- Email: [email protected]
Rhodium-catalyzed [2+2+2] cycloaddition reactions of terminal alkynes with N-sulfonyl ketimines
Tetrahedron Letters 56 (2015) 546–548
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Rhodium-catalyzed [2+2+2] cycloaddition reactions of terminal alkynes with N-sulfonyl ketimines Wei Zhang, Qian-Ru Zhang, Lin Dong ⇑ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
a r t i c l e
i n f o
Article history: Received 23 September 2014 Revised 19 November 2014 Accepted 27 November 2014 Available online 10 December 2014
a b s t r a c t A simple approach for the direct synthesis of 1,2-dihydropyridines was developed involving a one-step rhodium-catalyzed [2+2+2] cycloaddition between N-sulfonyl ketimines and two terminal alkynes. Mechanistic studies suggested a stepwise reaction of an imine and alkyne with rhodium(III), followed by the insertion of a second alkyne. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: 1,2-Dihydropyridines Rhodium Terminal alkynes [2+2+2] cycloaddition N-Sulfonyl ketimines
1,2-Dihydropyridines are widely used as intermediates to synthesize diverse organic molecules such as piperidines and pyridines, and they are also used as Diels–Alder partners.1–4 Research into their biological and synthetic applications5 has led to several methods for preparing them.6–10 For example, Wender et al. reported rhodium-catalyzed aza-[5+2] cycloaddition of cyclopropylimine and alkynes,6 while Ogoshi et al. used nickel catalysis to achieve oxidative cyclization of an imine and alkynes (Scheme 1, eq 1).7 The [2+2+2] cyclization between imines bearing a directing N-pyridyl group and two internal alkynes has also been studied.8 Recently, Gandon and Aubert described the first transition-metalcatalyzed asymmetric [2+2+2] cycloaddition of diynes to sulfonimines (Scheme 1, eq 2).9 This range of methods does not cover the full range of possible substrates and some of them are inefficient, highlighting the need to continue innovating new appro aches to prepare 1,2-dihydropyridines. Transition-metal-catalyzed cycloaddition allows efficient, simultaneous construction of polycyclic compounds,11 but it has been exploited to produce only a narrow range of 1,2-dihydropyridines.12 In particular, terminal alkynes have rarely been used in Rh(III)-catalyzed coupling reactions. Here we report a one-step Rh(III)-catalyzed reaction of N-sulfonyl ketimines with two terminal alkynes to provide 1,2-dihydropyridine while simultaneously
⇑ Corresponding author. Tel.: +86 28 85503538. E-mail address: [email protected] (L. Dong). http://dx.doi.org/10.1016/j.tetlet.2014.11.122 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
creating a quaternary carbon center via [2+2+2] cyclization (Scheme 1, eq 3).
Previous work:
R2 R2
NSO2 Ph + Ph
H
R1
0
cat. [Ni ] phosphine
R1
R1
R2
Ph N SO2 Ph
(1)
R1 NSO2Ph Ph
R2
R1 + X R2
H
This work: O O S N R1
+
R3
I
cat. [Rh ] ligand AgSbF6
cat. [RhIII] AgSbF6
N
X
SO2 Ph (2) Ph
R2
R2 O O S N
R3 (3)
R1 R3
Scheme 1. Transition-metal-catalyzed [2+2+2] cycloaddition of imines and alkynes.
