Heteropoly acid-catalyzed highly efficient alkylation of 1,3-dicarbonyl compounds with benzylic and propargylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2008.04.126

Various 1,3-dicarbonyl compounds reacted readily with benzylic and propargylic alcohols in the presence of 10 mol % of phosphomolybdic acid supported on silica gel (PMA/SiO₂) under mild reaction conditions to produce 2-benzylic- and 2-propargyl

Full text of DOI:10.1016/j.tetlet.2008.04.126

Tetrahedron Letters 49 (2008) 4296–4301
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Tetrahedron Letters
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Heteropoly acid-catalyzed highly efficient alkylation of 1,3-dicarbonyl
compounds with benzylic and propargylic alcohols
*
J. S. Yadav , B. V. Subba Reddy, T. Pandurangam, K. V. Raghavendra Rao, K. Praneeth,
G. G. K. S. Narayana Kumar, C. Madavi, A. C. Kunwar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Various 1,3-dicarbonyl compounds reacted readily with benzylic and propargylic alcohols in the presence
of 10 mol % of phosphomolybdic acid supported on silica gel (PMA/SiO2) under mild reaction conditions
to produce 2-benzylic- and 2-propargylic-1,3-dicarbonyl compounds in excellent yields and with high
selectivity.
Received 16 August 2007
Revised 12 April 2008
Accepted 23 April 2008
Available online 27 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Heteropoly acids
Benzylic/propargylic alcohols
1,3-Dicarbonyls
Nucleophilic substitution
The alkylation of 1,3-dicarbonyl compounds is a useful transfor-
mation involving C–C bond formation. In principle, direct nucleo-
philic substitution of the hydroxy group in alcohols with
nucleophiles generally requires preactivation of the alcohol
because of its poor leaving ability.1 Consequently, hydroxyl groups
are generally transformed into the corresponding halides, carbox-
ylates, carbonates, phosphonates or related compounds.2 However,
such processes inevitably produce stoichiometric amounts of salt
waste, and also substitution with halides requires a stoichiometric
amount of base which limits their use in scale-up. In most cases,
either a high reaction temperature or a promoter is required to
enhance the leaving ability of the hydroxyl group. Subsequently,
transition-metal based reagents such as palladium in the presence
of a base or acid and stoichiometric amounts of cobalt salts have
been reported for the direct nucleophilic substitution of unmodi-
fied alcohols.3 Most of these methods worked well only with allylic
alcohols but not with benzylic alcohols. Recently, acid catalysts
such as BF3ÁOEt2, InCl3, Bi(OTf)3, Yb(OTf)3, FeCl3 and H-montmoril-
lonite have been employed to perform nucleophilic substitution of
benzylic alcohols with active methylene compounds.4,5 However,
the use of high temperatures, extended reaction times and harsh
conditions in many of the above-mentioned methods limit their
practical utility in large scale synthesis. Moreover, little has been
explored on nucleophilic substitution of propargylic alcohols with
1,3-dicarbonyls.6 Therefore, the direct catalytic substitution of
alcohols with 1,3-dicarbonyls using an efficient, cost-effective
and recyclable catalyst is highly desirable.
Recently, the use of heteropoly acids, HPAs, as environmentally
friendly and economically viable solid acids, has gained increasing
attention owing to their ease of handling and high catalytic activ-
ities and reactivities.7 These compounds possess unique properties,
such as well-defined structure, Bronsted acidity, the possibility to
modify their acid–base and redox properties by changing their
chemical composition (substituted HPAs), ability to accept and
release electrons, high proton mobility, etc.8 In view of green
chemistry, the substitution of harmful liquid acids by reusable so-
lid HPAs as catalysts in organic synthesis is a promising application
of these acids.9 Among them, phosphomolybdic acid (PMA,
H3PMo12O40) is one of the less expensive and commercially avail-
able catalysts.10 However, there have been no reports on the use
of phosphomolybdic acid for the direct alkylation of 1,3-dicarbonyl
compounds with benzylic and propargylic alcohols.
In continuation of our efforts to explore the synthetic utility of
phosphomolybdic acid supported on silica gel (PMA/SiO2),11 we
herein report a direct and efficient protocol for the alkylation of
1,3-dicarbonyl compounds with benzylic and propargylic alcohols.
