Iridium-catalyzed enantioselective allylic substitutions with aliphatic nitro compounds as prenucleophiles

Article abstract of DOI:10.1055/s-2006-933121

Enantioselective Ir-catalyzed allylic alkylations with nitroalkanes and ethyl nitroacetate as nucleophiles are reported. Up to 99% ee was achieved using catalysts prepared by in situ activation of mixtures of phosphorus amidites and [Ir(COD)Cl]₂. The method was applied to a synthesis of the antidepressant (1S,2R)-trans-2-phenylcyclopentanamine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933121

LETTER
697
Iridium-Catalyzed Enantioselective Allylic Substitutions with Aliphatic Nitro
Compounds as Prenucleophiles
A
llylic Substitutio
x
ns
w
ith Nitro
e
C
ompound
l
s
Dahnz, Günter Helmchen*
Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: en4@ix.urz.uni-heidelberg.de
Received 11 January 2006
Dedicated to Professor Dieter Enders on the occasion of his 60th birthday.
R1R2CHNO2
Cs2CO3
R1
R2
NO2
Abstract: Enantioselective Ir-catalyzed allylic alkylations with ni-
troalkanes and ethyl nitroacetate as nucleophiles are reported. Up to
99% ee was achieved using catalysts prepared by in situ activation
of mixtures of phosphorus amidites and [Ir(COD)Cl]2. The method
was applied to a synthesis of the antidepressant (1S,2R)-trans-2-
phenylcyclopentanamine.
R
OCO2Me
[Ir(COD)Cl]2
Ligand
TBD
R
1a: R = Ph
2
a: R = Ph, R1 = H, R2 = Me
b: R = Ph, R1 = R2 = Me
Key words: allylic substitution, iridium, catalysis, nitroalkanes,
ring-closing metathesis
Scheme 2
with phosphorus amidites L1 or L2 (Figure 1).8 These
undergo CH activation upon treatment with base, TBD
{1,5,7-triazabicyclo-[4.4.0]dec-5-ene} in this work, thus
generating a P,C-chelate complex of high activity.4a,5
The transition-metal-catalyzed asymmetric allylic sub-
stitution is an established method for the generation of
stereogenic centers.1 Recently, the traditional palladium
catalysis has been supplemented by iridium catalysis.2
With Ir catalysts the nucleophilic displacement according
to Scheme 1 leads preferentially to the branched, chiral
substitution product, while Pd catalysts favor the linear
achiral product. Over the last few years, excellent results
with respect to regio- as well as enantioselectivity have
been achieved for Ir-catalyzed substitutions with C-,3
N-,4,5 and O-nucleophiles.6 As C-nucleophiles, mainly
malonates have so far been used. We have now success-
fully probed nitronates and a new variant of the versatile
combination of the allylic substitution with ring-closing
metathesis (RCM).
R'
S
O
aS
P
N
O
S
R'
L1: R' = H
L2: R' = OCH3
Figure 1
Nu
Application of the above protocol to the reaction between
cinnamyl methyl carbonate (1a) and a primary as well as
secondary nitro compound (Scheme 2, Table 1 and
General Procedure) furnished branched products 2 in
good yields and with excellent regio- and enantioselec-
tivity. Only the reaction with nitromethane gave poor re-
sults. Despite extensive screening of reaction conditions,
complex mixtures were obtained, which contained mono-
and bis-allylation product along with various unidentified
compounds.
preferred
with M = Ir
∗
R
Nu–
+
R
X
(ML*Ln)cat.
R
Nu
Scheme 1
Aliphatic nitro compounds are valuable intermediates in
organic synthesis due to the diversity of their chemistry.7
In asymmetric synthesis, nitro aldol additions and
Michael reactions have mainly been studied. The Ir-cata-
lyzed allylic substitutions according to Scheme 2 open an
access to chiral nitroalkenes of the type 2, which are not
directly accessible otherwise.
Primary nitro compounds are important intermediates,
which can be transformed, for example, into aldehydes10
or nitriles.11 Therefore, the reaction with ethyl nitroace-
tate, a synthesis equivalent of nitromethane, was investi-
gated (Scheme 3, Table 2). With this compound the
reaction proceeded fast without an additional base.
So far the best catalysts for the Ir-catalyzed allylic substi-
tution have been obtained by combining [Ir(COD)Cl]2
Saponification of the ester 3a with NaOH, prior to intend-
ed thermal decarboxylation, caused shift of the double
bond into conjugation with the phenyl group. Krapcho
deethoxycarbonylation experiments using standard
SYNLETT 2006, No. 5, pp 0697–0700
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933121; Art ID: G00406ST
© Georg Thieme Verlag Stuttgart · New York
1
7.
