Further studies on the pyrolytic domino cyclization of stabilized phosphonium ylides bearing an ortho-aminophenyl group

Article abstract of DOI:10.3390/molecules23092153

Four new, stabilized phosphonium ylides containing a 2-(benzyl(methyl)amino)phenyl group have been prepared and characterized and are found, upon pyrolysis under gas-phase flow conditions, to lose Ph₃PO and benzyl radicals to afford new heterocyclic products resulting from domino cyclization of both C- and N-centered radicals. Most products arise from processes of the former type and have quinoline, phenanthridine, or ring-fused phenanthridine structures, while in one case, a process of the latter type leads to a benzocarbazole product. The X-ray structure of a 2-(methyl(tosyl)amino)phenyl ylide is also reported.

Full text of DOI:10.3390/molecules23092153

molecules
Article
Further Studies on the Pyrolytic Domino Cyclization
of Stabilized Phosphonium Ylides Bearing an
Ortho-Aminophenyl Group
ID
R. Alan Aitken * ID , Lorna Murray and Alexandra M. Z. Slawin
EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK;
Lorna.Murray@ed.ac.uk (L.M.); amzs@st-and.ac.uk (A.M.Z.S.)
* Correspondence: raa@st-and.ac.uk; Tel.: +44-1334-463865
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 27 July 2018; Accepted: 24 August 2018; Published: 27 August 2018
Abstract: Four new, stabilized phosphonium ylides containing a 2-(benzyl(methyl)amino)phenyl
group have been prepared and characterized and are found, upon pyrolysis under gas-phase flow
conditions, to lose Ph3PO and benzyl radicals to afford new heterocyclic products resulting from
domino cyclization of both C- and N-centered radicals. Most products arise from processes of the
former type and have quinoline, phenanthridine, or ring-fused phenanthridine structures, while in
one case, a process of the latter type leads to a benzocarbazole product. The X-ray structure of
a 2-(methyl(tosyl)amino)phenyl ylide is also reported.
Keywords: phosphonium ylide; pyrolysis; quinoline; phenanthridine; benzocarbazole; X-ray structure
1. Introduction
The synthetic use of flash vacuum pyrolysis (FVP) is now well-established and provides the
method of choice to obtain certain, otherwise inaccessible products [
heterocyclic chemistry, the method has been applied to a wide variety of reaction types and product
classes [ ]. The inherent advantages of a clean, solvent-, reagent-, and catalyst-free method are further
enhanced if several reaction steps can be achieved in sequence in a single gas-phase flow pyrolysis
process, which is a good example of the “domino” reaction approach [ ]. In previous studies we
1]. Particularly in the area of
2
3–5
have developed a series of methods for the synthesis of fused-ring heterocyclic compounds by FVP of
suitably designed carbonyl-stabilized phosphonium ylides. The principle is demonstrated by the case
◦
of ylide
1
, which, at 850 C, eliminates both triphenylphosphine oxide and a methyl radical (Scheme 1).
The resulting alkynylphenoxyl radical
benzofuryl radical , bearing a suitably-placed styryl group to undergo (after E/Z isomerization) an
intramolecular SHAr process, leading to the fused ring product naphtho[2,1-b]benzofuran in 44%
isolated yield [ ]. Interestingly, in this case a second isomeric product could also be identified in
2 undergoes spontaneous 5-endo-dig cyclization to give the
3
4
6,
7
5
14% yield resulting from a rearrangement of 3 prior to cyclization.
Molecules 2018, 23, 2153; doi:10.3390/molecules23092153
www.mdpi.com/journal/molecules

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Scheme 1. Example of the domino cyclization approach to fused-ring heterocycles.
The method was later extended to a wide range of examples, including an eight-stage cascade
process leading from allyloxy ylide to the 7-(2-benzothienyl)benzofuran (Scheme 2) [ ], formation of
thieno[2,3-b]pyridine products including the benzofurothienopyridine from ylide ], formation of
a iminobenzopyranone 11 from ylide 10 10], and synthesis of a wide range of products with structure
13, including 24 different fused-ring systems from the general starting ylide structure 12 [11].
6
7
8
9
8 [9
[
Scheme 2. The range of previously reported cyclizations involving O or S.
All the preceding examples rely on cyclization of phenoxyl or thiophenoxyl radicals, and extension
of the method to ylides with a nitrogen-based cyclizing radical introduces an unexpected complication.
Preparation of the ylides requires a carbon-based protecting group on nitrogen as well as the leaving
group, and transfer of the reactive site from N to C may lead to different products. Thus, while simpler
ylides, such as the N-methyl-N-tosyl compound 14, give the 3-substituted quinoline 15 resulting from
cyclization of –NH-CH2 (Scheme 3), the more extended cinnamoyl-type analogues 16
the expected cyclization of -N(Me) to give ring-fused carbazole products, 19–21 [12].
–18 do undergo

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Scheme 3. Divergent outcomes resulting from cyclization involving C or N.
However, when N,N-dibenzyl ylides 22 25 were examined, a more complex picture emerged [13
–
]
with all four examples giving mainly the styrylquinoline products 27 (Scheme 4) as mixtures of (Z)-
and (mainly) (E)-isomers, together with the ring-fused carbazoles 26 for ylides 22 and 25 only, and the
product 28 resulting from further cyclization of 27 from 25 only. The loss of a phenyl group in formation
of products 27 and 28 is notable, and only for compound 24 were the products 29 and 30 retaining the
N-benzyl-derived phenyl obtained.
Scheme 4. Heterocyclic products derived from N,N-dibenzyl ylides.
It is clear from these results that it is not yet possible to predict the pyrolysis outcome for
the amino-functionalized ylides with any degree of certainty and further work is required to fully
understand the processes involved. In this paper, we describe the synthesis and characterization of
four new amino-functionalized ylides and the results of their pyrolysis, which leads to the formation
of seven new fused-ring heterocyclic products.
2. Results
2.1. X-ray Structure Determination of Ylide 14
Since many of the previously studied nitrogen-containing ylides were formed in disappointing
yield and showed severe restricted rotation leading to very broad signals in their room temperature
NMR spectra [12
,13], it was clear that steric hindrance may be an important factor in their reactivity.
To examine this further, we have determined the structure of the N-methyl-N-tosyl ylide 14
[
12] by
X-ray diffraction. The resulting structure (Figure 1) confirms that this is indeed a sterically congested
molecule with the two very bulky ortho substituents on the central benzene ring scarcely able to fit.
Within the crystal there are no significant intermolecular interactions. The following bond lengths
within the keto ylide functionality: P(7)-C(7) 1.746(2), C(7)-C(8) 1.408(2), C(8)-O(8) 1.263(2) A are
indicative of a good degree of delocalization and a high contribution from the charge-separated
structure with P+-C=C-O− rather than P=C-C=O. The torsion angle P(7)-C(7)-C(8)-O(8) is
−
9.0(2),

