Metal-free cascade radical cyclization of 1,6-enynes with aldehydes

Article abstract of DOI:10.1039/c3cc48339h

A new and efficient metal-free cascade cyclization of 1,6-enynes with aldehydes is developed for the synthesis of tricyclic fluorene derivatives. The reaction involves a radical process and one C(sp²)-C(sp²) and two C(sp²)-C(sp³) bonds are formed simultaneously in one pot by using PivOH and TBHP. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc48339h

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Metal-free cascade radical cyclization
of 1,6-enynes with aldehydes†
Cite this: Chem. Commun., 2014,
50, 1564
Jian-Yi Luo,a Hui-Liang Hua,a Zi-Sheng Chen,b Zhao-Zhao Zhou,a Yan-Fang Yang,a
Ping-Xin Zhou,a Yu-Tao He,a Xue-Yuan Liua and Yong-Min Liang*a
Received 31st October 2013,
Accepted 3rd December 2013
DOI: 10.1039/c3cc48339h
www.rsc.org/chemcomm
A new and efficient metal-free cascade cyclization of 1,6-enynes
with aldehydes is developed for the synthesis of tricyclic fluorene
derivatives. The reaction involves a radical process and one C(sp2)–
C(sp2) and two C(sp2)–C(sp3) bonds are formed simultaneously in
one pot by using PivOH and TBHP.
In the realm of polycyclic compounds synthesis, cascade cyclization
of enynes has evolved as a highly efficient strategy to achieve the
synthesis of natural products and pharmaceutical molecules.1,2 In
particular, transition-metal-catalyzed cyclization of 1,6-enynes offers
unprecedented efficiency, higher atom-economy and more opera-
tional simplicity in the synthesis of versatile polycyclic compounds.2
Despite these achievements, scalable synthesis has been hampered
by using eco-unfriendly, noble metal catalysts or expensive reagents.
Scheme 1 Existing free-radical carbonylation methods and a summary of
the present study.
Further, it is also problematic to separate the metal contaminants to 1,6-enynes could be carried out to form tricyclic fluorene com-
from products. As such, a more sustainable and practical approach pounds, which have played important roles in a wide range of fields,
is highly desirable towards the cyclization of 1,6-enynes.
including OFET (organic field-effect transistors), OPV (organic photo-
Radical-mediated reactions have motivated tremendous interest voltaic cells), organic synthesis, etc.6 Herein, we disclose a metal-free
due to their simple operation and high efficiency.3 Among them, free- TBHP–mediated cascade radical cyclization of 1,6-enynes with alde-
radical carbonylation involving an aldehyde C(sp2)–H bond with other hydes for the construction of fluorene derivatives (Scheme 1, eqn (3)).
bonds to form a new carbon–carbon bond has also received extensive
We chose 1,6-enyne 1a (0.2 mmol) and benzaldehyde 2a
attention and some progress has been made.4 Recently, Lei and (1.0 mmol) as our model substrates to investigate the reaction
co-workers have developed an efficient copper-catalyzed oxidative conditions, and the results are summarized in Table 1. At first, the
coupling of alkenes with aldehydes leading to the formation of reaction was carried out in the presence of 2.0 equivalents of tert-
a,b-unsaturated ketones (Scheme 1, eqn (1)).4h Later on, Li and his butylhydroperoxide (TBHP, 70% aqueous solution) at 120 1C under
group reported a metal-free oxidative tandem coupling of activated argon in CH3CN for 48 h. To our delight, the desired product
alkenes with carbonyl C(sp2)–H bonds and aryl C(sp2)–H bonds dimethyl 4-benzoyl-9,9-dimethyl-9,9a-dihydro-1H-fluorene-2,2(3H)-
(Scheme 1, eqn (2)).4i On the basis of our study towards radical and dicarboxylate 3a was isolated in 42% yield (Table 1, entry 1). Some
enyne cyclizations,5 we wish that the addition of aldehyde C–H bonds other oxidants proved to be less effective compared with TBHP
(70% aqueous solution) (Table 1, entries 1–3). Several additives were
also tested (Table 1, entries 4–7), and PivOH provided the highest
yield in 67% (Table 1, entry 4), because it could promote the reaction
to proceed smoothly and inhibit the side reactions.3j Other solvents,
such as DCE, and EtOAc, were applied instead of CH3CN, but no
better results were obtained (Table 1, entries 8 and 9). The control
experiment proved that the oxidant was essential in facilitating the
reaction (Table 1, entry 10). The temperature, additive and oxidant
loadings were key factors in terms of the reaction yield (Table 1,
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, and State
Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics,
Chinese Academy of Science, Lanzhou 730000, P.R. China.
