Three-component asymmetric catalytic ugi reaction - Concinnity from diversity by substrate-mediated catalyst assembly

Article abstract of DOI:10.1002/anie.201310491

The first chiral catalyst for the three-component Ugi reaction was identified as a result of a screen of a large set of different BOROX catalysts. The BOROX catalysts were assembled in situ from a chiral biaryl ligand, an amine, water, BH₃×SMe₂, and an alcohol or phenol. The catalyst screen included 13 different ligands, 12 amines, and 47 alcohols or phenols. The optimal catalyst system (LAP 8-5-47) provided α-amino amides from an aldehyde, a secondary amine, and an isonitrile with excellent asymmetric induction. The catalytically active species is proposed to be an ion pair that consists of the chiral boroxinate anion and an iminium cation. Harmonious arrangement of parts: A screen of BOROX catalysts that were generated in situ from 13 different ligands and 47 alcohols led to the identification of an effective combination for the catalytic asymmetric three-component Ugi reaction. Experimental results suggest that the catalyst is a chiral polyborate anion, which then forms an ion pair with the iminium cation that is generated from aldehyde and secondary amine.

Full text of DOI:10.1002/anie.201310491

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Angewandte
Communications
DOI: 10.1002/anie.201310491
Asymmetric Catalysis
Three-Component Asymmetric Catalytic Ugi Reaction—Concinnity
from Diversity by Substrate-Mediated Catalyst Assembly**
Wenjun Zhao, Li Huang, Yong Guan, and William D. Wulff*
Abstract: The first chiral catalyst for the three-component Ugi
reaction was identified as a result of a screen of a large set of
different BOROX catalysts. The BOROX catalysts were
assembled in situ from a chiral biaryl ligand, an amine,
water, BH3·SMe2 , and an alcohol or phenol. The catalyst
screen included 13 different ligands, 12 amines, and 47 alcohols
or phenols. The optimal catalyst system (LAP 8-5-47) provided
a-amino amides from an aldehyde, a secondary amine, and an
isonitrile with excellent asymmetric induction. The catalytically
active species is proposed to be an ion pair that consists of the
chiral boroxinate anion and an iminium cation.
Scheme 1. Four- and three-component Ugi reactions.
M
ulti-component coupling reactions that produce a-amino
amides from isonitriles have been of interest ever since the
first example of this process, which was discovered by Ugi in
1959.[1] Since that time, the Ugi reaction has been extensively
studied and widely used in organic synthesis;[2,3] the diversity
that is associated with the coupling of many components is
one of its most salient attractions.[4] The four-component Ugi
reaction can tolerate variations in the amine component
(primary or secondary amines, hydrazines, and hydroxyl-
amines) and in the acid component (carboxylic acids,
hydrazoic acids, cyanates, thiocyanates, secondary amine
salts, water, H2S, H2Se; Scheme 1).[2] The Ugi reaction can
also be effected in the absence of the acid component in
a three-component fashion; in this case, the amine component
can be either a primary or a secondary amine.[5,6] The Ugi
reaction can be catalyzed by both Brønsted and Lewis acids.[7]
Pan and List were recently the first to report turnover for
a three-component Ugi reaction with a primary amine and an
achiral organocatalyst.[5] Unlike for the related Passerini
reaction,[8] a chiral catalyst has yet to be reported for either
the three- or the four-component Ugi reaction.[2d,4c,6,9] How-
ever, chiral catalysts have been reported for closely related
Ugi-type processes that involve azomethine imines[10] or the
formation of oxazoles from a-isocyanoacetamides.[11]
application of the BOROX catalysts that we have developed
for asymmetric reactions that involve iminium ions in
aziridinations,[13] aza-Cope rearrangements,[14] and hetero-
Diels–Alder reactions.[15] The BOROX catalyst consists of an
ion pair containing a chiral boroxinate anion, while the
corresponding cation is derived from the protonated sub-
strate.[16] The BOROX catalyst is typically assembled in situ
from a ligand, B(OPh)3, and an imine (or amine; Scheme 2,
R1 = Ph).[17] We have also shown that the same BOROX
catalyst can be directly assembled in the presence of
a molecule of an imine (or amine) from the ligand, three
molecules of BH3·SMe2, three molecules of water, and two
molecules of phenol.[13d,e,18] This method should allow for the
facile and diversity-oriented generation of an array of
BOROX catalysts by incorporation of different ligands and
different phenols or alcohols into the boroxinate core during
in situ catalyst assembly (Scheme 2).[19] This essentially
instant access to diversity has enabled the identification of
the first effective chiral catalyst for the three-component Ugi
reaction.
