Palladium-catalyzed ring opening of aminocyclopropyl Ugi adducts

Article abstract of DOI:10.1055/s-0031-1290312

The ring opening of aminocyclopropanes triggered by activation with an intramolecular arylpalladium(II) iodide complex is an interesting strategy for the synthesis of nitrogen heterocycles and a valuable Ugi postcondensation-type transformation. Six- and

Full text of DOI:10.1055/s-0031-1290312

438
LETTER
Palladium-Catalyzed Ring Opening of Aminocyclopropyl Ugi Adducts
Ring Opening of
A
u
minocyclop
r
r
opyl
U
g
é
i
A
dducts lie Dos Santos, Laurent El Kaïm,* Laurence Grimaud,* Romain Ramozzi
Laboratoire DCSO ENSTA-Polytechnique-CNRS, UMR 7652, Ecole Nationale Supérieure de Techniques Avancées,
32 Bd Victor, 75739 Paris Cedex 15, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: grimaud@dcso.polytechnique.fr
Received 14 November 2011
Ugi reactions6 involving cyclopropylamines could serve
as a platform to study the potential intramolecular arylpal-
ladium(II) interaction with the cyclopropyl moiety. The
recent report by Rousseaux et al. suggesting that cyclo-
propylamine derivatives may ring open via a palladium-
triggered concerted metalation–deprotonation (CMD)
process7 prompted us to disclose our results obtained with
both different catalytic system and starting materials.
Abstract: The ring opening of aminocyclopropanes triggered by
activation with an intramolecular arylpalladium(II) iodide complex
is an interesting strategy for the synthesis of nitrogen heterocycles
and a valuable Ugi postcondensation-type transformation. Six- and
seven-membered-ring cyclic enamines may be obtained.
Key words: aminocyclopropanes, ring opening, palladium, Ugi,
Ugi–Smiles
Due to our ongoing interest in multicomponent reactions
(MCR), we decided to assemble a cyclopropyl moiety and
an aryl iodide precursor of the arylpalladium species via
Ugi-type coupling.
Cyclopropanes represent a unique class of compounds in
organic chemistry. The carbon–carbon s-bonds of these
strained compounds display reactivities closer to p-bonds
leading to their usual treatment as bent bonds or Walsh or-
bitals. This property has motivated a great number of cy-
clopropane ring-opening studies under transition-metal
catalysis.1 In these reactions, the cyclopropyl moiety in-
teracts as an alkene with a carbon–metal bond generated
in the vicinity of the strained cycle. Thus, cyclopropyl
equivalents of p-allyl complex may be involved in various
palladium-catalyzed cascades starting with vinyl or alky-
lidene cyclopropyl derivatives and leading to intermediate
palladacycles.2 Oxa analogues of these palladacycles have
been reported as well in various oxidative or reductive re-
arrangements of hydroxy or ketocyclopropane deriva-
tives.3 In comparison, the ring opening of amino-
cyclopropanes is less documented. Under thermal or acid-
ic conditions, aminocyclopropanes are known to rear-
range into enamine derivatives which may be further
transformed (for instance by oxidation to pyridines or acy-
lation).4 Following our study on the palladium ring open-
ing of furan-substituted Ugi adducts,5 we envisaged that
In order to test the feasibility of the ring opening, the Ugi–
Smiles8 reaction was carried out using an iodinated hy-
droxypyridine as the acidic partner. As such, the four-
component adduct was obtained in one step. The ring-
opening reaction was then evaluated under the conditions
previously developed for the furan cleavage. Thus, an ac-
etonitrile solution of the Ugi–Smiles adduct 1a was sub-
mitted to microwave irradiation after addition of 5 mol%
of PdCl2(PPh3)2 and 1.5 equivalents of diisopropylethyl-
amine. After heating the mixture at 130 °C for 20 minutes
the desired dihydropyridopyridine 2a was obtained in
quantitative yield (Scheme 2).
