Asymmetric Hydrogenation of Seven-Membered C=N-containing Heterocycles and Rationalization of the Enantioselectivity

Article abstract of DOI:10.1002/chem.201601464

Iridium(I) complexes with phosphine–phosphite ligands efficiently catalyze the enantioselective hydrogenation of diverse seven-membered C=N-containing heterocyclic compounds (eleven examples; up to 97 % ee). The P-OP ligand L3, which incorporates an ortho

Full text of DOI:10.1002/chem.201601464

DOI: 10.1002/chem.201601464
Full Paper
&
Asymmetric Hydrogenation
Asymmetric Hydrogenation of Seven-Membered C=N-containing
Heterocycles and Rationalization of the Enantioselectivity
Bugga Balakrishna,[a, d] Antonio Bauzꢀ,[b] Antonio Frontera,*[b] and Anton Vidal-Ferran*[a, c, d]
Dedicated to Prof. Dr. Josꢀ M. Saꢁ on the occasion of his 68th birthday.
Abstract: Iridium(I) complexes with phosphine–phosphite li-
gands efficiently catalyze the enantioselective hydrogenation
of diverse seven-membered C=N-containing heterocyclic
compounds (eleven examples; up to 97% ee). The P-OP
ligand L3, which incorporates an ortho-diphenyl substituted
octahydrobinol phosphite fragment, provided the highest
enantioselectivities in the hydrogenation of most of the het-
erocyclic compounds studied. The observed stereoselection
was rationalized by means of DFT calculations.
Introduction
We recently reported the hydrogenation of an array of struc-
turally diverse five- and six-membered heterocyclic compounds
1 mediated by iridium(I) complexes of phosphine–phosphite
ligands[5] [Ir(Cl)(cod)(P-OP)] (cod=cyclooctadiene) with high
catalytic activity (Scheme 1).[6] Ligand L1, which incorporates
an Ra configured [1,1’-binaphthalene]-2,2’-diol phosphite
group, provided the highest enantioselectivities in the asym-
metric hydrogenation of heterocyclic compounds 1. Interest-
ingly, we found that the addition of a Brønsted acid (catalytic
amounts of HCl for 2-alkyl substituted quinolines[6a] and qui-
noxalines[6a] and stoichiometric amounts of rac-camphorsulfon-
ic acid for indoles[6c]) increased the conversion of the hydroge-
nation reaction and even positively affected the enantioselecti-
vity.[6a] Herein, we report the development of Ir-(P-OP) com-
plexes as efficient catalysts for the enantioselective asymmetric
hydrogenation of diversely substituted seven-membered C=N-
containing heterocyclic compounds (see structures 3, 5, 7, 9,
and 11 in Scheme 1).
Many biologically active compounds contain a chiral heterocy-
clic structural motif.[1] The development of methods to access
partly or fully reduced enantiopure heterocycles has increased
in scope and importance in recent years. The enantioselective
reduction of heterocyclic compounds is becoming more im-
portant in the preparation of their partly or fully reduced ana-
logs, as this strategy benefits from a great diversity of starting
materials and minimizes the need for manipulation of function-
al groups during the preparation of target compounds.[2] Tran-
sition-metal-catalyzed asymmetric hydrogenation has been
employed to reduce a large number of nitrogenated heterocy-
clic compounds (for instance, pyridines and other monocyclic
nitrogenated derivatives, quinolines, isoquinolines, quinoxa-
lines and related compounds, benzoxazines and related deriva-
tives, indoles, etc.) with high catalytic efficiencies and enantio-
selectivities. Although nitrogenated seven-membered hetero-
cyclic motifs with stereogenic centers constitute an important
pharmacophore,[3] examples of the asymmetric reduction of
seven-membered heterocyclic derivatives are scarce in the lit- Results and Discussion
erature.[4]
Ir-catalyzed asymmetric hydrogenation: initial screening
and optimization
[a] B. Balakrishna, Prof. Dr. A. Vidal-Ferran
Institute of Chemical Research of Catalonia (ICIQ)
Avinguda Pa¨ısos Catalans 16, 43007 Tarragona (Spain)
E-mail: avidal@iciq.cat