The Ugi reaction is commonly thought to involve an
iminium ion,[2a,3,12] and the development of the first asym-
metric catalytic Ugi reaction was an attractive target for an
[*] W. Zhao, Dr. L. Huang, Dr. Y. Guan, Prof. W. D. Wulff
Department of Chemistry, Michigan State University
East Lansing, MI 48824 (USA)
E-mail: wulff@chemistry.msu.edu
Homepage: http://www2.chemistry.msu.edu/faculty/wulff/
myweb26/index.htm
[**] This work was supported by a grant from the National Institute of
General Medical Sciences (GM094478).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310491.
Scheme 2. Catalyst diversity by in situ substrate-induced assembly.
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Table 1: Initial screen with amines and VANOL, VAPOL, and BINOL
While optimizing the reaction conditions for the Ugi
reaction of benzaldehyde and tert-butyl isonitrile with the
BOROX catalyst that is derived from phenol (P-11) and the
VAPOL ligand L-4 (VAPOL = 2, 2’-diphenyl-[3, 3’-biphenan-
threne]-4,4’-diol), it was found that the use of primary amine
A-6 only led to formation of imine 4 in quantitative yield
(Table 1, entry 6). A number of secondary amines, including
diethylamine, pyrrolidine, and aniline derivatives, did not
produce a detectable amount of the desired product under
these conditions. The reaction with pyrrolidine was examined
more closely, and it was found that the only identifiable
compound that was present in the reaction mixture aside from
the starting materials was aminal 5 (50%; entry 1). Dibenzyl-
amine A-5 was found to give the Ugi product 3a in 76% yield,
but unfortunately only with an enantioselectivity of 59:41 e.r.
(entry 5). The use of bis(p-methoxybenzyl)amine (A-7) gave
essentially the same result (entry 7). The catalyst that is
derived from the VANOL ligand L-1 (VANOL = 3,3’-
diphenyl-[2,2’-binaphthalene]-1,1’-diol) gave an even lower
enantioselectivity. The most effective catalyst among those
that are derived from the BINOL ligands L-10 to L-13 led to
the formation of the Ugi product with 55:45 e.r., but with
a reduced yield compared to the VAPOL catalyst (entries 9–
12).
The next two phases of the screening process involved
1) the evaluation of 38 different BOROX catalysts that were
all prepared from the VAPOL ligand and various alcohols/
phenols, and 2) using the phenol/alcohol that is found to be
most effective during this study in combination with newly
prepared derivatives of the VANOL and VAPOL ligands. The
results for a selected set of eight of the 38 phenol/alcohols that
were used to generate VAPOL BOROX catalysts are given in
Table 2 (see also the Supporting Information). The phenol/
alcohol that leads to the most selective catalyst with VAPOL
is 2,4,6-trimethylphenol (P-36); the desired product was
obtained with an enantioselectivity of 70:30 e.r. (Table 2,
entry 8). The electronic nature of the phenol does not have
a significant effect on the asymmetric induction (entries 1 vs.
