Novel ether and thioether macrocycles from phthalaldehyde

Article abstract of DOI:10.1016/j.tetlet.2015.02.003

Abstract By reaction of phthalaldehyde (benzene-1,2-dicarbaldehyde) with ethane-1,2-diol or 2-mercaptoethanol, macrocycles containing respectively 14- and 12-membered polyether/thioether rings were obtained in low but reproducible yields, and their struct

Full text of DOI:10.1016/j.tetlet.2015.02.003

Accepted Manuscript
Novel ether and thioether macrocycles from phthalaldehyde
R. Alan Aitken, Clémence Hauduc, Ross S. McLennan, Alexandra M.Z. Slawin,
Heather S. Wilson
PII:
S0040-4039(15)00246-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.003
TETL 45866
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 October 2014
19 January 2015
1 February 2015
Please cite this article as: Alan Aitken, R., Hauduc, C., McLennan, R.S., Slawin, A.M.Z., Wilson, H.S., Novel ether
and thioether macrocycles from phthalaldehyde, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2
015.02.003
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R. Alan Aitken*, Clémence Hauduc, Ross S. McLennan, Alexandra M. Z. Slawin, Heather S. Wilson

1
Tetrahedron Letters
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Novel ether and thioether macrocycles from phthalaldehyde
a
a
a
a
a
R. Alan Aitken *, Clémence Hauduc , Ross S. McLennan , Alexandra M. Z. Slawin , Heather S. Wilson
a
EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, U. K.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
By reaction of phthalaldehyde (benzene-1,2-dicarbaldehyde) with ethane-1,2-diol or 2-
mercaptoethanol, macrocycles containing respectively 14- and 12-membered polyether/thioether
rings were obtained in low but reproducible yields, and their structures confirmed by X-ray
diffraction. The simple compounds (2-vinylphenyl)oxirane and 2-oxiranylbenzaldehyde have
also been prepared and characterised for the first time.
Available online
2
014 Elsevier Ltd. All rights reserved.
Keywords:
Macrocycle
Phthalaldehyde
Polyethers
Acetals
X-ray structures
In the course of a recent mechanistic study we required access
to both (2-vinylphenyl)oxirane (1), the monoepoxide of 1,2-
Our work began with an attempt to form 2 directly by reaction
of the readily available phthalaldehyde (7) with one equivalent of
dimethylsulfoxonium methylide in DMSO, but not surprisingly
5
divinylbenzene,
and
its
ozonolysis
product
2-
oxiranylbenzaldehyde (2), and were surprised to discover that
neither of these simple aromatic compounds has apparently been
reported before. In this paper we describe synthetic approaches to
these products based on selective reaction of one carbonyl group
this resulted in cooperative reaction of the adjacent aldehyde
functions to give a polymeric product. Interaction of the adjacent
aldehyde groups was also observed upon attempted Wittig
3 2
reaction of 7 using Ph P=CH in THF, but in this case a sequence
in
phthalaldehyde
(benzene-1,2-dicarbaldehyde),
which
of intra- and inter-molecular reactions resulted in the unexpected
formation of benzo[b]fluorenone (8), obtained in 48% yield after
chromatographic purification. The formation of this product,
unexpectedly led to new macrocyclic products, as well as a
different route to 1 and 2 which was ultimately successful.
1
13
which was readily identified by comparison of its H and
C
Although neither 1 or 2 have been reported before, there has
6
NMR spectra with literature values, is rationalised as shown in
Scheme 1. Equilibrium transfer of the reactive site from O to C in
the initial adduct allows attack at the second aldehyde function
and ring closure to give ultimately indan-1-one (9), a product
been work on the regioisomeric compounds. Thus, for example,
selective monoepoxidation of 1,3-divinylbenzene to give 3 was
achieved using H O in the presence of Mo and Sn catalysts,
2 2
while more recently the same product was formed
enantioselectively by asymmetric sulfonium ylide treatment of 3-
1
7,8
which is well known to undergo condensation with 7 under
2
basic conditions to afford 8. It should be noted that the
vinylbenzaldehyde. Epoxidation of the double bond in 3-
3 3
carbodiphosphorane Ph P=C=PPh also reacts directly with 7 to
9
give 8, presumably by a similar process.
*
4
Corresponding author. Tel. +44 (0)1334 463865; fax +44 (0)1334
63808. E-mail address: raa@st-and.ac.uk (R. A. Aitken)
2 2
vinylbenzaldehyde using H O and a molybdenum catalyst gave
4
Scheme 1: Proposed mechanism for the formation of 8
3
compound 4. In the 1,4-series, epoxide 5 has been prepared, while
the aldehyde 6 is apparently unknown.

