Copper-catalyzed coupling reaction of c-ome bonds adjacent to a nitrogen atom with terminal alkynes

Article abstract of DOI:10.1021/jo1007898

(Figure presented) The cross coupling of the C-OMe bond adjacent to a nitrogen atom in dialkoxy-N,N-dialkylmethanamines with terminal alkynes was efficiently approached in the presence of copper catalyst under mild conditions to give 3-amino-1,4-diynes in good yields. The reaction is promoted by phosphine ligands and the chemistry provides a simple and efficient route to 3-amino-1,4-diynes. Importantly, the Michael addition occurred with as-prepared 3-amino-1,4-diynes to give the useful Michael-adducts containing tert-alkylamines in a very convenient way. Further studies revealed that (E)-1,5-diarylpent-1-en-4-yn-3-one was formed through the rearrangement by using the neutral alumina column, and the corresponding imine 2-(1,5-diphenylpent-2- en-4-ynylideneamino)ethanol was obtained in the presence of AgOTf.

Full text of DOI:10.1021/jo1007898

pubs.acs.org/joc
Copper-Catalyzed Coupling Reaction of C-OMe Bonds Adjacent to a
Nitrogen Atom with Terminal Alkynes
Bangben Yao, Yuhong Zhang,* and Yong Li
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
yhzhang@zju.edu.cn
Received April 21, 2010
The cross coupling of the C-OMe bond adjacent to a nitrogen atom in dialkoxy-N,N-dialkylmetha-
namines with terminal alkynes was efficiently approached in the presence of copper catalyst under
mild conditions to give 3-amino-1,4-diynes in good yields. The reaction is promoted by phosphine
ligands and the chemistry provides a simple and efficient route to 3-amino-1,4-diynes. Importantly,
the Michael addition occurred with as-prepared 3-amino-1,4-diynes to give the useful Michael-
adducts containing tert-alkylamines in a very convenient way. Further studies revealed that (E)-1,5-
diarylpent-1-en-4-yn-3-one was formed through the rearrangement by using the neutral alumina
column, and the corresponding imine 2-(1,5-diphenylpent-2-en-4-ynylideneamino)ethanol was
obtained in the presence of AgOTf.
Inrtoduction
synthetic intermediates in organic chemistry.2 Methods for
their preparation by transition metal catalysis have been
investigated intensely over the past decades.3 However, the
general solutions for 3-amino-1,4-diynes from direct cataly-
tic couplings of terminal alkynes have not been presented. All
published methods for 3-amino-1,4-diynes rely on stoichio-
metric quantities of alkyne anions that are prepared from
Propargylamines are important structural elements in
natural products and drug molecules1 and also versatile
(1) (a) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715. (b) Huffman, M. A.; Yasuda,
N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590.
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Li, X.-M.; Paterson, I. A.; Yu, P.-H. Drug Dev. Res. 1997, 42, 150.
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Nugent, W. A. Org. Lett. 2000, 2, 3119.
(2) For cyclization reactions through propargylic amine intermediates
see: (a) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007,
46, 2295. (b) Yan, B.; Liu, Y.-H. Org. Lett. 2007, 9, 4323. (c) Zhang, X.;
Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358. (d) Cao, K.; Zhang, F.-M.;
Tu, Y.-Q.; Zhuo, X.-T.; Fan, C.-A. Chem.;Eur. J. 2009, 15, 6332. (e) Ohta,
Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2009, 11, 1979. (f) Chernyak, N.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2743.
(3) For recent works on metal-promoted coupling of alkynes, aldehydes,
and amines (A3 coupling) leading to propargylic amines see: (a) Li, C.-J.;
Wei, C.-M. Chem. Commun. 2002, 268. (b) Gommermann, N.; Koradin, C.;
Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763. (c) Wei,
C.-M.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584. (d) Wei, C.-M.; Li, Z.-P.;
Li, C.-J. Synlett 2004, 1472. (e) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.;
Fan, C.-A. Org. Lett. 2004, 6, 1001. (f) Lo, V. K.-Y.; Liu, Y.-G.; Wong,
M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529. (g) Li, P.-H.; Zhang, Y.-C.;
Wang, L. Chem.;Eur. J. 2009, 15, 2045. (h) Zhang, Y.-C.; Li, P.-H.; Wang,
M.; Wang, L. J. Org. Chem. 2009, 74, 4364.
4554 J. Org. Chem. 2010, 75, 4554–4561
Published on Web 06/10/2010
DOI: 10.1021/jo1007898
r
2010 American Chemical Society

Yao et al.
