Formation of an unexpected rearrangement product using Grubbs' second generation catalyst: 2-allyl-3,4-dihydro-2H-1,4-benzothiazines from diene precursors

Article abstract of DOI:10.1016/j.tetlet.2012.02.109

Application of sub-stoichiometric amounts of Grubbs' second generation catalyst to the substrate N-allyl-N-[2-(allylsulfanyl)phenyl]-4- methylbenzenesulfonamide afforded the ring-closed compound 6-[(4-methylphenyl) sulfonyl]-5,6-dihydro-2H-1,6-benzothiazo

Full text of DOI:10.1016/j.tetlet.2012.02.109

Tetrahedron Letters 53 (2012) 2384–2387
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Formation of an unexpected rearrangement product using Grubbs’ second
generation catalyst: 2-allyl-3,4-dihydro-2H-1,4-benzothiazines from
diene precursors
Garreth L. Morgans a, Dharmendra B. Yadav a, Manuel A. Fernandes a, Charles B. de Koning a,
Joseph P. Michael a, Willem A.L. van Otterlo a,b,
⇑
a Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050 Johannesburg, South Africa
b Department of Chemistry and Polymer Sciences, Stellenbosch University, Stellenbosch, 7602 Western Cape, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Application of sub-stoichiometric amounts of Grubbs’ second generation catalyst to the substrate
N-allyl-N-[2-(allylsulfanyl)phenyl]-4-methylbenzenesulfonamide afforded the ring-closed compound
6-[(4-methylphenyl)sulfonyl]-5,6-dihydro-2H-1,6-benzothiazocine, as well as the unexpected 2-allyl-4-
[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine. Use of similar conditions on an
analogous sulfoxide resulted in the expected product, 6-[(4-methylphenyl)sulfonyl]-5,6-dihydro-2H-
1,6-benzothiazocine 1-oxide, indicating that the sulfide was playing a key role in this novel transforma-
tion. Furthermore, the use of N-allyl-4-methyl-N-{2-[(2-methyl-2-propenyl)sulfanyl]phenyl}-benzene-
sulfonamide in the same reaction gave 2-(2-methyl-2-propenyl)-3,4-dihydro-2H-1,4-benzothiazine.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 22 September 2011
Revised 10 February 2012
Accepted 23 February 2012
Available online 5 March 2012
Keywords:
Ring-closing metathesis
Benzothiazocine
Benzothiazine
Ruthenium carbene
Rearrangements
Ring-closing metathesis (RCM) has become an established
methodology for the construction of medium-sized ring systems
containing various heteroatoms.1 Due to the extensive use of
metathesis catalysts, exemplified by the Grubbs’ first and second
generation catalysts, researchers occasionally report unforeseen
results from the use of RCM. These unexpected results represent
a wide selection of synthetic transformations including pre- and
post-metathetic isomerizations and oxidative rearrangements,
which have been reviewed by Alcaide and Almendros.2a,b Of inter-
est is that in terms of the amount of ruthenium carbene required,
examples of catalytic and stoichiometric reactions have been re-
corded. In addition, a number of these ruthenium-mediated side
reactions have found synthetic application.2c,d
In terms of the heteroatoms incorporated into ring systems
utilizing the RCM approach, the formation of sulfur-containing het-
erocycles has been less described than with atoms such as nitrogen
or oxygen.3 This may, in part, be due to the coordination of sulfur
with the metal carbene center, sometimes resulting in complex
reaction mixtures or in no reactions at all.
