Rapid and Effective Reaction of 2-Methylpyridin-N-oxides with Triphosgene via a [3,3]-Sigmatropic Rearrangement: Mechanism and Applications

Article

Rapid and Eﬀective Reaction of 2‑Methylpyridin‑N‑oxides with

Triphosgene via a [3,3]-Sigmatropic Rearrangement: Mechanism

and Applications

†

Hao Li, Hong-Cheng Xia, Fang-Yuan Nie, and Qin-Hua Song*

Cite This: J. Org. Chem. 2021, 86, 8308 −8318

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sı Supporting Information

ABSTRACT: A facile and eﬀective synthesis of 2-chloromethylpyridines was developed by a one-pot reaction of 2-alkylpyridin-N-

oxides and triphosgene at room temperature. As starting materials, N-oxides of 2-alkylpyridine derivatives, including 2-alkylpyridines,

-methyl quinolines, and phenanthroline, can react rapidly with triphosgene in the presence of triethylamine, aﬀording 2-

chloromethylpyridines in good to excellent yields (52−95%). Using the 2-methylquinoline substrate for the mechanistic study, it has

been well demonstrated that the chlorination reaction undergoes a [3,3]-sigmatropic rearrangement, which can be observed as a

reversible process by monitoring the intermediates. Moreover, the chlorination reaction can be used to construct a rapid and

sensitive ﬂuorescent probe for the detection of phosgene.

INTRODUCTION

picoline-N-oxide to 2-chloromethylpyridine using phosgene in

■

the presence of TEA.

chloromethylpyridines were produced in high yields (72−

2%) from N-oxides of three α-picolines with diphosgene or

In another work, three 2-

Chloromethylpyridines are an important class of compounds in

the preparation of drugs, dyes, and pesticides. 2-Chlorome-

thylpyridine was directly chlorinated from α-picoline but the

yields were low due to the formation of a large number of

dichloro- and trichloro-methylated pyridines. 2-Chlorome-

thylpyridine was prepared from 2-methylpyridine-N-oxides by

triphosgene in the presence of a tertiary amine at very low

temperatures −20 or −40 °C. In the two papers, however,

there is no mention of the reaction mechanism of α-picoline-

N-oxides with phosgene and its substitutes, diphosgene

(trichloromethyl chloroformate, TCF) and triphosgene (bis-

(trichloromethyl)carbonate, BTC).

various chlorinating agents, phosphoryl chloride, thionyl

dichloride, trichloroacetyl chloride, benzene sulfonyl chlor-

ide, or p-toluenesulfonyl chloride, shown in Scheme 1. In

these reactions, the yields of trichloroacetyl chloride (∼70%),

phosphoryl chloride (90%), and sulfonyl chloride (90%) are

acceptable or very high, but there are waste disposal problems

associated with organochlorinated agents and/or waste heat

energy (for a high reaction temperature). Moreover, the

chlorinating agents, phosphoryl chloride, trichloroacetyl

chloride, and sulfonyl chlorides, generate inorganic salts,

which have environmental and treatment problems.

In this work, we have developed a one-pot synthesis of 2-

chloromethylpyridines from N-oxides of 2-alkylpyridines with

BTC in the presence of TEA. The reactions were carried out at

room temperature for a very short time, generating only HCl

and CO as byproducts. The mechanism has been demon-

Received: March 31, 2021

Published: May 27, 2021

In the presence of a base, triethylamine (TEA), for utilizing

phosphoryl chloride, a highly eﬀective conversion (88%) of 2-

picoline-N-oxide to 2-chloromethylpyridine was achieved. In

the same work, a low yield (35%) was obtained from 2-

2021 American Chemical Society

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Scheme 1. Synthesis of 2-Chloromethylpyridines from 2-

2-alkylpyridine are generally prepared by the reaction of a 2-

alkylpyridine with 3-chloroperbenzoic acid (m-CPBA) at room

temperature for 12 h. Various 2-alkylpyridines were prepared

by routine methods or literature methods. Their synthesis

routes are described in Supporting information (SI).

3b,6b,7

Picoline N-Oxides in Previous Papers

and This Work

Since BTC can decompose into phosgene in the presence of

a tertiary amine such as TEA, the reaction of 2-methylpyridine

N-oxide with BTC in the presence of TEA can be regarded as

the reaction with phosgene. Optimization of the conditions

was achieved by performing the reaction of 2-methylquinoline

N-oxide in seven solvents at room temperature, including the

use of diﬀerent dosages of BTC and TEA (Table S1). In seven

solvents, the highest isolated yield of 57% was obtained in

dichloromethane (DCM), and the second highest yield (47%)

from acetonitrile. For the dosages of BTC and TEA, the

reaction with 0.5 equiv of BTC and 5 equiv of TEA aﬀorded

the highest yield of 68%. The reaction conditions were used in

the next synthesis.

According to the optimized conditions, that is, 0.5 equiv of

BTC and 5 equiv of TEA in DCM, we proceeded with the

identiﬁcation of the substrate scope, shown in Table 1. The

substrates include 18 N-oxides of various 2-methylpyridine

derivatives covering 2-alkylpyridines (2a−e), 7-substituted 2-

methyl quinolines (2f−h), 6-amino-substituted 2-methyl

quinolines (2i−q), and the 2-methyl phenanthroline (2r),

strated by tracking reaction processes and detecting

intermediates. Furthermore, another application of this

reaction has been exploited for the detection of highly toxic

phosgene gas with a 2-methylquinoline N-oxide as a

ﬂuorescent probe.

RESULTS AND DISCUSSION

prepared according to the literature, and the details are

■

Synthesis of 2-Chloromethylpyridines from 2-Meth-

provided as the SI . 2-Chlorinated methyl products 3 were

obtained from the reactions of the substrates with BTC/TEA

ylpyridine N-Oxides with BTC. The N-oxide derivatives of

Table 1. Substrate Scope and the Products with Yields

Yields determined by high-performance liquid chromatography (HPLC), and isolated yields in brackets.

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at room temperature for 10 min in good to excellent yields

shows their ﬂuorescence spectra of 2g and 3g as well as the

reaction mixture of 2g with phosgene, TCF, BTC, or BTC/

TEA in acetonitrile. Their ﬂuorescence spectra of the reaction

(

52−95%) (Table 1).

Taking 3r as an example, in another four-step procedure,

the N-oxide 2r was obtained with 1r as the starting material,

and 3r was prepared by the rearrangement of 2r with acetic

anhydride (90%), hydrolysis (86%), and treatment with PCl₃

mixtures of 2g with phosgene, TCF, or BTC are similar (λ_m_a_x,

367 nm) in the absence of TEA, and the ﬂuorescence spectra

of all three systems in the presence of TEA are similar to that

of 3g (λmax, 397 nm). This indicates that the reactions of 2g

with phosgene and its substitutes in the presence of TEA

generate the same end-product 3g via similar intermediates (in

the absence of TEA).

To further observe the reaction processes, tracking experi-

ments were performed by UV/vis absorption and ﬂuorescence

spectroscopies. In the absence of TEA, upon the addition of

diﬀerent amounts of BTC or TCF into 2g solution, their UV/

vis absorption and ﬂuorescence spectra display similar spectral

changes, a shorter absorption band with a peak at 345 nm than

that of 2g (Figure S3a ), and a turn-on ﬂ uorescence centered at

(72%), and the total yield of the last three steps was 56%. In

our synthesis, a one-pot reaction of 2r for 10 min at room

temperature can aﬀord 3r in 65% yield. In addition, although

incompletely alkylated amino for 2k, 2l, and 2q could react

with BTC, their target products were still obtained in good

yields (81, 52, and 75%). The results show a good substrate

compatibility for the reaction of 2-alkylpyridine N-oxides with

BTC/TEA under mild conditions.

Reaction Mechanism. As the conversion of 2g to 3g is

easy to be detected by UV/vis absorption spectroscopy and

ﬂuorescence spectroscopy, 2g was selected as a representative

for the mechanism study of the reactions of the N-oxides with

phosgene or its substitutes.

67 nm with a speciﬁc structure (Figure S3b), which reveals a

linear relationship with BTC or TCF in a low concentration

range (Figures 2c and S3 ).

First, the photophysical properties of 2g and 3g were

investigated by measuring their UV/vis absorption and

ﬂuorescence spectra in seven solvents (Figure S1). In seven

solvents, the ﬂuorescence response of 2g toward triphosgene in

Upon subsequent addition of TEA (1−2 equiv), the

ﬂuorescence continuously enhances. Beginning from 3 equiv

of TEA, a new ﬂuorescence peak at 397 nm appears and

enhances and reaches a maximum value at 5 equiv of TEA, and

it should be assigned to 3g (Figures 2b and S2b,d).

