Synergy between chemo- and bio-catalysts in multi-step transformations

Article abstract of DOI:10.1039/b901592b

Cascade synthetic pathways, which allow multi-step conversions to take place in one reaction vessel, are crucial for the development of biomimetic, highly efficient new methods of chemical synthesis. Theoretically, the complexity introduced by combining processes could lead to an improvement of the overall process; however, it is the current general belief that it is more efficient to run processes separately. Inspired by natural cascade procedures we successfully combined a lipase catalyzed amidation with palladium catalyzed coupling reactions, simultaneously carried out on the same molecule. Unexpectedly, the bio- and chemo-catalyzed processes show synergistic behaviour, highlighting the complexity of multi-catalyst systems.

Full text of DOI:10.1039/b901592b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synergy between chemo- and bio-catalysts in multi-step transformations†
Aldo Caiazzo,a Paula M. L. Garcia,b Ron Wever,a Jan C. M. van Hest,*b Alan E. Rowan*b and
Joost N. H. Reek*a
Received 26th January 2009, Accepted 23rd April 2009
First published as an Advance Article on the web 29th May 2009
DOI: 10.1039/b901592b
Cascade synthetic pathways, which allow multi-step conversions to take place in one reaction vessel, are
crucial for the development of biomimetic, highly efficient new methods of chemical synthesis.
Theoretically, the complexity introduced by combining processes could lead to an improvement of the
overall process; however, it is the current general belief that it is more efficient to run processes
separately. Inspired by natural cascade procedures we successfully combined a lipase catalyzed
amidation with palladium catalyzed coupling reactions, simultaneously carried out on the same
molecule. Unexpectedly, the bio- and chemo-catalyzed processes show synergistic behaviour,
highlighting the complexity of multi-catalyst systems.
for the production of pharmaceutically important compounds,11,12
the only successful examples so far involve dynamic kinetic
Introduction
resolution procedures.13,14 Clearly new strategies are required to
face the current challenges. We therefore decided to investigate
a simple cascade bio- and chemo-catalyzed transformation of a
model substrate, 4-bromobenzylamine (1a), using the widely used
catalysts lipase15–17 and palladium, to invoke simultaneously an
amidation and a C–N bond formation18–21 (Scheme 1).
Lipases are used for the acylation of a wide scope of alcohols
and amines. In particular Lipase B from Candida antarctica (Cal
B) has shown, besides a broad applicability in different types of
solvents, a remarkable thermo-stability, especially when anchored
to a solid support.22–24 There are several reports in which Cal B has
been used in combination with a transition metal catalyst; however,
this has been limited to racemization metal catalysts for the
dynamic kinetic resolution of racemic alcohols and derivatives.13,14
In our first combined system, we investigated the synergy between
lipase catalyzed amidation and the Buchwald–Hartwig coupling
(C–N bond formation). It was felt that if the known sensitive
C–N coupling can be successfully incorporated into a bio-chemo
cascade then the concept could be readily applied to other well-
known coupling procedures.
Catalysis has played a prominent role in the development of new
synthetic routes toward complex molecules, which have been of
tremendous value for various disciplines such as the pharmaceu-
tical sciences and food technology.1–3 Although the complexity
of molecules has increased, their synthesis generally involves a
sequential array of relatively simple single-step transformations.
Nature, on the other hand, carries out multi-step conversions in
complex systems, with high overall atom and energy efficiency.
There is a growing consensus that future synthetic processes should
comprise comparable one-pot multi-step conversions, in cascade
or in concert, in order to achieve a similar level of “sustainability”
in organic synthesis.4–8 Consequently, one of the current major
challenges in synthetic chemistry is the transformation of simple
single-step reactions to multi-step multi-component procedures
and, more importantly, a comprehension of the complex system
generated by integration of the processes in one-pot.9,10 Here we
report how the increase in complexity by carrying out bio- and
chemo-catalyzed reactions in one reaction vessel surprisingly leads
to synergistic effects between the two processes.
