Isonitrile trapping reactions under thermolysis of alkoxyamines for the synthesis of quinolines

Article abstract of DOI:10.1021/ol0604421

An efficient tandem radical process comprising a thermal alkoxyamine homolysis, an isonitrile trapping reaction, a 5-exo-trig cyclization, and a homolytic aromatic substitution leads to substituted dihydroquinolines. Depending on the substituent R¹, oxidation to dihydro-1H-cyclopenta- [b]quinolines (for R¹ = aryl) or tautomerization to tetrahydro-1H-cyclopenta[b]quinolines (for R¹ = CO₂Me, CN) occurs. The heterocycles are obtained in moderate to good yields. Upon using microwave-induced heating, the reaction time can be shortened from 3 days to 30 min.

Full text of DOI:10.1021/ol0604421

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1875-1878
Isonitrile Trapping Reactions under
Thermolysis of Alkoxyamines for the
Synthesis of Quinolines
Birgit Janza and Armido Studer*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, 48149 Mu¨nster, Germany
studer@uni-muenster.de
Received February 20, 2006
ABSTRACT
An efficient tandem radical process comprising a thermal alkoxyamine homolysis, an isonitrile trapping reaction, a 5-exo-trig cyclization, and
a homolytic aromatic substitution leads to substituted dihydroquinolines. Depending on the substituent R1, oxidation to dihydro-1H-cyclopenta-
[b]quinolines (for R1
)
aryl) or tautomerization to tetrahydro-1H-cyclopenta[b]quinolines (for R1
)
CO2Me, CN) occurs. The heterocycles are
obtained in moderate to good yields. Upon using microwave-induced heating, the reaction time can be shortened from 3 days to 30 min.
Over the last few decades, radical chemistry has gained
increasing importance in synthetic organic chemistry.1 Along
with other radical acceptors, isonitriles have been shown to
react efficiently with various C-radicals and sulfanyl radicals
to provide the corresponding imidoyl radicals which can
further react with various radical acceptors to afford interest-
ing heterocycles.2,3 Curran has elegantly used these tandem
reactions for the synthesis of substituted quinolines in radical
[4+1] annulation reactions.3b,4 Over the past few years, we
have successfully used alkoxyamines as clean sources for
the generation of C-centered radicals.5,6 C-radical formation
using this approach is reversible and is controlled by the
persistent radical effect (PRE).7 Alkoxyamine isomerizations
and intermolecular alkoxyamine additions have been con-
ducted using this methodology. In most of the cases, the
(4) (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1991, 113, 2127. (b)
Curran, D. P.; Sisko, J.; Yeske, P. E.; Liu, H. Pure Appl. Chem. 1993, 65,
1153. (c) Curran, D. P.; Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 2683. (d) Josien, H.; Curran, D. P. Tetrahedron 1997, 53, 8881.
(e) Josien, H.; Bom, D.; Curran, D. P.; Zheng, Y.-H.; Chou, T.-C. Bioorg.
Med. Chem. Lett. 1997, 7, 3189. (f) Josien, H.; Ko, S.-B.; Bom, D.; Curran,
D. P. Chem.-Eur. J. 1998, 4, 67. (g) Gabarda, A. E.; Du, W.; Isarno, T.;
Tangirala, R. S.; Curran, D. P. Tetrahedron 2002, 58, 6329. (h) Gabarda,
A. E.; Curran, D. P. J. Comb. Chem. 2003, 5, 617. (i) Tangirala, R. S.;
Antony, S.; Agama, K.; Pommier, Y.; Curran, D. P. Synlett 2005, 2843.
(5) (a) Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108. (b) Wetter,
C.; Jantos, K.; Woithe, K.; Studer, A. Org. Lett. 2003, 5, 2899. (c) Teichert,
A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477. (d) Wetter,
C.; Studer, A. Chem. Commun. 2004, 174. (e) Molawi, K.; Schulte, T.;
Siegenthaler, K. O.; Wetter, C.; Studer, A. Chem.-Eur. J. 2005, 11, 2335.
(f) Herrera, A. J.; Studer, A. Synthesis 2005, 1389. (g) Uenoyama, Y.;
Tsukida, M.; Doi, T.; Ryu, I.; Studer, A. Org. Lett. 2005, 7, 2985. See
also: Allen, A. D.; Cheng, B.; Fenwick, M. H.; Givehchi, B.; Henry-Riyad,
H.; Nikolaev, V. A.; Shikhova, E. A.; Tahmassebi, D.; Tidwell, T. T.; Wang,
S. J. Org. Chem. 2001, 66, 2611. Allen, A. D.; Fenwick, M. F.; Henry-
Riyad, H.; Tidwell, T. T. J. Org. Chem. 2001, 66, 5759. Leroi, C.; Fenet,
B.; Couturier, J.-L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5, 1079.
(6) Reviews: (a) Studer, A. Chem.-Eur. J. 2001, 7, 1159. (b) Studer,
A. Chem. Soc. ReV. 2004, 33, 267. (c) Studer, A.; Schulte, T. Chem. Rec.
2005, 5, 27.
(1) For reviews on radical chemistry, see: (a) Renaud, P., Sibi, M. P.,
Eds.; Radicals in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2001; Vols. 1 and 2. (b) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim, 1996. (c) Moth-
erwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis;
Academic: London, 1992.
(2) Nanni, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, p 44.
(3) (a) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, A.
Tetrahedron 1995, 51, 9045. (b) Curran, D. P.; Liu, H.; Josien, H.; Ko,
S.-B. Tetrahedron 1996, 52, 11385. (c) Camaggi, C. M.; Leardini, R.; Nanni,
D.; Zanardi, G. Tetrahedron 1998, 54, 5587.
10.1021/ol0604421 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/01/2006

