Synthesis of trisubstituted-4H-pyrans via unexpected cycloaddition of aldehydes with acetylenic ketones mediated by DMAP and 2, 4-pentanedione

Article abstract of DOI:10.2174/157017809789869438

A cycloaddition of aldehydes and acetylenic ketones mediated by 4-dimethylaminopyridine and 2, 4- pentanedione is reported. The method supplies a facile way to synthesize 3, 4, 5-trisubstituted-4H-pyrans in moderate to good yields under mild conditions.

Full text of DOI:10.2174/157017809789869438

560
Letters in Organic Chemistry, 2009, 6, 560-563
Synthesis of Trisubstituted-4H-Pyrans via Unexpected Cycloaddition of
Aldehydes with Acetylenic Ketones Mediated by DMAP and 2,4-
Pentanedione
Bin Hua, Qing-Fa Zhou*,b, Kai Tanga and Song Xue*,a
aDepartment of Applied Chemistry, Tianjin University of Technology, Tianjin 300384, China
bDepartment of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China
Received March 10, 2009: Revised August 04, 2009: Accepted August 27, 2009
Abstract: A cycloaddition of aldehydes and acetylenic ketones mediated by 4-dimethylaminopyridine and 2,4-
pentanedione is reported. The method supplies a facile way to synthesize 3,4,5-trisubstituted-4H-pyrans in moderate to
good yields under mild conditions.
Keywords: Cycloaddition, acetylenic ketones, aldehydes, 4H-pyran, DMAP, 2,4-pentanedione.
INTRODUCTION
RESULTS AND DISCUSSION
Heterocycles are of great importance due to their
potential in the discovery of new biologically active
compounds [1,2]. The development of an efficient hetero-
cyclization using metal-free catalyst has been drawing much
attention over the past decades [3-5]. Recently, reactions
based on nucleophilic catalysis via conjugate addition of N-
and P-nucleophiles have proven to be useful for the
development of new annulation reactions providing various
heterocycles [6-17]. Despite the reaction of aldehydes with
acetylides has been reported [18,19], there exist no reports
on the synthesis of 4H-pyrans through Zwitterionic species
with aldehydes [20]. Herein, we wish to report a hetero-
cyclization of aldehydes with acetylenic ketones mediated by
4-dimethylaminopyridine (DMAP) and 2,4-pentanedione.
Intrigued by this result, the reaction was carried out
under various conditions, and the results are shown in Table
1. Treatment of 3-butyn-2-one 1a with 4-nitrobenzaldehyde
2a in the presence of DMAP and 2,4-pentanedione for 12 h
afforded 4a in 84% yield (Table 1, entry 1). Since 2,4-
pentanedione was not involved in the product, the reaction
was performed without it. However, a lower yield of the
product (59%) was obtained in the absence of 2,4-
pentanedione. Prolonged reaction time of 24 h gave 78%
yield (Table 1, entriy 3). These results imply 2,4-
pentanedione mediated this hetero-cyclization reaction.
When the temperature was lowered to 0 ˚C, the yield was
decreased to 64% (Table 1, entry 4). THF or toluene as a
solvent was usable, and gave moderate yield. However, Et2O
and CH3CN gave trace amount of the product. Other
nitrogen Lewis bases were then examined in the reaction of
4-nitrobenzaldehyde with 3-butyn-2-one in the presence of
2,4-pentanedione. It was found that pyridine, DABCO and
Et3N are less efficient catalysts and gave the product 4a in
62%, 65% and 49% yields, respectively. No reaction
occurred when the reaction was catalyzed by DBU. Thus, the
optimal reaction conditions were established for this reaction
using 10 mol% DMAP and 50 mol% 2,4-pentanedione to
perform the reaction in CH2Cl2 at room temperature for 12 h.
Recently, we have described a three-component reaction
of aldehydes with acetylenic ketones and 1,3-dicarbonyl
moieties, catalyzed by triphenylphosphine to synthesize
multi-carbonyl compounds (Scheme 1) [21]. When DMAP,
in place of Ph3P, was tested as a catalyst, a new
cycloaddition reaction had happened. For example, reaction
of 3-butyn-2-one with 4-nitrobenzaldehyde and 2,4-
pentanedione in the presence of DMAP gave a new product.
