Efficient synthesis of N -(9-Xanthyl)-4-toluenesulfonamides enabled by an addition-cyclization cascade of arynes

Article abstract of DOI:10.1055/s-0032-1318311

An efficient synthesis of N-(9-xanthyl)-4-toluenesulfonamides is described in which salicyl N-tosylimines react with silylaryl triflates in the presence of CsF. This mild process involves an addition-cyclization cascade in which arynes are generated and t

Full text of DOI:10.1055/s-0032-1318311

640▌
LETTER
letter
Efficient Synthesis of N-(9-Xanthyl)-4-Toluenesulfonamides Enabled by an
Addition–Cyclization Cascade of Arynes
Addition–Cyclization Cascade of Arynes and Salicyl N-Tosylimines
Shan-Shan Lu,a,b Chong-Dao Lu*a
a
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, P. R. of China
Fax +86(991)3838708; E-mail: clu@ms.xjb.ac.cn
b
University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Received: 27.12.2012; Accepted after revision: 04.02.2013
cyclization cascade of salicyl N-tosylimines and silylaryl
Abstract: An efficient synthesis of N-(9-xanthyl)-4-toluenesulfon-
triflates in the presence of CsF.
amides is described in which salicyl N-tosylimines react with silyl-
aryl triflates in the presence of CsF. This mild process involves an
addition–cyclization cascade in which arynes are generated and
trapped in situ.
X(H)
O
X
R
Y
R
+
Key words: N-(9-xanthyl)-4-toluenesulfonamides, salicyl N-tosyl-
imines, arynes, addition–cyclization, cascade
HO
F–
A: X = O, Y = OR; Larock, ref. 5
B: X = O, Y = H; Okuma, ref. 6
Arynes are highly reactive intermediates widely used in
organic transformations to construct 1,2-disubstituted
arenes and other useful compounds containing aryl
groups.1 Ever since Kobayashi’s pioneering work on flu-
oride-mediated aryne formation from silylaryl triflates,2
these intermediates have usually been generated and cap-
tured under very mild reaction conditions. Synthetic
chemists have taken advantage of this mild protocol to
significantly extend the scope of aryne-trapping reaction
partners, leading to numerous useful methods for synthe-
sizing a variety of skeletons bearing at least one aryl
group.3
TMS
OTf
C: X = CH-EWG, Y = H; Huang, ref. 7
D: X = NTs, Y = H; this work
R
Scheme 1 Salicyl N-tosylimine, which serves as a reaction partner
of arynes
As a starting point for our studies, we used salicyl N-tosyl-
imine (2a) to trap the benzyne intermediate generated in
situ from 2-(trimethylsilyl)phenyl triflate (1a) in the pres-
ence of CsF in acetonitrile at room temperature (Table 1,
entry 1). The cascade reaction occurred smoothly and af-
forded the anticipated product N-(9-xanthyl)-4-toluene-
sulfonamide (3a) in high yield (92%).10 In this process,
the nucleophilic phenolic oxygen of 2a added to the ben-
zyne generated in situ, creating a new O–C bond and a
Aryne intermediates are usually captured using molecules
containing both electrophilic and nucleophilic sites.4 In
2006, Larock and co-workers reported an addition–cycli-
zation of arynes with salicylates to form xanthone
(Scheme 1, reaction A).5 Similar reaction pathways were
later described involving salicylaldehydes or phenols
bearing an ortho-Michael acceptor to provide, respective-
ly, 9-hydroxyxanthenes6 or 9-spiroxanthenes7 (Scheme 1,
reactions B and C). We envisaged that N-tosylimines de-
rived from salicyaldehydes would likewise react with
arynes to afford N-(9-xanthyl)-4-toluenesulfonamides
(Scheme 1, reaction D). In this reaction, the aryl carbanion
intermediate would be trapped not by the carbonyl groups
and Michael acceptor as in the examples above, but by the
azomethine group functioning as an electrophile. In this
way, the anticipated products, which are useful precursors
for benzylation,8 could be prepared more simply than
through conventional reactions involving relatively com-
plex molecules such as xanthones8 or 9-hydroxyxan-
thenes.9 Here we present our results on the facile synthesis
of N-(9-xanthyl)-4-toluenesulfonamides via an addition–
Table 1 Screening of Solvents and Sources of Fluoride Ion in the
Reaction of 1a with 2aa
NHTs
F–
NTs
TMS
OTf
solvent
r.t.
+
O
HO
2a
1a
3a
Entry
Fluoride source Solvent
Time (h) Yield (%)b
1
2
3
4
5
6
CsF
MeCN
CH2Cl2
THF
6
7
7
7
7
9
92
77
54
70
66
58
CsF
CsF
TBAF
KF
MeCN
MeCN
MeCN
TBAT
SYNLETT 2013, 24, 0640–0644
Advanced online publication: 20.02.2013
DOI: 10.1055/s-0032-1318311; Art ID: ST-2012-W1105-L
© Georg Thieme Verlag Stuttgart · New York
a Reactions were performed using 1.3 equiv of 1a, 1.0 equiv of 2a, and
2.5 equiv of fluoride source at r.t.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
b Isolated yields after silica gel chromatography.