The present work began with the enantioselective hydrogena-
tion of oxazepine 3a as the model substrate by using well-
established[6a] in-situ-prepared iridium complexes of P-OP li-
gands L1–L4 as pre-catalysts. The reaction conditions em-
ployed (1 mol% cat., [3a]=0.2m in THF, 80 bar H2, rt) efficient-
ly led to the hydrogenated product 4a with complete conver-
sion in the absence of HCl as additive (see entries 1, 3, 5, and 7
in Table 1) with enantioselectivities ranging from 16% ee for L4
to 79% ee for L3.[7] Enantioselectivities were improved by
using 10 mol% HCl in the case of ligands L1, L2, and L3 (com-
pare entries 1, 3, and 5 with entries 2, 4, and 6 in Table 1), with
ligand L3 providing the highest enantioselectivities (86% ee,
[b] A. Bauzꢁ, Prof. Dr. A. Frontera
Departament de Quꢂmica, Universitat de les Illes Balears (UIB)
Cra. de Valldemossa, km 7.5. Palma, 07122 Palma de Mallorca (Spain)
E-mail: toni.frontera@uib.es
[c] Prof. Dr. A. Vidal-Ferran
ICREA, Pg. Lluꢂs Companys 23, 08010 Barcelona (Spain)
[d] B. Balakrishna, Prof. Dr. A. Vidal-Ferran
The Barcelona Institute of Science and Technology
Avinguda Pa¨ısos Catalans 16, 43007 Tarragona (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601464.
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Table 1. Asymmetric hydrogenation[a] of 3a mediated by [Ir(Cl)(cod)(L1–
L4)].
Entry
Ligand
Reaction conditions
Conv.
[%][b]
ee [%][c]
(configuration)[d]
1
2
3
4
5
6
7
8
L1
L1
L2
L2
L3
L3
L4
L4
L3
L3
L3
L3
L3
no additive
10 mol% HCl
no additive
10 mol% HCl
No additive
10 mol% HCl
no additive
10 mol% HCl
99
99
99
99
99
99
99
99[f]
99
90
99
99
99
42 (S)
53 (S)
29 (S)
57 (S)
79 (R)
86 (R)
16 (S)
8 (S)
86 (R)
87 (R)
91 (R)
91 (R)
91 (R)
9
20 mol% HCl
10
11
12
13
10 mol% HCl, 08C
10 mol% HCl, CH2Cl2
10 mol% HCl, toluene
10 mol% HCl, MeTHF[e]
[a] Reaction
conditions:
[{Ir(m-Cl)(cod)}2]/P-OP
ligand/substrate=
0.5:1.1:100 for pre-catalyst levels of 1 mol%, at rt, for 20 h, and with
a substrate concentration of 0.20m in THF. If an additive was present, the
indicated amount of additive with respect to 3a was added to a solution
of the substrate before adding the catalyst. The values shown are the
1
average of at least two runs. [b] Conversions were determined by H NMR
spectroscopy. [c] Determined by HPLC analysis by using chiral stationary
phases. [d] Absolute configuration was assigned by comparison with liter-
ature data (see ref. [4c]). [e] MeTHF=2-methyltetrahydrofuran. [f] The se-
lectivity of the reaction towards 4a was 35%.
Scheme 1. Enantioselective partial hydrogenation of nitrogenated heterocy-
clic compounds.
Expanding the substrate scope
entry 6 in Table 1). The effect of addition of a set of achiral and
enantiomerically pure additives on the hydrogenation of sub-
strate 3a were also studied.[8] With the exception of HCl, other
acid additives scarcely affected the conversion and enantiose-
lectivity of the hydrogenation of this substrate (see Table SI2 in
the Supporting Information).[8] Further attempts to optimize
the hydrogenation conditions involved varying the amount of
HCl (see entry 9 in Table 1) and reducing the temperature (see
entry 10 in Table 1). Increasing the amount of additive did not
have any effect on the conversion and ee (compare entries 6
and 9 in Table 1). The hydrogenation of 3a was also run at
lower temperature (08C instead of rt), based on the premise
that lowering the temperature normally offers higher ee. As
listed in entry 10 of Table 1, the ee at 08C was 1% higher than
at rt. However, further hydrogenation studies at this tempera-
ture were not considered, as conversion was incomplete. The
enantioselectivity of the hydrogenation of 3a was solvent de-
pendent, and 2-methyltetrahydrofuran (MeTHF), dichloro-
methane (CH2Cl2), and toluene led to a noticeable increase in
the ee of the reaction (compare entries 11, 12, and 13 with
entry 6 in Table 1).