heterocycles containing sulfur in various oxidation states.5 For
example, we synthesized 1,4-benzoxathiin (3a) and 1,4-ben-
zodithiin (3b) by way of an isomerization-RCM strategy as
depicted in Scheme 1.5b
In this Letter, we report how the application of larger than usual
amounts of the Grubbs’ second generation catalyst (4)6 to N-allyl-
N-[2-(allylsulfanyl)phenyl]-4-methylbenzenesulfonamide
(1c)
gave the unexpected product 2-allyl-4-[(4-methylphenyl)sulfo-
nyl]-3,4-dihydro-2H-1,4-benzothiazine (5) (Scheme 2) as one of
the two major products.7
During research into the application of metathesis to sulfur-
containing compounds the allyl sulfides 1a–c were treated with
the Grubbs’ second generation catalyst 4 (Scheme 3). Unfortu-
nately, when applying the RCM reactions on compounds 1a and
1b in an attempt to obtain the benzannulated heterocycles 6a
and 6b, respectively, no products were obtained. In fact, from
TLC analysis, it appeared that the substrates were transformed di-
rectly into polymeric material which we were unable to character-
ize. The same reaction performed on diene 1c gave rise to a fairly
complex mixture of products.
We have been interested in exploring the synthesis of
benzo-fused heterocycles,4 including six- and seven-membered
After evaluation of the crude 1H NMR spectrum of the latter
experiment involving 1c, in which evidence existed supporting
the existence of products other than the starting material, it was
decided to repeat this particular reaction with a larger quantity
of catalyst to investigate the mixture of products formed.
⇑
Corresponding author.
E-mail addresses: wvo@sun.ac.za, Willem.vanOtterlo@wits.ac.za (W.A.L. van
Otterlo).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.02.109

G. L. Morgans et al. / Tetrahedron Letters 53 (2012) 2384–2387
2385
S
Y
S
Y
isomerization
2a Y = O
1a Y = O
1b Y = S
2b Y = S
S
Y
RCM
3a Y = O
3b Y = S
Scheme 1. Formation of 1,4-benzodithiin and 1,4-benzoxathiin as described in Ref.
5b.
N
Mes N
Cl
Mes
Ru
Cl
Ph
S
N
Ts
1c
PCy3
S
4
N
Ts
5
Figure 1. Single crystal X-ray structure for compound 5 (ORTEP diagram drawn at
50% probability level).
Scheme 2. Formation of allyl-substituted benzo[1,4]thiazines.
S
No
i
reaction
S
Y
S
Y
N
H
1d
RCM
O
S
S
1a Y = O
1b Y = S
1c Y = NTs
6a Y = O (no product)
6b Y = S (no product)
6c Y = NTs (mixture)
ii
N
Ts
N
Ts
1c
Scheme 3. Conditions for the attempted RCM to afford 6a,b: catalyst
15 mol %), CHCl3, see Ref. 5c for a description of the attempted synthesis of 6c.
4 (5–
8
O
S
iii
S
N
SH
RCM
steps
N
Ts
(reference 5b)
9
NH2
Ts
7
Scheme 5. Reagents and conditions: (i) catalyst 4 (20 mol %), 65–80 °C, 24 h (no
product observed); (ii) mCPBA (1.1 mol equiv), 0 °C to rt, CH2Cl2, N2, 18 h (92%); (iii)
catalyst 4 (10 mol %), CH2Cl2, N2, reflux, 20 h (95%).
1c
S
S
N
4
+
N
Ts
Having already determined that this interesting reaction was
not occurring when 1-(allyloxy)-2-(allylthio)benzene (1a) (Y@O)
or 1,2-bis(allylthio)benzene (1b) (Y@S) (Scheme 2) was used as
starting material, it was decided to probe a number of factors in-
volved in the reaction. Firstly, reactions at lower temperature
(ꢀ5 °C, rt and 40 °C) indicated that a higher temperature was re-
quired. In our hands, keeping the temperature in the range of
65–80 °C gave the best results. Secondly, we found it necessary
to add larger than catalytic amounts of the Grubbs’ second gener-
ation carbene (typically 50%) as at lower catalyst concentrations,
while the product spots were evident on TLC, only very low yields
of the products were obtained on work-up followed by chromatog-
raphy. It was also established that the tosyl group was important,
as substrate 1d did not give the desired rearranged product (under
the conditions employed it also did not give the ring-closed prod-
uct) (Scheme 5). To probe whether the oxidation state of the sulfur
atom was important, oxidation of 1c to the sulfoxide 8 provided a
product which readily gave the benzannulated heterocycle 9, even
under fairly mild conditions of dichloromethane at reflux. In
addition, we had previously demonstrated that the sulfone version
of this compound afforded the 8-membered 5,6-dihydro-2H-1,
Ts
6c (34%)
5 (30%)
Scheme 4. Reagents and conditions: catalyst 4 (5 ꢁ 10% over 24 h = 50 mol %),
ClCH2CH2Cl, N2, 65–80 °C, 24 h.
