Ni(NHC)]-catalyzed cycloaddition of diynes and tropone: Apparent enone cycloaddition involving an 8π insertion

Article abstract of DOI:10.1021/ja5105206

A Ni/N-heterocyclic carbene catalyst couples diynes to the C(α)-C(β) double bond of tropone, a type of reaction that is unprecedented for metal-catalyzed cycloadditions with aromatic tropone. Many different diynes were efficiently coupled to afford [5-6-7] fused tricyclic products, while [5-7-6] fused tricyclic compounds were obtained as minor byproducts in a few cases. The reaction has broad substrate scope and tolerates a wide range of functional groups, and excellent regioselectivity is found with unsymmetrical diynes. Theoretical calculations show that the apparent enone cycloaddition occurs through a distinctive 8π insertion of tropone. The initial intramolecular oxidative cyclization of diyne produces the nickelacyclopentadiene intermediate. This intermediate undergoes an 8π insertion of tropone, and subsequent reductive elimination generates the [5-6-7] fused tricyclic product. This initial product undergoes two competing isomerizations, leading to the observed [5-6-7] and [5-7-6] fused tricyclic products.

Full text of DOI:10.1021/ja5105206

Article
pubs.acs.org/JACS
Ni(NHC)]-Catalyzed Cycloaddition of Diynes and Tropone: Apparent
Enone Cycloaddition Involving an 8π Insertion
Puneet Kumar,†,‡,§ Ashish Thakur,†,§ Xin Hong,∥ K. N. Houk,*,∥ and Janis Louie*,†
†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States
∥Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: A Ni/N-heterocyclic carbene catalyst couples
diynes to the C(α)−C(β) double bond of tropone, a type of
reaction that is unprecedented for metal-catalyzed cyclo-
additions with aromatic tropone. Many different diynes were
efficiently coupled to afford [5−6−7] fused tricyclic products,
while [5−7−6] fused tricyclic compounds were obtained as
minor byproducts in a few cases. The reaction has broad
substrate scope and tolerates a wide range of functional groups,
and excellent regioselectivity is found with unsymmetrical
diynes. Theoretical calculations show that the apparent enone cycloaddition occurs through a distinctive 8π insertion of tropone.
The initial intramolecular oxidative cyclization of diyne produces the nickelacyclopentadiene intermediate. This intermediate
undergoes an 8π insertion of tropone, and subsequent reductive elimination generates the [5−6−7] fused tricyclic product. This
initial product undergoes two competing isomerizations, leading to the observed [5−6−7] and [5−7−6] fused tricyclic products.
oxygen atom as in (8 + 2)9 and (8 + 3)10 cycloaddition reac-
ropone is a readily available seven-membered nonbenzenoid
tions (Figure 1a).11
Reactions involving tropone as an enone moiety are rare.
The exception involves disrupting the conjugation of tropone
by precomplexation with iron−carbonyl (eq 1).12 Although this
Taromatic compound that can undergo cycloadditions to
afford complex bridged motifs of a variety of natural products
and medicinally important compounds (Figure 1a).1−4 The
approach affords the desired nonbridged bicyclic products,
such reactions require stoichiometric amounts of metal com-
plexes as a protecting group for the other two double bonds.
This inability to utilize tropones as enones is unfortunate, since
selective activation of a single C−C π-bond in cycloaddition
would greatly expand the synthetic utility of tropones, given the
frequent occurrence of nonbridged seven-membered ring sys-
tems in biologically relevant compounds.4 We describe a solu-
tion to the long-standing problem of utilizing tropone as an
enone through the use of a highly effective nickel catalyst that
couples diynes with a single double bond of a tropone selec-
tively to form fused tricyclic frameworks (vs bridged frame-
works) without the need for precomplexation.
Figure 1. (a) Common tropone cycloadditions. (b) Tropone−
tropylium oxide resonance. (c) LUMO of tropone computed by
HF/6-311+G(d,p).
