Design of a Br?nsted acid with two different acidic sites: Synthesis and application of aryl phosphinic acid-phosphoric acid as a Br?nsted acid catalyst

Article abstract of DOI:10.1039/c5cc06787a

A Br?nsted acid with two different acidic sites, aryl phosphinic acid-phosphoric acid, has been synthesized. Its catalytic performance was assessed in the hetero-Diels-Alder reaction of aldehyde hydrates with Danishefsky's diene, achieving high reaction efficiency.

Full text of DOI:10.1039/c5cc06787a

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DOI: 10.1039/C5CC06787A
Journal Name
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COMMUNICATION
Design of a Brønsted Acid with Two Different Acidic
Sites: Synthesis and Application of Aryl Phosphinic
Acid-Phosphoric Acid as a Brønsted Acid Catalyst
Cite this: DOI: 10.1039/x0xx00000x
N. Momiyama,*a T. Narumi,b,c and M. Terada*c,d
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
Brønsted acid with two different acidic sites, aryl
(a) Previous study
(b) This study
phosphinic acid-phosphoric acid, has been synthesized. Its
catalytic performance was assessed in the hetero-Diels–Alder
reaction of aldehyde hydrates with Danishefsky’s diene,
achieving high reaction efficiency.
G
Ar
R
O
OH
OH
O
P
P
O
“Same” acidic sites
with
“Different” acidity
O
“Different”
acidic sites
OH
O
OH
O
O
P
O
P
Brønsted acids are arguably one of the most conventional, yet
reliable, catalysts in organic synthesis.1 In the past decade, chiral
Brønsted acids have been studied enthusiastically and become
valuable tools in asymmetric synthesis.2 Recently, we contributed
to this field by developing a C1ꢀsymmetric bisꢀphosphoric acid
possessing both a sterically demanding 2,4,6ꢀtriisopropylphenyl
group and an electronꢀwithdrawing perfluorophenyl group (Fig. 1
(a)).3 We demonstrated that two phosphoric acid groups with
individually different acidities can play distinct roles in catalyst
behaviour through hydrogen bonding interactions. Hence, we were
interested to explore whether a combination of different acidic
functional groups, in particular an aryl phosphinic acidꢀphosphoric
acid, would function as an efficient Brønsted acid catalyst (Fig. 1
(b)). Although a variety of Brønsted acids have been designed and
exploited as chiral molecular catalysts, none are designed aryl
phosphinic acids, despite the inherent potential of their molecular
recognition abilities.4,5 We expected that the Brønsted acidꢀbase
nature of an aryl phosphinic acid, in combination with a phosphoric
acid, would offer a new approach to the design of chiral Brønsted
acid catalysts. However, research in this direction remains elusive,
even for racemic syntheses. This prompted us to develop a synthetic
methodology for this congested aryl phosphinic acid to verify the
potential of a Brønsted acid catalyst system containing two different
acidic sites.6 Here, we describe the synthesis of an aryl phosphinic
acidꢀphosphoric acid with a metaꢀquaterphenyl skeleton and its
successful application as a heteroꢀcombined Brønsted acid catalyst in
the highly efficient heteroꢀDiels–Alder reaction of aldehyde hydrates
with Danishefsky’s diene.7
O
O
G'
Ar
EWG
Fig. 1 Diagram of design components: (a) Chiral bis-phosphoric acid, (b) aryl
phosphinic acid–phosphoric acid, a Brønsted acid containing two different acidic
sites.
Our prime concern was synthesis of the sterically congested aryl
phosphinic acid essential to the design concept for the Brønsted acid
containing different acidic sites. Construction of the aryl phosphinic
acid moiety is generally conducted by nucleophilic substitution of
dichloroarylphosphine with aryllithium precursors, followed by
oxidation from trivalent to a pentavalent phosphorus compound
(Scheme 1 (a)).8 Unfortunately, during this study, we faced
difficulties applying this general oxidation procedure to other
strucures, presumably due to steric constrains.9 In addition, it was
hard to modify the substituent on phosphorous, preventing further
elaboration of the catalyst system. To circumvent this issue, we
sought to develop a reliable and a flexible synthetic route to aryl
phosphinic acidꢀphosphoric acid 1.
Our strategy to overcome this issue was through initial attachment
of a pentavalent phosphorus group (Scheme 1 (b)). We planned the
nucleophilic substitution of Grignard reagents to aryl phosphonic
chloride ethyl ester,10 followed by Miyaura borylation11 and Suzukiꢀ
Miyaura coupling.12 Since a variety of Grignard reagents are readily
available, this synthetic route was expected to be far more feasible
than previous route via a trivalent phosphorus compound.
