Stereo-controlledanti-hydromagnesiation of aryl alkynes by magnesium hydrides

Article abstract of DOI:10.1039/d0sc01773f

A concise protocol foranti-hydromagnesiation of aryl alkynes was established using 1?:?1 molar combination of sodium hydride (NaH) and magnesium iodide (MgI₂) without the aid of any transition metal catalysts. The resulting alkenylmagnesium intermediates could be trapped with a series of electrophiles, thus providing facile accesses to stereochemically well-defined functionalized alkenes. Mechanistic studies by experimental and theoretical approaches imply that polar hydride addition from magnesium hydride (MgH₂) is responsible for the process.

Full text of DOI:10.1039/d0sc01773f

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Stereo-controlled anti-hydromagnesiation of aryl alkynes by
magnesium hydrides
Received 00th January 20xx,
Accepted 00th January 20xx
Bin Wang,a Derek Yiren Ong,a Yihang Li,a Jia Hao Pang,a Kohei Watanabe,b Ryo Takita,*b and
Shunsuke Chiba*a
DOI: 10.1039/x0xx00000x
A concise protocol for anti-hydromagnesiation of aryl alkynes was established using 1:1 molar combination of sodium
hydride (NaH) and magnesium iodide (MgI2) without the aid of any transition metal catalysts. The resulting
alkenylmagnesium intermediates could be trapped with a series of electrophiles, thus providing facile accesses to
stereochemically well-defined functionalized alkenes. Mechanistic studies by experimental and theoretical approaches
imply that polar hydride addition from magnesium hydride (MgH2) is responsible for the process.
diketoiminato
magnesium
hydrides
undergo
syn-
hydromagnesiation onto diphenylacetylene.9 As such, the
stereochemical mode taking place in all the cases above is syn-
hydromagnesiation. Herein, we report anti-hydromagnesiation
of aryl alkynes using 1:1 molar combination of sodium hydride
(NaH) and magnesium iodide (MgI2), which does not need the
aid of any transition metal catalyst (Scheme 1C). The resulting
alkenylmagnesium species could be functionalized with a
series of electrophiles, to provide stereochemically well-
defined substituted alkenes. Discovery, optimization, and
substrate scope as well as preliminary mechanistic proposals
are described.
Introduction
Stereo-controlled construction of substituted alkenes is one of
the most fundamental yet important processes in synthetic
chemistry.1 For this purpose, hydrometallation of readily
available alkynes2 has been investigated as a powerful and
promising tactics of choice (Scheme 1A). Among various metals
involved, use of a magnesium element for hydrometallation of
alkynes (i.e. hydromagnesiation) allows for direct preparation
of alkenylmagnesium species, which is very useful for a
sequential bond-forming process with various electrophiles,3
thus providing facile accesses to multi-substituted alkenes. For
this purpose, alkyl Grignard reagents having β-hydrogen
atom(s) have been used as a hydrogen source in the presence
of a catalytic amount of titanocene dichloride (Cp2TiCl2)4 or
iron(II) chloride (FeCl2),5 in which metal hydride species (H-M:
M = Ti or Fe), generated via β-hydride elimination from the
corresponding alkylmetal intermediates, undergo syn-
hydrometallation onto alkynes (Scheme 1B-i). Ashby
demonstrated syn-hydromagnesiation of alkynes using
magnesium hydride (MgH2) in the presence of Cp2TiCl26 or CuI7
as a catalyst (Scheme 1B-ii). Very recently, Cavallo and Rueping
revealed in their magnesium-catalysed hydroboration of
alkynes that butylmagnesium hydride generated in situ from
A. Hydrometallation of alkynes
H
H
E+
H-[M]
[M]
E
R
R’
R
R
R’
R’
B. syn-Hydromagnesiation of alkynes
(i) with alkyl Grignard reagents and cat. Cp2TiCl2 or cat. FeCl2
cat. Cp2TiCl2
or
H
H
[Mg]
+
R
R’
MgX
R
cat. FeCl2
R’
(ii) with MgH2 and cat. Cp2TiCl2 or CuI
cat. Cp2TiCl2
H
or
[Mg]
+
MgH2
R
R’
dibutylmagnesium
and
pinacolborane
induces
syn-
R
hydromagnesiation (Scheme 1B-iii).8 Moreover, Mahon and
R’
R’
cat. CuI
(iii) with BuMgH generated from Bu2Mg and H-Bpin
Hill showed that structurally well-defined dimeric β-
H
Mg-Bu
+
BuMgH**
R
R’
R
(**generated in situ from Bu2Mg and H-Bpin)
C. anti-Hydromagnesiation of aryl alkynes (this work)
NaH-MgI2
(1:1)
H
H
E+
Ar
Ar
R
Ar
R
R
THF
[Mg]
E
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Scheme 1. Hydrometallation of alkynes.
