Tandem reaction of propargylic alcohol, sulfonamide, and N -iodosuccinimide: Synthesis of N -(2-Iodoinden-1-yl)arenesulfonamide

Article abstract of DOI:10.1021/ol103074d

An efficient and straightforward strategy for the synthesis of N-(2-haloinden-1-yl)arenesulfonamides from propargylic alcohols and sulfonamides is described. Allenesulfonamide is postulated to be the key intermediate for this tandem transformation.(Figure

Full text of DOI:10.1021/ol103074d

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1024–1027
Tandem Reaction of Propargylic Alcohol,
Sulfonamide, and N-Iodosuccinimide:
Synthesis of N-(2-Iodoinden-1-yl)-
arenesulfonamide
Yuanxun Zhu, Guangwei Yin, Deng Hong, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
pinglu@zju.edu.cn; orgwyg@zju.edu.cn
Received December 20, 2010
ABSTRACT
An efficient and straightforward strategy for the synthesis of N-(2-haloinden-1-yl)arenesulfonamides from propargylic alcohols and sulfonamides
is described. Allenesulfonamide is postulated to be the key intermediate for this tandem transformation.
Indenamine and indene moieties are key substructures in
both targets and building blocks for various biologically
activemolecules1 and functional materials.2 Consequently,
much attention has been paid to the synthesis of indene
derivatives,3 while synthesis of indenamines has been sel-
dom reported. In a few examples in recent literature, in-
denamine derivatives could be synthesized by intramolecular
Friedel-Crafts cyclization of β-aminoaldehyde,4 by car-
bocyclization of o-indobenzaldimine and alkyne,5 and by
annulation of N-unsubstituted aromatic ketimine and
internal alkyne.6 Herein, we report a new convenient
method for the synthesis of N-(2-haloinden-1-yl)arenesul-
fonamide from the corresponding propargylic alcohol,
sulfonamide, and NXS (X = I or Br), which was catalyzed
by BF3 Et2O.
3
In our ongoing efforts to construct the functionalized
indenes, we tested the readily available 4-methylbenzene-
sulfonamide (TsNH2) as the starting material instead of
aziridine, which we previously used.7 By screening various
Lewis acids for the reaction between 1a and 2a, such as
(1) (a) Ahn, J. H.; Shin, M. S.; Jung, S. H.; Kim, J. A.; Kim, H. M.;
Kim, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S. D.; Park, S. D.; Lee, J. M.;
Lee, J. H.; Cheon, H. G.; Kim, S. S. Bioorg. Med. Chem. Lett. 2007, 17,
5239. (b) Kim, K. R.; Lee, J. H.; Kim, S. J.; Rhee, S. D.; Jung, W. H.;
Yang, S.-D.; Kim, S. S.; Ahn, J. H.; Cheon, H. G. Biochem. Pharmacol.
2006, 72, 446. (c) Di Stefano, A.; Sozio, P.; Cacciatore, I.; Cocco, A.;
Giorgioni, G.; Costa, B.; Montali, M.; Lucacchini, A.; Martini, C.;
Spoto, G.; Di Pietrantonio, F.; Di Matteo, E.; Pinnen, F. J. Med. Chem.
2005, 48, 2646. (d) Yu, H.; Kim, I. J.; Folk, J. E.; Tian, X.; Rothman,
R. B.; Baumann, M. H.; Dersch, C. M.; Flippen-Anderson, J. L.;
Parrish, D.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2004, 47, 2624.
Yb(OTf)3,AgOTf,Sc(OTf)3,BF3 Et2O, and iodine chloride
3
(4) Katritzky, A. R.; Denisko, O. V.; Busont, S. J. Org. Chem. 2000,
65, 8066.
ꢀ
(2) (a) Barbera, J.; Rakitin, O. A.; Ros, M. B.; Torroba, T. Angew.
(5) Liu, C.-C.; Korivi, R. P.; Cheng, C.-H. Eur. J. Chem. 2008, 14,
9503.
(6) Sun, Z.-M.; Chen, S.-P.; Zhao, P. Eur. J. Chem. 2010, 16, 2619.
(7) Wang, S. Y.; Zhu, Y. X.; Wang, Y. G.; Lu, P. Org. Lett. 2009, 11,
2615.
Chem., Int. Ed. 1998, 37, 296. (b) Yang, J.; Lakshmikantham, M. V.;
Cava, M. P.; Lorcy, D.; Bethelot, J. R. J. Org. Chem. 2000, 65, 6739.
(3) (a) Chatterjee, P. N.; Roy, S. J. Org. Chem. 2010, 75, 4413. (b) Liu,
C.-R.; Yang, F.-L.; Jin, Y.-Z.; Ma, X.-T.; Cheng, D.-J.; Li, N.; Tian,
S.-K. Org. Lett. 2010, 12, 3832.
r
10.1021/ol103074d
Published on Web 01/26/2011
2011 American Chemical Society

