Development of a dual fries-claisen rearrangement strategy

Article abstract of DOI:10.1055/s-0031-1291158

In this paper we describe the development and application of a sequential Fries-Claisen rearrangement strategy as a new route for annelation on an aromatic ring. We demonstrate the potential utility of this protocol through the synthesis of a pyranonaphthoquinone target.

Full text of DOI:10.1055/s-0031-1291158

LETTER
▌1821
lDetteervelopment of a Dual Fries–Claisen Rearrangement Strategy
Development of a Dual Fries–Claisen Sequence
Liam J. Duffy,a Jason Garcia-Torres,b Raymond C. F. Jones,b Steven M. Allin*c
a
Research Institute for the Environment, Physical Sciences and Mathematics, Keele University, Keele ST5 5BG, UK
b
Chemistry Department, Loughborough University, Loughborough, Leics LE11 3TU, UK
c
School of Science & Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK
Fax +44(115)8486352; E-mail: steve.allin@ntu.ac.uk
Received: 28.03.2012; Accepted: 09.04.2012
which selective chemistry might then be carried out on the
‘upper’ or ‘lower’ edge of the product (as drawn) as the
molecular framework is further developed. We now report
our progress in developing a unique synthetic strategy
based on the coupling of the anionic ortho-Fries and ther-
mal Claisen rearrangements.
Abstract: In this paper we describe the development and applica-
tion of a sequential Fries–Claisen rearrangement strategy as a new
route for annelation on an aromatic ring. We demonstrate the poten-
tial utility of this protocol through the synthesis of a pyranonaphtho-
quinone target.
Key words: annelation, pericyclic reaction, rearrangement, Fries,
Claisen
Individually, the Claisen and anionic ortho-Fries
rearrangements3 are well-known synthetic routes, howev-
er, their incorporation into a dual (consecutive) process on
the same aromatic substrate has not, to the best of our
knowledge, been previously reported, although there has
been one report of an unsuccessful attempt to combine
and control these useful rearrangements.4 In this study,
Green and co-workers were able to perform a thermally
induced Claisen rearrangement on substrate 4, but unfor-
tunately the only product to be isolated in low yield from
a subsequent Fries rearrangement of 5 was the furan 6 as
a byproduct in a complex mixture, rather than the desired
allyl-substituted ketone 7 (Scheme 2).4
Whilst the application of double Claisen rearrangements
has been investigated by others,1 including in conjunction
with ring-closing metathesis (RCM) methodology, as a
method for annelating on a benzene ring,2 one advantage
of developing a process in which different classes of sig-
matropic rearrangement are combined and applied con-
secutively to an aromatic substrate is that of potential
differentiation of any resulting (possibly annelated) prod-
uct. Scheme 1 shows a typical product of double Claisen
rearrangement from the work of Kotha.2 Given the sym-
metrical nature of the substrate it is clear that this process
would not lead to ready differentiation of emerging func-
tionality within the new ring, whereas one can envisage an
alternative process in which a dual Fries–Claisen strategy
(Scheme 1) could lead to a more flexible target: one in
We began our study with an investigation of the rear-
rangement potential of substrate 8, obtained through a
simple two-step procedure from the readily available diol
6-benzyloxy-1,4-dihydroxynaphthalene.5
We
were
symmetrical "edges"
OMe
O
OMe
R
R
R
R
R
i) double Claisen
ii) methylation
RCM
R
O
O
OMe
OMe
OMe
differentiation
OMe
Fries-Claisen
sequence
R
R
R
R
R
annelate
X
X
R
O
X
OMe
O
OMe O
O
Scheme 1 A comparison of dual sigmatropic rearrangements, highlighting the opportunity for edge differentiation in a mixed-type rearrange-
ment process
SYNLETT 2012, 23, 1821–1823
Advanced online publication: 22.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291158; Art ID: ST-2012-D0281-L
© Georg Thieme Verlag Stuttgart · New York

