Copper-Catalyzed and Proton-Directed Selective Hydroxymethylation of Alkynes with CO2

Article abstract of DOI:10.1002/anie.202012768

An intriguing strategy for copper-catalyzed hydroxymethylation of alkynes with CO₂ and hydrosilane was developed. Switched on/off a proton source, for example, ^tBuOH, direct hydroxymethylation and reductive hydroxymethylation could be triggered selectively, delivering a series of allylic alcohols and homobenzylic alcohols, respectively, with high levels of Z/E, regio- and enantioselectivity. Such a selective synthesis is attributed to the differences in response of vinylcopper intermediate to proton and CO₂. The protonation of vinylcopper species is demonstrated to be prior to hydroxymethylation, thus allowing a diversion from direct alkyne hydroxymethylation to reductive hydroxymethylation in the presence of suitable proton.

Full text of DOI:10.1002/anie.202012768

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Copper-Catalyzed and Proton-Directed Selective
Hydroxymethylation of Alkynes with CO2
Authors: Mei-Yan Wang, Xin Jin, Xiaofei Wang, Shumei Xia, Yue
Wang, Shouying Huang, Ying Li, Liang-Nian He, and Xinbin
Ma
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012768
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10.1002/anie.202012768
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed and Proton-Directed Selective
Hydroxymethylation of Alkynes with CO2
Mei-Yan Wang, Xin Jin, Xiaofei Wang, Shumei Xia, Yue Wang, Shouying Huang, Ying Li, Liang-Nian
He*, and Xinbin Ma*
Abstract: An intriguing strategy for copper-catalyzed
a) Hydroxymethylation of alkenes with CO2
hydroxymethylation of alkynes with CO2 and hydrosilane was
Ru/L
H2
CH2OH
(Sasaki and Beller)
CH2OH
developed. Switched on/off a proton source, e.g. tBuOH, direct
hydroxymethylation and reductive hydroxymethylation could be
triggered selectively, delivering a series of allylic alcohols and
homobenzylic alcohols respectively, with high levels of Z/E,
regio- and enantioselectivity. Such a selective synthesis is
attributed to the differences in response of vinylcopper
intermediate to proton and CO2. The protonation of vinylcopper
species is demonstrated to be prior to hydroxymethylation, thus
allowing a diversion from direct alkyne hydroxymethylation to
reductive hydroxymethylation in the presence of suitable proton.
+
CO2
R
R
R
R2
R1
Ar
CH2OH
Cu/L*
Silane
R2
R1
or
+
CO2
or
(Yu)
R
*
Ar
Me
b) Hydroxymethylation of allenes with CO2
R1
CH2OH
CH2OH
Cu/L
R1
+
or
CO2
R1
R2
Silane
R2
R2
(Tsuji)
(Ding)
c) Selective hydroxymethylation of alkynes with CO2 (this work)
R2
R2
CH2OH
Cu/L
Proton source
Cu/L*, silane
R1
+
CO2
CH2OH
R1
Me (R2=H)
*
Silane
R1
✝
Development of catalytic conversion of CO2 are highly desirable
Reductive hydroxymethylation
Excellent regio- and enantioselectivity
A protonation strategy to control the chemoselectivity
as CO2 is
a
very attractive and environmentally friendly
Direct hydroxymethylation
Exclusive Z/E selectivity
✝
feedstock in chemical synthesis. Valorization of CO2 to value-
added chemicals, e.g. organic carbonate,[1] ureas,[2] carboxylic
acid,[3] heterocycle,[4] and methylamines[5], is one of the
important fields, especially for chemo- and enantioselective
incorporation of CO2 into organic molecules,[6] yet remains a
challenge due to the fact that CO2 is thermodynamically stable
and kinetically inert. Among these efforts, the direct production
of complex alcohols, particularly for enantioriched alcohols, from
CO2 represents a highly attractive process, since alcohols are
commonly encountered structural elements in natural products
and active pharmaceutical ingredients. The seminal
achievement in CO2 conversion to complex alcohol was attained
by Sasaki and Beller et al. via the Ru-catalyzed
hydroxymethylation of alkenes (Scheme 1a).[7] Using allene as
substrate, Tsuji’s group achieved the synthesis of homoallylic
alcohols as well (Scheme 1b).[8] While, the regio- or
enantioselectivity of alcohol products had not been studied. Until
recently, Yu and co-workers pioneered the enantioselective
reductive hydroxymethylation of styrene/1,3-dienes with CO2,
✝
Scheme 1. Strategies for CO2 conversion to complex alcohols via
hydroxymethylation of unsaturated hydrocarbons
giving a series of chiral homoallylic alcohols (Scheme 1a),[9]
which is undoubtedly of creativity and significance. The
asymmetric reductive C-C bond formation with allenes and CO2
was also subsequently developed (Scheme 1b).[10] Despite great
advances made in accessibility of higher alcohols with CO2 as
feedstock, chemo-, regio- and enantioselective incorporation of
CO2 into alkynes to produce distinct alcohols, however, remains
unreported and very challenging.