Having optimized the reaction conditions in hands (Table 1,
entry 4), we next investigated the substrate scope of alkynes
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DOI: 10.1039/D0SC01773F
for their trans-semi-reduction (Scheme 2A). Various
diarylalkynes 1b-1g could be converted selectively into the
corresponding trans-alkenes 2b-2g in good yields in general.
Stereoselectivity was slightly dropped when a sterically bulky
aryl group is installed onto the substrates (for 2c and 2d),
while the electronic nature of the aryl substituents does not
affect much onto the stereoselectivity (2e-2g vs 2h-2i). Alkynes
having heteroaryl motifs such as furan, thiophene, and indole
could also be reduced in efficient manners (for 2j-2l).
Reduction of 1-phenyl-2-t-butylacetylene (1m) afforded the
corresponding trans-alkene 2m in good yield, while that of 1-
phenyl-2-phenyldimethylsilylacetylene (1n) resulted in
formation of alkenyl silane 2n in only moderate yield.
However, this method was found not applicable for reduction
of dialkyl alkynes such as 5-decyne (1o). Deuterium labeling
experiments using D2O (for quenching) and NaD
unambiguously suggested the presence of alkenylmagnesium
species A as an intermediate, that is formed via anti-
hydromagnesiation (Scheme 2B).
Results and discussion
Our group has recently uncovered unprecedented hydride
reduction of polar π-electrophiles such as nitriles and amides
by NaH in the presence of dissolving iodide salts such as
sodium iodide (NaI),10 where counter ion metathesis between
bulk NaH and NaI is supposed to be a key to activate NaH.11,12
We also found NaH could be used as a hydride source for facile
generation of main group metal hydrides. For example, we
demonstrated controlled reduction of carboxamides into
alcohols or amines by a combination of NaH with ZnI2 or
ZnCl2.13,14 Based on these findings, our current attention is
directed to seek for reductive molecular transformations of
non-polar π-systems such as alkynes by main group metal
hydrides.
We embarked on our investigation of chemical reactivity of
various main group metal hydrides, derived from NaH and the
corresponding
metal
halides,
toward
reduction
diphenylacetylene (1a). Among main group metal iodides
examined for the optimization (see the ESI for details), we
found that a combination of NaH and MgI2 shows a promising
reactivity toward semi-hydrogenation of 1a to trans-stilbene
(2a) (Table 1).15 Use of NaH and MgI2 in 1:1 molar ratio
resulted in the best outcome for the formation of 2a (entries
1-3). Full conversion of 1a was attained at 100 °C as the
reaction temperature, providing stilbene 2a in 96% yield with
high trans-selectivity (trans:cis = 94:6) (entry 4). Interestingly,
the reactions with MgBr2 and MgCl2 gave comparable results
(entries 5 and 6),16 implying that a common reactive
magnesium hydride species is generated and responsible for
the present reduction of 1a (vide infra). It should be noted that
the reactions with other alkaline earth metal iodides based on
Ca, Sr, and Ba were not optimal for this transformation.
