Asymmetric α-amination of aldehydes catalyzed by PS-diphenylprolinol silyl ethers: Remediation of catalyst deactivation for continuous flow operation

Article abstract of DOI:10.1002/adsc.201200887

Polystyrene (PS)-supported diphenylprolinol silyl ethers have been developed as highly active catalysts for the enantioselective α-amination of aldehydes. Understanding the mechanism of catalyst deactivation has led to the development of reaction conditions notably extending catalyst life in repeated recycling (10 cycles; accumulated TON of 480) and has allowed the implementation of a continuous flow α-amination process (6 min residence time, 8 h operation). Copyright

Full text of DOI:10.1002/adsc.201200887

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DOI: 10.1002/adsc.201200887
Asymmetric a-Amination of Aldehydes Catalyzed by
PS-Diphenylprolinol Silyl Ethers: Remediation of Catalyst
Deactivation for Continuous Flow Operation
Xinyuan Fan,a Sonia Sayalero,a and Miquel A. Pericꢀsa,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Paꢁsos Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-9-77920222; e-mail: mapericas@iciq.es
Departament de Quꢂmica Orgꢀnica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
b
Received: October 2, 2012; Published online: October 30, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200887.
Abstract: Polystyrene (PS)-supported diphenylpro-
linol silyl ethers have been developed as highly
active catalysts for the enantioselective a-amination
of aldehydes. Understanding the mechanism of cat-
alyst deactivation has led to the development of re-
action conditions notably extending catalyst life in
repeated recycling (10 cycles; accumulated TON of
480) and has allowed the implementation of a con-
tinuous flow a-amination process (6 min residence
time, 8 h operation).
In spite of this intense study, reports on the a-ami-
nation of aldehydes mediated by reusable catalysts[12]
are scarce, and this is due to the high reactivity of
azodicarboxylate esters in the presence of amines.[13]
Indeed, azodicarboxylates react with amines to yield
triazanes (Scheme 1), a process which is generally
considered as a catalyst off-cycle reaction.[14] There-
fore, the development of an efficient catalyst, which
can be recovered and reused, and even applied in
continuous flow operation, remains a big challenge in
a-amination. Herein, we report the first enantioselec-
tive a-amination of aldehydes catalyzed by a polystyr-
ene (PS)-supported diphenylprolinol silyl ether cata-
lyst, the elucidation of the catalyst deactivation mode,
and the development of reaction conditions that pre-
vent deactivation, thus allowing its repeated reuse
and its application in a single-pass, continuous flow
process for the production of enantiopure a-hydrazi-
Keywords: asymmetric a-amination; continuous
flow operation; diphenylprolinol silyl ethers; orga-
nocatalysis; supported catalysts
Chiral a-aminated carbonyl compounds are important no alcohols.
molecules in organic synthesis as they can be easily
Based on our previous research on immobilization
transformed into bioactive compounds, such as a- of Jørgensen–Hayashi-type catalysts and their appli-
amino acids, amino esters and amino alcohols.[1] For cation in Michael reactions,[15] we decided to further
this reason, there is a great deal of interest in devel- study these catalytic species in the a-amination reac-
oping catalytic direct strategies for the electrophilic tion. Furthermore, in order to avoid silyl group loss
a-amination of carbonyl compounds and, in particu- from the catalyst during the reaction, TES, TBS and
lar, organocatalytic methods that avoid the use of TIPS protecting groups were used instead of the more
toxic metals.[2] The first direct enantioselective a-ami- labile TMS (trimethylsilyl). With this more robust
nation of aldehydes catalyzed by proline using azodi- OH-protection, it was expected that convenient, truly
carboxylate esters as electrophiles was simultaneously reusable catalysts could be developed that avoid the
reported by Jørgensen and List in 2002,[3] and the re- need of re-protection of the OH group after each re-
action was later extended to a-branched aldehydes[4] action cycle.[15a] In addition, more robust catalysts
and ketones.[5] At the same time, novel non-amino
acid organocatalysts such as pyrrolidinyl-tetrazoles,[6]
2-(arysulfonylaminomethyl)pyrrolidines,[7]
silyl-pro-
tected diarylprolinols,[8] Cinchona alkaloid deriva-
tives,[9] bifunctional ureas[10] and thiourea-based cata-
lysts[11] have been designed and succesfully applied in
the a-amination of carbonyl substrates via enamine
intermediates.
Scheme 1. Reaction of azodicarboxylates with secondary
amines.
