BiCl3-catalyzed propargylic substitution reaction of propargylic alcohols with C-, O-, S- and N-centered nucleophiles

Article abstract of DOI:10.1039/b606470a

A general and efficient BiCl₃-catalyzed substitution reaction of propargylic alcohols with carbon and heteroatom-centered nucleophiles such as allyl trimethylsilane, alcohols, aromatic compounds, thiols and amides, leading to the construction o

Full text of DOI:10.1039/b606470a

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BiCl3-Catalyzed propargylic substitution reaction of propargylic
alcohols with C-, O-, S- and N-centered nucleophiles{
Zhuang-ping Zhan,* Wen-zhen Yang, Rui-feng Yang, Jing-liang Yu, Jun-ping Li and Hui-juan Liu
Received (in Cambridge, UK) 9th May 2006, Accepted 12th June 2006
First published as an Advance Article on the web 27th June 2006
DOI: 10.1039/b606470a
chemical transformations.8 Bismuth trichloride is particularly
A general and efficient BiCl3-catalyzed substitution reaction of
attractive because it not only is commercially available and
inexpensive, but also of high stability. Herein, we report an
efficient BiCl3-catalyzed nucleophilic substitution reaction of
propargylic alcohols bearing not only terminal alkyne groups
but also internal alkyne groups with various carbon- and
heteroatom-centered nucleophiles, to afford the corresponding
products in high yields with complete regioselectivities under mild
reaction conditions.
propargylic alcohols with carbon and heteroatom-centered
nucleophiles such as allyl trimethylsilane, alcohols, aromatic
compounds, thiols and amides, leading to the construction of
C–C, C–O, C–S and C–N bonds, has been developed.
A direct and reliable approach to a wide variety of allylated
products is the allylic substitution reaction of allylic alcohol
derivatives with nucleophiles catalyzed by transition metals.1 In
contrast, related transition metal-catalyzed propargylic substitu-
tion reactions of propargylic alcohol derivatives with nucleophiles
are relatively rare. The flexibility of the alkyne functional group
makes propargylic substitution reaction assume a pivotal role in
organic synthesis. In addition to allowing access to saturated
products by hydrogenation, the alkyne moiety offers a handle for
transformation into various other functional groups.
At first, we investigated the BiCl3-catalyzed coupling reactions
of various propargylic alcohols with allyl trimethylsilane. We were
pleased to find that 10 mol% BiCl3 in acetonitrile at 35 or 60 uC,
successfully produced the substituted 1,5-enynes. Various aryl- and
alkyl-substituted propargylic alcohols (1a–1i) effectively underwent
the BiCl3-catalyzed substitution. Typical results are shown in
Table 1. The reaction proceeded smoothly without exclusion of
moisture or air from the reaction mixture. Electron-rich or
moderately electron-poor aromatic substrates (1g–1h) reacted
smoothly with allyl trimethylsilane affording the corresponding
allylated products in high yields (Table 1, entries 7 and 8), the
substrate with strongly electron-withdrawing CN2 group afforded
the adduct in low yield (Table 1, entry 9). Functional groups, such
as methoxy, bromo and cyano in propargylic alcohols did not
affect the course of the construction of carbon–carbon bonds.
Variation in the alkyne substituent from an alkyl to an aryl,
trimethylsilyl (1a–1c) is well tolerated. Gratifyingly, 1-phenylprop-
2-yn-1-ol (1e) bearing a terminal alkyne group was successfully
TheNicholasreactionhasbeenwidelyacceptedasapowerfultool
for propargylic substitution reaction2 but has some drawbacks: a
stoichiometric amount of [Co2(CO)8] is required, and several steps
are necessary to obtain the propargylic product from propargylic
alcohols via cationic propargylic complexes [Co2(CO)6-
(propargyl)]+.2,3 On the other hand, several transition metal-
catalysed propargylic substitution reactions have been recently
reported. Among them, a ruthenium-catalysed process is a versatile
anddirectmethod.4 Awidevarietyofnucleophilessuchasalcohols,
amines, amides and thiols are available for this reaction.