LETTER
Addition–Cyclization Cascade of Arynes and Salicyl N-Tosylimines
641
carbanion intermediate, which underwent intramolecular Our interest in applying N-tert-butanesulfinyl imines (t-
cyclization with an imine group to furnish the product 3a. BS imines) to the asymmetric synthesis of nitrogen-con-
The yield of this aryne-based transformation was not im- taining compounds13 led us to test the feasibility of using
proved by using other commonly used solvents (CH2Cl2, t-BS imines in this addition–cyclization cascade. Similar
THF; Table 1, entries 2 and 3) or sources of fluoride ion to the results obtained with N-tosylimines 2, the t-BS im-
(TBAF, KF, TBAT; Table 1, entries 4–6). Therefore, the ine 4 derived from 4-bromo-salicyladehyde reacted with
initial reaction conditions (1.3 equiv of 1a, 1.0 equiv of 1a to give N-tert-butanesulfinyl amide 5 in 71% yield
2a, 2.5 equiv of CsF, MeCN, r.t.) were used to investigate with poor diastereoselectivity (1.4:1 dr, Scheme 2). It also
the substrate scope.
generated the O-arylation product 6 in 18% yield; this
product formed when the nucleophilic addition of the phe-
nol group to the benzyne intermediate was followed by
protonation instead of cyclization. Attempts to improve
yield using Lewis acids to activate the imine were unsuc-
cessful. In fact, adding one equivalent of Yb(OTf)3,
In(OTf)3, or Ti(Oi-Pr)3Cl to the reaction reduced the yield
to 52–56%. In addition, the Lewis acids did not affect the
diastereoselectivity.
A range of salicyl N-tosylimines 2a–i (Table 2, entries 1–
9) could participate in the reaction, providing a variety of
N-(9-xanthyl)-4-toluenesulfonamides 3 substituted at var-
ious positions on the aryl ring with electron-donating or
electron-withdrawing groups. Yields were moderate to
good (59–92%). The reaction tolerated halogen substitu-
tions (3b,d,e,g,h), allowing structurally diverse products
to be prepared.5b To test the suitability of the reaction of
1a with 2a for preparative synthesis, the reaction was
scaled up to one gram. The scaled-up reaction provided 3a
in higher yield than the microscale reaction (Table 2, entry
1, 99% vs. 92%).
O
S
NH
TMS
The substrate scope was further investigated using a vari-
ety of aryne precursors (Table 2, entries 10–13). Substitut-
ed aryl triflates 1b–d underwent addition–cyclization and
gave products in good yield (72–83%). Only one regioiso-
mer was obtained in the reaction of 3-methoxy-2-(tri-
methylsilyl)phenyl triflate (1c, Table 2, entry 11), while
low regioselectivities were obtained using aryne precur-
sors 1d (1.5:1, Table 2, entry 12) and 1e (1.5:1, Table 2,
entry 13). These different results are because the arynes
generated from 1d and 1e, unlike that derived from 1c,
lack strong steric and electronic biases.1e,12
OTf
O
Br
1a
5
CsF (2.0 equiv)
MeCN, r.t., 6 h
71% yield, 1.4:1 dr
+
O
S
+
O
N
S
N
HO
Br
O
Br
4
6 18% yield
Scheme 2 Reaction of silylphenyl triflate 1a with N-tert-butanesul-
finyl imines 4
Table 2 Synthesis of N-(9-Xanthyl)-4-Toluenesulfonamides from Salicyl N-Tosylimines and 2-(Trimethylsilyl)aryl Triflatesa
NHTs
NTs
TMS
OTf
R1
CsF
R2
R1
R2
+
O
HO
2
3
1
Entry
N-Tosylimines
Silylaryl triflates
Time (h)
Products
Yield (%)
92 (99b)
NTs
NHTs
TMS
1
2
6
OTf
O
HO
1a
2a
3a
NHTs
NTs
TMS
10
90
OTf
HO
Cl
O
Cl
1a
2b
3b
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 640–644

642
S.-S. Lu, C.-D. Lu
LETTER
Table 2 Synthesis of N-(9-Xanthyl)-4-Toluenesulfonamides from Salicyl N-Tosylimines and 2-(Trimethylsilyl)aryl Triflatesa (continued)
NHTs
NTs
TMS
OTf
R1
CsF
R2
R1
R2
+
O
HO
2
3
1
Entry
3
N-Tosylimines
Silylaryl triflates
Time (h)
12
Products
Yield (%)
84
NTs
NHTs
TMS
OTf
HO
OMe
O
OMe
1a
2c
NTs
3c
3d
3e
3f
NHTs
TMS
4
5
6
7
8
8
7
4
9
9
70
59
75
70
72
OTf
HO
Cl
Br
O
Cl
1a
2d
NTs
NHTs
TMS
OTf
HO
O
Br
1a
2e
NTs
NHTs
TMS
OTf
HO
O
1a
2f
NHTs
NTs
TMS
Cl
Br
Cl
Br
OTf
O
HO
1a
2g
NTs
3g
3h
NHTs
TMS
OTf
HO
O
1a
2h
NTs
NHTs
TMS
9
5
83
OTf
HO
O
1a
2i
3i
NTs
NHTs
O
TMS
O
O
O
O
10
11
6
9
83
88
OTf
HO
1b
2a
3j
OMe
NHTs
O
OMe
NTs
TMS
OTf
HO
1c
2a
3k
Synlett 2013, 24, 640–644
© Georg Thieme Verlag Stuttgart · New York

