Synthesis of N-methyl-2-indolyl- and N-methyl-2-benzo[b]furyl-substituted sulfoximines by Pd/Cu co-catalyzed domino cross-coupling/cyclization reactions

Article abstract of DOI:10.1002/ejoc.201200573

Domino cross-coupling/cyclization reactions of N-propargyl sulfoximines and 2-iodophenols or 2-iodoanilides are catalyzed by a cooperative palladium/copper system to provide benzo[b]furan and indole derivatives in good to excellent yields. The reactions occur under mild conditions and tolerate a wide variety of functional groups. Domino cross-coupling/cyclization reactions of N-propargyl sulfoximines and 2-iodophenols or 2-iodoanilides are catalyzed by a cooperative palladium/copper system to provide benzo[b]furan and indole derivatives in good to excellent yields. The reactions occur under mild conditions and tolerate a wide variety of functional groups. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200573

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200573
Synthesis of N-Methyl-2-indolyl- and N-Methyl-2-benzo[b]furyl-Substituted
Sulfoximines by Pd/Cu Co-Catalyzed Domino Cross-Coupling/Cyclization
Reactions
Ricardo F. Schumacher,[a,b] Aurélien Honraedt,[a,c,d] and Carsten Bolm*[a]
Keywords: Sulfur / Heterocycles / Palladium / Cyclization / Domino reactions
Domino cross-coupling/cyclization reactions of N-propargyl
sulfoximines and 2-iodophenols or 2-iodoanilides are cata-
lyzed by a cooperative palladium/copper system to provide
benzo[b]furan and indole derivatives in good to excellent
yields. The reactions occur under mild conditions and toler-
ate a wide variety of functional groups.
stituted sulfoximines providing benzo[b]furans or indoles,
which we report here, are unprecedented.
Introduction
Benzo[b]furans and indoles are important classes of com-
pounds widely found in nature.[1] Furthermore, they are
common heterocyclic cores in drugs and agrochemicals,[2]
where they occur with a wide array of structural variations
offering chemical diversity from focused molecular scaf-
folds. Introducing a specific substitution pattern requires
flexible synthetic methods for both selective functionaliza-
tion of the existing heterocyclic cores and direct build-up
of functionalized derivatives from straightforward starting
materials. Recently, the latter field has significantly bene-
fited from major discoveries and advances in transition-
metal catalysis, which, for example, now allow the prepara-
tion of heterocycles through oxidative insertion of a palla-
dium species into an aryl halide bond followed by sequen-
tial intramolecular addition onto an unsaturated substitu-
ent, proceeded by extrusion and regeneration of the palla-
dium catalyst.[3] For the synthesis of benzo[b]furans and in-
doles, palladium- and copper-catalyzed domino cross-cou-
pling/cyclization reactions of this type are well documen-
ted.[4] Mostly, they involve substrates with a terminal triple
bond and start from 2-iodophenols or 2-iodoanilines to
generate the corresponding 2-substituted heterocycles. To
the best of our knowledge, cyclizations of N-propargyl-sub-
Sulfoximines are mono-aza analogs of sulfones, which
have widely been studied since their discovery in the
1940s.[5] Various synthetic methods for their preparation
have been developed, mainly directed to their use in asym-
metric synthesis[6] and potential applications in medicinal
chemistry[7] and crop protection.[8]
We now report domino cross-coupling/cyclization reac-
tions of N-propargyl-substituted sulfoximines with 2-iodo-
phenols and 2-iodoanilides catalyzed by a cooperative Pd/
Cu system leading to benzo[b]furans or indoles (Scheme 1).
Scheme 1. Benzo[b]furans or indoles prepared from N-propargyl-
substituted sulfoximines with functionalized 2-iodoarenes.
