Suzuki-Miyaura cross-coupling of 3-pyridyl triflates with Alk-1-enyl-2-pinacol boronates

Article abstract of DOI:10.1055/s-0030-1258237

Palladium-catalyzed Suzuki-type couplings of 3-pyridyl triflates with alkenylpinacol boronates proceed in good to excellent yields. Optimized conditions use Pd(PPh₃)₄ (10 mol%) as catalyst with K ₃PO₄ (3 equiv)

Full text of DOI:10.1055/s-0030-1258237

PAPER
3637
Suzuki–Miyaura Cross-Coupling of 3-Pyridyl Triflates with
Alk-1-enyl-2-pinacol Boronates
S
uzuki Co
a
uplings of
P
m
yridyl
T
riflates es R. Vyvyan,* Jennifer A. Dell (née Meyer), Toby J. Ligon, Kelsey K. Motanic, Hayley S. Wall
Department of Chemistry, Western Washington University, 516 High Street, Bellingham, WA 98225-9150, USA
Fax +1(360)6502826; E-mail: vyvyan@chem.wwu.edu
Received 8 July 2010; revised 15 July 2010
Dedicated to Professor Thomas R. Hoye on the occasion of his 60th birthday
triflate 4 with alkenyl boronate 6 (Scheme 1). Alternative-
ly, the roles of the components could be reversed, such
that pyridyl boronate 5 could be coupled with alkenyl tri-
flate 7. Since preparation of the coupling partners require
the same number of synthetic steps, we planned to explore
both permutations of the coupling reaction.8
Abstract: Palladium-catalyzed Suzuki-type couplings of 3-pyridyl
triflates with alkenylpinacol boronates proceed in good to excellent
yields. Optimized conditions use Pd(PPh3)4 (10 mol%) as catalyst
with K3PO4 (3 equiv) as base in 1,4-dioxane.
Key words: boron, cross-coupling, heterocycles, palladium, py-
ridines
Appropriately substituted 3-hydroxypyridines are more
readily available than the corresponding 3-halo deriva-
tives, and they are easily converted into the corresponding
aryl triflates 4 with Comins’ triflimide9 in the presence of
base. The simple pyridyl triflates 4a–c are known,10 and
we also desired to examine the cross-coupling reaction
with pyridines functionalized at the 2-position to provide
a functional group handle for subsequent manipulations
(Scheme 2). Triflate 4d was readily prepared from 3-hy-
droxy-6-methyl-2-pyridinemethanol (8). Selective pro-
tection of the primary hydroxy group as the pivaloate ester
using pivaloyl chloride and 4-dimethylaminopyridine
(DMAP) provided ester 9. The 3-hydroxy group was then
cleanly converted into the triflate using Comins’ triflim-
ide and triethylamine to give 4d in excellent yield. The
preparation of triflate 4e commenced with the protection
of the 3-hydroxy group of 8 as the allyl ether to yield 10.
Reaction of the primary hydroxy group with N-bromosuc-
cinimide and triphenylphospine provided bromide 11,
which in turn was converted into the sulfone 12 by treat-
ment of the bromide with sodium phenyl sulfinate. Cleav-
age of the allyl ether using standard conditions yielded 13,
which was converted into the triflate 4e with Comins’ tri-
flimide as described earlier. Thus, the preparation of 4e
was accomplished in five steps in 44% overall yield. Tri-
flate 4f was synthesized in a more straightforward man-
ner. Reaction of 8 with HBr and thiophenol gave the
phenyl sulfide that was directly converted into the triflate
4f in the usual manner.
Since its development 30 years ago,1 the Suzuki–Miyaura
cross-coupling of organoboron compounds has become
one of the most widely used methods for forming C–C
bonds.2 Given the myriad examples of Suzuki–Miyaura
couplings, and the fact that there are a number of interest-
ing branched 3-alkylpyridine natural products, such as
cananodine (1)3,4 and xestamine C (2),5 we were surprised
to find very few examples of reactions between 3-pyridyl
triflates and alkenyl/alkyl boronates.6 Similarly, there are
few examples of coupling 3-pyridyl boron derivatives
with alkenyl halides or triflates.7
In a retrosynthetic analysis of cananodine (1) and xesta-
mine C (2), we identified branched pyridyl alkene 3 as a
key intermediate prepared by cross-coupling a 3-pyridyl
Me
N
OMe
N
13
N
OH
1
2
cananodine
xestamine C
R3
R1
N
R2
3
Despite examining several sets of reaction conditions,11
we were unable to consistently convert the 3-pyridyl tri-
flates 4 into their corresponding pinacol boronates 5. In
Suzuki–Miyaura
coupling
X
1
R3
some cases, the H NMR spectrum of the crude reaction
Y
R1
N
R2
mixture appeared to contain the desired pyridyl boronate,
but 5 could not be isolated after chromatography. Our in-
ability to prepare the 3-pyridyl boronates 5 reliably fo-
cused our efforts entirely on the coupling of 3-pyridyl
triflates with alkenyl boronates (cf. 4 and 6, respectively).
6 Y = B(OR)2
7 X = OTf
4 X = OTf
5 X = B(OR)2
Scheme 1
SYNTHESIS 2010, No. 21, pp 3637–3644
x
x.
x
x
.
2
0
1
0
Next, we prepared alkenyl boronates with both trisubsti-
tuted and monosubstituted pendant alkenes to serve as
Advanced online publication: 30.08.2010
DOI: 10.1055/s-0030-1258237; Art ID: M04810SS
© Georg Thieme Verlag Stuttgart · New York

3638
J. R. Vyvyan et al.
PAPER
Table 1 Preparation of Alkenyl Boronates 15
OTf
4a R1 = H, R2 = H
4b R1 = H, R2 = Me
4c R1 = Me, R2 = H
R3
O
conditions
R1
N
R2
B
R3
Y
O
PvCl
Comins'
triflimide
14
15
OH
OH
OH
OTf
DMAP
Y
R3
Conditionsa Product Yield (%)
CH2Cl2
88%
Et3N
N
N
N
CH2Cl2
97%
14a
14b
14c
14d
OTf
OTf
Br
prenyl Pd
15a
15b
15b
15c
74
OPv
OPv
8
9
4d
allyl
allyl
Pd
Li
complex mixture
>99
>99
allyl bromide
K2CO3
NBS, Ph3P
CH2Cl2
OH
O
Br
propyl Li
acetone
96%
87%
N
N
N
a Pd conditions: Pd(PPh3)2Cl2 (3 mol%), Ph3P (6 mol%), bispinacola-
todiboron (1.1 equiv), KOPh (1.5 equiv), toluene, 50 °C. Li condi-
tions: t-BuLi (2.1 equiv), Et2O, –78 °C, then isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (1.5–3.0 equiv).
OH
O
OH
O
8
10
PhSO2Na
DMSO
Pd(PPh3)4
(cat.)
80 °C
72%
MeOH, K2CO3
78%
Yields for the coupling range from modest to very good.
