A metal-free approach to the synthesis of indoline derivatives by a phenyliodine(III) bis(trifluoroacetate)-mediated amidohydroxylation reaction

Article abstract of DOI:10.1021/jo061486q

A novel approach to the synthesis of indoline derivatives is presented. The key cyclization step features the phenyliodine-(III) bis(trifluoroacetate)- (PIFA-) mediated formation of a N-acylnitrenium ion and its succeeding intramolecular trapping by the o

Full text of DOI:10.1021/jo061486q

Aside from the role of the indole ring as the key substructure
in all molecules containing the amino acid tryptophan, the indole
and indoline frameworks are embedded in a wide range of
natural products and designed compounds with varied biological
activities (see Figure 1).3 On the basis of their promising
pharmacological applications, intensive research has been
directed to develop new and efficient protocols for the synthesis
of both types of heterocycles. However, the employment of
substantial quantities of either toxic or expensive metal salts,
and the high sensitivity of some of the required complexes to
air and moisture, limit the generality of most of the related
reported protocols.4 Thus, the development of a new metal-
free strategy for the synthesis of the target heterocycles remains
a challenge in synthetic organic chemistry.
A Metal-Free Approach to the Synthesis of
Indoline Derivatives by a Phenyliodine(III)
Bis(trifluoroacetate)-Mediated
Amidohydroxylation Reaction
Arkaitz Correa, Imanol Tellitu,* Esther Dom´ınguez,* and
Raul SanMartin
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y
Tecnolog´ıa, UniVersidad del Pa´ıs Vasco - Euskal Herriko
Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
imanol.tellitu@ehu.es
As part of our ongoing research work dealing with the devel-
opment of hypervalent iodine chemistry,5 we envisaged the syn-
thesis of a series of indoline derivatives by employing the
environmentally friendly iodine reagent PIFA [phenyliodine-
(III) bis(trifluoroacetate)]. Thus, in this paper we report a straight-
forward metal-free approach to the olefin amidation reaction
mediated by PIFA and its application to the synthesis of the
target heterocycles.6 The essential key step of our approach relies
on the ability of the employed iodine reagent to generate
N-acylnitrenium intermediates7 and, thus, provide the formation
of a novel C-N bond, as well as the introduction of a hydroxy
group (in one single step from B to A), in the final product
through an olefin amidation process, as depicted in Figure 2.
ReceiVed July 18, 2006
A novel approach to the synthesis of indoline derivatives is
presented. The key cyclization step features the phenyliodine-
(III) bis(trifluoroacetate)- (PIFA-) mediated formation of a
N-acylnitrenium ion and its succeeding intramolecular trap-
ping by the olefin fragment. In addition, difunctionalization
of the alkene moiety is achieved since the in situ generation
of an additional hydroxy group at the terminal position of
the original double bond accompanies the intramolecular
C-N bond formation.
(3) 2-Methylindoline derivatives constitute a structural class of hetero-
cycles from which several drugs have emerged, including antineoplastic
sulfonamides, 5-hydroxytryptamine receptor antagonists (5-HT3), and
muscarine receptor agonists and antagonists. See for example (a) Bermudez,
J.; Dabbs, S.; Joiner, K. A.; King, F. D. J. Med. Chem. 1990, 33, 1929-
1932. (b) Adachi, S.; Koike, K.; Takayanagi, I. Pharmacology 1996, 53,
250-258. (c) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV.
2003, 103, 893-930.
(4) For palladium-catalyzed synthesis of indolines, see (a) Lira, R.; Wolfe,
J. P. J. Am. Chem. Soc. 2004, 126, 13906-13907. (b) Alexanian, E. J.;
Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690-7691. For
copper-catalyzed synthesis of indolines, see (c) Sherman, E. S.; Chemler,
S. R.; Tan, T. B.; Gerlits, O. Org. Lett. 2004, 6, 1573-1575. (d) Zabawa,
T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005, 127, 11250-
11251. Other processes: (e) Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn,
J. A.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 2966-2967. (f) Yin, Y.;
Zhao, G. Heterocycles 2006, 68, 23-31. (g) Gleave, D. M.; Brickner, S.
