Propargylic phosphonium salts in cobalt-catalysed Diels-Alder reactions

Article abstract of DOI:10.1055/s-2006-951544

A straight forward one-pot reaction sequence consisting of a cobalt-catalysed Diels-Alder reaction for the generation of a dihydroaromatic phosphonium salt and a subsequent Wittig olefination generates polysubstituted dihydrostilbene derivatives which can

Full text of DOI:10.1055/s-2006-951544

LETTER
3247
Propargylic Phosphonium Salts in Cobalt-Catalysed Diels–Alder Reactions
Propargylic
Phosp
e
honiumSal
r
ts in Cob
h
alt-Catalyse
a
d Diels–Ald
r
er Rea
c
d
tions Hilt,* Christoph Hengst
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: Hilt@chemie.uni-marburg.de
Received 5 September 2006
nium salt such as 1 generates a dihydroaromatic allylic
phosphonium salt intermediate 2 prone for further modifi-
cations such as an in situ Wittig olefination (Scheme 2).
Abstract: A straight forward one-pot reaction sequence consisting
of a cobalt-catalysed Diels–Alder reaction for the generation of a di-
hydroaromatic phosphonium salt and a subsequent Wittig olefina-
tion generates polysubstituted dihydrostilbene derivatives which
can optionally be oxidised by DDQ to the corresponding stilbenes.
Several aldehydes, 1,3-dienes and also homopropargylic phospho-
nium salts can be applied.
The isolation of the phosphonium salt 2 was attempted;
however, because of the other inorganic ingredients in the
reaction mixture, 2 could not be obtained in pure form. In
addition, a control of the conversion by means of 31P
NMR directly from the reaction mixture was not applica-
ble because of paramagnetic cobalt catalyst components.
The addition of a base and an aldehyde (3) then converted
the phosphonium salt 2 in a Wittig olefination and subse-
quent oxidation with 2,3-dichloro-5,6-dicyano-1,4-quino-
ne (DDQ) into an organic product 4 which could then be
detected and isolated in the conventional manner. There-
fore, we determined the optimal time for the cobalt-catal-
ysed reaction before starting the Wittig olefination
reaction. Accordingly, the best results for this protocol
were obtained when the cobalt-catalysed Diels–Alder re-
action was stirred for 30 minutes at room temperature af-
ter the characteristic colour change towards a deep brown
colour.
Key words: catalysis, cobalt, 1,4-diene, stilbene, Wittig olefination
The Diels–Alder reaction of non-activated 1,3-dienes and
dienophiles is a well-established process if transition-met-
al catalysts are employed.1 The transition-metal catalysts
can either be added in their active forms or have to be ac-
tivated in situ. In both cases, the catalysts should react un-
der mild conditions and tolerate various functional
groups, and exclude harsh activating conditions or re-
agents.
The generation of functionalised dihydroaromatic com-
pounds by means of a cobalt-catalysed Diels–Alder reac-
tion of non-activated 1,3-dienes and dienophiles has long
been a focus of our research. Under these circumstances,
we were able to report a rather simple cobalt-catalyst sys-
tem, which is capable to convert various functionalised
building blocks containing boron-, silicon-, nitrogen-, ox-
ygen- or sulfur-functionalised 1,3-dienes or alkynes.2
1. KOt-Bu
RCHO (3)
R
BrPh3P
2. DDQ
2
4
In an attempt to include phosphorus containing starting
materials into the arsenal of building blocks suitable for a
cobalt-catalysed Diels–Alder reaction we report herein
the first use of propargylic phosphonium salts in such re-
actions (Scheme 1).
Scheme 2
The reaction conditions for the cobalt-catalysed Diels–Al-
der reactions are very mild since the cobalt precatalyst
(10–20 mol%) is stirred with 1.5–2.0 equivalents of dry
zinc iodide and 40–60 mol% zinc dust at ambient temper-
ature in dichloromethane. The amount of zinc iodide had
to be increased compared to previous cobalt-catalysed
Diels–Alder reactions because the bromide of the phos-
phonium salt retards the reactivity of the cobalt catalyst
and has to be quenched by stoichiometric amounts of a
Lewis acid.4
CoBr2(dppe)
Zn, ZnI2
BrPh3P
+
BrPh3P
1
2
Scheme 1
The use of phosphorus-containing compounds like a pro-
pargylic phosphonium salt seems to be of much higher
synthetic value in terms of possible follow-up chemistry
as the use of alkynyl phosphines.3 The envisaged cobalt-
catalysed Diels–Alder reaction of a propargylic phospho-
To determine the E/Z ratios of the in situ Wittig reactions,
the Diels–Alder cyclisations were firstly conducted with
the symmetrical 2,3-dimethyl-1,3-butadiene. Later, the
unsymmetrical dienes isoprene and 2-methoxy-1,3-buta-
diene (entries 7, 8) were also used. In these latter cases be-
sides the E/Z isomers, regioisomeric products from the
cycloaddition process were also encountered. The separa-
tion and isolation of these regioisomers in pure form were
not possible for most cases.5 Therefore, the overall yields
SYNLETT 2006, No. 19, pp 3247–3250
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951544; Art ID: G25006ST
© Georg Thieme Verlag Stuttgart · New York

