Phosphaannulation by palladium-catalyzed carbonylation of C-H bonds of phosphonic and phosphinic acids

Article abstract of DOI:10.1021/ol501066k

An efficient phosphaannulation by Pd-catalyzed carbonylation of C-H bonds of phosphonic and phosphinic acids for the synthesis of oxaphosphorinanone oxides is reported. These compounds are novel phosphorus heterocyclic scaffolds, thus opening a new avenue to sequential C-C/C-O bond formation in one pot.

Full text of DOI:10.1021/ol501066k

Letter
pubs.acs.org/OrgLett
Phosphaannulation by Palladium-Catalyzed Carbonylation of C−H
Bonds of Phosphonic and Phosphinic Acids
Seohyun Shin,† Yeonseok Jeong,† Woo Hyung Jeon, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: An efficient phosphaannulation by Pd-catalyzed
carbonylation of C−H bonds of phosphonic and phosphinic
acids for the synthesis of oxaphosphorinanone oxides is reported.
These compounds are novel phosphorus heterocyclic scaffolds,
thus opening a new avenue to sequential C−C/C−O bond
formation in one pot.
ecause inhibition of β-lactamases remains a practical
method to maintaining the efficacy of β-lactam antibiotics,
C−H bonds were demonstrated for the synthesis of acids,
esters, amides, and ketones,7 there is no synthetic method for
C−H bond carbonylation to prepare oxaphosphorinanone
oxide,8 which can be considered as an inhibitor of β-lactamase
and a bioisoster of acid anhydride. Therefore, C(sp2)−H bond
activation of phosphonic and phosphinic acids followed by
carbonylation has been an irresistible synthetic challenge. In
our continuing efforts to develop efficient C−H activation,9 we
report herein an efficient phosphaannulation by Pd-catalyzed
carbonylation of C−H bonds of phosphonic and phosphinic
acids, producing oxaphosphorinanone oxides, which are novel
phosphorus heterocyclic scaffolds (eq 4).
B
the investigation for inhibitors of these enzymes has continued
during the past 80 years.1 Since the cyclic phosphonates have
been known to be reversible covalent inhibitors of the P99 β-
lactamase, a new synthetic approach to these compounds was
required.2 In this context, we recently developed a wide range
of synthetic methods of cyclic phosphonates through
phosphoryl group-directed C−H bond activation: Rh-catalyzed
oxidative alkenylation/Michael reaction (eq 1),3 Rh- or Ru-
catalyzed C−H activation/cyclization (eq 2),4 and Pd-catalyzed
C−H activation/C−O bond formation (eq 3, Scheme 1).5
Initially, Pd-catalyzed carbonylation of C−H bonds was
examined with ethyl hydrogen dimethylbenzylphosphonate
(1a) (Table 1). First, we employed the optimum reaction
conditions5 of C(sp2)−H activation/C−O cyclization to Pd-
catalyzed carbonylation of 1a under CO atmosphere, thus
producing delightedly the desired carbonylated product 2a
(63%) together with 3a (37%) (entry 1). Although electron-
deficient palladium catalysts such as Pd(TFA)2 and Pd(OTf)2·
2H2O were used, the formation of 3a was still inevitable
(entries 2 and 3). However, when this transformation was
conducted at 60 °C, the carbonylated product 2a was
selectively obtained in 66% yield without the contamination
of 3a (entry 4). The present reaction at 40 °C did not
complete, but there was the selective formation of 2a (entry 5).
Thus, the carbonylation at 60 °C was employed to conduct a
selective formation of 2a. Gratifyingly, when Pd(OAc)2 loading
was lowered from 10 to 5 mol %, the carbonylation still
proceeded well and gave the similar yield (67%) of 2a (entry
6). Increasing the amount (1.5 equiv) of NaOAc failed to
improve the yield (entry 7). AgOAc gave the best result among
the bases such as NaOAc, LiOAc, KOAC, CsOAc, K2HPO4,
Li3PO4, NaHCO3, NaHPO4, and Na2CO3 (see the Supporting
Information). The best reaction conditions could be obtained
with AgOAc (1.5 equiv) and PhI(OAc)2 (1.5 equiv) in the
Scheme 1. Phosphaannulation through Phosphoryl Group-
Directed C−H Activation
Next, we envisioned that transition-metal-catalyzed carbon-
ylation of phosphonic and phosphinic acids would be a highly
desirable synthetic method to access cyclic phosphonates
because carbon monoxide is regarded as an economical and
atom-efficient C1 feed stock.6 Although a multitude of
transition-metal-catalyzed chelation-assisted carbonylation of
Received: April 12, 2014
Published: May 23, 2014
© 2014 American Chemical Society
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Letter
a
methyl and ethyl substituents at the α-position afforded the
carbonylated product 2f in 74% (dr = 2.0:1) yield (entry 6).
