Alkynylation of aldehydes mediated by zinc and allyl bromide: a practical synthesis of propargylic alcohols

Article abstract of DOI:10.1007/s11164-016-2859-2

Abstract: A practical synthesis of propargylic alcohols was developed by alkynylation of aldehydes mediated by zinc and allyl bromide. Aromatic, aliphatic and vinyl aldehydes react with phenylacetylene or 1-hexyne to obtain various propargylic alcohols at room temperature in up to 98% yield. This method is characterized with inexpensive materials, wide substrate scope, and mild reaction conditions, and is also easy to scale up. In addition, this protocol is applicable to the alkynylation of α-ketone esters and epoxides to generate α-tertiary-hydroxy esters and α-alkynyl alcohols, respectively. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-016-2859-2

Res Chem Intermed
DOI 10.1007/s11164-016-2859-2
Alkynylation of aldehydes mediated by zinc and allyl
bromide: a practical synthesis of propargylic alcohols
Ji-Cai Zhou1 Lei Zhao1 Yuan Li1 Ding-Qiang Fu1
•
•
•
•
Zi-Cheng Li1 Wen-Cai Huang1
•
Received: 20 November 2016 / Accepted: 30 December 2016
Ó Springer Science+Business Media Dordrecht 2017
Abstract A practical synthesis of propargylic alcohols was developed by alkynylation
of aldehydes mediated by zinc and allyl bromide. Aromatic, aliphatic and vinyl alde-
hydes react with phenylacetylene or 1-hexyne to obtain various propargylic alcohols at
room temperature in up to 98% yield. This method is characterized with inexpensive
materials, wide substrate scope, and mild reaction conditions, and is also easy to scale
up. In addition, this protocol is applicable to the alkynylation of a-ketone esters and
epoxides to generate a-tertiary-hydroxy esters and a-alkynyl alcohols, respectively.
Graphical Abstract
Keywords Alkynylation Á Zinc Á Propargylic alcohol Á a-Tertiary-hydroxy ester Á a-
Alkynyl alcohol
Introduction
Propargylic alcohols are versatile precursors for the synthesis of natural products
and pharmaceutically relevant compounds [1–3]. Especially, they can be trans-
formed to important carbocycles and heterocycles such as 1H-indenes [4], pyrazoles
&
Wen-Cai Huang
hwc@scu.edu.cn
1
Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan
University, Chengdu 610065, People’s Republic of China
123

J.-C. Zhou et al.
[5], isoxazoles [6], tetrazoles [7], benzofurans [8] and b-lactams [9]. Different
processes have been developed to prepare structurally diverse propargylic alcohols
over the past decades, among which alkynylation of aldehydes is a straightforward
and very useful method [10–16]. In most cases, organometallic reagents such as
diethylzinc [17–21], dimethylzinc [22–24] and n-butyllithium [25, 26] are needed to
abstract the active hydrogen of terminal alkynes to form metal acetylides, followed
by nucleophilic addition to aldehydes to afford propargylic alcohols. However, there
are some recognized limitations of this approach because these alkylmetal reagents
are sensitive toward air and moisture and thus inconvenient to handle.
Recently, some progress has been made in the alkynylation of aldehydes without
the use of the strong bases mentioned above. ZnO, a cheap and efficient catalyst, has
been reported to promote the direct addition of terminal alkynes to aldehydes under
solvent- and base-free conditions at 120 °C [27]; however, the comparatively high
temperature may limit the generality of this methodology. Similarly, a copper-silver
nanoparticles-catalyzed addition of terminal alkynes to aldehydes at 100 °C in good
yields has also been reported, but the substrate scope is limited to aromatic
aldehydes and aromatic alkynes [28]. In contrast to the traditional reaction medium,
a novel protocol using a Bu4NOH/H2O/DMSO catalytic system was developed to
achieve the alkynylation of aldehydes and ketones to generate propargylic alcohols
[29]. With a strong base solution as the solvent, the reaction system may not be
applicable to sensitive substrates such as esters, amides and epoxides. More
recently, the direct use of the inexpensive and easily manageable zinc powder in
combination with MeI [30], EtI [31] or iPrI [32] to promote the addition of alkynes
to aldehydes was disclosed, but 8 or 12 equiv of alkyl iodides and two different
solvents must be used to accomplish this two-step transformation.