Results and Discussion
Our investigation began with the preparation of required
N-propargyl-substituted sulfoximines 1. Based on literature
precedents and our own experience,[9] the most straightfor-
ward approach was the reaction of NH-sulfoximines 4 with
KH in DME at room temperature and treatment of the
resulting anion with propargyl bromide in the presence of
nBu4NBr as phase-transfer catalyst. In this manner, vari-
ously substituted derivatives 1 were obtained in moderate
to good yields (Table 1).
[a] Institut für Organische Chemie, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
Fax: +49-241-8092391
E-mail: Carsten.Bolm@rwth-aachen.de
[b] Laboratório de Síntese, Reatividade, Avaliação Farmacológica
e Toxicológica de Organocalcogênios, CCNE, UFSM, Santa
Maria,
Rio Grande do Sul, CEP 97105-900, Brazil
[c] CNRS, LCC,
205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4,
France
[d] Université de Toulouse, UPS, INPT,
31077 Toulouse Cedex 4, France
Next, the reaction conditions for the proposed cross-
coupling/cyclization sequence were optimized. N-Propargyl
phenyl methyl sulfoximine (1a) and 2-iodophenol (2a)
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200573.
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R. F. Schumacher, A. Honraedt, C. Bolm
SHORT COMMUNICATION
Table 1. Synthesis of N-propargyl sulfoximines 1.[a]
70 °C (Table 2, Entry 1). Disappointingly, the yield of
benzo[b]furan 3a was only 30%, and several unknown by-
products were detected. Changing the base to 1,1,3,3-tet-
ramethylguanidine (TMG) under otherwise identical reac-
tion conditions avoided the formation of the byproducts,
but the yield of 3a remained low (33%; Table 2, Entry 2).
An improvement was found when the sulfoximine amount
was raised to 1.5 equiv., and 3a was then isolated in 65%
yield (Table 2, Entry 3). In subsequent studies, this starting
material ratio was applied. A solvent screening revealed that
toluene was superior to other solvents such as DMF, aceto-
nitrile, THF, or dioxane (Table 2, Entries 3–7). The con-
comitant presence of both palladium and copper was criti-
cal for efficient product formation. When one of the metals
was absent, the yield of 3a was low or the product was not
formed at all (Table 2, Entries 12 and 13). Changing the
catalyst composition by altering the quantity and the ratio
of palladium and copper also affected the yield of 3a
(Table 2, Entries 7–11). To our delight, the amount of palla-
dium complex could significantly be reduced. Thus finally,
a combination of 1 mol-% of Pd(PPh3)2Cl2 and 5 mol-% of
CuI with TMG as base in toluene at 70 °C proved optimal.
Under those conditions, benzo[b]furan 3a was obtained in
90% yield (Table 2, Entry 10). Both the ratio between 1a
and 2a of 1:1.5 as well as the elevated temperature (70 °C)
proved critical for achieving this result (Table 2, Entry 10
vs. Entries 14 and 15).[10]
[a] Using 4 (1.0 equiv.) and KH (1.2 equiv.) in DMF at r.t. followed
by the addition of nBu4NBr (5 mol-%) and propargyl bromide
(2.0 equiv.).
served as test substrates, and a Pd(PPh3)2Cl2/CuI combina-
tion was chosen as the catalyst. The results are summarized
in Table 2.
Next, the substrate scope was evaluated with respect to
both starting materials. Various N-propargylic sulfoximines
(i.e., 1a–f) were applied in combination with 2-iodophenols
and 2-iodoanilides leading to the corresponding benzo[b]-
furan and indole derivatives, respectively (Table 3).
Table 2. Optimization of reaction conditions for the cross-coupling/
cyclization sequence.[a]
Generally, the cross-coupling/cyclization sequence pro-
ceeded well, providing the products in good to high yields
(up to 93%). Various functional groups on either substrate,
the N-propargylic sulfoximine or the 2-iodoarene, were tol-
erated, and no significant electronic effect was noted. Only
the use of sulfoximine 1d with a para-bromo substituent
gave a somewhat lower yield of the corresponding benzo[b]-
furan 3d (64%; Table 3, Entry 4). However, in the light of
the smooth reaction of 1e having an electron-withdrawing
group (NO2) in the para position as well (73% of 3e;
Table 3, Entry 5), this result should not be overinterpreted.
