A simple and efficient preparation of novel formaldehyde derivatives

Article abstract of DOI:10.1055/s-0028-1083305

New formaldehyde derivatives were prepared in good yields by a short and versatile route. Several crystal structures of corresponding thioacetic acid esters and thiols were determined. The thioacetates were cleaved under acidic or basic conditions affording the thiols in high yield, thus introducing the new substance classes of N-mercaptomethyl-alkylcarboxamides, N-mercapto- methylsulfonamides, and alkoxymethanethiols. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0028-1083305

PAPER
495
A Simple and Efficient Preparation of Novel Formaldehyde Derivatives
N
ovel Formaldeh
a
yde
D
eriva
i
tives ner Hartung, Gregor Golz, Susanne Schlaf, Gudrun Silvennoinen, Kurt Polborn, Peter Mayer, Hans Rudolf
Pfaendler*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, Haus F, 81377 München, Germany
Fax +49(89)218077771; E-mail: hrp@cup.uni-muenchen.de
Received 29 July 2008; revised 22 September 2008
Dedicated to Prof. Wolfgang Steglich, München, on the occasion of his 75th birthday
group.1 Acidic or basic cleavage of the thioacetates deliv-
ered the corresponding thiols 5 in good yields. Thioace-
tate 4b was prepared by direct reaction of 2b with
thioacetic acid in 64% yield.
Abstract: New formaldehyde derivatives were prepared in good
yields by a short and versatile route. Several crystal structures of
corresponding thioacetic acid esters and thiols were determined.
The thioacetates were cleaved under acidic or basic conditions af-
fording the thiols in high yield, thus introducing the new substance
classes of N-mercaptomethyl-alkylcarboxamides, N-mercapto-
methylsulfonamides, and alkoxymethanethiols.
H2C=O
SOCl2
R
H
R
OH
R
R
Cl
1
3
3
Key words: N-mercaptomethylcarboxamides, N-mercaptomethyl-
sulfonamides, methoxymethanethiol
2
HCl, MeOH or
O
NaOMe, MeOH or
KSAc
R
S
SH
pyrrolidine
O
4
5
The reactivity of formaldehyde is outstanding among al-
dehydes making it difficult to obtain the pure substance.
With traces of water formaldehyde immediately suffers
from nucleophilic attack rendering polymeric formalde-
hyde. This extraordinary reactivity is due to the lack of
electron-donating alkyl groups, which stabilize the carbo-
nyl group of larger homologues by the inductive effect.
O
O
O
R =
NH
H
NH
NH
O
F3C
NH
c
d
a
b
O
O
O
N
N
O
N
N
N
For our syntheses1 of orally active carbapenems we
searched for formaldehyde-derived N-mercaptomethyl-
alkylcarboxamides and HS/O-acetals. Surprisingly, the
former compounds have not been prepared yet, whereas
the latter could not be prepared by a route proposed in
1912.2 We wish to report here the synthesis of the follow-
ing three novel types of formaldehyde derivatives. As
they contain a reactive SH group they are versatile C1-
building blocks in organic synthesis.
e
f
g
O
O
O
O
N
S
S
N
S
N
MeO
N
N
h
i
k
j
Scheme 1 General reaction sequence used to prepare 5
Starting with pyrrolidin-2-one (1e) the intermediate lac-
tams 2e–4e and the cyclic thiol 5e were produced. Alter-
natively from the known4 3-chloromethyl-1,3,4-
oxadiazol-2(3H)-ones 3f,g and from 1,3,4-thiadiazol-
2(3H)-ones 1h5 and 1i5 the cyclic thiols 5f–i were synthe-
sized.
N-Mercaptomethylcarboxamides represent a first novel
class of thiols, prepared by a four-step synthesis starting
from carboxamides and formaldehyde according to
Scheme 1. The mildest method to prepare N-hydroxy-
methyl compounds 2 uses an aqueous formaldehyde solu-
tion with a catalytic amount of K2CO3, a reaction first
described by Einhorn.3 Accordingly, amides 1 reacted
easily in high yields. However, our attempts to purify the
products 2 by column chromatography or recrystallization
failed in most cases. The hydroxymethyl group was
cleaved, leaving only starting material 1 and formalde-
hyde. Adduct 2c could be recrystallized from toluene,
yielding pure product. The adducts 2 were converted to
chlorides 3 using thionyl chloride or oxalyl chloride. The
reaction of chlorides 3 with potassium thioacetate pro-
duced the desired 4 using a method developed in our
Pyrrolidin-2-one (1e) did not easily react with aqueous
formaldehyde, so we had to deviate from the standard
route. In a modified procedure,6 a mixture of paraformal-
dehyde and 1e was heated to 180 °C to give 2e, which was
chlorinated immediately affording 3e in 40% overall yield
after distillation. Crystal structures of thioacetates 4b,i as
well as of thiols 5d,g,h,i could be determined.7 The
ORTEP drawings of 5d and 4j are reproduced in Figures 1
and 2, respectively.
N-Mercaptomethylsulfonamide 5j exemplifies a second
class of novel formaldehyde HS/N-acetals. The formalde-
hyde adduct 2j of sultam 1j,8 synthesized by the general
procedure, did not yield any identifiable product with both
oxalyl chloride and thionyl chloride. Chlorination finally
SYNTHESIS 2009, No. 3, pp 0495–0501
x
x
.
x
x
.2
0
0
9
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083305; Art ID: T12708SS
© Georg Thieme Verlag Stuttgart · New York

496
R. Hartung et al.
PAPER
with a Varian NMR-System 300 MHz, a Varian NMR-System 400
MHz and a Varian NMR-System 600 MHz using TMS as internal
standard. HRMS were taken on a Finnigan MAT 95 mass spectrom-
eter.
All chemicals were of reagent grade and, if necessary, were purified
in the usual manner prior to use. Starting materials were obtained
from Sigma-Aldrich, Germany. TLC was performed on glass sheets
with Merck silica gel 60 F254 plates and column chromatography
was carried out using Merck silica gel 60 (0.040–0.063 mm). Ele-
mental analyses were obtained from the Microanalytical Laboratory
of the Faculty of Chemistry and Pharmacy (LMU Munich).
