Mild Iridium-Catalysed Isomerization of Epoxides. Computational Insights and Application to the Synthesis of β-Alkyl Amines

Article abstract of DOI:10.1002/adsc.201900372

The isomerization of epoxides to aldehydes using the readily available Crabtree's reagent is described. The aldehydes were transformed into synthetically useful amines by a one-pot reductive amination using pyrrolidine as imine-formation catalyst. The reactions worked with low catalyst loadings in very mild conditions. The procedure is operationally simple and tolerates a wide range of functional groups. A DFT study of its mechanism is presented showing that the isomerization takes place via an iridium hydride mechanism with a low energy barrier, in agreement with the mild reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.201900372

Title: Mild Iridium-Catalysed Isomerization of Epoxides. Computational
Insights and Application to the Synthesis of beta-Alkyl Amines
Authors: Albert Cabré, Juanjo Cabezas-Giménez, Giuseppe Sciortino,
Gregori Ujaque, Xavier Verdaguer, Agusti Lledos, and Antoni
Riera
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10.1002/adsc.201900372
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Mild Iridium-Catalysed Isomerization of Epoxides.
Computational Insights and Application to the Synthesis of β-
Alkyl Amines
Albert Cabré,a,b Juanjo Cabezas-Giménez,a,b Giuseppe Sciortino,c,d Gregori Ujaque,c
Xavier Verdaguer*a,b Agustí Lledós,*c and Antoni Riera*a,b
a
Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain.
antoni.riera@irbbarcelona.org. Tel (+34)934037093. xavier.verdaguer@irbbarcelona.org.
Departament de Química Inorgànica i Orgànica, Secció Orgànica. Universitat de Barcelona, Martí i Franquès 1,
b
Barcelona E-08028, Spain.
c
Departament de Química, Edifici C.n., Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193, Spain.
agusti@klingon.uab.es.
Dipt. di Chimica e Farmacia, Università di Sassari, via Vienna 2, I-07017 Sassari, Italy.
d
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The isomerization of epoxides to aldehydes conditions. The catalytic version using copper salts,[9]
indium chloride[10] or iridium chloride[11] has also been
described. However, a number of limitations, namely
using the readily available Crabtree’s reagent is described.
The aldehydes were transformed into synthetically useful
amines by a one-pot reductive amination using pyrrolidine
moderate product selectivity, high temperature and
as imine-formation catalyst. The reactions worked with low
catalyst loading, and toxicity of the catalysts, remain
catalyst loadings in very mild conditions. The procedure is
to be addressed when employing catalytic conditions.
operationally simple and tolerates a wide range of
functional groups. A DFT study of its mechanism is
presented showing that the isomerization takes place via an
iridium hydride mechanism with a low energy barrier, in
agreement with the mild reaction conditions.
In recent years, other alternative procedures have been
reported such as the use of metal-free self-assembled
organic supramolecular capsules[12] or heterogeneous
mesoporous aluminosilicate materials.[13] In the
organometallic field, Mazet and co-workers reported
the most relevant breakthrough using novel
palladium[14] and iridium[15] catalysts. However, high
temperatures (85-140°C and 100°C respectively) were
needed in both cases.
Keywords: iridium; epoxides; isomerization; Crabtree’s
catalyst; β-alkyl amines.
Epoxides can be interconverted into a variety of
functional groups and are thus valuable synthetic
intermediates.[1] The high reactivity of the strained 3-
membered ring of epoxides commonly enables a wide
range of stereospecific nucleophilic ring opening
reactions.[2] The isomerization into the corresponding
carbonyl analogs is usually referred to as the
Meinwald rearrangement.[3] Due to its excellent
efficiency and atom economy, this reaction has gained
relevance for the synthesis of carbonyl compounds,[4a]
ring
expansion
reactions,[4b,c]
and
tandem
processes.[4d,e] The Lewis acid-promoted Meinwald
rearrangement has found application in fine chemistry
and
industrial
processes.[4]
However,
the
regiochemical outcome is a common issue since it
depends on the promoter and the migratory capacity of
the substituents.[5] The use of stoichiometric amounts
of Lewis acids such as BF3·Et2O, [6] lithium salts[7] and
magnesium bromide[8] are the most widely used
Figure 1. Crabtree’s catalyst in isomerization reactions.
