Divergent reaction pathways in gold-catalyzed cycloisomerization of 1,5-enynes containing a cyclopropane ring: Dramatic: ortho substituent and temperature effects

Article abstract of DOI:10.1039/c6sc00058d

A gold(i)-catalyzed cycloisomerization of easily available 1,5-enynes containing a cyclopropane ring has been developed, efficiently providing cyclobutane-fused 1,4-cyclohexadiene, tricyclic cyclobutene, biscyclopropane and 1,3-cyclohexadiene derivatives in moderate to excellent yields. When the phenyl group was not ortho substituted, 1,4-cyclohexadienes could be produced. With an ortho substituent, three different products could be selectively synthesized by control of the temperature and the used gold(i) catalyst. The 1,5-enyne substrate first undergoes a classical enyne cycloisomerization to form a tricyclic cyclobutene key intermediate, which undergoes subsequent transformation to produce the desired products. A plausible reaction mechanism was proposed according to deuterium labeling experiments and intermediate trapping experiments, as well as DFT calculations. In our current reaction, the ortho substituent on the phenyl group controls the reaction outcome and the ortho substituent effect was found to originate from steric and electronic factors.

Full text of DOI:10.1039/c6sc00058d

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Divergent reaction pathways in gold-catalyzed
cycloisomerization of 1,5-enynes containing
a cyclopropane ring: dramatic ortho substituent
and temperature effects†
Cite this: DOI: 10.1039/c6sc00058d
Gen-Qiang Chen, Wei Fang, Yin Wei,* Xiang-Ying Tang* and Min Shi*
A gold(I)-catalyzed cycloisomerization of easily available 1,5-enynes containing a cyclopropane ring has
been developed, efficiently providing cyclobutane-fused 1,4-cyclohexadiene, tricyclic cyclobutene,
biscyclopropane and 1,3-cyclohexadiene derivatives in moderate to excellent yields. When the phenyl
group was not ortho substituted, 1,4-cyclohexadienes could be produced. With an ortho substituent,
three different products could be selectively synthesized by control of the temperature and the used
gold(I) catalyst. The 1,5-enyne substrate first undergoes a classical enyne cycloisomerization to form
a tricyclic cyclobutene key intermediate, which undergoes subsequent transformation to produce the
desired products. A plausible reaction mechanism was proposed according to deuterium labeling
experiments and intermediate trapping experiments, as well as DFT calculations. In our current reaction,
the ortho substituent on the phenyl group controls the reaction outcome and the ortho substituent
effect was found to originate from steric and electronic factors.
Received 6th January 2016
Accepted 3rd March 2016
DOI: 10.1039/c6sc00058d
www.rsc.org/chemicalscience
1
Transition metal-catalyzed enyne cycloisomerization is one of
On the other hand, cyclopropanes are versatile building
8
the most important strategies for the construction of cyclic blocks in organic synthesis. Their unique structure and
structures from simple acyclic enyne substrates, of which 1,4-,
2
intrinsic strain endow cyclopropanes with high reactivity. Thus
3
4
4k,5
1
,5-, 1,6- and 1,7-enynes
have been extensively examined. far, it has been well known that a cyclopropyl group can effec-
Among a range of transition metal catalysts for enyne cyclo- tively stabilize carbocations adjacent to it due to its p-char-
9
isomerization, gold(I) complexes are the most active and selec- acter, and the cyclopropylmethyl carbocation is a stable non-
6a,b
tive catalysts, probably due to relativistic effects. Reports on classical carbocation that has several resonance structures:
9
a,10,11
homogeneous gold catalysis have been increasing explosively homoallyl carbocation, cyclobutyl carbocation, etc.
