Comparative studies of cathodically-promoted and base-catalyzed michael addition reactions of levoglucosenone

Article abstract of DOI:10.1021/jo961019g

Regioselective Michael addition of nitro and heterocyclic compounds to levoglucosenone, 1, is effectively catalyzed by amines and also by cathodic electrolysis. In comparison to the base-catalyzed reaction, it was found that under electrochemical conditio

Full text of DOI:10.1021/jo961019g

8786
J . Org. Chem. 1996, 61, 8786-8791
Com p a r a tive Stu d ies of Ca th od ica lly-P r om oted a n d
Ba se-Ca ta lyzed Mich a el Ad d ition Rea ction s of Levoglu cosen on e
Alexander V. Samet, Murat E. Niyazymbetov,† and Victor V. Semenov
Zelinsky Institute: US Office: 923 White Clay Terrace, Bear, Delaware 19701;
Moscow Office: Leninsky Prospekt 47, 117913 Moscow, Russia
Andrei L. Laikhter and Dennis H. Evans*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19701
Received May 31, 1996X
Regioselective Michael addition of nitro and heterocyclic compounds to levoglucosenone, 1, is
effectively catalyzed by amines and also by cathodic electrolysis. In comparison to the base-catalyzed
reaction, it was found that under electrochemical conditions the reaction proceeds under milder
conditions and with higher yields. Cathodically-initiated Michael addition of thiols to levoglucose-
none using small currents produces the previously unknown threo addition product in several
instances. The normal erythro isomer, identified as the kinetic product, tends to be formed when
large currents are used. In contrast, slow, low current electrolyses promote equilibration of the
two forms so that erythro can be converted to threo by the retro reaction and readdition. Addition
of 2-naphthalenethiol to (R)-(+)-apoverbenone is also reported.
In tr od u ction
achieved for malonate only by use of Ni(II) complexes as
catalysts.11 It is probable that the suppressed yields were
caused by oligomerization of 1 under the basic conditions
used in the reaction.11 It should be noted that in all cases
only exo-addition was observed to occur forming the
4-axial derivatives, i.e., anti to the 1,6-anhydro bridge
as in compounds 3 below.
The presence of a nitro group in a 4-substitutent of 1
would be interesting owing to the possibility of further
transformation of the nitro group (e.g., reduction to the
amine) as well as the formation of new C-C bonds at its
activated R-carbon. In the literature, only the Michael
addition of 2-nitropropane and nitromethane to 1 have
been reported.10,12 It is interesting to consider the
addition of ethyl nitroacetate and its derivatives to 1,13
which allows the introduction of carbethoxy, nitro, alkyl,
and other functional groups to levoglucosenone. Subse-
quent transformation of these functionalities can be used
for the synthesis of both unnatural amino acids and
heterocycles. In this work we summarize our compara-
tive studies of the Michael addition reactions of different
kinds of organic acids to levoglucosenone under electro-
chemical and purely chemical conditions.
Levoglucosenone (1) is an interesting starting material
because it is chiral and contains an activated double
bond. Moreover, this compound can be obtained from
biomass by pyrolysis of wood wastes.1 An improved
method of pyrolysis of cellulose now allows the prepara-
tion of 1 in higher yield than previously achievable.2
Levoglucosenone has been successfully used as a chiral
starting material for syntheses of a variety of natural and
unnatural compounds such as food toxins,3 alkaloids,4
antibiotics,5 anhydrosugars,6 prostaglandin analogues,7
herbicides,8 etc.
One of the most attractive reactions for modification
of the carbohydrate skeleton of 1 is Michael addition.9-11
By base-catalyzed reaction of 1 with alcohols and thiols,
the corresponding alkoxy and alkylthioderivatives have
been obtained in good yields.1a,9 However, in the case of
the addition of malonate and cyanoacetate, the yields
were moderate (49-54%), and a yield of 70% could be
† Also affiliated with the University of Delaware.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) (a) Shafizadeh, F.; Chin, P. P. S. Carbohydr. Res. 1977, 58, 79-
87. (b) Shafizadeh, F.; Furneaux, R. H.; Stevenson, T. T. Carbohydr.
Res. 1979, 71, 169-171.
It is known that the Michael addition reaction is
effectively promoted by electrogenerated bases14 or by
direct cathodic electrolysis.15 Recently, it was shown that
ethyl nitroacetate and its derivatives electrocatalytically
react under mild conditions with Michael acceptors to
form coupling products in high yield.16a This approach
has been successfully applied for functionalization of 1.
(2) Levoglucosenone is commercially available from the Zelinsky
Institute, Inc.
(3) (a) Isobe, M.; Nishikawa, T.; Pikul, S.; Goto, T. Tetrahedron Lett.
1987, 28, 6485-8. (b) Isobe, M.; Fukuda, Y.;Nishikawa, T.; Chabert,
P.; Kawai, T.; Goto, T. Tetrahedron Lett. 1990, 31, 3327-3330.
