A general aminocatalytic method for the synthesis of aldimines

Article abstract of DOI:10.1021/ja4111418

A general and efficient biomimetic method for the synthesis of aldimines from aldehydes and compounds bearing the NH₂ group in the presence of pyrrolidine as a catalyst has been developed. These organocatalytic reactions, based on the application of the concept of nucleophilic catalysis, proceed with outstanding yields in the absence of acids and metals under simple conditions and minimum experimental manipulation. The method has been mainly applied to the synthesis of N-sulfinyl and N-sulfonyl imines, but its general validity has been proven with the preparation of representative N-phosphinoyl, N-alkyl, and N-aryl imines. These unprecedented reactions, which presumably occur via iminium activation without requiring acidic conditions, are an interesting and competitive alternative to the classical methods for preparing aldimines.

Full text of DOI:10.1021/ja4111418

Subscriber access provided by TAIPEI MEDICAL COLLEGE
Article
A General Aminocatalytic Method for the Synthesis of Aldimines
Sara Morales, Fernando G. Guijarro, José Luis García Ruano, and M. Belén Cid
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Dec 2013
Downloaded from http://pubs.acs.org on December 29, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
A General Aminocatalytic Method for the Synthesis of Al-
dimines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Sara Morales, Fernando G. Guijarro, José Luis García Ruano,* M. Belén Cid*
Department of Organic Chemistry. Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain
KEYWORDS Imines, Nucleophilic catalysis, Organocatalysis, Iminium ion, Secondary amines .
ABSTRACT: A general and efficient biomimetic method for the synthesis of aldimines from aldehydes and compounds
bearing the NH2 group in the presence of pyrrolidine as catalyst has been developed. These organocatalytic reactions,
based on the application of the concept of nucleophilic catalysis, proceed with outstanding yields in the absence of acids
and metals under simple conditions and minimum experimental manipulation. The method has been mainly applied to
the synthesis of N-sulfinyl and N-sulfonyl imines, but its general validity has been proven with the preparation of repre-
sentative N-phosphinoyl imines, N-alkyl and N-aryl imines. These unprecedented reactions, presumably occurring via
iminium activation without requiring acidic conditions, are an interesting and competitive alternative to the classical
methods for preparing aldimines.
Scheme 1. Organocatalyzed functionalization of alde-
INTRODUCTION
hydes using iminium activation.
The formation of the C=N bond by condensation of C=O
and NH2 groups has been a priority in organic synthesis
due to the relevance of imines in the fields of chemistry
and biology.1 But more importantly, imines are versatile
electrophiles that give rise to nitrogen-containing com-
pounds,2 widely distributed in nature and with many im-
portant pharmacological activities. Most of the methods
for the direct imine formation require acidic activation
(protic or metallic) of the corresponding carbonyl com-
pound and/or irreversible water removal.3
To our knowledge, aminocatalytic methods for the direct
preparation of imines from aldehydes and amines have
never been reported, which is surprising taking into ac-
count the great advances achieved in organocatalytic pro-
cesses.4 Contrasting with the profusion of enantioselective
reactions involving carbonyl compounds using proline
derivatives as catalysts,5 affecting to α−,5a β−,5b,c or
γ−,5e positions, those concerning the nucleophilic attack to
carbonyl carbon involving iminium intermediates I are
mostly limited to the Mannich and Knoevenagel reactions
(Scheme 1A).6 We reasoned that compounds containing
NH2 groups could act as nitrogenated nucleophiles and
evolve in a similar way under appropriated catalytic condi-
tions, allowing the formation of any kind of C=N bonds
(Scheme 1B). This transformation, astonishingly unexploit-
ed so far, could be considered as a new application of nu-
cleophilic catalysis, an old concept conceived many years
ago.7
respectively. Interestingly, the transimination process
indicated in Scheme 1B; would mimic transformations
occurring in nature. In particular, the formation of imines
III derived from pyridoxal phosphate (PLP) and aminoac-
ids (Scheme 1C), which are pivotal intermediates in trans-
formations of aminoacids, are not formed by direct con-
densation of these components, but through transimina-
Reactions A and B indicated in Scheme 1 can be considered
as organocatalytic C=N+/C=C and C=N+/C=N interchanges,
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 9
tion reaction with activated imines II resulting in the reac-
waste (titanium salts) that imposes purification process,
sometime tedious.
tion of pyridoxal phosphate and a lysine residue.8
1
2
3
4
5
6
7
8
9
The accelerating effect of aniline on the formation of semi-
carbazones and oximes in water at acidic pH, probably via
transamination of a protonated imine IV (Scheme 1D), is
known since 19629 and it has been recently used in the
preparation of hydrazones and oximes as linkage of bio-
conjugates.10 It is important to note that this is a non-
catalytic process that requires high concentration of ani-
line in a strong acidic media.11 On the contrary, the use of a
secondary amine in catalytic amount to generate iminium
intermediate I (instead of the protonated imine IV inter-
mediate) would allow the reaction of a variety of amines in
organic solvents without requiring acidic aqueous medium
(Scheme 1B).
Some recently published results put forward the viability
of our hypothesis. Mayr has reported that the electro-
philicity of the aromatic iminium intermediate I (Scheme
1B) is more than ten orders of magnitude higher than that
of the carbonyl group at the precursor aldehyde in reac-
tions with carbon nucleophiles and even higher (3 to 5
orders) for heteronucleophiles.12 Moreover, Mayr also de-
scribes the reaction of 2 equiv of benzylamine with the
preformed N,N-dimethyliminium triflate derived from p-
methoxybenzaldehyde to form the corresponding imine,
thus demonstrating that the C=N+/C=N interchange is
favored. Thus, it suggests that the pathway proposed in
Scheme 1B to obtain imines could take place satisfactorily,
even considering a low concentration of the iminium spe-
cies I and the low nucleophilic character of some R-NH2
(unable to react with aldehydes in the absence of a appro-
priated activator). It would confer the method a very gen-
eral scope, allowing the preparation of imines with elec-
tron-withdrawing groups joined to the nitrogen, probably
the most valuable precursors in the synthesis of amines.
In this paper we describe the scope and limitations of the
first aminocatalytic procedure for preparing almost any
type of aldimine, including N-sulfinyl, N-sulfonyl and N-
phosphinoyl derivatives in very high yields under mild
conditions and clear environmental advantages with re-
spect to those used by the methods so far reported.
