Fluorine as an ortho-directing group in aromatic metalation: A two step preparation of substituted benzo[b] thiophene-2-carboxylates

Article abstract of DOI:10.1016/S0040-4039(00)60806-7

A simple 2-step synthesis of B-ring substituted benzo[b]thiophene-2-carboxylates from aryl fluorides has been developed. The route involves a selective lithiation ortho to fluorine, followed by formylation, and subsequently, displacement of fluorine with

Full text of DOI:10.1016/S0040-4039(00)60806-7

$5.00 +
Ltd
Vol. 33. No. 49. pp.
Britain
1992
Fluorine as an ortho-Directing Group in Aromatic Metalation:
A Two Step Preparation of Substituted
Alexander J .
Lee, Emmanuel C. Maduakor and C. Eric Schwartz
Research Institute,
4
Drive, Andover
01810
Abstract: A simple
synthesis
substituted
from
has
been developed. The route involves a selective lithiation ortho
followed by
and subsequently,
with and base-induced ring closure in a single operation.
In connection with a pharmaceutical project we required a series of B-ring
2-carboxylates 1. From a practical point of view, a process was needed which fused the constant part of the
molecule. the thiophene ring, onto a readily available benzene derivative to ensure a wide array of B-ring
substituents. Such a strategy has been recently employed by
preparation, and by Johnson2 who used a directed-metalation based approach. The ester functionality of
allows the economical use of an intramolecular aldol of 2 to construct the ring. Several routes
in an elegant zirconocene mediated
1
can be envisioned to 2, but nucleophilic displacement by thloglycollate on a suitably 2-substituted benzaldehyde
3 appeared attractive, as many benzaldehydes are commercially available. However, the regioselective
introduction of a leaving group ortho to an aryl aldehyde is not a straightforward problem. One of the best
leaving groups in activated aromatic systems is fluorine? and this has been heavily exploited, especially in the
synthesis of the extremely potent quinolone antibiotics.
acidification of the ortho protons.5 This allows one to consider using the fluorine atom both as a leaving group
for nucleophilic substitution, and as a template to introduce an electron withdrawing substituent via
Another useful property of fluorine is the strong
directed-metalation. Both of these properties of fluorine have been exploited.6 Such a strategy leads to the
retrosynthetic analysis of Figure 1, where an aryl fluoride 4, of which a large number are commercially
available, is the precursor for benzothiophene 1.
1
2
3
4
Figure 1. Retrosynthetic Analysis for
Synthesis from Aryl Fluorides.
In the preceding communication.7 we have demonstrated that lithiation ortho to fluorine in aryl fluorides
is a very general and synthetically useful process, with very predictable regiocontrol by fluorine. In this
communication we wish to report that formylation of lithiated aryl fluorides, followed by a base induced
nucleophilic displacement of fluoride by thioglycollate and subsequent intramolecular aldol condensation, is a
very simple and general two pot preparation of a wide variety of B-ring substituted
carboxylate esters 1.
Metalations of aryl fluorides 4 were carried out with: lithium diisopropylamide (LDA, Method A) if
possible, n-butyllithium with or without
second choice, with or without TMEDA (Method
Method B) as the
or lithium
Parke.-Davis
Division, 2800
Rd. Ann Arbor
48105.

