Palladium-Catalyzed, ortho-Selective C-H Halogenation of Benzyl Nitriles, Aryl Weinreb Amides, and Anilides

Article abstract of DOI:10.1021/acs.joc.6b02731

A palladium-catalyzed, ortho-selective C-H halogenation methodology is reported herein. The highlight of the work is the highly selective C(sp²)-H functionalization of benzyl nitriles in the presence of activated C(sp³)-H bond, which results in good yields of the halogenated products with excellent regioselectivity. Along with benzyl nitriles, aryl Weinreb amides and anilides have been evaluated for the transformation using aprotic conditions. Mechanistic studies yield interesting aspects with respect to the pathway of the reaction and the directing group abilities.

Full text of DOI:10.1021/acs.joc.6b02731

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Article
Palladium-catalyzed, ortho-selective C-H halogenation
of benzyl nitriles, aryl Weinreb amides and anilides
Riki Das, and Manmohan Kapur
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02731 • Publication Date (Web): 28 Dec 2016
Downloaded from http://pubs.acs.org on December 28, 2016
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site-selectivity is often governed by the type of directing group employed. In such cases, a
distinction can be made between strongly coordinating (such as heterocyclic amines) as
against weakly coordinating directing groups (such as acyl groups). Thus, the stability of the
resulting metallacycle is dependent on the type of directing group employed and the outcome
of the C-H functionalization is then determined by the metallacycle.
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Preliminary reports by the groups of Sanford,5a,b,c Shi5d and Yu5e set the stage for further
exploration in the area of transition-metal catalyzed C-H halogenation (Scheme 1). A review
of literature on this topic reveals that almost all of the reports on C-H halogenations utilize
directing groups to mediate the proximal C-H bond functionalization. There are very few
reports that do not employ DG to govern the site-selectivity in this transformation.6 We also
realized that majority of the reports involved the use of protic media or protic additives to
assist the transformation. A variety of transition-metal catalysts have been employed, the
most prominent being Pd, Cu and Rh catalysts.7, 8
Scheme 1: Some of the previous strategies for C-H Halogenations
RESULTS AND DISCUSSION
We have been interested in the C-H functionalization of C(sp2)-H bonds9 and in this context
we report herein a new method for the C-H halogenation of substrates possessing weak
coordinating groups, viz., benzyl nitriles,10 Weinreb amides and anilides (Scheme 2). To the
best of our knowledge, transition-metal catalyzed ortho-C-H halogenations have not been
reported for benzyl cyanides and Weinreb amides. The ortho-C-H halogenation of anilides is
a big challenge due to poor regiocontrol in transformation. There are only a couple of
successful reports for this substrate.5d,11 The method utilizes aprotic media for the
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transformation and has good substrate scope. The mechanistic studies bring out interesting
aspects of the directing group abilities in this reaction.
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Scheme 2: Present work: Palladium catalyzed C-H Halogenation
The primary concern in such transformations is the functionalization of the benzylic C-H
when the reaction is performed with arylmethyl nitriles. To subvert this unwanted
transformation, we needed to develop a new method for the selective ortho-C-H halogenation
of benzyl nitriles. Initial attempts to standardize the reaction conditions for these as well as
Weinreb amides resulted in undesired transformations, especially under the protic conditions.
In case of the benzyl nitriles, when the reaction was carried out in protic medium, it resulted
mostly in benzylic bromination or very poor levels of conversions (Scheme 3). In case of the
Weinreb amides, use of acidic media resulted mostly in bromination at the meta-positions.
After considerable optimization,12 the best conditions were found to be
Pd(OAc)2/Cu(OTf)2/NXS in dichloroethane as the solvent.
Conditions
Result
Pd(OAc)2, TsOH, MeCN, rt
Mixture of ortho C-H bromination (5%) along
with benzylic bromination (27%)
Mixture of ortho C-H bromination(13%)
along with benzylic bromination (21%)
Benzylic bromination was the major product
(48%)
Pd(OAc)2, TfOH, DCE, rt
Pd(OAc)2, AcOH, Ag(TFA), DCE, 90 oC
[RhCp*Cl2]2, AgSbF6, PivOH, DCE, 90 oC Complex mixture
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Pd(OAc)2, Cu(OTf)2, DCE, 90oC
DCE, 90oC
Exclusively ortho C-H bromination (71%)
Exclusively benzylic bromination (75%)
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Scheme 3:Side reactions observed during C-H halogenations of benzyl nitriles under protic
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conditions
This reaction condition worked best for all three, the benzyl nitriles, the Weinreb amides as
well as the anilides. The transformation did not work without the palladium catalyst and the
copper additive. The substrate scope for the transformation is depicted in Table 1. The
reaction worked very well for benzyl nitriles under the aprotic conditions. The benzylic
bromination product was not observed under these conditions and the regioselectivity was
exclusive. The reaction conditions were well tolerated by electron-rich as well as electron-
deficient benzyl nitriles. The unique feature of this transformation was that halogen
functionalities were well tolerated under these conditions which immensely increases the
synthetic utility of this method. The advantage of having two different halogen functional
groups in the resulting C-H halogenation product is the amplified scope for further
chemoselective functionalization, leading to densely substituted products in fewer steps. For
the Weinreb amides, the reaction worked very decently and a variety of electronic factors
were tolerated under these conditions (Table 1).
A nitro-substituent on the arene was not tolerated and the reaction failed to result in any C-H
functionalization product and on the other hand the 4-fluoro substituent worked quite well
(Table 1, 5j, 5k). In the case of benzyl nitriles, we were unable to synthesize the starting
material with a nitro-substituent to check its effect on the reaction. In the case of Weinreb
amides too, the halogen functional groups were well tolerated. An olefin functional unit also
survived these reaction conditions, although, some amount of scrambling of the olefin
geometry was nonetheless observed (Table 1, 5r, 5s). Also notable is the fact that the Weinreb
amide functional group was unaffected under these reaction conditions and the N-O bond was
not reductively cleaved.14
In case of the anilides, the reaction was very efficient and was completed in a very short
period. This is probably due to the high reactivity of the anilides, capable of activating the
arene as well as being excellent directing groups themselves. In this case, the nitro-
substituent on the arene did not inhibit the transformation, and decent yields were obtained
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(Table 1, 6j, 6k). In some of the substrates, where strong electron-donating or activating
groups were present, the reaction expectedly resulted in the electrophilic halogenation
predominating the ortho-C-H halogenation pathway (Table 1, 4k, 4l, 4m).
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Table 1: Substrate scope for the C-H halogenation reaction.a
aAll yields are isolated yields. bBased on recovered starting material. cReaction time: 15 min. dCarried out at RT.
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In some cases, both C-H halogenation as well as electrophilic halogenations were obtained in
a single product (Table 1, 5u). In the case of the free anilides (Table 1, 6f), within 30 minutes,
the transformation resulted in over 50% of ortho-C-H halogenation at room temperature after
which the electrophilic halogenation at the para- position was also observed. At elevated
temperatures, the o-, p-dihalogenated product was the major product. Reactions carried out in
the absence of the palladium catalyst did not result in the arene ortho-C-H functionalization.
However, a competing copper-catalyzed pathway was also observed in the case of the
anilides, but the rate for this pathway was much lower than that for the palladium-catalyzed
transformation. In that case, the para-substituted product was the major transformation. In the
case of -excessive heterocycles such as furans, benzofurans and thiophenes, the electrophilic
halogenation dominated the directed C-H halogenations and these were therefore not
investigated further. Ortho-C-H halogenations were also observed for phenol carbamates
under our reaction conditions, but unfortunately, the reaction did not have a broad substrate
scope for this functionality and was therefore not developed further.
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The synthetic potential of this transformation was demonstrated in the dual functionalization
of some of the C-H halogenation products, in which two different halogen substituents were
available for sequential transformation (Scheme 4).15 In another important application, the
ortho-C-H halogenation of benzoic acid anilamides resulted in an important starting material
for building the phenanthridone skeleton,16 present in several important alkaloids (Scheme 4).
aYields are for the annulation step.
