Highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of diynes to sulfonimines

Article abstract of DOI:10.1021/ja309301n

A new asymmetric [2+2+2] cycloaddition of diynes to sulfonimines under rhodium catalysis that provides the corresponding enantioenriched 1,2-dihydropyridines in good yields is described.

Full text of DOI:10.1021/ja309301n

Communication
pubs.acs.org/JACS
Highly Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of
Diynes to Sulfonimines
Muriel Amatore, David Lebœuf, Max Malacria, Vincent Gandon,*,† and Corinne Aubert*
UPMC UNIV Paris 06, Institut Parisien de Chimie Molec
France
́
ulaire, UMR CNRS 7201, Case 229, 4 Place Jussieu, 75252 Paris Cedex 05,
S
* Supporting Information
starting materials were left untouched or cyclodimerization of
ABSTRACT: A new asymmetric [2+2+2] cycloaddition
of diynes to sulfonimines under rhodium catalysis that
provides the corresponding enantioenriched 1,2-dihydro-
pyridines in good yields is described.
the diyne took place. On the other hand, we found that catalytic
combinations of [Rh(cod)2]BF4 with chelating diphosphines
(10 mol% each) provided mixtures of the desired 1,2-
dihydropyridine 3a and cyclodimer 4 in 1,2-dichloroethane
(DCE) at 80 °C (Table 1). The best compromise between
he transition-metal-catalyzed [2+2+2] cycloaddition re-
Taction is recognized as one of the most powerful and
straightforward methods for the construction of polycyclic
compounds.1 There have been remarkable advances in terms of
chemo-, regio-, and stereoselectivity in this reaction, so it has
found many applications in the synthesis of complex
molecules.2 While access to various heterocyclic compounds
is permitted through the [2+2+2] cycloaddition of diynes to
C−heteroatom multiple bonds [nitriles, aldehydes, ketones,
iso(thio)cyanates, etc.], the use of imines as unsaturated
partners remains scarce. During their initial exploration of the
rhodium-catalyzed aza-[5+2] cycloaddition of a cyclopropyli-
mine to dimethyl fumarate, Wender et al.3 reported the
formation of a nondesired cycloadduct between two alkyne
units and one imine. Ogoshi et al.4 also described a related
chemoselective transformation under nickel catalysis, yet with a
restricted imine scope. Cyclizations between imines bearing a
directing N-pyridyl group and two alkynes that are believed to
involve [2+2+2] cycloaddition have also been reported.5 To the
best of our knowledge, these three reports are the only ones to
date for the direct synthesis of 1,2-dihydropyridines from
imines and alkynes. Despite these notable advances, a more
synthetically useful method should be broader in scope and
enantioselective.6,7 1,2-Dihydropyridines are useful intermedi-
ates for the preparation of a wide range of valuable organic
molecules.8 Specifically, they have found applications in the
synthesis of piperidines9 and pyridines10 and as Diels−Alder
partners.11 However, because of the lack of methods for the
regio- and stereoselective formation of 1,2-dihydropyridines,
their biological and synthetic potential remains largely
unexplored. Herein we report a new and efficient asymmetric
route to 1,2-dihydropyridines via rhodium-catalyzed [2+2+2]
cycloaddition of diynes to sulfonimines.
Table 1. Influence of Ligands and Reaction Conditions on
the Rh-Catalyzed [2+2+2] Cycloaddition of Diyne 1a to
Sulfonimine 2a
time
(h)
conv
b
yield of
ee of
a
c
entry
ligand
dppe
(R)-Binap
(%)
3a:4
3a (%)
3a (%)
1
2
3
4
5
14
14
14
14
14
0
100
100
50
−
−
−
−
−
−
−
−
−
−
−
1:3
1:2.9
1:1.4
−
(R)-H8-Binap
(R)-Segphos
(R)-DTBM-
0
Segphos
6
(R)-Tol-Binap
(R)-Tol-Binap
(R)-Tol-Binap
(R)-Tol-Binap
14
14
14
7
100
100
100
100
1:1.7
1:0
−
−
d
7
88
60
72
73
66
81
de
,
8
de
,
1:0
9
1:0
a
b
See ref 13 for abbreviations. Determined by 1H NMR spectroscopy.
c
d
Determined by chiral HPLC. With slow addition of 1a using a
e
syringe pump. 5 mol% [Rh(cod)2]BF4/(R)-Tol-Binap, 1.5 equiv of
2a.
chemoselectivity and conversion was reached when (R)-Tol-
Binap13 was used (entry 6), yet even under these conditions,
the diyne dimerization could not be annihilated. We anticipated
that this issue could be circumvented by slow addition of diyne
1a to a DCE solution of 2a and Rh(I)+/(R)-Tol-Binap (entries
7−9). As expected, the dimerization of diyne 1a was
suppressed, and dihydropyridine 3a was isolated in satisfactory
yields and enantioselectivities. Moreover, reducing the loading
of the catalytic mixture to 5 mol%, the amount of imine to 1.5
We started with diyne 1a bearing a gem-bis(methyl ester)
tether and commercially available sulfonimine 2a. Our study
began with the identification of an effective catalytic system.