Initially, we attempted the alkylation of acetyl acetone (1) with
diphenylmethanol (2) in the presence of 10 mol% of PMA/SiO2.
The reaction went to completion at room temperature within
2.0 h to give product 3a in 92% yield (Scheme 1).
This interesting catalytic activity of PMA/SiO2 provided the
incentive for further study of reactions with other active meth-
ylene compounds. Interestingly, 1,3-dicarbonyl compounds such
* Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.126

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 4296–4301
4297
O
O
OH
Me
Me
O
O
10 mol% PMA/SiO2
+
Me
Me
DCE, r.t.
1
3a
2
Scheme 1.
Table 1
PMA/SiO2-catalyzed alkylation of 1,3-diketones with benzylic alcohols
Entry
1,3-Diketone 1
Alcohol 2
Product 3a
Time (h)
Yieldb (%)
92
O
O
O
O
OH
O
O
a
2.0
Me
Me
Ph
Me
OEt
Ph
Me
Me
O
O
OH
OH
O
O
O
O
b
c
2.5
2.0
90
90
Me
Ph
OEt
Ph
O
O
O
O
OH
OH
O
O
O
O
Me
Me
Me
d
e
1.5
3.0
88
65
Me
Me
Me
OEt
OEt
O
O
O
O
O
O
OH
OH
OH
O
O
O
O
Ph
Ph
f
2.5
2.0
88
75
Ph
Ph
OEt
Ph
g
OEt
O
O
O
O
Ph
h
2.5
2.0
88
93
Ph
Ph
O
O
OH
Me
Me
i
Me
Me
MeO
MeO
MeO
MeO
OMe
OMe
O
O
OH
Me
OEt
O
O
j
2.5
82
Me
OEt
OMe
OMe
(continued on next page)

4298
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 4296–4301
Table 1 (continued)
Entry
1,3-Diketone 1
Alcohol 2
Product 3a
Time (h)
3.0
Yieldb (%)
88
OH
O
O
O
O
k
OEt
OEt
MeO
OMe
MeO
OMe
O
O
OH
OH
O
O
O
O
Me
Me
Me
l
1.5
2.0
90
75
Me
Me
Me
O
O
O
OEt
m
OEt
O
OH
O
O
OEt
n
3.0
90
OEt
a
All products were characterized by 1H, 13C NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
b
O
O
OH
OEt
O
O
10 mol% PMA/SiO2
DCE, r.t.
+
OEt
3n
Scheme 2.
Table 2
PMA/SiO2-catalyzed alkylation of 1,3-diketones with propargylic alcohols
Entry
1,3-Diketone 1
Alcohol 2
Product 4a
Time (h)
Yieldb (%)
O
O
O
O
OH
O
O
a
3.5
90
Me
Me
Ph
OMe
Me
OMe
O
O
OH
OH
Me
Ph
O
O
O
O
b
c
3.0
2.5
86
88
Me
Ph
Me
Ph
O
O
O
OH
OH
O
O
O
O
Me
Me
d
e
3.0
3.0
88
85
Me
Me
Me
Me
Me
O

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 4296–4301
4299
Table 2 (continued)
Entry
1,3-Diketone 1
Alcohol 2
Product 4a
Time (h)
2.5
Yieldb (%)
OH
O
O
O
O
f
90
Ph
Ph
Ph
Ph
Me
Me
Me
O
O
OH
O
O
O
O
Me
g
3.0
86
Me
Me
O
O
O
O
O
O
O
O
O
OH
OH
h
3.5
2.5
2.5
3.0
3.0
2.0
2.0
80
85
O
O
O
O
O
O
O
O
O
O
O
O
Ph
Ph
i
Ph
Me
Me
Ph
Me
Me
Ph
O
OH
OH
OH
Me
Me
Ph
OMe
Me
j
88
OMe
Me
Ph
O
O
O
O
k
l
85
Ph
86
OH
Me
Me
Me
Ph
m
90c
Ph
Ph
Me
Ph
Ph
Ph
OH
Ph
Ph
n
92c
All products were characterized by 1H, 13C NMR, IR and mass spectroscopy.
Isolated and unoptimized yield.