Interestingly, the addition of sub-stoichiometric amounts of ruthe-
nium carbene 4 (50 mol % applied in several portions during the
course of the reaction) to substrate 1c again gave rise to a mixture
of products from which two compounds were isolated by careful
column chromatography (Scheme 4).8 The first product was the ex-
pected dihydro-2H-1,6-benzothiazocine 6c (34%),9 while the other
was determined to be allyl-substituted benzo[1,4]thiazine 59 in an
approximately equal yield of 30%. Due to its unusual features the
structure of compound 5 was unambiguously proved by a single
crystal X-ray study (Fig. 1).9 Of interest is that the substituted
benzo[1,4]thiazine scaffold has elicited much interest in medicinal
chemistry circles over the past decade,10 making the development
of potential new approaches to this substrate a worthwhile
venture.

2386
G. L. Morgans et al. / Tetrahedron Letters 53 (2012) 2384–2387
In terms of a postulated mechanism, it seems reasonable that
Me
compound 1c is converted into the ylide 17 by the sulfur atom
trapping the ruthenium carbene via an intramolecular attack
(1c?15?16, Scheme 7). This would also account for the loss of
the methylene fragment observed in the product 5. There are then
various options resulting in the final product. It was first consid-
ered possible that the rearrangement of 1c into 5 occurs by way
of a [2,3]-sigmatropic rearrangement.13 In addition, it should be
mentioned that a [1,2]-carbon shift (a Stevens rearrangement) is
SH
S
i
ii
NH2
NH2
10
7
Me
Me
S
S
iii
also possible.14 The involvement of a ruthenium-mediated
p-allyl
NH
Ts
N
Ts
12
11
species with a subsequent reductive elimination to give 5 could
also be conceivable.14a Finally, a novel pericyclic reaction leading
to the product can at this stage also not be ruled out. In view of
the importance of allyl-transfer reactions in organic synthesis it
is also envisaged that the unexpected reaction observed could lead
to the development of novel C-allylation reactions.15
S
S
Me
iv
+
Me
N
Ts
N
Ts
13
(34%)
14
(18%)
Conclusion
Scheme 6. Reagents and conditions: (i) 3-bromo-2-methylprop-1-ene, NaOH,
MeOH, 18 h (84%); (ii) TsCl, pyridine, CH2Cl2, 0 °C to rt, N2, 18 h (quant.); (iii) allyl
bromide, K2CO3, acetone, rt, 24 h (94%); (iv) catalyst 4 (4 ꢁ 10 and 2 ꢁ 5 mol %),
ClCH2CH2Cl, N2, 65–80 °C, 24 h.
In conclusion, we have disclosed an unusual rearrangement
product obtained when using the Grubbs’ second generation car-
bene (4) on N-allyl-N-[2-(allylthio)phenyl]-4-methylbenzenesulf-
onamide (1c) and the related compound 12. Despite the problem
that the utilization of non-catalytic amounts of 4 poses, it is envis-
aged that this interesting rearrangement, which results in the
potentially useful allyl-substituted benzo[1,4]thiazine 5 frame-
work, will receive further synthetic attention. We intend to synthe-
size other substrates to see if the mechanism of this novel
transformation can be elucidated, with a secondary aim of devel-
oping a catalytic version of this reaction.
