Benzoyl radicals from (hetero)aromatic aldehydes. Decatungstate photocatalyzed synthesis of substituted aromatic ketones

Article abstract of DOI:10.1039/c0ob00066c

Benzoyl radicals are generated directly from (hetero)aromatic aldehydes upon tetrabutylammonium decatungstate ((n-Bu₄N)₄W ₁₀O₃₂), TBADT) photocatalysis under mild conditions. In the presence of α,β-unsaturated e

Full text of DOI:10.1039/c0ob00066c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Benzoyl radicals from (hetero)aromatic aldehydes. Decatungstate
photocatalyzed synthesis of substituted aromatic ketones†
Davide Ravelli,a Michele Zema,b Mariella Mella,a Maurizio Fagnoni*a and Angelo Albinia
Received 30th April 2010, Accepted 16th June 2010
First published as an Advance Article on the web 27th July 2010
DOI: 10.1039/c0ob00066c
Benzoyl radicals are generated directly from (hetero)aromatic aldehydes upon tetrabutylammonium
decatungstate ((n-Bu4N)4W10O32), TBADT) photocatalysis under mild conditions. In the presence of
a,b-unsaturated esters, ketones and nitriles radical conjugate addition ensues and gives the
corresponding b-functionalized aryl alkyl ketones in moderate to good yields (stereoselectively in the
case of 3-methylene-2-norbornanone). Due to the mild reaction conditions the presence of various
functional groups on the aromatic ring is tolerated (e.g. methyl, methoxy, chloro). The method can be
applied to hetero-aromatic aldehydes whether electron-rich (e.g. thiophene-2-carbaldehyde) or
electron-poor (e.g. pyridine-3-carbaldehyde).
toxic tin containing compound, e.g. Bu3SnH (Scheme 1, path b).5
Introduction
The photochemicalcleavage of aArC(=O)–X bondis aviablealter-
native, as shown with acyl tellurides (X = TeR)6 and benzoylphos-
phine oxides (X = P(=O)Ph2, path c),7 as well as starting from
a-hydroxy or a-amino ketones,7a–b,8 cyclic ketones (via the Norrish
type I cleavage)9 or esters (via the photo-Fries rearrangements).10
Moreover, Pattenden and coworkers have developed acylcobalt
salophen reagents (X = Co(salophen)Py, path c)11 that have the
advantage to generate acyl radicals by means of ambient light. The
generation of benzoyl radicals in this way has been demonstrated
in spectroscopical or kinetic studies and has found application for
polymerization initiation,7a as well as in synthesis, limitedly to Se
and Te derivatives. Phenyl selenoesters, however, required the use
of benzene as the solvent and of an excess of alkene (up to 2.5
equiv.) and variable amounts of dimers were usually formed as
side products.5 In addition, acylcobalt reagents led in most cases
to mixtures of alkylated ketones and conjugated enones.11b
Carbon centered radicals are a versatile tool for the formation
of C–C bonds in organic synthesis.1 As an example, ketones have
been obtained from the reaction of nucleophilic acyl radicals with a
double or a triple C–C bond.2,3 Preparing aromatic ketones by this
strategy requires the generation of benzoyl radicals (ArC(=O)∑).
Only in rare instances these have been formed by carbonylation
of aryl radicals (Scheme 1, path a),4 while the main approach
involves the homolytic cleavage of a suitable ArC(=O)–X bond as
illustrated in Scheme 1.
Se or Te esters have to be prepared, however, and thus cleaving
directly the C–H bond in benzaldehydes would be an obvious step
forward.12 This extension should be viable since the homolytic
H abstraction from aromatic aldehydes has been demonstrated
with electrophilic radicals, such as t-BuO∑
or nitrate12c (path
12b
d). However, synthetic applications reported are limited to a
few radical-chain hydroacylation reactions where thiols were
added to make the propagation of the chain reaction efficient.13
Photocatalysis14,15 offers a peculiar alternative. This method is
based on the ability by a photocatalyst of abstracting a hydrogen
atom from a reagent when in the excited state (P* in Scheme
1, path e) and of being regenerated by back H transfer to an
intermediate of the reaction, so that light is a stoichiometric
reagent.14a Decatungstate salts (e.g. the tetrabutylammonium salt,
TBADT) are emerging as convenient photocatalysts.16,17 Indeed,
Orfanopoulos et al. used TBADT to activate a few aromatic
aldehydes for the benzoylation of [60]Fullerene,18a but this required
a large excess both of the aldehyde (ca. 100 equiv.) and of TBADT
(2 equiv.) with respect to the fullerene used (that appeared to be one
of the absorbing species).18 In contrast, acylation occurred under
synthetically more sensible conditions with aliphatic aldehydes
and yielded dialkyl ketones.19,20 As a matter of fact, the BDE for
Scheme 1 Literature pathways for the generation of benzoyl radicals.
