Metal-Free Cyclopropanol Ring-Opening C(sp3)-C(sp2) Cross-Couplings with Aryl Sulfoxides

Article abstract of DOI:10.1021/acs.orglett.9b01908

A metal-free method for formal β-arylation/heteroarylation of ketones through efficient cyclopropanol ring-opening cross-couplings with aryl sulfoxides at room temperature has been developed. This protocol shows a broad substrate scope and promising scalability. In addition, the utility of the β-arylated ketones is further demonstrated through a variety of postcoupling transformations and synthetic applications.

Full text of DOI:10.1021/acs.orglett.9b01908

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free Cyclopropanol Ring-Opening C(sp3)−C(sp2) Cross-
Couplings with Aryl Sulfoxides
Dengfeng Chen,† Yuanyuan Fu,† Xiaoji Cao,‡ Jinyue Luo,† Fei Wang,† and Shenlin Huang*,†
†Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, College of Chemical Engineering, Jiangsu
Key Lab of Biomass-Based Green Fuels and Chemicals, Jiangsu Co-Innovation Center of Efficient Processing and Utilization of
Forest Resources, Nanjing Forestry University, Nanjing 210037, P. R. China
‡College of Chemical Engineering, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, Zhejiang 310014, P. R.
China
S
* Supporting Information
ABSTRACT: A metal-free method for formal β-arylation/
heteroarylation of ketones through efficient cyclopropanol
ring-opening cross-couplings with aryl sulfoxides at room
temperature has been developed. This protocol shows a broad
substrate scope and promising scalability. In addition, the
utility of the β-arylated ketones is further demonstrated
through a variety of postcoupling transformations and synthetic applications.
Scheme 1. Preparation of β-Arylated Ketones
β-Arylated/heteroarylated ketones are frequently found in
many bioactive molecules and natural products.1 Traditionally,
they are often accessed via the Michael addition of aryl
nucleophiles to α,β-unsaturated ketones;2 however, these
reactions often require the preformed organometallic reagents
and enones or harsh reaction conditions. As a result, a number
of novel approaches to address their syntheses have recently
emerged. In 2013, MacMillan disclosed a direct β-arylation of
cyclic ketones via merging photoredox and enamine catalysis,
in which electron-deficient dicyanobenzene was employed as
the aryl source.3 Arguably, the most common method involves
noble transition-metal-catalyzed direct β-arylation of ketones
with aryl carboxylic acids,4 arylboronic acids,5 diaryliodonium
salts,6 and aryl iodides,7 via either direct β-C(sp3)−H
activation or ketone dehydrogenation/conjugate addition
(Scheme 1A). Alternatively, β-arylated ketones can be accessed
by the palladium-catalyzed coupling of cyclopropanols, known
as homoenolate precursors, with aryl bromides (Scheme 1B).8
Nonetheless, these efforts are still plagued by at least one of the
following limitations: (1) the use of a sophisticated photo-
catalysis setup, (2) the use of expensive transition metals, (3)
the necessity of prefunctionalized coupling partners, (4) the
need for high reaction temperatures, and (5) a narrow
heteroarylation scope. Thus despite remarkable recent
advances in the direct β-arylation of ketones, a metal-free
approach to β-arylated/heteroarylated ketones under mild
conditions that avoids metal contamination of products,
especially in the pharmaceutical industry,9 would be highly
desirable and challenging.
cyclopropanols,12 a versatile building block that has found
diverse applications,13 are readily available from the Simmons−
Smith reaction or the Kulinkovich reaction. We envisioned that
cyclopropanols could serve as a nucleophile to react with the
activated sulfoxides A through a Pummerer-type mechanism
(Scheme 1C). Rearomatization of aryl/heteroaryl sulfonium
intermediates B would eventually give rise to the desired β-
arylated/heteroarylated ketones. The products, especially β-
heteroarylated ketones, are challenging targets for previous
transition-metal-catalyzed methods.
Initial investigations focused on the reaction of 1-phenyl-
cyclopropan-1-ol 1a with 2-methylsulfinyl naphthalene 2a to
With our continuous interest in exploring sustainable
synthetic transformations,10 we present herein a metal-free
method for the formal β-arylation/heteroarylation of ketones
through a Pummerer-like reaction11 of cyclopropanols and aryl
sulfoxides at room temperature. The starting material,
Received: June 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01908
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generate β-arylated 1-phenylpropan-1-one 3a. We were pleased
to find that with trifluoroacetic anhydride (TFAA) as the
activator, this reaction provided a 52% yield of the desired
product 3a after 8 h at room temperature (Table 1, entry 1).