E/Z ratio 9:1.
a
b
c
as ethyl 3-oxobutanoate and 1,3-diphenyl-1,3-propanedione
reacted smoothly with diphenylmethanol to give the correspond-
ing 2-benzylic-1,3-dicarbonyl compounds in excellent yields
(Table 1, entries b and c). Other benzylic alcohols such as,
1-phenyl-1-propanol, 1-phenylethanol and 1-(3,4-dimethoxy-
phenyl)-1-ethanol also reacted efficiently with 1,3-dicarbonyl
compounds at room temperature to furnish benzyl substituted
1,3-dicarbonyl compounds (Table 1, entries d–k). Interestingly,
O
O
Me
Me
OH
O
O
10 mol% PMA/SiO2
DCE, r.t.
Ph
+
Me
Me
Ph
4m
Scheme 3.

4300
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 4296–4301
doubly activated benzylic alcohols reacted rapidly with 1,3-dicar-
bonyl compounds at room temperature to afford the corresponding
C-2 benzylated 1,3-dicarbonyl compounds (Scheme 2, Table 1,
entries l–n).
Like benzylic alcohols, various propargylic alcohols including
1,3-diphenyl-2-propyn-1-ol, 1-(4-methylphenyl)-2-heptyn-1-ol,
1-phenyl-2-heptyn-1-ol and 2-naphthyl-2-heptyn-1-ol also re-
acted readily with various 1,3-dicarbonyl compounds to furnish
the respective 2-propargylic-1,3-dicarbonyl compounds (Table 2,
entries a–l). In addition, doubly activated (E)-1,5-diphenyl-1-pen-
ten-4-yn-3-ol also participated well in this reaction (Scheme 3,
Table 2, entries m and n).
The structure of 4m was established by various NMR experi-
ments. The product could have two possible structures depicted
as A and B. HSQC and HMBC experiments were carried out to
distinguish between the two possibilities. The HMBC correlation
between H10–C3 is very distinct (Fig. 1), which can only arise in
structure A. Further support for structure A came from the HMBC
correlation between the acetylenic carbon C2 attached to the
phenyl ring and the aliphatic proton at C4. Both these HMBC corre-
lations in B would not be observed, being between nuclei five
bonds apart. HMBC correlations between H4–C11, H4–C9, H5–
C10 and H10–C5 provide additional evidence for the structure A
for 4m. The absence of a correlation between C7–H10 further
supports structure A.
In all the cases, the reactions proceeded efficiently with high
selectivity and were complete within 1.5–3.5 h. In the absence of
PMA/SiO2, no reaction was observed. No addition or rearranged
products were observed in the cases of allylic and propargylic alco-
hols (Table 2, entries m and n). The nucleophilic substitution of the
chiral secondary propargyl alcohol, (R)-1-(naphthalen-2-yl)-3-phe-
nylprop-2-yn-1-ol with acetylacetone gave the racemic product.
This clearly indicates that the reaction follows an SN1 mechanism.
This method is compatible with alkene, alkyne, ester and aryl alkyl
ether functional groups. As solvent, dichloroethane gave the best
results. All the products were characterized by 1H, 13C NMR, IR
Figure 1. Characteristic HMBC and HSQC correlations of 4m.

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 4296–4301
4301
10. (a) Kishore Kumar, G. D.; Baskaran, S. Synlett 2004, 1719–1722; (b) Kishore
Kumar, G. D.; Baskaran, S. J. Org. Chem. 2005, 70, 4520–4523; (c) Kozhevnikova,
E. F.; Derouane, E. G.; Kozhevnikov, I. V. Chem. Commun. 2002, 1178–1179; (d)
Firouzabadi, H.; Iranpoor, N.; Amani, K. Synthesis 2003, 408–412.
11. (a) Yadav, J. S.; Raghavendra, S.; Satyanarayana, M.; Balanarsaiah, E. Synlett
2005, 2461–2464; (b) Yadav, J. S.; Satyanarayana, M.; Balanarsaiah, E.;
Raghavendra, S. Tetrahedron Lett. 2006, 47, 6095–6098.