A. Substrate scopea
Me
Ph
Ph
Ph
Ph
2b 93% (94:6)
MeO
2c 96% (85:15)
2d 91% (85:15)b
O
Me2N
O
Ph
Ph
2e 92% (94:6)
2f 95% (93:7)
2g 64% (93:7)b
Me
X
N
X
Ph
Ph
2h (X = F): 91% (94:6)
Ph
2j (X = O): 50% (>99:1)
2l 79% (97:3)b
2i (X = Cl): 93% (94:6) 2k (X = S): 85% (94:6)
Table 1 Optimization of reaction conditionsa
PhMe2Si
n-Bu
Ph
n-Bu
Ph
2m 70% (93:7)b,c
NaH (3 equiv)
MgX2
2n 35% (96:4)b,c
2o 0%d
Ph
B. Deuterium labelling experiment
+
Ph
Ph
Ph
Ph
Ph
THF, 24 h
conditions
then H2O
–Quench with D2O
1a
2a
2a’
H
NaH (3 equiv)
MgI2 (3 equiv)
H
Ph
D2O
Ph
Ph
Entry
MgX2
yield [%]c
2a 2a’
Ph
Ph
Ph
Temp
Conv.
D (>97%)
THF
[%]b
[Mg]
[°C]
1a
2a-d
92% (95:5)
(equiv)
100 °C, 24 h
A
–Use of NaD
1
2
3
4
5
6
MgI2 (1.5)
MgI2 (2)
MgI2 (3)
MgI2 (3)
MgBr2 (3)
MgCl2 (3)
80
80
80
100
100
100
60
62
73
>99
99
94
38
40
1
2
4
6
5
4
NaD (3 equiv)
D
D (>92%)
MgI2 (3 equiv)
H2O
Ph
Ph
68
1a
Ph
Ph
93c
93d
89
THF
100 °C, 24 h
[Mg]
A-d
H
2a-d
89% (96:4)
Scheme 2. trans-Selective reduction of aryl alkynes 1. a Unless otherwise stated,
the reactions were conducted using 0.5 mmol of alkynes 1 with NaH (3 equiv)
and MgI2 (3 equiv) THF (2.5 mL) at 100 °C. The trans/cis ratio was indicated in
the parentheses. b The reactions were performed using NaH (5 equiv) and MgI2
(5 equiv). c The reaction was performed at 120 °C. d Recovery of 5-decyne (1o)
in >90% yield.
a
b
All the reactions were conducted using 0.5 mmol of 1a in THF (2.5 mL). GC
yields with n-dodecane as an internal standard. c Isolated yield was 96% as a 94:6
trans/cis-mixture. d Isolated yield was 93% as a 94:6 trans/cis-mixture.
2 | J. Name., 2012, 00, 1-3
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achieved with pinacolborane by following the Singaram’s
View Article Online
A. Transformations of 1a
H
protocol,20 affording alkenylboronic esterD9OaI:in109.110%39/yDie0lSdC.01773F
We next questioned how the steric and electronic bias
could affect the regioselectivity on the hydromagnesiation of
unsymmetrical aryl alkynes (Scheme 3B). The reaction of 1c
having a sterically bulkier 1-naphthyl group underwent
selective hydromagnesiation to form alkenylmagnesium B with
installation of a hydride at the less hindered distal carbon
(marked in blue) as a major form, that could be trapped by
subsequent allylation to provide 6c in 66% yield.21 On the
other hand, hydromagnesiation of 1e having an electron-rich
4-dimethylaminophenyl group resulted in installation of
hydride on the proximal carbon (marked in red) to generate
alkenylmagnesium C, that was functionalized with BOMCl to
provide 7e in 66% yield. Hydromagnesiation of 1-phenyl-2-t-
butylacetylene (1m) occurred in regioselective manner, where
hydride attack was observed at the β-carbon (marked in red)
to the phenyl group, while the side was sterically shielded by
the t-Bu group. The resulting alkenylmagnesium D could be
further transformed into BOM adduct 7m in 77% yield.
