Synthesis of 3-deazathiamine

Article abstract of DOI:10.1039/b006962k

An efficient ten-step synthesis of deazathiamine is described. The synthesis starts from commercially available α-acetyl-γ-butyrolactone and proceeds via deamination of the key aminothiophene 6. The Gewald synthesis of thiophenes is shown to give a mixture of isomeric products with the unsymmetric ketone used here and so a modified procedure giving a single isomer is developed.

Full text of DOI:10.1039/b006962k

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Synthesis of 3-deazathiamine
a
b
a
Daniel Hawksley, David A. Griffin and Finian J. Leeper*
a
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
Zeneca Agrochemicals, Jealotts Hill Research Station, Bracknell, Berkshire, UK RG42 6ET
1
b
Received (in Cambridge, UK) 25th August 2000, Accepted 17th October 2000
First published as an Advance Article on the web 18th December 2000
An efficient ten-step synthesis of deazathiamine is described. The synthesis starts from commercially available
α-acetyl-γ-butyrolactone and proceeds via deamination of the key aminothiophene 6. The Gewald synthesis
of thiophenes is shown to give a mixture of isomeric products with the unsymmetric ketone used here and
so a modified procedure giving a single isomer is developed.
Deazathiamine diphosphate (deaza-TDP) 1 is an analogue of
thiamine diphosphate (TDP) 2, the biologically active form
aminothiophene 6 by reaction with sulfur in the presence of
diethylamine.
3
Attempts to repeat this strategy for the synthesis of 6 were
only partially successful. Ethyl cyanoacetate and 5-acetoxy-
pentan-2-one 4, generated from the acetolysis of commercially
available α-acetyl-γ-butyrolactone 3, were heated at reflux in
benzene in the presence of ammonium acetate and acetic acid
using a Dean–Stark apparatus, to give olefin 5 (1:1 ratio of E
and Z isomers) in yields of up to 73%. This was subsequently
reacted with flowers of sulfur in ethanol, in the presence of
3
diethylamine at 60 ЊC. Work-up however gave a thick black
oil which was difficult to purify by column chromatography.
1
Furthermore, H NMR revealed that the product was a mixture
of two compounds with identical R values. A sharp singlet at
f
5
.86 ppm and signals corresponding to three consecutive
methylene groups indicated that, along with the desired amino-
thiophene 6, there was also present the isomeric thiophene 7
(
Scheme 1). No way could be found to separate the two isomers
by column chromatography.
of thiamin† (vitamin B ), with a neutral thiophene replacing
1
the positively charged thiazolium ring. TDP is the co-enzyme
present in a number of enzymes, including pyruvate decarb-
oxylase, transketolase, acetolactate synthase, the pyruvate
dehydrogenase complex, pyruvate oxidase, and deoxyxylulose
5
-phosphate synthase.
Deaza-TDP is isoelectronic with TDP and so studies of its
binding to TDP-dependent enzymes would give accurate
information as to the polarity of the active site since the only
difference between the two is the difference in charge. Indeed,
previous studies have suggested that neutral analogues of TDP
1,2
may have increased binding affinity. Functionalisation of
deaza-TDP at C-2 would give rise to analogues which mimic
key reaction intermediates in TDP dependent enzymes. These
could then be tested for binding to, and inhibition of, such
enzymes. Such inhibitors may also lead to the development of
novel herbicides. In this paper we describe the first reported
synthesis of deazathiamine.
Scheme 1 (a) AcOH, HCl, 85%; (b) NCCH
CO Et, AcONH , AcOH,
2 4
C H , 73%; (c) see Table 1; (d) S, Et NH, EtOH, 34%; (e) S, morpho-
2
6
6
2
line, t-BuOH, 38%.
Results and discussion
The intended route to deazathiamine was via the key inter-
mediate aminothiophene 6. This tetrasubstituted thiophene
has been synthesised before using a synthesis of thiophenes
developed originally by Gewald in the mid 1960’s. The
It was also possible to effect this reaction in a simpler one-
4,5
pot, three-component condensation. 5-Acetoxypentan-2-one
was condensed with ethyl cyanoacetate and flowers of sulfur
4
in either ethanol or tert-butyl alcohol in the presence of a
disubstituted amine at 50–60 ЊC. However, these conditions
again gave a mixture of aminothiophenes 6 and 7. Varying the
solvent and increasing the steric demands of the base improved
the product ratio in favour of the desired aminothiophene,
but yields were low and purification remained laborious
(Table 1).
3
4,5
published synthesis of 6 involves the conversion of olefin 5 into
†
The IUPAC name for thiamin is 3-(4-amino-2-methylpyrimidin-5-
ylmethyl)-5-(2-hydroxyethyl)-4-methylthiazolium.
1
44
J. Chem. Soc., Perkin Trans. 1, 2001, 144–148
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b006962k

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Table 1 Formation of isomeric thiophenes 6 and 7 from ketone 4
aminothiophene 6, in a yield of 82% (Scheme 2), with none of
the isomer 7 being formed.