E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582
b Department of Chemistry and Chemical Engineering, College of Science, Northwest
A&F University, Yangling 712100, Shaanxi, China. E-mail: chenzsh@nwsuaf.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. CCDC 932707 (3n). For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c3cc48339h
1564 | Chem. Commun., 2014, 50, 1564--1566
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Table 1 Optimization of the reaction conditionsa
metal-catalyzed coupling reaction. Meanwhile, the structure of
compound 3n was confirmed by X-ray diffraction analysis (see ESI†).
Interestingly, the benzo[d][1,3]dioxole-5-carbaldehyde (2o) could also
undergo the reaction, giving product 3o in 45% yield. Notably, the 2-
thenaldehyde (2p) was a partner as well in this cascade reaction,
although the final outcome is not ideal (Table 2, 3p).
Entry
[O]
[Add.]b
Solvent
Yieldc
Encouraged by these promising results, we further applied the
optimized reaction conditions to examine the substrate scope of
1,6-enynes. In most cases, 1,6-enynes proceeded smoothly to give
the desired products 4a–n in moderate to good yields (Table 3).
However, only a trace amount of the desired product (9,9-dimethyl-
1,3,9,9a-tetrahydroindeno[2,1-c]pyran-4-yl)(phenyl)methanone (4o) was
detected because of the rapid decomposition of ether under the
standard conditions. A variety of 1,6-enynes substituted at the ortho,
meta or para position with electron-donating alkyl or alkoxy groups
were viable in the reaction (Table 3, 4a–4b and 4h–4i). Upon using
substrates with methyl-substituents at the meta position of the aryl ring
of the 1,6-enynes, a mixture of two regioisomers was isolated (Table 3,
4h and 4h0). The presence of either halogen or electron-withdrawing
groups also proved to be compatible with the reaction conditions
(Table 3, 4c–4f and 4j). Moreover, it is noteworthy that some functional
groups were also successfully applied in this transformation (Table 3,
1
TBHP
TBHP
DTBP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
—
—
—
—
PivOH
TFA
HOAc
Caproic acid
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
42
37
16
67
35
23
40
43
45
N.R.e
48
38
51
2d
3
4
5
6
7
8
9
10
11f
12g
13h
EtOAc
CH3CN
CH3CN
CH3CN
CH3CN
TBHP
TBHP
TBHP
a
Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol, 5.0 equiv.), TBHP
(0.4 mmol, 2.0 equiv., 70% aqueous solution), catalysts (5.0 mol%), 120 1C,
48 h, under argon, unless otherwise noted. b Additives (0.4 mml, 2.0 equiv.).
c
e
f
Isolated yield. d TBHP (5–6 M in decane). N.R. = no reaction. TBHP
(0.3 mmol, 1.5 equiv.). g Under 100 1C. h PivOH (1.0 equiv.).
entries 11–13). Therefore, the optimized reaction conditions were 4g and 4k–n). Interestingly, the tosylamide could react smoothly with
affirmed as follows: PivOH (2.0 equiv.) and TBHP (2.0 equiv.) at 2a, albeit in a somewhat low yield (Table 3, 4m–n).
120 1C under argon in CH3CN for 48 h (Table 1, entry 4).
