An expeditious, high-yielding construction of the food aroma compounds 6-acetyl-1,2,3,4-tetrahydropyridine and 2-acetyl-1-pyrroline

Article abstract of DOI:10.1021/jo051940a

The key compound responsible for the aroma of bread, 6-acetyl-1,2,3,4- tetrahydropyridine (1), has been constructed in an efficient three-step procedure from 2-piperidone in an overall yield of 56%. Compound 1 was liberated in the final step under basic conditions. A related synthetic route produced 2-acetyl-1-pyrroline (2), the principal component of cooked rice, in 10% overall yield.

Full text of DOI:10.1021/jo051940a

An Expeditious, High-Yielding
Construction of the Food Aroma
Compounds
6
-Acetyl-1,2,3,4-tetrahydropyridine and
2
-Acetyl-1-pyrroline
Tyler J. Harrison and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, University of
British Columbia, Vancouver, B.C., Canada, V6T 1Z1
FIGURE 1. Structures of bread and rice flavor components
and 2.
1
gdake@chem.ubc.ca
Received September 15, 2005
The key compound responsible for the aroma of bread,
6
-acetyl-1,2,3,4-tetrahydropyridine (1), has been constructed
in an efficient three-step procedure from 2-piperidone in an
overall yield of 56%. Compound 1 was liberated in the final
step under basic conditions. A related synthetic route
produced 2-acetyl-1-pyrroline (2), the principal component
of cooked rice, in 10% overall yield.
Simple heterocycles are formed by the nonenzymatic
browning reaction between reducing sugars and free
amine functions during the cooking process (the Maillard
FIGURE 2. Representative synthetic routes to 1.
1
reaction). Although present in relatively small quanti-
We learned of these compounds through literature
searches related to the preparation of substrates for an
unrelated research project ongoing in our laboratory.
Although a number of practical synthetic routes have
been disclosed for these flavor components 1 and 2, these
published routes all suffer to some extent from lengthy
reaction sequences or costly reagents (Figure 2). It has
previously been reported that 1 interconverts with its
tautomer and rapidly decomposes when isolated neat.
ties, these compounds can exhibit strong flavoring and
odorant properties. Two such compounds, 6-acetyl-1,2,3,4-
tetrahydropyridine (1) and 2-acetyl-1-pyrroline (2), are
believed to be responsible for the biscuit or cracker-like
6
2
3
4
odor present in baked goods, popcorn, tortilla products,
5
7,8
and aromatic varieties of cooked rice, respectively (Fig-
ure 1). The odor thresholds for 1 and 2 have been
determined to be 0.06 ng/L3b (in air) and 0.02 ng/L (in
air), respectively. As such, these and related compounds
have significant practical interest as additives in the food
industry.
3c
7g
It is also known that enamines and related structures
9
are sensitive to acid. Consequently, it should be advan-
tageous to miminize exposure of 1 to acid. In addition,
(
1) (a) Blank, I.; Devaud, S.; Matthey-Doret, W.; Robert, F. J. Agric.
(6) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023-5026.
(7) (a) Singh, P. N. D.; Klima, R. F.; Muthukrishnan, S.; Murthy,
R. S.; Sankaranarayanan, J.; Stahlecker, H. M.; Patel, B.; Gudmunds-
dottir, A. D. Tetrahedron Lett. 2005, 46, 4213-4217. (b) Adams, A.;
Tehrani, K. A.; Kersiene, M.; De Kimpe, N. J. Agric. Food Chem. 2004,
52, 5685-5693. (c) Hofmann, T.; Schieberle, P. J. Agric. Food Chem.
1998, 46, 616-619. (d) De Kimpe, N.; Keppens, M. J. Agric. Food Chem.
1996, 44, 1515-1519. (e) De Kimpe, N.; Stevens, C. Tetrahedron 1995,
51, 2387-2402. (f) De Kimpe, N.; Stevens, C. J. Org. Chem. 1993, 58,
2904-2906. (g) Rewicki, D.; Ellerbeck, U.; Burgert, W. German Offen.
