Synthesis of various acylating agents directly from carboxylic acids

Article abstract of DOI:10.1080/00397911.2020.1747631

A straightforward synthesis of acylating reagents such as Weinreb and MAP amides from aromatic, aliphatic carboxylic acids, and amino acids using PPh₃/NBS combination is described. A chemo-selective modification of the carboxylic acid group into Weinreb amide in the presence of more reactive aldehydes and ketones is presented. All reactions were performed at ambient temperature under air using undried commercial grade solvent. Furthermore, the present methodology could be performed at a gram scale under inert-free reaction conditions. In addition, 7-azaindoline amide auxiliary (used for catalytic asymmetric aldol- and Mannich-type reactions), which behaves like Weinreb amide is also synthesized under similar reaction conditions.

Full text of DOI:10.1080/00397911.2020.1747631

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of various acylating agents directly from
carboxylic acids
Fathima Pilathottathil, Doppalapudi Vineet Kumar & Alagiri Kaliyamoorthy
To cite this article: Fathima Pilathottathil, Doppalapudi Vineet Kumar & Alagiri Kaliyamoorthy
(2020): Synthesis of various acylating agents directly from carboxylic acids, Synthetic
Communications, DOI: 10.1080/00397911.2020.1747631
To link to this article: https://doi.org/10.1080/00397911.2020.1747631
View supplementary material
Published online: 14 Apr 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1747631
Synthesis of various acylating agents directly from
carboxylic acids
ꢀ
ꢀ
Fathima Pilathottathil , Doppalapudi Vineet Kumar , and Alagiri Kaliyamoorthy
School of Chemistry, Indian Institute of Science Education and Research, Thiruvananthapuram, India
ABSTRACT
ARTICLE HISTORY
Received 13 February 2020
A straightforward synthesis of acylating reagents such as Weinreb
and MAP amides from aromatic, aliphatic carboxylic acids, and amino
acids using PPh3/NBS combination is described. A chemo-selective
modification of the carboxylic acid group into Weinreb amide in the
presence of more reactive aldehydes and ketones is presented. All
reactions were performed at ambient temperature under air using
undried commercial grade solvent. Furthermore, the present meth-
odology could be performed at a gram scale under inert-free reac-
tion conditions. In addition, 7-azaindoline amide auxiliary (used for
catalytic asymmetric aldol- and Mannich-type reactions), which
behaves like Weinreb amide is also synthesized under similar reac-
tion conditions.
KEYWORDS
MAP amide; Meyers and
Comins amide; N-methoxy-
N-methylamide; N-
methylaminopyridine amide;
Weinreb amide
GRAPHICAL ABSTRACT
OMe
HN
Me
O
HCl
Me
N
H
N
R
O
O
OH
II
I
OMe
R
R1
R
N
N
Me
N
DMAP
+
R1 Me
R1
PPh3, NBS
Et3N
R = H, alkyl, aryl
R1= H, alkyl, aryl
NHFmoc
up to 97% yield
34 examples
R = H, alkyl, aryl
R1= H, alkyl, aryl
up to 86% yield
5 examples
N
H
N
III
O
N
R
N
R1
R = H, alkyl, aryl
R1= H, alkyl, aryl
up to 75% yield
5 examples
Introduction
Carbonyl functionality such as aldehyde and ketone is of the highest importance and
pervasive in several natural products and biologically active compounds. Also, they are
CONTACT Alagiri Kaliyamoorthy
alagiri@iisertvm.ac.in
School of Chemistry, Indian Institute of Science Education
and Research, Thiruvananthapuram, Kerala 695551, India.
ꢀ
These authors contributed equally to this work.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
