Phosphine-Catalyzed [8 + 2]-Annulation of Heptafulvenes with Allenoates and Its Asymmetric Variant: Construction of Bicyclo[5.3.0]decane Scaffold

Article abstract of DOI:10.1021/acs.orglett.8b01734

In this paper, a phosphine-catalyzed [8 + 2]-annulation of heptafulvene with allenoates has been achieved under mild conditions, giving functionalized bicyclo[5.3.0]decane derivatives in moderate to excellent yields. Using chiral phosphine as the catalyst, optically active products were obtained in moderate to high yields with excellent enantioselectivities.

Full text of DOI:10.1021/acs.orglett.8b01734

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phosphine-Catalyzed [8 + 2]-Annulation of Heptafulvenes with
Allenoates and Its Asymmetric Variant: Construction of
Bicyclo[5.3.0]decane Scaffold
Zhenzhen Gao,†,‡ Chang Wang,† Leijie Zhou,† Chunhao Yuan,† Yumei Xiao,† and Hongchao Guo*,†,§
†Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
‡School of Pharmacy, Liaocheng University, Liaocheng 252000, Shandong, P. R. China
§State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
S
* Supporting Information
ABSTRACT: In this paper, a phosphine-catalyzed [8 + 2]-
annulation of heptafulvene with allenoates has been achieved
under mild conditions, giving functionalized bicyclo[5.3.0]-
decane derivatives in moderate to excellent yields. Using chiral
phosphine as the catalyst, optically active products were
obtained in moderate to high yields with excellent enantiose-
lectivities.
annulation reaction of tropone with modified allylic com-
pounds including acetates, bromides, chlorides, or tert-butyl
carbonates derived from the Morita−Baylis−Hillman (MBH)
reaction, affording bridged nine-membered carbocycles
(Scheme 1, eq 2).4 In 2011, Yao, Yuan and co-workers grafted
triphenylphosphine groups in the 2D structure of layered
aminophenylsilica dodecyl sulfate.5 With the use of this type of
phosphine, an [8 + 3]-annulation of tropone with allyl halides
was achieved to produce bicyclic 2,6-dihydrocyclohepta[b]-
pyran derivative (Scheme 1, eq 3).5 However, there has been
no report on phosphine-catalyzed all-carbon higher-order
cycloadditions involving heptafulvene and chiral phosphine-
catalyzed asymmetric higher-order cycloaddition. In continu-
ation of our interest in developing phosphine-catalyzed
asymmetric cycloaddition reactions,6 we became interested in
phosphine-promoted higher-order cycloaddition reactions.
Herein, we report the phosphine-catalyzed [8 + 2]-annulation
of heptafulvenes with allenoates and its asymmetric variant,
which provides a practical, regiospecific, and enantioselective
approach to functionalized bicyclo[5.3.0]decane derivatives
(Scheme 1, eq 4). To the best of our knowledge, this
represents the first example of phosphine-catalyzed enantiose-
lective higher-order [8 + 2]-annulation of allenoates.
