A convenient method for the alkylation of tropolone derivatives and related α-keto hydroxy compounds

Article abstract of DOI:10.1055/s-1999-3523

A mild and general method of phase-transfer catalyzed O-alkylation of biologically promising tropolones with allyl, benzyl and heterocyclic primary halides was developed. This method was also applied successfully to various substituted or ring-fused tropo

Full text of DOI:10.1055/s-1999-3523

PAPER
1149
A Convenient Method for the Alkylation of Tropolone Derivatives and Related
a-Keto Hydroxy Compounds
Isabelle Tamburlin-Thumin,a Michel P. Crozet,a* Jean-Claude Barrièreb
a L.C.M.O, UMR 6517, CNRS-Universités d'Aix-Marseille 1 et 3, Avenue Escadrille Normandie-Niemen, F-13397 Marseille cedex 20,
France
Fax +33(4)91670944; E-mail: michel.crozet@LCMO.u-3mrs.fr
b Centre de Recherche Rhône-Poulenc Rorer S.A., 13 Quai Jules Guesde, BP 14, F-94403 Vitry sur Seine cedex, France
Received 16 September 1998; revised 27 January 1999
The reaction was first studied in the benzylic series with
Abstract: A mild and general method of phase-transfer catalyzed
the alkylating reagents 2a–f and the generality of the
method has been shown by using various substituents (i.e.
electron-withdrawing or electron-donating) on the arom-
O-alkylation of biologically promising tropolones with allyl, benzyl
and heterocyclic primary halides was developed. This method was
also applied successfully to various substituted or ring-fused tropo-
lones: hinokitiol, hydroxymethylhinokitiol and trimethylpurpuro- atic moiety to afford the alkylated products 3a–3f. Most of
gallin, and structurally-related maltol
the reactions were conducted in a stoichiometric mode
(Method A) without an excess of alkylating agent. The re-
sults obtained in the benzylic series prompted us to extend
the reaction to the heterocyclic series using 1-chlorometh-
Key words: O-alkylation, phase-transfer reaction, tropolone,
a-keto hydroxy compounds
ylisoquinoline
(2g),
6-chloromethyl-1,3-dimethyl-
1H,3H-pyrimidine-2,4-dione (2h) and 2-chloromethylim-
idazo[1,2-a]pyridine (2i) as alkylating agents. Despite
good results, a few limitations were observed when slight-
ly soluble alkylating agents were used. In these few cases,
neither alkylation product nor starting material were ob-
tained and only degradation occured. To complete the
study on the tropolone substrates, the method was extend-
ed to allylic (3k–3m) and cinnamylic (3n) series, as
shown in Table 1. Finally, to show the generality of the
method, we also used methyl iodide as the alkylating
agent and thus obtained a good yield for O-methylated
tropolone 3j.
Tropolone ethers are difficult to synthesize because of
their rearrangement to benzenoid compounds under the
basic conditions of nucleophilic substitution in protic sol-
vents.1 Studies carried out so far report only a few meth-
ods for tropolone O-alkylation, all of which suffers from
lack of generality.2–7
In the course of our work to prepare products for inhibi-
tion of ribonucleotide reductase,8 we were interested in O-
alkylated tropolone derivatives which were known to
demonstrate promising antitumor activity.9 The lack of
general alkylating procedures prompted us to develop a
new general method, based on phase-tranfer catalysis, to
alkylate tropolone with primary allyl, benzyl and hetero-
cyclic halides. As the observed biological activity seemed
to be related to the O-alkylated a-keto hydroxy moiety,
we have also extended this reaction to related compounds.
When substituents were present on the tropolone moiety,
two regioisomeric alkylation products were obtained with
allylic and benzylic halides (Scheme 2). As expected, in
the case of 4-isopropyltropolone (4), a 1:1 ratio of the
products 5a,c/5b,d was observed but in the case of 7-hy-
droxymethyl-4-isopropyltropolone (6), a 1:6 ratio of the
products 7a/7b was noted (Table 2). This could be ratio-
nalized by the presence of an hydroxy group which allows
different hydrogen bondings in the two anionic forms (Ta-
ble 2).
