A general method for the synthesis of the most powerful naturally?occurring Maillard flavors

Article abstract of DOI:10.1016/j.tet.2007.03.089

The natural flavors 2-acetyl-1-pyrroline 1a, 2-propionyl-1-pyrroline 1b, 2-acetyl-3,4,5,6-tetrahydropyridine 1c, 2-acetyl-2-thiazoline 1d, 2-propionyl-2-thiazoline 1e, and the artificial flavor 2-acetyl-5,6-dihydro-4H-1,3-thiazine 1f have been prepared by catalytic SeO₂ oxidation of the corresponding cyclic imines 6a-c and sulfur cyclic imines 7a-c using TBHP as co-oxidant. The oxidation of the pyrrolines 1a and b is completely regioselective. Professional olfactory evaluation together with the odor threshold of the new flavor 1f is reported.

Full text of DOI:10.1016/j.tet.2007.03.089

Tetrahedron 63 (2007) 4762–4767
A general method for the synthesis of the most powerful
naturally occurring Maillard flavors
*
Claudio Fuganti, Francesco G. Gatti and Stefano Serra
Dipartimento di Chimica, Materiali e Ingegneria Chimica del Politecnico, CNR—Istituto del, Riconoscimento molecolare,
Via Mancinelli, 7, I-20131 Milano, Italy
Received 10 November 2006; revised 24 February 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—The natural flavors 2-acetyl-1-pyrroline 1a, 2-propionyl-1-pyrroline 1b, 2-acetyl-3,4,5,6-tetrahydropyridine 1c, 2-acetyl-2-thi-
azoline 1d, 2-propionyl-2-thiazoline 1e, and the artificial flavor 2-acetyl-5,6-dihydro-4H-1,3-thiazine 1f have been prepared by catalytic
SeO oxidation of the corresponding cyclic imines 6a–c and sulfur cyclic imines 7a–c using TBHP as co-oxidant. The oxidation of the pyrro-
2
lines 1a and b is completely regioselective. Professional olfactory evaluation together with the odor threshold of the new flavor 1f is reported.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
simple synthetic routes to these compounds. Many synthe-
ses, concerning the preparation of 1a–c, have been reported.
They are distinguishable by two main strategies: (i)
modification of commercially available starting materials
Historically, the heterocycles 2-acetyl-1-pyrroline 1a and 2-
acetyl-3,4,5,6-tetrahydropyridine 1c have been identified as
the most important flavors of cooked rice and bread, more-
over, their flavor significance has been shown in many other
foods. They exhibit a pleasant bread like scent with very low
odor thresholds. The sulfur containing analogue of 1a is the
3
–9
containing already the heterocyclic unit,
acetyl-pyrrole or the 2-acetyl-pyridine, the methylester
such as the 2-
3
4
5
,6
7
8,9
of proline, the pyrrolidine, the 2-pyrrolidinone or the
2-piperidone, to give the final products in moderate to
9
2-acetyl-2-thiazoline 1d, it exhibits a similar odor, corre-
sponding to that of popcorn, and, it has been detected in
the roasted meat and in the beefbroth.
good overall yields and (ii) preparation of acyclic precur-
such as 2 or 3, which are then cyclized to give 1a
1
0–12
sors
or b (Scheme 1).
1
Recently, the 2-propionyl-1-pyrroline 1b and 2-propionyl-2-
thiazoline 1e have gained interest in the food industry, since
have been added to the FEMA-GRAS list of the naturally
In comparison to the preparation of 1a–c, little effort
has been dedicated to the synthesis of 1d and e. A method
of broad synthetic significance is that of Unilever,
1
3a,b
2
occurring aromas admitted for the food flavor formulations.
which consists of condensation of the required cysteamine
with nitriles 4a–d to give the 2-thiazolinic derivatives bear-
ing the carbonyl functionality protected as ketal 5a and b
or oxime 5c and d. Then, the carbonyl groups are revealed
by acidic hydrolysis of the latter to give 1d or e in an
overall yield of 12% or 19%, respectively (Scheme 1).