S
S
[Ru]-II
[Ru]
N
N
Ts
Ts
1c
15
S
S
Ru
-L
[Ru]
Acknowledgments
N
Ts
N
Ts
This work was supported by the National Research Foundation
(NRF), Pretoria, the University of the Witwatersrand (University
and Science Faculty Research Councils) and the Stellenbosch Uni-
versity (Faculty and Departmental funding). DBY thanks the Uni-
versity of the Witwatersrand Research Office and the NRF for a
postdoctoral fellowship. We also gratefully acknowledge Mr. R.
Mampa for the NMR spectroscopy service. Finally, Prof. Roger Hun-
ter (University of Cape Town) and Dr. Gareth Arnott (Stellenbosch
University) are thanked for enlightening discussions regarding the
possible mechanism of the reaction.
17
16
Various
mechanistic
S
N
possibilities
Ts
5
Scheme 7. A possible mechanism for the formation of compound 5.
6-benzothiazocine 1,1-dioxide in high yield under mild conditions
(Scheme 5).5c This set of results indicated strongly that the sulfide
was crucial to afford the rearrangement product 5.
References and notes
1. See, for example: (a) Fürstner, A. Chem. Commun. 2011, 47, 6505–6511; (b)
Nolan, S. P.; Clavier, H. Chem. Soc. Rev. 2010, 39, 3305–3316; (c) van Otterlo, W.
A. L.; de Koning, C. B. Chem. Rev. 2009, 109, 3743–3782.
2. (a) Alcaide, B.; Almendros, P.; Luna, A. Chem. Rev. 2009, 109, 3817–3858; (b)
Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1259–1262; (c) Schmidt, B. Eur.
J. Org. Chem. 2004, 1865–1880; (d) Trost, B. M.; Toste, F. D.; Pinkerton, A. B.
Chem. Rev. 2001, 101, 2067–2096.
We decided to further investigate this intriguing result with the
synthesis of substrate 12, the difference being that this time the S-
allyl group bears a 20-methyl group. To this end, 2-aminothiophe-
nol (7) was alkylated with 3-bromo-2-methylprop-1-ene to afford
10 in good yield. Tosylation and allylation of the aniline amino
group then gave the substituted bis-allyl compound 12. Applica-
tion of the Grubbs’ second generation catalyst (4) (50 mol %) affor-
ded the substituted benzothiazine 1411 in 18% yield, along with the
expected eight-membered dihydro-2H-1,6-benzothiazocine 13,12
presumably obtained by way of a normal metathetic cascade
(Scheme 6).
3. McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239–
2258.
4. See for example (a) Scalzullo, S. M.; Islam, R. U.; Morgans, G. L.; Michael, J. P.;
van Otterlo, W. A. L. Tetrahedron Lett. 2008, 49, 7403–7405; (b) Panayides, J. L.;
Pathak, R.; Panagiotopoulos, H.; Davids, H.; Fernandes, M. A.; de Koning, C. B.;
van Otterlo, W. A. L. Tetrahedron 2007, 63, 4737–4747; (c) Panayides, J. L.;
Pathak, R.; de Koning, C. B.; van Otterlo, W. A. L. Eur. J. Org. Chem. 2007, 4953–
4961; (d) Coyanis, E. M.; Panayides, J. L.; Fernandes, M. A.; de Koning, C. B.; van
Otterlo, W. A. L. J. Organomet. Chem. 2006, 691, 5222–5239.
The use of sub-stoichiometric amounts of Grubbs’ catalyst 4
was a serious problem regarding the applicability of this method-
ology. We thus attempted to stabilize any important organometal-
lic species with a number of phosphine ligands as an additive, but
unfortunately to no avail. It should be noted that during the course
of the reactions the color of the mixtures became progressively
darker with time, a possible indication that insoluble ruthenium
‘black’ was being precipitated.
5. (a) Yadav, D. B.; Morgans, G. L.; Aderibigbe, B. A.; Madeley, L. G.; Fernandes, M.
