Copper(I)-Catalyzed Stereo- and Chemoselective Borylative Radical Cyclization of Alkyl Halides Bearing an Alkene Moiety

Article abstract of DOI:10.1021/acs.orglett.7b00940

The stereoselective borylative radical cyclization of alkyl halides containing an alkene moiety was developed using a copper(I)/diboron catalyst system. The optimized reaction conditions allowed us to control the chemoselectivity between the allylic substitution and the borylative radical cyclization. The borylation products were subsequently converted to highly functionalized organic compounds by derivatization of the newly formed C-B bond. This borylative radical cyclization offers a novel methodology for the stereoselective synthesis of various heterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.7b00940

Letter
pubs.acs.org/OrgLett
Copper(I)-Catalyzed Stereo- and Chemoselective Borylative Radical
Cyclization of Alkyl Halides Bearing an Alkene Moiety
Hiroaki Iwamoto, Sota Akiyama, Keiichi Hayama, and Hajime Ito*
Division of Applied Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
S
* Supporting Information
ABSTRACT: The stereoselective borylative radical cycliza-
tion of alkyl halides containing an alkene moiety was
developed using a copper(I)/diboron catalyst system. The
optimized reaction conditions allowed us to control the
chemoselectivity between the allylic substitution and the
borylative radical cyclization. The borylation products were
subsequently converted to highly functionalized organic
compounds by derivatization of the newly formed C−B
bond. This borylative radical cyclization offers a novel methodology for the stereoselective synthesis of various heterocyclic
compounds.
methods involving the concomitant introduction of a C−B
adical cyclization reactions are useful methods for the
Rconstruction of cyclic organic compounds. The radical bond have been reported to date.11,12 Herein, we report a
1
stereoselective copper(I)-catalyzed borylative radical cyclization
reaction. This method enabled the synthesis of a wide variety of
highly functionalized cyclic organic compounds via the
transformation of the boryl group (Scheme 1, eq 2).
species involved in traditional radical cyclization reactions are
generated by homolytic cleavage of a C−X bond (X = halogen
or chalcogen atom) and react with a C−C double bond to form
the kinetically favorable cyclization intermediate.2 The resulting
terminal radical species is then trapped by a hydride source
such as Bu3SnH or TMS3SiH. In particular, the stereoselective
cyclization of alkenyl halide substrates derived from chiral allyl
compounds is an important method for the construction of
chiral saturated heterocyclic compounds (for R2 = OR, Ueno−
Stork reaction).1c,3,4 Several trapping reagents have been used
in this reaction, allowing for concomitant functionalization of
the radical intermediate with formation of C−O, C−N, C−X,
C−C, C−Sn, and C−Si bonds (Scheme 1, eq 1).1,5−9
Alkylboronates are versatile building blocks in synthetic organic
chemistry because their C−B bonds can be converted to a
variety of functional groups in a stereospecific manner.10
However, no practical stereoselective radical cyclization
Copper(I)-catalyzed borylation reactions with diboron
compounds have gained recent attention as efficient methods
for the synthesis of organoboron compounds.13 The key step in
most of these reactions involves the addition of an in situ-
generated borylcopper(I) species to an unsaturated C−C
(borylcupration). In 2012, our group and Marder’s group
independently reported novel radical-related reactions of
borylcopper(I) intermediates.11,12 The reaction of alkyl halides
with a copper(I) catalyst and diboron reagent gave the
corresponding alkylboronates. We conducted a mechanistic
study of the boryl substitution reaction, which suggested that it
proceeds through a radical pathway. Based on this study, we
envisaged that it would be possible to achieve the stereo-
selective borylative radical cyclization of alkyl halide 1, which is
synthesized from the corresponding allyl alcohol.8 Although a
wide variety of substrates are readily available for this
transformation, copper(I)-catalyzed reactions of this type
raise a fundamental chemoselectivity issue as to whether the
substrate will undergo borylcupration for allylic substitution
(path A) or generate a radical species for stereoselective
borylative cyclization (path B) (Scheme 2).13e,f
Scheme 1. Functionalization of Radical Intermediates in
Radical Cyclization Reactions: (A) Known Radical
Cyclization Chemistry; (B) Borylative Radical Cyclization
with Copper(I) Catalyst
We initially screened a series of ligands to identify a system
that favored borylative radical cyclization over allyl substitution
(Table 1). The reactions were performed with allyl ether 1a in
the presence of catalytic amounts of CuCl and ligand and
stoichiometric amounts of bis(pinacolato)diboron (2) and t-
Received: March 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00940
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Organic Letters
Letter
entry 6). However, low reactivity and selectivity were observed
with dtbpy (3a/4a = 48:52) (Table 1, entry 7). Furthermore,
the reaction without a ligand exhibited low reactivity and gave
the mixture of 3a and 4a (7%, 3a/4a = 38:62) (Table 1, entry
8). Use of PCy3, L1, and BPhen was thus optimal for the
stereoselective borylative radical cyclization of allyl ether
substrate 1.