Notably, the “normal” Pummerer product 3a′ was not
observed. We next examined other activators, as shown in
entries 2−4 of Table 1, revealing that perfluoropropionic
anhydride (PFPA) was the optimal activator. Furthermore,
various additives were evaluated with PFPA as the activator at
room temperature. The reaction did not take place in the
presence of more acidic TfOH (entry 5), which suggested that
pentafluoropropionic acid (CF3CF2CO2H), formed as the
reaction proceeds, might decrease the reaction efficiency.14
Hence, 2,6-lutidine or Et3N was used to decrease the
concentration of CF3CF2CO2H in the reaction mixture.
Unfortunately, inferior reaction performance was observed
(entries 6 and 7). Gratifyingly, an improved yield (72%) was
obtained with 2.0 equiv of CF3CO2Na (entry 11), whereas
lower (entries 9 and 10) or higher amounts (entries 12 and
13) of CF3CO2Na led to decreased yields. For further
improvement of reaction performance, different types of
molecular sieves were examined. The use of 5 Å molecular
sieves proved ideal (entry 16), with either 3 or 4 Å molecular
sieves leading to decreased yields (entries 14 and 15). Sodium
trifluoroacetate and molecular sieves might serve as a buffer for
the pentafluoropropionic acid generated in the reaction or
simply as a desiccant. Finally, the reaction efficiency was
reduced upon removing CF3CO2Na from the reaction (entry
17) or replacing PFPA with TFAA (entry 18).
a
Table 1. Optimization of the Reaction Conditions
b
entry
anhydride
additive (equiv)
yield (%)
1
2
3
4
5
6
7
8
TFAA
Tf2O
none
none
none
none
TfOH (1.5)
2,6-lutidine (1.5)
Et3N (1.5)
52
0
0
57
0
Ts2O
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
PFPA
TFAA
27
17
60
63
67
72
60
33
57
49
75
59
61
NaOTf (1.5)
9
CF3CO2Na (1.0)
CF3CO2Na (1.5)
CF3CO2Na (2.0)
CF3CO2Na (2.5)
CF3CO2Na (3.0)
CF3CO2Na (2.0), 3 Å MS
CF3CO2Na (2.0), 4 Å MS
CF3CO2Na (2.0), 5 Å MS
5 Å MS
CF3CO2Na (2.0), 5 Å MS
10
11
12
13
14
15
16
17
18
c
c
With the optimized reaction conditions in hand, we next
explored the scope of sulfoxides amenable to this cross-
coupling reaction (Scheme 2). 2-Methylsulfinyl naphthalene
2a underwent efficient coupling to both 1-phenyl-substituted
cyclopropanol 1a and 1-(naphthalen-2-yl)-substituted cyclo-
propanol 1b to give the desired products 3a and 3b in good
isolated yield. 2-(p-Tolylsulfinyl) naphthalene has also been
successfully coupled to 1b to provide 3c in 67% yield. Notably,
diphenyl sulfoxide successfully reacted with 1a to afford the
c
c
c
a
Reaction conditions: Anhydride (0.2 mmol) was added to a mixture
of 1a (0.1 mmol) and 2a (0.2 mmol) in CH2Cl2 (0.1 M) at rt.
b
c
HPLC yield with 1-nitronaphthalene as the internal standard. 0.05
g/mmol.
a b
,
Scheme 2. Scope of Sulfoxides
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), CF3COONa (0.4 mmol), 5 Å MS (10 mg), DCM (2 mL), followed by (CF3CF2CO)2O (0.4
b
c
mmol). Isolated yield. 70 °C for 8 h.