Table 1. Screening for the Reaction Conditionsa
Table 2. Tandem Synthesis of 2-Iodoindenaminesa
entry [Iþ] source additiveb temp (°C) time 3a/4a yield (%)c
1
2
3
4
5
6
7
8
9
ICl
I2
none
none
none
H2Od
reflux 24 h
reflux 24 h
reflux 24 h
reflux 72 h
32/11
n.d./n.d.
n.d./n.d.
46/15
61/0
entry
1 (R1/R2/R3)
2 (R4)
product yield (%)b
NIS
I2
1
2
1a (C6H5/H/H)
2a (4-CH3)
3a
3b
3c
3d
3e
3f
72
76
74
73
63
58
73
53c
45c
41d
70
73
75
55c
40d
70
63
77
75
60
61
57
ICl
I2
BF3 Et2O reflux 1 h
3
1b (4-t-BuC6H4/H/H) 2a
BF3 Et2O reflux 1 h
11/0
3
3
1c (4-MeC6H4/H/H)
1d (3-MeC6H4/H/H)
1e (2-MeC6H4/H/H)
1f (4-BrC6H4/H/H)
1g (C6H5/Me/Me)
2a
2a
2a
2a
2a
NIS
NIS
NIS
BF3 Et2O reflux 1 h
72/0
3
4
BF3 Et2O reflux 2 h
71/0
3
5
BF3 Et2O reflux 40 min
62/12
68/0
3
6
10 NIS
BF3 Et2O rt
12 h
36 h
3
7
3g
3h
3i
11 NIS
BF3 Et2O
0
30/37
0/23
3
8
1h (C6H5/OMe/OMe) 2a
12 IPy2BF4
BF3 Et2O reflux 48 h
3
3
9
1i (C6H5/OMe/Cl)
2a
13 I(coll)2PF6 BF3 Et2O reflux 1 h
0/19
10
11
12
13
14
15
16
17
18
19
20
21
22
1j (C6H5/Cl/Cl)
2a
3j
1k (n-Bu/H/H)
2a
3k
3l
a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), solvent (5 mL).
b Equivalent molar to [Iþ] source. c Isolated yields refer to 2. d Water (2.5
μL) was added.
1l (H/H/H)
2a
1m (H/Me/Me)
2a
3m
3n
3o
3p
3q
3r
3s
3t
1n (H/OMe/OMe)
2a
1o (H/Cl/Cl)
2a
(ICl), we unexpectantly obtained a cyclized product (3a) in
yield of 32% when the reaction was run with ICl and
performed in the solvent of fresh CH2Cl2, redistilled from
calcium hydride. The incomplete product 4a was isolated in
yield of 11%. Structures of 3a and 4a were established by
X-ray analysis. To our delight, 3a was indeed a N-(2-iodo-
inden-1-yl)arenesulfonamide derivative rather than a sim-
ple indene. To the best of our knowledge, this is the first
example that produces 2-iodoindene by using the tandem
strategy.
1a
1a
1a
1a
1a
1a
1a
2b (2-CH3)
2c (4-H)
2d (4-OMe)
2e (4-t-Bu)
2f (4-Br)
2g (3-Br)
2h (4-Cl)
3u
3v
a Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), NIS (0.6 mmol),
BF3 Et2O (0.6 mmol). b Isolated yields refer to 2. c 4 h. d DCE, 80 °C,
12 h.
3
Exhaustive studies of the reaction conditions were
first conducted (Table 1). Each reaction was performed
with 1.2 equiv of the iodinating reagent to 2a in fresh
CH2Cl2 with a concentration of 0.1 M 2a. Besides ICl,
N-iodosuccinimide (NIS) and iodine were applied as
iodinating reagents too. In fresh CH2Cl2, iodine was not
effective even after 24 h based on the TLC tracking
