Synthesis of chiral 3-substituted phthalides via rhodium(I)-catalyzed crossed alkyne cyclotrimerisation

Article abstract of DOI:10.1055/s-2002-34883

3-Substituted phthalides were synthesized for the first time by crossed alkyne cyclotrimerisations with Wilkinson's catalyst. Esterification of propiolic acids with chiral propargylic alcohols by either the DCC/DMAP or the Mitsunobu method allows the synt

Full text of DOI:10.1055/s-2002-34883

LETTER
1855
Synthesis of Chiral 3-Substituted Phthalides via Rhodium(I)-catalyzed
Crossed Alkyne Cyclotrimerisation
S
ynthesis of Chir
e
al 3-Substit
r
ute
d
Pht
n
halides hard Witulski,* Axel Zimmermann
Fachbereich Chemie, Universität Kaiserslautern, Erwin-Schrödinger-Straße, 67663 Kaiserslautern, Germany
Fax +49(631)2053921; E-mail: witulski@rhrk.uni-kl.de
Received 23 July 2002
Herein we describe a flexible and efficient method for the
assembly of substituted phathlides 4 that is based on two
complementary ways for the formation of diyne esters 3
and their use in crossed alkyne cyclotrimerisations with
Abstract: 3-Substituted phthalides were synthesized for the first
time by crossed alkyne cyclotrimerisations with Wilkinson’s cata-
lyst. Esterification of propiolic acids with chiral propargylic alco-
hols by either the DCC/DMAP or the Mitsunobu method allows the
synthesis of either enantiomeric form of diyne esters, that are used acetylene applying Wilkinson’s catalyst [RhCl(PPh3)3]
in crossed alkyne cyclotrimerisations with acetylene to provide 3-
substituted phthalides in both enantiomeric forms.
(Scheme 1).
Since the pioneering work of Müller11 and Grigg12 in uti-
Key words: phthalides, alkyne cyclotrimerisation, Wilkinson’s
lizing [RhCl(PPh3)3] for alkyne cyclotrimerisations, this
catalyst, propargylic alcohols, (S)-3-n-butylphthalide
protocol has been subsequently explored by others.13
Crossed alkyne cyclotrimerisations with Wilkinson’s cat-
alyst serve well for the synthesis of indanes,12 dihy-
Considerable interest is devoted to the synthesis of 3-sub-
droisobenzofuranes,12 isoindolines,12,13d indolines,13d and
stituted phthalides [1(3H)-isobenzofuranones] compris-
carbazoles.13g However, the applicability of electron defi-
cient diynes in a truly catalytic version of this method for
the synthesis of phthalides has not been reported so far.
ing a large and diverse group of naturally occurring and
biological active compounds.1 For example, (S)-3-n-
butylphthalide2 is a constituent of the Chinese medical
Propiolic acids 1 and propargylic alcohols 2 are readily
accessible substrates,14 and furthermore several methods
for the preparation of optically active propargylic alcohols
by asymmetric protocols are available.15 We therefore
thought that a strategy as outlined in Scheme 1 should not
only serve for the synthesis of optically active 3-substi-
tuted phthalides but also allow their assembly with a high
degree of structural diversity.
