Tandem Reactions Enable Trans- and Cis-Hydro-Tertiary-Alkylations Catalyzed by a Copper Salt

Article abstract of DOI:10.1021/acscatal.6b03343

A methodology to synthesize trans- and cis-alkenes via well-controlled hydroalkylation of alkyl radicals to alkynes is reported. α-Bromocarbonyl compounds are useful alkyl radical precursors in the presence of Cu(I) catalysts. Under copper catalyst conditions and in the presence of silane or alcohol/B₂pin₂, trans- and cis-hydroalkylation occurred with excellent stereoselectivities. The judicious choice of additives allowed for this stereodivergence, giving selective access to the trans-alkylated alkenes with HSiTMS₃ and cis-alkylated alkenes with t-BuOH/B₂pin₂ in good yields with selectivities.

Full text of DOI:10.1021/acscatal.6b03343

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Letter
Tandem reactions enable trans- and cis-hydro-
tertiary-alkylations catalyzed by a copper salt
Kimiaki Nakamura, and Takashi Nishikata
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03343 • Publication Date (Web): 29 Dec 2016
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ACS Catalysis
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Tandem reactions enable trans- and cis-hydro-tertiary-alkylations
catalyzed by a copper salt
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Kimiaki Nakamura, and Takashi Nishikata*
Graduate School of Science and Engineering, Yamaguchi University 2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611, Japan
KEYWORDS. alkylation, alkyne, addition, silane, diboron, copper
Supporting Information Placeholder
Our initial screening shown in Table 1 employed the reaction of
phenylacetylene (1a), α-bromoester (2a), CuI, Et3N, and additives
in toluene at 125 ºC (in a sealed tube). This reaction generally
gave atom-transfer radical adduct 5a in the presence of a copper
catalyst. As previously demonstrated by our group, 12 this reaction
did not occur in the presence of a radical scavenger such as
TEMPO or BHT, thereby indicating that this process involves a
radical reaction. A copper-TPMA (tris(2-pyridylmethyl)amine)
catalyst system underwent the desired hydroalkylation reaction
with concomitant formation of 5a, although poor cis and trans
selectivities were obtained (run 1). On the other hand, trans-
hydroalkylation leading to 3a prevailed over cis-hydroalkylation
to 4a in the presence of
ABSTRACT: A methodology to synthesize trans- and cis-
alkenes by well-controlled hydroalkylation of alkyl radicals to
alkynes is reported. α-bromocarbonyl compounds are useful alkyl
radical precursors in the presence of Cu(I) catalysts. Under copper
catalyst conditions and in the presence of silane or alcohol/B2pin2,
trans- and cis-hydroalkylation occurred with excellent stereoselec-
tivities. The judicious choice of additives allowed for this stereo-
divergence, giving selective access to the trans-alkylated alkenes
with HSiTMS3 and cis-alkylated alkenes with t-BuOH/B2pin2 in
good yields with selectivities.
Alkyl halides are very attractive compounds for alkylation of
molecules which are extensively described as reagents in funda-
mental organic chemistry text books. Among them, hydroalkyla-
tions including Giese and related radical alkylation reactions of
alkenes have been well-studied to load complex alkyl groups into
alkenes (Figure 1 A).1,2 Giese reaction involves addition of a nu-
cleophilic alkyl radical to an alkene bearing an electron-
withdrawing group (EWG) and is one of the applications of the
atom-transfer radical addition (ATRA) established by Kharasch3
and many chemists4,5,6, in which an organic halide is added to an
alkene to generate a newly formed C–C and C–X bond.7 On the
other hand, the stereocontrolled addition of alkyl groups to al-
kynes instead of alkenes as substrates is challenging because of
difficult control of cis- and trans-isomers (Figure 1 B).8 These
hydroalkylations with alkynes undergo either trans-
hydroalkylations leading to cis-alkenes9 or cis-hydroalkylations
leading to trans-alkenes by using nucleophilic alkyl radicals.10
While several excellent researches on the synthesis of trans- and
cis-alkenes11 have enabled various hydroalkylations with alkynes,
stereodivergent hydroalkylation of alkynes using an electrophilic
tertiary-alkyl radical has not yet been established.8 In this context,
we envisaged the development of controllable hydroalkylation of
alkynes with α-bromocarbonyl compounds in the presence of a
copper catalyst. Recently, α-bromocarbonyl compounds are em-
ployed as an alkyl radical source in olefinations by our group and
other groups.12 However, the control method of stereoselectivities
in the reactions of α-bromocarbonyl compounds and alkynes is
unknown. During the course of our study, we found that the reac-
tion of α-bromocarbonyl compound and alkyne in the presence of
hydrosilane undergoes trans-hydroalkylation to give cis-alkene,
whereas ROH/B2pin2, which is reductive borylation conditions,
undergoes cis-hydroalkylation to give trans-alkene. Herein, we
would like to report our discovery to synthesize trans- and cis-
tert-alkylated alkenes using copper-catalyzed hydroalkylations
(Figure 1 C).