Alternatively, Du n˜ ach et al. have shown that the oxidation
of the 2-acetylthiazolidine by a catalytic ruthenium complex
(10% in weight) in presence of TBHP furnishes 1d in 70%
n(
)
1a, n=1, X=CH , R=Me
2
X
1
b, n=1, X=CH , R=Et
R
2
2
N
1
c, n=2, X=CH , R=Me
O
1d, n=1, X=S, R=Me
1
e, n=1, X=S, R=Et
1f, n=2, X=S, R=Me
The presence of these compounds in many foods results
from the cooking process. The reaction between the amino
acids and the sugars present on the surface of foods gener-
ates, at high temperatures, these heterocycles (Maillard
1
4
yield.
However, all these synthetic procedures suffer to some ex-
tent from at least one of three following drawbacks: (i)
high cost of the reagents; (ii) length of the reaction sequence;
and (iii) requirement of acid or base work-up in the final
stages, which is incompatible with low chemical stability
of these imines. In addition, some of these procedures re-
quire the use of dangerous and/or toxic reagents such as
1
reaction). However, the reproduction of such a process in
laboratory is not suitable for the preparation of single Mail-
lard flavor on large scale. For this reason many chemists
have been engaged in the identification of efficient and
1
1,13a,b
7
7
NaCN, HCN, and tert-butyl hypochlorite or tert-
BuLi, and, finally, none of these synthetic routes is general
*
Corresponding author. Tel.: +39 02 23993070; e-mail: francesco.gatti@
polimi.it
9
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.089

C. Fuganti et al. / Tetrahedron 63 (2007) 4762–4767
4763
O
five
PPh3
1
a
N3
steps
(8%)
O
R
2
O
Penicillin
acylase
O
eight/nine
steps
1
a or 1b
N
H
(10-12%)
Ph
O
3, R=Me or Et
EtO
OEt
four steps
5)
R=Me, 4a
R=Et, 4b
S
6) H2SO4
R
CN
R
1d or 1e
12%)
NH4OAc
N
(
EtO OEt
R=Me, 5a
R=Et, 5b
H2N
SH
NH4OAc
CN
S
N
6) H2SO4
R
1d or 1e
(19%) (12%)
four steps
5) R
R=Me, 4c
R=Et, 4d
NH
NH
R=Me,5c
R=Et, 5d
Scheme 1. Selected synthetic routes to 1a and b and 1d and e. In brackets are reported the overall yields.
for the preparation of all flavors 1a–e. In the following we
report a new and straightforward synthesis of the naturally
occurring Maillard flavors 1a–e. In addition we report the
synthesis of the new flavor 1f together with its olfactory
description and odor threshold.
butyronitrile in presence of NH Ac in EtOH to give 7a or
4
b in 72% yield.
1
3a,18
The 2-ethyl-5,6-dihydro-4H-1,3-thiazine 7c was prepared
in 75% yield by treatment of the N-(2-hydroxyethyl)-propio-
namide with the Lawesson’s reagent followed by exposure to
1
9a,b
a solution of K CO to give 7c.
2
3
2
. Results and discussion
In the first instance, it was observed that when the pyrroline
6a, was treated with 1 equiv of SeO in Et O/EtOH (3:1) at
The final acidic or alkaline work-up in the final stage adopted
in most of the above cited procedures proved to be detrimen-
tal to the overall yield. Keeping this in mind, we designed
a new synthetic strategy suited to the preparation of these
compounds avoiding such a work-up in the final step. This
strategy is based on the regioselective oxidation of cyclic im-
2
2
room temperature, there was, within few hours, complete
disappearance of the starting material with the formation of
1a with 80% conversion was obtained (checked by GC–MS).
The oxidation of 6a also proved entirely regioselective (by
1
GC–MS and H NMR). However, the work-up of the reaction
ine precursors with SeO (Scheme 2). To the knowledge of
2
the authors, just one example of SeO oxidation of imines
2
1
5
n( )
a) RMgX, TMEDA,
THF, -78 °C, 2 h
has been reported in literature. Moreover, no study on
the regioselectivity has been done. The preparation of the
cyclic imine precursors is outlined in Scheme 3. The 2-alkyl
pyrrolines 6a and b, and the 2-ethyl-3,4,5,6-tetrahydropyri-
dine 6c were obtained by addition of the n-alkyl Grignard
n(
)
O
R
N
Boc
N
b) TFA, 0 °C
n=1,R=Et, 6a
n=1,R=Pr, 6b
n=2,R=Et, 6c
78-85%
1
6
reagent to the N-Boc-pyrrolidone or to the N-Boc-piperi-
done in presence of TMEDA (ꢀ78 C in THF) to give
1
7
ꢁ
the N-Boc-ketones that were treated with TFA in CH Cl
a) EtONa, EtOH, 0 °C
SH
2
2
S
b) RCN, reflux
72%
(
2:8) to give the cyclic imines in good yields (Scheme 3).
