Lewis acid catalyzed propargylation of arenes with O-propargyl trichloroacetimidates: Synthesis of 1,3-diarylpropynes

Article abstract of DOI:10.1021/jo0709192

(Chemical Equation Presented) The BF₃·OEt ₂-catalyzed Friedel-Crafts propargylation of aromatic compounds with O-propargyl trichloroacetimidates is highly efficient and affords 1,3-diarylpropyne derivatives in good yields.

Full text of DOI:10.1021/jo0709192

methods are usually limited to secondary propargyl alcohols
and electron-rich aromatic substrates, and the catalysts are
expensive and/or not easily available in some cases. Conse-
quently, the development of new methods for synthesizing 1,3-
diarylpropynes is still highly desirable.
Lewis Acid Catalyzed Propargylation of Arenes
with O-Propargyl Trichloroacetimidates:
Synthesis of 1,3-Diarylpropynes
Changkun Li and Jianbo Wang*
Friedel-Crafts propargylation of aromatics can afford aro-
matic compounds bearing propargyl substituents. This type of
reaction has been investigated previously with propargyl halides,
but the products are either propargylated or allenylated aromatic
products or a mixture of them.5,6 This is attributed to the
electronic and structure feature of the propargyl cation inter-
mediate, which has ambident reactivity that is largely dictated
by the substitution pattern (Scheme 1).7 Recently, Ishikawa and
Saito reported silyl ether as a leaving group in TMSOTf-
catalyzed reactions. It generated propargyl cation, which was
further reacted with electron-rich arenes.6a Rodr´ıguez and co-
workers have utilized p-TsOH as a catalyst in the substitution
of propargyl alcohol with aromatics.8 However, these reactions
need secondary alcohols and electron-rich arenes as substrates.
Here, we report a highly efficient BF3‚OEt2-catalyzed Friedel-
Crafts propargylation of unactivated arenes. This reaction
provides a powerful method for the synthesis of 1,3-diarylpro-
pyne derivatives.
Beijing National Laboratory of Molecular Sciences (BNLMS),
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry,
Peking UniVersity, Beijing 100871, China
wangjb@pku.edu.cn
ReceiVed May 2, 2007
The BF3‚OEt2-catalyzed Friedel-Crafts propargylation of
aromatic compounds with O-propargyl trichloroacetimidates
is highly efficient and affords 1,3-diarylpropyne derivatives
in good yields.
The key feature of this approach is the utilization of
O-propargyl trichloroacetimidates as the propargylation agents.
Trichloroacetimidates have been widely used in organic syn-
thesis.9 In particular, they have been frequently utilized in the
acid-catalyzed C-O bond forming reactions because the trichlo-
roacetimidoxy group can be a good leaving group under mild
acidic conditions.10 For example, converting the O,O-hemiac-
1,3-Diarylpropynes are versatile building blocks in organic
synthesis. The methods for access to this type of compounds
include reaction of aryl Grignard reagent with propargyl halide
and transition metal catalyzed cross-coupling reaction with
organometallic reagents.1,2 The reaction of arenes with dico-
balthexacarbonyl-complexd propargyl cation, known as the
Nicholas reaction, has been widely applied.3 However, its
drawback of the use of stoichiometric amounts of cobalt
complex cannot be neglected. Recently, transition metal cata-
lyzed propargylations of electron-rich arenes with propargyl
alcohols have been reported.2a-c,4 Although these reactions are
mechanistically interesting, they have limitations in one way
or another as synthetic methodologies. For example, these
(5) Olah, G. A. In Friedel-Crafts and Related Reactions; Interscience:
New York, 1964.
(6) (a) Ishikawa, T.; Okano, M.; Aikawa, T.; Saito, S. J. Org. Chem.
2001, 66, 4635-4642. (b) Mu¨ller, T. J. J. Eur. J. Org. Chem. 2001, 2021-
2033.
(7) (a) Olah, G. A.; Spear, R. J.; Westerman, P. W.; Denis, J. M. J. Am.
Chem. Soc. 1974, 96, 5855-5859. (b) Prakash, G. K. S.; Krishnamurthy,
V. V.; Olah, G. A.; Farnum, D. G. J. Am. Chem. Soc. 1985, 107, 3928-
3935. (c) Krishnamurthy, V. V.; Prakash, G. K. S.; Iyer, P. S.; Olah, G. A.
J. Am. Chem. Soc. 1986, 108, 1575-1579. (d) Olah, G. A.; Krishnamurthy,
R.; Prakash, G. K. S. J. Org. Chem. 1990, 55, 6061-6062.
(1) (a) Pe´rez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc. 2001,
123, 4155-4160. (b) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2004,
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Tetrahedron Lett. 2005, 46, 2927-2930.
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(9) For selected examples, see: (a) Oishi, T.; Ando, K.; Chida, N. Chem.
Commun. 2001, 1932-1933. (b) Oishi, T.; Ando, K.; Inomiya, K.; Sato,
H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151-154. (c) Armstrong, A.;
Brackenridge, I.; Jackson, R. F. W.; Kirk, J. M. Tetrahedron Lett. 1988,
29, 2483-2486. (d) Overman, L. E. Acc. Chem. Res. 1980, 13, 218-224.
(e) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
12225-12231. (f) Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc. 2005,
127, 2866-2867. (g) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc.
2003, 125, 12412-12413. (h) Hashmi, A. S. K.; Rudolph, M.; Schymura,
S.; Visus, J.; Frey, W. Eur. J. Org. Chem. 2006. 4905-4909.
(10) (a) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. 1980, 19,
731-732. (b) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun.
1981, 1240-1241. (c) Schmidt, R. R.; Michel, J. Tetrahedron Lett. 1982,
23, 409-412. (d) Wessel, H. -P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2247-2250. (e) Schmidt, R. R. Angew. Chem., Int.
Ed. 1986, 25, 212-235. (f) Roussel, F.; Knerr, L.; Grathwohl, M.; Schmidt,
R. R. Org. Lett. 2000, 2, 3043-3046. (g) Roussel, F.; Takhi, M.; Schmidt,
R. R. J. Org. Chem. 2001, 66, 8540-8548. (h) Abdel-Rahman, A. A.-H.;
Jonke, S.; El Ashry, E. S. H.; Schmidt, R. R. Angew. Chem., Int. Ed. 2002,
41, 2972-2974. (i) El-Nezhawy, A. O. H.; El-Diwani, H. I.; Schmidt, R.
R. Eur. J. Org. Chem. 2002, 4137-4142. (j) Abdel-Rahman, A. A. -H.;
Winterfeld, G. A.; Takhi, M.; Schmidt, R. R. Eur. J. Org. Chem. 2002, 713-
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(2) (a) Nishibayashi, Y.; Shinoda, A.; Miyake, Y.; Matsuzawa, H.; Sato,
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10.1021/jo0709192 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/23/2007
J. Org. Chem. 2007, 72, 7431-7434
7431

