Palladium-catalyzed allylation of 2-hydroxy-1,4-naphthoquinone: Application to the preparation of lapachol

Article abstract of DOI:10.1055/s-2007-967947

The Pd(PPh₃)₄-catalyzed reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with allyl alcohols and allyl esters offers an easy access to 3-allyl-2-hydroxy-1,4-naphthoquinones, compounds with interesting biological activity. The reaction finds application in the preparation of lapachol. Other 2-hydroxy-1,4-benzoquinones give allylation products in low yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967947

LETTER
427
Palladium-Catalyzed Allylation of 2-Hydroxy-1,4-naphthoquinone:
Application to the Preparation of Lapachol
P
alladium-Catalyz
e
e
d
A
llylatio
o
n of 2-Hydr
o
r
xy-1,4-
g
naphthoquino
i
ne a Kazantzi, Elizabeth Malamidou-Xenikaki, Spyros Spyroudis*
Laboratory of Organic Chemistry, Chemistry Department, University of Thessaloniki, Thessaloniki 54124, Greece
Fax +30(2310)997679; E-mail: sspyr@chem.auth.gr
Received 3 November 2006
O
Abstract: The Pd(PPh3)4-catalyzed reaction of 2-hydroxy-1,4-
OH
naphthoquinone (lawsone) with allyl alcohols and allyl esters offers
an easy access to 3-allyl-2-hydroxy-1,4-naphthoquinones, com-
pounds with interesting biological activity. The reaction finds appli-
cation in the preparation of lapachol. Other 2-hydroxy-1,4-
benzoquinones give allylation products in low yields.
O
1
O
O
OH
R
Keywords: allylation, lawsone, palladium-catalyzed, lapachol
PhI(OAc)2
O
O
Naturally occurring quinones constitute an important
group of compounds, as the majority of them exhibit some
kind of biological activity.1 This activity becomes most
intense and interesting in the case of a great variety of
naturally occurring hydroxyquinones 1, compounds with
the hydroxyl in the quinone ring. For this reason isolation,
structure elucidation and synthesis of hydroxyquinones
has drawn a lot of attention1 and their chemistry has been
reviewed recently.2
2
O
I-Ph
3
Scheme 1 Routes to 3-substituted-2-hydroxy-1,4-quinones
hydroxyquinones are obtained from the Suzuki-type
coupling of the corresponding ylides with aryl or alkenyl-
boronic acids.6
Biologically active hydroxyquinones vary in structure
complexity but in many cases 3-substituted hydroxy-
quinones 2 exhibit a broad spectrum of such activities.
The carbon substituent R can be an alkyl, aryl, alkenyl or
allyl group and most often has a simple structure. This
explains the fact that C–C bond-forming reactions of
hydroxyquinones leading to substituted derivatives 2 have
become of interest. This functionalization can be achieved
either directly or by the use of phenyliodonium ylides of
hydroxyquinones 3, the two routes presented in Scheme 1.
Regarding the direct route (1 → 2), simple alkyl groups
can be inserted by the use of either R3B7 or RTeTol,8 and
by radical coupling of hydroxyquinones with free alkyl
radicals produced from the decarboxylation of the corre-
sponding carboxylic acids.9 Allyl groups can be inserted
by a two-step sequence: formation of allyl ethers of 2-hy-
droxyquinones, under Mitsonubu reaction conditions, and
Claisen rearrangement of the latter to the desired 3-allyl-
2-hydroxy-1,4-quinones.9,10
Ylides 3, most easily prepared from the corresponding
hydroxyquinones 1 and diacetoxyiodobenzene,3 afford
furonaphthoquinones in a Sonogashira-type coupling
reaction with phenylacetylenes,4 without isolation of the
alkynyl intermediates, a reaction that can also proceed
photochemically.3a Stagliano developed a Stille-type cou-
pling methodology involving arylstannanes and aryliodo-
nium ylides of hydroxyquinones,3c,d on his way to prepare
trimeric quinones analogous to conocurvone, a natural
product and potential anti-HIV agent. Recently, we
reported5 the copper-catalyzed coupling of phenyliodoni-
um ylide of 2-hydroxy-1,4-naphthoquinone with indole
derivatives to afford indolylquinones, a most interesting
class of hydroxyquinones, related to the naturally oc-
curring asterriquinones.1,2 Finally, 2-aryl or 2-alkenyl-
Such allyl-substituted hydroxyquinones exhibit interest-
ing biological activity, the most prominent members of
the group being lapachol (4) and 2-(1,1-dimethyl-2-pro-
penyl)-3-hydroxy-1,4-naphthoquinone (5), illustrated in
Figure 1.