The aminocyclopropane ring opening turned out to be
quite general as several Ugi–Smiles adducts 1 were pre-
pared and submitted successfully to the palladium-cata-
lyzed reaction. Indeed, the reaction carried out with an
aryliode (Table 1, entry 1) or with an iodinated heterocy-
cle (Table 1, entries 2–6) affords the desired dihydropyri-
O
Pd(OAc)2 (5 mol%)
O
NH2
P(t-Bu)2Me•HBF4 (10 mol%)
X
2 steps
MeO
N
MeO
N
X
CsOPiv (30 mol%)
K3PO4 (1.5 equiv)
100 °C
X = Br, Cl
X = Br
87%
CMD
MeO2C
+
N
MeO2C
N
H
O
RO
Pd
Pd
t-Bu
O
A
B
Scheme 1 Ring opening reported by Rousseaux et al.
SYNLETT 2012, 23, 438–442
x
x.
x
x.
2
0
1
2
Advanced online publication: 19.01.2012
DOI: 10.1055/s-0031-1290312; Art ID: D66411ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ring Opening of Aminocyclopropyl Ugi Adducts
439
dine derivatives 2 in moderate to good yields. In the case former examples. As compiled in Table 2, the ring open-
of Ugi–Smiles adducts resulting from the coupling of an ing of the four-component adducts proceeded smoothly
aromatic aldehyde (Table 1, entry 4), the reaction is less under palladium catalysis, and the corresponding benzo-
efficient probably due to competitive fragmentation as azepinones 4 were isolated in good yields.
previously reported.9
These results must be analyzed in the light of the recent
The reaction was then extended to Ugi adducts 3 by re- study of Rousseaux et al. (Scheme 1). Their reported
placing the phenol with 2-iodobenzoic acid. The behavior structures are close to the ones we obtained with Ugi–
of these adducts towards the palladium catalyst is interest- Smiles adducts, but their work is limited to the reactivity
ing as both the functional environment of the cyclic nitro- of bromo and chloro derivatives together with the use of a
gen and size of the resulting cycle are different from the catalytic system [Pd(OAc)2, PivOH, PR3] prone to trigger
Table 1 Synthesis of Dihydropyridine Derivatives 2
NHR2
O
NHR2
O
R3
X
OH
I
R1
R1
Y
PdCl2(PPh3)2
i-Pr2NEt
R3
R3
X
X
N
I
N
R1CHO
R2NC
MeOH
R4
+
Y
Y
12 h, 65 °C
MeCN
130 °C, 20 min
MW
NH2
R5
R5
R4
R4
R5
1
2
Entry
1
Yield (%)
72
2
Yield (%)
86
NH(PMB)
NH(PMB)
O
Et
NO2
Et
NO2
O
1
N
N
I
NH(CH2C6H4-4-Cl)
O
NH(CH2C6H4-4-Cl)
O
Et
Et
2
3
30
92
85
N
N
N
N
I
O2N
O2N
NH(CH2C6H4-4-Cl)
O
NH(CH2C6H4-4-Cl)
O
100
N
I
N
N
N
N
N
MeO
Ph
MeO
Ph
NH(PMB)
O
NH(PMB)
O
4
5
6
38
77
37
25
64
N
N
N
N
I
N
N
NH(CH2C6H4-4-Cl)
O
NH(CH2C6H4-4-Cl)
O
i-Bu
i-Bu
Ph
N
Ph
N
N
N
N
N
I
NH(PMB)
O
NH(PMB)
O
4510
N
N
N
N
I
N
N
Ph
Ph
© Thieme Stuttgart · New York
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440
A. Dos Santos et al.
LETTER
NH2
R2
R2
R1CHO
R2NC
R1
R1
PdCl2(PPh3)2
i-Pr2NEt
N
OH
I
O
O
N
N
N
N
I
MeOH
12 h, 65 °C
MeCN
130 °C, 20 min
MW
O2N
O2N
2a R1 = i-Bu, R2 = PMB
O2N
quant.
1a R1 = i-Bu, R2 = PMB
Scheme 2 First aminocyclopropane ring opening (ACRO)
CH-activation processes. Under these conditions, it is not ed with the use of a multicomponent process to obtain the
surprising that their mechanistic study led them to con- starting cyclopropylamine may lead to interesting cas-
clude that the aminocyclopropane ring opening requires a cades. Thus, the Ugi coupling of iodobenzaldehyde, iodo-
prior CMD step to form an azapalladabicyclo[4.1.0]hep- benzoic acid, and cyclopropyl amine affords in one step a
tane intermediate A followed by the cyclopropyl ring suitable adduct for a palladium-triggered aminocyclopro-
opening to form palladacycle B (Scheme 1). Their conclu- pane ring opening–Heck cascade (Scheme 4). In this case,
sion is supported by the absence of reaction without piv- the regioselectivity issues raised by the presence of two
alic acid.11
different iodides may be controlled by the different elec-
tronic nature of the aryl moiety; the more electrophilic io-
dobenzamide being expected to react first with the
palladium(0) catalyst. The final tetracycle 8a was ob-
tained as a single diastereomer in a 60% isolated yield.