1
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10.1002/adsc.201900372
Advanced Synthesis & Catalysis
We recently reported that the readily available
Crabtree’s reagent[16] is an efficient catalyst for the
isomerization of N-sulfonyl aziridines into allyl
amines (Fig. 1A).[17] Encouraged by this result we
envisioned that this catalyst could also be used in the
isomerization of epoxides. We found that, after
activation,[18] Crabtree’s catalyst isomerized terminal
epoxides into aldehydes (Figure 1B). One of the
drawbacks of this transformation was the handling of
the resulting aldehydes. Therefore, we set up a one-pot
reductive amination procedure using primary amines
to isolate stable, easy to handle amines.
the reaction can be done using hydrogen at
atmospheric pressure (balloon). Purging the vessel to
degas H2 once the catalytic active species was formed
did not affect neither the reactivity nor the selectivity
(Table 1, entry 9).
Once the optimal conditions for the isomerization
reaction had been determined, we proceeded to study
the reductive amination. Otte and co-workers
pioneered
a
tandem Meinwald rearrangement-
[23]
reductive amination using B(C6F5)3 However, the
scope of the amine was limited to anilines.
We reasoned that benzhydrylamine would be a
convenient amine since it can be considered a
synthetic equivalent of ammonia due to its easy
hydrogenolysis. Therefore, we devised a two-step
procedure that could be done in situ. To avoid the use
of reagents such as TiCl4 or Ti(iPrO)4, which are
usually required for imine formation and could
interfere with our catalyst of choice we selected the
aminocatalytic procedure developed by Cid and co-
workers.[24] The addition of 10 mol % of pyrrolidine
led to the formation of the aldimine of
benzhydrylamine 5a with total conversion after 2 h.
With the optimal conditions for the imine formation in
hand, we sought a reducing agent. Since the reduction
could not be performed by hydrogen due to
deactivation of iridium catalyst by the amine, we tested
sodium cyanoborohydride (Table 2, entry 1).
Conversion after 2 h was low, so we then tested a
stronger reductant, NaBH4, and added MeOH to the
mixture. Under these conditions the reaction went to
completion and amine 6a was afforded in an isolated
yield of 67 % (Table 2, entry 2). The optimized
protocol was scaled up to 1g of epoxide using only 1
mol % of iridium catalyst 4B, yielding a remarkable
51% overall yield for the three steps.
Here, we describe the isomerization of terminal
epoxides into aldehydes using Crabtree’s catalyst
(Figure 1B), followed by the reductive amination of
the in situ formed aldimines to afford synthetically
useful amines (Scheme 1). Our one-pot procedure
gave excellent selectivity. The resulting amines,
containing an alkyl group in the β position, are
important motifs in numerous drugs and biologically
active compounds.[19]
Scheme 1. One-pot procedure of the Meinwald
rearrangement and reductive amination.
2-Methyl-2-phenyloxirane 1a, easily synthesized by
the Corey-Chaykosvky reaction,[20] was selected as
model substrate. Isomerization of 1a can, a priori,
afford aldehyde 2a or allylic alcohol 3a (Table 1). We
first tested Crabtree’s catalyst (4A) in 1 mol %,
without activation in dichloromethane. After 17 h,
1
only 35% of conversion was detected by H NMR
(Table 1, entry 1). Aldehyde was selectively formed as
the major product. We then activated the catalyst with
H2, to form a putative dihydride species.[21] Overnight
stirring at room temperature increased the conversion
up to 68% (Table 1, entry 2). Gratifyingly, the
aldehyde was not affected by the presence of H2.