RESULTS AND DISCUSSION
■
tropone cycloaddition reactivity can be generally understood by
its resonance contributor, tropylium oxide (Figure 1b). This re-
sonance structure explains the dipolar nature of tropone3a and
the large LUMO coefficients at the alpha-positions (Figure 1c).5
Therefore, tropone cycloaddition reactions usually lead to bond
formations at the α-positions as in (6 + 2),6 (6 + 3),7 and
(6 + 4)8 cycloaddition reactions or in one α-position and the
Simple enones are known to undergo Ni-catalyzed cyclo-
addition with diynes (eq 2).13 However, these conditions fail to
provide any cycloadduct product with tropone as shown in
Received: October 13, 2014
© XXXX American Chemical Society
A
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Table 2. Ni-Catalyzed Cycloaddition of Diynes (3−19) and
a,b
Tropone (a)
Table 1. Ni-Catalyzed Cycloaddition of Diyne with
a
Tropone
b
b
entry
Ln
Ni:Ln
% conv of 1
% yield of 1a
1
2
PPh3
PCy3
P(OiPr)3
PPh2Me
P(o-tolyl)3
DPPF
1:2
1:2
1:2
1:2
1:2
1:1
1:1
1:1
1:1
1:1
1:2
1:2
1:2
1:2
1:2
>99
>99
>99
>99
>99
>99
85
14
29
14
9
3
4
5
3
6
4
7
BINAP
DPPB
6
8
>99
>99
>99
96
6
9
Xantphos
tBu-Xantphos
IMes
−
−
79
71
10
11
12
13
14
15
ItBu
98
c
IPr
>99
>99
>99
>99 (92)
c
SIPr
>99 (92)
c,d
SIPr
>99 (95)
a
Reaction conditions: 10 mol % of Ni(cod)2, 20 mol % of L, diyne
b
(1 equiv, 0.1 M), tropone (1.1 equiv), toluene, 60 °C, 5 h. Deter-
mined by GC using naphthalene as an internal standard. Isolated
yield. THF was used instead of toluene.
c
d
eq 3. Thus, we focused our investigation on discovering an
alternative Ni-catalyzed cycloaddition protocol.
Diyne 1 and tropone a were used as model substrates and
were subjected to a catalytic amount of Ni(0) and a variety of
phosphine and N-heterocyclic carbene (NHC) ligands (eq 4).
Reactions run with monodentate and bidentate phosphines
mostly afforded dimerization of diyne along with traces or low
amounts of the desired cycloadduct (Table 1, entry 1−10).
However, reactions run with NHCs resulted in good to excel-
lent yields of cycloadduct 1a, which couples the diyne with a
single C−C double bond of the tropone selectively (entries 11−15).
Ultimately, SIPr proved to be the best ligand. Further optimization
led to our final reaction conditions: diyne (1 equiv), tropone
(1.1 equiv), 3 mol % of Ni(cod)2, 6 mol % of SIPr, THF, 60 °C,
and 5 h.
a
Reaction conditions: diyne (1 equiv, 0.1 M), tropone (1.2 equiv),
b
3 mol % of Ni(cod)2, 6 mol % of SIPr, THF, 60 °C, 5 h. Isolated
yields (in black), ratio of major and minor cycloadducts (in blue),
c
ratio of major and minor regioisomers (in red). The ratios were
d
determined by 1H NMR of crude reaction mixture. The reac-
The model substrates afforded the desired product 1a along
with another isomer 1a′ in excellent yield and >90% selectivity
for 1a (eq 5).14 Similarly, cycloaddition of sulfonamide diyne 2
tion was performed with 10 mol % catalyst loading at room
temperature.
B
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Figure 4. The heterocoupling pathway B of [Ni(IPr)]-catalyzed cyclo-
addition between nona-2,7-diyne and tropone. Free energies (298 K)
with respect to 21 are shown in kcal/mol.
