Sequential Conia-ene-type cyclization and Negishi coupling by cooperative functions of B(C6F5)3, ZnI2, Pd(PPh3)4and an amine

Article abstract of DOI:10.1039/d0ob01678k

We disclose a method for sequential Conia-ene-type cyclization/Negishi coupling for the union of alkynyl ketones and aryl iodides. This process is promoted through cooperative actions of Lewis acidic B(C₆F₅)₃, ZnI₂

Full text of DOI:10.1039/d0ob01678k

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DOI: 10.1039/D0OB01678K
COMMUNICATION
Sequential Conia-Ene-Type Cyclization and Negishi Coupling by
Cooperative Functions of B(C6F5)3, ZnI2, Pd(PPh3)4 and an Amine
Min Cao,a Ahmet Yesilcimen,a Soumil Prasad,a Jason Genova,a Tanner Myers,a and
Received 00th January 20xx,
Accepted 00th January 20xx
Masayuki Wasa*a
DOI: 10.1039/x0xx00000x
We disclose
a
method for sequential Conia-ene-type chiral BoxZn-activated alkyne units, followed by protonation
cyclization/Negishi coupling for the union of alkynyl ketones and of the resulting alkenyl ZnLn intermediate by [H–PMP] provides
aryl iodides. This process is promoted through cooperative actions the desired cyclopentene derivative 2a in up to 97:3 er. No C–C
of Lewis acidic B(C6F5)3, ZnI2, Pd-based complex, and a Brønsted bond formation was observed in the absence of each one of the
basic amine. The three Lewis acid catalysts with potential three catalysts. However, the roles of LnZn–Box complex, which
overlapping functions play their independent roles as activators of could activate either carbonyl and/or alkyne units of 1a,
carbonyl group, alkyne moiety, and alkenyl zinc intermediate, remained undetermined.6
respectively. A variety of 1,2,3-substituted cyclopentenes can be
A: Direct enantioselective Conia-ene-type cyclizations of alkynyl ketones
synthesized with high efficiency.
cat.
cat.
B(C6F5)3
PMP
Ar3B
O
O
O
Cooperative Lewis acid/Lewis base catalysts can promote
the union of nucleophilic and electrophilic intermediates that
are generated in situ from substrates that would not react
efficiently using a single acid or base catalyst.1-2 This mode of
substrate activation has been widely applied to the synthesis of
essential intermediates for bioactive compounds and natural
product synthesis.1-2 However, a fundamental problem remains
unaddressed. Specifically, undesirable catalyst deactivation
often occurs in a reaction mixture which contains Lewis acid and
base catalysts, together with other acid- and/or base-sensitive
substrates, intermediates, and products. Consequently, these
processes typically possess limited substrate scopes, poor
efficiency, and modest functional group tolerance.1-2 Such acid–
base complexation becomes more problematic when three or
more independent catalysts that can form stable acid/base
adducts are involved.
One approach to overcome the mutual quenching problem
has been to utilize a pair of Lewis acid and base catalysts that
have limited affinity to form stable adducts due to their steric
hindrance and electronic disparity.3 Using these “frustrated”
Lewis pair catalysts,4 we developed enantioselective Conia-ene-
type cyclization5 of alkynyl ketones 1a (Scheme 1A). We
proposed that Brønsted basic 1,2,2,6,6-pentamethylpiperidine
(PMP) deprotonates B(C6F5)3-activated carbonyl unit of 1a to
afford a boron–enolate and [H–PMP] (I). Enantioselective 5-
endo-dig carbocyclization involving the boron–enolate and
Ph
R
H
R1
Ph
H
H
ZnL*n
Bn Bn
cat.
H
n-Pr
O
O
R3N
R2
n-Pr
I
2a
, 95% yield
97:3 er
N
I
N
I
1a
Zn
Ph
Ph
B: Sequential Conia-ene-type cyclizations/Negishi coupling reaction
O
O
B(C6F5)3 1.0 equiv. NR3
cat.
R
R1
Ar I
Ar
H
+
R
Pd(PPh3)n
R1
R2
ZnI2
cat.
cat.