J.; Manninen, P. R.; Allwine, D. A.; Lovasz, K. D.; Rohrer, D. C.; Tucker,
J. A.; Zurenko, G. E.; Ford, C. W. Bioorg. Med. Chem. Lett. 1998, 8, 1231-
1236. (h) Gleave, D. M.; Brickner, S. J. J. Org. Chem. 1996, 61, 6470-
6474.
(5) For recent reviews on the synthetic applications of polyvalent iodine
reagents, see (a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523-
2284. (b) Stang, P. J. J. Org. Chem. 2003, 68, 2997-3008. (c) Wirth, T.
Top. Curr. Chem. 2003, 224, 1-264. (d) Tohma, H.; Kita, Y. AdV. Synth.
Catal. 2004, 346, 111-124. (e) Moriarty, R. M. J. Org. Chem. 2005, 70,
2893-2903. (f) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656-3665.
(6) For some other contributions by our group on the synthesis of other
N-containing heterocycles by employing this PIFA-promoted olefin ami-
dohydroxylation, see (a) Serna, S.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.;
SanMartin, R. Tetrahedron 2004, 60, 6533-6539. (b) Serna, S.; Tellitu, I.;
Dom´ınguez, E.; Moreno, I.; SanMartin, R. Tetrahedron Lett. 2003, 44,
3483-3486.
The pursuit of concise methods for rapid buildup of molecular
complexity is a major focus of the synthetic organic chemical
community. Strategies that allow multiple transformations in a
single-pot process without excessive functionalization of the
substrates are especially attractive. In this context, vicinal
difunctionalization of alkenes is among the most powerful
transformations known in the field of chemical synthesis.1 These
reactions are particularly appealing from the standpoint of green
chemistry because they usually display perfect atom economy,2
and therefore, we envisaged that such conception might be
applied to the preparation of 2-substituted indoline derivatives.
* Corresponding author: phone (34) 94 601 5438; fax (34) 94 601 2748.
(1) For some selected reviews and monographs on alkene vicinal
difunctionalization processes, such as dihydroxylation or aminohydroxylation
reactions, see (a) Kolb, H. C.; VanNienwenzhe, M. S.; Sharpless, K. B.
Chem. ReV. 1994, 94, 2483-2547. (b) Johnson, R. A.; Sharpless, K. B.
Catalytic Asymmetric Dihydroxylation: Discovery and Development. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York,
2000; pp 357-398. (c) Bolm, C.; Hildebrand, J. P.; Muniz, K. Recent
Advances in Asymmetric Dihydroxylation and Aminohydroxylation. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York,
2000; pp 399-428. (d) Schlingloff, G.; Sharpless, K. B.; Asymmetric
Aminohydroxylation. In Asymmetric Oxidation Reactions: A Practical
Approach in Chemistry; Katsuki, T., Ed.; Oxford University Press: New
York, 2001; pp 104-114.
(7) The hypervalent iodine reagent PIFA has been reported to generate
N-acylnitrenium ions from adequately substituted amides. See for example
(a) Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 581-582. (b) Romero,
A. G.; Darlington, W. H.; McMillan, M. W. J. Org. Chem. 1997, 62, 6582-
6587. (c) Wardrop, D. J.; Burge, M. S. Chem. Commun. 2004, 1230-1231.
(d) Correa, A.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMartin, R. J.
Org. Chem. 2005, 70, 2256-2264. (e) Correa, A.; Tellitu, I.; Dom´ınguez,
E.; SanMartin, R. J. Org. Chem. 2006, 71, 3501-3505.
(2) Block, E.; Schwan, A. L. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, L., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 4, pp 329-
362.
