Alkylation of Terminal Alkynes under Zinc Lewis Acid Catalysis and Its Mechanistic Studies

Article abstract of DOI:10.1002/adsc.201801685

With a zinc Lewis acid catalyst and proton sponge in toluene, terminal alkynes were found to undergo the alkylation by alkyl triflates to provide unsymmetrical internal alkynes. This is the first example that a simple alkyl chain other than benzylic and norbornyl units can be introduced onto the alkynyl carbon atom under Lewis acid catalysis. Mechanistic studies revealed that the activation of the alkyne by the zinc Lewis acid and proton sponge is the trigger of the reaction to give a monoalkynylzinc species, which successively reacts with the alkyl triflate to afford the internal alkyne. A radical pathway is unlikely in this system. (Figure presented.).

Full text of DOI:10.1002/adsc.201801685

Title: Alkylation of Terminal Alkynes under Zinc Lewis Acid Catalysis
and Its Mechanistic Studies
Authors: Mana Osano, Takeru Kida, Kyohei Yonekura, and Teruhisa
Tsuchimoto
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801685
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
Very Important Publication
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Alkylation of Terminal Alkynes under Zinc Lewis Acid
Catalysis and Its Mechanistic Studies
Mana Osano,a Takeru Kida,a Kyohei Yonekura,a and Teruhisa Tsuchimotoa,*
a
Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashimita, Tama-ku,
Kawasaki 214-8571, Japan.
Fax: (+81)-44-934-7228; e-mail: tsuchimo@meiji.ac.jp
Received: ((will be filled in by the editorial staff))
Dedicated to Professor Tamejiro Hiyama in commemoration of his retirement from Chuo University.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
instead of alkynes have been also developed: an
Abstract. With a zinc Lewis acid catalyst and proton
sponge in toluene, terminal alkynes were found to undergo oxidative type,[8] a decarboxylative type,[9] an
umpolung type with the alkynyl halide,[10] a type with
the alkylation by alkyl triflates to provide unsymmetrical
the alkynyl metal (metal = Li, B, Mg, Ag),[11] and
internal alkynes. This is the first example that a simple
others.[12] The remaining ATA strategy would be
alkyl chain other than benzylic and norbornyl units can be
Lewis acid catalysis.[13,14] However, in sharp contrast
introduced onto the alkynyl carbon atom under Lewis acid
catalysis. Mechanistic studies revealed that the activation of
to the remarkable growth of transition metal catalysis,
the alkyne by the zinc Lewis acid and proton sponge is the
this category has been limited to using benzylic and
trigger of the reaction to give a monoalkynylzinc species,
norbornyl electrophiles that easily form carbocations,
which successively reacts with the alkyl triflate to afford
to the best of our knowledge.
the internal alkyne. A radical pathway is unlikely in this
On the other hand, we have realized the zinc-
system.
Lewis-acid-catalyzed dehydrogenative silylation[15]
and borylation[16] of terminal alkynes 1 with the aid of
Keywords: Alkylation; Alkynes; Chemoselectivity; Lewis
the pyridine base in the nitrile medium (Scheme 1).
acids; Zinc
This our original system proceeds via the activation
mode of the Zn––H--met+ stabilized by pyridine (A)
for enhancing the electrophilicity of the “met” center
towards 1.[17] We envisaged that the formation of
Internal alkynes with a C≡C–alkyl unit are important
motifs in natural and bioactive molecules[1] as well as
functional materials.[2] The C≡C moiety has also been
attracting continuous attention as a platform to accept
addition of various bonds for further elaboration.[3]
Alkylation of terminal alkynes (ATA) with alkyl
electrophiles seems to be the most simple way to
offer the internal alkyne, and performing with NaNH2
has been known as a traditional textbook reaction.[4]
However, the poor functional group compatibility of
such a strong base has limited its use.[5] During the
last four decades, the Sonogashira–Hagihara coupling
has become a reliable tool to address the internal
alkyne.[6] This palladium-based process is useful to
construct the C(sp)–C(sp2) bond with aryl or alkenyl
electrophiles, but creating the C(sp)–C(sp3) bond with
alkyl electrophiles has been generally recognized to
be challenging due to the -hydride elimination from
the alkyl group as a major side reaction. Despite such
intrinsic nature of Pd and also other transition metals,
the meticulous ligand design for the transition metals
has greatly contributed to the achievement of the
ATA.[7] Other transition-metal-based ATA including
its variants using alkynyl halides or alkynyl metals
same mode A’ when using alkyl electrophiles 4 with
the polarized character of X(–)–alkyl(+) similarly
to H(–)–met(+) of 2 could lead to the first example
of the Lewis-acid-catalyzed ATA, thus making it
possible to install a simple alkyl chain other than the
benzylic and norbornyl frameworks. This study on
the zinc-catalyzed ATA proves to be the case.
