De Novo Construction of Substituted Terephthalates via Phosphine Catalyzed Domino Benzannulation Reactions

Article abstract of DOI:10.1002/adsc.202001513

The robustness of phosphine catalysis enabling the domino benzannulation reactions of allenoates with enamines is described. A broad array of substituted terephthalates were delivered under simple and practical reaction conditions. Furthermore, the reaction could be carried out on a gram scale with higher yield, and various conversions of the terephthalate products demonstrate the versatility of this transformation. (Figure presented.).

Full text of DOI:10.1002/adsc.202001513

COMMUNICATIONS
DOI: 10.1002/adsc.202001513
De Novo Construction of Substituted Terephthalates via
Phosphine Catalyzed Domino Benzannulation Reactions
Dan Wang,a Junhui Lin,a Yannan Zhu,a and You Huanga,*
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Fax: (+86)-22-2350-3159
E-mail: hyou@nankai.edu.cn
Manuscript received: December 4, 2020; Revised manuscript received: February 4, 2021;
Version of record online: Februar 9, 2021
Dedicated to 100th anniversary of Chemistry at Nankai University.
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001513
muconic acid, ethanol, and ethylene as the reactants,
through a cascade process combining esterification,
Abstract: The robustness of phosphine catalysis
enabling the domino benzannulation reactions of
Diels-Alder cycloaddition and dehydrogenation
allenoates with enamines is described. A broad array
(Scheme 1a).[5] Whereas, more rigorous conditions are
of substituted terephthalates were delivered under
still required to proceed this protocol. Alternatively,
simple and practical reaction conditions. Further-
transition-metal-catalyzed methods have long proven
more, the reaction could be carried out on a gram
to be valuable for transferring functional group to
scale with higher yield, and various conversions of
precursor substrates.[6] For instance, Ritter’s group
the terephthalate products demonstrate the versatil-
ity of this transformation.
showcased Ru-catalyzed CÀ H amination, leading to
amino-substituted terephthalate (Scheme 1a).[7] Ben-
zannulation was also pursued vigorously as a straight-
forward approach to polysubstituted aromatic
Keywords: Terephthalates; Benzannulation; Alle-
compounds.[8] Among of those, transition-metal cata-
noates; Enamines; Phosphine
lysts have demonstrated great potentials to carry out
the preparation of functionalized benzenes. In recent
advances, Moret’s group achieved [2+2+2] cyclo-
Terephthalate structure commonly occurs in molecules trimerization with the use of Ni(0) complexes,
within a diverse array of biological and pharmaceutical selectively affording carboxylate substituted terephtha-
activities, as well as finding significant applications in lates from terminal alkynes (Scheme 1a).[9] Although a
polymer materials.[1] It is noteworthy that the global small number of such methods have been exploited,
consumption of polyethylene terephthalate (PET) is multistep strategies and restriction on the substitution
estimated to be 108 million tons in 2020, which will
utilize immense amounts of fossil oil.[2] In addition,
introduction of terephthalate-containing systems allows
increasing structural novelty and adding its value as a
versatile building unit in pharmacologically relevant
compounds (Figure 1).[3] Given its great prominence,
seeking for efficient and selective methodologies to
generate substituted terephthalates has remained a
perennial interest. In principle, a conjugated diene and
an alkene may enable direct access to p-Xylene via
Diels-Alder reaction and dehydrogenation sequence,
which need further oxidation to afford terephthalate.[4]
Pleasantly, Xu’s group proposed a synthetic route to
diethyl terephthalate (DET), using biomass-derived
Figure 1. Sampling of pharmaceuticals containing terephtha-
lates.
Adv. Synth. Catal. 2021, 363, 1873–1877
1873
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
reaction of enamines and allenoates (Scheme 1b).
Notably, terephthalate molecules possessing diverse
ester groups, which are otherwise challenging to
synthesize, could be precisely prepared under our
reaction condition. In addition, this elegant strategy
constitute a credible transform leading to biphenyl
skeletons, versatile building blocks in synthetic organic
chemistry.
Exploratory studies began with the [4+2] annula-
tion of ethyl (Z)-2-((4-methylphenyl)sulfonamido)-3-
phenylacrylate (1a) and benzyl 2-(acetoxymethyl)buta-
2,3-dienoate (2a) as model substrates(Table 1). Ex-
pectedly, preliminary assessment with typical
phosphine was found to be very encouraging, which
produced the desired 5- benzyl 2-ethyl [1, 1’-biphen-
yl]-2, 5-dicarboxylate (3aa) in moderate yield when
the reaction completed within five hours (entry 1).
