Efficient oxidative spirocyclization of phenolic sulfonamides

Article abstract of DOI:10.1016/S0040-4039(02)00949-8

Treatment of various homotyramine sulfonamides with iodobenzene diacetate in hexafluoroisopropanol induces oxidative spirocyclization in high yield.

Full text of DOI:10.1016/S0040-4039(02)00949-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5193–5195
Efficient oxidative spirocyclization of phenolic sulfonamides
Sylvain Canesi, Philippe Belmont, Denis Bouchu,† Laurence Rousset† and Marco A. Ciufolini*
Laboratoire de Synthe`se et Me´thodologie Organique (LSMO), UMR CNRS 5078, Universite´ Claude Bernard Lyon 1 et Ecole
Supe´rieure de Chimie, Physique, Electronique de Lyon, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne ce´dex, France
Received 9 April 2002; revised 15 May 2002; accepted 16 May 2002
Abstract—Treatment of various homotyramine sulfonamides with iodobenzene diacetate in hexafluoroisopropanol induces
oxidative spirocyclization in high yield. © 2002 Elsevier Science Ltd. All rights reserved.
Ongoing investigations on the synthesis of cylindricines
and related alkaloids1 mandated the development of an
effective method for the oxidative cyclization of free
primary amines such as 2, or appropriately protected
variants thereof, to intermediates of general structure 1
(Scheme 1). Recent work from this laboratory has
established an avenue to spirolactams 4 via oxidative
cyclization of phenolic oxazolines 3 (Scheme 2) with
iodobenzene diacetate (‘DIB’).2 The analogous oxidative
cyclization of phenolic secondary amines (cf. 5“6, X=
N-alkyl) is possible,3 but it remains problematic. Yields
are often unsatisfactory, and the spirocyclic goals 6 are
accompanied by a host of byproducts. Such shortcom-
ings are magnified when the amino group in the substrate
is primary (5, X=NH),4 rendering the transformation
entirely unsuitable for multistep synthetic operations.
This has represented a major limitation of a valuable new
technology. Efforts to resolve this problem led us to
explore sulfonamides (cf. 5, X=R-SO2N) as equivalents
of primary amines. This choice was motivated by a
perceived analogy between the chemical behavior of
sulfonamides and that of alcohols. For instance, sulfon-
amides undergo N-acylation at a rate comparable to that
of primary alcohols.5 Oxidative treatment of furyl-
carbinols6 and N-sulfonyl furfurylamines7 efficiently pro-
duces dihydro-b-pyranones and dihydro-b-pyridones,
respectively, whereas N-acyl furfurylamines are not sub-
strates for this reaction.8 Because alcohols of the type 5
(X=O) cyclize efficiently to ethers 6 (X=O) upon
exposure to DIB,9 it seemed plausible that analogous
sulfonamides may behave in a like manner. We now
report that sulfonamide substrates indeed react with
unprecedented efficiency in these heretofore problematic
oxidative transformations.
O
H
C6H13-n
n-C6H13
O–R
OR
H
N
[ O ]
H
H
H
NH2
N
N
O
OH
( ? )
OH
HO
Lepadiformine
Cylindricine C
1
2
Scheme 1.
HO
R
O
O
N
H–X
PhI(OAc)2
X
PhI(OAc)2
R
N
O
HO
O
4
5
3
6
HO
Scheme 2.
Keywords: aminoacids; heterocycles; hypervalent iodine; phenols; sulfonamides.
* Corresponding author. E-mail: ciufi@cpe.fr
† Mass spectral facility of the LSMO.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00949-8

5194
S. Canesi et al. / Tetrahedron Letters 43 (2002) 5193–5195
Ts
4-TolSO2
HO
OCH2CF3
N
N
H
PhI(OAc)2
+
CF3CH2OH
O
NHTs
O
7a
8a
9
80 - 85 %
15 - 20 %
Scheme 3.
