New gas-phase cascade reactions of stabilized phosphorus ylides leading to ring-fused indoles and to quinolines

Article abstract of DOI:10.1021/jo801716z

(Chemical Equation Presented) Gas-phase cyclization processes of stabilized phosphorus ylides bearing a suitably substituted 2-aminophenyl group lead efficiently either to 3-substituted quinolines or benzo[c]-carbazole and heterocyclic-fused analogues depending on the substituents present.

Full text of DOI:10.1021/jo801716z

SCHEME 1
New Gas-Phase Cascade Reactions of Stabilized
Phosphorus Ylides Leading to Ring-Fused Indoles
and to Quinolines†
R. Alan Aitken* and Lorna Murray
School of Chemistry, UniVersity of St. Andrews, North
Haugh, St. Andrews, Fife KY16 9ST, U.K.
raa@st-and.ac.uk
ReceiVed August 1, 2008
SCHEME 2
Gas-phase cyclization processes of stabilized phosphorus
ylides bearing a suitably substituted 2-aminophenyl group
lead efficiently either to 3-substituted quinolines or benzo[c]-
carbazole and heterocyclic-fused analogues depending on the
substituents present.
Cascade processes in which a series of functions are formed
and immediately react with one another represent an attractive
synthetic approach to complex target structures. In previous
work, we showed that, under conditions of flash vacuum
pyrolysis (FVP), thermal extrusion of Ph3PO from ylides such
as 1 to give an alkyne could be accompanied by a loss of Me•
and cyclization leading to benzofurans and benzothiophenes.1
The same process was also possible using precursors 2 with
ylide and carbonyl functions interchanged,2 and by choosing
suitable R groups, including structures such as 3, cascade
processes leading to a variety of tetracyclic products were
developed.3-5 The key cyclization event in these sequences is
illustrated by intermediate 4 derived from 2 (R ) CHdCHPh)
cyclizing to 6, which then undergoes homolytic substitution with
loss of H• to afford 5 (Scheme 1).4 In this paper, we describe
for the first time the extension of this approach to ylides with
a nitrogen-based cyclizing group leading to the biologically and
medicinally significant ring-fused indole products.
As a suitable thermally labile precursor for the required
aminyl radical we first chose the p-toluenesulfonyl group and
prepared the two model compounds 8 and 9 (Scheme 2).
Sequential methylation6 and tosylation7 of anthranilic acid gave
7, which was converted into its acid chloride and then reacted
with 2 equiv of 1-propylidene- and benzylidenetriphenylphos-
phorane to give 8 and 9 in acceptable yields.
† This paper is dedicated to the memory of Professor A. I. Meyers.
(1) Aitken, R. A.; Burns, G. J. Chem. Soc., Perkin Trans. 1 1994, 2455–
2460.
(2) Aitken, R. A. ArkiVoc 2000, V, 798–805.
(3) Aitken, R. A.; Bradbury, C. K.; Burns, G.; Morrison, J. J. Synlett 1995,
53–54.
(4) Aitken, R. A.; Burns, G.; Morrison, J. J. J. Chem. Soc., Perkin Trans. 1
1998, 3937–3941.
(5) Aitken, R. A.; Garnett, A. N. Synlett 2001, 228–229.
(6) Houben, J.; Brassert, W. Ber. Dtsch. Chem. Ges. 1906, 39, 3233–3240.
(7) Schroetev, G. Liebigs Ann. Chem. 1919, 418, 161–257.
10.1021/jo801716z CCC: $40.75
Published on Web 11/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9781–9783 9781

TABLE 1. Synthesis of Ylides 16-20
ylide salt
routea yield (%) 31P NMR δ
SCHEME 3
X
R
16
17
18
19
20
13 Ts Ph
14 Ms CHdCHPh
15 Bn CHdCHPh
15 Bn CHdCH-2-furyl
15 Bn CHdCH-2-thienyl
A
A
B
B
B
5
20
74
53
44
17.4
16.8
16.6
16.8
16.6
a Key: A ) 0.5 equiv of RCOCl; B ) 1 equiv of RCOBt (Bt )
1-benzotriazolyl).
