C-C Bond-Forming Strategy by Manganese-Catalyzed Oxidative Ring-Opening Cyanation and Ethynylation of Cyclobutanol Derivatives

Article abstract of DOI:10.1002/anie.201510973

A novel C-C bond-forming strategy employing manganese-catalyzed ring-opening of cyclobutanol substrates, followed by cyanation or ethynylation, is described. A cyano C1 unit and ethynyl C2 unit are regiospecifically introduced to the γ-position of ketones at room temperature, providing a mild yet powerful method for production of elusive aliphatic nitriles and alkynes. All transformations described are based on a common sequence: 1) oxidative ring-opening of cyclobutanol substrates by C-C bond cleavage; 2) radical addition to triple bonds bearing an arylsulfonyl group; and 3) radical-mediated C-S bond cleavage.

Full text of DOI:10.1002/anie.201510973

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International Edition: DOI: 10.1002/anie.201510973
German Edition: DOI: 10.1002/ange.201510973
À
C C Bond-Forming Reactions
À
C C Bond-Forming Strategy by Manganese-Catalyzed Oxidative Ring-
Opening Cyanation and Ethynylation of Cyclobutanol Derivatives
Rongguo Ren, Zhen Wu, Yan Xu, and Chen Zhu*
À
Abstract: A novel C C bond-forming strategy employing
manganese-catalyzed ring-opening of cyclobutanol substrates,
followed by cyanation or ethynylation, is described. A cyano
C1unit and ethynyl C2unit are regiospecifically introduced to
the g-position of ketones at room temperature, providing
a mild yet powerful method for production of elusive aliphatic
nitriles and alkynes. All transformations described are based
on a common sequence: 1) oxidative ring-opening of cyclo-
À
butanol substrates by C C bond cleavage; 2) radical addition
to triple bonds bearing an arylsulfonyl group; and 3) radical-
À
mediated C S bond cleavage.
T
ertiary cycloalkanols have proven to be privileged precur-
Scheme 1. Manganese-catalyzed ring-opening functionalization of
cyclobutanol substrates. TBS=tert-butyldimethylsilyl.
sors for regiospecific synthesis of distally functionalized
[1]
À
ketones by cleavage of the strained cyclic C C bonds.
Compared to cyclopropanol, ring-opening of cyclobutanol is
more challenging owing to a lower strain energy and an
appreciable Thorpe–Ingold effect, which thus stabilizes cyclo-
suppressed. The new method involved manganese-catalyzed
ring-opening of cyclobutanol adducts to produce g-azido
ketones (Scheme 1A, right).[9] To further demonstrate the
utility and generality of the manganese-catalyzed method,
butanol.[2] Methods for cleavage of the C C bond of cyclo-
À
butanol include: a) transition-metal-catalyzed b-carbon elim-
ination (for example, palladium or rhodium),[3] and b) single
electron oxidation-triggered “radical clock” ring-opening;[4]
the later pathway has been investigated to a lesser extent by
comparison. Prompted by seminal work concerning the
radical-mediated ring-opening of cyclobutanol, which
employs stoichiometric amounts of oxidative metal reagents
(for example, Pb(OAc)4 and ceric ammonium nitrate),[5,6] we
recently disclosed the first silver-catalyzed ring-opening
fluorination of cyclobutanol-type molecules to generate g-
fluorinated ketones (Scheme 1A, left).[7] However, it later
transpired that silver-catalyzed ring-opening of cyclobutanol
had limited applications. Studies revealed that silver catalyzed
transformations favored intramolecular cyclization of the
alkyl radical intermediate (the open-chain tautomer of cyclo-
butoxyl radical) rather than capture by extrinsic radical
acceptors.[8] Consequently, a modified procedure was devel-
oped by which intramolecular cyclization was efficiently
À
herein we report a novel C C bond-forming strategy by
manganese-catalyzed oxidative ring-opening cyanation and
ethynylation of cyclobutanol. At room temperature, the
cyano and ethynyl groups are regioselectively introduced to
the g-position of ketones as a C1 and C2unit, respectively,
providing a mild but powerful method for production of
diverse ketone derivatives, which are sometimes difficult to
prepare. All of these transformations are based on a common
sequence: a) oxidative ring-opening of cyclobutanol mole-
À
cules by C C bond cleavage; b) radical addition to triple
bonds bearing an arylsulfonyl group; and c) radical-mediated
À
C S bond cleavage (Scheme 1B).