5). Essentially, the same induction was observed with tertiary
and secondary alcohols as with phenol (P-11), but the use of
ethanol stopped the reaction (not shown). The use of either
(À)-menthol or (+)-menthol gave the product with the same
sense of chirality, which indicates that chiral centers on the
alcohol component may not be used for modifying the
enantioselectivity. A series of BOROX catalysts that contain
2,4,6-trimethylphenol (P-36) were then generated from
a series of newly prepared VANOL and VAPOL ligands.
Catalysts that are prepared from P-36 and the 7,7’-disubsti-
tuted VANOL derivatives L-2 and L-3 were hardly any more
selective (entries 10 and 11) than those from the parent
VANOL ligand, which essentially gave racemic material
(entry 9).[20] However, the substituted VAPOL ligands L-5 to
L-9 were generally significantly more selective than the
parent VAPOL ligand. The optimal BOROX catalyst is
obtained from the VAPOL derivative L-8 and gave an e.r. of
85:15 (entry 15). The synergism between the ligand and the
phenol components on the asymmetric induction was
revealed experimentally: Whereas the enantioselectivity
increased only slightly when the substituted VAPOL ligand
ligands.[a]
Entry Ligand Amine Catalyst
t [h] Yield[b] [%] e.r.[c]
1
2
3
4
5
6
7
8
L-4
L-4
L-4
L-4
L-4
L-4
L-4
L-1
L-10
L-11
L-12
L-13
A-1
A-2
A-3
A-4
A-5
A-6
A-7
A-5
A-5
A-5
A-5
A-5
LAP 4-1-11
LAP 4-2-11
LAP 4-3-11
LAP 4-4-11
LAP 4-5-11
LAP 4-6-11
LAP 4-7-11
LAP 1-5-11
LAP 10-5-11
LAP 11-5-11
LAP 12-5-11
LAP 13-5-11
19
24
24
24
24
18
48
36
40
24
43
24
n.d.[d]
n.d.
n.d.
n.d.
76
–
–
–
–
41:59[e]
–
n.d.[f]
82
57:43
47:53[e]
44:56[e]
55:45
55:45
–
60
9
9[g]
10
11
12
37
30
trace
[a] Unless otherwise specified, all reactions were carried out with 1a
(0.25 mmol, 0.2m), amine (2.0 equiv), and 2 (1.5 equiv) in toluene at RT
for the indicated time with 20 mol% of the catalyst. The pre-catalyst was
prepared by heating a mixture of the R-configured ligand L (20 mol%),
phenol (P-11; 40 mol%), H2O (60 mol%), and BH3·SMe2 (60 mol%) in
toluene at 1008C for 1 h. After removal of all volatile components, the
BOROX catalyst was generated in situ by the addition of the amine at RT;
this was followed by the addition of the aldehyde and then the isonitrile.
[b] Yield of isolated product after column chromatography on silica gel.
[c] Determined by HPLC analysis. [d] Aminal 5 was formed in 50% yield
(determined by 1H NMR spectroscopy), amide 3 could not be detected.
Heating this mixture at 808C for 18 h resulted in a complex mixture with
3 still not detectable. [e] Catalyst generated from the S ligand. [f] Imine 4
was formed quantitatively as determined by 1H NMR spectroscopy with
an internal standard. After 89 h, the imine was still present in
1
quantitative amounts. [g] Yield determined by H NMR spectroscopy
with an internal standard. n.d.=not detected.
L-8 was used instead of VAPOL in combination with phenol
(P-11; entries 17 vs. 4), a much higher enantioselectivity was
observed when L-8 was used instead of VAPOL with P-36
(entries 15 vs. 8).
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Table 2: Synergism by an appropriate choice of substituents at the
contrast to the VAPOL-derived catalysts, which are insensi-
tive to the electronic nature of the phenol (Table 2, entries 1
vs. 5), the catalysts that are derived from the VAPOL
derivative L-8 are quite sensitive to the nature of the
phenol. The asymmetric induction slightly increased when
the p-methyl group in P-36 was replaced by a methoxy group
(P-47; entries 6 vs. 13) and decreased significantly when
a nitro-substituted phenol was employed (P-44; entries 6 vs.
