First highly enantioselective synthesis of benzodiazepinones by catalytic hydrogenation

Article abstract of DOI:10.1002/adsc.201000547

The first catalytic enantioselective synthesis of benzodiazepinones employing an efficient hydrogenation protocol has been developed. The corresponding products are obtained in good yields, with excellent enantioselectivities and broad functional group tolerance. In addition, a one-pot procedure involving in situ generation of benzodiazepin-2-ones followed by asymmetric reduction is presented.

Full text of DOI:10.1002/adsc.201000547

FULL PAPERS
DOI: 10.1002/adsc.201000547
First Highly Enantioselective Synthesis of Benzodiazepinones by
Catalytic Hydrogenation
Magnus Rueping,a,* Estꢀbaliz Merino,a and Renꢁ M. Koenigsa
a
Institute of Organic Chemistry, RWTH-Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2665; phone: (+49)-241-809-4710; e-mail: Magnus.Rueping@rwth-aachen.de
Received: July 12, 2010; Published online: October 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000547.
Abstract: The first catalytic enantioselective synthe- volving in situ generation of benzodiazepin-2-ones
sis of benzodiazepinones employing an efficient hy- followed by asymmetric reduction is presented.
drogenation protocol has been developed. The corre-
sponding products are obtained in good yields, with Keywords: b-amino acids; asymmetric hydrogena-
excellent enantioselectivities and broad functional tion; Brønsted acids; enantioselective reduction;
group tolerance. In addition, a one-pot procedure in- Hantzsch dihydropyridines; organocatalysis
Introduction
cused their efforts on their synthesis[13] and characteri-
zation.[14] In this context, despite several existing
Benzodiazepines are a family of psychotherapeutic methods for the synthesis of 4-substituted-4,5-dihy-
agents widely used for the treatment of anxiety neu- dro-1H-[1,5]benzodiazepin-2(3H)-ones,[13a,d,i,14c] which
rosis and insomnia.[1] Their ability to selectively bind resemble cyclic b-amino acids, an enantioselective ap-
to specific receptors[2] promotes them as a class of proach has not yet been described. So far chiral 4-sub-
privileged structures in medicinal chemistry.[2b] Fur- stituted derivatives are obtained from the racemic
thermore, the affinity for different receptor sites com- mixtures via resolution with d-(+)-3-bromocamphor-
bined with distinct dosages has considerably broad- 8-sulfonic acid.[14c]
ened the application field of benzodiazepines. Nowa-
Herein we report the first highly enantioselective
days, beside the aforementioned utilizations, the ther- reduction of 4-substituted-1H-[1,5]benzodiazepin-
apeutic applications of these compounds include their 2(3H)-ones. Initially, our work focused on the evalua-
usage as clinical anesthetics, dental sedatives, muscle tion of different chiral Ir, Rh and Ru catalysts in the
relaxants, analgesics, antidepressants, antiepileptic high-pressure hydrogenation of 1. However, these re-
drugs and as a substitute for alcohol in alcohol with- ductions so far did not deliver the desired results with
drawal.[3] Furthermore, benzodiazepines and deriva- regard to high reactivity and only low enantioselectiv-
tives showed activity as potential blood pressure regu- ities were observed.
lators,[4] anticancer agents (inhibitors of farnesyl pro-
tein transferase),[5] CCK antagonists,[6] inhibitors of
HIV replication[7] and of the caspase-3 protease.[8]
Although various benzodiazepine core structures
Results and Discussion
are known,[9] most of these biologically active com- Recently, we developed a biomimetic, Brønsted
pounds contain a [1,4]benzodiazepin or a [1,4]benzo- acid[15]-catalyzed enantioselective transfer hydrogena-
diazepin-2-one framework. In spite of the fact that tion employing dihydropyridines as the hydride
the first two synthesized benzodiazepines[10] are be- source.[16–18] The transformation proved to be applica-
longing to the 4,5-dihydro-1H-[1,5]benzodiazepin- ble to a large range of acyclic as well as cyclic sub-
2(3H)-one class, which is also represented by the bio- strates containing carbon-nitrogen double bonds.[17]
logically active lofendazam[11] and arfendazam,[11d,e,12] Thus, our preliminary investigation concentrated on
this group of compounds was less investigated. How- finding a suitable Brønsted acid catalyst for the enan-
ever, 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones tioselective reduction of 4-substituted-1H-[1,5]benzo-
recently attracted attention and several groups fo- diazepin-2(3H)-ones (Scheme 1). The initial reactions
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prisingly, the anthracenyl, SiACTHUNRTGNE(UNG C6H5)3, 2,4,6-(CH3)3-
C6H2 and 3,5-(CF3)2C6H4 derivatives afforded the op-
posite enantiomer, yet in almost racemic form
(Table 1, entries 6, 7, 9 and 10).
