One-pot enyne ring-closing metathesis-Diels-Alder reactions for the synthesis of polycyclic sulfamides

Article abstract of DOI:10.1016/j.tet.2014.04.014

Ring-closing metathesis (RCM) and sequential Yb(OTf)₃ promoted Diels-Alder reactions of sulfamide-linked enynes proceeded selectively in one-pot to afford a series of bicyclic and tricyclic sulfamides. Excellent levels of diastereoselectivity are observed for the cycloaddition step, with only the endo-adducts being isolated. The protocol was further extended to incorporate a one-pot RCM-cross metathesis (CM)-Diels-Alder sequence, permitting rapid access to high levels of molecular complexity from simple and easily accessible precursors.

Full text of DOI:10.1016/j.tet.2014.04.014

Tetrahedron 70 (2014) 3700e3706
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot enyne ring-closing metathesiseDielseAlder reactions for
the synthesis of polycyclic sulfamides
Joseph T. Hill-Cousins a, Sofia S. Salim a, Youssef M. Bakar a, Richard K. Bellingham b,
,
Mark E. Light a, Richard C.D. Brown a
*
a Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
b Synthetic Chemistry Department, Chemical Development, GlaxoSmithKline Pharmaceuticals, Old Powder Mills, Tonbridge, Kent TN11 9AN, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Ring-closing metathesis (RCM) and sequential Yb(OTf)3 promoted DielseAlder reactions of sulfamide-
linked enynes proceeded selectively in one-pot to afford a series of bicyclic and tricyclic sulfamides.
Excellent levels of diastereoselectivity are observed for the cycloaddition step, with only the endo-ad-
ducts being isolated. The protocol was further extended to incorporate a one-pot RCMecross metathesis
(CM)eDielseAlder sequence, permitting rapid access to high levels of molecular complexity from simple
and easily accessible precursors.
Received 27 January 2014
Received in revised form 24 March 2014
Accepted 7 April 2014
Available online 13 April 2014
Keywords:
Metathesis
Enyne
Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Sulfamide
DielseAlder
One-pot
1. Introduction
one-pot enyne RCMecycloaddition and enyne RCMeCMecy-
cloaddition sequences to produce polycyclic sulfamides (Scheme 1).
Enyne metathesis has progressed significantly as a practical
synthetic methodology since the advent of well-defined ruthenium
based carbene catalysts that are tolerant of a wide variety of
functionality.1 Enyne ring-closing metathesis (RCM) is formally
a cycloisomerisation process, thus providing an atom-efficient
means for the synthesis of structurally diverse carbocycles and
heterocycles and this strategy has attracted considerable interest in
the context of target synthesis.2 An additional appeal of enyne RCM
lies in the potential for manipulation of the 1,3-diene products,
particularly through the use of cycloaddition reactions, such as the
DielseAlder reaction to facilitate rapid access to bi- and tricyclic
structures.3 Hanson and co-workers recognised the benefit of ring-
closing diene metathesis as a method to construct cyclic sulfa-
mides, and applied this strategy in their synthesis of HIV protease
inhibitor analogues.4 We have previously reported strategies for
the construction of cyclic sulfonamides5 and sulfamides6 using
diene and enyne RCM, including a one-pot enyne RCMecross me-
tathesis (CM) protocol. Owing to the potential value of cyclic sul-
famide scaffolds for the development of small-molecule
therapeutics,7 we were attracted to the concept of sequential and
The results of our studies are described here.
Scheme 1. Enyne RCM(eCMe)cycloaddition sequence for the synthesis of polycyclic
sulfamides.
2. Results and discussion
Sulfamide-linked enyne metathesis substrates were conve-
niently prepared from chlorosulfonyl isocyanate (3, Scheme
2).4a,6b,8 Thus, sequential treatment of 3 with t-BuOH followed by
N-allylbenzylamine or N-allylaniline gave N-Boc protected
* Corresponding author. E-mail addresses: rcb1@soton.ac.uk, R.C.Brown@soton.
ac.uk (R.C.D. Brown).
0040-4020/$ e see front matter Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.014

J.T. Hill-Cousins et al. / Tetrahedron 70 (2014) 3700e3706
3701
sulfamides 4 and 5 in 89 and 73% yields, respectively. N-Alkylation
with either propargyl bromide or 1-bromo-2-butyne was carried
out in the presence of t-BuOK and 18-crown-6 to afford enynes
6e8, which underwent Boc cleavage in TFA to yield the deprotected
sulfamides 9e11. N-Alkylation of 9e11 under the basic conditions
described above gave five additional sulfamide substrates 12e16
for enyne RCM studies.
Scheme 4. Enyne RCM reactions of sulfamides containing disubstituted alkynes.
a
Synthesis previously reported in Ref. 6b.
Having demonstrated that sulfamide-linked enynes were able to
undergo RCM and RCMeCM reactions, we were intrigued by the
prospect of further one-pot transformation through cycloaddition
reactions of the 1,3-diene products. Towards this objective, an in-
vestigation of the DielseAlder reactions of the isolated enyne RCM
products 18, 19 and 22 was conducted (Scheme 5),9 using electron-
deficient dienophiles (di-iso-propylazodicarboxylate (DIAD), di-
methyl acetylenedicarboxylate (DMAD) and maleimide). The de-
sired polycyclic sulfamides 28e32 were obtained in yields of
65e86%, although these thermal DielseAlder reactions required
72 h heating at reflux in toluene to reach complete conversion.
a
Scheme 2. Synthesis of sulfamide-linked enyne metathesis substrates. Synthesis
previously reported in Ref. 6b.
