An efficient method for preparation of chiral arylmenthol glyoxylates

Article abstract of DOI:10.1055/s-1998-2198

Glyoxylates of three chiral alcohols were conveniently prepared by reaction of the alcohol with oxalyl chloride followed by reduction of the resulting alkoxy oxalyl chloride with tributyl- tin hydride. The products were isolated in 75-80% yield by straightforward flash chromatography.

Full text of DOI:10.1055/s-1998-2198

SYNTHESIS
Short Papers
1590
An Efficient Method for Preparation of Chiral Arylmenthol Glyoxylates
José M. Blanco, Olga Caamaño, Franco Fernández, Xerardo García-Mera,* Carmen López, José E. Rodríguez-Borges,
Antonio R. Hergueta.
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, E-15706 - Santiago de Compostela, Spain
E-mail: qoxgmera@usc.es
Received 16 March 1998
Abstract: Glyoxylates of three chiral alcohols were conveniently
prepared by reaction of the alcohol with oxalyl chloride followed
by reduction of the resulting alkoxy oxalyl chloride with tributyl-
ylisoneomenthol [(1R,3R,4R)-8-phenylmenthan-3-ol; 7]
tin hydride. The products were isolated in 75–80% yield by
The starting chiral alcohols, (–)-8-phenylmenthol
[(1R,3R,4S)-8-phenyl-p-menthan-3-ol; 6] and (–)-8-phen-
were prepared by Bouveault–Blanc reduction of (1R,4S)-
8-phenyl-p-menthan-3-one,13,14 which was easily ob-
tained by conjugate addition of phenylmagnesium bro-
mide to (+)-(R)-pulegone.15 Alcohols 6 and 7 were
straightforwardly separated by flash chromatography on
silica gel.
straightforward flash chromatography.
Key words: chiral glyoxylates, 8-phenylmenthol, 8-phenylisone-
omenthol, menthol
Chiral glyoxylates are used as chiral auxiliaries to control
the enantioselectivity of ene reactions,1 and in the asym-
metric synthesis of heterocyclic compounds from imine
glyoxylates.2 Our interest in these compounds stems from
their use in the enantioselective synthesis of 3-functional-
ized 2-azabicyclo[2.2.1]hept-5-enes 1 by Diels–Alder ad-
dition of imine glyoxylates to cyclopentadiene.3 Specifi-
cally, bicyclic alkenes of type 1 are used as intermediates
in the enantioselective synthesis of diverse biologically
active compounds,4 including several carbocyclic nucleo-
sides, among them the anti-HIV agent (–)-carbovir,5
amino acid analogs of GABA,6 the antibiotic amidomy-
cin,7 and several herbicides.8
Conversion of the chiral alcohols into the target glyoxy-
lates (Scheme 1) began by reacting them with excess ox-
alyl chloride in chloroform, which gave the corresponding
alkoxy oxalyl chlorides 2. Next, crude11 2 was treated
with excess tributyltin hydride in the presence of a catalyt-
ic amount of tetrakis(triphenylphosphine)palladium(0), so
that the reaction proceeded at room temperature without
loss of yield. Once reaction was complete, the excess
tributyltin hydride was destroyed by heating it with anhy-
drous chloroform, which meant that the only tin coproduct
was tributyltin chloride. Thus, the glyoxylate could be
separated from the reaction mixture by straightforward
column chromatography, rather than by the high-temper-
ature and/or low-pressure fractional distillation necessary
in the original method. All three glyoxylates were charac-
terized by determination of their spectroscopic and physi-
cal properties and those of their 2,4-dinitrophenylhydra-
zone derivatives 5a–c.12
Initially we tried preparing the requisite chiral glyoxylates
by periodate oxidation of the corresponding tartrates,
which gave satisfactory results when the alcohol was
(–)-menthol [(1R,3R,4S)-p-menthan-3-ol] or (–)-borneol
[(1S,endo)-2-bornanol].9 Seeking a shorter and less labo-
rious route, we then tried an approach using ozonolysis of
the corresponding fumarates, but this gave poor yields of
the glyoxylates (≤10%). Finally, we examined an approach
using reduction of alkoxy oxalyl chlorides with tributyltin
hydride that has been successfully used to obtain menthyl
glyoxylate.10 As it stands, this approach presents two draw-
backs: inefficient separation of the target compound from
the tin coproducts, which reduces the yield of the former;
and the use of distillation for isolation of the product, ruling
out this approach for preparation of glyoxylates with high
boiling point or those which are unstable at high tempera-
tures. To circumvent these problems and to improve the ef-
ficiency of this approach, we set about modifying it. In the
present work we describe our modified approach, using it
to prepare menthyl glyoxylate 3c in yield superior to that
reported earlier by Hub and Mosher,10 and 8-phenylisoneo-
menthyl and 8-phenylmenthyl glyoxylates 3a and 3b in
good yield (75–80%, based on starting alcohol).