Further studies focused on the influence of other
reactions parameters, including different solvents,
concentrations and temperatures. The best result with
respect to the enantioselectivity was obtained when
the reaction was performed with the N-triflyl phos-
phoramide 4b and dihydropyridine 2a in methyl tert-
Scheme 1. Reduction of 4-substituted-1H-[1,5]benzodiaze-
pin-2(3H)-ones.
were conducted with various chiral phosphoric acid butyl ether (MTBE) at 508C (Table 2 entry 7 vs. en-
diesters in toluene at different temperatures. Howev- tries 1–6). A slight increase in the selectivity was ob-
er, due to the basic nature of 1 only very low conver- tained by using a more diluted solution (Table 2 en-
sion was observed. Improved reactivity was finally ob- tries 8 and 9).
tained when the corresponding N-triflyl phosphor-
However, under these conditions only few sub-
ACHTUNGTRENNUNG
amides were employed as catalysts.[19,20] Among all N- strates afforded full conversion. In order to improve
triflyl phosphoramides investigated promising results the yields microwave irradiation[21] proved to be bene-
were achieved when 2-naphthyl-, phenyl- and p- ficial and the reduction of 1b to the desired product
MeOC6H4-substituted derivatives were used in con- 3b proceeded efficiently and, after subsequent acyla-
junction with the allyl Hantzsch ester 2a (Table 1, en- tion, 5b was isolated in 95% yield and with excellent
tries 2, 3 and 11). Slightly lower selectivities have enantiomeric excess of 94% ee (Table 3).[22]
been obtained when 1-naphthyl-, biphenyl-, phenan-
With the optimized conditions in hand we explored
thryl- and Br-substituted phosphoramides were em- the scope of the Brønsted acid-catalyzed transfer hy-
ployed as catalysts (Table 1, entries 1, 4, 5 and 8). Sur- drogenation of 4-aryl-substituted 1H-[1,5]benzodiaze-
pin-2(3H)-ones (Table 3). The reaction proved to be
general with respect to the substitution pattern of the
benzene ring and phenyl substituent affording the
acylated benzodiazepin-2-ones 5 in good yields and
with excellent enantioselectivities (83–99% ee).[23] Re-
garding the substitution pattern of the benzene ring,
the 7-substituted benzodiazepin-2-one substrates af-
Table 1. Evaluation of different catalysts and Hantzsch
esters in the reduction of 4-substituted-1H-[1,5]benzodiaze-
pin-2(3H)-ones.
Table 2. Influence of solvent and substrate concentration on
the enantioselective reduction of 4-substituted-1H-[1,5]ben-
zodiazepin-2(3H)-ones.
Entry[a]
Catalyst
R
ee[b]
Entry[a]
Solvent
Concentration
ee[b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
1-naphthyl
2-naphthyl
phenyl
biphenyl
phenanthryl
anthracenyl
51
68
63
58
46
-3
-1
54
-1
1
2
3
4
5
6
7
8
THF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.3
0.1
0.05
68
71
57
67
74
72
87
89
90
73
toluene
MeCN
CHCl3
CH2Cl2
n-Bu2O
MTBE
MTBE
MTBE
MTBE
Si
Br
(C6H5)3
9
10
11
2,4,6-(CH3)3-C6H2
3,5-(CF3)2C6H4
p-MeOC6H4
4j
4k
-13
64
9
10
[a]
[a]
Reaction conditions: 1,5-benzodiazepin-2-one, Hantzsch
ester (2.0 equiv.), 5 mol% of catalyst 4 in THF at 508C.
