6-exo versus 7-endo iodolactonizations of 2-(alkynyl)phenylacetic acids

Article abstract of DOI:10.1016/j.tetlet.2008.12.097

Exposure of 2-alkynylphenylacetic acids to excess iodine in acetonitrile containing anhydrous potassium carbonate delivers good yields, either of the corresponding isochroman-3-ones or benzo[d]oxepin-2(1H)-ones, depending upon the alkyne substituent: when

Full text of DOI:10.1016/j.tetlet.2008.12.097

Tetrahedron Letters 50 (2009) 1385–1388
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Tetrahedron Letters
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6-exo versus 7-endo iodolactonizations of 2-(alkynyl)phenylacetic acids
*
Mohamed Gomaa Ali Badry, Benson Kariuki, David W. Knight , Mohammed F.K.
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Exposure of 2-alkynylphenylacetic acids to excess iodine in acetonitrile containing anhydrous potassium
carbonate delivers good yields, either of the corresponding isochroman-3-ones or benzo[d]oxepin-2(1H)-
ones, depending upon the alkyne substituent: when this is alkyl, the former 6-exo products dominate,
otherwise the 7-endo products are formed largely or, more often, exclusively.
Received 14 November 2008
Revised 12 December 2008
Accepted 23 December 2008
Available online 7 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Baldwin’s rules have provided sound guidance in the design and
rationalisation of cyclisation processes, since these were first re-
ported.1 While there are arguably no or, at least, very few excep-
tions to these principles, there are occasional ambiguities
amongst some pairs of ‘favoured’ cyclisation pathways in various
combinations of substrate and cyclisation method. An example of
this is in cyclisations of 2-(alkynyl)benzoic acids and esters 1,
which can lead either to the ylidenephthalides 2 by a 5-exo-dig
process or to the isocoumarins 3 by a 6-endo-dig cyclisation; in
many cases, mixtures of both products are obtained (Scheme 1).
Thus, during electrophile-driven iodocyclisations of the acids
[1; R = H]2 or esters [1; R = alkyl]3 using iodine, mixtures of the
two products [2 and 3; X = I] were generally obtained, although
use of the more reactive iodine monochloride as an iodonium
source gave very largely or exclusively the 6-endo products [3;
X = I]. Of course, the successful use of iodonium ions to trigger such
cyclisations leaves an iodine atom attached to the product(s),
which is usually amenable to further manipulation, especially
using one of the myriad of modern palladium-catalysed coupling
reactions, as has been demonstrated in the foregoing reports.2,3
These palladium catalysts can even be utilized to induce these very
types of cyclisation, when a preponderance of the 5-exo ylideneph-
thalides [2; X = H] is obtained.4 Similarly, starting with the tribu-
tylstannyl ester of 2-iodobenzoic acid, sequential Sonogashira
coupling and Pd-catalysed cyclisation follows a 5-exo pathway to
give a stannyl ylidenephthalide.5 In contrast, use of silver-based
catalysts tends to favour 6-endo cyclisation to the isocoumarins
[3; X = H], although ylidenephthalides are occasionally the major
products in cyclisations, which appear to be both catalyst- and
substrate-dependent.6 In the latter report, copper catalysis is also
implicated in such cyclisations, but to give mixtures of products;
a later report suggests that 6-endo products are strongly favoured
by copper(I) catalysts in the presence of acid (TFA) and under
microwave conditions.7 Much simpler acidic or basic catalysts
can also be employed to activate the benzoic acid derivatives 1 to-
wards cyclisation: an early study of acid-catalysed cyclisations
indicates that the 5-exo ylidenephthalide products may be the ki-
netic isomers, which subsequently isomerise to the 6-endo iso-
coumarins, although in this particular example,
a suitably
positioned carboxylic acid group may well have provided assis-