Figure 1 ORTEP representation of thiol 5d
Adducts 2a,c,d,f,h–j; General Procedure
An aqueous solution of formaldehyde (37% w/w, 1 equiv) was add-
ed to a mixture of the appropriate amide (1 equiv) and either solid
K2CO3 (0.1 equiv; 2a,c,j) or aq 1 N NaOH (0.01 equiv, 2d,f,h,i).
The mixture was stirred at r.t. for 2 h. The H2O formed was removed
in vacuo. The residue was diluted with CHCl3, EtOAc, or MeOH (1
mL/mmol), dried (MgSO4), and filtered. After removal of the sol-
vent, the adduct was obtained and used for the next step without fur-
ther purification.
worked with PCl5 in refluxing Et2O to give 3j in 99%
yield.
Following the general reaction sequence, thioacetate 4j
crystallized from Et2O. X-ray crystal structure analysis
shows a planar CH2SAc group (Figure 2). Cleavage by
pyrrolidine produced the corresponding thiol 5j in 82%
yield.
N-Hydroxymethylformamide (2a)3
From formamide 1a (3.6 g, 80 mmol); yield: 5.96 g (99%); colorless
oil.
IR (ATR): 3290, 2962, 1657, 1532, 1386, 1233, 1016, 875, 697,
648, 605 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.27 (br s, 1 H), 4.67 (s, 1 H), 4.79
(m, 2 H), 8.18 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 63.8, 164.2.
HRMS (EI): m/z [M]+ calcd for C2H5NO2: 75.0320; found: 75.0316.
N-Hydroxymethyltrifluoroacetamide (2c)
From trifluoroacetamide 1c (11.3 g, 100 mmol); yield: 13.4 g
(94%). Crystallization from toluene yielded colorless crystals; mp
99 °C.
Figure 2 ORTEP representation of thioacetate 4j
IR (ATR): 3310, 2881, 1708, 1668, 1553, 1410, 1274, 1177, 1078,
1038, 841, 786, 674 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.61 (t, J = 6.8 Hz, 2 H), 6.01 (t,
J = 6.8 Hz, 1 H), 9.98 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 62.9, 115.8 (q, J = 288.6 Hz),
156.3 (q, J = 36.3 Hz).
Methoxymethanethiol 5k is a further new reagent. Thio-
acetic acid S-methoxymethyl ester (4k) was synthesized
by the reaction of chloromethyl methyl ether (3k) with po-
tassium thioacetate in 72% yield. Methoxymethanethiol
5k was prepared in aqueous solution under basic condi-
tions. The substance proved to be highly volatile and had
a characteristic, unpleasant odor. An analytical sample
could be distilled using a Vigreux column (bp 51 °C/760
Torr) but only at high losses of product. Therefore, true 5k
is much more volatile than earlier reported (bp. 52 °C/15
Torr).2 We found 5k is best handled and stored at –80 °C
as a 0.5 M solution in CDCl3.
Anal. Calcd for C3H4F3NO2: C, 25.19; H, 2.82; N, 9.79. Found: C,
25.20; H, 2.56; N, 9.69.
N-Hydroxymethylcyclopropanecarboxamide (2d)
From amide 1d (500 mg, 5.9 mmol); yield: 665 mg (98%); white
solid; mp 99 °C.
IR (ATR): 3276, 3093, 2951, 1650, 1551, 1464, 1430, 1407, 1380,
1278, 1240, 1080, 1015, 896, 666 cm–1.
In summary, we have applied a highly versatile and effec-
tive reaction sequence to prepare an alkoxymethanethiol,
as well as examples of N-mercaptomethylamides and N-
mercaptomethylsulfonamides. These new formaldehyde
derivatives have not been described in literature yet. Our
method involves commercially available reagents and is
carried out under mild reaction conditions, making it
viable for a wide range of substrates.
1H NMR (600 MHz, CDCl3): d = 0.80 (m, 2 H), 1.00 (m, 2 H), 1.37
(tt, J = 7.9, 4.6 Hz, 1 H), 3.37 (br s, 1 H), 4.76 (s, 2 H), 6.64 (br s, 1
H).
13C NMR (150 MHz, CDCl3): d = 7.7, 14.7, 64.9, 175.3.
HRMS (EI): m/z [M]+ calcd for C5H9NO2: 115.0633; found:
115.0593.
3-Hydroxymethyl-3H-[1,3,4]oxadiazol-2-one (2f)
From oxadiazolone 1f4 (1.720 g, 20.0 mmol); yield: 2.110 g (83%);
colorless oil.
Melting points were recorded on a Büchi melting point B-540 and
are uncorrected. IR spectra were taken on a Perkin-Elmer Spectrum
IR (ATR): 3405, 2962, 2924, 1752, 1578, 1367, 1051, 1012, 745,
702 cm–1.
1
BX FT-IR spectrometer. H and 13C NMR spectra were measured
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Novel Formaldehyde Derivatives
497
1H NMR (600 MHz, CDCl3–DMSO-d6): d = 4.94 (s, 2 H), 5.92 (br
s, 1 H), 7.57 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 48.5, 115.2 (q, J = 287.6 Hz),
157.2 (q, J = 38.7 Hz).
13C NMR (100 MHz, CDCl3–DMSO-d6): d = 68.7, 144.4, 153.1.
HRMS (EI): m/z [M + H]+ calcd for C3H5N2O3: 116.0222; found:
HRMS (EI): m/z [M]+ calcd for C3H3ClF3NO: 160.9855; found:
160.9834.
116.0208.
1-Chloromethylpyrrolidin-2-one (3e)6
Pyrrolidin-2-one (1e; 10 g, 118 mmol) and paraformaldehyde (3.54
g, 118 mmol) were mixed under N2 in a dry 25 mL flask equipped
with a reflux condenser. The mixture was heated to 180 °C. After
4.5 h, the mixture was cooled to 0 °C and SOCl2 (16.7 g, 141 mmol)
was slowly added. The mixture was stirred at r.t. for 72 h. Residual
SOCl2 was removed in high vacuum and the residue was distilled
(bp 71 °C/0.0135 Torr) to obtain pure 3e; yield: 6.00 g (40%); light
yellow oil.
