Aryl(sulfonyl)amino group: A convenient and stable yet activated modification of amino group for its intramolecular displacement

Article abstract of DOI:10.1021/ol101541p

Aryl(sulfonyl)amino groups, readily derived from sulfonyl- or arylamines by standard methods as well as the recently introduced methods of sulfonylation and arylation, proved to be good leaving groups in intramolecular substitution reactions by various nitrogen, oxygen, and carbon nucleophiles.

Full text of DOI:10.1021/ol101541p

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4137-4139
Aryl(sulfonyl)amino Group: A
Convenient and Stable Yet Activated
Modification of Amino Group for Its
Intramolecular Displacement
Yuzo Kato, Dinh Hoang Yen, Yasuhiro Fukudome, Takeshi Hata, and
Hirokazu Urabe*
Department of Biomolecular Engineering, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho, Midori-ku,
Yokohama, Kanagawa 226-8501, Japan
hurabe@bio.titech.ac.jp
Received July 8, 2010
ABSTRACT
Aryl(sulfonyl)amino groups, readily derived from sulfonyl- or arylamines by standard methods as well as the recently introduced methods of
sulfonylation and arylation, proved to be good leaving groups in intramolecular substitution reactions by various nitrogen, oxygen, and carbon
nucleophiles.
Substitution of an amino group or its protected group at
an ordinary sp3 carbon with a nucleophile, leading to other
functional groups, has not been thoroughly considered in
organic synthesis.1 This obviously comes from not only
their intrinsically low leaving ability but also the fact that
amino groups themselves are primarily prepared by
displacement of other functional groups, and thus, the
reversed transformation would be pointless.1 However,
recent rapid expansion of organic synthesis to the area of
biomolecules, which ubiquitously possess amino groups,
should cause the above transformation to gain more
importance.2 In addition, as asymmetric reactions often
inevitably produce (protected) amines in order to attain
high ee values,3 their subsequent conversion to other
functional groups appears to be in more demand. In this
paper, we report a dependable method for the intramo-
lecular substitution of (protected) amino groups, via their
conversion to aryl(sulfonyl) derivatives 3 (Scheme 1).
These aryl(sulfonyl)amino groups are readily prepared
from sulfonyl- or arylamines (1 or 2), which are, when
necessary, derived from parent amino groups by a variety
of standard4,5 and recently introduced6 methods of sulfo-
nylation and arylation as shown in Scheme 1.
Scheme 1. Formulation of Synthetic Utility
10.1021/ol101541p  2010 American Chemical Society
Published on Web 08/24/2010

