Organocatalysis by bimacrocyclic NHCs: Unexpected formation of a cyclic hemiacetal instead of a γ-butyrolactone

Article abstract of DOI:10.1039/b815828b

Two bimacrocyclic imidazolinium salts of different size, precursors to respective NHCs (N-heterocyclic carbenes), were tested as precatalysts in the reaction of aromatic aldehydes or ketones with enals. The expected lactones were produced in most cases, b

Full text of DOI:10.1039/b815828b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalysis by bimacrocyclic NHCs: unexpected formation of a cyclic
hemiacetal instead of a c-butyrolactone†‡
Ole Winkelmann,a Christian Na¨therb and Ulrich Lu¨ning*a
Received 10th September 2008, Accepted 14th October 2008
First published as an Advance Article on the web 10th December 2008
DOI: 10.1039/b815828b
Two bimacrocyclic imidazolinium salts of different size, precursors to respective NHCs (N-heterocyclic
carbenes), were tested as precatalysts in the reaction of aromatic aldehydes or ketones with enals. The
expected lactones were produced in most cases, but in the reaction of methyl 4-formylbenzoate with
cinnamaldehyde, the larger bimacrocycle led to the formation of a cyclic hemiacetal, while the smaller
bimacrocycle gave the anticipated lactone.
Introduction
The ability of thiamine to act as a nucleophilic catalyst after
deprotonation was recognized in 1958 by Breslow.1 He estab-
lished the mechanism for the acyloin condensation catalyzed by
thiamine, based on the umpolung of a carbonyl carbon atom by the
deprotonated thiazolium salt, in a fashion analogous to catalysis
by cyanide ions.2 The scope of this reaction was expanded by
Stetter in 1976, who reacted aldehydes with Michael acceptors in
the presence of either cyanide or thiazolium salts and base (Stetter
reaction).3
Deprotonated azolium salts have received great attention since
the isolation of a stable crystalline carbene (derived from an
imidazolium salt) by Arduengo in 1991,4 and the term N-
heterocyclic carbenes (NHCs) has been coined for these species,
which were called zwitterions by Breslow. NHCs are nowadays
Scheme 1 NHC-catalyzed formation of lactones 3.
frequently used in organocatalysis5 and they have also found
numerous applications as beneficial ligands in organometallic
vation of postulated intermediates by ESI mass spectrometry.9
chemistry.6 A number of chiral thiazolium and triazolium salts
It was reported that some other imidazolium salts with different
have been synthesized and successfully applied in asymmetric
N-substituents are less reactive and selective than 4,8b while
acyloin condensations and Stetter reactions.7
the use of some thiazolium-derived NHC catalysts has recently
Interestingly, neither acyloin nor Stetter products, but instead
been found to result in the predominant formation of unlike-3.10
g-butyrolactones 3 are formed if the imidazolium salt 4 is used
Imidazolinium salts have not yet been tested in this reaction.
as precatalyst in the reaction of aldehydes 1 (R1 = H) with a,b-
We haverecently reported the synthesis of bimacrocyclic
unsaturated aldehydes 2 (Scheme 1). Also ketones 1 may be used in
imidazolinium salts as precursors to respective NHC catalysts,
the reaction, and the favored formation of like-3 was observed in all
aiming to govern the selectivity in reactions catalyzed by these
cases.8 A reasonable mechanism was proposed for the reaction, in-
NHCs.11 We have therefore tested the bimacrocyclic salts 6a and 6b
volving the vinylogous umpolung of the b carbon atom of the enal
in the formation of g-butyrolactones 3 and compared them to the
2 caused by nucleophilic attack of the NHC on its carbonyl carbon
precatalyst 4 which was used in the literature. In order to study the
atom.8 The proposed catalytic cycle was supported by the obser-
influence of the nature of the heterocycle, the respective saturated
imidazolinium salt12 5 was also tested in the reaction (see Fig. 1).
aOtto-Diels-Institut fu¨r Organische Chemie, Christian-Albrechts-Universita¨t
zu Kiel, Olshausenstr. 40, D-24098, Kiel, Germany. E-mail: luening@
oc.uni-kiel.de; Fax: +49-431-880-1558; Tel: +49-431-880-2450
bInstitut fu¨r Anorganische Chemie der Christian-Albrechts-Universita¨t zu
Kiel, Olshausenstr. 40, D-24098, Kiel, Germany. E-mail: cnaether@
ac.uni-kiel.de; Fax: +49-431-880-1520; Tel: +49-431-880-2092
† Electronic supplementary information (ESI) available: NMR spectra
of compounds 7, 8 and 9. CCDC reference number 680462. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b815828b
‡ Concave Reagents, Part 57. For preceding publication (Part 56), see O.