Acyl selenides (X = SeR) have been largely exploited for this
purpose, but require the use of a radical chain carrier, usually a
aDepartment of Organic Chemistry, University of Pavia, Viale Taramelli 10,
27100 Pavia, Italy. E-mail: fagnoni@unipv.it
bDepartment of Earth Sciences, University of Pavia, Via Ferrata 1, 27100
Pavia, Italy
† Electronic supplementary information (ESI) available: Selected absorp-
1
tion spectra of starting aldehydes, TBADT and reaction mixture and H
NMR and 13C NMR data for compounds 3–9, 11–15. CCDC reference
numbers 784807. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob00066c
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Table 1 Photocatalyzed synthesis of substituted aromatic ketones.a
incomplete. Prolonging somewhat the irradiation time (30 h) and
using a slight excess (20%) of the olefin led to total conversion and
formation of 3 in 75% isolated yield (Scheme 2). Moreover, the
spectrum of the reaction mixture well fitted with the addition of
those of the identified components (see Figure S2, ESI†). A larger
excess of the olefin caused the formation of oligomers, as indicated
by GC analysis. On the other hand, the formation of ketone 3 was
satisfactory when using an excess (20%) of 1a. The rate of the
reaction is unaffected when increasing the amount of the photo-
catalyst (up to 4% equiv.); on the contrary when using 1% equiv. the
reaction became too sluggish and thus unpractical for synthesis.
Aromatic aldehydes
Olefins
Products (yields, %)b
1a (Ar = 4-MeO-C6H4)
1a
2a
2b
2c
2d
2e
2f
3; 75, 77c, 70d
4; 62
1a
5; 53, 39c
6; 36, 65c
7; 82, 59c
8; 55
1b (Ar = Ph)
1c (Ar = 4-Cl-C6H4)
1d (Ar = 2-Cl-C6H4)
1e (Ar = 3-Me-C6H4)
1f (Ar = 4-HO-C6H4)
1g (Ar = 4-t-BuMe2SiO–C6H4)
1h (Ar = 3-OHC-C6H4)
1i (Ar = 2-thienyl)
1j (Ar = 3-pyridyl)
1j
2f
9; 58
2f
10;e
2e
2c
2g
2h
2f
11; 81f
12; 78
13; 51f
14; 48
15; 41
a Reaction conditions: ArCHO (1a–j, 0.1 M), 2a–h (0.12 M), TBADT (2 ¥
10-3 M) in MeCN irradiated at 310 nm (unless otherwise stated). b Isolated
yields. c Reaction performed in acetone/water 4 : 1 v/v mixture. d 1a,
(0.2 M), 2a (0.25 M). e Compound not isolated but detected by GC-
MS analysis after 50% conversion of 1f. f Solution irradiated at 366 nm
wavelength.
the C–H bond in the formyl moiety is known to change little
in benzaldehyde (PhC(O)–H = 87 kcal mol-1)21a in comparison
with aliphatic aldehydes (e.g. CH3C(O)–H = 87.3 kcal mol-1.21b
Correspondingly, the rate constants for H abstraction by the
t-butoxyl12b and nitrate radicals12c is likewise similar (kH ca 2–7 ¥
107 M-1 s-1) for aliphatic aldehydes and benzaldehyde. Thus,
extension of the above reaction to aromatic aldehydes should
be possible, except for two possible limitations. The first one is
the strong dependence of the hydrogen abstraction rate on ring
substituents (the kH values by OH and NO3 radicals drop over
three order of magnitude in passing from electron-donating to the
less reactive electron-withdrawing substituted benzaldehydes).12c
The second is the strong absorption in the near UV by aromatic
aldehydes that may preclude excitation of the photocatalyst.
Scheme 2
Blank experiments showed that irradiation of a 0.1 M solution
of 1a in neat acetonitrile (24 h, 310 nm) did not cause appreciable
consumption of the aromatic aldehyde; on the contrary, when an
acetonitrile mixture of 1a and TBADT was likewise irradiated
a partial consumption of the aldehyde (ca. 40%) was measured
with no concomitant detection by GC-MS analysis of significant
amounts of byproducts. Substituting MeCN with a more eco-
friendly medium (acetone/water 4 : 1) gave likewise 3 in 77% yield.
Increasing the amount of 1a (up to 0.2 M) and 2a (up to 0.25 M)
allowed the photocatalyzed formation of 3 in a somewhat lower
yield (70%, See Experimental section).
