Palladium-Promoted Neutral 1,4-Brook Rearrangement/Intramolecular Allylic Cyclization Cascade Reaction: A Strategy for the Construction of Vinyl Cyclobutanols

Article abstract of DOI:10.1021/acs.orglett.7b01381

A cascade reaction to build vinyl cyclobutanol rings through activation of vinyl epoxides by palladium, followed by 1,4-Brook rearrangement and intramolecular cyclization with a palladium complex of the resulting carbon anion, is described. Through this cascade reaction, several highly substituted cyclobutanol substrates were achieved in good yields with high stereoselectivities.

Full text of DOI:10.1021/acs.orglett.7b01381

Letter
pubs.acs.org/OrgLett
Palladium-Promoted Neutral 1,4-Brook Rearrangement/
Intramolecular Allylic Cyclization Cascade Reaction: A Strategy for
the Construction of Vinyl Cyclobutanols
†
†
†
†
†
†
Hao Zhang, Shiqiang Ma, Ziyun Yuan, Peng Chen, Xingang Xie, Xiaolei Wang,
,†,‡
and Xuegong She*
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222
TianShui South Road, Lanzhou 730000, China
‡
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
*
S Supporting Information
ABSTRACT: A cascade reaction to build vinyl cyclobutanol
rings through activation of vinyl epoxides by palladium, followed
by 1,4-Brook rearrangement and intramolecular cyclization with a
palladium complex of the resulting carbon anion, is described.
Through this cascade reaction, several highly substituted
cyclobutanol substrates were achieved in good yields with high stereoselectivities.
ubstituted cyclobutanes are prevalent structures in
numerous drugs and biologically active natural products,
Scheme 1. Palladium-Promoted Brook Rearrangement/
Intramolecular Cyclization Cascade Reaction
1
S
such as melleolide, solanoeclepin A, marsupellin D, and
plumisclerin A. The most widely used method for constructing
2
cyclobutanes is [2 + 2] cycloadditions; however, this reaction
suffers from poor stereoselectivity. The undeniable benefits of
cascade reactions are well established, having been recounted
3
on numerous occasions. However, designing cascade reactions
with controllable product distributions, excellent molecular
efficiencies, and high selectivities is still a grand challenge in
chemistry. Our group has a long-standing interest in using
4
cascade reactions for natural product syntheses and designed
several methodologies based on the Brook rearrangemen-
4
e,f,6f,g
t.
Based on these backgrounds, we hypothesized the cascade
reaction outlined in Scheme 1. Palladium is known to activate
5
vinyl epoxide 1 to generate complex 2 with an oxygen anion
and then undergo 1,4-silicon migration to further form carbon
6
anion 3, which might attack the palladium complex to achieve
this cascade reaction. The resulting π-allyl palladium complex
can undergo intramolecular cyclization at three active sites,
which subsequently afford vinyl cyclobutanol 4 (path a),
reaction. Initially, after screening several palladium catalysts and
ligands, the best set of conditions included the Pd (dba) /dppe
2
3
system with THF as a solvent at 60 °C (Table 1, entry 7). The
relative configuration of 7b was established by NOE experi-
ments (see the Supporting Information for details). It is striking
to note that the palladium-promoted cascade reaction even
4h,5b
bicyclo[3.1.0]hexane 5
(path b), and cyclohexenol 6 (path
c). Elegant works have been reported by Amos B. Smith’s
group involving anion relay chemistry (ARC) employing Brook
7
9
rearrangements of various linchpins. To the best of our
tolerated 1,3-dithiane functional groups. We then turned our
attention to investigate the solvent effects for the cascade
annulations and found that THF was superior to other solvents
knowledge, a Pd(0)-promoted Brook rearrangement of a
linchpin has rarely been reported. Herein, we show the
power of the palladium-promoted tandem [1,4]-Brook
rearrangement/intramolecular allylic cyclization, which pro-
vides access to various functionalized vinyl cyclobutanols.
Then, trans-disubstituted vinylepoxide 7a derived from (E)-
(
Table 1, entries 11−13).
With the optimized conditions in hand, we next explored the
substrate scope of this cascade reaction (Table 2). All the
8
penta-2,4-dienoic acid was prepared to test this hypothesis.
Received: May 15, 2017
Table 1 illustrates an abbreviated optimization of this cascade
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01381
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions
Table 2. Tandem Palladium-Catalyzed Brook
Rearrangement/Intramolecular Allylic Cyclization for the
a
Construction of Vinyl Cyclobutanols
temp
7b yield
a
b
entry
1
Pd source
ligand
(°C)
solvent
THF
(%)
c
Pd (dba) ·
dppe
rt
n.r.
39
33
2
3
CHCl3
c
c
c
2
3
Pd (dba) ·
dppe
dppe
60
80
THF
THF
2
3
CHCl3
Pd (dba) ·
2
3
CHCl3
4
5
6
PdCl2
dppe
−
60
60
60
THF
THF
THF
trace
trace
60
Pd(PPh3)4
Pd (dba) ·
dppe
2
3
CHCl3
7
8
9
Pd (dba)3
dppe
dppf
60
60
60
60
60
60
60
60
THF
72
2
Pd (dba)3
2
THF
54
Pd (dba)3
2
TMEDA
P(OPh)3
dppe
THF
complex
complex
34
10
11
12
13
14
Pd (dba)3