Scheme 2. Ligand-Controlled Borylation of Allyl Ether 1
with Borylcopper(I) Intermediate
With the optimized conditions in hand, we investigated the
substrate scope of this reaction with the three suitable ligands
(Table 2). Boryl-containing tetrahydrofuran derivative 3a was
Table 2. Substrate Scope for the Borylative Radical
a
Cyclization of 1
Table 1. Ligand Screening for the Borylative Radical
a
Cyclization of 1a
b
b
entry
ligand
time (h) yield of 3a (%) yield of 4a (%) 3a/4a
1
2
3
4
5
6
7
8
Xantphos
PPh3
24
24
6
1
45
9
23
3
13:87
66:34
96:4
L1
80
PCy3
6
86 (78)
73
4
96:4
Phen
24
6
7
91:9
a
Common conditions: CuCl (0.025 mmol), ligand (0.025 mmol), 1
BPhen
dtbpy
80
7
92:8
(0.5 mmol), bis(pinacolato)diboron (2) (0.6 mmol), and t-BuOK (0.6
mmol) in THF (1.0 mL). Conditions A: PCy3, 0 °C. Conditions B:
BPhen, room temperature. Isolated yields. Diastereoselectivity was
24
6
19
21
12
48:52
38:62
7
a
b
c
1
Conditions: CuCl (0.025 mmol), ligand (0.025 mmol), 1a (0.5
mmol), bis(pinacolato)diboron (2) (0.6 mmol), and t-BuOK (0.6
mmol) in THF (1.0 mL). Determined by GC analysis using crude
determined by GC and H NMR analysis. Complex mixture. The
(E)-internal alkene substrate (R2 = CH3) was used.
b
material with an internal standard. Isolated yield is shown in
parentheses.
obtained in high yield with excellent diastereoselectivity (dr =
>95:5, 78%). Although use of PCy3 was ineffective for phenyl-
containing allyl ether substrate 1b, the reaction proceeded
smoothly with BPhen to give desired product 3b in good yield
(69%).14 Reaction of substrate (E)-1c containing a linear
internal alkene moiety gave the corresponding secondary
alkylboronate 3c (52%). Although the 5-membered ring was
formed with high diastereoselectivity (>95:5), the stereo-
chemistry of the C−B bond was not controlled, and 3c was
obtained as a diastereomixture (1:1). Furthermore, this
borylative radical cyclization reaction was successfully extended
to tertiary bromide 1d, providing highly functionalized
tetrahydrofuran 3d in high yield (82%). We subsequently
tested the reaction of nitrogen-tethered substrate 1e, which
provided facile access to borylation product 3e bearing a tosyl-
protected pyrrolidine moiety in good yield (68%). Borylation of
1f gave cyclopentane ring-containing product 3f in high yield
(74%). Finally, we obtained spirocyclic product 3g in high yield
using the same procedure (90%).
BuOK in THF at 0 °C.14 Use of Xantphos gave low conversion
with high selectivity for the allylic boryl substitution (1%, 3a/4a
= 13:87) (Table 1, entry 1). The reaction using PPh3, which
showed high halide selectivity in our previous work, gave a
mixture of cyclization and allylic substitution products 3a and
4a (45%, 3a/4a = 66:34) (Table 1, entry 2).12b In contrast, (2-
hydroxyphenyl)diphenyl phosphine (L1) showed excellent
chemoselectivity and gave the corresponding cyclization
product in good yield (80%, 3a/4a = 96:4) (Table 1, entry
3). Notably, this reaction also proceeded with excellent
diastereoselectivity observed in the cyclization (for C2 and
C3; dr = >95:5), which is consistent with a typical 5-exo-trig
radical cyclization.2b Use of PCy3 as the ligand also resulted in
excellent chemoselectivity, affording the desired cyclization
product in high yield (86%, 3a/4a = 96:4) (Table 1, entry 4).