In
6,7
during the last decade and 1,5-enynes have always been the 2010, Liu's group disclosed a novel PtCl -catalyzed cyclo-
proving ground for gold catalysis. In 2004, Malacria and isomerization of cyclopropyl group-tethered 1,4-enynes, effi-
F u¨ rstner reported their pioneering work on 1,5-enyne cyclo- ciently providing eight-membered carbocycles (Scheme 1, eqn
isomerization, affording bicyclo[3.1.0]hexenes from 1,5-enynes (1a)). Subsequently, we found that cyclopropyl-tethered 1,4-
with hydroxy or acyloxy groups at the propargylic position in the enynes could undergo a tandem Pauson–Khand type reaction in
2
3
o
3p
2
h
presence of PtCl
2
or gold(I), respectively. Subsequently, Toste's the presence of a Rh(I) catalyst under CO atmosphere (Scheme
2c
group found that gold(I)-catalyzed isomerization of 1,5-enynes 1, eqn (1b)). However, the reaction of 1,5-enynes tethered by
could efficiently produce bicyclo[3.1.0]hexane or tetracyclic
compounds. Kozmin’s
3
q
3h
a cyclopropane has been rarely reported, to the best of our
3j,3n
3k
3c
and Zhang's groups disclosed that knowledge (Scheme 1, eqn (2)).
cyclohexadiene derivatives could be synthesized from siloxy-1,5-
enynes or 3-carboxy-1,5-enynes under gold(I) catalysis.
On the basis of the research work of Liu's group, as well as
12g
gold-catalyzed cyclopropane chemistry from Schmalz
other groups and our long-term exploration of cyclopropane
and
12
13
chemistry, we envisaged that when the 1,5-enyne was tethered
with a cyclopropane moiety, the reaction should be different.
We postulate that a biscyclopropane gold carbene intermediate
I can be produced in the presence of a gold catalyst. The
intermediate I has a spiro and a fused cyclopropane moiety
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.
China. E-mail: weiyin@sioc.ac.cn; siocxiangying@mail.sioc.ac.cn; mshi@mail.sioc.
ac.cn
†
Electronic supplementary information (ESI) available: Experimental procedures, adjacent to the carbene center, and this unique structure makes
characterization data of new compounds. CCDC 1048653, 1033827 and 1036129.
For ESI and crystallographic data in CIF or other electronic format see DOI:
it undergo diverse reaction pathways, affording multiple kinds
of products (Scheme 1, eqn (2)).
1
0.1039/c6sc00058d
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Table 1 Au(I)-catalyzed cycloisomerization of 1 leading to 3
a
1
2
1
b
Entry
R , R
Time (h)
Yield (%)
2
1
2
3
4
5
6
7
8
1a, R ¼ Ph, R ¼ H
20
17
14
12
17
16.5
18
20
19
19
36
14
14
14
18
12
3a, 92
3b, 90
3c, 91
3d, 93
3e, 88
3f, 92
3g, 85
3h, 84
3i, 82
3j, 82
3k, 72
3l, 86
3m, 95
3n, 87
3o, 94
3p, 69
1
2
1b, R ¼ p-Me-Ph, R ¼ H
1
2
1c, R ¼ 3,5-di-Me-Ph, R ¼ H
1
2
1d, R ¼ p-MeO-Ph, R ¼ H
1
2
1e, R ¼ m-MeO-Ph, R ¼ H
1
2
1f, R ¼ p-Ph-Ph, R ¼ H
1
2
1g, R ¼ p-Br-Ph, R ¼ H
1
2
1h, R ¼ p-Cl-Ph, R ¼ H
1
2
9
1i, R ¼ p-F-Ph, R ¼ H
c
1
2
10
11
12
13
14
15
16
1j, R ¼ p-CF
3
-Ph, R ¼ H
Scheme 1 Previous work and this work.
