Radical Borylative Cyclization of 1,6-Dienes: Synthesis of Boron-Substituted Six-Membered Heterocycles and Carbocycles

Article abstract of DOI:10.1021/acs.orglett.8b00694

A radical borylative cyclization reaction of 1,6-dienes was developed to assemble boron-handled six-membered heterocycles and carbocycles. This reaction was initiated by the chemo- and regio-controlled addition of an N-heterocyclic carbene-boryl radical to one of the alkene tethers, followed by an intramolecular 6-exo cyclization to afford a six-membered ring framework. The utility of this method was demonstrated in the synthesis of diverse paroxetine analogues through late-stage derivatization of the boryl functional unit.

Full text of DOI:10.1021/acs.orglett.8b00694

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical Borylative Cyclization of 1,6-Dienes: Synthesis of Boron-
Substituted Six-Membered Heterocycles and Carbocycles
Jing Qi,†,§ Feng-Lian Zhang,†,§ Yun-Shuai Huang,† Ai-Qing Xu,† Shi-Chao Ren,† Zhen-Yu Yi,†
and Yi-Feng Wang*,†,‡
†Hefei National Laboratory for Physical Sciences at the Microscale, Center for Excellence in Molecular Synthesis of CAS, and
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, People’s Republic
of China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: A radical borylative cyclization reaction of 1,6-
dienes was developed to assemble boron-handled six-
membered heterocycles and carbocycles. This reaction was
initiated by the chemo- and regio-controlled addition of an N-
heterocyclic carbene−boryl radical to one of the alkene tethers,
followed by an intramolecular 6-exo cyclization to afford a six-
membered ring framework. The utility of this method was
demonstrated in the synthesis of diverse paroxetine analogues through late-stage derivatization of the boryl functional unit.
Scheme 1. Radical Borylative Cyclization of 1,6-Dienes
ix-membered heterocyclic and carbocyclic motifs are
Spresent as core structures in a variety of bioactive natural
products and pharmaceutical drugs.1 Therefore, developing
new, efficient methods to assemble these systems is a
preeminent goal in synthetic chemistry.2 In particular,
approaches that can construct boron-handled six-membered
rings3 are more desirable, because of the versatile chemistry of
the boryl functional unit for further synthetic and medicinal
applications.4
Borylative cyclization reactions represent a step-economical
strategy to make boron-substituted cyclic molecules, wherein
the ring systems and C−B bond are created in a single
operation.5 In this context, many transition-metal-catalyzed
reactions,6 as well as metal-free borylative cyclization reactions,7
have been reported for specific classes of alkene-containing
unsaturated substrates. However, most of them are relatively
limited to the formation of five-membered rings, and examples
to construct six-membered ones are very rare.6c,k,7 Thus, there
remains both a great demand and a great challenge to explore
conceptually distinct borylative cyclization methods that can
selectively construct six-membered rings with predictable
regiocontrol and stereocontrol. Herein, we describe a chemo-
selective, regioselective, and diastereoselective radical borylative
cyclization reaction of 1,6-dienes for the synthesis of boron-
handled six-membered heterocycles and carbocycles (see
Scheme 1). Notably, the present method could enable the
synthesis of diverse analogues of antidepressant paroxetine
through late-stage derivatization of the boryl group in the
products.
nitriles,12 and thioamides,13 polymerization of alkenes,14
homolytic substitution of disulfides,15 and inverse hydro-
boration of imines.16 However, the radical borylation of alkenes
and alkynes to access alkyl and alkenyl boron compounds
remains elusive.8d,17 Recently, Curran and Taniguchi,18 and our
group19 have independently disclosed N-heterocyclic carbene
(NHC)−boryl radical-promoted borylative cyclization reac-
tions of benzo[3,4]cyclo-dec-3-ene-1,5-diynes and 1,6-enynes,
resulting in facile construction of boron-tethered, unsaturated
cyclic ring systems. Stimulated by these results, we became
interested in the development of a radical borylative cyclization
of 1,6-dienes, from which boron-substituted saturated six-
membered heterocycles and carbocycles would be assembled.
However, this method should be challenging because of the
difficulties associated with control of the chemoselectivity,
regioselectivity, and diastereoselectivity for densely substituted
1,6-diene substrates.
