A survey on the reactivity of phenyliodonium ylide of 2-hydroxy-1,4- naphthoquinone with amino compounds

Article abstract of DOI:10.3390/10010226

The phenyliodonium ylide of 2-hydroxy-1,4-naphthoquinone reacts with aminoesters, ureas, aminoalcohols and aminophenols in refluxing dichloromethane to afford good yields of indanedione 2-carboxamido compounds, that in solution exist in an enol-amide form. The same reactants in a copper-catalyzed reaction afford mainly the corresponding N-arylo compounds. Arylhydrazines are mainly oxidized by the ylide and arylation occurs only in a low yield.

Full text of DOI:10.3390/10010226

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Molecules 2005, 10, 226-237
molecules
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A Survey on the Reactivity of Phenyliodonium Ylide of 2-
Hydroxy-1,4-Naphthoquinone with Amino Compounds
Konstantina Spagou, Elizabeth Malamidou-Xenikaki and Spyros Spyroudis*
Laboratory of Organic Chemistry, Chemistry Department, University of Thessaloniki, Thessaloniki
54124, Greece. Tel.: (+30) 2310-997833, Fax: (+30) 2310-997679
*Author to whom correspondence should be addressed; e-mail sspyr@chem.auth.gr
Received: 1 July 2004 / Accepted: 13 July 2004 / Published: 31 January 2005
Abstract: The phenyliodonium ylide of 2-hydroxy-1,4-naphthoquinone reacts with
aminoesters, ureas, aminoalcohols and aminophenols in refluxing dichloromethane to
afford good yields of indanedione 2-carboxamido compounds, that in solution exist in an
enol-amide form. The same reactants in a copper-catalyzed reaction afford mainly the
corresponding N-arylo compounds. Arylhydrazines are mainly oxidized by the ylide and
arylation occurs only in a low yield.
Keywords: Phenyliodonium ylides, 2-hydroxy-1,4-naphthoquinone, aminoesters, ureas.
Introduction
Quinones bearing hydroxy groups on the quinone ring represent an interesting class within the
quinone family. A great variety of these hydroxyquinones are found in nature [1] and almost all of
them exhibit some kind of biological activity. Synthesis and reaction patterns of hydroxyquinones
have been reviewed [2].
One of the most interesting properties of hydroxyquinones is the easy formation of aryliodonium
ylides upon reaction with bis(acetoxy)iodoarenes [2]. These ylides (better considered as 1,4-
zwitterionic compounds) are labile molecules which have found interesting applications in synthesis
[3]. Recently we reported the reaction of aryliodonium ylides of 2-hydroxy-1,4-naphthoquinone (1)
with amines [4]. In refluxing dichloromethane or under Pd(OAc)2 catalysis at room temperature a
ring contraction occurs and indanedione amides, stabilized in an unusual enol-amide form 2, are
isolated in good yields. In contrast the copper-catalyzed reaction affords arylated amines 3 and

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3-iodo-4-hydroxy-1,2-naphthoquinone (4), a rare example of an hydroxyquinone in o-tautomeric
form (Scheme 1).
Scheme 1
H
O
O
C
N
R
O
O
∆
H
O
O
or Pd(OAc)2 cat
2
RNH2
O
Cu2+(cat)
IAr
O
I
RNHAr
1
3
4
OH
The thermal reaction proceeds through Cquin- I bond fission, Wolff-rearrangement of the
resulting carbene to the corresponding dioxo ketene and reaction of the latter with the amino group.
As for the Cu2+-catalyzed reaction we proposed [4] a reaction pathway involving the complexation
of copper with 2-hydroxy-1,4-naphthoquinone (lawsone), formation of an intermediate iodane in an
o-quinonic form and degradation of the latter to arylated amine and iodoquinone 4. These findings
prompted us to extend our studies on the reactivity of ylide 1 with other classes of amino compounds
and we wish to report our results here.
Results and Discussion
Both thermal and Cu2+-catalyzed reactions of 1 with different aminoesters were tried first,
considering the importance of the aminoester moiety.
In refluxing CH2Cl2 equimolecular quantities of 1 and aromatic aminoesters, such as methyl
anthranilinate (5a) and ethyl p-aminobenzoate (5b), afforded high yields of the corresponding
carboxamide esters 6a,b (Scheme 2).
Scheme 2
H
O
R
O
∆
R
1
H2N
C
N
H
O
5a,b
a: R = o-COOMe, b: R = p-COOEt
6a 85%
6b 92%

