E. Rasolofonjatovo et al. / Tetrahedron Letters 52 (2011) 1036–1040
1039
clearly demonstrated that the substituent attached to the triple
bond had no deleterious effect on the Z/E distribution, and olefins
4g–j were isolated with a total Z-preference.
4b cyclized to afford after hydrolysis the arylthiochromenylium
hydroxide 11 in good yield (85%). When the cyclization reaction
of 4b was conducted in the presence of TfOH followed by addition
of Et3N, the expected 1-arylthiochromene 12 was isolated in a 78%
overall yield (Scheme 3).
In the coupling step of N-tosylhydrazones with aryl halides, a
migratory insertion of Pd carbene species has been suggested as
the key step.11a According to this reaction mechanism, coupling
of N-tosylhydrazone 6a with ortho iodoanisole (path a, Scheme
2) would form Pd carbene species I, whereas the reaction of ortho
methoxy N-tosylhydrazone 5a with 4-iodoanisole would furnish II
(path b, Scheme 2). These intermediate species I and II should
evolve according to the migratory insertion of the anisyl ring to
give the same alkylpalladium complex III. Further b-hydride elim-
ination on III would give olefin 4d, logically with the same diaste-
reoisomeric ratio. To check this hypothesis, we carry out the
coupling of ortho methoxy N-tosylhydrazone 5a with 4-iodoani-
sole according to path b (Scheme 2). Although 4d was formed in
a low 18% yield, a similar dr (Z/E = ca. 19:1) was observed and
may be compared to the one obtained according to path a (Table
1, entry 4).
Altogether, the results depicted in Table 1 show that the use of
ortho substituted aryl halides as electrophilic partners in the
coupling with N-tosylhydrazones provides mainly to exclusively
olefins 4 with a Z-configuration, even if the exact origin of this
diastereoselectivity remains unclear.
To achieve our goal, we next treated olefins having an ortho
OMOM substituent 4a, 4f, and 4g in acidic media. Thus, when heat-
ing 4a and 4f with PTSA in EtOH we were delighted to observe rap-
idly the formation of the desired 4-arylchromene derivatives 3a,b
in excellent yields (Scheme 3).17 With substrate 4g, TfOH was
found to be superior than PTSA, and achieved the cyclization reac-
tion efficiently providing the expected 5-aryl-2,3-dihydro-
benzo[b]oxepine 10.
In summary, we have described a convenient sequence to
4-arylchromenes and related heterocycles. This protocol is based
on the one-pot regioselective hydration of alkynes, N-tosylhydra-
zones formation, followed by their palladium-catalyzed coupling
with aryl halides to form trisubstituted olefins with Z-selectivity.
Further Brönsted acid-mediated cyclization provided the desired
oxygen- and sulfur-containing heterocycles. This process is very
convenient and efficient because it significantly reduced reaction
times and tedious procedures such as work-up and purification
at each step. Reaction is general with respect to alkyne and ortho
substituted aryl halides. Good yields and convenient isolation of
the targeted heterocycles are the distinct characteristics of the
developed protocol. Studies are currently under way for the syn-
thesis of heterocycles related to isoCA-4 and will be reported in
due course.
Acknowledgments
The CNRS is gratefully acknowledged for the financial support
of this research. We thank The MNRES for a doctoral fellowship
to E.R. and ICSN for a doctoral fellowship to B.T.
References and notes
1. (a) Le Bras, G.; Radanyi, C.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.; Marsaud, V.;
Stella, B.; Renoir, J. M. J. Med. Chem. 2007, 50, 6189–6200; (b) Radanyi, C.; Le
Bras, G.; Messaoudi, S.; Bouclier, C.; Peyrat, J.-F.; Brion, J.-D.; Marsaud, V.;
Renoir, J. M.; Alami, M. Bioorg. Med. Chem. Lett. 2008, 18, 2495–2498.
2. (a) Mousset, C.; Giraud, A.; Provot, O.; Hamze, A.; Bignon, J.; Liu, J. M.; Thoret,
S.; Dubois, J.; Brion, J.-D.; Alami, M. Bioorg. Med. Chem. Lett. 2008, 18, 3266–
3271; (b) Mousset, C.; Provot, O.; Hamze, A.; Bignon, J.; Brion, J.-D.; Alami, M.
Tetrahedron 2008, 64, 4287–4294; (c) Provot, O.; Giraud, A.; Peyrat, J.-F.; Alami,
M.; Brion, J.-D. Tetrahedron Lett. 2005, 46, 8547–8550.
To extend the scope of this transformation, we finally examined
the cyclization of olefin 4b having an ortho methylthio substituent.
We were pleased to find that upon heating in the presence of TfOH,
3. (a) Messaoudi, S.; Treguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; De Losada, J.
