Metal-Free Synthetic Shortcut to Octahydro-Dipyrroloquinoline Skeletons from 2,5-Cyclohexadienone Derivatives and l -Proline

Can Zhang, Jianbin Li, Xin Wang, Xuan Shen, Dunru Zhu, and Ruwei Shen*

Article

Metal-Free Synthetic Shortcut to Octahydro-Dipyrroloquinoline

Skeletons from 2,5-Cyclohexadienone Derivatives and L‑Proline

Cite This: J. Org. Chem. 2021, 86, 10397 −10406

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sı Supporting Information

ABSTRACT: The tandem decarboxylative condensation−dimeri-

zation reaction of L-proline with 2,5-cyclohexadienones including

p-quinone monoacetals, p-quinol ethers, and p-quinols is reported

to provide a concise and rapid synthesis of octahydro-

dipyrroloquinoline compounds. The reaction features the use of

cost-eﬀective and readily available starting materials, high

eﬃciency, metal-free and green reaction conditions. The reaction is applied to the synthesis of incargranine B aglycone. The

discovery of this reaction may suggest a biosynthetic pathway from 2,5-cyclohexadienones and proline for natural ingredients

containing pyrroloquinoline moieties.

INTRODUCTION

example, 2,5-cyclohexadienone derivatives such as p-quinone

monoacetals (p-QMAs), p-quinol ethers, and p-quinols, are all

versatile synthetic intermediates with wide utilities in organic

■

The concise and rapid synthesis of complex azacyclic

compounds is of high importance in organic synthesis because

of their abundance in valuable artiﬁcial and natural substances

including pharmaceutical compounds, therapeutic agents, and

,10

synthesis

and can be facilely obtained via oxidation of the

cheap and abundant arenols, not mention to the naturally

abundant and renewable L-proline. While the reaction enables a

highly eﬃcient assemble of these common building blocks to

construct the complex core structure from a synthetic

perspective, we further note that the discovery of this

transformation may also imply a possible biosynthetic origin

of natural ingredients bearing pyrroloquinoline moieties from

2,5-cyclohexadienone derivatives and proline in biosynthetic

scenarios. It is a truth that a large number of natural products

show structural motifs derived from 2,5-cyclohexadienone

derivatives biosynthetically, and many feature such structural

natural products (Figure 1A). The octahydro-dipyrroloquino-

line is among a new structurally interesting azatetracyclic

scaﬀold that has received increasing attention since it has been

identiﬁed in natural products of incargranine B and

seneciobipyrrolidine.

The total synthesis and structure

revision of incargranine B were ﬁrst reported by Lawrence

using a biomimetic strategy in 2013. Several other protocols

toward this core structure have also been described in literature

−8

(

Figure 1B).

For example, the Fustero group has already

shown a Au-catalyzed intramolecular hydroamination and

9c,d

moieties in their ﬁnal structural framework.

formal aza-Diels−Alder reaction sequence of propargylic

amino esters to access similar azatetracyclic compounds in

012. Dong and Liu reported the Au-catalyzed cyclization

RESULTS AND DISCUSSION

■

reactions of homopropargylic amines and further contributed

to a diastereo- and enantioselective variant of the reaction

enabled by a chiral silver phosphate catalyst. Recently, the

Schneider group reported an impressive modular synthesis of

stereodiverse dipyrroloquinoline derivatives via a one-pot

The reaction was discovered during a recent project on the

utilities of p-QMAs as arylation reagents for the synthesis of

nitrogen- and phosphorus-functionalized aromatics. Previ-

ously, we unexpectedly observed the formation of the

octahydro-dipyrroloquinoline compounds as byproducts from

the three-component reaction of p-QMA, L-proline, and

multicomponent reaction of arylamines, aldehydes, and bis-

(

silyl) dienediolates. Despite these excellent contributions, new

12f

naphthol. The subsequent study showed that p-QMA 1a

concise and eﬃcacious methods toward these structurally

interesting skeletons still remain desirable, particularly in the

context of green and sustainable chemistry of current interest.

Herein we report an alternative new synthesis of octahydro-

dipyrroloquinoline products via a tandem decarboxylative

condensation−dimerization reaction of 2,5-cyclohexadienone

derivatives with L-proline (Figure 1C). This new method has

advantages such as high eﬃciency, operational simplicity, totally

metal-free conditions, and the use of a green solvent. The

starting materials for the reaction are easily available, for

indeed coupled with L-proline (2a) to give octahydro-

dipyrroloquinolines 3a and 3b in moderate to good yields,

Received: May 9, 2021

Published: July 20, 2021

2021 American Chemical Society

The Journal of Organic Chemistry

J. Org. Chem. 2021, 86, 10397−10406

0397

e.g., K CO and NaOH) led to very poor yields due to the

Article

Table 1. Optimization of Reaction Conditions for the

Reaction of 1a and 2a

temp

(°C)

time

(h) yield (%)

ratio of

entry

solvent

additive

3a/3b

MeCN

100

69:31

59:41

55:45

HOAc

Ph P(O)

MeCN

DMF

CF CO H

100

decomp

ZnCl₂

56:44

Zn(OTf)₂

Sc(OTf)₃

51:49

THF

toluene

PhCF₃

hexane

EtOH

63:37

57:43

0.5

62:38

70:30

BuOH

(CF₃)

CHOH

decomp

H O

100

120

100

decomp

trace

HOAc

EtOH

0.5

61:39

50:50

60:40

54:46

Et N

Figure 1. Bioactive azacyclic agents and natural products containing a

pyrroloquinoline moiety and synthetic approaches for the octahydro-

dipyrroloquinoline framework.

pyridine

^K^C^O3

NaOH

Unless otherwise noted, a mixture of 1a (0.2 mmol), 2a (0.24

and the detailed survey on the reaction parameters for the

improvement of the reaction is present in Table 1. The reactions

mmol), and the solvent (2 mL) charged to a 10 mL screw-capped

Schlenk tube under dry nitrogen was heated to 80−120 °C for a

completed in 2 h in the presence of HOAc and Ph P(O)OH, but

speciﬁc time. Combined yields. Deduced from H NMR. 30 mol%.

e f g h i

the product yields were not improved (Table 1, entries 2 and 3).

The use of CF CO H resulted in the decomposition of starting

a was decomposed. Not determined. No reaction. 0.5 mL. 0.24

mL.

materials under the reaction conditions (Table 1, entry 4). The

presence of ZnCl also led to a decreased yield (Table 1, entry

), and no product was detected when Zn(OTf) or Sc(OTf)

2 3

Et N appears to be beneﬁcial for the improvement of the

reaction, giving the products in 77% yield with 60:40 dr (Table

was added (Table 1, entries 6 and 7). It was found that the

solvents have a signiﬁcant eﬀect on the outcome of the reaction.

THF, toluene, and (triﬂuoromethyl)benzene all gave the

products in poor yields (Table 1, entries 9−11). No reaction

took place in hexane because of the poor solubility of 2a (Table

, entry 20). The presence of pyridine did not foster a better

result (Table 1, entry 21), whereas the use of inorganic bases

, entry 12). In contrast, the reaction took place more eﬃciently

in protic solvents such as EtOH and BuOH (Table 1, entries 13

and 14). The reactions in these solvents were completed within

.5 h at 100 °C in a closed Schlenk tube. EtOH gave a much

better yield (72%), which was similar to that achieved using

MeCN as a solvent in 4 h (Table 1, entry 1 vs entry 13).

However, the use of hexaﬂuoropropan-2-ol, water, or HOAc as

the solvent led to the decomposition of starting materials, and

the product was not formed (Table 1, entries 15−17). The

reaction performed in EtOH at 120 °C gave the product in a

slightly low yield (Table 1, entry 18). When conducted at 80 °C,

the reaction turned out to be a little slower and completed in 1 h

to give the products in 68% yield (Table 1, entry 19). The

inﬂuence of some bases was also examined. The presence of

Figure 2. Molecular structures of octahydro-dipyrroloquinolines 3a

and 3b. (Ellipsoids shown at 50% probability level.)

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Table 2. Synthesis of Octahydro-Dipyrroloquinolines from QMAs and L-Proline

Unless otherwise noted, a mixture of 1 (0.2 mmol), 2a (1.2 equiv), EtOH (2 mL), and Et N (0.5 mL) in a screw-capped Schlenk tube was heated

to 100 °C under dry nitrogen for 0.5−1 h. Combined yields. Unless otherwise noted, the value of diastereo ratio (dr) was calculated based on the

isolated yields of the diastereoisomers. 6 mmol scale. Determined from H NMR. 0.5 mmol scale. 2 mmol scale. 1 mmol scale.

partial decomposition of the substrates (Table 1, entries 22 and

3).

The stereostructures of 3a and 3b were further determined by

formation of 5a (Table 2, entry 3). The 3-halide-substituted p-

QMA 1d was allowed to produce the corresponding products 6a

and 6b, albeit in a lower yield (Table 2, entry 4). The ethanol-

derived QMA 1e participated similarly in the reaction to furnish

the desired products 7a and 7b in a combined yield of 65% with

55:45 dr (Table 2, entry 5). The glycol-derived p-QMA 1f could

also be used to produce 8a and 8b in 53% yield with a dr value of

69:31 (Table 2, entry 6). In addition, common p-quinol ethers

1g−1h all reacted smoothly with 2a to give the corresponding

products in good yields (Table 2, entries 7−9). Remarkably, p-

quinol ethers that bear a benzyloxyl, an ester, and even a free

hydroxyl group were proved suitable for the present reaction to

the single-crystal X-ray diﬀraction analysis (Figure 2).

