Nucleophilic catalysis via phosphine conjugate addition: Vinyl sulfones as reacting partners in catalytic cross-Michael cycloisomerization

Article abstract of DOI:10.1055/s-2004-831191

Vinylsulfones serve as highly effective reacting partners in tributylphosphine catalyzed cross-Michael cycloisomerization. In all cases examined, the vinylsulfone moiety exclusively serves as the Michael acceptor to provide 5- and 6-membered ring products

Full text of DOI:10.1055/s-2004-831191

FEATURE ARTICLE
2579
Nucleophilic Catalysis via Phosphine Conjugate Addition: Vinyl Sulfones as
Reacting Partners in Catalytic Cross-Michael Cycloisomerization
N
ucleophilic Catal
n
ysis via
P
hos
a
phine Conjugate
LAddition iza Luis, Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin, TX 78712, USA
E-mail: mkrische@mail.utexas.edu
Received 12 May 2004
philic catalysis via conjugate addition of N- and P-
Abstract: Vinylsulfones serve as highly effective reacting partners
in tributylphosphine catalyzed cross-Michael cycloisomerization.
In all cases examined, the vinylsulfone moiety exclusively serves
as the Michael acceptor to provide 5- and 6-membered ring prod-
ucts as single constitutional isomers in good to excellent yields.
nucleophiles. In addition to the Morita–Baylis–Hillman
(MBH) reaction,4 a surprisingly broad family of transfor-
mations has been achieved in accordance with this ap-
proach: the addition of oxygen nucleophiles to activated
alkenes,5 the internal redox isomerization of activated
alkynes,6 nucleophilic a- and g-additions to activated
alkynes,7 inter- and intramolecular [3+2] cycloaddi-
tions,8,9 [4+2] cycloadditions,10 cycloallylation of activat-
ed alkenes,11 the coupling of allenic esters to activated
alkenes,12 the regiospecific substitution of MBH ace-
tates,13 and even Stetter-type condensations.14
Keywords: nucleophilic catalysis, vinyl sulfone, cycloisomeriza-
tion, conjugate addition, phosphine
Despite the fact that enolates are among the most ubiqui-
tous reactive intermediates employed in C-C bond forma-
tion, there are few catalytic methods for the regiospecific
generation and capture of enolate nucleophiles. As part of
a program in catalytic reaction development, the use of
enones as precursors in tandem conjugate addition-elec-
trophilic trapping is currently under investigation in our
lab. Specifically, enone hydrometallation (1,4-reduc-
tion),1 enone carbometallation (1,4-addition),2 and phos-
phine conjugate addition (nucleophilic catalysis)3 have
been applied to the regiospecific generation of enolate nu-
cleophiles, which are found to engage in subsequent addi-
tions to aldehydes,1a,c ketones,1d,e,2 esters,2c nitriles,2c
activated alkenes,1a,b,3a,b Pd(II)-p-allyls3c and triarylbis-
muth(V) reagents.3d Indeed, through application of this
simple enone-electrophile template, a family of catalytic
transformations has emerged (Scheme 1).
Contributing to this growing subset of organocatalytic
transformations, the present author and Roush concurrent-
ly reported an intramolecular variant of the phosphine cat-
alyzed dimerization of activated alkenes.3a,15 A related
study was subsequently reported by Murphy.16 Unlike the
parent transformation,17 the intramolecular process is
amenable to cross-condensation, which has led to its use
as a key bond formation in the total synthesis of complex
natural products.18 To extend the scope of this process,
studies aimed at expanding the repertoire of reacting part-
ners amenable to crossed cycloisomerization are ongoing.
Here, inspired by the versatility of the sulfone moiety in
organic syntheses,19 we report the highly chemoselective
cross-Michael cycloisomerization of vinylsulfones with
appendant enone and enoate partners to afford cyclopen-
tene and cyclohexene products (Scheme 2).
O
MLn
Electrophile
LnM H
R
R
R
Conjugate
Reduction
O
n
SO2Ar
H
O
SO2Ar
O
O
R
Bu3P (10–20 mol%)
SO2Ar
R
MLn
O
R
LnM R
X
n
Solvent (0.2 M)
25–130 °C
Electrophile
n
Electrophile
n
X
X
R
Conjugate
Addition
n
n
R
O
Ar = p-NO2Ph
>95:5
Chemoselectivity
for Cross-Cyclization
R = Ph, CH3, SEt
X = C, NTs, n = 0, 1
:Nu
Electrophile
n
Scheme 2
Nucleophilic
Catalysis
Nu
Initial studies focused on the identification of a concise
and modular synthetic route to the sulfone containing cy-
cloisomerization substrates. Among methods for the in-
troduction of vinyl sulfones,20 the indicated para-
nitrophenylsulfone-based Wittig–Horner–Wadsworth–
Emmons reagent A proved to be most versatile,21 enabling
access to sulfone containing substrates 6a–12a in good
overall yields from the corresponding aldehydes. The
para-nitrophenylsulfonyl moiety is required as the parent
phenylsulfone derivatives do not engage in cyclization.
