Electrophilic chemistry of biologically important α-ketoacids

Full text of DOI:10.1021/jo9901945

J . Org. Chem. 1999, 64, 7635-7637
7635
Electr op h ilic Ch em istr y of Biologica lly
diprotonated intermediates exhibit superelectrophilic
reactivity.5 The concept of superelectrophilic activation
was first proposed by Olah when an enhanced reactivity
-7
Im p or ta n t r-Ketoa cid s
9
Douglas A. Klumpp,*,† Siufu Lau, Manuel Garza,
†
†
was observed with nitronium salts in superacid. It was
‡
‡
proposed that protosolvation of the nitronium cation
generates the dication, which exhibits superelectrophilic
Brian Schick, and Katherine Kantardjieff
Department of Chemistry, California State
Polytechnic University, 3801 West Temple Avenue,
Pomona, California 91768, and W. M. Keck Center for
Molecular Structure, Department of Chemistry and
Biochemistry, California State University,
Fullerton, California, 92831
10
chemistry. Given the general reactivity of 1,2-dicarbonyl
groups in superacids, it seemed plausible to us that the
R-ketoacids might also exhibit superelectrophilic reactiv-
ity. In this paper, we report our studies of the electro-
philic chemistry of pyruvic acid (1), R-ketosuccinic acid
(2), R-ketoglutaric acid (3), and phenylpyruvic acid (4).
Received February 2, 1999
We describe several condensation reactions involving
these R-ketoacids and propose mechanisms that invoke
superelectrophilic activation.
In tr od u ction
The R-ketoacids 1-4 and their deprotonated anions
play central roles in a number of biochemical processes.1-4
Despite the importance of the R-ketoacids, little work has
been done to evaluate these compounds in their reactivi-
ties toward weak nucleophiles such as aromatic com-
pounds. Recently, there has been a considerable amount
Resu lts a n d Discu ssion
When pyruvic acid (1) is reacted with benzene in TfOH,
,1-diphenylethylene (5) is formed as the major product
eq 2). Previous studies of 1,2-dicarbonyl compounds have
1
(
indicated that superacid-catalyzed reactions with ben-
zene often lead to condensation reactions giving a gem-
diphenyl group (eq 1).5 The formation of 5 from pyruvic
acid (1) suggests that a gem-diphenyl group is formed
but that the intermediate product undergoes a dehydra-
tive-decarbonylation.
-7
of interest in the generation of strong electrophiles from
1
,2-dicarbonyl systems and the ability of these electro-
On the basis of these considerations, a mechanism is
proposed for the conversion of 1 to 5 in TfOH (Scheme
philes to react with aromatic compounds. Shudo and
Ohwada showed that 1,2-diketones formed highly reac-
tive, or superelectrophilic intermediates in trifluo-
1
). The first step involves a condensation reaction to
romethanesulfonic acid (CF
condensation reactions with C
3 3
SO H, TfOH) which led to
5
Sch em e 1
6
6
H (eq 1). Similar elec-
trophilic activation has been reported with the 1,2-
6
7
dicarbonyl groups of isatin, parabanic acid, and glyox-
8
ylic acid. In superacid solution, there is evidence that
the 1,2-dicarbonyl groups are diprotonated and that these
†
California State Polytechnic University.
California State University.
‡
(
1) Comparative Animal Biochemistry; Urich, K., Ed.; Springer-
Verlag: New York, 1994.
2) Essays in Cell Metabolism: Hans Krebs Dedicatory Volume;
Bartley, W., Kornberg, H. L., Quayle, J . R., Eds.; Wiley: New York,
970.
3) Biochemistry, 4th ed.; Stryer, L., Ed.; W. H. Freeman and Co.:
New York, 1995; Chapter 24.
4) (a) Amino Acid Metabolism, 2nd ed.; Bender, D. A., Ed.; Wiley:
produce 6. Like other 1,2-dicarbonyl systems, both car-
bonyl groups in 1 may be protonated to initiate the
electrophilic attack on benzene. Decarbonylation pro-
ceeds through the acyl cation 7, and loss of carbon
monoxide is facile due to the stability of cation 8. Product
(
1
1
1
(
(
New York, 1985. (b) Dietary Phenylalanine and Brain Function;
Wurtman, R. J ., Ritter-Walker, E., Eds.; Birkhauser: Boston, MA, 1988.
