Anionic n-fries rearrangement of n-alkyl-2-iodo anilides induced by lodine-magnesium exchange: Application for synthesis of strained 1,2,3-trisubstituted indoies

Article abstract of DOI:10.1021/ol7029905

A Superior, mild, high-yielding one-pot process for rapid access to oxo anilides has been developed that involves three cascade reactions: iodine-magnesium exchange, regiospecific ortho N-Fries rearrangement, and in situ trapping of the formed aniline ani

Full text of DOI:10.1021/ol7029905

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1067-1070
Anionic N-Fries Rearrangement of
N-Alkyl-2-iodo Anilides Induced by
Iodine−Magnesium Exchange:
Application for Synthesis of Strained
1,2,3-Trisubstituted Indoles
Fei Ding, Yongda Zhang, Bo Qu, Guisheng Li, Vittorio Farina,† Bruce Z. Lu,* and
Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals,
Inc. Ridgefield, Connecticut 06877
bruce.lu@boehringer-ingelheim.com
Received December 12, 2007
ABSTRACT
A superior, mild, high-yielding one-pot process for rapid access to oxo anilides has been developed that involves three cascade reactions:
iodine magnesium exchange, regiospecific ortho N-Fries rearrangement, and in situ trapping of the formed aniline anion. Coupled with McMurry
cyclization, the two-step process allows ready synthesis of strained 1,2,3-trisubstituted indoles regioselectively.
−
The prevalence of the indole structural motif in numerous
natural products and pharmaceutically active compounds is
responsible for the tremendous amount of efforts in develop-
ing new methods for access to this heterocyclic system.1
Although the classical Fischer indolization2 still remains a
general approach to indole compounds, it has a limited scope
with respect to regioselectivity, an issue pertaining not only
to the substituents on the aromatic ring of hydrazine but also
to the enamine intermediates formed from ketones and
hydrazines, which are highly dependent on the carbonyl
substrates and reaction conditions. Consequently, several Pd-
catalyzed indolization methods,3 including those recently
developed in this group,4 are aimed to tackle these problems
with respect to the chemo- and regioselectivity issues.
(1) For a recent review of indole-containing natural products, see: (a)
Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155. (b) Lounasmaa, M.; Tolvanen,
A. Nat. Prod. Rep. 2000, 17, 175. For reviews on indole syntheses, see:
(a) Sundberg, R. J., Ed. Indoles; Academic: London, 1996. (b) Sundberg,
R. J. Pyrroles and their Benzo Derivatives: Synthesis and Applications.
Katritzky, A. R., Rees, C. W., Eds.; Comprehensive Heterocyclic Chemistry,
Vol. 4; Pergamon: Oxford, 1984; pp 313. (c) For a recent review on Fischer
indole synthesis, see: Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607.
(2) Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 6.
† Current address: Johnson and Johnson Pharmaceutical R&D Turn-
houtseweg 30, 2340 Beerse, Belgium.
10.1021/ol7029905 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

