One-pot synthesis of Weinreb amides employing 3,3-dichloro-1,2-diphenylcyclopropene (CPI-Cl) as a chlorinating agent

Article abstract of DOI:10.1080/00397911.2018.1531295

The synthesis of N^α-protected amino alkyl Weinreb amides starting from the corresponding α-amino acids as well as carboxylic acids has been delineated through the in situ generation of acid chlorides using CPI-Cl as a chlorinating agent. The protocol is simple; the reaction conditions employed were mild, and compatible with all the three commonly used urethane protecting groups namely, Boc, Cbz and Fmoc groups. The resulting Weinreb amides are obtained in good yields as optically pure products.

Full text of DOI:10.1080/00397911.2018.1531295

Synthetic Communications
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One-pot synthesis of Weinreb amides employing
3,3-dichloro-1,2-diphenylcyclopropene (CPI-Cl) as a
chlorinating agent
Shekharappa M, Roopesh Kumar L & Vommina V. Sureshbabu
To cite this article: Shekharappa M, Roopesh Kumar L & Vommina V. Sureshbabu (2019)
One-pot synthesis of Weinreb amides employing 3,3-dichloro-1,2-diphenylcyclopropene
(CPI-Cl) as a chlorinating agent, Synthetic Communications, 49:6, 790-798, DOI:
10.1080/00397911.2018.1531295
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2019, VOL. 49, NO. 6, 790–798
https://doi.org/10.1080/00397911.2018.1531295
One-pot synthesis of Weinreb amides employing
3,3-dichloro-1,2-diphenylcyclopropene (CPI-Cl) as a
chlorinating agent
Shekharappa M, Roopesh Kumar L, and Vommina V. Sureshbabu
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore
University, Bangalore, India
ABSTRACT
ARTICLE HISTORY
The synthesis of Na-protected amino alkyl Weinreb amides starting
from the corresponding a-amino acids as well as carboxylic acids has
been delineated through the in situ generation of acid chlorides
using CPI-Cl as a chlorinating agent. The protocol is simple; the reac-
tion conditions employed were mild, and compatible with all the
three commonly used urethane protecting groups namely, Boc, Cbz
and Fmoc groups. The resulting Weinreb amides are obtained in
good yields as optically pure products.
Received 3 July 2018
KEYWORDS
Acid chloride; CPI-Cl;
Na-protected amino alkyl
Weinreb amides;
N,O-dimethylhydroxylamine
GRAPHICAL ABSTRACT
Introduction
Since Nahm and Weinreb first reported on the use of N-methoxy-N-methylamides as
carbonyl equivalents,[1] this functional group has rapidly become popular in organic
synthesis.[2] These amides react with organometallics, hydride reducing agents or Wittig
reagent to give aldehydes or ketones.[3] They are used in the preparation of an array of
compounds with functional groups such as ynones,[4] heterocycle[5] and in the total syn-
thesis of natural products.[6] Weinreb amides can be synthesized from a plethora of
functional groups such as carboxylic acids or its derivatives acid chlorides,[7] esters,[8]
amides,[9] anhydrides,[10] alcohols,[11] amino carbonylative coupling[12] and Stille cross-
coupling reactions.[13] Among the several approaches, direct conversion of carboxylic
acids into the corresponding Weinreb amides is most outstanding and attractive because
CONTACT Vommina V. Sureshbabu
sureshbabuvommina@rediffmail.com
109, Peptide Research Laboratory,
Department of Studies in Chemistry, Central College Campus, Dr. B.R. Ambedkar Veedhi, Bangalore University,
Bangalore 560 001, India.
Supplemental data for this article can be accessed here.
ß 2018 Taylor & Francis Group, LLC