It is generally unknown how substrates, products and side-
products of a reaction affect the progress of another reaction
carried out in the same vessel, which is one of the corner stones
of understanding the behaviour of complex catalyst systems.
Theoretically, multicatalyst systems could lead to an improvement
in the overall process; however, there is a general belief that it
is more efficient to run processes separately. This is especially
true if metal-mediated and bio-catalyzed processes are combined,
because generally these are applied under substantially different
conditions with limited functional group tolerance. Despite the
fact that these types of combined processes would be very relevant
Results and discussion
As shown in Scheme 1, the cascade process can follow several
pathways: i) the lipase catalyzed amidation occurs simultaneously
with the palladium catalyzed reaction; ii) the enzymatic reaction
precedes the Pd catalyzed transformation, or iii) the reversed
reaction order can dominate.
First the lipase-catalyzed reaction was subjected to pseudo-
cascade conditions. 4-bromobenzylamine (1a) was submitted to
enzymatic amidation by using the resin bound enzyme Novozym
aVan ‘t Hoff Institute for Molecular Sciences, University of Amsterdam,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands. E-mail:
reek@science.uva.nl; Fax: +31-20-5256422
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435ꢀ as a catalyst, in the presence of common reagents used
for Pd-catalyzed coupling (Pd precursors, and Cs2CO3 as base)
in toluene at 100 ◦C. The amidation indeed proceeded under
these basic conditions and also the presence of the palladium
sources (Pd(OAc)2, Pd(dba)2) did not inhibit the enzyme activity.
Thus, the enzyme proved to be surprisingly robust and active
bInstitute for Molecules and Materials, Radboud University Nijmegen,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 4a–f, 6a and 7a, and 19F NMR spectrum of
compound 4e. See DOI: 10.1039/b901592b
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Scheme 1 Proposed cascade reaction combining an enzymatic amidation and a transition metal catalyzed C–N bond formation.
Table 1 Palladium catalyzed amination carried out on N-(4-bromobenzyl)acetamide (2a) in the presence of aniline and the most representative ligands
used in the literature (entries 1–5)a; the combined amination/amidation cascade reaction carried out on 4-bromobenzylamine (1a) in the presence of
aniline, Novozym 435ꢀR and the most representative ligands used in literature (entries 6–15)b
Entry
Ligand
AcOR
Substrate
Conversion (%)c
2a (%)c,d
5 (%)c,d
4a (%)c,d
Cooperativity
e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PtBu3H BF4
NAg
2a
2a
2a
2a
2a
1a
1a
1a
1a
1a
40
20
1
12
9
99
94
94
97
99
99
94
99
92
99
NAg
NAg
NAg
NAg
NAg
18
6
28
59
92
8
4
–
25
25
44
9
8
37
8
15
4
3
92
96
–
75
75
38
85
64
4
NAg
NAg
NAg
NAg
NAg
+
++
++
–
0
+
++
++
0
XANTPHOSf
Ph-oC6H4-PtBu2
BINAPf
NAg
NAg
f
f
f
NAg
P(oTol)3
NAg
e
PtBu3H BF4
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
MeOAc 1a
MeOAc 1a
MeOAc 1a
MeOAc 1a
MeOAc 1a
e
XANTPHOSf
Ph-oC6H4-PtBu2
BINAPf
e
P(oTol)3
–
PtBu3H BF4
20
5
48
89
65
91
49
7
e
XANTPHOSf
Ph-oC6H4-PtBu2
BINAPf
4
3
e
P(oTol)3
97
–
–
a Reactions carried out at 100 ◦C in toluene; concentration of 2a: 0.21 mm; aniline (1.04 eq); catalyst precursor: Pd(dba)2 (2 mol%); Cs2CO3 as base
(1.4 eq). b Reactions carried out at 100 ◦C in toluene; concentration of 1a: 0.21 mM; aniline (1.04 eq); catalyst precursor: Pd(dba)2 (2 mol%); Cs2CO3 as
base (1.4 eq); Novozym 435ꢀR (100 mg); AcOR (3 eq). c Determined via GC analysis of the crude reaction mixtures after 24 h of stirring. d Percentage of
the total of GC products. e 4 mol%. f 3 mol%. g Not Applicable.
at this high temperature (100% conversion into the expected
product intermediate N-(4-bromobenzyl)acetamide 2a after 2 h).
