Au(I)-Catalyzed Pictet-Spengler Reactions All around the Indole Ring

pubs.acs.org/joc

Article

Au(I)-Catalyzed Pictet−Spengler Reactions All around the Indole

Ring

Pierre Milcendeau, Zhenhao Zhang, Nicolas Glinsky-Olivier, Elsa van Elslande, and Xavier Guinchard*

Cite This: J. Org. Chem. 2021, 86, 6406 −6422

Read Online

sı

*

Metrics & More

Article Recommendations

Supporting Information

ACCESS

ABSTRACT: Au(I) complexes catalyze iso-Pictet−Spengler reactions.

Ethylamine or methylamine chains were introduced at C2, C4, or the

nitrogen atom of the indole ring, and the corresponding substrates were

reacted in the presence of aldehydes and catalytic amounts of Au(I)

complexes, leading to a variety of polycyclic scaﬀolds. Selectivity could be

achieved in the course of a double iso-Pictet−Spengler reaction involving

two successive aldehydes, leading to highly complex molecules.

complexes^14,15(Scheme 1, eq 1). These reactions occur via a

mechanism involving the auration of the indole ring that we

INTRODUCTION

■

Indole alkaloids are an important class of heterocycles because

of their of prevalence natural and bioactive compounds.¹

Among these privileged scaﬀolds, tetrahydro-β-carbolines 1 are

important molecules, and their structural unit is embedded in

numerous natural products, among which a huge number are

bioactive.²The Pictet−Spengler reaction^3,4combining trypt-

amines and aldehydes is unarguably the easiest and fastest way

to prepare such scaﬀolds.^2bRich of more than a century of

research, this reaction and its mechanism has been intensively

studied⁵and applied to numerous total syntheses.^2bInterest-

ingly, because of the nucleophilicity of indole at C2 and C3,⁶

numerous variants of the Pictet−Spengler reaction lead to

structurally related compounds, such as 1,2,3,4-

tetrahydropyrazino[1,2-a]indoles 2,⁷tetrahydro-γ-carbolines

3,⁸and 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolines 4^7b,9

(Figure 1). These so-called iso-Pictet−Spengler reactions are

far less studied than the venerable historical reaction, despite

allowing access to interesting heterocycles.¹⁰

Scheme 1. Context of This Work

established through both experimental and computational

studies. We hypothesized that similar reactions catalyzed by

Au(I) complexes should occur from the use of other

regioisomeric alkylamines 5. Herein, we show that it is

possible to obtain regioisomeric compounds 2, 3, and 4 from

gold-catalyzed iso-Pictet−Spengler reactions (Scheme 1, eq 2).

For clarity purpose, we have deﬁned the reactions as N-iso-,

C2-iso-, and C4-iso-Pictet−Spengler reactions, depending on

the connecting atom of the indole ring to the alkylamine chain.

Our group has long been interested in the gold-catalyzed¹¹

functionalizations of indoles.^12,13Recently, we discovered that

Pictet−Spengler reactions could be catalyzed by Au(I)

Received: February 3, 2021

Published: April 23, 2021

Figure 1. Tetrahydro-β-carbolines and congeners.

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

6406

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

With a good knowledge of each of these diﬀerent versions of

the reaction, we could achieve a one-pot, selective process

including successively a C4-iso- and an N-iso-Pictet−Spengler

reaction for the synthesis of complex compounds 7 via the C3

then C2 ring-closures, with two diﬀerent aldehydes (Scheme 1,

eq 3). An initial version of this work was deposited

elsewhere.¹⁶

carbaldehydes then furnished compounds 2h and 2i in 87%

and 93% yields, respectively. However, aliphatic aldehydes are

not suitable substrates in this reaction, since 3-phenylpropanal

did not lead to the expected compounds 2j. An additional

experiment performed in the presence of both benzaldehyde

and 3-phenylpropanal (2 equiv each) led only to the product

2a, demonstrating the high chemoselectivity of this reaction

toward arylaldehydes.

RESULTS AND DISCUSSION

We switched to the gold-catalyzed C2-iso-Pictet−Spengler

reaction, performed from isotryptamine 5b and a range of

aldehydes (Scheme 2, C2-iso Pictet−Spengler reaction). Of

note, this reaction is characterized by a strong background

reaction when performed in the absence of catalyst (89%

conversion, see Table S2 in the Supporting Information). In

view of potential future enantioselective applications, we

sought the conditions ensuring a gold-catalyzed process. At 0

°C in the absence of catalyst, 23% conversion was obtained.