3248
G. Hilt, C. Hengst
LETTER
Table 1 Results of the Cobalt-Catalysed Diels–Alder–Wittig Olefi-
nation–DDQ Oxidation Reaction Sequence (continued)
for the regio- and stereoisomers are given. The ratios were
determined by integration of 1H NMR signals and by GC
analysis.
Entry Product (4)
E/Z
Yield (%)b
64
(1,3- vs. 1,4-)a
The Wittig-type reaction with aromatic aldehydes led to
dihydroaromatic stilbenes, whereas the reaction with an
aliphatic aldehyde led to a dihydroaromatic styrene prod-
uct. The aldehyde was added in one portion and, after one
hour stirring at ambient temperature, the dihydroaromatic
products could be detected by GC-MS analysis.
9
1.0:1.0
1.0:2.5
4i
10
44
Table 1 Results of the Cobalt-Catalysed Diels–Alder–Wittig Olefi-
nation–DDQ Oxidation Reaction Sequence
Entry Product (4)
E/Z
Yield (%)b
94
(1,3- vs. 1,4-)a
4j
1
1.1:1.0
2.2:1.0
a Ratio of Diels–Alder regioisomers determined from 1H NMR inte-
gration.
b Combined yield of stereo- and regioisomers.
4a
The dihydroaromatic compounds can be isolated follow-
ing the regular work-up protocol for dihydroaromatic
products but were preferably further oxidised by DDQ in
benzene solution to generate the corresponding aromatic
products 4. The results of the cobalt-catalysed Diels–Al-
der–Wittig olefination–DDQ oxidation sequence are sum-
marised in Table 1.6 In general, the conversions of the
proposed intermediate 2 with electron-deficient as well as
electron-rich aromatic aldehydes 3 led to the desired prod-
ucts 4 in acceptable to excellent overall yields of up to
94% after three chemical transformations. The E/Z ratios
observed in reactions with aromatic aldehydes slightly
favour the E-configuration of the newly generated double
bond. Therefore, the reactivity of dihydroaromatic phos-
phorus ylides seems to be in between the class of semi-
stabilised and stabilised ylides, judged from the observed
E/Z stereoselectivities.7
2
64
85
F3C
4b
3
1.5:1.0
O2N
4c
Br
4
5
6
7
8
1.9:1.0
1.7:1.0
1.4:1.0
66
84
63
68
57
4d
Of particular interest were mono- and higher-methoxylat-
ed benzaldehyde derivatives (entries 5–7) which led to in-
teresting products.8 The methoxy functionality can
alternatively be introduced by the 1,3-diene building
block (entry 8) which has a methoxy substituent in the 2-
position. When the unsymmetrical 2-methoxy-1,3-butadi-
ene is used also regioisomeric cycloadducts are observed.
For the present examples the regioisomer with the 1,4-re-
lation of the two substituents is preferred. As was illustrat-
ed earlier, the methoxy functionality can also be located in
the 1-position of the 1,3-diene. In these cases an elimina-
tion of methanol occurs under the reaction conditions and
the corresponding benzene derivative is formed removing
the functionality from the product.2f If cinnamic aldehyde
is used in the reaction sequence, a diaryl 1,3-butadiene
product (4i) can be accessed.
MeO
4e
MeO
MeO
4f
1.8:1.0
(1.0:2.8)
MeO
4g
1.2:1.0
(1.0:4.8)
On the other side, the application of aliphatic aldehydes
gave only relatively poor results for pivalyl aldehyde (en-
try 10). Whereas, notable seems the preferred Z-config-
ured product 4j for the sterically bulky pivalyl aldehyde.
Cl
OMe
4h
Synlett 2006, No. 19, 3247–3250 © Thieme Stuttgart · New York