B
DOI: 10.1021/acs.orglett.9b01908
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Organic Letters
Letter
desired product 3d, albeit in a suboptimal 34% yield. Phenyl
sulfoxides bearing electron-donating group(s) at the meta
position(s) exhibited better reactivity to give the desired
products 3e−3g, perhaps due to the fact that the electron-
donating group(s) at the meta position(s) could stabilize the
cationic intermediate B in Scheme 1C to facilitate the addition
of cyclopropanol to aryl sulfonium A.15 Interestingly, the
coupling took place selectively on the m-tolyl ring to deliver
3g, whereas the thiophene unit remained intact. On the
contrary, the coupling reaction occurred at the thiophene ring
instead of the o-tolyl or p-tolyl ring (3h and 3i). In the reaction
of unsymmetrical diaryl sulfoxides, cyclopropanols were
generally coupled to the naphthalene or thiophene unit with
weaker aromaticity (3c and 3h−k). The selectivity of the
coupling was further confirmed by single-crystal X-ray analysis
of 3k. Furthermore, a variety of alkylsulfinyl-substituted
thiophenes underwent regioselective coupling with cyclo-
propanols 1a and 1b to provide 3l−t in good yield.
Importantly, complex trans-androsterone derivative 3v proved
to be an exceptional coupling product. Additionally, 3-
dodecylsulfinyl thiophene was also a suitable substrate,
affording the C2-substituted product 3u in 59% yield. Finally,
other heterocyclic coupling partners also reacted smoothly
with cyclopropanols to give β-heteroarylated ketones 3w−y in
moderate to good yield.
reaction was observed with 1-methyl-2-phenylcyclopropan-1-
ol.
To highlight the practicality of this coupling, a 5.0 mmol
scale synthesis was carried out to give 4a in 83% yield (Scheme
4a). Moreover, the transformations of β-arylated ketone 3a are
Scheme 4. Gram-Scale Reaction and Synthetic Applications
Next, we proceeded to explore the scope of cyclopropanols
(Scheme 3). A variety of aryl-substituted cyclopropanols
a b
,
Scheme 3. Scope of Cyclopropanols
presented in Scheme 4b, thus further demonstrating the
synthetic utility of this method. Copper-catalyzed dehydrogen-
ation16 of ketone 3a generated enone 6 in 73% yield. The
Wittig reaction worked well, affording olefin 7 in 72% yield.
The reduction of ketone functionality proceeded smoothly
with NaBH4 to give alcohol 8 in 98% yield. In addition to
ketone elaboration, the sulfide group of 3a could also be
further manipulated. The oxidation of sulfide with 1 or 3 equiv
m-CPBA delivered sulfoxide 9a or sulfone 9b in excellent yield,
respectively.17 Furthermore, the methylthio substituent could
be easily excised by reduction with Ni(cod)2/EtMe2SiH in
toluene,18 leading to desulfurized product 10 in excellent yield.
Finally, ketone 10 was conveniently converted to 1,3-diketone
11, indole 12, alkane 13, enone 14, isoxazole 15, and 4,5-
dihydro-1H-pyrazole 16.
Finally, several control experiments were conducted (see
Supporting Information (SI)), indicating that the PFPA is
required to activate sulfoxides for the desired coupling
reaction. In addition, an in situ nuclear magnetic resonance
(NMR) study on the reaction of cyclopropanol 1b and
sulfoxide 2b was performed (see the SI). Pleasingly, O-
sulfenylated intermediate II was observed (Scheme 5). As
expected, intermediate II is unstable and undergoes either a
[3,3]-sigmatropic rearrangement or an intramolecular nucleo-
philic addition19 to afford sulfonium III, which provides β-
arylated ketone 3q after aromatization.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), CF3COONa (0.4
mmol), 5 Å MS (10 mg), DCM (2 mL), followed by (CF3CF2CO)2O
(0.4 mmol). Isolated yield.
b
underwent the desired coupling with 2-propylsulfinyl thio-
phene 2b to afford various β-heteroarylated ketones 4a−j in
good to excellent yield. Notably, functional groups such as
ester (4a), trifluoromethyl (4b), alkyl (4c, 4d, and 4j), 4-
methylbenzenesulfonate (4e), fluoride (4f), chloride (4g), and
bromide (4h and 4i) are well tolerated. Note that aryl halides,
not compatible with transition-metal-mediated cross couplings,
can be tolerated under the standard conditions, which could be
potentially further functionalized. 1-(6-Bromonaphthalen-2-yl)
cyclopropan-1-ol was also compatible under the standard
conditions, delivering the desired product 4k in 53% yield.