he higher-order cycloadditions involving more than six π
Telectrons have emerged as highly reliable tools for the
construction of important medium-sized ring-fused polycyclic
scaffolds.1 In the past two decades, various phosphine-
catalyzed annulation reactions have been achieved.2 Under
phosphine catalysis conditions, a few higher-order cyclo-
additions had been accomplished. In 2000, Ishar and co-
workers reported a Ph3P-catalyzed [8 + 2]-annulation reaction
of tropone with allenic esters/ketones to give 8-oxa-bicyclo-
[5.3.0]deca-1,3,5-trienes (Scheme 1, eq 1).3 In 2005, Lu and
co-workers developed a phosphine-catalyzed [6 + 3]-
Scheme 1. Phosphine-Catalyzed Higher-Order Formal
Cycloaddition Reactions
Initially, with the use of barbiturate-heptafulvene 1,7 which
has not been used as an 8π component in an [8 + 2]-
cycloaddition before, we carried out our study by examining
the reaction with α-benzyl allenoate (2aa) to probe the
feasibility of the reaction in toluene at rt in the presence of 20
mol % of Me2PPh (Table 1). To our delight, a new product
3aa was isolated in 55% yield (Table 1, entry 1). A subsequent
screening of solvents indicated that only THF and toluene are
Received: June 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Scope of Allenoates
b
entry
2, R1/R2
2aa, Bn/Et
t (h)
3
yield (%)
1
2
3
4
5
6
7
8
5
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
93
74
78
61
84
84
79
73
85
76
80
81
78
83
87
88
81
67
91
63
67
68
60
0
2ba, 2-MeC6H4CH2/Et
2ca, 3-MeC6H4CH2/Et
2da, 4-MeC6H4CH2/Et
2ea, 3-OMeC6H4CH2/Et
2fa, 4-t-BuC6H4CH2/Et
2ga, 2-FC6H4CH2/Et
2ha, 3-FC6H4CH2/Et
2ia, 4-FC6H4CH2/Et
2ja, 2-ClC6H4CH2/Et
2ka, 3-ClC6H4CH2/Et
2la, 4-ClC6H4CH2/Et
2ma, 2-BrC6H4CH2/Et
2na, 3-BrC6H4CH2/Et
2oa, 4-BrC6H4CH2/Et
2pa, 3-CF3C6H4CH2/Et
2qa, 4-CF3C6H4CH2/Et
2ra, 4-CO2MeC6H4CH2/Et
2sa, 2-naphthylCH2/Et
2ta, 3,5-OMe2C6H3CH2/Et
2ua, 2-F-5-ClC6H3CH2/Et
2va, 3-F-4-ClC6H3CH2/Et
2wa, CH2CO2Et/Et
2xa, CH3/Et
12
12
15
15
12
20
20
12
12
15
12
12
12
12
15
20
12
15
12
12
12
15
24
24
15
12
b
entry
PR3
solvent
temp (°C)
t (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Me2PPh
Me2PPh
Me2PPh
Me2PPh
Me2PPh
Me2PPh
Me2PPh
Me2PPh
PPh3
MePPh2
PBu3
Me2PPh
Me2PPh
Me2PPh
Me2PPh
toluene
CH2Cl2
DCE
THF
CH3OH
Et2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
25
25
25
25
25
25
40
60
40
40
40
40
40
40
40
48
48
48
48
48
48
5
55
trace
trace
45
NR
10
90
63
40
trace
53
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3ja
3ka
3la
5
10
10
10
5
5
12
24
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
3ua
3va
3wa
3xa
3ya
3ab
3ac
c
93
85
76
60
d
ce
,
14
15
cf
,
a
Unless otherwise indicated, all reactions were performed with 1 (0.1
b
mmol) and 2aa (0.12 mmol) in 2 mL of solvent. Isolated yield.
c
d
e
Using 3 Å MS (100 mg). Using 4 Å MS (100 mg). 15 mol % of
f
catalyst was used. 10 mol % catalyst was used.
2ya, H/Et
2ab, Bn/Me
2ac, Bn/Ph
0
85
78
compatible with this phosphine catalysis, providing the desired
product in moderate 45% and 55% yield, respectively (Table 1,
entries 2−6). Satisfactorily, increasing the reaction temperature
to 40 °C remarkably increased the conversion rate, giving the
product in 90% yield within 5 h (Table 1, entry 7). A further
increase of the temperature to 60 °C did not offer better results
(Table 1, entry 8). Despite employing other phosphines as the
catalyst, the yield could not be increased (Table 1, entries 9−
11). To further improve the reaction efficiency, the additives
were next screened. The 3 Å MS displayed a favorable effect,
leading to an increase of the yield to 93% (Table 1, entries 12).
When the loading of Me2PPh was decreased to 15 mol % and
10 mol %, the yields decreased to 76% and 60%, respectively
(Table 1, entries 14−15). Other heptafulvenes such as 2-
(cyclohepta-2,4,6-trien-1-ylidene)malononitrile (1′) and dieth-
yl 2-(cyclohepta-2,4,6-trien-1-ylidene)malonate (1′′) had also
been attempted in this reaction. Unfortunately, both
heptafulvenes 1′ and 1′′ did not work. According to the
above screening, the optimal conditions were determined as
using Me2PPh (20 mol %) as the catalyst and 3 Å MS (100
mg) as the additive in toluene at 40 °C.