0
3.
2
0
0
6

698
A. Dahnz, G. Helmchen
LETTER
Table 1 Allylic Substitutions (Scheme 2)9
Entry
Ligand
L2
R1
H
R2
Time (h)a
>48
Ratiob
Yield (%)c
ee (%)d
e
1
H
2
L1
H
Me
Me
Me
<16
99:1
99:1
96:4
71f
85f
84
95, 85
98, 96
99
3
L2
H
<16
4
L2
Me
<16
a Reaction time.
b Ratio of branched/linear products.
c Yield of isolated products.
d Determined by HPLC; column: Daicel Chiralcel AD-H, 250 × 4.6 mm, 5 mm, and guard cartridge 10 × 4 mm, 5 mm; eluent: n-hexane–i-PrOH,
99:1, flow: 0.5 mL/min; tR [(+)-2a] = 13.9 min (major), tR [(–)-2a] = 14.5 min, tR [(–)-epi-2a] = 14.6 min, tR [(+)-epi-2a] = 16.3 min (major),
tR[(–)-2b] = 12.3 min, tR[(+)-2b] = 13.1 min (major).
e Nonselective reaction, cf. text.
f 1:1 Mixture of epimers (relative configuration not determined), that were separated by column chromatography and analyzed individually.
EtO2C
NO2
LiI (5 equiv),
H2O (6 equiv)
EtO2C
R
NO2
NO2
3
4
EtO2C
NO2
R
150 °C, DMF
R
R
OCO2Me
+
[Ir(COD)Cl]2
ligand
TBD
a: R = Ph
b: R = PhCH2CH2
c: R = n-propyl
3
EtOOC
NO2
5
1
a: R = Ph
b: R = PhCH2CH2
c: R = n-Pr
R
Scheme 4
Scheme 3
compounds.14 Here we used this strategy for a synthesis of
(1S,2R)-trans-2-phenylcyclopentanamine (9, Scheme 5),
a compound that itself shows antidepressant activity,15
and its N-isopropylsulfonyl derivative, which displays
high activity as an AMPA potentiator.16 The securely
established absolute configurations of these compounds
corroborate the assignments given in Scheme 3 and
Table 2.
conditions12 did not give satisfactory results either. After
some experimentation we found modified conditions (LiI,
H2O, DMF) providing the desired primary nitro com-
pounds 5 in good to excellent yields (Scheme 4, Table 3,
General Procedure).
In previous work, the combination of the Ir-catalyzed
allylic substitution and RCM has been established as
powerful method for the synthesis of biologically active
The synthesis of (1S,2R)-9 is described in Scheme 5. The
first step is an Ir-catalyzed reaction of 1a with 4-nitro-1-
butene, which was carried out with ent-L2 as ligand
Table 2 Allylic Substitutions (Scheme 3)
Entry
Substrate
Ligand
L1
Time (h)
3/4
Yield (%)
eea (%)
96b
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
5
99:1
85
90
95
86
97
92
L2
0.5
5
99:1
98b
L1
63:37
78:22
77:23
90:10
96c
L2
3
98c
L1
4
95d
L2
0.5
99d
a Determined for compounds 5, which were prepared according to Scheme 4.
b Determined by HPLC; column: Daicel Chiralcel OD-H, 250 × 4.6 mm, 5 mm, and guard cartridge 10 × 4 mm, 5 mm; eluent: n-hexane–i-PrOH,
90:10, flow: 0.5 mL/min; tR [(–)-5a] = 20.4 min, tR [(+)-5a] = 31.2 min (major).
c Determined by HPLC; column: Daicel Chiralcel OJ-H, 250 × 4.6 mm, 5 mm, and guard cartridge 10 × 4 mm, 5 mm; eluent: n-hexane–i-PrOH,
90:10; flow: 0.5 mL/min; tR [(–)-5b] = 25.7 min (major); tR [(+)-5b] = 27.9 min.
d Determined by GC; column: Chrompack permethyl b-cyclodextrin, Cp-Cyclodextrin-B-236-M-19 (25 m × 0.25 mm), 60 °C for 120 min, then
gradient 1 °C/min; injection temp: 200 °C; tR [(–)-5c] = 133 min, tR [(+)-5c] = 135 min (major).
Synlett 2006, No. 5, 697–700 © Thieme Stuttgart · New York

LETTER
Allylic Substitutions with Nitro Compounds
699
Table 3 Modified Krapcho Deethoxycarbonylation (Scheme 4)13
NO2
Grubbs' I
O2N
Cs2CO3
(2 mol%)
Entry
Substrate
Product
5a
Yield (%)
1a
95%
[Ir(COD)Cl]2
ent-L2, TBD
82%
R
Ph
1
2
3
3a
3b
3c
70
75
95
6
5b
O2N
Ph
O2N
5c
S
Et3N
87%
R
R
Ph
no racemization
7a,b
7a
according to the General Procedure. The substitution
product 6 was obtained as mixture of epimers with excel-
lent regio- and enantioselectivity of 93%.17 The linear by-
product was not found. Another route to 6 was Pd-cata-
lyzed allylation of 5a with allyl methyl carbonate (65%
yield).