Considering the importance of propargylic alcohols in organic synthesis,
inexpensive and practical methods to achieve the direct alkynylation of aldehydes
are still in urgent need.
i
In our previous work, it was found that the combination of Zn (6 equiv), PrI (6
equiv), H8BINOL (0.4 equiv) and Ti(OiPr)4 (1 equiv) could accomplish the
enantioselective alkyne addition to aromatic, aliphatic and vinyl aldehydes to afford
various chiral propargylic alcohols at room temperature with up to 98% yield and
98% enantiomeric excess [32]. When lower amounts of allyl bromide (Allyl-Br)
i
were used in place of PrI, propargylic alcohol could still be obtained, but the ee
value decreased significantly (Table 1, entries 1–2). Inspired by these results, we
envisioned that high yields of racemic propargylic alcohols may be obtained via
further investigation of this addition reaction. Here, we report our findings on the
practical synthesis of a variety of propargylic alcohols by the alkynylation of
aldehydes mediated by Zn and allyl bromide under mild conditions.
Experimental
THF was distilled over sodium and benzophenone under nitrogen. Toluene,
dichloromethane and ether were dried over a 4A molecular sieve before use.
Aldehydes, acetophenone, methyl phenylglyoxylate, epoxides and alkynes were
123

Alkynylation of aldehydes mediated by Zinc and allyl…
distilled or recrystallized before use. Zinc powder was activated with dilute HCl,
dried at 90 °C for 2 h under vacuum, and stored under nitrogen. All the other
reagents and solvents were purchased from the commercial sources and used as
received. All the reactions were performed under nitrogen and monitored by TLC.
1H NMR spectra were recorded on a Bruker AVANCE III spectrometer (400 MHz)
in CDCl3 with TMS as an internal standard.
General procedure for the synthesis of propargylic alcohols
To a dry 10-mL round-bottom flask was added activated zinc powder (3 mmol,
3equiv), then dry THF (1 mL), allyl bromide (3 mmol, 3 equiv), and an alkyne
(3 mmol, 3 equiv) were added in turn via a syringe under nitrogen. After the mixture
was stirred at room temperature for 2–3 h and all the zinc powder disappeared, an
aldehyde (1 mmol, 1 equiv) was added via a syringe and the stirring was continued
for 10–20 h. When TLC showed the aldehyde had been consumed, saturated
ammonia chloride solution (0.5 mL) was added to quench the reaction. After
extraction with methylene chloride (29 10 mL) and concentration under vacuum,
the residue was purified by column chromatography on silica gel with hexane/ethyl
acetate (15/1) as the eluent to afford the pure product.
Spectral data of synthesized compounds
1,3-Diphenylprop-2-yn-1-ol (1a) Pale-yellow oil, 96% yield. 1H NMR (400 MHz,
CDCl3) d 7.59–7.51 (m, 2H), 7.49–7.43 (m, 2H), 7.40–7.35 (m, 2H), 7.34–7.26 (m,
4H), 5.65 (s, 1H), 2.69 (s, 1H).
1
1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol (1b) Pale-yellow oil, 96% yield. H
NMR (400 MHz, CDCl3) d 7.83–7.78 (m, 1H), 7.47–7.42 (m, 2H), 7.38–7.34 (m,
1H), 7.32–7.20 (m, 5H), 6.02 (s, 1H), 2.94 (s, 1H).
1
1-(3-Chlorophenyl)-3-phenylprop-2-yn-1-ol (1c) Pale-yellow oil, 98% yield. H
NMR (400 MHz, CDCl3) d 7.53 (s, 1H), 7.43–7.33 (m, 3H), 7.26–7.14 (m, 5H),
5.57 (s, 1H), 2.51 (s, 1H).
1
1-(2, 4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (1d) Colorless oil, 98% yield. H
NMR (400 MHz, CDCl3) d 7.75 (d, J = 8.4 Hz, 1H), 7.50–7.43 (m, 2H), 7.40 (d,
J = 2.0 Hz, 1H), 7.36–7.27 (m, 4H), 5.98 (d, J = 4.0 Hz, 1H), 2.68 (d, J = 4.0 Hz,
1H).
3-Phenyl-1-(o-tolyl) prop-2-yn-1-ol (1e) Pale-yellow oil, 93% yield. 1H NMR
(400 MHz, CDCl3) d 7.70–7.75 (m, 1H), 7.48–7.43 (m, 2H), 7.33–7.28 (m, 3H),
7.22–7.25 (m, 2H), 7.20–7.17 (m, 1H), 5.83 (s, 1H), 2.49 (s, 3H), 2.28 (s, 1H).