Moreover, alkyl-substituted cyclopropanols also participated in
this coupling reaction, leading to the desired products 4l−p in
moderate to good yield. Unfortunately, no desired coupling
In summary, we have described an efficient method to access
β-arylated/heteroarylated ketones via a metal-free coupling of
cyclopropanols and aryl sulfoxides at room temperature. This
C
DOI: 10.1021/acs.orglett.9b01908
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Myrica gale and structurally related acetophenones. Free Radical
Biol. Med. 1997, 22, 307.
Scheme 5. Proposed Reaction Mechanism
(2) (a) Fagnou, K.; Lautens, M. Rhodium-catalyzed carbon−carbon
bond forming reactions of organometallic compounds. Chem. Rev.
2003, 103, 169. (b) Hayashi, T.; Yamasaki, K. Rhodium-catalyzed
asymmetric 1,4-addition and its related asymmetric reactions. Chem.
Rev. 2003, 103, 2829.
(3) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W.
C. Photoredox activation for the direct β-arylation of ketones and
aldehydes. Science 2013, 339, 1593.
(4) Li, H.; Jiang, Q.; Jie, X.; Shang, Y.; Zhang, Y.; Goossen, L. J.; Su,
W. Rh/Cu-catalyzed ketone β-functionalization by merging ketone
dehydrogenation and carboxyl-directed C−H alkylation. ACS Catal.
2018, 8, 4777.
(5) Hu, X.; Yang, X.; Dai, X.-J.; Li, C.-J. Palladium-catalyzed direct
β-C-H arylation of ketones with arylboronic acids in water. Adv. Synth.
Catal. 2017, 359, 2402.
method was compatible with various aryl sulfoxides and
cyclopropanols with a wide range of functional groups and
showed promising scalability. Moreover, these resultant β-
arylated/heteroarylated ketones were demonstrated to be
versatile building blocks through a variety of synthetic
applications.
(6) Huang, Z.; Sam, Q. P.; Dong, G. Palladium-catalyzed direct β-
arylation of ketones with diaryliodonium salts: a stoichiometric heavy
metal-free and user-friendly approach. Chem. Sci. 2015, 6, 5491.
(7) (a) Huang, Z.; Dong, G. Catalytic direct β-arylation of simple
ketones with aryl iodides. J. Am. Chem. Soc. 2013, 135, 17747.
(b) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q.
Functionalization of C(sp3)−H bonds using a transient directing
group. Science 2016, 351, 252. (c) Zhu, R.-Y.; Liu, L.-Y.; Park, H. S.;
Hong, K.; Wu, Y.; Senanayake, C. H.; Yu, J.-Q. Versatile alkylation of
(hetero)aryl iodides with ketones via β-C(sp3)−H activation. J. Am.
Chem. Soc. 2017, 139, 16080.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01908.
(8) Rosa, D.; Orellana, A. Palladium-catalyzed cross-coupling of
cyclopropanol-derived ketone homoenolates with aryl bromides.
Chem. Commun. 2013, 49, 5420.
Experimental procedures and characterization data
(PDF)
(9) (a) Garrett, C. E.; Prasad, K. The art of meeting palladium
specifications in active pharmaceutical ingredients produced by Pd-
catalyzed reactions. Adv. Synth. Catal. 2004, 346, 889. (b) Rosso, V.
W.; Lust, D. A.; Bernot, P. J.; Grosso, J. A.; Modi, S. P.; Rusowicz, A.;
Sedergran, T. C.; Simpson, J. H.; Srivastava, S. K.; Humora, M. J.;
Anderson, N. G. Removal of palladium from organic reaction mixtures
by trimercaptotriazine. Org. Process Res. Dev. 1997, 1, 311.
(10) (a) Chen, D.; Feng, Q.; Yang, Y.; Cai, X.-M.; Wang, F.; Huang,
S. Metal-free O−H/C−H difunctionalization of phenols by o-
hydroxyarylsulfonium salts in water. Chem. Sci. 2017, 8, 1601.
(b) Feng, Q.; Chen, D.; Hong, M.; Wang, F.; Huang, S.
Phenyliodine(III) bis(trifluoroacetate) (PIFA)-mediated synthesis of
aryl sulfides in water. J. Org. Chem. 2018, 83, 7553. (c) Chen, D.;
Zhang, Y.; Pan, X.; Wang, F.; Huang, S. Oxidation of tertiary aromatic
alcohols to ketones in water. Adv. Synth. Catal. 2018, 360, 3607.
