A 1,3,2-Diazaphospholene-Catalyzed Reductive Claisen Rearrangement

Article abstract of DOI:10.1002/anie.201904411

1,3,2-Diazaphospholenes (DAPs) are an emerging class of organic hydrides. In this work, we exploited them as efficient catalysts for very mild reductive Claisen rearrangements. The method is tolerant towards a wide variety of functional groups and operates at ambient temperature. Besides being enantiospecific for substrates with existing stereogenic centers, the diastereoselectivity can be switched by varying solvents and DAP catalysts. The reaction kinetics show direct rearrangements of O-bound phospholene enolates and provide a proof-of-principle for catalytic enantioselective reactions.

Full text of DOI:10.1002/anie.201904411

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Accepted Article
Title: A 1,3,2-Diazaphospholene-Catalyzed Reductive Claisen
Rearrangement
Authors: John H. Reed, Pavel A. Donets, Solène Miaskiewicz, and
Nicolai Cramer
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A 1,3,2-Diazaphospholene-Catalyzed Reductive Claisen
Rearrangement
John H. Reed,[a] Pavel A. Donets,[a] Solène Miaskiewicz,[a] and Nicolai Cramer*[a]
Abstract: 1,3,2-Diazaphospholenes (DAPs) are an emerging class
of organic hydrides. Herein, we exploited them as efficient catalysts
for very mild reductive Ireland-Claisen rearrangements. The
methodology is tolerant towards a wide variety of functional groups
and operates at ambient temperature. Besides being enantiospecific
unsaturated carbonyl derivatives.[11b,f] Kinjo et al. reported a σ-
bond metathesis between pinacol borane (HBpin) and alkoxy-
substituted DAPs, enabling the regeneration of the hydridic DAP
for potential catalytic applications.[11a] Recent reports from our
group and Speed et al. independently devised chiral DAP
catalysts for asymmetric reductions.[12,13]
for
substrates
with
existing
stereogenic
centers,
the
diastereoselectivity can be switched by varying solvents and DAP
catalysts. Reaction kinetics show direct rearrangements of O-bound
phospholene enolates and provide a proof-of-principle for catalytic
enantioselective reactions.
The
Ireland-Claisen
rearrangement
remains
a
fundamentally important reaction in the toolbox of organic
synthesis due to its ability to construct a C–C bond in a
stereoselective fashion.[1,2] Crucially, it is one of the more reliable
methods for the synthesis of vicinal quaternary centers.[3] The
transformation offers a convenient way to generate the allyl vinyl
ether array for the [3,3]-rearrangement, which itself generally
proceeds at lower temperatures than the original Claisen
rearrangement.[1,4] However, the need for stoichiometric amounts
of a strong base to form the ester enolate under cryogenic
conditions precludes the use of base-sensitive substrates
(Scheme 1a).[5] The development of reductive Ireland-Claisen
rearrangements, whereby the enolate is generated by
a
conjugate reduction of α,β-unsaturated allyl ester substrates,
has provided an adroit strategy to circumvent this issue.[6]
Despite the utility of this approach, few examples have been
reported, typically employing transition-metal hydrides to
catalyze the reduction to the silyl-ketene acetal. The
rearrangement does not proceed at the transition-metal enolate
stage, but after the silylation step. Recently, Soós et al.
disclosed a reductive Ireland-Claisen rearrangement whereby
the reduction is catalyzed by a sterically encumbered borane.[7]
Interestingly, under these conditions, some substrates
underwent a 1,3-allylic shift of the ester group prior to the
Ireland-Claisen rearrangement, leading to structural isomers of
the targeted products. Due to these shortcomings, a mild and
general methodology for catalytic reductive Ireland-Claisen
reactions remains a desirable goal.
Since the seminal report by Gudat et al. in 2000, 1,3,2-
diazaphospholenes (DAPs) have emerged as an intriguing class
of molecular hydrides (Scheme 1b).[8] According to Cheng,
certain DAPs are among the most nucleophilic hydride donors
quantified according to the Mayr nucleophilicity scale.[9] They
have been shown to reduce aldehydes and ketones,[8,10,11a]
imines,[11b] pyridines,[11c,d] azobenzenes,[11e] as well as α,β-
Scheme 1. a) Ireland-Claisen rearrangement, and it’s reductive variant; b)
reactivity profile of 1,3,2-diazaphospholenes; c) 1,3,2-diazaphospholene-
catalyzed reductive Ireland-Claisen rearrangement.