d
1
2
1k, R ¼ p-NO
2
-Ph, R ¼ H
1
2
1l, R ¼ 2-thienyl, R ¼ H
1
2
1m, R ¼ 1-boc-5-indoly, R ¼ H
1
2
1n, R ¼ 2-naphthyl, R ¼ H
2
The cyclopropane-tethered 1,5-enyne substrate 1a was
synthesized and its reactivity was examined. We screened
various gold catalysts to nd the optimal catalyst. In the pres-
1
1o, R ¼ 6-MeO-2-naphthyl, R ¼ H
e
1
2
1p, R ¼ 9-phen, R ¼ Me
a
To a 25 mL ame- and vacuum-dried Schlenk tube was added 1 (0.2
3 6
ence of [PPh AuCl]/AgSbF , product 3a could be afforded in 82%
mmol), then the tube was evacuated and backlled with Ar. The
NMR yield. Aer further optimization of the reaction condi- catalyst (3 mol%) was dissolved in 2.5 mL DCM and then the solution
was degassed with Ar. The catalyst solution was added to the Schlenk
tube. The reaction was allowed to stir at the indicated temperature
6
tions, we found that when [JohnPhosAu$MeCN]SbF was used
as the catalyst, product 3a could be produced in 92% isolated
b
c
until TLC indicated complete conversion of 1. Isolated yield. The
ꢀ
ꢀ
d
yield aer 20 h at 0 C in DCM (dichloromethane). Other gold reaction was conducted at 10 C. The reaction was conducted at
ꢀ
60
C for 36 h, the product contained about 20% of 1,3-
e
catalysts, such as [(p-F-Ph) PAu$MeCN]SbF , [(p-CF -Ph) -
3
6
3
3
cyclohexadiene 9k and the total yield was 91%. IPrAuNTf
2
was used
PAu$MeCN]SbF
SbF
IPrAu$MeCN]SbF
obtained. Therefore, [JohnPhosAu$MeCN]SbF
6
, [P(OAr)
3
Au$MeCN]SbF
6
, [(t-Bu)
3
PAu$MeCN]
, and
were also evaluated, but no better result was
was identied as
as the catalyst instead of JohnPhosAuSbF
6
.
6
6 6
, [JackiePhosAu$MeCN]SbF , [XPhosAu$MeCN]SbF
[
6
6
the best catalyst for the current reaction (see Table SI-1 in the
ESI† for the detailed optimization of the reaction conditions).
With the optimal reaction conditions in hand, we next
turned our efforts to examine the substrate scope of the reac-
1
tion. We found that when R was an aromatic group with an
electron-donating or electron-withdrawing substituent (Table
1
, entries 1–9), the corresponding products could be obtained [JohnPhosAu$MeCN]SbF and two new compounds 5a and 6a
6
in good to excellent yields. Only when a strongly electron- were obtained in 37% and 54% yields, respectively (Table 2, entry
1
withdrawing group such as CF
3
or NO
2
was introduced (R ¼ 1). Inspired by this discovery, we optimized the reaction condi-
p-CF -Ph or p-NO -Ph), the reaction proceeded sluggishly and tions for the gold-catalyzed cycloisomerization of compound 2a.
3
2
elevation of temperature was required for the complete With JohnPhosAuOAc, the reaction could not proceed at all
ꢀ
conversion (Table 1, entries 10 and 11). When the substituents (Table 2, entry 2). When the temperature was lowered to 0 C,
were heteroaromatic groups, such as thienyl or 5-indolyl compound 5a was obtained in 84% yield, combined with a trace
groups, the reaction went smoothly to produce 3l and 3m in amount of compound 4a and a small amount of compound 6a,
excellent yields (Table 1, entries 12 and 13). The reaction also in the presence of [JohnPhosAu$MeCN]SbF (Table 2, entry 3).
6
worked very well when the substituent was a 2-naphthyl group By elevation of the reaction temperature, compound 6a could
or 6-methoxyl-2-naphthyl group (Table 1, entries 14 and 15). In be obtained in higher yield in the presence of IPrAuNTf2
2
addition, R could also be an alkyl group, and the corre- or [JohnPhosAu$MeCN]SbF6 (Table 2, entries 4 and 5) in
ꢀ
sponding product 3p could be obtained in 69% yield in the DCE. When the reaction of 2a was conducted at ꢁ20 C using
presence of IPrAuNTf (ref. 14) (Table 1, entry 16). The structure [JohnPhosAu$MeCN]SbF as the catalyst, 4a could be afforded in
2
6
of 3 was unambiguously determined by the X-ray diffraction of 5% yield combined with a trace amount of 5a (Table 2, entry 6).