2
Tetrahedron
From these studies it became clear that the use of protective
in the presence of various metal salts were uniformly
unsuccessful.
groups was more likely to allow successful access to 1 and 2, so
we prepared the monoacetal 10 by reaction of 7 with one
equivalent of ethanediol in the presence of catalytic p-TsOH
under Dean–Stark conditions (Scheme 2). The desired product
was obtained in acceptable yield and showed the expected
spectroscopic properties, but it was accompanied by a little of
the bis(acetal) 11 identified by comparison with literature data,
and a further previously unknown product.
1
0
1
1
12
To return to the synthesis of compounds 1 and 2, Wittig
reaction of the aldehyde 10 gave 2-(2-vinylphenyl)-1,3-dioxolane
1
(
18) whose identity was confirmed by comparison of its H NMR
spectrum with the recently reported literature data (Scheme
1
2,20
3
).
This was successfully epoxidised to compound 19 using
m-CPBA and 19 was also formed directly when 10 was treated
with dimethylsulfoxonium methylide in DMSO. The previously
unknown compound 19 gave the expected spectroscopic and
1
3
HRMS data, including separate C NMR signals for the slightly
non-equivalent dioxolane CH groups, but unfortunately no
2
Scheme 2: Acetal formation from 7
12
The NMR spectra showed this to be highly symmetrical with
only four H and five C environments and chemical shifts
indicating the presence of a symmetrically 1,2-disubstituted
2 2
benzene ring together with O–CH–O and O–CH CH –O
conditions were found to deprotect the dioxolane function to the
aldehyde while leaving the epoxide intact. Removal of the
dioxolane from 18 under acidic conditions gave 2-
vinylbenzaldehyde 20, but attempted epoxidation of its double
bond instead resulted in a Baeyer-Villiger reaction to afford
1
13
functions. The spectra were consistent with the formula 12 and
such trioxabicyclo[4.2.1]nonane ring systems have been prepared
before by condensation of appropriately configured dicarbonyl
2
1
mainly 2-vinylphenyl formate (21).
13–15
compounds with ethanediol, as exemplified by 13–15.
Phthalaldehyde is also well known to react with ethanol to
1
6
give the cyclic acetal 16. However the mass spectrum of the
new product showed it to have twice the molecular mass
expected for 12 and so most likely to have structure 17. As far as
we are aware, this appears to be the first example of macrocycle
formation from phthalaldehyde and a diol, although alkoxide-
initiated polymerisation to give the polymeric cyclic acetal has
Scheme 3: Attempted formation of 2 starting from 10
In an attempt to achieve deprotection under milder conditions
that would be compatible with the presence of an epoxide, we
considered using the 1,3-oxathiolane, which can be removed
17
been reported.
22
using Raney nickel. Treatment of phthalaldehyde with one
equivalent of 2-mercaptoethanol in the presence of catalytic p-
TsOH under Dean-Stark conditions (Scheme 4) resulted in
1
2
formation of the desired product 22 in reasonable yield.
Figure 1: Top and side view of the molecular structure of 17
The molecular structure of 17 was confirmed by single crystal
18
X-ray diffraction (Figure 1), which also showed the compound
to exist exclusively in the cis-syn-cis configuration rather than
the alternative and apparently less hindered cis-anti-cis or trans-
anti-trans forms 17a and 17b. In this configuration the oxygen to
oxygen distances across the 14-membered ring macrocycle of 17
are in the range 3.8–4.5 Å, which is lower than the typical values
19
of 4.6–5.0 Å encountered in 15-crown-5 for example, and
explains why the compound showed no affinity for metal ions.
Attempts to increase the yield of 17 by templating the synthesis
Scheme 4: Thioacetal formation from 7

3
This was accompanied by low yields of two diastereomeric
1
2
bis(oxathiolanes) 23 and 24. Chromatographic separation of
these products on silica gel also led to the formation and isolation
of a new crystalline compound that was not present in the crude
reaction product. Spectroscopic data were consistent with the
macrocyclic aldehyde structure 25 containing a 12-membered
18
1
2
ring, and this was confirmed by X-ray diffraction (Figure 2).
In this case the larger sulfur atoms led to transannular O–O and
O–S distances of only 3.6–4.6 Å making complexation to metal
ions unlikely.
For the successful synthesis of 1 and 2 we returned to 2-
vinylbenzaldehyde (20), obtained either by deprotection of 18 as
23
mentioned above, or more efficiently,
from 2-
bromobenzaldehyde by Wittig reaction with Ph P=CH
3
2
followed
by lithium/halogen exchange and reaction with DMF (Scheme 6).