A useful selectivity was observed in enyne RCM experiments;
treatment of enynes 6, 12 and 13 with Grubbs’ second generation
catalyst (2) resulted in RCMehomo-CM products,6b whereas the
corresponding reactions catalysed by Grubbs’ first generation cat-
alyst (1) favoured the products of formal cycloisomerisation, 17e19,
without significant CM (Scheme 3). The propensity for the initial
enyne RCM products to undergo further metathesis in the presence
of the second generation catalyst 2 was exploited to deliver a one-
pot enyne RCMeCM process by including 2e3 equiv of a mono-
substituted alkene in the reaction. As anticipated, sulfamides
20e24 were afforded in good yield, with excellent levels of E-se-
lectivity (ꢀ15:1 by 1H NMR). The internal alkyne substrates 7, 14
and 15 unsurprisingly displayed reduced reactivity towards me-
tathesis, and RCM of these compounds using Grubbs I was im-
practically slow. However, rapid conversion to the cyclised dienes
25e27 was achieved using Grubbs II under microwave irradiation,
without subsequent CM (Scheme 4).6b
Scheme 5. DielseAlder reactions of isolated enyne RCM products.
Sulfamides 31 and 32 were isolated as single diastereoisomers,
arising from endo selective addition of the dienophile.12 The ste-
reochemistry of sulfamide 32 was assigned using 2D 1H NOESY
NMR spectroscopy (Fig. 1). Additionally, sulfamide 30 was isolated
as a single diastereoisomer. The stereochemistry of sulfamide 30
was assigned by analogy with 32.
Scheme 3. Catalyst control in the metathesis reactions of sulfamide-linked enynes.
a
b
Synthesis previously reported in Ref. 6b. 17e19 were previously isolated in lower
yields (up to 8%, 60% and 63%, respectively) from mixtures with RCMeCM products
obtained using Grubbs II catalyst.
Fig. 1. Key cross-peaks in the 2D 1H NOESY NMR spectrum of sulfamide 32.

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J.T. Hill-Cousins et al. / Tetrahedron 70 (2014) 3700e3706
With respect to integration of the DielseAlder and metathesis
reactions into a one-pot process, it was considered that prolonged
heating should be avoided due to likely degradation of the me-
tathesis catalyst and undesired competing reactions mediated by
other ruthenium species.10 Therefore, promotion by Lewis-acids
was investigated, and while AlCl3 and Yb(OTf)3 were effective in
accelerating the cycloaddition only the lanthanide salt was com-
patible with the one-pot process.11
Gratifyingly, enyne RCM in toluene, followed by direct addition
of the dienophile (DIAD, DMAD, maleimide or N-phenylmaleimide)
and Yb(OTf)3 was effective in delivering the desired one-pot se-
quence, with the cycloaddition stage reduced to 12 h heating at
reflux as a result of Lewis-acid activation (Scheme 6). One equiva-
lent of Yb(OTf)3 was found to be necessary for the DielseAlder
reactions to proceed selectively and at an acceptable rate. Addi-
tionally, an excess of the dienophile (1.5 equiv) was necessary to
drive the DielseAlder reaction to completion, suggesting compet-
ing degradation of the dienophile under the one-pot reaction
conditions.
Fig. 2. X-ray structure of sulfamide 35.
By increasing the reactivity of the dienophile, the requirement
for Lewis-acid activation could be avoided. Thus, reaction of enyne
16 with Grubbs I in toluene followed by direct addition of N-
methyl-1,2,4-triazoline-3,5-dione13 and heating at reflux for 5 h
afforded DielseAlder cycloadduct 36 in 69% yield (Scheme 7).
Scheme 7. One-pot enyne RCMeDielseAlder sequence without Lewis-acid activation.
The methodology could be extended to encompass a one-pot
enyne RCMeCMeDielseAlder sequence, allowing for increased
product substitution. Enyne 13 underwent enyne RCMeCM on
exposure to Grubbs II and styrene, whereupon the addition of
Yb(OTf)3 and either DMAD or maleimide selectively led to sulfa-
mide 30 or 32, both in 79% yield (Scheme 8). It is also noteworthy
that for the synthesis of sulfamides 28e32 the one-pot procedure
was more efficient than the stepwise protocol, providing improved
isolated yields.
Scheme 6. One-pot enyne RCMeDielseAlder reactions.
In the one-pot process, the selectivity of the initial enyne RCM
was again controlled by selection of the appropriate catalyst, with
enynes 12, 13 and 16 being treated with Grubbs I prior to the
DielseAlder cycloaddition, ultimately affording bi- and tricyclic
sulfamides 28, 29, 31, 34 and 35 in high yields of 63e86%. Trans-
formation of the enyne 15 containing an internal alkyne required
the use of Grubbs II catalyst to effect RCM, with the subsequent
cycloaddition with DMAD proceeding smoothly to afford sulfamide
33 in 79% yield. As anticipated, the DielseAlder step again exhibited
high levels of diastereocontrol in the one-pot process with only the
endo-adducts 31, 34 and 35 being isolated.12 The stereochemistry of
sulfamide 35 was assigned by single crystal X-ray diffraction and
sulfamides 31 and 34 were assigned by analogy (Fig. 2), and com-
Scheme 8. One-pot enyne RCMeCMeDielseAlder reactions.
3. Conclusion
A one-pot procedure for the formation of polycyclic sulfamides
via an enyne RCMeDielseAlder sequence has been developed,
giving rise to the endo-adducts as the sole observed stereoisomers.
In the one-pot process, Yb(OTf)3 was required to promote the cy-
cloaddition of DIAD, DMAD, maleimide or N-phenylmaleimide,
whereas the corresponding reaction of the powerful dienophile N-
methyl-1,2,4-triazoline-3,5-dione proceeded in the absence of
added Lewis-acid. The protocol can be extended to a selective one-
parison of coupling constant data in the respective 1H NMR spectra.
