DMF Dimethyl Acetal as Carbon Source for α-Methylation of Ketones: A Hydrogenation-Hydrogenolysis Strategy of Enaminones

Article abstract of DOI:10.1021/acs.joc.5b00084

A novel heterogeneous catalytic hydrogenation-hydrogenolysis strategy has been developed for the α-methylation of ketones via enaminones using DMF dimethyl acetal as carbon source. This strategy provides a very convenient route to α-methylated ketones using a variety of ketones without any base or oxidant. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00084

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Note
DMF-Dimethyl Acetal as Carbon Source for alpha-Methylation of
Ketones: A Hydrogenation-Hydrogenolysis Strategy of Enaminones
Ashwini Borah, Limi Goswami, Kashmiri Neog, and Pranjal Gogoi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00084 • Publication Date (Web): 07 Apr 2015
Downloaded from http://pubs.acs.org on April 13, 2015
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DMF-Dimethyl Acetal as Carbon Source for α-Methylation of
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Ketones: A Hydrogenation-Hydrogenolysis Strategy of
Enaminones
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Ashwini Borah, Limi Goswami, Kashmiri Neog and Pranjal Gogoi*
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat
785006, India.
Eꢀmail: gogoipranj@yahoo.co.uk
ABSTRACTS: A novel heterogeneous catalytic hydrogenationꢀhydrogenolysis strategy has been
developed for the αꢀmethylation of ketones via enaminones using DMFꢀdimethyl acetal as carbonꢀ
source. This strategy provides a very convenient route to αꢀmethylated ketones using a variety of
ketones without any base or oxidant.
Methyl functionalization of a carbon centre using readily available catalyst and carbonꢀsource is a
challenging task for chemist. Methylation is not only associated with biological processes but also
have significant values in synthetic chemistry for fine chemical synthesis and functionalization of
biologically active molecules.1 αꢀMethylation of ketones is one of the most important and
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frequently used method in organic synthesis.2 Alkylation of enolate is the classical method for this
reaction, where the carbonyl compounds are intended to be an enolate nucleophile to attack an
electrophilic alkylating agent.3 Most commonly strong bases are used to ensure all the starting
carbonyl to convert into their corresponding enolate anion to avoid selfꢀcondensation of carbonyl
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o
compounds. Furthermore low temperature (about ꢀ78 C) is required for some reactive enolate
species to survive. To improve this reaction several methods have been developed, such as KHꢀ
BEt3 with MeI,4 Et3GeNaꢀYCl3 with MeI,5 PhSeCH2LiꢀmCPBA,6 CH2N2ꢀBF3ꢀEt2O,7 HCHOꢀbasic
zeolites,8 CH4ꢀMgO9 and N2CHCO2EtꢀLDAꢀRh2(OAc)410 have been used. However, these methods
use toxic or explosive reagents4,5,6,7,10 and requires harsh reaction conditions.8,9,10 Recently, few new
catalytic methods have been developed using sustainable feedstock of methyl source. Xiao and coꢀ
workers reported Rhꢀcatalyzed αꢀmethylation of ketones using DMF as carbon source; where
strong oxidant persulfate was used to form an iminium intermediate of DMF for the enolate
attack.11 Additionally Rhꢀ and Irꢀ catalyzed αꢀmethylation of ketones using methanol as methyl
source are reported by Donohoe12 and Obora13 groups independently. However, in both the cases,
strong bases are required and double methylation occurs. In this context, there is a strong desire for
the development of new synthetic strategy for the αꢀmethylation of ketone using readily available
reagent and catalyst without any base or oxidant.
Recently, we have developed a Pdꢀgraphene composite material as catalyst for CꢀC bond formation
and reduction of CꢀC double bonds. While screening the reaction conditions, we were surprised to
find that hydrogenation of enaminone derived from acetophenone and dimethylformamideꢀ
dimethylacetal (DMFꢀDMA) produced phenylpropanol. This finding prompted us to explore the
possibility of developing a novel synthetic strategy for the αꢀmethylation of carbonyl compounds.
On the other hand, enaminones are versatile synthetic intermediate for the synthesis of various
heterocycles14 and other valuable products.15 To the best of our knowledge, however, this
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intermediate has not been used for the αꢀmethylation of ketone. Herein, we report a novel synthetic
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strategy for αꢀmethylation of ketones. Our synthetic strategy consists of condensation of ketones
with DMFꢀDMA followed by hydrogenationꢀhydrogenolysis of enaminones. The novel
hydrogenationꢀhydrogenolysis step was catalyzed by Pd/C under H2 atmosphere. (Scheme 1)
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Scheme 1. α-Methylation of Ketones via enaminones
Initially, acetophenone 1a was chosen as the model substrate for the αꢀmethylation via enaminone
2a with various heterogeneous catalysts and extensive investigations were carried out to optimize
the reaction conditions (Table 1). The synthesis of enaminones from ketones and DMFꢀDMA is
well precedented and this intermediate was used for hydrogenationꢀhydrogenolysis reaction without
chromatographic purification.16 As a starting point, hydrogenation experiments were performed
using 10 mol% of Pd/C in the presence of H2 (balloon) for 12 h at rt, giving the phenylpropanol 4a.