Figure 2: Two views of the molecular structure of 25
The formation of macrocycle 25 is assumed to result from
Lewis acid catalysed dimerisation of the major product 22 on
silica (Scheme 5), although attempts to duplicate the process by
stirring solutions of either 22 alone, 7 and 23/24, or 7, 22 and
2
3/24 in diethyl ether with silica gel failed with no trace of 25
being formed.
Scheme 6: Successful synthesis of 1 and 2
When the product 20 was reacted with dimethylsulfoxonium
methylide, compound 1 was formed in a low but reproducible
yield and it was in turn converted into the epoxyaldehyde 2 by
ozonolysis in CH
Both compounds showed the expected spectroscopic properties,
and their use in a study of the mechanism of pyrolysis of
2
Cl at –78 °C followed by treatment with Ph P.
2
3
12
2
4
benzo[b]thiapyran S,S-dioxides will be reported shortly.
In conclusion, the formation of macrocyclic acetals by
condensation of phthalaldehyde with difunctional nucleophiles is
a useful new aspect of its reactivity, which may also be possible
for other compounds containing proximate reactive carbonyl
groups.
Scheme 5: Proposed mechanism for the formation of 25
On a single occasion, a crystal selected for X-ray diffraction
from a sample of 25 proved to have the new oxathiolane structure
1
8
2
6 (Figure 3), although this compound was present in such a
References and notes
small amount that it could not be detected spectroscopically. The
different processes taking place during the chromatographic
purification of the products from Scheme 4 are clearly complex
and require further study. It should be mentioned that no
macrocycle formation was observed on reaction of
phthalaldehyde with ethane-1,2-dithiol.
1
2
.
.
Inoue, M.; Nakayama, E.; Nakamura, Y.; Regakuji, S.; Nishibe,
K. Bull. Chem. Soc. Jpn. 1991, 64, 3442–3444.
Piccinini, A.; Kavanagh, S. A.; Connon, S. J. Chem. Commun.
2012, 48, 7814–7816.
3. Saisaha, P.; Buettner, L.; van der Meer, M.; Hage, R.; Feringa, B.
L.; Browne, W. R.; de Boer, J. W. Adv. Synth. Catal. 2013, 355,
2
591–2603.
Pogosyan, G. M.; Matsoyan, S. G. Russ. J. Org Chem. 1966, 2,
221.
Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–
364.
4
5
6
.
.
.
2
1
Levy, A.; Biedermann, P. U.; Cohen, S.; Agranat, I. J. Chem. Soc.,
Perkin Trans. 2 2001, 2329–2341.
7
8
.
.
Thiele, J.; Schneider, J. Liebigs Ann. Chem. 1909, 369, 287–299.
Thiele, J.; Wanscheidt, A. Liebigs Ann. Chem. 1910, 376, 269–
2
79.
9
.
Bestmann, H.-J., Pure Appl. Chem. 1980, 52, 771–788.
Figure 3: Molecular structure of 26
10. Hartman, G. D.; Phillips, B. T.; Halczenko, W. J. Org. Chem.
985, 50, 2423–2427.
11. Kmentova, I.; Toma, S. Collect. Czech. Chem. Commun. 2002, 67,
1
Treatment of compound 22 with dimethylsulfoxonium
1
2
methylide did afford the target epoxide 27, although in low
yield but we were ultimately unable to deprotect this using Raney
nickel in acetone to give the epoxy aldehyde 2.
1616–1622.
1
2. Macrocycle 17: colourless crystals, mp 138–139 °C (Found:
+
+
20 6 H
M +Na, 379.1147. C20H O Na (M +Na) requires, 379.1158); ꢀ

4
Tetrahedron
(
300 MHz, CDCl
.90 (8H, m, CH ); ꢀ
23.1 (CH), 105.8 (CH), 67.5 (CH
(75 MHz, CDCl ) 137.0 (C), 134.2 (C), 133.8
CH), 129.1 (CH), 127.6 (CH), 126.1 (CH), 125.9 (CH), 116.5
CH ), 101.6 (CH), 65.3 (2CH ). Epoxydioxolane 19: colourless
Na (M+Na) requires,
) 7.56–7.53 (1H, m, ArH), 7.36–
.30 (3H, m, ArH), 6.06 (1H, s, CH), 4.26 (1H, dd, J 4.2, 2.7,
), 3.15 (1H, dd, J 5.7, 4.2, CH), 2.70
(75 MHz, CDCl ) 136.5 (C), 135.4
C), 129.4 (CH), 127.6 (CH), 126.2 (CH), 124.4 (CH), 102.1
CH), 65.3 (CH ), 65.2 (CH ), 50.9 (CH), 49.7 (CH ). Oxathiolane
2: yellow crystals, mp 39–41 °C (Found: M +Na, 217.0293.
