Direct substitution of propargylic alcohol with oxygen, nitrogen, and carbon nucleophiles catalyzed by molybdenum(VI)

Article abstract of DOI:10.1016/j.tetlet.2009.12.128

Efficient and direct substitution of propargylic alcohol with a variety of oxygen, nitrogen, and carbon nucleophiles catalyzed by MoO₂(acac)₂/NH₄PF₆ system was developed. The functional alkynes were obtained in modest to good yields with this versatile and practical protocol.

Full text of DOI:10.1016/j.tetlet.2009.12.128

Tetrahedron Letters 51 (2010) 1176–1179
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct substitution of propargylic alcohol with oxygen, nitrogen,
and carbon nucleophiles catalyzed by molybdenum(VI)
a
a,b,
Ming Zhang a, Hongwei Yang a, Yixiang Cheng a, , Yuhua Zhu , Chengjian Zhu
*
*
a State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient and direct substitution of propargylic alcohol with a variety of oxygen, nitrogen, and carbon
nucleophiles catalyzed by MoO2(acac)2/NH4PF6 system was developed. The functional alkynes were
obtained in modest to good yields with this versatile and practical protocol.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 9 October 2009
Revised 14 December 2009
Accepted 14 December 2009
Available online 4 January 2010
Keywords:
Molybdenum
Nucleophilic substitution
Propargylation
Alcohols
It is well known that propargylic alcohols represent an impor-
tant group of chemical intermediates for the synthesis of many
natural products and pharmaceuticals.1 The direct substitution of
propargyl alcohols would constitute a straightforward method
for the synthesis of functional alkynes, which can readily convert
to a variety of other functional groups.2 Nucleophilic substitution
of the hydroxy group in propargylic alcohol usually requires a mul-
tistep synthesis because of its poor leaving ability. Consequently,
the hydroxyl group generally transforms into a more reactive sub-
stituent, such as halide, carboxylate, carbonate, phosphonate,
sulfonate, or other related compounds with good leaving ability.
However, in these processes, both preactivation process and subse-
quent substitution process of the halides and related compounds
inevitably produce stoichiometric amounts of salt waste. There-
fore, the direct catalytic substitution of propargylic alcohols is a
desirable method for development. The Nicholas group reported
the first example of the direct substitution of propargylic alcohol
catalyzed by cobalt.3 As it is considered an ideal and more efficient
way, the direct substitution of propargylic alcohols (Scheme 1) has
emerged as an attractive area of research.4 So far, direct substitu-
tion of propargylic alcohols has been examined with some transi-
tion metals or brønsted acid catalysts, including ruthenium,5
rhenium,6 gold,7 indium,8 bismuth2a,9 and p-toluenesulfonic acid,10
under different conditions. Nevertheless, these catalysts often
restrict to catalyze the substitution with limited nucleophiles.
Nu
R3
OH
R3
cat.
R1
R1
NuH
R2
R2
Scheme 1. The direct substitution of propargylic alcohols.
Table 1
Nucleophilic substitution of 1,3-diphenylprop-2-yn-1-ol (A) with phenylmethanol (B)
under different conditionsa
OH
A
O
MoO2(acac) 2, 10 mol%
NH4PF6, 10 mol% 65 °C
OH
+
B
C
Entry
Catalyst
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8c
MoO2(acac)2
MoO2(acac)2
—
MoO2(acac)2
MoO2(acac)2
MoO2(acac)2
MoO2(acac)2
MoO2(acac)2
—
CH3CN
CH3CN
CH3CN
Toluene
CH3NO2
Dioxane
DMF
18
67
—
56
61
11
24
15
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
CH3CN
a
Reaction conditions: A (0.5 mmol), B (1.5 mmol), catalyst (0.05 mmol), 65 °C,
6 h.
b
Isolated yields.
* Corresponding authors. Tel.: +86 25 83594886; fax: +86 25 83317761 (C.Z).
E-mail address: cjzhu@nju.edu.cn (C. Zhu).
c
A (0.5 mmol), B (1.5 mmol), catalyst (0.025 mmol), 65 °C, 6 h.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.128

