Chiral picolylamines for Michael and aldol reactions: Probing substrate boundaries

Article abstract of DOI:10.1039/c2ob26382c

Here we report on inroads concerning increased substrate breadth via the picolylamine organocatalyst template, a vicinal chiral diamine based on a pyridine-primary amine motif. The addition of cyclohexanone to β-nitrostyrene has many catalyst solutions, b

Full text of DOI:10.1039/c2ob26382c

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PAPER
Chiral picolylamines for Michael and aldol reactions: probing substrate
boundaries†
Thomas C. Nugent,* Ahtaram Bibi,‡ Abdul Sadiq,§ Mohammad Shoaib,§ M. Naveed Umar§ and
Foad N. Tehrani
Received 17th July 2012, Accepted 8th October 2012
DOI: 10.1039/c2ob26382c
Here we report on inroads concerning increased substrate breadth via the picolylamine organocatalyst
template, a vicinal chiral diamine based on a pyridine-primary amine motif. The addition of
cyclohexanone to β-nitrostyrene has many catalyst solutions, but cyclopentanone and isobutyraldehyde
additions continue to be challenging. PicAm-3 (10 mol%) readily allows the Michael addition of
cyclopentanone or isobutyraldehyde (5.0 equiv.) to β-nitrostyrene derivatives. By contrast, PicAm-1
(7.0 mol%) is optimal for catalyzing the aldol reaction of cyclohexanone or cycloheptanone (3.3 equiv.)
with aromatic aldehydes. Eighteen products are reported and for each reaction type new products are
reported (4b–d, 9c). Very good yields and stereoselectivities are generally noted. The reactions, which
require an acid additive, proceed via a transient chiral enamine and a mechanistic case is put forth for a
bifunctional catalysis model.
(S)-1-(2-pyrrolidinylmethyl)pyrrolidine (20 mol%, Fig. 1)
Introduction
allowed cyclopentanone addition to β-nitrostyrene in 78% yield
with a 4 : 1 syn-to-anti ratio in 78% and 71% ee respectively.5a,7
Enzymes often use multiple noncovalent interactions and transi-
ent covalent bonds in unison to control substrate conformation
and activation during bond forming and breaking processes.1,2
These enviable catalyst traits evolved hand in hand with the
narrow substrate tolerances demanded by a cellular milieu, but
accordingly dictate that broadening their substrate scope would
require a detailed knowledge of the critical versus the superflu-
ous units of an enzyme. This reality currently makes the rational
modification of enzymes less accommodating and helps in part
to explain the torrent of research activity recently devoted to
organocatalysis research.
The result was impressive at the time, but also represented a
clear target for optimization. Despite this and many reports
showing progress,8 it can be arguably stated that only the proline
catalyst derivatives of Zhao, Xu, and Chandrasekhar represent
clear multi-parameter reaction advancements (catalyst loading,
starting material stoichiometry, product profile, etc.) (Fig. 1).
Thus while many catalyst solutions already exist for cyclohexa-
none addition to β-nitrostyrene,9 those catalyst successes have
not translated into success with the cyclopentanone substrate, the
noted exceptions withstanding (Fig. 1, bottom line of catalysts).
Regarding monocarbonyl additions to β-nitrostyrene deriva-
tives, unmodified amino acids were found to be poor organocata-
lysts.3,4 But it was also noted very early5,6 that chiral diamine
catalysts with a pyrrolidine moiety (proline derivatives) were
important catalyst templates. For example Barbas showed that
Department of Chemistry, School of Engineering and Science, Jacobs
University Bremen, Campus Ring 1, 28759 Bremen, Germany.
E-mail: t.nugent@jacobs-university.de; Fax: (+49) 421 200 3229;
Tel: (+49) 421 200 3232
†Electronic supplementary information (ESI) available: 72 pages of
experimental description, HPLC traces, and NMR spectrums. See DOI:
10.1039/c2ob26382c
‡Current address: Department of Chemistry, Kohat University of
Science and Technology, Kohat 26000, Khyber Pakhtunkhwa, Pakistan.
§Current address: Department of Chemistry or Department of Pharmacy,
University of Malakand, Chakdara Lower Dir 18000, Khyber Pakh-
tunkhwa, Pakistan.
Fig. 1 Catalysts of historical and current value for cyclopentanone
addition to β-nitrostyrene.
