An Asymmetric Dehydrogenative Diels-Alder Reaction for the Synthesis of Chiral Tetrahydrocarbazole Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03251

An asymmetric dehydrogenative Diels-Alder reaction of 2-methyl-3-phenylmethylindoles and α,β-unsaturated aldehydes has been established. The successful in situ generation of the indole ortho-quinodimethane intermediate and the iminium activation of enals

Full text of DOI:10.1021/acs.orglett.7b03251

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Asymmetric Dehydrogenative Diels−Alder Reaction for the
Synthesis of Chiral Tetrahydrocarbazole Derivatives
Xiang Wu,*,† Hai-Jie Zhu,† Shi-Bao Zhao,† Shu-Sen Chen,‡ Yun-Fei Luo,† and You-Gui Li†
†Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei 230009, China
‡Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
S
* Supporting Information
ABSTRACT: An asymmetric dehydrogenative Diels−Alder reaction of 2-methyl-3-phenylmethylindoles and α,β-unsaturated
aldehydes has been established. The successful in situ generation of the indole ortho-quinodimethane intermediate and the
iminium activation of enals are the keys to success, providing various tetrahydrocarbazole derivatives with up to >99% ee.
he direct functionalization of C−H bonds represents a
Tpowerful strategy for the synthesis of structurally complex
molecules from commonly available precursors.1 The cross-
dehydrogenative coupling (CDC) of two C−H bonds provides
a new perspective on efficient C−C bond formation.2
Particularly, the dehydrogenative generation of diverse dienes
for a Diels−Alder reaction has emerged as a unique protocol for
one-step construction of six-membered carbocycles.3 In 2011,
White et al. reported a Pd-catalyzed allylic C−H dehydrogen-
ative oxidation of terminal olefins to generate dienes, which
were then trapped by maleimides.4 Later, Porco et al. employed
Pt/C-cyclopentene or DDQ to oxidize allylbenzene derivatives.
Diels−Alder reaction of the resulting diene and an enone
enabled the total synthesis of Brosimones A and B.5 Very
recently, the Antonchick group successfully expanded the scope
of diene precursors to simple alkyl arenes. A variety of electron-
deficient alkenes were used as the dienophiles in this Diels−
Alder reaction.6
Tetrahydrocarbazole containing multiple stereogenic centers,
as a privileged structural motif, is widely distributed in naturally
occurring indole alkaloids and synthetic pharmaceuticals, which
exhibit various significant bioactivities (Figure 1B).7,8 Despite
progress toward the synthesis of tetrahydrocarbazole deriva-
tives, novel and more efficient strategies are still needed to
improve the structural diversity, especially in the fields of
organic and medicinal chemistry. Dehydrogenative Diels−Alder
reaction has also been applied to tetrahydrocarbazole synthesis.
Zhang et al. discovered an indole-2,3-quinodimethane9,10
pathway for DDQ-promoted Diels−Alder reaction of 2-
methyl-3-arylmethylindoles and dienophiles (Figure 1A).9 3-
Ethyl indoles were also amenable to a dehydrogenative Diels−
Alder reaction in a similar manner, although further
aromatization dominated in this whole process.11 With our
Figure 1. Oxidative dehydrogenative Diels−Alder reactions of indole
compounds for synthesis of tetrahydrocarbazoles. EWG = electron-
withdrawing group.
continued interest in asymmetric oxidative C−H functionaliza-
tion, we anticipated developing an enantioselective version of
this reaction. To the best of our knowledge, there is no
precedent describing an oxidative construction of the chiral
tetrahydrocarbazoles, probably due to (1) compatibility issues
between oxidants and chiral catalysts12 and (2) undesired
overoxidation. Herein, we report the first asymmetric
Received: October 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03251
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Letter
dehydrogenative Diels−Alder reaction of 2-methyl-3-
arylmethylindoles and α,β-unsaturated aldehydes (Figure 1C).
In this reaction, the classical LUMO-lowering activation of α, β-
unsaturated aldehydes by a secondary chiral amine catalyst13
was able to deliver excellent stereocontrol, affording optically
active tetrahydrocarbazoles bearing three contiguous chiral
centers.