Winkelmann, C. Na¨ther and U. Lu¨ning, J. Organomet. Chem., 2008, 693,
2784.
Fig. 1 NHC-precatalysts tested in the formation of lactones 3.
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Table 1 Catalytic activity of the NHC-precursors 4–6 in the formation
of g-butyrolactones 3a
again observed going from 4 (unsaturated) to 5 (saturated), but less
expressed than for the products 3a and 3b. With the bimacrocyclic
precatalysts 6, the selectivity was reversed for product 3c, while
equal amounts of like- and unlike-3d were produced.
Product yield (%)b (like:unlike)c
Precatalyst
3a
3b
3c
3d
The poor yield of 3d obtained with the NHC precursor 6b could
be attributed to the formation of an additional product: hemiacetal
7 (see Scheme 2). It results from the connection of two aldehydes
1c with one enal 2a and was isolated in 42% yield from the
reaction mixture. Also, a small amount of benzil 8 was obtained.
By GC analysis alone, the new product 7 can be overlooked.
It decomposes under GC conditions and cinnamaldehyde (2a),
benzil 8 and benzoin 9 are detected. Small amounts of these
decomposition products are observed with all precatalysts in the
reaction of 1c and 2a, but they are found as the most prominent
peaks with 6b.
4 (10 mol%)
4 (10 mol%)e
5 (10 mol%)
5 (25 mol%)e
6a (10 mol%)
6a ((25 mol%)
6b (10 mol%)
6b (25 mol%)
6b (25 mol%)e
92 (67:33)
92 (65:35)e
93 (54:46)
—
38 (46:54)
86 (47:53)
39 (48:52)
80 (48:52)
88 (48:52)e
94 (68:32) 39 (82:18)d 52 (82:18)
—
—
—
95 (54:46)
—
—
72 (45:55)
—
8 (73:27)d
2 (74:26)
—
—
39 (73:27)e
—
4 (34:66)d 41 (52:48)e
—
—
68 (46:54)
—
2 (33:67)d
4 (36:64)e
3 (50:50)e
—
a Conditions: 0.5 mmol enal 2, 1 mmol a,a,a-trifluoroacetophenone (1a)
or benzaldehyde 1b/1c, azolium salt 4–6 (50 or 125 mmol), DBU (1 equiv.
based on azolium salt), 16 h in 2 mL of THF at room temperature.
b Determined by GC using n-hexadecane as the internal standard, average
of two experiments. c Diastereomeric ratio determined by GC, average of
two experiments. d 0.5 mmol enal 2a, 0.5 mmol substituted benzaldehyde
1b. e 16 h at 40 ◦C.
Results and discussion
Scheme 2
The results obtained with the different precatalysts are summa-
rized in Table 1. Using 10 mol% of the NHC-precursors 4 or 5
and DBU as the base, high yields of the products 3a and 3b were
obtained in the reaction of a,a,a-trifluoroacetophenone (1a) with
cinnamaldehyde (2a) or 4-methoxy-cinnamaldehyde (2b) at room
temperature. Higher loadings (25 mol%) of the precatalysts 6 were
needed to obtain comparable yields of the products 3a and 3b,
while the yields could not be raised significantly at elevated tem-
perature (40 ◦C). Even with 25 mol% of 6, incomplete conversion
of the enal 2b was observed in the formation of 3b after 16 h.
The favored formation of like-3a and like-3b was observed with
precatalyst 4 as reported by Glorius and Burstein.8a Interestingly
the diastereoselectivity dropped with the use of the analogous
saturated NHC-precursor 5, showing clearly that the selectivity
of the reaction is affected by the nature of the NHC (imidazol-
2-ylidene vs. imidazolidin-2-ylidene). The bimacrocycles 6 were
found to be similarly little selective as 5. While still a small
excess of like-3a and like-3b was produced with 5, a slight but
definite preference for unlike-3a and unlike-3b was observed with
both bimacrocycles 6a and 6b. The diastereoselectivities remained
unchanged at 40 ◦C.
An equilibrium between both anomeric forms (ratio 10:1) of 7
is observed in CDCl3 at room temperature, with the hydroxyl and
phenyl group being oriented trans in the major anomer, as can be
deduced from the NOESY spectrum. The relative stereochemistry
at the quaternary carbon atom could not be assigned undoubtedly.