In addition, the amidation runs described above were also carried
making the latter suitable as a nucleophile for the palladium
catalyzed amination reaction in the cascade process.
The amination reaction was studied using 2a as the substrate,
with palladium catalysts based on commonly used phosphorous
ligands. Under the conditions applied the palladium catalysts pro-
vided low to moderate conversions (1–40%), with the main product
being the aminated compound 4a (See Table 1, entries 1–6).
Following the traditional approach would imply optimization of
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out in the absence of Novozym 435ꢀ, in order to estimate the
contribution from background reactions; the results showed a
negligible conversion of substrate 1a after 2 h and no amide 2a
was present. Further control experiments revealed that Cal B was
sufficiently selective for 4-bromobenzylamine (1a) over aniline,
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Scheme 2 Combined amidation and amination reaction using Novozym 435ꢀR and a palladium catalyst.
this single step prior to investigation of the cascade reaction;
however, we decided to optimize the cascade process as a whole
(Scheme 2).
conversion after 24 h), likely as a result of the formation of CsOH
in the reaction mixture. A similar effect was observed when the
amination reaction was carried out in the presence of Novozym
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A series of cascade reactions was set up using 1a as the starting
substrate, aniline as the amine nucleophile, ethyl or methyl acetate
as the source of the acyl moiety and the same Pd ligands as used for
the single-step amination reaction (Table 1, Scheme 2). In all cases
the conversion of 1a into the reaction products was >90% after
24 h, confirming that the enzymatic amidation reaction proceeded
smoothly. More importantly, the amination reaction proved to be
startlingly more efficient in the cascade process when compared
to the single-step reaction, pointing to a positive cooperation
between the two processes. As a second surprise we found that
the organometallic catalyst that provided the highest conversion
was not the same for the cascade process as for the single-step
transformation, indicating that the cooperativity effect was also
catalyst dependent. (Some of the catalyst systems did not show
any cooperativity at all (entries 9, 10, 14, 15).) The cooperativity
effect also varied with the acyl source. The use of either ethyl or
methyl acetate indeed provided different results for the various
catalytic systems (compare entry 6 vs 11, and 8 vs 13 in Table 1).
These data clearly and unambiguously show that optimization of
the separate reaction steps is not useful for the current cascade
process.
435ꢀ (the conversion of the starting substrate increased to 33%
after 24 h); in this case sufficient amounts of water were introduced
by the supported enzyme. Indeed, an amination reaction carried
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out using a batch of Novozym 435ꢀ that had been evacuated
for 1 h at 0.1 mm Hg, gave the same activity as in the case
where no enzyme was present (22% vs. 20% conversion). The
above clearly demonstrates that the acceleration of the amination
reaction under cascade conditions is due to the combination of
the release of methanol, which is the byproduct formed during the
lipase-catalyzed step, and, to a lesser extent, the presence of water
introduced by the supported enzyme. Indeed the experiments
carried out under the conditions of f) showed that the conversion
of amide 2a increased up to 76%, with almost complete selectivity
for the product 4a.