Therefore, we increased the catalyst loading up to 3
mol %. The reaction went to completion after 17 h, and
an aldehyde/alcohol ratio of 80:20 was achieved
(Table 1, entry 3). We then performed a solvent
screening. Diethyl ether or toluene did not improve the
results (Table 1, entries 4 and 5). This result could be
explained by the low solubility of Crabtree’s catalyst
in these organic solvents. Therefore, we replaced PF6
by BArF as counter ion. Using the Pfaltz’s version of
Crabtree’s catalyst (4B)[22] in toluene we were pleased
to see that full conversion was achieved after 17 h and
with a slight improvement in selectivity (Table 1, entry
6). Finally, using either activated catalyst 4A or 4B in
THF the reaction was complete after overnight stirring
at room temperature reaching a selectivity of 93:7. Of
note the selectivity in THF was similar in both cases
(Table 1, entries 7 and 8). Since the hydrogen is only
necessary to activate the catalyst the pressure is not
important. We used 3 bars as standard procedure but
Table 1. Optimization of the isomerization reaction.
Yield 2a (%)[a]
Entry Cat. Solvent Conv.
(ratio 2a:3a)
1 [b] [c]
A
A
A
A
A
B
A
B
A
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Toluene 33%
Toluene
THF
35%
68%
>99
-
-
2 [b]
3
75 (80:20)
-
4
5
6
7
8
9 [d]
30%
>99
>99
>99
>99
79 (86:14)
85 (94:6)
84 (93:7)
84 (94:6)
THF
THF
Reactions were performed in a pressure tube, at room temperature and
stirring overnight. The catalyst (3 mol %) and substrate were weighted,
brought to a dry box, dissolved in anhydrous solvent and charged with
hydrogen. [a] NMR yield using 1,4-dimethoxybenzene as internal standard.
2
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10.1002/adsc.201900372
Advanced Synthesis & Catalysis
A small percentage of diol was observed in case of air moisture. [b] 1 mol %
of catalyst was used. [c] Without external activation. [d] H2 for 1 minute; then
degas.
towards the aldehyde and 6l and 6m were afforded in
57 % and 75 % yield, respectively (Table 3, entries 11-
12). Finally, as an example of dialkyl epoxide, the
phenethyl oxirane 1n was also studied. In this regard,
when using 5 mol % of 4B, the reaction went to
completion after 12 h with only few traces of alcohol
species and afforded the corresponding amine 6n in
79% yield (Table 3, entry 13).
Table 2. Optimization of the reductive amination.
Table 3. Epoxide scope of the reaction. All reactions were
performed in a pressure tube. Ratio 2:3 is the selectivity
towards the aldehyde when the isomerization reaction is
finished, measured by 1H NMR..
Conversion[a]
entry
Conditions
(3-step yield)[b]
1
1) pyrrolidine (10 mol%)
2) NaBH3CN in THF, 2h
1) pyrrolidine (10 mol%)
2) NaBH4 in MeOH, 2h
6a: 70% (54%)
6a: 100%
(67%;51%[c])
2
[c]
[a] Detected by 1H NMR. [b] Isolated yield. Isolated yield in gram scale,
using 1 mol% of catalyst 4B.
cat.
ratio Yield
entry
1
R1
R2
We then proceeded to study the scope of the reaction.
To this end, a set of 13 2,2-disubstituted epoxides (1b-
n) were tested (Table 3). The substituent pattern
slightly altered the optimal conditions found for the
isomerization reaction. We observed that the use of
electron-withdrawing substituents was well tolerated.
