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New synthesis of carbazole-1,4-quinone using a tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere, and its application to the synthesis of murrayaquinone A
Tetrahedron Letters 52 (2011) 3876–3878
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
New synthesis of carbazole-1,4-quinone using a tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere, and its application to the synthesis of murrayaquinone A Takashi Nishiyama, Tominari Choshi ⇑, Kohdai Kitano, Satoshi Hibino ⇑ Graduate School of Pharmacy Pharmaceutical Sciences, and Faculty of Pharmacy Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
a r t i c l e
i n f o
Article history: Received 19 April 2011 Revised 12 May 2011 Accepted 13 May 2011 Available online 27 May 2011
a b s t r a c t A tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere was newly developed to the synthesis of carbazole-1,4-quinones. This new tandem reaction was applied to the synthesis of murrayaquinone A in four steps. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Carbazole-1,4-quinone Murrayaquinone A Ring-closing metathesis Dehydrogenation Tandem reaction
O
1. Introduction A simple carbazole-1,4-quinone alkaloid, murrayaquinone B (2) was initially reported from the root bark of Murraya euchrestifolia Hayata (Rutaceae) in Taiwan.1,2 Two years later, the same group reported the isolation of various carbazole-1,4-quinone alkaloids, murrayaquinone A (1), and C–E (3–5) from the root or the stem bark of the same plant.1,3 Extracts of the leaves and bark of this tree have been used as a folk medicine in the treatment of several diseases.1,4 Among these alkaloids, murrayaquinone A (1) exhibits a cardiotonic activity on guinea pig papillary muscle.1,4 Total syntheses of murrayaquinone A (1) have been achieved by 14 groups1,5 including our formal total synthesis (Fig. 1).5n,o The ring-closing metathesis (RCM) reaction by Grubbs’s group is a well known reaction for the construction of many functionalized carbocycles and heterocycles.6 To our knowledge, there are few examples that make use of RCM reactions for the construction of carbazole framework from bisallylindoles.7 We planned a new total synthesis of murrayaquinone A (1) based on the application of the RCM reaction. In this paper, we describe a new methodology for the synthesis of carbazole-1,4-quinones using a tandem RCMoxidation reaction, and its application to a total synthesis of murrayaquinone A (1). ⇑ Corresponding authors. E-mail addresses: [email protected] (T. Choshi), hibino@ fupharm.fukuyama-u.ac.jp (S. Hibino). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.05.066
Me
R1 1: 2: 3: 4: 5:
N H R2 Murrayaquinone A Murrayaquinone B Murrayaquinone C Murrayaquinone D Murrayaquinone E
O R1 =R 2 =H R1 =OMe, R2 =prenyl R1 =OMe, R2 =geranyl R1 =OH, R 2=prenyl R1 =OH, R 2=geranyl
Figure 1.
2. Results and discussion We first attempted the synthesis of carbazole-1,4-quinones 1 according to our retro-synthetic analysis (Scheme 1). We envisaged that the 1,4-quinone moiety of 1 could be constructed by a new bond formation between the C2 and C3-positions in 1 through an RCM reaction of the bis(acryloyl)indole 2 derived from the 3-iodoindole-2-carbaldehyde (3). Based on the sequence in Scheme 2, a three-component Pd-catalyzed cross-coupling reaction between 3-iodoindole 4, CO, and alkenyl tributyltin according to Fukuyama’s procedure8 was carried out in DMF at 70 °C to provide 3-acryroylindoles 5. Subsequently, the Grignard reaction of the 3-acryroylindole 5a with vinylmagnesium bromide gave the 2-allyl alcohol 6a, which was
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T. Nishiyama et al. / Tetrahedron Letters 52 (2011) 3876–3878
O
O R
R
N O H 1a: R=Me (Murrayaquinone A) 1b: R=H
N H
O
N H 1
O
2
N H
O
R
OH 9
O R
I N H
HO
R
O
R
CHO 3
N H 6
Scheme 1.
N H
OH
OH 10
Scheme 3.