JOCArticle
SCHEME 1
TABLE 1. Optimization of Reaction Conditions a
entry
catalyst
ligandb
none
none
PPh3
dppb
dppe
dppp
bipyridine
L-proline
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
solvent
temp (°C)
yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16e
17f
CuBr
none
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
CuI
CuBr2
CuBr
CuBr
CuBr
CuBr
CuBr
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
THF
80
80
80
80
80
80
80
80
70
80
80
80
80
80
80
80
80
45
0d
68
65
72
85
36
52
68
58
83
43
62
75
0
terminal alkynes and organometal bases (Scheme 1).4 Direct
alkynylation with terminal alkynes would constitute a more
efficient approach because it eliminates the need for the
stoichiometric preparation of alkyne anions. Over the past
ten years, the direct coupling of terminal alkynes with acetals
have been studied.5 For instance, copper-mediated coupling
of alkynes with N-acylimine was reported by Li and co-
workers,6 which provides an attractive alternative to tradi-
tional method through alkyne anions. Sakai and co-workers
reported the use of the InBr3-Et3N system to promote the
alkynylation of N,O- or N,S-acetals.7 However, the applica-
tion of those methods is limited owing to the lack of a general
and mild method for their generation and the need for
stoichiometric amounts of metal in their reactions.
The development in transition metal-catalyzed transfor-
mations involving C-OMe coupling reactions has attracted
much interest due to being a highly attractive research area in
organic chemistry.8 We have recently studied the coupling of
the C-H bond adjacent to nitrogen and oxygen atoms,9,10
and the direct coupling of terminal alkynes with the C-H
DMF
toluene
toluene
75
84
aReaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), copper catalyst
˚
(0.05 mmol), ligand (0.05 mmol), 3 A MS (100 mg), solvent (3 mL), N2,
10 h. bdppe = 1,2-bis(diphenylphosphino)ethane; dppp = 1,2-bis(diphenyl-
phosphino)propane; dppb =1,2-bis(diphenylphosphino)butane. cIso-
lated yields. d1-Methoxy-N,N-dimethyl-3-phenylprop-2-yn-1-amine 4a
e
f
˚
was obtained in 32% yield. No 3 A MS added. 1a scaled up to 10 mmol.
bond adjacent to a nitrogen atom has been achieved under
oxidative conditions through a copper-catalyzed cross-de-
hydrogenative coupling process by Li and co-workers.11 In
light of these advances, our interest in new catalytic reactions
inspired us to explore the reactivity of C-OMe adjacent to a
nitrogen atom. Herein, we describe a method for the direct
alkynylation of N,N-dimethylformamide dialkyl acetals with
terminal alkynes by the use of copper catalyst and phosphine
ligand. The transformation involves the coupling of C-OMe
adjacent to a nitrogen atom with terminal alkynes under mild
reaction conditions to give 3-amino-1,4-diynes (Scheme 1).
(4) (a) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc.
2004, 126, 5968. (b) Murai, T.; Ohta, Y.; Mutoh, Y. Tetrahedron Lett. 2005, 46,
3637. (c) Mutai, T.; Ui, K.; Narengerile J. Org. Chem. 2009,74, 5703. (d) Mesnard,
D.; Miginiac, L. J. Organomet. Chem. 1989, 373, 1. (e) Gommermann, N.;
Koradin, C.; Knochel, P. Synthesis 2002, 2143.
(5) (a) Barluenga, J.; Campos, P. J.; Canal, G. Synthesis 1989, 33.
(b) Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 2028.
(6) Zhang, J.-H.; Wei, C.-M.; Li, C.-J. Tetrahedron Lett. 2002, 43, 5731.
(7) (a) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett. 2003,
44, 4171. (b) Sakai, N.; Kanada, R.; Hirasawa, M.; Konakahara, T. Tetra-
hedron 2005, 61, 9298.
(8) (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc.
1979, 101, 2246. (b) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli,
M. J. Org. Chem. 1984, 49, 4894. (c) Dankwardt, J. W. Angew. Chem., Int. Ed.
2004, 43, 2428. (d) Kakiuchi, F.; Usui, M.; Ueno, S.; Chatani, N.; Murai, S.
