Electrophilic Substitution of Aromatic Compounds
by Unsaturated Sugar Derivatives
Grzegorz Grynkiewicz* and Aleksander Zamojski
Institute of Organic Chemistry, Polish Academy of Sciences, 0 1 - 2 2 4 Warszawa, Poland
Z. Naturforsch. 35 b , 1024-1027 (1980); received March 20, 1980
Hexenopyranosyl Carbocations, Pent-2-enopyranos-4-ulosyl Carbocations
Glycals 1 and 2 react with methoxybenzene in the presence of SnCLj forming ^-substituted C-glycosyl compounds 4 and 5 + 6 respectively. Under similar conditions l - O benzoyl- or methyl pent-2-enopyranos-4-uloses (7) and (8) react with electron rich
aromatic compounds furnishing either C-glycosyl compounds or C-2 aryl substituted
products depending on the nature of the aromatic component as well as the kind of
substituent at C - l .
Glycosyl halides or esters are capable to alkylate
aromatic substrates in the presence of Lewis acids
[1]. This reaction gives a simple synthetic access to
C-glycosylic compounds, including biologically important C-nucleosides [2]. It is assumed that
glycosyl carbocation intermediates in these alkylations.
It has been noticed that double bond in position
2,3- of the pyranoside ring facilitates the formation
of the corresponding glycosyl carbocation [3], and
in consequence 1,2- or 2,3-unsaturated monosaccharide derivatives should be particularly active
as alkylating species. However no reaction of such
sugar substrates with aromatic compounds have
been reported so far. Therefore, we decided to
examine the reactivity of unsaturated monosaccharides toward aromatic substrates susceptible
to electrophilic alkylation under Friedel-Crafts
reaction conditions.
In our experiments easily available 3,4,6-tri-0acetyl-2-deoxy-D-hex-l-enitols (1) and (2) were
taken as a source of glycosyl carbocations. A
considerable number of nucleophilic allylic displacement reactions of 1 and 2 have been examined and
there is a general agreement that bidentate carbocation 3 intermediates in these reactions. It seems,
that regio- and stereoselectivity of such reactions
depends rather strongly on the kind of nucleophile
used.
For example, reaction of 1 with aliphatic alcohols
is remarkably selective, leading exclusively to alkyl
a-hex-2-enopyranosides [4] while all four possible
* Reprint requests to Dr. G. Grynkiewicz.
0340-5087/80/0800-1024/$ 01.00/0
products, resulting from nonstereospecific substitution in positions C-l and C-3, are formed in the
reaction with azide anion [5].
The reaction of 1 with an excess of methoxybenzene in the presence of stannic chloride afforded
a crystalline product, which on the basis of the
spectral and analytical evidence was assigned
l'-[4,6-di-0-acetyl-2,3-dideoxy-a-D-en//Aro-hex-2enopyranosylj-4'- methoxybenzene (4) structure. The
configuration at C-l was deduced from the *H N M R
spectrum. The signal corresponding to H - l displayed
a broad singlet at <5 5.19, H-2 and H-3 formed a
multiplet centered at <5 5.88 and H-4 was recorded
as a characteristic pair of doublets with spacings
,745 = 9.0 Hz and 1/34 = 2.7 Hz. These spectral features and also specific rotation value strongly
resemble the data for alkyl 2,3-dideoxy-a-D-erythrohex-2-enopyranosides [4]. Under the same reaction
conditions 2 afforded chromatographically homogeneous oily mixture of products, identified on
examination of its *H N M R spectrum as l'-[4,6di-0-acetyl-2,3-dideoxy-a,/?-D-£Äreo-hex-2-enopyranosyl]-4'-methoxybenzene (5) and (6). From the
signals of olefinic protons with the following
coupling constants: J12 = 3.2, J i 3 = 1 . 8 , «723= 10.0
and J 34 = 5.0 HZ, configuration a was assigned to
the component comprising about 3 5 % of the
mixture. W e feel that lack of 3-substituted pyranosides among the reaction products obtained from 1
and 2 reflects kinetical control of the alkylation
process. Alternative explanation of the observed
selectivity, based on HS A B principle [6], indicates
that p-anisyl anion should be regarded as a relatively
hard base.
