Palladium-catalyzed olefin migration and 7-endo-trig cyclization of dehydroalanines

Article abstract of DOI:10.1016/j.tetlet.2018.01.058

1,4- or 1,5-migration of a double bond of dehydroalanines under palladium catalysis is reported. The process occurred with several highly-substituted dehydroalanines under mild typical Heck reaction conditions. Although this was one of the first reports o

Full text of DOI:10.1016/j.tetlet.2018.01.058

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
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Palladium-catalyzed olefin migration and 7-endo-trig cyclization of
dehydroalanines
a
a
Ma. Carmen García-González , Eduardo Hernández-Vázquez , Fabio A. Vengochea-Gómez,
Luis D. Miranda
⇑
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S.N., Ciudad Universitaria, Coyoacán, Ciudad de Mexico 04510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
1,4- or 1,5-migration of a double bond of dehydroalanines under palladium catalysis is reported. The pro-
cess occurred with several highly-substituted dehydroalanines under mild typical Heck reaction condi-
tions. Although this was one of the first reports of a palladium-catalyzed 1,5-olefin migration, the
outcome of the reaction was susceptible to the starting material. Mechanistically, the process involved
a five- (1,4-migration) or six-membered ring (1,5-migration) organopalladium intermediate, which
cleaved a C–N bond in an b-amino elimination process.
Received 22 December 2017
Accepted 20 January 2018
Available online xxxx
Keywords:
Ugi reaction
Dehydroalanines
Palladium catalysis
Ó 2018 Elsevier Ltd. All rights reserved.
1
,4- and 1,5-olefin migration
b-Amino elimination
Undoubtedly, palladium-mediated carbon–carbon bond-form-
ing reactions are essential tools in the armory of the synthetic
organic chemist. Indeed, complex transformations, which in the
both on the nature of the ligand and the base used in the
reaction.
1
2
1
In our ongoing efforts to develop useful synthetic protocols
based on Pd-catalyzed domino processes applied to Ugi 4-CR-
derived (four-component reaction) dehydroalanines, we recently
observed that palladium-mediated 1,4- and 1,5-double bond
migrations are possible in the this system. Given the paucity of
information associated with this rearrangement, we decided to
explore its scope, and the preliminary results are disclosed herein
(Scheme 1).
past were not accessible by traditional methodologies, are now
possible with palladium chemistry.2 Within this field, the Heck-
Mizoroki cross-coupling reaction has been a great contribution to
3
organic synthesis. Several heterocyclic compounds of biological
4
5
significance or complex natural products have been assembled
6
using a Heck reaction. Thus, because of its versatility, this
methodology has also been applied in certain intramolecular reac-
7
tions to construct carbocycles and heterocycles of various sizes.
Our endeavour commenced with the study of the dehydroala-
nine 5a (Scheme 2) which was easily prepared from o-bromoben-
zyl amine, acetic acid, tert-butyl isocyanide and benzoyloxy
acetaldehyde in two steps (Ugi 4-CR/elimination) in 65% yield
Palladium catalysis has also been applied in particular types of
rearrangement processes. For example, ring expansion of spirocy-
8
clopropanes, synthesis of 4-arylnicotinates through a domino
9
10
13
reaction, and 1,4-hydrogen shift, have been mediated by palla-
dium catalysis. Interestingly, during the palladium catalyzed syn-
thesis of 7-, 8-, and 9-membered rings under typical Heck
conditions, Gibson detected the formation of the rearranged by-
product 2, derived from the ortho iodo precursor 1 (after 120 h!),
but no further details of this observation were disclosed
under previously reported conditions. Surprisingly, when 5a
2 3 2
was submitted to the action of PdCl (PPh ) (10 mol%) and 2 equiv-
alents of AcONa in refluxing dimethylacetamide (DMA), a mixture
of the pyrroloisoindolone 13a and the corresponding rearranged
acrylamide 6a was achieved in good yield (61%) after 6 h (entry
1, Table 1). In principle, both products could have been produced
through a Pd-catalyzed tandem process, consisting initially of a
5-exo Heck-type cyclization to generate intermediate palladium
species 12, which may then react by two different processes. It
may undergo the interesting formation of an sp3-sp3 bond
generating a second 5-membered ring to afford 13a, or undergo a
b-amino elimination process by C–N bond fragmentation with con-
comitant double bond regeneration to produce the rearranged
1
1
(
(
Scheme 1). More recently, Xu and co-workers observed the Pd
OAc) catalyzed formation of the styrene derivatives 4 from enam-
2
ine 3. In this study, the 1,4-alkene migration was highly dependent
⇑
Corresponding author.
