Heck reaction of amino acid derived vinyl substrates in the synthesis of homotyrosinol derivatives

Article abstract of DOI:10.1055/s-0029-1218830

An avenue to homotyrosinol derivatives through a Heck coupling of 4-iodophenyl acetate with a vinylglycinol derivative required extensive screening of catalysts and conditions. The use of Pd(OAc)₂ and N-phenylurea as the ligand ultimately provided excellent results. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218830

PAPER
2515
Heck Reaction of Amino Acid Derived Vinyl Substrates in the Synthesis of
Homotyrosinol Derivatives
Synthesis of
H
omo
u
tyrosinol De
a
rivatives n Liang, Yuan Zhou, Marco A. Ciufolini*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada
Fax +1(604)8228710; E-mail: ciufi@chem.ubc.ca
Received 2 February 2010; revised 30 March 2010
alogs appears to be problematic. Attempts to induce cross-
metathesis of 7 with 8 also ran into difficulties. As seen in
Table 1, the reaction stalled at about 40% conversion
when either Grubbs II12 or Hoveyda II13 catalysts were
used, and the desired product 2 was isolated in no more
than 21% yield. Use of first-generation catalysts14 was
even less satisfactory.
Abstract: An avenue to homotyrosinol derivatives through a Heck
coupling of 4-iodophenyl acetate with a vinylglycinol derivative re-
quired extensive screening of catalysts and conditions. The use of
Pd(OAc)2 and N-phenylurea as the ligand ultimately provided ex-
cellent results.
Key words: coupling, Heck reaction, homotyrosine, palladium,
N-phenylurea
These disappointments induced us to concentrate on the
Heck approach. The ‘ligandless’ procedure of Göbel
(Table 2) afforded excellent results in the coupling of 8
with 10 on scales up to about 400 mg of 8, but reactions
run with larger quantities of substrate proceeded in only
40–50% yield. The formation of a black precipitate (pre-
Ongoing efforts centering on the application of the oxida-
tive amidation of phenols1 in alkaloid synthesis unveiled
the desirability of a practical route to homotyrosinol sul-
fonamides such as 1 (Scheme 1). Past avenues to such
educts have relied on commercial, but expensive, homo-
tyrosine as the starting material.2 The high cost of that
amino acid3 prompted us to seek alternatives. Important
work by Göbel4 suggested that the desired product 1
might be accessible from vinylglycinol5 3 by Mizoroki–
Heck arylation6 with 6, followed by hydrogenation of the
intermediate 2. Plausible alternatives included an olefin
cross-metathesis reaction7 of 3 with styrene 5, also fol-
lowed by hydrogenation, and a Suzuki coupling8 of bo-
ronic acid 4 with an O-protected 4-iodophenol 6.
Table 1 Attempted Cross-Metathesis Reaction of 3 with 5a
NH–SO2Me
H
catalyst
+
conditionsa
OTBDPS
AcO
7
8
NHMs
H
OTBDPS
AcO
9
The implementation of a Suzuki approach required an ini-
tial hydroboration of 3. Such a reaction is documented for
BOC-protected vinylglycinols.9 In contrast, attempts to
hydroborate 3 with various reagents, including 9-borabi-
cyclo[3.3.1]nonane (9-BBN), catecholborane, and pina-
colborane in the presence of Wilkinson’s catalyst,10 met
with failure.11 Thus, the hydroboration of sulfonamide an-
Entry
Catalyst
Conversion (%) Yield (%)
1
2
3
4
Grubbs I
15
40
25
35
8
12
11
21
Grubbs II
Hoveyda I
Hoveyda II
a Reaction conditions: 7 (0.6 mmol), 8 (0.5 mmol), 0.2 M in CH2Cl2,
r.t. or in toluene at 100 °C (sealed tube); catalyst: 5, 10, 30 or
100 mol%.