H
CuCN
RX
Ph
Ph
DMFb
Ph
Ph
R
CHO
1aa
6a (R = allyl):e
94% (94:6)
7a (R = BnOCH2):f
3a 70%
H
ArCHOc
H
90% (94:6)
Ph
(1.2 equiv)
Ph
H
Ph
Ph
“Br+”g
Ph
Ph
[Mg]
HO
Ar
4a 87%
(Ar = 4-MeOC6H4)
Br
8a 60%
H
A
H
ArCHOd
(2.1 equiv)
Ph
Ph
Ph
HBpinh
Ph
Bpin
O
Ar
9a 91% (93:7)
5a 76% (92:8)
B. Transformations of unsymmetrical alkynes
–Steric bias–
Ph
H
NaHa
MgI2
CuCNe
allylBr
H
Ph
Ar
Ph
To elucidate the active hydride species responsible for the
present anti-hydromagnesiation of alkynes, we conducted
several control experiments (Scheme 4 and see the ESI). Ashby
reported preparation of magnesium hydride MgH2 in bulk
state by treatment of MgBr2 with 2 equiv of NaH in THF at
room temperature (in quantitative yield together with the
formation of inert sodium bromide).22,23 We observed that the
reaction of alkyne 1a with bulk MgH2, prepared from 3 equiv
of NaH and 1.5 equiv of MgBr2 by following the Ashby’s
protocol, resulted in selective formation of trans-stilbene (2a)
despite poor conversion of 1a (Scheme 4A). On the other
hand, treatment of 1a with bulk MgH2 in the presence of MgI2
(1.5 equiv) greatly enhanced the conversion of 1a, providing
almost the same outcome with that in the optimized reaction
[Mg]
B
6c 66%
1c
(Ar = 1-naphthyl)
–Electronic bias–
OBn
Ph
Ph
NaHi
MgI2
CuCNf
BOMCl
[Mg]
Ph
Ar
Ar
H
Me2N
1e
H
7e 66%
C
(Ar = 4-Me2NC6H4)
–Steric bias vs electronic bias–
OBn
NaHj
MgI2
CuCNf
BOMCl
[Mg]
Ph
Ph
Ph
H
H
1m
D
7m 77% (93:7)
a
Scheme 3. Functionalization with various electrophiles.
The reactions were
conducted using 0.5 mmol of 1 with NaH (3 equiv) and MgI2 (3 equiv) in THF (2.5
mL) at 100 °C. b DMF (4 equiv), 0-24 °C, 6 h. Minor isomer 3a’ was isolated in 9%
yield. c 4-MeOC6H4CHO (1.2 equiv), 0 °C, 3.5 h. Minor isomer 4a’ was isolated in
A. The reaction with bulk MgH2
d
e
NaH
(3 equiv)
7% yield. 4-MeOC6H4CHO (2.1 equiv), 0-24 °C, 15 h. CuCN•2LiCl (10 mol%),
1a
allylbromide (4 equiv), 0 °C, 3 h. f CuCN•2LiCl (10 mol%), BOMCl (1.2 equiv), 0 °C,
(0.5 mmol)
2 h. g BrCl2CCCl2Br (2.2 equiv), 0 °C, 30 min. h HBpin (1.1 equiv), 0-24 °C, 2.5 h.
i
Ph
bulk
MgH2
+
Ph
The reaction was conducted using 0.5 mmol of 1e with NaH (5 equiv) and MgI2 (5
equiv) in THF (2.5 mL) at 100 °C. j The reactions were conducted using 0.5 mmol
of 1m with NaH (5 equiv) and MgI2 (5 equiv) in THF (2.5 mL) at 120 °C. BOM =
benzyloxymethyl.
THF
24 °C, 48 h
100 °C, 24 h
MgBr2
(1.5 equiv)
2a 57%
(2a’ 5%)
(38% recovery of 1a)
IR:
1440-790 cm–1
790-500 cm–1
B. The reaction with bulk MgH2–MgI2
NaH
(3 equiv)
1a (0.5 mmol)
MgI2 (1.5 equiv)
Ph
bulk
MgH2
The alkenylmagnesium A could be further functionalized by
subsequent treatment with various electrophiles (Scheme
3A).17 Formylation with N,N-dimethylformamide (DMF)
proceeded smoothly to form 2,3-diphenylacrylaldehyde (3a) in
70% yield. Addition of 1.2 equiv of 4-anisaldehyde afforded
allylalcohol 4a in 87% yield, whereas use of 2.1 equiv of 4-
anisaldehyde resulted in Oppenauer-type oxidation18 to form
α,β-unsaturated ketone 5a in 76% yield. Allylation with
allylbromide was facilitated by a catalytic amount (10 mol%) of
CuCN•2LiCl19 to afford skipped diene 6a in 94% yield.
