Substituted 1,3-cyclohexadiene synthesis by NHC-Nickel(0) catalyzed [2+2+2] cycloaddition of 1,n-Enyne

Article abstract of DOI:10.1016/j.tet.2015.05.016

This paper describes a catalytic and selective synthesis of substituted 1,3-cyclohexadiene fused with xH-pyran and furan. By using terminal enynes as substrates, NHC-Ni(0) as catalyst, and an ether as spacer between the two unsaturated hydrocarbon termini

Full text of DOI:10.1016/j.tet.2015.05.016

Tetrahedron 71 (2015) 4426e4431
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Substituted 1,3-cyclohexadiene synthesis by NHCeNickel(0)
catalyzed [2þ2þ2] cycloaddition of 1,n-Enyne
*
Jian-Ping Zhao, Siu-Chung Chan, Chun-Yu Ho
Department of Chemistry, South University of Science and Technology of China, Shenzhen, China
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes a catalytic and selective synthesis of substituted 1,3-cyclohexadiene fused with xH-
pyran and furan. By using terminal enynes as substrates, NHCeNi(0) as catalyst, and an ether as spacer
between the two unsaturated hydrocarbon termini, the system competed with the terminal alkyne
cyclotrimerization and yielded the desired [2þ2þ2] cycloaddition.
Received 15 January 2015
Received in revised form 2 May 2015
Accepted 5 May 2015
Available online 12 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbene (NHC)
Nickel
Dimerization
Cycloaddition
1,3-Dienes
1. Introduction
cyclotrimerization to yield aromatic structures by a number of
metal centers.8,9
The development of new catalytic processes for the synthesis of
functionalized 1,3-dienes is important in organic synthesis. It is
because 1,3-dienes are key building blocks for constructing a wide
range of important organic frameworks for further applications,
such as DielseAlder reactions for higher substituted cyclic struc-
tures.1 Transition metal catalyzed cycloadditions via metallacycle
key intermediates have made remarkable progress in recent
years,2e6 and represents one of the most expedient ways of syn-
thesizing cyclic 1,3-dienes. However, current technology is still
awaiting further improvement because they are effective for only
a subset of the possible range of precursors and partners. The most
efficient cases are those either with structural features for confor-
mational freedom reduction, with diynes as one of the reaction
Recently, we have developed a ng-exo-trig cycloisomerization of
1,n-heterosubstituted dienes (1,n-heterodienes)10,11 by using an in
situ generated [NHCeNi(II)H(OTf)] catalyst (Fig. 1).12,13 That
Our previous work:
1,7-oxadienes
n-member rings
Cat.
NHC-Ni(II)H
O
O
γ
n
-exo-trig
Toluene
r.t.
R
R
This work:
1,n-oxaenynes
Oxacycles fused with
1,3-cyclohexadienes
y
components, or with polarized
p-systems to facilitate the key
R
Cat.
NHC-Ni(0)
O
O
metallacycle intermediates formation. Both enynes and 1-alkynes
are relatively less common substrates than diynes and internal al-
kynes,7 especially for those with heteroatoms in the spacer be-
tween the two unsaturated hydrocarbon termini. This is possibly
because 1) the enyne is electronically less activated, 2) the un-
favorably high rotational freedom associated with those flexible
heterosubstituted spacers, and 3) the highly competitive 1-alkyne
H
O
R
R
Toluene
r.t., y = 0, 1
y
y
H
rac-
rac-
Fig. 1. NHCeNi catalyzed 1,n-dienes cycloisomerization and enynes cycloaddition.
method synthesizes unsymmetrical n-member heterocycles out of
the other possible heterocycles selectively by making use of the
optimal g-heteroatom chelation with the NHCeNi(II) center. And
that is good even for 1,n-heterodienes with very limited confor-
mational constraints and/or with strong cycloisomerization
* Corresponding author. Tel.: þ86 755 88018318; e-mail address: jasonhcy@
sustc.edu.cn (C.-Y. Ho).
http://dx.doi.org/10.1016/j.tet.2015.05.016
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

J.-P. Zhao et al. / Tetrahedron 71 (2015) 4426e4431
4427
competitions. The above prompted us to subject other substrates
that may enjoy such a -heteroatom chelation and undergo
yield of 2a with less than 10% of alkyne cyclotrimerization were
obtained by using IPr as ligand (entry 4). The system accepted
substrates with R not only equals to phenyl, but also accepted those
with simpler and more general alkyl chains, such as benzyl and
nonyl (entries 5 and 6), yet not for 1 with R equals to H, which has
a much higher degree of rotational freedom (entry 7).
Next, we also subjected 1,6-oxaenynes 1e and 1f to our reaction
condition (entries 8e10). A [2þ2þ2] cycloaddition reactivity simi-
lar to the 1,7-oxaenynes was observed, yielded the corresponding
hydro-isobenzofurans 2e and 2f regioselectively with reasonable
yield. That bicyclic core was synthesized by using cationic Rh(I)
catalyzed [2þ2þ2] cycloaddition in boiling ethanol in the liter-
ature,14a,b our method here provided an alternative at a relatively
mild condition. It should be noted that Ni(cod)2 was successfully
used as stoichiometric catalyst in 1,6-enyne homo-[2þ2þ2] cyclo-
addition, the failure in entry 8 indicated that the importance of
using NHC as ligand when a 1,6-oxaenyne was used as substrate for
the preparation of oxacycles.14c,d
g
cycloisomerization with the NHCeNi(II)H catalyst, such as 1,n-
heterosubstituted enynes (1,n-heteroenynes) for heterocyclic 1,3-
dienes synthesis. In the meanwhile of that research, we found
that simple 1,7-oxaenynes are rarely studied substrates in both
cycloisomerization and cycloaddition. To tell apart the results from
Ni(II)H and Ni(0) species, and in view of the fact that Ni(II)H can be
reduced to Ni(0) under reaction conditions, we decided to step-
back and first study the cycloaddition of 1,7-oxaenynes under
Ni(0) condition with the relevant prior arts in the field in mind.
