Design of chiral urea-quaternary ammonium salt hybrid catalysts for asymmetric reactions of glycine Schiff bases

Article abstract of DOI:10.1039/c5ra14466c

Bifunctional chiral urea-containing quaternary ammonium salts can be straightforwardly synthesised in good yield and with high structural diversity via a scalable and operationally simple highly telescoped sequence starting from trans-1,2-cyclohexanediamine. These novel hybrid catalysts were systematically investigated for their potential to control glycine Schiff bases in asymmetric addition reactions. It was found that Michael addition reactions and the herein presented aldol-initiated cascade reaction can be carried out to provide enantiomeric ratios up to 95:5 and good yields under mild conditions at room temperature.

Full text of DOI:10.1039/c5ra14466c

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DOI: 10.1039/C5RA14466C
Journal Name
ARTICLE
Design of Chiral Urea-Quaternary Ammonium Salt Hybrid
Catalysts for Asymmetric Reactions of Glycine Schiff Bases
Received 00th January 20xx,
Accepted 00th January 20xx
Maximilian Tiffner,a Johanna Novacek,a Alfonso Busillo,b Katharina Gratzer,a Antonio Massa,b,* and
Mario Waser a,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Bifunctional chiral urea-containing quaternary ammonium salts can straightforwardly be synthesised in good yields and
with a high structural diversity via a scalable and operationally simple highly telescoped sequence starting from trans-1,2-
cyclohexanediamine. These novel hybrid catalysts were systematically investigated for their potential to control glycine
Schiff bases in asymmetric addition reactions. It turned out that Michael addition reactions and the herein presented
aldol-initiated cascade reaction can be carried out with enantiomeric ratios up to 95:5 and in good yields under mild
conditions at room temperature.
alkaloid-based catalyst 9 introduced by Dixon5b and Smith5c
gave the highest e.r. of 85:15 among the so far tested existing
bifunctional ammonium salt motives (Scheme 1, lower
Introduction
Chiral onium salt (phase-transfer) catalysis is one of the
fundamental non-covalent activation strategies in asymmetric
catalysis.1 Besides monofunctional chiral ammonium salt
catalysts, the use of bifunctional derivatives has emerged as a
powerful strategy for numerous applications.2 Whereas the
vast majority of such catalysts contains an additional OH-group
as the second coordination site,2-4 the design and application
of ammonium salts containing alternative H-bonding motives
has so far been less exhaustively investigated.2,5-7 While the
groups of Lassaletta and Fernandez,5a Dixon,5b Smith5c and Lin
and Duan5d introduced powerful Cinchona alkaloid-based
(thio)-urea containing bifunctional ammonium salt catalysts,
Zhao et al.6 recently developed a modular approach to access
α-amino acid-based (thio)-urea/ammonium salt hybrid
catalysts. Simultaneously, our groups introduced trans-1,2-
cyclohexane diamine-based bifunctional ammonium salts 1
(Scheme 1).7 An extensive screening of different salts allowed
us to identify 1a as the most efficient chiral catalyst for the
asymmetric α-fluorination of β-ketoesters 2.7a In addition,
catalyst 1b was found to be promising for the newly developed
aldol-initiated cascade reaction of glycine Schiff base 5 with
cyanobenzaldehyde 6.7b In the initial optimisation of this
powerful transformation only one cyclohexane diamine-based
catalyst 1 was tested and it also turned out that the Cinchona
reaction).7b
Scheme 1: Hybrid ammonium salts 1 and their applications reported previously.
These encouraging initial results with this novel family of
asymmetric catalysts prompted our groups to initiate a joint
project focusing on the further development and exploration
of hybrid salts 1 for stereoselective transformations. Thus we
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especially focused on the optimisation of the existing synthesis explained by a nucleophilic substitution of the benzylic
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route7a to fuel the demand for larger quantities of readily ammonium groups of compounds 13 (e.g. by the base or the
DOI: 10.1039/C5RA14466C
tuneable catalysts 1 and on the systematic testing of these iodide counter anion) under the harsh reaction conditions,
catalysts for asymmetric reactions of glycine Schiff bases 5 (i.e. giving the more reactive dimethyl-containing tert-amine,
the already mentioned cascade reaction and Michael addition which was then further methylated. This effect lowered the
reactions). Hereby a detailed screening of these catalysts to overall yields significantly and also made purification of the
increase the selectivity in the cascade synthesis of compounds ammonium salts rather difficult. In addition, when using
8 was considered to be particularly interesting, as our modular sterically even more demanding R1 residues like an anthracenyl
catalyst synthesis approach should allow us to overcome the group no product 13 could be obtained.
limitations of the existing catalyst motives. Interestingly, the To overcome these significant limitations, we first tested
groups of Liu and Soloshonok recently achieved the highly alternative (sterically less demanding) N-protecting groups
asymmetric synthesis of the analogous lactams in
a
(e.g. alloc) but with no success. Also other methylation agents
complementary approach by employing an asymmetric did not improve the outcome. Gratifyingly, after a very careful
auxiliary-based approach using chiral glycine Schiff base Ni(II) screening of different conditions we finally found that carrying
complexes.8 This report once again proves the high potential out the reaction with MeI (6 eq.) and solid K2CO3 (1.1 eq.) in
of this robust auxiliary approach for the synthesis of chiral α- DMF (60 °C) gave the target ammonium salts 13 in reliably high
amino acid derivatives.9
yields (around 70% in situ) and sufficient purities to be
telescoped further in the sequence without any purification.
Noteworthy, almost no tert-amine intermediates and no
trimethyl ammonium salt 13b were formed (traces of 13b
originating from methylation of remaining 11 could be
separated in the next step). This strategy was found to be very
robust for R1 being electron-rich, -neutral, and –poor giving
access to derivatives that were not accessible by the initial
route (e.g. 3,5-(CF3)-C6H3-). Unfortunately, when using
sterically demanding R1 groups (e.g. naphthyl or ortho-
substituted aromatics) this route was still not very satisfactory
(hereby the reactions mainly stalled on the tert-amine
intermediates). However, these ammonium salts could be
obtained in reasonable yields by first carrying out the
dimethylation of 11 (step C) and then a final quaternarization
with the appropriate benzylic halides (step D). Again the
products were obtained in sufficient purities for direct further
use. Thus, these newly developed quaternarization conditions
allowed us to obtain a much more diverse assembly of
ammonium salts 13 which were then transferred into the
catalysts 1 in two more steps. The only limitations in the
present synthesis are the fact that only one sterically
demanding group R1 can be introduced and that groups bigger
than a naphthyl group (e.g. anthracenyl) can only very slowly
be incorporated.