(d) Yang, Y.; Meng, X.; Zhu, B.; Jia, Y.; Cao, X.; Huang, S. A micellar
catalysis strategy for amidation of alkynyl bromides: synthesis of
ynamides in water. Eur. J. Org. Chem. 2019, 2019, 1166.
Accession Codes
CCDC 1886366 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: shuang@njfu.edu.cn.
ORCID
Shenlin Huang: 0000-0001-7322-6981
Notes
The authors declare no competing financial interest.
(11) For reviews, see: Bur, S. K.; Padwa, A. The Pummerer reaction:
methodology and strategy for the synthesis of heterocyclic
compounds. Chem. Rev. 2004, 104, 2401. (b) Feldman, K. S. Modern
Pummerer-type reactions. Tetrahedron 2006, 62, 5003. (c) Smith, L.
H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. J. Beyond the
Pummerer reaction: recent developments in thionium ion chemistry.
Angew. Chem., Int. Ed. 2010, 49, 5832. (d) Pulis, A. P.; Procter, D. J.
C−H coupling reactions directed by sulfoxides: teaching an old
functional group new tricks. Angew. Chem., Int. Ed. 2016, 55, 9842.
(e) Shafir, A. The emergence of sulfoxide and iodonio-based redox
arylation as a synthetic tool. Tetrahedron Lett. 2016, 57, 2673.
(f) Yorimitsu, H. Cascades of interrupted Pummerer reaction-
sigmatropic rearrangement. Chem. Rec. 2017, 17, 1156. (g) Yanagi,
T.; Nogi, K.; Yorimitsu, H. Recent development of ortho-C−H
functionalization of aryl sulfoxides through [3,3] sigmatropic
rearrangement. Tetrahedron Lett. 2018, 59, 2951 For selected recent
applications, see: . (h) Akai, S.; Morita, N.; Iio, K.; Nakamura, Y.;
Kita, Y. Ambident effect of a p-sulfinyl group for the introduction of
two carbon substituents to phenol rings: A convergent synthesis of
diverse benzofuran Neolignans. Org. Lett. 2000, 2, 2279. (i) Akai, S.;
ACKNOWLEDGMENTS
■
Financial support was provided by the Natural Science
Foundation of China (21502094 and 21602200), and the
Natural Science Foundation of the Jiangsu Higher Education
Institutions of China (17KJA220003) is acknowledged. We are
also grateful for the support of the advanced analysis and
testing center of Nanjing Forestry University. D.C. thanks the
Doctorate Fellowship Foundation of Nanjing Forestry
University and the Postgraduate Research & Practice
Innovation Program of Jiangsu Province.
REFERENCES
■
(1) (a) Mathiesen, L.; Malterud, E.; Sund, R. B. Antioxidant activity
of fruit exudate and C-methylated dihydrochalcones from Myrica gale.
Planta Med. 1995, 61, 515. (b) Mathiesen, L.; Malterud, E.; Sund, R.
B. Hydrogen bond formation as basis for radical scavenging activity: A
structure−activity study of C-methylated dihydrochalcones from
D
DOI: 10.1021/acs.orglett.9b01908
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Kawashita, N.; Satoh, H.; Wada, Y.; Kakiguchi, K.; Kuriwaki, I.; Kita,
Y. Highly regioselective nucleophilic carbon−carbon bond formation
on furans and thiophenes initiated by Pummerer-type reaction. Org.
Lett. 2004, 6, 3793. (j) Huang, X.; Maulide, N. Sulfoxide-mediated α-
arylation of carbonyl compounds. J. Am. Chem. Soc. 2011, 133, 8510.
(k) Eberhart, A. J.; Imbriglio, J. E.; Procter, D. J. Nucleophilic ortho
allylation of aryl and heteroaryl sulfoxides. Org. Lett. 2011, 13, 5882.
couplings with (fluoro)alkyl halides. Org. Lett. 2015, 17, 6074.
(f) Zhao, H.; Fan, X.; Yu, J.; Zhu, C. Silver-catalyzed ring-opening
strategy for the synthesis of β- and γ-fluorinated ketones. J. Am. Chem.