Similarly, installation of a benzyloxymethyl (BOM) unit was
achieved for synthesis of 7a using BOMCl. Use of 1,2-dibromo-
1,1,2,2-tetrachloroethane allowed for smooth bromination of
A to form alkenyl bromide 8a. Borylation of A could be
Ph
2a 93%
(2a’ 5%)
+
THF
100 °C, 24 h
MgBr2
24 °C, 48 h
(1.5 equiv)
C. The reaction of NaH and MgI2 in 1:1 molar ratio
NaH
(1 equiv)
0.5 MgH2 + 0.5 MgI2 (+ 1 NaI)
(confirmed by IR)
+
MgI2
(1 equiv)
THF
100 °C, 24 h
D. Counter ion metathesis between MgH2 and MgI2
MgH2 + MgI2 MgI2 + MgH2
“less hydridic”
*
“more hydridic”
in small units
in bulk state
Scheme 4. Elucidation of active hydride species.
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DOI: 10.1039/D0SC01773F
H
H
1.74
1.75
2.09
1.91
thf
thf
2.08
Mg
1.91
H
–for anti-hydromagnesiation
2.10
1.88
thf
1.94
1.89
Mg
H
H
H
1.74 Mg 1.92
thf
1.91
1.91
H
Mg
2.08
1.96
1.89
+7.9
∆G‡ +23.6
–53.3
1.90
H
2.10 thf
H
Mg
2.08
2.14
1.90
2.48
1.80
Mg
1.10
1.75
thf
2.90
1.35
H
H
1.81
H
1.26
1.21
H
thf
H
H
Mg
Mg
INT1anti
(7.9)
TSanti
(31.5)
INT2anti
(–21.8)
H
+
thf
H
H
1.73
1.96
1.74
1.92
H
H
1.88
INT0
(0.0)
Mg
2.09
Mg
1.94
2.10
thf
thf
1.92 2.08
1.90
H
1.75
H
H
thf
H
1.89
1.91
2.10
Mg
Mg
1.90
2.10
Mg
H1.88
2.10
1.75
H
1.81
H
1.09
1.91
1.90 Mg
2.60
thf
thf
∆G‡ +25.9
–52.9
2.14
thf
+8.2
H
2.45
1.79
1.35
1.25
1.21
–for syn-hydromagnesiation
INT1syn
(8.2)
TSsyn
(34.1)
INT2syn
(–18.8)
Scheme 5. DFT calculations for model reactions of diphenylacetylene with MgH2•thf dimeric 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.
conditions (Scheme 4B). The IR spectrum of the mixture at 60 °C, affording trans-alkene 11a as a single isomer in 87%
obtained from the reaction of NaH and MgI2 in 1:1 molar ratio yield (Scheme 6A). Based on the deuterium labelling
showed the presence of only MgH2 and MgI2 (NaI is experiments using NaD and D2O (Scheme 6A for use of NaD in
transparent in the IR window) (Scheme 4C). We reasoned that the reduction of 10a. See the ESI for details), we proposed that
while bulk MgH2 itself is less hydridic due to its polymerized the process is triggered by the formation of alkoxymagnesium
structure with high lattice energy,24 synergistic cooperation hydride E, that mediates hydromagnesiation to afford 5-
between bulk MgH2 and MgI2 through counter ion metathesis membered magnesiocycle F. This hydroxy-guided approach27
allows for freshly generating more hydridic MgH2 probably of allowed for trans-semi-reduction of various propargylic
smaller units (Scheme 4D), that is the key for the success in alcohols 10b-10g into the corresponding allylic alcohols 11b-
use of NaH and MgI2 in 1:1 molar ratio for the efficient anti- 11g (Scheme 6B). Heteroaromatic motifs such as 2-thienyl and
hydromagnesiation.
