Microwave-assisted synthesis of weinreb and MAP aryl amides via pd-catalyzed heck aminocarbonylation using Mo(CO)6 or W(CO) 6

Article abstract of DOI:10.1021/jo102151u

A simple and expedient process for the Heck aminocarbonylative synthesis of Weinreb and MAP amide acylating agents, from aryl halides, is reported. This methodology utilizes solid sources of CO making it readily accessible to chemists working in small-scale laboratory applications.

Full text of DOI:10.1021/jo102151u

pubs.acs.org/joc
Almost at the same time as the Weinreb amides were
Microwave-Assisted Synthesis of Weinreb and MAP
Aryl Amides via Pd-Catalyzed Heck
Aminocarbonylation Using Mo(CO)6 or W(CO)6
discovered, Meyers and Comins reported the use of N-methyl-
amino pyridyl amides (MAPA) as acylating agents.8,9
In contrast to the Weinreb amides, which form a stable
metal-chelated intermediate preventing a second nucleophilic
addition, the MAP amides can be more sensitive toward
further alkylation and the reaction outcome depends largely
on the organometallic reagent used. Nonetheless, the MAP
agents can be useful in the synthesis of aldehydes, ketones,
alcohols, amides and esters.9-11
Anna Wie-ckowska, Rebecca Fransson, Luke R. Odell,* and
Mats Larhed
Organic Pharmaceutical Chemistry, Department of Medicinal
Chemistry, Uppsala University, BMC, Box 574,
SE-751 23 Uppsala, Sweden
Traditionally, Weinreb amides have been prepared from
carboxylic acids5,12,13 and their derivatives, for example, acid
chlorides,1 esters,14 lactones, amides and anhydrides.5 More
recent methods have focused on transition metal-catalysis
and include the cross-coupling of N-methoxy-N-methylcar-
bamoyl chloride with vinyl and aryl stannanes15 or boronic
acids16 and the Heck aminocarbonylation17-21 of N,O-di-
methylhydroxylamine (1) with aryl bromides,22 aryl and
vinyl iodides,23 and lactam/lactone-derived triflates,24 under
a carbon monoxide (CO) atmosphere.
luke.odell@orgfarm.uu.se
Received October 29, 2010
Our interest in the Heck carbonylation reaction lies in the
development of CO-gas free methods, which are suitable for
small scale laboratory applications and parallel synthesis.
The benefits of these protocols are well established and
include their low cost, preparative ease (reactions do not
need to be carried out under an inert atmosphere) and, more
importantly, the in situ generation of toxic CO-gas. We25-32
A simple and expedient process for the Heck aminocarbo-
nylative synthesis of Weinreb and MAP amide acylating
agents, from aryl halides, is reported. This methodology
utilizes solid sources of CO making it readily accessible to
chemists working in small-scale laboratory applications.
(6) 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.
(7) Hisler, K.; Tripoli, R.; Murphy, J. A. Tetrahedron Lett. 2006, 47, 6293.
(8) Comins, D.; Meyers, A. I. Synthesis 1978, 403.
Since their discovery in 1981 by Nahm and Weinreb,1 the
N-methoxy-N-methylamides (i.e., Weinreb amides, see Figure 1)
have, over the past 20 years, been extensively developed and
utilized as acylating agents.2-5 Their clean interaction with
both Grignard and organolithium reagents to generate
ketones and with metalhydrides to form aldehydes, without
overaddition, makes them extremely useful in the prepara-
tion of carbonyl containing compounds. Recently, ylids were
reported to generate ketones and aldehydes from Weinreb
amides, offering even milder reaction conditions in compar-
ison to the organometallic reagents.6,7
(9) Meyers, A. I.; Comins, D. L. Tetrahedron Lett. 1978, 5179.
(10) Meyers, A. I.; Babiak, K. A.; Campbell, A. J.; Comins, D. L.;
Fleming, M. P.; Henning, R.; Heuschmann, M.; Hudspeth, J. P.; Kane,
J. M.; Reider, P. J.; Roland, D. M.; Shimizu, K.; Tomioka, K.; Walkup,
R. D. J. Am. Chem. Soc. 1983, 105, 5015.
(11) Comins, D. L.; Dernell, W. Tetrahedron Lett. 1981, 22, 1085.
(12) Braun, M.; Waldmuller, D. Synthesis 1989, 856.
(13) Niu, T.; Zhang, W. M.; Huang, D. F.; Xu, C. M.; Wang, H. F.; Hu,
Y. L. Org. Lett. 2009, 11, 4474.
(14) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(15) Murakami, M.; Hoshino, Y.; Ito, H.; Ito, Y. Chem. Lett. 1998, 163.
(16) Krishnamoorthy, R.; Lam, S. Q.; Manley, C. M.; Herr, R. J. J. Org.
Chem. 2010, 75, 1251.
(17) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39,
3318.
(18) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
€
(19) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2009, 48, 4114.
(20) Barnard, C. F. J. Organometallics 2008, 27, 5402.
(21) Grigg, R.; Mutton, S. P. Tetrahedron 2010, 66, 5515.
(22) Martinelli, J. R.; Freckmann, D. M. M.; Buchwald, S. L. Org. Lett.
2006, 8, 4843.
ꢀ
ꢀ
(23) Takacs, A.; Petz, A.; Kollar, L. Tetrahedron 2010, 66, 4479.
(24) Deagostino, A.; Larini, P.; Occhiato, E. G.; Pizzuto, L.; Prandi, C.;
Venturello, P. J. Org. Chem. 2008, 73, 1941.
FIGURE 1. General structures of Weinreb and MAP aryl amides
and their application as acylating agents.
(25) Wu, X.; Ekegren, J. K.; Larhed, M. Organometallics 2006, 25, 1434.
(26) Lagerlund, O.; Larhed, M. J. Comb. Chem. 2006, 8, 4.
(27) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6232.
(28) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Comb. Chem
2003, 5, 82.
(29) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750.
(30) Wu, X.; Larhed, M. Org. Lett. 2005, 7, 3327.
(31) Wu, X.; Wannberg, J.; Larhed, M. Tetrahedron 2006, 62, 4665.
*Fax: þ 46 18 4714474.
(1) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(2) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707.
(3) Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem. 2003, 7, 967.
(4) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prak. Chem. 2000, 342, 340.
(5) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
€
(32) Odell, L. R.; Savmarker, J.; Larhed, M. Tetrahedron Lett. 2008, 49, 6115.
978 J. Org. Chem. 2011, 76, 978–981
Published on Web 01/13/2011
DOI: 10.1021/jo102151u
r
2011 American Chemical Society

Wie-ckowska et al.
JOCNote
and others33-36 have previously reported on various palla-
dium-catalyzed Mo(CO)6-mediated carbonylative couplings
under classical heating37 and microwave-assisted condi-
tions.38-40
TABLE 1. Preparation of Weinreb Aryl Amides by Aminocarbonyla-
tion of Aryl Bromidesa
To the best of our knowledge, the synthesis of Weinreb
amides via a CO-gas free Heck carbonylation approach is
unknown in the literature. Furthermore, the direct carbony-
lative synthesis of MAP amides, from (hetero)aryl halide
precursors, is previously unreported. Herein we disclose the
first microwave-assisted palladium(0)-catalyzed protocol for
the synthesis of these valuable synthetic intermediates utiliz-
ing Mo(CO)6 or W(CO)6 as solid CO sources.
Our initial investigations focused on the preparation of
Weinreb amides and utilized 4-bromo-1,10-biphenyl as the
model substrate, microwave irradiation as the energy source
and catalytic conditions similar to those previously reported
by the Buchwald group.22 Thus, Pd(OAc)2 was used as the
palladium source, Xantphos as the ligand, K3PO4 as the base
and toluene as the solvent. Unfortunately, when employing
Mo(CO)6 as the CO source, these conditions provided only
trace amounts of the desired product (3c) after 20 min of
microwave irradiation at 120 °C. Furthermore, a screening
of ligands previously shown to promote Mo(CO)6 mediated
aminocarbonylations failed to provide an improved reaction
outcome.41 Due to the high propensity of aryl bromides to
undergo oxidative addition and CO insertion, we suspected
that the failure of the reaction was due to the sluggish attack
of the acylpalladium intermediate by 1.22,23 Encouraged by
our previous success of using N,N-dimethylaminopyridine
(DMAP) to facilitate the aminocarbonylation of hindered
and poorly nucleophilic amines,32 we decided to investigate
the effect of DMAP on this transformation. Gratifyingly, the
addition of 2 equiv of DMAP to the original reaction mixture
resulted in greater conversion of the starting material how-
ever, the reaction mixture consisted of the desired Weinreb
amide product 2c and the corresponding N-methylamide 3c
(2c:3c = 40:60 according to GC/MS analysis). The formation
of 3c is most probably a result of N-O bond cleavage under
the Mo(CO)6 mediated reaction conditions, a transforma-
tion with considerable literature precedent.42-45
In order to ascertain whether 1 or the Weinreb amide
product was being reduced, purified 2c was subjected to the
carbonylative reaction conditions. Interestingly, only intact
2c was recovered after this reaction suggesting that 1 is reduced
(33) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580.
(34) Liptrot, D.; Alcaraz, L.; Roberts, B. Adv. Synth. Catal. 2010, 352,
2183.
(35) Liptrot, D.; Alcaraz, L.; Roberts, B. Tetrahedron Lett. 2010, 51,
5341.
(36) Roberts, B.; Liptrot, D.; Alcaraz, L.; Luker, T.; Stocks, M. J. Org.
Lett. 2010, 12, 4280.
(37) Lindh, J.; Fardost, A.; Almeida, M.; Nilsson, P. Tetrahedron Lett.
2010, 51, 2470.
(38) Chen, J.-R.; Liao, J.; Xiao, W.-J. Can. J. Chem. 2010, 88, 331.
(39) Larhed, M.; Wannberg, J. In Modern Carbonylation Methods;
Kollar, L., Ed.; Wiley-VCH: Weinheim, 2008; p 93.
aAryl bromide (0.25 mmol), 0.75 mmol 1, 7.5 mol % Pd(OAc)2,
15 mol % Xantphos, 0.08 mmol W(CO)6, 0.50 mmol DMAP, 1.5 mmol
K3PO4, 1,4-dioxane (2 mL), 120 °C, 20 min, MW. bIsolated yields.
cDetermined by GC/MS analysis. dReaction conducted on 1 mmol scale.
eReaction conducted in an oil bath. fReaction time 40 min.
€
(40) Wu, X.; Ronn, R.; Gossas, T.; Larhed, M. J. Org. Chem. 2005, 70,
3094.
(41) For more details regarding screening conditions, see Table 1 in the
Supporting Information.
(42) Nielsen, S.; Smith, G.; Begtrup, M.; Kristensen, J. Chem.;Eur. J.
2010, 16, 4557.
(43) Nielsen, S. D.; Smith, G.; Begtrup, M.; Kristensen, J. L. Eur. J. Org.
Chem. 2010, 2010, 3704.
(44) Iyer, S.; Kulkarni, G. M. Synth. Commun. 2004, 34, 721.
(45) Spencer, J.; Rathnam, R. P.; Patel, H.; Anjum, N. Tetrahedron 2008,
64, 10195.
to methylamine, which in turn undergoes an aminocarbonyla-
tion to generate 3c. To overcome this problem we turned to the
use of alternative, and less reactive, solid CO sources.29 To our
delight, when the reaction was performed with 1 equiv. W(CO)6
the amount of 3c was reduced considerably (2c:3c = 70:30)
and, after fine-tuning of the reaction parameters, 2c could be
isolated in 88% yield (2c:3c = 93:7, 0.33 equiv. W(CO)6 see
J. Org. Chem. Vol. 76, No. 3, 2011 979

Wie-ckowska et al.
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TABLE 2. Preparation of Weinreb Aryl Amides by Aminocarbonyla-
TABLE 3. Preparation of MAP Aryl Amides by Aminocarbonylation of
Aryl Bromidesa
tion of Aryl Iodidesa
entry
ArI
product
yield (%)b (2:3)c
1
2
3
4
5
6
7
8
9
4-MeOC6H4I
2-naphthyl-I
4-PhC6H4I
C6H5I
4-MeCOC6H4I
4-PhCOC6H4I
4-CF3C6H4I
2-MeC6H4I
3-thienyl-I
2a
2b
2c
2d
2f
2g
2h
2i
82 (99:1)
84 (99:1)
81 (93:3)
80 (99:1)
74 (96:4)
64 (71:29)
39 (73:27)
69 (91:9)
77 (99:1)
2k
aAryl iodide (0.25 mmol), 0.75 mmol 1, 5 mol % Pd(OAc)2, 10 mol %
Xantphos, 0.08 mmol Mo(CO)6, 0.50 mmol DMAP, 1.5 mmol K3PO4,
1,4-dioxane (2 mL), 110 °C, 10 min. MW. bIsolated yields. cDetermined
by GC/MS analysis.
Table 1 for details). Despite this success the formation of
3c could never be completely suppressed and varying
amounts of this byproduct were always detected along
with the desired Weinreb amide (see Table 1 for details).
This procedure was then further evaluated for its scope
and general applicability.
The identified reaction conditions were applied to a series
of aryl and heteroaryl bromides and the preparative results
are outlined in Table 1. Generally, the reaction performed
well with electron-rich (entries 1-3), neutral (entry 4) and
electron-poor (entries 5-7) bromides. Importantly, full che-
moselectivity was observed for the aminocarbonylation of
4-bromochlorobenzene (entry 5) and no products arising
from the activation of the aryl chlorine bond were detected
by GC/MS analysis. Lower yields were obtained for the
highly electron deficient 4-trifluoromethylphenylbromide
(entry 8) and the sterically hindered 2-bromotoluene (entry 9).
Moreover, both of these substrates afforded the corre-
sponding methylamides as the major reaction product. This
could be explained by a reduced reactivity rate for these
electron-deficient or hindered substrates,27 leading to in-
creased concentrations of methylamine, at the expense of 1,
that can subsequently undergo aminocarbonylation. The
heterocyclic bromides 3-bromoquinoline (entry 10) and
3-bromothiophene (entry 11) were also cleanly transformed
into the corresponding Weinreb amides under these condi-
tions. Finally, the reaction was successfully conducted under
conventional heating conditions and on a 1 mmol scale
affording 2c in 77% and 94% yield, respectively.
Next, to further explore the scope of this transformation
we sought to apply the conditions to a range of aryl and
heteroaryl iodides. Surprisingly, these conditions failed to
provide more than trace amounts of the desired Weinreb
amide products. After considerable experimentation, it was
found that the reaction functioned well with Mo(CO)6 and,
after reoptimization, a suitable method was identified
(10 min, 110 °C, 0.33 equiv. Mo(CO)6, see Table 2). The
success of Mo(CO)6 in this reaction can be attributed to the
lower reaction temperature and the increased reactivity of
the iodide substrates and we believe that the carbonylation
occurs faster than the reduction of 1, resulting in the pre-
ferential formation of the desired products. These Mo(CO)6
mediated conditions were then applied to various aryl and
heteroaryl iodides and the results are presented in Table 2.
As can be seen from Table 2 good isolated yields were
obtained with range of electron-rich (entries 1-3), neutral
(entry 4) and moderately electron-poor substrates (entries 5
a4 (0.25 mmol), 1.25 mmol aryl bromide, 5 mol % Pd(OAc)2, 10 mol %
Xantphos, 0.25 mmol Mo(CO)6, 0.50 mmol DMAP, 0.75 mmol K3PO4,
1,4-dioxane (2 mL), 120 °C, 30 min, MW. bIsolated yields.
and 6). Again, the highly electron deficient 4-trifluoromethyl-
phenyl system performed poorly, presumably due to competing
reduction of the Ar-I bond (entry 7). The presence of an ortho
substituent was also well tolerated (entry 8), indicating that the
increased reactivity of the iodide outweighs the negative steric
effects of the ortho methyl group (cf. entry 9, Table 1).
Having demonstrated a wide scope for the direct prepara-
tion of Weinreb amides, we turned our attention to the
synthesis of MAP amides. Thus, 4-bromo-1,10-biphenyl
and 2-methylaminopyridine (4) were reacted under condi-
tions similar to those outlined in Table 2. This resulted in the
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Wie-ckowska et al.
JOCNote
TABLE 4. Preparation of MAP aryl amides by aminocarbonylation of
aryl iodidesa
activity due to coordination of 4 to palladium. This method
was then applied to a small range of aryl iodide substrates. As
illustrated in Table 4, aryl iodides bearing electron-donating
(entries 1 and 2), electron-withdrawing (entries 4-6) and
ortho substituents (entries 2 and 7) afforded the correspond-
ing products in moderate to good yields.
In conclusion, we have developed various palladium(0)-
catalyzed methods for the direct synthesis of Weinreb amide
and MAP amide acylating agents from (hetero)aryl bro-
mides and iodides. The reactions tolerate a range of different
functional groups and the desired products were obtained in
good yields with short reaction times. More importantly,
these methods utilize solid sources of CO making them
readily accessible to preparative chemists working in small-
scale laboratory applications.
entry
ArI
product
yield (%)b
1
2
4-MeOC6H4I
1-naphthyl-I
5a
5k
59
66c
69
63
40
50
57
62
3
4
5
6
7
C6H5I
5e
5l
5g
5h
5i
4-MeCOC6H4I
4-PhCOC6H4I
4-CF3C6H4I
2-MeC6H4I
aAryl iodide (0.25 mmol), 0.75 mmol 4, 10 mol % Pd(OAc)2, 20 mol %
Xantphos, 0.12 mmol Mo(CO)6, 0.75 mmol K3PO4, 1,4-dioxane
(2.5 mL), 100 °C, 20 min, MW. bIsolated yields. cMo(CO)6 (0.25 mmol).
modest consumption of the starting materials and the desired
product (5c) was isolated in only 35% yield. Subsequent
attempts to optimize this procedure (time, solvent, tempera-
ture, catalyst and ligand) were unsuccessful and full conver-
sion of the starting material was never achieved. Initially, we
believed that this was due to the electron-poor and sluggish
nature of nucleophile; however, the addition of a large excess
of the nucleophile (5-10 equiv) completely inhibited the
reaction. This suggests that 4 may in fact coordinate to
palladium, forming inactive Pd-pyridine complexes and
thus, poisoning the catalyst. To overcome this problem we
decided to conduct the reaction using an excess of the aryl
bromide, with respect to 4, and these results are shown in
Table 3.
It is evident from Table 3 that this strategy was successful
and the reaction performed well with a variety of electro-
nically diverse aryl bromides. Electron-withdrawing (entries
6-8) and electron-donating (entries 1-4) groups were well
tolerated as was the presence of a heterocyclic ring (entry 10).
Interestingly, the methylester group remained intact despite
the high reaction temperature and basic conditions (entry 6).
Finally, we decided to explore the synthesis of MAP
amides from aryl iodides. To begin with, we applied the
conditions from Table 3 and, with 1-naphthyliodide, this
furnished the desired MAP aryl amide product 5k in 77%
yield. To increase the applicability of the method, we were
interested in exploring whether the reaction could be con-
ducted with the aryl iodide as the limiting reagent. We
believed that the increased propensity of aryl iodides to
undergo oxidative addition could counteract the catalyst
poisoning effects of 4. Pleasingly, the reaction proceeded
well, and after screening of various reaction conditions, the
desired product 5k was obtained in 69% yield. The optimized
method requires a palladium loading of 10 mol %, a rela-
tively high value for an aryl iodide substrate in a palladium-
catalyzed coupling. This is consistent with reduced catalytic
Experimental Section
Representative Procedure for the Synthesis of Weinreb Amides
from Aryl Bromides. 4-Acetyl-N-methoxy-N-methylbenzamide
(2f).
A 2-5 mL process vial was charged with 1-(4-
bromophenyl)ethanone (49.7 mg, 0.250 mmol), W(CO)6 (29.0
mg, 0.082 mmol), Pd(OAc)2 (4.2 mg, 0.018 mmol, 7.5 mol %),
Xantphos (21.6 mg, 0.037 mmol, 15 mol %), DMAP (61.0 mg,
0.500 mmol), K3PO4 (318.0 mg, 1.500 mmol), O,N-dimethylhy-
droxylamine hydrochloride (72.0 mg, 0.750 mmol) and 1,4-
dioxane (2.0 mL). The vessel was sealed under air and exposed
to microwave heating for 20 min at 120 °C. The resulting
mixture was cooled to room temperature, filtered through a
cotton pad (eluting with dichloromethane), and concentrated
under reduced pressure. The crude product was thereafter
purified by flash column chromatography on silica gel
(EtOAc/i-Hexane 2:1) to provide the title compound as a color-
1
less solid (36 mg, 70%): mp 51-53 °C, H NMR (400 MHz,
CDCl3) δ 8.00-7.94 (m, 2H), 7.76-7.70 (m, 2H), 3.52 (s, 3H),
3.35 (s, 3H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 197.7,
169.1, 138.6, 138.5, 128.5, 128.1, 61.4, 33.6, 26.9. HRMS calcd
for C11H14NO3 [M þ Hþ] 208.0974, found 208.0968.
Caution! Pressurized reactions should not be conducted in
sealed vessels without an appropriate pressure release device due
as this could result in an explosion. Therefore the use of dedi-
cated instrumentation is recommended for these procedures.
Acknowledgment. We gratefully acknowledge the finan-
cial support from the Swedish Research Council and Knut
and Alice Wallenberg’s Foundation.
Supporting Information Available: All experimental proce-
dures and analytical data for newly synthesized compounds, as
well as copies of 1H and 13CNMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 76, No. 3, 2011 981