The structure of the product was assigned as 3,4,5-
trisubstitued-4H-pyrane 4a on the basis of spectroscopic
analysis. It is worth to note that classical approach for the
synthesis of 4H-pyrane is through Knoevenagel
condensation of aldehyde with ꢀ-dicarbonyl compound and
subsequent Michael addition with another ꢀ-dicarbonyl
compound. Five-substituted-4H-pyrans are generally formed.
But the synthesis of trisubstituted-4H-pyrans is somewhat
limited [22].
Under optimized reaction conditions, we next examined
the reaction of other aromatic aldehydes with 3-butyn-2-one,
and these results are summarized in Table 2. It was found
that the reactions of aromatic aldehydes with a strong
electron-withdrawing group, such as NO2 and CN groups, on
the aromatic ring afforded the corresponding products in
good yields. But the substituents of chloro-, bromo-, methyl-,
methoxyl, and CF3 groups at para position of their aromatic
rings gave 1,3,5-triacetylbenzene along with trace amount of
the desired products 4. The product of 1,3,5-triacetylbenzene
was formed through cyclotrimerization of 3-butyn-2-one
mediated by DMAP and 2,4-pentanedione [23].
Unfortunately, these arylaldehydes afforded small amount of
products 4 (<10%), when the reactions were carried out in
*Address correspondence to these authors at the Department of Applied
Chemistry, Tianjin University of Technology, Tianjin 300384, China; Fax:
+86-22-60214252; E-mail: xuesong@ustc.edu.cn
Department of Organic Chemistry, China Pharmaceutical University,
Nanjing 210009, China; E-mail: zqf@mail.ustc.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Synthesis of Trisubstituted-4H-Pyrans via Unexpected Cycloaddition
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
561
O
O
O
Ar
O
O
O
O
R1
R1
DMAP
ArCHO
Ph3P
+
+
CH2
R1
this work
R1
Ar
O
3
1
2
4
O
O
Scheme 1. Reactions of aldehydes with acetylenic ketones and 2,4-pentanedione catalyzed by Lewis bases.
Table 1. Reaction of 3-Butyn-2-one and 4-Nitrobenzaldehyde under Various Conditionsa
NO2
CHO
O
O
O
2,4-pentanedione (50 mol%)
Lewis base (10 mol%), N2, r.t.
+
NO2
O
1a
2a
4a
entry
Lewis base
Solvent
Time/h
Yield (%)b
1
2
3
4
5
6
7
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
12
12
24
24
12
12
12
84
59c
78c
64d
67
toluene
Et2O
53
Trace
8
DMAP
Pyridine
DABCO
Et3N
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
12
12
12
12
12
Trace
62
9
10
11
12
65
49
DBU
NRe
aUnless otherwised specified, all of the reactions were carried out in the presence of 2,4-pentanedione (50 mol%) and Lewis base (10 mol% ) based on acetylenic ketone.
bYields after purification by silica gel column chromatography.
cWithout 2,4-pentanedione.
dat 0 ˚C.
eNR = no reaction.
A
tentative mechanism to account for this new
the absence of 2,4-pentanedione. These results demonstrate
that, active arylaldehyde with NO2 or CN group is of great
importance for the formation of product 4. It should be noted
that 4-methyl-3-nitrobenzaldehyde gave the corresponding
product 4e in 8% yield under the typical conditions. The
yield was increased to 46%, when the reaction was
performed without 2,4-pentanedione. When 1-phenylprop-2-
yn-1-one as an aromatic acetylenic ketone instead of 3-
butyn-2-one was subjected to this reaction, the
corresponding products 4f-i were obtained in moderate
yields along with the byproduct of 1,3,5-tribenzoylbenzene,
which was formed through cyclotrimerization of 1-
phenylprop-2-yn-1-one.
cyclization is outlined in Scheme 2. DMAP acts as a
nucleophilic promoter to initiate the reaction and produce
zwitterionic intermediate 5. The intermediate 5 adds to
aldehyde to form 6, which generates 7 through an
intramolecular conjugate addition of the oxygen anion to the
ꢀ carbon of ketone. The intermediate 7 might be transformed
into oxetene 8 by elimination of DMAP. The unstable
oxetene 8 generates a polar intermediate 9 [24], followed by
cycloaddition with a second acetylenic ketone to give the
product 4 [25]. The 2,4-pentanedione might serve as
Brønsted acid to activate the conjugate addition step for the
formation of intermediate 6. The mechanistic details of this
reaction need further investigation.