We initiated our studies by evaluating the radical borylation/
cyclization of 1,6-diene (1a) with NHC−BH3 (2) as the boryl
radical precursor. Although there are two alkene moieties in the
Lewis base−boryl radicals that can be generated by hydrogen
abstraction of Lewis base−BH3 complexes8 have been emerging
as powerful species to enable a range of radical reactions,9
including the radical reduction of xanthates,10 organic halides,11
Received: March 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00694
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrate, based on our previous findings,19 we envisioned that
the initial addition of the NHC−boryl radical could occur
preferentially at the phenyl-substituted one. As expected, the
reaction proceeded in the presence of 2,2-azobis-
(isobutyronitrile) (AIBN) as the radical initiator, furnishing
3,4,5-trisubstituted piperidine (3a) in 32% yield (Table 1, entry
Table 2. Scope of Radical Borylative Cyclization of 1,6-
Dienes
a
a
Table 1. Optimization of Reaction Conditions
Yield (%)
initiator
b
c
entry
(x, mol %)
RSH (y, mol %)
3a
32
1a
d
1
2
3
4
5
6
AIBN (20)
AIBN (20)
AIBN (20)
AIBN (20)
TBHN (20)
65 (5:1)
trace
C9H19C(CH3)2SH (50)
C9H19C(CH3)2SH (20)
C9H19C(CH3)2SH (10)
C9H19C(CH3)2SH (20)
82
84
63
75
e
trace
d
26 (11:1)
trace
d
C9H19C(CH3)2SH (20) ND
98 (1:0)
a
Unless otherwise noted, the reactions were performed on a 0.2−0.5
mmol scale of 1a with 1.2 equiv of NHC−BH3 (2) in the presence of
an initiator (x mol %) and RSH (y mol %) in CH3CN (3 mL) at 80
b
°C, under a nitrogen atmosphere. NMR yield using tetrachloroethane
as an internal standard. Recovery yield of E/Z isomers of 1a. The
ratio of E/Z isomers of recovered 1a is shown in parentheses. Isolated
c
d
e
yield.
1). Remarkably, a single diastereomer was formed in the
cascade sequence to construct three consecutive stereogenic
centers. Interestingly, a mixture of E/Z (5:1) isomers of 1a was
recovered, even though the pure E isomer was utilized as the
starting material. This result indicated that the initial boryl
radical addition to the phenyl-substituted alkene tether should
be a reversible process. The addition of tert-dodecanethiol as
the polarity reversal catalyst11a,20 increased the yield to 82%
(Table 1, entry 2). Reducing the catalyst loading to 20 mol %
maintained a good isolated yield of 3a (Table 1, entry 3), while
further reduction to 10 mol % resulted in a diminished yield
(Table 1, entry 4). Moreover, the employment of di-tert-butyl
hyponitrite (TBHN) as the radical initiator gave a comparable
result (Table 1, entry 5). No reaction occurred in the absence
of a radical initiator, and 1a was recovered in a quantitative
yield (Table 1, entry 6), which suggested that a radical reaction
mechanism is involved in this transformation. On the other
hand, a series of transition-metal-catalyzed borylative cycliza-
tion reactions6 using 1a as the substrate were examined.
However, no cyclized product 3a was formed in all cases.21
Having developed the optimized reaction conditions, we
examined the generality of this radical borylative cyclization of
1,6-dienes 1 for the synthesis of borylated cyclic products 3
(Table 2). First, a gram-scale reaction of 1a was tested, and 3a
was isolated in 72% yield. 1,6-Dienes 1 bearing an aryl group as
R1 afforded borylated six-membered ring products 3 in good
yields. When R2 and R3 both are alkyl groups, only a single
diastereomer was formed. Benzene rings possessing various
functional groups were compatible, regardless of their
electronic nature and substitution pattern (for 3b−3f). A
range of cycloalkyl groups could be introduced onto the
piperidine ring with exclusive diastereoselectivity (for 3g−3j).
