Facile reductive oxy-Nazarov cyclization of 2-methoxy-2, 4-hexadienoates

Article abstract of DOI:10.1016/j.tetlet.2016.12.020

Reduction of 2-methoxy-2, 4-hexadienoates with Dibal-H in toluene at ?78 °C resulted in a facile formation of 5-hydroxyl cyclopentenone derivatives. This novel transformation was proposed as a variant of the oxy-Nazarov cyclization of the corresponding 2-

Full text of DOI:10.1016/j.tetlet.2016.12.020

Accepted Manuscript
Facile Reductive oxy-Nazarov Cyclization of 2-Methoxy-2, 4-Hexadienoates
Yang Chen, Wei-Dong Z. Li
PII:
S0040-4039(16)31647-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.020
TETL 48432
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 October 2016
4 December 2016
7 December 2016
Please cite this article as: Chen, Y., Li, W.Z., Facile Reductive oxy-Nazarov Cyclization of 2-Methoxy-2, 4-
Hexadienoates, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.020
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Facile Reductive oxy-Nazarov Cyclization of 2-Methoxy-2, 4-Hexadienoates
Yang Chen, Wei-Dong Z. Li 
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55
Daxuecheng South Road, Shapingba, Chongqing 401331, P. R. China

1
Tetrahedron Letters
Facile Reductive oxy-Nazarov Cyclization of 2-Methoxy-2, 4-Hexadienoates
Yang Chen, Wei-Dong Z. Li 
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road,
Shapingba, Chongqing 401331, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Reduction of 2-methoxy-2, 4-hexadienoates with Dibal-H in toluene at 78°C resulted in a facile
formation of 5-hydroxyl cyclopentenone derivatives. This novel transformation was proposed as a
variant of the oxy-Nazarov cyclization of the corresponding 2-methoxy aldehyde intermediate via
the cationic Al-chelate as depicted in Figure 2a.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Reduction
Dibal-H
oxy-Nazarov
5-Hydroxyl cyclopentenone
Introduction
then a seemingly reasonable cationic intermediates as depicted in
Figure 1 for this novel cyclopentenone annulation, we are
wondering the reactivity of other analogous substrates, such as
the 2-methoxy-2, 4-hexadienoates derivatives III toward the
hydride reductant (such as Dibal-H).
We reported in 2011 a facile and versatile reductive oxy-
Nazarov (RON) cyclization of vinylalkylidene dioxolanone
derivatives of type I structure (Figure 1a) by the action of Dibal-
H
under mild conditions leading to the 5-hydroxyl
cyclopentenone product of type II in good to excellent yield.1, 2
The synthetic application of this facile cyclopentenone
annulation was demonstrated in a novel total synthesis of
cephalotaxine as depicted in Figure 1b. Although we proposed
We report in this letter the preliminary results of the reduction
of 2-methoxy-2, 4-hexadienoates derivatives with Dibal-H.
Results and Discussion
HornerWadsworthEmmons (HWE) olefination of aldehyde
11, 3 with methoxylated phosphate 24 afforded the E-product 3
(34%) along with the corresponding Z-product 4 (52%). As
shown in Table 1, reduction of 3 with two equivalent of Dibal-H
in toluene at 78°C produced a major product 5 and a small
amount of 6 (2%). While with one equivalent of Dibal-H as the
hydride reductant, 5-hydroxy cyclopentenone 6 was obtained as
the major product along with 2% yield of 5 (Table 1, entry 4).
Interestingly, oxidation of allylic alcohol 5 with IBX in DMSO at
ambient temperature furnished a good yield of 6 (54%). It is also
reasonable that reduction of the olefinic isomer 4 with Dibal-H
(1.5 eq.) gave a good yield of 7, which can be further oxidized to
the corresponding aldehyde product 8 with IBX in DMSO. It is
apparent that the reasonable intermediate in the formation of 6
would be the corresponding aldehyde in both the reductive
cyclization of 3  6 and the oxidative cyclization of 5  6. We
thus suggested that the analogous cationic chelate species, as
depicted in Figure 2, are responsible for the facile oxy-Nazarov
cyclization under mild conditions. The reaction path might be
Figure 1 Reductive oxy-Nazarov cyclization of vinylalkylidene
dioxolanones.
———
 Corresponding author. Tel.: +0086-(0)23-65678459; fax: +0086-(0)23-65678459; e-mail: wdli@cqu.edu.cn

