π-allyl palladium complexes as efficient and powerful alternative for nucleophilic substitution on bicyclo[3.1.0]hexane sulfonates: Regio-, chemo- and stereoselectivity

Article abstract of DOI:10.1055/s-2006-939716

The preparation of cyclopropylidene bicyclo[3.1.0]hexane derivatives has been performed on both exo- and endo-bicyclo[3.1.0]hexane sulfonates, through nucleophilic substitution via π-allyl palladium complexes. While the endo- and exo-configurations do not

Full text of DOI:10.1055/s-2006-939716

LETTER
1407
p-Allyl Palladium Complexes as Efficient and Powerful Alternative for
Nucleophilic Substitution on Bicyclo[3.1.0]hexane Sulfonates: Regio-, Chemo-
and Stereoselectivity
Nucleophilic
S
r
ubstituti
é
on on Bicy
d
clo[3.1. 0]hex
é
ane Sulfon
r
ates ic Lecornué,b Florence Charnay-Pouget,a Jean Ollivier*a
a
Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Bât. 420, Université
Paris-Sud, 91405 Orsay, France
Fax +33(1)69156278; E-mail: jollivie@icmo.u-psud.fr
b
Synthèse et Réactivité des Substances Naturelles, Département de Chimie, SFA-UMR 6514, Université Poitiers, 40 Avenue du Recteur
Pineau, 86022 Poitiers, France
Received 14 February 2006
Cl
Cl
Abstract: The preparation of cyclopropylidene bicyclo[3.1.0]hex-
ane derivatives has been performed on both exo- and endo-bicyc-
lo[3.1.0]hexane sulfonates, through nucleophilic substitution via p-
allyl palladium complexes. While the endo- and exo-configurations
do not particularly affect the selectivities of the products, on the oth-
er hand, the ‘hard’ or ‘soft’ nature of nucleophiles dramatically en-
hances the conservation or not of the integrity of the cyclopropane
rings.
MgBr
OH
HO
Cl(CH2)2COOEt
+
:
Ti(Oi-Pr)4
(63%)
3
exo-4
endo-5
63
37
Scheme 1
Key words: palladium, chemoselectivity, complexes, nucleophilic
additions, regioselectivity, ring-opening
Thus, the exo-alcohol 4 was esterified to the tosylate 6
then dehydrochlorinated to furnish 1-vinylcyclopropyl-
tosylate (7) in 70% overall yield (Scheme 2).
Several years ago, Schöllkopf1 studied the acetolysis of
exo- and endo-bicyclo[3.1.0]hexane p-toluenesulfonates
and observed that the exo-ester 1a was recovered un-
changed to the extent of more than 90% after three months
at 150 °C in (acetate buffered) acetic acid (krel << 0.01)
while the endo-ester 1b underwent a very fast reaction
(krel = 25000) to produce the cis-2-cyclohexen-1-yl ace-
tate (2) through a strain free cyclohexenyl cation generat-
ed by an inward disrotatory cyclopropyl ring-opening
(Figure 1).
Cl
OTs
OTs
t-BuOK
NaH, TsCl
exo-4
THF, 65 °C, 3 h
DMF, 20 °C
6 (74%)
7 (95%)
Scheme 2
However, we were unfortunately unable to reproduce the
same sequence with the endo-alcohol 5. Indeed, the
tosylation reaction failed, certainly due to steric hin-
drance. Confirmation of our hypothesis was brought by
the fact that, while trapping the cyclopropanation reaction
with tosyl chloride before final hydrolysis, a mixture of
exo-tosylate 6 and endo-alcohol 5 was isolated, while no
trace of endo-sulfonate 8 was detected (Scheme 3).
OTs
TsO
+
OAc
1a
2
1b
Figure 1
In our recent work,2 we related that the titanium(IV)-me-
diated cyclopropanation of cyclopentylmagnesium bro-
mide with ethyl b-chloropropionate (3, Kulinkovich
reaction3) led in 63% yield to a mixture of (exo/endo =
63:37) 6-(2¢-chloroethyl)bicyclo[3.1.0]hexane-6-ols 4a,b
separable by silica gel chromatography (Scheme 1).
1) Ti(Oi-Pr)4, 3
Cl
THF, Et2O
TsO
+
+
endo-5
6
MgBr
2) TsCl, 20 °C
(15%)
(32%)
8 (0%)
Scheme 3
With the aim to achieve nucleophilic substitutions on
cyclopropyl moieties and to compare with Schöllkopf’s
results, the sulfonates of both exo-4 and endo-5 were
readily prepared.