As the next carbocation-forming unsaturated
sugar derivative l-0-benzoyl-2,3-dideoxy-DL-pent-
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G. Grynkiewicz-A. Zamojski • Electrophilic Substitution of Aromatic Compounds
2-enopyranos-4-ulose (7), a substrate in synthesis
of racemic ribose [7] and some disaccharides [8],
was taken. Its alkylating properties were earlier
observed in Lewis acid catalyzed reaction with
phenols [9]. Compound 7 reacted smoothly with
methoxybenzene in the presence of stannic chloride
yielding the expected C-glycosyl derivative 9 in
good yield. Analogously, the reaction of 7 with
1,4-dimethoxybenzene led to compound 10. However, when 2-methyl-furan was employed as the
aromatic substrate in the reaction with 7, instead of
the benzoate group displacement formation of an
adduct was observed, although in low yield. The use
of milder acidic catalyst, namely zinc chloride,
allowed to obtain the adduct identified as 1-0benzoyl-2-[2'-/5' methylfuryl/]-2,3-dideoxy-a-DLgrZycero-pent-4-ulose (11) in reasonable quantity.
The structure unequivocally followed from analytical and spectral data. Well resolved 100 MHz
X H NMR spectrum of 11 displayed signals corresponding to phenyl, 2-methylfuran and pyranos4-ulose ring protons. All signals were sharp,
pointing at homogenity of the adduct. The observed
coupling constant Ji2 = 4 . 5 H z exceeds values
expected for axial-equatorial arrangement of vicinal
protons thus indicating ^raws-disposition of the
substituents at C-l and C-2 with prepondering JC4
conformation.
11: Ar = 2-(5-methytfuran)
0C0Ph
To confirm this configurational assignment adduct
11 was reduced with sodium borohydride followed
by acetylation, which afforded compound 14.
L H NMR spectrum of 14 was fully compatible with
the structure and configuration indicated.
OCOPh
AcO
Ar
Ar
1 4 : Ar s 2 - (5 - methylfuran)
In particular </i2 = 6 . 7 H z points clearly in the
direction of <ra?is-diaxial coupling. Similarly, the
sum of the coupling constants observed for C-4
[J = 28.3 Hz] and values J 4 t 5 a = 7.3 Hz and J4.se =
4.2 Hz indicate considerable contribution of the
1025
conformation 4Ci with axial protons at C - l , C-2 and
C-4. The formation of adduct 11 in reaction of 7
with 2-methylfuran can be rationalized on assumption that apart from glycosyl cation 15 resulting
from dissociation of C-l substituent, another
cationic species can be generated via complexation
of the carbonyl group with an acidic catalyst.
Apparently the carbocation 16 can not compete
effectively in electrophilic substitution reaction
with the glycosylic one (15), unless: i. very reactive
aromatic substrate is taken, or ii. another leaving
group, less susceptible to dissociation as a complex
with Lewis acid is placed at C-l site.
In order to verify this assumption addition of
reactive aromatic species to methyl 2,3-dideoxyDL-pent-2-enopyranosid-4-ulose was tried. It was
found that 8 easily reacts with 2-methyl furan in
the presence of zinc chloride to give chromatographically homogeneous adduct (12). However,
examination of its *H N M R spectrum revealed the
presence of two isomeric adducts in comparable
amounts. Apart from two signals corresponding to
methoxyl group, two anomeric protons could be
recognized in the spectrum. The coupling constants
t/i2 = 2.5 and 3.7 Hz correspond to eis- and transarrangement of H - l and H-2. Similarly, prolonged
treatment of 8 with methoxybenzene in the presence
of zinc chloride leads to formation of methyl
2,3-dideoxy-2-C-[4'-methoxybenzene]-DL-grZyceropent-4-ulose (13) in moderate jaeld. The presence
of 1,2-eis and 1,2-trans adducts was evident from
*H NMR spectrum of 13 but the mixture could not
be resolved chromatographically.
The results described here demonstrate clearly
that electrophilic substitution of aromatic compounds by unsaturated sugars can be performed in
good yields under relatively mild conditions,
appreciably milder than those employed in the case
of saturated sugars. Products obtained represent
structures which can be converted into a variety of
biologically interesting compounds. It seems that
the potentially two-directional reactivity of 2-enopyranos-4-ulose derivatives can be controlled, by
proper selection of the C-l substituent, catalyst and
the kind of aromatic compounds.
