Enantioselective preparation of 3-Arylcycloalkylamines by rhodium-catalyzed 1,4-addition and subsequent stereodivergent reduction

Article abstract of DOI:10.1002/adsc.201400824

N-Sulfonylimines of cycloalk-2-enones are well-suited for the enantioselective rhodium(I)/ binap-catalyzed 1,4-additions of arylzinc halides. The cyclic enamides, obtained after quenching, are sensitive towards chromatography, but can undergo diastereosel

Full text of DOI:10.1002/adsc.201400824

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DOI: 10.1002/adsc.201400824
Enantioselective Preparation of 3-Arylcycloalkylamines by
Rhodium-Catalyzed 1,4-Addition and Subsequent
Stereodivergent Reduction
Sandra Gebhardt,a Christian H. Mꢀller,a Johannes Westmeier,a Klaus Harms,a
and Paultheo von Zezschwitza,*
a
Fachbereich Chemie, Philipps-Universitꢁt Marburg, Hans-Meerwein-Straße 4, 35032 Marburg, Germany
Fax : (+49)-6421-282-5362; e-mail: zezschwitz@chemie.uni-marburg.de
Received: August 19, 2014; Revised: October 10, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400824.
Abstract: N-Sulfonylimines of cycloalk-2-enones are group at C-5 of six-membered rings, providing fur-
well-suited for the enantioselective rhodium(I)/ ther configurational options. 3-Arylcycloalkylamines
binap-catalyzed 1,4-additions of arylzinc halides. The are subunits in a number of bioactive substances and
cyclic enamides, obtained after quenching, are sensi- can also be oxidatively transformed into cyclic g-
tive towards chromatography, but can undergo dia- amino acids.
stereoselective reductions to furnish cis- or trans-3-
arylcycloalkylamines with five- to seven-membered Keywords: asymmetric catalysis; conjugate addition;
rings. The 1,4-addition is not influenced by a methyl rhodium; sulfonamides; zinc
Introduction
the initially formed saturated imines – or their tauto-
meric enamines – were either hydrolyzed to the re-
The conjugate addition of non-stabilized carbon nu- spective carbonyls or transformed by oxidative cleav-
cleophiles to a,b-unsaturated carbonyls belongs to the age of the C,C double bonds of the enamines. Subse-
fundamental reactions in organic chemistry.[1] On the quent transformation to amines was reported in only
one hand, it leads to C,C bond formation, on the one single example by hydrogenation over Pd/C to
other hand, the saturated ketones thus obtained – or furnish an 82:18 mixture of diastereomers.[6c]
the enolates initially formed – can be used for various
Recently, we reported the first preparation of cyclo-
subsequent transformations.[2] Even 17 years after alk-2-enone-derived N-sulfonylimines[10] as well as
publication of the first highly enantioselective proto- their transformation in highly enantioselective Rh(I)/
col for such 1,4-additions,[3] much effort is still being binap-catalyzed additions of methyl- and arylalumi-
spent on further improvements and broadening of the num reagents.[11] The 1,2- versus 1,4-selectivity of this
synthetic applicability.[4] Besides enones, asymmetric reaction is influenced by several factors, and we have
catalysis has frequently been performed on substrates initially performed optimization towards 1,2-addition
activated by cyano, sulfonyl, phosphonyl, or nitro to deliver valuable a-tertiary cycloalk-2-enylamides,
groups,[1b,5] but only rarely using a,b-unsaturated which can be applied to the preparation of a-quater-
imines.[6–9] This is surprising in view of the high rele- nary a-amino acids. However, the products of 1,4-ad-
vance of nitrogen-containing moieties in nature, as dition are interesting compounds in their own right
especially amino groups occur ubiquitously in natural because subsequent diastereoselective reductions
and artificial bioactive compounds. Enantiopure could deliver 3-substituted cycloalkylamines with cis-
amines, however, ought to be efficiently prepared or trans-configuration at the ring. This structure, espe-
from the products of such conjugate additions to a,b- cially in the case of six-membered rings, is commonly
unsaturated imines. The reported examples of this found in pharmaceutically active compounds.[12,13] We
transformation comprise Cu-catalyzed enantioselec- now report on the highly regio- and enantioselective
tive 1,4-additions of dialkylzinc to acyclic N-sulfonyl- Rh-catalyzed conjugate additions of various aryl
ACHTUNGTRENNUNG
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In our previous study, we had observed that the transformation than the corresponding enone, but the
Rh(I)/binap-catalyzed addition of PhAlMe2 to the cy- facial selectivity is the same for both substrates.[16a]
clohex-2-enone-derived N-tosylimine occurs with Moreover, both (E)- and (Z)-1a reacted equally well.