Since the mobilities of the coupled products on silica gel
are similar to those of the pyridyl triflates 4, an excess of
15 (1.2–2 equiv) was used in all cases to ensure complete
conversion of the triflate partner.
N
N
Br
SO2Ph
12
11
13
Comins'
triflimide
OH
OTf
Et3N, CH2Cl2
93%
In head to head comparisons, Pd(PPh3)4 was a better cata-
lyst for this transformation than Pd(dppf)Cl2 (Table 2, en-
tries 8 vs. 9, and 11 vs. 12) and K3PO4 was a better base
than potassium acetate in the presence of Pd(dppf)Cl2 (en-
try 11 vs. 12). Pyridyl triflates 4a–c, lacking substitution
at the 2- and/or 6-position, gave lower yields of cross-
coupled product in most cases relative to triflate 4d that
has substitution at both the 2- and 6-positions. It is not
clear if the reduced yields of the less substituted com-
pounds are truly a result of less efficient cross-coupling,
or if product losses during chromatographic purification
of the less hindered pyridines on silica gel are responsible.17
N
SO2Ph
SO2Ph
4e
1) HBr, PhSH
OH
OH
OTf
2) Comins' triflimide
Et3N, CH2Cl2
88%, 2 steps
N
N
SPh
8
4f
Scheme 2 Preparation of pyridyl triflates
precursors for planned syntheses of 1 and 2. Alkenyl tri-
flate 14a12 was readily converted into the corresponding
alkenyl boronate 15a under conditions developed by
Miyaura (Table 1).13 Reaction of triflate 14b under these
conditions, however, produced a complex mixture, and 1H
NMR analysis of the reaction mixture indicated only a
small amount of 15b was formed. Other products ob-
Unfortunately, pyridyl triflates bearing a sulfone 4e or
sulfide 4f substituent failed to produce cross-coupled
products (entries 13–16). Sulfone 4e was consumed in the
reaction and converted into an unidentified product that
appears to arise after deprotonation of the activated CH2
at the C-2 of the pyridine under the basic reaction condi-
tions. Sulfide 4f was not consumed under the reaction
conditions. Presumably the sulfur substituent poisons the
Pd catalyst, perhaps through chelation of Pd between the
sulfur and pyridine nitrogen, and prevents the cross-
coupling reaction.
1
served in the H NMR spectrum included methylenecy-
cloalkenes, produced by intramolecular Heck reaction of
the monosubstitued alkene after insertion of the Pd cata-
lyst into the C–O bond of the triflate.14 Presumably the in-
creased steric bulk of the trisubstituted alkene in 14a
prevents the Heck reaction in that case. Fortunately, bor-
onate 15b could be produced in excellent yield from 2-
bromohexa-1,5-diene15 (14c) by lithium–bromide ex-
change followed by addition of the intermediate alkenyl-
lithium species to isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxoborolane.16 Boronate 15c was prepared from 2-bro-
mohex-1-ene (14d) in a similar fashion and in excellent
yield.
Next, we carried out the cross-coupling with a more func-
tionalized alkenyl boronate to advance our ongoing ef-
forts toward a convergent synthesis of cananodine (1).18
We initially chose an acetonide-protected diol group that
could eventually serve as a precursor to a trisubstituted
epoxide. Formation of the kinetic enolate of ketone 2819
using lithium diisopropylamide followed by trapping of
the enolate with Comins’ triflimide provided alkenyl tri-
flate 29 in modest yield (Scheme 3). Triflate 29 was con-
verted into the alkenyl boronate 30 in good yield using the
Results of the Suzuki–Miyaura coupling between pyridyl
triflates 4 and alkenyl boronates 15 are shown in Table 2.
Synthesis 2010, No. 21, 3637–3644 © Thieme Stuttgart · New York

PAPER
Suzuki Couplings of Pyridyl Triflates
3639
O
Table 2 Suzuki–Miyaura Cross-Coupling of 3-Pyridyl Triflates
with Alkenyl Boronates
OTf
1) LDA, THF, –78 °C
O
2) Comins' triflimide
34%
O
OTf
O
R3
O
O
conditions
B
+
28
29
O
R3
1,4-dioxane
80–100 °C
R1
N
R2
R1
N
R2
O
O
O
O
B
B
4a R1 = H, R2 = H
4b R1 = H, R2 = Me
4c R1 = Me, R2 = H
15a R3 = prenyl
15b R3 = allyl
16–27
BPin
15c R3 = propyl
PdCl2(PPh3)2 (3 mol%)
Ph3P (6 mol%)
KOPh, toluene, 50–60 °C
73%
4d R1 = Me, R2 = CH2OPv
4e R1 = Me, R2 = SO2Ph
4f R1 = Me, R2 = SPh
O
O
30
Entry
Pyridyl
triflate
Alkenyl
boronate
Conditionsa Product Yield
(%)b
30 (1.2–1.8 equiv)
Pd(PPh3)4 (10 mol%)
OTf
O
O
K3PO4 (3 equiv)
1,4-dioxane
90–100 °C
86%
1
2
4a
4a
4b
4b
4b
4c
4c
4d
4d
4d
4d
4d
4e
4e
4f
15b
15c
15a
15b
15c
15b
15c
15a
15a
15b
15c
15c
15a
15a
15a
15a
A
16
17
18
19
20
21
22
23
23
24
25
25
26
26
27
27
56
47
86
74
43
59
55
79
50
84
83
60
N
N
OPv
OPv
31
A
A
A
A
A
A
A
B
A
A
C
A
B
A
B
4d
3
Scheme 3
4
duce the cross-coupled product under Suzuki–Miyaura
type conditions. Given the accessibility of the precursors
and the high yields obtained, this coupling strategy is well
suited to the synthesis of a-branched 3-alkylpyridine tar-
gets.
5
6
7
8
All reactions involving air sensitive materials were carried out in
oven-dried glassware under an argon atmosphere. Acetone was
dried by stirring with B2O3 (5% w/v) overnight before filtration and
distillation.20 CH2Cl2, Et2O, THF, and toluene were dried by pass-
ing the solvent through a column of activated alumina under N2 im-
mediately prior to use. Anhyd DMSO and DMF were used as
received from commercial suppliers. 1,4-Dioxane was distilled
from sodium benzophenone ketyl under argon. Et3N was distilled
from CaH2 (bp 89 °C) and stored over KOH pellets. MeSO2Cl was
distilled from P2O5 (bp 57–58 °C/18 mmHg). KOAc was dried un-
der vacuum (100 °C/0.2 mmHg) with a Kügelrohr apparatus imme-
diately prior to use. Comins’ triflimide9 and KOPh21 were prepared
as reported in the literature. Pyridyl triflates 4a, 4b, and 4c have
been previously reported.10 Alkenyl triflate 14a,12 and alkenyl bro-
mides 14c and 14d15 were prepared according to literature proce-
dures.