We began our study by examining the [2+2+2] cycloaddition of N-sulfonyl ketimines (1a) with phenylacetylene (2a) (Table 1).13 No reaction was detected when we used Cu(OAc)2 or AgBF4 as additive (Table 1, entries 1 and 2). To our delight, the desired prod-
547
W. Zhang et al. / Tetrahedron Letters 56 (2015) 546–548 Table 1 Optimization of reaction conditionsa
O O S N +
1a
Ph
2a
Table 2 Scope of N-sulfonyl ketimine substratesa,b
[Cp*RhCl2]2 (2.5 mol%) additive (20 mol%) solvent, 80 °C
O O S N
3aa
O O S N +
Ph R2 1
Ph
Entry
Additive
Acid
Solvent
Yieldb (%)
1c 2c 3c,d 4c 5c,e 6c,f 7 8g 9g 10h 11 12 13 14 15 16i 17i,j 18i,k
Cu(OAc)2 AgBF4 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6/CuI AgSbF6/Cu(OTf)2 AgSbF6/Cu(OTf)2 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6
— — — — — — — — — — AcOH CH3SO3OH Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H
DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCM THF DCE DCE DCE
N.R. N.R. 15 18 Trace Mess 24 16 24 14 22 29 31 20 N.R. 35 42 46
R1
O2 S N
Ph [Cp*RhCl2]2 (10 mol %)
O2 S N
Ph
3ba, 35% O2 S N
Ph
R1 3 O2 S N
Ph
Ph
O2 S N
Ph
OMe 3ea, 44%
3da, 35% O2 S N
3ga, 42%
Ph
Ph
Ph
Ph
Ph
Ph 3ca, 21%
Ph
Ph
Ph
Cl
R2
AgSbF6 (80 mol %) Ph2CH3SiCO2H (80 mol %) 2a DCE, 110 °C, 48 h
3aa, 46% O2 S N
O O S N
Ph
Ph MeO 3fa, 52% O2 S N
3ha, 43%
Ph
Ph
a
Reaction conditions unless otherwise specified: 0.05 mmol of 1a, 0.2 mmol of 2a, 2.5 mol % of [Cp*RhCl2]2, 20 mol % of additive, 20 mol % of acid, 1.0 mL of solvent, 80 °C, 20 h, Ar atmosphere. b Isolated yield. c 5 mol % of [Cp*RhCl2]2. d 10 mol % of additive. e 50 mol % of additive. f 100 mol % of additive. g 5 mol % of copper salts. h 20 mol % of copper salts. i 110 °C. j Method: Every 12 h, 2.5 mol % of [Cp*RhCl2]2, 20 mol % of additive, 20 mol % of acid and 4 equiv of 2a were added to the reaction at 110 °C; this addition was performed 3 times over 36 h. k Method: The same addition as in note j was performed 4 times every 12 h, for a total reaction time of 48 h.
uct 3aa was formed when AgSbF6 was added as additive, and the loading strongly influenced yield (Table 1, entries 3–6). Conversely, reducing the loading of [Cp*RhCl2]2 improved yield to 24% (Table 1, entry 7). Adding copper salts to the reaction did not further increase the yield (Table 1, entries 8–10). Adding the acid Ph2CH3SiCOOH increased reaction efficiency (Table 1, entries 11–13), whereas changing the solvent to THF or DCM did not work effectively (Table 1, entries 14 and 15). Higher temperature promoted the reaction (Table 1, entry 16). In the end, 3aa was obtained in 46% yield when the catalysts and alkyne were added four times over 48 h (Table 1, entries 17 and 18). Even under these optimal conditions, some 1a remained unreacted, even after we further extended the time or increased the temperature. This may be because the terminal alkynes were undergoing homo-coupling and other side reactions also occurred in the reaction. With these optimized conditions, we further investigated the reactions of various N-sulfonyl ketimines with phenylacetylene 2a. The process tolerated a wide range of ketimine substrates (Table 2). Various 3-alkyl cyclic N-sulfonyl ketimines gave the corresponding products 3aa–3ca in moderate yields. Structure of 3ca was characterized by X–ray crystallography (Fig. 1).14 Aryl-substituted N-sulfonyl ketimines (1d–1f) also reacted smoothly, and even N-sulfonyl ketimines fused with a diversely substituted benzene ring underwent annulation to deliver the desired products in acceptable yields (3ga, 3ha). Other cyclic N-sulfonyl ketimines, however, gave disappointing results.13
a
Reaction conditions: 0.05 mmol of 1 and 1.0 mL of DCE at 110 °C under an Ar atmosphere, with addition of 2.5 mol % of [Cp * RhCl2]2, 20 mol % of AgSbF6, 20 mol % of Ph2CH3SiCOOH and 4 equiv of 2a four times every 12 h, for a total reaction time of 48 h. b Isolated yield.
