Palladium-catalyzed preparation of Weinreb amides from boronic acids and N-methyl-N-methoxycarbamoyl chloride

Article abstract of DOI:10.1021/jo902647h

(Chemical Equation Presented) A simple protocol for the synthesis of Weinreb benzamides and α,β-unsaturated Weinreb amides through a palladium-catalyzed cross-coupling reaction between organoboronic acids and N-methoxy-N-methylcarbamoyl chloride has been developed. The method is also applicable to the use of potassium organotrifluoroborates. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902647h

pubs.acs.org/joc
Palladium-Catalyzed Preparation of Weinreb Amides from Boronic Acids
and N-Methyl-N-methoxycarbamoyl Chloride
Ravi Krishnamoorthy, Sang Q. Lam, Christopher M. Manley, and R. Jason Herr*
Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, P.O. Box
15098, Albany, New York 12212-5098
rjason.herr@amriglobal.com
Received December 14, 2009
A simple protocol for the synthesis of Weinreb benzamides and R,β-unsaturated Weinreb amides
through a palladium-catalyzed cross-coupling reaction between organoboronic acids and N-meth-
oxy-N-methylcarbamoyl chloride has been developed. The method is also applicable to the use of
potassium organotrifluoroborates.
Introduction
lamides of both benzoic and aliphatic acids, with the most
widespread approach based on the condensation of carboxy-
lic acids with N,O-dimethylhydroxylamine.3 Among the
alternative tactics for Weinreb amide preparation include
the palladium-catalyzed aminocarboxylation of aryl bro-
mides4 and lactam/lactone-derived vinyl triflates5 with N,
O-dimethylhydroxylamine in a carbon monoxide atmo-
sphere (Scheme 1, eq 1) and the Stille-type cross-coupling
reaction between aryl and vinyl stannanes and N-methoxy-
N-methylcarbamoyl chloride (2) developed by Murakami
and co-workers (Scheme 1, eq 2).6,7 We were particularly
intrigued by this latter process and set out to examine
whether we could develop a general cross-coupling method
to prepare Weinreb amides by replacing the organotin
component with the less toxic and more widely available
boronic acid building blocks (eq 3, Scheme 1).
The use of N-methoxy-N-methylamides (Weinreb amides)
as synthetic precursors to ketones and aldehydes has become
a much-exploited strategy in organic synthesis since its
original description by Nahm and Weinreb in 1981.1,2 The
remarkable ability of these building blocks to undergo a
single substitution reaction in the presence of excess orga-
nometal reagents with minimal byproduct formation is key
to their popularity as acylating agents for laboratory synth-
eses as well as for industrial scale processes.
Over the intervening years, many synthetic methods have
been developed for the preparation of N-methoxy-N-methy-
(1) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(2) For reviews, see: (a) Balasubramaniam, S.; Aidhen, I. S. Synthesis
2008, 23, 3707. (b) Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem. 2003,
7, 967. (c) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000, 342,
340. (d) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339, 517. (e)
Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
(3) For examples, see: (a) Woo, J. C. S.; Fenster, E.; Dake, G. R. J. Org.
Chem. 2004, 69, 8984. (b) Hioki, K.; Kobayashi, H.; Ohkihara, R.; Tani, S.;
Kunishima, M. Chem. Pharm. Bull. 2004, 52, 470. (c) Kim, M.; Lee, H.; Han,
K.-J.; Kay, K.-Y. Synth. Commun. 2003, 33, 4013. (d) Colobert, F. C.;
We were encouraged by the work of Duan and Deng,8 who
showed that di-n-butylcarbamoyl chloride could be cross-
coupled with simple arylboronic acids under palladium/
copper cocatalysis, and by Kristensen and co-workers,9
who used neopentylglycol arylboronic esters to pre-
pare benzamides from carbamoyl chlorides with palladium
ꢀ
~
Des Mazery, R.; Solladie, G.; Carreno, M. C. Org. Lett. 2002, 4, 1723. (e)
De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66, 2534. (f)
ꢀ
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Bailen, M. A.; Chinchilla, R.; Dodsworth, D. J.; Najera, C. Tetrahedron Lett.
2001, 42, 5013. (g) Banwell, M.; Smith, J. Synth. Commun. 2001, 31, 2011. (h)
Tunoori, A. R.; White, J. M.; Georg, G. I. Org. Lett. 2000, 2, 4091. (i)
Gibson, C. L.; Hanada, S. Tetrahedron: Asymmetry 1996, 7, 1281. (j)
Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461. (k) Einhorn,
J.; Einhorn, C.; Luche, J.-L. Synth. Commun. 1990, 20, 1105.
(5) (a) Deagostino, A.; Larini, P.; Occhiato, E. G.; Pizzuto, L.; Prandi, C.;
Venturello, P. J. Org. Chem. 2008, 73, 1941. (b) Aungst, R. A.; Funk, R. L.
J. Am. Chem. Soc. 2001, 123, 9455.
(6) Murakami, M.; Hoshino, Y.; Ito, H.; Ito, Y. Chem. Lett. 1998, 2, 163.
(7) For preparations of Weinreb amides reacting N-methoxy-N-methyl-
carbamoyl chloride with organolithium or organomagnesium reagents, see:
(a) Lee, J. I. Bull. Korean Chem. Soc. 2007, 28, 695. (b) Lee, J. I.; Jung, H.
J. Korean Chem. Soc. 2005, 49, 609. (c) Lee, J. I.; Park, H. Bull. Korean Chem.
Soc. 2002, 23, 521. (d) Tius, M. A.; Busch-Petersen, J.; Yamashita, M.
Tetrahedron Lett. 1998, 39, 4219.
(4) (a) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder, T.
E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102. (b) Martinelli, J. R.;
Freckmann, D. M. M.; Buchwald, S. L. Org. Lett. 2006, 8, 4843. (c) Zhuang,
L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.; Egbertson, M. S.; Payne, L. S.;
Guare, J. P. Jr.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.;
Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.;
Leonard, Y. M.; Lynch, J. J. Jr.; Michelson, S. R.; Young, S. D. J. Med.
Chem. 2003, 46, 453.
(8) Duan, Y.-Z.; Deng, M.-Z. Synlett 2005, 2, 355.
ꢀ
(9) Lysen, M.; Kelleher, S.; Begtrup, M.; Kristensen, J. L. J. Org. Chem.
2005, 70, 5342.
DOI: 10.1021/jo902647h
r
Published on Web 01/20/2010
J. Org. Chem. 2010, 75, 1251–1258 1251
2010 American Chemical Society

Krishnamoorthy et al.
JOCArticle
SCHEME 1. Palladium-Catalyzed Preparation of Alkenyl and Aryl Weinreb Amides
TABLE 1. Conditions To Optimize Cross-Coupling of 4-Methoxyphenylboronic Acid (1a) with N-Methyl-N-methoxycarbamoyl Chloride (2)
entry
reaction conditionsa
equiv of 2
equiv of K3PO4 H2O
3
yield of 3a (%)
yield of 4 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
toluene, 100 °C, 2 h
toluene, 80 °C, 2 h
toluene, 80 °C, 2 h
toluene, 80 °C, 4 h
toluene, 80 °C, 2 h
toluene, 60 °C, 1 h
toluene, 60 °C, 1 h
toluene, 40 °C, 2 h
THF, 65 °C, 2 h
2.0
2.0
1.5
1.5
2.0
2.0
3.0
2.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
2.0
2.0
2.0
2.0
2.5
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
39
54
47
39
53
57
62
32
62
27
43
21
7
7
7
18
20
6
7
14
13
11
5
12
3
10
8
19
4
THF, 65 °C, 5 h
THF, 40 °C, 8 h
dioxane, 80 °C, 9 h
dioxane, 65 °C, 4 h
dioxane, 40 °C, 6 h
ethanol, 80 °C, 1 h
ethanol, 65 °C, 2 h
ethanol, 65 °C, 2 h
ethanol, 40 °C, 4 h
9
38
89
92
72
3
12
aReactions were run on 1 mmol scale and utilized 5 mol % of PdCl2(Ph3P)2 in 5 mL of anhydrous solvent. The reaction times are shown. Isolated yields
are based on arylboronic acid 1a.
catalysis. Herein we report a simple, efficient procedure for
the preparation of Weinreb amides through the palladium-
catalyzed cross-coupling of commercially available N-meth-
oxy-N-methylcarbamoyl chloride (2) with both (hetero)aryl
and alkenyl organoboronic acids.
of bis(triphenylphosphine)dichloropalladium(II) as catalyst,
which ultimately worked very well for the method. Early in
the investigation we found that the zerovalent catalyst
tetrakis(triphenylphosphine)palladium(0) did not work as
well, and in fact led to minor amounts of a byproduct in
which the N-methoxy functionality of 3a was removed,
similar to an observation made by Larhed and co-workers
in a palladium(0)-catalyzed aminocarboxylation reaction.11a
We also made a brief investigation into any effect played by
copper as an additive,8 but largely without success. Again, small
amounts of a byproduct in which the formed Weinreb amide 3a
underwent heterolytic cleavage of the nitrogen-oxygen bond
Results and Discussion
We began our investigation by screening various reaction
conditions for the cross-coupling of N-methoxy-N-methyl-
carbamoyl chloride (2)10 with 4-methoxyphenylboronic acid
(1a) as shown in Table 1. On the basis of the literature
precedents for similar systems,9 we decided to use 5 mol %
(11) For instances involving heterolytic cleavage of N-alkoxyamide
nitrogen-oxygen bonds of Weinreb amides under some cross-coupling
(10) For other examples of metal-catalyzed cross-coupling reactions
utilizing N-methoxy-N-methylcarbamoyl chloride, see ref 5 and: (a) Sato,
Y.; Tamura, T.; Kinbara, A.; Miwako, M. Adv. Synth. Catal. 2007, 349, 647.
(b) Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004, 43, 2436.
€
conditions, see: (a) Odell, L. R.; Savmarker, J.; Larhed, M. Tetrahedron
Lett. 2008, 49, 6115. (b) Zhang, Z.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2008,
10, 3005.
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was observed, similar to an observation by Zhang and Liebes-
kind in which copper salts were shown to lead to heterolytic
cleavage of N-alkoxyamides under some cross-coupling con-
ditions.11b
Of the inorganic bases surveyed (in toluene at 80 °C, not
shown), potassium phosphate monohydrate was found to be
the most successful, leading to the best reproducible yields of
Weinreb benzamide 3a and with minimal hydrolysis of the
carbamoyl chloride reagent 2. Interestingly, the use of anhy-
drous potassium phosphate failed to provide sufficient
amounts of the benzamide, analogous to reports that hydra-
ted potassium phosphate is preferable as a base in some types
of palladium-catalyzed reactions.12
Examination of solvent and temperature parameters on
the cross-coupling reaction is summarized in Table 1. In each
case, small amounts of the aryl homocoupling byproduct 4
were observed. Reactions at higher temperatures resulted in
significant decreases in isolated yields, presumably in part
due to greater thermal instability of carbamoyl chloride 2 in
the basic media. Interestingly, increasing the amount of 2 to
3 equiv did not significantly increase the yield of 3a (entries
6 vs. 7, 9 vs. 10 and 16 vs. 17), so 2 equiv was chosen for use as
a general method.
We applied the best conditions to other arylboronic acid
and heteroarylboronic acid substrates 1 and found that the
protocol worked quite well as a general method to effect
the preparation of N-methyl-N-methoxybenzamides and
heterocyclic congeners 3 (Table 2).
The optimized conditions of ethanol at 65 °C transformed
both electron-rich arylboronic acids 1a,b (entries 1 and 2) as
well as electron-poor substrates 1d-g (entries 4-7) and
conjugated aromatics 1h,i (entries 8 and 9) to the correspond-
ing Weinreb benzamides 3a-i equally well. Heterocyclic
substrates also provided heteroaryl Weinreb amides in
good yields and included a benzofuran 3j (entry 10),
(benzo)thiophenes 3k and 3l (entries 11 and 12), indoles 3m
and 3n (entries 13 and 14), pyridazine 3o (entry 15), and
quinoline 3p (entry 16). In several of these cases, the best
conditions for three different solvents were examined head-
to-head with the same substrate, in every case showcasing
superior yields with anhydrous ethanol. It should be noted
that none of the bis-amide byproduct arising from addition
of N-methoxy-N-methylamine (formed by decomposition of
2 in situ) to the carboxyethyl moiety of product 3f was
observed. It should be noted that none of the byproduct
arising from the N-acylation of the indole product 3n
by excess N-methoxy-N-methylcarbamoyl chloride was ob-
served. The exceptions to the generality of this transforma-
tion were seen in the use of 2-methoxyphenylboronic acid
(1c, entry 3) and pyridine-3-boronic acid (1q, entry 17). In the
former case, the use of 1c failed to provide useful amounts of
the corresponding amide 3c, although in any set of condi-
tions tried the starting materials were completely consumed.
Presumably the greater energy required to overcome the
steric bulkiness at the reactive site (longer reaction times
and higher temperatures examined, not shown) results in the
destruction of the reagents before the cross-coupling can
take place. Preliminary attempts to modify the procedure for
1c, such as employed by Buchwald and co-workers to over-
come the reduced reactivity of ortho-substituted substrates
in their palladium-catalyzed aminocarbonylation method
(Scheme 1),4a,b showed some initial promise, and will be
reported to address this substrate limitation in due course.
With the use of pyridine-3-boronic acid (1q), none of the
conditions examined provided any reasonable amounts of
the corresponding product 3q, even at prolonged reaction
times, which is consistent with observations from the litera-
ture that pyridine-derived 3-boronic acids usually do not
readily participate in many cross-coupling reactions.13
Nevertheless, given the overall generality of our cross-
coupling procedure for 2 with arylboronic acids, we were
pleased to find a method for preparing Weinreb benzamides
equivalent in yields with the palladium-catalyzed amino-
carboxylation of aryl bromide substrates reported by the
Buchwald group (for example, compare to literature yields of
89% for 3a, 87% for 3c, 87% for 3g, 94% for 3h, and 91% for
3k).4 In our case we cite several more examples of heteroaryl-
derived Weinreb benzamide products in addition to the
development of reaction conditions that avoid the use of
carbon monoxide as a reagent.
We next turned our attention to the preparation of
R,β-unsaturated N-methoxy-N-methylamides 6 from the
corresponding olefinic boronic acids 5 (Table 3).
As before, we examined several solvents and reaction
temperatures in order to optimize the transformation from
(E)-styrylboronic acid (5a) to the corresponding cinnamyl
Weinreb amide 6a (best results shown in Table 3). While we
were ultimately successful in establishing that our protocol in
anhydrous ethanol did indeed reproducibly provide a gen-
eral route to preparing the requisite vinylic Weinreb amides
6, the isolated yields ranged from only very modest to
satisfactory. Even so, we were pleased to provide the first
examples of R,β-unsaturated Weinreb amides generated
from linear and branched vinylboronic acids, differing
from the palladium-catalyzed methods5 in which only vinyl
triflates derived from (thio)lactones or lactams were found
to undergo aminocarboxylation to provide Weinreb amides
of cyclic olefins.14 It should also be noted that no byproducts
arising from a Michael-type 1,4 addition of N-methoxy-
N-methylamine (formed by decomposition of 2 in situ)
to the R,β-unsaturated amide moiety of products 6 were
observed.
We subsequently focused our attention to the application
of the method to cross-coupling using potassium organotri-
fluoroborates 7 and 8 as coupling partners for Weinreb
amide formation, given the rising interest in these air-stable
and increasingly available reagents in metal-catalyzed cross-
coupling reactions (Table 4).15
When developing the methods for this cross-coupling,
however, we found that the use sodium carbonate as a base
(13) Fu, X.-L.; Wu, L.-L.; Fu, H.-Y.; Chen, H.; Li, R.-X. Eur. J. Org.
Chem. 2009, 2051 and references cited therein.
(14) A report recently appeared describing the palladium(II)-catalyzed
addition of two arylboronic acids to alkynyl Weinreb amides to provide
trisubstituted R,β-unsaturated Weinreb amide products: Bush, A. G.; Jiang,
J. L.; Payne, P. R.; Ogilvie, W. W. Tetrahedron 2009, 65, 8502.
(15) For articles and reviews citing work with potassium organotrifluor-
oborates, see: (a) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org.
Chem. 2009, 74, 973. (b) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
(c) Stefani, H. A.; Cella, R.; Adriano, S. Tetrahedron 2007, 63, 3623. (d)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(12) (a) Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271. (b) Urawa,
Y.; Naka, H.; Miyazawa, M.; Souda, S.; Ogura, K. J. Organomet. Chem.
2002, 653, 269.
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TABLE 2. Cross-Coupling of Aryl- and Heteroarylboronic Acids 1 with 2
aIsolated yields based on (hetero)arylboronic acids 1. Unless noted otherwise, reactions were run on 1 mmol scale and utilized 5 mol % of
PdCl2(Ph3P)2, 2.0 equiv of carbamoyl chloride 2, and 2.0 equiv of K3PO4 H2O in 5 mL of solvent. Conditions A: toluene, 60 °C. Conditions B: THF,
3
65 °C. Conditions C: EtOH, 65 °C. The reaction times are shown. bThis reaction substituted 2.0 equiv of CsF in place of K3PO4 H2O.
3
in place of potassium phosphate was more reliable. Thus,
subjection of electron-rich potassium aryltrifluoroborate 7a
to the optimized reaction conditions with carbamoyl chlor-
ide 2 provided the corresponding 4-methoxybenzamide 3a in
good yields that were also very comparable to the method
using the corresponding boronic acid 1a (compare Table 4,
entry 1 with Table 2, entry 1). Likewise, the less-activated
substrate 7b provided a good isolated yield of the corres-
ponding Weinreb benzamide 3d when run in anhydrous
ethanol, and again comparable to the method using boronic
acid 1d (compare entry 2 with Table 2, entry 4). Thiophene-
derived 2-potassium trifluoroboronate substrate 7c under-
went cross-coupling to provide 3r in good yield (entry 3), as
did the use of thiophene-derived 3-potassium trifluorobor-
onate substrate 7d to provide 3k, comparable to the method
using the analogous heteroaryl boronic acid 1j (compare
entry 4 with Table 2, entry 11). Furthermore, two potassium
alkenyltrifluoroborates 8a,b underwent cross-coupling with
2 under these conditions to provide useful amounts of the
corresponding R,β-unsaturated Weinreb amides 6a and 6e.
In the former example, this yield is on par with the method
using the corresponding alkenylboronic acid 5a (compare
entry 5 with Table 3, entry 1).
In summary, we have demonstrated a mild palladium-
catalyzed cross-coupling reaction of (hetero)arylboronic
acids 1 and alkenylboronic acids 5 with commercially
available N-methoxy-N-methylcarbamoyl chloride (2) to
afford Weinreb (hetero)benzamides 3 and R,β-unsaturated
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TABLE 3. Coupling of Alkenyl Boronic Acids 5 with Carbamoyl Chloride 2
aIsolated yields based on vinylboronic acids 5. See Table 2 footnote for reaction details. bReaction run at 60 °C.
TABLE 4. Coupling of Potassium Organotrifluoroborates 7 and 8 with Carbamoyl Chloride 2
aIsolated yields based on potassium (hetero)aryltrifluoroborates 7 or potassium vinyltrifluoroborates 8. Unless noted otherwise, reactions were run
on 1 mmol scale and utilized 5 mol % of PdCl2(Ph3P)2, 2.0 equiv of carbamoyl chloride 2, and 5.0 equiv of Na2CO3 in 5 mL of solvent. Conditions A:
toluene, 60 °C. Conditions B: THF, 65 °C. Conditions C: EtOH, 65 °C. The reaction times are shown.
Weinreb amides 6, respectively, in good to excellent isolated
yields. The use of potassium phosphate monohydrate as a
base is key to the process as is the use of anhydrous ethanol as
a solvent. The method was also extended to the preparation
of Weinreb amides 3 and 6 by the analogous cross-coupling
reaction of N-methoxy-N-methylcarbamoyl chloride with
potassium (hetero)aryltrifluoroborates 7 and potassium al-
kenyltrifluoroborates 8 in comparable isolated yields. While
in each case presented in this study a commercially available
reagent was utilized to define the method, this protocol
should be an improvement upon existing methods for the
preparation of Weinreb amides in cases where other pre-
cursors are not commercially available or difficult to pre-
pare, including nontraditional preparations with metal-
catalyzed cross-coupling conditions in which the use of
carbon monoxide is to be avoided.
Experimental Section
General Experimental. All nonaqueous reactions were per-
formed under an atmosphere of dry nitrogen unless otherwise
specified. Commercial grade reagents and anhydrous solvents were
used as received from vendors and no attempts were made to purify
or dry these components further. Removalof solvents under reduced
pressure was accomplished with a rotary evaporator using a Teflon-
lined KNF vacuum pump. Flash column chromatography was
performed by using an automated medium-pressure chromatogra-
phy system using normal-phase disposable prepacked silica gel colu-
mns. Melting points are uncorrected. Data for proton NMR spectra
were obtained at 300 or 500 MHz and are reported in ppm δ values,
using tetramethylsilane as an internal reference. Low-resolution
mass spectroscopic analyses were performed on a single quadrupole
mass spectrometer utilizing electrospray ionization (ESI). High-
resolution mass spectroscopic analyses were performed on a time-
of-flight mass spectrometer utilizing electrospray ionization (ESI).
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Representative Procedure A: Preparation of N,4-Dimethoxy-
N-methylbenzamide (3a, Table 2) from 4-Methoxyphenylboronic
Acid.4a,16 A suspension of commercially available 4-methoxy-
phenylboronic acid (1a, 200 mg, 1.3 mmol, 1.0 equiv), commer-
cially available N-methoxy-N-methylcarbamoyl chloride (2,
325 mg, 2.6 mmol, 2.0 equiv), dichlorobis(triphenylphosphine)-
palladium(II) (46 mg, 5 mol %), and potassium phosphate
monohydrate (606 mg, 2.6 mmol, 2.0 equiv) in anhydrous
ethanol (5.0 mL) was heated at 65 °C under nitrogen for 2 h.
The cooled mixture was filtered through a pad of silica gel,
eluting with ethyl acetate, and the solvents were removed under
reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with ethyl acetate/hexanes
(gradient of 2:8 to 6:4), to provide N,4-dimethoxy-N-methyl-
benzamide (3a) as a yellow oil (229 mg, 89%): TLC Rf 0.50 (1:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.72 (dd,
J = 6.6, 1.8 Hz, 2H), 6.88 (dd, J = 6.6, 1.8 Hz, 2H), 3.85 (s, 3H),
3.56 (s, 3H), 3.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.7,
161.8, 130.8, 126.3, 113.5, 61.2, 55.6, 34.2; MS (ESI) m/z 196.1
[M þ H]þ.
d. Ethyl 3-(methoxy(methyl)carbamoyl)benzoate (3f, Table 2).
Using representative procedure A with commercially available
3-(ethoxycarbonyl)phenylboronic acid (1f), the product was
obtained as a colorless oil (213 mg, 87%): TLC Rf 0.40 (1:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.36 (s,
1H), 8.15 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.50 (t,
J = 7.8, 7.5 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.56 (s, 3H), 3.38
(s, 3H), 1.40 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
169.4, 166.2, 134.7, 132.7, 131.8, 130.8, 129.6, 128.5, 61.5, 61.4,
33.8, 14.6; HRMS (ESI) m/z 238.1076 [M þ H]þ (238.1079 calcd
for C12H15NO4 þ H).
e. N-Methoxy-N-methyl-3-nitrobenzamide (3g, Table 2).4a,18
Using representative procedure A with commercially available
3-nitrophenylboronic acid (1g), the product was obtained as a
yellow solid (223 mg, 89%): mp 39-41 °C; TLC Rf 0.45 (1:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.57 (s,
1H), 8.33-8.30 (m, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.61 (dd, J =
8.1, 7.8 Hz, 1H), 3.56 (s, 3H), 3.40 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.5, 148.1, 135.8, 134.7, 129.5, 125.6, 123.9, 61.7,
33.6; MS (ESI) m/z 211.0 [M þ H]þ.
f. N-Methoxy-N-methylbiphenyl-4-carboxamide (3h, Table 2).4b
Using representative procedure A with commercially available
biphenyl-4-ylboronic acid (1h), the product was obtained as a off-
white solid (230 mg, 95%): mp 78-80 °C; TLC Rf 0.60 (1:1
a. N,3-Dimethoxy-N-methylbenzamide (3b, Table 2).16b Using
representative procedure A with commercially available 3-methox-
yphenylboronic acid (1b), the product was obtained as a yellow oil
(235 mg, 91%): TLC Rf 0.50 (1:1 hexanes/ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 7.31-7.20 (m 3H), 7.01-6.97 (m, 1H), 3.83
(s, 3H), 3.58 (s, 3H), 3.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.1, 159.5, 135.8, 129.4, 120.7, 116.9, 113.7, 61.4, 55.7, 34.2; MS
(ESI) m/z 196.1 [M þ H]þ.
1
hexanes/ethyl acetate); H NMR (300 MHz, CDCl3) δ 7.79 (d,
J = 8.4 Hz, 2H), 7.65-7.61 (m, 4H), 7.48-7.35 (m, 3H), 3.59 (s,
3H), 3.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0, 143.7,
140.6, 133.1, 129.2, 129.1, 128.2, 127.5, 127.0, 61.4, 34.1; MS (ESI)
m/z 242.1 [M þ H]þ.
b. 4-Chloro-N-methoxy-N-methylbenzamide (3d, Table 2).4a,b,16c,17a,18
. Using representative procedure A with commercially available
4-chlorophenylboronic acid (1d), the product was obtained as a
yellow oil (222 mg, 87%): TLC Rf 0.45 (1:1 hexanes/ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 7.65 (dd, J = 6.3, 1.5
Hz, 2H), 7.37 (dd, J = 6.6, 1.8 Hz, 2H), 3.54 (s, 3H), 3.36 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 169.0, 137.1, 132.6, 130.2, 130.1,
128.6, 61.4, 33.9; MS (ESI) m/z 199.8 [M]þ.
g. N-Methoxy-N-methyl-2-naphthamide (3i, Table 2).20 Using
representative procedure
A with commercially available
naphthalen-2-ylboronic acid (1i), the product was obtained as
a yellow oil (225 mg, 90%): TLC Rf 0.55 (1:1 hexanes/ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 7.92-7.85
(m, 3H), 7.76 (dd, J = 8.7, 1.5 Hz, 1H), 7.58-7.49 (m, 2H), 3.56
(s, 3H), 3.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.2, 134.6,
132.8, 131.8, 129.2, 129.0, 128.0, 127.9, 127.7, 126.8, 125.4, 61.4,
34.2; MS (ESI) m/z 216.1 [M þ H]þ.
c. 3-Chloro-N-methoxy-N-methylbenzamide (3e, Table 2).19
Using representative procedure A with commercially available
3-chlorophenylboronic acid (1e), the product was obtained as a
yellow oil (228 mg, 89%): TLC Rf 0.50 (1:1 hexanes/ethyl
h. N-Methoxy-N-methylbenzofuran-2-carboxamide (3j, Table 2).
Using representative procedure A with commercially available
benzofuran-2-ylboronic acid (1j), the product was obtained as a
colorless oil (207 mg, 82%): TLC Rf 0.55 (1:1 hexanes/ethyl
1
acetate); H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.57 (d,
J = 7.5 Hz, 1H), 7.44 (dd, J = 8.1, 0.9 Hz, 1H), 7.36-7.31 (m,
1H), 3.54 (s, 3H), 3.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
168.7, 136.1, 134.3, 131.0, 129.7, 128.7, 126.7, 61.5, 33.9; MS
(ESI) m/z 199.8 [M]þ.
1
acetate); H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz,
1H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.42 (dt, J =7.5, 1.0 Hz,
1H), 7.29 (t, J = 7.5 Hz, 1H), 3.83 (s, 3H), 3.42 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 160.0, 155.2, 146.9, 127.7, 127.4, 123.8, 123.0,
113.5, 112.5, 61.9, 33.7; HRMS (ESI) m/z 206.0818 [M þ H]þ
(206.0817 calcd for C11H11NO3 þ H).
(16) (a) Lucas, S.; Heim, R.; Negri, M.; Antes, I.; Ries, C.; Schewe, K. E.;
Bisi, A.; Gobbi, S.; Hartmann, R. W. J. Med. Chem. 2008, 51, 6138.
(b) Bourne, C.; Roy, S.; Wiley, J. L.; Martin, B. R.; Thomas, B. F.;
Mahadevan, A.; Razdan, R. K. Bioorg. Med. Chem. 2007, 15, 7850.
(c) Lee, J. I. Bull. Korean Chem. Soc. 2007, 28, 695. (d) Sofikiti, N.; Tofi,
M.; Montagnon, T.; Vassilikogiannakis, G.; Stratakis, M. Org. Lett. 2005, 7,
2357.
(17) (a) Murphy, J. A.; Commeureuc, A. G. J.; Snaddon, T. N.; McGuire,
T. M.; Khan, T. A.; Hisler, K.; Dewis, M. L.; Carling, R. Org. Lett. 2005, 7,
1427. (b) Kokotos, C. G.; Baskakis, C.; Kokotos, G. J. Org. Chem. 2008, 73,
8623. (c) Pippel, D. J.; Mapes, C. M.; Mani, N. S. J. Org. Chem. 2007, 72,
5828. (d) Bariau, A.; Canet, J.-L.; Chalard, P.; Troin, Y. Tetrahedron:
Asymmetry 2005, 16, 3650.
i. N-Methoxy-N-methylthiophene-3-carboxamide (3k, Table 2).4a,b
Using representative procedure A with commercially available thio-
phene-3-boronic acid (1k), the product was obtained as a yellow oil
(230 mg, 86%): TLC Rf 0.50 (1:1 hexanes/ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 8.07 (dd, J = 3.0, 0.9 Hz, 1H), 7.58 (dd, J =
5.1, 1.8 Hz, 1H), 7.30 (dd, J = 5.1, 3.0 Hz 1H), 3.66 (s, 3H), 3.37 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 134.8, 131.2, 129.4, 125.1,
61.5, 33.6; MS (ESI) m/z 171.9 [M þ H]þ.
j. N-Methoxy-N-methylbenzo[b]thiophene-3-carboxamide (3l,
Table 2). Using representative procedure A with commercially
available benzo[b]thiophen-3-ylboronic acid (1l), the product
was obtained as a yellow oil (144 mg, 65%): TLC Rf 0.55 (1:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.24 (d,
J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H),
7.44-7.37 (m, 2H), 3.60 (s, 3H), 3.42 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 164.9, 139.6, 138.2, 131.0, 129.0, 125.3, 125.2,
(18) Mani, N. S.; Jablonowski, J. A.; Jones, T. K. J. Org. Chem. 2004, 69,
8115.
(19) (a) Liverton, N. J.; Butcher, J. W.; Claiborne, C. F.; Claremon, D. A.;
Libby, B. E.; Nguyen, K. T.; Pitzenberger, S. M.; Selnick, H. G.; Smith,
G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agarwal, L.; Dancheck, K.;
Forsyth, A. J.; Fletcher, D. S.; Frantz, B.; Hanlon, W. A.; Harper, C. F.;
Hofsess, S. J.; Kostura, M.; Lin, J.; Luell, S.; O’Neill, E. A.; Orevillo, C. J.;
Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Visco, D. M.; O’Keefe, S. J.
J. Med. Chem. 1999, 42, 2180. (b) Gallagher, T. F.; Seibel, G. L.; Kassis, S.;
Laydon, J. T.; Blumenthal, M. J.; Lee, J. C.; Lee, D.; Boehm, J. C.;
Fier-Thompson, S. M.; Abt, J. W.; Soreson, M. E.; Smietana, J. M.; Hall,
R. F.; Garigipati, R. S.; Bender, P. E.; Erhard, K. F.; Krog, A. J.; Hofmann,
G. A.; Sheldrake, P. L.; McDonnell, P. C.; Kumar, S.; Young, P. R.; Adams,
J. L. Bioorg. Med. Chem. 1997, 5, 49.
(20) (a) Matsuo, J.-I.; Aizawa, Y. Chem. Commun. 2005, 18, 2399. (b) Fry,
A. J.; Rho, A. K.; Sherman, L. R.; Sherwin, C. S. J. Org. Chem. 1991, 56,
3283.
1256 J. Org. Chem. Vol. 75, No. 4, 2010

Krishnamoorthy et al.