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noted that replacement of chloroform with dichloromethane
resulted in indistinguishable results (not shown in Table 1),
while other organic solvents, e.g. CH3CN, PhCH3, and hexane,
were simply inferior.
Results and discussion
The development of primary–tertiary (versus secondary–tertiary)
diamines for organocatalysis was less intuitive because they rely
on an efficient tautomerization of the in situ formed imine to an
unstable, but nucleophilic, enamine.10 Despite the late successful
entry of this template, primary amine based catalysts have gained
increasing attention due to their alternative chiral space filling
abilities which can benefit sterically encumbered donor carbonyl
substrates. Examples are the α-amination of aromatic ketones11
and Michael reactions forming quaternary carbons.4,12 Based on
these prior accomplishments, we considered 2-picolylamine to
be predisposed for development as an organocatalyst template
(Fig. 2).
To the best of our knowledge the primary amine template
found in 2-picolylamine (1,2-diamine) has not been examined
(Fig. 2), save for our initial report concerning PicAm-1 (Fig. 3)
for the aldol reaction.13 But 1,2- and 1,3- and 1,4-pyrrolidine–
pyridine combinations have been reported on for aldol14,15 and
Michael16,17 reactions. From these studies, only Kotsuki9h
employed protonation of the pyridine ring to give the active cata-
lyst. Here we investigate new PicAm catalysts (Fig. 3), each con-
taining a lone stereogenic center, and report on challenging
Michael substrate additions and less examined aldol reactions, in
the presence of an acid additive.
All of the experiments were performed in the presence of 2,4-
dinitrobenzenesulfonic acid (2,4-DNBSA), when it was removed
the rate of the reaction and diastereoselectivity decreased un-
acceptably (Table 1, compare entry 5 vs. 6). The positive
influence of a sulfonic acid (Table 2), on the stereoselectivity,
implied that a strong acid was required, but the structure of the
conjugate anion was critical. For example the use of HCl (4.0 M
in H2O) did not allow the reaction to proceed. Further investi-
gation of this point led us to the fact that adding a reduced mol%
of 2,4-DNBSA (2.5 mol%) in the presence of a sulfonic acid
salt, i.e. dodecylbenzenesulfonic acid sodium salt (DBSAS,
10 mol%), provided a positive stereochemical outcome (Table 2,
Fig. 3 Chiral picolylamine organocatalysts examined.
Table 1 Solvent screening: cyclopentanone addition to trans-
β-nitrostyrene
Michael reactions
Using 10 mol% of PicAm-1 cyclohexanone, cyclopentanone,
and isobutyraldehyde (5.0 equiv.) could not be induced to react
with β-nitrostyrene over extended reaction times (<10% product
formation). When examining PicAm-2 (10 mol%) with cyclo-
hexanone or cyclopentanone, the expected syn products formed
albeit in low yield (<40%) and with poor or mediocre ee,
respectively 41% and 77%. As with PicAm-1, PicAm-2 also
failed to provide an isobutyraldehyde donor product.
PicAm-3 has been previously synthesized in an enantiopure
form,18,19 but has not been investigated as an organocatalyst.
Examination of this catalyst (10 mol%) with cyclopentanone
permitted practical to quantitative yields of the Michael product
(4a), Table 1. Regarding protic solvent use, a dramatic yield
increase was noted upon replacing MeOH with H2O, and then
finally with brine, resulting in a quantitative yield of the desired
syn-product (4a) but with mediocre ee (74%) (entries 1–4).
Chloroform, on the other hand, proved to be optimal from the
perspective of diastereo- and enantioselectivity. It should be
Entry Solvent
Time (h) syn/antia eea (%) Yieldb (%)
1
2
3
4
5
6d
7
8
H2O
24
24
60 : 40
60 : 40
70 : 30
77 : 23
82 : 18
60 : 40
70 : 30
70 : 30
64
80
67
74
83
80
77
77
65
10
60
100
60
20
70
15
MeOH
MeOH/H2Oc 14
Brine
24
24
24
14
24
CHCl3
CHCl3
CHCl3/H2Oc
THF
a Determined by chiral HPLC analysis. b Yield estimated by TLC, large
error margins can be expected. HPLC analysis was not possible,
β-nitrostyrene could not be quantified (overlapped with (S)-PicAm-3)
from the crude reaction aliquots. c 1 : 1 ratio of the solvents. d The
reaction was performed without an acid.
Fig. 2 An unexplored primary amine-pyridine organocatalyst template.