NH4HCO2
Pd/C
TsNHNH2 65%
90%
NaOAc
partial racemization
O2N
H2N
Ph
NH4HCO2
Pd/C
S
R
S
R
90%
Ph
Transformation of 6 into 7a,b by RCM was effected by
heating a solution of 6 and Grubbs’ I catalyst (2 mol%) in
CH2Cl2 at reflux for five hours. The epimeric cyclo-
pentenes 7a and 7b were separated by column chromato-
graphy and their relative configurations were determined
by measurement of NOE between 1-H and 5-H: 0.4% for
the trans-isomer (7a) and 4.9% for the cis-isomer (7b).
8
9
Scheme 5
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 623). We thank David Fellhauer for experimental assistance.
Further steps required were epimerization of 7a,b to get
the pure trans-isomer 7a and reduction of the nitro group
and the C–C double bond. If the latter step is carried out
by transition-metal-catalyzed hydrogenation, it is usually
accompanied by epimerization in an allylic position.18 We
have shown that this problem can be overcome by use of
diimide as reducing agent.14a Hence, a solution of 7a,b,
TsNHNH2 (50 equiv) and NaOAc (100 equiv) in
dimethoxyethane–water was heated at reflux. We were
delighted that pure 8 was formed as product in 65% yield,
i.e., hydrogenation as well as epimerization had occurred.
However, the enantiomeric excess of 8 was only 84%, i.e.
racemization, probably via the intermediary nitronate,19
was a competing third reaction.
References and Notes
(1) (a) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000, 593.
(b) Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric
Catalysis I-III; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Springer: Berlin, 1999, 833. (c) Trost, B. M.; Crawley,
M. L. Chem. Rev. 2003, 103, 2921.
(2) Contrary to common believe, the prize of iridium is lower
than that of palladium.
(3) (a) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741.
(b) Bartels, B.; Garcia-Yebra, C.; Rominger, F.; Helmchen,
G. Eur. J. Inorg. Chem. 2002, 2569. (c) Lipowsky, G.;
Miller, N.; Helmchen, G. Angew. Chem. Int. Ed. 2004, 43,
4595. (d) Lipowsky, G.; Helmchen, G. Chem. Commun.
2004, 116. (e) Alexakis, A.; Polet, D. Org. Lett. 2004, 6,
3529. (f) Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky,
G.; Miller, N.; Helmchen, G. Chem. Commun. 2005, 2957.
(4) (a) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 14272. (b) Miyabe, H.; Yoshida, K.;
Kobayashi, Y.; Matsumura, A.; Takemoto, Y. Synlett 2003,
1031. (c) Takeuchi, R. Synlett 2002, 1954. (d) Tissot-
Croset, K.; Polet, D.; Alexakis, A. Angew. Chem. Int. Ed.
2004, 43, 2426. (e) Leitner, A.; Shu, C.; Hartwig, J. F. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5830. (f) Ohmura, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164.
(g) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dübon,
P.; Helmchen, G. Org. Lett. 2005, 7, 1239.
As a consequence, the epimerization and the hydrogena-
tion step were carried out separately. Thus, epimerization
of 7a,b by treatment with triethylamine in DMSO–water
according to a method of Kingsbury19 furnished a 10:1
mixture of trans- and cis-7. The ee was not altered under
these conditions. Column chromatography gave pure 7a
in 80% and 7b in 8% yield. The latter was subjected once
more to the epimerization conditions, giving a further 7%
yield of 7a, i.e. a total yield of 87% of diastereomerically
pure trans-7 was obtained.
Reduction of 7a with ammonium formate in methanol,
using Pd/C as catalyst,20 furnished the amine 9 in 90%
yield.21 The enantiomeric excess of both 7a and 9 was
93%. Furthermore, the latter contained less than 4% of the
cis-isomer (1H NMR).
(5) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem.
Commun. 2004, 896.
(6) (a) Lopez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 3426. (b) Kinetic resolution: Fischer, C.;
Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
2004, 126, 1628.
(7) Ono, N. The Nitro Group in Organic Synthesis; Wiley: New
York, 2001.
(8) For the synthesis of phosphorus amidite ligands see: Tissot-
Croset, K.; Polet, D.; Gille, S.; Hawner, C.; Alexakis, A.