Scheme 4: Synthetic utility of the sequential functionalization of C-H halogenation products
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This sequential halogenation and cyclization provides a quick access to this class of
compounds and a quick assembly of the natural product Phenaglydon (Scheme 4, 11c)16 was
achieved by employing this strategy. The most interesting observation was that a clear site-
selectivity was visible between the reactivity of the two possible C-H in (3j, 3k, 3l), the
anilide ortho-C-H was preferentially functionalized over the benzamide ortho-C-H, pointing
to the possibility of the electrophilic metallation being operational in activation of the anilide
ortho-C-H (Table 1, 6m, 6n, 6o). Our attempts to effect both the transformations in a single
pot unfortunately did not yield the desired products.
A plausible mechanism for the transformation, based on previous literature,7c, 8f is depicted in
Scheme 5. The first step is the coordination of the metal to the directing group followed by an
acetate-assisted proximal C-H bond activation to generate the palladacycle (B). Oxidative
addition of NXS gives rise to either a Pd(IV) species or a Pd(III)-bimetallic species.
Reductive elimination from this species results in the product.
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Scheme 5: Plausible mechanism
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The Pd(II) is regenerated via acetic acid assisted oxidation by Cu(II). The fact that the
reaction is completely inhibited in the presence of either TEMPO, BHT or 1,1-
diphenylethylene (> 1 equiv), points to a one-electron transfer pathway (Scheme 5).
Experiments conducted to check the reversibility of the palladacycle formation resulted in
interesting conclusions (Scheme 6). The metallation did not seem to be reversible in case of
the Weinreb amides and the benzyl nitriles, both in the presence of the halogenating agent
and in the absence of it. However, in case of anilides, it was reversible to a considerable
extent.
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Scheme 6: Reversibility of metallation
Studies were performed to determine whether the ortho-C-H bond cleavage was the rate-
determining step for the transformation (Scheme 7). Moderate values were obtained for the
KIE, both via parallel reactions as well as via competition reactions, indicating that the C-H
activation was not involved in the rate-determining step.17
To check the difference in the directing group abilities of the three weakly-coordinating
groups, we performed the relative-rate studies (Figure 1). The anilides were invariably the
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fastest of all, giving rise to complete consumption of the starting material within just 10
minutes. In this time period, the Weinreb amide had a higher initial rate as compared to the
benzyl nitrile, which, however slowed down with time. The reaction rate for the benzyl nitrile
was higher in the later part of the reaction. This clearly indicated the ability of the groups to
be effective directing groups in this kind of a transformation. The anilide seems to be
activating the arene towards C-H activation by a dual mode. Not only does it appear to be a
better coordinating group of the three, it seems be assisting the ortho-C-H functionalization
via an electrophilic palladation mechanism.18
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Scheme 7: Kinetic Isotope Effect studies
The observation of the preferential functionalization of the anilide ortho-C-H (3j-lScheme 4)
is also indicative of this fact. This mode of activation is not available to the aryl Weinreb
amides and the benzyl nitriles, and this probably could explain the huge difference in rates for
the same transformation. The transition state for the anilide ortho-C-H activation could thus
be a combination of the electrophilic activation pathway and the acetate-mediated concerted
metallation deprotonation (CMD) pathway.19 The considerable amount of ortho-deuteration
observed for the anilides (Scheme 6) in a way also supports this hypothesis.
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Nitrile
Weinreb amide
Anilide
Weinreb amide
Benzyl nitrile
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Anilide (p-methylacetanilide)
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time (min)
Figure 1.Studies for relative rate determination.
Conclusion:
In summary, we have developed a new method for the palladium catalyzed ortho C-H
halogenations of arenes bearing weak-coordinating groups. The strategy uses aprotic reaction
conditions, suitable for substrates bearing sensitive functional groups. Benzyl nitriles,
benzoic acid Weinreb amides and anilides were evaluated as directing groups and very
interesting observations resulted in intriguing aspects with respect to the pathway of the
reaction and the directing group abilities. The utility of this methodology is brought out by
quick assembly of densely functionalized molecules, which are normally prepared via several
synthetic steps. The methodology is particularly useful for benzyl nitriles, where the more
reactive C(sp3) benzylic C-H are left untouched in the transformation.
Experimental Section:
(i) General Methods:
All commercially available compounds were used without purification. Unless otherwise
noted, all reactions were performed in oven-dried glassware. All reactions were run under
argon or nitrogen atmosphere. All solvents used in the reactions were purified before use.
Tetrahydrofuran was distilled from sodium and benzophenone, whereas dry dichloromethane,
dimethylformamide, dioxane, toluene and dichloroethane were distilled from CaH2.
Petroleum ether with a boiling range of 40–60 °C was used. Melting points are uncorrected.
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1H, and 13C NMR spectra were recorded at 295 K in CDCl3 or DMSO-D6 using 400 MHz or
500 MHz spectrometer and chemical shifts are calibrated to the residual proton and carbon
resonance of the solvent: CDCl3 (1H δ 7.25; 13C δ 77.0). HRMS were recorded at HR-LCMS
with Q-ToF using electron spray ionization (ESI) or Atmospheric pressure chemical
ionization (APCI) techniques. IR spectra were recorded on a FT-IR spectrometer. GCMS
analysis was performed at GC with methyl silicone column and FID detector, using Electron
Impact (EI) technique.
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(ii) General Procedures:
Synthesis of benzyl bromide:
In a round bottom flask the substituted toluene (10 mmol) was taken in CCl4 (30 mL),
followed by addition of NBS (12 mmol), benzoyl peroxide (0.5 mmol). The reaction mixture
was then refluxed and the progress followed by TLC. Upon completion of the reaction and
subsequent cooling to room temperature, the reaction mixture was concentrated under
reduced pressure and then diluted with EtOAc. The organic layer was washed with water,
brine and dried over anhydrous Na2SO4. The extract was filtered and concentrated under
reduced pressure and the crude product was purified by silica gel flash column
chromatography.
(1) Methyl 4-(bromomethyl)benzoate:
Prepared according to the general procedure and the title compound was isolated as a
colourless gel (86% yield). Spectral data obtained were in good agreement with those
reported in the literature.20
(2) Methyl 3-(bromomethyl)benzoate:
Prepared according to the general procedure and the title compound was isolated as a
colourless gel (84% yield). Spectral data obtained were in good agreement with those
reported in the literature.20
(3) Methyl 2-(bromomethyl)benzoate:
Prepared according to the general procedure and the title compound was isolated as a
colourless gel (72% yield). Spectral data obtained were good in agreement with those
reported in the literature.20
(4) 1-(bromomethyl)-4-iodobenzene:
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Prepared according to the general procedure and the title compound was isolated as a white
solid (79% yield). Spectral data obtained were in good agreement with those reported in the
literature.21
(5) 1-(Bromomethyl)naphthalene:
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Prepared according to the general procedure and the title compound was isolated as a brown
gel (79% yield). Spectral data obtained were in good agreement with those reported in the
literature.21
(iii) General procedure for cyanation:
Synthesis of phenyl acetonitrile:
In a round bottom flask, the substituted benzyl bromide (2.1 mmol) was dissolved in dry
acetonitrile (10 mL) followed by the addition of sodium cyanide (5.8 mmol) and
tetrabutylammoniumiodide (0.44 mmol). The reaction mixture was refluxed and the progress
of the transformation was followed by TLC. Upon completion of the reaction and subsequent
cooling to room temperature, the reaction mixture was concentrated under reduced pressure
then diluted with EtOAc. The solution was washed with water, brine and dried over
anhydrous Na2SO4. The organic extract was filtered and concentrated under vacuum and the
crude product was purified by silica gel flash column chromatography.