Furthermore, the time proﬁles of the reactions were

recorded by recording the ﬂuorescence intensity of 2g solution

after the addition of BTC or TCF at diﬀerent times. As shown

in Figure S4 , slow and small ﬂuorescence response for 2g

toward BTC or TCF was observed at 367 nm (inset of Figure

S4a) and 397 nm (Figure S4b), and the intensity continued to

increase and reach a maximum at about 20 min. However,

upon the addition of TEA, the spectral response of 2g toward

BTC is very fast, reaching a ﬂuorescence maximum within 10 s

the presence of TEA is the largest in acetonitrile (CH CN).

This should be attributed to the low background ﬂuorescence

of 2g, the possible eﬃcient conversion from 2g to 3g, and the

high ﬂuorescence eﬃciency of 3g in acetonitrile. The N-oxide

2g is nonﬂuorescent, and 3g exhibits strong ﬂuorescence with a

peak at 397 nm in acetonitrile, and its ﬂuorescence quantum

yield (Φ ) was measured to be 0.1 with quinine sulfate (Φ =

.546 in 1 N H SO ) as a reference. For this reason,

2 4

acetonitrile was used as the solvent in all solution measure-

ments.

Next, UV/vis absorption and ﬂuorescence spectra were used

to detect the reactions of 2g with phosgene, TCF, or BTC.

Similar absorption and ﬂuorescence spectra were observed

from the reaction mixtures of 2g with phosgene or BTC in the

absence or presence of TEA (Figure S2). The absorption

spectra of the mixtures display a shorter absorption maximum

(

Figure S4b ).

On the basis of the chemistry of pyridine N-oxides,

intermediates A, including A1 (Y = CCl O for TCF or BTC)

and A2 (Y = Cl for phosgene), were suggested and shown in

Scheme 2. The nucleophilic oxygen of 2g attacks the carbonyl

of (tri/di)phosgenes, and chlorine for (di)phosgene and

trichloromethoxyl for BTC are removed as a leaving group

(

345 nm) than that of 2g. The ﬂuorescence spectra of 2g with

phosgene are similar to those with TCF or BTC, i.e., the

ﬂuorescence maximum is at 367 nm. As a comparison, Figure 1

−

to form the intermediate A, chlorine ion (Cl ), or/and

phosgene (COCl ). At a low TEA concentration (1−2 equiv),

the increase of the ﬂuorescence may be ascribed to the

formation of phosgene, which causes 2g to be converted to

intermediate A2.

After the addition of TEA at high concentrations (3−10

equiv), the intermediate A2 would deprotonate to another

intermediate B (Scheme 2), and subsequently convert into an

ester C via a [3,3]-sigmatropic rearrangement. The ester

decomposes into the ﬁnal product 3g and releases CO under

the catalysis of TEA. No diﬀerence in the ﬂuorescence spectra

between C and 3g was observed (see below). This reaction

was displayed to be highly eﬃcient, and the major formation of

the product 3g was observed in the reaction mixture of 2g with

BTC/TEA, by HPLC analysis (Figure S5).

High-resolution mass spectra (HRMS) provide evidence for

intermediates A, shown in Figure S6. The peaks of 349.9756

and 349.9755 were found in the reaction systems of 2g with

BTC and TCF, respectively, and were consistent with the

Figure 1. Fluorescence spectra of 20 μM 2g, 20 μM 3g, and the

reaction mixture of 20 μM 2g solution with phosgene gas, TCF (20

μM) or BTC (20 μM) as well as BTC (20 μM) in the presence of

theoretical value (349.9748, Y = CCl O) of intermediate A1.

The peak of 252.0447 was found in the mixture of 2g with

TEA (5 equiv) in CH CN, excitation at 325 nm.

phosgene gas, which matches with the theoretical value

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Figure 2. (a) UV/vis absorption and (b) ﬂuorescence spectra of 20 μM 2g in CH CN upon addition of BTC (0−1 equiv), or further addition of

TEA (1−10 equiv), and (c) the plot of intensity vs [BTC] of the above solutions without TEA, excitation at 325 nm.

Scheme 2. Reaction of 2g with Phosgene and Its Substitutes (Phos) in the Presence of TEA via a Claisen Rearrangement

Figure 3. Time-dependent ﬂuorescence spectra of 20 μM 2g with 30 μM TEA upon the addition 10 μM BTC for 10 min, further addition of 70

μM (a), or alternative addition of 10 μM TEA and 10 μM BF solutions (b), λ = 325 nm. (c) The ratio of intensity at 397 to 367 nm from (b).

(252.0422, Y = Cl) of intermediate A2. In addition, the

additional step is required to chlorinate the alcohol with

formation of the sensing product 3g was conﬁrmed by HRMS,

a dominant m/z peak at 208.0521 was captured in the test

solution, which was corresponding to [3g + H]⁺(calcd

POCl . The rearrangement has been explained as a radical-

pair or an ion-pair mechanism. More current reports

suggest a hetero-Claisen rearrangement or a [3,3]-sigmatropic

08.0524) (Figure S7 ).

The Boekelheide reaction is a well-established procedure.

rearrangement.

In our system, there is no correlation between the yield of 2f

and solvent polarity (Table S1). This result does not support a

radical-pair or an ion-pair mechanism. In addition, an

interesting reversible process provides strong evidence for

the [3,3]-sigmatropic rearrangement as a pericyclic reaction.

Figure 3a shows time-dependent ﬂuorescence spectra of 2g

For the classical Boekelheide reaction, the 2-picoline N-oxide

heated with a large excess of (triﬂuoro)acetic anhydride is

converted to the ester via a hetero-Claisen rearrangement, and

after the hydrolysis of the ester, the corresponding alcohol is

obtained. If 2-chloromethylpyridine is the target product, an

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J. Org. Chem. 2021, 86, 8308−8318

equiv), and (c) the plot of ﬂuorescence increments at 397 nm vs the concentration of BTC from (b), λ = 325 nm.

Article

Figure 4. (a) UV/vis absorption and (b) ﬂuorescence spectra of 20 μM 2g with TEA (5 equiv) upon addition of diﬀerent amounts of BTC (0−0.5

Figure 5. Fluorescence spectra of 20 μM 2g with 100 μM TEA in CH CN after the addition of 20 μM BTC or 100 μM various analytes: DCP,

DCNP, (COCl) , SOCl , SO Cl , POCl , TsCl, and CH COCl, for 2 min (a) and 15 min (b). (c) Fluorescence enhancements at 397 nm from (a)

and (b), excitation at 325 nm, and a photograph of solutions in (b).

with 30 μM TEA solution upon the addition of 10 μM BTC.

Owing to the addition of BTC for 1−2 min, a turn-on

ﬂuorescence appears at 397 nm for C and gradually shifts to

Sensing Reaction in the Detection of Phosgene.

Phosgene is a serious threat to human and public safety due to

its easy availability and various ways of poisoning. Thus, it is

67 nm for B. Since the interaction between BTC and TEA

essential to develop facile, fast, and reliable molecular probes.

In recent years, the design and synthesis of phosgene

leads to the consumption of TEA, the pericyclic reaction

proceeds in the opposite direction from C to B. From 3 to 10

min, no change in the ﬂuorescence intensity at 367 nm was

observed until further addition of 70 μM TEA, and the

ﬂuorescence peak comes back to 397 nm (Figure 3a). This

reaction may proceed in diﬀerent directions under diﬀerent

conditions: from B (or A2) to C in alkaline solutions or from

C to B (or A2) in acidic solutions.

ﬂuorescent probes have attracted extensive attention. As

described above, 2g may be a good candidate to be used as a

“

turn-on” ﬂuorescent probe for phosgene.

In the presence of 5 equiv of TEA, upon the addition of

diﬀerent amounts of BTC (0−10 μM) into 20 μM 2g

solutions, the absorption and ﬂuorescence spectra are shown in

Figure 4. A decrease in the long-wavelength band and an

increase in the short-wavelength band with an isosbestic point

at 350 nm (Figure 4a) show that the sensing reaction is a

single and eﬀective transformation. Meanwhile, the ﬂuores-

cence spectra of 2g solutions exhibit a turn-on response with a

ﬂuorescence peak at 397 nm as shown in Figure 4b. The

ﬂuorescence intensity increases sharply with the concentration

of BTC reaching an 80-fold increase after the addition of 0.5

equiv of BTC. Based on the titration experiment, the limit of

detection (LOD) was found to be as low as 3.4 nM obtained

from the calculation in terms of 3N/S (Figure 4c).

The response time of 2g toward phosgene and its substitutes

was estimated by determining time-dependent ﬂuorescence

intensities at 397 nm of 2g with TCF, BTC, and TEA/BTC.