F. PILATHOTTATHIL ET AL.
the central functionality in numerous organic synthesis due to their ease of chemical
manipulations to various functional groups. The realization of carbonyl compounds dir-
ectly from carboxylic acid derivatives through the addition of organometallic reagents
or metal-hydrides is a highly demanding task and it often leads to over-addition of such
reagents. To circumvent the excessive addition of organometallic reagents during the
selective acylation process, Nahm and Weinreb devised the specific class of acylating
reagents such as N-methoxy-N-methylamide (also termed as Weinreb amide),[1] which
provides an easy access to a wide range of carbonyl compounds. Organometallic
reagents like Grignard and organolithium reagents and metal-hydrides react with
Weinreb amide to furnish ketones and aldehydes, respectively. Alternatively, aldehydes
and ketones were accomplished through the Wittig reaction between phosphoranes and
Weinreb amides.[2] Commonly, Weinreb amides are synthesized from acid chlorides,[1,3]
anhydrides,[4] lactones,[5] esters,[6] amides,[7] and aryl halides/triflates.[8] Besides, plenty
of efforts have been invested toward the synthesis of Weinreb amides directly from car-
boxylic acids in the presence of peptide coupling reagents,[9] CBr4/PPh3/pyridine,[10a]
Cl3CCN/PPh3/Et3N,[10b] SOCl2,[10c] TiCl4,[10d] 1-methylpyridinium iodide derivatives,[11]
methanesulfonyl chloride,[12] and Deoxo-Fluor reagent.[13] Furthermore, a straightfor-
ward conversion of carboxylic acids to N-methoxy-N-methylamides was reported using
P[NMe(OMe)]3 as the stoichiometric amidating agent (Scheme 1A).[14]
Meyers and Comins amide, also called MAP (N-methylamino)pyridine amide is one
the important acylating reagents among the plethora of reagents developed for the
introduction of carbonyl functionality.[15] The characteristic feature of MAP amide is
that the presence of pyridine nitrogen makes the MAP amides to display reactivity simi-
lar to Weinreb amides. Besides, MAP amide holds multifaceted utility over Weinreb
amide, and offers an easy access to unsymmetrical secondary/tertiary alcohols via the
successive addition of two different metallo-nucleophiles to the MAP amide.[15a] In
2010, Odell and coworkers reported the synthesis of MAP aryl amides through micro-
wave-assisted Heck-aminocarbonylation reaction using Mo(CO)6 as a solid CO source
at 120 ꢁC.[8a] Recently, Shibasaki and coworkers have demonstrated the use of 7-azain-
doline amide as the auxiliary for various catalytic asymmetric reactions such as aldol-
and Mannich-type reactions.[16] The specific feature of this auxiliary is that it exhibits
reactivity similar to the Weinreb amide toward organometallic reagents (like organo-
lithium, Grignard reagents, and metal-hydrides) due to its stabilizing chelation with the
metal ion in the tetrahedral intermediate.
However, most of the reactions mentioned above are performed at either low tem-
perature or reflux condition under rigorous dry reaction conditions. Therefore, the
development of complementary methods using commercial grade solvent without pre-
clusion of air and moisture under ambient reaction conditions are highly desirable.
Recently, Prakash and coworkers[17a] documented a one-pot synthesis of acyl fluorides
directly from carboxylic acids using PPh3/N-bromosuccinimide (NBS) combinatio-
n,[17a,b] this strategy involves the activation of carboxylic acids to acyloxyphosphonium
ion, which is a crucial intermediate in this reaction and was corroborated by 31P NMR
study. Then, subsequent treatment of fluoride ion source with acyloxyphosphonium ion
furnishes the acyl fluorides. Intrigued by this report, and also by the high synthetic
importance of Weinreb and MAP amides in organic synthesis, we envisaged a

R
SYNTHETIC COMMUNICATIONSV
3
Scheme 1. (A) synthesis of Weinreb amides directly from carboxylic acids and P[NMe(OMe)]3. (B)
Synthesis of acyl fluorides from carboxylic acids. (C) A strategy for straightforward synthesis of
Weinreb amides, MAP amides and 7-azaindoline amides from various carboxylic acids.
straightforward, one-pot, and viable synthesis of Weinreb and MAP amides from car-
boxylic acids.
Results and discussion
The use of 1.1 equivalent of each PPh3 and NBS for the Appel type[17] in situ activation
of benzoic acid using undried commercial grade dichloromethane solvent (under inert-
free conditions) followed by addition of N,O-dimethylhydroxylamine hydrochloride (I)
and Et3N (1.1 equiv. of each) afforded the desired Weinreb amide (2a) in 73% yield in
1.25 h (Scheme 2A). Gratifyingly, increasing the equivalents of PPh3/NBS/N,O-dimethyl-
hydroxylamine combination to 1.5 equivalents furnished the requisite product 2a in
excellent yield (97%, Scheme 2B), and hence, this condition was used for fur-
ther studies.