(4) Isobe, M.; Fukami, N.; Goto, T. Chem. Lett. 1985, 71-74.
(5) Freskos, J . N.; Swenton, J . S. J . Chem.Soc., Chem. Commun.
1985, 658-659.
(6) (a) Matsumoto, K.; Ebata, T.; Koseki, K.; Kawakami, H.; Mat-
sushita, H. Heterocycles 1991, 32, 2225-2540. (b) Matsumoto, K.;
Ebata, T.; Koseki, K.; Kawakami, H.; Matsushita, H. Bull. Chem. Soc.
J pn. 1991, 64, 2309-2310.
Resu lts a n d Discu ssion
Rea ction of Levoglu cosen on e w ith Nitr o Com -
(7) (a) Tolstikov, G. A.; Valeev, F. A.; Gareev, A. A.; Khalilov, L.
M.; Miftakhov, M. S. Zh. Org. Khim. 1991, 27, 565-570. (b) Tolstikov,
G. A.; Miftakhov, M. S.; Valeev, F. A.; Gareev, A. A. Zh. Org. Khim.
1990, 26, 2461-2462.
p ou n d s.17 The anions of nitro compounds can be formed
(12) Forsyth, A. C.; Paton, R. M.; Watt, I. Tetrahedron Lett. 1989,
30, 993-996.
(8) Blattner, R.; Furneaux, R. H.; Mason, J . M.; Tyler, P. C. Pestic.
Sci. 1991, 31, 419-435.
(13) Laikhter, A. L.; Kislyi, V. P.; Semenov, V. V. Mendeleev
Commun. 1993, 20-21.
(9) (a) Furneaux, R. H.; Gainsford, G. J .; Shafizadeh, F.; Stevenson,
T. T. Carbohydr. Res. 1986, 146, 113-128. (b) Essig, M. G. Carbohydr.
Res. 1986, 156, 225-231.
(14) (a) Monte, W. T.; Baizer, M. M.; Little, R. D. J . Org. Chem.
1983, 48, 803-806. (b) Baizer, M. M.; Chruma, J . L.; White, D. A.
Tetrahedron Lett. 1973, 5209-5212.
(10) Shafizadeh, F.; Ward, D. D.; Pang, D. Carbohydr. Res. 1982,
102, 217-230.
(15) Niyazymbetov, M. E.; Konyushkin, L. D.; Niyazymbetova, Z.
I.; Litvinov, V. P.; Petrosyan, V. A. Isv. Akad. Nauk. SSSR, Ser. Khim.
1991, 260-261.
(11) Shafizadeh, F.; Furneaux, R. H.; Pang, D.; Stevenson, T. T.
Carbohydr. Res. 1982, 100, 303-13.
S0022-3263(96)01019-5 CCC: $12.00 © 1996 American Chemical Society

Michael Addition Reactions of Levoglucosenone
J . Org. Chem., Vol. 61, No. 25, 1996 8787
Sch em e 1
Sch em e 3
the anion reacts rapidly with 1 with the result that the
reaction medium remains essentially neutral, thus cir-
cumventing the base-catalyzed oligomerization of 1.
In an analogous fashion, the coupling products of 1
with ethyl 2-nitropropionate (3b), diethyl 2-nitroglutarate
(3c), 2-nitropropane (3d ), nitrocyclopentane (3e), ethyl
2-nitro-4-pentenoate (3f), and dinitromethane (3g) were
obtained (Scheme 1) in practically quantitative yields
(82-96% isolated).
Sch em e 2
It should be noted that in all cases exclusively exo
addition of the nitro-containing substituent was observed,
giving the erythro stereoisomers shown in Scheme 1.
Electrochemical syntheses are often amenable to mul-
tistep reactions without isolation of intermediate prod-
ucts. In earlier work,16a it was shown that under
electrochemical conditions alkylation of ethyl nitroacetate
and further Michael addition can be carried out in a one-
pot procedure. This approach was used for synthesis of
3f. Electrochemical alkylation of ethyl nitroacetate with
allyl bromide was first carried out to form ethyl 2-nitro-
4-pentenoate (2f). Levoglucosenone was then added, and
the cathodically-promoted Michael reaction resulted in
formation of 3f in moderate yield (Scheme 3).
In contrast to the present electrochemical method, the
reported chemical version10 of the reaction of 2-nitropro-
pane with 1 required heating for 48 h and was ac-
companied by side reactions, the yield of 3d being only
15%. A higher yield (67%) was achieved by using
2-nitropropane as solvent, but the isolation of the product
required column chromatography due to the presence of
byproducts.
In general, the most effective bases for catalyzing
Michael addition to 1 have proven to be nitrogen-
containing bases such as triethylamine, piperidine, or
tetramethylguanidine. For purposes of comparison with
the electrochemical method, we treated 1 with ethyl
nitroacetate at 20-25 °C in acetonitrile in the presence
of a catalytic amount of triethylamine. The exo-deriva-
tive 3a was obtained with an isolated yield of only 38%.