R
NH .HCl
N
2
The 2-alkyl-thiazolines 7a and b were obtained by conden-
sation of the cysteamine with the propionitrile or the
R=Et, 7a
R=Pr, 7b
X
N
X
N
n(
)
R
a) Lawesson's reagent,
PhMe, reflux
R
S
NH
O
OH
O
X=CH2,S
2 3
b) K CO
N
n=1,2
R=Me,Et
7c
Scheme 2.
Scheme 3.

4764
C. Fuganti et al. / Tetrahedron 63 (2007) 4762–4767
Method A
a) SeO2 (10% mol.)/ 1.1 eq.TBHP
CH2Cl2, RT, 6-9 h
R
R
N
N
b) PPh3,
O
0
°C, 12 h
R=Me, 6a
R=Et, 6b
y=29%, R=Me, 1a
y=32%, R=Et, 1b
O
Method A
+
N
N
N
H
N
O
O
6
c
y=25%, 1c
8
Method B
n(
)
S
a) SeO2 (20% mol.)/3 x 0.3 eq.TBHP
CH2Cl2, rt, 6-9 h
n( )
S
R
N
R
N
b) PPh3,
O
0
°C, 12 h
n=1, R=Me, 7a
n=1, R=Et, 7b
n=2, R=Me, 7c
y=40%, n=1, R=Me, 1d
y=44%, n=1, R=Et, 1e
y=35%, n=2, R=Me, 1f
Scheme 4.
mixture was troublesome; this was likely due to the presence
of colloidal Se and to the intrinsic chemical instability of 1a,
which after few hours started to decompose. Thus, the yield
of the pure material after column chromatography and bulb-
to-bulb distillation was just of 4% with purity around 90%.
Instead, the catalytic procedure (Method A) proved to be
0.3 equiv portions. This was done to minimise the formation
of the sulfoxide (detected by GC–MS). After the same
work-up adopted for the oxidation of 1a, was followed, e
and f, respectively, were isolated in a 40%, 44%, and 35%
yield.
2
0
more efficient (Scheme 4). The latter consisted in adding
a to a mixture of 1.1 equiv of TBHP and 0.1 equiv of SeO2
in CH Cl . Indeed, using this procedure, even if the conver-
Finally, the professional olfactory evaluation (Givaudan
Perfumers) of a sample of 1f gave the following odor de-
scription: bread, rice, moldy, musty, and pirazine-like with
an odor threshold of 0.54 ng/L in air. In conclusion this
new synthetic route allowed the preparation of these impor-
tant flavors on multi gram scale and in improved overall
yields (20%–30%). The oxidation of the pyrrolines 6a and
b, proceeds exclusively at the exocyclic position, such regio-
selectivity is apparently lost for the oxidation of six-atom
member rings such as 6c. Finally, this synthetic strategy
compares favorably with respect to other reported proce-
dures in terms of execution, costs, simplicity, flexibility, and
overall yields.
6
2
2
sion of 6a was lower than in the stoichiometric process
(
1
50%–60% by GC–MS and by H NMR, on three different
runs), the yield and the purity of 1a increased substantially,
since the work-up was much easier. The product 1a was iso-
lated by adding sufficient Ph P to the reaction mixture to
3
reduce all the residual TBHP, then, the organic phase was
stirred with charcoal to aid the elimination of residual colloi-
dal Se, and, after SiO chromatography and bulb-to-bulb
2
vacuum distillation 1a in 29% yield was obtained (98% pu-
rity). The oxidation of 6b and c, following the same proce-
dure, afforded 1b and c in a similar yields (32% and 25%).
It’s noteworthy that the oxidation of 6c proved to be non re-
gioselective, thus, together with the formation of 1c, in equi-
librium with its tautomer, was also isolated the regioisomer 8
3. Experimental part
3.1. General
(
in the ratio of 1:1 by GC–MS).
The conversions, during the oxidations, were deliberately
kept at around 50%, because longer exposure of the products
to the reaction conditions is not beneficial to the final yields,
moreover, the products are surprisingly less polar than the
reagents, thus, the chromatographic separation easily al-
lowed the recovery of non reacted starting materials.