DE 4217395A1 (C.I. C07C247/06), December 02, 1993. (h) B u¨ chi, G.;
Wuest, H. J. Org. Chem. 1971, 36, 609-610.
(8) (a) Srinivas, P.; Gurudutt, K. N. U.S. Patent Appl. US 6,723,-
856 B1 (C.I. C07D207/00), April 20, 2004. (b) Hofmann, T.; Schieberle,
P. J. Agric. Food Chem. 1998, 46, 616-619. (c) Favino, T. F.; Fronza,
G.; Fuganti, C.; Fuganti, D.; Grasselli, P.; Mele, A. J. Org. Chem. 1996,
61, 8975-8979. (d) De Kimpe, N. G.; Stevens, C. V.; Keppens, M. A. J.
Agric. Food Chem. 1993, 41, 1458-1461. (e) Duby, P.; Huynh, B. T.
European Patent Appl. EP 545, 085 (C.I. C07D207/20), June 09, 1993.
(f) Also see ref 7d.
Food Chem. 2003, 51, 3643-3650. (b) Hofmann, T.; Schieberle, P. J.
Agric. Food Chem. 1998, 46, 2721-2726. (c) De Kimpe, N. G.; Dhooge,
W. S.; Shi, Y.; Keppens, M. A.; Boelens, M. M. J. Agric. Food Chem.
1
994, 42, 1739-1742.
2) Schieberle, P.; Grosch, W. J. Agric. Food Chem. 1987, 35, 252-
(
2
57.
(
3) (a) Buttery, R. G.; Ling, L. C.; Stern, D. J. J. Agric. Food Chem.
1
2
1
997, 45, 837-843. (b) Schieberle, P. J. Agric. Food Chem. 1995, 43,
442-2448. (c) Schieberle, P. J. Agric. Food Chem. 1991, 39, 1141-
144.
(
4) (a) Buttery, R. G.; Ling, L. C. J. Agric. Food Chem. 1998, 46,
2
4
764-2769. (b) Buttery, R. G.; Ling, L. C. J. Agric. Food Chem. 1995,
3, 1878-1882.
(5) (a) Buttery, R. G.; Orts, W. J.; Takeoka, G. R.; Nam. Y. J. Agric.
Food Chem. 1999, 47, 4353-4356. (b) Buttery, R. G.; Turnbaugh, J.
G.; Ling, L. C. J. Agric. Food Chem. 1988, 36, 1006-1009. (c) Buttery,
R. G.; Ling, L. C.; Mon, T. R. J. Agric. Food Chem. 1986, 34, 112-114.
(
d) Buttery, R. G.; Ling, L. C.; Juliano, B. O.; Turnbaugh, J. G. J. Agric.
Food Chem. 1983, 31, 823-826.
10.1021/jo051940a CCC: $30.25 © 2005 American Chemical Society
10872
J. Org. Chem. 2005, 70, 10872-10874
Published on Web 11/30/2005

SCHEME 1
SCHEME 2. Telescoped Sequence to 1
the ketone function was typically protected as its corre-
sponding ketal in intermediates toward 1,7a,e,8f and the
requirement for acidic conditions in the final steps of
published synthetic routes were detrimental to overall
yields. An alternative route where 1 was produced with
use of basic conditions could be an important solution.
These compounds and their corresponding challenge of
a concise, potentially scalable construction intrigued us.
In addition, the lessons learned in the course of this
exercise would prove valuable for the synthesis of struc-
turally related compounds.
We focused on the construction of 1. Criteria under
consideration were (a) brevity for the overall sequence
and (b) avoiding acidic conditions in the reaction that
would ultimately produce 1. To that end, we developed
the following sequence (Scheme 1). The reaction of
DMSO tended to be “messier” and required a more
involved workup procedure.
Although the route was reasonably short, we were
interested in minimizing isolation steps to produce 1 as
efficiently as possible. To that end, optimization of the
sequence produced the following protocols (Scheme 2).
The reaction of 3 with the organolithium reagent pro-
duced from 3 equiv of ethyl vinyl ether and 2 equiv of
tert-butyllithium occurred smoothly in THF at -78 °C.