Determined by HPLC analysis on a chiral phase.
Reaction conditions: 1,5-benzodiazepin-2-one, Hantzsch
ester (2.0 equiv.), 5 mol% of catalyst 4b at 508C.
Determined by HPLC analysis on a chiral phase.
[b]
[b]
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Adv. Synth. Catal. 2010, 352, 2629 – 2634

First Highly Enantioselective Synthesis of Benzodiazepinones by Catalytic Hydrogenation
Table 3. Scope of the enantioselective Brønsted acid-catalyzed reduction of 4-substituted-1H-
[1,5]benzodiazepin-2(3H)-ones.[a,b,c]
[a]
The reduction was performed with 1H-[1,5]-benzodiazepin-2(3H)-one 1, Hantzsch ester 2a
(2.0 equiv.) and 5 mol% of catalyst 4b in MTBE at 508C (MW).
[b]
Yield of isolated product after column chromatography.
Enantiomeric excess was determined by HPLC on a chiral stationary phase.[22]
[c]
forded products in higher yields when compared to yield, the substrates bearing chloro-substituents on
the 8-substituted ones. Generally, in terms of reaction the benzene ring, performed better in the reduction
Adv. Synth. Catal. 2010, 352, 2629 – 2634
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Magnus Rueping et al.
FULL PAPERS
Based on this structure, the absolute configuration
was assigned as (S) (Figure 1).
Conclusions
In summary, we have developed a highly enantiose-
lective, hydrogenation of 1H-[1,5]benzodiazepin-
2(3H)-ones. This method represents the first enantio-
selective reduction of these substrates and provides
the corresponding valuable biologically active 4,5-di-
hydro-1H-[1,5]benzodiazepin-2(3H)-ones, which re-
semble cyclic b-amino acids, in good yields and with
excellent enantioselectivities (87–99% ee). Further-
more, we were able to extend this method to conduct
Scheme 2. One-pot synthesis of (4S)-5-acetyl-7,8-dichloro-4-
phenyl-4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-one (5p).
Reduction of the preformed benzodiazepine 1p afforded
the product 5p in 71% yield and 96% ee.
[a]
reaction compared to the bromo-substituted ones. an efficient one-pot reaction involving a condensation
Electronic effects of the phenyl substituent played a reaction followed by the catalytic enantioselective hy-
role in the case of 7,8-disubstituted substrates. Where- drogenation. It should also be noted that the metal-
as the selectivities were essentially the same, the yield free hydrogenation is also compatible with various
was influenced by the substituent of the phenyl ring halogenation patterns enabling easy variation of both
with higher yields being obtained with an electron- the aryl substituent as well as the benzodiazapinone
withdrawing group. It is important to stress that, in core. A further benefit of this method is that the nitro
contrast to most transition metal-catalyzed reactions, functionality has been shown to be entirely stable
the newly developed metal-free transfer hydrogena- under the reaction conditions described.
tion not only tolerates halogen substituents but also,
and equally important, nitro functionalities.
Thus, attractive features of this transformation in-
clude the mild reaction conditions, operational sim-
As an extension of this work, we wondered whether plicity and practicability, a broad substrate scope and
the unsaturated benzodiazepine-2-ones 1 could be functional group tolerance.
generated in situ and subsequently reduced and pro-
tected without the isolation of the intermediates. For
this purpose benzodiazepine-2-one 1p was synthesized Experimental Section
starting from diamine
6
and b-keto ester
7
(Scheme 2). The reaction was performed under micro- General Procedure for the Benzodiazepine Reduction
wave irradiation at 1508C. After 1.5 h catalyst 4b,
Hantzsch ester 2a and solvent were added and the re-
Benzodiazepine, N-triflyl phosphoramide 4b (5 mol%) and
Hantzsch ester dihydropyridine (2.0 equiv.) were suspended
action mixture was stirred for 16 h at 508C. After ace-
tylation, we isolated the product 5p in 56% yield with
the same enantioselectivity (95% ee) as obtained for
the preformed substrate 1p.