poor regioselectivity and yields a 2:3 mixture of the Performing the reaction at room temperature, the cat-
1,2- and the 1,4-adducts.[11] In contrast, the Hayashi– alyst loading could be reduced to 2 mol% rhodium
Miyaura reaction, i.e., the Rh-catalyzed enantioselec- without any deterioration (entry 2), while a slightly
tive addition of aryl nucleophiles to a,b-unsaturated lower chemoselectivity was observed with 1 mol%
ketones, proceeds with complete 1,4-selectivity when (entry 3). Slow addition of PhZnCl did not lead to an
using boron-, titanium-, zinc-, silicon-, or tin-based re- improvement (entry 4), and formation of the phenyl-
agents.[15] For conjugate addition to the respective zinc halide from the respective Grignard reagent
imines, the use of arylzinc halides[16] appeared to be rather than from phenyllithium caused a substantially
most attractive due to their smooth and efficient lower enantioselectivity (entries 5 and 6). The pres-
preparation, their functional group tolerance which is ence of magnesium salts may lead to some back-
paired with high reactivity, and their application in ground reactivity;[18] in contrast, no 1,4-addition was
aprotic media which precludes the risk of the N-tosyl- observed in the absence of the rhodium catalyst when
ACHTUNGTRENNUNGimines being hydrolyzed under the reaction condi- the zinc reagent was prepared from phenyllithium.
tions.
Quenching of the reaction mixture under slightly
alkaline conditions led to the isolation of the respec-
tive enamide 3aa as the sole product, however, it
could not be purified due to decomposition upon
column chromatography (Table 2). For the prepara-
Results and Discussion
As a starting point, we studied the Rh(I)/binap-cata- tion of cycloalkylamines, the crude enamide was
lyzed addition of PhZnCl to ketimine 1a which is ob- therefore directly subjected to reduction, but NaBH4
tained in a 66% yield by condensing cyclohex-2- led to an unselective hydride addition (entry 1). Simi-
enone and p-TsNH2.[10] The zinc reagent was prepared lar observations have been noted by Hutchins et al.
from the respective aryl bromide by sequential treat- when reducing the N-(diphenyl)phosphinylimine de-
ment with n-BuLi or t-BuLi and then ZnCl2 in rived from 3-methylcyclohexanone, while high cis- or
THF,[17] and after the addition reaction, the crude trans-selectivity was reported with t-BuNH2·BH3 or L-
mixtures were immediately hydrolyzed under acidic Selectrideꢃ, respectively.[19] Indeed, the former re-
conditions to enable convenient GC analysis of agent led to a 13:87 dr, and cis-4aa was obtained in
ketone 2aa (Table 1). With 5 mol% of rhodium, i.e.,
2.5 mol% of the dimeric pre-catalyst [Rh(cod)Cl]2,
a fast reaction was observed at 08C, and (S)-2aa was
obtained in excellent yield and ee (entry 1). Thus, to-
Table 2. 1,4-Addition and subsequent stereodivergent reduc-
tion.
sylimine 1a appears to be more reactive towards this
Table 1. Optimization of the 1,4-addition.
