Salt-free iridium-catalyzed asymmetric allylic animations with N,N-diacylamines and ortho-nosylamide as ammonia equivalents

Article abstract of DOI:10.1002/anie.200601472

(Chemical Equation Presented) New variants of the iridium-catalyzed allylic substitution allow N-protected and non-protected chiral allylamines to be prepared with high enantio- and regio-selectivity. The allylamines are used as nucleophiles in highly dia

Full text of DOI:10.1002/anie.200601472

Communications
Allylic Amination
DOI: 10.1002/anie.200601472
Salt-Free Iridium-Catalyzed Asymmetric Allylic
Aminations with N,N-Diacylamines and ortho-
Nosylamide as Ammonia Equivalents**
Robert Weihofen, Olena Tverskoy, and
Günter Helmchen*
Asymmetric allylic substitutions have been studied with great
success over the last few years.[1] With monosubstituted allylic
derivatives as substrates (Scheme 1), iridium complexes of
Scheme 1. Iridium-catalyzed allylic substitutions.
electron-poor ligands seem to be the catalysts of choice for
asymmetric allylic alkylations,[2] aminations,[3] and etherifica-
tions.[4] Using ligands L1 and L2,[5] regioselectivities of > 95:5
in favor of the branched products and enantioselectivities of
up to 99% ee have been obtained.
The method appears particularly suited for the synthesis
of N-heterocycles. Examples are 2-vinyl-azacycloalkanes,
[*]R. Weihofen, O. Tverskoy, Prof. Dr. G. Helmchen
Organisch-Chemisches Institut der Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-544-205
E-mail: g.helmchen@oci.uni-heidelberg.de
[**]This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 623) and the Fonds der Chemischen Industrie. We thank Prof.
K. Ditrich (BASF AG) for enantiomerically pure 1-arylethylamines
and Q. Stang for helpful information.
5546
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 5546 –5549

Angewandte
Chemie
product 2a was initially formed, but rearranged to the more
stable 3. It was also discovered that the parent compound o-
Ns-NH2 reacted with kinetic control to give the branched,
chiral product with excellent selectivity (Table 1). The
Table 1: Iridium-catalyzed allylic substitution with o-nosylamide accord-
ing to Scheme 3.[a]
obtained by intramolecular amination,[3a] and trans-2,5-
divinylpyrrolidine, prepared by sequential inter- and intra-
molecular amination.[6] We have now addressed the enantio-
and diastereoselective construction of 2,5-disubstituted 3,4-
dehydropyrrolidines (Scheme 2), compounds of considerable
Entry Substrate Ligand Additive[b]
t
Yield
[%][d]
2:3:4[e] ee
[%][f]
[h][c]
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
L1
L2
L2
L1
L2
L2
–
–
NEt3
NEt3
–
24
12
3
18
4
60
64
92
85
84
94
93:7:1
95:5:1
90:10:1 96
92:4:4
84:8:8
93:3:4
94
95
93
90
94
NEt3
2.5
[a]Reactions were carried out as described in the Experimental Section.
[b]1 equiv. [c]Reaction time. [d]Combined yield of isolated 2, 3, and 4.
[e]Determined by 1H NMR spectroscopy and/or isolation. [f]Deter-
mined by HPLC on a chiral column (Daicel Chiralcel AD-H, 250”
4.6 mm, 5 mm with guard cartridge AD-H 10”4 mm, 5 mm, n-hexane/
iPrOH 9:1, flow=0.5 mLminÀ1
52.2 min, tR[(+)-2a]=54.9 min (major), tR[(+)-2b]=28.8 min (major),
tR[(À)-2b]=31.7 min.