This method can be applied to tropolone (1) with a stoi-
chiometric amount of tetrabutylammonium hydroxide
(Method A), or to a preformed tropolone potassium salt of
1 with a catalytic amount of tetrabutylammonium brom-
ide (Method B). A primary benzyl or allyl or heterocyclic
halide (RX) is used as an alkylating agent in both cases
(Scheme 1).
Scheme 2
Scheme 1
Very good yields were obtained also in the alkylation of a
ring fused tropolone like trimethylpurogallin (8) with al-
Synthesis 1999, No. 7, 1149–1154 ISSN 0039-7881 © Thieme Stuttgart · New York

1150
I. Tamburlin-Thumin et al.
PAPER
Table 1 O-Alkylation Products 3a–n of Tropolone (1)
Halide
Product
Yield Appear- mp (°C)
(%) ance
1H NMR (CDCl3/TMS)
δ, J (Hz)
13C NMR (CDCl3)
δ
65a,b,c ochre
solid
82
5.26 (s, 2H), 6.76–7.00
(m, 3H), 7.14–7.45
(m, 7H)
71.00, 114.91, 127.18,
128.25, 128.78, 132.48,
135.52, 136.29, 137.48,
164.57, 180.76
87a,b,d beige
solid
166–168 5.33 (s, 2H), 6.66 (d, 2H,
89.47, 115.27, 123.93,
127.60, 128.08, 132.33,
J = 8.8), 6.79 (d, 1H,
J = 9.4), 6.86–7.08 (m, 2H), 136.63, 137.77, 142.91,
7.24 (d, 2H, J = 8.8), 7.25– 147.73, 163.60, 180.52
7.34 (m, 2H)
72a,b,d white
solid
96–98
2.07 (s, 3H), 2.09 (s, 3H),
2.18 (s, 3H), 3.53 (s, 3H),
3.58 (s, 3H), 5.06 (s, 2H),
11.75, 12.26, 12.61,
59.76, 61.63, 63.94,
113.93, 124.34, 127.60,
6.70 (m, 1H), 6.99 (m, 2H), 127.66, 128.07, 131.94,
61b,d,e
7.09 (m, 2H)
132.63, 136.07, 136.82,
152.95, 153.80, 164.60,
180.17
78a,b,d white
solid
130–132 3.84 (s, 3H), 3.85 (s, 6H),
5.18 (s, 2H), 6.66 (s, 2H),
6.77–7.01 (m, 3H), 7.22–
7.28 (m, 2H)
56.23, 60.86, 71.22,
104.25, 115.03, 128.44,
131.06, 132.59, 136.47,
137.50, 137.92, 153.63,
164.50, 180.76
78a,b,d white
solid
108–110 3.87 (s, 3H), 3.90 (s, 3H),
5.28 (s, 2H), 6.81–6.90
55.82, 61.25, 66.07,
112.51, 114.23, 120.23,
124.79, 128.01, 129.23,
132.75, 136.35, 137.28,
146.79, 152.60, 164.55,
180.66
(m, 3H), 7.01–7.08 (m,
3H), 7.19–7.29 (m, 2H)
68a,b,d white
solid
67–68
3.78 (s, 6H), 5.22 (s, 2H),
6.40 (t, 1H, J = 2.2), 6.58
(d, 2H, J = 2.2), 6.71–7.10
55.34, 70.82, 100.09,
104.61, 114.84, 128.24,
132.54, 136.33, 137.36,
(m, 3H), 7.20–7.28 (m, 2H) 137.79, 161.13, 164.34,
180.64
57a,b,c green
solid
_f
5.84 (s, 2H), 6.75–6.85
(m, 1H), 6.93–7.09
(m, 1H), 7.15–7.28
(m, 3H), 7.60–7.73