CO (1 atm) BHT PdCl2(dppf)
I N MOM 4
CHO
DMF 70oC, 24 h
O R
CHO N MOM 5a: R=Me (70%) 5b: R=H (51%) THF 0oC, 4 h
MgBr O R
O R act. MnO 2
N O MOM
CH2Cl2 reflux, 48 h
7a:R=Me (48%) 7b:R=H
N OH MOM 6a: R=Me (66%) 6b: R=H (26%)
Scheme 2.
oxidized with activated MnO2 to give the desired 2,3-bis(acryroyl)indole 7a. The oxidized product 7b, however, was not obtained from 6b in a similar manner. To construct a carbazole-1,4-quinone framework, we attempted an RCM reaction of the 2,3-bis(acryroyl)indole 7a, as shown in Table 1. When Grubbs 1st and 2nd generation catalysts were used in CH2Cl2 at room temperature, the carbazole-1,4-quinone 8 was actually formed in 20% and 33% yield, respectively (runs 1 and 2). Moreover, treatment of 7a with Grubbs 2nd generation catalyst in toluene at 70 °C afforded the carbazole-1,4-quinone 8 in 72% yield (run 3). Based on this preliminary result, we next attempted a direct synthesis of carbazole by an RCM reaction using the allyl alcohol
6, as shown in Scheme 3. We assumed that the 1,4-benzoquinone moiety of carbazole 1 would be converted by oxidation from carbazole-1,4-diol 9, which is equivalent to 10. Carbazole 10 might be derived from an allyl alcohol 6 through a new bond formation by an RCM reaction between the C2 and C3-positions in the carbazole 10. To examine whether a carbazole-1,4-diol 12 could be obtained, the allyl alcohol 6a was subjected to an RCM reaction under the conditions used for run 3 in Table 1 (Scheme 4). Although carbazole-1,4-quinone 8 was isolated as the sole product in 78% yield, the expected carbazole-1,4-diol 12 was not detected at all. This result suggested that not only an RCM reaction took place, but that dehydrogenation also occurred. When the reaction mixture was monitored by TLC, two new spots were observed. The upper spot was a carbazole-1,4-quinone 8, and the lower spot was concluded to be a carbazole-1,4-diol 12. Compound 12 of the lower spot could not be isolated because it disappeared during work-up of the reactant. It was considered that compound 12 was converted to 8 by the air oxidation. Similar reactions have been noted by a few research groups9 reporting that pyrrole was obtained from diallylamine by a tandem RCM and dehydrogenation reaction. This tandem reaction was further examined in detail using the allyl alcohol 6a as the substrate. As shown in Table 2, Grubbs catalysts (1st and 2nd) and Hoveyda–Grubbs catalysts (1st and 2nd) were used in the tandem RCM-oxidation reaction. Several reaction conditions including various times, temperatures, and solvents were also investigated. Treatment of 6a with Grubbs 1st generation catalyst afforded the quinone 8 in low yield (runs 1 and 2). When the Hoveyda–Grubbs 1st generation catalyst was used, many unknown compounds were obtained (run 6), but when its 2nd generation catalyst was used, product 8 was obtained in
O Me Table 1 Synthesis of carbazole-1,4-quinone 8 by RCM reaction
O Me
O Grubbs catalyst
*
Run
Catalyst
1 2 3
1st 2nd 2nd
Grubbs catalyst.
*
N OH MOM
Me
toluene 70 oC, 0.5 h
6a
O
Me
N OH MOM 11
HO
N O MOM 8
N O MOM 7a
Grubbs 2nd catalyst
O
Me +
Solvent
Temp (°C)
Time (h)
Yield (%)
CH2Cl2 CH2Cl2 Toluene
rt rt 70
1 2 1
20 33 72
N O MOM
N OH MOM 12: Not detected
8: 78% Work up
Scheme 4.
Me
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T. Nishiyama et al. / Tetrahedron Letters 52 (2011) 3876–3878
Table 2 Synthesis of N-MOM-murrayaquinone A 8 by RCM reaction
HO
O Me
O Me
N O MOM N OH MOM 6a
a b c
N O MOM
N OH MOM 12 Gasb
Solvent
Temp (°C)
Time (h)
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12
1st 1st 2nd 2nd 2nd Hoveyda 1st Hoveyda 2nd 1st 1st 2nd 2nd 2nd
N2 N2 N2 N2 N2 N2 N2 O2 O2 O2 O2 O2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene
rt Reflux rt Reflux 70 rt rt rt Reflux rt Reflux 70
2 2 1 0.5 0.5 12 2 1 1 2 15 min 5 min
27 25 64 70 78 —c 51 45 67 90 75 93
A new efficient synthesis of carbazole-1,4-quinone from allyl alcohol 6 was established using a tandem RCM and dehydrogenation reaction with Grubbs 2nd generation catalyst. In addition, we achieved the total synthesis of murrayaquinone A (1a) in four steps from 4 in 42.5% yield. Based on this result, we present an efficient method for use in synthetic studies of carbazole alkaloids and/or other natural products with a 1,4-quinone structure. Further research of the synthesis of carbazolequinone alkaloids is ongoing.
