Synthesis of trans-3-substituted cyclohexylamines via Br?nsted acid catalyzed and substrate-mediated triple organocatalytic cascade reaction

Article abstract of DOI:10.1055/s-2007-984877

We report a new organocatalytic cascade reaction. A combination of the amine substrate with a catalytic amount of a Br?nsted acid merges enamine and iminium catalysis with Br?nsted acid catalysis in a new organocatalytic cascade reaction. We found that the aniline substrate itself in combination with a catalytic amount of PTSA·H₂O can function as an aminocatalyst accomplishing an aldol condensation-conjugate reduction cascade, which terminates in a Br?nsted acid catalyzed reductive amination incorporating the amine substrate into the final product. This transformation furnishes trans-3-substituted cyclohexyl amines in good yields and good diastereoselectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984877

LETTER
2037
Synthesis of trans-3-Substituted Cyclohexylamines via Brønsted Acid Cata-
lyzed and Substrate-Mediated Triple Organocatalytic Cascade Reaction
Synthesis
iof tran
a
-
3-Substitu
n
ted Cyclohexyla
mZ
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062999; E-mail: list@mpi-muelheim.mpg.de
Received 17 May 2007
substituted cyclohexyl amines in good yields and dia-
stereoselectivities (Scheme 1).
Abstract: We report a new organocatalytic cascade reaction. A
combination of the amine substrate with a catalytic amount of a
Brønsted acid merges enamine and iminium catalysis with Brønsted
acid catalysis in a new organocatalytic cascade reaction. We found
that the aniline substrate itself in combination with a catalytic
amount of PTSA·H2O can function as an aminocatalyst accomplish-
ing an aldol condensation–conjugate reduction cascade, which
terminates in a Brønsted acid catalyzed reductive amination incor-
porating the amine substrate into the final product. This transforma-
tion furnishes trans-3-substituted cyclohexyl amines in good yields
and good diastereoselectivities.
We have previously demonstrated that salts consisting of
an achiral or chiral ammonium cation and a chiral
phosphate anion are powerful catalysts of transfer hydro-
genations of a,b-unsaturated aldehydes and ketones with
Hantzsch esters.7,8 We have also developed Brønsted acid
catalyzed imine reductions and reductive aminations with
Hantzsch esters.9 Based on these results, together with the
well-established capacity of amine salts to catalyze
aldolizations,10 we designed a new triple organocatalytic
cascade process which integrates enamine catalysis, imin-
ium catalysis, and Brønsted acid catalysis. Accordingly,
treating 2,6-heptanediones with an amine, a catalytic
amount of a Brønsted acid, and two equivalents of a
Hantzsch ester (HE), the corresponding saturated amines
should be formed via an aldol condensation–conjugate
reduction–reductive amination cascade (Scheme 1). The
first two steps of this reaction would be catalyzed by the
amine salt via enamine catalysis and via a combination of
iminium and Brønsted acid catalysis. The amine would
finally be incorporated into the product in a Brønsted acid
catalyzed reductive amination.11
Key words: organocatalytic cascade reaction, substrate co-cata-
lyzed, 3-substituted cyclohexyl amine, organocatalysis
The design of new catalytic cascade reactions is at the
forefront of modern organic synthesis because such pro-
cesses can effectively save time, energy, and materials.1
Especially, the modular combination of different organo-
catalytic reactions into cascades has recently become a
fruitful concept for complex molecule synthesis.2 This ap-
proach fundamentally relies on the reaction compatibility,
often realized in organocatalysis.3
Amines and their salts are particularly versatile for the de-
sign of organocatalytic cascade reactions because they
can trigger reactions either via enamine or iminium ion
formation.4 Combining enamine and iminium catalysis in
different sequences paves a facile way for the creation of
new carbon–carbon bonds and stereogenic centers in a
highly controlled fashion from readily available precur-
sors in one-pot operations.5 Meanwhile, Brønsted acid
catalysis have already found many applications in organic
synthesis, and been shown to be compatible with amine
substrates and products.6 However, the combination of
Brønsted acid catalysis with amine catalysis is largely un-
developed. In this communication, we wish to report a
new strategy for organocatalytic cascade reactions. We
found that the amine substrate itself in combination with
a catalytic amount of a Brønsted acid can function as both
enamine and iminium catalyst accomplishing an aldol
condensation–conjugate reduction cascade, which termi-
nates in a Brønsted acid catalyzed reductive amination
and the incorporation of the amine into the final product.