The amount of the dehalogenation product N-benzylacetamide
(5) in the reaction mixture is dependent on the type of catalyst
system and, more importantly, also on the ester-source used for the
amidation step. The latter again points at an involvement of the al-
cohol side-product from the enzymatic reaction, which was indeed
confirmed by labeling experiments. A cascade reaction carried out
in the presence of CH3COOCD3 (using pd(dba)2/PBu3H+BF4
-
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To understand this intriguing cooperativity we investigated the
influence of several additives on the single-step amination reaction
of 2a: a) the presence of the enzyme; b) the presence of deactivated
and Novozym 435ꢀ as catalysts) showed about 60% deuteration
on the aromatic ring of the dehalogenated side-product (measured
via GC/MS). In contrast, the other products did not have any
deuterium incorporated. The formation of 5 therefore likely occurs
through a b-hydride elimination reaction from a Pd-alkoxide
species (Scheme 3). This process is dependent on the electronic
and steric nature of the Pd species involved, accounting for the
ligand effects observed in the formation of the side product.
The cascade reaction was investigated on 1a applying various
amine nucleophiles and using the experimental conditions that
provided the highest amount of cascade products in the case
of aniline (Scheme 4). In all processes the conversion of the
starting substrate 1a was almost complete after 24 h (>95%)
and the selectivity for the expected cascade product 4 was always
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enzyme (Novozym 435ꢀ, evacuated in order to remove absorbed
water (3–5%); c) the presence of water; d) the presence of ethyl or
methyl acetate; e) the presence of methanol (side product formed
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during the amidation reaction); f) the presence of Novozym 435ꢀ,
methanol and methyl acetate, in order to mimic the situation when
the amidation step has already occurred but the amination step is
just beginning. All these amination reactions were studied using
XANTPHOS as the ligand to form the palladium catalyst, because
with this catalyst the maximum cooperativity was observed.
Whereas most control experiments showed similar or a small
increase in conversion, the presence of 3 equivalents of methanol
surprisingly led to complete conversion after 4 h, with 96%
selectivity for the expected amination product 4a. The most
plausible explanation for the behaviour observed with methanol is
the formation of small amounts of CsOMe in the reaction mixture,
facilitated by the high temperature employed. This methoxide
species is both a better base and more soluble in toluene than
Cs2CO3. As a consequence the rate of the amination reaction
is increased because the base is known to be involved in the
rate-determining step, which is the deprotonation of the Pd–
ammonium intermediate.20,25
1
higher than 80% (GC or H-NMR). In contrast to the cascade
process, the single-step aminations carried out on intermediate
2a, led to poor conversions (<25% after 24 h) indicating a
positive cooperativity effect for all cascades investigated. Anal-
ogous results were obtained in the cascade process using
3-bromobenzylamine (1b) as the starting material and aniline as
the nucleophile (97% conversion of 1b after 24 h, 98% GC selectiv-
ity in the cascade product N-[3-(phenylamino)benzyl]acetamide
(4f)), with the amination step proceeding much faster than in
the reaction with N-(3-bromobenzyl)acetamide (2b) as starting
substrate.
All other results are also explained by this phenomenon. The
presence of 3 equivalents of water, when reaction was carried
out under the same conditions, provided a higher yield (40%
As suggested in the introduction, the validity of this concept
was easily extended to two other Pd-catalyzed coupling reactions;
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Scheme 3 The proposed mechanism for the origin of the dehalogenation product 5.
Scheme 4 Combined amidation and amination reaction using various anilines.
Scheme 5 (a) Combined amidation and Suzuki reaction using Novozym 435ꢀR and a palladium catalyst. (b) Combined amidation and Sonogashira
reaction using Novozym 435ꢀR and a palladium catalyst.
the Suzuki–Miyaura (Scheme 5a) and Sonogashira (Scheme 5b)
reactions. In both cases the conversion of 1a was complete after
Conclusions
20 h whereas the selectivity in the cascade products, 6a and 7a, was
70% and 89%, respectively. This shows that our findings are indeed
rather general as several different chemo-bio cascade processes
were successfully carried out.
In these cascade processes a synergistic effect was obtained
between the two catalytic processes. The origin of this effect
appeared to be an acceleration of the Pd-catalyzed step, mainly due
to the presence of methanol generated during the lipase catalyzed
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amidation reaction. This type of feedback mechanism is also often
observed in Nature, in particular in the metabolic pathways of the
cell, and is a consequence of the complexity of the reaction mixture.