To overcome this problem, the formation of the mesylate
endo-9 could constitute an alternative, but the dehydro-
chlorination of this sulfonic ester would probably lead to
the undesired spirocyclopropylsulfonate 10 as previously
reported on a similar compound4 (Scheme 4) through
base-induced deprotonation of the mesyloxymethyl
SYNLETT 2006, No. 9, pp 1407–1409
Advanced online publication: 22.05.2006
0
1.
0
6.
2
0
0
6
DOI: 10.1055/s-2006-939716; Art ID: D04706ST
© Georg Thieme Verlag Stuttgart · New York

1408
F. Lecornué et al.
LETTER
group, followed by substitution of chloride and cycliza-
tion.
+
Pd(dba)2, PPh3
NaN3, DMF
exo-7
PdLn
endo-14
A
O
O
S
O
Cl
t-BuOK
THF, 65 °C
N3
CH3SO2Cl
Et3N
H3CO2SO
5
+
B
LnPd
10
9 (95%)
15 (80–84%)
Scheme 4
Scheme 7
Having nonetheless attempted the reaction, the chlorosul-
fonate 9 proved unstable and thus unsuitable for pursuing
any further development.
On the other hand, the use of sodium formate as a nucleo-
philic reductive agent in the palladium-catalyzed hydro-
genolysis only gave the O-formyl cyclohexene 16.8 As
depicted in Scheme 8, no trace of the expected vinylcyclo-
hexene 17 (generated from decarboxylation then reduc-
tive elimination of the complexes C and D, respectively)
was isolated even when carrying out the reaction with
dppe as palladium ligand.9
Finally, the solution consisted in protecting the alcohol
function as a MOM-ether 11 followed by dehydrochlori-
nation to afford the vinylcyclopropane 12 (Scheme 5).
Cl
O
O
O
O
t-BuOK
MOMCl
5
THF, 65 °C
NEt(i-Pr)2
O
H
O
H
11 (84%)
12 (76%)
O
Pd(dba)2, PPh3
HCOONa, DMF
O
LnPd
B
Scheme 5
+
Generation of the cyclopropanol 13 proceeded smoothly
and subsequent esterification yielded the expected air
sensitive mesylate 14 (Scheme 6). We note here that the
tosylation (NaH, TsCl) of the alcohol 13 proved un-
successful just as for the parent chloride 5.
16 (83%)
17 (0%)
C
H
LnPd
HO
CH3SO2Cl
Et3N
H3CO2SO
HCl
12
D
MeOH, 0 °C
Scheme 8
13 (78%)
14 (94%)
Scheme 6
Surprisingly, when the palladium-catalyzed nucleophilic
substitution was performed using ethyl malonate, beside
the formation of the expanded cyclohexene 18,10 cyclo-
propylidene 1911 was also obtained. The latter, which re-
tains the integrity of the [3.1.0]hexane results from direct
Pd-assisted nucleophilic substitution. The ratio for 18:19
was steadily at 68:32 whatever the endo- or exo-sulfonate
starting material used (Scheme 9). The synthetic utility of
such products has been reported in the literature.12
Nucleophilic substitution was carried out on both tosylate
exo-7 and mesylate endo-14 by sodium azide. When the
reaction was performed without catalyst, even in refluxing
THF or at 70 °C in DMF, no reaction occurred even for
the presumed very reactive endo-compound 14. However,
in the presence of a catalytic amount of palladium(0) at
–10 °C, azide 155 was quantitatively isolated as a single
product just as in the case of mesylate exo-7. Both these
results are the opposite to those of Schöllkopf. The mech-
anism implies the formation of an initial p-allyl palladium
complex A from the exo- or endo-sulfonates which rapid-
ly evolves by ring-opening toward a new internal p-allyl
intermediate B, itself then undergoing nucleophilic attack
leading to the azide 15 (Scheme 7). Such a 2-aminocyclo-
hexen-2-yl skeleton has been reported in the literature and
is present in natural6 and bioactive7 products.
CO2Et
A
CO2Et
Pd(dba)2, PPh3
exo-7
+
18 (68–72%)
endo-14
NaH, CH(CO2Et)
DMF, 20 °C
CO2Et
CO2Et
B
19 (14–18%)
Scheme 9
Synlett 2006, No. 9, 1407–1409 © Thieme Stuttgart · New York

LETTER
Nucleophilic Substitution on Bicyclo[3.1.0]hexane Sulfonates
(8) 2-Vinylcyclohex-2-en-1-yl formate (16)
1409
Finally, and interestingly, the nucleophilic substitution
performed using sulfonamide 20 provided only cyclo-
propylidene 2113 as a 62:38 inseparable mixture of dia-
stereomers (Scheme 10).