For greater flexibility in the synthesis of ylides with more
complex groups, phosphonium salts containing the o-aminophe-
nyl group were desirable. Thus, 7 was converted into its methyl
ester 10,8 and a sequence of LAH reduction, bromination using
PBr3, and treatment of the crude bromide solution with Ph3P
afforded the salt 13 in reasonable overall yield. The correspond-
ing N-methanesulfonylphosphonium salt 14 was prepared by a
similar sequence of reactions starting from the ester 11,9 while
the N-methyl-N-benzyl salt 15 was similarly prepared from the
ethyl ester 12, itself obtained in two steps from 2-fluorobenzoyl
chloride.10
With the three salts 13-15 in hand, a range of ylides 16-20
were prepared (Table 1). The standard method for preparation
of such acyl ylides involves treatment of the phosphonium salt
with BuLi followed by an acid chloride, but this is rather
wasteful since a 2:1 reacting ratio is needed and only half the
salt ends up in the ylide. While compounds 16 and 17 were
formed in low yield from 13 and 14 by this method, an improved
method involving acylation with the corresponding N-acylben-
zotriazoles11 was used to convert salt 15 into ylides 18-20 in
improved yield and with a 1:1 reacting ratio. It is of interest to
note that the ylides showed broadening of the NMR signals
attributable to the PPh groups and even at 55 °C not all signals
could be observed as the usual sharp doublets.
The ylides were now subjected to flash vacuum pyrolysis
(FVP), and 700 °C was found to be the optimum temperature,
bringing about clean extrusion of Ph3PO and loss of the leaving
group X. For ylides 8 and 9, the nitrogen-containing products
were quite unexpectedly found to be the 3-substituted quinolines
22 and 23 which were readily recognized by the distinctive high-
frequency doublets due to H-2 and H-4 in the 1H NMR spectra.
Thus, 8 gave 3-ethylquinoline 2212 (71%) while 9 gave
3-phenylquinoline 2313 (32%). The mechanism by which these
products are formed seems likely, as shown in Scheme 3, to
involve hydrogen atom transfer from CH3 to N in the aminyl
radical and cyclization to give the six-membered ring which
then aromatizes with loss of a hydrogen atom. The compound
16, isomeric with 9, behaved in the same way giving 23 (28%)
upon FVP.
same pattern was followed for the other ylides 18-20 giving,
respectively, 24 (66%), N-methylfuro[2,3-c]carbazole 25 (65%),
and N-methylthieno[2,3-c]carbazole 26 (60%). These latter
products are representatives of rather uncommon fused ring
systems, but the furo[2,3-c]carbazole system is present in the
natural product eustifoline D isolated from Murraya euchres-
tifolia Hayata, a shrub found in Taiwan,15 and a synthesis of
this natural product using the present approach is currently in
progress.
The divergent thermal behavior of the two groups of ylides
is apparently due to the reversibility of the various pathways
open to the initially formed aminyl radical in the gas phase
(Scheme 3).
For simple R groups such as Et or Ph, the intermediate 21
does not have any favorable route to produce a stable product
and so the reaction is diverted to the quinoline products. In
contrast, the further cyclization of 21 where R is a styryl group
or heterocyclic analogue is highly favorable and is followed by
irreversible aromatization giving entirely the carbazole products
in these cases.
When the ylide 17 with a pendant cinnamoyl group was
examined, a complete change in behavior was noted. In this
case, the desired cascade cyclization did occur, and the resulting
N-methylbenzo[c]carbazole 2414 was obtained in 75% yield. The
Experimental Section
(8) Chernova, N. I.; Ryabokobylko, Yu. S.; Brudz’, V. G.; Bolotin, B. M.
Russ. J. Org. Chem. (Engl. Transl.) 1971, 7, 1745–1751.
(9) Lombardino, J. G. J. Heterocycl. Chem. 1972, 9, 315–317.
