An asymmetric organocatalytic approach towards allylic amines and β-keto amino compounds

Article abstract of DOI:10.1039/b915439f

The enantioselective organocatalysed addition of β-keto benzothiazolesulfones to N-Boc-protected imines, leading to intermediates easily transformed into optically active allylic amines or β-keto amino compounds, is presented. The Royal Society of Chemist

Full text of DOI:10.1039/b915439f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
An asymmetric organocatalytic approach towards allylic amines
and b-keto amino compoundsw
Christian Borch Jacobsen, Lennart Lykke, David Monge, Martin Nielsen,
Lars Krogager Ransborg and Karl Anker Jørgensen*
Received (in Cambridge, UK) 29th July 2009, Accepted 22nd August 2009
First published as an Advance Article on the web 10th September 2009
DOI: 10.1039/b915439f
The enantioselective organocatalysed addition of b-keto
benzothiazolesulfones to N-Boc-protected imines, leading to
intermediates easily transformed into optically active allylic
amines or b-keto amino compounds, is presented.
A major goal in chemistry is the development of novel
transformations giving rise to enantioenriched products. The
stereoselective formation of allylic amines and b-keto amino
compounds are of special interest as these compounds are of
high value for e.g. in the life-science industry and are readily
transformed into a number of important products.
Scheme
1
Organocatalytic formation of optically active allylic
amines and b-keto amino compounds (BT = benzothiazole).
Traditionally, the task of forming optically active allylic
amines in an enantioselective catalytic manner has been
carried out by employing metal-catalysed allylic substitutions1
or pre-activated boron-based nucleophiles.2 The few existing
enantioselective organocatalytic examples in general comprise
desulfonylation reactions give the optically active Mannich
products 5. As previously described, accessing these
acetophenone-derived Mannich products in an organocatalytic
manner has been a difficult task, often leading to discouraging
outcomes.4 Therefore, an alternative protocol for the formation
of these compounds is very attractive.
alkenes adjacent to
a
conjugate electron-withdrawing
substituent,3 which limits the scope of compounds that can
be synthesised. Thus, it is important to develop diverse
procedures towards the allylic amine scaffold, giving access
to products otherwise difficult to obtain with a stereoselective
organocatalytic approach.
Previous studies have shown that thiourea-based catalysts
are prime specimens for conducting the activation of
N-Boc-protected imines towards nucleophilic attack in a
highly enantioselective manner.7 Hence, we performed our
initial screening (Table 1) using these catalysts.
Accessing enantioenriched molecules containing the important
b-keto amino functionality, by conducting organocatalytic
Mannich reactions, have received great attention.4 Given the
usefulness of this functionality it is of interest to develop new
versatile routes leading to new classes of optically active b-keto
amino compounds.
Table 1 Screening results for the enantioselective addition of 2a to 1a
catalysed by 6a
Herein, we disclose a new type of organocatalytic approach
towards synthetic applications of aryl imines, which may ease
e.g. combinatorial studies and total synthesis procedures.
Thus, the vision is to organocatalytically form a privileged
key intermediate, which is easily transformed into various
compounds based on a common carbon skeleton, otherwise
difficult to access in a stereoselective organocatalytic manner.
We envisioned that employing the heteroaryl b-ketosulfones
25 to react with N-Boc-protected imines 1 under organo-
catalytic conditions would allow us to produce the enantio-
enriched key intermediate 3 (Scheme 1). Under mild reductive
conditions, 3 can be transformed to optically active allylic
Entry
Solvent
T/1C
Time/h
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
CH2Cl2
À30
À30
À30
À30
À30
À30
À30
À30
À40
À40
18
24
48
24
42
24
24
48
72
54
Full
0
Full
Full
80
Full
Full
Full
Full
Full
70
n.d.