A molecule related to 7 has been reported to be produced
from cinnamaldehyde (2a), acetaldehyde and fermenting baker’s
yeast,13 and the reported NMR assignments support our structure
elucidation (also regarding the anomers). In analogy to the
mechanistic explanation of the enzymatic reaction, the isolation
of 7 implies the formation of benzoin 9, whose anion reacts with
the Michael-acceptor 2a.14,15 The resulting hydroxyaldehyde 10
undergoes ring closure to hemiacetal 7, as the NMR spectra prove
(see Scheme 3). The additionally isolated benzil 8 seems to result
from the oxidation of benzoin 9 during work-up.16
In the reaction of cinnamaldehyde (2a) with 4-substituted
benzaldehydes 1b and 1c (products 3c, 3d), a decrease in yield
compared to products 3a and 3b was observed with all NHC
precursors, and the saturated precatalysts 5 and 6 were found
to be inferior to 4. Although the best results were obtained
with the imidazolium salt 4, the yields reported in the literature
(54% for 3c, 70% for 3d) exceed our findings. The reported high
diastereoselectivities were reproduced for both products. In the
case of product 3c, the poor yields are caused by incomplete
conversion and by the formation of numerous unidentified by-
products. Incomplete conversion also prevented the formation
of high yields of 3d. Interestingly, reasonable amounts of 3d
could be obtained using 25 mol% of 5 or 6a at 40 ◦C, while 6b
produced only traces of the expected product under the same
conditions. Regarding the like/unlike-selectivity, a decrease was
Scheme 3
The new product 7 was only found starting from aldehyde
1c and only when using precatalyst 6b. 1c carries an electron-
withdrawing group in the p-position of the phenyl ring which
makes the aldehyde function more electrophilic. Instead of an
addition of the NHC to the carbonyl group of enal 2a, which
leads to the formation of lactone 3d, the NHC reacts with aldehyde
1c. The following benzoin reaction with 1c is also faster than the
competing Stetter reaction with 2a due to the electron withdrawing
effect of the ester group of 1c, and thus allows the formation of
hemiacetal 7.
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Remarkably, reasonable amounts of the hemiacetal 7 were only
found with precatalyst 6b in contrast to the NHC-precursors 4, 5
and 6a. How does the NHC derived from 6b differ from the other
NHCs that were tested in the reaction? There are four differences
to be discussed: (i) 6b yields an NHC which contains a saturated
heterocycle, (ii) the NHCs derived from 6 are more electron-rich
than the other NHCs,17 (iii) 6b is a bimacrocyclic compound, and
(iv) the bimacrocycle in 6b is larger than that in 6a. Although
the formation of either lactone 3d or benzoin 9 is catalyzed by
the respective NHC, the geometrical properties of the precatalysts
may reflect those of the NHCs.18 Both imidazolinium salts 6 have
been crystallized and X-ray analyses have been carried out. Fig. 2
shows the structure of the larger bimacrocycle 6b; Fig. 3 compares
it to the structure of 6a which has already been published.11a
In the non-C2-symmetric carbene derived from 4, the mesityl
substituents are oriented almost perpendicular to the heterocycle,
with interplanar angles of 80◦ and 71◦.20 In this respect, 6a can
probably behave more similar to the non-macrocyclic analogues 4
and 5, and thus 6b has a special combination of properties allowing
to form the new product 7.
Conclusions
Our observations indicate that the NHC derived from 6b is not
too sterically encumbered to allow the formation of benzoin 9, and
this reaction might be favored over lactone formation and Stetter
reaction due to the electron-poor benzaldehyde 1c. However, it
is still unclear why only NHC-precursor 6b led to the formation
of the new product, hemiacetal 7, and this new reaction pathway
requires further investigation.
Experimental
The azolium chlorides 4,18 18 and 611a were synthesized according
5
to literature procedures. Pure samples of the lactones 3 for
GC-calibration were obtained with precatalyst 4 after column
chromatography, matching the spectroscopic data given in the
literature.21 All aldehydes and ketones were purified by either
destillation (2a) or column chromatography on silica gel (1b,
1c, 2b) before use. Dry THF was obtained by heating at reflux
with lithium aluminium hydride.1H and 13C NMR spectra were
recorded with Bruker ARX 300, DRX 500 or AV 600 instruments
at room temperature and are referenced to tetramethylsilane.