IR (ATR): 3361, 1660, 1496, 1422, 1289, 1045, 757, 666 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.08 (tt, J = 7.8, 7.3 Hz, 2 H), 2.41
(t, J = 7.83 Hz, 2 H), 3.54 (t, J = 7.26 Hz, 2 H), 5.22 (s, 2 H).
3-Hydroxymethyl-3H-[1,3,4]thiadiazol-2-one (2h)
From thiadiazolone 1h5 (3.2 g, 32.0 mmol).
Yield: 3.95 g (93%); white solid; mp 60 °C.
IR (ATR): 3354, 3091, 2955, 1636, 1506, 1450, 1288, 1240, 1166,
1056, 931, 834, 686, 641 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 5.14 (d, J = 6.7 Hz, 2 H), 6.80
(t, J = 7.3 Hz, 1 H), 8.51 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 68.6, 139.4, 169.0.
HRMS (FAB): m/z [M + H]+ calcd for C3H5N2O2S: 133.0072;
found: 133.0075.
13C NMR (75 MHz, CDCl3): d = 17.5, 30.6, 45.6, 53.5, 175.6.
HRMS (FAB): m/z [M – Cl]+ calcd for C5H8NO: 98.0600; found:
98.0596.
3-Hydroxymethyl-5-methyl-3H-[1,3,4]thiadiazol-2-one (2i)
From thiadiazolone 1i5 (844 mg, 7.3 mmol); yield: 1.064 g (quant);
white solid; mp 72 °C.
3-Chloromethyl-3H-[1,3,4]oxadiazol-2-one (3f)
IR (ATR): 3370, 2962, 1641, 1567, 1433, 1399, 1379, 1272, 1197,
1059, 983, 679 cm–1.
1H NMR (600 MHz, CDCl3): d = 2.42 (s, 3 H), 3.18 (br s, 1 H), 5.33
(s, 2 H).
13C NMR (150 MHz, CDCl3): d = 18.1, 69.1, 149.4, 170.9.
HRMS (EI): m/z [M]+ calcd for C4H6N2O2S: 146.0150; found:
Adduct 2f (2.320 g, 20 mmol) was suspended in anhyd CH2Cl2 (10
mL) and cooled to –12 °C under N2. Oxalyl chloride (2.0 mL, 24
mmol, 1.2 equiv) was added via a syringe. After 10 min, the mixture
was stirred at r.t. for 24 h, concentrated in vacuo, and distilled (bp
85 °C/0.00188 Torr) to obtain pure 3f; yield: 1.810 g (68%); color-
less oil.
146.0144.
IR (ATR): 2953, 1713, 1533, 1349, 1254, 1213, 1174, 1017, 782,
645 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.53 (s, 2 H), 7.57 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 61.8, 143.9, 140.1.
HRMS (EI): m/z [M]+ calcd for C3H3ClN2O2: 133.9883; found:
133.9891.
(1,1-Dioxo-1l6-isothiazolidin-2-yl)methanol (2j)
From 1,1-dioxo-1l6-isothiazolidine 1j8 (1.260 g, 10.4 mmol); yield:
1.550 g (99%); white solid.
IR (ATR): 3476, 2921, 1455, 1377, 1290, 1128, 1002, 879, 749, 695
cm–1.
1H NMR (600 MHz, CDCl3): d = 2.40 (m, 2 H), 3.13 (t, J = 7.1 Hz,
2 H), 3.51 (t, J = 6.9 Hz, 1 H), 3.59 (t, J = 6.8 Hz, 1 H), 4.77 (s, 2 H).
Anal. Calcd for C3H3ClN2O2: C, 26.79; H, 2.25; N, 20.82. Found:
C, 26.84; H, 2.31; N, 20.75.
13C NMR (75 MHz, CDCl3): d = 19.5, 45.9, 56.7, 69.9.
3-Chloromethyl-3H-[1,3,4]thiadiazol-2-one (3h)
Adduct 2h (1.270 g, 9.6 mmol) was dissolved in anhyd CH2Cl2 (5.5
mL) and cooled to –20 °C under N2. SOCl2 (867 mL, 11.9 mmol, 1.2
equiv) was added via a syringe. After 10 min, the mixture was
stirred at r.t. for 8 h and concentrated in vacuo; yield: 1.354 g (94%);
yellow oil.
IR (ATR): 3065, 1665, 1516, 1282, 1241, 1064, 838, 693, 638 cm–1.
1H NMR (600 MHz, CDCl3): d = 5.67 (s, 2 H), 8.12 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 53.3, 139.4, 168.5.
N-Chloromethylformamide (3a)9
Under N2, N-hydroxymethylformamide (2a; 401 mg, 5.35 mmol)
was cooled to –10 °C using a MeOH/ice bath. Oxalyl chloride (674
mg, 126 mmol) was added via a syringe. After 30 min, the generated
HCl was removed in high vacuum and the white, amorphous residue
3a was used immediately without further purification; yield: 472
mg (95%); white amorphous solid.
IR (ATR): 3216, 1657, 1509, 1384, 1271, 1243, 1209, 1175, 1030,
963, 827 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.55 (br s, 1 H), 4.38 (s, 2 H), 7.85
(s, 1 H).
HRMS (EI): m/z [M]+ calcd for C3H3ClN2OS: 149.9655; found:
149.9644.
3-Chloromethyl-5-methyl-3H-[1,3,4]thiadiazol-2-one (3i)
Adduct 2i (1.019 g, 7.0 mmol) was dissolved in anhyd CH2Cl2 (4
mL) and cooled to –15 °C under N2. SOCl2 (644 mL, 8.9 mmol, 1.3
equiv) was added via a syringe. After 10 min, the mixture was
stirred at r.t. for 12 h and concentrated in vacuo; yield: 1.096 g
(96%); yellow oil.