The absolute configuration of the products was de-
termined by X-ray crystal structure analysis of 5f.
in MTBE (0.1M) in a test tube. The reaction mixture was
heated under microwave irradiation at 508C (reaction times
are indicated in the Supporting Information). The solvent
was evaporated and the crude reaction mixture was dis-
solved in DMF (0.1M). Pyridine (3 equiv.) and acetyl chlo-
ride (3 equiv.) were added and the reaction mixture was
stirred at room temperature for 2 h. The solution was
poured into water and extracted with EtOAc (3ꢃ15 mL).
The combined organic phase was washed with satutated
aqueous NaCl, dried over MgSO4 and evaporated. The resi-
due was purified by column chromatography.
(4S)-5-Acetyl-4-(4-nitrophenyl)-4,5-dihydro-1H-
[1,5]benzodiazepin-2(3H)-one (5b)
The title compound was synthesized according to the gener-
al procedure. Acetylbenzodiazepinone 5b was obtained as a
white solid (1st step 12 h); yield: 95%, mp >2508C;
1H NMR (400 MHz, CDCl3): d=8.95 (bs, 1H), 8.18 (d, J=
8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.47 (dd, J=7.7 and
1.4 Hz, 1H), 7.33–7.28 (m, 2H), 7.13 (dd, J=7.8 and 1.3 Hz,
1H), 6.33 (dd, J=13.8 and 4.8 Hz, 1H), 2.97 (t, J=13.6 Hz,
1H), 2.69 (ddd, J=13.1, 4.9 and 1.7 Hz, 1H), 1.80 (s, 3H);
Figure 1. Molecular structure of 5-acetyl-8-bromo-4-(4-nitro-
phenyl)-4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-one 5f.
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Adv. Synth. Catal. 2010, 352, 2629 – 2634

First Highly Enantioselective Synthesis of Benzodiazepinones by Catalytic Hydrogenation
13C NMR (75 MHz, CDCl3): d=171.83, 170.54, 147.52,
[5] a) G. L. James, J. L. Goldstein, M. S. Brown, T. E.
147.03, 136.17, 132.43, 131.21, 129.98, 127.64 (2C), 126.73,
Rawson, T. C. Somers, R. S. McDowell, C. W. Crowley,
B. K. Lucas, A. D. Levinson, J. C. Marsters Jr, Science
1993, 260, 1937–1942; b) R. M. J. Liskamp, Angew.
Chem. 1994, 106, 313–315; Angew. Chem. Int. Ed.
Engl. 1994, 33, 305–307.
˜
123.99 (2C), 123.31, 60.53, 38.89, 22.95; IR (capillary): n=
3065, 2917, 1659, 1599, 1516, 1499, 1435, 1374, 1344, 1107,
1035, 853, 809, 765, 713, 695 cmÀ1; MS (EI) m/z (%)=325.3
(11) [M]+, 282.3 (12), 240.0 (32), 194.1 (20), 132.1 (51), 119.1
(100), 107.2 (23), 91.1 (14), 77.1 (16), 63.0 (10), 51.1 (14);
[a]rD:t:: +51.60 (c 1.75, CHCl3, 94% ee); HPLC (conditions:
AD-H column, n-hexane/2-propanol=80/20, flow rate=
1.0 mLminÀ1): minor enantiomer: tR =22.1 min; major enan-
tiomer: tR =26.9 min.
[6] I. M. McDonald, C. Austin, I. M. Buck, D. J. Dunstone,
E. Griffin, E. A. Harper, R. A. D. Hull, S. B. Kalind-
jian, I. D. Linney, C. M. R. Low, M. J. Pether, J. Spenc-
er, P. T. Wright, T. Adatia, A. Bashall, J. Med. Chem.
2006, 49, 2253–2261, and the references cited therein.
[7] a) M.-C. Hsu, A. D. Schutt, M. Holly, L. W. Slice, M. I.
Sherman, D. D. Richman, M. J. Potash, D. J. Volsky,
Science 1991, 254, 1799–1802; b) H. J. Breslin, M. J.
Kukla, D. W. Ludovici, R. Mohrbacher, W. Ho, M. Mir-
anda, J. D. Rodgers, T. K. Hitchens, G. Leo, D. A.
Gauthier, C. Y. Ho, M. K. Scott, E. De Clercq, R. Pau-
wels, K. Andries, M. A. C. Janssen, P. A. Janssen, J.