9
10
11
12
13
14
15
16
0c
0c
0d
0d
4f
a Conditions: A = Pd(PPh3)4 (10 mol%), K3PO4 (3 equiv), 1,4-diox-
ane, 80–100 °C; B = Pd(dppf)Cl2 (10 mol%), K3PO4 (3 equiv), 1,4-
dioxane, 80–100 °C; C = Pd(dppf)Cl2 (3 mol%), dppf (3 mol%),
KOAc (3 equiv), 1,4-dioxane, 80 °C.
(3-Hydroxy-6-methylpyridin-2-yl)methyl Pivaloate (9)
DMAP (386 mg, 3.15 mmol) was placed in a 50 mL 2-necked
round-bottomed flask equipped with a solid addition bulb that con-
tained 3-hydroxy-6-methyl-2-pyridinemethanol (8; 416 mg, 3.00
mmol). The DMAP was dissolved in CH2Cl2 (30 mL) and the solu-
tion was cooled to 0 °C before pivaloyl chloride (0.37 mL, 362 mg,
3.00 mmol) was added dropwise. The solution was stirred for 30
min, before the 3-hydroxy-6-methyl-2-pyridinemethanol was added
at once. The solution was stirred and slowly warmed, and after 2 h
TLC analysis indicated complete consumption of the starting mate-
rial. H2O (15 mL) was added, the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 15 mL). The com-
bined organic layers were washed with sat. aq NaHCO3 (25 mL).
After drying the combined organic layers and evaporating the sol-
vent, purification by flash chromatography (3:1 hexanes–EtOAc +
2% EtOH) yielded 9 as a white solid (586 mg, 88%); mp 136.5–
141.5 °C (dec.).
b Isolated yield of analytically pure material.
c Pyridyl triflate 4e was consumed, alkenyl boronate 15a was recov-
ered.
d Both pyridyl triflate 4f and alkenyl boronate 15a recovered.
same conditions13 described above for the preparation of
15a.
Using the optimized cross-coupling conditions, triflate 4d
was coupled with alkenyl boronate 30 to produce cross-
coupled product 31 in excellent yield. Compound 31 con-
tains all of the carbon atoms necessary for preparation of
the bicyclic core of cananodine (1), and diene 16 is a rea-
sonable precursor for the synthesis of xestamine C (2).
In summary, we have demonstrated that reaction of 3-py-
ridyl triflates with alk-1-enyl-2-pinacol boronates pro-
IR (KBr): 2969, 2589, 1721, 1581, 1477, 1458, 1285, 1266, 1156,
1123, 1030, 968, 836 cm–1.
Synthesis 2010, No. 21, 3637–3644 © Thieme Stuttgart · New York

3640
J. R. Vyvyan et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.15 (d, J = 8.3 Hz, 1 H), 7.02 (d,
J = 8.3 Hz, 1 H), 5.16 (s, 2 H), 2.98 (br s, 1 H), 2.36 (s, 3 H), 1.20
(s, 9 H).
13C NMR (125 MHz, acetone-d6): d = 178.6, 150.6, 149.2, 142.8,
124.3, 124.0, 64.1, 39.4, 27.6, 23.4.
the solution was slowly warmed to r.t. After 2 h, TLC analysis indi-
cated the starting material had been consumed. The solution was di-
luted with Et2O (100 mL) and washed with sat. aq NaHSO3 (50
mL), sat. aq NaHCO3 (3 × 25 mL), and H2O (25 mL). After drying
the organic layer and removing solvent, bromide 11 was obtained as
a bright pink solid (4.08 g, 87%); mp 40.0–40.4 °C.
Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found: C,
64.48; H, 7.38; N, 6.75.
IR (KBr): 2904, 1650, 1574, 1472, 1444, 1407, 1382, 1283, 1258,
1207, 1174, 1154, 989, 927, 821 cm–1.
[6-Methyl-3-(trifluoromethylsulfonyloxy)pyridin-2-yl]methyl
Pivaloate (4d)
1H NMR (500 MHz, CDCl3): d = 7.08 (d, J = 8.5 Hz, 1 H), 7.03 (d,
J = 8.5 Hz, 1 H), 6.04 (ddt, J = 17.1, 10.5, 5.1 Hz, 1 H), 5.45 (app
dq, J = 17.1, 1.5 Hz, 1 H), 5.31 (app dq, J = 10.5, 1.5 Hz, 1 H), 4.63
(s, 2 H), 4.60 (dt, J = 5.1, 1.5 Hz, 2 H), 2.47 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 150.5, 149.4, 145.0, 132.2, 123.8,
120.0, 117.6, 68.8, 29.6, 23.1.
A 10 mL round-bottomed flask was charged with 9 (200 mg, 0.896
mmol) and Comins’ triflimide (375 mg, 0.955 mmol). After an ar-
gon atmosphere was established, CH2Cl2 (5 mL) was added to the
flask and the solution was cooled to 0 °C. Et3N (0.13 mL, 96 mg,
0.95 mmol) was added dropwise, and the solution was stirred at
0 °C for 1 h before the ice bath was removed. After an additional 45
min, TLC analysis indicated complete consumption of the starting
material. The solution was washed with aq 1 M NaOH (2 × 5 mL)
and half-saturated K2CO3 (5 mL). After drying the organic layer and
evaporating solvent, the crude product was purified by MPLC (6:1
hexanes–EtOAc) to afford 4d as a white solid (308 mg, 97%); mp
39.1–40.1 °C.
Anal. Calcd for C10H12BrNO: C, 49.61; H, 5.00; N, 5.79. Found: C,
49.88; H, 5.10; N, 5.77.
3-(Allyloxy)-6-methyl-2-(phenylsulfonylmethyl)pyridine (12)
PhSO2Na (2.61 g, 15.8 mmol) was added to a 100 mL round-bot-
tomed flask equipped with a reflux condenser. Anhyd DMSO (75
mL) was used to dissolve 11 (3.48 g, 14.4 mmol) and this solution
was then added to the flask with a syringe. The mixture was heated
gently for 1.5 h at which time TLC analysis showed complete con-
sumption of the starting material. The hot solution was poured over
ice at which time the product began to crystallize. Vacuum filtration
of the mixture through a Büchner funnel provided crude 12, which
was recrystallized from hexanes–CHCl3 to give white needles (4.21
g, 96%); mp 126.5–128.9 °C.
IR (NaCl; dep. CH2Cl2): 2975, 2936, 1737, 1481, 1462, 1427, 1283,
1252, 1218, 1144, 1095, 1040, 936, 871, 831 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.52 (d, J = 8.5 Hz, 1 H), 7.21 (d,
J = 8.5 Hz, 1 H), 5.25 (s, 2 H), 2.58 (s, 3 H), 1.24 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 177.9, 158.4, 147.5, 143.1, 129.4,
124.2, 118.4 (q, J = 318 Hz, CF3), 62.3, 38.8, 27.1, 23.9.