Trials based on cobalt [CpCo(CO)2, CpCo(C2H4)2, CpCo-
(CO)(dmfu)12], nickel [Ni(cod)2/PCy3], ruthenium [Cp*Ru-
(cod)Cl], iridium ([Ir(cod)Cl]2/dppe), and rhodium [RhCl-
(PPh3)3] catalysts13 all failed to achieve the title reaction, as the
Received: September 21, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja309301n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
equiv, and the addition time to 7 h afforded 3a in a decent yield
and, gratifyingly, with improved enantiomeric excess (entry 9).
We next looked for a milder catalytic process that would also
afford better enantiocontrol (Table 2). Removal of the cod
Table 3. Rhodium-Catalyzed [2+2+2] Cycloaddition: Imine
Scope
Table 2. Optimization of the Reaction Conditions for Rh-
Catalyzed [2+2+2] Cycloaddition of Diyne 1a to
Sulfonimine 2a
yield of
ee of
c
a
b
entry
[Rh]
ligand
[Ag]
none
3a (%)
3a (%)
d
1
[Rh(cod)2]BF4
L1
L1
L1
L2
L2
L2
L2
L2
72
82
89
77
84
67
0
76
83
71
92
82
90
0
e
2
[Rh(hexadiene)Cl]2
[Rh(hexadiene)Cl]2
[Rh(hexadiene)Cl]2
[Rh(hexadiene)Cl]2
[Rh(hexadiene)Cl]2
[Rh(hexadiene)Cl]2
[Rh(cod)Cl]2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgBF4
none
ef
,
3
4
5
6
7
8
9
e
ef
,
e
e
g
e
AgSbF6
AgSbF6
0
0
[Rh(hexadiene)Cl]2
none
0
0
a
b
L1 = (R)-Tol-Binap; L2 = (R)-3,5-ditBu-MeOBiphep. [Rh]/[Ag] =
c
d
1:1 when [Ag] was present. Determined by chiral HPLC. 5 mol%
[Rh(cod)2]BF4 with previous hydrogenation. 2.5 mol% [Rh-
(hexadiene)Cl]2. The reaction was carried out at 80 °C. 2.5 mol%
e
f
g
[Rh(cod)Cl]2.
ligand by hydrogenation14 allowed the catalyst to turn over at
room temperature and the reaction time to be reduced to 3 h
(entry 1). The product was still isolated in good yield (72%),
but no improvement in the ee was observed (76%). The
reaction could also be carried out with good efficiency in the
presence of the neutral rhodium complex [Rh(hexadiene)Cl]2
in association with a silver salt. Among the dimeric rhodium
species and silver salts we screened, [Rh(hexadiene)Cl]2/
AgSbF6 was the best combination at room temperature (3 h,
82%, 83% ee; entry 2). A subsequent survey of the biphosphane
motif unveiled promising effects of more hindered ligands. We
were pleased to find that the use of (R)-ditBu-MeOBiphep13
yielded 3a in 77% yield with an excellent ee of 92% (entry 4).
Control experiments revealed that the generation of a cationic
rhodium species by the action of a silver salt was essential, with
AgSbF6 as the best candidate (entries 6 and 7).15 Lastly,
[Rh(hexadiene)Cl]2 could not be replaced by the more
common [Rh(cod)Cl]2 (entry 8). Also, the use of a
biphosphane ligand was critical for reaction efficiency, as the
starting material remained unchanged without a biphosphane
ligand under these specific conditions (entry 9).
The scope of this asymmetric cycloaddition process was then
assessed through variation of the diyne and sulfonimine
components under the optimized conditions. We first examined
the reactivity of various imines toward diyne 1a (Table 3).
