An approach to cannabinoids by radical cyclisation of 1,7-dienes using diethyl thiophosphite

Article abstract of DOI:10.1055/s-2008-1032049

Various 1,7-dienes, prepared efficiently in five steps from salicylaldehyde, react with diethyl thiophosphite (in the presence of AIBN) to form substituted chromans, which are potential precursors to cannabinoids. The influence of the substitution of the

Full text of DOI:10.1055/s-2008-1032049

LETTER
329
An Approach to Cannabinoids by Radical Cyclisation of 1,7-Dienes Using
Diethyl Thiophosphite
Cannabinoids by
R
adic
a
al Cyclisat
r
ion k P. Healy,a Andrew F. Parsons,*b James G. T. Rawlinsonb
a
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)432516; E-mail: afp2@york.ac.uk
Received 24 September 2007
CB2 activity because compounds that bind selectively to
the CB2 receptor could act as potential therapeutic
agents.4
Abstract: Various 1,7-dienes, prepared efficiently in five steps
from salicylaldehyde, react with diethyl thiophosphite (in the pres-
ence of AIBN) to form substituted chromans, which are potential
precursors to cannabinoids. The influence of the substitution of the
1,7-diene on the efficiency of the radical cyclisation is discussed.
With the aim of developing a new, concise and general
synthetic route to bi- and tricyclic cannabinoid analogues,
the preparation of chromans of type 2 was developed. As
shown in Scheme 1, these compounds, which contain the
aromatic ring (called the A ring) and the dimethyltetrahy-
dropyran ring (the B ring) of D9-THC (1), were expected
to be formed upon radical cyclisation of 1,7-dienes of type
3 using diethyl thiophosphite (O,O-diethyl phosphono-
thioate).5 The intermediate phosphorus-centred radical,
(EtO)2P(S)·, was expected to add regioselectively to the
styrene C=C bond in 3, to give benzylic radical 4, which
could then undergo a 6-exo-trig cyclisation to form the
dimethylpyran ring in chroman 2.6 Chroman 2 could then
be converted into a variety of cannabinoid analogues
through manipulation of the phosphonothioate group.
Key words: addition reactions, cyclisations, ethers, radical reac-
tions, substituent effects
Cannabinoids are a class of more than 60 compounds iso-
lated from Cannabis sativa (the Indian hemp plant).1 Can-
nabis is widely used as a recreational drug for its
psychotropic effects and it has been shown to have some
important medicinal properties, mediated through binding
to two receptors, called CB1 and CB2.2
9
OH
1
C
(EtO)2P(S)
(EtO)2P(S)
R1
R1
R1
A
B
3
O
1
R
R
R
O
O
O
Figure 1
R
R
R
(EtO)2P(S)H,
AIBN or Et3B/O2
3
4
2
One particularly well-known cannabinoid is D9-THC (D9-
tetrahydrocannabinol; 1), which is the principal psychoac-
tive component of marijuana (Figure 1). Cannabinoids
such as D9-THC (1) exhibit a wide range of pharmacolog-
ical effects; this includes analgesic, antiemetic, anti-in-
flammatory, bronchodilatory and anticonvulsant effects
as well as reduction of blood ocular pressure in glaucomic
patients and alleviation of neurological disorders in mul-
tiple sclerosis and Huntington’s chorea. The diverse and
extremely important range of biological activities has led
to various QSAR (quantitative structure–activity relation-
ship) studies designed to probe the binding of cannabinoid
compounds to CB1 and CB2.2,3 This work has shown the
importance of the phenolic hydroxyl group at C1, the C9
position and the C-3 side chain with respect to binding at
the CB1 receptor. However, less is known about the SAR
(structure–activity relationship) of CB2-active com-
pounds and there is a need to separate CB1 activity from
Scheme 1
Initial studies concentrated on the reaction of diene 5 [pre-
pared in 90% yield by O-allylation and then Wittig reac-
tion of salicylaldehyde (6) using Ph3P=CH2] with
(EtO)2P(S)H (2 equiv) using Et3B (2 ꢀ 0.5 equiv) at room
temperature in cyclohexane (see Figure 2).7 Unfortunate-
ly, none of the desired cyclic product was isolated. In
comparison, when 1,7-octadiene was reacted with
(EtO)2P(S)H and Et3B under similar reaction conditions,
cyclohexane 7 was isolated in up to 62% yield (as an equal
mixture of diastereoisomers). Reaction of 5 with alterna-
tive phosphorus hydrides, using Et3B–O2 or AIBN as ini-
tiator, was also unsuccessful. For example, when diene 5
was treated with diphenylphosphine oxide [Ph2P(O)H;
2.15 equiv] and Et3B at room temperature in cyclohexane
for 24 hours, only benzylic alcohol 8 was recovered (in
13% yield) after column chromatography. The formation
of 8 is presumably explained by reaction of the intermedi-
ate benzylic radical (of type 4) with O2, followed by re-
duction of the resulting hydroperoxide.