Figure 1. X-ray crystal structure of 3ca.
Next we examined various terminal alkynes with different electronic properties (Table 3). To our delight, the reaction tolerated an array of aryl alkynes, giving the corresponding products in moderate yields. Similar yields were obtained when the alkyne carried a methyl group at the para- or meta-position of the benzene ring (3ab, 3ac). Yield was higher with a chlorine-substituted aryl alkyne than with bromine- or fluorine-substituted ones, probably owing to steric and electronic effects (3ad–3af). The 3-phenyl substituted N-sulfonyl ketimine 1d also reacted, producing 3de in 39% yield. However, neither internal alkynes nor terminal alkyl alkynes afforded any desired products.13 To verify the multifunctional properties of the 1,2-dihydropyridines produced using our approach, we subjected them to further transformations to prepare more complex polycyclic structures.
548
W. Zhang et al. / Tetrahedron Letters 56 (2015) 546–548
Table 3 Scope of N-sulfonyl ketimine and terminal alkyne substratesa,b
O O S N +
R3
AgSbF6 (80 mol %) Ph 2CH3 SiCO2 H (80 mol %) DCE, 110 °C, 48 h
R1 1
[Cp*RhCl2]2 (10 mol %)
2
O O S N
O O S N
R3
3aa
R1 3
R3
F O2 S N
O2 S N
3ab, 42%
O2 S N
RhI
O2 S N
3ae, 54% Cl
Ph
O O S Cp* N RhIII
2a
Ph
I Ph
Cl
Ph
O O S N RhIII Cp* Ph II
Scheme 3. Proposed mechanism.
Acknowledgments We are grateful for the financial support from the NSFC (No. 21202106), and Sichuan University ‘985 project-Science and technology innovation platform for novel drug development’.
3de, 39% Br
1a
2a
O2 S N
3af, 39%
AgI
O O S N RhIII Ph Cp* Ph III
Br
O2 S N
[RhIIICp*]
O O Cp* S RhIII Ph N
F Cl
O O S N
Ag0
Ph
IV
3ad, 31%
3ac, 38%
Ph
Cl
Supplementary data
a
Reaction conditions: 0.05 mmol of 1 and 1.0 mL of DCE at 110 °C under an Ar atmosphere, with addition of 2.5 mol % of [Cp*RhCl2]2, 20 mol % of AgSbF6, 20 mol % of Ph2CH3SiCOOH and 4 equiv of 2 four times every 12 h, for a total reaction time of 48 h. b Isolated yield.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014. 11.122. References and notes
Br O O2 S N
Ph
N O toluene,150 o C
3aa Ph
O2 Ph O Ph S N N H H O 4, 58%
Br
Scheme 2. Construction of complex bridged structures via Diels–Alder reaction.
These transformations proceeded efficiently. Diels–Alder reaction of 3aa with N-substituted maleimide in the presence of toluene at 150 °C gave the bridged compound 4 (Scheme 2). The NOE spectrum of the single product 4 revealed preferential formation of the endo isomer.13 Based on our experiments, we propose the following plausible mechanism for rhodium-catalyzed [2+2+2] cycloaddition (Scheme 3). In the first step, chelation by [Cp*RhCl2]2 of the nitrogen and alkyne generates the rhodium complex I, which then undergoes regioselective addition of the alkyne to generate rhodacyclopentadiene II. Then coordination of the second molecule of 2a by a rhodium species affords intermediate III, which regioselective insertion converts into a seven-membered rhodacycle IV. Subsequent reductive elimination gives the desired 1,2-dihydropyridine 3aa and a Rh(I) species. Finally, the Rh(I) species is oxidized by Ag(I) to complete the catalytic cycle. In summary, we have developed a new Rh(III)-catalyzed [2+2+2] cycloaddition reaction of N-sulfonyl ketimines with two terminal alkynes. The result is 1,2-dihydropyridine with a quaternary carbon center. Further studies are underway in our laboratory to understand the catalytic mechanism and explore the synthetic potential of this approach.