(m, 3H), 7.79–7.86
72.16, 115.27, 121.69,
125.37, 127.00, 127.30,
127.88, 128.29, 130.34,
132.50, 136.18, 136.41,
137.35, 141.20, 154.29,
(m, 1H), 8.48–8.55 (m, 2H) 164.16, 180.40
67a,b,c white
solid
>247
(dec)
3.22 (s, 3H), 3.34 (s, 3H),
5.15 (s, 2H), 5.94 (s, 1H),
6.99–7.17 (m, 4H), 7.31–
7.42 (m, 1H)g
–
Synthesis 1999, No. 7, 1149–1154 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Method for the Alkylation of Tropolone Derivatives
1151
Table 1 (continued)
Halide
Product
Yield Appear- mp (°C)
(%) ance
1H NMR (CDCl3/TMS)
δ, J (Hz)
13C NMR (CDCl3)
δ
82a,b,d light
brown
180–181 5.46 (s, 2H), 6.75–7.32
(m, 7H), 7.56 (d, 1H,
111.30, 112.57, 114.79,
117.36, 124.90, 125.95,
128.25, 132.72, 136.68,
137.25, 141.49, 144.96,
164.40, 180.61
solid
J = 9.1), 7.73 (s, 1H), 8.10
(d, 1H, J = 9.1)
MeI
(3j)
79a,b,c _2,5
–
–
–
–
–
88a,b,d _11
–
50a,b,c yellow
solid
40–42
4.80 (t, 2H, J = 1.4), 5.70
(quint, 1H, J = 2.3, 1.2),
6.04 (dd, 1H, J = 2.2, 1.6),
6.78–7.25 (m, 5H)
71.99, 116.03, 118.54,
124.86, 129.14, 132.27,
136.41, 137.68, 163.13,
180.19
46b,c,e
46a,b,d _1,2
–
–
–
–
54a,b,d brown
oil
2.17 (s, 3H), 2.19 (s, 3H),
2.22 (s, 3H), 3.55 (s, 3H),
12.18, 12.61, 13.11,
59.71, 59.77, 70.14,
3.65 (s, 3H), 4.96 (dd, 2H), 114.31, 126.96, 127.08,
J = 5.6, 1.2), 6.31 (dt, 1H,
J = 16.3, 5.7), 6.79 (br d,
1H, J = 16.4), 6.85–7.27
(m, 5H)
127.40, 127.83, 128.03,
128.52, 130.02, 132.31,
136.09, 136.90, 152.35,
152.81, 164.21, 180.41
a Stoichiometric conditions.
b Reaction performed in CH2Cl2.
c Reaction conducted at r.t.
d Reaction carried out at reflux temperature.
e Catalytic conditions.
f Unstable in air.
g Spectra recorded in DMSO-d6.
lylic and benzylic halides (Scheme 3, Table 2). Finally,
the reaction was applied to maltol (10) leading to excel-
lent results of the alkylation (Table 2).
To conclude, we have developed a new method for the
alkylation of tropolone, its derivatives and related com-
pounds with primary halides. It is easy to use and avoids
all the problems found in the previous strategies. All of
these products have been tested for potential biological
activity related to anticancer studies and the results will be
published elsewhere.
Scheme 3
Synthesis 1999, No. 7, 1149–1154 ISSN 0039-7881 © Thieme Stuttgart · New York

