Synthesis of the CD-ring of the anticancer agent streptonigrin: studies of aryl-aryl coupling methodologies

Article abstract of DOI:10.1016/j.tet.2006.04.074

A series of functionalized 4-bromopyridines, representing the C-ring of the anticancer agent streptonigrin have been prepared and their abilities to undergo Pd-catalyzed cross-coupling with streptonigrin D-ring siloxanes were evaluated. The coupling reaction was generally tolerant to the preparation of hindered CD biaryls; however, the electronic effects of both partners play a pivotal role in the success of the coupling process. Analogs of the CD biaryl were prepared by coupling of aryl siloxane derivatives (D-ring component) with highly functionalized 4-bromopyridines (C-ring); however, the CD biaryl of the natural product could not be prepared in high yield by siloxane coupling due to the facile formation of reduced pyridine under the coupling conditions. Alternatively, the fully functionalized CD biaryl of streptonigrin was prepared using a Suzuki coupling of appropriately functionalized C-ring bromide and D-ring aryl boronic acid. The described approach is highly convergent and readily amenable to the synthesis of analogs.

Full text of DOI:10.1016/j.tet.2006.04.074

Tetrahedron 62 (2006) 6945–6954
Synthesis of the CD-ring of the anticancer agent streptonigrin:
studies of aryl–aryl coupling methodologies
*
William T. McElroy and Philip DeShong
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
Received 2 April 2006; revised 21 April 2006; accepted 24 April 2006
Available online 22 May 2006
Abstract—A series of functionalized 4-bromopyridines, representing the C-ring of the anticancer agent streptonigrin have been prepared and
their abilities to undergo Pd-catalyzed cross-coupling with streptonigrin D-ring siloxanes were evaluated. The coupling reaction was generally
tolerant to the preparation of hindered CD biaryls; however, the electronic effects of both partners play a pivotal role in the success of the
coupling process. Analogs of the CD biaryl were prepared by coupling of aryl siloxane derivatives (D-ring component) with highly function-
alized 4-bromopyridines (C-ring); however, the CD biaryl of the natural product could not be prepared in high yield by siloxane coupling due
to the facile formation of reduced pyridine under the coupling conditions. Alternatively, the fully functionalized CD biaryl of streptonigrin was
prepared using a Suzuki coupling of appropriately functionalized C-ring bromide and D-ring aryl boronic acid. The described approach is
highly convergent and readily amenable to the synthesis of analogs.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
to exhibit potent anticancer and antiviral activity.16 It has
recently been shown that naturally occurring streptonigrin
exists as a single atrope isomer (the M configuration has
been assigned), with hindered rotation about the CD-ring
juncture (Fig. 1).17
The formation of carbon–carbon bonds remains the most
crucial transformation in synthetic chemistry, and the last
25 years have witnessed the development of a multitude
of transition metal-catalyzed reactions that have greatly
improved this process.1 No other metal has been as widely
studied for this purpose as palladium, and within this field
the Stille,2 Suzuki–Miyaura,3 and Negishi4 couplings have
been the most widely explored. However, each of these
processes suffers from limitations, including tedious prepa-
ration and purification of coupling precursors, reagent toxic-
ity, or lack selectivity exhibited by the coupling partner.
Organosilicon-based coupling strategies5 address these limi-
tations and offer an alternative to existing cross-coupling
methodologies. Research from these laboratories has shown
that aryltrialkoxysilanes, in the presence of fluoride and
catalytic Pd(0), undergo aryl group transfer to a range of
aryl halides and triflates.6–11 Several methods have been de-
veloped for the synthesis of siloxane derivatives,12–14 and
the coupling reaction has been found to be of broad utility.
The desirable biological properties as well as unique struc-
tural features of streptonigrin have made this agent a popular
target,18 and three total syntheses have been reported.19–21
Our interest in the natural product was based on the suppo-
sition that the tetracyclic core of streptonigrin could be
accessed using two sequential Pd-catalyzed cross-coupling
reactions (Scheme 1). This approach offers the advantage
of being highly convergent, as the AB, C, and D-rings may
be independently prepared and functionalized prior to the
coupling steps. In fact, several groups have reported the
O
O
O
O
MeO
H2N
MeO
H2N
N
CO2H
CH3
N
CO2H
CH3
N
N
During our continued effort to explore the scope and toler-
ances of this process, we became interested in the synthesis
of the anticancer agent streptonigrin (1). This fungal
metabolite was isolated over 40 years ago15 and was found
H2N
H2N
OH
HO
OMe
OMe
MeO
OMe
Keywords: Palladium-catalyzed; Cross-coupling; Organosiloxanes;
Streptonigrin.
* Corresponding author. Tel.: +1 301 405 1892; fax: +1 301 314 9121;
e-mail: deshong@umd.edu
(M)-1
(P)-1
Figure 1. Atrope isomers of streptonigrin.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.074

6946
W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
MeO
BOCHN
N
Si(OEt)3
OMe
O
A
O
MeO
H2N
2
+
B
N
C
CO2H
MeO
O2N
N
R1
N
H2N
CH3
OH
CH3
Br
Br
O2N
N
R1
D
4
OMe
CH3
R2
OMe
+
Stretonigrin (1)
OMe
Si(OEt)3
R2
OMe
3
OMe
OMe
5
Scheme 1. Retrosynthetic analysis of streptonigrin.
syntheses of streptonigrin model systems based on this
approach.22–30 These studies have demonstrated that the
coupling reaction to form the CD biaryl tolerates the use
of sterically hindered partners. The electronic effects of
the pyridine ring, though, significantly influence the success
of this strategy, and at present the natural product has yet to
succumb to total synthesis using this approach. We have
previously communicated preliminary results regarding
siloxane-based couplings to prepare CD model systems of
streptonigrin,31 and report herein our full findings. These
studies have culminated in a highly modular synthesis of
streptonigrin CD biaryl.
The starting points for our studies were the known pyridones
632 and 7.33 Trimethyl substituted pyridine 8 was readily
obtained upon methylation of pyridone 6 (Scheme 2).
H
MeO
H3C
N
CH3
CH3
O
N
CH3
CH3
MeI, Ag2CO3
PhH
H3C
quant.
Br
Br
6
8
Scheme 2. Synthesis of bromopyridine 8.
Pyridone 7 was subjected to ester hydrolysis and acid-pro-
moted decarboxylation to give 9 (Scheme 3). Replacement
of the C-4 hydroxyl group of pyridine 9 with a bromine
substituent proved to be problematic due to competitive
bromination at C-2. After significant experimentation, it
was found that reaction of 9 with 0.70 equiv POBr3 in
DMF led reproducibly to bromopyridone 10. Although the
bromopyridone could be purified, it was more convenient
to carry the crude material through the next step. Thus,
methylation of the reaction mixture gave pyridine 11 in
37% isolated yield over two steps. Introduction of a nitrogen
substituent at C-3 was accomplished in high yield by nitra-
tion of bromide 11 to provide nitropyridine 12. Reduction
of the nitro group occurred uneventfully to provide the
amino analog 13. These fully functionalized pyridine deriv-
atives were now available for preliminary coupling reactions
with siloxane derivatives.
2. Results and discussion
Our retrosynthetic analysis for streptonigrin (1) is outlined in
Scheme 1. The tetracyclic core was to be established through
the Pd-catalyzed coupling of quinoline siloxane 2 with
2-bromopyridine 3. Conversion to the natural product would
then be accomplished upon oxidation of the A-ring to the
quinone and global deprotection. Biaryl 3 was envisaged
as the product of a Pd-catalyzed coupling of 4-bromopyri-
dine 4 and aryl siloxane 5. Successful implementation of
this strategy would require the development of coupling con-
ditions amenable to the synthesis of highly functionalized
(and hindered) biaryl derivatives.