1
5
ꢀ
compound 3o.
When the reaction was conducted at ꢁ30 C in the presence of
It was a great surprise that compound 2a, in which Ar is IPrAuNTf , 4a was produced as the major product in 75% yield
2
a 9-phenanthrenyl group, could not produce 3 in the presence of along with a trace amount of 5a, and 6a could not be detected at
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Table 2 Optimization of reaction conditions for the gold-catalyzed cycloisomerization of 2a
a
Yield (%)
ꢀ
Entry
Catalyst (3 mol%)
Solvent
Temperature ( C)
4a
5a
6a
b
1
[JohnPhosAu(MeCN)]SbF
JohnPhosAuOAc
6
DCM
DCE
DCM
DCE
DCE
DCM
DCM
rt
rt
0
N.D.
37
N.R.
84
N.D.
N.D.
Trace
Trace
54
2
3
b
[JohnPhosAu(MeCN)]SbF
IPrAuNTf
[JohnPhosAu(MeCN)]SbF
[JohnPhosAu(MeCN)]SbF
IPrAuNTf
6
Trace
N.D.
N.D.
<5
90
95
N.D.
N.D.
4
2
80
60
ꢁ20
ꢁ30
5
6
b
d
6
6
5
b,c
7
2
75
a
b
c
d
Isolated yield. The reaction was quenched with DMS (dimethyl sulde). The reaction was conducted for 8 hours. NMR yield.
all (Table 2, entry 7). Entries 3, 5 and 7 were identied as the a methyl group, the reaction also proceeded efficiently to
optimal conditions for the formation of 5a, 6a and 4a, produce the desired product 5p in 78% yield. The structure of 5a
15
respectively.
was unambiguously determined by X-ray diffraction. Inter-
The substrate scope for the formation of 4 was also explored. estingly, the product 5 was detected as mixtures of two diaste-
When the aryl group was a substituted naphthyl group or reomers. Due to the following reasons, we believe that
a derivative such as pyrene or anthracene, the products 4 could compound 5 exists as a pair of rotamers: (1) compounds 5f and
be produced in moderate to good yields, ranging from 43% to 5l had no dr value; (2) four peaks could be found in the chiral
75% (Table 3, 4a–4h). The structure of 4a was determined by 2D- HPLC resolution (for the details see the ESI†); (3) when the
NMR spectroscopy (for details see the ESI†). bromine atom in compound 5m was removed, the dr value
1
The substrate generality for the formation of the biscyclo- disappeared (Scheme 12); (4) when the H-NMR spectrum of
propane product 5 was also examined. When the alkynyl
substituent was a naphthyl or substituted naphthyl group or its
derivatives, the reaction proceeded smoothly to produce prod-
Table 4 Au(I)-catalyzed cycloisomerization of 2 leading to 5
ucts 5 in high yields (Table 4, 5a–5c and 5e–5h); H
substrate 2j also worked well (Table 4, 5j); the desired products
could also be produced in moderate to high yields when the
phenyl group was substituted at the ortho position (Table 4, 5k–
m). In the case that the substituent on the allylic position was
4
-naphthyl
5
5
Table 3 Au(I)-catalyzed cycloisomerization of 2 leading to 4
a
1
b
The dr value was determined by H-NMR spectroscopy in CDCl
3
.
The
1
dr value was determined by H-NMR spectroscopy in CDCl
HPLC resolution.
3
as well as
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ꢀ
3
compound 5m was recorded at 65 C in CDCl , the two peaks
converged into one peak, indicating that the dr value dis-
appeared at higher temperature (for details, see the ESI†).