Interestingly, when a methyl group was installed at the internal
a
Unless otherwise noted, the reactions were performed on a 0.2−0.5
mmol scale of 1 (1.2 equiv) with NHC−BH3 (2) in the presence of
AIBN (20 mol %) and C9H19C(CH3)2SH (20 mol %) in CH3CN (3
b
mL) at 80 °C under a nitrogen atmosphere. Isolated yield of a gram
scale reaction. The stereochemistry of the major isomer was not
determined. Recovery yield of 1.
c
d
carbon of an alkene moiety, the desired six-membered ring
product 3k with a quaternary carbon was only isolated in 18%
yield, whereas a seven-membered ring 3k′, which could be
derived from a 7-endo cyclization step, was obtained in 57%
yield. The present method allowed the construction of
cyclohexane (for 3l) and pyran (for 3m) scaffolds. A pyridine
motif could be also installed (for 3n). In replacing an aryl
group, an ester (for 1o) and an amide moiety (for 1p) could be
utilized as the substituent R1, affording the desired products in
good selectivity and efficiency. The reaction of 1,6-dienes with a
hydrogen atom as the R2 substituent gave the cyclized products
in good yields, but with lower diastereoselectivity (for 1q and
1r), probably due to the diminished steric repulsion effect
during the ring closure step. As for the limitation, the present
method has thus far not proven successful with bis-styryl-
tethered 1s and terminal alkene 1t. In the case of 1s, the
reaction became messy, and no identifiable product was
isolated. This is probably due to the slow hydrogen transfer
rate from the thiol catalyst to the resulted benzyl radical
intermediates,20 thus leading to polymerization.
B
DOI: 10.1021/acs.orglett.8b00694
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The present method was also determined to be applicable to
the facile construction of boron-substituted polycyclic skeletons
(Table 3). The radical borylative cyclization of 1,6-dienes
intermediate A in the reaction sequence. Based on this result,
and previous findings for NHC−boryl radical chemistry,8,9
a
plausible mechanism for the formation of 3a was outlined in
Scheme 2b. The NHC−boryl radical I is initially generated by
hydrogen abstraction from 2.8b,c The addition of I takes place
specifically at the phenyl-substituted alkene part to give
intermediate II. Such an addition process should be reversible,
as the E/Z isomerization of 1a was observed when the reaction
was not completed (Table 1). The following radical 6-exo-trig
ring-closure step may proceed through 6-membered chairlike
transition states II-a or II-b, wherein the boryl moiety and the
phenyl group are both located in pseudo-equatorial positions.
However, the cyclization of II-a predominates, because of the
lower 1,3-diaxial steric strain, thus leading to exclusive trans
stereoselectivity. In the reactions of 1q and 1r, such a 1,3-diaxial
steric effect decreases, and a diastereomeric mixture is obtained.
Hydrogen atom transfer from the thiol catalyst to alkyl radical
III occurs to afford product 3a with the generation of a sulfur
radical (RS•), which, in turn, abstracts a hydrogen atom from 2
to regenerate RSH and II with the propagation of the radical
chain reaction.
Table 3. Scope for the Synthesis of Boron-Handled
a
Polycyclic Molecules
The synthetic practicability and utility of this radical
borylative ring construction method was demonstrated in the
synthesis of a diverse array of paroxetine analogues.24 The
reaction of 1ab and 2 afforded boryl-functionalized paroxetine
(3ab) in good yield, albeit with lower diastereoselectivity (see
Scheme 3). The oxidation of 3ab by H2O2 provided
a
Unless otherwise noted, the reactions were carried out on a 0.2−0.5
mmol scale of 1 (1.2 equiv) with NHC−BH3 (2) in the presence of
AIBN (20 mol %) and C9H19C(CH3)2SH (20 mol %) in CH3CN (3
mL) at 80 °C under a nitrogen atmosphere.
bearing a 5,6-dihydro-2H-pyran-2-one motif took place nicely
to assemble borylated 2-azabicyclo[3.3.1]nonanes as single
diastereomers in acceptable yields (for 3u and 3v). When 1w
was subjected to the reaction conditions, a 7-endo cyclization
proceeded to give unique boron-containing 2-azabicyclo[4.3.1]-
decane 3w. Notably, many structurally complex tricyclic
architectures, such as 3x, 3y, and 3z, were constructed from
1,6-dienes tethering a vince lactam unit. By replacing the phenyl
group (R in 1x) with a hydrogen atom, a mixture of some
inseparable boron-containing products was resulted, most likely
from the initial boryl radical addition to the bicyclic alkene
moiety,22 but with low regioselectivity and diastereoselectivity.
To verify the radical reaction mechanism of this borylative
cyclization process, a radical clock experiment was conducted.