tance.8 More recent studies, however, while confirming that acid
catalysis leads to isocoumarins and base-catalysis to the ylide-
nephthalides, strongly suggest this is all due to a mechanistic
change: under acidic conditions, the key is protonation of the car-
boxylic acid group, whereas under basic conditions, it is its depro-
tonation which is key.9
It was against this background that we wondered how the
homologous alkynylphenylacetic acids and derivatives might be-
have under these cyclisation conditions, particularly because, as
in the foregoing cases, both cyclisation modes, 6-exo-dig and
7-endo-dig, are favoured according to Baldwin.1 Further, if the lat-
ter pathway were to be followed, potentially useful benzo-oxepi-
none systems would be generated of a type, which are not
common in the literature. Indeed, only two very recent reports de-
tail any activity in this area of cyclisation methodology. A combina-
tion of a palladium catalyst and potassium hydroxide (DMF, 60 °C,
16 h) is necessary to give decent isolated 42–82% yields of the ben-
zazepinones 5 when the substituent ‘R’ is an alkyl group. In con-
trast to this 7-endo pathway, the corresponding (E)- and (Z)-
isomers of an unstable 3-isoquinolinone 6, the product of 6-exo
cyclisation, are formed from the 2-(phenylethynyl) derivative [4;
R = Ph] (Scheme 2).10
X
R1
R1
X
R1
+
O
O
O
O
OR
O
1
2 [5-exo]
Scheme 1.
3 [6-endo]
* Corresponding author.
E-mail address: knightdw@cardiff.ac.uk (D.W. Knight).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.097

1386
M. G. Ali Badry et al. / Tetrahedron Letters 50 (2009) 1385–1388
Table 1
Ph
R
NHR1
O
Iodolactonizations of 2-(alkynyl)phenylacetic acids 10
R
NR1
O
Pd(II)
KOH
NR1
O
I
R
O
R
I
R
3.I2, 3.K2CO3
MeCN, 20 ºC
+
4
5
6
O
CO2H
O
O
Scheme 2.
10
12
13
Entry
R
Timea
Yield
exo/endo ratio
13C NMR ppmb
In a search for alternative transition metal catalysts for carrying
out the cyclisations shown in Scheme 1, treatment of the acids [1;
R = H] with 10 mol % gold(I) chloride and potassium carbonate in
acetonitrile was found to generally give mixtures of both possible
products [2 and 3; R = X] usually with a preponderance of the 5-exo
when such was observed, whereas exposure of the corresponding
methyl esters [1; R = Me] to gold(III) chloride in wet acetonitrile
gave exclusively the 6-endo products 3.11 Presumably, water is
necessary to assist in hydrolysis of the intermediate methyl oxo-
nium species and to provide protons for a final exchange with
the gold(III). In contrast, exposure of 2-(phenylethynyl)acetic acid
10 to the gold(I) system gave mainly the 6-exo products, ylidene-
lactones, while gold(III) catalysts were inactive. One example,
when the alkyne substituent was n-propyl, gave a preponderance
(9:1) of the 7-endo product, a benzo-oxepinone (see below). We
were therefore intrigued to find out how such 2-(alkynyl)phenyla-
cetic acids would behave under iodolactonization conditions.
The starting materials were readily prepared from commercial
2-iodophenylacetic acid. Homologation of the derived methyl ester
7 by Sonogashira couplings12 with various 1-alkynes 8, using the
excellent, cheap and convenient procedure introduced by Batchu
and co-workers,13 followed by saponification delivered the neces-
sary acids 10 (Scheme 3). In cases where the required aryl alkyne
was not commercially available, this was prepared directly from
3-CH2
C@O
a
b
c
d
e
f
n-Bu
CH2OH
C6H5
4-NO2C6H4
4-MeOC6H4
3,4-CH2OCH2C6H3
2,3,4-(MeO)3C6H2
24
24
24
1
3
2
82
71
67
—
81
66
72
81:19
93:7
76:24
38.2
36.2
37.2
166.9
166.0
166.1
5:95
<5:>95
<5:>95
41.2
41.0
41.0
167.5
168.0
168.9
g
0.2
a
In hours.
b
Chemical shift (400 MHz, CDCl3) of the major isomer.
sulted in useful levels of regioselection, with the major products
being isolated in reasonable yields following column chromatogra-
phy. Use of sodium hydrogen carbonate as base resulted in slightly
lower regioselectivities.