Brief bases screening only showcased unconspicuous
advances (entries 1–5), and Na2CO3 proved to be the
best choice for this domino process, giving 3aa with
68% yield. Some solvents were attempted, whereas
toluene was still the optimum solvent (entry 3 vs
entries 6–10). Then meticulous optimization was
continued and a pronounced improvement was found
in yield under the catalysis of PPh3 after extensive
Table 1. Screening conditions of the reaction.[a]
Scheme 1. Overview of the work.
pattern still limit the generality. The pronounced
limitation of these strategies, coupled with the increas-
ing emphasis on sustainability, necessitates the devel-
opment of inclusive green approaches toward the
construction of polysubstituted aromatic compounds.[10]
From the viewpoint of diversity-oriented synthesis,
developing fundamentally distinct methods for the
construction of terephthalates in efficient but simple
manner is still in great demand as we deem necessary,
but remains a significant challenge.
Despite phosphine-catalyzed annulation of alle-
noates has become one of the most efficient strategy
for construction of cyclic compounds,[11] only one
benzannulation event occurred in 41% yield when
involving β’-acetoxy allenotes.[12] As readily accessible
feedstocks, enamines often serve as versatile reactive
intermediates for granting a direct access to cyclization
products due to their intrinsically tempered
nucleophilicity.[13] Since a benzannulation-reaction-
based approach to generate substituted terephthalates
has not been exploited thus far, continuing our on-
going research utilizing the reactivity β’-acetoxy
allenoates,[14] we designed a convenient alternative
protocol for the de novo construction of terephthalate
architecture via phosphine catalyzed benzannulation
entry cat.[mmol]
base
solvent
yield [%][b]
1
2
3
4
5
6
7
8
Ph2PEt
Ph2PEt
Ph2PEt
Ph2PEt
Ph2PEt
Ph2PEt
Ph2PEt
Ph2PEt
Cs2CO3 Toluene
K2CO3 Toluene
Na2CO3 Toluene
62
43
68
58
66
13
53
LiOH
Toluene
K3PO4 Toluene
Na2CO3 p-xylene
Na2CO3 Mesitylene
Na2CO3 Trichlorotoluene 22
Na2CO3 DMSO
Na2CO3 DMF
9[c] Ph2PEt
47
–
10[c] Ph2PEt
11
12
13
14
15
16
17
18
(4-FC6H4)3P
(4-CH3OC6H4)3P Cs2CO3 Toluene
Cs2CO3 Toluene
44
17
36
28
67
75
19
5
PhEt2P
Bu3P
PPh3
PPh3
PPh3
–
Cs2CO3 Toluene
Cs2CO3 Toluene
Cs2CO3 Toluene
Na2CO3 Toluene
–
Toluene
Cs2CO3 Toluene
[a] Reaction conditions, unless otherwise noted:1a (0.1 mmol),
2 a (0.12 mmol), phosphine (0.02 mmol) and base
(0.12 mmol) in 1 mL toluene were stirred at room tempera-
ture for 5 h.
[b] Isolated yield.
[c] The reaction time extended to 24 h.
Adv. Synth. Catal. 2021, 363, 1873–1877
1874
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
screening of organophosphines (entries 11–15). Build- 3ha, the ortho-halogen substituted aromatic ring
ing on the previous experimental results, we were system is relatively difficult to be prepared by other
prompted to consider Na2CO3 in place of Cs2CO3, methods. Substituent including strong electron with-
which increased the yield to 75% successfully (en- drawing group CF3 on the aryl ring of substrate 1 was
try 16). Control experiments indicated that phosphine also well tolerated, furnishing the corresponding 3la in
catalyst and base are both indispensable in this trans- high yields (83%). Ester-substituted enamine 1m was
formation (entries 17 and 18).
