Poly(methylhydrosiloxane) as a green reducing agent in organophosphorus-catalysed amide bond formation

Article abstract of DOI:10.1039/c7ob01510k

Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green reducing agent for in situ reduction of phosphine oxide to phosphine. The reported method enables the synthesis of a wide range of secondary and tertiary amides in very good to excellent yields.

Full text of DOI:10.1039/c7ob01510k

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Poly(methylhydrosiloxane) as a green reducing agent in
organophosphorus-catalysed amide bond formation
Daan F. J. Hamstra, Danny C. Lenstra, Tjeu J. Koenders, Floris P. J. T. Rutjes and Jasmin Mecinović*
Received 00th January 20xx,
Accepted 00th January 20xx
Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past
decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic
acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green
reducing agent for in situ reduction of phosphine oxide to phosphine. The reported method enables the synthesis of a
wide range of secondary and tertiary amides in very good to excellent yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Over the past decade, there has been a significant interest in
the development of catalytic versions of phosphine-mediated
reactions that are often used in organic synthesis, including
the Staudinger, Mitsunobu, Wittig and Appel reactions.1 The
formation of the relatively strong phosphine oxide bond (P=O,
128 kcal mol-1) is the driving force for the classic versions of
these commonly used reactions.1a However, the formation of
stoichiometric amounts of high molecular weight phosphine
oxide waste is highly undesired, as it results in poor overall
atom economy, and is often difficult to remove from the
desired products. In this regard, the organophosphorus-
catalysed reactions heavily rely on the efficient reduction of
phosphine oxides to phosphines. Recent reports have shown
that organophosphorus catalysis can be achieved by i)
activation of phosphine species, in this case the oxidation state
PV remains unaffected throughout the reaction2 or ii) PIII/PV
redox chemistry, i.e. the formed phosphine oxide (PV) is
reduced in situ to the corresponding phosphine (PIII).3
In the latter case, silanes, such as phenylsilane and
diphenylsilane, have been typically employed as reducing
agents due to their high reactivity and chemoselective nature.4
In PIII/PV redox organophosphorus catalysis 5-membered cyclic
phosphine oxides are generally used as pre-catalysts (Scheme
1). Cyclic phosphine oxides are more prone to reduction in
comparison to triphenylphosphine oxide, whilst the
corresponding cyclic phosphines (PIII) remain their nucleophilic
character against several types of electrophilic reagents, and
are therefore still able to effectively mediate various
transformations. For example, O’Brien et al. employed 3-
methyl-1-phenylphospholane-1-oxide 1 in the first
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organophosphorus-catalysed Wittig reaction.5 Diphenylsilane
Next, we tested phosphine oxides that were previously
was used to selectively reduce
alkene products remained unaffected by the
(Scheme 1). In situ reduction of dibenzophosphole oxide,
formed from , with diphenylsilane in a catalytic Appel reaction conditions. We were pleased that five-membered
reaction was first reported by van Delft et al. (Scheme 1).6 phosphine oxides
, and possess redox properties that are
Dibenzophosphole was later also used in the compatible with PMHS-mediated reduction (Table 1, entries 7–
organophosphorus-catalysed Staudinger reduction.7 Other 5- 9). Saturated phosphine oxides
and afforded 47% and 61%
membered cyclic phosphines that have been demonstrated to of the amide under standard conditions. Notably, we were
catalyse important chemical transformations include phenyl particularly pleased to observe that the commercially available
1
, while starting aldehyde and used in other well known organophosphorus-catalysed
-Ph2SiH2 system reactions (Scheme 1). A combination of the fused phospholane
and PMHS provided only 30% of amide under standard
1
2
5
2
1,
3
4
2
1
3
5
phospholane oxide
3
,
which was used in the catalytic 3-methyl-1-phenyl-2-phospholene oxide
4
, afforded the amide
Mitsunobu reaction,8 and phospholene oxide
diaza-Wittig reaction (Scheme 1).9
4
in the catalytic
5 in excellent 82% NMR yield (Table 1, entry 9).