Herein, the productive cyclization and ring opening with
a palladium catalyst traditionally used in standard cross-
coupling reactions indicates that an alternative mecha-
nism may be operating at least with aryl iodides. To ad-
dress whether this behavior could be attributed to the
more complex nature of the Ugi adducts, we decided to
prepare less complex starting aryliodocyclopropyl deriva-
tives using standard synthetic pathways (Scheme 3).
When 5a and 5b were treated with palladium under our
conditions, the expected fused dihydroquinolines were
isolated in moderate 40% and 74% yields. The latter could
be increased by replacing diisopropylethylamine with ce-
sium carbonate.
O
NHCy
NH2
O
I
O
I
O
I
H
OH MeOH
40%
N
+
I
CyNC
7a
MeCN
130 °C, 20 min
MW
PdCl2(PPh3)2 (5 mol%)
Cs2CO3 (1.1 equiv)
CONHCy
O
R
N
R
N
N
N
N
N
N
PdCl2(PPh3)2 (5 mol%)
base (1.1 equiv)
I
8a
60%
MeCN
130 °C, 20 min
MW
Scheme 4 Palladium-triggered cascade of Ugi adducts
base:
i-Pr2NEt
Cs2CO3
5a: R = Me
5b: R = Bn
6a: R = Me 40%
6b: R = Bn 74%
61%
83%
To conclude, we have extended the scope of the palladi-
um-triggered ring opening of amino cyclopropanes. Six-
and seven-membered-ring heterocycles may be easily
formed under palladium catalysis. The use of
PdCl2(PPh3)2 as catalyst indicates that the previously sug-
gested CMD mechanism may not be operative in this case.
The synthetic potential of this reaction has been demon-
strated in a palladium-triggered aminocyclopropane ring
opening–Heck cascade. We are currently studying the
mechanism of these ring openings as well as their integra-
tion in various cascades.
Scheme 3 Quinolines from standard starting materials
The mechanism involving a CMD or a direct ring opening
of the cyclopropyl through interaction with a cationic pal-
ladium intermediate species merits further consideration.
Such a mechanistic discussion could obviously be extend-
ed to the reported palladium-catalyzed ring opening of hy-
droxycyclopropanes such as the Fujiwara–Nakamura
intermolecular arylation3b,c or the more recent report of
Orellana.3h In the first case, the use of a starting triflate to-
gether with the lack of a suitably positioned directing
group to form a palladacycle intermediate through a CMD
is more in favor of a direct ring opening.
N-(4-Chlorobenzyl)-2-[cyclopropyl(5-iodo-2-isopropyl-6-meth-
ylpyrimidin-4-yl)amino]acetamide (1d)
To a solution of 5-iodo-2-isopropyl-6-methylpyrimidin-4-ol (278
mg, 1.0 mmol) in MeOH under argon atmosphere were added form-
aldehyde (75 mL, 1.0 mmol), cyclopropylamine (70 mL, 1.0 mmol),
and p-chlorobenzylisocyanide (150 mL, 1.0 mmol). The reaction
Besides the mechanistic challenge highlighted by these
results, one must not forget the synthetic interest of these
transformations. Indeed, the enamine formation associat-
Synlett 2012, 23, 438–442
© Thieme Stuttgart · New York

LETTER
Ring Opening of Aminocyclopropyl Ugi Adducts