The reaction of 1aa, in which a cyclopropyl radical clock23 was
installed at one end of the alkene, provided the ring-opening
product 3aa in good yield (Scheme 2a). This result strongly
supported the existence of the cyclopropyl carbinyl radical
Scheme 3. Synthesis and Diversification of Boryl-Handled
Paroxetine
a
a
Reagents and conditions: (a) H2O2 (30%, 8 equiv), MeOH/CH3CN,
Scheme 2. A Mechanistic Study and a Plausible Mechanism
for the Formation of 3a
room temperature (rt), 6 h; (b) aqueous HCl (2 M, 2.5 equiv), pinacol
(2 equiv), CH3CN, rt, 6 h; (c) (1) furan (6 equiv), n-BuLi (6 equiv),
THF, −20 °C, 1 h, (2) NBS (6 equiv), THF, −20 °C, 5 h; and (d) (1)
KHF2 (2.5 equiv), MeOH, rt, 3 h, (2) SiCl4 (10 equiv), BnN3 (3
equiv), toluene, rt to 60 °C, 11 h.
hydroxylated paroxetine (4) in 86% yield. Treatment of 3ab
with 2 M HCl25 in the presence of pinacol led to alkyl pinacol
boronic ester (5) in 82% yield. The subsequent arylation
reaction following Aggarwal’s protocol26 gave the furan-
substituted paroxetine (6). In addition, an aminated paroxetine
derivative 7 was obtained in 62% yield via the conversion of
boronic ester 5 to potassium alkyltrifluoroborate,27 followed by
amination with benzyl azide in the presence of SiCl4.28 It is
noteworthy that diastereomeric mixtures of compounds 4, 6,
and 7 could be easily separated by column chromatography,
C
DOI: 10.1021/acs.orglett.8b00694
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) For recent examples on hydro- and carbo-boration of cycloalkene
derivatives for the synthesis of boron-substituted six-membered rings,
see: (a) Feng, X.; Yun, J. Chem. Commun. 2009, 6577. (b) Lee, K.-s.;
Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 7253.
thus offering the potential for rapid testing of diastereomeric
analogues for biological activity.
In summary, we have disclosed a strategically new radical
borylative ring construction method to assemble boron-handled
six-membered rings from 1,6-dienes. A range of boron-
substituted cyclohexane, piperidine, pyran, and polycyclic
systems were constructed from C-, N-, and O-tethered 1,6-
dienes. This approach was successfully applied to the synthesis
of boryl-functionalized antidepressant drug paroxetine; the
following derivatization reactions afforded a diverse array of
analogues that would be potentially useful for drug develop-
ment.
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obtained free of charge via www.ccdc.cam.ac.uk/data_request/
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AUTHOR INFORMATION
■
̂
H.; Solovyev, A.; Yuan, X.; Geib, S. J.; Fensterbank, L.; Lacote, E.;
Corresponding Author
*E-mail: yfwangzj@ustc.edu.cn
ORCID
Malacria, M.; Newcomb, M.; Walton, J. C.; Curran, D. P. J. Am. Chem.
Soc. 2009, 131, 11256. (c) Walton, J. C.; Brahmi, M. M.; Fensterbank,
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L.; Lacote, E.; Malacria, M.; Chu, Q.; Ueng, S.-H.; Solovyev, A.;
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Brahmi, M. M.; Monot, J.; Fensterbank, L.; Malacria, M.; Curran, D.
Yi-Feng Wang: 0000-0003-1360-8931
Author Contributions
§These authors contributed equally.
P.; Laco
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ACKNOWLEDGMENTS
■
̂
This work was supported by the NSFC (Nos. 21672195 and
21702201), the Fundamental Research Funds for the Central
Universities (No. WK2060190082), and Recruitment Program
of Global Experts. F.-L.Z. is grateful for the grant from the
China Postdoctoral Science Foundation (No. 2016M602014).
We thank Prof. Shunsuke Chiba (NTU, Singapore) for valuable
discussions.
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(22) The radical hydroboration of vince lactam also proceeded under
the optimized reaction conditions, but a mixture of noncharacterized
isomers were obtained. This reaction requires further optimization.
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DOI: 10.1021/acs.orglett.8b00694
Org. Lett. XXXX, XXX, XXX−XXX