Samarium diiodide-induced intramolecular pinacol coupling of dinitrones: Synthesis of cyclic cis-vicinal diamines

Article abstract of DOI:10.1039/b511491h

Pinacol coupling of alkyl dinitrones mediated by SmI₂ was achieved in the presence of a proton source allowing the synthesis of cyclic vicinal diamines with good cis-selectivity. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b511491h

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COMMUNICATION
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Samarium diiodide-induced intramolecular pinacol coupling of
dinitrones: synthesis of cyclic cis-vicinal diamines{
Jean-Philippe Ebran, Rita G. Hazell and Troels Skrydstrup*
Received (in Cambridge, UK) 11th August 2005, Accepted 9th September 2005
First published as an Advance Article on the web 30th September 2005
DOI: 10.1039/b511491h
Attempts to promote the cyclisation of oxime 4 with t-BuOH
Pinacol coupling of alkyl dinitrones mediated by SmI2 was
achieved in the presence of a proton source allowing the
synthesis of cyclic vicinal diamines with good cis-selectivity.
(8 equiv.) as proton source led only to the simple reduction of
the nitrone, whereas addition of butyl acrylate provided the
c-hydroxylamino ester 6 with 40% yield (Scheme 2) suggesting
indeed that the nitrone was undergoing reduction.
Cyclic vicinal diamines are important constituents in numerous
biologically active compounds of medicinal value, as well as in a
multitude of chiral auxiliaries and chiral ligands.1 Most of the
methods described for the synthesis of cyclic vicinal diamines
rely on the creation of the C–N bond, by reductive amination,2
electrophilic amination,3 nucleophilic amination to conjugated
p-systems,4 olefin oxidation by dinitrogen tetroxide,5 or inter-
molecular 1,2-diamination of alkenes.6 Approaches involving C–C
bond formation using the reductive coupling of imine species have
also been developed, although only in specific cases involving the
preparation of ethylenediamine containing ring systems.7
As the dinitrone 7 was obtained as a side product in the
synthesis of 4, but is also available by the condensation of
glutaraldehyde with N-benzylhydroxylamine (see ESI), this
compound was submitted to reductive conditions. Whereas no
intramolecular pinacol coupling occurred at 278 uC with SmI2, the
reaction led at 0 uC to the corresponding cyclopentyl diamine 8 in
48% yield with good cis-selectivity (10 : 1) (Table 1, entry 2).
The desired product was obtained with dramatically increased
reaction rates in the presence of an additive (entries 3, 5 and 6),
except for t-BuOH (entry 4). Inclusion of methanol afforded the
desired cyclic compound with a cis : trans ratio up to 19 : 1 and
76% yield (entry 6). The cis-relationship between the two vicinal
nitrogens of the major cyclic product was determined by a single
crystal X-ray structure analysis of the corresponding cyclic urea 9a,
prepared by a two-step procedure from 8 involving N–O bond
cleavage with excess SmI2 and cyclisation with phosgene (Fig. 1).{
This intramolecular pinacol coupling was then applied to
various dialdonitrones 7 in order to study the influence of the ring
size, as well as the presence of heteroatoms in the ring. In order to
avoid product mixtures from a competing reaction involving the
over-reduction of the N-hydroxylamines to the corresponding
amines, the intramolecular couplings were carried out with excess
Previous reports from the Valle´e/Py group and us have
demonstrated the ability of alkyl nitrones to undergo SmI2-
mediated intermolecular radical addition to various acceptors
such as carbonyl compounds producing vicinal amino alcohols,8
and a,b-unsaturated amides or esters resulting in the synthesis
of c-N-hydroxyamino amides or esters.9,10 Moreover, Xu and
coworkers have described the asymmetric synthesis of vicinal
diamines by SmI2-promoted reductive cross-coupling of alkyl
nitrones to chiral sulfinyl imines,11 although the reactions appear
limited to aryl substrates. In this communication, we disclose an
alternative method for the preparation of this important class of
cyclic compounds via a cis-selective intramolecular pinacol type
coupling of dinitrones promoted by the single electron reducing
agent, samarium diiodide.12
Taking into consideration the previous work on SmI2-promoted
intramolecular cyclisations of ketyl-hydrazones13 or ketyl-oximes14
for the formation of five-, six- and seven-membered cyclic amino
alcohols, initial efforts were focused on the ability of a nitrone
group to undergo intramolecular coupling with either a hydrazone
or oxime. Hence, the nitrone hydrazone 1 was first submitted to
conditions reported by Sturino and Fallis13a for promoting ring
formation (SmI2 2.4 equiv./HMPA 8 equiv.). The major product
was surprisingly not the cyclic compound but the dihydroxylamine
2 from intermolecular pinacol coupling. The use of a proton
source such as H2O (8 equiv.) resulted in the reduction of the
nitrone to the hydroxylamine hydrazone 3 (Scheme 1).
Scheme 1 Attempts to cyclise the nitrone hydrazone 1.
