- Email: [email protected]
Construction of 9-functionalized xanthenes via Diels-Alder reaction of stable ortho-quinone methides and arynes
Accepted Manuscript Construction of 9-functionalized xanthenes via Diels-Alder reaction of stable ortho-quinone methides and arynes Hui Jian, Kai Liu, Wei-Hua Wang, Zhi-Juan Li, Bin Dai, Lin He PII: DOI: Reference:
S0040-4039(17)30174-0 http://dx.doi.org/10.1016/j.tetlet.2017.02.007 TETL 48618
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
4 November 2016 27 January 2017 3 February 2017
Please cite this article as: Jian, H., Liu, K., Wang, W-H., Li, Z-J., Dai, B., He, L., Construction of 9-functionalized xanthenes via Diels-Alder reaction of stable ortho-quinone methides and arynes, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Construction of 9-functionalized xanthenes via Diels-Alder reaction of stable ortho-quinone methides and arynes Hui Jian, Kai Liu, Wei-Hua Wang, Zhi-Juan Li, Bin Dai, Lin He* School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region 832000, People’s Republic of China, E-mail: [email protected]
Abstract: Diels-Alder reaction of stable o–quinone methides and arynes has been developed, providing 9–aryl and –cinnamyl substituted xanthenes in moderate to high yields. Key words:
arynes, ortho-quinone methides, Diels-Alder reaction,
xanthene Introduction ortho-Quinone methides (o-QMs) are important intermediates in the synthesis of natural products and biologically active compounds. 1 Owing to the strongly thermodynamic driving force of rearomatizations, o-QMs can easily undergo cycloaddition and Michael addition with 2π partners or
nucleophiles,
which
provide
great
opportunity
for
various
transformations.2 On the other hand, arynes are another type of reactive intermediates that are widely applied in organic synthesis. 3 Based on pericyclic reaction,4 insertion reaction5 and multicomponent reaction6 of arynes, a broad variety of pharmaceutically active heterocycles and
versatile building blocks have been synthesized. In particular, Diels-Alder reaction of arynes7 provides a powerful tool for constructing benzo-fused heterocycles. Xanthenes are an important class of structural motifs occurring both in biologically active compounds and medicinally interesting molecules. 8 Xanthenes and their derivatives can also be utilized as fluorescent dyes, 9 electrostatic sensors10 and photocatalysts.11 Due to the remarkable significance of xanthenes frameworks, continuous efforts has been exerted to develop efficient methods for the construction of this ubiquitous scaffold. In the past decades, several strategies have been well established for the preparation of xanthene derivatives, which typically involve the Friedel-Crafts reaction to form the central heterocyclic ring. However, multistep reaction, complicated manipulation or harsh reaction conditions limited the potential applications of these methodologies. Therefore, the development of efficient and mild approach for the synthesis of xanthenes and their derivatives are still of great importance. Recently, Larock,12 Okuma13 and Huang14 group developed a tandem insertion-cyclization reaction of arynes, which provides an efficient method
to
thioxanthones
construct and
9-alkyl substituted
acridines.