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which is within the range normally expected for keto-stabilized ylides [14
,
15], and indicates a high
probability of successful thermal extrusion of Ph3PO, as does the low value of 6 Hz [12] for 2JP–CO
.
Figure 1. X-ray structure of ylide 14 (ORTEP diagram, 50% level).
2.2. Preparation and Characterization of Ylides 35–38
The four new ylides chosen for study have structures 35–38 (Scheme 5). Compounds 35 and 36
are obviously isomeric with ylides 17 and 18, which were well-behaved upon pyrolysis and gave
the ring-fused carbazoles [12], but whose dibenzyl analogues 24 and 25 showed more varied and
unpredictable behaviour [13]. The 2-methylcinnamoyl ylide 37 is similarly the analogue of dibenzyl
ylide 23, and both it and its thiophene analogue 38 are of additional interest, since we previously
observed cyclization involving the methyl group to give vinylnaphthalenes and further cyclized
products when ylides analogous to 37 and 38 but only lacking the benzylmethylamino group were
subjected to FVP [16
N-acylbenzotriazoles as the acylating agents [18] rather than acid chlorides, and the four required
benzotriazole derivatives 31 34 (see Supplementary Material S1–S7) were prepared by treatment of
,17]. As we described previously, it was advantageous to prepare the ylides using
–
the appropriate carboxylic acids with thionyl chloride (1 equiv.) and benzotriazole (4 equiv.).
Scheme 5. Preparation of ylides 35–38.
The four ylides were prepared as shown in Scheme 5 by treatment of phosphonium salt 39 [12]
with butyllithium to generate the ylide 40, followed by addition of the appropriate N-acylbenzotriazole,

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and were obtained as stable crystalline solids with high melting points. The signals due to the P-phenyl
1
groups in the H NMR spectra were very broad, presumably due to similar steric hindrance and
restricted rotation to that revealed by◦ the X-ray structure of 14. The situation was significantly
improved by running the spectra at 55 C, as illustrated in the case of 36 (see Supplementary Material),
and the 13C NMR spectra for all four new ylides were run at this temperature. The value of the
two-bond coupling between C=O and P was 5–7 Hz in each case, indicating a good prospect for
successful thermal extrusion of Ph3PO [14].
2.3. Flash Vacuum Pyrolysis to Give Heterocyclic Products
The first ylide to be pyrolyzed, the 3-furyl compound 35, gave a surprising result.
◦
There was complete reaction at a furnace temperature of 700 C with formation of Ph3PO and
bibenzyl—as expected—but the sole heterocyclic product identified in low yield did not contain
1
a furan ring at all and was identified as the 9-methylphenanthridine 41, by comparison of its H
NMR data with literature values. A suggested mechanism for formation of this product (Scheme 6)
involves initial extrusion of Ph3PO and benzyl radical followed by transfer of the reactive site from
N to C, by means of a hydrogen atom transfer. Cyclization of the NH-CH2 onto the triple bond,
aromatization, and further cyclization gives an intermediate that could very easily lose a hydrogen
atom to form the expected furo[3,2-k]phenanthridine. However, this is apparently not favorable,
and instead, ring-opening of the dihydrofuran ring, followed by rearrangement and loss of carbon
monoxide leads to the observed stable methylphenanthridine product.
Scheme 6. Flash vacuum pyrolysis (FVP) of ylide 35 to form 41.
By way of contrast, the 3-thienyl ylide 36 behaved analogously to the N,N-dibenzyl 2-thienyl
ylide 25 [13] with mainly quinoline products 42, accompanied by a small amount of the tetracyclic
thieno[3,2-k]phenanthridine 43 formed by a further cyclization event (Scheme 7). The latter product
1
showed a distinctive H NMR spectrum (Supplementary Material S22) which, though complex,
was successfully analyzed to derive all coupling constants using simulation. Both chemical shifts and
coupling constants were in good agreement with those already reported for the isomeric system 28 [13]
,
thus supporting the structural assignment. Clearly, in this case, the process initially involves extrusion
of Ph3PO and benzyl radical, hydrogen atom transfer, and cyclization, as shown in Scheme 6—but the
greater thermodynamic stability of the thiophene ring means that it survives to appear in the products.
The contrast between the behaviour shown here for 35 and 36 and that for the corresponding 2-furyl
and 2-thienyl isomers 17 and 18, which give exclusively fused-ring carbazole products 20 and 21 [12],
is most surprising. The balance between the N- and C-centered radical as the cyclizing species is
obviously delicate.