1,4-Diketones 4 (62% yield) and 5 (53% yield) were also
prepared by the reaction of 1a with 2-cyclohexen-1-one (2b)
and 3-methylene-2-norbornanone (2c), respectively. Compound
5 was obtained as a single diastereoisomer. The norbornane
configuration issue was investigated by NMR through 2D-COSY
and NOESY experiments (see ESI†) and the data supported an
endo structure, although not conclusively (see Fig. 1).22
The endo configuration was confirmed, however, by a X-ray
structure determination (see Fig. 2). This demonstrated that
the hydrogen back-donation from the reduced photocatalyst
(TBADT-H∑) to the radical adduct intermediate took place as
expected from the less hindered side of the norbornanone moiety
and formed the endo isomer (see below).
In the synthesis of 5, changing to aqueous acetone was inap-
propriate, however, since the yield decreased (39%, Scheme 2). On
the contrary, the photocatalyzed addition of parent benzaldehyde
(1b) to methyl crotonate (2d) afforded the aromatic ketone 6 in a
Results and discussion
We report below a range of photocatalytic reactions of (het-
ero)aromatic aldehydes. The work aimed to establish if—and
within which limits—a synthesis of arylketones characterized by
a good atom economy could be achieved in this way. The results
obtained are reported in Table 1.
A number of (un)substituted olefins (a,b-unsaturated esters,
ketones, nitriles) and various functionalized aromatic aldehy-
des have been tested to explore the scope of the reaction. 4-
Anisaldehyde (1a), known to be highly reactive towards hydrogen
abstraction (kH 1.2 ¥ 109 M-1 s-1 by the nitrate radical),12c was first
tested by adopting the same reaction protocol used for aliphatic
derivatives,19 viz the irradiation (310 nm) of an equimolar solution
(0.1 M) of 1a and dimethyl maleate (2a) in acetonitrile in the
presence of a catalytic amount of TBADT (2% equiv.). The
hoped for ketone (dimethyl 2-(4-methoxybenzoyl)succinate, 3) was
indeed obtained, but the conversion of the starting aldehyde was
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Scheme 4
Fig. 1
Scheme 5
Under the conditions above, 4-hydroxybenzaldehyde (1f) did
react, though slowly (50% conversion after 30 h irradiation),
despite the presence of a reactive phenolic OH group, and gave
the expected ketone 10 with 2e. However, protection of this group
as a silyl ether (-OTBS, compound 1g) and shifting to irradiation
at 366 rather than 310 nm allowed the completion of the reaction
and afforded 1,4-dione 11 in 81% isolated yield (Scheme 6).
Scheme 6
Fig. 2 Perspective view of 5. Thermal ellipsoids are drawn at 50%
probability level.
Interesting was the case of isophthalaldehyde (1h) where two
equivalent formyl groups were present. The activation of a single
group was achieved, as demonstrated in the reaction with 2c,
where substituted benzaldehyde 12 was formed in 78% yield as
the exclusive product (Scheme 7). In analogy with compound 5,
the endo isomer was exclusively obtained.23
The extension of the method to heteroaromatic aldehydes was
next considered. Thiophene-2-carbaldehyde (1i) strongly absorbed
around 310 nm. Accordingly, 366 nm irradiation was adopted and
acylated thiophene 13 was prepared in 51% yield in the reaction
with methyl methacrylate (2g, Scheme 8).
low yield (36%) that was increased in acetone/water mixture (65%,
Scheme 3, right part).
The less H donating 4-chlorobenzaldehyde12c (1c) was tested
in the reaction with methyl vinyl ketone (2e) and gave diketone
7 in a high yield (82%, Scheme 3, left part). Isomeric 2-
chlorobenzaldehyde (1d) and methyl acrylate (2f) gave ketoester
8 in a lower yield (55%), presumably due to sterical hindering
(Scheme 4). Methyl 4-oxo-4-m-tolylbutanoate (9) was obtained
in 58% yield starting from 3-methylbenzaldehyde (1e) and 2f
(Scheme 5).
Scheme 3
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as in compounds 1a or 1e. No competitive paths from the acyl
radical (e.g. decarbonylation)27 or from the radical adduct (e.g.
polymerization) has been evidenced.
Noteworthy, a de-symmetrization of isophthalaldehyde has
been achieved maintaining one of the two formyl groups free for
further elaboration.
The only condition required for the success of the method
with the use of a photocatalyst was that this absorbed light.
The maximum of TBADT is at ca. 323 nm,17 but under the
conditions of the experiment the absorbance extends almost to
400 nm.28 Competitive light absorption by most of the aromatic
aldehydes considered somewhat slows down, but does not hinder,
the acylation, except when arriving at really high-absorbing
molecules, such as benzaldehydes with push-pull structure (the
4-dimethylamino derivative), or to polycondensed aromatic (e.g.
naphthalenes, see Figure S1, ESI†). In the other cases the yield
of benzoylation was little dependent on the aldehyde structure.