As shown in Figure S4, the ﬂuorescence intensity increases

rapidly and reaches a plateau within 10 s for the solution of 2g

with TEA after the addition of 0.5 equiv of BTC. However,

slow and small ﬂuorescence responses at 397 nm for the

To conﬁrm this idea, a tracking experiment was performed

by the alternative addition of TEA and BF to the reaction

mixture of 2g with BTC. As shown in Figure 3b, after the

second addition of TEA, the ﬂuorescence peak returns to 397

nm, that is, retransformation from B to C. Upon the addition

of BF , the ﬂuorescence peak at 397 nm comes back to that

centered at 367 nm again. This reversible process can be

repeated many times when TEA and BF are added alternately

(Figure 3c). Thus, the reaction can be “seen” as a [3,3]-

sigmatropic rearrangement.

As shown in Figure 3c, with the increasing number of cycles,

^t^h^eⁱⁿ^t^eⁿ^sⁱ^t^y^o^f^t^h^e^p^e^a^k^a^t³⁹⁷ⁿ^m⁽^o^r^t^h^e^r^a^tⁱ^o^o^f^F³97^/^F367

)

enhances after the addition of TEA, and the intensity of the

peak at 367 nm (or the ratio of F₃₉₇/F₃₆₇) reduces after the

addition of BF . This implies the gradual formation of 3g and

the consumption of intermediates A in the cyclic processes.

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solutions of 2g without TEA upon the addition of BTC or

TCF were observed at 397 nm (Figure S4b) or 367 nm (inset

of Figure S4a), and the intensity continued to increase and

reach a maximum at about 20 min. Therefore, speciﬁc

ﬂuorescence responses can be observed for 2g toward

phosgene or its substitutes, as a slow process with a peak at

analytes (Figure 7). These observations are completely in

agreement with the results from measurements in solutions.

Thus, the test strip exhibits good selectivity for phosgene over

other analytes.

67 nm for the solution without TEA, or a rapid process with a

peak at 397 nm for the solution with TEA.

To evaluate the selectivity of 2g with TEA for phosgene,

ﬂuorescence intensities at 397 nm were recorded before and

after the addition of various analytes. Various relevant analytes

were used to measure their ﬂuorescence response, including

nerve agent mimics (diethylchlorophosphate (DCP), dieth-

ylcyanophosphonate (DCNP)) and various acyl chlorides and

Figure 7. Photographs taken from 2g test strips upon exposure to 40

ppm phosgene and 80 ppm of various other analytes, except for NO

(1000 ppm), under room light (up) or 365 nm light (down). 0, blank;

, phosgene (BTC/TEA); 2, DCP; 3, DCNP; 4, (COCl) ; 5, SOCl ;

2 2

, SO Cl ; 7, CH COCl; 8, POCl ; 9, TsCl, in 10 μL of chloroform

analogues, oxalyl chloride ((COCl) ), thionyl chloride

solutions; and 10, NO.

(

SOCl ), sulfuryl chloride (SO Cl ), phosphorus oxychloride

2 2 2

POCl ), tosyl chloride (TsCl), and acetyl chloride

CH COCl). The ﬂuorescence spectra were recorded twice:

after the addition of an analyte for 2 and 15 min. Only BTC

induces two diﬀerent ﬂuorescence spectra, centered at 397 nm

at 2 min (Figure 5a) and 367 nm at 15 min, respectively

CONCLUSIONS

■

In summary, we have developed a highly eﬀective 2-methyl

chlorination method of N-oxides of 2-methylpyridines,

including four sets of compounds (18 substrates) with BTC

in the presence of TEA at room temperature. The reactions are

rapid and only HCl and CO are generated as byproducts, and

their yields are in the range of 52−95%. The reaction via a

3,3]-sigmatropic rearrangement has been demonstrated by

(Figure 5b). The largest ﬂuorescence increase of 2g solution

only toward BTC, a small increase for CH COCl, (COCl) ,

and POCl , and no signiﬁcant change for other analytes were

observed (Figure 5c). The ﬂuorescence proﬁles show excellent

selectivity for (tri)phosgene over other analytes. The sensing

behavior can be easily observed by naked eyes (inset in Figure

[

monitoring the intermediates. The rearrangement as a

reversible process, forward under alkaline conditions, and

backward under acidic conditions have been observed in the

reaction of 2g with BTC. Furthermore, 2g has been used as a

ﬂuorescent probe for phosgene and its substitutes with high

selectivity. The sensing reaction of 2g toward phosgene, TCF,

or BTC is very fast (10 s) and sensitive (3.4 nM for BTC) in

the presence of TEA, and the test strip with 2g was fabricated

for the rapid and selective detection of phosgene below the

level leading to health risk. Therefore, the reaction of α-

picoline-N-oxides will be eﬀectively used in the synthesis of 2-

chloromethylpyridine derivatives and the design of new

ﬂuorescent probes for phosgene.

c). Hence, 2g displays high selectivity for phosgene over other

relevant analytes.

To develop a facile, fast, and reliable detection method for

phosgene gas, the test strip with 2g with trioctylamine (a

tertiary amine with a higher boiling point over TEA) was

prepared using polyethylene oxide, immobilizing 2g on a ﬁlter

paper. A weighing bottle was used as the detection device

(Figure S8 ). A trace phosgene solution was placed at the

bottom of the bottle and the test paper was hanged in the

bottle. Upon exposure to various amounts of phosgene (0−40

ppm), the test papers emit blue ﬂuorescence under a portable

UV lamp, and the ﬂuorescence intensity increases with

increasing phosgene (Figure 6 ). Upon exposure to 20 ppm

EXPERIMENTAL SECTION

Materials and Instruments. All chemicals for synthesis were

■

purchased from commercial suppliers and used as received without

further puriﬁcation. H, C{ H}, and F NMR spectra were

measured in CDCl or dimethyl sulfoxide (DMSO)-d with a Bruker

AV spectrometer operating at 400 or 500 MHz, 100 or 125 MHz, and

76 MHz, respectively. Chemical shifts were reported in ppm using

tetramethylsilane (TMS) as the internal standard. Mass spectra were

obtained with a Thermo LTQ Orbitrap mass spectrometer. UV−vis

absorption and ﬂuorescence emission spectra were recorded with a

Shimadzu UV-2450 UV/vis spectrometer and a Shimadzu RF-5301pc

luminescence spectrometer, respectively. The reaction mixtures of the

2-methylpyridine N-oxide with triphosgene were analyzed by an

Agilent 1200 HPLC with a C-18 reversed-phase column.

Figure 6. Photographs taken from 2g test strips upon exposure to

various amounts of phosgene (0−40 ppm) under room light (up) or

365 nm light (down).

Synthesis and Characterization of Related Compounds.

19a 19a

19b

19c

19d

19c

19e

19f

of phosgene gas, the test strip can produce a notable

Compounds 1m, 4, 2a, 2b, 2c, 2d, 2e, 2f, and

19g

ﬂuorescence response. According to Matheson gas data

were obtained according to the methods in the literature.

7 20a 20b 20b 20c 6b 10

Compounds 3a, 3b, 3c,

3d,

3e, 3f, and 3r are the

book, the test strip with 2g can detect lower the

concentration level leading to a health risk.

known compounds, which were obtained by the method in this work.

Synthesis of tert-Butyl Ethyl(2-methylquinolin-6-yl)carbamate

1n). A mixture of N-ethyl-2-methylquinolin-6-amine (440 mg, 2.36

The selectivity of the test strip with 2g for phosgene over

related analytes was also investigated. After exposure to

phosgene gas or vapors of related analytes for 5 min, the test

strip exposed only to phosgene emits the blue ﬂuorescence and

no observable changes can be observed for vapors of other

(

mmol), tert-butyl dicarbonate (619 mg, 2.83 mmol), and dioxane (30

mL) was stirred at 80 °C under a N atmosphere for 12 h. After

cooling to room temperature, the solvent was evaporated to generate

a crude residue, the crude product was puriﬁed by silica gel

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chromatography using petroleum/acetic ether (15:1) as an eluent to

Synthesis of 7-Methoxy-2-methylquinoline 1-Oxide (2g). Follow-

ing the same general procedure as for the synthesis of 2, compound

isolate pure compound 1n as a white solid (460 mg, 75%): R = 0.50

(

petroleum ether (PE)/ethyl acetate (EA) 3:1); H NMR (400 MHz,

2g was obtained as a pale yellow solid (447 mg, 89%): R = 0.40

CDCl , 25 °C, TMS): δ = 8.01 (dd, J = 8.5, 5.1 Hz, 2H, Ar−H),

(MeOH/DCM 1:20); H NMR (400 MHz, CDCl , 25 °C, TMS): δ

.59−7.53 (m, 2H, Ar−H), 7.29 (d, J = 8.5 Hz, 1H, Ar−H), 3.78 (q, J

7.1 Hz, 2H, CH ), 2.76 (s, 3H, CH ), 1.45 (s, 9H, CH ), 1.20 (t, J

7.1 Hz, 3H, CH ); C{ H} NMR (100 MHz, CDCl , 25 °C,

= 8.14 (d, J = 2.4 Hz, 1H, Ar−H), 7.72 (d, J = 8.9 Hz, 1H, Ar−H),

7.61 (d, J = 8.4 Hz, 1H, Ar−H), 7.24−7.19 (m, 2H, Ar−H), 4.01 (s,

2 3 3

3H, CH ), 2.74 (s, 3H, CH ); C{ H} NMR (125 MHz, CDCl , 25

TMS): δ = 158.8, 154.5, 146.0, 139.9, 136.0, 129.8, 128.9, 126.5,

23.8, 122.2, 80.4, 45.1, 28.4, 25.3; HRMS (electrospray ionization

ESI)) m/z: [M + H]⁺calcd for C H N O 287.1754; found

°C, TMS): δ = 162.0, 146.5, 142.8, 129.3, 125.5, 124.2, 120.7, 120.4,

98.2, 55.9, 18.9; HRMS (ESI) m/z: [M + H] calcd for C H NO

(

190.0863; found 190.0863.