Once the optimal hydrogenation conditions for 3a had been
established, the hydrogenation of an array of seven-membered
heterocycles was studied. 2-Methyltetrahydrofuran was chosen
as the optimal solvent for further studies, given the good re-
sults in the hydrogenation of 3a. The heterocycles studied and
the optimal ligand (L1 or L3) for achieving the highest ee
values are summarized in Table 2. The results using 10 mol%
HCl are only indicated in Table 2 when this additive provided
higher conversions and/or ee. The reader is referred to the
Supporting Information (Table SI3) for the complete hydroge-
nation results employing L1 and L3 as ligands and in the ab-
sence or presence of anhydrous HCl as an additive.
Several trends can be extracted from the results listed in
Table 2. Firstly, L3 was the ligand of choice for heterocycles
with R=alkyl group (entries 1, 3–5, 7, 9, and 11 in Table 2). For
these substrates, ee values ranged from 70 to 91%, with the
highest ee being obtained for oxazepine 4a and thiazepine 9a
(both 91% ee; see entries 1 and 9 in Table 2). Secondly, the use
of HCl as an additive in the hydrogenation of substrates with R
being an alkyl group had, with the exception of substrates 3c
and 5a (see entries 3 and 5 in Table 2), a positive effect on the
ee values.[9] Examples of the use of Brønsted acids as substrate
activators in iridium-mediated hydrogenations are numerous,[2j]
however, despite the improvement in catalyst activity and/or
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Table 2. Asymmetric hydrogenation[a] of seven-membered N-heterocyclic
compounds mediated by [Ir(Cl)(cod)(L1 or L3)].
Entry Substrate
(X, R)
Ligand Additive
Conv. ee [%][c]
[%][b] (configuration)[d]
1
2
3
4
5
6
7
8
3a (O, Me)[e]
3b (O, Ph)
3c (O, iPr)
3d (O, Bn)
5a (CH2, Me)
5b (CH2, Ph)
7a (NMe, Me) L3
7b (NMe, Ph) L1
9a (S, Me)
9b (S, Ph)
L3
L1
L3
L3
L3
L3
10 mol% HCl 99
91 (R)
Scheme 2. Hydrogenation reactions of 3 leading to products 4.
none
none
97
99
83 (S)
73 (R)
87 (R)
70 (R)
9 (S)
84 (R)
36 (S)
91 (R)
97 (S)
77 (R)
10 mol% HCl 99[f]
none
99
which is the presence or absence of substituents at the 3- and
3’-positions of the binaphthyl motif, led to opposite enantio-
mers of 4, 6, and 8 depending on the nature of the R substitu-
ent (alkyl or aryl groups; as an example, see Scheme 2 for the
hydrogenation reactions leading to 4).
10 mol% HCl 33[g]
10 mol% HCl 99
none
10 mol% HCl 99
none
10 mol% HCl 99[f]
24[g]
9
10
11
L3
L3
72[f]
11 a (SO2, Me) L3
[a] Reaction
conditions:
[{Ir(m-Cl)(cod)}2]/P-OP
ligand/substrate=
Rationalization of the stereochemical outcome of the hydro-
genations by DFT calculations
0.5:1.1:100 for pre-catalyst levels of 1 mol%, at rt, for 20 h, and with
a substrate concentration of 0.20m in MeTHF. If an additive was present,
the indicated amount of additive with respect to substrate was added to
a solution of the substrate before adding the catalyst. The values shown
are the average of at least two runs. [b] Conversions were determined by
1H NMR spectroscopy. Isolated yields after chromatography were >95%,
unless otherwise stated. [c] Determined by HPLC analysis by using chiral
stationary phases. [d] Absolute configurations of 4a, 4b, 4d, 10a, and
10b were assigned by comparison with literature data (see ref. [4c] for
the oxazepines and ref. [4h] for the thiazepines). The configurations of
4c, 6a, 6b, 8a, and 8b were assumed by analogy. The absolute configu-
ration of 12a was determined by X-ray analysis (see the Supporting Infor-
mation for details). [e] These results have been already summarized in
Table 1, but are included here for comparison. [f] Isolated yields for 4d,
10b, and 12a were 32, 53, and 59%, respectively. [g] Isolation was not at-
tempted owing to low conversions and ee values.
