Catalytic Cyclooligomerization of Enones with Three Methylene Equivalents

Article abstract of DOI:10.1021/jacs.8b08296

Cyclic structures are highly represented in organic molecules, motivating a wealth of catalytic methods targeting their synthesis. Among the various ring-forming processes, cyclooligomerization reactions possess several attractive features but require addressing a unique challenge associated with controlling ring-size selectivity. Here we describe the catalytic reductive cocyclooligomerization of an enone and three carbene equivalents to generate a cyclopentane, a process that constitutes a formal [2 + 1 + 1 + 1]-cycloaddition. The reaction is promoted by a (quinox)Ni catalyst and uses CH₂Cl₂/Zn as the C₁ component. Mechanistic studies are consistent with a metallacycle-based pathway, featuring sequential migratory insertions of multiple carbene equivalents to yield cycloalkanes larger than cyclopropanes.

Full text of DOI:10.1021/jacs.8b08296

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Communication
Catalytic Cyclooligomerization of Enones with Three Methylene Equivalents
Conner Farley, You-Yun Zhou, Nishit Banka, and Christopher Uyeda
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Catalytic Cyclooligomerization of Enones with Three Methylene
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Conner M. Farley, You-Yun Zhou, Nishit Banka, and Christopher Uyeda*
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
Supporting Information Placeholder
ABSTRACT: Cyclic structures are highly represented in organic
molecules, motivating a wealth of catalytic methods targeting their
synthesis. Among the various ring-forming processes, cyclooli-
gomerization reactions possess several attractive features but re-
quire addressing a unique challenge associated with controlling
ring-size selectivity. Here we describe the catalytic reductive co-
cyclooligomerization of an enone and three carbene equivalents to
generate a cyclopentane, a process that constitutes a formal [2 + 1
+ 1 + 1]-cycloaddition. The reaction is promoted by a (Quinox)Ni
catalyst and uses CH2Cl2/Zn as the C1 component. Mechanistic
studies are consistent with a metallacycle-based pathway, featuring
sequential migratory insertions of multiple carbene equivalents to
yield cycloalkanes larger than cyclopropanes.
Cyclooligomerization reactions are a mechanistically interesting
subclass of cycloadditions that currently have limited utility in or-
ganic synthesis.1 The potential value of these reactions derives
from their ability to directly assemble cyclic molecules from the
repeated coupling of a simple building block. However, this same
feature introduces a significant challenge associated with control-
ling ring-size selectivity. The most prominent class of cyclooli-
gomerization reactions involves the use of alkynes as substrates.2
Cyclotrimers are favored under most transition metal-catalyzed
conditions due to the high thermodynamic stability of benzenes rel-
ative to cyclobutadienes, cyclooctatetraenes, and higher order an-
nulenes. Cyclooligomerization reactions using other -compo-
nents, such as 1,3-dienes1a,3 and allenes,4 have also been studied but
generally exhibit poor selectivity and narrow substrate scopes.
Catalytic alkyne cyclotrimerizations are commonly initiated by
an oxidative coupling reaction at a low-valent metal center to form
a metallacyclopentadiene (Figure 1a).5 This intermediate then un-
dergoes ring expansion through additional alkyne insertion events
until the cyclic product is eliminated from the catalyst. In principle,
a related mechanism may be accessible using a C1 component as
Figure 1. Cyclooligomerization Strategies for the Synthesis of Cy-
clic Molecules. (a) Transition metal-catalyzed cyclotrimerization
the monomer unit (Figure 1b). For example, a [2 + 2]-cycloaddition
between a M=CR2 species and an alkene would likewise generate
reactions of alkynes proceeding through metallacyclic intermedi-
a metallacycle, in this case a saturated metallacyclobutane. The re-
ates. (b) A proposed cyclooligomerization reaction using a carbene
action would then propagate by iterative insertions of carbene
as the propagating monomer. (c) A catalytic reductive [2 + 1 + 1 +
equivalents and terminate by C–C reductive elimination. Because
1]-cycloaddition of enones with CH2Cl2/Zn to generate cyclopen-
the cycloalkane would be constructed one carbon at a time, any ring
tanes.
size is potentially accessible by this pathway. Here, we describe a
catalytic reductive co-cyclooligomerization of an enone and three
methylene equivalents to generate a cyclopentane (Figure 1c). The
reaction constitutes a formal [2 + 1 + 1 + 1]-cycloaddition and uses
CH2Cl2 as the C1 partner in combination with Zn metal as a stoi-
chiometric reductant.