In view of our interest in copper(I) hydride (CuH) catalysis
which generally proceed via an alkylcopper species, [11] we were
hopeful
to
achieve
the
copper-catalyzed
direct
hydroxymethylation of alkynes with CO2 to produce allylic
alcohols. Meanwhile, enlightened by the CuH-catalyzed alkyne
semireduction and asymmetric addition of olefin-derived
nucleophiles to carbonyls,[12] we envisioned that a protic additive
could trigger a cascade sequence of alkyne semireduction to an
alkene and then hydroxymethylation of the alkene to an alkyl
[*] Dr. M.-Y. Wang, X. Jin, X. Wang, Y. Wang, S. Huang, Y. Li, Prof. X. Ma
Key Laboratory for Green Chemical Technology of Ministry of Education,
School of Chemical Engineering and Technology
Tianjin University
alcohol. As
a result, a diversion from the direct alkyne
hydroxymethylation to reductive hydroxymethylation may occur,
thus achieving the selective hydroxymethylation of alkynes with
CO2. Herein, we realized the copper-catalyzed selective
hydroxymethylation of alkynes with CO2 (Scheme 1c). By
adding proton source to intercept the vital intermediate of
vinylcopper species or not, allylic alcohols and chiral
homobenzylic alcohols could be delivered, respectively, with
high levels of regio-, enantio-, and Z/E-selectivities.
Tianjin 300072 (China)
E-mail: xbma@tju.edu.cn
S. Xia, Prof. L.-N. He
State Key Laboratory and Institute of Elemento-Organic Chemistry
Nankai University
Tianjin 300071(China)
E-mail: heln@nankai.edu.cn
Dr. M.-Y. Wang, Prof. L.-N. He, Prof. X. Ma
Collaborative Innovation Center of Chemical Science and Engineering
Tianjin University, Tianjin 300072 (China)
Dr. M.-Y. Wang, Prof. X. Ma
Joint School of National University of Singapore and Tianjin University
International Campus of Tianjin University
Fuzhou 350207 (China)
We began our investigation by exploring the direct
hydroxymethylation of alkyne with CO2 using 1,2-
diphenylacetylene (1a) as model substrate and triethoxysilane
as hydride donor under 1 atm of CO2. Cu(OAc)2 coupled with a
range of biphosphine ligands were tested to evaluate the
reactivity of direct alkyne hydroxymethylation (Table 1, entries
1-8). Although copper catalysts based on ligands (S,S)-Ph-BPE
(L2), Xantphos (L4), and DTBM-MeO-BIPHEP (L5) were
Supporting information for this article can be found under:
https://doi.org/10.1002/anie.xxxxx
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10.1002/anie.202012768
Angewandte Chemie International Edition
COMMUNICATION
Table 1 Reaction optimization[a]
butanol anion to copper which is in favor of the regeneration of
14]
copper catalyst.[12e,
Finally, increasing the amount of
Cu(OAc)2 to 7.5 mol% relative to 1a could enhance the yield to
89% (Table 1, entry 15).