Department of Chemistry, University of Aarhus, Langelandsgade 140,
8000, Aarhus C, Denmark. E-mail: ts@chem.au.dk; Fax: +45 8619 6199;
Tel: +45 8942 3932
{ Electronic supplementary information (ESI) available: X-ray crystal
structures of 9j and 9l and experimental procedures. See DOI: 10.1039/
b511491h
Scheme 2 Attempt to cyclise the nitrone oxime 4.
5402 | Chem. Commun., 2005, 5402–5404
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The dinitrones of entries 2 and 3 imply that the synthesis of
unsymmetrical ureas can be achieved in good yields and
diastereoselectivities. The trans-relationship between the methyl
substituent and the amine groups of 9i was confirmed by NOE
studies.15 The ring formation between aldonitrone and ketonitrone
moieties was also shown possible with slightly lower yields, but
an acceptable cis : trans selectivity was still maintained (entries 4
and 5). Finally, the pinacol coupling of diketonitrones afforded in
Table 1 Optimisation of cyclisation conditions promoted by SmI2
Additive
Entry (equiv.)
d.r.
Temperature Time/h Yield/% (cis : trans)a
Table 3 Pinacol coupling of various aldo- and ketonitrones
1
2
3
4
5
6
a
—
—
278 uC
0 uC
20
1
0.08
3
0.75
0.75
0
48
60
56
47
76
—
10 : 1
6 : 1
4 : 1
7 : 1
H2O (10)
t-BuOH (10)
HMPA (10)
MeOH (10)
0 uC
0 uC
0 uC
0 uC
. 19 : 1
Determined by 1H NMR.
d.r.
Yield/% (cis : trans)a
Entry Dinitrone
1
Product
52
4 : 1b
2
3
58
4 : 1
Fig. 1 X-ray crystal structure representation of the urea 9a.
65c
. 19 : 1
(. 9 : 1)d
Table 2 Influence of the ring size
4
5
6
42
44
28
7 : 1
5 : 1
4 : 1
—
Entry Dinitrone
n
X
Product Yield/% d.r. (cis : trans)a
1
2
3
4
5
6
a
7b
7a
7c
7d
7e
7f
0
1
1
1
2
3
CH2
CH2
O
NBoc 9d
CH2
CH2
9b
9a
9c
32
66
52
59
43b
35
. 19 : 1
. 19 : 1
5 : 1
. 19 : 1
5 : 1
3 : 1
9e
9f
b
Determined by 1H NMR. Result obtained with t-BuOH as
additive.
SmI2 (8 equiv.) in 14 h at 0 uC. Without isolation, the intermediary
cyclic diamines were subjected to phosgene generating the cyclic
ureas 9 with yields ranging from 32 to 66% (three steps) and cis :
trans ratios up to 19 : 1 (Table 2). In general, the highest yields
were obtained for the 5-membered ring products (entries 2–4)
where the yields dropped upon formation of both smaller and
larger rings.
7
—
—
Following these encouraging results, the intramolecular pinacol
coupling of various aldonitrones and ketonitrones was examined
as illustrated in Table 3. Cyclisation of the symmetrical aldonitrone
7g gave the tricyclic structure 9g with an endo-selectivity (entry 1).
a
b
c
Determined by 1H NMR. endo : exo ratio. Result obtained with
H2O as additive. anti : syn ratio.
d
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super-imposed by the 2-axis. CCDC 280863. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b511491h
1 For a review on the chemistry of vicinal diamines, see: D. Lucet,
T. Le Gall and C. Mioskowski, Angew. Chem., Int. Ed., 1998, 37, 2580.
2 G. Fraenkel and P. Pramanik, J. Org. Chem., 1984, 49, 1316.
3 P. Gmeiner and E. Hummel, Synthesis, 1994, 1026.
4 (a) M. A. Sturgess and D. J. Yarberry, Tetrahedron Lett., 1993, 34,
4743; (b) K. S. Feldman and J. C. Saunders, J. Am. Chem. Soc., 2002,
124, 9060.
Fig. 2 Plausible transition state for the intramolecular SmI2-promoted
pinacol cyclisation of dinitrones.
5 W. Zhang and E. N. Jacobsen, Tetrahedron Lett., 1991, 32, 1711.
6 G. L. J. Bar, G. C. Lloyd-Jones and K. I. Booker-Milburn, J. Am.
Chem. Soc., 2005, 127, 7308.
7 (a) N. Kise, H. Oide, E. Okazaki, M. Yoshimoto and T. Shono, J. Org.
Chem., 1995, 60, 3980; (b) R. Annunziata, M. Benaglia, M. Caporale
and L. Raimondi, Tetrahedron: Asymmetry, 2002, 13, 2727.
8 (a) G. Masson, S. Py and Y. Valle´e, Angew. Chem., Int. Ed., 2002, 41,
1772; (b) M. Chavarot, M. Rivard, F. Rose-Munch, E. Rose and S. Py,
Chem. Commun., 2004, 2330; (c) G. Masson, C. Philouze and S. Py,
Org. Biomol. Chem., 2005, 3, 2067.
