Sequences of yne-ene cross metathesis and Diels-Alder cycloaddition reactions - Modular solid phase synthesis of substituted octahydrobenzazepinones

Article abstract of DOI:10.1055/s-1999-2961

Reaction sequences involving yne-ene cross metathesis and Diels-Alder cycloaddition reactions in solution and on solid support provide rapid access to cyclic cores incorporating variable side chains. A combinatorial approach to substituted octahydrobenzo[

Full text of DOI:10.1055/s-1999-2961

LETTER
1879
Sequences of Yne-Ene Cross Metathesis and Diels-Alder Cycloaddition
Reactions – Modular Solid Phase Synthesis of Substituted
Octahydrobenzazepinones
Stephan C. Schürer, Siegfried Blechert*
Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 135, D-10623 Berlin, Germany
Fax+4930/31423619; E-mail: sibl@wap0105.chem.tu-berlin.de
Received 22 July 1999
type 4 or 5 (Scheme 1). We intended to establish general
reaction conditions that could also be adopted on solid
support. MeAlCl2 catalyzes the Diels-Alder transforma-
tion of several dienes 3 at –50 °C in CH2Cl2/toluene. This
Abstract: Reaction sequences involving yne-ene cross metathesis
and Diels-Alder cycloaddition reactions in solution and on solid
support provide rapid access to cyclic cores incorporating variable
side chains. A combinatorial approach to substituted octahydroben-
zo[c]azepin-3-ones has been developed applying this chemistry in provides a sequence of two mild reactions compatible
connection with a cyclization/cleavage strategy that gives rise to
products of high purity.
with a variety of functionalities that can be introduced in
a very efficient way and with high yields (Table 1). Prod-
Key words: yne-ene metathesis, 1,3-dienes, Diels-Alder reactions,
cyclization/cleavage, combinatorial chemistry
ucts 4a - 4c and 5a - 5c were obtained as diastereomeric
mixtures due to the formation of E/Z isomers of diene 3 in
the yne-ene metathesis, a known problem of all CMR that
has not been solved yet. The Diels-Alder reaction itself
proceeds with excellent regioselectivity.
Olefin metathesis has gained increased importance in or-
ganic synthesis during recent years.1 The potential of ring
closing metathesis (RCM)1b has now fully been recog-
nized but only few reports on efficient metathetical cross
coupling reactions of terminal olefins have been given to
date. Whereas each crossed metathesis reaction (CMR) of
two different terminal alkenes potentially suffers from the
formation of homodimeric by-products, a cross-coupling
reaction of a terminal alkyne 1 with a terminal alkene 2
proceeds remarkably selectively in the presence of
Grubbs’ ruthenium initiator Cl2(PCy3)2Ru = CHPh (Ru,
Cy = cyclohexyl) (Scheme 1).2 This yne-ene CMR show-
ing atom economy provides efficient access to 1,3-disub-
stituted butadienes 3 which represent attractive starting
materials for subsequent Diels-Alder transformations. A
sequence of yne-ene CMR and Diels-Alder reaction thus
represents a powerful method for the modular construc-
tion of carbo- and heterocycles. We were particularly in-
terested in the application of this concept to solid phase
synthesis as there has been considerable demand for new
synthetic methodology on solid phase due to the rapid de-
velopment of combinatorial chemistry during the last
years.3
Ru in schemes 1 - 4 means Cl2(PCy3)2Ru=CHPh
R1
R1
R1
O
ii or
iii
R2 R3
R1
4 R3 = H
5 R3 = Me
1
i
+
iv
R2
R2
2
CO2Me
3
6
CO2Me
R2
i: 5.0-7.5 % Ru, CH2Cl2; ii: HCOCH=CH2, MeAlCl2, CH2Cl2 / tolue-
ne, -50°C; iii: MeCOCH=CH2, MeAlCl2, CH2Cl2 / toluene, -50°C; vi:
MeO2C-C∫C-CO2Me, toluene, 140°C (sealed vial)
Scheme 1
Generally, nonactivated 1,3-dienes are regarded as poor
substrates in Diels-Alder reactions.4 However, 1,3-dienes
undergo Lewis acid catalyzed reactions employing a,b-
unsaturated reactive carbonyl compounds as dienophiles.5
Recently we also reported on aza-Diels-Alder reactions
under high pressure involving yne-ene CMR products.6
To the best of our knowledge, none of these transforma-
tions involving support-bound 1,3-dienes have been de-
scribed.
