Application of the BHQ benzannulation reaction to the synthesis of benzo-fused coumarins

Article abstract of DOI:10.1016/j.tetlet.2009.03.077

A new approach to the synthesis of the 6H-benzo[d]naphtha[1,2-b]pyran-6-one ring system present in the gilvocarcin family of antibiotics is described. The key feature of this approach is the application of a new benzannulation strategy (the 'BHQ Reaction'

Full text of DOI:10.1016/j.tetlet.2009.03.077

Tetrahedron Letters 50 (2009) 3617–3620
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Application of the BHQ benzannulation reaction to the synthesis
of benzo-fused coumarins
James A. Bull a, Cristina Luján a, Michael G. Hutchings b, Peter Quayle a,
*
a School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
b DyStar UK Ltd, School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach to the synthesis of the 6H-benzo[d]naphtha[1,2-b]pyran-6-one ring system present in
the gilvocarcin family of antibiotics is described. The key feature of this approach is the application of
a new benzannulation strategy (the ‘BHQ Reaction’) whereby readily available ortho-allylaryl trichloroac-
etates are transformed into naphthalene derivatives via a cascade of reactions involving an initial ATRC
reaction followed by the extrusion of CO2.
Received 13 January 2009
Revised 9 March 2009
Accepted 11 March 2009
Available online 16 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
ATRC
Kharasch
Cyclisation
Radical
Copper
Carbene
Benzannulation
Lactone
During our investigations into the use of Atom Transfer Radical
Cyclisation (ATRC) reactions in organic synthesis1 we recently
happened upon a new synthesis of naphthalene derivatives2 start-
ing from ortho-allylaryl trichloroacetates—the ‘BHQ Reaction’
(Scheme 1).
This unanticipated cyclisation sequence is compatible with a
wide range of common functional groups and can be promoted
using a variety of transition metal catalysts3 under either micro-
wave activation conditions1 or purely thermal conditions.4 Of the
catalysts screened so far those that are copper based, most notably
using a combination of 1 with CuCl or the preformed NHC carbene
complex 25, appeared to be particularly effective in promoting this
particular transformation.
The starting point of this study centred upon an investigation
into the benzannulation reactions of trichloroacetates 5 and 8, sub-
strates that were readily prepared in a three-step sequence from
either 6-hydroxycoumarin 3 or umbelliferone (Scheme 2).
Conversion of 3 or umbelliferone to their respective allyl ethers
followed by a thermally driven Claisen rearrangement (thermoly-
sis in either Ph2O or N,N-diethylaniline) resulted in the isolation
of phenols 49 and 710 in good overall yield. Acylation of 4 and 7
Cl
R
R
OCOCCl3
[M]
Mindful of the fact that there exist relatively few general ap-
proaches6 to the synthesis of carbocyclic aromatics from simple
acyclic precursors we have sought to define the scope and limita-
tions of this methodology and herein we present its application
to the synthesis of benzo-fused coumarin derivatives, a structural
motif common to a variety of natural products. In particular we
were interested in developing a general approach to the synthesis
of the 6H-benzo[d]naphtha[1,2-b]pyran-6-one ring system7 which
is common to a number of natural products such as gilvocarcin V8a
and arnottin I8b (Fig. 1).
CO2 + 2 x HCl
R= OR, Halogen, NO2, CO2R,
CHO, COR etc.
[M] = Redox-active TM catalyst
N
N
N
N
N
Cl
CuCl
N
1
2
* Corresponding author. Tel.: +44 161 275 4619; fax: +44 161275 4598.
E-mail address: peter.quayle@manchester.ac.uk (P. Quayle).