LETTER
Propargylic Phosphonium Salts in Cobalt-Catalysed Diels–Alder Reactions
3249
Soc. 1995, 117, 1843. (h) Brunner, H.; Reimer, A. Bull.
Chem. Soc. Fr. 1997, 134, 307. (i) Lautens, M.; Tam, W.;
Lautens, J. C.; Edwards, L. G.; Crudden, C. M.; Smith, A. C.
J. Am. Chem. Soc. 1995, 117, 6863.
On the other hand a 1,3-diaryl substituted propene deriv-
ative 8 was generated from the homopropargylic phos-
phonium tosylate 5 via intermediate 6 (Scheme 3).
(2) For cobalt-catalysed Diels–Alder reactions with
functionalised building blocks, see: (a) Hilt, G.; Hess, W.;
Harms, K. Org. Lett. 2006, 8, 3287. (b) Hilt, G.; Lüers, S.;
Smolko, K. I. Org. Lett. 2005, 7, 251. (c) Hilt, G.; Galbiati,
F. Synlett 2005, 829. (d) Hilt, G.; Lüers, S.; Harms, K. J.
Org. Chem. 2004, 69, 624. (e) Hilt, G.; Smolko, K. I.
Angew. Chem. Int. Ed. 2003, 42, 2795; Angew. Chem. 2003,
115, 2901. (f) Hilt, G.; Smolko, K. I.; Lotsch, B. V. Synlett
2002, 1081.
(3) The alkynyl phosphine derivatives seem to coordinate to the
cobalt catalyst via the phosphorus functionality, blocking the
free coordination sites necessary for the Diels–Alder
reaction. Higher catalyst loading did not restore the
reactivity, as it did in the case of alkynyl sulfide derivatives
(ref. 2d).
CoBr2(dppe)
Zn, ZnI2
TsOPh3P
+
KOt-Bu
4-MeOC6H4CHO
6
7
8
65%
5
PPh3OTs
MeO
MeO
TCNE 64%
(4) The reduction of the amount of zinc iodide reduced the
reactivity of the catalyst system considerably. The yields of
dihydroaromatic intermediates or the final products 4 were
not diminished by the considerable amount of inorganic
components.
Scheme 3
The Diels–Alder–Wittig olefination sequence gave a rea-
sonable amount of crude material 7 before DDQ oxidation
(up to 65% yield). The oxidation process of 7 to form the
aromatic product 8 revealed to be quite problematic re-
sulting in polymerisation or many unidentified decompo-
sition products. Therefore, an alternative and even milder
oxidation methodology was applied to dehydrogenate the
intermediate 7 and not initiate a decomposition process.
For this purpose, TCNE (tetracyanoethylene) in dioxane
was employed for the oxidation process. The desired aro-
matic product 8 was consequently isolated in 64% yield
(E:Z = 1.0:1.2) starting from the crude dihydroaromatic
material 7. Because 7 does not obtain a 1,3-diene subunit
such as the intermediates derived from propargylic phos-
phonium salts, a thermal Diels–Alder reaction does not
occur.9
(5) The separation of the E/Z stereoisomers is possible after
column chromatography.
(6) General Procedure.
Under an argon atmosphere, ZnI2 (319 mg, 1.0 mmol, 2.0
equiv), zinc dust (20 mg, 0.3 mmol, 60 mol%) and CoBr2
(dppe) (62 mg, 0.1 mmol, 20 mol%) were suspended in dry
CH2Cl2 (10 mL). After formation of the active catalytic
species, recognisable when the green suspension turned deep
brown, prop-2-ynyl(triphenyl)phosphoniumbromide(1, 191
mg, 0.5 mmol, 1.0 equiv) and 2,3-dimethyl-1,3-butadiene
(0.75 mmol, 62 mg, 85 mL, 1.5 equiv) were added. The
resulting mixture was stirred at r.t. for 30 min. After cooling
the solution down in an ice bath, t-BuOK (281 mg, 2.5
mmol, 5.0 equiv) and 4-nitrobenzaldehyde (91 mg, 0.6
mmol, 1.2 equiv) were added at 0 °C. After the addition was
completed, the reaction mixture was stirred one additional
hour at ambient temperature and then filtered over a short