E-mail address: lmiranda@unam.mx (L.D. Miranda).
These authors contributed equally to the work.
a
https://doi.org/10.1016/j.tetlet.2018.01.058
040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
0
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2
M.C. García-González et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. X-ray structure of: (A) tricycle 13a (CCDC number 1532303); (B) ben-
zoazepine 14a (CCDC 1532294). Hydrogen atoms were removed for clarity.
acrylamide 6a (The lack of an alpha hydrogen in 12a prevents the
1
4
typical b-hydride elimination of a Heck process).
The structure 13a was unambiguously established by single
crystal X-ray analysis (Fig. 1). It is worth noting that even though
the yield of the tricycle 13a was low (14%), the outcome is relevant
because it represents a novel example of a Pd-catalyzed formation
of an sp3-sp3 single bond, featuring a C–H functionalization. In an
attempt to increase the yield of the tricyclic compound, the reac-
tion temperature was maintained at reflux for three days, although
no significant differences were detected (51% for 6a and 10% for
1
3a). On the assumption that the acrylamide 6a might be an inter-
Scheme 1. Palladium-catalyzed rearrangements of alkenes.
mediate in the formation of the pyrroloisoindolone 13a, it was sub-
jected to the above conditions for 5 days. However, no
transformation of 6a into 13a was detected, thus indicating that
the generation of the two compounds follows independent path-
ways from intermediate 12.
When equivalents of the base were reduced, the rearrangement
product 6a was isolated in lower yields and longer reaction times
(
entry 2–3, Table 1). Interestingly, the tricyclic derivative 13a
was not observed under these conditions. When the load of the
palladium catalyst was reduced, 6a was obtained in only 27% yield
along with recovered starting material (25%, entry 4). Similar result
was found when chloride derivative was submitted to the same
conditions (entry 5); 25% yield of 6a and 38% of the starting mate-
rial was recovered after 48 h.
Surprisingly, when the tert-butyl group was replaced by cyclo-
hexyl in the amide moiety of 5b, the main product isolated was
the corresponding rearranged acrylamide 6b (47% yield), and the
benzofused heterocycle 13b was not detected (Scheme 2). Further
modification of the substituent in the amide with a 2,6-dimethyl-
phenyl group (5c) resulted in decomposition of the starting mate-
rial and no major product was isolated. The limited information
regarding such rearrangements led us to examine the scope of
Scheme 2. Pd-Catalyzed sp3-sp3 C–C bond formation and olefin 1,4-migration.
Table 1
Influence of the equivalents of catalyst, base and halide used in the transformation.
O
H
O
N
N
HN
O
PdCl
2
(PPh
3
)
2
HN
O
O
+
AcONa, DMA
reflux
N
O
NH
5a
X
6a
1
3a
Entry
X
Time (h)
Catalyst
Base
6a (%)
13a (%)
1
2
3
4
5
Br
Br
Br
Br
Cl
6
10%
10%
10%
5%
2.0 eq
1.5 eq
1.0 eq
2.0 eq
2.0 eq
61
33
30
27
25
14
–
–
–
–
12
12
12
48
a
b
10%
a
2
3
5% of starting material recovered.