To shed light on the correlation between the features of the
P-OP ligands and enantioselection in the hydrogenation to-
wards alkyl-substituted products, we performed a theoretical
investigation into the reactivity of the catalytic systems derived
from ligands L1 and L3 with substrate 3a. We considered this
substrate to be suited to our purposes as the configuration of
the final product depends on whether the substituents at the
3- and 3’-positions of the phosphite group are H (L1; S-config-
ured product, see entries 1 and 2 in Table 1 and Scheme 2) or
Ph groups (L3; R-configured product; see entries 5 and 6 in
Table 1 and Scheme 2) and the absolute stereochemistry of its
hydrogenated product was unequivocally assigned. Theoretical
studies of enantioselective processes usually focus on the
stereo-determining step and compare the energy of transition
states (TSs) for the paths leading to the R and S products.[11]
The mechanism for the hydrogenation of iminic bonds is com-
plex, but has been explored at the experimental and theoreti-
cal level by a number of groups.[12] Mechanistic studies from
Pfaltz and co-workers have revealed that the employed iridium
complexes react with acyclic C=N-containing substrates to
form stable cyclometalated iridium complexes that are the real
hydrogenation catalysts.[13] In addition, a number of mechanis-
tic studies from other research groups have revealed that the
hydrogenation process takes place by transfer of a proton and
hydride to the C=N bond of the heterocyclic derivative being
non-coordinated to the metal center.[14]
selectivity induced by these additives, their role remains in
many cases unclear.[2j] The third and last trend that can be
seen in the data summarized in Table 2 is that the hydrogena-
tion of the substrates with R=Ph (compounds 3b, 5b, 7b,
and 9b) was more complicated than that of their alkyl substi-
tuted analogs. Although the hydrogenation of the O- and S-
containing substrates took place efficiently in the absence of
HCl (conversions up to 97%, ee values up to 97%, entries 2
and 10 in Table 2), the hydrogenation of the carbon and nitro-
gen-analogs 5b and 7b proceeded with low conversions and
ee (entries 6 and 8 in Table 2).
Previous work from our group on asymmetric hydrogena-
tions mediated by Ir[6] or Rh complexes[10] of P-OP ligands
revealed that the phosphite group was the principal stereo-
chemical director in the reaction (opposite configurations for
the resulting hydrogenated products are obtained when the
configuration of the phosphite moiety is inverted). Moreover,
the introduction of substituents at the 3- and 3’-positions of
the [1,1’-biaryl]-2,2’-diol group did not change the configura-
tion of the final product in Rh-mediated hydrogenations.[10] In-
terestingly, ligands L1 (or L2) and L3, the main difference of
We first explored the possibility of the hydrogenation path-
way involving the formation of cyclometalated iridium com-
plexes derived from 3a. The stabilities of the plausible four-
membered iridacycles derived from 3a were computed at the
BP86/def2-SVP level of theory (see Figure SI68 in the Support-
ing Information), which is a good compromise between the
size of the system (up to 139 atoms for the iridacycle involving
L3) and the accuracy of the results (see Figure SI67 in the Sup-
porting Information for a comparison of this functional with
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the MP2 and M06-2X methods). The energy content of the re-
sulting four-membered iridacycles was very high, indicating
the highly strained nature of these compounds.[15] Therefore,
this hydrogenation pathway via the formation of such inter-
mediates derived from 3a was not further explored.[16] As
regards the hydrogenation pathway involving proton and
hydride transfers to the C=N bond of heterocyclic derivatives,
Crabtree and Eisenstein[14b] identified octahedral dihydrido
mono-dihydrogen iridium complexes as crucial intermediates
in the hydrogenation process. This is because hydrogen trans-
fer from H2 to the C=N bond starts with proton migration from
the dihydrogen ligand to the nitrogen atom. Once the C=N
bond is protonated,[17] the position alpha to nitrogen is activat-
ed for the subsequent hydride transfer, which is the stereo-
determining step (Scheme 2).