Sulfonimines 2a and 2b (Ar = Ph) afforded the corresponding
1,2-dihydropyridines 3a and 3b in good yields with excellent
enantiocontrol (entries 1 and 2). Unfortunately, sulfonimine 2c
bearing an electron-poor aryl group did not provide 3c even at
higher temperatures (entry 3). On the other hand, diyne 1a was
effectively converted into 1,2-dihydropyridines 3d−i when
reacted with sulfonimines bearing an electron-withdrawing
a
No more conversion to the desired dihydropyridine 3c could be
b
c
observed at 80 °C. The reaction was carried out at 80 °C. The
enantioselectivity could not be improved under various modified
conditions.
group such as Cl (entry 4) or an electron-rich aryl group
(entries 5−9). Ortho and meta substitution did not affect the
enantioselectivity of the reaction (entries 8 and 9), but it was
necessary to raise the temperature to 80 °C with these
substrates. Finally, substitution of the imine with a hetero-
aromatic furan group gave dihydopyridine 3j, albeit with
moderate enantioselectivity (entry 10).
We next focused on the diyne pattern, first varying the nature
of the tether (Table 4). From the outset, we realized that the
success of this reaction using diynes 1b−g would require
modified conditions. Knowing that slight variations in the
tether or the phosphine ligand can have a dramatic influence on
the reactivity of diyne systems,16 we tested the less hindered
(R)-Tol-Binap ligand. This time we observed satisfactory yields
and enantioselectivities. Moreover, in some cases, higher
temperatures favored initial conversion of the starting material
and/or the desired cycloaddition process versus cyclodimeriza-
tion. The nitrogen-tethered diyne 1b (tosyl protecting group)
remained unchanged at room temperature when reacted with
sulfonimine 2a, but at 80 °C, dihydropyridine 3k was isolated
in 99% yield at the expense of the enantioselectivity, which
dropped to 4% ee (entry 1). Changing the tosyl group to an
electron-poor benzene ring proved to be advantageous, giving
product 3l in good yield and ee at room temperature (entry 2).
B
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Journal of the American Chemical Society
Communication
Table 4. Rhodium-Catalyzed [2+2+2] Cycloaddition: Diyne
Scope
Scheme 2. Attempted Rh-Catalyzed [2+2+2] Cycloaddition
of Unsymmetrical Diyne 1i to Sulfonimine 2a
Scheme 3. Attempted Rh-Catalyzed [2+2+2] Cycloaddition
of Nonsubstituted Diyne 1j to Sulfonimine 2a
Scheme 4. Proposed Mechanism for the Rhodium-Catalyzed
Cycloaddition of Diynes and Sulfonimines
a
The reaction was carried out at 80 °C, and subsequent ligand
b
screening did not affect the enantioselectivity. The reaction was
carried out at room temperature. The reaction was carried out at 80
°C. The reaction was carried out at room temperature with 3 equiv of
c
d
2a.
Diynes displaying a carbon tether could be used as well, giving
rise to 1,2-dihydropyridines 3m−o at 80 °C in good yields with
ee’s of >90% (entries 3−5). Finally, the oxygen-tethered diyne
1g proved to be more reactive, with the cyclization taking place
at room temperature with very good enantiocontrol (entry 6).
Changing the methyl group at the alkyne termini had a
dramatic influence on the reactivity. While tolerated,
substitution with ethyl groups gave a moderate yield of the
corresponding 1,2-dihydropyridine 3q with low enantioselec-
tivity (31% yield, 8% ee; Scheme 1).
sulfonyl group to rhodium. Subsequent reductive elimination
(RE) would furnish the desired 1,2-dihydropyridine 3. In the
case of unsymmetrical or nonsubstituted diynes, a βH-
elimination/RE sequence may occur, leading to the nonisolated
intermediate D.18 A 6π electrocyclization of D would furnish
the more stable dihydropyridine 5, which could also arise from
dihydropyridine 3 by a classic [1,5]-H shift. In contrast with
Ogoshi’s and Yoshikai’s works under nickel catalysis,4,5 initial
formation of the corresponding rhodapyrroline after OC of one
alkyne moiety and the imine was not considered because of the
tendency of the diyne to cyclodimerize under these catalytic
conditions.
The low enantiocontrol observed with the tosylamide-linked
1,6-diyne 1b suggests that an alternative pathway is possible in
this case. The sulfonamide group would allow the formation of
a rhodapyrroline intermediate.14,19 Thus, the asymmetric
induction would be low because of the distance between the
ligand and the newly formed stereogenic center (Scheme 5).
Also, formation of a rhodacyclopentadiene with diyne 1h would
be sluggish because of steric hindrance due to the ethyl groups
(Scheme 1), so the former rhodapyrroline intermediate would
be involved, justifying the low enantioselectivity observed in
that case.