3
In particular, the JHeH coupling constants between H1 and H10b
a
(12e13 Hz) and H1 and H10b (2e3 Hz) are comparable for sulfa-
b
mides 31, 34 and 35.

J.T. Hill-Cousins et al. / Tetrahedron 70 (2014) 3700e3706
3703
pot RCMeCMeDielseAlder sequence, bringing together three
components, to produce high levels of molecular complexity from
easily accessible precursors in short order. The one-pot procedure
gave the additional benefit of superior yields in comparison to
performing the reactions separately.
28.1; IR (neat)
n
2981, 1725, 1646, 1595, 1492, 1367, 1313, 1247,
1139 cmꢃ1; HRMS (ESI) m/z calcd for C17H22N2NaO4Sþ [MþNa]þ
373.1192, found 373.1196.
4.1.3. N-Allyl-N-phenyl-(N0-(2-propynyl))sulfamide (11). To a solu-
tion of sulfamide 8 (5.38 g, 15.4 mmol) in CH2Cl2 (20 mL) was added
TFA (5.88 mL, 76.8 mmol) and the resulting mixture was allowed to
stir at rt for 16 h. The reaction was quenched by addition of satu-
rated aqueous NaHCO3 solution (40 mL) and the aqueous layer was
extracted with CH2Cl2 (3ꢂ30 mL). The combined extracts were
dried (Na2SO4) and solvent was removed in vacuo. Chromatography
on silica gel (EtOAc/hexane 1:4) afforded the title compound 11
(2.78 g, 11.1 mmol, 72%) as a colourless oil: 1H NMR (400 MHz,
4. Experimental section
4.1. General
All chemicals were used as received from standard chemical
suppliers unless otherwise stated. All reactions were performed
in oven or flame-dried apparatus under an inert atmosphere
using distilled dry solvents. Toluene was distilled from sodium,
THF from sodium/benzophenone and CH2Cl2 from CaH2. Re-
actions were monitored by analytical TLC using aluminium plates
pre-coated with silica gel 60 (Merck). Flash column chromatog-
CDCl3)
d
7.41e7.26 (m, 5H), 5.86 (dddd, J¼2.7, 6.4, 12.9, 16.6 Hz, 1H),
5.13 (m, 1H), 5.10 (m, 1H), 4.58 (s, 1H), 4.27e4.23 (m, 2H), 3.89e3.86
(m, 2H), 2.35 (dd, J¼2.5, 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
139.9, 133.0, 129.2, 128.7, 127.9, 118.9, 78.9, 73.0, 54.9, 33.2; IR
(neat) n
3286, 1644, 1594, 1492, 1330, 1221, 1152, 1069 cmꢃ1; HRMS
raphy was performed on silica gel with particle size 40e63
(Merck). 1H NMR and 13C NMR spectra were recorded at 400 and
100 MHz, respectively. Chemical shifts are reported in units
using CHCl3 7.15 ppm
7.27 ppm 1H, 77.0 ppm 13C), benzene (
1H, 128.0 ppm 13C) or DMSO ( 2.50 ppm 1H, 39.5 ppm 13C) as
mm
(ESI) m/z calcd for C12H14N2NaO2Sþ [MþNa]þ 273.0668, found
273.0665.
d
(
d
d
d
4.1.4. N-Allyl-N-phenyl-(N0-benzyl-N0-(2-propynyl))sulfamide
(16). To a solution of sulfamide 11 (2.23 g, 8.91 mmol) in THF
(75 mL) were sequentially added t-BuOK (1.01 g, 8.91 mmol), 18-
crown-6 (2.35 g, 8.91 mmol) and BnCl (1.02 mL, 8.91 mmol). The
resulting mixture was allowed to stir at rt for 42 h before being
quenched with distilled water. The mixture was extracted with
Et2O (3ꢂ75 mL) and the combined extracts were washed with brine
(2ꢂ75 mL) before being dried (Na2SO4). The solvent was removed
in vacuo and the residue purified by column chromatography on
silica gel (Et2O/hexane 3:17) to afford the title compound 16 (2.38 g,
7.00 mmol, 79%) as a colourless solid: mp¼47e49 ꢁC; 1H NMR
d
d
d
an internal standard. 1H NMR coupling constants J are reported in
hertz. Matching coupling constants are corrected. Infrared spec-
tra were recorded on a spectrometer fitted with a Diamond
platform, as solids or neat liquids. Electrospray mass spectra were
obtained using a Micromass platform mass analyser with an
electrospray ion source. Melting points are uncorrected. The
syntheses of sulfamides 4, 6, 7, 9, 10, 12e15 and 17e27 were
reported previously.6b
4.1.1. N-Allyl-N-phenyl-(N0-tert-butoxycarbonyl)sulfamide
(5). To
(400 MHz, CDCl3) d 7.44e7.42 (m, 2H), 7.39e7.35 (m, 2H), 7.32e7.25
a solution of chlorosulfonyl isocyanate (1.93 mL, 22.7 mmol) in
CH2Cl2 (50 mL) at 0 ꢁC was added t-BuOH (2.15 mL, 22.7 mmol) and
the resulting mixture was allowed to stir at 0 ꢁC for 10 min. Et3N
(3.07 mL, 22.7 mmol) was added, followed by N-allylaniline (3.00 g,
22.7 mmol) and the resulting suspension was warmed to rt and
stirred for 20 h. The reaction mixture was diluted with CH2Cl2
(40 mL) and washed with 1 M HCl (3ꢂ30 mL) followed by distilled
water (2ꢂ30 mL). The organic layer was dried (Na2SO4) and solvent
was removed in vacuo. Chromatography on silica gel (Et2O/hexane
1:4) afforded the title compound 5 (5.14 g, 16.5 mmol, 73%) as
a colourless solid: mp¼53e56 ꢁC; 1H NMR (400 MHz, CDCl3)
(m, 6H), 5.86 (dtdd, J¼1.1, 6.4, 10.2, 16.9 Hz, 1H), 5.12 (m, 1H), 5.09
(m, 1H), 4.39 (s, 2H), 4.31e4.28 (m, 2H), 3.88e3.87 (m, 2H), 2.34 (m,
1H); 13C NMR (100 MHz, CDCl3)
d
140.0, 135.2, 133.1, 129.1, 128.9,
128.6, 128.0, 127.7, 118.8, 77.9, 73.7, 55.0, 50.8, 36.1; IR (neat) 3282,
n
3064, 3032, 2919, 1644, 1594, 1493, 1332, 1219, 1151, 1060 cmꢃ1
;
HRMS (ESI) m/z calcd for C19H20N2NaO2Sþ [MþNa]þ 363.1138,
found 363.1141.
