Benzothiazines in synthesis. Eight-membered ring formation in an intramolecular Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tetlet.2009.02.227

Treatment of certain benzothiazines bearing allylic bromides side chains with indium tribromide resulted in the formation of eight-membered rings in addition to the expected six-membered rings.

Full text of DOI:10.1016/j.tetlet.2009.02.227

Tetrahedron Letters 50 (2009) 2326–2328
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Tetrahedron Letters
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Benzothiazines in synthesis. Eight-membered ring formation in an
intramolecular Friedel–Crafts reaction
*
Michael Harmata , Weijiang Ying, Charles L. Barnes
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of certain benzothiazines bearing allylic bromides side chains with indium tribromide resulted
in the formation of eight-membered rings in addition to the expected six-membered rings.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 February 2009
Revised 23 February 2009
Accepted 26 February 2009
Available online 9 March 2009
Elisapterosin B (1) is a complex natural product isolated by
Rodriguez and co-workers.1 The compound is not only structurally
intriguing, but biologically as well, as it possesses significant anti-
tubercular activity, inhibiting the growth of M. tuberculosis H37Rv.
These factors have stimulated interest in the compound in the syn-
thetic community and a number of syntheses have been re-
ported.2–6
HO
O
Me
H
S
steps
Me
O
C
MeO
Me
Ph
H
N
O
Me
OMe
2
Me
1, elisapterosin B
Our approach to this compound is centered on benzothiazine
chemistry, with which we have had success in the synthesis of a
number of natural products.7,13
H
MeO
Me
Our plan in the synthesis of elisapterosin B depends on the ster-
eoselective synthesis of 2, which we anticipate can be converted to
the natural product in short order (Scheme 1). One approach to 2
involves a stereoselective intramolecular Friedel–Crafts reaction
of an allylic cation (3) or its equivalent. This Letter describes sev-
eral approaches to 2 and the interesting observation of the forma-
tion of an eight-membered ring product in the Friedel–Crafts
reaction of one of the precursors.
3
Ph
S
O
N
OMe
Scheme 1. Partial retrosynthesis of elisapterosin B.
Our approach to precursors to 3 consisted of generating benzo-
thiazines via the stereoselective conjugate addition of sulfoximine
carbanions to alkenes bearing an electron-withdrawing group.8
These electron-withdrawing groups would be removed at some
point during the synthesis to afford 2, which could be carried for-
ward to the natural product.
The N-aryl sulfoximine needed for this study was prepared as
shown in Scheme 2. The commercially available benzoic acid 4
was reduced with LAH, brominated with NBS, and oxidized to
the corresponding aldehyde 5 in 93% overall yield. Protection of
the aldehyde afforded acetal 6 quantitatively. A Buchwald–Har-
twig reaction with (S)-8,9 followed by hydrolysis gave aldehyde 7
in 67% overall yield.
MeO
Me
CHO
Br
1. LAH
2. NBS
3. Swern
93%
MeO
Me
CO2H
OMe
CH(OMe)3
100%
OMe
OMe
OMe
4
5
CHO
Me
MeO
Me
MeO
Me
1. (
BINAP, Cs2CO3
2. HCl
S)-8, Pd(OAc)2,
OMe
Ph
S
N
Br
O
OMe
6
7
67%
Me
+
Ph
Sulfoximine 7 was used as a substrate for the generation of two
cyclization precursors. These were synthesized via a Horner–Em-
S
HN
(
_
O
S
)-8
* Corresponding author. Tel.: +1 573 882 1097; fax: +1 573 882 2754.
E-mail address: HarmataM@missouri.edu (M. Harmata).
Scheme 2. Synthesis of sulfoximine.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.227