To validate the working hypothesis, we initially
performed the butylation of phenylacetylene (1a)
H–met 2 (met = Si, B)
cat. Zn(OTf)2–pyridine
our previous work
R
R
met
EtCN
Zn–
Py+
3
5
H met
R
H
A
1
X–alkyl 4
cat. Zn(OTf)2–pyridine
alkyl
a working hypothesis
for this work
EtCN
Zn–
Py+
X
alkyl
A'
Scheme 1. A working hypothesis for alkylation of terminal
alkynes. Py = pyridine.
1
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
under essentially the same reaction conditions
established for the dehydrogenative silylation and
borylation of alkynes (Scheme 2). Thus, 1a and 1-
iodobutane (4’a) were treated with Zn(OTf)2 (20
mol%, Tf = SO2CF3) and pyridine (1.5 equiv.) in
EtCN at 50 °C for 24 h, but no desired reaction
occurred disappointingly. We then methodically
explored the proper reaction conditions for the
butylation, and the representative results are collected
in Table 1 [see the Supporting Information (SI) for
further details]. With BuOTf (4a) as an alkylating
agent, the use of pyridine and analogues thereof was
in vain again but of iPr2NEt as a tertiary amine, to our
delight, delivered desired 5aa albeit in low yield of
3%, which was slightly improved with 1,8-
bis(dimethylamino)naphthalene (proton sponge =
PrSp) (entries 1–8). With PrSp as an organic base,
other solvents including DMF, MeNO2, 1,4-dioxane
and hexane instead of EtCN were tested but totally
ineffective (entries 9–11 and 13). While the reaction
rate greatly decreased in toluene, a remarkable higher
reaction efficiency based on the yield/conversion (=
4%/7%) compared to that on the reaction of EtCN (=
6%/63%) was observed (entry 12 vs. 8). A
continuous survey on the effect of other zinc Lewis
acids in the presence of PrSp in the toluene medium
showed that the zinc salt with the NNf2 ligand (Nf =
SO2C4F9) affects most effectively, thereby the yield
of 5aa being drastically increased up to 85% (entries
14–20).[18] As a result, the following set was found to
be the promising reaction conditions to realize the
ATA efficiently: Zn(NNf2)2 as a catalyst, PrSp as a
base, and toluene as a solvent, which are thus totally
different from the original set (see Scheme 2). Under
the suitable reaction conditions, using alkyl halides
instead of 4a gave no 5aa unfortunately (entries 21–
23). However, due to the low conversions of the butyl
halides, these results may offer a good opportunity to
attain the TfO-selective ATA under the coexistence
of the halogen ones.