1152
I. Tamburlin-Thumin et al.
PAPER
Table 2 O-Alkylated Products 5a–d, 7a, b, 9a, b and 11a, b Prepared
Halide
Substrate
Product(s)
Yield
(%)
Appear- mp (∞C) or 1H NMR (CDCl3/TMS) 13C NMR
ance
bp (∞C)/
d, J (Hz)
(CDCl3)
mbar
d
42a,b,c
(ratio
5a/5b =
1:1)d
brown
oil
115/0.001
1.25 (d, 6H, J = 6.8),
2.84 (sept, 1H, J = 6.8), , 72.33, 118.79,
5.71 (quint, 1H, J = 2.3 125.58, 126.18,
1.1),5.86 (m, 2H) 6.01
(dd, 1H, J = 2.2, 1.7),
6.78 (s, 1H), 6.80 (m,
1H), 7.08–7.24
23.16, 38.73,
136.08, 136.86,
153.81, 162.43,
180.01
(m, 2H)
brown
oil
122/0.004
1.23 (d, 6H, J = 6.9),
2.79 (sept, 1H, J = 6.9), 71.69, 115.16,
4.79 (t, 2H, J = 1.4) 5.70 116.33, 124.97,
22.67, 36.20,
(dd, 1H, J = 2.4, 1.3),
130.64, 131.18,
6.02 (quint, 1H, J = 2.3, 135.01, 157.45,
1.7), 6.66 (m, 1H), 6.92 162.53, 179.96
(m, 2H), 7.20 (s, 1H)
83a,b,e
(ratio
5c/5d =
1:1)d
brown
oil
–
1.23 (d, 6H, J = 6.8),
2.82 (sept, 1H, J = 6.8), 56.05, 60.84,
(3.84 (s, 3H), 3.85
(s, 3H), 5.16 (s, 2H),
23.04, 38.35,
71.03, 104.13,
114.20, 129.91,
6.61 (s, 1H), 6.61–7.40 131.18, 131.53,
(m, 5H)
134.73, 137.67,
153.56, 157.57,
163.75, 180.44
–
white
solid
89–90
1.13 (d, 6H, J = 6.8),
2.75 (sept, 1H, J = 6.8), 56.19, 60.84,
23.19, 38.84,
3.83 (s, 3H), 3.85
(s, 6H), 5.23 (s, 2H),
6.68 (s, 2H), 6.77
71.18, 104.18,
117.12, 125.44,
131.44, 135.51,
136.90, 137.80,
153.62, 153.94,
163.41, 180.33
(m, 2H), 7.14 (m, 2H)
69a,b,c
(ratio
7a/7b =
1:6)
brown
oil
–
1.23 (d, 6H, J = 6.8),
2.77 (sept, 1H, J = 6.8)
3.83 (s, 6H), 3.85
(s, 3H), 4.59 (s, 2H),
5.18 (s, 2H), 6.64
–
(s, 2H), 6.72 (dd, 1H,
J = 11.9, 1.5), 6.90
(d, 1H, J = 1.5), 7.21
(d, 1H, J = 11.7)
–
brown
oil
–
1.16 (d, 6H, J = 6.8),
22.86, 38.17,
2.80 (sept, 1H, J = 6.8), 55.72, 60.34,
3.83 (s, 6H), 3.86 (s,3H) 64.81, 70.85,
4.67 (s, 2 ), 5.20 (s, 2H), 103.97, 117.20,
6.69 (s, 2H), 6.83
(d, 1H, J = 9.3), 6.88
(s, 1H), 7.45 (d, 1H,
J = 9.3)
124.97 (2¥),
131.03, 134.81,
137.29, 145.32,
153.06, 153.26,
161.55, 179.02
Synthesis 1999, No. 7, 1149–1154 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Method for the Alkylation of Tropolone Derivatives
1153
Table 2 (continued)
Halide
Substrate
Product(s)
Yield
(%)
Appear- mp (∞C) or 1H NMR (CDCl3/TMS) 13C NMR
ance
bp (∞C)/
d, J (Hz)
(CDCl3)
mbar
d
82a,b,c
yellow
semi-
solid
–
3.80 (s, 3H), 3.91 (s, 3H 55.73, 55.77,
), 3.96 (s, 3 ), 4.82 (t, 1 61.13, 77.70,
H, J = 1.2), 5.68 (quint, 1 104.96, 107.01,
H, J = 1.9, 1.0), 6.13 117.76, 123.33,
(br s, 1H), 6.18–6.20 (m, 125.20 (2×),
1H), 6.46–6.56
(m, 1H), 6.77–6.92
(m, 2H)
127.39, 128.61,
132.57, 143.02,
150.67, 154.92,
157.47, 184.05
86a,b,c
orange
oil
–
3.76 (s, 3H), 3.84
(s, 3H), 3.90 (s, 6H),
3.93 (s, 3H), 3.98 (s,
55.55, 55.61,
55.70, 60.43,
60.78, 76.69,
3H), 5.16 (s, 3H), 6.10 104.52, 105.36,
(m, 1H), 6.49 (m, 1H), 106.69, 123.12,
6.77–6.95 (m, 4H)
125.55, 128.47,
132.49, 132.85,
137.16, 143.22,
151.05, 152.69,
154.77, 158.32,
184.31
100
80a,b,e
color-
/
2.42 (2, 3H), 4.89
17.79, 74.88,
0.001
less oil
(br s, 2H), 5.65 (d, 1H, J 116.62, 120.79,
= 1.6), 5.94 (m, 1H), 127.72, 142.79,
6.99 [AB, Dn = 1.2 : 6.34 153.36, 159.14,
(d, 1H, J = 6.60), 6.34
(d, 1H, J = 5.6)]
174.21
94a,b,c
white
solid
77-78
2.19 (s, 3H), 3.84
(s, 3H), 3.86 (s, 6H),
14.80, 56.04,
60.77, 73.62,
5.06 (s, 2H), 7.00 [AB, 105.92, 117.08,
Dn = 1.2 : 6.38 (d, 1H,
J = 5.8), 7.63 (d, 1H,
J = 5.6)], 6.77 (s, 2H)
132.44, 137.87,
153.06, 153.47,
159.54, 174.95
a Stoichiometric conditions.