(Table 1, entry 2). The propargylic alcohol (1a) remained
mostly, similar to the case of NIS (Table 1, entry 3). Liang
et al. reported that a trace amount of water could react with
I2 to generate proton in situ, which eventually converted 1a
into an allenic carbocation.8 On the basis of this considera-
tion, we tested iodine with a trace amount of water. The
reaction proceeded slowly and 3a was isolated in yield of
46% after the reaction was conducted for 72 h (Table 1,
entry 4). It is also noteworthy that various combinations of
respectively (Table 1, entries 5-7). To our delight, the
combination of BF3 OEt2 and NIS gave 3a in the highest
3
yield. Moreover, incomplete product (4a) was not observed
in all of these examples. Prolonging the reaction time to 2 h
would barely influence the yield (Table 1, entry 8), while
shortening the reaction time to 40 min would make the
reaction incomplete (Table 1, entry 9). A similar situation
was observed for the reaction temperature survey (Table 1,
entries 10 and 11). Both combination of BF3 OEt2 with
3
bis(pyridine)iodonium tetrafluoroborate (IPy2BF4) and
combination of BF3 OEt2 with bis(2,4,6-collidine)iodonium
3
hexafluorophosphate (I(coll)2PF6) were not so effective for
this transformation (Table 1, entries 12 and 13). Therefore,
we selected the combination of BF3 OEt2 and NIS as
3
the iodinating reagent and refluxed the mixture in CH2Cl2
for 1 h.
BF3 OEt2 and iodinating reagent have recently been devel-
opedforefficient iodination (Wada’s work9). Therefore, we
tried to combine BF3 OEt2 with iodine, NIS, and ICl,
3
With the optimized reaction conditions in hand, we
subsequently tested the substrate diversity for this
transformation. The results were presented in Table 2.
With different aryl groups (R1, 1a-f) occupied on the
propargylic alcohol, reactions proceeded smoothly
(Table 2, entries 1-6). When the para position of the aryl
was substituted by Br, 3f was obtained in a decreased yield
of 58% (Table 2, entry 6). In cases of entries 7-10,
3
(8) Ji, K.-G.; Zhu, H.-T.; Yang, F.; Shu, X.-Z.; Zhao, S.-C.; Liu,
X.-Y.; Shaukat, A.; Liang, Y.-M. Eur. J. Chem. 2010, 16, 6151.
(9) (a) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett.
2008, 10, 4967. (b) Okitsu, T.; Sato, K.; Wada, A. Org. Lett. 2010, 12,
3506. (c) Okitsu, T.; Nakazawa, D.; Kobayashi, A.; Mizohata, M.; In,
Y.; Ishida, T.; Wada, A. Synlett 2010, 2010, 203.
Org. Lett., Vol. 13, No. 5, 2011
1025