To demonstrate the scope of this transformation, a myriad of
benzylphosphonic and phosphinic acid derivatives were
examined under the optimized reaction conditions (Scheme
2). Benzylphosphonic acid 1g having a 3-methyl group on the
Table 1. Optimization of Carbonylation Reaction
temp
(°C)
b
entry
Pd (mol %)
base (equiv)
yield (%)
Scheme 2. Scope of Benzyl Phosphonic and Phosphinic
a
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (10)
Pd(TFA)2 (10)
Pd(OTf)2·2H2O (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1.5)
AgOAc (1)
AgOAc (1.5)
80
80
80
60
40
60
60
60
60
63 (37)
52 (48)
38 (62)
66
Acids
18
67
61
70
c
90 (85)
a
Reaction conditions: 1a (0.2 mmol, 1 equiv), PhI(OAc)2 (1.5 equiv),
b
and DCE (2.0 mL) under CO atmosphere. 1H NMR yields of 2a
using CH2Br2 as an internal standard. Numbers in parentheses indicate
c
1H NMR yields of 3a. Isolated yield of 2a.
presence of Pd(OAc)2 (5 mol %) and selectively provided 2a in
90% yield (isolated yield 85%) in DCE at 60 °C for 20 h under
CO atmosphere (entry 9).
Next, the effect of substituents at the α-position in Pd-
catalyzed carbonylation was examined (Table 2). Introduction
Table 2. Effect of Substituents at the α-Position on Pd-
a
Catalyzed Carbonylation
b
entry
R1
R2
1
2
yield (%)
1
2
3
4
5
6
H
H
1b
1c
1a
1d
1e
1f
2b
2c
2a
2d
2e
2f
NR
NR
85
H
Me
Me
Et
Me
Et
75
n-Pr
Me
n-Pr
Et
63
c
74
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), Pd(OAc)2 (5 mol %),
PhI(OAc)2 (0.3 mmol), and AgOAc (0.3 mmol), 60 °C, 20 h, DCE
b
c
(2.0 mL) under CO atmosphere. Isolated yield. Diastereomeric ratio
= 2.0:1.
of a variety of substituents at the α-positions of ethyl hydrogen
benzylphosphonates 1 obviously influenced the effectiveness of
Pd-catalyzed carbonylation. Pd-catalyzed carbonylations of
ethyl hydrogen benzylphosphonate 1b and methyl-substituted
phosphonate 1c were totally ineffective (entries 1 and 2). These
results indicate that introduction of two substituents at the α-
position is essential for successful carbonylation. However,
introduction of more sterically hindered ethyl and propyl
groups rather than methyl at the α-position lowered slightly
yields of carbonylation and produced 2d and 2e in 75% and
63% yields, respectively (entries 4 and 5). These results are
evidently in contrast to Pd-catalyzed C(sp2)−H activation/C−
O cyclization,5 suggesting that ring size affects oppositely the
effectivness of cyclization in the carbonylation and C−O bond
formation. Ethyl hydrogen benzylphosphonate 1f having both
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), PhI(OAc)2
(0.3 mmol), and AgOAc (0.3 mmol), 60 °C, 20 h, and DCE (2.0 mL)
under CO atmosphere. Reaction time 36 h.
b
phenyl ring was subjected to Pd-catalyzed carbonylation
regioselectively at the sterically less hindered position to
provide the desired oxaphosphorinanone oxide 2g in 77% yield.
Benzylphosphonic acids 1h and 1i possessing 4-methyl and 4-
tert-butyl groups on the phenyl ring were smoothly transformed
to the desired carbonylated products 2h and 2i in 81% and 67%
yields, respectively. Substrates 1j and 1k having an electron-
donating methoxy group were cyclized to oxaphosphorinanone
oxides 2j and 2k in good yields. 2-Naphthalenyl-substituted
phosphonic acid 1l was also converted to the cyclized product
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Letter
2l in 73% yield. Phosphonic acids 1m, 1n, and 1o having
electron-withdrawing chloro and bromo groups on the phenyl
ring underwent Pd-catalyzed carbonylation with PhI(OAc)2 (2
equiv) to deliver the desired products 2m, 2n, and 2o in yields
ranging from 53% to 73%. The tolerance of chloro and bromo
groups is meaningful because of the possibility of a following
catalytic cross-coupling reaction. To our delight, the present
carbonylation proceeded despite the presence of a trifluor-
omethyl group on the phenyl ring and gave 2p in acceptable
yield. Interestingly, when phenyl dimethylbenzylphosphinic
acid 1q was used, the carbonylation reaction proceeded with
PhI(OAc)2 (2 equiv) after 36 h, affording oxaphosphorinanone
oxide 2q in 54% yield. Also, phenylphosphinic acid 1r bearing a
4-methyl group on the phenyl ring was transformed to the
desired carbonylated product 2r in 67% yield. Substrate 1s
having two ethyl groups at the α-position afforded the
carbonylated product 2s in 76% yield. Phosphonic acids 1t,
1u, and 1v having five- and six-membered rings of spiro type at
the α-position are also excellent substrates for the C−H
carbonylation, producing the desired oxaphosphorinanone
oxides in high yields ranging from 60% to 86%.
We carried out kinetic isotope effect (KIE) studies to prove
the reaction mechanism (Scheme 4). In the case of
Scheme 4. KIE Experiments with Isotopically Labeled
Compounds
intermolecular competition reaction using 1a and 1a-[D5], a
KIE was detected (kH/kD = 3.76). These results indicate that
the C−H cleavage at the ortho-position of benzylphosphonic
acids is most likely involved with the rate-limiting step.
A plausible mechanism for this catalytic carbonylation is
described in Scheme 5. The proposed catalytic cycle
Scheme 5. Proposed Mechanism of Carbonylation
Next, this transformation was employed to a cascade of
phosphonic acids 4 possessing biaryl moieties (Scheme 3). The
Scheme 3. Scope of Biaryl Phosphonic Acids
commences by coordination of the OH group in the
phosphonic and phosphinic acids 1 and 4 to Pd(II) catalyst
to provide palladium(II) phosphonate and phosphinate,
respectively. Subsequent ortho-metalation to provide pallada-
cycle intermediate I, CO binding, 1,1-migratory insertion, and
reductive elimination affords the corresponding carbonylated
products, oxaphosphorinanone oxides 2 and 5. However, the
possibility of a mechanism of carbonylation via a Pd(II)/
Pd(IV) process cannot be ruled out.
In conclusion, we have developed an efficient phosphaannu-
lation by Pd-catalyzed carbonylation of C−H bonds of
phosphonic and phosphinic acids, leading to the construction
of oxaphosphorinanone oxides, which are novel phosphorus
heterocyclic privileged structures. Thus, this transformation
opens a new avenue to sequential C−C/C−O bond formation
in one pot because carbon monoxide represents an economical
and atom-efficient C1 building block.
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), PhI(OAc)2
(0.3 mmol), and AgOAc (0.3 mmol), 60 °C, 20 h, DCE (2.0 mL)
under CO atmosphere. Reaction time 36 h. PhI(OAc)2 (0.4 mmol)
was used.
b
c
present carbonylation worked equally well with biaryl
phosphonic acid 4a, resulting in the production of 5a in 76%
yield. For biaryl substrates (4b and 4c) having 3-methyl and 4-
tert-butyl groups, the corresponding oxaphosphorinanone
oxides (5b and 5c) were obtained in 60% and 80% yields,
respectively. Biaryl phosphonic acid (4d and 4e) having the
strong electron-donating methoxy group turned out to be
compatible with the reaction conditions. An electron-with-
drawing chloro group was tolerated on the substituted aryl ring,
thus allowing an opportunity for further functionalization. We
were pleased to obtain 5h from substrate 4h possessing a five-
membered ring of spiro type at the α-position.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
C
NMR spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Letter
Chem. Commun. 2011, 47, 12224. (r) Xie, P.; Xie, Y.; Qian, B.; Zhou,
H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 9902. (s) Guan, Z.-
H.; Chen, M.; Ren, Z.-H. J. Am. Chem. Soc. 2012, 134, 17490. (t) Lang,
R.; Shi, L.; Li, D.; Xia, C.; Li, F. Org. Lett. 2012, 14, 4130. (u) Zhang,
H.; Shi, R.; Gan, P.; Liu, C.; Ding, A.; Wang, Q.; Lei, A. Angew. Chem.,
Int. Ed. 2012, 51, 5204.
(8) Miles, J. A.; Street, R. W. J. Org. Chem. 1978, 43, 4668.
(9) (a) Chary, B. C.; Kim, S.; Park, Y.; Kim, J.; Lee, P. H. Org. Lett.
2013, 15, 2692. (b) Chan, L. Y.; Kim, S.; Ryu, T.; Lee, P. H. Chem.
Commun. 2013, 49, 4682. (c) Park, S.; Seo, B.; Shin, S.; Son, J.-Y.; Lee,
P. H. Chem. Commun. 2013, 49, 8671. (d) Mo, J.; Lim, S.; Ryu, T.;
Kim, S.; Lee, P. H. RSC Adv. 2013, 3, 18296. (e) Kang, D.; Cho, J.;
Lee, P. H. Chem. Commun. 2013, 49, 10501. (f) Kim, J.; Kang, D.; Yoo,
E. J.; Lee, P. H. Eur. J. Org. Chem. 2013, 7902. (g) Ryu, T.; Min, J.;
Choi, W.; Jeon, W. H.; Lee, P. H. Org. Lett. 2014, DOI: 10.1021/
ol501250t. (h) Kim, Y.; Cho, S.; Lee, P. H. Org. Lett. 2014,
DOI: 10.1021/ol501207w. (i) Shin, S.; Kang, D.; Jeon, W. H.; Lee, P.