b Reaction carried out in CH2Cl2.
c Reaction performed at reflux temperature.
d Determined by 2D-NMR measurements.
e Reaction conducted at r.t.
Melting points were determined on a Büchi capillary melting point
apparatus and are uncorrected. Elemental analyses were performed
by the Centre de Microanalyses of the University of Aix-Marseille
3. Both 1H and 13C NMR spectra were recorded on a Bruker AC 200
spectrometer. The 1H NMR shifts were reported in ppm downfield
from TMS and the 13C NMR shifts were referenced to the solvent
peaks (CDCl3: 76.9 ppm or DMSO-d6: 39.6 ppm). Silica gel 60
(Merck, 0.063–0.200 mm, 70–230 mesh ASTM) was used for col-
umn chromatography. TLC was performed on 5 cm × 10 cm alumi-
num plates coated with silica gel 60F-254 (Merck) in an appropriate
solvent. All commercial alkylating agents, purpurogallin, and mal-
tol (10) were purchased from Aldrich Chemical Co. Commercial
products were of highest purity avalaible and were used as received.
Substituted benzyl chlorides were prepared from the corresponding
aldehydes by reduction with NaBH4 and subsequent chlorination.
Tropolone (1),13 4-isopropyltropolone (4),13,14 7-hydroxymethyl-4-
isopropyltropolone (6),15 trimethylpurpurogallin (8),16 1-chlorome-
thylisoquinoline (2g),17 6-chloromethyl1,3-dimethyl-1H,3H-pyri-
midine-2,4-dione (2h)18 and 2-chloromethylimidazo[1,2-a]pyridine
(2i) were prepared by literature procedures.
Alkylation of Tropolones; General Procedures
Stoichiometric Method: The appropriate tropolone (6.07 mmol)
was treated with Bu4NOH (40% in H2O, 3.82 mL, 6.07 mmol) un-
der an inert atmosphere at r.t. for 1 h. A solution of the appropriate
alkylating agent (6.07 mmol) in CH2Cl2 (2.5 mL/mmol) was added
slowly. The reaction was conducted at r.t. or at reflux depending on
the alkylating agent, (see Tables 1 and 2) and was monitored by
TLC (CH2Cl2/EtOAc, 7:3). After dilution with H2O (20 mL) and vi-
gourous stirring for 10 min, the aqueous layer was extracted with
CH2Cl2 (3 × 30mL). The combined organic layers were dried
(MgSO4), and concentrated under reduced pressure. Purification of
the residues was done by chromatography on silica gel, eluting with
30% EtOAc in CH2Cl2.
Synthesis 1999, No. 7, 1149–1154 ISSN 0039-7881 © Thieme Stuttgart · New York

1154
I. Tamburlin-Thumin et al.
PAPER
(6) Cabrino, R.; Cavazza, M. Pietra, F. J. Chem. Soc., Chem.
Commun. 1976, 721.
(7) a) Takeshita, H.; Mametsuka, H. Can. J. Chem. 1984, 62,
2035.
Catalytic Method: The appropriate tropolone (1 equiv, 8.20 mmol)
was added to 25% aq KOH solution (5 mL). After stirring at r.t., a
yellow coloration was observed and the H2O was evaporated under
0.005 mbar at r.t. (high vacuum pump connected to a rotavapor).