The coupling reaction to form the CD biaryl presented a
major synthetic challenge because a pentasubstituted pyri-
dine bearing electron-donating and electron-withdrawing
substituents would be one of the components. A siloxane
coupling reaction with such a complex aromatic precursor
had not been investigated previously and these studies would
ultimately define the scope and limitations of the siloxane
methodology. We therefore decided to develop a general
approach to C-ring coupling precursors that was amenable
to the preparation of analogs, in order that the steric and
electronic factors that influence the coupling reaction be
investigated in a systematic manner.
Comparison of the cross-coupling reactions of bromopyri-
dines 8 and 11 with an aryl siloxane was expected to provide
information regarding the role of steric effects in the cou-
pling process. Similarly, the cross-coupling of pyridines
11, 12, and 13, each with a substituent in the C-3 position,
would allow us to examine the influence of electronic factors
on the coupling reaction. The results of these coupling reac-
tions are summarized in Table 1. Coupling reactions were
performed under identical conditions employing 20 mol %

W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
6947
H
N
H
O
R
CH3
CH3
MeO
N
CH3
CH3
O
N
CH3
CH3
MeI, Ag2CO3
POBr3, DMF
CHCl3
37 % for 2 steps
OH
Br
Br
7, R = CO2Et
9, R = H
2M NaOH, then HCl
99 %
10
11
MeO
N
CH3
CH3
MeO
H2N
N
CH3
CH3
HNO3, H2SO4
97 %
Fe, HCl
65 %
O2N
Br
12
Br
13
Scheme 3. Synthesis of bromopyridines 11–13.
Pd(OAc)2 and 40 mol % PPh3, conditions which had proven
to be optimal in previous coupling studies: 2 equiv of aryl
siloxane and TBAF in DMF at 80 ꢀC.
However, the reaction of 11 with o-methyl siloxane 1414
gave only a 10% yield of the desired product (entry 2); the
major product of the reaction was not the desired biaryl
but the reduced (hydrodebrominated) pyridine. This result
was surprising in two respects: first, the reduced products
had not been observed previously in siloxane-based coupling
reactions so their formation in this procedure was unanti-
cipated. Secondly, o-tolyl siloxanes such as 14 underwent
coupling with a variety of bromobenzene derivatives in
excellent yield, demonstrating that steric effects on the
siloxane component were not typically important to the suc-
cess of the coupling reaction.34 In this case, however, the
coupling of the bromopyridine does not follow the typical
profile. As it will become apparent in subsequent experi-
ments, the reduction of the bromopyridine under coupling
conditions will prove to be a significant complication in
this approach (vide infra).
Coupling of pyridine 11 was investigated first, since this is
the least sterically hindered of the bromopyridine series
and its behavior should establish the baseline for the cou-
pling reaction. Coupling of 11 and PhSi(OMe)3 gave an
excellent yield of the expected adduct (Table 1, entry 1).
Table 1. Coupling reactions of 4-bromopyridine derivatives with various
aryl siloxanes
TBAF
MeO
N
CH3
CH3
MeO
R
N
CH3
CH3
Pd(OAc)2, PPh3
Ar-Si(OR')3
+
R
DMF
Br
Ar
Entry
1
R
Ar–Si(OR0)3
Yield (%)
97
In order to further assess the steric tolerance of the coupling
reaction, the coupling of trimethylbromopyridine 8 was
examined. The Pd-catalyzed reaction of 8 and PhSi(OMe)3
gave an 89% yield of the coupled adduct, while coupling
of 8 and o-methyl siloxane 14 provided only 10% of the
desired biaryl product (entries 3 and 4, respectively).
These results are analogous to those obtained with bromo-
pyridine 11, and demonstrate that ortho-disubstituted
bromopyridines are unsuitable coupling partners.
H, 11
H, 11
Me, 8
Me, 8
PhSi(OMe)3
Si(OEt)3
CH3
2
3
4
10a
89
14
PhSi(OMe)3
Si(OEt)3
CH3
10a
The reaction of bromopyridine 8 with methylenedioxy silox-
ane 1512 gave a 61% yield of the expected biaryl (entry 5).
This was a significant finding since it demonstrated that cou-
plings with siloxane derivatives lacking ortho-substituents
occurred uneventfully. In addition, the substitution pattern
of siloxane 15 is similar to the D-ring of streptonigrin,
thus demonstrating that this approach would be useful for
the synthesis of streptonigrin analogs lacking the ortho-phe-
nolic group. It was disappointing that bromopyridine 8 failed
to undergo the coupling reaction with siloxane 16 (entry 6),
the siloxane that would directly provide the CD-ring system
of the natural product. This result was not unexpected, how-
ever, based on the coupling results using o-tolyl siloxane. In
addition, we had previously observed that aryl siloxanes
with a heteroatom in the ortho-position to silicon underwent
rapid protodesilylation under coupling conditions.13 Even
employing a stoichiometric amount of Pd(0) provided no
improvement in the coupling outcome.
14
Si(OEt)3
5
Me, 8
61
O
O
15
Si(OEt)3
OMOM
6
Me, 8
0a
OMe
OMe
16
7
NO2, 12
PhSi(OMe)3
36a
a
The remainder of the mass balance was reduced bromopyridine.

6948
W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
The couplings of 4-bromopyridine derivatives bearing nitro-
gen containing substituents at C-3 were also studied.
Analogs of bromopyridine 12 with either an amino, azido,
and amido functionality at C-3 failed to yield biaryl with
PhSi(OMe)3. However, reaction of nitropyridine 12 and
PhSi(OMe)3 gave a 36% yield of the corresponding biaryl
(entry 7), along with 36% of the reduced (dehalogenated)
pyridine. Although the yield of biaryl in this reaction was
modest, studies with more complex siloxanes such as those
needed for the total synthesis of streptonigrin were under-
taken in the hope of improving and optimizing the yield of
coupling. Unfortunately, formation of the dehalogenated
pyridine was the major product observed from these studies.
An extensive study of alternative Pd catalysts, ligands, and
activators was performed, but the yield of cross-coupled
product never rose above 30% in these reactions. The con-
clusion that must be drawn from these studies is that the
electronic effects on both components played a pivotal role
in the coupling process.
this concern, the oxidation of pyridine 11 lacking a substitu-
ent at C-3 was investigated (Scheme 5). Treatment of 11 with
H2O2 in HOAc resulted in complete conversion to the corre-
sponding N-oxide, as determined by 1H NMR. The N-oxide
was not isolated but was treated immediately with Ac2O to
give rearranged product 20 in 93% yield over two steps.
The facile oxidation-rearrangement of pyridine 11 demon-
strated that the failure of pyridine 18 to undergo oxidation
was due to the presence of the nitrogen substituent(s) at
C-3, which must alter the relative basicity of the pyridine
lone pair.
OAc
1) H2O2, HOAc
2) Ac2O
MeO
N
CH3
CH3
MeO
N
MeOH, K2CO3
68 % over 3 steps
CH3
Br
Br
11
20
OH
OMe
CH3
MeO
N
MeO
N
MeI, Ag2O
HNO3, H2SO4
51 %
The difficulty experienced in preparing the streptonigrin CD
skeleton using the siloxane technology led us to wonder
if this unit may better be synthesized using organoboron
reagents as the coupling reagent (Scheme 4). Reaction of
bromopyridine 12 with boronic acid 17 gave a 78% yield
of the respective biaryl with no evidence of the dehalogen-
ated pyridine in the reaction products.
THF
86 %
CH3
Br
Br
21
22
B(OH)2
OMOM
OMe
OMe
17
Oxidation of the pyridine C-6 methyl group of 18 to its
carboxylic acid (the functional group present at this position
in streptonigrin) was explored. The intention was to convert
18 to its N-oxide, followed by application of the pyridine
N-oxide rearrangement34 to provide a benzylic alcohol at
the C-6 position of the pyridine ring. This strategy has
been executed previously in an earlier synthesis of strepto-
nigrin.20 Much to our surprise, conversion of pyridine 18
to N-oxide 19 could not be accomplished. Using a wide
variety of oxidants, the starting pyridine was recovered.
Reduction of the nitro group of 18 and protection of the
resulting amino group as its acetamide gave pyridine deriv-
atives that were resistant to oxidation under a variety of
conditions.