76
37
67
57
30
83
89
80
Toluene
Acetone
CHCl3
CH3CN
THF
Et2O
Propionitrile
Propionitrile
Propionitrile
amines
4 via a
Smiles rearrangement,5,6 while various
9
10d
a
All reactions performed on a 0.10 mmol scale (0.20 M) using 1a
b
(0.25 mmol), 2a (0.10 mmol) and 6 (0.01 mmol). Determined by
Center for Catalysis, Department of Chemistry, Aarhus University,
DK-8000 Aarhus C, Denmark. E-mail: kaj@chem.au.dk;
Fax: +45 8619 6199; Tel: +45 8942 3910
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data. See DOI: 10.1039/b915439f
1H NMR. Determined by chiral stationary-phase HPLC after
c
d
reduction with NaBH4 (see ESIw). Run as 0.40 M.
ꢀc
This journal is The Royal Society of Chemistry 2009
6554 | Chem. Commun., 2009, 6554–6556

View Article Online
Preliminary results showed that catalyst 6 was superior
in conducting the enantioselective reaction between the
N-Boc-protected imine 1a and the b-keto benzothiazole-based
nucleophile 2a (see ESIw for additional screening results).
A survey of the reaction parameters was performed, leading
to the finding that pre-dried propionitrile was the solvent of
choice, as full conversion was achieved and the enantiomeric
excess was superior to that obtained in other solvents (Table 1,
entries 1–8). Lowering the reaction temperature further
increased the enantioselectivity and the addition intermediate
3a was formed in 89% ee (entry 9). Increasing the concentration
led to a shorter reaction time, however, the enantioselectivity
was also slightly decreased to 80% ee (entry 10).
Table 2 Scope of the one-pot formation of allylic amines 4a
Yield
(%)
eec
Entry
1
Imine 1
Sulfone 2
E : Zb (%)
4a-63 9 : 1
89
With these optimised reaction conditions in hand, we
investigated the possible transformations of the privileged
key intermediate 3. As predicted, mild reductive conditions
provided the formation of the allylic amines 4 in a one-pot
procedure (Table 2). It was found that a change of solvent to
CH2Cl2 between the organocatalytic step and the reduction
was necessary in order to obtain the allylic amines 4 with
excellent E–Z-selectivity (See ESIw).
2
4b-65 12 : 1 90
3d
4d
5
4c-61 13 : 1 84
Employing nucleophiles 2a–c showed that the outcome of
the reactions was reasonably independent of aromatic
substitution pattern and the optically active allylic amines
4a–c were formed in good yields and enantioselectivities
(Table 2, entries 1–3). However, ortho-substituted nucleophiles
proved to be unreactive in the present catalytic system, unless
the temperature was increased significantly leading to inferior
enantioselectivity. The ring-expanded naphthyl-based
nucleophile 2d also gave rise to the corresponding allylic
amine 4d (entry 4) in good yield and enantioselectivity.
Interestingly, nucleophiles having electron-deficient aromatic
moieties can be employed as shown by the utilisation of
meta-chloro-substituted substrate 2e (entry 5). Employment
of the more electron rich ortho-substituted imine 1b improved
the enantioselectivity of the allylic amine 4f to an excellent
96% ee (entry 6 vs. entry 1) with a 61% yield. Importantly,
imines bearing an electron-deficient aromatic moiety can also
be employed as shown with ortho-bromo imine 1c, which gives
rise to 4g, formed exclusively as the E-isomer, in moderate
yield and high enantioselectivity (entry 7). Finally, the reaction
can also be performed with heteroaromatic imines and the
thiophene-based imine 1d gave rise to its corresponding allylic
amine 4h in good yield albeit with moderate enantioselectivity
(entry 8). It should be noted that in all cases good to excellent
E–Z-selectivities were obtained. It was found that alkyl-based
b-ketosulfones 2 were unreactive under the given conditions.
