Facile preparation of indoles and 1,2-benzothiazine 1,1-dioxides: Nucleophilic addition of sulfonamides to bromoacetylenes and subsequent palladium-catalyzed cyclization

Article abstract of DOI:10.1002/anie.201201024

Bromine as a double agent: The bromine atom in 1-bromo-1-alkynes works as an electron-withdrawing group to effect the nucleophilic addition of sulfonamides. It again plays a pivotal role in the palladium-catalyzed cyclization of the resultant (Z)-2-(sulfonylamino)-1-bromoalkenes into nitrogen heterocycles (see scheme). Copyright

Full text of DOI:10.1002/anie.201201024

Angewandte
Chemie
DOI: 10.1002/anie.201201024
Heterocycles
Facile Preparation of Indoles and 1,2-Benzothiazine 1,1-Dioxides:
Nucleophilic Addition of Sulfonamides to Bromoacetylenes and
Subsequent Palladium-Catalyzed Cyclization**
Masahito Yamagishi, Ken Nishigai, Azusa Ishii, Takeshi Hata, and Hirokazu Urabe*
Nucleophilic addition to an electron-deficient carbon–carbon
multiple bond is one of the most fundamental reactions in
organic chemistry.[1] Among the various electron-withdrawing
groups adjacent to an olefin or acetylene, thus making this
process feasible, the weakest possible substituents, such as
halogens, have recently attracted increasing attention.[2–7] We
have already reported that certain nitrogen-containing com-
pounds such as N-alkylsulfonamides,[8] imidazolines, or imid-
azoles undergo nucleophilic addition to 1-halo-1-alkynes.[5d,e]
Furthermore, the synthetic utility of the adducts obtained by
this reaction has been explored in a cyclization reaction
affording nitrogen heterocycles.[5d] Our continuing efforts
along these lines allow us to report herein, a novel entry to
indole synthesis,[9] which consists of the nucleophilic addition
of N-arylsulfonamides (i.e. N-sulfonylanilines) to bromoace-
tylenes with subsequent palladium-catalyzed cyclization of
the resultant cis-2-(N-aryl-N-sulfonylamino)-1-bromoalkenes
The nucleophilic addition of N-phenylmethanesulfon-
amide (2a) to 1-bromo-1-octyne (1a) proceeded under the
same reaction conditions as reported previously for N-
alkylsulfonamides,[5d] and gratifyingly the yield of the adduct
3aa (85%, entry 1, Table 1) was higher than those in the
Table 1: Fundamental data for nucleophilic addition.
Entry
2a (equiv)
t [h]
Yield [%][a]
Recovery of 2a [%][b]
1
2
3
2
6
8
85 (93)[c]
71
97
–
[a] Yield of isolated product is based on 1a. [b] Yield of isolated product
based on unreacted 2a. [c] Yield based on consumed 2a. DMF=N,N-
dimethylformamide, Ms=methanesulfonyl.
through aromatic C H bond activation[10] (Scheme 1). A new
ꢀ
synthesis of another interesting heterocycle, 1,2-benzothia-
zine 1,1-dioxide,[11] by a similar sequence is also described in
this report.
previous cases (up to 78%). The reaction was highly regio-
and stereoselective such that other isomers were not detected
in the crude reaction mixture. Although an excess amount of
the sulfonamide 2a (3 equiv relative to 1a) guarantees a good
product yield, it could be reduced to 2 equivalents and still
keep the yield within an acceptable range (entry 2). When
3 equivalents of 2a was used, the unreacted 2a was recovered
in 97% yield and could be recycled; the yield of 3aa based on
the consumed sulfonamide 2a was calculated to be 93%
(entry 1).