J. Am. Chem. Soc. 2004, 126, 2706. (e) Ueno, S.; Mizushima, E.; Chatani, N.;
Kakiuchi, F. J. Am. Chem. Soc. 2006, 128, 16516. (f) Tobisu, M.; Shimasaki,
T.; Chatani, N. Angew. Chem., Int. Ed. 2008, 47, 4866. (g) Shimasaki, T.;
Konno, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2009, 11, 4890. (h) Guan,
B.-T.; Xiang, S.-K.; Wang, B.-Q.; Sun, Z.-P.; Wang, Y.; Zhao, K.-Q.; Shi,
Z.-J. J. Am. Chem. Soc. 2008, 130, 3268. (i) Guan, B.-T.; Xiang, S.-K.; Wu,
T.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 12, 1437.
(9) (a) Cheng, K.; Huang, L.-H.; Zhang, Y.-H. Org. Lett. 2009, 11, 2908.
(b) Huang, L.-H.; Zhang, X.-B.; Zhang, Y.-H. Org. Lett. 2009, 11, 3730.
(c) Huang, L.-H.; Cheng, K.; Yao, B.-B.; Zhao, J.-L.; Zhang, Y.-H. Synthesis
2009, 3504.
Results and Discussion
Our initial studies focused on the coupling reaction of
cheap and commercially available N,N-dimethylformamide
dimethyl acetal 1a with phenyl acetylene 2a. The reaction
˚
was carried out in toluene at 80 °C for 10 h with the aid of 3 A
molecular sieve. Copper catalyst was absolutely required
for the production of 3aa and CuBr alone gave low yield
(Table 1, entries 1 and 2). However, the addition of phos-
phine ligand led to the rapid increase in activity, and an 85%
yield was obtained when 1,3-bis(diphenylphosphino)pro-
pane (dppp) was used as the ligand (Table 1, entries 3-6).
L-Proline and bipyridine showed a poor effect on the reaction
(Table 1, entries 7 and 8). The yield dropped to 68% when
the reaction temperature was decreased to 70 °C (Table 1,
entry 9). A number of Cu sources tested revealed that certain
species including CuCl, CuBr, and CuI were active in the
coupling, while CuBr2 showed low reactivity (Table 1, entries
(10) For recent works on activation of the C-H bond adjacent to
nitrogen and oxygen atoms by others see: (a) Chatani, N.; Asaumi, T.;
Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001,
123, 10935. (b) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am.
Chem. Soc. 2008, 130, 11005.
(11) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Li, Z.-P.; Li, C.-J.
J. Am. Chem. Soc. 2004, 126, 11810. (c) Li, Z.-P.; Li, C.-J. Org. Lett. 2004, 6,
4997. (d) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075.
J. Org. Chem. Vol. 75, No. 13, 2010 4555

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TABLE 2. Cu-Catalyzed Cross-Coupling of Acetals with Terminal Alkynesa
a
b
˚
Reaction conditions: 1a (0.5 mmol), terminal alkynes (1.5 mmol), CuBr (0.05 mmol), dppp (0.05 mmol), 3 A MS (100 mg), toluene (3 mL). Isolated
yields. cReaction run with (n-Bu)3P (0.05 mmol) in THF (3 mL) for 8 h. dN,N-Diethylformamide dimethyl acetal (1b) was used. eN-Formylpiperidine
dimethyl acetal (1c) was used. fN-Formylpyrrolidine dimethyl acetal (1d) was used. gN-Formylmorpholine dimethyl acetal (1e) was used.
10-12). Other solvents such as dioxane and THF furnished the
coupling product in lower yields (Table 1, entries 13 and 14).
It should be noted that N,N-dimethylformamide (DMF) was
totally inactive, even used as solvent (Table 1, entry 15). The
˚
addition of 3 A molecular sieve facilitated the coupling reaction
˚
and the yield decreased without the use of 3 A MS (Table 1,
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TABLE 4. Synthesis of 1,5-Diarylpent-1-en-4-yn-3-onea
TABLE 3. Cross-Coupling of Terminal Alkynes with 4aa
aReaction conditions: 1c (0.5 mmol), terminal alkynes (1.5 mmol),
˚
CuBr (0.05 mmol), dppp (0.05 mmol), 3 A MS (100 mg), toluene (3 mL),
110 °C, N2, 10 h. Treatment in neutral alumina column results in the
products. bIsolated yields.
