Ring-closing enyne metathesis (RCEYM) for the synthesis of cyclic sulfoximines

Article abstract of DOI:10.1055/s-0029-1217342

Heterocyclic sulfoximines have been synthesized by RCEYM reactions starting from N-alkynyl-S-alkenyl sulfoximines in up to 79% yield. The products can be converted to tricyclic derivatives by a domino Diels-Alder/aromatization reaction sequence. Georg Thi

Full text of DOI:10.1055/s-0029-1217342

LETTER
1601
Ring-Closing Enyne Metathesis (RCEYM) for the Synthesis of Cyclic
Sulfoximines
S
ynthesis of Cyc
e
S
ulfoxim
r
ines nhard Füger, Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
Received 22 March 2009
at –78 °C led, after N-deprotection, to N(H)-S-alkenyl-S-
phenyl sulfoximines 7a–c in yields ranging from 51–71%.
Even with only 1.0 equivalent of n-BuLi double a-alkyla-
tion of 5 was observed (at –78 °C), when the addition of
the alkenyl bromide was slow. The best results were ob-
tained when either an excess of 6 was rapidly added to the
preformed carbanion or when the latter was slowly trans-
ferred into a solution of the alkenyl bromide by syringe
pump. The subsequent N-functionalizations were easily
performed following a standard protocol.8 Thus, deproto-
nation of 7a–c with KH and treatment of the resulting an-
ion with the corresponding bromoalkynes 8a–c under
phase-transfer conditions at room temperature in DME
led to doubly unsaturated sulfoximines 3a–g in good
yields (68–88%). Sonogashira coupling of 3a with phenyl
iodide afforded phenyl-substituted derivative 3h in 63%
yield,9 and silylation of 3a with TESCl gave TES-protect-
ed alkyne 3i in 74% yield (Scheme 2).10
Abstract: Heterocyclic sulfoximines have been synthesized by
RCEYM reactions starting from N-alkynyl-S-alkenyl sulfoximines
in up to 79% yield. The products can be converted to tricyclic deriv-
atives by a domino Diels–Alder/aromatization reaction sequence.
Key words: enynes, heterocycles, ring-closing metathesis, sulfox-
imines, tricycles
Sulfoximines are valuable sulfur reagents, which have
been used in asymmetric synthesis1 and as building blocks
for pseudopeptides.2 Various strategies for the synthesis
of heterocyclic derivatives have been described,3–6 and
among them metathesis reactions are particularly attrac-
tive, because they open access to macrocyclic products,
which are difficult to synthesize by other means.
In 2005 we reported ring-closing olefin metathesis (RCM)
reactions of N,S-dialkenyl sulfoximines 1 affording het-
erocyclic sulfoximines 2 in yields up to 97%.5 We now en-
visaged to expand this concept. If analogous enyne
metathesis (RCEYM) reactions7 were applicable, sulfox-
imines 4 should result starting from N-alkynyl-S-alkenyl
sulfoximines 3. Subsequent conversions of 4 involving
the 1,3-diene moiety would then allow further variations
of the heterocyclic motif (Scheme 1).
1) n-BuLi, THF,
NTMS
NH
S
R1
–78 °C; then 6a–c
S
Ph
Me
Ph
R2
2) NH4Cl, MeOH, r.t.
O
O
5
7a–c
R1
a: R1 = R2 = H
(71%)
b: R1 = H; R2 = Me (51%)
Br
R2
c: R1 = R2 = Me
a: R1 = R2 = R3 = H
(67%)
6a–c
Doubly unsaturated sulfoximines 3a–i were synthesized
starting from N-TMS-protected S-methyl-S-phenyl sul-
foximine 5. Deprotonation of 5 with n-BuLi in THF and
treatment of the resulting anion with allyl bromides 6a–c
(82%)
(82%)
(75%)
(68%)
(80%)
(68%)
(88%)
KH, Bu4NBr,
DME, r.t.