The purity of 4 was acceptable after workup and solvent
removal to be used directly in the next reaction. It should
be noted that 4 does not store well; this material should
be carried on to the next reaction as soon as possible.
Addition of benzene (to produce a 0.5 M solution) and 10
mol % of p-TsOH‚H O followed by warming at 65 °C for
2
2
-piperidone and di-tert-butyl dicarbonate provided imide
1.5 h resulted in the production of 5 according to thin-
1
0
3
.
Subjecting 3 to 1-ethoxy-1-lithioethene (produced by
layer chromatography. Cooling of the reaction mixture
to 45 °C and direct addition of DMSO to produce a 2:1
DMSO/PhH solvent mixture was followed by the addition
of 5 equiv of aqueous potassium hydroxide solution. After
3 h and following workup and isolation, the desired bread
flavor component 1 was formed in 67% yield. As previ-
ously reported, 1 was found to equilibrate to a 2:1 mixture
of tautomers.
metalation of ethyl vinyl ether with tert-butyllithium in
8
e,11
THF
at -78 °C) produced ketone 4 after aqueous
workup. Reformation of the heterocycle occurred with use
of 10 mol % p-toluenesulfonic acid in benzene at 65 °C
after 1.5 h to produce enecarbamate 5. We did not make
a concerted effort to use alternate solvents in this
reaction, although reactions in THF or toluene do pro-
ceed. The use of benzene is precluded in industrial
processes. Importantly, the ketone function is now pro-
tected as a derivative that can be released with use of
basic hydrolysis conditions. We parenthetically note that
We also applied this sequence to the rice flavor
component 2 using 2-pyrrolidinone as a starting material
(
Scheme 3). In this context, a major complication could
arise. In the transformation of 7 to 8, the nitrogen atom
of the carbamate function presumably can react with
either the ketone function to form a five-membered ring
5
, as it possesses a strong, pleasant smell of “seasoning
salt on popcorn”, may have its own uses as a flavor
additive. Barium hydroxide in THF was initially used to
carry out the final transformation, giving rise to 30-40%
conversions of 1. In comparison, aqueous potassium
hydroxide in THF afforded only trace amounts of 1 after
extended reaction times. Optimization of the reaction
conditions revealed that potassium hydroxide in DMSO
was sufficient to remove the carbamate function and
produce 1 in 66% yield. From a practical perspective,
conditions with barium hydroxide in either THF or
(
desired) or the oxacarbenium ion produced from the enol
ether to form a six-membered ring (undesired). In the
event, only a 48% yield of 8 is obtained in the two-step
procedure. No byproducts containing a six-membered
ring were obtained. This compound, which smells of
“
buttery caramel corn”, can be deprotected by using
trifluoroacetic acid in dichloromethane to produce 2 in
2
2% isolated yield.
It should be noted during the deprotection step that
(
a) lengthy reaction times should be avoided, (b) cooling
(
9) (a) Capon, B.; Wu, Z. J. Org. Chem. 1990, 55, 2317-2324. (b)
the reaction mixture is necessary during the workup
procedure, and (c) a room temperature bath is used when
concentrating 2 in vacuo. Straying from these procedures
leads to the formation of an inseparable contaminant in
varying amounts whose H NMR spectrum matches that
of 9 as described by De Kimpe and Keppens.
In summary, a short construction of the bread flavor
component 1 has been established. A key feature is the
release of a “carbamate-ketal” function under basic
conditions to ultimately produce 1.
Cook, A. G. Enamines: Synthesis, Structure and Reactions, 2nd ed.;
Dekker: New York, 1988. (c) Jordan, F. J. Am. Chem. Soc. 1974, 39,
8
25-828. (d) Alt, G. H.; Gallegos, G. A. J. Org. Chem. 1971, 36, 1000-
002. (e) Cook, A. G.; Herscher, S. B.; Schulz, D. J.; Burke, J. A. J.
1
Org. Chem. 1970, 35, 1550-1554. (f) Coward, J. K.; Bruice, T. C. J.
Am. Chem. Soc. 1969, 91, 5329-5339. (g) Cook, A. G.; Schulz, C. R. J.