Entry
Reduction
dr[a]
(trans/cis)
Yield
[%][b]
ee[c]
[%]
Entry
[Rh(cod)Cl]2
[mol%]
t [min]/
T [8C]
Conversion
[%][a]
Yield/
ee [%][a]
[d]
1
2
3
NaBH4
52:48
13:87
>97:3
>97:3
>97:3
88[d]
62
83
78
93
–
1
2
3
2.5
1.0
0.5
0.5
2.5
2.5
30/0
98
98
95
87
98
98
93/99
>97/99
84/98
75/95
89/63
82/86
t-BuNH2·BH3
rac-5, HCOOH
(S,S)-5, HCOOH
(S,S)-5, HCOOH
99
99
99
99
30/r.t.
30/r.t.
30/r.t.
60/r.t.
30/r.t.
4
4[b]
5[c]
6[b,c]
5[e]
[a]
1
Determined by H NMR analysis of the crude product.
Isolated yield of the major diastereomer over 2 steps.
Determined by HPLC.
[b]
[c]
[d]
[e]
[a]
Determined by GC.
Slow addition of PhZnCl within 12 min.
PhZnCl prepared from PhMgBr instead of PhLi.
[b]
[c]
Combined yield of diastereomers, ee not determined.
(R)-binap was used to furnish ent-3aa/ent-4aa.
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Enantioselective Preparation of 3-Arylcycloalkylamines
a 62% yield (entry 2). For preparation of the trans-
diastereomer, L-selectrideꢃ could not be used, causing
only deprotonation of the enamide.[20] However, the
transfer hydrogenation catalyst RuCl(p-cymene)[Ts-
DPEN] (5),[21] which our group has already employed
for enantioselective C,N double bond reductions,[22]
furnished pure trans-4aa in very good yields (en-
tries 3–5).[23] This trans-selectivity must be due to pre-
vailing substrate control since the diastereomeric
Scheme 1. 1,4-Addition of phenylboronic acid.
ratio was the same when using either rac-5 (entry 3) double bond migration in the respective enamides 3
or its (S,S)-enantiomer (entry 4) for reduction of the and, thus, partial racemization.[24]
enamide from 1,4-additions with (S)-binap. Even
Besides arylzinc halides, the 1,4-addition was also
when performing the 1,4-addition with (R)-binap and performed using phenylboronic acid under classical
reducing ent-3aa with (S,S)-5 (entry 5), the same dia- conditions (Scheme 1).[15b] The aqueous reaction
stereoselectivity was observed. Drawn from the signif- medium, however, caused partial hydrolysis and the
icantly increased yield of ent-4aa, however, this latter yield of trans-4aa was significantly lowered. Neverthe-
combination ought to be the matched pair.
less, utilization of organoboron reagents should fur-
This protocol was then applied to the 1,4-addition ther enlarge the scope of transferable functionalized
of various aromatic residues (Table 3). Compared to aryl groups.
the phenyl group (entry 1), most aryl groups required
a higher catalyst loading for achieving high yields, dition–reduction sequence was applied to the 5,5-di-
while the enantioselectivity was always excellent. substitued imine 1b, leading to an even better yield
In order to evaluate the substrate scope, the 1,4-ad-
AHCTUNGTRENNUNG
Both electron-rich (entry 2) as well as electron-defi- compared with the unsubstituted imine 1a (Table 4,
cient aryl groups (entries 3 and 4) could be intro- entry 1 vs. Table 3, entry 1).[25,26] While the N-tosyl-
duced, slightly longer reaction times being needed for
ACHTUNGTRENiNGNU mine from cyclopent-2-enone is so far not available
the latter. Steric constraints were stated with the 2- in reasonable yield,[10] its 4,4-disubstituted derivative
tolyl reagent, yet a moderate yield was achieved 1c could be transformed into cis-4ca, however, the
(entry 5), and good results were obtained with 3,5- conversion was incomplete after 71 h at 508C even
xylyl or 2-naphthyl groups (entries 6–8). In some of with increased amounts of catalyst and PhZnCl
these transformations, the ee was significantly de- (entry 2). In contrast, this substrate readily undergoes
creased if the crude products of the 1,4-addition were 1,4-addition of AlMe3,[11] and accordingly, use of
not filtered over activated charcoal prior to reduction. PhAlMe2 led to complete conversion after 19 h at
Traces of remaining rhodium may then lead to C,C room temperature (entry 3). In the case of this sub-
strate, a reduction with NaBH4 was favourable, since
a transfer hydrogenation with rac-5 also led to cis-4ca
but with a lower diastereoselectivity of 84:16.
