Deprotection of 1,3-oxathiolanes to ketones promoted by base

Article abstract of DOI:10.1016/j.tetlet.2013.02.053

A variety of 1,3-oxathiolanes can be easily converted to the corresponding ketones in good yields with LTMP in THF. This deprotection methodology shows satisfactory chemoselectivity when other protecting groups, such as dimethylketal, 1,3-dioxolane, 1,3-dithiane, and other acid-sensitive groups, are present within the same substrates.

Full text of DOI:10.1016/j.tetlet.2013.02.053

Tetrahedron Letters 54 (2013) 2217–2220
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Deprotection of 1,3-oxathiolanes to ketones promoted by base
Biao Du a, Changchun Yuan a, Langzhong Zhang a, Li Yang a, Bo Liu a,b,
⇑
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 1,3-oxathiolanes can be easily converted to the corresponding ketones in good yields with
LTMP in THF. This deprotection methodology shows satisfactory chemoselectivity when other protecting
groups, such as dimethylketal, 1,3-dioxolane, 1,3-dithiane, and other acid-sensitive groups, are present
within the same substrates.
Received 19 December 2012
Revised 30 January 2013
Accepted 19 February 2013
Available online 1 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Deprotection
1,3-Oxathiolane
Ketone
H
Protection and deprotection play important roles and are usu-
ally unavoidable in the synthesis of complex molecules. Among
the various protecting groups for carbonyl, 1,3-oxathiolane is very
useful because of its stability under mild acidic condition, in which
the O,O-acetals are often not tolerant. Accordingly, many methods
have been exploited for the deprotection of 1,3-oxathiolanes. These
usual reagents include Lewis acids,1 oxidants,2 and those resulting
in sulfonium intermediates,3 such as NBS,3a–c I2–AgNO2,3d,3e and
Bi(NO3)3.3h Moreover, other special reagents4–10 proved effective
for this deprotection as well, including Raney nickel,4 Chloran-
mine-T,5 BSP/Tf2O,6 HgO,7 and benzyne.8 However, to the best of
our knowledge, deprotection of 1,3-oxathiolane solely with base
has never been explored.
B
O
Base
A
B
O
R1
O
R2
O
R1
O
R2
O-
R1
R2
O
H
B
B
a
O
R1
S
S-
R1
R1
R2
H2S
R2
Base
S
R1
O
R2
H
H2O
S
b
S
R1
O
O-
R2
R2
We have previously reported an interesting base-promoted
deprotection of 1,3-dioxolanes (Scheme 1A),11 adventitiously dis-
covered during the total synthesis of lindenane-type sesquiterpe-
noids.12 In view of reaction mechanism, we anticipated that
treating 1,3-oxathiolanes with base should potentially provide
Scheme 1.
À78 °C (entry 5). However, inferior yields were obtained when
we attempted n-butyl lithium, s-butyl lithium, and t-butyl lithium
(entries 6–8). To probe the possibility of further optimization, we
studied deprotection in different solvents. Interestingly, in the
ethereal solvents other than THF, the reaction proceeded sluggish
even at 0 °C, as was the situation in toluene (entries 9–12). Finally,
we achieved 84% yields with 5.0 equiv of LTMP in THF, while a low-
er yield was obtained with a less amount of base even at higher
reaction temperatures (entries 13–14).
Based on the above optimization, we investigated the sub-
strate scope for this reaction with 5.0 equiv of LTMP in THF.
The results are summarized in Table 2. First, aromatic substrates
with a different para-substituent were screened, showing that
both electron-donating and electron-withdrawing groups are tol-
erable (entries 2–4). Similarly, the ortho-substituted bromide also
the corresponding ketones via either path
a or path b
(Scheme 1B). Herein we present our results on this deprotection
with lithium 2,2,6,6-tetramethylpiperidide (LTMP).
Initially, 1,3-oxathiolane of a-tetralone (1a) was selected as the
test substrate and treated with various bases in THF (Table 1, en-
tries 1–8). Although potassium tert-butoxide and potassium and
lithium bis(trimethylsilyl)amides proved ineffective to deprotect
1a even at 0 °C (entries 1–3), lithium diisopropylamide (LDA) led
to a satisfactory 61% yield as a stronger base (entry 4). To our de-
light, LTMP behaved as the optimal base, affording 79% yield at
⇑
Corresponding author. Tel./fax: +86 28 8541 3712.
E-mail address: chembliu@scu.edu.cn (B. Liu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.053