1
1-(4-Nitrophenyl)-3-phenylprop-2-yn-1-ol (1f) Brown-yellow oil, 93% yield. H
NMR (400 MHz, CDCl3) d 8.23 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H),
7.49–7.42 (m, 2H), 7.38–7.28 (m, 3H), 5.79 (s, 1H), 2.86 (s, 1H).
123

J.-C. Zhou et al.
Table 1 Optimization of reaction conditions for the addition of phenylacetylene to benzaldehydea
Entry Zn
(equiv)
RX (equiv) Alkyne Solventb
(equiv) (mL)
Additive
(equiv)
Reaction
Isolated
timesc (h) yield (%)
1d
2e
3
6
Allyl-Br 6
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Allyl-Br 3
Bn-Br 3
4
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2
3
4
4
6
THF 1 ? Et2O 10 Ti(OiPr)4
THF 1 ? Et2O 10 Ti(OiPr)4
1
1
24 ? 16
24 ? 16
24 ? 16
24 ? 16
24 ? 16
24 ? 16
24 ? 16
5 ? 12
2 ? 10
2 ? 8
93
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2
2
2
3
6
81
65f
THF 1 ? Et2O 10
THF 1 ? Et2O 10
THF 10
/
4
/
92
5
/
90
6
THF 5
/
89
7
THF 1
/
91
8
THF 1
/
94
9
THF 1
/
96
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a
THF 1
/
90
THF 1
LiCl 1
KI 1
CuCl 1
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
2 ? 10
88
THF 1
85
THF 1
70
THF 1
CuCl2
1
50
Toluene 1
/
/
/
/
/
/
/
/
/
/
No product
CH2Cl2
Et2O 1
THF 1
THF 1
THF 1
THF 1
THF 1
THF 1
THF 1
1
No product
No product
50
Bn-Cl 3
No product
Allyl-Br 2
Allyl-Br 2
Allyl-Br 2
Allyl-Br 3
Allyl-Br 6
53
67
78
94
95
The reaction was conducted at room temperature (26 °C) in two steps: step 1 involved the reaction of
Zn, RX and phenylacetylene to generate organozinc, then 1.0 mmol (1 equiv) of benzaldehyde was added
to accomplish the addition reaction (step 2). After work-up, the product was isolated by column chro-
matography on silica gel
b
Different solvents may be used for step 1 and step 2
c
Reaction times for step 1 and step 2
d
0.4 equiv of (S)-H8BINOL was used and the ee value of the product was 64%
e
0.4 equiv of (S)-BINOL was used and the ee value of the product was 49%
f
Some addition product of allyl group to benzaldehyde was detected by TLC
123

Alkynylation of aldehydes mediated by Zinc and allyl…
1-(2-Nitrophenyl)-3-phenylprop-2-yn-1-ol (1g) Pale-yellow oil, 94% yield. 1H
NMR (400 MHz, CDCl3) d 7.96 (dd, J = 8.0, 2.0 Hz, 2H), 7.64 (t, J = 8.0 Hz,
1H), 7.50–7.39 (m, 3H), 7.33–7.25 (m, 3H), 6.22 (s, 1H), 3.63 (s, 1H).
1
1-(Furan-2-yl)-3-phenylprop-2-yn-1-ol (1h) Brown–red oil, 94% yield. H NMR
(400 MHz, CDCl3) d 7.50–7.46 (m, 2H), 7.43 (dd, J = 2.0, 0.8 Hz, 1H), 7.35–7.28
(m, 3H), 6.52 (d, J = 3.2 Hz, 1H), 6.37 (dd, J = 3.2, 2.0 Hz, 1H), 5.69 (s, 1H), 2.64
(s, 1H).
1-(Benzo[d] [1,3] dioxol-5-yl)-3-phenylprop-2-yn-1-ol (1i) Pale-yellow oil, 91%
1
yield. H NMR (400 MHz, CDCl3) d 7.50–7.43 (m, 2H), 7.34–7.28 (m, 3H), 7.12
(d, J = 1.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.97 (s,
2H), 5.59 (s, 1H), 2.33 (s, 1H).