(1) Methyl 4-(cyanomethyl)benzoate(1a):
Prepared according to the general procedure and the title compound was isolated as a white
solid (65% yield). Spectral data obtained were in good agreement with those reported in the
literature.22
(2) Methyl 3-(cyanomethyl)benzoate(1b):
Prepared according to the general procedure and the title compound was isolated as a white
solid (62% yield). Spectral data obtained were in good agreement with those reported in the
literature.23
(3) Methyl 2-(cyanomethyl)benzoate(1c):
Prepared according to the general procedure and the title compound was isolated as a white
solid (51% yield). Spectral data obtained were in good agreement with those reported in the
literature.23
(4) 2-(4-iodophenyl)acetonitrile(1d):
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Prepared according to the general procedure and the title compound was isolated as a pale
yellow gel (59% yield). Spectral data obtained were in good agreement with those reported
in the literature.22
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(5) 2-(naphthalen-1-yl)acetonitrile(1d):
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Prepared according to the general procedure and the title compound was isolated as a
yellow gel (67% yield). Spectral data obtained were in good agreement with those reported
in the literature.22
(iv) General procedures for the synthesis of Weinreb Amides:
(1) Synthesis of Weinreb amide (2a):24
Pyridine (2.1 equiv) was slowly added to a mixture of benzoyl chloride (1.0 equiv) and N,O-
o
dimethylhydroxylamine hydrochloride (1.05 equiv) in dry dichloromethane at 0 C. The
reaction mixture was allowed to warm up to room temperature and stirred for 12h. After the
addition of 1N HCl (100 mL), the phases were separated and the aqueous layer was extracted
with CH2Cl2 (3х25 mL). The combined organic phases were dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was purified by silica gel column
chromatography to result in the product as a colourless gel (78% yield). Spectral data
obtained were in good agreement with those reported in the literature.25
(v) General procedures for the synthesis of Weinreb amides from corresponding acids:26
In a two-neck round-bottomed flask, oxalyl chloride (1.2 equiv) was added dropwise into the
o
stirring solution of the benzoic acid (1 equiv) in CH2Cl2 at 0 C. This was followed by
addition of DMF (2 drops). The reaction mixture was allowed to warm to room temperature
o
and stirred for another 1.5 h and then re-cooled to 0 C. Et3N (3 equiv) and N,O-
dimethylhydroxylamine hydrochloride (1.05 equiv) were added. The reaction mixture was
once again allowed to warm to room temperature and stirred for a further 6 h. It was
quenched at room temperature with a saturated solution of NaHCO3 and the resulting mixture
was extracted twice with CH2Cl2. The combined organic extracts were washed with brine and
dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product
was purified by silica gel flash column chromatography .
(1) 4-(tert-butyl)-N-methoxy-N-methylbenzamide(2b):
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Prepared according to the general procedure and the title compound was isolated as white
solid (81% yield). Spectral data obtained were in good agreement with those reported in the
literature.27
(2)
N-methoxy-N,4-dimethylbenzamide(2c):
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60
Prepared according to the general procedure and the title compound was isolated as a brown
gel (86% yield). Spectral data obtained were in good agreement with those reported in the
literature.28
(3)
4-Fluoro-N-methoxy-N-methylbenzamide(2d):
Prepared according to the general procedure and the title compound was isolated as a pale
yellow liquid (91% yield). Spectral data obtained were in good agreement with those reported
in the literature.29
(4) 4-Bromo-N-methoxy-N-methylbenzamide(2e):
Prepared according to the general procedure and the title compound was isolated as a
colourless liquid (87% yield). Spectral data obtained were in good agreement with those
reported in the literature.30
(5) 4-Chloro-N-methoxy-N-methylbenzamide(2f):
Prepared according to the general procedure and the title compound was isolated as a
colourless liquid (83% yield). Spectral data obtained were in good agreement with those
reported in the literature.28
(6) N-3-Dimethoxy-N-methylbenzamide(2g):
Prepared according to the general procedure and the title compound was isolated as a pale
yellow liquid (72% yield). Spectral data obtained were in good agreement with those reported
in the literature.28
(7) N-Methoxy-N-methyl-4-nitrobenzamide(2h):
Prepared according to the general procedure and the title compound was isolated as a pale
yellow solid (83% yield). Spectral data obtained were in good agreement with those reported
in the literature.31
(8) N-methoxy-N-methyl-1-naphthamide(2i):
Prepared according to the general procedure and the title compound was isolated as a
colourless gel (79% yield). Spectral data obtained were in good agreement with those
reported in the literature.27
(9) 4-Iodo-N-methoxy-N-methylbenzamide(2j):
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9
Prepared according to the general procedure and the title compound was isolated as a
colourless gel (79% yield). Spectral data obtained were in good agreement with those
reported in the literature.31
(10) N-4-dimethoxy-N-methylbenzamide(2k):
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Prepared according to the general procedure and the title compound was isolated as a
colourless gel (81% yield). Spectral data obtained were in good agreement with those
reported in the literature.26
(vi) General procedures:
(1)
Methyl (E)-3-(4-(methoxy(methyl)carbamoyl)phenyl)acrylate(2l):32
In a pressure tube equipped with a stir bar, 4-Iodo-N-methoxy-N-methylbenzamide (0.344
mmol) in dry DMSO (2 mL) was taken. The reaction mixture was degassed with nitrogen for
about 10 min, followed by the addition of Pd(OAc)2 (7mol), K2CO3 (1.031 mmol) and
methyl acrylate (0.515 mmol). The tube was fitted with a Teflon screw cap under nitrogen
o
flow. The reaction mixture was heated to 80 C and stirred at that temperature and the
progress was followed by TLC. Upon completion of the reaction and subsequent cooling to
room temperature, the reaction mixture was diluted with EtOAc and filtered through a short
pad of Celite. The organic filtrate was washed with brine and dried over anhydrous Na2SO4,
filtered and concentrated under vacuum. The crude product was purified by silica gel flash
column chromatography, eluting with Petroleum ether-EtOAc (7:3); Yield: 80% (60 mg),
o
Physical appearance: White solid, M. p. 82-86 C, TLC Rf 0.30 (7:3, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.74-7.64 (m, 3H), 7.54 (d, J = 8.2 Hz, 1H),
6.47 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H), 3.54 (s, 3H), 3.35 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 169.1, 167.1, 143.8, 136.4, 135.6, 128.8, 127.6, 119.3, 61.2, 51.8, 33.6; IR (KBr,
cm-1): 2913, 2871, 2343, 2318, 1742, 1714, 1685, 1539, 1458, 1316, 1278, 1182, 1064, 984,
851, 781, 658; ESI-HRMS: Calculated for C13H15NO4 [M+H]+ 250.1074, found 250.1050.
(vii) General procedures for synthesis of anilides:
Synthesis of anilides and pivalamides33
In a round bottom flask, the substituted aniline was taken under a nitrogen atmosphere and
o
cooled to 0 C. Ac2O (or PivOCl) was added drop-wise with stirring. The reaction mixture
was allowed to warm to room temperature and stirred till the reaction was complete. The
reaction mixture was then diluted with DCM and quenched with saturated solution of
NaHCO3 and the resulting mixture was extracted twice with CH2Cl2.The combined organic
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layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated
under vacuum. The crude product was purified by silica gel column chromatography.
7
8
(1)
N-phenylacetamide(3a):
9
Prepared according to the general procedure and the title compound was isolated as a white
solid (98% yield). Spectral data obtained were in good agreement with those reported in the
literature.34
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(2)
N-(p-tolyl)acetamide(3b):
Prepared according to the general procedure and the title compound was isolated as a white
solid (97% yield). Spectral data obtained were in good agreement with those reported in the
literature.35
(3)
N-(4-nitrophenyl)acetamide(3c):
Prepared according to the general procedure and the title compound was isolated as a pale
yellow solid (93% yield). Spectral data obtained were in good agreement with those reported
in the literature.36
(4)
N-(naphthalen-2-yl)acetamide(3d):
Prepared according to the general procedure and the title compound was isolated as a pale
brown solid (86% yield). Spectral data obtained were in good agreement with those reported
in the literature.37
(5)
N-(quinolin-6-yl)acetamide(3e):
Prepared according to the general procedure and the title compound was isolated as a pale
brown solid (81% yield). Spectral data obtained were in good agreement with those reported
in the literature.38
(6)
N-(naphthalen-1-yl)acetamide(3f):
Prepared according to the general procedure and the title compound was isolated as a purple
solid (91% yield). Spectral data obtained were in good agreement with those reported in the
literature.39
(7)
N-(3-fluorophenyl)acetamide(3g):
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7
8
Prepared according to the general procedure and the title compound was isolated as a off-
white solid (84% yield). Spectral data obtained were in good agreement with those reported
in the literature.40
9
(8) N-(2-fluorophenyl)acetamide(3h):
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60
Prepared according to the general procedure and the title compound was isolated as a off-
white solid (81% yield). Spectral data obtained were in good agreement with those reported
in the literature.41
(9) N-(p-tolyl)pivalamide(3i):
Prepared according to the general procedure and the title compound was isolated as a purple
solid (91% yield). Spectral data obtained were in good agreement with those reported in the
literature.42
(viii) General procedure for the synthesis of N-arylbenzamides:
In a two-neck round-bottomed flask, oxalyl chloride (1.2 equiv) was added dropwise into the
o
stirring solution of the benzoic acid (1 equiv) in CH2Cl2 at 0 C. This was followed by
addition of DMF (2 drops). The reaction mixture was allowed to warm to room temperature
o
and stirred for another 1.5 h and then re-cooled to 0 C. Et3N (3 equiv) and aniline (1.05
equiv) were added. The reaction mixture was once again allowed to warm to room
temperature and stirred for a further 6 h. The reaction was quenched at room temperature
with a saturated solution of NaHCO3 and the resulting mixture was extracted twice with
CH2Cl2. The combined organic layer was washed with brine and dried over anhydrous
Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica
gel column chromatography .