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Carboxamides 6 were isolated by simple filtration and all spectroscopic evidence is consistent
with the enol-amide form presented in the scheme, a form which is stabilized by the two hydrogen
bonds.
In contrast the Cu2+-catalyzed reaction of ylide 1 with aminoesters 5 afforded, aside from the
expected arylation products 7 and 3-iodo-4-hydroxy-1,2-naphthoquinone (4), the iodo ether 9 and
the hydroxy amino-quinonic compounds 8. Ether 9 is the “normal” phenyl migration from iodine to
oxygen product [4] and 8 is the result of direct attack of the amino group to carbon-3 of the quinonic
ring with the simultaneous reductive elimination of iodobenzene (Scheme 3).
Scheme 3
O
O
OH
NH
OPh
I
R
Cu2+(cat)
1
5a,b
PhHN
R
4
O
O
7a 11%
7b 21%
8a 32%
8b 18%
4 16%
4 21%
9 20%
9 8%
It must be noted that compounds of type 8 were not isolated from the reaction of 1 with amines
and this difference in reactivity, as well as low yields of products 7, in our case can be explained by
the weaker nucleophilicity of the amino group. The lower yield of 7a, compared to 7b, could be
attributed to steric hindrance of the former.
The reaction of 1 with ethyl glycinate (10) followed the same reaction pathway affording the
enol-amide derivative 11, crystallized with one molecule of water (thermally) and the phenyl
aminoester 12, as well as iodoquinone 4, (catalytically) (Scheme 4).
Scheme 4
H
O
O
H2O
C
N
CH2COOCH2CH3
H
O
∆
11 48%
NH2CH2COOCH2CH3
1
Cu2+(cat)
10
PhNHCH2COOCH2CH3
4 40%
12 40%
When the same reactions were repeated using the aminoacid 13, instead of its ester, the results
were not satisfactory. Although spectroscopic evidence indicates the formation of 14 (Scheme 5), it
is very difficult to separate it from the considerable amount of unreacted amino acid 13. This was
achieved by repeated washings of the product with water but in this case hydrated 14 was obtained
with simultaneous partial hydrolysis of the product. Moreover, the product exists in solution in

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equilibrium with some other enolic form(s), perhaps due to its treatment with water. Nevertheless,
1
the H-NMR spectrum, characteristic 13C-NMR peaks (190.4 for C=O of the cyclopentane ring,
171.3 for the enolic carbon, 168.7 for the C=O of the acid, 97.5 for the ethylenic carbon of the ring)
and a molecular peak at 247 all indicate the formation of 14.
Scheme 5
H
O
O
C
H2O
∆
1
NH2CH2COOH
N
CH2COOH
13
H
O
14 37%
The corresponding Cu2+-catalyzed reaction did not proceed at all, probably due to the known [5]
chelation of copper ions with aminoacids, which leaves no available copper for complexation with
the hydroxyquinone moiety.
Finally the thermal reaction of 1 with the methyl 3-aminocrotonate (15) afforded the enol-amide
16 in low yield. The Cu2+-catalyzed reaction led to a complex mixture of products, difficult to
separate and identify, although the isolation of iodoquinone 4 in 37% yield indicates the transfer of
phenyl group to the enamino ester, analogously to the above reported reactions (Scheme 6).
Scheme 6
H
O
COOCH3
O
C
N
CH3
H
O
∆
H3C
H2N
1
16 22%
COOCH3
Cu2+(cat)
15
unidentified products
4 37%
An interesting issue to address was the reactivity of the amino group in the presence of a
hydroxy group in the molecule. For this reason the reactions of ylide 1 with an amino alcohol and an
amino phenol were investigated.
Whereas the thermal reaction of 1 with 3-amino-propanol (17) afforded the expected enol-amide
18 (crystallized with one molecule of water) in a good yield, from the corresponding Cu2+-catalyzed
reaction only 5% of phenylamino-propanol 19 was isolated (Scheme 7). This low yield can again be
attributed to a possible formation of a complex between 17 and copper ions.
It is also possible that the enol-amide 18 exists in solution (in CDCl3-DMSO-d6) in equilibrium
with other enolic forms (possibly with the participation of the free hydroxy group in hydrogen
1
bonds) as indicated by the broad signals in the H-NMR spectrum and an excess of small peaks in