Results and Discussion
Catalyst Syntheses
In contrast to recent reports by others who described
incorporation of the H-bonding donor first, followed by a final
quaternarization step,5,6 we have chosen to use the opposite
assembly strategy by carrying out the quaternarization of
mono-protected diamine 11 first, followed by deprotection
and coupling with an iso(thio)cyanate (Scheme 2).7a This
strategy allowed us to overcome some of the challenges of the
commonly used protocols,5,6 as side reactions of the
nucleophilic heteroatoms of the H-bonding donor with the
alkylating agent can be avoided, thus resulting in a broader
and more functional group tolerant synthesis route.
As outlined in Scheme 2, catalysts 1 can be obtained from the
known Boc-protected diamine 1110 in four chemical steps.
First, the introduction of bulkier (aromatic) residues R1 on the
ammonium side can be easily accomplished by means of a
reductive amination, giving the corresponding secondary
amines 12 in high yields (> 90% conversion) and without the
need of any further purification. However, the subsequent
quaternarization (step B, Scheme 2) was found to be the major
bottleneck in the initial protocol.7a It was not possible to
introduce any residues that are sterically more demanding
than a methyl group, thus allowing the syntheses of dimethyl-
containing ammonium salts 13 only. In addition, we found that
this exhaustive methylation is strongly dependent on the
nature of substituent R1. While smaller, electron rich or
electron neutral groups like a phenyl group allowed us to
obtain 13 in slightly more than 50% yield starting from 11,
electron-poor or sterically more demanding groups performed
significantly worse (down to around 25% yield). Hereby we
faced two problems: First the final quaternarization was rather
slow, leading to mixtures of tert-amine intermediates and the
quaternary ammonium salts even after long reaction times. In
addition, under the rather forcing and prolonged conditions
we observed formation of large quantities of the trimethyl
ammonium salt 13b (R1 = H). Formation of the latter can be
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best-suited solvent-base system for this reaction. Larger
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amounts of base favoured the racemicDbOaI:c1k0g.1r0o3u9n/Cd5RrAe1a4c4t6io6Cn
and non-aromatic solvents or aqueous (alternative) bases
generally gave significantly lower selectivities (these effects
were also carefully double-checked once the most active
catalyst was identified).
With these conditions set, we focused on the identification of
the most active catalyst. All the initial reactions were run for
24 h using the same setup (Schlenk flask, stirring rate, and
dilution) and stoichiometric ratio of the reagents to assure
reproducible and comparable biphasic reaction conditions.
It immediately turned out that ureas are better-suited than
thioureas (see entries 1 and 2) and that the use of benzylic
ammonium salts is beneficial (entry 3 vs 1). Thus a series of
hybrid catalysts with different aryl groups R1 on the
ammonium side (keeping the phenyl-urea group R2
unchanged) were tested under identical conditions (entries 3-8
give the most significant results). Contrary to our results
obtained in the α-fluorination of ketoesters7a (compare with
Scheme 1), the introduction of bulky naphthyl groups R1 was
found to have no beneficial effect. In contrast, increasing the
bulk by incorporating a t-butyl group on the aryl moiety (entry
6) significantly reduced the reaction rate. Also the introduction
of nitro substituents did not allow us to increase the selectivity
(entry 7). Luckily, as already discussed above, the new
synthesis protocol (Scheme 2) allowed us to introduce
trifluoromethyl-substituted aryl groups R1 (i.e. 3,5-(CF3)2-C6H3)
in good yields. This catalyst modification turned out to be the
most fruitful amongst all the tested R1 groups, giving 16a with
reasonable selectivity (e.r. = 84:16) and in high yield under the
standard conditions (entry 8). Based on this encouraging
result, we next systematically modified the urea-substituent
R2. The presence of electron-withdrawing groups lead to
reduced selectivities in the case of CF3-, nitro-, or diester-
containing R2 groups (entries 9-11). Noteworthy, the latter was
found to be the urea-modification of choice in our recent α-
fluorination protocol.7a Accordingly, these results show once
more that such reactions always require a detailed and
systematic screening of differently modified catalysts, thus
illustrating the need for a flexible and functional group-
tolerant catalyst synthesis as outlined in Scheme 2.
Scheme 2: Catalyst syntheses: A) R1CHO (1 eq.), NaBH4 (1.5 eq.), MeOH/THF, r.t., 15 h
(no purification, > 90% conversion); B) MeI (6 eq.), K2CO3 (1.1 eq.), DMF, 60 °C, 30 h (no
purification, around 70% crude yield over 2 steps); C) CH2O (2 eq.), Na(OAc)3BH (2 eq.),
DCE, r.t., 15 h (no purification, > 90% conversion); D) R1CH2X, DMF, 60 °C, 30 h (no
purification, 60-80% crude yield over 2 steps); E) HI (10 eq.), DCM, r.t., 2 h (extractive
work-up with Na2CO3); F) R2NCX (1.2 eq.), DCM, r.t., 2-6 h (simple purification by
column chromatography, 60-80% yield over 2 steps).
The Boc-deprotection (step E) was initially carried out with TFA
and the resulting salt (obtained by evaporation of the TFA and
the solvent) was directly used for the final coupling step.
However, this deprotection procedure gave mixtures of
ammonium trifluoroacetates and iodides, which showed
different catalytic properties and were difficult to separate.
The use of HI for the deprotection was found beneficiary for
this reaction and, accompanied with an extractive work up,
yielded the free amines 14 in good purities and yields. The
extraction also allowed us to remove residual trimethyl
ammonium salt 14b (R1 = H), which is significantly more
hydrophilic than aryl-containing derivatives. With this
optimized procedure in hand, the final coupling could be
carried out straightforwardly with different iso(thio)cyanates,
requiring only one final (and simple) purification by silica gel
column chromatography. Thus, a diversified assembly of
different catalysts 1 can now be obtained in a telescoped and
operationally simple manner and with satisfying overall yields
(> 30% based on 10) on a practical scale (up to 3 mmol).
