O-Alkyl S-(Pyridin-2-yl)carbonothiolates: Operationally Simple and Highly Nitrogen-Selective Reagents for Alkoxy Carbonylation of Amino Groups

Article abstract of DOI:10.1055/s-0039-1690856

Amino groups are selectively protected in good yields by reaction with O-Alkyl S-(pyridin-2-yl)carbonothiolates in an appropriate solvent at room temperature in air. Even glucosamine, which contains multiple hydroxyl groups, is selectively N-protected in methanol.

Full text of DOI:10.1055/s-0039-1690856

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
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T. Suzuki et al.
Letter
Synlett
O-Alkyl S-(Pyridin-2-yl)carbonothiolates: Operationally Simple
and Highly Nitrogen-Selective Reagents for Alkoxy Carbonylation
of Amino Groups
Tomoyuki Suzuki
O
Kosaku Tanaka, III
N
S
OR
Yoshimitsu Hashimoto
Nobuyoshi Morita
Osamu Tamura*
O
PySCO2R
CH2Cl2 or CH3OH
NH2
N
OR
H
(OH)n
(OH)n
80–98%
Showa Pharmaceutical University, Higashi-tamagawagakuen,
Machida, Tokyo 194-8543, Japan
PySCO2R: PyS-Moc, PyS-Eoc, PyS-Fmoc, PyS-Troc, PyS-Teoc, PyS-Boc, PyS-Cbz
tamura@ac.shoyaku.ac.jp
Received: 09.01.2020
Accepted after revision: 26.02.2020
Published online: 13.03.2020
to reinvestigate alkoxycarbonyl compounds having a (pyri-
dine-2-yl)thio leaving group as alternatives to conventional
reagents such as chloroformates. We found that O-alkyl S-
(pyridin-2-yl)carbonothiolates are reliable and highly nitro-
gen-selective alkoxy carbonylation reagents for amino
groups, working even in methanol as a solvent.
We began by preparing O-alkyl S-(pyridin-2-yl)car-
bonothiolates 1a–g (Scheme 1): MocSPy (1a),14 EocSPy
(1b),14 FmocSPy (1c), TrocSPy (1d), and CbzSPy (1g)12,13 by
treatment of the corresponding chlorides with 2-pyridine-
thione in the presence of Et3N in CH2Cl2. We synthesized
TeocSPy (1e) and BocSPy (1f)12,13 from 2-(trimethylsi-
lyl)ethyl 3-nitro-1,2,4-triazole-1-carboxylate2b (Teoc/NT) or
di-tert-butyl dicarbonate (Boc2O), respectively, and 2-pyri-
dinethione in the presence of Et3N and a catalytic amount
of DMAP in CH3CN at room temperature. Thiolates 1a–g
were all stable and could be purified by column chromatog-
raphy. They can be stored for several months in a refrigerator.
DOI: 10.1055/s-0039-1690856; Art ID: st-2020-u0003-l
Abstract Amino groups are selectively protected in good yields by re-
action with O-alkyl S-(pyridin-2-yl)carbonothiolates in an appropriate
solvent at room temperature in air. Even glucosamine, which contains
multiple hydroxyl groups, is selectively N-protected in methanol.