commercially available TEMPO (2,2,6,6-tetramethylpiperi-
dine-1-oxyl) radical was used as persistent nitroxide in these
tin-free PRE-controlled processes.
conducted in DMF (0.1 M) at 140 °C (sealed tube) with
equimolar amounts of 1 and the isonitrile (Table 1, entry 1).
In this communication, we present first results on the use
of aryl isonitriles as radical acceptors in TEMPO-mediated
radical cyclization processes for the synthesis of quinolines.
The synthetic strategy is depicted in Scheme 1. As a model
Table 1. Reaction of 1 with 3 under Different Conditions
entry 1 (M) time
solvent
temp (°C) 3 (equiv) 7 (%)a
1
2
3
4
0.1
0.1
0.1
0.1
0.1
0.1
3 days DMF
3 days DMF
3 days DMF
3 days DMF
3 days ClCH2CH2Cl
3 days DMF
140
140
140
140
140
140
140
140
180
180
1
2
5
10
5
5
5
5
5
5
traces
13
50
54
42
56
53
49
51
Scheme 1. PRE-Mediated Quinoline Synthesis
5
6b
7b
8b
9c
0.25 3 days DMF
0.05 3 days DMF
0.1
30 min DMF
30 min DMF
10b,c 0.1
28
a Isolated yields. b 10% CSA was added. c Microwave-induced heating.
Disappointingly, only trace amounts of the desired quinoline
7 were obtained. We found that at least 2 equiv of the
isonitrile are necessary to get sufficient amounts of 7 for
product isolation (entry 2). A 50% yield was obtained using
a 5-fold excess of the radical acceptor (entry 3). The yield
could be further increased if 10 equiv of 3 were added (54%,
entry 4); however, isolation of the product turned out to be
more difficult in that case. Therefore, a 5-fold excess was
used for all the following experiments. Any side products
could not be isolated in these experiments. We know that
the starting material slowly decomposes at 140 °C in DMF.9
Reaction in ClCH2CH2Cl was less efficient (entry 5).
Importantly, we found that the yield could be further
increased upon adding 10% of camphorsulfonic acid (CSA,
see entry 6). We have previously shown that CSA accelerates
TEMPO-mediated radical cyclization processes.5a Reaction
at a lower concentration (0.05 M) was less efficient (entry
8), whereas increasing the concentration did not affect the
yield to a large extent (entry 7). Pleasingly, we could shorten
the reaction time from 3 days to 30 min upon switching to
microwave-induced heating (entry 9).10 Microwave heating
in the presence of CSA provided lower yields of the desired
quinoline 7 (entry 10). The starting material rapidly decom-
poses under the harsh reaction conditions applied. It is
important to note that there are only a few papers published
on microwave-induced free-radical chemistry.5c,d,f,11
compound, we prepared alkoxyamine 1 (see Supporting
Information). We anticipated that the C-radical 2 generated
via thermal C-O bond homolysis will react either with
TEMPO to reform starting material 1 in a degenerate process
or with phenyl isonitrile (3) to afford the corresponding
imidoyl radical 4. Radical 4 can further react in a 5-exo-
type cyclization to give the primary alkyl radical 5 which
can undergo homolytic aromatic substitution to provide imine
6 which readily oxidizes during workup to the corresponding
quinolines 7.3b We have previously shown that homolytic
aromatic substitutions can be performed using TEMPO-
alkoxyamines as radical precursors.5c In these reactions,
TEMPO oxidizes the intermediately formed cyclohexadienyl
radicals (TEMPOH). It is also possible that the intermediately
formed cyclohexadienyl radicals are oxidized by the
isonitrile.3a,c,8
Under the optimized reaction conditions (method A: 140
°C, 3 days, 10% CSA, DMF; method B: 180 °C, micro-
waves, 30 min, DMF), a series of quinolines were synthe-
sized. We first tested the tandem reaction with alkoxyamine
(9) Ananchenko, G. S.; Fischer, H. J. Polym. Sci., Part A: Polym. Chem.
2001, 39, 3604.
(10) The microwave experiments were conducted using professional
laboratory microwave equipment. A MLS-Ethos 1600 Mikrowellen System
(Milestone) was used for the present studies. The reactions were run in 40
mL MLS-reaction high-pressure vessels (up to 15 bar) which contain
pressure-control valves. An advanced temperature control system from MLS
allowing direct contactless temperature monitoring was used. The microwave
power is continuously and dynamically adjusted to follow the defined
temperature profile. Temperature profile for the quinoline synthesis: from
25 to 100 °C in 10 s; from 100 to 150 °C in 10 s; from 150 to 180 °C in
10 s and then keep the temperature at 180 °C for 30 min.
The tandem process was optimized using phenyl isonitrile
(3) as the radical trapping reagent. The first experiment was
(7) (a) Daikh, B. E.; Finke, R. G. J. Am. Chem. Soc. 1992, 114, 2938.
(b) Fischer, H. J. Am. Chem. Soc. 1986, 108, 3925. (c) Kothe, T.; Marque,
S.; Martschke, R.; Popov, M.; Fischer, H. J. Chem. Soc., Perkin Trans. 2
1998, 1553. (d) Review: Fischer, H. Chem. ReV. 2001, 101, 3581.
(8) We thank a referee for this suggestion.
1876
Org. Lett., Vol. 8, No. 9, 2006