OMe
N
MeO
O2N
OMe
CH3
Pd(PPh3)4, CsF
DME
MeO
O2N
N
CH3
OMOM
87 %
Br
OMe
OMe
23
24
Scheme 5. Preparation and cross-coupling of bromopyridine 24.
Based on the inability to oxidize the C-6 methyl group of
C-ring once the aromatic D-ring had been introduced, the
order of C-ring oxidation and D-ring coupling was altered.
Treatment of 20 under the previously developed nitrating
conditions gave a number of undesired reaction products,
which had their origins in cleavage of the acid labile acetate
functionality at C-6. It was clear that a robust protecting
It was unclear whether the lack of reactivity of pyridine 18
and its derivatives to oxidation was the result of the elec-
tron-withdrawing nature of the C-3 substituent. To address
B(OH)2
OMOM
OMe
OMe
17
O
N
MeO
O2N
N
CH3
MeO
O2N
CH3
Pd(PPh3)4, Na CO3
PhCH3, EtOH,2H2O
MeO
O2N
N
CH3
CH3
[O]
CH3
OMOM
CH3
OMOM
78%
Br
OMe
OMe
OMe
12
OMe
18
19
Scheme 4. Suzuki coupling of bromopyridine 12 and boronic acid 17.

W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
6949
group for the 1ꢀ alcohol of 21 would be required to effect ni-
tration under the strongly acidic conditions. After extensive
investigation, methyl ether 22 was determined to be the most
suitable protected derivative. Nitration of methyl ether 22
gave nitropyridine 23 in 51% yield. We attribute the modest
yield of the nitration (compared to pyridine 13, Scheme 4) to
be the result of deactivation of the pyridine ring due to pro-
tonation of the pyridine nitrogen. Nevertheless, with 23 in
hand, the stage was set to explore the key coupling reaction
to prepare the CD biaryl. The Pd-catalyzed reaction of
bromopyridine 23 with siloxane derivatives was ineffective
(vide supra), however, boronic acid 17 coupled with 23 using
CsF as the activator in DME35 provided an 87% yield of
biaryl 24. Unfortunately, oxidation of ether 24 to the corre-
sponding C-6 carboxylic acid could not be achieved.
Deprotection of 24 with BCl3 gave only a 13% yield of the
such that the AB-rings of streptonigrin can be introduced
via a coupling reaction. The C-2 methyl ether was converted
into a suitable coupling substrate by treatment with PBr3 to
give pyridone 28 followed by conversion of the pyridone to
triflate 29. We anticipate that coupling of triflate 29 with
appropriate metalloid reagents (siloxanes or boronic acid
derivatives) will serve as a vehicle for the introduction of
the AB-ring precursors.
3. Conclusion
A series of 4-bromopyridone derivatives have been synthe-
sized and shown to undergo Pd-catalyzed coupling with
aryl siloxane and boronic acid derivatives. A fully function-
alized streptonigrin CD biaryl was synthesized using a
Suzuki coupling of bromopyridine 26 and boronic acid 17.
The biaryl was elaborated to triflate 29, thus setting the stage
for a second coupling with a streptonigrin AB-ring precur-
sor. Studies directed toward the utilization of triflate 29 to
complete the total synthesis of streptonigrin (1) are under-
way and will be reported in due course.
1
desired product. Analysis of the crude H NMR spectrum
indicated that several other reaction products, in which one
or more of the D-ring methyl ethers had underwent cleavage,
were present in the reaction mixture.
The successful endgame strategy for synthesis of the
CD-ring system of streptonigrin is outlined in Scheme 6.
Deprotection of the methyl group of bromide 23 with BCl3
proceeded in quantitative yield to afford alcohol 25.
Subsequent oxidation with KMnO4, followed by acid-cata-
lyzed esterification, gave bromide-ester 26 in 62% yield
over two steps. The cross-coupling of bromopyridine 26
with boronic acid 17, using CsF in DME gave biaryl 27 in
68% yield. Biaryl 27 bears all of the key functionalities
found in the CD-portion of streptonigrin. In addition, the
C-2 position of the pyridine ring (C-ring) is functionalized
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Bruker DRX-
400 spectrometer. Chemical shifts are reported in parts per
million (ppm). Coupling constants (J) are given in hertz
(Hz). Spin multiplicities are indicated by standard notation.
Infrared spectra were recorded on a Nicolet 560 FTIR spec-
trophotometer. Band positions are given in reciprocal centi-
meters (cmꢁ1) and relative intensities are listed as br (broad),
s (strong), m (medium), or w (weak).
OMe
CH3
OH
1) KMnO4, H2O
MeO
O2N
N
MeO
O2N
N
BCl3, CH2Cl2
quant.
2) MeOH, H2SO4
62 %
CH3
Br
Br
Melting points were taken in Kimax soft capillary tubes
using a Thomas–Hoover Uni-Melt capillary melting point
apparatus equipped with a calibrated thermometer.
23
25
B(OH)2
OMOM
Low resolution (LRMS) and high resolution (HRMS) were
obtained on a JEOL SX-102A instrument.
OMe
OMe
17
Thin layer chromatography (TLC) was performed on
0.25 mm Analtech silica-coated glass plates, with com-
pounds being identified in one or both of the following
manners: UV (254 nm) and vanillin/sulfuric acid/ethanol
charring. Flash chromatography was performed using glass
columns and ‘medium pressure’ silica gel (Sorbent
Technologies, 45–70 mm).
MeO
O2N
N
CO2Me
Pd(PPh3)4, CsF
DME
MeO
O2N
N
CO2Me
CH3
CH3
OMOM
PBr3, DCE
90 %
68 %
Br
OMe
OMe
26
27
Tetrahydrofuran (THF), diethyl ether, toluene, and 1,4-di-
oxane were distilled from sodium/benzophenone ketyl.
N,N-Dimethylformamide (DMF) was distilled from calcium
H
O
N
CO2Me
TfO
N
CO2Me
O2N
CH3
OMOM
O2N
CH3
OMOM
Tf2O, DMAP
˚
hydride and dried over 4 A molecular sieves. Pyridine, meth-
DCM
83 %
ylene chloride, and 1,2-dichloroethane (DCE) were distilled
from calcium hydride. N,N,N,N-Tetramethylethylene-
diamine (TMEDA) and 1,2-dimethoxyethane (DME) were
distilled from sodium metal. PBr3 and B(OMe)3 were dis-
tilled prior to use. Triphenylphosphine was recrystallized
from hexanes. All other reagents were purchased and used
OMe
OMe
OMe
OMe
28
29
Scheme 6. Synthesis of streptonigrin CD biaryl.

6950
W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
as received. Glassware used in the reactions was dried over-
night in an oven at 120 ꢀC. All reactions were performed
under an atmosphere of argon unless otherwise noted. All
new compounds were determined to be >95% pure by H
NMR spectroscopy.
4.1.4. 4-Bromo-2-methoxy-5,6-dimethyl-3-nitropyridine
(12). A solution of 1.32 g (6.11 mmol) of pyridine 11,
0.60 mL (8.6 mmol) of HNO3, and 15 mL of H2SO4 was
stirred at room temperature for 14 h. The solution was di-
luted with 100 mL of water and neutralized with Na2CO3.
The solution was extracted 2ꢂ with 100 mL Et2O and the
combined organic extracts dried over MgSO4 and concen-
trated in vacuo to yield 1.55 g (97%) of 12 as a yellow solid,
mp 86–89 ꢀC, which was used without further purification.
IR (CCl4) 3025 (w), 2998 (w), 2951 (w), 2924 (w), 2905
1
4.1.1. 4-Bromo-2-methoxy-3,5,6-trimethylpyridine (8).
