Transition-Metal-Free Base-Controlled C?N Coupling Reactions: Selective Mono Versus Diarylation of Primary Amines with 2-Chlorobenzimidazoles

Article abstract of DOI:10.1002/adsc.202001365

Herein, a base-controlled protocol was developed for the C?N coupling of primary amines and 2-chlorobenzimidazoles, affording a handful of secondary or tertiary amines in a selective fashion. Moreover, this protocol was realized under transition-metal-fre

Full text of DOI:10.1002/adsc.202001365

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DOI: 10.1002/adsc.202001365
Transition-Metal-Free Base-Controlled CÀ N Coupling Reactions:
Selective Mono Versus Diarylation of Primary Amines with 2-
Chlorobenzimidazoles
Wei Sang,a, b Yan-Yan Gong,c Hua Cheng,d Rui Zhang,d Ye Yuan,a
Guang-Gao Fan,a Zhi-Qin Wang,a Cheng Chen,a,* and Francis Verpoorta, e, f,
*
a
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122
Luoshi Road, Wuhan 430070, People’s Republic of China
phone: (+86)-27-88016035
fax: (+86)-27-87879468
E-mail: chengchen@whut.edu.cn; francis.verpoort@ghent.ac.kr
School of Materials Science and Engineering, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, People’s
Republic of China
State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of
Sciences, Jinan, People’s Republic of China
Department of Chemical Engineering and Food Science, Hubei University of Arts and Science, 296 Longzhong Road,
Xiangyang 441053, People’s Republic of China
b
c
d
e
f
National Research Tomsk Polytechnic University, Lenin Avenue 30, Tomsk 634050, Russian Federation
Ghent University - Global Campus, 119 Songdomunhwa-Ro, Yeonsu-Gu, Incheon 21985, Korea
Manuscript received: November 3, 2020; Revised manuscript received: January 9, 2021;
Version of record online: January 27, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001365
Abstract: Herein, a base-controlled protocol was developed for the CÀ N coupling of primary amines and 2-
chlorobenzimidazoles, affording a handful of secondary or tertiary amines in a selective fashion. Moreover,
this protocol was realized under transition-metal-free conditions, and the variation of the base from iPr2NH to
LiOtBu completely switched the selectivity from monoarylation to diarylation. Further investigations
elucidated that the variety, intrinsic basicity and amount of the utilized bases considerably affected these
reactions.
Keywords: transition-metal-free; base-controlled; CÀ N coupling; diarylation; monoarylation; 2-aminobenzimida-
zoles
Introduction
zole was also utilized as a ligand to modify the
structures of zeolitic imidazolate frameworks (ZIFs),
Benzimidazole and its derivatives are an important thereby adjusting the properties of the corresponding
class of N-heterocyclic compounds which are widely materials.[7] Besides, the 2-aminobenzimidazole skel-
distributed in pharmaceuticals, metal ligands, polymers eton is prevailing in chemical sensors for the detection
and materials.[1] More specifically, 2-aminobenzimida- of anions[8] as well as in corrosion inhibitors.[9]
zoles such as astemizole,[2] mizolastine[3] and
In view of the widespread applications, expedient
oxbendazole[4] are vital structural units which demon- synthetic approaches were described for accessing 2-
strate versatile biological and pharmaceutical activity.[5] aminobenzimidazoles. In particular, direct functionali-
In addition, these compounds have been used as zation of the benzimidazole framework via representa-
ligands for organometallic compounds or materials. tive CÀ N coupling strategies such as Buchwald-
For instance, Aleksandra Bocian et al. prepared several Hartwig amination[10] and Chan-Lam coupling[11] re-
iron complexes comprising 2-aminobenzimidazole veals an attractive pathway for the 2-aminobenzimida-
ligands and evaluated their potential as artificial zole synthesis, which includes Pd-catalyzed monoar-
biomimetic enzyme analogues.[6] 2-Aminobenzimida- ylation of 2-aminobenzimidazole with aryl halides,[12]
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the cross-coupling of 2-aminobenzimidazoles with secondary or tertiary amines (Scheme 1c). At the
arylboronic acids via Cu or Ni catalysis,[13] and treat- outset, plenty of inorganic bases were screened.