With the optimal conditions in hand, we then investigated
the substrate scope of the allenoates 2 in the [8 + 2]-
annulation (Table 2). A variety of allenoates 2aa−2ra and
2ta−2va bearing electron-rich, -neutral, and -deficient groups
on the benzene ring provided the corresponding products
3aa−3ra and 3ta−3va in moderate to excellent yields (61−
93%) (Table 2, entries 1−18, 20−22). The allenoate 2sa
bearing a 2-naphthyl group was also compatible with the
reaction to give the product 3sa in 91% yield (Table 2, entry
19). In addition, the α-(ethoxycarbonylmethyl)allenoate 2wa
a
All reactions were performed with 1a (0.1 mmol), 2 (0.12 mmol), 3
Å MS (100 mg), and PMe2Ph (0.02 mmol) in 2 mL of toluene at 40
°C. Isolated yield.
b
underwent the reaction to give the product 3wa in 60% yield
(Table 2, entry 23). The α-methyl allenoate (2xa) and ethyl
buta-2,3-dienoate (2ya) were inert in this reaction, and no
desired products were observed (Table 2, entries 24−25).
Changing the ester moieties in allenoates with Me and Ph
groups has no significant influence on the reactivity. These
allenoates led to the desired products in 85% and 78% yields
(Table 2, entries 26−27). The structure of the annulation
products was confirmed by single crystal X-ray analysis of the
product 3sa (CCDC 1587408).
With chiral phosphine as the catalyst, we attempted to
develop an asymmetric variant of this phosphine-catalyzed [8 +
2]-annulation of heptafulvene with allenoates (Table 3). In the
initial exploration, various chiral phosphines including cyclic
and multifunctional phosphines were screened (Table 3,
entries 1−6). Kwon’s endo phosphine P1 catalyzed the
reaction to give the desired product 3aa with 90% ee, albeit
in 24% yield. In contrast, the exo isomer P2 of the phosphine
P1 only led to a trace amount of the product (Table 3, entry
2). Thus, we next examined two of Kwon’s endo phosphines P3
and P4. In the presence of phosphine P3, the yield was slightly
increased to 30% (Table 3, entry 3). The phosphine P4
displayed similar activity to that of P3, leading to the product
in 35% yield, but the ee decreased to 84% (Table 3, entry 4).
B
DOI: 10.1021/acs.orglett.8b01734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Evaluation of Asymmetric [8 + 2]-Annulation
Reaction Conditions
Table 4. Scope of Allenoates in Asymmetric [8 + 2]-
a
a
Annulation
b
c
entry
R1/R2
3
yield (%)
ee (%)
1
2
3
4
5
6
7
8
2ac, Ph/Ph
3ac
3bc
3cc
3dc
3gc
3hc
3ic
3xc
3ad
3gd
3jd
3md
3ae
64
59
63
64
61
60
65
65
60
61
65
67
55
90
90
90
90
92
91
88
86
92
92
94
92
97
2bc, 2-MeC6H4/Ph
2cc, 3-MeC6H4/Ph
2dc, 4-MeC6H4/Ph
2gc, 2-FC6H4/Ph
2hc, 3-FC6H4/Ph
2ic, 4-FC6H4/Ph
2xc, 1-naphthyl/Ph
2ad, Ph/CH2CHF2
2gd, 2-FC6H4/CH2CHF2
2jd, 2-ClC6H4/CH2CHF2
2md, 2-BrC6H4/CH2CHF2
2ae, Ph/CH2CCl3
b
c
entry
Px
R
solvent
3
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
P1
P2
P3
P4
P5
P6
P3
P3
P3
P3
P3
Et
Et
Et
Et
Et
Et
Me
Ph
Ph
Ph
Ph
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhCF3
PhF
3aa
3aa
3aa
3aa
3aa
3aa
3ab
3ac
3ac
3ac
3ac
24
trace
30
35
trace
5
30
70
70
72
90
−
90
84
−
−60
87
82
88
88
90
9
10
11
12
13
d
a
Unless otherwise indicated, all reactions were carried out with 1 (0.1
mmol), 2 (0.12 mmol), P3 (20 mol %) and 3 Å MS (100 mg) in 2
b
c
mL of PhF at rt. Isolated yield. Determined by HPLC analysis using
a chiral stationary phase. The reaction was performed at 0 °C.
