1,3,2-Diazaphospholenes Catalyze the Conjugate Reduction of Substituted Acrylic Acids

Article abstract of DOI:10.1002/cctc.202000662

The potent nucleophilicity and remarkably low basicity of 1,3,2-diazaphospholenes (DAPs) is exploited in a catalytic, metal-free 1,4-reduction of free α,β-unsaturated carboxylic acids. Notably, the reduction occurs without a prior deprotonation of the carboxylic acid moiety and hence does not consume an additional hydride equivalent. This highlights the excellent nucleophilic character and low basicity of DAP-hydrides. Functional groups such as Cbz group or alkyl halides which can be problematic with classical transition-metal catalysts are well tolerated in the DAP-catalyzed process. Moreover, the transformation is characterized by a low catalyst loading, mild reaction conditions at ambient temperature as well as fast reaction times and high yields. The proof-of-principle for a catalytic enantioselective version is described.

Full text of DOI:10.1002/cctc.202000662

The European Society Journal for Catalysis
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Accepted Article
Title: 1,3,2-Diazaphospholenes Catalyze the Conjugate Reduction of
Substituted Acrylic Acids
Authors: Nicolai Cramer and John H. Reed
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01/2020

10.1002/cctc.202000662
ChemCatChem
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1,3,2-Diazaphospholenes Catalyze the Conjugate Reduction of
Substituted Acrylic Acids
John H. Reed and Nicolai Cramer*
[*]
J. H. Reed, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: https://www.epfl.ch/labs/lcsa/
Supporting information for this article is given via a link at the end of the document.
Abstract: The potent nucleophilicity and remarkably low basicity of
1,3,2-diazaphospholenes (DAPs) is exploited in a catalytic, metal-free
1,4-reduction of free α,β-unsaturated carboxylic acids. Notably, the
reduction occurs without a prior deprotonation of the carboxylic acid
moiety and hence does not consume an additional hydride equivalent.
This highlights the excellent nucleophilic character and low basicity of
DAP-hydrides. Functional groups such as Cbz group or alkyl halides
which can be problematic with classical transition-metal catalysts are
well tolerated in the DAP-catalyzed process. Moreover, the
transformation is characterized by a low catalyst loading, mild reaction
conditions at ambient temperature as well as fast reaction times and
high yields. The proof-of-principle for a catalytic enantioselective
version is described.
Figure 1. 1,3,2-Diazaphospholenes exhibit Umpolung reactivity of the P–H
bond leading to molecular hydrides that are competent reducing agents.
Non-steroidal anti-inflammatory drugs (NSAIDs) of the aryl
propionic acid class such as ibuprofen, naproxen or flurbiprofen[17]
are important drugs and could be accessed by a conjugate
reduction of corresponding substituted acrylic acids (Scheme 1).
Generally, a variety of homo- and heterogeneous transition-metal
catalyzed processes are reported for the direct hydrogenation of
substituted acrylic acids.[18-20] However, the inherent acidic nature
of a carboxylic acid presents a challenge for the development of
hydridic, metal-free alternatives. Of further note is the propensity
for carboxylic acids to undergo reduction at the carbonyl
carbon.[21] Therefore, a catalyst carrying a hydride with excellent
nucleophilicity and low basicity, capable of selectively delivering
the hydride faster than it deprotonates the acid, is desirable.
Herein, we report the direct conjugate reduction of α,β-
Reduction reactions constitute some of the most industrially and
academically important organic transformations.[1] For instance,
the selective conjugate reduction of widely distributed α,β-
unsaturated carbonyl compounds provides an economical means
to access value-added chemicals from readily available
substrates.[2] Numerous catalytic systems have been established
to facilitate such transformations.[3] These methodologies
commonly rely on the combination of a transition-metal catalyst
and a stoichiometric reductant such as H2.[4,5] In order to
circumvent the costs, environmental impact and purification
issues that may be associated with the use of rare transition-
metals, the search for efficient metal-free catalyst systems has
garnered growing interest.[6] Among a wide variety of metal-free
approaches,[7] including frustrated Lewis pairs (FLPs),[8] and
Hantzsch esters with amine catalysts[9] have emerged. In this
context, the ability of 1,3,2-diazaphospholenes (DAPs)[10] to
catalyze the reduction of functional groups such as aldehydes and
ketones,[11a] imines,[11b] pyridines,[11c,d] azobenzenes,[11e] and
CO2,[11f] has been recently discovered (Figure 1). Moreover, DAPs
display a profound selectivity for the 1,4-reduction of α,β-
unsaturated carbonyl compounds.[12,13] Further advances have
been made by developing chiral DAPs capable of
stereoselectively reducing prochiral substrates.[14] This reactivity
results from the Umpolung of the P–H bond of DAPs, which in turn
is a consequence of the partial delocalization of the 6π electrons
of the 5-membered ring.[15] Increased electron density in the σ*-
orbital of P–H bond simultaneously weakens the bond and
induces a reversal of the typical bond polarity. Cheng and co-
workers reported that the prototypical DAP (P1) is the most
nucleophilic hydride donor ever quantified on the Mayr
nucleophilicity scale.[16] We hypothesized that this remarkable
property should be leveraged to facilitate more challenging
hydride additions.
unsaturated carboxylic acids using
a
DAP-catalyst and
phenylsilane as the stoichiometric reductant.
Scheme 1. Aryl propionic acid NSAIDs are a biologically important class of
compounds; DAP-catalyzed metal-free conjugate reduction strategy.
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10.1002/cctc.202000662
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We commenced our investigations by studying the reduction of 2-
phenylacrylic acid (1a). The combination of DAP precatalyst P2
and pinacol borane as the terminal reductant in THF cleanly
provided 2-phenylpropionic acid (2a), in 93 % yield after just 10
minutes (Table 1, entry 1). We next examined whether other
convenient hydride sources such as silanes could also serve as
the terminal reductants. No conversion was observed when using
with Ph2SiH2 in combination with P2 (entry 2). However, switching
to pre-catalyst P3, bearing an acetate group instead of the
benzyloxy substituent on the phosphorous atom, complete
conversion of 1a was observed, furnishing 2a in 85 % yield (entry
3). Interestingly, while both Ph2SiH2 and PhSiH3 (87 %, entry 4)
delivered the desired product in excellent yields, no other silane,
including related Ph3SiH, gave any conversion at all (see SI for
full optimization). For both Ph2SiH2 and PhSiH3, all available
hydrides of the silane were able to induce catalyst turnover (0.35
eq. PhSiH3 corresponding to 1.05 hydride equivalents) (entry 5).
Selecting PhSiH3 as the reducing agent of choice, we examined
the effects of different solvents on the reaction outcome (entries
6-8). Complete consumption of starting material 1a occurred in
toluene or acetonitrile, although a significant decrease in yield of
2a was observed in the latter. Conversely, using Et2O caused a
dramatic decrease in the rate of catalyst turnover, with only 64 %
conversion observed, giving 2a in low yield (37 %). In contrast,
the catalyst loading could be reduced to 2 mol % in THF and full
conversion was maintained after 2 hours (97 % yield of, entry 9).
A control experiment with no catalyst resulted in complete
recovery of 1a (entry 10). When run on a gram scale (10 mmol
substrate 1a), the catalyst loading could be reduced to 0.5 mol%
(entry 11). The transformation maintained its excellent efficiency,
giving product 2a in quantitative isolated yield without the need
for temperature control (no heating or cryogenic conditions).
both the C-2 and C-3 positions of acrylic acids 1, leading to
propionic acids 2a-2u (Scheme 2). Products 2b and 2c, bearing
alkyl substitution at the C-2 position were accessed in excellent
yields. Trifluoromethylated derivative 2d was also well tolerated
in the reaction. Halo-substituted substrates 1e and 1f were
converted in excellent yields to corresponding saturated α-halo
acids 2e and 2f. Notably, no observable traces of elimination or
reduction of the C–X bond was detected. Ester groups were
equally well tolerated, permitting for instance access to 2g in 98
% yield. A second free carboxylic acid on the substrate proved to
be neither a hindrance to the reaction nor consumed a hydride
equivalent, giving product 2h in 77 % isolated yield. Electronically
modified acrylic acids, such as protected dehydroalanine
substrates 1i and 1j, were efficiently engaged in the reaction,
giving the mono-protected amino acids, 2i and 2j, in excellent
yields of 90 % and 85 % respectively. Of further note is the
chemoselectivity observed in the case of substrate 2j. Under
metal-catalyzed hydrogenation conditions, the benzyloxy-moiety
of the Cbz protecting group would likely undergo hydrogenolysis
leading to undesirable deprotection of the amino group. Under the
present DAP catalysis, no such side-reactivity occurs. Acrylic
acids bearing a variety of different aryl-substituents at the C-2
position were prepared, and in all cases, these were efficiently
reduced to the corresponding 2-arylpropionic acids (2k-2p).
Increased steric hindrance around the double bond was well
tolerated, giving 2l in 87 % yield. The more electron-rich 2-(4-
methoxyphenyl)acrylic acid was smoothly reduced to 2m in
excellent yield. Substrates bearing aryl fluorides could be used,
giving products 2n and 2o in excellent yields, while 2-(3,4-
dichlorophenyl)acrylic acid was equally adept in the reaction,
enabling the isolation of 2p in virtually quantitative yield.