IR spectra were recorded with a Perkin-Elmer Paragon 1000,
equipped with an ATR unit. Mass spectra were recorded with
a Finnigan MAT 8200 or MAT 8230. Elemental analyses were
carried out with a EuroEA 3000 Elemental Analyzer from Euro
Vector. GC analyses were performed on an Agilent 6890 N gas
chromatograph.
Fig. 2 Crystal structure of imidazolinium chloride 6b.19 The chloride
anion and two molecules of chloroform ◦are omitted for clarity. Se-
˚
lected bond lengths [A] and bond angles [ ]: N1-C17 1.315(3), N1-C18
1.483(4), N1-C1 1.429(4), C18-C18A 1.508(8); N1-C17-N1A 113.1(4),
C17-N1-C18 109.4(3), N1-C18-C18A 102.6(2); C17-N1-C1-C6 132.5(3),
C17-N1-C1-C2 -48.8(4).
General procedure for the synthesis of c-butyrolactones 3
A flask was charged with the respective catalyst (0.05 or
0.13 mmol), the flask was flushed with nitrogen and sealed with a
rubber septum. Via syringe, a solution of the enal 2 (0.50 mmol)
and the electrophilic aldehyde or ketone 1 (1.0 mmol) in dry THF
(2 mL) was added and the mixture was stirred for 5 min. DBU (1
equiv. based on catalyst) was added via microliter-syringe, and the
mixture was stirred at room temperature. After 16 h, the mixture
was passed through a short pad of silica gel and the silica gel was
rinsed with ethyl acetate (20 mL). To this solution was added n-
hexadecane as the internal standard and the mixture was analyzed
by GC; conditions: split ratio 11:1, injector temp. 250 ◦C, detector
temp. 300 ◦C; column: HP-5/30 m; temperature: 100 ◦C for 2 min,
15 ◦C/min until 300 ◦C, 10 min 300 ◦C.
Fig. 3 Comparison of the crystal structures of 6a (left) and 6b (right).
Hydrogen atoms and solvent molecules are omitted for clarity.
On first glance, the structures of both bimacrocycles 6a and
6b seem quite similar. The phenyl substituents are substan-
tially twisted out of a coplanarity with the heterocycle, and
the conrotatory fashion of this twist leads to a C2-symmetric
structure. However, a look at the interplanar angles between the
imidazolinium ring and the adjacent aryl rings (derived from the
torsion angles C17-N1-C1-C2, C17-N1-C1-C6) reveals that the
phenyl substituents twist more out of a coplanar geometry in 6a
(the interplanar angle is 54◦) than they do in the larger cycle 6b
(48◦).
5-Hydroxy-2-[4-(methoxycarbonyl)-phenyl]-2-[4-(methoxy-
carbonyl)-phenylcarbonyl]-3-phenyl-tetrahydrofuran (7)
Following the general procedure, cinnamaldehyde (2a, 66 mg,
0.50 mmol) and methyl 4-formylbenzoate (1c, 164 mg, 1.00 mmol)
were reacted with imidazolinium chloride 6b (75 mg, 0.13 mmol)
and DBU (20 mL, 0.13 mmol). After GC analysis, the solvent was
evaporated in vacuo and the crude product was purified by column
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chromatography [silica gel, cyclohexane/ethyl acetate (3:1), Rf =
0.27]. A colorless solid was obtained (96 mg, 42%). M.p. 163 ◦C.
1H-NMR (600 MHz, CDCl3)22: d (ppm) = 7.89 (mc, 4H, Ar-H),
7.72 (d, 3J = 8.8 Hz, 2H, Ar-H), 7.11 (mc, 2H, Ar-H), 7.05–7.00
(m, 3H, Ar-H), 6.93 (mc, 2H, Ar-H), 6.07 (dd, 3J = 5.0 Hz, 3J = 1.3
Hz, 1H, 5-H), 4.92 (dd, 3J = 8.9 Hz, 3J = 7.8 Hz, 1H, 3-H), 3.87
(s, 3H, COOCH3), 3.82 (s, 3H, COOCH3), 2.80 (br s, 1H, OH),
4 A. J. Arduengo III, R. L. Harlow and M. Kline, J. Am. Chem. Soc.,
1991, 113, 361.
5 N. Marion, S. Diez-Gonza´les and S. P. Nolan, Angew. Chem. Int. Ed.,
2007, 46, 2988.
6 (a) W. A. Herrmann, Angew. Chem. Int. Ed., 2002, 41, 1290; (b) E. A.
B. Kantchev, C. J. O’Brien and M. G. Organ, Angew. Chem. Int. Ed.,
2007, 46, 2768.