Scheme 1

SYNTHESIS
November 1998
1591
128.37 (C-3' + C-5'), 148.70 (C-1'), 159.04 [C(O)O], 184.31 (CH=O).
Anal.: calcd for C18H24O3: C, 74.97; H, 8.39; found: C, 74.85; H,
8.23.
A small amount of the mixture of 3a and 4a was left in contact with
water for several days. After the solid that formed had been recrystal-
lized from hexane, it was identified as the hydrate 4a; mp 118–120°C
(hexane).
The crude hydrate 4a was converted into the corresponding 2,4-dini-
trophenylhydrazone derivative, 5a, by the usual procedure;12 yield:
92%; mp 97–101°C (MeOH); [α]D25 –41.4 (c = 1, CHCl3).
IR (KBr): ν = 3257, 2938, 1710, 1618, 1578, 1507, 1458, 1424, 1340,
1261, 1211, 1137, 1090, 916, 833, 769, 742, 701 cm–1.
1H NMR (CDCl3): δ = 0.90 (d, 3H, J = 7.26 Hz, 1-CH3), 1.36 and 1.37
[2s, 6H, 8-(CH3)2], 1.50–1.70 (m, 5H), 1.77–1.97 (m, 3H), 5.173 (bs,
1H, 3eq-H), 6.86 (s, 1H, CH=N), 7.14–7.20 (m, 1H), 7.23–7.33 (m,
4H, C6H5), 8.14 (d, 1H, J = 9.45 Hz, 6-H), 8.41 (dd, 1H, J = 9.45, 2.56
Hz, 5-H), 9.16 (d, 1H, J = 2.56 Hz, 3-H), 14.42 (s, 1H, -NH-).
13C NMR (CDCl3): δ = 17.47, 20.79, 26.55, 26.65, 27.53, 32.34,
36.69, 40.52, 51.67, 74.46 (C-3), 117.23, 123.42, 126.31 (C-4'),
126.45 (C-2' + C-6'), 128.49 (C-3' + C-5'), 129.79, 130.22, 132.06,
140.59, 148.95 (C-1'), 161.52 (C(O)O).
Scheme 2
Although the target glyoxylates were isolated initially in
their anhydrous form, they are easily converted into their
hydrates 4a–c, which could be observed in the NMR spec-
tra of the products unless special measures were taken so
as to obtain only the anhydrate.9 The presence of this hy-
drate is not a problem, however, since both the anhydrate
and hydrate react with primary amines to give the desired
imines. Crystalline hydrates 4 could easily be obtained by
leaving the anhydrous form in contact with water.
Anal.: calcd for C24H28N4O6: C, 61.53; H, 6.02; N, 11.96; found: C,
61.31; H, 6.22; N, 12.14.