As for the olefin used, a,b-unsaturated esters such as maleate 2a
and crotonate 2d showed to be the best acyl radical trap for an
efficient and clean reaction. a,b-Unsaturated ketones (e.g. 2c, 2e),
however, are likewise good reaction partners providing that their
concentration does not exceed 0.1 M. Apart is the case of nitrile
2h, from which negligible yield of the end aromatic ketones are
obtained in most cases. This piece of evidence, along with the fact
that direct irradiation of the aldehydes in the absence of the catalyst
did not lead to significant reaction on the time scale considered,
support the role of TBADT as shown in Scheme 10. Both key steps,
H abstraction from the aldehydes and benzoylation of the alkenes
level to about the same rate at the relatively high concentration
used (ca. 0.1 M for both reagents).
Scheme 7
Scheme 8
Positive results were obtained also with pyridine-3-carbaldehyde
(1j), and the reactions with nitrile 2h and ester 2f allowed the
isolation of the corresponding 3-pyridine ketones 14 and 15 in 48
and 41% yield, respectively (Scheme 9).
Scheme 9
The reaction is distinguished by several favorable features. In
contrast to many radical processes, no toxic or foul-smelling
additives (such as a tin hydride or a thiol13) were required. Since
an ArC(=O)–H rather than an ArC(=O)–X bond is cleaved, no
competitive addition of the X radical to the olefin occurs and
thus no incorporation of that group in the end product (in
contrast to what commonly observed with acyl tellurides).6 The
acylation yields were mostly moderate. In many cases MeCN
was employed as the solvent; aqueous acetone, however, was
likewise satisfactory in several cases, though not with enones.
For the environmental point of view, the process seemed more
desirable than competing radicalic processes29 that make use of
toxic organoselenium compounds.
However, when using aromatic aldehydes having a strong
absorption also at 366 nm, such as 4-N,N-dimethylbenzaldehyde,
4-nitrobenzaldehyde or naphthaldehyde no acylation occurred.
The data above show that the generation of substituted benzoyl
radicals is in fact viable through a short path by decatungstate
photocatalyst from easily available aldehydes (see Scheme 10),
avoiding the preparation of Se or Te esters.
In fact, atom economy is good since ca. equimolar amounts of
the two reagents are used and TBADT is present in 2% molar
amount. Moreover, the method is simple since solutions were
irradiated in quartz tubes with no need of stirring. As for the
last point, 366 nm irradiation could be conveniently adopted in
all the synthesis described in this work and in the most favourable
cases the aldehyde concentration could be raised up to 0.2 M.
The end products are versatile 1,4 difunctionalized compounds.
1,4 Diketones, in particular, find large application in the synthesis
of five membered rings, such as cyclopentenones, furans, pyrroles,
thiophenes and related compounds.30 Pyridine derivatives are
likewise useful intermediates; in particular ketonitrile 14 has been
used as intermediate for the synthesis of Myosmine (a nicotiana
alkaloid)31a or nicotine-2-carboxamide31b and related derivatives of
15 were detected as nicotine31c or tobacco-specific nitrosamine31d
metabolites.
Scheme 10 TBADT Photocatalyzed aroylation of olefins.
TBADT photocatalysis is efficient and chemoselective17,18 even
when other labile C–H bonds are present in the starting aldehyde,
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and irradiated at 310 nm. Purification by column chromatography
(silica gel, eluent: cyclohexane : ethyl acetate = 9 : 1) afforded 216
mg of 3-(4-methoxybenzoyl)cyclohexanone (4, 62%) as a colorless
oil.
Experimental section
General
NMR spectra were recorded on a 300 MHz spectrometer. The
structure attributions were made on the basis of 1H and 13C NMR,
as well as DEPT experiments; chemical shifts are reported in ppm
downfield from TMS. Acetonitrile (HPLC purity grade), acetone
(purum for synthesis) and water (HPLC purity grade) were pur-
chased from Carlo Erba and used as received. The photochemical
reactions were performed by using nitrogen-purged solutions in
quartz tubes (diameter: 1 cm). Compounds 1a–f, 1h–j, 2a–h were
commercially available, and were freshly distilled or crystallized
before use.
1
4: H NMR (CDCl3)34 d 1.0–1.2 (m, 2 H), 1.8–2.0 (m, 2 H),
2.0–2.2 (m, 2 H), 2.4–2.5 (m, 2 H), 2.7–2.8 (m, 1 H), 3.8 (s, 3 H),
7.0–7.9 (AA’BB’ system, 4 H); 13C NMR (CDCl3) d 24.6 (CH2),
28.4 (CH2), 40.8 (CH2), 43.1 (CH), 44.6 (CH2), 55.4 (CH3), 113.9
(2 CH), 128.0, 130.6 (2 CH), 163.7, 198.9, 210.6; IR, (neat) n/cm-1
1712, 1672, 1601; Anal. Calcd. for C14H16O3: C, 72.39; H, 6.94.
Found: C, 72.2; H, 7.1.
