Bi(OTf)3-Catalyzed Multicomponent α-Amidoalkylation Reactions

Article abstract of DOI:10.1021/acs.joc.5b00662

A bismuth(III) triflate catalyzed three-component synthesis of α-substituted amides starting from amides, aldehydes, and (hetero)arenes is reported. The reaction has a broad substrate scope, encompassing formaldehyde as well as aryl and alkyl aldehydes. Low catalyst loadings are required, and water is formed as the only side product. The scope and limitation of this method will be discussed.

Full text of DOI:10.1021/acs.joc.5b00662

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Article
Bi(OTf)3–Catalyzed Multicomponent alpha–Amidoalkylation Reactions
Angelika E. Schneider, and Georg Manolikakes
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00662 • Publication Date (Web): 21 May 2015
Downloaded from http://pubs.acs.org on May 30, 2015
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Bi(OTf)
3
–Catalyzed Multicomponent α–Amidoalkylation Reactions
Angelika E. Schneider, Georg Manolikakes*
Department of Organic Chemistry and Chemical Biology,
Goethe University Frankfurt, Frankfurt am Main, Germany
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A bismuth(III) triflate catalyzed three–component synthesis of α–substituted amides starting
from amides, aldehydes and (hetero)arenes is reported. The reaction has a broad substrate
scope, encompassing formaldehyde as well as aryl and alkyl aldehydes. Low catalyst loadings
are required and water is formed as only side product. Scope and limitation of this method
will be discussed.
INTRODUCTION
Amino– and amidoalkyl moieties are important structural motifs in organic synthesis and
1ꢀ3
pharmaceutical chemistry. α–Substituted amides, in particular amidoalkylated arenes and
heteroarenes, are found in many important natural products and biological active molecules
2
3
such as luotonin–A , an alkaloid or the antiretroviral Raltegravir (Figure 1).
Figure 1. Amidoalkylated Moieties in Biologically Active Molecules
An important approach for the synthesis of this structural motif is the addition of nucleophilic
(hetero)arenes to electrophilic carbon–nitrogen double bonds. Especially, three–component
aza–Friedel–Crafts type amidoalkylations with in situ generated acylimines or acyliminium
4
,5
ions provide a useful synthetic tool for the synthesis of α–substituted amides. The in situ
preparation of these reactive imine compounds from an aldehyde and an amide represents an
6
atom–economical methodology for the synthesis of amidoalkylated (hetero)arenes.
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Generating water as only side product, these reactions could meet the requirements of modern
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sustainable organic synthesis. However, most common procedures require stoichiometric
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amounts of Lewis or Brønsted acids or are limited to the reaction of electron–rich aromatics
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ꢀ12
and heteroaromatics, such as indole and naphthol.
Our interest in developing novel multicomponent reactions for the rapid synthesis of
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pharmaceutical active molecules
component reactions. In the course of our investigations, we were able to develop a Bi(OTf)
catalyzed three–component reaction between amides, formaldehyde and arenes. This reaction
has led us to closer examination of these three–
3
–
13
provides straightforward access to amidomethylated arenes and heteroarenes. Recently the
group of Jaratjaroonphong reported a similar Bi(OTf) ꢀcatalyzed threeꢀcomponent reaction
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between carbamates, aldehydes and arenes. However, this reaction is limited to very
electronꢀrich trimethoxybenzene derivatives or reactive heteroarenes such as furan, thiophen
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7
or indol. Herein, we wish to report the extension of our method to aryl and alkyl aldehydes
as well as scope and limitations of the corresponding reactions and mechanistic
investigations.
RESULTS & DISCUSSION
1
. Three–Component Reaction with Formaldehyde
We started our investigations with the identification of a suitable catalyst using the reaction
between benzamide (1), paraformaldehyde (2) and m–xylene (3), a moderately reactive arene,
as test system (Table 1). From a multitude of tested metal triflates and Bi(III)–salts
(entries 1–3) only Bi(OTf)
3
efficiently catalyzed the transformation even at low catalyst
loadings (entries 4–8, 61–85% yield). Since Bi(OTf) is commercially available, non–toxic,
3
18ꢀ20
air and moisture stable, it is a very attractive catalyst.
Performing the reaction in
nitromethane led to an increased yield. Best results could be achieved with 2.5 mol%
Bi(OTf) (entry 5, 85% yield). Replacement of paraformaldehyde by aq. formalin solution as
3
formaldehyde source furnished the product in comparable yield (entry 7 and 8). TfOH, a
possible byproduct of the hydrolysis of Bi(OTf)
3
, displayed reduced catalytic activity
(
entry 9). To exclude a possible hidden Brønsted acid catalysis, the reaction was performed in
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presence of the selective proton scavenger 2,6–di–tert–butyl–pyridine (dbpy) (entry 10).
Since no significant decrease in catalytic activity was observed, the Bi(III)–species is
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assumed to be the active catalyst. In all cases the amidoalkylated product was obtained as a
mixture of regioisomers (15:1 ortho/paraꢀ vs. ortho/orthoꢀsubstitution)
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a,b
Table 1. Formaldehyde — Survey of Catalysts
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entry
catalyst [mol%]
M(OTf) (5.0)
M = Cu, Zn, In, Sc, Mg, Yb, etc.
yield [%]
x
< 5
1
2
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9
BiBr
3
(5.0)
(5.0)
< 5
< 5
71
85
61
84
79
10
75
BiCl
3
c,d
c,d
c
Bi(OTf) (1.0)
3
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
3
3
3
3
(2.5)
(5.0)
(5.0)
(5.0)
c,d
c,d,e
TfOH (5.0)
Bi(OTf) (5.0) + dbpy (10.0)
c,d
10
3
a
General reaction conditions: Benzamide (1.0 equiv.), paraformaldehyde (1.2 equiv.), m–xylene (3.0 equiv.),
catalyst (x mol%). Isolated yield of analytical pure product. Obtained as a 15:1 mixture of regioisomers.
Reaction in MeNO . Reaction with aqueous formalin.
2
b
c
d
e
With the optimized conditions established, the scope of reaction was examined (Scheme 1).
Conversion of substituted benzamides led to the products 6a and 6b in 65–70% yield. With
carbamates as amide component, the corresponding N–protected amidomethylarenes 6c and
6
d were obtained in 45% and 71% yield respectively. Deprotection of such products would
offer a straightforward access to α–aminomethylarenes, which are found in various bioactive
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substances. Reactions with various alkylamides furnished the corresponding amidoalkylated
products in good to excellent yields. Acid sensitive functionalities, such as an acrylamide,
were well tolerated (product 6e). With exception of oxazolidin–2–one (product 6j) secondary
amides did not react under the standard conditions. Similar regioselectivities are observed for
all different amide components.
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Scheme 1. Formaldehyde — Variation of Amides
O
O
O
H H
5
mol% Bi(OTf)3
MeNO2
00 °C, 16 h
R
NHR'
H
H
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N
R'
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1.0 equiv.
1.2 equiv.
3.0 equiv.
O
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H H
H H
H H
N
RO
N
N
H
H
H
X
6c: R = Et 71%b,c
6d: R = Bn 45% (14:1)b,c
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a: X = OMe 65%
6e
70% (24:1)b
55% (13:1)b
6b: X = Br
O
O
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O
H H
H H
H H
H H
Cl
NC
tBu
N
N
N
N
H
H
H
H
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f
6g
6h
51% (15:1)b
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77% (17:1)b
73% (18:1)b
96% (11:1)b
O
H H
N
O
6j
1% (> 25:1)b
7
a
b
Isolated yield of analytical pure product. Obtained as mixture of regioisomers, ratio of regioisomers given in
c
parentheses. Reaction at 60 °C.
Also highly functionalized amides are suitable substrates for this three–component reaction,
Thus, the reaction of the protected valinamide 7 provided the amino acid derivate 8 in 63%
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yield (Scheme 2).
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a
Scheme 2. Reaction of Phthalyl–Protected Valinamide
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a
b
Isolated yield of analytical pure product. Obtained as mixture of regioisomers, ratio of regioisomers given in
parentheses.