Scheme 1
Perhaps the mildest and most operationally simple meth-
od for regiospecific enolate generation involves nucleo-
SYNTHESIS 2004, No. 15, pp 2579–2585
Advanced online publication: 26.08.2004
DOI: 10.1055/s-2004-831191; Art ID: M03204SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4

2580
A. L. Luis, M. J. Krische
FEATURE ARTICLE
Using the Wittig–Horner–Wadsworth–Emmons reagent
A, the previously reported thioenoate-containing alde-
hydes 1 and 2 provide 6a and 7a in 89% and 90% yields,
respectively. In the case of the nitrogen-tethered substrate
8a, initial introduction of the vinyl sulfone moiety occurs
in 65% yield to afford, after acidic hydrolysis, the alde-
hyde 3. Exposure of 3 to the thiol acetic ester based Wit-
22
tig–Horner reagent EtSCOCHPPh3 affords 8a in 81%
yield. Finally, olefination of 4-pentenal and 5-hexenal us-
ing Wittig–Horner–Wadsworth–Emmons reagent A pro-
vides the olefinic vinylsulfones 4 and 5 in 91% and 93%
yields, respectively. Cross metathesis23 of the terminal
alkenes 4 and 5 using the second generation Grubbs cata-
lyst with phenyl vinyl ketone (PVK) provides substrates
9a and 10a in 57% and 59% yields, respectively. Similar-
ly, through the use of methyl vinyl ketone (MVK), sub-
strates 11a and 12a are obtained in 64% and 68% yields,
respectively (Scheme 3).
With substrates 6a–12a in hand, conditions for phosphine
catalyzed cross-Michael cycloisomerization were ex-
plored. As previously observed, the ideal choice of tem-
Scheme 3 Preparation of cross-Michael cycloisomerization sub-
strates 6a–12a. Reagents and conditions: (a) A, n-BuLi, THF, –78 °C
perature and reaction solvent was highly substrate to 25 °C. (b) 50% aq TFA, 25 °C. (c) EtSCOCHPPh3, THF, 66 °C. (d)
A, LHMDS, THF, –78 °C to 25 °C. (e) PVK, 5 mol% Grubbs II cata-
lyst, CH2Cl2, 40 °C. (f) MVK, 5 mol% Grubbs II catalyst, CH2Cl2, 40
°C.
dependent. Indeed, for the vinyl sulfone containing sub-
strates 6a–12a, optimal reaction conditions were unique
for each substrate. However, upon identification of suit-
able conditions, the cycloisomerization products 6b–12b
the cyclization. Isomeric products derived via direct addi-
were produced in good to excellent yields using 10–20
tion of tributylphosphine to the vinylsulfone moiety fol-
mol% of tributylphosphine as catalyst. In each case, the
lowed by cyclization onto the appendant enone or enoate
vinylsulfone moiety serves as the electrophilic partner in
were not observed (Table 1).
Biographical Sketches
Ana Liza Luis received a Chemistry from the Univer- Texas at Austin and an NIH
B.S. in Chemistry from the sity of Texas at Austin. She predoctoral fellow.
University of Texas at San is currently a doctoral candi-
Antonio and an M.S. in date at the University of
Michael J. Krische re- and then pursued post-doc- self-assembly and materials
ceived a B.S. in Chemistry toral studies with Jean- chemistry. Selected honors
from the University of Cali- Marie Lehn at the Univer- and awards include the
fornia at Berkeley under the sité Louis Pasteur as an NIH Camille Dreyfus Teacher
tutelage of Professor H. Post-Doctoral Fellow where Scholar Award (2003), the
Rapoport as a Presidents he was granted the title of Alfred P. Sloan Research
Undergraduate
Fellow, Maître de Conference, Col- Fellowship (2003), the Cot-
whereupon he was granted a lége de France. Dr. Krische trell Scholar Award (2002),
Fulbright Fellowship for joined the faculty at the Uni- the Frasch Foundation
study in Europe. Dr. Krische versity of Texas at Austin in Award in Chemistry (2002),
received his Ph.D. in Chem- Fall 1999, where he has es- the Eli Lilly Grantee for Un-
istry from Stanford Univer- tablished a program of re- tenured Faculty (2002), and
sity for studies performed search combining the topics the National Science Foun-
with Professor B. M. Trost catalytic reaction develop- dation-CAREER
as a Peter Veatch Fellow, ment, asymmetric synthesis, (2000).
Award
Synthesis 2004, No. 15, 2579–2585 © Thieme Stuttgart · New York

FEATURE ARTICLE
Nucleophilic Catalysis via Phosphine Conjugate Addition
2581
Table 1 Phosphine-Catalyzed Cross-Cycloisomerization of Substrates 6a–12aa–c
Entry
1
Substrate
Product
PBu3 (mol%) T (°C)
Solvent
Isolated Yield (%)
89
10
50
t-AmylOHc
O
SO2Ar
O
SO2Ar
EtS
EtS
6b
6a
O
2
3
10
25
MeCN
86
76
SO2Ar
SO2Ar
O
EtS
EtS
7a
7b
20
130
t-AmylOH
SO2Ar
SO2Ar
NTs
O
O
EtS
EtS
NTs
8a
8b
4
5
10
10
50
25
EtOAc
97
74
O
SO2Ar
O
SO2Ar
Ph
Ph
9b
9a
O
Acetone
SO2Ar
SO2Ar
SO2Ar
SO2Ar
O
Ph
Ph
10a
10b
6
7
20
20
82
60
t-BuOH
84
80
O
H3C
11b
11a
O
t-AmylOHc
SO2Ar
O
H3C
H3C
12a
12b
a Procedure: To a solution of substrate (100 mol%) in the indicated solvent (0.2 M) under an atmosphere of Ar was added tributylphosphine
(10–20 mol%). The reaction was allowed to stir at the indicated temperature until consumption of the starting material was observed, at which
point the solvent was removed under reduced pressure and the resulting oil was purified using flash chromatography (SiO2: hexane–EtOAc) to
provide cyclized products.
b Ar = p-nitrophenyl.
c Reactions were performed at a concentration of 0.1 M.
zophenone. Dichloromethane was distilled from calcium hydride.
