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Intramolecular radical additions to quinolines
TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 2907–2910
Pergamon
Intramolecular radical additions to quinolines David C. Harrowven,a,* Benjamin J. Suttona and Steven Coultonb a
b
Department of Chemistry, The University, Southampton S017 1BJ, UK GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK Received 25 January 2001; revised 8 February 2001; accepted 21 February 2001
Abstract—This paper is concerned with intramolecular radical additions to quinolines. Radical additions to C-2, C-3 and C-4 of a quinoline have all been shown to proceed under neutral conditions. In each case formation of heteroaromatic products, rather than dihydroquinolines, was observed (implicating the so called oxidative tin hydride pathway). © 2001 Elsevier Science Ltd. All rights reserved.
We recently completed a total synthesis of the alkaloid toddaquinoline in which an intramolecular addition of an aryl radical to a pyridine featured as the key step.1 This success prompted us to consider various extensions of that method. In particular we were keen to determine whether radical additions to quinolines were equally facile when conducted intramolecularly at neutral pH as this could be used to synthesise a host of interesting condensed heteroaromatics.2–4 In this Letter we present our preliminary observations which show that intramolecular radical additions to C-2, C-3 and C-4 of a quinoline are all facile under standard tin mediated radical cyclisation conditions and result in the
formation of heteroaromatic products (via the so called oxidative tin hydride pathway)5 rather than dihydroquinolines. Our first objective was to see if radical cyclisations to C-3 of a quinoline could be effected. To that end quinolines 2 and 4 were prepared and treated with tributyltin hydride under standard radical forming conditions.6 Notably, alkene 2 required more forcing conditions to induce cyclisation than alkane 4. In both cases a benzo[a]acridine derivative was provided, showing that these reactions follow the ‘oxidative tin hydride’ pathway (Scheme 1). O
O + - NaH, THF PPh3 Br 0 °C, 2 h then
O O
O I
I
1
N
CHO
O 5 eq. Bu3SnH 0.6 eq. AIBN, PhMe 100 °C, 72 h, 42%
N
N
2
0 °C, 2 h, 92% H2N-NHTs, NaOAc THF-H2O, 70 h, 90%
3 O
O
O
O 1.2 eq. Bu SnH 3 I N
0.1 eq. AIBN, PhMe 80 °C, 24 h, 70% N
4 Scheme 1.
Keywords: radicals and radical reactions; quinolines; nitrogen heterocycles; cyclisation. * Corresponding author. 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 0 - 4 0 3 9 ( 0 1 ) 0 0 3 2 1 - 5
5
D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 2907–2910
2908
Cyclisations to C-3 of the quinoline could also be envisioned when a radical precursor is tethered at C-4 of the quinoline. To probe that reaction course the alkenes 6 and 7 were synthesised from 4-quinolinecarboxaldehyde. Attempts to separate these diastereoiso-
1
mers proved intractable so the mixture was treated with tributyltin hydride under standard radical forming conditions. One major component, trans-alkene 12, was given in 83% yield together with traces (15%) of the desired cyclised product 11. This suggests that addition
O
NaH, 0 °C, THF, 2 h then 4-quinolinecarboxaldehyde THF, 0 °C, 2 h, 65% 1:1 - 6:7 inseparable
I
O
O
+
I
O N
N
6
7
1.2 eq. Bu3SnH, 0.2 eq. AIBN
O
O
+
•
O
PhMe, 80 °C, 18 h
I
O
•
+
O
•
O Bu3Sn
N
N
8
10
9
O
O
O
O
N
N
N
11, 15%
12, 83%
Scheme 2.