Scheme 1. The ‘BHQ reaction’.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.077

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J. A. Bull et al. / Tetrahedron Letters 50 (2009) 3617–3620
OMe OH
A more demanding test of the benzannulation sequence lay in
the cyclisation of trichloroacetate 12, which again was readily
available from umbelliferone via the known phenol 11.13 On this
occasion subjecting 12 to our standard benzannulation conditions
again proceeded without incident, affording the sterically con-
gested bi-aryl derivative 13 in good isolated yield (64% after chro-
matography). The ability to generate bi-aryls in this manner,
without recourse to one of the omnipresent batteries of Pd-medi-
ated coupling strategies now routinely adopted for such transfor-
mations, may have broader synthetic scope and is a facet of the
BHQ reaction which is currently under further investigation.
The fact that the BHQ reaction is also tolerant of functionality
attached to the heterocyclic ring system is exemplified by the
benzannulation of trichloroacetate 16, prepared from bromocou-
marin 1414, to the coumarin 17 with moderate efficiency (41% iso-
lated yield). Parenthetically the major practical drawback of this
particular sequence was the capricious nature of the initial Claisen
rearrangement. Also of note is the observation that optimal yields
of benzannulated product 17 were, in this case, obtained when the
NHC copper complex 2 was utilised as the catalyst under purely
thermal reaction conditions15 (diglyme, 162 °C) rather than under
conditions of microwave activation as employed previously.
In an attempt to extend the BHQ methodology further, benz-
annulation of trichloroacetate 19, a substrate which was readily
accessible from the known enol 189, was undertaken. Crucially,
subjection of the crystalline trichloroacetate 19 to our standard
benzannulation reaction conditions (CuCl (5 mol %); 1 (5 mol %);
O
OMe
OMe
OMe
OH
O
H
O
O
O
O
OH
O
OH
arnottin I
gilvocarcin V
Figure 1. Natural products possessing the 6H-benzo[d]naphtha[1,2-b]pyran-6-one
ring system.
(pyridine, 1.2 equiv; Cl3CCOCl, 1.2 equiv; DCM; 0 °C) afforded the
trichloroacetates 5 and 8 as crystalline solids which were used
without further purification in the crucial BHQ reaction. In the
event thermolysis of
a 0.23 M solution of 8 or 9 in DCE
(DCE = 1,2-dichloroethane) containing CuCl (5 mol %) and the li-
gand 1 (5 mol %) for 2 h at 200 °C in a microwave reactor11 afforded
the isomeric benzannulated products12 6 and 9 in 52% and 85% iso-
lated yields, respectively (Scheme 2).
HO
i
HO
ii
81%
82%
O
O
O
O
O
4
3
lW; 200 °C; 2 h) afforded the coumarin 20 in 38% isolated yield.
This result clearly demonstrated, for the first time, that enol tri-
chloroacetates rather than aryl trichloroacetates could also partic-
ipate in the benzannulation sequence, albeit with a somewhat
diminished yield (Scheme 3).
Cl3C
O
iii
Cl
O
52%
O
O
O
6
5
Given that hydrogen chloride is generated during the course of
BHQ reactions the synthesis of trichloroacetate 23 from esculin16
was undertaken (Scheme 4). This particular substrate possesses
an acid-labile O-glycosidic link whose stability to the relatively
harsh conditions of the benzannulation reaction could be moni-
tored with time as the reaction progressed. In this particular in-
stance optimum yields of the coumarin 24 were realised when a
solution of 23 and carbene complex 2 (5 mol %) in diglyme was
irradiated in a microwave reactor at 170 °C. Examination of the
1H NMR spectrum of the crude reaction mixture from this reaction
indicated the presence of only trace quantities of phenol 25 there-
by assuaging our initial fears that acid-labile functionality would
be incompatible to the reaction conditions used to promote the
benzannulation reaction.