b: R1 = R2 = H; R3 = Me
c: R1 = R2 = H; R3 = Et
d: R1 = H; R2 = Me; R3 = H
e: R1 = H; R2 = Me; R3 = Et
f: R1 = R2 = Me; R3 = H
g: R1 = R2 = Me; R3 = Et
R3
R1
N
S
then 8a–c
Ph
R2
O
R3
3a–g
Br
8a–c
n
N
n
N
S
RCM
S
Ph
TES
Ph
m
Ph
m
O
N
S
N
O
1
2
S
Ph
Ph
O
O
3h (63%)
3i (74%)
R3
R1
R1
R3
R1
Scheme 2 Synthesis of N-alkynyl-S-alkenyl sulfoximines
n
RCEYM
N
S
n
N
The search for the optimal reaction conditions to convert
3a efficiently to its cyclized product 9a started with test-
ing Grubbs I (G1) and Grubbs II (G2) metathesis catalysts
(10 mol%). Whereas G1 proved to be unsuitable leading
to a low yield of 9a due to only partial conversion of 3a
(Table 1, entries 1–3), the application of G2 (in toluene
under reflux) afforded 9a in 45% yield (with full conver-
sion of 3a after 1 h; Table 1, entry 4). Reducing the reac-
R2
Ph
m
S
O
Ph
m
O
3
4
Scheme 1 Approaches to heterocyclic sulfoximines by RCM and
RCEYM reactions
SYNLETT 2009, No. 10, pp 1601–1604
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217342; Art ID: G09209ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

1602
B. Füger, C. Bolm
LETTER
lyst additions did not substantially change the yield of 9a
Table 1 Optimization of the RCEYM Reaction Conditions
(Table 1, entries 14 and 15).
N
S
N
S
Next, the substrate scope was investigated (Scheme 3).11
Compared to 3a, having an unsubstituted alkynyl group,
methyl-substituted sulfoximine 3b delivered the corre-
sponding product 9b with a slightly higher yield (70%).
Sulfoximine 3c with an ethyl group at the alkynyl moiety
led to 9c in 79% yield, whereas 3h, bearing a phenyl sub-
stituent, yielded only 45% of RCEYM product 9h. Proba-
bly due to the steric hinderance induced by the bulky silyl
substituent, sulfoximine 3i with a TES group did not react
at all. Interestingly, homocoupled products were not de-
tected in any case. Experiments with methyl- or dimethyl-
substituted alkenes 3d–g remained unsuccessful indicat-
ing the required presence of an unsubstituted alkenyl moi-
ety.
RCEYM
Ph
toluene
Ph
O
O
3a
9a
N
O
Ph
S
S
Ph
O
N
10
Entry Cat.
Cat.amount Concn of Temp Time
Yield of
9a (%)
(mol%)
3a
(°C)
(h)
24
96
1
1a
2
G1
G1
G1
G2
G2
G2
G2
G2
G2
G2
G2
G2
G2
G2
G2
10
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
50
0b
12b
11b
45
10
120
120
120
120
120
80
3
10
R3
4
10
1
a: R3 = H (65%)
b: R3 = Me (70%)
c: R3 = Et (79%)
h: R3 = Ph (45%)
i: R3 = TES (--)
R3
Grubbs II
5
10
0.25
65
(10 mol%)
N
S
N
S
6
10
0,0167 41
toluene (0.01 M)
reflux, 15 min
Ph
Ph
O
O
7
10
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
36b
3a–c,h,i
9a–c,h,i
8c
9
10
120
120
120
120
120
120
120
120
45
33b
39
50
57
39
49
47
O
N
5
N
S
10
20
a:
b:
Ph
R = Me (87%)
R
O
O
(96%)
R = Ph
11
12
13
14c
15
3.3 (3×) 0.01
11a, b
R3
10
0.003
0.001
0.003
O
a: R3 = H (99%)
b: R3 = Me (74%)
c: R3 = Et (85%)
h: R3 = Ph (73%)
10
10
N
S
p-benzoquinone
9a–c,h
toluene, reflux, 3 h
Ph
O
O
3.3 (3×) 0.003
12a–c,h
a Use of CH2Cl2 instead of toluene.
Scheme 3 RCEYM and Diels–Alder–aromatization reactions lea-
ding to tricyclic sulfoximines
b Incomplete conversion, 3a remaining.
c Under an atmosphere of ethylene (1 atm).
