Enantioselective iridium-catalyzed allylic substitutions with hydroxamic acid derivatives as N-nucleophiles

Article abstract of DOI:10.1021/ol200688d

Enantioselective Ir-catalyzed allylic aminations with hydroxamic acid derivatives are described. Catalysts were prepared in situ from [Ir(cod)Cl] ₂ or [Ir(dbcot)Cl]₂, a phosphoramidite and base. In addition, pure (φ-allyl)Ir complexe

Full text of DOI:10.1021/ol200688d

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2810–2813
Enantioselective Iridium-Catalyzed Allylic
Substitutions with Hydroxamic Acid
Derivatives as N-Nucleophiles
€
Martin Gartner, Mascha Jakel, Manuel Achatz, Christoph Sonnenschein,
Olena Tverskoy, and Gunter Helmchen*
€
€
€
Organisch-Chemisches Institut der Ruprecht-Karls-Universitat Heidelberg,
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
g.helmchen@oci.uni-heidelberg.de
Received March 15, 2011
ABSTRACT
Enantioselective Ir-catalyzed allylic aminations with hydroxamic acid derivatives are described. Catalysts were prepared in situ from [Ir(cod)Cl]2
or [Ir(dbcot)Cl]2, a phosphoramidite and base. In addition, pure (π-allyl)Ir complexes containing cod or dbcot as auxiliary ligands were used. Very
high degrees of regio- and enantioselectivity were achieved. The reaction products were transformed into piperidine derivatives suited as
precursors for aza-sugars.
Transition metal catalyzed asymmetric allylic substitu-
tions have been intensely investigated over several
decades.1 Over the past few years, the iridium-catalyzed
reaction has become increasingly important as a method
for the synthesis of branched allylic compounds from
monosubstituted allylic derivatives, usually allylic carbo-
nates (eq 1). In its presently most often applied version,
catalysts are (π-allyl)Ir complexes of cyclometalated phos-
phoramidites that are used in pure form or generated in
situ.2
can be regarded as N-protected allylamines; however, they
are of interest themselves in natural products chemistry,3
for example, as precursors of N-hydroxy aza-sugars,4
antibiotics,5 and peptidomimetics.6
Hydroxylamine derivatives have been probed in various
Pd-catalyzed allylic substitutions.7 Asymmetric catalysis
withthesenucleophileswasonlyinvestigatedby Takemoto
et al., using Pd- and Ir-catalyzed allylic substitutions.8 For
the latter reactions a catalyst prepared from the tridentate
ligand Pybox and [Ir(cod)Cl]2 was used.
(4) Racine, E.; Bello, C.; Gerber-Lemaire, S.; Vogel, P.; Py, S. J. Org.
Chem. 2009, 74, 1766–1769.
(5) (a) Umezawa, K.; Ikeda, Y.; Kawase, O.; Naganawa, H.; Kondo,
S. J. Chem. Soc., Perkin Trans. 1 2001, 1550–1553. (b) Berge, J. M.;
Houge-Frydrych, C. S. V.; Jarvest, R. L. J. Chem. Soc., Perkin Trans. 1
2001, 2521–2523.
Recently we became interested in exploring this method
for the preparation of N-allylated hydroxylamines. These
(1) Reviews covering the whole field: (a) Lu, Z.; Ma, S. Angew.
Chem., Int. Ed. 2008, 47, 258–297. (b) Helmchen, G.; Kazmaier, U.;
Forster, S. In Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.;
(6) Li, X.; Wu, Y.-D.; Yang, D. Acc. Chem. Res. 2008, 41, 1428–1438.
(7) (a) Imada, Y.; Nishida, M.; Kutsuwa, K.; Murahashi, S.-I.;
Naota, T. Org. Lett. 2005, 7, 5837–5839. (b) Murahashi, S.-I.; Imada,
Y.; Taniguchi, Y.; Kodera, Y. Tetrahedron Lett. 1988, 29, 2973–2976. (c)
Genet, J. P.; Thorimbert, S.; Mallart, S.; Kardos, N. Synthesis 1993,
321–324. (d) Genet, J. P.; Thorimbert, S.; Touzin, A.-M. Tetrahedron
Lett. 1993, 34, 1159–1162. (e) Ohler, E.; Kanzler, S. Synthesis 1995, 539–
543. (f) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007,
46, 7259–7261.
€
Wiley-VCH: New York, 2010; pp 497ꢀ641.
€
(2) (a) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen,
R. Chem. Commun. 2007, 675–691. (b) Helmchen, G. In Iridium Com-
plexes in Organic Synthesis; Oro, L. A., Claver, C., Eds.; Wiley-VCH:
Weinheim, 2009; pp 211ꢀ250. (c) Hartwig, J. F.; Stanley, L. M. Acc.
Chem. Res. 2010, 43, 1461–1475.
€
(3) The Chemistry of Hydroxylamines, Oximes and Hydroxamic
Acids, Vol. 2; Rappoport, Z., Liebman, J. E., Eds.; Wiley: Chichester,
2011.
(8) (a) Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y.
Org. Lett. 2004, 6, 4631–4634. (b) Miyabe, H.; Yoshida, K.; Yamauchi,
M.; Takemoto, Y. J. Org. Chem. 2005, 70, 2148–2153.
r
10.1021/ol200688d
Published on Web 05/02/2011
2011 American Chemical Society

