PdII/IV catalyzed oxidative cyclization of 1,6-enynes derived by Ugi-4-component reaction

Article abstract of DOI:10.1016/j.tetlet.2011.09.094

A variety of 1,6-enynes were synthesized by an Ugi-reaction and further elaborated by a Pd^II/IV catalyzed oxidative cyclization to produce N-substituted 3-aza-bicyclo[3.1.0]hexan-2-ones. Different substitution patterns were tested to examine the scope and limitations of the amide tethered substrates.

Full text of DOI:10.1016/j.tetlet.2011.09.094

Tetrahedron Letters 52 (2011) 6295–6297
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PdII/IV catalyzed oxidative cyclization of 1,6-enynes derived by
Ugi-4-component reaction
Sebastian J. Welsch a,b, , Michael Umkehrer a, Günther Ross a, Jürgen Kolb a, Christoph Burdack a,
⇑
Ludger A. Wessjohann b
a Priaxon AG, Gmunder Str. 37-37a, 81379 München, Germany
b Leibniz-Institut für Pflanzenbiochemie, Weinberg 3, 06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
A variety of 1,6-enynes were synthesized by an Ugi-reaction and further elaborated by a PdII/IV catalyzed
oxidative cyclization to produce N-substituted 3-aza-bicyclo[3.1.0]hexan-2-ones. Different substitution
patterns were tested to examine the scope and limitations of the amide tethered substrates.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 20 May 2011
Revised 18 September 2011
Accepted 20 September 2011
Available online 28 September 2011
Keywords:
Multicomponent reaction
Ugi-reaction
1,6-Enyne
PdII/IV-catalysis
Cycloaddition
Palladium catalyzed transformations are among the most
powerful and versatile methods in organic synthesis to construct
C–C and C-heteroatom bonds and often offer a unique access to
structures which are otherwise difficult to obtain.1 While most of
these reactions proceed through Pd0/PdII catalytic cycles an
increasing number of reactions involving PdIV complexes as key
intermediates have been reported during the last years.2
As part of our ongoing research project to find new postmodifi-
cations for structures obtained by multicomponent reactions
(MCRs) we were interested if we could use this cyclization with
enynes generated by an Ugi-reaction (Fig. 1). While several Pd0/II
-
mediated postmodifications have been published,9 to the best of
our knowledge there are no examples involving PdII/IV-chemistry.
MCRs in general and especially the isocyanide based reactions
offer a robust, versatile, and fast access to molecules with several
points of diversity.10 The excellent atom economy and the inherent
high convergence in combination with cheap starting materials
make these reactions the optimal choice for our hit identification
and optimization program.
Compared to the Pd0/PdII catalysis PdII/PdIV has several advanta-
ges: (i) It requires the use of only weak bases and a strict exclusion
of air and moisture is not necessary making them operationally
simpler; (ii) the newly formed bonds (e.g., sp2 and sp3 C–OAc,
C–OCH2CF3, C–I, C–F) are often highly complementary to those
achievable by classical Pd0/II catalysis and so is (iii) the tolerance
for functional groups (e.g., Ar-Br and Ar-I are completely stable
under oxidative catalytic reaction conditions).1
As initial test system, phenylpropiolic acid was chosen because of
its high stability and good reactivity in Ugi-reactions. Allylamine
served as small and flexible unsubstituted alkene (the rates of olefin
insertion of substituted alkenes are known to be slow compared to
the undesired side reactions6). With bulky tert-butylisocyanide that
will minimize potential side reactions with the secondary amide
formed,9e and with benzaldehyde as the carbonyl compound, the
expected Ugi-product 1a was obtained in 64% yield. Subsequent
heating at 80 °C with 1.1 equiv of iodosobenzenediacetate, 5 mol %
Pd(OAc)2 and 6 mol % 2,20-bipyridyl in dry acetic acid under a N2
atmosphere4 lead to a cyclic product 1b. Although HPLC-analysis
showed no formation of any specific byproducts the conversion
did not proceed cleanly probably due to the Pd-mediated
intermolecular reactions between the unsaturated functionalities
and/or further reactions of the double acceptor-substituted cyclo-
propane ring moiety.11 1H NMR-analysis showed a mixture of two
The PdII/IV catalyzed oxidative cyclization of 1,6-enynes devel-
oped by the Sanford3 and Tse4 groups offers a facile entry to the
bicyclo[3.1.0]hexane skeleton. This structural motif is found in sev-
eral natural products with potent antibiotic activity5 and various
drugs,6 for example, anticonvulsant pregabalin or protein kinase
C-b inhibitor JTT-010. Furthermore it has been utilized as a key
intermediate in the synthesis of the cyclopropane containing natu-
ral product ambruticin S by Martin and co-workers7 and for the
stereoselective synthesis of highly functionalized organic mole-
cules via nucleophilic ring opening of the bicyclic core structure.8
⇑
Corresponding author. Tel.: +49 (0) 89 4521308 13; fax: +49 (0) 89 4521308 22.