also compatible for this reaction, and generated 3ma
Having identified the optimal reaction conditions, in excellent yield (93%). Unfortunately, when com-
we sought to investigate the diversity of this reaction pound 1n with p-OMe substitutent on the aromatic
(Table 2). By switching to aryl ring substituted ring was used as the substrate, the benzannulation
enamine, moderate conversion was acquired (3ba). product 3na couldn’t be obtained. The attempts to try
Due to the steric hindrance of ester groups substituted other enamines, e.g. alkyl substituted enamines, aryl
enamines, replacing the substitution pattern with substituted enamines with SMe, CF3, NO2, or CN on
aliphatic substitution on the aryl ring turned out to be the aromatic ring, all failed, because the starting
competent, while the aryl substituted derivatives material couldn’t be synthesized according to the
showed lower reactivity toward this transformation known methods.[15]
(3ca, 3da and 3ea). It is worth noting that the
presence of halogen substituents on the aryl rings has a
considerable impact on the efficiency of this reaction,
furnished the corresponding products (3fa–3ka) with
synthetically useful outcomes. Although the yield of
the ortho-chloro substituted product 3ka is lower than
When protecting group was changed into methane-
the meta and para substituential products 3ga and sulfonyl, 3aa could be still generated in 68% yield
(eq 1). The structure was initially deduced from the
NMR spectral data, and next was unambiguously
Table 2. Substrate scope with respect to the enamines.[a,b]
confirmed by single crystal X-ray diffraction analysis
(Table 2).[16]
Regarding the compatibility of substituted alle-
noates, steric repulsion of ester groups on allenoates
conspicuously influenced the chemoselectivities (Ta-
ble 3). Sterically encumbered substrates, such as
isopropyl and tert-butyl tend to perform poorly as the
Table 3. Substrate scope with respect to the β’-acetoxy
allenoates.[a,b]
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), PPh3
(0.02 mmol) and Na2CO3 (0.12 mmol) in 1 mL toluene were
stirred at room temperature for 5 h.
[a] Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), PPh3
(0.02 mmol) and Na2CO3 (0.12 mmol) in 1 mL toluene were
stirred at room temperature for 5 h.
[b] Isolated yields.
[b] Isolated yields.
Adv. Synth. Catal. 2021, 363, 1873–1877
1875
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
hinderance increases (3ab–3ae). Linear, branched, or being equal, 20 equiv. of D2O was introduced into the
aryl-bearing substitution on allenoates, all underwent reaction system. Incorporation of deuterium in the
the annulation reaction successfully to afford the corresponding positions was observed, clearly indicat-
corresponding products in acceptable yields (3ab– ing that intermediates with the carbanion involved in
3af). Pleasingly, the catalytic protocol also proceeded the benzannulation reaction.
smoothly when embedding o-fluorobenzyl, o-meth-
Supported by preliminary mechanistic studies com-
ylbenzyl, 1-naphthyl and 9-anthryl in substrates 2, bined with precedent literatures, a tentative mechanism
reflecting the mildness and high efficiency of this for the current benzannulation reaction is proposed
protocol (3ag–3aj).
(Scheme 3). 1,2-elimination of the acetate group
Since the substrate generality has been well- followed by the phosphine’s nucleophilic attack of
established, we thus focused on the further illustration phosphine at allenoate 1a released the intermediate A,
of the synthetic utilities. Gram experiment was which exhibited electrophilicity and next served as a
performed prior to the late-stage diversification, to our four-carbon reacting partner for the catalytic annula-
delight, nearly quantitative yield was achieved under tion reaction. With the help of base, enamine interacted
standard conditions (Scheme 2). It should be men- with A leading to intermediate C. Then, intermediate
tioned that presumably steric hindrance led to the G was delivered undergoing 1,2-elimination followed
regioselective products both in the hydrolysis and by intramolecular addition and proton transfer process.
reduction of 3ha. Specifically, treatment of 3ha under Finally, the aromaticity is constructed after deprotona-
inorganic basic conditions led to hydrolyzed product. tion and isomerization to afford the benzannulation
The following coupling of the corresponding acid to L- product 3a, along with the regeneration of phosphine
methionine methyl ester hydrochloride enabled access catalyst.
to 4, which can be further transformed to farnesyl-
In summary, we reported on the discovery of a
transferase inhibitors.[17] Additionally, the reduction strategically distinct approach to substituted terephtha-
proceeded well when LiAlH4 was employed, giving lates via domino benzannulation of β’-acetoxy alle-
product 5 in 75% yield. Furthermore, 5-benzyl 2- noates and enamines by environmentally friendly
methyl
(3ha) allowed for post-transformation modification lyst, which can be drove with synthetically useful
and afforded the Suzuki-coupling product 6. yields. This protocol features a broad substrate scope
4’-bromo-[1,1’-biphenyl]-2,5-dicarboxylates conditions and commercially available phosphine cata-
Deuterium experiment was conducted to elucidate and attractively mild conditions. Additionally, the late-
the further mechanism of this reaction (see the stage functionalization illustrated the synthetic utility.