Next, reactions with different aromatic components were examined. Various electron rich
arenes such as mesitylene, anisole and its halogenated derivatives furnished the desired α–
amidoalkylated products in good to excellent yields (10a–h, 42–88% yield). In general the α–
amidomethylated arenes were obtained with high regioselectivity. Only with anisole as arene,
a 1:3 mixture of ortho– and para–substituted regioisomers, typical for electrophilic aromatic
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substitutions, was obtained. Unprotected phenols or acid labile ester functionalities were
well tolerated under the reaction conditions (products 10m and 10j). The reaction with
sterically hindered pivaloyl amide proceeded in a chemoselective manner and the
amidoalkylated product 10k was obtained in 66% yield. Less electron–rich arenes, such as
toluene or benzene, did not react even under more forcing conditions. In the case of electron–
rich heteroarenes lower reaction temperatures were required to avoid direct addition of the
heteroarene to formaldehyde. Several electron rich heteroaromatics gave the corresponding
amidomethylated products in 33–94% yield (Scheme 3, products 10o–s). For some of these
reactions considerably higher yields could be obtained with aq. formalin as aldehyde source
(
10o, 10q, 10s). Regioselective amidoalkylation at the more reactive 2ꢀposition over the 3ꢀ
position was observed for benzofuran and thiophene.
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Scheme 3. Formaldehyde — Variation of (Hetero)Arenes
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Isolated yield of analytical pure product. Obtained as mixture of regioisomers, ratio of regioisomers given in
parentheses. Reaction at 80 °C. 4.0 equiv. of arene. Reaction at r.t. Reaction with aqueous formalin.
c
d
e
f
g
Reaction at 40 °C.
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1.1. Mechanistic Consideration
For the development of the three–component reaction, the in situ generation of a reactive
acylimine species as electrophilic amidoalkylating agent was assumed to be the first crucial
step. Therefore we investigated the two–component reaction between formaldehyde and
benzamide, which should lead to the corresponding acylimine or acyiminium ion. However,
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we were not able to detect or isolate any acylimine species. The only product we could
obtain from the two–component reaction was bisamide 11, derived from a two–fold addition
of benzamide to formaldehyde. This bisamide is formed very rapidly in almost quantitative
yield (Scheme 4).
Scheme 4. Formation of Bisamide
In the case of the three–component reactions we were able to observe the same rapid
formation of the bisamide and a slower subsequent conversion of the bisamide to the product
during the course of the reaction. It is worth mentioning, that we could observe the formation
of this bisamide during our initial catalyst screenings with almost every tested Lewis– or
2
7
Brønsted acid. Some Brønsted acids, e.g. TfOH, could catalyzed the bisamide formation
even more efficiently than Bi(OTf) . Treatment of the bisamide 11 with 2–bromoanisole as
3
3
nucleophilic arene component in the presence of 5 mol% Bi(OTf) furnished the expected
amidoalkylated product 10d in 67% yield (Scheme 5). The analogous N,O–aminal 12, the
formal mono–addition product of benzamide to formaldehyde, reacts in a similar manner.
3
Treatment of 12 with bromoanisole in the presence of 5 mol% Bi(OTf) leads to the formation
of the amidoalkylation product in 61% yield. No other tested Lewis– or Brønsted acid could
catalyze those two transformations with comparable efficiency.
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Scheme 5. Two–Component Reactions with Preformed Acylimine–Precursors
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Based on those experiments we assume the following mechanism as shown in Scheme 6. In
the first step the amide adds to the aldehyde to afford an aminal. Elimination of water leads to
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the formation of a reactive acylimine or acyliminium species. This electrophilic species
reacts immediately with a second molecule of the amide in azaꢀamidoalkylation to furnish the
observed and isolated bisamide. Considering the higher nucleophilicity of the amide nitrogen,
the fast addition of a second amide to the acylimine is not surprising. Under the reaction
conditions, the bisamide, favoured under kinetic control, can decompose to form the
acylimine. In the presence of a suitable nucleophilic arene, the electrophilic acylimine can
react in an aza–Friedel–Crafts reaction to afford the amidoalkylated product containing a
3
thermodynamically stable CꢀCꢀbond. The unique catalytic activity of Bi(OTf) can be
2
0b,
explained by two reasons. On the one hand Bi(OTf)
not lose its catalytic activity in the presence of higher amounts of water. On the other hand
Bi(OTf) is a strong Lewis acid and could further activate the formed acylimine towards the
addition of nucleophiles.
3
, although easily hydrolyzed,
does
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Scheme 6. Proposed Mechanism of the Three–Component α–Amidoalkylation Reaction
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During our studies we often observed the formation of bis(hetero)arylmethane derivatives,
especially for reactions with more reactive (hetero)arenes such as thiophene, furan or Nꢀ
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tosylindole.
Since we were never able to isolate the amidoalkylation products of very
reactive heteroarenes, such as indole, we cannot rule out that these products decompose under
our reaction conditions. Control experiments showed, that these side–products arise from the
direct addition of two (hetero)arenes to the aldehyde, presumably via in situ formed benzyl
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cations (Scheme 7).
Scheme 7. Side Reaction with Electron–Rich (Hetero)arenes
The amidoalkylated products proved to be stable under our reaction conditions. Prolonged
treatment of 4 with excess m–xylene in the presence of 5 mol% Bi(OTf)
formation of any diarylmethane (Scheme 8).
3
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Scheme 8. Stability of Amidoalkylated Products
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2. Three–Component Reaction with Alkylaldehydes
Encouraged by the results of the α–amidoalkylation reaction with formaldehyde, we turned
our attention to reactions with simple alkylaldehydes. Unfortunately, the reaction of
benzamide (1a), isobutyraldehyde (13) and mesitylene (9a) led to the selective formation of
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enamide 14 in 75% yield (Scheme 9).
Scheme 9. Multicomponent Reactions with Alkylaldehydes Fail at Elevated
Temperatures
Therefore the corresponding two–component reaction between benzamide and
isobutyraldehyde was investigated in more detail (Scheme 10). These investigations revealed
3
a rapid formation of the corresponding bisamide 15 in the presence of Bi(OTf) even at room
temperature. However, this bisamide is not stable at elevated temperatures. At temperatures
above 35 °C formation of the enamide occurs, presumably via elimination of one molecule of
3
3
benzamide. Enamide 14 is stable in the presence of Bi(OTf) at temperatures below 100 °C.
3
In the presence of stronger acids or at higher temperatures dimerization and polymerization of
the enamide is observed.
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Scheme 10. Two–Component–Reaction between Benzamide and Isobutyraldehyde
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From these results we can draw two conclusions. One the one hand, alkylaldehydes are not
suitable aldehyde components for our amidoalkylation reactions with moderately nucleophilic
arenes. On the other hand, the formation of bisamide 15 clearly shows that a reactive
acylimine species is formed even at room temperature. Therefore, trapping of the electrophilic
acylimine with more reactive, electron–rich (hetero)arenes at temperatures below 35 ºC
should be possible. With these considerations in mind we investigated the three–component
reaction between benzamide (1), isobutyraldehyde (13) and 2–methylfuran (16) as more
1
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3
nucleophilic arene component (Table 2). Indeed, Bi(OTf) can efficiently catalyze this
reaction at 2–5 mol% catalyst loading. The yield of the reaction can be improved by a slight
modification of the reaction protocol. Slow addition of the nucleophilic component over 2 h
leads to an increased yield and decreased direct addition of the arene to the aldehyde.
a,b
Table 2. Alkylaldehydes — Survey of Catalysts
entry
catalyst [mol%]
yield [%]
1
2
3
4
5
6
Bi(OTf)
3
3
(0.5)
(1.0)
–
Bi(OTf)
–
Bi(OTf) (2.0)
44
61
35
–
3
c
Bi(OTf)
3
3
(2.0)
(5.0)
Bi(OTf)
BiCl (5.0)
3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
3
3
3
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4
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4
4
5
5
5
5
5
5
5
5
5
5
6
7
a
BiNO
3
(5.0)
–
General reaction conditions: Benzamide (1.2 equiv.), isobutyraldehyde (1.0 equiv.), 2–methylfuran (3.0 equiv.),
b
c
Bi(OTf)
2
3
(x mol%). Isolated yield of analytical pure product. The arene was added dropwise over a period of
h to the reaction mixture.
With the optimized conditions in hand, we investigated reactions with different
alkylaldehydes. In general the desired amidoalkylated products were obtained in moderate to
high yields (Scheme 11). In the case of 2–benzyloxyacetaldehyde the corresponding 1,2–
aminoalcohol 19d could be isolated in 77% yield. Reactions of alkylaldehydes bearing a
stereocenter in α–position, furnished the amides 19b and 19f in good yields and moderate to
high diastereoselectivities.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Scheme 11. Alkylaldehydes — Variation of Aldehydes
a
c
b
Isolated yield of analytical pure product. The reaction mixture was cooled to 0° C, then the arene was added.