Under the same reaction conditions, other heterogeneous catalyst such as Pd/CaCO3, Pd/Al2O3,
Pd/SiO2, Ru/C gave moderate yield of 4a along with 3a. As a control experiment, the reaction was
performed in the absence of catalyst and no product was observed. The catalyst Pd/C was
considered and particularly focused in this strategy for the αꢀmethylation of ketones as it is
commercially available and inexpensive. With the optimized reaction conditions in hand, we
examined the scope of the reaction in order to establish the generality of our strategy. Various
ketones 1(a-t) were αꢀmethylated via enaminones 2(a-t) and are the results are summarized in
Table 2.
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Table 1. Optimization of conditions for the α-methylation of ketone, 1aa
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entry
catalyst
(10 mol%)
Pd/C
reaction conditions
yield (%)b
3a
4a
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3
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7
EtOH,rt, 12 h
EtOH,50 oC, 6 h
EtOH, rt, 12 h
EtOH, rt, 12 h
EtOH, rt, 12 h
EtOH, rt, 12 h
EtOH,50 oC, 24 h
traces
traces
12
79
Pd/C
Pd/CaCO3
Pd/Al2O3
PdꢀrGO
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72
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nd
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traces
10
Rh/C
No catalyst
nd
a Reaction conditions: acetophenone (1 mmol), DMFꢀDMA (~20 mmol), 120 oC, 24 h in an open flask, workꢀup and
added ethanol (7 mL), Pd/C (10 mol%), H2 (balloon), rt; b All yields are isolated yields; nd = Not detected; rGO:
reduced graphene oxide.
(E/Z)ꢀAryl and (E/Z)ꢀheteroaryl 3ꢀ(dimethylamino)ꢀ3ꢀpropꢀ2ꢀenone (enaminones); are efficiently
prepared by the condensation of respective aryl and heteroaryl methyl ketones with excess of DMFꢀ
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DMA at 120 C. In most of the cases enaminones were isolated for this strategy after a simple
workꢀup without chromatographic purification. Aryl and heteroaryl methyl ketones having neutral,
electronꢀdonating and electronꢀwithdrawing groups were smoothly converted to the corresponding
αꢀmethylated products 3 and 4 in 35−82% yields. The results show that electronic effect of
substituents as well as orthoꢀ, metaꢀ, and paraꢀsubstitution at aryl ring plays an important role in
this reaction. Specifically, aryl methyl ketones having electronꢀwithdrawing groups (Fꢀ and CF3ꢀ) at
metaꢀ and paraꢀsubstitution gave phenylpropanol products 4 in high yield (Table 2; entries 7 and 9).
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Table 2. Scope of the α-methylation of ketonesa
1. DMF-DMA, 120 oC
2. Pd/C, reaction conditions
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O
OH
O
R
R
R
+
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entry
1
ketone
1(a-j)
Reaction
conditions
yield (%)b entry
ketone
reaction
yield (%)b
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conditions
1(k-t)
3(a-j) 4(a-j)
3(k-t) 4(k-t)
H2(BP), RT, 12h trace 79
H2(BP), RT, 12h trace 69
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H2(2.5 bar), RT, 6h
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H2(BP), RT, 18h
H2(2.5 bar), RT, 7h
H2(BP), RT, 12h
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H2(BP), RT, 12h 18
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trace
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H2(BP), RT, 12h trace 71
H2(BP), RT, 12h trace 67
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H2(BP), RT, 12h
H2(BP), RT, 12h
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nd
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H2(BP), RT, 18h 12
H2(BP), RT, 12h nd
H2(BP), RT, 18h 21
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H2(2.5 bar), RT, 6h
H2(2.5 bar), RT, 6h
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77
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nd
H2(BP), RT, 8h
H2(BP), RT, 10h
H2(BP), RT, 10h
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67
73
trace
trace
trace
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H2(BP), RT, 12h trace 75
H2(BP), RT, 12h trace 82
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a Reaction conditions: ketone (1 mmol), DMFꢀDMA (~15ꢀ20 mmol), 120 oC, 24 h in an open flask, workꢀup; ethanol (7
mL), Pd/C (10 mol%), H2 (BP=balloon pressure or 2.5 bar pressure), rt; b All yields are isolated yields.
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Notably, substrates with strong electronꢀdonating group substituted at paraꢀposition of aryl ring
afforded phenylpropanol 4 in only moderate yields along with the αꢀmethylated ketoꢀproduct 3
(Table 2; entries 3, 6 and 8). However, electronꢀdonating group at metaꢀposition gave good yield of
alcohol 4 along with a traces of αꢀmethylated ketoꢀproduct 3 (Table 2; entry 4). Surprisingly, the
orthoꢀsubstituted aryl methyl ketones, regardless of their electronic nature as electronꢀdonating or
electronꢀwithdrawing exclusively gave the αꢀmethylated ketoꢀproducts 3, which might be due to the
steric effect (Table 2; entries 12ꢀ15). N,NꢀDimethylacetophenone 1j exceptionally gave the
corresponding phenylpropanol 4j in high yield, which could be used as a raw material for the
synthesis of potent histone deacetylase inhibitor, (±)trichostatin A.17 The cyclic ketones were also
investigated, and the αꢀmethylated ketoꢀproducts were obtained in good yields (Table 2; entries 18
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and 19). The yield of αꢀmethylated ketoꢀproducts 3r and 3s also might be caused by the steric effect
of fused rings. Having succeeded in the αꢀmethylation of aryl methyl ketones, we extended this
strategy for the methylation of heteroaryl methyl ketones. Accordingly, Nꢀprotected indole
derivative, 1ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)ethanone 1t was condensed with DMFꢀDMA followed by
hydrogenationꢀhydrogenolysis over Pd/C under H2 (balloon). The αꢀmethylated ketoꢀproduct, 1ꢀ(1ꢀ
methylꢀ1Hꢀindolꢀ3ꢀyl)propanꢀ1ꢀone 3t was obtained with 73% yield as the only isolable product.
