Zinc-mediated alkynylation of carbonyl compounds with iodoalkynes: a facile synthesis of propargyl alcohols

Article abstract of DOI:10.1016/j.tetlet.2008.09.156

A straightforward synthesis of propargyl alcohols from alkynyl iodides and carbonyl compounds using zinc is described.

Full text of DOI:10.1016/j.tetlet.2008.09.156

Tetrahedron Letters 49 (2008) 7132–7134
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Tetrahedron Letters
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Zinc-mediated alkynylation of carbonyl compounds with
iodoalkynes: a facile synthesis of propargyl alcohols
*
P. Srihari , Vinay K. Singh, Dinesh C. Bhunia, J. S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward synthesis of propargyl alcohols from alkynyl iodides and carbonyl compounds using
Received 12 August 2008
Revised 23 September 2008
Accepted 26 September 2008
Available online 1 October 2008
zinc is described.
Ó 2008 Elsevier Ltd. All rights reserved.
C–C bond formation reaction is a very important transforma-
tion in organic chemistry. Toward this direction, addition of alkyn-
yl halides to carbonyl compounds is a direct chain extension
reaction.1 Also, the resulting propargyl alcohol is an excellent han-
dle for further manipulation. They are versatile substrates for the
synthesis of pharmacologically relevant molecules.2 Recently,
there has been much focus on propargyl alcohols, specifically aryl
propargyl alcohols. Our own interest on Lewis acid catalyzed reac-
tions has initiated several projects in which iodine,3 NbCl5,4 and
OH
Zn, THF
+
I
R'
R
CHO
60 oC, 1-3 h, 77-85%
R
R = aryl
R'
R' = Ph, n-pentyl
Scheme 1.
product was isolated and characterized as the corresponding aryl
propargylic alcohol (Scheme 1).
5
PMA-SiO2 have been utilized for the substitution reactions on
With the success of this reaction, we studied the scope and gen-
erality of this transformation. Different solvents such as CH3CN,
DMSO, DMF, DCM, Et2O, and THF were investigated, and we found
that THF and Et2O were the best in terms of yield. The reaction did
not proceed in CH3CN, DMSO or DMF and the starting materials
were recovered even after heating the solution to 80 °C for 6 h.
Also, increasing the amount of zinc did not change the yield signif-
icantly. However, decreasing the quantity of zinc led to decreased
yields and increased reaction times. Thus, one equivalent of zinc
was necessary to obtain optimum yields in this transformation.
Various substituted aromatic aldehydes were subjected to this
protocol,16 and we found that all the reactions worked well and
yielded the expected products17 in good yields (see Table 1). Sur-
prisingly, nitrogen-containing substrates such as 2-nitro benzalde-
hyde, 4-nitrobenzaldehyde, and N-Boc-proline-carboxaldehyde did
not undergo this transformation, and the starting material was
recovered in all the cases.
benzylic and aryl propargylic alcohols. Although there are several
methods6 available for the preparation of propargyl alcohols using
metalated alkynes in the presence of various Lewis acids7 or
dialkylzinc8 reagents, many of these reactions are sensitive and
low temperatures are needed to stabilize the metal acetylides.
Halo alkynes also form good substrates for metalation with
magnesium9 or in Barbier-type reaction, for example, using
SmI2.10 The use of indium11 or Ti(OiPr)4, iPrMgBr,12 chromium
chloride,13 and Me3Ga14 for metalation followed by the nucleo-
philic addition onto the carbonyl compound has been described.
New protocols for this transformation are always welcome due
to the importance of propargyl alcohols.
While working on substitution reactions of aryl propargylic
alcohols, we investigated a simple procedure for the preparation
of aryl propargyl alcohols. We reasoned that zinc15 could serve as
a reagent for the carbonyl alkynylation. Initially, we treated an
alkynyl iodide with benzaldehyde in the presence of zinc dust
(1 equiv) in THF at room temperature and found that by heating
the reaction mixture to reflux for 2 h, the starting material was
completely consumed and a new spot developed (TLC). This
With the successful results obtained from aldehydes, we at-
tempted a similar transformation with ketones. We were pleased
to note that the reaction worked well with cyclohexanone.18 Mech-
anistically, we believe that zinc inserts into the iodoalkyne and
then participates in nucleophilic addition to the carbonyl com-
pound (see Scheme 2).
In conclusion, a simple protocol for the preparation of propargy-
lic alcohols starting from alkynyl iodides and carbonyl compounds
mediated by zinc has been described. Readily available zinc, clean
* Corresponding author. Tel.: +91 40 27191490; fax: +91 40 27160512.
E-mail addresses: srihari@iict.res.in, sriharipabbaraja@yahoo.com (P. Srihari).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.156