Asymmetric Reactions of Glycine Schiff Bases 5
The first transformation that we carefully investigated was the
Michael addition of glycine Schiff base 5 to acceptors like
methyl acrylate 15a. This has been a thoroughly investigated
reaction in asymmetric non-covalent organocatalysis in the
past and noteworthy most of the reported catalysts have there
own characteristics with respect to their application scope
(especially when using β-substituted acceptors).1,11-13 Thus we
were curious to see whether our hybrid catalysts can be used
(and systematically optimised) to control this important
transformation. Table 1 gives an overview on the most
significant results obtained in a very detailed screening of
different catalysts and reactions conditions. We first identified
the combination of toluene and solid Cs2CO3 (1.5 eq.) as the
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introducing different alkyl groups R2 allowed us to identify an
ethyl group as the most powerful urea-substituent giving 16a
Table 1: Identification of the most active catalyst 1 and the best-suited
reaction conditions for the addition of 5 to 15a.
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DOI: 10.1039/C5RA14466C
with an enantiomeric ratio of 89:11 under standard conditions
at room temperature. Further fine-tuning of the reaction
conditions showed that the selectivity increases with higher
dilutions, however resulting in a stepwise decrease of
conversion (entries 18-23). The highest selectivities were
obtained either by carrying out the reaction at 0.02M
concentration of 5 at 25 °C (entry 21) or at higher
concentration (0.08M) at 0 °C (entry 20), albeit with reduced
conversion. Furthermore, lowering the catalyst loading
resulted in a reduced catalytic performance (entry 22),
whereas further dilution did not allow us to improve the
selectivity any further (entry 23).
No
R1
H
R2
X
Conc.
[M]a
0.17
T
[°C]
25
Yieldb
[%]
60
69
90
72
35
6
e.r.c
(R:S)
1
2
3
4
5
6
Ph
O
S
O
67:33
60:40
76:24
78:22
74:26
79:21
Ph
α-Np
β-Np
4-tBu-
C6H4
4-NO2-
C6H4
3,5-
To prove the necessity of the bifunctional nature of catalysts 1
we also tested the simplified catalysts 17 and 18 which
performed much less selective or did not give any product at
all under the optimized reaction conditions (Scheme 3).
7
8
40
85
74:26
84:16
(CF3)2-
C6H3
9
10
3-NO2-C6H4
3,5-
83
85
81:19
75:25
(CO2Me)2-
C6H3
11
3,5-(CF3)2-
C6H3
95
75:25
12
13
14
15
16
17
18
19
20
21
Cy
88
90
70
5
91
94
96
87
45
85
87:13
81:19
92:8
40
0
-20
25
92:8
S
O
65:35
85:15
89:11
90:10
95:5
Scheme 3: Control experiments using the simplified catalysts 17 and 18.
tBu
Et
0.08
Having identified the best-suited catalyst and the optimum
reaction conditions (see entry 21, Table 1) we next
investigated the application scope for this reaction (Scheme 4).
One important fact that should be mentioned is that this
biphasic transformation was found to be rather sensitive (e.r.
and conversion) with respect to changes in the reaction setup
(i.e. shape of the used Schlenk flasks and stirring rate).
Therefore, when investigating the application scope we always
carried out each test reaction on a 0.1 mmol scale (based on 5)
with exactly the same setup and for comparison also on a
smaller scale (0.02 mmol). All the results shown in Scheme 4
were thus carefully double-checked and found to be
reproducible in at least two runs with two different setups
each!
Testing different esters of the glycine Schiff base 5 first, we
found that all gave good conversion within 24 h, but selectivity
depends on the nature of the ester group, with bulky t-butyl
esters 5 giving the highest enantioselectivity in the addition to
methyl acrylate 15a (see results for products 16a – 16c).
Interestingly, by changing the ester group of the Michael
acceptor 15 both, the conversion rate14 and the
enantioselectivity, were influenced (see products 16d – 16f).
This was most notable in the syntheses of the di-t-butyl
0
25
3,5-
(CF3)2-
C6H3
Et
O
0.02
95:5
22d
23
74
8
88:12
95:5
0.01
a) Based on 5; b) isolated yield; c) determined by HPLC using a chiral
stationary phase11; d) using 5 mol% catalyst.
Interestingly, at this stage we found that replacing aryl
moieties on the urea side by incorporating a cyclohexyl group
R2 instead resulted in a good selectivity of 87:13 (entry 12).
Based on the fact that aliphatic groups were never found to be
promising in any of our previously investigated reactions
(published7a or unpublished) this result came as a big surprise.
By testing the influence of reaction temperature we found that
the selectivity can be increased by lowering the temperature,
however accompanied by a reduced reaction rate (entries 14,
15). Again, the reduced selectivity when using thiourea-
moieties was proven by testing the analogous cyclohexyl-
thiourea catalyst (entry 16). Finally, additional modifications by
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containing diester 16e (only 15% conversion under standard
conditions and a reduced e.r. of 83:17). Here the conversion
could be increased by using 5 equivalent of base without
affecting the e.r. (when using other acceptors the use of a
larger excess of base usually resulted in a reduced e.r. because
of an increased rate of the racemic background reaction).
When testing phenyl vinyl sulfone as an acceptor (giving
product 16g) selectivity dropped significantly, whereas N,N-
dimethyl acrylamide and methyl vinyl ketone could be
employed with reasonable selectivities (16h and 16i).
Unfortunately, the acrylamide acceptor was found to react
rather slowly and in this case the use of more base did not
really allow us to overcome this limitation as the selectivity
was clearly affected hereby (this substrate was also very
difficult to control in an enantioselective manner in a recent
project using structurally different TADDOL-based PTCs11).