To a suspension of 3.45 g (0.0125 mol) of Ag2CO3 and
3.58 g (0.0177 mol) of pyridone 6 in 30 mL of benzene
was added 1.25 mL (0.0200 mol) of MeI. The resulting solu-
tion was heated in the dark at 45 ꢀC for 12 h. The mixture was
cooled to 0 ꢀC, filtered, and the filtrate washed with 50 mL
of 2% NaHCO3, followed by 50 mL water. The benzene was
evaporated under reduced pressure and the remaining
aqueous solution was extracted 3ꢂ with CH2Cl2. The com-
bined organic extracts were dried over MgSO4 and concen-
trated in vacuo to give 3.84 g (100%) of 8 as a white
crystalline solid, mp 44–45 ꢀC, which was used without fur-
ther purification. IR (CCl4) 3006 (w), 2953 (w), 2951 (m),
1
(w), 1581 (s) cmꢁ1. H NMR (CDCl3) d 2.33 (s, 3H), 2.51
(s, 3H), 3.97 (s, 3H). 13C NMR (CDCl3) d 18.5, 24.4, 55.0,
125.2, 127.5, 152.5, 156.9. FABMS m/z 263 (66), 261
(61), 155 (57), 152 (59), 119 (68), 103 (48), 85 (100).
HRMS for C8H9BrN2O3 calcd 260.9875, found 260.9872.
4.1.5. 4-Bromo-2-methoxy-5,6-dimethylpyridin-3-amine
(13). To a solution of 1.39 g (5.32 mmol) of nitropyridine
12, 28 mL of EtOH, and 7 mL of water were added 3.5 g
(63 mmol) of Fe and two drops of concd HCl. The resulting
solution was heated at reflux for 2 h. After cooling, the solu-
tion was filtered and the filtrate concentrated in vacuo.
Purification by column chromatography (9:1 hexanes/
EtOAc, Rf ¼0.40) gave 0.800 g (65%) of 13 as a yellow crys-
talline solid, mp 52–54 ꢀC. IR (CCl4) 3487 (s), 3394 (s),
3014 (w), 2983 (w), 2948 (m), 2920 (w), 2858 (w), 1654
1
2920 (w), 2893 (w), 2866 (w) cmꢁ1. H NMR (CDCl3)
d 2.19 (s, 3H), 2.22 (s, 3H), 2.37 (s, 3H), 3.83 (s, 3H). 13C
NMR (CDCl3) d 14.5, 19.1, 23.8, 53.9, 118.4, 124.0, 139.4,
151.1, 159.9. EIMS m/z 231 (100), 229 (87), 216 (29).
HRMS for C9BrH12NO2 calcd 229.0102, found 229.0104.
4.1.2. 4-Hydroxy-5,6-dimethylpyridin-2(1H)-one (9). A
solution of 61.78 g (0.2925 mol) of pyridone 7 and 111 g
of NaOH (2.78 mol) in 1.3 L of water was heated at reflux
for 2 h. The solution was cooled to 0 ꢀC, brought to pH¼7
with concd HCl, and stirred at room temperature for 12 h.
The precipitate thus obtained was filtered and washed with
water to yield 40.29 g (99%) of 9 as a white solid,
mp>320 ꢀC. IR (KBr) 3421 (w), 3266 (w), 3087 (m),
1
(m), 1612 (s) cmꢁ1. H NMR (CDCl3) d 2.29 (s, 3H), 2.41
(s, 3H), 3.98 (s, 3H), 4.05 (br s, 2H). 13C NMR (CDCl3)
d 18.2, 22.3, 53.3, 119.8, 122.7, 127.1, 140.7, 149.6. EIMS
m/z 232 (98), 230 (100), 189 (68), 187 (68). HRMS for
C8H11BrN2O calcd 232.0034, found 232.0049.
4.2. General procedure for the siloxane-based synthesis
of biaryls
3002 (m), 2928 (m), 2882 (m), 1662 (s), 1616 (s) cmꢁ1
.
1H NMR (DMSO-d6) d 1.79 (s, 3H), 2.09 (s, 3H), 5.49 (s,
1H), 10.53 (br s, 1H), 10.91 (br s, 1H). 13C NMR (DMSO-
d6) d 9.8, 16.7, 96.1, 104.2, 142.3, 163.7, 167.3. EIMS m/z
139 (100), 111 (76), 110 (80), 69 (72), 44 (84). HRMS for
C7H9NO2 calcd 139.0633, found 139.0638.
Coupling reactions were performed under identical condi-
tions using 20 mol % Pd(OAc)2 and 40 mol % PPh3, 2 equiv
of siloxane and 2 equiv of TBAF. The following example is
illustrative.
4.1.3. 4-Bromo-6-methoxy-2,3-dimethylpyridine (11).
This compound was obtained directly from pyridone 9.
A mixture of 22.06 g (0.1585 mol) of 9 and 30.54 g
(0.1068 mol) of POBr3 in 30 mL DMF were heated at
110 ꢀC for 45 min. After cooling, water was added and the
resulting solution brought to pH¼7 with Na2CO3. The pre-
cipitate thus obtained was filtered, washed with water and
then Et2O to yield 19.80 g of a yellow solid. Although the
intermediate bromopyridone could be purified, it was more
convenient to use the crude material in the next step.
4.2.1. 2-Methoxy-3,5,6-trimethyl-4-phenylpyridine
(Table 1, entry 3). To a solution of 261 mg (1.15 mmol)
of bromopyridine 8, 440 mg (2.22 mmol) of phenyltri-
methoxysilane, 52 mg (0.21 mmol) of Pd(OAc)2, and
110 mg (0.419 mmol) of PPh3 in 10 mL DMF was added
2.2 mL (2.2 mmol) of a 1 M solution of TBAF in THF.
The solution was degassed via a single freeze-pump-thaw
cycle and heated at 80 ꢀC for 12 h. The reaction was
quenched with water and the solution was extracted 3ꢂ
with Et2O. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (hexanes, Rf ¼0.14) afforded 230 mg
(89%) of the title compound as a colorless oil. IR (CCl4)
3084 (w), 3056 (w), 2967 (s), 2944 (s), 2924 (m), 2858
To a solution of the crude bromopyridone and 32.2 g
(0.117 mol) of Ag2CO3 in 110 mL CHCl3 was added
20.0 mL (0.314 mol) MeI and the mixture heated at
50 ꢀC for 24 h in the dark. After cooling, the mixture was
filtered and the filtrate concentrated in vacuo. Purification
by column chromatography (19:1 hexanes/EtOAc, Rf ¼
0.38) afforded 12.70 g (37% from 9) of 11 as a white crystal-
line solid, mp 38–41 ꢀC. IR (CCl4) 3014 (w), 2971 (w), 2944
(w), 2897 (w) cmꢁ1. 1H NMR (CDCl3) d 2.27 (s, 3H), 2.44
(s, 3H), 3.85 (s, 3H), 6.80 (s, 1H). 13C NMR (CDCl3) d 18.0,
24.1, 54.0, 111.6, 124.0, 137.3, 155.4, 161.9. EIMS m/z 216
(98), 214 (100), 187 (37), 185 (32).
1
(w) cmꢁ1. H NMR (CDCl3) d 1.82 (s, 3H), 1.83 (s, 3H),
2.42 (s, 3H), 3.94 (s, 3H), 7.05 (d, J¼6.8 Hz, 2H), 7.33 (d,
J¼6.8 Hz, 1H), 7.40 (t, J¼6.8 Hz, 2H). 13C NMR (CDCl3)
d 13.5, 16.3, 23.1, 53.6, 115.6, 121.9, 127.5, 128.8, 128.9,
140.9, 120.7, 152.0, 160.0. EIMS m/z 227 (70), 226 (100).
HRMS for C15H17NO calcd 226.1232, found 226.1228.
4.2.2. 6-Methoxy-2,3-dimethyl-4-phenylpyridine (Table
1, entry 1). Following column chromatography (19:1

W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
6951
hexanes/EtOAc, Rf ¼0.29), the biaryl was obtained in 97%
yield as a white crystalline solid, mp 52–54 ꢀC. IR (CCl4)
3087 (w), 3060 (w), 2948 (m), 2920 (m), 2850 (m) cmꢁ1
4.3. Siloxane 16 and boronic acid 17
.