3
) 7.38 (8H, s, ArH), 6.19 (4H, s, CH), 4.10–
(75 MHz, CDCl ) 138.5 (C), 129.5 (CH),
). Vinyldioxolane 18:
171.0422); ꢀ
(1H, m, ArH), 7.62–7.58 (1H, m, ArH), 7.54–7.47 (2H, m, ArH),
4.68 (1H, dd, J 4, 3, CH), 3.25 (1H, dd, J 6, 4, CH ), 2.61 (1H, dd,
J 6, 3, CH ). ꢀ (100 MHz, CDCl ) 192.8 (CHO), 140.1 (C), 134.2
H 3
(400 MHz, CDCl ) 10.20 (1H, s, CHO), 7.84–7.82
3
1
2
C
3
2
2
colourless liquid; ꢀ
C
3
2
C
3
(
(
(CH), 134.1 (C), 133.7 (CH), 127.9 (CH), 125.2 (CH), 51.0 (CH
2
),
2
2
50.4 (CH).
oil (Found: M+Na, 215.0679.
15.0684); ꢀ (300 MHz, CDCl
H 3
C
11
H
12
O
3
13. Sainsbury, M.; Webb, B.; Schinazi, R. J. Chem. Soc., Perkin
Trans. 1 1975, 289–298.
14. Heusler, K.; Ueberwasser, H.; Wieland, P.; Wettstein, A. Helv.
2
7
CH), 4.14–4.04 (4H, m, 2CH
1H, dd, J 5.7, 2.7, CH
2
Chim. Acta 1957, 40, 787–815.
(
(
(
2
); ꢀ
C
3
15. Mehta, G.; Rao, K. S.; Krishnamurthy, N.; Srinivas, V.;
Balasubramanian, D. Tetrahedron 1989, 45, 2743–2750.
16. Powell, M. R.; Rexford, D. R. J. Org. Chem. 1952, 17, 810–814.
17. Aso, C.; Tagami, S. Macromolecules 1969, 2, 414–419.
2
2
2
+
2
+
C
10
H
10
O
2
NaS (M +Na) requires, 217.0299); ꢀ
H
(300 MHz, CDCl
3
)
18. Compound 17: C20
20 6
H O , M = 356.37, monoclinic space group P
1
0.20 (1H, s, CHO), 7.82–7.76 (2H, m, ArH), 7.61–7.56 (1H, m,
ArH), 7.49–7.44 (1H, m, ArH), 6.73 (1H, s, CH), 4.65–4.55 (1H,
m, OCH ), 4.05–3.96 (1H, m, OCH ), 3.18–3.13 (2H, m, SCH );
(75 MHz, CDCl ) 192.3 (CHO), 141.9 (C), 133.8 (CH), 132.9
CH), 132.4 (C), 128.2 (CH), 126.0 (CH), 83.0 (CH), 72.2 (CH ),
3.3 (CH ). Bis(oxathiolanes) 23/24: (Found: M+Na, 277.0339.
NaS (M+Na) requires, 277.0333); ꢀ (300 MHz, CDCl
.66–7.60 (2H, m, ArH), 7.35–7.32 (2H, m, ArH), 6.34/6.29 (2H,
s, CH), 4.65–4.55 (2H, m, CH ), 3.98–3.89 (2H, m, CH ), 3.33–
(75 MHz, CDCl ) 136.44/136.39 (C),
28.71/128.74 (CH), 126.8/126.4 (CH), 83.6/83.8 (CH), 72.0/71.8
O), 34.2/34.0 (CH S). Macrocycle 25: colourless crystals, mp
82–184 °C (Found: M+Na, 411.0706. C20 NaS (M+Na)
(300 MHz, CDCl ) 10.07 (1H, s), 7.75
1H, dd, J 8, 1.5, ArH), 7.68–7.63 (1H, m, ArH), 7.55–7.45 (5H,
m, ArH), 7.33–7.28 (1H, m, ArH), 6.50 (1H, s, CH), 6.18 (2H, s),
2
1
; a = 9.253(4), b = 9.129(4), c = 10.515(4) Å, β = 105.373(11) °,
3
V = 856.4(6) Å , Z = 2, D = 1.382, R = 0.0363 and R
for 2436 data with I > 2σ(I) and 235 parameters. Compound 25:
, M = 388.50, monoclinic space group P 2 /c; a =
w
= 0.0687
2
2
2
ꢀ
C
3
C
20
H
20
O
4
S
2
1
(
3
C
7
2
7.896(5), b = 31.599(16), c = 7.454(4) Å, β = 100.180(15) °, V =
1830.6(17) Å , Z = 4, D = 1.410, R = 0.143 and Rw = 0.405 for
3
2
12
H
14
O
2
2
H
3