Upon completing these initial methodological investigations we
have begun to investigate its application to the synthesis of the
aromatic core of the gilvocarcins (Scheme 5). Regioselective O7-
allylation of esculetin (allyl bromide (1.2 equiv); K2CO3 (1.2 equiv);
acetone; 56 °C; 41%), followed O6-methylation (71%) afforded the
coumarin 26.17 Claisen rearrangement of 26 was best effected in
a microwave reactor13 (toluene; 217 °C) and was afforded the phe-
nol 27 in essentially quantitative yield after irradiation for 3 h.
ii
iii
92%
Cl
O
O
O
HO
HO
O
O
O
O
O
85%
8
7
9
O
CCl3
76%
i
iv
v
55%
61%
O
O
O
O
HO
O
11
O
10
umbelliferone
Ph
Ph
CCl3
iii
ii
94%
Cl
O
O
O
O
O
O
64%
Ph
Ph
12
13
Br
Br
O
vii
i, vi
100%
HO
O
O
34%
O
O
HO
15
14
Br
O
Br
O
CCl3
viii
41%
Cl
O
O
O
16
17
OH
O
O
O
O
ii
Cl
i
Scheme 2. Initial benzannulation sequences. (i) (a) allyl bromide (1.2 equiv); K2CO3
(1.2 equiv); acetone; 56 °C; 15 h; (b) for prepn. of 4: Ph2O; 260 °C; 1 h; for prepn. 7:
N,N-diethylaniline; 217 °C; 6 h; (ii) Cl3CCOCl (1.2 equiv); pyridine (1.2 equiv);
CCl3
38%
O
O
O
18
O
19
20
CH2Cl2; 0 °C; 3 h; (iii) 1 (5 mol %), CuCl (5 mol %), DCE,
cinnamyl chloride (1.2 equiv); K2CO3 (1.2 equiv); acetone; 56 °C; 24 h; (v) N,N-
diethylaniline; 217 °C; 2 h; (vi) toluene, W, 220 °C, 6 h; (vii) Cl3CCOCCl (1.2 equiv);
Et3N, (1.2 equiv) Et2O, 20 °C; 16 h; (viii) 2 (5 mol %); diglyme; 162 °C; 7 h.
lW, 200 °C, 2 h; (iv) trans-
Scheme 3. BHQ reaction using enol trichloroacetates. (i) Cl3CCOCCl (1.0 equiv);
Et3N, (1.0 equiv) Et2O, 20 °C; 16 h; (ii) 1 (5 mol %); CuCl (5 mol %), DCE; lW; 200 °C;
l
2 h.

J. A. Bull et al. / Tetrahedron Letters 50 (2009) 3617–3620
3619
AcO
AcO
AcO
AcO
HO
HO
O
O
O
O
O
O
O
AcO
AcO
HO
ii
94%
i
OAc
OAc
OH
50%
HO
O
O
O
O
O
HO
O
O
esculin
22
21
AcO
AcO
AcO
O
O
O
AcO
HO
Cl
AcO
iv
iii
60%
O
AcO
OAc
O
50%
O
O
Ac Cl
O
O
O
O
CCl3
O
23
25
24
Scheme 4. (i) (a) Allyl bromide (1.2 equiv); K2CO3 (1.2 equiv); DMF; 90 °C; 7 h; (b) acetic anhydride (1.2 equiv); pyridine, 20 °C; 17 h; (ii) Ph2O; 210–220 °C; 5 h; (iii)
ClCOCCl3, (1.2 equiv); Et3N (1.2 equiv), Et2O, 0 °C; 3 h; (iv) 2 (5 mol %); diglyme; W; 170 °C; 2 h.
l
with the aid of a CEM MARS Parallel System enabled 6 g of 34 to
HO
HO
MeO
MeO
~100%
O
ii
i
be prepared in a single operation. The regiochemical outcome asso-
ciated with the initial allylation reaction of 31 is based upon liter-
ature precedent17, NOE difference studies on 35 (Figure 2, Scheme
6) and confirmed by the independent synthesis of 32 starting from
iso-vanillin.19 Finally, dehydrogenation of 34 to the aromatic sys-
tem 35 was best effected (63% yield) using 10% Pd–C in refluxing
diphenyl ether20 under aerobic conditions. Interestingly when the
same reaction was conducted under anaerobic conditions methyl
ether 3621, the overall product of a redox process, was isolated in
the much reduced yield of 24%. In this case we presume that the
‘Pd–H’ species generated in the initial dehydrogenation reaction
are then responsible for reduction of the C–Cl bond in 35.