Aer further exploration of the substrate scope for the
formation of 6, we found that when the substituent on the
alkyne group was 1-naphthyl or a substituted 1-naphthyl group
or its derivatives, the corresponding products 6b–6i could be
obtained in good to excellent yields. The reaction also pro-
ceeded smoothly when the phenyl group was substituted at the
ortho position (Table 5, 6j–6n). In the case that the substituent
on the alkyne was a benzyl group, the reaction also proceeded
efficiently to produce the desired product 6o in 83% yield. For
the substrate in which the allylic position was substituted with
an alkyl group, the corresponding product 6p could also be
obtained in 91% yield (Table 5). If the alkene unit was
substituted at the terminal position, the desired product 6q was
produced as a mixture of two diastereomers (dr ¼ 6.4/1) in 90%
yield (Table 5). The structure of compound 6 was further
Scheme 2 Deuterium labeling experiment for formation of 3.
group during the reaction (Scheme 2, eqn (1) and (2)). When the
0
allylic hydrogen atoms were deuterated, compound [D ]-3a was
15
2
conrmed by the X-ray diffraction of compound 6c.
produced in 80% yield along with one deuterium shi (Scheme
2, eqn (3)).
Deuterium labeling experiments
2 1
The deuterium-labeled compounds [D ]-2b and [D ]-2b were
also synthesized and subjected to the standard reaction condi-
tions for the formation of products 4b, 5b and 6b. The corre-
Deuterium labeling experiments were conducted to gain further
insights into the reaction mechanism. For deuterium-labeled
sponding products [D
2 2 2 1
]-4b, [D ]-5b and [D ]-6b and [D ]-4b,
substrates [D
2 1
]-1a and [D ]-1n, the corresponding products
[
D ]-5b and [D ]-6b were produced in high yields with retention
1
1
[
D ]-3a and [D ]-3n were obtained without a deuterium shi,
2
1
of the deuterium content (Scheme 3 and 4). As can be seen from
the deuterium labeling experiment, the deuterated C–H bond
was not disturbed during the reaction process. Apparently, for
the formation of 4b, only the carbon skeleton was rearranged
and all the hydrogen atoms remained unaltered during the
reaction process; an allylic hydrogen shi was involved during
the formation of 5b and 6b.
suggesting that there is no carbon rearrangement of the allyl
Table 5 Au(I)-catalyzed cycloisomerization of 2 leading to 6
It appears that the reactions leading to 3 and 5 or 6 are
1
controlled by the nature of substituent R . The inherent rela-
tionship between them stimulated our further investigations.
Fortunately, by quenching the reaction of substrate 1j with DMS
aer 1 h at room temperature, we were able to capture 7j in 6%
yield, indicating that 7j was a key intermediate in the reaction
2
Scheme 3 Deuterium labeling experiment ([D ]-2b).
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0
gives intermediate B or its resonance structure B . Gold(I) car-
benoid-initiated ring expansion produces intermediate C,
0
which probably has other resonance structures illustrated as C
0
0
and C . Release of the catalyst from intermediate C affords
tricyclic cyclobutene 4 (Scheme 7, cycle I). An equilibrium
probably exists between tricyclic cyclobutene 4 and the gold
17
0
catalyst to give intermediate C , which can further undergo
subsequent transformations to generate other products. For
substrates having an aryl group without an ortho substituent,
0
the corresponding intermediate C undergoes cleavage of the
1
6
0
cyclopropyl ring to form cationic intermediates D and D ,
which are in resonance with each other. Subsequent 1,2-H shi
followed by release of the cationic Au(I) species results in
product 3 (Scheme 7, cycle II). On the other hand, for the
substrates having an aryl group with an ortho substituent or
1
Scheme 4 Deuterium labeling experiment ([D ]-2b).
