New aspects of catalytic intramolecular C-H amination: Unexpected formation of a seven-membered ring in nitrogen-containing systems

Article abstract of DOI:10.1021/ol061649x

The first example of the formation of a seven-membered ring by way of intramolecular-catalyzed amination of saturated C-H bonds is reported (Du Bois reaction). The influence of various structural parameters was studied, and it was shown that the unexpected regioselectivity observed in nitrogen-containing systems could be rationalized by conformational factors. These results open the way to innovative strategies for the general synthesis of polyfunctionalized piperidines.

Full text of DOI:10.1021/ol061649x

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4493-4496
New Aspects of Catalytic Intramolecular
H Amination: Unexpected Formation
C−
of a Seven-Membered Ring in
Nitrogen-Containing Systems
Sylvestre Toumieux,† Philippe Compain,*,† Olivier R. Martin,† and
Mohamed Selkti‡
ICOA, UMR 6005 CNRS/UniVersite´ d’Orle´ans, rue de Chartres, BP 6759,
45067 Orle´ans, France, and Laboratoire de Cristallographie et RMN Biologiques,
UMR 8015 CNRS, Faculte´ de Pharmacie-UniVersite Paris V, aV. de l'ObserVatoire,
75006 Paris, France
philippe.compain@uniV-orleans.fr
Received July 5, 2006
ABSTRACT
The first example of the formation of a seven-membered ring by way of intramolecular-catalyzed amination of saturated C−H bonds is reported
(Du Bois reaction). The influence of various structural parameters was studied, and it was shown that the unexpected regioselectivity observed
in nitrogen-containing systems could be rationalized by conformational factors. These results open the way to innovative strategies for the
general synthesis of polyfunctionalized piperidines.
Selective transformation of unactivated C-H bonds is a
tremendous challenge of wide-reaching consequences in
organic chemistry.1 Major advances have been made very
recently in the development of catalytic methods for the
amination of unactivated C-H bonds.2 In 2001, Du Bois
and co-workers reported a remarkable, Rh-catalyzed intra-
molecular C-H insertion process using carbamate or sulf-
amate ester substrates.3,4 Amination reactions performed with
sulfamate esters led to the formation of the corresponding
six-membered ring insertion products, more rarely to five-
membered rings, whereas carbamates afforded only five-
membered rings (Figure 1). The highly favored formation
† ICOA, UMR 6005 CNRS/Universite´ d′Orle´ans.
‡ Laboratoire de Cristallographie et RMN Biologiques.
(1) (a) Shilov, A. E.; Shul′pin, G. B. Chem. ReV. 1997, 97, 2879. (b)
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (c) Kakiuchi, F.;
Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (d) Schreiner, P. R.; Fokin,
A. A. Chem. Rec. 2004, 3, 247. (e) Gois, P. M. P.; Afonso, C. A. M. Eur.
J. Org. Chem. 2004, 3773. (f) Tobisu, M.; Chatani, N. Angew. Chem., Int.
Ed. 2006, 45, 1683. (g) Dick, A. R. M.; Sanford S. Tetrahedron 2006, 62,
2439. (h) Davies, H. M. L.; Beckwith, E. J. Chem. ReV. 2003, 103, 2861.
(i) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
Figure 1. Rh-catalyzed oxidative cyclization of sulfamate esters.
of the oxathiazinane ring may be rationalized by the
elongated S-N and S-O bond length and the N-S-O angle
of the sulfamate, which match the metrical parameters of
the heterocycle.3a Additional factors influence the regio-
selectivity of the reaction. Amination of tertiary C-H bonds
(2) (a) Davies, H. M. L.; Long, M. S. Angew. Chem., Int. Ed. 2005, 44,
3518. (b) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (c) Dauban, P.;
Dodd, R. H. Synlett 2003, 1571.
10.1021/ol061649x CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/07/2006

is generally preferred to secondary C-H bonds, and electron-
donating groups activate the R-C-H bond toward insertion.3c,5
In connection with our studies on carbohydrate mimics,6
we recently applied the Du Bois reaction to C-glycoside 1
and obtained spiranic oxathiazolidine 2 by regiospecific
insertion into the pseudoanomeric C-H bonds (Scheme 1).5
3 to PhI(OAc)2, MgO, and 5 mol % of Rh2(OAc)4 in
dichloromethane. Surprisingly, no product corresponding to
the formation of a six- or five-membered ring was observed.