Overall, we believe that should facilitate our development of
cycloisomerization by Ni(II)H later on. To our delight, we discov-
ered a [2þ2þ2] cycloaddition of 1,n-enynes 1 and 3 by using
a NHCeNi(0) catalyst (n¼0, 1), yielded pyrans and furans with
substituted 1,3-cyclohexadienes as products.
2. Results
To study the effect of branching and the ether position relative
to the unsaturated termini, racemic 1,n-oxaenynes 3 with branched
propargyl or homopropargyl ethers were prepared and examined
for the catalytic homo-[2þ2þ2] cycloaddition (Table 2). By simply
applying the same optimized reaction condition as in Table 1, a di-
astereomeric mixture of product 4, which has a structurally dif-
ferent bicyclic core as compared to 2, was obtained in reasonable
yield. Overall, the results in Tables 1 and 2 collectively showed that
branched homopropargyl, propargyl, homoallyl, and allyl ethers are
all compatible substrates of this system, and both aromatic and
aliphatic substituents are tolerated. Unfortunately, the attempts
that used oxaenynes with internal alkynes or alkenes, or nitrogen
spacers as substrates were not successful.
The racemic 1,n-oxaenynes 1 with branched allyl or homoallyl
ether structures, were prepared from the corresponding alcohol
and propargyl chloride. The study were carried out by subjecting 1
to several in situ generated L-Ni(cod)2 conditions at rt in toluene in
order to obtain basic reactivity information (Table 1). By using only
Ni(cod)2 as catalyst, we found that the common cycloaddition side
reactions, like 1-alkyne cyclotrimerization or isomerization of al-
kyne to allene, and cleavage of the propargylic ether were all ob-
served as the major reaction outcomes (entries 1 and 8). These
results showed that the structural features of the 1,n-oxaenyne 1a
and 1e alone did not favor the enyne oxidative cyclization with
Ni(0) and they just followed the typical side reactions of those
carbon analogs. Next, several NHCeNi(0) generated in situ were
screened as catalyst at rt in toluene (entries 2e4). A significant
difference in reactivity from the above was noted, and yielded
a diastereomeric mixture of homo-[2þ2þ2] cycloaddition product
2a. The cycloaddition preferred a syn-relative configuration at the
1H-2-benzopyran core, which is similar to the NHCeNi(0) cata-
lyzed cycloaddition of internal enyne with aldehyde.7a Up to 83%
Table 2
Catalytic homo-[2þ2þ2] cycloaddition of 1,n-oxaenynes 3 with branched propargyl
or homopropargyl ethersa
Entry
R¼
Butyl
Ph
Y¼
0
1
Enyne
Diene
Conver./Yieldb
Table 1
1
2
3a
3b
4a
4b
100/72%
100/63%
Catalytic homo-[2þ2þ2] cycloaddition of 1,n-enynes 1 with branched allyl or ho-
moallyl ethersa
a
See Experimental Section for details. Except otherwise indicated, all the re-
actions were carried out by adding the enyne to the following catalyst mixture: IPr
and Ni(cod)2 (10 mol % each, 0.05 mmol) with 2 mL toluene at rt. The relative ste-
reochemistry on substituted pyrans and furans 4 were determined by NOESY.
b
Determined by both NMR and isolation, as a diastereomeric mixture (1:1).
We also tested the 1,7-oxaenyne for [2þ2þ2] co-cycloaddition
(Fig. 2). Since the co-cycloaddition of benzaldehyde with the sim-
ple 1,7-enyne works efficiently (Eq. 1),7a we first examined the ef-
fect of ether spacer by using 1a.15,16
Entry
NHC
R¼
Ph
Ph
Ph
Ph
Bn
Nonyl
H
Ph
Y¼
Enyne
Diene
Conver./Yieldb
1
2
3
4
5
6
7
8
9
d
1
1
1
1
1
1
1
0
0
0
1a
1a
1a
1a
1b
1c
1d
1e
1e
1f
d
2a
2a
2a
2b
2c
d
d
2e
2f
100/0%
IMes
SIPr
IPr
IPr
IPr
IPr
d
100/54%
100/68%
100/83%
100/75%
100/81%
100/0%
100/0%
100/64%
100/72%
Co-cycloaddition product 5a and a diastereomeric mixture of 2a
were obtained in 3:1 ratio by using excess amount of benzaldehyde
(Eq. 2). This indicated that the co-cycloaddition efficiency with
benzaldehyde was lowered by the use of ether spacer (Eq. 1 vs 2). It
also indicated that the co-cycloaddition with 1-alkyne might be
favorable with the help of the ether spacer. Thus, we explored the
co-cycloaddition of 1a with additional 1-alkynes (1-hexyne or
phenylacetylene, 1.5 equiv) under the standard reaction condition
in Table 1. However, it did not undergo co-cycloaddition with 1a,
and yielded only 2a at lower yield (35% and 45%) and cyclo-
trimerization products of the 1-alkyne as major reaction outcome.
IPr
IPr
Ph
Nonyl
10
a
See Experimental Section for details. Except otherwise indicated, all the re-
actions were carried out by adding the enyne to the following catalyst mixture: NHC
and Ni(cod)2 (10 mol % each, 0.05 mmol) with 2 mL toluene at rt. The relative ste-
reochemistry on the substituted pyrans and furans 2 were assigned according to 2a
and 2e by NOESY, and was compared with 5a further (see later).
b
Determined by both NMR and isolation as a diastereomeric mixture (w1:1).