SYNLETT 2008, No. 3, pp 0329–0332
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.01.2008
DOI: 10.1055/s-2008-1032049; Art ID: D30307ST
© Georg Thieme Verlag Stuttgart · New York

330
M. P. Healy et al.
LETTER
(EtO)2P(S)
Me
Reaction of 13a with diethyl thiophosphite (2 equiv) was
then investigated (Table 1). Initial results using Et3B–O2
as the initiator were disappointing as no chroman products
were isolated. The major product isolated (in up to 11%
yield) was a secondary benzylic alcohol derived from ad-
dition of (EtO)2P(S)· to the styrene C=C bond followed by
reaction with O2 (cf. the formation of 8). Using more than
one equivalent of (EtO)2P(S)H also led to the formation of
the ‘simple’ addition product, derived from addition of
(EtO)2P(S)H to the styrene C=C bond. However, chang-
ing the initiator to AIBN (0.8 equiv) and using one equiv-
alent of (EtO)2P(S)H did lead to the isolation of chroman
14a in 28% yield as an equal mixture of two diastereoiso-
mers.10,11
Ph2P(O)
HO
Me
O
O
5 (E/Z = 5.7:1)
8
7
Figure 2
The unsuccessful cyclisation of 5 using (EtO)2P(S)H
could be explained by the relatively slow rate of cyclisa-
tion of the intermediate benzylic radical, the relatively
slow rate of reduction of the secondary radical formed on
6-exo-trig cyclisation (cf. the successful cyclisation of
1,7-octadiene to form 7) and/or the intermediate benzylic
radical could undergo a competitive 1,5-hydrogen atom
abstraction (to form an allylic radical).
Table 1 Radical Cyclisation of Dienes 13a–c Using (EtO)2P(S)H
(EtO)2P(S)
R
R
Studies then progressed to the synthesis of diene precur-
sors, which on cyclisation would form the dimethyltet-
rahydropyran ring present in the cannabinoids. It was
anticipated that the introduction of a geminal dimethyl
group in the allylic ether side-chain (3, R = Me) would fa-
cilitate the radical cyclisation: not only do the geminal
dimethyl groups prevent the intermediate benzylic radical
undergoing 1,5-hydrogen transfer, but the rate of 6-exo
cyclisation should be higher due to the Thorpe–Ingold ef-
fect.8
(EtO)2P(S)H,
AIBN, heat
R1
R1
cyclohexane
or THF
O
O
13a–c
14a–c
Diene 13
R
H
R1
Me
H
Chroman 14 Yield (%)/dra
a
b
c
a
b
c
28b/1:1
45c/1:0
54d/1:0
COMe
CO2Me
H
A concise and efficient route to diene 13a from salicylal-
dehyde (6) was developed as shown in Scheme 2. Follow-
ing a Wittig reaction of 6, the resulting phenol was treated
with chloroform, acetone and hydroxide ion to form car-
boxylic acid 10. Subsequent reduction of 10 gave primary
alcohol 11, which was oxidised to 12 using Swern condi-
tions. Finally, a Wittig reaction of 12 with Ph3P=CHMe
(prepared in situ) afforded diene 13a as the Z-isomer.9 It
was possible to convert 6 into 13a in an overall yield of
70% without the need to purify intermediates 9–12 by
chromatography; the crude products from each reaction
were taken on to give crude 13a, which was purified by
column chromatography.
a Calculated from the 1H NMR spectrum.
b Using 1 equiv of (EtO)2P(S)H in cyclohexane.
c Using 5 equiv of (EtO)2P(S)H in cyclohexane.
d Using 5 equiv of (EtO)2P(S)H in THF.
