Hydromagnesiation of 1,3-Enynes by Magnesium Hydride for Synthesis of Tri- and Tetra-substituted Allenes

Article abstract of DOI:10.1002/anie.202012027

A protocol for regio-controlled hydromagnesiation of 1,3-enynes was developed using magnesium hydride that is generated in situ by solvothermal treatment of sodium hydride (NaH) and magnesium iodide (MgI₂) in THF. The resulting allenylmagnesium species could be converted into tri- and tetra-substituted allenes by subsequent treatment with various carbon- and silicon-based electrophiles with the aid of CuCN as a catalyst.

Full text of DOI:10.1002/anie.202012027

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Hydromagnesiation of 1,3-enynes by magnesium hydride for
synthesis of tri- and tetra-substituted allenes
Authors: Bin Wang, Yihang Li, Jia Hao Pang, Kohei Watanabe, Ryo
Takita, and Shunsuke Chiba
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012027
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10.1002/anie.202012027
Angewandte Chemie International Edition
COMMUNICATION
Hydromagnesiation of 1,3-enynes by magnesium hydride for
synthesis of tri- and tetra-substituted allenes
Bin Wang,[a,+] Yihang Li,[a,+] Jia Hao Pang,[a] Kohei Watanabe,[b] Ryo Takita,*[b] and Shunsuke Chiba*[a]
[a]
[b]
[+]
Dr. B. Wang, Y. Li, Prof. Dr. S. Chiba
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
Dr. Kohei Watanabe, Prof. Dr. R. Takita
Graduate School of Pharmaceutical Sciences, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: takita@mol.f.u-tokyo.ac.jp
These authors contributed equally.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: A protocol for regio-controlled hydromagnesiation of 1,3-
enynes was developed using magnesium hydride that is generated
in situ by solvothermal treatment of sodium hydride (NaH) and
magnesium iodide (MgI2) in THF. The resulting allenylmagnesium
species could be converted into tri- and tetra-substituted allenes by
subsequent treatment with various carbon- and silicon-based
electrophiles with the aid of CuCN as a catalyst.
A. Hydrometallation by transition metal hydrides
H
H
R
E
E+
#
•
[M]
$
"
H
R
2
H-[M]
!-functionalization
4
3
1
H
R
H
E+
R
$
([M] = Pd, Cu, Ru, Ir)
E
#
•
"
R
[M]
H
!-functionalization
Hydrometallation of carbon-carbon unsaturated bonds such as
alkenes and alkynes is a promising protocol for generation of the
corresponding organometallic species, that can often function as
a nucleophile to undergo downstream formation of a new
covalent linkage with various electrophiles.[1] For this purpose,
regioselectivity of the hydrometallation would be of crucial
importance to efficiently enhance molecular complexity. If
conjugation of two carbon-carbon unsaturated bonds is present
in the substrates, multiple possibilities should be taken into
account for the regioselectivity of their hydrometallation and
ensuing downstream functionalization of the resulting
organometallic nucleophiles. In this regard, readily accessible
1,3-enynes have been employed as a substrate of choice for the
studies of their hydrometallation (Scheme 1), where transition-
metal catalysis has advanced the state-of-the-art (Scheme
B. Hydroalumination by aluminum hydrides
(i) non-guided approaches: alkyne selective
H
R’
H-[Al]
R’
then H2O
H
R
R
(ii) hydroxy-guided approach for allene construction
H
R
via
R
H-[Al]
H
•
OH
•
H
then H2O
R
[Al]
OH
H
O
C. anti-Hydromagnesiation of aryl alkynes by MgH2
MgH2
generated in situ
from NaH-MgI2
E+
Ar
H
Ar
H
Ar
R
E
R
[Mg]
R
1A).[2]
In this regard, transition-metal hydrides based on
D. Hydromagnesiation of 1,3-enynes by MgH2 (this work)
palladium,[3,4] copper,[5-7] and ruthenium/iridium complexes[8]
have commonly been engaged in 1,2/1,4-hydrometallation of
MgH2
generated in situ
from NaH-MgI2
R2
R2
[Mg]
R1
[Mg]
R2
H
•
1,3-enynes as
exceptions.[9,10]
a
typical reaction mode with several
The resulting propargyl/allenyl metal
H
R1
R3
R3
R1
R3
R2
intermediates could be functionalized with various sets of
electrophiles (E+) and the reaction course (i.e. α-
functionalization for allene synthesis or γ-functionalization for
alkyne synthesis) could vary depending on the types of the
electrophiles.