The arene was added dropwise over a period of 1 h to the reaction mixture. Obtained as mixture of
diastereomers, ratio of diastereomers given in parentheses. The arene was added dropwise over a period of 2 h
d
e
to the reaction mixture. Pht = N–phthalyl.
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1
2
3
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5
6
7
8
9
Different amides and carbamates are suitable amide components for this three–component
reaction. The reaction with alkyl amides or various carbamates leads to the formation of
amidoalkylated furans in 32–76% yield (Scheme 12). Tert–butyl carbamate is a suitable
substrate for this transformation (product 20e).
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
a
Scheme 12. Alkylaldehydes — Variation of Amides
a
b
Isolated yield of analytical pure product. The arene was added dropwise over a period of 2 h to the reaction
mixture. The bis(heteroaryl)phenylpropane species was formed as major product. The reaction mixture was
cooled to 0° C, then the arene was added. The arene was added dropwise over a period of 1 h to the reaction
c
d
e
mixture.
The acid–sensitive Boc–functionality is well tolerated under the very mild reaction conditions
(
Scheme 13). The reaction of Boc–protected valinamide 21 furnished the corresponding
product 22 in 62% yield and with a 2:1 diastereoselectivity .
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1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a,b,c
Scheme 13. Alkylaldehydes — Reaction of Boc–Protected Valinamide
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Isolated yield of analytical pure product. The arene was added dropwise over a period of 2 h to the reaction
c
mixture. Obtained as mixture of diastereomers, ratio of diastereomers given in parentheses.
As indicated above, three–component reactions with alkylaldehydes are limited to electron–
rich arenes and heteroarenes. Therefore the reaction of 2–methylthiophene and 1,3–
dimethoxybenzene furnished the products 23a and 23c in 61 and 58% yield (Scheme 14).
Further examination of this three–component reaction revealed a second limitation. Very
reactive heteroarenes, such as indole or pyrrole, are not suitable substrates for this
transformation. In the case of such highly reactive aromatic components only direct addition
to the aldehyde is observed.
a
Scheme 14. Alkylaldehydes — Variation of (Hetero)Arenes
a
b
c
d
Isolated yield of analytical pure product.
Reaction at 35 °C.
5 mol% Bi(OTf)3.
The
e
bis(heteroaryl)phenylpropane species was formed. The reaction mixture was cooled to 0° C, then the arene was
added.
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5
1
2
3
4
5
6
7
8
9
3
. Three–Component Reaction with Arylaldehydes
We next turned our attention to reactions with arylaldehydes as aldehyde component. In this
case enamide formation is not possible. During preliminary experiments rapid formation of
the bisamide intermediate was observed at temperatures higher than 50 °C. The reaction
between benzamide (1), benzaldehyde (24) and mesitylene (9a) was chosen as model system
to investigate the influence of various reaction parameters (Table 3). Surprisingly, high
temperatures of 130 °C were required for efficient product formation. Best yields were
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
obtained using 10 mol% Bi(OTf) (entry 4, 71%). We attribute these forcing reaction
3
conditions with the decreased electrophilicity of N–acylimines derived from arylaldehydes.
Comparable results in yields were provided either by lengthening of the reaction time to 48 h
or performing the reaction at 150 °C (entry 2–3, 63 and 60% yield). Addition of Brønsted
acids, such as TfOH, did not affect the yield (entry 5).
a,b
Table 3. Arylaldehydes — Optimization of Catalysts
entry
catalyst [mol%]
yield [%]
1
2
3
4
Bi(OTf)
3
3
(5.0)
(5.0)
23
63
60
71
25
c
Bi(OTf)
d
Bi(OTf) (5.0)
3
Bi(OTf)
3
3
(10.0)
5
a
Bi(OTf)
(5.0) + TfOH (5.0)
General reaction conditions: Benzamide (1.0 equiv.), benzaldehyde (1.2 equiv.), mesitylene (3.0 equiv.),
Bi(OTf) (x mol%), 130 °C, 24 h. Isolated yield of analytical pure product. Reaction time: 48 h. Reaction at
b
c
d
3
150 °C.
The use of TfOH as Brønsted–acid additive in the three–component reaction with less
reactive m–xylene led to considerable higher yield (Table 4, entry 1 and 3). Best yields of 26
were obtained by an additional increase of temperature to 150 °C (entry 4).
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1
1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a,b
Table 4. Arylaldehydes — Use of TfOH Elevates Yield in the Case of m–Xylene
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
catalyst [mol%]
yield [%]
c
1
2
3
Bi(OTf)
3
(5.0)
43
35
58
76
Bi(OTf) (10.0)
3
d,e
e,f
Bi(OTf)
3
3
(5.0) + TfOH (5.0)
(5.0) + TfOH (5.0)
4
Bi(OTf)
a
General reaction conditions: Benzamide (1.0 equiv.), benzaldehyde (1.2 equiv.), mesitylene (3.0 equiv.),
Bi(OTf) (x mol%), 130 °C, 24 h. Isolated yield of analytical pure product. Reaction time: 48 h. Reaction at
3
e f
b
c
d
100 °C. Benzamide (1.2 equiv.), benzaldehyde (1.0 equiv.). Reaction at 150 °C.
With the optimized reaction conditions at hand, we examined reactions with various
arylaldehydes (Scheme 15). Arylaldehydes bearing halogenes in meta and para position
afforded the products in good yields (28a–d, 54–72% yield). Reaction with 2–chloro–5–
nitrobenzaldehyde provided the product 28e in 66% yield. The α–amidoalkylated product 28f
of naphthylaldehyde was isolated in 29% yield.
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1
2
3
4
5
6
7
8
9
a
Scheme 15. Arylaldehydes — Variation of Aldehydes
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
a
Isolated yield of analytical pure product. Mes = mesityl (2,4,6–trimethylphenyl).
As shown in Scheme 16 variation of the amide component afforded the desired products 29a–
d; 29f–g in 33–89% yield. In the case of arylaldehydes, carbamates are not suitable amide
components. Only in the case of urethane, the desired product 29g was formed, albeit in only
3
3% yield. Most likely carbamates are not stable under these conditions.
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Scheme 16. Arylaldehydes — Variation of Amides
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Isolated yield of analytical pure product. Reaction at 100 °C. Mes = mesityl (2,4,6–trimethyl–phenyl).
Next we investigated reactions with various arenes (Scheme 17). Anisole and its halogenated
derivatives gave the desired amidoalkylated products 30a–d in 25–40% yield. Only in the
case of 3,5–di–methylanisole the α–substituted amide was isolated in a satisfactory yield of
74%. In general, reactions with various electron–rich heterocycles were not successful. The
intermediate species is efficiently generated at 50 °C, but the high reactivity of the
heteroarenes promotes synthesis of the direct addition products at these temperatures. Best
results were achieved with 2–bromothiophene (30f, 36% yield). The high reactivity of the
heteroarenes leads to a rapid direct addition to the aldehyde temperatures below 50 ºC,
necessary for the acylimine formation.
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2
3
4
5
6
7
8
9
a
Scheme 17. Arylaldehydes — Variation of (Hetero)Arenes
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
a
b
Isolated yield of analytical pure product. Obtained as mixture of regioisomers, ratio of regioisomers given in
c
d
e
f
parentheses. Reaction at 100 °C. Reaction with 5 mol% Bi(OTf)3. Reaction with 5 mol% TfOH. Reaction
at 80 °C. Reaction at 50 °C.
g
CONCLUSIONS
3
In summary, a general Bi(OTf) –catalyzed multicomponent between amides, aldehydes and
arenes was developed. Formaldehyde, alkylaldehydes and arylaldehydes were successfully
employed as aldehyde compounds. Scope and limitations for all three types of aldehyde
components were investigated.
These practical and operational simple multicomponent reactions provide straightforward and
versatile access to α–amidoalkylated (hetero)arenes. The use of the nontoxic catalyst and
generation of water as only side product constitute a valuable approach towards the concept of
sustainable chemistry.