O
O
OH
OH
O
O
4
5
Figure 1 Structures of lapachol (4) and 2-(1,1-dimethyl-2-prope-
nyl)-3-hydroxy-1,4-naphthoquinone (5)
SYNLETT 2007, No. 3, pp 0427–0430
1
5.
0
2.
2
0
0
7
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-967947; Art ID: D38906ST
© Georg Thieme Verlag Stuttgart · New York

428
G. Kazantzi et al.
LETTER
The importance of 3-allyl-2-hydroxyquinones prompted After some experimentation with temperature and time it
us to investigate the possibility of direct allylation of 2- was found that best yields of the desired allyl compounds
hydroxyquinones, in order to access conveniently in one were obtained when the mixture was heated at 100 °C for
step this biologically active class of compounds. As 35 minutes14 and the results with various allyl substrates
reported recently, direct allylic substitution of various car- are presented in Table 1.
bon nucleophiles can take place under Pd(0) catalysis ei-
The results of Table 1 show that the reaction affords
ther in a biphasic H2O–EtOAc system11 or in H2O,12 using
similar yields of allylhydroxyquinones by using either
allyl alcohols as allylating agents. In the second case acid-
ic catalysis (with 1-adamantanecarboxylic acid) was nec-
essary for the completion of the reaction. Later it was
allyl alcohols or their acetates as allylating agents (entries
a, b and c, d). In the case of a-vinylbenzylalcohol (7e), the
allylation product 8b was identical to that obtained from
shown that allylic substitution of carbon nucleophiles can
the reaction with cinnamyl alcohol or its acetate (entries c
take place in the presence of a Pd(0)/carboxylic acid cata-
and d). The same type of reactivity of a-vinylbenzyl and
cinnamyl alcohol was reported in the Pd-catalyzed allyla-
lyst under neat conditions.13
In our case lawsone (6) was selected as the model tion of b-diketones in water.12
hydroxyquinone, acting as a nucleophile, and the reaction
was conducted using 0.9 mmol of 6, 1.5 mmol of the allyl-
Analogous results are also obtained from the reaction of 6
with 3-buten-2-ol (7g) and crotyl alcohol (7h). In both
ating agent 7 (allyl alcohol or its acetate), Pd(Ph3P)4 (2
cases an inseparable mixture of trans (as the main
mol%) and two drops of AcOH, under neat conditions.
component) and cis isomers 8d and 8e was isolated. In
Table 1 Allylation of Lawsone (6) under Neat Conditions
Entry
a
Allylating agent
Product
Yield (%)
56
O
O
OH
H2C=CH–CH2OH
7a
8a
8a
H2C=CH–CH2OCOMe
7b
b
c
60
62
O
O
OH
PhCH=CH–CH2OH
7c
Ph
8b
8b
PhCH=CH–CH2OCOMe
7d
d
e
52
66
8b
Ph
H2C=CH
CHOHm
7e
O
OH
OH
Me
f
36
H2C=C CH2OHm
7f
O
O
8c
+
+
O
O
OH
Me
45
g
h
(8d:8e, 4:1)a
H2C=CH CHOHm
7g
O
8d
8d
8e
8e
MeCH=CH–CH2OH
38
7h
(8d:8e, 5:1)a
a Estimated by 1H NMR spectroscopy.
Synlett 2007, No. 3, 427–430 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Allylation of 2-Hydroxy-1,4-naphthoquinone
429
contrast, 2-methyl-2-propen-1-ol (7f) afforded the expect- volves the formation of the lithium salt of lawsone by
ed allylation product 8c, albeit in lower yield.
addition of LiH to a frozen solution of the quinone in di-
methyl sulfoxide and allylation with 3,3-dimethylallyl
bromide. In this case a considerable amount (30%) of
allylation takes place on the OH of lawsone, with the for-
mation of the corresponding allyl ether as a by-product.
Finally, no clear allylation product could be isolated from
the reaction of 6 with geraniol, geraniol acetate and phytol
as allylating agents.
Based on the above results, the reaction of 6 with 3-meth-
yl-2-buten-1-ol (7i) and 2-methyl-3-buten-2-ol (7j) would
hopefully lead to the biologically active allylhydroxy-
quinones, lapachol (4) and 2-(1,1-dimethyl-2-propenyl)-
3-hydroxy-1,4-naphthoquinone (5). In the first case the
reaction with 7i, conducted under the previously de-
scribed conditions, failed to afford lapachol. In contrast,
the corresponding reaction with 7j afforded the desired
lapachol 4 in 19% yield (Scheme 2).