We then screened nitrogen-containing ligands. Phenanthroline
ligands were effective for the borylative radical cyclization
(Table 1, entries 5 and 6). Furthermore, use of phenanthroline
resulted in the selective formation of 3a in high yield (73%, 3a/
4a = 91:9) (Table 1, entry 5). Notably, 4,7-diphenylphenan-
throline (BPhen) showed higher reactivity than phenanthroline
with a similarly high selectivity (80%, 3a/4a = 92:8) (Table 1,
To highlight the utility of this borylative radical cyclization,
we investigated its application to Ueno−Stork radical
cyclization for the synthesis of boryl-containing γ-lactol ethers
(Table 3).1c,3 Alkyl-chain-bearing substrate 5a was smoothly
converted to lactol ether 6a in good yield with high
diastereoselectivity for C2 and C3 on the tetrahydrofuran ring
B
DOI: 10.1021/acs.orglett.7b00940
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Table 3. Substrate Scope of Borylative Ueno−Stork
Scheme 3. Synthesis of Optically Active γ-Lactones
a
Cyclization of 5
(R,R)-9 in high yield (52% yield for four steps). Several other
synthetic applications of this reaction were also achieved
(Supporting Information).
To confirm the reaction mechanism, we investigated the
borylation of cyclopropyl-bearing substrate (E)-1h (Scheme 4).
Scheme 4. Radical Clock Experiment
a
Common conditions: CuCl (0.025 mmol), ligand (0.025 mmol) 5
This reaction failed to provide the corresponding cyclopropyl-
substituted borylation product, but instead gave ring-opened
product (E)-3h in high yield (83%), which suggests that the
borylation reaction proceeds through a radical intermedi-
ate.11,12
Based on the results of this mechanistic study, we propose a
plausible catalytic cycle for our newly developed borylative
radical cyclization reaction (Scheme 5). Copper(I) alkoxide A
(0.5 mmol), bis(pinacolato)diboron (2) (0.6 mmol), and t-BuOK (0.6
mmol) in THF (1.0 mL). Conditions A: PCy3, 0 °C. Conditions B:
BPhen, room temperature. Conditions C: L1, 0 °C. Isolated yields.
Diastereoselectivity was determined by GC and NMR analysis.
Complex mixture. Determined by GC analysis using crude material
with an internal standard.
b
c
(65%). The reaction of benzyl-protected alcohol 5b afforded
desired borylation product 6b in moderate yield (48%).
Secondary iodide substrates 5c and 5d were also amenable to
this catalytic system, affording corresponding borylation
products 6c and 6d in high yields with good diastereoselectivity
(6c: 81%, 6d: 75%). Substrate 5e also reacted as anticipated to
give acetal-bearing secondary alkylboronate 6e in moderate
yield with reasonable diastereoselectivity (60%). We then
investigated the reactions of substrates bearing an aryl group.
The results revealed high functional group compatibility,
affording the desired products bearing para-, meta-, and ortho-
substituted aryl groups in good yields with moderate stereo-
selectivity (6f−m, 48−68%).15
Scheme 5. Proposed Catalytic Cycle
Next, we investigated the borylative radical cyclization of an
optically active substrate synthesized from optically active chiral
allyl alcohol (R)-7f (Scheme 3).16 Optically active γ-lactone
moieties are found in a wide variety of natural products and
compounds containing these groups are useful synthetic
intermediates.4,17 Oxidation of the boryl group of (R,R)-6f,
followed by sequential silyl protection of the hydroxyl group
and oxidation of the acetal moiety provided (S,R)-8 in good
yield with excellent stereospecificity (48% for three steps).