Table 1 Results of yne-ene metathesis and Diels-Alder reactions.
yielda
of 3
yieldc
of 5
yieldb
of 4
yieldd
of 6
R2
R1
entry
a
-
CH2CH2OBn
CH2OAc
OBn
Ph
83
80
70
71
82
92
62
-
93
97
92
-
CH2CH2OBn
OTBS
b
c
75
58
TMS
d
e
CH2CH2OBn
CH2OAc
57
45
-
-
OTBS
77
a isolated yield of step i (%), b isolated yield of step ii (%),
c isolated yield of step iii (%), d isolated yield of step iv (%).
In our initial studies we investigated sequences of yne-ene
CMR and Lewis acid catalyzed Diels-Alder reactions
with acrolein and methyl vinyl ketone to yield products of
Synlett 1999, No. 12, 1879–1882 ISSN 0936-5214 © Thieme Stuttgart · New York

1880
S. C. Schürer, S. Blechert
LETTER
O
Apart from Lewis acid catalyzed Diels-Alder reactions we
employed acetylene dicarboxylic acid methyl ester as di-
enophile at 140 °C yielding products of type 6. The highly
substituted 1,4-cyclohexadienes 6 (Table 1) were ob-
tained in moderate to high yields and small amounts of the
corresponding phthalates were detected as side products.
For comparison purposes compound 6b was oxidized to
the dimethyl phthalate with DDQ in benzene (yield 87%).
O
O
O
Me
R
i - iii
O
O
O
HO
n
8
7a n = 2
7b n = 8
8a R = OBn, 48 %a
8b R = CH2CH2OBn, 55 %a
O
i - iii
Me
R
After successful demonstration of these reaction sequenc-
es in solution we focussed on solid phase synthesis. Al-
though intermolecular CMR have only rarely been used
on solid support,7 this transformation can serve as a mild
catalytic and combinatorial C,C-bond forming step in
contrast to intramolecular RCM reactions which have
been used frequently.8 The selective yne-ene CMR is par-
ticularly useful because it gives rise to synthetically at-
tractive 1,3-dienes in a very efficient way. We
demonstrated this reaction involving polystyrene-sup-
ported alkynes and alkenes in combination with their sol-
uble counterparts.7a,b Here, we show sequences of yne-ene
CMR and Diels-Alder transformations employing differ-
ent alkynes, alkenes and dienophiles providing flexible
access towards various substituted cyclic structures.
8
MeO2C
9
8
10
10a R = CH2CH2OBn, 42 %a
10b R =
, 36 %a
O
O
Me
R
n
O
i - iii
n
O
O
CO2Me
11a n = 1
11b n = 2
12a R = OBn, n = 1, 26 %a
12b R = CH2CH2OBn, n = 2, 26 %a
Attaching the alkyne component to Merrifield resin using
a dicarboxylic acid spacer provided 7a,b7b, which can be
transformed into 8a and 8b in good overall yields by a se-
quence of yne-ene CMR and MeAlCl2-catalyzed Diels-
Alder reaction, similar to the reaction sequence in solution
(Scheme 2). We employed loading levels between 0.6 and
0.8 meq/g and observed higher yields if a longer spacer
was used. Only one major diastereomer (ratio >10/1) of
Diels-Alder products was observed after nucleophilic
cleavage from the support due to basic equilibration at the
acidic a-carbon of the cyclohexene ring into the thermo-
dynamically more stable trans configuration. According-
ly, compounds 10a and 10b were prepared starting from
polystyrene-supported undecynoic acid ester 9, prepared
similarly to 7. Introducing support-bound alkynoxy- or
alkenoxy-(4-phenyl acetic acid esters) 11 and 13 to a se-
quence of yne-ene CMR, Diels-Alder reaction and nu-
cleophilic cleavage provided compounds 12a,b and 14a,b
respectively. However, lower yields were obtained due to
partial cleavage of the phenyl ether in the cleavage step.
