Polar effects in free-radical reactions. A novel homolytic acylation of heteroaromatic bases by aerobic oxidation of aldehydes, catalysed by N-hydroxyphthalimide and Co salts

Article abstract of DOI:10.1002/jhet.5570400220

A new process for the homolytic acylation of protonated heteroaromatic bases is described; an N-oxyl radical (PINO) generated from N-hydroxyphthalimide by air oxygen and Co(II) abstracts a hydrogen atom from an aldehyde. The resulting nucleophilic acyl radical adds to a heteroaromatic base, which is then rearomatised in a chain process. Quinazoline has an anomalous behaviour, giving 3H-quinazolin-4-one as the only reaction product.

Full text of DOI:10.1002/jhet.5570400220

Mar-Apr 2003 Polar Effects in Free-Radical Reactions. A Novel Homolytic Acylation
of Heteroaromatic Bases by Aerobic Oxidation of Aldehydes,
Catalysed by N-Hydroxyphthalimide and Co Salts.
325
Francesco Minisci*, Francesco Recupero, Andrea Cecchetto,
Carlo Punta, Cristian Gambarotti
Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via
Mancinelli 7, 20131 Milano Mi, Italy; E-mail francesco.minisci@polimi.it
Francesca Fontana
Università di Bergamo, Dipartimento di Ingegneria, viale Marconi 5, 24044 Dalmine BG, Italy
Gian Franco Pedulli
Università di Bologna, Dipartimento di Chimica Organica “A.Mangini”, via S.Donato 15,
I-40127 Bologna BO, Italy
Received July 12, 2002
A new process for the homolytic acylation of protonated heteroaromatic bases is described; an N-oxyl
radical (PINO) generated from N-hydroxyphthalimide by air oxygen and Co(II) abstracts a hydrogen atom
from an aldehyde. The resulting nucleophilic acyl radical adds to a heteroaromatic base, which is then rearo-
matised in a chain process. Quinazoline has an anomalous behaviour, giving 3H-quinazolin-4-one as the
only reaction product.
J. Heterocyclic Chem., 40, 325 (2003).
The great synthetic interest of the substitution of proto-
nated heteroaromatic bases by nucleophilic carbon-centred
radicals results from the high regio- and chemoselectivity,
due to polar effects, the large variety of inexpensive radical
sources and the simple experimental conditions. The over-
all polar effect in these reactions is the result of the polarity
and the polarisability of both the radicals and the substrates.
While carbon-centred radicals usually do not show an
extremely marked nucleophilic character, the electrophilic
polarity of heteroaromatic bases is greatly increased by pro-
tonation. The strongly induced activation of heteroaromatic
bases towards nucleophilic species, due to protonation,
cannot be exploited with ionic nucleophiles, whose primary
effect is deprotonation of the base. This problem is over-
come by the use of free-radical nucleophiles, which react
with protonated heteroaromatic bases in a large variety of
substitutions characterised by high reactivity and selectiv-
ity. These reproduce most of the features of the Friedel-
Crafts aromatic substitutions, but with opposite reactivity
and selectivity, so as to represent one of the main general
reactions of this class of aromatic compounds [1].
1. the t-BuOOH/Fe(III) redox system in the presence of
aldehydes [2] (eqs. 1, 2)
2. the oxidative decarboxylation of α-ketoacids by the
+
S O = Ag redox system [3] (eqs.3, 4)
2
8
In this Note we report a new homolytic acylation of het-
eroaromatic bases by aerobic oxidation of aldehydes,
catalysed by N-hydroxyphthalimide (NHPI) and Co salts.
+
The overall stoichiometry is given by eq. 5, [HetH ]
2
being the protonated base.
The reaction is carried out by bubbling air in a CH CN
3
Because of their high reactivity (absolute rate constants
or PhCN solution of the heteroaromatic base protonated by
5
8
-1 -1
in the range of 10 -10 M
s
at r.t.) the most reactive
CF COOH, the aldehyde, NHPI and the Co(II) salt. In the
3
bases are effective traps for revealing the presence of car-
bon-centred radicals in a reaction medium. Basically any
carbonyl (acyl, carbamoyl, alkoxycarbonyl) or alkyl radi-
cal not bearing electron-withdrawing groups directly
bonded to the radical centre can be successfully utilised to
this purpose [1].