cat. CuCN
E+
R1
regioselective 1,4-hydromagnesiation by MgH2.
no directing group required.
•
allene-selective functionalization with various E+.
E
H
R3
Scheme 1. Hydrometallation of 1,3-enynes and alkynes by metal hydrides.
On the other hand, the reductive molecular transformations of
1,3-enynes promoted by main group metal hydrides have been
underdeveloped and the reported examples have been strictly
limited to hydroalumination by aluminum hydrides (Scheme 1B).
As for the regioselectivity trend, aluminum hydrides commonly
target the alkyne moiety to form 1,3-dienes with subsequent
functionalization such as protonation (Scheme 1B-i),[11] whereas
1,4-hydroalumination towards allenes is enabled when
a
hydroxy group is installed adjacent to the alkene moiety
(Scheme 1B-ii).[12]
We recently disclosed unprecedented
reactivity of magnesium hydrides (MgH2)[13] generated in situ by
counter ion metathesis between sodium hydride (NaH) and
1
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10.1002/anie.202012027
Angewandte Chemie International Edition
COMMUNICATION
A. Hydromagnesiation-protonation of 1a[a]
survey of various reaction parameters (see the SI for details)
revealed that a combination of NaH and MgI2 is optimal for
efficient and regioselective 1,2/1,4-hydromagnesiation of 1a
(Scheme 2). Namely, treatment of 1a with NaH (1.5 equiv) and
MgI2 (1.5 equiv) in THF at 100 °C allowed for a full conversion of
1a within 2 h and subsequent aqueous work-up afforded 3-
methyl-1-(4-methoxyphenyl)allene (2a) in 81% yield along with
8% yield of alkyne 3a. Formation of 2a and 3a suggested the
formation of an equilibrium mixture of propargylmagnesium A
NaH (1.5 equiv)
MgI2 (1.5 equiv)
Ar
H
•
+
Ar
H
H
Ar
(Ar = 4-MeOC6H4)
THF, 100 °C, 2 h
1a
H
3a 8%
then H2O
2a 81%
Ar
[Mg]
H
[Mg]
•
Ar
H
A
H
B
• propargylmagnesium-allenylmagnesium equilibrium
and allenylmagnesium
B
through regioselective 1,2/1,4-
hydromagnesiation.[18] We observed that downstream allylation
of the resulting carbanion species A and B with allyl bromide
(4a) could be facilitated in the presence of a catalytic amount of
CuCN•2LiCl,[19] affording trisubstituted allenes 5aa in good yield
as a sole product (Scheme 2B). A deuterium labeling experiment
using NaD revealed that a deuterium was exclusively installed
on the methyl group of 5aa, unambiguously supporting the
B. Hydromagnesiation-allylation of 1a[b]
NaH(D) (1.5 equiv)[c]
MgI2 (2 equiv)
THF, 100 °C, 2 h
Ar
H
•
Ar
then
(D)H
5aa 88% (86%)[d]
1a
(Ar = 4-MeOC6H4)
CuCN•2LiCl (10 mol%)
allyl-Br 4a (1.2 equiv)
0 °C, 2 h
1,2/1,4-hydromagnesiation process.
Functionalization with
C. Hydromagnesiation-downstream functionalization of 1a[e]
external alkyl electrophiles for the synthesis of substituted
allenes through hydrometallation of 1,3-enynes has remained
elusive.[20-23] Encouraged by the preliminary outcome, we next
investigated the scope of the alkyl electrophiles (Scheme 2C).