Ratio Yield
The next step, deamination of aminothiophene 6, proved
more problematic than anticipated. This reaction had been
reported before; it was effected by diazotisation followed by loss
of nitrogen with the hydrogen coming from the solvent
a
b
Entry Solvent Base
Time /h 6:7
of 6 (%)
1
2
3
4
5
6
EtOH
EtOH
EtOH
Morpholine
10
14
36
6
10
16
2:1
3:1
5:1
2:1
3:1
35
31
25
33
30
18
Et NH
9
2
ethanol. However, the yield obtained was only 24%. When
i
Pr NH
2
t
we attempted this, we found that the diazonium salt could be
formed by slow addition of aqueous sodium nitrite to a vigor-
ously stirred solution of aminothiophene 6 in hydrochloric
acid, at Ϫ10 ЊC (it was important that the temperature did not
rise above Ϫ5 ЊC as this caused the solution to turn deep purple
and become very viscous, presumably due to polymerisation
and diazo-coupling reactions). A variety of reducing agents
Bu OH
Morpholine
t
Bu OH
Et NH
2
t
i
Bu OH
Pr NH
30:1
2
a
Reaction time at 50–60 ЊC required for consumption of 4, as deter-
mined by TLC. Determined by H NMR on the crude mixture.
b
1
10
11
The formation of two alternative products when unsym-
metrical ketones are used was not reported by Gewald or
other workers who reported the synthesis of aminothiophene 6
by this method. Formation of the two possible isomers has,
however, been reported in a more recent paper which employed
the Gewald method for the synthesis of slightly different
were tried, including hypophosphorous acid, thiophenol,
4,5
12
13
ethanol, and sodium azide. Deaminations using alkyl nitrites
14
in either DMF or acetonitrile (where the solvent acts as the
hydrogen donor) were also tried. Some of the desired product
12 was obtained using hypophosphorous acid or ethanol but
yields were poor and it was difficult to obtain pure product
from the thick purple oil. The reactions using thiophenol and
sodium azide failed to give the desired reduction product 12 but
instead gave the corresponding substitution products in good
yield.
3
6
thiophenes.
In order to improve the synthesis of 6 it was necessary to
modify the precursor to ensure that in the cyclisation reaction,
only the desired product was formed. This was achieved by
employing a route via an α-chloroketone. The chloride would
subsequently be displaced by a nucleophilic sulfur atom,
thus ensuring only one of the isomeric thiophenes would be
produced. α-Acetyl-γ-butyrolactone 3 was chlorinated with
sulfuryl chloride to give 8 in 89% yield (Scheme 2). This was
4,7
Eventually it was decided to first replace the amino group by
a halogen, and then replace that, in turn, with hydrogen. The
conditions which gave the best results with least side-reactions
15
was a modification of the conventional Sandmeyer procedure,
using tert-butyl nitrite and anhydrous cupric bromide in
16
acetonitrile. The resulting bromide 11 was treated, without
17
purification, with zinc and acetic acid to give the desired
α-free thiophene 12, which required no further purification, in
8
7% yield over the two steps (Scheme 2). This is far superior to
9
the reported direct deamination of 6.
The methodology to be used for the formation of the
aminopyrimidine ring was based upon a synthesis of trimeth-
18
oprim analogues, which involved condensation of an aromatic
aldehyde with β-anilinopropionitrile followed by reaction with
guanidine. In our case it would be necessary to use acetamidine
in place of guanidine. This chemistry was first tested using
benzaldehyde as a model. Reaction of benzaldehyde with
anilinopropionitrile gave the desired adduct 13 in 74% yield
(
Scheme 3). The second step, using acetamidine instead of
Scheme 3 (a) PhNHCH CH CN, t-BuOK, t-BuOH, DMSO, 74%;
2
2
(
b) CH C(᎐NH)NH ؒHCl, NaOEt, EtOH, 84%.
3
2
guanidine, was also successful, giving 2-methyl-4-amino-5-
benzylpyrimidine 14 in 84% yield. The aminopyrimidine ring of
14 is identical to that required for deazathiamine.
Returning to the synthesis of deazathiamine, conversion of
ester 12 into the corresponding aldehyde was accomplished in
Scheme 2 (a) SO Cl , 89%; (b) i) AcOH, HCl, ii) Ac O, 85%; (c)
2
2
2
NCCH CO Et, AcONH , AcOH, PhMe, 43%; (d) NaSH, EtOH, 82%;
2
2
4
(
e) CuBr , t-BuONO, CH CN; (f) Zn, AcOH, 87% (over 2 steps).
2
3
then decarboxylated and acetylated by heating with acetic and
hydrochloric acids followed by the addition of acetic anhydride
to give 5-acetoxy-3-chloropentan-2-one 9 in 85% yield. Con-
two steps. Firstly, reduction of the ester with LiAlH gave the
4
diol 15 (Scheme 4). Oxidation using freshly prepared activated
8
19
MnO2 then gave the aldehyde 16, with no apparent oxidation
densation of 9 with ethyl cyanoacetate, using the conditions
previously outlined for the analogous condensation of 4 with
ethyl cyanoacetate, gave the desired product (as a 1:1 mixture
of E and Z isomers) in a rather low 43% yield. However, the
starting materials were recovered, during the purification by
vacuum distillation, and could be recycled. The final step in the
sequence involved the addition of olefin 10 to a solution of
of the non-benzylic alcohol. Treatment of a solution of alde-
hyde 16 and β-anilinopropionitrile in DMSO at 50 ЊC with a
solution of sodium methoxide in methanol gave the conden-
sation product 17 in 94% yield. (Sodium methoxide in methanol
was found to give better results than potassium tert-butoxide
in tert-butyl alcohol. ) The major double-bond isomer of 17
(presumably the Z-isomer) precipitated upon addition of ice-
water, whereas the minor isomer could be obtained by extrac-
tion of the filtrate with ethyl acetate. In the final step the major
17
7
anhydrous sodium hydrogen sulfide in ethanol at Ϫ40 ЊC.