12). This is consistent with an ion pair mechanism in which the
strength of the electrostatic attraction is important for the
asymmetric induction (Scheme 4). The procedure that was
optimized for amine A-5 (entry 13) was applied to several
para-substituted dibenzylamines. All of these dibenzylamines
gave high selectivities (87:13–90:10 e.r.; entries 13–17) with
the exception of the para-nitro-substituted dibenzylamine
A-11, which led to a substantial decrease in yield and
enantioselectivity (entry 18); this result could be due to the
destabilization of iminium ion 7 (Scheme 4).
Having established the most effective combination of all
of the parts of the boroxinate catalyst, different aryl
aldehydes were evaluated as substrates for the Ugi reaction
with amine A-5 (Table 4). Most of the substrates, including
aryl aldehydes with both electron-withdrawing and electron-
donating groups, reacted to give a-amino amides with
enantiomeric ratios of 90:10 to 95:5. The reaction of
cyclohexane carboxaldehyde gave racemic product (47%
yield, not shown); this result will require further examination.
The reactions that are shown in in Table 4 were performed in
the presence of 4 ꢀ molecular sieves (M.S.), whereas most of
the previous reactions in this work had been run in the
absence of molecular sieves. The sieves have essentially no
effect on the enantioselectivity, but seem to accelerate the
reaction slightly. The rate is slower at 08C than at 258C, but
the asymmetric inductions are not substantially different. In
many cases, the a-amino amide 3 can be recrystallized, and
a few examples are shown for which the e.r. could be
enhanced to > 99.5:0.5. The ligand L-8 can also be recovered
from these reactions in high yield (ca. 90%) with no loss in
enantiomeric purity (> 99.5:0.5 e.r.). The reaction can be
extended to heterocyclic aldehydes, as illustrated by the
reaction with pyridine carboxaldehydes. 3-Pyridyl carboxal-
dehyde is the most reactive coupling partner, whereas the 4-
pyridyl isomer reacted more slowly (entries 27 and 28), and
the 2-pyridyl isomer did not react at all (not shown).
boroxinate core.[a]
Entry
Ligand
ROH
Catalyst
t [h]
Yield[b] [%]
e.r.[c]
1
2
3
4
5
6
7
8
L-4
L-4
L-4
L-4
L-4
L-4
L-4
L-4
L-1
L-2
L-3
L-5
L-6
L-7
L-8
L-9
L-8
L-8
P-3
P-5
P-6
LAP 4-5-3
LAP 4-5-5
LAP 4-5-6
36
39
24
24
36
39
39
36
39
42
45
39
39
39
39
42
39
39
64
86
91
76
75
82
71
72
52
62
62
89
64
93
94
90
74
93
57:43
58:42
58:42
59:41
59:41
64:36
60:40
70:30
49:51[d]
54:46
52:48
74:26
35:65[d]
74:26
15:85[d]
71:29
62:38[e]
78:22[e]
P-11
P-13
P-26
P-28
P-36
P-36
P-36
P-36
P-36
P-36
P-36
P-36
P-36
P-11
P-26
LAP 4-5-11
LAP 4-5-13
LAP 4-5-26
LAP 4-5-28
LAP 4-5-36
LAP 1-5-36
LAP 2-5-36
LAP 3-5-36
LAP 5-5-36
LAP 6-5-36
LAP 7-5-36
LAP 8-5-36
LAP 9-5-36
LAP 8-5-11
LAP 8-5-26
9
10
11
12
13
14
15
16
17
18
[a] Unless otherwise specified, all reactions were carried out with 1a
(0.25 mmol, 0.2m), A-5 (2.00 equiv), and 2 (1.5 equiv) in toluene at RT
for the indicated time with 20 mol% of the catalyst. The catalyst was
made from the S enantiomer of the ligand (ꢀ99% ee) according to the
procedure described in Table 1. [b] Yield of isolated product after column
chromatography on silica gel. [c] Determined by HPLC analysis.