1 using various isonitriles 8a-d. Reactions with para-
substituted aryl isonitriles worked well under both conditions
tested. Quinolines 9a,c and 9d were obtained in 43-56%
yield (Table 2, entries 1, 3, and 4). Similar yields were
To further study the scope and limitations of our method,
the alkoxyamine component was varied. Again, both pro-
tocols were tested for the substrates investigated. These
studies were performed using 3 as an isonitrile component.
The syntheses of the alkoxyamines 10a-c are described in
the Supporting Information. Reaction using bromide 10a with
phenyl isonitrile (3) provided quinoline 9e in 52 and 53%
yields using method A or B, respectively (entry 5). Impor-
tantly, the aryl bromides available via our route are ready
for further synthetic manipulations using transition-metal-
mediated C-C coupling reactions. Geminally disubstituted
system 10b provided slightly higher yields under both con-
ditions tested (entry 6). To our delight, homolytic aromatic
substitution works also for secondary alkyl radicals, as
documented by the successful transformation of alkoxyamine
10c into the the corresponding quinoline 9g (entry 7).
Table 2. Synthesis of Quinolines 9a-g from Alkoxyamine 1,
10a-c, and Various Aryl Isonitrilesa
We next tested whether the aryl substituent in the starting
alkoxyamines can be replaced by other radical stabilizing
groups. As previously shown, cyano and alkoxycarbonyl-
substituted TEMPO-alkoxyamines undergo clean thermal
C-O bond homolysis.5a Therefore, we decided to test
alkoxyamines 11a-c in the quinoline synthesis. The tandem
Scheme 2. Synthesis of
Tetrahydro-1H-cyclopenta[b]quinolines
a Conditions: (A) DMF, 140 °C, 10% CSA, 3 days; (B) DMF, 180 °C,
microwaves, 30 min.
obtained for both protocols (A or B). Importantly, bromo-
substituted aryl isonitriles, which are dehalogenated under
tin hydride conditions, can be used in the radical quinoline
synthesis presented herein. Ortho-substituted aryl isonitriles
can also be applied as shown in entry 2 (f 9b).
(11) Review on microwave chemistry: Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250. Microwave-induced heating in radical chemistry: (a)
Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org.
Chem. 1999, 64, 4539. (b) Lamberto, M.; Corbett, D. F.; Kilburn, J. D.
Tetrahedron Lett. 2003, 44, 1347. (c) Ericsson, C.; Engman, L. J. Org.
Chem. 2004, 69, 5143.
Org. Lett., Vol. 8, No. 9, 2006
1877