4428
J.-P. Zhao et al. / Tetrahedron 71 (2015) 4426e4431
Fig. 2. Effects of the 1,7-enyne spacers in co-cycloaddition.16
Scheme 2. A tentative mechanism for the [2þ2þ2] cycloaddition with structurally
flexible 1,7-enynes.
We tentatively assumed that the mechanism of the 1,3-
cyclohexadienes 2, 4 and 6 formation could be explained simply
according to the related [2þ2þ2] cycloadditions prior arts, which
employed internal enynes as one of the partners (Scheme 1).3b,7a
Lastly, the stability of the 1,3-cyclohexadiene 2 deserves fur-
ther attention. We found that the desired products 2aec reported
in Table 1 were not stable at rt after isolation (Fig. 3). 2aec were
converted completely to their isomeric structures 20 after left
those at rt for 10 days in neat form.17 This process was monitored
by TLC, 1H and 13C NMR according to the significant changes in Rf
value and NMR spectra (the upfield shift of one of the OCH2
signals, and the downfield shift of the diene CHs signals). After
a complete conversion, the isolated structure 20a was further
confirmed by HRMS and NMR as a 1:1 diastereomeric mixture,
but the relative stereochemistry on the rings could not be de-
termined by NOSEY. On the other hand, the product 4 was found
stable after isolation and did not undergo a similar isomerization.
Unfortunately, we cannot explain the differences in behavior
among 2 and 4.
Scheme 1. Proposed mechanism for the homo-[2þ2þ2] cycloaddition.
First, an intramolecular oxidative cyclization of the 1,n-enyne was
directed by the NHC steric and electronic effects, yielded the
nickelacyclopentene key intermediate (A) by using Ni(0) and the
1,n-oxaenyne. Next, the desired product was obtained and the
catalyst was regenerated by a regioselective insertion of another
enyne followed by a reductive elimination. It should be noted that
the above proposed mechanism alone may not fully account for
cases that employed 1,n-oxaenynes, in view of the following ob-
servations: i) the failure in using oxaenyne with internal alkyne as
substrate in our system,7a ii) the changes in reactivity in Fig. 2 (i.e.,
the changes in rate of benzaldehyde and alkyne insertions to the
common nickelacyclopentene intermediate), and iii) the attenu-
ated cyclotrimerization observed.8,9 As inspired by the facile 1-
alkyne cyclotrimerization mechanism,8 we hypothesize a minor
alternation of the mechanism when an 1,n-oxaenyne is employed
as substrate (Scheme 2). We believe that the formation of a sym-
metrical nickelacyclopentene intermediate (C) might be facilitated
by the highly flexible ether spacer on 1,n-oxaenynes like 1 and 3.
Next, an intramolecular insertion of one of the two pending alkenes
was allowed, which successfully suppressed the intermolecular
insertions of the third alkyne to form the undesired cyclo-
trimerization products and yielded the desired products 2 and 4.
Yet, we are not able to observe intermediate (C) by spectroscopic
technique or isolation, and thus a precise reaction mechanism
awaits further study.
Fig. 3. Isomerization of 2 to 20.
3. Conclusion
We have discovered the first catalytic synthesis of substituted
1,3-cyclohexadienes fused with pyrans or furans by NHCeNi(0)
catalyzed homo-[2þ2þ2] cycloaddition of 1,n-oxaenynes. The ex-
periments suggested that typical intramolecular oxidative cycliza-
tion intermediate formation may be not so favorable in case of
using 1,n-oxaenynes as substrates. The choices of the spacers and
the associated structural flexibility in the enynes may be the key
factors and a possible strategy in controlling the cycloaddition
outcomes and pathways. Hydro-isobenzofurans and 3 new types of
1H-2-benzopyrans like structures, 2, 20 and 4 were synthesized in
reasonable yield by this new approach. The obtained information
should be useful for our development in 1,n-hetero-substituted
enynes cycloisomerization.

J.-P. Zhao et al. / Tetrahedron 71 (2015) 4426e4431
4429
4. Experimental section
4.1. General
4.5. 1,n-Enynes preparation
The 1,n-enynes 1 and 3 were prepared from the corresponding
alcohol in 70e85% yield according to the related literature.
Unless otherwise indicated, all reactions were performed under
a nitrogen atmosphere from, which oxygen and moisture were
strictly excluded from the reagents and glassware. Ni(cod)2 [Bis(-
cyclooctadienyl)nickel(0)] was purchased from ACROS or IL, stored
in a glovebox, and used without further purification. Toluene was
distilled over sodium before use. IPr [1,3-Bis(2,6-diisopropyl
phenyl)imidazol-2-ylidene], IMes [1,3-Bis(2,4,6-trimethylphenyl)
imidazol-2-ylidene] and SIPr [1,3-Bis(2,6-di-i-propylphenyl)imi-
dazolidin-2-ylidene] were purchased from TCI or Aldrich. 1,7-
oxaenynes were dried with CaH2 or CaCl2 before use. Unless oth-
erwise indicated, enynes were synthesized according to the pro-
cedures in the literature. Analytical thin layer chromatography
(TLC) was performed with the use of EM Science silica gel 60 F254
plates. The developed chromatogram was analyzed by UV lamp
(254 nm), ethanolic phosphomolybdic acid (PMA) or potassium
permanganate (KMnO4). Flash liquid chromatography was per-
formed on a coarse fritted glass column packed with Grace Silica
Gel (230e400 mesh, 0.040e0.063 mm). The cycloaddition products
2 were found not stable to store at rt. We recommend storing those
below 0 ꢀC. The preferred water bath temperature for rotavap is
below 40 ꢀC. 1H and 13C NMR spectra were recorded on Bruker
spectrometers in CDCl3 (400 MHz for 1H and 100 MHz for 13C).