Org. Chem. 1967, 32, 473-475. (h) Alt, G. H.; Speziale, A. J. J. Org.
Chem. 1966, 31, 1340-1342. (i) Stamhuis, E. J.; Maas, W. J. Org.
Chem. 1965, 30, 2156-2160.
1
7d
(
10) (a) Hara, O.; Sugimoto, K.; Makino, K.; Hamada, Y. Synlett
004, 9, 1625-1627. (b) Williams, G. D.; Pike, R. A.; Wade, C. E.; Willis,
M. Org. Lett. 2003, 5, 4227-4230.
11) Friesen, R. W. J. Chem. Soc., Perkin Trans. 1 2001, 1969-2001.
2
(
J. Org. Chem, Vol. 70, No. 26, 2005 10873

SCHEME 3
Experimental Section
solution, dried over magnesium sulfate, and concentrated by
rotary evaporation in vacuo to afford an orange oil. Purification
by column chromatography on a thin band of triethylamine
washed silica gel (3:1 petroleum ether:diethyl ether) afforded
Procedure for the Conversion of 3 to 1. To a solution of
1
.44 mL of ethyl vinyl ether (15.0 mmol) in 25 mL of THF at
-
78 °C was added 6.6 mL of a solution of tert-butyllithium (1.53
4
11 mg (67%) of the title compound 1 as a yellow oil.
M in pentane, 10.0 mmol) dropwise. The bright yellow reaction
IR (film): 3407, 2942, 1697, 1667, 1630, 1254 cm-1. 1H NMR
400 MHz, CDCl ): δ (A) 5.57 (t, J ) 4.6 Hz, 1H), 4.15 (s, 1H),
3
mixture was stirred at -78 °C for 30 min and then warmed to
(
0
°C for 10 min. The resulting pale yellow solution was cooled
back down to -78 °C for 15 min and to this reaction mixture
was added a solution of 0.983 g of 3 (4.94 mmol) in 5 mL of THF.
The reaction was stirred for 45 min before being quenched with
3.10 (t, J ) 5.5 Hz, 2H), 2.22 (s, 3H), 2.17-2.24 (m, 2H), 1.70-
1.80 (m, 2H); (B) 3.77 (m, 2H), 2.30 (s, 3H), 2.27-2.34 (m, 2H),
1
3
1.58-1.67 (m, 2H), 1.50-1.58 (m, 2H). C NMR (100 MHz,
1
2
0 mL of H O and 20 mL of diethyl ether. The organic phase
CDCl
3
): δ 200.4, 194.5, 167.1, 141.8, 109.5, 50.1, 40.8, 24.3, 23.7,
+
was washed twice with a saturated aqueous solution of sodium
bicarbonate. The combined aqueous fractions were extracted
once with diethyl ether. The combined organic fractions were
washed with a saturated aqueous brine solution and then dried
over sodium sulfate and concentrated by rotary evaporation in
vacuo to afford 1.49 g of 4 as a pale yellow oil.
23.6, 22.5, 21.6, 21.4, 18.6. MS (ESI): 126 (M + H ).
Acknowledgment. The authors thank the Univer-
sity of British Columbia, the Natural Sciences and
Engineering Research Council (NSERC) of Canada,
Glaxo Smith Kline, and Merck-Frosst for the financial
support of our programs.
To a solution of 1.49 g of crude 4 in 10 mL of benzene was
added 95 mg of p-toluenesulfonic acid (0.50 mmol) and the
reaction mixture was stirred at 65 °C for 1.5 h. The reaction
temperature was cooled to 45 °C and 20 mL of dimethyl sulfoxide
was added followed by 9 mL of an aqueous 3 M NaOH solution
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
27.0 mmol). The red reaction mixture was stirred for 3 h before
being cooled to room temperature and diluted with a saturated
aqueous solution of ammonium chloride. The mixture was
extracted four times with diethyl ether. The combined organic
fractions were washed four times with a saturated aqueous brine
JO051940A
10874 J. Org. Chem., Vol. 70, No. 26, 2005