Table 3 Synthesis of carbazole-l,4-quinone 14 by RCM reaction
a b
O
N O MOM 14
Run
Catalysta
Gasb
Solvent
Temp (°C)
Time (h)
Yield (%)
1 2 3 4 5 6 7 8 9 10
1st 1st 2nd 2nd 2nd 1st 1st 2nd 2nd 2nd
N2 N2 N2 N2 N2 O2 O2 O2 O2 O2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene
rt Reflux rt Reflux 70 rt Reflux rt Reflux 70
0.5 0.5 2 45 min 0.5 0.5 1 2 2 10 min
29 28 38 28 36 56 34 79 79 90
Grubbs catalyst. The reaction proceeded in gas atmosphere.
1a: 99%
3. Conclusions
moderate yield (run 7). When using Grubbs 2nd generation catalyst, good results were obtained in CH2Cl2 at room temperature and/or at reflux (runs 3 and 4). An RCM reaction with Grubbs 2nd generation catalyst in toluene at 70 °C provided even more promising results (run 5). As illustrated in Scheme 4, we considered that quinone 8 was produced by oxidative dehydrogenation of the hydroquinone moiety of 12 with oxygen in the air, during work-up. Therefore, we attempted an RCM reaction under oxygen atmosphere (runs 8–12). When the reaction mixture was monitored by TLC, the lower spot of compound 12 was not detected in situ. Product 8 was obtained in the highest yield with Grubbs 2nd generation catalyst in toluene at 70 °C for 5 min (run 12). We then evaluated an RCM reaction of the allyl alcohol 6b under the same conditions (Table 3). Monitoring of the RCM reaction of 6b under conventional conditions by TLC revealed an absence of compound 13 and the production of quinone 14 in a relatively low yield (runs 1–5). By contrast, an RCM reaction of 6b under oxygen atmosphere as in runs 6–10 produced quinone 14 in excellent yield (run 10). Finally, treatment of N-MOM-carbazoles 8 with 6 M HCl according to Hanaoka’s procedure5i afforded murrayaquinone A (1a) in
N OH MOM 13
O
99% yield (Scheme 5). The synthetic murrayaquinone A (1a) was identical to natural or synthetic products in all respects.10
Grubbs catalyst. The reaction proceeded in gas atmosphere. Complex compound.
N OH MOM 6b
N H
Scheme 5.
Catalysta
HO
MeOH 60 oC, 1 h
8
8
Run
O
Me
6M HCl
O
Me
O
Me
References and notes 1. (a) Chakraborty, D. P.; Roy, S. In Progress in the Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby, G. W., Steglich, W., Tamm, C., Eds.; Springer: Wien, 1991; Vol. 57, p 71; (b) Chakraborty, D. P. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1993; Vol. 44, pp 257–364; (c) Furukawa, H. J. Indian Chem. Soc. 1994, 71, 303–308; (d) Moody, C. J. Synlett 1994, 681–688; (e) Choshi, T. Yakugaku Zasshi 2001, 121, 487–495; (f) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4427; (g) Knölker, H.-J. Top. Curr. Chem. 2005, 244, 115–148; (h) Knölker, H.-J.; Reddy, K. R. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008; Vol. 65, pp 1–430. 2. Wu, T.-S.; Ohta, T.; Furukawa, H. Heterocycles 1983, 20, 1267–1269. 3. Furukawa, H.; Wu, T.-S.; Ohta, T.; Kuoh, C.-S. Chem. Pharm. Bull. 1985, 33, 4132– 4138. 