Cu(OAc)2 (5 mol%)
Ph
H
CH2OH
Ph
L (5.5 mol%)
+
CO2
1atm, closed
Ligand Silane
Ph
R3SiH (8 equiv.)
CyH (0.2 M)
Ph
1a
2a
With optimized conditions, the feasibility of direct
hydroxymethylation of alkynes with CO2 was then evaluated. As
shown in Scheme 2, a diverse of alkynes with electron-donating
and mildly electron-withdrawing substituents at the para position
of aromatic ring, all performed smoothly to give the
corresponding trisubstituted allylic alcohols with complete
stereoselectivity (2b~2g). The stereochemistry was confirmed by
NMR spectroscopic analysis, being consistent with the data
available in literature.[15] Steric hindrance caused by a meta- or
ortho-substituent slightly diminished the yield of isolated product
(2h, 2i). The alkyne bearing a heteroarene i.e. thiophene ring
was tolerated, stereoselectively affording the (Z)-2,3-di(thiophen-
2-yl)prop-2-en-1-ol (2j) in 64% yield. Although unsymmetrical
internal alkynes output a mixture of regioisomers (2k~2m), an
improvement in regioselectivity was observed along with the
increase in structural differences between substituents on the
alkyne. Especially a remarkably high regioselectivity (95:5) was
attained in the hydroxymethylated product (2n) of
Entry
Yield[%][b]
c
1
L1
L2
L3
L4
L5
L6
L7
L8
L7
L7
L7
L7
L7
L7
L7
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
PhSiH3
–
2
17
c
3
–
4
19
5
65
6
trace
70
7
[c]
8
–
9
trace
69
10
11
12
13[e]
14[f]
15[e, g]
Me(MeO)2SiH
Me(EtO)2SiH
PMHS[d]
46
16
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
80
78
cyclopropylphenylethyne.
Furthermore,
anti-Markovnikov
89
regioselectivity was observed when terminal alkynes were used,
giving rise to linear allylic alcohols in mild yields (2o, 2p).
[a] Reaction was conducted in a 25 mL Schlenk tube. Conditions: 1a
(0.0712 g, 0.4 mmol), Cu(OAc)2 (0.0036 g, 0.020 mmol), L (0.022
mmol), silane (3.2 mmol), CO2 (99.999%, closed), cyclohexane (2 mL),
60 °C, 24 h. [b] Isolated yield. [c] Not detected. [d]
Polymethylhydrosiloxane. [e] CsOAc (0.0039 g, 0.02 mmol) was added.
Cu(OAc)2 (7.5 mol%)
L7 (8.25 mol%)
CsOAc (5 mol%)
R2
H
CH2OH
R2
+
CO2
R1
t
(EtO)3SiH (8 equiv.)
CyH (0.2 M)
R1
[f] BuOK (0.0022 g, 0.02 mmol). [g] Cu(OAc)2 (0.0054 g, 0.03 mmol),
L7 (0.0389 g, 0.033 mmol).
1
2
H
CH2OH
R= p-H, 2a, 89%
R= p-Me, 2b, 69%
R= p- nBu, 2c, 66%
Ph
Ph
Ph
P
Ph2P
PPh2
H
CH2OH
S
Ph
P
P
P
Ph
O
Ph
S
Ph
Ph
PPh2
PPh2
R= p-OMe, 2d, 51%
R= p-F, 2e, 85%
R= p-Br, 2g, 67%
R
R
DPPBz (L3)
(S,S)-Ph-BPE (L2)
DPPE (L1)
Xantphos (L4)
O
O
R= p-Cl, 2f, 70%
R= m-F, 2h, 81%
2j, 64%
R= o-F, 2i, 78%
O
O
PAr2
PAr2
MeO
MeO
PAr2
PAr2
O
O
PPh2
PPh2
H
CH2OH
CH2OH
H
Ar = Ph
O
SEGPHOS (L6)
Ar = 3,5-tBu-4-MeOC6H2
DTBM-SEGPHOS (L7)
O
Ar = 3,5-tBu-4-MeOC6H2
DTBM-MeO-BIPHEP (L5)
nC6H13
SYNPHOS (L8)
nC6H13
Et
Et
CH2OH
2k
2k’
2l’
66% (52:48)
84% (57:43)
H
HOH2C
H
effective in this context, the catalyst based on DTBM-SEGPHOS
(L7) was found to be the best choice, affording 70% yield of (E)-
2,3-diphenylprop-2-en-1-ol (2a) with a single geometric isomer
as determined by 1H NMR analysis (Table 1, entry 7).