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Table 1. Screening of reaction conditions for the a-amina-
tion of propanal.[a]
Entry Catalyst
(mol%)
Additive
(mol%)
Solvent Time
[min]
ee[b]
[%]
1[c]
2
1c (10%)
1c (10%)
None
PhCO2H
(10%)
MeCN 1710
MeCN 270
7
69
3
4
5
6
7
8
9
1a (10%)
1b (10%)
1b (10%)
1b (2%)
1b (1%)
1b (2%)
1b (2%)
PhCO2H
(10%)
PhCO2H
(10%)
PhCO2H
(10%)
PhCO2H
(10%)
PhCO2H
(10%)
PhCO2H
(2%)
PNBA (2%) CH2Cl2 50
TFA (2%) CH2Cl2 1440
AcOH (2%) CH2Cl2 1200
AcOH (8%) CH2Cl2 70
MeCN 180
MeCN 240
63
73
83
86
88
90
Figure 1. Catalysts developed for this work. TES=triethyl-
silyl, TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
CH2Cl2 3
CH2Cl2 30
CH2Cl2 65
CH2Cl2 90
could allow performing the reaction under continuous
flow conditions for more extended periods of time
than their TMS analogues.[15c] According to this
design, polymer-supported catalysts 1a–c (Figure 1)
were synthesized and studied in the a-amination of al-
dehydes with DBAD (dibenzyl azodicarboxylate).
Catalyst 1c was first tested in the a-amination of
propanal (3a) with DBAD in CH3CN, a common sol-
vent for this reaction.[2] However, only 18% conver-
sion was detected after 28.5 h (Table 1, entry 1). The
use of PhCO2H (10 mol%) as an additive (entries 2–
4) notably accelerated the reactions and showed that
1b offers the best compromise between catalytic activ-
ity and enantioselectivity (entry 4). Gratifyingly, when
CH2Cl2, a better resin-swelling solvent, was used with
the same amounts of catalyst and additive (entry 5)
the a-amination was completed in only 3 min and,
after reduction, 4a was obtained with 83% ee. Further
optimization of the amounts of catalyst and additive
76
64
87
93
93
10[d] 1b (2%)
11
12
13
1b (2%)
1b (2%)
1b (2%)
AcOH
(10%)
CH2Cl2 45
[a]
All reactions were carried out with 0.2 mmol of DBAD
and 0.3 mmol of propanal in 2 mL of solvent until com-
plete conversion.
[b]
[c]
The ee was determined by chiral HPLC of 4a.
A conversion of 18% was detected by H NMR.[d] A con-
1
version of 62% was detected by 1H NMR. TFA=tri-
fluoroacetic acid, PNBA=p-nitrobenzoic acid.
(entries 6–8) led to substantial reduction (2 mol% was also tested as the amination reagent with 3-phe-
each, entry 8) with significant improvement in enan- nylpropanal (entry 10); however, the reaction was no-
tioselectivity (90%). It is noteworthy that this level of tably slower (180 vs. 37 min) and took place with
catalyst loading is remarkably lower than those previ- slightly decreased enatioselectivity. The reaction with
ously used for the same reaction in spite of the heter- an aliphatic g-branched aldehyde, such as 4-methyl-
ogeneous nature of 1b.[3,6–8] While the effect of more pentanal (entry 9), worked also smoothly and afford-
acidic additives proved deleterious (entries 9 and 10), ed the corresponding a-amination product with 98%
the easily separable acetic acid (entries 11-13) led to ee and 90% yield in a short reaction time (75 min).
optimal results. Thus, the combination of 2 mol% 1b
and 10 mol% AcOH led to complete conversion in detected when a-branched or b-branched aldehydes
45 min, and afforded 4a with 93% ee (entry 13). were used in the reaction. A similar behaviour has
In sharp contrast with these results, no reaction was
The optimized reaction conditions were used to in- been also observed in Michael additions of aldehydes
vestigate the scope of the a-amination of aldehydes to b-nitrostyrenes promoted by TMS-protected PS-di-
with DBAD as shown in Table 2. Catalyst 1b worked phenylprolinol.[15a] In the present instance, this lack of
smoothly in the a-amination of linear aldehydes, high reactivity appears to be due to non-formation of the
yields and enantioselectivities being recorded in very requisite enamine intermediate between the rather
short reaction times at low catalyst loadings (en- hindered pyrrolidine catalyst 1b and the branched al-
tries 1–5 and 8). Excellent results in shorter reaction dehyde, since the presence of one such a-branched al-
times were also obtained with 3-phenylpropanal and dehyde does not modify the amination rate of a linear
3-(3-chlorophenyl)propanal (entries 6 and 7). DIAD one (see below).