However, this background reaction can be suppressed by

decreasing the temperature to −20 °C. At this temperature, the

tetrahydro-γ-carboline 3a was obtained in 56% yield when the

reaction was performed in the presence of Ph₃PAuNTf₂

catalyst b (5 mol %), testifying for a solely Au(I)-catalyzed

process. Interestingly, the reaction showed a total selectivity

between the nucleophilic C3 of the indole vs the potential

reaction that could occur at the nitrogen atom. We screened a

selection of functionalized arylaldehydes that could potentially

result in reactivity issues if the reaction was acid-catalyzed, and

for each of these aldehydes, the absence of the background

reaction was checked at rt and −20 °C (see Figure S1 in the

Supporting Information for details). In the presence of the

gold(I) catalyst b, compounds 3b and 3c bearing a 4-

quinolinyl and 4-pyridyl chain, respectively, were obtained in

good yields. Isophthalaldehyde led to the product 3d in 75%

yield as a single product (no trace of the doubly functionalized

compound). Remarkably, despite a lower conversion and the

need to react at rt, the reaction also tolerated an aldehyde

bearing a nitrone function, though known to be activated by

Au(I) complexes,¹⁸leading to compound 3e in 47% yield.¹⁹

Comparatively, this kind of aldehyde would not be suitable in

related acidic-catalyzed reactions because of the activation of

the highly electrophilic nitrone. All blank tests conducted with

these aldehydes in the absence of catalyst show no conversion

at −20 °C (and only little conversion at rt, see the Supporting

Information for details).

We further moved toward the introduction of the alkylamine

chain at the C4 atom of the indole ring and studied the

reaction of tryptamine 5c with p-bromobenzalehyde in the

presence (plain curves) of the absence of catalyst (dashed

curves) (Figure 2, see also Table S3 and Figure S2 in the

Supporting Information). When the reaction was performed at

0 °C, the reaction performed in the absence of catalyst barely

showed conversion (<5% conversion), while the same reaction

in the presence of 5 mol % of cat. b led to 50% conversion. At

room temperature, we also observed a strong diﬀerence in the

reaction kinetic, leading to 21% conversion in the absence of a

catalyst, while both 5 mol % and 2 mol % catalyst led to full

conversions. The role of the gold catalyst is here again crucial

to ensure full conversion over a reasonable time, while

conditions with solely Au(I)-catalyzed process can also be

applied if required.

■

Our journey started with the study of the N-iso-Pictet−

Spengler reactions from N-isotryptamine 5a and benzaldehyde

8a, reacted in toluene in the presence of molecular sieves over

a 40 h period (Table 1, see also Table S1 in the Supporting

Table 1. Optimisation of the N-Iso-Pictet−Spengler

Reaction

a

Conversion were measured by ¹H NMR by measuring the ratio 5a /

2a .

Information). In the absence of catalyst, no background

reaction occurred (entry 1). Though counterintuitive, the

reaction did not proceed either in the presence of an acidic

catalyst, as previously reported^7dfor C3-unsubstituted N-

isotryptamines (entry 2). We next screened a series of three

Au(I) catalysts (entries 3−5), for which only the Gagosz

catalyst¹⁷led to a moderate conversion (20%, entry 4). The

solvent was replaced by DCM, reaching a 69% conversion,

further optimized to 74% after a slight increase in the reaction

temperature (entries 6 and 7). We have further checked that

no background reaction occurs at this temperature in the

absence of a catalyst (entry 8).

We next engaged a number of aromatic aldehydes in the

reaction (Scheme 2, N-iso-Pictet−Spengler reaction). The

reactions performed with benzaldehyde and p-bromobenzalde-

hyde led to 2a and 2b in 87% and 51% yields, respectively. A

bromide group was tolerated at the meta and para positions,

leading to compounds 2c and 2d in good yields. The reaction

also proved compatible with aldehydes bearing electron-

withdrawing CF₃groups at the para and meta positions.

When m-methoxybenzaldehyde 8g was used, the correspond-

ing product 2g was obtained in 59% yield. 4- and 6-quinoline

Because of the attractively low 2 mol % catalyst loading, we

selected the conditions at room temperature to study the scope

of this reaction (Scheme 2, C4-iso-Pictet−Spengler reaction).