The effect of changing the substitution of the C=C bond in
the allylic ether side chain (on the efficiency of the radical
cyclisation) was investigated. Reaction of unsaturated ke-
tone 13b (prepared by reacting 12 with Ph3P=CHCOMe;
59% yield over two steps from 11) with (EtO)2P(S)H and
AIBN gave chroman 14b in 45% yield as a single diaste-
reoisomer. The stereochemistry of 14b was tentatively as-
signed as trans on the basis of a NOESY NMR
experiment. The higher yield of 14b compared to 14a pre-
sumably reflects the faster rate of 6-exo radical cyclisation
on to the electron-deficient C=C bond of 14b (hence cy-
clisation occurs even in the presence of five equivalents of
the thiophosphite), while the isolation of a single isomer
of 14b could be explained by a reversible radical cyclisa-
tion leading to the thermodynamic product.12
CHO
CO2H
a
b
OH
OH
O
6
9
10
c
OH
O
A similar result was observed on cyclisation of unsaturat-
ed ester 13c (prepared by reacting 12 with
Ph3P=CHCO2Me; 48% yield over two steps from 11) to
give chroman 14c in 54% yield as a single diastereoiso-
mer.13
e
d
O
O
O
13a
12
11
Scheme
2
Reagents and conditions: (a) BuLi (2 equiv),
Ph3(Me)P+Br– (1.5 equiv), THF, 0 °C to r.t. (98%); (b) CHCl3 (2
equiv), NaOH (2.7 equiv), acetone, 0 °C to r.t. (87%); (c) LiAlH4 (1.5
equiv), Et2O, 0 °C to r.t. (88%); (d) (COCl)2, Me2SO, CH2Cl2, –60 °C,
then Et3N, –40 °C, then r.t.; (e) BuLi (2 equiv), Ph3(Et)P+Br– (1.5
equiv), THF, –0 °C to r.t. (93% over two steps).
Preliminary studies to demonstrate the use of chromans
14a–c to prepare various cannabinoid analogues were also
investigated. For example, a Horner–Wadsworth–Em-
mons-type (HWE-type)5j reaction of chroman 14a using
s-BuLi (2 equiv) and benzophenone (2 equiv) in THF (–
Synlett 2008, No. 3, 329–332 © Thieme Stuttgart · New York

LETTER
Cannabinoids by Radical Cyclisation
331
78 °C to r.t.) gave trisubstituted alkene 1514 in 56% yield
after chromatography (as an inseparable mixture of dia-
stereoisomers in the ratio 6.5:1) (Figure 3). Unfortunate-
ly, an attempted intramolecular HWE-type reaction (using
NaH in DME) of 14b only gave the desired cyclopentene
16 in an unoptimised 10% yield (as a 4:1 mixture of iso-
mers). However, tricyclic cannabinoid derivatives, such
as 17, can be prepared in reasonable yield from 14c.
Hence, reaction of 14c with MCPBA gave the corre-
sponding phosphonate in 47% yield, which on deprotona-
tion with NaH (2 equiv) in refluxing DME15 underwent
cyclisation to form tricycle 17 in 62% yield (of unknown
stereochemistry). In comparison, the corresponding
phosphonothioate 18, formed on anionic cyclisation of
14c, was isolated in a reduced yield of 30%.
(3) For some previous synthetic approaches to cannabinoids,
see: (a) Papahatjis, D. P.; Kourouli, T.; Abadji, V.;
Goutopoulos, A.; Makriyannis, A. J. Med. Chem. 1998, 41,
1195. (b) Papahatjis, D. P.; Nikas, S. P.; Kourorli, T.; Chari,
R.; Xu, W.; Pertwee, R. G.; Makriyannis, A. J. Med. Chem.
2003, 46, 3221. (c) Sun, H.; Mahadevan, A.; Razdan, R. K.
Tetrahedron Lett. 2004, 45, 615. (d) Chu, C.; Ramamurthy,
A.; Makriyannis, A.; Tius, M. A. J. Org. Chem. 2003, 68,
55. (e) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,
T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.;
Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999,
121, 7582. (f) Lesch, B.; Toräng, J.; Nieger, M.; Bräse, S.