0
having a benzyl group, the corresponding intermediate C
probably has another resonance structure depicted as cationic
0
0
20
intermediate C , which is probably more favorable. The
0
0
cationic intermediate C undergoes ring contraction to form
4
p,18
carbenoid intermediate E.
1,2-H shi of intermediate E
Scheme 5 Capture of compound 7j.
produces intermediate F, which is in equilibrium with
compound 5. Carbocation-initiated cyclopropane ring opening
of intermediate F forms intermediate G. Finally, compound 6 is
obtained aer the ring expansion process (Scheme 7, cycle III).
that leads to 1,4-cyclohexadiene 3j (Scheme 5; for the details, see
the ESI†).
Furthermore, the control experiment showed that 5a could
ꢀ
be afforded from 4a at 0 C in the presence of [JohnPhos-
Rationalization of ortho-substituent
effects
6
Au$MeCN]SbF (Scheme 6, eqn (1)). Under the standard reac-
tion conditions, both compounds 4a and 5a could be
transformed to product 6a in almost quantitative yields, indi-
cating that both compounds 4a and 5a are the intermediates for
the formation of product 6a (Scheme 6, eqn (2) and (3)).
For substrate 1 having an aryl group without an ortho-substit-
uent, 1,4-cyclohexadiene 3 could be produced. In contrast,
substrate 2 having an aryl group with an ortho-substituent
afforded three different products. Based on the proposed reac-
tion mechanism, we speculate that the stability of intermediate
D is the key point to affect the reaction path. As depicted in
Scheme 8, when the phenyl group is substituted at the ortho
position, it cannot effectively stabilize the cationic intermediate
since the steric hindrance makes the coplanar conformation of
the phenyl ring and the allylic carbocation become unfavorable
in energy. Furthermore, the benzyl group is also not good
enough to stabilize the carbocation intermediate. Thus, in all
these cases, the energy level of intermediate D is high and the
reaction probably prefers to undergo cycle III.
To understand these ortho-substituent effects, we performed
DFT calculations on the possible reaction pathways using
substrates 1a and 2m. For substrate 1a, the reaction energy
prole is depicted in Scheme 9. Initially, coordination of the
Au(I) catalyst to the alkyne moiety of substrate 1a generates gold
complex IN1. The gold complex IN1 undergoes a 6-endo-dig
cyclization to give a gold carbene intermediate IN2 via transi-
Proposed reaction pathways
Based on the deuterium labeling experiments, intermediate
trapping experiments and theoretical investigations (Schemes 9
and 10), some possible reaction pathways are ruled out and the
most reasonable mechanism is proposed in Scheme 7 (for
details, see Schemes S9 and S10 in the ESI†). Product 4 is
formed through a classical 1,5-enyne cyclization. Coordination
of gold(I) to the alkyne moiety of substrate 1 or 2 forms inter-
mediate A. Nucleophilic attack of the alkyne by the alkene unit
ꢁ1
tion state TS1 with an energy barrier of 14.8 kcal mol
.
Subsequently, the intermediate IN2 undergoes ring enlarge-
ment via transition state TS2 with an energy barrier of 16.0 kcal
ꢁ
1
mol , producing another intermediate IN3. The intermediate
IN3 can undergo two possible reaction pathways to obtain
products 3 and 5. In Path 1, the cleavage of the cyclopropane
ꢁ
1
Scheme 6 Reactions of 4a and 5a under standard conditions.
ring via TS3 with an energy barrier of 17.9 kcal mol leads to
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Scheme 7 A plausible mechanism for the formation of 3, 4, 5 and 6.
for Path 2. Transition state TS5 is higher in energy than tran-
ꢁ
1
sition state TS6 by 3.3 kcal mol , and intermediates IN4 and
IN6 along Path 1 are thermodynamically more stable than
ꢁ
1
intermediates IN5 and IN7 along Path 2, by 3.8 kcal mol and
ꢁ
1
9
.9 kcal mol , respectively. These calculation results indicate
that Path 1 is thermodynamically favorable and the reaction of
a is thermodynamically controlled, which may account for the
Scheme 8 Our speculation for the reaction path divergence.