2
THF
Pd (dba)3
2
toluene
CH Cl
Pd (dba)3
2
dppe
trace
55
2
2
Pd (dba)3
2
dppe
Et O
2
Pd (dba)3
2
−
THF
n.r.
a
Reaction conditions: vinyl epoxide silane 7a (0.2 mmol), Pd source
b
(
10 mol %), ligand (25 mol %), Ar, 24 h. Yields of isolated products.
c
The amount of ligand used was 20 mol %. dba = dibenzylidenea-
cetone, dppe = 1,2-bisdiphenylphosphinoethane, dppf = 1,1′-bis-
(
diphenylphosphino)ferrocene, TMEDA = tetramethylethylene-
diamine.
substrates were achieved through substitution reactions with
bromovinylepoxide and lithiated TMS-dithiane (see the
Supporting Information for details). As outlined in Table 2,
several vinyl cyclobutanols were accessed with reasonable yields
and good diastereoselectivities through this method. The
influence of the configuration of epoxide was also studied.
The initial trans-disubstituted epoxide 7a was converted
efficiently to the corresponding 7b in good yield with high
diastereoselectivity (dr >20:1). cis-Disubstituted vinylepoxide
8a was also converted to the 8b and 7b in moderate yield with
a diastereoselectivity ratio of 1.2:1.
The good diastereoselectivity of 7a and the poor
diastereoselectivity of 8a can be explained as follows (Scheme
2
). The palladium(0) catalyst coordinates to alkene 8a,
followed by oxidation addition and Brook rearrangement,
forming the dithiane anion IV. Finally, the nucleophilic attack
of the π-allyl unit on the face opposite to palladium and its
attendant ligands resulted in the formation of the vinyl
cyclobtanol 8b. The steric interaction between the R
a
Reaction conditions: vinyl epoxide silane (0.2 mmol), Pd dba (10
2
3
b
mol %), dppe (25 mol %), 2 mL of THF, 60 °C, 24 h. Yields of
isolated products. Reaction time is 4 h.
c
3
substituent and η -allyl group of transition-state II would
The reaction worked well and smoothly afforded 11b, 12b, and
14b in moderate yields with high diastereoselectivities. We then
made a careful analysis of vinyl vicinal proton coupling
constants of 12b (Jab < 11.3 Hz) and 14b (Jab = 11.7 Hz),
which suggested the double bonds of 12b and 14b are in the cis
configuration. Retention of olefin configuration of 12b and 14b
can be explained by the high stability of the π-allylpalladium
favor rotation around the C3−C4 bond resulting in transition-
state I, which could be transformed to 7b. The lack of steric
interaction in the case of trans-vinylepoxide 7a resulted in good
diastereoselectivity.
To explore this scenario further, we next designed substrate
a to avoid the influence of the rotation around the C3−C4
9
10
bond. To our delight, the reaction worked well and smoothly
afforded the bridge [2.1.1] bicyclic skeleton 9b in moderate
yield with high diastereoselectivity. In contrast, 10a did not
afford the corresponding bicyclic structure 10b. We next
examined a series of substrates with substitution on the olefin.
resulting from the neighboring-group effect of the hydroxy.
When 13a was treated with the standard conditions, 13b was
obtained in good yield. Because of the steric interaction
between the dithiane anion and the adjacent quaternary
stereocenter at C4 (Scheme 3), the π-allyl palladium complex
B
DOI: 10.1021/acs.orglett.7b01381
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Transition-State Models to Rationalize the
Diastereoselectivity of 7a and 8a
the Lewis acidity of the palladium complex could not be
recommended in this tandem reaction.
In conclusion, we developed a tandem palladium-promoted
Brook rearrangement/intramolecular allylic cyclization reaction
of vinyl epoxide silanes. The method provided access to several
vinyl cyclobutanols in moderate to good yields with high
diastereoselectivities. Moreover, the method involved the
report of Pd(0)-promoted Brook rearrangement and initiated
the Brook rearrangement under neutral conditions. We believe
that this method will provide new insights into the Brook
rearrangement. Furthermore, this method might be utilized to
synthesize natural products and valuable drug molecules.
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.7b01381.
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
Scheme 3. Proposed Mechanism for the Formation of 13b
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: shexg@lzu.edu.cn.
ORCID
Xuegong She: 0000-0002-3002-2433
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
of China (21125207, 21372103, 21472079 and 21572088),
program 111, PCSIRT (IRT_15R28), and the Fundamental
Research Funds for the Central Universities (lzujbky-2016-
ct02).
was attacked by the dithiane anion at C2, resulting in the
4h,5a,b
formation of [3.1.0] 16,
which was transformed into 13b
in situ through the palladium-catalyzed isomerization of
1
1
cyclopropane. When 15a, containing trimethylsilyldiphenyl-
methane in place of 2-TMS-1,3-dithiane, was treated with the
standard conditions for 4 h, ethene-1,1-diyldibenzene 15b,
which might be formed by retroelectrocyclization of vinyl
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Org. Lett. XXXX, XXX, XXX−XXX