Nevertheless, with this method, the substrate is generally limited
to propargylic alcohols bearing a terminal alkyne group.5 More
recently, Toste and co-workers6 and Campagne and co-workers7
have described efficient rhenium [(dppm)ReOCl3] and gold
[NaAuCl4?2H2O]catalysednucleophilicsubstitutionofpropargylic
alcohols, respectively. However, the specific and high cost of such
catalysts makes a barrier to their large-scale use. Therefore,
development of a general, efficient, cheap and readily available
catalyst for propargylic substitution reaction is highly desirable.
Recently, bismuth(III) compounds have received attention in
organic synthesis due to their low toxicity, low cost and relative
insensitivity to air and to small amounts of moisture. Bismuth has
an electron configuration of [Xe]4f145d106s26p3. Due to the weak
shielding of the 4f electrons (lanthanide contraction), bismuth(III)
compounds exhibit Lewis acidity and they have been used in many
Table 1 BiCl3-Catalyzed substitution of various propargylic alcohols
1 with allyltrimethylsilane 2a
Isolated yield
Entry R1; R2; R3
Product Time/h of 3 (%)
1
2
3
4
5
6
7
8
9
a
1a, Ph; H; n-Bu
1b, Ph; H; Ph
1c, Ph; H; TMS
1d, CH3; CH3; Ph
1e, Ph; H; H
1f, CH3; H; Ph
1g, o-MeOC6H4; H; n-Bu 3ga
1h, p-BrC6H4; H; n-Bu
1i, p-CNC6H4; H; n-Bu
3aa
3ba
3ca
3da
3ea
3fa
0.5
0.5
3
91
89
78
2
70
24
48
0.5
4
24
61b
10c
86
Department of Chemistry and The Key Laboratory for Chemical Biology
of Fujian Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, 361005, Fujian, P. R. China.
E-mail: zpzhan@xmu.edu.cn; Fax: +86-592-2185780;
Tel: +86-592-2180318
3ha
3ia
87
17b
The reactions of 1 (1 mmol) with allyltrimethylsilane 2 (3 mmol)
were carried out in the presence of BiCl3 (0.1 mmol) in CH3CN
b
c
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b606470a
(2 mL) at 35 uC. At 60 uC for 24 h. At 60 uC for 48 h.
3352 | Chem. Commun., 2006, 3352–3354
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Table 2 BiCl3-catalyzed substitution of various propargylic alcohols
1 with various nucleophiles 2a
Table 2 BiCl3-catalyzed substitution of various propargylic alcohols
1 with various nucleophiles 2a (Continued)
Isolated yield
Isolated yield
Entry R1; R2; R3
Nu
Time/h of 3 (%)
Entry R1; R2; R3
Nu
Time/h of 3 (%)
1
2
3
4
5
1a, Ph; H; n-Bu
0.5
12
3ab, 89
3bb, 83
3cb, 85
3db, 65
3ac, 66
22
23
a
1b, Ph; H; Ph
6
3bk, 80
3ee, 46b
1b, Ph; H; Ph
1e, Ph; H; H
24
1c, Ph; H; TMS
1d, CH3; CH3; Ph
1a, Ph; H; n-Bu
3
2
1
The reactions of 1 (1 mmol) with 2 (3 mmol) were carried out in
b
the presence of BiCl3 (0.1 mmol) in CH3CN (2 mL) at 35 uC. The
reaction were carried out at 60 uC.