The only insertion product isolated was the oxathiazepane
derivative 4 produced in 67% yield (Table 1). Structural
evidence for 4, which corresponds to the insertion product
at C-6, was obtained unambiguously by X-ray crystal-
lographic analysis (Figure 2).7 To the best of our knowledge,
Scheme 1
Quite unexpectedly, this reaction was found to be strongly
dependent on the anomeric configuration since no insertion
product could be isolated from the pseudo-R-epimer of 1.
To evaluate the potential of this methodology for the
synthesis of original imino-C-glycosides, we first performed
a model study from piperidine 3, obtained in two steps from
2-piperidinemethanol (Table 1, entry 1). Amination of the
Figure 2. Perspective ORTEP view of compound 4.
4 is the first seven-membered ring ever obtained by way of
Du Bois reaction.8
Table 1. Study of the Influence of Various Structural
Parameters in Rh-Catalyzed C-H Insertion of Sulfamate Estersa
To rationalize this unexpected result, we decided to study
the influence of diverse structural parameters (Table 1).
Addition of an electron-donating or a strong electron-
withdrawing substituent on the phenyl group of the N-
benzenesulfonylpiperidine decreased the yield but did not
change the regioselectivity of the insertion process (entries
2 and 3). Ring size was found to play a key role since no
trace amount of an oxathiazepane product could be detected
from pyrrolidine 9. Compound 10 corresponding to the open-
chain imine form of the C-2 insertion product was isolated
in 29% yield from 9 (entry 4). The nature of the endocyclic
heteroatom was also found to be critical. Du Bois reaction
performed from pyran and furan derivatives 11 and 13 led
(3) (a) Espino, C. G.; Wehn, P.; Chow, M. J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935. (b) Espino, C. G.; Du Bois, J. Angew. Chem., Int.
Ed. 2001, 40, 598. (c) Fiori, K. W.; Flemming, J. J.; Du Bois, J. Angew.
Chem., Int. Ed. 2004, 43, 4349.
(4) For examples of related work, see: (a) Breslow, R.; Gellman, S. H.
J. Am. Chem. Soc. 1983, 105, 6728. (b) Fruit, C.; Mu¨ller, P. HelV. Chim.
Acta 2004, 87, 1607. (c) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-
Y. Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465. (d) Lebel, H.; Huard,
K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198. (e) Cui, Y.; He, C.
Angew. Chem., Int. Ed. 2004, 43, 4210. (f) Liang, C.; Robert-Peillard, F.;
Fruit, C.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. Angew. Chem., Int. Ed. 2006,
45, 4641.
(5) Toumieux, S.; Compain, P.; Martin, O. R. Tetrahedron Lett. 2005,
46, 4731.
(6) For selected references, see: (a) Godin, G.; Compain, P.; Masson,
G.; Martin, O. R. J. Org. Chem. 2002, 67, 6960. (b) Godin, G.; Compain,
P.; Martin, O. R. Org Lett. 2003, 5, 3269. (c) Compain, P.; Martin, O. R.;
Boucheron, C.; Godin, G.; Yu, L.; Ikeda, K.; Asano, N. ChemBioChem
2006, 7, 1356.
a Reaction conditions: CH2Cl2, 40 °C, 4-24 h, substrate/PhI(OAc)2/
MgO/Rh2(OAc)4 1:1.1:2.3:0.05. b Isolated yield. c Compound 14 was ob-
tained along with 22% of the corresponding spiranic cyclized product.
(7) Crystallographic data for structure 4 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 605300.
(8) For the synthesis of oxathiazepanes by way of PhIdO-mediated
copper-catalyzed aziridination of unsaturated sulfamates, see: (a) Duran,
F.; Leman, L.; Ghini, A.; Burton, G.; Dauban, P.; Dodd, R. H Org Lett.