2-pyridyl groups were compatible with the process (for 11b
The DFT calculations for the reactions of diphenylacetylene and 11c). Sterically more hindered substrates based on
(1a) with a MgH2 dimer as the model of activated (MgH2)n admantane (for 10d) and derived from (R)-carvone (for 10e)
species were thus carried out at the ωB97XD/6- generated homoallylic alcohols 11d and 11e in 56% and 77%
311++G**/SMD(THF)//ωB97XD/6-31++G** level of theory yields, respectively. Secondary propargylic alcohols 10f and
(Scheme 5). From INT1anti, the reduction of diphenylacetylene 10g could also be smoothly reduced. Formation of 11e and 11g
smoothly proceeded via TSanti (∆G‡ +23.6 kcal/mol), in the kept alkenyl moieties intact, suggesting that the present
manner
of
anti-hydromagnesiation
to
afford protocol is selective in the hydromagnesiation of alkynes.
alkenylmagnesium species INT2anti. In this event, the hydride in Phenol and aniline moieties were also capable in guiding trans-
the same plane as one of the benzene rings attacks on the semi-reduction of alkynes for providing the corresponding
proximal alkyne carbon center and, the magnesium cation 11h-11k in good to moderate yields.
successively shifts to the distal alkyne carbon, indicating the
The 5-membered magnesiocycle intermediate F could be
polar hydride transfer mechanism. Thus, the steric and further functionalized by CuCN-catalyzed allylation to form
electronic bias of the aromatic ring should result in profound skipped diene 12a in good yield (Scheme 6C). Treatment of F
effects on the regioselectivity (i.e. Scheme 3B). Further with diethyl carbonate allowed for construction of lactone 13a.
investigations led to find the syn-reduction pathway. In TSsyn
,
Furthermore, the reaction with pinacolborane followed by
diphenylacetylene is distorted, where two phenyl rings are workup with Si gel resulted in formation of 1,5-dihydro-1,2-
almost perpendicular (the dihedral angle is ca. 84°). oxaborole 14a. On the other hand, we found that the reaction
Accordingly, TSsyn was located 2.6 kcal/mol higher than TSanti
.
of 2-(phenylethynyl)phenol (10h) likely involves a mixture of 6-
These computed results well corroborated the reducing ability membered magnesiocycle G and 5-membered one H, which
of the NaH-MgI2 system for the anti-selective could be trapped under CuCN-catalyzed allylation reaction
hydromagnesiation.25
conditions to afford skipped dienes 12h (41% yield) and 12h’
We observed that the reaction of propargyl alcohol 10a (37% yield), respectively.
with 3 equiv of NaH26 and 2 equiv of MgI2 proceeded smoothly
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Conclusions
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DOI: 10.1039/D0SC01773F
A. Hydroxy-guided reduction of 10aa,b
In conclusion, we have developed a concise protocol for anti-
hydromagnesiation of aryl alkynes that operates with the
magnesium hydride species derived from NaH and MgI2 under
transition-metal free conditions. Subsequent treatment of the
resulting alkenylmagnesium intermediates with various
electrophiles allowed for the synthesis of stereochemically
defined tri-substituted alkenes. Efforts are currently underway
to apply the NaH-MgI2 system for reductive functionalization
of other π-conjugate systems.
NaH(D) (3 equiv)
MgI2 (2 equiv)
[Mg]
O
HO
(D)H
THF
60 °C, 8 h
Ph
Ph
E
10a
O
[Mg]
HO
Ph
then H2O
Ph
H(D)
H(D)
11a 87%
F
B. Substrate scopea
HO
HO
HO
Ph
N
S
Conflicts of interest
There are no conflicts to declare.
11b 85%
11c 56%
11d 56%
OH
HO
Ph
OH
Acknowledgements
Ph
Ph
This work was supported by funding from Nanyang
Technological University (NTU) and the Singapore Ministry of
Education (Academic Research Fund Tier 2: MOE2019-T2-1-
089) (for S.C.) as well as JSPS (Grant-in-Aid for Scientific
Research (C) (19K0662)), Uehara Memorial Foundation, and
the Naito Foundation (for R.T.). The computations were
performed using Research Center for Computational Science at
Okazaki, Japan.
