A straightforward entry to functionalized carbo- and heterocycles based on Pd-mediated cyclizations

Article abstract of DOI:10.1055/s-2004-829181

The efficient and practical syntheses of functionalized carbo-and heterocyclic compounds have been achieved employing a process based on an intramolecular palladium-mediated cyclization coupled with a carbon-carbon bond forming reaction.

Full text of DOI:10.1055/s-2004-829181

PRACTICAL SYNTHETIC PROCEDURES
2407
A Straightforward Entry to Functionalized Carbo- and Heterocycles Based on
Pd-Mediated Cyclizations
S
T
ynthesis of Ca
h
rbo- and
H
et
i
erocycl
e
e
s
Basedo
r
nPd-Me
r
diate
d
C
y
yclizations Lomberget, Emmanuel Bossharth, Didier Bouyssi, Nuno Monteiro, Geneviève Balme*
Laboratoire de Chimie Organique 1, associé au CNRS, Université Claude Bernard Lyon 1,
CPE, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
Fax +33(4)72431214; E-mail: balme@univ-lyon1.fr
PSP
Received 15 March 2004
No28
Abstract: The efficient and practical syntheses of functionalized carbo-and heterocyclic compounds have been achieved employing a pro-
cess based on an intramolecular palladium-mediated cyclization coupled with a carbon-carbon bond forming reaction.
Key words: palladium, cross-coupling, cyclizations, carbocycles, heterocycles
OTf
(
1.5 equiv)
CN
CO2Me
2
Procedure 1:
KH, 18-Crown-6 20%
[PdCl2(PPh3)2, n-BuLi]
THF, r.t., 5 h
1
NC
CO2Me
7%
3
7
n-BuLi
mol% PdCl2(PPh3)2
SO2Ph
CO2Me
PhO2S
CO2Me
Ph
Ph
5
PhI
+
+
Procedure 2:
THF/DMSO (1/1), 50 °C
Ph
OH
O
4
5
6
61% (dr = 85:15)
7
I
CO2Me
I
OBn
O
I
9
Procedure 3:
(1.4 equiv)
N
O
N
O
CO2Me
[
PdCl2(PPh3)2, n-BuLi,THF],
MeCN, 60 °C, 48 h
8
93%
10
Scheme 1
2
Introduction
(Scheme 2). This cyclization which involves an attack by
the nucleophile onto an unsaturation activated by an orga-
The development of new methods for the formation of nopalladium(II) species provides a new route to function-
several carbon-carbon bonds and carbon-heteroatom alized five or six membered-rings with the advantage that
bonds in a single operation has become an important area it proceeds in a completely stereoselective trans-manner.
1
of research in organic chemistry. Following this trend, The synthetic potential of this reaction has recently been
2
the cyclization of unsaturated substrates bearing a carbo- widely exploited. This is due to the wide range of orga-
or hetero-nucleophile promoted by an organopalladium nopalladium species, the accessibility of the cyclization
complex has recently emerged as a powerful method for precursors as well as the simplicity of the procedure
the synthesis of complex molecules in one reaction which make this process highly attractive. In this report,
we would like to describe a convenient preparation of
SYNTHESIS 2004, No. 14, pp 2407–2410
x
x.
x
x
.
2
0
0
4
Advanced online publication: 27.07.2004
DOI: 10.1055/s-2004-829181; Art ID: Z05004SS
Georg Thieme Verlag Stuttgart · New York
©

2
408
T. Lomberget et al.
PRACTICAL SYNTHETIC PROCEDURES
functionalized 1,3-bis exocyclic dienes (Scheme 1, Proce- In marked contrast, the competing Heck reaction is never
dure 1: reaction involving a carbonucleophile), the utiliza- observed in the cyclization of alkene substrates bearing a
tion of this carbopalladation-cyclization process to the cyano group. For the cyclization of the alkynes, a compet-
‘
one-pot synthesis’ of stereodefined arylidene tetrahydro- itive reaction arises with the terminal ones due to the
furans by means of a three-component reaction strong tendency to give a direct coupling reaction of the
4
(
Scheme 1, Procedure 2) and the preparation under neu- alkyne with the aryl halide. The choice of the base has
tral conditions of furo[2,3-b]pyridones (Scheme 1, Proce- proven to be crucial for the success of the methodology.
dure 3: reaction involving a heteronucleophile).