Although numerous procedures for the synthesis of amide Table 1 Optimisation of organophosphorus-catalysed amide
bonds are well known and described in literature, most rely on bond formation.a
the use of stoichiometric amounts of reagents.10 In order to
circumvent large amounts of unwanted waste (typically ureas),
the past decade has witnessed a great success in development
of efficient metal-11 and organocatalysed12 amide bond
formation reactions, starting from readily available starting
materials.
O
O
H2N
conditions
OH
N
H
O2N
O2N
5
NMR
Yieldc
48
Entry
Catalyst
Reagentb
1
2
Ph3P
PMHS390(9)/phosphate
PMHS390(9)/phosphate
PMHS390(9)/phosphate
PMHS390(9)/phosphate
PMHS390(9)/phosphate
PMHS390(9)/phosphate
PMHS390(9)/phosphate
PMHS390(9)/phosphate
PMHS390(9)/phosphate
TMDS(9)/phosphate
PMHS10k(9)/phosphate
PMHS2450(9)/phosphate
PMHS2450(6)/phosphate
PMHS2450(12)/phosphate
PMHS2450(9)/phosphate
PMHS2450(9)/phosphate
-
We have recently reported that unactivated carboxylic
acids and amines undergo Ph3P-catalysed direct amidation in
the presence of 2 equiv. of CCl4, 1.5 equiv. of (EtO)2MeSiH and
catalytic amounts (5 mol%) of bis(p-nitrophenyl) phosphate.12f
We envisioned that it would be beneficial to develop a
"greener" version of direct amidation of carboxylic acids using
an environmentally benign and cheap silane, instead of more
reactive methyldiethoxysilane, as a reducing agent for the vital
conversion of phosphine oxide to phosphine that provides the
key step in catalysis.
Ph3PO
36
3
(p-MePh)3P
50
4
(p-MeOPh)3P
46
5
(C6F5)3P
15
6
2
1
3
4
4
4
4
4
4
30
7
47
8
61
9
82
10
11
12
13
14
15
16
17
18
19d
20
21e
79
53
92
Results and discussion
74
Poly(methylhydrosiloxane) (PMHS) was considered as an
attractive candidate due to its low cost and environmentallly
friendly characteristics.13 It has been previously shown for
related organophosphorus-catalysed reactions that by
implementing PMHS, major reductions in cumulative energy
demand (CED) and greenhouse gas (GHG) emmisions can be
achieved.14 In a model reaction, p-nitrobenzoic acid and
benzylamine reacted in the presence of 0.25 equiv. of Ph3P,
2.0 equiv. of CCl4, 9 Si-H equiv. of poly(methylhydrosiloxane)
(PMHS, Mw 390 Da) and 0.05 equiv. of bis(p-nitrophenyl)
phosphate at 110 °C in toluene to yield 48% of N-benzyl-p-
73
4
4
(15 mol%)
82
(10 mol%)
62
4
4
-
trace
67
PMHS2450(9)
PMHS2450(9)
13
-
PMHS2450(9)/phosphate
PMHS2450(9)/phosphate
26
-
33
a
Conditions: p-nitrobenzoic acid (0.5 mmol), benzylamine 0.65 mmol),
phosphine (oxide) (0.125 mmol, 25 mol%), CCl4 (1.0 mmol), PMHS (0.12
mmol.; 9 Si-H eq.), bis(p-nitrophenyl) phosphate (0.025 mmol), 2.5 mL
nitrobenzamide
5 (Table 1, entry 1). Use of Ph3PO instead of
b
toluene, 110 °C, 20h.
PMHS = poly(methylhydrosiloxane); average
molecular weight in subscript, Si-H equivalents in parenthesis. c NMR yield
Ph3P afforded 36% of the amide under standard conditions,
indicating that an additional reduction step at the beginning of
the catalytic cycle lowers the overall yield of the amidation
reaction (Table 1, entry 2). Various phosphines that possess
either electron-donating or electron-withdrawing groups were
then tested, because we conceived that fine-tuning the
electronics of the P=O bond could have a significant effect on
the rate of silane-mediated phosphine oxide reduction.