562 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Hu et al.
Table 2. Reactions of Aldehydes and Acetylenic Ketones
O
Ar
O
2,4-pentanedione (50 mol %)
DMAP (10 mol %)
O
R1
R1
ArCHO
+
R1
CH2Cl2, N2, r.t., 12 h
O
1
2
4
Entry
R1
Ar
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Ph
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4a
4b
4c
4d
4e
4f
84
82
80
81
3-NO2-4-CH3C6H3
4-NO2C6H4
3-NO2C6H4
4-CNC6H4
8 (46b)
56
Ph
4g
4h
4i
59
Ph
55
Ph
2-CNC6H4
33
aYields after purification by silica gel column chromatography.
bwithout 2,4-pentanedione.
O
O
O
O
R1
R1
Ar
NR3
O
R1
R3N
ArCHO
R1
O
R3N
R3N
Ar
1
5
7
6
O
O
O
Ar
O
O
O
R1
R1
R1
R1
R1
O
O
Ar
Ar
R3N
4
8
9
Scheme 2. Possible mechanism for the formation of 3,4,5-trisubstituted-4H-pyrans.
CONCLUSION
Chromatographic purification was performed on silica gel
(100~200 mesh) and analytical thin layer chromatography
(TLC) on silica gel 60-F254, which was detected by
In summary, we have described a new cycloaddition of
aryl aldehydes with acetylenic ketones mediated by 4-
dimethylaminopyridine and 2,4-pentanedione. The reactions
of 3-butyn-2-one with active aryl aldehydes containing NO2
and CN groups on their aromatic rings gave 3,4,5-
trisubstituted-4H-pyrans in good yields under mild
conditions. 1-Phenylprop-2-yn-1-one as an aromatic
acetylenic ketone afforded the desired products in moderate
yields due to the competing cyclotrimerization reaction.
1
fluorescence. H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were measured with a Bruker AC 300 spectrometer
1
using tetramethylsilane (TMS) as an internal standard. H
NMR data are reported as follows: ꢀ, chemical shift;
coupling constants (J are given in Hertz, Hz) and integration.
High resolution mass spectra were obtained with
a
Micromass GCT-TOF mass spectrometer. IR spectra were
recorded as thin films on
spectrophotometer.
a
Perkin-Elmer FT210
EXPERIMENTAL SECTION
General
General Procedure for the Synthesis of 4H-Pyrans
To a solution of acetylenic ketone (0.3 mmol), 2,4-
pentanedione ( 0.15 mmol) and aromatic aldehyde (0.3
All reactions were conducted under nitrogen atmosphere
in oven-dried glassware with magnetic stirring.

Synthesis of Trisubstituted-4H-Pyrans via Unexpected Cycloaddition
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
563
mmol) in dry CH2Cl2 (2 mL) was added DMAP (0.03 mmol)
at 0 °C under nitrogen atmosphere. The resulting mixture
was stirred at room temperature for 12 h. The solvent was
removed in vacuo and the residue was purified by column
chromatography on silica gel (10:1 petroleum ether/EtOAc)
to give the desired product.
3,5-dibenzoyl-4-(4-cyanophenyl)-4H-pyran (4h)
1H-NMR: ꢀ = 8.17 (d, J = 8.4 Hz, 2H),7.66 (d, J = 8.7
Hz, 2H), 7.56-7.51 (m, 6H), 7.45-7.39 (m, 4H), 7.38 (s, 2H),
5.47 (s, 1H); 13C-NMR: ꢀ = 193.5, 151.4, 150.6, 147.1,
137.8, 132.4, 129.6, 128.8, 128.7, 123.9, 120.2, 120.1, 35.5;
IR (neat; cm-1): v 1629, 1597, 1516; HRMS (EI): calcd for
C26H17NO3 (M+), 391.1208; found, 391.1210.
3,5-diacetyl-4-(4-nitrophenyl)-4H-pyran (4a)
1H-NMR: ꢀ = 8.03 (d, J = 8.7 Hz, 2H), 7.58 (s, 2H), 7.42
(d, J = 8.7 Hz, 2H), 4.91 (s, 1H), 2.13 (s, 6H); 13C-NMR: ꢀ =
194.4, 150.8, 149.8, 146.9, 129.7, 123.6, 121.5, 33.8, 25.6;
IR (neat; cm-1): v 1693, 1597, 1519, 1346; HRMS (EI): calcd
for C15H13NO5 (M+), 287.0794; found 287.0790.