Having established the reaction conditions, the
scope of the butylation with different terminal
alkynes 1 was explored (Table 2). Besides 1a, a series
of arylacetylenes 1b–1h with the substituent (Y) of
different steric and electronic demands underwent the
butylation (5aa–5ha). The C(sp2)–Br and C(sp2)–
B(pin) (pin = pinacolate) units, which can participate
in transition metal catalysis, were tolerated. The
butylation of 1i with the thienyl ring, 1j with the C=C
bond, and 1k with the ferrocenyl group also occurred
to give 5ia–5ka in the yield over 85%. Moreover,
aliphatic alkynes 1l–1r with linear, branched and
functionalized alkyl groups were butylated to yield
5la–5ra. Among these, it was difficult to determine
isolated yield of 5na, due to its high volatility. In
addition, in contrast to the good compatibility of the
Cl and phthalimidoyl groups, the reaction of 1q with
the AcO group resulted in low yield, the reason of
which would be explained by the control experiment
shown in Scheme 3. Thus, the butylation of 1a under
the same reaction conditions as those for entry 20 of
Table 1 except including EtOAc (1.0 equiv.) resulted
in much lower yield of 5aa, showing that the ester
group partly retards the ATA. We next examined the
scope of alkylating agents (Table 3). In addition to
the butylation, the simple methylation and the 2-
phenylethylation occurred well (5eb and 5ec). Unlike
volatile 5na derived from tBuC≡CH (1n) and 4a (see
Table 2), 5nc with the larger CH2CH2Ph part than the
Bu group was purified safely. The O–benzyl bond of
4d was retained without acting as a benzylating site
under the Lewis acidic conditions (5ed).[19] When
using 4e, 4f and 4g, none of the C(sp3)–I, C(sp3)–Br
and C(sp3)–Cl moieties, which can be alkynylated
Zn(OTf)2 (20 mol%)
1:1.4
pyridine (1.5 equiv.)
Ph
H
I
Bu
4'a
Ph
Bu
+
EtCN, 50 ºC, 24 h
1a
5aa; <1% yield
Scheme 2. Zinc-catalyzed butylation of phenylacetylene.
The yield determined by 1H NMR is shown here.
Table
1.
Lewis-acid-catalyzed
butylation
of
phenylacetylene.[a,b]
Lewis acid (20 mol%)
organic base (1.5 equiv.)
Ph
H
TfO Bu
Ph
Bu
+
solvent, 50 ºC, 24 h
1a
4a
5aa
Entry Lewis
acid
Organic
base
Solvent Conv. Yield
[%][c] [%][d]
1
2
3
4
5
6
7
8
Zn(OTf)2
Zn(OTf)2
Py
4-CNPy
4-MePy
EtCN
EtCN
EtCN
12
<1
7
<1
<1
<1
<1
3
1
<1
6
<1
<1
<1
4
<1
4
<1
7
6
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
ZnBr2
Piperidine EtCN
1
iPr2NEt
DBU
PhNMe2
PrSp
EtCN
EtCN
EtCN
EtCN
DMF
51
32
8
63
40
9
PrSp
PrSp
PrSp
PrSp
PrSp
PrSp
PrSp
10
11
12
13
14
15
16
17
18
19
20
21[e]
22[e]
MeNO2 85
Dioxane
Toluene
Hexane
Toluene
Toluene <1
Toluene 33
5
7
6
8
ZnF2
Zn(OAc)2 PrSp
Zn(acac)2 PrSp
Zn(ONf)2 PrSp
Zn(NTf2)2 PrSp
Zn(NNf2)2 PrSp
Zn(NNf2)2 PrSp
Zn(NNf2)2 PrSp
Zn(NNf2)2 PrSp
Toluene
8
Toluene 31
Toluene 71
Toluene 85
Toluene
Toluene
Toluene
21
71
85
<1
<1
<1
6
9
7
23[e]
[a]
Reagents (unless otherwise noted): 1a (0.40 mmol), 4a
(0.56 mmol), Lewis acid (80 mol), organic base (0.60
mmol), solvent (0.40 mL). [b] Abbreviations: Py = pyridine;
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DMF = N,N-
dimethylformamide; Dioxane = 1,4-dioxane; Ac = acetyl;
acac = acetylacetonate. [c] Conversions of 1a determined by
GC are provided. [d] Determined by 1H NMR. [e] Performed
with IBu (4’a) for entry 21, BrBu for entry 22, or ClBu for
entry 23 instead of 4a, respectively.
2
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
Table 2. Zinc-catalyzed butylation of terminal alkynes.[a]
Table 3. Zinc-catalyzed alkylation of terminal alkynes
with alkyl triflates.[a]
Zn(NNf2)2 (20 mol%)
PrSp (1.5–2.1 equiv.)
Zn(NNf2)2 (20 mol%)
PrSp (1.5 equiv.)