Key words O-alkyl S-(pyridin-2-yl)carbonothiolates, protective group,
N-selective
Amino functionalities of biologically active natural and
unnatural compounds are generally indispensable for bio-
logical activity, and synthesis of these compounds often re-
quires adequate protection of the amino group.1 For this
reason, methods2–5 for introducing carbamate protecting
groups have been intensively investigated using different
reagents,2 catalysts,2f,3 microwave irradiation,4 and various
reaction media.5 However, in many cases, their usefulness is
limited to the Boc2e,5a,d or Fmoc4,5b,c group. On the other
hand, the (pyridin-2-yl)thio group was first introduced as a
leaving group for peptide synthesis6 and was later em-
ployed in ketone synthesis,7 macrolactonization,8 glycosyla-
tion,9 disulfide formation,10 and transition-metal-catalyzed
coupling reactions.11 O-tert-Butyl and O-benzyl S-(pyridin-
2-yl)carbonothiolates (1f and 1g) were reported by Kim’s
group as protective-group-incorporating reagents that
work in DMF.12 Quite recently we found that these com-
pounds also act as alkoxy carbonylation reagents of
Grignard reagents to give one-carbon homologated esters.13
During preparation of the thiolates,13 we found that the re-
agents were stable during chromatographic purification,
suggesting that they are inert to oxygen nucleophiles such
as water and alcohols, probably due to the softer electro-
philic nature of their carbonyl carbons resulting from the
presence of the soft sulfur atom. These results inspired us
ClCO2R or Teoc-NT, Et3N
O
CH2Cl2
N
S
N
S
OR
H
Boc2O, DMAP
Et3N, CH3CN
chromatographic purification
on silica gel
1a: R = Me (for Moc, 70%)
1b: R = Et (for Eoc, 54%)
1c: R = 9-fluorenylmethyl (for Fmoc, 96%)
1d: R = CH2CCl3 (for Troc, 81%)
1e: R = CH2CH2TMS (for Teoc, 97%)
1f: R = tBu (for Boc, 58%)
1g: R = Bn (for Cbz, 92%)
Scheme 1 Preparation of acylating reagents 1a–g
With 1a–g in hand, we examined their reactivity and
stability by using benzylamine (2) as a substrate in metha-
nol at room temperature (Table 1). In all cases, the corre-
sponding alkoxycarbonyl-protected benzylamines 3a–g
were obtained in high yields within 3 h, without any forma-
tion of double acylated compounds. The Fmoc group was
the most efficiently introduced into benzylamine (2), giving
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Suzuki et al.
Letter
Synlett
3c in 97% yield (Table 1, entry 3). It is noteworthy that even
the highly electrophilic Troc group can be incorporated into
2 in nucleophilic methanol, giving 3d in 84% yield.
pounds 7a–g in high yields. Interestingly, the reaction peri-
ods required for protection of valinol (6) were even shorter
than those for the protection of phenylalaninol (4). Again,
reagents 1d and 1g exhibited high reactivity, providing
Troc- and Cbz-protected compounds 7d and 7g in 94% and
96% yields, respectively (Table 3, entries 4 and 7).
Table 1 Reaction of Benzylamine (2) with Acylating Reagents 1a–g in
CH3OH
O
Table 3 Reaction of Valinol (6) with Acylating Reagents 1a–g in CH2Cl2
O
N
S
OR
NH2
1a–g (2 equiv)
O
N
H
OR
CH3
CH3
CH3OH, rt
N
S
OR
2
3a–g
1a–g (1.2 equiv)
H3C
OH
H3C
OH
OR
H
NH2
H HN
7a–g
Entry
R (protective group)
Time (h) Product 3 Yield (%)
CH2Cl2, rt
6
O
1
2
3
4
5
6
7
Me (Moc)
3
3a
3b
3c
3d
3e
3f
86
93
97
84
93
81
83
Et (Eoc)
3
Entry
R (protective group)
Time (h) Product 7 Yield (%)
9-fluorenylmethyl (Fmoc)
CH2CCl3 (Troc)
CH2CH2TMS (Teoc)
tert-Bu (Boc)
1
1
2
3
4
5
6
7
Me (Moc)
17
10
7a
7b
7c
7d
7e
7f
82
93
80
94
88
90
96
0.5
1.5
2.5
1
Et (Eoc)
9-fluorenylmethyl (Fmoc)
CH2CCl3 (Troc)
CH2CH2TMS (Teoc)
tert-Bu (Boc)
8.5
1.5
16
Bn (Cbz)
3g
14
6
To examine the chemoselectivity, the reactions of three
types of amino alcohols, phenylalaninol (4), valinol (6), and
prolinol (8), were conducted in CH2Cl2 at room temperature
(Tables 2–4). In the case of phenylalaninol (4), all reactions
were completed within one day to afford the N-protected
compounds 5a–g in 80–94% yields without the formation of
any O-protected compound (Table 2). The incorporation of
the Troc and Cbz groups was especially efficient, affording
5d and 5g in 89% and 94% yields, respectively.