1. For reviews and applications in total syntheses, see: (a) Varela, J. A.; Saá, C. Chem. Rev. 2003, 103, 3787; (b) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642; (c) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223; (d) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141; (e) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 13873; (f) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2007, 46, 5734; (g) Zhao, G.; Deo, U. C.; Ganem, B. Org. Lett. 2001, 3, 201; (h) Polniaszek, R. P.; Dillard, L. W. J. Org. Chem. 1992, 57, 4103; (i) Raucher, S.; Bray, B. L. J. Org. Chem. 1985, 50, 3236. 2. Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829. 3. Chai, L.-Z.; Zhao, Y.-K.; Sheng, Q.-J.; Liu, Z.-Q. Tetrahedron Lett. 2006, 47, 9283. 4. Krow, G. R.; Huang, Q.; Szczepanski, S. W.; Hausheer, F. H.; Carroll, P. J. J. Org. Chem. 2007, 72, 3458. 5. (a) Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem. 2008, 73, 1906; (b) Sun, Z.-K.; Yu, S.-Y.; Ding, Z.-D.; Ma, D.-W. J. Am. Chem. Soc. 2007, 129, 9300. 6. Wender, P. A.; Pedersen, T. M.; Scanio, M. J. C. J. Am. Chem. Soc. 2002, 124, 15154. 7. (a) Ogoshi, S.; Ikeda, H.; Kurosawa, H. Angew. Chem., Int. Ed. 2007, 46, 4930; (b) Hoshimoto, Y.; Ohata, T.; Ohashi, M.; Ogoshi, S. Chem. Eur. J. 2014, 20, 4105. 8. Adak, L.; Chan, W.-C.; Yoshikai, N. Chem.-Asian J. 2011, 6, 359. 9. Amatore, M.; Leboeuf, D.; Malacria, M.; Gandon, V.; Aubert, G. J. Am. Chem. Soc. 2013, 135, 4576. 10. (a) Oshima, K.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2011, 133, 7324; (b) Oshima, K.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2012, 134, 3699; (c) Xin, X.-Y.; Wang, D.-P.; Wu, F.; Li, X.-C.; Wan, B.-S. J. Org. Chem. 2013, 78, 4065; (d) Zhao, G.-L.; Shi, M. J. Org. Chem. 2005, 70, 9975; (e) Zhao, G.-L.; Huang, J.-W.; Shi, M. Org. Lett. 2003, 5, 4737; (f) Zhang, J.-W.; Xu, Z.; Gu, Q.; Shi, X.-X.; Leng, X.-B.; You, S.-L. Tetrahedron 2012, 68, 5263; (g) Yan, J.-W.; Cheng, M.; Hu, F.; Hu, Y.-H. Org. Lett. 2012, 14, 3206; (h) Love, B. E.; Raje, P. S. J. Org. Chem. 1994, 59, 3219; (i) Yang, Z.-L.; Yu, H.; Zhang, L.; Wei, H.; Xiao, Y.-M.; Chen, L.-Z.; Guo, H.-C. Chem.-Asian J. 2014, 9, 313. 11. (a) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741; (b) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209; (c) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830; (d) Cheng, M.; Yan, J.-W.; Hu, F.; Chen, H.; Hu, Y.-H. Chem. Sci. 2013, 4, 526. 12. (a) Nasrallah, D. J.; Croatt, M. P. Eur. J. Org. Chem. 2014, 18, 3767; (b) Imaizumi, T.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2012, 134, 20049; (c) Shintani, R.; Fu, G.-C. J. Am. Chem. Soc. 2003, 125, 10778; (d) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2012, 77, 2501. 13. For more details, see the Supporting information. 14. Crystallographic data for 3ca: CCDC 1012161, C27H25NO2S, M: 427.1606, Space group: P21/n, Bond precision: C–C = 0.0036 Å, Wavelength = 0.71073, Cell: a = 12.6891(12), b = 13.1768(7), c = 14.2163(10) Å, alpha = 90°, beta = 110.733(9)°, gamma = 90°, Temperature: 293 K, Dcalcd: 1.277 g/cm3.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Rhodium-catalyzed [2+2+2] cycloaddition reactions of terminal alkynes with N-sulfonyl ketimines Wei Zhang, Qian-Ru Zhang, Lin Dong ⇑ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