Interesting results where obtained when using prochiral
electrophiles 15j – 15m (as shown in the lower part of Scheme
4). Using dimethyl maleate 15j, the product 16j could be
obtained in good yield and with high diastereo- and
enantioselectivity. Noteworthy, Lambert and co-workers
recently found that this substrate is unreactive when using
their otherwise very powerful and highly selective
cyclopropenimine chiral base catalysts.12 Using dimethyl
fumarate 15j’ instead gave the diastereomeric 16j’ in good
View Article Online
DOI: 10.1039/C5RA14466C
yield and diastereoselectivity albeit
a
slightly lower
enantioselectivity. Another striking difference to chiral
cyclopropenimine base catalysis was also observed when
employing s-trans acceptors 15k and 15l. Although
cyclohexenone 15k underwent a slowly 1,4-addition under
standard conditions (which can be explained by a competing
dimerization under basic phase-transfer conditions15), the
stereoselectivity obtained is still reasonably high.16 Even more
interestingly, when using cyclopentenone 15l we were able to
obtain product 16l in high yield and with good
stereoselectivity.17 Finally, also chalcone was accepted well in
this reaction, providing the product 16k with reasonable
selectivity and in good yield. Here it is of course fair to mention
that for this substrate again Lambert’s chiral base catalyst was
reported to be more selective12 and therefore the results
obtained hereby may illustrate that our catalysts can provide a
complementary and useful activation platform for future
asymmetric organocatalytic transformations especially for
addition reactions to s-trans Michael acceptors.
Scheme 4: Application scope of the Michael addition of glycine Schiff bases 5 to
different Michael acceptors 15 using bifunctional catalyst 1c. The configuration of
products 16a, 16b, 16d-16g, 16i, 16j’, 16k and 16m was determined by comparison of
analytical details with literature data11-13, 16, 17 whereas the other products (16c, 16h, 16j
and 16l) were assigned by analogy.
Having shown that catalysts 1 can be systematically fine-tuned
to obtain high selectivities for the Michael addition of Schiff
bases 5 to different Michael acceptors 15, we next addressed
the recently developed aldol-initiated cascade reaction of 5
with cyanobenzaldehyde 6.7b As already discussed above, the
initial screening of existing catalysts showed that the Cinchona
alkaloid-based bifunctional ammonium salt 9 introduced by
Dixon5b and Smith5c gave the highest selectivity with d.r. = 4:1
and e.r. of 85:15 for the major diastereomer (see Scheme 1).
With our optimized synthesis for catalysts 1 in hand we put
our efforts on identifying an even more selective catalyst for
this powerful transformation. Table 2 gives an overview on the
most significant results obtained thereby. The screening was
carried out under the previously developed conditions7b using
solid K2CO3 as the base in CH2Cl2 (other solvents and bases
were tested too but found to be less useful). In addition, initial
tests showed that again ureas are more active and selective
than thioureas and thus the optimization was carried out with
ureas only.
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Entry 1 shows the initially reported result7b using the
trimethylammonium-based catalyst 1b and it soon turned out
that variation of the urea group alone does not significantly
change the catalytic performance (entries 1-4). Introducing
electron-neutral or bulky aryl groups on the ammonium side
(entries 5-8) did not result in any improvement either. In
contrast, the introduction of a naphthyl group even reduced
the dia- and enantioselectivity (entry 8). Also the presence of
aliphatic groups on the urea side (which was beneficial for our
Michael reaction) did not allow us to improve the catalyst
performance (entry 6) and a similar selectivity was obtained
upon incorporation of more electron-rich aryl groups R1
(entries 9 and 10).
In sharp contrast, the introduction of electron-withdrawing
groups on the aryl group R1 on the ammonium side
accompanied by the presence of an electron-poor aryl moiety
R2 on the urea side resulted in significantly superior catalysts
(entries 11-13). First, the dinitro-substituted catalyst used in
entry 11 almost matched the result previously obtained with
the Cinchona catalyst 9, both in terms of reactivity and
selectivity. Gratifyingly, as already observed for the Michael
addition, the introduction of the di-trifluoromethyl-phenyl
group R1 again significantly improved the yield and the
selectivity in this transformation (entries 12 and 13).
Modifying the R2 groups finally resulted in the most promising
catalyst shown in entry 12, which gave product 8 in 83%
isolated yield and with a good d.r. of 4:1 and excellent
enantioselectivity for the major diastereoisomer (e.r. = 95:5;
the minor diastereoisomer was always obtained with a lower
enantiomeric ratio only and no further improvement was
possible).
Determination of the relative and absolute configuration of 8
turned out to be rather difficult as both diastereomers only
crystallized as amorphous solids and thus X-ray structural
analysis was not possible (the same was the case for the other
derivatives shown in Scheme 5). On the other hand the
coupling constants of 7 and 8 did also not allow us to
unambiguously determine the relative configuration (NOESY
experiments were also not clear). However, it was possible to
assign the absolute configuration of the amino acid
stereogenic center of the major diastereomer to be (R) by
analysis of it’s corresponding Mosher amides.18 Subsequent
NMR studies of these compounds then indicated that the
major diastereomer is most presumably the anti isomer as
depicted in Table 1.19
Table 2: Identification of the most active catalyst 1 for the cascade reaction
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of 5 and 6.
DOI: 10.1039/C5RA14466C
No
R1
H
R2
t [h] Yielda
[%]
d.r.b
e.r.
major
(minor)c
77:23
(60:40)
77:23
(60:40)
76:24
(51:49)
80:20
(59:41)
77:23
(52:48)
67:33
(51:49)
80:20
(57:43)
77:23
(54:46)
70:30
(57:43)
77:23
(59:41)
85:15
(63:37)
95:5
1
2
3
4
5
6
7
8
9
3,5-(CF3)2-
C6H3
3-NO2-C6H4
24
24
48
48
48
72
48
48
96
48
26
24
24
82
66
63
52
52
68
60
52
13
59
65
83
79
1.5:1
1.4:1
1.3:1
1.2:1
1:1
4-CF3-C6H4
Ph
Ph
Cy
2:1
4-CF3-C6H4
Ph
1:1
β-Np
1:1
3,5-F2-4-
Ph
1.1:1
1.3:1
2.4:1
4:1
MeO-C6H2
4-MeO-
C6H3
3-NO2-
C6H4
3,5-(CF3)2-
C6H3
3,5-(CF3)2-
C6H3
10
11
12
13
3-NO2-C6H4
3-NO2-C6H4
3-NO2-C6H4
(75:25)
92:8
(73:27)
3,5-(CF3)2-
C6H3
3:1
a) Isolated yield of 8; b) determined by 1H NMR of the crude product; c)
determined by HPLC using a chiral stationary phase7b.