This downstream functionalization was found to be compatible
with use of t-butyl 2-bromomethylacrylate (4b), benzyloxymethyl
chloride (4c), propargyl bromide 4d and benzyl bromide (4e),
providing the corresponding tri-substituted allenes 5 in good to
moderate yields (Scheme 2C). To install a methyl group, use of
methyl tosylate (4f) was found to be optimal.[24] The protocol
also allowed for use of non-activated alkyl bromide 4g. The
protocol was also amenable to install a silyl group using
chlorosilanes 4h and 4i to afford synthetically useful
allenylsilanes 5ah and 5ai in good yields.
We next investigated the scope of the allene synthesis with
respect to the substituents (R1-R3) on enynes 1 (Scheme 3). As
for the substituent R1 on the alkyne moiety, the method was
suitable for installing various aryl groups including electron-rich
(hetero)arenes (for 5aa, 5ia, 5ja, and 5ka), haloarenes (for 5da-
5fa) and sterically demanding ones (for 5ha and 5ia). It would
be worthy of note that the process was not detrimentally
influenced by the presence of alkyl groups as the R1, providing
the corresponding trisubstituted allenes 5la and 5ma in good
yields. Similarly, the reaction of silyl-substituted enyne 1n also
proceeded smoothly to afford silyl-substituted allene 5na in an
Ar
H
Ar
H
Ar
H
Ar
H
•
•
•
•
Me
Ph
Me
CO2t-Bu
Me
Me
OBn
Ph
5ae 62%
5ab 83%
with
CO2t-Bu
5ac 83%
5ad 53%
with
with
with
Ph
Cl
OBn
Br
Ph
Br
Br
Ar
4b
4c
4d
4e
Ar
H
Ar
H
H
Ar
H
•
•
•
Me
Me
•
Me
Si
Me
Me
Si
Ph
Me
Me
Me
Me
Ph
5ag 68%[f]
5af 60%
with
5ah 66%
5ai 62%
with
with
with
Br
MeOTs
4f
PhMe2SiCl
(allyl)Me2SiCl
Ph
4h
4i
4g
Scheme 2. Hydromagnesiation of enyne 1a. [a] The reaction was conducted
using 0.5 mmol of enyne 1a in THF (2.5 mL, 0.2 M) with NaH (1.5 equiv) and
MgI2 (1.5 equiv) at 100 °C for 2 h. [b] The reactions were conducted using 0.5
mmol of enyne 1a in THF (2.5 mL, 0.2 M) with NaH (1.5 equiv) and MgI2 (1.5
equiv) at 100 °C for 2 h, followed by CuCN•LiCl (10 mol%) and allyl bromide
(4a) (1.2 equiv) at 0 °C for 2 h. [c] When sodium deuteride (NaD) was utilized
instead of NaH, deuterium was incorporated exclusively at the methyl group of
5aa (>93% incorporation). [d] The isolated yield of 5aa obtained from the
reaction in a 5 mmol scale. [e] The reactions were conducted using 0.5 mmol
of enyne 1a in THF (2.5 mL, 0.2 M) with NaH (1.5 equiv) and MgI2 (1.5 equiv)
at 100 °C for 2 h, followed by CuCN•LiCl (10 mol%) and electrophiles 4 (1.2
equiv) at 0 °C for 2-4 h. [f] The 2nd step alkylation was conducted using 2
equiv of 4g at 35 °C for 4 h.
excellent yield.
We also found that the present
hydromagnesiation was not disturbed by the presence of the
substituent R2 on the alkene moiety (for 5oc and 5pc).
Significantly, the protocol was amenable to transform enynes
1q-1v having internal substituent R3 on the alkene, providing
tetra-substituted allenes 5qc-5vc in good yields. As for R3,
methyl (for 5qc) and functionalized primary alkyl groups (for 5rc
and 5sc) as well as sterically bulkier cycloalkyl and t-butyl
groups (for 5tc-5vc) could be installed.
