Reductive Carbocyclization of Homoallylic Alcohols to syn-Cyclobutanes by a Boron-Catalyzed Dual Ring-Closing Pathway

Article abstract of DOI:10.1002/anie.201713285

The organoborane-catalyzed reductive carbocyclization of homoallylic alcohols has been developed by using hydrosilanes as reducing reagents to provide a range of 1,2-disubstituted arylcyclobutanes. The reaction proceeds in a cis-selective manner with high efficiency under mild conditions. Mechanistic studies, including deuterium scrambling and Hammett studies, and DFT calculations, suggest a dual ring-closing pathway.

Full text of DOI:10.1002/anie.201713285

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Accepted Article
Title: Reductive Carbocyclization of Homoallylic Alcohols to syn-
Cyclobutanes via Boron-Catalyzed Dual Ring-Closing Pathway
Authors: Chinmoy Kumar Hazra, Jinhoon Jeong, Hyunjoong Kim, Mu-
Hyun Baik, Sehoon Park, and Sukbok Chang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201713285
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10.1002/anie.201713285
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Reductive Carbocyclization of Homoallylic Alcohols to syn-
Cyclobutanes via Boron-Catalyzed Dual Ring-Closing Pathway
Chinmoy Kumar Hazra, Jinhoon Jeong, Hyunjoong Kim, Mu-Hyun Baik,* Sehoon Park,* and Sukbok
Chang*
cation with C–C bond formation. Inspired by these results, we
Abstract: Organoborane-catalyzed reductive carbocyclization of
envisioned that homoallylic alcohols bearing an aryl substituent at
homoallylic alcohols has been developed by using hydrosilanes
the C-3 position may undergo a carbocyclization with the
as a reducing reagent to provide a range of 1,2-disubstituted
anchimeric assistance by an adjacent alkenyl group to give
arylcyclobutanes. It proceeds in a cis-selective manner with high
cyclobutanes under a B(C6F5)3/silane catalytic system. Reported
efficiency under mild conditions. Mechanistic studies including
herein is the first boron-catalyzed reductive cyclobutanation of
deuterium scrambling and Hammett studies, and DFT
homoallylic alcohols with hydrosilanes (Scheme 1d). The present
calculations allowed to propose a dual ring-closing pathway.
catalysis
produces
a
range
of
1,2-disubstituted
(hetero)arylcyclobutanes with remarkably high efficiency and
excellent cis-selectivity. Experimental and computational
experiments strongly support a stepwise, dual ring-closing
pathway.
Four-membered carbocycles such as cyclobutanes and cy-
clobutenes are valuable intermediates in organic synthesis as
they can undergo a wide range of ring-opening, -contraction, or -
expansion reactions.[1] They give access to many scaffolds found
in biologically active molecules that are difficult to be prepared by
other means in drug design.[2] Conventional catalytic methods for
the synthesis of such four-membered carbocycles can be largely
divided in two types: (i) intra- or intermolecular [2+2]
cycloadditions[3,4] and (ii) ring-expansion of cyclopropylcarbinyl
precursors by a Wagner-Meerwein shift.[5,6] A powerful alternative
to the conventional approaches has been developed
independently by Ito and Buchwald, where alkene substrates
bearing (pseudo)halides undergo reductive cyclization via copper
catalysis. This reaction was proposed to involve a ring closure on
organocuprate intermediates formed in situ, accompanied by the
release of a (pseudo)halide salt (Scheme 1a).[7]
Recently, we reported
a
B(C6F5)3-catalyzed cascade
conversion of furans providing silicon-functionalized compounds,
in which a homoallylic intermediate was assumed to undergo a
concerted SN2'-type ring-closing process to furnish cyclopropanes
with exclusive trans-selectivity (Scheme 1b).[8] Gagné found that
B(C6F5)3 promotes a reductive cyclization of silyl-protected
unsaturated polyols to give cyclopropanes and cyclopentanes
depending on substituents adjacent to an alkenyl moiety (Scheme
1c).[9] Unlike in our previous work,[8] Gagné suggested a stepwise
pathway involving an intramolecular attack of a neighbouring
alkenyl group at the activated C–O bond of silaoxonium ion taking
advantage of an anchimeric assistance[10] to generate a benzylic
[*]
Dr. C. K. Hazra, J. Jeong, H. Kim, Prof. Dr. M-H. Baik, Dr. S. Park,
Prof. Dr. S. Chang
Center for Catalytic Hydrocarbon Functionalizations
Institute for Basic Science (IBS),
Daejeon 305-701 (South Korea)
and
Scheme 1. ac) Reductive catalytic approaches towards the synthesis of
carbocycles. d) B(C6F5)3-catalyzed reductive cyclobutanation (this work).