7500
Method D). We found that a
quench of the aryllithium with slightly more than 1 equivalent of
and a rapid aqueous workup, gave the benzaldehydes 3 in
major impurity was most often starting material, and in practice,
was usually needed prior to the next step.
experimentation, a simple procedure (Method 1) was devised for
at
equiv) in DMSO. The aldehyde 3 was then added rapidly to the mixture
and a vigorous exotherm, darkening to red-orange colors, and gas evolution occurred unchecked. If
these changes were not seen, the reaction was not successful. After 2-5 minutes the reaction mixture was poured
DMF. followed 10 minutes later by excess acetic
generally good
we found that no
After
(Table
mmol)
thiophene annulations. Methyl thioglycollate (1.1 equiv) was added
to a slurry of
washed
onto rapidly stirred ice-water, and the product
regardless of the purity of the starting aldehyde. Occasionally, nothing precipitated (Entry
extractions and further purification were out.
Although this procedure is marked by extreme rapidity and simplicity, it does not scale up well, giving
lower yields and less pure products above the 10 scale.
as an uncontrolled exotherm is required, whilst hydrogen is being evolved. A less spectacular
procedure (Method 2) was devised using (2-2.5 equiv) as the base in DMSO, this time heating to
for several hours. The could be readily followed by and when
complete, it was worked up by the same ice-water quench and filtration as before.
1
8
was collected by suction filtration, usually in
purity
and organic
was
Table 1 illustrates the usefulness and generality of this synthesis. If the substiment on the B-ring is itself
an ortho director for metalation, Csubstituents are very easy to incorporate, as shown in Entries 1-4, where
substituted fluorobenzenes are the starting materials. If the substituent does not ortho-direct metalation (eg
methyl) this is not a synthetically useful procedure, (although a protection&protection strategy would
presumably solve the problem, as in Entries 12 and 13.). A variant on the general process is shown in Entry 5,
where mono-displacement on
with sodium benzylthiolate was followed by
thioglycollate annulation. Many pant-substituted fluorobenzenes can be metalated ortho to the fluorine atom7
(Entries
and then annulated to form the desired
heterocycles. The very low yield
obtained in the annulation step of the
derivative (Entry
presumably reflects the deactivating effect
of a strong electron donor towards
nucleophilic attack on the ring. If the substituent is not ortho
compounds should be straightforward as the aromatic should
obtaining
preferentially on the less hindered side of the fluorine atom. The final product in Entry 11. however, was
contaminated with 20% of the 4-methyl benzothiophene. (Purification at the aldehyde stage was possible by
chromatography, but an extremely facile autooxidation of fluorotolualdehydes cut the yield to below 10%).
If the substituent is an ortho director (Entries 12 and
then the reactive 2-position of the original
fluoroaromatic was blocked by the Snieckus strategy of silylation. followed by another metalation and
formylation on the less acidic side of the fluorine atom. Partially desilylated products were produced from the
thiophene annulations, and Entry 12 was completely desilylated with TFA and Entry 13 with TBAF. Formation
of ‘I-substituted benzothiophenes (Entry 14) is straightforward and involves metalation of the appropriate
disubstituted fluorobenzene.7 More highly substituted compounds can be produced by starting with more highly
substituted benzene derivatives as illustrated in Entry 15.
Entries 1, 6, 12, 14 and 15 produce iodldes, which we have shown to undergo the usual
catalyzed coupling reactions of aryl
in excellent yields, allowing for the ready elaboration of B-ring
side chains. Entries 2 and 7 can be hydrolyzed to the corresponding aldehydes, and these too can act as excellent
platforms for new carbon-carbon bond formation. By the use of o-fluorobenzoates, o-fluorobenzonitriles or
fluoroacylphenones, one can also put hydroxy, amino, or alkyl substituents at the 3-position of the heterocycle,
although these cyclizations never worked as well as the aldehyde cyclizations.
In summary, this paper describes a very flexible and rapid two step synthesis of 2,n

7501
Table 1. Preparation of
from
A
u
56%
55%
1
1
1
87%
49%
A
62%
B+
F
63%
64%
7%
1
1
1
1
1
77%
77%
48%
82%“
63%
A
8
F
A
9
F
B+
10
11
F
61%“
A
12
13
I
F
D
A
then
D
26%
1
75%
F
NC
then
F
I
14
1
50%
97%
A
1
A
text,
with
Did
or
The strategy relies on the ability of a fluorine atom to acidify the neighboring aromatic
proton(s), allowing for an activating group to be via lithiation. The sequence then dies on
the ability of the fluorine atom on the activated aromatic systan to be subsequently displaced by