Initial results using the butyl-substituted acid 10a gave two iso-
mers in a ratio of 4.1:1, but the identity of the products was far
from clear. In contrast, the propargyl alcohol derivative 10b gave
almost a single isomer. In both cases, all spectroscopic and analyt-
ical data were consistent with either of the isomeric structures 12
and 13. Very fortunately, it proved to be possible to selectively re-
move the iodine atom from these two products by hydrogenolysis
to give high yields of the de-iodo derivatives, the 1H NMR spectra
of which, when obtained for dilute solutions in deuteriochloroform
at 400 MHz, clearly showed these to be derived from the 6-exo iso-
chromanone isomers 12a and 12b (Scheme 4); it is inconceivable
that such resonances could arise from the alternative regioisomers
15a,b.16
Hence, it was concluded that both the alkyl-substituted precur-
sors 10a,b had undergone selective 6-exo-dig iodolactonizations to
give the isochromanones 12a,b. The likelihood of an anti-addition
mechanism rather favoured formation of the (E)-isomers shown,
as did the identity of the hydrogenolysis products 14a,b when
compared with previously reported samples.11 However, there is
a slight uncertainty regarding this aspect. The major or exclusive
products derived from the remaining substrates 10c–g (Table 1),
all of which have an aryl substituent positioned at the terminus
of the alkyne group differed from these two initial products.
Although infrared carbonyl stretching data were inconclusive,
there was a distinct pattern in the chemical shifts associated with
the 3-methylene and carbonyl resonances in the 13C data (see
Table 1). While the two alkyl-substituted products 12a,b showed
methylene resonances around 37 ppm and carbonyl carbons
the corresponding benzaldehyde using the Ohira-Bestmann
zophosphonate in methanolic potassium carbonate.14 As another
option, more conventional Sonogashira coupling between
a-dia-
a
iodo-ester 7 and trimethylsilylacetylene followed by desilylation
delivered the terminal alkyne 11 in 83% yield for the two steps.
Subsequently, a second Sonogashira coupling with an aryl iodide,
again using the Batchu procedure, and hydrolysis provided an
alternative route to the precursors 10.
The various alkyne substituents employed are detailed in Table 1,
in which the results of our iodolactonizations of the 2-(alky-
nyl)phenylacetic acids 10 are summarized. Following a number
of trial reactions, acetonitrile appeared to be the optimum solvent,
in the presence of 3 equiv each of iodine and anhydrous potassium
carbonate. The requirement for three equivalents of iodine is a typ-
ical feature of such cyclisations; if less is used, cyclisations are usu-
ally incomplete. As yet, this phenomenon has not been
satisfactorily explained.15 As shown in Table 1, the cyclisations re-
R
I
10% Pd-C, PPh3, CuI
CO2Me
CO2Me
Et3N, H2O, 80 ºC
RCCH 8 [80~90%]
7
9
a) δH 5.58 (1H, t, J 7.8 Hz)
i) Pd(PPh3)2Cl2, PPh3, CuI
Et3N, THF 20 ºC,TMSCCH
ii) TBAF, CH2Cl2, 0.25 h, 20 ºC
b) δH 5.65 (1H, t, J 6.8 Hz)
aq. KOH
MeOH, 20 ºC
R
>90%
I
H
a) δH 2.40 (2H, app. q.
J 7.8 Hz)
b) δH 4.45 (2H, d,
O
J 6.8 Hz)
R
O
R
10% Pd-C, Et3N
O
10% Pd-C, PPh3, CuI
EtOAc, 20 ºC, 24 h
CO2Me
Et3N, H2O, 80 ºC
ArI [60~70%]
O
CO2H
12a,b
14a,b
a) R = (CH2)2CH3
b) R = OH
10
then as 9
10
11
Scheme 3.