Med. Chem. 1995, 38, 771–793.
Acknowledgements
The authors thank the Ministerio de Ciencia e Innovaciꢀn
(Spain) and the Fonds der Chemischen Industrie for stipends
given to E.M and R.M.K.
[8] N. Micale, R. Vairagoundar, A. G. Yakovlev, A. P. Kozi-
kowski, J. Med. Chem. 2004, 47, 6455–6458.
References
[9] Chemistry of Heterocyclic Compounds: A Series Of
Monographs. Chemistry of Heterocyclic Compounds:
Bicyclic Diazepines: Diazepines with an Additional
Ring, Volume 50, (Ed.: R. I. Fryer), John Wiley &
Sons, Inc., New York, Chichester, Brisbane, Toronto,
Singapore, 1991.
[10] a) G. B. Bachman, L. V. Heisey, J. Am. Chem. Soc.
1949, 71, 1985–1988; b) W. Ried, G. Urlass, Chem. Ber.
1953, 86, 1101–1106.
[11] a) O. Bub, Ger. Offen. DE 1913536, 1970; b) A. Bauer,
H. Merz, K. Zeile, P. Danneberg, K. H. Weber, R. Gie-
semann, Ger. Offen. DE1929656, 1970; c) A. Bauer,
K. H. Weber, M. Unruh, 1972, 305, 557–570; d) E. Mu-
eller, Pharmacopsychiatry 1985, 18, 10–11; e) W. E.
Mueller, B. Groh, O. Bub, H. P. Hofmann, H. Kreis-
kott, Pharmacopsychiatry 1986, 19, 314–315.
[1] a) L. H. Sternbach, Angew. Chem. 1971, 83, 70–79;
Angew. Chem. Int. Ed. Engl. 1971, 10, 34–43; b) M.
Lancel, A. Steiger, Angew. Chem. 1999, 111, 3024–
3037; Angew. Chem. Int. Ed. 1999, 38, 2852–2864;
c) R. R. Nadendla, in: Principles of Organic Medicinal
Chemistry, New Age International Ltd., New Dehli,
2005, pp 74–76.
[2] a) D. A. Horton, G. T. Boume, M. L. Smythe, Chem.
Rev. 2003, 103, 893–930; b) B. E. Evans, K. E. Rittle,
M. G. Bock, R. M. DiPardo, R. M. Freidinger, W. L.
Whitter, G. F. Lundell, D. F. Veber, P. S. Anderson,
R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J.
Kling, K. A. Kunkel, J. P. Springer, J. Hirshfield, J.
Med. Chem. 1988, 31, 2235–2246; c) H. Zeugner, W.
Benson, E. Finner, W. Milkowski, P. W. Thies, Nature
1982, 298, 759–760.
[3] a) L. H. Sternbach, J. Med. Chem. 1979, 22, 1–7;
b) K. T. Olkkola, J. Ahonen, in: Modern Anesthetics,
Handbook of Experimental Pharmacology, Vol. 182
(Eds.: J. Schꢄttler, H. Schwilden), Springer-Verlag, Hei-
delberg, 2008, pp 335–360; c) R. R. Nadendla, Princi-
ples of Organic Medicinal Chemistry, New Age Interna-
tional Ltd., New Dehli, 2005, pp 83–88 and 111–114;
d) Integrated Pharmacology, 1st edn., (Eds.: C. P. Page,
M. Curtis, M. Sutter, M. Walker, B. Hoffman), CV
Mosby, London, 1997; e) J. K. Landquist, in: Compre-
hensive Heterocyclic Chemistry, Vol. 1, (Eds.: A. R. Ka-
tritzky, C. W. Rees), Elsevier Science Ltd., Oxford,
1997, pp 166–170.
[4] a) J. W. Butcher, N. J. Liverton, D. A. Claremon, R. M.
Freidinger, N. K. Jurkiewicz, J. J. Lynch, J. J. Salata, J.
Wang, C. M. Dieckhaus, D. E. Slaughter, K. Vyas,
Bioorg. Med. Chem. Lett. 2003, 13, 1165–1168;
b) H. G. Selnick, N. J. Liverton, J. J. Baldwin, J. W.