Having developed a method for the concise construction of
functionalized allenes, we next explored derivatization of the
representative allene products to other scaffolds of potential use
(Scheme 4). One of the highlights in the present synthetic
strategy is a facile installation of the silicon-substituent onto the
allenes such as 5ah, 5na and 5sc. Therefore, we examined
their transformations into other silicon-substituted scaffolds. We
magnesium halides (MgX2: X = I, Br, or Cl) in THF, that perform
anti-hydromagnesiation of aryl alkynes and the resulting
alkenylmagnesium intermediates could be functionalized with
various electrophiles (Scheme 1C).[14-16] In this context, we
wondered how the hydridic reactivity of MgH2 works toward
reductive functionalization of 1,3-enynes. Herein, we report
regioselective hydromagnesiation of 1,3-enynes by MgH2
generated from NaH and MgI2 in THF for generation of
allenyl/propargyl magnesium species and their downstream
functionalization with carbon- and silicon-based electrophiles in
the presence of CuCN as
functionalized tri- and tetra-substituted allenes (Scheme 1D).[17]
We embarked on our investigation using 4-(4-
methoxyphenyl)-1-butene-3-yne (1a) as a model substrate.
a catalyst, liberating multi-
A
2
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10.1002/anie.202012027
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COMMUNICATION
NaH (1.5 equiv)
MgI2 (2 equiv)
THF, 100 °C, 2-18 h
A. Pd-catalyzed oxidative arylation
R3
ArB(OH)2 (1.3 equiv)
Pd(OAc)2 (1 mol%)
benzoquinone (1.1 equiv)
R1
R3
Ph
Me Si
Me
Ph
•
Me Si
Me
H
then
R2
R1
R2
•
E
CuCN•2LiCl (10 mol%)
E+ (4a or 4c, 1.2 equiv)
0 °C, 2-4 h
5
Ar
1
Me
acetone or THF
50 °C, 21 h
6 (Ar = Ph): 50%
7 (Ar = 4-MeOC6H4): 74%
5na
with
R1
X
5aa (X = OMe): 88%
5ba (X = H): 74%
5ca (X = Ph): 90%
5da (X= F): 81%
5ea (X = Cl): 84%
5fa (X = Br): 89%
B. Iodoarylation
MeO
MeO
H
H
Me
•
NIS (1.2 equiv)
•
Me
H
Me
•
MeCN
I
Me
rt, 20 min
Me Si
Me
5ga 86%
Si
Me
N
Me
Ph
Me Ph
Me
5ah
8 93%
C. Iododesilylation for synthesis of propargylic iodide
S
Me
OBn
Me Ph
H
H
H
H
I
Me Si
H
NIS (1.2 equiv)
•
•
•
•
•
Me
Me
Me
Me
Me
Me
MeNO2
rt, 2 h
5ja 84%
5ha 86%
Ph
5ia 89%
5ka 84%
5na
9 62%
D. Bromodesilylation for synthesis of 1,3-dienes
BnO
Me Me
Ph Si
H
H
H
Me
Ph
SiMe3
•
•
•
Ph
NBS (1.2 equiv)
•
Me
Me
Me
Me
5sc
BnO
Br
MeCN
–40 °C, 2 h
5la 63%[b]
5ma 58%[b]
5na 95%[c]
OBn
10 75% (Z/E = 69:31)
with
R1
Ph
H
•
Scheme 4. Derivatization of allenes.