Furthermore, the homologation of (R,R)-6f, followed by
sequential oxidation of the boryl group, benzyl protection,
and oxidation of the acetal moiety gave optically active lactone
reacts with diboron reagent 2 to give borylcopper(I)
intermediate B. Coordination of t-BuOK to the copper(I)
center of B gives cuprate C, which reacts selectively with the
alkyl halide moiety of substrate 1 or 5 to generate radical
intermediate D and copper(II) species E.18 Subsequent radical
cyclization of D gives intermediate F. Finally, radical
intermediate F reacts with copper(II) species E to give
C
DOI: 10.1021/acs.orglett.7b00940
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Organic Letters
Letter
1993, 115, 7027. (c) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J.
Am. Chem. Soc. 2001, 123, 5374. (d) Kim, S.; Lim, C. J.; Song, C.;
Chung, W. J. J. Am. Chem. Soc. 2002, 124, 14306.
(8) During the course of our study, copper(I)-catalyzed silylative
radical cyclization was reported; see: Xue, W.; Qu, Z. W.; Grimme, S.;
Oestreich, M. J. Am. Chem. Soc. 2016, 138, 14222.
(9) (a) Fujioka, T.; Nakamura, T.; Yorimitsu, H.; Oshima, K. Org.
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(10) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2nd revised ed.; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, 2011.
borylation product 3 or 6, and copper(I) alkoxide A is
regenerated.8,19
In summary, we have developed a new method for the
copper(I)-catalyzed borylative radical cyclization of alkyl
halides bearing alkene moieties. The optimized copper(I)
catalytic system provided high chemoselectivity that enables the
borylative radical cyclization and facile access to borylated
products containing various functional groups with high
stereoselectivity. The further mechanistic studies suggested
the radical related reaction pathway. Further work toward the
development of this reaction, including expansion of its
substrate scope and application of the borylated products, as
well as a detailed investigation of the reaction mechanism
including the ligand effect for the chemoselectivity, are
currently underway.
(11) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890.
(12) Borylative radical cyclization of 6-bromo-1-hexene was reported
as a mechanistic study: (a) Yang, C. T.; Zhang, Z. Q.; Tajuddin, H.;
Wu, C. C.; Liang, J.; Liu, J. H.; Fu, Y.; Czyzewska, M.; Steel, P. G.;
Marder, T. B.; Liu, L. Angew. Chem., Int. Ed. 2012, 51, 528.
(b) Iwamoto, H.; Kubota, K.; Yamamoto, E.; Ito, H. Chem. Commun.
2015, 51, 9655. (c) Fu and co-workers previously referred two
examples of borylative radical cyclization with nickel(II) catalysts, but
the details of these reactions such as yield and spectrum data were not
given; see: Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693.
(13) (a) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Tetrahedron
2015, 71, 2183. (b) Kubota, K.; Iwamoto, H.; Ito, H. Org. Biomol.
Chem. 2017, 15, 285. Examples of borylation of conjugated ketones
and esters, see: (c) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A.
Tetrahedron Lett. 2000, 41, 6821. (d) Takahashi, K.; Ishiyama, T.;
Miyaura, N. Chem. Lett. 2000, 29, 982. Examples of borylation of
allylic carbonates or ethers, see: (e) Ito, H.; Kawakami, C.; Sawamura,
M. J. Am. Chem. Soc. 2005, 127, 16034. (f) Ito, H.; Kunii, S.;
Sawamura, M. Nat. Chem. 2010, 2, 972.
(14) The detailed results of the optimization are shown in the
Supporting Information.
(15) 6f was obtained in 59% yield (dr = > 95:5), when 6.0 mmol of
5f was used (Supporting Information).
(16) Luo, L.; Yamamoto, H. Org. Biomol. Chem. 2015, 13, 10466.
(17) (a) MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984, 23,
1207. (b) Dar, A. A.; Arumugam, N. Bioorg. Chem. 2013, 50, 1.
(18) The investigation of the effect of base is shown in the
Supporting Information.
(19) The discussion of the possible reaction pathway through
borylcupration of alkene followed by intramolecular cyclization is
shown in the Supporting Information.
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.7b00940.
Experimental procedures and characterization data
(PDF)
X-ray data for compound (R,R)-9 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hajito@eng.hokudai.ac.jp.
ORCID
Hajime Ito: 0000-0003-3852-6721
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI (Grant
Nos. 15H03804 and 15K13633). H.I. thanks the JSPS for their
scholarship support (Grant No. 16J0141006).
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DOI: 10.1021/acs.orglett.7b00940
Org. Lett. XXXX, XXX, XXX−XXX