NH–SO2R
NH–SO2R
H
H
OP1
OP1
2
1
HO
HO
Table 2 The Göbel ‘Ligandless’ Heck Reaction of 8 with 10a
P1, P2 = protecting group
R = Me, Tol, ....
NHMs
H
I
Y
NH–SO2R
8, Pd(OAc)2 (10 mol%)
Z
H
Bu4NOTfa
+
OTBDPS
AcO
RO
P2–O
X
OP1
10
9 R = Ac
11 R = H
3 X, Y = π bond
4 X = H, Y = boryl group
5
6
Z = CH=CH2
Z = I
hydroboration
Mass of 8 (mg)
403
Yield of 9 (%)
63
Yield of 11 (%)
Scheme 1
21
46
SYNTHESIS 2010, No. 15, pp 2515–2520
Advanced online publication: 17.06.2010
x
x.
x
x
.
2
0
1
0
2000
not detected
DOI: 10.1055/s-0029-1218830; Art ID: M01010SS
© Georg Thieme Verlag Stuttgart · New York
a Conditions as described by Suhartono et al.4

2516
H. Liang et al.
PAPER
sumably, finely divided Pd) indicated that the use of a (purified by chromatography), respectively, upon scale-
suitable ligand that might stabilize intervening organome- up to 4.3 g of 8, while keeping all other reaction parame-
tallic species was desirable. A screen of various phos- ters unchanged. Since 11 is the ultimate desired product,
phines (Table 3) identified SPhos15 as the best such its formation is inconsequential.
ligand. Thus, the desired product 9 emerged in 91% yield
Optimization of the reaction defined the best combination
(after chromatography) from a reaction run on a scale of
of aryl and vinyl substrates and the ideal source of Pd, and
100 mg of 8 that employed 20 mol% of Pd(OAc)2 and 40
minimized the amount of metal and ligand required, both
of which are costly. The combination of variants of 8 and
10 under a constant set of conditions (Table 4) produced
inferior results. Consequently, further refinement focused
mol% of ligand. Scaling up of the process resulted in for-
mation of variable amounts of the deacetylated product
11. For instance, 9 and 11 emerged in 52 and 34% yield
Table 3 Heck Reaction of 8 with 10 in the Presence of Various Palladium–Phosphine Complexesa
NHMs
H
Pd(OAc)2
10 + 8
ligand
conditionsa
OTBDPS
RO
9 R = Ac
11 R = H
Entry
1
Ligand
PPh3
Time (h)
4.5
Yield of 9 (%)
Yield of 11 (%)
31
9
87 (100 mg of 8)
58 (2.7 g of 8)
–
–
2
3
PBu3
4
7
<10
<5
–
P
O
3
P(t-Bu)2
4
5
9
9
19
Ph
(JohnPhos)
P(Cy)2
22
58
–
Ph
(cyclohexyl JohnPhos)
i-Pr
P(Cy)2
6
4
24
i-Pr
i-Pr
(XPhos)
P(Cy)2
OMe
91 (100 mg of 8)
52 (4.7 g of 8)b
–
7
8
4
4
34b
MeO
(SPhos)
P(Cy)2
Oi-Pr
55
5
i-PrO
P(Cy)2
9
5 (only 72% conversion)
24
20
Me2N
(DavePhos)
a Reaction conditions: 8 (0.5 mmol), 0.35 M in degassed (Ar) DMF, Pd(OAc)2 (20 mol%), ligand (40 mol%), 10 (1.2 equiv), K2CO3 (1.2 equiv),
105 °C, yields of chromatographically purified products.
b Reaction carried out with 1.5 mmol of 8.
Synthesis 2010, No. 15, 2515–2520 © Thieme Stuttgart · New York

PAPER
Synthesis of Homotyrosinol Derivatives
2517
exclusively on the union of 8 and 10. The best source of The high price of SPhos translated into a significant finan-
Pd (Table 5) was Pd(OAc)2 and best results were obtained cial investment even at a 3 mol% catalyst load. Recent
when the reaction was carried out with 3 mol% each of work by Guo describes the use of inexpensive N-phenyl-
Pd(OAc)2 and SPhos.
urea as an excellent ligand in palladium-mediated reac-
tions.16 This remarkable discovery encouraged us to
examine that ligand in our own reaction.
