Phospholane-Phosphite Ligands for Rh Catalyzed Enantioselective Conjugate Addition: Unusually Reactive Catalysts for Challenging Couplings

Article abstract of DOI:10.1002/ejoc.202000336

The use of Rh catalysts derived from a phospholane-phosphite ligand were found to be more productive than the classic rhodium/BINAP system in enantioselective conjugate additions. These catalysts enable the use of lower amounts of aryl boronic acid in an

Full text of DOI:10.1002/ejoc.202000336

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Asymmetric Catalysis
Phospholane-Phosphite Ligands for Rh Catalyzed
Enantioselective Conjugate Addition: Unusually Reactive
Catalysts for Challenging Couplings
Sophie H. Gilbert,[a] José A. Fuentes,[a] David B. Cordes,[a] Alexandra M. Z. Slawin,[a] and
Matthew L. Clarke*[a]
Abstract: The use of Rh catalysts derived from a phospholane- an impractical excess of nucleophile. This catalyst was also
phosphite ligand were found to be more productive than the found to enable the coupling of a poorly reactive Michael ac-
classic rhodium/BINAP system in enantioselective conjugate ad- ceptor, N-CBz-2-3-dehydro-4-piperidone, or the coupling of
ditions. These catalysts enable the use of lower amounts of aryl poorly reactive 2-furyl boronic acids at ambient or near temper-
boronic acid in an asymmetric arylation reaction that required atures.
Introduction
were encouraged by the successful examples using bidentate
ligands with electronic asymmetry in references 5–8.
The last two decades have seen great advances in enantioselec-
tive conjugate additions of aryl (or alkenyl) boronic acids. These
reactions have received significant attention, and are a useful
tool for the asymmetric synthesis of quite a wide variety of
target molecules.[1] There are also quite a range of different
catalysts that have been developed and shown to be effective
from the perspective of promoting highly enantioselective cou-
pling reactions (Scheme 1). Rh/BINAP catalysts are especially
widely used catalysts since they deliver high ee for quite a range
of couplings, and because the BINAP ligand is commercially
available.[2] The protocols using the Rh/BINAP system have
been improved and modified to improve reactivity,[2f,2g] with
the protocols used as control reactions in this work being based
on reference 2g. Since this is now quite an important catalytic
reaction, there are many other catalysts that have been de-
signed and tested.[1b] Fluorinated BINAP analogues have been
shown to allow lower catalyst loadings to be used than the Rh/
BINAP system, and more practical conditions for one substrate
studied here.[3] Non-C2-symmetric Phosphine-alkene ligands,[5]
phosphine-amide ligands,[6] phosphine-sulfoxide[7] and phos-
phine-NHC ligands[8] have all been examined in Rh catalyzed
conjugate additions of important but generally unproblematic
substrates and also for novel target synthesis.[1c] The diversity
of ligands studied in these reactions is large, but no phosphine-
Scheme 1. Ligands used in this study, and a typical modified protocol using
Rh/BINAP catalysts.
We were aware of some problematic examples of Rh cata-
phosphite ligands seem to have been studied in this reaction lyzed conjugate addition, and felt attempting these with a new
thus far.[4] We felt it would be of interest to know how this type catalyst would be a good test for any genuine advance. For
of ligand fared in Rh catalyzed conjugate additions, since we example, in the course of developing an assisted tandem cataly-
sis protocol involving an asymmetric Rh catalyzed conjugate
addition,[9] we became aware that certain combinations of aryl
boronic acids and Michael acceptors did not deliver acceptable
product yields. There were additional cases that required im-
[a] Dr. S. H. Gilbert, Dr. J. A. Fuentes, Dr. D. B. Cordes, Prof. A. M. Z. Slawin,
Prof. M. L. Clarke
School of Chemistry, University of St Andrews
St Andrews, Fife, UK, KY16 9ST
E-mail: mc28@st-andrews.ac.uk
practical amounts of boronic acid (e.g. > 4 equivalents) in order
to deal with the issue of competing proto-deborylation.[3b,10] In
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000336.