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Scheme 7. FVP of ylide 36 to form 42 and 43.
This fact was emphasized by the result in the case of the 2-methylstyryl ylide 37 (Scheme 8).
This is the methyl analogue of 16 which gave the benzocarbazole product 19 as the only major product
in 66% yield [12]. Although products derived from cyclization of a C-centered radical, the quinolines
44 and the benzophenanthridine 45, amounted together to 33%, the largest single product was now
the dimethylbenzocarbazole 46, resulting from direct cyclization of an N-centered radical, formed in
22% yield.
Scheme 8. FVP of ylide 37 to form 44–46.
As mentioned in the introduction, one reason for trying ylide 37 was that in earlier work we
observed the involvement of an ortho-methyl group in such ylide pyrolyses to give naphthalenes [16,17].
This was not observed for 37 nor for the second methyl-containing ylide 38, which simply afforded the
(E)- and (Z)-thienylvinylquinolines 47, corresponding to 42 in low yield (Scheme 9). However, even in
this case, the contrast with the behavior of the ylide 18 caused by introduction of the single methyl
group remote from the reactive site for initial cyclization is remarkable.
Scheme 9. FVP of ylide 38 to form 47.
3. Experimental
3.1. General Experimental Details
NMR spectra were recorded on solutions in CDCl3 using Bruker instruments, and chemical shifts
are given in ppm to high frequency from Me4Si (H, C) or 85% H3PO4 (P) with coupling constants
J in Hz. Both low- and high-resolution mass spectra were recorded using electrospray ionization.
All chromatographic separation was carried out on silica gel.
Flash vacuum pyrolysis (FVP) was carried out in a conventional flow system by subliming the
starting material through a horizontal quartz tube (30
×
2.5 cm), externally heated by a tube furnace to
◦
700 C and maintained at a pressure of 2–3
×
10−2 torr by a rotary vacuum pump. The apparatus used
is illustrated, and a detailed experimental procedure is given in a recent publication [19]. Products were
collected in a liquid N2-cooled, U-shaped trap, and purified as noted.

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The phosphonium salt 39 was prepared as previously described [12]. The
α
,
β-unsaturated
carboxylic acids were prepared from the corresponding aldehydes by a standard Doebner reaction
with malonic acid in pyridine with catalytic piperidine.
3.2. X-ray Structure Determination for 14
The compound was prepared as previously reported [12] and recrystallized from ethyl
acetate/diethyl ether (1:1) to give crystals suitable for X-ray diffraction.
Crystal data for C40H34NO3PS, M = 639.71 g
0.10 × 0.10 × 0.10 mm, monoclinic, space group P21/n, a = 10.055(2), b = 18.021(3), c = 18.125(4)
A,
= 99.928(5)◦, V = 3234.9(11) A3, Z = 4, Dcalc = 1.313 g cm−3, T = 93(2) K, R = 0.033, Rw = 0.079 for
5185 reflections with I > 2 (I) and 418 variables. Data were collected using graphite-monochromated
Mo K radiation = 0.71073 A and have been deposited at the Cambridge Crystallographic Data
·
mol−1, yellow prism, crystal dimensions
β
·
σ
α
λ
Centre as CCDC 1849881. The data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
3.3. Preparation of N-Acylbenzotriazoles
3.3.1. 1-(3-(3-Furyl)propenoyl)benzotriazole 31
To a stirred solution of benzotriazole (17.15 g, 143.9 mmol) in CH2Cl2 (200 mL), thionyl chloride
(4.28 g, 2.61 mL, 35.9 mmol) was added dropwise. After stirring the resulting mixture for 30 min,
3-(3-furyl)acrylic acid [20] (5.00 g, 35.9 mmol) was added and the mixture stirred at rt for a further
3 h. The mixture was then filtered and the solid washed with CH2Cl2. The combined filtrate was
washed with 2M aq. NaOH water, then brine. Drying and evaporation, followe◦d by recrystallization
of the residue (CH2Cl2), gave 31 (3.25 g, 38%) as colorless needles, m.p. 169–170 C. (Found: M+ + Na,
262.0598. C13H9NaN3O2 (M+ + Na) requires, 262.0592); vmax/cm−1 1703, 1621 (CO), 1379, 1151 and
992; δH 8.41 (1 H, d, J 8, H-7), 8.15 (1 H, d, J 8, H-4), 8.06 (1 H, d, J 16, COCH=CH), 7.87–7.79 (2 H, m,
COCH=CH, furyl-H), 7.68 (1 H, t, J 8, H-5 or 6), 7.56–7.51 (2 H, m, H-5 or 6, furyl-H) and 6.83 (1 H,
d, J 2, H-4 of furyl); δC 163.9 (4ry, CO), 146.4 (CH), 146.2 (4ry, C-3a of Bt), 144.8 (CH), 138.6 (C-2 of
furyl), 131.4 (4ry, C-7a of Bt), 130.2 (CH), 126.1 (CH), 123.0 (4ry, C-3 of furyl), 120.1 (CH), 115.7 (CH),
114.7 (CH), and 107.6 (C-4 of furyl); m/z (ES+) 262.04 (M+ + Na, 100%).
3.3.2. 1-(3-(3-Thienyl)propenoyl)benzotriazole 32
This was prepared as in Section 3.3.1 using benzotriazole (15.25 g, 128.0 mmol), thionyl chloride
(3.81 g, 2.32 mL, 32.4 mmol), and 3-(3-thienyl)acrylic acid (5.00 g, 32.4 mmol). Drying and evaporation,
followed by recrystallization of the residue (CH2Cl2), gave 32 (5.30 g, 65%) as yellow needles, m.p.
154–156 ◦C. (Found: M+ + Na, 278.0370. C13H9NaN3OS (M+ + Na) requires, 278.0364); vmax/cm−1
1696 (CO), 1611, 1285, 1069, 993, 782 and 743; δH 8.42 (1 H, dt, J 8, 1, H-7), 8.15 (1 H, dt, J 8, 1, H-4),
8.14 (1 H, d, J 15, COCH=CH), 7.93 (1 H, d, J 15, COCH=CH), 7.76 (1 H, dd, J 3, 1, H-2 of thienyl),
7.68 (1 H, td, J 8, 1, H-5 or 6), 7.55 (1 H, dd, J 5, 1, H-5 of thienyl), 7.53 (1 H, td, J 8, 1, H-5 or 6) and
7.43 (1 H, ddd, J 5, 3, 1, H-4 of thienyl); δC 164.0 (4ry, CO), 146.1 (4ry, C-3a of Bt), 141.7 (CH), 137.5
(4ry, C-7a of Bt), 131.3 (4ry, C-3 of thienyl), 130.7 (CH), 130.1 (CH), 127.3 (CH), 126.0 (CH), 125.4 (CH),
120.0 (CH), 115.4 (CH) and 114.7 (CH); m/z (ES+) 277.98 (M+ + Na, 100%).
3.3.3. 1-(3-(2-Methylphenyl)propenoyl)benzotriazole 33
This was prepared as in Section 3.3.1 using benzotriazole (14.69 g, 123.3 mmol), thionyl chloride
(3.67 g, 2.24 mL, 30.8 mmol) and (E)-3-(2-methylphenyl)prop-2-enoic acid (5.00 g, 30.8 mmol).
Drying and evaporation, followed by recrystallization of the residue (CH2Cl2), gave 33 (1.77 g, 22%) as
◦
◦
a white powder, m.p. 124–125 C (Lit. [21] 127–129 C); δH 8.47 (1 H, d, J 15, COCH=CH), 8.42 (1 H, dt,
J 8, 1, H-4 or 7 of Bt), 8.16 (1 H, dt, J 8, 1, H-4 or 7 of Bt), 8.07 (1 H, d, J 15, COCH=CH), 7.86 (1 H, d, J 8),