Supporting Information for more details). All else
Scheme 2. Gram-scale synthesis and late-stage diversification.
Scheme 3. Plausible mechanism of the reaction of 1a and 2a.
Adv. Synth. Catal. 2021, 363, 1873–1877
1876
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
d) T. N. Poudel, R. J. I. Tamargo, H. Cai, Y. R. Lee,
Asian J. Org. Chem. 2018, 7, 985–1005.
Experimental Section
General Procedure for the Synthesis of 3: To a 10 mL glass
vial was added enamins 1 (0.12 mmol, 1.2 equiv.), allenoates 2
(0.1 mmol, 1.0 equiv.), Na2CO3 (0.12 mmol, 1.2 equiv.), PPh3
(0.02 mmol, 0.2 equiv.) and toluene (1 mL). The resulting
suspension was stirred at room temperature for 5 hours. After
the removal of the solvent under reduced pressure, the residue
was purified by flash column chromatography (petroleum ether:
ethyl acetate=5:1) to afford products 3.
[9] A. F. Orsino, M. Gutierrez Del Campo, M. Lutz, M. E.
Moret, ACS Catal. 2019, 9, 2458–2481.
[10] a) F. Gao, Y. Huang, Adv. Synth. Catal. 2014, 356, 2422–
2428; b) P. Xie, Y. Huang, R. Chen, Chem. Eur. J. 2012,
18, 7362–7366; c) J. Zheng, Y. Huang, Z. Li, Org. Lett.
2013, 15, 5064–5067; d) A. Jose, A. J. Jayakrishnan, B.
Vedhanarayanan, R. S. Menon, S. Varughese, E. Suresh,
V. Nair, Chem. Commun. 2014, 50, 4616–4619; e) M.
Chang, Y. Huang, Chem. Asian J. 2019, 14, 2588–2593;
f) M. Chang, C. Wu, J. Zheng, Y. Huang, Chem. Asian J.
2016, 11, 1512–1517; g) L. Satham, I. N. N. Namboo-
thiri, J. Org. Chem. 2018, 83, 9471–9477.
[11] For selected examples, see: a) Q. Zhang, L. Yang, X.
Tong, J. Am. Chem. Soc. 2010, 132, 2550–2551; b) J.
Hu, W. Dong, X. Y. Wu, X. Tong, Org. Lett. 2012, 14,
5530–5533; c) J. Hu, B. Tian, X. Wu, X. Tong, Org. Lett.
2012, 14, 5074–5077; d) C. Ni, X. Tong, J. Am. Chem.
Soc. 2016, 138, 7872–7875; e) C. Yuan, L. Zhou, M.
Xia, Z. Sun, D. Wang, H. Guo, Org. Lett. 2016, 18,
5644–5647; f) H. Ni, W. L. Chan, Y. Lu, Chem. Rev.
2018, 118, 9344–9411; g) H. Guo, Y. C. Fan, Z. Sun, Y.
Wu, O. Kwon, Chem. Rev. 2018, 118, 10049–10293;
h) E. Q. Li, Y. Huang, Chem. Commun. 2020, 56, 680–
694; i) B. R. Blank, I. P. Andrews, O. Kwon, Chem-
CatChem. 2020, 12, 4352–4372.
Acknowledgements
We are grateful to National Natural Science Foundation of
China (21871148, 21672109 and 21472097) for financial
supports
References
[1] Z. Bai, W. C. Phuan, J. Ding, T. H. Heng, J. Luo, Y. Zhu,
ACS Catal. 2016, 6, 6141–6145.
[2] J. Pang, M. Zheng, R. Sun, A. Wang, X. Wang, T. Zhang,
Green Chem. 2016, 18, 342–359.
[3] a) Q. Song, Y. Li, Z. Cao, H. Liu, C. Tian, Z. Yang, X.