Finally, no allylation products were isolated from the
reaction of other hydroxyquinones such as 5-methyl-2-
hydroxy-1,4-benzoquinone (9a),17a 5,6-dimethyl-2-hy-
droxy-1,4-benzoquinone (9b)17b and 2-hydroxy-1,4-
triptycenequinone3e under neat conditions. Such products
were obtained only from the palladium-catalyzed reaction
of quinones 9a and 9b (0.9 mmol) with excess (4 mL) of
refluxing allyl alcohol (7a, bp 96–98 °C) or 2-methyl-2-
propen-1-ol (7f, bp 113–115 °C), though in low yields
(Scheme 4). In this case dodecanedioic acid was the prop-
er acidic catalyst, as 1-adamantanecarboxylic acid was
eluted from the chromatography column along with the al-
lylation products 10, making thus their separation and pu-
rification difficult. Under the same conditions 2-hydroxy-
1,4-triptycenequinone failed again to afford allylation
products.
Me
C
cat. Pd(PPh3)4, cat. AcOH
neat, 100 °C, 35 min
4
6
Me
CH CH2OH
7i
Me
cat. Pd(PPh3)4, cat. AcOH
neat, 100 °C, 35 min
4
(19%)
6
H2C
CH COH
Me
7j
O
O
Scheme 2 Reaction of lawsone with methyl butenols 7i and 7j
cat. Pd(PPh3)4,
R2
R1
OH
OH
cat. HO2C(CH2)10CO2H
Aiming to the improvement of these results, the two reac-
tions were repeated under slightly different conditions: a
mixture of lawsone (0.9 mmol) and catalytic, as previous-
ly, amounts of Pd(Ph3P)4 and 1-adamantanecarboxylic
acid was refluxed for 1 hour in an excess (4 mL) of the
corresponding alcohol 7i (bp 143–144 °C) or 7j (bp 98–
99 °C). After the usual work-up lapachol was isolated in
43% yield from the first reaction,15 whereas the second
reaction afforded a mixture of 4 and 5 (3:1, estimated by
1H NMR spectroscopy) in 67% yield (Scheme 3).
R3
7a or 7f (excess),
reflux, 1 h
O
O
10a, R1 = Me, R2 = R3 = H, 14%
10b, R1 = R2 = Me, R3 = H, 11%
10c, R1 = R3 = Me, R2 = H, 15%
9a, R1 = Me, R2 = H
9b, R1 = R2 = Me
Scheme 4 Allylation of benzoquinones 9
In summary, transformation of lawsone to its 3-allyl de-
rivatives can be achieved in one step by the Pd(0)- and
acid-catalyzed reaction under neat conditions, using allyl
alcohols or their acetates as allylating agents. The reaction
can be used for the preparation of lapachol, an interesting
biologically active compound and main precursor to the
equally important naphthoquinone, b-lapachone.16 Better
yields of lapachol are obtained if the reaction is conducted
in refluxing 3-methyl-2-buten-1-ol (7i). The same method
affords allylation products of hydroxybenzoquinones with
certain allylic alcohols but yields are considerably lower.
This mixture is inseparable by column chromatography
but it can be separated by HPLC [column C18, mobile
phase MeOH–MeCN–H3PO4 (0.1%), 25:45:10]. More-
over, an amount of pure lapachol, corresponding to 20–
25% of the whole yield, can be obtained from this mixture
by crystallization from hexanes.
cat. Pd(PPh3)4, cat. 1-AdCO2H
4
(43%)
6
7i (excess), reflux
References and Notes
cat. Pd(PPh3)4, cat. 1-AdCO2H
4 + 5 (67%)
6
(1) Thomson, R. H. Naturally Occurring Quinones IV; Blackie
Academic and Professional: London, 1997, and preceding
editions.
7j, (excess), reflux
(3:1)
Scheme 3 Modified conditions for the reaction of lawsone with
methyl butenols 7i and 7j
(2) Spyroudis, S. Molecules 2000, 5, 1291.
(3) (a) Hatzigrigoriou, E.; Spyroudis, S.; Varvoglis, A. Liebigs
Ann. Chem. 1989, 167. (b) Papoutsis, I.; Spyroudis, S.;
Varvoglis, A. Tetrahedron Lett. 1994, 35, 8449.