(1)
N-(p-tolyl)benzamide(3j):
Prepared according to the general procedure and the title compound was isolated as white
solid (89% yield). Spectral data obtained were in good agreement with those reported in the
literature.43
(2)
4-methyl-N-(p-tolyl)benzamide(3k):
Prepared according to the general procedure and the title compound was isolated as white
solid (86% yield). Spectral data obtained were in good agreement with those reported in the
literature.44
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(3)
4-methyl-N-phenylbenzamide(3l):
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9
Prepared according to the general procedure and the title compound was isolated as white
solid (91% yield). Spectral data obtained were in good agreement with those reported in the
literature.45
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(ix) General procedure for the Pd-catalyzed ortho-C-H halogenation reaction:
In a pressure tube equipped with a stir bar, the substrate (0.303 mmol) in dry dichloroethane
(1.5 mL) was taken. The solution was degassed with nitrogen for about 10 min, followed by
the addition of Pd(OAc)2 (0.03 mmol), Cu(OTf)2 (0.151 mmol) and the N-halosuccinimide
(0.606 mmol). The tube was fitted with a Teflon screw cap under nitrogen flow and the
o
reaction mixture was heated to 80 C and stirred at that temperature. The progress was
followed either by GCMS or by TLC. Upon completion of the reaction and subsequent
cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered
through a short pad of Celite, and the filtrate was washed with brine. The organic layer was
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the crude
product was purified by silica gel flash column chromatography.
2-(2-Bromophenyl)acetonitrile(4a)
Yield: 71% (59 mg), Physical appearance: Yellow gel, TLC Rf 0.30 (19:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.7 Hz,
13
1H), 7.38 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 3.83 (s, 2H); C NMR (100 MHz,
CDCl3): δ 133.1, 129.9, 129.7, 128.2, 123.6, 116.2, 24.9; IR (KBr, cm-1): 3063, 2928, 2252,
1571, 1472, 1441, 1413, 1194, 1120, 1028, 951, 817, 752, 661, 427; APCI-HRMS:
Calculated for C8H7BrN [M+H]+ 195.9846 and 197.9834, found 195.9846 and 197.9834.
2-(2-Iodophenyl)acetonitrile(4b)
Yield: 62% (65 mg), Physical appearance: Pale yellow gel, TLC Rf 0.30 (19:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.9 Hz,
13
1H), 7.39 (t, J = 7.9 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 3.80 (s, 2H); C NMR (100 MHz,
CDCl3): δ 139.8, 133.3, 129.9, 129.1, 129.0, 117.1, 99.0, 30.0; IR (KBr, cm-1): 2961, 2352,
1462, 1407, 1245, 1184, 1065, 800, 657; APCI-HRMS: Calculated for C8H5I N [M-H]-
241.9461, found 241.9489.
Methyl 3-bromo-4-(cyanomethyl)benzoate(4c)
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Yield: 72% (78 mg), Physical appearance: Pale yellow semi-solid, M. p. less than 40 oC, TLC
Rf 0.30 (9:1, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 8.04 (d, J
= 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 165.1, 134.6, 134.1, 131.9, 129.6, 129.1, 123.5, 116.2, 52.6, 25.1; IR (KBr, cm-1):
2953, 2916, 2847, 2361, 1728, 1605, 1562, 1435, 1292, 1260, 1194, 1119, 1042, 972, 758;
APCI-HRMS: Calculated for C10H7BrNO2 [M-H]- 251.9655 and 253.9635, found 251.9648
and 253.9624.
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2-(2-Bromonaphthalen-1-yl)acetonitrile(4d)
Yield: 70% (51 mg), Physical appearance: Brownish gel, TLC Rf 0.30 (9:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, DMSO-D6): δ 8.26-8.12 (m, 1H), 8.11-8.04 (m, 1H), 7.89
(d, J = 7.7 Hz, 1H), 7.79-7.63 (m, 2H), 7.50 (d, J = 7.7 Hz, 1H), 4.49 (s, 2H); 13C NMR (100
MHz, CDCl3): δ 132.4, 132.3, 131.9, 131.7, 131.1, 130.3, 128.9, 128.7, 128.5, 128.3, 128.1,
128.0, 127.9, 127.7, 127.6, 127.4, 124.8, 124.3, 123.2, 122.7, 119.3, 119.2, 21.2, 21; IR (KBr,
cm-1): 2918, 2340, 2253, 1595, 1506, 1414, 1379, 1198, 1039, 945, 893, 785, 667; APCI-
HRMS: Calculated for C12H8BrN [M]+ 244.9835 and 246.9814 found 244.9818 and
246.9797.
2-(2-Iodonaphthalen-1-yl)acetonitrile(4e)
o
Yield: 63% (55 mg), Physical appearance: Yellow solid, M. p. 77-81 C, TLC Rf 0.30 (9:1,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.20-8.02 (m, 2H), 7.86-7.73 (m,
1H), 7.65-7.50 (m, 1H), 7.26 (d, J = 7.6 Hz, 1H), 4.06 (s, 2H); 13C NMR (100 MHz, CDCl3):
δ 138.2, 137.1, 134.4, 133.6, 133.5, 131.3, 128.2, 128.0, 127.5, 127.4, 127.2, 126.9, 126.4,
123.3, 123.0, 117.4, 100.9, 100.7, 21.7, 21.7; IR (KBr, cm-1): 2975, 2353, 1601, 1572, 1431,
1380, 1211, 1020, 945, 900, 708; APCI-HRMS: Calculated for C12H7IN [M-H]+ 291.9618
found 291.9597.
2-(2,4-Dibromophenyl)acetonitrile(4f)
o
Yield: 61% (43 mg), Physical appearance: White solid, M. p. 59-60 C, TLC Rf 0.30 (9:1,
Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 1.9 Hz, 1H), 7.49 (dd, J
13
= 8.3, 1.9 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 3.78 (s, 2H); C NMR (100 MHz, CDCl3): δ
135.5, 131.4, 130.7, 129.0, 124.2, 116.4, 24.5; IR (KBr, cm-1): 2924, 2389, 2313, 2249, 1578,
1406, 1377, 1088, 1038, 926, 816, 704; APCI-HRMS: Calculated for C8H4Br2N [M-H]-
271.8707, 273.8685 and 275.8664 found 271.8702, 273.8687 and 275.8662.
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2-(4-Bromo-2-iodophenyl)acetonitrile(4g)
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6
7
8
o
Yield: 58% (49 mg), Physical appearance: White solid, M. p. 88-91 C, TLC Rf 0.30 (9:1,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.52 (d, J = 8.2 Hz,
9
13
1H), 7.38 (d, J = 8.2 Hz, 1H), 3.75 (s, 2H); C NMR (100 MHz, CDCl3): δ 141.7, 132.4,
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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34
35
36
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131.2, 130.0, 122.7, 116.7, 99.4, 29.5; IR (KBr, cm-1): 2963, 2332, 1464, 1400, 1261, 1085,
1024, 800, 687; APCI-HRMS: Calculated for C8H4BrIN [M-H]- 319.8566 and 321.8546,
found 319.8590 and 321.8560.