While in most reactions of N-propargyl-substituted aryl
methyl sulfoximines 1a–e were applied, it was also shown
that analogous diphenyl sulfoximine 1f reacted well to af-
ford the corresponding benzo[b]furan 3f in 84% yield
(Table 3, Entry 6). On the 2-iodoarenes, carbonyl groups
were tolerated (Table 3, Entries 7 and 8), and also the cross-
coupling/cyclization sequence between 2-iodo-3-hydroxy-
pyridine (2d) and 1a worked well to provide aza-substituted
benzofuran 3i in high yield (92%; Table 3, Entry 9). With
N-substituted 2-iodoanilides 2e and 2f as reaction partners,
sulfoximine 1a led to the corresponding indole derivatives
Entry
1a
[Pd]/[Cu]
[mol-%]
Base
Solvent
Yield
[%]
[equiv.]
1
2
3
4
5
6
7
8
1
1
5:5
5:5
5:5
5:5
5:5
5:5
5:5
5:10
2.5:5
1:5
1:1
1:–
–:1
1:5
1:5
Et3N
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
DMF
DMF
DMF
MeCN
THF
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
30
33
65
65
60
70
80
80
84
90
54
16
–
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.5
9
10
11
12
13
14
15
42
[b]
–
[a] Performed on a 0.5 mmol scale with respect to 2-iodophenol
(2a) using 3 equiv. of the base and Pd(PPh3)2Cl2 and CuI as metal
sources at 70 °C. [b] At room temperature instead of 70 °C.
Initially, 1 equiv. of both starting materials, 1a and 2a, in 3j and 3k, respectively, in high yields (Table 3, Entries 10
combination with a catalytic amount of [5 mol-% Pd- and 11). While the N-tosyl group of 2e remained in the
(PPh3)2Cl2 and CuI each] was applied. Triethylamine was product (for 3j), the trifluoroacetyl group of 2f was cleaved
added as base, and the reaction was performed in DMF at during the process leading to NH-indole 3k.[10]
2
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Pd/Cu Co-Catalyzed Domino Cross-Coupling/Cyclization Reactions
Table 3. Synthesis of benzo[b]furan and indoles.[a]
[a] Use of N-propargyl sulfoximine 1 (0.45 mmol), 2-iodoarene 2 (0.30 mmol), Pd(PPh3)2Cl2 (1 mol-%), and CuI (5 mol-%) in toluene at
70 °C. [b] Use of 3 equiv. of sulfoximine 1a.
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R. F. Schumacher, A. Honraedt, C. Bolm
SHORT COMMUNICATION
Finally, 2,4-diiodo-6-methoxyphenol (2g) was used as a
coupling partner for sulfoximine 1a. As expected, a double
cross-coupling occurred, and one of these cross-couplings
was followed by intramolecular ring closure to provide 4-
alkynyl-substituted benzo[b]furan 3l (Table 3, Entry 12).
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Conclusions
In summary, we have developed a domino cross-cou-
pling/cyclization reaction sequence catalyzed by a coopera-
tive palladium/copper system to provide benzo[b]furan and
indole derivatives starting from N-propargyl sulfoximines
and 2-iodophenols or 2-iodoanilides, respectively. The
products have sulfoximidoyl substituents connected through
their nitrogen atom and a methylene linker in the 2-position
of the heterocyclic cores. Various additional functional
groups are tolerated, which allows access to compounds
with a substitution pattern that is otherwise difficult to
achieve.
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Experimental Section
General Procedure for the Domino Pd/Cu-Catalyzed Cross-Cou-
pling/Cyclization Reaction Sequence: Into a dried Schlenk tube un-
der an atmosphere of Ar containing a solution of N-propargyl sulf-
oximine 1 (0.45 mmol, 1.5 equiv.) in dry toluene (1.0 mL) was
added PdCl2(PPh3)2 (2.1 mg, 1 mol-%) and CuI (2.9 mg, 5 mol-%).