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DOI: 10.1039/C5CC06787A
Table 1 Nucleophilic substitution of phosphinic acid monoester 5a
(a) Reported protocol
G
Ph
Ph
1) SOCl2, cat. DMF
/ toluene, 60 ° C
MX
G
Ar
O
O
Cl
Cl
P
R
P
P
R
Cl
2) reagents / THF, ꢀ78 °C
OEt
OEt
P
R
Nucleophilic
Substitution
Cl
OH
Cl
Ar
Trivalent-phosphorus
5
6
Entry
Reagents
Yield (%)b
G
G
1
2
3
4
5
PhMgBr
3,5ꢀ(CF3)2C6H3MgBr
BnMgCl
BnMgCl, CeCl3
iꢀPrMgCl, CeCl3
96
73
41
80
45
OH
O
P
P
R
Hydrolysis
Oxidation
OH
Ar
R
Ar
(b) This study : Development of synthetic route to 1
a See ESI for details. b Isolated yield. c Chlorination reactions were conducted
without DMF, see ESI for details.
G
G
R—MX
Borylation
O
O
P
Y
P
R
OEt Nucleophilic
OEt
Among the synthesized arylphosphinates, 6a was chosen as a
representative strucure for further synthesis. Preparation of 4,4,5,5ꢀ
tetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl arylphosphinate 7a was
achieved by a palladiumꢀcatalyzed borylation reaction17 (Scheme 3).
For instance, the reaction of 6a with bis(pinacolato)diboron in the
presence of Pd2dba3·CHCl3, XPhos, and K3PO4 in 1,4ꢀdioxane/H2O
at 80 °C for 15 h gave rise to desired product 7a in 82% yield. To
consolidate the aryl phosphinate unit into a biphenol framework, the
wellꢀestablished SuzukiꢀMiyaura cross coupling18 was conducted,
and an aryl phosphinate 7a was easily introduced. In the consecutive
MOM ether deprotection, employment of Amberlystꢀ15 turned out
to be essential to obtain desired product 8a,19 while treatment with
aqueous conc. HCl solution was totally unsuccessful, affording only
9a (Scheme 4). Construction of the cyclic phosphoric acid core was
realized by deprotonation of 8a with NaH and subsequent
phosphorylation. Finally, removal of the ethyl group in 10a by
trimethylsilyl iodide afforded the requisite aryl phosphinic acidꢀ
phosphoric acid 11a (Scheme 5).20
Substitution
Cl
Cl
Pentavalent-phosphorus
G
Y = OH
Y = Cl
O
P
OEt
B
R
G
G
Ar—X'
O
O
P
P
R
OEt
Deporotection
OH
Coupling
of Et Group
Ar
Ar
R
1
Scheme 1 Key steps in the synthesis of aryl phosphinic acid-phosphoric acid.
As shown in Scheme 2, we initially prepared diethyl [1,1’ꢀ
biphenyl]ꢀ2ꢀylphosphonate (3) from commercially available 2ꢀ
bromobiphenyl (2) via standard procedure.13 Selective orthoꢀ
lithiation14 of 3 and subsequent chlorination were then performed,
affording phosphate 4 in 85% yield. Subsequent saponification of 4
resulted in the formation of phosphonic acid monoethyl ester 5
(98%).15
Ph
Pd2dba3—CHCl3 (2.5 mol%)
XPhos (10 mol%)
K3PO4 (2 eq)
O
6a
P
OEt
+
B
Ph
O
O
O
O
1,4ꢀdioxane : H2O = 10 : 1
80 °C, 15 h
O
O
Ph
Ph
Ph
B
B
Ph
Br
a, b
c, d
e
O
O
82% yield
O
7a
P
P
P
OEt
OEt
OEt
Cl
OEt
Cl
OH
OEt
Scheme 3 Palladium-catalyzed borylation.
2
3
4
5
Ph
Ph
Scheme 2 Synthesis of phosphonic acid monoester 5. (a) n-BuLi, THF, –90 °C; (b)
ClP(=O)(OEt)2, THF, –90 °C, 90%; (c) s-BuLi, TMEDA, Et2O, –78 °C; (d) C2Cl6, –78 °C
to rt; 85%; (e) 25% KOH aq., 1,4-dioxane, 100 °C, 98%.
EtO
P
Pd2dba3—CHCl3 (5 mol%)
I
SPhos (20 mol%)
O
7a (1.1 eq), K3PO4 (2 eq)
OMOM
OMOM
OMOM
OMOM
With phosphonic acid monoethyl ester 5 in hand, we examined the
nucleophilic substitution of 5, which was key to delivering
structurally diverse aryl phosphinic acid units (Table 1). Treatment
of 5 with thionyl chloride (10 equiv.) in the presence of a catalytic
amount of DMF in toluene at 60 °C for 9 h, then reaction with aryl
Grignard reagents at –78 °C furnished ethyl diarylphosphinates 6a
and 6b in yields of 96% and 73%, respectively (Entries 1 and 2).10
With the same procedure, a considerable decline in the yield was
observed when the reaction was conducted using benzyl Grignard
reagent (Entry 3). Fortunately, adding cerium chloride significantly
improved the yield of 6c from 41% to 80% (Entry 4).16
Furthermore, this allowed other alkyl Grignard reagents, such as isoꢀ
propyl Grignard, to become applicable, affording the substitution
product 6d in a moderate yield (Entry 5).
1,4ꢀdioxane : H2O = 10 : 1
110 °C, 15 h
> 95% conv.
Ph
Ph
Ph
EtO
P
O
O
P
condition
Ph
+
O
OH
OH
OH
8a
9a
condition
8a
9a
major
<5% yield
A
B
conc. HCl aq. / CH2Cl2–MeOH
Amberlystꢀ15 / CH2Cl2
<1% yield
57% yield
Scheme 4 Synthesis of biphenol-containg phosphinic acid monoester 8a
.
2 | J. Name., 2012, 00, 1-3
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DOI: 1C0.O10M39M/CU5CNCI0C6A78T7IOA N
Ph
Ph
TBSO
O
CCl3
HO
CCl3
1) 11a (5 mol%)
Ph
+
RO
P
O
MS4Å
toluene
O
OH
P
O
OR
O
OMe
a, b, c
10 °C, 24 h
Ph
P
O
12
13b
14b
81% yield
OH
OH
OH
2) CF3CO2H
O
Scheme 6 Hetero-Diels–Alder reaction of chloral hydrate (13b) with
Danishefsky’s diene 12 catalyzed by Phosphinic acid–phosphoric acid 11a.
10a : R = Et
11a : R = H
8a : R = Et
d
Scheme 5 Synthesis of phosphinic acid-phosphoric acid 11a. (a) NaH, THF, 0 °C;
(b) POCl3, –78°C to rt; (c) H2O, >95% conv.; (d) NaI, Me3SiCl, CH2Cl2, rt, 44% (from
8a).
In summary, we have developed a reliable synthetic route to
sterically congested aryl phosphinic acids and have validated the
utility of the design concept with a Brønsted acid with two different
acidic sites, aryl phosphinic acidꢀphosphoric acid. The capability of
this compound as a Brønsted acid catalyst has been demonstrated by
successfully applying to a highly efficient heteroꢀDiels–Alder
reaction of hydrated aldehydes, phenylglyoxal hydrate (13a) and
chloral hydrate (13b), with Danishefsky’s diene 12. We believe that
the concept of heteroꢀcombined Brønsted acids provides a new
paradigm for cultivating the potential functions of chiral Brønsted
acid catalysts by taking full advantage of the sophisticated hydrogenꢀ
bonding network between catalyst and substrate. Further studies
regarding chiral Brønsted acid catalysts with two different acidic
sites are ongoing and will be reported in due course.
With an effective synthetic protocol in hand, we evaluated the
activity of aryl phosphinic acidꢀphosphoric acid 11a as a Brønsted
acid catalyst to demonstrate the efficacy of the design. For this
purpose, we initially chose the heteroꢀDiels–Alder reaction of
phenylglyoxal hydrate (13a) with Danishefsky’s diene 1221 (Table 2)
due to these expected noteworthy advantages: (1) adequate acidity22
from the phosphinic acidꢀphosphoric acid combination that directly
generates
a nonꢀhydrate form of glyoxal, as a beneficial
consequence, 13a could exert a prominent electrophile without
arduous distillation and manipulation7; (2) exquisite acidity from the
phosphinic acidꢀphosphoric acid combination that could
accommodate the use of acidꢀsusceptible dienes such as
Danishefsky’s dienes without decomposition during the reaction.
We found that the heteroꢀDiels–Alder reaction of 13a with 12, 11a
(5 mol%), and 4Å molecular sieves in toluene at –20 °C for 48 h
gave rise to product 14a in 82% yield (Entry 1). In contrast,
reactions conducted in the presence of a commercially available
phosphoric acid diphenyl ester, diphenyl phosphinic acid, or an
easily synthesized biphenolꢀderived phosphoric acid, gave
insufficient yields with even twice the catalyst loading (Entries 2, 3,
and 4). Additionally, chloral hydrate (13b) was applicable,23 with
heteroꢀDiels–Alder adduct 14b obtained in 81% yield (Scheme 6).
These results suggested that aryl phosphinic acidꢀphosphoric acid
11a would be a useful and valuable Brønsted acid catalyst for
achieving high yields in the heteroꢀDiels–Alder reaction of hydrated
aldehydes with acidꢀsusceptible dienes, such as Danishefsky’s diene.
Notes and references
a Institute for Molecular Science, and SOKENDAI (the Graduate School
for Advanced Studies), Okazaki, Aichi 444ꢀ8787, Japan
b Cooperative Education Program of IMS with Tohoku University
c Department of Chemistry, Graduate School of Science, Tohoku
University, Aobaꢀku, Sendai 980ꢀ8578, Japan
d Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, Aobaꢀku, Sendai 980ꢀ8578, Japan
†
Electronic Supplementary Information (ESI) available: General
experimental, reaction data, and spectra; copies of all the new
compounds. See DOI: 10.1039/c000000x/. See DOI: 10.1039/c000000x/
1
2
For selected reviews of Brønsted acid catalysts, see: (a) T. Akiyama,
Chem Rev. 2007, 107, 5744ꢀ5758. (b) C. H. Cheon, H. Yamamoto,
Table 2 Evaluation of phosphinic acid–phosphoric acid catalyst in the
heteroꢀDiels–Alder reaction of phenylglyoxal hydrate (13a) with
Danishefsky’s diene 12a
.
Chem. Commun. 2011, 47, 3043ꢀ3056. (c) H. Miyabe, Y. Takemoto,
in Comprehensive Organic Synthesis 2nd Ed., ed. P. Knochel and G.
A. Molander, Elsevier, Oxford, 2014, 1, pp. 751ꢀ769.
TBSO
O
O
1) catalyst
O
HO
For selected reviews of chiral Brønsted acid catalysts, see: (a) T.
Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999ꢀ
1010. (b) D. Kampen, C. M. Reisinger, B. List, Top. Curr. Chem.
2010, 291, 395ꢀ456. (c) F. Z. Peng, Z. H. Shao, Curr. Org. Chem.
2011, 15, 4144ꢀ4160. (d) Y. E. Trkmen, Y. Zhu, V. H. Rawal, in
+
Ph
Ph
MS4Å
toluene
ꢀ20 °C, 48 h
O
OH
OMe
12
13a
14a
2) CF3CO2H
Entry
Catalyst (mol%)
11a (5)
Ph2P(=O)OH (10)
(PhO)2P(=O)OH (10)
Yield (%)b
82
21
15
1
2
3
Comprehensive Enantioselective Organocatalysis ed. P. I. Dalko,
Wiley, Weinheim, 2013, 2, pp. 241ꢀ288. (e) N. Mase, Y. Hayashi, in
Comprehensive Organic Synthesis 2nd Ed., ed. P. Knochel and G. A.
Molander, Elsevier, Oxford, 2014, 1, pp. 751ꢀ769.
O
O
P
4
(10)
10
OH
O
3
4
N. Momiyama, K. Funayama, H. Noda, M. Yamanaka, N. Akasaka,
S. Ishida, T. Iwamoto, M. Terada, Manuscript is in preparation.
For reported examples of aryl phosphinic acid as Brønsted acid
catalyst, see: (a) G. B. Rowland, H. Zhang, E. B. Rowland, S.
Chennamadhavuni, Y. Wang, J. C. Antilla, J. Am. Chem. Soc. 2005,
a See ESI for details. b Isolated yield.
127, 15696ꢀ15697. (b) D. M. Rubush, T. Rovis, Synlett, 2014, 25
,
713ꢀ717.
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5CC06787A
5
For selected examples of aryl phosphinic acids and their analogs as
hydrogen bonding motif, see: (a) Y. Kobayashi, F. Morisawa, K.
Saigo, Org. Lett. 2004, , 4227ꢀ4230. (b) F. Ma, X. Shen, J. O. Yang,
6
Z. Deng, C. Zhang, Tetrahedron Asymmetry 2008, 19, 31ꢀ37. (c) N.
Riberiro, Y. Kobayashi, J. Maeda, K. Saigo, Chirality, 2011, 23, 438ꢀ
448.
6
For reported examples of Brønsted acid catalyst with two different
acidic sites, see: (a) N. Momiyama, H. Yamamoto, J. Am. Chem. Soc.
2005, 127, 1080ꢀ1081. (b) A. Hasegawa, Y. Naganawa, M. Fushimi,
K. Ishihara, Yamamoto, H. Org. Lett. 2006,
(a) T. Tonoi, K. Mikami, Tetrahedron Lett. 2005, 46, 6355ꢀ6358. (b)
N. Momiyama, H. Tabuse, M. Terada, J. Am. Chem. Soc. 2009, 131
8, 3175ꢀ3178.
7
8
,
12882ꢀ12883. (c) B. Zhao, T. P. Loh, Org. Lett. 2013, 15, 2914ꢀ2917.
(a) E. Rivard, A. D. Sutton, J. C. Fettinger, P. P. Power, Inorg. Chim.
Acta. 2007, 360, 1278ꢀ1286. (b) B. Hoge, B. Kurscheid, S. Peuker,
W. Tyrra, H. T. M. Fischer, Z. Anorg. Allg. Chem. 2007, 633, 1679ꢀ
1685. (c) J. P. Abell, H. Yamamoto, J. Am. Chem. Soc. 2009, 131
,
15118ꢀ15119.
9
Initial study based on reported protocol was shown in Electronic
supplementary information (ESI).
10 M. Hatano, R. Gouzu, T. Mizuno, H. Abe, T. Yamada, K. Ishihara,
Catal. Sci. Technol. 2011, , 1149ꢀ1158.
11 For representative review, see: T. Ishiyama, N. Miyaura, Chem. Rec.
2004, , 271ꢀ280.
1
3
12 For representative reviews, see: (a) A. Suzuki, J. Organomet. Chem.
1999, 576, 147ꢀ168. (b) A. J. J. Lennox, G. C. L. Jones, Angew.
Chem., Int. Ed. 2013, 52, 7362ꢀ7370. (c) A. J. J. Lennox, G. C. L.
Jones, Chem. Soc. Rev. 2014, 43, 412ꢀ443.
13 L. Deng, J. Diao, P. Chen, V. Pujari, Y. Yao, G. Cheng, D. C. Crick,
B. V. V. Prasad, Y. Song, J. Med. Chem. 2011, 54, 4721ꢀ4734.
14 E. Vedejs, O. Daugulis, S. T. Diver, D. R. Powell, J. Org. Chem.
1998, 63, 2338ꢀ2341.
15 S. Saito, J. Kawabata, Helv. Chimi. Acta. 2006, 89, 1395ꢀ1407.
16 T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima, Y. Kamiya, J.
Am. Chem. Soc. 1989, 111, 4392ꢀ4398.
17 K. L. Billingsley, T. E. Barder, S. L. Buckwald, Angew. Chem., Int.
Ed. 2007, 46, 5359ꢀ5363.
18 T. E. Barder, S. D. Walkler, J. R. Martinelli, S. L. Buchwald, J. Am.
Chem. Soc. 2005, 127, 4685ꢀ4696.
19 (a) H. Dulphy, J. L. Gras, T. Lejon, Tetrahedron, 1996, 52, 8517ꢀ
8524. (b) K. Tangdenpaisal, S. Sualek, S. Ruchirawat, P. Ploypradith,
Tetrahedron, 2009, 65, 4316ꢀ4325.
20 G. M. Blackburn, D. Ingleson, J. Chem. Soc., Perkin, Trans. 1 1980,
1150ꢀ1153.
21 Representative reports of Danishefsky’s dienes, see: (a) D.
Danishefsky, T. Kitahara, J. Am. Chem. Soc. 1974, 96, 7807ꢀ7808.
(b) S. Danishefsky, Acc. Chem. Res. 1981, 14, 400ꢀ406. (c) S. J.
Danishefsky, M. P. DeNinno, Angew. Chem., Int. Ed. 1987, 26, 15ꢀ
23.
22 A. N. Matveeva, I. Y. Kudryavtsev, A. A. Grigoreva, E. I. Matrosov,
E. K. Kuznetsova, L. S. Zakharov, M. I. Kabachnik, B. Acad. Sci.
USSR Ch+, 1982, 31, 1329ꢀ1335.
23 (a) W. J. Dale, A. J. Sisti, J. Am. Chem. Soc. 1954, 76, 81ꢀ82. (b) A.
Sera, Y. Iwasaki, M. Umeda, K. Itoh, Heterocycles, 1991, 32, 273ꢀ
278.
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