3,5-dibenzoyl-4-(2-cyanophenyl)-4H-pyran (4i)
1H-NMR: ꢀ = 7.71 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.58-
7.51 (m, 6H), 7.46-7.39 (m, 6H), 7.37 (s, 2H), 5.40 (s, 1H);
13C-NMR: ꢀ = 193.5, 151.4, 145.0, 137.8, 133.8, 132.4,
131.9, 130.9, 129.3, 128.8, 128.7, 120.3, 118.9, 112.86, 35.1;
IR (neat; cm-1): v 1648, 1597, 1522. HRMS (EI): calcd for
C26H17NO3(M+), 391.1208; found, 391.1211.
3,5-diacetyl-4-(3-nitrophenyl)-4H-pyran (4b)
1H-NMR: ꢀ = 7.95-7.92 (m, 2H), 7.74 (d, J = 7.6 Hz,
1H), 7.60 (s, 2H), 7.37-7.31 (m, 1H), 4.92 (s, 1H), 2.14 (s,
6H); 13C-NMR: ꢀ = 194.4, 149.9, 148.6, 145.8, 135.9, 128.9,
123.0, 122.1, 121.5, 33.6, 25.6; IR (neat; cm-1): v 1672,
1602, 1529. HRMS (EI): calcd for C15H13NO5 (M+),
287.0794; found 287.0795.
ACKNOWLEDGEMENTS
We are grateful to the National Natural Science
Foundation of China (20772116) and the Tianjin Natural
Science Foundation (09JCZDJC24400) for financial
supports.
3,5-diacetyl-4-(2-nitrophenyl)-4H-pyran (4c)
1H-NMR: ꢀ = 7.75-7.53 (m, 1H), 7.72 (s, 2H), 7.53-7.38
(m, 1H), 7.30-7.20 (m, 2H), 5.67 (s, 1H), 2.19 (s, 6H); 13C-
NMR: ꢀ = 195.0, 150.1, 149.8, 137.4, 132.6, 131.3, 127.8,
124.8, 121.1, 29.9, 25.9; IR (neat; cm-1): v 1672, 1602, 1529.
HRMS (EI): calcd for C15H13NO5 (M+), 287.0794; found
287.0791.
REFERENCES
[1]
Couladouros, E.A.; Strongilos, A.T. Angew. Chem. Int. Ed. Engl.,
2002, 41, 3677-3680.
[2]
Moonen, K.; Laureyn, I.; Stevens, C. Chem. Rev., 2004, 104, 6177-
6215.
[3]
[4]
[5]
Lu, X; Zhang, C.; Xu, Z. Acc. Chem. Res., 2001, 34, 535-544.
Fu, G.C. Acc. Chem. Res., 2004, 37, 542-547.
Dalko, P.I.; Moisan, L. Angew. Chem. Int. Ed. Engl., 2004, 43,
5138-5175.
Wang, J.-C.; Ng, S.-S.; Krische, M.J. J. Am. Chem. Soc., 2003,
125, 3682-3683.
Nair, V.; Menon, R.S.; Beneesh, P.B.; Sreekumar, V.; Bindu, S.
Org. Lett., 2004, 6, 767-769.
Jung, C.-K.; Wang, J.-C.; Krische, M.J. J. Am. Chem. Soc., 2004,
126, 4118-4119.
Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc., 2003, 125, 4716-
4717.
Zhu, X.F.; Henry, C.E.; Wang, J.; Dudding, T.; Kwon, O. Org.
Lett., 2005, 7, 1387-1390.
Du, Y.; Lu, X.; Yu, Y. J. Org. Chem., 2002, 67, 8901-8905.
Tejedor, D.; Santos-Exposito, A.; Gonzalez-Cruz, D.; Marrero-
Tellado, J.J.; Garcia-Tellado, F. J. Org. Chem., 2005, 70, 1042-
1045.
Wang, Y.-G.; Cui, S.-L.; Lin, X.-F. Org. Lett., 2006, 8, 1241-1244.
Nair, V.; Pillai, A. N.; Menon, R. S.; Suresh, E. Org. Lett., 2005, 7,
1189-1191.