6407

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Scheme 2. Scope of the Diﬀerent Versions of the Iso-Pictet−Spengler Reactions Studied

a

b

c

d

Performed at room temperature in the absence of a catalyst. Performed at −20 °C in the absence of a catalyst. Performed at rt. Performed with

e

5 mol % of Ph₃PAuNTf₂. Conversion is 0% in the absence of a catalyst.

decrease of the reactivity (4e, 38% yield). The phthalaldehyde

led to compound 4f in 46% yield, this time accompanied by

the dimeric product (ratio 4f/dimer: 10:4). A boronate ester at

the para position was tolerated, leading to 4g in 53% yield,

opening opportunities for subsequent cross-coupling function-

alizations. Compound 4h, bearing a quinolyl moiety, was

formed in 71% yield. Interestingly, aliphatic aldehydes were

well converted to compounds 4i−k in moderate to good yields,

while the same reactions performed in the absence of a catalyst

resulted in no conversions (see Table S4 and Figure S3 in the

Supporting Information for details). To date, this is the ﬁrst

time that we observed conversion in the course of any version

of the four diﬀerent Au(I)-catalyzed (iso)Pictet−Spengler

reactions that we studied with aliphatic aldehydes.

We next considered the possibility that an indole ring

functionalized with two alkylamine chains at the N- and C4-

position could undergo C2−C3 difunctionalization via a C4-

iso- and an N-iso-Pictet−Spengler cyclization cascade. For this

purpose, we designed the diamine 5d, keeping the same groups

on the nitrogen atoms and slightly increased the temperature

to 40 °C to ensure maximum conversion.

1

Figure 2. Reaction kinetic. Conversions were measured by H NMR

by measuring the ratio 5c/4a.

The reaction of 5c with p-bromobenzaldehyde in DCM at

room temperature in the presence of only 2 mol % of Gagosz

catalyst led to the corresponding 1,3,4,5-tetrahydropyrrolo-

[4,3,2-de]isoquinoline 4a in 75% isolated yield. Benzaldehyde

and m-triﬂuoromethylbenzaldehyde also led to excellent yields

in 4b,c. A ﬂuorine group at the ortho position was well

tolerated, while a methoxy group at the para position led to a

Indeed, the gold-catalyzed reaction of 5d with benzaldehyde

at 40 °C led to tetracyclic 2,3,8,9,10,11-hexahydro-1H-

6408

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

a

Scheme 3. Selective Bis-functionalization

a

The relative stereochemistry indicated is that of the major diastereomer.

pyrazino[1′,2′:1,5]pyrrolo[4,3,2-de]isoquinoline 9a in 68%

yield and a 70:30 diatereomeric ratio, in favor of the anti-

diastereoisomer (Scheme 3 a, see also Table S5 in the

Supporting Information for optimization).²⁰To the best of our

knowledge, this scaﬀold has never been reported. When the

meta-triﬂuoromethylbenzaldehyde was used, compound 9b

was obtained in 58% yield, with the diasteromeric ratio in favor

of the syn-isomer. 4-Quinoline carboxaldehyde led to the

amine 9c in 88% yield and full anti-diastereoselectivity. We

next reasoned that the C4-iso Pictet−Spengler reaction,

operating with lower catalyst loading and temperature, should

occur faster than the N-iso-reaction, requiring higher catalyst

loading and temperature. Indeed, when 5d was engaged in the

reaction with 1 equiv of p-bromobenzaldehyde, the C4-iso-

Pictet−Spengler product 10a was selectively obtained at room

temperature in 71% yield with 10 mol % cat. b (Scheme 3b, eq

1).

Control experiments revealed that (1) no background

reaction occurs in the absence of Au(I) catalyst on substrate

5d and that (2) it is necessary to increase the catalyst loading

to ensure a good conversion in this step. Compound 10a was

then engaged in the N-iso-Pictet−Spengler reaction with

benzaldehyde that led to 11a in 70% yield as a mixture of

diastereomers (Scheme 3b, eq 2, dr 25:75).

(Scheme 3c). After 15 h of reaction in the presence of p-

bromobenzaldehyde (1 equiv) at room temperature, benzalde-

hyde was added to the reaction mixture and further 24 h

reaction led to compound 11a in 72% yield (dr 35:65) in favor

of the syn-isomer.

The same protocol was applied to another couple of

aromatic aldehydes, leading to compound 11b in good yields

and good diastereoselectivity (dr 20:80). Gratifyingly, we

obtained the X-ray structure of the syn-diastereomer of 11b

(CCDC 2046851). Beyond conﬁrming its structure, it was

helpful to further identify all other diastereomers of the series

of compounds 9 and 11. When 4-quinolinecarboxaldehyde was

used in the ﬁrst C4-iso-Pictet−Spengler step (requiring a

higher 40 °C temperature), followed by benzaldehyde for the

N-iso-step, compound 11c was obtained in 71% yield and

diastereoselectivity in favor of the anti-isomer (CCDC

2046871).