Under the same conditions, the products of condensation
of 1 with ethyl 2-nitropropionate (3b) and diethyl 2-ni-
troglutarate (3c) were obtained with isolated yields of 35
and 37%, respectively. The use of Triton B, piperidine,
or tetramethylguanidine as well as increasing the tem-
perature did not improve the yield of the products.
Only when the reaction was carried out in CHCl3 at
40-50 °C for 48 h were the yields of 3a (75%), 3b (86%),
and 3c (83%) comparable to those obtained by the
electrochemical method.
by direct reduction at the cathode with concomitant
discharge of hydrogen. However, when the nitro com-
pound contains a second electron-withdrawing group, it
has been found16 that production of the anion is ac-
companied by elimination of the nitro group, even in the
case of relatively strong organic acids as, for example,
ethyl nitroacetate16a (pKa(H2O)18a ) 5.75; pKa(DMSO)18b
) 9.2). Thus, the desired anion, necessary for catalytic
addition to 1, is not formed efficiently. This difficulty
was easily overcome when electrogenerated superoxide
was used as an electrogenerated base (EGB) for genera-
tion of the carbanion of nitro compounds.16a
Cathodic electrolysis of ethyl nitroacetate (2a ) in the
presence of an equimolar amount of levoglucosenone in
an air-saturated solution of 0.01 M Bu4NBr in MeCN
produced 3a (Scheme 1) in 85% isolated yield. Only 0.10
F/mol of electricity was consumed, and the reaction was
completed in 1 h at room temperature (see general
catalytic Scheme 2).19 Isolation of the product was very
simple: a solution of the crude product was filtered
through a layer of silica gel, and after evaporation of the
solvent, the analytically pure product was obtained.
The key step of the reaction is the cathodic generation
of EGB, which deprotonates ethyl nitroacetate with
formation of the corresponding carbanion. The use of tet-
raalkylammonium salts as supporting electrolyte results
in a very high reactivity of this carbanion.20 Therefore,
(16) (a) Niyazymbetov, M. E.; Evans, D. H. J . Org. Chem. 1993, 58,
779-783. (b) Ru¨hl, J . C.; Evans, D. H.; Neta, P. J . Electroanal. Chem.
1992, 340, 257-272.
(17) For the preliminary publication see: Laikhter, A. L.; Niyazym-
betov, M. E.; Evans, D. H.; Samet, A. V.; Semenov, V. V. Tetrahedron
Lett. 1993, 34, 4465-4468.
(18) (a) Adolf, H. G.; Kamlet, M. J . J . Am. Chem. Soc. 1966, 88,
4761-4763. (b) Bordwell, F. G. Pure Appl. Chem. 1977, 49, 963-968.
(19) The two reactions in Scheme 2 constitute a chain process by
which a small amount of anion initiates the catalytic addition of RH
to the acceptor. The term F/mol denotes the number of equivalents of
electrical charge per mole of reactant. In the limit of infinitely effective
catalysis, this quantity approaches zero.
Interesting results have been reported for the conden-
sation of 1 with nitromethane. Forsyth et al.12 reported
that the reaction of nitromethane and 1 in the presence
of tetramethylguanidine led to excellent yields of either
a coupling product with two molecules of 1 and one of
nitromethane (3h ) or one with one 1 and two molecules
(20) Niyazymbetov, M. E.; Evans, D. H. J . Chem. Soc., Perkin Trans.
2 1993, 1333-1338.

8788 J . Org. Chem., Vol. 61, No. 25, 1996
Samet et al.
Sch em e 4
Sch em e 5
Sch em e 6
of nitromethane, depending upon the ratio of reactants.
When an equimolar mixture was used, a mixture of the
two products was obtained with yields of 18% and 61%
yields, respectively. Results from the electrochemical
method were more selective. Electrolysis of an equimolar
mixture of nitromethane and 1 gave exclusively 3h
(isolated yield of 92% based on 1 Scheme 4).
It should be noted that stereoselectivity at the carbon
center attached to 1 is low and identical for both the
electrochemical and chemical reactions. According to 1H-
NMR data the ratio of diastereomers for the compound
3a is close to 1:1 (structures not assigned). For other
compounds (3b,c,f) the ratio was 3:4. The same ratio was
obtained when 5-nitro-2-phenacyltetrazole, 2i, was chemi-
cally added to 1 (the yield of 3i was 64%). So, the
stereoselectivity is low both for compounds with an acidic
proton (where epimerization is possible) and those with
much less acidic protons. The situation was different
when addition was accompanied by cyclization. As was
already mentioned, in the case of nitromethane only one
stereoisomer (3h ) is formed. It was found that chemical
addition of the amide O2NCH2CONH2 (2j) to 1 also is
accompanied by cyclization and formation of only one
stereoisomer (3j) in 62% yield (Scheme 4).