Table 2 shows the representative examples of octahydro-

dipyrroloquinolines prepared from diﬀerent substituted 2,5-

cyclohexadienones 1 and L-proline (2a) by taking advantage of

the present method. Thus, 3-methyl-substituted p-QMA 1b

reacted with 2a to give 4a and 4b in high yields (Table 2, entry

). Notably, 3,3′-dimethyl-substituted p-QMA 1c gave 5a and

b in a combined yield of 74%, and the reaction demonstrated

remarkably high diastereoselectivity up to 91:9 in favor of the

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deliver the expected products in good yields (Table 2, entries

Scheme 3. Failed Substrates for the Reaction

0−12). It is worth mentioning that the diastereoisomers of

products 3, 4, 5, 7, and 9−12 were separable by common ﬂash

chromatography and well-characterized. The products 6, 8, 13,

and 14 were obtained as diastero mixtures due to the similar

polarity of the compounds. In addition, the reaction of 1a and 2a

on a 6 mmol scale was performed to aﬀord 3a and 3b in 36% and

2% yields, respectively (total: 68%; dr: 53:47).

The present transformation was also found to take place

between p-quinol 1m and L-proline (2a) (Scheme 1). MeCN

Scheme 1. Reaction of p-Quinol 1m and L-Proline

Scheme 4. Deuterium-Labeling Experiment

was a better solvent for choice, and the reaction cleanly gave

products 9a and 9b in 26% and 20% yields, respectively. In

contrast, the reaction in EtOH gave slightly low yields (38%−

0% total yield) in 0.5 h, and the formation of unidentiﬁed

byproducts was observed.

Furthermore, the reactions of other cyclic amino acids were

investigated but did not give similar products. For example, the

reactions of 4-hydroxyl-proline (2b) with p-QMA 1a and p-

quinol ether 1g both took place smoothly to give N-arylated

pyrroles 15 and 16 in moderate yields (Scheme 2). The results

can be rationalized by a cascade process involving condensation,

decarboxylation, demethoxylation, and dehydration (Scheme

provide the deuterium-labeled products 3a-d3 and 3b-d3 in

38% and 33% yields, respectively. It is interesting to observe that

approximately three hydrogen atoms were replaced by

deuterium atoms in the products 3a-d3 and 3b-d3 as indicated

Scheme 2. Reactions of 4-Hydroxyl-Proline with QMAs to

Aﬀord N-Arylated Pyrroles

from their H NMR spectra (Scheme 4). Particularly, it is clearly

observed that the coupling splitting disappeared with respect to

the hydrogens (as highlighted in red in Scheme 4) attached to

the tertiary carbon atoms adjacent to the nitrogen atoms.

Accordingly to the above results, we proposed a reaction

mechanism as shown in Scheme 5. Iminium zwitterion

intermediate A may be generated from the condensation

reaction of 1a and 2a at ﬁrst. After decarboxylation, A is

converted to the iminium intermediate C through a conjugated

azomethine ylide intermediate B. An alternative straightforward

pathway is also possible for the generation of C from A after

decarboxylation. An equilibrium between the intermediate C

13,14

and the N,O-acetal species D should be present.

Elimination

of one molecule of MeOH from the intermediates C and/or D

leads to an enamine intermediate E. As indicated from the

results of the deuterium-labeling experiment, the conversion

between intermediates D and E should be reversible. Thus,

when EtOD was used as a solvent, the formation of deuterium-

labeled intermediates D-d1, E-d1, C-d2, and D-d2 were

dominated. The reaction of C-d2 and E-d1 forms the

intermediate F-d3. Finally, an intramolecular Pictet−Spengler-

On the other hand, the reactions of the six-membered

piperidine-2-carboxylic acid (2c) and (S)-1,2,3,4-tetrahydro-3-

isoquinolinecarboxylic acid (2d) with 1a failed to give any

identiﬁable product (Scheme 3, eq 1). In addition, 2-methyl-

substituted QMA 1n did not react with 2a to give any product,

indicative of the steric hindering eﬀect retarding the

condensation step (Scheme 3, eq 2).

type reaction takes place to give the products 3a/b-d3.

At last, we applied the present reaction to the synthesis of the

aglycone of incargranine B. As described above, the aglycone of

incargranine B could be obtained from the reaction of 1l and 2a

but as a diastereo mixture of 14a and 14b. The separation of the

The reaction of 1a and 2a in a deuterium-labeling solvent

EtOD) was performed to better understand the reaction

(

mechanism (Scheme 4). The reaction took place smoothly to

two diastereoisomers usually required preparative HPLC. This

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Scheme 5. Proposed Reaction Mechanism

Scheme 6. Synthesis of Incargranine B Aglycone and

Analogue

may limit the practical application of the methods. Fortunately,

we found that the tert-butyldimethylsilyl (TBDMS)-protected

ethers could be easily separated by common ﬂash chromatog-

raphy. Accordingly, a modiﬁed route starting from tyrosol (17)

was successfully executed by using the present reaction (Scheme

EXPERIMENTAL SECTION

). First, the selective silylation of 17 with tert-butyldimethylsilyl

■

General Information. All reactions were performed in sealable

Schlenk ﬂasks with Teﬂon plug valves. The solvents used were distilled

prior to use using the appropriate drying agents. Flash chromatography

was performed on silica gel using petroleum ether and EtOAc as an

eluent. Melting points were measured with a Shanghai Jingke WRS-2A

digital melting point apparatus instrument and were uncorrected.

chloride (TBDMSCl) aﬀorded the protected precursor 18,

which was used without further puriﬁcation for the next step.

The treatment of the crude 18 with PhI(OAc) in MeOH then

gave the desired p-quinol ether 19 in 61% yield over two steps.

The reaction of 19 and L-proline in EtOH under reﬂux provided

the products 20a and 20b in 39% and 26% yields, which were

facilely separated by the mean of ﬂash column chromatography

on silica. Finally, the removal of the TBDMS groups by

treatment of tetrabutylammonium ﬂuoride (TBAF) in THF at 0

Proton nuclear magnetic resonance ( H NMR) and carbon nuclear

magnetic resonance ( C{ H} NMR) spectra were acquired on a

Bruker Ascend 400 spectrometer at 400 and 100 MHz, respectively.

HRMS analysis was performed on an Agilent 6540 UHD accurate-mass

quadrupole time-of-ﬂight (Q-TOF) mass spectrometer in the electro-

spray ionization mode (positive mode). The X-ray crystallographic

analysis of products 3a and 3b was performed on a Bruker SMART

APEX II CCD diﬀractometer using graphite-monochromated Mo Kα

C gave the pure products 14a and 14b in high yields,

respectively (for details, see Experimental Section).

16a

CONCLUSION

(λ = 0.71073 Å) radiation. The starting materials 1a, 1b, ₁₆_d1c,

■

16b 16a 16c 16d 16d 16e 16e 16f

d, 1e, 1f, 1g, 1h, 1i, 1l, 1m, and 1n were

In conclusion, we have reported a simple method for the

synthesis of complex azacyclic compounds featuring the

octahydro-dipyrroloquinoline skeleton via the decarboxylative

condensation−dimerization reaction of 2,5-cyclohexadienone

derivatives with L-proline. The reaction would be synthetically

useful because of the simplicity of starting chemicals, high

reaction eﬃciency, and the green reaction conditions. The

metal-free synthetic route toward the aglycone of incargranine B

was also developed by using the present method. Given the wide

occurrence of the 2,5-cyclohexadienone motif in a natural

source, we suppose that the identiﬁcation of the reaction may

imply a potential biosynthetic pathway for the origins of natural

products containing pyrroloquinolines from cyclohexadienones

and amino acids. Conclusive proofs are still required for

biological chemistry.

synthesized by known methods in literatures. Compounds 1j and 1k

were new compounds, and the synthetic procedures and character-

ization data were given as below.

Synthesis of p-Quinol Ether 1j. To a stirred solution of 4-(2-

(benzyloxy)ethyl)phenol (1.140 g, 5.0 mmol) in MeOH (10 mL) at 0

°C was added phenyliodonium diacetate (1.770 g, 5.5 mmol)

portionwise. The mixture was stirred at 0 °C for 45 min, warmed to

room temperature, and kept stirring for another 8 h. The reaction was

slowly quenched with aq NaHCO solution (20 mL). The mixture was

then extracted with EtOAc (3 × 30 mL). The combined organic layers

were washed with brine, dried over MgSO , and concentrated under

reduced pressure. The residue was puriﬁed by ﬂash chromatography on

silica gel using PE/EtOAc (6:1 v/v) as an eluent to aﬀord 4-(2-

(

benzyloxy)ethyl)-4-methoxycyclohexa-2,5-dien-1-one (1j) (1.150 g,

89%). H NMR (CDCl , 400 MHz): δ = 7.36−7.26 (m, 5H), 6.79 (d, J

= 10.4 Hz, 2H), 6.35 (d, J = 10.4 Hz, 2H), 4.43 (s, 2H), 3.53 (t, J = 6.4

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Hz, 2H), 3.19 (s, 3H), 2.05 (t, J = 6.4 Hz, 2H). C{ H} NMR (CDCl ,

Compounds 4a: white solid. Mp: 126−127 °C. H NMR (CDCl ,

00 MHz): δ = 185.4, 150.9, 138.0, 131.1, 128.4, 127.7, 127.6, 74.4,

3.0, 65.1, 52.9, 39.7. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for

400 MHz): δ = 6.92 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 2.8

Hz, 1H), 6.62 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.26 (s, 1H), 5.03 (d, J

C H O , 259.1334; found, 259.1335.

Synthesis of p-Quinol Ether 1k. Following a similar procedure for

the synthesis of 1j, the reaction of methyl 2-(4-hydroxyphenyl)acetate

= 7.2 Hz, 1H), 3.80 (s, 3H), 3.52 (s, 3H), 3.52−3.48 (m, 1H), 3.46−

3.39 (m, 2H), 3.22−3.10 (m, 2H), 2.56−2.49 (m, 1H), 2.24 (s, 3H),

2.16 (s, 3H), 2.10−1.87 (m, 4H), 1.74−1.64 (m, 1H). C{ H} NMR

(

0.841 g, 5.0 mmol) and phenyliodonium diacetate (2.420 g, 7.5 mmol)

conditions: 10 mL of MeOH, 0 °C, 45 min; room temperature: 24 h)

(CDCl , 100 MHz): δ = 149.3, 149.1, 143.7, 138.0, 127.5, 126.3, 122.0,

114.7, 113.5, 112.2, 112.1, 109.2, 58.4, 57.4, 56.3, 56.0, 48.0, 47.0, 40.6,

aﬀorded methyl 2-(1-methoxy-4-oxocyclohexa-2,5-dien-1-yl)acetate

29.8, 23.2, 22.9, 16.6, 16.1. HRMS (ESI/Q-TOF) m/z: [M + H] calcd

(

1k) (0.721 g, 73%). H NMR (CDCl , 400 MHz): δ = 6.89 (d, J =

for C H N O , 379.2386; found, 379.2388.