Substrates 7 were prepared by conventional methods,10
and their DIB oxidation was studied in both tri-
fluoroethanol (TFE) and hexafluoroisopropanol
(HFIP). As observed by Kita,11 the use of such fluori-
nated alcohols as solvents is essential for the success of
many DIB-mediated processes. A proclivity to form
byproducts of the type 9 (Scheme 3) was observed when
the reaction was carried out in TFE, signaling that this
alcohol is an inappropriate solvent for the present
transformation. An analogous problem was detected
during our prior work with oxazoline substrates.2c On
the other hand, clean, rapid, and efficient conversion to
spirocycles 8 (Table 1) ensued upon reaction of 7 with
DIB in HFIP. This is in strident contrast to the behav-
ior of oxazolines, which normally afford moderate
yields (45–50%) of spirocyclic products under similar
conditions, let alone that of free secondary amines, for
which yields are generally in the neighborhood of
30%.12
The oxidative cyclization of sulfonamide 10, leading to
spiropiperidine 11 (Scheme 4) occurred in a modest
20–30% yield (estimated by NMR and unoptimized),
and induced formation of much polymeric material.
Analogous difficulties with six-membered ring forma-
tion had also been observed with oxazolines sub-
strates.2c Spiropiperidine synthesis thus remains
problematic even via sulfonamide technology.
A typical experimental procedure to effect spirocycliza-
tion of phenolic sulfonamides is as follows. A 1 M
solution of DIB in HFIP (1.05 equiv. of DIB) is added
dropwise at room temperature to a 10% (w/w) solution
of the substrate (1 equiv.) in HFIP, with good stirring.
No inert atmosphere is necessary. The initially colorless
solution changes to yellow and then to blue-green as
the reaction progresses. After 30 min at rt, the solution
is concentrated in vacuo and the crude residue is
purified by chromatography.14
In summary, a practical and efficient new method for
the creation of nitrogen spirocycles is now available.
Synthetic applications of the methodology will be
described in due course.
The reaction appears to be largely insensitive to the
steric demand of the sulfonamide unit. Thus, N-mesyl
and N-tosyl substrates 5a and 5b cyclized with equal
efficiency. Especially significant is the cyclization of
Fukuyama-type13 4-nitrobenzenesulfonamide 5c, which
may be elaborated to intermediates that are deblocked
under mild conditions. The methyl ester of N-tosyl
homotyrosine, 7d, reacted normally and in high yield;
however, the reaction of bis-sulfonamide 7e proceeded
less efficiently. The reasons for this remain unclear.
Acknowledgements
We thank the MENRT, the CNRS, and the Re´gion-
Rhoˆne-Alpes, for support of our research program.
M.A.C. is the recipient of a Merck Academic Develop-
ment Award (2000 and 2001).
Table 1. Oxidative spirocyclizations of phenolic sulfon-
amide substrates
H
H
N
H
Y
Y
X–SO2
X–SO2
N
PhI(OAc)2
References
Z
Z
(CF3)2CHOH
1. For previous synthetic work and bibliography in this
area, see for example: (a) Liu, J. F.; Heathcock, C. H. J.
Org. Chem. 1999, 64, 8263; (b) Molander, G. A.; Ro¨nn,
M. J. Org. Chem. 1999, 64, 5183; (c) Oppolzer, W.;
Bochet, C. G. Tetrahedon: Asymmetry 2000, 11, 4761
(cylindricines); (d) Maeng, J. H.; Funk, R. L. Org. Lett.
2002, 4, 331; (e) Abe, H.; Aoyagi, S.; Kibayashi, C. J.
Am. Chem. Soc. 2000, 122, 4583 (fasicularine); (f) Sun, P.;
Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507; (g)
Greshock, T. J.; Funk, R. L. Org. Lett. 2001, 3, 3511; (h)
Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688
(lepadiformine; see also Ref. 1e).
2. (a) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.;
Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534; (b)
Ousmer, M.; Braun, N. A.; Ciufolini, M. A. Org. Lett.