In conclusion we have demonstrated that the BHQ
benzannulation reaction can be applied to the synthesis of the 6H-
benzo[d]naphtha[1,2-b]pyran-6-one ring system. This basic strat-
egy—one which involves the utilisation of simple, yet robust,
ortho-Claisen rearrangements followed by ATRC reactions—enables
the rapid synthesis of polycyclic coumarin-containing systems, from
readily available starting materials. Further application to the syn-
thesis of gilvocarcins is now in hand.
Representative experimental procedure: A solution of trichloro-
acetate 33 (919 mg, 2.3 mmol), CuCl (5 mol %, 11 mg, 0.12 mmol)
and ligand 1 (5 mol %, 33 mg, 0.115 mmol) in freshly distilled
1,2-dichloroethane (10 mL) was placed in 20 mL microwave reac-
tion vial and flushed with dry nitrogen. The sealed vial was heated
to 200 °C for 2 h in a microwave reactor11 and then allowed to cool
to room temperature. The solvent was removed in vacuo and the
residue purified by column chromatography (silica; eluent 1:9
ethyl acetate:petrol) to afford the title compound, 34 as a yellow
O
O
O
O
29%
HO
O
O
esculetin
26
27
MeO
MeO
Cl
iii
iv
84%
O
O
O
98 %
O
O
28
Cl3C
O
29
Scheme 5. (i) (a) Allyl bromide (1 equiv); K2CO3 (1 equiv); acetone; 52 °C; 12 h; (b)
MeI (1.2 equiv); K2CO3 (1 equiv); acetone; 20 °C; 15 h; (iii) (a) toluene; W; 217 °C;
3 h; (b) Cl3COCl (1.2 equiv); pyridine (1.2 equiv); DCM; 0 °C; (iv) 1 (5 mol %), CuCl
(5 mol %); DCE; W; 200 °C; 2 h.
l
l
Trichloroacetylation (Cl3CCOCl (1.2 equiv); pyridine (1.2 equiv);
DCM; 0 °C; 3 h; 98%) of 27 followed by benzannulation of the crys-
talline ester 28 again proceeded smoothly, leading to the isolation
of the coumarin 29 in 84% after chromatography. With the success-
ful outcome of this study the same sequence was repeated using
diol 31 which itself was prepared in 67% yield via a Pechmann con-
densation18 of 30 with 2-ethoxycarbonylcyclohexanone. Regiose-
lective etherification (88%) of 31 followed by Claisen
rearrangement (ꢀquantitative) in a microwave reactor and subse-
quent trichloroacetylation enabled rapid access to multi-gram
quantities of the key intermediate 33 (Scheme 6).
Most gratifyingly subjecting 33 to our standard benzannulation
conditions (1 (5 mol %); CuCl (5 mol %); DCE;
sulted in the isolation of 34 in 92% yield. Scaling up this reaction
lW; 200 °C 2 h) re-
MeO
MeO
O
AcO
AcO
HO
HO
iii
ii
EtO2C
OAc
i
H H2C
O
O
O
83%
O
O
O
67%
62%
O
O
CH3O
O
32
31
33
30
Cl3C
O
O
H
O
CH2
iv
v
MeO
MeO
Cl
MeO
Cl
94%
63%
= nOe
O
O
O
O
O
O
Figure 2
36
34
35
vi; 24%
Scheme 6. (i) H2SO4 (75%, w/v); 60 °C for 0.5 h then 20 °C for 15 h; (ii) (a) allyl bromide (1 equiv); K2CO3 (1 equiv); acetone; 52 °C; 12 h; 88%; (b) MeI (1.2 equiv); K2CO3
(1 equiv); acetone; 20 °C; 15 h; 94%; (iii) (a) toluene; W; 217 °C; 3 h; ꢀ100%; (b) Cl3COCl (1.2 equiv); pyridine (1.2 equiv); DCM; 0 °C; 62%; (iv) 1 (5 mol %), CuCl (5 mol %);
DCE; W; 200 °C; 2 h; (v) 10% Pd–C; Ph2O; 259 °C; in air; 15 h; (vi) 10% Pd–C; Ph2O; 259 °C; under N2; 48 h then at 259 °C in air; 24 h.