1
fact that product 3 is experimentally obtained as the major
product if using 1a as substrate. For comparison, we switched
the ligand to PPh , and also investigated the possible reaction
3
pathways of substrate 1a (for details, see Scheme S11 in the
ESI†). The DFT calculation results indicate that the phosphorus
ligand does not signicantly affect the reaction energy prole.
This is in line with the experimental ndings that the product 3
can be obtained in acceptable yield in the presence of [PPh3-
the carbocation intermediate IN4. Subsequently, 1,2-H shi of
the intermediate via TS5 leads to intermediate IN6, which
undergoes deauration to give product 3. Transition state TS5 is
ꢁ1
located 18.6 kcal mol above intermediate IN3 and 0.7 kcal
ꢁ
1
mol above transition state TS3, indicating that the 1,2-H shi
step is the rate-limiting step for Path 1. Another possible reac-
tion pathway (Path 2) for the carbocation intermediate IN3 is
skeletal rearrangement via TS4 with an energy barrier of 10.6
AuCl]/AgSbF . From a practical use point of view, the JohnPhos
6
ligand is more stable due to its steric bulkiness in our reaction
conditions for gold catalysis. Moreover, for the comparison with
the substrates having an ortho-substituent, JohnPhos ligand is
chosen as the primary ligand for the gold catalysis.
We further investigated the reaction energy proles for the
reaction of substrate 2m having an aryl group with ortho-
substituent Br, and the results are shown in Scheme 10. In
ꢁ
1
kcal mol , leading to gold carbene intermediate IN5. Inter-
mediate IN5 also undergoes 1,2-H shi via TS6, affording
intermediate IN7, which undergoes deauration to give product
ꢁ
1
5
. Transition state TS6 is located 15.3 kcal mol above inter-
ꢁ
1
mediate IN3 and 4.7 kcal mol above transition state TS4,
indicating that the 1,2-H shi step is also the rate-limiting step
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Scheme 9 Calculated reaction pathway for the reaction of 1a having an aryl group without an ortho substituent.
ꢁ1
a similar manner, coordination of the Au(I) catalyst to the alkyne barrier of 19.6 kcal mol leads to the carbocation intermediate
moiety of substrate 2m generates gold complex IN8. The gold IN11. Subsequently, 1,2-H shi of the intermediate via TS11
complex IN8 undergoes a 6-endo-dig cyclization to give a gold leads to intermediate IN13, which undergoes deauration to give
ꢁ
1
carbene intermediate IN9 via transition state TS7, with an product 3. Transition state TS11 is located 20.4 kcal mol
ꢁ1
ꢁ1
energy barrier of 13.5 kcal mol . Subsequently, the interme- above intermediate IN10 and 0.8 kcal mol above transition
diate IN9 undergoes ring enlargement via transition state TS8 state TS9, indicating that the 1,2-H shi step is the rate-limiting
with an energy barrier of 17.1 kcal mol , producing another step for Path 3. Another possible reaction pathway (Path 4) for
ꢁ
1
intermediate IN10. The intermediate IN10 can also undergo two the carbocation intermediate IN10 is skeletal rearrangement via
ꢁ
1
possible reaction pathways to obtain products 3 and 5. In Path TS10 with an energy barrier of 8.9 kcal mol , leading to gold
, the cleavage of the cyclopropane ring via TS9 with an energy carbene intermediate IN12. Intermediate IN12 also undergoes
3
Scheme 10 Calculated reaction pathway for the reaction of 2m having an aryl group with an ortho substituent.