To investigate the synthetic prospect of this method, a variety of aromatic carboxylic
acids were explored under the reaction conditions given in Scheme 2B, and the results
are summarized in Table 1. Both 1-naphthoic acid (1b) and 2-naphthoic acid (1c)
underwent a smooth amidation reaction to give the corresponding Weinreb amides in

4
F. PILATHOTTATHIL ET AL.
PPh3
NBS
Et3N (1.1 equiv)
O
OMe
HN
O
OMe
+
HCl
Ph
N
Ph
OH
CH2Cl2, 1.25 h
0 °C to rt
Me
Me
1a
I
2a
(A). N,O-dimethylhydroxylamine•HCl (1.1 equiv)
= 73%
= 97%
PPh3 (1.1 equiv), NBS (1.1 equiv)
(B). N,O-dimethylhydroxylamine•HCl (1.5 equiv)
PPh3 (1.5 equiv), NBS (1.5 equiv)
Scheme 2. Direct synthesis of Weinreb amide from carboxylic acid.
93% yield (entries 2b and 2c, Table 1). Besides, aromatic carboxylic acids bearing elec-
tron-donating substituents such as methyl (1d, 1e), methoxy (1f–h), dimethylamino (1i)
groups afforded the ensuing products in good to excellent yields (entries 2d–2i, Table
1). The amidation reaction was very proficient in the case of diversely halo-substituted
benzoic acids (1j–1n) and provided the associate products (2j–2n) in significant yields.
The presence of electron-withdrawing nitro-group at the ortho, meta, and para- position
of benzoic acids (1o–1r), and 4-trifluoromethyl benzoic acid (1s) afforded the related
Weinreb amides (entries 2o–2s, Table 1) in 74–97% yields. Interestingly, the chemose-
lective conversion of carboxylic acids to N-methoxy-N-methylamides can be achieved in
the presence of more reactive functional groups like aldehyde and ketones (entries 2t
and 2u, Table 1). We surmise that the high reactivity of in situ generated acyloxyphos-
phonium ion over carbonyl groups could be the possible reason for this excellent che-
moselectivity. Besides, benzoic acid tethered with allylic ether functionality (1v) and
benzoic acid bearing Cbz-protected amino group (1w) underwent smooth amidation
reaction to render the corresponding target amides in 67% and 83% yields, respectively
(entries 2v and 2w, Table 1). Besides, this method can be extended to chemoselective
conversion of carboxylic acid functionality of a-keto acids, such as phenyl glyoxylic acid
to the corresponding Weinreb amide without affecting the activated keto-group in
appreciable yield (entry 2x, Table 1).
Next, we shifted our focus toward the synthesis of Weinreb amides from aliphatic
carboxylic acids and amino acids (Table 2). Along these lines, phenylacetic acid and its
substituted congeners were subjected for the amidation reaction under the present reac-
tion conditions, and the requisite Weinreb amides were obtained in good to excellent
yields (entries 3a–3d, Table 2). Further, sterically hindered carboxylic acid such as ada-
mantane-1-carboxylic acid was converted to the corresponding Weinreb amide in
appreciable yield (entry 3e, Table 2). A variety of Fmoc-protected amino acids (such as
L-alanine, L-leucine, L-norvaline, glycine, and O-benzyl-L-serine) were converted into
corresponding Weinreb amides in good to excellent yields without erosion in the optical
25
purity (entries 3f–3j; The observed optical purity of Fmoc-alanine f[a]D ¼ þ1.9 (c
20
0.68, CHCl3)g is similar to the reported literature value f[a]D ¼ þ2.1 (c 0.68,
CHCl3)g, and suggests that the optically pure substrates do not undergo racemization
under the present reaction conditions).[18] However, the decomposition of starting

R
SYNTHETIC COMMUNICATIONSV
5
Table 1. Direct synthesis of aromatic Weinreb amides from various aromatic carboxylic acids.a
PPh3 (1.5 equiv)
NBS (1.5 equiv)
Et3N (1.1 equiv)
O
O
OMe
OMe
+
HN
HCl
OH
N
R
O
R
CH2Cl2, 1.25 h
0 °C to rt
Me
Me
1a-z
I
2a-z
1.5 equiv
OMe
OMe
N
Me
O
OMe
O
N
O
OMe
OMe
N
Me
Me
O
N
N
Me
Me
Me
Me
Me
2a, 97%
2b, 93%
2c, 93%
OMe
2d, 81%
2e, 62%
OMe
OMe
OMe
N
O
N
O
N
O
OMe
Me
Me
Me
O
N
O
N
Me
Me
OMe
NMe2
OMe
MeO
OMe
F
2g, 82%
2j, 75%
2f, 86%
2h, 87%
2i, 77%
OMe
N
OMe
OMe
N
O
N
O
O
OMe
OMe
N
Me
Me
Me
O
N
O
Me
Me
I
NO2
Cl
Br
I
2k, 85%
2l, 83%
2m, 97%
2n, 81%
2o, 78%
OMe
N
OMe
N
OMe
O
O
OMe
N
O
N
OMe
Me
Me
Me
O
O
N
Me
Me
Cl
Me
NO2
NO2
O2N
CF3
O
H
2p, 97%
2q, 74%
2r, 94%
2s, 95%
2t, 82%
OMe
N
OMe
N
OMe
N
O
O
O
Me
O
Me
Me
OMe
O
N
Me
O
Me
2u, 81%
NHCbz
2w, 83%
Ph
O
2v, 67%
2x, 75%
aIsolated yields.

6
F. PILATHOTTATHIL ET AL.
Table 2. Synthesis of Weinreb amides directly from various aliphatic carboxylic acids and
aminoacids.a
PPh3 (1.5 equiv)
NBS (1.5 equiv)
Et3N (1.1 equiv)
O
O
OMe
HN
OMe
R
R
+
HCl
OH
N
CH2Cl2, 1.25 h
0 °C to rt
Me
R1
R1 Me
3a-j
I
1.5 equiv
R = H, alkyl, aryl
R1= H, alkyl, aryl
NHFmoc
O
OMe
N
O
O
OMe
N
OMe
Me
N
OMe
N
O
Me
Me
Me
Ph
OMe
Me
N
Cl
Ph Me
O
3a, 94 %
3b, 80%
3c, 80%
3d, 82%
3e, 68%
O
O
O
O
H
OBn O
Me
FmocHN
3f, 80 %
Me
Me
n-Pr
FmocHN
3h, 94 %
Me
N
Me
Me
N
i-Pr
N
N
Fmoc
N
N
OMe
FmocHN
OMe
OMe
OMe FmocHN
OMe
3g, 89 %
3j, 89 %
3i, 78 %
aIsolated yields
PPh3 (1.5 equiv)
NBS (1.5 equiv)
Et3N (1.1 equiv)
O
OMe
HN
O
OMe
+
HCl
Ph
N
CH2Cl2, 1.25 h
Ph
OH
Me
Me
0 °C to rt
1a
I
2a
1 g
1.5 equiv
1.002 g, 75%
Scheme 3. Gram scale synthesis of Weinreb amide.
material was observed in the case of Boc- and Cbz-protected amino acids. A gram scale
synthesis of Weinreb amide derived from benzoic acid was performed using commercial
grade solvent, and the target amide (2a) was obtained in 75% yield (Scheme 3).
After a successful demonstration of direct synthesis of a series of Weinreb amides
from carboxylic acids, we envisioned a straightforward synthesis of MAP amides and 7-
azaindoline amides from carboxylic acids under the same reaction conditions outlined
for the synthesis of Weinreb amides (Tables 1 and 2). In the case of MAP amide syn-
thesis, 20 mol% DMAP was employed as a nucleophilic catalyst to facilitate the acyl
transfer reaction. The treatment of aromatic carboxylic acids, such as benzoic acid and
1-naphthoic acid with PPh3/NBS/DMAP combination followed by the addition of 2-
(methylamino)pyridine (II) gave the corresponding MAP amides in 86% and 74%,
respectively (Table 3, entries 4a and 4b). Aromatic carboxylic acid bearing electron-
donating methoxy group, aliphatic carboxylic acids such as diphenylacetic acid and ster-
ically hindered adamantane-1-carboxylic acid furnished the requisite amides in good to
excellent yields (Table 3, entries 4c–4e). Next, we explored the synthesis of a diverse

R
SYNTHETIC COMMUNICATIONSV
7
Table 3. Direct synthesis of MAP amides and 7-azaindoline amides from various carboxylic acidsa.
O
Me
N
H
N
II
N
H
N
III
R
OH
+
O
O
N
1.1 equiv
1.1 equiv
PPh3 (1.5 equiv)
NBS (1.5 equiv)
Et3N (1.1 equiv)
CH2Cl2, 1.25 h
0 °C to rt
R
N
R
N
N
DMAP (20 mol%)
Me
4a-f
5a-e
R = alkyl, aryl
R = alkyl, aryl
N
N
N
N
O
N
Me
N
O
N
O
O
N
O
N
Me
Me
Me
N
Me
OCH3
Ph
Ph
4a, 86%
4b, 74%
4c, 68%
4d, 58 %
4e, 81%
O
N
O
Me
O
O
N
O
O2N
Ph
N
N
N
Ph
N
O2N
N
N
N
N
5a, 73%
5b, 71%
5c, 75%
5d, 62%
5e, 75%
aIsolated yields.
range of 7-azaindoline amide derivatives with the reaction conditions used for the syn-
thesis of Weinreb amides. Several aromatic and aliphatic carboxylic acids were subjected
for the amidation reaction using 7-azaindoline (III) as the nucleophile in the presence
of PPh3/NBS combination, and the respective 7-azaindoline amides were obtained in
high yields (Table 3, entries 5a–5e).