H
R2
•
OBn
Me
Ph
OBn
5pc 71%
5oc 66%
Finally, the origin of regioselectivity observed in the present
1,2/1,4-hydromagnesiation of 1,3-enynes was elucidated by the
theoretical means (Scheme 5). We recently uncovered that
solvothermal treatment of a mixture of NaH and MgI2 in THF
generates highly hydridic MgH2 in small units,[14] which should
be responsible for the present transformation. To gain insights
into the reactivity and selectivity, we carried out the DFT
calculations at the ωB97XD/6-311++G**/SMD(THF)//ωB97XD/6-
31++G** level of theory using phenyl-substituted enyne 1b and a
MgH2 dimer as the model substrates. We found that the process
is initiated by smooth 1,2-hydromagnesiation of 1b via TSA-1
(∆G‡ +16.2 kcal/mol), where the Mg–H moiety comes from the
upper side of the alkene plane to afford the corresponding
propargylmagnesium species INTA-2 (i.e. A in Scheme 2A)
(Scheme 5A). We observed that the energy barrier of the
R3
with
R1
OBn
MeO
Me3Si
Ph
Ph
•
•
Me
Me
•
Me
Me
OBn
OBn
OBn
5sc 74%
5rc 83%
5qc 61%
Ph
Ph
Ph
•
•
•
Me
Me
Me
OBn
OBn
OBn
5tc 79%
5uc 85%
5vc 79%
Scheme 3. Scope with respect to enynes 1. [a] Unless otherwise stated, the
reactions were conducted using 0.5 mmol of enynes 1 in THF (2.5 mL, 0.2 M)
with NaH (1.5 equiv) and MgI2 (1.5 equiv) at 100 °C for 2-18 h, followed by
CuCN•LiCl (10 mol%) and electrophiles 4a or 4c (1.2 equiv) at 0 °C for 2-4 h.
[b] 1.5 equiv of MgI2 was used. [c] The reaction was conducted using 7 mmol
(1.31 g) of enyne 1n.
isomerization
from
propargylmagnesium
INTA-2
to
allenylmagnesium INTA-3 is reasonably small (∆G‡ +5.0 kcal/mol)
and so is their energy difference (∆∆G 5.3 kcal/mol), indicating
that these species should exist in an equilibrium, where the
presence of allenyl INTA-3 should be predominant over propargyl
observed that palladium-catalyzed oxidative arylation of 5na with
arylboronic acids under the Bäckvall’s reaction conditions[25]
delivered silicon-substituted 1,3,6-trienes 6 and 7 (Scheme 4A).
Iodoarylation of allene 5ah was found to be facilitated by N-
iodoscuccinimide (NIS) in MeCN to afford 2-iodo-3-silylindene 8
in excellent yield (Scheme 4B).[26] In turn, we also attempted
desilylative transformations. For example, a facile treatment of
silylallene 5na with NIS allowed for desilylative propargylic
iodination, providing 9 in 62% yield (Scheme 4C). Moreover,
bromodesilylation of silylmethylallene 5sc by the treatment with
NBS delivered functionalized diene 10 (Scheme 4D).[27]
INTA-2
.
We also examined another 4,1-hydromagnesiation
pathway, that should be initiated by hydromagnesiation of the
alkyne moiety (Scheme 5B). In this case, the hydride was forced
to access the alkyne from the same plane of the benzene ring.
Therefore, the large distortion was observed in TSB-1, resulting in
larger deformation energy (DEFenyne: 18.8 kcal/mol) than that for
TSA-1 (DEFenyne: 5.1 kcal/mol) and thus higher activation energy
(∆G‡ +22.2 kcal/mol). In this event, the magnesium cation
instantly moved to the C1, giving the homoallenylmagnesium
species INTB-2 in one step. These theoretical outcomes well
corroborated the experimental observations.[28]
3
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10.1002/anie.202012027
Angewandte Chemie International Edition
COMMUNICATION
A. 1,4-Hydromagnesiation pathway
MOE2019-T2-1-089 for S.C.) as well as JSPS KAKENHI grant
JP19K06992 (for R.T.) and the Naito Foundation (for R.T.).
Computational calculations were performed using the resources
of the Research Center for Computational Science at Okazaki,
Japan.