The use of a strong base such as KH gives exclusively the
cyclized product while the use of a weaker base such as
Cs CO drastically changes the course of the reaction
since only compounds resulting from a Sonogashira cou-
pling reaction are obtained. The efficiency of this palladi-
um-mediated cyclization/coupling reaction has also been
shown to be strongly affected by the nature of the catalyst
system and best results were obtained in the presence of a
palladium(0) catalyst issued from the in situ reduction of
RX + Pd(0)
R
RPd(II)X
2
3
Pd
X
RPd
R
R'
R'
R'
Nu
Nu
Nu
- Pd(0)
recycled
R = alkyl, aryl, vinyl, propargyl, allenyl, alkynyl
R' = aryl, alkyl
PdCl (PPh ) with n-BuLi. A typical example of the for-
2
3 2
X = OAc, OTs, Cl, Br, I, OTf, OR''
mation of cyclohexane derivatives is shown in Procedure
1
. The stereodefined conjugated triene 3 is formed
Scheme 2
through a cyclization/coupling reaction involving the tri-
flate 2 and the conjugated enyne 1 having a stabilizing
carbon nucleophile. This procedure can be extended to a
wide range of aryl iodides and unsaturated bromides and
triflates.
Scope and Limitations
Procedure 1 represents the reactions involving a carbonu-
cleophile.
Procedure 2 illustrates the synthesis of the highly substi-
tuted tetrahydrofuran 7 by means of a multicomponent re-
action based on this palladium-mediated cyclization
Alkenes and acetylenes tethered with a stabilizing carbon
nucleophile are good substrates for the palladium-mediat-
ed preparation of functionalized five-membered carbocy-
cles. A large variety of stabilized carbanions may be
involved in these reactions such as malononitrile, b-di-
5
process. In this reaction, the enolate resulting from the
initial 1,4-addition of the propargyl alkoxide 5 to the con-
jugate acceptor 6 is followed by the palladium-mediated
cyclization reaction involving the aryl halide 4. This prep-
aration of furans from easily available and inexpensive
starting materials can be applied to a series of propargyl
alcohols, gem-diactivated olefins, aryl iodides and vinyl
esters, b-keto-, cyano- or sulfonyl esters. (pK in the range
a
of 9–19). Less stabilized anion such as methyl 2-phenyl-
sulfinylacetate does not give the expected cyclization. The
use of a strong base such as KH or tert-BuOK is necessary
to favor the intramolecular attack of the nucleophile. The
yields of carbocycles obtained are independent of the na-
ture of the aryl halide substituents.
6
bromides or triflates. To keep the procedure as simple as
possible, we developed a protocol involving equal
amounts of each partner, the reaction being carried out
generally at room temperature in the presence of the pal-
ladium catalyst in a mixture of THF and DMSO. The pres-
ence of DMSO is needed to inhibit the competitive
formation of 3-(4)-methylene tetrahydrofurans as side-
products. Temperature above 50 °C in the reaction with
less reactive substrates such as secondary and tertiary pro-
pargyl alcohols or gem-diactivated olefins bearing an ar-
ylsulfonyl group is needed. In this last case, the presence
of the allylic sulfone moiety provides an opportunity for
the introduction of another element of diversity or for fur-
The formation of the corresponding six-membered rings
proved to be more difficult since competing side reactions
occur. To delineate the scope of this reaction, we can
make the following observations. For the reactions in-
volving alkene substrates, the course of the reaction is
strongly affected by the nature of the nucleophile
3
(
Scheme 3). The linear substrate having a b-diesters gave
only the product of addition of the arylpalladium iodide to
the olefin (classical Heck reaction) without the formation
of the 6 exo-cyclization product.
Z, Z' = CN
Ar
Z
Z'
Z
ArI, Pd(0)
Base
Ar
Z'
Z
Z'
Z = CN, Z' = CN,
CO2Me, SO2Ph
Scheme 3
Synthesis 2004, No. 14, 2407–2410 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Functionalized Carbo- and Heterocycles
2409
ther functionalizations. This procedure can be extended to to use. KH (35% in mineral oil) was washed with anhyd THF, dried
propargyl amines.7
and stored under nitrogen before use.