R.; Liu, J. M.; Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.;
Alami, M. J. Med. Chem. 2009, 52, 4538–4542; (b) Hamze, A.; Giraud, A.;
Messaoudi, S.; Provot, O.; Peyrat, J.-F.; Bignon, J.; Liu, J. M.; Wdzieczak-Bakala,
J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. ChemMedChem 2009, 4, 1912–
1924.
4. Hamze, A.; Provot, O.; Brion, J. D.; Alami, M. J. Org. Chem. 2007, 72, 3868–3874.
5. (a) Brachet, E.; Hamze, A.; Peyrat, J. F.; Brion, J. D.; Alami, M. Org. Lett. 2010, 12,
4042–4045; (b) Rasolofonjatovo, E.; Provot, O.; Hamze, A.; Bignon, J.; Thoret, S.;
Brion, J. D.; Alami, M. Eur. J. Med. Chem. 2010, 45, 3617–3626.
6. (a) Eguchi, T.; Hoshino, Y.; Ayame, A. Bull. Chem. Soc. Jpn 2002, 75, 581–585; (b)
Kinoyama, I.; Miyamoto, S.; Miyazaki, T.; Koganemaru, Y.; Kawamoto, Y.;
Shiraishi, N.; Hoshii, H.; Kuroda, A.; Yamazaki, M.; Yasuda, M.; Mizuno, H. Eur.
Patent, 2010, EP 2177505A1.
7. Donnelly, D. M. X.; Finet, J.-P.; Guiry, P. J.; Nesbitt, K. Tetrahedron 2001, 57, 413–
423.
OEt
O
O
OMOM
a
MeO
MeO
MeO
MeO
4a
3a
OEt
OMOM
a
4f
3b
8. Li, S.-R.; Chen, L.-Y.; Tsai, J.-C.; Tzeng, J.-Y.; Tsai, I.-L.; Wang, E.-C. Tetrahedron
Lett. 2007, 48, 2139–2141.
OEt
9. (a) Foroumadi, A.; Samzadeh-Kermani, A.; Emami, S.; Dehghan, G.; Sorkhi, M.;
Arabsorkhi, F.; Heidari, M. R.; Abdollahi, M.; Shafiee, A. Bioorg. Med. Chem. Lett.
2007, 17, 6764–6769; (b) Mukerjee, S. K.; Saroja, T.; Seshadri, T. R. Tetrahedron
1971, 27, 799–803; (c) Pinard, E.; Gaudry, M.; Hénot, F.; Thellend, A.
Tetrahedron Lett. 1998, 39, 2739–2742; (d) Whitehead, A.; Moore, J. D.;
Hanson, P. R. Tetrahedron Lett. 2003, 44, 4275–4277.
10. (a) Olivi, N.; Thomas, E.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synlett 2004, 2175–
2179; (b) Le Bras, G.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron
Lett. 2006, 47, 5497–5501; (c) Le Bras, G.; Hamze, A.; Messaoudi, S.; Provot, O.;
Le Calvez, P. B.; Brion, J.-D.; Alami, M. Synthesis 2008, 1607–1611; (d) Jacubert,
M.; Hamze, A.; Provot, O.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett.
2009, 50, 3588–3592.
11. For the coupling of N-tosylhydrazones with aryl halides or triflates, see: (a)
Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46,
5587–5590; (b) Barluenga, J.; Tomas-Gamasa, M.; Moriel, P.; Amar, F.; Valdes,
C. Chem. Eur. J. 2008, 14, 4792–4795; (c) Barluenga, J.; Escribano, M.; Moriel, P.;
Aznar, F.; Valdés, C. Chem. Eur. J. 2009, 15, 13291–13294; (d) Treguier, B.;
Hamze, A.; Provot, O.; Brion, J. D.; Alami, M. Tetrahedron Lett. 2009, 50, 6549–
6552; (e) Barluenga, J.; Escribano, M.; Aznar, F.; Valdés, C. Angew. Chem., Int. Ed.
2010, 49, 6856–6859; For the coupling with benzyl halides, see: (f) Xiao, Q.;
Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2009, 11, 4732–4735; For the
O
OMOM
b
MeO
MeO
MeO
4g
10
MeO
S
OH
c
OEt
SMe
11
S
d
MeO
4b
12
Scheme 3. Reagents and conditions: (a) PTSA (3 equiv) EtOH, reflux, 1 h, 3a: 98%,
3b: 78%. (b) TfOH cat. dioxane, reflux, 15 h, 62%. (c) TfOH cat. CH2Cl2, rt, 30 min.,
85% (d) (i) TfOH cat. CH2Cl2, 20 °C, 30 min; (ii) Et3N (2 equiv) EtOH, 20 °C, 78%.