pad of silica gel (eluent: pentane–MTBE, 1:1). The filtrate
was concentrated under reduced pressure to give an oily
residue that was dissolved in benzene (10 mL) and oxidised
with DDQ (170 mg, 0.75 mmol, 1.5 equiv) at r.t. After 2 h
the reaction mixture was washed twice with aq basic
thiosulfate solution (10% NaOH, 10% Na2S2O3, 2 × 10 mL).
The aqueous phases were combined, extracted with MTBE
(20 mL) and the combined organic phases were dried over
MgSO4. After evaporating the solvent under reduced
pressure, the crude product was purified by column
chromatography on silica gel (eluent: pentane–MTBE,
100:1) to give 108 mg (85%) of 4e as a yellow solid.
E-isomer: 1H NMR (500 MHz, CDCl3): d = 8.20 (d, 2 H,
J = 8.8 Hz), 7.60 (d, 2 H, J = 8.8 Hz), 7.33 (s, 1 H), 7.29 (d,
1 H, J = 7.8 Hz), 7.22 (d, 1 H, J = 16.3 Hz), 7.16 (d, 1 H,
J = 7.8 Hz), 7.08 (d, 1 H, J = 16.3 Hz), 2.31 (s, 3 H), 2.30 (s,
3 H). 13C NMR (125 MHz, CDCl3): d = 146.5, 144.2, 137.8,
137.0, 133.8, 133.4, 130.1, 128.2, 126.6, 125.1, 124.6,
124.1, 19.8, 19.6.
The first successful use of propargylic phosphonium salts
in cobalt-catalysed Diels–Alder reactions broadens the
usefulness of such cycloaddition reactions so that a strong
increase in complexity starting from simple, mostly com-
mercially available, educts can be realised. Therefore, the
presented protocol provides a variable three-component
access towards unsymmetrical polysubstituted dihydro-
stilbene derivatives, which can be easily oxidised by DDQ
to the corresponding stilbenes.
References and Notes
(1) For selected examples of transition-metal-catalysed [4+2]
cycloadditions, see: (a) Lautens, M.; Klute, W.; Tam, W.
Chem. Rev. 1996, 96, 49. (b) tom Dieck, H.; Diercks, R.
Angew. Chem., Int. Ed. Engl. 1983, 22, 778; Angew. Chem.
1983, 95, 801. (c) Bakhtiar, R.; Drader, J. J.; Jacobsen, D. B.
J. Am. Chem. Soc. 1992, 114, 8304. (d) Wender, P. A.;
Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432.
Z-isomer: 1H NMR (500 MHz, CDCl3): d = 8.07 (d, 2 H,
J = 8.7 Hz), 7.40 (d, 2 H, J = 8.7 Hz), 7.01 (s, 1 H), 7.01 (d,
1 H, J = 7.0 Hz), 6.94 (d, 1 H, J = 7.8 Hz), 6.76 (d, 1 H,
J = 12.2 Hz), 6.54 (d, 1 H, J = 12.2 Hz), 2.26 (s, 3 H), 2.20
(s, 3 H). 13C NMR (125 MHz, CDCl3): d = 146.3, 144.5,
136.7, 136.5, 134.0, 133.5, 130.0, 129.7, 129.5, 127.0,
126.1, 123.4, 19.5, 19.5. IR (KBr): 3070, 2972, 1590, 1514,
(e) Wender, P. A.; Smith, T. E. J. Org. Chem. 1995, 60,
2962. (f) Jolly, R. S.; Luedtke, G.; Sheehan, D.;
Livinghouse, T. J. Am. Chem. Soc. 1990, 112, 4965.
(g) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem.
Synlett 2006, No. 19, 3247–3250 © Thieme Stuttgart · New York

3250
G. Hilt, C. Hengst
LETTER
(7) For recent examples of Wittig reactions with allylic-type
1452, 1344, 1183, 1109, 972, 866, 834, 814, 750, 710, 690
cm–1. MS (EI): m/z = 253 [M+], 223, 207, 192, 178, 165, 91.
HRMS (EI): m/z calcd for C16H15NO2: 253.1103; found:
253.1106.
phosphonium salts, see: (a) Ackermann, M.; Berger, S.
Tetrahedron 2005, 61, 6764. (b) Otero, M. P.; Torrado, A.;
Pazos, Y. J. Org. Chem. 2002, 67, 5876. (c) Qing, F.-L.;
Yue, X.-J. Chin. J. Chem. 2000, 18, 76. (d) Qing, F.-L.;
Yue, X.-J. Tetrahedron Lett. 1997, 38, 8067.
(8) Investigations towards the synthesis of combretastatin
derivatives are underway.
(9) Hilt, G.; Lüers, S.; Polborn, K. Isr. J. Chem. 2001, 41, 317.
Synlett 2006, No. 19, 3247–3250 © Thieme Stuttgart · New York