plant Dong Quai and of celery seed oil3 and other 3-alkyl-
phthalides form parts of several alkaloids with pharma-
ceutical relevance, such as noscapin, bicucullin and
hydrastin.4 Furthermore, phthalides bearing an aryl sub-
stituent at the 3-position are used as key intermediates for
the synthesis of tri- and tetracyclic aromatic natural prod-
ucts, such as the anthracycline antibiotics.5 Although a va-
riety of methods for the preparation of phthalides has been
reported6 there are only a few reports on their synthesis by
catalytic means.7 Many of these start from already func-
tionalised aromatic rings and focus on the formation of the
δ-lactone moiety, whereas strategies relying on the con-
struction of the aromatic core are rare.8–10 For instance,
phthalides obtained from transition metal promoted
alkyne cyclotrimerisations have so far only been reported
for a few simple cases using either a nickel(0) catalyst9 or
stoichiometric amounts of nickel(0) complexes.10
At the outset of our studies we investigated the DMAP-
catalyzed (5 mol%) ester formation between propiolic
acids 1 and propargylic alcohols 2 in the presence of dicy-
clohexyl carbodiimide (DCC).16 Optimal yields of diyne
esters 3 were obtained when a twofold excess of either 1
or 2 was used. The reactions were carried out in CH2Cl2 at
–78 °C and then brought to room temperature over a peri-
od of several hours (8–10 h). The products 3a–i could be
purified by column chromatography on silica gel using
hexanes/diethyl ether and were obtained in yields ranging
from 42–84% (Method A, Table 1).17
O
R1
R1
O
O
Method A: DCC / DMAP
OH
R1
R2
H
H
1
retention
O
O
+
Method B: DEAD / PPh3
5 mol% [RhCl(PPh3)3]
toluene, r.t. or 40 °C
OH
*
R3
*
R3
inversion
R2
3
R2
*
R3
2
4
Scheme 1 Synthesis of substituted phthalides 4 via crossed alkyne cyclotrimerisations with Wilkinson’s catalyst
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1855,1859,ftx,en;G20402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1856
B. Witulski, A. Zimmermann
LETTER
Table 1 Formation of Diyne Esters 3 via Method A (DCC/DMAP) and Method B (Mitsunobu Reaction)17
Entry
1
1
R1
H
2
R2
R3
H
3
Method
Yield (%)a
1a
2a
3a
A
B
84
81
N
Ts
2
3
4
1b
1a
1a
2b
2c
2d
H
H
H
H
3b
3c
3d
A
B
83
89
H
H
A
B
60
65
Br
O
A
B
60
65
O
5
1a
1a
H
H
2e
2f
H
H
3e
A
B
60
75
6b
3f
A
B
56
18
7
8
1a
1a
H
H
(S)-2g
(S)-2h
H
H
(S)-3g
A
59
CH3
CH3
(S)-3h
(R)-3h
A
B
42
46
9
1b
(S)-2h
H
(S)-3i
(R)-3i
A
B
79
71
a Isolated yields after column chromatography on silica gel.
b A 1:1 mixture of E/Z-isomers of the propargylic alcohol 2f was used.
Alternatively, 1 and 2 were coupled to form esters 3 by the tion. Following this protocol the optically active
Mitsunobu reaction (Method B, Table 1). Addition of phthalides 4f–h were obtained in good yields without any
PPh3 (2.8 mmol) to a THF solution containing alcohol 2 detectable racemisation (Table 2, entries 6–10). For ex-
(1.4 mmol), propiolic acid 1 (2.1 mmol) and DEAD (2.8 ample, the valuable natural product (S)-3-n-butylphtha-
mmol) at room temperature gave 3a–i in yields of the lide [(S)-4f, Table 2, entry 6] was obtained in 79% yield
same order of magnitude as method A, with the exception (88% ee) after cyclotrimerisation of (S)-3g (88% ee)14
of allylic alcohol 2f (entry 6). Since ester formations un- with acetylene at room temperature. Furthermore, both
der DCC conditions proceeded with complete retention, enantiomeric forms of 4g were obtained with better than
and those by the Mitsunobu reaction with complete inver- 94% ee (68% yield) starting either from (S)-3h or (R)-3h,
sion,18 both methods complemented each other perfectly whereas the latter was obtained by esterification with
allowing the synthesis of either enantiomer of the esters complete inversion of the configuration of (S)-2h (94%
3h or 3i starting from (S)-2h.19
ee) after the Mitsunobu reaction.
Gratifyingly, the electron deficient diyne esters 3a–i un- Finally, we investigated the chemoselective outcome of
derwent crossed alkyne cyclotrimerisations with acety- the reaction of triyne 3e with acetylene in the presence of
lene efficiently to give the substituted phthalides 4 in good 10 mol% of Wilkinson’s catalyst at room temperature
to excellent yields (Table 2).20 Best results were obtained (Scheme 2). Products 5a and 5b were obtained in 54%
when the reactions were carried out in toluene (0.03 M so- yield and the observed product ratio (5a:5b = 6:1) indi-
lution of 3) under 1 atm of acetylene and in the presence cates that crossed alkyne cyclotrimerisations preferential-
of 5 mol% Wilkinson’s catalyst. Crossed alkyne cyclotri- ly involve terminal alkyne moieties.
merisations with the terminal diynes 3c–h and acetylene
(1 atm) proceeded readily at room temperature, whereas
the monosubstituted diyne esters 3a, 3b and 3i needed
smooth heating to 40 °C for completion of the reaction.