The condensation of benzaldehyde and p-tolylsulfinamide
2a was used as model reaction. Results obtained under
different conditions are indicated in Table 1. All reactions
were accomplished at 60 oC in a sealed vial using solutions
containing equimolar amounts of the reagents. In the
absence of catalyst the reaction did not take place (entry 1)
as could be expected from the low nucleophilicity of the
nitrogen at p-tolylsulfinamide 2a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Evaluation of different amines as catalysts in
the synthesis of imines.
Entrya
Cat
(mol%)
-----
Solvent
T
time
(h)
7
7
7
7
7
7
7
7
6
7
7
7
7
7
8
Conv %b
(oC)
60
60
60
60
60
60
60
60
60
60
60
60
40
40
60
60
60
60
60
(yield %)c
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
0
100
50
0
50
30
60
20
0
99
80
79
66
83
89
4a (20)
4b (20)
4c (20)
4d (20)
4e (20)
4f (20)
4g (20)
4h (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (10)
10
11
THF
12
13d
14
15
16
17e
18
19
20
CH3CN
Toluene
CH2Cl2
CH2Cl2
4a (10) CH2Cl2/4ÅMS
4a (10) CH2Cl2/4ÅMS
4a (10)
4a (10) CH3CN/4ÅMS
1
2
4.5
4.5
4.5
100
100 (94)
100 (90)
100 (92)
100 (91)
THF/4ÅMS
RESULTS AND DISCUSION
4a (10) Toluene/4ÅMS 60
a Reactions were performed in a sealed vial using equimolar amount of
We focused our initial efforts in the organocatalytic prepa-
ration of aldimines activated by electron-withdrawing
groups because of their synthetic importance. Enantio-
merically pure N-sulfinyl imines are one of the activated
imines most used in the asymmetric synthesis of primary
amines due to the dual role played by the sulfinyl group as
activating and stereodirecting group and its easy removal.13
The method most commonly used for preparing these
compounds is based on the reaction of aldehydes with
optically pure R-SONH2 (R = p-Tol or t-Bu) in the presence
of a large excess of Ti(OEt)4 (usually 5 equiv) which acti-
vates the aldehyde and acts as dehydrating reagent.14 The
main drawback of this method, that provides imines in
usually high yields, is the excess of the Lewis acid required,
generating a large amount of environmentally undesired
aldehyde and p-tolylsulfinamide in a 0.2 mmol scale and the indicated
b
1
catalyst (20 or 10 mol%) in 0.6 mL of solvent. Determined by H-NMR
c
on the spectrum of the crude material. Isolated yield after filtration
through a short pad of silica gel. d 1.5 equiv of 1a were used. Reaction
e
performed starting from 1 g of 2a
.
We studied the efficiency of a variety of secondary amines
4 (20 mol %) as catalysts in CH2Cl2 (entries 2-8). Almost all
of them provided the desired N-sulfinyl imine 3aa in some
extent, demonstrating the potential of nucleophilic cataly-
sis. In the presence of the tertiary amine 4h as catalyst, the
reaction did not work (entry 9). Pyrrolidine 4a was the
only amine that afforded full conversion after 7 h (entry 2).
Other five membered ring amines, like 4b and 4c, widely
used in asymmetric organocatalysis15 are less efficient (en-
tries 3 and 4). Analogously, in the presence of pyperidine
(4d, entry 5), other six-membered cyclic secondary amines
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
these smooth conditions are also efficient in other sol-
(4e and 4f, entries 6 and 7), and the bulky bis-
1
2
3
4
5
6
7
8
trimethylsilyl amine 4g (entry 8), conversions observed
after 7h were lower than those achieved with 4a.
vents, like THF, MeCN, and toluene (entries 18-20), which
could be interesting for connecting the preparation of the
imines with their reactions with different nucleophiles in
one-pot processes. Finally, we have checked that all these
reactions take place without epimerization at the sulfur
atom.17
We next investigated the scope of the reaction with differ-
ent aromatic aldehydes. The reactions have been per-
formed using two sets of conditions. The results obtained
under conditions of entry 2, Table 1 (without 4Å MS) are
recorded in SI, whereas those obtained under conditions of
entry 16, Table 1 (in the presence of 4Å MS) are gathered in
Table 2. All compounds were obtained in high purity after
a simple filtration through a short pad of silica gel.
Starting from substituted benzaldehydes (entries 2-10)
almost quantitative yields were obtained regardless the
electronic character and the position of the substituents. A
similar result was obtained from 2-naphthyl carbaldehyde
(entry 11).
We then checked the role of the solvent. The reaction
progressed in all the used solvents but, after 7 h under the
studied conditions, complete conversion is only observed
in CH2Cl2 and EtOH (entry 2 and 10). By lowering the tem-
perature (entry 14) or the catalyst loading (to 10 mol%,
entry 15) in CH2Cl2, conversions after 7 hours are not com-
plete.
Better results were obtained in the presence of molecular
sieves (4Å) as water scavenger. Thus, the time to get a
complete conversion by using only 10 mol% of catalyst
loading decreased to 1 h (entry 16).16 The use of these con-
ditions, considered as the optimal ones, allowed us to
obtain pure 3aa in almost quantitative yield by simple
filtration through a short pad of silica gel to remove pyr-
rolidine and 4Å MS. Similar results were obtained at the
gram scale, being possible to obtain 3aa in 94 % isolated
yield after 2 h in sealed tube (entry 17) and after 75 min
under conventional CH2Cl2 reflux (see SI). Remarkably,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Scope of the synthesis of N-sulfinyl imines derived from aromatic aldehydes.
Entrya
Aldehyde R1
Amide
t(h)
1
2.5
2
4
3
5
3
4
Product
Previous methodc
(yield %)b
Conditions
yield (%)
1
2
3
4
5
6
7
8
9
1a C6H5
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
3aa (100)
3ba (93)
3ca (96)
3da (92)
3ea (95)
3fa (90)
3ga (89)
3ha (96)
3ia (99)
3ja (91)
3ka (90)
3la (88)
3ma (91)
3na (70)
3oa (90)
3pa (99)
3qa (97)
3ra (88)
3sa (98)
3ta(93)
9914
8518
9214
6019
8420
Ti(OEt)4 (5),4h
Ti(OEt)4 (5)
1b p-NO2-C6H4
1c p-OMe-C6H4
1d p-CN-C6H4
Ti(OEt)4 (5),4h
Ti(OEt)4 (5),4h
Yb(OTf)3 (0.1)d,12h
Yb(OTf)3 (0.1)d,12h
1e p-Cl-C6H4
1f o-NO2-C6H4
1g o-OH-C6H4
1h o-Br-C6H4
1i o-OMe-C6H4
1j m-OMe-C6H4
1k 2-naphthyl
8120
i
-Not described-
Ti(OEt)4 (5),4h
KF (2), THF,-78 oC,12h
6519
9121
3
3
4
9214
9422
Ti(OEt)4 (5), 4h
10
11
Ti(OEt)4 (5), 4h
CsCO3 (5), 45 oC, 8h.