Soc. 2015, 137, 3490. (g) Ren, S.; Feng, C.; Loh, T.-P. Iron- or silver-
catalyzed oxidative fluorination of cyclopropanols for the synthesis of
β-fluoroketones. Org. Biomol. Chem. 2015, 13, 5105. (h) Murali, R. V.
N. S.; Rao, N. N.; Cha, J. K. C-alkynylation of cyclopropanols. Org.
Lett. 2015, 17, 3854. (i) Kananovich, D. G.; Konik, Y. A.; Zubrytski,
̀
(l) Huang, X.; Patil, M.; Fares, C.; Thiel, W.; Maulide, N. Sulfur(IV)-
mediated transformations: from ylide transfer to metal-free arylation
of carbonyl compounds. J. Am. Chem. Soc. 2013, 135, 7312.
(m) Eberhart, A. J.; Cicoira, C.; Procter, D. J. Nucleophilic ortho-
allylation of pyrroles and pyrazoles: An accelerated Pummerer/thio-
Claisen rearrangement sequence. Org. Lett. 2013, 15, 3994.
(n) Eberhart, A. J.; Procter, D. J. Nucleophilic ortho-propargylation
of aryl sulfoxides: An interrupted Pummerer/allenyl thio-Claisen
rearrangement sequence. Angew. Chem., Int. Ed. 2013, 52, 4008.
̈
D. M.; Jarving, I.; Lopp, M. Simple access to β-trifluoromethyl-
substituted ketones via copper-catalyzed ring-opening trifluoromethy-
lation of substituted cyclopropanols. Chem. Commun. 2015, 51, 8349.
(j) Zhou, X.; Yu, S.; Kong, L.; Li, X. Rhodium(III)-catalyzed coupling
of arenes with cyclopropanols via C−H activation and ring opening.
ACS Catal. 2016, 6, 647. (k) Jia, K.; Zhang, F.; Huang, H.; Chen, Y.
Visible-light-induced alkoxyl radical generation enables selective
C(sp3)−C(sp3) bond cleavage and functionalizations. J. Am. Chem.
Soc. 2016, 138, 1514. (l) Davis, D. C.; Walker, K. L.; Hu, C.; Zare, R.
N.; Waymouth, R. M.; Dai, M. Catalytic carbonylative spirolactoniza-
tion of hydroxycyclopropanols. J. Am. Chem. Soc. 2016, 138, 10693.
(m) Zhang, H.; Wu, G.; Yi, H.; Sun, T.; Wang, B.; Zhang, Y.; Dong,
G.; Wang, J. Copper(I)-catalyzed chemoselective coupling of
cyclopropanols with diazoesters: ring-opening C−C bond formations.
Angew. Chem., Int. Ed. 2017, 56, 3945. (n) Zhou, X.; Yu, S.; Kong, L.;
Li, X. Rhodium(III)-catalyzed coupling of arenes with cyclopropanols
via C−H activation and ring opening. ACS Catal. 2016, 6, 647.
(o) Ye, Z.; Cai, X.; Li, J.; Dai, M. Catalytic cyclopropanol ring
opening for divergent syntheses of γ-butyrolactones and δ-ketoesters
containing all-carbon Quaternary centers. ACS Catal. 2018, 8, 5907.
(14) Kawashima, H.; Yanagi, T.; Wu, C.-C.; Nogi, K.; Yorimitsu, H.
Regioselective C−H sulfanylation of aryl sulfoxides by means of
Pummerer-type activation. Org. Lett. 2017, 19, 4552.
́
(o) Fernandez-Salas, J. A.; Eberhart, A. J.; Procter, D. J. Metal-free
CH−CH-type cross-coupling of arenes and alkynes directed by a
multifunctional sulfoxide group. J. Am. Chem. Soc. 2016, 138, 790.
̈
(p) Eberhart, A. J.; Shrives, H.; Zhang, Y.; Carrer, A.; Parry, A. V. S.;
Tate, D. J.; Turner, M. L.; Procter, D. J. Sulfoxide-directed metal-free
cross-couplings in the expedient synthesis of benzothiophene-based
components of materials. Chem. Sci. 2016, 7, 1281. (q) Shrives, H. J.;
́
Fernandez-Salas, J.; Hedtke, C.; Pulis, A. P.; Procter, D. J.