(10) Le´ost, F.; Chantegrel, B.; Deshayes, C. Tetrahedron 1997, 53, 7557–
7576.
(11) Katritzky, A. R.; Meher, N. K.; Singh, S. K. J. Org. Chem. 2005, 70,
7792–7794.
(12) O’Murchu, C. Synthesis 1989, 880–882.
(13) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Tetrahedron
1996, 52, 10225–10240.
[1-(2-N-Methyl-N-p-toluenesulfonylamino)benzoyl)benzylidene]-
triphenylphosphorane (9). A suspension of benzyltriphenylphos-
phonium bromide (6.26 g, 16.1 mmol) in THF (50 mL) was stirred
under nitrogen while a solution of BuLi (6.44 mL, 2.5 M, 16.1
mmol) in hexanes was added. The resulting brightly colored solution
was stirred for 2 h, a solution of 2-(N-methyl-N-tosylamino)benzoyl
chloride (2.60 g, 8.1 mmol) in THF (5 mL) was added, and the
(14) Grellmann, K. H.; Schmitt, U. J. Am. Chem. Soc. 1982, 104, 6267–
6272.
(15) Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1990, 38, 1548–1550.
9782 J. Org. Chem. Vol. 73, No. 24, 2008

mixture was stirred for a further 18 h. Water (50 mL) was added
to the solution, and the mixture was extracted using ethyl acetate
(2 × 50 mL). The combined extracts were washed with water, dried,
and evaporated. The resulting solid was recrystallized (Et2O/EtOAc)
to give the title product (2.23 g, 43%) as pale yellow crystals: mp
(C), 134.9 (d, J ) 2 Hz, 3CH), 134.2 (d, J ) 10 Hz, 6CH), 131.8
(d, J ) 5 Hz, CH), 130.1 (d, J ) 13 Hz, 6CH), 129.7 (d, J ) 3 Hz,
CH), 128.9 (2CH), 128.1 (2CH), 127.4 (CH), 125.0 (d, J ) 3 Hz,
CH), 123.2 (d, J ) 8 Hz, C), 122.4 (d, J ) 4 Hz, CH), 118.0 (d,
J ) 85 Hz, 3C), 62.1 (CH2), 40.6 (CH3), 25.5 (d, J ) 47 Hz, CH2);
31P NMR δ 23.0. Anal. Calcd for C33H31NPBr: C, 71.74; H, 5.66;
N, 2.54. Found: C, 71.59; H, 5.63; N, 2.59.
213-214 °C; IR (Nujol) 1496 (CO), 1342 (SO2), 1154 (SO2) cm-1
;
1H NMR δ 7.87-7.67 (m, 8H), 7.53-7.37 (m, 9H), 7.30 (d, J )
8 Hz, 2H), 7.20 (d, J ) 8 Hz, 1H), 7.14 (d, J ) 8 Hz, 2H),
6.99-6.88 (m, 2H), 6.87-6.74 (m, 3H), 6.43 (d, J ) 8 Hz, 1H),
3.15 (s, 3H), 2.46 (s, 3H); 13C NMR δ 184.2 (d, J ) 6 Hz, C),
144.1 (d, J ) 12 Hz, C), 142.9 (C), 139.5 (C), 137.4 (d, J ) 12
Hz, C), 136.2 (C), 134.6 (d, J ) 5 Hz, 2CH), 133.8 (d, J ) 10 Hz,
6CH), 131.4 (d, J ) 3 Hz, 3CH), 130.7 (CH), 129.3 (2CH), 128.5
(d, J ) 12 Hz, 6CH), 128.2 (2CH), 127.6 (CH), 126.9 (3CH), 126.7
(d, J ) 91 Hz, 3C), 126.4 (CH), 124.2 (d, J ) 2 Hz, CH), 74.0 (d,
J ) 107 Hz, C), 41.1 (CH3), 21.6 (CH3); 31P NMR δ 16.2; HRMS
(ESI, M + Na ion) calcd for C40H34NaNO3PS 662.1895, found
662.1879.