Compounds 1 and 2 were prepared according to known literature
procedure.24 Analytical TLC was carried out using 0.2 mm com-
mercial silica gel plates (DC-Fertigplatten Krieselgel 60 F254). Pre-
parative column chromatography employing silica gel was
performed according to the method of Still.25 Solvents for chroma-
tography are listed in volume/volume ratios. IR spectra were re-
corded on a Perkin-Elmer 1420 spectrometer. HRMS were obtained
on a Micromass ZAB-2E and are reported as m/z (relative intensity).
Accurate masses are reported for the molecular ion [M + 1] or a suit-
able fragment ion. 1H NMR spectra were recorded in CDCl3 at 300
MHz using a Varian spectrometer. Chemical shifts are reported in
delta (d) units, ppm downfield from TMS. Coupling constants are
reported in Hz. 13C NMR spectra were recorded in CDCl3 at 75
MHz using a Varian spectrometer. Chemical shifts are reported in
delta (d) units, ppm relative to the center of the triplet at 77.0 ppm
for CDCl3. 13C NMR spectra were routinely run with broadbrand
decoupling.
In summation, p-nitrophenyl substituted vinylsulfones
serve as highly effective reacting partners in phosphine
catalyzed cross-Michael cycloisomerization. For all sub-
strates examined, good to excellent yields of 5- and 6-
membered ring products were obtained using 10–20
mol% tributylphosphine. Moreover, as the vinylsulfone
moiety exclusively serves as the Michael acceptor, cy-
clized products appear as single constitutional isomers.
Future studies will be devoted to the development of relat-
ed catalytic transformations, including enantioselective
variants of the reactions described herein.
All experiments involving water-sensitive compounds were con-
ducted under an atmosphere of Ar. Anhydrous solvents were trans-
ferred by an oven-dried syringe. Flasks were flame-dried and
cooled under a stream of N2. THF was distilled over sodium-ben-
Synthesis 2004, No. 15, 2579–2585 © Thieme Stuttgart · New York

2582
A. L. Luis, M. J. Krische
FEATURE ARTICLE
Synthesis of 4 and 5; General Procedure
2.88 (q, J = 7.5 Hz, 2 H), 2.45 (q, J = 6.9 Hz, 2 H), 2.37 (q, J = 6.9
Hz, 2 H), 1.22 (t, J = 7.52 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 189.4, 150.4, 147.6, 146.1, 141.3,
130.4, 129.8, 128.9, 124.5, 29.7, 29.6, 23.1, 14.6.
To a stirred solution of (4-nitro-benzenesulfonylmethyl)-phosphon-
ic acid dimethyl ester (5.60 g, 18.1 mmol, 100 mol%) in THF (0.2
M) under Ar at –78 °C was added lithium hexamethyldisilazide
(18.1 mL, 1.0 M in THF, 100 mol%). The solution was allowed to
stir at –78 °C for 1 h, at which point aldehyde (23.8 mol, 130 mol%)
in CH2Cl2 (1.6 M) was added. The reaction was allowed to warm to
r.t. over a period of 1 h. The reaction mixture was poured into a so-
lution of sat. NH4Cl, and the aqueous layer was extracted with Et2O
(3 × 150 mL). The organic extracts were combined, washed with
brine, dried (MgSO4) and concentrated under reduced pressure. The
resulting residue was subjected to chromatographic purification
[SiO2: hexane–EtOAc (9:1)] to afford compounds 4 and 5 as yellow
oils.
HRMS: m/z [M + 1] calcd for C14H16NO5S: 356.0633; found:
356.0626.
8-(4-Nitro-benzenesulfonyl)-octa-3,8-dienethioic Acid S-Ethyl
Ester (7a)
Yield: 90%; mp 81–82 ºC.
FTIR (film): 3055, 2987, 2685, 2305, 1667, 1631, 1535, 1422,
1350, 1265, 1149, 1086, 972, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.35 (d, J = 8.55 Hz, 2 H), 8.04 (d,
J = 8.89 Hz, 2 H), 7.04 (dt, J = 15.0, 6.75 Hz, 1 H), 6.75 (dt, J =
15.7, 7.01 Hz, 1 H), 6.32 (d, J = 15.0 Hz, 1 H), 6.03 (d, J = 15.7 Hz,
1 H), 2.89 (q, J = 7.41 Hz, 2 H), 2.28 (q, J = 6.84 Hz, 2 H), 2.19 (q,
J = 7.18 Hz, 2 H), 1.64 (qt, J = 7.61 Hz, 2 H), 1.23 (t, J = 7.35 Hz,
3 H).
1-(Hexa-1,5-diene-1-sulfonyl)-4-nitro-benzene (4)
Yield: 91%.
FTIR (film): 3056, 2986, 2686, 2305, 1639, 1607, 1535, 1422,
1351, 1266, 1149, 1087, 1013, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.34 (d, J = 9.7 Hz, 2 H), 8.04 (d,
J = 10.7 Hz, 2 H), 7.06 (dt, J = 15.1, 6.6 Hz, 1 H), 6.32 (d, J = 15.1
Hz, 1 H), 5.70 (m, 1 H), 4.9 (m, 2 H), 2.36 (q, J = 6.5 Hz, 2 H), 2.21
(m, 2 H).