For preparative work, the mixture of 9 and 11 thus ob-
tained was directly subjected to deacetylation, affording
the desired product 11 in about 85% yield.
Table 6 Heck Reaction of 8 with 10 in the Presence of N-Phenylurea
Complexes of Palladiuma
Table 4 Heck Reaction of Variants of the Aryl and Vinyl Compo-
nentsa
NHMs
H
NHMs
PhNHCONH2
H
NHMs
10 + 8
X
conditionsa
H
OTBDPS
Pd(OAc)2
conditionsa
RO
+
9 R = Ac
11 R = H
OP
RO
RO
OP
Entry
R
X
P
Yield (R = Ac) Yield (R = H)
Entry
8
Pd
(mol%)
Base
Yield of 9 Yield of 11
(%)b
41
0
(%)b
(mmol)
(%)
38
76
84
23
59
63
(%)
48
13
0
1
2
3
4
5
Ac
Ac
Ac
H
I
I
OAc
0
1
2
3
4
5
6
0.5
10
10
10
10
5
K2CO3
TBS
21
0
0.5
NaHCO3
NaHCO3
Na2HPO3
K2CO3
Br
I
TBDPS
TBDPS
H
15
0
0.5
10
36
0.5
0b
H
I
0
2.5
28
20c
a Reaction conditions: 8 (0.5 mmol), 0.35 M in degassed (Ar) DMF,
10 (1.2 equiv), Pd(OAc)2 (10 mol%), SPhos (20 mol%), K2CO3 (1.2
equiv), 105 °C, 4 h; NMR monitoring.
11.0
5
K2CO3
a Reaction conditions: 8 (0.5 mmol), 0.35 M in degassed (Ar) DMF,
10 (1.2 equiv), base (1.2 equiv), Pd(OAc)2/N-phenylurea [1:2 (mol/
mol)], 105 °C, 2 h; 1H NMR monitoring, yields of chromatographical-
ly purified products.
b Yields of chromatographically purified products.
Table 5 Heck Reaction of 8 with 10 in the Presence of SPhos Com-
b 30% conversion after 4 h.
plexes of Palladiuma
c Ratio calculated by integration of the 1H NMR spectrum of the prod-
uct.
NHMs
H
Pd•SPhos
10 + 8
conditionsa
OTBDPS
In accord with Guo’s observations, we found that N-phe-
nylurea is indeed an outstanding substitute for SPhos in
the Heck coupling of 8 with 10. To wit, when 8 (0.5
mmol) in degassed DMF (1.5 mL; i.e., 0.35 M) containing
Pd(OAc)2 (10 mol%), N-phenylurea (20 mol%), 10 (0.6
mmol), and K2CO3 (0.6 mmol) was heated at 105 °C (re-
action monitored by NMR analysis), complete consump-
tion of 8 was detected after about two hours.
Chromatographic purification of the crude product deliv-
ered 9 in 38% yield and 11 in 48% yield (86% overall,
Table 6, entry 1). Replacing the base with milder
NaHCO3 resulted in exclusive formation of 9 in 84% yield
after chromatography. It further transpired that the new
ligand permitted the use of only 5 mol% of Pd(OAc)2 even
on substantial scales (entries 5 and 6). Clearly, use of
Guo’s inexpensive N-phenylurea afforded even better re-
sults than use of the more costly SPhos. For preparative
purposes (entry 6), we favored the use of 5 mol% of metal,
10 mol% ligand, K2CO3 as the base, and two hours reac-
tion time; use of these conditions afforded a mixture of 9
(63% by NMR) and 11 (20% by NMR) in 83% yield after
chromatographic purification. This mixture was deacety-
lated (K2CO3 in MeOH) to furnish pure 11 directly.