We hypothesized that the σ-aromaticity[14] induced stability
of the DAP cation[15] may render them tamed organic surrogates
for metal cations. This unique property might be exploitable for
developing the transient enolate chemistry. To verify this
hypothesis, we aimed to develop a DAP-catalyzed reductive
Ireland-Claisen rearrangement (Scheme 1c). A DAP-enolate
might provide enough P-O bond polarization[16] to trigger the
Claisen rearrangement at low temperatures, but at the same
time would not suffer from the typical lability and α-elimination
propensity of classical alkali ester enolates.[17] Alternatively, σ-
bond metathesis with a borane as the terminal reductant would
constitute a smooth entry into boron-enolate reactivity.[18] Our
investigation of the catalytic reductive Ireland-Claisen
rearrangement commenced by exposing allyl 2-phenylacrylate
(1a) to 10 mol% pre-catalyst P1 and 1.5 equivalents of pinacol
borane in acetonitrile at ambient temperature (Table 1). To our
delight, we observed not only the 1,4-reduction product (3a) in
11 % yield, but also carboxylic acid 2a, the desired product of
the reductive rearrangement in 57 % (Entry 1). Among the
solvents tested, tetrahydrofuran (THF) proved to be the most
[a]
J. H. Reed, Dr. P. A. Donets, Dr. S. Miaskiewicz, 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://lcsa.epfl.ch/
Supporting information for this article is given via a link at the end of
the document.
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adept at promoting the rearrangement (Entry 2). In this case, the
desired rearrangement product 2a was formed in 81 % yield,
along with 15 % recovered starting material, but no observable
quantities of 3a. Alternative terminal reductants were studied.
While catechol borane (HBcat) was less effective than pinacol
borane (Entry 3), ammonia borane resulted in a highly efficient
reduction giving 3a in virtually quantitative yield (Entry 4).
However, as no rearrangement occurred, this may suggest a
slightly different mechanism.[11e] Dimethylphenylsilane as well as
dimethyl-chlorosilane were not competent terminal reductants,
indicating that they do not generate the catalytically active P–H
species from P1 (Entries 5 and 6). The high performance of P1
enabled the catalyst loading to be reduced to 1.0 mol% while still
maintaining an acceptable reaction rate (Entry 7). Using an
increased two molar concentration enabled the reaction to run to
completion within 4 hours, giving the 2a in an excellent yield of
96 % (Entry 8). In the absence of P1, no reaction was observed
(Entry 9), demonstrating the importance of the catalyst. A gram-
scale reaction with just 1.1 equivalents of the HBpin reductant
resulted in 86 % isolated yield of 2a (Entry 10). Notably, the
reaction conditions are very mild, requiring neither heat nor
cryogenic conditions.
reaction. As showcased by products 2g-2p, the system proved
highly adept at constructing vicinal all-carbon quaternary centres,
structural motifs that remain challenging propositions to
synthetic chemists.[19] The exceptionally mild conditions under
which these compounds could be accessed underscores the
synthetic utility of this methodology. Variations of the steric and
electronic properties of the aromatic portion of substrates 1g-1p
showed no deleterious effects. Substrates having either
electron-donating or electron-withdrawing aryl groups were
smoothly reduced and rearranged. Importantly, 1-naphthyl
derivative 1k was a competent substrate, indicating that ortho-
substitution did not hinder the rearrangement. Aryl fluorides,
chlorides and bromides were all maintained through the reaction
to give acids 2l, 2m, and 2n respectively. Notably, bromo
acrylate 1o could also be reduced before undergoing a highly
efficient rearrangement to yield acid 2o with its tertiary bromide,
evidencing the mildness of the transformation. Concerning
modifications of the allyl portion, both trifluoromethylated variant
1q and cyclic ether 1r could be engaged in the reaction with
excellent yields. Notably, when masked in situ with an extra
equivalent of HBpin, a free alcohol (1s) is tolerated and inhibits
neither the reduction nor the rearrangement. Instead of the usual
carboxylic acid, lactone 2s was obtained in excellent yield after
work-up. Complementary, the TBS-group of silyl-protected
analogue 1t was not cleaved during the reaction. Acetylated
derivative 1u was successfully converted to acid 2u with no
observable products arising from the reduction of its acetate unit.
Enantiomerically enriched allylic ester 1v was used to check for
transfer of chirality during the rearrangement. Indeed, chiral acid
2v was obtained in 96 % yield with essentially complete transfer
of chirality emphasizing the excellent enantiospecificity of the
rearrangement. Finally, propargyl ester 1w proved to be a viable
substrate, illustrating the potential of our method for the
synthesis of allenes.
Investigating the diastereoselectivity of the rearrangement,
we found it to be dependent on the nature of the employed DAP
catalyst (Table 3). Moreover, the diastereoselectivity could be
reversed through a simple solvent switch. For instance, reaction
of 1x and catalyst P2 gave corresponding acid 2x in 81 % yield
and a 4.2:1 anti/syn ratio when conducted in toluene. The same
reaction conducted in MeCN afforded 2x in 75 % yield and a
1:2.7 anti/syn ratio. P3 catalyzed the reductive rearrangement of
1y giving 2y in 93 % yield with a 3.3:1 anti/syn ratio in toluene
and in 75 % with a 1:7.2 anti/syn ratio in MeCN. Similarly, 2z
was obtained in 93 % with a 3:1 anti/syn ratio in toluene and
70 % with, a 1:5.6 anti/syn ratio in MeCN. Acid 2aa was
obtained in 68 % yield with a 5.6:1 dr using catalyst P4.
However, no solvent induced selectivity switch could was
observed in this case.
Table 1. Selected optimization studies of the reductive rearrangement.[a]
Conc.
Entry
Reductant mol% P1
% Yield 2a[b]
% Yield 3a[b]
(M)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
1[c]
2
HBpin
10
57
81
57
0
11
0
HBpin
10
10
10
10
10
1
3
HBcat
0
4
H3NBH3
Me2PhSiH
Me2ClSiH
HBpin
99
0
5
0
6
0
0
7
70
96
0
0
8
HBpin
0
1
9
HBpin
2
0
0
10[d]
HBpin
2
86[e]
0
1
[a] 50 μmol 1a, 75 μmol reductant, cat. P1 at the indicated concentration in
THF for 4 h at 23 °C; [b] Yields determined by 1H NMR, with 1,3,5-
trimethoxybenzene as the internal standard; [c] in MeCN;[d] 7.0 mmol 1a,
7.7 mmol HBPin; [e] isolated yield.
Next, we turned our focus towards a better understanding of
the possible reaction pathways (Scheme 2). The initial addition
of [P]-H (generated from P1 and HBpin) across substrate 1 can
give either intermediate I or II. Their ratio, as determined by 31P
nuclear magnetic resonance (NMR) spectroscopy, was found to
be both catalyst and substrate dependent. P-C intermediate II
does not convert to P-O intermediate I. It can only react via σ-
bond metathesis with HBpin forming boron enolate III. In turn, III
rearranges to V. The diastereoselectivity of the rearrangement is
a reflection of the E/Z ratio of III and/or any chair/boat TS ratio.
P-O intermediate I has more options to react. It either undergoes
σ-bond metathesis with HBpin entering again the B-[3,3]
pathway. However, the direct rearrangement of P-O
intermediate I to IV by the P-[3,3] pathway would be more
Having optimized the conditions for the reductive Ireland-
Claisen rearrangement, the reaction scope was examined
(Table 2). A broad array of allylic acrylates bearing various
functional groups were found to be suitable substrates for the
reaction, giving rise to the carboxylic acids 2a-2w in excellent
yields. Aryl or alkyl substitution at the α-position of the acrylate
(1a, 1b) is well tolerated, as is the cyclic trisubstituted acrylate
1c. β-Alkyl and aryl substitution is also tolerated (1d-f), albeit
giving the corresponding acids with slightly diminished yields.
The 2-thienyl group on 1f remained unscathed throughout the
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Table 2. Scope of the DAP-catalyzed reductive Ireland-Claisen rearrangement.[a]
Entry
1
1
2
% Yield[b]
Entry
15
1
2
% Yield[b]
96
98
2
3
81
91
16
17
89
99
4
5
80
67
18
19
93
86
6
7
75
82
20
90
21
22[c]
23
86
96
79
8
1h (Ar=PMP)
1i (Ar=4-F3C-C6H4)
1j (Ar=4-Me-C6H4)
1k (Ar=1-naphthyl)
1l (Ar=3,5-F2-C6H3)
1m (Ar=3,4-Cl2-C6H3)
1n (Ar=4-Br-C6H4)
2h
2i
86
94
99
81
88
78
98
9
10
11
12
13
14
2j
2k
2l
2m
2n
[a] 0.1 mmol 1, 0.15 mmol HBpin, 1.0 μmol P1, 2 M in THF at 23 °C for 4 h; [b] isolated yields; [c] with 0.25 mmol HBpin.
desirable. This would allow for a maximum control of the
diastereoselectivity and the enantioselectivity by the bound DAP.
Experimentally, we found that the nature of the reaction
intermediates is highly substrate dependent. For instance,
treatment of substrate 1b with stoichiometric amounts of [P]–H
rapidly and selectively gives carbon-bound phosphorus species
IIb (Equation 1). Neither direct rearrangement nor conversion to
O-bound intermediate I of this species was observed. In turn,
addition of HBpin regenerates [P]–H and leads to boron enolate
IIIb and its concomitant rearrangement yielding Vb.