2-(2-Bromo-3-chlorophenyl)acetonitrile(4h)
o
Yield: 47% (36 mg), Physical appearance: White solid, M. p. 92-93 C, TLC Rf 0.30 (19:1,
Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.53-7.51 (m, 2H), 7.20 (dd, J = 8.5,
13
2.4 Hz, 1H), 3.80 (s, 2H); C NMR (100 MHz, CDCl3): δ 134.3, 134.1, 131.6, 129.7, 121.4,
116.2, 24.8; IR (KBr, cm-1): 2937, 2914, 2369, 2246, 1649, 1457, 1403, 1095, 1029, 931,
856, 824; APCI-HRMS: Calculated for C8H4ClBrN [M-H]- 227.9210 and 229.9189, found
227.9215 and 229.9184.
2-(5-Chloro-2-iodophenyl)acetonitrile(4i)
o
Yield: 53% (49 mg), Physical appearance: White solid, M. p. 89-94 C, TLC Rf 0.30 (19:1,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 1H), 7.51 (d, J
13
= 2.4 Hz, 1H), 7.03 (dd, J = 8.4, 2.4 Hz, 1H), 3.77 (s, 2H); C NMR (100 MHz, CDCl3): δ
140.7, 135.4, 135.0, 130.2, 129.2, 116.5, 96.0, 29.8; IR (KBr, cm-1): 2359, 2334, 1643, 1452,
1397, 1259, 1093, 1012, 818, 740; APCI-HRMS: Calculated for C8H4ClIN [M-H]- 275.9071,
found 275.9054.
Methyl 4-bromo-3-(cyanomethyl)benzoate(4j)
o
Yield: 52% (38 mg), Physical appearance: White solid, M. p. 88-90 C, TLC Rf 0.30 (9:1,
Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 1.7 Hz, 1H), 7.87 (dd, J
= 8.3, 1.9 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 165.7, 133.4, 130.8, 130.7, 130.5, 130.3, 129.0, 116.3, 52.3, 24.9; IR (KBr, cm-1):
2360, 2330, 1718, 1303, 1256, 1195, 1109, 1032, 758; APCI-HRMS: Calculated for
C10H7BrNO2 [M-H]- 251.9655and 253.9635, found 251.9632 and 253.9601.
2-(3-Bromo-4-methoxyphenyl)acetonitrile(4k)
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o
Yield: 72% (55 mg), Physical appearance: Yellow solid, M. p. 45-47 C, TLC Rf 0.30 (9:1,
Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 2.1 Hz, 1H), 7.22 (dd, J
= 8.4, 2.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 3.87 (s, 3H ), 3.65 (s, 2H); 13C NMR (100 MHz,
CDCl3): δ 155.8, 132.8, 128.1, 123.2, 117.6, 112.3, 112.2, 56.4, 22.4; IR (KBr, cm-1): 2963,
2839, 2251, 1603, 1501, 1462, 1414, 1285, 1259, 1184, 2153, 1055, 1020, 923, 856, 803,
754, 675; APCI-HRMS: Calculated for C9H7BrNO [M-H]- 223.9706 and 225.9685, found
223.9712 and 225.9698.
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60
2-(3-Iodo-4-methoxyphenyl)acetonitrile(4l)
o
Yield: 68% (63 mg), Physical appearance: greenish-yellow solid, M. p. 59-61 C, TLC Rf
1
0.30 (9:1, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 2.1 Hz, 1H),
7.25 (dd, J = 8.6, 1.9 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 3.86 (s, 3H ), 3.64 (s, 2H); 13C NMR
(100 MHz, CDCl3): δ 158.0, 138.8, 129.1, 123.7, 117.7, 111.1, 86.4, 56.5, 22.2; IR (KBr, cm-
1): 2247, 1599, 1489, 1260, 1094, 1047, 1018, 802; APCI-HRMS: Calculated for C9H7INO
[M-H]- 271.9567, found 271.9563.
2-(3-bromo-4-iodophenyl)acetonitrile(4m)
Yield: 58% (38 mg), Physical appearance: Yellow gel, TLC Rf 0.30 (9:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 6.97 (d,
13
J = 8.2 Hz, 1H), 3.67 (s, 2H); C NMR (100 MHz, CDCl3): δ 140.9, 132.1, 131.7, 130.6,
128.0, 116.7, 100.8, 22.9; APCI-HRMS: Calculated for C8H4BrIN [M-H]- 319.8566 and
321.8546, found 319.8548 and 321.8516.
2-Bromo-N-methoxy-N-methylbenzamide(5a)
Yield: 81% (60 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 1H), 7.39-7.19 (m, 3H),
4.19-2.88 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 169.1, 137.5, 132.5, 130.3, 127.6, 127.0,
119.3, 61.3, 32.3; IR (KBr, cm-1): 3459, 2098, 1644, 982, 767, 741, 662; ESI-HRMS:
Calculated for C9H11BrNO2 [M+H]+ 243.9968 and 245.9947, found 243.9964 and 245.9947.
2-Iodo-N-methoxy-N-methylbenzamide(5b)
Yield: 68% (60 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 7.3 Hz,
13
1H), 7.27-7.20 (m, 1H), 7.07 (td, J = 7.8, 1.5 Hz, 1H), 4.31-2.84 ( m, 6H); C NMR (100
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MHz, CDCl3): δ 138.9, 133.4, 130.3, 128.4, 127.6, 127.2, 92.5, 61.4, 32.6; IR (KBr, cm-1):
3475, 2091, 1645, 1420, 1385, 1263, 1215, 1176, 1115, 1674, 1016, 984, 886, 769, 653; ESI-
HRMS: Calculated for C9H11INO2 [M+H]+ 291.9829, found 291.9849.
3
4
5
6
7
8
9
2-Chloro-N-methoxy-N-methylbenzamide(5c)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield: 62% (37 mg), Physical appearance: Colourless gel, TLC Rf 0.40 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.39-7.37 (m, 1H), 7.35-7.26 (m, 3H), 4.17-
2.87 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 168.5, 135.2, 130.7, 130.2, 129.5, 127.6,
126.5, 61.3, 32.3; IR (KBr, cm-1): 3484, 2098, 1646, 1437, 1386, 1267, 1214, 1175, 1128,
1080, 1048, 986, 889, 768, 743, 678, 576; ESI-HRMS: Calculated for C9H11ClNO2 [M+H]+
200.0473, found 200.0497.
2-Bromo-4-(tert-butyl)-N-methoxy-N-methylbenzamide(5d)
Yield: 68% (46 mg), Physical appearance: Yellow gel, TLC Rf 0.30 (4:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.54 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.21 (d,
J = 8.0 Hz, 1H), 4.10-2.84 (m, 6H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 154.0,
137.5, 130.2, 129.7, 127.5, 124.2, 119.2, 61.4, 34.9, 32.3, 31.1; IR (KBr, cm-1): 3449, 2966,
2246, 1652, 1602, 1547, 1417, 1383, 1277, 1259, 1175, 1113, 1037, 987, 881, 832, 750, 677,
660; ESI-HRMS: Calculated for C13H19BrNO2 [M+H]+ 300.0594 and 302.0574, found
300.0614 and 302.0595.
2-Iodo-4-(tert-butyl)-N-methoxy-N-methylbenzamide(5e)
o
Yield: 71% (56 mg), Physical appearance: Pale yellow solid, M. p. 46-47 C, TLC Rf 0.30
1
(4:1, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.36 (d, J = 8.0
Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.34-2.79 (m, 6H), 1.28 (s, 9H); 13C NMR (100 MHz,
CDCl3): δ 154.0, 138.5, 136.2, 128.1, 126.9, 124.9, 92.6, 61.4, 34.7, 32.6, 31.1; IR (KBr, cm-
1): 3448, 1646, 1261, 985, 884, 833, 748; ESI-HRMS: Calculated for C13H19INO2 [M+H]+
348.0455, found 348.0477.