2001, 3, 765; (c) Braun, N. A.; Bray, J. D.; Ousmer, M.;
Peters, K.; Peters, E.-M.; Bouchu, D.; Ciufolini, M. A. J.
Org. Chem. 2000, 65, 4397 and references cited therein.
HO
O
7
8
Entry
X
Y
Z
Yield (%)
a
b
c
d
e
4-Me-C6H4
Me
4-O2N-C6H4
4-Me-C6H4
Me
H
H
H
H
97
97
84
92
CH2Br
COOMe
H
H
H
NHSO2-4-Tol 60
Ms
N
PhI(OAc)2
(CF3)2CHOH
20 - 30 %
Ms
N
H
O
HO
10
11
Scheme 4.

S. Canesi et al. / Tetrahedron Letters 43 (2002) 5193–5195
5195
12. An efficient transformation of this type that proceeds in
an exceptional 69% yield has recently been reported. See:
Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Tetra-
hedron Lett. 2002, 43, 2411.
13. (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron
Lett. 1995, 36, 6373; (b) Fukuyama, T.; Cheung, M.;
Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997,
38, 5831.
3. This noteworthy transformation may rightfully be termed
the ‘Sorensen reaction’. See: Scheffler, G.; Seike, H.;
Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39, 4593.
4. Unpublished observations from this laboratory.
5. For instance, during our synthesis of FR901483 (Ref. 2a)
we observed that a secondary sulfonamide and a primary
alcohol are acylated at the same rate upon reaction with
Ac2O/pyridine.
6. For example, see: (a) Achmatowicz, O. In Organic Syn-
thesis Today and Tomorrow; Trost, B. M.; Hutchinson, C.
R., Eds.; Pergamon Press: Oxford, UK, 1981; (b) Gin-
gerich, S. B.; Jennings, P. W. In Advances in Oxygenated
Processes; Baumstark, A. L., Ed.; JAI Press: Greenwich,
CT, 1990; Vol. 2.
7. For example, see: Zhou, W. S.; Lu, Z. H.; Xu, Y. M.;
Liao, L. X.; Wang, Z. M. Tetrahedron 1999, 55, 11959
and references cited therein. See also Ref. 8.
8. For a review, see: Ciufolini, M. A.; Hermann, C. Y. W.;
Dong, Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett
1998, 105.
14. Physical data for compounds 8 [NMR: l, CDCl3, cou-
pling constants J in Hz); IR (film, cm−1); mass spectra
1
(m/z)]. Compound 8a: mp 106°C; H NMR: 6.88 (d, 2H,
J=10.2), 6.26 (d, 2H, J=10.2), 3.68 (t, 2H, J=6.8), 2.89
(s, 3H), 2.16 (m, 4H); 13C NMR: 184.8, 149.4, 128.4,
63.4, 49.2, 40.3, 39.3, 23.6; IR: 1661; HRMS (CI) calcd
for C10H14NO3S (M+H) 228.0694, found 228.0692. Com-
pound 8b: mp >300°C; 1H NMR: 7.64 (d, 2H, J=8.3),
7.29 (d, 2H, J=8.3), 6.69 (d, 2H, J=10.2), 6.17 (d, 2H,
J=10.2), 3.69 (t, 2H, J=6.4), 2.41 (s, 3H), 2.07 (m, 4H);
13C NMR: 185.3, 150.1, 143.9, 136.2, 129.6, 127.9, 127.8,
63.7, 49.1, 40.4, 23.5, 21.6; IR: 1665; HRMS (CI) calcd
for C16H18NO3S (M+H) 304.1007, found 304.1002. Com-
1
pound 8c: foam; H NMR: 8.34 (d, 2H, J=9.0), 8.02 (d,
9. See: Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org.
Chem. 1987, 52, 3927.