With optimized reaction conditions in hand, the substrate
scope was explored (Table 2). The cycloaddition occurred
smoothly with the diyne bearing a sulfone backbone to form 3a
along with minor isomer 3a′. Notably, this diyne is completely
unreactive in several reported Ni-catalyzed cycloadditions.16
Although Ni catalysts have been reported to catalyze the cyclo-
addition of nitriles and diynes to form pyridines,16b,d diyne 4,
which has a nitrile group in the backbone, selectively reacted
with tropone to afford the desired cycloadducts (4a and 4a′) in
excellent yield. Inspired by Carreira’s work, we performed the
cycloaddition reaction with 5, a diyne with a metabolically
Figure 2. Ortep diagram of 2a and 2b.
afforded a mixture of major and minor isomers 2a and 2a′
respectively, which on subsequent treatment with p-bromo-
benzoyl chloride/NEt3/DMAP afforded major isomer 2a in
74% yield and p-bromobenzoyl derivative of minor isomer (2b)
in 13% yield (eq 6) as crystalline solids (Figure 2). Surprisingly,
2b (and, therefore, 2a′ as well) has [5−7−6] ring fusion com-
pared to [5−6−7] in the case of the major isomer, 2a.15
Figure 3. The homocoupling pathway A of [Ni(IPr)]-catalyzed cycloaddition between nona-2,7-diyne 1 and tropone. Free energies (298 K) with
respect to 21 are shown in kcal/mol.
C
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The use of different aryl groups (i.e., 3,4-dimethoxyphenyl and
naphthyl) on alkyne terminals is also possible (10a and 11a).
Due to recent interest in indole bearing novel compounds,19
diynes 12 and 13 were investigated. Biaryl cycloadducts
(12a, 13a) were formed in very good yield and high regio-
selectivity. Interestingly, the regioselectivity was higher in the case
of 3-substituted indole diyne than 5-substituted indole diyne
(13a vs 12a). Cycloaddition of phenyl−ethyl diyne 14 and
phenyl−silyloxymethyl 15 afforded regioisomers 14a and 15a,
where the carbonyl resides next to the phenyl ring, exclusively,
while a diyne with covalently bound δ-tocopherol can also be
easily clicked together with tropone to afford regioselective cyclo-
adduct 16a. An unsymmetrical diyne bearing an internal gem-
dimethyl group reacted with tropone to afford an exclusive
regioisomer 17a, which suggests that regioselectivity is highly
dependent on the substituents on the alkyne units of a diyne
rather than backbone.20 The cycloaddition of unsymmetrical
isopropyl−methyl diyne (18) afforded products 18a and 18a′,
where the bulkier group is next to the carbonyl of tropone.
Cycloaddition of phenyl−isopropyl diyne 19 affords a product
where the isopropyl group is away from the carbonyl group
(19a), suggesting that electronic factors override the steric factors
(19a). Unfortunately, terminal diynes did not afford any cyclo-
addition product with tropone due to their high propensity to
oligomerize under our reaction conditions.21,22
Figure 5. Optimized structures, Gibbs free energies, and distortion and
interaction energies of transition states of 8π insertion (TS25) and 2π
insertion (TS37) of tropone. The Gibbs free energy changes (298 K)
with respect to 24 are shown in kcal/mol.
stable backbone,17 to give cycloadduct 5a in good yield along
with minor isomer 5a′. Aryl substituted internal diynes are one
of the most challenging substrates in Ni/NHC-catalyzed cyclo-
addition reactions.16e,18 Nevertheless, the reaction of aryl sub-
stituted symmetrical diynes with tropone afforded 6a and 7a in
good yields. Interestingly, no minor cycloadduct (6a′ or 7a′)
was obtained in these cases. To investigate the effect of elec-
tronics on the regioselectivity, we subjected unsymmetrical
diynes 8 and 9 to standard reaction conditions; remarkably,
exclusive formation of one regioisomer was detected (8a and 9a).
The lack of general methods to access troponoids prompted
our investigation on the ability to convert the cycloadduct
to a fully aromatized product. We found that compound 2a
Figure 6. Transition states for the intermoleculer insertion of tropone into Ni(IPr)−unsymmetrical diyne complexes.
D
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Figure 7. Proposed mechanism for the Ni-catalyzed cycloaddition of diynes and tropone.
can be consistently converted to tropone 20a by a three-step
protocol.23 The hydrogenation of alkene 2a led to a saturated
cycloheptanone, which was then subjected to dibromination.