M. Harmata et al. / Tetrahedron Letters 50 (2009) 2326–2328
2327
n-BuLi, t-BuLi
then TMSCl
66%
TMS
TMS
OH
TMS
OH
R
H
R
9
10
MeO
Me
MeO
1. 2 equiv LiHMDS
2. NH4Cl
Ph
O
P
Me
EtO
Ph
O
1. P2-Ni, H2
S
R
S
O
N
EtO
+
Br
Me
N
NaH
TMS
2. NBS, Ph3P
OMe
11
OMe
12a, R = CO2Et
12b, R = SO2Ph
15a, R = CO2Et(α)
15a', R = CO2Et(β)
(80%, α:β = 1:2.5)
15b, R = SO2Ph(α)
15b', R = SO2Ph(β)
(86%, α:β = 1:4.1)
14a, R = CO2Et
14b, R = SO2Ph
OEt
EtO
P
R
13a, R = CO2Et, 47% from 10
13b, R = SO2Ph, 52% from 10
O
TMS
Scheme 3. Preparation of phosphonates 13a and 13b.
16a, R = CO2Et(α)
(83%, dr = 7.7:1)
16a', R = CO2Et(β)
(84%, dr = 2.5:1)
16b', R = SO2Ph(β)
(82%, dr = 5.8:1)
R
mons reaction. The preparation of the appropriate reagents is
shown in Scheme 3. The conversion of 2-butyn-1-ol (9) into 10,10
followed by hydrogenation with P2-nickel,11 afforded alcohol 12
in good yield. Alcohol 12 was converted into the corresponding
allylic bromide 11, which served as an electrophile to furnish phos-
phonates 13a and 13b.
Br
NBS, -10 o
MeCN
C
H
MeO
Me
Ph
O
S
N
OMe
Scheme 5. Synthesis of allylic bromides.
Benzothiazines were prepared by coupling 13a/b with 7 fol-
lowed by intramolecular conjugate addition. The coupling se-
quence is shown in Scheme 4. Stereoselectivity in the formation
of 14a and 14b was acceptable.12 The E and Z isomers of each com-
pound were separable and only the E isomers were taken forward.
Diastereomeric mixtures were obtained when 14a and 14b
were treated with base (Scheme 5). All of our results to date dem-
onstrate that diastereomers result from non-selective protonation
of the anions that arise from the intramolecular conjugate addition.
We have had success in achieving relatively high diastereoselectiv-
ity in some cases,13 but the selectivity in this study was low. Ste-
reochemical assignments of the individual stereoisomers were
based on several factors, including the idea that the major stereo-
isomers would bear the stereochemistry of similar compounds pre-
pared in other studies.
Treatment of the individual benzothiazine diastereomers with
NBS resulted in the formation of the corresponding secondary
allylic bromides in low to good diastereoselectivities.14 The exact
stereochemistry of the bromide-bearing carbon was not ascer-
tained. Rather, the compounds were treated with InBr3 in refluxing
CH2Cl2 in the presence of molecular sieves (Scheme 6).15 The ste-
reochemistry of the major isomer 17b in the cyclization of 16a
was assigned by NOESY, a correlation being seen between the
methylene group of the ethyl ester and one hydrogen on the meth-
ylene of the vinyl group. The major isomer obtained from the cycli-
zation of 16a0 was crystalline and the stereochemistry was
established by X-ray analysis. These data imply the stereochemis-
try of the other products and of the starting materials as well.
It is interesting to note that there is a close correlation between
the diastereomeric ratios of the bromides and the corresponding
Br
CO2Et
H
CO2Et
H
MeO
InBr3, CH2Cl2
MeO
Ph
O
S
reflux, 24 h
Ph
S
O
Me
N
Me
N
82%
OMe
OMe
16a, dr = 7.7:1
17a, β-vinyl
17b, α-vinyl
β:α, 1:6.7
Br
CO2Et
H
CO2Et
H
MeO
Me
InBr3, CH2Cl2
reflux, 24 h
86%
MeO
Me
Ph
S
Ph
N
O
S
N
OMe
O
OMe
16a', dr = 2.5:1
17a', β-vinyl
17b', α-vinyl
β:α, 2.5:1
Scheme 6. Intramolecular Friedel–Crafts reaction of 16 and 16a0.
cyclization products. The implication is that the substitution pro-
cess occurs in an SN2 fashion, though we have by no means rigor-
ously established this.
Interestingly, when 16b0 was treated with excess indium bro-
mide in CH2Cl2 for 24 h at room temperature, an eight-membered
ring product (18) was obtained, in addition to the two expected
six-membered ring diastereomers. A brief investigation of reaction
conditions demonstrated some variability in product distribution
as a function of temperature. Thus, the ratio of the three products
formed changed from 8.5:4.7:1 (18:19a0:19b0) at room tempera-
ture to 9.1:4.8:1 in refluxing dichloroethane. In a reaction run at
ꢀ78 °C to room temperature, the product ratio was 5.1:5.5:1.16
Exposure of the product mixture from a low temperature experi-
ment to reagent and heat did not result in equilibration to a new
product mixture. This suggests a larger entropy of activation (less
negative) for the formation of 18 vis-à-vis the six-membered ring
regioisomer (Scheme 7).
TMS
CHO
Me
MeO
Me
R
13a/b, LiHMDS
Ph
S
O
MeO
Me
LiCl, THF
N
Me
OMe
S
O
Ph
N
OMe
7
14a, R = CO2Et, 86%,
dr = 8:1
14b, R =SO2Ph, 83%.
dr = 8:1
Interestingly, the formation of the six-membered ring products
from 16a0 proceeded with moderate diastereoselectivity in the
direction desired for the synthesis of elisapterosin B, but also clo-
Scheme 4. Horner–Wadsworth–Emmons reactions of 7.