24 31

(

0.4 Hz, 2H), 6.35 (d, J = 10.4 Hz, 2H), 3.64 (s, 3H), 3.16 (s, 3H), 2.68

Compound 4b: oil. H NMR (CDCl , 400 MHz): δ = 6.78 (d, J = 8.8

s, 2H). ¹³C NMR (CDCl , 100 MHz): δ = 184.8, 168.8, 149.0, 131.6,

Hz, 1H), 6.69 (s, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.56−6.54 (m, 2H),

4.31 (d, J = 9.2 Hz, 1H), 3.80 (s, 3H), 3.66−3.61 (m, 1H), 3.61 (s, 3H),

72.7, 53.0, 52.0, 44.3. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for

C H O , 197.0814; found, 197.0817.

3.46 (td, J = 8.8 Hz, J = 2.8 Hz, 1H), 3.30−3.24 (m, 1H), 2.86−2.80

1 2

General Procedure for the Synthesis of Octahydro-Dipyrro-

loquinolines. To an oven-dried Schlenk tube (10 mL) were added p-

QMA or p-quinol ether 1 (0.2 mmol), L-proline (2a) (1.2 equiv), EtOH

(m, 1H), 2.71−2.63 (m, 1H), 2.46−2.39 (m, 1H), 2.25 (s, 3H), 2.22 (s,

3H), 2.19−2.11 (m, 3H), 2.03−1.95 (m, 1H), 1.84−1.68 (m, 2H).

C{ H} NMR (CDCl , 100 MHz): δ = 150.9, 150.1, 143.9, 140.6,

(

2 mL), and Et N (0.5 mL) under an atmosphere of dry nitrogen. The

127.1, 126.9, 124.8, 116.6, 114.8, 111.5, 111.4, 111.1, 65.1, 60.7, 56.1,

56.0, 50.3, 47.80, 47.76, 31.6, 30.3, 22.4, 16.5, 16.1. HRMS (ESI/Q-

tube was sealed, and the mixture was stirred and heated to 100 °C in an

oil bath for 0.5−1 h. After the reaction was cooled down to room

temperature, silica gel (ca. 200 mg) was added, and the volatiles were

removed in vacuo to aﬀord a dry powder. The residue was puriﬁed by

column chromatography on silica (pretreated with 1%−5% Et N) using

PE/EtOAc as an eluent to aﬀord the pure products or a diastereo

mixture.

TOF) m/z: [M + H] calcd for C H N O , 379.2386; found,

379.2387.

Synthesis of Octahydro-Dipyrroloquinolines 5a and 5b. Follow-

ing the general procedure, the reaction of 1c (37.4 mg, 0.2 mmol) and

2a (28.4 mg, 0.24 mmol) in EtOH (2 mL) and Et N (0.5 mL) at 100 °C

for 1 h aﬀorded 5a (27.4 mg, 67% yield) and 5b (2.7 mg, 7% yield),

which were puriﬁed by column chromatography (pretreated with 1%

Synthesis of Octahydro-Dipyrroloquinolines 3a and 3b. Follow-

ing the general procedure, the reaction of 1a (30.9 mg, 0.2 mmol) and

for 0.5 h aﬀorded 3a (15.7 mg, 45% yield) and 3b (11.1 mg, 32% yield),

which were puriﬁed by column chromatography on silica (pretreated

with 1% Et N) using PE/EtOAc (50:1 v/v) as an eluent. Total yield:

Et N) using PE/EtOAc (100:1 v/v) as an eluent. Total yield: 74%.

a (28.1 mg, 0.24 mmol) in EtOH (2 mL) and Et N (0.5 mL) at 100 °C

Compound 5a: white solid. Mp: 75−77 °C. H NMR (CDCl , 400

MHz): δ = 6.53 (s, 2H), 6.20 (s, 1H), 4.99 (d, J = 7.6 Hz, 1H), 3.69 (s,

3H), 3.60 (s, 3H), 3.48−3.43 (m, 1H), 3.37−3.27 (m, 2H), 3.19−3.12

(m, 1H), 3.01−2.95 (m, 1H), 2.72−2.67 (m, 1H), 2.26 (s, 3H), 2.25 (s,

7%.

6H), 2.05 (s, 3H), 1.96−1.84 (m, 4H), 1.71−1.62 (m, 2H). C{ H}

Compound 3a: white solid. Mp: 144−145 °C. H NMR (CDCl ,

00 MHz): δ = 6.97 (s, 1H), 6.88 (d, J = 7.2 Hz, 2H), 6.77 (d, J = 8.8

NMR (CDCl , 100 MHz): δ = 149.6, 148.6, 147.1, 143.9, 132.2, 130.7,

129.5, 121.5, 116.1, 111.1, 60.0, 59.9, 59.6, 59.2, 50.8, 47.8, 40.2, 29.7,

Hz, 2H), 6.71 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 8.8 Hz, 1H), 5.03 (d, J =

24.1, 22.9, 16.5, 16.4, 13.3. HRMS (ESI/Q-TOF) m/z: [M + H] calcd

.8 Hz, 1H), 3.79 (s, 3H), 3.60 (s, 3H), 3.57−3.55 (m, 1H), 3.45−3.37

for C H N O , 407.2699; found, 407.2705.

(

m, 2H), 3.23−3.13 (m, 2H), 2.56−2.50 (m, 1H), 2.10−2.05 (m, 1H),

Compound 5b: oil. H NMR (CDCl , 400 MHz): δ = 6.26 (s, 2H),

.03−1.87 (m, 4H), 1.75−1.65 (m, 1H). C{ H} NMR (CDCl , 100

6.23 (s, 1H), 3.90 (d, J = 4.0 Hz, 1H), 3.73−3.70 (m, 1H), 3.61 (s, 3H),

3.52 (s, 3H), 3.48−3.46 (m, 1H), 3.43−3.29 (m, 2H), 3.22−3.16 (m,

1H), 2.29 (s, 3H), 2.23−2.19 (m, 1H), 2.08 (s, 6H), 1.98−1.88 (m,

MHz): δ = 150.9, 150.8, 143.9, 138.4, 125.2, 115.2, 115.0, 113.5, 112.3,

compound has been reported in a previous publication. The structure

was further conﬁrmed by a single-crystal X-ray diﬀraction study.

11.3, 58.4, 57.2, 56.0, 55.7, 48.2, 47.1, 40.6, 29.9, 23.3, 23.0. This

12f

1H), 1.72−1.62 (m, 3H), 1.53 (s, 3H), 1.48−1.41 (m, 2H). C{ H}

NMR (CDCl , 100 MHz): δ = 151.3, 147.3, 143.9, 141.0, 132.6, 130.8,

Compound 3b: white solid. Mp: 102−103 °C. H NMR (CDCl ,

129.8, 120.1, 116.3, 110.0, 62.0, 60.1, 59.9, 58.0, 47.9, 46.9, 39.4, 31.7,

00 MHz): δ = 6.84 (d, J = 8.8 Hz, 2H), 6.73−6.72 (m, 2H), 6.65−6.61

26.0, 23.8, 16.6, 16.3, 12.4. HRMS (ESI/Q-TOF) m/z: [M + H] calcd

(

m, 3H), 4.33 (d, J = 9.2 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.64−3.61

for C H N O , 407.2699; found, 407.2704.

m, 1H), 3.43 (td, J = 8.8 Hz, J = 2.8 Hz, 1H), 3.28−3.22 (m, 1H),

Synthesis of Octahydro-Dipyrroloquinolines 6a and 6b. Follow-

ing the general procedure, the reaction of 1d (94.7 mg, 0.5 mmol) and

.81−2.66 (m, 2H), 2.39−2.33 (m, 1H), 2.27−2.14 (m, 4H), 2.12−

.93 (m, 1H), 1.78−1.73 (m, 1H). C{ H} NMR (CDCl , 100 MHz):

2a (69.6 mg, 0.6 mmol) in EtOH (2 mL) and Et N (0.5 mL) at 100 °C

δ = 153.0, 151.6, 143.9, 141.2, 130.2, 114.7, 114.0, 113.8, 112.5, 111.6,

5.3, 60.5, 55.8, 55.5, 50.0, 48.0, 47.7, 31.6, 30.4, 22.3. HRMS (ESI/Q-

for 1 h aﬀorded 6a and 6b as a mixture (total amount: 44.3 mg, total

yield: 41%, dr: 74:26), which were obtained after column

TOF) m/z: [M + H] calcd for C H N O , 351.2073; found,

diﬀraction study.

chromatography (pretreated with 1% Et N) using PE/EtOAc (30:1

51.2075. The structure was further conﬁrmed by a single-crystal X-ray

v/v) as an eluent. H NMR (CDCl

, 400 MHz): δ = 6.93−6.92 (m,

1.1H), 6.90 (s, 0.3H), 6.85−6.83 (m, 1.0H), 6.77 (d, J = 3.2 Hz, 0.3H),

Procedure for the Gram-Scale Reaction for the Synthesis of

a and 3b. To an oven-dried Schlenk tube (50 mL) were added p-

6.70 (s, 0.2H), 6.68−6.64 (m, 1.1H), 6.51 (dd, J = 9.2 Hz, J = 3.2 Hz,

0.3H), 6.42 (s, 0.7H), 4.96 (d, J = 7.2 Hz, 0.74H), 4.23 (d, J = 9.2 Hz,

0.26H), 3.85−3.84 (m, 3.0H), 3.65 (s, 0.7H), 3.62−3.58 (m, 3.0H),

3.39−3.29 (m, 1.6H), 3.21−3.15 (m, 1.5H), 2.81 (q, J = 8.8 Hz, 0.3H),

2.73−2.64 (m, 0.3H), 2.57−2.50 (m, 0.7H), 2.46−2.40 (m, 0.3H),

QMA 1a (926.1 mg, 6 mmol), L-proline (2a) (830.1 mg, 7.2 mmol),

EtOH (24 mL), and Et N (6 mL) under an atmosphere of dry nitrogen.