Interestingly,
xanthenes, Yoshida,
xantheones, Kunai
and
co-workers15 found that aldehydes can react with two equiv of arynes to form 9-arylxanthenes and o-quinone methide was postulated as a
transient intermediate in these process. However, only electron-rich aromatic aldehydes were successful, electron-neutral and deficient aldehydes were inefficient substrates for this reaction. Based on this work, Huang and co-workers reported16 that enals can also be employed for the reaction to generate o-QMs intermediates, which further underwent intramolecular 6e-electrocyclization reaction to produce 2H-chromenes. In recent years, we began interested in the synthesis of heterocycles using aryne intermediates.17 As a continuation, we proposed that arynes can undergo Diels-Alder reaction with stable o-QMs to form 9-functionalited xanthenes. Herein, we wish to report this result. Results and disscussion Initially, the reaction of Kobayash,s reagent, o-trimethylsilylphenyl triflate 1a18 and stable o-quinone methide 2a was examined (Table 1). With 2.0 equiv TBAT (Tetrabutylammonium triphenyldifluorosilane) as fluoride source, this hetero-Diels-Alder reaction smoothly proceeded in THF at ambient temperature to produce the desired xanthone 3a in 73% yield (Table 1, entry 1). Encouraged by this result, several other fluoride sources were next investigated for the reaction. TMAF can promote the reaction in moderate yield, while TBAF gave the product in low yield (Table 1, entries 2-3). Surprisingly, when CsF was used for the reaction, which was proved to be efficient promoter in many reactions of arynes, only 21% yield was obtained (Table 1, entry 4). And as anticipated, KF
showed lower efficiency for the reaction (Table 1, entry 5). But fortunately, when 2.0 equiv 18-crown-6 was added as co-additive, both CsF and KF can efficiently promote this cycloaddition to furnish xanthene 3a in high yield (Table 1, entries 6-7). A brief screening of reaction media indicated that THF is still the best choice with respect to the reaction yield (Table 1, entries 8-10). Reduction KF and 18-crown-6 to 1.0 equiv resulted in dramatic decrease in reaction yield (Table 1, entry 11). Table 1 Evaluation of reaction conditions a
entry
additives
solvent
yield (%) b
1
TBAT (2.0 equiv)
THF
73
2
TMAF (2.0 equiv)
THF
38
3
TBAF (2.0 equiv)
THF
19
4
CsF (2.0 equiv)
THF
21
5
KF (2.0 equiv)
THF
<10
6
KF(2.0 equiv), 18-C-6(2.0 equiv)
THF
84
7
CsF(2.0 equiv), 18-C-6(2.0 equiv)
THF
79
8
KF(2.0 equiv), 18-C-6(2.0 equiv)
toluene
trace
9
KF(2.0 equiv), 18-C-6(2.0 equiv)
CH2Cl2
55
10
KF(2.0 equiv), 18-C-6(2.0 equiv)
CH3CN
52
11
KF(1.0 equiv), 18-C-6(1.0 equiv)
THF
56
a. Reaction conditions: 1a (1.0 equiv), 2a (1.5 equiv), room temperature. b. Isolated yield. The generality of this reaction was subsequently examined under the optimal reaction conditions (Table 1, entry 6). As shown in Table 2, symmetrical arynes with electron-neutral, -donating, and withdrawing substituents efficiently underwent this hetero-Diels-Alder reaction with o-quinone methide to produce the corresponding products in good yields (Table 2, entries 1-4). Owing to the electric and steric effects,19 the unsymmetrical 3-methoxy aryne and 4-chloro aryne (from 2e and 2f) coupled with o-quinone methide with nearly complete regioselectivity in 54％ and 63% yield, respectively (Table 2, entries 5 and 6). Similarly, unsymmetrical aryne precursor 2g resulted in the formation of 3g in 56％ yield with high regioselectivity (Table 2, entry 7). Unsymmetrical aryne precursor 2h was also proved to be good reactant, producing the desired product 3h in 58% yield with 6:1 regioselectivity (Table 2, entry 8). However, when α, β-naphthalene was employed for this cycloaddition, two regioisomers were obtained as an inseperable mixture in low ratios with 75% combined yield (Table 2, entry 9). Similar as the mono substituted o-QMs, multisubstituted substrates can also efficiently
undergo the reaction, producing the corresponding products in high yields (Table 2, entries 10 and 11).