87.1752.

Synthesis of 2-Methyl-7-(triﬂuoromethyl)quinoline 1-Oxide (2h).

Following the same general procedure as for the synthesis of 2,

Synthesis of N-Ethyl-N-(2-methylquinolin-6-yl)acetamide (1o). A

mixture of N-ethyl-2-methylquinolin-6-amine (250 mg, 1.34 mmol)

compound 2h was obtained as a white solid (534 mg, 88%): R = 0.43

and Ac O (164 mg, 1.61 mmol) in pyridine (10 mL) was stirred at 25

(MeOH/DCM 1:20); H NMR (400 MHz, CDCl , 25 °C, TMS): δ

C for 1 hour. After completion of the reaction time, pyridine was

= 9.11 (s, 1H, Ar−H), 7.98 (d, J = 8.5 Hz, 1H, Ar−H), 7.79 (dd, J =

8.5, 1.6 Hz, 1H, Ar−H), 7.72 (d, J = 8.6 Hz, 1H, Ar−H), 7.47 (d, J =

evaporated to generate a crude residue, which was puriﬁed by silica

gel chromatography to give compound 1o as a pale yellow oil (276

8.6 Hz, 1H, Ar−H), 2.76 (s, 3H, CH ); C{ H} NMR (100 MHz,

mg, 90%): R = 0.43 (PE/EA 1:3); H NMR (400 MHz, CDCl , 25

CDCl , 25 °C, TMS): δ = 147.1, 141.0, 132.0 (q, J

= 33.3 Hz),

C−F

C, TMS): δ = 8.09 (t, J = 8.3 Hz, 2H, Ar−H), 7.60 (s, 1H, Ar−H),

.49 (d, J = 8.5 Hz, 1H, Ar−H), 7.37 (d, J = 8.3 Hz, 1H, Ar−H), 3.85

q, J = 7.0 Hz, 2H, CH ), 2.79 (s, 3H, CH ), 1.88 (s, 3H, CH ), 1.16

130.8, 129.4, 125.2, 124.4, 123.7 (q, J_C₋_F= 3.2 Hz), 124.6 (q, J

C−F

273.9 Hz), 118.0 (q, JC−F = 4.6 Hz), 18.8; F NMR (376 MHz,

(

CDCl

for C11

Synthesis of 6-(Diethylamino)-2-methylquinoline 1-Oxide (2i). A

mixture of acetaldehyde (150 mg, 3.40 mmol) and 3 M H SO (0.2

, 25 °C, TMS): δ = −62.6; HRMS (ESI) m/z: [M + H] calcd

t, J = 6.9 Hz, 3H, CH ); C{ H} NMR (100 MHz, CDCl , 25 °C,

H F

9 3

NO 228.0631; found 228.0630.

TMS): δ = 170.0, 160.0, 146.7, 140.0, 136.1, 130.4, 129.8, 126.7,

calcd for C H N O 229.1335; found 229.1332.

Synthesis of N-Ethyl-2,2,2-triﬂuoro-N-(2-methylquinolin-6-yl)-

acetamide (1p). A mixture of N-ethyl-2-methylquinolin-6-amine

(

26.3, 122.9, 44.0, 25.3, 23.0, 13.1; HRMS (ESI) m/z: [M + H]

mL) was stirred in tetrahydrofuran (THF) at 0 °C for 10 min and

then added to the solution of 2k (100 mg, 0.49 mmol) in THF (5

mL) and NaBH (40 mg, 1.06 mmol). The mixture was stirred at

330 mg, 1.77 mmol), triethylamine (233 mg, 2.30 mmol), and DCM

15 mL) was stirred at 0 °C for 10 min, and then triﬂuoroacetic

room temperature for 5 h. The residue was neutralized with ammonia,

and the organic phase was dried with MgSO , and the ﬁltrate was

anhydride (TFAA) (485 mg, 2.30 mmol) was added dropwise to the

mixture over 30 min. The solution was stirred at room temperature

until the thin-layer chromatography (TLC) showed no raw material.

After completion of the reaction time, the solution was washed with

evaporated to aﬀord a crude product. The crude product was puriﬁed

by column chromatography to aﬀord compound 2i as a brown oil (64

mg, 56%): R = 0.54 (MeOH/DCM 1:20); H NMR (400 MHz,

CDCl , 25 °C, TMS): δ = 8.57 (d, J = 9.7 Hz, 1H, Ar−H), 7.44 (d, J

saturated aqueous NaHCO solution (1 × 5 mL), the organic phase

= 8.6 Hz, 1H, Ar−H), 7.25 (d, J = 2.7 Hz, 1H, Ar−H), 7.14 (d, J =

8.6 Hz, 1H, Ar−H), 6.74 (d, J = 2.3 Hz, 1H, Ar−H), 3.46 (q, J = 7.1

Hz, 4H, CH ), 2.65 (s, 3H, CH ), 1.23 (t, J = 7.1 Hz, 6H, CH );

was then dried over anhydrous Na SO . The ﬁltrate was evaporated to

aﬀord a crude product, which was puriﬁed by silica gel

chromatography to give compound 1p as a yellow liquid (400 mg,

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ = 146.6, 141.5,

0%): R = 0.46 (PE/EA 2:1); H NMR (400 MHz, CDCl , 25 °C,

134.5, 131.2, 124.3, 123.0, 120.5, 118.8, 104.1, 44.7, 18.3, 12.5;

TMS): δ = 8.09 (t, J = 7.7 Hz, 2H, Ar−H), 7.64 (d, J = 1.5 Hz, 1H,

Ar−H), 7.51 (dd, J = 8.9, 2.3 Hz, 1H, Ar−H), 7.38 (d, J = 8.5 Hz, 1H,

Ar−H), 3.88 (s, 2H, CH ), 2.79 (s, 3H, CH ), 1.24 (t, J = 7.2 Hz, 3H,

HRMS (ESI) m/z: [M + H] calcd for C H N O 231.1492; found

231.1492.

Synthesis of 6-(Ethyl(methyl)amino)-2-methylquinoline 1-Oxide

(2j). A mixture of 37% formaldehyde solution (60 mg, 3.40 mmol)

and 3 M H SO (0.2 mL) was stirred in THF at 0 °C for 10 min and

CH ); C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ = 160.7,

56.5 (q, J

= 35.7 Hz), 147.2, 136.3, 135.9, 130.4, 129.3, 127.1,

C−F

26.2, 123.1, 116.3 (q, J

= 288.5 Hz), 46.9, 25.4, 12.2; F NMR

then added to the solution of 2k (100 mg, 0.49 mmol) in THF (5

C−F

(

376 MHz, CDCl , 25 °C, TMS): δ = −67.2; HRMS (ESI) m/z: [M

mL) and NaBH (40 mg, 1.06 mmol). The mixture was stirred at

room temperature for 5 h. The residue was neutralized with ammonia,

H] calcd for C H F N O 283.1053; found 283.1054.