GC–MS: HP 6890 gas chromatograph equipped with a 5973
mass-detector, using a HP-5MS column (30 mꢂ0.25ꢂ
0.25 mm). The following temperature program was em-
ꢁ
ꢁ
ꢁ
ꢁ
ployed: 60 C (1 min)/6 C/min–12 C/min/280 C (5 min).
H and C NMR are recorded on a Bruker AMX 400
1
13
(400 MHz) or AC 250 (250 MHz); CDCl solns at room
3
temperature, chemical shifts d in parts per million relative
to internal TMS, J values in hertz. TLC analyses: Merck
Kieselgel 60 F254 plates. All the gravimetric chromato-
graphic columns were carried out using silica. All solvents
and reagents were purchased from Fluka and were used
without any further purification.
The procedure adopted for the oxidation of the sulfur cyclic
imines 7a–c was slightly modified (Scheme 4, Method B).
This consisted of adding the imine to a mixture of 0.3 mol
equiv of TBHP and 0.2 equiv of SeO in CH Cl . Every
2
2
2
3
h was added the remaining stoichiometric TBPH in

C. Fuganti et al. / Tetrahedron 63 (2007) 4762–4767
4765
3
.1.1. Preparation of cyclic imines 6a–c.
.1.1.1. Representative synthesis: 2-ethyl-1-pyrroline
6a). A freshly prepared solution of EtMgBr (Mg (5.8 g) in
THF (50 mL) plus EtBr (21.2 g, 195.0 mmol) in THF
150 mL)) and TMEDA (30 mL) was added drop-wise to
6.11); dH (250 MHz, CDCl ) 4.21 (2H, tt, J¼7.3, 1.6 Hz,
3
3
H–C(4)), 3.28 (2H, t, J¼8.0 Hz, H–C(5)), 2.51 (2H, qt,
J¼7.7, 1.6 Hz, CH CH ), 1.22 (3H, t, J¼7.4 Hz, CH ); d
(
2
3
3
C
(62.5 MHz, CDCl ) 171.9, 64.4, 36.3, 31.8, 15.8; m/z: 115
3
+
(
(95, [M] ), 69 (5), 60 (100%).
a mechanically stirred solution of N-Boc-pyrrolidinone
(
ꢁ
a N atmosphere. After 12 h the reaction was quenched with
30.0 g, 162.0 mmol) in THF (300 mL) at ꢀ78 C and under
3.1.2.2. 2-Propyl-2-thiazoline (7b). The compound 7b
(41 g, 72%) was obtained following the same procedure de-
scribed above; [Found: C, 55.5; H, 8.8. C H NS requires C,
2
a solution of 2 M HCl (300 mL) and washed with Et O
2
5 9
(
3ꢂ200 mL). The combined organic phases were washed
55.77; H, 8.58]; Chemical purity 97% by GC–MS (t 8.02);
R
with brine (2ꢂ200 mL) and a satd solution of NaHCO
d (250 MHz, CDCl ) 4.19 (2H, br t, J¼7.5 Hz, H–C(4)),
3
H
3
(
200 mL), dried over Na SO . Evaporation of the solvent un-
4
3.25 (2H, t, J¼8.0 Hz, H–C(5)), 2.47 (2H, br t, J¼7.7 Hz,
2
der reduced pressure gave the N-Boc-4-oxo-hexilamine of
sufficient purity for the next step. The latter was dissolved
in a mixed solvent system of DCM/TFA (100 mL, 8:2) and
]CCH CH ), 1.66 (2H, m, CH CH ), 0.94 (3H, t,
2
2
2
3
J¼7.4 Hz, CH ); d (62.5 MHz, CDCl ) 172.2, 64.4, 36.3,
3
C
3
+
33.8, 21.1, 13.8; m/z: 129 (10, [M] ), 114 (5), 101 (80), 60
(100%).