[d] Catalyst generated from the R ligand. [e] Ligand with 97% ee.
At this point, a solvent screen was performed with the
optimized catalyst system, which is prepared from the
substituted VAPOL ligand L-8 and 2,4,6-trimethylphenol
(P-36; see the Supporting Information). The asymmetric
induction dropped substantially with coordinating solvents
such as THF and acetonitrile (54:46 and 64:36 e.r., respec-
tively), which is consistent with an ion pair mechanism.
Mesitylene was found to be the most suitable solvent
(87:13 e.r.; Table 3, entry 6), and all further optimization
reactions were performed in this solvent. The stoichiometry
of the amine with respect to the other components does not
seem to have a strong impact on the reaction as the yields and
enantioselectivities decreased only slightly in the range of 2.0
to 1.02 equivalents (entries 6–8). With the identification of the
VAPOL derivative L-8 as the optimal ligand, a final screen of
this ligand and 13 different phenols was performed in
mesitylene (for selected results, see Table 3; see also the
Supporting Information). 2,6-Dimethyl-4-methoxyphenol
(P-47) was found to be the most suitable phenol, and the
resultant catalyst (LAP 8-5-47) gave the desired product with
an enantiomeric ratio of 90:10 in 91% yield (entry 13). In
Scheme 3. Effect of molecular sieves on yield and enantioselectivity at
different catalyst loadings. Bn=benzyl.
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Table 3: Screen of additional phenols and amines with ligand L-8.[a]
The involvement of a BOROX catalyst that
contains a boroxinate core is supported by H and
1
11B NMR studies (see the Supporting Information).
It is considered to be likely that the boroxinate
anion 8, which exists as an ion pair with the iminium
ion 7, acts as the catalyst; therefore, this Ugi reaction
is an example of “chiral anion catalysis”.[22] The
mechanism can be envisioned to involve the addition
of the isonitrile to the iminium cation 7 to give the
nitrilium cation 9, which also exists as an ion pair
with the chiral anion catalyst 8 (Scheme 4). We
propose that the next step is exchange of the
OH group between the nitrilium cation 9 and hemi-
aminal 10, which would result in the regeneration of
the iminium ion 7 and the formation of the product
in the form of tautomer 11. It is also possible that the
hemiaminal 10 is protonated and releases H2O,
which adds to nitrilium ion 9. Evidence against the
presence of free H2O in this reaction stems from the
fact that the presence of molecular sieves does not
greatly affect the rate of the reaction. Furthermore,
the addition of H2O slows down the reaction (see the
Supporting Information, sections VIII and XVIII).
When the reaction is followed by 1H NMR spectros-
copy, an initial build-up of aminal 12 (ca. 15% at ca.
25% conversion) was observed; the aminal then
slowly disappears and is gone at the end of the
reaction. Finally, a four-component version of this
reaction with the optimized BOROX catalyst (LAP
8-5-47) was attempted with benzaldehyde and ben-
zoic acid, but the product of this Ugi reaction was
obtained as a racemic mixture (see the Supporting
Information).