SCHEME 2
alkynes possessing aryl, thiophenyl, alkenyl, alkyl, cyclopro-
pyl, and TIPS were nearly equally efficient in the alkynyla-
tion. It is important to note that fluoride, chloride, and
bromide groups are tolerated in the reaction (Table 2, entries
6-8). These valuable functional groups should enable
further elaboration of the alkynylation products. In the case
of methyl propiolate, no desired product could be obtained
(Table2, entry 15). The substrate scope in N,N-dialkylfor-
mamide dimethyl acetal was evaluated with phenyl acetylene
aReaction conditions: 4a (0.5 mmol), terminal alkynes (0.6 mmol),
˚
CuBr (0.05 mmol), dppp (0.05 mmol), 3 A MS (100 mg), toluene (3 mL).
bIsolated yields. cReaction run with (n-Bu)3P (0.05 mmol) in THF (3 mL).
entry 16). The reaction could be scaled up to 10 mmol to give an
84% isolated yield (Table 1, entry 17).
This new cross-coupling reaction displayed good func-
tional group tolerance toward terminal alkynes 2. Terminal
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TABLE 5. Michael-Type Addition Reaction of 3-Amino-1,4-diynesa
aReaction conditions: 3-amino-1,4-diynes (1 equiv), 8 (1.5 equiv), NaHCO3 (2 equiv), 12 h. bIsolated yields. cThe amount of 8c was 2 equiv. dReaction
temperature was 80 °C, and the amount of 8d was 2.5 equiv.
4558 J. Org. Chem. Vol. 75, No. 13, 2010

Yao et al.
JOCArticle
as the coupling partner. Both acyclic and cyclic formamide
dimethyl acetals are accommodated with good efficiency
(Table 2, entries 16-19). Attempted cross-coupling with
1,1-dimethoxy-N,N-dimethylethanamine failed to afford
the desired product, with only unreacted starting material
recovered.
cleanly, without any competitive formation of second Michael
addition products. The reaction tolerated a wide range of
3-amino-1,4-diynes, including symmetric and asymmetric
3-amino-1,4-diynes (3 and 5, Table 5, entries 8-26). The
analogous addition to an electron-deficient double bond
failed possibly due to the lower reactivity.
We next conceived to extend the coupling reaction with
1-methoxy-N,N-dimethyl-3-phenylprop-2-yn-1-amine 4a to
prepare unsymmetrical 3-amino-1,4-diynes. We are pleased
to find that the optimized conditions also could be success-
fully applied to the coupling reaction of 4a to give the
corresponding asymmetric 3-amino-1,4-diynes 5 (Table 3).
Good alkynylation yields were obtained for various terminal
alkynes. This method would provide avenues for the deve-
lopment of asymmetric processes leading to C-C bond
formation.
Conclusion
In summary, we have developed a copper-catalyzed pro-
cess for the cross-coupling of the C-OMe bond adjacent to a
nitrogen atom with terminal alkynes. The simple and effi-
cient catalytic system worked well with a broad range of
terminal alkynes and allowed the facile synthesis of 3-amino-
1,4-diynes under mild reaction conditions. It was found that
3-amino-1,4-diynes were interesting building blocks in the
straightforward synthesis of various useful molecules. The
easy rearrangement by the use of petroleum ether/ethyl
acetate as eluant gives the mono configuration of (E)-1,5-
diarylpent-1-en-4-yn-3-ones, and the treatment of N,N-di-
methyl-1,5-diphenylpenta-1,4-diyn-3-amine with 2-amino-
ethanol in the presence of 5 mol % AgOTf led to the
formation of the corresponding imine. Notably, the as-
prepared 3-amino-1,4-diynes can be used as a Michael donor
to addition toward the electron-deficient triple bonds to
give the Michael adducts containing tert-alkylamines. The
exploration of other new coupling reactions of N,N-dialkyl-
formamide dimethyl acetals is in progress in our labora-
tories.
The plausible mechanism for this copper-catalyzed coupling
reaction of the C-OMe bond adjacent to a nitrogen atom
might take place through the elimination of MeOH from N,N-
dimethylformamide dialkyl acetals to form iminium salt.3 The
subsequent nucleophilic addition of copper acetylide gives
the final product. The phosphine ligands significantly improve
˚
the reaction and the absorption of produced MeOH by 3 A
molecular sieve facilitates the generation of products.
