Formation of pentacyclic structures by a domino sequence on cyclic enamides

Article abstract of DOI:10.1039/b820636h

Novel spiropentacyclic compounds 11 were obtained from cyclic enamides of type 9, featuring a (2-bromophenyl)propyl substituent in the 5-position, through a Pd-mediated domino sequence taking place via Heck insertion and C-H activation.

Full text of DOI:10.1039/b820636h

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Formation of pentacyclic structures by a domino sequence on cyclic
enamidesw
a
b
a
¨
Gedu Satyanarayana, Caecilia Maichle-Mossmerz and Martin E. Maier*
Received (in Cambridge, UK) 18th November 2008, Accepted 6th January 2009
First published as an Advance Article on the web 30th January 2009
DOI: 10.1039/b820636h
Novel spiropentacyclic compounds 11 were obtained from cyclic
enamides of type 9, featuring a (2-bromophenyl)propyl substituent
in the 5-position, through a Pd-mediated domino sequence taking
place via Heck insertion and C–H activation.
Domino reactions represent a powerful strategy for the synthesis
of polycyclic organic molecules.1–3 Since several reactions take
place in a sequential fashion, this can result in a large structural
Scheme
1 The formation of spirocyclic compounds by Heck
change in going from the starting material to the product.
Typically, a reactive intermediate formed in the initial step is
translocated within the substrate via double or triple bonds with
concomitant bond formation. In this regard, organometallic
intermediates are of special use, since they are easily generated
and can undergo unique termination steps, such as b-hydride
elimination or C–H activation followed by reductive elimination.
With a view towards the synthesis of nitrogen-containing
polycyclic structures, we recently investigated Heck cyclizations
on substrates featuring a cyclic enamide.4 For example, we
showed that the Pd-mediated transformation of 3,4-dihydro-
2(1H)-pyridinones having a (2-bromophenyl)ethyl substituent in
the 5-position leads to spirocyclic imides 2 and amides 3
(Scheme 1). These compounds arose from insertion of the
enamide double bond into the initial aryl–Pd bond, followed
by oxidation or reduction of the organopalladium intermediate.5
Clearly, short and efficient access routes to complex aza-
polyclic structures are of current interest since they might serve
as scaffolds for medicinal chemistry or as alkaloid analogues.6,7
In delineating the scope of the above transformation, we
extended the tether between the aryl bromide and enamide by
one methylene group. To our surprise, we observed a striking
distance dependence on the reaction outcome. Thus, with a three
carbon tether, the domino sequence did not stop at the tricyclic
imides or amides, but rather terminated in a final C–H activa-
tion step at the N-benzyl group, resulting in unique pentacyclic
structures. Pd-catalyzed C–H bond activation is quite common
for sp2 C–H bonds,8 but it has also been observed for certain sp3
C–H bonds.9 For direct arylation reactions, a proton abstraction
mechanism on a arylpalladium intermediate seems likely.10
cyclization to cyclic enamides.
The substrates of type 9 for the present study were prepared
in a similar fashion to those outlined in previous work.4,11
Thus, bromoiodobenzenes12–15 4a–f were subjected to
a
Jeffery–Heck coupling16 with pentenol, resulting in the corres-
ponding 4-(2-bromo)phenylpentanals 5a–f in acceptable yields
(Scheme 2 and Table 1). In most instances, a small amount of
the inner Heck coupling product, 6a–f, (roughly 10%) was
also observed. However, the linear and branched aldehydes
could only be separated by chromatography in the cases of
5f and 6f. The aldehydes were added in a Michael fashion
to ethyl acrylate via the derived enamine 7a–f, resulting in
formyl esters 8a–f. These aldehyde esters could be easily
cyclized to enamides 9aa–fa by heating them with benzyl- or
to 4-methylbenzylamine in presence of acetic acid.
The palladium-catalyzed transformation of parent enamide
9aa was studied using the same conditions (Pd(OAc)2, PPh3,
Cs2CO3, DMF, 120 1C, 72 h) we employed previously
(Table 2).4 Under these conditions, two products were formed,
a Institut fur Organische Chemie, Universitat Tubingen, Auf der
¨
¨
Morgenstelle 18, 72076 Tubingen, Germany.