13C NMR (75 MHz, CDCl3): d = 149.1, 136.0, 129.6, 128.9, 124.4,
116.3, 31.3, 30.7.
13C NMR (75 MHz, CDCl3): d = 189.7, 150.4, 148.6, 146.2, 142.8,
129.8, 129.5, 128.9, 124.5, 31.1, 30.8, 25.7, 23.1, 14.7.
HRMS: m/z [M + 1] calcd for C15H18NO5S: 370.0781; found:
370.0783.
4-{[3-(4-Nitro-benzenesulfonyl)-allyl]-(toluene-4-sulfonyl)-ami-
no}-but-2-enethioic Acid S-Ethyl Ester (8a)
HRMS: m/z [M + 1] calcd for C12H14NO4S: 268.0648; found:
To a stirred solution of (4-nitro-benzenesulfonylmethyl)-phosphon-
ic acid dimethyl ester (1.43 g, 4.62 mmol, 100 mol%) in THF (36
mL, 0.15 M) at –78 °C under an atmosphere of Ar was added n-
BuLi (1.85 mL, 2.5 M in hexanes, 100 mol%). The solution was
stirred at –78 °C for 1 h, at which point N-(2,2-diethoxy-ethyl)-4-
methyl-N-(2-oxo-ethyl)-benzenesulfonamide (1.50 g, 4.62 mmol,
100 mol%) in THF (12 mL) was added dropwise. The reaction was
allowed to warm to r.t. over a period of 45 min. The reaction mix-
ture was then poured into a solution of sat. aq NH4Cl. The aqueous
layer was extracted with Et2O (3 × 150 mL). The organic extracts
were combined, washed with brine, dried (MgSO4) and concentrat-
ed under reduced pressure. The resulting residue was subjected to
chromatographic purification [SiO2: hexane–EtOAc (9:1)] to afford
N-(2,2-diethoxy-ethyl)-4-methyl-N-[3-(4-nitro-benzenesulfonyl)-
allyl]-benzenesulfonamide (1.54 g, 3.01 mol) as a yellow oil in 65%
yield.
268.0644.
1-(Hepta-1,5-diene-1-sulfonyl)-4-nitro-benzene (5)
Yield: 93%.
FTIR (film): 3056, 2986, 2686, 2305, 1639, 1607, 1535, 1422,
1351, 1266, 1148, 1086, 1013, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.35 (d, J = 8.9 Hz, 2 H), 8.04 (d,
J = 9.0 Hz, 2 H), 7.06 (dt, J = 15.1, 6.8 Hz, 1 H), 6.31 (d, J = 15.1
Hz, 1 H), 5.71 (m, 1 H), 4.96 (m, 2 H), 2.27 (q, J = 7.3 Hz, 2 H),
2.05 (q, J = 7.1 Hz, 2 H), 1.56 (qt, J = 7.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 149.7, 146.5, 137.2, 129.4, 128.9,
124.4, 115.6, 32.8, 26.5.
HRMS: m/z [M + 1] calcd for C13H16NO4S: 282.0798; found:
282.0800.
To a solution of N-(2,2-diethoxy-ethyl)-4-methyl-N-[3-(4-nitro-
benzenesulfonyl)-allyl]-benzenesulfonamide (1.50 g, 2.93 mmol,
100 mol%) in CH2Cl2 (9.0 mL, 0.33M) at 0 °C was added dropwise
an 50% aq solution of trifluoroacetic acid (3.0 mL). Reaction was
allowed to stir at ambient temperature for 24 h, at which point the
reaction mixture was filtered and the solid dried under vacuum to
give 4-methyl-N-[3-(4-nitro-benzenesulfonyl)-allyl]-N-(2-oxo-eth-
yl)-benzenesulfonamide (3; 1.02 g, 2.34 mol) as a white solid in
80% yield.
Synthesis of Substrates 6a and 7a; General Procedure
To (4-nitro-benzenesulfonylmethyl)-phosphonic acid dimethyl es-
ter (3.06 g, 9.90 mmol, 100 mol%) in THF (0.20 M) under Ar at
–78 °C was added n-BuLi (4.0 mL, 2.5 M in THF, 100 mol%) drop-
wise. After 1 h, 1 or 2 (10.39 mmol, 105 mol%) was added in THF
(0.7 M) dropwise. Reaction was allowed to warm to r.t. over a peri-
od of 1 h and poured into a solution of sat. aq NH4Cl. The aqueous
layer was extracted with three portions of Et2O and the combined
organic extracts were dried (Na2SO4), filtered and concentrated un-
der vacuum. The resulting residue was subjected to chromatograph-
ic purification [SiO2: hexane–EtOAc (9:1)] to afford compounds 6a
and 7a as white solids.
To a solution of 4-methyl-N-[3-(4-nitro-benzenesulfonyl)-allyl]-N-
(2-oxo-ethyl)-benzenesulfonamide (1.00 g, 2.28 mol, 100 mol%) in
THF (24 mL, 0.1 M) was added (triphenyl-l5-phosphanylidene)-
thioacetic acid S-ethyl ester (1.20g, 3.42 mmol, 150 mol%). The re-
action mixture was heated to reflux and was allowed to stir over-
night. Upon cooling, the reaction mixture was concentrated under
vacuum and the resulting residue was subjected to chromatographic
purification [SiO2: hexane–EtOAc (9:1)] to provide 8a (0.970 g,
1.85 mmol) as a white solid in 81% yield; mp 134–136 ºC.