R ea ct ion of Levoglu cosen on e w it h Nit r ogen -
Con tain in g Heter ocycles. Nitrogen-containing 5-mem-
bered heterocyclic compounds substituted on nitrogen by
a carbohydrate moiety could be interesting as biologically
active compounds due to a structural analogy with
nucleosides. These kinds of compounds can be easily
synthesized by Michael addition of NH-azoles to the
activated double bond of LG in the presence of bases. It
was found that NH-heterocycles that are relatively strong
acids react with 1 smoothly in 24-48 h at room temper-
ature in the presence of triethylamine. The yields of
isolated products were 67-81% (see Scheme 5) except in
the case of the reaction of 1 with 3-nitro-1,2,4-triazole
(4e) where only 52% was obtained. This example was
selected for comparison with the electrochemical version
of the reaction. Cathodic electrolysis of a mixture of 1
and 4e resulted in formation of addition product 5e in
good isolated yield (85%). In this reaction, electrogen-
erated superoxide ion was used as an EGB.
Less acidic heterocycles require stronger base and
higher temperature. Thus, for 4h -j, piperidine was used
as a base and the reaction was carried out at 40-50 °C
for 24-48 h. It was found that the reaction is ac-
companied by addition of residual water to 5h -j, either
during the electrolysis or during workup, forming gem-
diols 6h -j (Scheme 6). It has been shown previously that
the carbonyl group of compounds with a 1,6-anhydro-
hexos-2-ulose structure (such as 5) can be easily hy-
drated, giving an equilibrium mixture of hydrate and
starting carbonyl compound.1b
Addition of phthalimide (4k ) to 1 (MeCN/EtOH 3:1;
room temperature) in the presence of triethylamine also
proceeds with formation of product 5k in relatively good
yield. But once again the electrochemical version of that
reaction gave a significantly higher yield, 95% (Scheme
7). Succinimide (4l) and saccharin (4m ) can also be
added to 1 in the presence of triethylamine with forma-
tion of 5l and 5m (74% and 66% yields, respectively).
Interesting results were obtained with pyrazole under
electrochemical conditions. The chemical addition of that
compound to 1 in MeCN in the presence of piperidine
resulted in formation of 5i (33%) and the hydration
product 6i (32%) (Scheme 6). By contrast, the cathodi-
cally-promoted addition produced a selective self-coupling
of 1, giving dimer 7 in quantitative yield (Scheme 8). This
product was previously found in low yield (8%) after
heating 1 in aqueous triethylamine.11
The behavior of the diols 6 was dependent on structure.
6h was formed in only trace amounts but was detectable
by 13C-NMR. Hydration of 5i was more extensive, and
substantial amounts of 6i were detected during attempts

Michael Addition Reactions of Levoglucosenone
J . Org. Chem., Vol. 61, No. 25, 1996 8789
Sch em e 7
with such nucleophiles; viz., the nitrogen most distant
from an electron-withdrawing substituent will attack the
electrophile. Determination of isomeric identity was
3
based on NMR results. For the compounds 5a ,b,d ,e, J
coupling between the nonsubstituted carbon of the het-
rocyclic group and H4 of the levoglucosenone moity was
seen in the 13C-NMR spectra. For the other isomer this
coupling would be observed for the substituted carbon
atom, C5. For the nitrotetrazole derivative 5g, the
chemical shift of the carbon atom in the tetrazole addend
was observed at 167.8 ppm, which is characteristic for
2-N-substituted tetrazoles.21 In the case of 5f, the signals
of the two carbons of the heterocycle as well as signals
for the ester groups are identical, indicating 2-N substi-
tution.
Only in reaction of 3-methylpyrazole, 4h , were both
isomers of the adduct 5h observed. They are designated
1,3 and 1,5 indicating attachment at 1-N with methyl in
the 3-position and attachment at 1-N with methyl in the
5-position respectively. For the 1,3-isomer, the 13C-NMR
spectrum contains signals at 129.29 ppm (C5) and 148.53
ppm (C3) that are characteristic for a 1,3-substituted
pyrazole. For the 1,5-isomer, the signals are at 138.17
ppm (C5) and 138.36 ppm (C3). The signals for the CH3
group at 13.53 (1,3-isomer) and 10.78 ppm (1,5-isomer)
are also characteristic for 1,3- and 1,5-substituted pyra-
zoles.24 Moreover, there is additional coupling for one of
the isomers on nonsubstituted carbon atom C5 (see
above). According to the NMR data the ratio of 1,3- and
1,5-isomers is 6:1 (see Scheme 6).
Sch em e 8
Cath odically-P r om oted Addition of Th iols to Levo-
glu cosen on e. New Ster eoisom er s of Alk yl- a n d
Ar ylth io Der iva tives of Levoglu cosen on e.26 As was
shown above, a variety of derivatives of levoglucosenone
can be obtained in high yield by the cathodic generation
(via electrogenerated base) of anions of nitro and het-
erocyclic compounds that subsequently undergo Michael
addition to 1. The nitro and heterocyclic derivatives that
were obtained arose from attack of the nitronate or
heterocyclic anion at the less hindered exo face to produce
the erythro isomers (i.e., the added group occupied an
axial position in the ketone-containing six-member ring,
cf. Scheme 1). In fact, this is the only isomer that has
been reported for the chemical version of the Michael
addition of different CH-acids,10,12 alcohols,9a and thiols9b
to levoglucosenone.
