Organocatalytic asymmetric synthesis of trans-1,3-disubstituted tetrahydroisoquinolines via a reductive amination/aza-michael sequence

Article abstract of DOI:10.1002/chem.201001623

(Figure Presented) Benzothiazoline better than Hantzsch: A stereoselective Bronsted acid catalyzed reductive amination/aza-Michael approach towards the important class of tetrahydroisoquinolines is presented (see scheme). A biphenyl-substituted benzothiazoline is used as the reducing agent and leads to superior yields and enantiomeric excesses compared with the frequently used Hantzsch ester. The cyclization of the amine intermediate occurs smoothly with potassium tert-butoxide as the base and affords the trans-1,3-disubstituted tetrahydroisoquinolines.

Full text of DOI:10.1002/chem.201001623

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DOI: 10.1002/chem.201001623
Organocatalytic Asymmetric Synthesis of trans-1,3-Disubstituted
Tetrahydroisoquinolines via a Reductive Amination/Aza-Michael Sequence
Dieter Enders,* Jens X. Liebich, and Gerhard Raabe[a]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
In the rapidly evolving field of organocatalysis[1] chiral
Brønsted acids have become one of the most powerful and
versatile catalysts for a wide range of transformations.[2] One
of the most important reactions catalyzed by this class of
catalysts is the enantioselective reductive amination,[3] which
leads to a broad range of chiral amines that are frequently
found in natural products or pharmaceutically interesting
compounds. While several organocatalytic reductions of
imines using chiral Brønsted acids have been reported in the
literature,[4] so far only very few organocatalytic protocols
for the enantioselective direct reductive amination employ-
ing chiral Brønsted acid catalysis have been developed.[5]
Recently, Akiyama et al. applied benzothiazolines as novel
reducing agents for the stereoselective reduction of imines,[6]
but to the best of our knowledge no direct reductive amina-
tion of ketones with this hydride source has been reported
so far.
ed acid catalyzed reductive amination/aza-Michael sequence
could lead to the title heterocycles A, starting under multi-
component conditions from keto enones B, p-anisidine (C),
and benzothiazolines D, thereby allowing a great substitu-
tion pattern flexibility (Scheme 1).
Scheme 1. Retrosynthetic analysis of the tetrahydroisoquinoline synthe-
sis.
The tetrahydroisoquinoline motif is frequently found in
biologically active substances,[7] such as antibiotics and anti-
tumor agents and therefore the development of new diaster-
eo- and enantioselective routes to this important substance
class is desirable.[8,9] The most recent approaches to these
compounds are metal-catalyzed reactions such as the asym-
To test this approach we synthesized the methylketone
enoate 1 and submitted it to reductive amination conditions
using MacMillansꢀ Ph3Si-substituted phosphoric acid catalyst
and commercially available Hantzsch ester (2) as hydride
source (Table 1, entry 1). The desired product 3 was ob-
tained even though in only poor yield and enantioselectivity.
List’s TRIP (3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-binaphth-
yl-2,2’-diyl hydrogenphosphate) catalyst[13] in turn showed
very good conversions with high enantioselectivities
(Table 1, entry 2).
metric reduction of cyclic imines,[10] ring-contraction reac-
[12]
tions[11] or C H activation.
À
We now wish to report that a three-component reductive
amination using a novel 2-biphenyl-substituted benzothiazo-
line derivative as reducing agent leads to high yields and ste-
reoselectivities in the asymmetric synthesis of 1,3-disubsti-
tuted tetrahydroisoquinolines. We envisioned that a Brønst-
N-Triflylamide catalysts gave very good yields and reac-
tions rates, but unfortunately the asymmetric induction was
low in each case. A catalyst loading of 10 mol% was neces-
sary in order to obtain high yields, even though the stereose-
lectivity is only little affected when lower loadings are used
(Table 1, entry 5 and 6). Next, the effect of the solvent and
the type of hydride source was examined (Table 2). In
[a] Prof. Dr. D. Enders, Dipl.-Chem. J. X. Liebich, Prof. Dr. G. Raabe
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1,52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: enders@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001623.