3,5-diacetyl-4-(4-cyanophenyl)-4H-pyran (4d)
1H-NMR: ꢀ = 8.04 (d, J = 8.7 Hz, 2H), 7.58 (s, 2H), 7.42
(d, J = 8.7 Hz, 2H), 4.92 (s, 1H), 2.13 (s, 6H); 13C-NMR: ꢀ =
194.4, 150.8, 149.8, 146.8, 129.7, 129.5, 123.6, 121.5, 33.8,
25.6; IR (neat; cm-1): v 1656, 1600, 1515. HRMS (EI): calcd
for C16H13NO3 (M+), 267.0895; found, 267.0898.
[6]
[7]
[8]
[9]
[10]
3,5-diacetyl-4-(4-methyl-3-nitrophenyl)-4H-pyran (4e)
1H-NMR: ꢀ = 7.77 (s, 1H), 7.65 (s, 2H), 7.61 (d, J = 7.8
Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 4.92 (s, 1H), 2.52 (s, 3H),
2.22 (s, 6H); 13C-NMR: ꢀ = 194.6, 149.8, 143.4, 134.3,
132.6, 124.3, 121.7, 33.2, 25.8, 20.3; IR (neat; cm-1): v 1661,
1598, 1525. HRMS (ESI): calcd for C16H15NO5 (M+Na) +,
324.0842; found, 324.0837.
[11]
[12]
[13]
[14]
3,5-dibenzoyl-4-(4-nitrophenyl)-4H-pyran (4f)
1H-NMR: ꢀ = 8.17 (d, J = 8.7 Hz, 2H),7.66 (d, J = 8.7
Hz, 2H), 7.63-7.51 (m, 6H), 7.45-7.39 (m, 4H), 7.38 (s, 2H),
5.47 (s, 1H); 13C-NMR: ꢀ = 193.56, 151.4, 150.6, 147.0,
137.7, 132.4, 129.6, 128.79, 128.74, 123.9, 120.1, 35.5; IR
(neat; cm-1): v 1641, 1597, 1517, 1345. HRMS (EI): calcd
for C25H17NO5 (M+), 411.1107; found, 411.1094.
[15]
Nair, V.; Sreekanth, A. R.; Vinod, A. U. Org. Lett., 2001, 3, 3495-
3497.
[16]
[17]
[18]
[19]
[20]
Zhao, G.-L.; Shi, M. J. Org. Chem., 2005, 70, 9975-9984.
Zhao, G.-L.; Shi, M. Org. Biomol. Chem., 2005, 3, 3686-3694.
Trost, B. M.; Li, C.-J. J. Am. Chem. Soc., 1994, 116, 10819-10820.
Ma, C.; Ding, H.; Wang, Y. Org. Lett., 2006, 8, 3133-3136.
For DBU catalyzed [3+3]cycloaddition of 1,3-conjugated enyne
with ꢀ-keto compounds for preparation of 4H-pyrans, see: Yu, X.-
Z.; Ren, H.-J.; Xiao, Y.-J.; Zhang, J.-L. Chem. Eur. J., 2008, 14,
8481-8485.
Xue, S.; Zhou, Q.-F.; Li, L.-Z.; Guo, Q.-X. Synlett, 2005, 2990-
2992.
Reynolds, G.A.; Chen, C.H. J. Org. Chem., 1981, 46, 184-185.
Zhou, Q.-F.; Yang, F.; Guo, Q.-X.; Xue, S. Synlett, 2007, 215-218.
Martino, P.C.; Shevlin, P.B. J. Am. Chem. Soc., 1980, 102, 5429-
5430.
Khoshkholgh, M.J.; Balalaie, S.; Bijanzadeh, H.R.; Gross, J.H.
Synlett, 2009, 55-58.
3,5-dibenzoyl-4-(3-nitrophenyl)-4H-pyran (4g)
1H-NMR: ꢀ = 8.28 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.92
(d, J = 7.8 Hz, 1H), 7.57-7.48 (m, 6H), 7.57-7.42 (m, 5H),
7.39 (s, 2H), 5.48 (s, 1H); 13C-NMR: ꢀ =193.6, 151.5, 148.8,
145.6, 137.8, 135.8, 132.4, 129.4, 128.8, 128.7, 122.9, 122.3,
120.1, 35.2; IR (neat; cm-1): v 1647, 1597, 1528. HRMS
(EI): calcd for C25H17NO5 (M+), 411.1107; found, 411.1104.
[21]
[22]
[23]
[24]
[25]