A new and practical PIFA-promoted olefin amidohydroxylation: Six- versus five-membered ring formation

Article abstract of DOI:10.1016/S0040-4039(03)00670-1

A novel access to the isoindolinone and isoquinolin-2-one skeletons from adequately substituted aromatic precursors is described. The key intramolecular cyclization step was performed by the action of phenyliodine(III)bis(trifluoroacetate) (PIFA) on the c

Full text of DOI:10.1016/S0040-4039(03)00670-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3483–3486
A new and practical PIFA-promoted olefin amidohydroxylation:
six- versus five-membered ring formation
Sonia Serna, Imanol Tellitu,* Esther Dom´ınguez,* Isabel Moreno and Rau´l SanMart´ın
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencias, Universidad del Pa´ıs Vasco–Euskal Herriko Unibertsitatea
(UPV/EHU), PO Box 644, 48080 Bilbao, Spain
Received 21 January 2003; revised 11 March 2003; accepted 11 March 2003
Dedicated to Professor A. Varvoglis on the occasion of his 65th birthday
Abstract—A novel access to the isoindolinone and isoquinolin-2-one skeletons from adequately substituted aromatic precursors is
described. The key intramolecular cyclization step was performed by the action of phenyliodine(III)bis(trifluoroacetate) (PIFA) on
the corresponding vinyl or allyl substituted N-(p-methoxyphenyl)benzamide derivatives leading to the heterocyclic compounds
through 5-exo-trig and 6-exo-trig processes, respectively. © 2003 Elsevier Science Ltd. All rights reserved.
In the search for novel approaches to the preparation
of different heterocyclic derivatives, our group has
recently focussed on the enormous potentiality that
some hypervalent iodine reagents can provide in
organic synthesis.1 For example, the clean transforma-
tions achieved, the mild conditions employed, and the
low toxicity associated to it, prompted us to include
one of these iodine(III) reagents, PIFA [phenyl-
iodine(III)-bis(trifluoroacetate)], in our synthetic plans
as a promising agent to carry out new reactions for the
access to a number of heterocycles. The desirability of
this type of reactions can be appreciated considering
the importance of heterocyclic derivatives, mainly N-
heterocycles, in chemical biology and drug discovery
fields.
Following these master lines, we have explored the
feasibility of this strategy in the synthesis of isoindoli-
none and isoquinolinone skeletons through a PIFA-
promoted olefin amidation process.7 This process, could
be eventually employed in the construction of a number
of related natural and synthetic products of interest by
the direct formation of CꢀN bonds. The preliminary
results are now presented in this letter.
The retrosynthetic disconnection of the target molecules
led us to conclude that amides 2a,b and 3a,b would be
the precursors of choice since, with these substrates in
hand, two important aspects of the cyclization step
could be studied. Firstly, the presence or absence (2/3b
Thus, the synthesis of a series of phenanthridines,
phenanthrenes and phenanthrenoids by the construc-
tion of the biaryl linkage,2 and the synthesis of different
heterocyclic-fused quinolinones3 and 1,4-benzodiazepin-
2-ones4 by an electrophilic aromatic amidation process
have been recently reported in which the I(III) reagent
PIFA displays a prominent contribution. Therefore,
when the mildly oxidant reagent PIFA reacts with
arene rings or properly substituted amides, radical-
cation5 and N-acylnitrenium6 intermediates are gener-
ated, respectively. Finally, in the presence of
nucleophilic species, the so-obtained electrophilic inter-
mediates are trapped inter- or intramolecularly to form
new linkages.
Scheme 1. Preparation of precursors 2a,b and 3a,b. Reagents
and conditions: (i) PIDA, I2, AcOH, Ac2O, H2SO4, rt; (ii)
SOCl2, Tol, reflux; (iii) p-anisidine, pyridine, CH2Cl2, rt; (iv)
tributylvinyltin, Pd(PPh3)2Cl2, diox., reflux (70% overall for
2a from 1a, and 49% overall for 2b from 1b); (iv) allyl-
tributyltin, Pd(PPh3)2Cl2, diox., reflux (90% overall for 3a
from 1a, and 58% overall for 3b from 1b).
* Corresponding authors.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00670-1

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S. Serna et al. / Tetrahedron Letters 44 (2003) 3483–3486
versus 2/3a) of electron-donating groups in the aro-
matic ring will inform about the electronic requirements
of the reaction. And, secondly, both vinyl and allyl
groups include, a priori, the possibility of exo-trig
versus endo-trig cyclization modes.