(9) (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767. (b)
Saito, S.; Sato, Y.; Ohwada, T.; Shudo, K. J . Am. Chem. Soc. 1994,
116, 2312. (c) Olah, G. A.; Wang, Q.; Neyer, G. Synthesis 1994, 276.
(10) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. A. J . Am.
Chem. Soc. 1975, 97, 2928.
(11) For related acid-catalyzed conversions, see: (a) Cozens, F. L.;
Cano, M. L.; Garcia, H.; Schepp, N. P. J . Am. Chem. Soc. 1998, 120,
5667. (b) Ciuhandu, G.; Dumitreanu, A. J . Prakt. Chem. 1981, 324(4),
595. (c) Puri, J . K.; Dhillon;, D. S. Inorg. Chim. Acta 1984, 90(3), 165.
(
5) (a) Yamazaki, T.; Saito, S.-i.; Ohwada, T.; Shudo, K. Tetrahedron
Lett. 1995, 36, 5749.
6) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. J .
Org. Chem. 1998, 63, 4481.
7) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A.
Synlett 1998, 918.
8) Clark, L. F.; Hegarty, A. F.; O’Neill, P. J . Org. Chem. 1992, 57,
62.
(
(
(
3
1
0.1021/jo9901945 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/09/1999

7
5
636 J . Org. Chem., Vol. 64, No. 20, 1999
Notes
is formed upon aqueous workup of the reaction. A small
triprotonated (14) superelectrophilic intermediate. Based
in part on an earlier study of the Friedel-Crafts chem-
istry of â-phenylcinnamic acid,13 it is proposed that a
dehydrative-decarbonylation gives the resonance-stabi-
lized dication (15) and reaction with a third benzene is
followed by cyclization to give product 13.
amount of 1,1-diphenylethanol can also be detected in
the product mix by GCMS. In accord with the proposed
mechanism, 2,2-diphenylpropionic acid also reacts with
TfOH and C H to give 5 as the only major product.
6 6
Phenylpyruvic acid (4) reacts with benzene in TfOH
to give the condensation products 9 and 10 in 50% and
The electrophilic chemistry of R-ketosuccinic acid (2)
was also examined. When 2 is reacted with C H in TfOH,
6 6
2
9% yields, respectively. As described in Scheme 2, 4
1
7 is formed as the major product in 90% yield (eq 3).
Sch em e 2
Similar to the conversion of 3 to 13, condensation at the
ketone group of 2 is followed by a dehydrative-decarbon-
ylation to give the dication 16, and reaction of 16 with a
1
3
third benzene is followed by a cyclization to provide 17.
Compounds 1-4 were also reacted with benzene in H
2
-
SO
4
, and none of the products (5, 9 and 10, 13, and 17,
SO
respectively) were formed. Reactions of 1-4 with H
2
4
and benzene gave complex product mixtures. The con-
trasting chemistry in superacid (TfOH) and strong acid
(
H
2
SO
Phenylpyruvic acid (4) does not react with chlorobenzene
in H SO ; however, 4 gives the expected product (18) in
TfOH. Since TfOH is up to 10 times stronger acid than
4
) is seen in the reaction of 4 with chlorobenzene.
condenses with two benzenes as an initial reaction step
to give 11, and this is followed by loss of water to generate
the acyl cation 12. Cation 12 may then react according
to pathway A to give 9 or react by pathway B to lose CO
and give 10. Compound 9 is formed as the major product,
which indicates that the cyclization occurs more rapidly
than loss of CO. Like other 1,2-dicarbonyl systems,
phenylpyruvic acid (4) generates strong electrophilic
intermediates upon solvation in superacid.
2
4
2
14
H
2
SO
4
,
and carboxylate groups are extensively proto-
15
nated in H
2
SO
4
,
these results suggest that an equilib-
rium is established in TfOH between the mono- and
diprotonated phenylpyruvic acid (19).
6 6
When R-ketoglutaric acid (3) is reacted with C H in
TfOH, tetralone derivative 13 is formed in 89% yield as
the only major product (Scheme 3). The structure of 13
Sch em e 3
In the work described above, the R-ketoacids 1-4 are
reacted with benzene in superacidic TfOH and two
characteristic types of reaction steps are observed. In all
cases, the electrophilic condensations occur at the ketone
to give products or intermediates having the gem-
diphenyl group. Carbonyl condensation with benzene has
1
6
often been an indication of dicationic intermediates. The
other characteristic reaction step involves the dehydra-
tive-decarbonylations of the acid groups from the con-
densation products. Although it is not certain if dications
are involved in the dehydrative-decarbonylations, solva-
tion of the product water molecule may be an important
driving force.
was established by NMR analysis and confirmed by the
X-ray crystal structure.12 The condensation with benzene
is consistent with the formation of a diprotonated or
(
13) Begitt, K.; Heesing, A. Chem. Ber. 1979, 112, 689.