Scheme 1. Rh-Catalyzed [2+2+2] Cycloaddition of Diyne 1h
to Sulfonimine 2a
At 80 °C, the unsymmetrical diyne 1i was transformed into a
mixture of three products that could be partially separated
(Scheme 2). Two were the expected dihydropyridines 3ra and
3rb, which were obtained with low regioselectivity (2:1, 31%
yield). The major product was the regioisomeric dihydropyr-
idine 5a (56% yield). Additional experiments showed that 5a
did not arise from 3ra.17 Finally, fully nonsubstituted diyne 1j
afforded 5b exclusively (Scheme 3).
To explain the formation of the various products depicted
above, the following mechanism is proposed (Scheme 4).
Typically, initial coordination of diyne 1 followed by oxidative
cyclization (OC) would generate rhodacyclopentadiene A.
Next, regioselective insertion of sulfonimine 2 would afford
rhodadihydroazepine B stabilized by the coordination of the
C
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Journal of the American Chemical Society
Communication
(4) Ogoshi, S.; Ikeda, H.; Kurosawa, H. Angew. Chem., Int. Ed. 2007,
46, 4930.
Scheme 5. Mechanistic Proposal for Tosylamide-Linked
Diyne 1b
(5) Adak, L.; Chan, W. C.; Yoshikai, N. Chem.Asian J. 2011, 6, 359.
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R. E.; Arndtsen, B. A. J. Org. Chem. 2008, 73, 1906. (b) Sun, Z.; Yu, S.;
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Soc. 2004, 126, 11808.
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dihydropyridines, see: (a) Oshima, K.; Ohmura, T.; Suginome, M. J.
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In conclusion, the first asymmetric transition-metal-catalyzed
[2+2+2] cycloaddition of diynes to sulfonimines is reported,
providing a new, efficient method for the synthesis of
enantioenriched 1,2-dihydropyridines. These heterocycles can
be readily accessed through a Rh-catalyzed cyclization under
mild conditions. Further investigations regarding this enantio-
selective reaction are underway, including its extension to the
challenging case of unsymmetrical diynes and computational
studies to elucidate the mechanistic details and the origin of the
selectivity.
̀
́
2145. (g) Fructos, M. R.; Alvarez, E.; Díaz-Requejo, M. M.; Perez, P. J.
J. Am. Chem. Soc. 2010, 132, 4600.
(8) For reviews and applications in total syntheses, see: (a) Bull, J. A.;
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ASSOCIATED CONTENT
* Supporting Information
Spectroscopic data and experimental details for cycloadducts.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
vincent.gandon@u-psud.fr; corinne.aubert@upmc.fr
■
Present Address
(10) Chai, L. Z.; Zhao, Y. K.; Sheng, Q. J.; Liu, Z. -Q. Tetrahedron
Lett. 2006, 47, 9283.
(11) Krow, G. R.; Huang, Q.; Szczepanski, S. W.; Hausheer, F. H.;
Carroll, P. J. J. Org. Chem. 2007, 72, 3458.
(12) Geny, A.; Agenet, N.; Iannazzo, L.; Malacria, M.; Aubert, C.;
Gandon, V. Angew. Chem., Int. Ed. 2009, 48, 1810.
(13) Abbreviations: dmfu, dimethyl fumarate; cod, 1,5-cyclo-
octadiene; dppe, 1,2-bis(diphenylphosphino)ethane; DTBM-Segphos,
(R)-(−)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-
4,4′-bi-1,3-benzodioxole; (R)-Tol-Binap, (R)-(+)-2,2′-bis(di-p-tolyl-
phosphino)-1,1′-binaphthyl; (R)-ditBu-MeOBipheph, (R)-(+)-(6,6′-
dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5-di-tert-butylphenyl)phos-
phine].
(14) Otake, Y.; Tanaka, R.; Tanaka, K. Eur. J. Org. Chem. 2009, 2737.
(15) Kondoh, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007,
129, 6996.
†V.G.: Institut de Chimie Molec
́
ulaire et des Mater
Paris-Sud 11, Batiment 420, 15 rue
enceau, 91405 Orsay Cedex, France
́
iaux d’Orsay,
UMR 8182, Universite
Georges Clem
Notes
́
̂
́
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by Universite
Marie Curie-Paris 6, CNRS, IUF, and Servier Corporation.
■
́
Pierre et
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D
dx.doi.org/10.1021/ja309301n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX