One-Pot Direct Synthesis of Weinreb Amides from Aryl and Hetero Aryl Halides Using Co 2(CO) 8 as an Effective CO Source under Conventional Thermal Heating

Article abstract of DOI:10.1080/00397911.2014.974610

A successful protocol for the synthesis of Weinreb amides directly from aryl halides via aminocarbonylation with N,O-dimethyl hydroxylamine using Co₂(CO)8 as an in situ CO source has been demonstrated. The effects of various reaction parameters such as temperature, base, and CO source have also been investigated and optimized. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.974610

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One-Pot Direct Synthesis of Weinreb Amides from Aryl
and Hetero Aryl Halides Using Co2(CO)8 as an Effective
CO Source Under Conventional Thermal Heating
Poongavanam Baburajana & Kuppanagounder P. Elangoa
a Department of Chemistry, Gandhigram Rural Institute (Deemed University), Gandhigram,
India
Accepted author version posted online: 03 Nov 2014.
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To cite this article: Poongavanam Baburajan & Kuppanagounder P. Elango (2014): One-Pot Direct Synthesis of Weinreb
Amides from Aryl and Hetero Aryl Halides Using Co2(CO)8 as an Effective CO Source Under Conventional Thermal Heating,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2014.974610
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One-Pot Direct Synthesis of Weinreb Amides from Aryl and Hetero Aryl Halides
Using Co2(CO)8 as an Effective CO Source Under Conventional Thermal Heating
Poongavanam Baburajan1, Kuppanagounder P. Elango1
1Department of Chemistry, Gandhigram Rural Institute (Deemed University),
Gandhigram, India
E-mail:drkpelango@rediffmail.com
Abstract
A successful protocol for the synthesis of Weinreb amides directly from aryl halides via
aminocarbonylation with N,O-dimethyl hydroxylamine using Co2(CO)8 as an in situ CO
source has been demonstrated. The effect of various reaction parameters such as
temperature, base and CO source has also been investigated and optimized.
KEYWORDS: aryl halides; Palladium acetate; Co2(CO)8; carbonylation; Weinreb
amides;
INTRODUCTION
Weinreb amides are one of the key intermediates in organic chemistry for the simple
reason that they can be further converted to variety of acyl derivatives by using
organometallic reagents.[1] Ever since its inventive report by Nahm and Weinreb in
1981,[2] continuing efforts have been made for their preparation by using variety of
starting materials.[1,3] Mostly, these methods involve traditional acid amine coupling
1

reactions using expensive acid derivatives and coupling reagents.[1,4] Murakami et al. has
developed a strategy for the synthesis of vinyl and aryl Weinreb amides using a Stille-
type cross-coupling of N-methoxy-N-methylcarbamoyl chloride with vinyl or aryl
stannanes.[5] Aminocarbonylation methods using carbon monoxide gas have also been
reported in literature. Buchwald et al. have reported a general palladium catalysed
process for the conversion of aryl bromides to corresponding Weinreb amides using N,O-
dimethyl hydroxylamine at 1 atm COg.[6] The direct synthesis of Weinreb amides from
lactam-, lactone-, and thiolactone derived triflates via aminocarbonylation has also been
reported.[7] Although the methodology is useful on an industrial scale, the toxicity and
flammability of carbon monoxide make it inconvenient to use in a laboratory scale
synthesis. Hence, the search for alternative CO source is still on. The use of solid metal
carbonyls in these reactions is reported to be a friendly method which the synthetic
chemists can operate with ease.[8] In 2011, Mats Larhed and his co-workers reported a
synthesis of Weinreb amides from aryl halides using metal carbonyls such as Mo(CO)6
and W(CO)6 under MW irradiation.[9] Though this is a useful and COg free method of
making Weinreb amides, the formation (1% to 83%) of undesired N-methylamide 4a is
considerable and also with W(CO)6 only the aryl bromides are converted to Weinreb
amides but not the aryl iodides. The proposed reaction conditions also require excess
equivalents of metal carbonyls at high temperature.
The main objective of this paper therefore is to develop a suitable method of making
Weinreb amides from aryl halides under mild reaction conditions and also with the
formation of lesser or no undesired product. Recently, we have demonstrated that
2

Co2(CO)8 can be used as an effective in situ CO source in carbonylation reactions.[10]
Hence, we began our study using Co2(CO)8 as the CO source in the synthesis of Weinreb
amides from variety of aryl halides (Br/I) and N-O-dimethoxyhydroxylamine
hydrochloride under thermal conditions.
RESULT AND DISCUSSION
The various effects on the reaction investigated to optimize the reaction conditions are
collected in Table 1. The aminocarbonylation protocol for the synthesis of N-Methoxy-
3,N-dimethyl-benzamide via microwave irradiation (Table 1, Entry 1) is similar to the
one we have stabilised earlier for such reactions.[10] The result indicated that the desired
product is formed in good yield (74%), along with 16% of demethoxylated by-product
(3,N-dimethyl-benzamide). Even though the isolated yield is good, further attempts were
made to increase the yield of the product and to reduce the formation of the by-product.
The by-product can be formed by the cleavage of N-O bond either in 2 or 3a by the base
or high temperature of the reaction.[11] Hence, the reaction temperature was reduced to 70
°C (Table 1, Entry 2) and it was found that the by-product formation is still there. The
same reaction was also carried out under traditional thermal heating at 90°C for 1 h
(Entry 3). To our delight, the reaction worked well with an excellent isolated yield of 3a
(82%) along with 4a (10%). Further reduction in temperature gave reduced yield of the
product with the formation of the by-product. Therefore, the effect of different bases on
the reaction was studied (Entries 3-9). The results showed that with strong bases like
KHMDS, DABCO and DBU, the isolated yield of the by-product 4a is more. Also, with
3

the use of n-Bu3N, though the amount of the by-product was less, the yield of the desired
3 product is relatively low. Hence, from the results, it is evident that Et3N is
comparatively a better choice for the reaction as the yield of the desired product is
relatively high. The base variation studies suggested that the formation of the undesired
N-methyl amide can occur via base initiated cleavage of N-O bond either in 2 or 3a.
When the isolated desired product 3a was subjected to react under identical reaction
conditions with either DMAP or Et3N, there was no by-product (4a) formation. Hence, it
is concluded that the formation of the by-product may occur through the reduction of
Weinreb amine 2 to methylamine which undergoes aminocarbonylation. This is further
substantiated by the results of the studies with varying amounts of 2 (Entries 9-14).
It is evident from the results depicted in Table 1 that use of Et3N base with 1.5
equivalents of 2 at 90 oC thermal heating is the optimum condition for the synthesis of
Weinreb amide 3a in excellent yield with very less amount of the by-product (Entry 14).
The same reaction was also carried out using Mo(CO)6 (Entry 15) and W(CO)6 (Entry 16)
as the CO source under the optimized conditions. The formation of excess by-product 4a
(N-benzamide) was observed in both the case. This may be due to the Mo(CO)6 promoted
cleavage of N-O bond which is known in literature.[12] The result showed that Co2(CO)8
is relatively a better in situ CO source in the above reaction. To further demonstrate this
observation, the reactions were performed with different aryl halides using cobalt and
molybdenum metal carbonyls and the results are shown in Table 2.
4

The results clearly indicated that the use cobalt carbonyl as CO source produced excellent
yields of the desired products with no/very less amounts of the undesired by-product. In
the case of nitro substituted aryl halide (Entry 6) with molybdenum carbonyl, the yield of
3f is very low (7%). This is due to the fact that the nitro group is non-tolerant in the
presence of Mo(CO)6.12
Encouraged by the above results, variety of aryl/hetero aryl halides (Br/I) possessing
different functional groups were subjected to aminocarbonylation under similar reaction
conditions to yield corresponding Weinreb amides. The results are collected in Table 3.
As seen from the results shown in Table 3, both bromo- and iodo-arylhalides delivered
the corresponding Weinreb amides in good to excellent yields with by-product in the
range of 0-8% only. The bromo derivatives gave relatively higher yields than the iodo
compounds. More importantly, the nitro substituted aryl halides produced the
corresponding Weinreb amides in good yields. With an aim to check the practical utility
of the Weinreb amides prepared, compound 3a (1 mmol) was successfully taken to next
step (as a representative case) to synthesis 3-methylbenzaldehyde by reacting with
DIBAL-H at -78 °C for 1 h, and isolated was found to be good (102 mg, 84.5%).
CONCLUSION
In conclusion, we have developed a simple, suitable and effective one-pot Pd-catalysed
synthesis of Weinreb amides by amino carbonylation of aryl and heteroaryl halides by
using Co2 (CO)8 as an effective in situ CO source. Using this proposed synthetic protocol,
variety of aryl halides and hetero aryl halides containing different functional groups can
5