As the beginning of this work, we evaluated the model
reaction of 3-benzyl-2-methyl-1H-indole 2a with cinnamalde-
hyde 3a, in the presence of 4 Å MS, using DDQ (2,3-dichloro-
5,6-dicyanohydroquinone) as the oxidant and α,α-diphenyl-
prolinoltrimethylsilyl ether14 1/benzoic acid as the catalysis
system (Table 1). Gratifyingly, the reaction in CHCl3, at 50 °C,
favored Diels−Alder reaction of indole-2,3-quinodimetha-
nes.11c−f,h,i
With the optimal conditions in hand, the generality of 2-
methyl-3-arylmethylindoles 2 was then investigated. In most
cases, substrates with electron-donating or -withdrawing
substitutions (2b−2n) were amenable to this reaction,
delivering the corresponding tetrahydrocarbazoles 4ba−4na
in moderate yields (38%−73%), with excellent diastereoselec-
tivities (all dr >10:1) and enantioselectivities (up to >99% ee)
(Scheme 1). The reaction of substrate 2j bearing a cyano group
a
Scheme 1. Scope of 2-Methyl-3-arylmethylindoles
a
Table 1. Optimization of the Reaction Conditions
a
Unless indicated otherwise, the reaction of 2a (0.15 mmol), 3a (0.3
mmol), acid (0.03 mmol), catalyst 1 (0.03 mmol), DDQ (0.18 mmol),
and 4 Å MS (50 mg) was carried out in solvent (1.0 mL) at 50 °C for
b
72 h. n.d. = not determined. Isolated yields of 4aa for two steps.
c
d
Determined by 1H NMR spectroscopic analysis. Determined by
e
HPLC analysis. The reaction was carried out under a N2 atmosphere.
gave very promising results. After reduction with NaBH4 in
MeOH, a 3:1 dr was observed and the major diastereomer 4aa
was isolated in 57% yield with 99% ee along with a minor
amount of the oxidative byproduct of 3-benzoyl-2-methyl-1H-
indole (entry 1). Varying the Brønsted acids generally led to
diminished yields (entries 2−4). It is noteworthy that a
stronger Brønsted acid improved the diastereoselectivity
(entries 2, 4 vs 1). Investigation of solvents, including 1,2-
dichloroethane (DCE), tetrahydrofuran (THF), toluene, and
DMSO, suggested that CHCl3 was still the best (entries 5−8 vs
1). With the goal of improving the diastereoselectivity, we
continued to evaluate the effect of additional additives. A
catalytic amount of transition-metal salts indeed improved the
result (entries 9−12). For example, the addition of 20 mol %
CuCl2 or NiCl2 would give >10:1 dr, however, at the cost of
lower enantioselectivities (entries 9−10). In the case of
Pd(OAc)2, positive effects on both the yield and diaster-
eoselectivity were observed (70% yield, dr >10:1) without
erosion of the enantioselectivity (entry 11). Finally, the reaction
under a N2 atmosphere provided 4aa in 74% isolated yield, with
>10:1 dr and 99% ee (entry 12). The structure and absolute
configuration of product 4aa were assigned by X-ray analysis
(see Supporting Information), disclosing an unusual 2,3-cis
a
Reaction conditions: 2b−2n (0.15 mmol), 3a (0.3 mmol), benzoic
acid (0.03 mmol), catalyst 1 (0.03 mmol), Pd(OAc)2 (0.03 mmol),
DDQ (0.18 mmol), 4 Å MS (50 mg) in CHCl3 (1.0 mL) under N2 at
50 °C for 72 h. dr >10:1.
at the para-position of the phenyl ring gave product 4ja with
slightly lower 89% ee. 1-Naphthyl-substituted 3-indolemethane
also provided product 4ma with excellent enantioselectivity
(98% ee), albeit in low yield. Moreover, 2-thienyl substituted
substrate 2n was tolerated in this reaction, affording 4na in
moderate yield with 99% ee.
Substituents on the indole ring were also well tolerated
(Scheme 2). Regardless of the position and electronic character
of the substituents, reactions proceeded smoothly under the
optimal conditions, furnishing chiral tetrahydrocarbazoles 4oa−
B
DOI: 10.1021/acs.orglett.7b03251
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no substantial differences in the stereoselectivities and afforded
the corresponding products 4ab−4ag in 41−66% yield, with
98% to >99% ee. Moreover, a β-(1-naphthyl) substituted enal
substrate gave the product 4ah in 57% yield and with 96% ee.