The cis relationship between the bromide and sulfonylani-
line moieties in the adduct 3aa appears suitable for a variety
of cyclizations,[12] one of which is the palladium-catalyzed ring
ꢀ
closure through activation of the aromatic C H bond as
illustrated in Equation (1). In fact, treatment of 3aa with
[10i]
Pd(OAc)2
effected the cyclization to give the N-sulfonyl-
Scheme 1. Facile preparation of two types of heterocycles by a novel
synthetic strategy.
indole 4aa contaminated with a small amount of desulfonyl-
ated 5aa in 88% yield upon isolation. Despite considerable
effort, the simultaneous production of 5aa was hard to
suppress and the ratio of 4aa to 5aa changed slightly from run
to run. While 4aa and 5aa were separable by HPLC,[13] the
mixture was subjected to either desulfonylation with TBAF
(Bu4NF)[14] or 10% ethanolic KOH,[15] thus leading to indole
5aa in either 97 or 88% yield.[16]
[*] M. Yamagishi, K. Nishigai, A. Ishii, Dr. T. Hata, Prof. Dr. H. Urabe
Department of Biomolecular Engineering, Graduate School of
Bioscience and Biotechnology, Tokyo Institute of Technology
4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama
Kanagawa 226-8501 (Japan)
E-mail: hurabe@bio.titech.ac.jp
Table 2 summarizes other results of the indole synthesis.
In this sequence, the mixture of cyclization products 4 and 5
was directly submitted to the subsequent desulfonylation with
TBAF. The yields of 4 and 5, listed for reference, were
Homepage: http://www.urabe-lab.bio.titech.ac.jp
[**] This work was supported by a Grant-in-Aid for Challenging
Exploratory Research (22655014) from the JSPS (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201024.
1
estimated by H NMR spectroscopy using an internal stan-
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the adducts 3aa, 3ba–ea, and 3ab–ag prompted us to
investigate the generality of the subsequent cyclization
ꢀ
through an intramolecular C H activation (3!4 + 5). As
previously described for the preparation of 5aa from 3aa
[Eq. (1)], all reactions inevitably produced a mixture of
sulfonylated indole 4 and a small amount of its parent indole
5. The crude reaction mixtures were converted into indoles
(5aa, 5ba–ea, and 5ab–ag) through desulfonylation with
TBAF in good overall yields (entries 1–11). As a whole, these
reaction conditions were compatible with various functional
groups both on the acetylene side chain and aromatic ring,
thus demonstrating broad applicability.[17]
In Table 2, we separately listed each result for the
nucleophilic addition and the subsequent cyclization/desulfo-
nylation. However, more practically, these steps can be
carried out in one pot without isolation of the intermediate
products. Scheme 2 shows such an example in which indole
5aa was obtained from the primary starting materials 1a and
2a in an excellent yield.
While the synthesis of unprotected indoles from N-
arylmethanesulfonamides was established as above, sulfo-
nyl-protected indoles could be cleanly produced from more
robust N-aryl-p-toluenesulfonamides 6 as shown in Table 3.
The nucleophilic addition of N-(p-toluenesulfonyl)aniline
(6a) to bromoacetylenes 1a–e (entries 1–5) required
a longer reaction period (12 h) than that of the corresponding
methanesulfonamides (6 h, see
dard to determine the amount of TBAF needed to insure the
desulfonylation step; typically 2 equivalents of TBAF were
used relative to 4. As far as the nucleophilic addition of N-
phenylmethanesulfonamide (2a) to various bromoacetylenes
(1b–e) is concerned, the corresponding adducts 3ba–ea were
obtained in good yields (entries 2–5). The mild reaction
conditions allow the presence of representative functional
groups, even an unprotected hydroxy group, on the side chain
of bromoacetylenes. Likewise, 1-bromo-1-octyne (1a) and
a variety of aniline derivatives, 2b–g, afforded the desired
products 3ab–ag in good yields. The successful preparation of
Table 2: Preparation of indoles 5 from 1 and 2.[a]
Table 2), but the product yields
remained at a similar level. The
longer reaction time might be due
to the enhanced steric hindrance of
6. The subsequent palladium-cata-
lyzed cyclization of the adducts
7aa–ea and 7ab proceeded in the
same way as that of methanesulfon-
amides to give sulfonylindoles 8aa–
ea and 8ab, respectively, however
Entry
R
Ar
Yield [%][b]
Yield [%][c]
4/5
Yield [%][d]
the desulfonylated products were
not detected in all cases (entries 1–
6, Table 3). It should be emphasized
that the palladium-catalyzed cycli-
zation exclusively occurred on the
N-aryl group in preference to the N-
tosyl group, thus producing only N-
sulfonylindoles 8.