[(2-(N-Methyl-N-benzylamino)phenyl)(3-(2-furyl)propenoyl)-
methylene]triphenylphosphorane (19). A suspension of salt 15 (1.00
g, 1.81 mmol) in THF (10 mL) was stirred under nitrogen while a
solution of BuLi (0.80 mL, 2.25 M, 1.81 mmol) in hexanes was
added. The resulting brightly colored solution was stirred for 2 h,
a solution of 1-(3-(2-furyl)propenoyl)benzotriazole17 (0.43 g, 1.81
mmol) in THF (5 mL) was added, and the mixture was stirred for
a further 18 h. Water (20 mL) was added to the solution, and the
mixture was extracted using ethyl acetate (2 × 20 mL). The
combined extracts were washed with water, dried, and evaporated.
The resulting solid was recrystallized (Et2O/EtOAc) to give the title
product (0.45 g, 53%) as yellow crystals: mp 188-189 °C; IR
FVP of Ylide 9 Giving 3-Phenylquinoline (23). Ylide 9 (0.690
g, 1.08 mmol) was subjected to FVP at 700 °C and 2-3 × 10-2
torr. NMR analysis of crude product showed a mixture of Ph3PO,
toluene, and 3-phenylquinoline. Purification by acid/base extraction
gave 3-phenylquinoline (0.0704 g, 32%) as a brown solid: mp
1
(Nujol) 1617 (CdC) cm-1; H NMR δ 7.46 (d, J ) 8 Hz, 1H),
7.39-7.14 (m, 20H), 7.08-6.97 (m, 4H), 6.91 (d, J ) 8 Hz, 1H),
6.41 (d, J ) 8 Hz, 1H), 6.27 (dd, J ) 6, 3 Hz, 1H), 6.21 (s, 1H),
4.40 (d, J ) 14 Hz, 1H), 3.79 (d, J ) 14 Hz, 1H), 2.10 (s, 3H);
13C NMR (55 °C) δ 178.8 (d, J ) 6 Hz, C), 154.1 (d, J ) 4 Hz,
C), 153.4 (d, J ) 2 Hz, C), 142.5 (CH), 138.5 (d, J ) 5 Hz, CH),
136.9 (C), 133.8 (d, J ) 10 Hz, 6CH), 132.0 (d, J ) 10 Hz, C),
131.2 (d, J ) 3 Hz, 3CH), 129.7 (2CH), 128.2 (d, J ) 12 Hz,
6CH), 127.7 (2CH), 127.5 (d, J ) 3 Hz, CH), 127.0 (d, J ) 90
Hz, 3C), 126.8 (CH), 124.9 (d, J ) 13 Hz, CH), 122.8 (d, J ) 2
Hz, CH), 122.3 (d, J ) 2 Hz, CH), 111.5 (CH), 110.8 (CH), 74.9
(d, J ) 108 Hz, C), 60.0 (CH2), 39.5 (CH3); 31P NMR δ 16.8;
HRMS (ESI, M + 1 ion) calcd for C40H35NO2P 592.2405, found
592.2414.
49-50 °C (lit.16 mp 49-52 °C); H NMR δ 9.19 (d, J ) 2 Hz,
1
1H), 8.32 (d, J ) 2 Hz, 1H), 8.15 (d, J ) 8 Hz, 1H), 7.90 (d, J )
8 Hz, 1H), 7.73 (d, J ) 8 Hz, 2H), 7.63-7.49 (m, 4H), 7.45 (t, J
) 8 Hz, 1H) (good agreement with ref 13).