N-Chloromethyltrifluoroacetamide (3c)
N-Hydroxymethylacetamide (2c; 715 mg, 5.0 mmol) was suspend-
ed in anhyd CH2Cl2 (5 mL). SOCl2 (885 mg, 7.5 mmol) was added
and the mixture was refluxed for 3 h. The solvent was evaporated in
high vacuum and the resulting colorless oil was used immediately
without further purification; yield: 739 mg (92%); colorless oil.
IR (ATR): 3056, 1675, 1571, 1428, 1383, 1336, 1283, 1194, 1011,
691 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H), 5.62 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.4, 53.2, 150.5, 169.9.
IR (ATR): 3314, 1720, 1544, 1440, 1390, 1342, 1308, 1209, 1157,
992, 929, 723, 696 cm–1.
1H NMR (600 MHz, CDCl3): d = 5.21 (d, J = 7.36 Hz, 2 H), 7.30 (br
s, 1 H).
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HRMS (EI): m/z [M]+ calcd for C4H5ClN2OS: 163.9811; found:
163.9812.
IR (ATR): 3308, 1684, 1545, 1356, 1206, 1152, 1130, 970, 941, 703
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H), 4.73 (d, J = 6.6 Hz,
2-Chloromethylisothiazolidine 1,1-Dioxide (3j)
2 H), 7.21 (br s, 1 H).
A solution of adduct 2j (1.570 g, 10.4 mmol) in anhyd Et2O (11 mL)
under N2 was cooled to 0 °C and PCl5 (2.165 g, 10.4 mmol) was
added in small portions. The suspension was stirred at r.t. for 2 h and
refluxed for 1 h. The mixture was filtered and the filtrate was
washed with Et2O (2 × 10 mL). The solvent was removed in vacuo
and the residue 3j was used immediately without further purifica-
tion; yield: 1.750 g (99%); colorless oil.
13C NMR (150 MHz, CDCl3): d = 30.7, 39.0, 115.4 (q, J = 287.5
Hz), 157.0 (q, J = 157.0 Hz), 196.9.
HRMS (EI): m/z [M]+ calcd for C5H6F3NO2S: 201.0071; found:
201.0072.
Anal. Calcd for C5H6F3NO2S: C, 29.85; H, 3.01; N, 6.96. Found: C,
30.37; H, 2.75; N, 7.02.
IR (ATR): 2959, 1693, 1453, 1371, 1298, 1268, 1137, 1006, 742,
681 cm–1.
S-(2-Oxopyrrolidin-1-yl)methyl Thioacetate (4e)
1H NMR (200 MHz, CDCl3): d = 2.45 (m, 2 H), 3.09 (t, J = 7.5 Hz,
2 H), 3.56 (t, J = 7.1 Hz, 2 H), 5.25 (s, 2 H).
From 3e (2.004 g, 15 mmol). The product was purified by column
chromatography (silica gel, EtOAc–MeOH, 9:1); yield: 2.070 g
(80%); white crystals; mp 37 °C; Rf = 0.45 (EtOAc–MeOH, 9:1).
Thioacetates 4a–c,e–j; General Procedure
IR (ATR): 2997, 1683, 1418, 1401, 1259, 1125, 1091, 960, 688, 622
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.00 (m, 2 H), 2.34 (t, J = 7.94 Hz,
2 H), 2.38 (s, 3 H), 3.39 (t, J = 7.17 Hz, 2 H), 4.80 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 17.7, 30.6, 30.7, 41.5, 46.5, 175.4,
195.3.
KSAc (1.1 equiv), dried several hours in high vacuum prior to use,
and K2CO3 (0.1 equiv) were added to a solution of the appropriate
chloride (1 equiv) in anhyd CH2Cl2 and/or anhyd Et2O (1 mL/
mmol) under N2. The mixture was stirred at r.t. for 18 h. The mix-
ture was diluted with CH2Cl2 or EtOAc (2.5 mL/mmol) and washed
with H2O (1.5 mL/mmol). The organic phase was dried (MgSO4),
filtered, and concentrated in vacuo to obtain the crude thioacetates.
HRMS (EI): m/z [M]+ calcd for C7H11NO2S: 173.0510; found:
173.0514.
S-(Formylamino)methyl Thioacetate (4a)
Anal. Calcd for C7H11NO2S: C, 48.53; H, 6.40; N, 8.09. Found: C,
48.33; H, 6.30; N, 8.06.
Starting from 3a (175 mg, 1.58 mmol). The product was purified by
column chromatography (silica gel, toluene–EtOAc, 1:1); yield: 85
mg (40%); white crystals; mp 62 °C; Rf = 0.21 (toluene–EtOAc,
1:1).
S-(2-Oxo[1,3,4]oxadiazol-3-yl)methyl Thioacetate (4f)
From 3f (2.700 g, 20 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 4:1); yield: 1.410 g
(60%); yellow oil; Rf = 0.44 (toluene–EtOAc, 1:1).
IR (ATR): 3322, 2927, 2846, 1620, 1568, 1535, 1309, 1242, 1085,
890 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.37 (s, 3 H), 4.68 (d, J = 6.8 Hz,
2 H), 6.54 (br s, 1 H), 8.15 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 30.7, 37.5, 160.6, 197.4.
HRMS (EI): m/z [M]+ calcd for C4H8O2S: 133.0197; found:
IR (ATR): 2965, 1727, 1594, 1389, 1265, 1049, 1025, 1006, 774,
667 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H), 5.26 (s, 2 H), 7.56
(s, 1 H).
133.0196.
13C NMR (75 MHz, CDCl3): d = 31.0, 44.1, 144.4, 152.3, 192.5.
Anal. Calcd for C4H7NO2S: C, 36.08; H, 5.30; N, 10.52. Found: C,
36.20; H, 5.35; N, 10.35.
HRMS (EI): m/z [M]+ calcd for C5H6N2O3S: 174.0099; found:
174.0103.
Anal. Calcd for C5H6N2O3S: C, 34.48; H, 3.42; N, 16.08; S, 18.41.
Found: C, 34.57; H, 3.49; N, 16.14; S, 18.27.