12. Experimental procedure: A mixture of 1,3-dicarbonyl compound (1.0 mmol),
alcohol (1.0 mmol) and PMA/SiO2 (10 mol %) in dichloroethane (5 mL) was
stirred at room temperature for the appropriate time (Tables 1 and 2). After
completion of the reaction as indicated by TLC, the reaction mixture was
filtered and diluted with water and extracted with dichloromethane
(2 Â 15 mL). The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo and purified by column chromatography on
silica gel (Merck, 100–200 mesh, ethyl acetate/hexane, 1:9) to afford pure 2-
substituted 1,3-dicarbonyl compounds. The spectroscopic data of the products
were identical with the data reported in the literature.
and mass spectroscopy. The effects of various silica-supported acid
catalysts such as HClO4/SiO2, H2SO4/SiO2 and NaHSO4/SiO2 were
screened for this reaction. Of these catalysts, PMA/SiO2 was found
to give the best results in terms of conversion and reaction time.
The scope and generality of this process was illustrated with
respect to various 1,3-dicarbonyl compounds and benzylic as well
as propargylic alcohols, and the results are presented in Tables 1
and 2.12 The advantages of this method are the ready availability
of alcohols, high atom efficiency, no salt formation and water as
the only by-product.
In summary, we have described a simple, convenient and effi-
cient protocol for the benzylation and propargylation of 1,3-dicar-
bonyl compounds with benzylic and propargylic alcohols using
recyclable PMA/SiO2 as the catalytic system. In addition to its
efficiency, simplicity and mild reaction conditions, this method
provides high yields of 2-benzyl- and 2-propargyl-1,3-dicarbonyl
compounds in short reaction times with high selectivity.
Spectral data for selected products:Compound 3b: Ethyl 2-benzhydryl-3-
oxobutanoate: Colourless solid, mp 89–91 °C; IR (KBr): 3084, 2993, 2955, 1736,
1600, 1456, 1363, 1320, 1246, 1143, 1013, 914, 840, 753, 700, 631, 542 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 0.98 (t, 3H, J = 6.7 Hz), 2.06 (s, 3H), 3.95 (q, 2H,
J = 6.7 Hz), 4.42 (d, 1H, J = 12.0 Hz), 4.72 (d, 1H, J = 12.0 Hz), 7.10–7.27 (m,
10H); 13C NMR (75 MHz, CDCl3): d 13.7, 29.8, 50.8, 61.3, 65.1, 126.7, 126.8,
127.6, 127.7, 128.4, 128.7, 141.1, 141.5, 167.5; EIMS (M+Na): m/z: 319; HRMS
calcd for C19H20O3Na: 319.1310. Found: 319.1296.
Acknowledgement
Compound 3f: 1,3-Diphenyl-2-(1-phenylpropyl)propane-1,3-dione: Colourless
solid, mp 154–156 °C; IR (KBr): 3061, 2959, 2870, 1684, 1593, 1447, 1270,
1190, 1021, 962, 840, 760, 684, 598 cmÀ1 1H NMR (300 MHz, CDCl3): d 0.71 (t,
;
T.P., K.V.R.R., K.P. and G.G.K.S.N.K. thank CSIR, New Delhi for the
award of fellowships.
3H, J = 6.7 Hz), 1.55–1.83 (m, 2H), 3.75–3.85 (m, 1H), 5.49 (d, 1H, J = 10.5 Hz),
7.05–7.57 (m, 11H), 7.67–7.74 (m, 2H), 8.02–8.08 (m, 2H); 13C NMR (75 MHz,
CDCl3): d 11.9, 27.0, 29.7, 48.7, 64.6, 126.6, 128.2, 128.3, 128.4, 128.6, 128.8,
132.8, 133.5, 137.0, 137.4, 141.2, 194.3, 195.1; EIMS (M+Na): m/z: 365; HRMS
calcd for C24H22O2Na: 365.1517. Found: 365.1507.
References and notes
Compound 3h: 1,3-Diphenyl-2-(1-phenylethyl)propane-1,3-dione: Colourless
solid, mp 126–128 °C; IR (KBr): 3061, 3028, 2963, 1692, 1594, 1446, 1324,
1. (a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944; (b) Ma, S.; Yu,
S.; Peng, Z.; Guo, H. J. Org. Chem. 2006, 71, 9865–9868.