Time[b] 2:3 (%)[c]
4A; 17
94:6
1
1b
p-F-Ph
Me
57
h
4A; 2h
2
3
4
5
1c
1d
1e
1f
p-Cl-Ph
p-Br-Ph
p-I-Ph
Me
Me
95:5
>99
67
74
63
80
4B;
12h
4B;
12h
4A:
48h
Amine 6b derived from 2-(4-fluorophenyl)-2-
methyloxirane 1b was obtained with an overall yield
of 57 % (Table 3, entry 1). The isomerization reaction
starting from the p-chlorophenyl oxirane 1b (Table 3,
entry 2), took place in only 2 h and the corresponding
amine 6c was obtained in 67 % isolated yield. In the
case of p-Br and p-I derivatives 1d-e the reaction
lasted longer (48 h). However, this drawback could be
solved by modifying the counter ion from PF6 to BArF.
In these cases, the reaction times were reduced to 12 h
and the alcoholic species were minimized. After the
reductive amination procedure, the resulting amines
6d-e were obtained in synthetically useful yields (63-
74 %)(Table 3, entries 3-4).
Me
Me
92:8
97:3
o-Me-Ph
4A;
12h
p-Me-Ph
6
1g
Me
94:6
45
4A;
12h
4A;
12h
7
8
1h o-MeO-Ph Me
1i p-MeO-Ph Me
98:2
>99
71
45
4A;
12h
1j
9
2-Naphth Me
91:9
>99
62
70
We then studied the effect of electron-donating groups
(methyl and methoxy) in ortho or para-position of the
aromatic ring. Using the optimized conditions, all
reactions were completed after 12 h (Table 3, entries
6-8) with the exception of the ortho-methyl compound
1f which due to steric hindrance, lasted 48 h (Table 3,
entry 5). The ratio of alcoholic species formed were
minimal in all cases, thus demonstrating the high
selectivity of this transformation. The 2-naphthy
substituent 1j afforded the corresponding amine 6j in
62 % yield (Table 3, entry 9) using standard conditions.
To prove the versatility of this reaction, the methyl
group was also modified. When using an ethyl
substituent, the amine 6k was afforded in 70 % yield
and no alcoholic species were detected after the
isomerization reaction (Table 3, entry 10).
4A;
12h
10
11
1k
1l
Ph
Ph
Ph
Et
iPr 4B; 3h >99
57
75
4B;
12 1m
Cy
>99
12h
4B;
12h
13[a] 1n PhCH2CH2 Me
98:2
79
[a] 5 mol % of catalyst 4B was used. [b]Isomerization time. [c] Overall
isolated yields.
The benzhydrylamine moiety can be easily removed
by hydrogenolysis to afford free amines that can be
further derivatized (See ESI†).
The isomerization reaction also took place in epoxides
with different substitution patterns. Using 1 mol % of
4B in dichloromethane, 2-methyl-3-phenyloxirane 1o
isomerized to methyl ketone 2o in excellent yield
For the branched alkyl substituent, catalyst 4B was
necessary for completion of the reaction. The
isomerization reaction showed excellent selectivity
3
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10.1002/adsc.201900372
Advanced Synthesis & Catalysis
(Scheme 2). In the case of trisubstituted epoxide 1p,
instead of hydride migration we observed phenyl
migration yielding aldehyde 2p as a single product
(89% isolated yield). Again, the hydrogen pressure did
not affect the reaction. 2,2-Diaryloxiranes are
concluding that the most stable configurations are
those with the H and PCy3 ligands mutually cis and the
second hydride in the axial position. An isomer with
the hydride trans to the phosphine ligand was found ca.
17.0 kcal·mol-1 above. The equatorial hydride can be
coordinated trans a vacancy or trans pyridine with
very similar energies (G of 1.1 kcal·mol-1) and easy
interconversion (Gibbs energy barrier 9.0 kcal·mol-1)
highlighting a fast equilibrium between these two
relative orientations (Scheme SI1 of the ESI†).
Between them, the species with H trans pyridine can
better accommodate the incoming substrate and has
been taken as the catalytic configuration.
extremely
reactive.
