[Ir(P-OP)]-catalyzed asymmetric hydrogenation of diversely substituted C=N-containing heterocycles

Article abstract of DOI:10.1021/ol400854a

Iridium(I) complexes of enantiomerically pure phosphine-phosphite ligands ([Ir(Cl)(cod)(P - OP)]) efficiently catalyze the enantioselective hydrogenation of diverse C=N-containing heterocyclic compounds (benzoxazines, benzoxazinones, benzothiazinones, and quinoxalinones; 25 examples, up to 99% ee). A substrate-to-catalyst ratio as high as 2000:1 was reached.

Full text of DOI:10.1021/ol400854a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
[Ir(PÀOP)]-Catalyzed Asymmetric
Hydrogenation of Diversely Substituted
CdN-Containing Heterocycles
†
Jose Luis Nunez-Rico and Anton Vidal-Ferran*
,†,‡
ꢀ
ꢀ~
Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans 16,
¨
43007 Tarragona, Spain, and Catalan Institution for Research and Advanced Studies
´
(ICREA), P. Lluıs Companys 23, 08010 Barcelona, Spain
avidal@iciq.cat
Received March 28, 2013
ABSTRACT
Iridium(I) complexes of enantiomerically pure phosphine-phosphite ligands ([Ir(Cl)(cod)(P;OP)]) efficiently catalyze the enantioselective hydrogenation
of diverse CdN-containing heterocyclic compounds (benzoxazines, benzoxazinones, benzothiazinones, and quinoxalinones; 25 examples, up to 99% ee).
A substrate-to-catalyst ratio as high as 2000:1 was reached.
Heterocyclic compounds are ubiquitous in biology and,
therefore, are a mainstay in life, biotechnological, and
materials science research.1 Method development to access
achiral heterocyclic compounds has been growing in scope
and importance since the onset of organic synthesis.
However, the development of general synthetic routes to
enantiomerically pure (or highly enantioenriched) hetero-
cyclic compounds remains challenging. Enantiomerically
pure heterocyclic compounds are employed as important
chiral building blocks in the synthesis of many
pharmaceuticals.2
Enantioselective reduction of heteroaromatic com-
pounds is one promising method: it benefits from a near
infinite diversity of starting materials and minimizes the
functional group manipulation inherent in many N-, O-,
and S-heterocycle syntheses. Transition metal catalyzed
asymmetric hydrogenation has been employed to reduce
certain heteroaromatic derivatives (mainly quinolines and
quinoxalines).3 However, few reports of thischemistrydeal
† Institute of Chemical Research of Catalonia (ICIQ).
(3) For examples of the hydrogenation of quinolines and quinox-
alines, see reviews aÀc and the references cited therein: (a) Zhou, Y.-G.
Acc. Chem. Res. 2007, 40, 1357. (b) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.;
Zhou, Y.-G. Chem. Rev. 2012, 112, 2557. (c) Chen, Q.-A.; Ye, Z.-S.;
Duan, Y.; Zhou, Y.-G. Chem. Soc. Rev. 2013, 42, 497. For examples
of the asymmetric hydrogenation of other types of heterocycles, see:
(d) Kuwano, R.; Kameyama, N.; Ikeda, R. J. Am. Chem. Soc. 2011, 133,
7312 (oxazoles). (e) Shi, L.; Ye, Z.-S.; Cao, L.-L.; Guo, R.-N.; Hu, Y.;
Zhou, Y.-G. Angew. Chem., Int. Ed. 2012, 51, 8286 (isoquinolines).
(f) Ye, Z.-S.; Chen, M.-W.; Chen, Q.-A.; Shi, L.; Duan, Y.; Zhou, Y.-G.
Angew. Chem., Int. Ed. 2012, 51, 10181 (pyridines). (g) Ding, Z.-Y.;
Chen, F.; Qin, J.; He, Y.-M.; Fan, Q.-H. Angew. Chem., Int. Ed. 2012, 51,
5706 (benzodiazepines). (h) Urban, S.; Beiring, B.; Ortega, N.; Paul, D.;
Glorius, F. J. Am. Chem. Soc. 2012, 134, 15241 (thiophenes). (i) Ortega,
N.; Urban, S.; Beiring, B.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
1710 (benzofurans). (j) Iimuro, A.; Yamaji, K.; Kandula, S.; Nagano, T.;
Kita, Y.; Mashima, K. Angew. Chem., Int. Ed. 2013, 52, 2046
(isoquinolines).
‡ Catalan Institution for Research and Advanced Studies (ICREA).