6+7
8 eq. H2N-NHTs 8 eq. NaOAc THF-H2O, 72 h, 87%
O O
I
1.4 eq. Bu3SnH
O
0.2 eq. AIBN, PhMe 80 °C, 48 h, 67%
O N
N
14
13 Scheme 3. O
O
O
O
Br
N
1.2 eq. Bu3SnH 0.9 eq. AIBN PhMe, 80 °C 18 h, 88% 8:4:3 - 16:17:18
O O
15
N
+
+
O O
N
N
16
17
18
THF-H2O reflux, 72 h, 59%
H2N-NHTs NaOAc
O O
O Br
N O O
19 Scheme 4.
O
1.2 eq. Bu3SnH 0.1 eq. AIBN PhMe, 80 °C 72 h, 72% (+25% 19) 3:2:2 - 20:21:22
N
+
+
O O
N
N
20
21
22
D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 2907–2910
2909
OH Br N
23
OH 1 eq. Bu3SnH
n-BuLi, Et2O, -100 ˚C, 2 h then 2-bromobenzaldehyde -100 to -60 ˚C, 2 h, 77%
N
Br
24 MnO2, DCM
0.1 eq. AIBN, PhMe 80 ˚C, 18 h, 50%
N
25
RT, 24 h, 94% O
O 1.2 eq. Bu3SnH
N
Br
26
0.2 eq. AIBN, PhMe 80 ˚C, 48 h, 75%
N
27
Scheme 5.
of tributyltin radical to the alkene 6 outpaces homolysis of the carbon to iodine bond in this case (Scheme 2).
Acknowledgements
Pleasingly, cyclisation of the corresponding alkane 13 proceeded smoothly to give dihydrobenzo[i ]phenanthridine 14 in 67% yield (Scheme 3).
The authors thank GlaxoSmithKline and the EPSRC for a CASE award (to B.J.S.), the EPSRC National Crystallographic Service Centre at The University of Southampton for the X-ray analysis of 5 and Joan Street for some invaluable NOE studies.
Our next objective was to tether a radical precursor at C-3 of a quinoline to see if such substrates gave rise to products derived from ipso-attack or cyclisation to C-2/C-4. To that end alkene 15 was synthesised and treated with tributyltin hydride under the aforementioned conditions.6 Though cyclisation to benzo[k]phenanthridine 16 and benzo[c]acridine 17 was achieved, considerable quantities of recovered starting material accompanied these products. Indeed, only when the reaction was conducted with a near stoichiometric quantity of AIBN was all the starting material consumed! Importantly, and in contrast to radical additions to pyridines, cyclisation to C-4 of the quinoline was favoured over cyclisation to C-2.1 This regiochemical preference was mirrored with alkane 19: treatment with tributyltin hydride giving a complex mixture of products including dihydrobenzo[k]phenanthridine 20, dihydrobenzo[c]acridine 21 and quinoline 22 (Scheme 4). Finally, it is worth noting that all our attempts to effect a radical cyclisation leading to the creation of a five membered ring met with failure. For example, bromides 24 and 26 were each reduced to the corresponding arene on exposure to tributyltin hydride—suggesting that the cyclisation pathway is more akin to a 5-endotrig than a 5-exo-trig process in such cases (Scheme 5). In conclusion, we have shown that intramolecular radical additions to quinolines are facile processes that can be used to effect the synthesis of various condensed heterocycles. Radical additions to C-2, C-3 and C-4 of a quinoline have all been demonstrated and in each case formation of a heteroaromatic product, rather than dihydroquinoline, was observed. A rapid, stannyl radical mediated cis to trans isomerisation of a C-4 tethered styrene has also been uncovered.
References 1. (a) Harrowven, D. C.; Nunn, M. I. T.; Blumire, N. J.; Fenwick, D. R. Tetrahedron Lett. 2000, 41, 6681; (b) Harrowven, D. C.; Nunn, M. I. T. Tetrahedron Lett. 1998, 39, 5875. 2. For an overview of radical additions to heteroaromatic bases, see: (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489. For recent examples, see: (b) Russell, G. A.; Rajaratnam, R.; Wang, L. J.; Shi, B. Z.; Kim, B. H.; Yao, C. F. J. Am. Chem. Soc. 1993, 115, 10596; (c) Russell, G. A.; Wang, L. J.; Yao, C. F. J. Org. Chem. 1995, 60, 5390. 3. For recent reviews on the synthesis of heterocycles by radical chemistry, see: (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1 2000, 1; (b) Aldabbagh, F.; Bowman, W. R. Contemp. Org. Synth. 1997, 4, 261. 4. For related work from our group, see: (a) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40, 4443; (b) Harrowven, D. C.; Hannam, J. C. Tetrahedron 1999, 55, 9341; (c) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40, 1187; (d) Harrowven, D. C.; Browne, R. Tetrahedron Lett. 1995, 36, 2861; (e) Harrowven, D. C. Tetrahedron Lett. 1993, 34, 5653. 5. ‘Oxidative tin hydride reaction’ is a term used to describe reactions mediated by a trialkyltin hydride in which a radical cyclisation step is followed by an oxidation step in the absence of an added oxidising agent. For examples, see: (a) Bowman, W. R.; Mann, E.; Parr, J. J. Chem. Soc., Perkin Trans. 1 2000, 2991; (b) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991, 47, 10119; (c)
D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 2907–2910
2910
Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951; (d) de Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 141; (e) Murphy, J. A.; O
OH
a.
O
O
OH
O
cal characteristics. The Wittig reagent 1 and bromoarene 15 were synthesised according to the following sequences (Scheme 6). b.
O O
I
Br
+ PPh3 Br-
O
c.
O
I
I
1
d. O O
Br Br
e.
+ PPh3 Br
O O
Br
O f.
15 +
Br
O
separable
28
N
Scheme 6. Reagents and conditions: (a) I2, AgOCOCF3, CHCl3, 5 min, 83%;7 (b) PBr3, Et3N, 0°C, DCM–THF, then 40°C, 30 min, 83%;7 (c) PPh3, xylene, 100°C, 24 h, 95%; (d) Br2, AcOH, 0°C, 2 h, 67%;8 (e) PPh3, xylene, 80°C, 5 h, 100%; (f) NaH, THF, 0°C, 2 h, then 3-quinolinecarboxaldehyde, 84%, 3:1 - 15:28. Sherburn, M. S. Tetrahedron 1991, 47, 4077; (f) Harrowven, D. C.; Nunn, M. I. T.; Newman, N. A.; Fenwick, D. R. Tetrahedron Lett. 2001, 42, 961. 6. All new compounds gave satisfactory spectral and analyti-
.
7. Cossy, J.; Tresnard, L.; Pardo, D. G. Eur. J. Org. Chem. 1999, 1925. 8. Padwa, A.; Cochran, J. E.; Kappe, C. O. J. Org. Chem. 1996, 61, 3706.
Pergamon
Intramolecular radical additions to quinolines David C. Harrowven,a,* Benjamin J. Suttona and Steven Coultonb a
b
Department of Chemistry, The University, Southampton S017 1BJ, UK GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK Received 25 January 2001; revised 8 February 2001; accepted 21 February 2001
Abstract—This paper is concerned with intramolecular radical additions to quinolines. Radical additions to C-2, C-3 and C-4 of a quinoline have all been shown to proceed under neutral conditions. In each case formation of heteroaromatic products, rather than dihydroquinolines, was observed (implicating the so called oxidative tin hydride pathway). © 2001 Elsevier Science Ltd. All rights reserved.
We recently completed a total synthesis of the alkaloid toddaquinoline in which an intramolecular addition of an aryl radical to a pyridine featured as the key step.1 This success prompted us to consider various extensions of that method. In particular we were keen to determine whether radical additions to quinolines were equally facile when conducted intramolecularly at neutral pH as this could be used to synthesise a host of interesting condensed heteroaromatics.2–4 In this Letter we present our preliminary observations which show that intramolecular radical additions to C-2, C-3 and C-4 of a quinoline are all facile under standard tin mediated radical cyclisation conditions and result in the
formation of heteroaromatic products (via the so called oxidative tin hydride pathway)5 rather than dihydroquinolines. Our first objective was to see if radical cyclisations to C-3 of a quinoline could be effected. To that end quinolines 2 and 4 were prepared and treated with tributyltin hydride under standard radical forming conditions.6 Notably, alkene 2 required more forcing conditions to induce cyclisation than alkane 4. In both cases a benzo[a]acridine derivative was provided, showing that these reactions follow the ‘oxidative tin hydride’ pathway (Scheme 1). O
O + - NaH, THF PPh3 Br 0 °C, 2 h then
O O
O I
I
1
N
CHO
O 5 eq. Bu3SnH 0.6 eq. AIBN, PhMe 100 °C, 72 h, 42%
N
N
2
0 °C, 2 h, 92% H2N-NHTs, NaOAc THF-H2O, 70 h, 90%
3 O
O
O
O 1.2 eq. Bu SnH 3 I N
0.1 eq. AIBN, PhMe 80 °C, 24 h, 70% N
4 Scheme 1.
Keywords: radicals and radical reactions; quinolines; nitrogen heterocycles; cyclisation. * Corresponding author. 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 0 - 4 0 3 9 ( 0 1 ) 0 0 3 2 1 - 5
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D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 2907–2910
2908
Cyclisations to C-3 of the quinoline could also be envisioned when a radical precursor is tethered at C-4 of the quinoline. To probe that reaction course the alkenes 6 and 7 were synthesised from 4-quinolinecarboxaldehyde. Attempts to separate these diastereoiso-
1
mers proved intractable so the mixture was treated with tributyltin hydride under standard radical forming conditions. One major component, trans-alkene 12, was given in 83% yield together with traces (15%) of the desired cyclised product 11. This suggests that addition
O
NaH, 0 °C, THF, 2 h then 4-quinolinecarboxaldehyde THF, 0 °C, 2 h, 65% 1:1 - 6:7 inseparable
I
O
O
+
I
O N
N
6
7
1.2 eq. Bu3SnH, 0.2 eq. AIBN
O
O
+
•
O
PhMe, 80 °C, 18 h
I
O
•
+
O
•
O Bu3Sn
N
N
8
10
9
O
O
O
O
N
N
N
11, 15%
12, 83%
Scheme 2.
6+7
8 eq. H2N-NHTs 8 eq. NaOAc THF-H2O, 72 h, 87%
O O
I
1.4 eq. Bu3SnH
O
0.2 eq. AIBN, PhMe 80 °C, 48 h, 67%
O N
N
14
13 Scheme 3. O
O
O
O
Br
N
1.2 eq. Bu3SnH 0.9 eq. AIBN PhMe, 80 °C 18 h, 88% 8:4:3 - 16:17:18
O O
15
N
+
+
O O
N
N
16
17
18
THF-H2O reflux, 72 h, 59%
H2N-NHTs NaOAc
O O
O Br
N O O
19 Scheme 4.
O
1.2 eq. Bu3SnH 0.1 eq. AIBN PhMe, 80 °C 72 h, 72% (+25% 19) 3:2:2 - 20:21:22
N
+
+
O O
N
N
20
21
22
D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 2907–2910
2909
OH Br N
23
OH 1 eq. Bu3SnH
n-BuLi, Et2O, -100 ˚C, 2 h then 2-bromobenzaldehyde -100 to -60 ˚C, 2 h, 77%
N
Br
24 MnO2, DCM
0.1 eq. AIBN, PhMe 80 ˚C, 18 h, 50%
N
25
RT, 24 h, 94% O
O 1.2 eq. Bu3SnH
N
Br
26
0.2 eq. AIBN, PhMe 80 ˚C, 48 h, 75%
N
27
Scheme 5.
of tributyltin radical to the alkene 6 outpaces homolysis of the carbon to iodine bond in this case (Scheme 2).
Acknowledgements
Pleasingly, cyclisation of the corresponding alkane 13 proceeded smoothly to give dihydrobenzo[i ]phenanthridine 14 in 67% yield (Scheme 3).
The authors thank GlaxoSmithKline and the EPSRC for a CASE award (to B.J.S.), the EPSRC National Crystallographic Service Centre at The University of Southampton for the X-ray analysis of 5 and Joan Street for some invaluable NOE studies.