Table 4 highlights the utilization of as-prepared 3-amino-
1,4-diynes as useful building blocks. The treatment of crude
products of 3ca-3cg in neutral alumina columnled tothe easy
rearrangement by the use of petroleum ether/ethyl acetate as
eluant to give the mono configuration of (E)-1,5-diarylpent-
1-en-4-yn-3-one (Table 4), which are important intermediates
in organic synthesis.12 Arylalkynes with both electron-with-
drawing (-F) or electron-donating (-OMe) groups in the
aromatic ring worked well under the reaction conditions to
afford the products of rearrangement smoothly (Table 4,
entries 1-5). Notably, heterocyclealkyne (2g) could also give
its corresponding rearrangement product 6g in 68% yield. In
addition, the treatment of N,N-dimethyl-1,5-diphenylpenta-
1,4-diyn-3-amine 3aa with 2-aminoethanol in the presence of
5 mol % AgOTf led to the formation of imine 7, 2-(1,5-
diphenylpent-2-en-4-ynylideneamino)ethanol, in 62% yield
(Scheme 2).
It should be noted that as-prepared 3-amino-1,4-diynes
reacted with both terminal and internal electron-deficient
alkynes to deliver the corresponding Michael adducts 4-ami-
no-2-en-5-ynoates containing tert-alkylamines13 in the pre-
sence of 2 equiv of NaHCO3 (Table 5). In general, dialkyl but-
2-ynedioate showed higher reactivity than alkyl propiolate
and prop-2-yn-1-one (Table 5, entries 1-7). It was found that
dimethyl but-2-ynedioate and diethyl but-2-ynedioate pro-
vided the Michaeladductsin highyields (Table 5, entries1 and
2), while methyl propiolate, but-3-yn-2-one, 1-phenylprop-2-
yn-1-one, 1-(furan-2-yl)prop-2-yn-1-one, and 1-(thiophen-2-
yl)prop-2-yn-1-one were less active to give the corresponding
addition products in relatively lower yields (Table 5, entries
3-7). In all cases, the Michael addition reaction took place
Experimental Section
A Typical Procedure for the Preparation of 3aa-3ai and
3ba-3ea (Method A). Under nitrogen atmosphere, an oven-
dried Schlenk tube equipped with a magnetic stir bar was char-
ged with terminal alkynes 2a-2i (1.5 mmol), N,N-dialkyllfor-
mamide dimethyl acetals 1a-1e (0.5 mmol), CuBr (0.05 mmol),
˚
dppp (0.05 mmol), 3 A molecular sieves (100 mg), and toluene
(3.0 mL). The resulting mixture was stirred at 80-110 °C for
10 h. After cooling to room temperature, the mixture was
filtered through a pad of Cellite and the solvent was removed
under reduced pressure. The residue was subjected to flash
column chromatography on a silica gel column to afford the
desired products 3aa-3ai and 3ba-3ea.
A Typical Procedure for the Preparation of 3aj-3an (Method
B). Under nitrogen atmosphere, an oven-dried sealed tube
equipped with a magnetic stir bar was charged with terminal
alkynes 2j-2n (1.5 mmol), N,N-dimethylformamide dimethyl
acetal 1a (0.5 mmol), CuBr (0.05 mmol), (n-Bu)3P (0.05 mmol),
˚
3 A molecular sieves (100 mg), and THF (3.0 mL). The result-
ing mixture was stirred at 110 °C for 8 h. After cooling to
room temperature, the mixture was filtered through a pad
of Cellite and the solvent was removed under reduced pres-
sure. The residue was subjected to flash column chromatog-
raphy on a silica gel column to afford the desired product
3aj-3an.
A Typical Procedure for the Preparation of 5ab-5ai (Method
C). Under nitrogen atmosphere, an oven-dried Schlenk tube
equipped with a magnetic stir bar was charged with terminal
alkynes 2a-2i (0.6 mmol), 1-methoxy-N,N-dimethyl-3-phenyl-
prop-2-yn-1-amine 4a (0.5 mmol), CuBr (0.05 mmol), dppp
(12) (a) Waldo, J. P.; Mehta, S.; Larock, R. L. J. Org. Chem. 2008, 73,
6666. (b) Rosiak, A.; Christoffers, J. Tetrahedron Lett. 2006, 47, 5095.
ꢀ
(c) Alonso, D. A.; Najera, C.; Pacheco, M. C. J. Org. Chem. 2004, 69,
1615.
(13) (a) Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59. (b) Clive, D. L. J.;
Yu, M.-L.; Wang, J.; Yeh, V. S. C.; Kang, S.-Z. Chem. Rev. 2005, 105, 4483.
(c) Dake, G. Tetrahedron 2006, 62, 3467.
˚
(0.05 mmol), 3 A molecular sieves (100 mg), and toluene
(3.0 mL). The resulting mixture was stirred at 110 °C for 10 h.