Compared to the β-(2-thienyl) substituted enal 3j, β-(3-
thienyl) substituted compound 3i furnished the product in
higher yield and enantioselectivity. Notably, the furan ring of
substrate 3k was compatible with the oxidant and delivered the
product 4ak in 62% yield, with 95% ee.
Scheme 2. Scope of Substituted 2-Methyl-3-
phenylmethylindoles
a
In order to fully understand the reaction process for the
generation of the unusual 2,3-cis product, two control
experiments were performed. In the above oxidation reaction
system, DDQH2 (2,3-dichloro-5,6-dicyanohydroquinone)9 was
finally produced as a byproduct which might promote the
configuration transformation. Therefore, when the 2,3-trans
aldehyde 511e was treated with DDQH2 (1.0 equiv) in the
presence of cat. 1 and PhCO2H, the 2,3-cis product could be
obtained in 90% yield (eq 1). Moreover, the additive Pd(OAc)2
a
Reaction conditions: 2o−2u (0.15 mmol), 3a (0.3 mmol), benzoic
acid (0.03 mmol), catalyst 1 (0.03 mmol), Pd(OAc)2 (0.03 mmol),
DDQ (0.18 mmol), 4 Å MS (50 mg) in CHCl3 (1.0 mL) under N2 at
50 °C for 72 h. dr >10:1.
4ua in moderate yields (48−65%), with excellent diaster-
eoselectivities (>10:1) and enantioselectivities (94−99% ee).
An array of α,β-unsaturated aldehydes with mono-β-aryl or
heteroaryl substitutions was examined (Scheme 3). The
substituents on the phenyl ring of the cinnamaldehyde had
(20 mol %) played a similar role in this transformation and the
aldehyde 5 converted to the product 4aa′ (29% yield) partly
(eq 2). These facts clearly demonstrated that the unusual 2,3-cis
product was produced from 2,3-trans aldehydes in the presence
of DDQH2 and Pd(OAc)2.
a
Scheme 3. Scope of α,β-Unsaturated Aldehydes
To account for the stereochemical outcome of the reaction,
we propose a plausible mechanism (Scheme 4). First, the
Scheme 4. Proposed Mechanism
indole ortho-quinodimethane intermediate A is formed from 2a
under the assistance of DDQ which leads to DDQH2. Iminium
ion B is generated from the aldehyde 3a in the presence of cat.
1 and PhCO2H. Then, the Diels−Alder reaction of
intermediates A and B proceeds smoothly and provides the
cycloadduct intermediate C. DDQH2 and Pd(OAc)2 promote
the epimerization of the 3-position of the tetrahydrocarbazole
unit and gives the 2,3-cis intermediate E via chiral enamine D.
a
Reaction conditions: 2a (0.15 mmol), 3b−3k (0.3 mmol), benzoic
acid (0.03 mmol), catalyst 1 (0.03 mmol), Pd(OAc)2 (0.03 mmol),
DDQ (0.18 mmol), 4 Å MS (50 mg) in CHCl3 (1.0 mL) under N2 at
50 °C for 72 h. dr >10:1.
C
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Letter
2016, 81, 343. (m) Gini, A.; Brandhofer, T.; Mancheno, O. G. Org.
Biomol. Chem. 2017, 15, 1294.
Finally, upon hydrolysis and release of the catalyst 1, iminium
ion E furnishes 2,3-cis 4aa′.
(3) Li, W.; Zhou, L.; Zhang, J. Chem. - Eur. J. 2016, 22, 1558.
(4) Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133, 14892.
(5) (a) Qi, C.; Cong, H.; Cahill, K. J.; Muller, P.; Johnson, R. P.;
Porco, J. A., Jr. Angew. Chem., Int. Ed. 2013, 52, 8345. Similar reaction;
see: (b) Feng, H.-X.; Wang, Y.-Y.; Chen, J.; Zhou, L. Adv. Synth. Catal.
2015, 357, 940.