4.1.5. Diisopropyl 8-benzyl-6-methyl-5,6,9,9a-tetrahydropyridazino
[3,4-d][1,2,7]thiadiazepine-1,2(3H,8H)-dicarboxylate 7,7-dioxide (28)
d
7.42e7.31 (m, 5H), 5.83 (tdd, J¼6.2, 10.2, 17.1 Hz, 1H), 5.14 (qd,
J¼1.2, 17.1 Hz, 1H), 5.09 (qd, J¼1.2, 10.2 Hz, 1H), 4.51 (td, J¼1.2,
6.2 Hz, 2H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3)
150.5, 138.8,
133.3, 129.3, 128.8, 128.3, 118.4, 83.2, 56.7, 28.0; IR (neat) 2981,
4.1.5.1. From 1,3-diene 18. To a solution of 1,3-diene 18 (50 mg,
0.18 mmol) in toluene (10 mL) was added DIAD (55 mg, 0.27 mmol)
and the reaction was stirred under reflux for 72 h. The reaction
mixture was then cooled and concentrated in vacuo and the
resulting crude residue was purified by column chromatography on
silica gel (Et2O/hexane 2:8) to yield the title compound 28 as a col-
ourless solid (67 mg, 0.14 mmol, 78%).
d
n
2834, 1738, 1645, 1363, 1134, 1492 cmꢃ1; HRMS (ESI) m/z calcd for
C
14H20N2NaO4Sþ [MþNa]þ 335.1036, found 335.1042.
4.1.2. N-Allyl-N-phenyl-(N0-tert-butoxycarbonyl-N0-(2-propynyl))
sulfamide (8). To a solution of sulfamide 5 (5.06 g, 16.2 mmol) in
THF (120 mL) were sequentially added t-BuOK (2.01 g,
17.0 mmol), 18-crown-6 (4.48 g, 17.0 mmol) and propargyl bro-
mide (2.58 mL, 17.0 mmol). The resulting mixture was allowed to
stir at rt for 48 h, then distilled water was added. The mixture was
extracted with Et2O (3ꢂ75 mL) and the combined extracts were
washed with brine (2ꢂ75 mL) and dried (Na2SO4). The solvent
was removed in vacuo and the residue purified by column chro-
matography on silica gel (EtOAc/hexane 1:9) to afford the title
compound 8 (5.42 g, 15.5 mmol, 96%) as a colourless oil: 1H NMR
4.1.5.2. One-pot sequence from enyne 12. To a solution of enyne
12 (50 mg, 0.18 mmol) in toluene (10 mL) was added Grubbs I
(15 mg, 0.018 mmol). The reaction was stirred at 50 ꢁC for 12 h,
whereupon DIAD (55 mg, 0.27 mmol) and Yb(OTf)3 (111 mg,
0.18 mmol) were added and the reaction was stirred for a further
12 h under reflux. The mixture was cooled and concentrated in
vacuo and the resulting brown oil was purified by column chro-
matography on silica gel (EtOAc/hexane 3:7) to yield the title
compound 28 as a colourless solid (66 mg, 0.14 mmol, 78%):
mp¼120e121 ꢁC; 1H NMR (400 MHz, DMSO-d6, 353 K)
d 7.39e7.34
(400 MHz, CDCl3)
d
7.40e7.28 (m, 5H), 5.81 (tdd, J¼6.2, 10.2,
(m, 2H), 7.32e7.27 (m, 3H), 5.96 (m, 1H), 4.92 (m, 1H), 4.82 (septet,
J¼6.2 Hz, 1H), 4.74 (septet, J¼6.2 Hz, 1H), 4.49 (d, J¼15.3 Hz, 1H),
4.40 (dd, J¼3.3, 18.0 Hz, 1H), 4.25 (d, J¼15.3 Hz, 1H), 3.85 (d,
J¼14.6 Hz, 1H), 3.74 (d, J¼18.0 Hz, 1H), 3.65 (d, J¼14.6 Hz, 1H), 3.38
(dd, J¼6.2, 14.0 Hz, 1H), 2.93 (dd, J¼8.9, 14.0 Hz, 1H), 2.82 (s, 3H),
17.1 Hz, 1H), 5.13 (qd, J¼1.3, 17.1 Hz, 1H), 5.08 (qd, J¼1.3, 10.2 Hz,
1H), 4.52 (td, J¼1.3, 6.2 Hz, 2H), 4.16 (d, J¼2.4 Hz, 2H), 1.89 (t,
J¼2.4 Hz, 1H), 1.58 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 150.8,
138.2, 133.3, 129.3, 129.1, 128.3, 118.3, 84.3, 78.2, 71.1, 57.3, 38.3,

3704
J.T. Hill-Cousins et al. / Tetrahedron 70 (2014) 3700e3706
1.18 (d, J¼6.2 Hz, 6H), 1.16e1.07 (br m, 3H), 1.06e0.77 (br m, 3H);
13C NMR (100 MHz, DMSO-d6, 353 K)
153.5, 153.4, 136.1, 131.1,
128.1, 127.3, 127.2, 124.5, 69.7, 69.0, 55.3, 53.7, 53.1, 47.7, 35.9, 21.2,
53.0, 52.5, 52.4, 52.2, 51.8, 51.7, 45.4, 38.8; IR (neat) n 3029, 2951,
d
1721, 1494, 1350, 1259, 1154, 1094 cmꢃ1; HRMS (ESI) m/z calcd for
C
32H33N2O6Sþ [MþH]þ 573.2054, found 573.2044.