The tube was sealed, and the resulting mixture was stirred and heated to

room temperature, the volatiles were removed in vacuo. The residue

was puriﬁed by column chromatography on silica (pretreated with 1%

Et N) using PE/EtOAc (50:1) as an eluent to aﬀord the pure products

00 °C in an oil bath for 0.5 h. After the reaction was cooled down to

2.28−2.18 (m, 0.6H), 2.13−1.65 (m, 6H). C{ H} NMR (CDCl , 100

MHz): δ = 148.0, 147.3, 146.1, 146.0, 144.3, 144.1, 141.6, 138.8, 123.8,

123.3, 122.5, 122.4, 122.2, 120.9, 115.5, 114.7, 114.3, 114.0, 113.9,

113.3, 113.0, 112.8, 112.0, 110.3, 64.7, 60.6, 58.0, 57.3, 57.1, 57.0, 56.9,

56.8, 50.1, 47.8, 47.7, 47.6, 47.0, 40.3, 31.8, 30.2, 30.0, 23.22, 23.15,

a (382.2 mg, 36%) and 3b (339.1 mg, 32%). Total yield: 68%.

Synthesis of Octahydro-Dipyrroloquinolines 4a and 4b. Follow-

22.4. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H Cl N O ,

ing the general procedure, the reaction of 1b (34.1 mg, 0.2 mmol) and

419.1293; found, 419.1296.

a (28.2 mg, 0.24 mmol) in EtOH (2 mL) and Et N (0.5 mL) at 100 °C

Synthesis of Octahydro-Dipyrroloquinolines 7a and 7b. Follow-

ing the general procedure, the reaction of 1e (91.7 mg, 0.5 mmol) and

for 1 h aﬀorded 4a (14.3 mg, 38% yield) and 4b (12.1 mg, 32%), which

were puriﬁed by column chromatography (pretreated with 1% Et N)

using PE/EtOAc (50:1 v/v) as an eluent. Total yield: 70%.

2a (69.4 mg, 0.6 mmol) in EtOH (2 mL) and Et N (0.5 mL) at 100 °C

for 1 h aﬀorded 7a (34.1 mg, 36% yield) and 7b (27.9 mg, 29% yield),

0402

J. Org. Chem. 2021, 86, 10397−10406

The Journal of Organic Chemistry

Article

which were puriﬁed by column chromatography (pretreated with 1%

3.62−3.58 (m, 1H), 3.46 (t, J = 8.4 Hz, 1H), 3.41−3.35 (m, 1H), 3.24−

3.17 (m, 2H), 2.45−2.40 (m, 1H), 2.26 (s, 3H), 2.21 (s, 3H), 2.18 (s,

Et N) using PE/EtOAc (150:1 v/v) as an eluent. Total yield: 65%.

Compound 7a: white solid. Mp: 112−114 °C. H NMR (CDCl ,

00 MHz): δ = 6.94 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 9.2 Hz, 2H), 6.74

3H), 2.04 (s, 3H), 1.98−1.85 (m, 5H), 1.72−1.65 (m, 1H). C{ H}

NMR (CDCl , 100 MHz): δ = 147.8, 141.5, 137.2, 136.1, 130.4, 130.1,

(

d, J = 9.2 Hz, 2H), 6.69 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.34 (d, J =

.8 Hz, 1H), 5.01 (d, J = 7.2 Hz, 1H), 4.00 (d, J = 6.8 Hz, 2H), 3.78 (d, J

123.9, 123.3, 121.3, 112.9, 112.1, 108.8, 57.9, 56.8, 48.2, 46.7, 40.4,

30.1, 23.3, 23.1, 20.5, 19.9, 18.9, 18.6. HRMS (ESI/Q-TOF) m/z: [M +

6.8 Hz, 2H), 3.59−3.54 (m, 1H), 3.44−3.36 (m, 2H), 3.22−3.12 (m,

H] calcd for C H N , 347.2487; found, 347.2490.

H), 2.54−2.47 (m, 1H), 2.10−2.05 (m, 1H), 1.99−1.86 (m, 4H),

Compound 10b: oil. H NMR (CDCl , 400 MHz): δ = 7.0 (d, J = 8.0

.73−1.66 (m, 1H), 1.39 (t, J = 6.8 Hz, 3H), 1.26 (t, J = 6.8 Hz, 3H).

Hz, 1H), 6.92 (s, 1H), 6.55 (d, J = 2.8 Hz, 1H), 6.53 (s, 1H), 6.47 (dd, J₁

C{ H} NMR (CDCl , 100 MHz): δ = 150.2, 149.9, 143.9, 138.3,

= 8.4 Hz, J = 2.8 Hz, 1H), 4.38 (d, J = 9.2 Hz, 1H), 3.65 (t, J = 8.0 Hz,

25.1, 116.1, 115.6, 114.4, 112.2, 111.2, 64.4, 63.9, 58.4, 57.2, 48.2,

1H), 3.45 (td, J = 8.8 Hz, J = 2.8 Hz, 1H), 3.32−3.25 (m, 1H), 2.85−

1 2

7.0, 40.5, 29.9, 23.3, 23.0, 15.1, 15.0. HRMS (ESI/Q-TOF) m/z: [M +

2.78 (m, 1H), 2.73−2.65 (m, 1H), 2.42−2.36 (m, 1H), 2.26 (s, 3H),

2.24 (s, 3H), 2.21−2.01 (m, 3H), 2.21 (s, 3H), 2.13 (s, 3H), 2.02−1.92

H] calcd for C H N O , 379.2386; found, 379.2390.

Compound 7b: oil. H NMR (CDCl , 400 MHz): δ = 6.84 (d, J = 8.8

(m, 1H), 1.83−1.68 (m, 2H). C{ H} NMR (CDCl , 100 MHz): δ =

Hz, 2H), 6.74−6.72 (m, 2H), 6.64−6.61 (m, 3H), 4.34 (d, J = 9.2 Hz,

148.1, 145.2, 137.1, 135.0, 130.2, 128.3, 126.8, 126.4, 124.4, 114.3,

113.8, 110.4, 65.1, 59.8, 49.7, 48.1, 47.6, 31.9, 30.6, 22.3, 20.3, 19.9,

H), 3.99 (q, J = 7.2 Hz, 2H), 3.90−3.81 (m, 2H), 3.65−3.61 (m, 1H),

.43 (td, J = 8.8 Hz, J = 2.8 Hz, 1H), 3.29−3.22 (m, 1H), 2.81−2.68

19.0, 18.6. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H N ,

24 31

(m, 2H), 2.39−2.33 (m, 1H), 2.27−2.09 (m, 3H), 1.99−1.94 (m, 1H),

347.2487; found, 347.2489.

Synthesis of Octahydro-Dipyrroloquinolines 11a and 11b.

Following the general procedure, the reaction of 1i (30.5 mg, 0.2

.78−1.68 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 6.8 Hz, 3H).

C{ H} NMR (CDCl , 100 MHz): δ = 152.4, 150.9, 144.1, 141.2,

30.4, 115.7, 114.5, 114.0, 112.6, 112.6, 65.4, 64.2, 63.8, 60.7, 50.1,

mmol) and 2a (27.7 mg, 0.24 mmol) in EtOH (2 mL) and Et N (0.5

mL) at 100 °C for 1 h aﬀorded 11a (13.1 mg, 38% yield) and 11b (9.5

mg, 27% yield), which were puriﬁed by column chromatography

8.1, 47.8, 31.7, 30.5, 22.4, 15.1, 15.0. HRMS (ESI/Q-TOF) m/z: [M +

H] calcd for C H N O , 379.2386; found, 379.2389.

Synthesis of Octahydro-Dipyrroloquinolines 8a and 8b. Follow-

ing the general procedure, the reaction of 1f (31.1 mg, 0.2 mmol) and

(pretreated with 1% Et

Total yield: 65%.

Compound 11a: white solid. Mp: 114−115 °C. H NMR (CDCl

400 MHz): δ = 7.18 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.95 (dd, J

N) using PE/EtOAc (30:1 v/v) as an eluent.

a (28.1 mg, 0.24 mmol) in EtOH (2 mL) and Et N (0.5 mL) at 100 °C

for 0.5 h aﬀorded 8a and 8b as a mixture (total amount: 22.1 mg, yield:

3%, dr: 67:33), which were obtained after column chromatography

= 8.4

Hz, J = 2.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.37 (d, J = 8.0 Hz, 1H),

(pretreated with 5% Et N) using PE/EtOAc (1:1 v/v) as an eluent. H

5.05 (d, J = 6.8 Hz, 1H), 3.68−3.63 (m, 1H), 3.46 (t, J = 8.4 Hz, 1H),

3.40−3.36 (m, 1H), 3.27−3.21 (m, 2H), 2.61 (q, J = 7.2 Hz, 2H),

2.51−2.41 (m, 3H), 2.13−1.87 (m, 5H), 1.75−1.65 (m, 1H), 1.26 (t, J

NMR (CDCl , 400 MHz): δ = 6.92−6.84 (m, 2.9H), 6.74−6.61 (m,

.5H), 6.33 (d, J = 8.4 Hz, 0.6H), 5.00 (d, J = 6.0 Hz, 0.67H), 4.31 (d, J

8.8 Hz, 0.33H), 4.04−3.80 (m, 8.0H), 3.60−3.57 (m, 1.0H), 3.42−

= 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H). C{ H} NMR (CDCl , 100

.37 (m, 1.2H), 3.19−3.15 (m, 1.4H), 2.81−2.69 (m, 0.7H), 2.51 (s,

MHz): δ = 147.5, 141.4, 131.7, 131.2, 128.6, 128.5, 127.2, 123.6, 111.3,

.8H), 2.37−1.66 (m, 8.9H). C{ H} NMR (CDCl , 100 MHz): δ =

110.5, 58.2, 56.8, 48.1, 46.2, 40.3, 30.2, 28.0, 27.9, 23.3, 23.2, 16.1, 16.0.