To gain a better understanding of the mechanism, some control
Under the optimized reaction conditions (Table 1, entry 4), we experiments were carried out. Initially, the intramolecular and inter-
examined the scope of aldehydes in the cascade oxidative cyclization molecular kinetic isotope effect (KIE) experiments were performed
reactions. As summarized in Table 2, various aromatic and hetero- under the standard reaction conditions. No kinetic isotope effect
aromatic aldehydes were able to participate in this reaction to afford (kH/kD = 1.0, Scheme 2, eqn (1) and (2)) was observed, which suggests
the desired fluorene derivatives (Table 2, 3a–p), while only a trace that the reaction proceeds via a free radical process or SEAR routing
amount of the product of aliphatic aldehydes (Table 2, 3q–r) was which was similar to the previous reports.7 Furthermore, when
obtained. Both electron-donating and electron-withdrawing groups 4.0 equivalents of TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) was
on the aromatic ring were well suited (Table 2, 3a–n). Specifically, the added into the reaction system, no reaction was observed (see ESI†),
halogen substituents were tolerated under the PivOH-promoted
Table 3 Synthesis of fluorenes from various 1,6-enynes 1 with benzalde-
reaction conditions (Table 2, 3c–3d, 3g–3h, 3j–3l, and 3n), which
hyde 2aa
provided the possibility for further functionalization in the transition
Table 2 Synthesis of fluorenes from various aldehydes 2 with 1,6-enyne 1aa
a
a
All the reactions were carried out with 1 (0.2 mmol, 1.0 equiv.), 2a
All the reactions were carried out with 1 (0.2 mmol, 1.0 equiv.), 2a
(1.0 mmol, 5.0 equiv.), TBHP (0.4 mmol, 70% aqueous solution,
2.0 equiv.), PivOH (0.4 mmol, 2.0 equiv.), and CH3CN (1 mL), at
120 1C, for 48 h, under argon, all the yields refer to isolated products
after chromatography on silica gel.
(1.0 mmol, 5.0 equiv.), TBHP (0.4 mmol, 70% aqueous solution,
2.0 equiv.), PivOH (0.4 mmol, 2.0 equiv.), and CH3CN (1 mL), at
120 1C, for 48 h, under argon, all the yields refer to isolated products
after chromatography on silica gel.
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from the ‘‘111’’ Project and Program for Changjiang Scholars and
innovative Research Team in the University (IRT1138).
Notes and references
1 For reviews on enyne cyclizations, see: (a) I. Ojima, M. Tzamar-ioudaki,
Z. Li and R. J. Donovan, Chem. Rev., 1996, 96, 635; (b) C. Aubert,
O. Buisine and M. Malacria, Chem. Rev., 2002, 102, 813; (c) S. T. Diver
and A. J. Giessert, Chem. Rev., 2004, 104, 1317; (d) C. Bruneau, Angew.
Chem., Int. Ed., 2005, 44, 2328; (e) L.-M. Zhang, J.-W. Sun and
S. A. Kozmin, Adv. Synth. Catal., 2006, 348, 2271; ( f ) V. Michelet,
ˆ
P. Y. Toullec and J. P. Genet, Angew. Chem., Int. Ed., 2008, 47, 4268.
2 For selected examples on transition metals catalyzed cyclizations, see:
´
´
´
(a) C. Nieto-Oberhuber, P. Perez-Galan, E. Herrero-Gomez, T. Lauterbach,
´
´
´
´
C. Rodrıguez, S. Lopez, C. Bour, A. Rosellon, D. J. Cardenas and A. M.
Echavarren, J. Am. Chem. Soc., 2008, 130, 269; (b) B. M. Trost, D. L. Romero
and F. Rise, J. Am. Chem. Soc., 1994, 116, 4268; (c) A. Fu¨rstner, H. Szillat and
F. Stelzer, J. Am. Chem. Soc., 2000, 122, 6785; (d) C. Nieto-Oberhuber,
Scheme 2 Control experiments.
˜
˜
´
M. PazMunoz, E. Bunuel, C. Nevado, D. J. Cardenas and A. M.
´
Echavarren, Angew. Chem., Int. Ed., 2004, 43, 2402; (e) N. Mezailles,
L. Ricard and F. Gagosz, Org. Lett., 2005, 7, 4133; ( f) J.-K. Fu, H. Shang,
W.-F. Wang, L. Chang, W.-B. Shao, Z. Yang and Y.-F. Tang, Angew. Chem., Int.