21.1, 21.0; IR (neat) n 2981, 2935, 1707, 1454, 1410, 1364, 1288, 1152,
1106 cmꢃ1; HRMS (ESI) m/z calcd for C22H33N4O6Sþ [MþH]þ
4.1.8. (7aS*,10aR*,10bS*)-2,4-Dibenzyl-4,5,7,7a,10a,10b-hexahydro-
1H-[1,2,7]thiadiazepino[4,5-e]isoindole-8,10(2H,9H)-dione 3,3-
dioxide (31)
481.2115, found 481.2112.
4.1.6. Dimethyl 2,4-dibenzyl-1,2,4,5,5a,8-hexahydrobenzo[d][1,2,7]
thiadiazepine-6,7-dicarboxylate 3,3-dioxide (29)
4.1.8.1. From 1,3-diene 19. To a solution of 1,3-diene 19 (50 mg,
0.14 mmol) in toluene (10 mL) was added maleimide (21 mg,
0.21 mmol) and the reaction was stirred under reflux for 72 h. The
reaction mixture was then cooled and concentrated in vacuo and
the resulting crude residue was purified by column chromatogra-
phy on silica gel (Et2O/hexane 9:1) to yield the title compound 31 as
a colourless solid (48 mg, 0.11 mmol, 79%).
4.1.6.1. From 1,3-diene 19. To a solution of 1,3-diene 19 (50 mg,
0.14 mmol) in toluene (10 mL) was added DMAD (25 mL, 0.21 mmol)
and the reaction was stirred under reflux for 72 h. The reaction
mixture was then cooled and concentrated in vacuo and the
resulting crude residue was purified by column chromatography on
silica gel (Et2O/hexane 9:1) to yield the title compound 29 as a col-
ourless oil (60 mg, 0.12 mmol, 86%).
4.1.8.2. One-pot sequence from enyne 13. To a solution of enyne
13 (50 mg, 0.14 mmol) in toluene (10 mL) was added Grubbs I
(23 mg, 0.028 mmol). The reaction was stirred at 50 ꢁC for 12 h,
whereupon maleimide (21 mg, 0.21 mmol) and Yb(OTf)3 (87.0 mg,
0.14 mmol) were added and the mixture was stirred for a further
12 h under reflux. The mixture was cooled and concentrated in
vacuo and the resulting mixture was purified by column chroma-
tography on silica gel (EtOAc/hexane 1:1) to yield the title com-
4.1.6.2. One-pot sequence from enyne 13. To a solution of enyne
13 (50 mg, 0.14 mmol) in toluene (10 mL) was added Grubbs I
(12 mg, 0.014 mmol). The reaction was stirred at 50 ꢁC for 12 h,
whereupon DMAD (25
mL, 0.21 mmol) and Yb(OTf)3 (112 mg,
0.14 mmol) were added and the mixture was stirred for a further
12 h under reflux. The mixture was cooled and concentrated in
vacuo and the resulting mixture was purified by column chroma-
tography on silica gel (EtOAc/hexane 1:4) to yield the title com-
pound 29 as a colourless oil (61 mg, 0.12 mmol, 86%): 1H NMR
pound 32 as
a colourless solid (56 mg, 0.12 mmol, 86%):
mp¼208e210 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d 11.14 (s, 1H),
7.43e7.25 (m, 10H), 5.76 (m, 1H), 4.72 (d, J¼15.2 Hz, 1H), 4.59 (d,
J¼14.5 Hz,1H), 4.42 (d, J¼15.2 Hz,1H), 4.42 (dd, J¼12.6,16.0 Hz,1H),
4.21 (d, J¼15.7 Hz, 1H), 3.89 (d, J¼14.5 Hz, 1H), 3.27 (d, J¼15.7 Hz,
1H), 3.16e3.02 (m, 4H), 2.46e2.34 (m, 2H); 13C NMR (100 MHz,
(400 MHz, C6D6)
d
7.41 (d, J¼7.4 Hz, 2H), 7.30 (d, J¼7.4 Hz, 2H),
7.17e7.03 (m, 6H), 4.92 (m, 1H), 4.60 (d, J¼14.7 Hz, 1H), 4.33 (d,
J¼15.1 Hz, 1H), 4.25 (d, J¼15.1 Hz, 1H), 4.10 (d, J¼14.7 Hz, 1H), 3.42
(m, 1H), 3.35 (s, 3H), 3.33 (s, 2H), 3.27 (s, 3H), 3.12 (dd, J¼2.9,
14.4 Hz, 1H), 3.04 (dd, J¼9.6, 14.4 Hz, 1H), 2.73 (dd, J¼4.5, 23.3 Hz,
1H), 2.54 (ddd, J¼4.7, 4.8, 23.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
DMSO-d6) d 180.7, 179.6, 137.3, 137.0, 136.1, 129.1, 128.5, 128.4, 128.0,
127.7, 127.4, 50.6, 50.4, 49.0, 45.7, 44.2, 40.7, 36.1, 24.2; IR (neat)
n
1693, 1355, 1324, 1155, 1131, 921, 789 cmꢃ1; HRMS (ESI) m/z calcd
for C24H26N3O4S [MþH]þ 452.1639, found 452.1640.
d
167.7, 167.1, 136.4, 136.2, 135.5, 132.8, 132.6, 128.8, 128.6, 128.5,
128.2, 127.9, 53.5, 52.4, 52.4, 50.3, 38.3, 28.4; IR (neat) n 3030, 2951,
1721, 1648, 1495, 1352, 1261, 1154, 1198, 1154, 1091 cmꢃ1; HRMS
(ESI) m/z calcd for C26H28N2O6SNaþ [MþNa]þ 519.1560, found
519.1567.