R2
3
1
4
"Frustrated" acid/base catalysts
O
Proposed mechanism:
R
R1
O
H
+
Ar
I
Ar
ZnI2
B(C6F5)3
R
1
R2
R1
R2
Pd(PPh3)n
NR3
4
reductive
elimination
Ar3B
Ar3B
O
Ar
O
Pd(PPh3)n
R
R
R1
H
R1
Ar
I
R2
ZnI2
Pd(PPh3)n
R3N
R2
ZnI2
II
V
transmetalation
Ar3B
R3N
Ar
O
Pd(PPh3)n
I
R
Ar3B
5-endo-dig
cyclization
R1
I
O
Zn
ZnI
R
H
I
IV
R2
Pd(PPh3)n
R1
R2
Ar
III
a. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut
Hill, Massachusetts 02467, United States.
I
H
R3N
I
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1. Transformations involving 5-endo-dig cycloaddition
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can be promoted by cooperative functions of the Pd-based complex
To shed light on the mechanism of the Conia-ene-type
reaction, we investigated if the proposed alkenyl ZnI
intermediate IV derived from 1 by 5-endo-dig carbocyclization
(via 1  II  III  IV; Scheme 1B) can undergo transmetallation
with an appropriate Pd(II)-based complex (IV  V). The latter
species may be formed in situ through oxidative addition of
Pd(PPh3)4 and an aryl iodide 3. The resulting [(Ar)(I)PdII(PPh3)n]
V can undergo CAr bond forming reductive elimination to
afford 1,2,3-substituted cyclopentene derivative 4. The
sequential Conia-ene-type carbocyclization/Negishi coupling
reactions could provide evidence supporting the mechanistic
hypothesis that the -philic Zn-based catalyst is responsible for
activation of alkyne unit in 1, thereby generating IV.7-8 Here, we
describe a process promoted by B(C6F5)3, N-alkylamine, ZnI2,
and Pd(PPh3)4 that play their independent catalytic roles while
overcoming the undesirable acid–base complexation to afford
1,2,3-substituted cyclopentenes in high efficiency.
View Article Online
and PMP.9 This process was found to require a stoichiometric
DOI: 10.1039/D0OB01678K
amount of PMP because the formation of [PMP–H]+[I]– in the 5-endo-
dig carbocyclization step (III  IV; Scheme 1B) may inhibit the
regeneration of PMP; when the loading of PMP was lowered to 50
mol%, 4b was obtained in 52% (entry 6). When the loading of ZnI2
was lowered to 20 mol%, the yield of 4b declined to 41% (entry 7).10
This sequential cycloaddition/cross-coupling reaction could proceed
with a minimal amount of Pd(PPh3)4 (1.0 mol%), as 4b could be
obtained in >95% yield (entry 8). Under none of the reaction
conditions tested, PdLn-catalyzed -arylation of 1b-derived enolate
was observed.11
A variety of alkynyl ketones with different carbonyl and
alkyne substituents proved to be suitable substrates for the
sequential Conia-ene-type carbocyclization/Negishi coupling
with iodobenzene 3a (4b–4g; Table 2). Phenyl, naphthalen-2-yl,
2-methoxyphenyl, and furan-2-yl-substituted ketones gave the
corresponding products (4b–4f) in 65 to 98% yield. An alkyl
substituted ketone was also found to be a suitable substrate as
To begin, we probed the ability of B(C6F5)3, PMP, ZnI2, and
Pd(PPh3)4 to catalyze the cyclization of 1-phenylnon-5-yn-1-one
1b to give the alkenyl ZnI complex IV, followed by Negishi
coupling of IV with iodobenzene 3a (CH2Cl2, 12 h, 22 °C) to 4g was obtained in 91% yield. However, the use of internal
generate 4b (Table 1). The combination of 10 mol% B(C6F5)3, 1.0
equivalent of PMP, 50 mol% ZnI2, and 2.0 mol% Pd(PPh3)4,
produced 4b in >95% yield (entry 1). In addition, cyclopentene
Table 2. Sequential Conia-Ene-Type Carbocyclization/Negishi
Coupling Reactions with Different Ketones a,b
O
10 mol%
B(C6F5)3
O
derivative 2b formed by protonation of cyclopentene–ZnI
intermediate was obtained in <5% yield. In the absence of
Pd(PPh3)4, only 2b was generated in >95% yield (entry 2). When
ZnI2 or PMP was not added, neither 4b nor 2b were produced
(entries 3–4). However, PMP, ZnI2, and Pd(PPh3)4 were found to
promote the formation of 4b in the absence of B(C6F5)3,
although only 20% yield of 4b was obtained (entry 5). This
observation suggests that deprotonation of alkynyl ketone 1b
R1
ZnI2
50 mol%
R1
+
Ar
I
H
1.0 mol% Pd(PPh3)4
100 mol% PMP
R2
Ar
R2
CH2Cl2, 22 °C, 12 h
1
3
4b 4m

O
O
O
Me
Et
Me
Ph
Ph
Ph
Table 1. Evaluation of Reaction Parameters a,b
4b
4c
4d
, 95% yield
O
, 98% yield
O
, 91% yield
O
B(C6F5)3
ZnI2
cat.
cat.
cat.