The preparation of precursors 2 and 3 started (see
Scheme 1) from commercially available 2-iodobenzoic
acid (1a) and 3,4-dimethoxybenzoic acid (1b). In the
latter case, a combination of PIDA [phenyliodine-
(III)diacetate)] and iodine was employed to incorporate
the halogen atom in the required position with com-
plete regioselectivity.8 Then, amide formation, using
p-anisidine, and Stille processes, employing either tri-
butylvinyltin or allyltributyltin, rendered the desired
precursors 2a,b and 3a,b in 49–90% overall yields.
Scheme 3. Reaction of amide 2b with PIFA. Reagents and
conditions: (i) PIFA, CF3CH2OH, −20°C (95%); (ii) Ac2O,
pyridine, rt (99%); (iii) PIDA, CF3CH2OH, −20°C (27%).
apparent. Nevertheless, to the view of the obtained
results we can propose that this novel intramolecular
amidohydroxylation process takes place through the
formation of a nitrogen-centered cation (see Fig. 1).6,17
With these substrates in hand, optimization of the
cyclization conditions included solvent selection, tem-
perature, and the presence of additives such as TFA9 or
BF3·OEt2.10 Under all the employed experimental con-
ditions the starting materials reacted completely to
afford complex mixtures of products. Thus, when
amide 2a reacted (see Scheme 2) with PIFA in the
presence of BF3·OEt2 using CH2Cl2 as solvent at
−20°C, isoindolinone 4 was obtained in a modest 23%
yield through a 5-exo-trig process.11 Conversely,12 by
using TFA instead of BF3·OEt2, isoquinolinone 5 was
obtained through an, a priori, less favored13 6-endo-trig
cyclization mode in a 28% yield. Finally, amide 2a was
made to react with PIFA in CF3CH2OH as solvent14 at
low temperature in the absence of any activating agent.
Under these conditions isoindolinone 4 was obtained in
a very poor yield (16%).
The species II, generated from I by the action of PIFA,
is intramolecularly attacked by the olefine fragment to
form the heterocyclic core III stabilized as an aziri-
dinium ion by the donating properties of the para-
methoxyphenyl (PMP) group. This new intermediate
is opened by a free trifluoroacetate group (delivered
from PIFA), and the resulting non-isolated18 ester V
is hydrolyzed during the work up (Na2CO3, H2O)
to render derivative 6a. In this case, conversely to 4
(:IV), the elimination process is not facilitated because
of the diminished acidity of the benzylic proton.19
Despite of the absence or diminished reactivity that
PIDA [phenyliodine(III)-diacetate)] had shown, when
compared to PIFA, in our previous investigations,2–4
we decided to check its behavior in a high yielding
transformation presented here. Thus, when amide 2b
was reacted with PIDA in trifluoroethanol as solvent
(see Scheme 3), ester 6b was obtained directly in a poor
27% yield along with extensive degradation of the
starting material. This result not only confirms the
superior reactivity of PIFA over PIDA for the olefine
amidation process, but it also supports, by analogy, the
proposed structure V as an intermediate in the reaction
mechanism depicted in Figure 1.
In order to improve results, we envisaged that an
increased nucleophilicity of the styrene fragment would
facilitate the cyclization onto the electronically deficient
nitrogen atom generated. For that purpose, amide 2b
was prepared and made to react with PIFA in
CF3CH2OH as solvent at low temperature in the
absence of any activating agent (see Scheme 3).15 As
anticipated, the 5-exo-trig cyclization took place
smoothly to afford isoindolinone 6a in 95% yield.16
This compound was subsequently acetylated to yield
derivative 6b for a full structural identification.
Then, in order to expand the suitability of the designed
synthesis, the behavior of amides 3a,b was also studied
Although the PIFA mediated carbonꢀnitrogen bond
formation readily provided access to N-heterocyclic
derivatives, the exact mechanism of the reaction is not
Scheme 2. Reaction of amide 2a with PIFA. Reagents and
conditions: (i) PIFA, BF3·OEt2, CH2Cl2, −20°C (23%); (ii)
PIFA, CF3CH2OH, −20°C (16%); (iii) PIFA, TFA, CH2Cl2,
0°C (28%).
Figure 1. Proposed mechanism for the olefine amidation.

S. Serna et al. / Tetrahedron Letters 44 (2003) 3483–3486
3485
2. (a) For a revision of the chemistry of hypervalent iodine
compounds in the oxidative coupling reaction, see:
Moreno, I.; Tellitu, I.; Herrero, M. T.; SanMart´ın, R.;
Dom´ınguez, E.; Curr. Org. Chem. 2002, 6, 1433–1452; (b)
For the PIFA mediated oxidative coupling reaction in the
synthesis of phenanthridines, see: Moreno, I.; Tellitu, I.;
Etayo, J.; Dom´ınguez, E.; SanMart´ın, R. Tetrahedron
2001, 57, 5403–5411; (c) For the synthesis of phenanthre-
nes and phenanthrenoids, see: Moreno, I.; Tellitu, I.;
SanMart´ın, R.; Dom´ınguez, E. Eur. J. Org. Chem. 2002,
2126–2135; (d) Moreno, I.; Tellitu, I.; SanMart´ın, R.;
Dom´ınguez, E. Synlett 2001, 1161–1163.