Synthesis 2005, 1888. (g) Nikas, S. P.; Thakur, G. A.;
Parrish, D.; Alapafuja, S. O.; Huestis, M. A.; Makriyannis,
A. Tetrahedron 2007, 63, 8112.
(4) Mahadevan, A.; Siegel, C.; Martin, B. R.; Abood, M. E.;
Beletskaya, I.; Razdan, R. K. J. Med. Chem. 2000, 43, 3778.
(5) For related addition reactions of phosphorus-centred
radicals, see: (a) Jessop, C. M.; Parsons, A. F.; Routledge,
A.; Irvine, D. J. Eur. J. Org. Chem. 2006, 1547. (b) Jessop,
C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. Tetrahedron
Lett. 2003, 44, 479. (c) Jessop, C. M.; Parsons, A. F.;
Routledge, A.; Irvine, D. J. Tetrahedron Lett. 2004, 45,
5095. (d) Cho, D. H.; Jang, D. O. Synlett 2005, 59.
(e) Hunt, T. A.; Parsons, A. F.; Pratt, R. J. Org. Chem. 2006,
71, 3656. (f) Montchamp, J.-L. J. Organomet. Chem. 2005,
690, 2388. (g) Leca, D.; Fensterbank, L.; Lacôte, E.;
Malacria, M. Chem. Soc. Rev. 2005, 34, 858. (h) Parsons,
A. F.; Sharpe, D. J.; Taylor, P. Synlett 2005, 2981. (i) Hunt,
T.; Parsons, A. F.; Pratt, R. Synlett 2005, 2978. (j) Healy,
M. P.; Parsons, A. F.; Rawlinson, J. G. T. Org. Lett. 2005, 7,
1597. (k) Carta, P.; Puljic, N.; Robert, C.; Dhimane, A.-L.;
Fensterbank, L.; Lacote, E.; Malacria, M. Org. Lett. 2007, 9,
1061.
Ph
O
(EtO)2P(X)
Ph
Et
O
O
O
16
15
17 X = O
18 X = S
Figure 3
In conclusion, we have developed a concise and efficient
synthesis of 1,7-dienes of type 13a–c and shown, for the
first time, that these compounds react with (EtO)2P(S)H
and AIBN to form chromans 14a–c; the efficiency and
diastereoselectivity of the cyclisation being influenced by
the structure of the 1,7-diene. Chromans of type 14a–c
have the potential to act as useful building blocks for the
synthesis of a variety of novel bi- and tricyclic cannab-
inoid analogues of biological interest. In addition, this
work further illustrates the synthetic use of (EtO)2P(S)H
in radical cyclisations of dienes; this method of cyclisa-
tion offers an attractive alternative to traditional ap-
proaches using Bu3SnH, which are hampered by the
toxicity of the metal hydride.
(6) For complementary 6-exo-trig radical cyclisation
approaches to tetrahydropyrans, see: (a) Lee, E. Pure Appl.
Chem. 2005, 77, 2073. (b) Hiramatsu, N.; Takahashi, N.;
Noyori, R.; Mori, Y. Tetrahedron 2005, 61, 8589.
(c) Hartung, J.; Gottwald, T. Tetrahedron Lett. 2004, 45,
5619. (d) Evans, P. A.; Roseman, J. D. Tetrahedron Lett.
1997, 38, 5249. (e) Leeuwenburgh, M. A.; Litjens, R. E. J.
N.; Codée, J. D. C.; Overkleeft, H. S.; van der Marel, G. A.;
van Boom, J. H. Org. Lett. 2000, 2, 1275. (f) Burke, S. D.;
Rancourt, J. J. Am. Chem. Soc. 1991, 113, 2335.
(7) All new compounds gave consistent spectral and high
resolution mass spectroscopic data.
(8) See for example: (a) Journet, M.; Lacôte, E.; Malacria, M.
J. Chem. Soc., Chem. Commun. 1994, 461. (b) Maulide, N.;
Markov, I. E. Chem. Commun. 2006, 1200.