RO
9 R = Ac
11 R = H
Entry Pd source
Pd
Pd/ligand Yield of 9 Yield of 11
(mol%)
(%)
40
9
(%)
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd(PPh3)4
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
10
10
10
10
10
5
1:2
1:2
1:2
1:2
1:1
1:2
1:1
1:2
0b
0c
49
73
21
43
34
31
0d
11
62
4
3
52
21e
1
a Reaction conditions: 8 (0.5 mmol), 0.35 M in degassed (Ar) DMF,
10 (1.2 equiv), K2CO3 (1.2 equiv), 105 °C, 4 h; yields of chromato-
graphically purified products.
b 80% conversion after 4 h.
c 30% conversion after 4 h.
d 65% conversion after 4 h.
e 70% conversion after 9 h.
Synthesis 2010, No. 15, 2515–2520 © Thieme Stuttgart · New York

2518
H. Liang et al.
PAPER
All such Mizoroki–Heck reactions provided geometrical- sulfide functionality, which may hamper the progress of
ly pure (within the limits of 300 MHz 1H NMR spectros- transition-metal mediated reactions and/or require the use
copy) trans-isomers of the products. The enantiomeric of special phosphine ligands.18 Yet, N-phenylurea per-
purity was determined by the Mosher method.17 Thus, formed well even in this instance, wherein the overall
desilylation of 9 (HF·py), esterification of the primary al- yield of 15d (44%) reflects the efficiency of the Heck
cohol with (R)-a-methoxy-a-trifluoromethylphenylacetic step, in that the subsequent hydrogenation reaction was
acid [(R)-MTPA] chloride and analysis of the resulting es- essentially quantitative.
ter by 19F NMR spectroscopy revealed the presence of a
In summary, this research has defined a robust method for
single diastereomer, signifying that no erosion of optical
the preparation of homotyrosinol derivatives and related
integrity had occurred during the synthetic sequence.
intermediates through a Mizoroki–Heck coupling be-
tween an aryl iodide and appropriate amino acid derived
NHMs
OH
NHMs
OH
olefins. A key aspect of the work is the use of inexpensive
N-phenylurea as the ligand for palladium during the Heck
reaction. The results obtained in the course of these stud-
ies are essential to the progress of various synthetic efforts
ongoing in our laboratory.
H
H
1. K2CO3
MeOH
H2, Pd(C)
MeOH, r.t.
9, 11
2. HF⋅Py
HO
HO
12
13
90% overall
Unless otherwise indicated, 1H (300 MHz) and 13C (75 MHz) NMR
(Bruker 300 Ultrashield™) spectra were recorded at r.t. from CDCl3
solutions. Chemical shifts (d) are reported as ppm and coupling con-
stants (J) are reported in Hz. Multiplicities are described as s (sin-
glet), d/dd/ddd (doublet/doublet of doublets/doublet of doublet of
doublets), t (triplet), q (quartet), m (multiplet). Infrared (IR) spectra
(cm–1) were recorded with a Perkin–Elmer model 1710 Fourier
transform spectrophotometer from films deposited on NaCl plates.
Optical rotations were measured with a Jasco P-1010 polarimeter at
the sodium D line (589 nm). Unless otherwise stated, low-resolution
mass spectra (m/z) were obtained, in the electrospray (ESI) mode or
the atmospheric pressure chemical ionization (APCI) mode on a
Waters Micromass ZQ mass spectrometer. High-resolution mass
spectra (m/z) were recorded in the ESI or APCI mode with a Micro-
mass LCT mass spectrometer. Melting points (uncorrected) were
measured with a Mel-Temp apparatus. Elemental analyses were
measured on Carlo Erba Elemental Analyzer EA 1108. All reagents
and solvents were commercial products and were used without fur-
ther purification, except for THF (freshly distilled from Na/ben-
zophenone under Ar) and CH2Cl2 (freshly distilled from CaH2
under Ar). Flash chromatography was performed on Silicycle 230–
400 mesh silica gel. All reactions were performed under anhydrous
Ar in flame- or oven-dried flasks equipped with Teflon™ stirbars.