Synthesis of 3-(2-(4-methoxyphenyl)-2-oxoethyl)bicyclo[2.2.1]-
heptan-2-one (5, endo isomer)
Compound 1g was prepared following the procedure pre-
viously described by Aizpurua et al.32 starting from 4-
hydroxybenzaldehyde (1f) and tert-butyldimethylsilyl chloride in
the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (sol-
vent: benzene; temperature: 25 ◦C; reaction time: 90 min; pu-
rification by distillation under vacuum; yield: 95%; spectroscopic
data of compound 1g in accordance with literature data33).
365 mL of 4-anisaldehyde (1a, 3.0 mmol, 0.1 M), 440 mL
of 3-methylenebicyclo[2.2.1]heptan-2-one (2c - 3-methylene-2-
norbornanone -, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile
and irradiated at 310 nm. Purification by column chromatography
(silica gel, eluent: cyclohexane : ethyl acetate = 9 : 1) yielded 205 mg
of 3-(2-(4-methoxyphenyl)-2-oxoethyl)bicyclo[2.2.1]heptan-2-one
(5, 53%, endo isomer) as a colorless oil which solidified upon
standing (mp 81–84 ◦C). The same reaction, when performed using
an acetone-water (4 : 1 v/v) mixture as the solvent, afforded again
5 in 39% yield.
General procedure for the photocatalyzed acylation of
electron-poor olefins
A solution (30 mL) of an aromatic aldehyde (1, 0.1 M) and an
olefin (2, 0.12 M) in the presence of 200 mg of TBADT28 (2 ¥
10-3 M) in MeCN (except when otherwise noted) was poured in
quartz tubes and purged for 10 min with nitrogen, serum capped
and irradiated for 30 h with ten (emission centered at 310 nm) or
twelve (366 nm) 15-W phosphor-coated lamps. The solvent was
removed in vacuo from the photolyzed solution and the products
isolated by purification of the residue by column chromatography
(cyclohexane/ethyl acetate as eluents).
5: 1H NMR (CDCl3) d 1.3–1.8 (m, 4 H), 1.9–2.0 (m, 2 H), 2.7–2.9
(m, 4 H), 3.3 (dd, 1 H, J = 17, 2 Hz), 3.8 (s, 3 H), 6,9–8,0 (AA’BB’
system, 4 H); 13C NMR (CDCl3) d 21.3 (CH2), 25.6 (CH2), 34.5
(CH2), 37.2 (CH2), 38.9 (CH), 49.8 (CH), 50.0 (CH), 55.4 (CH3),
113.7 (2 CH), 129.5, 130.2 (2 CH), 163.5, 196.6, 219.3; IR, (KBr)
n/cm-1 1737, 1676, 1601; Anal. Calcd. for C16H18O3: C, 74.39; H,
7.02. Found: C, 74.2; H, 7.0. The 1H NMR spectrum was recorded
also in C6D6 (see text) d 1.14 (bd, 1H, J = 10 Hz), 1.25–1.50 (m,
5H), 2.49 (m, 1H), 2.71 (dd, 1 H, J = 17.5, 10 Hz), 2.72 (m, 1H),
2.88 (m, 1H), 3.30 (s, 3 H), 3.50 (dd, 1 H, J = 17.5, 3 Hz), 6.73 and
7.95 (AA’BB’ system, 4 H).
Synthesis of dimethyl 2-(4-methoxybenzoyl)succinate (3)
365 mL of 4-anisaldehyde (1a, 3.0 mmol, 0.1 M), 450 mL of
dimethyl maleate (2a, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile and
irradiated at 310 nm. Purification of the raw product by column
chromatography (silica gel, eluent: cyclohexane : ethyl acetate =
8 : 2) gave 315 mg of dimethyl 2-(4-methoxybenzoyl)succinate (3,
75%) as a colorless oil.
Synthesis of methyl 3-methyl-4-oxo-4-phenylbutanoate (6)
305 mL of benzaldehyde (1b, 3.0 mmol, 0.1 M), 385 mL of
methyl crotonate (2d, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile and
irradiated at 310 nm. After purification by column chromatogra-
phy (silica gel, eluent: cyclohexane : ethyl acetate = 9 : 1), 111 mg of
methyl 3-methyl-4-oxo-4-phenylbutanoate (6, 36%) were obtained
as a colorless oil. The same reaction, when performed using an
acetone–water (4 : 1 v/v) mixture as the solvent, afforded again 6
in 65% yield. Spectroscopic data of 6 in accordance with literature
data.35
The same reaction, when performed using a 0.2 M amount
of 1a and a 0.25 M amount of 2a gave 3 in 70% yield whereas
when adopting an acetone-water (4 : 1 v/v) mixture as the solvent,
afforded again 3 in 77% yield.