4. Takeya, K.; Itoigawa, M.; Furukawa, H. Eur. J. Pharmacol. 1989, 169, 137–145. 5. (a) Ramesh, K.; Kapil, R. S. Chem. Ind. (London) 1986, 614–615; (b) Idem J. Nat. Prod. 1987, 50, 932–934; (c) Martin, T.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1988, 235–240; (d) Yogo, M.; Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1991, 39, 328–334; (e) Miki, Y.; Hachiken, H. Synlett 1993, 333–334; (f) Matsuo, K.; Ishida, S. Chem. Express 1993, 8, 321–324; (g) Idem Chem. Pharm. Bull. 1994, 42, 1325–1327; (h) Knölker, H.-J.; Bauermeister, M. Tetrahedron 1993, 49, 11221– 11236; (i) Wada, A.; Hirai, S.; Hanaoka, M. Chem. Pharm. Bull. 1994, 42, 416– 418; (j) Akermark, B.; Oslob, J. D.; Heuschert, U. Tetrahedron Lett. 1995, 36, 1325–1326; (k) Murakami, Y.; Yokoo, H.; Watanabe, T. Heterocycles 1998, 49, 127–132; (l) Murphy, W. S.; Bertrand, M. J. Chem. Soc., Perkin Trans. 1 1998, 4115–4119; (m) Chowdhury, B. K.; Jha, S.; Kar, B. R.; Saha, C. Indian J. Chem., Sect B: Org. Chem. Incl. Med. Chem. 1999, 38B, 1106–1107; (n) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Chem. Pharm. Bull. 1998, 46, 1948–1949; (o) Hagiwara, H.; Choshi, T.; Nobuhiro, J.; Fujimoto, H.; Hibino, S. Chem. Pharm. Bull. 2001, 49, 881–886; (p) Bouaziz, Z.; Nebois, P.; Poumaroux, A.; Fillion, H. Heterocycles 2000, 52, 977–1000; (q) Mal, D.; Senapati, B. K.; Pahari, P. Tetrahedron 2007, 63, 3768–3781. 6. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140; (b) Compain, P. Adv. Synth. Catal. 2007, 349, 1829–1846. 7. (a) Selvakumar, N.; Khera, M. K.; Reddy, B. Y.; Srinivas, D.; Azhagan, A. M.; Iqbal, J. Tetrahedron Lett. 2003, 44, 7071–7074; (b) Bennasar, M.-L.; Zulaica, E.; Tummers, S. Tetrahedron Lett. 2004, 45, 6283–6285; (c) Yang, X.; Althammer, A.; Knochel, P. Org. Lett. 2004, 6, 1665–1667; (d) van Otterlo, W. A. L.; de Koning, C. B. Chem. Rev. 2009, 109, 3743–3782. 8. Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis 2000, 429–434. 9. (a) Evans, P.; Grigg, R.; Monteith, M. Tetrahedron Lett. 1999, 40, 5247–5250; (b) Yang, C.; Murray, W. V.; Wilson, L. J. Tetrahedron Lett. 2003, 44, 1783–1786; (c) Dieltiens, N.; Stevens, C. V.; Vos, D. D.; Allaert, B.; Drozdzak, R.; Verpoort, F. Tetrahedron Lett. 2004, 45, 8995–8998; (d) Yang, Q.; Li, X.-Y.; Wu, H.; Xiao, W.-J. Tetrahedron Lett. 2006, 47, 3893–3896; (e) Dieltiens, N.; Stevens, C. V.; Allaert, B.; Verpoort, F. Arkivoc 2005, (i) 92–97. 10. Data of murrayaquinone A (1a): mp 240–241 °C; IR (ATR) m: 3209, 1662, 1600 cm 1. 1H NMR (300 MHz, CDCl3) d: 9.12 (1H, br s, NH), 8.26 (1H, d, J = 7.3 Hz, H-5), 7.33–7.50 (3H, m, H-6, -7, and -8), 6.52 (1H, q, J = 1.5 Hz, H-2), 2.19 (3H, d, J = 1.5 Hz, 3-CH3). 13C NMR (75 MHz, CDCl3+DMSO-d6) d: 182.4, 179.4, 147.3, 136.8, 135.1, 130.7, 125.1, 123.1, 122.7, 121.1, 115.1, 112.8, 15.1. MS m/z: 211 (M+). HR-MS (EI) m/z: 211.0619 (M+) (calcd for C13H9NO2: 211.0633).