(14) (a) Saito, S.; Saito, S.-i.; Ohwada, T.; Shudo, K. Chem. Pharm.
Bull. 1991, 39, 2718. (b) Superacids; Olah, G. A., Prakash, G. K. S.,
Sommer, J ., Eds.; Wiley: New York, 1985.
(
15) (a) Deno, N. C.; Pittman, C. U., J r.; Wisotsky, M. J . J . Am.
(
12) Crystal data for 13: C22
H
18O, MW 298.36, colorless irregular
Chem. Soc. 1964, 86, 4370. (b) Reference 14b, Chapter 3.
(16) (a) Ohwada, T.; Shudo, K. In Stable Carbocation Chemistry;
Prakash, G. K. S., Schleyer, P. v. R., Eds.; Wiley: New York, 1997; pp
525-548. (b) A reviewer also pointed out that electron-deficient
aldehydes and ketones may condense with benzene or chlorobenzene
via monocationic intermediates; see, for example: Creary, X. Chem.
Rev. 1991, 91, 1625.
trapezoid, triclinic, space group P-1 (No. 2), a ) 9.2401(10) Å, b )
9
6
(
.4511(10) Å, c ) 11.247(12) Å, R ) 86.117(2)°, â ) 69.114(2)°, γ )
3
3
c
1.266(2)°, U 798.19(15) Å , Z ) 2, D ) 1.241 g/cm , F(000) 316, µ
-1
Mo KR) 0.075 mm , graphite-monochromated Mo KR λ )0.710 73 Å,
T ) 293(2) K. Final discrepance factors: R1 ) 0.0443 and wR2 )
.0734 for 2545 reflections with F > 4σ
0
o
F
.

Notes
J . Org. Chem., Vol. 64, No. 20, 1999 7637
Exp er im en ta l Section
2
141.5, 151.4, 204.4; GCMS (M+) 352; HRMS C21H14OCl m/z
calcd 352.0422, found 352.0439.
1H NMR spectra were recorded at 300 MHz, and 13C NMR
spectra were recorded at 75 MHz. High-resolution mass spectra
were recorded at the Southern California Mass Spectrometry
Facility, University of California, Riverside. Triflic acid was
obtained from 3M and distilled prior to use. Benzene was dried
over Na. Pyruvic acid, phenylpyruvic acid, 2,2-diphenylpropionic
acid, and R-ketoglutaric acid were purchased from Aldrich;
R-succinic acid was purchased from Lancaster. Reactions were
Rea ction of r-Ketoglu ta r ic Acid (3). Using a procedure
similar to that for pyruvic acid, 0.72 g (4.9 mmol) of R-ketoglu-
6 6
taric acid was combined with 15 mL of TfOH and 2 mL of C H .
Isolation of 1.41 g (4.3 mmol, 89%) of the crude product was
followed by recrystallization from C to give 0.67 g (2.2 mmol,
6%) of 4,4-d ip h en yl-1-tetr a lon e (13): mp 188-189 °C (lit.
6
H
6
18
4
1
mp 189-190 °C); H NMR (CDCl
2
3
) δ 2.31 (t, J ) 6.3 Hz, 2H),
.76 (t, J ) 6.6 Hz, 2H), 6.53 (m, 1H), 6.81 (m, 4H), 7.04-7.11
done under a dry, N
Rea ction of P yr u vic Acid (1). In a vented flask, 0.325 g
3.7 mmol) of pyruvic acid (1) was suspended in 1 mL of C
2
atmosphere.
13
3
(m, 6H), 7.18 (m, 2H), 7.93 (m, 1H). C NMR (CDCl ) δ 35.7,
3
1
2
6.9, 53.2, 126.8, 127.2, 127.5, 128.2, 129.2, 130.9, 132.8, 133.1,
45.7, 149.6, 197.8. GCMS (M ), 298; HRMS C22
98.1358, found 298.1357.