Figure 1. Hydroxamic acid derivatives used as N-pronucleo-
philes in allylic substitutions.
While the Takemoto group successfully probed a range
of hydroxylamine derivatives as O-nucleophiles, only the
N-nucleophiles Nu1 and Nu2 (Figure 1) were investigated
with a few highly reactive arylallyl phosphates (X =
OPO(OEt)2) as substrates, which gave moderate selectivity
except in one case (R = 1-naphthyl).8a
Our own investigation commenced with experiments
using O-benzyl- and O-methylhydroxylamine as nucleo-
philes, which did not give satisfactory results. Next hydro-
xamic acid derivatives were considered with the following
conditions in mind: (a) The reaction must be feasible with
aliphatic and functionalized substituents R. (b) The pro-
nucleophiles should be sufficiently acidic to allow the
substitution to be run with allylic carbonates as substrates
under “salt-free” conditions, i.e., directly with the pronu-
cleophiles rather than their salts.9 (c) The protecting
groups at O and/or N should be removable selectively
under mild conditions.
Figure 2. Phosphoramidite ligands, achiral auxiliary ligands,
and (π-allyl)Ir complexes used in this work.
in situ by adding the base TBD (1,5,7-triazabicyclo-
[4.4.0]dec-5-ene)12 to a mixture of [Ir(cod)Cl]2 and a phos-
phoramidite;13 phosphoramidites L2 and L3 (Figure 2),
introduced by Alexakis, gave particularly good results.14
With other nucleophiles (see below) isolated (π-allyl)Ir
complexes C1ꢀC3 were additionally used.15
Scheme 2. Synthesis of a Chiral Tetrahydro-1,2-oxazine
Scheme 1. Ir-Catalyzed Allylic Substitutions with Hydroxamic
Acid Derivatives Nu3 and Nu4 as Pronucleophiles
The first nucleophile successfully probed was Nu3. This
compound was introduced as a pronucleophile for con-
jugate additions by MacMillan et al.10 Accordingly, the
salt-free conditions should be applicable. Indeed, reactions
with a representative set of allylic carbonates 1 (Scheme 1)
proceeded smoothly with remarkably high regio- and
excellent enantioselectivity.11 The catalysts were prepared
To indicate possible uses of the substitution products
and as a test of O-deprotection, the reaction sequence
described in Scheme 2 was carried out. Hydroboration of
2c with 9-BBN followed by a SuzukiꢀMiyaura reaction
with methyl (E)-3-iodo-acrylate gave the enoate 6 in 88%
yield. Treatment of 6 with TBAF at ꢀ78 °C effected
O-deprotection and oxa-Michael addition togivethe tetra-
hydro-1,2-oxazine 7 in 84% yield as a single stereoiso-
(9) (a) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem., Int.
Ed. 2006, 45, 5546–5549. (b) Spiess, S.; Berthold, C.; Weihofen, R.;
Helmchen, G. Org. Biomol. Chem. 2007, 5, 2357–2360. (c) Singh, O. V.;
Han, H. Tetrahedron Lett. 2007, 48, 7094–7098.
(10) (a) Chen, J. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2006, 128, 9328–9329. (b) Simmons, B.; Walji, A. M.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2009, 48, 4349–4353.
(12) It is very important that this compound be carefully dried (see
Supporting Information).
(13) Review: Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed.
2010, 49, 2486–2528.
(11) The assignment of the absolute configuration is based on a rule
on the configurational course of the Ir-catalyzed allylic substitution,
which was always found valid so far (ref 2).
(14) (a) Polet, D.; Alexakis, A. Org. Lett. 2005, 7, 1621–1624. (b)
Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K.
Chem.;Eur. J. 2006, 12, 3596–3609.
Org. Lett., Vol. 13, No. 11, 2011
2811