O
O
MeO
O
PhI
+
+
O
H
n-Bu
Pd(PPh3)4
PMP
Me
Me
Ph
H
n-Bu
n-Pr
Me
Me
Ph
Ph
Ph
CH2Cl2, 22 °C, 12 h
1b
3a
4b
2b
4f
4e
, 65% yield
O
4g
, 75% yield
O
, 91% yield
O
ZnI2
entry
B(C6F5)3
(mol%)
PMP
(mol%)
Pd(PPh3)4
(mol%)
yield(%)
2b
4b
(mol%)
1
2
3
10
10
10
100
50
2
>95
0
<5
Me
Me
Me
100
100
50
none
>95
0
none
2
2
2
2
2
1
0
OMe
Cl
4i
4h
, 95% yield
O
4j
, 92% yield
O
, 93% yield
O
0
4
5
6
7
8
10
none
100
50
50
50
50
20
50
0
0
none
10
20
52
41
>95
<5
<5
<5
Me
Me
Me
S
10
100
100
Cl
CF3
10
4l
, 92% yield
4m
, 85% yield
4k
, 91% yield
a
Conditions: 1-phenylnon-5-yn-1-one (1a, 0.10 mmol), iodobenzene (3a, 0.12 mmol)
a Conditions: Alkynl ketone (1, 0.10 mmol), aryl iodide (3, 0.12 mmol), B(C6F5)3 (10 mol%),
1,2,2,6,6-pentamethylpiperidine (100 mol%), ZnI2 (50 mol%), Pd(PPh3)4 (1.0 mol%),
CH2Cl2 (0.5 mL), under N2, 22 °C, 12 h. b Yield of isolated and purified product.
B(C6F5)3, 1,2,2,6,6-pentamethylpiperidine, ZnI2, Pd(PPh3)4, CH2Cl2 (0.5 mL), under N2, 22
°C, 12 h. b Yield was determined by 1H NMR analysis of unpurified reaction mixtures with
mesitylene as the internal standard.
2 | J. Name., 2012, 00, 1-3
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alkynes was found to be necessary; with 1-phenylhex-5-yn-1- Financial support was provided by the NIH (GM-V1ie2w8A6rt9ic5le),Ontlhinee
one, containing a terminal alkyne moiety (R2 = H), the Sloan Foundation, and Boston College. A. Y. was supported as a
DOI: 10.1039/D0OB01678K
transformation was inefficient (<5% yield, see the Supporting John LaMattina Graduate Fellow in Chemical Synthesis. T. M.
Information for details).
was supported as a Kozarich Summer Undergraduate Research
An array of aryl- and heteroaryl-iodides reacted efficiently Fellow.
with 1b to afford 4h–4m. Cyclopentene derivatives with 1-
naphthyl group (4h) as well as those containing arenes with
Notes and references
electron-donating (4i) and electron-withdrawing (4j–4l) groups
were obtained in 91 to 95% yield. Thiophen-2-yl-substituted 4m
could also be produced in 85% yield. The reaction of 1b with
more sterically hindered 2,6-dimethyliodebenzene and 1-iode-
2-methoxynaphthalele only gave the Conia-ene-type product
2b (see the Supporting Information for details). This sequential
Conia-ene-type cycloaddition/Negishi coupling reaction was
found to proceed only with iodoarenes; bromoarenes gave no
desired product (Conia-ene-type product 2b was obtained using
bromobenzene: see the Supporting Information for details).
Furthermore, for the reaction of 1b and 1-chloro-3-
iodobenzene to afford 4l, no byproduct formed through
oxidative addition into Ar–Cl bond was detected. The treatment
of 1b with allyl iodide under the standard catalytic conditions
lead to the formation of 2b (see the Supporting Information for
details). These results suggest, in order to effectively trap the
alkenyl ZnI species by Pd(II) complexes through
transmetallation (IV  V; Scheme 1B), the use of aryl iodides that
undergo facile oxidative addition with Pd(PPh3)4 to afford
reactive [(Ar)(I)PdII(PPh3)n] intermediates is necessary.