2218
B. Du et al. / Tetrahedron Letters 54 (2013) 2217–2220
Table 1
Optimization of the reaction conditiona
O
n
HO Bu
O
S
Base (4.0 equiv.)
Solvent
2a
3
1a
Entry
Solvent
Base
Temperature (°C)
Yield of 2ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
THF
THF
THF
THF
THF
THF
THF
THF
DME
t-BuOMe
Et2O
Toluene
THF
t-BuOK
KHMDS
LHMDS
LDA
À78 to 0
À78 to 0
À78 to 0
À78
NRc
NR
NR
61
79
14d
59
25
15
29
25
14
84
69
LTMP
n-BuLi
s-BuLi
t-BuLi
LTMP
LTMP
LTMP
LTMP
LTMPe
LTMPf
À78
À78
À78
À78
À78 to 0
À78 to 0
À78 to 0
À78 to 0
À78
THF
À78 to rt
a
Unless otherwise specified, the reaction was carried out with 1a (0.5 mmol) and the corresponding base
(2.0 mmol) in solvent (4 mL) under argon atmosphere.
b
Isolated yields.
NR = no reaction.
By-product 3 formed in 58% yield.
2.5 mmol of LTMP was used.
c
d
e
f
1.5 mmol of LTMP was used.
Table 2
Deprotection of 1,3-oxathiolane of ketones
O
O
S
R
LTMP (5.0 equiv.)
THF
R
R
R
1
2
1
2
a
1a-l
2a-l
Entry
1
Starting materialb
Temperature (°C)
À78
Product
Yieldc (%)
84
O
S
O
1a
1b
2a
2b
O
S
O
2
3
À78
À78
77
79
O
S
S
O
1c
2c
O
O
O
O
4
5
1d
1e
À78
À78
2d
2e
81
74
Br
Br
O
S
O
Br
Br
S
O
O
6
1f
À78
2f
88

B. Du et al. / Tetrahedron Letters 54 (2013) 2217–2220
2219
Table 2 (continued)
Entry
Starting materialb
Temperature (°C)
À78
Product
Yieldc (%)
O
S
O
7
8
9
1g
1h
1i
2g
2h
2i
89
72
86
O
S
O
À78
À78
O
OH
O
OH
S
O
S
O
10
11
1j
À30
À30
0
2j
82
86
76
O
S
O
CH
3
1k
1l
2k
2l
H3C(H2C)7H2C
O
CH3
H C(H C) H C
3
2
7
2
S
O
12
a
Unless otherwise specified, the reaction was carried out with 1 (0.5 mmol) and LTMP (2.5 mmol) in THF (4 mL) under argon atmosphere. The reaction time is not more
than 5 h (see Supplementary data).
b
All starting materials were prepared in the presence of trimethyl orthoformate and a catalytic amount of tetrabutylammonium tribromide (TBATB) in 2-mercaptoethanol.
Isolated yields.
c
furnished satisfactory yield (entry 5). When extending the benzyl
to the - or b-substitutednaphthyl, the corresponding ketones are
obtained smoothly as well, although compound 1h afforded a
lower yield probably due to the bulkiness of isopropyl group (en-
tries 6–8). Notably, compound 1i provided b-hydroxyl ketone 2i
very cleanly in the typical condition (entry 9), which is
potentially unstable in the alkaline environment. As for aliphatic
substrates, the reactions went well along at elevated tempera-
tures (entries 10–12), manifesting the wide scope of this
deprotection.
a
Table 3
Chemoselective deprotection of 1,3-oxathiolanea
Entry
1
Starting material
Temperature (°C)
Product
Yieldb (%)
72
O
S
S
S
O
O
O
4a
4b
4c
0
5a
5b
5c
OMOM
OMOM
O
O
2
3
0
75
72
OTBS
O
OTBS
O
À30
O
S
O
S
O
O
S
S
O
O
4
5
4d
4e
0
0
5d
5e
76
74
S
S
O
O
O
O
a
The reaction was carried out with 4 (0.5 mmol) and LTMP (2.5 mmol) in THF (4 mL) under argon atmosphere.
Isolated yields.
b