H
H
1.74
1.74
thf Mg
1.89
1.90
2.09 Mg
1.91 H
2.10
1.91
H1.94 thf
2.11
∆G‡
+16.2
thf
H
H
1.95
1.89
(–40.9)
1.94
2.53
Mg
2.56
Mg
thf
2.11
1.81
1.75
1.41
1.22
H
H
1.79
4
3
1.39
2
Keywords: allenes • enynes • magnesium hydride • sodium
1.21
1.34
TSA-1 (16.2)
1
hydride • hydromagnesiation
DEFenyne = 5.1 kcal/mol
DEFMgH2 = 3.2 kcal/mol
INTA-1 (0.0)
[1]
[2]
[3]
For reviews, see: a) J. Chen, J. Guo, Z. Lu, Chin. J. Chem. 2018, 36,
1075; b) M. D. Greenhalgh, A. S. Jones, S. P. Thomas, ChemCatChem
2015, 7. 190.
H
1.74
H
1.74
2.07
Mg
1.92
∆G‡
+5.0
2.07
Mg
1.91
1.93
1.94
thf
thf
H
H
1.89
1.88
H
For a review on transition-metal catalyzed conversion of 1,3-enynes
into allenes, see: L. Fu, S. Greβies, P. Chen, G. Liu, Chin. J. Chem.
2020, 38, 91.
H
1.90
1.90
Mg
thf
H
Mg
2.15
thf
2.12
2.29
2.10
2.57
1.43
1.22
1.39
1.25
H
a) Y, Matsumoto, M. Naito, Y. Uozumi, T. Hayashi, J. Chem. Soc.,
Chem. Commun. 1993, 1468; b) Y. Matsumoto, M. Naito, T. Hayashi,
Organometallics 1992, 11, 2732; c) M. Satoh, Y. Nomoto, N. Miyaura, A.
Suzuki, Tetrahedron Lett. 1989, 30, 3789.
INTA-2 (–24.7)
TSA-2 (–19.7)
[4]
[5]
a) M. Ogasawara, A. Ito, K. Yoshida, T. Hayashi, Organometallics 2006,
25, 2715; b) J. W. Han, N. Tokunaga, T. Hayashi, J. Am. Chem. Soc.
2001, 123, 12915.
1.31 1.32
•
1.95
(–10.3)
1.90
H
Mg
1.88
2.07
H
1.93
thf
H
thf 2.10 Mg 1.95
1.73
a) Y. Huang, J. del Pozo, S. Torker, A. H. Hoveyda, J. Am. Chem. Soc.
2018, 140, 2643; b) H. L. Sang, S. Yu, S. Ge, Org. Chem. Front. 2018,
5, 1284; c) D.-W. Gao, Y. Xiao, M. Liu, Z. Liu, M. K. Karunananda, J. S.
Chen, K. M. Engle, ACS Catal. 2018, 8, 3650.
H
INTA-3 (–30.0)
B. 4,1-Hydromagnesiation pathway
H
[6]
a) R. Y. Liu, S. L. Buchwald, Acc. Chem. Res. 2020, 53, 1229; b) Y.
Yang, I. B. Perry, G. Lu, P. Liu, S. L. Buchwald, Science 2016, 353,
144; c) L. Bayeh-Romero, S. L. Buchwald, J. Am. Chem. Soc. 2019,
141, 13788.
H
2.09
Mg 1.74
1.75
thf
1.92
Mg
thf
1.89
2.09
1.89
1.92
H
H
∆G‡
+22.2
H
1.95
1.90
H
1.95
2.81
1.90
thf
Mg
Mg
thf
2.87
2.10
2.96
[7]
[8]
S. Yu, H. L. Sang, S.-Q. Zhang, X. Hong, S. Ge, Commun. Chem. 2018,
1, 64.
1.42
1.25
2.11
1.74
H
1.79
1.35
1.43
1.87
a) K. D. Nguyen, D. Herkommer, M. J. Krische, J. Am. Chem. Soc.