ꢁ
cooled to 0 C. After 24 h at room temperature, the reaction
ꢁ
mixture was cooled at 0 C and treated with sufficient NaOH
(
2 M) to reach pH¼10–11. Then, the aqueous solution was
3.1.2.3. 2-Ethyl-5,6-dihydro-4H-1,3-thiazine (7c). A
solution of N-(2-hydroxyethyl)-propionamide (11.7 g,
100 mmol) and Lawesson’s reagent (40.4 g, 100 mmol) in
toluene (400 mL) was heated at reflux for 1 h under a nitro-
gen atmosphere. The reaction mixture was concentrated,
stirred with a solution of 2 M K CO (200 mL) for 1 h,
washed with Et O (2ꢂ200 mL), the combined organic
2
phases were then washed with 1 M HCl (3ꢂ200 mL). The
combined aqueous solution was washed with Et O
2
(
100 mL), brought at pH¼10–11 with 2 M NaOH and then
washed with Et O (4ꢂ150 mL). The organic phases were
2
2
3
washed with brine (2ꢂ100 mL), dried over Na SO , and
and extracted with Et O (5ꢂ200 mL). The organic phase
2
4
2
the solvent was removed by distillation (40 cm Vigreux col-
umn). Then, the residual yellowish liquid was distilled (bp
was washed with a solution of 1 M HCl (3ꢂ100 mL) and
the aqueous solution treated with a solution of 1 M NaOH
until pH¼7, then, was washed with Et O (5ꢂ200 mL).
ꢁ
C, 74.3; H, 11.5. C H N requires C, 74.17; H, 11.41];
1
24 C) to give 6a (12.0 g, 78%) as colorless liquid; [Found:
2
The organic phase was dried over Na SO and concentrated
2
6
11
4
Chemical purity 99% by GC–MS (t 4.62); m/z: 97 (5,
R
under reduced pressure. The crude was distilled to give 7c
(9.7 g, 75%) as pale yellow liquid; [Found: C, 55.6; H, 8.7.
C H NS requires C, 55.77; H, 8.58]; Chemical purity 99%
+
1
13
[M] ), 83 (100%). The H and C data fit well with those
reported.
2
1
5
9
by GC–MS (t 9.01); d (250 MHz, CDCl ) 3.66 (2H, br t,
3
R
H
3
.1.1.2. 2-Propyl-1-pyrroline (6b). The compound 6b
15.2 g, 85%) was obtained following the same procedure
described above; [Found: C, 75.5; H, 11.9. C H N requires
J¼7.5 Hz, H–C(4)), 3.00 (2H, t, J¼8.0 Hz, H–C(6)), 2.32
(
(2H, q, J¼7.7 Hz, ]CCH CH ), 1.79 (2H, m, H–C(5)),
2
3
1.17 (3H, t, J¼7.4 Hz, CH ); d (62.5 MHz, CDCl )
7
13
3
C
3
+
C, 75.62; H, 11.79]; Chemical purity 99% by GC–MS (t
ꢁ
162.2, 47.3, 35.1, 26.3, 19.2, 11.8; m/z: 129 (10, [M] ),
129 (100), 101 (10), 94 (5), 82 (31%).
R
6
.11); bp 70–80 C at 100 mmHg; d (400 MHz, CDCl3)
H
3
.78 (2H, tt, J¼7.3, 1.6 Hz, H-C(5)), 2.43 (2H, br t, J¼8.0,
H-C(3)), 2.29 (2H, br t, J¼7.7, 2.3 Hz, ]CCH CH ), 1.83
3.1.3. Method A: oxidation of 6a–c.
3.1.3.1. Representative synthesis: 2-acetyl-1-pyrroline
(1a). To a mixture of SeO (1.5 g, 13.5 mmol) in CH Cl
2
2
(
2H, m, H–C(4)), 1.60 (2H, m, CH CH ), 0.93 (3H, t,
2
3
J¼7.4 Hz, CH ); d (100.6 MHz, CDCl ) 178.2, 60.6, 36.8,
3
C
3
2
2
2
2
+
3
5.7, 22.4, 19.6, 10.5; m/z: 111 (95, [M] ), 83(5), 60 (100%).
(50 mL) was added a solution of 2 M TBHP in CH Cl
2
(68 mL). After 30 min a solution of 6a (13.1 g, 135.1 mol)
in CH Cl (30 mL) was added dropwise. After 9 h sufficient
3
.1.1.3. 2-Ethyl-3,4,5,6-tetrahydropyridine (6c). The
2
2
compound 6c (14.7 g, 82%) was obtained following the
same procedure described above; [Found: C, 75.7; H, 11.9.