,
room temperature): tR[(À)-2a]=
Scheme 2. Synthesis of the four stereoisomeric 2,5-disubstituted 3,4-
dehydropyrrolidines by allylic substitution in combination with ring-
closing metathesis (RCM).
reaction proceeds directly with o-Ns-NH2 (“salt-free” con-
ditions) because the liberated methyl carbonate or methoxide
is acting as base (Table 1, entries 1, 2, and 5). The addition of
NEt3 led to improved reaction rate, yield, and enantiomeric
excess (Table 1, entries 3 and 6), regioselectivity was lowered
with 1a (entry 3) or increased with 1b (Table 1, entry 6).[10]
Experiments with carboxamides as prenucleophiles were
not successful to date. However, excellent results were
obtained with N,N-diacylamines. Thus, the iridium-catalyzed
allylic substitution with phthalimide (Scheme 4, Table 2) gave
importance for medicinal chemistry and alkaloid synthesis.
We have shown that intramolecular allylic aminations are
catalyst rather than substrate controlled.[6] This result means
that the configurations of both chirality centers can be
controlled at will by the choice of the chirality sense of the
chiral ligand (L*). As 3,4-dehydropyrrolidines are extremely
sensitive, our aim was the synthesis of N-unprotected allyl-
amines,[7] that is, we have developed iridium-catalyzed allylic
substitutions with ammonia equivalents as nucleophiles.
To date mainly benzylamines have been used as N-
nucleophiles. Because of problematic deprotection of the
products with methods other than catalytic hydrogenation, we
have probed anionic N-nucleophiles, in particular sulfonami-
des.[8,2b] Deprotection of their reaction products was also not
generally successful. Therefore, we have extended this work
and present the successful substitutions with o-nosylamide (o-
Ns-NH2), phthalimide, di-tert-butyl imidodicarbonate, tert-
butyl formylcarbamate, and related compounds. The products
were readily transformed into primary amines which allowed
us to turn Scheme 2 into reality for the first time.[9]
Scheme 4. Substitutions with phthalimide.
regioselectivity ꢀ 90:10 in favor of the branched products and
ꢀ 96% ee with 1a and 1b as substrates. Additional base for
deprotonation of the prenucleophile was not required. With
potassium phthalimide no reaction was possible, presumably
because of its very low solubility in THF (Table 2, entry 2).
Results very similar to those with phthalimide were obtained
with succinimide as prenucleophile.[11]
We have already found that the reaction between N-(o-
Ns)-NHCH2Ph and carbonate 1a (ligand: L2) was fast,
however, gave exclusively the linear product 3 (Scheme 3).[8]
Subsequently, careful monitoring revealed that the branched
The prenucleophile HN(Boc)2 ((Boc = 1,1-dimethyl-
ethoxycarbonyl) is electronically similar to phthalimide;
however, it is sterically more demanding and more soluble
than phthalimide. It has been successfully used in palladium-
catalyzed allylic substitutions.[12] In contrast to phthalimide, it
reacted very slowly under salt-free conditions. With substrate
1a a best yield of 51% was reached, however, regioselectivity
Scheme 3. Iridium-catalyzed allylic substitutions with o-nosylamide.
Angew. Chem. Int. Ed. 2006, 45, 5546 –5549
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5547

Communications
Table 2: Iridium-catalyzed allylic substitutions according to Schemes 4 and 5.[a]
Entry Substrate Ligand NuH or NuM
t[h][b] Products Yield [%][c] b:l[d]
(Scheme 6).[16] The Boc-protected
amines 7a and 9a were hydro-
lyzed to give hydrochloride
11a·HCl, which was converted
into the volatile free amine 11a
(Scheme 6).[17]
ee [%][e]
1
2
3
1a
1a
1a
1b
1b
1a
1a
1b
1b
1a
1a
1b
1b
L1
L1
L2
L1
L2
L1
L2
L1
L2
L1
L2
L1
L2
Phth
KPhth
Phth
Phth
18
–
5a+6a
–
66
–
93:7
–
96:4
96
–
98
2.5
18
2.5
18
0.7
18
0.7
5a+6a
5b+6b
5b+6b
7a+8a
7a+8a
7b+8b
7b+8b
9a+10a
9a+10a
9b+10b
9b+10b
95
86
82
80
80
86
86
86
96
98
98
4[f]
5
90:10 95
With primary allylamines
available, the preparation of
unsymmetrically substituted 2,5-
disubstituted 3,4-dehydropyrroles
could be addressed (Scheme 7).