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Table 1. Evaluation of the chiral Brønsted acid catalysts in the three-
The enantioselectivity of the reductive amination turned
out to be very temperature dependent. Therefore careful
monitoring of the reaction temperature was required. To
find out the optimal conditions for the cyclisation of the
amines obtained, several bases were screened, however,
component. reductive amination reaction of ketone 1.[a]
only strong bases such as 1,5-diazabicycloACHTNUTRGNEUNG[4.3.0]non-5-ene
(DBN) or potassium tert-butoxide were able to induce cycli-
zation (Table 3). When tBuOK was used the cyclization oc-
Table 3. Screening of bases for the aza-Michael cyclisation.
Entry
R
X
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
Ph3Si
OH
OH
NHTf
NHTf
OH
45
45
45
30
30
30
30
28
92
89
99
64
56
72
30
89
30
26
91
84
7
(2,4,6-iPr)Ph
(2,4,6-iPr)Ph
(2,4,6-iPr)Ph
(2,4,6-iPr)Ph
(2,4,6-iPr)Ph
3,5-CF3Ph
Entry
Base
Solvent
Yield [%][a]
d.r.[b]
5
6[d]
7
OH
NHTf
1
2
3
4
5
K2CO3
Et3N
DBN
tBuOK
tBuOK
H2O/Et2O
THF
toluene
Et2O
no reaction
no reaction
n.d.
no reaction
60
–
–
2:1.1
–
6:1
[a] Unless otherwise specified, the reactions were performed on
a
0.16 mmol scale of p-anisidine using 2 equiv of ketone 1, 1.4 equiv of
Hantzsch ester 2 and 10 mol% catalyst. [b] Yield of isolated amine 3.
[c] Determined by chiral stationary phase HPLC analysis. [d] 5 Mol% of
catalyst was used.
THF
[a] Yield of isolated 6. [b] Determined by NMR.
curred within seconds and gave exclusively the trans-diaste-
reomer of the desired tetrahydroisoquinoline product in
good yields. As a side product the corresponding tert-buty-
lester was also observed, obviously formed via transesterifi-
cation. Therefore in subsequent reactions the tert-butylacry-
late substituted ketone was used. We noticed that no cycliza-
tion occurred when older batches of tBuOK were employed
and only freshly sublimed reagent gave optimal results.
In order to test the substrate scope of the reaction several
methyl ketones bearing different a,b-unsaturated Michael
acceptors in ortho position were synthesized and used in the
reductive amination/aza-Michael sequence (Scheme 2,
Table 2. Effects of solvent and reducing agent in the reductive amination
reaction of ketone 1.[a]
Entry Solvent
T [8C] Reducing agent Yield [%][b] ee [%][c]
1
2
3
4
5
benzene
toluene
xylenes
mesitylene 30
mesitylene 50
30
30
30
2
2
2
2
5
79
64
38
74
98
88
91
89
93
88
Scheme 2. Three-component reductive amination/aza-Michael sequence.
[a] Unless otherwise specified, the reactions were performed on
a
0.16 mmol scale of p-anisidine using 2 equiv of ketone, 1.4 equiv of reduc-
ing agent and 10 mol% catalyst 4. [b] Yield of isolated amine 3. [c] De-
termined by chiral stationary phase HPLC analysis.