1H NMR (250 MHz, CDCl3): d = 8.09 (s, 1 H), 6.22 (dd,
J = 17.5, 11.0 Hz, 1 H), 6.08 (t, J = 5.4 Hz, 1 H), 5.81 (m,
1 H), 5.09 (d, J = 17.5 Hz, 1 H), 4.98 (d, J = 11.0 Hz, 1 H),
2.35–1.80 (m, 3 H), 1.80–1.60 (m, 3 H). 13C NMR (90 MHz,
CDCl3): d = 160.6, 136.8, 135.1, 133.4, 111.5, 64.8, 28.5,
25.5, 17.0. IR (neat): 2945, 1718, 1647 cm–1. MS (EI):
m/z (%) = 106 (95), 91 (100), 79 (35), 78 (45). MS (CI,
NH3): m/z (%) = 170 (100) [M+ + 18]. HRMS (ES+):
m/z calcd for C15H22O4Na: 289.1410; found: 289.1416.
(9) Oshima, M.; Yamayaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J.
J. Am. Chem. Soc. 1989, 111, 6280.
O
Pd(dba)2, PPh3
S
exo-7
O
(R)-20, NaH, THF, reflux
N
(10) Diethyl (2-Vinylcyclohex-2-en-1-yl)malonate (18)
1H NMR (360 MHz, CDCl3): d = 6.21 (dd, J = 17.6, 11.2 Hz,
1 H), 5.87 (t, J = 4.0 Hz, 1 H), 5.11 (d, J = 17.6 Hz, 1 H),
4.91 (d, J = 11.2 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.09 (q,
J = 7.2 Hz, 2 H), 3.62 (d, J = 7.9 Hz, 1 H), 3.31 (m, 1 H),
2.25–2.10 (m, 2 H), 1.90–1.65 (m, 4 H), 1.28 (t, J = 7.2 Hz,
3 H), 1.24 (q, J = 7.2 Hz, 3 H). 13C NMR (63 MHz, CDCl3):
d = 159.6, 138.6, 131.1, 114.3, 61.3, 61.1, 55.0, 54.8, 33.0,
25.7, 25.2, 18.0, 14.1, 13.9. IR (neat): 2936, 1732, 1641
cm–1. MS (EI): m/z (%) = 175 (20), 161 (67), 160 (78), 133
(44), 119 (20), 115 (24), 106 (100), 91 (93), 79 (25), 78 (34).
MS (CI, NH3): m/z (%) = 267 (100) [M+ + 1], 284 (52) [M+
+ 18]. HRMS (ES+): m/z calcd for C15H22O4Na: 289.1417;
found: 289.1416.
21 (73%, 62:38)
O
(R)-20 =
S
O
HN
Scheme 10
In conclusion, we describe herein an efficient preparation
of both highly interesting vinylcyclohexene derivatives
and fused cyclopropylidene derivatives. Finally, in the nu-
cleophilic substitutions that we developed on such com-
pounds, it is shown that the configurations of the starting
sulfonates are not restrictive, as compared with previous
data from Schöllkopf. The extension of this efficient path-
way to other nucleophiles and towards enantioselective
syntheses is currently under investigation.
(11) Diethyl (2-Bicyclo[3.1.0]hex-6-ylideneethyl)malonate
(19)
1H NMR (360 MHz, CDCl3): d = 5.70 (t, J = 6.6 Hz, 1 H),
4.18 (q, J = 7.2 Hz, 4 H), 3.46 (t, J = 7.5 Hz, 1 H), 2.71 (dd,
J = 7.2, 6.6 Hz, 2 H), 1.92–1.65 (m, 8 H), 1.28 (t, J = 7.1 Hz,
3 H), 1.26 (t, J = 7.1 Hz, 3 H). 13C NMR (63 MHz, CDCl3):
d = 173.0, 132.9, 115.2, 61.3, 52.0, 31.0, 29.6, 29.4, 21.2,
20.7, 20.5, 14.0. IR (neat): 2938, 2863, 1750, 1733 cm–1. MS
(EI): m/z (%) = 175 (37), 161 (20), 147 (37), 119 (100), 118
(44), 117 (27), 106 (51), 105 (20), 101 (33), 92 (27), 91 (81),
79 (31). MS (CI, NH3): m/z (%) = 267 (67) [M+ + 1], 284
(100) [M+ + 18]. HRMS (ES+): m/z calcd for C15H22O4Na:
289.1417; found: 289.1415.
References and Notes
(1) Schöllkopf, U. Angew. Chem., Int. Ed. Engl. 1968, 7, 590.