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0
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4
5
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
EXPERIMENTAL SECTION
General Considerations
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Solvents for reactions and column chromatography were obtained from different commercial
suppliers in > 97 % purity and used as received. Reagents: (S)–N–(2,4–Dimethylbenzyl)–3–
34
35
methyl–2–(1,3–dioxoisoindolin–2–yl)butanamide , N–benzyl–2–oxoacetamide , ethyl–4–
36
37
38
38
methoxybenzoate , 3,5–dimethylanisole , 2–methylpivalanilide , 3– ethylpivalanilide , N–
39
40
tosylindole and N–tosylpyrrole , were synthesized according to literature. All other starting
materials were purchased from commercial sources and used without further purification.
Anhydrous Bi(OTf)
precautions were taken to avoid exposure of Bi(OTf)
out the formation of Bi(OTf) ·xH O during storage. Indeed depending on the provider and
3
was obtained from different providers and used directly. No special
3
to moisture. Therefore we cannot rule
3
2
storage time (or even the time for weighting out a defined amount for elemental analysis)
Bi(OTf) contained up to six molecules of water. However no changes in catalytic activity
and yield even upon prolonged storage (>1 year) were observed. Therefore the amount of
Bi(OTf) used is always calculated on anhydrous Bi(OTf) . The actual catalyst loading for
3
3
3
particular reactions might be slightly lower, depending on the batch quality and storage time.
Column chromatography was performed with Silica 0.04–0.063 mm/ 230–400 mesh. Thin
2
layer chromatography was done using aluminum plates coated with SiO . The spots were
1
13
visualized by ultraviolet light, iodine or CAM. NMR spectroscopy: H– and C–NMR spectra
were recorded at 300 or 400 MHz and 75 or 101 MHz, respectively. Mass spectrometry
spectra (MS) were measured using ESI (electrospray ionization) coupled to a quadrupole
mass mass analyzer. High resolution mass spectra (MALDIꢀHRMS) were measured using
MALDI (matrixꢀassisted laser desorption/ionization) coupled to an ion trap mass
spectrometer. Melting points are uncorrected. All yields refer to isolated yields of compounds
1
estimated to be > 95% pure as determined by H–NMR or elementary analysis.
Typical Procedures
All reactions were performed in vials sealed with a screw cap to avoid evaporation of the
solvent. For reactions performed at room temperature the screw cap can be replaced with a
rubber septum. For reaction performed at temperatures below the boiling point of the solvent
culture tubes with a PTFE lined screw cap were used. For reaction performed at or above the
boiling point of the solvent special thickꢀwalled pressure tubes have to be used.
TP 1 — Reactions with Formaldehyde
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9
3
A 10 mL screw cap vial was charged with Bi(OTf) (5 mol%), amide (1.0 equiv),
formaldehyde (1.2 equiv), (hetero)arene (3–4 equiv.) and nitromethane and closed with a
Teflon lined screw cap. The reaction mixture was stirred at 25–100 °C for the specified time.
After cooling to room temperature the reaction mixture was diluted with EtOAc and filtered
over a short plug of celite and silica gel. The plug was rinsed with additional EtOAc. The
combined filtrates were concentrated under reduced pressure. Purification of the crude residue
by column chromatography (hexane/EtOAc) afforded the analytically pure product.
TP 2 — Reactions with Arylaldehydes
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
A 10 mL screw cap vial was charged with Bi(OTf) (10 mol%), amide (1.0 equiv),
3
arylaldehyde (1.2 equiv), (hetero)arene (3–4 equiv.) and nitromethane and closed with a
Teflon lined screw cap. The reaction mixture was stirred at 50–130 °C for the specified time.
After cooling to room temperature the reaction mixture was diluted with EtOAc and filtered
over a short plug of celite and silica gel. The plug was rinsed with additional EtOAc. The
combined filtrates were concentrated under reduced pressure. Purification of the crude residue
by column chromatography (hexane/EtOAc) afforded the analytically pure product.
N–(2,4–Dimethylbenzyl)benzamide (4) was synthesized according to TP 1 from benzamide
(
242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), m–xylene (0.74 mL, 6.0 mmol,
3
.0 equiv.) and Bi(OTf) (66 mg, 0.1 mmol, 5 mol%) in nitromethane (4 mL) at 100 °C for
3
16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as colorless
1
solid (403 mg, 84%, ratio of regioisomers 15:1). m.p.: 94 –95 °C. H–NMR (CDCl
3
,
4
00 MHz) (peaks are listed only for major regioisomer): δ = 7.77 (d, J = 8 Hz, 2H), 7.51 –
7.47 (m, 1H), 7.44 – 7.40 (m, 2H), 7.19 (d, J = 8 Hz, 1H), 7.04 – 7.00 (m, 2H), 6.17 (bs, 1H),
1
3
4
.61 (d, J = 5 Hz, 2H), 2.34 (s, 3H), 2.32 (s, 3H). C–NMR (CDCl , 75 MHz) (peaks are
3
listed only for major regioisomer): δ = 167.3, 137.8, 136.7, 134.6, 132.9, 131.6, 129.1, 128.7,
+
128.7, 127.0, 127.0, 42.3, 21.1, 19.1. MS (ESI) m/z: [M+H] Calcd. for C16
H
18NO 240.14,
–
found 240.40. EA (%): Calcd.: C 80.30 H 7.16 N 5.85 found: C 80.13 H 7.06 N 5.78. IR (cm
1
)
: 3284 (m), 1626 (s), 1578 (m), 1524 (m), 1487 (w), 1474 (w), 1363 (w), 1308 (m), 1281
(m), 1219 (w), 1182 (w), 1144 (w), 1057 (w), 1055 (w), 1026 (w), 968 (w), 920 (w), 877 (w),
31 (w), 823 (m), 800 (m), 769 (m), 704 (w), 690 (s), 660 (w). R (hexane/ EtOAc 4:1) = 0.3.
8
f
N–(2,4–Dimethylbenzyl)–4–methoxybenzamide (6a) was synthesized according to TP 1 from
4–methoxybenzamide (76 mg, 0.5 mmol), paraformaldehyde (19 mg, 0.6 mmol), m–xylene
(
0.24 mL, 2.0 mmol, 4 equiv.) and Bi(OTf) (16 mg, 0.025 mmol) in nitromethane (2 mL) at
3
8
0 °C for 24 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
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1
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4
5
6
7
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
colorless solid (87 mg, 65%). m.p.: 134–135 °C. H–NMR (CDCl
3
, 400 MHz): δ = 7.73 (d,
J = 8.3 Hz, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.03 – 6.99 (m, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.07
1
3
(
bs, 1H), 4.58 (d, J = 5.1 Hz, 2H), 3.84 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H). C–NMR (CDCl ,
3
101 MHz): δ = 166.8, 162.3, 137.8, 136.7, 133.1, 131.6, 129.1, 128.9, 127.0, 126.8, 113.9,
5
5.5, 42.3, 21.1, 19.1. MS (ESI) m/z: Calcd. for C17
H19NO
2
Na 292.13; found 292.21
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
–1
[
M+Na] . EA (%): Calcd.: C 75.81 H 7.11 N 5.20; found: C 75.61 H 6.91 N 5.10. IR (cm ):
3284 (m), 1618 (s), 1574 (w), 1531 (m), 1497 (m), 1462 (m), 1408 (w), 1367 (w), 1304 (m),
281 (m), 1250 (s), 1176 (m), 1111 (w), 1032 (m), 968 (w), 533 (w), 883 (w), 843 (m), 823
s), 771 (m), 683 (w). R (hexane/ EtOAc 4:1) = 0.1.
1
(
f
N–(2,4–Dimethylbenzyl)–4–bromobenzamide (6b) was synthesized according to TP 1 from 4–
bromobenzamide (400 g, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), m–xylene
(
0.74 mL, 6.0 mmol, 3.0 equiv.) and Bi(OTf) (66 mg, 0.1 mmol) in nitromethane (4 mL) at
3
100 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colorless solid (448 mg, 70%, ratio of regioisomers 24:1). m.p.: 174–175 °C. H–NMR
(CDCl
3
, 400 MHz) (peaks are listed only for major regioisomer): δ = 7.63 (d, J = 7.6 Hz, 2H),
7.55 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.04 – 7.00 (m, 2H), 6.12 (bs, 1H), 4.59 (d,
13
J = 5.1 Hz, 2H), 2.33 (s, 3H), 2.32 (s, 3H). C–NMR (CDCl
3
, 101 MHz): δ = 166.3, 138.0,
1
36.7, 133.4, 132.6, 132.0, 131.7, 129.2, 128.7, 127.1, 126.3, 42.4, 21.2, 19.1. MS (ESI) m/z:
+
[M+H] Calcd. for C16H17BrNO 318.04, found 318.00. EA (%): Calcd.: C 60.39 H 5.07 N
–
1
4
.40 found: C 60.23 H 5.02 N 4.21. IR (cm ): 3286 (w), 2906 (w), 1626 (s), 1589 (w),
529 (m), 1481 (m), 1358 (w), 1304 (w), 1277 (w), 1180 (w), 1146 (w), 1072 (w), 1009 (m),
(hexane/ EtOAc 4:1) = 0.4.