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
New synthesis of carbazole-1,4-quinone using a tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere, and its application to the synthesis of murrayaquinone A Takashi Nishiyama, Tominari Choshi ⇑, Kohdai Kitano, Satoshi Hibino ⇑ Graduate School of Pharmacy Pharmaceutical Sciences, and Faculty of Pharmacy Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
a r t i c l e
i n f o
Article history: Received 19 April 2011 Revised 12 May 2011 Accepted 13 May 2011 Available online 27 May 2011
a b s t r a c t A tandem ring-closing metathesis and dehydrogenation reaction under oxygen atmosphere was newly developed to the synthesis of carbazole-1,4-quinones. This new tandem reaction was applied to the synthesis of murrayaquinone A in four steps. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Carbazole-1,4-quinone Murrayaquinone A Ring-closing metathesis Dehydrogenation Tandem reaction
O
1. Introduction A simple carbazole-1,4-quinone alkaloid, murrayaquinone B (2) was initially reported from the root bark of Murraya euchrestifolia Hayata (Rutaceae) in Taiwan.1,2 Two years later, the same group reported the isolation of various carbazole-1,4-quinone alkaloids, murrayaquinone A (1), and C–E (3–5) from the root or the stem bark of the same plant.1,3 Extracts of the leaves and bark of this tree have been used as a folk medicine in the treatment of several diseases.1,4 Among these alkaloids, murrayaquinone A (1) exhibits a cardiotonic activity on guinea pig papillary muscle.1,4 Total syntheses of murrayaquinone A (1) have been achieved by 14 groups1,5 including our formal total synthesis (Fig. 1).5n,o The ring-closing metathesis (RCM) reaction by Grubbs’s group is a well known reaction for the construction of many functionalized carbocycles and heterocycles.6 To our knowledge, there are few examples that make use of RCM reactions for the construction of carbazole framework from bisallylindoles.7 We planned a new total synthesis of murrayaquinone A (1) based on the application of the RCM reaction. In this paper, we describe a new methodology for the synthesis of carbazole-1,4-quinones using a tandem RCMoxidation reaction, and its application to a total synthesis of murrayaquinone A (1). ⇑ Corresponding authors. E-mail addresses: [email protected] (T. Choshi), hibino@ fupharm.fukuyama-u.ac.jp (S. Hibino). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.05.066
Me
R1 1: 2: 3: 4: 5:
N H R2 Murrayaquinone A Murrayaquinone B Murrayaquinone C Murrayaquinone D Murrayaquinone E
O R1 =R 2 =H R1 =OMe, R2 =prenyl R1 =OMe, R2 =geranyl R1 =OH, R 2=prenyl R1 =OH, R 2=geranyl
Figure 1.
2. Results and discussion We first attempted the synthesis of carbazole-1,4-quinones 1 according to our retro-synthetic analysis (Scheme 1). We envisaged that the 1,4-quinone moiety of 1 could be constructed by a new bond formation between the C2 and C3-positions in 1 through an RCM reaction of the bis(acryloyl)indole 2 derived from the 3-iodoindole-2-carbaldehyde (3). Based on the sequence in Scheme 2, a three-component Pd-catalyzed cross-coupling reaction between 3-iodoindole 4, CO, and alkenyl tributyltin according to Fukuyama’s procedure8 was carried out in DMF at 70 °C to provide 3-acryroylindoles 5. Subsequently, the Grignard reaction of the 3-acryroylindole 5a with vinylmagnesium bromide gave the 2-allyl alcohol 6a, which was
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T. Nishiyama et al. / Tetrahedron Letters 52 (2011) 3876–3878
O
O R
R
N O H 1a: R=Me (Murrayaquinone A) 1b: R=H
N H
O
N H 1
O
2
N H
O
R
OH 9
O R
I N H
HO
R
O
R
CHO 3
N H 6
Scheme 1.
N H
OH
OH 10
Scheme 3.