Siloxane 16 and boronic acid 17 were each prepared from
2,3-dimethoxybenzaldehyde as outlined below.
1H NMR (CDCl3) d 2.06 (s, 3H), 2.46 (s, 3H), 3.90
(s, 3H), 6.45 (s, 1H), 7.25 (d, J¼8.4 Hz, 2H), 7.37 (m,
3H). 13C NMR (CDCl3) d 14.4, 22.1, 52.3, 106.6, 120.2,
126.5, 127.2, 127.6, 139.2, 151.7, 135.8, 160.3. EIMS m/z
213 (94), 212 (100), 184 (49), 183 (56), 128 (51), 127
(38). HRMS for C14H15NO calcd 213.1154, found
213.1149.
4.3.1. 2,3-Dimethoxyphenol. To a mixture of 9.3 mL
(0.066 mol) of 30% H2O2 and 9.3 g of boric acid
(0.15 mol) in 90 mL of THF was added 3 mL of sulfuric
acid. The mixture was stirred at room temperature for
30 min and a solution of 5.0 g (0.030 mol) of 2,3-dimeth-
oxybenaldehyde in 30 mL of THF was added. The mixture
was heated at 50 ꢀC for 24 h, quenched with saturated
NaHCO3, and filtered. The filtrate was extracted 3ꢂ with
Et2O and the combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (3:1 hexanes/EtOAc, Rf ¼0.29) afforded
3.22 g (70%) of the title compound as a pale yellow oil.
Spectral data matched that of the reported compound.36
4.2.3. 6-Methoxy-2,3-dimethyl-4-o-tolylpyridine (Table
1, entry 2). Following column chromatography (19:1 hex-
anes/EtOAc, Rf¼0.32), the biaryl was obtained in 10% yield
1
as a colorless oil. H NMR (CDCl3) d 1.86 (s, 3H), 2.04
(s, 3H), 2.46 (s, 3H), 3.90 (s, 3H), 6.36 (s, 1H), 7.02
(d, J¼8.0 Hz, 1H), 7.23 (m, 3H), 7.23 (m, 3H).
4.2.4. 2-Methoxy-3,5,6-trimethyl-4-o-tolylpyridine
(Table 1, entry 4). Following column chromatography
(19:1 hexanes/EtOAc, Rf ¼0.23), the biaryl was obtained
in 10% yield as a pale yellow oil. IR (CCl4) 3072 (w),
4.3.2. 1,2-Dimethoxy-3-(methoxymethyl)benzene. NaH
(60% dispersion in mineral oil, 1.2 g, 30 mmol) was washed
2ꢂ with 3 mL of hexanes. To the solid was added 20 mL of
DMF and the resulting suspension cooled to 0 ꢀC. A solution
of 3.42 g (22.2 mmol) of the phenol in 15 mL of DMF was
added and the resulting solution stirred at 0 ꢀC for 30 min.
To the solution was added 2.3 mL (30 mmol) of MOM-Cl,
causing the immediate evolution of gas. The solution was
allowed to warm to room temperature and quenched with
50 mL of water. The solution was extracted 3ꢂ with ether
and the combined organic extracts were dried over MgSO4
and concentrated in vacuo to afford 4.40 g (100%) of the title
compound as a pale yellow oil, which was used without
further purification. IR (CCl4) 2998 (m), 2955 (s), 2932
1
3002 (m), 2921 (m), 1581 (m) cmꢁ1. H NMR (CDCl3)
d 1.70 (s, 3H), 1.71 (s, 3H), 1.87 (s, 3H), 2.36 (s, 3H),
3.89 (s, 3H), 6.84 (d, J¼6.8 Hz, 1H), 7.24 (m, 3H). 13C
NMR (CDCl3) d 13.1, 15.8, 19.8, 23.0, 53.5, 115.5,
121.9, 126.4, 127.9, 128.6, 130.4, 135.6, 139.6, 150.8,
151.5, 160.1. EIMS m/z 241 (100), 240 (84), 226 (94),
216 (65).
4.2.5. 4-(Benzo[d][1,3]dioxol-5-yl)-2-methoxy-3,5,6-tri-
methylpyridine (Table 1, entry 5). Following column chro-
matography (19:1 hexanes/EtOAc, Rf ¼0.30), the biaryl was
obtained in 61% yield as a colorless oil. IR (CCl4) 3072 (w),
1
(s), 2834 (m), 1596 (s) cmꢁ1. H NMR (CDCl3) d 3.47 (s,
1
3002 (m), 2948 (s), 2920 (s), 2829 (s), 1581 (m) cmꢁ1. H
3H), 3.82 (s, 3H), 3.83 (s, 3H), 5.18 (s, 2H), 6.58 (d,
J¼8.2 Hz, 1H), 6.74 (d, J¼8.2 Hz, 1H), 6.92 (t, J¼8.2 Hz,
1H). 13C NMR (CDCl3) d 56.4, 56.6, 61.3, 95.7, 106.7,
109.9, 124.1, 139.6, 151.4, 154.1.
NMR (CDCl3) d 1.79 (s, 3H), 1.81 (s, 3H), 2.35 (s, 3H),
3.87 (s, 3H), 5.93 (s, 2H), 6.43 (d, J¼7.2 Hz, 1H), 6.44 (s,
1H), 6.79 (d, J¼7.2 Hz, 1H). 13C NMR (CDCl3) d 13.5,
16.4, 23.1, 53.6, 101.5, 108.8, 109.5, 116.0, 122.1, 122.2,
133.7, 147.0, 148.1, 150.1, 151.6, 160.0. EIMS m/z 271
(74), 270 (100). HRMS for C16H17NO3 calcd 270.1130,
found 270.1125.
4.3.3. Triethoxy(3,4-dimethoxy-2-(methoxymethoxy)-
phenyl)silane (16). A solution of 1.88 g (9.49 mmol) of
the MOM ether and 2.2 mL (1.4 mmol) of TMEDA in
40 mL of THF was cooled to ꢁ78 ꢀC. To this solution was
added dropwise BuLi (15.3 mL of a 0.80 M solution,
0.014 mol) and the resulting solution stirred at ꢁ78 ꢀC for
10 min and then allowed to warm to 0 ꢀC and stirred for
an additional 2 h. This solution was added over 30 min to
4.3 mL (1.9 mmol) of Si(OEt)4 dissolved in 40 mL of THF
at ꢁ78 ꢀC. The resulting solution was allowed to warm to
room temperature, quenched with water, and extracted 3ꢂ
with Et2O. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (15% EtOAc/hexanes, Rf ¼0.24) afforded
850 mg (25%) of 16 as a pale yellow oil. IR (CCl4) 2971
4.2.6. 2-Methoxy-5,6-dimethyl-3-nitro-4-phenylpyridine
(Table 1, entry 7). These compounds were prepared accord-
ing to the general siloxane coupling procedure outlined
previously. Following column chromatography (hexanes,
Rf ¼0.19), the biaryl was isolated in 36% yield as a white,
crystalline solid, mp 79–82 ꢀC. IR (CCl4) 3087 (w), 3064
(w), 3025 (w), 2990 (w), 2955 (w), 2920 (w), 2901 (w),
1
2874 (w) cmꢁ1. H NMR (CDCl3) d 1.95 (s, 3H), 2.50 (s,
3H), 4.00 (s, 3H), 7.16 (m, 2H), 7.40 (m, 3H). 13C NMR
(CDCl3) d 16.0, 23.8, 54.6, 123.2, 128.6, 129.1, 129.3,
133.9, 134.4, 144.3, 152.1, 157.1. EIMS m/z 250 (100),
211 (57). HRMS for C14H14N2O3 calcd 258.1004, found
258.0997.