With the most active catalyst 1d in hand we quickly tested two
halide- and one methoxy-containing cyanobenzaldehydes 6
under the same conditions and found that these substrates
were also well tolerated, albeit the stereoselectivities slightly
decreased in these cases, especially for the minor
diastereoisomers (Scheme 5). Nevertheless, a first proof-of-
principle for the generality of this reaction was clearly made,
thus illustrating the potential of these catalysts for such
cascade-reactions and providing a complementary approach to
the recently reported analogous auxiliary-based protocol.8
6 | J. Name., 2012, 00, 1-3
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(428 mg,
2 mmol)
(prepared View Article fOrnolimne
(S,S)-cyclohexanediamine-5-dihydrochDloOrIi:d1e0.10in39/aCn5aRlAo1g4y466tCo
literature10) in 10 mL THF:methanol (1:1) and the solution
was stirred at r.t. overnight. After the addition of NaBH4
(114 mg, 3 mmol, 1.5 eq), stirring was continued for
another 2 h at r.t.. The reaction was quenched by addition
of water and extracted with water/diethyl ether. The
organic phase was washed with brine, dried over Na2SO4,
and evaporated to dryness to obtain the crude product 12c
in almost quantitative yield (95%, 824 mg, 1.9 mmol), which
could be directly used without any purification. Compound
12c (R1 = 3,5-(CF3)2-C6H3): 1H NMR (300 MHz, δ, CDCl3,
298 K): 1.08-1.35 (m, 4H), 1.42 (s, 9H), 1.61-1.85 (m, 2H),
1.96 (s (b), 1H), 1.99-2.15 (m, 2H), 3.31-3.47 (m, 1H), 3.83
(d, 1H, J = 14.1 Hz), 4.00 (d, 1H, J = 14.1 Hz), 4.48 (d, 1H, J =
7.3 Hz), 7.73 (s, 1H), 7.82 (s, 2H) ppm.
Step 2 (B): The amine 12c (1.7 mmol) was dissolved in 3 ml
DMF. After the addition of K2CO3 (287 mg, 2.1 mmol, 1.2 eq)
and methyl iodide (646 μl, 10.4 mmol, 6 eq), the suspension
was stirred for 30 h at 60 °C. After removal of excess methyl
iodide under reduced pressure, the suspension was extracted
with dichloromethane/brine. The organic phase was dried over
Na2SO4 and removal of the solvent under reduced pressure
gives 13c (70%, 1.13 g, 1.2 mmol), which was used without
further purification. Compound 13c (R1 = 3,5-(CF3)2-C6H3):
[α]D (c = 1.8, CH2Cl2) = -7.4°; H NMR (500 MHz, δ, CDCl3,
298 K): 1.32-1.40 (m, 1H), 1.46 (s, 9H), 1.58-1.66 (m, 1H),
1.66-1.74 (m, 1H), 1.77-1.84 (m, 1H), 1.95-2.06 (m, 3H),
2.59-2.64 (m, 1H), 3.22 (s, 3H), 3.28 (s, 3H), 4.11-4.18 (m, 1H),
4.93-5.00 (m, 1H), 5.16 (d, 1H, J = 12.8 Hz), 5.36 (d, 1H, J = 12.8
Hz), 5.87 (d, 1H, J = 9.9 Hz), 8.01 (s, 1H), 8.13 (s, 2H) ppm; 13C
NMR (126 MHz, δ, CDCl3, 298 K): 24.8, 24.8, 27.7, 28.5, 35.7,
49.7, 51.1, 51.7, 63.1, 77.8, 81.5, 122.8 (q, J = 273 Hz), 124.9,
130.3, 133.0 (q, J = 34 Hz), 133.6, 155.9 ppm; 19F NMR (282
Scheme 5: Use of cyanobenzaldehydes 6 for the cascade reaction.
Experimental
General Information
1H- and 13C-NMR spectra were recorded on a Bruker Avance III
300 MHz spectrometer, on a Bruker Avance III 700 MHz
spectrometer with TCI cryoprobe or on Bruker DRX 400, 300,
250 MHz spectrometers. All NMR spectra were referenced on
the solvent peak. High resolution mass spectra were obtained
using an Agilent 6520 Q-TOF mass spectrometer with an ESI
source and an Agilent G1607A coaxial sprayer or using a
Thermo Fisher Scientific LTQ Orbitrap XL with an Ion Max API
Source. Additional mass spectral analyses were carried out
21
1
using an electrospray spectrometer, Waters
4
micro
MHz, δ, CDCl3, 298 K): -62.8 ppm; IR (film):
= 3431, 3270,
quadrupole. Elemental analyses were performed with a
FLASHEA 1112 series-Thermo Scientific for CHNS-O apparatus.
IR spectra were recorded on a Bruker Tensor 27 FT-IR
spectrometer with ATR unit. HPLC analysis were performed
either by using a Waters instrument or using a Dionex Summit
HPLC system with a Chiralcel OD-H (250 x 4.6 mm, 5 µm), a
Chiralcel OD-R (250 x 4.6 mm, 10 µm), or a Chiralpak AD-H
(250 x 4.6 mm, 5 µm) chiral stationary phase. Optical rotations
were recorded on a Perkin Elmer Polarimeter Model 241 MC
and on a Schmidt + Haensch Polarimeter Model UniPol L 1000.
All chemicals were purchased from commercial suppliers and
used without further purification unless otherwise stated. All
reactions were performed under an Ar-atmosphere.
3011, 2980, 2939, 2867, 1695, 1625, 1516, 1467, 1455, 1393,
1370, 1323, 1281, 1242, 1176, 1138, 1048, 1024, 904, 870,
844, 737, 709, 683 cm-1; HRMS (ESI) m/z calcd for
+
C22H31F6N2O2 : 469.2284 [M+], found: 469.2281.