CO (1 atm) BHT PdCl2(dppf)
I N MOM 4
CHO
DMF 70oC, 24 h
O R
CHO N MOM 5a: R=Me (70%) 5b: R=H (51%) THF 0oC, 4 h
MgBr O R
O R act. MnO 2
N O MOM
CH2Cl2 reflux, 48 h
7a:R=Me (48%) 7b:R=H
N OH MOM 6a: R=Me (66%) 6b: R=H (26%)
Scheme 2.
oxidized with activated MnO2 to give the desired 2,3-bis(acryroyl)indole 7a. The oxidized product 7b, however, was not obtained from 6b in a similar manner. To construct a carbazole-1,4-quinone framework, we attempted an RCM reaction of the 2,3-bis(acryroyl)indole 7a, as shown in Table 1. When Grubbs 1st and 2nd generation catalysts were used in CH2Cl2 at room temperature, the carbazole-1,4-quinone 8 was actually formed in 20% and 33% yield, respectively (runs 1 and 2). Moreover, treatment of 7a with Grubbs 2nd generation catalyst in toluene at 70 °C afforded the carbazole-1,4-quinone 8 in 72% yield (run 3). Based on this preliminary result, we next attempted a direct synthesis of carbazole by an RCM reaction using the allyl alcohol
6, as shown in Scheme 3. We assumed that the 1,4-benzoquinone moiety of carbazole 1 would be converted by oxidation from carbazole-1,4-diol 9, which is equivalent to 10. Carbazole 10 might be derived from an allyl alcohol 6 through a new bond formation by an RCM reaction between the C2 and C3-positions in the carbazole 10. To examine whether a carbazole-1,4-diol 12 could be obtained, the allyl alcohol 6a was subjected to an RCM reaction under the conditions used for run 3 in Table 1 (Scheme 4). Although carbazole-1,4-quinone 8 was isolated as the sole product in 78% yield, the expected carbazole-1,4-diol 12 was not detected at all. This result suggested that not only an RCM reaction took place, but that dehydrogenation also occurred. When the reaction mixture was monitored by TLC, two new spots were observed. The upper spot was a carbazole-1,4-quinone 8, and the lower spot was concluded to be a carbazole-1,4-diol 12. Compound 12 of the lower spot could not be isolated because it disappeared during work-up of the reactant. It was considered that compound 12 was converted to 8 by the air oxidation. Similar reactions have been noted by a few research groups9 reporting that pyrrole was obtained from diallylamine by a tandem RCM and dehydrogenation reaction. This tandem reaction was further examined in detail using the allyl alcohol 6a as the substrate. As shown in Table 2, Grubbs catalysts (1st and 2nd) and Hoveyda–Grubbs catalysts (1st and 2nd) were used in the tandem RCM-oxidation reaction. Several reaction conditions including various times, temperatures, and solvents were also investigated. Treatment of 6a with Grubbs 1st generation catalyst afforded the quinone 8 in low yield (runs 1 and 2). When the Hoveyda–Grubbs 1st generation catalyst was used, many unknown compounds were obtained (run 6), but when its 2nd generation catalyst was used, product 8 was obtained in
O Me Table 1 Synthesis of carbazole-1,4-quinone 8 by RCM reaction
O Me
O Grubbs catalyst
*
Run
Catalyst
1 2 3
1st 2nd 2nd
Grubbs catalyst.
*
N OH MOM
Me
toluene 70 oC, 0.5 h
6a
O
Me
N OH MOM 11
HO
N O MOM 8
N O MOM 7a
Grubbs 2nd catalyst
O
Me +
Solvent
Temp (°C)
Time (h)
Yield (%)
CH2Cl2 CH2Cl2 Toluene
rt rt 70
1 2 1
20 33 72
N O MOM
N OH MOM 12: Not detected
8: 78% Work up
Scheme 4.
Me
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T. Nishiyama et al. / Tetrahedron Letters 52 (2011) 3876–3878
Table 2 Synthesis of N-MOM-murrayaquinone A 8 by RCM reaction
HO
O Me
O Me
N O MOM N OH MOM 6a
a b c
N O MOM
N OH MOM 12 Gasb
Solvent
Temp (°C)
Time (h)
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12
1st 1st 2nd 2nd 2nd Hoveyda 1st Hoveyda 2nd 1st 1st 2nd 2nd 2nd
N2 N2 N2 N2 N2 N2 N2 O2 O2 O2 O2 O2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene
rt Reflux rt Reflux 70 rt rt rt Reflux rt Reflux 70
2 2 1 0.5 0.5 12 2 1 1 2 15 min 5 min
27 25 64 70 78 —c 51 45 67 90 75 93
A new efficient synthesis of carbazole-1,4-quinone from allyl alcohol 6 was established using a tandem RCM and dehydrogenation reaction with Grubbs 2nd generation catalyst. In addition, we achieved the total synthesis of murrayaquinone A (1a) in four steps from 4 in 42.5% yield. Based on this result, we present an efficient method for use in synthetic studies of carbazole alkaloids and/or other natural products with a 1,4-quinone structure. Further research of the synthesis of carbazolequinone alkaloids is ongoing.