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Table 2 Effect of acid and salt addition during cyclopentanone addition to trans-β-nitrostyrene
Entry
Acid and salt additivea
Time (h)
syn/antib
eeb (%)
Yieldc (%)
1
2
3
4
5
6
7
8
9
2,4-Dinitrobenzenesulfonic acid
p-Toluenesulfonic acid
p-Nitrobenzoic acid
Camphorsulfonic acid
Trifluoroacetic acid
14
14
14
14
24
14
14
14
14
82 : 18
75 : 25
40 : 60
75 : 25
90 : 10
50 : 50
81 : 19
82 : 18
90 : 10
84
60
65
73
80
73
90
87
94
55
60
35
35
10
40
60
55
55
2,4-Dinitrophenol
2,4-DNBSA (10 mol%) + DBSAS (10 mol%)
2,4-DNBSA (5.0 mol%) + DBSAS (10 mol%)
2,4-DNBSA (2.5 mol%) + DBSAS (10 mol%)
a 10 mol% acid added unless otherwise indicated. b Determined by chiral HPLC. c Yield estimated by TLC, large error margins can be expected.
HPLC analysis was not possible, β-nitrostyrene could not be quantified (overlapped with (S)-PicAm-3) from the crude reaction aliquots.
Table 3 Asymmetric Michael addition of challenging carbonyl donors to nitroalkenesa
Entry
Product
R1
R2
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
R3
Ar
Time (h)
Yieldb (%)
syn/antic
eed (%)
1
2
3
4
5
6
7
8
4a
4ae
4b
4c
4d
5a
5b
5c
H
H
H
H
–Ph
–Ph
24
33
21
24
30
36
40
52
45
70
20
76
98
92
85
89
58
53
59
70
31
27
81/19
77/23
76/24
88/12
57/43
—
—
—
—
—
87
74
–C6H4-4-Me
–C6H4-4-OMe
-2-Furyl
–Ph
–C6H4-4-Me
–C6H4-4-OMe
-2-Furyl
–Ph
88, >99f
77
H
81
78
80
90
90
92
74
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
9
10
11
5d
6a
6ae
–(CH2)5–
–(CH2)5–
–Ph
—
a General reaction conditions: nitroalkene (1.0 equiv.), carbonyl donor (5.0 equiv.), (S)-PicAm-3 (10 mol%), DBSAS: dodecylbenzenesulfonic acid
sodium salt (10 mol%), 2,4-DNBSA: 2,4-dinitrobenzenesulfonic acid (2.5 mol%), CHCl3 (2.0 M), room temperature. b Isolated yield after column
1
chromatography on silica gel. c Determined by H NMR, crude and purified material were consistent. d Determined by chiral HPLC after silica gel
purification. e Reaction conditions: trans-β-nitrostyrene (1.0 equiv.), carbonyl donor (5.0 equiv.), catalyst (S)-PicAm-3 (4 mol%), DBSAS (4 mol%),
2,4-DNBSA (1.5 mol%), brine (0.5 M), room temperature. f anti Product ee.
compare entries 1, 7–9), whereas adding the sodium salt of 2,4-
dinitrobenzenesulfonic acid in various ratios with 2,4-dinitro-
benzenesulfonic acid (2.5 mol%) did not improve the reaction
profile. These combined results imply a yet underappreciated
role for the counter ion.20
catalyst loading from 10 to 4 mol%, and using brine instead of
CHCl3, enabled a significantly increased isolated yield (98%),
but unfortunately with decreased diastereo- and enantioselectiv-
ity (Table 3, entry 2). These results are consistent with our
screening studies (Tables 1and 2).
Using the combined reaction screening information, we per-
formed the challenging benchmark reaction: cyclopentanone
addition to β-nitrostyrene with PicAm-3 (10 mol%). Product 4a
was formed with an 81 : 19 syn/anti ratio, the major syn product
was observed in 87% ee, and the TLC inseparable syn/anti
product was noted in 76% yield (Table 3, entry 1). Only the
results of Zhao8f and Chandrasekhar8a would be considered
superior when considering literature reports with a catalyst
loading of <20 mol%, while also bearing in mind the starting
material ratio, reaction time, and product profile.8 Decreasing the
Encouraged by these initial yield and stereoselectivity results
(Table 3, entries 1and 2), further enantioselective cyclopenta-
none additions with β-nitrostyrenes (p-Me and p-MeO substi-
tuted) and 2-(2-nitrovinyl)furan were performed under the
optimal conditions (Table 3, entries 3–5). Products 4b and 4c
have been previously synthesized but only in the achiral form,21
while 4d is reported here for the first time. That asymmetric
syntheses of 4b–d have not been previously reported justify and
attest to the challenge (and perhaps the avoidance) of synthesiz-
ing cyclopentanone products in general.