Scheme 4. Reaction of amide 3a,b with PIFA. Reagents and
conditions: (i) PIFA, CF3CH2OH, rt (72% from 3a); (ii)
PIFA, CF3CH2OH, rt (93% from 3b); (iii) Ac2O, pyridine, rt
(99%).
3. Herrero, M. T.; Tellitu, I.; Herna´ndez, S.; Dom´ınguez,
E.; Moreno, I.; SanMart´ın, R. Tetrahedron 2002, 58,
8581–8589.
4. Herrero, M. T.; Tellitu, I.; Moreno, I.; Dom´ınguez, E.;
Moreno, I.; SanMart´ın, R. Tetrahedron Lett. 2002, 43,
8273–8275.
5. It is accepted that these reactions take place through a
single-electron transfer (SET) mechanism. See: Kita, Y.;
Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh,
S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116,
3684–3691.
6. Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 581–582.
7. For related works on metal-assisted nitrogen atom trans-
fer to olefins employing hypervalent iodine reagents, see:
(a) Levites-Agababa, E.; Menhaji, E.; Perlson, L. N.;
Rojas, C. M. Org. Lett. 2002, 4, 863–865; (b) Padwa, A.;
Stengel, T. Org. Lett. 2002, 4, 2137–2139.
8. (a) Kryska, A.; Skulski, L. J. Chem. Res. (S) 1999,
590–591; (b) For physical and spectroscopic information
of the so-obtained 4,5-dimethoxy-2-iodobenzoic acid, see:
Harayama, T.; Shibaike, K. Heterocycles 1998, 49, 191–
195.
giving the following results (see Scheme 4). When amide
3a was treated with PIFA in CF3CH2OH as solvent at
room temperature, a 6-exo-trig cyclization took place
to afford isoquinolinone 7a in 72% yield. Analogously,
amide 3b rendered isoquinolinone 7b in very good yield
working at room temperature. So, conversely to the
vinyl substituted benzamides, in this case the presence
of activating substituents in the aryl ring was not
necessary for the reaction to take place with excellent
yield. As commented before, a hydroxylation process
took place in both cases along with the ring formation.
Once again, both heterocyclic compounds were subse-
quently acetylated as derivatives 8a,b for a full struc-
tural identification.
In summary, a novel I(III) mediated intramolecular
amidohydroxylation process leading to CꢀN bond for-
mation is presented and employed in the construction
of the isoindolinone and isoquinolinone nucleus.
Besides, the additional hydroxylic functional group cre-
ated will facilitate the construction of new and more
complex heterocycles and represents a new tool for
future investigations in the field of heterocyclic
chemistry.
9. Romero has employed TFA as additive in a PIFA-medi-
ated oxidative cyclization of a N-methoxyamide to obtain
the tetrahydroquinoline skeleton with excellent results.
However, the role of TFA remains unknown. See:
Romero, A. G.; Darlington, W. H.; McMillan, M. W. J.
Org. Chem. 1997, 62, 6582–6587.
10. It has been proposed that the coordination of this Lewis
acid with the trifluoroacetoxy ligands activates the
iodine(III) reagent. See: Takada, T.; Arisawa, M.;
Gyoten, M.; Hamada, R.; Tohma, H.; Kita, Y. J. Org.
Chem. 1998, 63, 7698–7706.
11. (a) Data of compound 4 can be found in: Kundu, N. G.;
Khan, M. W. Tetrahedron 2000, 56, 4777–4792; (b) In all
cases under study, reported in Scheme 2, heterocycles 4
and 5 were isolated from complex mixtures of non-iden-
tified compounds. Temperature selection was optimized
for each case without modification of the regioselectivity
of the cyclization.
Acknowledgements
Financial support from the University of the Basque
Country (9/UPV 41.310-13656/2001), the Spanish Min-
istry of Science and Technology (MCYT BQU 2001-
0313) is gratefully acknowledged. The Basque
Government is also acknowledged for a fellowship
granted to S.S.
12. By altering the reaction conditions, ortho-allylanilines
have also been transformed regioselectively into indoles
via a 5-exo-trig process (Hegedus, L. S. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 1113–1126) and into quinolines
via a 6-endo-trig cyclization mode (Larock, R. C.;
Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org.
Chem. 1996, 61, 3584–3585).
13. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734–736; (b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.;
Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J.
Am. Chem. Soc. 2002, 124, 2233–22344.