P. Srihari et al. / Tetrahedron Letters 49 (2008) 7132–7134
7133
Table 1
Zinc-mediated addition of iodocetylenes to carbonyl compounds
Entry
Iodoacetylene
Carbonyl compounds
Producta
Time (h)
1.0
Yieldb (%)
OH
OH
I
OHC
1
85
2a
1a
3a
I
OHC
OHC
OMe
2
3
1.5
1.0
2.0
2.0
1.5
2.0
1.0
2.0
2.0
2.0
3.0
2.0
80
77
82
80
78
80
78
85
82
81
80
50
OMe
2b
1a
3b
OH
OH
I
2c
1a
3c
I
OHC
Me
4
Me
2d
2e
1a
3d
OH
OH
I
OHC
OHC
5
1a
3e
I
6
OMe
2f
OMe
1a
3f
OH
OHC
OHC
I
7
2g
2a
1a
3g
OH
I
I
I
I
8
1b
1b
1b
1b
3h
OH
OHC
OHC
OHC
9
2f
OMe
OMe
3i
OH
OH
F
10
11
12
F
2h
3j
Me
Me
2d
3k
OH
O
I
1a
2i
3l
OH
O
OHC
I
O
O
13
O
O
O
1b
2j
3m
a
Product were characterized by IR, 1H, 13CNMR and mass spectroscopy.
Isolated yields after column chromatography.
b