2-Chloro-4-(tert-butyl)-N-methoxy-N-methylbenzamide(5f)
Yield: 73% (42 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.29-7.16 (m, 2H), 4.28-2.57 (m,
13
6H), 1.25 (s, 9H); C NMR (100 MHz, CDCl3): δ 154.1, 132.1, 130.3, 127.4, 126.6, 123.7,
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61.9, 34.9, 32.3, 31.3; IR (KBr, cm-1): 3431, 2092, 1638, 748, 438; ESI-HRMS: Calculated
for C13H19ClNO2 [M+H]+ 256.1099, found 256.1090.
3
4
5
6
7
8
2-Bromo-N-methoxy-N,4-dimethylbenzamide(5g)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield: 83% (59 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.09 (d,
J = 7.8 Hz, 1H), 4.18-2.86 (m, 6H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.4,
140.8, 134.4, 133.0, 127.7, 127.5, 119.1, 61.3, 32.3, 21.0; IR (KBr, cm-1): 3457, 2093, 1645,
814, 747, 676, 583; ESI-HRMS: Calculated for C10H13BrNO2 [M+H]+ 258.0124 and
260.0104, found 258.0131 and 260.0113.
2-Iodo-N-methoxy-N,4-dimethylbenzamide(5h)
Yield: 58% (49 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.27 (d,
J = 8.0 Hz, 1H), 3.57 (s, 3H), 3.36 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
167.7, 144.2, 138.7, 133.1, 129.1, 128.1, 100.2, 61.1, 33.7, 28.1; IR (KBr, cm-1): 3464, 2934,
1637, 1380, 1210, 1069, 1034, 980, 898, 832, 807, 743, 660; ESI-HRMS: Calculated for
C10H13INO2 [M+H]+ 305.9985, found 305.9982.
2-Chloro-N-methoxy-N,4-dimethylbenzamide(5i)
Yield: 51% (30 mg), Physical appearance: Pale yellow gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.21-7.13 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H),
13
3.54-3.11 (s, 6H), 2.30 (s, 3H); C NMR (100 MHz, CDCl3): δ 170.0, 140.7, 130.4, 129.9,
128.6, 128.3, 127.6, 61.3, 32.3, 21.1; IR (KBr, cm-1): 3464, 2938, 1652, 1418, 1386, 1270,
1173, 1117, 1081, 1045, 986, 901, 856, 749, 688; ESI-HRMS: Calculated for C10H13ClNO2
[M+H]+ 214.0629, found 214.0658.
2-Bromo-4-fluoro-N-methoxy-N-methylbenzamide(5j)
Yield: 68% (48 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.30-7.24 (m, 2H), 7.09-6.98 (m, 1H), 4.33-
2.58 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 168.4, 162.4 (d, J = 252.2 Hz, 1C), 133.5,
130.8 (d, J = 8.6 Hz, 1C), 129.0, 120.1 (d, J = 9.6 Hz, 1C), 114.8 (d, J = 53.0 Hz, 1C), 61.3,
32.4; IR (KBr, cm-1): 3484, 3090, 2975, 2938, 2084, 1651, 1600, 1420, 1385, 1264, 1203,
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1168, 1072, 986, 858, 748, 678; ESI-HRMS: Calculated for C9H10BrFNO2 [M+H]+ 261.9873
and 263.9853, found 261.9886 and 263.9863.
3
4
5
6
7
8
2-Iodo-4-fluoro-N-methoxy-N-methylbenzamide(5k)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield: 71% (60 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.55 (dd, J = 8.1, 2.4 Hz, 1H), 7.28-7.20 (m,
1H), 7.09 (td, J = 8.1, 2.3 Hz, 1H), 4.39-2.63 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 170.0,
162.0 (d, J = 249.9 Hz, 1C), 137.8, 129.5, 128.5, 126.2 (d, J = 23.2 Hz, 1C), 115.1 (d, J =
21.5 Hz, 1C), 93.4 (d, J = 8.1 Hz, 1C), 61.4, 32.6; IR (KBr, cm-1): 3479, 3086, 2936, 1652,
1592, 1418, 1264, 1222, 1071, 1030, 986, 851, 748, 584; ESI-HRMS: Calculated for
C9H10FINO2 [M+H]+ 309.9735, found 309.9756.
2,4-Dibromo-N-methoxy-N-methylbenzamide(5l)
Yield: 82% (54 mg), Physical appearance: Pale yellow gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.60-7.39 (m, 1H), 7.16 (d, J =
13
8.1 Hz, 1H), 4.44-2.74 (m, 6H); C NMR (100 MHz, CDCl3): δ 168.3, 135.1, 131.2, 130.3,
130.0, 128.8, 120.2, 61.5, 32.4; IR (KBr, cm-1): 3448, 1646, 1261, 983, 884, 833, 748; ESI-
HRMS: Calculated for C9H10Br2NO2 [M+H]+ 321.9073, 323.9053 and 325.9032, found
321.9074, 323.9061 and 325.9041.
4-Bromo-2-iodo-N-methoxy-N-methylbenzamide(5m)
Yield: 69% (52 mg), Physical appearance: Pale yellow gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.65-7.41 (m, 3H), 4.09-2.90 (m, 6H); 13C
NMR (100 MHz, CDCl3): δ 168.7, 141.0, 132.8, 131.2, 130.0, 125.1, 93.1, 61.1, 33.5; IR
(KBr, cm-1): 3489, 2971, 2935, 2096, 1644, 1589, 1573, 1456, 1417, 1382, 1214, 1177, 1111,
1072, 981, 887, 836, 744; ESI-HRMS: Calculated for C9H10BrNO2I [M+H]+ 369.8934 and
371.8914, found 369.8938 and 371.8913.
2-Bromo-4-chloro-N-methoxy-N-methylbenzamide(5n)
Yield: 62% (43 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 7.40-7.13 (m, 2H), 4.04-2.96 (m,
13
6H); C NMR (100 MHz, CDCl3): δ 168.2, 135.9, 135.5, 132.4, 128.5, 127.4, 120.0, 61.5,
32.3; IR (KBr, cm-1): 3450, 2067, 1647, 1213, 1037, 983, 824, 782, 673; ESI-HRMS:
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Calculated for C9H10BrClNO2[M+H]+ 277.9578 and 279.9557, found 277.9594 and
279.9579.
3
4
5
6
7
8
2-Iodo-4-chloro-N-methoxy-N-methylbenzamide(5o)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield: 62% (46 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 8.1 Hz,
13
1H), 7.21 (d, J = 8.1 Hz, 1H), 4.33-2.41 (m, 6H); C NMR (100 MHz, CDCl3): δ 169.7,
140.0, 138.5, 135.3, 128.8, 128.0, 92.7, 61.5, 32.6; IR (KBr, cm-1): 3432, 2098, 1638, 984,
826, 745; ESI-HRMS: Calculated for C9H10ClINO2 [M+H]+ 325.9439, found 325.9455.
2,4-Dichloro-N-methoxy-N-methylbenzamide(5p)
Yield: 49% (29 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (4:1, Petroleum
ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.33 (d,
J = 8.5 Hz, 1H), 4.36-2.78(m, 6H); 13C NMR (100 MHz, CDCl3): δ 168.6, 136.7, 132.4,
131.7, 129.5, 128.3, 61.1, 33.5; IR (KBr, cm-1): 3450, 2090, 1647, 1388, 1213, 1092, 984,
839, 801, 746; ESI-HRMS: Calculated for C9H10Cl2NO2 [M+H]+ 234.0083, found and
234.0086.
2-Bromo-N,3-dimethoxy-N-methylbenzamide(5q)
Yield: 64% (29 mg), Physical appearance: Pale yellow gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.8 Hz, 1H), 6.90-6.74 (m, 2H),
4.20-2.84 (m, 9H); 13C NMR (100 MHz, CDCl3): δ 158.5, 138.2, 133.4, 133.3, 116.4, 113.2,
109.6, 61.4, 55.6, 32.3; IR (KBr, cm-1): 3448, 2066, 1649, 1290, 1082, 1019, 825, 745, 601;
ESI-HRMS: Calculated for C10H13BrNO3 [M+H]+ 274.0073 and 276.0053, found 274.0063
and 276.0037.