11g 76%d
11f 76%c
11e 77%
Ph
Ph
HO
X
H
OH
OH
S
Ph
11h (X = O): 84%e
11i (X = NH): 55%e
11j 86%e
11k 51%f
C. Derivatizationa
–from 10a
CuCNg
allylBr
Notes and references
HO
1
For selected reviews, see: (a) A. Fürstner, J. Am. Chem. Soc.,
2019, 141, 11; (b) C. Oger, L. Balas, T. Durand and J.-M.
Galano, Chem. Rev., 2013, 113, 1313; (c) E. Negishi, Z. Huang,
G. Wang, S. Mohan, C. Wang and H. Hattori, Acc. Chem. Res.,
2008, 41, 1474; (d) A. B. Flynn and W. W. Ogilvie, Chem. Rev.,
2007, 107, 4698; (e) J. Wang, Stereoselective Alkene
Synthesis, Top. Curr. Chem. 2012. Springer.
For reviews, see: (a) J. Chen, J. Guo and Z. Lu, Chin. J. Chem.,
2018, 36, 1075; (b) T. G. Frihed and A. Fürstner, Bull. Chem.
Soc. Jpn., 2016, 89, 135; (c) M. D. Greenhalgh, A. S. Jones and
S. P. Thomas, ChemCatChem, 2015, 7. 190.
Ph
O
12a 79%
O
O
O
h
conditions
[Mg]
Ph
O=C(OEt)2
10a
Ph
F
13a 51%
14a 71%
HBpini
HO
then Si gel
B
2
Ph
–from 10h
HO
3
4
G. S. Silverman and P. E. Rakita, Handbook of Grignard
Reagents, Marcel Decker, New York, 1996.
O
Ph
[Mg]
Ph
HO
(a) Y. Gao and F. Sato, J. Chem. Soc., Chem. Commun., 1995,
659; (b) F. Sato, H. Ishikawa, H. Watanabe, T. Miyake and M.
Sato, J. Chem. Soc., Chem. Commun., 1981, 718; (c) F. Sato,
H. Ishikawa and M. Sato, Tetrahedron Lett., 1981, 22, 85.
L. Ilies, T. Yoshida and E. Nakamura, J. Am. Chem. Soc., 2012,
134, 16951.
E. C. Asyby and T. Smith, J. Chem. Soc., Chem. Commun.,
1978, 30.
E. C. Ashby, J. J. Lin and A. B. Goel, J. Org. Chem., 1978, 43,
757.
M. Magre, B. Maity, A. Falconnet, L. Cavallo and M. Rueping,
Angew. Chem. Int. Ed., 2019, 58, 7025.
L. Garcia, M. F. Mahon and M. S. Hill, Organometallics, 2019,
38, 3778.
CuCNg
allylBr
12h 41%
H
conditions
+
+
Ph
O
10h
[Mg]
HO
5
6
7
8
9
Ph
Ph
G
12h’ 37%
Scheme 6. Guided reduction. a The reactions were conducted using 0.5 mmol of
10 with NaH (3 equiv) and MgI2 (2 equiv) THF (2.5 mL) at 60 °C. The reaction
with NaD installed a deuterium on the β-styryl moiety in 93% incorporation rate
b
c
d
(see the ESI for details). Trans:cis = 99:1. 11g was isolated as its TBS ether.
See the ESI for details. e The alkyne reduction was conducted at 80 °C.
The
f
alkyne reduction was conducted using NaH (6 equiv) and MgI2 (4 equiv) at 100
°C. g CuCN•2LiCl (10 mol%), allylbromide (4 equiv), 0 °C, 2 h. h Diethyl carbonate
i
10 (a) G. H. Chan, D. Y. Ong, Z. Yen and S. Chiba, Helv. Chim.
Acta, 2018, 101, e1800049; (b) G. H. Chan. D. Y. Ong and S.
Chiba, Org. Synth., 2018, 95, 240; (c) Y. Huang, G. H. Chan
and S. Chiba, Angew. Chem. Int. Ed., 2017, 56, 6544; (d) P. C.