(
6
H
6
,
+
H
18O m/z calcd
and 4 mL of TfOH was added. The mixture was stirred for 12 h
at 25 °C and then poured over ca. 20 g of ice. The resulting
Rea ction of r-Ketosu ccin ic Acid (2). Using a procedure
similar to that for pyruvic acid, 1.01 g (7.6 mmol) of R-ketosuc-
cinic acid was combined with 10 mL of TfOH and 2 mL of C
solution was extracted with CHCl
washed with H O followed by brine and dried over MgSO
Concentration in vacuo gave a white solid (1,1-d ip h en yleth en e,
) that was further purfied by flash chromatography (9:1
3
, and the organic extracts were
2
4
.
6
6
H .
Isolation of 2.10 g (6.8 mmol, 90%) of the crude product was
followed by column chromatography (4:1 hexane/ether) to give
5
hexanes/ether) to give 0.353 g (2.0 mmol, 60%).
1
1
2
7
6
2
.07 g (3.88 mmol, 51%) of 3,3-d ip h en yl-1-in d a n on e (17): mp
Rea ction of P h en ylp yr u vic Acid (4). Using a procedure
similar to that of pyruvic acid, 0.146 g (0.88 mmol) of phe-
nylpyruvic acid was reacted with 4 mL of TfOH and 2 mL of
19
1
28-130 °C (lit. mp 130-131 °C); H NMR (CDCl
3
) δ 3.55 (s,
H), 7.21-7.37 (m, 10H), 7.42-7.50 (m, 2H), 7.64 (dt, J ) 1.2,
13
.5 Hz, 1H), 7.87 (d, J ) 7.5 Hz, 1H); C NMR (CDCl
5.8, 123.6, 126.5, 127.9, 128.0, 128.4, 134.7, 135.7, 146.7, 159.8,
04.9; GCMS (M+), 284. HRMS C21 16O m/z calcd 284.1201,
3
) δ 56.0,
6 6
C H . Isolation of the crude product mixture was followed by
column chromatography (4:1 hexanes/ether), which gave 1,2,2-
tr ip h en yleth en e (10) 0.066 g (0.26 mmol, 29%) and 2,2-
d ip h en yl-1-in d a n on e (9): 0.125 g (0.44 mmol, 50%); mp 92-
H
found 284.1203.
1
7
1
9
(
)
4
1
2
3
4 °C (lit. mp 96-97 °C); H NMR (CDCl ) δ 3.95 (s, 2H), 7.14
Ack n ow led gm en t. This work has been funded by
the National Institutes of Health (SO6GM53933-0251),
and this support is gratefully acknowledged.
m, 1H), 7.25-7.44 (m, 10H), 7.53 (d, J ) 7.2 Hz, 1H), 7.65 (t, J
1
3
3
7.2 Hz, 1H), 7.85 (d, J ) 4.5 Hz, 1H); C NMR (CDCl ) δ
4.6, 62.6, 125.0, 125.7, 126.6, 127.1, 127.8, 128.0, 128.3, 135.2,
+
43.3, 151.9, 205.1; GCMS (M ), 284; HRMS C21
84.1201, found 284.1203.
H16O m/z calcd
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
compounds 9, 13, 17, and 18; X-ray structure and data of
compound 13 including a list of atomic coordinates, bond
lengths, and bond angles. This material is available free of
charge via the Internet at http:pubs.acs.org.
Using 0.335 g (2.0 mmol) of phenylpyruvic acid, 4 mL of TfOH,
and 2 mL of C Cl, 2,2-bis(4-ch lor op h en yl)-1-in d a n on e (18)
was isolated (0.25 g, 0.71 mmol, 35%; 4:1 hexane/ether); mp 117-
6
H
5
1
1
4
1
4
20 °C; H NMR (CDCl
H), 7.23 (d, J ) 8.8 Hz, 4H), 7.41 (m, 1H), 7.51 (d, J ) 7.8 Hz,
H), 7.66 (m, 1H), 7.78 (d, J ) 7.8 Hz, 1H); 13C NMR (CDCl
) δ
4.4, 61.7, 125.3, 125.9, 128.2, 128.6, 129.4, 132.9, 135.2, 135.7,
3
) δ 3.83 (s, 2H), 7.16 (d, J ) 8.7 Hz,
3
J O9901945
(
18) Repinskaya, I. B.; Barkhutova, D. D.; Makarova, Z. S.; Alek-
(
17) Beringer, F. M.; Daniel, W. J .; Galton, S. A.; Rubin, W. J . J .
seeva, A. V.; Koptyug, V. A. Zh. Org. Khim 1985, 21(4), 836.
(19) Koelsch, C. F.; LeClaire, C. D.. J . Org. Chem. 1941, 6, 516.
Org. Chem. 1966, 31, 4315.