S-(Acetylamino)methyl Thioacetate (4b)
Thioacetic acid (14.3 g, 187.5 mmol) was added to acetamidometh-
anol 2b (13.4 g, 150 mmol; Fluka) in a 100 mL flask fitted with a
reflux condenser. The mixture was stirred under N2 at 40 °C. After
70 h, the mixture was treated with toluene–EtOAc (10 mL, 1:1) and
pure 4b could be isolated by column chromatography (silica gel,
toluene–EtOAc, 1:1); Rf = 0.18 (toluene–EtOAc, 1:1); yield: 14.19
g (64%); white crystals; mp 97 °C.
S-(5-Methyl-2-oxo[1,3,4]oxadiazol-3-yl)methyl Thioacetate (4g)
From 3g5 (1.691 g, 11.4 mmol). The product was purified by col-
umn chromatography (silica gel, toluene–EtOAc, 9:1); yield: 1.824
g (85%); colorless oil; Rf = 0.24 (toluene–EtOAc, 9:1).
IR (ATR): 1776, 1701, 1636, 1390, 1307, 1276, 1126, 1069, 945,
842, 742, 615 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.23 (s, 3 H), 2.39 (s, 3 H), 5.16
(s, 2 H).
13C NMR (75 MHz, CDCl3): d = 12.1, 30.5, 43.5, 152.9, 153.8,
192.3.
HRMS (EI): m/z [M]+ calcd for C6H8N2O3S: 188.0256; found:
188.0267.
IR (ATR): 3234, 3059, 1684, 1631, 1551, 1372, 1267, 1135, 1097,
1008, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.96 (s, 3 H), 2.35 (s, 3 H), 4.63
(d, J = 6.7 Hz, 2 H), 6.54 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.1, 30.8, 39.3, 170.0, 197.7.
HRMS (EI): m/z [M]+ calcd for C5H9NO2S: 147.0354; found:
147.0342.
Anal. Calcd for C6H8N2O3S: C, 38.29; H, 4.28; N, 14.88; S, 17.04.
Found: C, 38.00; H, 4.33; N, 14.96; S, 17.38.
Anal. Calcd for C5H9NO2S: C, 40.80; H, 6.16; N, 9.52. Found: C,
40.92; H, 6.17; N, 9.52.
S-(2-Oxo[1,3,4]thiadiazol-3-yl)methyl Thioacetate (4h)
From 3h (3.600 g, 24 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 15:1); yield: 3.580 g
(78%); colorless oil; Rf = 0.23 (toluene–EtOAc, 15:1).
S-(2,2,2-Trifluoroacetylamino)methyl Thioacetate (4c)
From 3c (5.86 g, 36 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 19:1); yield: 6.55 g
(99%); colorless oil; Rf = 0.17 (toluene–EtOAc, 19:1).
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IR (ATR): 3098, 1662, 1510, 1404, 1311, 1270, 1237, 1125, 962,
835, 719, 654, 614 cm–1.
1H NMR (600 MHz, CDCl3): d = 2.41 (s, 3 H), 5.43 (s, 2 H), 8.02
(s, 1 H).
13C NMR (150 MHz, CDCl3): d = 30.5, 44.6, 138.2, 168.5, 192.5.
HRMS (EI): m/z [M]+ calcd for C5H6N2O2S2: 189.9871; found:
S-(Cyclopropanecarbonylamino)methyl Thioacetate (4d)
To a suspension of 2d (502 mg, 4.36 mmol) in anhyd CHCl3 (8.7
mL) at –15 °C was added SOCl2 (317 mL, 4.36 mmol, 1.0 equiv) un-
der N2. The suspension was stirred for 50 min, until a clear solution
resulted. After short evacuation, the flask was flushed with N2. This
process was repeated for at least 20 times to remove residual SOCl2
from the reaction mixture. Solid K2CO3 (153 mg, 1.11 mmol) and
dry KSAc (548 mg, 4.80 mmol, 1.1 equiv) were added and the mix-
ture was stirred at r.t. for 18 h. After removal of the solvent in vacuo,
4d was purified by column chromatography (silica gel, toluene–
EtOAc, 4:1); yield: 310 mg (41%); white solid; mp 110 °C;
Rf = 0.22 (toluene–EtOAc, 4:1).
189.9855.
S-(5-Methyl-2-oxo[1,3,4]thiadiazol-3-yl)methyl Thioacetate (4i)
From 3i (775 mg, 4.7 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 9:1); yield: 684 mg
(71%); yellow solid; mp 65 °C; Rf = 0.24 (toluene–EtOAc, 9:1).
IR (ATR): 3270, 1687, 1645, 1536, 1400, 1355, 1224, 1133, 1112,
988, 957, 892, 828, 686, 622 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.77 (m, 2 H), 0.99 (m, 2 H), 1.32
(tt, J = 7.9, 4.6 Hz, 1 H), 2.37 (s, 3 H), 4.68 (d, J = 6.7 Hz, 2 H),
6.52 (br s, 1 H).
IR (ATR): 2999, 1698, 1680, 1570, 1405, 1335, 1259, 1200, 1135,
1103, 960, 775, 668 cm–1.
1H NMR (600 MHz, CDCl3): d = 2.39 (s, 3 H), 2.40 (s, 3 H), 5.36
(s, 2 H).
13C NMR (150 MHz, CDCl3): d = 7.8, 14.7, 30.9, 39.4, 173.4,
13C NMR (150 MHz, CDCl3): d = 18.3, 30.8, 44.6, 149.5, 170.0,
197.9.
192.8.
HRMS (EI): m/z [M]+ calcd for C7H11NO2S: 173.0510; found:
173.0527.
HRMS (EI): m/z [M]+ calcd for C6H8N2O2S2: 204.0027; found:
204.0016.
Anal. Calcd for C6H8N2O2S2: C, 35.28; H, 3.95; N, 13.71; S, 31.39.
Found: C, 35.45; H, 4.00; N, 13.70; S, 31.28.
S-Methoxymethyl Thioacetate (4k)
Chloromethyl methyl ether (3k; 15.2 mL, 200 mmol) was added at
0 °C to a suspension of KSAc (25.08 g, 220 mmol) in anhyd, dis-
tilled Et2O (100 mL) over 1 h. The mixture was stirred overnight,
filtered, and the Et2O carefully removed in vacuo. The residue was
purified by vacuum distillation (bp 55 °C/10.5 Torr) to obtain pure
4k; yield: 17.154 g (72%); colorless oil.