Ed., 2013, 52, 4198.
3 (a) D. P. Curran and H. Liu, J. Am. Chem. Soc., 1992, 114, 5863;
(b) C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem. Rev., 1999,
99, 1991; (c) Radicals in Organic Synthesis, ed. P. Renaud and M. P. Sibi,
Wiley-VCH, Weinheim, 2001, vol. 1 and 2; (d) S. Kim, K.-C. Lim and S. Kim,
Chem. Commun., 2007, 4507; (e) P. Renaud and M. P. Sibi, Radicals in Organic
Synthesis, Wiley-VCH, 2008; ( f) A. Beyer, J. Buendia and C. Bolm, Org. Lett.,
2012, 14, 3948; (g) U. Wille, Chem. Rev., 2013, 113, 813; (h) Y.-M. Li, L.-N. Ma,
F. Jia and Z.-P. Li, J. Org. Chem., 2013, 78, 5638; (i) H. Wang, L.-N. Guo and
X.-H. Duan, Adv. Synth. Catal., 2013, 355, 2222; ( j) D.-K. Li, M. Wang, J. Liu,
Q. Zhao and L. Wang, Chem. Commun., 2013, 49, 3640.
4 (a) P. Gottschalk and D. C. Neckers, J. Org. Chem., 1985, 50, 3498;
(b) H.-S. Dang and B. P. Roberts, J. Chem. Soc., Perkin Trans. 1, 1998, 67;
(c) V. Chudasama, R. J. Fitzmaurice and S. Caddick, Nat. Chem., 2010,
2, 592; (d) M. Conte, H. Miyamura, S. Kobayashi and V. Chechik, Chem.
Commun., 2010, 46, 145; (e) C.-L. Li, L. Wang, P.-H. Li and W. Zhou,
Chem.–Eur. J., 2011, 17, 10208; ( f ) W.-P. Liu, Y.-M. Li, K.-S. Liu and Z.-P. Li,
J. Am. Chem. Soc., 2011, 133, 10756; (g) Y.-N. Wu, B.-Z. Li, F. Mao, X.-S. Li
and F. Y. Kwong, Org. Lett., 2011, 13, 3258; (h) J. Wang, C. Liu, J.-W. Yuan
and A.-W. Lei, Angew. Chem., Int. Ed., 2013, 52, 2256; (i) M.-B. Zhou,
R.-J. Song, X.-H. Ouyang, Y. Liu, W.-T. Wei, G.-B. Deng and J.-H. Li, Chem.
Sci., 2013, 4, 2690; ( j) K. Matcha and A. P. Antonchick, Angew. Chem., Int.
Ed., 2013, 52, 2082; (k) S. Wertz, D. Leifert and A. Studer, Org. Lett., 2013,
15, 928; (l) Z.-Z. Shi and F. Glorius, Chem. Sci., 2013, 4, 829.
5 (a) K.-G. Ji, X.-Z. Shu, J. Chen, S.-C. Zhao, Z.-J. Zheng, L. Lu, X.-Y. Liu
and Y.-M. Liang, Org. Lett., 2008, 10, 3919; (b) F. Yang, K.-G. Ji,
H.-T. Zhu, A. Shaukat, X.-Y. Liu and Y.-M. Liang, Chem.–Eur. J., 2011,
17, 4986; (c) Y.-T. He, L.-H. Li, Y.-F. Yang, Y.-Q. Wang, J.-Y. Luo,
X.-Y. Liu and Y.-M. Liang, Chem. Commun., 2013, 49, 5687.
6 (a) H. Nishida, T. Eguchi and K. Kakinuma, Tetrahedron, 2001, 57, 8237;
(b) M. R. Paleo, N. Aurrecoechea, K.-Y. Jung and H. Rapoport, J. Org.