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7.69 (1 H, ddd, J 8, 7, 1, H-5 or 6 of Bt), 7.54 (1 H, ddd, J 8, 7, 1, H-5 or 6 of Bt), 7.40–7.27 (3 H, m) and
2.56 (3 H, s, Me).
3.3.4. 1-(3-(3-Methyl-2-thienyl)propenoyl)benzotriazole 34
This was prepared as in Section 3.3.1 using benzotriazole (14.16 g, 118.9 mmol), thionyl chloride
(3.53 g, 2.16 mL, 79.7 mmol), and (E)-3-(3-methyl-2-thienyl)prop-2-enoic acid (5.00 g, 29.7 mmol).
Drying and evaporation, followed by recrystallization of the residue (CH2Cl2), gave 34 (4.20 g, 60%)
◦
as pale yellow powder, m.p. 169–170 C. (Found: M+ + Na, 292.0521. C14H11NaN3OS (M+ + Na)
requires, 292.0521); vmax/cm−1 1699 (CO), 1601, 1380, 1278 and 988; δH 8.39 (1 H, dt, J 8, 1, H-4 or 7 of
Bt), 8.32 (1 H, dd, J 16, 1, COCH=CH), 8.14 (1 H, dt, J 8, 1, H-4 or 7 of Bt), 7.80 (1 H, d, J 16, COCH=CH),
7.67 (1 H, ddd, J 8, 7, 1, H-5 or 6 of Bt), 7.52 (1 H, ddd, J 8, 7, 1, H-5 or 6 of Bt), 7.42 (1 H, br d, J 5), 6.94
(1 H, dd, J 5, 0.3) and 2.46 (3 H, s, Me); δC 169.9 (4ry, CO), 146.2 (4ry), 144.0 (2C, 4ry), 139.2 (CH), 134.0
(4ry), 131.4 (CH), 130.1 (CH), 129.2 (CH), 126.0 (CH), 120.1 (CH), 114.7 (CH), 113.2 (CH), and 14.4 (CH3);
m/z (ES+) 292.01 (M+ + Na, 100%).
3.4. Preparation of Ylides
3.4.1. [(2-(N-Methyl-N-benzylamino)phenyl)(3-(3-furyl)propenoyl)methylene]triphenylphosphorane 35
A suspension of the phosphonium salt 39 (2.00 g, 3.62 mmol) in dry THF (10 mL) was stirred
under nitrogen while a solution of butyllithium in hexanes (1.60 cm3, 2.25 M, 3.62 mmol) was added.
The resulting red solution of 40 was stirred at rt for 2 h, after which a solution of the N-acylbenzotriazole
31 (0.86 g, 3.62 mmol) in THF (5 mL) was added and the mixture stirred for a further 18 h. Water (20 mL)
was then added, and the resulting mixture extracted with ethyl acetate (2
×
20 mL). The combined
extracts were washed with water, dried, and evaporated. The resulting solid was recrystallized
(Et2O/EtOAc) to give 35 (0.89 g, 41%) as yellow crystals, m.p. 184–185 ◦C; (Found: M+ + H, 592.2411.
−1
C40H35NO2P (M+ + H), requires 592.2405);
νmax/cm 1633, 1434, 1105, 970, 748 and 692; δH 7.87–7.27
(15 H, m), 7.21–7.09 (6 H, m), 7.07–6.79 (7 H, m), 6.40 (1 H, d, J 8, H-3 of Ar), 4.45 (1 H, d, J 14, CHHPh),
3.75 (1 H, d, J 14, CHHPh) and 2.10 (3 H, s, Me); δC (+55 ◦C) 178.9 (d, J 6, C=O), 154.1 (d, J 4, ArC-N),
143.3 (furyl C-O), 142.7 (furyl C-O), 138.4 (d, J 5, CH), 136.9 (C), 133.8 (d, J 10, C-2 of PPh), 131.8 (d, J 10,
P=C-C), 131.4 (d, J 2, C-4 of PPh), 129.5 (2CH), 128.3 (d, J 12, C-3 of PPh), 127.8 (2CH), 127.7 (d, J 3),
126.9 (CH), 126.7 (d, J 91, C-1 of PPh), 126.3 (d, J 12, CH), 124.7 (CH), 124.1 (furyl C-3), 122.8 (d, J 2,
CH), 121.3 (d, J 2, CH), 107.9 (furyl C-4), 75.3 (d, J 107, P=C), 60.1 (CH2), and 39.6 (NMe); δP + 15.3;
m/z (ES+) 592.09 (M+ + H, 100%).
3.4.2. [(2-(N-Methyl-N-benzylamino)phenyl)(3-(3-thienyl)propenoyl)methylene]triphenylphosphorane 36
This was prepared as in Section 3.4.1 using salt 39 (1.35 g, 2.44 mmol), a solution of butyllithium
(1.08 cm3, 2.25 M, 2.44 mmol) and N-acylbenzotriazole 32 (0.55 g, 2.44 mmol). The resulting solid
was recrystallized (Et2O/EtOAc) to give 36 (0.51 g, 35%) as orange crystals, m.p. 178–180 ◦C. (HMRS:
−1
found M+ + H, 608.2175. C40H35NOPS (M+ + H) requires, 608.2177); vmax/cm 1624, 1492, 1197, 1101,
750 and 691; δH (+55 ◦C) 7.68–7.54 (8 H, m), 7.45–7.33 (5 H, m), 7.30–7.21 (4 H, m), 7.19–7.11 (5 H, m),
7.09–7.02 (2 H, m), 6.99–6.89 (4 H, m),◦6.52 (1 H, d, J 8), 4.40 (1 H, d, J 14, CHHPh), 3.84 (1 H, d, J 14,
CHHPh) and 2.19 (3 H, s, Me); δC (+55 C) 179.1 (d, J 5, C=O), 154.2 (d, J 4, ArC-N), 139.8 (thienyl C-3),
138.4 (d, J 5, CH), 137.0 (C), 133.8 (d, J 10, C-2 of PPh), 131.8 (d, J 10, P=C-C), 131.4 (d, J 3, C-4 of PPh),
129.5 (2CH), 129.1 (d, J 1, CH), 128.3 (d, J 12, C-3 of PPh), 127.8 (2CH), 127.8 (d, J 3), 126.9 (CH), 126.7
(d, J 91, C-1 of PPh), 126.4 (d, J 12, CH), 126.0 (CH), 125.6 (CH), 124.6 (CH), 122.8 (d, J 2, CH), 121.3 (d,
J 2, CH), 75.7 (d, J 108, P=C), 60.1 (CH2), and 39.6 (NMe); δP + 15.3; m/z (ES+) 608.01 (M+ + H, 100%).