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Table 1. Effect of Catalyst Structure on Ring-Size Selectivity.a,b
1
2
3
4
5
6
Ni(acac)2 (15 mol%)
Ligand
O
(15 mol%)
Ph
+
CH2Cl2
Ph
Ph
Zn (6.0 equiv)
22 °C, 24 h
DMA
Ph
Ph
Ph
Ph
Ph
O
(excess)
O
Ph
O
O
Ph
7
8
C3
2
C4
C5
3
C6
1
(not detected)
(not detected)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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60
Ph
Me Me
N
O
O
O
N
N
N
Ph
N
N
N
N
N
Ph
Ph
N
t-Bu
L2:
L4:
L6:
L8:
L10:
+71%
–63%
–28%
–3%
+41%
Excess
C5
Excess
C3
t-Bu
O
t-Bu
O
O
N
Me2N
Me
N
N
t-Bu
NMe2
N
N
N
N
t-Bu
N
t-Bu
L1:
L3:
L5:
L7:
–89%
–63%
–21%
+23%
L9:
+49%
Entry
1
Metal Source
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(dme)Br2
Co(acac)2
Fe(acac)2
Ni(acac)2
Ligand
L1
Conversion of 1
38%
Yield C3 (2)
36%
26%
27%
16%
26%
32%
18%
25%
21%
12%
21%
0%
Yield C5 (3)
2%
2
40%
6%
L2
3
38%
6%
L3
4
85%
9%
L4
5
93%
17%
30%
29%
60%
62%
70%
42%
0%
L5
6
92%
L6
7
92%
L7
8
85%
L8
9
89%
L9
10
11
12
13
14
95%
L10
L10
L10
L10
None
85%
0%
46%
0%
0%
10%
0%
0%
aConversions of 1, yields of 2 (C3), and yields of 3 (C5) were determined from crude reaction mixtures by GC analysis against mesitylene
as an internal standard. Reaction conditions: 1 (0.7 mmol, 1.0 equiv), Zn (6.0 equiv), metal source (0.15 equiv), ligand (0.15 equiv), 1.25:1
CH2Cl2/DMA (0.3 mL). Selectivities for cyclopropane vs. cyclopentane formation are expressed as excess values, defined as: [(C5–
b
C3)/(C5+C3)]100%.
We discovered the reductive cyclooligomerization unexpectedly
while studying transition metal-catalyzed variants of the Simmons–
Smith reaction. The key intermediates of the classical Simmons–
Smith reaction are Zn carbenoids (XZnCH2Y species), which are
electrophilic in character and known to react preferentially with
electron-rich alkenes.6 Kanai observed that electron-deficient al-
kenes, such as enones, are also amenable to cyclopropanation under
CH2X2/Zn conditions by the addition of NiX2 salts in catalytic load-
ings.7 The active carbenoid species could not be unambiguously
identified but was hypothesized to be a nucleophilic Ni=CH2 com-
plex that undergoes cyclopropanation by a stepwise [2 + 2]-cy-
cloaddition/C–C reductive elimination pathway. Studies by
Grubbs, Miyashita,8 and Hillhouse9 probing the stoichiometric re-
activity of Ni=CR2 species and their associated nickelacyclobu-
tanes lend credence to this proposal.
Our initial interest was in examining ligand effects in the nickel-
catalyzed Simmons–Smith reaction. Accordingly, catalysts gener-
ated from Ni(acac)2 and nitrogen-based bidentate ligands (L1–L10)
were tested in the cyclopropanation of model enone 1 (Table 1).