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Asymmetric a-Amination of Aldehydes Catalyzed by PS-Diphenylprolinol Silyl Ethers
Table 2. a-Amination of aldehydes catalyzed by 1b.[a]
Entry R (3)
Time
[min]
Product Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
Me (3a)
Et (3b)
n-Pr (3c)
n-Bu (3d)
n-C5H11 (3e)
Bn (3f)
3-ClC6H4CH2
(3g)
CH2=CH-
ACHTUNGTRENNUNG
45
47
53
70
100
37
40
4a
4b
4c
4d
4e
4f
4g
92
94
91
91
88
89
92
93
94
90
95
91
95
98
Scheme 2. Chemoselective and enantioselective a-amination
of butanal with DBAD catalyzed by 1b in the presence of 2-
methylpropanal.
ments with propanal, DBAD, acetic acid and with the
reaction product for 75 min before the a-amination
reaction. Neither propanal nor AcOH nor the reac-
tion product had a significantly negative effect on the
catalyst, as full conversion was obtained in short reac-
tion time in those reactions.[17] However, premixing
the catalyst with DBAD made the catalyzed reaction
much slower.[14] Thus, only 17% conversion was de-
tected after 95 min under the optimal reaction condi-
tions.
To better understand the effect of azodicarboxylate
on catalyst deactivation, monomeric catalyst 2 was de-
signed and synthesized. DBAD was then stirred to-
gether with 2 (DBAD/2: 2/1) in CH2Cl2 at room tem-
perature. The reaction was completed in 1.5 h giving
8
9
90
4h
4i
90
90
88
95
98
91
ACHTUNGTRENNUNG
(3i)
10[d] Bn (3f)
180
4j
[a]
All reactions were carried out with 0.25 mmol of DBAD
and 0.375 mmol of propanal in 2.5 mL of CH2Cl2 at room
temperature.
[b]
[c]
[d]
Isolated yield.
The ee was determined by chiral HPLC of 4a–j.
DIAD (diisopropyl azodicarboxylate) was used instead
of DBAD.
Mixtures of linear and a-methyl-substituted alde- imine 5 and dibenzyl hydrazine-1,2-dicarboxylate in-
hydes commonly arise from the hydroformylation of stead of triazane C (Path 1 in Scheme 3). While it is
terminal olefins.[16] Reactions exclusively involving the known that pyrrolidines react with azodicarboxylates
linear component of such mixtures would make its via Michael-type additions to generate triazanes, and
separation unnecessary, notably increasing its com- previous work has shown that triazanes involving i-Pr
mercial value.
and t-Bu carboxylates are isolable, it has been also re-
We reasoned that the direct, chemoselective and ported that those containing Et and Bn carboxylates
enantioselective a-amination of these mixtures of are prone to decomposition[18] and that even no tria-
linear and branched aldehydes[16] could be the key zane formation occurs with DBAD due to fast reverse
step in a convenient synthesis of enantiomerically reactions.[13] In the case of catalyst 2, the presence of
pure a-amino acids from olefins. To demonstrate the the 1,2,3-triazole unit in the substituent at C-4 on the
viability of this approach, a typical 1.6:1 mixture of pyrrolidine ring could trigger Path 2 by favouring an
butanal (3b) and 2-methylpropanal (3k) in CD2Cl2 internal proton abstraction at C-5 with subsequent
À
was treated with DBAD in the presence of 1b and N N cleavage leading to the formation of imine 5
AcOH (1b/AcOH/DBAD/3b/3k=0.02/0.1/1/1.6/1; see and dibenzyl hydrazine-1,2-dicarboxylate. During op-
Scheme 2). Under these conditions, the amination eration, Path 1 and Path 2 must competitively coexist
product of butanal was obtained with quantitative in the reaction medium. Under the acceleration by
yield and 94% ee after 40 min, the a-amination prod- AcOH, the reaction takes preferentially place through
uct of 2-methylpropanal not being detectable by Path 2, and all the employed azodicarboxylate (the
1H NMR in the reaction crude.
limiting reagent) is consumed to form product 4. In
Since one of the major advantages associated to the this manner, the catalyst is protected from deactiva-
use of polymer-supported catalysts is the possibility of tion. Interestingly, when catalyst 2 (or its heterogen-
recycling and reuse, the recycling of 1b in a-amination ized counterpart 1b) is used in combination with an
reactions was next studied. However, low conversion a- or b-branched aldehyde, the absence of a-amina-
(37%) in the second cycle indicated that the catalyst tion reaction is accompanied by catalyst deactivation
was partially deactivated during the reaction. To gain by imine formation. This provides a solid indication
a comprehensive understanding of the catalyst deacti- for Path 1 being the main source of catalyst deactiva-
vation, catalyst 1b was pre-treated in separate experi- tion during the attempted recycling of 1b.