Our own studies[6a] and those of others[5b] have demonstrat-
ed that the complexation of P-OP ligands with [{Ir(m-Cl)(cod)}2]
quantitatively leads to compounds [Ir(Cl)(cod)(P-OP)], which
correspond to the expected neutral pentacoordinated irid-
ium(I) complexes. Removal of the cod ligand under hydrogena-
tive conditions led to a complex mixture of P-OP–iridium com-
plexes. Unfortunately, neither NMR nor X-ray analysis allowed
us to unequivocally establish the structure of the iridium com-
plexes present in solution (no crystals suitable for X-ray analy-
sis could be isolated from this mixture). For this reason, the rel-
ative stabilities of the plausible [Ir(Cl)(H)2(H–H)(L1 or L3)] com-
plexes were computed at the BP86/def2-SVP level of theory.
From among all the possible isomers in an octahedral iridium
complex with one bidentate (L1 or L3) and one chlorido
ligand, only those with the two hydrido and dihydrogen
ligands in a fac[18] (facial) geometry were considered.[19] This is
because hydrogen transfer from [Ir(Cl)(H)2(H–H)(L1 or L3)] com-
plexes will lead to a trihydrido iridium complex and metal tri-
hydrides have an intrinsic preference[14b] for a fac geometry to
avoid hydrido ligands that are mutually placed in a trans fash-
ion. Interestingly, in [Ir(Cl)(H)2(H–H)(L1)], the favorable fac iso-
mers (Figure 1) contain chlorido ligands pointing in the same
direction and perpendicular to the plane that contains the
P-OP and Ir atoms (Figure 1a, b). The slightly more favored
complex (by 0.3 kcalmolÀ1) has the H–H ligand cis to the phos-
phite group. With regard to [Ir(Cl)(H)2(H–H)(L3)], the lowest
energy isomers also contain chlorido ligands perpendicular to
the same plane but pointing in the opposite direction with re-
spect to the [Ir(Cl)(H)2(H–H)(L1)] complexes (Figure 1c, d). This
is due to the formation of intramolecular CÀH···Cl bonds (see
Figure 1 and Figure SI70 in the Supporting Information). This
differentiating feature is very important for rationalizing the
opposite enantioselectivity observed for L1 and L3 with
methyl substituted substrates such as 3a (see below).
Figure 1. a–d) Optimized geometries of the most stable isomers of
[Ir(Cl)(H)2(H–H)(L1 or L3)] (some H atoms are omitted for clarity; distances in
ꢂ; energies in kcalmolÀ1).
derstanding the stereochemical outcome of the reaction from
the protonated substrate (H3a). Beginning from the initial geo-
metry after proton transfer, where the NÀH group points to
the IrÀH motif (Figure 2a, b), we examined different orienta-
tions of the protonated substrate (H3a) interacting with
[Ir(Cl)(H)3(L1 or L3)]. Remarkably, we found a pre-TS complex
for each ligand (Figure 2c, d) that was lower in energy than
the initial assembly owing to the formation of favorable non-
covalent interactions. In the case of L1, the preferred arrange-
ment is governed by two interactions that fix the geometry of
the substrate [hydrogen-bonds (HB) and CH3···p interactions,
see Figure 2c]. This pre-organized complex facilitates the nu-
cleophilic attack of the hydrido group that is located 3.0 ꢂ
away from the C atom in the C=N group (pro-(S) attack). In the
case of L3, the presence of the chlorido ligand at the position
opposite the P-OP containing plane with respect to L1 and the
formation of a strong NÀH···Cl interaction fixes the substrate in
a different arrangement compared with L1. Moreover, the for-
mation of a CÀH···HÀIr noncovalent interaction[20] (Figure 2d)
fixes the position of the substrate, facilitating the pro-(R) attack
of the hydrido ligand (located at 3.1 ꢂ). The pre-TS complexes
that would organize the protonated substrate towards the
minor enantiomer (i.e., pro-(R) attack for L1 and pro-(S) attack
for L3) were not found on the potential hypersurface.