7502
REFERENCES AND NOTES.
1.
2.
3.
S. L.; Fang, Q. J. Org.
Johnson, F.; Subramanian, R. J. Org.
Reinheimer, J. D.; Taylor, R. C.; Rohrbaugh, P. E. J. Am.
E. W.; Pruitt, K. M. ibid 385.
1989.54, 2793.
5040.
835.
J. F.;
1951. 2340.
C. W. L. J.
Beckwith. A. L.; Miller, D.;
G. D. ibid, 1952 3552. Idoux. J. P.; Madenwald, M. L.; Garcia, B.
S.; Chu, D.-L.; Gupton, J. T. J. Org.
1876.
4.
Chu. D. T. W.; Prabhavathi, B. F.; Akiyo, K. C.; Pihuleac, E.; Nordeen, C. W.; Maleczka, R. E.;
A. G. J. Med. Chem.
1558. Miyamoto. T.; Matsumoto, J.;
K.; Egawa, H.;
K.; Minamida, A.; Nishimura, Y.;
H.; Kataoka, M.;
M.;
T.; Nakano.
J. ibid
1645. Sanchez, J. P.; Domagala, J. M.;
S. E.; Heifetz, C. L.; Hutt, M. J.;
Nichols, J. B.; Trehan. A. K. ibid
983.
5.
6.
Streitweiser, A.; Mares. F. J. Am.
644. Streitweiser. A.; P. J.;
Niemeyer, H. M. ibid
7936. Bridges, A. J.; Patt, W. C.; Stickney, T. M. J. Org. Chem
1990.55. 773.
Semmelhack, M. F.; Bisaha, J.; Czarny, M. J. Am. Chem
1979,101, 768. Meyers, A.
B. E. Tetrahedron
1978,223. Sanchez, J. P.; Bridges, A. J.; Busch, R.; Domagala,
J. M.; Gogliotti, R. D.;
S. E.; Heifetz, C. L.; Joannides, E. T.; Sesnie, J. C.; Shapiro, M. A.;
Szotek, D. L. J. Med. Chem 1992.35, 361. Domagala, J. M.; Bridges, A. J.; Culbertson, T. P.;
Gambino, L.;
Szotek, D. L.; Wemple. J. ibid
Bridges, A. J.; Lee, A.; Maduakor. E. C.; Schwartz, C.
S. E.; Karrick, G.; Portere, K.; Sanchez, J. P.; Sesnie, J. C.;
F. G.;
10 mmol)
DMF
1142.
7.
see preceding paper “this journal.
8. A sample experimental for Entry 3 is described: n-Butyllithium (2.3 M in hexanes, 4.35
was added
over 5 min to a solution of diisopropylamine (1.113 g, 11 mmol) in THF (20
stirred under
at
After 10
(1.643 g, 10.0 mmol) was added
11 mmol) was added over 5 min. After a further 10 min at
the reaction mixture was cooled to
and
over 5 min. After 1 h at
(0.80
the reaction mixture
The cold
washed
The
was quenched by the rapid addition of acetic acid (2
solution was quickly extracted with ether (3 x 25
followed quickly by
and the combined organic extracts
saturated brine (25 and dried
removed under reduced pressure to give crude
(1.85 g, 18% by weight solvent, 80%) as a light yellow oil:
(50
with dilute
(0.2 M. 25
water (25
solvent was
NMR (CDC13) 10.43
sl br s), 7.69
sl br dt, J = 5.2, 8.0 Hz), 7.62
br d, J = 7.6 Hz),
7.42
br dd. J = 8.4, 10.2 Hz).
Methyl thioglycollate (0.72
8
was added over 10 min to a
suspension of
hexanewashed
(60% oil suspension, 0.50 g, 12.5 mmol) in DMSO (10
stirred under
on a
water bath. When gas evolution died down the bath was removed and the light yellow solution was
for 15 min. Crude
mmol) in DMSO (2
(1.85 g, 18% by weight solvent, 8
was added rapidly, and an exotherm, gas evolution and considerable darkening of
the reaction mixture were observed. After 3 min the mixture was poured onto rapidly stirred ice-water
(100 and the precipitate was collected by suction filtration, rinsed with water (2 x 25 and air
dried to give methyl
pale beige powder:
7.5, 0.7 Hz), 7.54
(1.17 g, 56%) as
a
NMR (CDC13) 8.27
sl br dd, J
sl br s). 8.06
s).
d, J = 8.2 Hz), 7.73
dq. J =
Hz), 3.98
9.
10. Heck, R. F. “Palladium Reagents in
Stille, J. K. Angew. Chem., Ed.
Mills, R. J.; Taylor, N. J.;
V. J. Org. Chem..
4372.
Syntheses,” Academic Press, London, 1985. pp. 299-306.
508.
(Received in USA 14 May 1992; accepted 2 September 1992)