TABLE 2. Reaction of 2a-k and Benzene with BF3‚OEt2 as
SCHEME 1. Friedel-Crafts Propargylation of Aromatics
Catalysta
TABLE 1. Reaction of 2a and Benzene with Various Acid
Catalystsa
reaction
time
yieldb
(%)
entry
cat. (mol %)
TMSOTf (10)
AuCl (5) + AgOTf (5)
AuPPh3Cl (5) + AgSbF6 (5)
BF3‚OEt (30)
TfOH (10)
TsOH·H2O (10)
Zn(OTf)2 (5)
T (°C)
1
2
3
4
5
6
7
8
25
80
80
25
25
25
25
25
2 h
74
35
65
20 min
20 min
5 min
12 h
18 h
12 h
85
NRc
NR
NR
NR
a The reaction was carried out in benzene solution. b Isolated yield. c The
reaction gave a complex mixture.
Cu(CH3CN)4PF6 (5)
12 h
a Bezene used as solvent. b Isolated yield. c Starting material remains
unchanged.
catalysts, including TMSOTf, AuOTf, AuPPh3Cl/AgSbF6, and
BF3‚OEt2 (Table 1, entries 1-4). Among them, BF3‚OEt2 was
found to be particularly effective. With 30 mol % of BF3‚OEt2,
the reaction could be completed in 5 min at room temperature,
affording 3a in 85% isolated yield (entry 4). When less BF3‚
OEt2 was used, the reaction took a longer time and the yield
was diminished. Since BF3‚OEt2 is cheap and easily available,
the propargylation under the BF3‚OEt2-catalyzed conditions is
therefore practically useful. It was also noted that acids such as
TfOH, TsOH, Cu(MeCN)4PF6, and Zn(OTf)2 did not catalyze
this reaction (entries 5-8).
With the optimized conditions in hand, we next examined
the scope and limitation of this reaction. First, the scope of
O-propargyl trichloroacetimidates was examined. As shown in
Table 2, the reaction has good substituent tolerance in the alkyne
moiety. The substrate with strong electron-withdrawing sub-
stituent such as p-NO2 worked well to give the expected
propargylation product 3e in high yield (entry 5). This might
be attributed to the destabilization effects of p-NO2, which
makes the allenyl cation structure unfavorable as compared with
the propargyl cation in the resonance structures (Scheme 1).
On the contrary, strong electron-donating substituent such as
p-MeO worked in the opposite way. The reaction of 2d under
the identical condition gave a complex mixture with only trace
amount of 3d (entry 4). We speculate that in this case strong
stabilization effect of p-MeO makes allenyl cation more
favorable as compared with the corresponding propargylic cation
(Scheme 1). This will lead to side reactions. Finally, it is
worthwhile to note that substrate with alkyl substituent on alkyne
moiety also worked well (entry 11).
etals into O-trichloroacetimidoyl derivatives and their acid-
catalyzed activation have been frequently applied in the
formation of glycoside bonds. Schmidt and Michel have reported
that the arylation reaction of O-glycosyl trichloroacetimidates
with activated aromatic compounds under mild Lewis acid
catalysis gives C-aryl glycosides.10c The study by Cramer and
Hennrich has revealed that the BF3‚OEt2-catalyzed reaction of
O-allyl trichloroacetimidates with benzene gives the Friedel-
Crafts products in low yields, accompanied by the formation
of trichloroacetyl amides.11 Very recently, Zhang and Schmidt
have disclosed their study on the TMSOTf-catalyzed Friedel-
Crafts benzylation with O-benzyl trichloroacetimidate.10l How-
ever, to the best of our knowledge, the utilization of O-propargyl
trichloroacetimidates in Friedel-Crafts propargylation has not
been documented in the literature.
O-Propargyl trichloroacetimidates 2a-k can be easily pre-
pared from the corresponding propargyl alcohols in good yields
by standard procedure.9 Compounds 2a-k are stable com-
pounds, which can be kept at room temperature (eq 1).
The scope of the aromatic substrates was then examined under
the same reaction conditions (Table 3). With monosubstituted
or ortho-disusbstituted benzene, the reaction with 2a gave the
expected propargylation products, but as mixture of regioiso-
mers, because of high reactivity of these arenes (entries 1, 3,
and 4). The reaction with furan or thiophene also worked well
to give the corresponding 2-propagylated furan or thiophene as
major products (entries 7 and 8). It should be noted that for the
reaction with electron-rich arenes, the aromatic substrates were
With 2a-k in hand, we first used 2a as the model substrate
in acid-catalyzed reaction with benzene. Thus, 2a was dissolved
in benzene, followed by the addition of a catalytic amount of
acid. As shown in Table 1, the Friedel-Crafts propargylation
product 3a could be obtained with a variety of Lewis acid
(11) Cramer, F.; Hennrich, N. Chem. Ber. 1961, 94, 976-989.
7432 J. Org. Chem., Vol. 72, No. 19, 2007