1
(s), 2924 (s), 2889 (s), 2835 (m) cmꢁ1. H NMR (CDCl3)
d 1.22 (t, J¼7.0 Hz, 9H), 3.62 (s, 3H), 3.81 (s, 3H), 3.85
(s, 3H), 3.86 (q, J¼7.0 Hz, 6H), 5.17 (s, 2H), 6.67 (d,
J¼8.2 Hz, 1H), 7.32 (d, J¼8.2 Hz, 1H). 13C NMR
(CDCl3) d 18.6, 56.3, 57.9, 59.0, 61.1, 99.6, 108.0, 117.2,
123.6, 141.9, 155.5, 156.6. EIMS m/z 360 (87), 271 (95),
270 (100), 255 (53), 166 (56), 45 (53). HRMS for
C15H28O7Si calcd 360.1590, found 360.1604.
The reduced pyridine was obtained in 36% yield as a white
crystalline solid, mp 69–72 ꢀC, Rf ¼0.15 (hexanes). IR
(CCl4) 3025 (m), 2994 (m), 2955 (m), 2928 (m), 2866
1
(m) cmꢁ1. H NMR (CDCl3) d 2.25 (s, 3H), 2.45 (s, 3H),
4.05 (s, 3H), 8.03 (s, 1H). 13C NMR (CDCl3) d 18.2, 23.1,
54.9, 124.8, 131.5, 136.4, 154.4, 161.8.

6952
W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
4.3.4. 3,4-Dimethoxy-2-(methoxymethoxy)phenyl-
boronic acid (17). A solution of 1.08 g (5.45 mmol) of the
MOM ether and 0.90 mL (5.4 mmol) TMEDA in 30 mL
THF was cooled to ꢁ78 ꢀC. To the solution was added drop-
wise 7.0 mL (5.6 mmol) of a 0.8 M solution of n-BuLi in
hexanes and the resulting solution allowed to warm to
0 ꢀC. After 1.5 h at 0 ꢀC the solution was cooled to
ꢁ78 ꢀC and 1.2 mL (11 mmol) of B(OMe)3 in 30 mL THF
was added over 10 min. The resulting solution was allowed
over 1 h to warm to room temperature and stirred an addi-
tional 16 h. HCl (30 mL, 5%) was added and the solution
was extracted 3ꢂ with Et2O. The combined organic layers
were extracted with 2 M KOH. The aqueous layer was neu-
tralized with concd HCl and extracted 3ꢂ with CH2Cl2. The
combined organic extracts were dried over MgSO4 and
concentrated in vacuo. An analytical sample was obtained
following recrystallization from hexanes/Et2O as a white
crystalline solid, mp 125–129 ꢀC. IR (CCl4) 3526 (br),
3468 (br), 2998 (m), 2955 (m), 2928 (m), 2854 (m), 2835
4.3.7. (4-Bromo-6-methoxy-3-methylpyridin-2-yl)metha-
nol (21). This compound was obtained directly from pyri-
dine 11. A solution of 701 mg (3.24 mmol) of pyridine 11,
0.50 mL (4.4 mmol) 30% H2O2, and 22 mL acetic acid
was heated at 60 ꢀC for 3 d. After cooling, the solution
was concentrated in vacuo and the residue dissolved in
7 mL of acetic anhydride. This solution was heated at
120 ꢀC for 2 h. After cooling, the solution was concentrated
in vacuo. To the residue was added 2.28 g (16.5 mmol)
K2CO3 and 25 mL methanol. The resulting solution was
stirred at room temperature for 18 h and concentrated in
vacuo. The residue was suspended in water and extracted
3ꢂ with Et2O. The combined organic extracts were dried
over MgSO4 and concentrated in vacuo to yield 509 mg
(68%) of 21 as a white crystalline solid, mp 49–52 ꢀC, which
was used without further purification. IR (CCl4) 3456 (br),
3021 (m), 2983 (m), 2951 (m), 2928 (m), 2866 (m) cmꢁ1
.
1H NMR (CDCl3) d 2.15 (s, 3H), 3.82 (br s, 1H), 3.92
(s, 3H), 4.62 (s, 2H), 6.90 (s, 1H). 13C NMR (CDCl3)
d 15.3, 54.2, 62.3, 112.7, 122.0, 138.2, 154.4, 161.9.
1
(m) cmꢁ1. H NMR (CDCl3) d 3.49 (s, 3H), 3.79 (s, 3H),
3.87 (s, 3H), 5.25 (s, 2H), 6.29 (br s, 2H), 6.72 (d,
J¼8.4 Hz, 1H), 7.52 (d, J¼8.4 Hz, 1H). 13C NMR
(CDCl3) d 56.4, 58.6, 61.1, 100.7, 108.5, 131.8, 140.8,
156.5, 156.8.
4.3.8. 4-Bromo-6-methoxy-2-(methoxymethyl)-3-methyl-
pyridine (22). To a solution of 2.16 g (9.31 mmol) of alco-
hol 21 and 3.31 g (14.3 mmol) of Ag2O in 40 mL THF
was added 2.0 mL (32 mmol) of iodomethane. The resulting
solution was heated in the dark at 65 ꢀC for 4 d. The suspen-
sion was filtered through a pad of Celite and the filtrate
concentrated in vacuo to yield 1.97 g (86%) of 22 as a white
crystalline solid, mp 48–50 ꢀC, which was used without
further purification. IR (CCl4) 3014 (w), 2986 (w), 2951
4.3.5. 2-Methoxy-4-(3,4-dimethoxy-2-(methoxymethoxy)-
phenyl)-5,6-dimethyl-3-nitropyridine (18). A mixture of
the crude boronic acid, 645 mg (2.47 mmol) 4-bromopyri-
dine 12, 615 mg (5.32 mmol) Pd(PPh3)4, and 579 mg
(5.46 mmol) Na2CO3, 60 mL toluene, 6 mL H2O, and
6 mL EtOH was heated at reflux for 40 h. After cooling,
60 mL of water was added and the solution was extracted
3ꢂ with Et2O. The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. Purification by
column chromatography (3:1 hexanes/EtOAc, Rf¼0.25)
afforded a yellow solid, which was recrystallized from
hexanes/Et2O to yield 737 mg (78%) of 18 as a white crys-
talline solid, mp 128–129 ꢀC. IR (CCl4) 2990 (m), 2955
(m), 2928 (m), 2893 (w), 2918 (w) cmꢁ1 1H NMR
.
(CDCl3) d 2.34 (s, 3H), 3.39 (s, 3H), 3.88 (s, 3H), 4.50
(s, 2H), 6.93 (s, 1H). 13C NMR (CDCl3) d 17.0, 54.1, 58.9,
75.6, 114.0, 125.9, 138.3, 153.6, 162.0.
4.3.9. 4-Bromo-2-methoxy-6-(methoxymethyl)-5-methyl-
3-nitropyridine (23). A solution of 914 mg (3.71 mmol) of
pyridine 22 in 1.5 mL of HNO3 and 8.5 mL of H2SO4 was
stirred at room temperature for 2 d. The solution was diluted
with water, neutralized with Na2CO3, and extracted 3ꢂ with
Et2O. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (9:1 hexanes/EtOAc, Rf ¼0.11) afforded
550 mg (51%) of 23 as a white, crystalline solid, mp 47–
50 ꢀC. IR (CCl4) 3025 (m), 2990 (m), 2959 (m), 2928 (m),
(m), 2924 (m), 2874 (m), 2831 (m) cmꢁ1 1H NMR
.
(CDCl3) d 1.97 (s, 3H), 2.49 (s, 3H), 3.11 (s, 3H), 3.85 (s,
3H), 3.86 (s, 3H), 3.99 (s, 3H), 4.80 (d, J¼5.6 Hz, 1H),
5.08 (d, J¼5.6 Hz, 1H), 6.69 (d, J¼8.4 Hz, 1H), 6.76 (d,
J¼8.4 Hz, 1H). 13C NMR (CDCl3) d 15.9, 23.7, 54.5,
56.4, 57.1, 61.4, 99.4, 108.3, 121.1, 124.2, 124.9, 134.8,
141.4, 142.8, 148.5, 152.2, 155.0, 156.5. EIMS m/z 378
(100), 332 (37). HRMS for C18H22N2O7 calcd 378.1427,
found 378.1443.