10.1021/jo061486q CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/06/2006
8316
J. Org. Chem. 2006, 71, 8316-8319

TABLE 1. Selected Assays Performed on Anilides 3a,b
entry
solvent
T
4aa (%)
4ba (%)
1
2
3
4
CH2Cl2
CH3CN
TFEA
rt
rt
rt
0b
0b
0b
0b
71
52
41c
20c
TFEA
80 °C
a Isolated yield after purification by flash chromatography. b Unreacted
starting material was recovered. c The reaction reached only 50% conversion.
FIGURE 1. Selected examples of 2-substituted indolines of interest.
SCHEME 2. Synthesis of Indolines 4c-fa
FIGURE 2. Proposed strategy for the synthesis of the indoline skeleton.
SCHEME 1. Preparation of Indolines 4a,ba
a Reagents and conditions: (i) BrCH2CHdCH2, K2CO3, DMF, 80 °C,
overnight (69% for 1c, 64% for 1d, 67% for 1e, 59% for 1f); (ii) BF3‚OEt2,
xylene, 180 °C, sealed tube, 2 h (72% for 2c, 77% for 2d, 66% for 2e,
58% for 2f); (iii) BzCl, pyridine, CH2Cl2, 0 °C f room temperature,
overnight (73% for 4c, 75% for 4d, 84% for 4e, 96% for 4f); (iv) PIFA,
TFEA, room temperature, 3 h (61% for 4c, 70% for 4d, 73% for 4e, 56%
for 4f).
a Reagents and conditions: (i) BF3‚OEt2, xylene, 180 °C, sealed tube, 2
h (66%); (ii) BzCl, pyridine, CH2Cl2, 0 °C f room temperature, overnight
(98% for 3a); (iii) TsCl, pyridine, CH2Cl2, 0 °C f room temperature,
overnight (90% for 3b); (iv) PIFA (see Table 1); (v) Ac2O, pyridine, room
temperature (quantitative for 4a, quantitative for 4b).
reaction was performed at higher temperatures (entry 4), but
unfortunately, the yields for both indolines 4a,b slightly
decreased. Therefore, it can be pointed out that the optimal
reaction conditions for the amidation reaction involve the
treatment of substrates 3a,b with PIFA (1.5 equiv) in trifluo-
roethanol at room temperature for 3 h (entry 3). Since both
indolines 4a,b were unstable, they were efficiently transformed
into the corresponding acetyl derivatives 4a′ and 4b′, respec-
tively, for a full structural characterization.
The first issue we had to address in our research was referred
to the nature of the N-substituent.8 Thus, our synthesis started
by the preparation of N-protected amides 3a,b in a two-step
sequence, as outlined in Scheme 1. Thus, o-allylanilides 3a,b
were efficiently obtained from commercially available N-
allylaniline (1a) by a known aza-Claisen rearrangement9 fol-
lowed by a subsequent N-protection process of the so-obtained
2-allylaniline (2a).
Having established the optimal protocol for the projected
process, the scope of the presented transformation was expanded
to prepare a short family of indoline derivatives 4a-f. For this
purpose, and selecting the benzoyl group over the tosyl group
as the optimal substituent for the amino group, a series of
benzamides 3c-f were easily prepared following the synthetic
sequence depicted below in good overall yields and starting from
the commercially available anilines 5c-f (see Scheme 2).
When substrates 3c-f were submitted to the action of the
hypervalent iodine reagent PIFA, the proposed amidohydroxy-
lation reaction proved to be suitable for the projected transfor-
mation and, hence, they rendered successfully the corresponding
indoline derivatives 4c-f.10 In general, the cyclization reaction
of benzamides bearing substituents in the para position with
respect to the amino group, independently of their electronic
nature, proceeded in higher yields than when substituents were
placed in the orthq position. This result may be attributed to an
unfavorable steric hindrance developed in intermediate D, a
species that results from the mechanistic proposal shown below.