a r t i c l e
i n f o
Article history: Received 23 September 2014 Revised 19 November 2014 Accepted 27 November 2014 Available online 10 December 2014
a b s t r a c t A simple approach for the direct synthesis of 1,2-dihydropyridines was developed involving a one-step rhodium-catalyzed [2+2+2] cycloaddition between N-sulfonyl ketimines and two terminal alkynes. Mechanistic studies suggested a stepwise reaction of an imine and alkyne with rhodium(III), followed by the insertion of a second alkyne. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: 1,2-Dihydropyridines Rhodium Terminal alkynes [2+2+2] cycloaddition N-Sulfonyl ketimines
1,2-Dihydropyridines are widely used as intermediates to synthesize diverse organic molecules such as piperidines and pyridines, and they are also used as Diels–Alder partners.1–4 Research into their biological and synthetic applications5 has led to several methods for preparing them.6–10 For example, Wender et al. reported rhodium-catalyzed aza-[5+2] cycloaddition of cyclopropylimine and alkynes,6 while Ogoshi et al. used nickel catalysis to achieve oxidative cyclization of an imine and alkynes (Scheme 1, eq 1).7 The [2+2+2] cyclization between imines bearing a directing N-pyridyl group and two internal alkynes has also been studied.8 Recently, Gandon and Aubert described the first transition-metalcatalyzed asymmetric [2+2+2] cycloaddition of diynes to sulfonimines (Scheme 1, eq 2).9 This range of methods does not cover the full range of possible substrates and some of them are inefficient, highlighting the need to continue innovating new appro aches to prepare 1,2-dihydropyridines. Transition-metal-catalyzed cycloaddition allows efficient, simultaneous construction of polycyclic compounds,11 but it has been exploited to produce only a narrow range of 1,2-dihydropyridines.12 In particular, terminal alkynes have rarely been used in Rh(III)-catalyzed coupling reactions. Here we report a one-step Rh(III)-catalyzed reaction of N-sulfonyl ketimines with two terminal alkynes to provide 1,2-dihydropyridine while simultaneously
⇑ Corresponding author. Tel.: +86 28 85503538. E-mail address: [email protected] (L. Dong). http://dx.doi.org/10.1016/j.tetlet.2014.11.122 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
creating a quaternary carbon center via [2+2+2] cyclization (Scheme 1, eq 3).
Previous work:
R2 R2
NSO2 Ph + Ph
H
R1
0
cat. [Ni ] phosphine
R1
R1
R2
Ph N SO2 Ph
(1)
R1 NSO2Ph Ph
R2
R1 + X R2
H
This work: O O S N R1
+
R3
I
cat. [Rh ] ligand AgSbF6
cat. [RhIII] AgSbF6
N
X
SO2 Ph (2) Ph
R2
R2 O O S N
R3 (3)
R1 R3
Scheme 1. Transition-metal-catalyzed [2+2+2] cycloaddition of imines and alkynes.