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of the easy availability of the precursors.[14] The reported methods for the synthesis of
Weinreb amides through in situ generation of acid halides using phosphorous trichlor-
ide (PCl3),[15] PPh3/Cl3CCN,[16] PPh3/I2,[17] PPh3/CBr4,[18] and [bis(2-methoxyethyl)a-
mino]sulfur trifluoride (Deoxo-Fluor).[19] However, PCl3, PPh3/Cl3CCN are not
compatible with acid-labile protecting groups. PPh3/CBr4 is expected to result in race-
mization. The protocol using Deoxo-Fluor requires longer reaction duration (3–8 h).
Weinreb amides from the corresponding Na-Fmoc amino/peptide acid chlorides gener-
ated using SOCl2 has been reported by our group. Due to the instability of acid chlor-
ides, the protocol could not be extended to Na-Boc/Cbz amino acids.[20] Vilsmeier
reagent is an efficient chlorinating agent employed for the acid chloride formation,
which can be prepared by the combination of (COCl)2 and DMF with the formation of
HCl as by-product, which cleaves acid sensitive Boc group.[21] Katritzky developed a
method for the synthesis of different Weinreb amides including Boc-protected amino
Weinreb amides from corresponding carboxylic acids. N-Acyl benzotriazole was
refluxed with N,O-dimethylhydroxylamine hydrochloride, for 6–12 h.[22] Peptide cou-
pling reagents such as BOP,[23] DCC,[24] DEPC,[25] HBTU,[26] CDMT[27] and
DMTMM[28] are also employed. Furthermore, CDI,[29] COMU,[30] T3P/DBU[31] and
mixed anhydride[32] method have been utilized for the synthesis of the title compounds.
These protocols suffer from many disadvantages viz, longer reaction time, side reactions
due to elevated temperature, poor yields, racemization, etc. In this paper, we delineate
an efficient method for the synthesis of N-methoxy-N-methyl amides of a-amino acids
through in situ generation of acid chlorides employing 3,3-dichloro-1,2-diphenylcyclo-
propene (CPI-Cl).
The cyclopropenium cation is the smallest member of the Hu€ckel aromatic system.
There are several investigations on this cation ever since the first synthesis of triphenylcy-
clopropenylium perchlorate by Breslow.[33] Lambert et al., employed the reactions involv-
ing cyclopropenium intermediates, for the rapid conversion of alcohols and carboxylic
acids into the corresponding alkyl chlorides and acid chlorides respectively.[34] A similar
strategy was applied for the dehydrative cyclization of diols to cyclic ethers.[35]
Nucleophilic substitution of alcohols by methane sulfonate ion with inversion of configur-
ation is also known.[36] The conversion of ketoximes to amides/ketones by Beckmann
rearrangement is also known.[37] Recently our group reported CPI-Cl mediated synthesis
of amino acid azides and their conversion to a-ureidopeptides.[38] In continuation of our
interest in using CPI-Cl as a useful reagent for functional group conversions, herein we
report our results on the synthesis of Weinreb amides from the corresponding carbox-
ylic acids.
Results and discussions
Initially, we have chosen benzoic acid 1a as a model substrate to establish the optimal
reaction conditions. In a typical experiment to the in situ generated CPI-Cl (generated by
the treatment of 2,3-diphenylcyclopropenone with oxalyl chloride in CH2Cl2), a solution
of benzoic acid (1.0 equiv.) and diisopropylethylamine (DIPEA, 1.2 equiv.) in dry CH2Cl2
was added at room temperature under an argon atmosphere. After 5 min, a solution of
N,O-dimethylhydroxylamine (1.2 equiv.) in CH2Cl2 was added to the above in situ

792
S. M ET AL.
Table 1. Optimization of Weinreb amidation reaction.
Entry
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Acetonitrile
Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Base (equiv)
HN(OMe)Me
Time(min)
Yield (%)
1
2
3
4
5
6
7
8
DIPEA (1.2)
DIPEA (1.2)
DIPEA (1.5)
DIPEA (2.0)
DIPEA (2.2)
DIPEA (2.2)
DIPEA (2.2)
DIPEA (2.2)
TEA (2.2)
1.2a
1.2b
1.5a
2.0a
2.2a
2.0a
2.0a
2.0a
2.0a
2.0a
2.0a
2.0a
90
90
35
20
20
40
40
40
40
40
40
40
55
53
79
93
93
75
68
65
80
78
74
79
9
10
11
12
NEM (2.2)
Pyridine (2.2)
NMM (2.2)
areaction was carried out at r.t.; reaction was carried out at 0 ꢀC.
b
generated acid chloride. As monitored by TLC analysis, the desired Weinreb amide 2a was
obtained in 55% after 90 min along with unreacted benzoic acid (entry 1). The yield of 2a
was 53% when the same reaction was performed at 0 ꢀC (entry 2). In order to improve
the yield of 2a, the amount of DIPEA and N,O-dimethylhydroxylamine was increased to
1.5 equiv., the yield of 2a increased to 79%. We obtained a 93% yield of desired product
2a, using the DIPEA (2.0 equiv.) and N,O-dimethylhydroxylamine (2.0 equiv.) in 20 min
duration of the reaction (TLC analysis). It is evident that among the screened solvents
(CH2Cl2, THF, acetonitrile and dioxane) and bases (DIPEA, TEA, NEM, pyridine and
NMM), CH2Cl2 and DIPEA were found to be more efficient (Table 1). After a simple
work-up, the crude compound was purified by column chromatography using hexane and
ethyl acetate [hexane:EtOAc; (70:30)] as eluents to afford pure Weinreb amide 2a. Further
2,3-diphenylcyclopropenone was also recovered quantitatively through column chromatog-
raphy and reused. Benzoyl Weinreb amide to substituted and heterocyclic weinreb amides
have been synthesized in good yields (Scheme 1).
After the optimized reaction conditions were established, we tested the methodology
with an array of Na-Fmoc/Boc/Cbz protected amino acids including bifunctional as well as
sterically hindered amino acids. Furthermore, side-chain-modified Weinreb amide of the N
and C terminally protected aspartic acid (5g) is also synthesized in good yield (Scheme 2).
ꢁ
The Fmoc-L-Phe-N(Me)O(Me) and Fmoc-D-Phe-N(Me)O(Me), 5a and 5a made
using the optimized conditions were chosen as model compounds to study racemiza-
tion. The RP-HPLC analysis was carried out. The chromatograms had peaks at
ꢁ
Rt ¼ 8.241 min (5a) and Rt ¼ 7.187 min (5a ), respectively. Also, intentionally
prepared equimolar mixture of L- and D-Phe-N(Me)O(Me) had distinct peaks
ꢁ
at Rt ¼ 8.213 and 7.228 min (5a and 5a ). These observations inferred that the
protocol is free from racemization and the amino Weinreb amides were obtained
as optically pure compounds (method: gradient 0.1% TFA water-methanol (60-40);
flow rate: 0.5 mL/min, 10 min).