(1) For example, see: (a) Pharmaceutical Substances; Kleemann, A.,
Engel, J., Kutscher, B., Reichert, D., Eds.; Thieme: Stuttgart, NY, 2001.
(b) Roy, B.; De, N.; Majumdar, K. C. Chem.;Eur. J 2012, 18, 14560.
(c) Yook, K. S.; Lee, J. Y. Adv. Mater. 2012, 24, 3169.
(2) For general texts on pharmaceutical applications of the types of
chiral heterocycles described in this work, see ref 1, the following
references and those cited therein: (a) Ilas, J.; Anderluh, P. S.; Dolenc,
M. S.; Kikelj, D. Tetrahedron 2005, 61, 7325 (benzoxazinones).
(b) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J. W.;
Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370 (quinoxalinones).
(c) Smil, D. V.; Manku, S.; Chantigny, Y. A.; Leit, S.; Wahhab, A.;
Yan, T. P.; Fournel, M.; Maroun, C.; Li, Z.; Lemieux, A.-M.; Nicolescu,
A.; Rahil, J.; Lefebvre, S.; Panetta, A.; Besterman, J. M.; Deziel, R.
Bioorg. Med. Chem. Lett. 2009, 19, 688 (quinoxalinones). (d) Rueping,
M.; Stoeckel, M.; Sugiono, E.; Theissmann, T. Tetrahedron 2010, 66,
6565 (benzoxazines).
r
10.1021/ol400854a
XXXX American Chemical Society

with the direct enantioselective hydrogenation of other
CdN-containing heterocycles. Although the asymmetric
reduction of other CdN-containing heterocycles has been
efficiently achieved by chiral Brønsted acid catalyzed
transfer hydrogenation (2H-benzo[b][1,4]oxazines 3,2d,4
2H-benzo[b]-[1,4]oxazin-2-ones 5,4a and quinoxalin-2(1H)-
ones 9;5 Scheme 1) and by relay-catalyzed organocatalytic
reduction6 (3 and 57), both with remarkably high enantio-
selectivities, only limited success has been reported in the
standard asymmetric hydrogenation of the benzoxazines 3.8
Furthermore, to the best of the authors’ knowledge, there
are no reports of metal-mediated asymmetric hydrogenation
of the other heterocyclic classes (5, 2H-benzo[b][1,4]thiazin-
2-ones 7 and 9).
Scheme 1. Enantioselective Partial Hydrogenation of Hetero-
cyclic Compounds
We recently reported the hydrogenation of quinolines 1
mediated by iridium(I) complexes ([Ir(Cl)(cod)(P-OP)])
with high enantioselectivities (Scheme 1).9 Herein we
report the evaluation of these IrÀ(PÀOP) complexes as
precatalysts for asymmetric hydrogenation of diversely
substituted CdN-containing heterocyclic compounds 3,
5, 7, and 9 (see Tables 1 and 2). Deuterium labeling experi-
ments on the hydrogenation of 2-methylquinoline and 5a
have provided new insights into the involved tautomeriza-
tion processes during hydrogenation and the stereoselec-
tivity of H-delivery.
The present work began with enantioselective hydro-
genation of the benzoxazines 3 (Table 1). Catalytic studies
on the asymmetric hydrogenation of the diversely substi-
tuted benzoxazines 3aÀh were done using well-established
iridium(I) complexes.9 Optimal hydrogenation reaction con-
ditions (catalyst loading, solvent, pressure, and temperature)
were studied on model compound 3a, which was effi-
ciently hydrogenated with full conversion and 95% ee
in THF at rt under 40 bar of H2 using 0.5 mol % of
[Ir(Cl)(cod)(L1)] as a precatalyst,10 (see entry 1 in Table 1,
and the Supporting Information (SI)). The enantioselec-
tivity of the hydrogenation of 3a was strongly solvent
dependent: THF was among the solvents that provided
the highest enantioselectivity.11
Additives are commonly used to improve catalytic
activity in this chemistry.3b,12 Unfortunately, addition
of an array of achiral and chiral Brønsted acids did not
lead to increased enantioselectivities in the hydrogenation
of 3a.11 Once the optimal hydrogenation conditions for 3a
had been established, the hydrogenation of the remaining
benzoxazines (3bÀh) was studied. These results are sum-
marized in Table 1. The catalyst efficiently mediated the
asymmetric hydrogenation of 3bÀh, with high conversions
and enantioselectivities (91 to 95% ee). Regardless of the
position and the electronic nature of the substituents at
the phenyl R1 substituent, or replacing the R2 group with
chlorine, the enantioselectivities were high (91À93% ee;
entries 2À8 in Table 1).