this paper we show how the commercially available phosphol-
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ane-phosphite, L1, known as BOBPHOS,[11] gives enhanced re- the good results previously obtained with electron-deficient
activity relative to the use of BINAP as the ligand and enabled fluorinated BINAP analogues, the bis-phospholane might be too
the preparation of some of the compounds that couldn't be electron-donating to be an effective catalyst. Consistent with
easily be made following standard Rh/BINAP promoted proto-
cols.
this, quite a large amount of aryl boronic acid (not fully quanti-
fied due to solubility issues) remains in this reaction, in contrast
to both successful reactions using Rh/(R,R,R)-L1 and an unsuc-
cessful reaction using Rh/Kelliphite. It is possible the phosphite
hydrolytically degrades or is too sterically hindered to form a
good catalyst for this transformation. In any case, despite the
parent diphosphite or bis-phospholane being unsuccessful, the
results represent a new example where a ligand with two phos-
phorus donors with quite different steric and electronic envi-
ronments is beneficial to some part of a catalytic process.
Results and Discussion
The reaction of para-fluorophenylboronic acid with 6-methyl
coumarin was used as an assay for catalyst performance. The
literature describes successful coupling of this Michael acceptor
using an Rh/Segphos catalyst.[10a] Catalyst loadings of 3 mol-%
and 10 equivalents of boronic acid were required for high
yields. In this case, there was a subsequent publication describ-
ing a bespoke fluorinated ligand that makes this reaction more
practical with lowered amounts of aryl boronic acid.[3c] How-
ever, this seemed a good model example of a challenging cou-
pling, and was amenable to measuring conversion and proto-
deboration using 19F{1H} NMR spectroscopy.
The results described in Table 1 compare catalysts derived
from phospholane-phosphite, L1 with other relevant ligands.
As expected, the use of just 3 equivalents of aryl boronic acid
delivers almost no product for the Rh/BINAP catalyst (Table 1,
Entry 2). Pleasingly, changing to phospholane-phosphite, BOB-
PHOS, (R,R,R)-L1 as ligand, but keeping the smaller excess of
aryl boronic acid led to essentially quantitative conversion to
product. BOBPHOS is a hybrid of ligands L3[12] and L4.[13] How-
ever, surprisingly, neither of the ligands from which BOBPHOS
is derived show any competence in this reaction, even if you
We also report here the synthesis of a new derivative of the
BOBPHOS ligand, (S,S,S)-L5. This ligand was studied here since
we felt it could shed light on how the alkene coordinates in
these reactions. Models built using extensive data with previous
conjugate addition catalysts strongly suggest that the enantio-
face selective binding of the alkene leads to the enantioselec-
tivity. Our working hypothesis was that a bulkier phospholane
would only significantly alter the enantioselectivity if the alkene
was binding cis to it. The synthesis of this new ligand proved
quite long, resulting in only small batches of ligand being easily
available. So far, attempts at more streamlined routes have
proven unworkable. The synthesis of the new ligand is shown
in Scheme 2. The absolute configuration was determined by X-
ray crystal structure determination on the resolved phosphol-
anic acid (also represented in Scheme 2).
The key finding here is that the new phospholane-phosphite,
increase the aryl boronic acid loading to ten equivalents. Given L5 with a larger phospholane unit delivers higher enantioselec-
Table 1. Effect of ligand structure on catalyst performance in a challenging conjugate addition.
Entry
Ligand [mol-%]
Rha [mol-%]
Nuc. [equiv.][a]
Conv. [%][b,e]
PhF[b] [equiv.]
Yield [%][c]
ee[d][%]
1
2
L1 (1.7)
L2 (1.7)
L2 (1.7)
L3 (1.7)
L3 (1.7)
L4 (1.7)
L4 (1.7)
L1 (0.6)
L1 (0.6)
L1 (0.6)
L1 (1.7)
1.6
1.6
3.0
1.6
3.0
1.6
3.0
0.4
0.4
0.4
1.6
3
3
10
3
10
3
10
4.5
4.5
4.5
3
97
1.3
0.7
10
0
2.5
0
78
80 (–)
ND
98 (–)
ND
ND
–
trace
ND
trace
trace
0
0
57
66
75
ND[f]
17[f]
ND
ND[f]
–
3[f,g]
4
5[f]
6
7[f]
8
7
–
47
60
73
–
1.0
3.3
3.8
n.d.
80 (–)
75 (–)
75 (–)
81 (–)
9[h]
10[h,i]
10[i]
99
78
[a] General conditions: The given amounts of [Rh(NBD)2]BF4 are pre-mixed with a slight excess of ligand w.r.t Rh for 2 h (using the enantiomer of ligand
shown in Scheme 1); 0.75 mmol of 1, Nuc. = 4-fluorophenylboronic acid, 0.75 mmol Et3N,1 mL of dioxane, 25 °C, 16 hours. [b] Determined by 19F{1H} NMR
relative to 1-fluoronaphthalene. [c] Isolated yield. [d] ee determined by chiral HPLC (see ESI for details). [e] 19F{1H} NMR integration shows approximate
amounts of the partially soluble 4-fluorophenylboronic acid at the end of the reaction, with experiments (entries) 2 and 3 showing around two equivalents
boronic acid, and expt. 5 around seven equivalents. [f] Catalyst is [Rh(acac)(COD)] (3.0 mol-%), ligand (3.3 mol-%), with no base added as per ref. 10a. [g]
Heated to 60 °C. [h] Heated to 70 °C. [i] MeTHF as solvent.
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Scheme 3. Improved enantioselectivity using a phospholane-phosphite with
larger phospholane substituents, and the same sense of stereoselectivity is
observed using the mis-matched diastereomer of BOBPHOS.
(S,R,R)-L6.[14] In the Michael additions promoted by Rh/(S,R,R)-
L6, one might expect a switch in enantiopreference if the alkene
was binding cis to this phosphite group, since the opposite
enantiomer of phosphite component is used. In contrast, if the
phosphite is remote from the enantio-face binding of the
alkene, it would give the same configuration of product as
Rh/(R,R,R)-L1 catalyst, and significant enantioselectivity. The
Rh/(S,R,R)-L6 catalyst not only gives the same configuration of
product, but the ee of 2a is actually slightly greater using this
catalyst (Scheme 3). This is fully consistent with the alkene bind-
ing cis to the phospholane. The picture is a little more compli-
cated however, and when the Rh/(S,R,R)-L6 catalyst was tested
in the conjugate addition of cyclohexanone, while the same
enantiomer was formed, the ee of 4 is significantly lower.
The Rh/(R,R,R)-L1 catalyst is more productive, and also en-
ables lower amounts of the aryl boronic acid to be used. The
rate-determining step of Rh catalyzed arylation of an activated
Michael acceptor has been determined to be transmetala-
tion.[2f] However, since less activated Michael acceptors of the
type studied here show much lower rates, the C-C bond-form-
ing process can also clearly impact on the rate, so it is likely the
two stages are quite finely balanced for less activated Michael
acceptors. A partial solution to get high yields for less activated
Michael acceptors is to use a very large excess of the aryl bor-
onic acid; this suggests it is important to maintain a large
enough concentration of the Rh-aryl species that must undergo
the more challenging C-C bond forming reaction. Thus, the effi-
Scheme 2. Reactions and conditions: i) KtBuO (2.5 equiv.), DMF, r.t, 2 h. ii) (a)
AlCl3 (1.15 equiv.), Me2NPCl2 (1.15 equiv.), DCM, 0 °C, 16 h, (b) NaHCO3 (aq),
EDTA, 0 °C, 4 h. iii) H2 (50 bar), Pd/C (10 %), EtOAc, 60 °C, 17 h. iv) KtBuO
(3 equiv.), MeOH, 50 °C, 24 h. v) HCl (6
quinine, MeOH, 80 °C, 30 min. (28 % is out of 50 % max theoretical yield. (b)
acetone, (c) NaOH (2 ), DCM. vii) (a) PhSiH3 (2 equiv.), toluene, 110 °C, 4 h,
N)/dioxane 1:2, 85 °C, 22 h. vi) (a)
M
(b) BH3.SMe2 (1 equiv.), r.t, 19 h. viii) (CH2O)n, KOH, MeOH, r.t, overnight. ix)
PBr3 (1.5 equiv.), Et3N (3 equiv.), toluene, 0 °C to r.t, overnight. x) Alcohol from
step (viii) (1 equiv.), DABCO (5 equiv.), toluene, r.t, 17 h. Scheme 2 (bottom).
Representation of the X-ray crystal structure of the new phospholanic acid,
(S,S)-PreL5b, after resolution with quinine.
tivity in the two model reactions tested (Scheme 3). However,
this is accompanied by conversions more typical to Rh/BINAP
catalysts under these conditions, removing the reactivity advan-
tage that catalysts derived from L1 exhibit. This rather inaccessi-
ble catalyst was therefore not pursued further in terms of scope.
The selectivity observed is consistent with the alkene binding
cis to the phospholane, although it is not absolute proof of this,
since it is just about possible subtle conformation changes
could lead to an unexpected influence of chiral substituents
trans to the alkene.
To add further support, or refute this mechanistic hypothesis, cient formation of the Rh-aryl intermediate is important in Rh
we also tested the mis-matched diastereomer of ligand, (R,R,R)- catalyzed arylations, regardless of which step has the largest
L1 in which the opposite enantiomer of chiral biphenol is used, energy barrier.
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We therefore wanted to investigate if Rh/L1 showed an en-
We decided to test our Rh/BOBPHOS catalyst with this
hanced rate of transmetalation relative to Rh/BINAP. To study challenging conjugate addition substrate. We found that the
this, we reacted para-fluorophenylboronic acid with water in Rh/(R,R,R)-L1 catalyst gave us good yields, clearly surpassing
the presence of various catalysts to study the overall rate of the Rh/(S)-L2 catalysts. For the synthesis of 6a, the Rh/(R,R,R)-L1
process of transmetalation and protonolysis that makes up a Rh catalyst gave higher enantioselectivity than the Rh/BINAP one
catalyzed proto-deboronation (Scheme 4, and for full data, see using 0.6 mol-% catalyst (Scheme 5).
ESI). Since we have already established that the Rh/L1 catalysts
are more productive than the Rh/BINAP catalyst, it is a reasona-
ble assumption that the former must either enhance the rate
of transmetalation, or deliver a Rh-aryl species that is more sta-
ble to protonolysis, and in this way delivers a greater proportion
of the desired product in catalytic arylations. Our assumption is
to consider it impossibly unlikely that the Rh/L1 catalysts could
be similar or worse than Rh BINAP at transmetalation, and more
prone to unproductive Rh-aryl protonolysis, yet somehow de-
liver more product in the catalytic arylation reactions.
Scheme 5. Improved protocol for arylation of CbZ-dehydropiperidone using
Rh/BOBPHOS catalyst.
In our previous study we also found the use of heteroaryl-
boronic acids, in particular 2-furylboronic acid were challenging
substrates for conjugate addition reactions.[9] This is because
heteroarylboronic acids are prone to protodeborylation.[19]
There are studies aiming to overcome this using alternative bor-
onate substrates such as MIDA, trifluoroborates or triol-bor-
ates,[20] but the use of the boronic acid would be desirable. The
coupling of the two enone substrates in a conjugate addition
with 2-furylboronic acid was compared using Rh/(R,R,R)-L1 and
Rh/(S)-L2 catalysts. These results show that Rh/BOBPHOS cata-
lysts are more reactive than Rh/BINAP again; in the formation
Scheme 4. Transmetalation-protodeboration reactions are faster for Rh/L1
of 4b and 6c, Rh/BINAP catalysts gave 15 % and 0 % yields
respectively, while moderate to good yields can be achieved
using the Rh/(R,R,R)-L1 combination (Scheme 6).
catalysts.