Experimental
3,4,6-Tri-0-acetyl-2-deoxy-D-hex-l-enitols (1, 2)
[10] and pent-2-enopyranos-4-ulose derivatives (7)
[7], 8 [11] were prepared as reported in the literature.
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1026
G. Grynkiewicz-A. Zamojski • Electrophilic Substitution of Aromatic Compounds 1026
Remaining substrates were commercial grade reagents purified b y distillation or crystallization before
use. Melting points are not corrected, boiling points
refer to air bath temperature during microscale
distillations. X H NMR spectra were recorded on
JEOL-4H-100 [100 MHz] spectrometer for CDC13
solutions with TMS as internal standard. I R spectra
were taken on Unicam SP-200 spectrophotometer.
Optical rotations were measured with PerkinElmer 141 Polarimeter in CH2CI2 solutions [c « 1 ] ,
TLC was performed on plates coated with silica
gel G, Merck, and Kieselgel 230-400 mesh (Merck)
was used for column chromatography.
l'-[4,6-di-0-acetyl-2,3-dideoxy-a-D-erythro-hex-2eno-pyranosyl]-4'-methoxybenzene (4)
T o a solution of 1 (0.272 g, 1 mmole) in dry 1,2dichloroethane (5 ml) anisole (0.5 ml) was added
followed b y two drops of stannic chloride. The
reaction mixture, protected from atmospheric
moisture, was kept at ambient temperature for two
hours. Then methylene chloride (20 ml) was added
and the mixture was washed twice with aqueous
sodium carbonate and with water. After drying the
solvent over MgS04 and evaporation the oily
residue was applied onto silica gel column. Elution
with light petroleum-ethyl acetate 9 : 1 afforded 4
as colorless crystals, 0.227 g, 7 1 % yield, m.p. 101 to
102°, [a]p + 253°, IR K B r: 3000, 1740, 1610, 1520,
1370, 1250, 1220, 1140, 1125, 830, 8 1 0 c m - i ;
i H N M R <5: 2.08, 2.12 2 s, 6 H , 2 x AcO, 3.81 s, 3 H ,
OCH3, 3.80-4.30 m, 3 H , H-5, C H 2 - O A c 5.18 b.s.,
1 H , H - l , 5.42 p.d. 1H, H-4, J45 = 9.0 Hz, J 3 4 =
2.7 Hz, 5.88 s, 2 H , H-2, H-3, 7.13 A B q , 4 H , aromatic.
Found
Calcd
C 63.84
C 63.74
H 6.41,
H 6.29.
Obtained from 2 and anisole as described in
preceding experiment in 6 4 % yield as an oil, b.p.
160 o /0.1 torr [a]p —88.5°, I R m m : 3000, 1745, 1615,
1520, 1375, 1240, 1050, 1030, 830 c m - i ; *H NMR <5:
2.00-2.12 m, 6 H , 2 x AcO, 3.81 s, 3 H , OCH 3 , 4.00
to 4.40 m, 3 H , H-5, CH 2 - O A c , 5.12 and 5.35 2 x
b.s. 2 H , H - l and H-4, 6.05-6.47 m, 2 H , H-2, H-3,
7.13 A B q , 4 H , aromatic.
C 63.89
C 63.74
H 6.28,
H 6.29.
l'-[2,3-dideoxy-DL-pent-2-enopyranos-4-ulosyl]
4'-methoxybenzene (9)
NMR 6:3.82 s, 3 H , OCH 3 ,4.26 s, 2 H , CO-CHa-O,
5.32 b.s., 1H, H - l , 6.26 p.d., 1H, H-3, J u = 2.0Hz,
«723 = 10.5 Hz, 7.11 p.d., 1H, H-2, J 1 2 = 2 . 5 H z ,
7.14 ABq, 4 H , aromatic.
Found
Calcd
-
Obtained in SnCL catalysed reaction of 7 with
excess of anisole as described above in 7 2 % yield.
Colourless oil, b.p. 120°/0.4 torr. I R u i m : 3000, 1695,
1615, 1520, 1250, 1170, 1090, 1030, 830 cm-i,
C 70.57
C 70.57
H 5.84,
H 5.92.