¨
¨
E-mail: martin.e.maier@uni-tuebingen.de; Fax: +49 7071 5137;
Tel: +49 7071-2975247
b Institut fur Anorganische Chemie, Universitat Tubingen,
¨
¨
¨
Auf der Morgenstelle 18, 72076 Tubingen, Germany
¨
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization for all new compounds reported, and
copies of NMR spectra for important intermediates. CCDC 710107.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/b820636h
Scheme 2 The synthesis of cyclic enamides via Heck coupling,
Michael addition of enamines to an acrylate and cyclization of formyl
esters with a benzylamine.
z X-Ray structure determination.
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Table 1 Yields for the transformations leading to piperidinones
9aa–fa
Table 3 The palladium-catalyzed domino cyclization of 5-(bromophenyl)-
propyl-substituted enamides 9aa–faa
Cyclization
Coupling
product
(% yield)
Michael
product
(% yield)
to enamide
product
(% yield)
R1
R2
R3
H
H
H
H
H
H
Me
Me
CO2Me
H
5a (70)
5b (67)
8a (64)
8b (60)
H
Me
H
Me
H
H
Me
H
Me
H
9aa (83)
9ab (72)
9ba (78)
9bb (80)
9ca (79)
9da (70)
9db (78)
9ea (80)
9eb (78)
9fa (90)
H
5c (34)
5d (72)
8c (67)
8d (67)
OMe
OMe
H
H
OMe
H
OMe
OMe
OMe
5e (68)
5f (74)
8e (66)
8f (63)
10aa–fa
Entry Substrate (% yield)
11aa–fa
(% yield)
Pentacycle 11aa–fa
1
9aa
29
51
Table 2 The reaction of piperidinone 9aa with a palladium catalyst,
base and phosphine ligand under different conditionsa
2
3
9ab
9ba
30
27
46
49
10aa
(% yield)
11aa
(% yield)
Entry
Catalyst
Ligand
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PCy3
P(otolyl)3
BINAP
AsPh3
12
27
39
32
50
23
29
46
41
43
26
30b
51
4
5
6
7
8
9bb
9cab
9da
9db
9ea
30
29
25
30
34
49
a
Typical conditions: catalyst (0.1 equiv.), phosphine ligand (0.2 equiv.),
Cs2CO3 (4 equiv.), aryl bromide 9aa (0.15–0.18 M), 120 1C, 72 h;
abbreviations: Cy = cyclohexyl. 30% of unreacted 9aa was recovered.
0
b
namely debrominated enamide 10aa (27%) and spiropentacyclic
product 11aa (46%). However, even after flash chromatography,
the spiro compound 11aa contained impurities derived from the
PPh3 ligand; therefore, other ligands were screened. Using the
more electron-rich Cy3P ligand, more of the debrominated
compound was formed (Table 2, entry 2). Similar results were
observed with the BINAP ligand (Table 2, entry 4). The ligand
Ph3As seemed to slow down the reaction, as some starting
material still remained after 72 h (Table 2, entry 5). The Buchwald
aminophosphine17 12 provided spiropentacyclic compound 11aa
in good yield and purity after chromatography of the reaction
mixture (Table 2, entry 6). Only starting material was observed
with DMSO as the solvent and Pd(dba)2 as the catalyst.
50
44
45
Recrystallization of polycycle 11aa gave crystals suitable for
X-ray analysis. A rendering of the crystal structure is shown in
the ESI.y It can be seen that the two aryl rings on the former
enamide double bond are cis to each other, as one would
expect from a classical insertion mechanism. The isoindoline
ring is then formed by a final C–H activation.
9
9eb
28
43
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Table 3 (continued)
Z = 4, 21754 reflections measured, 3269 unique used for calculation
(Rint = 0.0666). The final wR(F2) was 0.1096 (all data).w
10aa–fa
Entry Substrate (% yield)
11aa–fa
(% yield)
Pentacycle 11aa–fa
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5 For some recent examples of palladium-catalyzed domino reactions,
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D. G. Hulcoop, F. Jafarpour, A. Joushaghani, B. Laleu and
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Bertrand, J. D. Neukom and J. P. Wolfe, J. Org. Chem., 2008, 73,
8851–8860.