All flasks were fitted with rubber septa for the introduction of sub-
strates, reagents, and solvents via syringe.
Scheme 2
The conversion of 9–11 into the desired final product 1
entails the hydrogenation of the olefin and the release of
the protecting groups. Preliminary studies determined that
it was best to fully deblock the substrate prior to hydroge-
nation. Thus, sequential treatment of a mixture of 9 and 11
with K2CO3 in MeOH (release of the phenolic acetate) and
with HF·pyridine (which was superior to the use of TBAF
in the present case; release of the TBDPS group), fol-
lowed by hydrogenation, afforded compound 13 in 90%
overall yield after chromatography (Scheme 2). In sum-
mary, the desired 13 was now available in 4.5 g batches in
four steps from 8 and 10 with an overall yield of 75%.
The optimized sequence thus devised was extended to the
preparation of other intermediates of current interest in
our laboratory; Table 7 provides four such examples. The
successful preparation of 15d merits comment. This mol-
ecule, and its vinyl precursor 14d, incorporate a dialkyl
Table 7 Heck Reaction of 10 with Amino Acid Derived Vinyl Sub-
stratesa
(S,E)-N-[1-(tert-Butyldiphenylsilyloxy)-4-(4-hydroxyphe-
nyl)but-3-en-2-yl]methanesulfonamide (11); General Proce-
dure for Heck Coupling
NHMs
H
NHMs
Solid Pd(OAc)2 (139 mg, 0.6 mmol, 5 mol%) was added to a de-
gassed (Ar), well stirred DMF (35 mL) solution of 4-iodophenyl
acetate (7; 3.9 g, 14.9 mmol), vinylglycinol derivative 8 (5.0 g, 12.4
mmol), and N-phenylurea (168 mmg, 1.2 mmol, 10 mol%) contain-
ing suspended K2CO3 (2.1 g, 14.9 mmol). The mixture was heated
to 100–105 °C under argon. The progress of the reaction was mon-
10
R
H
conditionsa
R
HO
14
15
Entry
R
Overall yield (%)
1
itored by H NMR analysis. The reaction was complete after 2 h,
a
b
c
d
i-Pr
89
84
66
44
whereupon the mixture was cooled to r.t., neutralized with aq sat.
NH4Cl (15 mL) and extracted with EtOAc (2 × 20 mL). The com-
bined extracts were sequentially washed with aq sat. NH4Cl (3 × 15
mL) and aq sat. NaCl (2 × 10 mL), dried (Na2SO4) and evaporated.
The crude residue was redissolved in MeOH (30 mL) containing
K2CO3 (1.7 g, 12.4 mmol), and the mixture was stirred at r.t. After
3 h, the reaction was complete. The solution was diluted with
EtOAc (20 mL) and filtered through Celite. The filtrate was sequen-
tially washed with aq sat. NH4Cl (3 × 10 mL) and aq sat. NaCl
(2 × 10 mL), dried (Na2SO4) and evaporated. Flash chromatogra-
phy of the residue (EtOAc–hexanes, 3:1) afforded 11.
Me
CH2Ph
CH2CH2SMe
a Reaction conditions: (i) 14 (0.5 mmol), 0.35 M in degassed (Ar)
DMF, 10 (1.2 equiv), base (1.2 equiv), Pd(OAc)2 (5 mol%), N-phen-
ylurea (10 mol%), 105 °C, 2 h; 1H NMR monitoring; (ii) K2CO3,
MeOH; (iii) HF·py; (iv) H2, Pd/C, MeOH. Yields refer to chromato-
graphically purified products.