Next, to test the viability of the proposed amidation reaction,
we briefly examined the behavior of anilides 3a,b under the
action of PIFA to optimize the experimental conditions (see
Table 1). Thus, when amides 3a,b were treated with PIFA with
dichloromethane (entry 1) or acetonitrile (entry 2) as solvents,
the projected amidation reaction did not take place, and the
starting material was recovered unaltered in both cases. How-
ever, when the reaction was carried out in trifluoroethanol
(TFEA) at room temperature (entry 3), indoline 4a was
satisfactorily obtained after a 3-h period of time. Nevertheless,
under these conditions total conversion did not occur for 3b,
and the corresponding indoline 4b was obtained in lower yield.
In an effort to optimize these results, the olefin amidation
(8) Unless a nitrenium ion is stabilized by a proper neighboring group,
such as an aryl or alkoxy group, its existence as a reaction intermediate is
quite fleeting. Thus, the selection of an adequate N-substituent is of key
importance. For some reviews on nitrenium intermediates, see (a) Falvey,
D. E. In ReactiVe Intermediate Chemistry Moss, R. A.; Platz, M. S.; Jones,
M., Jr., Eds.; Wiley-Interscience: New York, 2004; pp 594-650. (b)
Shubin, V. G.; Borodkin, G. I. Russ. J. Org. Chem. 2005, 41, 473-504.
(9) (a) Beholz, L. G.; Stille, J. R. J. Org. Chem. 1993, 58, 5095-5100.
(b) Anderson, W. K.; Lai, G. Synthesis 1995, 1287-1290.
(10) Due to its labile nature, indoline 4c had also to be acetylated for a
full structural identification.
J. Org. Chem, Vol. 71, No. 21, 2006 8317

SCHEME 3. Proposed Mechanism for the Olefin Amidohydroxylation of Benzamides of Type C
(C); IR (film) 1710; MS (EI) m/z (%) 295 (M+, 74), 235 (76), 193
(87), 165 (62), 105 (100), 90 (65); HRMS calcd for C18H17NO3
295.1208, found 295.1201.
The described transformation can be rationalized as depicted
in Scheme 3. Thus, the N-acylnitrenium ion E generated by
the action of PIFA on C through the formation of D can be
intramolecularly trapped by the olefin moiety by a 5-exo-trig
cyclization mode. The so-obtained primary carbocationic species
created, preferably stabilized as the aziridinium ion F, can be
subsequently opened by the nucleophilic attack of a free
trifluoroacetate group delivered from the employed iodine
reagent. The resulting nonisolated ester G is hydrolyzed during
the basic workup of the reaction to afford the final indoline
derivatives H.
2-Acetoxymethyl-N-tosylindoline (4b′). According to the gener-
al procedure, indoline 4b was obtained from amide 3b (100 mg,
0.35 mmol) in 41% yield (50% conversion) as a yellowish oil after
purification by column chromatography (hexanes/EtOAc 1:1). Due
to its labile nature, indoline 4b was quantitatively transformed into
the corresponding acetyl derivative 4b′ as expressed above, and
its spectral data were in total concordance with those described in
the literature.4b
2-Acetoxymethyl-N-benzoyl-5-methoxyindoline (4c′). Accord-
ing to the general procedure, indoline 4c was obtained from amide
3c (100 mg, 0.37 mmol) in 61% yield as a colorless oil after
purification by column chromatography (hexanes/EtOAc 1:1). Due
to its labile nature, indoline 4c was quantitatively transformed into
the corresponding oily acetyl derivative 4c′ by following the typical
procedure: 1H NMR (CDCl3) δ 2.11 (s, 3H), 3.01-3.24 (m, 2H),
3.81 (s, 3H), 4.33-4.35 (m, 2H), 4.76-4.80 (m, 1H), 6.66-6.83
(m, 2H), 7.34-7.43 (m, 4H), 8.08-8.10 (m, 2H); 13C NMR
(CDCl3) δ 20.8 (CH3), 38.4 (CH2), 55.4 (CH3), 65.8 (CH2), 78.8
(CH), 112.4 (CH), 114.1 (CH), 127.9 (CH), 128.1 (CH), 130.2 (CH),
130.8 (CH), 133.5 (C), 135.2 (C), 136.4 (C), 149.6 (C), 156.9 (C),
170.7 (C); IR (film) 1740; MS (EI) m/z (%) 325 (M+, 68), 252
(30), 160 (47), 105 (100); HRMS calcd for C19H19NO4 325.1314,
found 325.1325.