ment of 2-halobenzimidazoles with amines.[14] It was Interestingly, LiOtBu efficiently promoted two consec-
noted that the above-mentioned methods went through utive CÀ N coupling processes, delivering tertiary
one amination sequence to give the aminated products, amines in a highly selective manner. In addition to
while rare examples were reported for the direct inorganic bases, organic bases were also attempted. To
formation of tertiary amines from primary amines (as our delight, diisopropylamine (iPr2NH) was identified
outlined in Scheme 1). As the first example, Ohta et al. as an optimum base to selectively give secondary
reported a Pd-catalyzed protocol to generate the amines. Furthermore, additional experiments implied
tertiary amine in 15% yield, with the concurrent that the types, strength and equivalents of the bases
formation of the secondary amine in 12% yield were pivotal factors for regulating the selectivity of
(Scheme 1a).[15] In our previous work, selective diary- mono vs. diarylation.
lation was accomplished via a ligandless Pd-catalyzed
strategy (Scheme 1b).[16] During the investigations,
Results and Discussion
secondary amines were occasionally provided. Inspired
by this work, we envisaged that adjusting various 2-Chloro-1-methyl-benzimidazole (1a) and aniline
reaction parameters may allow for controlling the (2a), the two coupling partners, were chosen to
mono vs. diselectivity. Gratifyingly, a transition-metal- optimize the reaction conditions (as listed in Table 1).
free protocol was discovered to exclusively deliver It was anticipated that either secondary amine 3a or
tertiary amine 4a was obtained with high yield and
Table 1. The effect of various bases on the reaction of 1a and
2a.[a]
Entry
Base
Yield (%)[b]
Unreacted 1a
3a
4a
(mmol)
1
2
3
4
5
6
7
8
Cs2CO3
K2CO3
LiOH
NaOH
KOH
LiOtBu
NaOtBu
KOtBu
LDA
4
3
47
–
52
–
65
78
51
30
5
40
65
95
–
–
–
–
0.144
0.170
0.110
0.084
–
0.030
–
–
30
16
73
28
6
25
35
–
–
–
–
–
9
–
–
10
11
12
13
14
15
NaH
TMEDA
Pyridine
Et3N
iPr2NH
–
0.170
0.070
0.084
0.090
0.108
[a] 1a (0.2 mmol), 2a (0.1 mmol), base (0.4 mmol) and toluene
(0.5 mL) were heated at reflux under argon for 16 h;
[b] NMR yield using 1,3,5-trimethoxybenzene as an internal
standard (average of two consistent runs).
Scheme 1. The design strategy of this work.
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excellent selectivity. In our previous paper, an unsat- cated reaction mixtures were obtained (entries 9–10).
isfactory result was obtained for Cs2CO3 without a Pd Furthermore, several organic bases were screened
catalyst (entry 1).[16] In order to develop an efficient (entries 11–14).
N,N,N’,N’-Tetrameth-
and transition-metal-free synthetic approach, a number ylethylenediamine (TMEDA) was not effective for this
of other inorganic bases were screened without a transformation, with only 5% of 3a being observed
transition metal catalyst (entries 2–10). It appeared that (entry 11). Pyridine produced the formation of 3a in
K2CO3 did not effectively navigate the CÀ N coupling moderate yield, with 35% of 1a remaining (entry 12).
process, with the detection of 3a in only 3% yield To our delight, Et3N and diisopropylamine (iPr2NH)
(entry 2). In addition, different hydroxides were resulted in the secondary amine (3a) as the major
attempted (entries 3–5). LiOH selectively provided 3a product (entries 13–14). Especially, iPr2NH selectively
in moderate yield (entry 3), while NaOH delivered 4a provided 3a in excellent yield (entry 14). As a
as the major product (entry 4). With regard to the comparative study, neither 3a or 4a was detected for
stronger base (KOH), 52% of 3a and 16% of 4a were the reaction of 1a and 2a under base-free conditions
observed (entry 5). Next, alkoxides including LiOtBu, (entry 15).
NaOtBu and KOtBu were also employed (entries 6–8).