(2) Lecornué, F.; Ollivier, J. Chem. Commun. 2003, 584.
(3) (a) Kulinkovich, O. Russ. Chem. Bull., Int. Ed. 2004, 53,
1065. (b) Kulinkovich, O. Eur. J. Org. Chem. 2004, 4517.
(4) Sylvestre, I.; Ollivier, J.; Salaün, J. Tetrahedron Lett. 2001,
4991.
(12) (a) Davidson, E. R.; Gajewski, J. J.; Shook, C. A.; Cohen, T.
J. Am. Chem. Soc. 1995, 117, 8495. (b) Shook, C. A.;
Romberger, M. L.; Jung, S.-H.; Xiao, M.; Sherbine, J. P.;
Zhang, B.; Lin, F.-T.; Cohen, T. J. Am. Chem. Soc. 1993,
115, 10754; and references cited therein. (c) McCullough,
D. W.; Cohen, T. Tetrahedron Lett. 1988, 29, 27.
(5) 6-Azido-1-vinylcyclohex-1-ene (15)
1H NMR (250 MHz, CDCl3): d = 6.33 (dd, J = 17.7, 10.9 Hz,
1 H), 6.06 (t, J = 3.9 Hz, 1 H), 5.30 (d, J = 17.7 Hz, 1 H),
5.08 (d, J = 10.9 Hz, 1 H), 4.12 (br s, 1 H), 2.32–2.00 (m, 3
H), 1.81–1.65 (m, 3 H). 13C NMR (63 MHz, CDCl3): d =
137.4, 134.2, 132.8, 111.8, 53.9, 29.0, 25.4, 17.4. IR (neat):
2943, 2100, 1643 cm–1. MS (EI): m/z (%) = 149 (4) [M+],
120 (31), 93 (69), 91 (66), 79 (100), 77 (35). HRMS: m/z
calcd for C8H11N3: 149.0952; found; 149.0950.
(d) Gajewski, J. J.; Chou, S. K. J. Am. Chem. Soc. 1977, 99,
5696.
(13) N-(2{(1R,5S)-Bicyclo[3.1.0]hex-6-ylidene}ethyl)-4-
methyl-N-[(1R)-1-phenylethyl] Benzenesulfonamide (21)
1H NMR (250 MHz, CDCl3): d = 7.73 (d, J = 7.0 Hz, 4 H),
7.35–7.20 (m, 14 H), 5.52 (t, J = 6.5 Hz, 1 H, minor), 5.48 (t,
J = 6.5 Hz, 1 H, major), 5.26 (q, J = 7.0 Hz, 1 H, major), 5.21
(q, J = 7.0 Hz, 1 H, minor), 3.90 (t, J = 6.5 Hz, 1 H, minor),
3.85 (t, J = 6.5 Hz, 1 H, major), 3.73 (d, J = 6.5 Hz, 1 H,
major), 3.68 (d, J = 6.5 Hz, 1 H, minor), 2.45 (s, 6 H), 1.80–
1.60 (m, 16 H), 1.49 (d, J = 7.0 Hz, 3 H, minor), 1.47 (d,
J = 7.0 Hz, 3 H, major). 13C NMR (63 MHz, CDCl3): d =
142.8, 140.3 (major), 140.2 (minor), 138.8 (major), 138.6
(minor), 136.8, 133.1, 131.9, 129.5, 129.2, 128.1, 128.0,
127.7, 127.5, 127.3, 127.1, 117.3 (major), 117.2 (minor),
55.5 (minor), 55.3 (major), 45.6 (minor), 45.3 (major), 29.5
(major), 29.3 (minor), 21.5 (minor), 21.3 (major), 20.9, 20.5,
17.6 (minor), 17.1 (major). IR (neat): 2939, 2863, 1599 cm–1.
MS (EI): m/z (%) = 381 (3.4) [M+], 276 (20), 207 (100), 155
(21), 120 (23), 105(69), 91 (33), 79 (20). HRMS: m/z calcd
for C23H27NO2S: 381.1757; found: 381.1752.
(6) Ngadjui, B.; Tamboue, H.; Ayafor, J. F.; Connolly, J.
Phytochemistry 1995, 39, 1249.
(7) (a) Kato, T.; Ishii, H.; Kawai, K.; Sawa, Y. Chem. Pharm.
Bull. 1984, 32, 2279. (b) Kuroda, S.; Akahane, A.; Itani, H.;
Nishimura, S.; Durhin, K.; Tenda, Y.; Sakane, K. Bioorg.
Med. Chem. 2000, 8, 55.
Synlett 2006, No. 9, 1407–1409 © Thieme Stuttgart · New York