)
2
C
9
2
3
963 data with I > 2σ I) and 236 parameters. Compound 26:
, M = 448.61, monoclinic, space group P 2 /n; a =
.225(3), b = 7.899(3), c = 28.799(8) Å, β = 92.220(9) °, V =
097.0(11) Å , Z = 4, D = 1.421, R = 0.0598 and R
141 data with I > 2σ I) and 262 parameters. Crystallographic
22
H
24
O
4
S
3
1
2
2
3
1
.17 (4H, m, CH
2
) ꢀ
C
3
3
w
= 0.1544 for
(
CH
2
2
data (excluding structure factors) for the structures in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 1025482 (17),
1
H
20
O
4
2
requires, 411.0701); ꢀ
(
H
3
1
025483 (25) and 1025484 (26). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
4
.12 (4H, dd, J 6, 5), 3.11 (2H, dt, J 15, 5), 2.67 (2H, dt, J 15, 6);
(75 MHz, CDCl ) 191.0 (CHO), 143.4 (C), 138.1 (C), 133.8
ꢀ
C
3
(
(
CH), 130.1 (2CH), 129.4 (CH), 128.5 (CH), 127.9 (CH), 123.1
2CH), 106.1 (2CH), 71.1 (2CH ), 47.9 (CH), 32.4 (2CH ) [one
1
2
9. Parsons, S. Acta Crystallogr., Sect. E 2007, 63, o3130.
0. Xing, S.; Pan, W.;Liu, C.; Ren, J.; Wang, Z. Angew. Chem. Int.
Ed. 2010, 49, 3215–3218.
2
2
quaternary aromatic C not apparent]. Epoxyoxathiolane 27: ꢀ
300 MHz, CDCl ) 7.60–7.50 (1H, m, ArH), 7.35–7.25 (3H, m,
ArH), 6.35 (1H, s), 4.63–4.57 (1H, m), 4.16 (1H, dd, J 4.2, 2.7),
H
(
3
2
2
1. Konishi, H.; Ueda, T.; Muto, T.; Manabe, K. Org. Lett. 2012, 14,
4
722–4725.
2. Djerassi, C.; Shamma, M.; Kan, T. Y. J. Am. Chem. Soc. 1958, 80,
723–4732.
4
2
.02–3.94 (1H, m), 3.30–3.23 (2H, m), 3.17 (1H, dd, J 5.7, 4.2),
.70 (1H, dd, J 5.7, 2.7); ꢀ (75 MHz, CDCl ) 137.1 (C), 135.1
C
3
4
(
7
C), 128.7 (CH), 127.9 (CH), 125.6 (CH), 124.4 (CH), 84.2 (CH),
1.9 (CH O), 51.0 (CH O), 49.7 (CHO), 34.0 (CH S). 2-
Vinylphenyloxirane (1): a very pale yellow liquid, bp 210 °C
oven temp.)/20 Torr; ꢀ (300 MHz, CDCl ) 7.50–7.45 (1H, m,
ArH), 7.30–7.24 (3H, m, ArH), 7.06 (1H, dd, J 17, 11, CH), 5.69
1H, dd, J 17, 1, CH ), 5.38 (1H, dd, J 11, 1, CH ), 4.08 (1H, dd, J
, 3, CH), 3.15 (1H, dd, J 6, 4, CH ), 2.71 (1H, dd, J 6, 3, CH ). ꢀ
75 MHz, CDCl ) 136.8 (C), 134.7 (C), 133.5 (CH=CH ), 127.9
CH), 127.8 (CH), 125.7 (CH), 124.5 (CH), 116.9 (CH=CH ), 50.5
CH), 50.3 (CH ). 2-Oxiranylbenzaldehyde (2): colourless liquid
2
2
3. Dieltiens, N.; Stevens, C. Synlett 2006, 2771–2776.
4. Aitken, R. A.; Hauduc, C.; Hossain, M. S.; McHale, E.; Schwan,
A. L.; Slawin, A. M. Z.; Stewart, C. A. Aust. J. Chem. 2014, 67,
2
2
2
(
H
3
1
288–1295.
(
4
(
(
(
(
2
2
Supplementary Material
2
2
C
3
2
1
13
2
Detailed experimental procedures and copies of H and
NMR spectra for all new compounds.
C
2
+
+
Found: M +Na, 171.0424.
9 8 2
C H O Na (M +Na) requires