Conclusion
In summary, we have demonstrated a direct conversion of various aromatic and ali-
phatic carboxylic acids to the corresponding Weinreb amides in the company of PPh3,
NBS, and N,O-dimethylhydroxylamine hydrochloride (I) using commercial grade solv-
ent under open-air atmosphere. The carboxylic acid functionality was chemoselectively
transformed into Weinreb amide in the presence of more reactive carbonyl groups such
as aldehyde and ketone. Besides, the present protocol was used for the synthesis of
Weinreb amides of various amino acids without loss in the optical purity. The manifest-
ation of gram scale synthesis of Weinreb amide of benzoic acid exhibits the viability of
the present protocol for further scale-up. Further, we extended this strategy for the syn-
thesis of a number of MAP amides and 7-azaindoline amides directly from aromatic
and aliphatic carboxylic acids under identical reaction conditions.

8
F. PILATHOTTATHIL ET AL.
Experimental section
General procedure for the synthesis of Weinreb amides
To a mixture of benzoic acid (50 mg, 0.41 mmol, 1 equiv.), PPh3 (160 mg, 0.61 mmol,
1.5 equiv.), and NBS (108.5 mg, 0.61 mmol, 1.5 equiv.), CH2Cl2 (2 mL) was added and
the reaction was stirred at 0 ꢁC for 15 min. The reaction was brought to room tempera-
ture and N,O-dimethylhydroxylamine hydrochloride (59.5 mg, 0.61 mmol, 1.5 equiv.)
and Et3N (45.5 mg, 63 lL, 0.45 mmol, 1.1 equiv.) were added and the reaction mixture
was stirred for 1 h at room temperature. The reaction mixture was quenched with aque-
ous sodium bicarbonate solution and diluted with CH2Cl2. The bicarbonate washings
were again extracted with CH2Cl2 and the combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. Column chromatography
was performed using EtOAc/Petroleum ether (1:5).
N-methoxy-N-methylbenzamide (2a)
Prepared according to the general procedure using benzoic acid (50 mg, 0.41 mmol).
1
Yield: 97% (66 mg).[14a] The title compound was obtained as a pale yellow oil. H NMR
(500 MHz, CDCl3): d (ppm) 7.60–7.58 (m, 2H), 7.39–7.31 (m, 3H), 3.47 (s, 3H), 3.28 (s,
3H). 13C NMR (125 MHz, CDCl3): d (ppm) 170.1, 134.2, 130.6, 128.2, 128.1, 61.1, 33.9.
HRMS (m/z): calculated for C9H11NO2 (M þ H): 166.0860, found (M þ H) 166.0825.
The data is in accordance with reported literature.
General procedure for synthesis of 2-(methylamino)pyridine amides
To a mixture of benzoic acid (50 mg, 0.41 mmol, 1 equiv.), PPh3 (160 mg, 0.61 mmol,
1.5 equiv.), and NBS (108.5 mg, 0.61 mmol, 1.5 equiv.), CH2Cl2 (2 mL) was added and
the reaction was stirred at 0 ꢁC for 15 min. The reaction was brought to room tempera-
ture, then, DMAP (10 mg, 0.082 mmol, 20 mol%), 2-(methylamino)pyridine (59.5 mg,
0.61 mmol, 1.5 equiv.), and Et3N (45.5 mg, 63 lL, 0.45 mmol, 1.1 equiv.) were added
and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture
was quenched with aqueous sodium bicarbonate solution and diluted with CH2Cl2. The
bicarbonate washings were again extracted with CH2Cl2 and the combined organic
layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Column chromatography was performed using EtOAc/Petroleum ether (1:5).