1' - [2,3-dideoxy-DL-pent-2-enopyranos-4-ulosyl]
2',5'-dimethoxybenzene (10)
-
Obtained in 7 7 % yield, oil b.p. 130°/0.1 torr,
IRmm: 3000, 2700, 1695, 1615, 1510, 1210, 1095,
1040, 1020, 815, 740 cm-i, *H N M R d: 3.77 and 3.85
2s, 6H, 2 x OCH3, 4.32 A B q , 2 H , CO-CHa-O, 5.72
b.s., 1H, H - l , 6,18 p.d. 1 H , H-2, Ji 2 = 2 . 5 H z ,
J23 = 10.5 Hz 6.75-7.20 m, 4 H , H-3 + aromatic.
Found
Calcd
C 66.67
C 66.65
H 6.22,
H 6.02.
l-0-Benzoyl-2,3-dideoxy-2-C-[2'-5'-methylfuryl]a-DL-glyceropent-4-ulose (11)
To a solution of 7 (0.218 g, 1 mmole) and 2methylfuran (0.5 ml) in dry 1,2-dichloroethane
(5 ml) anhydrous zinc chloride (0.2 g) was added
and the reaction mixture was stirred 4 h at room
temperature, then diluted with CH2CI2 and filtered
through basic alumina. The colourless oil obtained
after evaporation of the solvents was chromatographed on silica gel column. Elution with light
petroleum-ethyl acetate 9 : 1 gave oily 11 (0.207 g,
6 9 % ) , IRfiim: 2900, 1730, 1460, 1260, 1080, 1060,
1025, 950, 710 c m - 1 , iH N M R <5: 2.26 s, 3 H , CH 3 ,
2.41-2.50 m, 2 H , H-3a, H-3e, 3.70 p.d. I H , H-2,
Ji2 = 4.5 Hz, 4.25 ABq, 2 H , H-5a, H-5e, 5.88 and
6.08 2 m , 2 H , H-3 andH-4,6.63 d, 1H, H - l , 7.30-8.20
m, 5 H , aromatic.
Found
Calcd
l'-[4,6-di-0-acetyl-2,3-dideoxy-a,ß-D-threo-hex-2enopyranosyl]-4'-methoxybenzene (5, 6)
Found
Calcd
XH
C 67.81
C 67.99
H 5.46,
H 5.37.
l-0-benzoyl-4-0-acetyl-2,3-dideoxy-2-C[2'-5'-methylfuryl]-a-DL-erythro-pentose
(14)
11 (0.15 g, 0.5 mmole) was dissolved with stirring
in tetrahydrofuran (5 ml) containing 0.5 ml of water
and treated with excess of sodium borohydride
(0.05 g). After 15 min few drops of acetic acid was
added to the reaction mixture and the solvents were
evaporated under reduced pressure. The reduction
product was taken up into CH2CI2 (20 ml), and
evaporated again. Treatment of the residue with
pyridine-acetic anhydride 1:1 and usual work up
gave 14 (0.146, 8 5 % ) as an oil. IRmm: 2900, 1735,
1455, 1375, 1240, 1080, 1065, 1040, 1020, 780,
700 cm-i. m N M R 6: 2.06 s, 3 H , CH 3 , 2.14 s, 3 H ,
AcO, 2.20-2.65 m, 2 H , H - 3 a , H-3e, 3.24 m, I H ,
H - 2 , H J = 21.3 H z , 3.68 p . d . , I H , H - 5 a , J45a
=
7.3 Hz, Jsa.se = 11.7 Hz, 4.21 p.d., I H , H-5e,
J 4 5 e = 4.2 Hz, «73e5e » 1 . 0 Hz, 5.80-6.20 m, 3 H , H - l ,
H-3, H-4, 7.30-8.15 m, 5 H . aromatic.
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G. Grynkiewicz-A. Zamojski • Electrophilic Substitution of Aromatic Compounds
Found
Calcd
C 66.51
C 66.27
H 6.17,
H 5.85.
Methyl-2,3-dideoxy-2-C-[
a,ß-DL-glycero-pent-4-ulose
Methyl-2,3-dideoxy-2-C-[2'-5'-methylfuryl]a,ß-DL-glyeero-pent-4-ulose
(12)
Obtained from 8 and 2-methylfuran in reaction
catalyzed by ZnCl 2 (65%). An oil, b.p. 100°/1 torr.