12
13
14e
15
16 f
17f
18f
19f
20
21
22
23
1l 2-pyridyl
1m 2-pyrrolyl
4
4
8
4
9523
i
-Not described-
-Not described-
-Not described-
Ti(OEt)4 (5),4h
i
1n 2-Methylindolyl
1o 5-NO2-tiophenyl
1p C6H4-CH=CH-
1q p-NO2-C6H4-CH=CH-
1r p-OMe-C6H4-CH=CH-
1s o-OMe-C6H4-CH=CH-
1t CO2Et
4
3
3.5
3.5
5
8022
-Not described-
-Not described-
-Not described-
4Å MS,rt,1h
CuSO4 (2), rt g
CuSO4 (2), rt,24h h
CuSO4 (2), rt g
6727
9124
9625
8124
1a C6H4
1b p-NO2-C6H4
1c p-OMe-C6H4
4
4
4
3ab (99)
3bb (91)
3cb (99)
aAll reactions were carried out in a 0.2 mmol scale. bIsolated yield. cConditions providing the highest yield found in the literature. Unless otherwise stated,
reactions were carried out under reflux of CH2Cl2 using 1 equiv of the starting aldehyde. d Reported procedure in THF at rt using 3.5 equiv of aldehyde.e 1.2
equiv of 1n in the absence of 4Å MS. f Reaction was carried out at room temperature. g 1.1 equiv of aldehyde were used. h 1.5 equiv of aldehyde were used. i
We have proven that these reactions also work in high yields using Ti(OEt)4 (5) as shown in SI.
The reaction was also effective with heteroaryl aldehydes
(entries 12-15) providing N-sulfinyl imines that in some
cases (3ma, 3na, and 3oa) had never been reported. Under
the standard conditions, 2-pyridyl, 2-pyrrolyl and 5-NO2-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 9
tiophenyl carboxaldehydes respectively produce 3la (88%), far reported in the literature to obtain the different N-
1
2
3
4
5
6
7
8
3ma (91%), and 3oa (90 %) in 4 hours (entries 12, 13 and
15), whereas unprotected 2-methylindolyl carboxaldehyde
afforded 3na (70%) after 8 h, but using 1.2 equiv of 1n
without 4Å MS (entry 14).
sulfinyl imines that we have prepared. Almost all of these
methods use acidic catalysts, whereas pyrrolidine is em-
ployed in our method, constituting an interesting alterna-
tive for avoiding possible undesired reactions. Moreover,
the yields obtained with pyrrolidine (left part of Table 2)
are always comparable and, in many cases better than
those provided by using acidic catalysis (right part of
Table 2). It is also remarkable the simplicity of the exper-
imental manipulation required for obtaining pure N-
sulfinyl imines (by NMR) under pyrrolidine catalysis (fil-
tration of the reaction crude through a short pad of silica
gel), which fulfills the main requirements of the green
chemistry28 (minimal waste, no hazardous materials and
catalytic conditions), conferring to our procedure a po-
tential interest in its application at industrial scale.
Encouraged by the excellent results obtained by using
nucleophilic catalysis for the synthesis of N-sulfinyl imines
we set up to investigate the preparation of other syntheti-
cally important imine derivatives, like N-sulfonyl imines,29
by condensation of the aromatic aldehydes with RSO2NH2.
The main problem associated to this reaction is related to
the large electron-withdrawing character of the sulfonyl
group, determining a very low nucleophilicity of the nitro-
gen at the RSO2NH2 (much lower than that of the
RSONH2) and, therefore, the need of a very high activation
of the carbonyl. The use of acid catalysts under very strong
conditions allows solving this problem, but the instability
of the resulting N-sulfonyl imines, more prone to hydroly-
sis than the N-sulfinyl ones, imposes restrictions to the
catalysts that can be used. Despite these drawbacks, there
is a plethora of methods for the preparation of the syn-
thetically important N-sulfonyl imines.30
Unsaturated aldehydes 1p-1s (entries 16-19) also reacted to
form the imines 3pa-3sa in almost quantitative yields. This
complete regioselectivity towards the products resulting in
the attack of sulfinamide 2a to C-1 is remarkable because
carbonated nucleophiles only produce the attack to C-3 in
reactions catalyzed by 4b or 4c. This change in the regiose-
lectivity could be due to the reversibility observed in the
attack to C-3 of some heteronucleophiles,26 and/or to the
fact that the reaction of N-nucleophiles with C-1 is more
favored than that of C-nucleophiles, as a consequence of
the anomeric stabilization of the aminal species resulting
in the first case.12 The incorporation of electron donating
and electron withdrawing groups to the aromatic ring of
these enals has not any consequence on the efficiency of
the process (entries 17-19), being possible to obtain excel-
lent yields of the N-sulfinyl imines 3qa-3sa, so far never
reported.
Finally, the excellent result obtained in the synthesis of 3ta
from ethyl glyoxylate (93% yield, entry 20) is remarkable
due to the relevance of this compound as amino acids
precursor as well as to the rather modest yield (67%) pre-
viously reported in the literature.27
Our method is also appropriate for obtaining N-t-
butylsulfinyl imines, one of the most used for synthetic
purposes.13b-c We have illustrated this fact with the synthe-
sis in high yields of three representative N-t-butylsulfinyl
imines (3ab-3cb, entries 21-23) derived from benzaldehyde
and aromatic aldehydes bearing electron-withdrawing and
electron donating substituents.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With comparative purposes, we have indicated in the
right part of Table 2 the conditions of the best yields so
Table 3. Scope of the synthesis of N-sulfonyl imines with aromatic aldehydes.