7-(4-Nitro-benzenesulfonyl)-hepta-2,6-dienethioic Acid S-Ethyl
Ester (6a)
Yield: 89%; mp 78–79 ºC.
FTIR (film): 3055, 2987, 2685, 2305, 1667, 1631, 1535, 1422,
1350, 1265, 1149, 1086, 972, 896 cm–1.
FTIR (film): 3055, 2987, 2685, 2305, 1670, 1631, 1536, 1422,
1350, 1265, 1163, 1152, 1086, 972, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.37 (d, J = 8.8 Hz, 2 H), 8.03 (d,
J = 8.8 Hz, 2 H), 7.62 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 7.8 Hz, 2 H),
1H NMR (300 MHz, CDCl3): d = 8.33 (d, J = 9.2 Hz, 2 H), 8.01 (d,
J = 8.5 Hz, 2 H), 7.02 (dt, J = 15.0, 6.6 Hz, 1 H), 6.70 (dt, J = 15.7,
6.6 Hz, 1 H), 6.34 (d, J = 15.4 Hz, 1 H), 6.03 (d, J = 15.4 Hz, 1 H),
Synthesis 2004, No. 15, 2579–2585 © Thieme Stuttgart · New York

FEATURE ARTICLE
Nucleophilic Catalysis via Phosphine Conjugate Addition
2583
6.92 (dt, J = 15.0, 4.9 Hz, 1 H), 6.52 (d, J = 15.0 Hz, 1 H), 6.42 (dt,
J = 15.4, 5.9 Hz, 1 H), 5.97 (d, J = 15.4 Hz, 1 H), 3.94 (d, J = 4.7
Hz, 2 H), 3.88 (d, J = 6.1 Hz, 2 H), 2.89 (q, J = 7.4 Hz, 2 H), 2.40
(s, 3 H), 1.23 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 188.8, 150.6, 145.4, 144.5, 143.2,
136.1, 135.5, 131.8, 131.2, 130.1, 129.1, 127.1, 124.6, 49.1, 47.7,
23.3, 21.5, 14.5.
13C NMR (75 MHz, CDCl3): d = 197.8, 150.6, 147.5, 146.1, 144.2,
132.2, 130.5, 129.0, 124.5, 30.0, 29.9, 27.2.
HRMS: m/z [M + 1] calcd for C14H16NO5S: 310.0747; found:
310.0749.
9-(4-Nitro-benzenesulfonyl)-nona-3,8-diene-2-one (12a)
Yield: 68%; mp 81–82 ºC.
HRMS: m/z [M + 1] calcd for C22H25N2O7S3: 525.0836; found:
525.0824.
FTIR (film): 3054, 2987, 2685, 2305, 1675, 1628, 1535, 1422,
1351, 1265, 1149, 1086, 979, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.32 (d, J = 8.9 Hz, 2 H), 8.02 (d,
J = 8.9 Hz, 2 H), 7.03 (dt, J = 15.0, 7.0 Hz, 1 H), 6.68 (dt, J = 16.1,
6.7 Hz, 1 H), 6.32 (d, J = 15.0 Hz, 1 H), 6.0 (d, J = 16.1 Hz, 1 H),
2.24 (m, 7 H), 1.65 (qt, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 198.2, 150.4, 148.6, 146.1, 146.1,
131.8, 129.7, 128.9, 124.4, 31.4, 30.8, 26.9, 25.7.
Synthesis of Substrates 9a–12a; General Procedure
To
a
solution of tricyclohexylphosphine[1,3-bis(2,4,6-tri-
methylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthe-
nium(IV) dichloride (72.8 mg, 0.0858 mmol, 3 mol%) in CH2Cl2
(15 mL) under an atmosphere of Ar was added 1 or 2 (2.86 mmol,
100 mol%) in anhyd CH2Cl2 (5 mL) and phenyl vinyl ketone or
methyl vinyl ketone (3.56 mmol, 124 mol%). The reaction mixture
was heated to reflux for 12 h, at which point it was allowed to cool
to r.t. The reaction mixture was stirred open to the air for 20 min and
concentrated under vacuum. The resulting residue was subjected to
chromatographic purification [SiO2: hexane–EtOAc (8:2)] to afford
the title compounds 9a–12a as yellow crystalline solids (9a and
10a) and white crystalline solids (11a and 12a).
HRMS: m/z [M + 1] calcd for C15H18NO5S: 324.0906; found:
324.0906.
Cyclization of Substrates 6a–12a; General Procedure
To a solution of substrate (100 mol%) in the indicated solvent (0.2
M) under an atmosphere of Ar was added tributylphosphine (10–20
mol%). The reaction was allowed to stir at the indicated temperature
until consumption of the starting material was observed, at which
the solvent was removed under reduced pressure and the resulting
oil was purified using flash chromatography (SiO2: hexane–EtOAc)
to provide cyclized products 6b–12b.
7-(4-Nitro-benzenesulfonyl)-1-phenyl-hepta-2,6-diene-1-one
(9a)
Yield: 57%; mp 60–61 ºC.
FTIR (film): 3054, 2987, 2685, 2305, 1686, 1606, 1535, 1421,
1350, 1266, 1149, 1086, 1013, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25 (d, J = 8.9 Hz, 2 H), 8.00 (d,
J = 8.9 Hz, 2 H), 7.86 (d, J = 8.2 Hz, 2 H), 7.55 (dt, J = 7.3, 1.4 Hz,
1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.08 (m, 1 H), 6.87 (m, 2 H), 6.38 (d,
J = 15.0 Hz, 1 H), 2.52 (t, J = 2.7 Hz, 4 H).