Control reactions without any Rh catalyst present did not
undergo any proto-deboronation, meaning the transmetal-
ation/protonation mechanism produces all the fluorobenzene
detected. If the Rh/(R,R,R)-L1 catalysts were better Michael addi-
tion catalysts because they give a more hydrolytically stable
Rh-aryl species, less fluorobenzene would be formed in this ex-
periment, since the catalysts would not readily turnover. The
fact that we observed significantly faster fluorobenzene forma-
tion when catalyzed by Rh/(R,R,R)-L1, when considered along-
side the higher yields at lower aryl boronic acid concentrations
for Rh/(R,R,R)-L1 is consistent with faster transmetalation than
Rh/BINAP.
Scheme 6. Challenging couplings of 2-furyl boronic acids are possible.
The results obtained reveal Rh/BOBPHOS catalysts to be es-
pecially promising from the point of view of reactivity, and we
Conclusion
next studied some challenging couplings that did not proceed This project spun out of a desire to prepare multigram amounts
well using Rh/BINAP catalysts during our previous study.[9] The of some of the products here using commercially available
synthesis of chiral piperidones is also a desirable, yet challeng- rhodium catalyst systems. Fully exploring the scope of the pre-
ing conjugate addition. Most approaches focus on alternative viously unused Rh/L1 catalysts is outside of this study, but we
air sensitive and expensive nucleophiles such as arylzinc rea- would predict advantageous productivity in other difficult Rh
gents,[15] alkenyl alanes,[16] or organostannane reagents.[17] Jagt catalyzed arylations. The results present clear evidence that cat-
et al. developed a method of coupling arylboroxines with N- alysts derived from ligand L1 are more efficient at the trans-
Substituted-2–3-dehydro-4-piperidones using a Rh-Phosphor- metalation step in Rh catalyzed conjugate addition. It is likely
amidite ligand, but this required high loadings of arylboroxines that other phosphine-phosphites are unusually reactive ligands
and the slow addition of water.[18a,18b] It should be noted that for Rh catalyzed conjugate additions, and are worthy of investi-
there is an example using 3 mol-% of a Pd chiral NHC complex gation for challenging couplings. Transmetalation could be
to give very high ee for this difficult substrate.[18c]
rate-determining in itself, or part of the rate determining states
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Supporting Information (see footnote on the first page of this
article): For full experimental details available.
that lead to a challenging C-C bond-forming event, with the
efficient generation of a reasonable concentration of Rh-aryl
species being critical to the success of the reaction. If C-C bond
formation is slow, more significant amounts of proto-deboron-
ation can occur when using challenging Michael acceptors. It
is hoped this new catalyst, or as yet undiscovered phosphine-
phosphite derived catalysts could be used in the future to ex-
tend the scope of Rh catalyzed conjugate additions.
Acknowledgments
We would like to thank the University of St Andrews, and the
EPSRC Centre for Doctoral Training in Critical Resource Catalysis
(CRITICAT) for financial support [Ph.D. studentship to SG;
Grant code: EP/L016419/1], and the EPSRC for funding of JAF
(EP/M003868/1).
Experimental Section
Keywords: Asymmetric arylation · Michael addition · Aryl
boronic acids · Phospholane ligands · Asymmetric catalysis
General: Commercially available starting materials were purchased
from Sigma Aldrich, Alfa Aesar, Acros, STREM or Apollo Scientific
and were used without further purification. (R,R,R)-BOBPHOS,[11b]
(S)-Kelliphite,[13] benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxyl-
ate[9,21] were synthesized in house according to published proce-
dures.
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All catalytic reactions and all air sensitive procedures were carried
out under inert conditions or under hydrogen pressure using stan-
dard Schlenk techniques. All solvents used for these systems were
dry and degassed; taken from solvent purification systems, or com-
mercially supplied anhydrous bottles. Removal of solvent was as-
sisted by a rotary evaporator. Analytical thin layer chromatography
(TLC) was performed on pre-coated alumina plates (Kieselgel 60
F254 silica), before analyzing under ultraviolet light (254 nm). All
SiO2 column chromatography was performed with Kieselgel 60
silica. The research data underpinning this publication can be
accessed at https://doi.org/10.17630/bf27a028-7eb7-472b-8891-
c3558bbcae8a[22]
Synthesis of 6a: The pre-dried vial was filled with 4-fluorophenyl-
boronic acid (73.5 mg, 0.525 mmol), [Rh(NBD)2]BF4 (1.1 mg, 0.6 mol-
%), (R,R,R)-BOBPHOS (2.1 mg, 0.64 mol-%), a magnetic stirrer bar,
and sealed with crimped caps. The reaction vessel was purged with
N2 3 times, before the addition of the dioxane (0.5 mL) via syringe.