O
O
Me
O
R
iv, ii, iii
O
O
14a R = nC5H11, 26 %a
14b R = OBn, 20 %a
13
CO2Me
i: RCH2CH=CH2, 10% Ru, CH2Cl2, 45°C; ii: MeCOCH=CH2,
MeAlCl2, CH2Cl2 / toluene, -35°C; iii: NaOMe, THF / MeOH (3:1);
iv: RCH2C∫CH, 10% Ru, CH2Cl2, 45°C.
a Isolated overall yield of purified material.
Scheme 2
Acidic cyclization of the hydroxy ester in solution provid-
ed 16 in 44% overall yield.
To demonstrate the value of the presented methodology
we developed a combinatorial approach towards fused
ring systems displaying side chain functionality. A syn-
thesis of 1,2,7-trisubstituted octahydrobenzo[c]azepin-3-
ones (21) was designed utilizing the described new solid
phase yne-ene CMR / Diels-Alder cycloaddition chemis-
try in connection with further functionalization (Scheme
4). Ru-catalyzed yne-ene CMR between a support-bound
terminal alkenoic acid ester 17 and a terminal alkyne
yielded support-bound 1,3-diene 18, which was trans-
formed into 19 by MeAlCl2-catalyzed Diels-Alder reac-
tion employing an a,b-unsaturated ketone or aldehyde as
dienophile as shown above. A major issue of our synthetic
strategy was the purity in which the final products are ob-
tained after cleavage. Our concept was to introduce a nu-
cleophilic group in the last synthetic step before the
cleavage reaction. This nucleophile should enable in-
Adaptation of CMR and Diels-Alder reactions from solu-
tion to solid phase was possible without problems, al-
though higher temperatures and reactant concentrations
were employed.
The dimethyl phthalate 15 was obtained in moderate over-
all yield from resin 9 in a sequence of yne-ene CMR, Di-
els-Alder reaction with acetylenedicarboxylic acid methyl
ester as dienophile, oxidation of the 1,4-cyclohexadiene
with DDQ, and nucleophilic cleavage (Scheme 3). Lac-
tone 16 was synthesized utilizing a similar sequence.
Here, trityl protected 3-butenol was introduced as alkene
component to the CMR reaction and the trityl group was
removed before cleavage of the product from support.
Synlett 1999, No. 12, 1879–1882 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Sequences of Yne-Ene Cross Metathesis and Diels-Alder Cycloaddition Reactions
1881
R
The cyclization and simultaneous cleavage of 21 was
achieved after treatment of 20 with Me3Al in the presence
of Et3N at 60 °C.9 1,2,7-Trisubstituted octahydroben-
zo[c]azepin-3-ones 21 were obtained as diastereomeric
mixtures in high purity after filtration through silica gel to
remove the aluminum salts.10,11 The best resin for this cy-
clization/cleavage approach was 4-hydroxymethylbenzo-
ic acid aminomethyl polystyrene (HMBA-AM resin),
which was employed with a loading level of about 1.0
meq/g. No significant change in yields or purity was ob-
served between HMBA-AM resins from different
sources12 nor between higher and lower loaded resins (1.0
versus 0.4 meq/g).
