for 1 h; (vi) CH2Cl2, ‘Bobbitt’s’ reagent16; (vii) THF, )40 °, Kþ)N(TMS)2, warm to
ambient; (viii) )40 °C, stir to ambient temp for 90 min; (ix) CH2Cl2, )78 °C, 1 M BBr3.
Heck chemistry conditions did not form any coupled
products.
Failure of this chemistry led us to investigate longer
synthetic routes based on formation of the central olefin
from 3-formyl-1,2,5-thiadiazole using Wittig or
McMurray coupling methods. We hoped to prepare the
formyl derivative by oxidation of known 3-hydroxy-4-
hydroxymethyl-1,2,5-thiadiazole (17). A seldom-used
method for formation of thiadiazole rings by treatment
of a-aminocarboxamide 15 with a silylating agent (16)
and SO2 was used for the preparation of thiadiazole
17.14 This synthetic method is attractive since it does not
involve potent electrophiles such as SOCl2, S2Cl2 or
SO2Cl2. Although the mechanism was not discussed, the
Figure 2. A single crystal X-ray structure analysis of 21.
ylides are known to exclusively react with aldehydes to
form trans-alkenes (Fig. 2).17
amino acid is probably converted to a bis-trimethylsilyl
derivative, which upon exposure to liquid SO2 produces
17 (45%). This method for synthesis of thiadiazoles is
notcovered in any of hte reviews, and we have not
uncovered any other published examples (Scheme 2).15
Final deprotection of the bis-benzyl derivative 21 was
attempted several ways using nonhydrogenation debenz-
ylation techniques. Initially, the use of excess BBr3 at
low temperatures did deprotect 21 to yield 1 in a matter
of 2–3 h. However, the initial, isolated, crude product (1)
was contaminated with boron impurities. Final purifi-
cation of 1 was achieved by basification of an aqueous
mixture of 1, followed by filtration and subsequent
reprecipitation of 1 via acidification with HCl. This
deprotection sequence yielded 1 in >80%. With regard to
some of the physical properties of 1, itwas found ht at
the material had a very high melting/decomposition
point(>300 °C) and was quite insoluble in most tradi-
tional solvents, with the exception of being marginally
soluble in DMSO. Like phenol, the hydroxyl groups of
this thiadiazole are quite acidic.
The acidic hydroxyl group of thiadiazole 17 was pro-
tected as the benzyl ether 18. The conversion of 18 to 20
required a mild oxidizing agent to avoid electrophilic
attack on the thiadiazole ring. This was accomplished by
using the heterogeneous oxidant, 4-acetylamino-2,2,6,6-
tetramethylpiperidine-1-oxoammonium
perfluorobo-
rate, which formed aldehyde 20 in >90% yield.16
A McMurray coupling reaction (Ti3þ under reductive
conditions) of aldehyde 20 was initially attempted, but
the desired olefin 21 was notdetected. Upon workup, a
strong mercaptan odor was observed, possibly indicat-
ing that the thiadiazole ring had been degraded under
these reaction conditions. Next, our attention focused
on Wittig chemistry. The phosphonium salt 19 was
prepared from the hydroxymethyl derivative using
standard techniques. Reaction of the ylide with the
aldehyde formed the symmetrical olefin 21 in 89% yield.
A single crystal X-ray structure analysis confirmed the
geometry of the double bond (C6-C6A 1.33 A) to be E,
depicting the thiadiazole rings disposed about the dou-
ble bond at180 °. The formation of 21 with a trans
configuration reflects the stability of the ylide, due to the
carbanion-stabilizing thiadiazole ring substituent on the
negatively charged carbon of the ylide. Such stable
In conclusion, this work focused on the synthesis of 1,
which we were able to produce in four steps with an
overall yield of 36%. The metal complexation of 1 is now
being pursued, but the poor solubility of 1 has made the
subsequent metalation of 1 challenging. Accordingly, we
have been unable to test the validity of this ligand metal
complex as a polar monomer catalyst.
References and notes
1. Brookhart, M. S. et al., WO 96/23010 assigned to DuPont
published August1, 1996.

5444
D. M. Philipp et al. / Tetrahedron Letters 45 (2004) 5441–5444
2. (a) Stockland, R. A.; Jordan, R. F. J. Am. Chem. Soc.
58.80, H, 3.95, N, 13.72. Found: C, 58.58, H, 3.97, N,
13.67. 1H NMR (CDCl3) d 5.5 (s, 4H), 7.39 (m, 10H), 7.78
(s, 2H) ppm. 13C NMR (CDCl3) 72.88, 123.94, 128.53,
128.92, 129.05, 135.98, 146.54, 163.39 ppm. (1) mp 300–
2000, 122, 6315–6316; (b) Foley, S. R.; Stockland, R. A.,
Jr.; Shen, H.; Jordan, R. F. J. Am. Chem. Soc. 2003,
125(14), 4350–4361; (c) Stockland, R. A., Jr.; Foley, S. R.;
Jordan, R. F. J. Am. Chem. Soc. 2003, 125(3), 796–809; (d)
Stockland, R. A., Jr.; Jordan, R. F. J. Am. Chem. Soc.
2000, 122(26), 6315–6316.
1
305 °C. H NMR (DMSO) d 7.7 (s, 2H), 13.3 (br s, 2H)
ppm. 13C NMR (d6-DMSO) 123.96, 146.58, 163.94 ppm.
HRMS (ES) m/z calcd for C7H6N4O2S2: 227.9775 found
227.9776.
3. Boone, H. W.; Athey, P. S.; Mullins, M. J.; Philipp, D.;
Muller, R.; Goddard, W. A. J. Am. Chem. Soc. 2000,
124(30), 8790–8791.
