One-step synthesis and isolation of N-(tert-butoxycarbonyl)-N′- methylthiourea on a large scale

Article abstract of DOI:10.1080/00397910802238700

Simple preparation and isolation of N-(tert-butoxycarbonyl)-N′- methylthiourea on a large scale are described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802238700

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One-Step Synthesis and
Isolation of N-(tert-
Butoxycarbonyl)-N′-
methylthiourea on a Large
Scale
Teresa Andreani a , Yan Jin a , Jianshe Kong a , Xian
Liang a , Tao Meng a & Jesse K. Wong a
a Schering-Plough Research Institute , Kenilworth,
New Jersey, USA
Published online: 14 Oct 2008.
To cite this article: Teresa Andreani , Yan Jin , Jianshe Kong , Xian Liang , Tao Meng &
Jesse K. Wong (2008) One-Step Synthesis and Isolation of N-(tert-Butoxycarbonyl)-N′-
methylthiourea on a Large Scale, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:21, 3834-3839, DOI:
10.1080/00397910802238700
To link to this article: http://dx.doi.org/10.1080/00397910802238700
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Synthetic Communications1, 38: 3834–3839, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802238700
One-Step Synthesis and Isolation
of N-(tert-Butoxycarbonyl)-N0-methylthiourea
on a Large Scale
Teresa Andreani, Yan Jin, Jianshe Kong, Xian Liang,
Tao Meng, and Jesse K. Wong
Schering-Plough Research Institute, Kenilworth, New Jersey, USA
Abstract: Simple preparation and isolation of N-(tert-butoxycarbonyl)-N0-
methylthiourea on a large scale are described.
Keywords: 1,5-Dimethy-4,6-dithioxo-[1,3,5]-triazinan-2-one, guanidine, methyl
isothiocyanate, N-methyl-thiourea, tert-butyl carbamate
INTRODUCTION
Recently a large quantity of N-(tert-butoxycarbonyl)-N0-methylthiourea
(2) was required for preparation of a cyclic guanidine compound for
our ongoing project. Guanidines can be prepared in many ways as
described in a communication by Poss et al.[1] He also described how
compound 2 could be prepared in two ways. However, the exact prepara-
tion and isolation of 2 was not detailed. In this article, we describe a
one-step synthesis and isolation of a large quantity of this material. We
also characterized the major unavoidable impurity, which was removed
without chromatography separation.
Received January 29, 2008.
Address correspondence to Jesse K. Wong, Schering-Plough Research
Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. E-mail: jesse.
wong@spcorp.com
3834

N-(tert-Butoxycarbonyl)-N0-methylthiourea
3835
Scheme 1. NaH, THF, Boc2O.
RESULTS AND DISCUSSION
According to Poss et al.,[1] N-propyl-thiourea can be acylated (Boc2O,
NaH, tetrahydrofuran [THF]) to give the desired N-(tert-butoxycarbo-
nyl)-N0-propylthiourea in 95% yield. However, when we tried to acylate[2]
N-methyl-thiourea 1 with Boc2O in the presence of NaH in THF, an
inseparable mixture containing minor amounts desired product 2
(Scheme 1) was obtained. This method was abandoned. [Note: We used
2 equivalents of NaH to acylate N-propyl-thiourea with Boc2O in THF
to obtain 93% of N-(tert-butoxycarbonyl)-N0-propylthiourea: The experi-
ments were performed using 1 or 2 equivalents of NaH: To a slurry of
NaH in THF at 0 ꢀC was added 1 eq. of methyl-thiourea in THF. After
stirring for 30 min at 0 ꢀC, 1 eq. of Boc2O in THF was added. The reac-
tion was stirred at rt overnight. After usual workup, a complex mixture
were found. Compound 1 was bought from Acros or can be prepared
1
in two steps as described by Poss et al.[1] LC-MS and H NMR analyses
found the inseparable mixture to be a mixture of acylated thioureas,
NHBoc2, MeNHBoc, and desired product 2].
The other method Poss described was a reaction of benzyl isothiocya-
nate and tert-butyl carbamate 4 in the presence of NaH in THF to give
N-(tert-butoxycarbonyl)-N0-benzylthiourea in 43% yield. We used methyl
isothiocyanate 3 to react with tert-butyl carbamate 4 in the presence of
NaH (1.1 eq.) in THF. We found this method provided predominately
a mixture of product 2 and by-product 1,5-dimethy-4,6-dithioxo-
[1,3,5]triazinan-2-one 5 in a ratio of 3:1 (Scheme 2). (The reaction was
acidified with saturated aqueous citric acid, and then extracted with
Scheme 2. NaH, THF, 0 deg. to rt.