Figure 1. Hydroalkylations
A) Giese and related radical addition of alkenes
Alkyl
+
EWG
X
EWG
conditions
[H]
Alkyl
H
B) Hydroalkylation of alkynes
H
Alkyl
Alkyl
trans-hydroalkylation
R
conditions
[H]
R
+
or
Alkyl
X
R
-hydroalkylation
cis
H
C) This work
H
H-[Si]
Alkyl
(cis)-
R
trans-
hydroalkylation
R
+
Cu(I)
Alkyl
X
Alkyl
H
ROH/B2pin2
(trans)-
cis-
R
hydroalkylation
a proton generated from i-PrOH (run 2). This result encouraged us
to investigate additional hydrogen sources. Finally, HSi(SiMe)3
(HSiTMS3) was found to be the best hydrogen source. Although
the detailed reaction mechanism is still under investigation, the
first radical addition process seems to be very important to carry
out trans-hydroalkylation. Lalic’s group reported cis-
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hydroalkylation of alkynes in the presence of a silane and a cop-
philic. Other electronically neutral compounds (1d, 1e, and 1f)
1
2
3
4
5
6
7
8
per catalyst, with hydrocupration being one of the most important
steps.10b,c We obtained the opposite selectivity as compared to
their results. In the absence of a base, no reaction occurred. There-
fore, various bases such as t-BuOK, KOAc, Cs2CO3, Na2CO3, and
K3PO4 were screened, but the bases did not affect the yield (runs
3–7). Increasing the reaction temperature was very effective in
this regard. When the reaction was carried out at 160 ºC, a 94:6
(3a:4a) mixture was obtained in 75% yield (run 8)13. Although 3a
is very bulky, no isomerization to 4a was observed at the high
temperature. Surprisingly, the use of different additives switched
the reaction selectivity (runs 9 and 10). Thus, the reaction in the
presence of both silane and diboron at 100 ºC resulted in lower
chemical yield of 3a, whereas the reaction in the presence of both
alcohol and diboron resulted in 57% yield with 10:90 (3a:4a)
selectivity (runs 9 and 10)14. When the reaction was carried out at
160 ºC under the conditions, yield and selectivity were not
changed. Although the Marder’s group reported that the reaction
of alkyl halide with diboron underwent borylation15, no borylation
with 2a was observed in our case. A proton is necessary to under-
go cis-hydroalkylation, but other proton sources were not effec-
tive in this reaction. We expect that the reaction involves a Suzuki
type coupling. Therefore, various transition metal catalysts were
screened as co-catalysts, with Pt(dba)2 showing optimum co-
catalyst characteristics. For example, the reaction in the presence
of Pt(dba)2 and an alcohol such as EtOH, i-PrOH, and t-BuOH
resulted in high yields ranging from 81 to 99% with high trans-
selectivities. Without alcohols or alcohols larger than t-BuOH
dramatically retarded the reaction, and 5a was obtained instead of
the hydroalkylation product (run 14).
with acyclic and cyclic bromides (2a, 2c, and 2d) resulted in good
yields and high selectivities. Heteroaromatic ring-substituted al-
kynes 1g and 1i can be used for current hydroalkylation reactions.
Both nitrogen and sulfur atoms are sometimes not good to main-
tain the catalytic activities of copper, but trans- and cis-products
were smoothly obtained in the reaction with 2b and 2e. In the case
of the reaction of 1h, cis-product 3h was obtained in good yield
and selectivity but trans-product 4h was poor. We optimized
again about this substrate 1h and found that the reaction condi-
tions without Pt catalyst were very effective to give the product in
80% with 97% trans-selective. The reason for the conditions
without Pt catalyst is not clear, but in situ generated alkenyl boron
from 1h might be very reactive for Suzuki type reaction. And in
the case of 1h, borylation reaction was inhibited by Pt catalyst but
the borylation with other alkynes were no problem in the presence
of Pt (See SI). Alkenyl-substituted alkyne 1j also gave the desired
products in good yields with high trans and cis selectivities.