Entry Ligand Amine ROH Catalyst
t [h] Yield[b] [%] e.r.[c]
1
2
3
4
5
6
7
8
L-4
L-4
L-8
L-8
L-8
L-8
L-8
L-8
L-8
L-6
L-8
L-8
L-8
L-8
L-8
L-8
L-8
L-8
A-5
A-5
A-5
A-5
A-5
A-5
A-5
A-5
A-12
A-5
A-5
A-5
A-5
A-7
A-8
A-9
A-10
A-11
P-11
P-36
P-11
P-26
P-28
P-36
P-36
P-36
P-36
P-36
P-39
P-44
P-47
P-47
P-47
P-47
P-47
P-47
LAP 4-5-11
LAP 4-5-36
LAP 8-5-11
LAP 8-5-26
LAP 8-5-28
LAP 8-5-36
LAP 8-5-36
LAP 8-5-36
LAP 8-12-36
LAP 6-5-36
LAP 8-5-39
LAP 8-5-44
LAP 8-5-47
LAP 8-7-47
LAP 8-8-47
LAP 8-9-47
LAP 8-10-47
LAP 8-11-47
38
42
41
39
39
39
39
39
39
41
38
38
38
24
24
24
24
24
71
90
72
94
72
92
86
75
65
53
95
76
91
91
85
80
79
22
61:39
71:29
33:67[d]
83:17
68:32
87:13
86:14[e]
84:16[f]
61:39
9
10
11
12
13
14
15
16
17
18
32:68[d]
82:18
59:41
10:90[d,g,h]
12:88[d]
10:90[d]
12:88[d]
13:87[d]
27:73[d]
[a] Unless otherwise specified, all reactions were carried out with 1a (0.25 mmol,
0.2m), amine (2.0 equiv), and 2 (1.5 equiv) in mesitylene at RT for the indicated time
with 20 mol% of the catalyst. Entries 14–18 were carried out in the presence of 4 ꢀ
molecular sieves. The catalyst was prepared according to the procedure in Table 1
with the S ligand unless otherwise specified. (S)-L-8: 97% ee; (R)-L-8, (S)-L-4, and
(R)-L-6: >99% ee. [b] Yield of isolated product after column chromatography on
silica gel. [c] Determined by HPLC analysis. [d] Catalyst generated from the R ligand.
[e] Amine (1.2 equiv). [f] Amine (1.02 equiv). [g] 89:11 e.r. with (S)-L-8 (97% ee).
[h] 86% yield after 24 h.
A great diversity of BOROX catalysts can be
quickly generated, and the most suitable combina-
tion of the ligand, amine, and phenol/alcohol com-
ponents of the catalyst was sought and found for the
three-component asymmetric Ugi reaction. The
catalytically active species is proposed to involve
Although tert-butyl isonitrile was the optimal isonitrile,
a number of other isonitriles were suitable substrates for the
reaction with benzaldehyde and gave the corresponding
products with enantioselectivities ranging from 51:49 to
88:12 e.r. under the conditions that are described in Table 4
(see the Supporting Information). The catalyst loading can be
reduced to 10 mol% with no significant drop in yield or
asymmetric induction when molecular sieves are employed
(Scheme 3). The e.r. drops from 90:10 to 87:13 when the
catalyst loading is reduced from 20 mol% to 10 mol%.[21]
Both of these the mixtures (90:10 and 87:13 e.r.) were
recrystallized to give the product with an enhanced e.r. of
> 99.5:0.5 in 70–71% recovery yield for the first crop. The
absolute configuration was determined by removal of the
benzyl groups to give 6a; the other a-amino amides were
assumed to be homochiral with 3a.
Scheme 4. Proposed mechanism for the three-component Ugi reac-
tion.
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Molecules 2003, 8, 53 – 66; c) Multicomponent Reac-
tions (Eds.: J. Zhu, H. Bienayme), Wiley-VCH,
Weinheim, 2005; d) A. Dçmling, Chem. Rev. 2006,
106, 17 – 89; e) L. A. Wessjohann, D. G. Rivera, O. E.
Vercillo, Chem. Rev. 2009, 109, 796 – 814; f) L.
El Kaim, L. Grimaud, Tetrahedron 2009, 65, 2153 –
2171; g) B. B. Toure, D. G. Hall, Chem. Rev. 2009,
109, 4439 – 4486; h) C. de Graaff, E. Ruijter, R. V. A.
Orru, Chem. Soc. Rev. 2012, 41, 3969 – 4009.