1
972 (w), 881 (w), 843 (m), 823 (m), 771 (w), 756 (w), 677 (w). R
f
Ethyl–2,4–dimethylbenzylcarbamate (6c) was synthesized according to TP 1 from urethane
45 mg, 0.5 mmol), paraformaldehyde (19 mg, 0.6 mmol), m–xylene (0.18 mL, 1.5 mmol,
3.0 equiv.) and Bi(OTf) (16 mg, 0.025 mmol, 5 mol%) in nitromethane (2 mL) at 60 °C for
4 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as colourless
(
3
2
1
3
solid (73 mg, 71%). m.p.: 54–55 °C. H–NMR (CDCl , 400 MHz): δ = 7.13 (d, J = 7.4 Hz,
1H), 6.99 – 6.97 (m, 2H), 4.76 (bs, 1H), 4.32 (d, J = 5.2 Hz, 2H), 4.14 (q, J = 6.9, 6.9 Hz,
13
2
H), 2.31 (s, 6H), 1.25 (t, J = 7.0 Hz, 3H). C–NMR (CDCl , 101 MHz): δ = 156.6, 137.5,
3
+
1
36.2, 133.3, 131.5, 128.5, 126.9, 61.0, 43.0, 21.1, 19.0, 14.8. MS (ESI) m/z: [M+Na] Calcd.
+
for C12
H17NO
2
Na 230.12, found 230.23. HRMS (MALDI) m/z: [M+H] Calcd. for
–1
C H NO 208.1332, found 208.1333. IR (cm ): 3321 (m), 2979 (m), 2921 (w), 1686 (s),
12
18
2
1
617 (w), 1525 (m), 1479 (m), 1470 (m), 1375 (m), 1356 (m), 1301 (m), 1243 (s), 1160 (m),
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1128 (m), 1047 (s), 965 (m), 925 (m), 880 (m), 822 (s), 780 (m), 638 (m), 580 (s), 550 (m),
05 (m). R (hexane/ EtOAc 4:1) = 0.4.
5
f
Benzyl–2,4–dimethylbenzylcarbamate (6d) was synthesized according to TP 1 from
benzylcarbamate (76 mg, 0.5 mmol), paraformaldehyde (19 mg, 0.6 mmol), m–xylene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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28
29
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39
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58
59
60
(
3
0.18 mL, 1.5 mmol, 3.0 equiv.) and Bi(OTf) (16 mg, 0.025 mmol, 5 mol%) in nitromethane
(2 mL) at 60 °C for 24 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the
1
product as colorless solid (61 mg, 45%, ratio of regioisomers 14:1). m.p.: 74–76 °C. H–NMR
(CDCl
3
, 400 MHz) (peaks are listed only for major regioisomer): δ = 7.36 – 7.30 (m, 5H),
7
.12 (d, J = 7.5 Hz, 1H), 6.99 – 6.97 (m, 2H), 5.13 (s, 2H), 4.85 (bs, 1H), 4.35 (d, J = 5.5 Hz,
1
3
2H), 2.30 (s, 3H), 2.29 (s, 3H). C–NMR (CDCl
3
, 101 MHz) (compound exists as a mixture
of rota– and regioisomers, peaks are not assigned): δ = 156.3, 137.5, 136.7, 136.2, 133.1,
1
31.5, 128.7, 128.5, 128.3, 128.0, 126.9, 126.8, 66.9, 43.2, 21.1, 19.0. MS (ESI) m/z:
+
[M+Na] Calcd. for C17
H
19NO
2
Na 292.13, found 292.21. EA (%): Calcd.: C 75.81 H 7.11 N
–1
5
.20; found: C 75.67 H 7.09 N 4.97. IR (cm ): 3318 (w), 2946 (w), 2921 (w), 1683 (s), 1519
s), 1505 (s), 1463 (m), 1453 (m), 1379 (w), 1356 (m), 1303 (w), 1241 (s), 1159 (w), 1118
(m), 1080 (w), 1047 (s), 1028 (m), 1003 (w), 965 (m), 925 (w), 912 (m), 881 (w), 852 (m),
23 (m), 780 (m), 756 (s), 719 (m), 706 (m), 693 (m), 627 (m), 588 (s), 568 (m), 538 (m), 504
m), 468 (m). R (hexane/ EtOAc 4:1) = 0.5.
(
8
(
f
N–(2,4–Dimethylbenzyl)–2–acrylamide (6e) was synthesized according to TP 1 from
acrylamide (142 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), m–xylene (0.74 mL,
6
3
.0 mmol, 3.0 equiv.) und Bi(OTf) (66 mg, 0.1 mmol) in nitromethane (4 mL) at 100 °C for
16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as colorless
1
solid (207 mg, 55%, ratio of regioisomers 13:1). m.p.: 122–123 °C. H–NMR (CDCl , 400
3
MHz) (peaks are listed only for major regioisomer): δ = 7.14 – 7.12 (m, 1H), 7.01 – 6.68 (m,
2H), 6.31 (dd, J = 17.0, 1.5 Hz, 1H), 6.12 – 6.08 (m, 1H), 5.65 (dd, J = 10.2, 1.5 Hz, 1H),
13
4
.48 (d, J = 5.4 Hz, 2H), 2.31 (s, 3H), 2.30 (s, 3H). C–NMR (CDCl , 101 MHz) (peaks are
3
listed only for major regioisomer): δ = 165.3, 137.8, 136.6, 132.7, 131.6, 130.8, 129.1, 127.0,
+
126.7, 41.8, 38.5, 21.1, 19.0. MS (ESI) m/z: [M+Na] Calcd. for C12
H15NONa 212.11, found
–1
2
12.17. EA (%): Calcd.: C 76.16 H 7.99 N 7.40 found: C 76.02 H 7.79 N 7.32. IR (cm ):
3
286 (m), 2916 (w), 1653 (s), 1620 (s), 1537 (m), 1464 (w), 1404 (w), 1352 (w), 1304 (w),
(hexane/ EtOAc
1234 (s), 1046 (m), 995 (s), 145 (s), 879 (w), 822 (m), 775 (w), 688 (m). R
:1) = 0.1.
f
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N–(2,4–Dimethylbenzyl)–2–chloroacetamide (6f) was synthesized according to TP 1 from 2–
chloroacetamide (187 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), m–xylene (0.74
mL, 6.0 mmol, 3.0 equiv.) und Bi(OTf) (66 mg, 0.1 mmol) in nitromethane (4 mL) at 100 °C
3
for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colourless solid (308 mg, 73%, ratio of regioisomers 18:1). m.p.: 120–121 °C. H–NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
CDCl , 300 MHz) (peaks are listed only for major regioisomer): δ = 7.13 (d, J = 7.5 Hz, 1H),
3
7.02 – 7.00 (m, 2H), 6.63 (bs, 1H), 4.45 (d, J = 5.4 Hz, 2H), 4.09 (s, 2H), 2.32 (s, 3H), 2.30 (s,
1
3
3
H). C–NMR (CDCl
3
, 75 MHz) (peaks are listed only for major regioisomer): δ = 165.7,
+
1
38.0, 136.5, 132.0, 131.6, 128.9, 127.1, 42.7, 42.0, 21.1, 19.1. MS (ESI) m/z: [M] Calcd. for
11
C H14ClNO 211.08, found 211.40. EA (%): Calcd.: C 62.41 H 6.67 N 6.62; found: C 62.33
–1
H 6.57 N 6.43. IR (cm ): 3282 (m), 3003 (w), 1645 (s), 1541 (m), 1466 (w), 1416 (w), 1362
w), 1319 (w), 1225 (m), 1157 (w), 1061 (w), 1034 (w), 995 (w), 124 (w), 879 (w), 820 (m),
771 (w), 702 (s), 667 (m). R (hexane/ EtOAc 4:1) = 0.3.
