One-Shot Radical Cross Coupling Between Benzyl Alcohols and Alkenyl Halides Using Ni/Ti/Mn System

Article abstract of DOI:10.1002/adsc.202000945

A “one-shot” cross coupling between benzyl alcohols and alkenyl halides has been established. A combination of low-valent Ti-mediated C?OH homolysis and the prominent chemistry of Ni-based radical catalysis afforded the desired cross-coupled product with good efficiency. The reaction proceeded regardless of the electronic property of benzyl alcohols, and Ar?B bond remained intact throughout the reaction. Alkenyl bromides with various substitution patterns were applicable to this reaction. Attempts for utilizing sterically demanding tri-substituted alkenes indicated that the steric hinderance mainly inhibited the radical-trapping by Ni species. This reaction can be a simple and efficient strategy for synthesizing densely substituted allylbenzene derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.202000945

Title: One-Shot Radical Cross Coupling Between Benzyl Alcohols and
Alkenyl Halides Using Ni/Ti System
Authors: Takuya Suga, Yuuki Takahashi, and Yutaka Ukaji
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000945
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10.1002/adsc.202000945
Advanced Synthesis & Catalysis
Very Important Publication
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DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
One-Shot Radical Cross Coupling Between Benzyl Alcohols and
Alkenyl Halides Using Ni/Ti/Mn System
Takuya Suga*[a], Yuuki Takahashi[a] and Yutaka Ukaji*[a]
a
Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma,
Kanazawa, Ishikawa 920-1192, Japan
E-mail: suga-t@se.kanazawa-u.ac.jp; ukaji@staff.kanazawa-u.ac.jp
Received: (will be filled in by the editorial staff)
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.(Please
delete if not appropriate))
schemes with simpler and less expensive alcohol-
based schemes.[7] We have been tackling this challenge
Abstract. A “one-shot” cross coupling between benzyl
alcohols and alkenyl halides has been established. A
and have recently resolved it in part by combining the
combination of low-valent Ti-mediated C–OH homolysis low-valent Ti-mediated C–OH homolysis and Ni-
catalyzed radical cross coupling.[5] For instance, the
and the prominent chemistry of Ni-based radical catalysis
afforded the desired cross-coupled product with good
efficiency. The reaction proceeded regardless of the
electronic property of benzyl alcohols, and Ar–B bond
remained intact throughout the reaction. Alkenyl bromides
with various substitution patterns were applicable to this
reaction. Attempts for utilizing sterically demanding tri-
substituted alkenes indicated that the steric hinderance
mainly inhibited the radical-trapping by Ni species. This
reaction can be a simple and efficient strategy for
synthesizing densely substituted allylbenzene derivatives.
reaction between benzyl alcohols and aryl halides
successfully afforded the corresponding coupling
products in the Ni/Ti/Mn reaction system.[8] However,
the product, diarylmethane, has a narrow scope for
application in organic synthesis because of the relative
difficulties in undergoing further transformations. We
herein report a one-shot cross-coupling between
benzyl alcohols and alkenyl halides for preparing
allylbenzenes, that can be derivatized by known facile
transformations of alkenes.
Keywords: Cross-coupling; Radicals; Alcohols;
Titanium; Nickel
Scheme 1. Cross-coupling between Bn–X and Alkenyl
Bromides.
Ni-catalyzed radical cross-coupling is emerging as a
powerful tool for realizing coupling reactions using
nontraditional reactants. Mechanistic studies of the
seminal discoveries on the cross-coupling reactions
between aryl bromides and alkyl bromides[1] revealed
the participation of alkyl radical species derived from
the alkyl bromides.[2] These studies triggered intense
collaborations of the single-electron redox reaction of
various carbon radical precursors (borates, carboxylic
acids, oxalates, etc.) and Ni-catalyzed reactions.[3,4]
However, the direct use of alcohol C–OH bonds as
carbon radical precursors in such cross couplings was
largely underexplored because of the lack of reliable
methods for C–OH homolysis, till before our previous
work.[5]
Alcohols constitute a large part of our chemical
feedstocks, and thus, its direct application to organic
transformations is indeed desirable.[6] In particular,
their use in cross-coupling reactions could replace the
conventional organometallic reagent-based synthetic
The reductive C–C bond formation reaction
between Bn–X (X = heteroatom) and alkenyl halides
commonly involves multiple steps that include the
preparation of organometallic reagents.[9,10] In contrast,
1
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10.1002/adsc.202000945
Advanced Synthesis & Catalysis
a simplified “one-shot” cross coupling approach has
also been developed.[11] Lipshutz reported the Pd-
catalyzed coupling between benzyl chlorides and
alkenyl halides.[12] Gosmini reported the Co-catalyzed
coupling,[13] while Ni-catalyzed reactions were
reported by Weix[14], Gong[15] and Reisman.[16]
Although benzyl (pseudo)halides have been widely
employed as described, benzyl alcohol, their common
precursor, is not used for this purpose.