IRfiim: 2900, 1730, 1620, 1570, 1130, 1100, 1060,
1020, 960, 780 c m - i ; i H N M R <5: 2.30 s, 3 H , CH 3 ,
2.70-2.91 m, 2 H , H - 3 a , H-3e, 3.25-3.50 m, 1H,
H-2, 3.47 and 3.51 2 s, 3 H , OCH 3 , 3.85-4.28 m, 2 H ,
H-5a, H-5e, 4.92-5.00 m, 1H, H - l , J i 2 m = 2.5 and
Ji2trans — 3.7 Hz. 5.82-6.00 m, 2 H , H-3, H-4.
Found
Calcd
C 62.70
C 62.84
Found
Calcd
,
U ,l\
AcO
1 : R1 = H .
R
2
J
,
-
-
C 65.88
C 66.08
H 6.89,
H 6.83.
u
O
A:R1 =R3=H, R2=OAC, R1=4-CSH1OCH3
=0Ac
2:R1=OAC, R2 = H
4'-methoxybenzene]
(13)
Obtained by stirring 8 with an excess of methoxybenzene in the presence of ZnCl2 suspended in
1,2-dichloroethane. Reaction time at room temperature: ten days. The product isolated in 4 7 %
yield as an oil b.p. 130°/1.5 torr. IRfiim: 2900, 2700,
1725, 1610, 1520, 1245, 1175, 1120, 1100, 1050,
830 c m - i ; i g NMR d: 2.43-3.30 m, 3 H , H-2, H-3e,
H-3a, 3.40, 3.44, 3.79 3s, 6 H , 2 x OCH 3 , 3 . 9 8 ^ . 3 1
m, 2 H , H-5e, H-5a, 4.70-4.78 m, 1H, H - l , Ji 2c i» =
2.7 Hz, Ji2tran8 = 4.7 Hz, 7.02 A B q , 4 H , aromatic.
H 6.83,
H6.71.
-
1027
,
7: R=OCOC6H5
5:R'=OAC, R2=R3=H. R4 =4-C6H4OCHJ
8:R=OCH3
6:R'=OAC. R2=R*=H, R3=4-C6H4OCH3
9:R=4-C6H<OCH3
10:R = 2,5-CSH3(OCH3)2
C)
O
/OR
%
Ar
11:R=C0C6H5.
,
Ö
ACO\
1A:
0
o=
/OCOCSH5
,
0
\
/
C/
Ar=2-(5-methylfuryl)
Z"CL2/
0
/OR
5®
15
—
Z"CL2/
V
O
-O
/OR
®
16
Ar = 2-(5-methylfuryl)
12:R=CH3.
Ar=2-(5-methylfuryl)
13:R=CH3.
Ar = 4-C6H<0CH3
[1] S. Hanessian and A . G. Pernet, Adv. Carbohydr.
Chem. Biochem. 88, 111 (1976).
[2] L . Kalvoda, J. Farkas, and F . Sorm, Tetrahedron
Lett. 1970, 2297.
[3] R . J. Ferier, A d v . Carbohydr. Chem. Biochem.
24, 199 (1969) and the references cited therein.
[4] G. Grynkiewicz, W . Priebe, and A . Zamojski,
Carbohydr. Res. 68, 33 (1979).
[5] K . Heyns, M . T . Lim, and J. I. Park, Tetrahedron
Lett. 1976, 1477; K . Heyns and M. T. Lim, ibid.
1978, 8 9 1 ; R . D . Guthrie and R. W . Irwine,
Abstracts of I X International Symposium on
Carbohydrate Chemistry (IUPAC) London, April
1978, B 12.
[6] R . G. Pearson (ed.): Hard and Soft Acids and
[7]
[8]
[9]
[10]
[11]
Bases. Dowden, Hutchinson and Ross, Stroundsburg, Pa. (1973); W . Priebe and A . Zamojski,
Tetrahedron 36, 287 (1980).
O. Achmatowicz (Jr.) and G. Grynkiewicz,
Carbohydr. Res. 54, 193 (1977).
G. Grynkiewicz, Carbohydr. Res. 80, 53 (1980).
G. Grynkiewicz, J. W . Krajewski, Z. UrbanczykLipkowska, P. Gluzinski, and A . Zamojski,
Polish. J. Chem. 53, 2025 (1979).
R . L. Whistler and M. L. W o l f r o m (eds.): Methods
in Carbohydrate Chemistry, Vol. I I , 405 (1963).
O. Achmatowicz (Jr.), P. Bukowski, B. Szechner,
Z. Zwierzchowska, and A . Zamojski, Tetrahedron
27, 1973 (1971).
Unauthenticated
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