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3.4.3. [(2-(N-Methyl-N-benzylamino)phenyl)(3-(2-methyl)phenylpropenoyl)methylene]tripheny
lphosphorane 37
This was prepared as in Section 3.4.1 using salt 39 (1.00 g, 1.81 mmol), a solution of
butyllithium in hexanes (0.89 mL, 2.04 M, 1.81 mmol) and N-acylbenzotriazole 33 (0.48 g, 1.81 mmol).
Recrystallization of the residue (diethyl ether/EtOAc) gave the title product 37 (0.55 g, 50%) as yellow
◦
crystals, m.p. 207–208 C. (Found: M+ + H, 616.2753. C43H39NOP (M+ + H) requires, 616.2769);
ν
max/cm−1 1634, 1433, 1172, 1086, 710 and 677; δH 7.75 (1 H, d, J 15, CH = CH), 7.70–7.59 (5 H, br s),
7.51–7.31 (11 H, m), 7.24–7.16 (3 H, m), 7.12–6.93 (9 H, m), 6.55 (1 H, d, J 8, H-3 of Ar), 4.51 (1 H, d, J 14,
CHHPh), 3.85 ( 1 H, d, J 14, CHHPh), 2.39 (3 H, s, Me) and 2.24 (3 H, s, Me); δC (+55 ◦C) 179.7 (d, J 7,
C=O), 154.3 (d, J 4, ArC-N), 138.8 (d, J 5, CH), 137.3 (C), 137.0 (C), 136.3 (C), 133.8 (d, J 10, C-2 of PPh),
132.3 (d, J 10, P=C-C), 132.2 (CH), 131.1 (d, J 3, C-4 of PPh), 130.3 (CH), 129.5 (2CH), 128.5 (d, J 12, CH),
128.4 (CH), 128.2 (d, J 12, C-3 of PPh), 127.8 (2CH), 127.6 (CH), 127.4 (d, J 90, C-1 of PPh), 126.8 (CH),
126.3 (CH), 125.7 (CH), 122.6 (d, J 2, CH), 121.0 (d, J 2, CH), 72.8 (d, J 109, P=C), 60.0 (CH2), 39.5 (NMe),
and 20.0 (Me); δP + 15.4; m/z (ES+) 616.08 (M+ + H, 100%).
3.4.4. [(2-(N-Methyl-N-benzylamino)phenyl)(3-(3-methyl-2-thienyl)propenoyl)methylene]triphenyl
phosphorane 38
This was prepared as in Section 3.4.1 using salt 39 (1.00 g, 1.81 mmol), a solution of butyllithium
in hexanes (0.89 mL, 2.04 M, 1.81 mmol) and N-acylbenzotriazole 34 (0.49 g, 1.81 mmol). The resulting
solid was recrystallized (Et2O/EtOAc) to give the title product 38 (0.55 g, 49%) as orange crystals, m.p.
197–198 ◦C. (Found: M+ + H, 622.2347. C41H37NOPS (M+ + H) requires, 622.2333); vmax/cm−1 1720, 1605,
◦
1196, 1094, 719 and 686; δH (+55 C) 7.71–7.51 (7 H, br m), 7.48–7.27 (10 H, m), 7.19–7.14 (3 H, m), 7.05–6.88
(5 H, m), 6.81 (1 H, d, J 15, P=C), 6.70 (1 H, d, J 5), 6.44 (1 H, d, J 8, C-3 of Ar), 4.45 (1 H, d, J 14, CHHPh),
3.72 (1 H, d, J 14, CHHPh), 2.22 (3 H, s, Me) and 2.15 (3 H, s, Me); δC (+55 ◦C) 179.1 (d, J 6, C=O), 153.9 (d,
J 4, ArC-N), 138.5 (d, J 5, CH), 136.8 (C), 136.5 (d, J 1, C), 133.8 (d, J 10, C-2 of PPh), 132.1 (d, J 10, P=C-C),
131.2 (d, J 2, C-4 of PPh), 130.7 (CH), 129.8 (2CH), 128.4 (d, J 12, CH), 128.2 (d, J 12, C-3 of PPh), 127.7 (2CH),
127.4 (d, J 2), 127.2 (d, J 92, C-1 of PPh), 126.7 (CH), 126.1 (d, J 1, CH), 126.0 (C), 123.6 (CH), 122.6 (CH),
121.3 (d, J 2, CH), 72.9 (d, J 108, P=C), 60.0 (CH2), 39.3 (NMe), and 14.0 (Me); δP + 15.7; m/z (ES+) 622.03
(M+ + H, 100%).
3.5. Flash Vacuum Pyrolysis of Ylides
3.5.1. FVP of Ylide 35
◦
−2
10 torr. NMR analysis
Ylide 35 (0.3234 g, 0.54 mmol) was subjected to FVP at 700 C and 2–3
×
of the crude product showed a mixture of Ph3PO, bibenzyl, and other products. Separation by column
chromatography (9:1 diethyl ether:hexane) followed by preparative TLC (60:40 diethyl ether:hexane)
gave 9-methylphenanthridine 41 (0.031 g, 30%), δH 9.25 (1 H, s, H-6), 8.59 (1 H, ddd, J 8, 1, 0.4, H-1),
8.42 (1 H, d, J 1, H-10), 8.20 (1 H, dd, J 8, 1, H-8), 8.00 (1 H, d, J 8, H-7), 7.75 (1 H, tdd, J 8, 1, 0.4, H-2 or
3), 7.68 (1 H, tdd, J 8, 1, 0.4, H-2 or 3), 7.56 (1 H, ddd, J 8, 1, 0.4, H-4) and 2.68 (3 H, ArMe) [Lit. [22] δH
(DMSO) 9.05 (1 H, s), 8.28 (1 H, dd, J 8.2, 1.3), 8.12 (1 H, dd, J 8.1, 1.2), 7.64–7.58 (2 H, m), 7.52–7.46
(1 H, m), 7.23 (1 H, dd, J 8.1, 1.2), and 2.41 (3 H, s).]; m/z (ES+) 194.09 (M+ + H, 10%).
3.5.2. FVP of Ylide 36
Ylide 36 (0.2147 g, 0.35 mmol) was subjected to FVP at 700 ◦C and 2–3
×
10−2 torr.
NMR analysis of the crude product showed a mixture of Ph3PO, bibenzyl, and other products.
The mixture was separated by column chromatography (60:40 diethyl ether:hexane) giving
3-(2-(3-thienyl)ethenyl)quinoline 42 (E, 0.0235 g, 28%. Z, 0.0126 g, 15%); (Found: M+ + H, 238.0689.
C15H12NS (M++H) requires, 238.0690); δH (E) 9.09 (1 H, d, J 2, H-2), 8.14 (1 H, d, J 2, H-4), 8.09 (1 H, ddd,
J 8, 1.2, 0.6, H-8), 7.81 (1 H, ddd, J 8, 1.2, 0.6, H-5), 7.67 (1 H, ddd, J 8, 7, 1.2, H-6 or 7), 7.54 (1 H, ddd, J 8,
0
0
0
7, 1.2, H-6 or 7), 7.43 (1 H, m, H-4 ), 7.38–7.35 (2 H, m, H-2 and 5 ), and 7.35 and 7.09 (2 H, AB pattern,