The relatively inert CH2Cl2 reagent was selected as the methylene
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(a)
1
2
3
4
5
Ni(acac)2 (15 mol%)
(±)-t-Bu-Quinox (15 mol%)
O
+
CH2Cl2
Zn (6.0 equiv)
DMA, 22 °C, 24 h
O
(excess)
O
6
C5
(±)-
C3
(±)-
7
4
(±)-(t-Bu-Quinox)Ni(acac)2
8
9
3
5
6
7
8
R = H
71% Yield (5.8:1 C5/C3)
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R = F
68% Yield (5.9:1 C5/C3)
71% Yield (9.1:1 C5/C3)
62% Yield (>20:1 C5/C3)
R = CF3
R = CN
Ph
R
Ph
OBn
O
O
R = SMe 51% Yield (5.4:1 C5/C3)
R = OMe 41% Yield (3.8:1 C5/C3)
Ph
O
9
11 54% Yield
(5.6:1 C5/C3)
12 72% Yield
(>20:1 C5/C3)
10
R = Cl
72% Yield (6.7:1 C5/C3)
Boc
F
F
N
MeO
Me
O
Ph
Ph
O
O
O
N
Bn
MeO
13
14
15
16
77% Yield
(7.7:1 C5/C3)
57% Yield
(5.7:1 C5/C3)
63% Yield
(6.3:1 C5/C3)
50 % Yield
(3.8:1 C5/C3)
Me
O
OMe
Ph
O
Me
Me
N
F
O
F
Cl
O
O
O
O
17
18
19
20
62% Yield
(7.1:1 C5/C3)
42% Yield
(2.9:1 C5/C3)
78% Yield
(>20:1 C5/C3)
69% Yield
(4.3:1 C5/C3)
Me
=
O
Ph
Ph
Me
Ph
O
O
OMe
21
22
23
50% Yield
(6.1:1 C5/C3)
37% Yield
(1.4:1 C5/C3)
45% Yield
(2.2:1 C5/C3)
(b)
mCPBA (6.0 equiv)
TFA (2.0 equiv)
mCPBA (6.0 equiv)
TFA (2.0 equiv)
O
O
MeO
F3C
22 °C, 48 h, CH2Cl2
45 °C, 48 h, CH2Cl2
O
Ar
O
Ph
Ph
Ph
Ar
Ph
O
O
24
25
80% Yield
(rr = 14:1)
65% Yield
(rr = >20:1)
Figure 2. Substrate Scope Studies. (a) Yields are of the isolated cyclopentane following purification. C5/C3 ratios were determined from the
crude reaction mixtures by 1H NMR integration. Reaction conditions: enone (1.0 equiv, 0.21 mmol); Zn (6.0 equiv); Ni(acac)2 (0.15 equiv);
(±)-L10 (0.15 equiv); CH2Cl2 (0.5 mL); DMA (0.4 mL); 22 °C, 16 h. (b) Baeyer–Villiger oxidations of aryl cyclopentyl ketone products.
source due to the absence of any background cyclopropanation us-
ing Zn as a stoichiometric reductant. Across the range of ligand
types examined, the yield of cyclopropane 2 was found to vary sig-
nificantly but never exceed 36%. GC-MS analyses of the crude re-
action mixtures indicated the formation of a single major byproduct
with a mass corresponding to the enone (1) bearing three additional
CH2 equivalents. Subsequent isolation and spectroscopic character-
ization of this species revealed its structure to be a trans-disubsti-
tuted cyclopentane, derived from a formal reductive [2 + 1 + 1 +
1]-cycloaddition process. To the extent that other cyclooligomers,
such as cyclobutanes or cyclohexanes, are formed, they fall below
the limits of GC-MS detection—masses corresponding to these
other cyclooligomers are found in trace quantities using other
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the substituent  parameters ( = 0.45).14 Electron-withdrawing
substituents result in the highest selectivities for cyclopentane for-
mation. One possible interpretation of this trend is in the context of
the metallacycle-based mechanism proposed by Kanai. In this path-
way, the selectivity for cyclopropanation vs. cyclooligomerization
would be governed by the relative rates of reductive elimination
(termination) and carbene insertion (propagation). Carbon–carbon
reductive elimination reactions are known to be accelerated by the
presence of an electron-donating group conjugated to one of the
carbons undergoing bond formation—electron-donating groups
generally destabilize M–C bonds to a greater extent than the prod-
uct C–C bond.15 On the other hand, the carbene insertion step
would likely be insensitive to the electronic properties of the aryl
group. Previous kinetics studies have shown that CO migratory in-
sertion reactions occur preferentially at more electron-rich M–C
bonds.16 The analogous process in the reductive cyclooligomeriza-
tion would therefore favor carbene insertion into the Ni–alkyl over
the Ni–enolate bond such that the aryl group would exert only an
indirect effect on the rate of this step.
enones. The ratio of cyclopropane to cyclopentane is strongly de-
pendent on the identity of the supporting ligand. For example, t-
Bu-Biox L1 forms cyclopropane nearly exclusively (2:3 = 18:1),
whereas t-Bu-Quinox L10 is selective for cyclopentane formation
(2:3 = 1:5.8).
1
2
3
4
5
6
7
8
Summarized in Figure 2a is the substrate scope of the nickel-
catalyzed reductive cyclooligomerization reaction under conditions
that were optimized for cyclopentane formation. Yields are of the
isolated cyclopentane following separation from the cyclopropane
byproduct. Common functional groups are tolerated, including ni-
triles, ethers, protected alcohols, protected amines, electron-rich
heterocycles, and esters. Thioethers are susceptible to ylide for-
mation in the Simmons–Smith reaction but are left untouched un-
der the catalytic cyclooligomerization conditions (8).10 Likewise,
aryl chlorides, which participate in nickel-catalyzed reductive
cross-coupling reactions,11 are not competitively activated. A sub-
strate possessing two alkenes, one conjugated with a ketone and the
other substituted only with alkyl groups, reacts exclusively at the
electron-deficient alkene (19). The highest selectivities for cyclo-
pentane formation were observed using substrates containing an
aryl ketone and an alkyl substituent at the -position of the alkene.