2
classified as the iso-Nazarov cyclization.5 The relatively lower
yield of 6 in the reactions of 3 with 1.2 or 0.8 equivalent of
Dibal-H (Table 1, entries 3 and 5) could be explained by more
effective further reduction of the corresponding pentadienal
intermediate in the presence of excess Dibal-H than the oxy-
Nazarov cyclization of the Al-chelate intermediate as depicted in
Figure 2a.
To further confirm the above mechanistic suggestion, the
isomeric Weinreb amide analogs 9 and 10 were prepared
following a reported protocol.6 Reduction of 9 with one
equivalent of Dibal-H produced a good yield of 6, while
reduction of 10 gave the corresponding aldehyde 8 solely in
moderate yield (Scheme 2).
Scheme 2 RON cyclization of 9 and reduction of 10.
The reductive cyclization reactivity of the 2-methoxy-2, 4-
hexadienoate derivatives by the action of Dibal-H were further
probed with more elaborated substrate, i.e. 111. Reduction of 11
with Dibal-H gave alcohol 13 as the major product and a small
yield of 12. Analogously, oxidation of 13 with IBX in DMSO
afforded 12, although in a relatively low yield (Scheme 3). It is
obvious that the corresponding dioxolanone derivative (i.e.
Figure 1b) is more effective substrate for the reductive oxy-
Nazarov cyclization.
Scheme 1 RON cyclization of 3.
Table 1 Optimization of reaction conditionsa
Yield (%)b
Dibal-H
(equiv.)
Ratio
Conv.c
(%)
Entry
Scheme 3 RON cyclization of 11.
:
(5 6)
5
6
1
2
3
4
2.0
1.5
1.2
1.0
50
17
43
2
2
25: 1
1: 2.1
1.2: 1
1: 39
100
100
91
36
37
77
80
5
0.8
23
30
1: 1.3
68
a Reactions were carried out with substrate 3 (1.6 mmol) in entry
1, 4.8 mmol in entries 2 to 4, 2.0 mmol in entry 5.
bYields described herein are of isolated product after column
chromatography.
c Conversion based on recovered starting material.
Figure 2 Reactive cationic chelates for oxy-Nazarov cyclization.