At the outset of this study, we chose one representative
homoallylic O-silyl ether (Scheme 1d, R = Me; X = OSiEt3) and
optimized reaction conditions (see the S.I.). It underwent a
condensative cyclization when 1.5 equiv of EtMe2SiH was used in
the presence of 2.0 mol % of B(C6F5)3 in dichloromethane to afford
1,2-disubstituted cyclobutane quantitatively in 0.5 h at 23 oC. The
stereochemistry of the product was determined to be syn by 2D
NMR experiments, and its diastereomeric ratio (dr.) was
calculated by 1H NMR of the crude reaction mixture (dr. >95:5).
Department of Chemistry
Korea Advanced Institute of Science & Technology (KAIST)
Daejeon 305-701 (South Korea)
E-mail: mbaik2805@kaist.ac.kr
sehoonp@kaist.ac.kr
sbchang@kaist.ac.kr
Supporting information for this article is given via a link at the end of
the document.
1
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Table 1: Substrate scope in the ring-closing of silyl-protected and parent homoallylic alcohols.[a]
[a] B(C6F5)3 (2.0~5.0 mol %), substrate (0.2 mmol), EtMe2SiH or PhSiH3 (1.5~2.2 equiv) in CH2Cl2 at 23 oC for 0.5 h: Isolated products yields are presented. Diastereomeric ratio
t
(dr.) was determined by 1H NMR analysis of the crude reaction mixture. Si = SiMe3, SiEt3, or SiMe2 Bu. [b] 2.2 equiv of PhMe2SiD was used instead of EtMe2SiH.
With the optimized conditions in hand [2.0 mol % B(C6F5)3,
1.5 equiv of EtMe2SiH, CH2Cl2, 23 oC], we investigated substrate
scope in the cyclobutanation of silyl-protected homoallylic
alcohols (Table 1, top). In general, the reaction was highly facile
to be completed within 0.5 h and diastereoselectivity was
excellent in most cases. Functional groups such as phenoxy or
thioether, which were known to be labile under the reductive
conditions,[11] were compatible (3a and 3b, respectively).
Significantly, the olefinic geometry (E or Z) of substrates was not
a stereochemistry-determining factor as demonstrated in the
formation of syn-cyclobutane 3c. Analogous substrates bearing
biphenyl or naphthyl groups were also reactive and selective for
this cyclizative transformation (3d and 3e, respectively). A
substrate bearing an alkynyl moiety was also smoothly cyclized
leading to syn-3f. However, an O-silyl homoallyl ether having a
dibenzofuranyl group underwent the desired cyclization in
decreased diastereoselectivity (3g). As in the case of 3c, when a
series of (Z)-O-silyl homoallyl ethers of a 3-hexenyl skeleton (R
alcohols. Pleasingly, the cyclization of homoallylic alcohols
occurred under slightly modified conditions (Table 1, middle: 5.0
mol % B(C6F5)3, 2 equiv of PhSiH3).[13] A series of homoallylic
alcohols having aryl groups were reactive to be converted to the
corresponding cyclobutanes in high syn-selectivity (3a3d and
3l3o). Notably, a vinyl substituent at the phenyl moiety remained
intact although the diaseteroselectivity was slightly decreased
(3p). Replacing an olefinic substituent from methyl (R = CH3) to
ethyl (R = CH2CH3) and pentyl (R = (CH2)4CH3) did not deteriorate
the reaction efficiency and diastereoselectivity (3j3k and
3q3w).