R
H
TfO Bu
R
Bu
+
toluene, 50–60 ºC, 24–72 h
1
4a
5
R
H
TfO alkyl
R
alkyl
+
toluene, 50 ºC, 24 h
1
4
5
Bu
Bu
5ia; 85% yield
Bu
S
Ph
Y
MeO
Me
MeO
5ja; 91% yield
5aa (Y = H); 85% yield
5ba (Y = o-Me); 60% yield
5ca (Y = m-Me); 80% yield
5da (Y = p-Me); 74% yield
5ea (Y = p-MeO); 93% yield
5fa (Y = p-Br); 78% yield
5ga (Y = p-CF3);[b] 47% yield[c]
5ha [Y = p-(pin)B]; 74% yield
5eb; 88% yield
Ph
5ec; 85% yield
Hex
Bu
Fe
Bu
5la; 73% yield
MeO
O
Ph
5ed; 65% yield
5ka; 97% yield
Bu
5nc;[b] 50% yield[c]
5ma; 81% yield
5 Br
MeO
I
Ph
Bu
Bu
Cl
Bu
5ee; 79% yield
5af; 84% yield
5na;[d] 53% yield[e]
5oa; 84% yield
5pa; 70% yield
3 Cl
O
N
MeO
Bu
O
5ag; 82% yield
5eh;[d] 51% yield[c]
O
O
Bu
[a]
Reagents (unless otherwise noted): 1 (0.40 mmol), 4
5qa; 36% yield
5ra; 82% yield
(0.56 mmol), Zn(NNf2)2 (80 mol), PrSp (0.60 mmol),
toluene (0.40 mL). Yields of isolated 5 based on 1 are
[a]
Reagents (unless otherwise noted): 1 (0.40 mmol), 4a
[b]
shown here.
Performed with 1n (2.4 mmol), 4c (0.40
(0.56–0.80 mmol), Zn(NNf2)2 (80 mol), PrSp (0.60–0.84
mmol), toluene (0.40 mL). Yields of isolated 5 based on 1
are shown here. See the SI for further details. [b] Performed
with 1g (1.2 mmol), 4a (0.40 mmol) and PrSp (0.44 mmol).
mmol) and PrSp (0.44 mmol) for 48 h. [c] Yields of isolated
[d]
5 based on 4 are provided.
mmol), 4h (0.40 mmol) and PrSp (0.84 mmol) in 4-
chlorotoluene instead of toluene for 72 h.
Performed with 1e (0.80
[c]
The yield of isolated 5ga based on 4a is provided.
Performed with 1n (2.4 mmol), 4a (0.40 mmol) and
[d]
[e]
1
PrSp (0.44 mmol).
based on 4a is provided.
The yield determined by H NMR
(HO)2B
Hex
[a]
6a
5
Ph
Hex
7afa; 72% yield
Zn(NNf2)2 (20 mol%)
PrSp (1.5 equiv.)
EtOAc (1 equiv.)
(HO)2B Ph
1:1.4
5 Br
5 Ph
[a]
[b]
6b
Ph
H
TfO Bu
Ph
Bu
+
Ph
Ph
Ph
toluene, 50 ºC, 24 h
5af
7afb; 71% yield
1a
4a
5aa; 21% yield
Me3SiCF3
5 CF3
6c
Scheme 3. Zinc-catalyzed butylation of phenylacetylene in
the presence of EtOAc. The yield determined by H NMR
1
7afc; 72% yield
is shown here.
Scheme 4. Synthetic application of 5af. Yields of isolated
7 based on 5af are shown here. Reagents and conditions:
[a] 6a or 6b (1.5 equiv.), Pd(OAc)2 (5 mol%),
[HP(tBu)2Me]BF4 (10 mol%), KOtBu (3 equiv.), 2-methyl-
2-butanol (tamyl alcohol), rt, 24 h; [b] 6c (1.7 equiv.), CsF
(1.7 equiv.), 15-crown-5 (3.4 equiv.), 1,2-dimethoxyethane,
–18 °C to rt, 1 h.