Different Ph3P derivatives, however, did not improve the yield
of the model reaction (Table 1, entries 3–5).
d
(%) determined using tri-tert-butylbenzene as an internal standard.
Reaction performed without CCl4. e 15 mol% phosphate.
PMHS is available in various lengths, therefore we tested
whether the shortest analog tetramethyldisiloxane (TMDS,
Table 1, entry 10) and longer analogs, with average molecular
weights of 10 kDa and 2450 Da (Table 1, entries 11 and 12)
resulted in improved yields of the amide bond formation.
Similar yields were obtained for TMDS and PMHS (Mw 390),
2 | J. Name., 2012, 00, 1-3
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whereas longer PMHS (Mwavg 2450) afforded the amide in
substantially increased 92% yield. The longest PMHS analog,
with an average molecular weight of 10 kDa, only afforded
Table 2 Organophosphorus-catalysed amide bond formation of
various carboxylic acids.
53% of amide 5. Decreasing or increasing the amount of PMHS
resulted in lower NMR yields; 6 and 12 hydride equiv. of PMHS
afforded 74 and 73% of the target amide, respectively (Table 1,
entries 13 and 14). Employing lower amounts (15 mol% and 10
mol%) of phosphine oxide
4 resulted in slightly decreased, but
still very good yields of the desired amide (82% and 62%)
(Table 1, entries 15 and 16). When the model reaction was
carried out in the absence of PMHS/phosphate, we detected
only traces of the target amide in 1H NMR spectra (Table 1,
entry 17). Importantly, when the model reaction was
performed without bis(p-nitrophenyl) phosphate, only 67% of
amide was obtained; this result demonstrates the positive
contribution of phosphate to the overall yield (Table 1, entry
18). Due to the fact that silanes have the ability to promote
direct amidation of carboxylic acids,15 we also examined
potential PMHS-mediated formation of the target amide
5
under standard conditions. In the presence of PMHS, p-
nitrobenzoic acid and benzylamine yielded only 13% of amide
(Table 1, entry 19); the observed low yield is comparable with
our previously observed formation of the amide (9%), when
only p-nitrobenzoic acid and benzylamine were heated in
toluene at 110 °C.12f Moreover, in the presence of CCl4, PMHS,
and phosphate, a small amount of amide was formed: 26% in
the presence of 5 mol% phosphate, and 33% with 15 mol%
phosphate (Table 1, entries 20 and 21).
The most optimal ratios of the reagents (Table 1, entry 12)
served as a base for additional experiments in which we
examined the role of the solvent, reaction time, and the
amount of amine on the catalytic reaction. Among common
and high boiling point solvents, toluene was found to be the
preferred one; 42–52% of the amide
5 was formed in n-
heptane, 1,4-dioxane and o-xylene (Table S1). Due to fewer
catalytic cycles, shorter reaction times also resulted in lower
yields (Table S2). Increasing or decreasing the equivalents of
benzylamine in the reaction resulted in decreased yields: 81%
amide with 1.1 equiv. benzylamine and 72% amide with 2.0
equiv. benzylamine (Table S3).
a
b
Isolated yield, 15 mol% pre-catalyst 4. Isolated yield, 25 mol% pre-
catalyst 4.