2-(N-Benzyl-N-methylamino)benzyl Alcohol. Under a nitrogen
atmosphere, a solution of 14 (19.92 g, 73.87 mmol) in dry THF
(400 mL) was added dropwise to a stirred suspension of LAH (3.09
g, 81.34 mmol) in dry THF (80 mL), and the resulting mixture
was stirred at room temperature for 18 h. To destroy the excess of
LAH, water (3 mL) in THF (21 mL) was added to the mixture
followed by 15% solution sodium hydroxide (3 mL) and finally
water (9 mL). The suspension was stirred for 0.5 h, MgSO4 was
added, and the mixture was stirred overnight. The mixture was
filtered, the solid was washed with ethyl acetate, and the combined
filtrate and washings were evaporated to give the title product (14.08
g, 84%) as a yellow oil: 1H NMR δ 7.33-7.18 (m, 8H), 7.09 (t, J
) 8 Hz, 1H), 5.25 (br s, 1H, OH), 4.80 (s, 2H), 4.00 (s, 2H), 2.58
(s, 3H); 13C NMR δ 151.2 (C), 137.4 (C), 135.7 (C), 128.8 (2CH),
128.3 (2CH), 128.3 (CH), 127.9 (CH), 127.2 (CH), 124.5 (CH),
121.2 (CH), 63.8 (CH2), 61.6 (CH2), 41.3 (CH3); HRMS (ESI, M
+ Na ion) calcd for C15H17NaNO 250.1208, found 250.1213.
2-(N-Benzyl-N-methylamino)benzyltriphenylphosphonium Bro-
mide (15). A solution of 2-(N-benzyl-N-methylamino)benzyl alcohol
(12.61 g, 55.3 mmol) in toluene (500 mL) was stirred with
phosphorus tribromide (12.11 mL, 127.5 mmol) at room temperature
for 18 h. The mixture was added to water (200 mL) and stirred for
0.5 h and the organic layer separated, washed with water (2 × 50
mL), and dried. The dried toluene solution was heated under reflux
with triphenylphosphine (14.48 g, 55.3 mmol) for 8 h. The
precipitate was filtered off, washed with diethyl ether, and oven-
dried to give the title product (12.89 g, 39%) as a colorless solid:
FVP of Ylide 19 Giving N-Methylfuro[2,3-c]carbazole (25).
Ylide 19 (0.56 g, 0.95 mmol) was subjected to FVP at 700 °C at
2-3 × 10-2 torr. NMR analysis of crude product showed a mixture
of Ph3PO, bibenzyl, and other products. The mixture was purified
by preparative TLC (80:20 diethyl ether/hexane) to give the title
1
product (0.136 g, 65%): mp 65-67 °C; H NMR δ 8.20 (dt, J )
8, 1 Hz, 1H), 7.82 (dd, J ) 2.4, 0.3 Hz, 1H), 7.65 (dd, J ) 9, 1
Hz, 1H), 7.48 (dd, J ) 6, 1 Hz, 1H), 7.47 (dd, J ) 2.7, 1 Hz, 1H),
7.35 (dd, J ) 9, 1 Hz, 1H), 7.325 (dd, J ) 2.4, 1 Hz, 1H), 7.29
(ddd, J ) 8, 6, 2.7 Hz, 1H), 3.92 (s, 3H); 13C NMR δ 150.3 (C),
145.4 (CH), 140.7(C), 137.2(C), 124.9 (CH), 122.3 (C), 121.1 (CH),
120.6 (C), 118.8 (CH), 114.2 (C), 109.3 (CH), 108.7 (CH), 105.37
(CH), 105.32 (CH), 29.5 (CH3); HRMS (ESI, M + 1 ion) calcd
for C15H12NO 222.0919, found 222.0920.
Acknowledgment. We thank EPSRC (UK) for a studentship
(L.M.).
Supporting Information Available: Full experimental pro-
cedures and characterization data for all compounds and NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
mp 206-207 °C; H NMR δ 7.80-7.71 (m, 5H), 7.67-7.55 (m,
14H), 7.14-6.94 (m, 5H), 5.35 (br d, J ) 15 Hz, 2H), 3.73 (br s,
2H), 2.04 (br s, 3H); 13C NMR δ 153.5 (d, J ) 6 Hz, C), 137.2
JO801716Z
(16) Cadogan, J. I. G. J. Chem. Soc. 1962, 4257–4258.
(17) Katritzky, A. R.; Wang, M.; Zhang, S. ArkiVoc 2001, ix, 19–23.
J. Org. Chem. Vol. 73, No. 24, 2008 9783