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G. R. Dake, Org. Lett., 2007, 9, 367–370; (b) E. Prusov and
M. E. Maier, Tetrahedron, 2007, 63, 10486–10496;
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10, 4291–4294 and references therein.
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a
Reaction conditions: aryl bromide 9 (0.15 M in DMF), Cs2CO3
(4 equiv.), ligand 12 (20 mol%), Pd(OAc)2 (10 mol%), 120 1C,
3 d. Instead of ligand 12, Ph3P (20 mol%) was used.
b
Scheme 3 Proposed mechanism for the formation of pentacycles 11.
In a similar manner, the other enamides, 9ab–fa, were
transformed to spiro compounds 11ab–fa (Table 3). In all cases,
some of the corresponding debrominated product, 10ab–fa, was
also observed. Except for ester substrate 9ca and dimethoxy
substrate 9fa, the Buchwald aminophosphine ligand 12 was
used. For these two cases, PPh3 served as the ligand, since the
aminophosphine derivatives co-eluted with the products 11ca
and 11fa. In case of substrate 9ca, the pentacyclic product 11ca
was not formed at all (Table 3, entry 5). This can be attributed
to the ester function, since it had already caused a drop in yield
in the Jeffrey–Heck coupling of iodobromide 4c to aldehyde 5c.
In pentacycles 11, the methine hydrogen next to the nitrogen
typically appears at around d 4.8 in their 1H NMR spectrum. In
their 13C NMR spectrum, the corresponding carbon atom
resonates at d 70 and the spiro carbon is found at around d 42.
The formation of these pentacyclic spiro derivatives can
be explained by a Heck cyclization process (Scheme 3). Thus,
the initial arylpalladium species inserts into the enamide double
bond in a typical cis fashion, resulting in intermediate A.
The palladium is then able to leave the molecule via a final
C–H activation and HBr elimination.
1253–1264;
(e)
S.
Pascual,
P.
de
Mendoza
A. M. Echavarren, Org. Biomol. Chem., 2007, 5, 2727–2734.
and
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792–799; (b) T. Watanabe, S. Oishi, N. Fujii and H. Ohno, Org.
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´
D. J. Cardenas, B. Martin-Matute and A. M. Echavarren,
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13 Compound 4c: C. B. Vu, E. G. Corpuz, T. J. Merry, S. G. Pradeepan,
C. Bartlett, R. S. Bohacek, M. C. Botfield, C. J. Eyermann,
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S. L. Buchwald, J. Am. Chem. Soc., 2001, 123, 12202–12206;
In summary, we have discovered a facile synthesis for novel
spiropentacyclic compounds 11 from cyclic enamides of type 9.
These enamides feature
a (2-bromophenyl)propyl sub-
stituent in the 5-position that allows a palladium-mediated
domino sequence. The initial arylpalladium intermediate
inserts into the enamide double bond, generating another
organopalladium intermediate. The sequence is terminated
by a final C–H activation and the expulsion of Pd(0).
Financial support by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie is gratefully
acknowledged. G. S. thanks the Alexander von Humboldt
foundation for a postdoctoral fellowship.
(b) A. Furstner and J. W. J. Kennedy, Chem.–Eur. J., 2006, 12,
¨
7398–7410.
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H. Suginome, Synthesis, 1995, 1273–1277; (b) T. Jensen, H. Pedersen,
B. Bang-Andersen, R. Madsen and M. Joergensen, Angew. Chem.,
2008, 120, 902–904 (Angew. Chem., Int. Ed., 2008, 47, 888–890).
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1996, 52, 7525–7546; (c) D. Bruyere, D. Bouyssi and G. Balme,
Tetrahedron, 2004, 60, 4007–4017.
Notes and references
y Crystal data for 11aa: C21H21NO, M = 303.39, monoclinic, a =
11.3172(13), b = 7.6048(6), c = 18.468(2) A, b = 104.156(9)1,
V = 1541.2(3) A3, T = 173 K, space group P21/n (no. 1014),
17 H. Tomori, J. M. Fox and S. L. Buchwald, J. Org. Chem., 2000, 65,
5334–5341.
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Chem. Commun., 2009, 1571–1573 | 1573