N-methyl-N-(pyridin-2-yl)benzamide (4a)
Prepared according to the general procedure using benzoic acid (50 mg, 0.41 mmol).[8]
Yield: 86% (75 mg). The title compound was obtained as a yellow oil. 1H NMR
(500 MHz, CDCl3): d (ppm) 8.37–8.36 (m, 1H), 7.37–7.34 (m, 1H), 7.27–7.22 (m, 3H),
7.16–7.13 (m, 2H), 6.97–6.95 (m, 1H), 6.73 (d, J ¼ 8.0 Hz, 1H), 3.51 (s, 3H). 13C NMR
(125 MHz, CDCl3): d (ppm) 171.1, 156.9, 148.8, 137.4, 136.1, 130.2, 128.6, 128.1, 121.7,
121.0, 36.1. HRMS (m/z): calculated for C13H12N2O (M þ H): 213.1022, found (M þ H)
213.1023. The data is in accordance with reported literature.

R
SYNTHETIC COMMUNICATIONSV
9
General procedure for the synthesis of 2,3-dihydro-7-azaindole amides
A reaction tube with a teflon coated magnetic stir bar was charged with benzoic acid
(50 mg, 0.41 mmol, 1 equiv.), PPh3 (160 mg, 0.61 mmol, 1.5 equiv.), and NBS (108.5 mg,
0.61 mmol, 1.5 equiv.). CH2Cl2 (2 mL) was added and the reaction was stirred at 0 ꢁC
for 15 min. The reaction was brought to room temperature and 2,3-dihydro-7-azaindole
(54 mg, 0.45 mmol, 1.1 equiv.) and Et3N (45.5 mg, 63 lL, 0.45 mmol, 1.1 equiv.) were
added and the reaction mixture was stirred for 1 h at room temperature. The reaction
mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate solution.
The bicarbonate washings were again extracted with EtOAc and the combined organic
layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Column chromatography was performed using EtOAc/Petroleum ether (1:5).
(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone (5a)
Prepared according to the general procedure using benzoic acid (50 mg, 0.41 mmol).
Yield: 73% (66.8 mg). The title compound was obtained as a white solid, mp ¼ 114 ꢁC.
1H NMR (500 MHz, CDCl3): d (ppm) 7.85 (d, J ¼ 5.0 Hz, 1H), 7.59 (d, J ¼ 7.0 Hz, 2H),
7.48–7.45 (m, 2H), 7.38 (t, J ¼ 7.5 Hz, 2H), 6.81 (dd, J ¼ 7.5, 5 Hz, 1H), 4.22 (t,
J ¼ 8.0 Hz, 2H), 3.11 (t, J ¼ 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): d (ppm) 169.3,
156.2, 146.3, 136.1, 133.3, 130.7, 128.5, 127.8, 125.8, 118.5, 47.9, 25.1. IR (ATR, cmꢂ1):
1643, 1593, 1420, 1379, 1347, 1245, 790, 712. HRMS (m/z): Calculated for C14H12N2O
(M þ H) 225.1022, found (M þ H) 225.1022.
1
Full experimental details, characterization data for compounds with copies of H and
13C NMR spectra and HRMS of all new compounds. This material can be found via the
“Supporting Information” section of this article’s webpage.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The authors thank IISER Thiruvananthapuram for financial support. One of the authors (F.P)
thank UGC, New-Delhi for senior research fellowship.
ORCID
Alagiri Kaliyamoorthy
http://orcid.org/0000-0002-5183-8191
References
[1] (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818. DOI: 10.1016/S0040-
4039(01)91316-4. (b) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 2008, 3707–3738.
(c) Sibi, M. P. C. Org. Prep. Proced. Int. 1993, 25, 15–40. DOI: 10.1080/
00304949309457931.(d) Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem. 2003, 7,

10
F. PILATHOTTATHIL ET AL.
967–993. DOI: 10.2174/1385272033486639.(e) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J.
Prakt. Chem. 2000, 342, 340–347. DOI: 10.1002/(SICI)1521-3897(200004)342:4<340::AID-
PRAC340>3.0.CO;2-1.(f) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339,
517–524. DOI: 10.1002/prac.19973390194.
[2] (a) Murphy, J. A.; Commeureuc, A. G. J.; Snaddon, T. N.; McGuire, T. M.; Khan, T. A.;
Hisler, K.; Dewis, M. L.; Carling, R. Org. Lett. 2005, 7, 1427. DOI: 10.1021/ol050337b. (b)
Hisler, K.; Tripoli, R.; Murphy, J. A. Tetrahedron Lett. 2006, 47, 6293–6295. DOI: 10.
1016/j.tetlet.2006.06.118.
[3] Goel, O. P.; Krolls, U. Org. Prep. Proced. Int. 1987, 19, 75–78. DOI: 10.1080/
00304948709354877.