Entrya Aldehyde R1
Amide
Product
(yield,%)b
5ac (99)
5bc (87)
5cc (97)
5dc (95)
5ic (86)f
5pc (99)
5qc (98)
5rc (92)
5uc (86)
5vc (83)j
5ad (96)
Previous highest yieldc
Conditions
yield (%)
(95)31
1d
1a C6H5
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2d
BF3.Et2O (0.8 equiv) Tol, 120 oC, 12 h
Amb. 15, 5Å MS, Tol, Dean-Stark, 16 h.
p-TsOH, Tol, 120 oC Dean-Stark, 16 h
BF3Et2O (0.8 equiv), 120 oC Dean-Stark
Si(OEt)4 (1.1 equiv), 160 oC, 10 h
2
1b p-NO2-C6H4
(95)32
(99)33
(99)34
(94)35
(95)22
(80)36
(82)37
(68)31
(99)34
(96)22
3e
4
1c p-OMe-C6H4
1d p-CN-C6H4
5d
6g
7g
8g,h
9i
10d
11
1i o-OMe-C6H4
1p C6H5-CH=CH-
1q p-NO2-C6H4-CH=CH-
1r p-OMe-C6H4-CH=CH-
1u 2,4-(OMe)2-C6H3
1v 3,4,5-(OMe)3-C6H2
Oxidation of N-sulfinyl imines with MCPBA
BF3.Et2O, Benzene, Dean-Stark, 2h
Si(OEt)4 (1.1 equiv), 160 oC, 5 h
BF3.Et2O (0.8 equiv), Tol, 120oC, 12 h
BF3Et2O (0.8 equiv), 120 oC Dean-Stark
Oxidation of N-sulfinyl imines with MCPBA
d
1a C6H5
aAll the reactions were carried in a 1.2 mmol scale. b Isolated yield. c Conditions providing the highest yield found in the literature. d 1.2 equiv of aldehyde
were used. e Reaction time 20 h. f Purified by precipitation in THF/hexane. g Reaction carried out at rt. h Reaction time 16 h. I Reaction time 6 h. j Purified
by flash chromatography.
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
The results obtained in the reactions of aromatic alde-
than that of the so far used methods for preparing these
compounds (right, Table 4).41,42,43
1
hydes with sulfonamides under similar conditions to those
used for obtaining N-sulfinyl imines (4Å MS38 and 10 mol%
of pyrrolidine) are depicted in Table 3. Sulfonamide 2c
reacts with benzaldehyde yielding pure 5ac (after filtration
of the reaction mixture through a short pad of celite to
remove both pyrrolidine and 4Å MS) in quantitative yield
(entry 1, Table 3) after 24 h. The reaction times required for
getting the complete conversion into 5ac are longer (24 h)
than those of the N-sulfinyl imine 3aa (1 h, entry 1, Table
2), which was expected from the lower nucleophilicity of
the sulfonamide 2c with respect to the sulfinamide 2a.
Under similar conditions, substituted benzaldehydes with
electron-withdrawing (entries 2 and 4) and electron-
donating substituents (entries 3 and 5), and unsaturated
aldehydes 1p-1r (entries 6-8) provided excellent yields.
Finally, compounds 1u and 1v, bearing 2 and 3 OMe groups
also gave very good results (entries 9 and 10). We also
carried out the preparation of 5bc in a 1.1 g scale without
losing efficiency (see SI). Moreover, we have demonstrated
that 4Å molecular sieves could be successfully reused after
MW activation without erosion of the yield (see SI).
t-Butylsulfonyl imines can be prepared under similar con-
ditions, as we have demonstrated in the case of the reac-
tion of t-butylsulfonamide 2d with benzaldehyde (entry
11).
The comparison of our conditions and yields with those of
the previously reported methods affording the highest
yields for the different N-sulfonyl imines (right, Table 3)
reveals similar advantages to those mentioned in the syn-
thesis of N-sulfinyl imines (analogous or better yields,
softer conditions, and simpler experimental manipula-
tion). Moreover, the dispersion of methods based on acidic
catalysis used for preparing the different N-sulfonyl imines
shown in Table 3, contrasts with the fact that all of them
are accessible under the same conditions employing pyr-
rolidine as catalyst.
The reaction of sulfinamides and sulfonamides with ke-
tones was unsuccessful. Probably due to the high steric
interactions around the iminium carbon at the tetrasubsti-
tuted generated intermediates.39
We have also checked that the aminocatalytic conditions
used for preparing N-sulfinyl and N-sulfonyl imines are
appropriated for N-diphenylphosphinoyl imines, which
have particular importance in some catalytic processes
leading to enantioenriched primary amines.40
Under similar conditions to those of tables 2 and 3, ben-
zaldehyde (1a) and aromatic aldehydes bearing electron-
withdrawing (1b) and electron-donating (1c) substituents,
can be easily transformed into the N-phosphinoyl imines
6ae-6ce in high yields by reaction with N,N-diphenyl
phosfinic amide 2e (Table 4). The indicated results were
obtained starting from a little excess of aldehyde (1.2
equiv), and thus, for obtaining pure phosphinoyl imines,
reaction crudes were filtered through a short pad of celite
and then crystallized or column chromatographied. De-
spite this, the experimental manipulation is much simpler
2
3
4
5
6
7
8
9
Table 4. Synthesis of some N-phosphinoyl imines 6
Entrya Aldehyde R1
Product
(yield%)
6ae (90)c
6be (98)c
6ce (85)d
Previous methodb
(yield, %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1a C6H5
In 3 steps (82) 41b
In 2 steps(20) 42b
(85)43
1
1b p-NO2-C6H4
1c p-OMe-C6H4
2
3
a
All reactions were carried out in a 0.4 mmol scale. b Method providing
c
the highest yield found in the literature. Purified by precipitation from
CH2Cl2/pentane. d Purified by flash chromatography.
A priori, the synthesis of imine derivatives from aliphatic
aldehydes should be troublesome because it is well estab-
lished that they react with secondary amines to form
mainly enamines V (Scheme 2), thus activating their α-
position towards its reaction with electrophiles (HOMO
activation).4 However, to our surprise, we were also suc-
cessful in applying our aminocatalytic approach (involving
LUMO activation via iminium intermediates) to the syn-
thesis of aliphatic N-sulfinyl imines, which suggests that
the reaction of the sulfinamide with the iminium I is fast
enough to shift the equilibrium shown in Scheme 2 to-
wards the N-sulfinyl imine.