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1,2-H shi via TS12, affording intermediate IN14, which yield of product 3 was obtained using IPr as the ligand. There is
undergoes deauration to give product 5. Transition state TS12 is no signicant difference between the reaction energy prole
ꢁ
1
located 11.9 kcal mol above intermediate IN10 and 3.0 kcal along Path 4 and that along Path 6. The experimental results in
ꢁ
1
mol above transition state TS10, indicating that the 1,2-H Table 2 show that the catalysts affect the product selectivity,
shi step is also the rate-limiting step for Path 4. Due to the probably mainly due to the temperature effect, and are not
ortho substituent effect, the carbocation intermediate IN11 is signicantly inuenced by the ligand effect.
less stable than the gold carbene intermediate IN12 by 4.7 kcal
ꢁ
1
mol ; the energy gap between transition states TS11 and TS12
ꢁ1
is increased to 8.5 kcal mol , which is signicantly larger than
Rationalization of the temperature
ꢁ
1
that between TS5 and TS6 (3.3 kcal mol ), indicating that the
intermediate IN11 can less easily cross over this energy barrier.
The reaction using substrate 2m is probably kinetically
controlled, thus the kinetically favorable product 5 is obtained.
The calculation results can explain why using a substrate having
an aryl group with an ortho-substituent can give product 5 as the
major product in experiments. For comparison, we switched the
ligand to IPr, and also investigated the possible reaction path-
ways of substrate 2m, and the results are shown in Scheme 11.
In general, the calculated reaction energy proles using IPr as
the ligand are similar to those using JohnPhos as the ligand.
The carbocation intermediate IN18 is less stable than the gold
effect
The sterically bulky and electron-rich IPr ligand was crucial for
ꢀ
the selective formation of product 4 at ꢁ30 C because the
2
gold complex IPrAuNTf also becomes sterically bulky and
electron-rich and thus will be less reactive to activate the
alkene unit in 4. On the other hand, JohnPhos is a bulky
phosphine ligand as well; however, it is not as electron-rich as
IPr. Thus, compound 4 could be transformed into compound
ꢀ
5
at 0 C. At higher temperature, compound 6 was produced as
the nal product.
Compounds 5m and 6m could be transformed to
ꢁ
1
carbene intermediate IN19 by 7.7 kcal mol , which is similar to
their analogues IN11 and IN12, indicating that the key inter-
mediates' stabilities are hardly inuenced by the phosphorus
ligand. It is notable that the cleavage of the cyclopropane ring
0
0
compounds 5m and 6m by halogen–lithium exchange and
subsequent quenching with water, indicating that the bromine
atom at the ortho position can serve as a removable directing
group to control the reaction pathway, and it can be easily
removed when the reaction is complete (Scheme 12).
ꢁ1
via TS15 has an energy barrier of 22.2 kcal mol , which is
slightly higher than that of the 1,2-H shi step via TS17 in Path
In conclusion, a novel gold(I)-catalyzed cycloisomerization of
5
, thus the cleavage of the cyclopropane ring becomes the rate-
1,5-enynes containing a cyclopropane ring has been developed.
ꢁ1
limiting step. Moreover, the energy barrier (22.2 kcal mol ) of
the rate-limiting step along Path 5 is higher than that (20.4 kcal
mol ) of the rate-limiting step along Path 3, indicating that it is
more difficult to obtain product 3 using IPr as the ligand. This
result partially agrees with the experimental nding that a poor
The cyclopropane functionality in the substrates has a great
inuence on the reaction pathway, and the suggested gold
carbene intermediate I involving two cyclopropyl moieties is
critical to result in the divergent reaction pathways. With this
methodology, cyclobutane-fused 1,4-cyclohexadiene, 1,3-
19
ꢁ
1
Scheme 11 Calculated reaction pathway for the reaction of 2m having an aryl group with an ortho substituent, using IPr as the ligand.
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Notes and references
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Acknowledgements
We are grateful for the nancial support from the National
Basic Research Program of China (973)-2015CB856603, and the
National Natural Science Foundation of China (20472096,
2
2
1372241, 21361140350, 20672127, 21421091, 21372250,
1121062, 21302203, 20732008, and 21572052).
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