In conclusion, crossed alkyne cyclotrimerisations with the
electron deficient diyne esters 3 mediated by Wilkinson’s
catalyst offer a flexible and efficient access to chiral 3-
substituted phthalides. The diyne esters themselves are
All reactions showed good chemoselectivity with no readily available by either esterification following the
homo cyclotrimerisation of 3. It is noteworthy to mention, Mitsunobu or the DCC/DMAP protocol allowing the syn-
that neither an arylbromide (entry 3) nor an olefin func- thesis of 3-substituted phthalides in either enantiomeric
tionality (entry 5) disturbed the overall efficiency of the form starting from one configuration of the same chiral
catalytic process. The method served well for the synthe- propargylic alcohol. Further investigations towards the
sis of phthalides having an aryl substituent at the 3-posi- extension of this methodology to the synthesis of natural
Synlett 2002, No. 11, 1855–1859 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Chiral 3-Substituted Phthalides
1857
Table 2 Crossed Alkyne Cyclotrimerisations of Diynes 3 with
Acetylene (1 atm) in Toluene Catalyzed by 5 mol% [RhCl(PPh3)3] to
Give Substituted Phthalides 420 (continued)
products and drug related targets as well as applications of
this strategy to other heterocycles are underway in our
laboratories.
Entry
Diyne 3
T (°C)a
Phthalide 4
Yield
(%)b
Table 2 Crossed Alkyne Cyclotrimerisations of Diynes 3 with
Acetylene (1 atm) in Toluene Catalyzed by 5 mol% [RhCl(PPh3)3] to
Give Substituted Phthalides 420
O
O
O
Entry
Diyne 3
T (°C)a
Phthalide 4
Yield
(%)b
O
H
CH3
H
CH3
O
O
7
8
(S)-3h
(R)-3h
20
20
(S)-4g
68
68
O
O
(R)-4g
TsN
O
NTs
O
O
1
3a
40
4a
51
CH3
H
O
O
CH3
H
O
O
O
9
(R)-3i
(S)-3i
40
40
(R)-4h
(S)-4h
89
88
10
2
3b
3c
3d
40
4b
86
a Reaction times were not optimized and vary between 2–15 h.
b Isolated yields after column chromatography on silica gel.
O
O
O
O
O
O
O
H
H
1 atm
O
O
+
O
10 mol% Rh-cat.
toluene, r.t. (54%)
(6 : 1)
Ph
Br
Br
Ph
Ph
3
20
4c
98
3e
5a
5b
O
O
Scheme 2 Selectivity of the crossed alkyne cyclotrimerisations of
3e with acetylene
O
O
Acknowledgement
Financial support of this work by the Fonds der Chemischen Indu-
strie is gratefully acknowledged.
O
O
O
O
4
20
4d
86
References
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3f
20
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79
79
O
O
O
O
H
H
(S)-3g
(S)-4f
Synlett 2002, No. 11, 1855–1859 ISSN 0936-5214 © Thieme Stuttgart · New York

1858
B. Witulski, A. Zimmermann
LETTER
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(15) For recent achievements in the synthesis of optical active
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(b) Alexakis, A.; Sedrani, R.; Normant, J. F.; Mangeney, P.
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Nakano, H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.;
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Hashimoto, N.; Araki, S.; Butsugan, Y. J. Org. Chem. 1992,
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Another example: Olivero, A. G.; Weidmann, B.; Seebach,
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Tetrahedron 1988, 44, 7309. (b) Maier, S.; Kazmaier, U.
Eur. J. Org. Chem. 2000, 1241.
(17) Selected data for diyne esters 3:
3a: Mp: 101–103 °C. 1H NMR (400 MHz, CDCl3):
= 7.99–7.94 (m, 1 H), 7.79–7.74 (m, 3 H), 7.64–7.59 (m, 1
H), 7.40–7.20 (m, 4 H), 5.06 (s, 2 H), 2.97 (s, 1 H), 2.33 (s,
3 H). 13C NMR (100 MHz, CDCl3): = 151.9, 145.4, 134.7,
134.0, 130.5, 130.0, 129.9, 126.9, 125.5, 123.8, 120.4,
113.5, 103.7, 85.9, 78.9, 75.9, 73.9, 54.4, 21.5. MS (EI):
m/z (%) = 377 (100) [M+]. Anal. Calcd for C21H15NO4S: C,
66.83; H, 4.01; N, 3.71. Found: C, 66.99; H, 3.99; N, 3.60.