Scheme 2. Formation of N-sulfinyl imines from ali-
phatic aldehydes under pyrrolidine catalysis.
Reaction of 2a with propanal 7a, under conditions of the
entry 16 at Table 1, afforded complex mixtures containing
8aa. Cleaner reactions and higher yields of 8aa were ob-
tained after longer reaction times than those required for
aromatic aldehydes by using an excess of the aldehyde,
with the best results being obtained starting from 2 equiv
of 7a after 24 hours (entry 1, Table 5). A similar behavior
was observed for 2-methybutanal, which afforded 8ba in
72% yield after 6h, using 3 equiv of 7b (entry 2). Chroma-
tographic purification of the p-tolylsulfinyl imines was
necessary. Better yields were achieved with t-
butylsulfinamide 2b than with 2a. Reactions with different
aliphatic aldehydes evolved in high yields regardless the
primary, secondary and even tertiary nature of the alkyl
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
residue (entries 3-7). The isolated N-t-butylsulfinyl imines experimental simplicity and the yields obtained with this
1
2
3
4
were obtained by using an excess of aldehyde (1.5 or 3
equiv) after simple filtration through a short pad of silica
gel and elimination of the excess of aldehyde under vacu-
um with similar yields to the best ones described in the
method are clear advantages in comparison with the other
ones reported in the literature to prepare aliphatic N-
sulfonyl imines. These methods are based on their in situ
generation from the corresponding amidosulfones50 or on
the oxidation of their N-sulfinyl imine precursors.22
20,44,45
5
literature, which mainly use a large excess of Ti(OEt)4
6
(see previous method, Table 5).
7
Table 6. Preparation of alkyl N-sulfonyl imines.
8
Table 5. Preparation of alkyl N-sulfinyl imines.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
Aldehyde
R1 (equiv)
R2
T
(h)
Conv
(%)a
Previous
method
(yield%)b
7850
En-
trya
Aldehyde R1
(equiv)
Ami
ne
t
(h)
Product
(yield,%)
Previous
method
(yield%)c
8720
1
7c n-Bu (3)
7g n-Octyl (3)
7d i-Bu (3)
7f t-Bu (2)
7a Et (3)
2c
2c
2c
2c
24
24
24
72
9cc (90)
9gc (100)
9dc (88)
9fc (99)c
9ad (80)
1
7a Et (2)
2a
2a
2b
2b
2b
2b
2b
24
6
8aa (83)b
8ba (72)b
8cb (99)d
8db (89)d
8bb (92)d
8eb (99)d
8fb (70)d
8051
2
3
4
5
2
3
4
5
6
7
7b s-Bu (3)
7c n-Bu (2)
7d i-Bu (1.5)
7b s-Bu (1.5)
7e Cy (1.5)
8020
6450
24
18
18
18
45
8146
9622
9647
(-)52
2d 36
8720
a
1
9844
Determined by H-NMR on the spectrum of the crude material after
filtration through a short pad of silica gel. b Highest yield found in the
literature. Yield obtained after filtration through a short pad of silica
and removed the excess of 7f.
7f t-Bu (3)
8745
c
a All reactions were carried out in a 0.4 mmol scale. b Isolated yield after
column chromatography. c Highest yield found in the literature. d Yield
after filtration through short pad of silica gel and removed the excess of
aldehyde under vacuum.
Finally, we have tested the power of our methodology by
preparing representative examples of N-alkyl and N-aryl
imines derived from both aromatic and aliphatic aldehydes
(Tables 7 and 8).53
Unfortunately, the reactions of the less nucleophilic sul-
fonamides with aliphatic aldehydes in the presence of
pyrrolidine were not successful, yielding complex reaction
mixtures. These negative results suggested us that the
formation of the enamine must be avoided in order to
achieve a general aminocatalytic method allowing the
preparation of sulfonylimines derived from aliphatic alde-
hydes. We reasoned that the use of a similar strategy to
those depicted in scheme 1D, consisting in the formation
of a protonated imine, could provide a possible solution. It
would require the use of primary amines as catalysts in the
presence of a protons source, thus precluding the unde-
sired enamine pathway.48 By assuming that intramolecular
protonation of the imine could facilitate the process
(scheme 1C), we though in a β-amino acid as the catalyst,
and chose the anthranilic acid because the aromatic ring
would act as rigid tether between both functionalities,
thus avoiding flexibility and making the protonation more
effective (see specie VI in Table 6).49
We were glad to observe that a catalytic amount (10% mol)
of anthranilic acid, in the presence of 4Å MS, was able to
promote the direct condensation of aliphatic aldehydes
with sulfonamides. By using an excess of the starting alde-
hydes (2 or 3 equiv), almost quantitative conversions were
obtained, regardless the linear or ramified nature of the
alkyl chain and the p-tolyl or t-butyl residue joined to
sulfur (Table 6). As these imines are extremely prone to
hydrolysis no chromatographic purification was undertak-
en. Nevertheless, after removal of the excess of aldehyde
under vacuum, the crude products are pure enough to be
As aliphatic amine model we chose L-PEA 2f due to its
synthetic interest.54 Reaction of this amine with benzalde-
hyde in the presence of pyrrolidine and 4Å MS afforded
10af in almost quantitative yield after 20 min (entry 1,
Table 7). This reaction also occurs in the absence of cata-
lysts, but it is clearly slower (see SI). The procedure was
also very efficient with the more challenging aliphatic
aldehydes 7b and 7c (entries 2 and 3), also affording the
scarcely stable imines 10bf and 10cf, so far never reported,
in almost quantitative yield, by using a small excess (1.2
equiv) of the starting aldehydes.
Table 7. Preparation of N-alkyl aldimines.