Additionally, the αꢀmethylation of 3ꢀacetylpyridine was attempted using the same reaction strategy,
interestingly, 1ꢀ(pyridinꢀ3ꢀyl)propanꢀ1ꢀol 4u along with another reduced product 1ꢀ(1,4,5,6ꢀ
tetrahydropyridinꢀ3ꢀyl)propanꢀ1ꢀone 5u were obtained with 25% and 51% yield respectively. This
result encourage us to further explore our strategy, in this regard 2ꢀacetylbenzofuran 1v was
considered and transformed into the corresponding enaminone followed by hydrogenation over
Pd/C. Interestingly, a αꢀmethylated overꢀreduced product 5v was obtained in 80% yield as mixture
of diastereomers in 1.2:1 ratio (Scheme 2).
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Scheme 2. α-Methylation of heteroaryl methyl ketone
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We planned to employ our synthetic method to prepare 4ꢀaminopropiophenone (PAPP)18 5w, which
is a biologically important molecule and a raw material for the synthesis of pharmaceutically
important compounds19 was planned to synthesize using our synthetic strategy. The desired
compound 5w was derived from 4ꢀnitroacetophenone via enaminone followed by our synthetic
strategy and the PAPP was obtained with 43% overall yield (Scheme 3).
Scheme 3 . Synthesis of 4-aminopropiophenone (PAPP)
With a view toward economic and environmental concerns, the recyclability of the catalyst was
explored. In this regards the purified (E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀphenylpropꢀ2ꢀenꢀ1ꢀone 2a was
chosen and hydrogenated under H2 (balloon). Upon completion of the reaction, the catalyst was
filtered and washed with ethanol and reused at least three times. Although the catalytic activity
gradually diminished (yield of 4a: 1st reuse 92%, 2nd reuse 88%, 3rd reuse 81%), the yield was still
80% even after the third reuse (Scheme 4).
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Scheme 4. Recyclability of catalyst
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A plausible reaction mechanism for the αꢀmethylation of ketone is proposed in Scheme 5. Ketone
1a undergoes condensation with DMFꢀDMA affords enaminone 2a, which undergoes
hydrogenation followed by hydrogenolysis of intermediate I. To elucidate the mechanism the
intermediate I 20was independently synthesized from acetophenone 1a and treated with Pd/C under
hydrogen atmosphere at room temperature for overnight. The expected phenylpropanol 4a was
obtained in 88% yield, whereas the keto product 3a was not observed in this experiment. These
results suggested that 3ꢀ(dimethylamino)propiophenone I is the key intermediate for
phenylpropanol 4a. The formation of keto product 3a is not clear at present. However, it is
proposed that it is proceed via the intermediate II as shown in the scheme 5. 21
Scheme 5. Plausible reaction mechanism
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Scheme 6. Independent experiment for mechanism
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In summary, we have developed a novel oneꢀpot hydrogenationꢀhydrogenolysis strategy for the αꢀ
methylation of ketones via enaminones. This method offers significant advantages such as
commercially available reagents and catalyst, operationally simple procedure, high conversions, and
use of recyclable catalyst. The present reaction will serve as an alternative strategy for the αꢀ
methylation of ketones without any base or oxidant.
EXPERIMENTAL SECTION
1
General Information. All chemicals were used as received without further purification. H NMR
and 13C NMR spectra were recorded at ambient temperature on a 300 or 500 MHz NMR
spectrometer (75 or 125 MHz for 13C). NMR chemical shifts are reported on the δ scale (ppm)
downfield from tetramethylsilane (δ=0.0 ppm) using the residual solvent signal at δ=7.26 ppm (1H)
or δ=77 ppm (13C) as internal standard. Data are reported as follows: chemical shift, multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). IR spectra were recorded
on a spectrophotometer using CHCl3. Hydrogenation under pressure (2.5 bar) was carried out in
hydrogenation apparatus. Column chromatography was performed with silica gel 60 (100ꢀ200
mesh).
Experimental procedure for the synthesis of enaminones 2(a-w) (2a as an example).