8% of starting material recovered.
b
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M.C. García-González et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
the process with different dehydroalanines. Interestingly, these
Table 2
Scope of the migration reaction via palladium catalysis.
starting materials are likely to rapidly accessed through the same
Ugi-4CR/elimination protocol used for the preparation of 5a–c
1
3
(
Scheme 2). At the outset, we envisioned that since the Ugi 4-
CR couples four different substrates (an aldehyde, a carboxylic acid,
an amine, and an isocyanide) in a single adduct, this approach
would offer the opportunity to prepare diversely functionalized
dehydroalanines. Thus, several of these molecules were synthe-
sized in good yields using benzyl and phenethyl amines, and vari-
ous carboxylic acids and isocyanides (Table 1). 2-benzoyloxy
acetaldehyde was used in all experiments, since this component
is the source of the double bond in the final product (See Table 1
in the Supplementary material structures and yields of the synthe-
sis of dehydroalanines).
With the starting materials in hand, we turned our attention to
the scope and limitations of the Pd-catalyzed olefin-rearrangement
process. Straightforwardly, a wide range of dehydroalanines with
different substitution patterns were used in this reaction, affording
the corresponding 2-arylacrylamides in moderate to good yields
(
Table 2).
When 5d (Table 2, R = tert-butyl, R = ethyl) was exposed to the
palladium-mediated transformation used for 5a [10 mol% of
PdCl (PPh and 2 equivalents of AcONa in refluxing DMA], the
,4-migration product 6d was obtained exclusively in high yield
92%). This styrene derivative remained as the main product even
when the experiment was conducted at reflux temperature for
6 h. Neither the 5-exo cyclization nor the pyrroloisoindolone
1
2
2
3 2
)
1
(
9
products were detected. Firstly, we were interested in determining
if the isocyanide used in the Ugi 4-CR had an effect on the course of
the transformation. Gratifyingly, when the tert-butyl group was
replaced by a cyclohexyl, we observed the formation of a struc-
turally analogous rearrangement product (6e) in 76% yield, indicat-
ing that the nature of the isocyanide had only a minor effect on the
1
,4-migration process.
We next modified the structure of the carboxylic acids utilized
in the Ugi 4-CR set and subjected these compounds to the rear-
rangement conditions. Both the isobutyric and benzoic acid
derived Ugi compounds afforded the expected styrene derivatives
(6f–g and 6h–i) respectively in yields of 21–76%. Furthermore, are-
nes substituted with different methoxy substitution patterns (6j–
q) when submitted to the 1,4-migration conditions also gave the
expected styrene derivatives. Notably, neither electron withdraw-
ing nor electron donating substituents in the benzylamine ring
(6p and 6q, respectively) had a significant effect on the global
yield. In a similar way, when the phenyl ring was decorated with
an electron withdrawing (F, 6r) or an electron donating group
(
3
OCH , 6s), the reaction also proceeded.
At this point, the viability of the 1,4-migration was corroborated
with the synthesis of several examples in modest to good yields.
Nonetheless, in the search for expanding the molecular diversity
in the chemical space and the scope of the methodology, we
extended the reaction by using dehydroalanines derived from
phenethylamine. We envisioned that this slight change in the
structure of the starting materials would provide 1,5-migration
products that have been scarcely reported in the literature. We
treated the dehydroalanine obtained from phenethylamine, tert-
butyl isocyanide, and acetic acid with the standard 1,4-migration
conditions and, satisfactorily, the expected 1,5-migration product
styrene 6t was obtained in moderate yield. Guided by this result,
several phenethyl-containing dehydroalanines were obtained and
reacted under the same migration conditions. This transformation
was effective with aliphatic chains in moderate yields (6u–w) and
also with aromatic rings with or without electron donating groups
Reaction conditions: PdCl
reflux, 6–12 h.