Gagné et. al. showed that 3,6-dihydro-2H-pyrans undergo
selective allylic C–O bond cleavage to generate silyl-protected
homoallylic alcohols via B(C6F5)3 catalysis (Table 1, bottom-
dotted box).[9c] Inspired by this report, we envisaged to test C-4
aryl-substituted dihydropyrans as substrates for the
cyclobutanation. Indeed, a series of 4-aryl-dihydro-2H-pyrans
were smoothly transformed to syn-cyclobutanes under the similar
conditions (Table 1, bottom: 2.0 mol % B(C6F5)3, 2.2 equiv of
EtMe2SiH). As in the reaction of O-silyl homoallyl ethers, the
cyclobutanation of pyran substrates bearing electronic and/or
steric variations showed good to excellent reactivity and syn-
selectivity. The reaction of a pyran substrate with a deuterated
=
Et) were subjected to the standard conditions, the
corresponding 1,2-arylethylcyclobutanes were formed with syn-
stereochemistry (3h3k).[12]
Next, we were curious as to whether unprotected homoallylic
alcohols could be viable for the reductive cyclobutanation. This
route was envisioned to be synthetically more convenient since
the above O-silyl homoallyl ethers were prepared from the parent
hydrosilane
afforded
3a-d2
with
excellent
syn-
diastereoselectivity, demonstrating the selective ring-opening
2
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10.1002/anie.201713285
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and closing cascade of the pyran substrates. It is noteworthy that
the reaction of a 2H-pyran possessing a benzofuranyl group
cleanly gave the desired product 3y in good yield.
Based on the present selectivity and precedent reports,[8,9]
three cyclization pathways can be proposed (Scheme 2): (i) SN2'-
type concerted mechanism (path A), (ii) stepwise cyclobutanation
(path B), and (iii) stepwise ring-closing and ring-expansion
cascade (path C). All three possible pathways are assumed to be
initiated by the formation of a silaoxonium ion complexed with
borohydride (I).[14]
Scheme 2. Possible reaction pathways for cyclobutanation.
0.3
0.25
0.2
To validate the mechanistic details in the present cyclization,
we carried out a series of experimental mechanistic studies. A
reaction of (E)-1a-[OSi] with Ph2SiD2 (1.2 equiv) in the presence
of B(C6F5)3 catayst proceeded to afford syn-3a-d1 with a
complete deuterium incorporation (Scheme 3a). The B(C6F5)3-
catalyzed reaction of 1:1 mixture of E/Z isomeric 1l-[OH] with
PhSiH3 furnished a single product 3l in 93% yield with 93:7 of dr.
(Scheme 3b). This result may support the stepwise pathways B
or C, where a cyclobutyl benzylic carbocation III (Scheme 2) will
be generated as a common intermediate irrespective of the
olefinic geometry in homoallylic alcohol substrates.[15]
0.15
0.1
0.05
0
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
-0.05
-0.1
y = -0.58x - 0.036
R² = 0.95
-0.15
-0.2
Scheme 3. Experimental mechanistic studies. “conditions“: B(C6F5)3 (2~10
mol %) in CH2Cl2 at 23 oC.
We designed a reaction of a bis-deuterated homoallylic
alcohols at the C-1 position (1a-[OH]-d2) to see the involvement
of path B and/or path C (Scheme 3c). In path C, a 1:1 mixture of
cyclobutane products incorporating bis-deuteriums at the C-3
and C-4 position (3a-d2/3a-d2') is predicted while a single labeled
product 3a-d2 only will be obtained if it follows path B since a
direct formation of a cyclobutyl carbocation III from the
presupposed silaoxonium ion I will be assumed. Intruigingly, the
reaction of 1a-[OH]-d2 afforded a ~ 7:3 mixture of 3a-d2 and 3a-
d2′ in 92% crude yield, suggesting that path B and C are
operative in a bifurcation manner for the ring-closing process.[16]
To identify the rate-determining step (RDS), kinetic isotope
effect (KIE) was measured to be 1.0 in cyclization reactions of
1a-[OSi] with Et3SiH and its deuterium analogue (Scheme 3d).
Again, this result may suggest that a SN2'-type nucleophilic attack
of (C6F5)3BH– at the C-3 position of a silaoxonium ion I is less
likely.[17] When substrates possessing different types of leaving
groups at the C-1 position were allowed to react, the cyclizative
reaction efficiency was observed to decrease in this order: LG =
OSiEt3 > OTs ~ OMs >> Cl (Scheme 3e). Together with KIE data,
this result corroborates that the RDS step would be a
condensative intramolecular cyclization to form a carbocation
intermediate.