In addition, o-QM having a cinnamyl
substituent also served as suitable substrate in this cycloaddition, affording 9-cinnamyl substituted xanthene 3l in 64% yield (Table 2, entry 12). Once again, the employment of unsymmetrical 3-methoxyaryne resulted in excellent regioselectivity with good yield (Table 2, entry 13). It’s worthy to note that o-QMs bearing an electron-donating group exhibited
much
higher
reactivity
than
that
bearing
an
electron-withdrawing group (Table 2, entries 14-16). Additionally, different positions of the substituents can be well tolerated in the reaction (Table 2, entries 14-16). Table 2 Evaluation of substrates scope a
entry aryne precursors time(h)
1
13
products
Yield(％)b
84
2
13
67
3
18
68
4
12
63
54 5
15
(>20:1)c
63 6
12
(>20:1)c
56 7
17
(14:1)c
58 8
17
(6:1)c
75 9
13
10
15
81
11
18
73
(1:1)c
12
13
64
65 13
13
14
12
89
15
13
63
16
14
46
(>20:1)c
a. Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), KF (2.0 equiv),
18-crown-6 (2.0 equiv) at room temperature. b. Isolated yield. c. Determined by analysis of 1H NMR. In conclusion, we have demonstrated the cycloaddition reaction of stable o-QMs and arynes to produce 9-functionalized xanthenes in moderate to high yields. The mild conditions and simple procedure provide a novel protocol for the construction of these versatile heterocyclic compounds.
Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 21428302) and Shihezi University (Nos. 2012ZRKXJQ06, gxjs2013-zdgg02).
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17. (a) He, L.; Pian, J. X.; Shi, J. F.; Du, G. F.; Dai, B. Tetrahedron. 2014, 70, 2400-2405; (b) Pian, J. X.; He, L.; Du, G. F.; Guo, H.; Dai, B. J. Org. Chem. 2014, 79, 5820-5826; (c) Liu, K.; Liu, L. L.; Gu, C. Z.; Dai, B.; He, L. RSC Adv. 2016, 6, 33606-33610; (d) He, L.; Pian, J. X.; Zhang J.; Li, Y. Z. Chin. Chem. Lett., 2012, 23, 1359; (e) Liu, L.-L.; Li, Z.; Gu, C.; He, L.; Dai, B. J. Saudi. Chem. Soc. Doi: 10.1016/j.jscs.2016.09.002. 18. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211−1214. 19. (a) Garr, A. N.; Luo, D.; Brown, N.; Cramer, C. J.; Buszek, K. R.; VanderVelde, D. Org. Lett. 2010, 12, 96−99; (b) Cheong, P.-H.-Y.; Paton, R. S.; Bronner, S. M.; Im, G-Y. J.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267; (c) Bronner, S. M.; MackeyK, J. L.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2012, 134, 13966; (d) Karmakar, R.; Yun, Y. S.; Wang, K.-P.; Lee. D. Org. Lett. 2014, 16, 6-9; (e) Hamura, T.; Ibusuki, Y.; Sato, K.; Matsumoto, T.; Osamura, Y.; Suzuki, K. Org. Lett. 2003, 5, 3551-3554.
Graphical Abstract Construction
of
9-functionalized
ortho-quinone methides and arynes
xanthenes
via
Diels-Alder
reaction
of
stable
Highlights
The stable o–quinone methides can undergo normal Diels-Alder reation with electron-deficient arynes.
9–Aryl and 9–cinnamyl substituted xanthenes can be constructed under mild conditions without using of transition-metal catalysts.
All products are new compounds.