R
R
8
15 36 %a
i - iv
9
v, ii, iii, vi,
vii, iv
R
O
O
R
8
R = CO2Me
16 44 %a
Table 2 shows compounds that have successfully been
synthesized. Different side chains have been incorporated
at all three positions from readily available building
blocks. Although only about 20% overall yield was
reached, all products were obtained in 80-95% purity after
filtration through silica gel as determined by TLC and
GC/MS.
i: CH2=CHCH2CH(Me)(CH2)3CHMe2, 10% Ru, CH2Cl2, 45°C; ii:
MeO2C-C∫C-CO2Me, toluene, 150°C (sealed vial); iii: DDQ, ben-
zene, 50°C; iv: NaOMe, THF/MeOH (3:1); v: CH2=CHCH2CH2OTr,
10% Ru, CH2Cl2, 45°C; vi: 5% TFA, CH2Cl2, vii: 1%TFA, toluene,
60°C.
a Isolated overall yield of purified material.
Scheme 3
Table 2 Results of solid-phase synthesis of octahydrobenzazepinones.
tramolecular cyclization and concomitant cleavage of the
final products from the support. The ketone or aldehyde
19 was reductively aminated employing a primary amine
to yield resin 20, containing a secondary amine, the de-
sired nucleophilic group. A cyclization/cleavage reaction
was assumed to provide product 21 in high purity, leaving
side products due to incomplete reaction steps attached to
the support.
yielda (%)
19
R2
R3
R1
entry
Me
21a
Ph
Me
4
Me
Me
21b
21c
28
20
Ph
Me
Me
4
4
Me
Me
21d
21eb
21fb
21gb
21h
Ph
22
15
15
O
O
R1
H
H
H
i
4
O
O
O
HO
HO
Ph
17
18
ii
Me
3
O
R1
O
R1
HO
15
14
H
H
Me
Me
O
H
iii
N
R2
R3
Ph
Cbz
O
N
R2
20
19
O
21i
15
iv
H
Me
Me
aOverall mass balance yields (%) of purified material. b The hydroxy group was
incorporated trityl protected and deprotected before cleavage of the product from
the support.
H
N
R1
O
O
N
PS
R3
21
R2
PS = polystyrene, 1% DVB
In summary an yne-ene CMR / Diels-Alder cycloaddition
sequence providing efficient access to core motifs incor-
porating side chain functionality has been developed and
was demonstrated in solution and on solid support. The
methodology was utilized for the combinatorial construc-
tion of substituted octahydrobenzo[c]azepin-3-ones,
which were obtained in high purity due to a cyclization/
cleavage step allowing only the final products to be re-
leased from the support.
i: 3-5 equiv R1CH2C∫CH, 10% Ru, CH2Cl2, 45°C, 24h; ii: 1.0M
R2COCH=CH2, 0.1M MeAlCl2, CH2Cl2 / toluene (2/1), -35°C, 18h;
iii: 1.0M R3-NH2, CH2Cl2 / HC(OMe)3 (1/1), RT, 2h, then 0.15M
Bu4NBH4, DMF, 1M AcOH, RT, 12h; iv: 0.2M Me3Al, CH2Cl2 / to-
luene (1/1), RT, 30 min then 0.05M Et3N, CH2Cl2 / toluene (1/1),
60°C, 1d, then filtration through silica gel.
Scheme 4
Synlett 1999, No. 12, 1879–1882 ISSN 0936-5214 © Thieme Stuttgart · New York

1882
S. C. Schürer, S. Blechert
LETTER
–78 °C followed by filtration, rinsing (3 x CH2Cl2, 3 x MeOH,
3 x DMF, 3 x CH2Cl2, 3 x MeOH), and drying. A suspension
of 250 mg of resin 19 and the primary amine (1M) was shaken
in CH2Cl2 / HC(OMe)3 (1/1, 3 mL) for 2h at RT. DMF (2.5
mL) and Bu4NBH4 (final concentration 0,15M) was then
added, followed by slow addition of AcOH to reach a final
concentration of 1M. The suspension was shaken for 12h at
RT and filtered. The resin was rinsed with DMF (3x), CH2Cl2
(3x), MeOH (3x), CH2Cl2 (2x), 2% Et3N in CH2Cl2 (2x),
CH2Cl2 (4x), MeOH (2x) and dried in high vacuum over P2O5
for 12h. Nitrogen was bubbled through a suspension of 250
mg of resin 20 in 5 mL of CH2Cl2 / toluene (1/1) containing
Me3Al (0,2M) for 30 min at RT. The resin was filtered under
a N2 atmosphere and CH2Cl2 / toluene (1/1, 3 mL) and Et3N
(0,05M) was added and the suspension shaken at 60 °C for 1d
followed by filtration and rinsing (3 x CH2Cl2, 3 x MeOH).