There is apparently no energetic reason that the threo
isomers should not be obtained. This notion was sup-
ported by AM1 calculations that showed, for a variety of
addends, that the two isomers have very similar energies
with calculated heats of formation differing by <3 kcal/
mol. We now report that both erythro and threo isomers
can be selectively prepared by addition of thiols to
levoglucosenone under cathodic electrolysis conditions.
Electrolysis of thiols at a platinum cathode in the
presence of an equimolar amount of levoglucosenone was
conducted in a divided cell in a solution of 0.002 M Bu4-
NBr in MeCN. Only a catalytic amount of electricity
(0.02-0.12 F/mol) was required to give the addition
products in almost quantitative yields (Table 1). The
cathode compartment was purged with nitrogen to avoid
air oxidation of thiolate anions. After removal of MeCN,
the electrolysis products were isolated by column chro-
matography (silica gel, eluent: hexane/ethyl acetate).
to purify 5i. Likewise, we were unable to separate 6j
from 5j, and the yield is based on NMR analysis. In the
case of the nitropyrazole adduct 5c, it was found that
some hydrate 6c was formed upon storing 5c in acetone
solution for a long time (90 days). The 13C-NMR spectra
of diols 6 feature a signal for the gem-diol carbon at ∼90
ppm and absence of the characteristic signal for the
carbonyl carbon at ∼195-200 ppm. In the IR spectra, a
broad band at 3300-3500 cm-1 replaces the character-
istic carbonyl absorption. Apparently, the diols 6 are
formed by reaction1b,21 of the carbonyl group of 5 with
residual water present in the solvent, silica gel, air, etc.
As with the nitro derivatives 3, the heterocyclic deriva-
tives 5 and 6 are formed by attack of the heterocyclic
anion at the less hindered exo face of 1 to produce the
erythro isomers. For all compounds, 1H-NMR spectra
showed a coupling constant for H3a and H4 of about 7.5-
8.0 Hz, a value characteristic of erythro isomers.
In cases where more than one nitrogen is present in
the nucleophile, the nitrogen that attaches to 1 is in
accordance with the known22-25 reactions of electrophiles
(21) Pecka, J .; Stanek, J .; Cerny, M. Collect. Czech. Chem. Commun.
1974, 39, 1192-1209.
(22) Semenov, V. V.; Ugrak, B. I.; Shevelev, S. A.; Kanishchev, M.
I.; Baryshnikov, A. T.; Fainzil’berg, A. A. Isv. Akad. Nauk. SSSR,. Ser.
Khim. 1990, 1827-1837.
(23) Terpigorev, A. N.; Shcherbinin, M. B.; Bazanov, A. G.; Tselinsky,
I. V. Zh. Organ. Khim. 1982, 18, 463.
(24) Einberg, F. J . Org. Chem. 1970, 35, 3978-3980.
(25) Elguero, J .; Marzin, C.; Roberts, J . D. J . Org. Chem. 1974, 39,
357-363.
(26) For the preliminary publication see: Niyazymbetov, M. E.;
Laikhter, A. L.; Semenov,V. V.; Evans, D. H. Tetrahedron Lett. 1994,
35, 3037-3040.

8790 J . Org. Chem., Vol. 61, No. 25, 1996
Samet et al.
Ta ble 1. Electr och em ica l Mich a el Ad d ition of Th iols to
Sch em e 10
Cyclic En on es (P t-Ca th od e; Bu 4NBr -MeCN)
charge, time,
enone F/mol
yield, %
(isol)
thiol
h
product
n-C8H17SH
n-C8H17SH
n-C10H21SH
n-C10H21SH
2-naphthalenethiol
p-ClC6H4SH
p-ClC6H4SH
p-MeOC6H4SH
p-MeOC6H4SH
p-MeOC6H4SH
p-O2NC6H4SH
2-naphthalenethiol
1
1
1
1
1
1
1
1
1
0.05
0.10
0.02
0.10
0.04
0.05
0.11
0.05
0.10
0.03
0.05
0.04
1
4
0.5
6
0.5
1
5
1
6
1
8a
9a
8b
9b
86
86
93
82
8c
95
threo isomer was detected in the crude product, but
attempted isomerization of 8c to 9c was not successful.
Fast, high current electrolysis of the p-chloro- and
p-methoxybenzenethiols produces mainly the expected
erythro isomers 8d ,e, but under slow electrolysis condi-
tions 9d and 9e are formed in larger amounts, threo/
erythro being about 1.5 for the former and 3 for the lat-
ter. Electrolytic equilibration was achieved by elec-
trolysis of pure isolated threo (9d ) or erythro (8d ) isomers
of the p-chlorobenzenethiol derivative. The resulting
threo/erythro (about 1.5; the same ratio was found start-
ing with either isomer) was identical to that obtained
above by addition at low current. So, in these two cases
it appears that the two isomers have almost identical free
energies.