4.1. 9. (7S*, 7aS*,10aR*,10bS*)-2, 4-Dibenzyl-7-phenyl-
4,5,7,7a,10a,10b-hexahydro-1H-[1,2,7]thiadiazepino[4,5-e]isoindole-
8,10(2H,9H)-dione 3,3-dioxide (32)
4.1.9.1. From 1,3-diene 22. To a solution of 1,3-diene 22 (60 mg,
0.14 mmol) in toluene (10 mL) was added maleimide (21 mg,
0.21 mmol) and the reaction was stirred under reflux for 72 h. The
reaction mixture was then cooled, concentrated in vacuo and the
resulting crude residue was purified by column chromatography on
silica gel (Et2O/hexane 9:1) to yield the title compound 32 as a col-
ourless solid (48 mg, 0.091 mmol, 65%).
4.1.7. (5aR*,8R*)-Dimethyl 2,4-dibenzyl-8-phenyl-1,2,4,5,5a,8-
hexahydrobenzo[d][1,2,7]thiadiazepine-6,7-dicarboxylate 3,3-dioxide
(30)
4.1.7.1. From 1,3-diene 22. To a solution of 1,3-diene 22 (60 mg,
0.14 mmol) in toluene (10 mL) was added DMAD (25 mL, 0.21 mmol)
and the reaction was stirred under reflux for 72 h. The reaction
mixture was then cooled and concentrated in vacuo and the
resulting crude residue was purified by column chromatography on
silica gel (Et2O/hexane 9:1) to yield the title compound 30 as a col-
ourless oil (69 mg, 0.12 mmol, 86%).
4.1.9.2. One-pot sequence from enyne 13. To a solution of enyne
13 (50 mg, 0.14 mmol) in toluene (10 mL) were added Grubbs II
(7 mg, 0.084 mmol) and styrene (100 mL, 0.42 mmol). The mixture
was stirred at 50 ꢁC for 12 h, whereupon maleimide (21 mg,
0.21 mmol) and Yb(OTf)3 (87.0 mg, 0.14 mmol) were added and the
mixture was stirred for a further 12 h under reflux. The mixture was
cooled and concentrated in vacuo and the resulting mixture was
purified by column chromatography on silica gel (EtOAc/hexane
1:1) to yield the title compound 36 as a colourless solid (60 mg,
4.1.7.2. One-pot sequence from enyne 13. To a solution of enyne
13 (50 mg, 0.14 mmol) in toluene (10 mL) were added Grubbs II
(7 mg, 0.084 mmol) and styrene (100
m
L, 0.42 mmol). The mixture
was stirred at 50 ꢁC for 12 h, whereupon DMAD (25
mL, 0.21 mmol)
and Yb(OTf)3 (87 mg, 0.14 mmol) were added and the mixture was
stirred for a further 12 h under reflux. The mixture was cooled and
concentrated in vacuo and the resulting mixture was purified by
column chromatography on silica gel (EtOAc/hexane 1:4) to yield
the title compound 35 as a colourless oil (64 mg, 0.11 mmol, 79%): 1H
0.11 mmol, 79%): mp¼190e191 ꢁC; 1H NMR (400 MHz, CDCl3)
d 7.52
(s, 1H), 7.43e7.22 (m, 15H), 6.11 (m, 1H), 4.83 (d, J¼14.2 Hz,1H), 4.76
(dd, J¼12.1, 16.1 Hz, 1H), 4.67 (d, J¼14.5 Hz, 1H), 4.53 (d, J¼16.2 Hz,
1H), 4.48 (d, J¼14.5 Hz, 1H), 3.83 (d, J¼14.2 Hz, 1H), 3.71 (m, 1H),
3.48 (d, J¼16.2 Hz, 1H), 3.37 (dd, J¼8.0, 8.3 Hz, 1H), 3.16 (dd, J¼2.9,
16.1 Hz, 1H), 3.04 (dd, J¼4.9, 8.3 Hz, 1H), 2.77 (m, 1H); 13C NMR
NMR (400 MHz, CDCl3)
d
7.45e7.20 (m, 15H), 5.62 (d, J¼4.3 Hz, 1H),
4.68 (d, J¼14.8 Hz, 1H), 4.61 (d, J¼15.0 Hz, 1H), 4.43 (m, 1H), 4.35 (d,
J¼14.8 Hz, 1H), 4.32 (d, J¼15.0 Hz, 1H), 3.84 (d, J¼14.8 Hz, 1H), 3.67
(s, 3H), 3.59 (s, 3H), 3.59 (d, J¼14.8 Hz, 1H), 3.57 (m, 1H), 3.51 (dd,
J¼2.3, 14.5 Hz, 1H), 3.27 (dd, J¼10.1, 14.5 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 178.9, 176.9, 139.4, 137.8, 136.9, 136.3, 131.9,
128.5, 128.4, 127.8, 127.7, 127.5, 127.4, 126.2, 50.5, 50.5, 49.1, 47.4,
45.4, 45.2, 40.9, 36.7; IR (neat)
n 3300, 3026, 1780, 1712, 1336,
(100 MHz, CDCl3)
d
167.6, 166.9, 139.4, 139.3, 136.4, 136.2, 131.9,
1146 cmꢃ1; HRMS (ESI) m/z calcd for C30H30N3O4Sþ [MþH]þ
131.0, 129.0,128.7,128.6,128.5,128.1,128.0,127.9,127.8,127.5,127.5,
528.1952, found 528.1947.