Table 3 Synthesis of carbazole-l,4-quinone 14 by RCM reaction
a b
O
N O MOM 14
Run
Catalysta
Gasb
Solvent
Temp (°C)
Time (h)
Yield (%)
1 2 3 4 5 6 7 8 9 10
1st 1st 2nd 2nd 2nd 1st 1st 2nd 2nd 2nd
N2 N2 N2 N2 N2 O2 O2 O2 O2 O2
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene
rt Reflux rt Reflux 70 rt Reflux rt Reflux 70
0.5 0.5 2 45 min 0.5 0.5 1 2 2 10 min
29 28 38 28 36 56 34 79 79 90
Grubbs catalyst. The reaction proceeded in gas atmosphere.
1a: 99%
3. Conclusions
moderate yield (run 7). When using Grubbs 2nd generation catalyst, good results were obtained in CH2Cl2 at room temperature and/or at reflux (runs 3 and 4). An RCM reaction with Grubbs 2nd generation catalyst in toluene at 70 °C provided even more promising results (run 5). As illustrated in Scheme 4, we considered that quinone 8 was produced by oxidative dehydrogenation of the hydroquinone moiety of 12 with oxygen in the air, during work-up. Therefore, we attempted an RCM reaction under oxygen atmosphere (runs 8–12). When the reaction mixture was monitored by TLC, the lower spot of compound 12 was not detected in situ. Product 8 was obtained in the highest yield with Grubbs 2nd generation catalyst in toluene at 70 °C for 5 min (run 12). We then evaluated an RCM reaction of the allyl alcohol 6b under the same conditions (Table 3). Monitoring of the RCM reaction of 6b under conventional conditions by TLC revealed an absence of compound 13 and the production of quinone 14 in a relatively low yield (runs 1–5). By contrast, an RCM reaction of 6b under oxygen atmosphere as in runs 6–10 produced quinone 14 in excellent yield (run 10). Finally, treatment of N-MOM-carbazoles 8 with 6 M HCl according to Hanaoka’s procedure5i afforded murrayaquinone A (1a) in
N OH MOM 13
O
99% yield (Scheme 5). The synthetic murrayaquinone A (1a) was identical to natural or synthetic products in all respects.10
Grubbs catalyst. The reaction proceeded in gas atmosphere. Complex compound.
N OH MOM 6b
N H
Scheme 5.
Catalysta
HO
MeOH 60 oC, 1 h
8
8
Run
O
Me
6M HCl
O
Me
O
Me
References and notes 1. (a) Chakraborty, D. P.; Roy, S. In Progress in the Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby, G. W., Steglich, W., Tamm, C., Eds.; Springer: Wien, 1991; Vol. 57, p 71; (b) Chakraborty, D. P. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1993; Vol. 44, pp 257–364; (c) Furukawa, H. J. Indian Chem. Soc. 1994, 71, 303–308; (d) Moody, C. J. Synlett 1994, 681–688; (e) Choshi, T. Yakugaku Zasshi 2001, 121, 487–495; (f) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–4427; (g) Knölker, H.-J. Top. Curr. Chem. 2005, 244, 115–148; (h) Knölker, H.-J.; Reddy, K. R. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: Amsterdam, 2008; Vol. 65, pp 1–430. 2. Wu, T.-S.; Ohta, T.; Furukawa, H. Heterocycles 1983, 20, 1267–1269. 3. Furukawa, H.; Wu, T.-S.; Ohta, T.; Kuoh, C.-S. Chem. Pharm. Bull. 1985, 33, 4132– 4138. 