mer.16 This procedure supplements syntheses of dihydro-
1,2-oxazines from O,N-diallylhydroxamic acids via ring
closing metathesis.17 Tetrahydro-1,2-oxazines are valuable
intermediates, for example, for syntheses of pyrrolidine
alkaloids.18
Table 2. Ir-Catalyzed Allylic Substitutions with the Pronucleo-
phile Nu4 a
en-
sub-
time yield
ee
(%)d
try strate
catalyst
base
(h)
(%)b
b/lc
1
2
3
4
1a
1a
1a
1b
in situ/L2
in situ/L2
C1
TBD
DBU
TBD
24
58
92
59
76
94:6
97:3
96:4
98:2
94
99
98
98
Table 1. Ir-Catalyzed Allylic Substitutions with the Pronucleo-
phile Nu3 a
2
1.5
1
in situ/ent- TBD
sub-
time
(h)
yield
(%)b
ee
L2
entry
strate
L*
b/lc
(%)d
5
1b
1c
1c
1d
1d
1d
1d
1d
1e
ent-C1
TBD
TBD
TBD
TBD
DBU
TBD
TBD
DMAP
1
75
74
80
80
88
83
86
88
47
99:1
98
98
99
97
98
98
94
98
86
6
in situ/L2
C1
2.5
1
90:10
93:7
1
1a
1a
1c
1c
1d
1d
L2
L3
L2
L3
L2
L3
3
20
2.5
43
2.5
16
83
65
90
56
72
74
98:2
98:2
98:2
98:2
97:3
96:4
99
99
99
98
96
97
7
2
8
in situ/L2
in situ/L2
C1
5
87:13
87:13
88:12
95:5
3
9
4.5
2
4
5e
6e
10
11e
12e
13
in situ/L2
in situ/L2
3
3
96:4
a Reactions were carried out with THF as solvent at rt; the catalyst
was prepared in situ using [Ir(cod)Cl]2, L*, and dry TBD. b Isolated yield
of branched product 2. c Determined by 1H NMR of the crude product.
d Determined by HPLC. e Reaction was carried out at 50 °C.
in situ/ent- DBU
2
71:29
L2
14
15
16
1e
1e
1e
C1
C2
C3f
DBU
DBU
DBU
1
1
63
71
72
78:22
90:10
94:6
91
88
93
20
a All reactions were carried out at 50 °C. b Combined yield of 4 þ 5.
The pronucleophile Nu3 fulfills conditions (a)ꢀ(c) en-
umerated above. Likely, Weinreb type reactions19 cannot
be carried out with hydroxamates derived from Nu3.
Therefore, Nu420 was probed. This was found to be slightly
less reactive than Nu3; therefore, reactions were run at
50 °C rather than at rt (Table 2). Regioselectivity was
slightly lower with Nu4 than with Nu3 for reactions of
substrates 1a, 1c, and 1d (Table 1, entries 1, 3, 5 vs Table 2,
entries 1, 6, 8). Enantioselectivities were excellent for the
substrates 1aꢀd.
c Determined by 1H NMR of the crude product. d Determined by HPLC
or GC. e [Ir(dbcot)Cl]2 was used instead of [Ir(cod)Cl]2. f 2.7 mol % of
the catalyst were used. The yield refers to pure 4e.
As an application of the hydroxamates, the sequence
described in Scheme 3 was carried out. Removal of the Boc
protecting group with TFA followed by acylation with
vinylacetic acid furnished the diene 8 (81%), which was
subjected to ring closing metathesis (RCM) to give the
piperidone 9 in 96% yield. Finally, an approach toward
aza-sugars, a catch and release strategy,22 was employed
by epoxidation and base-catalyzed elimination to give
compound 10. The epoxidation, using a procedure of
Knight,22b,c proceeded with a diastereoselectivity of 95:5.23
Reactions catalyzed with the (π-allyl)Ir complex C1
were particularly fast and proceeded with very high regio-
and enantioselectivity with substrates1aꢀc (entries 3, 5, 7).
For substrates 1d and 1e, typically,21 lower regioselectivity
was obtained; in these cases improvement was possible
with dbcot as an auxiliary ligand (entries 11, 15, 16).
Further improvement was possible by replacement of
TBD as a base, used for in situ activation or as an additive,
by DBU9c (entries 2, 9) or 4-(dimethylamino)pyridine
(DMAP) (entry 12). For substrate 1e the best result was
obtained with C3 as the catalyst (entry 16).
Scheme 3. Short Approach toward Aza-Sugars
(15) For preparation, see: (a) Spiess, S.; Raskatov, J. A.; Gnamm, C.;
€
Brodner, K.; Helmchen, G. Chem.;Eur. J. 2009, 15, 11087–11090. (b)
€
Raskatov, J. A.; Spiess, S.; Gnamm, C.; Brodner, K.; Rominger, F.;
Helmchen, G. Chem.;Eur. J. 2010, 16, 6601–6615. (c) Madrahimov,
S. T.; Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 133, 7228–
€
7229. (d) Gartner, M.; Mader, S.; Seehafer, K.; Helmchen, G. J. Am.
Chem. Soc. 2011, 133, 2072–2075.
(16) The assignment of the relative configuration of 7 is tentative.
(17) (a) Le Flohic, A.; Meyer, C.; Cossy, J.; Desmurs, J.-R. Tetra-
hedron Lett. 2003, 44, 8577–8580. (b) Reddy, V. K.; Miyabe, H.;
Yamauchi, M.; Takemoto, Y. Tetrahedron 2008, 64, 1040–1048.
(18) (a) Bates, R. W.; Snell, R. H.; Winbrusch, S. Synlett 2008, 1042–
1044. (b) Bates, R. W.; Song, P. Synthesis 2009, 655–659.
(19) Review: Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008,
3707–3738.
After the promising results presented in Scheme 3, a
shorter route using pronucleophile Nu5 was investigated
(Scheme 4). It was anticipated that the substitution prod-
ucts, e.g., 11, derived from Nu5 could be directly cyclized
(20) Kawase, M.; Kitamura, T.; Kikugawa, Y. J. Org. Chem. 1989,
54, 3394–3403.
€
(21) (a) Gnamm, C.; Franck, G.; Miller, N.; Stork, T.; Brodner, K.;
Helmchen, G. Synthesis 2008, 3331–3350. (b) Lee, J. H.; Shin, S.; Kang,
J.; Lee, S. J. Org. Chem. 2007, 72, 7443–7446.
2812
Org. Lett., Vol. 13, No. 11, 2011