With respect to the benzoxazines 3, complete hydroge-
nation of their carbonyl-containing analogs 5 required
higher pressure (80 instead of 40 bar H2) and catalyst
loadings (2 mol % instead of 0.5 mol %). Under these
conditions and with THF as solvent, compound 5a was
hydrogenated with excellent enantioselectivity (95% ee;
entry 9 in Table 1). Addition of catalytic amounts of
anhydrous HCl to the hydrogenation of 5a enabled a re-
duction in the amount of catalyst used (down to 1 mol %),
although at the expense of a slight decrease in ee.11 To
obtain the highest possible enantioselectivity, the asym-
metrichydrogenation of the benzoxazinones5bÀe (3-[p-X-
phenyl]-, 6-chloro-, and 6-tBu-substituted derivatives),
using [Ir(Cl)(cod)(L1)] as precatalysts and in the absence
of HCl, was then studied. Although the hydrogenation of
5a and of its methyl substituted analog 5b proceeded with
full conversion under the optimized reaction conditions,
only partial hydrogenation of the remaining benzoxazi-
nones (5cÀe) was observed. Nevertheless, the enantio-
selectivities obtained with all the studied compounds were
(4) (a) Rueping, M.; Antonchik, A. P.; Theissmann, T. Angew.
Chem., Int. Ed. 2006, 45, 6751. (b) Rueping, M.; Sugiono, E.; Steck,
A.; Theissmann, T. Adv. Synth. Catal. 2010, 352, 281. (c) Rueping, M.;
Theissmann, T. Chem. Sci. 2010, 1, 473. (d) Bleschke, C.; Schmidt, J.;
Kundu, D. S.; Blechert, S.; Thomas, A. Adv. Synth. Catal. 2011, 353,
3101. (e) Kundu, D. S.; Schmidt, J.; Bleschke, C.; Thomas, A.; Blechert,
S. Angew. Chem., Int. Ed. 2012, 51, 5456.
(5) Rueping, M.; Tato, F.; Schoepke, F. R. Chem.;Eur. J. 2010, 16,
2688.
(6) Shi, F.; Gong, L.-Z. Angew. Chem., Int. Ed. 2012, 51, 11423.
(7) Chen, Q.-A.; Gao, K.; Duan, Y.; Ye, Z.-S.; Shi, L.; Yang, Y.;
Zhou, Y.-G. J. Am. Chem. Soc. 2012, 134, 2442.
(8) (a) Gao, K.; Yu, C.-B.; Wang, D.-S.; Zhou, Y.-G. Adv. Synth.
Catal. 2012, 354, 483. (b) Hu, J.; Wang, D.; Zheng, Z.; Hu, X. Chin. J.
Chem. 2012, 30, 2664. (c) Fleischer, S.; Zhou, S.; Werkmeister, S.; Junge,
K.; Beller, M. Chem.;Eur. J. 2013, 19, 4997.
ꢀ~
ꢀ
ꢀ
(9) (a) Nunez-Rico, J. L.; Fernandez-Perez, H.; Benet-Buchholz, J.;
ꢀ
ꢀ
Vidal-Ferran, A. Organometallics 2010, 29, 6627. (b) Fernandez-Perez,
H.; Etayo, P.; Panossian, A.; Vidal-Ferran, A. Chem. Rev. 2011, 111,
2119.
(10) The catalytic performance of a set of neutral and cationic iridium
complexes derived from the PÀOP ligands developed by the authors has
been assessed in the asymmetric hydrogenation of these types of
substrates. For the complete set of results, see the SI.
(11) For a complete summary of the hydrogenation results of these
types of substrates, see section G of the SI.
(12) For example, see: Nagano, T.; Iimuro, A.; Schwenk, R.;
Ohshima, T.; Kita, Y.; Togni, A.; Mashima, K. Chem.;Eur. J. 2012,
18, 11578 and the references cited therein.
B
Org. Lett., Vol. XX, No. XX, XXXX

R1 (9aÀb, 9dÀe, and 9gÀi) than for the alkyl-substituted
compounds 9c and 9f (ee ca. 90%; entries 6 and 9 in
Table 2). To the best of the authors’ knowledge, these
are the first-ever reported examples of asymmetric hydro-
genation of the quinoxalinones 9.
Table 1. Asymmetric Hydrogenation of Compounds 3aÀh and
5aÀe Mediated by Complex [Ir(Cl)(cod)(L1)]
In summary, Ir(I) complexes of the enantiomerically
pure phosphine-phosphite ligand L1 efficiently catalyze
the enantioselective hydrogenation of a wide array of
heterocyclic CdN-containing derivatives (benzoxazines,
benzoxazinones, benzothiazinones, and quinoxalinones;
25 examples, up to 99% ee). In the best case, a substrate-
to-catalyst ratio of up to 2000 was used. To the best of the
authors’ knowledge, the work described here includes the
first-ever reported examples of transition metal catalyzed
asymmetric hydrogenation of the benzoxazinones 5, the
benzothiazinones 7, and the quinoxalinones 9.