3836
T. Andreani et al.
Scheme 3. NaH, THF, 0 deg. to rt.
EtOAc. The ratio was measured by 1H NMR of the corresponding
methyl peaks).
The by-product 5 occurred during the reaction because product 2
competed with tert-butyl carbamate 4 for the electrophile 3 under the
reaction conditions. This theory was validated by reacting 2 with methyl
isothiocyanate 3 in the presence of NaH (1.1 eq.) in THF to give 73%
isolated yield of 5 (Scheme 3). [Compound 5 (2.9 g) was also obtained
by extraction with EtOAc (1 ꢁ 300 mL, 1 ꢁ 100 mL) from the acidified
aqueous phase in a 10-g-scale reaction as describled in method B].
The identification of triazine 5 as the major by-product explained the
moderate yield of desired product 2. Similar substituted triazine 2,4-
dithiones can also be prepared according to the method of Joshua et al.[3]
Our first method (method A) in large synthesis of 2 was described
previously. After an SiO2 column separation, product 2 was isolated in
46% yield. This method requires a large amount of solvents and a large
column separation. THF [(11 L) was used for 400 g of 4, 250 g of 3,
and 210 g of NaH (60%)].
The second method (method B) is more efficient than the first one.
We replaced THF with DMF and the amount of solvent was reduced
by >65% (from 11 L to 3.5 L). DMF (3.5 L) was used for the same
amount of chemicals. Column separation was eliminated after we found
out that the triazine 5 was soluble in NaOH solution. Thus product 2 was
directly extracted with diethylether in 51% yield from the reaction mix-
ture after quenching with ice=water.
Our preferred method (method C) is to use 2 equivalents of NaH
instead of 1, and compounds 3 and 4 have to be added together to a
slurry of NaH in DMF at 0 ꢀC. Either tert-butyl methyl ether or diethyl
ether can be used for extraction. Using this variation, 58% of desired
compound 2 was isolated. The extra equivalent of NaH increased the
yield from 51 to 58%. A small-scale reaction (4 g of 4) was run using
method C and afforded 68% yield of 2. It appears that the formation
of di-anion 2 reacts with 3 slower than the mono-anion. Unfortunately,
we were unable to increase the yield further regardless of changing
temperature, inverse addition of NaH, using potassium tert-butoxide

N-(tert-Butoxycarbonyl)-N0-methylthiourea
3837
instead of NaH, adding tert-butyl carbamate 4 first and then methyl iso-
thiocyanate 3, or adding both 3 and 4 together to a slurry of NaH in THF
at 0 ꢀC. An attempt to generate the anion of NH2Boc with NaH in DMF
at room temperature for an hour first, following addition of methyl iso-
thiocyanate 3, provided minor product 2.
CONCLUSION
A simple preparation and isolation of N-(tert-butoxycarbonyl)-N0-
methylthiourea 2 in a large quantity was developed for the first time in
moderate yield. By using this method, a many similar substituted thiour-
eas can be prepared easily. Further elaboration of substituted thioureas
can lead to substituted guanidines.[1] The triazine impurity, like com-
pound 5, can be removed by basic aqueous washing.
EXPERIMENTAL
Starting materials, reagents, and solvents were purchased from commer-
cial suppliers and used without further purification. Melting points were
determined with a MELT-TEMP instrument from Electrothermal. Col-
umn chromatography was performed on silica gel, 230–400 mesh. Chemi-
cal shifts (d) are reported in parts per million. All 1H NMRs were
recorded with Varian 400-MHz spectrometer with solvents indicated.
Mass spectra were obtained either from Waters-ZQ mass spectrometer
or JUL Mstation magnetic factor mass spectrometer. Elemental analyses
were performed by QTI Technologies Inc., Whitehouse, New Jersey.
Preparation of N-(tert-Butoxycarbonyl)-N0-methylthiourea 2
Method A
To a cold (2 ꢀC) stirred suspension of 60% NaH (210 g, 5.3 mol, 1.55 eq.)
in mineral oil in anhydrous THF (8 L) in a 22-L, three-neck, round-bot-
tom flask under N2 atmosphere, a solution of NH2Boc 4 (400 g, 3.4 mol,
1.0 eq.) in THF (2 L) was added over 20 min. After stirring for 30 min,
methyl isothiocyanate 3 (250 g, 3.4 mol, 1.0 eq.) in THF (1) was added
over 20 min, keeping the temperature colder than 5 ꢀC. The bath was
removed, and the reaction was stirred overnight (ꢂ18 h) while warming
up to room temperature. The reaction was chilled to 10 ꢀC and acidified
by pouring it in to a stirred solution of 10% citric acid (5 L). THF was