5-(4-Nitro-benzenesulfonylmethyl)-cyclopent-1-enecarbothioic
Acid S-Ethyl Ester (6b)
Yield: 89%; mp 102–103 ºC.
FTIR (film): 3054, 2987, 2685, 2410, 2305, 1650, 1609, 1536,
1422, 1351, 1265, 1151, 1087, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 8.9 Hz, 2 H), 8.12 (m,
J = 8.5 Hz, 2 H), 6.89 (d, J = 1.7 Hz, 1 H), 3.79 (dd, J = 14.4, 1.9
Hz, 1 H), 3.24 (m, 1 H), 3.03 (dd, J = 14.0, 10.9 Hz, 1 H), 2.82 (m,
2 H), 2.55 (m, 2 H), 2.23 (m, 2 H), 1.18 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 188.7, 150.8, 145.3, 145.1, 145.1,
143.1, 129.5, 124.4, 58.1, 39.6, 32.1, 28.8, 23.0, 14.6.
13C NMR (75 MHz, CDCl3): d = 189.8, 150.4, 147.8, 146.1, 145.8,
137.3, 133.0, 130.5, 128.9, 128.6, 128.4, 127.0, 124.5, 30.4, 30.0.
HRMS: m/z [M + 1] calcd for C19H18NO5S: 372.0904; found:
372.0906.
8-(4-Nitro-benzenesulfonyl)-1-phenyl-octa-2,7-diene-1-one
(10a)
HRMS: m/z [M + 1] calcd for C14H16NO5S: 356.0626; found:
356.0631.
Yield: 59%; mp 63–65 ºC.
FTIR (film): 3054, 2987, 2685, 2305, 1686, 1606, 1535, 1421,
1350, 1266, 1149, 1086, 1013, 896 cm–1.
6-(4-Nitro-benzenesulfonylmethyl)-cyclohex-1-enecarbothioic
Acid S-Ethyl Ester (7b)
Yield: 86%; mp 104–105 ºC.
1H NMR (300 MHz, CDCl3): d = 8.33 (d, J = 8.9 Hz, 2 H), 8.04 (d,
J = 8.9 Hz, 2 H), 7.87 (d, J = 8.9 Hz, 2 H), 7.53 (dt, J = 7.3, 1.20 Hz,
1 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.08 (dt, J = 15.0, 6.8 Hz, 1 H), 6.95
(dt, J = 15.4, 6.7 Hz, 1 H), 6.86 (d, J = 15.4 Hz, 1 H), 6.35 (m, 1 H),
2.33 (q, J = 6.8 Hz, 4 H), 1.70 (qt, J = 7.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 190.3, 150.4, 148.7, 147.5, 146.2,
137.5, 132.8, 129.8, 128.9, 128.5, 128.4, 126.6, 124.4, 124.4, 31.8,
30.9, 25.9.
FTIR (film): 3054, 2987, 2685, 2410, 2305, 1650, 1609, 1536,
1422, 1351, 1265, 1151, 1087, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.40 (d, J = 8.5 Hz, 2 H), 8.12 (d,
J = 8.5 Hz, 2 H), 7.06 (t, J = 3.4 Hz, 1 H), 3.34 (d, J = 3.7 Hz, 1 H),
3.07 (m, 2 H), 2.76 (m, 2 H), 2.21 (m, 3 H), 1.63 (m, 3 H), 1.14 (t,
J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 192.1, 150.7, 144.7, 142.2, 138.4,
129.6, 124.3, 57.3, 28.8, 25.5, 24.9, 23.0, 16.7, 14.6.
HRMS: m/z [M + 1] calcd for C20H20NO5S: 386.1068; found:
386.1062.
HRMS: m/z [M + 1] calcd for C15H18NO5S: 384.0943; found:
384.0939.
8-(4-Nitro-benzenesulfonyl)-octa-3,7-diene-2-one (11a)
Yield: 64%; mp 78–79 ºC.
3-(4-Nitro-benzenesulfonylmethyl)-1-toluene-4-sulfonyl)-
1,2,3,6-tetrahydro-pyridine-4-carbothioic Acid S-Ethyl Ester
(8b)
FTIR (film): 3054, 2987, 2685, 2305, 1675, 1628, 1535, 1422,
1351, 1265, 1149, 1086, 979, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.3 (d, J = 7.9 Hz, 2 H), 8.03 (d,
J = 7.8 Hz, 2 H), 7.05 (dt, J = 14.9, 6.2 Hz, 1 H), 6.67 (dt, J = 15.9,
6.4 Hz, 1 H), 6.36 (d, J = 15.1 Hz, 1 H), 6.06 (d, J = 15.9 Hz, 1 H),
2.43 (qt, J = 5.6 Hz, 4 H), 2.19 (s, 3 H).
Yield: 76%; mp 134–136 ºC.
FTIR (film): 3055, 2987, 2685, 2305, 1670, 1631, 1536, 1422,
1350, 1265, 1163, 1152, 1086, 972, 896 cm–1.