Scheme 4.

M. G. Ali Badry et al. / Tetrahedron Letters 50 (2009) 1385–1388
1387
I
around 166–167 ppm, these latter products 13e–g showed ranges
R
δ+
I
of ꢀ41 and 168 ppm for the corresponding resonances. Hence, it
was concluded that these were the benzo[d]oxepinones 13e–g,
arising by a 7-endo-dig pathway. These conclusions were also con-
sistent with some appropriate data shown by similar compounds
obtained by Marchal et al. during their work on the related gold-
catalysed cyclisations.11 These data were also consistent with the
probable formation of small amounts of the alternative ring sizes
in each example. Thus, although partly obscured in the initial
iodinated product 12a, the 1H NMR spectrum of the hydrogenolysis
product 14a displayed a distinct olefinic singlet centred on dH 6.21,
which was assigned to the seven-membered ring product [15;
R = C3H7].11 The phenyl case 10c appears to be an exception. Some
further evidence was obtained by hydrogenolysis of the 4-methoxy
derivative 12e, which delivered a product 15 [R = 4-MeOC6H4] dis-
playing an olefinic proton at dH 6.86, a position very similar to that
quoted by Marchal et al.11 for the same compound. By contrast, the
isomeric isochromanone is reported to show an olefinic resonance
at dH 6.28, a clear difference. Unfortunately, other data (remaining
1H and 13C NMR data, m.p.s, ir) were closely similar and could not
realistically be used for definitive assignments.
R
δ+
O
O
>
O
H
O
H
16
17
Figure 2.
OMe
OMe
I
I
I
C
O
O
O
O
H
O
H
O
H
18
19
20
Figure 3.
derivative 10d, while reacting rapidly with iodine, failed to give
meaningful products, a pity, as the product(s) arising could have
contributed significantly to these ideas.
In any event, these examples indicate that this chemistry can be
used to prepare the structural types 12 or 13 with often high reg-
ioselectivities, but only when the correct substituent is present on
the alkyne terminus.
H
R
O
O
15
Acknowledgement
We are grateful to the Egyptian Government for the award of a
Scholarship (to M.G.A.B.).
Final proof of the seven-membered ring structures 13 was obtained
by X-ray crystallographic analysis of the 2,3,4,-trimethoxyphenyl
product 13g, the ORTEP diagram of which is shown in Figure 1.17
Hence, our conclusion is that iodolactonizations of 2-(alky-
nyl)phenylacetic acids 10 favour the 6-exo pathway to give iso-
chromanones 12 when the alkyne substituent is alkyl, but the
alternative 7-endo route leading to benzo[d]oxepinones 13 when
the same substituent is aryl. This may possibly be explained by
considering the process to involve a relatively late transition state.
In the case of an alkyl-substituted intermediate, perhaps the mes-
omeric effect of the aryl ring (16) outweighs the inductive effect of
the alkyl group (17) in stabilizing the developing electron-deficient
carbon centre (Fig. 2).
The relatively poor level of stereoselection shown by the phe-
nyl-substituted example 10c may simply be due to the rather sym-
metrical nature of the intermediate 18, together with the usual
preference for an exo cyclisation mode over a competing endo path-
way (Fig. 3). Participation by a para-methoxy group 19, repre-
sented in extreme form by structure 20, could override all other
factors and explain the very high preference for formation of the
7-endo-dig products 13e–g. Unfortunately, the related 4-nitro
References and notes
1. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. and 738; Johnson, C. D.
Acc. Chem. Res. 1993, 26, 476.
2. (a) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 43,
5023; (b) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron
2003, 59, 2067; For earlier work on bromolactonizations, see: Kraft, G. A.;
Katzenellenbogen, J. A. J. Am. Chem. Soc. 1981, 103, 5459.
3. Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936.