After cooling to room temperature, the mixture was filtered
through a pad of Cellite and the solvent was removed under
J. Org. Chem. Vol. 75, No. 13, 2010 4559

Yao et al.
JOCArticle
reduced pressure. The residue was subjected to flash column
chromatography on a silica gel column to afford the desired
product 5ab-5ai.
1.54-1.65 (m, 8 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS)
δ 135.1, 120.1, 85.9, 81.0, 49.8, 41.1, 29.2, 25.5, 22.2, 21.4 ppm; IR
(neat) v 3026, 2933, 2858, 2823, 2778, 2219, 1451, 1284, 1024, 918,
841 cm-1; HRMS (ESI) calcd for C19H26N ([M þ H]þ) 268.2065,
found 268.2064.
A Typical Procedure for the Preparation of 5aj-5ao (Method D).
Under nitrogen atmosphere, an oven-dried sealed tube equipped
with a magnetic stir bar was charged with terminal alkynes
2j-2o (1.0 mmol), 1-methoxy-N,N-dimethyl-3-phenylprop-
2-yn-1-amine 4a (0.5 mmol), CuBr (0.05 mmol), (n-Bu)3P
N,N-Dimethyl-1-phenyl-5-p-tolylpenta-1,4-diyn-3-amine (5ab).
Preparation according to method C with 1-methoxy-N,N-dimeth-
yl-3-phenylprop-2-yn-1-amine 4a (95 mg, 0.5 mmol) and 1-ethy-
nyl-4-methylbenzene (70 mg, 0.6 mmol) provided 5ab (114 mg;
84% yield) after flash chromatography with a solution of EA/Pet
=1/6 as eluent. Yellow liquid; 1H NMR (CDCl3, 400 MHz, TMS)
δ 7.48-7.49 (m, 2 H), 7.37-7.39 (d, J = 7.6 Hz, 2 H), 7.30 (m, 3
H), 7.10-7.11 (d, J = 7.6 Hz, 2 H), 4.77 (s, 1 H), 2.47 (s, 6 H), 2.33
(s, 3 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS) δ 138.5, 131.9,
131.8, 129.0, 128.4, 128.2, 122.6, 119.5, 84.6, 84.4, 83.7, 82.8, 50.1,
41.4, 21.5 ppm; IR (neat) v 3073, 3056, 2977, 2944, 2861, 2824,
2780, 2227, 1594, 1509, 1489, 1489, 1453, 1324, 1292, 1037, 817,
756, 691 cm-1; HRMS (EI) calcd for C20H19N (Mþ) 273.1517,
found 273.1516.
1-Cyclohexenyl-N,N-dimethyl-5-phenylpenta-1,4-diyn-3-amine
(5aj). Preparation according to method D with 1-methoxy-N,N-
dimethyl-3-phenylprop-2-yn-1-amine 4a (95 mg, 0.5 mmol) and
1-ethynylcyclohex-1-ene (66 mg, 0.6 mmol) provided 5aj (106 mg;
81% yield) after flash chromatography with a solution of EA/
Pet =1/6 as eluent. Yellow liquid; 1H NMR (CDCl3, 400 MHz,
TMS) δ 7.46-7.48 (m, 2 H), 7.28-7.32 (m, 3 H), 6.16-6.18 (m,
1 H), 4.66 (s, 1 H), 2.41 (s, 6 H), 2.07-2.18 (m, 4 H), 1.56-1.65
(m, 4 H) ppm; 13C NMR(CDCl3, 100 MHz, TMS) δ 135.4, 131.8,
128.3, 122.7, 120.1, 86.3, 84.1, 83.9, 80.6, 49.9, 41.3, 29.2, 25.6,
22.2, 21.4 ppm; IR (neat) v 3055, 3025, 2975, 2936, 2859, 2824,
2779, 2222, 1599, 1489, 1452, 1443, 1323, 1288, 1026, 918, 756,
691 cm-1; HRMS (EI) calcd for C19H21N (Mþ) 263.1674, found
263.1682.