Mps are uncorrected and were determined in a Reichert Kofler Ther-
mopan or in capillary tubes in a Büchi 510 apparatus. Observed rota-
tions at the Na-D line were determined at 25°C in a Perkin–Elmer 241
polarimeter. IR were recorded in a Perkin–Elmer 681 spectrophotom-
eter. 1H NMR spectra (300 MHz) and 13C NMR (75.47 MHz) spectra
were recorded in a Bruker WM spectrometer, using TMS as internal
standard (chemical shifts in δ values, J in Hz). MS were recorded on
a Kratos MS-59 spectrometer. Microanalyses were performed in a
Perkin–Elmer 240B element analyser by the Microanalysis Service of
the University of Santiago. Flash chromatography was performed on
silica gel (Merck 60, 230–240 mesh); analytical TLC was performed
on pre-coated silica gel plates (Merck 60 F254, 0.25 mm).
(1R,3R,4S)-8-Phenylmenthyl Glyoxylate (3b):
Isolated in 77% yield as a colorless oil that was identified by 1H NMR
to be a mixture of anhydrate 3b and hydrate 4b (proportions varied).
A small amount of this oil left in contact with water for several days
slowly solidified, and after recrystallization from hexane was identi-
fied as (1R,3R,4S)-8-phenylmenthyl 2,2-dihydroxyacetate (4b); mp
146–148°C (hexane).
IR (KBr): ν = 3464, 2955, 2924, 2870, 1732, 1497, 1389, 1370, 1289,
1227, 1094, 980, 766, 702 cm–1.
1H NMR (CDCl3): δ = 0.85 (d, 3H, J = 6.39 Hz, 1-CH3), 0.98–1.18
(m, 2H), 1.30 and 1.38 [2s, 6H, 8-(CH3)2], 1.40–1.77 (m, 7H), 2.01
(td, 2H, Jt = 11.40 Hz, Jd = 3.36 Hz), 4.87 (td, 1H, Jt = 10.68 Hz, Jd =
4.42 Hz, 3ax-H), 7.10–7.15 (m, 1H), 7.23–7.29 (m, 4H, C6H5).
13C NMR (CDCl3): δ = 22.12, 25.35, 28.06, 29.23, 31.74, 34.77,
40.60, 41.61, 50.89, 77.51 (C-3), 125.78 (C-4'), 126.11 (C-2' + C-6'),
128.38 (C-3' + C-5'), 150.64 (C-1'), 159.90 (CH(OH)2), 162.87
[C(O)O].
Preparation of Glyoxylates 3; General Procedure:
A solution of the chiral alcohol (100 mmol) in anhyd CHCl3 (110 mL)
was added slowly, over 2 h, to a solution of oxalyl chloride (17.5 g,
200 mmol) in anhyd CHCl3 (25 mL) stirring at –10°C under argon.
The mixture was stirred at r.t. for 2 h and then the solvent and excess
oxalyl chloride were removed on a rotary evaporator (50°C/13 Torr),
using liquid N2 to cool the solvent trap. The crude alkoxy oxalyl chlo-
ride, isolated as a colorless oil, was dissolved in anhyd benzene (110
mL), to which Pd(Ph3P)4 (46 mg, 0.038 mmol) was added, followed
slowly, over 1.5 h, by Bu3SnH (29.8 g, 102.5 mmol). The mixture was
stirred at r.t. for 2.5 h and then diluted with anhyd CHCl3 (25 mL) and
refluxed for a further 1 h. The solvents were evaporated in vacuo, and
the oily residue was column chromatographed [silica gel, 900 g, hex-
ane (6.5 L), hexane/CH2Cl2 1:1 (4 L), CH2Cl2 (3.5 L) and EtOAc (6.5
L)]. All the glyoxylates 3 eluted in the EtOAc fraction.
Anal.: calcd for C18H26O4: C, 70.56; H, 8.55; found: C, 70.31; H,
8.71.