Step 3 (E): The ammonium salt 13c (1.1 mmol) was dissolved in
12 ml dichloromethane and hydroiodic acid (57w% aq.
solution, 1.45 ml, 11 mmol, 10 eq) was added. After stirring for
2 h at r.t., the reaction was basified with saturated Na2CO3
solution and extracted with dichloromethane. The organic
phase was dried over Na2SO4 and removal of the solvent under
reduced pressure gave crude 14c in quantitative yield (689 mg,
1.1 mmol). Compound 14c (R1 = 3,5-(CF3)2-C6H3): 1H NMR
(300 MHz, δ, CDCl3, 298 K): 1.31-1.76 (m, 5H), 1.84-1.95 (m,
1H), 1.96-2.07 (m, 1H), 2.27-2.37 (m, 1H), 3.06 (s, 3H), 3.17 (s,
3H), 3.46 (s (b), 2H), 3.56-3.68 (m, 1H), 4.06-4.17 (m, 1H), 5.12
(d, 1H, J = 12.7 Hz), 5.48 (d, 1H, J = 12.7 Hz), 7.96 (s, 1H), 8.16
(s, 2H) ppm.
A detailed experimental section including all the procedures
and analytical data of catalysts and asymmetric reaction
products as well as copies of NMR spectra and HPLC
chromatograms can be found in the online supporting
information.
Step 4 (F): A solution of 14 and the corresponding isocyanate
(1.2 eq) in dichloromethane (20 ml per mmol 14) was stirred
for 4 h at r.t.. Evaporation of the solvent under reduced
pressure gave crude 1, which was further purified by column
Syntheses of Catalysts 1c and 1d
Step
1 (Step A in Scheme 2): 3,5-Bis(trifluoromethyl)-
benzaldehyde (484 mg, 2 mmol) was added to a solution of 11
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chromatography (dichloromethane:methanol = 50:1 to 10:1) IR (film):
to obtain pure catalysts 1 in the reported yields.
= 2978, 2926, 1738, 1707, 1661, 1599V,ie1w5A7r8tic,le1O4n4lin9e,
1369, 1319, 1279, 1260, 1234, 1153, 943, 920, 849, 812 cm ;
-1
DOI: 10.1039/C5RA14466C
Compound 1c: Obtained in 65% (123 mg, 0.217 mmol starting The enantioselectivity was determined by HPLC (Chiralcel AD-
from 0.33 mmol 13c) as a colourless oil. [α]D21 (c = 1.3, H, eluent: n-hexane:i-PrOH = 95:5, 0.5 mL/min, 10 °C,
1
CHCl3) = 13.0°; H NMR (300 MHz, δ, CDCl3, 298 K): 1.16 (t, retention
times:
10.9 min (major;
R-enantiomer),
J = 7.2 Hz 3H), 1.24-1.41 (m, 1H), 1.43-1.66 (m, 2H), 1.67- 12.3 min (minor; S-enantiomer)); Absolute configuration was
1.87 (m, 2H), 1.90-2.12 (m, 2H), 1.49-1.61 (m, 1H), 3.06 (s, 3H), determined by comparison of the retention times and [α]D
3.18-3.34 (m, 5H), 4.22-4.38 (m, 1H), 4.59-4.52 (m, 1H), 5.32- value with literature data.12 HRMS (ESI): m/z calcd for
5.47 (m, 2H), 5.99 (s, 1H), 6.92 (d, J = 9.7 Hz, 1H), 7.97 (s, 1H), C23H27NO4: 382.2013 [M+H]+; found: 382.2013.
8.00 (s, 2H), 13C NMR (75 MHz, δ, CDCl3, 298 K): 15.5, 24.7,
General Procedure for the Cascade Reactions of 5
25.1, 27.4, 35.2, 35.9, 48.1, 50.9, 51.0, 65.3, 78.0, 122.7 (q,
J = 273Hz), 124.8, 130.5, 133.0 (q, J = 34 Hz), 133.4, 157.7 ppm;
19F NMR (282 MHz, δ, CDCl3, 298 K): -62.9 ppm IR (film):
= 3295, 3021, 2988, 2936, 2864, 2349, 2288, 1656, 1546,
1449, 1373, 1278, 1174, 1130, 904, 843, 751, 719, 682, 663,
593, 463, cm-1; HRMS (ESI): m/z calcd for C20H28F6N3O+:
440.2131 [M+]; found: 440.2118.
In a round-bottom flask, 2-cyanobenzaldehydes 6 (0.10 mmol)
were added at room temperature to a stirred solution of
glycine Schiff base 5 (1.1 eq., 0.11 mmol), K2CO3 (1 eq.), and
catalyst 1d (5% mol) in CH2Cl2 (3 mL). The mixture was stirred
at r.t. for 24 h (1000 rpm). After, the mixture was purified
directly by flash chromatography on silica gel with
hexane:ethyl acetate = 8:2 to give the intermediates 7 as a
mixture of diastereoisomers. The products 7 were dissolved in
a cooled solution of 0.5 M HCl (1 mL) and THF (3 mL) (0 °C).
The mixtures were stirred at the same temperature for 2 h and
then concentrated under vacuum. The resulting residue was
treated with saturated NaHCO3 (20 mL), extracted with CH2Cl2
(4 x 30 mL), and purified by flash chromatography (silica gel,
hexanes:EtOAc = 2:1).