4. Rossi, R.; Bellina, F.; Biagetti, M.; Catanese, A.; Mannina, L. Tetrahedron Lett.
2000, 41, 5281; See also: Sashida, H.; Kawamukai, A. Synthesis 1999, 1145;
Bouyssi, D.; Balme, G. Synlett 2001, 1191.
5. Duchene, A.; Thibonnet, J.; Parrain, J.-L.; Anselmi, E.; Abarbri, M. Synthesis 2007,
597.
6. Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron 2000, 56, 2533.
7. Hellal, M.; Bourguignon, J.-J.; Bihel, F. J.-J. Tetrahedron Lett. 2008, 49, 62; See
also: Ogawa, Y.; Maruno, M.; Wakamatsu, T. Heterocycles 1995, 41, 2587.
8. Letsinger, R. L.; Oftedahl, E. N.; Nazy, J. R. J. Am. Chem. Soc. 1965, 87, 742, and
references therein.
9. Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.;
Sakamoto, T. Org. Lett. 2006, 8, 5517; Kanazawa, C.; Terada, M. Tetrahedron Lett.
2007, 48, 933; For theoretical calculations of the basis of the 5-exo selectivity
under basic conditions, see: Terada, M.; Kanazawa, C.; Yamanaka, M.
Heterocycles 2007, 74, 819.
10. Yu, Y.; Stephenson, A.; Mitchell, D. Tetrahedron Lett. 2006, 47, 3811.
11. Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.; van de Weghe, P. Tetrahedron
2007, 63, 9979.
12. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467;
Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
13. Batchu, V. R.; Subramanian, V.; Parasuraman, K.; Swamy, N. K.; Kumar, S.; Pal,
M. Tetrahedron 2005, 61, 9869.
14. Sahu, B.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2007,
2477. and references therein.
15. Knight, D. W. Prog. Heterocycl. Chem. 2002, 14, 19.
16. For an alternative method for carrying out this selective deiodination, see Ref.
2a.
OMe
I
OMe
OMe
O
O
13g
17. Compound 13g crystallized from ethyl acetate/petrol, mp 157–159 °C.
C19H17IO5, Mr = 452.23, monoclinic, P21/c, a = 16.4140(6) Å, b = 11.5730(4) Å,
c = 9.5930(3) Å, b = 98.675(2)°, V = 1801.43(11) Å3, Z = 4, DX = 1.667 Mg mÀ3
,
k(Mo
Ka) = 0.71073 Å, l , F(000) = 896, T = 296(2) K, crystal
= 1.803 cmÀ1
size = 0.40 Â 0.35 Â 0.20 mm3, Reflections collected = 10,605, Independent
reflections = 4009, 2676 with Fo > 4(Fo), Rint = 0.0395, Final R1 = 0.0402,
wR2 = 0.0836 for I > 2r(I), and R1 = 0.0710, wR2 = 0.0946 for all data.Data
Figure 1. ORTEP diagram of the 2,3,4-trimethoxybenzo[d]oxepinone 13g.

1388
M. G. Ali Badry et al. / Tetrahedron Letters 50 (2009) 1385–1388
were recorded on a Nonius Kappa CCD diffractometer equipped with an Oxford
refined using a riding model. Anisotropic displacement parameters were used
for all non-H atoms; H-atoms were given isotropic displacement parameters
equal to 1.2 or 1.5 times the equivalent isotropic displacement parameter of
the atom, to which the H-atom is attached. The CIF file has been deposited at
the Cambridge Crystallographic Deposit Centre with registry number CCDC
702984.
Cryosystem cryostat. The structure was solved by direct methods with
additional light atoms found by Fourier methods using SHELX97 (SHELX97—
Programs for Crystal Structure Analysis (Release 97-2). G.M. Sheldrick, Institüt
für Anorganische Chemie der Universität, Tammanstrasse 4, D-3400 Göttingen,
Germany, 1998.). Hydrogen atoms were added at calculated positions and