(c) Stagliano, K. W.; Malinakova, H. C. J. Org. Chem. 1999,
64, 8034. (d) Emadi, A.; Hardwood, J. S.; Kohanim, S.;
Stagliano, K. W. Org. Lett. 2002, 4, 521. (e) Spyroudis, S.;
Xanthopoulou, N. J. Org. Chem. 2002, 67, 4612.
The yields of lapachol (43% from the first reaction and
20–25% pure isolated from the second reaction) are con-
sidered satisfactory compared to the 40% yield of
lapachol obtained according to a literature method.16 This
method, probably the most efficient one until now, in-
Synlett 2007, No. 3, 427–430 © Thieme Stuttgart · New York

430
G. Kazantzi et al.
LETTER
(4) Kobayashi, K.; Uneda, T.; Kawakita, M.; Morikawa, O.;
Konishi, H. Tetrahedron Lett. 1997, 38, 837.
(5) Koulouri, S.; Malamidou-Xenikaki, E.; Spyroudis, S.;
Tsanakopoulou, M. J. Org. Chem. 2005, 70, 5627.
(6) Kazantzi, G.; Malamidou-Xenikaki, E.; Spyroudis, S.
Synlett 2006, 2597.
(7) Bieber, L. W.; Neto, P. J. R.; Generino, R. M. Tetrahedron
Lett. 1999, 40, 4473.
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Cahill, M. R. Pestic. Sci. 1997, 50, 291.
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(11) Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004,
6, 4085.
(12) Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 3241.
(13) Patil, N. T.; Yamamoto, Y. Tetrahedron Lett. 2004, 45,
3101.
Representative Data for Allylation Products.
2-Hydroxy-3-(3-phenylallyl)-1,4-naphthoquinone (8b): mp
168–170 °C (lit.18 170 °C). IR (KBr): n = 3289, 1671, 1641
cm–1. 1H NMR (300 MHz, CDCl3): d = 8.14 (1 H, d, J = 7.3
Hz), 8.09 (1 H, d, J = 7.3 Hz), 7.77 (1 H, t, J = 7.3 Hz), 7.69
(1 H, t, J = 7.3 Hz), 7.41 (1 H, s, OH), 7.35–7.17 (5 H, m),
6.57 (1 H, d, J = 15.9 Hz), 6.30 (1 H, dt, J1 = 15.9 Hz,
J2 = 7.5 Hz), 3.52 (2 H, d, J = 7.5 Hz). 13C NMR (75 MHz,
CDCl3): d = 184.3, 181.5, 153.1, 137.3, 135.0, 133.0, 132.0,
129.4, 128.4, 127.2, 126.9, 126.1, 125.4, 26.7. MS (EI): m/z
(%) = 290 (94) [M+], 199 (81), 91 (100). Anal. Calcd for
C19H14O3: C, 78.61; H, 4.86. Found: C, 78.42; H, 4.89.
(15) Preparation of Lapachol (4).
A mixture of lawsone (6, 157 mg, 0.9 mmol), Pd(Ph3P)4 (50
mg, 0.045 mmol), 1-AdCOOH (16 mg, 0.09 mmol) and 3-
methyl-2-buten-1-ol (7i, 4 mL) was refluxed for 1 h. After
removal of excess butenol in vacuum, the residue was
subjected to column chromatography (silica gel, hexane–
EtOAc, 5:1) to afford lapachol(4) in 43% yield; mp 137–
139 °C (lit.16 139–140 °C) and 1H NMR data identical to
those reported in the literature.16
(14) General Procedure for the Allylation Reaction of
Lawsone under Neat Conditions.
A mixture of lawsone (157 mg, 0.9 mmol), Pd(Ph3P)4 (50
mg, 0.045 mmol), AcOH (6 mg, 0.09 mmol, ca. 2 drops) and
the proper allylating agent (alcohol or ester, 1.5 mmol) was
thoroughly mixed and was put in an oven preheated at
100 °C. After 35 min the gummy material was subjected to
column chromatography (silica gel, hexane–EtOAc, 5:1) to
afford the allyl derivatives 8a–e.
(16) Sun, J. S.; Geiser, A. H.; Frydman, B. Tetrahedron Lett.
1998, 39, 8221.
(17) (a) Woodward, R. B.; Sondheimer, F.; Toup, D.; Heusler,
K.; McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223.
(b) Fieser, L. F.; Ardao, M. L. J. Am. Chem. Soc. 1956, 78,
774.
(18) Fieser, L. F. J. Am. Chem. Soc. 1926, 48, 3201.
Synlett 2007, No. 3, 427–430 © Thieme Stuttgart · New York