Table 2. Asymmetric Hydrogenation of Compounds 7aÀc and
9aÀi Mediated by Complex [Ir(Cl)(cod)(L1)]
a Reaction conditions: [{Ir(μ-Cl)(cod)}2]/PÀOP ligand/substrate =
1:2.2:100, 0.5:1.1:100, or 0.25:0.55:100 for precatalyst levels of 2, 1, or
0.5 mol %, respectively, at rt, 20 h and 0.20 M in THF. The values shown
are the average of at least two runs. b Conversions were determined by
1H NMR. Typical isolated yields after column chromatography were
>95%. c Determined by HPLC analysis using chiral stationary phases.
d Absolute configurationwasassigned bycomparisonwith literature data.
e Isolated yields: 4e, 93%; 6c, 45%; 6d, 54%; and 6e, 42%. f Absolute
configuration was tentatively assigned by analogy based on the stereo-
chemical outcome for analogous substrates.
very high (89 to 99% ee for 5aÀe; see entries 9À13, in
Table 1).
Hydrogenation of the thio- and aza-analogs of benzox-
azinones 5 (compounds 7 and 9, respectively) was subse-
quently explored. The benzothiazinones 7aÀc were effi-
ciently hydrogenated under 80 bar of H2 using 2 mol % of
the standardcatalyst (full conversion, up to96% ee; entries
1À3, Table 2), regardless of the electronic nature of the
substituents at R1.
a Reaction conditions: [{Ir(μ-Cl)(cod)}2]/PÀOP ligand/substrate =
1:2.2:100, 0.5:1.1:100, or 0.25:0.55:100 for precatalyst levels of 2, 1, or
0.5 mol %, respectively, at rt, 20 h and 0.20 M in THF. The values shown
are the average of at least two runs. b Conversions were determined by
1H NMR. Typical isolated yields after column chromatography were
>95%. c Determined by HPLC analysis using chiral stationary phases.
d Absolute configuration was assigned by comparison with literature data.
e Isolated yield: for 10b, 92%; for 10d, 92%; for 10e, 85%. f Absolute
configuration was tentatively assigned by analogy based on the stereo-
chemical outcome for analogous substrates.
To the best of the authors’ knowledge, this is the first-
ever reported asymmetric hydrogenation of these sulfur-
containing heterocycles. The quinoxalinones 9aÀ9i also
were hydrogenated very efficiently (conversions from 89
to 99%, and ee from 90 to 99%; entries 4À12 in Table 2)
using the [Ir(Cl)(cod)(L1)] complex as precatalysts at
lower pressure and lower catalyst loading than their
sulfur analogs (see Table 2). Interestingly, the catalytic
systems tolerate diverse substitution at the N1 position of
the quinoxalinones: either no protecting group (9a) or a
wide variety of protecting groups, including Me (9d),
MOM (9h), and Bn (9i), with excellent enantioselectivity
(99% ee; entries 4, 7, 11 and 12, respectively, in Table 2).
For the N-methyl substituted derivative, a catalyst loading
as low as 0.05 mol % resulted in almost full conver-
sion (96%) and perfect enantioselectivity (99%, entry 7
in Table 2). Higher enantioselectivities were consistently
observed for the quinoxalinones with an aryl substituent at
The literature includes only a few experimental or
theoretical mechanistic studies on the hydrogenation
of heteroaromatic compounds (mainly, of quinolines).13
ꢀ
(13) For example, see: (a) Baralt, E.; Smith, S. J.; Hurwitz, J.; Horvath,
I. T.; Fish, R. H. J. Am. Chem. Soc. 1992, 114, 5187. (b) Sanchez-Delgado,
R. A.; Rondon, D.; Andriollo, A.; Herrera, V.; Martin, G.; Chaudret, B.
Organometallics 1993, 12, 4291. (c) Bianchini, C.; Meli, A.; Vizza, F. Eur. J.
Inorg. Chem. 2001, 43. (d) Wang, D.-W.; Wang, X.-B.; Wang, D.-S.; Lu,
S.-M.; Zhou, Y.-G.; Li, Y.-X. J. Org. Chem. 2009, 74, 2780. (e) Dobereiner,
G. E.; Nova, A.; Schley, N. D.; Hazari, N.; Miller, S. J.; Eisenstein, O.;
Crabtree, R. H. J. Am. Chem. Soc. 2011, 133, 7547.