In order to achieve cascade catalytic systems which approach the
complexity of the cell, an alternative approach to one pot catalytic
systems needs to be developed. Importantly, the cooperativity
effect is dependent on the palladium catalyst used and the alcohol
side-product formed, highlighting that the optimal approach to
efficient cascade processes may lie in the study of the system as a
whole from the onset of investigation.
recorded on a Varian INOVA 500 MHz and the data are reported
in ppm. GC analyses were performed on a Shimadzu GC-17A
instrument, column type DB-1 (J & W; 30 m x 0.32 mm).
Mass spectra (EI, 70 eV) were recorded on an Agilent Tech-
nology 6890/5973-GC/MS instrument, column type HP-5 MS
(30 m x 0.25 mm). Melting points were determined using a
ꢀ
C
GALLENKAMP apparatus and they should be considered
estimates.
Amidation reaction on bromobenzylamine
The classical approach to considering complicated processes
normally involves the partitioning of the problem; for cascade pro-
cesses this implies optimizing separate reactions before combining
them (Figure 1). These procedures are only advantageous if the
processes do not interact with each other, i.e in the absence of any
synergy between the systems. An alternative, more counterintu-
itive approach, as demonstrated above, involves an optimization
procedure of the overall cascade process after identification of
a compatibility window. In this case, all factors affecting the
outcome of the reaction are present during the optimization,
which enables a more efficient search for optimal experimental
conditions. As we could extend this cascade process to other
substrates and other reactions we believe that this work represents
a small but important step towards process intensification.
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Bromobenzylamine (1) (1.20 mmol), 200 mg Novozym 435ꢀ, ethyl
acetate (3.60 mmol) and 6 mL toluene were inserted in a Schlenk
flask under argon and the resulting mixture was heated up to
100 C and stirred for 2 h. The mixture was then cooled down,
diluted with ethyl acetate (10 mL) and extracted with 10 mL
of 2% aqueous HCl solution. The water layer was extracted
two times with 10 ml ethyl acetate and the combined organic
layers were washed in sequence with water (10 mL), 5% aqueous
sodium bicarbonate (10 mL), water (10 mL) and then dried on
magnesium sulphate. The solvent was removed in vacuo to provide
N-(bromobenzyl)acetamide (2).
◦
N-(4-Bromobenzyl)acetamide (2a, white solid, 87%). dH
(500 MHz; CDCl3; Me4Si) 7.43 (2H, d, J 8.2), 7.15 (2H, d, J 8.2),
5.75 (1H, bs), 4.37 (2H, d, J 6.0) and 2.02 (3H, s); dC (125.7 MHz;
CDCl3; Me4Si) 170.2, 137.5, 132.0, 129.7, 121.6, 43.3 and 23.5;
m/z (EI) 229 (M◦+, 44%), 227 (47%), 186 (25%), 184 (28%) and 106
(100%); mp 120 C (from ethyl acetate; lit.28 118.5–120 ◦C).
N-(3-Bromobenzyl)acetamide (2b, white solid, 93% isolated
yield). dH (500 MHz; CDCl3; Me4Si) 7.37 (2H, m), 7.17 (2H,
d, J 5), 6.45 (1H, bs), 4.33 (2H, d, J 6) and 1.98 (3H, s); dC (125.7
MHz; CDCl3; Me4Si) 170.5, 141.0, 130.8, 130.7, 130.4, 126.5,
122.9, 43.2 and 23.3; m/z (EI) 229 (M+, 98%), 227 (100%), 186
(56%), 184 (57%) and 106 (100%); mp 79 ◦C (from ethyl acetate).