be converted into their corresponding Weinreb amides in good to excellent yields. The
success of this method of synthesis of valuable intermediate (Weinreb amides) is no
doubt, very useful in academic and medicinal chemistry fields as it involves no CO gas.
The proposed protocol can be used in small scale synthesis in laboratories as it involves
no CO cylinder and the reaction is very easy to perform. Also, the method is very useful
in parallel synthesis reactions.
EXPERIMENTAL
Commercially available reagents were used as received in this work. The solvents were
freshly distilled and used. Purification of products was performed by silica gel column
chromatography. 1H NMR spectra were obtained using a 300 MHz or 400 MHz
spectrometer. 13C NMR spectra were obtained from a 75 MHz or 100 MHz spectrometer.
All 1H and 13C NMR experiments are reported in parts per million (ppm) downfield from
tetramethylsilane and were measured relative to the signals for residual chloroform in the
deuterated solvents. The mass spectra were recorded on Liquid Chromatography-Mass
Spectrometry (LCMS). All the spectral data matched well with the literature descriptions.
GENERAL PROCEDURE
Commercially available reagents were used as received in this work. The solvents were
freshly distilled and used. Purification of products was performed by silica gel column
chromatography. 1H NMR spectra were obtained using a 300 MHz or 400 MHz
spectrometer. 13C NMR spectra were obtained from a 75 MHz or 100 MHz spectrometer.
All 1H and 13C NMR experiments are reported in parts per million (ppm) downfield from
6

tetramethylsilane and were measured relative to the signals for residual chloroform in the
deuterated solvents. The mass spectra were recorded on Liquid Chromatography-Mass
Spectrometry (LCMS). All the spectral data matched well with the literature descriptions.
A mixture of aryl halide (I, Br) (1 mmol), Weinreb amine hydrochloride (1.5 mmol),
Pd(OAc)2 (5 mol %), Xantphos (6 mol %), triethylamine (3 mmol) and cobalt carbonyl
(0.3 mmol) in 1,4-dioxane was heated at 90 °C for 1 h in a septum closed sealed tube.
After cooling, the reaction mixture was concentrated in vacuum and the residue was
extracted with ethyl acetate and water. The ethyl acetate layer was concentrated and the
residue obtained was purified by flash column chromatography to get the desired product.
Note: Carbon monoxide gas is highly toxic and should be handled by trained
professionals in well ventilated fume hood with appropriate ventilation. In all the
reactions, Co2(CO)8 was handled carefully in Fume hoods and by using appropriate
personal protective clothing and equipment.
3a. N-Methoxy-4,N-dimethyl-benzamide. Following the general procedure, 3a was
obtained as a colourless liquid; Yield: (164 mg, 91%); 1H-NMR (300 MHz, CDCl3): δ =
7.44-7.46 (m, 2H), 7.25-7.27 (m, 2H), 3.57 (s, 3H), 3.35 (s, 3H), 2.38 (s, 3H); 13C NMR
(CDCl3, 75 MHz): δ = 170.2, 137.7, 134.1, 131.2, 128.6, 127.8, 124.9, 60.9, 21.26; MS
ESI calcd. For C9H11NO2 [M + H]+ = 180.
SUPPORTING INFORMATION
7

Supplemental data for this article can be accessed on the publisher’s website.
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Toczko, J. F.; Roberts, J. C. J. org. Chem. 2002, 67, 5032. (c) Khlestkin, D. G.;
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Lett. 2005, 7, 1427. (e) Hisler, K.; Tripoli, R.; Murphy, J. A. Tetrahedron Lett. 2006, 47,
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(b) Baburajan, P.; Elango, K. P. Tetrahedron Lett. 2014, 55, 1006. (c) Baburajan, P.;
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9

Table-1. Optimisation of reaction condition for the synthesis of N-Methoxy-3,N-
dimethyl-benzamide.
Entry Base
Reaction condition
Weinreb
Yield (%)a
amine 2 (eq)
3a
4a
1
DMAP
90 °C, M/W, 30 min
2
2
2
2
2
2
2
2
2
4
4
74
69
82
7
16
12
10
16
30
36
18
<1
2
2
DMAP
DMAP
70 °C, M/W, 30 min
3
90 °C, thermal heating, 1 h
4
KHMDS 90 °C, thermal heating, 1 h
DABCO 90 °C, thermal heating, 1 h
5
40
51
69
6
DBU
90 °C, thermal heating, 1 h
7
Pyridine 90 °C, thermal heating, 1 h
8
n-Bu3N
Et3N
90 °C, thermal heating, 1 h
90 °C, thermal heating, 1 h
90 °C, thermal heating, 1 h
90 °C, thermal heating, 1 h
60
9
87
80
62
30
75
91
35
10
11
12
13
14
15b
Et3N
10
23
11
<1
<1
40
DMAP
DMAP
Et3N
90 °C, thermal heating, 1 h 0.5
90 °C, thermal heating, 1 h
1
Et3N
90 °C, thermal heating, 1 h 1.5
90 °C, thermal heating, 1 h 1.5
Et3N
10