Table 3. 1,4-Addition of various aryl groups.
In addition to N-tosylimines, N-tert-butylsulfonyl-
AHCTUNGTRENNUNG
imines (Bus-imines)[10] were also suitable, albeit slight-
ly less reactive, requiring increased amounts of cata-
lyst and a reaction temperature of 408C. Moreover,
the yield was significantly lower in the case of the six-
membered ring 1d even when using the matched pair
of catalysts (Table 4, entry 4 vs. Table 2, entry 5). With
the cyclopent-2-enone derived imine 1e, the transfer
hydrogenation with (S,S)-5 furnished preferentially
the cis-diastereomer of 4ea, and both a higher yield
and diastereoselectivity were achieved in the matched
pair with (R)-binap (entries 5 and 6). In the case of
the cycloheptenone-derived imine 1f, the trans-diaste-
reomer was formed as the major product in a high
yield (entry 7). A special feature of the cycloalkyl-
Entry
Ar
[Rh(cod)Cl]2
[mol%]
Yield
[%][a]
ee
[%][b]
1
2
C6H5 (a)
1.0
2.5
2.5
2.5
2.5
2.5
1.0
1.0
83
91
68
89
53
quant.
82
99
99
99
>99
99
99
99
99
4-MeOC6H4 (b)
4-FC6H4 (c)
4-CF3C6H4 (d)
2-MeC6H4 (e)
3,5-xylyl (f)
3,5-xylyl (f)
2-naphthyl (g)
3[c]
4[c]
5
6
7
8
AHCTUNGTREGUNaNN mides 4da–4fa is the possibility to cleave the Bus
group by acidic hydrolysis[27] in contrast to the tosyl
group which is usually removed under reductive con-
ditions (see below).
70
[a]
Isolated yield.
Determined by HPLC.
1,4-Addition performed for 1 h.
[b]
[c]
As an acyclic substrate, the chalcone-derived imine
1g was subjected to a 1,4-addition of 3,5-xylylZnCl,
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Table 4. 1,4-Addition to various a,b-unsaturated imines.
Entry Imine
[Rh(cod)Cl]2/ligand Reagent
t/T
Reduction
dr[a]
(trans/cis)
Product
Yield/ee
[%][b]
1
1.0 mol%/(S)-binap PhZnCl (1.5 equiv.) 3 h/r.t.
rac-5, HCOOH
>97:3
3:97
95/>99
2
2.5 mol%/(S)-binap PhZnCl (4.5 equiv.) 71 h/508C NaBH4
71/96
3
4
5
1.0 mol%/(R)-binap PhAlMe2 (1.5 equiv.) 19 h/r.t.
NaBH4
4:96
92/97
58/98
50[c]/99
2.5 mol%/(R)-binap PhZnCl (1.5 equiv.) 0.5 h/408C (S,S)-5, HCOOH >97:3
2.5 mol%/(S)-binap PhZnCl(1.5 equiv.)
1.5 h/408C (S,S)-5, HCOOH 21:79
6
2.5 mol%/(R)-binap PhZnCl (1.5 equiv.) 1.5 h/408C (S,S)-5, HCOOH 13:87
63[c]/99
85/97
7
2.5 mol%/(R)-binap PhZnCl (1.5 equiv.) 1.5 h/408C (S,S)-5, HCOOH 94:6
[a]
1
Determined by H NMR analysis of the crude product.
Isolated yield; ee determined by HPLC.