IR (NaCl; dep. CHCl3): 2973, 2909, 1573, 1473, 1446, 1303, 1277,
1265, 1144, 1080, 999, 945, 829, 737, 687 cm–1.
Anal. Calcd for C13H16F3NO5S: C, 43.94; H, 4.54; N, 3.94; S, 9.02.
Found: C, 43.53; H, 4.45; N, 4.20; S, 9.13.
1H NMR (500 MHz, CDCl3): d = 7.70 (m, 2 H), 7.59 (tt, J = 7.7, 1.1
Hz, 1 H), 7.45 (m, 2 H), 7.01 (s, 2 H), 5.91 (ddt, J = 17.1, 10.5, 5.1
Hz, 1 H), 5.35 (app dq, J = 17.1, 1.5 Hz, 1 H), 5.28 (app dq,
J = 10.5, 1.5 Hz, 1 H), 4.69 (s, 2 H), 4.36 (dt, J = 5.1, 1.5 Hz, 2 H),
2.34 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 151.8, 149.9, 139.4, 137.8, 133.2,
132.4, 128.7, 128.5, 123.8, 119.9, 118.0, 69.2, 59.0, 23.2.
[3-(Allyloxy)-6-methylpyridin-2-yl]methanol (10)
To a 200 mL round-bottomed flask was added the diol 8 (3.00 g,
21.5 mmol), K2CO3 (5.94 g, 43.0 mmol), and acetone (100 mL).
The suspension was stirred vigorously and allyl bromide (2.33 mL,
3.25 g, 26.9 mmol) was added dropwise. A reflux condenser was at-
tached on the flask, and the mixture was heated to reflux. After 3.5
h at reflux, TLC analysis indicated the starting material had been
consumed. The solid K2CO3 was removed by filtration and the ace-
tone was evaporated under reduced pressure. The solid thus ob-
tained was dissolved in EtOAc (25 mL) and H2O (25 mL) was
added. The aqueous layer was extracted with EtOAc (2 × 25 mL).
After drying the combined organic layers and removing solvent, 10
(3.65 g, 96%) was obtained as tan crystals; mp 51.9–52.8 °C.
Anal. Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62; S, 10.57.
Found: C, 62.99; H, 5.47; N, 4.51; S, 10.20.
6-Methyl-2-(phenylsulfonylmethyl)pyridin-3-ol (13)
To a 25 mL two-necked round-bottomed flask was added pyridine
sulfone 12 (2.87 g, 9.40 mmol) and Pd(PPh3)4 (0.105 g, 0.098
mmol, 1 mol%). An argon atmosphere was established and MeOH
(65 mL) was added via syringe. The resulting pale yellow solution
was stirred for 5 min before K2CO3 (4.01 g, 29.4 mmol) was added.
A cloudy white solution resulted. After stirring for 3 h, TLC analy-
sis indicated complete consumption of the starting material. The
MeOH was removed by evaporation under reduced pressure. The
residue was then treated with pH 5.2 NaOAc/AcOH buffer, extract-
ed with EtOAc (3 × 50 mL), and the combined organic layers were
dried (Na2SO4). After removing the solvent, recrystallization of the
residue from CHCl3–EtOH and EtOAc–EtOH yielded 13 as color-
less plates (1.95 g, 78%); mp 196.9–199.5 °C.
IR (NaCl; dep. CDCl3): 3131, 2920, 2872, 1651, 1481, 1460, 1279,
1140, 1015, 995, 928, 814 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.04 (d, J = 8.3 Hz, 1 H), 6.99 (d,
J = 8.3 Hz, 1 H), 6.01 (ddt, J = 17.1, 10.5, 5.1 Hz, 1 H), 5.39 (app
dq, J = 17.1, 1.5 Hz, 1 H), 5.30 (app dq, J = 10.5, 1.5 Hz, 1 H), 4.73
(s, 2 H), 4.55 (dt, J = 5.1, 1.5 Hz, 2 H), 2.49 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 149.1, 148.1, 147.2, 132.5, 121.6,
118.6, 117.2, 68.7, 59.8, 23.0.
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
66.84; H, 7.29; N, 8.26.
IR (diamond ATR): 1575 (m), 1492 (s), 1449 (m), 1302 (s), 1283
(s), 1264 (s), 1141 (s), 1081 (s), 884 (m), 839 (s), 785 (s), 729 (s),
722 (s), 682 cm–1 (s).
1H NMR (500 MHz, CDCl3): d = 7.76 (m, 2 H), 7.64 (tt, J = 7.3, 1.4
Hz, 1 H), 7.50 (m, 2 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.02 (d, J = 8.3
Hz, 1 H), 4.69 (s, 2 H), 2.27 (s, 3 H).
3-(Allyloxy)-2-(bromomethyl)-6-methylpyridine (11)
Ph3P (5.39 g, 20.5 mmol) and 10 (3.53 g, 19.5 mmol) were placed
in a 100 mL two-necked round-bottomed flask equipped with a sol-
id addition funnel. N-Bromosuccinimide (NBS) (3.55 g, 19.9
mmol) was placed in the solid addition funnel and an argon atmo-
sphere was established. The CH2Cl2 solution (50 mL) was cooled to
–40 °C (dry ice/MeCN) and the NBS was added in small portions
over 15 min. After the addition, the cooling bath was removed and
13C NMR (125 MHz, CDCl3): d = 151.3, 150.7, 137.2, 135.7, 134.2,
129.1, 128.4, 127.3, 124.9, 62.0, 23.1.
Synthesis 2010, No. 21, 3637–3644 © Thieme Stuttgart · New York

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Suzuki Couplings of Pyridyl Triflates
3641
Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32; S, 12.18.
Found: C, 58.92; H, 4.96; N, 5.19; S, 12.03.
followed by alkenyl triflate 14a (521 mg, 2.02 mmol). The solution
was heated to 50 °C using a heating mantle. After 2 h, TLC analysis
indicated complete consumption of triflate 14a. The reaction was
then cooled to r.t. and H2O (10 mL) was added. The resulting layers
were separated and the aqueous layer was extracted with hexanes
(3 × 20 mL). After drying the combined organic layers and remov-
ing solvent, the residue was purified by MPLC (12:1 hexanes–
EtOAc) to yield boronate ester 15a as a colorless liquid (350 mg,
74%).
6-Methyl-2-(phenylsulfonylmethyl)pyridin-3-yl Trifluoro-
methanesulfonate (4e)
The procedure was the same as that described for the preparation of
4d. Sulfone 13 (910 mg, 3.00 mmol), Comins’ triflimide (1.21 g,
3.15 mmol), CH2Cl2 (15 mL), and Et3N (0.44 mL, 320 mg, 3.2
mmol) provided triflate 4e as a slightly yellow solid (1.10 g, 93%);
mp 117.2–118.6 °C.