Bn (Cbz)
7g
Finally, the secondary amino alcohol prorinol (8) was
examined (Table 4). The reaction rates with 8 were higher
than those with 4 or 6, and high yields of N-protected com-
pounds 9a–g were obtained. Once again, incorporation of
the Troc group was the fastest reaction, affording 9d in 97%
yield (Table 4, entry 4).
Table 4 Reaction of Prolinol (8) with Acylating Reagents 1a–g in CH2Cl2
Table 2 Reaction of Phenylalaninol (4) with Acylating Reagents 1a–g
in CH2Cl2
O
N
S
OR
OH
N
O
1a–g (1.2 equiv)
OH
N
CH2Cl2, rt
O
OR
N
S
OR
H
1a–g (1.2 equiv)
OH
OH
OR
8
9a–g
H
NH2
H HN
CH2Cl2, rt
4
5a–g
O
Entry
R (protective group)
Time (h) Product 9 Yield (%)
1
2
3
4
5
6
7
Me (Moc)
4
9a
9b
9c
9d
9e
9f
83
94
94
97
98
88
93
Entry
R (protective group)
Time (h) Product 5 Yield (%)
Et (Eoc)
2.5
1
1
2
3
4
5
6
7
Me (Moc)
24
24
15
3
5a
5b
5c
5d
5e
5f
83
85
80
89
87
80
94
9-fluorenylmethyl (Fmoc)
CH2CCl3 (Troc)
CH2CH2TMS (Teoc)
tert-Bu (Boc)
Et (Eoc)
0.5
1.5
3.5
1.5
9-fluorenylmethyl (Fmoc)
CH2CCl3 (Troc)
CH2CH2TMS (Teoc)
tert-Bu (Boc)
22
24
10
Bn (Cbz)
9g
Bn (Cbz)
5g
One of the features of PySCO2R 1 is high stability in the
presence of hydroxyl groups. For example, N-protection of
phenylalaninol (4) with the most electrophilic reagent
TrocSPy (1d, 1.2 equiv) in methanol at room temperature
Next, we examined a sterically demanding -branched
amino alcohol, valinol (6, Table 3). All the reactions pro-
ceeded without difficulty to afford the N-protected com-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
T. Suzuki et al.
Letter
Synlett
proceeded rapidly to give the N-protected product 5d in
97% yield within 10 min (Scheme 2).15,16 The acceleration of
this reaction compared to that in CH2Cl2 (Table 2, entry 4) is
probably due to activation of the acylating reagent by hy-
drogen bonding with methanol.5a,b,d
Funding Information
This work was supported by the Japan Society for the Promotion of
Science (JSPS KAKENHI Grant Number 17K0821 to O.T.).
J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(1
7
K
0
8
2
1)
The observed stability of the present reagents in alcohol
(Table 1 and Scheme 2) should be very useful for protecting
highly polar amines that are insoluble in conventional sol-
vents such as CH2Cl2. Furthermore, N-protection of glucos-
amine, which contains multiple hydroxyl groups, in metha-
nol was conducted to confirm the N-selectivity of reagent 1
(Scheme 3). Thus, the reaction of glucosamine hydrochlo-
ride (11) with FmocSPy (1c) in the presence of Et3N in
methanol at room temperature proceeded to generate the
N-selectively protected compound 12, which, without isola-
tion, was acetylated to afford 13 in 82% yield. Notably, com-
pound 12 exhibits self-assembly on the surface of cancer
cells.17
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690856.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References and Notes
(1) Greene’s Protective Groups in Organic Synthesis; Wuts, P. G. M.,
Ed.; John Wiley & Sons: Hoboken, 2014, Chap. 8.