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R = Substituted aryl or heterocyclic compound
Scheme 1. Synthesis of aryl/heterocyclic Weinreb amides.
The putative mechanism for Weinreb amidation reaction is now presented in
Scheme 3. Cyclopropene i bearing two geminal chlorides may exist in equilibrium with
cyclopropenium salt ii. Addition of carboxylate to ii resulting in cyclopropenium acti-
vated carboxylate iv [iii dissociates to iv by reionization]. Nucleophilic addition
[NH(OMe)Me] to iv to give expected product v.
Conclusion
A simple and efficient strategy for the construction of Weinreb amides through in
situ generation of acid chlorides using CPI-Cl as a useful chlorinating agent from the
corresponding carboxylic acid is reported. The advantage that the protocol offers is
the use of in situ generated CPI-Cl in chlorinating the carboxyl acid of Boc-protected
amino acids. Generally, other chlorinating agents cleaves the Boc-group. Therefore, in
terms of compatibility offered by present chlorinating reagent to obtain Weinreb
amides bearing acid labile moieties is advantageous. Furthermore, diphenylcyclopro-
penone is recovered quantitatively at the end of the reaction through column chro-
matography and reused.
Experimental section
General procedure for the preparation of Weinreb amides
To a solution of in situ generated CPI-Cl (generated by the treatment of 2,3 diphenylcy-
clopropenone with oxalyl chloride in CH2Cl2) was added aryl/heterocyclic/Na-protected

794
S. M ET AL.
Scheme 2. Synthesis of Na-protected amino Weinreb amides.
amino acid (1 mmol), DIPEA (2 mmol) stirring at room temperature. After the forma-
tion of acid chloride solution of N,O-dimethylhydroxylamine (2 mmol) in CH2Cl2 was
added. After the completion of the reaction (determined by TLC), solvent was evapo-
rated under vacuo and diluted with EtOAc, washed with 5% citric acid and Na2CO3
(10 mL ꢂ2), water, brine and dried over anhydrous Na2SO4. After filtration, the solvent
was evaporated and purified by column chromatography using hexane and EtOAc
as eluents.
1
Fmoc-Phe-N(OMe)Me [5a]: White solid, yield 90%. H NMR (400 MHz, CDCl3): d
7.85–7.16 (m, 13 H), 5.69 (d, J ¼ 7.2 Hz, 1 H), 4.4 (d, J ¼ 7.2 Hz, 2 H), 4.28 (q, J ¼ 6.8 Hz,
1 H), 4.17 (t, J ¼ 6.8 Hz, 1 H), 3.67 (s, 3 H), 3.19 (s, 3 H), 3.06–2.91 (m, 2 H). 13 C NMR
(100 MHz, CDCl3) d 160.83, 156.51, 143.57, 141.36, 136.36, 129.15, 127.70, 126.99,
125.97, 125.57, 125.20, 120.17, 67.31, 63.63, 51.39, 47.17, 37.40, 31.26. HRMS: m/z calcu-
lated for C26H27N2O4 [M þ H]þ 431.1971; found: 431.1966.

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795
Scheme 3. Putative mechanism for Weinreb amidation.
Acknowledgment
One of the authors, Roopesh Kumar. L, thanks DST-Nano Mission for fellowship.
Funding
We are grateful to acknowledge the financial support from UGC-NFSC and SERB, New Delhi,
Government of India.
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