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Table 2. Substrate scope
Table 1. Optimization
Conducted at proper temperature for 12-20 h in toluene with CuI
(10 mol%), TPMA (10 mol%), Et3N (1.5 equiv), and additives A,
B and C. The yields were determined by 1H NMR analysis and the
ratios were determined by GC analysis. All reactions were carried
out in a sealed tube.
Conditions A: CuI (10 mol%), TPMA (10 mol%), HSiTMS3 (1.5
equiv), K3PO4 (20 mol%), Et3N (1.5 equiv), toluene, 160ºC, 12h.
Conditions B: CuI (10 mol%), Pt(dba)2 (2 mol%), TPMA (10
mol%), B2pin2 (1.5 equiv), K2CO3 (20 mol%), tBuOH (2.0 equiv),
Et3N (1.5 equiv), toluene, 100ºC, 20h. The yields were isolated
and the ratios were determined by GC analysis. All reactions were
carried out in a sealed tube. a Run at 125ºC. b Without Pt cat. Pure
isomer can be obtained after GPC (if separable).
Under optimal conditions, we evaluated the reactivities of al-
kynes 1 and α-bromoesters 2 bearing various structures for trans-
and cis-hydroalkylation reactions (Table 2). Although electron-
rich alkyne 1b resulted in good yields and selectivities, electron-
poor alkyne 1c gave moderate yields with good selectivities. The-
se results might imply that generated radical species are electro-
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ACS Catalysis
We also tried alkyl substituted alkynes but the results were poor.
size of α-bromoesters 2 decreased the yields. In this case, α-
1
2
3
4
5
6
7
8
Overall, indications of good functional group tolerance can be
found from the products 3b–3j and 4b–4j, likely reflecting the
mildness of the hydroalkylation event despite high temperatures.
bromoesters 2 underwent reduction via debromohydrogenation.
To suppress this side-reaction during cis-hydroalylations, the
reactions were carried out at 125 ºC instead of 160 ºC or increas-
ing the amounts of Cu and ligand and the yields were slightly
increased as a result (2b, 2e, 2f, 2h, 2l, 2m, 2o, and 2p). β-
Hydrogen elimination of 2 is another possibility to decrease the
product yields, although such by-products were not observed in
both alkylations. The electronic effects of α-bromoesters 2 were
not observed. For example, electron-rich or -deficient aryl-
substituted esters 2k, 2l, 2m, and 2p and allylic or benzylic esters
2e, and 2o did not show significant differences. It is noteworthy
that the alkyl–Br bond in 2n and alkene in 2o, a well-known reac-
tant for metal-catalyzed reactions, remained fully intact. On the
other hand, secondary-alkyl bromides were sluggish (no ATRA
and any couplings but consumed the starting materials).
We next examined functionalized α-bromoesters 2 with 1h,
which shows nice reactivity without Pt catalyst in the synthesis of
4, under conditions A and C (without Pt catalyst) (Table 3). The
size of α-alkyl groups affected the yields and selectivities (2f, 2g,
and 2h). Large substrate 2g gave poor result but selectivity was
good. No clear selectivity trends were observed in all cases. The
selectivities of trans- or cis-hydroalkylations with slightly small
α-bromoesters 2c, 2d, and 2i were also no problem to obtain good
results, whereas α-bromoesters 2l, 2m, 2n, 2p, and 2q possessing
a slightly large ester moiety resulted in excellent selectivities for
both alkylations. To our surprise, cis-alkylations generated incred-
ibly congested cis-alkene structures 3, although the steric bulki-
ness of α-bromoesters 2 did not affect the selectivities (2q). Al-
ternatively, increasing the
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The obtained products via our protocol can be transformed to
various functionalized quaternary carbon centers (Scheme 1). For
example, borylated alkyne 1k reacted with 2a to produce 3aa in
77% yield without the loss of the carbon–boron bond. The ob-
tained 3aa can be transformed to two benzene substituted com-
pounds 6 in 80% yield via Suzuki–Miyaura coupling. We also
obtained cis- and trans-epoxides from each isomers (see supple-
mentary information). These results show that our controlled addi-
tion reaction is a powerful technique for synthesizing useful build-
ing blocks.