(
f
N–(2,4–Dimethylbenzyl)–2–cyanoacetamide (6g) was synthesized according to TP 1 from 2–
cyanoacetamide (168 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), m–xylene
(0.74 mL, 6.0 mmol, 3.0 equiv.) und Bi(OTf)
3
(66 mg, 0.1 mmol) in nitromethane (4 mL) at
1
00 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colourless solid (387 mg, 96%, ratio of regioisomers 11:1). m.p.: 136–137 °C. H–NMR
(CDCl , 400 MHz) (peaks only for major regioisomer listed): δ = 7.11 (d, J = 7.6 Hz, 1H),
.03 – 7.00 (m, 2H), 6.15 (bs, 1H), 4.44 (d, J = 5.3 Hz, 2H), 3.37 (s, 2H), 2.32 (s, 3H), 2.30 (s,
3
7
3
1
3
3
H). C–NMR (CDCl , 101 MHz) (peaks not assigned to regioisomers): δ = 160.5, 138.3,
136.5, 131.8, 131.5, 129.1, 128.8, 127.2, 114.7, 52.3, 42.5, 25.9, 21.1, 19.9, 19.1. MS (ESI)
+
m/z: [M+H] Calcd. for C H N O 203.12, found 203.40. EA: Calcd.: C 71.26 H 6.98 N
1
2
15
2
–1
1
3.85; found: C 71.28 H 7.05 N 13.66. IR (cm ): 3275 (m), 1647 (w), 1645 (s), 1571 (m),
1504 (w), 1468 (w), 1367 (m), 1365 (m), 1325 (w), 1232 (m), 1066 (w), 991 (w), 922 (w),
76 (w), 822 (m), 793 (m), 768 (w), 687 (m). R (hexane/ EtOAc 1:1) = 0.5.
8
f
N–(2,4–Dimethylbenzyl)acetamide (6h) was synthesized according to TP 1 from acetamide
(29 mg, 0.5 mmol), paraformaldehyde (19 mg, 0.6 mmol), m–xylene (0.18 mL, 1.5 mmol,
3
.0 equiv.) and Bi(OTf) (16 mg, 0.025 mmol, 5 mol%) in nitromethane (2 mL) at 100 °C for
3
8
h. Purification by chromatography (hexane/EtOAc 1:1) yielded the product as colorless
1
solid (45 mg, 51%, ratio of regioisomers 15:1). m.p.: 110–112 °C. H–NMR (CDCl
3
, 400
MHz) (peaks are listed only for major regioisomer): δ = 7.11 (d, J = 7.6 Hz, 1H), 7.01 – 6.98
13
(
m, 2H), 5.54 (bs, 1H), 4.39 (d, J = 5.3 Hz, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 1.99 (s, 3H). C–
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NMR (CDCl
3
, 75 MHz) (peaks are not assigned to regioisomers): δ = 169.8, 137.7, 137.6,
1
36.5, 134.0, 132.9, 131.5, 129.0, 158.6, 128.1, 127.0, 41.8, 38.6, 23.3, 23.2, 21.1, 19.8, 19.0.
+
MS (ESI) m/z: [M+H] Calcd. for C H NO 178.12, found 178.21 . EA (%): Calcd.: C 74.54
1
1
16
–
1
H 8.53 N 7.90; found: C 74.20 H 8.65 N 7.75. IR (cm ): 3289 (w), 3000 (w), 2920 (w), 2871
w), 1689 (w),1634 (s), 1538 (s), 1463 (s), 1377 (s), 1352 (w), 1300 (w), 1275 (s), 1215 (w),
159 (w), 1124 (w), 1092 (m), 1037 (w), 998 (m), 951 (w), 886 (w), 816 (s), 770 (w), 713 (s),
617 (m), 598 (s), 573 (s), 552 (w), 508 (w), 467(s). R (hexane/ EtOAc 1:1) = 0.2.
(
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
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51
52
53
54
55
56
57
58
59
60
1
f
N–(2,4–Dimethylbenzyl)–2,2,2–trimethylacetamide (6i) was synthesized according to TP 1
from 2,2,2–trimethylacetamide (202 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol),
m–xylene (0.74 mL, 6.0 mmol, 3.0 equiv.) und Bi(OTf)
3
(66 mg, 0.1 mmol) in nitromethane
(
4 mL) at 100°C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the
1
product as colorless solid (337 mg, 77%, ratio of regioisomers 17:1). m.p.: 85–86 °C. H–
NMR (CDCl , 400 MHz) (peaks are listed only for major regioisomer): δ = 7.10 (d, J = 8 Hz,
H), 7.01 – 6.98 (m, 2H), 5.67 (bs, 1H), 4.39 (d, J = 5 Hz, 2H), 2.31 (s, 3H), 2.28 (s, 3H),
3
1
1
13
3
.21 (s, 9H). C–NMR (CDCl , 101 MHz) (peaks are listed only for major regioisomer): δ =
178.1, 137.6, 136.6, 133.2, 131.5, 128.9, 126.9, 41.9, 38.9, 27.8, 21.1, 19.0. MS (ESI) m/z:
+
[
M+H] Calcd. for C14
H
22NO 220.17, found 220.80. EA (%): Calcd.:
C 76.67 H 9.65 N
–
1
6
.39; found: C 76.42 H 9.75 N 6.11. IR (cm ): 3317 (m), 2954 (w), 1633 (s), 1539 (m), 1504
(w), 1425 (w), 1365 (w), 1296 (w), 1225 (w), 1213 (m), 1005 (m), 931 (w), 866 (w), 814 (m),
787 (m), 702 (w), 677 (m). R
f
(hexane/ EtOAc 1:1) = 0.4.
3
–(2,4–Dimethylbenzyl)oxazolidin–2–one (6j) was synthesized according to TP 1 from
oxazolidin–2–one (44 mg, 0.5 mmol), paraformaldehyde (19 mg, 0.6 mmol), m–xylene
0.18 mL, 1.5 mmol, 3.0 equiv.) and Bi(OTf) (16 mg, 0.025 mmol) in nitromethane (2 mL) at
(
3
1
00 °C for 6 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colorless oil (73 mg, 71 %, ratio of regioisomers >25:1). H–NMR (CDCl
3
, 400 MHz): δ =
7
.08 (d, J = 7.6 Hz, 1H), 7.02 – 6.98 (m, 2H), 4.42 (s, 2H), 4.30 – 4.26 (m, 2H), 3.38 – 3.34
1
3
(m, 2H), 2.31 (s, 3H), 2.31 (s, 3H). C–NMR (CDCl
3
, 101 MHz): δ = 158.3, 138.1, 136.9,
+
131.7, 130.7, 129.3, 126.9, 61.9, 46.5, 44.1, 21.1, 19.1. MS (ESI) m/z: [M+Na] Calcd. for
C H NO Na 228.10, found 227.80. EA (%): Calcd.: C 70.22 H 7.37 N 6.82; found: C 69.94
12
15
2
–
1
H 7.35 N 6.74. IR (cm ): 3491 (w), 2919 (w), 1740 (s), 1616 (w), 1484 (m), 1424 (s), 1376
(m), 1355 (m), 1320 (w), 1252 (s), 1204 (m), 1185 (m), 1158 (m), 1119 (m), 1067 (s), 1034
(
s), 975 (m), 954 (m), 921 (m), 878 (w), 833 (m), 803 (m), 778 (m), 760 (s), 728 (m), 717
m), 693 (m), 652 (m), 581 (m), 538 (w), 490 (m). R (hexane/ EtOAc 4:1) = 0.1.