Table 4). In general, substitution on the aromatic ring had
no negative effects on the reaction even when doubly ortho-
substituted substrates were used. Also primary and secon-
dary acrylamides are possible substrates and can be convert-
ed to the corresponding tetrahydroisoquinolines (entry 4
and 5). In all cases complete trans-diastereoselectivity was
observed. Reactions on a larger scale (1.6 mmol) did not in-
fluence the selectivity or yield and for instance tetrahydro-
isoquinoline 8e could be synthesized in 81% yield (480 mg,
Table 4, entry 4). So far, the reaction is limited to methyl ke-
agreement with the previously reported results,[5,6] aromatic
and highly non-polar solvents gave the best results. Interest-
ingly, the substituted 2-biphenyl-substituted benzothiazole
derivate 5 proved to be more reactive as well as more selec-
tive as compared to the Hantzsch ester 2 thereby increasing
the yield and enantioselectivity of the reaction.
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Chem. Eur. J. 2010, 16, 9763 – 9766

Organocatalytic Asymmetric Synthesis
COMMUNICATION
tones, since all other synthesized derivatives show only low
conversion, most probably due to the slower imine forma-
tion.[14]
quent reaction with camphanic chloride.[16] Additionally, the
trans-configuration of the products was confirmed by
NOESY NMR measurements in each case (Figure 1).
Table 4. Scope of the reductive amination/aza-Michael sequence.[a]
Entry Ketone
Product Yield [%][b] ee [%][c] d.r.[d]
1
8a
8b
8c
93
87
93
94
96
94
>95:5
>95:5
>95:5
2
3
Figure 1. Determination of the relative (NOE) and absolute configura-
tion (X-ray).
In analogy to the previously reported results by Goodman
et al.[17] we propose a transition state in which the (Z)-imine
is protonated by the acidic phosphoric acid group while the
benzothiazoline coordinates with the Lewis basic oxygen
atom. The hydride is then transferred to the Si face of the
imine (see below).
4
5
8d
8e
81
97
93
98
>95:5
>95:5
[a] The reactions were performed on 0.25-1.6 mmol scale of p-anisidine
using 2 equiv of ketone, 1.4 equiv of reducing agent and 10 mol% cata-
lyst 4. See Supporting Information for details. [b] Yield of isolated 8.
[c] Determined by chiral stationary phase HPLC analysis. [d] Determined
by NMR spectroscopy.
Gratifyingly also indole-derived acrylates are possible
substrates for the three-component reductive amination/aza-
Michael sequence leading to the important class of b-carbo-
lines. When indole enoate 9 was subjected to the reaction
conditions, the corresponding trans-disubstituted b-carbon-
line 10 was obtained in 85% yield, >90% de, and 94% ee
(Scheme 3).
The absolute configuration of the stereogenic centers cre-
ated in the reductive amination step and the aza-Michael
addition was determined to be R by X-ray analysis of a cam-
phanoyl derivative,[15] which could be obtained by DIBAl-H
reduction of the tert-butyl ester moiety of 8a and subse-
In conclusion, we have developed an efficient organocata-
lytic reductive amination procedure using a biphenyl-substi-
tuted benzothiazoline as hydride source and employed it in
a reductive amination/aza-Michael sequence for the highly
diastereo- and enantioselective synthesis of trans-1,3-disub-
stituted tetrahydroisoquinolines. Starting from an indole-de-
rived keto enoate the corresponding trans-disubstituted b-
carboline is obtained as well in excellent yield and stereose-
lectivity.
Experimental Section
General procedure for the synthesis of trans-1,3-disubstituted tetrahy-
droisoquinolines: A flame-dried Schlenk tube was charged with p-anisi-
dine (1 equiv), ketone 7 (2 equiv), thiazoline 5 (1.4 equiv), chiral Brønst-
ed acid 4 (0.1 equiv) and activated 5 ꢂ molecular sieves. Dry mesitylene
(0.1m) was added and the reaction mixture was stirred at 408C until TLC
analysis indicated full conversion (usually 2–3 d). The crude product was
directly purified by column chromatography and then dissolved in THF
(0.1m). Freshly sublimed tBuOK was added at room temperature and the
Scheme 3. Extension of the methodology for the diastereo- and enantio-
selective synthesis of b-carbolines.