Subsequent examination for several copper compounds showed
Cu(OAc)2 was the optimal catalyst (Supporting Information,
Table S1, entries 1-4). Hydrosilane screening revealed that the
stronger reductant phenylsilane[13] in comparison with (EtO)3SiH
was inactive for the allylic alcohol generation (Table 1, entry 9),
because the phenylsilane is more favorable for the
hydrosilylation of CO2, a side reaction. Methylmethoxysilane
gave a comparable yield of 2a compared to (EtO)3SiH (Table 1,
Br
Br
2l
H
CH2OH
HOH2C
H
MeO
MeO
2m
2m’
88% (60:40)
90% (95:5)
H
CH2OH
HOH2C
H
2n
2n’
entry
10
vs.
7).
While,
hydrosilanes
such
as
CH2OH
CH2OH
diethoxymethylsilane and polymethylhydrosiloxane showed poor
reactivity, probably due to the difficult formation of CuH species
(Table 1, entries 11,12). Further optimization showed additives
such as CsOAc and tBuOK could facilitate the direct
hydroxymethylation of 1a with CO2 (Table 1, entries 13, 14),
accounting for the strong coordination ability of acetate and tert-
MeO
Et
2o, 42%
2p, 47%
Scheme 2. Hydroxymethylation of various alkynes. Conditions: 1 (0.4 mmol),
Cu(OAc)2 (0.0054g, 0.030 mmol), L7 (0.0389 g, 0.033 mmol), CsOAc (0.0039
g, 0.02 mmol), (EtO)3SiH (0.6 mL, 3.2 mmol), CO2 (1 atm, 99.999%, closed),
cyclohexane (2 mL), 60 °C, 24 h. Isolated yields (average of two runs).
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10.1002/anie.202012768
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COMMUNICATION
Cu(OAc)2 (7.5 mol%)
L7 (8.25 mol%)
CsOAc (5 mol%)
a)
As previously described, we were hopeful the addition of a
proton source could trigger the reductive hydroxymethylation via
a cascade sequence. Hence, several proton sources were
evaluated (see Supporting Information, Table S2, entries 1-4).
The result demonstrated that tBuOH is the most suitable
choice,[16] delivering homobenzylic alcohol (3a) in good yield
(71% yield, Table S2, entries 3). By adding water, mild yield of
3a could also be attained (Table S2, entry 4). What’s more,
investigation for several chiral ligands revealed (R)-L7 showed
remarkable performence in the reductive hydroxymethylation
reaction not only in reactivity but the enantioselectivity (97% ee
of 3a, Table S2, entries 3 vs. 5, 6). We attribute the success of
catalysts based on (R)-L7 to its outstanding ability to form CuH
species and to stabilize the vinyl/alkyl copper intermediate.[11g]
With the optimal reductive hydroxymethylation protocol, a
range of enantiopure homobenzylic alcohol derivatives were
synthesized with high levels of enantioselectivity (85-98% ee,
Scheme 3). Common functional groups including alkyl (3b, 3c),
alkoxy (3d), aryl halides (3e-3g), thiophene (3h), and aromatic
fused ring (3i) were well tolerated. Phenylacetylenes bearing
electron-rich groups were also derived to the corresponding
alcohols (3j, 3k). While, internal alkynes and electron-deficient
terminal alkynes failed to be transformed, presumably due to the
CH2OH
Ph
O
Ph
H
Si(OEt)3
+
H
+
O
Ph
(EtO)3SiH (8 equiv.)