Butcher, D. A. Claremon, J. M. Elliotte, R. M. Frei-
dinger, S. A. King, B. E. Libby, C. J. McIntyre, D. A.
Pribush, D. C. Remy, G. R. Smith, A. J. Tebben, N. K.
Jurkiewicz, J. J. Lynch, J. J. Salata, M. C. Sanguinetti,
P. K. S. Siegal, D. E. Slaughter, K. Vyas, J. Med. Chem.
1997, 40, 3865–3868.
[12] O. Bub, L. Friedrich, H. P. Hofmann, H. Kreiskott, F.
Zimmermann, Ger. Offen. DE 2052840, 1972.
[13] a) J. Lee, D. Gauthier, R. A. Rivero, J. Org. Chem.
1999, 64, 3060–3065; b) T. F. Herpin, K. G. Van Kirk,
J. M. Salvino, S. T. Yu, R. F. Labaudiniꢅre, J. Comb.
Chem. 2000, 2, 513–521; c) W. Nawrocka, B. Sztuba,
M. Zimecki, Arch. Pharm. Pharm. Med. Chem. 2001,
334, 11–16; d) X. Wang, X. Zou, J. Li, Q. Hu, Synlett
2005, 3042–3046; e) R. Pathak, S. Nag, S. Batra, Syn-
thesis 2006, 4205–4211; f) H.-Y. Zhao, G. Liu, J. Comb.
Chem. 2007, 9, 1164–1176; g) M. Rida, H. El Meslouhi,
N. H. Ahabchane, B. Garrigues, N. Es-Safi, E. M. Essas-
si, The Open Org. Chem. J. 2008, 2, 83–87; h) S. B.
Hoyt, C. London, M. J. Wyvratt, M. H. Fisher, D. E.
Cashen, J. P. Felix, M. L. Garcia, X. Li, K. A. Lyons,
D. E. MacIntyre, W. J. Martin, B. T. Priest, McH. M.
Smith, V. A. Warren, B. S. Williams, G. J. Kaczorowski,
W. H. Parson, Bioorg. Med. Chem. Lett. 2008, 18,
1963–1966; i) X. Wang, Z. Li, X. Zhu, H. Mao, X. Zou,
L. Kong, X. Li, Tetrahedron 2008, 64, 6510–6521.
[14] a) M. C. Aversa, P. Giannetto, G. Romeo, P. Ficarra,
M. G. Vigorita, Org. Magn. Reson. 1981, 15, 394–398;
b) F. Malik, M. Hassan, D. Rosenbaum, H. Duddeck,
Mag. Reson. Chem. 1989, 27, 391–395; c) N. Kalyanam,
P. S. Srinivasan, Tetrahedron Lett. 1993, 34, 119–122;
Adv. Synth. Catal. 2010, 352, 2629 – 2634
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2633

Magnus Rueping et al.
FULL PAPERS
d) F. Malik, M. Hasan, K. M. Khan, S. Perveen, G.
Snatzke, H. Duddeck, W. Voelter, Liebigs Ann. 1995,
1861–1869; e) N. Rashid, M. Hasan, M. K. Tahir, N. M.
Yusof, B. M. Yamin, Anal. Sci. 2008, 24, 199–200.
13075; g) J. W. Yang, M. T. H. Fonseca, B. List, J. Am.
Chem. Soc. 2005, 127, 15036–15037; h) J. B. Tuttle,
S. G. Ouellet, D. W. C. MacMillan, J. Am. Chem. Soc.
2006, 128, 12662–12663; i) N. J. A. Martin, B. List, J.
Am. Chem. Soc. 2006, 128, 13368–13369; j) R. I.
Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J.
Am. Chem. Soc. 2006, 128, 84–86; k) Q. Kang, Z. A.
Zhao, S. L. You, Adv. Synth. Catal., 2007, 349, 1657–
1660; l) G. L. Li, Y. X. Liang, J. C. Antilla, J. Am.
Chem. Soc. 2007, 129, 5830–5831; m) N. J. A. Martin,
L. Ozores, B. List, J. Am. Chem. Soc. 2007, 129, 8976–
8977; n) N. J. A. Martin, X. Cheng, B. List, J. Am.