E-mail addresses: welsch@priaxon.de, welsch@priaxon.com (S.J. Welsch).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.094

6296
S. J. Welsch et al. / Tetrahedron Letters 52 (2011) 6295–6297
R
CN
R'
R
R'
O
1.1 eq PhI(OAc)2
5 mol% Pd(OAc)2
6 mol% bipy
(abs. AcOH),
80° C, N2
H
N
R''
NH2
H
N
N
R''
N
RT
R''
OH
+
O
(MeOH)
R
O
O
Ph
O
O
Ph
O
R'
Ph
1-13a
1-13b
Figure 1. General reaction scheme.
Table 1
Synthezised Ugi- and cyclization products
Entry
R, R0
R00
Ugi-product
Isolated yield (%)
Cyclization product
Isolated yield (%)
dr
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph, H
H, H
H, H
H, H
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Et
1a
2a
64
96
1b
2b
51
47
45
—
52
49
17d
9
3:2
—
—
—
—
2ba
2bb
2bc
3b
H, H
Me, Me
3a
4a
5a
6a
7a
8a
9a
10a
11a
70
99
92
93
80
33
89
88
91
—
iPr, H
4b
5b
6b
7b
8b
9b
10b
11b
11bc
12be
13b
5:4
1.1:1
—
—
—
—
—
—
—
p-Cl–C6H4, H
p-MeO–C6H4, H
H, H
H, H
H, H
—
38
20
43
29
0
40
—
32
Ph
Bn
H, H
H, H
CH2COOMe
C2H4OMe
C2H4OMe
Et
H, H
iPr, H
12a
13a
85
84
—
1.1:1
Ph, H
Bn
a
b
c
Microwave.
Without bipy.
No aqueous workup.
Purity 85%.
105 °C.
d
e
diastereomers in a ratio of 3:2 (Table 1, entry 1).12 In order to sim-
plify the spectra achiral compounds 2a and 3a were synthesized in
good to excellent yields. Subsequent cyclization was slower for both
of them compared to 1a and accordingly the cyclopropanes 2b and
3b were isolated in lower yield (entries 2 and 6). Compound 3b dem-
onstrates that a bulky substitution at the lactam nitrogen is
tolerated.
Reaction monitoring for 2b showed increased side product for-
mation and therefore the reaction was repeated using microwave
heating. It was expected that a shorter reaction time would pro-
duce less side products and polymer. Indeed complete conversion
was achieved after 9 h at 80 °C with a substantial decrease in
byproducts, but disappointingly the isolated yield was lower than
with the conventional heating. Closer investigation revealed that
the product degrades during the purification on silica. Switching
to neutral aluminum oxide could obviate this problem. When iod-
osobenzenediacetate was substituted with hydrogen peroxide as a
milder oxidant2 the reaction proceeded with more side products
and a worse conversion.
palladium and it may alter the catalytic properties of the interme-
diate palladium complexes. Finally, the tolerance for functional
groups can be easily tested by placing them at the distant (isocya-
nide derived) end. The results are summarized in Table 1.
First the steric influence of the aldehyde derived residue was
tested with iso-butyraldehyde as the carbonyl component. While
the MCR went smoothly subsequent cyclization led to a complex
mixture with only minor amounts of the product (entry 7). Replace-
ment of the bulky tert-butyl isocyanide with ethylisocyanide and
therefore reduction in the steric strain in the Ugi-product did not im-
prove the reaction. An increase of the reaction temperature to 105 °C
caused complete degradation of the starting material (entry 16).
Substituted benzaldehydes were examined next. Again, the Ugi-
reaction afforded the enynes 5a and 6a in very good yields but in
contrast to the unsubstituted benzaldehyde the cyclization went
poorly, yielding only small amounts of the desired cyclopropanes
5b (9%) and traces of 6b which degraded during the aqueous work-
up (entries 8 and 9).