1822
L. J. Duffy et al.
LETTER
A range of conditions was investigated during the devel-
opment of the anionic ortho-Fries step on our substrates
with varying degrees of success at a reaction temperature
of –78 °C, including the use of LDA as base (0% yield of
11), s-BuLi in DME (0%) and s-BuLi in a THF–DMPU
co-solvent system (30%). Clearly emerging from this
study is the importance of the order of events in this meth-
odology, with ‘Fries before Claisen’ being the rule of
thumb. One possible explanation (Figure 1) may involve
an enhanced relative stability of the C-lithiated intermedi-
ate 14a formed on deprotonation of substrate 8, compared
to 14b obtained from deprotonation of 10. In the case of
substrates such as 10 there is an increased steric crowding
of the aromatic component following Claisen rearrange-
ment. There is also the possibility of competing deproton-
ation of the benzylic/allylic carbon atom, which has
precedent.6 Such additional factors may lead to an unfa-
vorable rearrangement scenario for substrates such as 10
(via 14b).
OMe
O
i, ii
OMe OAc
OMe OAc
5
4
iii
OMe
O
not
OMe OH
O
OMe OH
O
6
7
Scheme 2 Reagents and conditions: i, 220 °C; ii, methylation; iii,
BF3.
pleased to find that thermal Claisen rearrangement of allyl
ether 8 could be achieved in mesitylene at reflux for 24
hours, giving phenol 9 (79%), which was then methylated
to access the Fries precursor 10. N,N-Dimethyl carbamate
10 was subjected to typical conditions for anionic ortho-
Fries rearrangement,3 but we were only able to isolate
starting material, 10, from this attempted reaction
(Scheme 3, step iii). Undeterred by this outcome we re-
versed the order of the rearrangements and were pleased
to find that anionic ortho-Fries rearrangement could be
carried out on substrate 8 to give acyl phenol 11 (67%),
and whilst direct thermal Claisen rearrangement of phenol
11 could not be induced, methylation of 11 to yield ether
12 led, in turn, to us being able to successfully achieve the
desired Claisen step to generate 13 (76%), the first report-
ed product of a dual Fries–Claisen rearrangement process.
O
O
OMe
O
NMe2
Li
O
Li
O
OBn
OBn
O
O
OBn
O
NMe2
NMe2
14a
14b
15
Figure 1 Proposed intermediates and alternative substrate
Intriguingly, application of the isomeric compound 15 to
the Fries–Claisen sequence caused unexpected problems:
we were unable to achieve an anionic ortho-Fries rear-
rangement on this substrate under any reaction conditions
attempted, with either recovery of the starting material or
formation of complex, intractable product mixtures being
observed. At present we are unable to offer an explanation
for this outcome. Given our experience that anionic ortho-
Fries rearrangement must precede the Claisen rearrange-
ment on substrate 8 in order to successfully couple these
protocols we did not investigate compound 15 further.
O
OR
i, ii
iii
NO
REACTION
OBn
OBn
O
NMe2
O
NMe2
8
O
O
9 R = H
The use of N,N-diethyl carbamates as alternative sub-
strates in this strategy has also been investigated and al-
though such substrates undergo a successful Fries–
Claisen sequence (as in Scheme 3), the yield of the initial
ortho-Fries step is, in our hands, lower, typically 40–45%.
The Claisen step performs well with yields generally over
80% for this conversion. We have also, briefly, investigat-
ed Lewis acid catalysis of the Claisen step but have found
that neither BF3 nor BCl3 result in successful rearrange-
ment at 0 °C in CH2Cl2 as solvent.
10 R = Me
iv, v
OH
O
vi
NMe2
NMe2
OBn
OR
O
OBn OR
O
13
11 R = H
12 R = Me
Having demonstrated7 a working sequence that, as out-
lined in Scheme 1, could potentially have advantages
when used for annelation, we wished to take a typical
product of the Fries–Claisen sequence onwards to gener-
ate more interesting targets. Compound 16, obtained
through an analogous synthetic route to 8, was subjected
Scheme 3 Reagents and conditions: i, mesitylene, reflux 24 h; ii,
KOH, MeI, DMF, 20 °C, 4 h; iii, s-BuLi, TMEDA, THF, –78 °C; iv,
s-BuLi, TMEDA, THF, –78 °C; v, NaH, MeI, THF, 20 °C, 4 h; vi,
mesitylene, reflux 3 h.
Synlett 2012, 23, 1821–1823
© Georg Thieme Verlag Stuttgart · New York