Thin layer chromatography (TLC) was carried out with MERCK
Analogously, this type of palladium-initated cyclization/
6
0F254 silica gel plates (supported on aluminum); visualization was
coupling reactions may be developed on alkynes tethered
with heteronucleophiles such as nitrogen or oxygen.2a,c,d
done by UV lamp (254 nm and 365 nm) and chemical staining
acidic solution of p-anisaldehyde in EtOH). Preparative flash chro-
(
Indeed, while a number of examples of intramolecular re-
actions of stabilized carbon nucleophiles on an alkene co-
ordinated by an organopalladium complex are known, to
the best of our knowledge, there is no example of the same
reaction performed in the presence of heteronucleophile.2
This palladium-initiated cyclization/cross-coupling reac-
matography was carried out under medium pressure using Merck
silica gel 60 Å (40–63 mm); volumetric composition of the eluent is
indicated in parentheses.
IR spectra were recorded on a Perkin-Elmer FT-IR PARAGON 500
spectrometer. NMR spectra were recorded at r.t. on BRUKER AM
3
00, ALS 300, DRX 300 and BRUKER AC 200 apparatus. Internal
tion involving heteronucleophiles generally needs the references are tetramethylsilane (d = 0.0 ppm) or residual protons of
1
presence of an anionic nucleophile. A typical example is deuterated solvents (d = 7.26 ppm for H NMR and d= 77.16 ppm
8
13
for C NMR for CDCl ). Letters s, d, t, q, quint, hept, m and br, re-
shown in Scheme 4.
3
spectively, refer to singlet, doublet, triplet, quadruplet, quintuplet,
heptuplet, multiplet and broad. Low- and high-resolution mass
spectra were recorded with a Thermoquest Finnigan MAT 95 XL
Procedure 3 illustrates the preparation of the furo[2,3-
b]pyridone 10 through an intramolecular palladium-medi-
ated cyclization of the 4-benzyloxy-N-methyl-2-pyridone apparatus operating at 70eV (for chemical ionizations, isobutane
8
with the 1,4-diiodobenzene (9); the reaction being per- was used). Melting points were measured on a Büchi B-540 appara-
tus and are uncorrected. Elemental analyses were performed by the
formed here under neutral conditions as no base is need-
9
Service Central d’Analyses du CNRS, Solaize, France.
ed. The furo[2,3-b]pyridone 10 results from an attack of
the amide onto the palladium-activated triple bond. This is
followed by an in situ cleavage of the benzyl ether group,
apparently by a Pd(II) species. In this cyclization/coupling Few drops of n-BuLi (2.6 M in hexanes) were added to a stirred sus-
(
E)-1-Cyano-2-cyclohex-1-enyl-methylene-3-cyclohexancar-
boxylic Acid Methyl Ester (3); Typical Procedure
reaction, good yields were obtained with arylic halides pension of PdCl (PPh ) (35 mg, 0.05 mmol) in THF (2 mL) until
2
3 2
the solution turned dark green. The resulting solution was heated
with a heat gun until the solution turned dark red.
bearing electron-withdrawing groups while electron-rich
aryl iodides gave poor results. In this last case, as we have
a weak nucleophile, it is necessary to have an organopal- In a separate flask, KH (48 mg, 1.2 mmol) and 18-crown-6 (53 mg,
0
.2 mmol) were suspended in THF (6 mL). Enyne 1 (191 mg, 1
ladium intermediate able to strongly coordinate to the un-
saturation in order to trigger the intramolecular attack of
the heteronucleophile to the alkyne. To our knowledge,
this cyclization/cross-coupling reaction constitutes the
only example of such a reaction performed under com-
pletely neutral conditions.
mmol) in THF (2 mL) was added dropwise followed by cyclohexe-
nyl triflate 2 (345 mg, 1.5 mmol) and the resulting solution was
stirred during 15 min. Then, palladium catalyst solution was added
to the reaction mixture. The reaction conversion was monitored by
TLC until the disappearance of the starting enyne 1. The crude prod-
uct was directly filtered onto a pad of celite, and concentrated under
vacuum. The residue was purified by chromatography on silica gel
In summary, the procedures described here provide an ef-
ficient and practical route for the preparation of a variety
of carbo- and heterocyclic compounds. The reactions pro-
ceed under mild reaction conditions and various function-
al groups are well tolerated.
(
petroleum ether–Et O, 70:30) to yield 3 as a yellow pale solid;
2
yield: 208 mg (77%); mp 81–82 °C.
IR (KBr): 3080, 2920, 2850, 2830, 2240, 1745, 1630, 1445, 1430,
1
6
1
245, 1200, 1180, 1170, 1075, 1030, 1005, 935, 900, 880, 840, 740,
40 cm .