52.0, 150.6, 149.8, 149.7, 144.4, 144.2, 141.7, 138.7, 130.2, 125.0,

16.3, 115.8, 114.7, 114.3, 114.1, 112.65, 112.58, 112.3, 111.2, 70.3,

0.1, 69.7, 69.6, 65.3, 61.75, 61.70, 61.58, 61.55, 60.7, 58.4, 57.1, 50.1,

HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C24

, 347.2487;

found, 347.2488.

Compound 11b: oil. H NMR (CDCl

, 400 MHz): δ = 7.09 (d, J =

8.2, 48.0, 47.8, 47.1, 40.5, 31.7, 30.5, 30.0, 23.3, 23.1, 22.4. HRMS

8.4 Hz, 2H), 7.03 (dd, J

= 7.6 Hz, J

= 1.6 Hz, 1H), 6.98 (s, 1H), 6.67−

(

ESI/Q-TOF) m/z: [M + H] calcd for C H N O , 411.2284; found,

6.64 (m, 3H), 4.38 (d, J = 9.2 Hz, 1H), 3.67 (t, J = 8.0 Hz, 1H), 3.46 (td,

J = 9.2 Hz, J = 2.8 Hz, 1H), 3.35−3.28 (m, 1H), 2.87−2.80 (m, 1H),

11.2288.

Synthesis of Octahydro-Dipyrroloquinolines 9a and 9b. Follow-

ing the general procedure, the reaction of 1g (69.4 mg, 0.5 mmol) and

a (69.3 mg, 0.6 mmol) in EtOH (2 mL) and Et N (0.5 mL) at 100 °C

2.77−2.68 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.52 (q, J = 7.2 Hz, 2H),

2.46−2.40 (m, 1H), 2.29−2.09 (m, 3H), 2.03−1.92 (m, 1H), 1.85−

1.70 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H). C{ H}

for 1 h aﬀorded 9a (34.5 mg, 44% yield) and 9b (30.5 mg, 38% yield),

which were puriﬁed by column chromatography (pretreated with 1%

Et N) using PE/EtOAc (30:1 v/v) as an eluent. Total yield: 82%.

NMR (CDCl , 100 MHz): δ = 147.7, 145.1, 134.8, 132.4, 128.7, 128.4,

126.9, 126.1, 113.0, 111.9, 64.9, 60.3, 49.7, 48.3, 47.5, 31.9, 30.6, 28.4,

27.9, 22.4, 16.1, 16.0. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for

Compound 9a: white solid. Mp: 144−145 °C. H NMR (CDCl ,

00 MHz): δ = 7.14 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.0

C H N , 347.2487; found, 347.2489.

24 31

Synthesis of Octahydro-Dipyrroloquinolines 12a and 12b.

Following the general procedure, the reaction of 1j (129.1 mg, 0.5

Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.33 (d, J = 8.0 Hz, 1H), 5.02 (d, J =

.2 Hz, 1H), 3.66−3.63 (m, 1H), 3.47 (t, J = 8.4 Hz, 1H), 3.41−3.35

m, 1H), 3.26−3.19 (m, 2H), 2.49−2.45 (m, 1H), 2.30 (s, 3H), 2.13 (s,

(

mmol) and 2a (69.1 mg, 0.6 mmol) in EtOH (4 mL) and Et N (1 mL)

at 100 °C for 1 h aﬀorded 12a (32.1 mg, 23%) and 12b (30.8 mg, 22%),

which were puriﬁed by column chromatography (pretreated with 1%

H), 2.08−1.84 (m, 5H), 1.74−1.64 (m, 1H). The data above is in

17a

agreement with that which has been previously reported.

Et N) using PE/EtOAc (30:1 v/v) as an eluent. Total yield: 45%.

Compound 9b: oil. H NMR (CDCl , 400 MHz): δ = 7.06 (d, J = 8.0

Procedure for 2 mmol Scale Reaction for the Synthesis of 12a and

12b. To an oven-dried Schlenk tube (25 mL) were added 1j (517.0 mg,

2 mmol), L-proline (2a) (277.1 mg, 2.4 mmol), EtOH (8 mL), and

Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.62 (d, J = 8.0 Hz, 3H),

.38 (d, J = 9.2 Hz, 1H), 3.65 (t, J = 8.4 Hz, 1H), 3.45 (t, J = 8.0 Hz,

H), 3.32−3.26 (m, 1H), 2.83−2.69 (m, 2H), 2.41−2.35 (m, 1H), 2.29

Et N (2 mL) under an atmosphere of dry nitrogen. The tube was sealed,

(

s, 3H), 2.21−2.12 (m, 6H), 2.02−1.94 (m, 1H), 1.83−1.69 (m, 2H).

and the resulting mixture was stirred and heated to 100 °C in an oil bath

for 1 h. After the reaction was cooled down to room temperature, the

volatiles were removed in vacuo. The residue was puriﬁed by column

The data above is in agreement with that which has been previously

17b

reported.

Synthesis of Octahydro-Dipyrroloquinolines 10a and 10b.

Following the general procedure, the reaction of 1h (76.3 mg, 0.5

chromatography on silica (pretreated with 1%−5% Et N) using PE/

EtOAc (50:1) as an eluent to aﬀord the pure products 12a (120.1 mg,

mmol) and 2a (69.8 mg, 0.6 mmol) in EtOH (2 mL) and Et N (0.5

mL) at 100 °C for 1 h aﬀorded 10a (29.5 mg, 34% yield) and 10b (23.4

mg, 27% yield), which were puriﬁed by column chromatography

21%) and 12b (103.7 mg, 19%). Total yield: 40%.

Compound 12a: white solid. Mp: 107−108 °C. H NMR (CDCl ,

400 MHz): δ = 7.34 (d, J = 4.4 Hz, 4H), 7.31−7.24 (m, 6H), 7.14 (s,

1H), 7.10 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.8

Hz, 2H), 6.34 (d, J = 8.0 Hz, 1H), 5.01 (d, J = 6.8 Hz, 1H), 4.55 (s, 2H),

4.44 (s, 2H), 3.69−3.64 (m, 3H), 3.56−3.52 (m, 2H), 3.45−3.32 (m,

2H), 3.25−3.18 (m, 2H),2.87 (t, J = 7.2 Hz, 2H), 2.70 (t, J = 7.2 Hz,

2H), 2.49−2.42 (m, 1H), 2.11−2.04 (m, 1H), 2.00−1.81 (m, 4H),

(

pretreated with 1% Et N) using PE/EtOAc (30:1 v/v) as an eluent.

Total yield: 61%.

Compound 10a: white solid. Mp: 149−151 °C. H NMR (CDCl ,

00 MHz): δ = 7.10 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 6.60

(

dd, J = 8.0 Hz, J = 2.8 Hz, 2H), 6.24 (s, 1H), 4.99 (d, J = 6.4 Hz, 1H),

1 2

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.72−1.65 (m, 1H). C{ H} NMR (CDCl , 100 MHz): δ = 147.8,

was carefully quenched by the addition of saturated aq NaHCO₃

41.8, 138.6, 138.6, 129.8, 129.3, 128.5, 128.4, 128.3, 127.7, 127.7,

27.5, 127.4, 125.9, 125.5, 123.4, 111.3, 110.5, 73.0, 72.8, 72.0, 71.8,

8.1, 56.6, 47.9, 46.7, 40.2, 35.4, 35.4, 30.2, 23.3, 23.2. HRMS (ESI/Q-

solution and then extracted with EtOAc (3 × 50 mL). The combined

organic layers were dried over anhydrous MgSO and ﬁltered. The

solvent was removed in vacuo to yield an oil, which was puriﬁed by

TOF) m/z: [M + H] calcd for C H N O , 559.3325; found,

chromatography (PE/EtOAc = 10:1) to aﬀord the product 19 as a

59.3327.

yellow oil (1.723 g, 61%). H NMR (CDCl , 400 MHz): δ = 6.80 (d, J =

Compound 12b: oil. H NMR (CDCl , 400 MHz): δ = 7.33−7.24

10.0 Hz, 2H), 6.32 (d, J = 10.0 Hz, 2H), 3.68 (t, J = 6.4 Hz, 2H), 3.19 (s,

(

m, 10H), 7.07−7.03 (m, 3H), 6.96 (s, 1H), 6.63−6.58 (m, 3H), 4.53

s, 2H), 4.43 (s, 2H), 4.35 (d, J = 9.2 Hz, 1H), 3.67−3.61 (m, 3H),

3H), 1.94 (t, J = 6.4 Hz, 2H), 0.85 (s, 9H), 0.00 (s, 6H). C{ H} NMR

(CDCl , 100 MHz): δ = 185.5, 151.2, 130.8, 74.4, 57.9, 52.8, 42.9, 25.8,

.58−3.54 (m, 2H), 3.44 (td, J = 8.8 Hz, J = 2.8 Hz, 1H), 3.31−3.25

18.1, −5.5. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for C H O Si,

283.1729; found, 283.1733.

15 27

m, 1H), 2.87−2.76 (m, 5H), 2.73−2.67 (m, 1H), 2.44−2.38 (m, 1H),

.27−2.08 (m, 3H), 2.00−1.92 (m, 1H), 1.81−1.67 (m, 2H). C{ H}

To an oven-dried Schlenk tube (10 mL) were added 19 (282.5 mg,

1.0 mmol), L-proline 2a (139.5 mg, 1.2 mmol), EtOH (10 mL) and

NMR (CDCl , 100 MHz): δ = 148.0, 145.6, 138.6, 138.6, 129.8, 129.2,

28.6, 128.4, 128.3, 127.7, 127.7, 127.6, 127.6, 127.5, 127.4, 126.7,

12.9, 112.0, 73.0, 72.8, 71.9, 71.8, 64.8, 60.1, 49.5, 48.3, 47.5, 35.8,

5.4, 32.0, 30.6, 22.4. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for

C H N O , 559.3325; found, 559.3328.

Synthesis of Octahydro-Dipyrroloquinolines 13a and 13b.