IR (neat): 2979, 2926, 2859, 1616, 1437, 1370, 1308, 1144, 911,
734 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.76 (d, J = 3.4 Hz, 1 H), 5.60 (br
s, 1 H), 5.13 (m, 1 H), 2.17 (m, 2 H), 2.10 (m, 2 H), 1.68 (s, 3 H),
1.60 (s, 3 H), 1.27 (s, 12 H, 4 × CH3).
13C NMR (125 MHz, CDCl3): d = 145.8, 131.2, 128.9, 124.3, 83.2,
35.5, 27.9, 25.6, 24.8, 24.74, 24.70, 24.67, 24.6, 17.6.
IR (KBr): 3085, 3010, 2951, 1595, 1465, 1428, 1316, 1253, 1166,
1148, 903, 872, 841, 745 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.77 (m, 2 H), 7.66 (tt, J = 7.6, 1.4
Hz, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.52 (m, 2 H), 7.21 (d, J = 8.8
Hz, 1 H), 4.64 (s, 2 H), 2.45 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.7, 144.1, 141.2, 138.6, 134.0,
129.5, 129.0, 128.6, 124.8, 118.3 (q, J = 320 Hz, CF3), 59.3, 23.8.
HRMS-ESI: m/z [M + Na] calcd for C14H26BO2 + Na: 259.1845;
HRMS-ESI: m/z [M + H] calcd for C14H13F3NO5S2: 396.0187;
found: 259.1842.
found: 396.0207.
2-(Hexa-1,5-dien-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(15b)
6-Methyl-2-(phenylthiomethyl)pyridin-3-yl Trifluoromethane-
sulfonate (4f)
A 50 mL round-bottomed flask, equipped with thermometer and
septum, was charged with bromide 14c (1.61 g, 10.0 mmol) diluted
in THF (15 mL). The flask was then cooled to –78 °C. t-BuLi (11.8
mL 1.7 M in pentane, 20.1 mmol) was added dropwise, keeping the
reaction temperature below –70 °C. The mixture was stirred for 30
min before adding 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (3.0 mL, 2.80 g, 15.0 mmol) diluted in THF (10 mL) drop-
wise. The reaction was warmed slowly to r.t. Dilute HCl (1.0 M,
10.8 mL) was added while stirring, and the mixture was extracted
with CH2Cl2 (3 × 15 mL). The combined organic extracts were
dried (MgSO4), the solution was gravity filtered, and the filtrate
concentrated in vacuo. The crude product was filtered through a
plug of Celite eluting with hexanes to yield 15b as a clear colorless
oil after solvent removal (2.081 g, 10.0 mmol, ~100%).
Intermediate Phenyl Sulfide: Diol 8 (1.00 g, 7.20 mmol) was added
to a 50 mL two-necked round-bottomed flask equipped with a mag-
netic stir bar and water-cooled reflux condenser. Concd HBr (20
mL) was added followed by thiophenol (0.81 mL, 870 mg, 7.90
mmol). An immediate color change from red/brown to yellow was
observed. The mixture was refluxed for 5 h at which time the solu-
tion was allowed to cool to r.t. and extracted with Et2O (3 × 25 mL).
The aqueous layer was brought to pH 8 by the slow, careful addition
of solid K2CO3. This solution was then extracted again with Et2O
(3 × 20 mL). The combined organic layers were washed with H2O
(25 mL), dried, and concentrated to provide the phenyl sulfide as a
white solid (1.1 g, 67%) that was used in the next step without fur-
ther purification.
1H NMR (500 MHz, CDCl3): d = 7.38 (m, 2 H), 7.24 (m, 2 H), 7.18
(m, 1 H), 7.04 (d, J = 8.3 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 5.30
(s, 2 H), 4.36 (s, 1 H), and 2.41 (s, 3 H).
IR (NaCl, neat): 2979 (s), 2933 (s), 1638 (m), 1611 (m), 1427 (m),
1370 (s), 1309 (s), 1143 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 5.83 (ddt, J = 17.2, 10.2, 6.5 Hz,
1 H), 5.79 (d, J = 3.9 Hz, 1 H), 5.61 (br s, 1 H), 5.02 (app dq,
J = 17.2, 1.5 Hz, 1 H), 4.94 (app dq, J = 10.2, 1.5 Hz, 1 H), 2.21 (m,
4 H), 1.27 (s, 12 H).
Triflate 4f: The procedure was the same as that described for the
preparation of 4d. The phenyl sulfide obtained above (902 mg, 3.90
mmol), Comins’ triflimide (1.61 g, 4.10 mmol), CH2Cl2 (25 mL),
and Et3N (0.57 mL, 410 mg, 4.1 mmol) provided pyridyl triflate 4f
as a yellow liquid (1.40 g, ~100%).
13C NMR (125 MHz, CDCl3): d = 141.0 (weak, br),22 138.8, 129.3,
114.4, 83.3, 34.8, 33.5, 24.8.
IR (diamond ATR): 3062, 2993, 2928, 1582, 1481 (m), 1459, 1422,
1250, 1211, 1135, 1070, 884, 854, 826, 738, 690 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.45 (d, J = 8.3 Hz, 1 H), 7.40 (m,
2 H), 7.3–7.2 (m, 3 H), 7.10 (d, J = 8.3 Hz, 1 H), 4.28 (s, 2 H), 2.53
(s, 3 H).
HRMS-FAB: m/z [M – H] calcd for C12H20BO2: 207.1556; found:
207.1559.
2-(Hex-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(15c)
A 250 mL round-bottomed flask equipped with thermometer and
stir bar was brought under argon atmosphere and then charged with
Et2O (39 mL) and t-BuLi (11.8 mL, 1.7 M in pentane, 20.0 mmol).
The flask was cooled with a dry ice/i-PrOH slurry and after the mix-
ture had reached –78 °C, a solution of bromide 14d (1.630 g, 10.0
mmol) in Et2O (15 mL) was added dropwise. The mixture was
stirred 45 min before 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (6.16 mL, 5.617 g, 30.0 mmol) diluted in Et2O (10 mL)
was added dropwise. The reaction was then slowly warmed over the
next 3 h. Dilute HCl (1.0 M, 100 mL) was added and the mixture
was stirred for 30 min. The aqueous layer was extracted with Et2O
(3 × 50 mL) and the combined organic layers were dried (Na2SO4).
The solution was gravity filtered and the filtrate was concentrated
in vacuo. The crude product was filtered through a plug of Celite
eluting with hexanes to remove the white solid and 15c was ob-
13C NMR (125 MHz, CDCl3): d = 158.3, 149.7, 142.7, 134.6, 131.3,
129.2, 128.8, 127.1, 123.2, 118.4 (q, J, = 314), 36.2, 23.9.
HRMS-ESI: m/z [M + H] calcd for C14H13F3NO3S2: 364.0289;
found: 364.0283.