Acknowledgment
(9) (Z)-1-(2-Methylpent-3-en-2-yloxy)-2-vinylbenzene (13a):
yellow oil. IR (CDCl3): 3085, 3065, 2958, 2927, 1603, 1487,
1456, 1439, 1377, 1174, 1120 cm–1. 1H NMR (400 MHz,
CDCl3): d = 6.80–7.70 (m, 4 H, 4 ꢀ ArCH), 7.10 (dd, J =
17.5, 11.0 Hz, 1 H, CH=CHAHB), 5.72 (dd, J = 17.5 1.5 Hz,
1 H, CH=CHAHB), 5.64 (dq, J = 12.0, 1.5 Hz, 1 H,
We thank GlaxoSmithKline and the University of York for funding.
References and Notes
(1) (a) Fichera, M.; Cruciani, G.; Bianchi, A.; Musumarra, G.
J. Med. Chem. 2000, 43, 2300. (b) Turner, C. E.; Elsohly,
M. A.; Boeren, E. G. J. Nat. Prod. 1980, 43, 169.
CH=CHMe), 5.54 (dq, J = 12.0, 7.0 Hz, 1 H, CH=CHMe),
5.22 (dd, J = 11.0, 1.5 Hz, 1 H, CH=CHAHB), 1.70 (d, J = 7.0
Hz, 3 H, Me), 1.53 (s, 6 H, MeCMe). 13C NMR (100 MHz,
CDCl3): d = 153.5 (ArCO), 135.1, 132.0, 128.4, 127.4,
126.1, 120.7, 118.1 (4 ꢀ ArCH, CH=CHAHB, CH=CHMe),
128.6 (ArCCH=C), 113.7 (CH=CHAHB), 79.4 (MeCMe),
28.8 (MeCMe), 13.7 (CH=CHMe). MS (CI, NH3): m/z (%) =
203 (8) [MH+], 83 (100). HRMS (CI): m/z calcd for C14H19O
[M + H+]: 203.1436; found: 203.1436.
(2) See for example: (a) Keimowitz, A. R.; Martin, B. R.;
Razdan, R. K.; Crocker, P. J.; Mascarella, S. W.; Thomas, B.
F. J. Med. Chem. 2000, 43, 59. (b) Howlett, A. C.; Barth, F.;
Bonner, T. I.; Cabral, G.; Casellas, P.; Devane, W. A.;
Felder, C. C.; Herkenham, M.; Mackie, K.; Martin, B. R.;
Pertwee, R. G. Pharmacol. Rev. 2002, 54, 161. (c) Salo, O.
M. H.; Raitio, K. H.; Savinainen, J. R.; Nevalainen, T.;
Lahtela-Kakkonen, M.; Laitinen, J. T.; Järvinen, T.; Poso, A.
J. Med. Chem. 2005, 48, 7166.
(10) Synthesis of O,O-Diethyl (3-Ethyl-2,2-dimethyl-3,4-
dihydro-2H-chromen-4-yl)methylphosphonothioate
(14a): 1,7-Diene 13a (0.150 g, 0.74 mmol, 1 equiv), diethyl
Synlett 2008, No. 3, 329–332 © Thieme Stuttgart · New York