M. Zhang et al. / Tetrahedron Letters 51 (2010) 1176–1179
1177
Table 2
MoO2(acac)2-catalyzed substitution of propargylic alcohol with various oxygen, nitrogen and carbon nucleophiles
Entry
Propargylicalcohol
NuH
Time (h)
Product
Yieldsa (%)
OH
O
OH
1
6
67
53
93
A
OMe
OEt
2b
3b
A
MeOH
EtOH
18
12
A
A
O
S NH2
O
O
NH
S
O
4
10
65
NO2
NH2
NO2
NH
5
6
A
A
1
82
70
O2N
O2N
NH2
NH
0.5
S
S
7
8
A
A
4
41
40
HN
N
H
12
OMe
OMe
OH
9
A
A
1
90
81
OH
10
0.5
O
O
O
O
O
O
O
11
12
A
6
5
83
75
OH
O
D
OM e
OMe
O
S NH2
O
O
NH
S
O
13
14
D
5
5
5
68
OMe
NO2
OH
O
O
O
O
E
NR
NR
NO2
O
S NH2
O
O
S
NH
O
15
A
NO2
a
Isolated yields .
Thirty-three equivalents of nucleophiles were used.
b

1178
M. Zhang et al. / Tetrahedron Letters 51 (2010) 1176–1179
Therefore, a versatile catalyst which can catalyze the substitution
with a wide scope of nucleophiles is desirable.
reactivity is lower. When anisole and phenol were used, the corre-
sponding para-carbon-substituted products were obtained in 90%
and 81% yields, respectively (entries 9 and 10). The desired product
was also obtained in good isolated yield when A was treated with
1,3-diketone.
Other propargylic alcohols were also examined as substrates.
The reaction of 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-ol (D)
with acetylacetone and 4-methylbenzenesulfonamide at 65 °C for
5 h gave the corresponding propargylic products (entries 12, and
13) in moderate yields. Unfortunately, 1-(4-nitrophenyl)-3-phe-
nylprop-2-yn-1-ol (E) failed to give the products under the same
conditions. 3-Phenylprop-2-yn-1-ol and 1-phenylpent-1-yn-3-ol
were also explored with this catalyst system, and no products were
detected.
A possible mechanism for molybdenum-catalyzed direct substi-
tution of propargylic alcohol with different nucleophiles is shown
in Scheme 2. It is supposed that the transition state involves prop-
argyl alcohol combined with molybdenum complex to form inter-
mediate F, which was followed by [3,3] rearrangement to form
allenolate G.6a,18 Nucleophile attacks allenolate G to give the corre-
sponding product. In the cases of 3-phenylprop-2-yn-1-ol and 1-
phenylpent-1-yn-3-ol, it could not be easy for the transformation
of intermediate F to G with less conjugated effect. So they showed
no reactivity with this catalyst system.
In summary, we have developed direct substitution of propar-
gylic alcohol using MoO2(acac)2/NH4PF6 as catalyst. The reaction
is compatible with a wide range of nitrogen, oxygen, and carbon
nucleophiles. The functional alkynes can be obtained in modest
to good yields with this versatile and practical protocol.
Molybdenum(VI) compounds constitute a family of significant
compounds in chemistry. Several industrial processes such as ole-
fin epoxidation, olefin metathesis, and ammoxidation are carried
out with molybdenum(VI) catalysts.11 Furthermore, molybde-
num(VI) has been found to have a role in the biological systems,
many molybdenum(VI) complexes have been studied as models
of molybdoenzymes.12 However, most of the applications of
molybdenum(VI) complexes in organic synthesis are focused on
oxidation and polymerization.13 Reddy reported the direct amida-
tion of secondary benzyl alcohols with sulfonamides and carba-
mates in the presence of molybdenum(V) chloride in 2007.14 We
have recently reported the molybdenum-catalyzed asymmetric
pinacol coupling reaction of aromatic aldehydes15 and direct
nucleophilic substitution of allylic alcohols with various nucleo-
philes.16 In this context, the direct nucleophilic substitution of
propargylic alcohols catalyzed by MoO2(acac)2/NH4PF6 system
with oxygen, nitrogen, and carbon nucleophiles will be discussed.
Asapreliminarystudy, wetreated1,3-diphenylprop-2-yn-1-ol(A)
with phenylmethanol (B) (3 equiv) in the presence of MoO2(acac)2
(10 mol %) in acetonitrile, the reaction mixture was heated to 65 °C
for 6 h, and the desired product (3-(benzyloxy)prop-1-yne-1,3-
diyl)dibenzene (C) could be obtained in 18% (Table 1, entry 1). The
higher yield was obtained by using NH4PF6 (10 mol %) as an additive
(Table 1, entry 2), whereas NH4PF6 alone showed no catalytic activity
(Table 1, entry 3). The reaction took place without exclusion of air or
moisture from the reaction mixture. When the reaction was carried
out in toluene or nitromethane, a decrease in reactivity was observed