In conclusion, we have developed a novel asymmetric
dehydrogenative Diels−Alder reaction between 2-methyl-3-
phenylmethylindoles and α,β-unsaturated aldehydes. The
combination of DDQ-promoted generation of the key indole-
2,3-quinodimethane intermediate and the iminium activation of
enals provided direct access to chiral tetrahydrocarbazole
derivatives, along with excellent levels of diastereo- and
enantioselectivity. Importantly, this protocol provides a step-
economical strategy for synthesis of valuable chiral compounds.
(6) Manna, S.; Antonchick, A. P. Chem. - Eur. J. 2017, 23, 7825.
(7) Selected reviews on tetrahydrocarbazoles: (a) Schmidt, A. W.;
Reddy, K. R.; Knoelker, H.-J. Chem. Rev. 2012, 112, 3193. (b) Zhu, X.-
Y.; An, X.-L.; Li, C.-F.; Zhang, F.-G.; Hua, Q.-L.; Chen, J.-R.; Xiao, W.-
J. ChemCatChem 2011, 3, 679. (c) Knoelker, H.-J.; Reddy, K. R. Chem.
Rev. 2002, 102, 4303. Selected recent examples of asymmetric
synthesis of tetrahydrocarbazoles: (d) Jaiswal, P. K.; Biswas, S.; Singh,
S.; Pathak, B.; Mobin, S. M.; Samanta, S. RSC Adv. 2013, 3, 10644.
(e) Harada, S.; Morikawa, T.; Nishida, A. Org. Lett. 2013, 15, 5314.
(f) Loh, C. C. J.; Raabe, G.; Enders, D. Chem. - Eur. J. 2012, 18, 13250.
(g) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51,
1680. (h) Zheng, C.; Wu, Q.-F.; You, S.-L. J. Org. Chem. 2013, 78,
4357. (i) Xiao, Y.-C.; Yue, C.-Z.; Chen, P.-Q.; Chen, Y.-C. Org. Lett.
2014, 16, 3208. (j) Zhao, R.-R.; Sun, Z.-W.; Mo, M.-J.; Peng, F.-Z.;
Shao, Z.-H. Org. Lett. 2014, 16, 4178. (k) Wang, Y.; Tu, M.-S.; Yin, L.;
Sun, M.; Shi, F. J. Org. Chem. 2015, 80, 3223. (l) Huang, Y.; Song, L.;
Gong, L.; Meggers, E. Chem. - Asian J. 2015, 10, 2738. (m) Zheng, H.;
He, P.; Liu, Y.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. Chem. Commun.
2014, 50, 8794. (n) Huang, L. J.; Weng, J.; Wang, S.; Lu, G. Adv.
Synth. Catal. 2015, 357, 993. (o) Zhao, X.; Mei, H.; Xiong, Q.; Fu, K.;
Lin, L.; Liu, X.; Feng, X. Chem. Commun. 2016, 52, 10692. (p) Zhao,
F.; Li, N.; Zhu, Y.-F.; Han, Z.-Y. Org. Lett. 2016, 18, 1506.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03251.
1
General and characterization data, H and 13C NMR
spectra (PDF)
Accession Codes
CCDC 1569813 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(8) (a) Stoermer, D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 564.
(b) Mihalic, J. T.; Chen, X.-Q.; Fan, P.-C.; Chen, X.; Fu, Y.; Liang, L.-
L.; Reed, M.; Tang, L.; Chen, J.-L.; Jaen, J.; Li, L.; Dai, K. Bioorg. Med.
Chem. Lett. 2011, 21, 7001. (c) Feng, Y.-Q.; Majireck, M.-M.; Weinreb,
S. M. Angew. Chem., Int. Ed. 2012, 51, 12846. (d) Busto, E.; Gotor-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wuxiang@hfut.edu.cn.
ORCID
́
Fernandez, V.; Gotor, V. J. Org. Chem. 2012, 77, 4842.
(9) (a) Zhou, L.; Xu, B.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54,
9092. (b) Liu, T. X.; Ma, J. L.; Chao, D.; Zhang, P. L.; Ma, N. N.; Liu,
Q. F.; Shi, L.; Zhang, Z. G.; Zhang, G. S. Org. Lett. 2016, 18, 4044.
(10) Kuo, C. W.; Konala, A.; Lin, L.; Chiang, T. T.; Huang, C. Y.;
Yang, T. H.; Kavala, V.; Yao, C. F. Chem. Commun. 2016, 52, 7870.