References
1. See for example: (a) Varvoglis, A. Chem. Soc. Rev. 1981,
10, 377–407; (b) Moriarty, R. M.; Vaid, R. K. Synthesis
1990, 431–447; (c) Stang, P. J.; Zhdankin, V. V. Chem.
Rev. 1996, 96, 1123–1178; (d) Varvoglis, A.; Spyroudis, S.
Synlett 1998, 221–232; (e) For a very recent revision of
the chemistry of hypervalent iodine compounds, see:
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523–2584.

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S. Serna et al. / Tetrahedron Letters 44 (2003) 3483–3486
14. Polar and low nucleophilic protic solvents, such as
CF3CH2OH or (CF3)2CH2OH, have been successfully
employed in PIFA-mediated reactions. In certain cases,
these protic solvents have afforded considerably better
yields than the usual CH2Cl2 or CH3CN solvents. See for
example: (a) Kita, Y.; Takada, T.; Mihara, S.; Whelan,
B. A.; Tohma, H. J. Org. Chem. 1995, 60, 7144–7148; (b)
Ward, R. S.; Pelter, A.; Abd-El-Ghani, A. Tetrahedron
1996, 52, 1303–1336.
15. Again, a vast array of assays was carried out to establish
the optimal conditions. In this case, conversely to the
previous experiments, better yields were obtained employ-
ing CF3CH2OH as solvent without any activating agent.
16. Typical procedure for the amidohydroxylation reaction.
(q-Carom), 156.1 (CO); IR (KBr): 3500–3200 (OH), 1637
(CO); MS (EI) m/z (%): 329 (M+, 100), 314 (12), 207 (23);
HRMS calculated for C18H19NO5 329.1263, found
329.1261.
17. For related mechanistic studies using IBX as the hyperva-
lent iodine reagent, see: Nicolaou, K. C.; Baran, P. S.;
Kranich, R.; Zhong, Y.-L.; Sugita, K.; Zou, N. Angew.
Chem., Int. Ed. 2001, 40, 202–206.
18. The putative structure of trifluoroacetyl ester V was
proposed based on the close similarity between the pro-
ton NMR of the reaction mixture from 2b to 6a (prior to
basification) and the ester 6b.
19. The isolation of dimer 9 (trace amounts) probably reveals
a contribution of a radical mechanism. For a precedent
of the formation of dimeric compounds, see Ref. 2b. The
observed deep coloration of the mixture, after the addi-
tion of PIFA, can be also in agreement with the forma-
tion of radical species (Landais, Y.; Robin, J.-P.
Tetrahedron 1992, 48, 7185–7196).
Synthesis
of
5,6-dimethoxy-3-hydroxymethyl-2-(p-
(6a):
methoxyphenyl)-2,3-dihydro-1H-isoindolin-1-one
Over a solution of amide 2b (70 mg, 0.3 mmol) in
CF3CH2OH (3 mL) at −20°C a solution of PIFA (178
mg, 0.4 mmol) in CF3CH2OH (3 mL) was added. The
mixture was stirred at −20°C until total consumption of
the starting material (TLC, 80 min). Then, a solution of
Na2CO3 (aq. 10%, 10 mL) was added, and the aqueous
phase was extracted with CH2Cl2 (3×10 mL). The com-
bined organic extracts were dried over anh. Na2SO4,
filtered, and the solvent was removed under vacuum. The
resulting oil was crystallized from hexanes/EtOAc (80/20)
to render isoindolinone 6a as a white solid (95%). mp
1
161–163°C (EtOAc/hexanes); H NMR: l 2.78 (br s, 1H,
1H NMR: l 3.89 (s, 6H, OCH3), 5.46 (d, J=10.7, 2H,
CHꢁCH6 H), 5.80 (d, J=17.4, 2H, CHꢁCHH6 ), 6.96 (dd,
J=8.7, 2.4, 2H, Harom), 7.12 (d, J=2.4, 2H, Harom),
7.38–7.52 (m, 4H, Harom), 7.67–7.85 (m, 6H, Harom,
OH), 3.80 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.97 (s,
3H, OCH3), 4.34 (d, J=3.1, 2H, CH2
1H, H-3), 6.84–6.88 (m, 3H, Harom), 7.18 (d, J=8.7, 2H,
arom), 7.70 (s, 1H, Harom); 13C NMR: l 55.3, 56.1, 56.2
6 ), 4.71 (t, J=3.1,
H
CH
6 ꢁCH2), 8.09 (d, J=7.5, 2H, Harom); HRMS calculated
(OCH3), 64.8 (C-3), 71.5 (CH2OH), 108.7, 109.9, 113.7,
124.6 (t-Carom), 119.4, 131.1, 139.3, 149.3, 151.3, 152.0
for C32H28N2O4 504.2049, found 504.2041.