441
Table 2 Synthesis of Benzoazepinones 4
O
R1
NHR2
O
O
I
R1
OH
PdCl2(PPh3)2
NHR2
I
R1CHO
R2NC
MeOH
i-Pr2NEt
N
N
O
+
O
MeCN
130 °C, 20 min
12 h, 65 °C
NH2
MW
R3
4
R3
R3
3
Entry
3
Yield (%)
95
4
Yield (%)
i-Bu
O
N
I
i-Bu
NH(CH2C6H4-4-Cl)
O
NH(CH2C6H4-4-Cl)
1
2
79
70
N
O
O
Et
NH(PMB)
O
O
Et
NH(PMB)
NHt-Bu
65
59
N
N
N
O
O
I
NHt-Bu
O
O
N
O
3
4
6510
O
I
Ph
Ph
OMe
OMe
O
I
60
78
NH(CH2C6H4-4-Cl)
O
NH(CH2C6H4-4-Cl)
N
N
O
O
NH(CH2C6H4-4-Cl)
NH
i-Bu
O
O
I
5
6
80
66
55
69
Ph
N
N
NHt-Bu
N
N
O
NH(PMB)
O
NH
O
I
N
N
NH(PMB)
N
N
Ph
O
mixture was stirred for 3 d at 60 °C. The solvent was removed under
reduced pressure and purification by flash column chromatography
on silica with a PE–Et2O mixture (75:25) gave the adduct 1d as a
white solid (461 mg, 92%); mp 121–122 °C. Rf = 0.1 (PE–Et2O,
N-(4-Chlorobenzyl)-2-{2-isopropyl-4-methylpyrido[2,3-d]pyri-
midin-8(5H)-yl}acetamide (2d)
To a solution of 1d (100 mg, 0.200 mmol) in MeCN (0.1 M) were
added a catalytic amount of PdCl2(PPh3)2 (7 mg, 0.010 mmol) and
DIPEA (34 mL, 0.200 mmol). The mixture was stirred for 20 min at
130 °C under MW irradiation (100 W, 13 bar). The solvent was re-
moved under reduced pressure and purification by flash column
chromatography on silica, eluting with a PE–Et2O mixture (30:70),
gave 2d as a white solid (74 mg, quant.); mp 168–169 °C. Rf = 0.1
(100% Et2O). 1H NMR (400 MHz, CDCl3): d = 7.18 (d, J = 8.3 Hz,
2 H), 7.07 (d, J = 8.3 Hz, 2 H), 6.71 (br s, 1 H), 5.93 (d, J = 7.6 Hz,
1 H), 4.73 (dt, J = 7.6, 4.0 Hz, 1 H), 4.33 (d, J = 5.8 Hz, 2 H), 4.20
(s, 2 H), 3.41 (s, 2 H), 2.80 (sept, J = 6.8 Hz, 1 H), 2.16 (s, 3 H), 1.08
1
5:5). H NMR (400 MHz, CDCl3): d = 7.34 (br s, 1 H), 7.18 (d,
J = 8.1 Hz, 2 H), 7.05 (d, J = 8.1 Hz, 2 H), 4.33 (d, J = 5.8 Hz, 2 H),
4.23 (s, 2 H), 3.14–3.12 (m, 1 H), 2.80 (sept, J = 6.8 Hz, 1 H), 2.59
(s, 3 H), 1.09 (d, J = 6.8 Hz, 6 H), 0.76–0.74 (m, 2 H), 0.50–0.48
(m, 2 H). 13C NMR (100.6 MHz, CDCl3): d = 172.5, 170.9, 170.8,
165.1, 136.6, 133.2, 129.1, 128.7, 81.3, 55.8, 42.7, 36.4, 35.7, 30.3,
21.5, 11.2. HRMS: m/z calcd for C20H24ClIN4O: 498.0683; found:
498.0683. IR: n = 1666, 1536, 1436, 1356, 1264, 1231, 1091, 1015
cm–1.
© Thieme Stuttgart · New York
Synlett 2012, 23, 438–442

442
A. Dos Santos et al.
LETTER
Kuwajima, I. J. Am. Chem. Soc. 1988, 110, 3296.
(d, J = 6.8 Hz, 6 H). 13C NMR (100.6 MHz, CDCl3): d = 172.0,
169.4, 163.6, 156.5, 136.5, 133.2, 130.3, 128.9, 128.7, 108.2, 101.7,
52.0, 42.6, 37.0, 24.2, 21.6, 21.3. HRMS: m/z calcd for
C20H23ClN4O: 370.1560; found: 370.1557. IR: n = 1649, 1559,
1538, 1459, 1396, 1263, 1220, 1091 cm–1.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
R.R. thanks the Ecole Normale Superieure de Lyon for a Fel-
lowship. We thank ENSTA and CNRS for financial support and
Céline Pereira for assistance.
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Synlett 2012, 23, 438–442
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