Synthesis 2010, No. 15, 2515–2520 © Thieme Stuttgart · New York

PAPER
Synthesis of Homotyrosinol Derivatives
2519
Yield: 4.9 g (9.9 mmol, 80% yield over 2 steps); light-yellow oil;
(S)-N-(Methanesulfonyl)homotyrosinol (13)
[a]D21 –3.8 (c 1.75, acetone).
Hydrogen gas was bubbled into a well-stirred solution of 10 (1
mmol) in MeOH (5 mL) containing suspended K2CO3 (138 mg, 1
mmol) and 10% Pd/C (53 mg, 5 mol%). Upon completion of the re-
action, the mixture was filtered through a 2-inch silica pad using
EtOAc as eluent. The filtrate was concentrated to afford 13.
IR (NaCl): 3295, 2931, 1362, 1152 cm–1.
1H NMR: d = 7.70–7.61 (m, 4 H), 7.48–7.34 (m, 6 H), 7.16 (d, J =
8.6 Hz, 2 H), 6.78 (d, J = 8.6 Hz, 2 H), 6.54 (d, J = 15.4 Hz, 1 H),
5.98–5.85 (m, 2 H), 5.01 (d, J = 6.5 Hz, 1 H), 4.24–4.13 (m, 1 H),
3.89–3.67 (m, 2 H), 2.95 (s, 3 H), 1.09 (s, 9 H).
13C NMR: d = 155.9, 135.58, 135.56, 132.9, 132.65, 132.63, 130.07,
130.03, 128.5, 127.97, 127.94, 127.91, 123.4, 115.6, 66.5, 57.8,
42.2, 26.9, 19.3.
Yield: 2.3 g (8.9 mmol, 95%); light-yellow solid; mp 112.5–
113.5 °C; [a]D23 –6.0 (c 0.63, acetone).
IR (NaCl): 3417, 1644 cm–1.
1H NMR (acetone-d6): d = 8.08 (br, 1 H), 7.07 (d, J = 8.5 Hz, 2 H),
6.75 (d, J = 8.5 Hz, 2 H), 5.94 (d, J = 8.5 Hz, 1 H), 3.99 (br, 1 H),
3.63 (d, J = 5.5 Hz, 2 H), 3.49–3.38 (m, 1 H), 2.98 (s, 3 H), 2.81–
2.56 (m, 2 H), 1.98–1.65 (m, 2 H).
13C NMR (acetone-d6): d = 155.4, 132.7, 129.2, 115.1, 64.7, 55.8,
40.8, 34.4, 30.9.
ESI-MS: m/z = 518 [M + Na]+.
HRMS-ESI: m/z [M + Na]+ calcd for C27H33NO4SSi: 518.1797;
found: 518.1797.
Anal. Calcd for C27H33NO4SSi: C, 65.42; H, 6.71; N, 2.83. Found:
C, 65.23; H, 6.36; N, 2.69.
ESI-MS: m/z = 282 [M + Na]+.
(S,E)-N-[1-(tert-Butyldiphenylsilyloxy)-4-(4-acetoxyphe-
nyl)but-3-en-2-yl]methanesulfonamide (9)
HRMS-ESI: m/z [M + Na]+ calcd for C11H17NO4SNa: 282.0776;
found: 282.0778.
A sample of 9 was obtained by flash chromatographic purification
of the Heck product (EtOAc–hexanes, 3:1) prior to K2CO3/MeOH
treatment.
Anal. Calcd for C11H17NO4S: C, 50.95; H, 6.61; N, 5.40. Found: C,
50.98; H, 6.59; N, 5.39.
Light-yellow oil; [a]D20 –16.6 (c 1.17, CH2Cl2).
IR (NaCl): 3288, 1750, 1324, 1156 cm–1.
(R)-N-[1-(4-Hydroxyphenyl)-4-methylpent-3-yl]methane-
sulfonamide (15a)
Chromatographic purification (EtOAc–hexanes, 1:1).
Pale-yellow oil; [a]D17 –2.3 (c 0.97, acetone).