LETTER
Development of a Dual Fries–Claisen Sequence
1823
13709. (e) Assimomytis, N.; Sariyannis, Y.; Stavropoulos,
G.; Tsoungas, P. G.; Varvounis, G.; Cordopatis, P. Synlett
2009, 2777.
to the Fries–Claisen protocol (Scheme 4), yielding ad-
vanced product 17 which was then converted by acid-
mediated lactonization8 into the known pyranonaphtho-
quinone 18.9 The pyranonaphthoquinones are an interest-
ing class of naturally occurring antibiotic compound that
also display a wide range of other biological activities,
such as antifungal, antiviral, and anticancer activity.10 Our
current work on the application of this novel dual Fries–
Claisen rearrangement strategy to the synthesis of pyra-
nonaphthoquinone natural product targets will be reported
in due course.
(4) Green, I. R.; Nefdt, S.; Hugo, V. I.; Snijman, P. W. Synth.
Commun. 1994, 24, 3189.
(5) 6-Benzyloxy-1,4-dihydroxynaphthalene was prepared by
a route analogous to that used to access the 6-methoxy
derivative described in detail in: Masquelin, T.; Hengartner,
U.; Streith, J. Synthesis 1995, 780.
(6) Sibi, M. P.; Dankwardt, J. W.; Snieckus, V. J. Org. Chem.
1986, 51, 273.
(7) General Procedure for the Fries–Claisen
Rearrangements: Claisen Rearrangement of 8
4-(Allyloxy)-8-(benzyloxy)naphthalen-1-yl dimethyl
carbamate (8, 1.0 g, 2.65 mmol) was heated under reflux in
mesitylene (10 mL) for 24 h. The solvent was removed under
reduced pressure to yield a tarry brown solid. The crude solid
was dissolved in hexanes (30 mL) and placed under reduced
pressure in order to azeotropically remove any residual
mesitylene. The resulting solid was filter-washed with cold
hexane (30 mL) to yield 9 as a dark brown solid (793 mg,
79%); mp 89–91 °C. IR (thin film, CH2Cl2): 3416, 1634,
1262 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.58, 2.75, 3.26
(2 H, d, J = 6.4 Hz), 5.10 (2 H, s), 5.11–5.12 (1 H, m), 5.15
(1 H, q, J = 2.0 Hz), 5.90–5.97 (1 H, m), 6.14 (1 H, s), 6.74
(1 H, s), 6.82 (1 H, d, J = 7.6 Hz), 7.20 (1 H, t, J = 8.4 Hz),
7.36–7.49 (5 H, m), 7.65 (1 H, d, J = 8.4 Hz). 13C NMR (100
MHz, CDCl3): δ = 34.3, 35.7, 36.4, 70.7, 106.5, 115.0,
116.2, 119.1, 120.1, 121.5, 125.0, 126.9, 128.0, 128.2, 128.5
(2 C), 129.2, 136.2, 137.0, 139.6, 147.0, 154.4, 156.3.
HRMS–FAB: m/z calcd for C23H23NO4: 377.1627; found:
377.1621 [M+].
O
OMe
i–iv
NMe2
OMe
16
O
NMe2
O
OMe
v
OMe
17
O
O
O
O
O
OMe
18
Scheme 4 Reagents and conditions: i, s-BuLi, TMEDA, THF,
–78 °C (92%); ii, NaH, MeI, THF, 20 °C, 4 h (80%); iii, mesitylene,
reflux 3 h (92%); iv, K2CO3, MeI, acetone reflux, 24 h, 83%; v, 6 M
HCl aq, heat, 24 h (59%).
Fries Rearrangement of 12
4-(Allyloxy)-8-(benzyloxy)-1-methoxy-N,N-dimethyl-2-
naphthamide (12, 1.68 g, 4.30 mmol) was heated to 160 °C
in mesitylene, and the reaction was monitored by 1H NMR
analysis. After 3 h the mesitylene was removed by eva-
poration under reduced pressure. The crude tarry brown
solid was dissolved in hexanes and placed under reduced
pressure in order to azeotropically remove any residual
mesitylene. This process was repeated three times to give a
light brown solid which was chromatographed on silica gel,
eluting with light PE–EtOAc (1:1), to give 13 as a white
solid (1.28 g, 76%); mp 169–170 °C. IR (ATR): 1594, 1570,
1261, 1058 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.82 (3
H, s), 3.16 (3 H, s), 3.24 (1 H, dd, J = 7.2, 16.2 Hz), 3.37 (1
H, dt, J = 1.8, 16.2 Hz), 3.73 (3 H, s), 5.12–5.18 (2 H, m),
5.22 (2 H, q, J = 12.0 Hz), 5.87–5.99 (1 H, m), 6.22 (1 H, s),
6.92 (1 H, d, J = 7.8 Hz), 7.31–7.43 (4 H, m), 7.54 (2 H, d,
J = 6.9 Hz), 7.81 (1 H, dd, J = 0.6, 8.4 Hz). 13C NMR (100
MHz, CDCl3): δ = 32.3, 34.6, 38.5, 63.7, 71.3, 108.2, 115.2,
116.2, 117.1, 119.7, 126.0, 127.5 (2 C), 127.8, 128.5 (2 C),
128.7, 129.0, 135.6, 137.0, 145.8, 146.8, 155.0, 169.4.
HRMS (EI, CI): m/z calcd for C24H25NO4: 392.1856; found:
392.1853 [MH+].
Acknowledgment
We thank EPSRC for financial support of this project
(EP/F026552/1), Keele and Loughborough Universities for faci-
lities and financial support, and the EPSRC Mass Spectrometry Ser-
vice Centre (Swansea) for HRMS data.
References and Notes
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(2) Kotha, S.; Mandal, K. Tetrahedron Lett. 2004, 45, 2585.
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