In order to show further possible transformations, the
key intermediate 3 (Scheme 1) was subjected to different
desulfonylation reaction conditions, obtaining two classes of
highly valuable Mannich-type products (Scheme 2). Treating 3
with sodium ethanethiolate furnished the N-Boc-protected
b-keto amines 5a–c in generally good to excellent yields
(Scheme 2, upper reaction). Importantly, the enantio-
selectivities of 5a–c were only slightly reduced compared to
the enantioselectivities of the allylic amines 4. To the best of
our knowledge, this process constitutes the most efficient and
general procedure for making these N-Boc-protected aceto-
phenone-derived Mannich products with an organocatalytic
4d-65 9 : 1
85
4e-54 10 : 1 82
6
4f-61 10 : 1 96
420 :
1
7e
4g-42
87
58
8d
4h-65 n.d.f
a
All reactions performed on
propionitrile) using 1 (0.25 mmol), 2 (0.10 mmol) and 6 (0.01 mmol)
a
0.10 mmol scale (0.20 M in
at À40 1C. Determined by 1H NMR. Determined by chiral
b
c
d
e
stationary-phase HPLC. Reactions performed at À30 1C. Reaction
f
performed at 0 1C. In both NMR and GC, the signals overlapped.
approach, in terms of yield, enantioselectivity or catalyst
loading.4a–c,f
Treating the intermediate 3 with TFA resulted in N-Boc-
deprotection, after which an intramolecular nitrogen-based
Smiles rearrangement between the BT-group and the primary
amine is proposed to occur, leading to the b-keto amino
compounds 5d–f (Scheme 2, lower reaction). These products
contain the highly valuable 2-aminobenzothiazole moiety,8
often present in biologically active compounds.9 The
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6554–6556 | 6555

View Article Online
P. Diner and K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128,
12973; (c) S. Kobbelgaard, S. Brandes and K. A. Jørgensen,
Chem.–Eur. J., 2008, 14, 1464; (d) C. Cassani, L. Bernadi,
F. Fini and A. Ricci, Angew. Chem., Int. Ed., 2009, 48, 5694;
(e) G. Ma, S. Cao and M. Shi, Tetrahedron: Asymmetry, 2009, 20,
1086; (f) T. Zhang, L. Dai and X. Hou, Tetrahedron: Asymmetry,
2007, 18, 1990; (g) Z. Wang, X. Ye, S. Wei, P. Wu, A. Zang and
J. Sun, Org. Lett., 2006, 8, 999.
4 For recent reviews see: (a) M. M. B. Marques, Angew. Chem., Int.
Ed., 2006, 45, 348; (b) A. Ting and S. E. Schaus, Eur. J. Org.
Chem., 2007, 5797; (c) J. M. M. Verkade, L. J. C. van Hemert,
P. J. L. M. Quaedflieg and F. P. J. T. Rutjes, Chem. Soc. Rev.,
2008, 37, 29; For selected recent examples see: (d) M. Terada,
K. Machioka and K. Sorimachi, Angew. Chem., Int. Ed., 2006, 45,
2254; (e) N. S. Chowdari, M. Ahmad, K. Albertshofer, F. Tanaka
and C. F. Barbas III, Org. Lett., 2006, 8, 2839; (f) A. L. Tillman
and D. J. Dixon, Org. Biomol. Chem., 2007, 5, 606; (g) M. Rueping,
E. Sugiono and F. Schoepke, Synlett, 2007, 1441; (h) D. Uraguchi,
Y. Ueki and T. Ooi, J. Am. Chem. Soc, 2008, 130, 14088;
(i) J. W. Yang, C. Chandler, M. Stadler, D. Kampen and
B. List, Nature, 2008, 452, 453; (j) H. Yang and R. G. Carter,
J. Org. Chem., 2009, 74, 2246; (k) P. Dziedzic, P. Schyman,
M. Kullberg and A. Cordova, Chem.–Eur. J., 2009, 15, 4044.
5 M. Nielsen, C. B. Jacobsen, M. W. Paixao, N. Holub and
K. A. Jørgensen, J. Am. Chem. Soc., 2009, 131, 10581.
Scheme 2 Transformation of intermediate 3 into optically active
b-keto amino compounds 5.
products 5d–f were obtained in good to excellent yields and
enantiomeric excess. Moreover, both desulfonylation methods
presented here represent, to the best of our knowledge, the first
reactions of this type performed in an organomediated manner.10
The absolute configurations of the products 4 and 5 were
correlated to the absolute configuration of 5b, which was
determined to be R by comparison with the literature.11
In conclusion, we have reported a new enantioselective
organocatalytic addition of b-keto benzothiazolesulfones to
N-Boc-protected imines. The resultant key intermediate can
easily be transformed into optically active trans-allylic amines,
absent of a conjugate electron-withdrawing substituent, or
optically active b-keto amino compounds in good yields and
enantioselectivities.