S0040-4039(17)30174-0 http://dx.doi.org/10.1016/j.tetlet.2017.02.007 TETL 48618
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
4 November 2016 27 January 2017 3 February 2017
Please cite this article as: Jian, H., Liu, K., Wang, W-H., Li, Z-J., Dai, B., He, L., Construction of 9-functionalized xanthenes via Diels-Alder reaction of stable ortho-quinone methides and arynes, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Construction of 9-functionalized xanthenes via Diels-Alder reaction of stable ortho-quinone methides and arynes Hui Jian, Kai Liu, Wei-Hua Wang, Zhi-Juan Li, Bin Dai, Lin He* School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region 832000, People’s Republic of China, E-mail: [email protected]
Abstract: Diels-Alder reaction of stable o–quinone methides and arynes has been developed, providing 9–aryl and –cinnamyl substituted xanthenes in moderate to high yields. Key words:
arynes, ortho-quinone methides, Diels-Alder reaction,
xanthene Introduction ortho-Quinone methides (o-QMs) are important intermediates in the synthesis of natural products and biologically active compounds. 1 Owing to the strongly thermodynamic driving force of rearomatizations, o-QMs can easily undergo cycloaddition and Michael addition with 2π partners or
nucleophiles,
which
provide
great
opportunity
for
various
transformations.2 On the other hand, arynes are another type of reactive intermediates that are widely applied in organic synthesis. 3 Based on pericyclic reaction,4 insertion reaction5 and multicomponent reaction6 of arynes, a broad variety of pharmaceutically active heterocycles and
versatile building blocks have been synthesized. In particular, Diels-Alder reaction of arynes7 provides a powerful tool for constructing benzo-fused heterocycles. Xanthenes are an important class of structural motifs occurring both in biologically active compounds and medicinally interesting molecules. 8 Xanthenes and their derivatives can also be utilized as fluorescent dyes, 9 electrostatic sensors10 and photocatalysts.11 Due to the remarkable significance of xanthenes frameworks, continuous efforts has been exerted to develop efficient methods for the construction of this ubiquitous scaffold. In the past decades, several strategies have been well established for the preparation of xanthene derivatives, which typically involve the Friedel-Crafts reaction to form the central heterocyclic ring. However, multistep reaction, complicated manipulation or harsh reaction conditions limited the potential applications of these methodologies. Therefore, the development of efficient and mild approach for the synthesis of xanthenes and their derivatives are still of great importance. Recently, Larock,12 Okuma13 and Huang14 group developed a tandem insertion-cyclization reaction of arynes, which provides an efficient method
to
thioxanthones
construct and
9-alkyl substituted
acridines.
Interestingly,
xanthenes, Yoshida,
xantheones, Kunai
and
co-workers15 found that aldehydes can react with two equiv of arynes to form 9-arylxanthenes and o-quinone methide was postulated as a
transient intermediate in these process. However, only electron-rich aromatic aldehydes were successful, electron-neutral and deficient aldehydes were inefficient substrates for this reaction. Based on this work, Huang and co-workers reported16 that enals can also be employed for the reaction to generate o-QMs intermediates, which further underwent intramolecular 6e-electrocyclization reaction to produce 2H-chromenes. In recent years, we began interested in the synthesis of heterocycles using aryne intermediates.17 As a continuation, we proposed that arynes can undergo Diels-Alder reaction with stable o-QMs to form 9-functionalited xanthenes. Herein, we wish to report this result. Results and disscussion Initially, the reaction of Kobayash,s reagent, o-trimethylsilylphenyl triflate 1a18 and stable o-quinone methide 2a was examined (Table 1). With 2.0 equiv TBAT (Tetrabutylammonium triphenyldifluorosilane) as fluoride source, this hetero-Diels-Alder reaction smoothly proceeded in THF at ambient temperature to produce the desired xanthone 3a in 73% yield (Table 1, entry 1). Encouraged by this result, several other fluoride sources were next investigated for the reaction. TMAF can promote the reaction in moderate yield, while TBAF gave the product in low yield (Table 1, entries 2-3). Surprisingly, when CsF was used for the reaction, which was proved to be efficient promoter in many reactions of arynes, only 21% yield was obtained (Table 1, entry 4). And as anticipated, KF