In previous works we have developed two general
sources of acyl radicals, useful for the acylation of het-
eroaromatic bases:
absence of NHPI no reaction occurs under the same condi-
tions. The reactivity of acyl radicals towards protonated
heteroaromatic bases is so high that, even in the case of
aldehydes R-CHO where R is a tertiary alkyl group, addi-
tion of the acyl radical to the heterocyclic ring competes
with decarbonylation (eq. 6), which is a fast process [4].

326
F. Minisci, F. Recupero, A. Cecchetto, C. Punta,
C. Gambarotti, F. Fontana and G. F. Pedulli
Vol. 40
The ratio between acylation and alkylation of the hetero-
These features, as well as the absence of acylation in
experiments without NHPI, find a satisfactory explanation
in the competition between oxygen and heteroaromatic base
towards reaction with the acyl radical (eq. 7). They also sug-
gest that the acyl radical is formed by hydrogen abstraction
from the aldehyde by the phthalimido-N-oxyl radical
(PINO, eq. 8) and not by the acylperoxyl radical (eq. 9).
The importance of the polar effect in this new acylation
method is particularly marked; this is shown by the quanti-
tative conversion and complete selectivity in the acylation
of 4-cyanopyridine as compared with the behaviour of
pyridine, which reacts only in traces under the same condi-
tions. With pyridine, reaction 7a is much faster than 7b and
cyclic ring depends on the temperature: decarbonylation,
being a unimolecular process, is more affected by temper-
ature, so that alkylation increases at higher temperatures.
When R in eq. 5 is an aryl or primary alkyl group no decar-
bonylation is observed, while with secondary alkyl groups
only minor decarbonylation occurs. The results are
reported in the Table. The selectivity of acylation in the α
and γ positions of the heterocyclic ring (the positions of
higher nucleophilic reactivity) is in all cases good, while
conversions depend on the reactivity of the heterocyclic
ring. Quinoxaline is more reactive than quinoline and
gives better conversions under the same conditions.
Table
Acylation of Heteroaromatic Bases by Aerobic Oxidation of Aldehydes, R-CHO
Run
1
Heterocycle
R
Conv. (%)
50
Products (%)
Quinoline [ a ]
Ph
2-Acyl (1) (34), 4-Acyl (2) ( 41),
2,4-Diacyl (3) ( 22)
2
3
4
5
6
7
8
9
10
11
12
13
14
4-Methylquinoline
Quinoxaline [ b ]
Quinoxaline [ c ]
Quinoxaline
Quinoxaline [ d ]
Quinoxaline [ e ]
Quinoxaline [ f ]
Quinoxaline [ e ][ f ]
Quinoxaline [ f ]
Quinoxaline
“
“
“
“
“
“
“
“
15
76
88
86
0
80
39
33
100
100
51
91
100
2-Acyl (4) ( 98)
2-Acyl (5) ( 86), 2,3-Diacyl (6) ( 12)
2-Acyl (5) (75), 2,3-Diacyl (6) (21)
2-Acyl (5) (85), 2,3-Diacyl (6) (14)
—
2-Acyl (5) (82), 2,3-Diacyl (6) (15)
2-Acyl (5) (98)
“
2-Acyl (5) (99)
t-Bu
“
2-Acyl (7) (45), 2-t-Bu (8) (52)
2-Acyl (7) (26), 2-t-Bu (8) (72)
2-Acyl (9) (78), 2-i-Pr (10) (16)
2-Acyl (11) (77), 2,3-diacyl (12) (14)
2-Acyl (13) (43), 2,3-diacyl (14) (32),
2-Acyl-3-cyclohexyl (15) (12)
3H-Quinazolin-4-one (16) (96)
3H-Quinazolin-4-one (16) (98)
2-Acyl (17) (96)
s-C H
3
7
“
“
n-C H
7
15
Cyclohexyl
15
16
17
18
19
20
21
Quinazoline
“
Pyrazine
n-C H
100
100
85
82
100
14
6
13
13
Ph
n-C H
6
“
Ph
“
2-Acyl (18) (97)
2-Acyl (19) (96)
4-Acyl (20) (98)
4-Cyanopyridine [ e ]
Pyrimidine
Pyridine
n-C H
6
13
Ph
traces
—
[a] Reaction time 6 h, 9.1 mmol of PhCOOH are formed; [b] Reaction time 2 h, 2 mmol of PhCOOH are formed; [c] Oxygen
instead of air, reaction time 0.7 h, 13.3 mmol of PhCOOH are formed; [d] Without NHPI; [e] CH CN instead of PhCN as solvent;
3
[f] 20 °C instead of 70 °C.