6
7
8
1a, Ph; H; n-Bu
1d, CH3; CH3; Ph
1c, Ph; H; TMS
2
15
3
3ad, 84
3dc, 75
3cc, 75
allylated in 61% isolated yield at 60 uC, and no polymerization was
detected (Table 1, entry 5). Compared with secondary benzylic
alcohols 1b and 1e, secondary aliphatic substrate 1f reacted more
sluggishly to give the desired 1,5-enyne product in lower yield
(Table 1, entry 6 cf. entries 2 and 5). The primary aliphatic alcohol
3-phenylprop-2-yn-1-ol (R1, R2 = H) failed to give allylated
product. The experimental results suggest a mechanism through
the formation of a propargylic cation intermediate. The instability
of the propargylic cation intermediate clearly made the substitu-
tion reaction less favourable. Under the same conditions, the
reaction of propargylic alcohols with allyltrimethylsilane, catalyzed
by Lewis acid B(C6F5)3, did not afford the desired 1,5-enynes but
instead the corresponding silyl ether; while with propargylic esters
substitution proceeded successfully to give the desired 1,5-enynes in
good yields.9c Several Lewis acid-catalyzed nucleophilic substitu-
tion reactions of propargylic esters have been reported.9a–e
We next extended the propargylic substitution by employing
heteroatom-centered and aromatic nucleophiles. All reactions
proceeded in the presence of 10 mol% BiCl3 in acetonitrile.
Typical results are shown in Table 2.
9
1b, Ph; H; Ph
1b, Ph; H; Ph
0.5
3bc, 93
3bd, 85
10
0.5
1
11
12
1e, Ph; H; H
1b, Ph; H; Ph
3eb, 50
3be, 60
4
13
1b, Ph; H; Ph
0.5
0.5
3bf, 94
14
15
16
1b, Ph; H; Ph
1e, Ph; H; H
1b, Ph; H; Ph
3bg, 90
3ec, 62b
3bh, 90
A series of alcohols as the nucleophiles were firstly treated with
various propargylic alcohols (1a–1d) and the corresponding
propargylic ethers were obtained in good yields with complete
regioselectivity (Table 2, entries 1–7). Functional groups such as
alkenyl (Table 2, entry 2) and chloro (Table 2, entries 1, 3 and 4) in
the alcohol were readily carried through the reaction, allowing for
the subsequent elaboration of the products after the propargylic
etherification event. The reaction is not limited to benzylic
substrates. For example, tertiary alcohol 1d readily undergoes
propargylic etherification to give the tertiary ether in 65 and 75%
isolated yield, respectively (Table 2, entries 4 and 7). Notably, the
use of ethanol as nucleophile did not lead to the formation of
the rearranged enone which was obtained as the main product in
the process catalyzed by gold(III) (Table 2, entries 6 and 7).10
Similarly, reactions of propargylic alcohols bearing a terminal
alkyne group or an internal alkyne group with various aromatic
compound nucleophiles were also carried out (Table 2, entries
8–15). The corresponding Friedel–Crafts arylated products were
obtained from the heteroaromatic furan and pyrrole in 85, 50, 60%
yields with complete regioselectivity (Table 2, entries 10–12).
24
0.5
17
18
19
1b, Ph; H; Ph
1a, Ph; H; n-Bu
1e, Ph; H; H
1
3bi, 89
3ae, 90
3ed, 55b
0.5
6
20
21
1b, Ph; H; Ph
3
7
3bj, 75b
3af, 60b
1a, Ph; H; n-Bu
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Propargylation occurred selectively at the a-position of the
heterocyclic rings. Electron-rich aromatic compounds such as
1,3-dimethoxybenzene, phenol, b-naphthol and 2-methoxy-
naphthalene reacted smoothly with propargylic alcohols affording
the corresponding propargylated compounds in moderate to
excellent yields (Table 2, entries 8, 9 and 13–15). The high yield
formation of Friedel–Crafts arylated products were obtained in the
reaction of phenol, b-naphthol and 2-methoxynaphthalene with
1,3- diphenylprop-2-yn-1-ol (1b) (Table 2, entries 9, 13 and 14). In
the processes involving furan and b-naphthol, the substrate
bearing a terminal alkyne group gave the propargylic adduct in
lower yields (Table 2, entry 11 cf. 10; entry 15 cf. 13). In all cases,
propargylation occurred selectively at the electron-rich position of
aromatic compounds. The result indicated that the reaction
proceeds electrophilically.