After one hour at Ϫ10 ЊC, addition of water precipitated out
J. Chem. Soc., Perkin Trans. 1, 2001, 144–148
145

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isomer of 17 was heated at reflux in dry ethanol with acet-
amidine overnight, in the presence of excess base, to give
deazathiamine 18 in 81% yield (Scheme 4).
Fig. 1 Crystal structure of deazathiamine 18 (one of the two molecules
in the unit cell).
MHz) spectrometer. APT spectra (J-resolved spin echo) were
also run to assist in the assignment. Chemical shifts (δ) are
reported in ppm downfield from tetramethylsilane. Mass
spectra were run on either a Micromass Q-Tof or a Micromass
Concept spectrometer using electron impact (EI) or electro-
spray ionisation (ESI) in positive ion mode. Analytical TLC
was performed on commercial Merck glass plates, coated to a
thickness of 0.25 mm with Kieselgel 60 F254 silica. Column
chromatography was performed using Merck Kieselgel 60
(
230–400 mesh) silica using a small positive pressure of air. All
solvents were redistilled before use. Solvents and reagents for
20
anhydrous reactions were dried by conventional methods and
such reactions were performed under a small positive pressure
of argon.
Scheme 4 (a) LiAlH , Et O, 81%; (b) MnO , CHCl , 74%; (c) PhNH-
4
2
2
3
CH CH CN, NaOMe, DMSO, MeOH, 94%; (d) CH C(᎐NH)NH ؒ
2
2
3
2
HCl, NaOEt, EtOH, 81%.
5
-Acetoxypentan-2-one 4
A crystal structure of the final product, deazathiamine
8, was obtained.‡ This showed two molecules of 18 in the unit
cell along with one molecule of water (which is confirmed by
elemental analysis). Fig. 1 shows the structure of one of the two
molecules of 18.
α-Acetylbutyrolactone 3 (5 g, 39 mmol) was stirred with AcOH
(4 ml), water (0.7 ml) and concentrated HCl (0.3 ml) for 16 h at
90 ЊC, then cooled, and concentrated under reduced pressure to
give a brown oil. Bulb-to-bulb distillation gave ketone 4 (4.8 g,
1
21
85%) as a liquid, bp 40 ЊC (0.1 mmHg) [lit. bp 91 ЊC
Ϫ1
(
11 mmHg)]; νmax(film)/cm 1740 (CO–O) and 1717 (C᎐O);
δ (250 MHz, CDCl ) 1.86 (2 H, m, CH CH CH ), 2.00 (3 H, s,
H
3
2
2
2
Conclusion
OAc), 2.12 (3 H, s, CH ), 2.48 (2 H, t, J 7.2, CH CH CH ) and
3
2
2
2
The synthesis of deazathiamine 18 was effected in ten chemical
steps, though it was not necessary to isolate in pure form either
the bromide 11 or nitrile 17. Furthermore, the first six steps can
be carried out on a large scale without the need for chrom-
atography. Deamination of aminothiophene 6 via the bromide
4.02 (2 H, t, J 6.4, CH
2
O).
Ethyl 6-acetoxy-2-cyano-3-methylhex-2-enoate 5
A solution of 5-acetoxypentan-2-one 4 (2.26 g, 15.6 mmol) and
ethyl cyanoacetate (1.77 g, 15.6 mmol) in benzene (10 ml) was
heated at reflux in a Dean–Stark apparatus with AcOH (0.37 g,
1
1 was very efficient, displaying none of the side reactions and
complications observed with more direct methods. The readily
available and inexpensive starting materials and reagents, and
the lack of protection–deprotection steps makes this a partic-
ularly efficient synthesis. Conversion of deazathiamine to its
pyrophosphate ester 1 and enzymic experiments with the deaza-
TDP will be described in a future publication.
6
.2 mmol) and AcONH (0.19 g, 2.5 mmol) for 4 h, and then
4
cooled, diluted with ethyl acetate and washed with successive
portions of water and brine. The organic layer was dried
(
MgSO ) and concentrated under reduced pressure to give a
4
brown oil. Bulb-to-bulb distillation gave alkene 5 (130 ЊC, 0.1
mmHg) as an oil (2.73 g, 73%) containing a 1:1 mixture of
E- and Z-isomers [Found: M (EI), 239.1147. C H NO
requires M, 239.1157]; νmax(film)/cm 2254 (CN) and 1743
ϩ
12
17
4
Ϫ1
Experimental
General procedures
(
CO–O); δ (250 MHz, CDCl ) 1.32 (3 H, t, J 7.1, CH CH ),
H 3 3 2
1
.86 (2 H, m, CH CH CH ), 2.04 and 2.05 (3 H, 2 × s, OAc),
2 2 2
Mps were determined on a Reichert melting point apparatus
and are uncorrected. IR spectra were recorded on a Perkin-
Elmer 297 FTIR spectrophotometer, using sodium chloride
plates for thin film spectra and spectra recorded in Nujol mulls.