1,5-Diphenyl-pent-1-en-4-yn-3-ol (1j) Pale-yellow oil, 93% yield. 1H NMR
(400 MHz, CDCl3) d 7.48 (dd, J = 7.2, 2.0 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H),
7.36–7.28 (m, 6H), 6.84 (d, J = 7.6 Hz, 1H), 6.39 (dd, J = 7.6, 2.0 Hz, 1H), 5.29
(d, J = 7.6 Hz, 1H), 2.12 (s, 1H).
1-Phenylpent-1-yn-3-ol (1k) Pale-yellow oil, 81% yield. 1H NMR (400 MHz,
CDCl3) d 7.46–7.40 (m, 2H), 7.34–7.28 (m, 3H), 4.55 (t, J = 6.4 Hz, 1H), 2.04 (s,
1H), 1.87–1.78 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H).
1-Phenylhex-1-yn-3-ol (1l) Pale-yellow oil, 80% yield. 1H NMR (400 MHz,
CDCl3) d 7.46–7.38 (m, 2H), 7.33–7.27 (m, 3H), 4.61 (t, J = 6.4 Hz, 1H), 2.04 (s,
1H), 1.83–1.75 (m, 2H), 1.62–1.49 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).
4-methyl-1-phenylpent-1-yn-3-ol (1m) Pale-yellow oil, 80% yield. 1H NMR
(400 MHz, CDCl3) d 7.46–7.40 (m, 2H), 7.33–7.28 (m, 3H), 4.40 (d, J = 5.6 Hz,
1H), 1.98 (td, J = 8.4, 2.8 Hz, 1H), 1.29–1.15 (m, 1H), 1.07 (dd, J = 8.8, 2.8 Hz,
6H).
1-Phenylono-1-yn-3-ol (1n) Colorless oil, 95% yield. 1H NMR (400 MHz,
CDCl3) d 7.48–7.38 (m, 2H), 7.35–7.30 (m, 3H), 4.59 (t, J = 8.0 Hz, 1H), 2.02
(s, 1H), 1.88–1.74 (m, 2H), 1.56–1.44 (m, 2H), 1.42–1.22 (m, 6H), 0.89 (t,
J = 7.2 Hz, 3H).
1
1-Cyclohexyl-3-phenyl-prop-2-yn-1-ol (1o) Pale-yellow oil, 93% yield. H NMR
(400 MHz, CDCl3) d 7.48–7.39 (m, 2H), 7.34–7.26 (m, 3H), 4.37 (d, J = 5.6 Hz,
1H), 1.92 (d, J = 8.8 Hz, 3H), 1.79 (d, J = 8.8 Hz, 2H), 1.73–1.60 (m, 2H),
1.34–1.21 (m, 3H), 1.20–1.08 (m, 2H).
1-Phenylhept-2-yn-1-ol (2a) Colorless oil, 85% yield. 1H NMR (400 MHz,
CDCl3) d 7.54 (d, J = 7.2 Hz, 2H), 7.34–7.28 (m, 3H), 5.44 (s, 1H), 2.28 (t,
J = 6.4, 2H), 2.11 (s, 1H), 1.58–1.48 (m, 2H), 1.47–1.36 (m, 2H), 0.91 (t,
J = 7.2 Hz, 3H).
1-(2-Chlorophenyl)hept-2-yn-1-ol (2b) Colorless oil, 85% yield. 1H NMR
(400 MHz, CDCl3) d 7.76 (dd, J = 7.2, 1.6 Hz, 1H), 7.37 (dd, J = 7.2, 1.6 Hz,
123

J.-C. Zhou et al.
1H), 7.33–7.23 (m, 2H), 5.81 (t, J = 1.6 Hz, 1H), 2.27 (td, J = 7.2, 2.0 Hz, 2H),
2.04 (s, 1H), 1.57–1.48 (m, 2H), 1.46–1.36 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).
1-(3-Chlorophenyl)hept-2-yn-1-ol (2c) Colorless oil, 88% yield. 1H NMR
(400 MHz, CDCl3) d 7.54 (s, 1H), 7.40–7.37 (m, 1H), 7.33–7.26 (m, 2H), 5.42
(s, 1H), 2.28 (td, J = 7.2, 2.0 Hz, 2H), 2.04 (s, 1H), 1.58–1.49 (m, 2H), 1.47–1.37
(m, 2H), 0.92 (t, J = 7.2 Hz, 3H).