Reactions of RCEYM product 9a with N-methyl maleiim-
ide and N-phenyl maleiimide in toluene under reflux for
three hours gave Diels–Alder products 11a and 11b in
87% and 96% yield, respectively.11 Under the same con-
ditions, attempts to use maleic acid anhydride, maleiic
acid methyl ester, and diethylacetylenedicarboxylate as
dienophiles in combination with 9a remained unsuccess-
ful. When p-benzoquinone was applied, aromatized prod-
uct 12a stemming from a domino Diels–Alder–
aromatization reaction sequence was obtained in 99%
yield. Analogously, RCEYM products 9b,c,h gave the ar-
omatized products 12b,c,h in yields ranging from 73–
85%.
tion time to 15 minutes led to an increased yield of 65%
(entry 5). After one minute reaction time 9a was obtained
in a remarkable 41% yield (entry 6). Lowering the reac-
tion temperature from 120 °C to 80 °C resulted in incom-
plete conversion of the substrate affording 9a in 36%
yield (entry 7). When the reaction was performed under an
atmosphere of ethylene 9a was obtained in 45% yield (en-
try 8). Neither varying the catalyst amount from 10 mol%
to 5 mol% or 20 mol% nor applying sequential catalyst
additions (three times 3.3 mol% each of G2 with 5 min in-
tervals) led to an improvement in the yield of 9a (Table 1,
entries 9–11). Because in all reactions 10–20% of byprod-
uct 10 (stemming from a homocoupling of 9a) was detect-
ed, substrate concentration effects were studied.
However, even when the reaction mixture was diluted by
a factor of 3 or 10, the yield of 9a did not increase and a
small amount of 10 remained detectable (entries 12 and
13). Also performing these high dilution experiments un-
der an atmosphere of ethylene or applying multiple cata-
With the goal to expand the reaction scope and to open
synthetic access to new heterocyclic sulfoximines with
larger rings, doubly unsaturated substrates 13–18 with
various tether lengths were prepared (Figure 1). Unfortu-
nately, however, none of them reacted well under the
RCEYM conditions described in Scheme 3, and low con-
Synlett 2009, No. 10, 1601–1604 © Thieme Stuttgart · New York

LETTER
Synthesis of Cyclic Sulfoximines
1603
(4) For overviews on metathesis reactions affording sulfur-
containing heterocycles, see: (a) Karsch, S.; Freitag, D.;
Schwab, P.; Metz, P. Synthesis 2004, 1696.
(b) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R.
Chem. Rev. 2004, 104, 2239.
(5) Villar, H.; Bolm, C. Synthesis 2005, 1421.
(6) For other olefin metathesis reactions with sulfoximine-based
substrates, see: (a) Lejkowski, M.; Gais, H.-J.; Banerjee, P.;
Vermeeren, C. J. Am. Chem. Soc. 2006, 128, 15378.
(b) Lejkowski, M.; Banerjee, P.; Runsink, J.; Gais, H.-J.
Org. Lett. 2008, 10, 2713.
(7) For selected reviews on RCEYM metathesis, see:
(a) Giessert, A. J.; Diver, S. T. Chem. Rev. 2004, 104, 1317.
(b) Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007,
36, 55. (c) Maifeld, S. V.; Lee, D. Chem. Eur. J. 2005, 11,
6118. (d) Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.;
Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007,
63, 3919. (e) Mori, M. Adv. Synth. Catal. 2007, 349, 121.
(8) Johnson, C. R.; Lavergne, O. M. J. Org. Chem. 1993, 58,
1922.
N
S
N
S
N
S
Ph
( )3
Ph
O
Me
O
Ph
O
13
14
15
O
Me
O
Me
( )7
( )7
N
N
S
N
S
S
( )6
( )2
Ph
Ph
Ph
O
O
O
16
17
18
Figure 1 Doubly unsaturated sulfoximines, which were unreactive
in the RCEYM reaction
versions led at best to trace amounts (<10%) of cyclized
products.