JOCArticle
124.7, 122.6, 61.7, 33.9; HRMS (ESI) m/z 222.0595 [M þ H]þ
(222.0589 calcd for C11H11NO2S þ H).
available (()-4-methylcyclohex-1-enylboronic acid (5c), the pro-
duct was obtained as a colorless oil (76 mg, 58%): TLC Rf 0.55 (1:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 6.14-6.13
(m, 1H), 3.65 (s, 3H), 3.23 (s, 3H), 2.32-2.17 (m, 3H), 1.79-1.59
(m, 3H), 1.33-1.20 (m, 1H), 0.99 (d, J = 6.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 172.3, 133.8, 130.9, 61.3, 34.1, 33.9, 30.7, 28.0,
25.9, 21.9; HRMS (ESI) m/z 184.1341 [M þ H]þ (184.1338 calcd
for C10H17NO2 þ H).
k. N-Methoxy-N-methyl-1-tosyl-1H-indole-3-carboxamide (3m,
Table 2). Using representative procedure A with commercially
available 1-tosyl-1H-indol-3-ylboronic acid (1m), the product
was obtained as a yellow oil (58 mg, 72%): TLC Rf 0.50 (1:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.28 (s,
1H), 8.27 (dd, J = 7.2, 1.8 Hz, 1H), 7.98 (dd, J = 7.2, 1.5 Hz,
1H), 7.81 (d, J = 8.4 Hz, 2H), 7.36-7.31 (m, 2H), 7.26 (d,
J = 9.3 Hz, 2H), 3.71 (s, 3H), 3.40 (s, 3H), 2.35 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 164.1, 145.9, 135.1, 134.4, 130.4,
130.3, 130.0, 127.3, 125.5, 124.5, 123.2, 113.9, 113.3, 61.4, 33.3,
21.9; HRMS (ESI) m/z 359.1064 [M þ H]þ (359.1066 calcd for
C18H18N2O4S þ H).
r. (E)-N-Methoxy-N-methylhex-2-enamide (6d, Table 3).22
Using representative procedure A with commercially available
(E)-pent-1-enylboronic acid (5d), the product was obtained as a
colorless oil (223 mg, 81%): TLC Rf 0.55 (1:1 hexanes/ethyl
acetate); 1H NMR (500 MHz, CDCl3) δ 6.99-6.93 (m, 1H), 6.40
(d, J = 15.5 Hz, 1H), 3.69 (s, 3H), 3.22 (s, 3H), 2.23-2.18 (m,
2H), 1.51-1.47 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.4, 148.0, 119.1, 61.9, 34.8, 32.7, 21.9, 14.0;
MS (ESI) m/z 158.1 [M þ H]þ.
l. N-Methoxy-N-methyl-1H-indole-5-carboxamide (3n, Table 2).
Using representative procedure A with commercially available 1H-
indol-5-ylboronic acid (1n), the product was obtained as an off-
white solid (199 mg, 78%): mp 136-138 °C; TLC Rf 0.45 (1:1
hexanes/ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H),
8.06 (d, J= 1.5 Hz, 1H), 7.55 (dd, J= 8.5, 1.5 Hz, 1H), 7.35 (d, J=
8.5 Hz, 1H), 7.22 (t, J = 3.0 Hz, 1H), 6.59-6.58 (m, 1H), 3.59 (s,
3H), 3.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.6, 137.4,
127.4, 125.7, 125.6, 122.7, 122.2, 110.9, 103.6, 61.2, 35.0;
HRMS (ESI) m/z 205.0982 [M þ H]þ (205.0977 calcd for C11H12-
N2O2 þ H).
Representative Procedure B: Preparation of N,4-Dimethoxy-
N-methylbenzamide (3a, Table 4) from Potassium 4-Methoxy-
phenyltrifluoroborate (7a). A suspension of commercially avail-
able potassium 4-methoxyphenyltrifluoroborate (7a, 100 mg,
0.47 mmol, 1.0 equiv), commercially available N-methoxy-N-
methylcarbamoyl chloride (2, 325 mg, 0.94 mmol, 2.0 equiv),
dichlorobis(triphenylphosphine)palladium(II) (17 mg, 5 mol
%), and sodium carbonate (249 mg, 2.35 mmol, 5.0 equiv) in
anhydrous ethanol (5.0 mL) was heated at 65 °C under nitrogen
for 2 h. The cooled mixture was filtered through a pad of silica
gel, eluting with ethyl acetate, and the solvents were removed
under reduced pressure. The residue was purified by flash
column chromatography on silica gel, eluting with ethyl acet-
ate/hexanes (gradient of 2:8 to 6:4), to provide N,4-dimethoxy-
N-methylbenzamide (3a) as a yellow oil (79 mg, 87%): see data
listed above.
m.N,5-Dimethoxy-N-methylpyrazine-2-carboxamide(3o,Table2).
Using representative procedure A with commercially available 5-
methoxypyrazin-2-ylboronic acid (1o), the product was obtained as a
colorless oil (107 mg, 84%): TLC Rf 0.30 (1:1 hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 8.97 (s, 2H), 4.08 (s, 3H), 3.61 (s,
3H), 3.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.5, 165.1, 160.6,
121.6, 61.6, 55.7, 33.3; HRMS (ESI) m/z 198.0876 [M þ H]þ
(198.0879 calcd for C8H11N3O3 þ H).
a. 4-Chloro-N-methoxy-N-methylbenzamide (3d, Table 4). Using
representative procedure B with commercially available potassium
(4-chlorophenyl)trifluoroborate (7b), the product was obtained as a
yellow oil (163 mg, 89%): see data listed above.
n. N-Methoxy-N-methylquinoline-3-carboxamide (3p, Table 2).