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J 16, H-a and b); δH (Z) 8.82 (1 H, d, J-2, H-2), 8.05 (1 H, d, J 2, H-4), 8.07 (1 H, ddd, J 8, 1.2, 0.6, H-8),
7.73 (1 H, ddd, J 8, 1.2, 0.6, H-5), 7.69 (1 H, ddd, J 8, 6, 1.2, H-6 or 7), 7.53 (1 H, ddd, J 8, 7, 1.2, H-6 or
7), 7.18–7.15 (2 H, m, H-20 and 50), 6.86 (1 H, ddd, J 3, 2.5, 1, H-40) and 6.76 and 6.65 (2 H, AB pattern,
J 12, H-a and b); m/z (ES+) 238.01 (M+ + H, 100%). Also obtained was thieno[3,2-k]phenanthridine 43
(0.0066 g, 8%); (Found: M+ + H, 236.0535. C15H10NS (M+ + H) requires 236.0534); δH 9.46 (1 H, s, H-6),
9.09 (1 H, ddd, J 9.2, 1.2, 0.8, H-11), 8.39 (1 H, ddd, J 9.2, 1.2, 0.8, H-8), 8.22 (1 H, d, J 8, H-4 or 5), 8.08
(1 H, d, J 8, H-4 or 5), 7.91 (1 H, d, J 5.6, H-2 or 3), 7.90 (1 H, ddd, J 9.2, 7.6, 1.2, H-9 or 10), 7.88 (1 H,
ddd, J 9.2, 7.6, 1.2, H-9 or 10), and 7.71 (1 H, d, J 5.6, H-2 or 3); m/z (ES+) 236.04 (M+ + H, 100%).
3.5.3. FVP of Ylide 37
◦
Ylide 37 (0.1971 g, 0.32 mmol) was subjected to FVP at 700 C and 2–3
×
10−2 torr. NMR analysis of
the crude product showed a mixture of Ph3PO, bibenzyl, and other products. The mixture was roughly
separated into two fractions by column chromatography (50:50 diethyl ether:hexane). The first fraction
was purified by preparative TLC (10:90 diethyl ether:hexane) to give 4,7-dimethylbenzo[c]carbazole 46
(0.0179 g, 22%); (Found: M+ + H, 246.1279. C18H16N (M+ + H) requires, 246.1283); δH 8.71 (1 H, ddd,
J 8.4, 0.8, 0.5, H-1), 8.605 (1 H, ddd, J 8, 1.2, 0.5, H-11), 8.119 (1 H, dd, J 9.2, 0.5, H-5), 7.696 (1 H, d, J 9.2,
H-6), 7.602 (1 H, dd, J 8.4, 6.8, H-2), 7.562 (1 H, ddd, J 8, 1.2, 0.5, H-8), 7.515 (1 H, ddd, J 8, 7.2, 1.2, H-9),
7.385 (1 H, ddd, J 8, 7.2, 1.2, H-10), 7.324 (1 H, dd, J 6.8, 0.8, H-3), 4.00 (3H, s, NMe) and 2.82 (3H, s,
ArMe); δC 130.1 (4ry), 126.5 (CH), 124.1 (CH), 124.0 (CH), 123.1 (CH), 122.2 (CH), 121.6 (CH), 120.9
(4ry), 120.3 (4ry), 119.6 (CH), 115.6 (4ry), 114.6 (4ry), 113.9 (4ry), 110.0 (CH), 109.0 (CH), 29.3 (NMe)
and 20.4 (ArMe); m/z (ES+) 246.08 (M+ + H, 100%). The second fraction was purified by preparative
TLC (10:90 diethyl ether:hexane) to give 3-(2-(2-methylphenyl)ethenyl)quinoline 44 (E, 0.0134 g, 17%.
Z, 0.0101 g, 14%); (Found: M+ + H, 246.1291. C18H16N (M+ + H) requires, 246.1283); δH (E) 9.13 (1 H, d,
J 2, H-2), 8.18 (1 H, d, J 2, H-4), 8.10 (1 H, d, J 8, H-5 or 8), 7.84 (1 H, dd, J 8, 1, H-5 or 8), 7.69 (1 H, ddd,
J 8, 7, 1, H-6 or 7), 7.66 (1 H, d, J 8), 7.56 (1 H, half of AB pattern, J 16, H-a or b), 7.55 (1 H, ddd, J 8, 7, 1,
H-6 or 7), 7.29–7.20 (3 H, m), 7.15 (1 H, half of AB pattern, J 16, H-a or b) and 2.49 (3 H, s, Me); δH (Z)
8.62 (1 H, d, J 2, H-2), 8.09 (1 H, d, J 8, H-5 or 6), 7.84 (1 H, d, J 2, H-4), 7.63 (1 H, ddd, J 8, 6.5, 1, H-6
or 7), 7.61 (1 H, d, J 8), 7.46 (1 H, ddd, J 8, 6.5, 1, H-6 or 7), 7.19 (1 H, br t, J 7.5), 7.12 (1 H, d, J 8), 7.04
(1 H, br t, J 7.5), 6.89 and 6.75 (2 H, AB pattern, J 12, H-a and b) and 2.32 (3 H, s, Me); m/z (ES+) 246.00
(M+ + H, 100%). Also isolated from the same preparative TLC was 9-methylbenzo[k]phenanthridine
45 (0.0017 g, 2%), (Found: M+ + H, 244.1120. C18H15N (M+ + H) requires, 244.1126); δH 9.37 (1 H, s,
H-6), 9.07 (2 H, t, J 8, H-1 and 12), 8.38 (1 H, dd, J 8, 2, H-4), 8.25 (1 H, d, J 9, H-8), 8.00 (1 H, d, J 9, H-7),
7.81 (1 H, ddd, J 8, 7, 1, H-2 or 3), 7.74 (1 H, ddd, J 8, 7, 1, H-2 or 3), 7.67 (1 H, t, J 7, H-11), 7.59 (1 H, d,
J 7, H-10), and 2.87 (3 H, s, Me); m/z (ES+) 244.03 (M+ + H, 100%).
3.5.4. FVP of Ylide 38
Ylide 38 (0.1072 g, 0.17 mmol) was subjected to FVP at 700 ◦C and 2–3
×
10−2 torr.
NMR analysis of the crude product showed a mixture of Ph3PO, bibenzyl, and other products.
The mixture was purified by column chromatography (50:50 diethyl ether:hexane) followed by
preparative TLC (30:70 diethyl ether:hexane) to give a low yield of what appeared to be impure
3-(2-(3-methyl-2-thienyl)ethenyl)quinoline 47 as a dark brown oil. Indicative peaks at δH 9.09 (1 H, d,
J 2, H-2 E), 8.83 (1 H, d, J 2, H-2 Z), 2.39 (3 H, s, ArMe E or Z), and 2.20 (3 H, s, ArMe, E or Z) indicated
a 1:1 mixture of E/Z—however, further purification and analysis was not possible.
4. Conclusions
The results from FVP of these four ylides further emphasize the sensitivity of the outcome in
these reactions on the precise combination of substituents present. As compared to the previously
studied N-benzyl-N-methylamino ylides, the present compounds show an almost complete change
·
from carbazole products derived from cyclization of N(Me) to quinoline and phenanthridine products
·
derived from hydrogen atom transfer and cyclization of the resulting NHCH2 . The results are more