In summary, the PIFA-mediated amidohydroxylation reaction
has proven to be an efficient and rapid method for the synthesis
of indoline derivatives. Besides, unlike other metal-based
approach to the target heterocycles, the proposed strategy allows
not only the formation of a new C-N bond but also the
introduction of a hydroxy group in the final product, which
facilitates the construction of more complex molecules by further
structural modifications. Finally, it must be pointed out that the
presented protocol avoids the use of toxic and expensive metals
by using the easy-to-handle hypervalent iodine reagent PIFA.
Experimental Section
Typical Procedure for the Synthesis of Indolines 4a-f:
Synthesis of 2-Acetoxymethyl-N-benzoylindoline (4a′). A solution
of PIFA (5.16 g, 12.00 mmol) in 120 mL of trifluoroethanol (TFEA)
was slowly added at room temperature to a solution of benzamide
3a (1.58 g, 6.66 mmol) in 66 mL of the same solvent. The mixture
was stirred at room temperature until total consumption of the
starting material was observed (TLC, 3 h). Then, a solution of Na2-
CO3 (aqueous 10%, 50 mL) was added, and the aqueous phase
was extracted with CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried over Na2SO4 and filtered, and the solvent was
evaporated at reduced pressure. The resulting residue was purified
by column chromatography (hexanes/EtOAc 1:1) to afford indoline
4a (71%) as a colorless oil. Due to its labile nature, indoline 4a
was subsequently acetylated for a full structural identification. For
this purpose, Ac2O (0.5 mL, 5.54 mmol) was added at room
temperature to a solution of indoline 4a (700 mg, 2.77 mmol) in
pyridine (10 mL), and the mixture was stirred overnight. Then, the
mixture was diluted with CH2Cl2 (30 mL) and washed with a
saturated solution of CuSO4 (3 × 30 mL). The combined organic
extracts were dried over Na2SO4 and filtered, and the solvent was
evaporated at reduced pressure. The resulting residue was purified
by column chromatography (CH2Cl2) to afford quantitatively
indoline 4a′ as a yellowish oil: 1H NMR (CDCl3) δ 2.12 (s, 3H),
3.04-3.25 (m, 2H), 4.33-4.35 (m, 2H), 4.78-4.83 (m, 1H), 7.10-
7.11 (m, 2H), 7.28-7.47 (m, 5H), 8.18 (d, J ) 7.7 Hz, 2H); 13C
NMR (CDCl3) δ 20.6 (CH3), 37.8 (CH2), 65.6 (CH2), 80.1 (CH),
124.9 (CH), 127.5 (CH), 127.9 (CH), 128.2 (CH), 128.6 (CH), 128.9
(CH), 130.4 (CH), 132.1 (C), 134.9 (C), 143.0 (C), 150.9 (C), 170.4
N-Benzoyl-5-ethyl-2-hydroxymethylindoline (4d). According
to the general procedure, indoline 4d was obtained from amide 3d
(100 mg, 0.39 mmol) in 70% yield as a white solid after purification
by column chromatography (hexanes/EtOAc 1:1) followed by
crystallization from hexanes: mp 99-100 °C (hexanes); 1H NMR
(CDCl3) δ 1.28 (t, J ) 7.7, 3H), 2.35 (br s, 1H), 2.64 (q, J ) 7.7
Hz, 2H), 3.00-3.19 (m, 2H), 3.82-3.85 (m, 2H), 4.59-4.61 (m,
1H), 6.92-7.26 (m, 2H), 7.34-7.43 (m, 4H), 8.10-8.12 (m, 2H);
13C NMR (CDCl3) δ 15.5 (CH3), 28.2 (CH2), 37.9 (CH2), 65.3
(CH2), 82.5 (CH), 124.6 (CH), 126.7 (CH), 127.9 (CH), 128.3 (CH),
129.0 (CH), 130.3 (CH), 132.6 (C), 135.3 (C), 140.7 (C), 141.2
(C), 150.7 (C); IR (KBr) 3364-3390, 1645; MS (EI) m/z (%) 281
(M+, 100), 250 (95), 222 (83), 206 (93), 193 (54), 158 (98), 146
(85), 105 (99); HRMS calcd for C18H19NO2 281.1416, found
281.1417.