7. Newman, H. J. Heterocycl. Chem. 1974, 11(3), 449–
451.
4. Philipp, D. M.; Muller, R. P.; Goddard, W. A., III; Storer,
J.; McAdon, M.; Mullins, M. J. Am. Chem. Soc. 2002,
124(34), 10198–10210.
8. The chloride in the structure shown was omitted for
clarity. Diffraction data are described in the Supplemental
materials section.
5. Pesin, V. G. Russian Chem. Rev. 1970, 39(11), 923–943.
6. Select data for structural intermediates and products: (8)
1H NMR (DMSO-d6) d 8.86 (br s, 4H), 4.21 (m, 4H), 3.99
(br s, 2H), 1.98 (m, 4H), 1.23 (t, 3H, J ¼ 7:1 Hz). 13C NMR
(DMSO-d6) 169.0, 61.9, 51.1, 25.8, 14.0 ppm. (9) 1H NMR
(DMSO-d6) d 8.4 (br s, 3H), 8.1 (s, 1H), 7.6 (s, 1H), 7.1 (s,
1H), 4.85 (m, 1H), 4.7 (1H, m), 2.2 (m, 2H), 1.7 (m, 2H).
13C NMR (DMSO-d6) 172.9, 167.4, 55.3, 48.7, 24.5 ppm.
9. Kouvetakis, J.; Grotjahn, D. Chem. Mater. 1994, 6, 636.
10. Carpita, A. L. A.; Lessi, L. A.; Rossi, R. Synthesis 1984,
571.
11. Mal’kina, A. G.; Brandsma, L.; Vasilevsky, B. A.;
Trofimov, B. A. Synthesis 1996;(5), 589–590.
12. Mizsak, S. A.; Perelman, M. J. Org. Chem. 1966, 31, 1964–
1965.
13. Preparation of PhNSO: A 1 L 4-neck flask equipped with
mechanical stirring, addition funnel, and condenser was
charged with aniline (40.0 mL, 40.9 g, 0.439 mol) and
200 mL benzene. Nitrogen was flowed through a tee at
the top of the condenser to a water bubbler to trap HCl
gas. The addition funnel was charged with SOCl2
(41.6 mL, density 1.631 g/mL, 67.9 g, 0.571 mol), which
was added over a 15 min period. A solid formed during
this addition. After addition, the reactor was gradually
heated to 80 °C. The solid mostly dissolved to form a
yellow solution. Pure product (55 g) was isolated by
distillation at 200 °C.
1
(14) H NMR (CDCl3) d 10.4 (very br s, 1H), 3.1 (t, 2H,
J ¼ 7 Hz), 2.95 (t, 2H, J ¼ 7 Hz). 13C NMR (CDCl3) 162.7,
1
150.8, 31.3, 28.8, 15.4 ppm. (12) H NMR (CDCl3) d 12.0
(br s, 1H), 6.90 (d of d, 1H, J ¼ 17:7, 11.4 Hz), 6.45 (d, 1H,
J ¼ 11:4 Hz); 13C NMR (CDCl3) d 162.8, 147.3, 126.2,
122.1. (17) 13C NMR (CDCl3) d 161.6, 150.4, 57.5. Anal.
Calcd for C3H4N2O2S: C, 27.27, H, 3.03, N, 21.21. Found:
C, 27.14, H, 3.23, N, 21.28. (18) Anal. Calcd for
C10H10N2O2S: C, 54.05, H, 4.50, N, 12.6. Found: C,
1
53.80, H, 4.52,N, 12.35. H NMR (CDCl3) d 3.78 (br s,
1H), 4.75 (s, 2H), 5.46 (s, 2H), 7.40 (m, 5H) ppm. 13C NMR
(CDCl3) 59.1, 72.64, 128.70, 128.89, 129.01, 129.07, 135.96,
151.1, 162.1 ppm. (19) Anal. Calcd for C28H24N2OSPI: C,
56.58, H, 4.04, N, 4.71. Found: C, 55.64, H, 4.08, N, 4.71.
13C NMR (CDCl3) 162.3, 140.0, 139.9, 134.8, 133.5, 133.3,
131.6, 131.1, 129.7, 118.4, 117.0, 71.8, 65.9 ppm. 31P NMR
(CDCl3) 31.0 ppm. (20) mp 39–40.5 °C. Anal. Calcd for
C10H8N2O2S: C, 54.55, H, 3.64, N, 12.72. Found: C, 54.33,
14. Huff, B. U.S. Patent 5,284,957, 1994.
15. See, for example, ‘1,2,5-thiadiazoles and their benzo
derivatives’ by Weinstock, L. M.; Shinkai, I. In Compre-
hensive Heterocyclic Chemistry; Katritsky, A. R., Rees,
C. W., Eds.; 1984; Vol. 6.
16. (a) Kernag, C.; Bobbitt, J.; McGrath, D. Tetrahedron Lett.
1999, 40, 1635; (b) Bobbitt, J. M. J. Org. Chem. 1998, 63,
9367.
17. (a) Liu, Y. Y.; Thom, E.; Liebman, A. A. J. Heterocycl.
Chem. 1979, 16, 799; (b) Wittig, G.; Haag, W. Chem. Ber.
1955, 88, 1654.
1
H, 3.69, N, 12.71. H NMR (CDCl3) d 5.55 (s, 2H), 7.40
(m, 5H), 10.11 (s, 1H) ppm. 13C NMR (CDCl3) 73.16,
128.58, 129.05, 129.08, 135.52, 145.17, 165.49, 182.21 ppm.
(21) mp 138–140 °C. Anal. Calcd for C20H16N4S2O2: C,