Chem. Soc. 2007, 129, 13862–13863; o) Z. Zhang, P. R.
Schreiner, Synlett 2007, 1455–1457; p) Q. Kang, Z. A.
Zhao, S. L. You, Org. Lett. 2008, 10, 2031–2034; q) C.
Metallinos, F. B. Barrett, S. Xu, Synlett 2008, 720–724;
r) Q. S. Guo, D. M. Du, J. Xu, Angew. Chem. 2008, 120,
771–774; Angew. Chem. Int. Ed. 2008, 47, 759–762;
s) Z.-Y. Han, H. Xiao, L.-Z. Gong, Bioorg. Med. Chem.
Lett. 2009, 19, 3729–3732; t) G. L. Li, J. C. Antilla,
Org. Lett. 2009, 11, 1075–1078.
[15] Recent reviews on Brønsted acid catalysis: a) T. Akiya-
ma, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348,
999–1010; b) M. S. Taylor, E. N. Jacobsen, Angew.
Chem. 2006, 118, 1550–1573; Angew. Chem. Int. Ed.
2006, 45, 1520–1543; c) T. Akiyama, Chem. Rev. 2007,
107, 5744–5758; d) A. G. Doyle, E. N. Jacobsen, Chem.
Rev. 2007, 107, 5713–5743; e) M. Terada, Chem.
Commun. 2008, 4097–4112; f) M. Terada, Synthesis
2010, 1929–1982; g) H. Yamamoto, N. Payette, in Hy-
drogen Bonding in Organic Synthesis, (Ed.: P. M.
Pihko), Wiley-VCH, Weinheim, 2009, pp 73–140.
[16] For recent reviews on HEH reductions, see: a) S. G.
Ouellet, A. M. Walji, D. W. C. MacMillan, Acc. Chem.
Res. 2007, 40, 1327–1339; b) S. L. You, Chem. Asian J.
2007, 2, 820–827; c) S. J. Connon, Org. Biomol. Chem.
2007, 5, 3407–3417; d) C. Wang, X. F. Wu, J. L. Xiao,
Chem. Asian J. 2008, 3, 1750–1177; e) M. Rueping, E.
Sugiono, F. R. Schoepke, Synlett 2010, 852–865. For a
study on the hydride-donor abilities of HEH, see: f) D.
Richter, H. Mayr, Angew. Chem. 2009, 121, 1992–1995;
Angew. Chem. Int. Ed. 2009, 48, 1958–1961;.
[17] For Brønsted acid-catalyzed reductions from our group,
see: a) M. Rueping, C. Azap, E. Sugiono, T. Theiss-
mann, Synlett 2005, 2367–2369; b) M. Rueping, E. Su-
giono, C. Azap, T. Theissmann, M. Bolte, Org. Lett.
2005, 7, 3781–3783; c) M. Rueping, T. Theissmann,
A. P. Antonchick, Synlett 2006, 1071–1074; d) M.
Rueping, A. P. Antonchick, T. Theissmann, Angew.
Chem. 2006, 118, 3765–3768; Angew. Chem. Int. Ed.
2006, 45, 3683–3686; e) M. Rueping, T. Theissmann, S.
Raja, J. W. Bats, Adv. Synth. Catal. 2008, 350, 1001–
1006; f) M. Rueping, A. P. Antonchick, Angew. Chem.
2007, 119, 4646–4649; Angew. Chem. Int. Ed. 2007, 46,
4562–4565; g) M. Rueping, A. P. Antonchick, T.
Theissmann, Angew. Chem. 2006, 118, 6903–6907;
Angew. Chem. Int. Ed. 2006, 45, 6751–6755; h) M.
Rueping, A. P. Antonchick, Angew. Chem. 2008, 120,
5920–5922; Angew. Chem. Int. Ed. 2008, 47, 5836–
5838; i) M. Rueping, F. Tato, F. R. Schoepke, Chem.
Eur. J. 2010, 16, 2688–2691; j) M. Rueping, M. Stoeck-
el, E. Sugiono, T. Theissmann, Tetrahedron 2010, 66,
6565–6568; k) M. Rueping, T. Theissmann, Chem. Sci.