This transformation provides a useful access to trans 3-
This concept was realized by treating 2,6-heptanedione
(1a) with 1.5 equivalents of p-ethoxy aniline (PEP-NH2,
2), 2.2 equivalents of Hantzsch ester 3, and 5 mol% of
PTSA·H2O, in toluene at 40 °C. After 48 hours, cyclo-
hexyl amine 4a was isolated in 72% yield (Scheme 2).
The relative configuration of 4a was confirmed by NMR
analysis, the trans isomer being the major product
(dr = 4:1).12 We have investigated various solvents with-
out significantly affecting the diastereoselectivity.
H
R
O
N
HX (cat.), RNH2 (1 equiv)
Hantzsch ester (2 equiv)
O
R1
R1
NHR
+
+
NHR
X–
NHR
X–
O
R1
R1
R1
enamine
iminium &
Brønsted acid
catalysis
Brønsted acid
catalysis
catalysis
SYNLETT 2007, No. 13, pp 2037–2040
1
3
.0
8
.2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984877; Art ID: G14907ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2038
J. Zhou, B. List
LETTER
H
H
Several substituted 2,6-diones (1a–k) react smoothly to
the desired products 4 (Table 1). All the substrates afford-
ed good to high yield and the trans-diastereomer was the
major product with selectivities of up to 8:1.
OEt
EtO2C
CO2Et
H2N
O
HN
N
H
OEt
2 (1.5 equiv)
3 (2.2 equiv)
The initial aldol condensation is fast and seems to be
kinetically controlled. This reaction almost exclusively
takes place between the 1-methyl- and the 6-carbonyl
group of the substrate.14 Even in the case of substrate 1b
and 1c, apt to give regioisomeric mixtures, less than 5%
of the regioisomers could be detected in a careful GC-MS
study. The aldolization is catalyzed by the amine substrate
and the acid catalyst; either reagent alone is inefficient in
catalyzing the reaction. The formation of 2,6-disubstitut-
ed piperidines, which may have been expected from a
double reductive amination, was not observed.
O
PTSA·H2O (5 mol%)
40 °C, MS 5 Å, toluene, 48 h
72%
1a
4a (dr = 4:1)
Scheme 2
The highest reactivity was observed in toluene. The use of
1.5 equivalents of the amine was found to minimize the
amount of byproduct 3-methylcyclohexanone 6a. This
intermediate serves as the precursor for the terminating re-
ductive amination. Molecular sieves (5 Å) accelerated the
reaction. The substrate scope was then examined under The conjugate reduction step is Brønsted acid and amine
the optimized reaction conditions (Table 1).
co-catalyzed and in the absence of either catalyst, no fur-
ther conversion of the enone intermediate is observed.