Table 4: Substrate scope of the catalytic asymmetric three-component Ugi reac-
tion.[a]
Entry Series
R
t [h] T [8C] Yield [%][b] e.r.[c]
1
a
a
a
b
b
c
d
d
d
e
e
f
C6H5
C6H5
C6H5
7
40
25
0
25
0
25
25
0
0
25
0
25
0
25
0
25
0
25
25
25
0
25
25
25
25
0
87[e]
86 (71)
75
86:14
90:10 (>99.5:0.5)
92:8
93:7
92:8
91:9
93:7
95:5
95:5
93:7
92:8
94:6
95:5
91:9
94:6
93:7
93:7
[3] For a discussion of the mechanism, see: N. Chꢂron, R.
Ramozzi, L. El Kaim, L. Grimaud, P. Fleurat-Lessard,
J. Org. Chem. 2012, 77, 1361 – 1366, and references
therein.
[4] For reviews, see: a) H. Bienaymꢂ, C. Hulme, G.
Oddon, P. Schmitt, Chem. Eur. J. 2000, 6, 3321 –
3329; b) I. Akritopoulou-Zanze, Curr. Opin. Chem.
Biol. 2008, 12, 324 – 331; c) J. E. Biggs-Houck, A.
Younai, J. T. Shaw, Curr Opin. Chem. Biol. 2010, 14,
371 – 382; d) E. Ruijter, R. Scheffelaar, R. V. A. Orru,
Angew. Chem. 2011, 123, 6358 – 6371; Angew. Chem.
Int. Ed. 2011, 50, 6234 – 6246.
2[d]
3
24
66
24
66
24
24
48
48
22
66
24
66
24
67
4[f]
5[f]
6
7
8
4-NO2C6H4
4-NO2C6H4
4-CF3C6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
3-BrC6H4
3-BrC6H4
3,4-Cl2C6H3
3,4-Cl2C6H3
4-FC6H4
4-FC6H4
83
51[e]
85
85
65[g]
75[h,i]
82
9[f]
10[f]
11
12
13
14
15
16
17[f]
18
19
20[f]
21
22
23
24
25
26
27
28
66[h]
85
f
54[e]
87[e]
62
[5] S. C. Pan, B. List, Angew. Chem. 2008, 120, 3678 – 3681;
Angew. Chem. Int. Ed. 2008, 47, 3622 – 3625. This
publication includes one example of a three-compo-
g
g
h
h
i
4-MeO2CC6H4 24
4-MeO2CC6H4 67
80
62
86
77 (47)
84 (47)
80[e]
76 (56)
83
nent Ugi reaction with
a chiral catalyst, which
proceeds with very low asymmetric induction.
[6] Y. Tanaka, T. Hasui, M. Suginome, Org. Lett. 2007, 9,
4407 – 4410, and references therein.
[7] B. O. Okandeji, J. R. Gordon, J. K. Sello, J. Org. Chem.
2008, 73, 5595, and references therein.
4-AcOC6H4
4-AcNHC6H4
4-MeC6H4
4-MeC6H4
2-MeC6H4
4-tBuC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-pyridyl
24
24
24
66
24
24
40
24
66
25
70
85:15
j
85:15 (96:4)
91:9 (>99.5:0.5)
92:8
78:22 (>99:1)
84:16
88:12
89:11
92:8
90:10 (>99:1)
89:11
k
k
l
m
n
n
n
o
p
[8] a) S. E. Denmark, Y. Fan, J. Am. Chem. Soc. 2003, 125,
7825 – 7827; b) U. Kusebauch, B. Beck, K. Messer, E.
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84[j]
70
51
80 (61)
66
25
25
4-pyridyl
[a] Unless otherwise specified, all reactions were carried out with 1 (0.25 mmol,
0.2m), amine (2.0 equiv), and 2 (1.5 equiv) in mesitylene at RT in the presence of
4 ꢀ M.S. for the indicated time with 20 mol% of the catalyst. The catalyst was made
from the R enantiomer of the ligand (ꢀ99% ee) according to the procedure in
Table 1. [b] Yield of isolated product after chromatography on silica gel. The value in
parentheses denotes the recovery yield for the first crop of the recrystallization.