1-(o-Tolyl)hept-2-yn-1-ol (2d) Colorless oil, 84% yield. 1H NMR (400 MHz,
CDCl3) d 7.69–7.62 (m, 1H), 7.31–7.09 (m, 3H), 5.61 (s, 1H), 2.39 (s, 3H), 2.26 (t,
J = 6.4 Hz, 2H), 2.04 (s, 1H), 1.58–1.48 (m, 2H), 1.46–1.38 (m, 2H), 0.92 (t,
J = 7.2 Hz, 3H).
1-(4-Nitrophenyl)hept-2-yn-1-ol (2e) Brown-yellow oil, 88% yield. 1H NMR
(400 MHz, CDCl3) d 8.23 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 5.54 (s,
1H), 2.39 (s, 1H), 2.28 (td, J = 6.4, 2.0 Hz, 2H), 1.57–1.48 (m, 2H), 1.46–1.37 (m,
2H), 0.92 (t, J = 7.2 Hz, 3H).
1-(2-Nitrophenyl)hept-2-yn-1-ol (2f) Pale-yellow oil, 86% yield. 1H NMR
(400 MHz, CDCl3) d 7.94 (dd, J = 7.2, 2.0 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H),
7.49 (t, J = 7.6 Hz, 1H), 5.97 (s, 1H), 3.11 (s, 1H), 2.24 (td, J = 7.2, 2.0 Hz, 2H),
1.56–1.46 (m, 2H), 1.44-1.33 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).
1-(Furan-2-yl)hept-2-yn-1-ol (2g) Pale brown-red oil, 90% yield. 1H NMR
(400 MHz, CDCl3) d 7.40 (d, J = 0.8 Hz, 1H), 6.43 (d, J = 0.8 Hz, 1H), 6.35
(dd, J = 3.2, 2.0 Hz, 1H), 5.44 (d, J = 5.0 Hz, 1H), 2.28 (td, J = 5.0, 2.0 Hz, 3H),
1.58–1.49 (m, 2H), 1.48–1.37 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).
1
1-(Benzo[d] [1, 3] dioxol-5-yl)hept-2-yn-1-ol (2h) Pale-yellow oil, 90% yield. H
NMR (400 MHz, CDCl3) d 7.05 (d, J = 1.6 Hz, 1H), 7.00 (dd, J = 8.0, 1.2 Hz,
1H), 6.79 (d, J = 8.0 Hz, 1H), 5.96 (s, 2H), 5.39–5.32 (m, 1H), 2.27 (td, J = 7.2,
2.0 Hz, 2H), 2.08 (s, 1H), 1.56–1.49 (m, 2H), 1.47–1.37 (m, 2H), 0.92 (t,
J = 7.2 Hz, 3H).
1-Phenylnon-1-en-4-yn-3-ol (2i) Pale-yellow oil, 88% yield. 1H NMR (400 MHz,
CDCl3) d 7.40 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.6 Hz,
1H), 6.75 (d, J = 6.4 Hz, 1H), 6.30 (dd, J = 6.4, 2.0 Hz, 1H), 5.04 (s, 1H), 2.27 (t,
J = 5.6 Hz, 2H), 1.97 (s, 1H), 1.57–1.48 (m, 2H), 1.47–1.39 (m, 2H), 0.92 (t,
J = 7.2 Hz, 3H).
1
Non-4-yn-3-ol (2j) Colorless oil, 78% yield. H NMR (400 MHz, CDCl3) d 4.30
(s, 1H), 2.21 (t, J = 5.2 Hz, 2H), 1.70 (s, 1H), 1.69–1.60 (m, 2H), 1.53–1.46 (m,
2H), 1.44–1.36 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).
1
Dec-5-yn-4-ol (2k) Colorless oil, 77% yield. H NMR (400 MHz, CDCl3) d 4.36
(tt, J = 6.6, 2.0 Hz, 1H), 2.21 (td, J = 6.6, 2.0 Hz, 2H), 1.78 (s, 1H), 1.73–1.58 (m,
2H), 1.53–1.35 (m, 6H), 0.93 (dt, J = 7.2, 2.4 Hz, 6H).