To gain better results for both conditions, further
Interestingly, LiOtBu selectively provided disubstituted screening of other parameters was carried out (as listed
product 4a with high yield and superb selectivity in Tables 2, S1 and S2). At the outset, adjustment of
(entry 6), while NaOtBu and KOtBu gave rise to a the base amounts and substrate ratios resulted in
mixture of both products, with 3a as the major product improved results, which gave rise to 88% of 4a and
(entries 7–8). In terms of even stronger bases such as 95% of 3a, respectively (as listed in entries 1–4 of
lithium diisopropylamide (LDA) and NaH, compli- Table 2 and detailed in Tables S1 and S2 of the
Table 2. Further screening of reaction conditions.[a]
Entry
x
y
Base (z)
solvent
Temperature
Yield (%)[a]
Unreacted 1a
3a
4a
(mmol)
°
1
2
3
4
0.200
0.200
0.125
0.200
0.125
0.200
0.125
0.200
0.125
0.200
0.125
0.200
0.125
0.200
1.25
0.100
0.100
0.100
0.150
0.100
0.150
0.100
0.150
0.100
0.150
0.100
0.150
0.100
0.150
1.00
iPr2NH (0.400)
LiOtBu (0.400)
iPr2NH (0.400)
LiOtBu (0.400)
iPr2NH (0.400)
LiOtBu (0.400)
iPr2NH (0.400)
LiOtBu (0.400)
iPr2NH (0.400)
LiOtBu (0.400)
iPr2NH (0.400)
LiOtBu (0.400)
iPr2NH (0.400)
LiOtBu (0.400)
iPr2NH (4.00)
LiOtBu (4.00)
iPr2NH (20.0)
LiOtBu (20.0)
toluene
toluene
toluene
toluene
THF
THF
DMF
DMF
dioxane
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
120 C
95
–
73
0.090
0.170
0.019
–
0.085
0.050
0.028
0.026
–
0.030
0.106
0.156
0.112
0.178
0.113
0.160
2.81
°
120 C
–
120 C
95 (93[b])
–
°
120 C
–
–
28
68
12
90
–
12
88 (85[b])
°
5[c]
6[c]
7
120 C
–
30
–
35
–
65
–
14
°
°
120 C
°
120 C
°
8
9
120 C
°
120 C
°
10
11
12
13
14
15[d]
16[d]
17[e]
18[e]
120 C
°
100 C
°
100 C
–
–
–
°
80 C
–
–
–
°
80 C
120 C
86 (82[b])
°
2.00
6.25
10.0
1.50
5.00
7.50
120 C
–
80 (76[b])
–
°
120 C
48 (45[b])
–
°
120 C
56 (51[b])
3.80
°
[a] NMR yield using 1,3,5-trimethoxybenzene as an internal standard (average of two consistent runs);
[b] Isolated yield;
[c] A sealed tube was used;
[d] 1 mmol-scale reactions;
[e] 5 mmol-scale reactions.
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supporting information). Moreover, different solvents on the backbone of the benzimidazole framework. If a
were attempted under the same temperature (entries 5– Me group was applied as R1, 58% of product 3p and
10). The results indicated that THF and DMF did not 55% of 4p were provided, respectively. When a Cl
provide good results (entries 5–8). In contrast, dioxane group was incorportated into the R1 position, the
led to moderate to high yield of the desired products corresponding products 3q and 4q were isolated in
with excellent selectivity (entries 9–10), but it exhib- 25% and 22%, respectively. Apart from aromatic
ited lower performance in comparison with toluene primary amines, benzyl amine (2r) and n-hexylamine
(entry 9 vs. entry 3, entry 10 vs. entry 4). Next, the (2s) were also tolerated, providing the respective
influence of the reaction temperatures on this reaction products 3r–3s or 4r–4s in 20–31% yield. Finally,
was also explored (entries 11–14). Lowering the heteroaromatic primary amines 2t–2v were explored.
°
°
temperature from 120 C to 100 C led to significantly Very limited reactivity was observed under the
reduced yield of 3a or 4a (entries 11–12), while iPr2NH-promoted conditions, whereas higher reactivity
almost no reaction occurred if a further decreased was detected in terms of the LiOtBu-mediated con-
°
temperature of 80 C was used (entries 13–14). Fur- ditions. Under the diarylation conditions, tertiary
thermore, the protocol was applicable for 1 mmol-scale amine 4t was selectively yielded in 57% yield, while
reactions, with the selective formation of 3a (or 4a) in only secondary amines 3u–3v (without the observation
high yield under the iPr2NH-promoted (or LiOtBu- of tertiary amines 4u–4v) were isolated in good yield.
based) conditions (entries 15–16). Excellent selectivity Probably, the weak nucleophilicity of heteroaromatic
remained for each base at an even larger scale of amines 2u–2v could not promote the second amina-
5 mmol, despite moderate yield of 3a or 4a was tion.
obtained (entries 17–18). From the above observations,
To provide the rational for the base-controlled
it was noteworthy that switchable mono and diary- switch between mono and diarylation, the relationship
lation were realized simply by altering the base from between the intrinsic basicity of our selected bases and
iPr2NH to LiOtBu under transition-metal-free condi- the product selectivity was investigated (as listed in
tions.