The research was financially supported by the National Natural
Science Foundation of China (NO. 30572250).
Notes and references
1 For recent reviews, see: (a) J. Tsuji, Palladium Reagents and Catalysts,
John Wiley & Sons, New York, 1995; (b) B. M. Trost and D. L.
Van Vranken, Chem. Rev., 1996, 96, 395; (c) B. M. Trost and C. Lee, in
Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New York,
2000, ch. 8E.
2 Review articles: (a) K. M. Nicholas, Acc. Chem. Res., 1987, 20, 207; (b)
A. J. M. Caffyn and K. M. Nicholas, in Comprehensive Organometallic
Chemistry II, ed. E. W. Abel, F. G. A. Stone and G. Wilkinson,
Pergamon Press, Oxford, 1995, vol. 12, ch. 7.1, p. 685; (c) J. R. Green,
Curr. Org. Chem., 2001, 5, 809; (d) B. J. Teobald, Tetrahedron, 2002, 58,
4133; (e) O. Kuhn, D. Rau and H. Mayr, J. Am. Chem. Soc., 1998, 120,
900.
3 K. M. Nicholas, M. Mulvaney and M. Bayer, J. Am. Chem. Soc., 1980,
102, 2508.
Transition metal-catalysed coupling of propargylic alcohols with
thiols has seldom been reported, probably due to that sulfur-
containing compounds are catalyst poisons because of their strong
coordinating properties.11,5b Gratifyingly, by employing 10 mol%
BiCl3 as the catalyst, the construction of sp3 C–S bonds was
achieved by the nucleophilic substitution of propargylic alcohols
with a series of thiols. Propargylic alcohols possessing alkyl or aryl
substituents on the alkyne part reacted rapidly with various thiols
such as benzenethiol and mercaptoethanol affording the corre-
sponding sulfide products in excellent yields with complete
regioselectivity (Table 2, entries 16–18). In contrast to the result
obtained when using phenol as nucleophile, no Friedel–Crafts
arylated product was detected while using benzenethiol as the
nucleophile, and the propargylic sulfide was the only product
(Table 2, entry 16 cf. 9). Remarkably, the hydroxy moiety is well
tolerant in the reaction; 10 mol% BiCl3 efficiently catalysed the
propargylation of mercaptoethanol while avoiding competitive
O-alkylation and the formation of the propargylic ethers. Hydroxy
and phenyl moieties contained in the propargylic sulfides provide a
handle for transformation into a variety of other functional
groups. However, the propargylic alcohol bearing terminal alkyne
group participated in the substitution reaction to give propargylic
adduct in lower yields (Table 2, entry 19).