7 D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606.
8 (a) C. Burstein and F. Glorius, Angew. Chem. Int. Ed., 2004, 43, 6205;
(b) S. S. Sohn, E. L. Rosen and J. W. Bode, J. Am. Chem. Soc., 2004,
126, 14370.
9 W. Schrader, P. P. Handayani, C. Burstein and F. Glorius, Chem
Commun., 2007, 716.
10 K. Hirano, I. Piel and F. Glorius, Adv. Synth. Catal., 2008, 350, 984.
A possible explanation for the different diastereoselectivities is given in
the supporting information.
11 (a) O. Winkelmann, C. Na¨ther and U. Lu¨ning, Eur. J. Org. Chem.,
2007, 981; (b) O. Winkelmann, D. Linder, J. Lacour, C. Na¨ther and U.
Lu¨ning, Eur. J. Org. Chem., 2007, 3687.
12 Imidazolinium salts are sometimes also called dihydroimidazolium
salts.
2
3
3
2.47 (ddd, J = 13.3 Hz, J = 9.0 Hz, J = 5.0, 1H, 4-Ha), 2.41
3
3
(ddd,2J = 13.3 Hz, J = 7.7 Hz, J = 1.5, 1H, 4-Hb). 13C-NMR
(150 MHz, CDCl3)23: d (ppm) = 198.2 (CO), 166.7 (COOCH3),
166.2 (COOCH3), 142.8 (Ar-C), 138.7 (Ar-C), 138.6 (Ar-C), 133.0
(Ar-C), 130.5 (Ar-CH), 129.3 (Ar-CH), 129.2 (Ar-CH), 129.1 (Ar-
CH), 127.9 (Ar-CH), 126.7 (Ar-CH), 125.5 (Ar-CH), 99.2 (C-5),
94.9 (C-2), 52.3 (COOCH3), 52.0 (COOCH3), 49.6 (C-3), 40.3 (C-
-1
˜
4). IR: n (cm ) = 3509, 2932, 1713, 1674, 1606, 1567, 1498, 1434,
1273, 1228, 1108, 1068, 1016, 990, 956, 821, 720, 696, 588. MS
(EI): m/z (%) = 429 (3) [M - OCH3]+, 297 (100) [M - C9H7O3]+,
163 (58) [C9H7O3]+. MS (CI): m/z (%) = 461 (22) [M + H]+. Found:
C, 70.35; H, 5.57. C27H24O7 requires C, 70.42; H, 5.25
13 G. Bertolli, G. Fronza, C. Fuganti, P. Grasselli, L. Majori and F.
Spreafico, Tetrahedron Lett., 1981, 22, 965.
14 In the absence of cinnamaldehyde 2a, all precatalysts (4, 5, 6a and 6b)
led to very little conversion of benzaldehyde 1c, and only small amounts
of benzoin 9 could be obtained.
1,2-Bis-(4-methoxycarbonylphenyl)-ethane-1,2-dione (8)
15 Hemiacetal 7 could also be obtained when preformed benzoin 9 was
reacted with cinnamaldehyde 2a in the presence of DBU.
16 Dehydrogenation also occurs when pure benzoin 9 is investigated by
GC. Besides 9, benzil 8 is also detected. Respective benzoins are known
to be easily oxidizable: E. Masatsugu, M. Shunichi and I. Hiroo, Jpn.
Kokai Tokkyo Koho, 1993(JP 05–213 824).
17 O. Winkelmann, C. Na¨ther and U. Lu¨ning, J. Organomet. Chem.,
2008, 693, 923. By measuring CO stretching frequencies of related
NHC complexes, it was shown that the NHC derived from the smaller
bimacrocycle 6a is more electron-rich than the NHC derived from 5.
The electronic differences between 6a and 6b are expected to be small.
The structure of 6b (see Fig. 2 and 3 and discussion) may actually
allow a better conjugation between the electron-rich bridgeheads and
the heterocycle, leading to an even more electron-rich NHC compared
to 6a.