(9) Sonogashira Coupling
In summary, we investigated the RCEYM reaction of N-
alkynyl-S-alkenyl sulfoximines. The product yields were
highly dependent on the substrate structure. Seven-mem-
bered heterocyclic sulfoximines were obtained in up to
79% yield. The resulting RCEYM products could be con-
verted to more complex heterocycles by Diels–Alder
reactions. With p-benzoquinone as dienophile a domino
Diels–Alder–oxidation sequence led to products with aro-
matized cores in up to 99% yield. Heterocylic sulfox-
imines with larger ring or aromatic tethers remained
inaccessible.
A mixture of 3a (0.286 mmol, 1.0 equiv), PhI (0.858 mmol,
3.0 equiv), [Pd(PPh3)2Cl2] (0.029 mmol, 10 mol%), CuI
(0.057 mmol, 20 mol%), and Ph3P (0.029 mmol, 10 mol%)
was dissolved in dry Et3N–DMF (5.71 mL/2.86 mL, 2:1) and
stirred under Ar at 70 °C for 4 h. After workup (CH2Cl2,
brine) and column chromatography [silica gel, pentane–
EtOAc (3:1)] 3h was obtained as orange oil (0.181 mmol,
63%).
(10) Silylation
A soln of 3a (0.715 mmol, 1.0 equiv) in dry THF (10 mL)
was cooled to –78 °C. n-BuLi in hexane (0.787 mmol, 1.1
equiv) was added dropwise via syringe. After 30 min at this
temperature, TESCl (1.431 mmol, 2.0 equiv) was added
slowly. After stirring for 1 h at –78 °C, the reaction was
quenched with brine. After workup (Et2O, brine) and column
chromatography [silica gel, pentane–EtOAc (6:1)] 3i was
obtained as colorless oil (0.526 mmol, 74%).
Acknowledgment
This research was supported by the Fonds der Chemischen Industrie
and a grant from the G.I.F., the German-Israeli Foundation for sci-
entific Research and development (I-871-62.5/2005). B.F. thanks
DFG (GRK 440) for a predoctoral fellowship and B. Schulte for
supporting work in the lab.
(11) The RCEYM reactions were performed under argon using
standard Schlenk techniques. N(H)- and N-alkynyl
sulfoximines (7a–c and 3a–i) were synthesized according to
literature procedures8,12 and used as racemates.
Ring-Closing Enyne Metathesis Reactions – Typical
Procedure for the Synthesis of 9c
References and Notes
A dried Schlenk flask was charged with doubly unsaturated
sulfoximine 3c and dry toluene (0.01 M). After heating to
120 °C under argon, the catalyst (Grubbs II, 10 mol%) was
added under vigorous stirring in one batch. The dark brown
reaction mixture was refluxed for 15 min. After cooling to
r.t., the mixture was concentrated in vacuo. The residue was
subjected to column chromatography [silica gel, pentane–
EtOAc (3:1)], which afforded 9c as a light brownish oil in
79% yield. 1H NMR (400 MHz, CDCl3): d = 8.07–8.04 (m,
2 Harom.), 7.62–7.57 (m, 1 Harom.), 7.55–7.49 (m, 2 Harom.),
5.91–5.84 (m, 1 H), 5.06 (br s, 1 H), 4.92 (br s, 1 H), 4.43 (d,
1 H, J = 16.5 Hz), 3.97 (d, 1 H, J = 16.5 Hz), 3.56 (ddd, 1 H,
J = 13.5, 9.6, 1.9 Hz), 3.09 (ddd, 1 H, J = 13.3, 9.6, 1.9 Hz),
2.80–2.69 (m, 1 H), 2.64–2.54 (m, 1 H), 2.27 (q, 2 H, J = 7.4
Hz), 1.08 (t, 3 H, J = 7.4 Hz). 13C NMR (100 MHz, CDCl3):
d = 150.3, 146.5, 138.8, 133.0, 128.9, 128.0, 123.4, 110.0,
55.6, 42.8, 27.2, 22.1, 13.2. IR (CHCl3): 2965, 2846, 1447,
1231, 1135, 887, 754, 688 cm–1. MS (EI): m/z (%) = 261.1
(16) [M]+, 246.1 (4) [M – CH3]+. HRMS (EI): m/z calcd for
C15H19NOS: 261.1187; found: 261.1186.