Synthesis 2004, No. 15, 2579–2585 © Thieme Stuttgart · New York

2584
A. L. Luis, M. J. Krische
FEATURE ARTICLE
1H NMR (300 MHz, CDCl3): d = 8.37 (d, J = 8.9 Hz, 2 H), 8.03 (d,
J = 8.9 Hz, 2 H), 7.62 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 7.9 Hz, 2 H),
6.92 (dt, J = 15.0, 4.9 Hz, 1 H), 6.52 (d, J = 15.0 Hz, 1 H), 6.42 (dt,
J = 15.4, 5.9 Hz, 1 H), 5.97 (d, J = 15.4 Hz, 1 H), 3.94 (d, J = 4.8
Hz, 2 H), 3.88 (d, J = 6.2 Hz, 2 H), 2.89 (q, J = 7.4 Hz, 2 H), 2.40
(s, 3 H), 1.23 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 188.8, 150.6, 145.4, 144.5, 143.2,
136.1, 135.5, 131.8, 131.2, 130.1, 129.1, 127.1, 124.6, 49.1, 47.7,
23.3, 21.5, 14.5.
1H NMR (300 MHz, CDCl3): d = 8.40 (d, J = 8.7 Hz, 2 H), 8.14 (d,
J = 8.7 Hz, 2 H), 7.00 (t, J = 3.9 Hz, 1 H), 3.27 (d, J = 14.0 Hz, 1
H), 3.07 (m, 1 H), 2.90 (d, J = 10.4 Hz, 1 H), 2.29 (m, 2 H), 2.15 (s,
3 H), 1.70 (m, 2 H), 1.56 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 198.1, 150.7, 145.1, 144.8, 139.2,
129.8, 124.2, 57.2, 27.6, 25.8, 25.2, 24.6, 16.5.
HRMS: m/z [M + 1] calcd for C15H18NO5S: 324.0895; found:
324.0906.
HRMS: m/z [M + 1] calcd for C22H25N2O7S3: 525.0836; found:
525.0824.
References
(1) (a) Baik, T.-G.; Luiz, A.-L.; Wang, L.-C.; Krische, M. J. J.
Am. Chem. Soc. 2001, 123, 5112. (b) Wang, L.-C.; Jang, H.-
Y.; Roh, Y.; Schultz, A. J.; Wang, X.; Lynch, V.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 9448. (c) Jang, H.-Y.;
Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002,
124, 15156. (d) Huddleston, R. R.; Krische, M. J. Org. Lett.
2003, 5, 1143. (e) Huddleston, R. R.; Cauble, D. F.; Krische,
M. J. J. Org. Chem. 2003, 68, 11. (f) Marriner, G. A.;
Garner, S. A.; Jang, H.-Y.; Krische, M. J. J. Org. Chem.
2004, 69, 1380. (g) Koech, P. K.; Krische, M. J. Org. Lett.
2004, 6, 691.
(2) (a) Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem.
Soc. 2003, 125, 1110. (b) Bocknack, B. M.; Wang, L.-C.;
Krische, M. J. Proc. Nat. Acad. Sci.U.S.A. 2004, 101, 5421.
(c) Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem.
Soc. 2004, 126, 4528.
[5-(4-Nitro-benzenesulfonylmethyl)-cyclopent-1-enyl]-phenyl-
methanone (9b)
Yield: 97%; mp 105–106 ºC.
FTIR (film): 3054, 2987, 2685, 2305, 1686, 1606, 1535, 1421,
1350, 1266, 1149, 1086, 1013, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 9.0 Hz, 2 H), 8.15 (d,
J = 8.9 Hz, 2 H), 7.62 (d, J = 7.5 Hz, 2 H), 7.51 (t, J = 7.4 Hz, 1 H),
7.39 (t, J = 7.4 Hz, 2 H), 6.64 (q, J = 2.3 Hz, 1 H), 3.91 (dd, J = 13.9,
2.4 Hz, 1 H), 3.46 (m, 1 H), 3.14 (m, 1 H), 2.72, (m, 1 H), 2.58 (m,
1 H), 2.39 (m, 1 H), 2.24 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 193.3, 150.8, 149.6, 145.2, 143.1,
138.2, 132.4, 129.5, 128.7, 128.3, 57.9, 40.2, 32.8, 28.8.
HRMS: m/z [M + 1] calcd for C19H18NO5S: 372.0907; found:
372.0906.
(3) (a) Wang, L.-C.; Luiz, A.-L.; Agapiou, K.; Jang, H.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402.
(b) Agapiou, K.; Krische, M. J. Org. Lett. 2003, 5, 1737.
(c) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. J. Am.
Chem. Soc. 2003, 125, 7758. (d) Koech, P. K.; Krische, M.
J. J. Am. Chem. Soc. 2004, 126, 5350.
(4) For an authoritative review, see: Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(5) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem.
Soc. 2003, 125, 8696.
(6) (a) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114,
7933. (b) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1
1993, 1921.
(7) (a) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 62,
5670. (b) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997,
119, 7595.
(8) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b)Xu,
Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (c) Zhu, G.;
Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am.
Chem. Soc. 1997, 119, 3836. (d) Xu, Z.; Lu, X. Tetrahedron
Lett. 1999, 40, 549. (e) Xu, Z.; Lu, X. J. Org. Chem. 1998,
63, 5031. (f) Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002, 67,
8901.
[6-(4-Nitro-benzenesulfonylmethyl)-cyclohex-1-enyl]-phenyl-
methanone (10b)
Yield: 74%; mp 127–128 ºC.
FTIR (film): 3054, 2987, 2685, 2305, 1686, 1606, 1535, 1421,
1350, 1266, 1149, 1086, 1013, 896 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 8.9 Hz, 2 H), 8.14 (d,
J = 8.9 Hz, 2 H), 7.47 (m, 3 H), 7.36 (m, 2 H), 6.70 (t, J = 3.6 Hz, 1
H), 3.46 (d, J = 13.3 Hz, 1 H), 3.23 (m, 2 H), 2.33 (m, 2 H), 2.22 (m,
1 H), 1.76 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 196.9, 150.6, 147.8, 144.7, 138.2,
137.9, 131.7, 129.6, 128.9, 128.1, 124.3, 57.5, 28.7, 25.8, 25.4,
17.2.