C H N requires C, 75.62; H, 11.79]; Chemical purity
PPh was added portion wise to the ice cooled reaction mix-
3
2
3
ture, which was kept in the fridge overnight. After that
time, the reaction mixture was stirred with charcoal (3 g)
and dried over Na SO . Evaporation of the solvent under re-
7
13
ꢁ
9% by GC–MS (t 6.75); bp 85–90 C at 100 mmHg; the
R
9
2
4
1
13
22
H and C fit well with those reported.
duced pressure (in a cold bath) afforded crude material that
was triturated with a cold mixture of 1:1 hexane/Et O
2
3
.1.2. Preparation of sulfur cyclic imines 7a–c.
.1.2.1. Representative synthesis: 2-ethyl-2-thiazoline
7a). To an ice cooled solution of EtONa (from 10.1 g of
(50 mL), the solid was then filtered off and the solvent was
removed under reduce pressure (in a cold bath), affording
a yellow liquid, which was submitted to the column chroma-
3
(
Na) in EtOH (200 mL) was added portion wise the cyste-
amine hydrochloride (50 g, 0.44 mol). Then, to the reaction
mixture was added the propionitrile (115.3 mL, 1.32 mol)
tographic purification (hexane/Et O, 6:4) to obtain a pale
2
yellow liquid, which after bulb-to-bulb distillation (60 C,
ꢁ
100 mmHg,) gave 1a (4.3 g, 29%) as slightly yellow liquid;
and NH OAc (20 g). After 12 h at reflux the reaction mixture
4
[Found: C, 64.7; H, 8.2. C H NO requires C, 64.84; H, 8.16];
6 9
was concentrated, the residue was diluted with Et O
2
R (hexane/Et O, 6:4) 0.47; Chemical purity 98% by GC–
f 2
+
(
over Na SO . The solvent was removed under reduced pres-
400 mL) and washed with brine (2ꢂ100 mL), and dried
MS (t 5.90); m/z: 111 (30, [M] ), 97 (100), 69 (80%).
R
1
13
11
The H and C data fit well with those reported.
2
4
sure to give 7a (36.1 g, 72%) as liquid of sufficient purity for
the next step; [Found: C, 52.3; H, 7.9. C H NS requires C,
3.1.3.2. 2-Propionyl-1-pyrroline (1b). The compound
1b (5.4 g, 32%) was obtained following the same procedure
5
9
5
2.13; H, 7.87]; Chemical purity 98% by GC–MS (tR

4766
C. Fuganti et al. / Tetrahedron 63 (2007) 4762–4767
described above; [Found: C, 67.3; H, 8.9. C H NO requires
7
CDCl ) 196.5, 170.6, 66.2, 23.7, 23.3, 7.7; m/z: 143 (50,
3
11
+
1
C, 67.17; H, 8.86]; R (hexane/Et O, 6:4) 0.56; Chemicalpur-
2
[M] ), 115 (50), 87 (30), 60 (25), 57 (100%). These H
NMR data fit well with those reported.
f
ꢁ
13a
ity 99% by GC–MS (t 7.26); bp 115 C (70 mmHg); d
R
H
(
2
2
400 MHz, CDCl ) 4.10 (2H, tt, J¼7.5, 2.4 Hz, H–C(5)),
3
.92 (2H, q, J¼7.3 Hz, CH CH ), 2.73 (2H, tt, J¼8.4,
3.1.4.3. 2-Acetyl-5,6-dihydro-4H-1,3-thiazine (1f). The
compound 1f (4.1 g, 25%) was obtained following the same
procedure described above; [Found: C, 50.3; H, 6.4.
C H NOS requires C, 50.32; H, 6.33]; R (hexane/Et O,
2
3
.3 Hz, H–C(3)), 1.93 (2H, m, H–C(4)), 1.12 (3H, t,
J¼7.4 Hz, CH ); d (100.6 MHz, CDCl ) 203.4, 177.0,
3
C
3
+
6
6
5.5, 36.4, 36.3, 24.9, 10.5; m/z: 125 (30, [M] ), 97 (100),
9 (80%).