Regioselective synthesis of C3 alkylated and arylated benzothio-
phenes. Nat. Commun. 2017, 8, 14801. (r) Shang, L.; Chang, Y.; Luo,
F.; He, J.-N.; Huang, X.; Zhang, L.; Kong, L.; Li, K.; Peng, B. Redox-
neutral α-arylation of alkyl nitriles with aryl sulfoxides: A rapid
electrophilic rearrangement. J. Am. Chem. Soc. 2017, 139, 4211.
(s) Kaldre, D.; Klose, I.; Maulide, N. Sterodivergent synthesis of 1,4-
dicarbonyls by traceless charge-accelerated sulfonium rearrangement.
̌
̌
Science 2018, 361, 664. (t) Siauciulis, M.; Sapmaz, S.; Pulis, A. P.;
Procter, D. J. Dual vicinal functionalisation of heterocycles via an
interrupted Pummerer coupling/[3,3]-sigmatropic rearrangement
cascade. Chem. Sci. 2018, 9, 754. (u) He, Z.; Shrives, H. J.;
(15) Yanagi, T.; Otsuka, S.; Kasuga, Y.; Fujimoto, K.; Murakami, K.;
Nogi, K.; Yorimitsu, H.; Osuka, A. Metal-free approach to biaryls
from phenols and aryl sulfoxides by temporarily sulfur-tethered
regioselective C−H/C−H coupling. J. Am. Chem. Soc. 2016, 138,
14582.
́
́
Fernandez-Salas, J. A.; Abengozar, A.; Neufeld, J.; Yang, K.; Pulis, A.
P.; Procter, D. J. Synthesis of C2 Substituted Benzothiophenes via an
Interrupted Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of
Benzothiophene S-Oxides. Angew. Chem., Int. Ed. 2018, 57, 5759.
(16) (a) Jie, X.; Shang, Y.; Zhang, X.; Su, W. Cu-catalyzed sequential
dehydrogenation−conjugate addition for β-functionalization of
saturated ketones: scope and mechanism. J. Am. Chem. Soc. 2016,
138, 5623. (b) Shang, Y.; Jie, X.; Jonnada, K.; Zafar, S. N.; Su, W.
Dehydrogenative desaturation-relay via formation of multicenter-
stabilized radical intermediates. Nat. Commun. 2017, 8, 2273.
(17) The sulfides, sulfoxides, sulfoniums, and sulfones have been
proved to be versatile reagents for cross-coupling. For reviews, see:
(a) Dubbaka, S. R.; Vogel, P. Organosulfur compounds: electrophilic
reagents in transition-metal-catalyzed carbon−carbon bond-forming
reactions. Angew. Chem., Int. Ed. 2005, 44, 7674. (b) Wang, L.; He,
W.; Yu, Z. Transition-metal mediated carbon−sulfur bond activation
and transformations. Chem. Soc. Rev. 2013, 42, 599. (c) Modha, S. G.;
Mehta, V. P.; Van der Eycken, E. V. Transition metal-catalyzed C−C
bond formation via C−S bond cleavage: an overview. Chem. Soc. Rev.
2013, 42, 5042. (d) Pan, F.; Shi, Z. J. Recent advances in transition-
metal-catalyzed C−S activation: from thioester to (hetero)aryl
thioether. ACS Catal. 2014, 4, 280. (e) Gao, K.; Otsuka, S.; Baralle,
A.; Nogi, K.; Yorimitsu, H.; Osuka, A. Cross-coupling of aryl sulfides
powered by N-heterocyclic carbene ligands. Yuki Gosei Kagaku
Kyokaishi 2016, 74, 1119. (f) Otsuka, S.; Nogi, K.; Yorimitsu, H. C−S
bond activation. Top. Curr. Chem. 2018, 376, 13.
(18) Barbero, N.; Martin, R. Ligand-free Ni-catalyzed reductive
cleavage of inert carbon−sulfur bonds. Org. Lett. 2012, 14, 796.
(19) (a) Akai, S.; Kawashita, N.; Wada, Y.; Satoh, H.; Alinejad, A.