[4] Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron Lett. 1984, 25, 4859–4862.
DOI: 10.1016/S0040-4039(01)91243-2.
[5] Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685–2688. DOI: 10.1016/
S0040-4039(97)00429-2.
[6] (a) Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831. DOI: 10.1021/
ꢀ
~
jo010853p. (b) Colobert, F.; Mazery, R. D.; Solladie, G.; Carreno, M. C. Org. Lett. 2002, 4,
1723. DOI: 10.1021/ol025778z.
[7] Dineen, T. A.; Zajac, M. A.; Myers, A. G. J. Am. Chem. Soc. 2006, 128, 16406–16409.
DOI: 10.1021/ja066728i.
[8] (a) Wieckowska, A.; Fransson, R.; Odell, L. R.; Larhed, M. J. Org. Chem. 2011, 76, 978.
DOI: 10.1021/jo102151u. (b) Masahiro, M.; Yujiro, H.; Hajme, I.; Yoshohiko, I. Chem.
Lett. 1998, 27, 163.(c) Martinelli, J. R.; Freckmann, D. M. M.; Buchwald, S. L. Org. Lett.
2006, 8, 4843. DOI: 10.1021/ol061902t.
[9] (a) Angelastro, M. R.; Peet, N. P.; Bey, P. J. Org. Chem. 1989, 54, 3913–3916. DOI: 10.
1021/jo00277a031. (b) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51,
5106–5110. DOI: 10.1021/jo00376a010.(c) Goel, O. P.; Krolls, U.; Sterr, M.; Kesten, S. Org.
€
Synth. 1989, 67, 69.(d) Braun, M.; Waldmuller, D. Synthesis 1989, 1989, 856–858. DOI:
10.1055/s-1989-27410.(e) Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y. J. Org. Chem.
1995, 60, 1727–1732. DOI: 10.1021/jo00111a034.(f) Gibson, C. L.; Handa, S. Tetrahedron:
Asymmetry 1996, 7, 1281–1284. DOI: 10.1016/0957-4166(96)00144-9.(g) Theisen, P. D.;
Heathcock, C. H. J. Org. Chem. 1988, 53, 2374–2378. DOI: 10.1021/jo00245a051.(h) Jones,
T. K.; Mills, S. G.; Reamer, R. A.; Askin, P.; Desmond, R.; Volante, R. P.; Shinkai, I. J.
Am. Chem. Soc. 1989, 111, 1157–1159. DOI: 10.1021/ja00185a071.(i) Nitz, T. J.; Volkots,
D. L.; Aldous, D. J.; Oglesby, R. C. J. Org. Chem. 1994, 59, 5828–5832. DOI: 10.1021/
jo00098a054.
[10] (a) Einhorn, J.; Einhorn, C.; Luche, J.-L. Synth. Commun. 1990, 20, 1105–1112. DOI: 10.
1080/00397919008052817. (b) Kim, J.-G.; Jang, D. K. Bull. Korean Chem. Soc. 2010, 31,
171–173. DOI: 10.5012/bkcs.2010.31.01.171.(c) Leggio, A.; Belsito, E. L.; Luca, G. D.;
Gioia, M. L. D.; Leotta, V.; Romio, E.; Siciliano, C.; Liguori, A. RSC Adv. 2016, 6,
ꢁ
34468–34475. DOI: 10.1039/C5RA24527C.(d) Leggio, A.; Bagala, J.; Belsito, E. L.;
ꢁ
Comande, A.; Greco, M.; Ligouri, A. Chem. Cent. J. 2017, 11, 87. DOI: 10.1186/s13065-
017-0318-9.(e) Kumar, A.; Akula, H. K.; Lakshman, H. K. Eur. J. Org. Chem. 2010, 2010,
2709–2715. DOI: 10.1002/ejoc.200901420.
[11] Sibi, M. P.; Stessman, C. C.; Schultz, J. A.; Christensen, J. W.; Lu, J.; Marvin, M. A. Synth.
Commun. 1995, 25, 1255–1264. DOI: 10.1080/00397919508012689.
[12] Woo, J. C. S.; Fenster, E.; Dake, G. R. J. Org. Chem. 2004, 69, 8984–8986. DOI: 10.1021/
jo048385h.
[13] White, J. M.; Tunoori, A. R.; Turunen, B. J.; Georg, G. I. J. Org. Chem. 2004, 69,
2573–2576. DOI: 10.1021/jo035658k.
