Suzuki-Miyaura coupling of simple ketones via activation of unstrained carbon-carbon bonds

Article abstract of DOI:10.1021/jacs.8b02462

Here, we describe that simple ketones can be efficiently employed as electrophiles in Suzuki-Miyaura coupling reactions via catalytic activation of unstrained C-C bonds. A range of common ketones, such as cyclopentanones, acetophenones, acetone and 1-indanones, could be directly coupled with various arylboronates in high site-selectivity, which offers a distinct entry to more functionalized aromatic ketones. Preliminary mechanistic study suggests that the ketone α-C-C bond was cleaved via oxidative addition.

Full text of DOI:10.1021/jacs.8b02462

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Suzuki-Miyaura Coupling of Simple Ketones via
Activation of Unstrained Carbon-Carbon Bonds
Ying Xia, Jianchun Wang, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02462 • Publication Date (Web): 13 Apr 2018
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Suzuki–Miyaura Coupling of Simple Ketones via Activation of Unꢀ
strained Carbon−Carbon Bonds
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Ying Xia, Jianchun Wang and Guangbin Dong*
Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
Supporting Information Placeholder
broadly useful if an intermolecular cross coupling could be realꢀ
ized with readily available simple ketones as substrates. Hence,
we were motivated to merge a transmetalation process and imineꢀ
directed C−C activation, and envisaged that subsequent reductive
elimination/protonation would furnish a general crossꢀcoupling
reaction between simple common ketones and arylboronic acid
derivatives (Scheme 1B).
ABSTRACT: Here, we describe that simple ketones can be effiꢀ
ciently employed as electrophiles in Suzuki–Miyaura coupling
reactions via catalytic activation of unstrained C−C bonds. A
range of common ketones, such as cyclopentanones, acetopheꢀ
nones, acetone and 1ꢀindanones, could be directly coupled with
various arylboronates in high siteꢀselectivity, which offers a disꢀ
tinct entry to more functionalized aromatic ketones. Preliminary
mechanistic study suggests that the ketone αꢀC−C bond was
cleaved via oxidative addition.
Scheme 1. The Development of Suzuki–Miyaura Coupling
(SMC) Reactions
Crossꢀcoupling reactions catalyzed by transition metals have
greatly influenced bondꢀdisconnection strategies in modern organꢀ
1
ic synthesis. In particular, the Suzuki–Miyaura coupling (SMC),
2a
the coupling between organoboranes and carbon electrophiles ,
represent one of the most frequently utilized reactions in pharmaꢀ
2
b
ceutical, agrichemical and material research , which is largely
attributed to the wide availability, decent stability and excellent
reactivity of boron reagents. Classical SMC reaction employs
organohalides or pseudohalides as electrophiles (Scheme 1A).
Given the increasing importance of this transformation, substanꢀ
tial attentions have been paid on extending the scope of electroꢀ
3ꢀ5
philes for SMC. The recent advance of nickel catalysis has alꢀ
lowed aryl ethers, phenols and esters to serve as electrophiles for
3
SMC through C–O bond activation. In addition, use of aryl amꢀ
ides, ammonium salts and nitro compounds has also been demonꢀ
4
strated via a metalꢀmediated C–N bond activation. Apart from
cleaving the more polarized C–X (X = halogen), C–O and C–N
bonds, SMC reactions via activation of less polar, unstrained C–C
bonds in common feedstock would be highly valuable, which
6
,7
however remained a challenge to date.
Transition metalꢀcatalyzed C−C bond activation has become an
emerging area for enabling novel transformations of organic molꢀ
8,9
ecules. Small ring systems are commonly employed to drive the
9
a,b
C−C bond cleavage process through strain relief, consequently
leading to valuable methods for building bridged and fused
rings. In contrast, catalytic activation of lessꢀ or nonꢀstrained
At the outset, cyclopentanone (1a) was chosen as the model
9c
substrate for the coupling with arylboronate 1b (Table 1). After an
extensive survey of the reaction conditions, the desired coupling
product (1c) was ultimately obtained in 68% yield (Entry 1). The
optimized catalytic system contains 6 mol% [Rh(C H ) Cl] , 14
systems has been rather challenging, especially in a constructive
8d,10
manner.