The reaction of the amine (S)-
11a with carbonate 1b was first
carried out using ligand L2. The
substitution product (S,R)-13 was
obtained in 80% yield. Analysis of
crude product by GC-MS indi-
cated as side products approxi-
mately 3% of the diastereomer
(S,S)-13 and only about 1% of the
linear substitution product. The
corresponding reaction using
ligand ent-L2 proceeded with
essentially identical selectivity to
give the diastereomer (S,S)-13.
This result demonstrates that the
Phth
94:6
97:3
97:3
92:8
96:4
97:3
98:2
92:8
97:3
96
97.5
99
6[f,g]
7
NaN(Boc)2
NaN(Boc)2
NaN(Boc)2
NaN(Boc)2
HN(Boc)(CHO) 18
HN(Boc)(CHO)
8
9
10
96(À)
99
97.5
98.5
97(+)
96
11
0.7
12[f]
13
HN(Boc)(CHO) 24
HN(Boc)(CHO)
1
[a]See Experimental Section; NaN(Boc) 2 was used as suspension in THF (1.0 mL). [b]Reaction time.
[c]Yield of the combined isolated products. [d]Branched (b) and linear (l) substitution products;
1
determined by H NMR spectroscopy. [e]Determined by HPLC on a chiral column (Daicel columns,
250”4.6 mm, 5 mm with guard cartridge, 10”4 mm, 5 mm, flow=0.5 mLminÀ1, room temperature); 5a
(Chiralcel OD-H, n-hexane/iPrOH 95:5): tR[(+)-5a]=18.4 min, tR[(À)-5a]=22.0 min (major); 5b
(Chiralcel OJ-H, n-hexane/iPrOH 98.5:1.5): tR[(+)-5b]=18.0 min, tR[(À)-5b]=19.1 min (major); 7a
(Chiralcel OJ-H, n-hexane/iPrOH 99.5:0.5): tR[(+)-7a]=11.3 min, tR[(À)-7a]=13.0 min (major). The ee
values of products 7b and 9b were determined after transformation into 12 (see Scheme 6); 12
(Chiralcel OD-H, n-hexane/iPrOH 99:1): tR[(À)-12]=11.0 min (major), tR[(+)-12]=12.7 min; 9a
(Chiralcel OJ-H, n-hexane/iPrOH 95:5): tR[(À)-9a]=14.3 min (major), tR[(+)-9a]=28.2 min.
[f]5 mmol scale. [g]1.1 Equivalents of nucleophile were used.
was very high (branch:linear (b:l) = 99:1). Finally, complete
conversion (yield 80%) and excellent selectivity were
obtained with the sodium salt NaN(Boc)2 (Scheme 5 and
Table 2, entries 6–9).[13] Selectivities as well as rates were
again slightly higher with ligand L2 than ligand L1.
steric course of the allylic amination is controlled by the
catalyst rather than the substrate.
Scheme 5. Substitutions with Boc- and formyl-protected tert-butyl car-
bamate.
Scheme 6. Deprotection of substitution products. a) 1. PhSH, K2CO3,
DMF, 608C, 5 h; 2. 6n HCl, column chromatography, 94%; b) 1. H2N-
(CH2)2NH2, EtOH, reflux; 2. 6n HCl, column chromatography, 94%;
c) 5% HCl in MeOH, 608C, 89%; d) 6n KOH (10 equiv), Et2O or
Dowex MWA-1, CH2Cl2/MeOH 9:1, quant.; e) TFA (1.5 equiv), CH2Cl2,
96%; f) cat. KOH, MeOH, 97%.
To make N-Boc derivatives available by substitution
under salt-free conditions, we probed the new prenucleophile
HN(Boc)(CHO), which was expected to be more acidic than
HNBoc2. This readily available compound[14] indeed gave
excellent results with respect to yield as well as regio-and
enantioselectivity (Table 2, entries 10–13).