IR (NaCl): 3256, 1706, 1359, 1220 cm–1.
1H NMR (acetone-d6): d = 7.07 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.6
Hz, 2 H), 3.32–3.23 (m, 1 H), 2.94 (s, 3 H), 2.80–2.52 (m, 2 H),
2.01–1.66 (m, 3 H), 0.95 (dd, J = 9.1, 6.7 Hz, 6 H).
13C NMR (CDCl3): d = 154.1, 133.1, 129.3, 115.4, 59.4, 42.0, 34.3,
31.6, 31.4, 18.5, 17.6.
1H NMR (CDCl3): d = 7.68–7.60 (m, 4 H), 7.49–7.31 (m, 8 H), 7.06
(d, J = 8.6 Hz, 2 H), 6.62 (d, J = 15.7 Hz, 1 H), 6.07 (dd, J = 15.7,
7.5 Hz, 1 H), 4.93 (d, J = 6.7 Hz, 1 H), 4.25–4.15 (m, 1 H), 3.90–
3.68 (m, 2 H), 2.93 (s, 3 H), 2.31 (s, 3 H), 1.08 (s, 9 H).
13C NMR (CDCl3): d = 169.4, 150.4, 135.56, 135.54, 133.7, 132.5,
132.3, 130.07, 130.04, 127.95, 127.90, 127.50, 126.5, 121.8, 66.4,
57.4, 42.2, 26.8, 21.1, 19.2.
HRMS-ESI: m/z [M + Na]+ calcd for C29H35NO5SSiNa: 560.1903;
found: 560.1894.
HRMS-ESI: m/z [M + Na]+ calcd for C13H21NO3SNa: 294.1140;
Anal. Calcd for C29H35NO5SSi: C, 64.77; H, 6.56; N, 2.60. Found:
C, 64.50; H, 6.52; N, 2.79.
found: 294.1143.
(S)-N-[1-(4-Hydroxyphenyl)but-3-yl]methanesulfonamide
(15b)
Chromatographic purification (EtOAc–hexanes, 1:1).
(S,E)-N-[1-Hydroxy-4-(4-hydroxyphenyl)but-3-en-2-yl]meth-
anesulfonamide (12)
Commercial HF-pyridine solution (70% HF, 7 mL) was added
dropwise to a cold (0 °C) solution of 11 (4.9 g, 9.9 mmol) in THF
(30 mL) under Ar, with good stirring. The mixture was stirred over-
night, during which time it warmed to r.t., then was neutralized with
solid NaHCO3 added in small portions, with good stirring, until no
more bubbling ensued (CAUTION! foaming). The mixture was
then filtered through Celite and evaporated. Chromatographic puri-
fication of the residue (EtOAc–hexanes, 3:1) afforded pure 12.
Pale-yellow oil; [a]D17 –1.9 (c 0.85, acetone).
IR (NaCl): 3421, 1285, 1127 cm–1.
1H NMR (acetone-d6): d = 8.11 (br, 1 H), 7.07 (d, J = 8.1 Hz, 2 H),
6.76 (d, J = 8.1 Hz, 2 H), 5.94 (d, J = 8.2 Hz, 1 H), 3.54–3.39 (m,
1 H), 2.92 (s, 3 H), 2.75–2.55 (m, 2 H), 1.88–1.68 (m, 2 H), 1.28 (d,
J = 6.5 Hz, 3 H).
13C NMR (acetone-d6): d = 155.4, 132.6, 129.2, 115.0, 49.5, 40.6,
39.7, 31.2, 21.7.
HRMS-ESI: m/z [M + Na]+ calcd for C11H17NO3SNa: 266.0827;
found: 266.0821.
Yield: 2.4 g (9.4 mmol, 95%); light-yellow solid; mp 142–143 °C;
[a]D23 –63.6 (c 0.79, acetone).
IR (NaCl): 3426, 1644 cm–1.