Finally we tested the influence of the exocyclic amide substitu-
ent using an array of different isocyanides (small and bulky ali-
phatic, phenylic, benzylic, functionalized aliphatic). Most MCR-
products were easily obtained with good to excellent yields and
the following cyclization produced the corresponding bicycles.
Among the tested isocyanides benzyl isocyanide performed best
(entry 12) whereas phenyl isocyanide gave the lowest yield in this
series indicating that the cyclization is susceptible to subtle
changes in the substrate structure. Cyclization of 10a and 11a so
far showed the cleanest conversion (judged by HPLC). This may
be attributed to the oxygen atom(s) acting as an intramolecular li-
gand for the catalyst, stabilizing the intermediates. Both reactions
suffered from severe degradation during aqueous workup (entries
Entry 4 shows an experiment without using 2,20-bipyridyl as an
additional ligand which leads only to the degradation of the start-
ing material and demonstrates the necessity of this additive to
avoid side reactions13,14 such as b-hydride elimination or protonol-
ysis of the carbon–palladium bond (which is in agreement with the
results published by Lyons and Sanford6).
After this proof of concept the influence of both the aldehyde
and the isocyanide moieties on the cyclization was examined.
Though they may seem remote to the alkene and alkyne they have
been found to influence the cyclization by altering the electronic
properties of the lactam nitrogen.15,16 Additionally, the secondary
amide stemming from the isocyanide can act as ligand for the

S. J. Welsch et al. / Tetrahedron Letters 52 (2011) 6295–6297
6297
cooling the reaction mixture to 0 °C 1 mmol of phenylpropiolic acid and
1 mmol of tert-butylisocyanide were added and the mixture was stirred for
another 16 h. After evaporation of the solvent the crude product was washed
with small quantities of cold acetone to yield the product as a white solid
(64%). 1H NMR (400 MHz, CDCl3): major diastereomer only: 7.53–7.51 (m, 2H),
7.43–7.33 (m, 8H), 5.92 (s, 1H), 5.66 (s(br), 1H), 5.58–5.49 (m, 1H), 4.98–4.88
(m, 2H), 4.39 (dd, 1H, 3J = 5.7 Hz, 2J = 16.7 Hz), 4.20 (dd, 1H, 3J = 6.0 Hz,
2J = 16.7 Hz), 1.36 (s, 9H). Typical reactions procedure for the synthesis of 3a:
1 mmol of allylamine and acetone were dissolved in 1 ml of methanol and
stirred for 2 h at 0 °C. Then 1 mmol of phenylpropiolic acid and 1 mmol of tert-
butylisocyanide were added and the mixture was stirred overnight. After
evaporation of the solvent the crude product was purified by column
chromatography over silica gel (ethyl acetate–hexane = 1:2, Rf = 0.36, 70%).
1H NMR (400 MHz, CDCl3), main rotamer only: 7.62–7.58 (m, 2H), 7.55–7.45
(m, 3H), 6.46 (s(br), 1H), 6.04–5.94 (m, 1H), 5.39 (d, 1H, 3J = 16.4 Hz), 5.23 (d,
1H, 3J = 10.5 Hz), 4.39 (d, 1H, 3J = 5.5 Hz), 1.37 (s, 3H), 1.23 (s, 9H). Typical
reactions procedure for the synthesis of 9a: In a pressure tube 1 mmol of each
allylamine, para-formaldehyde, benzylisocyanide and phenylpropiolic acid
were dissolved in 1 ml of 2,2,2-trifluoroethanol and stirred at 50 °C for 36 h.
After evaporation of the solvent the product was purified by column
chromatography (ethyl acetate–hexane = 1:2, Rf = 0.19) yielding 295 mg
(89%) of a white solid. 1H NMR (400 MHz, CDCl3), main rotamer only: 7.54
(d, 2H), 7.47–7.22 (m, 8H), 6.60 (s(br), 1H), 5.93–5.72 (m, 1H), 5.32–5.21 (m,
2H), 4.45 (d, 2H, 3J = 6.0 Hz), 4.37 (d, 2H, 3J = 6.0 Hz), 4.09 (s, 2H).
13 and 14). Indeed, 11b could only be obtained after skipping the
extraction step (entry 15). Transferring this procedure to substrate
2a improved the yield slightly (entry 5). Compound 7a performed
similar but showed an increased tendency for degradation upon
prolonged heating.