4. Takeya, K.; Itoigawa, M.; Furukawa, H. Eur. J. Pharmacol. 1989, 169, 137–145. 5. (a) Ramesh, K.; Kapil, R. S. Chem. Ind. (London) 1986, 614–615; (b) Idem J. Nat. Prod. 1987, 50, 932–934; (c) Martin, T.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1988, 235–240; (d) Yogo, M.; Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1991, 39, 328–334; (e) Miki, Y.; Hachiken, H. Synlett 1993, 333–334; (f) Matsuo, K.; Ishida, S. Chem. Express 1993, 8, 321–324; (g) Idem Chem. Pharm. Bull. 1994, 42, 1325–1327; (h) Knölker, H.-J.; Bauermeister, M. Tetrahedron 1993, 49, 11221– 11236; (i) Wada, A.; Hirai, S.; Hanaoka, M. Chem. Pharm. Bull. 1994, 42, 416– 418; (j) Akermark, B.; Oslob, J. D.; Heuschert, U. Tetrahedron Lett. 1995, 36, 1325–1326; (k) Murakami, Y.; Yokoo, H.; Watanabe, T. Heterocycles 1998, 49, 127–132; (l) Murphy, W. S.; Bertrand, M. J. Chem. Soc., Perkin Trans. 1 1998, 4115–4119; (m) Chowdhury, B. K.; Jha, S.; Kar, B. R.; Saha, C. Indian J. Chem., Sect B: Org. Chem. Incl. Med. Chem. 1999, 38B, 1106–1107; (n) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Chem. Pharm. Bull. 1998, 46, 1948–1949; (o) Hagiwara, H.; Choshi, T.; Nobuhiro, J.; Fujimoto, H.; Hibino, S. Chem. Pharm. Bull. 2001, 49, 881–886; (p) Bouaziz, Z.; Nebois, P.; Poumaroux, A.; Fillion, H. Heterocycles 2000, 52, 977–1000; (q) Mal, D.; Senapati, B. K.; Pahari, P. Tetrahedron 2007, 63, 3768–3781. 6. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140; (b) Compain, P. Adv. Synth. Catal. 2007, 349, 1829–1846. 7. (a) Selvakumar, N.; Khera, M. K.; Reddy, B. Y.; Srinivas, D.; Azhagan, A. M.; Iqbal, J. Tetrahedron Lett. 2003, 44, 7071–7074; (b) Bennasar, M.-L.; Zulaica, E.; Tummers, S. Tetrahedron Lett. 2004, 45, 6283–6285; (c) Yang, X.; Althammer, A.; Knochel, P. Org. Lett. 2004, 6, 1665–1667; (d) van Otterlo, W. A. L.; de Koning, C. B. Chem. Rev. 2009, 109, 3743–3782. 8. Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis 2000, 429–434. 9. (a) Evans, P.; Grigg, R.; Monteith, M. Tetrahedron Lett. 1999, 40, 5247–5250; (b) Yang, C.; Murray, W. V.; Wilson, L. J. Tetrahedron Lett. 2003, 44, 1783–1786; (c) Dieltiens, N.; Stevens, C. V.; Vos, D. D.; Allaert, B.; Drozdzak, R.; Verpoort, F. Tetrahedron Lett. 2004, 45, 8995–8998; (d) Yang, Q.; Li, X.-Y.; Wu, H.; Xiao, W.-J. Tetrahedron Lett. 2006, 47, 3893–3896; (e) Dieltiens, N.; Stevens, C. V.; Allaert, B.; Verpoort, F. Arkivoc 2005, (i) 92–97. 10. Data of murrayaquinone A (1a): mp 240–241 °C; IR (ATR) m: 3209, 1662, 1600 cm 1. 1H NMR (300 MHz, CDCl3) d: 9.12 (1H, br s, NH), 8.26 (1H, d, J = 7.3 Hz, H-5), 7.33–7.50 (3H, m, H-6, -7, and -8), 6.52 (1H, q, J = 1.5 Hz, H-2), 2.19 (3H, d, J = 1.5 Hz, 3-CH3). 13C NMR (75 MHz, CDCl3+DMSO-d6) d: 182.4, 179.4, 147.3, 136.8, 135.1, 130.7, 125.1, 123.1, 122.7, 121.1, 115.1, 112.8, 15.1. MS m/z: 211 (M+). HR-MS (EI) m/z: 211.0619 (M+) (calcd for C13H9NO2: 211.0633).