3838
T. Andreani et al.
removed under reduced pressure, and the residue was extracted with
EtOAc (2 ꢁ 6 L, 1 ꢁ 4 L). The combined organic phase was washed with
brine (2 ꢁ 1 L), dried over MgSO4, and then concentrated to give a crude
product, which was chromatographed on an SiO2 column, using 10 to
15% EtOAc in hexane to give compound 2 (296 g, 46%) as a white solid:
mp 97–99 ꢀC; 1H NMR (CDCl3) d 9.7 (s, br. 1 H), 7.9 (s, br. 1 H), 3.1 (d,
J ¼ 4.4 Hz, 3 H), 1.4 (s, 9 H). Anal. calc. for C7H14N2O2S: C, 44.19; H,
7.42; N, 14.72; S, 16.85. Found: C, 44.32; H, 7.41; N, 14.52; S, 16.95.
Method B
To a cold (2 ꢀC) stirred suspension of NaH (60% in mineral oil, 155 g,
3.8 mol, 1.1 eq.) in DMF (2.5 L) in a 12-L, three-neck, round-bottom
flask under an N2 atmosphere, a solution of NH2Boc (400 g, 3.4 mol,
1.0 eq) and methyl isothiocyanate (246 g, 3.4 mol, 1.0 eq.) in DMF
(1.0 L) was added in 2.05 h, keeping temperature colder than 5 ꢀC. After
complete addition, the bath was removed and, reaction was stirred over-
night while warming it to room temperature. The reaction mixture was
poured into a stirred mixture of ice (2 kg) and water (12 L) and extracted
with Et2O (2 ꢁ 10 L, 1 ꢁ 5 L, and 1 ꢁ 3 L). The combined Et2O layers
were dried over MgSO4 and then filtered. Solvents were removed under
reduced pressure until solids started to precipitate. Hexane (800 mL)
was added, chilled in ice bath, and stirred vigorously. A white solid
was collected by filtration to give 2 (332 g, 51%).
Method C
To a cold (0 ꢀC) stirred suspension of NaH (60% in mineral oil), 315 g,
7.8 mol, 2.3 eq.) in DMF (2.4 L) in a 12-L, three-neck, round-bottom
flask under N2 atmosphere, a solution of NH2Boc (400 g, 3.4 mol, 1.0
eq) and methyl isothiocyanate (246 g, 3.4 mol, 1.0 eq.) in DMF (1.1 L)
was added in 1 h, keeping the temperature between ꢃ2 to 2 ꢀC. After
complete addition, the reaction was stirred overnight while warming it
to room temperature. The reaction mixture was poured into a stirred
mixture of ice (2 kg) and water (12 L) and extracted with TBME
(5 ꢁ 6L). The combined tert-butyl methyl ether (TBME) extracts were
washed with brine (1 ꢁ 10L, 1 ꢁ 5L), dried over MgSO4, and then filtered.
Solvents were removed under reduced pressure. The precipitate was tritu-
rated with pentane (500 mL), chilled in ice bath, and stirred vigorously.
White solids were filtered to give 2 (379 g, 58 %).

N-(tert-Butoxycarbonyl)-N0-methylthiourea
3839
Preparation of 1,5-Dimethy-4,6-dithioxo-[1,3,5]triazinan-2-one 5
To a cold (2 ꢀC) stirred suspension of NaH (60% in mineral oil, 3.87 g,
97 mmol, 1.8 eq.) in anhydrous THF (200 mL), a solution of 2 (10.2 g,
54 mmol, 1.0 eq.) and 3 (8.4 g, 87 mmol, 1.6 eq.) in THF (80 mL) was
added over 50 min. The temperature rose to 5.3 ꢀC. The reaction was stir-
red at room temperature overnight. The reaction was chilled, and ice
(100 g) was added. It was acidified to pH 3 with saturated citric acid.
The precipitated solids were collected by filtration, washed with water,
and dried over P2O5 in vaccum oven at rt to give 5 (7.4 g, 73%) as a light
yellow solid: mp 179–181 ꢀC; 1H NMR (CDCl3) d 9.9 (s, br. 1 H), 4.1 (s, 3
H), 3.7 (s, 3 H); 13C NMR (CDCl3) 177, 174, 43, 36; MS: 190 (M þ þ H,
80%). Anal. calc. for C5H7N3S2O: C, 31.73; H, 3.73; N, 22.20; S, 33.88.
Found: C, 31.90; H, 3.61; N, 21.80; S, 34.30.
ACKNOWLEDGMENT
We thank Alexei Buevich, T. M. Chan, L.-K. Zhang, and Rebecca
Osterman for spectroscopic analyses, Dr. McNamara for advice and
support, and H. Yun for library research.
REFERENCES
1. Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. A mild and efficient
method for the preparation of guanidines. Tetrahedron Lett. 1992, 33, 5933–5936.
2. Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Preparation of N-tert-butoxycar-
bonylthiourea opens the way to protected 2-aminothiazoles. Synth. Commun.
2002, 32(11), 1671–1674.
3. Joshua, C. P.; Thomas, S. K. Synthesis of 1,3,-trisubstituted 6-substituted imi-
nohexahydro-1,3,5-triazine-2,4-dithiones—A new approach from thioureas.
Synthesis 1982, 1070–1971.