Chem. Eur. J. 2010, 16, 9763 – 9766
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9765

D. Enders et al.
reaction was quenched with brine after 1 min. Extraction with diethyl
ether and filtration through a plug of silica yielded the pure 1,3-disubsti-
tuted tetrahydroisoquinolines 8.
[4] For the reduction of ketimines, see: a) M. Rueping, E. Sugiono, C.
Azap, T. Theissmann, M. Bolte, Org. Lett. 2005, 7, 3781–3783; b) S.
Hoffmann, A. M. Seayad, B. List, Angew. Chem. 2005, 117, 7590–
7593; Angew. Chem. Int. Ed. 2005, 44, 7424–7427; c) M. Rueping,
A. P. Antonchick, T. Theissmann, Angew. Chem. 2006, 118, 3765–
3768; Angew. Chem. Int. Ed. 2006, 45, 3683–3686; d) M. Rueping,
A. P. Antonchick, T. Theissmann, Angew. Chem. 2006, 118, 6903–
6907; Angew. Chem. Int. Ed. 2006, 45, 6751–6755. For the reduction
of a-imino esters, see: e) G. L. Li, Y. X. Liang, J. C. Antilla, J. Am.
Chem. Soc. 2007, 129, 5830–5831; f) Q. Kang, Z. A. Zhao, S. L. You,
Adv. Synth. Catal. 2007, 349, 1657–1660; g) Q. Kang, Z. A. Zhao,
S. L. You, Org. Lett. 2008, 10, 2031–2031; h) G. Li, J. C. Antilla,
Org. Lett. 2009, 11, 1075–1078; for reviews, see: i) S. J. Connon,
Org. Biomol. Chem. 2007, 5, 3407–3417; j) S.-L. You, Chem. Asian
J. 2007, 2, 820–827.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (pri-
ority program Organocatalysis) and the Fonds der Chemischen Industrie.
We thank BASF AG for the donation of chemicals.
Keywords: asymmetric synthesis
· Michael addition ·
[5] a) R. Storer, D. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem.
Soc. 2006, 128, 84–86; b) S. Hoffmann, M. Nicoletti, B. List, J. Am.
Chem. Soc. 2006, 128, 13074–13075; for a theoretical study, see:
c) T. Marcelli, P. Hammar, F. Himo, Adv. Synth. Catal. 2009, 351,
525–529.
organocatalysis · phosphoric acid · reductive amination
[1] For selected recent reviews, see: a) A. Berkessel, H. Grçger, Asym-
metric Organocatalysis, Wiley-VCH, Weinheim, 2005; b) P. I. Dalko,
Enantioselective Organocatalysis: Reactions and Experimental Proce-
dures, Wiley-VCH, Weinheim, 2007; c) H. Pellissier, Tetrahedron
2007, 63, 9267–9331; d) Special issue on organocatalysis (Ed.: B.
List): Chem. Rev. 2007, 107, 5413–5883; e) R. Marcia De Figueiredo,
M. Christmann, Eur. J. Org. Chem. 2007, 2575–2600; f) D. Enders,
C. Grondal, M. R. M. Hꢃttl, Angew. Chem. 2007, 119, 1590–1601;
Angew. Chem. Int. Ed. 2007, 46, 1570–1581; g) A. Dondoni, A.
Massi, Angew. Chem. 2008, 120, 4716–4739; Angew. Chem. Int. Ed.
2008, 47, 4638–4660; h) D. Enders, A. A. Narine, J. Org. Chem.
2008, 73, 7857–7870; i) H. Kotsuki, H. Ikishima, A. Okuyama, Het-
erocycles 2008, 75, 757–797; j) H. Kotsuki, H. Ikishima, A. Okuya-
ma, Heterocycles 2008, 75, 493–529; k) P. Melchiorre, M. Marigo, A.
Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232–6265; Angew.