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Table 4 Asymmetric
tetrahydrothiopyran-4-one, and cycloheptanone, with various aldehydes
aldol
reactions
of
cyclohexanone,
α-Branched aldehyde addition to nitroalkenes provides access
to contiguous quaternary–tertiary carbon centers, and like cyclo-
pentanone additions are known to be problematic regarding
stereoselectivity.22 Isobutyraldehyde addition to the same set of
nitroalkene substrates provided products 5a–d in good ee
(78–90%), albeit with a mediocre yield (53–70%) as shown in
Table 3 (entries 6–9). Regarding the cyclohexanecarboxaldehyde
donor substrate (entry 10), a 31% yield was observed after the
reaction with β-nitrostyrene. Examination of this substrate in
brine, PicAm-3 (4 mol%), overcame the requirement for
extended reaction times as observed with CHCl3 (PicAm-3,
10 mol%), but did not increase the already low yield (Table 3,
compare entries 10 and 11).
Entry
1e
Producta
Time (h)
16
Yieldb
92
drc
eed
99
22 : 1
In conclusion, the results for PicAm-3 (10 mol%) with cyclo-
pentanone (5.0 equiv.) are noteworthy, e.g., when literature cata-
lyst loadings are not considered, only the results of Zhao, Xu,
and Chandrasekhar exceed those reported here.8a,d,f,23 Further-
more we have reported the first substituted products (4b–d) and
these advances were achieved without a proline based catalyst.
2
3
9
50
85
6 : 1
96
96
14
34 : 1
Aldol reactions
4
5
6
7
8
9
16
30
26
24
30
30
92
90
40
90
85
86
20 : 1
15 : 1
17 : 1
5 : 1
98
99
95
94
94
90
Earlier we reported on the use of PicAm-1 (Fig. 3) for the enan-
tioselective aldol reaction of cyclohexanone with five electroni-
cally and sterically varied aromatic aldehyde substrates,13,24 but
we noted that this catalyst excelled in particular when examining
more functional group rich six-membered ring carbonyl donor
substrates, e.g. N-Boc-piperidone and a 4-ketalcyclohexanone.
Here we devote most of our attention (six compounds) to further
extending the donor ketone diversity, by examining tetra-
hydrothiopyran-4-one and cycloheptanone additions to aromatic
aldehydes. Furthermore we report, in the ESI,† on an improved
resolution method for arriving at enantiopure (R)- or (S)-PicAm-
1 which is robust. Using the PicAm-1 catalyst, obtained using
our new resolution procedure (see ESI†), we recommend using
7.0 mol% of PicAm-1 for reliably fast reactions instead of
5.0 mol% as initially reported.13 For our new aldol results
(Table 4, entries 2–9), we performed all of the reactions in water
at 45 °C using 3.3 equiv. of the carbonyl donor and PicAm-1
(7.0 mol%).
15 : 1
4 : 1
Cyclohexanone addition to benzaldehyde is difficult, and we
observed the corresponding aldol product (7b) in 50% yield,
6 : 1 dr, and 96% ee, after 9 h. Singh and Hayashi have reported
far superior results, e.g. using cyclohexanone (4.0 or 2.0 equiv.,
respectively) and different proline based catalysts (0.5 mol%25a
or 1.0 mol%26a,d), 7b was afforded with very good yield, 99 : 1
or 10 : 1 dr respectively, and 99% ee within 48 h. Our final sub-
strate examination with cyclohexanone was with 2-naphthalde-
hyde, producing 7c (Table 4, entry 3) in 85% yield, 34 : 1 dr,
and 96% ee in 14 h. Aldol product 7c has been reported on at
least thirty five times and the reports by Singh, Hayashi, Grutta-
dauria, Fu, and Zhao/Wang are of high value.25,26d Of those, the
lowest catalyst loading is reported by Singh at just 0.5 mol%,
providing a 69–85% yield, 99 : 1 dr, and 98% ee, within
20–48 h, at −10 °C using cyclohexanone (4.0 equiv.).25a The
next best catalyst achievement was reported by Hayashi using a
1.0 mol% catalyst loading, resulting in a 96% yield, 12 : 1 dr,
and 98% ee for 7c in 42 h using cyclohexanone (2.0 equiv.).26d
a Reaction conditions: ketone (3.3 equiv.), aldehyde (1.0 equiv.,
0.5 mmol), (S)-PicAm-1 (7.0 mol%), 2,4-DNBSA (7 mol%), H2O (0.5
M), 45 °C. b Isolated yield after column chromatography. c 1H NMR data
of the crude product after work-up, the major product is anti. d HPLC
data (Chiralpak AS-H or OD-H column) after silica gel chromatography.