1
2
For selected reviews on enantioselective cooperative
catalysis, see: (a) H. Yamamoto and K. Futatsugi, Angew.
Chem., Int. Ed. 2005, 44, 1924. (b) S. Kobayashi; Y. Mori, J. S.
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Shibasaki and N. Kumagai, in Cooperative Catalysis: Designing
Efficient Catalysts for Synthesis, Peters, R., Eds.; Wiley-VCH:
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Chem 2020, 6, 1520.
3
Conclusions
In brief, we have developed a cooperative catalyst system
which constitutes of B(C6F5)3, an amine, ZnI2, and Pd(PPh3)4 to
promote sequential Conia-ene-type cycloaddition/Negishi
coupling reactions. This process affords 1,2,3-substituted
cyclopentenes with various carbonyl, alkyl, and aryl substitutes from
readily available alkynyl ketones and aryl iodides. Furthermore,
the results obtained provide a mechanistic insight into how the Lewis
acidic catalysts with potential overlapping functions serve as
activators of carbonyl, alkyne, and alkenyl–ZnI intermediate. The
principles outlined here demonstrate that a combination of four
different catalyst units with different functions can be used to
promote the union of in situ generated reactive intermediates from
poorly acid- and base-sensitive starting materials. This discovery
4
5
(a) J. Z. Chan, W. Yao, B. T. Hastings, C. K. Lok and M. Wasa,
Angew. Chem., Int. Ed. 2016, 55, 13877. (b) M. Shang, X.
Wang, S. M. Koo, J. Youn, J. Z. Chan, W. Yao, B. T. Hastings and
M. Wasa, J. Am. Chem. Soc. 2017, 139, 95. (c) M. Shang, M.
Cao, Q. Wang and M. Wasa, Angew. Chem., Int. Ed. 2017, 56,
13338. (d) M. Cao, A. Yesilcimen and M. Wasa, J. Am. Chem.
Soc. 2019, 141, 4199. (e) Y. Chang, A. Yesilcimen, M. Cao, Y.
Zhang, B. Zhang, J. Z. Chan and M. Wasa, J. Am. Chem. Soc.
2019, 141, 14570.
For selected reviews and examples on Conia-ene-type
carbocyclizations, see: (a) J. M. Conia and P. L. Perchec,
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Chem. Soc. 2005, 127, 17168. (c) B. K. Corkey and F. D. Toste,
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provides
a rational framework for further development of
cooperative multi-catalyst systems that facilitate transformations
that cannot be realized by single or dual-catalyst systems. Studies
aimed at achieving these objectives are currently underway.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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6
We cannot rule out the possibility that BoxZnLn and PMP
View Article Online
DOI: 10.1039/D0OB01678K
activates the carbonyl unit of 1 while the B(C6F5)3 activates the
alkynyl moieity. For activation of alkynes by B(C6F5)3, see: (a)
M. A. Dureen, C. C. Brown and D. W. Stephan,
Organometallics 2010, 29, 6422. (b) M. M. Hansmann, R. L.
Melen, F. Rominger, A. S. K. Hashmi and D. W. Stephan, J. Am.
Chem. Soc. 2014, 136, 777. (c) Y. Soltani, L. C. Wilkins and R.
L. Melen, Angew. Chem., Int. Ed. 2017, 56, 11995.
7
For selected examples on Negishi cross coupling, see: (a) E.
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8
9
We are unable to rule out the possibility that B(C6F5)3
activates the alkyne unit of 1 to form an [alkenylB(C6F5)3]–
intermediate which can then undergo Suzuki cross coupling.
See: C. Chen, G. Kehr, R. Fröhlich and G. Erker, J. Am. Chem.
Soc. 2010, 132, 13594. However, there is no literature
precedent for Suzuki coupling reactions involving
[alkenylB(C6F5)3]–.
For selected examples of transformations involving palladium
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Org. Chem. 1995, 60, 2648. (b) M. Sodeoka, R. Tokunoh, F.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01678K
Sequential Conia-ene-type cyclizations/Negishi coupling reaction
O
O
B(C6F5)3
ZnI2
1.0 equiv. NR3
cat.
R
R1
Ar I
Ar
H
+
R
R1
Pd(PPh3)n
R2
cat.
cat.
R2
3
1
4
"Frustrated" acid/base catalysts
A hybrid catalyst system for sequential Conia-ene-type cyclization/Negishi coupling for union of
alkynyl ketones and aryl iodides has been developed.