1
2
3
C6H13
(1a)
(1b)
(1c)
Ph (2a)
Ph (2a)
Ph (2a)
3aa: 85
3ba: 92
3ca: 87
94/6
5aa: 87
5ba: 84
5ca: 76
89/11
83/17
4
(1d)
Ph (2a)
3da: 64
53/47
5da: 79
5
(1e)
Ph (2a)
3ea: 82
44/23
5ea: 65
In conjunction with the indole
synthesis discussed above, we noted
in the preceding paragraph that the
palladium-catalyzed cyclization of
7aa–ea and 7ab exclusively oc-
curred at the aniline moiety to
give 8aa–ea and 8ab, respectively,
and the aromatic ring in the p-
toluenesulfonyl group remained
untouched. However, if the aniline
moiety is not present in the mole-
cule, then a similar cyclization did
proceed toward the p-toluenesul-
fonyl group, thus leading to a new
6
7
8
9
10
11
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
p-MeC6H4 (2b)
3ab: 79
3ac: 85[e]
3ad: 92
3ae: 92[f]
3af: 87
90/10
89/8
89/11
95/5
89/10
78/18
5ab: 80
5ac: 78
5ad: 83
5ae: 82
5af: 92
5ag: 85[h]
3,5-Me2C6H3 (2c)
p-MeOC6H4 (2d)
p-(Me2N)C6H4 (2e)
p-(AcHN)C6H4 (2 f)
p-ClC6H4 (2g)
3ag: 78[g]
[a] Reaction conditioins: a) Bromoacetylene 1 (1 equiv), sulfonamide 2 (3 equiv), K3PO4 (1.5 equiv),
DMF, 1208C, 6 h; b) Pd(OAc)2 (5 mol%), PCy3 (15 mol%), K2CO3 (2 equiv); DMF, 1308C, 4 h; crude
reaction mixture was directly used in the next step; c) TBAF (2 equiv to 4); THF, reflux, 4.5–5.5 h.
[b] Yield of isolated product based on 1. [c] Yield of crude product before desulfonylation and
determined by 1H NMR spectroscopy with an internal standard. These data are shown only for reference.
[d] Overall yield of the isolated product from 3. [e] The reaction period was extended to 8 h. [f] Unreacted
2e was recovered in 97% yield upon isolation and may be recycled. Thus, the yield of 3ae based on
consumed 2e was 94%. [g] The reaction period was extended to 12 h. [h] The cyclization was performed
for 1 h. Bn=benzyl.
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Scheme 2. One-pot synthesis of indole 5aa from 1a and 2a. THF=
tetrahydrofuran.
Table 3: Preparation of N-sulfonylindoles 8 from 1 and 6.[a]
Table 4: Preparation of 1,2-benzothiazine 1,1-dioxides 11 from 1a and
9.[a]
Entry
R
Ar
Yield [%][b] Yield [%][c]
1
2
3
C6H13
(1a) Ph (6a)
(1b) Ph (6a)
(1c) Ph (6a)
7aa: 80
7ba: 72
7ca: 70
8aa: 83
8ba: 77
8ca: 89
4
(1d) Ph (6a)
7da: 69
8da: 88
Entry
Ar
Yield [%][b]
Yield [%][c]
5
6
(1e) Ph (6a)
7ea: 81
8ea: 60
1
2
3
4
5
6
p-MeC6H4 (9a)
Ph (9b)
p-MeOC6H4 (9c)
p-NO2C6H4 (9d)
p-ClC6H4 (9e)
m-MeC6H4 (9 f)
10 aa: 52
10 ab: 52
10 ac: 48
10 ad: 53
10 ae: 61
10 af: 51
11 aa: 77
11 ab: 71
11 ac: 73
11 ad: 77[d]
11 ae: 58[e]
11 af: 66[f]
C6H13
(1a) 3,5-Me2C6H3 7ab: 72[d] 8ab: 70
(6b)
[a] Reaction conditions: a) Bromoacetylene 1 (1 equiv), sulfonamide 6
(3 equiv), K3PO4 (1.5 equiv); DMF, 1208C, 12 h; b) Pd(OAc)2 (5 mol%),
PCy3 (15 mol%), K2CO3 (2 equiv); DMF, 1308C, 4 h. [b] Yield of isolated
product based on 1. [c] Yield of isolated product from 7. [d] The reaction
period was extended to 14 h. Ts=4-toluenesulfonyl.