Table 3). The pKa values of the corresponding con-
After the reaction conditions were optimized, the jugate acids were used to indicate the intrinsic basicity
substrate scope of this protocol was expanded (as of these bases. At the beginning, inorganic bases were
depicted in Scheme 2). Initially, the coupling of 1a studied (entries 1–10). It appeared that weak bases
with different anilines were attempted. For the iPr2NH- including the carbonates (pKa=10.3) could not
promoted reactions, electron-rich anilines 2b–2e efficiently promote this CÀ N coupling reaction (en-
yielded products 3b–3e in excellent yield, while tries 1–2). For stronger bases such as the hydroxides
electron-deficient counterparts 2f–2i afforded the (pKa=15.7), the cross-coupling reactions could take
corresponding secondary amines (3f–3i) in slightly place, but with moderate conversion or selectivity
lower yield (75–90%). Unfortunately, highly electron- (entries 3–5). In terms of the tert-butoxides (pKa=
deficient amines 2j and 2k provided the desired 17.0) as even stronger bases, CÀ N coupling efficiently
products (3j and 3k) in merely 12–18% yield. occurred with good conversion (entries 6–8), with
Similarly, desired products 4b–4i were furnished in LiOtBu as the ideal base for the diarylation (entry 6)
78–91% yield for the LiOtBu-promoted reactions, and the other two tert-butoxides leading to a mixture
whereas highly electron-poor products 4j and 4k were of 3a and 4a (entries 7–8). It was found that very
isolated in only 14–32% yield. Afterwards, the effects strong bases such as LDA (pKa=35.7) and NaH
of the substituent positions on the phenyl ring were (pKa= ~36) resulted in relatively complicated reaction
then evaluated. Under the monoarylation conditions, 4- mixtures with poor product selectivity (entries 9–10).
methylaniline (2b) and 3-methylaniline (2l) exhibited Apart from inorganic bases, organic bases having good
similar reactivity, whereas 2-methylaniline (2m) pro- solubility in toluene were also examined (entries 11–
vided product 3m in merely 21% yield even if a 14). Pyridine (pKa=5.21) and TMEDA (pKa=8.97)
smaller amount of 1a was used. As for the diarylation were not efficient coupling promoters, resulting in 3a
conditions, 2l and 2m generated the desired products in 5–40% yield (entries 11–12). However, stronger
in marginally lower yield than 2b. Moreover, the bases including Et3N (pKa=10.75) and iPr2NH
suitability of the current protocol was examined for the (pKa=11.05) were better promoters (entries 13–14),
reactions of 2a with 1-substituted 2-chlorobenzimida- with iPr2NH being identified as the optimized base for
zoles. If R2 was changed from Me to more hindered Et the monoarylation (entry 14).
and iPr groups, 0.4 mmol of iPr2NH promoted the
Further exploration using 1a and 2a as the
formation of products 3n and 3o in 84% and 81% reactants was also carried out (as depicted in Figure 1).
yield, respectively. Under the diarylation conditions, At the outset, product distribution was explored at
product 4n (or 4o) was delivered in 61% (or 50%) different amounts of iPr2NH (Figure 1a). As the base
yield, albeit an elevated temperature was required. usage gradually increased from 0.1 mmol to 0.5 mmol,
Furthermore, different R1 substituents were introduced the yield of 3a was steadily improved from 20% to
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Scheme 2. The substrate exploration.
96%, with no formation of 4a under all the circum- accomplish the subsequent coupling of 3a and 1a.
stances. This result indicated that the weak organic Subsequently, the amounts of LiOtBu were also
base (iPr2NH) could effectively promote the CÀ N evaluated for the coupling of 1a and 2a (Figure 1b
coupling of 1a and 2a to afford 3a, but was unable to and Table S3). If 0.1 mmol of LiOtBu was used, 15%
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selectively give 3a, while 0.4 mmol of LiOtBu
facilitated two consecutive amination sequences to
exclusively provide 4a. On the other hand, the
regulation of the base types, basicity and concentration
is pivotal for the product selectivity between 3a and
4a.
Table 3. The relationship between the intrinsic basicity of our
selected bases and the product selectivity.
Furthermore, the coupling of 1a and secondary
amine 3a under a few selected bases was performed
(as shown in Scheme 3). Expectedly, no diarylation
product 4a was detected in the presence of iPr2NH,
while 88% of 4a was observed applying LiOtBu.
Besides, NaOtBu and KOtBu were also utilized.