Qiang, Z. Tan, Y. Deng, Bioorg. Med. Chem. 2018, 26,
6115–6127; b) X. Du, D. Liu, J. Huang, C. Zhang, P.
Proksch, W. Lin, Fitoterapia. 2018, 130, 190–197;
c) H. H. Otto, T. Schirmeister, Chem. Rev. 1997, 97,
133–171; d) R. M. Mohareb, T. M. Klapotke, E. Rein-
hardt, Med. Chem. Res. 2018, 27, 2494–2511; e) R.
Dayam, T. Sanchez, N. Neamati, J. Med. Chem. 2005,
48, 8009–8015; f) D. Wang, L. Pan, G. Cao, H. Lei, X.
Meng, J. He, M. Dong, Z. Li, Z. Liu, Int. J. Antimicrob.
Agents 2012, 40, 463–466.
[4] a) C. L. Williams, C. C. Chang, P. Do, N. Nikbin, S.
Caratzoulas, D. G. Vlachos, R. F. Lobo, W. Fan, P. J.
Dauenhauer, ACS Catal. 2012, 2, 935–939; b) Y. T.
Cheng, G. W. Huber, Green Chem. 2012, 14, 3114.
[5] R. Lu, F. Lu, J. Chen, W. Yu, Q. Huang, J. Zhang, J. Xu,
Angew. Chem. Int. Ed. 2016, 55, 249–253.
[12] Y. Gu, P. Hu, C. Ni, X. Tong, J. Am. Chem. Soc. 2015,
137, 6400–6406.
[13] a) G. Peng, J. J. Liu, Y. Y. Wei, Org. Lett. 2013, 15, 11,
2872–2875; b) M. R. Friedfeld, H. Zhong, R. T. Ruck,
M. Shevlin, P. J. Chirik, Science. 2018, 360, 888–893;
c) L. S. Monteiro, J. J. Andrade, A. C. Suárez, Eur. J.
Org. Chem. 2011, 2011, 6764–6772; d) D. R. Carbery,
Org. Biomol. Chem. 2008, 6, 3455–3460; e) V. G.
Granik, V. A. Makarov, C. Párkányi, Adv. Heterocycl.
Chem. 1998, 72, 283–359.
[14] a) Q. Zhang, H. Jin, J. Feng, Y. Zhu, P. Jia, C. Wu, Y.
Huang, Org. Lett. 2019, 21, 1407–1411; b) Y. Zhu, D.
Wang, Y. Huang, Org. Lett. 2019, 21, 908–912.
[6] a) Y. Ouyang, X. H. Xu, F. L. Qing, Angew. Chem. Int.
Ed. 2018, 57, 6926–6929; b) B. Yang, D. Yu, X. H. Xu,
F. L. Qing, ACS Catal. 2018, 8, 2839–2843; c) E. Tan,
O. Quinonero, M. Elena de Orbe, A. M. Echavarren, ACS
Catal. 2018, 8, 2166–2172.
[15] a) B. M. Trost, G. R. Dake, J. Am. Chem. Soc. 1997, 119,
7595–7596; b) D. Chen, L. Guo, J. Liu, S. Kirtane, J. F.
Cannon, G. Li, Org. Lett. 2005, 7, 921–924.
[16] CCDC 2021955 contains the supplementary crystallo-
graphic data for 3ea. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre
viawww.ccdc.cam.ac.uk/data_request/cif.
[7] W. S. Ham, J. Hillenbrand, J. Jacq, C. Genicot, T. Ritter,
Angew. Chem. Int. Ed. 2019, 58, 532–536.
[8] a) T. J. Katz, T. M. Sivavec, J. Am. Chem. Soc. 1985,
107, 737–738; b) R. R. Schrock, A. H. Hoveyda, Angew.
Chem. Int. Ed. 2003, 42, 4592–4633; c) S. Kotha, S.
Misra, S. Halder, Tetrahedron. 2008, 64, 10775–10790;
[17] D. J. Augeri, S. J. OConnor, D. Janowick, B. Szczepan-
kiewicz, G. Sullivan, J. Larsen, D. Kalvin, J. Cohen, E.
Devine, H. Zhang, S. Cherian, B. Saeed, S. C. Ng, S.
Rosenberg, J. Med. Chem. 1998, 41, 4288–4300.
Adv. Synth. Catal. 2021, 363, 1873–1877
1877
© 2021 Wiley-VCH GmbH