332
M. P. Healy et al.
LETTER
thiophosphite (0.114 g, 0.74 mmol, 1 equiv) and AIBN
(0.097 g, 0.59 mmol, 0.8 equiv, 1 portion) were heated to
reflux in degassed cyclohexane (20 mL) overnight. After
cooling to r.t., the solvent was evaporated and purification of
the crude product by column chromatography (silica, petrol)
afforded 14a (0.073 g, 28%) as a colourless oil, as an
inseparable 1:1 mixture of cis- and trans-diastereoisomers as
indicated by the 1H NMR spectrum. IR (CH2Cl2): 3055,
2983, 2937, 2904, 2879, 1606, 1581, 1487, 1452, 1387,
1371, 1302, 1261, 1225, 1159, 1026 cm–1. 1H NMR (400
MHz, CDCl3; both diastereoisomers): d = 7.40, 7.29 (2 ꢀ d,
2 ꢀ J = 8.0 Hz, 1 H, ArCH), 7.11, 7.09 (2 ꢀ t, 2 ꢀ J = 8.0 Hz,
1 H, ArCH), 6.98, 6.86 (2 ꢀ t, 2 ꢀ J = 8.0 Hz, 1 H, ArCH),
6.78, 6.74 (2 ꢀ d, 2 ꢀ J = 8.0 Hz, 1 H, ArCH), 3.96–4.28 (m,
4 H, 2 ꢀ OCH2Me), 3.58, 3.32 (2 ꢀ app. ddt, J = 19.0, 6.0,
5.0 Hz and J = 24.0, 5.5, 5.0 Hz, 1 H, PCHAHBCH), 2.40–
2.62, 2.27 (m and app. td, J = 16.0, 5.0 Hz, 2 H, PCHAHB),
1.19–1.83 (m, 15 H, MeCMe, CHCH2Me, 2 ꢀ OCH2Me),
1.04, 1.02 (2 ꢀ t, 2 ꢀ J = 7.5 Hz, 3 H, CHCH2Me). 13C NMR
(100 MHz, CDCl3; both diastereoisomers): d = 153.6, 152.9
(ArCO), 127.8, 127.7, 127.5, 2 ꢀ 125.7 (2 ꢀ d, 3JCP = 10.5,
7.0 Hz, PCHAHBCHArC), 120.5, 120.0, 2 ꢀ 117.3 (4 ꢀ ArCH),
78.7 (MeCMe), 62.7, 62.6, 62.3, 62.2 (4 ꢀ d, 2JCP = 4 ꢀ 7.0
Hz, 2 ꢀ OCH2Me), 48.1 (d, 3JCP = 5.5 Hz, PCHAHBCHCH),
42.3, 34.6 (2 ꢀ d, 1JCP = 109.0, 110.5 Hz, PCHAHB), 33.1,
32.0 (2 ꢀ d, 2JCP = 2.5, 1.5 Hz, PCHAHBCH), 28.7, 27.8, 26.3,
24.3 (MeCMe), 23.2, 19.5 (CHCH2Me), 3 ꢀ 16.2, 16.1 (4 ꢀ
d, 3JCP = 4 ꢀ 7.0 Hz, 2 ꢀ OCH2Me), 14.2, 13.7 (CHCH2Me).
MS (CI, NH3): m/z (%) = 357 (100) [MH+]. HRMS (CI):
m/z calcd for C18H30O3PS [M + H+]: 357.1653; found:
357.1652.
between additions) were heated to reflux in anhyd degassed
THF (20 mL) overnight. After cooling to r.t., the solvent was
evaporated and excess diethyl thiophosphite was removed
by distillation (75 °C/3 mmHg). Purification of the residue
by column chromatography (silica; PE–Et2O, 9:1) afforded
14c (0.221 g, 54%) as a yellow oil. IR (CH2Cl2): 2982, 2953,
2853, 1735, 1608, 1582, 1488, 1453, 1437, 1388, 1372,
1302, 1249, 1228, 1170, 1138, 1116, 1098, 1026 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.48 (d, J = 7.5 Hz, 1 H,
ArCH), 7.11 (t, J = 7.5 Hz, 1 H, ArCH), 6.90 (t, J = 7.5 Hz,
1 H, ArCH), 6.76 (d, J = 7.5 Hz, 1 H, ArCH), 4.06–4.28 (m,
4 H, 2 ꢀ OCH2Me), 3.70 (s, 3 H, CO2Me), 3.05–3.18 (m, 1
H, PCH2CH), 2.69 (dd, J = 16.0, 3.5 Hz, 1 H, CHAHB), 2.32–
2.55 (m, 4 H, PCH2CHCHCHAHB), 1.35 (s, 3 H, MeCMe),
1.34 (t, J = 7.0 Hz, 6 H, 2 ꢀ OCH2Me), 1.21 (s, 3 H, MeCMe).