2220
B. Du et al. / Tetrahedron Letters 54 (2013) 2217–2220
Li
Acknowledgments
O-Li+
O
S
We appreciate the financial support from NSFC (21021001,
excess LTMP
S-Li+
21172154, J1103315), National Basic Research Program of China
(973 program, 2010CB833200) and Sichuan University
(2011SCU04B33).
C5H11
C5H11
Supplementary data
LTMP
O
TBDPSCl
Supplementary data (characterization data for new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.02.053.
O
OSiPh2tBu
S
(1) LTMP (5.0 equiv.)
THF, 0 oC
SSiPh2tBu
(2) TBDPSCl
(5.0 equiv.)
References and notes
C5H11
C5H11
C5H11
1. (a) Ballini, R.; Bosica, G.; Maggi, R.; Mazzacani, A.; Righi, P.; Sartori, G. Synthesis
2001, 12, 1826–1829; (b) Shirini, F.; Sadeghzadeh, P.; Abedini, M. Chin. Chem.
Lett. 2009, 20, 1457–1460; (c) Chavan, S. P.; Soni, P.; Kamat, S. K. Synlett 2001,
1251–1252; (d) Mondal, E.; Sahu, P. R.; Bose, G.; Khan, A. T. Tetrahedron Lett.
2002, 43, 2843–2846; (e) Ravindranathan, T.; Chavan, S. P.; Varghese, J. P.;
Dantale, S. W.; Tejwani, R. B. J. Chem. Soc., Chem. Commun. 1994, 1937–1938; (f)
Ravindranathan, T.; Chavan, S. P.; Awachat, M. M. Tetrahedron Lett. 1994, 35,
8835–8838; (g) Mondal, E.; Bose, G.; Khan, A. T. Synlett 2001, 785–786; (h)
Ravindranathan, T.; Chavan, S. P.; Dantale, S. W. Tetrahedron Lett. 1995, 36,
2285–2288; (i) Yadav, J. S.; Reddy, B. V. S.; Raghavendra, S.; Satyanarayana, M.
Tetrahedron Lett. 2002, 43, 4679–4681; (j) Shirini, F.; Abedini, M.; Ghasemi, M.;
Sakhaei, A. R. Bull. Korean Chem. Soc. 2009, 30, 2479–2480.
2. (a) Reddy, M. S.; Narender, M.; Mahesh, A.; Nageswar, Y. V. D.; Rao, K. R. Synth.
Commun. 2006, 36, 3771–3775; (b) Kirihara, M.; Ochiai, Y.; Arai, N.; Takizawa,
S.; Momose, T.; Nemoto, H. Tetrahedron Lett. 1999, 40, 9055–9057; (c) Mondal,
E.; Sahu, P. R.; Khan, A. T. Synlett 2002, 463–467; (d) Chavan, S. P.; Dantale, S.
W.; Pasupathy, K.; Tejwani, R. B.; Kamat, S. K.; Ravindranathan, T. Green Chem.
2002, 4, 337–338; (e) Mondal, E.; Sahu, P. R.; Bose, G.; Khan, A. T. J. Chem. Soc.,
Perkin Trans. 1 2002, 1026–1028; (f) Khan, A. T.; Mondal, E.; Sahu, P. R. Synlett
2003, 377–381.
3. (a) Iranpoor, N.; Firouzabadi, H.; Shaterian, R. H. Tetrahedron Lett. 2003, 44,
4769–4773; (b) Karimi, B.; Seradj, H.; Tabaei, M. H. Synlett 2000, 1798–1800;
(c) Shaterian, H. R.; Hadadzadeh, H. Phosphorus, Sulfur Silicon 2006, 181, 1059–
1071; (d) Nishide, K.; Nakamura, D.; Yokota, K.; Sumiya, T.; Node, M.
Heterocycles 1997, 44, 393–404; (e) Nishide, K.; Yokota, K.; Nakamura, D.;
Sumiya, T.; Node, M. Tetrahedron Lett. 1993, 34, 3425–3428; (f) Perrier, H.;
Huyer, G.; Young, R. N. Tetrahedron Lett. 1992, 33, 725–728; (g) Lynch, J. E.;
Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943–2948; (h) Komatsu, N.; Taniguchi,
A.; Wada, S.; Suzuki, H. Adv. Synth. Catal. 2001, 343, 475–480; (j) Fuji, K.;
Ichikawa, K.; Fujita, E. Tetrahedron Lett. 1978, 38, 3561–3562; (k) Wilson, G. E.,