H.; Kakiguchi, K.; Kuriwaki, I.; Kita, Y. Regioselective, nucleophilic
carbon−carbon bond formation at the C4-position of indoles initiated
by the aromatic Pummerer-type reaction. Tetrahedron Lett. 2006, 47,
1881. (b) Feldman, K. S.; Vidulova, D. B. Extending Pummerer
Reaction Chemistry. Application to the Oxidative Cyclization of
Indole Derivatives. Org. Lett. 2004, 6, 1869. (c) Feldman, K. S.;
Skoumbourdis, A. P. Extending Pummerer Reaction Chemistry.
Synthesis of ( )-Dibromophakellstatin by Oxidative Cyclization of an
́
(v) Aukland, M. H.; Talbot, F. J. T.; Fernandez-Salas, J. A.; Ball, M.;
Pulis, A. P.; Procter, D. J. An Interrupted Pummerer/Nickel-Catalysed
Cross-Coupling Sequence. Angew. Chem., Int. Ed. 2018, 57, 9785.
(w) Zhang, Z.; Luo, Y.; Du, H.; Xu, J.; Li, P. Synthesis of α-
heterosubstituted ketones through sulfur mediated difunctionalization
of internal alkynes. Chem. Sci. 2019, 10, 5156.
(12) For reviews, see: (a) Gibson, D. H.; DePuy, C. H.
Cyclopropanol chemistry. Chem. Rev. 1974, 74, 605. (b) Kulinkovich,
O. G. The chemistry of cyclopropanols. Chem. Rev. 2003, 103, 2597.
(c) Mack, D. J.; Njardarson, J. T. Recent advances in the metal-
catalyzed ring expansions of three-and four-membered rings. ACS
Catal. 2013, 3, 272. (d) Nikolaev, A.; Orellana, A. Transition-metal-
catalyzed C−C and C−X bond-forming reactions using cyclo-
propanols. Synthesis 2016, 48, 1741. (e) Fumagalli, G.; Stanton, S.;
Bower, J. F. Recent methodologies that Exploit C−C single-bond
cleavage of strained ring systems by transition metal complexes. Chem.
Rev. 2017, 117, 9404. (f) Ebner, C.; Carreira, E. M. Cyclopropanation
strategies in recent total syntheses. Chem. Rev. 2017, 117, 11651.
(13) For selected recent applications, see: (a) Parida, B. B.; Das, P.
P.; Niocel, M.; Cha, J. K. C−acylation of cyclopropanols: preparation
of functionalized 1,4-diketones. Org. Lett. 2013, 15, 1780. (b) Cheng,
K.; Walsh, P. J. Arylation of aldehyde homoenolates with aryl
bromides. Org. Lett. 2013, 15, 2298. (c) Li, Y.; Ye, Z.; Bellman, T. M.;
Chi, T.; Dai, M. Efficient synthesis of β-CF3/SCF3-substituted
carbonyls via copper-catalyzed Electrophilic ring-opening cross-
coupling of cyclopropanols. Org. Lett. 2015, 17, 2186. (d) Ye, Z.;
Dai, M. An Umpolung strategy for the synthesis of β-aminoketones
via copper-catalyzed electrophilic amination of cyclopropanols. Org.
Lett. 2015, 17, 2190. (e) Ye, Z.; Gettys, K. E.; Shen, X.; Dai, M.
Copper-catalyzed cyclopropanol ring opening Csp3−Csp3 cross-
E
DOI: 10.1021/acs.orglett.9b01908
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Imidazole Derivative. Org. Lett. 2005, 7, 929. (d) Feldman, K. S.;
Vidulova, D. B.; Karatjas, A. G. Extending Pummerer Reaction
Chemistry. Development of a Strategy for the Regio- and Stereo-
selective Oxidative Cyclization of 3-(ω-Nucleophile)-Tethered
Indoles. J. Org. Chem. 2005, 70, 6429. (e) Feldman, K. S.; Karatjas,
A. G. Extending Pummerer Reaction Chemistry. Asymmetric
Synthesis of Spirocyclic Oxindoles via Chiral Indole-2-sulfoxides.
Org. Lett. 2006, 8, 4137. (f) Feldman, K. S.; Fodor, M. D. Extending
Pummerer Reaction Chemistry: ( )-Dibromoagelaspongin Synthesis
and Related Studies. J. Org. Chem. 2009, 74, 3449.
F
DOI: 10.1021/acs.orglett.9b01908
Org. Lett. XXXX, XXX, XXX−XXX