2 3 2
(PPh ) (10 mol%), AcONa (20 mol%), DMA (0.06 M),
Interestingly, when dehydroalanine contained a phenethyl moi-
ety, bearing an electron withdrawing group (F, Cl, NO ), the major
isolated product corresponded to the benzoazepine 14a, formed
through an uncommon 7-endo cyclization (Entry 1–3, Table 3).11
The structure of 14a was confirmed by X-ray crystallography (CCDC
number 1532294). Similarly, the 7-endo cyclization products were
2
(6x–z, Table 2). This outcome was significant since, to our
knowledge, only one example concerning a related 1,5-double
11
bond migration has been reported so far.
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4
M.C. García-González et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 3
Synthesis of benzoazepines 14a–f and 1,5-migration products.
Entry
Substrate
R1
R2
14 (%yield)
6 (%yield)
1
2
3
4
5
6
5aa
5ab
5ac
5ad
5ae
5af
t-Bu
t-Bu
t-Bu
Cy
Adamantyl
Cy
m-NO
p-Cl
p-F
p-Cl
p-Cl
p-F
2
48
43
43
–
17
18
–
–
–
11
20
Traces
2 3 2
Reaction conditions: PdCl (PPh ) (10 mol%), AcONa (20 mol%), DMA (0.06 M), reflux, 6–12 h.
Fig. 2. Selected HMBC correlation of 6t. Red and blue arrows show two and three
bond correlations, respectively.
1
observed when dehydroalanines 5aa and 5ab, (R = tert-butyl) were
reacted under the same conditions. Nonetheless, when the tert-
butyl group was replaced by cyclohexyl or adamantly groups (Entry
4
–6, Table 3) both cyclization and rearrangement products were
observed, although in low yields.
Even though the desired 1,5-double bond migration was not
observed, the 7-endo cyclization makes this result significant, since
normally 6-exo paths are expected to predominate over the 7-endo
1
1,15
counterparts.
Apparently, the electron-withdrawing groups
strongly affect the electronic nature of the double bond and the
molecular conformation of the dehydroalanine, in a way that the
7-endo pathway efficiently competes with the 6-exo cyclization.
However, the actual reason for this preference remains unclear
so far. Nevertheless, these experiments streamline and expand
the scope of the 7-endo Heck cyclization.11 In this context, Over-
man and co-workers have described a related cyclization through
typical Heck conditions during the synthesis of the terpene gua-
1
6
nacastepene N, while Gevorgyan reported a 7-endo cyclization
of phenolic ethylsilyl ethers to construct allyl silanes through a
1
7
Pd-radical process.
The characterization of all compounds was made through con-
ventional spectroscopy and spectrometry. Additional bidimen-
sional experiments (COSY, HSQC and HMBC) and DEPT-135 were
necessary to confirm the structure of alkene-migration products
(
see Supplementary material). As an example, the NMR character-
1
ization of 6t will be discussed. H NMR signals indicated the pres-
ence of a terminal alkene, thus no cyclization had occurred.
Moreover, the existence of four hydrogens in the aromatic region
confirmed that two positions of the aromatic ring were substi-
tuted. Furthermore, the methyl of the acetyl group also remained
unchanged. On the other hand, DEPT-135 confirmed the presence
of three methylenes, one being an alkene. A COSY experiment indi-
cated that the methylene from the aliphatic region was coupled
Scheme 3. Proposed mechanism for 1,4- and 1,5-double bond rearrangement of
dehydroalanines.
with the NH proton (broad signal). Finally, the expected correla-
tions were observed in the bidimensional HMBC experiment
(Fig. 2): correlations for H-12 (alkene) with C-13 (d 166.6), C-10
(d 137.5), C-11 (d 145.3). Additionally, H-3 was correlated with
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M.C. García-González et al. / Tetrahedron Letters xxx (2018) xxx–xxx
5
C-2 (d 170.2) and C-5 (d 137.2), and H-4 with C-5(d 137.2) and C-6
d 129.7).
A plausible mechanism for the 1,4- and 1,5-double bond migra-
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A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.01.058.
Please cite this article in press as: García-González M.C., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.01.058