13C NMR (100 MHz, CDCl3): d = 173.6 (CO2Me), 152.6
(ArCO), 129.3, 127.7, 120.7, 117.3 (4 ꢀ ArCH), 125.5 (d,
3JCP = 7.5 Hz, PCH2CHArC), 76.8 (MeCMe), 62.8, 62.6 (2
ꢀ d, 2JCP = 2 ꢀ 7.0 Hz, 2 ꢀ OCH2Me), 51.9 (CO2Me), 44.1 (d,
3JCP = 7.0 Hz, PCH2CHCH), 41.3 (d, 1JCP = 111.0 Hz, PCH2),
35.6 (CH2CO2), 33.6 (d, 2JCP = 1.5 Hz, PCH2CH), 27.3, 21.7
(MeCMe), 16.2, 16.1 (2 ꢀ d, 3JCP = 2 ꢀ 7.0 Hz, 2 ꢀ OCH2Me).
MS (CI, NH3): m/z (%) = 401 (100) [MH+]. HRMS (CI):
m/z calcd for C19H29O5PS [M + H+]: 401.1552; found:
401.1551.
(14) 4-(2,2-Diphenylvinyl)-3-ethyl-2,2-dimethylchromane
(15): colourless oil (6.5:1 mixture of diastereoisomers). IR
(CH2Cl2): 3019, 2958, 2931, 1598, 1581, 1484, 1451, 1386,
1302, 1148, 1030 cm–1. 1H NMR (400 MHz, CDCl3; both
diastereoisomers): d = 7.20–7.42 (m, 11 H, 11 ꢀ ArCH), 7.11
(t, J = 7.0 Hz, 1 H, ArCH), 6.85 (t, J = 7.0 Hz, 1 H, ArCH),
6.77 (d, J = 7.0 Hz, 1 H, ArCH), 6.29, 5.95 (2 ꢀ d, J = 2 ꢀ
10.5 Hz, 1 H, cis-C=CH and trans-C=CH), 3.42 (app. t, J =
10.5 Hz, 1 H, CHCH=C), 1.54 (dt, J = 10.5, 4.5 Hz, 1 H,
CHCH2Me), 0.98, 1.42 (2 ꢀ s, 2 ꢀ 3 H, MeCMe), 1.20–1.40
(m, 2 H, CH2Me), 0.80–0.92 (m, 3 H, CH2Me). 13C NMR
(100 MHz, CDCl3; both diastereoisomers): d = 153.1
(ArCO), 143.2, 142.3, 139.8 (3 ꢀ ArC), 131.1, 2 ꢀ 129.6, 2
ꢀ 128.4, 2 ꢀ 128.2, 127.8, 2 ꢀ 127.3, 2 ꢀ 127.2, 124.1, 119.7,
117.0 (14 ꢀ ArCH, C=CH), 78.0 (MeCMe), 48.9
(11) For other examples of 6-exo cyclisations of benzylic
radicals, see: (a) Studer, A. Angew Chem. Int. Ed. 2000,
1108. (b) Pattenden, G.; Reddy, L. K.; Walter, A.
Tetrahedron Lett. 2004, 45, 4027. (c) Binot, G.; Quiclet-
Sire, B.; Saleh, T.; Zard, S. Z. Synlett 2003, 382.
(12) Resonance-stabilised radicals are known to undergo
reversible cyclisations. See for example: (a) Walling, C.;
Cioffari, A. J. Am. Chem. Soc. 1972, 94, 6064. (b) Julia, M.
Acc. Chem. Res. 1971, 4, 386. (c) Julia, M. Pure Appl.
Chem. 1974, 40, 553.
(13) Synthesis of Methyl 2-{4-[(Diethoxyphosphoro-
thioyl)methyl]-2,2-dimethyl-3,4-dihydro-2H-chromen-3-
yl}acetate (14c): 1,7-Diene 13c (0.250 g, 1.02 mmol,
1 equiv), diethyl thiophosphite (0.782 g, 5.08 mmol, 5 equiv)
and AIBN (0.042 g, 0.25 mmol, 0.25 equiv, 5 portions, 1 h
(CHCH2Me), 40.1 (CHCH=C), 28.3 (MeCMe), 23.6
(CH2Me), 20.3 (MeCMe), 15.2 (CH2Me). MS (CI, NH3):
m/z (%) = 369 (45) [MH+], 357 (100). HRMS (CI): m/z calcd
for C27H28O [M + H+]: 369.2218; found: 369.2217.
(15) For a related cyclisation, see: Samarat, A.; Landais, Y.;
Amri, H. Tetrahedron Lett. 2004, 45, 2049.
Synlett 2008, No. 3, 329–332 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.