1
3: H NMR (CDCl3) d 3.0 (d, 2 H, J = 7 Hz), 3.6 (s, 6 H),
3.8 (s, 3 H), 4.8 (t, 1 H, J = 7 Hz), 6.9–8.0 (AA’BB’ system, 4
H); 13C NMR (CDCl3) d 33.0 (CH2), 48.8 (CH), 51.9 (CH3), 52.6
(CH3), 55.4 (CH3), 113.8 (2 CH), 128.5, 131.2 (2 CH), 164.0, 169.3,
171.7, 192.2; IR, (neat) n/cm-1 1739, 1677, 1602; Anal. Calcd. for
C14H16O6: C, 59.99; H, 5.75. Found: C, 60.1; H, 5.7.
Synthesis of 1-(4-chlorophenyl)pentane-1,4-dione (7)
422 mg of 4-chlorobenzaldehyde (1c, 3.0 mmol, 0.1 M), 300 mL of
methyl vinyl ketone (2e, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile
and irradiated at 310 nm. Purification of the residue by column
chromatography (silica gel, eluent: cyclohexane : ethyl acetate =
9 : 1) gave 259 mg of 1-(4-chlorophenyl)pentane-1,4-dione (7, 82%)
Synthesis of 3-(4-methoxybenzoyl)cyclohexanone (4)
365 mL of 4-anisaldehyde (1a, 3.0 mmol, 0.1 M), 350 mL of 2-
cyclohexen-1-one (2b, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile
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as a colorless oil, which solidified upon standing (mp 69–71 ◦C, lit33
70–72 ◦C). The same reaction, when performed using an acetone–
water (4 : 1 v/v) mixture as the solvent, afforded again 7 in 59%
yield. Spectroscopic data of 7 in accordance with literature.36
Synthesis of 3-(2-(3-oxobicyclo[2.2.1]heptan-2-yl)acetyl)-
benzaldehyde (12, endo isomer)
402 mg of isophtalaldehyde (1h, 3.0 mmol, 0.1 M), 440 mL
of 3-methylenebicyclo[2.2.1]heptan-2-one (2c - 3-methylene-2-
norbornanone -, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetoni-
trile and irradiated at 310 nm. Purification of the residue by
column chromatography (silica gel, eluent: cyclohexane : ethyl
acetate = 8 : 2) gave 300 mg of 3-(2-(3-oxobicyclo[2.2.1]heptan-2-
yl)acetyl)benzaldehyde (12, 78%, endo isomer) as a colorless oil,
which solidified upon standing (mp 72–74 ◦C).
Synthesis of methyl 4-(2-chlorophenyl)-4-oxobutanoate (8).37
340 mL of 2-chlorobenzaldehyde (1d, 3.0 mmol, 0.1 M), 325 mL
of methyl acrylate (2f, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile
and irradiated at 310 nm. Purification by column chromatography
(silica gel, eluent: cyclohexane : ethyl acetate = 9 : 1) yielded
187 mg of methyl 4-(2-chlorophenyl)-4-oxobutanoate (8, 55%) as
a colorless oil.
1
12: H NMR (CDCl3) d 1.3–1.7 (m, 4 H), 1.8–2.0 (m, 2 H),
2.7–3.0 (m, 4 H), 3.3 (dd, 1 H, J = 17, 2 Hz), 7.7 (t, 1 H, J = 8 Hz),
8.1 (dt, 1 H, J = 8, 2 Hz), 8.3 (dt, 1 H, J = 8, 2 Hz), 8.5 (t, 1 H, J =
2 Hz), 10.1 (s, 1 H); 13C NMR (CDCl3) d 21.3 (CH2), 25.7 (CH2),
35.2 (CH2), 37.2 (CH2), 39.0 (CH), 49.5 (CH), 49.9 (CH), 129.2
(CH), 129.5 (CH), 133.4 (CH), 133.5 (CH), 136.6 (C), 137.2 (C),
191.3, 197.0, 218.8; IR, (KBr) n/cm-1 1740, 1699; Anal. Calcd. for
C16H16O3: C, 74.98; H, 6.29. Found: C, 75.1; H, 6.3.
1
8: H NMR (CDCl3) d 2.7 (t, 2 H, J = 7 Hz), 3.2 (t, 2 H, J =
7 Hz), 3.6 (s, 3 H), 7.1–7.3 (m, 3 H), 7.4–7.5 (m, 1 H); 13C NMR
(CDCl3) d 28.1 (CH2), 37.4 (CH2), 51.7 (CH3), 126.8 (CH), 129.1
(CH), 130.4 (CH), 130.7, 131.8 (CH), 138.6, 172.9, 200.9; IR,
(neat) n/cm-1 1737, 1702; Anal. Calcd. for C11H11ClO3: C, 58.29;
H, 4.89. Found: C, 58.3; H, 4.8.