e Performed in brine (0.5 M).
Fu used a 5.0 mol% catalyst loading, providing a 93% yield,
93 : 7 dr, and 99% ee for 7c in 20 h using cyclohexanone (2.0
equiv.).25c From these top performing organocatalysts only Fu
used a non-proline based catalyst: a primary amine derivative of
threonine.
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Stereochemistry and mechanistic considerations
Concerning higher value substrate donor carbonyl additions,
tetrahydrothiopyran-4-one (3.3 equiv.) adds smoothly to p-NO2-
PhC(O)H in the presence of PicAm-1 (7.0 mol%), providing 8a
(Table 4, entry 4) in 92% yield, 20 : 1 dr, and 98% ee within
16 h. From no less than twenty four earlier reports, this is argu-
ably the best currently known. For example, the independent
work of Alonso, Guillena/Nájera, Pedrosa/Andŕes, Xiao, and
Bolm is of high value regarding the synthesis of product 8a.27
The lowest documented catalyst loading to date (5.0 mol%)
afforded an 82% yield, 32 : 1 dr, and 88% ee, in 40 h using tetra-
hydrothiopyran-4-one (2.0 equiv.).27a The most favorable 10 mol
% result is Bolm’s because he uses commercially available
L-proline (10 mol%) with only 1.2 equiv. of tetrahydrothio-
pyran-4-one, providing a 79% yield, 24 : 1 dr, and 90% ee,
within 36 h.27e Unlike the primary amine catalyst used here
(PicAm-1) all of these top performing organocatalysts for acces-
sing 8a are proline or proline based.
Using Newman projection rules in combination with concepts
originating from allylic 1,2- and 1,3-strain,33 it seems reasonable
that conformational isomers A and B represent the two low
energy enamine intermediates from the dehydrative combination
of organocatalyst (S)-PicAm-3 with cyclopentanone (Scheme 1).
The reaction of enamine A or B with β-nitrostyrene can lead to
the (S,R)-syn stereochemistry observed in the major product
(4a). Since the relative and absolute stereochemistry are known,
the possible transition states can be restricted to those rep-
resented by I and II (Scheme 1). Transition state II is less likely
due to the presence of a phenyl ring blocking the Re face of
enamine B (steric repulsion between the nitro group of β-nitro-
styrene with the phenyl ring of the catalyst). A more plausible
stereochemical explanation foresees PicAm-3 operating as a
bifunctional catalyst, transition state I, where the pyridium
species acts as a hydrogen bond donor.
Examination of tetrahydrothiopyran-4-one addition to p-Cl-
PhC(O)H resulted in a 90% yield, 15 : 1 dr, and 99% ee for 8b
in 30 h using our standard conditions (Table 4, entry 5). Bolm27e
and Pihko28a independently reported the best prior (lowest) cata-
lyst loading, 10 mol% L-proline, for the synthesis of 8b; the
former with the following attributes: 85% yield, 19 : 1 dr, and
85% ee, in 35 h with 1.1 equiv. of the ketone, while the latter
observed a 54% yield, 20 : 1 dr, and 98% ee, in 72 h using 1.0
equiv. of the ketone. These are commendable results because
of the practical ketone-to-aromatic aldehyde ratio and the com-
mercial availability of the catalyst, versus our and all other
reports.28
Literature support for transition state I originates from List’s
work with L-proline, which set the stage for the use and exploita-
tion of bifunctional catalysts.34 In the same manner chiral
diamine catalysts, in the presence of an acid co-catalyst, have
been exploited and without exception an ammonium species
(protonated tertiary amine) is always shown in the transition
state. It is common that these ammonium species have the
defined role of a hydrogen bond donor,35 imposing high facial
selectivity via electrostatic guidance of the approaching electro-
phile. But, there are also reports in which the ammonium species
is defined solely as a steric blocking unit (Fig. 4), here the
Indicative of how substrate dependent catalysts can be, a high
value result could not be achieved when we examined tetra-
hydrothiopyran-4-one addition to benzaldehyde (Table 4, entry
6), in this instance several other groups reported far superior
results.25a,26a,c,29
Cycloheptanone addition represents yet another diversification
possibility and it smoothly added to p-NO2-PhC(O)H under
PicAm-1 catalysis. Using our standard conditions, a 94% yield,
5 : 1 dr, and 96% ee were observed for 9a (Table 4, entry 7).