We began our study by examining the [2+2+2] cycloaddition of N-sulfonyl ketimines (1a) with phenylacetylene (2a) (Table 1).13 No reaction was detected when we used Cu(OAc)2 or AgBF4 as additive (Table 1, entries 1 and 2). To our delight, the desired prod-
547
W. Zhang et al. / Tetrahedron Letters 56 (2015) 546–548 Table 1 Optimization of reaction conditionsa
O O S N +
1a
Ph
2a
Table 2 Scope of N-sulfonyl ketimine substratesa,b
[Cp*RhCl2]2 (2.5 mol%) additive (20 mol%) solvent, 80 °C
O O S N
3aa
O O S N +
Ph R2 1
Ph
Entry
Additive
Acid
Solvent
Yieldb (%)
1c 2c 3c,d 4c 5c,e 6c,f 7 8g 9g 10h 11 12 13 14 15 16i 17i,j 18i,k
Cu(OAc)2 AgBF4 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6/CuI AgSbF6/Cu(OTf)2 AgSbF6/Cu(OTf)2 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6 AgSbF6
— — — — — — — — — — AcOH CH3SO3OH Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H Ph2CH3SiCO2H
DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCM THF DCE DCE DCE
N.R. N.R. 15 18 Trace Mess 24 16 24 14 22 29 31 20 N.R. 35 42 46
R1
O2 S N
Ph [Cp*RhCl2]2 (10 mol %)
O2 S N
Ph
3ba, 35% O2 S N
Ph
R1 3 O2 S N
Ph
Ph
O2 S N
Ph
OMe 3ea, 44%
3da, 35% O2 S N
3ga, 42%
Ph
Ph
Ph
Ph
Ph
Ph 3ca, 21%
Ph
Ph
Ph
Cl
R2
AgSbF6 (80 mol %) Ph2CH3SiCO2H (80 mol %) 2a DCE, 110 °C, 48 h
3aa, 46% O2 S N
O O S N
Ph
Ph MeO 3fa, 52% O2 S N
3ha, 43%
Ph
Ph
a
Reaction conditions unless otherwise specified: 0.05 mmol of 1a, 0.2 mmol of 2a, 2.5 mol % of [Cp*RhCl2]2, 20 mol % of additive, 20 mol % of acid, 1.0 mL of solvent, 80 °C, 20 h, Ar atmosphere. b Isolated yield. c 5 mol % of [Cp*RhCl2]2. d 10 mol % of additive. e 50 mol % of additive. f 100 mol % of additive. g 5 mol % of copper salts. h 20 mol % of copper salts. i 110 °C. j Method: Every 12 h, 2.5 mol % of [Cp*RhCl2]2, 20 mol % of additive, 20 mol % of acid and 4 equiv of 2a were added to the reaction at 110 °C; this addition was performed 3 times over 36 h. k Method: The same addition as in note j was performed 4 times every 12 h, for a total reaction time of 48 h.
uct 3aa was formed when AgSbF6 was added as additive, and the loading strongly influenced yield (Table 1, entries 3–6). Conversely, reducing the loading of [Cp*RhCl2]2 improved yield to 24% (Table 1, entry 7). Adding copper salts to the reaction did not further increase the yield (Table 1, entries 8–10). Adding the acid Ph2CH3SiCOOH increased reaction efficiency (Table 1, entries 11–13), whereas changing the solvent to THF or DCM did not work effectively (Table 1, entries 14 and 15). Higher temperature promoted the reaction (Table 1, entry 16). In the end, 3aa was obtained in 46% yield when the catalysts and alkyne were added four times over 48 h (Table 1, entries 17 and 18). Even under these optimal conditions, some 1a remained unreacted, even after we further extended the time or increased the temperature. This may be because the terminal alkynes were undergoing homo-coupling and other side reactions also occurred in the reaction. With these optimized conditions, we further investigated the reactions of various N-sulfonyl ketimines with phenylacetylene 2a. The process tolerated a wide range of ketimine substrates (Table 2). Various 3-alkyl cyclic N-sulfonyl ketimines gave the corresponding products 3aa–3ca in moderate yields. Structure of 3ca was characterized by X–ray crystallography (Fig. 1).14 Aryl-substituted N-sulfonyl ketimines (1d–1f) also reacted smoothly, and even N-sulfonyl ketimines fused with a diversely substituted benzene ring underwent annulation to deliver the desired products in acceptable yields (3ga, 3ha). Other cyclic N-sulfonyl ketimines, however, gave disappointing results.13
a
Reaction conditions: 0.05 mmol of 1 and 1.0 mL of DCE at 110 °C under an Ar atmosphere, with addition of 2.5 mol % of [Cp * RhCl2]2, 20 mol % of AgSbF6, 20 mol % of Ph2CH3SiCOOH and 4 equiv of 2a four times every 12 h, for a total reaction time of 48 h. b Isolated yield.