Anal. Calcd for C14H12F3NO3S2: C, 46.27; H, 3.33; N, 3.85; S,
17.65. Found: C, 46.12; H, 3.31; N, 4.14; S, 17.71.
4,4,5,5-Tetramethyl-2-(6-methylhepta-1,5-dien-2-yl)-1,3,2-di-
oxaborolane (15a)
A 25 mL three-necked round-bottomed flask equipped with a reflux
condenser, magnetic stir bar, and thermometer was charged with
PdCl2(PPh3)2 (45 mg, 0.060 mmol, 3 mol%), Ph3P (28 mg, 0.12
mmol), bis(pinacolato)diboron (555 mg, 2.18 mmol), and KOPh
(401 mg, 3.03 mmol). The flask was evacuated and flushed with ar-
gon (6 ×). Anhyd toluene (12 mL) was then added with a syringe
Synthesis 2010, No. 21, 3637–3644 © Thieme Stuttgart · New York

3642
J. R. Vyvyan et al.
PAPER
tained as a clear colorless oil after solvent removal (2.101 g, 10.0
mmol, ~100%).
Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C,
83.78; H, 9.67; N, 6.67.
IR (NaCl; neat): 2928 (s), 1615 (w), 1426 (w), 1370 (s), 1308 (s),
1214 (w), 1144 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 5.75 (d, J = 6.0 Hz, 1 H), 5.59 (br
s, 1 H), 2.14 (t, J = 7.0 Hz, 2 H), 1.4–1.2 (4 H, m), 1.26 (12 H, s),
0.89 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 141.1, 128.6, 83.2, 35.0, 31.4, 24.7,
22.3, 14.0.
3-(Hexa-1,5-dien-2-yl)-2-methylpyridine (19)
IR (NaCl; neat): 2927, 1712, 1639, 1566, 1432, 1399, 1227, 1205,
1130, 1086, 996, 906, 807, 740 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.41 (dd, J = 1.9, 4.6 Hz, 1 H),
7.36 (dd, J = 7.5, 1.9 Hz, 1 H), 7.08 (dd, J = 7.5, 4.6 Hz, 1 H), 5.80
(m, 1 H), 5.25 (d, J = 1.4 Hz, 1 H), 5.03 (dd, J = 1.4, 17.1 Hz, 1 H),
4.99 (dd, J = 10.5, 1.4 Hz, 1 H), 4.96 (d, J = 1.4 Hz, 1 H), 2.52 (s, 3
H), 2.44 (t, J = 7.5 Hz, 2 H), 2.15 (td, J = 7.5, 6.5 Hz, 2 H).
HRMS-FAB: m/z calcd for C12H23BO2: 210.1791; found: 210.1793.
13C NMR (125 MHz, CDCl3): d = 155.4, 147.6, 147.5, 137.8, 136.0,
Cross-Coupling of 3-Pyridyl Triflates and Alkenyl Boronates;
3-(Hexa-1,5-dien-2-yl)pyridine (16); Typical Procedure
A large screw top culture tube equipped with a stir bar and charged
with Pd(PPh3)4 (115 mg, 0.10 mmol) and K3PO4 (636 mg, 3.00
mmol) was brought under argon atmosphere. 1.4-Dioxane (18 mL)
was added followed by 4a (227 mg, 1.00 mmol) and 15b (260 mg,
1.25 mmol). The septum was replaced with a screw cap and the tube
was placed in a hot oil bath (90–95 °C). The mixture was stirred and
heated overnight before H2O (10 mL) was added and the aqueous
layer was extracted with Et2O (3 × 10 mL). The combined organic
layers were dried (Na2SO4) and the solution was gravity filtered and
concentrated in vacuo. Flash chromatography (3:1 hexanes–
EtOAc) of the residue provided 16 (89 mg, 0.56 mmol, 56%) as a
clear, yellow oil.
120.7, 115.4, 115.1, 36.7, 31.8, 22.8.
Anal. Calcd for C12H15N: C, 83.19; H, 8.73; N, 8.08. Found: C,
83.22; H, 8.79; N, 7.82.
3-(Hex-1-en-2-yl)-2-methylpyridine (20)
IR (NaCl; neat): 3077, 3045, 2958, 2931, 2861, 1636, 1565, 1458,
1432, 1218, 1140, 1106, 902, 809, 742 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.40 (dd, J = 4.9, 1.5 Hz, 1 H),
7.35 (dd, J = 7.8, 1.5 Hz, 1 H), 7.08 (dd, J = 7.8, 4.9 Hz, 1 H), 5.22
(app q, J = 1.5 Hz, 1 H), 4.90 (m, 1 H), 2.52 (s, 3 H), 2.33 (t, J = 6.8
Hz, 2 H), 1.35 (m, 4 H), 0.88 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 155.4, 148.4, 147.4, 138.2, 135.9,
120.6, 114.8, 37.2, 29.9, 22.8, 22.4, 13.9.
IR (Diamond ATR; dep. CH2Cl2): 3079, 2925, 1639, 1629, 1585,
1565, 1022, 997, 950, 814, 718 cm–1.
Anal. Calcd for C12H17N: C, 82.23; H, 9.78; N, 7.99. Found: C,
82.08; H, 9.67; N, 7.81.
1H NMR (500 MHz, CDCl3): d = 8.65 (d, J = 2.4 Hz, 1 H), 8.51 (dd,
J = 4.4, 1.4 Hz, 1 H), 7.67 (dt, J = 2.4, 1.4 Hz, 1 H), 7.25 (dd,
J = 4.4, 2.4 Hz, 1 H), 5.82 (ddt, J = 17.0, 10.3, 6.5 Hz, 1 H), 5.34 (d,
J = 2.4 Hz, 1 H), 5.17 (d, J = 2.4 Hz, 1 H), 4.99 (m, 2 H), 2.59 (t,
J = 7.3 Hz, 2 H), 2.22 (td, J = 7.3, 6.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 148.6, 147.6, 144.9, 137.6, 136.6,
133.4, 123.1, 115.1, 114.3, 34.4, 32.2.
5-(Hexa-1,5-dien-2-yl)-2-methylpyridine (21)
IR (NaCl; dep. CH2Cl2): 2918, 1627, 1437, 1377, 1120, 909, 731
cm–1.
1H NMR (500 MHz, CDCl3): d = 8.54 (d, J = 2.0 Hz, 1 H), 7.56 (dd,
J = 8.5, 2.5 Hz, 1 H), 7.12 (dd, J = 8.5, 2.5 Hz, 1 H), 5.81 (ddt,
J = 17.0, 10.5, 6.5 Hz, 1 H), 5.29 (d, J = 1.1 Hz, 1 H), 5.12 (d,
J = 1.1 Hz, 1 H), 4.98 (m, 2 H), 2.57 (t, J = 1.1 Hz, 2 H), 2.56 (s, 3
H), 2.20 (dt, J = 7.5, 6.5 Hz, 2 H).
HRMS-ESI: m/z [M + H] calcd for C11H15N: 160.1126; found:
160.1121.
13C NMR (125 MHz, CDCl3): d = 157.1, 146.6, 144.8, 137.7, 133.9,
122.8, 115.1, 113.5, 34.4, 32.2, 29.7, 23.9.