The geometries of the TSs are shown in Figure 3. It is impor-
tant to note the existence of strong NÀH···Cl hydrogen
bonds[21] in the favored TSs. These interactions are crucial in ra-
tionalizing the observed stereoselection. The difference in
energy between the two transition states derived from L1
(DDG# =2.2 kcalmolÀ1) is mainly governed by the different
strength of the two hydrogen-bond interactions: an NÀH···Cl
hydrogen-bond for the TS leading to the major enantiomer
(TSS; see Figure 3a) and an NÀH···O hydrogen-bond[22] for the
TS leading to the minor enantiomer (TSR; see Figure 3c). As
the NÀH···Cl interaction involves an anionic ligand, it is electro-
statically favored with respect to the NÀH···O interaction. As re-
gards L3, the transition state leading to the major enantiomer
Protonation of 3a by [Ir(Cl)(H)2(H–H)(L1 or L3)][17] leads to
the assembly of [H3a][Ir(Cl)(H)3(L1 or L3)] (Figure 2a, b). Both
isomers of complex [Ir(Cl)(H)2(H–H)(L1)] (Figure 1a, b) yield the
same fac trihydrido iridium complex upon proton transfer
(same behavior for L3), which simplifies the study. Proton
transfer is not the stereo-determining step and the configura-
tion of the final product is determined at the later stages of
the catalytic cycle. Therefore, we employed calculations for un-
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Figure 2. a,b) Optimized geometries of [H3a][Ir(Cl)(H)3(L1 or L3)] assemblies.
c,d) Key distances [ꢂ] of pre-TS complexes found for [H3a][Ir(Cl)(H)3(L1 or
L3)] (some H atoms are omitted for clarity).
is also stabilized by an NÀH···Cl hydrogen-bond (TSR; see Fig-
ure 3b), whilst that leading to the minor enantiomer is stabi-
lized by a weaker NÀH···p interaction involving a phenyl group
(Figure 3c). As this NÀH··· p interaction involving the TSS de-
rived from L3 is also weaker than the NÀH···O hydrogen bond
in TSR derived from L1 (both leading to the minor enantiomers
of the hydrogenation product of 3a), the DDG# value for L3
(4.3 kcalmolÀ1) is higher than that for L1 (2.2 kcalmolÀ1). This
observation is in agreement with the higher enantioselectivity
observed experimentally in the hydrogenation of 3a with L3
than that with L1 (compare entry 5 with entry 1 in Table 1).
Figure 3. Optimized geometries of the transition states of: a) L1, and b) L3
and their energetic profiles in kcalmolÀ1 (some H atoms are omitted for
clarity). c) Optimized structures of the high energy transition states (distan-
ces in ꢂ).
rationalizing the stereochemical outcome of the reactions with
ligands L1 and L3. We are currently expanding the scope of
the hydrogenation reaction mediated by these ligands to new
heterocycles and will report on this work in due course.
Conclusions
This catalytic screening of enantioselective hydrogenation reac-
tions indicates that the iridium complexes of chiral P-OP li-
gands L1 and L3 are excellent catalysts in the hydrogenation
of various seven-membered heterocycles that contain C=N
bonds. The “lead” pre-catalyst for alkyl substituted seven-mem-
bered heterocycles (derived from ligand L3) in combination
with catalytic amounts of HCl exhibits excellent catalytic prop-
erties in this transformation. The hydrogenation of aryl substi-
tuted seven-membered heterocycles was more complicated
and highly efficient hydrogenation conditions could only be
developed for phenyl substituted oxa- and thiazepines by em-
ploying L1 without any additive. The enantioselectivity has
been rationalized by means of DFT calculations, which identi-
fied the position of the Cl ligand in the catalytically relevant iri-
dium structures and a number of noncovalent interactions (i.e.,
NÀH···Cl, CH···p, and CH···HÀIr interactions[23]) as key features in
Experimental Section
General procedure for the Ir-catalyzed asymmetric hydroge-
nation
A solution of the required amount of [{Ir(m-Cl)(cod)}2] (0.005 mmol)
and the P-OP ligand (0.011 mmol) in the corresponding dry and de-
oxygenated solvent (5.0 mL) was loaded into an autoclave under
N2, in which the required amounts of substrate (1 mmol) and anhy-
drous HCl (0.1m solution in the required solvent), if necessary,
were placed beforehand. The concentration of the substrate was
adjusted to a final concentration of 0.20m. The autoclave was
purged three times with H2 (at a pressure not higher than the one
selected) and finally, the autoclave was pressurized with H2 to the
desired pressure. The reaction mixture was stirred at the desired
temperature for the stated reaction time. The autoclave was subse-
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Suꢀrez, M. A. Mꢄndez-Rojas, A. Pizzano, Organometallics 2002, 21,
4611–4621 and reference [6].