From the twenty three prior literature reports on product 9a, the
top organocatalysts are proline based and have been indepen-
dently reported by Mase, Fu, Lombardo/Trombinia, and Zhao/
Wang.30 The lowest catalyst loading reported is 1.0 mol%, pro-
viding a 28% yield, 52 : 48 dr, and 71% ee, within 96 h,
using 2.0 equiv. of cycloheptanone.30a The most favorable 5 mol
% catalyst loading result provided a 97% yield, 3 : 1 dr, and 98%
ee, after 3.5 h in the presence of 5.0 equiv. of cycloheptanone.30c
Surprisingly little else has been documented regarding
other electrophile combinations with cycloheptanone. It
consequently made sense to examine other substrates, e.g.
its reaction with o-nitrobenzaldehyde resulted in 9b (Table 4,
entry 8) in 85% yield, 15 : 1 dr, and 94% ee. A lone
previous report by Córdova obtained the same product in 76%
yield, 10 : 1 dr, and 96% ee, using a 10 mol% catalyst loading
and 10 equiv. of cycloheptanone.31 We also examined the
addition of cycloheptanone to p-chlorobenzaldehyde, which pro-
vided a new compound, 9c, in 86% yield, 4 : 1 dr, and 90% ee
(Table 3, entry 9).32 These combined aldol results demonstrate
the value of our new catalyst concerning the scope of this
reaction.
Scheme 1 Relevant Michael transition states for (S)-PicAm-3.
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Fig. 4 Top performing catalysts that employ acid additives for carbonyl
addition to β-nitrostyrenes.
electrophile is redirected to the opposite face of the enamine and
the ammonium species abdicates its role as a hydrogen bond
donor in the transition state.36 For example, the Barbas report3a
of an ammonium cation (protonated tertiary amine) acting as a
blocking unit is convincing,37 while the examination of two
other catalyst examples (Fig. 4, left column, lower two catalysts)
showed them to hold the possibility of operating as bifunctional
catalysts and simultaneously providing the correct (reported)
stereochemistry.38
Consideration of these points and the details of our particular
primary amine catalyst, as outlined above, increasethe likelihood
that PicAm-3 is operating as a bifunctional catalyst (Scheme 1).
Furthermore, transition state I (Scheme 1) provides a definitive
argument for why the α-branched aldehyde substrates are slow
to reaction versus cyclopentanone, a strong gauche steric repul-
sion between the phenyl moiety (β-nitrostyrene) and the two
methyl groups of isobutyraldehyde (not shown). This repulsion
would increase considerably when considering the cyclohexane-
carboxaldehyde donor (Table 3, entries 10 and 11) and directly
reflects the lack of reactivity for this substrate. Regarding the
aldol reactions shown here, a similar line of reasoning concludes
that a bifunctional catalyst model is more likely (Scheme 2).
Scheme 2 Relevant aldol transition states for (S)-PicAm-1.
In particular, here we have demonstrated that the picolylamine
organocatalyst template provides good to excellent results for
challenging Michael additions to β-nitrostyrenes and for broad-
ening the ketone donor substrates for aldol reactions with aro-
matic aldehydes.
Conclusions
Functional group manipulations of proline, the cinchona alka-
loids, and 1,2-trans-cyclohexadiamine have dominated the
design space of amine based organocatalysts and excellent
results have been noted, but their limitations are also now
increasingly understood. As new emphasis is placed on more
complex, drug-like, substrates, new catalysts will be required. In
this context we have developed a simple (one stereogenic center)
modular primary–tertiary bifunctional organocatalyst that can be
sterically and electronically fine-tuned for further development.