In summary it was shown that the Ugi-reactions is well suited
to synthesize enynes in excellent yields. The resulting 1,6-enynes
were further elaborated by a PdII/IV catalyzed oxidative cyclization
to produce varied N-substituted 3-aza-bicyclo[3.1.0]hexan-2-ones
with three points of diversity. Different substitution patterns were
tested to examine the scope and limitations of the amide tethered
substrates. The reactions perform best with benzylic amide sub-
stituents or with substituents bearing a functional group that can
act as an intramolecular ligand for the catalyst.
References and notes
1. Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924–1935. and references
cited therein.
General reaction procedure for the synthesis of 1b, 3b, 9b: In a dry pressure
tube with a stirring bar filled with an inert gas (argon or nitrogen) to 150 mg of
enyne, 5 mol % Pd(OAc)2, 6 mol % 2,20-bipyridyl and 1.1 equiv of
iodosobenzenediacetate were added and dissolved in 4 ml of dry acetic acid.
The reaction mixture was heated at 80 °C (oil bath temperature) until TLC or
HPLC showed complete conversion of the starting material. Then 30 ml of
water were added to form a milky suspension which was extracted with
2 ꢀ 25 ml ethyl acetate, the combined organic phase were washed with
2 ꢀ 50 ml water and 1 ꢀ 50 ml brine, dried over Na2SO4, filtrated and the
solvent evaporated. The crude product was further purified by column
chromatography. 1b: ethyl acetate–hexane = 1:5?4:1, off-white solid, 51%.
1H NMR (400 MHz, CDCl3), 2 diastereomers A/B = 3:2: 7.97–7.93 (m, 2H, A),
7.82–7.77 (m, 2H, B), 7.56–7.51 (m, 2 ꢀ 1H, AB), 7.46–7.28 (m, 2 ꢀ 7H, AB),
5.70 (s, 1H, B), 5.68 (s(br), 1H, A), 5.56 (s, 1H, A), 5.47 (s(br), 1H, B), 4.27 (dd, 1H,
J = 5.8 Hz, J = 10.8 Hz, A), 3.90 (d, 1H, J = 10.5 Hz, B), 3.23 (dd, 1H, J = 5.9 Hz,
J = 10.5 Hz, B), 3.04 (d, 1H, J = 10.9 Hz, A), 2.36–2.28 (m, 2 ꢀ 1H, AB), 2.05 (dd,
1H, J = 4.2 Hz, J = 8.2 Hz, A), 1.99 (dd, 1H, J = 4.9 Hz, J = 7.8 Hz, B), 1.50–1.45 (m,
1H, B), 1.35 (s, 9H, A), 1.31 (s, 9H, B), 0.93 (t, 1H, J = 4.8 Hz, A). 3b: ethyl
acetate–hexane = 1:1?9:1, off-white solid, 49%. 1H NMR (400 MHz, CDCl3):
7.87 (m, 2H), 7.54 (m, 1H), 7.44 (m, 1H), 5.97 (s(br), 1H), 3.95 (dd, 1H,
J = 5.6 Hz, J = 10.3 Hz), 3.63 (d, 1H, J = 10.3 Hz), 2.37 (dt, 1H, J = 7.9 Hz,
J = 5.6 Hz), 2.07 (dd, 1H, J = 7.9 Hz, J = 4.6 Hz), 1.54 (s, 3H), 1.50 (s, 3H), 1.30
(s, 9H), 1.12 (t, 1H, J = 4.6 Hz). 9b: (ethyl acetate–hexane = 1:2, Rf = 0.30) and
yielded 51 mg (43%)of a white-brown solid. 1H NMR (400 MHz, CDCl3): 7.87 (d,
2H, 3J = 7.4 Hz), 7.52 (t, 1H, 3J = 7.4 Hz), 7.38 (t, 2H, 3J = 7.9 Hz), 7.33–7.22 (m,
5H), 6.46 (s(br), 1H), 4.46–4.35 (m, 2H), 3.97 (dd, 1H, J = 5.8 Hz, J = 10.3 Hz),
3.96 (d, 1H, 2J = 15.7 Hz), 3.80 (d, 1H, 2J = 15.7 Hz), 3.65 (d, 1H, J = 10.3 Hz), 2.47
(dt, 1H, J = 7.8 Hz, J = 5.8 Hz), 2.05 (dd, 1H, J = 4.9 Hz, J = 7.8 Hz), 1.22 (t, 1H,
J = 4.9 Hz).
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