That the amine is a true catalyst of at least the initial two
steps of the cascade reaction is revealed when the reaction
is carried out in the presence of only one equivalent of the
Hantzsch ester and a substoichiometric amount of the
amine. Under these conditions the product of the aldol–
conjugate reduction sequence is observed as the major
product after passing the crude mixture through a short
pad of silica gel. The regioselectivity in the conjugate re-
duction step (1,4- vs. 1,2-reduction) is excellent. Only
when R1 is aromatic (entries 9–11), small amounts of the
1,2-reduction products 7i–k (Figure 1) are formed as
byproducts in 10–15% yield. Similar electronic effects
have been observed in reductions of preformed a,b-un-
saturated iminium ions.15
Table 1 Substrate Scope13
H
H
EtO
EtO2C
CO2Et
O
PEP
NH2
2 (1.5 equiv)
N
HN
H
3 (2.2 equiv)
O
PTSA·H2O (5 mol%)
MS 5 Å, toluene, 40 °C, 48–72 h
R1
R1
1
4
Entry
1
R1
Product 4
Yield (%)
dra
Me
4a
72
65
72
73
4:1
4:1
3:1
6:1
2
3
4
4b
4c
4d
Ph
Ph
PEP
NH
7i R1 = 2-naphthyl
7j R1 = p-ClC6H4
7k R1 = Ph
R1
5
6
4e
4f
86
75
5:1
4:1
Figure 1
Interestingly, with t-Bu-substituted diketone 1l, the de-
sired product 4l could be obtained in only 10%
(Scheme 3). In this case, compound 8 was formed as
major product. Presumably reductive amination is faster
than aldol condensation in this case.
7
8
9
4g
4h
4i
68
83
63
5:1
4:1
8:1
NHPEP
O
NHPEP
2 (1.5 equiv), 3 (2.2 equiv)
+
O
O
PTSA·H2O (10 mol%)
40 °C, toluene, 144 h
t-Bu
t-Bu
8 (58%)
10
11
Ph
4j
60
66
5:1
5:1
t-Bu
4l (10%)
1l
4k
Scheme 3
Cl
a Determined by GC-MS or 1H NMR analysis.
Synlett 2007, No. 13, 2037–2040 © Thieme Stuttgart · New York

LETTER
Synthesis of trans-3-Substituted Cyclohexylamines
2039
(3) For important reviews, see: (a) List, B.; Yang, J. W. Science
2006, 313, 1584. (b) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719. (c) Dalko, P. I.; Moisan, L. Angew. Chem. Int.
Ed. 2004, 43, 5138.
(4) (a) List, B. Chem. Commun. 2006, 819. (b) Lelais, G.;
MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79.
(c) Palomo, C.; Mielgo, A. Angew. Chem. Int. Ed. 2006, 45,
7876.
This method can also be used for the synthesis of
heterocyclic compounds. For example, thiodiketone 1m
could be transformed to the corresponding heterocyclic
compound 4m in excellent diastereoselecitivity (92:8)
and in moderate yield (Scheme 4).
O
NHPEP
2 (1.5 equiv), 3 (2.2 equiv)
(5) For recent examples, see: (a) Yang, J. W.; Hechavarria
Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127,
15036. (b) Huang, Y.; Walji, A. M.; Larsen, C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.
(c) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J.
Am. Chem. Soc. 2005, 127, 15710. (d) Enders, D.; Hüttl, M.
R. M.; Grondal, C.; Raabe, G. Nature (London) 2006, 441,
861. (e) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem.
Soc. 2006, 128, 10354. (f) Brandau, S.; Maerten, E.;
Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 14986.
(g) Enders, D.; Hüttl, M. R. M.; Runsink, J.; Raabe, G.;
Wendt, B. Angew. Chem. Int. Ed. 2007, 46, 467.
(h) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2007, 46, 1101. (i) Li, H.; Wang, J.;
E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem.
Commun. 2007, 507.
PTSA·H2O (5 mol%)
50 °C, toluene, 48 h
24%
S
O
S
4m (dr = 11:1)
1m
Scheme 4
The PEP group can be readily removed in high yield using
H5IO6, a method recently reported by researchers at DSM
(Scheme 5).17
NHPEP
NH2
H5IO6 (1.5 equiv)
H2SO4 (1 M)
MeCN–H2O
(6) For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2006, 45, 1520. (b) Akiyama, T.; Itoh, J.;
Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999. (c) Connon,
S. J. Angew. Chem. Int. Ed. 2006, 45, 3909. (d) Takemoto,
Y. Org. Biomol. Chem. 2005, 3, 4299. (e) Bolm, C.;
Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem. Int. Ed.