Experimental
General procedure for enantioselective Michael reactions
To a mixture of the nitroolefin (1.00 equiv.), (S)-PicAm-3 (free
amine, 10 mol% unless otherwise stated) in the presence of
p-dodecylbenzenesulfonic acid sodium salt (10 mol%) and 2,4-
dinitrobenzenesulfonic acid (2.5 mol%, sold as an undefined
hydrate by Sigma-Aldrich) in chloroform (2.0 M) was added the
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7 Ley’s early report also provided inspiration for other researchers, see:
A. J. A. Cobb, D. A. Longbottom, D. M. Shaw and S. V. Ley, Chem.
Commun., 2004, 1808–1809.
ketone or aldehyde (5.00 equiv.). The reactions were performed
at room temperature and monitored by HPLC and/or TLC. At
the indicated reaction time (see Table 3) the reaction was concen-
trated (low vacuum, then short exposure to high vacuum) and
the resulting crude Michael product was purified by column
chromatography. 4b–d are new compounds and have been fully
characterized in the ESI.†
8 For a representative list of the top performing catalysts for cyclopenta-
none, see: (a) S. Chandrasekhar, T. P. Kumar, K. Haribabu, C. R. Reddy
and C. R. Kumar, Tetrahedron: Asymmetry, 2011, 22, 697–702;
(b) T. Mandal and C.-G. Zhao, Angew. Chem., Int. Ed., 2008, 47, 7714–
7717; (c) S. Luo, J. Li, L. Zhang, H. Xu and J.-P. Cheng, Chem.–Eur. J.,
2008, 14, 1273–1281; (d) D.-Q. Xu, L.-P. Wang, S.-P. Luo, Y.-F. Wang,
S. Zhang and Z.-Y. Xu, Eur. J. Org. Chem., 2008, 1049–1053;
(e) S. Chandrasekhar, B. Tiwari, B. B. Parida and C. R. Reddy, Tetra-
hedron: Asymmetry, 2008, 19, 495–499; (f) T. Mandal and C.-G. Zhao,
Tetrahedron Lett., 2007, 48, 5803–5806; (g) Y. Xiong, Y. Wen, F. Wang,
B. Gao, X. Liu, X. Huang and X. Feng, Adv. Synth. Catal., 2007, 349,
2156–2166; (h) S. Luo, H. Xu, X. Mi, J. Li, X. Zheng and J.-P. Cheng,
J. Org. Chem., 2006, 71, 9244–9247; (i) N. Mase, K. Watanabe,
H. Yoda, K. Takabe, F. Tanaka and C. F. Barbas, J. Am. Chem. Soc.,
2006, 128, 4966–4967; ( j) C.-L. Cao, M.-C. Ye, X.-L. Sun and Y. Tang,
Org. Lett., 2006, 8, 2901–2904; (k) S. Luo, X. Mi, L. Zhang,
S. Liu, H. Xu and J.-P. Cheng, Angew. Chem., Int. Ed., 2006, 45,
3093–3097.
9 For some of the top reported results (cyclohexanone addition to β-nitro-
styrene), see ref. 8a,d,f and (a) S. Anwar, P.-H. Lee, T.-Y. Chou,
C. Chang and K. Chen, Tetrahedron, 2011, 76, 1171–1177; (b) B. Ni,
Q. Zhang, K. Dhungana and A. D. Headley, Org. Lett., 2009, 11, 1037–
1040; (c) P. Li, L. Wang, Y. Zhang and G. Wang, Tetrahedron, 2008,
7633–7638; (d) G. Lv, R. Jin, W. Mai and L. Gao, Tetrahedron: Asymme-
try, 2008, 19, 2568–2572; (e) S. Luo, J. Li, L. Zhang, H. Xu and
J.-P. Cheng, Chem.–Eur. J., 2008, 14, 1273–1281; (f) B. Ni, Q. Zhang
and A. D. Headley, Tetrahedron Lett., 2008, 1249–1252;
(g) S. V. Pansare and K. Pandya, J. Am. Chem. Soc., 2006, 128, 9624–
9625; (h) T. Ishii, S. Fujioka, Y. Sekiguchi and H. Kotsuki, J. Am. Chem.
Soc., 2004, 31, 9558–9559.
General procedure for enantioselctive aldol reactions
The (S)-PicAm-1/2,4-dinitrobenzenesulfonic acid 1 : 1 salt (MW
= 550.58, 0.035 mmol, 7.0 mol%) was added to a mixture of the
aldehyde (0.5 mmol, 1.0 equiv.) and ketone (1.65 mmol, 3.3
equiv.) in distilled water (1.0 mL), the reaction mixture was
stirred at 45 °C for the specified reaction time (see Table 4).