Nu5 was readily prepared according to a modified proce-
dure of Rajendra and Miller.24 Allylic amination of 1d with
Nu5 (Scheme 4) under salt-free conditions proceeded with
excellent enantioselectivity albeit with a somewhat low degree
of regioselectivity. Ring closing metathesis of 11 proceeded
smoothly to give the piperidone 12 with the same substitution
pattern as that for 9.
Scheme 4. Ir-Catalyzed Allylic Amination with Nu5 Followed
by Ring Closing Metathesis
In conclusion, we have found that asymmetric Ir-cata-
lyzed allylic aminations with hydroxamic acid derivatives
can be carried out with excellent regio- and enantioselec-
tivities. Hydroxamic acids derived from vinylacetic acid
yield products that can be directly subjected to RCM to
yield piperidines suitable for transformation into aza-
sugars and alkaloids.
by RCM to give piperidines of interest in the synthesis of
biologically active compounds. On the other hand, Nu5
and the allylation product are prone to suffer base-cata-
lyzed rearrangement to the corresponding crotonamides.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 623) and the
Fonds der Chemischen Industrie. We thank Robert Wei-
hofen of our group for preliminary experiments with Nu3
and Prof. K. Ditrich (BASF SE) for enantiomerically pure
1-arylethylamines.
€
(22) (a) Franck, G.; Brodner, K.; Helmchen, G. Org. Lett. 2010, 12,
3886–3889. (b) Knight, J. G.; Tchabanenko, K. Tetrahedron 2003, 59,
281–286. (c) Robertson, J.; Abdulmalek, E. Tetrahedron Lett. 2009, 50,
3516–3518.
Supporting Information Available. Experimental pro-
cedures, characterization of compounds, determination
of regio- and enantioselectivities. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(23) The feasibility of Weinreb type chemistry was checked with amide
8. Upon addition of DIBAL-H at ꢀ78 °C the deacylation product,
N-{(1S)-1-[(benzyloxy)methyl]prop-2-en-1-yl}-O-methylhydroxylamine
(4e0), was isolated in 96% yield.
(24) Rajendra, G.; Miller, M. J. Tetrahedron Lett. 1985, 26, 5385–5388.
Org. Lett., Vol. 13, No. 11, 2011
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