(
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N–(2,4–Dimethylbenzyl)–3–methyl–2–(1,3–dioxoisoindolin–2–yl)butanamide
(8)
was
synthesized according to TP 1 from (S)–3–methyl–2–(1,3–dioxoisoindolin–2–yl)butanamide
123 mg, 0.5 mmol), paraformaldehyde (19 mg, 0.6 mmol), m–xylene (0.18 mL, 1.5 mmol,
3.0 equiv.) and Bi(OTf) (16 mg, 0.025 mmol, 5 mol%) in nitromethane (2 mL) at 100 °C for
4 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as colorless,
(
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
very viscous foam (115 mg, 63%, mixture of regioisomers as determined by analytical HPLC
1
12:1). H–NMR (CDCl
3
, 400 MHz) (mixture of regioisomer and rotamers, peaks are not
assigned): δ = 7.87 – 7.85 (m, 2H), 7.76 – 7.74 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 – 7.02
m, 1H), 6.98 – 6.94 (m, 2H), 4.49 – 4.42 (m, 2H), 4.35 – 4.31 (m, 1H), 2.85 – 2.85 (m, 1H),
(
1
3
2.29 (s, 3H), 2.26 (s, 3H), 1.10 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H). C–NMR
CDCl , 75 MHz) (mixture of regioisomer and rotamers, peaks are not assigned): δ = 168.6,
68.6, 137.5, 136.3, 134.6, 132.7, 131.5, 131.5, 128.7, 128.6, 128.0, 127.0, 123.8, 63.3, 41.7,
(
3
1
+
38.6, 27.8, 21.1, 20.0, 19.8, 19.6, 19.1. MS (ESI) m/z: [M+H] Calcd. for C22
25 2 3
H N O 365.19,
found 365.90. EA (%): Calcd.: C 72.50 H 6.64 N 7.69; found: C 72.20 H 6.60 N 7.58. IR
–1
(
cm ): 3329 (w), 2966 (m), 2926 (w), 2874 (w), 1770 (m), 1706 (s), 1660 (m), 1615 (m),
1530 (m), 1467 (m), 1381 (s), 1355 (s), 1332 (s), 1288 (m), 1225 (m), 1192 (m), 1172 (m),
157 (m), 1123 (w), 1070 (s), 1014 (m), 988 (m), 961 (w), 927 (w), 888 (m), 817 (m), 791
m), 716 (s), 660 (m), 627 (m), 575 (m), 560 (m), 530 (s). R (hexane/ EtOAc 4:1) = 0.2.
1
(
f
N–(2,4,6–Trimethylbenzyl)benzamide (10a) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), mesitylene (0.83 mL,
6
3
.0 mmol, 3.0 equiv.) and Bi(OTf) (66 mg, 0.1 mmol, 5 mol%) in nitromethane (4 mL) at
100 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colorless solid (371 mg, 73%). m.p.: 151–152 °C. H–NMR (CDCl , 400 MHz): δ = 7.73 (d, J
3
=
8.1 Hz, 2H), 7.48 (t, J = 7.1 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 6.91 (s, 2H), 5.89 (bs, 1H),
13
4.64 (d, J = 4.4 Hz, 2H), 2.37 (s, 6H), 2.29 (s, 3H). C–NMR (CDCl
3
, 101 MHz): δ = 167.5,
1
37.9, 137.7, 136.6, 134.5, 131.6, 130.9, 129.7, 129.4, 128.7, 127.0, 38.9, 21.1, 19.8. MS
+
(
ESI) m/z: [M+H] Calcd. for C17
H 7.56 N 5.53; found: C 80.72 H 7.65 N 5.13. IR (cm ): 3296 (m), 1626 (s), 1578 (m), 1516
s) 1471 (m), 1377 (w), 1269 (w), 1178 (w), 1076 (w), 1022 (w), 906 (w), 854 (m), 802 (m),
71 (w), 692 (s), 660 (w). R (hexane/ EtOAc 4:1) = 0.3.
H20NO 254.15, found 254.40. EA (%): Calcd.: C 80.60
–1
(
7
f
N–(2–Methoxybenzyl)benzamide (10b) was synthesized according to TP 1 from benzamide
61 mg, 0.5 mmol), formalin (45 µL, 37 wt% solution in H O, 0.6 mmol), anisole (0.22 mL,
(
2
2
3
.0 mmol, 4 equiv.) and Bi(OTf) (16 mg, 0.1 mmol, 5 mol%) in nitromethane (2 mL) at
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100 °C for 24 h. Purification by chromatography (hexane/EtOAc 9:1→4:1) yielded the
1
product as yellow solid (82 mg, 68%, ratio of regioisomers 3:1). m.p.: 110–111 °C. H–NMR
(
CDCl , 400 MHz) (peaks are listed only for para–regioisomer): δ = 7.75 – 7.71 (m, 2H),
3
7.47 – 7.30 (m, 3H), 7.24 – 7.22 (m, 2H), 6.92 – 6.81 (m, 2H,), 6.33 (bs, 1H), 4.55 (d, J = 5.5
13
3
Hz, 2H), 3.77 (s, 3H). C–NMR (CDCl , 101 MHz) (peaks are not assigned to ortho and
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para–isomer): δ = 167.4, 137.2, 136.1, 135.7, 134.6, 131.6, 130.1, 129.9, 129.5, 128.7, 128.7,
+
127.2, 127.1, 127.1, 125.9, 125.6, 44.1, 43.3, 20.6, 19.9, 19.5, 15.1. MS (ESI) m/z: [M+H]
2
Calcd. for C15H16NO 242.12, found 242.40. EA (%): Calcd.: C 74.67 H 6.27 N 5.81; found:
–1
C 74.44 H 6.26 N 5.63. IR (cm ): 1300 (w), 3223 (w), 3055 (w), 2924 (w), 2831 (w), 1630
(s), 1546 (w), 1539 (m), 1489 (m), 1460 (c), 1429 (w), 1350 (w), 1296 (m), 1238 (s), 1176
(m), 1109 (m), 1072 (w), 1032 (s), 172 (w), 926 (w), 812 (m), 752 (s), 694 (s), 667 (s).
R (hexane/ EtOAc 4:1) = 0.2.
f
N–(3–Chloro–4–methoxybenzyl)benzamide (10c) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), 2–chloroanisol
3
(0.76 mL, 6.0 mmol, 3.0 equiv.) and Bi(OTf) (66 mg, 0.1 mmol, 5 mol%) in nitromethane (4
mL) at 100 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the
1
product as yellow solid (462 mg, 84%). m.p.: 117–118 °C. H–NMR (CDCl
3
, 400 MHz): δ =
7.79 – 7.77 (m, 2H), 7.51 – 7.47 (m, 1H), 7.43 – 7.39 (m, 2H), 7.35 (d, J = 2 Hz, 1H), 7.20
(dd, J1 = 2 Hz, J2 = 8 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 6.57 (bs, 1H), 4.54 (d, J = 6 Hz, 2H),
1
3
3
3
.87 (s, 3H). C–NMR (CDCl , 101 MHz): δ = 167.5, 154.6, 134.3, 131.8, 131.6, 129.9,
128.7, 127.5, 127.1, 122.7, 112.3, 56.3, 43.2. MS (ESI) m/z: [M+H] Calcd. for C15H15ClNO
2
+
276.08, found 276.00 . EA (%): Calcd.: C 65.34 H 5.12 N 5.08; found: C 65.05 H 5.10 N
–1
4
.91. IR (cm ): 3311 (w), 3242 (w), 3059 (w), 3010 (w), 2943 (w), 2927 (w), 2833 (w), 1626
(m), 1574 (w), 1541 (s), 1504 (m), 1462 (w), 1427 (w), 1354 (w), 1282 (s), 1182 (w), 1147
(w), 1063 (s), 1094 (m), 974 (m), 937 (w), 872 (m), 814 (m), 756 (m), 698 (s), 654 (w).
R (hexane/ EtOAc 4:1) = 0.1.
f
N–(3–Bromo–4–methoxybenzyl)benzamide (10d) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), 2–bromoanisole
(
0.74 mL, 6.0 mmol, 3.0 equiv.) and Bi(OTf) (66 mg, 0.1 mmol) in nitromethane (4 mL) at
3
100 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
yellow solid (563 mg, 88%) m.p.: 112–113 °C. H–NMR (CDCl
3
, 400 MHz): δ = 7.79 – 7.77
(m, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.49 – 7.47 (m, 1H), 7.43 – 7.39 (m, 2H), 7.27 – 7.24 (m,
1
3
1
H), 6.84 (d, J = 6.8 Hz, 1H), 6.58 (bs, 1H), 4.54 (d, J = 4.5 Hz, 2H), 3.87 (s, 3H). C–NMR
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(CDCl
3
, 101 MHz): δ = 167.5, 155.5, 134.3, 133.0, 132.1, 131.7, 128.7, 128.3, 127.1, 112.2,
+
111.9, 56.4, 43.1. MS (ESI) m/z: [M+H] Calcd. for C15
H15BrNO
2
320.03, found 320.00. EA
–
1
(
%): Calcd.: C 56.27 H 4.41 N 4.37; found: C 56.08 H 4.39 N 4.25. IR (cm ): 3307 (w), 3240
(w), 3055 (w), 3008 (w), 2964 (w), 2926 (w), 2831 (w), 1626 (m), 1539 (s), 1493 (s), 1460
(
w), 1427 (w), 1402 (w), 1352 (w), 1261 (s), 1259 (s), 1180 (w), 1147 (w), 1061 (w), 1024
m), 1022 (m), 170 (w), 137 (w), 885 (w), 860 (w), 814 (m), 754 (m), 698 (s), 667 (w).