The diastereoselectivity of these reactions may be the result

of electronic eﬀects. Indeed, the X-ray structure of the syn-11b

shows a pretty good superposition of the phenyl and the

triﬂuoromethylphenyl ring with a distance between the two

aryl planes of ca. 3.30 Å. As reviewed by Iverson, interactions

between electron-poor/electron rich aryls may be referred to

the favored “aromatic donor- acceptor interactions” or polar/π

model.²¹This would explain the general trend to lead to the

syn-diastereomer with electron-poor aryl (9b, 11a, 11b) while

destabilizing interactions operating with electron-rich aryl rings

We then developed the one-pot formation of compounds 11

by sequential addition of two diﬀerent aldehydes from 5d in

the presence of 10 mol % of the gold complex b as catalyst

6409

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

couples (phenyl, quinoline and their combination) lead mainly

to the anti-isomer (9a, 9c, 11c).

EXPERIMENTAL SECTION

■

Reactions were performed using oven-dried glassware under an argon

atmosphere. All separations were carried out under ﬂash chromato-

graphic conditions on silica gel (prepacked column, 230−400 mesh)

at medium pressure (20 psi) with the use of a CombiFlash

Companion. Reactions were monitored by thin-layer chromatography

on Merck silica gel plates (60 F254 aluminum sheets), which were

rendered visible by ultraviolet and spraying with vanillin (15%) +

sulfuric acid (2.5%) in EtOH followed by heating. Reagent-grade

chemicals were obtained from diverse commercial suppliers (Sigma-

Aldrich, Acros Organics, Fluorochem, TCI, and Alfa-Aesar) and were

used as received. ¹H NMR (500 or 300 MHz) and ¹³C NMR (125 or

Gratifyingly, no need for an addition batch of catalyst was

required for the application of this protocol. The formation of

these compounds, as the result of two successive iso-Pictet−

Spengler reactions with diﬀerent aldehydes, opens avenues for

the synthesis of highly functionalized and complex compounds.

This strategy potentially oﬀers unique opportunities for the

exploration of chemical space in biological studies.

The mechanistic hypothesis for these reactions relies on our

previous gold-catalyzed “classical” Pictet−Spengler reactions^14a

and is illustrated below with the N-iso-version of the reaction

(Scheme 4), with the following steps. (i) The spontaneous

75 MHz) spectra were recorded on Brucker Avance spectrometers at

̈

298 K. Chemical shifts are given in ppm (δ) and are referenced to the

internal solvent signal or to TMS used as an internal standard.

Multiplicities are declared as follows: s (singlet), brs (broad singlet), d

(doublet), t (triplet), q (quadruplet), dd (doublet of doublet), ddd

(doublet of doublet of doublet), dt (doublet of triplet), m (multiplet).

Coupling constants (J) are given in hertz (Hz). Carbon multiplicities

were determined by the DEPT135 experiment. Diagnostic correla-

tions were obtained by two-dimensional COSY, HSQC, and NOESY

experiments. Infrared spectra (IR) were recorded on a PerkinElmer

FT-IR system using diamond window Dura SamplIR II, and the data

are reported in reciprocal centimeters (cm⁻¹). High-resolution mass

spectra (HRMS) were recorded using a Micromass LCT Premier XE

instrument (Waters) and were determined by electrospray ionization

(ESI, TOF analyzer).

Scheme 4. Mechanistic Pathway in N-Iso-Pictet−Spengler

Reactions

All reactions were accordingly performed using puriﬁed aldehydes.

Aldehydes were puriﬁed by washing a solution of the aldehyde in

Et₂O by NaOH (2 M in H₂O), followed by drying on MgSO₄and

ﬁltration of the resulting solution on a short pad of silica gel, followed

by concentration under a vacuum. In addition, tryptamines were

dissolved in EtOAc and washed by NaOH (2 M in H₂O) on a regular

basis to avoid undesired catalysis from potential protonated amines.

Finally, molecular sieves must be powdered and activated for 2 h

under a vacuum at 200 °C before use. All reactions requiring heating

were heated with an oil bath.

N-Iso-Pictet−Spengler Reaction. Synthesis of 2-(1H-Indol-1-

yl)-N-(2,4,6-trimethylbenzyl)ethan-1-amine 5a.

addition of the amine to the aldehyde leads to a hemiaminal

(this step being potentially catalyzed by the Au(I) complex).

(ii) The coordination of the indole ring leads to the η²and η¹-

gold complexes A and B. (iii) The conversion of the latter to

an iminium via an intramolecular abstraction of a proton and

release of water generates C.²²(iv) The nucleophilic addition

to the iminium via C2 forms complex D. (v) The elimination

of a proton via E and protodeauration then leads to product 2

and the regeneration of the cationic Au(I) complex. Similar

mechanisms can be involved for the C2- and C4-iso-Pictet−

Spengler reactions (see Schemes S1 −S3 in the Supporting

Information).