A.; Michael, J. P.; de Koning, C. B.; van Otterlo, W. A. L. Tetrahedron 2011, 67,
2991–2997; (b) Morgans, G. L.; Ngidi, E. L.; Madeley, L. G.; Khanye, S. D.;
Michael, J. P.; de Koning, C. B.; van Otterlo, W. A. L. Tetrahedron 2009, 65,
10650–10659; (c) van Otterlo, W. A. L.; Morgans, G. L.; Khanye, S. D.;
Aderibigbe, B. A. A.; Michael, J. P.; Billing, D. G. Tetrahedron Lett. 2004, 45,
9171–9175.
6. Trnka, T. M.; Grubbs’, R. H. Acc. Chem. Res. 2001, 34, 18–29.
7. Experimental work performed by GLM (PhD) and DBY (postdoctoral fellow);
crystallography by Dr M.A. Fernandes.

G. L. Morgans et al. / Tetrahedron Letters 53 (2012) 2384–2387
2387
8. Procedure giving rise to compounds 5 and 6c with Grubbs’ second generation
catalyst 4. Catalyst 4 (10 mol %) was added to N-allyl-N-[2-(allylthio)phenyl]-4-
methylbenzenesulfonamide (1c) (0.096 g, 0.27 mmol) dissolved in 1,2-
dichloroethane (25 mL) under N2. The reaction was then stirred at 65–80 °C
for 24 h with further portions of the catalyst being added until complete
consumption of starting material was observed by TLC (another 40 mol % in
10 mol % portions). The reaction mixture was then filtered through a pad of
Celite and silica gel (1:1) and the solvent removed under reduced pressure. The
resulting residue was purified by flash silica gel column chromatography (5–
20% EtOAc/hexane) to afford compounds 5 (0.028 g, 30%) as white solid prisms
(mp: 120–123 °C) and 6c (0.031 g, 34%) as yellow solid cubic prisms (mp: 170–
175 °C).
128.5, 127.9, 126.7, 125.8, 49.4, 29.8, 21.6; m/z (EI): 332 (M++1, 100%), 282
(10), 177 (15); HRMS calculated for C17H18NO2S2 (M+H)+ 332.0773, found
332.0774.
10. (a) Fringuelli, R.; Milanese, L.; Schiaffella, F. Mini-Rev. Med. Chem. 2005, 5,
1061–1073; (b) Phenothiazines and 1,4-Benzothiazines Chemical and Biomedical
Aspects; Gupta, R. R., Ed.; Elsevier: Amsterdam, The Netherlands, 1988. Vol. 4;
(c) For other examples based on 6-membered benzannulated motifs from our
research, see: Pathak, R.; Naicker, P.; Thompson, W. A.; Fernandes, M. A.; de
Koning, C. B.; van Otterlo, W. A. L. Eur. J. Org. Chem. 2007, 5337–5345; (d) van
Otterlo, W. A. L.; Pathak, R.; de Koning, C. B.; Fernandes, M. A. Tetrahedron Lett.
2004, 45, 9561–9563; (e) de Koning, C. B.; van Otterlo, W. A. L.; Michael, J. P.
Tetrahedron 2003, 59, 8337–8345.
11. 4-[(4-Methylphenyl)sulfonyl]-2-(2-methyl-2-propenyl)-3,4-dihydro-2H-1,4-
benzothiazine (14). 1H NMR (300 MHz, CDCl3): d (ppm) 7.66–7.52 (1H, m),
7.41 (2H, d, J 8.1 Hz), 7.25–7.07 (2H, m), 7.04–6.95 (3H, m), 4.78 (1H, s),
4.66 (1H, s), 4.47 (1H, dd, J 14.4, 3.6 Hz), 3.24–3.11 (1H, m), 3.00–2.80 (1H,
m), 2.32 (3H, s), 2.20 (1H, dd, J 14.2, 6.5 Hz), 2.14–1.96 (1H, m), 1.58 (3H,
s); 13C NMR (75 MHz, CDCl3): d (ppm) 144.0, 140.2, 137.4, 133.9, 129.8,
128.8, 127.5, 127.1, 126.4, 126.3, 124.4, 113.8, 50.1, 42.1, 36.8, 22.0, 21.6;
m/z (EI): 360 (M++1, 50%); HRMS calculated for C19H22NO2S2 (M+H)+
360.1087, found 360.1087.