Finally, didehydrobromination afforded the desired tropone,
20a (eq 7).
The tropone piece of complex 26 can coordinate to nickel in
four different fashions, generating the complexes 26 to 29.27
The four isomers have similar stabilities, and complex 29
undergoes reductive elimination via TS30 to give the product-
coordinated complex 31. Product extrusion from 31 is exergonic
by 2.8 kcal/mol to release the product and regenerate the nickel−
diyne complex 22. The tautomerization of intermediate complex
29 to 29-enol is endergonic by 5.8 kcal/mol, and subsequent
reductive elimination from 29-enol will form the 5−7−6 tricyclic
product; however, the irreversible reductive elimination via TS30
suggests that the 5−7−6 tricyclic product arises from Ni-free
tautomerization.
The calculations indicate that the resting state of pathway A
is [Ni(IPr)2] complex 21, and oxidative cyclization through
TS23 is the rate-limiting step of the catalytic cycle. The overall
reaction barrier is 20.4 kcal/mol, which is consistent with the
experimental conditions (60 °C, 5 h). In contrast, the hetero-
coupling pathway of [Ni(IPr)]-catalyzed cycloaddition between
nona-2,7-diyne and tropone displays higher free energies
(Figure 4). Specifically, from nickel−diyne complex 22, the inter-
molecular oxidative cyclization between alkyne and tropone can
occur via TS34, with the carbonyl group of tropone distal to the
forming C−C bond. This step requires a barrier of 42.5 kcal/mol
with respect to the [Ni(IPr)2] complex 21, which is much less
favorable as compared to the homocoupling pathway discussed
above (Figure 4). Alternatively, the intermolecular cyclization can
occur with the tropone carbonyl group proximal to the forming
C−C bond, as in TS36. TS36 is 31.6 kcal/mol higher in free
energy than the resting state 21, which is also less favorable than
the productive homocoupling pathway. Therefore, unlike other
COMPUTATIONAL MECHANISTIC ANALYSIS
■
We also undertook a mechanistic investigation of this reaction.
Specifically, we studied the catalytic cycles for [Ni(IPr)2]-
catalyzed cycloaddition of nona-2,7-diyne and tropone with DFT
calculations.24 Homocoupling,25 where two alkynes undergo
initial oxidative coupling, and heterocoupling,26 where an alkyne
and the tropone undergo initial oxidative coupling, were both
investigated.
The free energy changes for the homocoupling pathway are
shown in Figure 3. From [Ni(IPr)2] complex 21, the coordi-
nation of diyne to form intermediate 22 is endergonic by
7.0 kcal/mol. Subsequent intramolecular oxidative cyclization
via TS23 requires a 13.4 kcal/mol barrier with respect to 22,
generating the metallacyclopentadiene intermediate 24. This
intermediate undergoes a facile 8π insertion (instead of 2π
insertion, vide infra) of tropone via TS25, with a barrier of only
9.8 kcal/mol. The 8π insertion produces the eight-membered ring
intermediate 26 with the tropone oxygen coordinated to nickel.
E
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Ni-catalyzed couplings between alkynes and carbonyls,16e,28
heterocoupling mechanism is not operative in the [Ni(IPr)]-
catalyzed cycloaddition between diyne and tropone.
a
tropone in the cycloaddition with diynes. We have also
successfully converted these cycloadducts to useful troponoids.
The mechanism of this novel cycloaddition reaction has been
investigated using DFT calculations. It involves a unique 8π
insertion of tropone to form the observed major and minor
products. The mechanistic studies to further understand this
unique reactivity of tropone and application of this chemistry
are underway in our laboratories.
Next, insertion of the tropone was investigated, and two
probable pathways emerged: a traditional 2π insertion and a
distinctive 8π insertion. The transition states of 8π (TS25) and
2π insertion (TS37) of tropone were both located, and their free
energies and structures are shown in Figure 5.29 Interestingly, the
8π insertion is found to be more favorable by 12.3 kcal/mol.