acid, 70% of the corresponding amide was obtained (Table 2,
14). The reaction between benzylamine and disubstituted
m-chloro-p-trifluoromethoxybenzoic acid proceeded very well
and afforded the corresponding disubstituted benzamide in
excellent 89% yield (Table 2, 15). Heteroaromatic carboxylic
acids, such as picolinic acid and nicotinic acid, also underwent
organophosphorus-catalysed amide bond formation in
excellent 99% and 77% yields, respectively (Table 2, 16 and
17). Furan-2-carboxylic acid and electron-deficient 5-
nitrofuran-2-carboxylic acid reacted with benzylamine under
standard conditions to provide 65% and 56% of the desired
amides, respectively (Table 2, 18 and 19). In general,
organophosphorus-catalysed reaction in the presence of 25
With the optimised reaction conditions in hand, we set out
to explore the scope of the reaction with both 15 and 25 mol%
of phosphine oxide
4
(Tables 2 and 3). N-Benzylbenzamide
6
was obtained in 76% isolated yield with 15 mol% of
4, while
increasing the catalyst loading to 25 mol% afforded 80% of
amide
6. Various para-substituted benzoic acid derivatives,
bearing
electron-donating and electron-withdrawing
functional groups, were reacted with benzylamine (Table 2,
12). In general, very good to excellent isolated yields were
obtained with both 15 mol% and 25 mol% of . The formed
7-
4
benzamides that bear various halogen substituents at the
aromatic ring could be further functionalised employing well
established cross-coupling reactions. A moderate yield of 62%
was obtained for o-nitrobenzoic acid in the presence of 15
mol% of
4
resulted in increased isolated yields (on average
~15%) of amides, when compared to reactions that used 15
mol% of
4 (Table 2). Aliphatic carboxylic acids were not
mol% of
4
, whereas the yield increased significantly (79%) in
(Table 2, 13). For m-nitrobenzoic
examined, because they undergo direct amidation at elevated
temperatures.11a
the presence of 25 mol% of
4
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We further explored the scope of the reaction by formation also tolerates the use of secondary amines, as
examining various amines with p-nitrobenzoic acid under tertiary amides derived from piperidine and morpholine were
optimised conditions (Table 3). Primary aliphatic amines, such prepared in 74% and 73% yields, respectively (Table 3, 31 and
as
phenethylamine,
p-chlorobenzylamine, 32). Notably, no reduction of tertiary amide 32 to the
p-methoxybenzylamine, and cycloalkylamines with various ring corresponding tertiary amine was observed under our reaction
size, yielded amides in very good yields, ranging from 62 to conditions. Acyclic dipropylamine also reacted under standard
82% (Table 3, 20
sterically hindered 1-adamantylamine, which afforded the 67% isolated yield. Aniline, the simplest example of arylamine,
corresponding amide 26 with yield of 61%. yielded 56% of amide 34, the result that is likely due to the
–25). The reaction also proceeded well with conditions to afford the corresponding tertiary amide 33 with
a
Thiophenemethylamine and furfurylamine gave moderate decreased nucleophilicity of the amine group; our previously
yields of 63%, and 59%, respectively (Table 3, 27 and 28). As established method only afforded 25% of the same isolated
expected, with racemic and enantriomerically pure amide.12f Introducing a p-methoxy substituent on aniline
1-phenylethylamine similar yields of amide were obtained: increases the nucleophilicity of the amine functionality, and
65% (R,S) and 63% (S), respectively (Table 3, 29 and 30). We indeed p-anisidine gave a slightly increased yield of 65% amide
were pleased to find that the reaction proceeds with virtually 35. Again, use of 25 mol%, instead of 15 mol%, of
4 led to
complete retention of configuration (>98%), as confirmed by increased yields (
~
15%) of amides (Table 3).
chiral HPLC analyses (Figures S1 and S2). Amide bond
Table 3 Organophosphorus-catalysed amide bond formation of
various amines.
O
4 (0.15 or 0.25 eq.),
CCl4 (2.0 eq.), PMHS (9 Si-H eq.)
OH
O
a)
phosphate (0.05 eq.)
R3
O2N
N
+
R3
R2
toluene (2.5 mL)
reflux, 20 h
HN
R2
O2N
O
O
O
R1
N
R1
N
R1
N
H
H
H
Cl
OMe
20: 73%[a] (85%[b]
)
21: 65%
22: 63% (78%)
(72%)
O
O
O
H2
H2'
R1
N
H
R1
N
R1
N
H
H
23: 82%
24: 67% (77%)
25: 62% (80%)
100
80
60
40
20
0
O
O
O
PMHS + phosphate
PMHS
b)
R1
N
S
O
R1
N
H
R1
N
H
H
26: 61% (72%)
27: 63% (79%)
28: 59% (85%)
O
O
O
R1
N
H
R1
N
H
R1
N
O
29: 65% (76%)
30: 63% (73%)
31: 73% (92%)
O
0
20
40
60
80
100
120
X
O
O
R1
N
Time (min.)