Org. Lett., Vol. XX, No. XX, XXXX
C

Although most of the early studies on iridium-mediated
hydrogenations suggested mechanistic pathways involving
inner-sphere coordination of the substrate to the metal
center,13aÀd recent computational studies14 have revealed
that outer-coordination mechanistic pathways involving
stepwise proton and hydride transfers15 are more favored.13e
Crabtree, Eisenstein et al. have shown that the catalytic cycle
for iridium-mediated hydrogenation of 2-methylquinoline13e
starts with its protonation followed by delivery of hydride
to C4. Tautomerization of the resulting dihydroquinoline
11C2ÀC3 to the CdN containing tautomer 11NÀC2, followed
by a second protonation and hydride transfer to this
tautomer,13e leads to the final tetrahydroquinoline 2.
Scheme 2. Possible Pathways for the Hydrogenation of CdN-
Containing Heterocycles
To gain deeper insight into the hydrogenation process,
a series of labeling experiments were performed in which
2-methylquinoline 1a and the benzoxazinone 5a were
hydrogenated using H2/10 mol % of DCl, D2/10 mol %
of HCl, and D2/10 mol % of DCl. Benzoxazinone 5a reacted
as expected with the labeled reagents. When D2 was
used, full incorporation of deuterium at C2 was observed
(see Scheme 2; the H-atoms marked in red indicate the
deuterium-labeled positions).16 Conversely, no observable
incorporation of deuterium was observed when H2/10 mol %
of DCl was used.17
Hydrogenation of 2-methylquinoline (1a) with the la-
beled reagents afforded a mixture of isotopic isomers
incorporating deuterium atoms at C2, C3, and C4, as well
at the methyl carbon of the quinoline (see structure 2a in
Scheme 2; the H-atoms marked in red indicate the deute-
rium-labeled positions).16 When D2 was used, full incor-
poration of deuterium at C2 was observed in the reduced
product in all cases. Variable degrees of deuterium incor-
poration at C3, C4 and at the methyl group were obtained,
depending on the labeling conditions. Surprisingly, when
10 mol % of DCl was used, a ca. 8% degree of deuterium
incorporation at the methyl group was observed in the
absence of D2.17 Deuteriation at the methyl group clearly
indicates that dihydroquinoline 11C2ÀCexo is formed and
that it participates in the tautomeric equilibrium after the
addition of the first H2 molecule. A detailed analysis of the
structure of deuteriated derivatives of 2a revealed that, while
deuterium is incorporated at C3 with no facial preference,
deuteride is delivered with moderate stereoselectivity to C4
(ca. 2:1 incorporation ratio in favor of the pro-(S) posi-
tion in C4 in the deuteriated derivatives of 2a).17 Overall,
several labeling studies on the asymmetric reduction of
analogous heterocycles have been published to date,18 but
the findings reported here demonstrate several important
unreported issues in this chemistry. First, they elucidate the
nature of the tautomerization processes after the first addi-
tion of H2 and reveal a complex scenario, in which the
11C2ÀCexo isomer also participates in the equilibria previous
to the addition of the second H2 molecule. Second, they
suggest that the stereoselectivity of hydrogen incorporation
at C4 would be compatible with asymmetric induction at
this carbon during hydrogenation, in the event of being
substituted.
Acknowledgment. The authors thank MICINN (Grant
CTQ2011-28512), DURSI (Grant 2009SGR623) and the
ICIQ Foundation for financial support.
(14) DFT calculations on iridium-mediated hydrogenations involv-
ing CdN bonds (imines: Hopmann, K. H.; Bayer, A. Organometallics
2011, 30, 2483; quinoline: see ref 13e) suggest that inner-sphere mecha-
nisms are less favored.
(15) See the seminal work of Oro and co-workers ( Martin, M.; Sola,
E.; Tejero, S.; Andres, J. L.; Oro, L. A. Chem.;Eur. J. 2006, 12, 4043),
who proposed and applied this stepwise concept.
(16) DeuteriumÀhydrogen exchange took place at nitrogen either
during the chromatographic purification or during spectroscopic anal-
ysis, and N-deuterated compounds were not observed.
Supporting Information Available. Text and figures
covering experimental procedures, analytical and spectral
characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) See refs 3j , 4c, and: Yan, P.-C.; Xie, J.-H.; Hou, G.-H.; Wang,
L.-X.; Zhou, Q.-L. Adv. Synth. Catal. 2009, 351, 3243.
(17) For a summary of the labeling studies, see section K of the SI.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX