The groups of Zhdankin8 and Ochiai9 reported that
active iodine(III) generated in situ from iodobenzene and
oxidants could be finitely employed for the Hofmann
rearrangement of aliphatic amides. Furthermore, the
Hofmann rearrangement of aromatic and aliphatic im-
ides is a very important strategy for the construction of
anthranilic acid derivatives and amino acid derivatives
possessing biological and medicinal activities10 and found
in a variety of natural products.11 Nevertheless, studies
for the preparation of anthranilic acid derivatives by
means of the Hofmann rearrangement are extremely
limited and lacking in versatility,12 and the desired pro-
duct is obtained in low yield. To the best of our knowl-
edge, the direct transformation into aromatic and ali-
phatic amino acid derivatives via the Hofmann-type
rearrangement of cyclic imides using hypervalent iodines
has not been established. Conventional methods for the
preparation of anthranilic acid derivatives require transi-
tion metals, such as Pd13 and Cu.14
Information). The optimum reaction was found to involve
1a, K2CO3 (4.0 equiv), Na2SO4 (2.0 equiv), and hyper-
valent iodine, which was prepared from iodobenzene (1.3
equiv), m-CPBA (1.4 equiv), and TsOH H2O (1.4 equiv)
3
in situ, in MeOH at room temperature (Scheme 1). In
contrast, the previous active iodines(III) generated in situ
from iodobenzene8,9 were not effective for the Hofmann-
type rearrangement of 1a.
Scheme 1. Hofmann-Type Rearrangement of Phthalimide 1a by
Hypervalent Iodine Generated in Situ
The potential of direct oxidative transformation using
imide-combined hypervalent iodine(III) remains widely
unexplored.15 We report here the metal-free direct trans-
formation of phthalimides and aliphatic imides into the
corresponding anthranilic acid derivatives and aliphatic
amino acid derivatives by alcoholysis, followed by the
Hofmann rearrangement of imides via the formation of
imide-combined hypervalent iodines(III) generated in situ
from an iodoarene and oxidant (eq 1).
To explore the scope of the Hofmann-type rearrange-
ment, various phthalimides 1 were examined using hyper-
valent iodine under the optimized reaction conditions
(Scheme 2). The reactions of 4-monosubstituted phthali-
mides bearing an Me (1b), t-Bu (1c), Br (1d), or NO2 (1e)
group gave corresponding monosubstituted anthranilic
acid derivatives (2bꢀ2e) in high yields, respectively. Elec-
tron-donating 4-methoxy phthalimide (1f) was converted
into desired product (2f) in 54% yield. 3-Fluoro phthali-
mide (1g) was also transformed into the corresponding
product (2g) in high yield (90%). When symmetrical aro-
matic imides, such as 4,5-dimethylphenyl (1h), 4,5-dichlor-
ophenyl (1i), naphthyl (1j), and biphenyl (1k) imides, were
used, rearrangement products 2h, 2i, 2j, and 2k were
obtained in good yields (62ꢀ72%), respectively. Hetero-
cyclic 3,4-pyridine dicarboximide (1l) was efficiently con-
verted into an aminoisonicotinic acid derivative(2l) in high
yield. Moreover, the use of other alcohols, such as EtOH
and CF3CH2OH, instead of MeOH as solvent for the
rearrangement of 1a provided corresponding esters 2m
and 2n in good yields, respectively. Treatment of 4,40-
oxybisphthalimide (1o) with double the amount of each
reagent gave an oxybisanthranilic acid derivative (2o)
in 60% yield with three regioisomers (4,50-/4,40-/5,50- =
61:22:17). In many cases, a small amount of decarboxyla-
tion product (3, X = H) was obtained as a byproduct with
First, we screened a series of iodoarenes and bases for
the Hofmann-type rearrangement of phthalimide (1a)
using hypervalent iodine (Table S1 in the Supporting
(8) Zagulyaeva, A. A.; Banek, C. T.; Yusubov, M. S.; Zhdankin,
V. V. Org. Lett. 2010, 12, 4644–4647.
(9) Miyamoto, K.; Sakai, Y.; Goda, S.; Ochiai, M. Chem. Commun.
2012, 48, 982–984.
(10) (a) Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.;
Ramana, A. V. Tetrahedron Lett. 2004, 45, 6517–6521. (b) Connolly,
D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61,
10153–10202. (c) Yoo, C. L.; Fettinger, J. C.; Kurth, M. J. J. Org. Chem.
2005, 70, 6941–6943. (d) Ma, Z.; Hano, Y.; Nomura, T. Heterocycles
2005, 65, 2203–2219. (e) Congiu, C.; Cocco, M. T.; Lilliu, V.; Onnis, V.
J. Med. Chem. 2005, 48, 8245–8252. (f) Roy, A. D.; Subramanian, A.;
Roy, R. J. Org. Chem. 2006, 71, 382–385. (g) Gellibert, F.; Fouchet,
M.-H.; Nguyen, V.-L.; Wang, R.; Krysa, G.; de Gouville, A.-C.; Huet,
S.; Dodic, N. Bioorg. Med. Chem. Lett. 2009, 19, 2277–2281.
(11) (a) Liu, J.-F.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.;
Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339–6345. (b)
Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787–9826. (c)
Tillequin, F. Phytochem. Rev. 2007, 6, 65–79.
(13) (a) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773–2777.
(b) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler,
ꢀ
S. N. G.; Gagne, M. R.; Lioyd-Jones, G. C.; Booker-Milburn, K. I.
Angew. Chem., Int. Ed. 2009, 48, 1830–1833. (c) Kumar, C. H. V.;
Shivananda, K. N.; Raju, C. N.; Jagadeesh, R. V. Synth. Commun. 2010,
40, 3480–3487.
(14) (a) Zhao, H.; Fu, H.; Qiao, R. J. Org. Chem. 2010, 75, 3311–
3316. (b) Tao, C.; Liu, W.; Lv, A.; Sun, M.; Tian, Y.; Wang, Q.; Zhao, J.
Synlett 2010, 1355–1358.
€
ꢀ
(15) (a) Roben, C.; Souto, J. A.; Gonzalez, Y.; Lishchynskyi, A.;
~
(12) (a) Smyth, N.; Engen, D. V.; Pascal, R. A., Jr. J. Org. Chem.
1990, 55, 1937–1940. (b) Liu, Z.; Yuan, Q.; Wang, W. Amino Acids 2009,
36, 71–73.
Muniz, K. Angew. Chem., Int. Ed. 2011, 50, 9478–9482. (b) Kim, H. J.;
Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2011, 133, 16382–
16385.
Org. Lett., Vol. 14, No. 3, 2012
947