However, both bases could not efficiently promote this
cross-coupling reaction, with only 18% of 4a for
NaOtBu and 0% of 4a for KOtBu, respectively. This
result clearly indicated that NaOtBu and KOtBu, two
stronger bases than LiOtBu (especially with excess
amounts), could not effectively mediate the second
amination (the CÀ N coupling of 1a and 3a) to give
4a, which clarified the essential role of the base types
and basicity in this coupling.
Based on the above results, we proposed the
possible pathways for this protocol (as illustrated in
Scheme S1). By screening a variety of bases, iPr2NH
and LiOtBu were identified as the optimized bases for
the selective mono and diarylation, respectively. It was
found that both iPr2NH and LiOtBu facilitated the first
amination (the coupling of 1 and 2) to give secondary
amines 3. In addition, iPr2NH was not capable of
promoting the second amination (the CÀ N coupling of
3 with 1), whereas LiOtBu was proven as the optimal
base for the diarylation. Except the types and basicity
of the bases, their quantities also accounted for the
yield and selectivity of either secondary or tertiary
amines.
Entry
Base
pKa of the
conjugate acid
Yield (%)[a]
3a
4a
1
2
3
4
5
6
7
8
K2CO3
Cs2CO3
LiOH
NaOH
KOH
LiOtBu
NaOtBu
KOtBu
LDA
10.3[b]
10.3[b]
15.7[b]
15.7[b]
15.7[b]
17.0[b]
17.0[b]
17.0[b]
35.7[c]
~36[b]
5.21[b]
8.97[b]
10.75[b]
11.05[b]
3
–
4
–
47
–
52
–
65
78
51
30
40
5
–
30
16
73
28
6
25
35
–
9
10
11
12
13
14
NaH
Pyridine
TMEDA
Et3N
–
65
95
–
–
iPr2NH
[a] NMR yield using 1,3,5-trimethoxybenzene as an internal
standard (average of two consistent runs);
[b] in water;
[c] in THF.
of 3a, 20% of 4a and 64% of unreacted 1a were
observed. Enhancement of the base amount triggered
Conclusion
higher selectivity of 4a vs. 3a, with 0.4 mmol as the In summary, a transition-metal-free base-controlled
optimal result. To have a clearer understanding about protocol was developed for the CÀ N coupling of 2-
the counter-ion effect in the three tert-butoxides, chlorobenzimidazoles and primary amines. Through a
NaOtBu and KOtBu were also examined (Figure 1c-d
and Table S3). In the case of NaOtBu, fewer amounts
(0.1–0.2 mmol) triggered 4a as the major product. In
contrast, higher amounts (0.3–0.5 mmol) gradually
switched the main product from 4a to 3a, affording
81% of 3a with 0.5 mmol of NaOtBu. An even
stronger base, KOtBu, led to a mixture of 3a and 4a
when the base amounts were 0.1–0.2 mmol. Similar
with NaOtBu, 0.3–0.5 mmol of KOtBu also delivered
3a as the major product. Even though the three bases
contain the same anion, the distinct radii of their
counter ions make their basicity follow the trend of
LiOtBu<NaOtBu<KOtBu,[17] which should be a
crucial factor for the selectivity of 3a and 4a in this
coupling. It was concluded that 0.4 mmol of iPr2NH
effectively promoted one amination sequence to
Scheme 3. The reactions of 1a and 3a applying different bases.
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Figure 1. Selectivity of 3a vs. 4a at different amounts of (a) iPr2NH, (b) LiOtBu, (c) NaOtBu, (d) KOtBu.
For the NMR analyses, CDCl3, DMSO-d6 or acetone-d6 was
systematic investigation of various bases, iPr2NH and
LiOtBu were identified to exclusively afford a series of
secondary and tertiary amines, respectively. Originally,
plenty of substituted anilines were smoothly converted
into the corresponding products. With regard to the
reactions of aniline (2a) and different 2-chlorobenzi-
midazoles, the desired products were selectively
yielded under both conditions. Besides, aliphatic/
heteroaromatic primary amines were also compatible.
Furthermore, additional experiments were carried out
to rationalize this base-controlled protocol, which
indicated that an appropriate base and a suitable
used as the deuterated solvent, and tetramethylsilane (TMS)
was utilized as the internal reference. Melting points were taken
on a Buchi M-560 melting point apparatus without calibration.