Diastereomeric mixture.
[b]
[c]
and hydrolysis of the 1,4-adduct furnished the respec- actions of moderate enantioselectivity altogether re-
tive ketone with 56% ee (Table 5, entry 1).[28] Per- sults in a strong enhancement of the enantiopurity.
forming a racemic 1,4-addition with subsequent re-
The smooth 1,4-addition to the 5,5-dimethyl-substi-
duction with (S,S)-5 led to a 62:38 dr and about 70% tuted imine 1b (Table 4, entry 1) led to the assump-
ee for both diastereomers of 4gf (entry 2). The se- tion that – similar to the respective enones[25] – cata-
quence was then repeated with (R)- and (S)-binap fur- lyst control would outpace substrate control in the
nishing a 70:30 and a 42:58 dr, respectively (entries 3 case of 5-monosubstituted derivatives making it possi-
and 4). In both pairs, the major diastereomer was ob- ble to override a stereocenter at C-5 of the ring. Com-
tained with 92% ee, thus, the combination of two re- bined with the stereodivergent reductions, this ought
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Enantioselective Preparation of 3-Arylcycloalkylamines
Table 5. 1,4-Addition to the imine derived from chalcone.
reomer 7a was obtained in a 62% isolated yield (left
column, second entry).[29]
In contrast, (R)-binap led to a trans-selective 1,4-
addition of the phenyl group and, with respect to this
substituent, the reduction occurred with increased
trans-selectivity when using (S,S)-5 instead of rac-5
(right column, first entry). This afforded diastereomer
7c in a very high yield. With t-BuNH2·BH3 as reduc-
tant, the directing influence of the phenyl group was
again predominant leading to a 1:1.6 mixture of 7c
and 7d which could not be separated by column chro-
matography (right column, second entry). Altogether,
formation of diastereomer 7d occurs with the lowest
selectivity, but calculated from the isolated diastereo-
meric mixture, it is still formed in a synthetically
useful 54% yield.
Entry binap dr[a] crude/purified Yield [%][b] ee [%][c]
[d]
1
2
3
4
(R)
rac
(R)
(S)
–
53[d]
52
95
56[d]
69/71
92/15
1/92
62:38/54:46
70:30/70:30
42:58/31:69
57
[a]
1
Determined by H NMR analysis, relative configuration
not determined.
[b]
[c]
[d]
Isolated yield of purified diastereomeric mixture.
Determined by HPLC and stated for both diastereomers.
The 1,4-adduct was not reduced, but hydrolyzed with 6m
HCl; yield and ee refer to the respective ketone.
An inherent property of the tosyl group is its chem-
ical robustness, frequently requiring harsh conditions
for its removal.[30] After carbamate protection, how-
AHCTUNGTREGeNNUN ver, detosylation can smoothly be accomplished with
to lead to a selective synthesis of all stereoisomers of magnesium in MeOH under ultrasonication.[31] Ac-
3,5-disubstituted cyclohexylamines. This assumption cordingly, tosylamides trans-4aa and trans-4ab were
was studied using imine (R)-6 which was prepared transformed into their Boc derivatives 9a and 9b in
from (R)-5-methylcyclohexenone (Scheme 2). Trans- very high yields (Scheme 3). The Boc protection also
formation with the racemic catalysts in both steps re- proceeded well with the zinc aza-enolate initially ob-
vealed that the 1,4-addition occurs with a poor 2:1 tained from 1,4-addition of PhZnCl to imine 1a, i.e.,
trans/cis-selectivity (upper section, ratio of 7c+7d vs. when performing a one-pot sequence. In contrast, this
7b) and, concerning the reduction, that the trans-di- reaction was very slow if applied to the enamide 3aa
recting influence of the phenyl group is stronger than obtained after aqueous quenching of the 1,4-addition.