(S)-3g: 1H NMR (400 MHz, CDCl3): = 5.40 (dt, J = 6.7
Hz, J = 2.2 Hz, 1 H), 2.93 (s, 1 H), 2.52 (d, J = 2.2 Hz, 1 H),
1.87–1.81 (m, 2 H), 1.49–1.26 (m, 4 H), 0.93 (t, J = 7.2 Hz,
3 H). 13C NMR (100 MHz, CDCl3) = 151.6, 80.0, 75.4,
74.6, 74.3, 65.9, 34.1, 26.9, 22.1, 13.8. MS (EI): m/z (%) =
164 (8) [M+].
(S)-3i: Mp: 59–61 °C. 1H NMR (400 MHz, CDCl3):
= 7.61–7.58 (m, 2 H), 7.48–7.43 (m, 1 H), 7.40–7. 35 (m,
2 H), 5.56 (dq, J = 6.6, J = 2.2 Hz, 1 H), 2.53 (d, J = 2.2 Hz,
1 H), 1.60 (d, J = 6.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
= 152.8, 133.0, 130.8, 128.6, 119.4, 87.1, 81.2, 80.2, 73.8,
61.7, 21.1. MS (EI): m/z (%) = 198(7) [M+]. Anal. Calcd for
C13H10O2: C, 78.77; H, 5.09. Found: C, 78.82; H, 4.98.
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1981, 1.
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(7) BINAP-Ru(II) hydrogenation: (a) Kitamura, M.; Ohkuma,
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(19) The enantiopurity of the esters 3g–i was analyzed after their
conversion to the phthalides 4f–h, that proceeded without
any detectable racemisation.
(20) Selected data for phthalides 4:
(S)-4f: Oil; [ ]D22 = –42 (c 0.45, CHCl3); 88% ee as
Synlett 2002, No. 11, 1855–1859 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
determined by chiral capillary GLC analysis with Supleco
Synthesis of Chiral 3-Substituted Phthalides
1859
Beta-Dex 325. (R)-4g: [ ]D22 = +21.4 (c 0.81, MeOH);
94% ee as determined by chiral capillary GLC analysis with
Supleco Beta-Dex 325.
Beta-Dex 325; {lit.6l [ ]D22 –62 (c 0.42, CHCl3)}. 1H
NMR (400 MHz, CDCl3): = 7.89 (d, J = 7.6 Hz, 1 H), 7.67
(dt, J = 7.6 Hz, J = 3.3 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H),
7.46 (d, J = 7.6 Hz, 1 H), 5.49 (dd, J = 7.9 Hz, J = 4.1 Hz, 1
H), 2.10–2.01 (m, 1 H), 1.81–1.71 (m, 1 H), 1.53–1.33 (m, 4
H), 0.88 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
= 170.5, 150.0, 133.8, 128.9, 126.0, 125.5, 121.7, 81.3,
34.3, 26.7, 22.3, 13.7. MS (EI): m/z (%) = 190(5) [M+].
(S)-4g: oil; [ ]D22 = –22.1 (c 0.83, MeOH); 94% ee as
determined by chiral capillary GLC analysis with Supleco
(S)-4h: [ ]D22 = –15.6 (c 0.94, CHCl3). (R)-4h:
[ ]D22 = +14.9 (c 0.98, CHCl3).1H NMR (400 MHz, CDCl3):
= 7.71 (t, J = 7.6 Hz, 1 H), 7.58–7. 55 (m, 2 H), 7.50–7.41
(m, 5 H), 5.56 (q, J = 6.6 Hz, 1 H), 1.69 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): = 169.1, 152.5, 142.7,
136.4, 133.8, 130.8, 129.5, 128.3, 127.9, 121.8, 120.3, 76.1,
20.6. MS (EI): m/z (%) = 224(100) [M+].
Synlett 2002, No. 11, 1855–1859 ISSN 0936-5214 © Thieme Stuttgart · New York