l
l

3620
J. A. Bull et al. / Tetrahedron Letters 50 (2009) 3617–3620
1117.7, 797.0 cmÀ1; MS (EI+) m/z 195 ([MÀCl]+, 16%), 230 (M+, 100%); HRMS
(EI+) C13H7O2Cl (M+) requires 230.0129, found 230.0120. Compound 9: 1H NMR
(500 MHz, CDCl3) d 8.52 (d, 1H, J = 9 Hz), 8.17 (d, 1H, J = 10 Hz), 7.89 (d, 1H,
J = 10 Hz), 7.77 (d, 1H, J = 8 Hz), 7.62–7.56 (m, 2H), 6.60 (d, 1H, J = 10 Hz) ppm;
IR mmax (KBr) 1728.8, 1653.2, 1602.7, 1559.1, 1378.2, 1330.2, 1262.8, 1102.4,
923.0, 837.4, 758.7 cmÀ1; MS (EI+) m/z 201 ([MÀCOH]+, 100%), 229 ([MÀH]+,
78%); HRMS (EI+) C13H7O2Cl (M+) requires 230.0129, found 230.0128.
Compound 13: 1H NMR (500 MHz, CDCl3) d 8.19 (d, 1H, J = 9 Hz), 7.68 (t, 1H,
J = 8 Hz), 7.52 (d, 1H, J = 9 Hz), 7.41–7.38 (m, 3H), 7.31 (d, 1H, J = 8 Hz), 7.28–
crystalline solid. Yield 664 mg (92%); mp 148 °C. 1H NMR
(500 MHz, CDCl3) d 8.37 (d, 1H, J = 8 Hz), 7.53 (d, 1H, J = 7 Hz),
7.38 (t, 1H, J = 8 Hz), 6.75 (s, 1H), 3.90 (s, 3H), 2.76–2.73 (m,
2H), 2.58–2.56 (m, 2H), 1.87–1.82 (m, 2H), 1.80–1.75 (m, 2H)
ppm; IR mmax (KBr) 2935.1, 1705.5, 1696.5, 1584.9, 1570.0,
1396.1, 112.9 cmÀ1; MS (EI+) m/z 299 ([MÀCH3]+, 3%), 314 (M+,
39%). (CI+) 315 ([M+H]+, 100%); HRMS (EI+) C18H15O3Cl (M+) re-
quires 314.0698, found 314.0704.
7.26 (m, 2H), 6.30 (d, 1H, J = 10 Hz) ppm; IR mmax (KBr) 2364.2, 1722.5, 1602.6,
1497.6, 1340.8, 1101.4, 937.6, 877.0 830.9, 699.9 cmÀ1; MS (EI+) m/z 306 (M+,
100%); HRMS (ES+) C19H15O2NCl ([M+NH4]+) requires 324.0786, found
324.0781. Compound 17: 1H NMR (300 MHz, CDCl3)
d
8.48 (brd. d, 1H,
J = 8 Hz); 8.24 (s 1H); 8.16 (d, 1H, J = 9 Hz), 7.78 (1H, dd, J = 8 Hz), 7.58 (1H, apt.