Following the general procedure, the reaction of 1k (98.1 mg, 0.5

mmol) and 2a (69.4 mg, 0.6 mmol) in EtOH (4 mL) and Et N (1 mL)

at 100 °C for 1 h aﬀorded 13a and 13b as a mixture (total amount: 59.5

mg, yield: 55%, dr: 67:33), which were obtained after column

Et N (2.5 mL) under an atmosphere. The tube was sealed, and the

reaction was heated to 80 °C in an oil bath for 2 h. After the reaction was

cooled down to room temperature, the reaction mixture wasconcen-

tratedd to dryness. The residue was puriﬁed by column chromatog-

raphy on silica gel (pretreated with 1% Et N) using PE/EtOAc (150:1

v/v) as an eluent to aﬀord 20a (120.5 mg, yield: 39%) and 20b (76.0

mg, yield: 26%).

Compound 20a: white solid. Mp: 84−86 °C. H NMR (CDCl , 400

MHz): δ = 7.14−7.10 (m, 3H), 6.94 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H),

chromatography (pretreated with 5% Et N) using PE/EtOAc (6:1 v/

6.74 (d, J = 8.4 Hz, 2H), 6.34 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 6.8 Hz,

1H), 3.80 (t, J = 8.0 Hz, 2H), 3.67−3.63 (m, 3H), 3.46−3.34 (m, 2H),

v) as an eluent. H NMR (CDCl , 400 MHz): δ = 7.20−7.09 (m, 3H),

.02−6.99 (m, 1H), 6.77 (d, J = 8.8 Hz, 1.33H), 6.68−6.62 (m, 1H),

.37 (d, J = 8.4 Hz, 0.67H), 5.05 (d, J = 6.8 Hz, 0.67H), 4.38 (d, J = 9.2

.27−3.19 (m, 2H), 2.78 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 8.0 Hz, 2H),

.48−2.43 (m, 1H), 2.14−2.08 (m, 1H), 2.03−1.82 (m, 4H), 1.74−

.66 (m, 1H), 0.93 (s, 9H), 0.86 (s, 9H), 0.062 (s, 3H), 0.058 (s, 3H),

Hz, 0.33H), 3.72−3.22 (m, 15 H), 2.88−2.69 (m, 0.76H), 2.51−2.42

(

m, 1H), 2.26−1.66 (m, 5.33H). C{ H} NMR (CDCl , 100 MHz): δ

−0.024 (s, 3H), −0.027 (s, 3H). C{ H} NMR (CDCl , 100 MHz): δ

172.96, 172.87, 172.8, 172.6, 148.5, 148.2, 146.2, 142.3, 130.1, 129.9,

147.6, 141.7, 130.0, 129.4, 128.6, 125.9, 125.5, 123.4, 111.2, 110.4,

29.6, 128.8, 128.5, 127.94, 127.92, 124.3, 123.1, 121.8, 121.0, 120.7,

12.9, 112.3, 111.4, 110.6, 64.6, 59.9, 57.9, 56.5, 52.0, 51.9, 51.85,

1.79, 49.4, 48.3, 47.8, 47.3, 46.7, 40.7, 40.38, 40.32, 40.28, 40.1, 32.0,

0.5, 30.2, 23.3, 22.4. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for

C H N O , 435.2284; found, 435.2289.

Synthesis of Octahydro-Dipyrroloquinolines 14a and 14b.

Following the general procedure, the reaction of 1l (168.2 mg, 1.0

mmol) and 2a (139.1 mg, 1.2 mmol) in EtOH (8 mL) and Et N (2 mL)

at 100 °C for 1 h aﬀorded 14a and 14b as a mixture (total amount:

19.1 mg, yield: 63%, dr: 60:40), after column chromatography

pretreated with 5% Et N) using PE/EtOAc (1:1 v/v) as an eluent.

Synthesis of 1-(4-Methoxyphenyl)-1H-pyrrole (15). The reaction of

a (30.9 mg, 0.2 mmol) and 2b (32.1 mg, 0.24 mmol) in EtOH (2 mL)

and Et N (0.5 mL) at 100 °C for 3 h aﬀorded 1-(4-methoxyphenyl)-

H-pyrrole (15) (19.4 mg, yield: 56%), which was puriﬁed by column

chromatography (PE/EtOAc = 60:1). H NMR (CDCl , 400 MHz): δ

7.33 (d, J = 8.8 Hz, 2H), 7.02 (t, J = 2.4 Hz, 2H), 6.96 (d, J = 8.8 Hz,

H), 6.34 (t, J = 2.4 Hz, 2H), 3.85 (s, 3H). The data above is in

agreement with that which has been previously reported.

Synthesis of 1-(p-Tolyl)-1H-pyrrole (16). The reaction of 1g (27.9

mg, 0.2 mmol) and 2b (32.1 mg, 0.24 mmol) in EtOH (2 mL) and Et N

0.5 mL) at 100 °C for 6 h aﬀorded 1-(p-tolyl)-1H-pyrrole (16) (14.6

mg, yield: 46%), which was puriﬁed by column chromatography (PE/

EtOAc = 60:1). H NMR (CDCl , 400 MHz): δ = 7.29 (d, J = 8.4 Hz,

H), 7.23 (d, J = 8.4 Hz, 2H), 7.07 (t, J = 2.0 Hz, 2H), 6.35 (t, J = 2.0

Hz, 2H), 2.38 (s, 3H). The data above is in agreement with that which

has been previously reported.

Synthetic Procedure of Octahydro-Dipyrroloquinolines 14a

and 14b from 2 to 4-(2-Hydroxyethyl)phenol 17. To a mixture of

5.4, 65.3, 57.6, 56.6, 47.9, 46.7, 40.2, 38.9, 38.8, 30.2, 26.1, 26.0, 23.3,

3.2, 18.5, 18.4, −5.22, −5.31, −5.33. HRMS (ESI/Q-TOF) m/z: [M +

H] calcd for C H N O Si , 607.4115; found, 607.4118.

36 59

Compound 20b: white solid. Mp: 75−77 °C. H NMR (CDCl , 400

MHz): δ = 7.07 (d, J = 8.4 Hz, 2H), 7.02 (dd, J = 8.0 Hz, J = 1.6 Hz,

H), 6.94 (s, 1H), 6.64−6.60 (m, 3H), 4.37 (d, J = 9.2 Hz, 1H), 3.78 (t,

J = 7.2 Hz, 2H), 3.72−3.64 (m, 3H), 3.47−3.43 (m, 1H), 3.33−3.26

m, 1H), 2.84−2.75 (m, 4H), 2.68 (t, J = 7.6 Hz, 2H), 2.42−2.36 (m,

H), 2.28−2.14 (m, 3H), 2.02−1.94 (m, 1H), 1.82−1.70 (m, 2H), 0.91

s, 9H), 0.84 (s, 9H), 0.04 (s, 6H), −0.05 (s, 3H), −0.07 (s, 3H).

(

C{ H} NMR (CDCl , 100 MHz): δ = 147.9, 145.6, 129.7, 129.5,

−

28.7, 127.8, 127.8, 126.6, 112.7, 112.0, 65.3, 65.1, 65.1, 60.0, 49.6,

8.4, 47.5, 39.1, 38.8, 31.9, 30.7, 26.1, 26.0, 22.4, 18.5, 18.4, −5.2,

5.35, −5.42. HRMS (ESI/Q-TOF) m/z: [M + H] calcd for

Si , 607.4115; found, 607.4119.

The compound 20a (40.0 mg, 0.07 mmol) was dissolved in THF (1

mL). Then, a solution of tetrabutylammonium ﬂuoride (0.3 mL, 1 M in

THF) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1

h. The volatiles were removed in vacuo, and the residue was puriﬁed by

column chromatography on silica gel (PE/EtOAc = 1:1) to aﬀord 14a

18a

as a white solid (23.1 mg, yield: 87%). Mp: 116−118 °C. H NMR

(

CDCl , 400 MHz): δ = 7.14 (d, J = 8.4 Hz, 3H), 6.95 (dd, J = 8.0 Hz,

J₂= 1.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 8.4 Hz, 1H), 5.06

d, J = 6.8 Hz, 1H), 3.85 (t, J = 6.4 Hz, 2H), 3.68−3.63 (m, 2H), 3.42−

.34 (m, 3H), 3.26−3.20 (m, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.62 (t, J =

(

18b

6.4 Hz, 2H), 2.56−2.49 (m, 2H), 2.13−2.07 (m, 1H), 2.03−1.83 (m,

H), 1.74−1.64 (m, 2H). The data above is in agreement with that

which has been previously reported.

−4-(2-hydroxyethyl)phenol 17 (1.391 g, 10 mmol) and imidazole

The compound 20b (64.2 mg, 0.11 mmol) was dissolved in THF (1

mL). A solution of tetrabutylammonium ﬂuoride (0.4 mL) was added

at 0 °C. The reaction mixture was stirred at 0 °C until TLC analysis

indicated complete consumption of the starting material (1 h). The

volatiles were removed in vacuo, and the residue was puriﬁed by column

(

0.824 g, 12 mmol) in dry THF (10 mL) at 0 °C was added dropwise a

solution of TBDMSCl (1.823 g, 12 mmol in 5 mL of dry THF)

dropwise. The mixture was allowed to stir at 0 °C for 2 h before dilution

with Et O (50 mL) and aqueous 10% citric acid solution (30 mL). The

mixture was partitioned, and the organic layer was collected. The

aqueous layer was extracted with Et O (3 × 50 mL). The organic layers

chromatography on silica gel (PE/EtOAc = 1:1) to aﬀord 14b as a

white solid (39.1 mg, yield: 94%). Mp: 135−137 °C. H NMR (CDCl

were washed with water and brine and dried over anhydrous MgSO₄.