6
9
f
2
6:4) 0.49; Chemical purity 99% by GC–MS (t 13.34); bp
R
ꢁ
9
0–100 C at 2 mmHg; d (400 MHz, CDCl ) 3.89 (2H, t,
3
H
3.1.3.3. 2-Acetyl-3,4,5,6-tetrahydropyridine (1c). The
compound 1c (4.2 g, 25%) was obtained following
the same procedure described above; [Found: C, 67.2; H,
J¼8.5 Hz, H–C(4)), 3.01 (2H, t, J¼8.6 Hz, H–C(6)), 2.37
(3H, s, CH ), 1.82 (2H, m, H–C(6)); d (100.6 MHz,
3
C
CDCl ) 196.7, 159.5, 48.1, 25.0, 24.2, 18.7; m/z: 143 (50,
3
+
8
Et O, 6:4) 0.53; Chemical purity 99% by GC–MS
.8. C H NO requires C, 67.17; H, 8.86]; R (hexane/
[M] ), 115 (50), 101 (30), 73 (40), 43 (75%).
7
11
f
2
ꢁ
1
(
[
tR 7.63); bp 90–100 C (60–70 mmHg); m/z: 125 (30,
M] ), 97 (100%). The H and C data fit well with those
reported.
+
13
Acknowledgements
9
The authors are indebted to Dr. Philip Kraft (Givaudan
Schweiz AG, Fragrance research, Switzerland) for the
odor descriptions. Cofin-Murst is acknowledged for finan-
cial support.
3.1.3.4. 2-Ethyl-5,6-dihydropyridine-3(4H)-one (8).
Chemical purity 93% by GC–MS (tR 7.46); R (hexane/
f
Et O, 6:4) 0.59; d (400 MHz, CDCl ) 4.11 (2H, tt, J¼6.9,
2
H
3
2
.3 Hz, H–C(6)), 2.95 (2H, q, J¼7.3 Hz, CH CH ), 2.74
2
3
(
1
2
2H, tt, J¼6.9, 2.3 Hz, H–C(4)), 1.94 (m, 2H, H–C(5)),
.12 (t, J¼7.4 Hz, 3H, CH ); d (100.6 MHz, CDCl )
References and notes
3
C
3
01.1, 174.8, 63.2, 34.1, 32.2, 22.6, 8.2; m/z: 125 (30,
M] ), 97 (100%).
+
[
1. For an exhaustive review on these compounds, see: Adams, A.;
De Kimpe, N. Chem. Rev. 2006, 106, 2299–2319.
2. Allured’s Flavor and Fragrance Materials; Allured Publishing:
Carol Stream, IL, 2004; p 505.
3. Buttery, R. G.; Ling, L. C.; Juliano, B. O.; Turnbaugh, J. C.
J. Agric. Food Chem. 1983, 31, 823–826.
3
.1.4. Method B: oxidation of 7a–c.
.1.4.1. Representative synthesis: 2-acetyl-2-thiazo-
line (1d). To a mixture of SeO (2.6 g, 23.3 mmol) in
3
2
CH Cl (50 mL) was added a solution of TBHP in CH Cl
2
2
2
2
(
1
3
17 mL, 2 M). After 30 min a solution of 7a (13.3 g,
16.3 mol) in CH Cl (30 mL) was added drop wise. After
2 2
h and 6 h was added drop wise a 2 M solution of TBHP
4. B €u chi, G.; W €u st, H. J. Org. Chem. 1971, 36, 609.
5. Srinivas, P; Gurudutt, K. N. U.S. Patent 6,723,856, 2004;
Chem. Abstr. 2004, 140, 321720.
in CH Cl (17 mL). After 3 h, sufficient PPh was added
2
6. Hofmann, T.; Scieberle, P. J. Agric. Food Chem. 1998, 46, 616–
619.
7. De Kimpe, N.; Stevens, C.; Keppens, M. J. Agric. Food Chem.
1993, 41, 1458–1461.
8. Duby, P.; Huynh-Ba, T., European Patent 0545085 A1, 1993;
Chem. Abstr. 1993, 119, 138068.
9. Harrison, T. J.; Dake, G. R. J. Org. Chem. 2005, 70, 10872–
10874.
10. Rewicki, D.; Tressl, R.; Ellerbeck, U.; Kersten, E.; Burgert, W.;
Gorzynski, M.; Hauck, R. S.; Helak, B. Progress in Flavor
Precursor Studies; Schreir, P., Winter Halter, P., Eds.;
Allured Publishing: Carol Stream, IL, 1993; p 301.
11. Favino, T.; Fronza, G.; Fuganti, C.; Fuganti, D.; Grasselli, P.;
Mele. J. Org. Chem. 1996, 61, 8975–8979.