R1
N
R1
N
H
Figure 1 a) Stacked 1H NMR spectra showing the reduction of 4 to 4a
in the presence of PMHS and bis(p-nitrophenyl) phosphate and b)
conversion of 4 to 4a plotted against time in the presence of PMHS
and bis(p-nitrophenyl) phosphate (black squares), and just PMHS
(red dots).
32: 74% (95%)
33: 67% (71%)
34 (X = H):
35 (X = OMe): 65% (69%)
56% (77%)
a
b
Isolated yield, 15 mol% pre-catalyst 4. Isolated yield, 25 mol% pre-
catalyst 4.
4 | J. Name., 2012, 00, 1-3
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In comparision with our recently reported amidation
reaction that is based on the Ph3P-(EtO)2MeSiH system,[12f] the
method reported here possesses three advantages: i) it uses
the environmentally benign and cheap PMHS as a reducing
agent; ii) it uses a low catalyst loading of 15 mol% of
O
R3
O
Ph
R1
N
R2
P
PMHS,
phosphate
R2
H
phosphine oxide
4 (instead of 25 mol% of Ph3P); and iii)
N
R3
pre-catalyst
despite using a lower catalyst loading and requiring an
additional reduction step at the beginning of the catalytic
cycle, the isolated yields for various amides are significantly
4
O
higher (on average
version of the reaction.
The rate of reduction of phosphine oxide
~
15%) when compared with the first
Ph
P
O
R1
4c
Ph
P
4
to the
4a
corresponding phosphine 4a by PMHS and bis(p-nitrophenyl)
phosphate was also investigated. For this purpose in situ
quantitative variable-temperature (VT) 1H NMR spectroscopy
(Figures 1, S3, and S4) was used because i) we observed a
precipitation of phosphine species when the reaction mixture
was cooled to room temperature and subsequently analysed in
room temperature NMR experiments and ii) the rate of
reduction was too high for detailed analyses by in situ
quantitative VT 31P NMR spectroscopy. The ratios between two
CCl4
Cl
Ph
P
O
R1 OH
4b
distinct peaks of the starting phosphine oxide
'
4
(H2 δ 5.55
ppm) and the formed phosphine 4a (H2 δ 5.70 ppm) were
followed over time (Figure 1a). In line with our results that
show that a combination of
phosphate leads to very efficient amide bond formation, we
observed almost complete conversion of phosphine oxide to
4 and PMHS/bis(p-nitrophenyl)
corresponding phosphine 4a in the presence of PMHS and
bis(p-nitrophenyl) phosphate. Phosphine 4a then reacts with
carbon tetrachloride (CCl4) to form the chlorophosphonium
intermediate 4b that possesses the PV oxidation state.
4
the corresponding phosphine 4a within 90 minutes at 100 °C in
toluene (Figure 1b). In the absence of phosphate, however,
Nucleophilic substitution of 4b by
a carboxylate anion
only 40% of phosphine oxide 4 was reduced to phosphine 4a
~
subsequently leads to a new intermediate 4c, in which the
carboxylate is now converted into a good leaving group. The
formed 4c is susceptible towards nucleophilic attack by an
amine, thereby forming the desired amide product and
(Figure 1b), the result that is consistent with our
organophosphorus-catalysed amidation reaction (Table 1,
entry 18). It is noteworthy that Beller and coworkers
demonstrated that bis(p-nitrophenyl) phosphate is essential
for (EtO)2MeSiH-mediated reduction of phosphine oxides to
corresponding phosphines.4b As expected, we observed that
phosphine oxide
4
. It is also possible that 4c first reacts with
and acyl chloride,16 which then reacts
chloride ion to yield
4
with amine to afford the amide product. The formed
subsequently used in the new catalytic cycle.
4 is
the rate of PMHS/phosphate-mediated reduction of
4 is even
higher at 110 °C (>95% in 20 minutes, Figure S5), the
temperature at which the presented amidation reaction is
performed.