(Table 1, entries4 and 5). When dioxaneandDMF were used, only11%
and24% yieldswereobtained, respectively(Table 1, entries6 and7). It
should be noted that lower yield would be obtained when decreasing
the catalyst loading (Table 1, entry 8).
Acknowledgments
We gratefully acknowledge the National Natural Science
Foundation of China (20672053, 20832001, and 20972065) and
the National Basic Research Program of China (2007CB925103,
2010CB923303) for their financial support. The program for New
Century Excellent Talents in the University of China (NCET-06-
0425) is also acknowledged.
We applied the optimized reaction procedure17 to the reaction
of 1,3-diphenylprop-2-yn-1-ol with methanol and ethanol. The re-
sults for alcohols are shown in Table 2 (entries 1–3). Methanol gave
the desired propargylic ether in moderate yields, while ethanol
provided the product in excellent yield. Campagne reported that
the rearranged unsaturated ketones were obtained in high yields
in gold-catalyzed the substitution reaction of propargylic alcohols
in the presence of ethanol and 5% of NaAuCl4Á2H2O.7a
References and notes
1. (a) Trost, B. M.; Krische, M. J. J. Am. Chem. Soc. 1999, 121, 6131; (b) Fox, M. E.; Li,
C.; Marino, J. P. J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467; (c) Corey, E.
J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151; (d) Vourloumis, D.; Kim, K.
D.; Petersen, J. L.; Magriotis, P. A. J. Org. Chem. 1996, 61, 4848.
2. (a) Zhan, Z. P.; Yang, W. Z.; Yang, R. F.; Yu, J. L.; Li, J. P.; Liu, H. J. Chem. Commun.
2006, 3352; (b) Zhan, Z. P.; Yu, J. L.; Liu, H. J.; Cui, Y. Y.; Yang, R. F.; Yang, W. Z.;
Li, J. P. J. Org. Chem. 2006, 71, 8298.
3. (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207; (b) Green, J. R. Curr. Org. Chem.
2001, 5, 809; (c) Teobald, B. J. Tetrahedron 2002, 58, 4133.
4. Reviews see: (a) Kabalka, G. W.; Yao, M. L. Curr. Org. Synth. 2008, 5, 28; (b)
Ljungdahl, N.; Kann, N. Angew. Chem., Int. Ed. 2009, 48, 642.
5. (a) Nishibayashi, Y.; Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S. Angew.
Chem., Int. Ed. 2003, 42, 1495; (b) Inada, Y.; Nishibayashi, Y.; Uemura, S. Angew.
Chem., Int. Ed. 2005, 44, 7715; (c) Nishibayashi, Y.; Shinoda, A.; Miyake, Y.;
Matsuzawa, H.; Sato, M. Angew. Chem., Int. Ed. 2006, 45, 4835; (d) Matsuzawa,
H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2007, 46, 6488.
6. (a) Sherry, B. D.; Radosevich, A. T.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 6076;
(b) Luzung, M. R.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 15760; (c) Kennedy-
Smith, J. J.; Yong, L. A.; Toste, F. D. Org. Lett. 2004, 6, 1325.
7. (a) Georgy, M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc. 2005, 127, 14180;
(b) Georgy, M.; Boucard, V.; Ddbleds, O.; Zotto, C. D.; Campagne, J.-M.
Tetrahedron 2009, 65, 1758.
8. Yadav, J. S.; Reddy, B. V. S.; Rao, K. V. R.; Kumar, G. G. K. S. N. Synthesis 2007,
3205.
In order to check the scope of this process, we performed a set
of experiments with several nitrogen nucleophiles. The results are
summarized in Table 2 (entries 4–6). TsNH2 provided the corre-
sponding product in a long time with moderate yield (entry 4).
On the other hand, the electron-withdrawing group-substituted
aromatic amines, 2-nitroaniline and 4-nitroaniline, showed higher
reactivity (entries 5 and 6).
To further demonstrate the utility of this catalytic system, thio-
phene (entry 7) and pyrrole (entry 8) were also investigated as
nucleophiles. The
a-carbon-substituted products were obtained
in the yields of 41% and 40%, respectively. This implies that the
C–C bond can be formed through this procedure, although the
OH
Nu
R1
MoO2(acac)2
R1
R2
R2
9. Qin, H.; Yamagiwa, N.; Matsunaga, Y.; Matsunaga, S.; Sbibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409.
10. (a) Sanz, R.; Martinez, A.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Eur. J. Org.
Chem. 2006, 1383; (b) Sanz, R.; Miguel, D.; Martinez, A.; Alvarez-Gutierrez, J.
M.; Rodriguez, F. Org. Lett. 2007, 9, 727.
11. (a) Stiefel, E. L. Molybdenum, 4th ed.. In Kirk-Othmer Encyclopedia of Chemical
Technology; Wiley: New York, 1995; Vol. 16, p 940; (b) Braithwaite, E. R.;
Haber, J. Molybdenum: An Outline of Its Chemistry and Uses; Elsevier:
Amsterdam, 1994.
NuH
O
O
Ln
Mo
Ln
Mo
O
O
O
O
R1
R1
R2
[3, 3]
R2
F
G
Scheme 2. The plausible reaction mechanism.