Methyl (E)-3-(3-bromo-4-(methoxy(methyl)carbamoyl)phenyl)acrylate(5r)
o
Yield: 80% (42 mg), Physical appearance: White solid, M. p. 51-53 C, TLC Rf 0.30 (7:3,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.58 (d, J = 16.1 Hz),
7.46 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 6.43 (dd, J = 16.1, 1.5 Hz, 1H), 3.79 (d, J =
2.4 Hz, 3H), 3.64-3.04 (m, 6H);13C NMR (100 MHz, CDCl3): δ 168.5, 166.7, 142.3, 138.8,
136.7, 131.8, 128.1, 126.5, 120.1, 120.1, 61.5, 53.8; IR (KBr, cm-1): 2943, 2820, 2363, 1726,
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2
3
4
5
6
1650, 1433, 1385, 1317, 1296, 1110, 1175, 1078, 1037, 986, 833, 739, 677; ESI-HRMS:
Calculated for C13H15BrNO4 [M+H]+ 328.0179 and 330.0159, found 328.0198 and 330.0187.
7
8
Methyl (Z)-3-(4-(methoxy(methyl)carbamoyl)phenyl)acrylate(5s)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield: 80% (10 mg), Physical appearance: Colourless gel, TLC Rf 0.40 (7:3, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 1.4 Hz, 1H), 7.49-7.25 (m, 2H),
13
5.25 (d, J = 11.7 Hz, 1H), 4.37 (d, J = 11.7 Hz, 1H), 3.88 (s, 3H), 3.58-2.78 (m, 6H); C
NMR ( 100 MHz, CDCl3): δ 168.5, 166.7, 142.3, 138.8, 136.7, 131.8, 128.1, 126.5, 120.1,
120.0, 61.5, 53.8; IR (KBr, cm-1): 2943, 2820, 2363, 1726, 1650, 1433, 1385, 1317, 1296,
1110, 1175, 1078, 1037, 986, 833, 739, 677; ESI-HRMS: Calculated for C13H15BrNO4
[M+H]+ 328.0179 and 330.0159, found 328.0198 and 330.0187.
2-Bromo-N-methoxy-N-methyl-1-naphthamide(5t)
Yield: 74% (50 mg), Physical appearance: Colourless gel, TLC Rf 0.30 (3:2, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 7.8 Hz,
13
2H), 7.57-7.47 (m, 2H), 7.35-7.26 (m, 1H), 3.40 (s, 2H), 3.29 (s, 2H); C NMR (100 MHz,
CDCl3): δ 173.1, 135.3, 134.1, 132.9, 130.4, 128.8, 127.0, 126.5, 125.3, 119.3, 60.6, 34.0; IR
(KBr, cm-1): 2970, 2934, 2359, 1715, 1655, 1497, 1460, 1379, 1360, 1182, 1105, 1016, 978,
822, 768; ESI-HRMS: Calculated for C13H13BrNO2 [M+H]+ 294.0124 and 296.0104, found
294.0149 and 296.0124.
2,5-Dibromo-N,4-dimethoxy-N-methylbenzamide(5u)
Yield: 68% (61 mg), Physical appearance: Pale yellow gel, TLC Rf 0.30 (4:1, Petroleum
1
ether:EtOAc); H NMR (400 MHz, CDCl3): δ 7.48 (s, 1H), 7.05 (s, 1H), 3.90 (s, 3H), 3.65-
3.11 (m, 6H);13C NMR (100 MHz, CDCl3): δ 156.8, 132.1, 130.5, 119.1, 116.0, 61.3, 56.6,
29.7; IR (KBr, cm-1): 3591, 2940, 1658, 1579, 1424, 1362, 1268, 1246, 1183, 1107, 874, 830,
752, 651; ESI-HRMS: Calculated for C10H12Br2NO3 [M+H]+ 351.9178, 353.9162 and
355.9132 found 351.9179, 353.9174 and 355.9138.
N-(2-bromo-4-methylphenyl)acetamide(6a)
o
Yield: 83% (63 mg), Physical appearance: White solid, M. p. 88-89 C, TLC Rf 0.30 (3:2,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 8.3 Hz, 1H), 7.49 (s,
13
1H), 7.33 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 2.27 (s, 3H), 2.20 (s, 3H); C NMR (100 MHz,
CDCl3): δ 168.1, 135.2, 133.2, 129.0, 121.9, 113.2, 24.8, 20.5; IR (KBr, cm-1): 3277, 2355,
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2325, 1650, 1292, 1042, 821, 680; ESI-HRMS: Calculated for C9H11BrNO [M+H]+ 228.0019
and 229.9998, found 228.0035 and 230.0013.
3
4
5
6
7
8
N-(2-bromo-4-methylphenyl)pivalamide(6b)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
Yield: 83% (58 mg), Physical appearance: White solid, M. p. 49-51 C, TLC Rf 0.40 (9:1,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.4 Hz, 1H), 7.89 (s,
13
1H), 7.09 (d, J = 8.4 Hz, 1H), 2.27 (s, 3H), 1.33 (s, 9H); C NMR (100 MHz, CDCl3): δ
176.5, 134.9, 133.3, 132.3, 129.0, 121.5, 113.5, 40.1, 27.6, 20.5; IR (KBr, cm-1): 3318, 2970,
2351, 1650, 1517, 1169, 1040, 809, 737, 601; ESI-HRMS: Calculated for C12H17BrNO
[M+H]+ 270.0488 and 272.0468, found 270.0517 and 272.0495.
N-(2-iodo-4-methylphenyl)pivalamide(6c)
Yield: 81% (67 mg), Physical appearance: Greenish solid, M. p. 52-55 oC, TLC Rf 0.40 (9:1,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.1 Hz, 1H), 7.71 (s,
13
1H), 7.60 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 2.20 (s, 3H), 1.37 (s, 9H); C NMR (100 MHz,
CDCl3): δ 176.6, 138.8, 135.9, 135.6, 129.9, 121.6, 40.0, 27.7, 20.3; IR (KBr, cm-1): 3402,
2960, 1681, 1600, 1506, 1395, 1295, 1158, 1037, 920, 870, 768, 542, 438; ESI-HRMS:
Calculated for C12H17INO [M+H]+ 318.0349, found 318.0365.
N-(2-chloro-4-methylphenyl)pivalamide(6d)
o
Yield: 58% (34 mg), Physical appearance: White solid, M. p. 52-55 C, TLC Rf 0.40 (9:1,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.4 Hz, 1H), 7.92 (s,
13
1H), 7.07 (d, J = 8.4 Hz, 1H), 2.30 (s, 3H), 1.35 (s, 9H); C NMR (100 MHz, CDCl3): δ
176.5, 134.4, 132.2, 129.1, 128.3, 122.8, 121.4, 40.1, 27.6, 20.6; IR (KBr, cm-1): 3317, 2957,
2356, 1658, 1509, 1492, 1398, 1248, 1176, 1056, 937, 890, 865, 841, 815, 777, 687; ESI-
HRMS: Calculated for C12H17NOCl [M+H]+ 226.0993, found 226.1019.
N-(2-bromonaphthalen-1-yl)acetamide(6e)
Yield: 82% (58 mg), Physical appearance: White solid, M. p. 170-174 oC, TLC Rf 0.30 (3:2,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CD3OD): δ 8.25-8.20 (m, 1H), 8.04-8.01 (m,
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1H), 7.79 (d, J = 8.0 Hz, 1H), 7.67-7.56 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 2.26 (s, 3H); C
NMR (100 MHz, CD3OD): δ 171.5, 133.2, 132.5, 132.1, 131.8, 131.4, 129.2, 128.9, 128.1,
127.9, 127.2, 126.3, 123.8, 123.0, 122.0, 120.5, 120.0, 21.2; IR (KBr, cm-1): 2334, 1647,
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1373, 1116, 754, 677; ESI-HRMS: Calculated for C12H11BrNO [M+H]+ 264.0019 and
265.9998, found 264.0016 and 265.9995.