CyH (0.2 M)
Ph
2a, not detected
1a
5
Cu(OAc)2 (10 mol%)
(R)-L7 (11 mol%)
H
CH2OH
O
tBuOK (5 mol%)
Me
Si(OEt)3
H
O
(EtO)3SiH (10 equiv.)
tBuOH (1 equiv.), CyH (0.2 M)
Ph
Ph
1qa
5
3a, not detected
b)
H
Cu(OAc)2 (10 mol%)
(R)-L7 (11 mol%)
tBuOK (5 mol%)
(EtO)3SiH (3 equiv.)
tBuOH (1 equiv.), CyH (0.2 M)
Ph
Ph
4, 73% NMR yield
1qa
Cu(OAc)2 (10 mol%)
(R)-L7 (11 mol%)
tBuOK (5 mol%)
CH2OH
Me
+
CO2
(EtO)3SiH (10 equiv.)
CyH (0.2 M)
Ph
Ph
Ph
4
3a, 90% yield, 97% ee
c)
H
Cu(OAc)2 (10 mol%)
(R)-L7 (11 mol%)
CsOAc (5 mol%)
CH2OH
CH2D
+
CO2
(EtO)3SiH (10 equiv.)
D2O (1equiv.), CyH (0.2 M)
1qa
Ph
3a, 45% yield
Scheme 4. Mechanistic experiments
enantioselectivity (65%, 97% ee) of 3a was obtained when the
copper-catalyzed reductive hydroxymethylation of 4-ethynyl-1,1’-
biphenyl (1qa) with CO2 was performed on a 5 mmol scale (for
details, see Supporting Information).
impediments of hydrocupration.[11c]
A yield decrease for
reductive hydroxymethylation was observed compared with that
in direct hydroxymethylation, due to the inevitable Glaser
coupling and over reduction of alkynes. It is noteworthy that in all
tested aryl-substituted alkynes, the corresponding alcohol
To gain
a
better understanding of the selective
series of
hydroxymethylation reactions, we carried out
a
mechanistic experiments. Firstly, silyl formate (5) was detected
in the reaction mixture. However, the reaction of 5 with 1a or
1qa under the standard conditions failed to give product 2a or 3a
(Scheme 4a), suggesting that the silyl formate was not an active
intermediate. Instead, the unproductive hydrosilylation of CO2 to
silyl formate, silyl acetal and silyl methoxide was a competitive
side reaction,[5f,
hydrosilane is essential to obtain a good production of alcohols
(Table S1, entry 6 vs. 5). The semireduction of 1qa to 4-vinyl-
products
were
delivered
in
exclusive
Markovnikov
regioselectivity, which is in accord with the reported results for
the
copper-catalyzed
alkyne
semireduction
and
hydroamination.[11g, 12b, 12c] Moreover, a satisfactory yield and
17]
and that is exactly why an excess of
Cu(OAc)2 (10 mol%)
(R)-L7 (11 mol%), tBuOK (5 mol%)
H
CH2OH
+
CO2
Ar
1q
(EtO)3SiH (10 equiv.)
tBuOH (1 equiv.), CyH (0.2 M)
Ar
Me
t
1,1’-biphenyl (4) in the presence of BuOH was explored and
3
CH2OH
Me
CH2OH
Me
73% yield of 4 was obtained. Further reaction of compound 4
with CO2 under standard direct hydroxymethylation conditions
could proceed efficiently to deliver 3a in 90% yield and 97% ee
(Scheme 4b). Further isotope-labelling study was carried out by
using deuterated water as a proton source under standard
conditions. The incorporation of deuterium in the methyl moiety
of 3a was observed by 1H NMR and GC-MS (see Supporting
Information, Figure S1 and S2). All of the above results are in
agreement with our hypothesis that vinylcopper species I
undergo protonation to deliver an alkene, thus allowing the
reductive hydroxymethylation as a cascade reaction to be
successfully triggered.