1
2921 (m), 2819 (m) cmꢁ1. H NMR (CDCl3) d 2.40 (s,
3H), 3.40 (s, 3H), 4.00 (s, 3H), 4.53 (s, 2H). 13C NMR
(CDCl3) d 17.5, 55.1, 59.1, 75.1, 111.3, 127.2, 128.7,
152.9, 154.8. EIMS m/z 292 (6), 290 (8), 262 (91), 260
(100), 247 (30), 245 (28). HRMS for C9H11BrN2O4 calcd
291.9882, found 291.9893.
4.3.6. (4-Bromo-6-methoxy-3-methylpyridin-2-yl)methyl
acetate (20). This compound was prepared directly from
pyridine 11. A solution of 520 mg (2.41 mmol) pyridine
11 and 1.0 mL (7.2 mmol) of 30% H2O2 in 15 mL HOAc
were heated at 60 ꢀC for 3 d. After cooling, the solution
was concentrated in vacuo and the residue dissolved in
10 mL acetic anhydride. This solution was heated at
120 ꢀC for 24 h and concentrated in vacuo to give 628 mg
(93%) of 20 as a pale brown oil, which was used without fur-
ther purification. IR (CCl4) 3017 (m), 2983 (m), 2948 (m),
4.3.10. 2-Methoxy-4-(3,4-dimethoxy-2-(methoxymethoxy)-
phenyl)-6-(methoxymethyl)-5-methyl-3-nitropyridine
(24). Boronic acid 17 was prepared as described above. A
solution of 287 mg (1.19 mmol) of the crude boronic acid,
190 mg (0.653 mmol) of bromopyridine 23, 350 mg
(2.30 mmol) CsF, and 138 mg (0.119 mmol) Pd(PPh3)4 in
6 mL DME was heated at reflux for 20 h. After cooling, the
solution was diluted with water and extracted 3ꢂ with
Et2O. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. Purification by column
1
2924 (m), 2905 (m), 2854 (m), 1748 (s) cmꢁ1. H NMR
(CDCl3) d 2.11 (s, 3H), 2.28 (s, 3H), 3.85 (s, 3H), 5.14 (s,
2H), 6.93 (s, 1H). 13C NMR (CDCl3) d 16.9, 21.2, 54.0,
66.3, 114.4, 124.9, 138.1, 151.1, 162.2, 171.1.

W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
6953
chromatography (3:1 hexanes/EtOAc, Rf ¼0.09) yielded
233 mg (87%) of the title compound as a white crystalline
solid, mp 71–73 ꢀC. IR (CCl4) 2994 (m), 2963 (m), 2932
2948 (m), 2932 (m), 2897 (m), 2839 (m), 1740 (s) cmꢁ1. 1H
NMR (CDCl3) d 2.16 (s, 3H), 3.11 (s, 3H), 3.84 (s, 3H), 3.87
(s, 3H), 3.96 (s, 3H), 4.04 (s, 3H), 4.84 (d, J¼5.6 Hz, 1H),
5.10 (d, J¼5.6 Hz, 1H), 6.71 (d, J¼8.4 Hz, 1H), 6.76 (d,
J¼8.4 Hz, 1H). 13C NMR (CDCl3) d 15.9, 53.2, 55.2,
56.5, 57.2, 61.4, 99.5, 108.4, 119.6, 124.2, 127.7, 137.6,
142.8, 143.6, 146.7, 148.5, 152.6, 155.5, 166.7. EIMS m/z
422 (100), 300 (32), 272 (36). HRMS for C19H22N2O9 calcd
422.1325, found, 422.1332.
(m), 2893 (m), 2835 (m), 1600 (m) cmꢁ1 1H NMR
.
(CDCl3) d 2.07 (s, 3H), 3.09 (s, 3H), 3.43 (s, 3H), 3.84 (s,
3H), 3.86 (s, 3H), 4.02 (s, 3H), 4.52 (d, J¼12.0 Hz, 1H),
4.56 (d, J¼12.0 Hz, 1H), 4.80 (d, J¼5.6 Hz, 1H), 5.08 (d,
J¼5.6 Hz, 1H), 6.69 (d, J¼8.6 Hz, 1H), 6.76 (d, J¼8.6 Hz,
1H). 13C NMR (CDCl3) d 14.8, 54.7, 56.4, 57.1, 59.1, 61.4,
74.9, 99.4, 108.3, 120.5, 124.3, 126.8, 136.0, 142.5, 142.8,
148.5, 152.3, 154.3, 155.1. EIMS m/z 408 (46), 286 (100).
HRMS for C19H24N2O8 calcd 408.2498, found 408.2484.
4.3.14. Methyl 1,6-dihydro-4-(3,4-dimethoxy-2-(methoxy-
methoxy)phenyl)-3-methyl-5-nitro-6-oxopyridine-2-car-
boxylate (28). A solution of 81 mg (0.192 mmol) pyridine
27 and 0.12 mL (1.27 mmol) PBr3 in 4 mL of DCE was
heated at reflux for 12 h. After cooling, the reaction was
quenched with water and the mixture was extracted 3ꢂ
with CH2Cl2. The combined organic extracts were concen-
trated in vacuo, the residue was washed with Et2O to obtain
63 mg (90%) of 28 as a white solid, mp 225–235 ꢀC
(decomp.), which was used without further purification. IR
(CHCl3) 3515 (br), 3344 (br), 2843 (w), 1750 (w) 1685
4.3.11. (4-Bromo-6-methoxy-3-methyl-5-nitropyridin-
2-yl)methanol (25). A solution of 403 mg (1.38 mmol) of
methyl ether 23 in 20 mL CH2Cl2 was cooled to 0 ꢀC and
3.0 mL (3.0 mmol) of a 1.0 M solution of BCl3 in CH2Cl2
was added dropwise. The resulting solution was stirred
16 h at room temperature and quenched with water. The
phases were separated and the aqueous layer was extracted
2ꢂ with CH2Cl2. The combined organic extracts were dried
over MgSO4 and concentrated in vacuo to give 383 mg
(100%) of 25 as a white crystalline solid, mp 96–99 ꢀC,
which was used without further purification. IR (CCl4)
3483 (br), 3026 (m), 2991 (m), 2949 (m), 2925 (m), 2898
1
(s) cmꢁ1. H NMR (CDCl3) d 2.18 (s, 3H), 3.87 (s, 3H),
3.92 (s, 3H), 3.98 (s, 3H), 6.02 (br s, 1H), 6.51 (d,
J¼8.8 Hz, 1H), 6.72 (d, J¼8.8 Hz, 1H), 10.35 (br s). 13C
NMR (CDCl3) d 15.44, 54.1, 56.3, 61.6, 105.0, 111.6,
122.8, 123.6, 130.6, 135.9, 146.1, 146.4, 146.9, 153.7,
154.0, 161.5. FABMS m/z 365 (100). HRMS for
C16H16N2O8 calcd 365.0985, found 365.0979.
(m) cmꢁ1 1H NMR (CDCl3) d 2.26 (s, 3H), 3.83 (t,
.
J¼4.6 Hz, 1H), 4.05 (s, 3H), 4.70 (d, J¼4.6 Hz, 2H). 13C
NMR (CDCl3) d 16.0, 55.4, 62.8, 123.5, 128.9, 153.3, 155.9.
4.3.12. Methyl 4-bromo-6-methoxy-3-methyl-5-nitro-
pyridine-2-carboxylate (26). To a suspension of 397 mg
(1.43 mmol) of alcohol 25 and 64 mg (1.6 mmol) NaOH in
30 mL water was added 710 mg (4.49 mmol) KMnO4 and
the resulting mixture stirred at room temperature for 24 h.
MeOH was added and the suspension stirred 30 min and
filtered. The filtrate was acidified with 1 M HCl and concen-
trated in vacuo. The residue was dissolved in 20 mL MeOH
and 4 mL H2SO4, and the solution heated at reflux for 16 h.