The versatile cyano functional group is used extensively
for preparation of amines, amides, aldehydes, and carboxylic
acids.[10] Owing to its robust transformable properties, nitrile
synthesis is of great significance in both academia and
industry.[11] With this in mind, we commenced our investiga-
tions into manganese-catalyzed ring-opening cyanation of
cyclobutanol-type molecules using tosyl cyanide.[12] After
considerable efforts, the reaction parameters were defined
(Table 1; for details see the Supporting Information). We
found that 1) manganese acetate was superior to other
common manganese catalysts; 2) use of N,N-bidentate
ligand 2,2’-bipyridine (bipy) significantly improved product
yields; 3) hypervalent iodine oxidant was crucial to the
reaction outcome; and 4) TMSCN used in lieu of TsCN did
not enable the cyanation reaction.
[*] R. Ren, Z. Wu, Y. Xu, Prof. Dr. C. Zhu
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University
199 Ren-Ai Road, Suzhou, Jiangsu 215123 (China)
E-mail: chzhu@suda.edu.cn
Prof. Dr. C. Zhu
Key Laboratory of Synthesis Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Science
With the optimized reaction conditions in hand, we set out
to evaluate the substrate scope of the cyanation reaction
(Scheme 2). Both electron-rich and deficient substrates
345 Lingling Road, Shanghai 200032 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510973.
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Table 1: Effect of ligand and oxidant.
Entry
Variation of reaction conditions
Yield [%][a]
1
2
3
4
5
6
7
8
none
no bipy
86
30
66
<10
56
49
Phen instead of bipy
Py instead of bipy
BI-OH instead of PIDA
IBX instead of PIDA
DMP instead of PIDA
TMSCN instead of TsCN
68
0
[a] Yields of isolated products.
afforded the g-cyanated ketones in synthetically useful yields.
It seemed that steric hindrance had little impact on the
reaction, as all ortho-, meta-, and para-substituted substrates
led to similar yields (2d–2 f). The presence of halide, such as
chloride or bromide, was valuable in the product (2i and 2j)
because it provided a platform for further product manipu-
lation during cross-coupling reactions. Besides phenyl
adducts, cyanation of polyaryl cyclobutanol molecules also
delivered good yields (2n–2o). Heteroaryl and alkyl cyclo-
butanol substrates were also suitable substrates for produc-
tion of the corresponding g-cyanated ketones (2p–2s). The
transformation of susceptible alkenyl cyclobutanol was note-
worthy, though the material yielded a reasonably low product
yield (2u). Moreover, cyanation of less reactive substrates
bearing multiple substituents on the cyclobutyl ring still
proceeded smoothly to give the desired cyanation products
(2v and 2w).
Encouraged by the cyanation reaction, we then inves-
tigated the ring-opening ethynylation of cyclobutanol sub-
strates.[13] Although alkynylation reactions are achievable
with costly palladium catalyst and perishable alkynylating
reagents, alkynyl bromides or alkynyl hypervalent iodine for
example,[14] a general method that uses inexpensive catalyst
and routine reagents is still desired. Under the previously
described reaction conditions, but employing TBS-protected
phenylsulfonyl ethyne 3 as the alkynylating agent, cyclo-
butanol was readily converted into the g-ethynylated ketone 4
(Scheme 3). Variation of oxidant from PIDA to DMP
improved the yields of alkynylation reactions attempted, but
in some cases PIDA produced better conversions (4 f, 4h, 4n,
and 4s). Both electron-rich and deficient aryl substituted
cyclobutanol adducts were tolerated during reaction, demon-
strating the broad functional group compatibility of the
method. While a variety of phenyl substituted substrates
resulted in good product yields, the reaction of naphthyl
Scheme 2. Ring-opening cyanation of tert-cyclobutanol substrates.