N-Nosyl-amides can be deprotected under mild and
specific conditions with thiols.[15] This situation is also true
for 2a (Scheme 6), except that purification of the amine 11a
by flash chromatography was difficult, but its hydrochloride
11a·HCl could be conveniently isolated by chromatography
on silica gel. Deprotection of the phthalimide derivative 5a,
to give the primary amine 11a, with 1,2-diaminoethane in
refluxing ethanol proceeded with excellent yield
Ring-closing metathesis (RCM)[18] required protection of
the nitrogen by salt formation. With the hydrobromide (S,S)-
13·HBr the reaction proceeded at 808C within 4 h to give cis-
14·HBr without any by-products. The reaction of the corre-
sponding hydrochloride (13·HCl) was accompanied by partial
decomposition.
In conclusion, we have developed new variants of the
iridium-catalyzed allylic substitution, allowing the prepara-
tion of conveniently N-protected or non-protected chiral
allylic amines, which were used as nucleophiles in highly
5548
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 5546 –5549

Angewandte
Chemie
Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. 2004, 116,
2480; Angew. Chem. Int. Ed. 2004, 43, 2426.
[3] a) C. Welter, O. Koch, G. Lipowsky, G. Helmchen, Chem.
Commun. 2004, 896; b) A. Leitner, C. Shu, J. F. Hartwig, Proc.
Natl. Acad. Sci. USA 2004, 101, 5830; c) C. Shu, A. Leitner, J. F.
Hartwig, Angew. Chem. 2004, 116, 4901; Angew. Chem. Int. Ed.
2004, 43, 4797; d) A. Leitner, C. Shu, J. F. Hartwig, Org. Lett.
2005, 7, 1093; e) D. Polet, A. Alexakis, Org. Lett. 2005, 7, 1621;
f) C. Welter, R. Moreno, S. Streif, G. Helmchen, Org. Biomol.
Chem. 2005, 3, 3266.
[4] a) F. Lopez, T. Ohmura, J. F. Hartwig, J. Am. Chem. Soc. 2003,
125, 3426; b) C. Shu, J. F. Hartwig, Angew. Chem. 2004, 116,
4898; Angew. Chem. Int. Ed. 2004, 43, 4794.
[5] a) L1: B. L. Feringa, Acc. Chem. Res. 2000, 33, 346; b) L2: K.
Tissot-Croset, D. Polet, S. Gille, C. Hawner, A. Alexakis,
Synthesis 2004, 2586.
[6] C. Welter, A. Dahnz, B. Brunner, S. Streiff, P. Dübon, G.
Helmchen, Org. Lett. 2005, 7, 1239.
[7] For further asymmetric syntheses of amines with a stereogenic
center in a-position to N see: a) J. A. Ellman, T. D. Owens, T. P.
Tang, Acc. Chem. Res. 2002, 35, 984; b) D. Enders, U. Reinhold,
Tetrahedron: Asymmetry 1997, 8, 1895; c) M. Johannsen, K. A.
Jørgensen, Chem. Rev. 1998, 98, 1689.
Scheme 7. Enantioselective synthesis of 2,5-disubstituted 3,4-dehydro-
pyrroles. a) [{Ir(cod)Cl}2](2 mol%), L* (4 mol%), TBD (8 mol%),
THF, room temperature, 12 h; b) 1. HBr/CH3CO2H; 2. Grubbs II cata-
lyst (6 mol%), 1,2-dichloroethane (0.03m), reflux, 4 h; cod=cycloocta-
diene, TBD=1,5,7-triazabicyclo[4.4.0]-unedec-5-one.
[8] R. Weihofen, Axel Dahnz, O. Tverskoy, G. Helmchen, Chem.
Commun. 2005, 3541.
[9] P. A. Evans et al. have prepared corresponding N-tosyl deriva-
tives by stereoconservative Rh-catalyzed allylic substitution at
enantioenriched derivatives of allylic alcohols, which does not
constitute an asymmetric synthesis. Surveys: a) D. K. Leahy,
P. A. Evans in Modern Rhodium-Catalyzed Organic Reactions
(Ed.: P. A. Evans), Wiley, New York, 2005, p. 191; b) P. A. Evans,
J. E. Robinson, Org. Lett. 1999, 1, 1929.
diastereoselective, catalyst-controlled allylic aminations. The
products were subjected to ring-closing metathesis to give
non-protected 2,5-disubstituted 3,4-dehydropyrrolidines.