As an initial step towards the goal of developing synꢀ
2
4 2
2
thetically useful methods via activating unstrained C−C bonds, we
recently reported a catalytic tandem C−C/C−H activation of 3ꢀ
Me
.
mol% IMes, 20 mol% TsOH H O, 45 mol% 2ꢀaminoꢀ3ꢀpicoline
2
1
1
(C1) and 25 mol% ethyl crotonate; 2 equiv of H O was used as
2
arylcyclopentanones. In this reaction, 3ꢀarylcyclopentanones
underwent oxidation addition into α C−C bonds through an in situ
generated ketimine intermediate, a mode of reactivity originally
the proton source with MeTHF (2ꢀmethyltetrahydrofuran) as the
solvent. Note that no additional base was required for this ketoneꢀ
mediated SMC reaction. A series of control experiments were
then carried out to gain more insights to this reaction. It was reꢀ
vealed that the rhodium preꢀcatalyst and the amine coꢀcatalyst
8i,10b,10c
discovered by Jun,
followed by an intramolecular C−H
metalation and reductive elimination, eventually providing funcꢀ
tionalized αꢀtetralones or 1ꢀindanones. This intramolecular reacꢀ
tion shows promise for synthetic applications capitalizing on C−C
activation of unstrained systems; however, it would be more
(
C1) were both crucial, and no product was produced without
.
either of them (Entries 2 and 3). In the absence of TsOH H O or
2
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Me
IMes, 1c was only formed in less than 10% yield (Entries 4 and
the strained cyclobutane ring remained intact during the reaction
(Entry 6). A number of para and metaꢀsubstituted arylboronates
were successfully coupled, but the orthoꢀsubstituted ones are
more difficult likely caused by the steric hindrance during the
transmetalation step. Nevertheless, coupling with diꢀ and trisubstiꢀ
tuted arylboronates smoothly delivered the corresponding polyꢀ
substituted aromatic ketones in modest to good yields (Entries 21ꢀ
29).
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5). H O serves as a reactant, and the yield dropped to 20% when
no H O was added (Entry 6). The catalytic amount of ethyl crotoꢀ
nate can slightly increase the efficiency, which likely plays a role
as a π acid to promote the reductive elimination step (Entry 7).
Apart from 2ꢀaminoꢀ3ꢀpicoline (C1), several other amine coꢀ
catalysts were also tested. Without the methyl group (Entry 8) or
having methyl at other positions (Entries 9ꢀ11), the amine coꢀ
catalysts were much less active. A comparable result was
achieved when replacing the methyl with an ethyl group (Entry
2
2
12
The reactivity of different types of ketones was inspected. 3ꢀ
Alkyl and aryl substituted cyclopentanones (2aꢀ4a) are competent
substrates (Chart 1B), in which both the C1−C2 and C1−C5 bonds
can be activated (Entries 30ꢀ32). Surprisingly, the siteꢀselectivity
slightly favored the more sterically hindered side, though the exꢀ
act reason is unclear. In addition, 3ꢀester substituted cyclopentaꢀ
none (5a) and norcamphor (6a) showed excellent siteꢀselectivity
at the bulkier side to give the desired coupling products, albeit in
low yields (Entries 33 and 34). Ringꢀfused cyclopentanone (7a)
also worked; the low reactivity is presumably caused by the steric
hindrance of the ketone substrate (Entry 35). To extend the scope
of the ketone component, substituted 1ꢀindanones were found to
be an efficient class of substrates in this reaction (Chart 1C). The
discovery was rather unexpected as aryl ketones are typically less
reactive due to the larger conjugated π system compared to the
corresponding alkyl ketones. To the best of our knowledge, C−C
activation of 1ꢀindanones has not been reported to date. Although
1ꢀindanones have two different αꢀC−C bonds, gratifyingly the
1
2), while no product was produced when the pyridyl group was
Me
replaced by a phenyl group (Entry 13). Compared with the IMes
ligand, other NHC ligands also promoted this reaction albeit in
lower yields (Entries 14ꢀ16). When the reaction temperature was
0
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o
lowered to 130 C or less arylboronate 1b was used, the coupling
product was still obtained in 46% and 56% yields, respectively
(Entries 17 and 18). With regard to the arylboron reagents, 1,3ꢀ
propanediolꢀdrived boronate (1b) offers a nice balance between
stability and reactivity. Similar reactivity was observed using
glycolꢀderived arylboronate (1b1), but other diolꢀderived arylꢀ
boronates or boronic acid was less effective (Entries 19ꢀ22).
a
Table 1. Selected Optimization of Reaction Conditions
C−C cleavage/coupling occurred
exclusively at the
C(aryl)−C(carbonyl) bond to provide dihydrochalcone derivatives
up to 75% isolated yield. The substituents on 1ꢀindanones exhibit
great influence on the reactivity, in which the electronꢀdeficient 1ꢀ
indanones were typically more efficient substrates than the elecꢀ
tronꢀrich ones. When 1ꢀindanone bearing an acetyl group (13a)
was employed, dihydrochalcone (41c) and pꢀmethylacetophenone
(42c) were isolated in 62% total yield with a ratio of 1.8:1, which
suggests that the reactivity of the carbonyl in 1ꢀindanone appears
to be higher than the one in acetophenone.