N-Benzoyl-5-bromo-2-hydroxymethylindoline (4e). According
to the general procedure, indoline 4e was obtained from amide 3e
(100 mg, 0.32 mmol) in 73% yield as a white solid after purification
by column chromatography (hexanes/EtOAc 1:1) followed by
crystallization from hexanes: mp 111-112 °C (hexanes); 1H NMR
(CDCl3) δ 2.60-3.09 (m, 2H), 3.09 (br s, 1H), 3.58-4.21 (m, 2H),
5.09-5.15 (m, 1H), 6.55 (d, J ) 8.3 Hz, 2H), 7.12-7.42 (m, 2H),
7.55-7.60 (m, 2H), 8.02-8.06 (m, 2H); 13C NMR (CDCl3) δ 31.9
(CH2), 62.3 (CH2), 74.8 (CH), 122.7 (CH), 125.3 (CH), 129.2 (CH),
129.5 (CH), 130.5 (CH), 130.8 (CH), 133.6 (C), 136.3 (C), 141.2
(C), 144.6 (C), 166.7 (C); IR (KBr) 3367-3390, 1708; MS (EI)
8318 J. Org. Chem., Vol. 71, No. 21, 2006

m/ z (%) 351 (M+ + 20, 5), 349 (M+ + 18, 4), 227 (24), 186 (24),
105 (100), 77 (75); HRMS calcd for C16H14BrNO2 331.0208, found
331.0218.
Acknowledgment. Financial support from the University of
the Basque Country (9/UPV 41.310-13656/2001) and the
Spanish Ministry of Science and Technology (CTQ 2004-03706/
BQU) is gratefully acknowledged. A.C. thanks the Basque
Government for a predoctoral fellowship.
N-Benzoyl-7-ethyl-2-hydroxymethylindoline (4f). According
to the general procedure, indoline 4f was obtained from amide 3f
(100 mg, 0.39 mmol) in 56% yield as a colorless oil after
purification by column chromatography (hexanes/EtOAc 1:1): 1H
NMR (CDCl3) δ 1.30 (t, J ) 7.7 Hz, 3H), 2.14 (br s, 1H,), 2.94-
3.86 (m, 4H), 3.84-3.86 (m, 2H), 4.74-4.80 (m, 1H), 6.87-7.22
(m, 3H), 7.43-7.52 (m, 3H), 8.16-8.20 (m, 2H); 13C NMR
(CDCl3) δ 15.2 (CH3), 25.7 (CH2), 37.5 (CH2), 65.5 (CH2), 84.6
(CH), 124.9 (CH), 126.3 (CH), 127.6 (CH), 128.1 (CH), 128.3 (CH),
130.4 (CH), 132.6 (C), 135.7 (C), 140.9 (C), 142.0 (C), 150.1 (C);
IR (film) 3367-3390, 1649; MS (EI) m/z (%) 281 (M+, 13), 264
(23), 249 (32), 222 (17), 176 (42), 158 (86), 105 (100); HRMS
calcd for C18H19NO2 281.1416, found 281.1417.
Note Added after ASAP Publication. There was a typo-
graphical error in the title of the version published ASAP
September 6, 2006; the corrected version was published ASAP
September 8, 2006.
Supporting Information Available: Experimental details for
amides 3a-f and 1H NMR and 13C NMR spectra of all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO061486Q
J. Org. Chem, Vol. 71, No. 21, 2006 8319