123

Alkynylation of aldehydes mediated by Zinc and allyl…
Tridec-5-yn-7-ol (2l) Colorless oil, 86% yield. 1H NMR (400 MHz, CDCl3) d 4.34
(t, J = 6.4 Hz, 1H), 2.21 (td, J = 6.4, 1.6 Hz, 2H), 1.77 (s, 1H), 1.71–1.59 (m, 2H),
1.53–1.37 (m, 6H), 1.35–1.24 (m, 6H), 0.93–0.85 (m, 6H).
1
1-Cyclohexylhept-2-yn-1-ol (2m) Colorless oil, 92% yield. H NMR (400 MHz,
CDCl3) d 4.13 (d, J = 6.4 Hz, 1H), 2.22 (t, J = 6.4 Hz, 2H), 1.88–1.80 (m, 2H),
1.79–1.66 (m, 4H), 1.52–1.47 (m, 2H), 1.44–1.35 (m, 2H), 1.28–1.18 (m, 3H),
1.17–0.99 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).
2,4-Diphenylbut-3-yn-2-ol (3a) Yellow oil, 72% yield. 1H NMR (400 MHz,
CDCl3) d 8.04–7.96 (m, 2H), 7.60–7.52 (m, 3H), 7.50–7.37 (m, 5H), 2.60 (s, 1H),
1.58 (s, 3H).
1
Methyl 2-hydroxy-2, 4-diphenylbut-3-ynoate (4a) Pale-yellow oil, 93% yield. H
NMR (400 MHz, CDCl3) d 7.77–7.72 (m, 2H), 7.56–7.51 (m, 2H), 7.44–7.30 (m,
6H), 4.25 (s, 1H), 3.82 (s, 3H).
1
Methyl 2-hydroxy-2-phenyloct-3-ynoate (4b) Colorless oil, 75% yield. H NMR
(400 MHz, CDCl3) d 7.70–7.63 (m, 2H), 7.40–7.30 (m, 3H), 4.12 (s, 1H), 3.77 (s,
3H), 2.33 (t, J = 7.2 Hz, 2H), 1.61–1.52 (m, 2H), 1.50–1.39 (m, 2H), 0.93 (t,
J = 7.2 Hz, 3H).
1
1,4-Diphenylbut-3-yn-1-ol (5a) Pale-yellow oil, 84% yield. H NMR (400 MHz,
CDCl3) d 7.50–7.43 (m, 4H), 7.40–7.34 (m, 2H), 7.33–7.27 (m, 4H), 4.08 (t,
J = 6.8 Hz, 1H), 3.85 (d, J = 6.8 Hz, 2H), 1.82 (s, 1H).
2-(Phenylethynyl)cyclohexan-1-ol (5b) Pale-yellow oil, 60% yield. 1H NMR
(400 MHz, CDCl3) d 7.45–7.39 (m, 2H), 7.33–7.28 (m, 3H), 4.47 (d, J = 7.2 Hz,
1H), 2.38–2.23 (m, 1H), 2.23–1.81 (m, 3H), 1.72–1.65 (m, 2H), 1.61–1.46 (m, 4H),
1.37–1.24 (m, 1H).
2-(Hex-1-yn-yl)cyclohexan-1-ol (5c) Colorless oil, 40% yield. 1H NMR
(400 MHz, CDCl3) d 4.22 (dt, J = 7.2, 2.0 Hz, 1H), 2.21 (td, J = 6.8, 2.0 Hz,
2H), 2.18–2.09 (m, 1H), 1.81–1.66 (m, 4H), 1.65–1.52 (m, 4H), 1.49–1.45 (m, 2H),
1.43–1.38 (m, 3H), 0.91 (t, J = 7.2 Hz, 3H).
Results and discussion
To begin the study, phenylacetylene and benzaldehyde were chosen as the model
substrates, and the variations of reaction conditions and experimental results are
summarized in Table 1 (entries 3–24).
First, the reaction was performed without the addition of Ti(OiPr)4 and chiral
ligand, racemic product 1a was obtained in moderate yield (entry 3). We reasoned
that a lower amount of phenylacetylene (2 equiv) than that of allyl bromide and Zn
(3 equiv) may result in an unsatisfactory yield because the remaining allylzinc
bromide which did not react with phenylacetylene may attack the benzaldehye
competitively to produce a by-product. To testify our hypothesis, we carried out a
123

J.-C. Zhou et al.
control experiment in which the operations were the same as that in entry 3 except
that no phenylacetylene was added; the results revealed that the addition product
was the same major by-product as in entry 3. Hence, the amount of phenylacetylene
was increased from 2 equiv to 3 equiv, and the yield of 1a improved significantly to
92% (entry 4).