LETTER
Addition–Cyclization Cascade of Arynes and Salicyl N-Tosylimines
643
Table 2 Synthesis of N-(9-Xanthyl)-4-Toluenesulfonamides from Salicyl N-Tosylimines and 2-(Trimethylsilyl)aryl Triflatesa (continued)
NHTs
NTs
TMS
OTf
R1
CsF
R2
R1
R2
+
O
HO
2
3
1
Entry
N-Tosylimines
Silylaryl triflates
Time (h)
Products
Yield (%)
NHTs
O
NTs
3l
TMS
72
12
10
(3l/3l′ = 1.5:1)c
OTf
NHTs
HO
1d
2a
3l'
O
NHTs
3m
NTs
O
TMS
83
13
6
(3m/3m′ = 1.5:
NHTs
1)c
HO
OTf
2a
1e
3m'
O
a All reactions were carried out in MeCN using 1.3 equiv of 1, 1.0 equiv of 2 and 2.5 equiv of CsF at r.t.
b Reaction on 1-gram scale.
c Regioisomeric ratios were determined by 1H NMR spectroscopy; 3l′ = 3f; 3m = 3i.
Angew. Chem. Int. Ed. 2003, 42, 502. (h) Pellissier, H.;
Santelli, M. Tetrahedron 2003, 59, 701.
In summary, a new general method has been developed
that allows a wide range of N-(9-xanthyl)-4-toluenesul-
fonamides to be constructed. The process involves the in
situ generation of aryne intermediates, which then partic-
ipate in an addition–cyclization cascade with salicyl N-to-
sylimines.
(2) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211. For imidazolylsulfonate-based benzyne
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McAusland, D.; Greaney, M. F. Angew. Chem. Int. Ed. 2012,
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Okada, K.; Ohshita, J.; Takaki, K. Angew. Chem. Int. Ed.
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Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20972182 and 21172251) and the Chinese Academy
of Sciences.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2012, 77,
2279. (h) Rogness, D. C.; Markina, N. A.; Waldo, J. P.;
Larock, R. C. J. Org. Chem. 2012, 77, 2743.
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 640–644

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S.-S. Lu, C.-D. Lu
LETTER
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(10) General Procedure for the Preparation of N-(9-Xanthyl)-
4-Toluenesulfonamides Synthesized from Salicyl
N-Tosylimines and 2-(Trimethylsilyl)aryl Triflates
To a solution of salicyl N-tosylimine11 (0.38 mmol, 1.0
equiv) and triflate (0.49 mmol, 1.3 equiv) in MeCN (5 mL)
was added CsF (0.95 mmol, 2.5 equiv) in one portion. After
stirring at r.t. for the indicated time (Table 2), the reaction
mixture was poured into 10% aq Na2CO3 (5 mL). The
resulting mixture was extracted with EtOAc (3 × 5 mL). The
combined extracts were dried over Na2SO4, filtered, and
evaporated to give a crude product, which was purified by
silica gel column chromatography using elution with
EtOAc–PE to afford N-(9-xanthyl)-4-toluenesulfonamide.
The general procedure was followed using salicyl N-tosyl-
imine (2a, 105 mg, 0.38 mmol), silylaryl triflate 1a (146 mg,
0.49 mmol), and CsF (144 mg, 0.95 mmol). The reaction
mixture was stirred for 6 h and purified by silica gel
chromatography using PE–EtOAc (5:1) as eluent to give
cyclization product 3a (122 mg, 92% yield) as a white solid;
mp 196–198 °C (lit.9 mp 197–197.5 °C). 1H NMR (400
MHz, CDCl3): δ = 7.80 (d, J = 8.1 Hz, 2 H), 7.37–7.20 (m, 4
H), 7.15 (d, J = 7.8 Hz, 2 H), 7.08 (d, J = 8.2 Hz, 2 H), 6.99
(t, J = 7.5 Hz, 2 H), 5.77 (d, J = 8.6 Hz, 1 H), 4.87 (d, J = 8.6
Hz, 1 H), 2.47 (s, 3 H). 13C NMR (101 MHz, CDCl3):
δ = 151.5, 143.8, 138.8, 130.0, 129.7 (overlap, 2 C), 127.4,
123.8, 120.6, 116.9, 49.4, 21.8. ESI-HRMS: m/z calcd for
C20H17NO3SNa [M + Na]+: 374.0821; found: 374.0825. See
the Supporting Information for experimental details and
characterization data for all new compounds.
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Synlett 2013, 24, 640–644
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