The filtrate was then filtered through silicagel (CH2Cl2 /
MeOH) and concentrated to yield crude product 21 in high
purity.
Acknowledgement
This work was supported by the Fonds der Chemischen Industrie
(FCI). S.C.S. further thanks the FCI for a scholarship.
References and Notes
(1) For recent reviews see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371. (c) Fürstner, A. Top.
Organomet. Chem. 1998, 1, 37. (d) Schuster, M.; Blechert, S.
Angew. Chem. 1997, 109, 2124; Angew. Chem. Int. Ed. Engl.
1997, 36, 2036.
(2) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem. 1997,
109, 2628; Angew. Chem. Int. Ed. Engl. 1997, 36, 2518.
(3) For recent reviews see e.g.: (a) Ellman, J. A.; Gallop, M. A.
Curr. Opin. Chem. Biol. 1998, 2, 317. (b) Balkenhohl, F.; von
dem Bussche-Hünnefeld, C.; Lansky, A.; Zechel, C. Angew.
Chem. 1996, 108, 2436; Angew. Chem. Int. Ed. Engl. 1996,
35, 2289. (c) Thompson, L. A.; Ellman, J. A. Chem. Rev.
1996, 96, 555.
(11) As a representative example spectroscopical data of
compound 21d as obtained after purification by coloumn
chromatography are given (diastereomeric mixture cis/
trans = 0.9). trans-isomer: 1H NMR (500 MHz, CDCl3): d
(ppm) 0.92 (t, J = 7Hz, 3H), 1.06-1.15 (m, 1H), 1.24-1.53 (m,
12H), 1.88-2.00 (m, 5H), 2.67-2.74 (m, 2H), 2.98 (d,
(4) (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder
Reaction; John Wiley & Sons; New York, 1990. (b) Oppolzer,
W. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press; Oxford, 1991, Vol. 5, p. 315.
J = 15Hz, 1H), 3.40 (dd, J = 15Hz, J = 10Hz, 1H), 4.45 (d,
J = 15Hz, 1H), 4.85 (d, J = 15Hz, 1H), 5.13 (s, 1H), 7.27-7.39
(m, 5H). 13C NMR (125.77 MHz, CDCl3): d (ppm) 14.09
(CH3), 22.61 (CH2), 27.57 (CH2), 28.85 (CH2), 28.96 (CH2),
30.76 (CH2), 31.72 (CH2), 36.89 (CH2), 37.10 (CH2), 41.78
(CH), 46.18 (CH), 51.35 (CH2), 54.92 (CH2), 125.16 (CH),
127.31 (CH), 128.16 (CH), 128.53 (CH), 137.80 (Cq), 138.04
(Cq), 175.36 (Cq). IR (ATR): n (cm-1) 700 (w), 1173 (w), 1450
(m), 1647 (vs), 2854 (m), 2924 (s), 2954 (w). MS (EI): m/z
(%): 339 (M+, 10), 248 (27), 219 (8), 153 (22), 136 (23), 107
(40), 77 (100). HRMS: calcd for C23H33NO (m/z) 339.2562,
measured 339.2567. cis-isomer: 1H NMR (400 MHz, C6D6,
80 °C): d (ppm) 0.94 (t, J = 7Hz, 3H), 1.17-1.69 (m, 13H),
1.71-1.79 (m, 2H), 1.88-1.95 (m, 2H), 2.05-2.11 (m, 1H), 2.39
(ddd, J = 14Hz, J = 9Hz, J = 3Hz, 1H), 2.54 (ddd, J = 14Hz,
J = 9Hz, J = 3Hz, 1H), 2.91 (d, J = 15Hz, 1H), 3.13 (dd,
J = 15Hz, J = 9Hz, 1H), 3.35 (d, J = 14Hz, 1H), 4.86 (d,
J = 14Hz, 1H), 5.16 (br, s, 1H), 7.09-7.33 (m, 5H). IR (ATR):
n (cm-1) 700 (w), 1155 (w), 1451 (m), 1648 (ss), 2856 (m),
2925 (s), 2953 (w). MS (EI): m/z (%): 339 (M+, 49), 310 (6),
282 (5), 268 (5), 248 (4), 220 (8), 120 (43), 91 (100). HRMS:
calcd for C23H33NO (m/z) 339.2562, measured 339.2563.
(12) HMBA-resin is commercially available (NovaBiochem) or
can be prepared from aminomethylated polystyrene by
standard amide coupling (DICI, HOBt, iPr2EtN, DMF) with 4-
hydroxymethylbenzoic acid followed by hydrolysis of ester
side products (0.2M NaOMe in 3/1 THF / MeOH).
(5) (a) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119,
7402. (b) Schürer, S. C.; Blechert, S. Chem. Commun. 1999,
1203.
(6) Schürer, S. C.; Blechert, S. Tetrahedron Lett. 1999, 40, 1877.
(7) For examples see: (a) Schuster, M.; Blechert, S. Tetrahedron
Lett. 1998, 39, 2295. (b) Schürer, S. C.; Blechert, S. Synlett
1998, 166. (c) Schuster, M.; Lucas, N.; Blechert. S. Chem.
Commun. 1997, 823.
(8) Selected examples: (a) Schuster, M.; Pernerstorfer, J.;
Blechert. S. Angew. Chem. 1996, 108, 2111; Angew. Chem.
Int. Ed. Engl. 1996, 35, 1979. (b) J. Pernerstorfer, M. Schuster,
S. Blechert Chem. Commun. 1997, 1949. (c) Miller, S. J.;
Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118,
9606. (d) Nicolaou, K. C.; Vourloumis, D.; Li, T.; Pastor, J.;
Winssinger, N.; He, Y.; Ninkovic, S.; Sarabia, F.; Vallberg,
H.; Roschangar, F.; King, N. P.; Finlay, M. R. V.;
Giannakakou, P.; Verdier-Pinard, P.; Hamel, E. Angew.
Chem. 1997, 109, 2181; Angew. Chem. Int. Ed. Engl. 1997,
36, 2097.
(9) Me3Al-mediated conversion of esters into amides have been
described: Bashda, A.; Lipton, M.; Weinreb, S. M.
Tetrahedron Lett. 1977, 48, 4171.
(10) General procedure follows:1,0 g of resin 17 and 3-5 equiv of
alkyne in CH2Cl2 (12 mL) was shaken with 5 mol% Ru at
45 °C in a sealed vial for 12h after which time another 5 mol%
Ru was added and the reaction continued for 12h followed by
filtration, rinsing (6 x CH2Cl2, 3 x MeOH), and drying. To a
suspension of 500 mg of resin 18 and dienophile (1M) in 6 mL
of CH2Cl2 / toluene (2/1) cooled to –78 °C was added 0.7 mL
of MeAlCl2 (1M solution in hexanes). The suspension was
warmed to –35 °C and shaken for 18h and then cooled to
Article Identifier:
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Synlett 1999, No. 12, 1879–1882 ISSN 0936-5214 © Thieme Stuttgart · New York