9. Allyl-4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine (5). 1H
NMR (300 MHz, CDCl3): d (ppm) 7.67–7.62 (1H, m), 7.48 (2H, d, J 8.3 Hz),
7.21 (2H, d, J 8.3 Hz), 7.14–6.95 (3H, m), 5.77–5.63 (1H, m), 5.22–5.00 (2H, m),
4.55 (1H, dd, J 14.3, 3.8 Hz,), 3.28–3.12 (1H, m), 3.06–2.98 (1H, m), 2.40 (3H, s),
2.39–2.13 (2H, m); 13C NMR (75 MHz, CDCl3): d (ppm) 143.9, 137.3, 134.1,
132.9, 129.7, 128.7, 127.2, 127.1, 126.5, 126.3, 124.5, 118.6, 49.8, 38.9, 37.9,
21.6; m/z (EI): 345 (M+, 76%), 190 (96), 148 (100), 136 (36), 109 (25), 91 (33),
65 (26), 55 (25); HRMS calculated for C18H19NO2S2 345.0857, found 345.0837.
Crystallized from EtOAc–hexane, formula: C18H19NO2S2, M = 345.46, colour of
crystal: colourless, needle, crystal size = 0.46 0.31 0.08 mm3, a = 14.0109(19) Å,
b = 13.1138(18) Å, c = 9.3095(12) Å, b = 94.714(2)° V = 1704.7(4) Å3,
12. Tori, M.; Mizutani, R. Molecules 2010, 15, 4242–4260.
13. Zhang, Y.; Wang, J. B. Coord. Chem. Rev. 2010, 254, 941–953.
14. (a) Doyle, M. P. Chem. Rev. 1986, 86, 919–939; For a short review on the
proposed mechanism of the [1,2]-carbon shift (Stevens rearrangement) see: (b)
Bhakat, S. J. J. Chem. Pharm. Res. 2011, 3, 115–121; (c) Vanecko, J. A.; Wan, H.;
West, F. G. Tetrahedron 2006, 62, 1043–1062; (d) Marko, I. E. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
p 913.
15. For examples of recent reviews dealing with the importance of allyl reagents in
organic synthesis, see the following representative examples: (a) Weaver, J. D.;
Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846–1913; (b)
Ramadhar, T. R.; Batey, R. A. Synthesis 2011, 1321–1346; (c) Pigge, F. C. Synthesis
2010, 1745–1762; (d) Lachance, H.; Hall, D. G. Org. React. 2008, 73, 1–573.
calc = 1.346 mg/m3,
l , F(000) = 728, Z = 4, monoclinic, space
= 0.321 mmꢀ1
group P2(1)/c, T = 153(2) K, 9737 reflections collected, 3337 [R(int) = 0.0311]
independent reflections, hmax 26.00° 209 refined parameters, maximum
residual electron density 0.741 and ꢀ0.499 e.Åꢀ3, R1 = 0.0525, wR2 = 0.1114.
Crystallographic data for the structure have been deposited with the
Cambridge Crystallographic Data Centre as deposition No. CCDC-819331;
6-[(4-Methylphenyl)sulfonyl]-5,6-dihydro-2H-1,6-benzothiazocine (6c). 1H
NMR (300 MHz, CDCl3): d (ppm) 7.69 (2H, d, J 8.1 Hz), 7.36–7.31 (3H, m),
7.23–7.18 (1H, m), 7.11–7.06 (1H, m), 6.74 (1H, d, J 7.8 Hz), 5.72–5.63 (1H, m),
5.48–5.40 (1H, m), 4.54–3.71 (4H, br m), 2.46 (3H, s); 13C NMR (75 MHz,
CDCl3):
d (ppm) 143.8, 138.3, 138.0, 136.2, 131.4, 129.6, 129.1, 128.9,