S-(1,1-Dioxo-1l6-isothiazolidin-2-yl)methyl Thioacetate (4j)
From 3j (1.80 g, 10.6 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 9:1); yield: 943 mg
(43%); white crystals; mp 43 °C; Rf = 0.20 (toluene–EtOAc, 9:1).
IR (ATR): 1693, 1314, 1294, 1187, 1118, 1003, 961, 879, 733, 672
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.31 (m, 2 H), 2.35 (s, 3 H), 3.04
(t, J = 7.5 Hz, 2 H), 3.24 (t, J = 6.8 Hz, 2 H), 4.70 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.7, 30.8, 44.6, 45.0, 46.7, 195.3.
HRMS (FIB): m/z [M + H]+ calcd for C6H12NO3S2: 210.0259;
IR (ATR): 2932, 1695, 1186, 1131, 1084, 934, 679 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.39 (s, 3 H), 3.31 (s, 3 H), 5.03
(s, 2 H).
13C NMR (75 MHz, CDCl3): d = 31.0, 56.99, 71.9, 194.7.
HRMS (EI): m/z [M]+ calcd for C4H8O2S: 120.0245; found:
120.0239.
found: 210.0261.
Anal. Calcd for C4H8O2S: C, 39.98; H, 6.71; S, 26.68; found: C,
39.80; H, 6.81; S, 26.52.
Anal. Calcd for C6H11NO3S2: C, 34.43; H, 5.30; N, 6.69. Found: C,
34.73; H, 5.31; N, 7.07.
Cleavage of Thioacetates 4a–c, 4e, and 4g–j General Procedure
A solution of the appropriate thioacetate in anhyd CH2Cl2 or anhyd
CHCl3 (2 mmol/mL) was treated with pyrrolidine (1.1 equiv) under
N2 at 0 °C. After 1–5 h, cleavage of the thioacetate was complete.
The solvent was removed in vacuo and the residue was purified by
column chromatography.
X-ray Crystallographic Data7
Single crystals of 4j were grown from Et2O at r.t. Empirical formula
C6H11NO3S2; T = 275(2) K; crystal system = monoclinic; Space
group P21/c; unit cell dimensions a = 10.902(2) Å, b = 8.3342(12)
Å, c = 10.7923(17) Å, a = 90°, b = 107°, g = 90°; Z = 4;
Dcalc = 1.484 g/cm3; crystal size 0.33 × 0.33 × 0.57 mm; MoKa radi-
ation; Max q for data collection 26.3°; reflections collected 1999;
independent reflections 1894 [R(int) = 0.0188]. Refinement meth-
od: full matrix least squares based on F2; 110 parameters; goodness-
of-fit on F2 1.107; Final R indices [I > 2s (I)] R1 = 0.0383, wR2 (all
data) = 0.1034; Largest diff. peak and hole 0.403 and –0.382 eÅ–3.
The hydrogen atoms were recalculated into idealized positions
(riding model).
N-Mercaptomethylformamide (5a)
From 4a (75 mg, 0.56 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 1:1); yield: 45 mg
(88%); colorless oil; mp –13 °C; Rf = 0.09 (toluene–EtOAc, 1:1).
IR (ATR): 3286, 1651, 1510, 1383, 1211, 1032, 678 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (t, J = 8.9 Hz, 1 H), 4.38 (dd,
J = 8.9, 6.6 Hz, 2 H), 6.55 (br s, 1 H), 8.15 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 33.6, 161.0.
Selected bond lengths (Å) and angles (°): N(1)–C(4) 1.440(3),
N(1)–C(3) 1.475(3), N(1)–S(1) 1.657(2), S(1)–O(1) 1.429(2), S(1)–
O(2) 1.425(2), S(2)–C(4) 1.828(2), S(2)–C(5) 1.776(2), C(5)–O(3)
1.198(3), C(5)–C(6) 1.484(3).
HRMS (EI): m/z [M]+ calcd for C2H5NOS: 91.0092; found:
91.0080.
C(4)–N(1)–C(3) 117.06(18), C(4)–N(1)–S(1) 118.1(14), O(2)–
S(1)–O(1) 117.45(13), N(1)–S(1)–C(1) 95.90(11), C(4)–S(2)–C(5)
101.74(10), O(3)–C(5)–C(6) 1.239(2), O(3)–C(5)–S(2) 123.03(18).
N-Mercaptomethylacetamide (5b)
From 4b (2.94 g, 20 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 1:1); yield: 2.05 g
(98%); colorless oil; mp –8 °C; Rf = 0.10 (toluene–EtOAc, 1:1).
C(1)–S(1)–N(1)–C(3) 15.9(2), S(1)–N(1)–C(3)–C(2) 6.7(3), C(1)–
S(1)–N(1)–C(4) –123.6(2), C(4)–S(2)–C(5)–C(6) 179.6(2), C(4)–
S(2)–C(5)–O(3) –1.0(2).
IR (ATR): 3274, 1648, 1530, 1418, 1369, 1268, 1095, 1039, 677
cm–1.
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1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3 H), 2.41 (t, J = 8.75 Hz,
1 H), 4.32 (dd, J = 8.75, 1.8 Hz, 2 H), 6.76 (br s, 1 H).
HRMS (EI): m/z [M]+ calcd for C3H4N2OS2: 147.9765; found:
147.9738.
13C NMR (75 MHz, CDCl3): d = 23.2, 35.2, 170.3.
HRMS (EI): m/z [M]+ calcd for C3H7NOS: 105.0248; found:
3-Mercaptomethyl-5-methyl-3H-[1,3,4]thiadiazol-2-one (5i)
From 4i (200 mg, 1 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 19:1); yield: 148 mg
(93%); colorless oil; Rf = 0.24 (toluene–EtOAc, 19:1).
105.0250.
Anal. Calcd for C3H7NOS: C, 34.26; H, 6.71; N, 13.32. Found: C,
34.27; H, 6.99; N, 13.36.