3-(Hex-1-en-2-yl)pyridine (17)
IR (NaCl; neat): 3083, 3033, 2958, 2931, 2861, 1628, 1585, 1566,
HRMS-ESI: m/z [M + H] calcd for C12H16N: 174.1283; found:
174.1277.
1467, 1022, 898, 815, 719 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.65 (dd, J = 2.5, 1.0 Hz, 1 H),
8.50 (dd, J = 4.9, 1.5 Hz, 1 H), 7.67 (dt, J = 7.8, 1.5 Hz, 1 H), 7.24
(ddd, J = 7.8, 4.9, 1.0 Hz, 1 H), 5.30 (br s, 1 H), 5.15 (app q, J = 1.4
Hz, 1 H), 2.32 (t, J = 6.8 Hz, 2 H), 1.4 (m, 2 H), 1.33 (m, 2 H), 0.88
(t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 148.4, 147.6, 145.7, 136.8, 133.3,
123.1, 113.8, 34.8, 30.2, 22.3, 13.9.
5-(Hex-1-en-2-yl)-2-methylpyridine (22)
IR (NaCl; neat): 3082, 3013, 2956, 2929, 2860, 1626, 1596, 1556,
1488, 1458, 1378, 1301, 1245, 1140, 1023, 892, 835, 742 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.54 (d, J = 1.5 Hz, 1 H), 7.58 (dd,
J = 8.0, 1.5 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 5.27 (br s, J = 1.5
Hz, 1 H), 5.10 (m, 1 H), 2.55 (s, 3 H), 2.48 (t, J = 6.8 Hz, 2 H), 1.42
(m, 2 H), 1.35 (m, 2 H), 0.88 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 157.1, 146.8, 145.7, 133.8, 133.7,
122.7, 112.9, 34.8, 30.2, 24.1, 22.3, 13.9.
HRMS-ESI: m/z [M + H] calcd for C11H16N: 162.1283; found:
162.1277.
Anal. Calcd for C11H15N: C, 81.94; H, 9.38; N, 8.69. Found: C,
82.09; H, 9.07; N, 8.33.
Anal. Calcd for C12H17N: C, 82.23; H, 9.78; N, 7.99. Found: C,
81.89; H, 9.64; N, 7.65.
2-Methyl-3-(6-methylhepta-1,5-dien-2-yl)pyridine (18)
IR (Diamond ATR; dep. CDCl3): 2967, 2856, 1565, 1558, 1433,
1376, 903, 807, 740 cm–1.
[6-Methyl-3-(6-methylhepta-1,5-dien-2-yl)pyridin-2-yl]methyl
Pivaloate (23)
IR (Diamond ATR; dep. CDCl3): 2959, 2930, 2873, 1635, 1731,
1H NMR (500 MHz, CDCl3): d = 8.40 (dd, J = 4.8, 1.8 Hz, 1 H),
7.35 (dd, J = 7.5, 1.8 Hz, 1 H), 7.08 (dd, J = 7.5, 4.8 Hz, 1 H), 5.25
(d, J = 1.2 Hz, 1 H), 5.09 (br t, J = 7.5 Hz, 1 H), 4.92 (d, J = 1.2 Hz,
1 H), 2.52 (s, 3 H), 2.37 (t, J = 7.0 Hz, 2 H), 2.07 (dt, J = 7.5 Hz, 2
H), 1.67 (s, 3 H), 1.53 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 155.4, 147.9, 147.4, 137.8, 135.9,
132.1, 123.4, 120.6, 115.1, 37.3, 26.2, 25.6, 22.7, 17.7.
1464, 1238, 1151 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36 (d, J = 7.8 Hz, 1 H), 7.08 (d,
J = 7.8 Hz, 1 H), 5.24 (d, J = 1.3 Hz, 1 H), 5.12 (s, 2 H), 5.07 (app
t, J = 7.0 Hz, 1 H), 4.95 (d, J = 1.3 Hz, 1 H), 2.54 (s, 3 H), 2.37 (t,
J = 7.6 Hz, 2 H), 2.06 (app q, J = 7.6 Hz, 2 H), 1.67 (s, 3 H), 1.53
(s, 3 H), 1.22 (s, 9 H).
Synthesis 2010, No. 21, 3637–3644 © Thieme Stuttgart · New York

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Suzuki Couplings of Pyridyl Triflates
3643
13C NMR (125 MHz, CDCl3): d = 178.1, 156.6, 151.1, 146.3, 136.6,
135.6, 132.2, 123.4, 122.3, 115.8, 65.6, 38.7, 37.7, 27.2, 26.1, 25.6,
24.1, 17.7.
( )-4,4,5,5-Tetramethyl-2-[4-(2,2,5,5-tetramethyl-1,3-dioxolan-
4-yl)but-1-en-2-yl]-1,3,2-dioxaborolane (30)
To a large culture tube was added bis(pinacolato)diboron (616 mg,
2.42 mmol), PdCl2(PPh3) (49 mg, 0.070 mmol), Ph3P (37.5 mg,
0.132 mmol), and KOPh (443 mg, 3.35 mmol). An argon atmo-
sphere was established, before toluene (15 mL) and triflate ( )-29
(730 mg, 2.20 mmol) were added. The solution was heated to 60 °C
in an oil bath and stirred for 1.5 h at which time TLC analysis indi-
cated complete consumption of the starting material. The reaction
was quenched with H2O (10 mL) and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The com-
bined organic layers were washed with sat. aq NaHCO3 (10 mL).
After drying and solvent removal, the crude product was purified by
flash chromatography (9:1 hexanes–EtOAc) to give ( )-30 as a col-
orless oil (496 mg, 73%).
Anal. Calcd for C20H29NO2: C, 76.15; H, 9.27; N, 4.44. Found: C,
76.08; H, 9.57; N, 4.71.
[3-Hexa-1,5-dien-2-yl)-6-methylpyridin-2-yl]methyl Pivalate
(24)
IR (NaCl; neat): 2974, 2933, 2872, 1731, 1593, 1462, 1428, 1397,
1367, 1283, 1218, 1152, 911 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36 (d, J = 7.7 Hz, 1 H), 7.08 (d,
J = 7.7 Hz, 1 H), 5.78 (m, 1 H), 5.25 (d, J = 3.0 Hz, 1 H), 5.13 (s, 2
H), 5.01 (d, J = 3.0 Hz, 1 H), 4.99 (m, 2 H), 2.55 (s, 3 H), 2.42 (t,
J = 7.1 Hz, 2 H), 2.15 (m, 2 H), 1.22 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 178.2, 156.8, 151.2, 145.9, 137.6,
136.7, 134.8, 122.4, 117.9, 116.1, 65.7, 38.7, 37.1, 31.7, 27.3, 24.2.