2005, 44, 1758. (f) Schreiner, P. R. Chem. Soc. Rev. 2003,
32, 289.
r.t., 12 h
90%
4a
9
Scheme 5
In conclusion, we demonstrate that combining enamine
catalysis and iminium catalysis with Brønsted acid cata-
lysis constitutes a powerful strategy for developing orga-
nocatalytic cascade reactions. Based on this strategy, we
have developed a new triple organocatalytic cascade reac-
tion for preparing trans-3-substituted (hetero) cyclohexyl
amines from 2,6-diones, which are constituents in several
pharmaceutically active compounds.17 The use of a cata-
lytic amount of Brønsted acid in combination with a
stoichiometric amount of an achiral amine as self-sacrific-
ing aminocatalyst is a new concept for organocatalysis.
Further extensions of this strategy are under investigation
in our laboratory.
(7) (a) Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45,
4193. (b) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006,
128, 13368.
(8) For chiral amine-catalyzed conjugate reductions of a,b-
unsaturated carbonyl compounds, see: (a) Yang, J. W.;
Hechavarria Fonseca, M. T.; List, B. Angew. Chem. Int. Ed.
2004, 43, 6660. (b) Yang, J. W.; Hechavarria Fonseca, M.
T.; Vignola, N.; List, B. Angew. Chem. Int. Ed. 2005, 44,
108. (c) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 32. (d) Tutlle, J. B.; Ouellet,
S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
12662.
(9) (a) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int.
Ed. 2005, 44, 7424. (b) Hoffmann, S.; Nicoletti, M.; List, B.
J. Am. Chem. Soc. 2006, 128, 13074. Also see: (c)Rueping,
M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org.
Lett. 2005, 7, 3781. (d) Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. For
the reduction of quinolines, benzoxazines, benzothiazines,
and benzoxazinones, see: (e) Rueping, M.; Antonchick, A.
P.; Theissmann, T. Angew. Chem. Int. Ed. 2006, 45, 3683.
(f) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem. Int. Ed. 2006, 45, 6751. For achiral version, see:
(g) Rueping, M.; Azap, C.; Sugiono, E.; Theissmann, T.
Synlett 2005, 2367. (h) Rueping, M.; Theissmann, T.;
Antonchick, A. P. Synlett 2006, 1071.
Acknowledgment
We thank Dr. R. Mynott for careful NMR studies. We also thank
Degussa, Merck, Saltigo, and Wacker for the donation of chemicals
and Novartis for a Young Investigator award to BL. Our work was
supported by the Max-Planck-Gesellschaft, the Deutsche For-
schungsgemeinschaft (Priority Program 1179 Organocatalysis),
and the Fonds der Chemischen Industrie.
References and Notes
(1) For leading reviews, see: (a) Ramón, D. J.; Yus, M. Angew.
Chem. Int. Ed. 2005, 44, 1602. (b) Nicolaou, K. C.;
Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
(c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Wasilke, J.-
C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001.
(10) For a review on amine-catalyzed aldol reactions, see: List, B.
In Modern Aldol Reactions, Vol. 1; Mahrwald, R., Ed.;
Wiley-VCH: Weinhein Germany, 2004, 161–200.
(11) For a recent nonasymmetric amine mediated aldol
condensation, Pd-catalyzed hydrogenation–reductive
amination cascade in the synthesis of Fenpropimorph, see:
Forsyth, S. A.; Gunaratne, H. Q. N.; Hardacre, C.;
McKeown, A.; Rooney, D. W. Org. Process Res. Dev. 2006,
10, 94.
(2) For an excellent review, see: Enders, D.; Grondal, C.; Hüttl,
M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570.