2-(1 H -Indol-1-yl)ethan-1-amine (prepared according to the proce-

dure described by Verma in 84% yield)^7e(1.5 g, 9.4 mmol, 1.00

equiv) and 2,4,6-trimethylbenzaldehyde (1,32 g, 8.9 mmol, 0.95

equiv) were stirred in methanol (40 mL) under an argon atmosphere

for 36 h. Then, the reaction medium was cooled to 0 °C before

NaBH₄(2 × 262 mg, 13.8 mmol, 1.80 equiv) was added; then the

mixture was allowed to reach room temperature. After 1 h of stirring,

the volatiles were removed, and the crude mixture was next diluted in

ethyl acetate and water. After the phases were separated, the aqueous

phase was extracted twice by ethyl acetate, and then the combined

organic phases were dried over MgSO₄and evaporated under a

vacuum. The desired product 5a was obtained after column

chromatography on silica gel (gradient from 20 to 100% heptane/

EtOAc) as a greenish oil (1.37 g, 4.7 mmol, 50%). IR (neat): ν_max

CONCLUSION

■

1

2915, 1612, 1511, 1462, 1313, 1113, 1012 cm⁻¹. H NMR (CDCl₃,

To conclude, we have developed Au(I)-catalyzed iso-Pictet−

Spengler reactions by the introduction of the alkylamine chain

around all of the diﬀerent positions of the indole ring, allowing

a trapping of the in situ generated iminium ion by either the C2

or C3 atom. This led to the isolation of numerous heterocyclic

scaﬀolds. We have shown the high chemoselectivity enabled by

Au(I)-catalyzed processes in these reactions, in particular by

the design of the in situ sequential cascade of C4- and N-iso-

Pictet−Spengler reactions, leading to highly complex poly-

cyclic indolic arrangements. We are currently studying the

enantioselective gold-catalyzed version of these reactions.

500 MHz): δ 7.67 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.24

(td, J = 7.3, 0.7 Hz, 1H), 7.18−7.11 (m, 2H), 6.84 (s, 2H), 6.52 (d, J

= 3.1 Hz, 1H), 4.29 (d, J = 6.3 Hz, 2H), 3.76 (s, 2H), 3.15 (t, J = 6.3

Hz, 1H), 2.29 (s, 6H), 2.27 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 75

MHz): δ 137.1 (C_q), 136.8 (C_q), 136.2 (C_q), 133.2 (C_q), 129.2

(CH), 128.9 (C_q), 128.2 (CH), 121.7 (CH), 121.2 (CH), 119.5

(CH), 109.5 (CH), 101.5 (CH), 49.5 (CH₂), 47.7 (CH₂),46.8

(CH₂), 21.0 (CH₃), 19.7 (CH₃). HRMS (ESI): m/z calcd for

+

C₂₀H₂₅N₂, 293.2017 [M + H]⁺; found, 293.2007.

General Procedure 1 for the Synthesis of Tetrahydropyrazino-

[1,2-a]indoles 2. A mixture of N-isotryptamine 5a (0.15 mmol), cat. b

6410

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(5 mol %, 0.0075 mmol, 5.3 mg), and 3 Å molecular sieves (150 mg

for 0.15 mmol of 5a, powdered) in dichloromethane (1.5 mL of 0.15

mmol of 5a) was stirred for 5 min at room temperature under an

argon atmosphere. Subsequently, aldehyde (2.0 equiv, 0.30 mmol)

was added, and the mixture was stirred for 40 h at 30 °C. For practical

reasons, the excess of aldehyde was reduced at the end of the reaction

by the mean of NaBH₄to facilitate the puriﬁcation. The reaction

mixture was then cooled to 0 °C and methanol (1.5 mL of 0.15 mmol

of 5a) alongside sodium borohydride (2.0 equiv) was added to the

reaction mixture. It was then allowed to reach room temperature and

stirred for 1 h. Then it was ﬁltered under Celite, and silica was added.

After evaporation of the volatiles, the silica mixture was puriﬁed by

chromatography under silica gel to give the desired product 2.

1-Phenyl-2-(2,4,6-trimethylbenzyl)-1,2,3,4-tetrahydropyrazino-

[1,2-a]indole 2a.

1-(3-Bromophenyl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2c.