Compound 4b was converted into the corresponding 2,4-dinitrophe-
nylhydrazone derivative, 5b, by the usual procedure;12 yield: 89%;
mp 159–162°C (MeOH); [α]D25 –17.5 (c = 1, CHCl3).
IR (KBr): ν = 3272, 2965, 1687, 1618, 1596, 1570, 1423, 1336, 1310,
1215, 1139, 1085, 1052, 920, 871, 834, 763, 742, 700 cm–1.
1H NMR (CDCl3): δ = 0.91 (d, 3H, J = 6.50 Hz, 1-CH3), 0.95–1.17
(m, 2H), 1.12 and 1.32 [2s, 6H, 8-(CH3)2], 1.49–1.60 (m, 2H), 1.70–
1.78 (m, 1H), 1.91–1.97 (m, 2H), 2.18 (td, 1H, Jt = 11.37 Hz, Jd =
3.36 Hz), 5.03 (td, 1H, Jt = 10.71 Hz, Jd = 4.36 Hz, 3ax-H), 6.07 (s,
1H, CH=N), 7.06–7.11 (m, 1H), 7.19–7.29 (m, 4H, C6H5), 8.04 (d,
1H, J = 9.47 Hz, 6-H), 8.38 (dd, 1H, J = 9.47, 2.56 Hz, 5-H), 9.154
(d, 1H, J = 2.56 Hz, 3-H), 14.08 (s, 1H, -NH-).
(1R,3R,4R)-8-Phenylisoneomenthyl Glyoxylate (3a):
Isolated in 75% yield as a colorless oil that was identified by 1H NMR
to be a mixture of anhydrate 3a and hydrate 4a (proportions varied).
A small amount of this mixture was treated with active charcoal in hot
CHCl3, then filtered hot and concentrated to a residue. After drying
this residue under vacuum for 2 h, an oil was obtained that consisted
of more than 85% of the anhydrate 3a.
Anal.: calcd for C24H28N4O6: C, 61.53; H, 6.02; N, 11.96; found: C,
61.46; H, 6.18; N, 12.02.
(1R,3R,4S)-Menthyl Glyoxylate (3c):
IR (NaCl): ν = 3464, 2957, 2924, 1736, 1599, 1497, 1458, 1445,
Isolated in 86% yield as a colorless oil that was identified by 1H NMR
to be a mixture of anhydrate 3c and hydrate 4c (proportions varied).
A small amount of this mixture left in contact with water for several
days afforded a solid, which was recrystallized from hexane and iden-
tified as the hydrate 4c; mp 80–81°C (hexane).10
1389, 1371, 1225, 1094, 980, 766, 702 cm–1.
1H NMR (CDCl3): δ = 0.97 (d, 3H, J = 7.45 Hz, 1-CH3), 1.36 and 1.38
[2s, 6H, 8-(CH3)2], 1.55–1.70 (m, 5H), 1.76–1.98 (m, 3H), 4.97 (bs,
1H, w1/2 = 8.30 Hz, 3eq-H), 7.12–7.20 (m, 1H), 7.23–7.30 (m, 4H,
C6H5), 9.19 (s, 1H, -CH=O).
13C NMR (CDCl3): δ = 17.55, 20.48, 25.72, 26.39, 28.13, 32.19,
36.29, 40.33, 51.63, 75.49 (C-3), 126.14 (C-4'), 126.24 (C-2' + C-6'),
IR (KBr): ν = 3413, 3353, 2957, 2866, 1742, 1461, 1273, 1231, 1113,
1060, 959, 655 cm–1.