To the resulting suspension,
a solution of 2-iodoarene 2
(0.30 mmol, 1.0 equiv.) in dry toluene (1.5 mL) was added. After
rapid addition of TMG (0.90 mmol, 3.0 equiv.), the reaction mix-
ture was heated at 70 °C. The substrate conversion and product
formation was monitored by TLC (pentane/Et2O or ethyl acetate
1:1). After full conversion, the reaction mixture was warmed to
room temperature and a saturated aqueous solution of NH4Cl
(3 mL) was added. The product was extracted with DCM
(5ϫ5 mL). The combined organic layers were washed successively
with water (3 mL) and brine (3 mL), dried with anhydrous MgSO4,
and filtered. The products were purified by column chromatog-
raphy on silica gel.
[7]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and NMR spectra.
Acknowledgments
[8]
For selected examples in crop protection chemistry, see: a) O.
García Mancheño, J. Dallimore, A. Plant, C. Bolm, Adv. Synth.
Catal. 2010, 352, 309; b) Y. Zhu, M. R. Loso, G. B. Watson,
T. C. Sparks, R. B. Rogers, J. X. Huang, B. C. Gerwick, J. M.
Babcock, D. Kelley, V. B. Hegde, B. M. Nugent, J. M. Renga,
I. Denholm, K. Gorman, G. J. DeBoer, J. Hasler, T. Meade,
J. D. Thomas, J. Agric. Food Chem. 2011, 59, 2950; c) J. M.
Babcock, B. C. Gerwick, J. X. Huang, M. R. Loso, G. Naka-
mura, S. P. Nolting, R. B. Rogers, T. C. Sparks, J. Thomas,
G. B. Watson, Y. Zuh, Pest Manage. Sci. 2011, 67, 328; d) C.
We are grateful to the German-Israeli Foundation for Scientific
Research and Development (GIF) and the Fonds der Chemischen
Industrie for financial support. The Conselho Nacional de Desen-
volvimento Científico e Tecnológico (SWE - 201697/2010-6) is
thanked for a student exchange fellowship for R.F.S. A.H. ac-
knowledges the Université Paul Sabatier, Toulouse (ATUPS 2011),
as well as the Association Nationale de la Recherche et de la Techn-
ologie (ANRT) and Minakem SAS for student exchange support
and CIFRE funding.
4
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Pd/Cu Co-Catalyzed Domino Cross-Coupling/Cyclization Reactions
Gnamm, A. Jeanguenat, A. C. Dutton, C. Grimm, D. P. Kloer,
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1922; b) B. Füger, C. Bolm, Synlett 2009, 1601.
[10] In the attempt to react 1a with 2f to give the corresponding
indole, an uncyclized (N-deprotected) Sonogashira-type cou-
pling product was identified by NMR spectroscopy.
Received: May 1, 2012
Published Online: ᭿
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R. F. Schumacher, A. Honraedt, C. Bolm
SHORT COMMUNICATION
Heterocyclic Chemistry
R. F. Schumacher, A. Honraedt,
C. Bolm* ........................................... 1–6
Synthesis of N-Methyl-2-indolyl- and N-
Methyl-2-benzo[b]furyl-Substituted Sulfox-
imines by Pd/Cu Co-Catalyzed Domino
Cross-Coupling/Cyclization Reactions
Domino cross-coupling/cyclization reac-
tions of N-propargyl sulfoximines and 2-
iodophenols or 2-iodoanilides are catalyzed
by a cooperative palladium/copper system
to provide benzo[b]furan and indole deriva-
tives in good to excellent yields. The reac-
tions occur under mild conditions and tol-
erate a wide variety of functional groups.
Keywords: Sulfur
/ Heterocycles / Pal-
ladium / Cyclization / Domino reactions
6
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