2-(4-Chlorophenyl)-2-
phenyloxirane (1q) gave 30% yield of the
corresponding aldehyde (2q), along with 65% of
demethylenation product in only 2 h of reaction and
using 1 mol % of 4A (See ESI†)
The O-coordination of 1a at the empty equatorial
position generates intermediate I at 1.9 kcal·mol-1 and
gives rise to the catalytic cycle depicted in Scheme 3.
Scheme 2. Iridium-catalyzed isomerization of 1,2-di-
and tri-substituted epoxides.
On the other hand, the amine scope could also be
expanded. p-Methoxyaniline (Table 4, entry 1),
benzylamine (Table 4, entry 2) and enantiomerically
pure (R)-(+)-1-phenylethan-1-amine (Table 4, entry 3)
were successfully tested with synthetically useful
yields. In the latter example, the separation of the two
diastereoisomers enabled the formation of
enantioenriched amines after hydrogenolysis (See
ESI†).
Table 4. Amine scope of the reaction. Reactions were
performed in a pressure tube, using 4B (5 mol %) as catalyst
and 1.1 equiv. of amine.
Scheme 3. DFT computed mechanism (B3LYP-D3 in THF)
for the Ir-catalysed isomerization of epoxide 1a to aldehyde
2a. Relative Gibbs energies (in purple) in kcal·mol-1 are
referred to the separated catalytically active species
[IrIII(H)2(py)(PCy3)]+ and substrate 1a; transition state
energies are shown in parenthesis and blue.
entry
1
2
amine
Yield (%)[a]
7a, 64%
8a, 55%
p-OMe-aniline
Benzylamine
(R)-(+)-1-
3
9a, 56% (3:2 dr)
Phenylethylamine
[a] Isolated yields.
The associated Gibbs energy profile can be found at
ESI† (Figure SI1). Subsequent concerted ring-opening
and C-coordination leads to the formation of a five-
member ring metallacycle, II, with a relative energy of
11.2 kcal·mol-1, overcoming an energy barrier of 19.9
kcal·mol-1, TSI-II (Figure 2a). This transition state is
the highest point in the Gibbs energy profile, making
the ring-opening step the rate-determining step.
Intermediate II is a highly distorted octahedron with
the oxygen in the axial position and the equatorial
hydride close to the β-carbon of 1a (Cβ ···HIr 2.219 Å).
From this intermediate an easy hydride insertion to the
γ-carbon-Ir bond opens the metallacycle leading to
To gain a thorough understanding of the isomerization
step, we performed a DFT study of its reaction
mechanism using the B3LYP-D3[25] functional and a
continuum model of the THF solvent[26] (see ESI† for
details). We initially studied the activation of the
Crabtree’s catalyst, entailing hydrogenation of the
COD ligand and cyclooctane release and formation of
the unsaturated dihydride complex. This step is very
exergonic (G= -30.6 kcal·mol-1) and generates the
catalytic active specie [IrIII(H)2(py)(PCy3)]+ in a
octahedral arrangement with two vacancies. Several
possible isomers were evaluated for this species,
4
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10.1002/adsc.201900372
Advanced Synthesis & Catalysis
Intermediate III, falling at 2.4 kcal·mol-1. This is
practically a barrierless process with its transition sate
(TSII-III, Figure 2b) at the same energy (11.1 kcal·mol-
1) than intermediate II. According to this mechanism
the reaction should proceed with retention of
configuration. This was confirmed experimentally.