d
d
11
PhF
64
To further evaluate the synthetic utility of the current
reaction, the reaction on the gram scale was investigated
(Scheme 2). The reaction of the heptafulvene 1 (0.73 g) with
a
Unless otherwise indicated, all reactions were carried out with 1 (0.1
mmol) and 2a (0.12 mmol) in the presence of 3 Å MS (100 mg) in 2
b
c
mL of solvent. Isolated yield. Determined by HPLC analysis using a
chiral stationary phase. The reaction was performed at rt for 72 h.
d
Scheme 2. Scale-up and Further Transformations
Spirocyclic chiral phosphine P5 was noneffective, giving only a
trace amount of the product 3aa (Table 3, entry 5). The
multifunctional phosphine P6 showed extremely weak activity,
resulting in the product in approximately 5% yield with 60% ee
(Table 3, entry 6). With the use of chiral phosphine P3, we
then investigated the influence of the variation of the ester
moiety in allenoate (Table 3, entries 7−8). The results indicate
the phenyl ester proved to be superior to other esters, and the
yield and ee of the product could be increased to 70% yield
and 82% ee, respectively (Table 3, entry 8). Concise solvent
screening revealed that fluorobenzene is the optimal solvent,
resulting in the product 3ac in 72% yield with 88% ee (Table 3,
entries 9−10). Decreasing the temperature to rt slightly
enhanced the ee to 90% (Table 3, entry 11).
Under the optimized conditions, and in the presence of
chiral phosphine P3, the substrate scope of the asymmetric [8
+ 2]-cycloaddition of heptafulvene 1 with allenoate 2 was
examined (Table 4). The allenoates substituted with an aryl
bearing either an electron-rich or electron-deficient group
smoothly underwent the reaction, delivering the corresponding
products in 59−65% yields with 88−92% ee (3bc−3ic). The
2-naphthyl substituted allenoate 2xc was also a suitable
reaction partner, affording the product 3xc in 65% yield with
86% ee. Several halo-substituted ethyl allenoates worked well
under the optimal conditions, providing the product with
acceptable yields and enantioselectivities (Table 4, entries 9−
13). The absolute configuration of chiral product was
confirmed by single crystal X-ray analysis of the product 3ad
(CCDC 1587409).
allenoate 2aa proceeded smoothly to give the product 3aa in
73% yield. Treatment of 3aa with 1.5 equiv of DDQ (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) at rt for 12 h
produced the oxidized product 4 in 88% yield. In the presence
of Pd(Ph3P)4, the cycloadduct 3oa underwent a Suzuki
coupling reaction to afford the derivative 5 in 80% yield.
More interestingly, a novel tetrabromo derivative 6 (CCDC
C
DOI: 10.1021/acs.orglett.8b01734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
1587410) was obtained in 82% yield through treatment of the
cycloadduct 3ac with NBS at rt.
A plausible reaction mechanism has been proposed in
Scheme 3. The phosphine undergoes conjugate addition to
Hongchao Guo: 0000-0002-7356-4283
Notes
The authors declare no competing financial interest.
Scheme 3. A Plausible Reaction Mechanism for the
Annulation
ACKNOWLEDGMENTS
■
This work is supported by the NSFC (21372256 and
21572264), the State Key Laboratory of Chemical Resource
Engineering, the Program for Changjiang Scholars and
Innovative Research Team Project IRT1042, and the
Shandong Provincial Natural Science Foundation of China
(ZR2018BB028).
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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.8b01734.
Experimental procedures, characterization data, HPLC
analysis dada, NMR spectra and X-ray crystallographic
data (PDF)
(7) (a) Naya, S.-i.; Nitta, M. Tetrahedron 2003, 59, 3709. (b) Naya,
S.-i.; Yamaguchi, Y.; Nitta, M. Tetrahedron 2008, 64, 3225.
Accession Codes
CCDC 1587408−1587410 contain the supplementary crys-
tallographic 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.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hchguo@cau.edu.cn.
D
DOI: 10.1021/acs.orglett.8b01734
Org. Lett. XXXX, XXX, XXX−XXX