[c] Determined by HPLC analysis. The e.r. values in parentheses are for the first crop.
1
[d] Average of four runs. [e] Yield determined by H NMR spectroscopy with an
[10] T. Hashimoto, H. Kimura, Y. Kawamata, K. Maruoka,
Angew. Chem. 2012, 124, 7391 – 7393; Angew. Chem.
Int. Ed. 2012, 51, 7279 – 7281.
internal standard (Ph3CH). [f] Average of two runs. [g] 46% yield after 24 h.
[h] Reaction at 0.4m. [i] 76% yield after 66 h. 60% yield after 66 h in the absence of
4 ꢀ M.S. [j] No 4 ꢀ M.S.
[11] a) T. Yue, M.-X. Wang, D.-X. Wang, G. Masson, J. Zhu,
Angew. Chem. 2009, 121, 6845 – 6849; Angew. Chem.
Int. Ed. 2009, 48, 6717 – 6721; b) Y. Su, M. J. Bouma, L.
Alcaraz, M. Stocks, M. Furber, G. Masson, J. Xhu,
Chem. Eur. J. 2012, 18, 12624.
an ion pair between a chiral boroxinate anion and an achiral
iminium ion.
[12] Hemiaminals have also been proposed as intermediates; see
Ref. [3].
Received: December 3, 2013
Revised: January 3, 2014
Published online: February 19, 2014
[13] a) A. K. Gupta, M. Mukherjee, W. D. Wulff, Org. Lett. 2011, 13,
5866 – 5869; b) H. Ren, W. D. Wulff, Org. Lett. 2010, 12, 4908 –
4911; c) M. Mukherjee, A. K. Gupta, Z. Lu, Y. Zhang, W. D.
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b) H. Ren, W. D. Wulff, Org. Lett. 2013, 15, 242 – 245.
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Soc. 2007, 129, 7216 – 7217.
Keywords: asymmetric catalysis · b-amino amides ·
.
BOROX catalyst · multicomponent reactions · Ugi reaction
[1] a) I. Ugi, R. Meyr, U. Fetzer, C. Steinbrꢁckner, Angew. Chem.
1959, 71, 386; b) I. Ugi, C. Steinbrꢁckner, Angew. Chem. 1960,
72, 267.
[2] For reviews, see: a) A. Dçmling, I. Ugi, Angew. Chem. Int. Ed.
2000, 39, 3169 – 3210; b) I. Ugi, I. Werner, A. Dçmling,
[16] G. Hu, A. K. Gupta, R. H. Huang, J. Mukherjee, W. D. Wulff, J.
Am. Chem. Soc. 2010, 132, 14669 – 14675.
3440 www.angewandte.org
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Angew. Chem. Int. Ed. 2014, 53, 3436 –3441

Angewandte
Chemie
[17] A. K. Gupta, M. Mukherjee, G. Hu, W. D. Wulff, J. Org. Chem.
2012, 77, 7932 – 7944.
[20] Y. Guan, Z. Ding, W. D. Wulff, Chem. Eur. J. 2013, 19, 15565 –
15571.
[18] For a procedure for catalyst generation that employs boric acid
instead of BH3·SMe2, see: Z. Wang, F. Li, L. Zhao, Q. He, F.
Chen, C. Zheng, Tetrahedron 2011, 67, 9199 – 9203.
[19] We have reported one example of a slightly improved catalyst
with 2,4,6-trimethylphenol; see Ref. [14].
[21] With 5 mol% of catalyst, 3a was formed in 62% yield (74:26
e.r.) after 73 h with molecular sieves and in 7% yield in the
absence of molecular sieves.
[22] R. J. Phipps, G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4,
603 – 614.
Angew. Chem. Int. Ed. 2014, 53, 3436 –3441
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www.angewandte.org
3441