Chemical shifts in 1H NMR spectra are reported in parts per million
1b: 1H NMR (400 MHz, CDCl3)
d: 7.38e7.14 (m, 5H), 5.95e5.77
(m, 1H), 5.13e5.05 (m, 2H), 4.13e4.08 (m, 2H), 3.78 (m, 1H), 2.86
(dd, J¼14.0, 6.4 Hz, 1H), 2.76 (dd, J¼14.0, 6.4 Hz, 1H), 2.37 (t,
J¼2.3 Hz, 1H), 2.34e2.20 (m, 2H). 13C NMR (100 MHz, CDCl3)
d:
138.6, 134.6, 129.6, 128.4, 126.3, 117.6, 80.2, 79.5, 74.1, 56.8, 40.2,
38.0. HRMS ESI (m/z): [MþNa]þ calcd for C14H16ONa:223.1099;
found 223.1094.
1c: 1H NMR (400 MHz, CDCl3)
d
5.83 (ddt, J¼17.2, 10.0, 7.2 Hz,
1H), 5.08 (m, 2H), 4.18e4.17 (m, 2H), 3.53 (m, 1H), 2.39 (t, J¼2.4 Hz,
1H), 2.31e2.26 (m, 2H), 1.54e1.20 (m, 16H), 0.88 (t, J¼6.9 Hz, 3H).
13C NMR (100 MHz, CDCl3)
d: 134.8, 117.1, 80.6, 78.3, 77.5, 77.2, 76.8,
73.8, 56.2, 38.1, 33.6, 32.0, 29.7, 29.7, 25.3, 22.8, 14.2. HRMS ESI (m/
z): [MþH]þ calcd for C16H28O:237.2174; found 237.2213.
1e: 1H NMR (400 MHz, CDCl3)
d 7.41e7.28 (m, 5H), 5.99e5.91
(m, 1H), 5.35e5.24 (m, 2H), 5.04e5.02 (d, J¼8.0 Hz, 1H), 4.42e4.08
(m, 2H), 2.44e2.43 (t, J¼4.0 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d
140.0, 137.9, 128.6, 128.0, 127.2, 117.4, 81.3, 79.8, 74.5, 55.3. HRMS
ESI (m/z): [MþH]þ calcd for C12H13O: 173.0966; found 173.0962.
1f: 1H NMR (400 MHz, CDCl3)
d 5.67e5.58 (m, 1H), 5.25e5.21
(m, 2H), 4.10 (ddd, J¼64.8, 15.6, 2.4 Hz, 2H), 3.85 (dd, J¼14.4, 6.8 Hz,
1H), 2.38 (t, J¼2.4 Hz, 1H),1.60e1.58 (m, 1H), 1.53e1.43 (m, 1H),
1.15e1.18 (m, 14H), 0.88 (t, J¼9.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
138.2, 118.1, 80.4, 80.3, 73.8, 55.2, 35.3, 32.0, 29.7, 29.6, 29.4, 25.4,
on the
(7.27 ppm). Chemical shifts of 13C NMR spectra are reported in ppm
from the central peak of CDCl3 (77.16 ppm) on the scale. Cyclo-
d
scale from an internal standard of residual chloroform
22.8, 14.2. HRMS ESI (m/z): [MþH]þcalcd for C15H27O: 223.2062;
found 223.2058.
d
3b: 1H NMR (400 MHz, CDCl3)
d 7.40e7.28 (m, 5H), 5.97e5.83
addition precursors conversion and products ratio was determined
by integration of areas of selected peaks in crude 1H NMR with
relaxation time d1¼10 s and nitromethane/benzaldehyde as stan-
dard. High-resolution mass spectra (HRMS) were obtained on
a Finnigan MAT 95XL.
(m, 1H), 5.31e5.13 (m, 2H), 4.50 (m, 1H), 3.98 (ddt, J¼12.8, 6.0,
1.2 Hz, 1H), 3.83 (ddt, J¼12.8, 6.0, 1.2 Hz, 1H), 2.72 (ddd, J¼16.8, 6.4,
2.8 Hz, 1H), 2.57 (ddd, J¼16.8, 6.4, 2.8 Hz, 1H), 1.97 (t, J¼2.7 Hz, 1H).
13C NMR (100 MHz, CDCl3)
d: 134.7, 128.5, 128.2, 126.9, 117.3, 81.0,
79.4, 76.2, 70.1, 69.9, 28.2. HRMS ESI (m/z): [MþH]þ calcd for
C26H28O2:187.1078; found 187.1117.