Too, G. H. Chan, Y. L. Tnay, H. Hirao and S. Chiba, Angew.
Chem. Int. Ed., 2016, 55, 3719.
(4 equiv), 40 °C, 15 h. HBpin (1.1 equiv), 0-24 °C, 0.5 h then treatment with Si
gel.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Chemical Science
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ARTICLE
Journal Name
11 Z. Hong, D. Y. Ong, S. K. Muduli, P. C. Too, G. H. Chan, Y. L.
Tnay, S. Chiba, Y. Nishiyama, H. Hirao and H. S. Soo, Chem.
Eur. J., 2016, 22, 7108.
View Article Online
DOI: 10.1039/D0SC01773F
12 For a review on synergistic cooperation of main group metal
elements, see: S. D. Robertson, M. Uzelac and R. E. Mulvey,
Chem. Rev., 2019, 119, 8332.
13 D. Y. Ong, Z. Yen, A. Yoshii, J. Revillo Imbernon, R. Takita and
S. Chiba, Angew. Chem. Int. Ed. 2019, 58, 4992.
14 For controlled reduction of nitriles to aldehydes by NaH-
ZnCl2 system, see: D. Y. Ong and S. Chiba, Synthesis, DOI:
10.1055/s-0039-1690838.
15 For a review on semi-hydrogenation of alkynes, see: K. C. K.
Swamy, A. S. Reddy and S. A. Kalyani, Tetrahedron Lett.,
2018, 59, 419.
16 MgI2 (98%, powder, Sigma-Aldrich, 394599), MgBr2 (>99%,
powder, anhydrous, Sigma-Aldrich, 495093), and MgCl2
(>99%, beads, -10 mesh, anhydrous, Sigma-Aldrich, 449164)
were used. See the ESI for details.
17 For reports on functionalization of alkenylmagnesium
species
generated
through
Fe-catalyzed
syn-
carbomagnesiation of alkynes, see: (a) E. Shirakawa, D.
Ikeda, S. Masui, M. Yoshida and T. Hayashi, J. Am. Chem.
Soc., 2012, 134, 272; (b) T. Yamagami, R. Shintani, E.
Shirakawa and T. Hayashi, Org. Lett., 2007, 9, 1045.
18 C. F. de Graauw, J. A. Peters, H. van Bekkum and J. Huskens,
Synthesis, 1994, 1007.
19 I. Klement, M. Rottländer, C. E. Tucker, T. N. Majid and P.
Knochel, Tetrahedron, 1996, 52, 7201.
20 J. W. Clary, T. J. Rettenmaier, R. Snelling, W. Bryks, J.
Banwell, W. T. Wipke and B. Singaram, J. Org. Chem., 2011,
76, 9602.
21 The structures of 6c and 7e were confirmed by the X-ray
crystallographic analyses.
22 E. C. Asyby and R. D. Schwartz, Inorg. Chem., 1971, 10, 355.
23 For a review on molecular magnesium hydrides, see: D.
Mukherjee and J. Okuda, Angew. Chem. Int. Ed., 2018, 57,
1458.
24 (a) R. W. P. Wagemans, J. H. van Lenthe, P. E. de Jongh, A. J.
van Dillen and K. P. de Jong, J. Am. Chem. Soc., 2005, 127,
16675; (b) C. M. Stander and R. A. Pacey, J. Phys. Chem.
Solids, 1978, 39, 829.
25 The reaction profile on the conversion of 1a to 2a generated
using GC analysis clearly showed anti-hydromagnesiation is a
predominant pathway over syn-one. See the ESI for details.
26 1 equiv of NaH is used for deprotonation of alcohols.
27 A. H. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993,
93, 1307.
6 | J. Name., 2012, 00, 1-3
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Chemical Science
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DOI: 10.1039/D0SC01773F
TOC
We herein report a concise protocol for anti-hydromagnesiation of aryl alkynes that
operates with the magnesium hydride species derived from NaH and MgI2 under
transition-metal free conditions.
Subsequent treatment of the resulting
alkenylmagnesium intermediates with various electrophiles allows for the synthesis of
stereochemically defined tri-substituted alkenes.