–1
H NMR (CDCl ): d = 1.53 (m, 4 H), 1.81–2.17 (m, 7 H), 2.29 (t,
3
All the reactions were carried out under a positive pressure of nitro-
gen and with oven-dried glassware. Petroleum ether (PE) refers to
J = 6.3 Hz, 2 H), 2.49 (ddd, J = 13.4, 6.8, 4.4 Hz, 1 H), 3.82 (s, 3 H),
4.88 (d, J = 2.2 Hz, 1 H), 5.10 (s, 1 H), 5.84 (br s, 1 H), 6.09 (s, 1 H).
4
0–60 °C boiling point fraction. All the reaction solvents were dis-
13
C NMR (CDCl ): d = 22.0, 22.9, 23.6, 26.1, 28.2, 35.3, 35.5, 53.3,
3
tilled prior to use: over Na/benzophenone for THF and over CaH2
for CH CN and DMSO. All reagents, except commercial products
of satisfactory quality, were purified via literature procedures prior
53.5, 116.8, 118.4, 131.7, 133.0, 134.7, 142.6, 142.7, 167.6.
3
Anal. Calcd for C H NO : C, 75.25; H, 7.80; N, 5.16. Found: C,
1
7
21
2
7
5.50; H, 7.63; N, 5.18.
R1
R
t-BuOK, DMSO
Pd(OAc) , TFP
R2
CO H
2
O
2
O
R2
R1
R
Br
1
2
R , R = H, CH
R = aryl, alkyl
3
Scheme 4
Synthesis 2004, No. 14, 2407–2410 © Thieme Stuttgart · New York

2
410
T. Lomberget et al.
PRACTICAL SYNTHETIC PROCEDURES
1
Methyl (±)-3-Benzenesulfonyl-4-benzylidene-2-phenyltetrahy-
drofuran-3-carboxylate (7); Typical Procedure
H NMR (300 MHz, DMSO-d ): d = 3.85 (s, 3 H), 3.86 (s, 3 H), 6.01
6
(d, J = 7.5 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 2 H), 7.55 (d, J = 8.3 Hz, 2
n-BuLi (2.0 M in hexanes, 550 mL, 1.1 mmol) was slowly added to
H), 7.62 (d, J = 7.5 Hz, 1 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.92 (d, J =
8.3 Hz, 2 H).
an ice cooled solution of propargyl alcohol (5) (75 mL, 1.1 mmol) in
THF (2.5 mL) under N , and stirring was continued for 5 min, at
13
2
C NMR (75 MHz, DMSO-d ): d = 37.2, 53.0, 95.2, 112.0, 115.4,
6
which time the ice bath was removed. Methyl trans-a-benzene-
sulfonyl cinnamate 6 (234 mg, 1.0 mmol) was then added and the
resulting enolate solution was stirred at r.t. for an additional 5 min.
Meanwhile, in a separate flask, n-BuLi (2.0 M in hexanes, approx
1
1
21.8, 126.8, 129.8, 130.4, 131.3, 133.2, 134.2, 137.8, 138.1, 143.5,
54.7, 166.5, 174.9.
+
+
HRMS (CI): m/z [MH ] calcd for C H INO : 486.0203; found:
22 17
4
4
86.0202.
5
0 mL, 0.1 mmol) was added dropwise to a well stirred suspension
of PdCl (PPh ) (35 mg, 0.05 mmol) in DMSO (2.5 mL) under N
2
3 2
2
until a dark red homogeneous solution was obtained. Iodobenzene
225 mg, 1.1 mmol) was then added and the resulting palladium
References
(
complex solution was subsequently transferred via cannula to the
enolate solution. The reaction mixture was stirred at 50 °C for 1 h
(
1) (a) Negishi, E. I. Pure Appl. Chem. 1992, 64, 323.
b) Overman, L. E.; Abelman, M. M.; Kucera, D. J.; Tran, V.
(
and then partitioned between EtOAc and aq NH Cl solution. The
4
D.; Ricca, D. J. Pure Appl. Chem. 1992, 64, 1813. (c) Hok,
T. L. Tandem Organic Reactions; Wiley Interscience: New
York, 1992. (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. Engl. 1993, 32, 131. (e) Bunce, R. A. Tetrahedron
aqueous phase was extracted with EtOAc (3 ×), and the combined
organic layers were dried over Na SO and concentrated in vacuo.