under transition metal catalysis, participated in the
ATA, as expected (5ee, 5af and 5ag).[7a–e] The C=C
of 4h remained intact without undergoing radical
clock cyclization towards cyclopentylmethylation,[20]
thus giving a 1,7-enyne framework that is a useful
scaffold
for
further
transformation,
e.g.,
cycloisomerization (5eh).[21]
As already demonstrated, we realized the TfO-
selective ATA without losing the halogen groups and
then tried the C–C bond elongation by utilizing the
bromo group remained in 5af (Scheme 4). Without
suffering -hydrogen elimination, the C–Br bond was
successfully converted to the alkenyl and aryl units
under the Pd-catalyzed Suzuki–Miyaura cross-
coupling conditions to give 7afa and 7afb in good
yields.[22] The system consisting of Me3SiCF3–CsF–
15-crown-5 worked well for the trifluoromethylation
to afford 7afc.[23] Therefore, combining our strategy
and C–C bond elongation can be expected to be a
reliable tool for constructing elaborate alkynes.
As Scheme 2 shows, the present ATA receives no
benefit from the reaction conditions of our preceding
dehydrogenative coupling, starting with the activation
3
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
of H–met 2 by Zn(OTf)2. This may imply that the
substrate to be activated first by ZnX2 is not alkyl
triflate 4 but the other one, alkyne 1. To get insight
into the reaction mechanism, several attempts were
performed. We first deduced that ZnX2-mediated
deprotozincation of 1 to form an alkynylzinc species
[(RC≡C)nZn, n = 1 or 2], which reportedly reacts with
aldehydes,[24] may be one possibility of the pathway
induced by the alkyne activation. The observation on
treating 1a with aldehyde 8a instead of 4 led to
forming adduct 9aa even at room temperature (rt) for
30 min (Scheme 5). The same reaction but performed
at 50 °C for 2 h occurred much more efficiently over
90%, while enone 9’aa probably formed via in situ
Oppenauer oxidation of 9aa by 8a was coproduced,
as previously reported.[25] To the contrary, neither 9aa
nor 9’aa was produced without PrSp. These results
suggest that the (RC≡C)nZn is a possible intermediate
for the progress of the ATA, which requires the
assistance of PrSp. We then focused on pursuing
which of a dialkynylzinc or monoalkynylzinc species
is more plausible (Scheme 6). Thus, mixing authentic
(PhC≡C)2Zn (10’a)[26] and BuOTf (4a) along with
PrSp in toluene at 50 °C for 24 h gave product 5aa
but in low yield. On the other hand, on the similar
handling of PhC≡CZnNNf2 (10a) prepared by the
reported recipe,[27] 5aa was obtained in much higher
yield even at rt for 1 h, regardless of the presence or
absence of PrSp. These results exhibit that
monoalkynylzinc 10 rather than 10’ is a more
plausible candidate capable of efficiently reacting
with 4,[28] and, in addition, that PrSp is unlikely to
play an important role after the formation of 10.
The above results strongly support the possibility
that the ATA starts with the activation of 1 by ZnX2
and PrSp to give 10 as the intermediate. We next
examined the possibility of the other route that starts
with the activation of 4 by ZnX2 and selected the
Friedel–Crafts alkylation to verify whether Zn(NNf2)2
can activate 4 as a Lewis acid catalyst under the ATA
conditions (Scheme 7).[29,30] No butylation of benzene
with 4a proceeded when both of Zn(NNf2)2 and PrSp
are present, while the butylated benzenes as a mixture
of 11 and 11’ were formed when only Zn(NNf2)2 is
present, thus showing that Zn(NNf2)2 has an ability to
activate 4a but not under the ATA conditions wherein
PrSp coexists. Accordingly, this finding is in accord
with those obtained in Schemes 5 and 6, in terms of
the validity of the pathway in which ZnX2 and PrSp
first encounter 1 to give 10.
The participation of a radical species in the ATA
was next examined (Scheme 8). The butylation of 1a
occurred smoothly in the presence of a stoichiometric
amount of 1,1-diphenylethylene or 2,6-di-tert-butyl-
p-cresol as a radical scavenger. These results, in
addition to that of giving only 5eh from 4h (see Table
3), reveal no involvement of a radical species in the
ATA.