(1) Reviews: (a) Worch, C.; Mayer, A. C.; Bolm, C. In
Organosulfur Chemistry in Asymmetric Synthesis; Toru, T.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008, 209.
(b) Bolm, C. In Asymmetric Synthesis with Chemical and
Biological Methods; Enders, D.; Jaeger, K.-E., Eds.; Wiley-
VCH: Weinheim, 2007, 149. (c) Hais, H.-J. Heteroat.
Chem. 2007, 18, 472. (d) Okamura, H.; Bolm, C. Chem.
Lett. 2004, 33, 482. (e) Harmata, M. Chemtracts 2003, 16,
660. (f) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(2) Bolm, C.; Müller, D.; Dalhoff, C.; Hackenberger, C. P. R.;
Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13, 3207; and
references therein.
(3) (a) Williams, T. R.; Cram, D. J. J. Am. Chem. Soc. 1971, 93,
7333. (b) Williams, T. R.; Cram, D. J. Org. Chem. 1973, 38,
20. (c) Schaffner-Sabba, K.; Tomaselli, H.; Henrici, B.;
Renfroe, H. B. J. Org. Chem. 1977, 42, 952. (d) Hwang,
K.-J.; Logusch, E. W.; Brannigan, L. H. J. Org. Chem. 1987,
52, 3435. (e) Ghosh, S. K.; Harmata, M. Org. Lett. 2001, 3,
3321. (f) Rayanil, K.; Gomes, M. G.; Zheng, P.; Calkins,
N. L.; Kim, S.-Y.; Fan, Y.; Bumbu, V.; Lee, D. R.;
Wacharasindhu, S.; Hong, X.; Harmata, M. Org. Lett. 2005,
7, 143.
Synlett 2009, No. 10, 1601–1604 © Thieme Stuttgart · New York

1604
B. Füger, C. Bolm
LETTER
Diels–Alder Reactions – Typical Procecure for the
Synthesis of 12c
3.81–3.71 (m, 2 H), 3.05–2.93 (m, 3 H), 1.33 (t, 3 H, J = 7.7
Hz). 13C NMR (100 MHz, CDCl3): d = 187.5, 184.8, 150.1,
147.7, 141.9, 140.5, 139.0, 136.8, 133.2, 131.5, 129.0,
128.4, 127.6, 126.9, 55.4, 40.3, 28.0, 23.0, 15.7. IR (KBr):
3441, 2967, 1657, 1578, 1308, 1117, 844, 783 cm–1. MS
(CI): m/z (%) = 365.8 (100) [M + H]+, 240.4 (86) [M –
C6H5SO]+. HRMS (EI): m/z calcd for C21H19NO3SC6H5SO:
240.1019; found: 240.1010.
To a soln of 9c in toluene (0.032 M) was added p-benzo-
quinone (5 equiv). The reaction mixture was refluxed at
120 °C for 3 h. After cooling to r.t., the yellowish solution
was concentrated in vacuo and subjected to column chromat-
ography [silica gel, pentane–EtOAc (2:1)]. Tricyclic product
12c was obtained as a yellow solid in 85% yield. 1H NMR
(400 MHz, CDCl3): d = 7.98 (m, 3 Harom.), 7.62–7.57 (m, 1
(12) (a) Gaillard, S.; Papamicaël, C.; Dupas, G.; Marsais, F.;
Levacher, V. Tetrahedron 2005, 61, 8138. (b) Sedelmeier,
J.; Bolm, C. J. Org. Chem. 2005, 70, 6904.
Harom.), 7.53–7.47 (m, 3 Harom.), 6.90 (d, 1 H, J = 10.4 Hz),
6.86 (d, 1 H, J = 10.2 Hz), 4.96 (d, 1 H, J = 15.1 Hz), 4.59
(d, 1 H, J = 14.8 Hz), 4.54 (ddd, 1 H, J = 14.8, 7.7, 1.1 Hz),
Synlett 2009, No. 10, 1601–1604 © Thieme Stuttgart · New York

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