CH2OH
Me
Ph
Et
nPr
3b, 70%, 98% ee
CH2OH
3a, 71%, 97% ee
3c, 79%, 97% ee
CH2OH
CH2OH
Me
Me
Me
MeO
F
Cl
3d, 59%, 85% ee
3e, 55%, 94% ee
3f, 61%, 94% ee
CH2OH
CH2OH
CH2OH
Me
Me
Me
Br
S
On the basis of experimental results and previous
literatures,[9a, 10, 12e, 18] a catalytic cycle for the copper-catalyzed
selective hydroxymethylation of alkynes with CO2 is proposed
(Scheme 5). The formation of allylic and homobenzylic alcohols
both commence with hydrocupration of CuH to the alkyne
substrate to give vinylcopper intermediate I. In the absence of a
proton source, direct interception by CO2 would deliver the
copper carboxylate II, which is further reduced to intermediate III
that, upon transmetallation with hydrosilane, regenerates the
CuH species. While in the presence of a proton source, prior
protonation of vinylcopper I forms the alkene 4, followed by
3g, 49%, 87% ee
3h, 72%, 96% ee
3i, 47%, 96% ee
CH2OH
CH2OH
Me
Me
MeO
Et
3j, 45%, 96% ee
3k, 51%, 99% ee
Scheme 3. Reductive hydroxymethylation of alkynes. Conditions: 1q (0.4
mmol), Cu(OAc)2 (0.0072 g, 0.04 mmol), (R)-L7 (0.0518 g, 0.044 mmol),
tBuOK (0.0022 g, 0.02 mmol), (EtO)3SiH (0.75 mL, 4.0 mmol), CO2 (1 atm,
99.999%, closed), cyclohexane (2 mL), tBuOH (37 uL, 0.4 mmol), 65 °C, 36 h.
Isolated yields (average of two runs). Enantiomeric excesses (ee) were
determined by HPLC analysis. For 3j and 3k, the reaction temp. was 75 °C.
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10.1002/anie.202012768
Angewandte Chemie International Edition
COMMUNICATION
CH2OH
CH2OSiR3
CH2OSiR3
CH2OH
H+
3511-3515; Angew. Chem. 2019, 131, 3549-3553; e) X. Wang, Y. Zhou,
Z. Guo, G. Chen, J. Li, Y. Shi, Y. Liu, J. Wang, Chem. Sci. 2015, 6,
6916-6924; f) L. Wang, G. Zhang, K. Kodama, T. Hirose, Green Chem.
2016, 18, 1229-1233; g) N. Tenhumberg, H. Buttner, B. Schaffner, D.
Kruse, M. Blumenstein, T. Werner, Green Chem. 2016, 18, 3775-3788;
h) Y. A. Rulev, V. A. Larionov, A. V. Lokutova, M. A. Moskalenko, O. L.
Lependina, V. I. Maleev, M. North, Y. N. Belokon, ChemSusChem 2016,
9, 216-222.
H+
H
H
R’
R’
LCuX
CsOAc
*
VIII
*
R
Me
R
Me
R
3
IV
R
R3SiH
2
R3SiH
CH2OCuL*
R3SiH
H
*
VII
Me
R
LCuH
R3SiH
R’
CH2OCuL
R
R’
COOCuL*
R
III
[2]
[3]
a) M. Yoshida, N. Hara, S. Okuyama, Chem. Commun. 2000, 151-152;
b) M. Xu, A. Jupp, M. Ong, K. Burton, S. Chitnis, D. W. Stephan,
Angew. Chem., Int. Ed. 2019, 58, 5707-5711; Angew. Chem. 2019, 131,
5763-5767.
*
R
Me
VI
H
CuL
CO2
I
R3SiH
H
R
R’
R
COOCuL
Me
*LCu
*
Selected reviews and examples on carboxylation of CO2: a) M.
Börjesson, T. Moragas, D. Gallego, R. Martin, ACS Catal. 2016, 6,
6739-6749; b) R. Martin, A. Tortajada, F. Juliá-Hernández, M.
Borjesson, T. Moragas, Angew. Chem., Int. Ed. 2018, 57, 15948-
15982; Angew. Chem. 2018, 130, 16178-16214; c) J. Artz, T. E. Müller,
K. Thenert, J. Kleinekorte, R. Meys, A. Sternberg, A. Bardow, W.
Leitner, Chem. Rev. 2018, 118, 434-504; d) F. Juliá-Hernández, T.