2010, in print; l) M. Rueping. R. M. Koenigs, Chem.
Commun. 2010, DOI: 10.1039/c0cc02167A.
[18] For selected HEH reductions from other groups, see:
a) J. W. Yang, M. T. H. Fonseca, B. List, Angew. Chem.
2004, 116, 6829–6832; Angew. Chem. Int. Ed. 2004, 43,
6660–6662; ; b) J. W. Yang, M. T. H. Fonseca, N. Vi-
gnola, B. List, Angew. Chem. 2005, 117, 110–112;
Angew. Chem. Int. Ed. 2005, 44, 108–110; c) S. G.
Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem.
Soc. 2005, 127, 32–33; d) Y. Huang, A. M. Walji, C. H.
Larsen, D. W. C. MacMillan, J. Am. Chem. Soc. 2005,
127, 15051–15053; e) S. Hoffmann, A. M. Seayad, B.
List, Angew. Chem. 2005, 117, 7590–7593; Angew.
Chem. Int. Ed. 2005, 44, 7424–7427; f) S. Hoffmann, M.
Nicoletti, B. List, J. Am. Chem. Soc. 2006, 128, 13074–
[19] For the application of N-triflyl phosphoramides in
enantioselective catalysis, see: a) S. A. Yamamoto, D.
Nakashima, H. Yamamoto, J. Am. Chem. Soc. 2006,
128, 9626–9627; b) P. Jiao, D. Nakashima, H. Yamamo-
to, Angew. Chem. 2008, 120, 2445–2447; Angew. Chem.
Int. Ed. 2008, 47, 2411–2413; c) D. Enders, A. Narine,
F. Toulgoat, T. Bisschops, Angew. Chem. 2008, 120,
5744–5748; Angew. Chem. Int. Ed. 2008, 47, 5661–
5665; d) M. Zeng, Q. Kang, Q.-L. He, S.-L. You, Adv.
Synth. Catal. 2008, 350, 2169–2173; e) S. Lee, S. Kim,
Tetrahedron Lett. 2009, 50, 3345–3348; f) D. Enders, M.
Seppelt, T. Beck, Adv. Synth. Catal. 2010, 352, 1413–
1418; For the application of N-triflyl thiophosphora-
mides, see: g) C. H. Cheon, H. Yamamoto, J. Am.
Chem. Soc. 2008, 130, 9246–9247; h) C. H. Cheon; H.
Yamamoto, Org. Lett. 2010, 12, 2476–2479.
[20] For reports from our group regarding N-triflyl phos-
phoramide-catalyzed reactions, see: a) M. Rueping, W.
Ieawsuwan, A. P. Antonchick, B. J. Nachtsheim, Angew.
Chem. 2007, 119, 2143–2146; Angew. Chem. Int. Ed.
2007, 46, 2097–2100; b) M. Rueping, W. Ieawsuwan,
Adv. Synth. Catal. 2009, 351, 78–84; c) M. Rueping,
B. J. Nachtsheim, S. A. Moreth, M. Bolte, Angew.
Chem. 2008, 120, 603–606; Angew. Chem. Int. Ed.
2008, 47, 593–596; d) M. Rueping, T. Theissmann, A.
Kuenkel, R. M. Koenigs, Angew. Chem. 2008, 120,
6903–6906; Angew. Chem. Int. Ed. 2008, 47, 6798–
6801; e) M. Rueping, M.-Y. Lin, Chem. Eur. J. 2010, 16,
4169–4172; f) M. Rueping, B. J. Nachtsheim, Synlett
2010, 119–122; g) M. Rueping, B. J. Nachtsheim, R. M.
Koenigs, W. Ieawsuwan, Chem. Eur. J. 2010, DOI:
10.1002/chem.201001438.
[21] Microwaves in Organic Synthesis, (Ed.: A. Loupy),
Wiley-VCH, Weinheim, 2002.
[22] In order to be able to determine the enantiomeric
excess by HPLC, acylation of the very polar products
was carried out.
[23] The reduction of alkyl-substituted benzodiazepin-2-
ones resulted in moderate enantioselectivities. Catalyst
optimization studies are currently under investigation.
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Adv. Synth. Catal. 2010, 352, 2629 – 2634