To simplify the operation and minimize the amount of solvent, we avoided the
addition of ether in step 2 and lowered the volume of THF stepwise to 1 mL, and no
obvious decrease of the yield was observed (entries 5–7). Based on the observation
that activated zinc powder reacted with allyl bromide quickly in THF and
disappeared in about 1 h, we shortened the reaction times of step 1 and step 2, and
slight increases of yield were observed which may have resulted from less
deterioration of the active intermediate and product 1a (entries 8–9). However,
when the reaction time of step 2 was reduced from 10 to 8 h, the yield decreased by
6% (entry 10). Next, halides such as lithium chloride, potassium iodide, copper
chloride and cuprous chloride were used as additives, but the yields of 1a were all
lower than 96% (entries 11–14). THF, toluene, dichloromethlene and ether were
also used as the solvent for the two-step transformation, but, unfortunately, the zinc
powder could not react completely and no product was detected by TLC (entries
15–17). Thus, THF was necessary for the effective generation and reaction of the
organozinc reagent involved in the transformation. Moreover, the possibility of
employing benzyl bromide or benzyl chloride in place of allyl bromide to promote
the addition reaction was also investigated, but when benzyl bromide was used, 1a
was separated in 50% yield (entry 18), and when benzyl chloride was used, no
product was detected (entry 19). Finally, the molar ratios of Zn, allyl bromide and
phenylacetylene to benzaldehyde were varied, the results showing that lower molar
ratios than that in entry 9 led to lower yields of 1a (entries 20–22) and higher molar
ratios did not increase the yield (entries 23–24). Therefore, the optimized reaction
conditions for the direct addition of phenylacetylene to benzaldehyde mediated by
Zn and allyl bromide were determined as listed in entry 9.
In agreement with the above experimental observations, a tentative mechanism
that accounts for the synthesis of propargylic alcohol 1a has been proposed in
Scheme 1. Initially, zinc reacts with allyl bromide in THF to provide allylzinc
bromide [33], then it abstracts the active hydrogen of phenylacetylene to form the
active intermediate I which attacks the carbonyl group of benzaldehyde, leading to
the formation of compound 1a.
With the optimal reaction conditions and tentative mechanism established, the
addition reactions of phenylacetylene or 1-hexyne to various aldehydes, including
substituted benzaldehydes, aliphatic and vinyl aldehydes, were performed, and the
results are set out in Table 2.
Scheme 1 Plausible steps in the formation of propargylic alcohol 1a
123

Alkynylation of aldehydes mediated by Zinc and allyl…
Table 2 Addition of alkynes to
aldehydes mediated by Zn and
allyl bromidea
Entry
R1
R2
Product
Isolated yield (%)
1
Ph
Ph
1a
1b
1c
1d
1e
1f
96
96
98
98
93
93
94
94
91
93
81
80
80
95
93
85
85
88
84
88
86
90
90
88
78
77
86
92
2
Ph
2-ClC6H4
3-ClC6H4
2,4-Cl2C6H3
2-MeC6H4
4-NO2C6H4
2-NO2C6H4
2-furanyl
piperonyl
cinnamyl
ethyl
3
4b
Ph
Ph
5
6b
7b
Ph
Ph
Ph
1g
1h
1i
8
9b
Ph
Ph
10
Ph
1j
11c
12c
13c
14c
15c
16d
17d
18d
19d
20b,d
21b,d
22d
23b,d
24d
25e
26e
27f
28f
Ph
1k
1l
Ph
n-propyl
i-propyl
Ph
1m
1n
1o
2a
2b
2c
2d
2e
2f
Ph
n-hexyl
Ph
cyclohexyl
Ph
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
2-ClC6H4
3-ClC6H4
2-MeC6H4
4-NO2C6H4
2-NO2C6H4
2-furanyl
piperonyl
cinnamyl
ethyl
a
Conditions of entry 9 in
Table 1 were applied unless
indicated otherwise
b
The solid aldehyde was
dissolved in 0.5 mL of THF and
then added via syringe
2g
2h
2i
c
The reaction times were
2 h ? 16 h
d
The reaction times were
3 h ? 12 h
2j
e
The reaction times were
3 h ? 20 h
n-propyl
n-hexyl
2k
2l
f
The reaction times were
3 h ? 16 h
cyclohexyl
2m
It can be seen from Table 2 that most of the reactions proceeded smoothly to
afford propargylic alcohols in good yields. The addition of phenylacetylene to
aromatic, heteroaromatic or cinnamic aldehydes gave the desired products 1a–1j in
91–98% yields and it appears that the position and electronic property of the
substituents of aromatic aldehydes have a very limited effect on the results of this
reaction. Although the phenylacetylene addition to propanal, n-butanal and iso-
butanal gave slightly lower yields (1k–1m), it is noteworthy that when heptanal and
cyclohexanecarboxaldehyde were employed, the yields were 95 and 93% respec-
tively (1n, 1o). When 1-hexyne was subjected to this reaction, the yields ranged
from 84 to 90% for aromatic, heteroaromatic and cinnamic aldehydes (2a–2i) and
from 77 to 92% for aliphatic aldehydes (2j–2m).