[10] The absolute configurations of the products described herein
were as anticipated (Ref. [8]); for independent determinations
see a) M. Atobe, N. Yamazaki, C. Kibayashi, J. Org. Chem. 2004,
69, 5595; b) M. Alcꢀn, M. Canas, M. Poch, A. Moyano, M. A.
Pericꢁs, A. Riera, Tetrahedron Lett. 1994, 35, 1589.
[11] For substrate 1a (in combination with L2) a reaction time of
2.5 h was required to give the substitution product in 87% yield
with 98% ee and a regioselectivity of 96:4.
[12] a) R. D. Connell, T. Rein, B. ꢂkermark, P. Helquist, J. Org.
Chem. 1988, 53, 3845; b) D. A. Evans, K. R. Campos, J. S.
Tedrow, F. E. Michael, M. R. Gagnꢃ, J. Am. Chem. Soc. 2000,
122, 7905.
[13] Similar results were obtained with NaN(CHO)2, which has
previously been used in Pd-catalyzed allylic substitutions (Y.
Wang, K. Ding, J. Org. Chem. 2001, 66, 3238).
[14] To our knowledge, this compound has not been previously
described. We prepared it according to a general procedure (Y.
Lin, S. A. Lang, Jr, Synthesis 1980, 119) in 88% yield.
[15] a) T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995,
36, 6373; b) T. Fukuyama, M. Cheung, C.-K. Jow, Y. Hidai, T.
Kan, Tetrahedron Lett. 1997, 38, 5831.
Experimental Section
General procedures: Success with the following procedures requires
dry THF (< 35 mg of H2O/mL, Karl Fischer titration).
Under argon, TBD (0.08 mmol) was added to a solution of
[{Ir(cod)Cl}2](0.02 mmol) and L* (0.04 mmol) in dry THF (0.5 mL).
After stirring for 2 h at room temperature the allylic carbonate 1
(1.0 mmol) was added, and the mixture was stirred for 5 min at room
temperature. Then the prenucleophile (1.2 mmol) and, when
required, NEt3 (1 mmol) were added and the mixture was stirred
until thin-layer chromatography (TLC) indicated complete conver-
sion. The reaction mixture was concentrated in vacuo and the residue
subjected to flash chromatography. The content of branched and
linear product was determined by 1H NMR spectroscopy and/or
isolation of both products by flash chromatography on silica.
Received: April 13, 2006
Published online: July 20, 2006
Keywords: allylic amination · enantioselectivity · iridium ·
.
[16] O. Kanie, S. C. Crawley, M. M. Palcic, O. Hindsgaul, Carbohydr.
Res. 1993, 243, 139.
[17] The ee values of the free amines were determined and found to
agree, within the range of precision, with those of the protected
precursors.
pyrrolidines · ring-closing metathesis
[1] a) B. M. Trost, C. Lee in Catalytic Asymmetric Synthesis, 2nd ed.
(Ed.: I. Ojima), Wiley, New York, 2000, p. 593; b) A. Pfaltz, M.
Lautens in Comprehensive Asymmetric Catalysis I–III (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999,
p. 833; c) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921.
[2] a) B. Bartels, G. Helmchen, Chem. Commun. 1999, 741; b) B.
Bartels, C. Garcia-Yebra, F. Rominger, G. Helmchen, Eur. J.
Inorg. Chem. 2002, 2569; c) G. Lipowsky, N. Miller, G. Helm-
chen, Angew. Chem. 2004, 116, 4695; Angew. Chem. Int. Ed.
2004, 43, 4595; d) G. Lipowsky, G. Helmchen, Chem. Commun.
2004, 116; e) D. Polet, A. Alexakis, Org. Lett. 2004, 6, 3529; f) K.
[18] Handbook of Metathesis (Ed.: R. H. Grubbs), Wiley, New York,
2003.
Angew. Chem. Int. Ed. 2006, 45, 5546 –5549
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5549