16c
Et3N
90 °C, thermal heating, 1 h 1.5
63
29
All the reactions were performed with 3-bromo anisole 1 (1 mmol), Pd(OAc)2 (5 mol %),
Xantphos (6 mol %), Weinrebamine 2, base, cobalt carbonyl (0.3 mmol) in 1,4-dioxane
in sealed tube. a Yields quoted are isolated yields. b Mo(CO)6 (0.5 eq) used as CO source.
c W(CO)6 (0.5 eq) used as CO source.
11

Table 2. The comparative study between Co2(CO)8 and Mo(CO)6 carbonyl sources.
O
ClH.HN
2
O
O
Pd/L, Et3N,
CO source,
O
Br
NH
N
R
R
R
Dioxane,
90 °C.
4a-f
Yield (%)a
3a-f
1a-f
Entry
Product
(3a-f)
CO source
R
3a-f
4a-f
O
O
O
O
O
N
O
Co2(CO)8
Mo(CO)6
91
35
<1
54
1
2
3
4
5
6
3-Me
H
3a
3b
3c
3d
3e
3f
N
O
Co2(CO)8
Mo(CO)6
84
51
0
40
N
O
Co2(CO)8
Mo(CO)6
94
47
-
42
4-OMe
O
N
O
Co2(CO)8
Mo(CO)6
74
29
4
40
t
4 - Bu
N
O
Co2(CO)8
Mo(CO)6
80
44
<1
29
4-F
F
O
N
O
Co2(CO)8
Mo(CO)6
71
7
<1
0
4-NO
2
O2N
Reaction Condition: Aryl halide 1a-f (1 mmol), Pd(OAc)2 (5 mol %), Xantphos (6 mol %), Weinrebamine
2 (1.5 mmol), Triethyl amine (3 mmol), cobalt carbonyl (0.3 mmol) or molebdenum carbonyl (0.5 mmol) in
1,4-dioxane, 90 °C, 1h in sealed tube. a Yields quoted are isolated yields.
12

Table 3. Synthesis of Weinreb amides from various aryl and heteroaryl halides (Br/I).
O
ClH.HN
2
O
Pd(OAc)2, Xantphos
O
Ar
N
Ar
X
Et3N, Co2(CO)8,
Dioxane, 90 °C,
1 h
1g - x
3g - x
Product (3g-x)
O
Entry
1
Ar
X
Ar Br, I
Yield ( % )a
Yield ( % )a
Entry
10
Product (3g-x)
O
X
X
X
N
O
N
O
X=Br, 80
X=I, 54
X=Br, 82
X=I, 85
3p
3q
3g
N
Cl
Cl
N
O
O
Br
Br
Br
N
O
N
O
X=Br, 80
X=I, 72
3h
3i
2
3
4
11
12
13
69
79
74
O
O
Cl
F3C
O
N
Cl
N
O
O
O
Br
N
O
N
O
74d
86
3r
3s
MeO2S
MeO2S
N
F3C
N
O
Br
N
O
N
O
3j
O
O
O
N
H
N
H
Ph
Ph
O
O
X
X
X
N
O
N
O
X=Br, 87
X=I, 71
X=Br, 80
X=I, 75
3t
3k
14
5
6
7
S
S
Ph
Ph
O
O
O
O2N
O2N
N
O
X=Br, 65
X=I, 58
N
O
Br
Br
15
3u
75
3l
S
S
O
X
N
O
X=Br, 89
X=I, 80
N
O
16
3m
72
3v
EtOOC
EtOOC
NC
S
S
O
O
O
Br
NC
I
N
O
N
8
69
90
3n
3o
3w
61
80
17
18
O
O
O
N
O
MeO
MeO
Br
MeO
MeO
Br
N
N
3x
O
N
O
N
9
N
Reaction Condition: Aryl halide 1g-x (1 mmol), Pd(OAc)2 (5 mol %), Xantphos (6 mol %), Weinrebamine
2 (1.5 mmol), Triethyl amine (3 mmol), cobalt carbonyl (0.3 mmol) in 1,4-dioxane, 90 °C, 1h in sealed
tube. a Yields quoted are isolated yields.
13