J.T. Hill-Cousins et al. / Tetrahedron 70 (2014) 3700e3706
3705
4.1.10. Dimethyl 2,4-dibenzyl-9-methyl-1,2,4,5,5a,8-hexahydrobenzo
[d][1,2,7]thiadiazepine-6,7-dicarboxylate 3,3-dioxide (33). To a solu-
tion of enyne 15 (51 mg, 0.14 mmol) in toluene (10 mL) was added
9,11(2H,7H)-dione 3,3-dioxide (36). To a solution of enyne 16
(100 mg, 0.29 mmol) in toluene (20 mL) was added Grubbs I
(24 mg, 0.029 mmol). The reaction was stirred at 50 ꢁC for 15 h,
Grubbs II (3.5 mg, 4.2
m
mol). The mixture was stirred at 50 ꢁC for
L, 0.21 mmol) and Yb(OTf)3 (87 mg,
whereupon
N-methyl-1,2,4-triazoline-3,5-dione
(68
mg,
12 h, whereupon DMAD (25
m
0.59 mmol) was added and the mixture was stirred for a further 5 h
under reflux. The mixture was cooled and concentrated in vacuo
and the resulting mixture was purified by column chromatography
on silica gel (EtOAc/hexane 1:1) to yield the title compound 34 as
a colourless solid (92 mg, 0.20 mmol, 69%): mp¼178e181 ꢁC; 1H
0.14 mmol) were added and the mixture was stirred for a further
12 h under reflux. The mixture was cooled and concentrated in
vacuo and the resulting mixture was purified by column chroma-
tography on silica gel (EtOAc/hexane 1:4) to yield the title com-
pound 30 as
a
colourless solid (56 mg, 0.11 mmol, 79%):
NMR (400 MHz, CDCl3) d 7.37e7.18 (m, 10H), 5.71 (m, 1H), 4.78 (dd,
mp¼122e123 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.44e7.29 (m, 10H),
J¼4.3, 10.0 Hz, 1H), 4.51 (d, J¼14.8 Hz, 1H), 4.21 (d, J¼14.8 Hz, 1H),
4.20 (d, J¼16.9 Hz, 1H), 4.14 (dd, J¼4.3, 13.6 Hz, 1H), 4.00 (d,
J¼15.6 Hz, 1H), 3.89 (d, J¼16.9 Hz, 1H), 3.61 (d, J¼15.6 Hz, 1H), 3.56
(dd, J¼10.0, 13.6 Hz, 1H), 2.97 (s, 3H); 13C NMR (100 MHz, CDCl3)
4.69 (d, J¼14.9 Hz, 1H), 4.44 (d, J¼14.5 Hz, 1H), 4.36 (d, J¼14.9 Hz,
1H), 4.33 (d, J¼14.5 Hz, 1H), 4.10 (d, J¼15.2 Hz, 1H), 3.76 (s, 3H), 3.65
(s, 3H), 3.60 (m, 1H), 3.41 (d, J¼15.2 Hz, 1H), 3.24 (dd, J¼3.1, 14.2 Hz,
1H), 3.05 (dd, J¼3.7, 23.1 Hz, 1H), 2.98 (dd, J¼9.4, 14.2 Hz, 1H), 2.87
d
154.1, 152.7, 141.8, 135.5, 131.1, 129.4, 128.8, 128.2, 128.1, 127.5,
(d, J¼23.1 Hz, 1H), 1.61 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
167.7,
126.9, 121.6, 55.4, 52.9, 52.3, 50.1, 43.4, 25.1; IR (neat) n 3063, 3032,
167.0, 136.6, 136.3, 135.4, 133.3, 128.8, 128.6, 128.5, 128.4, 128.3,
127.9, 127.8, 126.1, 54.3, 52.8, 52.4, 51.2, 48.4, 39.9, 34.6, 18.3; IR
2929, 1770, 1700, 1592, 1493, 1353, 1210, 1152, 1018 cmꢃ1; HRMS
(ESI) m/z calcd for
454.1534.
C
22H24N5O4Sþ [MþH]þ 454.1544, found
(neat)
n
3031, 2950, 2862, 1721, 1434, 1346, 1154, 1078, 941 cmꢃ1
;
HRMS (ESI) m/z calcd for C27H31N2O6Sþ [MþH]þ 511.1897, found
511.1905.
Acknowledgements
4.1.11. (7aS*,10aR*,10bS*)-2-Benzyl-4-methyl-4,5,7,7a,10a,10b-hex-
ahydro-1H-[1,2,7]thiadiazepino[4,5-e]isoindole-8,10(2H,9H)-dione
3,3-dioxide (34). To a solution of enyne 12 (44 mg, 0.16 mmol) in
toluene (10 mL) was added Grubbs I (13 mg, 0.016 mmol). The re-
action was stirred at 50 ꢁC for 12 h, whereupon maleimide (23 mg,
0.24 mmol) and Yb(OTf)3 (98 mg, 0.16 mmol) were added and the
mixture stirred for a further 12 h under reflux. The mixture was
concentrated in vacuo and the resulting mixture was purified by
column chromatography on silica gel (EtOAc/hexane 2:1) to yield
the title compound 31 as a colourless solid (39 mg, 0.10 mmol, 63%):
The authors acknowledge EPSRC and GlaxoSmithKline for
a CASE award (S.S.S.), the Royal Society for a University Research
Fellowship (R.C.D.B.) (516002) and the European Regional De-
velopment Fund (ERDF) (4494/4196 AI-Chem Channel) for funding
the AI-Chem project through the INTERREG IVa program 4061.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.04.014.