Synthesis 2004, 2586.
Synlett 2006, No. 5, 697–700 © Thieme Stuttgart · New York

700
A. Dahnz, G. Helmchen
LETTER
(14) (a) Welter, C.; Moreno, R. M.; Streiff, S.; Helmchen, G.
(9) General Procedure for Allylic Alkylation
Under argon at r.t., a solution of [Ir(COD)Cl]2 (0.02 mmol)
and L* (0.04 mmol) in dry THF (1.0 mL) was treated with
TBD (0.08 mmol). After stirring for 2 h at r.t. the allylic
carbonate (1.0 mmol) was added, and the mixture was stirred
for 5 min at r.t. Then the nitro compound (1.5 mmol) and
eventually Cs2CO3 (1.0 mmol) were added and the mixture
was stirred until GCMS indicated complete conversion. The
mixture was partitioned between H2O and EtOAc. The
organic layer was dried over Na2SO4 and concentrated in
vacuo. The residue was analyzed with respect to the content
of branched and linear product by 1H NMR. The pure
reaction products were obtained by flash chromatography
and kugelrohr distillation.
Org. Biomol. Chem. 2005, 3, 3266. (b) Shu, C.; Hartwig, J.
F. Angew. Chem. Int. Ed. 2004, 43, 4794. (c) Weihofen, R.;
Dahnz, A.; Tverskoy, O.; Helmchen, G. Chem. Commun.
2005, 28, 3514. (d) Schelwies, M.; Dübon, P.; Helmchen, G.
Angew. Chem. Int. Ed. 2006, in press.
(15) Mc Grath, W. R.; Kuhn, W. L. Arch. Int. Pharmacodyn.
Ther. 1968, 16, 679.
(16) Shepherd, T. A.; Aikins, J. A.; Bleakman, D.; Cantrell, B. E.;
Rearick, J. P.; Simon, R. L.; Smith, E. C. R.; Stephenson, G.
A.; Zimmermann, D. M. J. Med. Chem. 2002, 45, 2101.
(17) Both enantiomers of 6 were prepared. The ee was obtained
after transformation to 7a. The ee of the latter was
determined by HPLC; column: Daicel Chiralcel OJ-H,
250 × 4.6 mm, 5 mm, and guard cartridge 10 × 4 mm, 5 mm;
eluent: n-hexane–i-PrOH, 90:10; flow: 0.5 mL/min;
tR [(–)-7a] = 23.5 min, tR [(+)-7a] = 29.9 min (major).
(18) (a) Montenegro, E.; Gabler, B.; Paradies, G.; Seemann, M.;
Helmchen, G. Angew. Chem. Int. Ed. 2003, 42, 2419.
(b) Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91.
(19) Kingsbury, C. A. J. Org. Chem. 1998, 63, 3838.
(20) Pasyek, Z.; Koenig, H.; Tabaczka, B. Synthesis 2003, 2023.
(21) (a) The absolute configuration of 9 was assigned by
comparison of HPLC data of the N-isopropylsulfonyl
derivative of 9 with reported data (ref. 16) and on the basis
(10) Pinnick, H. W. Org. React. 1990, 39, 655.
(11) Czekelius, C.; Carreira, E. M. Angew. Chem. Int. Ed. 2005,
44, 612.
(12) Peel, M. R.; Sternbach, D. D.; Johnson, M. R. J. Org. Chem.
1991, 56, 4990.
(13) General Procedure for the Preparation of Primary Nitro
Compounds 5 from Esters 3 (Scheme 4)
Under argon, a solution of ester 3, LiI (5 equiv), H2O (6
equiv) and a trace of di-tert-butyl-1,4-hydroquinone in DMF
was heated at 150 °C over a period of 5 h. Then, sat. NaCl
solution was added and the mixture was extracted with Et2O.
The combined organic layers were dried over Na2SO4,
concentrated in vacuo, and the residue was subjected to flash
chromatography.
20
of the optical rotation of (1S,2R)-9·HCl (93%ee): [a]D
+56.6; reported: [a]D23 +68.8 (99% ee), see ref. 21b. The ee
of 9 was determined by HPLC; column: Daicel Chiracel OD-
H, 250 × 4.6 mm, 5 mm, and guard cartridge 10 × 4 mm, 5
mm; eluent: n-hexane–i-PrOH, 99:1; flow: 0.5 mL/min; tR
[(1S,2R)-9] = 36.9 min, tR [(1R,2S)-9] = 40.6 min.
(b) Brown, H. C.; Kim, K.-W.; Cole, T. E.; Singaram, B. J.
Am. Chem. Soc. 1986, 108, 6761.
Synlett 2006, No. 5, 697–700 © Thieme Stuttgart · New York