2
4
The residue was subjected to silica gel chromatography (EtOAc–
petroleum ether, 1:4) to afford the tetrahydrofuran 7 (265 mg (61%)
as a mixture of diastereomers (cis:trans = 15:85). A pure sample of
the trans isomer was obtained for analysis; solid; mp 122–124 °C
1995, 51, 13103. (f) Tsuji, J. Palladium Reagents and
Catalysts: Innovations in Organic Chemistry; Wiley:
Chichester, 1995. (g) Tetrahedron, Symposium-in-Print
(
EtOH).
1996, Vol. 52(35). (h) Bräse, S.; de Meijere, A. In Metal-
Catalyzed Cross-coupling Reactions; Diederich, F.; Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998, 99. (i) De
Meijere, A.; Bräse, S. J. Organomet. Chem. 1999, 576, 88.
2) (a) Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro, N.
Synthesis 2003, 2115. (b) For reactions involving
Trans-isomer
1
H NMR (300 MHz, CDCl ): d = 8.05 (d, J = 8.5 Hz, 2 H), 7.75–
3
7
4
3
.25 (m, 11 H), 7.12 (d, J = 8.5 Hz, 2 H), 6.83 (s, 1 H), 5.98 (s, 1 H),
.87 (dd, J = 13.2, 1.9 Hz, 1 H), 4.23 (dd, J = 13.2, 2.6 Hz, 1 H),
.29 (s, 3 H).
(
carbonucleophiles, see: Balme, G.; Monteiro, N.; Bouyssi,
D. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; Wiley & Sons: New York,
1
3
C NMR (50 MHz, CDCl ): d = 165.2, 137.1, 136.3, 135.7, 134.4,
3
1
8
33.3, 131.8, 131.5, 128.9, 128.7, 128.6, 128.5, 128.4, 128.2, 127.1,
6.8, 84.1, 70.8, 52.6.
2002, 2245–2265. (c) For oxygen nucleophiles see: Cacchi,
S.; Arcadi, A. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., Ed.; Wiley & Sons:
New York, 2002, 2193–2210. (d) For nitrogennucleophiles,
see: Cacchi, S.; Marinelli, F. In Handbook of
+
HRMS (CI): m/z [MH ] calcd for C H O S: 435.1266; found:
2
5
23
5
4
35.1265.
Cis-isomer
1
Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I., Ed.; Wiley & Sons: New York, 2002, 2227–
Deduced from mixture of isomers. H NMR (300 MHz, CDCl ):
3
d = 7.97 (d, J = 8.5 Hz, 2 H), 7.75–7.25 (m, 11 H), 7.12 (d, J = 8.5
Hz, 2 H), 6.40 (s, 1 H), 6.05 (s, 1 H), 5.21 (dd, J = 13.9, 2.3 Hz, 1 H),
.92 (dd, J = 13.9, 2.6 Hz, 1 H), 3.94 (s, 3 H).
2244.
(
(
(
(
(
(
(
3) Bouyssi, D.; Coudanne, I.; Uriot, H.; Goré, J.; Balme, G.
Tetrahedron Lett. 1995, 36, 8019.
4) Lomberget, T.; Bentz, E.; Bouyssi, D.; Balme, G. Org. Lett.
4
4
-[3-(4-Iodophenyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]py-
ridin-2-yl]-benzoic Acid Methyl Ester (10)
2
003, 5, 2055.
5) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem.
003, 4101.
n-BuLi (2.5 M in hexanes) was added dropwise to a suspension of
PdCl (PPh ) (6.5 mg, 0.009 mmol) in THF (1mL) until the mixture
turned dark green. A heat gun was then used to gently heat the mix-
ture and obtain a homogeneous dark red solution. MeCN (3 mL),
the pyridone derivative 8 (0.19 mmol) and the aromatic halide 9
0.27 mmol) were then successively added. The reaction mixture
was left to stir for 48 h at 60 °C and concentrated in vacuo. The res-
idue was purified by chromatography on silica gel (acetone) to yield
2
2
3 2
6) Bottex, M.; Cavicchioli, M.; Hartmann, B.; Monteiro, N.;
Balme, G. J. Org. Chem. 2001, 66, 175.
7) Azoulay, S.; Monteiro, N.; Balme, G. Tetrahedron Lett.
2
002, 44, 9311.
8) Bouyssi, D.; Goré, J.; Balme, G. Tetrahedron Lett. 1992, 33,
811.
(
2
9) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org.
Lett. 2003, 5, 2441.
1
0 as a yellow solid; yield: 85 mg (93%); mp 272 °C (decomp.)
Synthesis 2004, No. 14, 2407–2410 © Thieme Stuttgart · New York