reaction. The presence of electron-donating or
electron-withdrawing substituents did not affect the
yield significantly (1h and 1i). It is notable that
boronic ester 1j was neatly converted to the desired
product with retention of the boronic ester moiety,
despite its known reactivity in cross-coupling
reactions (64% yield).[17]
Table 2. Scope of Alcohols.a
Table 1. Optimization of Reaction Conditions.a
Yield/%b
Entry Deviation
1
2
None
70
38
TiCl4 (collidine) 5b and collidine
instead of 5a and lutidine
TiCl4(tmeda) 5c instead of 5a
[Ni] 4b instead of 4a
No Mn
3
4
5
6
40
50
0
No 2,6-lutidine
6
a)Reactions were performed at 0.20 mmol scale.
Abbreviations: lutidine = 2,6-lutidine, collidine = 2,4,6-
collidine, tmeda = N,N’,N’,N-tetramethylethylenediamine.
b)NMR yields of 3aa.
The optimum conditions were determined using
2-naphthalenemethanol 1a and (E)-1-bromo-1-hexene
2a as substrates (Table 1). The highest yield (70%)
was obtained when TiCl4(lutidine) 5a, 4.6 mol% Ni
catalyst 4a, Mn powder, and additional 2,6-lutidine
were used in THF at 70 °C (entry 1). Gratifyingly, no
positional isomerization of the alkene moiety was
observed in any reactions, including those in the later
studies. Other Ti reagents such as TiCl4(collidine) 5b
and TiCl4(tmeda) 5c could also be used for this
reaction, although the yields were low (entries 2 and
3). The use of Ni catalyst 4b also resulted in a low
yield (entry 4). The combination of Ni catalyst 4 and
Ti reagent 5 was optimized as described, but further
investigation revealed that the best combination
depended on alcohols 1 and alkenyl bromides 2 (see
Table S1 and S2 in ESI for details). The control
experiments clearly demonstrated the need for Mn and
the added 2,6-lutidine (entries 5 and 6).
The scope of alcohol was tested using alkenyl
bromide 2a (Table 2). For all the reactions studied, the
isolated yields of the products were mostly in a
relatively narrow range of 50% to 70%, establishing
that the reaction efficiency remained nearly constant
regardless of the substituents on the aromatic moiety.
In addition to naphthalene derivative 1a, various
substituted benzyl alcohols were suitable for this
a)Reactions were performed at 0.4 mmol scale. Isolated
yields of 3 are shown. b)5a and lutidine were used instead of
5b and collidine.
Our major interest was to investigate the scope of
alkenes in the Ni/Ti/Mn systems, as there is only a
handful of detailed information on the effect of
substitution patterns on the Ni-catalyzed radical cross-
coupling.[11a, 15,18] For this purpose, a series of mono-,
di-, and tri-alkyl-substituted alkenyl bromides were
examined (Table 3). To better understand the
correlation between the steric hindrance around the C–
Br bond and the reaction efficiency, the amount of
alkene (except volatile alkenes 2c and 2f) was reduced
(1.2 equiv). All the mono- and di-substituted alkenyl
bromides reacted to give satisfactory yields. For
obtaining higher yields, increasing the alkene loadings
can be helpful to some extent. For example, increasing
the amount of 2d from 1.2 to 3.0 equiv improved the
yield by 17%. Linear alkenyl bromide 2f with E/Z =
30/70 was converted to the product with E/Z = 37/63.
The virtual retention of the E/Z ratio in the presence of
excess 2f (3.0 equiv) indicated that the (E)-isomer was
only slightly more reactive than the (Z)-isomer. In
2
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10.1002/adsc.202000945
Advanced Synthesis & Catalysis
contrast, the (Z)-isomer of 2d was apparently less
reactive than the (E)-isomer. Further comparison
between the E/Z isomers is provided in the ESI.