9 (a) D. Ribber and T. Skrydstrup, Org. Lett., 2003, 5, 229; (b)
S. A. Johannesen, S. Albu, R. G. Hazell and T. Skrydstrup, Chem.
Commun., 2004, 1962.
10 (a) G. Masson, P. Cividino, S. Py and Y. Valle´e, Angew. Chem., Int. Ed.,
2003, 42, 2265; (b) S. Desvergnes, S. Py and Y. Valle´e, J. Org. Chem.,
2005, 70, 1459.
the case of dinitrone 7l the desired cyclic urea 9l with a low yield
and a d.r. of 4 : 1 (entry 6), whereas no cyclisation took place in the
case of dinitrone 7m (entry 7). Single crystal X-ray structure
analysis of the compound 9l again allowed confirmation of the cis-
stereoselectivity observed for this SmI2-induced intramolecular
pinacol coupling.§
To explain the cis-selectivity observed in these reactions, we
propose a plausible chelated transition state invoking coordination
of the Sm(III) of the nitrone radical anion to the oxygen of the
other nitrone as depicted in Figure 2. Similar chelated transition
states have been proposed for the cis-selective pinacol coupling of
dicarbonyl compounds.16
11 Y.-W. Zhong, M.-H. Xu and G.-Q. Lin, Org. Lett., 2004, 6, 3953.
12 For recent reviews on the application of SmI2 in organic synthesis,
see: (a) H. Kagan, Tetrahedron, 2003, 59, 10351; (b) D. J. Edmonds,
D. Johnston and D. J. Procter, Chem. Rev., 2004, 104, 3371; (c)
P. G. Steel, J. Chem. Soc., Perkin Trans. 1, 2001, 2727; (d)
G. A. Molander and C. R. Harris, Tetrahedron, 1998, 54, 3321; (e)
A. Krief and A.-M. Laval, Chem. Rev., 1999, 99, 745.
13 (a) C. F. Sturino and A. G. Fallis, J. Am. Chem. Soc., 1994, 116, 7447;
(b) A. Fallis and I. M. Brinza, Tetrahedron, 1997, 53, 17543 and
references cited therein; (c) D. Riber, R. Hazell and T. Skrydstrup,
J. Org. Chem., 2000, 65, 5382.
14 (a) K. C. Nicolaou, P. B. Rao, J. Hao, M. V. Reddy, G. Rassias,
X. Huang, D. Y.-K. Chen and S. A. Snyder, Angew. Chem., Int. Ed.,
2003, 42, 1753; (b) I. Storch de Gracia, S. Bobo, M. D. Mart`ın-Ortega
and J. L. Chiara, Org. Lett., 1999, 1, 1705 and references cited therein;
(c) H. Miyabe, M. Torieda, K. Inoue, K. Tajiri, T. Kiguchi and
T. Naito, J. Org. Chem., 1998, 63, 4397.
In summary, we have developed an intramolecular pinacol
coupling of alkyl dinitrones allowing the synthesis of cyclic
diamines with good to excellent cis-stereoselectivities. Attempts to
find conditions suitable for the preparation of the corresponding
trans-isomers using this reductive cyclisation process are in
progress and will be reported in due course.
We gratefully acknowledge the Danish Natural Science
Research Council, the Villum Kann Rasmussen Foundation and
the University of Aarhus for financial support of this project.
Notes and references
{ Crystal data for 9a: C20H22N2O, M 5 306.40, orthorhombic, a 5
3
˚
˚
˚
˚
20.478 (2) A, b 5 8.647 (1) A, c 5 9.235 (1) A, U 5 1635.3 (3) A , T 5
100 K, space group: Cmc21, Z 5 4, m(Mo-Ka) 5 0.077 mm21. A total of
16485 reflections measured, 1845 independent, 1316 with I . 3 s (I); 108
parameters were refined, final R 5 0.037, RW 5 0.043. CCDC 280862. For
crystallographic data in CIF or other electronic format see DOI: 10.1039/
b511491h
15 A strong NOE was observed between the methyl group of 9i and the
two protons of the urea group
§ Crystal data for 9l: C22H26N2O, M 5 334.45, orthorhombic, a 5
3
˚
˚
˚
˚
12.1490 (4) A, b 5 20.4254 (9) A, c 5 7.2291 (3) A, U 5 1793.89 (12) A ,
T 5 100 K, space group: Aba2, Z 5 4, m(Mo-Ka) 5 0.076 mm21; 23313
reflections measured, 1826 independent, 1590 with I . 3 s (I); 115
parameters refined, final R 5 0.042, RW 5 0.050. The structure is
disordered such that the cyclopentane ring and the two methyl groups are
.
16 For a detailed discussion see ref. 12 and references cited therein.
5404 | Chem. Commun., 2005, 5402–5404
This journal is ß The Royal Society of Chemistry 2005