o
Acetophenone 1a (1 mmol) and DMFꢀDMA (20 mmol) was stirred at 120 C (oil bath) in an open
flask. After disappearance of the reactant (monitored by TLC), water was added to the mixture (50
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mL), and the mixture was extracted with EtOAc (3×30 mL). The extract was dried over anhydrous
Na2SO4 and concentrated. The crude residue was used for the oneꢀpot hydrogenationꢀ
hydrogenolysis reaction without chromatographic purification. [Lꢀproline (5 mol %) was added
during the synthesis of 2p, 2q, 2t and 2v]16
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Experimental procedure for the hydrogenation-hydrogenolysis of enaminones (4a as an
example). Crude enaminone 2a as obtained from the previous step was dissolved in ethanol (20
mL). 10% Pd/C (106 mg, 10 mol% of 1a) was added and the heterogeneous mixture was vigorously
stirred at room temperature under atmospheric hydrogen pressure (balloon) for 12 h. The reaction
mixture was filtered (using a Buchner funnel with sintered disc) and washed with ethanol (2x10
mL). The filtrate and washings were combined and concentrated under reduced pressure. After the
evaporation, the residue was purified by column chromatography on silica gel (ethyl acetate/
hexanes, 1:10) to afford the product 4a. [For crude substrate 2k, 2l, 2p, 2q and 2w, 2.5 bar
hydrogen pressure was used instead of hydrogen balloon in a hydrogenation apparatus]
1-Phenylpropan-1-ol (4a).22,23,24 Flash column chromatography on silica gel (ethyl acetate/hexanes
1
1:10) gave 4a (107 mg, 79% yield) as liquid; H NMR (300 MHz, CDCl3): δ 7.18ꢀ7.45 (m, 5H),
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4.59 (t, J = 6.6 Hz, 1H), 1.9 (br s, 1H), 1.66ꢀ1.90 (m, 2H), 0.92 (t, J=7.4 Hz, 3H); C NMR (75
MHz, CDCl3): δ 144.6, 128.4, 127.5, 126.0, 75.9, 31.8, 10.2; IR (CHCl3): 3368, 2964, 2932, 2876,
1453, 974 cmꢀ1.
1-(p-Tolyl)propan-1-ol (4b).23,24 Flash column chromatography on silica gel (ethyl acetate/hexanes
1
1:10) gave 4b (104 mg, 69% yield) as liquid; H NMR (300 MHz, CDCl3): δ 7.22 (d, J=7.9 Hz,
2H), 7.14 (d, J=7.8 Hz, 2H), 4.54 (t, J=6.6 Hz, 1H), 2.34 (s, 3H), 1.99 (br s, 1H), 1.61ꢀ1.9 (m, 2H),
0.90 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 141.6, 137.1, 129.1, 125.9, 75.9, 31.8, 21.1,
10.2; IR (CHCl3): 3367, 2962, 2927, 2875, 1456, 1098, 1040, 1014, 874 cmꢀ1.
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1-(4-Methoxyphenyl)propan-1-one (3c).11 Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:12) gave 3c (30 mg, 18% yield) as liquid; 1H NMR (300 MHz, CDCl3): δ 7.95 (d,
J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 3.87 (s, 3H), 2.96 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 199.5, 163.3, 130.2, 130.0, 113.6, 55.4, 31.4, 8.4; IR (CHCl3):
2974, 2936, 1679, 1601, 1257, 1227, 1170 cmꢀ1.
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1-(4-Methoxyphenyl)propan-1-ol (4c).23,25 Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:12) gave 4c (91 mg, 55% yield) as liquid; 1H NMR (300 MHz, CDCl3): δ 7.17 (d,
J=8.5 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 4.44 (t, J=6.7 Hz, 1H), 3.71 (s, 3H), 1.99 (br s, 1H), 1.53ꢀ
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1.81 (m, 2H), 0.81 (t, J=7.4 Hz, 3H); C NMR (75 MHz, CDCl3): δ 158.9, 136.8, 127.2, 113.6,
75.6, 55.3, 31.7, 10.2; IR (CHCl3): 3391, 2962, 2933, 2876, 1612, 1513, 1248, 1175, 1038 cmꢀ1.
1-(3-Methoxyphenyl)propan-1-ol (4d).24 Flash column chromatography on silica gel (ethyl
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acetate/hexanes 1:10) gave 4d (118 mg, 71% yield) as liquid; H NMR (300 MHz, CDCl3): δ 7.25
(t, J=8 Hz, 1H), 6.92 (s, 1H), 6.90 (s, 1H), 6.81 (d, J=8.4 Hz, 3H), 4.56 (t, J=6.5 Hz, 1H), 3.80 (s,
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3H), 1.86 (br s, 1H), 1.68ꢀ1.84 (m, 2H), 0.92 (t, J=7.4 Hz, 3H); C NMR (75 MHz, CDCl3): δ
159.6, 146.5, 129.3, 118.4, 118.0, 112.8, 111.5, 75.7, 55.1, 31.8, 10.1; IR (CHCl3): 3392, 2964,
2935, 1602, 1586, 1487, 1455, 1261, 1042 cmꢀ1.
1-(Benzo[d][1,3]dioxol-5-yl)propan-1-ol (4e).23,25 Flash column chromatography on silica gel
(ethyl acetate/hexanes 1:10) gave 4e (121 mg, 67% yield) as liquid; 1H NMR (300 MHz, CDCl3): δ
6.83 (s, 1H), 6.75 (s, 2H), 5.92 (s, 2H), 4.47 (t, J=6.6 Hz, 1H), 2.08 (br s, 1H), 1.58ꢀ1.86 (m, 2H),
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0.87 (t, J=7.4 Hz, 3H); C NMR (75 MHz, CDCl3): δ 147.7, 146.8, 138.7, 119.4, 107.9, 106.4,
100.9, 75.8, 31.8, 10.2; IR (CHCl3): 3379, 2965, 2932, 2877, 1504, 1487, 1441, 1248, 1040, 931,
811 cmꢀ1.