[14] (a) Niu, T.; Zhang, W.; Huang, D.; Xu, C.; Wang, H.; Hu, Y. Org. Lett. 2009, 11, 4474.
DOI: 10.1021/ol901886u. (b) Niu, T.; Wang, K.-H.; Huang, D.; Xu, C.; Su, Y.; Hu, Y.; Fu,
Y. Synthesis 2013, 46, 320–330. DOI: 10.1055/s-0033-1340317.
[15] (a) Meyers, A. I.; Comins, D. L. Tetrahedron Lett. 1978, 19, 5179–5182. DOI: 10.1016/
S0040-4039(01)85843-3. (b) Comins, D.; Meyers, A. I. Synthesis 1978, 1978, 403–404.

R
SYNTHETIC COMMUNICATIONSV
11
DOI: 10.1055/s-1978-24767.(c) 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.
; et al. J. Am. Chem. Soc. 1983, 105, 5015–5024. DOI: 10.1021/ja00353a027.(d) Comins,
D. L.; Dernell, W. Tetrahedron Lett. 1981, 22, 1085–1088. DOI: 10.1016/S0040-
4039(01)90243-6.(e) Monticelli, S.; Parisi, G.; Rui, M.; Karen, d. l V.-H.; Murgia, I.;
Senatore, R.; Holzer, W.; Urban, E.; Langer, T.; Pace, V. Nat. Prod. Commun. 2016, 11,
1729.
[16] (a) Kumagai, N.; Shibasaki, M. Synthesis 2019, 51, 185–193. (b) Weidner, K.; Kumagai, N.;
Shibasaki, M. Angew. Chem. Int. Ed. 2014, 53, 6150–6154. DOI: 10.1002/anie.201403118.
(c) Yin, L.; Brewitz, L.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2014, 136,
17958–17961. DOI: 10.1021/ja511458k.(d) Weidner, K.; Sun, Z.; Kumagai, N.; Shibasaki,
M. Angew. Chem. Int. Ed. 2015, 54, 6236–6240. DOI: 10.1002/anie.201501607.(e) Arteaga,
F. A.; Liu, Z.; Brewitz, L.; Chen, J.; Sun, B.; Kumagai, N.; Shibasaki, M. Org. Lett. 2016,
18, 2391–2394. DOI: 10.1021/acs.orglett.6b00879.(f) Sun, B.; Pluta, R.; Kumagai, N.;
Shibasaki, M. Org. Lett. 2018, 20, 526–529. DOI: 10.1021/acs.orglett.7b03609.(g) Sun, Z.;
Sun, B.; Kumagai, N.; Shibasaki, M. Org. Lett. 2018, 20, 3070–3073. DOI: 10.1021/acs.
orglett.8b01109.(h) Pluta, R.; Kumagai, N.; Shibasaki, M. Angew. Chem. Int. Ed. 2019, 58,
2459–2463. DOI: 10.1002/anie.201814607.
[17] (a) Munoz, S. B.; Dang, H.; Rodriguez, X. I.; Mathew, T.; Prakash, G. K. S. Org. Lett.
2019, 21, 1659. DOI: 10.1021/acs.orglett.9b00197. (b) FrØyen, P. Phosphorus, Sulfur
Silicon Relat. Elem. 1994, 91, 145. DOI: 10.1080/10426509408021940.(c) FrØyen, P.
Tetrahedron Lett. 1997, 38, 5359–5362. DOI: 10.1016/S0040-4039(97)01172-6.(d)
Duangkamol, C.; Wangngae, S.; Pattarawarapan, M.; Phakhodee, W. Eur. J. Org. Chem.
2014, 2014, 7109–7112. DOI: 10.1002/ejoc.201403076.(e) Matveeva, E. D.; Podrugina, T.
A.; Sandakova, N. G.; Zefirov, N. S. Russ. J. Org. Chem. 2004, 40, 1517.(f) Kang, D. H.;
Joo, T. Y.; Lee, E. H.; Chaysripongkul, S.; Chavasiri, W.; Jang, D. O. Tetrahedron Lett.
2006, 47, 5693–5696. DOI: 10.1016/j.tetlet.2006.06.013.(g) Bandgar, B. P.; Bettigeri, S. V.
Synth. Commun. 2004, 34, 2917–2924. DOI: 10.1081/SCC-200026630.
[18] Wu, Y.; Xu, J. Tetrahedron 2001, 57, 8107–8113. DOI: 10.1016/S0040-4020(01)00789-X.