Synthesis of 2,2,2-Triﬂuoro-N-(2-methylquinolin-6-yl)acetamide

and the organic phase was dried with MgSO , and the ﬁltrate was

evaporated to aﬀord a crude product. The crude product was puriﬁed

(

1q). Following the same procedure as for the synthesis of 1p, using 2-

methylquinolin-6-amine (500 mg, 3.18 mmol), triethylamine (420

mg, 4.13 mmol), and TFAA (870 mg, 4.13 mmol) as materials in 20

by column chromatography to aﬀord compound 2j as a yellow oil (60

mg, 56%): R = 0.49 (MeOH/DCM 1:20); H NMR (400 MHz,

mL DCM, 1q was obtained as a white solid (570 mg, 70%): R = 0.46

CDCl , 25 °C, TMS): δ = 8.59 (d, J = 9.6 Hz, 1H, Ar−H), 7.43 (d, J

(

PE/EA 2:1); H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 8.90

= 8.6 Hz, 1H, Ar−H), 7.29 (dd, J = 9.6, 2.6 Hz, 1H, Ar−H), 7.14 (d, J

= 8.6 Hz, 1H, Ar−H), 6.73 (d, J = 2.6 Hz, 1H, Ar−H), 3.51 (q, J = 7.1

Hz, 2H, CH ), 3.02 (s, 3H, CH ), 2.65 (s, 3H, CH ), 1.18 (t, J = 7.1

s, 1H, Ar−H), 8.33 (d, J = 2.4 Hz, 1H, Ar−H), 8.03 (d, J = 8.5 Hz,

H, Ar−H), 7.98 (d, J = 9.0 Hz, 1H, Ar−H), 7.64 (dd, J = 9.0, 2.5 Hz,

H, Ar−H), 7.32 (d, J = 8.5 Hz, 1H, Ar−H), 2.74 (s, 3H, CH );

Hz, 3H, CH ); C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ =

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ = 159.3, 155.2 (q,

154.3, 146.7, 141.7, 134.3, 129.2, 128.0, 122.1, 119.2, 105.2, 47.1,

²J

= 37.6 Hz), 145.7, 136.3, 132.5, 129.7, 126.7, 123.1, 122.9,

37.7, 24.9, 11.4; HRMS (ESI) m/z: [M + H] calcd for C H N O

C−F

13 17

17.9, 115.7 (q, J_C₋_F= 289.78 Hz), 25.1; F NMR (376 MHz,

217.1335; found 217.1332.

CDCl , 25 °C, TMS): δ = −75.5; HRMS (ESI) m/z: [M + H] calcd

Synthesis of 6-(Ethylamino)-2-methylquinoline 1-Oxide (2k).

Compound 2p (300 mg, 1.00 mmol) and NaOEt (680 mg, 10.00

mmol) were dissolved in EtOH (10 mL). The mixture was stirred at

54 °C. After 20 h, the reaction mixture was allowed to cool to room

temperature, CH Cl (5 mL) and saturated ammonium chloride

for C H F N O 255.0740; found 255.0743.

General Method for the Synthesis of 2-Methylpyridine N-Oxide

Derivatives (2). 2-Methylpyridine (2.66 mmol, 1.0 equiv) was

dissolved in DCM (20 mL) and cooled to 0 °C. Next, 85% 3-

chloroperbenzoic acid (m-CPBA) (2.66 mmol, 1.0 equiv) was added

to the solution in portions over 30 min and then stirred for 12 h at

room temperature. Finally, solid K CO (3.99 mmol, 1.5 equiv) was

solution (5 mL) were added and the phases were separated. The

organic phase was dried (Na SO ) and concentrated, which was

puriﬁed by silica gel chromatography to give compound 2k as a yellow

added, and the resulting mixture was stirred for an additional 30 min.

The solid was separated by ﬁltration, and the ﬁltrate was evaporated

to aﬀord a crude product, which was puriﬁed by silica gel

chromatography to give 2-methylpyridine N-oxide.

solid (150 mg, 75%): R = 0.24 (MeOH/DCM 1:20); H NMR (400

MHz, CDCl , 25 °C, TMS): δ = 8.53 (d, J = 9.4 Hz, 1H, Ar−H), 7.42

(d, J = 8.6 Hz, 1H, Ar−H), 7.15 (d, J = 8.6 Hz, 1H, Ar−H), 7.06 (dd,

J = 9.4, 2.5 Hz, 1H, Ar−H), 6.66 (d, J = 2.5 Hz, 1H, Ar−H), 3.23 (q, J

314

J. Org. Chem. 2021, 86, 8308−8318

The Journal of Organic Chemistry

Article

7.2 Hz, 2H, CH ), 2.64 (s, 3H, CH ), 1.32 (t, J = 7.2 Hz, 3H, CH );

(d, J = 8.6 Hz, 1H, Ar−H), 7.59 (d, J = 8.6 Hz, 1H, Ar−H), 2.56 (s,

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ = 147.2, 141.8,

3H, CH ); C{ H} NMR (100 MHz, DMSO, 25 °C, TMS): δ =

35.7, 131.2, 124.0, 123.1, 121.4, 120.4, 103.0, 38.3, 18.3, 14.5;

155.4 (q, JC−F = 37.4 Hz), 145.1, 138.8, 136.0, 129.7, 124.8, 124.6,

HRMS (ESI) m/z: [M + H] calcd for C H N O 203.1179; found

124.4, 120.4, 118.9, 116.1 (q, JC−F = 289.6 Hz), 18.5; F NMR (376

203.1180.

MHz, DMSO, 25 °C, TMS): δ = −73.9; HRMS (ESI) m/z: [M +

Synthesis of 6-Amino-2-methylquinoline 1-Oxide (2l). Using

H] calcd for C12

271.0689; found 271.0691.

compound 2q (270 mg, 1.00 mmol), NaOEt (680 mg, 10.00 mmol),

and EtOH (10 mL) as materials to follow the same procedure as for

the synthesis of 2k, compound 2l was obtained as a yellow solid (155

mg, 89%): R = 0.46 (MeOH/DCM 1:30); H NMR (400 MHz,

General Method for the Synthesis of 2-Chloromethylpyridine

Derivatives (3). Compound 2 (2.11 mmol, 1.0 equiv) and TEA

(

¹⁰^.⁵⁵^m^m^o^l^,⁵^.⁰^e^q^uⁱ^v⁾^w^e^r^e^dⁱ^s^s^o^l^v^e^dⁱⁿ^D^C^M⁽²⁰^m^L⁾^uⁿ^d^e^r^a^N2

atmosphere and cooled to 0 °C. Next, the DCM solution (2 mL) of

triphosgene (1.06 mmol, 0.5 equiv) was added to the solution in

portions over 10 min. After removing the ice bath, the solution was

stirred for 20 min at room temperature. The reaction mixture was

DMSO, 25 °C, TMS): δ = 8.26 (d, J = 9.2 Hz, 1H, Ar−H), 7.46 (d, J

8.6 Hz, 1H, Ar−H), 7.31 (d, J = 8.6 Hz, 1H, Ar−H), 7.13 (d, J =

.3 Hz, 1H, Ar−H), 6.83 (d, J = 2.2 Hz, 1H, Ar−H), 5.77 (s, 2H,

13 1

adjusted to neutral with NaHCO solution and then extracted with

NH ), 2.46 (s, 3H, CH ); C{ H} NMR (100 MHz, DMSO, 25 °C,

TMS): δ = 148.5, 140.4, 134.7, 131.4, 123.7, 122.6, 121.6, 120.1,

DCM (2 × 10 mL). The organic phase was washed with water twice,

05.9, 18.2; HRMS (ESI) m/z: [M + H]⁺calcd for C H N O

dried with anhydrous Na SO , and ﬁltered, and the solvent was

removed in vacuo. The residue was chromatographed on silica gel to

get the corresponding 2-chloromethylpyridine derivatives 3.

Compounds 3a−f and 3r were prepared by following the same

general procedure as for the synthesis of 3: 3a as a yellow oil (151 mg,

56%), 3b as a yellow oil (105 mg, 35%), 3c as a pale red oil (114 mg,

75.0866; found 175.0869.

Synthesis of 6-(tert-Butoxycarbonyl(butyl)amino)-2-methylqui-

noline 1-Oxide (2m). Following the same general procedure as for the

synthesis of 2, 2m was obtained as a pale yellow solid (819 mg, 93%):

R = 0.53 (MeOH/DCM 1:20); H NMR (400 MHz, CDCl , 25 °C,

8%), 3d as a claybank oil (90 mg, 30%), 3e as a yellow oil (127 mg,

6%), 3f as a pale yellow oil (210 mg, 56%), and 3r as a white solid

TMS): δ = 8.72 (d, J = 9.2 Hz, 1H, Ar−H), 7.64 (t, J = 8.9 Hz, 3H,

Ar−H), 7.33 (d, J = 8.5 Hz, 1H, Ar−H), 3.74 (t, J = 3.7 Hz, 2H,

CH ), 2.73 (s, 3H, CH ), 1.59−1.52 (m, 2H, CH ), 1.45 (s, 9H,

(189 mg, 37%).

Synthesis of 2-(Chloromethyl)-7-methoxyquinoline (3g). Follow-

ing the same general procedure as for the synthesis of 3, 3g was

CH ), 1.35−1.30 (m, 2H, CH ), 0.90 (t, J = 7.4 Hz, 3H, CH );

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ = 154.3, 145.9,

obtained as a pale yellow solid (285 mg, 65%): R = 0.60 (PE/EA

42.2, 139.4, 130.5, 129.5, 125.4, 123.9, 123.4, 120.1, 80.8, 49.8, 30.7,

8.3, 19.9, 18.8, 13.8; HRMS (ESI) m/z: [M + H] calcd for

6:1); H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 8.12 (d, J = 8.3

Hz, 1H, Ar−H), 7.70 (d, J = 9.0 Hz, 1H, Ar−H), 7.47 (d, J = 8.3 Hz,

C H N O 331.2016; found 331.2012.