Proton NMR spectra were recorded on either a Bruker AM/
DPX 250 (250 MHz), a Bruker AM/DPX 400 (400 MHz) or a
Bruker DPX 500 (500 MHz) spectrometer. All coupling con-
stants (J) are given in Hz. C NMR spectra were recorded with
proton decoupling on either a Bruker AC/DPX 250 (62 MHz),
a Bruker AC/DPX 400 (100 MHz) or a Bruker DPX 500 (125
2.28 and 2.37 (3 H, 2 × s, CH ), 2.64 and 2.84 (2 H, 2 × dd, J 7.4
3
and 8.0, and J 7.7 and 8.0, CH CH CH ), 4.08 and 4.09 (2 H,
2
2
2
2 × t, J 6.2, and J 6.4, CH CH CH ), and 4.24 and 4.25 (2 H,
2
2
2
2 × q, J 7.1 and J 7.1, CH CH ); δ (100 MHz, CDCl ) 13.9
3
2
C
3
(CH CH ), 20.7 (CH CO), 20.8 and 25.0 (CH C), 25.5 and 26.3
3
2
3
3
(CH CH CH ), 31.9 and 36.9 (CCH ), 61.6, 62.8 and 63.5
2
2
2
2
(2 × CH O), 105.3, 105.4, 115.1 and 115.4 (C᎐C and CN), and
2
13
161.2, 161.6, 170.7, 170.7, 175.5 and 175.9 (C᎐C and 2 × CO).
Ethyl 6-acetoxy-2-cyano-3-methyl-4-chlorohex-2-enoate 10
To a solution of ethyl cyanoacetate (34.2 g, 0.30 mol), AcOH
‡
CCDC reference number 207/498. See http://www.rsc.org/suppdata/
(
(
6.7 g, 0.11 mol) and AcONH (3.4 g, 43.8 mmol) in toluene
4
p1/b0/b006962k/ for crystallographic files in .cif format. Crystal data:
C H N O1.5S, M = 272.36, monoclinic, C2/c, a = 47.033(2), b =
500 ml) containing 3 Å molecular sieves (25 g) was added
1
3
18
3
8
3
Ϫ1
5-acetoxy-3-chloropentan-2-one 9 (45 g, 0.25 mol) with stir-
ring. The reaction mixture was heated at reflux for 6 h, cooled,
diluted with ethyl acetate and washed with a mixture of
1
1.2180(7), c = 10.5570(5) Å, V = 5564.7(5) Å , Z = 16, µ = 0.230 mm
,
5
846 measured reflections, 3532 unique reflections, R = 0.1063,
wR = 0.2368. Data collected at 220(2) K.
1
46
J. Chem. Soc., Perkin Trans. 1, 2001, 144–148

View Article Online
water and saturated aqueous sodium hydrogen carbonate (4:1),
which was subsequently re-extracted with ethyl acetate. The
combined organic layers were washed with brine, dried
Ethyl 5-(2-acetoxyethyl)-2-bromo-4-methylthiophene-3-
carboxylate 11
To a stirred solution of aminothiophene 6 (13.9 g, 51.3 mmol)
and tert-butyl nitrite (10.1 ml, 77 mmol) in acetonitrile (200 ml)
at 0 ЊC was added dropwise, a solution of copper() bromide
(
MgSO ) and concentrated under reduced pressure. Distillation
4
gave firstly a mixture of the two unreacted starting materials
76–79 ЊC, 0.15 mmHg) and then alkene 10 (130 ЊC, 0.15
(
(
13.7 g, 61.6 mmol) in acetonitrile (20 ml) over 15 min. The
mmHg), as an oil (29.3 g, 43%) containing a 1:1 mixture of
mixture was stirred for a further 30 min at 0 ЊC, until gas
evolution was complete, then allowed to warm to room tem-
perature, and poured into 2 M hydrochloric acid (400 ml) and
extracted with ethyl acetate (3 × 100 ml). The combined organic
ϩ
E- and Z-isomers [Found: M ϩ Na (ESI), 296.0673. C -
1
2
35
Ϫ1
H16 ClNO requires M ϩ Na, 296.0666]; νmax(film)/cm 2250
4
(
CN), and 1740 (CO–O); δ (250 MHz, CDCl ) 1.35 (3 H, t,
H
3
J 7.1, CH CH ), 2.07 and 2.09 (3 H, 2 × s, OAc), 2.17 (2 H, m,
3
2
layers were washed with brine, dried (MgSO ) and concentrated
4
CHCH CH ), 2.36 and 2.40 (3 H, 2 × s, CH ), 4.16 and 4.24
2
2
3
under reduced pressure to give the bromide 11 as a dark brown
(
2 H, t, J 6.3 and J 6.6, CHCH CH ), 4.28 and 4.31 (2 H, 2 × q,
2 2
oil (16.1 g, 93%), which was used without further purification
J 7.1 and J 7.1, CH CH ), and 5.27 and 6.23 (2 H, 2 × dd, J 6.2
3
2
Ϫ1
in the next step; νmax(film)/cm 1744 and 1715 (2 × CO–O);
and 8.2, and J 6.2 and 8.2, CHCH CH ); δ (100 MHz, CDCl )
2
2
C
3
δ (250 MHz, CDCl ) 1.38 (3 H, t, J 7.1, CH CH ), 2.06 (3 H, s,
H
3
3
2
1
3.8 and 13.9 (CH CH ), 15.5 and 15.5 (CH CO), 19.4 and 20.7
3
2
3
OAc), 2.26 (3 H, s, CH ), 2.99 (2 H, t, J 6.6, ArCH CH ), 4.18
3
2
2
(
CH C), 34.9 and 35.0 (CH CHCl), 53.9 and 59.2 (CHCl), 60.0,
3
2
(
2 H, t, J 6.6, ArCH CH ), and 4.36 (2 H, q, J 7.1, CH CH );
2
2
3
2
6
0.3, 62.4 and 62.5 (2 × CH O), 106.2, 107.1, 113.7 and 114.6
2
δ (62 MHz, CDCl ) 13.8, 14.2 and 20.9 (3 × CH ), 27.2
C
3
3
(
(
C᎐C and CN), and 160.5, 160.9, 169.3, 170.3, 170.6 and 170.7
C᎐C and 2 × CO).