8d ; 9d
8d ; 9d
8e; 9e
8e; 9e
8e
63; 29
36; 54
70; 21
23; 68
93a
1
1
10
14 days 9f
11
60
95
1
a
Undivided electrolysis: Pt-cathode and Mg-anode.
Sch em e 9
It should be noted that when electrolysis of p-meth-
oxybenzenethiol was carried out in an undivided elec-
trolysis cell with a sacrificial Mg anode the erythro-isomer
was formed exclusively. We suggest that the nucleophilic
reactivity of the thiolate anions was decreased by Mg2+
ions20 generated at the anode. Thus, only the kinetic
product (erythro) was formed and there was no op-
portunity for equilibration to occur by retro Michael
addition.
The structures of new threo-isomer of the p-chloroben-
zenethiol derivative of levoglucosenone as well as the
erythro-isomer of the 3,4-dinitropyrazole adduct were
confirmed by X-ray crystallography.28
Addition of p-nitrobenzenethiol proceeded very slowly
and only after 2 weeks in carefully purged solution was
a moderate yield of threo isomer 9f obtained. The slower
reaction is consistent with the fact that this thiol is a
weaker nucleophile. The erythro isomer has not yet been
detected.
For comparison, 2-naphthalenethiol was added under
cathodic electrolysis conditions to (R)-(+)-apoverbenone
(10) for which conjugative 1,4-addition trans to the
geminal-dimethyl-bearing bridge has been reported.29
Only one isomer (11) was isolated (Scheme 10), and
isomerization was not observed apparently because the
retro Michael reaction does not occur under the electroly-
sis conditions or because 11 is the thermodynamically
more stable form. The structure of 11 was also confirmed
by X-ray crystallography.28
The key step of the reaction is the cathodic generation
of thiolate anions by direct cleavage of the S-H bond with
the formation of hydrogen. Because thiolate anions with
tetraalkylammonium cations as counterions are such
strong nucleophiles,20 the addition proceeds rapidly and
in high yield.
When n-octanethiol or n-decanethiol was reduced in
the presence of 1 at normal current densities (ca. 0.2-
0.3 mA/cm2; 0.5-1 h), the erythro isomers, 8a ,b, were
obtained in high yield. However, when the electrolysis
was performed at 0.01-0.02 mA/cm2 for a longer period
of time (4-6 h), 90% (isolated yield) of the products found
in the catholyte were the threo isomers 9a ,b. Slow
electrolysis at low current density appears to be the key
to obtaining the threo isomer. In fact, it was found that
the isolated and purified erythro isomers 8a ,b could be
converted to 9a ,b in excellent yield simply by subjecting
a solution of 8a ,b to these same low current electrolysis
conditions.
We propose that in these two cases the threo isomer is
the thermodynamically favored product that is formed
when the solution is maintained for a sufficient time
under basic conditions where the retroaddition reaction27
can occur. Multiple separation and readdition of the
thiolate will eventually allow thermodynamics to prevail
(Scheme 9).
Obviously, the stereochemistry of the addition is af-
fected by the size of the incoming group. For example,
addition of the more voluminous 2-naphthalenethiol
produced the erythro isomer 8c in >90% yield. Some
In summary, a wide variety of derivatives of levoglu-
cosenone have been synthesized by electrochemically
promoted Michael additions as well as by purely chemical
base catalysis. The electrochemical reaction proceeds
under very mild conditions without using any base and
in most cases gives superior yields. These studies
illustrate the suitability of the electrochemical method
for functionalization of 1. We are presently investigating
(28) Crystallography Laboratory of the University of Delaware.
Stereoisomeric identity was established for 3e, 5b, 9d and 11. The
author has deposited atomic coordinates for these structures with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(29) Tius, M.; Kannangara, G. S. K. J . Org. Chem. 1990, 55, 5711-
5714.
(27) (a) Abramovitch, R. A.; Rogic, M. M.; Singer, S. S.; Venkateswa-
ran, N. J . Org. Chem. 1972, 37, 3577-3584. (b) Abramovitch, R. A.;
Singer, S. S.; Rogic, M. M.; Struble, D. L. J . Org. Chem. 1975, 40, 34-
41.

Michael Addition Reactions of Levoglucosenone
J . Org. Chem., Vol. 61, No. 25, 1996 8791
and 5a -e,g,j-m were crystals or crystallizing oils. All
heterocyclic derivatives of levoglucosenone except 5f can be
recrystallized from MeCN.
the addition to levoglucosenone of other organic sub-
stances containing activated element-hydrogen bonds.
6c. Compound 5c was dissolved in acetone and left in an
NMR tube for 3 months. According to the NMR spectra, 6c
was formed. The ratio of 5c to 6c was 3:2.