Examples 2o and 2p demonstrate that electron poor aryl groups
are tolerated, further highlighting the generality of this method.
We then examined the suitability of a range of 2,3-disubstituted
substrates. While still viable, we observed a decrease in their rate
of reduction, for which we could compensate with an extra
equivalent of hydride. Under these conditions, products 2q and 2r
were cleanly obtained after 6 hours. Additionally, under the
modified conditions, product 2c was obtained from (E)-2-methyl-
3-phenylacrylic acid in 86 % yield. The use of C-3 substituted
substrates (lacking the additional substitution at C-2) do not
require neither any extra hydride equivalents nor prolonged
reaction times. Instead, 2s and 2t were obtained in yields of 99 %
and 79 % respectively after 2 hours with 0.35 equivalents of
PhSiH3 (1.05 equivalent total hydride). Moreover, we also
demonstrated that this methodology can be used for the reduction
of other acidic substrates such as α,β-unsaturated hydroxamic
acid 1u. Notably, in this case, no catalyst turnover occurred from
the reduced hydroxamate. However, the addition of 2 mol % N-
methylimidazole as a co-catalyst promoted the necessary σ-bond
metathesis, enabling the formation of 2u in 77 % isolated yield.
We believe that this additive is able to coordinate to the
phosphorus atom of the catalyst, thereby weakening the bond
between the DAP and the hydroxamate. Consequently, the σ-
bond metathesis with the silane is accelerated. The conjugated
diacids, fumaric acid and mesaconic acid, were efficiently
reduced to their saturated congeners, 2v and 2w, in respective
yields of 81 % and 86 %. In order to further prove the general
applicability and synthetic utility of the methodology, selected
substrates (1g, 1i, 1o, 1q, 1r and 1u) were reduced on a
increased scale (either 5 or 10 mmol of substrate). Pleasingly, for
these larger scale reactions, the catalyst loading could be further
reduced to 0.05 mol% and full conversion was still observed.
Moreover, on each case, the isolated yield of the product on these
Table 1. Optimization of the acrylic acid reduction.
Entry Cat. (mol %) Reductant (eq.) Solvent t (min) % Yield
1[a]
2[a]
3[a]
4[a]
5[a]
6[a]
7[a]
8[a]
9[a]
10[a]
P2 (10)
P2 (10)
P3 (10)
P3 (10)
P3 (10)
P3 (10)
P3 (10)
P2 (10)
P3 (2)
-
PinBH (1.1)
THF
THF
THF
THF
THF
PhMe
MeCN
Et2O
THF
THF
THF
10
10
93
0
Ph2SiH2 (1.1)
Ph2SiH2 (1.1)
PhSiH3 (1.1)
PhSiH3 (0.35)
PhSiH3 (0.35)
PhSiH3 (0.35)
PhSiH3 (0.35)
PhSiH3 (0.35)
PhSiH3 (0.35)
PhSiH3 (0.35)
10
85
87
92
88
67
37
97
0
10
10
10
10
10
120
360
360
11[b] P3 (0.5)
>99
[a] 14.82 mg (0.1 mmol) of 1a with the specified amount of reductant and
catalyst in 100 μL of the specified solvent (1.00 M) for the indicated time at 23
°C; [b] 1.482 g (10 mmol) of 1a, 432 µL (3.50 mmol) PhSiH3, 12.9 mg (0.05
mmol) P3, in 10 mL THF for 6 h at 23 °C.
Using the optimized reaction conditions, the scope of the reaction
was investigated. A wide variety of functionality was tolerated at
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10.1002/cctc.202000662
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larger scales was found to be superior to the yield of the
exploratory 0.2 mmol scale.
instantaneously cleanly giving P4 as the only observable product.
Upon addition of PhSiH3 to the reaction reaction mixture, a slow
conversion of P4 to 3a with concomitant regeneration of P1 was
observed, indicating this to be the rate-limiting step of the catalytic
cycle (d).
Scheme 3. Mechanistic studies of the DAP-catalyzed acrylic acid reduction: a)
deuterium labelling shows that proton transfer occurs prior to aqueous
quenching of the reaction, the erroneously low value for deuterium incorporation
of substrate 1a-d1 is most likely because of exchange between the labile
deuterium with trace water; b) quenching of the DAP-hydride with an acidic
proton occurs very slowly; c) reduction of the substrate and subsequent
tautomerization occurs rapidly; d) stoichiometric experiments indicate the rate
limiting step of the catalytic cycle is the σ-bond metathesis.