6 C. Aıssa, Eur. J. Org. Chem., 2009, 1831.
7 For recent reviews see e.g.: (a) A. G. Doyle and E. N. Jacobsen,
Chem. Rev., 2007, 107, 5713; (b) Z. Zhang and P. R. Schreiner,
Chem. Soc. Rev., 2009, 38, 1187.
8 For a recent article concerning the synthesis of compounds containing
this moiety see: G. W. Stewart, C. A. Baxter, E. Cleator and
F. J. Sheen, J. Org. Chem., 2009, 74, 3229.
9 For a few recent examples see: As HIV-1 protease inhibitors:
(a) D. L. N. G. Surleraux, H. A. Kock, W. G. Verschueren,
G. M. E. Pille, L. J. R. Maes, A. Peeters, S. Vendeville,
S. D. Meyer, H. Azijn, R. Pauwels, M. Bethune, N. M. King,
M. Prabu-Jeyabalan, C. A. Schiffer and P. B. T. P. Wigerinck,
J. Med. Chem., 2005, 48, 1965; As vanilloid receptor-1 antagonists:
(b) E. M. Doherty, C. Fotsch, A. W. Bannon, Y. Bo, N. Chen,
C. Dominguez, J. Falsey, N. R. Gavva, J. Katon, T. Nixey,
V. I. Ognyanov, L. Pettus, R. M. Rzasa, M. Stec, S. Surapaneni,
R. Tamir, J. Zhu, J. J. S. Treanor and M. H. Norman, J. Med.
Chem., 2007, 50, 3515; As c-Src kinase and nitric oxide synthase
inhibitors: (c) X. Cao, Q. You, Z. Li, Q. Guo, J. Shang, M. Yan,
J. Chernc and M. Chenc, Bioorg. Med. Chem., 2008, 16, 5890; As
CYP26 inhibitors see: (d) M. S. Gomaa, J. L. Armstrong,
B. Bobillon, G. J. Veal, A. Brancale, C. P. F. Redfern and
C. Simons, Bioorg. Med. Chem., 2008, 16, 8301.
This work was made possible by a grant from The Danish
National Research Foundation, OChemSchool and Carlsberg
Foundation. D.M. thanks the ‘‘Ministerio de Ciencia e
Innovacion’’ of Spain for a postdoctoral fellowship.
Notes and references
1 For reviews on allylic amination see e.g.: (a) M. Johannsen and
K. A. Jørgensen, Chem. Rev., 1998, 98, 1689; (b) B. M. Trost and
M. L. Crawley, Chem. Rev., 2003, 103, 2921.
2 For recent examples see e.g.: (a) S. Lou and S. E. Schaus, J. Am.
Chem. Soc., 2008, 130, 6922; (b) J. A. Bishop, S. Lou and
S. E. Schaus, Angew. Chem., Int. Ed., 2009, 48, 4337; (c) K. Brak
and J. A. Ellman, J. Am. Chem. Soc., 2009, 131, 3850.
10 For a review on desulfonylation reactions see: C. Najera and
M. Yus, Tetrahedron, 1999, 55, 10547.
11 The absolute configuration was determined to be R by comparison
of the specific rotation of 5b with the literature: A. L. Tillman and
D. J. Dixon, Org. Biomol. Chem., 2007, 5, 606.
3 (a) T. B. Poulsen, C. Alemparte and K. A. Jørgensen, J. Am. Chem.
Soc., 2005, 127, 11614; (b) S. Bertelsen, M. Marigo, S. Brandes,
ꢀc
This journal is The Royal Society of Chemistry 2009
6556 | Chem. Commun., 2009, 6554–6556