In stark contrast, reduction of 1x with [P]-H at 0 °C very
rapidly forms exclusively oxygen-bound phosphorus species
Ix.[20] Species Ix rearranges smoothly to give P-ester IVx (Figure
1a). To compare the rearrangement rate of Ix and the rate of σ-
bond metathesis with HBpin, mock substrate 4 was treated with
[P]-H (Figure 1b). Importantly, enolate I4 reacts with HBpin at a
lower rate than the rate at which Ix rearranges (see SI for
graphs of the progression of each reaction). This clearly
indicates that substrates involving O-bound phosphorus
intermediates, bear the potential for a catalytic enantioselective
rearrangement with a suitable chiral DAP catalyst.
Accordingly, when chiral DAP catalyst P5 was used in the
reductive rearrangement of 1x, desired acid 2x was obtained in
an excellent yield of 96 % and a diastereoselectivity of 11.7:1
(Scheme 3). More importantly, 2x was formed with an
enantiomeric ratio of 68.5:31.5, consisting of the first proof-of-
concept for a catalytic asymmetric reaction. Notably, when
conducted with stoichiometric amounts of preformed P5-H the
identical enantioselectivity was observed. This is evidence that
the rearrangement occurs under full catalyst control. Of further
note is that the reduction of both 1x and 4 generated only one
single enolate species, as observed in both the 1H and 31P NMR
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spectra. However, upon rearrangement of Ix, two diastereomeric
products are formed, implying that the diastereomeric mixtures
arise from a small energy difference between the boat and chair
transition states, rather than a mix of enolate geometries.
Table 3. Diastereoselective reductive Ireland-Claisen rearrangements.[a]
Entry Solvent
1[d] toluene
1
2 (major isomer) % Yield[b] anti/syn[c]
Figure 1. a) 1x (0.05 mmol), [P]-H (0.05 mmol) in THF-d8 (500 μL); b) 4 (0.05
mmol), [P]-H (0.05 mmol) in THF-d8 (500 μL), then HBpin (0.05 mmol).
81
75
4.2:1
1:2.7
2[d] MeCN
3[e] toluene
4[e] MeCN
5[e] toluene
93
71
93
3.3:1
1:7.2
3:1
Scheme 3. Proof-of-principle of a catalytic asymmetric reductive Ireland-
Claisen rearrangement with DAP P5.
In conclusion, we report a very mild and efficient reductive
Ireland-Claisen rearrangement that displays a particular efficacy
for the synthesis of vicinal quaternary centers. The process is
catalyzed by 1 mol% of a simple 1,3,2-diazaphospholene, is
tolerant towards a wide variety of functional groups and
proceeds at ambient temperature. Moreover, it was found to be
enantiospecific for substrates with existing stereogenic centers.
The diastereoselectivity of the reaction can be controlled by
appropriate solvents and DAP choices. Mechanistic studies
revealed that different pathways and intermediates can be
formed depending on the nature of the catalyst and substrate.
We have further showed that O-bound phospholene enolates
rapidly rearrange and provided a preliminary example of a
catalytically enantioselective rearrangement. Further studies to
identify the optimal chiral DAP for a catalytic and highly
enantioselective process are underway in our laboratory.
6[e] MeCN
7[f] toluene
8[f] MeCN
70
68
91
1:5.6
5.6:1
4.9:1
[a] 0.1 mmol 1, 0.15 mmol HBpin, 10 μmol P, 1.0 M in solvent at 23 °C for 4
h; [b] isolated yields; [c] ratio determined by 1H NMR of the crude product;
[d] with P2; [e] with P3; [f] with P4. DIPP=2,6-diisopropylphenyl
Acknowledgements
This work is supported by the Swiss National Science
Foundation (no 1175507).
Keywords: 1,3,2-diazaphospholenes • phosphorus • Ireland-
Claisen rearrangement • enolate reactivity • molecular hydride
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observable formation of VIw.
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J. H. Reed, P. A. Donets, S.
Miaskiewicz, and Nicolai Cramer*
Page No. – Page No.
A 1,3,2-Diazaphospholene-Catalyzed
Reductive Ireland-Claisen
Rearrangement
1,3,2-Diazaphospholenes (DAPs) are efficient catalysts for ambient temperature
reductive Ireland-Claisen rearrangements, tolerating a wide variety of functional
groups. It is enantiospecific for substrates with existing stereogenic centers. The
diastereoselectivity can be controlled by different solvents and DAP catalysts.
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