Adv. Synth. Catal. 2012, 354, 2971 – 2976
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Scheme 3. Proposed catalytic cycle and off-cycle deactivation of the catalyst.
In an attempt to develop a practical solution to the tion warranted the application of 1b in continuous
deactivation of 1b, we checked the slow addition of flow processing, nowadays a fundamental goal and
DBAD in CH2Cl2 to a mixture of propanal, AcOH challenge in synthetic organic chemistry.[19,20] To this
and catalyst 1b in CH2Cl2. As it can be seen in end, a 300-mg sample of 1b was swollen with CH2Cl2
Table 3, the presence of an excess of aldehyde in the
reaction medium seems to efficiently control the oper-
Table 3. Recycling of 1b in the a-amination of 3a with slow
ation of the catalytic pathway, since the employed
addition of DBAD.[a]
sample of 1b could be reused for 6 times without de-
Cycle
Yield [%][b]
ee [%][c]
crease of either isolated yield or enantioselectivity. It
is to be mentioned that the catalyst recycling could be
further extended by simply increasing the amount of
aldehyde reagent. Thus, in a recycling test using
5 equiv. of propanal, a sample of 2 mol% of 1b could
be reused for 10 times, affording an overall 96% yield
of 4a with 88% ee. This represents an accumulated
TON of 480, nearly two orders of magnitude above
those of standard catalysts for a-amination. From
a practical perspective, it is worth mentioning that es-
sentially pure 4a could be easily obtained by filtering
off the polymer and removing the water-soluble addi-
tive and the excess of volatile propanol.
1
2
3
4
5
6
94
95
93
97
94
91
89
90
90
89
90
88
[a]
The reactions were carried out with slow addition of a so-
lution of DBAD (0.25 mmol) in CH2Cl2 (2.0 mL) to
a
mixture
of
propanal
(0.375 mmol),
AcOH
(0.025 mmol) and 1b (0.005 mmol) in CH2Cl2 (0.5 mL).
The catalyst was simply washed with CH2Cl2 between
cycles.
Isolated product.
By chiral HPLC after reduction (NaBH4).
[b]
[c]
The extremely high activity depicted by the immo-
bilized catalyst 1b and the easy control of its deactiva-
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Asymmetric a-Amination of Aldehydes Catalyzed by PS-Diphenylprolinol Silyl Ethers
and loaded into a packed-bed reactor (see Supporting and, even, long-standing continuous flow operation
Information for more details). To protect the catalyst with very short residence time (6 min).
from deactivation by reaction with DBAD (see
above), a five-fold excess of aldehyde was used in the
flow experiments. A mixture of propanal (1.25M) and Experimental Section
AcOH (0.125M) in CH2Cl2 was initially pumped into
the reactor for 60 min at
a
flow rate of Experimental Procedure for a-Amination of
0.075 mLminÀ1 to promote enamine formation. After Aldehydes
this time, and using a different pump, the circulation
PS-catalyst (2 mol%, 0.004 mmol, 9.28 mg) and the corre-
of a DBAD solution in CH2Cl2 (0.25M) was started
at the same flow rate, the two flows being combined
in a mixing chamber before entering the reactor. The
device was kept in operation for 8 h, the product
being collected in a flask at 08C. As shown in Table 4,
full conversion was achieved during the first 6 h of
operation with residence times of 6 min, and the
enantioselectivity did not decrease over the whole
process. A slight decrease in conversion was observed
in the last 2 h of operation, but remained in all cases
higher than 87%. After 8 h of continuous flow opera-
tion, 7.6 mmol of 4a could be isolated.