1-(4-Cyclohexylphenyl)propan-1-one (3f).26 Flash column chromatography on silica gel (ethyl
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acetate/hexanes 1:10) gave 3f (26 mg, 12% yield) as gummy; H NMR (300 MHz, CDCl3): δ 7.89
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(d, J=8.2 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 2.98 (q, J=7.2 Hz, 2H), 2.56 (br s, 1H), 1.34ꢀ1.95 (m,
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10H), 1.21 (t, J=7.3 Hz, 3H); C NMR (75 MHz, CDCl3): δ 200.6, 153.5, 134.8, 128.2, 127.0,
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44.6, 34.1, 31.6, 26.7, 26.0, 8.3; IR (CHCl3): 2926, 2852, 1685, 1606, 1222 cmꢀ1.
1-(4-Cyclohexylphenyl)propan-1-ol (4f). Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:10) gave 4f (50 mg, 23% yield) as liquid; 1H NMR (300 MHz, CDCl3): δ 7.23 (d,
J=8.1 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 4.51 (t, J=6.5 Hz, 1H), 2.48 (br s, 1H), 1.98 (br s, 1H), 1.66ꢀ
1.92 (m, 7H), 128ꢀ1.51 (m, 5H), 0.89 (t, J=7.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 147.3,
142.1, 126.8, 126.0, 75.8, 44.3, 34.5, 31.9, 26.9, 26.2, 10.3; IR (CHCl3): 3367, 2925, 2851, 1448,
826 cmꢀ1. MS (EI) m/z: 218.1 (M)+; Anal. Calcd (%) for C15H22O: C, 82.52; H, 10.16; Found: C,
82.47; H, 10.22.
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1-[3,5-bis(Trifluoromethyl)phenyl]propan-1-ol (4g).25 Flash column chromatography on silica
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gel (ethyl acetate/hexanes 1:10) gave 4g (209 mg, 77% yield) as liquid; H NMR (300 MHz,
CDCl3): δ 7.81 (s, 2H), 7.78 (s, 1H), 4.76 (t, J=6.4 Hz, 1H), 2.00 (br s, 1H), 1.73ꢀ1.86 (m, 2H), 0.96
(t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 147.1, 131.6 (q, J=33.3 Hz), 126.1 (q, J=2.8 Hz),
123.4 (q, J=272.6 Hz), 121.3 (q, J=3.7 Hz), 74.6, 32.2, 9.7; IR (CHCl3): 3199, 2979, 1463, 1383,
1291, 1116 cmꢀ1.
1-(4-Isobutylphenyl)propan-1-one (3h). Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:15) gave 3h (40 mg, 21% yield) as liquid; 1H NMR (300 MHz, CDCl3): δ 7.88 (d,
J=8.1 Hz, 2H), 7.22 (d, J=8 Hz, 2H), 2.97 (q, J=7.3 Hz, 2H), 2.52 (d, J=7.2 Hz, 2H), 1.68ꢀ1.99 (m,
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1H), 1.21 (t, J=7.3 Hz, 3H), 0.91 (d, J=6.6 Hz, 6H); C NMR (75 MHz, CDCl3): δ 200.5, 147.3,
134.7, 129.3, 127.9, 45.4, 31.6, 30.1, 22.3, 8.3; IR (CHCl3): 2957, 2934, 2870, 1686, 1608, 1465,
1415, 1225, 1182, 953 cmꢀ1; MS (EI) m/z: 190.1 (M)+; Anal. Calcd (%) for C13H18O: C, 82.06; H,
9.53; Found: C, 82.17; H, 9.60.
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1-(4-Isobutylphenyl)propan-1-ol (4h). Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:15) gave 4h (85 mg, 44% yield) as liquid; 1H NMR (500 MHz, CDCl3): δ 7.16 (d,
J=8.0 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 4.48 (t, J=6.6 Hz, 1H), 2.39 (d, J=7.2 Hz, 2H), 1.58ꢀ1.95
(m, 4H), 0.54ꢀ1.11 (m, 9H); 13C NMR (125 MHz, CDCl3): δ 141.7, 140.9, 129.0, 125.6, 75.8, 45.0,
31.7, 30.1, 22.3, 10.1; IR (CHCl3): 3393, 2957, 1464, 1383, 846, 893 cmꢀ1; MS (EI) m/z: 192.1
(M)+; Anal. Calcd (%) for C13H20O: C, 81.20; H, 10.48; Found: C, 81.11; H, 10.53.
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1-(4-Fluorophenyl)propan-1-ol (4i).23,24 Flash column chromatography on silica gel (ethyl
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acetate/hexanes 1:10) gave 4i (116 mg, 75% yield) as liquid; H NMR (500 MHz, CDCl3): δ 7.21ꢀ
7.26 (m, 2H), 6.96 (t, J=8.6 Hz, 2H), 4.52 (t, J=6.6 Hz, 1H) 1.57ꢀ1.80 (m, 3H), 0.82 (t, J=7.3 Hz,
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3H); C NMR (75 MHz, CDCl3): δ 162.1 (d, J=245.1 Hz), 140.3 (d, J=3.2 Hz), 127.6 (d, J=8.0
Hz), 115.2 (d, J=21.3 Hz), 75.4, 32.0, 10.1; IR (CHCl3): 3367, 2963, 2930, 1605, 1509, 1222, 1015,
834 cmꢀ1.