Compound 2c was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 3-bromobenzaldehyde

(55 mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075 mmol) in

DCM (1.5 mL). The desired product 2c was obtained after column

chromatography on silica gel (gradient from 0 to 50% heptane/

EtOAc) as a green amorphous solid (46 mg, 0.10 mmol, 67%). IR

(neat): ν_max2922, 2853, 1739, 1571, 1452, 1375, 1319, 1217, 1149,

1070 cm⁻¹. ¹H NMR (CDCl₃, 500 MHz): δ 7.61 (s, 1H), 7.50 (d, J =

7.7 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.29

(d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H),

7.10 (t, J = 7.9 Hz, 1H), 6.85 (s, 2H), 5.82 (s, 1H), 4.64 (s, 1H),

4.15 −4.10 (m, 1H), 3.94 (td, J = 10.6, 4.4 Hz, 1H), 3.66 (d, J = 12.5

Hz, 1H), 3.39 (d, J = 12.5 Hz, 1H), 3.18 (dt, J = 11.9, 3.8 Hz, 1H),

2.79 (td, J = 11.0, 4.0 Hz, 1H), 2.27 (s, 9H). ¹³C{¹H} NMR (CDCl₃,

75 MHz): δ 144.2 (C_q), 138.6 (C_q), 138.0 (C_q), 137.0 (C_q), 136.0

(C_q), 132.7 (CH), 131.2 (CH), 131.1 (C_q), 129.8 (CH), 129.4 (CH),

128.3 (CH), 128.3 (C_q), 122.4 (C_q), 121.2 (CH), 120.5 (CH), 120.1

(CH), 109.0 (CH), 100.2 (C_q), 99.9 (CH), 66.7 (CH), 52.5 (CH₂),

46.8 (CH₂), 41.8 (CH₂), 21.1 (CH₃), 20.6 (CH₃). HRMS (ESI): m /z

calcd for C₂₇H₂₈N₂Br⁺, 459.1436 [M + H]⁺; found, 459.1428

1-(2-Bromophenyl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2d.

Compound 2a was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), benzaldehyde (32 mg,

0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075 mmol) in DCM

(1.5 mL). The desired product 2a was obtained after column

chromatography on silica gel (gradient from 0 to 50% heptane/

EtOAc) as a green amorphous solid (49 mg, 0.13 mmol, 87%). IR

(neat): ν_max2919, 1612, 1451, 1375, 1312, 1265, 1228, 1148, 1074

1

cm⁻¹. H NMR (CDCl₃, 500 MHz): δ 7.52 (d, J = 7.8 Hz, 1H),

7.50 −7.46 (m, 2H), 7.42 −7.36 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H),

7.20 (td, J = 7.0, 0.6 Hz, 1H), 7.12 (td, J = 7.0, 0.6 Hz, 1H), 6.88 (s,

2H), 5.82 (s, 1H), 4.69 (s, 1H), 4.16 (dt, J = 11.3, 3.6 Hz, 1H), 3.98

(dt, J = 10.4, 4.6 Hz, 1H), 3.71 (d, J = 12.5 Hz, 1H), 3.39 (d, J = 12.5

Hz, 1H), 3.21 (dt, J = 12.1, 4.1 Hz, 1H), 2.81 (td, J = 12.1, 4.0 Hz,

1H), 2.31 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 141.7 (C_q),

139.1 (C_q), 138.6 (C_q), 136.8 (C_q), 136.0 (C_q), 131.5 (C_q), 129.9

(CH), 129.3 (CH), 128.4 (C_q), 128.2 (CH), 128.1 (CH), 120.9

(CH), 120.4 (CH), 120.0 (CH), 108.9 (CH), 100.2 (C_q), 99.7 (CH),

67.6 (CH), 52.4 (CH₂), 47.0 (CH₂), 42.0 (CH₂), 21.1 (CH₃), 20.7

Compound 2d was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 2-bromobenzaldehyde

(55 mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075 mmol) in

DCM (1.5 mL). The desired product 2d was obtained after column

chromatography on silica gel (gradient from 0 to 50% heptane/

EtOAc) as a green amorphous solid (37 mg, 0.083 mmol, 55%). IR

(neat): ν_max2922, 2853, 1739, 1451, 1375, 1323, 1218, 1117, 1024

cm ⁻¹¹H NMR (CDCl₃, 500 MHz): δ 7.54 (d, J = 7.9 Hz, 1H), 7.45

(dd, J = 7.9, 1.5 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.21 −7.14 (m,

