Photoacylations of 2-substituted 1,4-naphthoquinones: A concise access to biologically active quinonoid compounds

Article abstract of DOI:10.1016/j.tetlet.2005.12.060

Photochemical acylations of 2-substituted-1,4-naphthoquinones with various aldehydes furnished acylated hydroquinones and acylated quinones in moderate to good combined yields. All reactions are easily performed and open a rapid access to biologically act

Full text of DOI:10.1016/j.tetlet.2005.12.060

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1329–1332
Photoacylations of 2-substituted 1,4-naphthoquinones:
a concise access to biologically active quinonoid compounds
Prashant A. Waske,a Jochen Mattaya,* and Michael Oelgemo¨llerb,*
aOrganische Chemie I, Fakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Postfach 10 01 31, D-33501 Bielefeld, Germany
bDublin City University, School of Chemical Sciences and National Institute for Cellular Biotechnology, Glasnevin, Dublin 9, Ireland
Received 23 September 2005; revised 25 October 2005; accepted 12 December 2005
Available online 9 January 2006
Abstract—Photochemical acylations of 2-substituted-1,4-naphthoquinones with various aldehydes furnished acylated hydroquin-
ones and acylated quinones in moderate to good combined yields. All reactions are easily performed and open a rapid access to
biologically active compounds. For the 2-methyl-1,4-naphthoquinone/butyraldehyde pair, a novel tri-keto compound has been
additionally isolated.
Ó 2005 Elsevier Ltd. All rights reserved.
O
O
O
Acylated quinone derivatives based on 2-substituted 1,4-
naphthoquinones represent an important class of natu-
ral products.1 A versatile pathway for the construction
of these compounds is the photochemical acylation of
quinones with aldehydes, for which we introduced the
term ‘photo Friedel–Crafts acylation’.2,3 This extremely
useful photoreaction was discovered by Heinrich Klin-
ger in 1888, who exposed solutions of the starting mate-
rials to natural sunlight over long periods of time.4
During the last few decades, a number of additional
reports appeared in the literature, but most of the
studies focused on unsubstituted 1,2- or 1,4-quinones.5
In contrast, reports based on 2-substituted 1,4-naphtho-
quinones remained rare.6
Me
OR
( )10
CO2H
X
O
DHN X = CO, R = H
M5
Acequinocyl X = CH2, R = Ac
Figure 1. Structures of M5, 2-dodecanoyl-3-hydroxy-1,4-naphthoquin-
one (DHN) and acequinocyl.
knowledge, only a single brief example of a photoacyla-
tion involving 2-methyl-1,4-naphthoquinone has been
reported so far by Schenck and Koltzenburg.6a
In order to fill this gap, we have studied photochemical
acylation reactions of 2-methyl- and 2-methoxy-1,4-
naphthoquinone with different aliphatic as well as aro-
matic aldehydes. The selected compounds provide a
convenient access to potent antimalarials as M5,7 quino-
noid antibiotics as 2-dodecanoyl-3-hydroxy-1,4-naph-
thoquinone8 or pesticides as the important acaricide
acequinocyl (Fig. 1),9 respectively. To the best of our
Irradiations of 2-methyl-1,4-naphthoquinone 1 with
various aliphatic as well as aromatic aldehydes gave
the corresponding acylated quinones 2 in moderate
yields of 23–49% (Scheme 1; Table 1)10 indicating that
the ‘hydroquinones’ formed initially are oxidized during
workup. All compounds showed characteristic 13C
O
O
Me
Me
O
O
hν419 nm
+
Keywords: Photoacylation; Quinones; Aldehydes; Addition reactions;
R
H
R
benzene
Photochemistry.
*
Corresponding authors. Tel.: +49 521 106 2072; fax: +49 521 106
6417 (J.M.); tel.: +353 1 700 5312; fax: +353 1 700 5503 (M.O.);
e-mail addresses: mattay@uni-bielefeld.de; michael.oelgemoeller@
dcu.ie
O
O
1
2
3
Scheme 1. Photoacylations of 2-methyl-1,4-naphthoquinone 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.060

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P. A. Waske et al. / Tetrahedron Letters 47 (2006) 1329–1332
Table 1. Isolated product yields for 2-methyl-1,4-naphthoquinone 1
and 2-methoxy-1,4-naphthoquinone 5
two clearly separated doublets for the CH2 group at
2.73 and 3.36 ppm with a large 2J coupling of
16.9 Hz.12 The formation of 4a may be best explained
by the following in-cage scenario: hydrogen transfer
from the aldehyde to the excited quinone 1* leads to
the corresponding semiquinone radical pair A and B.