We also pursued PrSp-based byproducts on the
butylation of 1a and confirmed the generation of not
only PrSp•HOTf (12) as a major form but also 12’ as
the HNNf2 salt (Scheme 9). Since TfOH is produced
Zn (20 mol%)
PrSp (1.5 equiv.)
OH
tBu
O
Ph
Ph
+
Ph
H toluene
tBu
rt, 30 min
1a
9aa; 58% yield 9'aa; <1% yield
+
O
same as above
H
9aa; 71% yield + 9'aa; 22% yield
tBu
8a
50 ºC, 2 h
+ TfOBu
+
without PrSp: 9aa; <1% yield 9'aa; <1% yield
50 ºC, 24 h
+
4a
11
11'
with Zn(NNf2)2 + PrSp: <1% yield
with Zn(NNf2)2: 1% yield
<1% yield
21% yield
Scheme 5. Trapping experiments of an alkynylzinc
intermediate with pivalaldehyde. Zn = Zn(NNf2)2.
Scheme 7. The Friedel–Crafts butylation of benzene:
evaluation of the possibility of starting with the activation
of 4 by Zn(NNf2)2. Yields determined by GC are shown
here. Reagents: 4a (0.56 mmol), Zn(NNf2)2 (80 mol),
PrSp (0.60 mmol), benzene (0.40 mL).
removal of
volatiles
ZnEt2 (0.5 equiv.)
Ph
H
6 Pa, rt, 2 h
toluene/THF
110 ºC, 10 h
1a
TfOBu 4a (1.4 equiv.)
PrSp (0.5 equiv.)
Ph
Bu
Ph
Ph
2 Zn
Ph
H
Zn(NNf2)2 (20 mol%)
PrSp (1.5 equiv.)
toluene, 50 ºC, 24 h
10'a
5aa; 31% yield
1a
radical scavenger (1.0 equiv.)
Ph
Bu
+
TfOBu 4a (1.4 equiv.)
PrSp (1 equiv.)
toluene, 50 ºC, 24 h
5aa
TfOBu
ZnNNf2
Ph
Bu
rt, 1 h
4a
10a
5aa; 76% yield
OH
tBu
tBu
without PrSp: 5aa; 73% yield
Ph
Ph
radical scavenger:
Zn(NNf2)2
(1 equiv.)
BuLi (1 equiv.)
Ph
H
rt, 20 min
toluene
1a
–70 ºC, 10 min
5aa; 75% yield 5aa; 81% yield
Scheme 6. Stoichiometric reaction of alkynylzinc species
with butyl triflate.
Scheme 8. Evaluation of the possibility of a radical route.
Yields determined by 1H NMR are shown here.
4
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
with the progress of the ATA, the trapping of the
TfOH by PrSp is considered to lead to salt 12. On the
other hand, the formation of 10 from 1, Zn(NNf2)2
and PrSp will be one possibility to afford salt 12’.
Lastly, the kinetic isotope effect (KIE) experiments
were conducted (Scheme 10). The kH/kD value for the
butylation of 1a or 1a-d (95%-d) was estimated to be
2.5, suggesting that the stage of the C(sp)–H
bondscission, followed by the formation of 10, is the
rate-determining step.
two ligands on the zinc catalyst would have to be
NNf2 for the efficient ATA.
In closing, we have disclosed that Lewis acid
Zn(NNf2)2 efficiently behaves as a catalyst to alkylate
terminal alkynes by alkyl triflates with the assistance
of PrSp in toluene. This is the first Lewis-acid-
catalyzed ATA without relying on the benzylic and
norbornyl electrophiles as alkylating agents. The
TfO-selective ATA in the presence of the C(sp3)–X
(X = I, Br, Cl) functionalities is the unique aspect of
this ATA system. Mechanistic studies provided the
following significant insights: 1) the ATA starts with
the activation of not alkyl triflates 4 but alkynes 1 by
Zn(NNf2)X (X = NNf2 or OTf) and PrSp; 2) as a
result, the monoalkynylzinc species is formed as the
key intermediate; 3) the stage on the cleavage of the
C(sp)–H bond is the rate-determining step; 4) a
radical species is unlikely involved in this ATA. We
hope that this technology disclosed herein will
contribute to the development of next zinc-Lewis-
acid-catalyzed transformation.