Note, the aldol products, in particular, are prone to α-epimeriza-
tion, do not extend the reaction times. Work-up: add EtOAc and
H2O, extract with EtOAc (15 mL × 3). The combined organic
extracts were dried (Na2SO4), evaporated (Rot Vap), and high
vacuum dried. 1H NMR of the crude product allowed the dr
assessment. The crude sample was then purified by chromato-
graphy (petroleum ether/EtOAc) for yield and ee assessment. 9c
is a new aldol compound and has been fully characterized in the
ESI.†
10 S. Bahmanyar and K. N. Houk, J. Am. Chem. Soc., 2001, 123, 11273–
11283 and references cited therein.
11 For example, see: T.-Y. Liu, H.-L. Cui, Y. Zhang, K. Jiang, W. Du,
Z.-Q. He and Y.-C. Chen, Org. Lett., 2007, 9, 3671–3674.
Acknowledgements
We are grateful for financial support from Jacobs University
Bremen and the Higher Education Commission of Pakistan via
the University of Malakand and Kohat University of Science and
Technology. We also thank Professor Nikolai Kuhnert for MS/
HRMS measurements (Jacobs University Bremen). This work
has been performed within the graduate program of Nanomole-
cular Science at Jacobs University Bremen.
12 For example, see: (a) T. Mandal and C.-G. Zhao, Angew. Chem., Int. Ed.,
2008, 47, 7714–7717; (b) S. H. McCooey and S. J. Connon, Org. Lett.,
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13 For our initial report on this template, see: T. C. Nugent, M. N. Umar and
A. Bibi, Org. Biomol. Chem., 2010, 8, 4085–4089.
14 For a 2-picolylamine based pyrrolidine catalyst (aldol reaction), see struc-
ture 2a within: T. J. Dickerson and K. D. Janda, J. Am. Chem. Soc., 2002,
124, 3220–3221.
15 For
a 3-picolylamine based pyrrolidine catalyst, see ref. 14 and
A. Córdova, W. Notz and C. F. Barbas III, Chem. Commun., 2002, 3024–
3025.
16 For 1,3- and 1,4-pyrrolidine-pyridines, for cyclic ketone and aldehyde
additions to β-nitrostyrene, see ref. 9h.
17 For a 2,6-bis(pyrrolidine-triazole) substituted pyridine Michael catalyst
(cyclohexanone additions to β-nitrostyrene derivatives), see:
T. Karthikeyan and S. Sankararaman, Tetrahedron: Asymmetry, 2008, 19,
2741–2745.
18 (a) G. Alvaro, G. Martelli and D. Savoia, J. Chem. Soc., Perkin Trans. 1,
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20 Other reports exist in which similar effects have been previously reported.
For example, see: S. Luo, H. Xu, J. Li, L. Zhang, X. Mi, X. Zheng and
J.-P. Cheng, Tetrahedron, 2007, 63, 11307–11314.
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22 See for example, ref. 3a and: (a) T. C. Nugent, M. Shoaib and A. Shoaib,
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32 The anti stereochemistry assigned to 9b and 9c is assumed based on
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35 Regarding catalysts with ammonium species acting as hydrogen bond
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37 Our examination of hand held models confirmed either a poor or non-
existent ‘geometric fit’ for hydrogen bond formation between the cata-
lyst’s protonated tertiary amine and the nitro group of β-nitrostyrene for
the synthesis of 4a with Barbas’ catalyst (Fig. 4).
38 Our examination of hand held models of the Kotsuki and Luo/Cheng
catalysts (Fig. 4) confirmed a reasonable or good ‘geometric fit’ for
hydrogen bond formation between the catalyst’s protonated tertiary amine
and the nitro group of β-nitrostyrene when adding cyclohexanone to
β-nitrostyrene (the reactions examined by the noted groups). It should be
made clear that our current steric vs bifunctional model assessment has
benefited from having many more literature examples to ponder and draw
conclusions from than were available to Luo/Cheng (2006) or Kotsuki
(2004) when they disclosed their findings. Mechanism grounded exper-
iments would be required to better understand which catalyst model is
truly operative.
9294 | Org. Biomol. Chem., 2012, 10, 9287–9294
This journal is © The Royal Society of Chemistry 2012