Starting from enantiomerically pure (R)-1a,
enantiomerically enriched (S)-2a was obtained, albeit
with low ee (26% ee) due to substantial racemization
to the γ-carbon and β hydride elimination yields the
aldehyde. Despite this general mechanistic similarity,
some differences arise between the palladium and
iridium hydride-catalysed epoxide isomerization. First,
ring-opening of the epoxide is notably easier in
presence of the iridium catalyst (Gibbs energy barriers
in THF of 24.0 and 19.9 kcal mol-1 for the Pd and Ir
complexes, [14,15] respectively). This behaviour can be
related to the highly unsaturated nature of the Ir-
catalyst, which has two vacant sites. This feature also
allows the stabilization of a metallocycle intermediate
(II) absent in the palladium system. Correspondingly,
the overall barrier for the isomerization is lower for the
Ir-catalyst than for Pd (19.9 vs. 26.4 kcal mol-1) in
agreement with the milder conditions at which the
reaction takes place (room temperature, see Tables 1
and 3).
of the aldehyde in the reaction conditions (See ESI†)
[27]
To complete the isomerization, a hydrogen from the
substrate must end up at the metal. Consequently, -
hydride elimination is the last step of the isomerization
process. Previously, substrate reorientation in
intermediate III is required to place the β H near to the
vacant equatorial position at iridium. The rotation
process occurs barrierless and leads to the more stable
conformation of intermediate IV at -8.5 kcal·mol-1
(βH···Ir 2.927 Å). β-hydride elimination from
intermediate IV is a two-step process in which, first a
strong βH-Ir agostic interaction takes place (βH···Ir
1.736 Å, V, -7.0 kcal·mol-1), followed by the β-H-C
elimination, with relative Gibbs energies of -2.8 and -
6.3 kcal·mol-1 for TSIV-V and TSV-VI, respectively
(Figures 2c and 2d). Finally, from intermediate VI (-
17.4 kcal·mol-1) the replacement of the aldehyde by a
reactant molecule closes the catalytic cycle.
In conclusion, the selective isomerization of terminal
epoxides to aldehydes has been accomplished using
low catalyst loadings (up to 1 mol%) of the readily
available Crabtree’s reagent. The pre-catalyst requires
activation with hydrogen but there is no need to degas
the vessel afterwards. The reaction occurs under
milder conditions than in previous reports were high
temperatures were required. DFT calculations reveal
that the isomerization takes place via a hydride
mechanism similar to that described for a palladium
hydride complex,[14] but with a considerably lower
barrier, in agreement with the milder reaction
conditions (room temperature). The reductive
amination of the resulting aldehydes can be performed
in situ. We have optimised a one-pot protocol based on
the imine formation catalysed by pyrrolidine followed
by reduction with NaBH4. Using benzhydrylamine, up
to 14 amines have been synthesized in good to
excellent yields. The reaction can be easily scaled up.
Other aryl or alkyl amines –including chiral ones- have
been successfully used.
Acknowledgements
We thank institutional funding from the Spanish Ministry of
Economy, Industry and Competitiveness (MINECO, CTQ2017-
87840-P and CTQ2017-87889-P) through the Centres of
Excellence Severo Ochoa award, and from the CERCA
Programme of the Catalan Government. A.C. and G.S. thank
MINECO and UAB for Ph.D. fellowships (FPU and UAB-PIF).
References
Figure 2. Transition state optimised geometries for:
ring opening, TSI-II; hydride transfer, TSII-III; (Cβ-H)-Ir
agostic formation, TSIV-V; β-H elimination, TSV-VI. The
most important distances are also reported in Å.
Hydrogen atoms and cyclohexyl (Cy) groups have been
omitted for clarity.
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5
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10.1002/adsc.201900372
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10.1002/adsc.201900372
Advanced Synthesis & Catalysis
UPDATE
Mild Iridium-Catalysed Isomerization of Epoxides.
Computational Insights and Application to the
Synthesis of β-Alkyl Amines
Adv. Synth. Catal. 2019, Volume, Page – Page
Albert Cabré,a,b Juanjo Cabezas-Giménez,a,b
Giuseppe Sciortino,c,d Gregori Ujaque,c Xavier
Verdaguer*a,b Agustí Lledós,*c and Antoni Riera*a,b
7
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