123

J.-C. Zhou et al.
Fig. 1 Products of the addition of alkynes to ketone, a-ketone ester and epoxidesa (a For compound 3a,
the molar ratios of ketone:Zn:allyl bromide:alkyne were 1:6:6:6 and the reaction times were 3 h ? 16 h.
For compound 4b, the reaction times were 2 h ? 12 h and for compounds 5b and 5c, the reaction times
were 2 h ? 16 h)
With the good results obtained from aldehydes, we attempted similar transfor-
mations with other substrates and the results are shown in Fig. 1. Unless indicated
otherwise, the conditions of entry 9 in Table 1 were applied for these addition
reactions. Initially, acetophenone was subjected to the alkynylation process, but
incomplete conversion of the ketone was observed owing to its lower reactivity than
aldehyde. When the molar ratios of Zn, allyl bromide and phenylacetylene to ketone
were increased from 3 equiv to 6 equiv, 3a was obtained in 72% yield. Then, methyl
phenylglyoxylate was employed in place of aldehyde. To our delight, a-tertiary-
hydroxy esters 4a and 4b were obtained in 93 and 75% yields, respectively. It is
noteworthy that the ester group is tolerable to this transformation. Epoxide is
another important electrophilic reagent with wide synthetic utility and the direct
addition of alkyne to it will afford a-alkynyl alcohol, an analogue of propargylic
alcohol. We envisioned that our protocol was also applicable to the alkyne addition
to epoxide under mild conditions, hence, the addition of phenylacetylene to styrene
oxide was conducted under the standard reaction conditions. As shown in Fig. 1, the
reaction proceeded smoothly, providing compound 5a in 84% yield. Also, the
alkynylation of cyclohexene oxide provided 5b and 5c in moderate yields.
Generally, the addition of phenylacetylene to styrene oxide involved the use of
active intermediates such as phenylethynyl lithium [34–36] and phenylethynyld-
ifluoroborane [37] and suffered from harsh reaction conditions and low yield. To the
best of our knowledge, there has thus far been no report on the Zn-promoted
alkynylation of epoxide with alkyne, so our methodology provides a practical and
convenient synthesis of a-alkynyl alcohol via the direct alkynlation of epoxide.
To demonstrate practical utility, the reaction of 10.20 mL phenylacetylene and
3.09 mL benzaldehyde was carried out at the 30-mmol scale. The operations were
the same as that of entry 9 in Table 1 except that an ice-water bath was used to cool
the flask when allyl bromide was added in batches and the reaction times were
prolonged to 3 and 14 h for step 1 and step 2, respectively. Finally, 6.03 g of 1a was
isolated after column chromatography and the yield was 96%. The result suggests
that the alkynylation of aldehydes mediated by Zn and allyl bromide is easy to scale
up.
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Alkynylation of aldehydes mediated by Zinc and allyl…
Conclusion
In summary, we have developed a practical method for the direct alkynylation of
aldehydes mediated by Zn and allyl bromide, and a variety of propargylic alcohols
could be obtained by the reaction of terminal alkynes and aromatic, aliphatic and
vinyl aldehydes. These reactions proceeded under very mild conditions (at room
temperature) in high yields (77–98%). Furthermore, when a-ketone esters and
epoxides were subjected to this protocol, a-tertiary-hydroxy esters and a-alkynyl
alcohols could also be obtained in moderate to high yields.
Acknowledgement We thank the Analytical and Testing Center of Sichuan University for NMR
measurements.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
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