Zn(NNf2)2 (20 mol%)
PrSp (1.5 equiv.)
Ph
H
+
1:1.4
TfOBu
toluene, 50 ºC, 24 h
1a
4a
PrSp•HOTf
+
PrSp•HNNf2
12'; 7% yield
+
Ph
Bu
12; 74% yield
5aa; 74% yield
Scheme 9. Identification of PrSp-based byproducts. The
yield of isolated 12 (based on PrSp) and yields of 12’
1
(based on PrSp) and 5aa (based on 1a) determined by H
NMR are provided, respectively.
Experimental Section
Zn(NNf2)2 (20 mol%)
PrSp (1.5 equiv.)
Ph
Ph
H
D
Zinc-Catalyzed Alkylation of Terminal Alkynes with
Alkyl Triflates. A General Procedure for Tables 2 and
3.
or
+
1:1.4
TfOBu
Ph
Bu
toluene, 50 ºC
30–180 min
4a
5aa
Zn(NNf2)2 (98.1 mg, 80.0 mol) was placed in a 20 mL
Schlenk tube, which was heated at 150 ºC in vacuo (6 Pa)
for 2 h. The tube was cooled down to room temperature
and filled with argon. Toluene or 4-chlorotoluene (0.40
mL) was added to the tube, and the mixture was then
stirred at room temperature for 3 min. To this were added
alkyne 1 (0.400, 0.800, 1.20 or 2.40 mmol) and alkyl
triflate 4 (0.400, 0.560 or 0.800 mmol) and PrSp [(94.3 mg,
0.440 mmol), (129 mg, 0.600 mmol) or (180 mg, 0.840
mmol)] successively, and the resulting solution was stirred
at 50 or 60 ºC for 24–72 h. A saturated NaHCO3 or NH4Cl
aqueous solution (0.5 mL) was added to the mixture, and
the aqueous phase was extracted with EtOAc (5 mL × 3).
The combined organic layer was washed with brine (1 mL)
and then dried over anhydrous sodium sulfate. Filtration
through a pad of Celite and evaporation of the solvent
followed by purification gave product 5.
1a or 1a-d
kH/kD = 2.5
Scheme 10. Kinetic isotope effect experiments.
Taking all of the results on the mechanistic studies
into consideration, a plausible reaction mechanism is
proposed in Scheme 11. First up is the PrSp-assisted
deprotozincation of 1 with Zn(NNf2)X (X = NNf2)
through the cleavage of the C(sp)–H bond as the rate-
determining step (RDS) to furnish monoalkynylzinc
species 10 and PrSp•HNNf2 (12’). Intermediate 10
then reacts with 4 to deliver product 5 and
Zn(NNf2)OTf, which may exchange the OTf ligand
with the NNf2 of 12’ to regenerate Zn(NNf2)2 and to
afford PrSp•HOTf (12), or may directly participate in
the next catalytic cycle to give 5 and Zn(NNf2)OTf
again as well as 12. As already shown in entry 12 of
Table 1, Zn(OTf)2 shows almost no catalytic activity
towards the ATA. Accordingly, at least one of the
Further experimental details on each reaction of Tables
2 and 3, and details on other experimental procedures,
and characterization data of new compounds and their
NMR spectra are given in the Supporting Information.
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5
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.201801685
Advanced Synthesis & Catalysis
COMMUNICATION
Alkylation of Terminal Alkynes under Zinc Lewis
Acid Catalysis and Its Mechanistic Studies
NMe2
NMe2
cat.
R
H
Adv. Synth. Catal. Year, Volume, Page – Page
+
Zn
R
alkyl
TfO
alkyl
Me2
N
Mana Osano, Takeru Kida, Kyohei Yonekura,
Teruhisa Tsuchimoto*
–OTf
H
R
Zn
+
N
Me2
8
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