4.2. General procedure for the NHCeNi(0) catalyzed Homo-
[2D2D2] cycloaddition of 1,n-Oxaenynes
4.6. Spectroscopic data of 2 and 20
2a: 1H NMR (400 MHz, CDCl3)
: 7.38e7.27 (m, 10H), 5.81e5.50
In a glove box, Ni(cod)2 and IPr (0.05 mmol, 10 mol % each) were
added to an oven-dried test tube equipped with a stir bar. After
being sealed with a septum and brought out of the glove box, the
tube was connected to a N2 line. The mixture was dissolved in 2 mL
dried degassed toluene and stirred at rt for 1 h. The racemic 1,n-
oxaenyne 1 or 3 (n¼0, 1) was added to the above catalyst at rt. After
stirring at rt for 12 h, the mixture was diluted with 4 mL of hexane,
and was stirred in open air for 30 min. The mixture was then fil-
tered through a short plug of silica gel and rinsed with 50 mL of 33%
EA/hexane. The solvent was removed under a vacuum. Purification
via silica gel column chromatography (1e5% EA/Hexane) yielded
the racemic 1,3-cyclohexadiene product 2 or 4 as a mixture of di-
astereomers, respectively.
d
(m, 3H), 5.11e4.90 (m, 3H), 4.52e4.18 (m, 4H), 3.97e3.68 (m, 1H),
2.87e1.67 (m, 6H), 1.67e1.54 (m, 1H). 13C NMR (100 MHz, CDCl3)
d
:
142.4, 142.1, 142.0, 142.0, 138.1, 138.0, 136.8, 136.7, 135.2, 135.1, 135.1,
134.8, 134.7, 128.5, 128.5, 127.8, 127.7, 127.6, 127.0, 126.9, 125.9,
120.7, 120.7, 117.5, 117.4, 117.1, 117.0, 81.7, 81.7, 81.6, 81.6, 81.4, 81.3,
81.1, 81.0, 80.7, 79.7, 71.9, 71.6, 71.6, 71.3, 70.4, 70.3, 70.2, 70.2, 68.2,
68.0, 42.8, 42.7, 34.1, 32.5, 32.2. HRMS ESI (m/z): [MþNa]þ calcd for
C
26H28O2Na: 395.1987; found 395.1980.
2a0: 1H NMR (400 MHz, CDCl3)
d: 7.41e7.27 (m, 10H), 5.80e5.69
(m, 1H), 5.65e5.22 (m, 2H), 5.17e4.90 (m, 2H), 4.58 (td, J¼10.4,
3.5 Hz, 1H), 4.38e4.16 (m, 3H), 3.32e3.15 (m, 2H), 2.76e2.62 (m,
1H), 2.59e2.17 (m, 6H). 13C NMR (100 MHz, CDCl3)
d: 142.5, 142.4,
142.4, 142.3, 135.2, 128.6, 128.5, 128.5, 127.7, 127.7, 126.8, 126.8,
126.6, 126.4, 126.4, 126.4, 126.1, 126.0, 125.6, 125.6, 123.4, 123.4,
116.9, 82.5, 82.3, 76.2, 76.2, 71.1, 71.0, 68.0, 68.0, 42.8, 37.3, 37.3,
34.7, 34.6, 30.6, 30.5. HRMS ESI (m/z): [MþNa]þ calcd for
4.3. Procedure for the NHCeNi(0) catalyzed [2D2D2] co-
cycloaddition of 1,7-oxaenynes with benzaldehyde
The procedure is the same as the general procedure in 4.2, ex-
cept 1.5 equiv of benzaldehyde was added before the addition of the
oxaenyne.
C
26H28O2Na: 395.1987; found 395.1980.
2b: 1H NMR (400 MHz, CDCl3)
(m, 1H), 5.71e5.57 (m, 2H), 5.11e5.02 (m, 2H), 4.53e3.50 (m, 6H),
3.08e2.39 (m, 4H), 2.38e1.66 (m, 5H). 13C NMR (100 MHz, CDCl3)
d
7.39e7.16 (m, 10H), 5.90e5.82
d
:
4.4. Isomerization of 2 to 20
139.4, 139.3, 138.7, 138.6, 135.9, 135.8, 134.9, 134.9, 129.7, 129.5,
128.4, 128.4, 128.4, 128.3, 128.2, 126.4, 126.4, 126.2, 126.1, 121.0,
120.7, 117.5, 117.4, 117.2, 117.1, 79.5, 78.8, 78.3, 78.3, 72.5, 72.0, 71.3,
71.2, 42.7, 40.7, 40.6, 39.9, 39.7, 38.3, 38.0, 33.4, 33.3, 32.1, 32.0.
HRMS ESI (m/z): [MþNa]þ calcd for C28H32O2Na: 423.2300; found
423.2293.
The 1,3-cyclohexadiene product 20 was obtained by simply left
the isolated 2 in a rubber septum sealed round bottom flask at rt for
10 days in neat form. In all cases examined, 20 is less polar than 2
and can be separated easily by column chromatography.

4430
J.-P. Zhao et al. / Tetrahedron 71 (2015) 4426e4431
2b0: 1H NMR (400 MHz, CDCl3)
d: 7.27e7.17 (m, 10H), 5.92e5.79
4.8. Spectroscopic data of 5
(m, 1H), 5.59 (dd, J¼9.5, 2.9 Hz, 1H), 5.60e5.42 (m, 1H), 5.13e5.04
(m, 2H), 4.18e4.04 (m, 2H), 3.81e3.68 (m, 1H), 3.54e3.41 (m, 1H),
3.40e3.11 (m, 2H), 2.97 (ddd, J¼13.7, 6.7, 2.6 Hz, 1H), 2.78e2.69 (m,
3H), 2.58e2.42 (m, 1H), 2.26 (dd, J¼12.0, 6.1 Hz, 2H), 2.10e1.72 (m,
5a: 1H NMR (400 MHz, CDCl3)
d 7.99e7.22 (m, 10H), 5.00e4.76
(m, 2H), 4.65e4.62 (m, 1H), 4.41e4.22 (m, 2H), 3.42e2.93 (m, 3H),
2.14e2.10 (m, 1H), 1.54e1.39 (m, 1H). 13C NMR (101 MHz, CDCl3)
4H). 13C NMR (100 MHz, CDCl3)
d
: 139.4, 139.2, 138.5, 135.1, 135.0,
d 198.8, 146.3, 142.1, 137.2, 133.4, 128.8, 128.5, 128.2, 127.7, 126.0,
129.7, 129.7, 129.5, 128.5, 128.3, 126.4, 126.2, 126.1, 125.4, 125.2,
123.5, 123.5, 117.4, 117.3, 81.0, 80.7, 75.0, 71.6, 71.4, 67.6, 42.4, 40.7,
40.6, 38.4, 38.3, 35.0, 35.0, 34.7, 34.6, 30.4, 30.1. HRMS ESI (m/z):
[MþNa]þ calcd for C28H32O2Na: 423.2300; found 423.2293.