13
Besides cyclic ketones , a range of acyclic ketones also exꢀ
pressed considerable reactivity (Chart 1D). Various acetopheꢀ
nones (16aꢀ22a) can react with arylboronate 1b to provide the
“arylꢀexchanged” products. While the conversions were moderate,
high brsm yields were obtained in these reactions. Again, the C−C
cleavage occurred exclusively at the C(aryl)−C(carbonyl) bond
and the electronꢀdeficient acetophenones gave higher conversion
than the electronꢀrich ones. It is noteworthy that the potential
Scheme 2. Synthetic Utilities of the KetoneꢀSMC Reaction
O
Me
O
A.
Me
O
H
H
2
3a
H
H
Me
Me
H
a
All the reactions were run with 0.2 mmol of 1a, 0.5 mmol of arylboronate,
Me
F
H
o
O
Ketone SMC
0
.4 mmol of H
2
O and 0.15 mL of MeTHF in a 4 mL vial at 150 C for 120
B
O
50c, 52% yield
O
Me
b
1
30b, from estrone
h. Determined by H NMR using 1,1,2,2ꢀtetrachloroethane as the internal
standard. Isolated yield; the yield was 40% for 60 h and 59% for 96 h. Ts,
pꢀtoluenesulfonyl, MeTHF, 2ꢀmethyltetrahydrofuran.
O
c
H
O
H
F
F
H
Ketone SMC
O
The substrate scope of this ketoneꢀmediated SMC reaction was
then investigated (Chart 1). Firstly, a series of 1,3ꢀpropanediol
arylboronates were tested in the reaction with cyclopentanone
F 15a
5
1c, 41% yield, 78% brsm
B.
Ketone SMC
O
B
O
O
F
H
1. NaBH4 or
MeMgBr
p-Tol
F
(
Chart 1A). In general, more electronꢀrich arylboronates worked
cross
p-Tol
better probably due to a faster transmetalation process, whereas
the more electronꢀdeficient ones gave sluggish reactions (Entries
1
in cross coupling reactions, such as trimethylsilyl (TMS) (Entry
9), aryl chloride (Entry 18), aryl fluoride (Entry 13), methyl ethers
(Entries 7 and 15) and phenolic hydroxyl group (Entry 20), were
found compatible under the optimized conditions. Interestingly,
coupling
standard conditions
2. NaH
F
O
SNAr
F
Gram-Scale
44c, 65% yield, 0.85 gram
ꢀ20). A range of functional groups that are known to participate
15a
5
mol% Ni(acac)2
5 mol PO ligand
1.5 equiv. PhMgBr
Et2O, rt., 1 h
F
O
p-Tol
Ph
O
p-Tol
Me
R
5
2, R = H, 98% yield
54, 85% yield (from 53)
53, R = Me, 95% yield
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a
Chart 1. Scope of the Ketone SMC Reaction
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a
c
b
o
All the reactions were run on 0.2 mmol scale under the standard conditions depicted in Table 1 unless otherwise noted. 140 C using IMes as the ligand.
d
Using 150 mol% of H
O were not added in these reactions; 0.10 mL MeTHF (instead of 0.15 mL) was used. See Supporting information for more experiꢀ
mental details. brsm, based on recovered starting material; r.r.: regioisomer ratio.
2
O. Arylboronates were used as the limiting reagents; arylboronate (0.2 mmol, 1.0 equiv) and acetone (2 mmol, 10 equiv) were used;
ethyl crotonate and H
2
1
4
ortho C−H arylation directed by the carbonyl group was not
observed. Moreover, the simplest ketone, i.e. acetone, was also a
suitable substrate to give acceptable yields of the coupling prodꢀ
ucts (Entries 55ꢀ57). Finally, the unsymmetrical acyclic aliphatic
ketone (24a) afforded a mixture of dihydrochalcone (36c) and pꢀ
methylacetophenone (42c) with a ratio of 2.8:1 (Entry 58).