Alkenyl iodides 2i and 2j as well as the corresponding
bromides reacted when Ni catalyst 4b was used (71%
and 82% yield, respectively). Although most of the
tested alkenes reacted efficiently, the most sterically
demanding tri-substituted alkenyl bromide 2h was
exceptionally unsuitable, similar to that reported by
Gong (18% yield).[15] These similar observations
suggest that this is a common difficulty in Ni-
catalyzed radical cross-coupling reactions. To
overcome this, we further investigated the factors that
could improve the yield.
Table 4. Optimization of Reaction Conditions for Tri-
Substituted Alkene 2h.a
Yield/%b
2h
4a
Temp.
/ºC
Entry
x/equiv y/mol %
3ah
6
7
1
2
3
4
5
1.2
3.0
1.2
3.0
1.2
4.6
4.6
9.2
9.2
9.2
70
70
70
70
50
18
26
40
47
54c
45 26
21 48
31 28
21 32
Table 3. Scope of Alkenes.a
4
16
a)Reactions were performed at 0.40 mmol scale. b)NMR
yields, unless otherwise stated. c)Isolated yield.
Scheme 2. Proposed Mechanism and Possible Yield-
Limiting Steps (A and B).
slower than the C–O bond homolysis, because of
which the Ni species is not ready for trapping the
radical (step A). In light of the reaction kinetics,
increase in both alkene 2h and catalyst 4a loadings
should improve the yield; else, the radical-trapping
step can be affected by the steric hindrance (step B). In
this case, only an increase in catalyst 4a loading
improves the yield.
a)Reactions were performed at 0.40 mmol scale. Isolated
yields of 3 are shown unless otherwise stated. b)NMR yield.
c)5b and collidine were used instead of 5a and lutidine. d)[Ni]
4b was used instead of 4a.
To rationalize these hypotheses, we increased
either or both the alkene and Ni catalyst loadings.
Increasing the alkene 2h loading from 1.2 to 3.0 equiv
improved the yield only slightly (entry 2, 26% yield),
indicating that the concentration of 2h is not critical
for the efficiency. In contrast, doubling the Ni catalyst
loading (9.2 mol%) almost doubled the yield of the
cross-coupling product (entry 3, 40% yield). A
simultaneous increase in the 2h and 4a loadings
further increased the reaction yield, but incremental
(entry 4, 47% yield). This indicates that the oxidative
addition step (step A) is not necessarily critical even
with a small excess of alkenes, while an inefficient
radical-trapping step (step B) is mainly responsible for
the poor yield.[19] Lowering the reaction temperature
The low yield (18%) with tri-substituted alkenyl
bromide 2h was accompanied by the substantial
formation of radical dimer 6 (45% yield) and
deoxygenated product 7 (26% yield, Table 4, entry 1).
We have previously shown that such a Ni/Ti/Mn
system consists of two independent processes—Ti-
mediated C–O bond homolysis and Ni-catalyzed
cross-coupling, while the reaction rate is controlled by
the radical-formation step (Scheme 2).[5] The reaction
of 2h in this catalytic cycle can be influenced by a
couple of factors. In the Ni-catalyzed process, it is
possible that the oxidative addition step is reasonably
3
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10.1002/adsc.202000945
Advanced Synthesis & Catalysis
could suppress the formation of dimer 6, because
dimerization is sensitive to the concentration of the
radical species in comparison to the other reaction
pathways. Indeed, at 50 °C, the yield of 6 dramatically
decreased to 4% while that of 3ah increased to 54%
(entry 5).
In conclusion, we have developed a Ni-catalyzed
radical cross-coupling between benzyl alcohols and
alkenyl bromides. The reaction tolerates various
benzyl alcohols, including those with bromo and
boronic ester groups. The low sensitivity to the
substitution pattern of the alkene moiety in alkenyl
bromides promises a broad scope of alkenes. An
attempt with the tri-substituted alkenyl bromide
provided new insights into the challenging and
sterically demanding cross-coupling reaction. We
hope that this study will lead to the development of an
alcohol-based radical strategy for transition metal-
catalyzed alkenylation.
Molander, O. Gutierrez, J. Am. Chem. Soc. 2020, 142,
7225-7234.
[3] a) C. Lévêque, C. Ollivier, L. Fensterbank, M. J.
Goldfogel, L. Huang, D. J. Weix in Nickel Catalysis in
Organic Synthesis: Methods and Reactions (Ed.: S.
Ogoshi), Wiley-VCH, Weinheim, 2019, pp. 151-222; b)
A. Kaga, S. Chiba, ACS Catal. 2017, 7, 4697-4706; c) E.
Richmond, J. Moran, Synthesis 2018, 50, 499-513; d) J.