᎐
᎐
(
CH CH ), 61.0 and 63.6 (2 × CH O), 114.8, 132.7, 134.8 and
3
2
2
1
3
35.0 (4 × arylC), and 163.3 and 170.7 (2 × CO); MS (ESI) m/z
ϩ 81 ϩ 79
58.97 [MNa ( Br)], 356.97 [MNa ( Br)].
Ethyl 5-(2-acetoxyethyl)-2-amino-4-methylthiophene-3-
carboxylate 6
Ethyl 5-(2-acetoxyethyl)-4-methylthiophene-3-carboxylate 12
Method a. To a stirred mixture of 5-acetoxypentan-2-one 4
3 g, 20.8 mmol), ethyl cyanoacetate (2.22 ml, 20.8 mmol), and
A mixture of crude bromothiophene 11 (16.1 g, 48 mmol) and
zinc dust (15.7 g, 240 mmol) were heated at reflux in acetic acid
(
flowers of sulfur (0.67 g, 20.8 mmol) in tert-butyl alcohol (10 ml)
was added morpholine (1.82 ml, 20.8 mmol) dropwise. The
mixture was heated to 60 ЊC for 6 h, cooled and concentrated
under reduced pressure. The resultant oil was dissolved in ethyl
acetate and washed successively with 0.2 M aqueous sulfuric
acid, water and brine. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. Silica gel chrom-
(
100 ml) for 16 h. After cooling, the mixture was poured onto
ice and neutralised by the cautious addition of sodium hydro-
gen carbonate. The resulting aqueous suspension was extracted
with ethyl acetate (3 × 100 ml). The combined organic layers
were washed with brine, dried (MgSO ) and concentrated under
reduced pressure to give thiophene 12 as a mobile oil (11.5 g,
4
ϩ
9
4%) [Found: M ϩ Na (ESI), 279.0670. C H SO requires
1
2
16
4
atography (dichloromethane–ethyl acetate, 9:1, R 0.4) and
Ϫ1
f
M ϩ Na, 279.0667]; νmax(film)/cm
CO–O); δ (250 MHz, CDCl ) 1.34 (3 H, t, J 7.1, CH CH ),
2
1739 and 1715 (2 ×
then crystallisation from hexane–diethyl ether afforded crystals
H
3
3
2
(
3.05 g) composed of thiophenes 6 (38% effective yield) and 7
.06 (3 H, s, OAc), 2.37 (3 H, s, CH ), 3.07 (2 H, t, J 6.8, Ar-
3
(
16% effective yield).
CH CH ), 4.22 (2 H, t, J 6.8, ArCH CH ), 4.29 (2 H, q, J 7.1,
2
2
2
2
CH CH ), and 7.94 (1 H, s, ArH); δ (125 MHz, CDCl )
3
2
C
3
Method b. To a stirred mixture of alkene 5 (1.45 g, 6.1 mmol)
1
3.1, 13.9 and 20.6 (3 × CH ), 27.1 (ArCH ), 60.0 and 63.7
3
2
and flowers of sulfur (0.19 g, 6.1 mmol) in ethanol (5 ml) was
added diethylamine (0.47 g, 6.1 mmol). The mixture was heated
to 50–60 ЊC for 14 h, cooled, and concentrated under reduced
pressure. Work-up and purification as in method a gave pale
yellow crystals (0.74 g) composed of 6 (34% effective yield) and
(
2 × CH O), 130.9 (arylCH), 132.4, 134.3 and 134.8 (3 ×
2
arylC), and 163.0 and 170.5 (2 × CO).
5
-(2-Hydroxyethyl)-4-methylthiophene-3-methanol 15
A suspension of LiAlH (0.63 g, 16.7 mmol) in dry diethyl ether
(
4
7
(11% effective yield).
100 ml) was heated to reflux until most of the LiAlH had
4
dissolved. A solution of ester 12 (7.12 g, 27.8 mmol) in dry
diethyl ether (50 ml) was added dropwise at such a rate that
the ether refluxed gently. The mixture was heated at reflux for a
further 3 h, then cooled, diluted with ethyl acetate (200 ml)
and washed successively with 1 M hydrochloric acid, water and
Method c. Acetic acid (9.9 g, 0.17 mol) was added dropwise
to a stirred solution of Na S (13.3 g, 0.17 mol) in dry ethanol
2
(
200 ml) at Ϫ40 ЊC. A solution of chloroalkene 10 (18 g, 66
mmol) in EtOH (30 ml) was added dropwise, over 15 min. The
mixture was stirred at Ϫ40 ЊC for 1 h, then allowed to warm
slowly to Ϫ10 ЊC, stirred for a further hour and then quenched
by the addition of ice–water. The precipitated solid was separ-
ated, washed with ice–water and dried to give thiophene 6 as a
solid (14.6 g, 82%), mp 64–65 ЊC (from EtOH) [Found: C, 53.1;
brine. The combined organic layers were dried (MgSO ) and
4
concentrated under reduced pressure. Chromatography over
silica gel (ethyl acetate–hexane, 2:1, R 0.2) gave the diol 15
f
ϩ
as an oil (3.87 g, 81%) [Found: M ϩ Na (ϩESI), 195.0464.