TABLE 3. Reaction of 2a with Various Aromatic Compounds
SCHEME 2. Reaction with O-Propargyl
Trichloroacetimidates Derived from Secondary Propargyl
Alcohols
cation to follow other reaction pathways. These results are
consistent with the previous investigation which has revealed
that the ambident reactivity of propargyl cation is largely
dependent on the substitution pattern at the R- and γ-positions.5,7
In summary, we have reported a highly efficient Friedel-
Crafts method to synthesize 1,3-diarylpropynes in good to
excellent yields in the presence of a catalytic amount of BF3‚
OEt2 at room temperature. The reaction conditions are mild,
and the catalyst is cheap and easily available. The use of
O-propargyl trichloroacetimidates derived from primary prop-
argyl alcohols in this reaction is complementary to the transition
metal catalyzed propargylations of arenes, which usually work
with secondary propargyl alcohols only.2a-c This reaction is
expected to find application in the preparation of 1,3-diaryl-
propynes.
1
a Isolated yield. b The ratio of the regioisomers was determined by H
NMR and 13C NMR. The regioisomers could not be separated by silica gel
column. c The reaction gave only one compound. d For entries 5-8, CH2Cl2
is used as solvent. e The product was a 2:1 mixture of 2- and 3-propargylated
regioisomers. f The product was a 10:1 mixture of 2- and 3-propargylated
regioisomers.
Experimental Section
Typical Procedure for the Preparation of Substituted Prop-
2-yn-1-yl Trichloroacetimidate. To a solution of 3-phenylprop-
2-yn-1-ol 1a (894 mg, 6.77 mmol) in CH2Cl2 was added DBU (103
mg, 0.68 mmol), and the mixture was stirred for 5 min at room
temperature. Trichloroacetonitrile (1.96 g, 13.4 mmol) was added
with ice cooling, and the resulting mixture was stirred for 10 min
at room temperature. Then the solvent was removed under reduced
pressure and the resulting crude product was purified by column
chromatography (petroleum ether/ethyl acetate 100:1) to give the
desired 3-phenylprop-2-yn-1-yl trichloroacetimidate 2a (1.6 g, 93%
yield) as a yellow oil.
3-Phenylprop-2-ynyl trichloroacetimidate (2a): 93%; light
yellow oil; 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 7.50-7.46
(m, 2H), 7.35-7.31(m, 3H), 5.15(s, 2H); 13C NMR (75 MHz
CDCl3) δ 161.9, 131.9, 128.8, 128.2, 122.0, 90.9, 87.1, 82.3, 57.5;
IR (neat, cm-1) 3341 (w), 2238 (w), 1667 (s), 1289 (s); HRMS
calcd for C11H8NOCl3 274.9672, found 274.9676.
used in 3 or 5 equiv amounts (entries 5-8), while in other cases
the substrate arenes were the reaction solvent.
Finally, O-propargyl trichloroacetimidates derived from sec-
ondary propargyl alcohols were examined (Scheme 2). With
trichloroacetimidate 6, the BF3‚OEt2-catalyzed reaction in
benzene gave enyne 7 and amide 8, together with trace amounts
of Friedel-Crafts propargylation product which could not be
purified. Enyne 7 was formed through 1,2-methyl shift of the
propargyl cation. The reaction of in situ generated 10, on the
other hand, afforded amide 11 in 63% yield. The rearrangement
of trichloroacetimidate to the corresponding amide has been
previously reported.11 Finally, BF3‚OEt2-catalyzed reaction of
12 gave allene 13 in 49% yield with trace amount of unidentified
isomer. All of these results, together with the selective prop-
argylations summarized in Tables 1 and 2, can be explained on
the grounds of the steric effects of the substituents on the alkyne
moiety. Bulky substituents will obviously prevent the approach
of aromatic nucleophiles, thus enabling the intermediate carbon
Typical Procedure for the BF3‚OEt2-Catalyzed Friedel-
Crafts Reaction. To benzene (3 mL) were added 3-phenylprop-
2-yn-1-yl trichloroacetimidates 2a (107 mg, 0.387 mmol) and BF3‚
J. Org. Chem, Vol. 72, No. 19, 2007 7433