Chem. Int. Ed. 2008, 47, 6138–6171; l) K. A. Jørgensen, S. Bertelsen,
Chem. Soc. Rev. 2009, 38, 2178–2189; m) M. Bella, T. Gasperi, Syn-
thesis 2009, 1583–1614; n) C. Grondal, M. Jeanty, D. Enders, Nat.
Chem. 2010, 2, 167–178.
[2] For reviews on phosphoric acid catalysis, see: a) T. Akiyama, J. Itoh,
K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999–1010; b) T. Akiyama,
Chem. Rev. 2007, 107, 5744–5758; c) S. J. Connon, Angew. Chem.
2006, 118, 4013–4016; Angew. Chem. Int. Ed. 2006, 45, 3909–3912;
d) X. Yu, W. Wang, Chem. Asian J. 2008, 3, 516–532; e) T. Akiyama,
Acid Catalysis in Modern Organic Synthesis, Vol. 1 (Eds.: H. Yama-
moto, K. Ishihara), Wiley-VCH, Weinheim, 2008, pp. 62–107; f) M.
Terada, Chem. Commun. 2008, 4097–4112.
[6] C. Zhu, T. Akiyama, Org. Lett. 2009, 11, 4180–4183.
[7] a) J. R. F. Allen, B. R. Holmstedt, Phytochemistry 1980, 19, 1573–
1582; b) V. G. Kartsev, Med. Chem. Res. 2004, 13, 325–336; c) K. W.
Bentley, Nat. Prod. Rep. 2006, 23, 444–463, and references therein;
d) L. Grycovꢄ, J. Dost, R. Marek, Phytochemistry 2007, 68, 150–
175.
[8] For the asymmetric synthesis of isoquinoline alkaloids, see: a) M.
Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104, 3341–
3370; b) J. D. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669–
1730; c) P. Siengalewicz, U. Rinner, J. Mulzer, Chem. Soc. Rev. 2008,
37, 2676–2690.
[9] For the synthesis of 1,3-substituted derivatives, see: a) P. Magnus,
K. S. Matthews, V. Lynch, Org. Lett. 2003, 5, 2181–2184; b) T. S.
Kaufman, Synthesis 2005, 339–360; c) J. Eustache, P. Van de Weghe,
D. Le Nouen, H. Uyehara, C. Kabuto, Y. J. Yamamoto, J. Org.
Chem. 2005, 70, 4043–4053; d) R. Ferraccioli, C. Giannini, G. Mol-
teni, Tetrahedron: Asymmetry 2007, 18, 1475–1480.
[10] L. Evanno, J. Ormala, P. Pihko, Chem. Eur. J. 2009, 15, 12963–
12967.
[11] J. Zhang, A. Zhang, Chem. Eur. J. 2009, 15, 11119–11122.
[12] J. J. Li, T.-S. Mei, J.-Q. Yu, Angew.Chem. 2008, 120, 6552–6555;
Angew. Chem. Int. Ed. 2008, 47, 6452–6455.
[13] G. Adair, S. Mukherjee, B. List, Aldrichim. Acta 2008, 41, 31–39.
[14] For example the corresponding ethyl ketone of 7e could be reduced
with 92% ee but only 23% yield was obtained.
[15] CCDC-773769 contains the supplementary crystallographic data for
this paper (excluding structure factors). These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[3] a) T. Ohkuma, M. Kitamura, R. Noyori in Catalytic Asymmetric
Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000,
Chapter 1; b) H. Nishiyama, K. Itoh in Catalytic Asymmetric Synthe-
sis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, Chapter 2;
c) T. Ohkuma, R. Noyori in Comprehensive Asymmetric Catalysis,
Suppl. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
New York, 2004; d) For an account on asymmetric reductive amina-
tions, see: V. I. Tararov, A. Bçrner, Synlett 2005, 203–211.
[16] See the Supporting Information for details.
[17] L. Simꢅn, J. M. Goodman, J. Am. Chem. Soc. 2008, 130, 8741–8747.
Received: June 9, 2010
Published online: July 26, 2010
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