Ϫ1
C H O S requires M ϩ Na, 195.0456]; νmax(film)/cm 3324
ϩ
8
12
2
H, 6.3; N, 5.1%; M (EI), 271.0879. C H NO requires: C,
12
17
4
(
OH); δ (250 MHz, CDCl ) 2.15 (3 H, s, CH ), 2.98 (2 H, t,
Ϫ1
H 3 3
5
3
3.1; H, 6.3; N, 5.2%; M, 271.0878]; νmax(Nujol)/cm 3425 and
315 (NH ), 1734 and 1718 (2 × CO–O) and 1589 (NH );
J 6.5, ArCH CH ), 3.81 (2 H, t, J 6.5, ArCH CH ), 4.57 (2 H, s,
2
2
2
2
2
2
ArCH OH), and 7.04 (1 H, s, ArH); δ (62 MHz, CDCl ) 11.9
2
C
3
δ (250 MHz, CDCl ) 1.34 (3 H, t, J 7.1, CH CH ), 2.05 (3 H, s,
H
3
3
2
(
(
CH ), 31.5 (ArCH CH ), 60.3 and 63.1 (2 × CH OH), 120.1
arylCH), and 132.8, 135.3 and 141.7 (3 × arylC).
3
2
2
2
OAc), 2.20 (3 H, s, CH ), 2.87 (2 H, t, J 6.9, ArCH CH ), 4.13
3
2
2
(
2 H, t, J 6.9, ArCH CH ), 4.27 (2 H, q, J 7.1, CH CH ), and
2
2
2
2
5
.97 (2 H, br s, NH ); δ (62 MHz, CDCl ) 14.4, 14.9 and 21.0
2 C 3
5
-(2-Hydroxyethyl)-4-methylthiophene-3-carbaldehyde 16
(
3 × CH ), 26.6 (CH CH ), 59.3 and 64.2 (2 × CH O), 107.0,
3
3
2
2
1
14.3 and 132.2 (3 × ArC), and 161.7, 166.0 and 170.9 (2 × CO
To a stirred solution of diol 15 (2.12 g, 12.2 mmol) in chloro-
19
and CNH ).
form (60 ml) was added activated manganese dioxide (10.6 g,
122 mmol). The mixture was stirred at room temperature for
5 h, filtered and concentrated. Chromatography over silica gel
2
For thiophene 7 δ (250 MHz, CDCl ) 1.35 (3 H, t, J 7.1,
H
3
CH CH ), 1.89 (2 H, m, ArCH CH CH ), 2.05 (3 H, s, OAc),
3
2
2
2
2
2
.75 (2 H, t, J 7.5, ArCH CH CH ), 4.09 (2 H, t, J 6.6, ArCH -
(ethyl acetate–hexane, 1:1, R 0.2) gave the aldehyde 16 as an oil
2
2
2
2
f
ϩ
CH CH ), 4.27 (2 H, q, J 7.1, CH CH ), 5.86 (1 H, s, ArH) and
(1.55 g, 74%) [M ϩ Na (ϩESI), 193.0299. C H SO requires
2
2
3
2
8
10
2
Ϫ1
6
.07 (2 H, br s, NH ).
M ϩ Na 193.0299]; νmax(film)/cm 3402 (OH), 2802 and 2720
2
J. Chem. Soc., Perkin Trans. 1, 2001, 144–148 147

View Article Online
(
CHO), and 1681 (C᎐O); δ (250 MHz, CDCl ) 2.41 (3 H, s,
122.3 (CN), 122.6 (ArCH), 129.5 (2 × m-CH), 133.0, 136.0,
᎐
H
3
CH ), 3.02 (2 H, t, J 6.4, ArCH CH ), 3.86 (2 H, t, J 6.4,
136.6 and 139.8 (4 × ArC), and 140.6 (CHNH).
3
2
2
ArCH CH ), 7.93 (1 H, s, ArH), and 9.91 (1 H, s, CHO);
The filtrate was extracted with ethyl acetate, washed with
2
2
δ (62 MHz, CDCl ) 12.4 (CH ), 30.5 (ArCH ), 62.4 (CH OH),
brine, dried (MgSO ) and concentrated under reduced pressure
C
3
3
2
2
4
1
1
33.2 (arylC), 136.9 (arylCH), 137.0 and 141.1 (2 × arylC), and
85.9 (CHO).
to give the other isomer of 17 as an oil (56 mg, 4%); δ (250
H
MHz, CDCl ) 2.10 (3 H, s, CH ), 3.01 (2 H, t, J 6.4, ArCH -
3
3
2
CH ), 3.38 (2 H, s, C᎐CCH Ar), 3.83 (2 H, t, J 6.4, ArCH CH ),
2
2
2
2
6
6
.71 (1 H, br d, J 13.0, NH), 6.82 (2 H, d, J 7.8, phenyl o-H),
.93 (1 H, s, thiopheneH), 6.99 (1 H, t, J 7.4, phenyl p-H), 7.06
2
-Benzyl-3-(phenylamino)acrylonitrile 13
A mixture of benzaldehyde (5.30 g, 50 mmol) and β-anilino-
propionitrile (8.04 g, 55 mmol) was heated in dry Me SO
(
2 H, d, J 13.0, CH), and 7.30 (2 H, dd, J 7.4 and J 7.8, phenyl
2
m-H).