2
3
portion wise to the ice cooled reaction mixture, which was
then kept in the fridge overnight. After that time, the reaction
mixture was stirred with charcoal (5 g) and dried over
Na SO . Evaporation of the solvent under reduced pressure
2
4
in a cold bath afforded a crude solid that was triturated with
a cold mixture of 4:1 hexane/Et O (50 mL), the solid was fil-
2
tered off and the solvent was removed under reduce pressure
to afford a yellow liquid, which was submitted to the column
chromatographic purification (hexane/Et O, 8:2) to afford
2
a pale yellow liquid, which after bulb-to-bulb distillation
ꢁ
(
50 C, 2 mmHg) gave 5 (6.0 g, 40%); [Found: C, 46.7; H,
5
Et O, 6:4) 0.45; Chemical purity 99% by GC–MS (t
.7. C H NOS requires C, 46.49; H, 5.46]; R (hexane/
5 7 f
2
R
9
.21); dH (400 MHz, CDCl ) 4.52 (2H, t, J¼8.7 Hz, H–
12. De Kimpe, N.; Stevens, C.; Keppens, M. J. J. Agric. Food
Chem. 1996, 61, 1515–1519.
13. (a) Doornbos, T.; Peer, H. G. Recl. Trav. Chim. Pays-Bas 1972,
91, 711–728; (b) Copier, H.; Herman, C.; Tonsbeek, T. U.S.
Patent 3,678,064, 1970.
3
C(4)), 3.33 (2H, t, J¼8.7 Hz, H–C(5)), 2.52 (3H, s, CH );
3
d (100.6 MHz, CDCl ) 194.2, 171.6, 66.7, 33.4, 26.8;
m/z: 129 (100, [M] ), 101 (50), 87 (10), 60 (70%). These
C
3
+
1
13a
H NMR data fit well with those reported.
1
4. Fernandez, X.; Fellous, R.; Du n˜ ach, E. Tetrahedron Lett. 2000,
41, 3381–3384.
15. Martin, H.; Herrmann, R. Z. Naturforsch., B: Chem. Sci. 1986,
41B, 1260–1264.
3.1.4.2. 2-Propionyl-2-thiazoline (1e). The compound
e (7.3 g, 44%) was obtained following the same procedure
1
described above; [Found: C, 50.4; H, 6.4. C H NOS requires
6
9
C, 50.32; H, 6.33]; R (hexane/Et O, 6:4) 0.48; Chemicalpur-
f
16. Giovannini, A.; Savoia, D.; Umani-Rochi, A. J. Org. Chem.
1989, 54, 228–234.
2
ꢁ
ity 99% by GC–MS (t 11.63); bp 80–90 C at 2 mmHg; d
R
H
(
(
400 MHz, CDCl ) 4.50 (2H, t, J¼8.7 Hz, H–C(4)), 3.31
17. Rudolph, A. C.; Machauer, R.; Martin, S. F. Tetrahedron Lett.
2004, 45, 4895–4898.
18. Khun, R.; Drawert, F. Liebigs Ann. Chem. 1954, 590, 55–71.
3
2H, t, J¼8.7 Hz, H–C(5)), 2.92 (2H, q, J¼7.3 Hz,
CH CH ), 1.14 (3H, t, J¼7.3 Hz, CH ); d (100.6 MHz,
2
3
3
C

C. Fuganti et al. / Tetrahedron 63 (2007) 4762–4767
4767
1
9. (a) Maguet, M.; Poirier, Y.; Guglielmetti, R. Bull. Soc. Chim.
Fr. 1978, II, 568–574; (b) Kodama, Y.; Ori, M.; Nishio, T.
Helv. Chim. Acta 2005, 88, 187–193.
22. Asensio, G.; Gonzales-Nunez, M. E.; Bernardini, C. B.;
Mello, R.; Adam, W. J. Am. Chem. Soc. 1993, 115, 7250–7253.
23. The correct amount of residual TBHP was determined by the
1
2
2
0. Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99,
ratio of the H NMR integrals of the signals at d¼1.22
5
526–5528.
1. Tehrani, K. A.; Borreamans, D.; De Kimpe, N. Tetrahedron
999, 55, 4123–4152.
(TBHP) and d¼1.23 (tert-butyl alcohol) of a sample’s reaction
mixture diluted in CDCl
was added.
3 3
(z1:4), then 1.1 mol equiv of PPh
1