1-[4-(Dimethylamino)phenyl]propan-1-ol (4j).17 Flash column chromatography on neutral
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alumina (ethyl acetate/hexanes 1:12) gave 4j (147 mg, 82% yield as gummy; H NMR (300 MHz,
CDCl3): δ 7.19 (d, J=8.5 Hz, 2H), 6.70 (d, J=8.5 Hz, 2H), 4.45 (t, J =6.7 Hz, 1H), 2.92 (s, 6H), 2.14
(br s, 1H), 1.61ꢀ1.90 (m, 2H), 0.87 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 150.2, 132.8,
127.0, 112.67, 75.7, 40.7, 31.6, 10.4.
1-[3-Fluoro-4-methoxyphenyl]propan-1-one (3k).27 Flash column chromatography on silica gel
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(ethyl acetate/hexanes 1:10) gave 3k (36 mg, 20% yield) as white solid; mp 76ꢀ80 °C; H NMR
(500 MHz, CDCl3): δ 7.60ꢀ7.70 (m, 2H), 6.92 (t, J=8.4 Hz, 1H), 3.87 (s, 3H), 2.86 (q, J=7.3 Hz,
2H), 1.14 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 198.5, 151.9 (d, J=247 Hz), 151.6 (d,
J=10.9 Hz), 130.2 (d, J=4.7 Hz), 125.1 (d, J=3.2 Hz), 115.6 (d, J=18.9 Hz), 112.2, 56.1, 31.8, 8.2;
IR (CHCl3): 2978, 1673, 1614, 1580, 1516, 1432, 1285, 1140, 1017, 801 cmꢀ1.
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1-[3-Fluoro-4-methoxyphenyl]propan-1-ol (4k). Flash column chromatography on silica gel
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MHz, CDCl3): δ 152.2 (d, J=245 Hz), 146.7 (d, J=10.8 Hz), 137.6 (d, J=5.3 Hz), 121.6 (d, J=3.4
Hz), 113.6 (d, J=18.5 Hz), 113.0, 74.9, 56.2, 31.6, 9.9; IR (CHCl3): 3391, 2965, 2935, 1518, 1275,
1127, 1027 cmꢀ1; MS (EI) m/z: 184 (M)+; Anal. Calcd (%) for C10H13FO2: C, 65.20; H, 7.11;
Found: C, 65.27; H, 7.13.
1-(2,5-Dimethoxyphenyl)propan-1-one (3l).28 Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:10) gave 3l (161 mg, 83% yield) as gummy; 1H NMR (300 MHz, CDCl3): δ 7.25
(d, J=2.8 Hz, 1H), 7.01 (dd, J1=2.8 Hz, J2=8.9 Hz, 1H), 6.90 (d, J=8.9 Hz, 1H), 3.85 (s, 3H), 3.79
(s, 3H), 2.99 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 203.0,
153.4, 153.0, 128.7, 119.6, 113.9, 113.1, 56.0, 55.8, 36.9, 8.4; IR (CHCl3): 2973, 2939, 2836, 1675,
1496, 1464, 1412, 1278, 1223, 1168, 1049, 1023, 814 cmꢀ1.
1-(2,4-Difluorophenyl)propan-1-one (3m). Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:10) gave 3m (110 mg, 65% yield) as liquid; 1H NMR (500 MHz, CDCl3): δ 7.87ꢀ
8.03 (m, 1H), 6.92ꢀ6.98 (m, 1H), 6.83ꢀ6.89 (m, 1H) 2.97 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3): δ 197.4 (d, J=4.7 Hz), 165.5 (dd, J1=12.2 Hz, J2=256 Hz), 162.6 (dd,
J1=12.5 Hz, J2=257 Hz), 132.5 (dd, J1=4.4 Hz, J2=10.6 Hz), 122.0 (dd, J1=4 Hz, J2=14 Hz), 111.9
(dd, J1=3.3 Hz, J2=21.3 Hz), 104.6 (dd, J1=25 Hz, J2=27 Hz), 36.6 (d, J=7.6 Hz), 7.8 (d, J=2.2 Hz);
IR (CHCl3): 2982, 2941, 1691, 1428, 1236, 973 cmꢀ1; MS (EI) m/z: 170 (M)+; Anal. Calcd (%) for
C9H8F2O: C, 63.53; H, 4.74; Found: C, 63.39; H, 4.79.
1-(2,6-Dimethoxyphenyl)propan-1-one (3n).29 Flash column chromatography on silica gel (ethyl
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acetate/hexanes 1:10) gave 3n (155 mg, 80% yield) as white solid; H NMR (500 MHz, CDCl3): δ
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7.17 (t, J=8.4 Hz, 1H), 6.47 (d, J=8.4 Hz, 2H), 3.70 (s, 6H), 2.68 (q, J=7.2 Hz, 2H), 1.07 (t, J=7.2
Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 205.9, 156.5, 130.3, 120.4, 103.8, 55.8, 37.8, 7.5; IR
(CHCl3): 2988, 2943, 1702, 1595, 1474, 1260, 1113 cmꢀ1.
1-(2,3,5,6-Tetramethylphenyl)propan-1-one (3o).30 Flash column chromatography on silica gel
(ethyl acetate/hexanes 1:10) gave 3o (135 mg, 71% yield) as gummy; 1H NMR (500 MHz, CDCl3):
δ 6.87 (s, 1H), 2.62 (q, J=7.2 Hz, 2H), 2.13 (s, 6H), 1.97 (s, 6H), 1.13 (t, J=7.2 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 212.5, 142.8, 134.2, 131.3, 127.8, 38.4, 19.3, 15.8, 7.4; IR (CHCl3): 2970,
2938, 1699, 1467, 1447, 1408, 1260, 1022, 1003 cmꢀ1.