Figure 1. X-ray crystal structure of 3ca.
Next we examined various terminal alkynes with different electronic properties (Table 3). To our delight, the reaction tolerated an array of aryl alkynes, giving the corresponding products in moderate yields. Similar yields were obtained when the alkyne carried a methyl group at the para- or meta-position of the benzene ring (3ab, 3ac). Yield was higher with a chlorine-substituted aryl alkyne than with bromine- or fluorine-substituted ones, probably owing to steric and electronic effects (3ad–3af). The 3-phenyl substituted N-sulfonyl ketimine 1d also reacted, producing 3de in 39% yield. However, neither internal alkynes nor terminal alkyl alkynes afforded any desired products.13 To verify the multifunctional properties of the 1,2-dihydropyridines produced using our approach, we subjected them to further transformations to prepare more complex polycyclic structures.
548
W. Zhang et al. / Tetrahedron Letters 56 (2015) 546–548
Table 3 Scope of N-sulfonyl ketimine and terminal alkyne substratesa,b
O O S N +
R3
AgSbF6 (80 mol %) Ph 2CH3 SiCO2 H (80 mol %) DCE, 110 °C, 48 h
R1 1
[Cp*RhCl2]2 (10 mol %)
2
O O S N
O O S N
R3
3aa
R1 3
R3
F O2 S N
O2 S N
3ab, 42%
O2 S N
RhI
O2 S N
3ae, 54% Cl
Ph
O O S Cp* N RhIII
2a
Ph
I Ph
Cl
Ph
O O S N RhIII Cp* Ph II
Scheme 3. Proposed mechanism.
Acknowledgments We are grateful for the financial support from the NSFC (No. 21202106), and Sichuan University ‘985 project-Science and technology innovation platform for novel drug development’.
3de, 39% Br
1a
2a
O2 S N
3af, 39%
AgI
O O S N RhIII Ph Cp* Ph III
Br
O2 S N
[RhIIICp*]
O O Cp* S RhIII Ph N
F Cl
O O S N
Ag0
Ph
IV
3ad, 31%
3ac, 38%
Ph
Cl
Supplementary data
a
Reaction conditions: 0.05 mmol of 1 and 1.0 mL of DCE at 110 °C under an Ar atmosphere, with addition of 2.5 mol % of [Cp*RhCl2]2, 20 mol % of AgSbF6, 20 mol % of Ph2CH3SiCOOH and 4 equiv of 2 four times every 12 h, for a total reaction time of 48 h. b Isolated yield.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014. 11.122. References and notes
Br O O2 S N
Ph
N O toluene,150 o C
3aa Ph
O2 Ph O Ph S N N H H O 4, 58%
Br
Scheme 2. Construction of complex bridged structures via Diels–Alder reaction.
These transformations proceeded efficiently. Diels–Alder reaction of 3aa with N-substituted maleimide in the presence of toluene at 150 °C gave the bridged compound 4 (Scheme 2). The NOE spectrum of the single product 4 revealed preferential formation of the endo isomer.13 Based on our experiments, we propose the following plausible mechanism for rhodium-catalyzed [2+2+2] cycloaddition (Scheme 3). In the first step, chelation by [Cp*RhCl2]2 of the nitrogen and alkyne generates the rhodium complex I, which then undergoes regioselective addition of the alkyne to generate rhodacyclopentadiene II. Then coordination of the second molecule of 2a by a rhodium species affords intermediate III, which regioselective insertion converts into a seven-membered rhodacycle IV. Subsequent reductive elimination gives the desired 1,2-dihydropyridine 3aa and a Rh(I) species. Finally, the Rh(I) species is oxidized by Ag(I) to complete the catalytic cycle. In summary, we have developed a new Rh(III)-catalyzed [2+2+2] cycloaddition reaction of N-sulfonyl ketimines with two terminal alkynes. The result is 1,2-dihydropyridine with a quaternary carbon center. Further studies are underway in our laboratory to understand the catalytic mechanism and explore the synthetic potential of this approach.
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