In our recent studies toward the synthesis of indole
intermediates 1 containing a bulky quaternary carbon sub-
stituent at C3 (Scheme 1), we realized that there are few
derivatives of anilines.10 Furthermore, the chemo- and
regioselectivities, as well as the cryogenic conditions (-78
°C), are issues often related to anionic Fries rearrangement
induced by directed ortho lithiation. We envisoned that these
issues could be circumvented by incorporating halogen-
magnesium exchange11 of 2-haloaniline (Scheme 1).
Scheme 1. Synthetic Strategy to Strained 1,2,3-Trisubstituted
Our study began with the sequential magnesium-iodine
exchange and the tandem anionic Fries rearrangement of
N-pivaloyl-N-methyl-2-iodoanilide (6) (Scheme 2). When a
Indoles
Scheme 2. Anionic Fries Rearrangement of o-(N,N-Methyl
pivaloylamido)benzene Magnesium Chloride
practical methods to introduce the bulky C3 substituent
regioselectively. The cyclization of oxo anilides 2 via the
McMurry reaction to afford the pyrrole ring has been
reported;5 however, the lack of an efficient method to prepare
the oxo anilides 2 prompted us to develop a practical process
for synthesis of these key intermediates.6 Herein we report
on the first high-yielding, one-pot process for rapid access
to oxo anilides 2 via the sequence of anionic Fries rear-
rangement7 induced by halogen-magnesium exchange of 5
and in situ amidation. Its application to the synthesis of
strained 1,2,3-trisubstituted indoles is also described herein.
solution of 6 in THF was treated with one equivalent of
iPrMgCl at 0 °C, iodine-magnesium exchange occurred
instantly, followed by pivaloyl migration in 3 min to afford
N-methyl-2-pivaloyl-aniline in a quantitative yield. The
migration was further evidenced by quenching an aliquot of
the reaction mixture with D2O, and finding no deuterium
incorporation into the product, N-methyl-2-pivaloyl-aniline.
The proton NMR spectrum of the isolated product featured
four aromatic resonances at 7.89 (d), 7.33 (dd), 6.71 (d),
6.57 (dd) ppm as well as a doublet of the methyl group at
2.87 ppm with a coupling constant of 5.2 Hz. This evidence
supported the formation of the acyl migration intermediate
anion 9. Furthermore, the intermediate anion 9 was easily
trapped by addition of benzoyl chloride to afford quantita-
tively the oxo anilide 10 in one pot. Obviously, this is a
very superior process, considering the excellent yield, mild
reaction conditions, and the feature of three cascade reactions
in one pot.
Although Fries rearrangement of phenol-based carbamates,
carbonates, benzoates, and pivalates, induced by the directed
ortho lithiation, has been well reported,8 the aniline version
of anionic Fries rearrangement involving migration of the
N-acyl group has been rarely documented9 except for a few
reports on the migration of phosphorus, sulfur, and silicon
(3) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(4) (a) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina,
V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129. (b) Liu, J. X.; Shen, M.;
Zhang, Y. D.; Li, G.; Khodabocus, A.; Rodriguez, S.; Qu, B.; Farina, V.;
Senanayake, C. H.; Lu, B. Z. Org. Lett. 2006, 8, 3573. (c) Lu, B. Z.; Zhao,
W.; Wei, H.-X.; Dufour, M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006,
8, 3271.
(5) (a) McMurry, J. E. Chem. ReV. 1989, 89, 1513. (b) Lenoir, D.
Synthesis 1989, 883. (c) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E.
J. Org. Chem. 1994, 59, 5215. (d) Fu¨rstner, A.; Hupperts, A.; Seidel, G.
Org. Synth. 1999, 76, 142.
(6) (a) Rees, C. W.; Storr, R. C.; Whittle, P. J. Tetrahedron Lett. 1976,
4647. (b) Dyall, L. K. Austr. J. Chem. 1977, 30, 2669. (c) Grammaticakis,
P. C. R. Acad. Sci. 1952, 235, 546.
(7) (a) Fries, K.; Finck, G. Ber. 1908, 41, 2447. (b) Fries, K.; Pfaffendorf,
W. Ber. 1910, 43, 212. (c) Blatt, A. H. Org. React. 1942, 1, 342. (d)
Effenberger, F.; Klenk, H.; Reiter, P. L. Angew. Chem., Int. Ed. Engl. 1973,
12, 775.
(8) (a) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935. (b)
Hellwinkel, D.; La¨mmerzahl, F.; Hofmann, G. Chem. Ber. 1983, 116, 3375.
(c) Miller, J. A. J. Org. Chem. 1987, 52, 323. (d) Horne, S.; Rodrigo, R. J.
Org. Chem. 1990, 55, 4520.
To elucidate the scope of this protocol, a variety of oxo
anilides were prepared readily. The results are summarized
in Table 1. Bulky admantane carbonyl group underwent
N-Fries rearrangement under these conditions with excellent
yields (entries 2, 3, Table 1). Other acyl groups which contain
heteroatoms such as F, O, and N (entries 4-6, Table 1) were
also able to migrate under the iodine-magnesium exchange
conditions. The reaction conditions also tolerated the N-
benzyl group (entry 7, Table 1). Presumably, in this case,
(9) Only two reports described migration of benzoyl and carbamoyl
groups which are not within the scope of Fries rearrangement: (a) Horne,
S.; Rodrigo, R. Chem. Commun. 1991, 1046. (b) MacNeil, S.; Wilson, B.
J.; Snieckus, V. Org. Lett. 2006, 8, 1133. For a recent paper on
photochemically induced Fries rearrangement, see: Ferrini, S.; Ponticelli,
F.; Taddei, M. Org. Lett. 2007, 9, 69.
(10) (a) Safer, S. J.; Closson, W. D. J. Org. Chem. 1975, 40, 889. (b)
Hellwinkel, D.; Supp, M. Chem. Ber. 1976, 109, 3749. (c) Reference 8b.
(d) Jardine, A. M.; Vather, S. M. J. Org. Chem. 1988, 53, 3983.
(11) For a review, see: Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.,
Int. Ed. 2003, 42, 4302.
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Org. Lett., Vol. 10, No. 6, 2008