that of the methyl group (7c vs. 7d). With (S)-binap, The carbamate group stabilizes enamide 10 towards
the 1,4-addition occurred with complete cis-selectivity, chromatography on silica gel and enables isolation
and only diastereomer 7b was obtained after a trans- and purification. Thus, this is a first alternative em-
selective reduction with rac-5 (left column, first ployment of the aza-enolates from the 1,4-addition
entry). Applying (S)-binap but a subsequent reaction than just protonation.
with t-BuNH2·BH3, a good 4.6:1 cis/trans-selectivity
The cis-diastereomer of 3-aminocyclohexanecarbox-
was observed in the reduction, and the all-cis-diaste- ylic acid has attracted some interest in recent years as
Scheme 2. Stereodivergent transformation of imine (R)-6.
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trol whether the carboxy or the amino group adopts
the axial position. To prove this concept, the para-
anisyl group was added to the racemic ketimine 6,
and after trans-selective reduction, the diastereomers
12a and 12b were obtained in 42% and 32% yield,
respectively. These compounds were then separately
transformed into their Boc derivatives 13a/13b, which,
after oxidative cleavage, furnished the g-amino acids
14a/14b.[36]
Conclusions
a,b-Unsaturated N-sulfonylimines react similarly to
the corresponding carbonyl compounds in Hayashi–
Miyaura-type reactions with arylzinc halides. Com-
bined with a suitable reduction method, this can be
Scheme 3. Synthesis of Boc-protected cyclohexyl- and cyclo-
hexenylamines.
an inhibitor of GABA uptake[32] and as a structural utilized for the enantioselective preparation of vari-
motif in modified peptides.[33] It is easily accessible by ous 3-arylcycloalkylamines with either cis- or trans-
hydrogenation of 3-aminobenzoic acid which can be configuration at the ring. In the case of cyclohex-
succeeded by chiral resolution to obtain enantiopure
ACHTUNGTRENeNGNU none-derived imines, stereocontrol by the Rh(I)/
material.[34] In contrast, the trans-diastereomer is binap catalyst prevails over substrate control by a ste-
much more difficult to prepare,[35] yet it could also be reocenter at C-5 of the ring; this can be used for the
an interesting structure as one of the substituents selective synthesis of all four diastereomers of 3-
must necessarily reside in an axial position. Therefore, methyl-5-phenylcyclohexylamine. Moreover, the in-
an oxidative cleavage of the para-anisyl group in car- troduced aryl rings can be degraded to carboxy moiet-
bamate 9b was performed and the desired g-amino ies furnishing conformationally rigid cyclic g-amino
acid 11 was obtained in a 60% yield (Scheme 4).
acids. We are now working on employing other classes
This cyclohexane derivative is conformationally of chiral ligands for less reactive or acyclic substrates
flexible, but a third substituent at the ring would con- and on using the initially formed zinc aza-enolates or
the respective enamides for subsequent C,C bond for-
mations.
Experimental Section
Rh-Catalyzed 1,4-Addition of Arylzinc Chloride
A mixture of [Rh(cod)Cl]2, binap, and ketimine (400 mmol)
was stirred for 30 min under reduced pressure. THF
(2.5 mL) was added, and the resulting solution was stirred
for 45 min at room temperature. The arylzinc chloride (solu-
tion in THF, 1.5 equiv.) was added in one portion, and the
dark red solution was stirred for the given time. The mixture
was then poured into a stirred mixture of methyl tert-butyl
ether (MTBE, 32 mL), NaHCO3 (1.50 g), and H2O (0.8 mL),
stirred for 15 min, and dried over Na2SO4. After addition of
activated charcoal, the suspension was filtered over Celiteꢃ,
and the filtrate was concentrated under reduced pressure.
The crude product was immediately subjected to the respec-
tive subsequent transformation.
Reduction with t-BuNH2·BH3
A solution of t-BuNH2·BH3 (73.1 mg, 840 mmol) in CH2Cl2
(2.0 mL) was added to the crude product of the respective
1,4-addition (400 mmol) at 08C and stirred for the given
time. The reaction mixture was quenched by addition of
Scheme 4. Synthesis of 3-aminocyclohexanecarboxylic acids.