[a] Reaction conditions: a) Bromoacetylene 1a (1 equiv), sulfonamide 9
(3 equiv), K3PO4 (1.5 equiv); DMF, 1208C, 2 h; b) Pd(OAc)2 (10 mol%),
PCy3 (30 mol%), K2CO3 (2 equiv); DMA, 1108C, 8 h. [b] Yield of isolated
product based on 1a. [c] Yield of isolated product from 10. [d] The
reaction period was 2 h. [e] The reaction period was 3.5 h. [f] Combined
yield of the regioisomers as shown below.
preparation of 1,2-benzothiazine 1,1-dioxides as shown in
Equation (2) (DMA = N,N-dimethylacetamide). For exam-
ple, the N-alkyl-p-toluenesulfonamide 9a underwent the
nucleophilic addition to the bromoacetylene 1a as described
before[5d] to give exclusively the Z-bromoalkene 10aa. Its
cyclization under the same reaction conditions as those in
Table 3 gave 1,2-benzothiazine 1,1-dioxide 11aa in 61% yield,
which was increased to 77% under a new set of optimized
reaction conditions. As expected from the fact that the
cyclization to the p-toluenesulfonyl group is a less favorable
path, the optimized reaction conditions required a larger
amount of the palladium catalyst (10 mol%) relative to the
original indole synthesis (5 mol%) to attain comparable
product yields.
stereoselective manner to give (Z)-2-(sulfonylamino)-1-bro-
moalkenes in good yields. The cis structure of sulfonylamino
and bromo substituents in the products should be quite useful
for a variety cyclizations, as demonstrated by the palladium-
catalyzed cyclization involving aromatic C H bond activa-
tion, thus providing a new and facile preparation of indoles,
ꢀ
Results similar to those shown in Equation (2) are
summarized in Table 4. 1-Bromo-1-octyne (1a) and N-alkyl-
sulfonamides 9 derived from various arenesulfonyl groups
afforded the corresponding Z-bromoalkenes 10aa–af in good
yields (entries 1–6). These products were successfully trans-
formed into 1,2-benzothiazine 1,1-dioxides 11aa–af
(entries 1–6), wherein the cyclizations of 10ad and 10ae,
having an electron-deficient aromatic ring (entries 4 and 5),
were complete in shorter reaction periods than that of the
others. Bromoalkene 10af, having an unsymmetrical aromatic
ring, cyclized to 11af with a good regioselectivity (entry 6).
In conclusion, the nucleophilic addition of various sulfon-
amides to 1-bromo-1-alkynes took place in a highly regio- and
N-sulfonylindoles, and 1,2-benzothiazine 1,1-dioxides.
Received: February 7, 2012
Published online: May 13, 2012
Keywords: alkynes · cyclizations · indoles ·
.
nucleophilic addition · palladium
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[16] To the contrary, mesylation of a mixture of 4 and 5 could provide
the N-mesylindoles 4. P. G. M. Wuts, T. W. Greene, Greeneꢀs
Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken,
2007, pp. 873 – 874.
[17] Amines such as butyl- and diethylamines in place of sulfon-
amides afforded an intractable mixture of products in the
addition to 1-bromo-1-octyne. On the other hand, an aromatic
haloacetylene such as bromo(phenyl)acetylene and sulfonamide
2b afforded the desired addition product 3 in a low yield (ca.
30%).
[8] For our reports on the synthetic application of sulfonamides, see:
a) Y. Fukudome, H. Naito, T. Hata, H. Urabe, J. Am. Chem. Soc.
2008, 130, 1820 – 1821; b) H. Naito, T. Hata, H. Urabe, Org. Lett.
2010, 12, 1228 – 1230; c) Y. Kato, D. H. Yen, Y. Fukudome, T.
Hata, H. Urabe, Org. Lett. 2010, 12, 4137 – 4139.
[9] For recent reviews on the indole synthesis, see: a) J. Barluenga,
C. Valdꢀs, Modern Heterocyclic Chemistry, Vol. 1 (Eds.: J.
6474 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 6471 –6474