2H, J=9.0), 6.81 (dd, 1H, J=3.4, 10.2), 6.51 (dd, 1H,
J=3.4, 10.2), 6.23 (dd, 1H, J=2.0, 10.7), 6.13 (dd, 1H,
J=2.0, 10.7), 4.44 (m, 1H), 3.90 (dd, 1H, J=2.6, 10.6),
3.60 (dd, 1H, J=8.7, 10.6), 2.55 (m, 1H), 2.20–2.27 (m,
2H), 1.94 (m, 1H); HRMS (CI) calcd for C16H16BrN2O5S
(M+H) 426.9963, found 426.9961. Compound 8d: oil;
[h]D=+30 (c 1.5, EtOH, 20°C); 1H NMR: 7.62 (d, 2H,
J=8.3), 7.26 (d, 2H, J=8.3), 6.95 (dd, 1H, J=3.2, 10.9),
6.72 (dd, 1H, J=3.2, 10.9), 6.12 (d, 2H, J=10.2), 4.72 (d,
1H, J=6.4), 3.71 (s, 3H), 2.38 (m, 5H), 2.10 (m, 1H), 1.94
(m, 1H); 13C NMR: 184.9, 172.5, 151.6, 148.9, 144.3,
136.6, 129.5, 128.1, 128.0, 64.2, 62.2, 52.7, 38.6, 28.7,
21.6; IR: 1734, 1688; HRMS (CI) calcd for C18H20NO5S
(M+H) 362.1062, found 362.1069. Compound 8e: 1H
NMR: 7.73 (d, 2H, J=8.3), 7.34 (d, 2H, J=8.3), 7.05
(dd, 1H, J=2.6, 10.6), 6.84 (dd, 1H, J=2.6, 10.6), 6.22
(d, 2H, J=10.2), 6.00 (d, 1H, J=5.3), 3.98 (m, 1H), 3.82
(dd, 1H, J=6.8, 10.2), 3.58 (dd, 1H, J=5.3, 10.2), 2.88 (s,
3H), 2.43 (s, 3H), 2.18 (m, 2H); 13C NMR: 184.7, 149.1,
148.4, 144.3, 136.0, 130.0, 128.1, 128.0, 126.8, 62.3, 53.4,
50.5, 44.7, 39.4, 21.4; IR: 1667; HRMS (CI) calcd for
C17H21N2O5S2 (M+H) 397.0892, found 397.0897.
10. Preparation of 7a: From the dimesylate of p-hydroxy-
dihydrocinnamyl alcohol by: (a) NaN3/DMF; (b) PPh3/
THF/H2O, 80% a–b; (c) TsCl/TEA/CH2Cl2; (d) aq.
NaOH/dioxane, 90% c–d; 7b: procedure as for 7a except
that MsCl was used in step (c); 7c: from (R)-p-methoxy-
homophenylalaninol [obtained by Evans azidation of 4-p-
(methoxyphenyl)butyric acid followed by reduction. See:
(a) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow,
R. L. J. Am. Chem. Soc. 1990, 112, 4011] by: (a) TES-Cl/
TEA/CH2Cl2; (b) 4-O2N-C6H4-SO2Cl/TEA/CH2Cl2, 85%
a–b; (c) BBr3, CH2Cl2, 69%; 7d: by N-tosylation of
methyl
D-homotyrosinate [see: (b) Fischer, E.; Lipschitz,
W. Ber. Dtsch. Chem. Ges. 1915, 48, 360; (c) McChesney,
E. V.; Swann, W. K., Jr. J. Am. Chem. Soc. 1937, 59,
1116]; 7e: from the N-tosyl derivative of methyl L-tyrosi-
nate (see Refs. 10b,c above) by: (a) LAH; (b) MsCl/TEA/
CH2Cl2, 78% a–b; (c) NaN3/DMF; (d) H2/Pd(c)/THF;
(d) MsCl/TEA/CH2Cl2; (e) aq. NaOH/dioxane, 75% c–e.
11. See: Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.;
Yakura, T. J. Org. Chem. 1991, 56, 435.