IR (ATR): 3019, 2924, 2554, 1666, 1565, 1410, 1332, 1271, 1198,
1012, 940, 699, 662 cm–1.
2,2,2-Trifluoro-N-mercaptomethylacetamide (5c)
From 4c (159 mg, 0.99 mmol). The product was purified by column
chromatography (silica gel, CH2Cl2); yield: 81 mg (51%); colorless
crystals; mp 46 °C; Rf = 0.36 (CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H), 2.58 (t, J = 9.1 Hz,
1 H), 4.95 (d, J = 9.1 Hz, 2 H).
13C NMR (150 MHz, CDCl3): d = 18.2, 41.6, 149.5, 169.5.
IR (ATR): 3288, 1702, 1556, 1428, 1355, 1172, 1151, 1044, 1024,
875, 694 cm–1.
HRMS (EI): m/z [M]+ calcd for C4H6N2OS2: 161.9922; found:
161.9914.
1H NMR (300 MHz, CDCl3): d = 2.52 (t, J = 9.2 Hz, 1 H), 4.45 (dd,
J = 9.2, 6.4 Hz), 6.92 (br s, 1 H).
13C NMR (150 MHz, CDCl3): d = 35.3, 115.4 (q, J = 287 Hz), 157
(q, J = 37.7 Hz).
19F NMR (282 MHz, CDCl3/CFCl3): d = –76.1.
HRMS (EI): m/z [M]+ calcd for C3H4F3NOS: 158.9966; found:
(1,1-Dioxo-1l6-isothiazolidin-2-yl)methanethiol (5j)
From with 4j (313 mg, 1.5 mmol). The product was purified by col-
umn chromatography (silica gel, CH2Cl2); yield: 206 mg (82%);
colorless oil; Rf = 0.40 (CH2Cl2).
IR (ATR): 2548, 1420, 1367, 1283, 1266, 1121, 1068, 1012, 975,
745, 665 cm–1.
1H NMR (600 MHz, CDCl3): d = 2.16 (t, J = 8.6 Hz, 1 H), 2.35 (tt,
J = 7.0 Hz, J = 7.3 Hz, 2 H), 3.02 (t, J = 7.3 Hz, 2 H), 3.41 (t, J = 7.0
Hz, 2 H), 4.32 (d, J = 8.6 Hz, 2 H).
13C NMR (150 MHz, CDCl3): d = 18.8, 42.5, 44.1, 47.2.
158.9952.
1-Mercaptomethylpyrrolidin-2-one (5e)
From 4e (260 mg); The product was purified by column chromatog-
raphy (silica gel, EtOAc); yield: 186 mg (95%); colorless oil;
Rf = 0.23 (EtOAc).
HRMS (FAB): m/z [M + H]+ calcd for C4H9N2S2: 168.0153; found:
168.0147.
IR (ATR): 2947, 2883, 2533, 1670, 1415, 1254, 1163, 1021, 969,
682 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.03 (m, 2 H), 2.11 (t, J = 8.8 Hz,
1 H), 2.34 (t, J = 8.1 Hz, 2 H), 3.47 (t, J = 7.0 Hz, 2 H), 4.39 (d,
J = 8.8 Hz, 2 H).
Anal. Calcd for C4H9NO2S2: C, 28.73; H, 5.42; N, 8.37. Found: C,
28.96; H, 5.62; N, 8.38.
N-Mercaptomethylcyclopropanecarboxamide (5d)
Under N2, thioacetate 4d (122 mg, 0.70 mmol) was dissolved in
MeOH (1 mL) at 0 °C and HCl (845 mL, 1.5 equiv, 1.25 M in
MeOH) was added. After stirring for 15 min at 0 °C, the mixture
was stirred at r.t. for 18 h. The mixture was brought to pH 5 with
NaOMe (2.0 M in MeOH) and concentrated in vacuo. The colorless
residue was extracted with CH2Cl2 (2.5 mL) and filtered. After re-
moval of the solvent in vacuo, 5d could be isolated as white crys-
tals; yield: 90 mg (97%); mp 83 °C; Rf = 0.56 (EtOAc).
13C NMR (75 MHz, CDCl3): d = 17.5, 30.9, 38.1, 45.5, 174.8.
HRMS (EI): m/z [M]+ calcd for C5H9NOS: 131.0405; found:
131.0403.
Anal. Calcd for C5H9NOS: C, 45.77; H, 6.91; N, 10.68. Found: C,
45.84; H, 7.17; N, 10.84.
3-Mercaptomethyl-5-methyl-3H-[1,3,4]oxadiazol-2-one (5g)
From 5g (500 mg, 2.7 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 9:1); yield: 345 mg
(89%); white solid; mp 50 °C; Rf = 0.29 (toluene–EtOAc, 9:1).
IR (ATR): 3261, 3072, 2550, 1636, 1542, 1400, 1227, 1105, 1034,
914, 824, 672 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.78 (m, 2 H), 1.00 (m, 2 H), 1.33
(tt, J = 7.9, 4.6 Hz, 1 H), 2.44 (t, J = 8.7, 1 H), 4.38 (dd, J = 8.7, 6.7
Hz, 2 H), 6.11 (br s, 1 H).
IR (ATR): 2575, 1760, 1630, 1414, 1378, 1304, 1279, 1134, 1072,
977, 946, 848, 721, 680 cm–1.
13C NMR (75 MHz, CDCl3): d = 7.6, 14.9, 35.3, 173.3.
HRMS (EI): m/z [M]+ calcd for C5H9NOS: 131.0405; found:
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H), 2.49 (t, J = 9.1 Hz,
1 H), 4.78 (d, J = 9.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 12.2, 40.7, 152.7, 153.9.
131.0408.
HRMS (EI): m/z [M]+ calcd for C4H6N2O2S: 146.0150; found:
146.0143.