Amination reaction on N-(4-bromobenzyl)acetamide (2a)
Caesium carbonate (560 mg, 1.72 mmol), the chosen ligand
(0.0367–0.0488 mmol), Pd(dba)2 (14 mg, 0.0244 mmol) and N-(4-
bromobenzyl)acetamide (2a) (275 mg, 1.20 mmol) were inserted
into a Schlenk flask under an argon atmosphere. The system was
then briefly evacuated and backfilled with argon (3 cycles). At this
point the amine nucleophile (1.20 mmol), freshly deoxygenated
toluene (6 mL) and the additive, if required, were inserted into the
Schlenk flask under argon and the resulting mixture was heated
up to 100 ◦C. The reaction was then analyzed by GC.
Fig. 1 Two different approaches to designing and developing a cascade
process.
Experimental section
General considerations
Amination/amidation cascade reaction
Materials. The starting materials were purchased from com-
mercial sources (Acros and Aldrich) and used without further
purification. Methyl acetate-d3 was prepared following a literature
Caesium carbonate (560 mg, 1.72 mmol), Pd(dba)2 (14 mg,
0.0244 mmol), the chosen ligand (L, 0.0366–0.0488 mmol) and
the amine nucleophile (if solid, 1.25 mmol), were inserted into
a Schlenk flask under an argon atmosphere. The system was
then briefly evacuated and backfilled with argon (3 cycles). At
this point freshly deoxygenated toluene (6 mL) was inserted
into the Schlenk flask under argon and the mixture was briefly
stirred (5 seconds). Then bromobenzylamine (1a) (1.20 mmol), the
amine nucleophile (if liquid, 1.25 mmol), ethyl or methyl acetate
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procedure.26 Novozym 435ꢀ was purchased from Aldrich, stored
at +4 ◦C and used as received. Toluene was distilled from
sodium.27 Ethyl acetate and methyl acetate were used directly from
the commercial sources. All experiments were performed using
standard Schlenk flask techniques under an argon atmosphere.
Analytical techniques. Separations were performed on silica
ꢀ
gel (BIOSOLVEC , 60 A, 0.063–0.200 mm). NMR spectra were
(3.60 mmol) and 200 mg Novozym 435ꢀ were inserted into the
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˚
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Schlenk flask under an argon atmosphere. The resulting mixture
was then heated up to 100 ◦C and analyzed by GC. Pure samples of
the final products N-[(phenylamino)benzyl]acetamides (4) could
be obtained by filtering the crude mixtures on celite, concentrating
the filtrates under vacuum and eluting the resulting crude oils on
silica (gradient dichloromethane/methanol from 100:0 to 98:2).
Suzuki/amidation cascade reaction
Phenyl boronic acid (148 mg, 1.21 mmol), potassium fluoride
(188 mg, 3.23 mmol), Pd(dba)2 (12.5 mg, 0.0217 mmol) and
-
PtBu3H+ BF4 (8 mg, 0.0270 mmol) were inserted into a Schlenk
flask under an argon atmosphere. The system was then briefly
evacuated and backfilled with argon (3 cycles). At this point freshly
deoxygenated toluene (6 mL) was inserted into the Schlenk flask
under argon and the mixture was briefly stirred (5 seconds). Then
4-bromobenzylamine (1a) (1.08 mmol), ethyl acetate (3.60 mmol)
N-[4-(Phenylamino)benzyl]acetamide (4a, pale yellow solid).
dH (500 MHz; CDCl3; Me4Si) 7.26 (2H, dd, J 8 and 7.5), 7.14
(2H, d, J 8.5), 7.06 (2H, d, J 8), 7.01 (2H, d, J 7.5), 6.93 (1H,
t, J 7.5), 6.46 (1H, bs), 6.07 (1H, bs), 4.31 (2H, d, J 5.5) and
1.97 (3H, s); dC (125.7 MHz; CDCl3; Me4Si) 170.5, 143.4, 142.8,
130.7, 129.6, 129.2, 121.1, 118.0, 117.9, 43.527 and 23.4; m/z (EI)
240 (M+, 100%), 197 (29%) and 182 (92%); mp 103 ◦C (from
CH2Cl2/MeOH).