reaction was conducted under the optimized conditions using
phenyl isonitrile as an acceptor. To our surprise, the targeted
quinoline of type 7 was not formed in these cases. Instead,
tetrahydro-1H-cyclopenta[b]quinolines 12a-c were isolated
in acceptable yields (Scheme 2, 48-55%). Hence, for hetero-
cycles of type A obtained after homolytic aromatic substitu-
tion bearing acidifying R groups such as CN or CO2Me,
tautomerization to B occurs after homolytic aromatic sub-
stitution. The compounds 12a-c are stable toward further
oxidation. Interestingly, reaction of vinyl bromide 11d with
3 afforded quinoline 7 in good yields. In this reaction, the
intermediately formed dihydroquinoline D undergoes HBr
elimination to provide 7. Air oxidation is not necessary in
this case.
performed with olefin-terminated alkoxyamines, slightly
lower yields were obtained (Scheme 3).12
In summary, we presented an efficient method for the
preparation of quinolines starting from readily available
alkoxyamines. The reactions are very easy to conduct. Simple
mixing and heating of the starting compounds delivers the
desired quinolines in moderate to good yields. For alkoxy-
amines bearing acidifying R groups at the R-position of the
alkoxyamine, tetrahydro-1H-cyclopenta[b]quinolines are ob-
tained. These thermal radical tandem processes can be
conducted without the use of toxic tin compounds.13 Fur-
thermore, bromides are tolerated under the applied condi-
tions. These tandem reactions can also be performed under
microwave conditions. Reaction times can be reduced by a
factor of 140 upon using microwave-induced heating.
Acknowledgment. We thank the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft DFG for
funding. LONZA AG and DEGUSSA AG are acknowledged
for supporting our research (donation of chemicals).
Scheme 3. Quinoline Synthesis Using Alkyne 13
Supporting Information Available: Experimental pro-
cedures and analytical data of all new quinolines and
alkoxyamines. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0604421
Finally, we tested whether the tandem reaction can also
be conducted with alkyne terminated alkoxyamines. As
expected, reaction of alkyne 13 with phenyl isonitrile under
the optimized conditions afforded the desired quinoline 7.
However, as compared to the above-described experiments
(12) As compared to the alkene-terminated alkoxyamines, compound 13
turned out to be thermally less stable for unknown reasons. This may lead
to the lower yields observed.
(13) (a) Baguley, P. A.; Walton, J. C. Angew. Chem. Int. Ed. 1998, 37,
3072. (b) Studer, A.; Amrein, S. Synthesis 2002, 835.
1878
Org. Lett., Vol. 8, No. 9, 2006