H. Beilstein J. Org. Chem. 2014, 10, in press.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Author Contributions
†These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSIP) (2014001403). This paper is dedicated to Professor
Sunggak Kim (Nangyang Technological University) on the
occasion of his honorable retirement.
REFERENCES
■
(1) (a) Pratt, R. F. In The Chemistry of β-Lactams; Page, M. I., Ed.;
Chapman & Hall: London, 1992; pp 229−271. (b) Pratt, R. F. Science
1989, 246, 917. (c) Medeiros, A. A. Clin. Infect. Dis. 1997, 24 (Suppl.
1), 519. (d) Miller, L. A.; Ratnam, K.; Payne, D. J. Curr. Opin.
Pharmacol. 2001, 1, 451.
(2) (a) Kaur, K.; Lan, M. J. K.; Pratt, R. F. J. Am. Chem. Soc. 2001,
123, 10436. (b) Kaur, K.; Adediran, S. A.; Lan, M. J. K.; Pratt, R. F.
Biochemistry 2003, 42, 1529. (c) Silvaggi, N. R.; Kaur, K.; Adediran, S.
A.; Pratt, R. F.; Kelly, J. A. Biochemistry 2004, 43, 7046.
(3) Ryu, T.; Kim, J.; Park, Y.; Kim, S.; Lee, P. H. Org. Lett. 2013, 15,
3986.
(4) (a) Seo, J.; Park, Y.; Jeon, I.; Ryu, T.; Park, S.; Lee, P. H. Org.
Lett. 2013, 15, 3358. (b) Park, Y.; Seo, J.; Park, S.; Yoo, E. J.; Lee, P. H.
Chem.Eur. J. 2013, 19, 16461. (c) Park, Y.; Jeon, I.; Shin, S.; Min, J.;
Lee, P. H. J. Org. Chem. 2013, 78, 10209.
(5) Eom, D.; Jeong, Y.; Kim, Y. R.; Lee, E.; Choi, W.; Lee, P. H. Org.
Lett. 2013, 15, 5210.
(6) (a) Schoenberg, A.; Bartoleti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(c) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082. (d) Yoo, E.
J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378. (e) Giri, R.;
Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686. (f) Wriggles-
worth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org.
Lett. 2011, 13, 5326. (g) Lu, Y.; Leow, D.; Wang, X.; Engle, K. M.; Yu,
J.-Q. Chem. Sci. 2011, 2, 967. (h) Haffemayer, B.; Gaunt, M. J. Chem.
Sci. 2011, 2, 312.
(7) (a) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am.
Chem. Soc. 1996, 118, 493. (b) Fukuyama, T.; Chatani, N.; Tatsumi, J.;
Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1998, 120, 11522. (c) Chatani,
N.; Yorimitsu, S.; Asaumi, T.; Kakiuchi, F.; Murai, S. J. Org. Chem.
2002, 67, 7557. (d) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.;
Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem.
Soc. 2004, 126, 14342. (e) Asaumi, T.; Matsuo, T.; Fukuyama, T.; Ie,
Y.; Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004, 69, 4433. (f) Houlden,
C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagne,
M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int. Ed.
2009, 48, 1830. (g) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J.
Am. Chem. Soc. 2009, 131, 6898. (h) Guan, Z.-H.; Ren, Z.-H.; Spinella,
S. M.; Yu, S.; Liang, Y.-M.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 729.
(i) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2010, 49, 7316. (j) Haffemayer, B.; Gulias, M.; Gaunt, M. J.
Chem. Sci. 2011, 2, 312. (k) Lang, R.; Wu, J.; Shi, L.; Xia, C.; Li, F.
́
Chem. Commun. 2011, 47, 12553. (l) Lopez, B.; Rodriguez, A.; Santos,
D.; Albert, J.; Ariza, X.; Garcia, J.; Granell, J. Chem. Commun. 2011, 47,
1054. (m) Du, Y.; Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47,
12074. (n) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.;
Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070. (o) Wrigglesworth, J.
W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett. 2011,
13, 5326. (p) Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem.
Eur. J. 2011, 17, 9581. (q) Chen, H.; Cai, C.; Liu, X.; Li, X.; Jiang, H.
2933
dx.doi.org/10.1021/ol501066k | Org. Lett. 2014, 16, 2930−2933