2002, 4, 2481. (b) Duran, F. J.; Ghini, A.; Dauban, P.; Dodd, R. H.; Burton,
G. J. Org. Chem. 2005, 70, 8613.
C-3 position would open the way to a general synthesis of
imino-C-glycoside analogues of hexosamine whereas nitro-
gen atom insertion at C-2 would yield a functionalized
piperidine containing an aminal structure that could serve
as surrogate iminium ions. We thus submitted test substrate
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Org. Lett., Vol. 8, No. 20, 2006

only to products corresponding to the insertion into the C-H
bond at C-2 (entries 5 and 6).
experiment (J2ax,3ax ) 11.1 Hz; J2ax,3eq ) 1.7 Hz), pyran 13
adopts a chair conformation with the sulfamoyloxymethyl
substituent occupying an equatorial position. This conforma-
tion makes the addition into the reactive axial C-H bond11
at C-2 highly favorable and prevents amination of the C-6
position. In contrast, as supported by X-ray crystallographic
analysis (see the Supporting Information) and literature
precedent,12 the piperidine ring of compound 3 may be close
in solution to a chair conformation in which the sulfamoyl-
oxymethyl substituent occupies an axial position. Such a
conformation minimizes the pseudo A1,3 strain between the
C-2 substituent and the N-tosyl group caused by the partial
double bond character of the S-N sulfonamide bond.12 This
conformation favored the insertion into the reactive axial
C-H bond in C-6 to form a seven-membered ring in which
the values observed for the S-N and S-O bond lengths
(1.59 and 1.56 Å, respectively) and the N-S-O angle
(∼106°) are very close to those obtained for oxathiazinane
derivatives.3a Amination at C-2 is penalized by the formation
of a less favored five-membered ring and by the fact that
the insertion would occurred in a less reactive equatorial
C-H bond.11
Puzzling results obtained from C-glycoside 1 and its
R-epimer make more sense in light of conformational factors
(Scheme 1).5 In 1, the sulfamoyloxymethyl substituent
occupied an equatorial position and thus the oxathiazolidine
was readily obtained. In the R-epimer of 1, this reacting
group shifted to an axial position and the insertion could
occurred into two activated R-oxygenated axial C-H bonds
at C-3 and C-5 leading to the formation of unstable hemi-
aminal derivatives and thus to degradation.
The amination reaction was then performed with com-
pound 15, which was designed to strongly favored the
insertion into the ethereal CR-H bonds and thus the
formation of the six-membered ring (entry 7). Even in this
case, the oxathiazinane derivative 17 was not obtained as
the major product as judged by NMR analysis of the crude
reaction mixture (ratio 16/17 ∼1/1). In another test substrate,
the tetrahydroisoquinoline derivative 18 (Scheme 2), the two
Scheme 2
secondary C-H bonds at C-1 and C-4 are benzylic; the
amination of the C-4 position may be facilitated by the
formation of a six-membered ring whereas insertion into the
C-H bond at C-1 may be favored by the presence of an
N-tosyl group in R.
Under typical amination conditions, the oxathiazepane
derivative 19 was obtained as the major product in 65% yield,
along with minor amount of the oxathiazinane derivative 20
in 18% yield. The regioselectivity of the reaction was slightly
improved by using Rh2(esp)2, a new C-H amination catalyst
(86% yield, ratio 19/20 87/13).9
To reduce conformational control of reaction selectivity,
we performed the reaction with acyclic substrates 23 and
27 (Scheme 4). As expected, compounds corresponding to
Remarkably, the amination process could be extended to
the synthesis of eight-membered rings as it was demonstrated
by the reaction performed from sulfamate ester 21, which
was prepared from piperidine-2-ethanol (Scheme 3).
Scheme 4
Scheme 3
In view of the results obtained, it became clear that the
regioselectivity of the amination reaction cannot be attributed
solely to electronic factors and that decisive conformational
factors were at play. The distinct regioselectivity obtained
in the pyran and in the piperidine series may be explained
by conformational preferences which placed the nitrene
center in a favorable position to the reacting C-H bond.10
As expected and demonstrated by selective irradiation NMR
the formation of a five- and more importantly a seven-
membered rings were observed from amination reaction of
(11) (a) Wardrop, D. J.; Zhang, W.; Fritz, J. Org. Lett. 2002, 4, 489. (b)
Malatesta, V.; Ingold, K. U. J. Am. Chem. Soc. 1981, 103, 609.