Our next objective was to tether a radical precursor at C-3 of a quinoline to see if such substrates gave rise to products derived from ipso-attack or cyclisation to C-2/C-4. To that end alkene 15 was synthesised and treated with tributyltin hydride under the aforementioned conditions.6 Though cyclisation to benzo[k]phenanthridine 16 and benzo[c]acridine 17 was achieved, considerable quantities of recovered starting material accompanied these products. Indeed, only when the reaction was conducted with a near stoichiometric quantity of AIBN was all the starting material consumed! Importantly, and in contrast to radical additions to pyridines, cyclisation to C-4 of the quinoline was favoured over cyclisation to C-2.1 This regiochemical preference was mirrored with alkane 19: treatment with tributyltin hydride giving a complex mixture of products including dihydrobenzo[k]phenanthridine 20, dihydrobenzo[c]acridine 21 and quinoline 22 (Scheme 4). Finally, it is worth noting that all our attempts to effect a radical cyclisation leading to the creation of a five membered ring met with failure. For example, bromides 24 and 26 were each reduced to the corresponding arene on exposure to tributyltin hydride—suggesting that the cyclisation pathway is more akin to a 5-endotrig than a 5-exo-trig process in such cases (Scheme 5). In conclusion, we have shown that intramolecular radical additions to quinolines are facile processes that can be used to effect the synthesis of various condensed heterocycles. Radical additions to C-2, C-3 and C-4 of a quinoline have all been demonstrated and in each case formation of a heteroaromatic product, rather than dihydroquinoline, was observed. A rapid, stannyl radical mediated cis to trans isomerisation of a C-4 tethered styrene has also been uncovered.
References 1. (a) Harrowven, D. C.; Nunn, M. I. T.; Blumire, N. J.; Fenwick, D. R. Tetrahedron Lett. 2000, 41, 6681; (b) Harrowven, D. C.; Nunn, M. I. T. Tetrahedron Lett. 1998, 39, 5875. 2. For an overview of radical additions to heteroaromatic bases, see: (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489. For recent examples, see: (b) Russell, G. A.; Rajaratnam, R.; Wang, L. J.; Shi, B. Z.; Kim, B. H.; Yao, C. F. J. Am. Chem. Soc. 1993, 115, 10596; (c) Russell, G. A.; Wang, L. J.; Yao, C. F. J. Org. Chem. 1995, 60, 5390. 3. For recent reviews on the synthesis of heterocycles by radical chemistry, see: (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1 2000, 1; (b) Aldabbagh, F.; Bowman, W. R. Contemp. Org. Synth. 1997, 4, 261. 4. For related work from our group, see: (a) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40, 4443; (b) Harrowven, D. C.; Hannam, J. C. Tetrahedron 1999, 55, 9341; (c) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron Lett. 1999, 40, 1187; (d) Harrowven, D. C.; Browne, R. Tetrahedron Lett. 1995, 36, 2861; (e) Harrowven, D. C. Tetrahedron Lett. 1993, 34, 5653. 5. ‘Oxidative tin hydride reaction’ is a term used to describe reactions mediated by a trialkyltin hydride in which a radical cyclisation step is followed by an oxidation step in the absence of an added oxidising agent. For examples, see: (a) Bowman, W. R.; Mann, E.; Parr, J. J. Chem. Soc., Perkin Trans. 1 2000, 2991; (b) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991, 47, 10119; (c)
D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 2907–2910
2910
Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951; (d) de Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 141; (e) Murphy, J. A.; O
OH
a.
O
O
OH
O
cal characteristics. The Wittig reagent 1 and bromoarene 15 were synthesised according to the following sequences (Scheme 6). b.
O O
I
Br
+ PPh3 Br-
O
c.
O
I
I
1
d. O O
Br Br
e.
+ PPh3 Br
O O
Br
O f.
15 +
Br
O
separable
28
N
Scheme 6. Reagents and conditions: (a) I2, AgOCOCF3, CHCl3, 5 min, 83%;7 (b) PBr3, Et3N, 0°C, DCM–THF, then 40°C, 30 min, 83%;7 (c) PPh3, xylene, 100°C, 24 h, 95%; (d) Br2, AcOH, 0°C, 2 h, 67%;8 (e) PPh3, xylene, 80°C, 5 h, 100%; (f) NaH, THF, 0°C, 2 h, then 3-quinolinecarboxaldehyde, 84%, 3:1 - 15:28. Sherburn, M. S. Tetrahedron 1991, 47, 4077; (f) Harrowven, D. C.; Nunn, M. I. T.; Newman, N. A.; Fenwick, D. R. Tetrahedron Lett. 2001, 42, 961. 6. All new compounds gave satisfactory spectral and analyti-
.
7. Cossy, J.; Tresnard, L.; Pardo, D. G. Eur. J. Org. Chem. 1999, 1925. 8. Padwa, A.; Cochran, J. E.; Kappe, C. O. J. Org. Chem. 1996, 61, 3706.