Synlett 2007, No. 13, 2037–2040 © Thieme Stuttgart · New York

2040
J. Zhou, B. List
LETTER
(12) For the determination of the relative configuration and a
highly enantioselective synthesis of the corresponding cis-
products, see: Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129,
7498.
[M + H]+, 190 (40), 108 (39), 176 (32), 204 (22), 137 (18),
97 (10). HRMS (EI): m/z calcd for C15H24NO [M + H]+:
234.1852; found: 234.1852.
(14) This is in contrast to the corresponding NaOH-catalyzed
cyclization of 2,6-heptanediones, see: Danishefsky, S.;
Zimmer, A. J. Org. Chem. 1976, 41, 4059.
(15) For a related investigation, see: De Nie-Sarink, M. J.; Pandit,
U. K. Tetrahedron Lett. 1979, 26, 2449.
(16) Verkade, J. M. M.; van Hermert, L. J. C.; Quaedflieg, P. J.
L. M.; Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T.
Tetrahedron Lett. 2006, 47, 8109.
(17) Based on a SciFinder survey, there are more than 300
patented structures containing a 3-methylcyclohexylamine
moiety. For selected pharmaceutically active compounds
incorporating a 3-substituted cyclohexylamine, see:
(a) Johnston, T. P.; McCaleb, G. S.; Clayton, S. D.; Frye, J.
L.; Krauth, C. A.; Montgomery, J. A. J. Med. Chem. 1977,
20, 279. (b) Palomba, M.; Pau, A.; Boatto, G.; Asproni, B.;
Auzzas, L.; Cerri, R.; Arenare, L.; Filippelli, W.; Falcone,
G.; Motola, G. Arch. Pharm. Pharm. Med. Chem. 2000, 333,
17. (c) Norman, B. H.; Lander, P. A.; Gruber, J. M.; Kroin,
J. S.; Cohen, J. D.; Jungheim, L. N.; Starling, J. J.; Law, K.
L.; Self, T. D.; Tabas, L. B.; Williams, D. C.; Paul, D. C.;
Dantzig, A. H. Bioorg. Med. Chem. Lett. 2005, 15, 5526.
(13) Typical Procedure: To a Schlenk tube was added 2,6-dione
1 (0.2 mmol), p-ethoxyphenyl amine 2 (0.3 mmol), Hantzsch
ester 3 (0.45 mmol) and PTSA·H2O (2 mg, 0.01 mmol), and
then charged with argon, followed by adding MS 5 Å (50
mg) and anhyd toluene (0.5 mL). The mixture was stirred at
40 °C for 24–72 h. To determine the ratio of trans- to cis-
product, 20 mL of the reaction mixture was taken for GC-MS
analysis, or 0.2 mL of crude mixture for 1H NMR analysis.
The sample for analysis and the rest were emerged together
for column chromatography purification using hexane–
EtOAc (96:4) or CH2Cl2 as eluent. Compound trans-4a was
obtained as colorless liquid (0.144 mmol, 72%) after
chromatography with hexane–EtOAc (96:4). 1H NMR (300
MHz, CDCl3): d = 0.91 (d, J = 6.4 Hz, 3 H), 0.99–1.10 (m, 1
H), 1.27–1.37 (m, 1 H), 1.36 (t, J = 6.9 Hz, 3 H), 1.47–1.78
(m, 7 H), 3.20–3.50 (s, br, 1 H), 3.56–3.60 (m, 1 H), 3.95
(q, J = 6.9 Hz, 2 H), 6.53–6.58 (m, 2 H), 6.74–6.79 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 15.05, 20.52, 21.69,
27.13, 30.54, 33.98, 38.96, 48.54, 64.17, 114.60, 115.88,
141.68, 151.04. MS (EI): m/z (%) = 233 (100) [M+], 234 (14)
Synlett 2007, No. 13, 2037–2040 © Thieme Stuttgart · New York

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