1271, 1197, 972, 754, 697, 602, 539 cmÀ1 1H NMR (200 MHz, CDCl3): d 1.33 (d,
;
3H, J = 7.5 Hz), 4.02–4.12 (m, 1H), 5.44 (d, 1H, J = 9.8 Hz), 7.01–7.56 (m, 11H),
7.70–7.77 (m, 2H), 7.99–8.07 (m, 2H); 13C NMR (75 MHz, CDCl3): d 20.5, 41.3,
65.2, 125.0, 126.6, 127.7, 128.3, 128.4, 128.5, 128.8, 132.9, 133.5, 135.1, 136.1,
137.2, 194.6, 195.0; EIMS (M+Na): m/z: 351. HRMS calcd for C23H20O2Na:
351.1360. Found: 351.1352.
2. (a) Westermaier, M.; Mayr, H. Org. Lett. 2006, 8, 4791–4794; (b) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6, 3199–3202; (c) De la Herrán,
G.; Segura, A.; Csáky, A. G. Org. Lett. 2007, 9, 961–964.
3. (a) Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 3241–3244; (b) Mukhopadhyay,
M.; Iqbal, J. Tetrahedron Lett. 1995, 36, 6761–6764.
Compound 4a: Methyl 2-acetyl-3,5-diphenyl-4-pentynoate: Liquid, IR (KBr): m
4. (a) Bisaro, F.; Pretat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823–1826; (b) Yasuda,
M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793–796; (c) Rueping,
M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9, 825–828.
5. (a) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron Lett. 2007, 48, 3969–
3973; (b) Jana, U.; Biswas, S.; Maiti, S. Tetrahedron Lett. 2007, 48, 4065–4069;
(c) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew.
Chem., Int. Ed. 2006, 45, 2605–2609.
3028, 2921, 2851, 1739, 1598, 1490, 1439, 1354, 1280, 1249, 1149, 755 cmÀ1
.
1H NMR (200 MHz, CDCl3): d 2.42 (s, 3H), 3.81 (s, 3H), 3.97 (d, 1H, J = 10.1 Hz),
4.60 (d, 1H, J = 10.1 Hz), 7.25–7.45 (m, 10H). 13C NMR (75 MHz, CDCl3): d 24.0,
35.1, 75.5, 84.8, 85.4, 126.6, 127.7, 128.2, 128.3, 128.6, 128.8, 131.6, 138.1,
201.5; LCMS: m/z: (M+Na) 329. HRMS calcd for C20H18O3Na: 329.1153. Found:
329.1155.
Compound 4m: 3-[3-Phenyl-1-(2-phenyl-1-ethynyl)-(E)-2-propenyl]-2,4-
pentanedione: Liquid, IR (KBr): m 3027, 2923, 2853, 1702, 1597, 1490, 1444,
6. Sanz, R.; Miguel, D.; Martinez, A.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Org.
Lett. 2007, 9, 727–730.
7. Misono, M.; Ono, I.; Koyano, G.; Aoshima, A. Pure Appl. Chem. 2000, 72, 1305.
8. Kozhevnikov, I. V. Chem. Rev. 1998, 98, 171–198.
9. (a) Saidi, M. R.; Torkiyan, L.; Azizi, N. Org. Lett. 2006, 8, 2079–2082; (b)
Baskaran, S.; Kumar, G. D. K. Chem. Commun. 2004, 1026–1027; (c) Kita, Y.;
Tohma, H.; Kumar, G. A.; Hamamoto, H. Chem. Eur. J. 2002, 8, 5377–5383; (d)
Rafiee, E.; Jafari, H. Bioorg. Med. Chem. Lett. 2006, 16, 2463–2466; (e) Okumura,
K.; Yamashita, K.; Hirano, M.; Niva, M. Chem. Lett. 2005, 34, 716–717.
1418, 1356, 1262, 1151, 967, 755 cmÀ1 1H NMR (500 MHz, CDCl3): d 7.45–7.21
.
(m, 10H, Ar), 6.75 (dd, 1H, dd, 1H, J = 1.0, 15.7, Hz, H6), 6.06 (dd, 1H, J = 6.7,
15.7 Hz, H5), 4.31 (ddd, 1H, J = 1.0, 6.7, 10.3 Hz, H4), 3.96 (d, 1H, J = 10.3 Hz,
H10), 2.34 (s, 3H, Me), 2.23 (s, 3H, Me). 13C NMR (75 MHz, CDCl3): d 28.8, 34.7,
73.6, 85.8, 86.4, 122.5, 124.6, 126.4, 127.9, 128.2, 128.5, 128.6, 131.6, 133.1,
136.1, 201.2. LCMS: m/z: (M+Na) 339. HRMS calcd for C22H20O2Na: 339.1360.
Found: 339.1366.