(
25 ml) to 40 ЊC under N and a solution of potassium tert-
2
butoxide (6.5 g, 55 mmol) in tert-butyl alcohol (40 ml) was
added dropwise. The mixture was stirred for 1.5 h at 55 ЊC, then
cooled and slurried with ice–water (100 ml). The precipitated
solid was separated and dried to give crude 13 (8.6 g, 74%)
which was used directly in the next step. A small portion was
recrystallised to give pure acrylonitrile 13, mp 157–158 ЊC (from
3
-Deazathiamin 18
To a stirred solution of 17 (0.78 g, 2.6 mmol) in dry ethanol
7 ml) was added dropwise a suspension containing acetamidine
hydrochloride (0.50 g, 5.3 mmol) and sodium ethoxide (0.72 g,
0.6 mmol) in ethanol. The mixture was heated at reflux for
(
1
ϩ
48 h and cooled. Ice-water (30 ml) was added and the precipi-
tated solid was separated and dried to give 3-deazathiamine 18
(0.56 g, 81%), mp 204–205 ЊC (from CHCl –MeOH–H O)
toluene) [Found: C, 81.9; H, 6.1; N, 12.0%; M ϩ Na (ϩES),
2
57.1051. C H N requires C, 82.0; H, 6.0; N, 12.0%;
16 14 2
Ϫ1
M ϩ Na, 257.1055]; νmax(film)/cm 3310 (NH), 2196 (CN), and
603, 1585 and 1498 (Ph); δ (250 MHz, CDCl ) 3.51 (2 H, s,
3
2
ϩ
[
Found: C, 57.05; H, 6.6; N, 15.1%; M , 263.1100. C H -
1
13 17
H
3
N OSؒ0.5H O requires C, 57.3; H, 6.7; N, 15.4%; M, 263.1092];
νmax(Nujol)/cm 3385 and 3323 (NH ), 3142 (OH), and 1653
CH ), 6.73 (1 H, d, J 12.8, NH), 6.85 (2 H, d, J 7.7, anilino
3
2
2
Ϫ1
o-H), 7.00 (1 H, t, J 7.4, anilino p-H), 7.13 (1 H, d, J 12.8, CH),
and 7.30 (7H, m, ArH); δ (125 MHz, CDCl ) 32.7 (CH ), 82.4
2
(
NH ); δ (400 MHz, DMSO) 1.96 and 2.27 (2 × 3 H, s, CH ),
2
H
3
C
3
2
2
.83 (2 H, t, J 7.0, ArCH CH ), 3.58 (2 H, s, ArCH Ar), 3.58
2 2 2
(
(
CCN), 115.0 (anilino o-CH), 122.3 (CN), 122.6 and 127.0
2 × p-CH), 127.9, 128.8 and 129.5 (benzyl o-CH and 2 × m-
(
(
2 H, dt, J 5.3 and 7.0, CH OH), 4.76 (1 H, t, J 5.3, OH), 6.58
2 H, br s, NH ), 6.76 (1 H, s, thiopheneH), and 7.57 (1 H, s,
2
CH), 136.6 and 139.8 (2 × phenylC), and 140.3 (CHNH).
2
pyrimidineH); δ (100 MHz, DMSO) 12.3 and 25.4 (2 × CH ),
C
3
2
1
7.8 and 32.1 (2 × ArCH ), 62.1 (CH OH), 112.0 (CCNH ),
18.6 (thiopheneCH), 132.8, 135.5 and 138.5 (3 × ArC), 154.5
2
2
2
4
-Amino-5-benzyl-2-methylpyrimidine 14
To a stirred solution of 13 (0.50 g, 2.14 mmol) in dry ethanol
5 ml) was added dropwise a suspension containing acetamidine
hydrochloride (0.61 g, 6.41 mmol) and sodium ethoxide (0.48 g,
.06 mmol) in dry ethanol (2 ml). The mixture was heated under
(pyrimidineCH), and 162.1 and 164.9 (CNCNH ).
2
(
Acknowledgements
7
reflux for 40 h and cooled. Ice–water (30 ml) was added and the
precipitated solid was separated and dried to give pyrimidine 14
We thank the BBSRC for a studentship (D. H.) and Zeneca
Agrochemicals for a CASE award and financial support.
(
0.36 g, 84%), mp 140–141 ЊC (from toluene) [Found: C, 72.2;
ϩ
H, 6.65; N, 21.1%; MH (ϩES), 200.1178. C H N requires
12
13
3
References
Ϫ1
C, 72.3; H, 6.6; N, 21.1%; MH, 200.1188]; νmax(Nujol)/cm
290 (NH ), 1655 (NH ), and 1593 and 1587 (Ph); δ (400 MHz,
1
R. Kluger, G. Gish and G. Kauffman, J. Biol. Chem., 1984, 259,
960.