The yellow solid was recrystallized from acetone to give the potas-
sium salt of the starting tropolone in 95% yield. The appropriate
alkylating agent (1 equiv) was added slowly to the above potassium
salt of tropolone (1 equiv) followed by Bu4NBr (0.1 equiv) in H2O
(0.4 mL/mmol). The reaction was conducted at r.t. or reflux depend-
ing on the alkylating agent (see Table 1), and monitored by TLC
(CH2Cl2/EtOAc, 7:3). Workup and purification were identical to
stoichiometric method.
b) Takeshita, H.; Mametsuka, H. Heterocycles 1984, 22, 663.
c) Takeshita, H.; Mametsuka, H. J. Heterocycl. Chem. 1986,
23, 1211.
(8) Lammers, M. and Follmann, H. The Ribonucleotide
Reductases: A unique Group of Metalloenzymes Essential for
Cell Proliferation Springer-Verlag: Berlin, 1983; pp 27-91.
(9) Yamato, M.; Ando, J.; Sakaki, K.; Hashigaki, K.; Wataya, Y.;
Tsukagoshi, S.; Tashiro, T.; Tsuruo, T. J. Med. Chem. 1992,
35, 267.
(10) Irvine, N.; Majewski, M. Org. Prep. Proced. Int. 1995, 27,
592.
Acknowledgement
(11) Bushby, R.; Jarecki, C. J. Chem. Soc, Perkin Trans. 1 1990,
2335.
(12) Takeshita, H.; Mametsuka, H.; Matsuo, N. Bull. Chem. Soc.
Jpn. 1982, 55, 1137.
(13) Minns, R. A.; Elliott, A. J.; Sheppard, W. A. Org. Synth. 1977,
57, 117.
(14) Tanaka, K.; Yoshikoshi, A. Tetrahedron 1971, 27, 4889.
(15) a) Nozoe, T.; Mukai, T.; Takase, K. Science. Repts. Tôhoku
Univ. 1952, 36, 40; Chem. Abstr. 1954, 48, 3946.
b) Nozoe, T.; Mukai, T.; Takase, K. Proc. Jpn Acad. 1951, 27,
561; Chem. Abstr. 1952, 46, 7561.
(16) Barltrop, J. A.; Nicholson, J. S. J. Chem. Soc. 1948, 116.
(17) Vanelle, P.; Rathelot, P.; Maldonado, J.; Crozet, M. P.;
Heterocycl. Commun. 1994, 1, 41.
This work has been made possible by the generosity of Rhône-Pou-
lenc Rorer with a BDI grant co-financed by Rhône-Poulenc Rorer
and the CNRS. Special thanks go to Dr. F. Lavelle and his team at
Rhône-Poulenc Rorer for the biological tests and helpful suggesti-
ons. The authors thank Maxime D. Crozet for his contribution to
this work.
References
(1) Pietra, F. Chem. Rev. 1973, 73, 293.
(2) Pauson, P. L. Chem. Rev. 1966, 55, 9.
(3) a) Harrison, R. M.; Hobson, J. D.; Al Holly, M. M. J. Chem.
Soc. C 1971, 3084.
b) Harrison, R. M.; Hobson, J. D. J. Chem. Soc., Perkin Trans.
1 1973, 1958.
(18) Crozet, M. P.; Gellis, A.; Pasquier, C.; Vanelle, P.; Aune, J.-
P. Tetrahedron Lett. 1995, 36, 525.
c) Harrison, R. M.; Hobson, J. D. J. Chem. Soc., Perkin Trans.
1 1973, 1960.
(19) Vanelle, P.; Madadi, N.; Roubaud, C.; Maldonado, J.; Crozet,
M. P. Tetrahedron 1991, 47, 5173.
d) Harrison, R. M.; Hobson, J. D. J. Chem. Soc., Perkin Trans.
1 1976, 2403.
(4) Takeshita, H.; Mori, A.; Suizu, H. Bull. Chem. Soc. Jpn. 1987,
60, 1429.
(5) Bass, R. J.; Gordon, D. W. Synth. Commun. 1985, 15, 225.
Article Identifier:
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Synthesis 1999, No. 7, 1149–1154 ISSN 0039-7881 © Thieme Stuttgart · New York