tone or 1ꢀindanone 15a smoothly provided two ketoneꢀderived
estrone analogues without the need for strong acylating agents. In
addition, the reaction was scalable (Scheme 2B). On a gram scale
the coupling product 44c was afforded in 65% yield from comꢀ
mercially available 1ꢀindanone 15a. After reduction or 1,2ꢀ
addition with ketone 44c, the resulting alcohols underwent intraꢀ
molecular nucleophilic aromatic substitution to deliver the correꢀ
sponding chromane derivatives 52 and 53 in excellent yields. The
remaining fluoride on the arene can further undergo
The utility of this ketoneꢀmediated SMC reaction was first exꢀ
amined in the derivatization of steroid natural products (Scheme
A). For examples, reactions between arylboronate 30b and aceꢀ
2
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Kumadaꢀtype coupling with Grignard reagents under Nakamura’s
(1) (a) MetalꢀCatalyzed CrossꢀCoupling Reactions; Diederich, F., Stang,
15
P. J., Eds; WileyꢀVCH: Weinhein, Germany, 1998. (b) MetalꢀCatalyzed
CrossꢀCoupling Reactions and More; de Meijere, A., Bräse, S., Oestreich,
M., Eds; WileyꢀVCH: Weinheim, Germany, 2014. (c) Negishi, E.ꢀi. Anꢀ
gew. Chem. Int. Ed. 2011, 50, 6738. (d) Johansson Seechurn, C. C. C.;
Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012,
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conditions. As a result, the whole synthetic sequence provides a
rapid and modular approach to access functionalized chromanes, a
16
common structural motif found in bioactive compounds.
To gain insights about how the C−C bond is cleaved in this keꢀ
toneꢀSMC reaction, control experiments were carried out (Scheme
5
1, 5062.
2) (a) Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6722. (b) Brown, D.
(
3
). In addition to oxidative addition of Rh(I) into ketone α C−C
G.; Boström, J. J. Med. Chem. 2016, 59, 4443.
bond, a potential alternative way involves 1,2ꢀaddition of the aryl
nucleophile into the carbonyl or imine intermediate, followed by a
(3) For recent reviews, see: (a) Yu, D.ꢀG.; Li, B.ꢀJ; Shi, Z.ꢀJ. Acc. Chem.
Res. 2010, 43, 1486. (b) Rosen, B. M.; Quasdorf, K.W.; Wilson, D. A.;
Zhang, N.; Resmerita, A.ꢀM.; Garg, N. K.; Percec, V. Chem. Rev. 2011,
111, 1346. (c) Tobisu, M.; Chatani, N. Top. Curr. Chem. 2016, 374, 1. (d)
Zarate, C.; van Gemmeren, M.; Somerville, R. J.; Martin, R. Adv. Organꢀ
omet. Chem. 2016, 66, 143. For recent examples, see: (e) Chaꢀ
tupheeraphat, A.; Liao, H.ꢀH.; Srimontree, W.; Guo, L.; Minenkov, Y.;
Poater, A.; Cavallo, L.; Rueping, M. J. Am. Chem. Soc. 2018, 140, 3724.
(f) Ben Halima, T.; Zhang, W.; Yalaoui, I.; Hong, X.; Yang, Y.ꢀF., Houk,
K. N.; Newman, S. G. J. Am. Chem. Soc. 2017, 139, 1311.
17
βꢀcarbon elimination process. To investigate the hypothetical βꢀ
carbon elimination pathway, tertiary alcohol 55 and amine 57
were independently synthesized, which were then subjected to the
standard conditions (in the absence of ketone and boronate reacꢀ
tants). The desired SMC product 1c was not observed; instead,
olefin 56 was produced in a quantitative yield. Combining the fact
that olefin 56 was not observed in our standard ketoneꢀSMC reacꢀ
tions (Table 1), the βꢀcarbon elimination pathway is unlikely.
Hence, the results of these control experiments are consistent with
our hypothesis (Scheme 1B) that the C−C bond cleavage involves
oxidative addition with a Rh(I) species.
0
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(4) (a) Takise, R.; Muto, K.; Yamaguchi, J. Chem. Soc. Rev. 2017, 46,
5
864. (b) Dander, J. E.; Garg, N. K. ACS Catal. 2017, 7, 1413. (c) Blakey,
S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 6046. (d)
Weires, N. A.; Baker, E. L; Garg, N. K. Nat. Chem. 2016, 8, 75. (e)
Yadav, M. R.; Nagaoka, M.; Kashihara, M.; Zhong, R. L.; Miyazaki, T.;
Sakaki, S.; Nakao, Y. J. Am. Chem. Soc. 2017, 139, 9423.
Scheme 3. Control Experiments to Examine an Alternative
βꢀCarbon Elimination Pathway
(5) For selected examples of other electrophiles used in SMC reactions,
see: (a) Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128,
1
5964. (b) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Comꢀ
mun. 2015, 6, 7508. (c) Wang, J.; Qin, T.; Chen, T. G.; Wimmer, L.; Edꢀ
wards, J. T.; Cornella, J.; Vokits, B.; Shaw, S. A.; Baran, P. S. Angew.