SYNTHESIS
Short Papers
1592
1H NMR (CDCl3): δ = 0.77 (d, 3H, JMe,CH = 6.98 Hz), 0.90 and 0.91
[2d, 3H, JMe,CH = 7.01 Hz, -CH(CH3)2], 0.92 and 0.93 (2d, 3H, JMe,CH
= 6.48 Hz, -1-CH3), 0.86–1.20 (m, 3H, menthyl), 1.43–1.60 (m, 2H,
menthyl), 1.66–1.78 (m, 2H, menthyl), 1.86–1.89 [2 d × sept, 1H,
JCH,Me = 6.98 Hz, JCH,4ax = 2.73 Hz, -CH(CH3)2], 1.90–2.10 (m, 1H,
2eq-H), 3.70 [bs, 2H, -CH(OH)2], 4.81 (dt, J3ax,2ax = J3ax,4ax = 11.00
Hz, J3ax,2ax = 4.30 Hz), 4.88 (dt, J3ax,2ax = J3ax,4ax = 10.89 Hz, J3ax,2ax
= 4.55 Hz, 3ax-H), 5.22 [s, 1H, -CH(OH)2], 9.40 (s, 1H, -CH=O).
A sample of anhydrate 3c was prepared by heating a solution of 4c
(0.5 g) and pyridine tosylate (1 mg) in anhyd benzene (50 mL) under
argon in a Dean–Stark apparatus for 4 h. A sample of the resulting
solution was removed, concentrated to dryness and redissolved in
deuterobenzene for analysis by 1H NMR, which confirmed it to con-
tain greater than 99% 3c.
Compound 6: [α]D25 –25.3 (c = 0.5, CHCl3). Spectroscopic data
matched the published data for this compound.14, 15
Compound 7: [α]D25 –4.2 (c = 0.5, CHCl3). Spectroscopic data
matched the published data for this compound.16
Authors thank Spanish Ministry of Education and Science (MEC-
DGICYT, PB94-0617) and Xunta de Galicia (XUGA 20307B94) for
financially supporting this work.
(1) Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions;
American Chemical Society: Washington, D.C., 1976.
(2) Blondet, D.; Morin, C. Heterocycles 1982, 19, 2155.
van Vliet, M. R. P.; Jastrzebski, J. T. B. H.; Klaver, W. J.; Gou-
bitz, K.; van Koten, G. Recl. Trav. Chim. Pays-Bas 1987, 106,
132.
Palomo, C.; Ontoria, J. M.; Odriozola, J. M.; Alzpurua, J. M.;
Gamboa, I. J. Chem. Soc., Chem. Commun. 1990, 248.
(3) Stella, L.; Abraham, H.; Fenau-Dupont, J.; Tinant, B.; Declercq,
J. P. Tetrahedron Lett. 1990, 31, 2603.
(4) Palmer, C. F.; McCague, R. J. Chem. Soc., Perkin Trans. I 1995,
1201.
(5) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Chaland, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 36, 10611, and re-
ferences cited therein.
(6) Allan, R. D.; Johnston, G. A. R. Med. Res. Rev. 1983, 3, 91, and
references cited therein.
(7) Nakamura, S. Chem. Pharm. Bull. 1961, 9, 641.
(8) Bush, B. D.; Fitchett, G. V.; Gates, D. A.; Langely, D. Phyto-
chemistry 1993, 32, 737.
Isaac, B. G.; Ayer, S. W.; Letendre, L. J.; Stonard, R. J. J. Anti-
biot. 1991, 44, 729.
(9) Fernández, F.; García-Mera, X.; Rodríguez-Borges, J. E. Synth.
Commun. 1990, 20, 2837.
(10) Hub, L.; Mosher, H. S. J. Org. Chem. 1970, 35, 3691.
(11) Experiment showed that the overall yield of the sequence was
not improved by distilling the menthoxy oxalyl chloride, 4c (bp
86–97 ºC/0.5 Torr) prior to reducing it.
(12) Vogel, A. I. Practical Organic Chemistry, 5th ed.; Longmans
Scientific & Technical: London, 1989; p 1122.
(13) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
(14) Herzog, H.; Scharf, H. D. Synthesis 1986, 420.
Ort, O. Org. Synth. 1987, 65, 203.