108.1, 80.0, 73.9, 42.1, 40.8, 36.4. HRMS ESI (m/z): [MþNa]þcalcd for
C
20H20O2Na: 315.1361; found 315.1354.
Acknowledgements
2c: 1H NMR (500 MHz, CDCl3)
d 5.92e5.55 (m, 3H), 5.17e5.01
(m, 2H), 4.88e3.82 (m, 4H), 3.58e3.28 (m, 2H), 2.66e1.85 (m, 6H),
1.52e1.37 (m, 5H), 1.29 (d, J¼24.7 Hz, 28H), 0.88 (t, J¼6.8 Hz, 6H).
C.Y.H. thanks Prof. Masato Kitamura, the Editor of the Special
Symposium-in-Print entitled ‘Progress in organic synthesis: new
reactions, strategies, and targets’ in honor of Prof. Yoshiaki Nakao’s
Tetrahedron Young Investigator Award, for the kind invitation. This
work is supported by Thousand Young Talents Program Award,
SUSTC start up fund and Guangdong Province Matching Fund
(K12213101)
13C NMR (100 MHz, CDCl3)
d: 136.1, 135.4, 135.2, 124.3, 123.9, 120.6,
120.5, 117.7, 117.1, 116.8, 78.8, 78.4, 78.3, 77.6, 74.6, 74.4, 72.2, 72.2,
71.3, 70.9, 68.6, 68.3, 40.8, 40.7, 38.5, 38.4, 36.3, 34.0, 33.9, 33.7,
33.6, 32.7, 32.1, 32.1, 29.9, 29.9, 29.9, 29.8, 29.8, 29.8, 29.5, 25.8, 25.7,
25.5, 24.6, 23.7, 22.8, 14.2. HRMS ESI (m/z): [MþH]þ calcd for
C
32H56O2: 473.4314; found 473.4352.
2c0: 1H NMR (500 MHz, CDCl3)
d
: 5.88e5.76 (m, 1H), 5.67e5.58
Supplementary data
(m, 2H), 5.15e5.02 (m, 2H), 4.18e4.04 (m, 2H), 3.53e3.45 (m, 1H),
3.40e3.23 (m, 3H), 2.67e2.58 (m, 1H), 2.30e2.19 (m, 2H), 2.16e2.10
(m, 2H), 2.06e1.89 (m, 2H), 1.45 (m, 4H), 1.26 (m, 28H), 0.88 (t,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.05.016.
J¼6.9 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d: 135.4, 135.4, 126.4,
126.3, 126.2, 125.6, 123.6, 123.6, 116.8, 79.5, 79.5, 74.3, 71.3, 71.2,
67.6, 38.6, 38.6, 36.1, 35.6, 35.6, 34.9, 34.1, 34.1, 32.1, 30.7, 30.7, 29.9,
29.9, 29.8, 29.8, 29.7, 29.5, 29.5, 25.7, 25.6, 22.8, 14.2. HRMS ESI (m/
z): [MþH]þ calcd for C32H56O2: 473.4314; found 473.4353.
References and notes
1. (a) Du, H.; Ding, K. In Comprehensive Enantioselective Organocatalysis; Dalko, P. I.
, Ed.; 2013; 3, p 1131; (b) Xiao, Y.-C.; Chen, Y.-C. In Comprehensive Enantiose-
lective Organocatalysis; Dalko, P. I., Ed.; 2013; 3, p 1069; (c) Knall, A.-C.; Slugovc,
C. Chem. Soc. Rev. 2013, 42, 5131.
2. (a) Methods and Applications of Cycloaddition Reactions in Organic Syntheses;
Nishiwaki, N., Ed.; 2014; (b) Transition Metal Catalyzed CyclizationOrganome-
tallics in Synthesis: Fourth Manual; Montgomery, J., Lipshutz, B. H., Eds.; 2013;
p 319.
2e: 1H NMR (400 MHz, CDCl3)
d 7.37e7.26 (m, 10H), 5.98e5.79
(m, 3H), 5.28e5.15 (m, 2H), 4.81e4.74 (m, 2H), 4.58e4.51 (m, 2H),
4.00e3.93 (m, 2H), 2.77e2.72 (m, 1H), 2.25e2.12 (m, 2H). 13C NMR
(101 MHz, CDCl3)
d 143.9, 142.5, 142.4, 141.1, 140.5, 139.0, 138.8,
134.6, 133.3, 128.6, 128.6, 128.1, 127.8, 127.1, 127.0, 126.2, 122.4,
122.2, 120.9, 116.6, 116.5, 114.3, 113.5, 113.4, 87.9, 81.9, 81.8, 81.8,
71.4, 71.2, 70.4, 69.5, 48.0, 48.0, 47.7, 26.8, 25.1, 22.6. HRMS ESI (m/
z): [MþNa]þ calcd for C24H24O2Na: 367.1776; found 367.1667.
3. For review on Ni catalyzed cyclization: (a) Montgomery, J. Acc. Chem. Res. 2000,
33, 467; (b) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307.