The mixture was ﬁltered, and solvent was removed in vacuo to yield the

crude product 18, which was dissolved in MeOH (20 mL). PhI(OAc)₂

400 MHz): δ = 7.09 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.88

(s, 1H), 6.67−6.63 (m, 3H), 4.32 (d, J = 9.2 Hz, 1H), 3.82 (t, J = 6.0 Hz,

2H), 3.69 (t, J = 6.0 Hz, 2H), 3.64−3.60 (m, 1H), 3.46−3.41 (m, 1H),

3.32−3.26 (m, 1H), 2.90−2.84 (m, 1H), 2.79 (t, J = 6.0 Hz, 2H), 2.70−

2.63 (m, 3H), 2.53−2.47 (m, 1H), 2.29−2.19 (m, 2H), 2.16−2.11 (m,

(

4.25 g, 12 mmol) was added portionwise at 0 °C. The resultant mixture

was stirred at 0 °C for 1 h and room temperature for 24 h. The reaction

0404

J. Org. Chem. 2021, 86, 10397−10406

The Journal of Organic Chemistry

S. G.; Spring, D. R. Diversity-Oriented Synthesis: Producing Chemical

Article

H), 2.02−1.95 (m, 1H), 1.84−1.68 (m, 4H). The data above is in

Chem. Rev. 2011, 111 , 7157 −7259. (c) O ’Connor, C. J.; Beckmann, H.

Tools for Dissecting Biology. Chem. Soc. Rev. 2012, 41, 4444−4456.

(d) Quan, M. L.; Wong, P. C.; Wang, C.; Woerner, F.; Smallheer, J. M.;

Barbera, F. A.; Bozarth, J. M.; Brown, R. L.; Harpel, M. R.; Luettgen, J.

M.; Morin, P. E.; Peterson, T.; Ramamurthy, V.; Rendina, A. R.; Rossi,

K. A.; Watson, C. A.; Wei, A.; Zhang, G.; Seiffert, D.; Wexler, R. R.

Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa

Inhibitors. J. Med. Chem. 2014, 57 , 955 −969. (e) Sridharan, V.;

Suryavanshi, P. A.; Menéndez, J. C. Advances in the Chemistry of

Tetrahydroquinolines. Chem. Rev. 2011 , 111 , 7157 −7259. (f) Weinreb,

S. M. Studies on Total Synthesis of the Cylindricine/Fasicularin/

Lepadiformine Family of Tricyclic Marine Alkaloids. Chem. Rev. 2006,

106, 2531−2549.

agreement with that which has been previously reported.

ASSOCIATED CONTENT

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01083.

X-ray crystallographic structures for compounds 3a and

b and copies of H and C{ H} NMR spectra for all of

the products (PDF )

Accession Codes

CCDC 2057583 and 2057584 contain the crystallographic data

of compounds 3a and 3b for this article. These data can be

obtained free of charge from The Cambridge Crystallographic

Data Centre via www.ccdc.cam.ac.uk/data_request/cif, or by

emailing data_request@ccdc.cam.ac.uk, or by contacting The

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

(2) Shen, Y. H.; Su, Y. Q.; Tian, J. M.; Lin, S.; Li, H. L.; Tang, J.;

Zhang, W. D. A Unique Indolo-[1,7]Naphthyridine Alkaloid from

Incarvillea Mairei Var. Grandiflora (Wehrh.) Grierson. Helv. Chim. Acta

4) (a) Brown, P. D.; Willis, A. C.; Sherburn, M. S.; Lawrence, A. L.

010, 93, 2393−2396.

3) Tan, D.; Chou, G.; Wang, Z. Three New Alkaloids from Senecio

Scandens. Chem. Nat. Compd. 2014, 50, 329−332.

Total Synthesis and Structural Revision of the Alkaloid IncargranineB.

Angew. Chem., Int. Ed. 2013 , 52 , 13273 −13275. (b) Brown, P. D.;

Lawrence, A. L. The Importance of Asking “How and Why?” In Natural

Product Structure Elucidation. Nat. Prod. Rep. 2017, 34, 1193−1202.

AUTHOR INFORMATION

Corresponding Author

Ruwei Shen − State Key Laboratory of Materials-Oriented

Chemical Engineering, College of Chemical Engineering,

Nanjing Tech University, Nanjing 211816, China;

orcid.org/0000-0002-8834-3256; Email: shenrw@

njtech.edu.cn

■

(5) (a) Miro, J.; Sánchez-Rosello, M.; González, J.; Del Pozo, C.;

̃ ̃

Fustero, S. Gold-Catalyzed Tandem Hydroamination/Formal Aza-

Diels-Alder Reaction of Homopropargyl Amino Esters: A Combined

Computational and Experimental Mechanistic Study. Chem. - Eur. J.

015, 21, 5459−5466. (b) Fustero, S.; Bello, P.; Miro, J.; Sanchez-

Rosello, M.; Maestro, M. A.; Gonzalez, J.; Pozo, C. d. Gold Catalyzed

Stereoselective Tandem Hydroamination-Formal Aza-Diels-Alder

Reaction of Propargylic Amino Esters. Chem. Commun. 2013, 49,

Authors

Can Zhang − State Key Laboratory of Materials-Oriented

Chemical Engineering, College of Chemical Engineering,

Nanjing Tech University, Nanjing 211816, China

Jianbin Li − State Key Laboratory of Materials-Oriented

Chemical Engineering, College of Chemical Engineering,

Nanjing Tech University, Nanjing 211816, China

Xin Wang − State Key Laboratory of Materials-Oriented

Chemical Engineering, College of Chemical Engineering,

Nanjing Tech University, Nanjing 211816, China

Xuan Shen − State Key Laboratory of Materials-Oriented

Chemical Engineering, College of Chemical Engineering,

Nanjing Tech University, Nanjing 211816, China

Dunru Zhu − State Key Laboratory of Materials-Oriented

Chemical Engineering, College of Chemical Engineering,

Nanjing Tech University, Nanjing 211816, China;

orcid.org/0000-0003-2124-498X

(

336−1338.

6) (a) Ma, C. L.; Li, X. H.; Yu, X. L.; Zhu, X. L.; Hu, Y. Z.; Dong, X.

W.; Tan, B.; Liu, X. Y. Gold-Catalyzed Tandem Synthesis of Bioactive

Spiro-Dipyrroloquinolines and Its Application in the One-Step

Synthesis of Incargranine B Aglycone and Seneciobipyrrolidine (I).

Org. Chem. Front. 2016, 3 (3), 324−329. (b) Yu, X. L.; Kuang, L.; Chen,

S.; Zhu, X. L.; Li, Z. L.; Tan, B.; Liu, X. Y. Counteranion-Controlled

Unprecedented Diastereo- and Enantioselective Tandem Formal

Povarov Reaction for Construction of Bioactive Octahydro-Dipyrro-

loquinolines. ACS Catal. 2016, 6, 6182 −6190. (c) Liu, L.; Wang, C.;

Liu, Q.; Kong, Y.; Chang, W.; Li, J. Copper(II) Trifluoromethanesul-

fonate Catalyzed Hydroamination Cyclization-Dimerization Cascade

Reaction of Homopropargylic Amines for the Construction of Complex

Fused Nitrogen-Containing Tetracycles. Eur. J. Org. Chem. 2016, 2016,

684−3690.

(7) Appun, J.; Stolz, F.; Naumov, S.; Abel, B.; Schneider, C. Modular

Synthesis of Dipyrroloquinolines: A Combined Synthetic and

Mechanistic Study. J. Org. Chem. 2018, 83, 1737−1744.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01083

(

8) For others, also see: (a) Kerr, G. H.; Meth-Cohn, O.; Mullock, E.

B.; Suschitzky, H. Reactions of NN-Dialkylanilines with Diethyl

Azodicarboxylate and with Ozone T. J. Chem. Soc., Perkin Trans. 1 1974,

Notes

The authors declare no competing ﬁnancial interest.

614−1619. (b) Buswell, M.; Fleming, I.; Ghosh, U.; Mack, S.; Russell,

M.; Clark, B. P. The Extraordinary Reactions of Phenyldimethylsi-

ACKNOWLEDGMENTS

lyllithium with N,N-Disubstituted Amides. Org. Biomol. Chem. 2004 , 2 ,

■

006 −3017. (c) Min, C.; Sanchawala, A.; Seidel, D. Dual C-H

Financial support from the Natural Science Foundation of

Jiangsu Province (BK20181374), Postgraduate Research &

Practice Innovation Program of Jiangsu Province

Functionalization of N-Aryl Amines: Synthesis of Polycyclic Amines via

an Oxidative Povarov Approach. Org. Lett. 2014 , 16 , 2756 −2759.

(d) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. First Total Synthesis of

(

SJCX20_0361), NSFC (21302095), and Nanjing Tech

Martinellic Acid, a Naturally Occurring Bradykinin Receptor

Antagonist. Org. Lett. 2001 , 3 , 2189 −2191. (e) Ma, D.; Xia, C.; Jiang,

J.; Zhang, J.; Tang, W. Aromatic Nucleophilic Substitution or CuI-

Catalyzed Coupling Route to Martinellic Acid. J. Org. Chem. 2003 , 68 ,

442 −451. (f) Honzawa, S.; Uchida, M.; Tashiro, T.; Sugihara, T. Alpha-

Oxidation of Amine Derivatives by Bis(2,2,2-Tri-Chloroethyl)

Azodicarboxylate and Application of Its Products as Iminium Ion

Equivalents. Heterocycles 2017, 95, 994−1029. (g) Buswell, M.;

University is acknowledged.

REFERENCES

■

1) (a) Weinreb, S. M. Studies on Total Synthesis of the Cylindricine/

Fasicularin/Lepadiformine Family of Tricyclic Marine Alkaloids. Chem.

Rev. 2006, 106, 2531 −2549. (b) Sridharan, V.; Suryavanshi, P. A.;

Menéndez, J. C. Advances in the Chemistry of Tetrahydroquinolines.

0405

J. Org. Chem. 2021, 86, 10397−10406

The Journal of Organic Chemistry

Fleming, I. The Reaction of Phenyldimethylsilyllithium with N-

Article

Phenylpyrrolidone. Chem. Commun. 2003, 34 , 202 −203. (h) Li, S. S.;

Zhou, L.; Wang, L.; Zhao, H.; Yu, L.; Xiao, J. Organocatalytic C(Sp3)-

H Functionalization via Carbocation-Initiated Cascade [1,5]-Hydride

Transfer/Cyclization: Synthesis of Dihydrodibenzo[b, e]Azepines.