H2O (2.0 mL) and stirred for 0.5 h. More H2O (10 mL) was
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added and the aqueous phase was extracted with CH2Cl2
(3ꢄ10 mL). The combined organic layers were washed with
brine (10 mL), dried over Na2SO4, and filtered, and the fil-
trate was concentrated under reduced pressure. The crude
product was purified by column chromatography over silica
gel.
[7] For the related asymmetric 1,4-addition of boron nucle-
ophiles, see: a) A. D. J. Calow, C. Solꢆ, A. Whiting, E.
Fernꢅndez, ChemCatChem 2013, 5, 2233–2239; b) T.
Kitanosono, P. Xu, S. Isshiki, L. Zhu, S. Kobayashi,
Chem. Commun. 2014, 50, 9336–9339.
[8] For the related chiral auxiliary-based diastereoselective
1,4-addition of organometallic reagents to imines, see:
a) A. I. Meyers, J. D. Brown, D. Laucher, Tetrahedron
Lett. 1987, 28, 5283–5286; b) A. I. Meyers, G. P. Roth,
D. Hoyer, B. A. Barner, D. Laucher, J. Am. Chem. Soc.
1988, 110, 4611–4624; c) J. P. McMahon, J. A. Ellman,
Org. Lett. 2005, 7, 5393–5396; d) K. Sammet, C. Gastl,
A. Baro, S. Laschat, P. Fischer, I. Fettig, Adv. Synth.
Catal. 2010, 352, 2281–2290.
[9] For related enantioselective additions to alkenyl-substi-
tuted azaarenes, see: a) G. Pattison, G. Piraux, H. W.
Lam, J. Am. Chem. Soc. 2010, 132, 14373–14375;
b) A. A. Friedman, J. Panteleev, J. Tsoung, V. Huynh,
M. Lautens, Angew. Chem. 2013, 125, 9937–9940;
Angew. Chem. Int. Ed. 2013, 52, 9755–9758; c) I. D.
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[10] S. Hirner, J. Westmeier, S. Gebhardt, C. H. Mꢀller, P.
von Zezschwitz, Synlett 2014, 1697–1700.
Transfer Hydrogenation
RuCl(p-cymene)[Ts-DPEN] (5, 12.7 mg, 20.0 mmol) and the
crude product of the respective 1,4-addition (400 mmol)
were dissolved in CH3CN (4.0 mL), a mixture of HCOOH
and Et3N (5/2, 252 mL, 600 mmol) was added, and the solu-
tion was stirred for 16 h at room temperature. The reaction
mixture was poured into H2O (10 mL) and extracted with
EtOAc (5ꢄ10 mL). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure and
purified by column chromatography over silica gel.
Acknowledgements
[11] S. Hirner, A. Kolb, J. Westmeier, S. Gebhardt, S.
Middel, K. Harms, P. von Zezschwitz, Org. Lett. 2014,
16, 3162–3165.
We thank the Konrad-Adenauer-Stiftung, Bonn for a scholar-
ship for J.W., the BASF SE, Ludwigshafen for the generous
donation of chemicals, and Lucas Millbrodt, Philipps-Univer-
sitꢀt Marburg for technical assistance.
[12] 3-Substituted cyclohexylamines can be prepared by an
organocatalytic reaction cascade. For enantioselective
formation of the cis-diastereomers, see: a) J. Zhou, B.
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Beilstein J. Org. Chem. 2014, 10, 1333–1338.
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8
asc.wiley-vch.de
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Enantioselective Preparation of 3-Arylcycloalkylamines by
Rhodium-Catalyzed 1,4-Addition and Subsequent
Stereodivergent Reduction
9
Adv. Synth. Catal. 2015, 357, 1 – 9
Sandra Gebhardt, Christian H. Mꢀller, Johannes Westmeier,
Klaus Harms, Paultheo von Zezschwitz*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!