Molecules 2018, 23, 2153
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similar to those obtained from certain N,N-dibenzyl ylides, but even then, significant differences in
product distribution are caused by the slightest change in ylide structure. The difference in pyrolysis
outcome between the isomeric compounds 35 and 36 and 17 and 18 is striking, as is the effect of adding
a single methyl substituent remote from the reactive site, as seen going from 16 to 37 or from 18 to 38
We conclude that, as also found in our recent synthesis of Eustifoline D using this method [13], model
studies are of little value in this area, and which pyrolytic routes will predominate in a given case can
only be determined by experimentation.
.
Supplementary Materials: The following are available online. Figures S1–S27: NMR spectra of new compounds.
Cif and check-cif files for X-ray structure of 14.
Author Contributions: L.M. performed the experiments; A.M.Z.S. collected the X-ray data and solved the
structure; R.A.A. designed the experiments, analyzed the data and wrote the paper.
Funding: We thank EPSRC (UK) for a DTA studentship (Grant No. EP/P501768/1).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Wentrup, C. Flash vacuum pyrolysis: Techniques and reactions. Angew. Chem. Int. Ed. Engl. 2017, 56,
14808–14835. [CrossRef] [PubMed]
2.
Aitken, R.A.; Boubalouta, Y. Recent advances in the synthesis of heterocyclic compounds using flash vacuum
pyrolysis. Adv. Heterocycl. Chem. 2015, 115, 93–150. [CrossRef]
3.
4.
Tietze, L.F. Domino reactions in organic synthesis. Chem. Rev. 1996, 96, 115–136. [CrossRef] [PubMed]
Tietze, L.; Brasche, G.; Gericke, K.M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2006; ISBN 978-3-527-29060-4.
5.
6.
Tietze, L.F. (Ed.) Domino Reactions: Concepts for Efficient Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2014; ISBN 978-3-527-33432-2.
Aitken, R.A.; Bradbury, C.K.; Burns, G.; Morrison, J.J. Tandem radical cyclisation in the flash vacuum
pyrolysis of 2-methoxyphenyl and 2-methylthiophenyl substituted phosphorus ylides. Synlett 1995, 53–54.
[CrossRef]
7.
Aitken, R.A.; Burns, G.; Morrison, J.J. Flash vacuum pyrolysis of stabilised phosphorus ylides. Part 14.
Tandem cyclisation of intermediate aryloxy and arylthio radicals leading to tri- and tetra-cyclic aromatic
heterocycles. J. Chem. Soc. Perkin Trans. 1 1998, 3937–3941. [CrossRef]
8.
9.
Aitken, R.A.;
Garnett, A.N. 0 An eight-stage gas-phase cascade reaction leading to
7-(2-benzothienyl)benzofuran and 2,7 -bi(benzofuran). Synlett 2001, 228–229. [CrossRef]
Aitken, R.A.;
Garnett, A.N. Cascade synthesis of new tetracyclic heteroaromatic
thieno[2,3-b]pyridine-containing ring systems. New J. Chem. 2009, 33, 2402–2404. [CrossRef]
10. Aitken, R.A.; Chang, D. New gas-phase domino processes leading to benzopyranones and benzofurans.
Heterocycles 2016, 93, 164–1284. [CrossRef]
11. Aitken, R.A.; Garnett, A.N. Versatile pyrolytic synthesis of fused polycyclic heteroaromatic compounds.
Synthesis 2017, 49, 4955–4977. [CrossRef]
12. Aitken, R.A.; Murray, L. New gas-phase cascade reactions of stabilised phosphorus ylides leading to
ring-fused indoles and to quinolines. J. Org. Chem. 2008, 73, 9781–9783. [CrossRef] [PubMed]
13. Aitken, R.A.; Murray, L. Gas-phase domino cyclisation of phosphonium ylides leading to the total synthesis
of Eustifoline D. Tetrahedron Lett. 2017, 58, 4328–4332. [CrossRef]
14. Aitken, R.A.; Boubalouta, Y.; Chang, D.; Cleghorn, L.P.; Gray, I.P.; Karodia, N.; Reid, E.J.; Slawin, A.M.Z.
The value of 2JP-CO as a diagnostic parameter for the structure and thermal reactivity of carbonyl-stabilised
phosphonium ylides. Tetrahedron 2017, 73, 6275–6285. [CrossRef]
15. Aitken, R.A.; Karodia, N.; Lightfoot, P. The solid-state conformation of oxo stabilised ylides: X-ray structures
of four new polyoxo phosphorus ylides. J. Chem. Soc. Perkin Trans. 2 2000, 333–340. [CrossRef]
16. Aitken, R.A.; Boeters, C.; Morrison, J.J. Novel Thermal Cyclisation of o-Methylstyrylalkynes to give
2-Alkenylnaphthalenes. Tetrahedron Lett. 1995, 36, 1303–1306. [CrossRef]