2328
M. Harmata et al. / Tetrahedron Letters 50 (2009) 2326–2328
Supplementary data
Br
SO2Ph
H
SO2Ph
MeO
Me
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.227.
H
InBr3, CH2Cl2
rt, 24 h, 87%
8.5:4.7:1
MeO
Me
+
Ph
S
Ph
S
N
O
N
O
OMe
References and notes
OMe
18
18:19a':19b'
16b', dr = 5.8:1
1. Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Barnes, C. L. J. Org. Chem. 2000, 65,
1390–1398.
SO2Ph
H
SO2Ph
H
2. Kim, A. I.; Rychnovsy, S. D. Angew. Chem., Int. Ed. 2003, 42, 1267–1270.
3. Waizumi, N.; Stankovic, A. R.; Rawal, V. H. J. Am. Chem. Soc. 2003, 125, 13022–
13023.
4. Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 6046–6060.
5. Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485–2490.
6. Werle, S.; Fey, T.; Neudorfl, J. M.; Schmalz, H. Org. Lett. 2007, 7, 3555–3558.
7. (a) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581–3583; (b) Harmata, M.; Hong,
X.; Schreiner, P. R. J. Org. Chem. 2008, 73, 1290–1296; (c) Harmata, M.; Hong, X.
Tetrahedron Lett. 2005, 46, 3847–3849; (d) Harmata, M.; Hong, X.; Barnes, C. L.
Tetrahedron Lett. 2003, 44, 7261–7264.
MeO
MeO
Me
+
Ph
Ph
S
O
S
Me
N
N
O
OMe
OMe
19b'
19a'
Scheme 7. Intramolecular Friedel–Crafts reaction of 16b0.
8. Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754–5756.
9. (a) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419–2422; (b) Bolm,
C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731–5734.
10. Tong, R.; Valentine, J. C.; McDonald, F. E.; Cao, R.; Fang, X.; Hardcastle, K. I. J. Am.
Chem. Soc. 2007, 129, 1050–1051.
sely reflected the diastereomer ratio of the precursor allylic
bromides.
In conclusion, we have discovered that it is possible to prepare
potential precursors to elisapterosin B as well as a unique cyclooc-
tanoid via an intramolecular Friedel–Crafts alkylation process. The
basis of substituent effects on this process with respect to both reg-
iochemistry and stereochemistry is presently not clear and further
work is necessary to determine it. Such studies and application of
the method to the synthesis of various targets will be reported in
due course.17
11. (a) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226–2230; (b) Kwon, S.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796–16797; (c) Dussault, P. H.; Eary,
C. T.; Lee, R. J.; Zope, U. R. J. Chem. Soc., Perkin Trans. 1 1999, 2189–2204.
12. Diastereomer ratios were determined by analysis of the 1H NMR data for crude
reaction products.
13. Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201–2203.
14. We did not explore the bromination of benzothiazine 15b as we could not
obtain it in large amounts in pure form.
15. Hayashi, R.; Cook, G. R. Org. Lett. 2007, 9, 1311–1314.
16. Other experiments we have performed show that the reaction does not take
place to any significant extent at ꢀ10 °C.
17. Crystallographic data (excluding structure factors) for some structures
reported in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers CCDC
716164 (17a0) and 716143 (18). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033; Email: deposit@ccdc.ac.uk].
Acknowledgment
This work was supported by the NIH (1R01-AI59000-01A1) to
whom we are grateful.