Conclusions
Although there is in principle a possibility that the reported
reaction involves the formation of silyl chloride and/or silyl
ester via an alternative pathway, our VT NMR experiments
demonstrate that the rate of the PMHS-mediated reduction of
In conclusion, we have developed
a green version of
organophosphorus-catalysed amide bond formation between
unactivated aromatic carboxylic acids and amines. The
commercially available pre-catalyst 3-methyl-1-phenyl-2-
phosphine oxide
4 into phosphine 4a is compatible with the
phospholene oxide
4 is reduced in situ by inexpensive and
yields of the formed amide products. We were not able to
detect any clear formation of silyl chloride or related silyl ester
in 1H and 29Si NMR spectra of the reaction mixture. In addition,
environmentally benign poly(methylhydrosiloxane) and bis(p-
nitrophenyl) phosphate. With our newly developed method a
wide variety of secondary and tertiary amides could be
synthesised in very good to excellent yields. It is envisioned
that organophosphorus catalysis will be a subject of extensive
investigations in the upcoming years. Moreover, we believe
that poly(methylhydrosiloxane) will find practical applications
in several other common reactions in organic chemistry.
1
we did not detect any formation of H2 in H NMR during the
catalytic reaction,15b a result that furthermore suggests that
silyl ester is not formed during the reported
organophosphorus-catalysed amide bond formation reaction.
Based on methodological and mechanistic investigations of
related organophosphorus-catalysed reactions, our 1H NMR
studies, and control experiments, a proposed catalytic cycle is
outlined in Scheme 2. First, a pre-catalyst 4 is reduced to the
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Lin, Org. Lett., 2016, 18, 3758-3761; (l) M. L. Schirmer, S.
Adomeit and T. Werner, Org. Lett., 2015, 17, 3078-3081.
(a) D. Herault, D. H. Nguyen, D. Nuel and G. Buono, Chem. Soc.
Rev., 2015, 44, 2508-2528; (b) Y. H. Li, L. Q. Lu, S. Das, S.
Pisiewicz, K. Junge and M. Beller, J. Am. Chem. Soc., 2012, 134,
18325-18329; (c) M. Mehta, I. Garcia de la Arada, M. Perez, D.
Porwal, M. Oestreich and D. W. Stephan, Organometallics,
2016, 35, 1030-1035; (d) M.-L. Schirmer, S. Jopp, J. Holz, A.
Spannenberg and T. Werner, Adv. Synth. Catal., 2016, 358, 26-
29.
C. J. O'Brien, J. L. Tellez, Z. S. Nixon, L. J. Kang, A. L. Carter, S. R.
Kunkel, K. C. Przeworski and G. A. Chass, Angew. Chem. Int. Ed.,
2009, 48, 6836-6839.
H. A. van Kalkeren, S. H. A. M. Leenders, C. R. A. Hommersom, F.
P. J. T. Rutjes and F. L. van Delft, Chem. Eur. J., 2011, 17, 11290-
11295.
Experimental
A Radleys tube equipped with a magnetic stirbar was charged
4
with carboxylic acid (0.5 mmol, 1.0 equiv.), phosphine oxide
4
(0.075 mmol or 0.125 mmol; 0.15 or 0.25 equiv.), and bis(p-
nitrophenyl) phosphate (0.025 mmol, 0.05 equiv.).
Subsequently toluene (2.5 mL, 0.2 M) was added, and to the
formed suspension were added benzylamine (0.65 mmol, 1.3
equiv.),
CCl4
(1.0
mmol,
2.0
equiv.),
and
poly(methylhydrosiloxane) (Mw 2450 Da, 0.12 mmol, 9 Si-H
equiv.). The reaction was stirred at 110 °C for 20 hours. After
cooling to room temperature, toluene was removed under
reduced pressure and the crude product was resuspended in
ethyl acetate (20 mL). The organic phase was washed with sat.
aqueous NaHCO3 (2 x 20 mL), brine (1 x 20 mL), dried over
Na2SO4, filtered, and evaporated. The crude product was
purified by silica column chromatography (ethyl acetate and n-
heptane) to afford the desired amide.
5
6
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Table of contents
In situ reduction of phosphine oxide by poly(methylhydrosiloxane) leads to efficient
amidation reaction between carboxylic acids and amines.