(12) (a) Johnson, F. Chem. ReV. 1968, 68, 375. (b) Hoffman, R. W. Chem.
ReV. 1989, 89, 1841. (c) Kuznetsov, N. Y.; Khrustalev, V. N.; Godovikov,
I. A.; Bubnov, Y. N. Eur. J. Org. Chem. 2006, 113. (d) Cariou, C. A. M.;
Snaith, J. S. Org. Biomol. Chem. 2006, 4, 51. (e) Jourdant, A.; Zhu, J.
Tetrahedron Lett. 2000, 41, 7033.
(9) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 125, 15378.
(10) For conformational control of selectivity in intramolecular carbenoids
reactions of diazoacetoacetamides, see, for example: Doyle, M. P.; Pieters,
R. J.; Taunton, J.; Pho, H. Q. J. Org. Chem. 1991, 56, 820.
Org. Lett., Vol. 8, No. 20, 2006
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ether 23 (65% of conversion, ratio 25/26 3/7). Because of
the relative instability of hemi-aminal derivatives, cyclic
sulfonimine 26, which probably resulted from the corre-
sponding R-ethoxy tosylamide was obtained after purification
along with the seven-membered ring 25. In a similar way,
tosylamides 28 and 29 were isolated after treatment of 27
with Rh2(OAc)4, PhI(OAc)2, and MgO. These compounds
most likely came from fragmentation of the corresponding
seven- and five-membered ring aminals, respectively.13
Beyond its mechanistic interest, the major synthetic
significance of the reported process is the substitution of a
C-H bond in a 1,7- or 1,8-relationship with respect to the
activating group. In addition, the resulting aminals are
precursors of N-tosyliminium ion: to our knowledge, only
one prior report on a related system has shown that such a
process is indeed possible.14,15 A preliminary result obtained
with 4 and allylsilane in the presence of BF3‚OEt2 nicely
demonstrated the feasibility of this approach. The disubsti-
tuted piperidine 24 was obtained in good yield and high
diastereoselectivity from 4 (Scheme 5).
Figure 3. Perspective ORTEP view of compound 24.
In conclusion, we have reported the first example of the
formation of a seven- or eight-membered ring by Du Bois
reaction. On the basis of results obtained with various test
substrates, it was shown that the unusual regioselectivity
observed in nitrogen-containing systems could be rationalized
by conformational factors. Our results reveal a completely
new aspect of intramolecular C-H amination and further
expands its synthetic scope through conformational control
of reaction regioselectivity. These findings open the way to
unique sequential strategies for the general synthesis of
polyfunctionalized piperidines, a major class of biologically
active compounds.17 Further studies along these lines are
currently in progress in our laboratory.
Scheme 5
X-ray crystallographic analysis (see the Supporting Infor-
mation) indicated that piperidine 24 adopted a 2,6-cis diaxial
conformation since the cis diequatorial conformation would
cause strong A1,3 strain (Figure 3).12,16 This step allowed the
completely stereocontrolled formation of a C-C bond and
also regenerate the sulfamate ester that may be used again
for further intramolecular C-H amination of the piperidine
ring.
Acknowledgment. Financial support by grants from
CNRS, the French department of research, and the “Agence
Nationale de Recherche sur le Sida” (ANRS) is gratefully
acknowledged.
Supporting Information Available: Characterization
data for new compounds, experimental procedures, and X-ray
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) A trace amount of compound 26 was also detected by NMR analysis
of the crude reaction mixture.
(14) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629.
(15) It is noteworthy that aminals 4, 6, 8, 16, 19, and 22 are stable for
several weeks at room temperature and may be stored for months at 4 °C.
(16) Crystallographic data for structure 24 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 605301.
OL061649X
(17) See, for example: Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borchedering, D. R. Tetrahedron 2003, 59, 2953 and references cited
therein.
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Org. Lett., Vol. 8, No. 20, 2006