(E)-1,5-Di(p-tolyl)pent-1-en-4-yn-3-one (6b). Preparation ac-
cording to method E with as-prepared N-formylpiperidine
dimethyl acetal 1c (90 mg, 0.5 mmol) and 1-ethynyl-4-methyl-
benzene (174 mg, 1.5 mmol) provided 6b (95 mg; 73% yield)
after flash chromatography at 25 °C on neutral Al2O3 with a
solution of EA/Pet =1/10 as eluent. White solid, mp 147-
148 °C; 1H NMR (CDCl3, 400 MHz, TMS) δ 7.86-7.90 (d, J =
16.4 Hz, 1 H), 7.54-7.55 (d, J = 7.6 Hz, 2 H), 7.49-7.51 (d, J =
8.0 Hz, 2 H), 7.21-7.26 (m, 4 H), 6.81-6.85 (d, J = 15.6 Hz, 1
H), 2.40 (s, 6 H) ppm; 13C NMR (CDCl3, 100 MHz, TMS)
δ 178.3, 148.2, 141.8, 141.2, 132.9, 131.4, 129.8, 129.4, 128.7,
127.7, 117.1, 92.0, 86.5, 21.7, 21.6 ppm; IR (KBr) v 2916,
2211, 2161, 1622, 1598, 1504, 1380, 1307, 1288, 1169, 816
cm-1; HRMS (EI) calcd for C19H16O (Mþ) 260.1201, found
260.1196.
˚
(0.05 mmol), 3 A molecular sieves (100 mg), and THF (3.0
mL). The resulting mixture was stirred at 110 °C for 8 h. After
cooling to room temperature, the mixture was filtered through
a pad of Cellite and the solvent was removed under reduced
pressure. The residue was subjected to flash column chroma-
tography on a silica gel column to afford the desired product
5aj-5ao.
A Typical Procedure for the Preparation of 6a-6g (Method E).
Under nitrogen atmosphere, an oven-dried Schlenk tube
equipped with a magnetic stir bar was charged with terminal
alkynes 2a (1.5 mmol), N-formylpiperidine dimethyl acetal 1c
˚
(0.5 mmol), CuBr (0.05 mmol), dppp (0.05 mmol), 3 A molecular
sieves (100 mg), and toluene (3.0 mL). The resulting mixture was
stirred at 110 °C for 10 h. After cooling to room temperature, the
mixture was filtered through a pad of Cellite and the solvent was
removed under reduced pressure. The residue was subjected to
flash column chromatography on neutral Al2O3 (ethyl acetate/
petroleum ether = 1:10, v/v) at 25 °C to afford the desired pro-
duct 6a-6g.
A Typical Procedure for the Preparation of 7 (Method F).
Under nitrogen atmosphere, an oven-dried Schlenk tube equip-
ped with a magnetic stir bar was charged with N,N-dimethyl-
1,5-diphenylpenta-1,4-diyn-3-amine 3aa (0.5 mmol), 2-ami-
noethanol (1.0 mmol), AgOTf (6 mg, 0.025 mmol), and toluene
(3.0 mL). The resulting mixture was stirred at 80 °C for 12 h.
After cooling to room temperature, the mixture was filtered
through a pad of Cellite and the solvent was removed under
reduced pressure. The residue was subjected to flash column
chromatography on a silica gel column to afford the desired
product 7.
A Typical Procedure for the Preparation of 9aaa-9alz
(Method G). Under nitrogen atmosphere, an oven-dried Schlenk
tube equipped with a magnetic stir bar was charged with
3-amino-1,4-diynes 3 or 5 (1 equiv), 8 (1.5-2.5 equiv), NaHCO3
(2 equiv), and dioxane (3 mL). The resulting mixture was stirred
at 80-100 °C for 12 h. After cooling to room temperature, the
mixture was filtered through a pad of Cellite and the solvent was
removed under reduced pressure. The residue was subjected to
flash column chromatography on a silica gel column to afford
the desired product 9aaa-9alz.