(2) For a review, see: (a) Subirós-Funosas, R.; Khattab, S. N.; Nieto-
Rodríguez, L.; El-Faham, A.; Albericio, F. Aldrichimica Acta 2013,
46, 21. See also: (b) Shimizu, M.; Sodeoka, M. Org. Lett. 2007, 9,
5231. (c) Khattab, S. N.; Subiós-Funosas, R.; El-Faham, A.;
Albericio, F. Tetrahedron 2012, 68, 3056. (d) Kumar, A.; Sharma,
A.; Haimov, E.; El-Faham, A.; de la Torre, B. G.; Albericio, F. Org.
Process Res. Dev. 2017, 21, 1533. (e) Du, F.; Zhou, Q.; Fu, Y.; Zhao,
H.; Chen, Y.; Chen, G. New J. Chem. 2019, 43, 6549. (f) Dobi, Z.;
Reddy, B. N.; Renders, E.; Van Raemdonck, L.; Mensch, C.; De
Smet, G.; Chen, C.; Bheeter, C.; Sergeyev, S.; Herrebout, W. A.;
Maes, B. U. W. ChemSusChem 2019, 12, 3103.
O
N
S
OCH2CCl3
1d (1.2 equiv)
OH
OH
OCH2CCl3
H
NH2
H HN
CH3OH, rt
(3) Zeng, R.; Bao, L.; Sheng, H.; Sun, L.; Chen, M.; Feng, Y.; Zhu, M.
RSC Adv. 2016, 6, 78576.
within 10 min
4
5d
97%
O
Scheme 2 N-Selective Troc-protection of phenylglycinol (4) in methanol
(4) Godoi, M.; Botteselle, G. V.; Rafique, J.; Rocha, M. S. T.; Pena, J.
M.; Braga, A. L. Asian J. Org. Chem. 2013, 2, 746.
(5) (a) Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006, 8,
3259. (b) Gawande, M. B.; Branco, P. S. Green Chem. 2011, 13,
3355. (c) Giola, M. L.; Gagliardi, A.; Leggio, A.; Leotta, V.; Romio,
E.; Liguori, A. RSC Adv. 2015, 5, 63407. (d) Ingale, A. P.; More, V.
K.; Gangarde, U. S.; Shinde, S. V. New J. Chem. 2018, 42, 10142.
(6) For a review, see: (a) Mukaiyama, T. Angew. Chem., Int. Ed. Engl.
1976, 15, 94. See also: (b) Mukaiyama, T.; Matsueda, R.; Suzuki,
M. Tetrahedron Lett. 1970, 11, 1901. (c) Lloyd, K.; Young, G. T.
J. Chem. Soc. C 1971, 2890.
OH
Fmoc-SPy (1c)
(1.4 equiv)
OH
OH
O
HO
HO
O
HO
HO
OH
Et3N (1 equiv)
CH3OH, rt, 20 h
HN
H2N
• HCl
Fmoc
11
12
OAc
O
AcO
AcO
OAc
HN
O
(7) Mukaiyama, T.; Araki, M.; Takei, H. J. Am. Chem. Soc. 1973, 95,
4763.
Ac2O
O
pyridine
(8) (a) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
(b) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S. Jr. J. Am. Chem. Soc.
1975, 97, 653. (c) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S. Jr.
J. Am. Chem. Soc. 1975, 97, 654. (d) Barry, C. S.; Bushby, N.;
Charmant, J. P. H.; Elsworth, J. D.; Harding, J. R.; Willis, C. L.
Chem. Commun. 2005, 5097.
82% 13
(2 steps)
Scheme 3 N-Selective protection of glucosamine in methanol
(9) (a) Hanessian, S.; Conde, J. J.; Lou, B. Tetrahedron Lett. 1995, 36,
5865. (b) Hanessian, S.; Mascitti, V.; Rogel, O. J. Org. Chem. 2002,
67, 3346. (c) Hanessian, S.; Wang, X.; Ersmark, K.; Del Valle, J. R.;
Klegraf, E. Org. Lett. 2009, 11, 4232.