Catalyst 1d: Obtained in 67% (96 mg, 0.14 mmol, starting from
21
0.22 mmol 13c) as an orange oil. [α]D (c = 0.75, CH2Cl2) =
1
-29.3°; H NMR (300 MHz, δ, CDCl3, 298 K): 1.29-1.46 (m, 1H),
1.56-2.06 (m, 5H), 2.11-2.23 (m, 1H), 2.55-2.67 (m, 1H), 3.19 (s,
3H), 3.28 (s, 3H), 4.40-4.62 (m, 2H), 5.37 (s, 2H), 7.39 (t, 1H, J =
8.2 Hz), 7.47 (d, 1H, J = 9.2 Hz), 7.73 (dd, 2H, J1 = 8.1 Hz, J2 = 1.5
Hz), 7.84 (dd, 1H, J1 = 8.1 Hz, J2 = 1.8 Hz), 7.94 (s, 1H), 8.03 (s,
2H), 8.69 (t, 1H, J = 2.1 Hz), 9.11 (s, 1H) ppm; 13C NMR (75
MHz, δ, CDCl3, 298 K): 24.5, 25.0, 27.3, 36.0, 49.1, 50.6, 50.9,
65.0, 78.4, 113.0, 117.5, 122.5 (q, J = 275 Hz), 124.3, 124.9,
129.6, 130.2, 133.1 (q, J = 34 Hz), 133.3, 140.4, 148.6, 155.1
ppm; 19F NMR (282 MHz, δ, CDCl3, 298 K): -63.0 ppm; IR (film):
= 3462, 3254, 3031, 2944, 2866, 1692, 1600, 1548, 1529,
1485, 1451, 1434, 1372, 1352, 1325, 1280, 1206, 1178, 1137,
904, 843, 830, 798, 737, 709, 683 cm-1; HRMS (ESI): m/z calcd
(-)-8a: Obtained as an amorphous solid in 83% yield (22 mg,
0.083 mmol) with d.r. = 4:1 and e.r. = 95:5 for the major
diastereoisomer. [α]D20 = (c = 0.5, CHCl3) = - 2.5°. H-NMR (300
1
MHz, δ, CDCl3, 298 K): 1.40 (s, 9H), 1.61 (br s, 2H), 4.04 (d, J =
3.6 Hz, 1H), 5.77 (d, J = 3.5 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.58
(t, J = 7.42 Hz, 1H), 7.68 (t, J = 6.48 Hz, 1H), 7.92 (d, J = 7.6 Hz,
1H); 13C-NMR (100 MHz, δ, CDCl3): 29.1, 58.7, 83.3, 83.9, 123.8,
126.9, 128.3, 130.8, 135.2, 147.5, 171.3, 171.5; MS (ESI): m/z =
264.1 (M+H)+; Anal. calcd for C14H17NO4: C, 63.87; H, 6.51; N,
5.32. Found: C, 63.97; H, 6.41; N, 5.37%. The enantioselectivity
was determined by HPLC (Chiralcel OD-H, eluent: n-hexane:
+
for C24H27F6N4O3 : 533.1982 [M+]; found: 533.1998.
General Procedure for the Asymmetric Michael Reactions of 5
Degased toluene (5 mL) was added to a mixture of the Schiff i-PrOH = 90:10, 0.7 mL/min, 25 °C, retention times (major
base 5 (0.1 mmol), catalyst 1c (10 mol%), and Cs2CO3 (1.5 eq) diastereomer): 25.3 min (minor), 34.3 min (major)).
in a Schlenk tube. Stirring rate was set to 1000 rpm and the
corresponding electrophile 15 (1.5 eq.) was added. After 24 h
at 25 °C the reaction mixture was filtered over a plug of
Na2SO4. The solvents were removed under reduced pressure.
Conclusions
The crude products were purified by column chromatography
(silica gel, heptanes:EtOAc = 20:1 to 2:1) giving the Michael
addition products 16 in the reported yields.
A flexible and highly telescoped synthesis strategy for a
structurally diverse library of chiral cyclohexanediamine-based
urea-containing quaternary ammonium salts was developed.
The catalysts were successfully employed in asymmetric
Michael addition reactions and a new powerful aldol-initiated
R-(+)-16a: Obtained as a colourless oil in 85% yield (> 95%
conv.) and with e.r. = 95:5 upon reacting Schiff base 5a with
acrylate 15a in the presence of 10 mol% 1c at 25 °C under the
general procedure conditions. Analytical data are in full
cascade
reaction
of
glycine
Schiff
bases
with
cyanobenzaldehyde derivatives. In both cases the flexible
catalyst strategy allowed us to systematically fine-tune the
catalysts for these reactions, thus resulting in high
enantioselectivities and good to excellent yields. Besides the
high enantioselectivities it was also shown that these catalysts
are very promising in the control of s-trans Michael acceptors,
thus providing a powerful catalyst platform for further
challenging asymmetric transformations.
21
accordance with those reported in literature.11,12 [α]D
1
(c = 0.70, CHCl3) = 74.9°; H NMR (300 MHz, δ, CDCl3, 298 K):
1.44 (s, 9H), 2.16 - 2.27 (m, 2H), 2.33 - 2.41 (m, 2H), 3.59 (s,
3H), 3.93 - 3.99 (m, 1H), 7.14 - 7.21 (m, 2H), 7.28 - 7.47 (m,
6H), 7.60 - 7.68 (m, 2H) ppm; 13C NMR (75 MHz, δ, CDCl3,
298 K): 28.2, 28.8, 30.5, 51.7, 64.9, 81.3, 127.9, 128.1, 128.6,
128.7,128.9, 130.5, 136.6, 139.6, 170.8, 170.9, 173.7 ppm;
8 | J. Name., 2012, 00, 1-3
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69, 5104-5111; b) H.-Y. Wang, J.-X. Zhang, D.-D. Cao and G.
View Article Online
Zhao, ACS Catal. 2013, 3, 2218-2221.
DOI: 10.1039/C5RA14466C
7
For trans-1,2-cyclohexane diamine-based (thio)-urea
containing ammonium salts developed by our groups see: a)
J. Novacek and M. Waser, Eur. J. Org. Chem., 2014, 802-809;
b) M. Perillo, A. Di Mola, R. Filosa, L. Palombi and A. Massa,
RSC Adv. 2014, 4, 4239-4246.
Acknowledgements
This work was supported by the Austrian Science Funds (FWF):
Project No. P26387-N28. Financial support by the Federal State
Government of Upper Austria (Research Fellowship to J. N.) is
kindly acknowledged. We are grateful to Dr. Markus
Himmelsbach for his support with HRMS analysis. The used
NMR spectrometers at JKU Linz were acquired in collaboration
with the University of South Bohemia (CZ) with financial
support from the European Union through the EFRE INTERREG
IV ETC-AT-CZ program (project M00146, "RERI-uasb").
8
9
T. Li, S. Zhou, J. Wang, J. L. Acena, V. A. Soloshonok and H.
Liu, Chem. Commun., 2015, 51, 1624-1626.
a) A. E. Sorochinsky, J. L. Acena, H. Moriwaki, T. Sato and V.
A. Soloshonok, Amino Acids, 2013, 45, 691–718; b) A. E.
Sorochinsky, J. L. Acena, H. Moriwaki, T. Sato and V. A.
Soloshonok, Amino Acids, 2013, 45, 1017–1033.
10 D. W. Lee, H.-J. Ha and W. K. Lee, Synth. Commun., 2007, 37,
737-742.