H, Ar−H), 7.41 (d, J = 2.3 Hz, 1H, Ar−H), 7.22 (dd, J = 8.9, 2.5 Hz,

Synthesis of 6-(tert-Butoxycarbonyl(ethyl)amino)-2-methylqui-

13 1

H, Ar−H), 4.82 (s, 2H, CH −Cl), 3.95 (s, 3H, CH ); C{ H}

noline 1-Oxide (2n). Following the same general procedure as for the

synthesis of 2, 2n was obtained as a pale yellow solid (645 mg, 80%):

NMR (100 MHz, CDCl , 25 °C, TMS): δ = 161.2, 156.8, 149.1,

137.1, 128.6, 122.7, 120.4, 118.3, 106.9, 55.6, 47.2; HRMS (ESI) m/z:

R = 0.52 (MeOH/DCM 1:20); H NMR (400 MHz, CDCl , 25 °C,

[

M + H] calcd for C H ClNO 208.0524; found 208.0523.

TMS): δ = 8.72 (d, J = 9.2 Hz, 1H, Ar−H), 7.66−7.62 (m, 3H, Ar−

11 11

Synthesis of 2-Methyl-7-(triﬂuoromethyl)quinoline 1-Oxide (3h).

Following the same general procedure as for the synthesis of 3, 3h was

H), 7.32 (t, J = 7.1 Hz, 1H, Ar−H), 3.80 (q, J = 7.1 Hz, 2H, CH ),

.74 (s, 3H, CH ), 1.45 (s, 9H, CH ), 1.21 (t, J = 7.1 Hz, 3H, CH );

obtained as a pale green solid (265 mg, 51%): R = 0.65 (PE/EA 6:1);

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ = 154.1, 145.9,

H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 8.42 (d, J = 0.8 Hz,

42.1, 139.4, 130.4, 129.5, 125.4, 123.8, 123.4, 120.2, 80.9, 45.0, 28.3,

₈_.₈_,₁₄_.₀_;_H_R_M_S₍_E_S_I₎_m_/_z_:_[_M₊_H_]+ calcd for C H N O

03.1703; found 303.1703.

Synthesis of 6-(N-Ethylacetamido)-2-methylquinoline 1-Oxide

2o). Following the same general procedure as for the synthesis of 2,

o was obtained as a pale yellow solid (600 mg, 92%): R = 0.35

1H, Ar−H), 8.29 (d, J = 8.5 Hz, 1H, Ar−H), 7.97 (d, J = 8.5 Hz, 1H,

Ar−H), 7.75 (d, J = 8.5 Hz, 2H, Ar−H), 4.87 (s, 2H, CH −Cl);

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ = 158.3, 146.4,

(

137.2, 131.8 (q, JC−F = 32.9 Hz), 128.8, 128.8, 127.1 (q, JC−F = 4.5

Hz), 123.8 (q, JC−F = 273.6 Hz), 122.7 (q, JC−F = 3.0 Hz), 122.4, 46.9;

(

MeOH/DCM 1:20); H NMR (400 MHz, CDCl , 25 °C, TMS): δ

F NMR (376 MHz, CDCl

, 25 °C, TMS): δ = −62.7; HRMS (ESI)

8.85 (d, J = 9.1 Hz, 1H, Ar−H), 7.66 (dd, J = 5.0, 3.3 Hz, 2H, Ar−

H), 7.55 (d, J = 9.2 Hz, 1H, Ar−H), 7.41 (d, J = 8.6 Hz, 1H, Ar−H),

.85 (q, J = 7.1 Hz, 2H, CH ), 2.73 (d, J = 16.0 Hz, 3H, CH ), 1.87

m/z: [M + H] calcd for C11

ClF N 246.0292; found 246.0293.

Synthesis of 2-(Chloromethyl)-N,N-diethylquinolin-6-amine (3i).

Following the same general procedure as for the synthesis of 3, 3i was

(

s, 3H, CH ), 1.16 (t, J = 7.0 Hz, 3H, CH ); C{ H} NMR (100

obtained as a yellow oil (226 mg, 43%): R

NMR (400 MHz, CDCl

= 0.65 (PE/EA 6:1); H

MHz, CDCl , 25 °C, TMS): δ = 169.6, 146.5, 142.2, 140.6, 130.5,

, 25 °C, TMS): δ = 7.91 (dd, J = 13.2, 9.0

29.8, 126.7, 124.6, 124.2, 121.8, 44.0, 23.0, 18.8, 13.2; HRMS (ESI)

Hz, 2H, Ar−H), 7.42 (d, J = 8.5 Hz, 1H, Ar−H), 7.30 (dd, J = 9.4, 2.8

m/z: [M + H] calcd for C H N O 245.1285; found 245.1281.

Hz, 1H, Ar−H), 6.75 (d, J = 2.5 Hz, 1H, Ar−H), 4.79 (s, 2H, CH

−

);

Synthesis of 6-(N-Ethyl-2,2,2-triﬂuoroacetamido)-2-methylqui-

Cl), 3.47 (q, J = 7.1 Hz, 4H, CH ), 1.23 (t, J = 7.1 Hz, 6H, CH

noline 1-Oxide (2p). Following the same general procedure as for the

synthesis of 2, compound 2p was obtained as a white solid (692 mg,

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ 151.5, 146.3,

140.8, 135.0, 129.9, 129.5, 120.8, 119.3, 103.7, 47.7, 44.7, 12.6;

7%): R = 0.60 (MeOH/DCM 1:20); H NMR (400 MHz, CDCl ,

5 °C, TMS): δ = 8.87 (d, J = 9.2 Hz, 1H, Ar−H), 7.71 (s, 1H, Ar−

HRMS (ESI) m/z: [M + H] calcd for C H ClN 249.1153; found

14 18

249.1150.

H), 7.67 (d, J = 8.6 Hz, 1H, Ar−H), 7.58 (dd, J = 9.2, 2.0 Hz, 1H,

Ar−H), 7.43 (d, J = 8.6 Hz, 1H, Ar−H), 3.89 (d, J = 5.8 Hz, 2H,

Synthesis of 2-(Chloromethyl)-N-ethyl-N-methylquinolin-6-

amine (3j). Following the same general procedure as for the synthesis

CH ), 2.75 (s, 3H, CH ), 1.24 (t, J = 7.1 Hz, 3H, CH ); C{ H}

of 3, 3j was obtained as a yellow oil (134 mg, 27%): R

= 0.54 (PE/EA

1:3); H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 7.90 (d, J = 8.5

NMR (100 MHz, CDCl , 25 °C, TMS): δ = 156.3 (q, J

Hz), 147.2, 141.1, 138.1, 130.1, 129.3, 127.6, 124.8, 124.5, 121.8,

= 36.0

C−F

Hz, 1H, Ar−H), 7.86 (d, J = 9.4 Hz, 1H, Ar−H), 7.38 (d, J = 8.5 Hz,

116.2 (q, J_C₋_F= 298.2 Hz), 46.9, 18.9, 12.3; F NMR (376 MHz,

1H, Ar−H), 7.29 (dd, J = 9.4, 2.8 Hz, 1H, Ar−H), 6.70 (d, J = 2.8 Hz,

CDCl , 25 °C, TMS): δ = −67.1; HRMS (ESI) m/z: [M + H] calcd

for C H F N O 299.1002; found 299.1004.

1H, Ar−H), 4.74 (s, 2H, CH

(s, 3H, CH

MHz, CDCl , 25 °C, TMS): δ = 151.8, 147.6, 140.9, 135.3, 129.6,

), 3.46 (q, J = 7.1 Hz, 2H, CH

), 2.97

), 1.12 (t, J = 7.1 Hz, 3H, CH ); C{ H} NMR (100

3 3

Synthesis of 2-Methyl-6-(2,2,2-triﬂuoroacetamido)quinoline 1-

Oxide (2q). Following the same general procedure as for the synthesis

of 2, compound 2q was obtained as a white solid (534 mg, 74%): R =

129.3, 120.9, 119.6, 104.4, 47.6, 47.0, 37.7, 11.5; HRMS (ESI) m/z:

[M + H] calcd for C H ClN 235.0997; found 235.1002.

13 16

.26 (MeOH/DCM 1:20); H NMR (400 MHz, DMSO, 25 °C,

Synthesis of 2-(Chloromethyl)-N-ethylquinolin-6-amine (3k).