6i. A brown oil was obtained after reaction that according
to the NMR data is mostly 5i with some impurities. After
column chromatography, a yellow oil was obtained that
solidified and according to the NMR spectrum was a 1:1
mixture of 5i and 6i.
5j/6j. A white precipitate separated during the reaction that
according to NMR and IR data was a 3:1 mixture of 5j and 6j.
The product of the reaction of 1 with 4h was purified by
chromatography. A small amount of pure 1-N-addition isomer
was isolated.
The assignment of the 4-axial (erythro) structure to the
derivatives is based on comparison of 1H-NMR spectra (shifts
and coupling constants for H4 and H5) with analogous com-
pounds8,9,11 as well as by comparison of physicochemical data
for 3d , 3h , 7, and 8b, which have been previously reported.8,9,11
Selected NMR data (see the Supporting Information for
remainder): 1H and 13C NMR (compounds 3a -c,f are mixtures
of diastereomers), ppm/TMS, CDCl3, for 3a -g, 8, 9, 11; DMSO-
d6 for 5i,j, 6i,j and acetone-d6 for all others.
er yth r o-Ad d u ct of eth yl n itr oa ceta te a n d levoglu cose-
n on e, 3a . 1H: 1.26t, 1.27t (3H, J ) 5.5 Hz); 2.25d, 2.30d (1H,
J ) 17 Hz); 2.84dd, 2.91dd (1H, J ) 17, 4 Hz); 3.13dd, 3.15dd
(1H, J ) 6, 4 Hz); 4.03dd (1H, J ) 8, 5 Hz); 4.10d (1H, J ) 8
Hz); 4.23q, 4.29q (2H, J ) 5.5 Hz); 4.54d, 4.88d (1H, J ) 5
Hz); 5.07s, 5.08s (1H Hz); 5.27d, 5.31d (1H, J ) 6 Hz). 13C:
13.73, 32.77, 33.50, 41.33, 41.43, 63.79, 67.68, 67.95, 73.15,
73.24, 87.88, 88.56,101.40,163.01, 163.22, 196.34, 196.66.
Anal. Calcd for C10H13NO7: C, 46.34; H, 5.05; N, 5.40.
Found: C, 46.67; H, 5.08; N, 5.26.
Exp er im en ta l Section
P r ep a r a tion of Levoglu cosen on e. Cotton cellulose con-
taining ∼2% phosphoric acid was pyrolyzed in 300-g batches
in an evacuable metal reaction vessel. Before addition of the
phosphoric acid, the cellulose was treated with hot 1% HCl
for 2.5 h in order to remove amorphous parts of the macro-
molecule, followed by washing with water and drying. The
pyrolysis was carried out under vacuum (4 mmHg) at 350-
400 °C for a period of 2-3 h, which was sufficient to complete
the evolution of the pyrolysis gases. The tarry products were
collected in a cooled condenser (-20 °C). Further isolation and
purification of the product were carried out according to the
procedure described in ref 1b. The yield of levoglucosenone
after distillation was 5-8% (2% in ref 1b).
Rea gen ts. Acetonitrile and chloroform were from Fisher.
Triethylamine, piperidine, tetraethylammonium bromide, ni-
trocyclopentane, 2-nitropropane, all thiols, (R)-(-)-carvone,
phthalimide, succinimide, and saccharin were obtained from
Aldrich and were used as received. Ethyl nitroacetate (2a ),
ethyl 2-nitropropionate (2b), diethyl 2-nitroglutarate (2c), and
the amide of nitroacetic acid (2j) were obtained from the
Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, Moscow. Dinitromethane30 (2g), 5-nitro-2-phena-
cyltetrazole22 (2i), ethyl 2-nitro-4-pentenoate16a (2f), the
nitropyrazoles31a,b 4a ,c,d ,32 nitrotetrazole31c (4g), 3-nitro-1,2,4-
triazole32a (4e), 4,5-bis(methoxycarbonyl)-1,2,3-triazole32b (4f),
3,4-dinitropyrazole32c (4b), and (R)-(+)-apoverbenone33 were
prepared as described in the literature.
Sta n d a r d P r oced u r e. Electr olysis w ith EGB for Ad -
d ition of Nitr o Com p ou n d s. The electrolysis was carried
out in a divided cell under galvanostatic conditions at a current
density of 0.5-2 mA/cm2 with vigorous stirring at room
temperature. A platinum mesh cathode and platinum wire
anode were used. Ten mL of 0.05-0.1 M Bu4NBr in absolute
MeCN containing 0.25 g of 1 (0.002 M) and an equimolar
amount of nitroalkane was used as catholyte. The cathode
compartment was air-saturated. After passing 0.07-0.1 F/mol,
the electrolysis was terminated. The solvent was evaporated,
and a solution of the residue in a mixture of ethyl acetate and
hexane (1:3) was filtered through a 2-3 cm layer of silica gel.
After evaporation of the solvent, the analytically pure sub-
stances were obtained.