Consequently, the tautomerization process takes place while the
DAP is still covalently bound to the intermediate and in close
proximity. This implies that a suitable chiral DAP catalyst might be
able to induce an enantioselective tautomerization, leading to
enantio-enriched propionic acid derivatives. To verify this
hypothesis, chiral DAP pre-catalyst P5[13b] was employed in the
reduction of 1a with pinacol borane (Scheme 4). Pleasingly, this
reaction led to the formation of 2a in 84 % yield with an
enantiomeric ratio of 64:36 as determined by chiral HPLC
analysis. This result is a first proof-of-principle that chiral DAPs
can catalyze an enantioselective reduction of substituted acrylic
acids.
Scheme 2. Scope of the DAP-catalyzed acrylic acid reduction. [a] 0.2 mmol
substrate, 8.63 µL (0.07 mmol) PhSiH3, 1.03 mg (4 µmol) P3 in 0.2 mL THF for
2 h at 23 °C; [b] 10 mmol substrate, 432 µL (3.50 mmol) PhSiH3, 12.9 mg (0.05
mmol) P3, in 10 mL THF for 6 h at 23 °C; [c] 5 mmol substrate, 216 µL (1.75
mmol) PhSiH3, 6.5 mg (25 μmol) P3, in 5 mL THF for 6 h at 23 °C; [d] 0.2 mmol
substrate, 17.3 µL (0.14 mmol) PhSiH3, 1.03 mg (4.00 µmol) P3 in 0.2 mL THF
for 6 h at 23 °C; [e] 10 mmol substrate, 863 µL (7 mmol) PhSiH3, 12.9 mg (0.05
mmol) P3, in 10 mL THF for 6 h at 23 °C; [f] 0.2 mmol substrate, 8.63 µL (0.07
mmol) PhSiH3, 1.03 mg (4.00 µmol) P3, 0.3 µL (4 µmol) 1-methylimidazole in
0.2 mL THF for 2 h at 23 °C; [g] 5.0 mmol substrate, 216 µL (1.75 mmol) PhSiH3,
6.5 mg (25.0 µmol) P3, 2 µL (0.025 mmol) 1-methylimidazole in 5 mL THF for 2
h at 23 °C.
Scheme 4. Catalytic reduction of 1a followed by enantioselective proton-
transfer.
To better understand the transformation, a series of experiments
were conducted to elucidate the underlying processes (Scheme
3). Deuterated acrylic acid 1a-d1 (70 % D) was subjected to the
standard reaction conditions (a). Analysis of the formed product
revealed selective deuterium incorporation at the α-position of the
acid occurred (80 % D). This indicates that the carboxylic acid
proton tautomerises prior to the work-up reaction quench. The
reaction between preformed DAP-hydride (P1) and saturated
carboxylic acid 2a confirmed the low basicity of the DAPs (b).
Deprotonation of acid 2a by stoichiometric amounts of P1
occurred very slowly at ambient temperature and less than 50 %
conversion to P4 was observed after 5 h (see SI for details). To
compare this value to the relative rates of the reduction process,
1a was reacted with one equivalent of P1 (c). Both the reduction
and tautomerization of intermediate Int-I occurred virtually
In conclusion, we have developed a 1,3,2-diazaphospholene
catalyzed 1,4-reduction of free acrylic acids. This reaction occurs
under mild conditions and exhibits excellent functional group
tolerance. The low catalyst loading, fast reaction times and the
use of PhSiH3 as convenient terminal reductant are salient
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features of this transformation. The methodology is particularly
attractive as it showcases the unique properties of the 1,3,2-
diazaphospholenes whereby they are very potent nucleophiles,
yet displaying remarkably low basicity. As such, the reaction
proceeds without quenching by the acidic proton of the carboxylic
acid. The process can be rendered enantioselective. We will
dedicate future efforts towards developing new chiral
diazaphospholene catalysts capable of achieving improved levels
of enantioinduction.
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Keywords: diazaphospholene • reduction • catalysis • molecular
hydride • nucleophilic
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10.1002/cctc.202000662
ChemCatChem
Entry for the Table of Contents
A 1,3,2-diazaphospholene (DAP) catalyst in conjunction with PhSiH3 enables the direct conjugate reduction of substituted α,β-
unsaturated carboxylic acids without prior deprotonation, highlighting its remarkably potent nucleophilicity and yet low basicity. The
transformation is characterized by a low catalyst loading, mild reaction conditions at ambient temperature as well as fast reaction times
and tolerates functional groups such as Cbz group or alkyl halides that can be problematic with classical reduction catalysts.
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