showed lower efficiency for the reaction (Table 1, entry 5). But fortunately, when 2.0 equiv 18-crown-6 was added as co-additive, both CsF and KF can efficiently promote this cycloaddition to furnish xanthene 3a in high yield (Table 1, entries 6-7). A brief screening of reaction media indicated that THF is still the best choice with respect to the reaction yield (Table 1, entries 8-10). Reduction KF and 18-crown-6 to 1.0 equiv resulted in dramatic decrease in reaction yield (Table 1, entry 11). Table 1 Evaluation of reaction conditions a
entry
additives
solvent
yield (%) b
1
TBAT (2.0 equiv)
THF
73
2
TMAF (2.0 equiv)
THF
38
3
TBAF (2.0 equiv)
THF
19
4
CsF (2.0 equiv)
THF
21
5
KF (2.0 equiv)
THF
<10
6
KF(2.0 equiv), 18-C-6(2.0 equiv)
THF
84
7
CsF(2.0 equiv), 18-C-6(2.0 equiv)
THF
79
8
KF(2.0 equiv), 18-C-6(2.0 equiv)
toluene
trace
9
KF(2.0 equiv), 18-C-6(2.0 equiv)
CH2Cl2
55
10
KF(2.0 equiv), 18-C-6(2.0 equiv)
CH3CN
52
11
KF(1.0 equiv), 18-C-6(1.0 equiv)
THF
56
a. Reaction conditions: 1a (1.0 equiv), 2a (1.5 equiv), room temperature. b. Isolated yield. The generality of this reaction was subsequently examined under the optimal reaction conditions (Table 1, entry 6). As shown in Table 2, symmetrical arynes with electron-neutral, -donating, and withdrawing substituents efficiently underwent this hetero-Diels-Alder reaction with o-quinone methide to produce the corresponding products in good yields (Table 2, entries 1-4). Owing to the electric and steric effects,19 the unsymmetrical 3-methoxy aryne and 4-chloro aryne (from 2e and 2f) coupled with o-quinone methide with nearly complete regioselectivity in 54％ and 63% yield, respectively (Table 2, entries 5 and 6). Similarly, unsymmetrical aryne precursor 2g resulted in the formation of 3g in 56％ yield with high regioselectivity (Table 2, entry 7). Unsymmetrical aryne precursor 2h was also proved to be good reactant, producing the desired product 3h in 58% yield with 6:1 regioselectivity (Table 2, entry 8). However, when α, β-naphthalene was employed for this cycloaddition, two regioisomers were obtained as an inseperable mixture in low ratios with 75% combined yield (Table 2, entry 9). Similar as the mono substituted o-QMs, multisubstituted substrates can also efficiently
undergo the reaction, producing the corresponding products in high yields (Table 2, entries 10 and 11).
In addition, o-QM having a cinnamyl
substituent also served as suitable substrate in this cycloaddition, affording 9-cinnamyl substituted xanthene 3l in 64% yield (Table 2, entry 12). Once again, the employment of unsymmetrical 3-methoxyaryne resulted in excellent regioselectivity with good yield (Table 2, entry 13). It’s worthy to note that o-QMs bearing an electron-donating group exhibited
much
higher
reactivity
than
that
bearing
an
electron-withdrawing group (Table 2, entries 14-16). Additionally, different positions of the substituents can be well tolerated in the reaction (Table 2, entries 14-16). Table 2 Evaluation of substrates scope a
entry aryne precursors time(h)
1
13
products
Yield(％)b
84
2
13
67
3
18
68
4
12
63
54 5
15
(>20:1)c
63 6
12
(>20:1)c
56 7
17
(14:1)c
58 8
17
(6:1)c
75 9
13
10
15
81
11
18
73
(1:1)c
12
13
64
65 13
13
14
12
89
15
13
63
16
14
46
(>20:1)c
a. Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), KF (2.0 equiv),
18-crown-6 (2.0 equiv) at room temperature. b. Isolated yield. c. Determined by analysis of 1H NMR. In conclusion, we have demonstrated the cycloaddition reaction of stable o-QMs and arynes to produce 9-functionalized xanthenes in moderate to high yields. The mild conditions and simple procedure provide a novel protocol for the construction of these versatile heterocyclic compounds.
Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 21428302) and Shihezi University (Nos. 2012ZRKXJQ06, gxjs2013-zdgg02).
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Graphical Abstract Construction
of
9-functionalized
ortho-quinone methides and arynes
xanthenes
via
Diels-Alder
reaction
of
stable
Highlights
The stable o–quinone methides can undergo normal Diels-Alder reation with electron-deficient arynes.
9–Aryl and 9–cinnamyl substituted xanthenes can be constructed under mild conditions without using of transition-metal catalysts.
All products are new compounds.