3
Conclusion
In summary, we have shown that 2-methoxy-2E, 4-hexa
dienonate derivatives are effective substrate type for the facile
reductive oxy-Nazarov cyclization. This cyclopentenone
annulation represents
a new variant of the iso-Nazarov
cyclization.5 Some typical examples of iso-Nazarov cyclization
of pentadienals leading to substituted cyclopentenones are
illustrated in Figure 3.
Figure 3 Typical examples of iso-Nazarov of pentadienals.
Further studies on the scope and application of this facile
transformation in natural product synthesis will be reported in
due course.
Scheme 4 RON cyclization of 17.
To our delight, the Dibal-H reduction of the isomeric
precursor 17, which was prepared analogously from the aldehyde
15 via the HWE olefination reaction as shown in Scheme 4,
produced the cyclopentenone 19 in 26% yield along with 42%
yield of alcohol product 18, which was oxidized with IBX in
DMSO effectively to give 19 in 56% yield (Scheme 4). The
relative stereochemistry of compound 19 was further confirmed
by X-ray crystallographic analysis.7 Cyclopentenone product 19
serves as a key intermediate in the cephalotaxine total synthesis.8
Other 3-substituted 2-methoxy-2, 4-hexadienoates such as 20
can be cyclized by the action of Dibal-H to give cyclopentenone
22 less effectively (Scheme 5a). Intriguingly, it seems that proton
chelate species of type b intermediate (Figure 2b) of the
corresponding aldehyde of 21 underwent smooth oxy-Nazarov
cyclization (22  21). In contrast, 3-methyl substituted
dioxalanone analog of type I, such as 23, undergo oxy-Nazarov
cyclization in moderate yield (Scheme 5b). The above results
imply that the reactivity of this novel variant of iso-Nazarov
cyclization depends largely on the olefinic geometry and the
nature of substituents which deserves further systematic study.
Acknowledgments
We are grateful to Mr. Ning-Dong Zhao for partial
experimental work. We thank the National Natural Science
Foundation (21132006) for financial support. The scholars
program of Chongqing University is gratefully acknowledged.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at
(web link).
References and notes
1. Li, W. D. Z.; Duo, W. G.; Zhuang, C. H. Org. Lett. 2011, 13, 3538-3541.
2. For recent reviews, see: a) Frontier, A. J.; Collison, C. Tetrahedron
2005, 61, 7577-7606; b) Pellissier, H. Tetrahedron 2005, 61, 6479-6517;
c) Tius, M. A. Eur. J. Org. Chem. 2005, 2193-2206; d) Shimada, N.;
Stewart, C.; Tius, M. A. Tetrahedron 2011, 67, 5851-5870; e) Vaidya, T.;
Eisenberg, R.; Frontier, A. J. Chemcatchem 2011, 3, 1531-1548; f)
Audran, G.; Brémond, P.; Feuerstein, M.; Marque, S. R. A.; Santelli, M.
Tetrahedron 2013, 69, 8325-8348; g) Brooks, J. L.; Huang, Y. W.;
Frontier, A. J. Org. Synth. 2014, 91, 93-105; h) Di Grandi, M. J. Org.
Biomol. Chem. 2014, 12, 5331-5345; i) Tius, M. A. Chem. Soc. Rev.
2014, 43, 2979-3002.
3. For preparation of 1, see: Chowdari, N. S.; Barbas, C. F., III. Org. Lett.
2005, 7, 867-870.
4. For preparation of 2, see: Seneci, P.; Leger, I.; Souchet, M.; Nadler, G.
Tetrahedron 1997, 53, 17097-17114.
5. For selected examples of the iso-Nazarov, see: a) Miller, A. K.;
Banghart, M. R.; Beaudry, C. M.; Suh, J. M.; Trauner, D. Tetrahedron
2003, 59, 8919-8930; b) Yoshimatsu, M.; Matsuura, Y.; Gotoh, K.
Chem. Pharm. Bull. 2003, 51, 1405-1412; c) Kuroda, C.; Honda, S.;
Nagura, Y.; Koshio, H.; Shibue, T.; Takeshita, T. Tetrahedron 2004, 60,
319-331; (d) Jung, M. E.; Yoo, D. J. Org. Chem. 2007, 72, 8565-8568;
e) Riveira, M. J.; Mischne, M. P. J. Org. Chem. 2014, 79, 8244-8254
6. For method of preparation of 9 and 10, see: Maddess, M. L.; Tackett, M.
N.; Watanabe, H.; Brennan, P. E.; Spilling, C. D.; Scott, J. S.; Osborn,
Scheme 5 RON cyclization of 20 and 23.

4
D. P.; Ley, S. V. Angew. Chem., Int. Ed. 2007, 46, 591-597.
7. CCDC 1515005 contains the supplementary crystallographic data for
compound 19. X-ray crystallographic data of 19: C23H31NO6Si, FW
445.59, orthorhombic, space group P2(1)2(1)2(1), a = 6.0550(3) Å, b =
16.1551(10) Å, c = 28.2228(17) Å, Volume/Å3, Z = 4, dcalcd
= 1.072 g/cm3. Final R indexes [I>=2σ (I)] R1 = 0.1672, wR2 = 0.4048.
Final R indexes [all data] R1 = 0.2108, wR2 = 0.4372. See Supporting
Information for details. The X-ray structure of compound 19:
8. On-going work in our laboratory.

5
Highlights
A facile method for synthesis of 5-hydroxyl
cyclopentenone derivatives was reported.
This transformation represents a new variant of the
iso-Nazarov cyclization.
The approach has great potential application in
natural product synthesis.