N,N-Dimethyl-(1,5-di-p-tolylpenta)-1,4-diyn-3-amine (3ab). Pre-
paration according to method A with N,N-dimethylformamide
dimethyl acetal 1a (64 mg, 0.5 mmol), 1-ethynyl-4-methylben-
zene (174 mg, 1.5 mmol) at 85 °C provided 3ab (122 mg; 85%
yield) after flash chromatography with a solution of EA/Pet =1/
(2Z)-2-((E)-1,5-Diphenylpent-2-en-4-ynylideneamino)ethanol
(7). Preparation according to method F with as-prepared N,N-
dimethyl-1,5-diphenylpenta-1,4-diyn-3-amine 3aa (129 mg, 0.5
mmol) and 2-aminoethanol (61 mg, 1.0 mmol) provided 7
(85 mg; 62% yield) after flash chromatography with a solution
1
1
6 as eluent. Gray solid, mp 68-69 °C; H NMR (CDCl3, 400
of EA/Pet = 1/2 as eluent. Yellow solid, mp 106-107 °C; H
MHz, TMS) δ 7.37-7.39 (d, J = 8.0 Hz, 4 H), 7.10-7.12 (d, J =
NMR (d6-DMSO, 400 MHz, TMS) δ 7.70-7.74 (t, J = 8.2 Hz, 4
H), 7.35-7.56 (m, 7 H), 7.05-7.09 (d, J = 16.8 Hz, 1 H),
4.70-4.73 (t, J=5.6 Hz, 1 H), 3.87-3.90 (t, J=6.2 Hz, 2 H),
3.71-3.76 (q, J = 6.1 Hz, 2 H) ppm; 13C NMR (d6-DMSO, 100
MHz, TMS) δ 151.7, 139.0, 135.8, 132.7, 130.6, 129.9, 129.65,
129.4, 129.3, 128.0, 121.0, 98.0, 80.5, 61.5, 59.4 ppm; IR (KBr) v
3422, 3214, 291, 2221, 1631, 1565, 1489, 1446, 1384, 1321, 1056,
964, 762, 689 m-1; MS (ESI) m/z 276.1 ([M þ H]þ); HRMS (ESI)
calcd for C19H17NO (M)þ 275.1310, found 275.1308.
7.6 Hz, 4 H), 4.76 (s, 1 H), 2.47 (s, 6 H), 2.34 (s, 6 H) ppm; 13
C
NMR (CDCl3, 100 MHz, TMS) δ 138.2, 131.5, 128.4, 119.3,
84.3, 82.7, 49.8, 41.1, 21.2 ppm; IR (neat) v 3208, 2976, 2944,
2860, 2823, 2780, 2244, 1509, 1293, 1035, 816 cm-1; MS (ESI) m/
z 288.2 ([M þ H]þ); HRMS (ESI) calcd for C21H22N ([M þ H]þ)
288.1752, found 288.1747.
N,N-Dimethyl-1,5-dicyclohexenyl-1,4-diyn-3-amine (3aj). Pre-
paration according to method B using N,N-dimethylformamide
dimethyl acetal 1a (64 mg, 0.5 mmol) and 1-ethynylcyclohex-1-
ene (159 mg, 1.5 mmol) at 110 °C provided 3aj (107 mg; 80%
yield) after flash chromatography with a solution of EA/Pet =1/
20 as eluent. Yellow liquid; 1H NMR (CDCl3, 400 MHz, TMS)
δ 6.13 (m, 2 H), 4.53 (s, 1 H), 2.34 (s, 6 H), 2.07-2.13 (m, 8 H),
(Z)-Dimethyl-2-(3-(dimethylamino)-1,5-diphenylpenta-1,4-diyn-
3-yl)maleate (9aaa). Preparation according to method G with N,
N-dimethyl-1,5-diphenylpenta-1,4-diyn-3-amine 3aa (129 mg,
0.5 mmol) and dimethyl but-2-ynedioate (106 mg, 0.75 mmol)
at 85 °C provided 9aaa (166 mg; 83% yield) after flash
4560 J. Org. Chem. Vol. 75, No. 13, 2010

Yao et al.
JOCArticle
chromatography with a solution of EA/Pet = 1/6 as eluent.
Yellow solid, mp 87-88 °C; 1H NMR (CDCl3, 400 MHz, TMS)
δ 7.51-7.53 (m, 4 H), 7.33-7.35 (m, 6 H), 6.69 (s, 1 H), 3.91 (s,
3 H), 3.76 (s, 3 H), 2.49 (s, 6 H) ppm; 13C NMR (CDCl3, 100
MHz, TMS) δ 166.1, 164.9, 150.3, 132.0, 128.8, 128.3, 122.0,
121.97, 87.7, 83.1, 62.5, 52.7, 52.1, 40.1 ppm; IR (neat) v 3057,
2994, 2952, 2866, 2829, 2785, 2231, 1743, 1649, 1597, 1490,
1434, 1350, 1252, 1198, 1168, 1069, 1007, 985, 889, 757, 691
cm-1; HRMS (EI) calcd for C25H23NO4 (Mþ) 401.1627, found
401.1634.
Acknowledgment. Funding from Natural Science Foun-
dation of China (No. 20872126) and Zhejiang Provincial
Natural Science Foundation of China (R407106) is acknowl-
edged.
Supporting Information Available: Experimental proce-
dure, crystallographic information files (CIF) for 9aaa and
9aac, and spectroscopic data (1H NMR, 13C NMR, MS, and
HRMS) for the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 13, 2010 4561