Moragas, J. Cornella, R. Martin, Nature 2017, 545, 84-88; e) V. R.
Yatham, Y. Shen, R. Martin, Angew. Chem., Int. Ed. 2017, 56, 10915-
10919; Angew. Chem. 2017, 129, 11055-11059; f) S. Wang, P. Shao, C.
Chen, C. Xi, Org. Lett. 2015, 17, 5112-5115; g) S.-S. Yan, D.-S. Wu, J.-
H. Ye, L. Gong, X. Zeng, C.-K. Ran, Y.-Y. Gui, J. Li, D.-G. Yu, ACS
Catal. 2019, 9, 6987-6992; h) S.-S. Yan, Q. Fu, L.-L. Liao, G.-Q. Sun,
J.-H. Ye, L. Gong, Y.-Z. Bo-Xue, D.-G. Yu, Coord. Chem. Rev. 2018,
374, 439-463.
R
’
=H
R’
R
II
tBuOH
V
CO2
R
4
*LCuH
Scheme 5. Proposed mechanism.
carboxylation of benzylic copper species V and reduction of
carboxylcopper species VI to afford the homobenzylic
alcohols.[19] What is worth mentioning, the sequential generation
of β-vinyl copper I and benzylic copper species V accounts for
excellent regioselectivity of homobenzylic alcohols. We
rationalize the anti-Markovnikov regioselectivity observed from
the β-vinyl copper intermediate as arising from the strong
electronegativity of terminal alkynyl carbon atom. In contrast, the
Markovnikov regioselectivity observed from benzylic copper
species was attributed to electronic stabilization of the benzylic
copper species by an adjacent aryl group.[11g]
In summary, we have for the first time achieved the copper-
catalyzed hydroxymethylation of alkynes with CO2. With a
protonation strategy, direct alkyne hydroxymethylation and
reductive hydroxymethylation can be performed selectively. Both
direct hydroxymethylation and reductive hydroxymethylation
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undergo the generation of
a
vinylcopper intermediate.
Protonation or hydroxymethylation of the vinylcopper species,
controlled by the presence or absence of a protic additive,
determines the product. The alkyne hydroxymethylation protocol
not only furnishes a facile option for CO2 conversion but also
provides a straightforward method to access a broad range of
functionalized alcohols of interest in pharmaceutical research
and other related areas.
[5]
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Acknowledgements
The authors gratefully acknowledge financial support from
National Natural Science Foundation of China (21808164),
Tianjin Key Science and Technology Project (19ZXNCGX00030),
and China Postdoctoral Science Foundation (2018M631744,
2020T130466).
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Keywords: alkynes • carbon dioxide fixation• copper catalysis•
hydroxymethylation • synthetic methods
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[19] At the current temperature of 65 oC, the protonation of benzylic copper
intermediate is slower compared to its carboxylation. In additon, the
t
protonation of vinylcopper intermediate consumes most of the BuOH,
further suppressing the protonation of benzylic copper intermediate. For
details, see Supporting Information, section 3.4.
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COMMUNICATION
M.-Y. Wang, X. Jin, X. Wang, S. Xia, Y.
Wang, S. Huang, Y. Li, L.-N. He*, X. Ma*
R2
R2
+
CH2OH
Proton source
Cu/Lꢀꢁsilane
R1
CO2
R1
CH2OH
(R2=H)
R1
*
Me
Cu/L*, silane
Page No. – Page No.
Direct hydroxymethylation
Exclusive Z/E selectivity
Reductive hydroxymethylation
Excellent regio- and enantioselectivity
Copper-Catalyzed
Directed
and
Proton-
Selective
Hydroxymethylation of Alkynes with
CO2
CO2 transformation to complex alcohols: A protic switch was applied into the
newly-developed copper-catalyzed hydroxymethylation of alkynes with CO2,
selectively delivering allylic alcohols and β-chiral branched alkyl alcohols with high
levels of Z/E, regio- and enantioselectivity.
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