Radical combination with the acyl radical followed by
tautomerization affords the observed products 3a (after
further oxidation) and 4a.
An alternative out-of-cage attack of the acyl radical (not
shown) to a ground state quinone 1 would lead preferen-
tially to the acylated quinone 3a via the most stable radi-
cal intermediate. Steric hindrance by the methyl group
in 1 would furthermore prevent an addition at position
2. Thus, the isolation of 4a suggests that an in-cage
mechanism is indeed operating, at least in parts.13
NMR resonances between 183 and 186 ppm for their
quinonoid carbons. Hence, this protocol represents a
straightforward pathway to 2-acyl-3-methyl-1,4-quin-
ones. Solely with p-methoxybenzaldehyde, larger
amounts (ca. 10–20%) of the regioisomeric monoesters
The reaction of 2-methoxy-1,4-naphthoquinone 5 with
butyraldehyde furnished a mixture of the monoacylated
hydroquinone 6a and its acylated quinone 7a (Scheme 3,
Table 1).14 The phenolic protons of 6a gave broad sing-
lets at 5.60 and 13.89 ppm, which were unambiguously
assigned via H–D exchange with D2O. Surprisingly,
compound 6a remained rather stable in solution but
was rapidly oxidized in the solid state to its correspond-
ing quinone 7a. Irradiation of 5 in the presence of
dodecanal solely gave the acylated quinone 7b, which
represents an important key intermediate for the synthe-
sis of the antibiotic.
1
of 1 were detected in the crude H NMR spectrum but
could not be isolated in sufficient amounts and purities.
Their formation accounts for the more electrophilic
character of the corresponding p-methoxybenzoyl
radical.5a,11
Another exceptional case was the reaction of 1 with
butyraldehyde and the unusual tri-keto compound 4a
was obtained in 10% yield next to 49% of the acylated
quinone 3a (Scheme 2). The structure of 4a was unam-
biguously confirmed by 2D-NMR techniques such as
1H–1H COSY, 1H–13C HMBC and HSQC analysis,
1
As for 1, the presence of the electron donating methoxy
group obviously makes the primary hydroquinones 6
sensitive towards oxidation by oxygen.6b,15 The lack of
any bisacylation products, that is acylated monoesters
formed through secondary O-acylation, supports the
assumption that the quinones 7 are indeed formed dur-
ing workup.
respectively. In CDCl3, its H NMR spectrum showed
O
Me
O
+
H
Pr
In conclusion, the photochemical acylation of 2-substi-
tuted 1,4-naphthoquinones proceeds with the formation
of acylated hydroquinones and/or quinones in moderate
to good yields. The photoacylation protocol could be
O
1
hν419 nm
benzene
OH
O
O
O
Me
Me
O
O
OMe
O
+
Pr
Pr
H
R
OH
O
A
B
5
2
[O]
hν419 nm
benzene
O
O
Me
OH
O
Me
O
Pr
OMe
R
OMe
R
Pr
O
+
O
O
OH
O
O
O
3a
4a
6
7
Scheme 2. Photoacylations of 2-methyl-1,4-naphthoquinone 1 with
butyraldehyde.
Scheme 3. Photoacylations of 2-methoxy-1,4-naphthoquinone 5.

P. A. Waske et al. / Tetrahedron Letters 47 (2006) 1329–1332
1331
1948, 176, 1363; (d) Fieser, L. F.; Berliner, E.; Bondhus, F.
J.; Chang, F. C.; Dauben, W. G.; Ettlinger, M. G.; Fawaz,
G.; Fields, M.; Fieser, M.; Heidelberger, C.; Heymann, H.;
Seligman, A. M.; Vaughan, W. R.; Wilson, A. G.; Wilson,
E.; Wu, M.-I.; Leffler, M. T.; Hamlin, K. E.; Hathaway,
R. J.; Matson, E. J.; Moore, E. E.; Moore, M. B.; Rapala,
R. T.; Zaugg, H. E. J. Am. Chem. Soc. 1948, 70, 3151, and
following papers.
used as a straightforward preparation of synthetically
important precursors to quinonoid pharmaceuticals
and agrochemicals.