We studied the origins of this preference by employing
the distortion/interaction model on TS25 and TS37.30 The
distortion energy reflects the structural changes from nickel
complex 24 or tropone to the corresponding geometries in the
transition states, and the interaction energy is the energy of
interactions between the distorted fragments, computed as the
difference between the activation energy and the total distortion
energy. The difference between the distortion energies of TS25
and TS37 is the major reason for the preference for 8π inser-
tion. The distortion energy is 17.8 kcal/mol energy for 24 and
13.7 kcal/mol energy for tropone to achieve the distorted geo-
metries in TS25, while it requires much larger distortions
(24.3 kcal/mol for 24 and 16.6 kcal/mol for tropone) in TS37.
Stronger steric repulsions are generated between the nickel-
acyclopentadiene moiety and tropone in TS37 as compared to
those in TS25. This difference between the steric repulsions
eventually leads to the preference of the unconventional 8π inser-
tion, and this is the highest order of poly-π insertion so far.31
Regioselectivity. The transition states for the 8π insertion
of tropone with unsymmetrical diynes were also studied. For
the isopropyl−methyl diyne (Figure 6), the transition state
TS38-C1 that contains the bulky isopropyl group on the diyne
next to tropone is more stable than TS38-C2 by 0.7 kcal/mol
to avoid steric repulsions between the isopropyl group and IPr
ligand. For phenyl−methyl diyne, the transition state TS39-C1
is 4.7 kcal/mol more stable than TS39-C2 mainly due to the
steric repulsions between the phenyl group and
the bulky NHC ligand in TS39-C1. Also, for phenyl−isopropyl
diyne, the phenyl group is more sterically demanding, and a 4.0
kcal/mol preference to the TS40-C1 is found.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental information, synthesis of diynes, spec-
troscopic characterizations, crystallographic analyses (CIF), and
computational data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
louie@chem.utah.edu
houk@chem.ucla.edu
Present Address
‡P.K.: Discovery Chemistry, Merck & Co. Inc., Rahway,
New Jersey, United States.
Author Contributions
§P.K. and A.T. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.L. thanks the NIH (GM076125) and NSF (CHE-0911017)
for financial support of this work. K.N.H. thanks the NSF
(CHE-1361104) for financial support of this research. We
thank Drs. J. Muller and A. Arif for providing HRMS and X-ray
spectroscopic data, respectively. Calculations were performed
on the Hoffman2 Cluster at UCLA and the Extreme Science
and Engineering Discovery Environment (XSEDE), which is
supported by the NSF (OCI-1053575).
Overall, our data suggest that Ni-catalyzed cycloaddition
occurs via the mechanism shown in Figure 7. The homo-oxidative
coupling of diyne on Ni(0) forms Ni(II)−cyclopentadiene inter-
mediate I that undergoes 8π insertion of tropone to afford seven-
membered ring complex II. Intermediate II isomerizes from
oxygen coordination to η3-coordination resulting in intermediate
III, which can subsequently isomerize to an η3-coordinated-
Ni(II) complex V through intermediates IV. Finally intermediate
V reductively eliminates to give VI, which releases the tricyclic
product, VII, and regenerates the Ni(0) catalyst. At this point,
compound VII can preferentially aromatize via sigmatropic shifts
to afford major product VIII. However, a minor pathway involves
tautomerization of VII to cycloheptatrienol IX, which undergoes
further 6π electrocyclization to afford an interesting bis(divinyl)−
cyclopropane intermediate, X. Intermediate X can either revert to
IX or irreversibly rearrange to [5−7−6] fused intermediate XI,
which undergoes further sigmatropic shifts to yield the observed
minor product, XII. This sigmatropic shift could be catalyzed
by a trace amount of water through the bridge of one or multiple
molecules of water.32 Due to the uncertainty of the catalyst,
we did not perform computational studies on the isomerization of
the tricyclic product VII.
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computed with the M06 method, and the SDD basis set for nickel and
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included in the Supporting Information.
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1
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favorable ones are shown in Figure 5.
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