Table 1. Anionic N-C Migration of Carbonyl Groupa
Table 2. Synthesis of Strained 2,3-Disubstituted Indoles via
McMurry Cyclization
DME. The results are summarized in Table 2. Despite the
bulky C2 and C3 substituents in the indole products, the
reaction proceeded smoothly with good yields even in the
presence of functional groups prone to reduction such as
carboxylate (26), chloride (29), and benzyl (22) (entries 1-4,
Table 2). Interestingly, when the acyl group at the C2
position of the oxo anilide was R-methoxydimethylcarbonyl
(16), the ring cyclization was concomitant with reduction
of the methoxy group to give C3 isopropyl indole product
33 (entry 6, Table 2). When the substrate containing
trifluoroacetyl 18 was subjected to McMurry conditions, the
reaction generated an intractable mixture.
a All the substrates were prepared with high yields from corresponding
2-iodoanilines in an acylation-alkylation sequence.
the iodine-magnesium exchange was able to surpass the
potential deprotonation at the benzylic position. In the
N-acylation step, both benzoyl chloride and acetic anhydride
can be used as electrophiles toward the formed aniline anions.
Taking advantage of the fast iodine-magnesium exchange,
the sequence was able to tolerate substitution on the aromatic
ring of iodoanilines. Electron-donating groups such as
methoxy had no effect on the reaction profile, giving the
product 24 in a quantitative yield (entry 8, Table 1). Even
in the presence of the labile methyl carboxylate functionality,
the desired product 26 was obtained uneventfully, although
the yield was compromised (entry 9, Table 1). It is
noteworthy that the reaction of iodoaniline with p-cyano
substitution resulted in a complex mixture.
In an effort to expand the scope of this N-Fries rearrange-
ment, the iodoaniline 34 was examined. When it was reacted
i
with PrMgCl followed by quenching with D2O, deuterium
substitution was only observed at the position ortho to the
aniline, suggesting that the R-proton of the amide remained
intact. However, no acyl migration was observed (Scheme
3). More hindered substrate 35 was prepared, in attempt to
facilitate the N-acyl migration by increasing the strain
between the two substituents on the nitrogen atom. 1H NMR
of 35 showed clearly two split doublets of benzylic protons
at 5.82 and 4.02 ppm, which is similar to the characteristics
of substrate 21, suggesting a rigid conformation of the benzyl
Next, with dicarbonyl compounds in hand, McMurry
cyclization was carried out to generate indoles under standard
McMurry conditions using TiCl3 and zinc by refluxing in
Org. Lett., Vol. 10, No. 6, 2008
1069

Scheme 3. Iodine-Magnesium Exchange of Anilides 34, 35
Scheme 4. Cross-over Experiment of the N-Fries
Rearrangement
a 4-exo-trig nucleophilic addition. Proton NMR of the
starting N-alkyl 2-iodoanilides showed broadening or, in
some cases, even splitting pattern for the two substituents
attached to the nitrogen atom. The restricted rotation of the
two groups suggested by this NMR feature indicated a strong
steric interaction between the two groups, which could be
the driving force of the migration.
In summary, we developed a superior one-pot process for
rapid preparation of oxo anilides, involving iodine-
magnesium exchange, regiospecific ortho N-Fries rear-
rangement, and in situ trapping of the formed aniline anion.
The acyl groups capable of migration possess an sp3 ter-
tiary carbon center with carbon or heteroatom substit-
uents. The acyl migration, coupled with acylation and
McMurry cyclization, allows ready access to 1,2,3-trisub-
stituted indoles with tertiary carbon substituent at the C3
position.
group due to steric hindrance. However, the reaction of 35
with PrMgCl again stopped at the iodine-magnesium
i
exchange stage without further acyl migration. Activation
of the amide carbonyl by a variety of Lewis acids failed to
facilitate the intramolecular nucleophilic attack. A similar
result was observed with N-benzoyl 2-iodoanilide. No
migration of the benzoyl group occurred. These results imply
that the N-Fries rearrangement was limited to acyl groups
with quaternary sp3 R-carbon.
Mechanistically, the N-acyl migration reported herein
proceeded in an intramolecular fashion, similar to the ortho
O-Fries rearrangement. In a crossover experiment, an
equimolar mixture of 11 and 21 was treated with two equiv
Supporting Information Available: Experimental
procedures and physical data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
i
of PrMgCl. The reaction only afforded two corresponding
migration products 12 and 22 with no trace amount of
scrambled products 42 and 43 (Scheme 4). Presumably, the
acyl migration proceeded through a transition state involving
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Org. Lett., Vol. 10, No. 6, 2008