Acknowledgements
This research project was financially supported by the
Arbeitsgemeinschaft Solar Nordrhein-Westfalen (The-
menfeld 3: Solare Chemie und Solare Materialunter-
suchungen) and Dublin City University (Research
Alliance Fund). P.A.W. thanks the Universita¨t Bielefeld
for a research fellowship. The authors would also like to
thank Dr. J. O. Bunte for his support and Dr. M. Letzel,
Mr. E. Westermeier and Mr. P. Mester for technical
assistance.
8. (a) Hase, J.; Nishimura, T. Yakugaku Zasshi—J. Pharm.
Soc. Jpn. 1955, 75, 203; (b) Hase, J.; Nishimura, T.
Yakugaku Zasshi—J. Pharm. Soc. Jpn. 1955, 75, 207.
9. (a) Suganuma, H. J. Synth. Org. Chem. Jpn. 2001, 59, 23;
(b) Koura, Y.; Kinoshita, S.; Takasuka, K.; Koura, S.;
Osaki, N.; Matsumoto, S.; Miyoshi, H. J. Pesticide Sci.
1998, 23, 18.
10. General procedure for irradiation: In a typical photo-
chemical experiment, a solution of 1 mmol of the naph-
thoquinone and 9 mmol of aldehydes in 60 ml of dry
benzene was split over 5 Pyrex tubes (capacity 12 ml each),
degassed with argon and irradiated for 12–18 h using a
Rayonet Photochemical reactor (RPR–100; Southern New
England Ultraviolet Company) equipped with RPR 4190
References and notes
˚
A lamps (kmax = 419 15 nm). The reaction was contin-
1. (a) The Chemistry of the Quinonoid Compounds; Patai, S.,
Ed.; John Wiley & Sons: New York, 1974; (b) Thompson,
R. H. Naturally Occurring Quinones, 2nd ed.; Academic
Press: New York, 1971; (c) Biochemistry of Quinones;
Morton, R. A., Ed.; Academic Press: New York, 1965.
2. (a) Oelgemo¨ller, M.; Schiel, C.; Fro¨hlich, R.; Mattay, J.
Eur. J. Org. Chem. 2002, 2465; (b) Schiel, C.; Oelgemo¨ller,
M.; Mattay, J. Synthesis 2001, 1275; (c) Schiel, C.;
Oelgemo¨ller, M.; Ortner, J.; Mattay, J. Green Chem.
2001, 3, 224; (d) Oelgemo¨ller, M.; Schiel, C.; Ortner, J.;
Mattay, J. In Solare Chemie und solare Materialforschung,
AG-Solar NRW, Ed.; 2002; Chapter 2.2., ISBN: 3-89336-
306-8 (CD-Rom).
3. For other ‘photo Friedel–Crafts’ reactions, see: (a) Mar-
tens, J.; Praefcke, K.; Schulze, U. Synthesis 1976, 532; (b)
Bryce-Smith, D.; Deshpande, R.; Gilbert, A.; Grzonka, J.
Chem. Commun. 1970, 561.
4. (a) Klinger, H. Justus Liebigs Ann. Chem. 1888, 249, 137;
(b) Klinger, H.; Standke, O. Ber. Dtsch. Chem. Ges. 1891,
24, 1340; (c) Klinger, H.; Kolvenbach, W. Ber. Dtsch.
Chem. Ges. 1898, 31, 1214.
5. For a recent review on the photoacylation of quinones,
see: (a) Oelgemo¨ller, M.; Mattay, J. In CRC Handbook of
Organic Photochemistry and Photobiology; Horspool, W.
M., Lenci, F., Eds., 2nd ed.; CRC Press: Boca Raton,
2004; Chapter 88, pp 1–45; For general reviews on the
photochemistry of quinones, see: (b) Maruyama, K.;
Osuka, A. In The Chemistry of Quinonoid Compounds;
Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: New
York, 1988; Vol. 2, Chapter 13, pp 759–878; (c) Bruce, J.
M. Quart. Rev. 1967, 21, 405; (d) Rubin, M. B. Fortschr.
Chem. Forsch. 1969, 13, 251.
ued until GC analysis indicated complete consumption of
the quinone. The combined solutions were evaporated
under vacuum and the crude residue was purified by flash
column chromatography (silica gel, 30% ethyl acetate in
cyclohexane), followed, if required, by preparative HPLC.