Chem., 2003, 68, 130; (c) Y. Qi, X. Jiang and D. Rong, Org. Lett., 2007,
9, 4371; (d) H.-C. Yeh, C.-H. Chien, P.-I. Shih, M.-C. Yuan and C.-F. Shu,
Macromolecules, 2008, 41, 3801; (e) K. D. Belfield, S. Yao and M. V. Bondar,
Adv. Polym. Sci., 2008, 213, 97; ( f ) K.-Y. Pu, R. Zhan and B. Liu, Chem.
Commun., 2010, 46, 1470.
7 (a) W. D. Jones and F. J. Feher, J. Am. Chem. Soc., 1986, 108, 4814;
(b) R. Taylor, Electrophilic Aromatic Substitution, Wiley, New York,
1990, p. 25; (c) O. Lauenstein, A. A. Fokin and P. R. Schreiner, Org.
Lett., 2000, 2, 2201; (d) W. D. Jones, Acc. Chem. Res., 2003, 36, 140.
8 (a) X. Jia, S. Zhang, W. Wang, F. Luo and J. Cheng, Org. Lett., 2009, 11, 3120;
(b) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (c) Y. Meng, L.-N. Guo, H. Wang and
X.-H. Duan, Chem. Commun., 2013, 49, 7540; (d) W.-T. Wei, M.-B. Zhou,
J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie and J.-H. Li, Angew. Chem.,
Int. Ed., 2013, 52, 3638; (e) Y.-M. Li, M. Sun, H.-L. Wang, Q.-P. Tian and
S.-D. Yang, Angew. Chem., Int. Ed., 2013, 52, 3972; ( f) M. Ishida and K. Tanaka,
Org. Lett., 2013, 15, 2120; (g) G.-B. Deng, Z.-Q. Wang, J.-D. Xia, P.-C. Qian,
R.-J. Song, M. Hu, L.-B. Gong and J.-H. Li, Angew. Chem., Int. Ed., 2013,
52, 1535; (h) K. Matcha, R. Narayan and A. P. Antonchick, Angew. Chem., Int.
Ed., 2013, 52, 7985; (i) S.-L. Zhou, L.-N. Guo, H. Wang and X.-H. Duan,
Chem.–Eur. J., 2013, 19, 12970.
Scheme 3 Proposed mechanism.
which clearly indicated that the reaction was involved in a radical
substitution process. A large KIE (kH/kD = 9.1) for the reaction
involving a 1 : 1 mixture of aldehyde and [D6]-aldehyde was obtained
(Scheme 2, eqn (3)), implying that the cleavage of the carbonyl C–H
bond is the rate-determining step.
A possible mechanism is proposed on the basis of the results
described above and previous work in this field (Scheme 3).4h,i,8
Firstly, alkyloxy and hydroxy radicals are generated from TBHP
under heating conditions. Subsequently, the alkyloxy and/or hydroxy
radicals capture a hydrogen atom from aldehyde 2a to produce acyl
radical I, and then acyl radical I attacks the carbon–carbon triple
bond of enyne 1a to afford radical intermediate II. Tertiary carbon
radical III was generated successively through an intramolecular
cyclization. Again, intramolecular cyclization of intermediate III with
an aryl ring gives rise to radical intermediate IV. Finally, the direct
oxidation by TBHP and deprotonation of radical intermediate IV
takes place to furnish the product 3a.
In summary, we have described a metal-free cascade radical
cyclization of 1,6-enynes with aldehydes for the synthesis of functiona-
lized fluorene derivatives in one pot. Another notable feature of the
developed process is cascade-type formation of one C(sp2)–C(sp2) and
two C(sp2)–C(sp3) bonds by using PivOH and TBHP, which is significant
in organic synthesis. Further investigations on the detailed mechanisms
and applications of this methodology are in progress in our laboratory.
We thank the National Science Foundation (NSF21072081) and
the National Basic Research Program of China (973 Program)
2010CB8–33203 for financial support. We also acknowledge support
1566 | Chem. Commun., 2014, 50, 1564--1566
This journal is ©The Royal Society of Chemistry 2014