Following the same general procedure as for the synthesis of 3, 3k

TMS): δ = 11.67 (s, 1H, NH), 8.57 (d, J = 9.4 Hz, 1H, Ar−H), 8.44

(d, J = 2.2 Hz, 1H, Ar−H), 7.97 (dd, J = 9.4, 2.3 Hz, 1H, Ar−H), 7.86

was obtained as a pale yellow solid (247 mg, 53%): R = 0.55 (PE/EA

315

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Article

:1); H NMR (500 MHz, CDCl , 25 °C, TMS): δ = 8.23 (d, J = 8.5

7.66 (d, J = 8.5 Hz, 1H, Ar−H), 7.51 (d, J = 2.1 Hz, 1H, Ar−H), 7.48

Hz, 1H, Ar−H), 8.15 (d, J = 8.9 Hz, 1H, Ar−H), 7.72 (s, 1H, Ar−H),

(dd, J = 8.9, 2.3 Hz, 1H, Ar−H), 4.85 (s, 2H, CH −Cl); C{ H}

.70 (d, J = 3.2 Hz, 1H, Ar−H), 7.58 (d, J = 8.4 Hz, 1H, Ar−H), 4.85

NMR (125 MHz, CDCl , 25 °C, TMS): δ = 157.4, 146.1, 141.8,

(

s, 2H, CH −Cl), 3.90 (s, 2H, CH ), 1.27 (t, J = 6.7 Hz, 3H, CH );

137.4, 133.6 (q, J = 43.6 Hz), 130.7, 127.5, 123.8, 121.5, 117.8, 116.8

C{ H} NMR (100 MHz, CDCl , 25 °C, TMS) δ 158.0, 146.6,

(q, J = 278.1 Hz), 47.1; F NMR (376 MHz, CDCl

, 25 °C, TMS):

39.8, 137.4, 131.0, 130.3, 127.5, 126.9, 121.4, 48.3, 47.1, 13.0;

HRMS (ESI) m/z: [M + H] calcd for C H ClN 221.0840; found

21.0840.

Synthesis of 2-(Chloromethyl)quinolin-6-amine (3l). Following

the same general procedure as for the synthesis of 3, 3l was obtained

as a yellow solid (118 mg, 29%): R = 0.5 (PE/EA 2:1); H NMR

δ = −71.6; HRMS (ESI) m/z: [M + H] calcd for C12

89.0350; found 289.0353.

Synthesis of N-Ethyl-2-methylquinolin-6-amine (5). A mixture

9 3 2

ClF N O

of 2-methylquinolin-6-amine (500 mg, 3.16 mmol), iodoethane (592

mg, 3.79 mmol), K CO (1.1 g, 7.9 mmol), and dimethylformamide

(

DMF) (15 mL) was stirred at 80 °C, reﬂuxed until the TLC showed

that no raw material exists. After cooling to room temperature, the

mixture was extracted with dichloromethane (10 mL × 3), the organic

phases were combined, then washed with water, and dried over

(

400 MHz, DMSO, 25 °C, TMS): δ = 8.01 (d, J = 8.5 Hz, 1H, Ar−

H), 7.72 (d, J = 9.0 Hz, 1H, Ar−H), 7.44 (t, J = 5.3 Hz, 1H, Ar−H),

.21 (dt, J = 8.9, 4.4 Hz, 1H, Ar−H), 6.84 (d, J = 2.5 Hz, 1H, Ar−H),

13 1

MgSO . The ﬁltrate was evaporated to generate a crude residue, and

.86 (s, 2H, CH −Cl); C{ H} NMR (100 MHz, DMSO, 25 °C,

the crude product was puriﬁed by silica gel chromatography using

TMS): δ = 151.4, 147.9, 141.2, 134.9, 129.7, 129.6, 122.7, 121.6,

petroleum/acetic ether (5:1) as an eluent to isolate compound 5 as a

05.3, 48.1; HRMS (ESI) m/z: [M + H] calcd for C H ClN

93.0527; found 193.0528.

Synthesis of tert-Butyl Butyl(2-(chloromethyl)quinolin-6-yl)-

carbamate (3m). Following the same general procedure as for the

synthesis of 3, 3m was obtained as a white solid (472 mg, 64%): R =

.68 (PE/EA 3:1); H NMR (500 MHz, CDCl , 25 °C, TMS): δ =

10 10 2

yellow oil (342 mg, 58%): H NMR (400 MHz, CDCl , 25 °C,

TMS): δ = 7.81 (t, J = 9.4 Hz, 2H, Ar−H), 7.15 (d, J = 8.4 Hz, 1H,

Ar−H), 7.05 (dd, J = 9.0, 2.6 Hz, 1H, Ar−H), 6.68 (d, J = 2.6 Hz, 1H,

Ar−H), 3.82 (s, 1H, NH), 3.24 (q, J = 7.1 Hz, 2H, CH ), 2.66 (s, 3H,

CH ), 1.32 (t, 3H, J = 7.1 Hz, CH ).

(

HPLC Analysis of the Yields of 2-Methylpyridine N-Oxides

with Triphosgene. The reaction mixtures of the 2-methylpyridine

N-oxide with triphosgene were analyzed by an Agilent 1200 HPLC

with a C-18 reversed-phase column. A solution of 0.1 mM 2-

methylpyridine N-oxide with 0.5 mM TEA was placed into a

centrifuge tube, then 0.05 mM triphosgene solution was added for 10

min, and ﬁnally analyzed by HPLC. First, pure compounds 2 and 3

were analyzed, the chromatographic peaks were assigned, and the

standard curve between the peak area and the concentration was

obtained. Then, the reaction mixture was analyzed and the yield was

obtained.

.15 (d, J = 8.5 Hz, 1H, Ar−H), 8.03 (d, J = 8.8 Hz, 1H, Ar−H), 7.61

dd, J = 13.1, 5.5 Hz, 3H, Ar−H), 4.84 (s, 2H, CH −Cl), 3.75 (t, J =

.5 Hz, 2H, CH ), 1.59−1.53 (m, 2H, CH ), 1.45 (s, 9H, CH ),

13 1

.37−1.29 (m, 2H, CH ), 0.90 (t, J = 7.4 Hz, 3H, CH ); C{ H}

NMR (125 MHz, CDCl , 25 °C, TMS): δ = 156.5, 154.5, 145.5,

41.2, 137.1, 130.4, 129.5, 127.5, 123.6, 120.8, 80.6, 49.9, 47.3, 30.7,

8.3, 19.9, 13.8; HRMS (ESI) m/z: [M + H] calcd for

C H ClN O 349.1677; found 349.1671.

Synthesis of tert-Butyl 2-(Chloromethyl)quinolin-6-yl(ethyl)-

carbamate (3n). Following the same general procedure as for the

synthesis of 3, 3n was obtained as a brown solid (407 mg, 60%): R =

.50 (PE/EA 6:1); H NMR (400 MHz, CDCl , 25 °C, TMS): δ =

Preparation of the 2g Test Paper. 2g (2 mg) with trioctylamine

3.74 mg) were dissolved in 20 mL of DCM. Then, poly(ethylene

−

(

.16 (d, J = 8.5 Hz, 1H, Ar−H), 8.03 (d, J = 8.8 Hz, 1H, Ar−H), 7.63

oxide) (1.5 g) was added in batches. The mixture was stirred until

poly(ethylene oxide) dissolved completely. The ﬁlter paper was

immersed in the solution and then taken out to dry in air. Finally, the

7.60 (m, 3H, Ar−H), 4.84 (s, 2H, CH −Cl), 3.80 (q, J = 7.1 Hz,

13 1

H, CH ), 1.46 (s, 9H, CH ), 1.21 (t, J = 7.1 Hz, 3H, CH ); C{ H}

NMR (100 MHz, CDCl , 25 °C, TMS): δ = 156.5, 154.3, 145.4,

41.1, 137.1, 130.4, 129.5, 127.6, 123.5, 120.8, 80.6, 47.2, 45.1, 28.4,

₄_.₀_;_H_R_M_S₍_E_S_I₎_m_/_z_:_[_M₊_H_]+ calcd for C H ClN O

21.1364; found 321.1366.

Synthesis of N-(2-(Chloromethyl)quinolin-6-yl)-N-ethylaceta-

mide (3o). Following the same general procedure as for the synthesis

paper with 2g was cut into strips (1.0 × 2.0 cm ) as the test paper for

the detection of phosgene in the gas phase.

Detection of the Gaseous Phase with the Testing Paper.