High resolution mass spectrometry (HRMS) analyses were done
with a Bruker Daltonics microTOF-QII or a Thermo Fisher Q
ExactiveTM UHMR OrbitrapTM instrument. All the common
reagents, solvents and primary amines 2a–2v were purchased
from commercial suppliers and directly used. Besides, 2-chloro-
1-methyl-1H-benzo[d]imidazole (1a),[18] 2-chloro-1-ethyl-1H-
benzo[d]imidazole (1n),[19] 2-chloro-1-isopropyl-1H-benzo[d]
imidazole
(1o),[19]
2-chloro-1,5,6-trimethyl-1H-benzo[d]
imidazole (1p),[20] 2,5,6-trichloro-1- methyl-1H-benzo[d]
amount were equally paramount for the superb imidazole (1q)[16] were synthesized using the previously
reported procedures. The pKa values of LDA[21] and TMEDA[22]
selectivity and excellent yield of cross-coupled prod-
ucts 3 or 4.
were obtained from the literature sources, while those of the
other bases could be found via https://organicchemistrydata.org/
hansreich/resources/pka/#pka_general.
Experimental Section
General Considerations
General Procedures for the Base-Controled CÀ N
Coupling of Substituted 2-Chlorobenzimidazoles
The reactions were carried out using standard Schlenk
with Primary Amines
techniques or in an argon-filled glovebox unless otherwise
mentioned. 1H-NMR spectra were recorded on a Bruker Avance
500 (500 MHz) spectrometer, and 13C-NMR spectra were
measured on a Bruker Avance 500 (126 MHz) spectrometer.
The iPr2NH-promoted reactions: Inside an argon-filled glove-
box, iPr2NH (56 μL, 0.4 mmol),
a 2-chlorobenzimidazole
derivative (0.125 mmol), a primary amine (0.1 mmol) and
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toluene (0.5 mL) were added to a 25 mL Schlenk flask, which
was then taken out of the glovebox. Subsequently, the mixture
was refluxed under argon atmosphere for 16 h. For the 1 mmol-
scale reaction, a mixture of iPr2NH (0.56 mL, 4.0 mmol), 1a
(208.3 mg, 1.25 mmol), 2a (91 μL, 1.0 mmol) and toluene
(2.5 mL) were refluxed under argon for 48 h, and pure 3a
(183.1 mg) was isolated in 82% yield. For the 5 mmol-scale
reaction, a mixture of iPr2NH (2.8 mL, 20.0 mmol), 1a (1.04 g,
6.25 mmol), 2a (457 μL, 5.00 mmol) and toluene (6.0 mL)
were refluxed under argon for 48 h, and pure 3a (502.4 mg)
was isolated in 45% yield.
cial Department of Education (B2019135), the Foundation of
Hubei University of Arts and Science (Grant No. 2059057), The
Open Foundation of Discipline of Hubei University of Arts and
Science (Grant No. XK2019038).
References
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The LiOtBu-promoted reactions: To a 25 mL Schlenk flask
were added LiOtBu (32.0 mg, 0.4 mmol), a 2-chlorobenzimida-
zole derivative (0.2 mmol), a primary amine (0.15 mmol) and
toluene (0.5 mL) in the glovebox. The Schlenk tube was capped
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(1.60 g, 20.0 mmol), 1a (1.67 g, 10.0 mmol), 2a (685 μL,
7.50 mmol) and toluene (6.0 mL) were heated at reflux under
argon for 48 h, affording pure 4a (901.2 mg) in 51% yield.
General Procedure for the Calculations of NMR
Yield
After the indicated time, the reaction mixture was cooled down
to room temperature and concentrated by a vacuum pump (for
the reactions utilizing LiOtBu, NaOtBu, KOtBu or NaH, a few
drops of water were added to quench the reactions). Afterwards,
1,3,5-trimethoxybenzene (16.8 mg, 0.1 mmol) and CDCl3
(1.0 mL) were added. The insoluble solid was filtered off, and
0.5 mL of the filtrate was added to an NMR tube. The NMR
yield was obtained based on the exact amount of 1,3,5-
trimethoxybenzene.
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The reaction mixture was cooled down and the solvent was
removed under reduced pressure. Subsequently, silica-gel
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3 or 4. Petroleum ether was used as the starting eluent and
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Acknowledgments
This research was supported by the National Natural Science
Foundation of China (No. 21502062), and the Fundamental
Research Funds for the Central Universities (No. 205201026),
the National Natural Science Foundation Cultivation Project of
Hubei University of Arts and Science (No. 2019kypygp003),
Scientific Research Program Guiding Project of Hubei Provin-
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