Electronic effects on the cyclization rate were subsequently
investigated (Scheme 3f). Plot of vi(x)/vi(H) against the σ+ Hammett
constants provided  value of –0.58 (R2 = 0.95), indicating that
substrates having more electron-rich aryl groups lead to
increased reaction rates.[18] This small  value can be taken to
indicate an early transition state,[19] where no strong resonance
interaction occurs,[20] while there is a small positive charge
polarization at the C-3 position in the RDS.
Scheme
4 visualizes the mechanism of cyclobutane
formation starting from the silaoxonium ion intermediate A that
we obtained from extensive explorations of the mechanism using
density functional calculations. For the forward reaction, the
intermediate A first traverses the transition state A-TS-B which
is 16.0 kcal/mol higher in energy than A. From A-TS-B, the
reaction affords the cyclopropane B which is energetically
downhill by –5.9 kcal/mol. However, with the given energy
landscape, there is a very shallow minimum for B, which is
presumed to lead some portion of activated molecules at the
transition state to directly proceed to the intermediate C not via
B.[21]
3
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In summary, we have developed a borane-catalyzed
carbocyclization of homoallylic alcohols and dihydro-2H-pyrans
to produce syn-1,2-disubstituted cyclobutanes in high yields and
with excellent selectivity. Mechanistic studies indicate that
stepwise dual ring-closing pathways are operative, while the
condensative intramoelcular cyclization is turnover limiting.
Tuning the electronic nature of C4-aryl groups of homoallyl
substrates can alter the reaction path to lead to cyclopropanes.
Acknowledgements
This research was supported by the Institute for Basic Science
(IBS-R010-D1) in Korea.
Conflict of interest
Scheme 4. DFT-derived energetics of the B(C6F5)3-mediated carbocyclization
of (E)-3-phenylpent-3-en-1-ol with Et3SiH (All structures were optimized at the
M06/6-31G** level of theory).
The authors declare no conflict of interest.
Keywords: Carbocyclization • Cyclobutanes • Homoallylic
alcohols •Anchimeric assistance • Stepwise dual pathways
Starting from intermediate B, the reaction may proceed
through either intermolecular hydridation to form a cyclopropane
product E or intramolecular ring-expansion to generate a
cyclobutane intermediate C. The barriers for both possibilities are
too low at 5.6 and 3.8 kcal/mol, respectively, to infer any
significant difference in the rate of these steps. Instead, it is more
meaningful that the hydridation to proceed to the left hand side
in Scheme 4 is an intermolecular process, whereas the ring-
expansion to the right hand side is an entropically beneficial
intramolecular event. Therefore, C at –10.4 kcal/mol should be
formed exclusively. The intermediate C may then be attacked by
a borohydride to give the product D, traversing another low
barrier of 5.4 kcal/mol. The hydridation from the top side is
estimated to be preferred by ~3 kcal/mol over the bottom side
attack to give the syn-selective product D.
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4
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[15] The calculated barrier for a SN2’-type concerted pathway is 8.72 kcal/mol
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5
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10.1002/anie.201713285
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Chinmoy Kumar Hazra, Jinhoon Jeong,
Hyunjoong Kim, Mu-Hyun Baik,* Sehoon
Park,* and Sukbok Chang*
Page No. – Page No.
Reductive Carbocyclization of
Homoallylic Alcohols to syn-
Cyclobutanes via Boron-Catalyzed
Dual Ring-Closing Pathway
Transition-metal free, organoborane-catalyzed reductive cyclobutanation of homoallylic alcohols and
their O-silyl ethers has been developed giving rise to 1,2-disubstituted arylcyclobutanes with high
efficiency and excellent cis-selectivity. Experimental and computational mechanistic studies led us to
propose stepwise dual ring-closing pathways driven by carbocation rearrangements.
[*]
Dr. C. K. Hazra, J. Jeong, H. Kim, Prof. Dr. M.-H. Baik, Dr.
Prof. Dr. S. Chang
Center for Catalytic Hydrocarbon Functionalizations
6
This article is protected by copyright. All rights reserved.
Institute for Basic Science (IBS),
Daejeon 305-701 (South Korea)