4. For recent examples of NHCeNi(0) catalyzed cycloaddition to synthesize het-
erocycles: 2-pyrones: (a) Louie, J.; Gibby, J. E.; Farnworth, M. V.; Tekavec, T. N. J.
Am. Chem. Soc. 2002, 124 2-pyridones: (b) Duong, H. A.; Cross, M. J.; Louie, J. J.
Am. Chem. Soc. 2004, 126, 11438 Pyran: (c) Tekevac, T. N.; Louie, J. Org. Lett. 2005,
7, 4037 Pyridine: (d) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am.
Chem. Soc. 2005, 127, 5030; (e) Tekavec, T. N.; Zuo, G.; Simon, K.; Louie, J. J. Org.
Chem. 2006, 71, 5834; (f) Stolley, R. M.; Duong, H. A.; Louie, J. Organometallics
2013, 32, 4952 Cyclohexadienones: (g) Kumar, P.; Troast, D. M.; Cella, R.; Louie,
J. J. Am. Chem. Soc. 2011, 133 8-member rings: (h) Kumar, P.; Zhang, K.; Louie, J.
Angew. Chem., Int. Ed. 2012, 51, 8602.
5. Other recent cycloaddition examples by Ni(0): [4þ2þ1] of TMS diazomethane
with alkynes tethered to dienes: (a) Ni, Y.; Montgomery, J. J. Am. Chem. Soc.
2004, 126, 11162 Reductive [3þ2] of enal with alkyne: (b) Herath, A.; Mont-
gomery, J. J. Am. Chem. Soc. 2006, 128 [2þ2þ2] with 2 enones and an alkyne: (c)
Ogoshi, S.; Nishimura, A.; Ohashi, M. Org. Lett. 2010, 12 [2þ2þ1] with alkynes,
acrylates and isocyanates: (d) Ozawa, T.; Horie, H.; Kurahashi, T.; Matsubara, S.
Chem. Commun. 2010, 8055 Dehydrogenative [4þ2] of formamides with al-
kynes: (e) Nakao, Y.; Morita, E.; Idei, H.; Hiyama, T. J. Am. Chem. Soc. 2011, 133 8-
member rings: (f) Thakur, A.; Facer, M. E.; Louie, J. Angew. Chem., Int. Ed. 2013,
52, 12161.
2f: 1H NMR (400 MHz, CDCl3)
d 5.91e5.59 (m, 3H), 5.19e5.13 (m,
2H), 4.58e4.53 (m, 1H), 4.40e4.35 (m, 1H), 4.07e3.98 (m, 1H),
3.88e3.77 (m, 1H), 3.73e3.51 (m, 2H), 2.55e2.37 (m, 1H),
2.34e2.20 (m, 1H), 2.05e1.86 (m, 1H), 1.72e1.55 (m, 4H), 1.39e1.16
(m, 28H), 0.88 (t, J¼6.4 Hz, 6H). 13C NMR (101 MHz, CDCl3)
d 144.4,
143.2, 139.5, 139.4, 139.3, 122.2, 120.5, 116.9, 114.1, 113.9, 113.0, 86.3,
86.3, 80.7, 80.6, 80.4, 71.5, 70.4, 70.3, 69.0, 45.3, 45.1, 44.8, 35.7, 35.6,
35.6, 35.5, 34.6, 32.0, 30.0, 29.7, 29.7, 29.5, 27.5, 26.3, 25.7, 25.7, 25.6,
25.6, 25.5, 22.8, 14.3. HRMS ESI (m/z): [MþH]þcalcd for C30H53O2:
445.4046; found 445.4041.
4.7. Spectroscopic data of 4
4a: 1H NMR (400 MHz, CDCl3)
d 5.97e5.67 (m, 3H), 5.30e5.13
6. For theoretic calculation: Hong, X.; Holte, D.; Gotz, D. C. G.; Baran, P. S.; Houk,
K. N. J. Org. Chem. 2014, 79, 12177 Hong, X., Liu, P.; Houk, K. N. J. Am. Chem. Soc.
2013, 135, 1456.
(m, 2H), 4.55e4.41 (m, 1H), 4.31e4.19 (m, 1H), 4.08e3.87 (m, 1H),
3.83e3.71 (m, 2H), 3.51e3.39 (m,1H), 2.99e2.80 (m,1H), 2.40e2.21
(m, 1H), 1.96e1.72 (m, 1H), 1.54e1.10 (m, 12H), 0.94e0.86 (m, 6H).
7. (a) Tekavec, T. N.; Louie, J. J. Org. Chem. 2008, 73, 2641 and the reference
therein; (b) Shin, S.; RajanBabu, T. V. J. Am. Chem. Soc. 2001, 123, 8416; (c) Te-
kavec, T. N.; Louie, J. Tetrahedron 2008, 64, 6870; (d) Sato, Y.; Takimoto, M.;
Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771.
8. (a) Kurahashi, T.; Matsubara, S. In Transition-metal-mediated Aromatic Ring
Construction; Tanaka, K., Ed.; 2013; p 323; (b) Hilt, G.; Punner, F. In Transition-
metal-mediated Aromatic Ring Construction; Tanaka, K., Ed.; 2013; p 341 For
recent review on [2þ2þ2]-cyclo(co)trimerization: (c) Broere, D. L. J.; Ruijter, E.
Synthesis 2012, 44, 2639 Recent catalytic cyclotrimerization of terminal alkynes
by Ni: (d) Xi, C.; Sun, Z.; Liu, Y. Dalton Trans. 2013, 42, 13327.