mp¼254 ꢁC (dec); 1H NMR (400 MHz, DMSO-d6)
d 11.15 (s, 1H),
7.41e7.29 (m, 5H), 6.02 (m, 1H), 4.67 (d, J¼15.4 Hz, 1H), 4.40 (d,
J¼15.4 Hz, 1H), 4.33 (dd, J¼13.1, 15.7 Hz, 1H), 4.26 (d, J¼15.5 Hz, 1H),
3.49 (d, J¼15.5 Hz, 1H), 3.15e3.08 (m, 2H), 3.01 (dd, J¼2.3, 15.7 Hz,
1H), 2.92 (m, 1H), 2.60 (s, 3H), 2.46 (dd, J¼7.3, 15.2 Hz, 1H), 2.26 (m,
References and notes
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Chem. Rev. 2004, 104, 1317e1382; (b) Villar, H.; Frings, M.; Bolm, C. Chem. Soc.
Rev. 2007, 36, 55e66; (c) van Otterlo, W. A. L.; de Koning, C. B. Chem. Rev. 2009,
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N. P.; Brown, R. C. D. Org. Lett. 2007, 9, 1867e1869; (b) Li, J.; Park, S.; Miller, R. L.;
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3634e3647.
3. For examples of enyneemetathesiseDielseAlder sequences see: (a) Kotha, S.;
Sreenivasachary, N.; Brahmachary, E. Tetrahedron Lett. 1998, 39, 2805e2808; (b)
Kotha, S.; Sreenivasachary, N. Chem. Commun. 2000, 503e504; (c) Saito, N.;
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Spandl, R. J.; Rudyk, H.; Spring, D. R. Chem. Commun. 2008, 3001e3003; (f)
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O’Leary-Steele, C.; Pedersen, P. J.; James, T.; Lanyon-Hogg, T.; Leach, S.; Hayes, J.;
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1H); 13C NMR (100 MHz, DMSO-d6)
d 180.8, 179.6, 138.0, 137.3,
128.7, 128.5, 127.6, 127.4, 53.7, 51.3, 45.6, 44.3, 40.8, 36.7, 34.2, 24.2;
IR (neat) n
1696, 1350, 1332, 1146, 1126, 914, 781 cmꢃ1; HRMS (ESI)
m/z calcd for C18H22N3O4Sþ [MþH]þ 376.1326, found 376.1324.
4.1.12. (7aS*,10aR*,10bS*)-4-Benzyl-2,9-diphenyl-4,5,7,7a,10a,10b-
hexahydro-1H-[1,2,7]thiadiazepino[4,5-e]isoindole-8,10(2H,9H)-di-
one 3,3-dioxide (35). To a solution of enyne 16 (100 mg, 0.29 mmol)
in toluene (20 mL) was added Grubbs I (24 mg, 0.029 mmol). The
reaction was stirred at 50 ꢁC for 15 h, whereupon N-phenyl-
maleimide (76 mg, 0.44 mmol) and Yb(OTf)3 (181 mg, 0.29 mmol)
were added and the mixture was stirred for a further 8 h under
reflux. The mixture was cooled and concentrated in vacuo and the
resulting mixture was purified by column chromatography on silica
gel (EtOAc/hexane 2:3) to yield the title compound 33 as a colourless
solid (118 mg, 0.23 mmol, 79%): mp¼206e209 ꢁC; 1H NMR
(400 MHz, DMSO-d6)
d
7.47e7.29 (m, 13H), 7.12 (d, J¼7.4 Hz, 2H),
5.90 (m, 1H), 4.87 (dd, J¼12.2, 15.6 Hz, 1H), 4.50 (d, J¼14.6 Hz, 1H),
4.31 (d, J¼15.7 Hz, 1H), 4.01 (d, J¼14.6 Hz, 1H), 3.72 (dd, J¼3.1,
15.6 Hz,1H), 3.50 (dd, J¼5.1, 8.3 Hz,1H), 3.49 (d, J¼15.7 Hz,1H), 3.36
(m, 1H), 2.97 (m, 1H), 2.58 (dd, J¼7.1, 14.8 Hz, 1H), 2.47 (m, 1H); 13
C
NMR (100 MHz, DMSO-d6)
d 178.5, 177.3, 142.7, 136.9, 135.9, 132.0,
4. (a) Dougherty, J. M.; Probst, D. A.; Robinson, R. E.; Moore, J. D.; Klein, T. A.;
Snelgrove, K. A.; Hanson, P. R. Tetrahedron 2000, 56, 9781e9790; (b) Jun, J. H.;
Dougherty, J. M.; Jimenez, M. D.; Hanson, P. R. Tetrahedron 2003, 59, 8901e8912.
5. (a) Brown, R. C. D.; Castro, J. L.; Moriggi, J. D. Tetrahedron Lett. 2000, 41,
3681e3685; (b) Moriggi, J. D.; Brown, L. J.; Castro, J. L.; Brown, R. C. D. Org.
Biomol. Chem. 2004, 2, 835e844.
129.2, 129.1, 128.8, 128.5, 128.3, 128.0, 127.7, 127.5, 127.2, 126.9, 52.0,
50.2, 49.5, 43.5, 24.8; IR (neat) n 3033, 2935, 1697, 1621, 1493, 1375,
1357, 1152 cmꢃ1; HRMS (ESI) m/z calcd for C29H28N3O4Sþ [MþH]þ
514.1795, found 514.1801.
6. (a) Salim, S. S.; Bellingham, R. K.; Satcharoen, V.; Brown, R. C. D. Org. Lett. 2003,
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4.1.13. 4-Benzyl-10-methyl-2-phenyl-4,5,10,12a-tetrahydro-1H-
[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-d][1,2,7]thiadiazepine-

3706
J.T. Hill-Cousins et al. / Tetrahedron 70 (2014) 3700e3706
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