For example, methyl ketone 22 and chalcone 23, which do not ful-
fill these criteria, were viable substrates for the reaction but af-
forded only modest selectivities for cyclopentanation (≤2.2:1). The
product of this latter reaction (23) proved to be a crystalline solid,
whose structure was assigned by X-ray diffraction analysis.
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In summary, zinc carbenoid additions to alkenes have been ex-
tensively studied since the seminal work of Emschwiller,17 Sim-
mons, and Smith.18 However, in no cases have these reactions been
observed to access pathways that lead to multiple CH2 addition,
presumably due to the concerted nature of the carbene transfer
mechanism. In this context, transition metal-bound carbenes are at-
tractive as alternative CH2 transfer agents due to their potential to
react through stepwise organometallic pathways. By intercepting
transient metallacyclic intermediates prior to C–C reductive elimi-
nation, it is possible to develop new transformations that form ring
systems other than cyclopropanes. This strategy is demonstrated
here in the context of a nickel-catalyzed [2 + 1 + 1 + 1]-cycloaddi-
tion of enones using three methylene equivalents derived from
CH2Cl2 and six reducing equivalents supplied by Zn metal. To-
gether, these results point to opportunities for the development of
other multi-component cycloaddition reactions using reductively
generated CH2 as a C1 partner.
The aryl ketones present in the cyclopentanation products may
be converted to other useful functional groups by the Baeyer–Vil-
liger oxidation (Figure 2b).12 For example, 9 bearing an electron-
rich 4-methoxyphenyl group is oxidized to ester 24 with high regi-
oselectivity (rr = 14:1). The alternative regioisomeric ester is also
accessible by employing the electron-deficient 4-trifluoromethyl
group (25), which possesses a low migratory aptitude (rr = >20:1).
Upon ester hydrolysis, the former product would provide a cyclo-
pentane carboxylic acid and the latter a cyclopentanol.
Given the unusual nature of this transformation, our first mech-
anistic experiment sought to confirm the origin of the –(CH2)3–
fragment in product 3 (Figure 3a). When the catalytic cyclopen-
tanation of 1 was conducted using CD2Cl2 in the place of CH2Cl2,
the expected CD2-incorporation was observed to form 3-d6 (60%
isolated yield). Second, a tandem cyclopropanation–ring-opening
mechanism was ruled out by subjecting the separately synthesized
cyclopropane 2 to the standard catalytic condition (Figure 3b). In
this experiment, the cyclopropane was recovered in >98% yield,
and no conversion to cyclopentane 3 was observed. Third, we ex-
amined a potential mechanism involving the oxidative coupling of
enone 1 with ethylene, which could be generated from the reductive
coupling of two CH2Cl2 equivalents (Figure 3c). Miyashita previ-
ously observed the formation of ethylene from the dimerization of
a proposed transient Ni=CH2 species.8b Furthermore, ethylene is
known to undergo nickel-mediated oxidative coupling reactions
with electron-deficient -systems.13 The catalytic cyclopentanation
of enone 1 was carried out using labelled CD2Cl2 under an atmos-
phere of non-deuterated ethylene gas. The presence of ethylene was
found to inhibit the rate of cyclopentanation, but product 3-d6 was
nonetheless obtained in fully deuterium-labeled form. This result
suggests that either ethylene is not an intermediate in the reaction
or that it is generated but remains tightly bound to Ni and thus can-
not exchange with free ethylene.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
X-ray crystallography data (CIF)
Experimental procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*cuyeda@purdue.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was supported by the NIH (R35 GM124791). X-ray
diffraction data were collected using an instrument funded by the
NSF (CHE-1625543). We thank Matthias Zeller for assistance with
X-ray crystallography. C.U. is an Alfred. P. Sloan Foundation Re-
search Fellow.
Finally, during our substrate scope studies, we noted a pro-
nounced dependence of the selectivity for cyclopropane vs. cyclo-
pentane formation on the electronic properties of the aryl ketone
(Figure 3d). For a series of 4-substituted aryl enones (3, 5–10),
there is a linear relation between the selectivity values (C5/C3) and
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Figure 3. Mechanistic Studies. (a) Experiment identifying the origin of the –(CH2)3– fragment in product 3. (b) Excluding a mechanism
involving cyclopropane ring-opening. (c) Excluding a mechanism involving a coupling of enone 1 and ethylene. (d) Hammett plot of the
C5/C3 selectivity vs. the substituent  parameters. (e) A proposed cyclooligomerization mechanism involving metallacycle ring expansion.
The branch point for cyclopentane vs. cyclopropane formation is highlighted.
(4) Benson, R. E.; Lindsey, R. V. "Chemistry of allene. I.
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