Org. Lett. 2018, 20, 138−141.

(13) Zhang, C.; Seidel, D. Nontraditional Reactions of Azomethine

Ylides: Decarboxylative Three-Component Couplings of α -Amino

Acids. J. Am. Chem. Soc. 2010, 132, 1798−1799.

(14) The reaction of cyclohexanone (0.2 mmol), p-quinone

monoacetal (0.2 mmol), and L-proline (0.4 mmol) under similar

conditions produced 3a and 3b in a combined yield of 60%, and no

cross-over products were detected, which may be attributed to the high

reactivity of QMA.

(9) (a) For recent reviews, see: Dohi, T.; Kita, Y. Quinone Monoacetal

Compounds in Application to Controlled Reactions with Nucleophiles;

Price, E. R., Johnson, S. C., Eds.; NOVA Science: New York, 2013.

(

15) For a recent review on the Pictet−Spengler reaction, see:

Calcaterra, A.; Mangiardi, L.; Delle Monache, G.; Quaglio, D.; Balducci,

S.; Berardozzi, S.; Iazzetti, A.; Franzini, R.; Botta, B.; Ghirga, F. The

Pictet-Spengler Reaction Updates Its Habits. Molecules 2020, 25, 414−

(b) Kamitanaka, T.; Morimoto, K.; Dohi, T.; Kita, Y. Controlled-

Coupling of Quinone Monoacetals by New Activation Methods:

Regioselective Synthesis of Phenol-Derived Compounds. Synlett 2019,

496.

30, 1125−1143. (c) Al-Tel, T. H.; Srinivasulu, V.; Ramanathan, M.;

(16) (a) Shu, C.; Liao, L.-H.; Liao, Y.-J.; Hu, X.-Y.; Zhang, Y.-H.;

Soares, N. C.; Sebastian, A.; Bolognesi, M. L.; Abu-Yousef, I. A.;

Majdalawieh, A. Stereocontrolled Transformations of Cyclohexadie-

none Derivatives to Access Stereochemically Rich and Natural Product-

Inspired Architectures. Org. Biomol. Chem. 2020 , 18 , 8526 −8571.

Yuan, W.-C.; Zhang, X.-M. Lewis Acid Catalyzed [3 + 2] Coupling of

Indoles with Quinone Monoacetals or Quinone Imine Ketal. Eur. J. Org.

Chem. 2014 , 2014 , 4467 −4471. (b) Bodipati, N.; Peddinti, R. K.

Hypervalent Iodine Mediated Synthesis of Carbamate Protected p -

Quinone Monoimine Ketals and p -Benzoquinone Monoketals. Org.

Biomol. Chem. 2012, 10, 4549−4553. (c) Bayón, P.; Marjanet, G.;

Toribio, G.; Alibés, R.; March, P. de; Figueredo, M.; Font, J. An

Efficient Protocol for the Enantioselective Preparation of a Key

Polyfunctionalized Cyclohexane. New Access to (R)- and (S)-4-

Hydroxy-2-cyclohexenone and (R)- and (S)-trans -Cyclohex-2-ene-1,4-

diol. J. Org. Chem. 2008, 73, 3486−3491. (d) Camps, P.; González, A.;

(d) Chandra, G.; Patel, S. Molecular Complexity from Aromatics:

Recent Advances in the Chemistry of ParaQuinol and Masked Para-

Quinone Monoketal. ChemistrySelect 2020, 5, 12885−12909.

(10) For selected examples of the synthetic use of QMAs in organic

synthesis, see: (a) Yu, M.; Danishefsky, S. J. A Direct Route to

Fluostatin C by a Fascinating Diels-Alder Reaction. J. Am. Chem. Soc.

2008, 130, 2783−2785. (b) Hayden, A. E.; DeChancie, J.; George, A.

H.; Dai, M.; Yu, M.; Danishefsky, S. J.; Houk, K. N. Origins of the

Regioselectivities in the Diels-Alder Reactions of Vinylindenes with 1,4-

Quinone Monoketal and Acrolein Dienophiles. J. Org. Chem. 2009 , 74 ,

Munoz- Torrero, D.; Simon, M.; Zuniga, A.; Martins, M. A.; Font-

̃ ̃

Bardia, M.; Solans, X. Synthesis of Polysubstituted Bicyclo[3.3.1]-

nonane-3,7-diones from Cyclohexa-2,5-dienones and Dimethyl 1,3-

Acetonedicarboxylate. Tetrahedron 2000 , 56 , 8141 −8151. (e) Taneja,

N.; Peddinti, R. K. Iodobenzene and m -Chloroperbenzoic Acid

Mediated Oxidative Dearomatization of Phenols. Tetrahedron Lett.

6770 −6776. (c) Liang, H.; Ciufolini, M. A. Tandem Phenolic Oxidative

Amidation-Intramolecular Diels-Alder Reaction: An Approach to the

Himandrine Core. Org. Lett. 2010, 12, 1760−1763. (d) Zhang, J.; Yin,

Z.; Leonard, P.; Wu, J.; Sioson, K.; Liu, C.; Lapo, R.; Zheng, S. A

Variation of the Fischer Indolization Involving Condensation of

Quinone Monoketals and Aliphatic Hydrazines. Angew. Chem., Int. Ed.

016, 57, 3958 −3963. (f) Wu, W.; Li, X.; Huang, H.; Yuan, X.; Lu, J.;

Zhu, K.; Ye, J. Asymmetric Intramolecular Oxa-Michael Reactions of

Cyclohexadienones Catalyzed by a Primary Amine Salt. Angew. Chem.,

Int. Ed. 2013, 52, 1743−1747.

2013, 52, 1753−1757. (e) Kamitanaka, T.; Morimoto, K.; Tsuboshima,

K.; Koseki, D.; Takamuro, H.; Dohi, T.; Kita, Y. Efficient Coupling

Reaction of Quinone Monoacetal with Phenols Leading to Phenol

Biaryls. Angew. Chem., Int. Ed. 2016, 55, 15535−15538. (f) Wang, J. Z.;

17) (a) Rao, G. A.; Periasamy, M. Cycloaddition of Enamine and

Iminium Ion Intermediates Formed in the Reaction of N

-Arylpyrrolidines with T-HYDRO. Synlett 2015, 26, 2231−2236.

(b) Anastasiou, D.; Campi, E. M.; Chaouk, H.; Fallon, G. D.; Jackson,

W. R.; McCubbin, Q. J.; Trnacek, A. E. The Stereochemistry of

Organometallic Compounds. LX. Rhodium-Catalyzed Reactions of

Hydrogen and Carbon Monoxide With Alkenylanilines. Aust. J. Chem.

1994, 47, 1043−1059.

(18) (a) Ma, H. C.; Jiang, X. Z. N-Hydroxyimides as Efficient Ligands

for the Copper-Catalyzed N-Arylation of Pyrrole, Imidazole, and

Indole. J. Org. Chem. 2007, 72, 8943−8946. (b) Dreher, S. D.; Lim, S.

E.; Sandrock, D. L.; Molander, G. A. Suzuki-Miyaura Cross-Coupling

Reactions of Primary Alkyltrifluoroborates with Aryl Chlorides. J. Org.

Chem. 2009, 74 (10), 3626−3631.

Zhou, J.; Xu, C.; Sun, H. B.; Kurti, L.; Xu, Q. L. Symmetry in Cascade

Chirality-Transfer Processes: A Catalytic Atroposelective Direct

Arylation Approach to BINOL Derivatives. J. Am. Chem. Soc. 2016 ,

38 , 5202 −5205. (g) Yi, C.; She, Z.; Cheng, Y.; Qu, J. Redox-Neutral α -

C-H Functionalization of Pyrrolidin-3-ol. Org. Lett. 2018, 20, 668−671.

11) Moriarty, R. M.; Prakash, Oxidation of Phenolic Compounds with

Organohypervalent Iodine Reagents; Wiley-VCH: Weinheim, Germany,

001; pp 327−415.

12) (a) Shen, R.; Zhang, M.; Xiao, J.; Dong, C.; Han, L.-B. Ph P-

(

Mediated Highly Selective C(α )-P Coupling of Quinone Monoacetals

with R P(O)H: Convenient and Practical Synthesis of Ortho -

Phosphinyl Phenols. Green Chem. 2018, 20, 5111−5116. (b) Zhang,

M.; Jia, X.; Zhu, H.; Fang, X.; Ji, C.; Zhao, S.; Han, L.-B.; Shen, R. Zinc-

Catalyzed Regioselective C-P Couplings of p -Quinol Ethers with

Secondary Phosphine Oxides to Afford 2-Phosphinylphenols. Org.

Biomol. Chem. 2019, 17, 2972 −2984. (c) Xiao, J.; Li, Q.; Shen, R.;

Shimada, S.; Han, L.-B. Phosphonium Phenolate Zwitterion vs

Phosphonium Ylide: Synthesis, Characterization and Reactivity Study

of a Trimethylphosphonium Phenolate Zwitterion. Adv. Synth. Catal.

019, 361, 5715−5720. (d) Shen, R.; Wang, X.; Zhang, S.; Dong, C.;

Zhu, D.; Han, L.-B. Three-Component Reaction of p -Quinone

Monoacetals, Amines and Diarylphosphine Oxides to Afford m -

(Phosphinyl)anilides. Adv. Synth. Catal. 2020 , 362 , 942 −948.

(e) Wang, X.; Zhang, C.; Shen, R.; Han, L.-B. Three-Component

Reactions of α -Amino Acids, p -Quinone Monoacetals, and Diary-

lphosphine Oxides to Selectively Afford 3-(Diarylphosphinyl)Anilides

and N -Aryl-2-Diarylphosphinylpyrrolidines. J. Org. Chem. 2020 , 85 ,

4753 −14762. (f) Wang, X.; Li, G.; Li, X.; Zhu, D.; Shen, R. One-Pot

Three-Component Reaction of: P-Quinone Monoacetals, l-Proline and

Naphthols to Afford N-Aryl-2-Arylpyrrolidines. Org. Chem. Front.

2021, 8, 297−303.

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