Using representative procedure A with commercially available
quinolin-3-ylboronic acid (1p), the product was obtained as a
yellow oil (131 mg, 52%): TLC Rf 0.40 (1:1 hexanes/ethyl acetate);
1H NMR (500 MHz, CDCl3) δ 9.21 (s, 1H), 8.56 (s, 1H), 8.14 (d, J
= 8.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0, 7.0 Hz,
1H), 7.59 (t, J = 7.5 Hz, 1H), 3.56 (s, 3H), 3.44 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.4, 149.7, 148.9, 137.3, 131.3, 129.6, 128.9,
127.5, 127.2, 127.2, 61.6, 33.5; HRMS (ESI) m/z 217.0983 [M þ
H]þ (217.0977 calcd for C12H12N2O2 þ H).
b. N-Methoxy-N,5-dimethylthiophene-2-carboxamide (3r, Table 4).23
Using representative procedure B with commercially available potas-
sium 5-methyl-2-thiophenetrifluoroborate (7c), the product was ob-
tained as a yellow oil (152 mg, 84%): TLC Rf 0.65 (1:1 hexanes/ethyl
acetate); 1H NMR (500 MHz, CDCl3) δ7.77(d,J= 4.0 Hz, 1H), 6.77
(d, J = 3.5 Hz, 1H), 3.76 (s, 3H), 3.34 (s, 3H), 2.51 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 162.8, 147.7, 135.1, 130.9, 125.7, 61.8, 33.3, 15.6;
MS (ESI) m/z 186.1 [M þ H]þ.
o. (E)-N-Methoxy-N-methylcinnamamide (6a, Table 3).17a,21
Using representative procedure A with commercially available
(E)-styrylboronic acid (5a), the product was obtained as a yellow
oil (197 mg, 76%): TLC Rf 0.55 (1:1 hexanes/ethyl acetate); 1H
NMR (300 MHz, CDCl3) δ 7.76 (d, J = 15.6 Hz, 1H), 7.59-7.56
(m, 2H), 7.40-7.37 (m, 3H), 7.06 (d, J = 15.6 Hz, 1H), 3.77 (s,
3H), 3.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.3, 143.7,
135.5, 130.1, 129.1, 128.3, 116.1, 62.2, 32.8; MS (ESI) m/z 192.1
[M þ H]þ.
c. N-Methoxy-N-methylthiophene-3-carboxamide (3k, Table 4).
Using representative procedure B with commercially available
potassium 3-thiophenetrifluoroborate (7d), the product was ob-
tained as a yellow oil (145 mg, 81%): see data listed above.
d. (E)-N-Methoxy-N-methylcinnamamide (6a, Table 4). Using
representative procedure B with commercially available potas-
sium (E)-styryltrifluoroborate (8a), the product was obtained as
a yellow oil (145 mg, 79%): see data listed above.
p. N-Methoxy-N-methyl-2-phenylacrylamide (6b, Table 3).
Using representative procedure A with commercially available
1-phenylvinylboronic acid (5b), the product was obtained as a
yellow oil (93 mg, 36%): TLC Rf 0.50 (1:1 hexanes/ethyl
e. (E)-N-Methoxy-N-methylundec-2-enamide (6e, Table 4).
Using representative procedure B with commercially available
potassium (E)-1-decenyltrifluoroborate (7e), the product was
obtained as a colorless oil (166 mg, 72%): TLC Rf 0.60 (1:1
hexanes/ethyl acetate); 1H NMR (500 MHz, CDCl3) δ
6.99-6.94 (m, 1H), 6.40 (d, J = 15.5 Hz, 1H), 3.69 (s, 3H),
3.23 (s, 3H), 2.25-2.20 (m 2H), 1.47-1.44 (m, 2H), 1.33-1.26
(m, 10H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 167.5, 148.4, 118.9, 61.9, 32.8, 32.7, 32.1, 29.7, 29.5 (2), 28.6,
1
acetate); H NMR (300 MHz, CDCl3) δ 7.42-7.31 (m, 5H),
5.70 (s, 1H), 5.50 (s, 1H), 3.45 (s, 3H), 3.25 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 145.3, 136.5, 128.9, 128.7, 126.2, 115.8, 61.3;
HRMS (ESI) m/z 192.1021 [M þ H]þ (192.1025 calcd for
C11H13NO2 þ H).
q. (()-N-Methoxy-N,4-dimethylcyclohex-1-enecarboxamide (6c,
Table 3). Using representative procedure A with commercially
(22) Shintani, R.; Kimura, T.; Hayashi, T. Chem. Commun. 2005, 25,
3213.
(21) (a) Kokotos, C. G.; Baskakis, C.; Kokotos, G. J. Org. Chem. 2008,
73, 8623. (b) Pippel, D. J.; Mapes, C. M.; Mani, N. S. J. Org. Chem. 2007, 72,
5828. (c) Bariau, A.; Canet, J.-L.; Chalard, P.; Troin, Y. Tetrahedron:
Asymmetry 2005, 16, 3650.
(23) (a) Boyd, R. E.; Rasmussen, C. R.; Press, J. B.; Raffa, R. B.; Codd, E.
E.; Connelly, C. D.; Li, Q. S.; Martinez, R. P.; Lewis, M. A.; Almond, H. R.;
Reitz, A. B. J. Med. Chem. 2001, 44, 863. (b) Whipple, W. L.; Reich, H. J.
J. Org. Chem. 1991, 56, 2911.
J. Org. Chem. Vol. 75, No. 4, 2010 1257

Krishnamoorthy et al.
JOCArticle
22.9, 14.4; HRMS (ESI) m/z 228.1969 [M þ H]þ (228.1963 calcd
effort and Kent Kaltenborn for high-resolution mass spec-
trometry data.
for C13H25NO2 þ H).
Acknowledgment. The authors with to thank AMRI col-
leagues William G. Earley, Paul E. Zhichkin, and Larry Yet
for many helpful discussions during several stages of this
Supporting Information Available: Proton and carbon
NMR spectra for all compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
1258 J. Org. Chem. Vol. 75, No. 4, 2010