Table 3. Substrate scope
O
O
R
R'
O
Conditions A
O
O
OR''
O
O
R
Br
O
R
R'
OR''
or
O
R'
OR''
Conditions C
1h
2
3
4
Conditions A Conditions C
Conditions A Conditions C
Yield (%)
(3 : 4)
Yield (%)
(3 : 4)
Yield (%)
(3 : 4)
Yield (%)
(3 : 4)
Substrate 2
Substrate 2
3t: 71a,b,c
4t: 70
3k: 73a,b,c
4k: 84b
O
Br
(99:<1)
(8:92)
Br
CO2Et
2f
(99:<1)
(8:92)
O
CO2Me
Scheme 1. Transformations
2l
3l: 25
4l: 37
3u: 70a,b,c
4u: 72
O
(99:1)
(17:83)
Br
Br
Br
CO2Et
2g
(99:<1)
(6:94)
O
OMe
2m
3m: 73a,b
4m: 78
Br
O
3v: 46
4v: 55
(99:<1)
(13:87)
Br
Br
CO2Et
2h
Br
(99:<1)
(<1:99)
O
2n
3n: 85
4n: 83
(83:17)
(10:90)
Br
Br
O
CO2Me
2c
3w: 70a,b
4w: 77
O
Br
(99:<1)
(13:87)
In summary, we found a new control methodology to synthesize
trans- and cis-alkenes. The key to successful synthesis might lie in
the atom-transfer radical addition to produce brominated alkene
followed by its reduction with hydrosilane. On the other hand, cis-
hydroalkylation is carried out via reductive borylation followed
by Suzuki-type cross-coupling. Mechanistic studies including the
effect of additives, catalyst and temperature are currently under-
way.
2e
O
O
3o: 60
4o: 64
(90:10)
(6:94)
Br
2d
Ph
3x: 76a,
4x: 85
O
Br
(99:<1)
(11:89)
3p: 79
4p: 68
O
2o
(87:13)
(25:75)
Br
CO2Et
2i
O
3y: 72a
4y: 86b
EtO2C CO2Et
Br
3q: 75a,b,c
4q: 94
O
(95:5)
(<1:99)
Br
(84:16)
(15:85)
CO2Me
ASSOCIATED CONTENT
2b
2p
Supporting Information
EtO2C
3r: 60
4r: 65
Experimental procedures and spectroscopic data for all new com-
pounds are available free of charge via the Internet at
http://pubs.acs.org.”
Br
CO2Et
(99:<1)
(<1:99)
2j
H
H
H
3z: 44
4z: 53
O
O
3s: 70
4s: 75
(99:<1)
(5:95)
Br
O
AUTHOR INFORMATION
(99:<1)
(20:80)
O
2q
Br
2k
Corresponding Author
Conditions A: CuI (10 mol%), TPMA (10 mol%), HSiTMS3 (1.5
equiv), K3PO4 (20 mol%), Et3N (1.5 equiv), toluene, 160ºC, 12h.
Conditions C: CuI (10 mol%), TPMA (10 mol%), B2pin2 (1.5
equiv), K2CO3 (20 mol%), tBuOH (2.0 equiv), Et3N (1.5 equiv),
toluene, 100ºC, 20h. All reactions were carried out in a sealed
tube. The yields were isolated and the ratios were determined by
GC analysis. Pure isomer can be obtained after GPC (if separa-
nisikata@yamaguchi-u.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
a
b
c
ble). Run at 125ºC. 20 mol% of CuI was used. 20 mol% of
TPMA was used.
Financial support provided by program to disseminate tenure
tracking system, MEXT, Japan is gratefully acknowledgement.
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Angew. Chem., Int. Ed, 2016, 55, 10008-10012. See other related works:
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Soc. 2013, 135, 16372-16375. (b) Nishikata, T.; Ishida, S.; Fujimoto, R.
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ACS Catalysis
SYNOPSIS TOC (Word Style “SN_Synopsis_TOC”). If you are submitting your paper to a journal that requires a synopsis
graphic and/or synopsis paragraph, see the Instructions for Authors on the journal’s homepage for a description of what
needs to be provided and for the size requirements of the artwork.
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To format double-column figures, schemes, charts, and tables, use the following instructions:
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Place the insertion point where you want to change the number of columns
From the Insert menu, choose Break
Under Sections, choose Continuous
Make sure the insertion point is in the new section. From the Format menu, choose Columns
In the Number of Columns box, type 1
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Choose the OK button
Now your page is set up so that figures, schemes, charts, and tables can span two columns. These must appear at the top of
the page. Be sure to add another section break after the table and change it back to two columns with a spacing of 0.33 in.
Table 1. Example of a Double-Column Table
Column 1
Column 2
Column 3
Column 4
Column 5
Column 6
Column 7
Column 8
Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title,
should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem,
etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications.
Insert Table of Contents artwork here
H
Alkyl
Cu cat.
H[Si]
Cu cat.
R
X
H
H
Alkyl
H
H
R
Alkyl
ROH/B2pin2
R
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ACS Catalysis
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