Jr.; Huang, M. g. J. Org. Chem. 1976, 41, 966–968; (l) Rohman, Md. R.;
Rajbangshi, M.; Laloo, B. M.; Sahu, P. R.; Myrboh, B. Tetrahedron Lett. 2010, 51,
2862–2864; (m) Chen, L.; Wang, H. Org. Prep. Proced. Int. 1999, 31, 562–564.
4. Djerassi, C.; Shamma, M.; Kan, T. Y. J. Am. Chem. Soc. 1958, 80, 4723–4732.
5. Emerson, D. W. Tetrahedron Lett. 1971, 37, 3445–3448.
1m
2m, 64% 6, 14%
7, 86%
Scheme 2. Trapping experiment.
Chemoselectivity is crucial for the applicability of a protection
or deprotection strategy. Thus, to illustrate the selectivity of our
methodology, we prepared and examined several compounds
embracing other functional groups coexisting with 1,3-oxathiolane
(Table 3). In the presence of MOM ether and TBS ether, 1,3-oxathio-
lane could be selectively converted to the ketone (entries 1 and 2).
Dimethyl ketal and 1,3-dithiane showed also their stability under
the condition (entries 3 and 4). Importantly, even the chemo-selec-
tivity between 1,3-dioxolane and 1,3-oxathiolane could be realized
due to the difference of their deprotection rates (entry 5). It is
worth noting that those selectivities cannot be implemented in
the presence of acid (for compounds 4a–c, 4e) or mercury salt or
oxidants (for compound 4d).
The deprotection of 1,3-oxathiolane can be initiated from the
deprotonation at either S-attached carbon or O-attached carbon
(path a or path b, Scheme 1B). Considering that the reactions with
1,3-oxathiolanes are generally faster than those with 1,3-dioxalane
even at lower temperatures, we prefer a mechanism through the
path of a sulfur-stabilizing anion, which results in the decomposi-
tion or 1,3-oxathiolane. To testify our assumption, a trapping
experiment was conducted. After compound 1m was treated with
LTMP, TBDPSCl was added to trap the intermediates, resulting in
the formation of compounds 6 and 7, which supports our prelimin-
6. Crich, D.; Picione, J. Synlett 2003, 1257–1258.
7. Degani, I.; Fochi, R.; Regondi, V. Synthesis 1981, 51–53.
8. Nakayama, J.; Sugiura, H.; Shiotsuki, A.; Hoshino, M. Tetrahedron Lett. 1985, 26,
2195–2198.
9. Ghorbani-Vaghei, R.; Khazaei, A. Phosphorus, Sulfur Silicon 2004, 179, 1787–
1791.
10. Yeung, L. L.; Yip, Y. C.; Luh, T. Y. J. Org. Chem. 1990, 55, 1874–1881.
11. Yuan, C.; Yang, L.; Yue, G.; Yu, T.; Zhong, W.; Liu, B. Tetrahedron Lett. 2012, 53,
6972–6976.
12. (a) Yue, G.; Yang, L.; Yuan, C.; Jiang, X.; Liu, B. Org. Lett. 2011, 13, 5406–5408;
(b) Yue, G.; Yang, L.; Yuan, C.; Du, B. Tetrahedron 2012, 68, 9624–9637.
ary mechanistic suppose (Scheme 2)11
.
In general, we have developed an effective methodology for
deprotecting various 1,3-oxathiolanes to the corresponding ke-
tones, showing admirable chemoselectivity in the presence of dim-
ethylketal, 1,3-dioxolane, 1,3-dithiane, and other acid-labile
protecting groups. We believe it would get potentially a wide
application in organic synthesis.