Chem. Int. Ed. 2016, 55, 9676. (d) Zhang, L.; Lovinger, G. J.; Edelstein,
E. K.; Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P. Science 2016,
3
51, 70.
6) For a related coupling of arylboronates using highly strained ketones,
see: Matsuda, T.; Makino, M.; Murakami, M. Org. Lett. 2004, 6, 1257.
7) For seminal works on coupling of arylboronates using 8ꢀ
(
(
acylqunolines, see: (a) Wang, J.; Chen, W.; Zuo, S.; Liu, L.; Zhang, X.;
Wang, J. Angew. Chem. Int. Ed. 2012, 51, 12334. (b) Dennis, J. M.; Comꢀ
pagner, C. T.; Dorn, S. K.; Johnson, J. B. Org. Lett. 2016, 18, 3334.
(8) For selected recent reviews, see: (a) Rybtchiski, B.; Milstein, D. Anꢀ
gew. Chem. Int. Ed. 1999, 38, 870. (b) Murakami, M.; Ito, Y. Top. Organꢀ
omet. Chem. 1999, 3, 97. (c) Ruhland, K. Eur. J. Org. Chem. 2012, 2683.
In summary, we describe the development of a SMC reaction
between simple ketones and arylboronates via Rhꢀcatalyzed actiꢀ
vation of unstrained C−C bonds. While the efficiency of the reacꢀ
tion still has room for further improvement, the general applicaꢀ
bility is nevertheless encouraging. The use of unstrained C−C
bond as electrophiles in cross couplings should have broad impliꢀ
cations. Detailed mechanistic study (experimental and computaꢀ
tional) and efforts to accelerate the reaction rate is ongoing.
(d) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613. (e) C−C
Bond Activation; Dong, G., Ed.; Topics in Current Chemistry 346; Springꢀ
er: Berlin, 2014. (f) Cleavage of Carbon−Carbon Single Bonds by Transiꢀ
tion Metals; Murakami, M., Chatani, N., Eds.; WileyꢀVCH: Weinheim,
2
015. (g) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410. (h) Muraꢀ
kami, M.; Ishida, N. J. Am. Chem. Soc. 2016, 138, 13759. (i) Kim, D.ꢀS.;
Park, W.ꢀJ.; Jun, C.ꢀH. Chem. Rev. 2017, 117, 8977. (j) Fumagalli, G.;
Stanton, S.; Bower, J. F. Chem. Rev. 2017, 117, 9404.
(9) (a) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem. Int.
ASSOCIATED CONTENT
Ed. 2011, 50, 7740. (b) Mack, D. J.; Njardarson, J. T. ACS Catal. 2013, 3,
272. (c) Chen, P.; Billett, B.; Tsukamoto, T.; Dong, G. ACS Catal. 2017,
Supporting Information Experimental procedures; spectral
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
7
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AUTHOR INFORMATION
(11) (a) Xia, Y.; Lu, G.; Liu, P.; Dong, G. Nature 2016, 539, 546. (b)
Xia, Y.; Wang, J.; Dong, G. Angew. Chem. Int. Ed. 2017, 56, 2376.
(12) (a) Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am. Chem. Soc.
1971, 93, 3350. (b) PerezꢀRodriguez, M.; Braga, A. A.; GarciaꢀMelchor,
M.; PerezꢀTemprano, M. H.; Casares, J. A.; Ujaque, G.; de Lera, A. R.;
Alvarez, R.; Maseras, F.; Espinet, P. J. Am. Chem. Soc. 2009, 131, 3650.
Corresponding Author
gbdong@uchicago.edu
Notes
(
c) Motti, E.; Della Ca, N.; Deledda, S.; Fava, E.; Panciroli, F.; Catellani,
M. Chem. Commun. 2010, 46, 4291.
13) We have attempted the use of cyclohexanones and –heptanones as
The authors declare no competing financial interests.
(
ACKNOWLEDGMENT
substrates; unfortunately, they do not yield any desired product. The reaꢀ
son is unclear at this moment.
(
14) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem.
Soc. 2003, 125, 1698.
15) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem. Soc. 2009,
31, 9590.
16) Pratap, R.; Ram, V. Ji. Chem. Rev. 2014, 114, 10476.
This project was supported by NIGMS (R01GM109054). Y. X.
acknowledges the International Postdoctoral Exchange Fellowship
Program 2015 from the Office of China Postdoctoral Council (No.
38 Document of OCPC, 2015).
(
1
(
REFERENCES
ACS Paragon Plus Environment

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