t, J = 8 Hz), 7.53 (d, 1H, J = 9 Hz) ppm; IR
max (KBr) 1732.5 cmÀ1; MS (EI+) m/z;
Acknowledgement
m
HRMS (ES+). Compound 20: 1H NMR (500 MHz, acetone-d6) d 8.22 (d, 1H,
J = 8 Hz), 8.13 (d, 1H, J = 8 Hz), 7.71 (t, 1H, J = 8 Hz), 7.57 (d, 1H, J = 8 Hz), 7.44
(t, 1H, J = 8 Hz), 7.25 (t, 1H, J = 8 Hz), 7.19 (d, 1H, J = 8 Hz) ppm; IR mmax (KBr)
1732.8, 1728.8, 1447.3, 1249.2, 1219.1, 1045.9, 1015.5, 804.8, 742.1 cmÀ1; MS
(EI+) m/z 195 ([MÀC]+l, 3%), 230 (M+, 21%). (CI+) m/z 214 ([MÀO]+, 14%), 231
([M+H]+, 100%); HRMS (ES+) C13H7O2Cl (M+) requires 230.0133, found
230.0129. Compound 24: 1H NMR (500 MHz, CDCl3) d 8.47 (1H, dd, J = 8,
J = 1 Hz), 7.75 (1H, d, J = 9 Hz), 7.68 (1H, dd, J = 8 Hz, J = 1 Hz), 7.51 (1H, apt. t,
J = 8 Hz), 7.13 (1H, s), 6.56 (1H, d, J = 9 Hz), 5.48 (1H, dd, J = 10 Hz, J = 8 Hz),
5.33 (2H, apt. t, J = 9 Hz), 5.32 (1H, d, J = 8 Hz), 5.27 (1H, apt. t, J = 9 Hz), 4.32
(1H, apt t, J = 12 Hz, J = 5 Hz), 4.24 (1H, dd, J = 12 Hz, J = 3 Hz), 3.98 (1H, ddd,
J = 7 Hz, J = 5 Hz, J = 3 Hz), 2.08 (3H, s, OCOCH3), 2.06 (3H, s, OCOCH3), 2.06 (6H,
J.A.B. and C.L. thank DyStar UK Ltd for support of this research
programme.
References and notes
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s, 2 x OCOCH3) ppm; IR mmax(film): 1746.14, 1560.2, 1458.9, 1424.18, 1366.6,
1318.1, 1233.8, 1041.5, 911.7 cmÀ1; HRMS (ES+) C27H25ClNaO12 ([M+Na]+)
requires 599.0932; found 599.0942. Compound 25: 1H NMR (500 MHz, CDCl3)
d 8.55 (1H, d, J = 9 Hz), 8.02 (1H, s), 7.75 (1H, d, J = 9 Hz), 7.61 (1H, d, J = 8 Hz),
7.53 (1H, apt. t, J = 8 Hz), 7.01 (1H, s,), 6.56 (1H, d, J = 9 Hz) ppm. Compound 29:
1H NMR (500 MHz, CDCl3) d 8.37 (d, 1H, J = 9 Hz), 7.67 (d, 1H, J = 10 Hz), 7.59
(d, 1H, J = 8 Hz), 7.42 (t, 1H, J = 8 Hz), 6.69 (s, 1H), 6.47 (d, 1H, J = 10 Hz), 3.91 (s,
3H, CH3O) ppm; IR mmax (KBr) 2923.7, 1715.9, 1590.6, 1559.8, 1379.6, 1322.3,
1123.8, 1103.6, 904.4, 750.0 cmÀ1; MS (CI+) m/z 245 ([MÀCH3]+, 11%), 260 (M+,
100%); HRMS (EI+) C14H9O3Cl (M+) requires 260.0235, found 260.0229.
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2H), 8.04 (d, 1H, J = 8.2 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.50 (t, 1H, J = 8 Hz), 7.43 (d,
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1H, J = 9 Hz), 6.52 (d, 1H, J = 10 Hz) ppm; IR
m
max (KBr) 1732.9, 1651.9, 1567.8,
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