Entry Aldehyde R1
(equiv)
t
Yield
(%)a
Previous
method
(yield%) b
99c
not described
not described
1
2
3
1a C6H5 (1)
7b s-Bu (1.2)
7c n-Bu (1.2)
20 min
1.5 h
1.5 h
10af 90
10bf 99
10cf 98
a Isolated yield after filtration through a short pad of celite without fur-
ther purification. Excess of aldehyde in entries 2 and 3 was eliminated by
evaporation. b Highest yield found in the literature. c Conditions: NaHCO3
(5 equiv), reflux of benzene, 16h54b
1
used in further reactions (see H-NMR spectra in SI). The
6
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
the previous experiment (Scheme 3), the attack of the
As aromatic amine model for preparing N-aryl imines we
1
2
3
4
5
6
7
8
chose the p-methoxyaniline (2g) because of the easy con-
version of the N-PMP moieties into the free NH2.3 We have
studied reactions of 2g with aromatic (1c, entry 1, Table 8)
and aliphatic aldehydes (7b, 7d, and 7f, entries 2-4), all of
them evolving with excellent yields. Reaction with the
ethyl glyoxylate 1t (entry 5) is interesting because of the
usefulness of the resulting imine 11tg in the synthesis of
aminoacids. Finally we have studied the reaction of the
poorly nucleophilic p-nitroaniline (2h) with the scarcely
electrophilic p-methoxy benzaldehyde 1c, with analogously
good result (entry 6) and where the accelerating role of
both pyrrolidine and 4Å MS can also be clearly appreciated
(see SI).
amino derivative to the highly electrophilic iminium I,
must be highly favored, even for scarcely nucleophilic
compounds, like those bearing electron-withdrawing
groups joined to the NH2. The transformation of the so
formed aminal VII into the imine could occur through a
favored concerted process involving a four membered
transition state according the route recently proposed by
Di Stefano et al.60 The liberation of the pyrrolidine would
complete the catalytic cycle, reacting with another mole-
cule of aldehyde, more reactive than the resulting imine in
most of the cases. The water scavenger would prevent the
hydrolysis of the formed imine (mainly the more reactive
N-sulfonyl and N-phosphinoyl derivatives) into the start-
ing products, shifting the equilibrium shown in Scheme 4
and therefore accelerating the reaction.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 8. Preparation of N-aryl aldimines.
Scheme 4. Mechanistic proposal.
Entry Aldehyde R1 (equiv)
/ amine
t
(h)
Product
Previous
Yield(%)a method
(yield%)d
1
1c p-OMe-C6H4 (1)/2g 0.25 11cg (89)b 9955
a
2
3
4
5 c
6
7b s-Bu (1.2) / 2g
7d i-Bu (2) / 2g
7f t-Bu(2) / 2g
1t CO2Et (1) / 2g
0.5 11bg(86)b 9956
0.5 11dg(87)b 8857
22
1
11fg (99)
11tg (94)
9358
9956b
1c p-OMe-C6H4 (1)/2h 16
11ch (100) 9559
CONCLUSIONS
a Isolated yield after filtration through a short pad of silica
We have applied the concept of nucleophilic catalysis to
the synthesis of different types of aldimines, including
those bearing EWG at the nitrogen (N-sulfinyl, N-sulfonyl,
and N-phosphinoyl derivatives), which are of special syn-
thetic relevance. Contrasting with the so far reported
methods, usually based on the activation of the carbonyl
with a large amount of acid, our surprisingly unprecedent-
ed procedure takes place under smooth catalytic condi-
tions in the presence of pyrrolidine (10% mol) and 4Å MS,
providing excellent yields of aldimines from a wide variety
of aldehydes (aryl, heteroaryl, alkyl and unsaturated), after
minimum lab manipulation. We envision a great potential
for this biomimetic and organocatalytic methodology as
useful tool in imine preparation. The search of new amino-
catalytic systems for these and similar reactions is current-
ly ongoing in our laboratory.
gel. b Conversion determined by H-NMR on the spectrum
1
of the crude material. c 5 mol% of 4a was used. d Highest
yield found in the literature.
In order to corroborate our C=N+/C=N transimination
hypothesis outlined in Scheme 1B, we carried out some
NMR studies (see SI). We demonstrated that the pre-
formed iminium chloride of pyrrolidine and benzaldehyde
12 reacted instantaneously with both p-tolylsulfinamide 2a
and p-tolylsulfonamide 2c to afford the corresponding
imines 3aa and 5ac (Scheme 3).
Scheme 3. Instantaneous reaction of iminium 12 with
p-tolylsulfinamide 2a and p-tolylsulfonamide 2c.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data for all new com-
pounds. This material is available free of charge via the In-
ternet at http://pubs.acs.org.
A mechanistic proposal explaining the nucleophilic cataly-
sis exerted by pyrrolidine in the synthesis of different types
of aldimines is depicted in Scheme 4. The secondary amine
would react to some extent with the starting aldehyde to
form an iminium ion I. As it has been demonstrated with
AUTHOR INFORMATION.
Corresponding Author
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
Belen.cid@uam.es, joseluis.garcia.ruano@uam.es
1
2
3
Notes
4
5
6
7
8
9
The authors declare no competing financial interest.
(12) R. Appel, S. Chelli, T. Tokuyasu, K. Troshin, H. Mayr. J. Am.
Chem. Soc. 2013, 135, 6579.
(13) (a) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60,
8003. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984.(c) Robak, M.T.; Herbage, M.A.; Ellman, J.A. Chem.
Rev. 2010, 110, 3600.
ACKNOWLEDGMENT
We thank the Spanish Government (CTQ-2012-35957) and
Comunidad Autónoma de Madrid (S2009/PPQ-1634) for
financial support. SM thanks the Spanish Ministry of Econo-
my and Competitiveness for a predoctoral fellowship (FPI).
(14) Davis, F. A.; Zhang, Y.; Andemichae, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) (a) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T.C.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (b) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed. 2005,
44, 4212.
(16) Reaction of 1a with 2a in the presence of 4Å MS affords 3aa
in a modest 52 % yield, after 24 hours (see ref. 14)
REFERENCES
(17) We have compared the optical rotation value of compound
(1) Belowich, M. E.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41, 2003
and references cited therein.
(2) (a) Bloch R. Chem. Rev. 1998, 98, 1407. (b) For chiral amines
see: Chiral Amine Synthesis: Methods, Developments and Applica-
tions Thomas C. Nugent, Wiley-VCH: Weinheim, Germany,
2010. 494 pp.
ͦͤ
ʞ ʟ
(S)-(+)-3aa obtained following our method
+117.7° (c= 1,77,
ꢀ
ͦͤ
ʞ ʟ
CHCl3)with the one described in the literature:
+119.3° (c =
ꢀ
1.77, CHCl3), Davis, F. A.; Reddy, R.E.; Szewczyk, J. M. J. Org.
Chem. 1995, 60, 7037.