Mar-Apr 2003
Polar Effects in Free-Radical Reactions
327
the only result is the oxidation of benzaldehyde to benzoic
acid.
Recently, the Ishii group utilised the NHPI catalysis to per-
form a variety of aerobic oxidations of organic compounds
[5], in all of which hydrogen abstraction by PINO radical
from the C-H bonds plays a key role. The formation of acyl
radicals from aldehydes according to eq. 8 has also been sug-
gested by the same group for the catalytic free-radical addi-
tion of aldehydes to alkenes [6]. The presence of NHPI in
this case somewhat improves the conversion and the selec-
tivity of the addition; this, however, at variance with our
process, must be carried out in the absence of oxygen, since
Carboxylic acids, R-COOH, from the aldehydes R-CHO
are formed as by-products, deriving from the oxidation of
aldehydes by peracids (eq. 15).
the reaction of acyl radicals with O (eq. 7a) is much faster
Since the ratio between acylation of the heterocycle and
formation of the carboxylic acid depends on the competi-
tion represented in eq. 7, its value increases with increas-
ing reactivity of the heteroaromatic base and with decreas-
ing oxygen concentration. Thus, with quinoxaline a higher
ratio has been obtained by working with air than with oxy-
gen (entries 4 and 5 in the Table); moreover, more car-
boxylic acid is formed with quinoline (entry 1) than with
the more reactive quinoxaline under the same conditions.
Quinazoline has an anomalous behaviour compared to
the other heteroaromatic bases; no acylation occurs under
the same conditions, while 3H-quinazolin-4-one is the
only reaction product. The formation of this latter com-
2
than the addition of nucleophilic acyl radicals [1] to electron-
rich alkenes. With electron-poor alkenes yields and selectiv-
ity are high regardless of the presence of NHPI. We have
shown how hydrogen abstraction (eq. 8) is strongly affected
by polar and enthalpic effects in the selective oxidation of
alcohols [7], amines [8], amides [9] and silanes [10]. We
have also evaluated [11] the bond dissociation energy (BDE)
-1
of the O-H bond in NHPI (88.1 kcal mol ) so that eq. 8,
which is almost thermoneutral (BDE of the RCO-H bond is
-1
87 kcal mol ), can be considered an equilibrium process.
This is however shifted to the right by the subsequent fast
reaction of the acyl radical with the heteroaromatic base or
with oxygen (eq. 7). Moreover, we have evaluated [12] that
hydrogen abstraction from the =N-OH group in NHPI by
pound by oxidation of quinazoline with H O in acetic
2
2
acid is well-known [13]; in this case we explain its forma-
tion by a similar oxidation of the heteroaromatic base by
the peracid (eq. 16), formed in eqs. 10 and 12.
3
-1 -1
peroxyl radical ROO• , (7.2 × 10 M
s at r.t.) is much
-3
-1 -1 -1
faster than from C-H bonds (10 – 10 M s ) and we can
reasonably expect that hydrogen abstraction by the acylper-
oxyl radical, RCO-OO , should also be much faster from
.
=N-OH (eq. 10) than from C-H bonds in aldehydes (eq. 9).
This should allow regeneration of the PINO radical in a chain
process (in full agreement with the assumption that the acyl
radical is formed according to eq. 8 and not to eq. 9).
PINO radical can also be regenerated from NHPI by oxi-
dation with Co(III) salt (eq. 11) formed by the peroxyl oxi-
dation of Co(II) salt through a redox chain (eq. 12).
EXPERIMENTAL
The heteroaromatic bases and the aldehydes were commercial
products. The reaction products were all known and prepared by
the previously developed procedure of acylation and alkylation
by aldehydes and the redox system t-BuOOH/Fe(II).
General Procedure.