From the above-described reaction was isolated 8 (Rf = 0.44) as
1
a yellow solid (5 mg, 4%). H-NMR (500 MHz, d6-DMSO): d
(ppm) = 8.17 (d, 3J = 8.6 Hz, 4H, Ar-H), 8.11 (d, 3J = 8.6 Hz, 4H,
Ar-H), 3.91 (s, 6H, COOCH3). 13C-NMR (125 MHz, d6-DMSO):
d (ppm) = 192.9 (s, CO), 165.3 (s, COOCH3), 135.3 (Ar-C), 135.1
˜
(Ar-C), 130.2 (Ar-CH), 129.9 (Ar-CH), 52.7 (COOCH3). IR: n
(cm-1) = 2925, 1717, 1663, 1569, 1500, 1281, 1188, 1102, 1012,
949, 889, 859, 820, 781, 730, 713, 674, 629, 534. MS (EI): m/z
(%) = 326 (2) [M]+, 163 (100) [C9H7O3]+. MS (CI): m/z (%) = 327
(100) [M + H]+.
18 A. J. Arduengo III, R. Krafczyk, R. Schmutzler, H. A. Craig, J. R.
Goerlich, W. J. Marshall and M. Unverzagt, Tetrahedron, 1999, 55,
14523: The geometrical differences between 1,3-bis(2,6-diisopropyl-
phenyl)imidazolium chloride and the respective NHC are rather small,
for example.
2-Hydroxy-1,2-bis-(4-methoxycarbonylphenyl)-ethanone (9)24
Methyl 4-formylbenzoate (1c, 16.4 g, 100 mmol) was heated to
50 ◦C with sodium cyanide (1.50 g, 30.0 mmol) in a mixture of
ethanol (40 mL) and water (20 mL). After 10 min, the precipitate
was collected by filtration and washed with water and ethanol. The
residue was dried in vacuo. A colorless solid was obtained (13.5 g,
82%). 1H-NMR (300 MHz, d6-DMSO): d (ppm) = 8.11 (d, 3J =
8.6 Hz, 2H, Ar-H), 8.00 (d, 3J = 8.7 Hz, 2H, Ar-H), 7.91 (d, 3J =
19 Suitable crystals were grown by diffusion of diethyl ether into a solution
of 6b in chloroform. Crystal data. C35H51ClN2O4·2CHCl3, M = 837.96,
˚
monoclinic, a = 26.471(3), b = 12.5614(7), c = 16.7632(14) A, b =
◦
3
˚
128.674(9) , U = 4351.6(6) A , T = 220(2) K, space group C2/c (no.
15), Z = 4, 9095 reflections measured, 3828 unique (Rint = 0.0469)
which were used in all calculations. The final wR(F2) was 0.1870 (all
data). The solvent molecules are disordered over two positions.†.
20 A. J. Arduengo III, H. V. R. Dias, R. L. Harlow and M. Kline, J. Am.
Chem. Soc., 1992, 114, 5530.
3
8.4 Hz, 2H, Ar-H), 7.57 (d, J = 8.3 Hz, 2H, Ar-H), 6.50 (br s,
1H, HCOH), 6.19 (s, 1H, HCOH), 3.85 (s, 3H, COOCH3), 3.80
-1
˜
(s, 3H, COOCH3). IR: n (cm ) = 3459, 2953, 1718, 1677, 1608,
21 C. Burstein, S. Tschan, X. Xie and F. Glorius, Synthesis, 2006, 2418.
22 Only the signals of the major anomer are listed. Most of the signals of
the minor anomer are not observed due to overlap. Selected signals of
the minor anomer: d (ppm) = 5.78 (mc, 1H, 5-H), 4.60 (dd, 3J = 10.1
Hz, 3J = 7.7 Hz, 3-H), 2.61 (ddd, 2J = 13.4 Hz, 3J = 7.7 Hz, 3J =
1571, 1436, 1273, 1094, 982, 963, 814, 765, 719, 614, 535. MS (EI):
m/z (%) = 163 (100) [C9H7O3]+. MS (CI): m/z (%) = 329 (100)
[M + H]+.
2
3
3
5.5 Hz, 1H, 4-Ha), 2.32 (ddd, J = 13.5 Hz, J = 10.0 Hz, J = 6.0
Hz, 1H, 4-Hb). The 10:1 ratio between the anomers was deduced from
integration.
References and notes
23 Only the signals of the major anomer are listed. One quaternary
aromatic carbon atom was not observed, possibly due to overlap or
low intensity.
1 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
2 (a) F. Wo¨hler and J. Liebig, Ann. Pharm., 1832, 3, 249; (b) A. Lapworth,
J. Chem. Soc., 1903, 83, 995.
24 M. Shunichi and I. Hiroo, Jpn. Kokai Tokkyo Koho, 1992(JP 04–364
151).
3 H. Stetter, Angew. Chem. Int. Ed. Engl., 1976, 15, 639.
556 | Org. Biomol. Chem., 2009, 7, 553–556
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