3
2
2
H
8
DMSO) 2.28 (3 H, s, CH ), 3.72 (2 H, s, CH ), 6.58 (2 H,
3
2
2
P. N. Lowe, F. J. Leeper and R. N. Perham, Biochemistry, 1983, 22,
br s, NH ), 7.20 (5H, m, phenyl-H), and 7.78 (1 H, s, ArH);
2
150.
δ (125 MHz, CDCl ) 25.9 (CH ), 35.0 (CH ), 113.0 (CCNH ),
C
3
3
2
2
3 V. I. Shvedov, V. K. Ryzhkova and A. N. Grinev, Khim Geterotsikl.
Soedin., 1967, 3, 239.
4 K. Gewald, Chem. Ber., 1965, 98, 3571.
5
6
1
1
27.5 (p-C), 128.6 and 129.4 (o-C and m-C), 137.5 (CCH ),
2
56.3 (CHN), and 162.0 and 166.8 (CNCNH ).
2
K. Gewald, E. Schinke and H. Böttcher, Chem. Ber., 1966, 99, 94.
G. D. Madding and M. D. Thompson, J. Heterocycl. Chem., 1987,
3
-(2-Cyano-3-phenylaminoprop-2-en-1-yl)-5-(2-hydroxyethyl)-4-
2
4, 581.
methylthiophene 17
7 A. Rosowsky, C. E. Mota, J. E. Wright, J. H. Freisheim, J. J. Heusner,
J. J. McCormack and S. F. Queener, J. Med. Chem., 1993, 36, 3103.
A mixture of aldehyde 16 (0.75 g, 4.4 mmol) and β-anilino-
8
S. Archer and C. Perianayagam, J. Med. Chem., 1979, 22, 306.
propionitrile (0.77 g, 5.3 mmol) was heated in dry Me SO
2
9 V. I. Shvedov, V. K. Ryzhkova and A. N. Grinev, Khim. Geterotsikl.
Soedin., 1967, 3, 1010.
10 J. Taylor, J. Am. Chem. Soc., 1950, 72, 3013.
(
15 ml) to 40 ЊC under N and a solution of sodium meth-
2
oxide (0.29 g, 5.3 mmol) in methanol (2 ml) was added
dropwise. The mixture was stirred for 2 h at 40 ЊC, then cooled
and slurried with ice–water (50 ml) and left in the refrigerator
overnight. The resultant precipitate was separated and dried
to give one isomer of crude 17 (1.10 g, 84%) which was used
directly in the next step. A small portion was recrystallised to
1
1
1
1 T. Shono, Y. Matsumura and K. Tsubata, Chem. Lett., 1979, 1051.
2 R. H. Mitchell and V. S. Iyer, J. Am. Chem. Soc., 1996, 118, 722.
3 Y. Yamada, H. Yasuda and A. Takayama, Heterocycles, 1998, 48,
1
185.
1
4 M. P. Doyle, J. F. Dellaria, Jr., B. Siegfried and S. W. Bishop, J. Org.
Chem., 1977, 42, 3494.
15 H. H. Hodgson, Chem. Rev., 1947, 40, 251.
16 M. P. Doyle, B. Siegfried and J. F. Dellaria, Jr., J. Org. Chem., 1977,
give pure acrylonitrile 17 as white crystals, mp 134–135 ЊC
ϩ
(
(
from toluene) [Found: C, 68.4; H, 6.1; N, 9.4%; M ϩ Na
ϩES), 321.1022. C H N OS requires C, 68.4; H, 6.1; N, 9.4%;
4
2, 2426.
17
18
2
1
1
7 A. Rössler and P. Boldt, J. Chem. Soc., Perkin Trans. 1, 1998, 685.
8 B. Roth, E. Aig, B. S. Rauckman, J. Z. Strelitz, A. P. Phillips,
R. Ferone, S. R. M. Bushby and C. W. Sigel, J. Med. Chem., 1981,
24, 933.
Ϫ1
M ϩ Na, 321.1038]; νmax(Nujol)/cm 3406 (OH), 2178 (CN),
and 1601, 1584 and 1508 (Ph); δ (400 MHz, CDCl ) 2.14 (3 H,
H
3
s, CH ), 3.01 (2 H, t, J 6.4, ArCH CH ), 3.45 (2 H, s,
3
2
2
C᎐CCH Ar), 3.83 (2 H, t, J 6.4, ArCH CH ), 6.29 (1 H, br d,
19 J. Attenburrow, A. F. B. Cameron, J. H. Chapman, R. M. Evans,
᎐
2
2
2
B. A. Hems, A. B. A. Janson and T. Walker, J. Chem. Soc., 1952,
J 12.9, NH), 6.75 (2 H, d, J 7.9, phenyl o-H), 6.97 (1 H, s,
thiopheneH), 6.99 (1 H, t, J 7.4, phenyl p-H), 7.27 (2 H, dd,
J 7.4 and J 7.9, phenyl m-H), and 7.34 (1 H, d, J 12.9, CH);
1
094.
2
0 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, 2nd edn., Pergamon Press, Oxford, 1980.
21 Y. Ishido, H. Tsutsumi and S. Inaba, J. Chem. Soc., Perkin Trans. 1,
δ (100 MHz, CDCl ) 12.1 (CH ), 27.9 and 31.5 (2 × ArCH ),
C
3
3
2
6
2.8 (CH OH), 81.0 (CCN), 114.9 (2 × o-CH), 118.8 (ArCH),
1977, 521.
2
1
48
J. Chem. Soc., Perkin Trans. 1, 2001, 144–148