Selected physical and spectral data for the product 2-
butyryl-3-methyl-1,4-naphthoquinone 3a: light yellow
solid, mp 76–79 °C. 1H NMR (500 MHz, CDCl3):
d = 0.98 (t, 3H, J = 7.5 Hz, CH2CH3), 1.72 (dq, 2H,
J = 7.5 Hz, CH2CH3), 2.06 (s, 3H, CH3), 2.69 (t, 2H,
J = 7.5 Hz, COCH2), 7.74 (m, 2H, Ar-H), 8.03 (m, 1H,
Ar-H), 8.08 ppm (m, 1H, Ar-H). 13C NMR (125 MHz,
CDCl3): d = 13.1 (CH3), 13.7 (CH3), 16.5 (CH2), 46.1
(CH2), 126.1 (CH), 126.6 (CH), 131.4 (C), 131.7 (C), 134.0
(CH), 134.1 (CH), 142.4 (C), 145.7 (C), 183.5 (C@O),
185.1 (C@O), 203.9 ppm (C@O). IR (KBr): m = 2961,
2935, 2875, 2362, 1702, 1663, 1594, 1458, 1375, 1326, 1289,
1151, 1006, 958, 793, 703 cmÀ1. MS (EI): m/z (%) = 242
(M+, 80), 228 (4), 227 (23), 200 (20), 199 (95), 196 (2), 174
(12), 171 (100), 143 (21), 116 (12), 115 (69), 89 (17), 89
(16), 76 (18), 67 (16), 58 (14), 43 (36). HR-MS (EI+):
242.09425 (calcd 242.09429).
11. The formation of C- versus O-acylation products was
explained on the basis of the nucleophilicity of the acyl
radical intermediate and the redox properties of the
quinone and the acyl radical: (a) Bruce, J. M.; Creed,
D.; Ellis, J. N. J. Chem. Soc. C 1967, 1486; (b) Takuwa, A.
Bull. Chem. Soc. Jpn. 1977, 50, 2973.
12. Selected physical and spectral data for the product 2-
butyryl-3-methyl-2,3-dihydro-1,4-naphthoquinone 4: col-
1
orless oil. H NMR (500 MHz, CDCl3): d = 0.68 (t, 3H,
J = 7.2 Hz, CH2CH3), 1.36–1.46 (m, 2H, CH2CH3), 1.58
(s, 3H, CH3), 2.30 (ddd, 1H, J = 17.9, 7.8, 6.2 Hz,
COCH2), 2.46 (ddd, 1H, J = 17.9, 7.7, 6.6 Hz, COCH2),
2.73 (d, 1H, J = 16.9 Hz, CH2), 3.36 (d, 1H, J = 16.9 Hz,
CH2), 7.69 (m, 2H, Ar-H), 7.98 (m, 1H, Ar-H), 8.06 ppm
(m, 1H, Ar-H). 13C NMR (125 MHz, CDCl3): d = 13.3
(CH3), 16.9 (CH2), 20.0 (CH3), 39.2 (CH2), 46.9 (CH2),
65.1 (C), 126.7 (CH), 127.2 (CH), 133.9 (C), 134.2 (CH),
134.7 (CH), 135.3 (C), 193.4 (C@O), 195.3 (C@O), 206.8
ppm (C@O). IR (KBr): m = 2963, 2934, 2874, 1687, 1665,
1594, 1458, 1379, 1286, 1265, 1216, 978 cmÀ1. MS (EI):
m/z (%) = 244 (M+, 16), 228 (3), 201 (5), 185 (12), 175 (14),
174 (100), 159 (91), 159 (9), 149 (11), 131 (6), 128 (5), 117
(4), 105 (10), 91 (5), 76 (14), 71 (45), 55 (2), 43 (66). HR-
MS (EI+): 244.10967 (calcd 244.10994).
6. The reaction of 1 and acetaldehyde gave exclusively 2-
methyl-3-acetyl-naphthohydroquinone,
although
no
experimental details were reported: (a) Schenck, G. O.;
Koltzenburg, G. Naturwiss. 1954, 41, 452; For benzophen-
one mediated photoacylations of 2-arylamino- and 2-
alkylamino 1,4-naphthoquinones, see: (b) Kobayashi, K.;
Suzuki, M.; Takeuchi, H.; Konishi, A.; Sakurai, H.;
Suginome, H. J. Chem. Soc., Perkin Trans. 1 1994, 1099.
7. For Antimalarials based on 1, see: (a) Biot, C.; Bauer, H.;
Schirmer, R. H.; Davioud-Charvet, E. J. Med. Chem.
2004, 47, 5972; (b) Davioud-Charvet, E.; Delarue, S.; Biot,
C.; Schwo¨bel, B.; Boehme, C. C.; Mussigbrodt, A.; Maes,
¨
L.; Sergheraert, C.; Grellier, P.; Schirmer, R. H.; Becker,
K. J. Med. Chem. 2001, 44, 4268; For Antimalarials based
on 5, see: (c) Fieser, L. F.; Heymann, H. J. Biol. Chem.