1H NMR (acetone-d6): d = 8.46 (br, 1 H), 7.30 (d, J = 8.6 Hz, 2 H),
6.82 (d, J = 8.6 Hz, 2 H), 6.65 (d, J = 16 Hz, 1 H), 6.17–6.06 (m,
2 H), 4.21–4.06 (m, 2 H), 3.76–3.62 (m, 2 H), 2.96 (s, 3 H).
13C NMR (acetone-d6): d = 157.2, 131.7, 128.3, 127.7, 124.5, 115.4,
65.1, 58.3, 41.0.
(R)-N-[1-(4-Hydroxyphenyl)-4-phenylbut-3-yl]methane-
sulfonamide (15c)
Chromatographic purification (EtOAc–hexanes, 1:2).
Pale-yellow oil; [a]D18 –6.1 (c 0.96, acetone).
IR (NaCl): 3313, 1297, 1137 cm–1.
ESI-MS: m/z = 280 [M + Na]+.
1H NMR (acetone-d6): d = 8.13 (br, 1 H), 7.38–7.17 (m, 5 H), 7.03
(d, J = 8.3 Hz, 2 H), 6.74 (d, J = 8.3 Hz, 2 H), 6.10 (d, J = 8.9 Hz,
1 H), 3.71–3.55 (m, 1 H), 2.99–2.54 (m, 4 H), 2.45 (s, 3 H), 1.93–
1.68 (m, 2 H).
13C NMR (acetone-d6): d = 155.4, 139.1, 132.6, 129.7, 129.1, 128.3,
126.3, 115.1, 56.0, 41.9, 40.2, 37.9, 31.0.
HRMS-ESI: m/z [M + Na]+ calcd for C11H15NO4SNa: 280.0619;
found: 280.0616.
Anal. Calcd for C11H15NO4S: C, 51.35; H, 5.88; N, 5.44. Found: C,
51.75; H, 5.80; N, 5.49.
Synthesis 2010, No. 15, 2515–2520 © Thieme Stuttgart · New York

2520
H. Liang et al.
PAPER
2002, 41, 4176. (e) Braese, S.; de Meijere, A. Cross-
HRMS-ESI: m/z [M + Na]+ calcd for C17H21NO3SNa: 342.1140;
found: 342.1138.
coupling of organic halides with alkenes: The Heck reaction,
In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 2004.
(7) (a) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH:
Weinheim, 2003. (b) Grubbs, R. H.; Trnka, T. M.
Ruthenium-Catalyzed Olefin Metathesis, In Ruthenium in
Organic Synthesis; Murahashi, S.-I., Ed.; Wiley-VCH:
Germany, 2004. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2000, 34, 18.
(R)-N-[5-(4-Hydroxyphenyl)-1-(methylthio)but-3-yl]methane-
sulfonamide (15d)
1H NMR (CDCl3): d = 7.02 (d, J = 7.9 Hz, 2 H), 6.76 (d, J = 7.9 Hz,
2 H), 3.58–3.50 (m, 1 H), 2.97 (s, 3 H), 2.64–2.57 (m, 4 H), 2.11 (s,
3 H), 1.93–1.74 (m, 4 H).
Acknowledgment
(8) For a review, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457.
We thank the University of British Columbia, the Canada Research
Chair Program, CFI, BCKDF, NSERC, CIHR, and MerckFrosst
Canada for support of our program. H.L. is the recipient of a UBC
Graduate Fellowship and a Gladys Estella Laird Research Fel-
lowship.
(9) Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.;
Taylor, R. J. K. J. Org. Chem. 2002, 67, 1802.
(10) (a) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G.
J. Chem. Soc. A 1966, 1711. (b) Mannig, D.; Noth, H.
Angew. Chem. Int. Ed. 1985, 24, 878.
(11) There was no reaction in THF at temperatures below 60 °C.
At reflux, the substrate was converted into complex mixtures
of products.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
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Synthesis 2010, No. 15, 2515–2520 © Thieme Stuttgart · New York