13C NMR (101 MHz, CDCl3)
d 146.7, 146.6, 136.6, 135.4, 135.3, 123.5,
123.2, 116.7, 113.3, 113.1, 82.7, 82.6, 80.0, 79.3, 74.1, 72.7, 69.2, 69.1,
40.5, 35.3, 34.6, 32.7, 28.2, 28.1, 25.1, 22.9, 22.8, 14.2, 14.2. HRMS ESI
(m/z): [MþH]þcalcd for C20H33O2: 305.2481; found 305.2475.
1
4b: H NMR (400 MHz, CDCl3)
d 7.44e7.24 (m, 10H), 6.00e5.60
(m, 3H), 5.31e5.14 (m, 2H), 4.52e4.37 (m, 1H), 4.38e4.22 (m, 2H),
3.98e3.87 (m, 1H), 3.82e3.48 (m, 1H), 3.34e3.28 (m, 1H),
2.75e2.46 (m, 3H), 2.49e2.29 (m, 2H), 2.28e1.94 (m, 1H), 1.83e1.76
9. Recent advances in cross-cyclotrimerization that employed alkene with alkyne:
Hara, J.; Ishida, M.; Kobayashi, M.; Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed.
2014, 53, 2956.
(m, 1H). 13C NMR (100 MHz, CDCl3)
d: 142.4, 142.4, 135.0, 134.2,
10. In the special issue Ho, C.-Y.; He, L. J. Org. Chem. 2014, 79, 11873.
11. Recent advance in Ni catalyzed cycloisomerization: (a) Leitner, W. Adv. Synth.
Catal. 2008, 350, 1073; (b) Biswas, S.; Zhang, A.; Raya, B.; RajanBabu, T. V. Adv.
Synth. Catal. 2014, 356, 2281; (c) Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc.
1998, 120, 8007 For recent review: (d) Aissa, C. Synlett 2014, 2379; (e)
134.1,133.1,133.0,128.5,128.5,127.7,127.7,126.9,126.8,125.9,120.9,
120.7, 119.3, 119.2, 117.0, 117.0, 80.9, 80.5, 80.1, 80.1, 74.8, 74.8, 69.7,
69.6, 46.1, 46.1, 40.9, 40.8, 34.4, 30.0, 29.9. HRMS ESI (m/z):
[MþNa]þ calcd for C26H28O2Na: 395.1987; found 395.1980.

J.-P. Zhao et al. / Tetrahedron 71 (2015) 4426e4431
4431
Yamamoto, Y. Chem. Rev. 2012, 112, 4736; (f) Lloyd-Jones, G. C. Org. Biomol.
Chem. 2003, 215.
12. For related applications of the NHCeNi(II)H in catalytic gem-olefin syntheses:
found that our general procedure is also applicable to an 1,6-enyne, diethyl 2-
allyl-2-propargylmalonate, yielded the homo-[2þ2þ2] cycloaddition product 6
(35% yield c.f. 45% in (c)).
Tail-to-tail styrene
a
-olefin cross hydrovinylation: (a) Ho, C.-Y.; He, L. Angew.
15. For examples of PeNi(0) directed oxanickelacycle formation from benzalde-
hyde and unactivated alkenes: (a) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem.
Soc. 2004, 126, 11802; (b) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem.
Soc. 2005, 127, 12810; (c) Murakami, M.; Ashida, S. Chem. Commun. 2006, 4599
For an example with NHC-Ni(0): (d) Ho, C.-Y.; Jamison, T. F. Angew. Chem., Int.
Ed. 2007, 46, 782 For an account: (e) Ho, C.-Y.; Schleicher, K. D.; Chan, C.-W.;
Jamison, T. F. Synlett 2009, 2565.
Chem., Int. Ed. 2010, 49, 9182 Organometalloid syntheses: (b) Ho, C.-Y.; He, L.
Chem. Commun. 2012 Vinylether dimerization: (c) Ho, C.-Y.; He, L. Synlett 2014,
2738 With electronically modified chiral NHC as ligand: (d) Ho, C.-Y.; Chan, C.-
W.; He, L. Angew. Chem., Int. Ed. 2015, 54, 4512.
13. For recent review on hydrovinylation: (a) RajanBabu, T. V. Chem. Rev. 2003, 103,
2845; (b) RajanBabu, T. V. Synlett 2009, 853; (c) Ho, C.-Y.; He, L.; Chan, C.-W.
Synlett 2011, 1649; (d) Hilt, G. Eur. J. Org. Chem. 2012, 4441; (e) Ceder, R. M.;
Grabulosa, A.; Muller, G.; Rocamora, M. Cat. Sci. Tech. 2013, 3, 1446.
14. There are only two examples reported in the literature that have synthesized
the bicyclic core 2 from 1,6-oxaenynes [2þ2þ2] cycloaddition, see: (a) Grigg, R.;
Scott, R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1988, 1365 For an account,
see: (b) Tanaka, K. Synlett 2007, 1977 For an Example of homo-[2þ2þ2] Cy-
cloaddition of 1,6-enyne by Using Stoichiometric Amount of Ni(cod)2; (c) Saito,
A.; Oka, Y.; Nozawa, Y.; Hanzawa, Y. Tetrahedron Lett. 2006, 47, 2201; (d) We
16. The reaction was conducted as in Table 1 standard condition except that 1.
5 equiv of benzaldehyde was added before the addition of 1a.
17. Conceivably, 2 could be thermodynamically less stable product than 20. Un-
fortunately, the relative stereochemistry among the shifted H and the CH at the
other side of the ring system cannot be determined accurately by NOESY be-
cause they are located too far away. For a recent example of 1,5-H shift in
oxacycles with 1,3-diene: Ghosh, A. K.; Xi, K. J. Org. Chem. 2009, 74, 1163.