0
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0
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7
8
9
0
(
f
R (hexane/ EtOAc 4:1) = 0.1.
N–(3–Iodo–4–methoxybenzyl)benzamide (10e) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), 2–iodoanisole
(0.78 mL, 6.0 mmol, 3.0 equiv.) and Bi(OTf)
3
(66 mg, 0.1 mmol) in nitromethane (4 mL) at
1
00 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colorless solid (578 mg, 79%). m.p.: 106–107 °C. H–NMR (CDCl , 400 MHz): δ = 7.79 –
3
7.76 (m, 3H), 7.50 (t, J = 7.3 Hz, 1H), 7.43 (t, J =7.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 6.78
1
3
(
d, J = 8.4 Hz, 1H), 6.42 (bs, 1H), 4.54 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H). C–NMR (CDCl
3
,
1
01 MHz): δ = 167.4, 157.8, 139.1, 134.4, 132.6, 131.8, 129.5, 128.8, 127.1, 111.1, 86.3,
+
56.6, 43.0. MS (ESI) m/z: [M+H] Calcd. for C15
Calcd.: C 49.07 H 3.84 N 3.81; found: C 49.03 H 3.88 N 3.66. IR (cm ): 3280 (w), 3030 (w),
927 (w), 2831 (w), 1626 (s), 1578 (w), 1527 (m), 1485 (m), 1460 (m), 1400 (w), 1363 (w),
1288 (m), 1250 (m), 1225 (m), 1178 (w), 1144 (w), 1074 (w), 1047 (m), 1018 (m), 978 (w),
22 (w), 887 (w), 841 (w), 798 (m), 692 (s), 667 (m). R (hexanes/ EtOAc 4:1) = 0.1.
2
H15INO 368.01, found 368.40. EA (%):
–1
2
9
f
N–(5–Chloro–2–methoxybenzyl)benzamide (10f) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), 4–chloroanisole
(
0.73 mL, 6.0 mmol, 3.0 equiv.) and Bi(OTf) (66 mg, 0.1 mmol) in nitromethane (4 mL) at
3
1
00 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colorless solid (459 mg, 83%). m.p.: 138–139 °C. H–NMR (CDCl
3
, 400 MHz): δ = 7.77 (d, J
=
8.0 Hz, 2H), 7.48 (t, J = 7.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.31 (bd, J = 2.1 Hz, 1H),
7
.22 (dd, J = 8.7, 2.3 Hz, 1H), 6.81 (d, 1H, J = 8.7 Hz), 6.65 (bs, 1H), 4.60 (d, J = 6.0 Hz,
13
2H), 3.86 (s, 3H). C–NMR (CDCl
3
, 101 MHz): δ = 167.3, 156.3, 134.7, 131.6, 129.7, 128.7,
+
1
28.6, 128.2, 127.1, 125.8, 111.7, 55.9, 39.5. MS (ESI) m/z: [M+H] Calcd. for C H ClNO
15
15
2
2
76.08, found 275.90. EA (%): Calcd.: C 65.34 H 5.12 N 5.08; found: C 65.19 H 5.07 N 4.93.
–
1
IR (cm ): 3269 (m), 3055 (w), 1624 (m), 1576 (m), 1543 (m), 1487 (m), 1443 (w), 1423 (w),
1
352 (w), 1294 (w), 1254 (w), 1244 (m), 1176 (w), 1174 (w), 1126 (m), 1053 (w), 1049 (w),
1
f
026 (m), 989 (w), 930 (w), 877 (w), 806 (m), 692 (s), 667 (w). R (hexane/ EtOAc 4:1) = 0.1.
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N–(5–Bromo–2–methoxybenzyl)benzamide (10g) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), 4–bromoanisole
(
0.75 mL, 6.0 mmol, 3.0 equiv.) and Bi(OTf) (66 mg, 0.1 mmol) in nitromethane (4 mL) at
3
100 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as
1
colorless solid (494 mg, 77%). m.p.: 123–124 °C. H–NMR (CDCl
3
, 400 MHz): δ = 7.78 –
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12
13
14
15
16
17
18
19
20
21
22
23
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60
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.75 (m, 2H), 7.53 – 7.40 (m, 4H), 7.38 – 7.35 (m, 1H), 6.76 (d, J = 9 Hz, 1H), 6.61 (bs, 1H),
13
4.61 (d, J = 6 Hz, 2H), 3.86 (s, 3H). C–NMR (CDCl
3
, 75 MHz): δ = 167.3, 156.8, 134.7,
+
1
32.6, 131.6, 131.6, 128.7, 128.6, 127.1, 113.1, 112.2, 55.9, 39.5. MS (ESI) m/z: [M+H]
Calcd. for C H BrNO 320.03, found 320.00. EA (%): Calcd.: C 56.27 H 4.41 N 4.37;
15
15
2
–1
found: C 56.15 H 4.52 N 4.27. IR (cm ): 3265 (w), 3055 (w), 1624 (m), 1576 (m), 1541 (m),
1
489 (m), 1443 (w), 1421 (w), 1398 (w), 1350 (w), 1292 (w), 1244 (m), 1176 (w), 1174 (w),
120 (w), 1055 (w), 1051 (w), 1024 (m), 987 (w), 131 (w), 856 (w), 806 (m), 692 (s), 667
1
f
(w). R (hexanes/ EtOAc 4:1) = 0.2.
N–(5–Iodo–2–methoxybenzyl)benzamide (10h) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), 4–iodoanisole (1.40 g,
6.0 mmol, 3.0 equiv.) and Bi(OTf)
3
(66 mg, 0.1 mmol) in nitromethane (4 mL) at 100 °C for
1
6 h. Purification by chromatography (hexane/EtOAc 4:1) yielded the product as colorless
1
solid (465 mg, 64%). m.p.: 117–118 °C. H–NMR (CDCl
3
, 300 MHz): δ = 7.78 – 7.74 (m,
2H), 7.63 (d, J = 2.3 Hz, 1H), 7.58 – 7.40 (m, 4H), 6.66 (d, J = 8.6 Hz, 1H), 6.59 (bs, 1H),
13
4
.58 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H). C–NMR (CDCl
3
, 75 MHz): δ = 167.3, 157.7, 138.4,
+
1
37.8, 134.7, 131.6, 129.0, 128.7, 127.1, 112.9, 83.1, 55.8, 39.4. MS (ESI) m/z: [M+H]
Calcd. for C15
C 49.18 H 3.89 N 3.69. IR (cm ): 3267 (w), 3061 (w), 3008 (w), 2947 (w), 2835 (w) 2158
w), 1992 (w), 1633 (s), 1551 (w), 1539 (s), 1495 (f), 458 (m), 1433 (m), 1360 (w), 1309 (m),
1279 (m), 1263 (m), 1242 (w), 1215 (s), 1118 (m), 1151 (w), 1059 (w), 1045 (m), 1020 (m),
93 (w), 924 (w) 906 (w), 879 (m), 825 (m), 795 (s), 710 (s), 665 (w).
(hexanes/ EtOAc 4:1) = 0.1.
2
H15INO 368.01, found 368.40. EA (%): Calcd.: C 49.07 H 3.84 N 3.81; found:
–1
(
9
R
f
N–(3,6–Dimethoxybenzyl)benzamide (10i) was synthesized according to TP 1 from
benzamide (242 mg, 2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol), 1,4–
3
dimethoxybenzene (1.128 g, 8.0 mmol, 4 equiv.) and Bi(OTf) (66 mg, 0.1 mmol, 5 mol%) in
nitromethane (4 mL) at 80 °C for 16 h. Purification by chromatography (hexane/EtOAc 4:1)
1
yielded the product as yellow solid (0.18 g, 42%). m.p.: 101–102 °C. H–NMR (CDCl ,
3
4
00 MHz): δ = 7.76 (d, J = 8 Hz, 2H), 7.48 (t, J = 7 Hz, 1H), 7.41 (t, J = 7 Hz, 2H), 6.94 (d,
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