quently depressurized, the reaction mixture passed through
a short pad of SiO2 and further eluted with EtOAc (2ꢃ1 mL). The
resulting solution was evaporated in vacuo. The conversion was
determined by H NMR spectroscopy and enantioselectivities were
determined by HPLC analysis on chiral stationary phases.
[6] a) J. L. NfflÇez-Rico, H. Fernꢀndez-Pꢄrez, J. Benet-Buchholz, A. Vidal-
Ferran, Organometallics 2010, 29, 6627–6631; b) J. L. NfflÇez-Rico, A.
Vidal-Ferran, Org. Lett. 2013, 15, 2066–2069; c) J. L. NfflÇez-Rico, H.
Fernꢀndez-Pꢄrez, A. Vidal-Ferran, Green Chem. 2014, 16, 1153–1157.
[7] The ligands with opposite configuration at the phosphite fragment
were also studied in this transformation and led in all cases to lower
enantioselectivities than those obtained with the corresponding diaste-
reomeric ligands L1–L4. See the Supporting Information for details (Ta-
ble SI1).
1
Acknowledgments
The authors would like to thank MINECO (CTQ2014-60256-P,
CTQ2014-57393-C2-1-P and Severo Ochoa Excellence Accredi-
tation 2014-2018 SEV-2013-0319) and the ICIQ Foundation for
financial support. B.B. thanks the AGAUR for a pre-doctoral fel-
lowship (2013FI-B 00545). Dr. Josꢄ Luis NfflÇez-Rico and Dr.
Hꢄctor Fernꢀndez-Pꢄrez are gratefully acknowledged for proof-
reading the manuscript and Dr. J. Benet-Buchholz for the X-ray
crystallographic data.
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Keywords: asymmetric
hydrogenation
·
enantiopure
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[16] The Pfaltz mechanism (ref. [13]) cannot be excluded for substrates
where cyclometalation can be expected to be favored, such as for the
aryl substituted substrates studied in this work.
[17] The use of catalytic amounts of HCl as additive translates to partial pro-
tonation of the substrate (HCl is added to the substrate before the cat-
alyst). However, it should be recalled at this point that dihydrogen li-
gands in iridium complexes might certainly play a role in the protona-
tion of the substrate: most of the heterocycles studied are fully hydro-
genated with high enantioselectivities by employing sub-stoichiometric
amounts of HCl, or even in the absence of HCl (see Tables 1, SI1, SI2,
and SI3).
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Received: March 29, 2016
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Published online on && &&, 0000
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FULL PAPER
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Asymmetric Hydrogenation
B. Balakrishna, A. Bauzꢁ, A. Frontera,*
A. Vidal-Ferran*
&& – &&
Asymmetric Hydrogenation of Seven-
Membered C=N-containing
Heterocycles and Rationalization of
the Enantioselectivity
Cl switch: Efficient enantioselective hy-
drogenation of seven-membered N-het-
erocycles mediated by Ir-(P-OP) com-
plexes is described (11 examples, up to
97% ee; see figure). The position of the
Cl ligand in the catalytically relevant Ir
species (amongst other factors) is key
for rationalizing the stereochemical out-
come.
&
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Chem. Eur. J. 2016, 22, 1 – 8
www.chemeurj.org
8
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!