Aldehyde- and ketone-induced tandem decarboxylation-coupling (Csp 3-Csp) of natural α-amino acids and alkynes

Article abstract of DOI:10.1021/jo902319h

(Chemical Equation Presented) An interesting aldehyde- and ketone-induced intermolecular tandem decarboxylation-coupling (Csp³-Csp) catalyzed by copper with use of natural α-amino acids as starting materials is developed under neutral condition

Full text of DOI:10.1021/jo902319h

pubs.acs.org/joc
Aldehyde- and Ketone-Induced Tandem Decarboxylation-Coupling
(Csp3-Csp) of Natural r-Amino Acids and Alkynes
Hai-Peng Bi,†,‡ Qingfeng Teng,‡ Min Guan,‡ Wen-Wen Chen,† Yong-Min Liang,*,‡
Xiaojun Yao,*,‡ and Chao-Jun Li*,†
†Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A 2K6,
Canada and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
People’s Republic of China
‡
liangym@lzu.edu.cn; xjyao@lzu.edu.cn; cj.li@mcgill.ca
Received October 29, 2009
An interesting aldehyde- and ketone-induced intermolecular tandem decarboxylation-coupling
(Csp3-Csp) catalyzed by copper with use of natural R-amino acids as starting materials is developed
under neutral conditions with the production of CO2 and H2O as the only byproducts. Various
functionalized nitrogen-containing compounds were obtained by this method. In these processes,
interesting regioselectivites of the alkylation were observed, which has been rationalized by the
relative stability of proposed resonance structures based on computation methods.
Introduction
transition metal catalysts and producing stoichiometric
quantities of unwanted metal/metalloid byproducts in the
transmetalation steps. Recently, interest in the area of decar-
boxylative coupling has increased rapidly due to the fact that
these reactions occur under relatively neutral conditions,
avoiding the use of preformed “organometallic reagents”
that are typically necessary for transmetalation and elimi-
nating the stoichiometric quantities of unwanted metal/
metalloid byproducts.8,9
The transition metal-catalyzed cross-coupling reactions
(e.g., Negishi,1 Stille,2 Suzuki-Miyaura,3 Sonogashira,4 and
Kumada5 couplings) have been established as convenient,
practical, and effective methods for constructing C-C bonds
in modern organic synthesis.6 Although they have been
employed in a broad range of applications,7 there are still
disadvantages such as the requirement of usually expensive
(1) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
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4374–4376. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun.
1972, 144a. (c) Kumada, M. Pure Appl. Chem. 1980, 52, 669–679.
(6) (a) Diederich, F.; Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: New York, 1998. (b) de Meijere, A.; Diederich, F., Eds.
Metal Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Chichester,
UK, 2004; Vols. 1 and 2.
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2002, 124, 11250–11251. (b) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am.
Chem. Soc. 2005, 127, 10323–10333. (c) Rayabarapu, D. K.; Tunge, J. A.
J. Am. Chem. Soc. 2005, 127, 13510–13511. (d) Gooβen, L. J.; Deng, G.;
Levy, L. M. Science 2006, 313, 662–664. (e) Burger, E. C.; Tunge, J. A. J. Am.
Chem. Soc. 2006, 128, 10002–10003. (f) Forgione, P.; Brochu, M.-C.;
St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem.
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Soc. 2005, 127, 17180–17181. (m) Bourgeois, D.; Craig, D.; King, N. P.;
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DOI: 10.1021/jo902319h
r
Published on Web 01/07/2010
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2010 American Chemical Society

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SCHEME 1. Copper-Catalyzed Oxidative Decarboxylative
Coupling of Tertiary R-Amino Acids (Path A) and Aldehyde-
Induced Decarboxylation-Coupling of Secondary R-Amino Acids
(Path B)
TABLE 1. Optimization of Reaction Conditionsa
entry
catalyst
temp (°C)
NMR yieldb (%)
1
2
3
4
5
6
7
8
9
10
Au(PPh3)Cl
AuCl3
Ag(PPh3)F
CuOTf
Cu(OTf)2
CuBr2
CuBr
CuI
CuI
CuI
100
100
100
100
100
100
100
100
130
130
<5c
28c
32
33
28
32
44
45
90
95d
To date, while seeking selective methods to functionalize
the R Csp3-H bond of nitrogen-containing compounds,10
we have developed various Cross-Dehydrogenative-
Coupling (CDC) by directly utilizing two different C-H
bonds.11 While these reactions provided the simplest and
most direct approach to generate such compounds, the scope
of the reactions and the regioselectivity of the C-C bond
to be formed are still relatively limited. Alternatively, the
carboxylic group of R-amino acids provides the possibility
for site-specific functionalization of R-amino acids skeletons,
using decarboxylative coupling reactions to generate amine
derivatives. In the meantime, R-amino acids are often more
readily accessible than other compounds in nature and are
among the most attractive synthons for cross-coupling.12
With this notion in mind, very recently, we have developed a
C-C bond-forming reaction based on a copper- and iron-
catalyzed oxidative decarboxylative coupling of sp3-hybri-
dized carbons of R-amino acids (Scheme 1, path A).13
Although these results provide new and alternative ways to
construct different Csp3-Csp, Csp3-Csp2, and Csp3-Csp3
bonds, there are still several limitations for these methods.
First, a stoichiometric quantity of peroxide was used. Avoid-
ing the use of peroxide would offer a more atom-economical
and much safer process.14 Second, the tertiary R-amino acids
described by Path A (protected by benzyl groups) require
preparation in separate steps in advance, which also gener-
ates waste. Finally, the oxidative coupling methods are
not applicable to secondary R-amino acids, which are
more prevalent in nature. Thus, the direct R-functionaliza-
tion of existing secondary R-amino acids is highly desirable
and synthetically useful. To address these challenges, herein
aReactions were carried out on a 0.3 mmol scale in 1.5 mL of toluene
under argon overnight with 1.0 equiv of 1a, 1.5 equiv of 2a, 1.4 equiv of
b
3a, and 0.15 equiv of catalyst. Reported yields were based on 1a and
c
determined by NMR with use of an internal standard. 0.05 equiv of
catalyst was used. d1.4 equiv of 1a, 1.5 equiv of 2a, and 1.0 equiv of 3a
were used and the reported yield was based on 3a.
we report an interesting aldehyde- and ketone-induced inter-
molecular tandem decarboxylation-coupling of secondary
R-amino acids with alkynes catalyzed by copper to afford
propargylic amine derivatives,11,15 releasing H2O and CO2 as
the only byproducts (Scheme 1, path B).
Results and Discussion
Our study began with the reaction of 1.0 equiv of
4-nitrobenzaldehyde 1a, 1.5 equiv of proline 2a, 1.4 equiv
of phenylacetylene 3a, and 5 mol % of AuCl(PPh3) as the
catalyst in toluene at 100 °C under argon overnight. A trace
amount of the desired pyrrolidine heterocycle 4a was ob-
tained (Table 1, entry 1). To improve the yields, various
catalysts such as AuCl3, Ag(PPh3)F, and various copper salts
were examined (entries 2-8), which were shown to be
effective for similar reactions.15 Among them, CuI provided
the highest yield. Different temperatures were also tested.
When the reaction was performed at 130 °C, an excellent
yield was obtained (entry 9). Later, we found that the use of
1.4 equiv of 1a, 1.5 equiv of 2a, and 1.0 equiv of 3a gave the
best yield (entry 10). The optimum reaction conditions thus
far developed employ 1.4 equiv of aldehyde 1, 1.5 equiv of
amino acid 2, 1.0 equiv of alkyne 3, and 15 mol % of CuI, in
toluene at 130 °C under argon.
To examine the scope of this aldehyde-assisted decarboxy-
lation-coupling reaction, various alkynes were examined
under the above optimized conditions, and the results are
summarized in Table 2. For aromatic alkynes, the reaction
often afforded the corresponding products in moderate to
good yields (Table 2, entries 1-5). In addition, alkynes
containing an aliphatic group or a 1-cyclohexenyl group
were also applicable in this transformation (entries 6 and 7).
Meanwhile, the use of benzaldehyde bearing an electron-
withdrawing group at different positions gave the corre-
sponding products 4h, 4i, and 4j, respectively (entries
8-10). However, benzaldehyde bearing an electron-donat-
ing group gave a lower yield (entry 11).16 When 4-methoxy-
benzaldehyde 1f was used, two types of C-C bond
(10) Godula, K.; Sames, D. Science 2006, 312, 67–72.
(11) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810–11811. (b) Li,
Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928–8933.
(c) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075–7078. (d) Zhao,
ꢀ
L.; Basle, O.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4106–4111.
For an account, see: (e) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344.
(12) (a) Tyrrell, E.; Brookes, P. Synthesis 2004, 469–483. (b) Handy, S. T.;
Sabatini, J. J. Org. Lett. 2006, 8, 1537–1539. (c) Flegeau, E. F.; Popkin, M. E.;
Greaney, M. F. Org. Lett. 2006, 8, 2495–2498. (d) Moon, J.; Jeong, M.; Nam,
H.; Ju, J.; Moon, J. H.; Jung, H. M.; Lee, S. Org. Lett. 2008, 10, 945–948.
(13) (a) Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed.
2009, 48, 792–795. (b) Bi, H.-P.; Chen, W.-W.; Liang, Y.-M.; Li, C.-J. Org.
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(14) (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M. Acc.
Chem. Res. 2002, 35, 695–705.
(15) We also developed other methods for the synthesis of propargyla-
mines, see: (a) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268–269. (b) Wei, C.;
Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584–9585. For accounts, see: (c) Wei,
C.; Li, Z.; Li, C.-J. Synlett 2004, 1472–1483. (d) Li, C.-J. Acc. Chem. Res.
accepted for publication.
(16) Dose, K. Chem. Ber. 1957, 90, 1251–1258.
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TABLE 2. Tandem Decarboxylation-Coupling of Secondary R-Amino Acids and Alkynesa
aAldehyde (1.4 equiv), amino acid (1.5 equiv), alkyne (1.0 equiv), and CuI (15 mol %) in toluene (1.5 mL). bIsolated yield of 5a is given in parentheses.
formation products 4l and 5a were obtained (entry 12).
Furthermore, the use of R-naphthaldehyde and β-naphthal-
dehyde gave the corresponding coupling products in good
yields (entries 13 and 14). The reactions of benzaldehyde with
different alkynes were also examined; the corresponding
coupling products were obtained in moderate yields
(entries 15-20). In these reactions, only trace amounts of
regioisomers resulting from the coupling at the benzylic
carbon were observed by 1H NMR or GC-MS of the crude
reaction mixture. We were unable to isolate and purify these
trace amounts of regioisomers.
acid 2b was used, N-benzylpiperidine derivative 4u was
obtained in a moderate yield (Table 3, entry 1). For catenar-
ian amino acid N-methylleucine 2c, the corresponding pro-
duct 4v was formed (entry 2). Similarly, N-methylalanine
was also applicable, however, affording a mixture of two
regioisomers (entry 3). To our surprise, when amino acid 2e
without an R-substituent was used, the reaction gave almost
exclusively the isomeric benzylic alkynylation product; only
a very small amount of the “ipso”- coupling product was
observed (entry 4). The reactions of amino acid 2f with
different aldehydes also gave the regioisomers 5d, 5e and
trace amounts of the “ipso”-coupling products (entries 5
and 6).
Subsequently, our investigations were focused on the use
of various amino acids. When cyclic amino acid pipecolic
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TABLE 3. Tandem Decarboxylation-Coupling of Different R-Amino
TABLE 4. Decarboxylation-Coupling for the Synthesis of Amino Acids
Derivativesa
Acidsa
aAldehyde (1.4 equiv), amino acid (1.5 equiv), alkyne (1.0 equiv), and
CuI (15 mol %) in toluene (1.5 mL). b4w:5b = 3:1. cAldehyde (1.0 equiv),
amino acid (1.5 equiv), and alkyne (1.4 equiv) were used. dNMR yield of
4x is given in parentheses.
Interestingly, ethyl glyoxalate17 can also be used in this
reaction readily when using CuBr and N,N-diisopropylethyl-
amine (DIPEA) as the catalytic system at 110 °C. Alkynes
containing an aromatic, 1-cyclohexenyl, or aliphatic group
were subjected to the tandem decarboxylation-coupling
reactions and moderate to good yields were obtained
(Table 4, entries 1-8). Six-member-ring amino acid 2b can
also be used to give a new amino acid derivative 6i in 38%
yield (entry 9). The use of CuI as catalyst gave a lower yield of
the corresponding decarboxylation-coupling product.
Encouraged by these results of this aldehyde-induced
tandem decarboxylation-coupling reaction, we then tried
to incorporate ketone as the substrate in this coupling
process. Subsequently, We were pleased to find that ethyl
pyruvate 7 led to the formation of coupling products
smoothly using CuBr and N(Et)3 as the catalytic system at
110 °C. The results were summarized in Table 5. However,
attempts to use other ketones such as acetophenone and
ethyl 3,3,3-trifluoro-2-oxopropanoate were not successful.
To further understand the role of aldehyde and copper in
this process, we examined the reaction of proline 2a with
aEthyl glyoxalate (1.4 equiv), amino acid (1.5 equiv), alkyne (1.0
equiv), CuBr (15 mol %), and DIPEA (30 mol %) in toluene (1.5 mL).
alkyne 3a under the optimized reaction conditions above. No
direct coupling product 9 was obtained. However, when no
copper catalyst is used, only a trace amount of the coupling
product 4o was observed with GC-MS analysis (Scheme 2).
These results confirmed that aldehyde is essential to induce
decarboxylation16,18 and CuI catalyst is important in the
C-C bond formation step.
A tentative mechanism was proposed in Scheme 3. The
first step is most likely the formation of an imine-type inter-
mediate 10, which then undergoes decarboxylation16,19 to
form intermediate B. The intermediate will be in equilibrium
(18) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. Tetra-
hedron 1988, 44, 519–541.
(19) (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2809.
(b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484–4517.
(17) Ethyl glyoxalate is in toluene (50 wt % in toluene).
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SCHEME 3. Proposed Mechanism of the Aldehyde-Induced
Decarboxylation-Coupling
TABLE 5. Decarboxylation-Coupling of Ketonesa
SCHEME 4. Explanation of Regioselectivity
aEthyl pyruvate (1.4 equiv), amino acid (1.5 equiv), alkyne (1.0
equiv), CuBr (15 mol %), and NEt3 (30 mol %) in toluene (1.5 mL).
bDetected by NMR.
SCHEME 2. The Effect of Aldehyde and Copper
structures B and C were calculated with use of Gaussian98
programs.20 The calculation shows that the energy of B1 is
ca. 15.28 kJ/mol lower than that of C1, and thus the regio-
selecitivty of this reaction is likely determined by resonance
structure B1 (Path B). If there is no R-substituent, the
energies of B2 and C2 are nearly the same. Therefore, there
is the same possibility to form either structure B3 or C3.
However, the energy of B3 is ca. 48.07 kJ/mol higher than
C3. Thus, path C is more favorable in this case (Scheme 4 and
Figure 1).
with intermediate C. Reaction of B or C with acetylide
intermediate resulted in the generation of an organocopper
intermediate, which undergoes intramolecular nucleophilic
addition to give the desired products and regenerates the
copper catalyst for further reactions.11,13,15
(20) Frisch, M. J.; Trucks, G. W.;Schlegel, H. B.; Scuseria, G. E.; Robb, A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson,
G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts,
R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Gonzalez, C.; Challacombe, M.;Gill, P. M. W.;Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J. A. Gaussian98, revision A.7; Gaussian, Inc.:
Pittsburgh, PA, 1998.
Theoretical Basis of the Regioselectivity
To have a better understanding of factors controlling the
coupling regioselectivity of the reaction and thus provide a
predictable and synthetically useful tool, we decided to look
at the relative stability as well as the effect of substituents on
resonance structures B and C. We reasoned that the regio-
selecivity could be due to the relative stability of these two
resonance structures when bearing different substituents. To
validate this hypothesis, the relative energies of resonance
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residue was purified by column chromatography (hexanes/diethyl
ether = 15:1-4:1) on silica gel to afford propargylamine deriva-
tives 4a in 81% (74.4 mg) isolated yield as a yellow oil. 1H NMR
(300MHz, CDCl3, ppm) δ8.19-8.15(m, 2H), 7.58-7.54 (m, 2H),
7.46-7.40 (m, 2H), 7.33-7.29 (m, 3H), 4.11 (d, J = 13.8 Hz, 1H),
3.72 (d, J = 13.8 Hz, 1H), 3.66-3.61 (m, 1H), 2.81-2.74 (m, 1H),
2.61-2.53 (m, 1H), 2.26-1.80 (m, 4H).
Table 4, entry 1: To a solution of N,N-diisopropylethylamine
(11.6 mg, 0.09 mmol) in toluene (1.5 mL) was added CuBr
(6.4 mg, 0.045 mmol, 15 mol %). The mixture was stirred for
10 min under argon. Aldehyde 5 (83.2 μl, 0.42 mmol), amino
acids 2a (51.8 mg, 0.45 mmol), and alkyne 3a (30.6 mg, 0.30
mmol) were added. The reaction temperature was raised to 110
°C as soon as possible. The resulting mixture was stirred at the
same temperature overnight, and then was cooled to room
temperature. The resulting suspension was diluted with ethyl
acetate and filtered through a short fluorisil column eluting with
ethyl acetate. Solvent was evaporated and the residue was purified
by column chromatography (hexane/diethyl ether=10:1-4:1) on
silica gel to afford the coupling products 6a in 67% (51.7 mg)
isolated yield as a yellow oil. 1H NMR (300 MHz, CDCl3, ppm) δ
7.43-7.39 (m, 2H), 7.30-7.26 (m, 3H), 4.23-4.16 (m, 2H),
3.95-3.91 (m, 1H), 3.67-3.44 (m, 2H), 2.96-2.88 (m, 1H),
2.83-2.76 (m, 1H), 2.27-2.20 (m, 1H), 2.09-1.85 (m, 3H),
1.30-1.25 (m, 3H); 13C NMR (ppm) δ 170.8, 131.7, 128.2,
128.0, 123.0, 87.8, 85.0, 60.6, 54.4, 53.7, 51.7, 31.8, 22.3, 14.2;
HRMS calcd for C16H20NO2 [M þ H]þ 258.1489, found 258.1488.
Table 5, entry 1: To a solution of NEt3 (9.1 mg, 0.09 mmol) in
toluene (1.5 mL) was added CuBr (6.4 mg, 0.045 mmol, 15 mol
%). The mixture was stirred for 10 min under argon. Ketone 7
(48.7 mg, 0.42 mmol), amino acids 2a (51.8 mg, 0.45 mmol), and
alkyne 3a (30.6 mg, 0.30 mmol) were added. The reaction
temperature was raised to 110 °C as soon as possible. The
resulting mixture was stirred at the same temperature overnight,
and then was cooled to room temperature. The resulting suspen-
sion was diluted with ethyl acetate and filtered through a short
fluorisil column eluting with ethyl acetate. Solvent was evapo-
rated and the residue was purified by column chromatography
(hexane/diethyl ether = 15:1-5:1) on silica gel to afford the
coupling products 8a in 64% (52.0 mg) isolated yield as a yellow
oil. Major isomer: 1H NMR (300 MHz, CDCl3, ppm) δ
7.43-7.39 (m, 2H), 7.29-7.26 (m, 3H), 4.19 (q, J = 7.2 Hz,
2H), 4.06-4.02 (m, 1H), 3.77 (q, J = 6.9 Hz, 1H), 3.00-2.93 (m,
1H), 2.87-2.79 (m, 1H), 2.28-2.19 (m, 1H), 2.06-1.81 (m, 3H),
1.43 (d, J = 7.2 Hz, 3H), 1.35-1.22 (m, 3H); 13C NMR (ppm) δ
173.5, 131.7, 128.1, 127.9, 123.2, 88.6, 84.7, 60.3, 57.6, 52.7, 46.9,
32.1, 22.2, 17.8, 14.3; HRMS calcd for C17H21O2N 271.1572,
FIGURE 1. Calculation of the relative energies of resonance struc-
tures by Gaussian98.
Conclusion
1
found 271.1567. Minor isomer: H NMR (300 MHz, CDCl3,
In summary, we have developed an interesting aldehyde- and
ketone-induced tandem decarboxylation-coupling (Csp3-Csp)
reaction catalyzed by copper using secondary R-amino acids as
starting materials under neutral conditions providing CO2 and
H2O as the only byproducts. In these processes, an interesting
regioselectivity was observed. Such regioselectivities were ex-
plained by using computation methods.
ppm) δ 7.43-7.38 (m, 2H), 7.30-7.25 (m, 3H), 4.23-4.10 (m,
3H), 3.46 (q, J = 6.9 Hz, 1H), 2.96-2.89 (m, 1H), 2.71-2.63 (m,
1H), 2.28-2.17 (m, 1H), 2.08-1.83 (m, 3H), 1.45 (d, J = 6.9 Hz,
3H), 1.35-1.25 (m, 3H); 13C NMR (ppm) δ 174.2, 131.7, 128.2,
128.0, 123.1, 87.6, 85.0, 60.6, 59.9, 51.5, 49.6, 31.6, 22.3, 17.1,
14.2; HRMS calcd for C17H21O2N 271.1572, found 271.1566.
Acknowledgment. We are grateful to the Canada Re-
search Chair (Tier I) Foundation (to C.J.L.), CFI, NSERC,
and the program for New Century Excellent Talents in
University (Grant No. NCET-07-0399) for support of our
research. H.-P.B. thanks the national graduate student
program of building world-class universities grant (Grant
No.[2007]3020) for financial support.
Experimental Section
General Procedure. Table 2, entry 1: To a solution of proline
2a (51.8 mg, 0.45 mmol) in toluene (1.5 mL) was added CuI (8.6
mg, 0.045 mmol, 15 mol %). The mixture was stirred for 10 min
under argon. Aldehyde 1a (63.4 mg, 0.42 mmol) and alkyne 3a
(30.6 mg, 0.30 mmol) were added. The reaction temperature was
raised to 130 °C as soon as possible. The resulting mixture was
stirred at the same temperature overnight, and then cooled to
room temperature. The resulting suspension was diluted with
ethyl acetate (2.0 mL) and filtered through a short fluorisil column
eluting with ethyl acetate (15 mL). Solvent was evaporated and the
Supporting Information Available: Typical experimental
procedure, characterization data, NMR spectra, and computa-
tional data. This material is available free of charge via the
Internet at http://pubs.acs.org.
788 J. Org. Chem. Vol. 75, No. 3, 2010