Detection of Phosgene Gas in Various Concentrations. Four

concentrations of triphosgene solutions, 0.97, 1.94, 2.90, and 3.87

mM, were prepared with DCM as a solvent, and 10 μL of solutions

were added to a container (65 mL) with an HPLC injection needle,

followed by the addition of 10 μL of DCM containing 0.1% TEA,

respectively, and ﬁnally the container was closed. After 5 min, a

photograph of the ﬂuorescence of the test papers together with a

blank was taken under 365 nm light.

of 3, 3o was obtained as a pale yellow oil (489 mg, 88%): R = 0.5

PE/EA 1:2); H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 8.23

(

d, J = 8.5 Hz, 1H, Ar−H), 8.15 (d, J = 8.9 Hz, 1H, Ar−H), 7.69 (d, J

8.5 Hz, 1H, Ar−H), 7.65 (d, J = 2.1 Hz, 1H, Ar−H), 7.55 (dd, J =

.9, 2.2 Hz, 1H, Ar−H), 4.86 (s, 2H, CH −Cl), 3.86 (q, J = 7.1 Hz,

13 1

H, CH ), 1.88 (s, 3H, CH ), 1.17 (t, J = 7.1 Hz, 3H, CH ); C{ H}

Selective Detection of Phosgene Gas over Vapor of Other

Analytes. DCM solutions of triphosgene (3.87 mM), NO (65 μL),

^aⁿ^d^o^t^h^e^r^aⁿ^a^l^y^t^e^s⁽²³^.²¹^m^M⁾^c^oⁿ^t^aⁱⁿⁱⁿ^g^D^C^P^,^D^C^N^P^,⁽^C^O^C^l⁾2^,

NMR (100 MHz, CDCl , 25 °C, TMS): δ = 169.8, 157.7, 146.3,

41.2, 137.3, 131.1, 130.4, 127.7, 126.3, 121.4, 47.1, 44.0, 23.0, 13.2;

HRMS (ESI) m/z: [M + H] calcd for C H ClN O 263.0946;

found 263.0942.

Synthesis of N-(2-(Chloromethyl)quinolin-6-yl)-N-ethyl-2,2,2-tri-

ﬂuoroacetamide (3p). Following the same general procedure as for

the synthesis of 3, 3p was obtained as a pale yellow oil (495 mg,

4%): R = 0.48 (PE/EA 3:1); H NMR (400 MHz, CDCl , 25 °C,

SOCl , SO Cl , CH COCl, POCl , and TsCl were prepared. Using an

HPLC injection needle, 10 μL of the above solution was placed at the

bottom of a weighing bottle, respectively (see the legend in Figure

S8). The concentration of analytes was calculated to be 40 ppm for

phosgene, 1000 ppm for NO, and 80 ppm for others.

TMS): δ = 8.25 (d, J = 8.5 Hz, 1H, Ar−H), 8.16 (d, J = 8.9 Hz, 1H,

Ar−H), 7.71 (d, J = 8.5 Hz, 2H, Ar−H), 7.57 (dd, J = 8.9, 2.3 Hz, 1H,

Ar−H), 4.86 (s, 2H, CH −Cl), 3.90 (s, 2H, CH ), 1.24 (t, J = 7.2 Hz,

ASSOCIATED CONTENT

■

* Supporting Information

The Supporting Information is available free of charge at

sı

H, CH ); C{ H} NMR (100 MHz, CDCl , 25 °C, TMS): δ =

58.3, 156.4 (q, J

= 35.8 Hz), 146.8, 137.5, 137.1, 131.1, 129.9,

C−F

27.2, 127.2, 121.6, 117.7 (q, J_C₋_F= 289.5 Hz), 47.0, 46.9, 12.3;

NMR (376 MHz, CDCl , 25 °C, TMS): δ = −67.1; HRMS (ESI) m/

Optimization of the reaction conditions; screening of

solvents in the reaction; spectral response of 2g toward

phosgene and its substitutes; HPLC analysis; HRMS for

the reaction mixture; detection in the gas phase; and

synthesis routes of related compounds as well as their

copies for NMR spectra (PDF)

z: [M + H] calcd for C H ClF N O 317.0663; found 317.0660.

Synthesis of N-(2-(Chloromethyl)quinolin-6-yl)-2,2,2-triﬂuoroa-

cetamide (3q). Following the same general procedure as for the

synthesis of 3, 3q was obtained as a pale yellow solid (305 mg, 50%):

R = 0.54 (PE/EA 5:1); H NMR (400 MHz, CDCl , 25 °C, TMS): δ

8.22 (d, J = 8.5 Hz, 1H, Ar−H), 8.15 (d, J = 8.9 Hz, 1H, Ar−H),

316

J. Org. Chem. 2021, 86, 8308−8318

The Journal of Organic Chemistry

10) Newkome, G. R.; Theriot, K. J.; Gupta, V. K.; Fronczek, F. R.;

Article

(

AUTHOR INFORMATION

■

Baker, G. R. Mono-a-Functionalization of 2,9-Dimethyl-1,10-Phenan-

throline. J. Org. Chem. 1989, 54, 1766−1769.

Corresponding Author

Qin-Hua Song − Department of Chemistry, University of

Science and Technology of China, Hefei 230026, P. R.

China; orcid.org/0000-0001-6501-1382;

Email: qhsong@ustc.edu.cn

(11) Dawson, W. R.; Windsor, M. W. Fluorescence Yields of

Aromatic Compounds. J. Phys. Chem. A 1968, 72, 3251−3260.

(

12) Li, J.-J. Boekelheide Reaction. Name Reaction. A Collection of

Detailed Reaction Mechanisms, 4th ed.; Springer-Verlag: Berlin, 2009;

pp 54−55.

(13) (a) Oae, S.; Kitao, T.; Kitaoka, Y. The Mechanism of the

Authors

Reaction of 2-Picoline N -Oxide with Acetic Anhydride. J. Am. Chem.

Soc. 1962 , 84 , 3359 −3362. (b) Oae, S.; Kozuka, S. Rearrangement of

Tertiary Amine Oxides. IX. Mechanism of Reaction of Quinaldine N -

oxide with Benzoyl Chloride. Tetrahedron 1964 , 20 , 2671 −2676.

Hao Li − Department of Chemistry, University of Science and

Technology of China, Hefei 230026, P. R. China

Hong-Cheng Xia − Department of Chemistry, University of

Science and Technology of China, Hefei 230026, P. R. China;

Present Address: Xinxiang Medical University, Xinxiang

c) Oae, S.; Kitaoka, Y.; Kitao, T. Rearrangement of Tertiary Amine

Oxides. XI. Solvent Effects on Reactions of 2- and 4-Picoline N -oxides

with Acetic Anhydride. Tetrahedron 1964 , 20 , 2685 −2689.

53003, P. R. China.

Fang-Yuan Nie − Department of Chemistry, University of

Science and Technology of China, Hefei 230026, P. R. China

(14) (a) Koenig, T. The Reaction of 2-Picoline N -oxide with

Substituted Acetic Anhydrides. J. Am. Chem. Soc. 1966 , 88 , 4045 −

4049. (b) Bodalski, R.; Katritzky, A. R. New Rearrangement Types in

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00749

Reactions of Acetic Anhydride with 2-Alkylpyridine 1-Oxide.

Tetrahedron Lett. 1968 , 257 −260. (c) Bodalski, R.; Katritzky, A. R.

N -Oxides and Related Compounds. Part XXXIII. The Mechanism of

the Acetic Anhydride Rearrangement of 2-Alkylpyridine 1-Oxides. J.

Chem. Soc. B 1968, 831−838. (d) Katritzky, A. R.; Lagowski, J. M.

Chemistry of the Heterocyclic N-Oxides; Academic Press: NY, 1971.

Author Contributions

H.L. and H.-C.X. contributed equally to this work.

†

Notes

(

e) Galatsis, P. Pyridines. In Name Reactions in Heterocyclic Chemistry;

Li, J.-J.; Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2005;

The authors declare no competing ﬁnancial interest.

Chapter 8, pp 340−349.

(

15) (a) Mori, T.; Satouchi, Y.; Tohmiya, H.; Higashibayashi, S.;

ACKNOWLEDGMENTS

■

Hashimoto, K.; Nakata, M. Synthetic Studies on Thiostrepton Family

of Peptide Antibiotics: Synthesis of the Dihydroquinoline Portion of

Thiostrepton, the Siomycins, and the Thiopeptins. Tetrahedron Lett.

2005, 46, 6417 −6422. (b) Wang, C.-S.; Roisnel, T.; Dixneuf, P. H.;

Soulé, J.-F. Synthesis of 2-Pyridinemethyl Ester Derivatives from

Aldehydes and 2-Alkylheterocycle N -Oxides via Copper-Catalyzed

Tandem Oxidative Coupling −Rearrangement. Org. Lett. 2017, 19,

6720−6723. (c) Yang, Y.; Qu, C.; Chen, X.; Sun, K.; Qu, L.; Bi, W.;

Hu, H.; Li, R.; Jing, C.; Wei, D.; Wei, S.; Sun, Y.; Liu, H.; Zhao, Y. A

Multiheteroatom [3,3]-Sigmatropic Rearrangement: Disproportiona-

tive Entries into 2-(N-Heteroaryl)methyl Phosphates and α -Keto

Phosphates. Org. Lett. 2017 , 19 , 5864 −5867. (d) Wang, C.-S.;

We are grateful for ﬁnancial support from the National Natural

Science Foundation of China (nos. 22074135 and 21772188)

and the Anhui Province Key Research and Development

Program Project (no. 201904d07020012).

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