St a n d a r d P r oced u r e. E lect r olysis for Ad d it ion of
Th iols. The procedure was the same as above except that the
cathode compartment was purged with nitrogen to remove
dissolved oxygen. Bu4NBr (0.002 M) was used, and the current
densities were ca. 0.2-0.3 mA/cm2 for rapid electrolysis (0.5-1
h) and 0.01-0.02 mA/cm2 for slow electrolysis (4-6 h).
Sta n d a r d P r oced u r e. Ba se-Ca ta lyzed Ad d ition of Ni-
tr o Com p ou n d s a n d Heter ocycles. A solution of 1 (5 mmol
in 5 mL) in MeCN was added dropwise for 40 min to the
preheated (40-50 °C) solution of 2a -c,i,j or 4a -m in 3 mL
of CHCl3 (for 2a -c) or MeCN (for 2i,j and 4a -m ) containing
EtOH (25% vol.; only for 4k ) and 0.5 mmol of Et3N (for 2a -
c,i,j and 4a -g,k -m ) or piperidine (for 4h -j). The reaction
was continued for 2 days at the same temperature (for 4h -j)
or room temperature followed by removal of solvent. Com-
pounds 3a -c,i and 5f were obtained as yellow oils while 3j
5a . 1H: 2.91dm (1H; J ) 17.8 Hz); 3.45dd (1H; J ) 17.8,
7.8 Hz); 4.08dd (1H; J ) 5.6, 8.3 Hz); 4.43dd (1H; J ) 8.3; 1.0
Hz); 5.09bd (1H; J ) 5.6 Hz); 5.19s (1H Hz); 5.33d (1H; J )
7.8 Hz); 7.03d (1H; J ) 2.6 Hz); 7.98d (1H; J ) 2.6 Hz). 13C:
36.47, 63.38, 66.84, 77.41, 102.40, 103.84, 132.88, 156.69,
197.45. Anal. Calcd for C9H9N3O5: C, 45.19; H, 3.79; N, 17.57.
Found: C, 45.22; H, 3.90; N, 17.74.
6c (not isolated; small amount detected on storage of 5c).
1H: 2.26dm (1H; J ) 15.6 Hz); 2.55dd (1H; J ) 15.6, 7.4 Hz);
3.89dd (1H; J ) 5.5, 8.0 Hz); 4.11dd (1H; J ) 8.0, 1.1 Hz);
4.75d (1H; J ) 7.4 Hz); 4.79bd (1H; J ) 5.5 Hz); 5.10s (1H);
5.95bs (1H); 6.20bs (1H); 8.09s (1H); 9.17s (1H). 13C: 35.07,
60.96, 66.45, 75.69, 90.93, 104.63, 131.31, 135.31, 138.02.
9a . 1H: 0.88t (3H); 1.15-1.65m (12H); 2.35dd (1H; J ) 16.2,
8.3 Hz); 2.57td (2H); 2.67dd (1H; J ) 16.2, 6.4 Hz); 3.36m (1H);
3.87dd (1H; J ) 8.0, 5.4 Hz); 4.30d (1H; J ) 8 Hz); 4.58bs (1H);
5.14s (1H). Anal. Calcd for C14H24O3S: C, 61.78; H, 8.82; S,
11.78. Found: C, 61.34; H, 8.40; S, 12.17.
11. 1H: 0.87s (3H); 1.31s (3H); 1.90d (1H; J ) 11.0 Hz);
2.31bt (1H; J ) 4.7 Hz); 2.3-2.7m (3H); 2.84dd (1H; J ) 19.0,
8.1 Hz); 3.88t (1H; J ) 8.1 Hz); 7.4-7.9 m (7H). Anal. Calcd
for C19H20OS: C, 77.05; H, 6.75; S, 10.82. Found: C, 77.18;
H, 6.80; S, 10.09.
Ack n ow led gm en t. This research was supported by
the National Science Foundation (Grant CHE9322773)
and the CAST Program, National Research Council. We
gratefully acknowledge X-ray crystallographic results
from Professor Arnold L. Rheingold of the University
of Delaware.
(30) Laikhter, A. L.; Cherkasova, T. I.; Mel’nikova, L. G.; Ugrak, B.
I.; Fainzil’berg, A. A.; Semenov, V. V. Izv. Akad. Nauk SSSR, Ser.
Khim. 1991, 1849-1855.
Su p p or tin g In for m a tion Ava ila ble: ORTEP representa-
tions and structure determination summaries for 5b, 9d , and
11 and NMR data and elemental analyses for 3b-j, 5b-m ,
6i,j, 8a -e, and 9b-f (16 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(31) (a) J anssen, J . W. A. M.; Habraken, C. L. J . Org. Chem. 1971,
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N. I. Khim. Geterotsikl.. Soedin. 1970, 259-264. (b) Woerner, F. P.;
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(33) Grimshaw, J .; Grimshaw, J . T.; J uneja, H. R. J . Chem. Soc.,
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J O961019G