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N-(2-bromophenyl)acetamide(6f)
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Prepared according to the general procedure and the title compound was isolated as a white
solid (79% (62 mg) yield). Spectral data obtained were in agreement with those reported in
the literature.46
N-(2-bromo-5-fluorophenyl)acetamide and N-(2-bromo-3-fluorophenyl)acetamide(6g)
Prepared according to the general procedure and the title compounds were isolated as a white
solid (mixture of isomers, 77% (59 mg) yield). Spectral data obtained were in good
agreement with those reported in the literature.11b
N-(1-bromonaphthalen-2-yl)acetamide(6h)
o
Yield: 78% (54 mg), Physical appearance: Off-white solid, M. p. 103-107 C, TLC Rf 0.30
(2:3, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 8.6 Hz, 1H), 8.13
(d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.43 (t, J
= 7.3 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.5, 134.3, 131.9, 131.6,
128.3, 128.2, 127.7, 126.6, 125.6, 121.0, 111.7, 24.9; IR (KBr, cm-1): 3268, 2355, 2329,
1664, 1519, 1290, 1018, 811, 747, 668; ESI-HRMS: Calculated for C12H11BrNO [M+H]+
264.0019 and 265.9998, found 264.0021 and 266.0000.
N-(7-bromoquinolin-6-yl)acetamide(6i)
o
Yield: 72% (51 mg), Physical appearance: White solid, M. p. 123-125 C, TLC Rf 0.30 (2:3,
1
Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.85 (d, J = 3.2 Hz, 1H), 8.69 (d, J
= 8.6 Hz, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.53-7.40 (m,
13
1H), 2.30 (s, 3H); C NMR (100 MHz, CDCl3): δ 177.3, 168.5, 149.7, 145.9, 143.0, 135.0,
129.7, 127.6, 124.3, 122.5, 29.6; IR (KBr, cm-1): 3271, 2963, 2335, 1707, 1670, 1518, 1437,
1335, 1277, 1186, 934, 808; ESI-HRMS: Calculated for C11H10BrN2O [M+H]+ 264.9971 and
266.9951, found 264.9966 and 266.9945.
N-(2-bromo-4-nitrophenyl)acetamide(6j)
o
Yield: 72% (51 mg), Physical appearance: Pale-yellow solid, M. p. 88-89 C, TLC Rf 0.30
(3:2, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.63 (d, J = 9.2 Hz, 1H), 8.42
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(s, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.88 (s, 1H), 2.29 (s, 3H); C NMR (100 MHz, CDCl3): δ
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168.5, 143.2, 141.4, 127.9, 124.2, 120.2, 111.9, 25.1; IR (KBr, cm-1): 3292, 3099, 1672,
1587, 1538, 1505, 1389, 1348, 1308, 1278, 1139, 1118, 1041, 903, 831, 746, 633, 591, 443;
ESI-HRMS: Calculated for C8H8BrN2O3 [M+H]+ 258.9713 and 260.9693, found 258.9732
and 260.9720.
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N-(2-Iodo-4-nitrophenyl)acetamide(6k)
Yield: 69% (58 mg), Physical appearance: Pale yellow solid, M. p. 109-112 oC, TLC Rf 0.30
(3:2, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 2.5 Hz, 1H), 8.49
13
(d, J = 9.2 Hz, 1H), 8.18 (dd, J = 9.2 Hz, 2.5 Hz, 1H), 7.72 (s, 1H), 2.28 (s, 3H); C NMR
(100 MHz, CDCl3): δ 168.5, 143.8, 143.4, 134.2, 124.9, 119.8, 87.3, 25.1; IR (KBr, cm-1):
3393, 2365, 2330, 1649, 1263, 1031, 743; ESI-HRMS: Calculated for C8H8IN2O3 [M+H]+
306.9574, found 306.9592.
N-(2-bromo-6-fluorophenyl)acetamide(6l)
Prepared according to the general procedure and the title compound was isolated as a white
solid (67% (50 mg) yield). Spectral data obtained were in good agreement with those
reported in the literature.11b
N-(2-bromo-4-methylphenyl)benzamide(6m)
Prepared according to the general procedure and the title compound was isolated as a white
solid (52% (18 mg) isolated yield, 81% yield based on recovered starting material). Spectral
data obtained were in good agreement with those reported in the literature.47
N-(2-bromo-4-methylphenyl)-4-methylbenzamide(6n)
Prepared according to the general procedure and the title compound was isolated as a white
solid (48% (16 mg) isolated yield, 92% yield based on recovered starting material). M. p. 80-
85oC, TLC Rf 0.40(4:1, Petroleum ether:EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.38 (d, J =
8.4 Hz, 1H), 8.33 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.38 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H),
13
7.15 (d, J = 8.4 Hz, 1H), 2.43 (s,3H), 2.31 (s, 3H); C NMR (100 MHz, CDCl3): δ 165.1,
142.7, 135.2, 133.4, 132.5, 131.9, 129.6, 129.1, 127.1, 113.6, 21.5, 20.6; IR (KBr, cm-1):
3303, 2386, 2352, 1650, 1301, 1075, 698; ESI-HRMS: Calculated for C15H15BrNO[M+H]+
304.0332 and 306.0312, found 304.0334 and 306.0306.
N-(2-bromophenyl)-4-methylbenzamide(6o)
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Prepared according to the general procedure and the title compound was isolated as a white
solid (56% (19 mg)isolated yield, 94% yield based on recovered starting material). M. p. 61-
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64oC, TLC Rf 0.40(4:1, Petroleum ether:EtOAc); H NMR (400 MHz, CDCl3): δ 8.54 (dd, J
= 8.3, 1.3 Hz, 1H), 8.43 (s, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.55 (dd, J = 8.3, 1.3 Hz, 1H), 7.35
(t, J = 8.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 6.99 (td, J = 8.3, 1.3 Hz, 1H), 2.42 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 165.2, 142.8, 136.0, 132.2, 131.8, 129.6, 128.5, 127.1, 125.1,
121.7, 113.7, 21.5; IR (KBr, cm-1): 3346, 2403, 2358, 1665, 1281, 1026, 800; ESI-HRMS:
Calculated for C14H13BrNO[M+H]+ 290.0175 and 292.0155, found 290.0170 and 292.0149.
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(IX) Synthetic Utility:
i)
Synthesis of methyl (E)-3-(5-bromo-2-
(methoxy(methyl)carbamoyl)phenyl)acrylate(8):
In a pressure tube equipped with a stir bar, the substrate (0.081 mmol) was dissolved in dry
dimethylformamide (0.5 mL). The solution was degassed with nitrogen for about 10 min,
followed by the addition of Pd(OAc)2 (0.004 mmol), PPh3 (0.008 mmol), K2CO3 (0.243
mmol) and the methylacrylate (0.01 mmol). The tube was fitted with a Teflon screw cap
under nitrogen flow. The reaction mixture was heated to 80 oC and stirred at that temperature.
The reaction was followed either by GCMS or by TLC. Upon completion of the reaction and
cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered
through a short pad of Celite. The organic filtrate was washed with water and brine and dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure and the crude
product was purified by silica gel column chromatography. Pure product was isolated as
colourless gel (77% (21 mg)yield). TLC Rf 0.30(4:1, Petroleum ether:EtOAc); 1H NMR (400
MHz, CDCl3): δ 7.80 (d, J = 1.7 Hz, 1H), 7.68 (d, J = 15.9 Hz, 1H), 7.55 (dd, J = 8.2, 1.7 Hz,
1H), 7.37 and 7.29 (d, J = 4.6 Hz, 1H), 3.81 (s, 3H), 3.63-3.13 (m, 6H); 13C NMR (100 MHz,
CDCl3): δ 166.5, 140.1, 134.6, 133.9, 132.5, 129.4, 128.9, 128.5, 127.6, 127.0, 121.4, 61.3,
53.4, 51.9; IR (KBr, cm-1): 3598, 3472, 3103, 2936, 2369, 1932, 1699, 1680, 1501, 1471,
1229, 1184, 743; ESI-HRMS: Calculated for C13H15BrNO4[M+H]+ 328.0179and 330.0159,
found 328.0180 and 330.0175.
ii)
Synthesis of methyl (E)-3-(4'-methoxy-4-(methoxy(methyl)carbamoyl)-[1,1'-
biphenyl]-3-yl)acrylate(9):
In a RB flask, the substrate (0.06 mmol) was dissolved in IPA-H2O mixture (0.6 mL, 1:1).
This was followed by the addition of Pd(OAc)2 (4 mol), 4-aminobenzoic acid (8 mol),
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