2H), 7.10 (td, J = 5.0, 1.5 Hz, 1H), 7.06 (t, J = 5.0 Hz, 1H), 6.97 (t, J

= 4.9 Hz, 1H), 6.74 (s, 2H), 5.68 (s, 1H), 5.25 (s, 1H), 4.04 (dt, J =

11.2, 2.7 Hz, 1H), 3.87 (dt, J = 11.2, 4.2 Hz, 1H), 3.53 (d, J = 12.5

Hz, 1H), 3.42 (d, J = 12.5 Hz, 1H), 3.07 (dq, J = 11.7, 2.0 Hz, 1H),

2.74 (td, J = 11.6, 3.6 Hz, 1H), 2.18 (s, 3H), 2.16 (6H). ¹³C{¹H}

NMR (CDCl₃, 75 MHz): δ 141.1 (C_q), 138.7 (C_q), 138.4 (C_q), 136.9

(C_q), 135.7 (C_q), 132.7 (CH), 132.6 (CH), 131.2 (C_q), 129.5 (CH),

129.3 (CH), 128.4 (C_q), 127.6 (CH), 125.4 (C_q), 121.0 (CH), 120.4

(CH), 120.0 (CH), 108.8 (CH), 100.2 (C_q), 99.0 (CH), 66.3 (CH),

52.3 (CH₂), 47.5 (CH₂), 42.5 (CH₂), 21.1 (CH₃), 20.8 (CH₃).

HRMS (ESI): m /z calcd for C₂₇H₂₈N₂Br⁺, 459.1436 [M + H]⁺;

found, 459.1430

+

(CH₃). HRMS (ESI): m /z calcd for C₂₇H₂₉N₂, 381.2331 [M + H]⁺;

found, 381.2335

1-(4-Bromophenyl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2b.

Compound 2b was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 4-bromobenzaldehyde

(55 mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075 mmol) in

DCM (1.5 mL). The desired product 2b was obtained after column

chromatography on silica gel (gradient from 0 to 50% heptane/

EtOAc) as a green amorphous solid (35 mg, 0.076 mmol, 51%). IR

1-(4-(Triﬂuoromethyl)phenyl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2e.

1

(neat): ν_max2970, 1737, 1451, 1366, 1217, 1011 cm⁻¹. H NMR

(CDCl₃, 500 MHz): δ 7.42 −7.36 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H),

7.18 (d, J = 8.1 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.4 Hz,

1H), 6.75 (s, 2H), 5.69 (s, 1H), 4.55 (s, 1H), 4.07 −4.01 (m, 1H),

3.90 −3.81 (m, 1H), 3.57 (d, J = 12.5 Hz, 1H), 3.28 (d, J = 12.5 Hz,

1H), 3.08 (d, J = 12.0 Hz, 1H), 2.81 (t, J = 9 Hz, 1H), 2.18 (s, 3H),

2.17 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 140.9 (C_q), 138.5

(C_q), 138.2 (C_q), 137.0 (C_q), 136.0 (C_q), 131.5 (CH), 131.4 (CH),

131.2 (Cq), 129.3 (CH), 128.3 (C_q), 122.0 (Cq), 121.2 (CH), 120.5

(CH), 120.1 (CH), 110.7 (C_q), 108.9 (C_q), 99.9 (CH), 66.6 (CH),

52.4 (CH₂), 46.8 (CH₂), 41.8 (CH₂), 21.1 (CH₃), 20.7 (CH₃).

HRMS (ESI): m /z calcd for C₇H₂₈N₂Br⁺, 459.1436 [M + H]⁺; found,

459.1421

Compound 2e was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 4-tri ﬂ uorobenzalde-

hyde (52 mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075

mmol) in DCM (1.5 mL). The desired product 2e was obtained after

column chromatography on silica gel (gradient from 0 to 50%

heptane/EtOAc) as a green amorphous solid (29 mg, 0.065 mmol,

43%). IR (neat): ν_max2924, 1739, 1452, 1366, 1322, 1217, 1164,

1126, 1067, 1018 cm⁻¹. ¹H NMR (CDCl₃, 500 MHz): δ 7.52 (d, J =

6411

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

8.4 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.21

(d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H),

6.76 (s, 2H), 5.70 (s, 1H), 4.69 (s, 1H), 4.07 (dt, J = 11.6, 4.1 Hz,

1H), 3.92 −3.85 (m, 1H), 3.57 (d, J = 12.4 Hz, 1H), 3.33 (d, J = 12.4

Hz, 1H), 3.11 (dt, J = 12.2, 4.2 Hz, 1H), 2.74 (td, J = 10.8, 3.8 Hz,

1H), 2.18 (s, 3H), 2.17(s, 6H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ

δ −62.6 HRMS (ESI): m /z calcd for C₂₈H₃₁N₂O⁺, 411.2436 [M +

H]⁺; found, 411.2436

1-(Quinolin-4-yl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2h.