In summary, we have developed PS-supported di-
phenylprolinol silyl ethers as efficient and selective
catalysts for the a-amination of a,b-unsubstituted al-
dehydes. High conversions and enantioselectivities
can be achieved in very short reaction times at low
(1–2 mol%) catalyst loading with the optimal 1b. The
mechanism of catalyst deactivation has been elucidat-
ed, and a simple solution to the deactivation problem
has been developed. This has allowed repeated recy-
cling and reuse (10 cycles; accumulated TON of 480)
sponding aldehyde (0.3 mmol) were mixed in a 5-mL vial
with CH2Cl2 (2 mL). Then AcOH (10 mol%, 0.02 mmol)
and DBAD (0.2 mmol, 60.8 mg) were added and the mix-
ture was shaken at room temperature. When DBAD was
completely consumed (TLC), the catalyst was filtered off
and washed with CH2Cl2 (2ꢄ2 mL). To the filtrate, EtOH
(0.4 mL) and NaBH4 (3 equiv.) were added and the mixture
was stirred for 20 min. Then the reaction mixture was
quenched with saturated aqueous NH4Cl solution (10 mL)
and extracted with CH2Cl2 (3ꢄ5 mL). The organic fraction
was dried over MgSO4 and concentrated under reduced
pressure at room temperature. When volatile aldehydes
were used, pure a-hydrazino alcohols were isolated by
simple evaporation. Otherwise, products were purified by
fast flash chromatography on silica gel (hexanes/ethyl ace-
tate).
Recycling of Catalyst 1b
Polymer supported catalyst 1b (2 mol%, 0.005 mmol,
11.6 mg) and propanal (1.5 equiv., 0.375 mmol) were mixed
in a 5-mL vial with CH2Cl2 (0.5 mL). AcOH (10 mol%,
0.025 mmol) was added followed by DBAD (1 equiv.,
0.25 mmol, 76 mg) in CH2Cl2 (2 mL) was slowly added with
a syringe pump into the shaken mixture over 1 h at room
temperature. The reaction mixture was kept shaking until
DBAD was consumed completely (ca. 5 min, TLC) and
then the catalyst was filtered off and washed with CH2Cl2
(2ꢄ2 mL). The catalyst was directly used in the next recy-
cling run. To the filtrate phase, 0.4 mL of EtOH and 3 equiv.
of NaBH4 were added respectively. After 20 min, the reac-
tion mixture was treated with saturated aqueous NH4Cl so-
lution (10 mL) and extracted with CH2Cl2 (3ꢄ5 mL). The
organic fraction was dried over MgSO4 and concentrated
under reduced pressure at room temperature. The ee was
determined directly with the crude product.
Table 4. Continuous flow a-amination of 3a catalyzed by
1b.[a]
Entry
Time [h]
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
0.5
1
2
3
4
5
6
7
8
>95
>95
>95
>95
>95
>95
>95
90
85
83
89
89
89
91
91
91
88
Continuous Flow Operation
Catalyst 1b (300 mg) swollen in CH2Cl2 was loaded into
a packed-bed reactor (10 mm pore size and up to a maximal
70 mm of adjustable bed height glass chromatography
column, ca. 15 mm bed height of catalyst). A mixture of
propanal (1.25M) and AcOH (0.125M) in CH2Cl2 was
pumped into the reactor at first for 60 min with a flow rate
of 0.075 mLminÀ1. A DBAD solution in CH2Cl2 (0.25M)
was then pumped by another pump under the same flow
rate (0.075 mLminÀ1). The two flows were mixed in a T-type
mixing chamber before pumping into the reactor. The prod-
uct was collected in an ice-water cooled flask, which was
connected to the reactor outlet. Analytic sample (1 mL) was
collected at each given time point, to which 0.5 mL EtOH
87
[a]
Conditions: a) channel 1: mixture of propanal (1.25M)
and AcOH (0.125M) in CH2Cl2, 0.075 mLminÀ1; b) chan-
nel 2: DBAD (0.25M) in CH2Cl2, 0.075 mLminÀ1.
By H NMR after reduction with NaBH4.
By chiral HPLC after reduction with NaBH4.
[b]
[c]
1
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2975

Xinyuan Fan et al.
COMMUNICATIONS
and 10 mg NaBH4 were added. And then the mixture was
stirred at room temperature. After 10 min, the reaction was
quenched with 20 mL saturated NH4Cl aqueous solution
and extracted with CH2Cl2 (2ꢄ20 mL). The combined or-
ganic phase was washed once with brine, dried over MgSO4
and the solvent was removed under reduced pressure. The
crude product was directly submitted to HPLC and
1H NMR analysis.
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[12] For some examples involving catalyst immobilization in
ˇ
Financial support from Institute of Chemical Research of
Catalonia (ICIQ) Foundation, MINECO (CTQ2008-00947/
ionic liquids, see: a) P. Kotrusz, S. Alemayehu, S. Toma,
H.-G. Schmalz, A. Adler, Eur. J. Org. Chem. 2005,
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Cheng, Tetrahedron Lett. 2010, 51, 6105–6107.
BQU
and
CTQ2012-38594-C02-01)
and
DIUE
(2009SGR623) is gratefully acknowledged.
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Adv. Synth. Catal. 2012, 354, 2971 – 2976