Equation 1 illustrates the above strategy.7 The Ts-protected
amino moiety in 4 was first converted to an ONP(Ts)N-
group by o-nitrophenylation to attain the activation of the
amino group (to 5).5 This amino-derived leaving group was
still stable enough8 to allow the modification of the other
side of molecule 5 to afford 6. However, once its displace-
ment became necessary, simple heating effected the ring
closure to give pyrrolidine derivative 7.
Scheme 2.
Substitution of Aryl(sulfonyl)amino Groupsa
Scheme 2 shows the generality of this substitution
reaction. In addition to nitrogen nucleophiles (eqs 2 and
3), oxygen (eqs 4-8) and carbon nucleophiles (eqs 9 and
10) entered the reaction, producing azacycles, cyclic ethers
or a lactone, and carbocyclic compounds. Gratifyingly,
when a few optically active substrates were submitted to
the reaction (eqs 5, 6, and 14), each product maintained
virtually the same ee value as that of the original
compound with inversion of configuration. While oxygen-
(1) Textbooks of organic chemistry allot many pages to substitution
reactions by amino and related groups, but little is described on the reversed
transformation, substitution of amino and related groups. For example, see:
(a) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, 5th ed.;
Springer: New York, 2007; Part A, pp 389-472; Part B, pp 215-242. (b)
McMurry, J. Organic Chemistry, 5th ed.; Brooks/Cole: Belmont, CA, 2000;
pp 976-1029. (c) Morrison, R. T.; Boyd, R. N. Organic Chemistry, 6th
ed.; Prentice Hall: Upper Saddle River, NJ, 1997; pp 821-888. (d) Malpass,
J. R. In ComprehensiVe Organic Chemistry; Barton, D., Ollis, W. D.,
Sutherland, I. O., Eds.; Pergamon Press: Oxford, 1979; Vol. 2, pp 3-59.
In practice, substitution of amino group at ordinary sp3 carbon, apart from
activated carbon centers such as those at the allylic, benzylic, or acetal
position, is usually carried out by its diazotization and quaternarization prior
to the substitution. For example, see: (e) Smith, M. B.; March, J. March’s
AdVanced Organic Chemistry, 6th ed.; Wiley: Hoboken, NJ, 2007; pp
498-500. (f) Solomons, T. W. G.; Fryhle, C. B. Organic Chemistry, 8th
ed.; Wiley: Hoboken, NJ, 2004; pp 963-964. For substitution via
quaternarization of amines to pyridinium salts, see: (g) Katritzky, A. R.;
Musumarra, G. Chem. Soc. ReV. 1984, 13, 47–68. (h) Katritzky, A. R.
Tetrahedron 1980, 36, 679–699. For a broad survey of methods for C-N
bond cleavage, see: (i) Harrison, I. T.; Harrison, S.; Hegedus, L. S.; Wade,
L. G., Jr.; Smith, M. B. Compendium of Organic Synthetic Methods; Wiley:
New York, 1971-1992; Vols. 1-7.
a The reactions were performed with K3PO4 in DMF at 150 °C, except
for eq 14 where Cs2CO3 was used instead of K3PO4. The isolated yield and
reaction period (in parentheses) are indicated for each product.
ated or polyamine substrates are frequently encountered
in the manipulation of biomolecules, the nucleophilic
displacement in these systems is known to be retarded.9
However, the present method did not suffer from any
apparent decrease in the product yields, as evidenced by
the reactions in eqs 3, 6, and 7. An efficient amino-based
leaving group is not limited to ONP-plus-Ts derivatization.
Even the electron-rich PMP group, which has been used
as an amino-protecting group,10 worked well as a leaving
group as demonstrated in eq 11, where the effect of the
sulfonyl group is also shown. Thus, the PMP group,
(2) (a) Hughes, A. B., Ed. Amino Acids, Peptides and Proteins in
Organic Chemistry; Wiley-VCH: Weinheim, 2009; Vols. 1 and 2. (b)
Dewick, P. M. Medicinal Natural Products, 3rd ed.; Wiley: Chichester,
2009. (c) Trauner, D. Chem. ReV. 2008, 108, 1499–1796. (d) Gladysz, J. A.
Chem. ReV. 2005, 105, 4235–4812. (e) Walsh, C. T.; Wright, G. D. Chem.
ReV. 2005, 105, 391–774.
(6) For reviews on recent progress in transition-metal-catalyzed N-
arylation of both amines and sulfonamides, see: (a) Prim, D.; Campagne,
J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041–2075. (b)
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
(c) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439. (d) Monnier,
F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096–3099. (e) Ma, D.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450–1460. (f) Hartwig, J. F. Acc. Chem.
Res. 2008, 41, 1534–1544. For arylation of sulfonamides, see: (g) Deng,
W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-X. Tetrahedron Lett. 2005, 46,
7295–7298. (h) Steinhuebel, D.; Palucki, M.; Askin, D.; Dolling, U.
Tetrahedron Lett. 2004, 45, 3305–3307. (i) Yin, J.; Buchwald, S. L. Org.
Lett. 2000, 2, 1101–1104.
(3) (a) Nugent, T. C., Ed. Chiral Amine Synthesis; Wiley-VCH:
Weinheim, 2010. (b) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007,
63, 2541–2569. (c) List, B. Chem. ReV. 2007, 107, 5413–5883. (d) Weinreb,
S. M.; Orr, R. K. Synthesis 2005, 1205–1227.
(4) For sulfonylation of amines and anilines, see: (a) Wuts, P. G. M.;
Greene, T. W. Greene’s ProtectiVe Groups in Organic Synthesis, 4th ed.;
Wiley: Hoboken, NJ, 2007; pp 851-868. (b) Kocienski, P. J. Protecting
Groups; Georg Thieme Verlag: Stuttgart, 1994; pp 212-216.
(5) For o-nitrophenylation of amines or sulfonamides, see: (a) Ku-
lagowski, J. J.; Rees, C. W. Synthesis 1980, 215. (b) Burke, P. O.; Spillane,
W. J. Synthesis 1985, 935–937. (c) Newington, I.; Perez-Arlandis, J. M.;
Welton, T. Org. Lett. 2007, 9, 5247–5250. An actual procedure adopted in
our laboratory is simpler; see the Supporting Information.
(7) Some fundamental results of cyclization are shown in the Supporting
Information.
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Org. Lett., Vol. 12, No. 18, 2010