A. Milligan, J. P. Phelan, S. O. Badir, G. A. Molander,
Angew. Chem. Int. Ed. 2019, 58, 6152-6163; Angew.
Chem. 2019, 131, 6212-6224.
[4] a) J. C. Tellis, D. N. Primer, G. A. Molander, Science
2014, 345, 433-436; b) Z. Zuo, D. T. Ahneman, L. Chu,
J. A. Terrett, A. G. Doyle, D. W. C. MacMillan, Science
2014, 345, 437-440; c) V. Corcé, L.-M. Chamoreau, E.
Derat, J.-P. Goddard, C. Ollivier, L. Fensterbank,
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Nojima, Y. Nishibayashi, Angew. Chem. Int. Ed. 2016,
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8008; f) X. Zhang, D. W. C. MacMillan, J. Am. Chem.
Soc. 2016, 138, 13862-13865.
Experimental Section
General procedure for cross-coupling: The representative
procedure using 1a and 2a is as follows; to a dried test tube,
Mn
powder
(44
mg,
0.80
mmol)
and
NiCl₂ (Me₄ Phen)•2H₂ O (7.3 mg, 0.018 mmol) were
added under air atmosphere, and the gaseous phase was
replaced with argon. Next, TiCl4(lutidine) (131 mg, 0.44
mmol), THF (1.0 mL) and 2,6-lutidine (92 µL, 0.80 mmol)
were added, and the mixture was stirred for 10 min. To this,
THF (1.0 mL) solution of 2-naphthalenemethanol (1a, 63
mg, 0.40 mmol) and (E)-1-bromo-1-hexene (2a, 65 μL, 0.48
mmol) were added dropwise while stirring the mixture
vigorously. Following this, the mixture was stirred at 70 ºC
for 20 h. After cooling, hexane/ethyl acetate (1/1 (v/v), ca.
2 mL) was added. The mixture was stirred under air until the
black color almost disappeared. The gray precipitate formed
was filtered with a short plug of silica gel (hexane/ethyl
acetate 1/1 (v/v) as an eluent), and the resulting solution was
concentrated under reduced pressure. The crude product
was purified by preparative TLC (hexane) to afford the
coupling product 3aa as a pale-yellow oil (68.2 mg, 76%
yield).
[5] T. Suga, Y. Ukaji, Org. Lett. 2018, 20, 7846-7850.
[6] a) B. Sundararaju, M. Achard, C. Bruneau, Chem. Soc.
Rev. 2012, 41, 4467-4483; b) T. Irrgang, R. Kempe,
Chem. Rev. 2019, 119, 2524-2549; c) L. Alig, M. Fritz,
S. Schneider, Chem. Rev. 2019, 119, 2681-2751.
[7] Cross-coupling reaction using benzyl alcohols: a) D.-G.
Yu, X. Wang, R.-Y. Zhu, S. Luo, X.-B. Zhang, B.-Q.
Wang, L. Wang, Z.-J. Shi, J. Am. Chem. Soc. 2012, 134,
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Wei, Z.-J. Shi, Chem. Commun. 2015, 51, 2683-2686; c)
V. K. Chenniappan, D. Peck, R. Rahaim, Tetrahedron
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[8] Selected examples of other Ni/Ti/reductant systems: a)
A. G. Campaꢀa, B. Bazdi, N. Fuentes, R. Robles, J. M.
Cuerva, J. E. Oltra, S. Porcel, A. M. Echavarren, Angew.
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Chem. Soc. 2015, 137, 3237-3240; d) V. K.
Chenniappan, S. Silwal, R. J. Rahaim, ACS Catal. 2018,
8, 4539-4544. e) Z. Lin, Y. Lan, C. Wang, Org. Lett.
2019, 21, 8316-8322.
Acknowledgements
This work was supported in part by Mitsui Chemicals Award in
Synthetic Organic Chemistry, Japan; UBE Industries Foundation
Award; Hokuriku Bank Research Grant for Young Scientists; and
the Kanazawa University SAKIGAKE project.
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4
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10.1002/adsc.202000945
Advanced Synthesis & Catalysis
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5
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One-Shot Radical Cross Coupling Between Benzyl
Alcohols and Alkenyl Halides using Ni/Ti/Mn
System
Adv. Synth. Catal. Year, Volume, Page – Page
Takuya Suga*, Yuuki Takahashi, Yutaka Ukaji*
6
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