HRMS: m/z [M + 1] calcd for C20H20NO5S: 386.1060; found:
386.1062.
1-[5-(4-Nitro-benzenesulfonylmethyl)-cyclopent-1-enyl]-etha-
none (11b)
Yield: 84%; mp 100–101 ºC.
FTIR (film): 3054, 2987, 2935, 2870, 2305, 1661, 1606, 1533,
1422, 1351, 1302, 1265, 1152, 1086, 896 cm–1.
(9) (a) Wang, J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 3682. (b) Wang, J.-C.; Krische, M. J. Angew.
Chem. Int. Ed. 2003, 42, 5855.
(10) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716.
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 7.8 Hz, 2 H), 8.13 (d,
J = 8.5 Hz, 2 H), 6.83 (t, J = 1.0 Hz, 1 H), 3.79 (d, J = 14.0 Hz, 1
H), 3.24 (m, 1 H), 2.99 (t, J = 12.3 Hz, 1 H), 2.60 (m, 2 H), 2.23 (m,
5 H).
13C NMR (75 MHz, CDCl3): d = 196.0, 150.7, 147.6, 145.1, 144.5,
129.5, 124.4, 57.9, 39.0, 32.3, 28.6, 26.8.
(11) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. J. Am. Chem.
Soc. 2003, 125, 7758.
(12) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125,
12394.
HRMS: m/z [M + 1] calcd for C14H16NO5S: 310.0752; found:
310.0749.
(13) (a) Gong, J. H.; Kim, H. R.; Ryu, E. K.; Kim, J. N. Bull. Kor.
Chem. Soc. 2002, 23, 789. (b) Kim, J. N.; Lee, H. J.; Lee, K.
Y.; Gong, J. H. Synlett 2002, 173. (c) Basavaiah, D.;
Kumaragurubaran, N.; Sharada, D. S.; Reddy, R. M.
Tetrahedron 2001, 57, 8167. (d) Ciclosi, M.; Fava, C.;
Galeazzi, R.; Orena, M.; Sepulveda-Arques, J. Tetrahedron
Lett. 2002, 43, 2199. (e) Kim, J. N.; Lee, H. J.; Gong, J. H.
1-[6-(4-Nitro-benzenesulfonylmethyl)-cyclohex-1-enyl]-etha-
none (12b)
Yield: 80%; mp 126–127 ºC.
FTIR (film): 3054, 2987, 2935, 2870, 2305, 1661, 1606, 1533,
1422, 1351, 1302, 1265, 1152, 1086, 896 cm–1.
Synthesis 2004, No. 15, 2579–2585 © Thieme Stuttgart · New York

FEATURE ARTICLE
Tetrahedron Lett. 2002, 43, 9141.
(14) Gong, J. H.; Im, Y. J.; Lee, K. Y.; Kim, J. N. Tetrahedron
Lett. 2002, 43, 1247.
(15) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc.
2002, 124, 2404.
(16) Brown, P. M.; Kappel, N.; Murphy, P. J. Tetrahedron Lett.
2002, 43, 8707.
(17) For selected examples of the Rauhut–Currier reaction, see:
(a) Rauhut, M. M.; Currier, H. US Patent 3074999, 1963.
(b) McClure, J. D. J. Org. Chem. 1970, 35, 3045.
(c) Basavaiah, D.; Gowriswari, V. V. L.; Bharathi, T. K.
Tetrahedron Lett. 1987, 28, 4591. (d) Drewes, S. E.;
Emslie, N. D.; Karodia, N. Synth. Commun. 1990, 20, 1915.
(e) Jenner, G. Tetrahedron Lett. 2000, 41, 3091.
(18) (a) Mergott, D. J.; Frank, S. A.; Roush, W. R. Org. Lett.
2002, 4, 3157. (b) Agapiou, K.; Krische, M. J. Org. Lett.
2003, 5, 1737. (c) Mergot, J. L.; Roush, W. R. Org. Lett.
2003, 5, 4223.
Nucleophilic Catalysis via Phosphine Conjugate Addition
2585
(19) For a review, see: (a) Najera, C.; Yus, M. Tetrahedron 1999,
55, 10547. (b) Prilezhaeva, E. N. Russ. Chem. Rev. 2001, 70,
897. (c) Carretero, J. C.; Arrayas, R. G.; Buezo, N. D.;
Garrido, J. L.; Alonso, I.; Adrio, J. Phosphorus, Sulfur
Silicon Relat. Elem. 1999, 153, 259. (d) Magnus, P. D.
Tetrahedron 1977, 33, 2019.
(20) (a) Ager, D. J. J. Chem. Soc., Perkin Trans. 1 1986, 183.
(b) Van Leusen, A. M.; Reith, B. A.; Iedema, A. J. W.;
Strating, J. Recl. Trav. Chim. Pays-Bas 1972, 91, 37.
(c) Simpkins, N. S. Tetrahedron 1990, 46, 6951.
(21) Jang, W. B.; Jeon, H. J.; Oh, D. Y. Synth. Commun. 1998, 28,
1253.
(22) Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem.
1985, 50, 709.
(23) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 3783.
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(25) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
Synthesis 2004, No. 15, 2579–2585 © Thieme Stuttgart · New York