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and 200 mg Novozym 435ꢀ were inserted into the Schlenk flask
under an argon atmosphere. The resulting mixture was then heated
up to 100 ◦C and analyzed by GC. A pure sample of the final
product N-[4-phenylbenzyl]acetamide (6a) could be obtained by
filtering the crude mixture on celite, concentrating the filtrate
under vacuum and eluting the resulting crude oil on silica (gradient
dichloromethane/methanol from 100:0 to 98:2).
N-[4-(2-Methylphenylamino)benzyl]acetamide (4b, yellow oil).
dH (500 MHz; CDCl3; Me4Si) 7.21 (2H, d, J 8), 7.15 (3H, m),
6.95 (1H, dd, J 8 and 6.5), 6.91 (2H, d, J 8), 5.92 (1H, bs), 4.34
(2H, d, J 5.5), 2.25 (3H, s) and 2.00 (3H, s); dC (125.7 MHz; CDCl3;
Me4Si) 170.1, 143.8, 141.2, 131.2, 130.1, 129.3, 128.9, 127.0, 122.5,
119.3, 117.6, 43.6, 23.5 and 18.1; m/z (EI) 254 (M+, 100%), 211
(26%) and 196 (81%).
N-[4-Phenylbenzyl]acetamide (6a; light brown solid). dH
(500 MHz; CDCl3; Me4Si) 7.57 (4H, m), 7.45 (2H, t, J 7.5),
7.36 (3H, m), 5.73 (1H, bs), 4.49 (2H, d, J 5.5) and 2.06 (3H,
s); dC (125.7 MHz; CDCl3; Me4Si) 170.3, 140.9, 140.8, 137.4,
129.0, 128.6, 127.7, 127.6, 127.3, 43.7 and 23.5; m/z (EI) 225
(M+, 100%) and 182 (66%); mp 182 ◦C (from CH2Cl2/MeOH;
lit.29 180–182 ◦C).
N-[4-(4-Methoxyphenylamino)benzyl]acetamide (4c, white
solid). dH (500 MHz; CDCl3; Me4Si) 7.12 (2H, d, J 8.5), 7.06
(2H, bs), 6.86 (4H, m), 5.78 (1H, bs), 4.33 (2H, bs), 3.80 (3H, s)
and 2.00 (3H, s); dC (125.7 MHz; CDCl3; Me4Si) 170.0, 155.7,
144.9, 135.7, 129.4, 122.5, 115.9, 114.9, 55.8, 43.6 and 23.5; m/z
(EI) 270 (M+, 100%), 255 (43%), 227 (11%) and 212 (40%); mp
121–123 ◦C (from CH2Cl2/MeOH).
Sonogashira/amidation cascade reaction
Caesium carbonate (560 mg, 1.72 mmol), 2-(ditertbutyl-
phosphino)biphenyl (22.5 mg, 0.0756 mmol), Pd(dba)2 (15.5 mg,
0.0270 mmol) were inserted into a Schlenk flask under an argon
atmosphere. The system was then briefly evacuated and backfilled
with argon (3 cycles). At this point freshly deoxygenated toluene
(6 mL) was inserted into the Schlenk flask under argon and the
mixture was briefly stirred (5 seconds). Then 4-bromobenzylamine
(1a) (1.08 mmol), phenylacetylene (1.51 mmol), methyl acetate
N-[4-(3-Nitrophenylamino)benzyl]acetamide (4d, red solid). dH
(500 MHz; CDCl3; Me4Si) 7.83 (1H, t, J 2), 7.70 (1 H, dd, J 8
and 2), 7.37 (1H, t, J 8), 7.27 (3H, m), 7.11 (2H, d, 8.5), 6.06
(1H, bs), 5.81 (1H, bs), 4.41 (2H, d, J 5.5) and 2.05 (3H, s);
dC (125.7 MHz; CDCl3; Me4Si) 170.1, 149.9, 145.2, 140.6, 133.2,
130.3, 129.6, 122.1, 120.3, 115.0, 110.4, 43.6 and 23.6; m/z (EI)
(M+, 100%), 268 (81%), 242 (46%) and 227 (66%); mp 158 ◦C
(from CH2Cl2/MeOH).