M. Zhang et al. / Tetrahedron Letters 51 (2010) 1176–1179
1179
12. Enemark, J. H.; Cooney, J. J. A.; Wang, J. J.; Holm, R. H. Chem. Rev. 2004, 104,
1175.
was added to a solution of MoO2(acac)2 (16 mg, 0.05 mmol) and NH4PF6 (9 mg,
0.05 mmol) in acetonitrile (2 ml) at 65 °C, and the resulting mixture was stirred
for 5 min before the addition of propargylic alcohol (0.5 mmol). The mixture
was stirred at this temperature and the reaction was monitored by TLC
analysis. After the reaction was complete, the mixture was then cooled to room
temperature and directly purified by flash chromatography on silica gel to
afford the corresponding product.
13. Kühn, F. E.; Santos, A. M.; Abrantes, M. Chem. Rev. 2006, 106, 2455.
14. Reddy, C. R.; Madhavi, P. P.; Reddy, A. S. Tetrahedron Lett. 2007, 48, 7169.
15. Yang, H. W.; Wang, H. S.; Zhu, C. J. J. Org. Chem. 2007, 72, 10029.
16. Yang, H. W.; Fang, L.; Zhang, M.; Zhu, C. J. Eur. J. Org. Chem. 2009, 666.
17. General procedure for MoO2(acac)2-catalyzed direct substitution of propargylic
alcohol with versatile nucleophiles: The corresponding nucleophile (1.5 mmol)
18. Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230.