11 Use of TADDOL-based PTCs: G. N. Gururaja, T. Herchl, A.
Pichler, K. Gratzer and M. Waser, Molecules, 2013, 18, 4357-
4372.
12 Use of cyclopropenimine-based chiral base catalysts: a) J.
Bandar and T. H. Lambert, J. Am. Chem. Soc., 2012, 134,
5552-5555; b) J. Bandar, G. S. Sauer, W. D. Wulff, T. H.
Lambert and M. J. Vetticatt, J. Am. Chem. Soc., 2014, 136,
10700-10707; c) J. Bandar, A. Barthelme, A. Y. Mazori and T.
H. Lambert, Chem. Sci., 2015, 6, 1537-1547.
13 Use of oxo-pyrimidinium-based catalysts: A. E. Sheshenev, E.
V. Boltukhina, A. J. P. White and K. K. Hii, Angew. Chem. Int.
Ed., 2013, 52, 6988-6991.
14 In those cases where the conversion was at least 60-70 %
after 24 h, stirring for another day was usually sufficient to
ensure > 95% conversion of starting material 5.
15 R. Ceccarelli, S. Insogna and M. Bella, Org. Biomol. Chem.,
2006, 4, 4281-4284.
16 For other reports on the synthesis of this compound see: a)
E. J. Corey, M. C. Noe and F. Xu, Tetrahedron Lett., 1998, 39,
5347-5350; b) R. Chinchilla, P. Mazón, C. Nájera, F. J. Ortega
and M. Yus, ARKIVOC, 2005, 222-232; c) V. I. Maleev, M.
North, V. A. Larionov, I. V. Fedyanin, T. F. Savel’yeva, M. A.
Moscalenko, A. F. Smolyakov and Y. N. Belokon, Adv. Synth.
Cat., 2014, 356, 1803-1810.
17 For a highly enantio- but only moderately diastereoselective
copper-catalyzed protocol of this reaction see: M.
Strohmeier, K. Leach, and M. A. Zajak, Angew. Chem., 2011,
123, 12543-12546.
18 For a comprehensive overview see: J. M. Seco, E. Quinoa,
and R. Riguera, Chem. Rev., 2004, 104, 17-117.
19 Detailed VCD studies to unambiguously proof this
assignment will soon be carried out in collaboration with
specialists.
Notes and references
1
For selected reviews about asymmetric phase-transfer
catalysis see: a) K. Maruoka, Asymmetric Phase Transfer
Catalysis, WILEY-VCH, Weinheim, 2008; b) M. J. O’Donnell, in
Catalytic Asymmetric Syntheses, 2nd ed. (Ed: I. Ojima), WILEY-
VCH, New York, 2000, pp. 727-755; c) K. Maruoka and T. Ooi,
Chem. Rev., 2003, 103, 3013-3028; d) M. J. O’Donnell, Acc.
Chem. Res., 2004, 37, 506-517; e) T. Ooi and K. Maruoka,
Angew. Chem., Int. Ed., 2007, 46, 4222-4266; f) S. Shirakawa
and K. Maruoka, Angew. Chem. Int. Ed., 2013, 52, 4312-4348;
g) S.-S. Jew and H.-G. Park, Chem. Commun., 2009, 7090-
7103; h) R. Herchl and M. Waser, Tetrahedron, 2014, 70,
1935-1960.
2
3
For a review about bifunctional chiral ammonium salt-based
catalysts see: J. Novacek and M. Waser, Eur. J. Org. Chem.,
2013, 637-648.
For pioneering reports using Cinchona alkaloid-based free
OH-containing ammonium salt catalysts see: a) R. Helder, J.
C. Hummelen, R. W. P. M. Laane, J. S. Wiering and H.
Wynberg Tetrahedron Lett., 1976, 17, 1831-1834; b) U. H.
Dolling, P. Davis and E. J. J. Grabowski, J. Am. Chem. Soc.,
1984, 106, 446-447; c) M. J. O’Donnell, W. D. Bennett and S.
Wu, J. Am. Chem. Soc., 1989, 111, 2353-2355.
For selected very recent examples describing the beneficial
use of free OH-containing chiral ammonium salt catalysts
see: a) J. R. Wolstenhulme, A. Cavell, M. Gredicak, R. W.
Driver and M. D. Smith, Chem. Commun., 2014, 50, 13585-
13588; b) B. Xiang, K. M. Belyk, R. A. Reamer and N. Yasuda,
Angew. Chem. Int. Ed., 2014, 53, 8515-8518; c) R. J.
Armstrong and M. D. Smith, Angew. Chem. Int. Ed., 2014, 53,
12822-12826; d) S. Shirakawa, L. Wang, R. He, S. Arimitsu
and K. Maruoka, Chem. Asian J., 2014, 9, 1586-1593. e) S.
Shirakawa, T. Tokuda, S. B. J. Kan and K. Maruoka, Org.
Chem. Front., 2015, 2, 336-339.
For (thio)-urea containing Cinchona alkaloid-based
ammonium salt catalysts see: a) P. Bernal, R. Fernández and
J. M. Lassaletta, Chem. Eur. J., 2010, 16, 7714-7718; b) K. M.
Johnson, M. S. Rattley, F. Sladojevich, D. M. Barber, M. G.
Nunez, A. M. Goldys and D. J. Dixon Org. Lett., 2012, 14,
2492-2495; c) M. Li, P. A. Woods and M. D. Smith, Chem. Sci.,
2013, 4, 2907-2911; d) B. Wang, Y. Liu, C. Sun, Z. Wei, J. Cao,
D. Liang, Y. Lin and H. Duan, Org. Lett., 2014, 16, 6432-6435;
e) P. G. K. Clark, L. C. C. Vieira, C. Tallant, O. Fedorov, D. C.
Singleton, C. M. Rogers, O. P. Monteiro, J. M. Bennett, R.
Baronio, S. Müller, D. L. Daniels, J. Mendez, S. Knapp, P. E.
Brennan and D. J. Dixon, , Angew. Chem. Int. Ed., 2015, 54,
6217-6221.
4
5
6
For amino acid-based (thio)-urea containing ammonium salts
see: a) H.-Y. Wang, Z. Chai and G. Zhao, Tetrahedron, 2013,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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