IR (neat): 2979, 2934, 2866, 1617, 1370, 1310, 1216, 1143, 1002,
860 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.82 (d, J = 2.9 Hz, 1 H), 5.66 (br
m, 1 H), 3.70 (dd, J = 9.3, 3.9 Hz, 1 H), 2.39 (ddd, J = 14.6, 9.7, 4.8
Hz, 1 H), 2.20 (ddd, J = 14.6, 9.1, 6.5 Hz, 1 H), 1.67 (m, 1 H), 1.55
(m, 1 H), 1.42 (s, 3 H), 1.32 (s, 3 H), 1.27 (s, 12 H), 1.24 (s, 3 H),
1.10 (s, 3 H).
Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C,
75.37; H, 8.87; N, 4.70.
[3-(Hex-1-en-2-yl)-6-methylpyridin-2-yl]methyl Pivalate (25)
IR (NaCl; neat): 2959, 2930, 2873, 1731, 1464, 1238, 1151 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36 (d, J = 7.8 Hz, 1 H), 7.08 (d,
J = 7.8 Hz, 1 H), 5.21 (d, J = 1.4 Hz, 1 H), 5.12 (s, 2 H), 4.92 (d,
J = 1.4 Hz, 1 H), 2.55 (s, 3 H), 2.32 (t, J = 6.8 Hz, 2 H), 1.33 (m, 2
H), 1.22 (s, 9 H), 0.88 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 178.2, 156.6, 151.1, 146.7, 136.7,
135.9, 122.3, 115.5, 65.7, 38.7, 37.6, 29.8, 27.3, 24.1, 22.4, 13.9.
13C NMR (125 MHz, CDCl3): d = 141 (br), 129.5, 106.3, 83.3, 82.4,
80.0, 32.3, 28.5, 28.4, 26.8, 26.0, 24.7, 24.6, 22.8.
HRMS-ESI: m/z [M + Na] calcd for C17H31BO4 + Na: 333.2213;
found: 333.2211.
( )-{6-Methyl-3-[4-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)but-
1-en-2-yl]pyridin-2-yl}methyl Pivaloate (31)
Anal. Calcd for C18H27NO2: C, 74.70; H, 9.40; N, 4.94. Found: C,
74.57; H, 8.98; N, 5.22.
The procedure used for the preparation of 16 was followed. Pyridyl
triflate 4d (343 mg, 0.958 mmol), Pd(PPh3)4 (110 mg, 0.0958 mmol,
10 mol%), and anhyd K3PO4 (624 mg, 2.87 mmol) were reacted
with alkenyl boronate ( )-30 (357 mg, 1.15 mmol) in anhyd 1,4-di-
oxane (8 mL) at 100 °C. Workup and purification by flash chroma-
tography yielded 31 as a pale yellow oil (321 mg, 86%).
( )-4-(2,2,5,5-Tetramethyl-1,3-dioxolan-4-yl)but-1-en-2-yl
Trifluoromethanesulfonate (29)
Ketone acetonide 2818 (1.003 g, 5.0 mmol) in THF (30 mL) was
added dropwise to a cold (–78 °C) solution of LDA [prepared from
(i-Pr)2NH (0.88 mL, 0.637 g, 6.3 mmol) and n-BuLi (2.5 M in hex-
anes, 2.4 mL, 6.0 mmol) in THF (15 mL)] such that the temperature
of the reaction mixture was kept below –60 °C. After 30 min,
Comins’ triflimide (2.376 g, 6.0 mmol) dissolved in THF (10 mL)
was added quickly dropwise (the temperature of the reaction mix-
ture rose to –58 °C during the addition). The mixture was warmed
slowly overnight. At that point, TLC analysis indicated the presence
of unreacted ketone, so the mixture was recooled to –78 °C and ad-
ditional LDA (3.0 mmol) was added dropwise. After 80 min, addi-
tional Comins’ triflimide (0.894 g, 2.3 mmol) as added as a solution
in THF (5 mL). The mixture was slowly warmed to r.t. before
quenching with sat. aq NaHCO3 (20 mL) and extracting with Et2O
(3 × 20 mL). The combined Et2O layers were washed with brine (25
mL) and dried (MgSO4). Solvent removal and flash chromatogra-
phy (gradient elution 9:1 hexanes–EtOAc to 1:1 hexanes–EtOAc)
of the residue provided 29 as a colorless oil (0.567 g, 34%).
IR (neat): 2979, 2934, 2870, 1731, 1593, 1465, 1370, 1282, 1217,
1152, 1003 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38 (d, J = 7.8 Hz, 1 H), 7.09 (d,
J = 7.8 Hz, 1 H), 5.28 (br s, 1 H), 5.13 (s, 2 H), 4.99 (br s, 1 H), 3.67
(dd, J = 9.8, 2.9 Hz, 1 H), 2.61 (ddd, J = 15.6, 10.5, 4.8 Hz, 1 H),
2.55 (s, 3 H), 2.39 (ddd, J = 15.6, 10.3, 5.8 Hz, 1 H), 1.64 (dddd,
J = 14.2, 10.3, 9.8, 4.8 Hz, 1 H), 1.47 (dddd, J = 14.2, 10.5, 5.8, 2.9
Hz, 1 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.22 (s, 9 H), 1.21 (s, 3 H),
1.06 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 178.1, 156.8, 151.1, 145.8, 136.6,
135.4, 122.3, 116.0, 106.6, 82.6, 80.0, 65.6, 38.7, 35.0, 28.5, 27.3,
27.2, 26.8, 25.9, 24.1, 22.9.
Anal. Calcd for C23H35NO4: C, 70.92; H, 9.06; N, 3.60. Found: C,
70.54; H, 8.85; N, 3.87.
IR (neat): 2938, 2936, 1670, 1419, 1371, 1214, 1141, 1004, 951,
896, 857 cm–1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
1H NMR (500 MHz, CDCl3): d = 5.15 (d, J = 3.6 Hz, 1 H), 5.01 (d,
J = 3.6 Hz, 1 H), 3.69 (dd, J = 10.3, 2.9 Hz, 1 H), 2.64 (ddd,
J = 16.1, 10.0, 4.9 Hz, 1 H), 2.44 (ddd, J = 16.1, 9.3, 7.0 Hz, 1 H),
1.71 (dddd, J = 13.0, 10.3, 9.3, 4.9 Hz, 1 H), 1.65 (dddd,, J = 13.0,
10.0, 7.0, 2.9 Hz, 1 H), 1.42 (s, 3 H), 1.34 (s, 3 H), 1.26 (s, 3 H), 1.11
(s, 3 H).
Acknowledgment
This work was supported by the National Cancer Institute, National
Institutes of Health (R15 CA122084).
13C NMR (75 MHz, CDCl3): d = 156.0, 118.4 (q, J = 320 Hz, CF3),
106.9, 104.7, 81.6, 80.0, 31.5, 28.4, 26.8, 25.9, 25.8, 22.9.
References
Anal. Calcd for C12H19F3O5S: C, 43.37; H, 5.76; S, 9.65. Found: C,
43.04; H, 5.45; S, 9.26.
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