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1-(Naphthalen-1-yl)propan-1-one (3p).31 Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:10) gave 3n (88 mg, 48% yield) as liquid; 1H NMR (300 MHz, CDCl3): δ 8.55 (d,
J=8.4 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.86 (t, J=8 Hz, 2H), 7.42ꢀ7.63 (m, 3H), 3.08 (q, J=7.3 Hz,
2H), 1.28 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 205.3, 136.2, 133.9, 132.3, 130.2,
128.4, 127.8, 127.2, 126.4, 125.8, 124.4, 35.4, 8.7; IR (CHCl3): 3049, 2977, 2937, 1682, 1508,
1230, 1110, 932, 796 cmꢀ1.
1-(Naphthalen-1-yl)propan-1-ol (4p).23,25 Flash column chromatography on silica gel (ethyl
acetate/hexanes 1:10) gave 4n (41 mg, 22% yield) as liquid; 1H NMR (500 MHz, CDCl3): δ 8.05 (d,
J=7.5 Hz, 1H), 7.83 (dd, J1=2.5 Hz, J2=6.8 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H),
7.37ꢀ7.50 (m, 3H), 5.27ꢀ5.33 (m, 1H), 2.2 (br s, 1H), 1.78ꢀ2.02 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ 140.2, 133.7, 130.4, 128.8, 127.7, 125.8, 125.4, 125.3, 123.2, 122.8,
72.4, 31.0, 10.4; IR (CHCl3): 3369, 2964, 2931, 1510. 1460, 968, 798, 770 cmꢀ1.
1-(1-Methoxynaphthalen-2-yl)propan-1-one (3q). Flash column chromatography on silica gel
(ethyl acetate/hexanes 1:10) gave 3o (165 mg, 77% yield) as gummy; 1H NMR (300 MHz, CDCl3):
δ 8.22 (br s, 1H), 7.85 (br s, 1H), 7.52ꢀ7.67 (m, 4H), 3.98 (s, 3H), 3.13 (q, J=7.2 Hz, 2H), 1.24 (t,
J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 203.8, 156.6, 136.6, 128.1, 128.0, 126.6, 125.5,
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124.2, 123.3, 63.8, 36.3, 8.6; IR (CHCl3): 3468, 3059, 2976, 2937, 1677, 1370, 1206, 1102, 1078,
988 cmꢀ1; MS (EI) m/z: 214 (M)+; Anal. Calcd (%) for C14H14O2: C, 78.48; H, 6.59; Found: C,
78.55; H, 6.66.
6-Methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one (3r).32 Flash column chromatography on
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silica gel (ethyl acetate/hexanes 1:10) gave 3p (135 mg, 71% yield) as liquid; H NMR (300 MHz,
CDCl3): δ 8.01 (d, J=8.7 Hz, 1H), 6.82 (dd, J1=1.8 Hz, J2=8.7 Hz, 1H), 6.68 (s, 1H), 3.85 (s, 3H),
2.86ꢀ3.08 (m, 2H), 2.46ꢀ2.62 (m, 1H), 2.11ꢀ2.24 (m, 1H), 1.76ꢀ1.96 (m, 1H), 1.26 (d, J=6.8 Hz,
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31.4, 29.2, 15.5; IR (CHCl3): 2962, 2932, 2859, 2839, 1675, 1599, 1494, 1458, 1358, 1252, 1134,
1032, 970 cmꢀ1.
7-Methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one (3s).32 Flash column chromatography on
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silica gel (ethyl acetate/hexanes 1:10) gave 3q (127 mg, 67% yield) as liquid; H NMR (300 MHz,
CDCl3): δ 7.43 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.94 (dd, J1=2.2 Hz, J2=8.4 Hz, 1H), 3.73 (s, 3H),
2.16ꢀ2.94 (m, 2H), 2.39ꢀ2.54 (m, 1H), 2.02ꢀ2.15 (m, 1H), 1.67ꢀ1.84 (m, 1H), 1.17 (d, J=6.7 Hz,
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42.4, 31.5, 27.9, 15.4; IR (CHCl3): 2961, 2931, 1683, 1609, 1496, 1271, 1246 cmꢀ1.
1-(1-Methyl-1H-indol-3-yl)propan-1-one (3t).11 Flash column chromatography on neutral alumina
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(300 MHz, CDCl3): δ 8.34ꢀ8.41 (m, 1H), 7.71 (s, 1H), 7.31 (s, 3H), 3.85 (s, 3H), 2.87 (q, J=7.4 Hz,
2H), 1.25 (t, J=1.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 196.4, 137.5, 135.1, 126.3, 123.2,
122.5, 122.4, 116.2, 109.6, 33.4, 32.9, 9.0; IR (CHCl3): 2974, 2935, 1645, 1529, 1468, 1374, 1217,
1211, 7899 cmꢀ1. MS (EI) m/z: 187 (M)+.