OEt2(15 µL,0.116 mmol). The solution was stirred for 5 min at
room temperature, the solvent was removed in vacuo, and the crude
product was purified by column chromatography on silica gel with
petroleum ether to give 1,3-diphenylprop-1-yne 3a (63 mg, 85%)
as a light yellow oil.
126.5, 120.5, 86.7, 82.7, 25.7, 21.4; IR (neat, cm-1) 3029 (w),
1605 (w), 1509 (m); HRMS calcd for C16H14 206.1096, found
206.1091.
Acknowledgment. The project is generously supported by
Natural Science Foundation of China (Grant Nos. 20572002
and 20521202) and the Ministry of Education of China.
1,3-Diphenylprop-1-yne (3a):1d 1H NMR (300 MHz, CDCl3)
δ 7.46-7.24 (m, 10H), 3.83 (s, 2H); 13C NMR (75 MHz CDCl3)
δ 136.9, 131.7, 128.6, 128.3, 128.1, 127.8, 126.7, 123.9, 87.6, 82.8,
25.7.
Supporting Information Available: Characterization data and
1H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
1-(3-p-Tolylprop-2-ynyl)benzene (3b): H NMR (300 MHz,
CDCl3) δ 7.42-7.07 (m, 9H), 3.80 (s, 2H), 2.31 (s, 3H); 13C
NMR (75 MHz CDCl3) δ 137.7, 136.8, 131.5, 128.9, 128.5, 127.9,
JO0709192
7434 J. Org. Chem., Vol. 72, No. 19, 2007