X-ray Crystallographic Data7
Single crystals of 5d were grown from Et2O at –30 °C. Empirical
formula C5H9NOS; T = 200 K; crystal system = monoclinic; Space
group P21; unit cell dimensions a = 6.2372(6) Å, b = 4.8628(4) Å,
c = 11.0960(11) Å, a = 90°, b = 95°, g = 90°, Z = 2; Dcalc = 1.299 g/
cm3; crystal size 0.12 × 0.18 × 0.33 mm; MoKa radiation; Max q for
data collection 25.5°; reflections collected 2124; independent re-
flections 1144 [R(int) = 0.039]. Refinement method: full matrix
least squares based on F2; 73 parameters; goodness-of-fit on F2
1.05; Final R indices [I > 2s (I)] R1 = 0.0339, wR2 (all
data) = 0.0881; largest diff. peak and hole 0.18 and –0.18 eÅ–3. The
hydrogen atoms were recalculated into idealized positions (riding
model).
3-Mercaptomethyl-3H-[1,3,4]thiadiazol-2-one (5h)
From 4h (1.020 g, 5 mmol). The product was purified by column
chromatography (silica gel, toluene–EtOAc, 9:1); yield: 664 mg
(84%); colorless oil; Rf = 0.33 (toluene–EtOAc, 9:1).
IR (ATR): 3093, 2553, 1650, 1508, 1408, 1325, 1272, 1234, 997,
936, 838, 701, 649 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.62 (t, J = 9.1 Hz, 1 H), 5.02 (d,
J = 9.1 Hz, 2 H), 8.05 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 42.0, 138.3, 168.2.
Synthesis 2009, No. 3, 495–501 © Thieme Stuttgart · New York

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Novel Formaldehyde Derivatives
501
Selected bond lengths (Å) and angles (°): S–C(1) 1.805(3), S–H(1)
1.20, O–C(2) 1.232(2), N–C(2) 1.334(3), N–C(1) 1.441(3), N–H(2)
0.88, C(2)–C(3) 1.480(3), C(3)–C(4) 1.496(3), C(3)–C(5) 1.501(3),
C(4)–C(5) 1.469(3), C(3)–H(3) 1.00.
IR (ATR): 2923, 1697, 1446, 1183, 1019, 800, 648 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.97 (t, J = 9.3 Hz, 1 H), 3.37 (s,
3 H), 4.72 (d, J = 9.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.7, 69.4.
C(1)–S–H(1) 109.0, C(1)–N–C(2) 122.8(2), S–C(1)–N 113.72(17),
O–C(2)–N 122.2(2), C(4)–C(3)–C(5) 58.73(15), C(3)–C(4)–C(5)
60.82(15), C(3)–C(5)–C(4) 60.46(15).
An analytical sample could be obtained by the following method:
after neutralization, the reaction mixture was saturated with NaCl at
0 °C. An oily layer separated, which was dried (MgSO4), filtered,
and distilled (bp 51 °C/760 Torr) using a Vigreux column (10 cm)
to give pure 5k.
C(2)–N–C(1)–S –103.6(2), C(1)–N–C(2)–O –3.3(3), C(1)–N–
C(2)–C(3) 177.88(18).
GCMS (EI): m/z (%) = 78 (68, [M+]), 45 (19, [M+ – SH]).
3-Mercaptomethyl-3H-[1,3,4]oxadiazol-2-one (5f)
Under N2, thioacetate 4f (100 mg, 0.57 mmol) was treated with HCl
(1.4 mL, 3.0 equiv, 1.25 M in MeOH). After stirring for 18 h at r.t.,
the mixture was brought to pH 5 with NaOMe (2.0 M in MeOH) and
concentrated in vacuo. The residue was purified by column chroma-
Anal. Calcd for C2H6OS: C, 30.75; H, 7.74. Found: C, 30.65; H,
7.50.
tography (silica gel, toluene–EtOAc, 9:1); yield: 54 mg (72%); col- References
orless oil; Rf = 0.50 (toluene–EtOAc, 1:1).
(1) Pfaendler, H. R. US Patent 6482818, 2002; Chem. Abstr.
IR (ATR): 3164, 3104, 2921, 2559, 1756, 1574, 1372, 1289, 1264,
1162, 1094, 1014, 976, 783, 738, 710, 667, 618 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.56 (t, J = 9.2 Hz, 1 H), 4.86 (d,
J = 9.2 Hz, 2 H), 7.61 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 41.0, 143.9, 152.0.
HRMS (EI): m/z [M]+ calcd for C3H4N2O2S: 131.9994; found:
2000, 132, 137202.
(2) De Lattre, J. Chem. Zentralbl. 1912, 83, 1192.
(3) Einhorn, A.; Ladisch, C. Liebigs Ann. Chem. 1905, 343, 264.
(4) Rüfenacht, K. Helv. Chim. Acta 1972, 55, 1174.
(5) Kristinsson, H.; Winkler, T. Helv. Chim. Acta 1982, 65,
2606.
(6) Böhme, H.; Driesen, G.; Schünemann, D. Arch. Pharm.
131.9990.
(Weinheim, Ger.) 1961, 294, 344.
(7) CCDC 678213 (4b), CCDC 694690 (4i), CCDC 678214
(4j), CCDC 694363 (5d), CCDC 694364 (5g), CCDC
694362 (5h) and CCDC 694365 (5i) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk.
(8) White, E. H.; Lim, H. M. J. Org. Chem. 1987, 52, 2162.
(9) Böhme, H.; Broese, R.; Dick, A.; Eiden, F.; Schünemann, D.
Chem. Ber. 1959, 92, 1599.
Methoxymethanethiol (5k)
Thioacetic acid S-methoxymethyl ester (4k; 3.00 g, 25 mmol) was
slowly added to aq 1 M NaOH (125 mL, 125 mmol) at 0 °C. The
mixture was stirred vigorously for 1 h. The aqueous phase was
washed with CHCl3 (25 mL), brought to pH 5 with aq 5.7 M HCl
(18 mL) and thoroughly shaken with CDCl3 (25 mL). The organic
phase was dried (MgSO4), filtered, and concentrated to exactly 30
mL. The yield of thiol 5k was determined by 1H NMR spectroscopy
using 0.7 mL of the solution and 20 mL benzene as internal standard.
This solution was used directly for further reactions;1 yield: 1.73 g
(89%); colorless solution.
Synthesis 2009, No. 3, 495–501 © Thieme Stuttgart · New York