R
(3.60 mmol) and 200 mg Novozym 435ꢀ were inserted into the
Schlenk flask under an argon atmosphere. The resulting mixture
was then heated up to 100 ◦C and analyzed by GC. A pure sample
of the final product N-[4-(2-phenylethynyl)benzyl]acetamide (7a)
could be obtained by filtering the crude mixture on celite,
concentrating the filtrate under vacuum and eluting the resulting
crude oil on silica (gradient dichloromethane/methanol from
100:0 to 98:2).
N-[4-(3-Fluorophenylamino)benzyl]acetamide (4e, yellow oil).
dH (500 MHz; CDCl3; Me4Si) 7.17 (3H, m), 7.06 (2H, d, J 8.5), 6.74
(2H, m), 6.58 (1H, m), 5.92 (2H, bs), 4.35 (2H, d, J 5.7) and 2.01
(3H, s); dC (125.7 MHz; CDCl3; Me4Si) 170.2, 164.0 (d, J 244),
145.4 (d, J 11.8), 141.7, 131.8, 130.7 (d, J 9.7), 129.3, 119.3, 112.8,
107.2 (d, J 20.7), 103.7 (d, J 24.4), 43.5 and 23.5; dF (470.5 MHz;
CDCl3; CFCl3) -112.2; m/z (EI) 258 (M+, 100%), 215 (31%) and
200 (74%).
N-[4-(2-Phenylethynyl)benzyl]acetamide (7a; light brown solid).
dH (500 MHz; CDCl3; Me4Si) 7.53 (2H, m), 7.50 (2H, d, J 8.0),
7.35 (3H, m), 7.26 (2H, d, J 8.0), 5.81 (1H, bs), 4.45 (2H, d, J
6.0) and 2.04 (3H, s); dC (125.7 MHz; CDCl3; Me4Si) 170.1, 138.7,
132.1, 131.8, 128.6, 128.5, 128.0, 123.4, 122.8, 89.8, 89.2, 43.7 and
23.5; m/z (EI) 249 (M+, 100%), 206 (66%), 191 (30%) and 178
(31%); mp 156 ◦C (from CH2Cl2/MeOH).
N-[3-(Phenylamino)benzyl]acetamide (4f, pale yellow solid). dH
(500 MHz; CDCl3; Me4Si) 7.27 (2H, dd, J 8.5 and 7.5), 7.21 (1H,
t, J 7.5), 7.07 (2H, d, J 8.5), 6.99 (1H, d, J 8), 6.94 (2H, m), 6.81
(1H, d, J 7.5), 6.04 (1H, bs), 5.88 (1H, bs), 4.35 (2H, d, J 6) and
1.99 (3H, s); dC (125.7 MHz; CDCl3; Me4Si) 170.3, 143.9, 143.0,
139.8, 129.9, 129.6, 121.5, 120.2, 118.4, 117.0, 116.5, 43.968 and
23.465; m/z (EI) 240 (M+, 100%), 197 (58%) and 180 (20%); mp
135–137 ◦C (from CH2Cl2/MeOH).
Acknowledgements
The authors would like to acknowledge fruitful discussions with
Professor Roeland J.M. Nolte (University of Nijmegen) and
Professor Piet W.N.M. van Leeuwen (University of Amsterdam),
and NWO-ACTS and Synthon BV for financial support.
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The Royal Society of Chemistry 2009
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15 K. Faber, in Biotransformation in Organic Chemistry, 5th ed.; Springer-
Verlag, Berlin (Germany), 2004.
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