Synthesis of methyl 4-oxo-4-m-tolylbutanoate (9)38
Synthesis of methyl 2-methyl-4-oxo-4-(thiophen-2-yl)butanoate
(13)39
355 mL of 3-methylbenzaldehyde (1e, 3.0 mmol, 0.1 M), 325 mL
of methyl acrylate (2f, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile and
irradiated at 310 nm. After purification of the residue by column
chromatography (silica gel, eluent: cyclohexane : ethyl acetate =
9 : 1), 182 mg of methyl 4-oxo-4-m-tolylbutanoate (9, 58%) were
obtained as a colorless oil.
280 mL of thiophene-2-carbaldehyde (1i, 3.0 mmol, 0.1 M), 385 mL
of methyl methacrylate (2g, 3.6 mmol, 0.12 M) and 200 mg of
TBADT (0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of
acetonitrile and irradiated at 366 nm. Purification of the residue
by column chromatography (silica gel, eluent: cyclohexane : ethyl
acetate = 95 : 5) yielded 162 mg of methyl 2-methyl-4-oxo-4-
(thiophen-2-yl)butanoate (13, 51%) as a colorless oil.
1
9: H NMR (CDCl3) d 2.4 (s, 3 H), 2.8 (t, 2 H, J = 7 Hz), 3.3
(t, 2 H, J = 7 Hz), 3.8 (s, 3 H), 7.3–7.4 (m, 2 H), 7.8–7.9 (m, 2
H); 13C NMR (CDCl3) d 21.2 (CH3), 27.9 (CH2), 33.3 (CH2), 51.7
(CH3), 125.1 (CH), 128.4 (CH), 128.5 (CH), 133.9 (CH), 136.5,
138.3, 173.3, 198.1; IR, (neat) n/cm-1 1740, 1687; Anal. Calcd. for
C12H14O3: C, 69.88; H, 6.84. Found: C, 70.0; H, 6.9.
1
13: H NMR (CDCl3) d 1.2 (d, 3 H, J = 7 Hz), 2.9–3.5 (2 H,
AB part of an ABX system), 3.0–3.2 (X part of an ABX system),
3.7 (s, 3 H), 7.1 (m, 1 H), 7.7 (m, 1 H), 7.8 (m, 1 H); 13C NMR
(CDCl3) d 17.1 (CH3), 34.8 (CH), 42.3 (CH2), 51.8 (CH3), 128.0
(CH), 131.9 (CH), 133.6 (CH), 143.7 (C), 176.1, 190.8; IR, (neat)
n/cm-1 1735, 1634; Anal. Calcd. for C10H12O3S: C, 56.58; H, 5.70.
Found: C, 56.6; H, 5.6.
Synthesis of 1-(4-(tert-butyldimethylsilyloxy)phenyl)pentane-
1,4-dione (11)
709 mg of 4-(tert-butyldimethylsilyloxy)benzaldehyde (1g,
3.0 mmol, 0.1 M), 300 mL of methyl vinyl ketone (2e, 3.6 mmol,
0.12 M) and 200 mg of TBADT (0.06 mmol, 2 ¥ 10-3 M)
were dissolved in 30 mL of acetonitrile and irradiated at 366
nm. Purification by column chromatography (silica gel, eluent:
cyclohexane : ethyl acetate = 9 : 1) afforded 372 mg of 1-(4-
(tert-butyldimethylsilyloxy)phenyl)pentane-1,4-dione (11, 81%) as
a colorless oil. When the reaction was performed by using 4-
hydroxybenzaldehyde (1f) in place of 1g, the consumption of the
aldehyde was ca. 50% after 30 h irradiation. The formation of 1-(4-
hydroxyphenyl)pentane-1,4-dione (10) was confirmed by GC-MS
analysis: MS (m/z) 192 (10, M+), 177 (20), 121 (100), 93 (10), 66
(10).
11: 1H NMR (CDCl3) d 0.2 (s, 6 H), 1.0 (s, 9 H), 2.2 (s, 3 H), 2.8
(t, 2 H, J = 7 Hz), 3.2 (t, 2 H, J = 7 Hz), 6.8–7.8 (AA’BB’ system,
4 H); 13C NMR (CDCl3) d -4.5 (2 CH3), 18.1 (C), 25.4 (3 CH3),
29.9 (CH3), 31.9 (CH2), 36.9 (CH2), 119.8 (2 CH), 130.1 (2 CH),
130.2 (C), 160.1 (C), 196.9, 207.2; IR, (neat) n/cm-1 1719, 1681,
1600, 842; Anal. Calcd. for C17H26O3Si: C, 66.62; H, 8.55. Found:
C, 66.7; H, 8.5.