(11) Two reviews of indole-based oQDMs: (a) Pindur, U.; Erfanian-
Abdoust, H. Chem. Rev. 1989, 89, 1681. (b) Magnus, P.; Gallagher, T.;
Brown, P.; Pappalardo, P. Acc. Chem. Res. 1984, 17, 35. For recent
examples, see: (c) Kuroda, N.; Takahashi, Y.; Yoshinaga, K.; Mukai, C.
Org. Lett. 2006, 8, 1843. (d) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.;
Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212. (e) Xiao, Y.-C.;
Zhou, Q.-Q.; Dong, L.; Liu, T.-Y.; Chen, Y.-C. Org. Lett. 2012, 14,
5940. (f) Liu, Y.-K.; Nappi, M.; Escudero-Adan, E. C.; Melchiorre, P.
Org. Lett. 2012, 14, 1310. (g) Chen, X. K.; Yang, S.; Song, B.-A.; Chi,
Y. R. Angew. Chem., Int. Ed. 2013, 52, 11134. (h) Rassu, G.; Curti, C.;
Zambrano, V.; Pinna, L.; Brindani, N.; Pelosi, G.; Zanardi, F. Chem. -
Eur. J. 2016, 22, 12637. (i) Gu, B.-Q.; Zhang, H.; Su, R.-H.; Deng, W.-
P. Tetrahedron 2016, 72, 6595.
Xiang Wu: 0000-0001-5428-9063
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (NNSFC) (Grant 21672049) and
Hefei University of Technology. We sincerely thank Dr. Dian-
Feng Chen (Columbia University, US) for helpful discussions.
REFERENCES
■
(1) Selected recent reviews: (a) Bering, L.; Manna, S.; Antonchick, A.
P. Chem. - Eur. J. 2017, 23, 10936. (b) Qin, Y.; Zhu, L.; Luo, S. Chem.
Rev. 2017, 117, 9433. (c) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S.-g.
Chem. Soc. Rev. 2017, 46, 4299. (d) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J.
Angew. Chem., Int. Ed. 2017, 56, 1960. (e) Hartwig, J. F. J. Am. Chem.
Soc. 2016, 138, 2. (f) Narayan, R.; Matcha, K.; Antonchick, A. P. Chem.
- Eur. J. 2015, 21, 14678.
(12) (a) Chow, C. P.; Shea, K. J. J. Am. Chem. Soc. 2005, 127, 3678.
(b) Dumoulin, A.; Masson, G. J. Org. Chem. 2016, 81, 10154. (c) Yao,
Y.; Zhu, H.-J.; Li, F.; Zhu, C.-F.; Luo, Y.-F.; Wu, X.; Kantchev, E. A. B.
Adv. Synth. Catal. 2017, 359, 3095.
(2) Selected reviews on the CDC reaction: (a) Li, C.-J. Acc. Chem.
Res. 2009, 42, 335. (b) Scheuermann, C. J. Chem. - Asian J. 2010, 5,
436. (c) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem. 2009, 292, 281.
(d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (e) Liu, C.;
Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (f) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
(g) Klussmann, M.; Sureshkumar, D. Synthesis 2011, 2011, 353.
(h) Zhang, C.; Tang, C. H.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
(i) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53,
74. (j) Batra, A.; Singh, P.; Singh, K. N. Eur. J. Org. Chem. 2016, 2016,
4927. (k) Krylov, I. B.; Vil, V. A.; Terent’ev, A. O. Beilstein J. Org.
Chem. 2015, 11, 92. (l) Davies, H. M. L.; Morton, D. J. Org. Chem.
(13) (a) Vicario, J. L. Synlett 2016, 27, 1006. (b) Halskov, K. S.;
Donslund, B. S.; Paz, B. M.; Jorgensen, K. A. Acc. Chem. Res. 2016, 49,
974. (c) Afewerki, S.; Cordova, A. Chem. Rev. 2016, 116, 13512.
(d) Brazier, J. B.; Tomkinson, N. C. O. Top. Curr. Chem. 2010, 291,
281.
(14) (a) Marigo, M.; Wabnitz, T. C.; Fielen-bach, D.; Jørgensen, K.
A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212.
(c) Jensen, K. L.; Dick-meiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K.
A. Acc. Chem. Res. 2012, 45, 248.
D
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