7134
P. Srihari et al. / Tetrahedron Letters 49 (2008) 7132–7134
Tetrahedron Lett. 2003, 44, 4171–4174; (e) Harada, S.; Takita, R.; Oshmia, T.;
O
OH
Matsunaga, S.; Shibasaki, M. Chem. Commun. 2007, 948–950.
8. For recent representative examples see: (a) Wang, Q.; Chen, S.-Y.; Yu, H.-Q.; Pu,
L. Tetrahedron 2007, 63, 4422–4428; (b) Trost, B. M.; Weiss, A. H.; Wangelin, A.
J. J. Am. Chem. Soc. 2006, 128, 8–9.
R"
R'
R'
R"
Zn
R
ZnI
R
I
R
9. Brezhnev, L. Yu.; Vartanyan, M. M.; Khandin, A. V. Chem. Heterocycl. Compd.
1991, 27, 132–134.
Scheme 2. Proposed mechanism for the alkynylation of carbonyl compounds.
10. (a) Munetaka, K.; Shinobu, T.; Kazuhiro, K.; Kazuhito, H.; Shohei, T. Tetrahedron
Lett. 1995, 36, 3707–3710; (b) Munetaka, K.; Daisuke, N.; Shinobu, T.; Kazuhito,
H.; Shohei, T. Tetrahedron 2000, 56, 9927–9936.
11. Jacques, A.; Nadege, L. G.; Latifa, S. Tetrahedron Lett. 2002, 5255–5256.
12. Natalia, M.-V.; Julia, K.; Ilan, M. Synthesis 2000, 917–920.
13. Kazuhiko, T.; Tooru, K.; Shigeki, N.; Koichiro, O.; Hitosi, N. Tetrahedron Lett.
1985, 45, 5585–5588.
reaction conditions and an easy workup procedure make this an
attractive protocol for the synthesis of various aryl propargylic
alcohols.
14. Xuefeng, J.; Hongwei, Y.; Ling, F.; Chengjian, Z. Tetrahedron Lett. 2008, 49,
1370–1372.
Acknowledgments
15. For our earlier contributions with zinc mediated organic transformations see:
(a) Srihari, P.; Singh, A. P.; Basak, A. K.; Yadav, J. S. Tetrahedron Lett. 2007, 48,
5999–6001; (b) Yadav, J. S.; Reddy, B. V. S.; Kondaji, G.; Srinivasa Rao, R.;
Praveen Kumar, S. Tetrahedron Lett. 2002, 43, 8133–8135; (c) Yadav, J. S.;
Meshram, H. M.; Sudershan Reddy, G.; Muralidhar Reddy, M. Synth. Commun.
1998, 28, 2203–2206; (d) Yadav, J. S.; Barma, D. K. Tetrahedron 1996, 52, 4457–
4466.
VKS thanks UGC, New Delhi, and DCB thanks CSIR, New Delhi,
for financial assistance.
References and notes
16. Typical experimental procedure: To
a solution of aldehyde (1 mmol) and
1. (a) Pu, L. Tetrahedron 2003, 59, 9873–9886; (b) Stephane, G.; Aline, B.; Karen, P.;
Annie, L.; Arnaud, H. Chem. Rev. 2006, 106, 2355–2403; (c) Koyuncu, H.; Dogan,
O. Org. Lett. 2007, 9, 3477–3479; (d) Hudrlik, P. F.; Hudrlik, A. M. The Chemistry
of the Carbon–Carbon Triple Bond Part 1. In Patai, S., Ed.; John Wiley and Sons:
New York, 1978; p 256.
2. For examples see: (a) Sierra, M. A.; Torres, M. R. J. Org. Chem. 2007, 72, 4213–
4219; (b) Tominaga, H.; Maezaki, N.; Yanai, M.; Kojima, N.; Urabe, D.; Ueki, R.;
Tanaka, T. Eur. J. Org. Chem. 2006, 1422–1429; (c) Trost, B. M.; Weiss, A. H. Org.
Lett. 2006, 8, 4461–4464.
3. Srihari, P.; Bhunia, D. C.; Sreedhar, P.; Yadav, J. S. Synlett 2008, 1045–
1049.
4. Yadav, J. S.; Bhunia, D. C.; Vamshi Krishna, K.; Srihari, P. Tetrahedron Lett. 2007,
48, 8306–8310.
5. (a) Srihari, P.; Shyam Sunder Reddy, J.; Bhunia, D. C.; Mandal, S. S.; Yadav, J. S.
Synth. Commun. 2008, 38, 1448–1455; (b) Srihari, P.; Shyam Sunder Reddy, J.;
Mandal, S. S.; Satyanaraya, K.; Yadav, J. S. Synthesis 2008, 1853–1860.
6. (a) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984, 25, 4233–
4236; (b) Brown, H. C.; Molander, G. A.; Singh, S. M.; Racherla, U. S. J. Org. Chem.
1985, 50, 1577–1582; (c) Hirao, T.; Misu, D.; Agawa, T. Tetrahedron Lett. 1986,
27, 933–934; (d) Ahn, J. H.; Joung, M. J.; Yoon, N. M.; Oniciu, D. C.; Katrizky, A. R.
J. Org. Chem. 1999, 64, 488–492 and references therein.
7. For a few representative examples see: (a) Yamaguchi, M.; Hayashi, A.; Hirama,
M. Chem. Lett. 1992, 2479–2482; (b) Han, Y.; Huang, Y.-Z. Tetrahedron Lett.
1995, 36, 7277–7280; (c) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem.
Soc. 1999, 121, 11245–11246; (d) Sakai, N.; Hirasawa, M.; Konakahara, T.
iodoacetylene (1 mmol) in THF (3 mL) was added zinc dust (1 mmol), and
the mixture was refluxed for completion of the reaction (TLC). The reaction
mixture was cooled and filtered, and the filtrate was washed with saturated aq
NH4Cl solution. The organic layer was concentrated and the residue was
purified by column chromatography (ethyl acetate/hexane) to yield the pure
product.
17. Spectroscopic data of a few representative examples: 1,3- Diphenyl-prop-2-yn-ol
(3a): Yellow liquid. 1H NMR (200 MHz, CDCl3): d 2.29 (s, 1H), 5.62 (s, 1H), 7.26–
7.46 (m, 8 H), 7.54–7.59 (m, 2H). 13C NMR (75 MHz, CDCl3): 65.02, 86.60, 88.67,
122.34, 126.69, 128.25, 128.37, 128.54, 128.61, 131.70, 140.56. IR (thin film):
757, 1026, 1449, 1489, 1629, 2854, 2924, 3425 cmÀ1. ESIMS: m/z 231 (M++Na).
HRMS calcd for C15H12ONa, 231.0785: found 231.0779. 1,5-Diphenyl-pent-1-en-
4-yn-3-ol (3c): Yellow liquid. 1H NMR (300 MHz, CDCl3): 1.94 (d, J = 5.2 Hz, 1H),
5.22 (t , J = 4.5 Hz, 1H), 6.34 (dd, J = 6.0, 15.8 Hz, 1H), 6.80 (d, J = 15.8 Hz, 1H),
7.20–7.33 (m, 6H), 7.39–7.46 (m, 4H). 13C NMR (75 MHz, CDCl3): d 63.64,
86.65, 88.15, 122.57, 123.56, 127.03, 128.25, 128.32, 128.42, 128.98, 132.22,
123.51, 136.28. IR (thin film): 691, 756, 963, 1489, 2924, 3396 cmÀ1. ESIMS:
m/z 257 (M++Na). HRMS calcd for C17H14ONa,257.0942: found 257.0943. 1-
Cyclohexyl-3-phenyl-prop-2-yn-1-ol (3e): Light yellow liquid. 1H NMR
(200 MHz, CDCl3): d 1.08–1.33 (m, 5H), 1.63–1.94 (m, 7H), 4.31, (t, J = 5.8 Hz,
1H), 7.25–7.30 (m, 3H), 7.37–7.41 (m, 2H). 13C NMR (75 MHz, CDCl3): d 25.59,
25.82, 28.58, 44.21, 67.47, 85.45, 89.31, 122.74, 128.12, 128.2, 131.57. IR (thin
film): 756, 1026, 1447, 2853, 2926, 3387 cmÀ1. ESIMS: m/z 214 (M+). HRMS
calcd for C15H18ONa, 237.1255: found 237.1250.
18. Acetophenone and benzophenone did not respond to the present protocol.