Air was bubbled in a solution of the heteroaromatic base (3
mmol), CF COOH (0.23 mL, 3 mmol), aldehyde (15 mmol),
3
-3
NHPI (49 mg, 0.3 mmol), Co(acac) (1.3 mg, 5 × 10 mmol) and
Co(acac) (3,6 mg, 10 mmol) in 8 mL of Ph-CN heated at 70 °C
2
-2
3
for 12h. Some experiments were carried out in CH CN solution,
3
Co(III) may also play a significant role in the rearomati-
sation of the heterocyclic radical adduct (eqs.13, 14).
at 20 °C and for shorter reaction times. The solution was diluted
with 30 mL of 5% H SO aqueous solution and extracted by
2
4

328
F. Minisci, F. Recupero, A. Cecchetto, C. Punta,
C. Gambarotti, F. Fontana and G. F. Pedulli
Vol. 40
ethyl acetate to separate the excess aldehyde and the formed car-
boxylic acid. 10% NaOH (15 mL) were then added to the aque-
ous solution and the basic products were extracted with ethyl
acetate. The reaction products were identified by gc-ms analysis
and comparison with authentic samples prepared according to
known procedures [2-4], [12] and analysed by gc with internal
standard. Compound 4 was utilised as internal standard for reac-
tion products 1-3 and 5-20, while compound 5 was used as inter-
nal standard for compound 4. The results of the gc analyses are
reported in the Table.
+
methanone (15) was obtained in 7% yield; MS (m/z): 322 (M ),
240, 129, 102, 83, 55, 41.
Quinazoline with n-Heptanal.
3H-Quinazolin-4-one (16) was obtained in 91% yield; MS
+
(m/z): 146 (M ), 118, 90, 76, 63, 50.
Quinazoline with Benzaldehyde.
3H-Quinazolin-4-one (16) was obtained in 91% yield.
Pyrazine with n-Heptanal.
The reaction products were isolated by flash chromatography
on silica gel (n-hexane-ethyl acetate 5:1), obtaining the following
acylation products (yields % of acylation are based on converted
heterocyclic substrates).
2-Heptanoylpyrazine (17) was obtained in 90% yield; MS
+
(m/z): 192 (M ), 182, 167, 122, 104, 80, 44.
Pyrazine with bBnzaldehyde.
Quinoline with Benzaldehyde.
2-Benzoylpyrazine (18) was obtained in 92% yield; MS (m/z):
184 (M ), 156, 105, 77, 51.
+
2-Benzoylquinoline (1) was obtained in 29% yield; MS (m/z):
+
233 (M ), 216, 176, 156, 128, 105, 77, 51. 4-Benzoylquinoline
4-Cyanopyridine with Benzaldehyde.
+
(2) was obtained in36% yield; MS (m/z): 233 (M ), 204, 176,
151, 128, 105, 77, 51. 2,4-Dibenzoylquinoline (3) was obtained
in18% yield; MS (m/z): 337 (M ), 308, 280, 232, 176, 155, 127,
2-Benzoyl-4-cyanopyridine (19) was obtained in 93% yield;
+
+
MS (m/z): 208 (M ), 180, 153, 105, 77, 51.
105, 77, 51.
Pyrimidine with n-Heptanal.
4-Methylquinoline with Benzaldehyde.
2-Benzoyl-4-methylquinoline (4) was obtained in 91% yield;
4-Heptanoylpyrimidine (20) was obtained in 91% yield; MS
(m/z): 192 (M ), 149, 135, 107, 94, 80, 52, 43.
+
+
MS (m/z): 247 (M ), 218, 140, 115, 105, 77, 51.
REFERENCES AND NOTES
Quinoxaline with Benzaldehyde.
In run 3, 2-benzoylquinoxaline (5) was obtained in 79% yield;
[1] Reviews in the subject: F. Minisci, Synthesis, 1 (1973); Top.
Curr. Chem. 62, 1 (1976); F. Minisci, E. Vismara and F. Fontana,
Heterocycles 28, 489 (1989); F. Minisci, F. Fontana and E. Vismara J.
Heterocyclic Chem. 27, 79 (1990).
+
MS (m/z): 234 (M ), 206, 129, 105, 77, 51; 2,3-dibenzoylquinox-
+
aline (6) was obtained in 7% yield; MS (m/z): 338 (M ), 310,
233, 105, 77, 51. In run 8, 2-benzoylquinoxaline (5) was obtained
[2] F. Minisci, T. Caronna and G. P. Gardini, J. Chem. Soc.
Chem. Commun. 201 (1969); T. Caronna, G. Fronza, F. Minisci and O.
Porta, J. Chem. Soc. Perkin Trans. 2 2035 (1972); F. Minisci, A. Citterio,
E. Vismara and C. Giordano, Tetrahedron 41, 4157 (1985).
[3] F. Fontana, F. Minisci, M. C. Nogueira Barbosa and E.
Vismara, J. Org. Chem. 56, 2866 (1991).
[4] H. Schuh, E. J. Hamilton, H. Paul and H. Fischer,
Helv.Chim.Acta 57, 2011 (1974); M. Bellatti, T. Caronna, A. Citterio and
F. Minisci, J. Chem. Soc. Perkin Trans. 2 1835 (1976).
[5] A review: Y. Ishii, S. Sakaguchi and T. Iwahama, Adv. Synth.
Catal. 343, 393 (2001).
[6] S. Tsujimoto, T. Iwahama, S. Sakaguchi and Y. Ishii, Chem.
Commun. 2352 (2001).
[7] F. Minisci, C. Punta, F. Recupero, F. Fontana and G. F.
Pedulli, Chem. Commun. 688 (2002).
[8] A. Cecchetto, F. Minisci, F. Recupero, F. Fontana and G. F.
Pedulli, Tetrahedron Lett. 43, 3605 (2002).
[9] F. Minisci, C. Punta, F. Recupero, F. Fontana and G. F.
Pedulli, J. Org. Chem. 67, 2671 (2002).
in 93% yield.
Quinoxaline with Pivalaldehyde.
In run 10, 2-pivaloylquinoxaline (7) was obtained in 41%
yield; MS (m/z): 214 (M ), 186, 171, 158, 144, 130, 102, 76, 50,
41; 2-t-butylquinoxaline (8) was obtained in 46% yield; MS
(m/z): 186 (M ), 171, 144, 129, 102, 76, 50, 41.
+
+
Quinoxaline with 2-Butanal.
2-Butanoylquinoxaline (9) was obtained in 71% yield; MS
(m/z): 234 (M ), 200, 185, 159, 111, 71, 56, 43; 2-isopro-
+
pylquinoxaline (10) was obtained in 9% yield; MS (m/z): 172
+
(M ), 185, 157, 129, 102, 76, 41.
Quinoxaline with n-Octanal.
2-Octanoylquinoxaline (11) was obtained in 72% yield; MS
(m/z): 256 (M ), 229, 185, 157, 144, 129, 102, 76, 57, 41; 2,3-
+
dioctanoylquinoxaline (12) was obtained in 8% yield; MS (m/z):
[10] F. Minisci, C. Punta, F. Recupero, C. Guidarini, F. Fontana
and G. F. Pedulli, Synlett, 1173 (2002).
+
382 (M ), 354, 312, 270, 228, 185, 144, 129, 102, 57.
[11] F. Minisci, C. Punta, F. Recupero, C. Gambarotti, F.
Antonietti, F. Fontana and G. F. Pedulli, Chem. Commun., 2496 (2002)
[12] R. Amorati, M. Lucarini, V. Mugnaini, G. F. Pedulli, F.
Minisci, F. Recupero, F. Fontana, P. Astolfi and L. Greci, J. Org. Chem.
in press.
Quinoxaline with Cyclohexancarboxaldehyde.
Cyclohexyl-quinoxalin-2-yl methanone (13) was obtained in
+
36% yield; MS (m/z): 240 (M ), 212, 144, 130, 102, 76, 55, 41;
(3-cyclohexanecarbonyl-quinoxalin-2-yl)-cyclohexyl-methanone
(14) was obtained in 26% yield; MS (m/z): 350 (M ), 322, 240,
129, 102, 85, 55; cyclohexyl-(3-cyclohexyl-quinoxalin-2-yl)-
+
K. Adachi, Yakugaku Zasshi 77, 507 (1957); Chem. Abstr., 51, 14744
(1957).