(15) Potin, P.; Dumas, F.; Maddaluno, J. Synth. Commun. 1990, 20,
2805.
(16) Halterman, R. L.; Vollhardt, P. C. Organometallics 1988, 7,
883.
1H NMR (C6D6): δ = 0.73 (d, 3H, JMe,CH = 6.99 Hz), 0.84 [d, 3H,
JMe,CH = 7.01 Hz, -CH(CH3)2], 0.85 (d, 3H, JMe,CH = 6.50 Hz, -1-
CH3), 0.80–1.09 (m, 3H, menthyl), 1.35–1.49 (m, 2H, menthyl),
1.54–1.63 (m, 2H, menthyl), 1.83 [d × sept, 1H, JCH,Me = 7.00 Hz,
JCH,4ax = 2.80 Hz, -CH(CH3)2], 1.91–2.00 (m, 1H, 2eq-H), 4.81 (dt,
J3ax,2ax = J3ax,4ax = 10.79 Hz, J3ax,2ax = 4.63 Hz, 3ax-H), 9.10 (s, 1H, -
CH=O).
The corresponding 2,4-dinitrophenylhydrazone derivative, 5c, could
be prepared from 3c or 4c by the usual procedure.12 Average yield,
81%; mp 145–146°C (hexane/CH2Cl2 9:1);10 [α]D25 –104.8 (c = 1,
CHCl3).
IR (KBr): ν = 3209, 2929, 1695, 1625, 1576, 1526, 1424, 1309, 1266,
1211, 1141, 1093, 954, 854, 710 cm–1.
1H NMR (CDCl3): δ = 0.79 (d, 3H, JMe,CH = 6.93 Hz), 0.92 [d, 3H,
JMe,CH = 7.00 Hz, -CH(CH3)2], 0.94 (d, 3H, JMe,CH = 6.52 Hz, -1-
CH3), 0.88–1.20 (m, 3H, menthyl), 1.46–1.60 (m, 2H, menthyl),
1.69–1.77 (m, 2H, menthyl), 1.88 [d × sept, 1H, JCH,Me = 6.98 Hz,
JCH,4ax = 2.68 Hz, -CH(CH3)2], 2.05–2.15 (m, 1H, 2eq-H), 4.94 (dt,
1H, J3ax,2ax = J3ax,4ax = 10.89 Hz, J3ax,2ax = 4.43 Hz, 1ax-H), 7.05 (s,
1H, -CH=N-), 8.14 (d, 1H, Jortho = 9.49 Hz, arom. 6-H), 8.40 (d, 1H,
Jortho = 9.49 Hz, Jmeta = 2.55 Hz, arom. 5-H), 9.16 (d, 1H, Jmeta = 2.55
Hz, arom. 3-H), 14.42 (s, 1H, -NH-).
13C NMR (CDCl3): δ = 16.74, 21.11, 22.36, 23.77, 26.72, 31.83,
34.42, 41.03, 47.18, 76.90 (C-3), 117.24, 123.41, 129.97, 130.24,
132.03, 140.56, 144.57, 161.91 (C(O)O).
Anal.: calcd for C18H24N4O6: C, 55.10; H, 6.16; N, 14.28; found: C,
55.30; H, 6.05; N, 14.34.
(1R,3R,4S)-8-Phenylmenthol (6) and (1R,3R,4R)-8-Phenylisoneo-
menthol (7):
Bouveault–Blanc reduction13, 14 of (1R,4S)-8-phenyl-p-menthan-3-
one15 gave an 89:1 mixture of 6 and 7 (12.97 g), which was separated
by flash chromatography (silica gel, 325 g, hexane/CH2Cl2 5:4 (6.5
L)). Compound 7 eluted first (1.10 g, 10%) and was found to be
≥99.5% pure by GC. Compound 6 (7.7 g, 60%) eluted alone in later
fractions and was also found to be ≥99.5% pure by GC.