Synthesis of 4-oxo-4-(pyridin-3-yl)butanenitrile (14)
280 mL of pyridine-3-carbaldehyde (1j, 3.0 mmol, 0.1 M), 235
mL of acrylonitrile (2h, 3.6 mmol, 0.12 M) and 200 mg of
TBADT (0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of
acetonitrile and irradiated at 310 nm. Purification by column
chromatography (silica gel, eluent: cyclohexane : ethyl acetate =
1 : 1) gave 115 mg of 4-oxo-4-(pyridin-3-yl)butanenitrile (14, 48%)
◦
as a co◦lorless oil, which solidified upon standing (mp 65–67 C,
lit40 74 C). Spectroscopic data of 14 in accordance with literature
data.40
Synthesis of methyl 4-oxo-4-(pyridin-3-yl)butanoate (15)
280 mL of pyridine-3-carbaldehyde (1j, 3.0 mmol, 0.1 M), 325 mL
of methyl acrylate (2f, 3.6 mmol, 0.12 M) and 200 mg of TBADT
(0.06 mmol, 2 ¥ 10-3 M) were dissolved in 30 mL of acetonitrile and
irradiated for 30 h at 310 nm. Purification of the residue by column
chromatography (silica gel, eluent: cyclohexane : ethyl acetate =
6 : 4) yielded 119 mg of methyl 4-oxo-4-(pyridin-3-yl)butanoate
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(15, 41%) were obtained as a colorless oil, which solidified upon
standing (mp 69–71 ◦C).
16 M. D. Tzirakis, I. N. Lykakis and M. Orfanopoulos, Chem. Soc. Rev.,
2009, 38, 2609.
17 For selective examples of TBADT photocatalyzed reactions, see: D.
Dondi, A. M. Cardarelli, M. Fagnoni and A. Albini, Tetrahedron, 2006,
62, 5527(a) D. Dondi, M. Fagnoni and A. Albini, Chem.–Eur. J., 2006,
12, 4153; (b) S. Angioni, D. Ravelli, D. Emma, D. Dondi, M. Fagnoni
and A. Albini, Adv. Synth. Catal., 2008, 350, 2209; (c) D. Dondi, D.
Ravelli, M. Fagnoni, M. Mella, A. Molinari, A. Maldotti and A. Albini,
Chem.–Eur. J., 2009, 15, 7949.
18 (a) M. D. Tzirakis and M. Orfanopoulos, J. Am. Chem. Soc., 2009, 131,
4063; (b) M. D. Tzirakis and M. Orfanopoulos, Org. Lett., 2008, 10,
873.
15: 1H NMR (CDCl3)41 d 2.8 (t, 2 H, J = 7 Hz), 3.3 (t, 2 H, J =
7 Hz), 3.7 (s, 3 H), 7.4 (dd, 1 H, J = 8, 4 Hz), 8.2 (dt, 1 H, J = 8, 2
Hz), 8.8 (dd, 1 H, J = 4, 2 Hz), 9.2 (d, 1 H, J = 2 Hz); 13C NMR
(CDCl3)41 d 27.6 (CH2), 35.5 (CH2), 51.8 (CH3), 123.5 (CH), 131.7
(C), 135.2 (CH), 149.5 (CH), 153.6 (CH), 172.9, 196.9; IR, (neat)
n/cm-1 1734, 1686; Anal. Calcd. for C10H11NO3: C, 62.17; H, 5.74.
Found: C, 62.2; H, 5.8.
19 S. Esposti, D. Dondi, M. Fagnoni and A. Albini, Angew. Chem., Int.
Ed., 2007, 46, 2531.
20 S. Protti, D. Dondi, M. Fagnoni and A. Albini, Green Chem., 2009, 11,
239.
21 (a) H. Yamamoto, M. Miura, M. Nojima and S. Kusabayashi, J. Chem.
Soc., Perkin Trans. 1, 1986, 173; (b) H. L. Fang, D. M. Meister and R.
L. Swofford, J. Phys. Chem., 1984, 88, 410.
Acknowledgements
Partial support of this work by Murst, Rome is gratefully
acknowledged.
22 Thus, in C6D6 the aliphatic part of the spectrum was best resolved,
allowing to distinguish H-3 (2.88 ppm), H-1 (2.50 ppm), H-4 (2.72
ppm) and H-8 methylene hydrogens (2.70 and 3.50 ppm). One of H-7
hydrogen was separated (1.14 ppm) whereas the second one (1.40 ppm
from COSY correlation) unfortunately overlapped with H-5 and H-
6. Under these conditions, no long-range coupling between H-3 and
one of H-7 which would be diagnostic for H-3 endo was revealed in
either COSY-90 (not reported) or COSY-LR spectra (see ESI†). No
correlation was found between H-3 with H-1 or H-4 in the NOESY
spectrum, whereas the only significant cross peak appeared at 1.4 ppm,
probably involving one of H-7.
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