The reaction mixture was stirred for 2 hours before the addition of
H2O (0.15 mL), Et3N (70 μL, 0.5 mmol) and a stock solution of
benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate in dioxane (1 M,
0.5 mmol, 0.5 mL). The reaction was then left to stir at room temper-
ature for 16 hours. The reaction mixture was dissolved in a hept-
ane:methyl tert-butyl ether (10:3, 8 mL) and washed with water (2 ×
5 mL). The combined aqueous layers were then extracted with fur-
ther heptane: methyl tert-butyl ether (2:1, 5 mL). The combined
organic layers were dried (MgSO4) and solvent was removed in
vacuo. Purification was carried out by column chromatography
(SiO2 9:1, hexane/ethyl acetate) to yield a yellow oil as the isolated
product (125 mg, 76 %, 90 % ee). Enantiomeric excess was deter-
1
mined by HPLC. H NMR (500 MHz, CDCl3) δ = 7.41–7.36 (m, 5H, 9-
3
3
H, 10-H, 11-H), 7.25–7.21 (m, 2H, 13-H), 7.03 (“t”, JHH = JHF = 8.7,
2H, 14-H), 5.84 (br s, 1H, 5-H), 5.28–5.20 (m, 2H, 7-H), 4.36–4.27 (m,
3
1H, 1-H), 3.18 (t, JHH = 12.0, 1H, 1-H), 2.97 (dd, JHH = 15.4, 2.1, 1H,
4-H), 2.89 (dd, JHH = 15.4, 6.9, 1H, 4-H), 2.60–2.53 (m, 1H, 2-H), 2.39
(d, JHH = 15.4, 1H, 2-H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ =
207.2 (s, 3-C), 162.2 (d, 1JCF = 247.6 Hz 15-C), 155.4 (s, 6-C), 136.1 (s,
3
8-C), 135.5 (s, 12-C), 128.6 (s, Ar-CH), 128.5 (d, JCF = 5.1 Hz 13-C),
15921–15932; (S,S,S)-BOBPHOS is available
2
Am. Chem. Soc. 2017, 139,
128.4 (s, Ar-CH), 128.1 (s, Ar-CH), 115.7 (d, JCF = 21.5 Hz 14-C), 67.9
from Strem chemicals.
(s, 7-C), 54.1 (s, 5-C), 44.3 (s, 4-C), 40.6 (s, 2-C), 38.9 (s, 1-C) ppm.
19F{1H} NMR (376 MHz, CDCl3) δ = –114.4 (s, 15-F) ppm. HRMS (ES+)
m/z: 350.1155 [M + Na]+, [C19H18O3NF + Na] requires 350.1163.
HPLC (Chiralpack OD-H, hexane/2-propanol 80:20, 0.5 mL/min, RT):
tR = 35.5 min (S), 43.3 min (R). Optical rotation: [α]D20 = –70.3 (c =
1.0, CHCl3).
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Received: March 19, 2020
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Asymmetric Catalysis
S. H. Gilbert, J. A. Fuentes,
D. B. Cordes, A. M. Z. Slawin,
M. L. Clarke* ........................................ 1–7
Phospholane-Phosphite Ligands for
Rh Catalyzed Enantioselective Con-
jugate Addition: Unusually Reactive
Catalysts for Challenging Couplings
Rh catalysts derived from the phos- leads to some difficult asymmetric
pholane-phosphite ligand, BOBPHOS arylations becoming feasible for the
(L1 in picture) promote transmetala- first time, or for others to operate us-
tion of aryl boronic acids more readily ing much lower excess of aryl boronic
than a Rh/BINAP control systems. This acid.
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