Scheme 1. Formation of 2-Bromoindenamines
Scheme 2. Proposed Mechanism for the Tandem Transfor-
mation
methoxy substitution (1h, 1i) decreased the yields ap-
parently in comparison with methyl substitution (1g),
while chloro substitution (1j) only afforded R-iodo-R,
β-unsaturated sulfonamide (4b) in refluxing CH2Cl2. By
raising the reaction temperature to 80 °C by changing
the solvent into dichloroethane (DCE), 3j was expec-
tantly obtained in a yield of 41%. Moreover, when the
unsymmetrical ketone derived proparglic alcohol (1i)
was used as the substrate, 3i was regioselectively gener-
ated (Table 2, entry 9). The methoxy group would
exclusively appear on the indene skeleton,10 and the
structure of 3i was verified by crystal analysis. Aliphatic
alkyne 1k also afforded the corresponding product 3k in
a yield of 70%. Terminal alkynes 1l-o gave the desired
products 3l-o, accordingly. A similar electronic effect
was observed for cases of entries 12-15. By tuning the
electron density of the arylsulfonamide part (2b-h), it
was obvious that the electron donating (2d) on the aryl-
sulfonamide would benefit the reaction (Table 2, entries
16-22).
Scheme 3. Further Elaboration of Compounds 3
This reaction protocol could also be readily applied to
the synthesis of N-(2-bromoinden-1-yl)arenesulfonamides
by simply replacing NIS with N-bromosuccinimide (NBS)
(Scheme 1). In this case, the yields were slightly lower.
On the basis of the aforementioned experiments, a
plausible mechanism is outlined in Scheme 2. Propargyl
alcohol (1a) was first converted to the allenic carboca-
tion A via a Meyer-Schuster rearrangement.11 Then, A
was trapped by 2a and the key intermediate allenesul-
fonamide B was afforded. Isolation of B was a futile
effort because of its instability. Meanwhile, in the
reaction promoted by BF3 Et2O. As evidence for this
3
proposed mechanism, 4a could be isolated when the
reaction was conducted at lower temperature (Table 1,
entry 11) or in a shorter duration (Table 1, entry 9).
More significantly, 4a could also be quantitatively con-
verted into 3a in the presence of BF3 Et2O. Conse-
3
quently, three σ-bonds were efficiently constructed in
this three-component reaction, including C-C, C-N,
and C-I covalent bonds.
Having in mind that 2,3-diarylindenamines are known
to exhibit high biological activities,14 we decided to employ
the synthesized N-(2-iodoinden-1-yl)arenesulfonamides as
precursors for introduction of an aryl substituent at the 2
position of the indene moiety by a Suzuki cross-coupling
reaction. In this way, 2,3-diarylindensulfonamides 7 were
obtained in high yields (Scheme 3).
presence of BF3 OEt2, NIS was activated to iodonium
3
species C. The internal carbon of allenesulfonamide was
electron rich because of the electron donating nature of
the nitrogen (Hsung’s review12). It reacted with active
species C in situ to afford R-iodo-R,β-unsaturated sul-
fonimide 4a.13 4a was subsequently transferred into the
final product 3a via an intramolecular Friedel-Crafts
In summary, we have developed an efficient method to
generate N-(2-iodo/bromoinden-1-yl)arenesulfonamides
through a BF3 Et2O catalyzed tandem reaction of pro-
3
(10) Zhou, X.; Zhang, H.; Xie, X.; Li, Y. J. Org. Chem. 2008, 73,
3958.
pargyl alcohol, sulfonamide, and NXS (X = I, Br). A
(11) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429.
(12) Wei, L. L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003,
36, 773.
(13) Hayashi, R.; Walton, M. C.; Hsung, R. P.; Schwab, J. H.; Yu, X.
Org. Lett. 2010, 12, 5768.
(14) (a) Anstead, G. M.; Peterson, C. S.; Pinney, K. G.; Wilson, S. R.;
Katzenellenbogen, J. A. J. Med. Chem. 1990, 33, 2726. (b) Huang, H.-C.;
Chamberlain, T. S.; Selbert, K.; Koboldt, C. M.; Isakson, P. C.; Reitz,
D. B. Bioorg. Med. Chem. Lett. 1995, 5, 2377.
1026
Org. Lett., Vol. 13, No. 5, 2011

possible mechanism for this reaction was proposed, which
involves an active allenesulfonamide intermediate. Further
research on the chemistry of allenesulfonamide is ongoing
in our laboratory.
Fundamental Research Funds for the Central Universities
(2010QNA3011) for financial support.
Supporting Information Available. Detailed experimen-
tal procedures, characterizaton data, copies of 1H, 13C NMR
spectra, and crystallographic information files (CIF) for
compounds 3a, 4a, and 3i. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Nature Science
Foundation of China (Nos. 21032005 and 20872128) and the
Org. Lett., Vol. 13, No. 5, 2011
1027