1332
P. A. Waske et al. / Tetrahedron Letters 47 (2006) 1329–1332
13. Both, in-cage and out-of-cage mechanisms have been
described in the literature and both mechanisms operate
more-or-less simultaneously depending on the specific
reaction conditions of the irradiation experiment (i.e.,
temperature, solvent, quinone/aldehyde applied).5a Fur-
ther mechanistic investigations are currently carried out
for the 2-methyl-1,4-naphthoquinone/butyraldehyde using
either thermally or chemically generated acyl radicals.
14. Selected physical and spectral data for the product 1-(1,4-
dihydroxy-3-methoxy-naphthalen-2-yl)-butan-1-one 6a:
brown solid, mp 109–110 °C. 1H NMR (500 MHz,
CDCl3): d = 0.98 (t, 3H, J = 7.5 Hz, CH2CH3), 1.76 (dq,
2H, J = 7.5 Hz, CH2CH3), 3.11 (t, 2H, J = 7.5 Hz,
COCH2), 3.79 (s, 3H, OCH3), 5.60 (s, 1H, OH), 7.47
(ddd, 1H, J = 1.3, 6.9, 8.2 Hz, Ar-H), 7.63 (ddd, 1H,
J = 1.3, 6.9, 8.2 Hz, Ar-H), 8.08 (d, 1H, J = 8.1 Hz, Ar-
H), 8.38 (d, 1H, J = 8.1 Hz, Ar-H), 13.89 ppm (s, 1H,
OH). 13C NMR (125 MHz, CDCl3): d = 13.9 (CH3), 18.3
(CH2), 44.3 (CH2), 62.3 (OCH3), 108.8 (C), 121.4 (CH),
123.1 (C), 124.5 (CH), 125.6 (CH), 128.4 (C), 129.9 (CH),
135.9 (C), 138.4 (C), 157.3 (C), 206.3 ppm (C@O). IR
(KBr): m = 3427, 2964, 2937, 2365, 1708, 1679, 1626, 1600,
1570, 1454, 1399, 1332, 1772, 1216, 1124, 1046, 911,
729 cmÀ1. MS (EI): m/z (%) = 260 (M+, 94), 258 (52), 257
(6), 246 (36), 231 (34), 230 (57), 227 (57), 217 (27), 209
(14), 199 (19), 190 (66), 181 (11), 174 (16), 163 (22), 159
(13), 128 (12), 115 (21), 105 (37), 89 (22), 79 (4), 71 (77).
Selected physical and spectral data for the product 2-
butyryl-3-methoxy-1,4-naphthoquinone 7a: brown solid,
mp 144–146 °C. 1H NMR (500 MHz, CDCl3): d = 0.98 (t,
3H, J = 7.5 Hz, CH2CH3), 1.73 (dq, 2H, J = 7.5 Hz,
CH2CH3), 2.73 (t, 2H, J = 7.5 Hz, COCH2), 4.10 (s, 3H,
OCH3), 7.74 (m, 2H, Ar-H), 8.04 (m, 2H, Ar-H). 13C
NMR (125 MHz, CDCl3): d = 13.6 (CH3), 16.6 (CH2),
46.9 (CH2), 61.4 (OCH3), 126.1 (CH), 126.6 (CH), 130.0
(C), 131.0 (C), 131.2 (C), 133.8 (CH), 134.6 (CH), 155.3
(C), 181.5 (C@O), 183.8 (C@O), 202.0 (C@O). IR (KBr):
m = 3441, 2699, 2877, 2359, 1709, 1662, 1581, 1440, 1274,
1071, 902, 735 cmÀ1. MS (EI): m/z (%) = 258 (M+, 4), 257
(1), 243 (8), 230 (6), 228 (9), 215 (100), 209 (1), 187 (71),
173 (10), 167 (5), 149 (4), 129 (4), 104 (23), 89 (7), 87 (2), 76
(21), 71 (13). HR-MS (EI+): 258.08939 (calcd 258.08921).
15. (a) Couladouros, E. A.; Plyta, Z. F.; Papageorgiou, P. J.
Org. Chem. 1996, 61, 3031; (b) Pearson, M. S.; Jensky, B.
J.; Greer, F. X.; Hangstrom, J. P.; Well, N. M. J. Org.
Chem. 1978, 43, 4617.