(10) Muguruma, K.; Shirasaka, T.; Akiyama, D.; Fukumoto, K.;
Taguchi, A.; Takayama, K.; Taniguchi, A.; Hayashi, Y. Angew.
Chem. Int. Ed. 2018, 57, 2170.
(11) (a) Kumar, V. P.; Babu, V. S.; Yahata, K.; Kishi, Y. Org. Lett. 2017,
19, 2766. (b) Ai, Y.; Ye, N.; Wang, O.; Yahata, K.; Kishi, Y. Angew.
Chem. Int. Ed. 2017, 56, 10791. (c) Yahata, K.; Ye, N.; Ai, Y.; Iso,
K.; Kishi, Y. Angew. Chem. Int. Ed. 2017, 56, 10796.
(12) Kim, S.; Lee, J. I.; Yi, K. Y. Bull. Chem. Soc. Jpn. 1985, 58, 3570.
(13) Usami, S.; Suzuki, T.; Mano, K.; Tanaka, K. III; Hashimoto, Y.;
Morita, N.; Tamura, O. Synlett 2019, 30, 1561.
In conclusion, the highly nitrogen-selective protecting
reagents PySCO2R (1a–g) are readily available and storable.
The reaction of 1 is operationally very simple, involving
only the reaction of an amine with PySCO2R reagent in an
appropriate solvent under air at room temperature. Al-
though various reagents including ROCO-OSu and ROCO-NT
for protection of amino groups have been explored, the
present method provides a new option that should be espe-
cially useful for amines with limited availability, such as
amine groups of intermediates in the late stages of natural
product synthesis.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
T. Suzuki et al.
Letter
Synlett
(14) In addition to usual abbreviations for carbamates, Moc (methy-
loxycarbonyl) and Eoc (ethyloxycarbonyl) are used in this paper.
(15) Typical Procedure
Hz), 4.03–3.91 (1 H, m), 3.75–3.64 (1 H, m), 3.63–3.51 (1 H, m),
2.89 (2 H, d, J = 6.9 Hz), 2.52–2.38 (1 H, m). 13C NMR (75 MHz,
CDCl3):  = 154.5, 137.3, 129.2, 128.6, 126.7, 95.5, 74.4, 63.4,
54.2, 37.2. HRMS (ESI): m/z calcd for C12H14Cl3NNaO3 [M + Na]+:
347.9937; found: 347.9948.
To a stirred solution of phenylalaninol (4, 53.0 mg, 0.350 mmol)
in methanol (1 mL) was added dropwise a solution of 1d (121
mg, 0.422 mmol) in methanol (1 mL). After 10 min, completion
of the reaction was confirmed by TLC. The mixture was concen-
trated in vacuo, and the residue was purified by column chro-
matography on silica gel (hexane–EtOAc, 5:1 to 2:1) to afford 5d
(111 mg, 97%). IR (KBr): 3422, 2953, 1720, 1541, 1252, 1092
cm–1. 1H NMR (300 MHz, CDCl3):  = 7.34–7.17 (5 H, m), 5.44 (1
H, br d, J = 8.4 Hz), 4.72 (1 H, d, J = 12.3 Hz), 4.66 (1 H, d, J = 12.3
(16) Under similar conditions using N-(2,2,2-trichloroethoxycarbon-
yloxy)succinimide (Troc-OSu) or 2,2-trichloroethoxycarbonyl
chloride (TrocCl), 5d was obtained 93% or 27% yield, respec-
tively.
(17) Pires, R. A.; Abul-Haija, Y. M.; Costa, D. S.; Novoa-Carballal, R.;
Reis, R. L.; Ulijn, R. V.; Pashkuleva, I. J. Am. Chem. Soc. 2015, 137,
576.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D