(18) García Ruano. J.L.; Alemán, J.; Fajardo, C.; Parra, A. Org.
Lett. 2005, 7, 5493.
(19) García Ruano J. L.; Alemán, J.; Soriano, J. F. Org. Lett. 2003,
5, 677.
(20) Jiang, Z-Y.; Chan, W.H.; Lee, A.W. J. Org. Chem. 2005, 70,
1081.
(21) Davis, F.A.; Reddy, R. E.; Szewczyk, J.M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy; T. R.; Zhou, P.;
Carroll, P. J. J. Org. Chem. 1997, 62, 2555.
(22) García Ruano J. L.; Alemán, J.; Cid, M.B.; Parra, A. Org. Lett.
2005, 7, 179.
(23) Higashibayashi, S; Tohmiya, H; Mori, T; Hashimoto, K;
Nakata, M. Synlett 2004, 457.
(24) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278.
(25) Forbes, D.C.; Bettigeri, S.V.; Amin, S.R.; Bean, C.J.;. Law, A.
M.; Stockman, R.A. Synth. Commun. 2009, 39, 2405.
(26) (a) Marigo, M.; Schulte. T.; Franzén, J.; Jørgensen. K.A. J.
Am. Chem. Soc. 2005, 127, 15710.(b) Dinér, P.; Nielsen, M.;
Marigo, M.; Jørgensen. K.A. Angew. Chem. Int. Ed. 2007, 46, 1983.
(27) Davis, F.A.; McCoull, W. J. Org. Chem. 1999, 64, 3396.
(28) Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and
Practice, Oxford University Press: New York, 1998. A more de-
tailed description of the environmental advantages is included in
SI.
(29) (a) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131. (b) Go-
hain, N. Synlett 2003, 2097.
(30) See references 22 and 31-37 in Table 3.
(31) Yoshida, K.; Akashi, N.; Yanagisawa, A. Tetrahedron: Asym-
metry 2011, 22, 1225.
(32) Barbarotto, M.; Geist, J.; Choppin,S.; Colobert. F. Tetrahe-
dron: Asymmetry 2009, 20, 2780.
(3) (a) Tehrani, K. Abbaspour; De Kimpe, N. Product class 7:
imines. Science of Synthesis, Georg Thieme Verlag: Germany
2004, 27, 245-312. (b) Charette, A. B. in ref 2 Chapter 1.
(4) (a) MacMillan, D. W. C. Nature, 2008, 455, 304. (b) Gaunt, M.
J.; Johansson, C.C.C.; McNally, A.; Vo, N. T. Drug Discov. Today
2007, 12, 8. (c) Science of Synthesis, Asymmetric Organocatalysis.
Edited by List, B., Maruoka, K. Thieme Chemistry: Germany,
2012, 1928 pp. 2-volume set.
(5) (a) Mukherjee, S.; Yang, J. W.; Hoffmann. S.; List, B. Chem.
Rev. 2007, 107, 5471. (b) Erkkilä, A.; Majander, I.; Pihko, P. M.
Chem. Rev. 2007, 107, 5416. (c) Vicario, J. L.; Reyes, E.; Badia, D.;
Carrillo, L. Catalytic Asymmetric Conjugate Reactions. Ed. A.
Cordova, Wiley-VCH: Weinheim, Germany, 2010, chapter. 6. (d)
Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.;
Jørgensen, K.A. Chem. Commun. 2011, 47, 632. (e) For a review
see: Jurberg, I. D.; Chatterjee, I.; Tannert, R.; Melchiorre, P. Chem.
Commun., 2013, 49, 4869.
(6) (a) Knoevenagel, E. Chem. Ber., 1894, 27, 2345. (b) Ingold, C.
K. In Structure and Mechanism in Organic Chemistry; Cornell
University Press: Ithaca N. Y. 1953, 685 pp.
(7) See for example: (a) Crowell, T. I. Peck, D.W. J. Am. Chem.
Soc., 1953, 75, 1075. (b) Schroeder, C. Preis, S., Link, K. P.
Tetrahedron Lett. 1960, 13, 23. (c) Spencer, T. A. In Bioorganic
Chemistry. Chapter 13 Studies of Amine Catalysis via Iminium Ion
Formation. Academic Press: New York, 1977, 313-337.
(8) McMurry, J. E.; Begley, T. In The Organic Chemistry of Biolog-
ical Pathways, 7ª ed.; Roberts and Company Publishers: Colora-
do, USA, 2005, 490 pp.
(9) Cordes, E. H.; Jencks, W. P. J. Am. Chem. Soc, 1962, 84, 826.
(10) (a) Dirksen, A.; Hackeng, T. M.; Dawson, P. E. Angew. Chem.
Int. Ed. 2006, 45, 7581. (b) Dirksen, A.; Dirksen, S.; Hackeng, T.
M.; Dawson, P. E. J. Am. Chem. Soc. 2006, 128, 15602.
(11) Aniline has also been used in transimination reactions: (a)
Kovaříček, P.; Lehn J-M. J. Am. Chem. Soc. 2012, 134, 9446. (b)
The use of proline in DMF as moderate accelerator of these
interchanges has been recently reported by Lehn and used in
dynamic covalent chemistry: Wilhelms, N.; Kulchat, S.; Lehn, J-
M. Helv. Chim. Acta 2012, 95, 2635.
(33) Regiani, T.; Santos, V.G.; Godoi, M. N.; Vaz, B. G.; .Eberlin,
M.N.; Coelho, F. Chem. Commun. 2011, 47, 6593.
(34) Fuyuhiko, T. Ohyun, K.; Masaru, W.; Hannah, F. WO
2007111948, 2007.
(35) Love, B. E.; Raje, P. S.; Williams II, T. C. Synlett 1994, 493.
(36) Stokes, S.; Bekkam, M.; Rupp, M.; Mead K. T. Synlett 2012,
389.
8
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
(37) Yamada, K.; Umeki, H.; Maekawa, M.; Yamamoto, Y.;
Akindele, T.; Nakano, M.; Tomioka. K. Tetrahedron 2008, 64,
7258.
26. See: Lanter, J C.; Chen, H.; Zhang, X.; Sui, Z. Org. Lett. 2005,
7, 5905. The yield is not reported.
(53) For a method to form N-alkyl and N-aryl imines in water
see: Simion, A.; Simion, C.; Kanda, T.; Nagashima, S.; Mitoma, Y.;
Yamada, T.; Mimura, K.; Tashiro, M. J. Chem. Soc., Perkin Trans.