2016, 138, 5238; b) L. M. Geary, S. K. Woo, J. C. Leung, M. J. Krische,
Angew. Chem. Int. Ed. 2012, 51, 2972; Angew. Chem. 2012, 124, 3026.
H
1.34
1.21
TSB-1 (22.2)
INTB-1 (0.0)
DEFenyne = 18.8 kcal/mol
DEFMgH2 = 2.0 kcal/mol
[9]
For 4,1-hydroamination of 1,3-enynes by a cationic palladium(II)-
hydride complex, see: N. J. Adamson, H. Jeddi, S. J. Malcomson, J.
Am. Chem. Soc. 2019, 141, 8574.
H
1.74
2.08
Mg
1.92
[10] Iron-catalyzed hydromagnesiation of 1,3-enyne targeted the alkyne
moiety to provide 1,3-diene after protonation, see: L. Ilies, T. Yoshida,
E. Nakamura, J. Am. Chem. Soc. 2012, 134, 16951.
thf
1.93
H
1.91
H
H
(–42.4)
1.90
thf
Mg
2.10
•
1.32 1.32
2.14
[11] a) A. Bismuto, S. P. Thomas, M. J. Cowley, Angew. Chem. Int. Ed.
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1.49
INTB-2 (–20.2)
Scheme 5. DFT calculations for model reactions of 1b with dimeric MgH2•thf
species. Energy changes and bond lengths at the ωB97XD/6-
311++G**/SMD(THF)//ωB97XD/6-31++G** level of theory are shown in
kcal/mol and Å, respectively. thf = tetrahydrofuran.
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The key enabling advance in the present method takes
advantage of the unique hydridic reactivity of magnesium
hydride for regio-controlled hydromagnesiation of 1,3-enynes
without the aid of transition-metal catalysts and directing groups.
Thus, the present protocol demonstrates potential of s-block
metal hydrides for the selective functionalization of various π-
conjugated organic molecules. Further studies in this direction
are currently in progress at our laboratory.
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Acknowledgements
This work was supported by funding from Nanyang
Technological University (NTU) (for S.C.) and the Singapore
Ministry of Education (Academic Research Fund Tier 2:
4
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S. Chiba, Angew. Chem. Int. Ed. 2016, 55, 3719; Angew. Chem. 2016,
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example of Cu-catalyzed 1,4-hydro-allylation of 1,3-enyne was
demonstrated using allyl phosphate as an electrophile and
polymethylhydrosiloxane as a hydride source, see ref. 5a.
[21] For Cu-catalyzed 1,4-hydrocupration followed by intramolecular 1,4-
addition, see: C.-Y. He, Y.-X. Tan, X. Wang, R. Ding, Y.-F. Wang, F.
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reagents and allyl bromide, see: H. Todo, J. Terao, H. Watanabe, H,
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[24] During benzylation and methylation, we observed oxidative dimerization
of propargyl/allenylmagnesium species as a minor pathway, where
electrophiles 4e and 4f worked as a single-electron-oxidant. See the SI.
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[28] As for the other possible processes initiated by 2,1-hydromagnesiation
and 3,4-hydromagnesiation of 1,3-enynes, the obtained transition
states are located at higher energies (∆G‡: +29.1 and +23.0 kcal/mol,
respectively). We also carried out DFT calculations to track the 1,2/1,4-
hydromagnesiation of 1-penten-3-yne,
a model substrate for alkyl-
substituted enynes 1l and 1m, which provided a substantially the same
reaction profile as that of 1b with reasonable energy barrier (∆G‡ +19.6
kcal/mol) for the rate-determining 1,2-hydromagnesiation. See the SI
for details.
5
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Entry for the Table of Contents
Regio-controlled hydromagnesiation of 1,3-enynes was enabled by magnesium hydride and subsequent downstream alkylation and
silylation allowed for construction of tri- and tetra-substituted allenes.
6
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