Reaction conditions: 1 (0.20 mmol), TsCN (0.30 mmol, 1.5 equiv),
Mn(OAc)3·2H2O (0.04 mmol, 0.2 equiv), bipy (0.044 mmol,
0.22 equiv), and PIDA (0.40 mmol, 2.0 equiv) in CH3CN (1.5 mL) at
RT. Yields of isolated products are given.
cyclobutanol gave a surprisingly low yield (4b). In contrast,
yield did not drop significantly when a strong electron-
withdrawing group, such as CF3, was present in the substrate
(4m). Heteroaryl and alkyl cyclobutanol substrates reacted
readily to afford the corresponding alkynes in synthetically
useful yields (4o–4r). Highly functionalized cyclobutanol
substrates were also suitable (4s and 4t), though less reactive.
Notably, alkynylation of bicyclic tertiary alcohols predom-
inantly furnished the thermodynamically favored anti-iso-
mers, as determined by NOE experiments, which was
supposed to be controlled by the steric congestion apparent
at the reaction site (4u and 4v). In this way, reaction of 1-
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phenylcyclopropanol also led to the corresponding b-alkyny-
lated ketone in 65% isolated yield, whereas cyclopentanol
substrates were incompatible with the reaction conditions.
The TBS group present in the products is easily removed by
fluoride reagent, delivering carbonyl-containing terminal
alkynes.
The alkynylation method could be applied to preparation
of internal alkynes. For example, reaction of cyclobutanol 1a
with phenylsulfonyl alkyne 5 or 7 readily generated the
corresponding alkyne 6 or 8, respectively [Scheme 4, Eq. (1)
and (2)]. Remarkably, synthesis of the asymmetric dialkyl
alkyne 8 is challenging and has not been accessed by
previously reported procedures.[14] Moreover, preliminary
results indicated that this method could be harnessed for
allylation of cyclobutanol substrates, affording elusive car-
bonyl-containing linear alkenes by three-carbon growth
[Scheme 4, Eq. (3)].
À
Scheme 4. Other examples of ring-opening C C bond formation.
Based on the experimental observations, a mechanistic
pathway was postulated (Figure 1). Initially, interaction
between a MnIII salt and hypervalent iodine generates an
oxidized MnV species a.[15] Subsequently, a incorporates
cyclobutanol 1 to form complex b, which undergoes a simul-
taneous single-electron transfer (SET) process to give cyclo-
butyloxy radical d. Radical d can tautomerize into an alkyl
carbon radical e after ring-opening. The interaction between
À
radical e and arylsulfone results in cleavage of the C S bond,
which eventually gives rise to cyanation product 2 or
alkynylation product 4.
À
In summary, we described a novel and general C C bond-
forming strategy by the manganese-catalyzed ring-opening
cyanation and ethynylation of cyclobutanol-type substrates. A
variety of g-cyanated and alkynylated alkyl ketones were
regioselectively synthesized at room temperature, providing
mild but powerful methods for production of elusive aliphatic
nitriles and alkynes. The procedure could be further applied
to ring-opening allylation. Other applications are under
investigation in our laboratory.
Scheme 3. Ring-opening ethynylation of tert-cyclobutanol substrates.
Reaction conditions: 1 (0.20 mmol), 3 (0.30 mmol, 1.5 equiv), Mn-
(OAc)3·2H2O (0.04 mmol, 0.2 equiv), bipy (0.044 mmol, 0.22 equiv),
and DMP (0.40 mmol, 2.0 equiv) in CH3CN (1.5 mL) at RT. Yields of
isolated products are given. [a] PIDA (2.0 equiv) was used instead of
DMP. [b] Mn(OAc)3·H2O (1.5 equiv) was used instead of the combina-
tion of Mn(OAc)3·H2O, bipy, and DMP.
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Acknowledgements
C.Z. is grateful for the financial support from Soochow
University, the National Natural Science Foundation of China
(Grant no. 21402134), the Natural Science Foundation of
Jiangsu Province (Grant no. BK20140306), and the Priority
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Keywords: alkynylation · cyanation · cyclobutanol ·
manganese catalysis · ring-opening
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Received: November 26, 2015
Published online: January 22, 2016
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