1, 2001, 2071.
(54) (a) Patel, M.S.; Worsley, M. Can. J. Chem. 1970, 48,1881. (b)
Samec, J.S.M.; Bäckvall, J-E. Chem. Eur. J. 2002, 8, 2955. (c)
Huang,L.; Zhang, Y.; Staples, R J.; Huang, R.H.; Wulff, W.D.
Chem. Eur. J. 2012, 18, 5302.
(55) Experimental procedure: SiO2 (5 equiv), EtOH, US, rt, 10
min. See: Guzen, K.P.; Guarezemini, A.S.; Órfão, A.T.G.; Cella, R.;
Pereira, C.M.P.; Stefani, H.A. Tetrahedron Lett. 2007, 48, 1845.
(56) Experimental procedure: MgSO4, DCM, 1h ,rt. See: (a) Ro-
dríguez-Solla, H.; Concellón, C.; Alvaredo, N.; Soengas, R.G.
Tetrahedron 2012, 68, 1736. (b) Künzi, S.A.; Morandi, B.; Carreira,
E.M. Org. Lett. 2012, 14, 1900.
(57) A modified Wadsworth-Emmons procedure was used:
Ciufolini, M.A.; Spencer, G.O. J. Org. Chem. 1989, 54, 4739.
(58) Vara, Y.; Bello, T.; Aldaba, E.; Arrieta, A.; Pizarro, J.L.; Ar-
riortua, M.I.; López, X.; Cossio, F.P. Org. Lett. 2008, 10, 4759.
(59) Experimental procedure: Mg(ClO4)2 (5%), DCE, 8h.
Chakraborti, A. K.; Bhagat, S.; Rudrawar, S. Tetrahedron Lett.
2004, 45, 7641.
(38) 4Å MS has been used to accelerate the formation of N-p-
tolylsulfonyl imines and their use in tandem processes, see: Guo,
Q.; Zhao J. C-G Org. Lett. 2013, 15, 508. Nevertheless, we have
proven, in the case of the imine 5cc derived from p-
anisaldehyde, that the combination of pyrrolidine and 4Å MS is
more efficient than the use of only the molecular sieves or pyr-
rolidine where reactions do not go to completion (see SI).
(39) Primary amines and acidic additives have been used to sort
out this problem and have been successfully employed for the
Michael addition of unsaturated ketons via iminium activation,
see for example: Bartoli, G.; Melchiorre, P. Synlett 2008, 12, 1759.
It could be expected that this strategy could be used in the future
to apply the methodology presented herein to the preparation of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ketimines
.
(40) For a review: Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205.
(41) Experimental procedure requires three steps: i) preparation
of TolSO2H from TolSO2Na; ii) Formation of amidosulfone with
RCHO (1.5 equiv), TolSO2H (1,5 equiv) and Ph2P(O)NH2 (1
equiv); iii) generation of the imine with K2CO3 (5 equiv) See: (a)
Desrosiers, J-N.; Cote, A.; Boezio, A.A.; Charette, A. B Proc. Natl.
Acad. Sci., USA 2004, 101, 5405. (b) Desrosiers, J-N.; Cote, A.;
Boezio, A.A.; Charette, A. B. Org. Synth. 2006, 83, 5.
(42) Experimental procedure requires two steps: i) formation of
aldoxime ii) alkylation with chlorodiphenylphosphine at low
temperature under inert anhydrous conditions. See: (a) Boyd, D.
R.; Malone, J. F.; McGuckin, M. R.; Jennings, W. B.; Rutherford,
M.; Saket, B. M. J. Chem. Soc., Perkin Trans. 2, 1988, 1145; (b)
Krzyzanowska, B. Stec, W. Synthesis, 1978, 521; 1982, 270.
(43) Experimental procedure: Et3N (3,5 equiv), TiCl4 (0.5 equiv),
CH2Cl2, rt. 1.5h. See: (a) Banerjee, S.; Groeper, J.A.; Standard,
J.M.; Hitchcock, S.R. Tetrahedron: Asymmetry 2009, 20, 2154.(b)
Jennings, W.B.; Lovely, C.J. Tetrahedron Lett. 1988, 29, 3725.
(44) Experimental procedure: Ti(OEt)4 (5 equiv), refluxing DCM,
4h. Bolshan, Y.;.Batey, R.A. Org.Lett. 2005, 7, 1481.
(60) M. Ciaccia, R. Cacciapaglia, P. Mencarelli, L. Mandolini and
S. Di Stefano. Chem. Sci. 2013, 4, 2253.
(45) Experimental procedure: Ti(OEt)4 (2 equiv), neat, MW,
70ºC, 40W, 10 min. Collados, J. F.; Toledano, E., Guijarro, D.; Yus,
M. J. Org. Chem. 2012, 77, 5744.
o
(46) Experimental procedure: KHSO4, toluene, 45 C, 24h. See:
Huang, Z.; Zhang, M.; Wang, Y.; Qin, Y. Synlett 2005, 1334.
(47) Experimental procedure: PPTS (5 mol%), aldehyde (2
equiv), MgSO4 (5 equiv), DCM, rt, 5h. See: Asada, M.; Obitsu, T.;
Kinoshita, A.; Nagase, T.; Yoshida, T.; Yamaura, Y.; Takizawa, H.;
Yoshikawa, K.; Sato, K.; Narita, M.; Nakai, H.; Toda, M.; Tobe, Y.
Bioorg. Med. Chem. 2010, 18, 3212.
(48) This strategy is commonly used for activating unsaturated
ketones in enantioselective aminocatalysis. See ref. 39
(49) Antranilic acid has also been recently used in a large excess
to form hydrazones and oximes in aqueous media. See: (a)
Crisalli, P.; Kool, E. T. J. Org. Chem. 2013, 78, 1184. (b) Crisalli, P.;
Kool, E. T. Org. Lett. 2013, 15, 1646.
(50) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
(51) Experimental procedure: cyanuric chloride (0.15 equiv), neat,
110 °C, 2.5h. See: Wua, L.; Yang ,X.; Wang, X.; Yan, F. J. Sulf.
Chem. 2010, 31, 509.
(52) This compound was prepared by MCPBA oxidation of the
corresponding N-sulfinyl imine following the procedure of ref
9
ACS Paragon Plus Environment