combined with a more electron-withdrawing sulfonyl
group (Ms (26) < Ts (28) < Ns (29) < Tf (30)), increased
the leaving capacity of the modified amino group. Other
examples for PMP-amino substrates are shown in eqs
12-14.
and 41 afforded 42, whose similar treatment as above
afforded the same heterocycle 39. It should be noted that
the nitrogen atom in 39 comes from electrophile 36 in the
upper equation, but from nucleophile 40 in the lower one,
and that these reactions are solely taking advantage of amino
groups.
In addition to eq 1, a couple of applications of this method
Equation 15 shows a direct conversion of amino alcohol
45, which represents frequently encountered synthetic in-
termediates or can be derived from parent amine 44,6,11 to a
conjunctive reagent 46. Upon reaction with catechol, this
reagent underwent double substitution to afford benzodioxane
(R)-17. Thus, (protected) 1,2-amino alcohols could be
converted to bis-electrophilic units by the present method.
are shown in Scheme 3 and eq 15. The addition of lithium
Scheme 3
.
Synthetic Manipulation Solely Based on Amino
Groups
In conclusion, we reported a convenient method for the
displacement of an amino group with inversion of config-
uration. Further extension of this reaction and its synthetic
applications are now under investigation.
reagent 35 to imine 36 produced diamine 37, but its further
synthetic elaboration appears to be hampered. However,
selective activation of a PhNH group in 37 to the leaving
group and the subsequent cyclization of the resultant 38 gave
heterocycle 39. On the other hand, the reaction between 40
Acknowledgment. This work was supported by the
Nagase Science and Technology Foundation (Japan) and
Ajinomoto Award in Synthetic Organic Chemistry, Japan
(to T.H.).
(8) Although disulfonylamine (sulfonimide) has been known to work
as a leaving group since the late 1960s, its synthetic utility has not been
well explored. To the best of our knowledge, intramolecular cyclization
with this group has not been reported. This most likely comes from the
fact that the requisite disulfonylamine is difficult to prepare in the presence
of an (incipient) nucleophile, as this functional group is rather labile and
behaves, at the same time, as a sulfonylating agent. For selected initial
studies, see: (a) DeChristopher, P. J.; Adamek, J. P.; Lyon, G. D.; Galante,
J. J.; Haffner, H. E.; Boggio, R. J.; Baumgarten, R. J. J. Am. Chem. Soc.
1969, 91, 2384–2385. (b) Mu¨ller, P.; Phuong, N. T. M. Tetrahedron Lett.
1978, 4727–4730, and references cited therein. For recent reports, see: (c)
Wang, X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520–7521.
(d) Toulgoat, F.; Langlois, B. R.; Me´debielle, M.; Sanchez, J.-Y. J. Org.
Chem. 2008, 73, 5613–5616. (e) Said, S. A.; Fiksdahl, A. Tetrahedron:
Asymmetry 2001, 12, 893–896. (f) Lescop, C.; Me´vellec, L.; Huet, F. J.
Org. Chem. 2001, 66, 4187–4193. For sulfonylation with disulfonylamines,
see: (g) Hendrickson, J. B.; Sternbach, D. D.; Bair, K. W. Acc. Chem. Res.
1977, 10, 306–312. (h) Zeller, W. E. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol. 6,
pp 4096-4097.
Supporting Information Available: Some fundamental
data of cyclization, experimental procedures, and physical
properties of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101541P
(9) Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55, 4417–
4422, and references cited therein.
(10) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in
Organic Synthesis, 4th ed.; Wiley: Hoboken, NJ, 2007; pp 813-814.
(11) For chemoselective N-arylation of amino alcohols, see: (a) Job,
G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703–3706. (b) Shafir, A.; Lichtor,
P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490–3491. (c) Willis,
M. C. Angew. Chem., Int. Ed. 2007, 46, 3402–3404.
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