4 (a) Y. Nishibayashi, I. Wakiji and M. Hidai, J. Am. Chem. Soc., 2000,
122, 11019; (b) Y. Nishibayashi, I. Wakiji, Y. Ishii, S. Uemura and
M. Hidai, J. Am. Chem. Soc., 2001, 123, 3393; (c) Y. Nishibayashi,
M. Yoshikawa, Y. Inada, M. Hidai and S. Uemura, J. Am. Chem. Soc.,
2002, 124, 11846; (d) Y. Nishibayashi, M. Yoshikawa, Y. Inada,
M. D. Milton, M. Hidai and S. Uemura, Angew. Chem., Int. Ed., 2003,
42, 2681; (e) M. D. Milton, Y. Inada, Y. Nishibayashi and S. Uemura,
Chem. Commun., 2004, 2712; (f) Y. Nishibayashi, M. D. Milton,
Y. Inada, M. Yoshikawa, I. Wakiji, M. Hidai and S. Uemura, Chem.-
Eur. J., 2005, 11, 1433; (g) Y. Nishibayashi, Y. Inada, M. Hidai and
S. Uemura, J. Am. Chem. Soc., 2002, 124, 7900.
5 The ruthenium-catalyzed propargylic substitution was reported to run
via allenylidene complex intermediates which can be produced only from
propargylic alcohols bearing a terminal alkyne group, see ref. 4; on the
other hand, ruthenium-catalyzed substitution of propargylic alcohols
bearing an internal alkyne group were also investigated, see: (a)
Y. Nishibayashi, Y. Inada, M. Yoshikawa, M. Hidai and S. Uemura,
Angew. Chem., Int. Ed., 2003, 42, 1495; (b) Y. Inada, Y. Nishibayashi,
M. Hidai and S. Uemura, J. Am. Chem. Soc., 2002, 124, 15172.
6 (a) M. R. Luzung and F. D. Toste, J. Am. Chem. Soc., 2003, 125, 15760;
(b) B. D. Sherry, A. T. Radosevich and F. D. Toste, J. Am. Chem. Soc.,
2003, 125, 6076; (c) J. J. Kennedy-Smith, L. A. Young and F. D. Toste,
Org. Lett., 2004, 6, 1325.
7 M. Georgy, V. Boucard and J. M. Campagne, J. Am. Chem. Soc., 2005,
127, 14180.
8 (a) H. Suzuki, T. Ikegami and T. Matano, Synthesis, 1997, 249; (b)
N. M. Leonard, L. C. Wieland and R. S. Mohan, Tetrahedron, 2002, 58,
8373; (c) M. Postel and E. Dunach, Coord. Chem. Rev., 1996, 155, 127.
9 The significant characteristic feature of this reaction is the direct use of
propargylic alcohols as the substrates. For nucleophilic substitution of
propargylic esters, see: (a) R. Mahrwald and S. Quint, Tetrahedron Lett.,
2001, 42, 1655; (b) Y. Imada, M. Yuasa, I. Nakamura and
S. I. Murahashi, J. Org. Chem., 1994, 59, 2282; (c) T. Schwier,
M. Rubin and V. Gevorgyan, Org. Lett., 2004, 6, 1999; (d)
R. Mahrwald, S. Quint and S. Scholtis, Tetrahedron, 2002, 58, 9847;
(e) A. Bartels, R. Mahrwald and S. Quint, Tetrahedron Lett., 1999, 40,
5989; (f) T. Kondo, Y. Kanda, A. Baba, K. Fukuda, A. Nakamura,
K. Wada, Y. Morisaki and T. A. Mitsudo, J. Am. Chem. Soc., 2002,
124, 12960.
Finally, selected amides also acted as efficient nucleophiles to
give corresponding propargylic amides in moderate to good yields.
The employing of benzamide and p-toluenesulfonamide effectively
led to the formation of C–N bonds. Unfortunately, no
propargylation occurred under these conditions when acetamide,
aniline and piperidine were used as the nucleophiles.
In summary, we have developed a general and efficient BiCl3-
catalyzed substitution reaction of propargylic alcohols with carbon
and heteroatom-centered nucleophiles such as allyl trimethylsilane,
alcohols, aromatic compounds, thiols and amides, leading to the
construction of C–C, C–O, C–S and C–N bonds. Propargylic
alcohols bearing a terminal alkyne group or internal alkyne group
are readily available.9 The corresponding propargylic products
were obtained in high yields with complete regioselectivity. In
comparison with cobalt, rhenium, ruthenium and gold complexes,
which are usually used to catalyse the nucleophilic substitution of
propargylic alcohols, BiCl3 as the catalyst offers several relevant
advantages including cheapness and commercial availability,
broad scope and mild reaction conditions of this transformation.
Further development on this methodology is currently under way
in our laboratory.
10 In gold(III)-catalyzed nucleophilic substitution of propargylic alcohol
with ethanol, the rearranged unsaturated ketones are obtained in good
yield. For details, see: M. Georgy, V. Boucard and J. M. Campagne,
J. Am. Chem. Soc., 2005, 127, 14180.
11 L. L. Hegedus and R. W. McCabe, Catalyst Poisoning, Marcel Dekker,
New York, 1984.
3354 | Chem. Commun., 2006, 3352–3354
This journal is ß The Royal Society of Chemistry 2006