Molecules 2018, 23, 2153
12 of 12
17. Aitken, R.A.; Boeters, C.; Morrison, J.J. Flash vacuum pyrolysis of stabilised phosphorus ylides.
Part 10. Generation of 2-methylstyrylalkynes and their thermal cyclization to 2-alkenylnaphthalenes.
J. Chem. Soc. Perkin Trans. 1 1997, 2625–2631. [CrossRef]
18. Katritzky, A.R.; Vincek, A.; Suzuki, K. Microwave-assisted synthesis of peptidyl phosphorus ylides. Arkivoc
2005, v, 116–126. [CrossRef]
19. Aitken, R.A.; Horsburgh, C.E.R. Flash Vacuum Pyrolysis of O-phenylene Sulfite: Formation and Purification
of Cyclopentadienone Dimer. In Comprehensive Organic Chemistry Experiments for the Laboratory Classroom;
Afonso, C.A.M., Candeias, N.R., Simao, D.P., Trinidade, A.F., Coelho, J.A.S., Tan, B., Franzén, R., Eds.;
Royal Society of Chemistry: Cambridge, UK, 2017; pp. 690–693. ISBN 978-1-84973-963-4.
20. Shizuri, Y.; Ojika, M.; Yamada, K. Structure of an antitumor antibiotic, reductiomycin. Tetrahedron Lett. 1981
22, 4291–4294. [CrossRef]
,
21. Pardin, C.; Pelletier, J.N.; Lubell, W.D.; Keillor, J.W. Cinnamoyl inhibitors of tissue transglutaminase.
J. Org. Chem. 2008, 73, 5766–5775. [CrossRef] [PubMed]
22. Patra, P.K.; Suresh, J.R.; Ila, H.; Junjappa, H. A new regiospecific method for the synthesis of
substituted phenanthridines and benzo[j]phenanthridines via aromatic annelation of 1-N-benzenesulfonyl-3-
[bis(methylthio)methylene]-1,2,3,4-tetrahydroquinoline-4-one. Tetrahedron 1998, 54, 10167–10178. [CrossRef]
Sample Availability: Not Available.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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