1-(Pyridin-3-yl)propan-1-ol (4u).23 Flash column chromatography on neutral alumina (ethyl
acetate/hexanes 1:15) gave 4s (35 mg, 25% yield) as liquid; 1H NMR (300 MHz, CDCl3): δ 8.44 (s,
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1-(1,4,5,6-tetrahydropyridin-3-yl)propan-1-one (5u). Flash column chromatography on neutral
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CDCl3): δ 7.51 (d, J=5.7 Hz, 1H), 5.35 (br s, 1H), 3.23 (s, 2H), 2.46 (q, J=7.5 Hz, 2H), 2.34 (t,
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J=6.2 Hz, 2H), 1.74ꢀ1.86 (m, 2H), 1.10 (t, J=7.5 Hz, 3H); C NMR (75 MHz, CDCl3): δ 197.7,
145.6, 106.7, 40.8, 28.7, 20.6, 19.9, 10.6; IR (CHCl3): 3293, 2934, 1664, 1618, 1571, 1525, 1354,
1239, 1193 cmꢀ1; MS (EI) m/z: 139.1 (M)+; Anal. Calcd (%) for C8H13NO: C, 69.03; H, 9.41; N,
10.06; Found: C, 69.11; H, 9.45; N, 10.19.
1-(2,3-Dihydrobenzofuran-2-yl)propan-1-ol (5v). Flash column chromatography on silica gel
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(ethyl acetate/hexanes 1:10) gave 5t (143 mg, 80% yield; 1.2:1 dr) as liquid; H NMR (CDCl3, 500
MHz, mixture of two diastereomers): δ 7.13ꢀ7.18 (m, 1H), 7.07ꢀ7.13 (m, 1H), 6.81ꢀ6.86 (m, 1H),
6.77 (t, J=7.9 Hz, 1H), 4.70ꢀ4.76 (m, 0.6H), 4.61ꢀ4.67 (m, 0.5H), 3.84ꢀ3.95 (m, 0.6H), 3.53ꢀ3.63
(m, 0.5H), 3.16ꢀ3.30 (m, 1H), 2.99ꢀ3.12 (m, 1H), 1.87 (br s, 1H), 1.44ꢀ1.71 (m, 2H), 1.01ꢀ1.09 (m,
3H); 13C NMR (CDCl3, 125 MHz, mixture of two diastereomers): δ 159.3, 159.0, 127.9, 127.7,
126.9, 126.6, 124.9, 124.8, 120.5, 120.4, 109.3, 109.0, 85.5, 85.4, 75.0, 73.4, 31.8, 29.2, 25.8, 25.0,
10.1, 9.9; IR (CHCl3): 3428, 2964, 2933.5, 2878, 1598, 1481, 1461, 1233, 975, 750 cmꢀ1; MS (EI)
m/z: 179 (M)+; Anal. Calcd (%) for C11H14O2: C, 74.13; H, 7.92; Found: C, 74.17; H, 7.98.
1-(4-Aminophenyl)propan-1-one (5w).33 Flash column chromatography on silica gel (ethyl
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acetate/hexanes 1:10) gave 5u (64 mg, 43% yield) as brown solid; mp 141ꢀ144 °C; H NMR (500
MHz, CDCl3): δ 7.73 (d, J=8.7 Hz, 2H), 6.56 (d, J = 8.7 Hz, 2H), 4.12 (br s, 2H), 2.81 (q, J = 7.3
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Hz, 2H), 1.11 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 199.3, 150.9, 130.3, 127.3, 113.6,
31.8, 8.6.
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Independent experiment for mechanism: The intermediate, 3ꢀ(dimethylamino)ꢀ1ꢀphenylpropanꢀ
1ꢀone I was synthesized according to the literature procedure20 with 75% yield as oil; 1H NMR (500
MHz, CDCl3): δ 7.97 (d, J=6.8 Hz, 2H), 7.56 (t, J=7.4 Hz, 1H), 7.46 (t, J=7.7 Hz, 2H), 3.16 (t,
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J=7.1 Hz, 2H), 2.76 (t, J=7.3 Hz, 2H), 2.29 (s, 6H); C NMR (125 MHz, CDCl3): δ 199.0, 136.8,
133.0, 128.5, 127.9, 54.2, 45.4, 36.8; IR (CHCl3): 2973, 2944, 2819, 2769, 1684, 1597, 1580, 1460,
1449, 1380, 1330, 1235, 1207 cmꢀ1.
3ꢀ(Dimethylamino)ꢀ1ꢀphenylpropanꢀ1ꢀone I (177 mg, 1 mmol) as obtained from the
previous step was dissolved in ethanol (20 mL). 10% Pd/C (106 mg, 10 mol% of I) was added and
the heterogeneous mixture was vigorously stirred at room temperature under atmospheric hydrogen
pressure (balloon) for 12 h. The reaction mixture was filtered (using a Buchner funnel with sintered
disc) and washed with ethanol (2x10 mL). The filtrate and washings were combined and
concentrated under reduced pressure. After the evaporation, the residue was purified by column
chromatography on silica gel (ethyl acetate/ hexanes, 1:10) to afford 4a (120 mg; 88% Yield).
ACKNOWLEDGEMENTS
We acknowledge the CSIR, New Delhi for their financial support. We are grateful to the Director,
CSIRꢀNEIST, Jorhat for his keen interest.
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ASSOCIATED CONTENT
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Supporting Information for this note is available (copies of H and 13C NMR spectra of all
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products). This material is available free of charge via the Internet at http://pubs.acs.org
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AUTHOR INFORMATION
Corresponding Author*
Fax: +913762370011. Eꢀmail: gogoipranj@yahoo.co.uk
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