The solution was diluted with water and basicified with
K2CO3. The MeOH was removed in vacuo and the remain-
ing aqueous solution was extracted 3ꢂ with EtOAc. The
combined organic extracts were dried over MgSO4 and
concentrated invacuo to give 269 mg (62%) of 26 as a yellow
crystalline solid, mp 90–93 ꢀC, which was used without
further purification. IR (CCl4) 3029 (w), 3002 (w), 2951
4.3.15. 6-(Methoxycarbonyl)-4-(3,4-dimethoxy-2-
(methoxymethoxy)phenyl)-5-methyl-3-nitropyridin-2-yl
trifluoromethanesulfonate (29). A suspension of 63 mg
(0.172 mmol) of pyridone 28 and 23 mg (0.188 mmol)
DMAP in 4 mL CH2Cl2 was cooled to 0 ꢀC and 35 mL
(0.21 mmol) Tf2O was added. The resulting solution was
allowed to warm to room temperature and stirred 12 h.
The reaction was quenched with water and the mixture
extracted 3ꢂ with CH2Cl2. The combined organic extracts
were dried over MgSO4 and concentrated in vacuo.
Recrystallization from hexanes/Et2O gave 71 mg (83%) of
29 as a white crystalline solid, mp 163–165 ꢀC. IR (CCl4)
3515 (br), 3010, (w), 2955 (w), 2936 (w), 2839 (w), 1740
1
(m) cmꢁ1. H NMR (CDCl3) d 2.32 (s, 3H), 3.89 (s, 3H),
3.93 (s, 3H), 3.98 (s, 3H), 6.01 (br s, 1H), 6.55 (d, J¼
8.4 Hz, 1H), 6.72 (d, J¼8.4 Hz, 1H). 13C NMR (CDCl3)
d 16.6, 53.7, 56.4, 61.7, 105.1, 110.9, 123.9, 136.1, 137.8,
139.5, 143.4, 146.1, 147.1, 147.5, 154.3, 164.8. EIMS m/z
496 (98), 418 (52), 317 (100). HRMS for C17H15F3N2O10S
calcd 496.0400, found 496.0385.
(m), 2924 (m), 2850 (w), 1740 (s) cmꢁ1 1H NMR
.
(CDCl3) d 2.48 (s, 3H), 3.96 (s, 3H), 4.02 (s, 3H). 13C
NMR (CDCl3) d 18.5, 53.5, 55.6, 127.6, 129.6, 147.0,
153.3, 165.7. EIMS m/z 306 (65), 304 (59), 274 (89), 272
(100), 246 (58), 244 (59). HRMS for C9H9BrN2O5 calcd
303.9695, found 303.9683.
Acknowledgements
4.3.13. Methyl 6-methoxy-4-(3,4-dimethoxy-2-(methoxy-
methoxy)phenyl)-3-methyl-5-nitropyridine-2-carboxyl-
ate (27). A solution of 682 mg (2.24 mmol) of ester 26,
1.20 g (4.96 mmol) boronic acid 17, 387 mg (0.335 mmol)
Pd(PPh3)4, and 673 mg (4.43 mmol) CsF in 35 mL DME
was heated at 75 ꢀC for 24 h. After cooling, the solution
was diluted with water and extracted 3ꢂ with CH2Cl2. The
combined organic extracts were dried over MgSO4 and con-
centrated in vacuo. Purification by column chromatography
(4:1 hexanes/EtOAc, Rf ¼0.20) gave 646 mg (68%) of 27 as
a white crystalline solid, mp 90–93 ꢀC. IR (CCl4) 3002 (m),
We wish to thank the National Cancer Institute (CA-82169)
and the University of Maryland for generous financial
support of this program.
References and notes
1. Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: New York, NY, 1998.
2. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–523.
3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.

6954
W. T. McElroy, P. DeShong / Tetrahedron 62 (2006) 6945–6954
4. Negishi, E. Palladium- or Nickel-Catalyzed Cross-Coupling
with Organometals Containing Zinc, Magnesium, Aluminum,
and Zirconium. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, NY,
1998.
21. Boger, D. L.; Panek, J. S. J. Am. Chem. Soc. 1985, 107, 5745–
5754.
´
22. Godard, A.; Rovera, J. C.; Marsais, F.; Ple, N.; Queguiner, G.
´
Tetrahedron 1992, 48, 4123–4134.
23. Godard, A.; Rocca, P.; Fourquez, J. M.; Rovera, J. C.; Marsais,
´
5. Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61–85.
6. Mowery, M. E.; DeShong, P. Org. Lett. 1999, 1, 2137–2140.
7. Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 3266–
3270.
F.; Queguiner, G. Tetrahedron Lett. 1993, 34, 7919–7922.
24. Godard, A.; Fourquez, J. M.; Tamion, R.; Marsais, F.;
´
Queguiner, G. Synlett 1994, 235–236.
25. Godard, A.; Rocca, P.; Pomel, V.; Thomas-dit-Dumont, L.;
´
Rovera, J.; Thaburet, J.; Marsais, F.; Queguiner, G.
8. Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 1684–
1688.
9. DeShong, P.; Handy, C. J.; Mowery, M. E. Pure Appl. Chem.
2000, 72, 1655–1658.
10. Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137–
1143.
11. Handy, C. J.; Manoso, A. S.; McElroy, W. T.; Seganish, W. M.;
DeShong, P. Tetrahedron 2005, 61, 12201–12225.
12. Manoso, A. S.; DeShong, P. J. Org. Chem. 2001, 66, 7449–
7455.
13. Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 6790–
6795.
14. Manoso, A. S.; Ahn, C.; Soheili, A.; Handy, C. J.; Correia, R.;
Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 8305–
8314.
15. Rao, K. V.; Cullen, W. P. Antibiot. Annu. 1959–1960, 950–953.
16. Harding, M. M.; Long, G. V. Curr. Med. Chem. 1997, 4,
405–420.
17. Tennant, S.; Rickards, R. Tetrahedron 1997, 53, 15101–15114.
18. Bringmann, G.; Reichert, Y.; Kane, V. Tetrahedron 2004, 60,
3539–3574.
J. Organomet. Chem. 1996, 517, 25–36.
26. Pomel, V.; Rovera, J.; Godard, A.; Marsais, F.; Queguiner, G.
´
J. Heterocycl. Chem. 1996, 33, 1995–2005.
27. Holzapfel, C.; Dwyer, C. Heterocycles 1998, 48, 215–219.
28. Crous, R.; Dwyer, C.; Holzapfel, C. Heterocycles 1999, 51,
721–726.
29. Kimber, M.; Anderberg, P.; Harding, M. Tetrahedron 2000, 56,
3575–3581.
30. Harding, M.; Anderberg, P. J. Inorg. Biochem. 2001, 86,
250.
31. McElroy, W. T.; DeShong, P. Org. Lett. 2003, 5, 4779–
4782.
32. Mittelbach, M.; Schmidt, H. W.; Urau, G.; Junek, H.; Lamm,
B.; Ankner, K.; Brandstrom, A.; Simonsson, R. Acta Chem.
Scand. B 1988, 42, 524–529.
33. Seeman, J. I.; Secor, H. V.; Chavdarian, C. G.; Sanders, E. B.;
Bassfield, R. L.; Whidby, J. F. J. Org. Chem. 1981, 46, 3040–
3048.
34. Handy, C. J. Doctoral Dissertation, University of Maryland,
College Park, MD, 2002.
19. Kende, A. S.; Lorah, D. P.; Boatman, R. J. J. Am. Chem. Soc.
1981, 103, 1271–1273.
35. Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095–6097.
20. Weinreb, S. M.; Basha, F. Z.; Hibino, S.; Khatri, N. A.; Kim, D.;
Pye, W. E.; Wu, T. T. J. Am. Chem. Soc. 1982, 104, 536–544.
36. Roy, A.; Reddy, K. R.; Mohanta, P. K.; Ila, H.; Junjappa, H.
Synth. Commun. 1999, 29, 3781–3791.