146.0 (C_q), 138.5 (C_q), 137.6 (C_q), 137.1 (C_q), 136.1 (C_q), 131.1

1

(C_q), 130.0 (CH), 129.4 (CH), 128.3 (C_q), 127.9 (q, C−F, J_C−F

=

3

267.1 Hz, CF₃), 125.3 (q, C−F, J_C−F= 3.3 Hz, CH), 121.3 (CH),

120.5 (CH), 120.2 (CH), 109.0 (CH), 100.2 (C_q), 100.0 (CH), 66.4

(CH), 52.4 (CH₂), 46.7 (CH₂), 41.6 (CH₂), 21.1 (CH₃), 20.7

(CH₃). ¹⁹F NMR (CDCl₃, 282 MHz): δ −62.4. HRMS (ESI): m /z

Compound 2h was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 4-quinolinaldehyde (47

mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075 mmol) in

DCM (1.5 mL). The desired product 2h was obtained after column

chromatography on silica gel (gradient from 0 to 100% heptane/

EtOAc) as a green amorphous solid (56 mg, 0.13 mmol, 87%). IR

(neat): ν_max2920, 1739, 1591, 1452, 1357, 1218, 1010 cm⁻¹. ¹H

NMR (CDCl₃, 500 MHz): δ 8.76 (d, J = 4.5 Hz, 1hH), 8.05 (d, J =

8.3 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.57 (td, J = 7.6, 0.9 Hz, 1H),

7.39 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 7.5 Hz,

1H), 7.22 (d, J = 5.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5

Hz, 1H), 6.79 (s, 2H), 5.81 (s, 1H), 5.34 (s, 1H), 4.18 (dt, J = 11.5,

5.2 Hz, 1H), 4.05 (tt, J = 7.8, 4.0 Hz, 1H), 3.66 (d, J = 12.7 Hz, 1H),

3.44 (d, J = 12.7 Hz, 1H), 3.26 (dt, J = 12.7, 5.0 Hz, 1H), 2.89 −2.82

(m, 1H), 2.22 (s, 3H), 2.11 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 75

MHz): δ 150.0 (CH), 149.1 (C_q), 147.2 (C_q), 138.7 (C_q), 137.3

(C_q), 136.2 (C_q), 136.0 (Cq), 130.7 (C_q), 130.1 (CH), 129.4 (CH),

129.3 (CH), 128.3 (C_q), 127.2 (C_q), 126.2 (CH), 125.5 (CH), 122.7

(CH), 121.3 (CH), 120.6 (CH), 120.3 (CH), 109.0 (CH), 101.2

(C_q), 100.0 (CH), 62.7 (CH), 52.5 (CH₂), 46.7 (CH₂), 40.7 (CH₂),

+

calcd for C₂₈H₂₈N₂F₃, 449.2205 [M + H]⁺; found, 449.2195

1-(3-(Triﬂuoromethyl)phenyl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2f.

Compound 2f was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 3-tri ﬂ uorobenzalde-

hyde (52 mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075

mmol) in DCM (1.5 mL). The desired product 2f was obtained after

column chromatography on silica gel (gradient from 0 to 50%

heptane/EtOAc) as a green amorphous solid (46 mg, 0.10 mmol,

67%). IR (neat): ν_max2921, 1739, 1451, 1320, 1163, 1127, 1072 cm⁻¹.

¹H NMR (CDCl₃, 500 MHz): δ 7.76 (s, 1H), 7.64 (d, J = 7.6 Hz,

1H), 7.62 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.47 (d, J =

7.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.11

(t, J = 7.4 Hz, 1H), 6.86 (s, 2H), 5.78 (s, 1H), 4.73 (s, 1H), 4.16 (dt, J

= 10.6, 3.7 Hz, 1H), 3.97 (td, J = 10.7, 4.3 Hz, 1H), 3.63 (d, J = 12.5

Hz, 1H), 3.40 (d, J = 12.5 Hz, 1H), 3.20 (dt, J = 12.3, 4.1 Hz, 1H),

2.82 (td, J = 11, 3.8 Hz, 1H), 2.28 (s, 3H), 2.27 (s, 6H). ¹³C{¹H}

NMR (CDCl₃, 75 MHz): δ 143.0 (C_q), 138.5 (C_q), 137.9 (C_q), 137.1

(C_q), 136.1 (C_q), 133.1 (CH), 131.0 (C_q), 129.4 (CH), 128.7 (CH),

+

21.1 (CH₃), 20.7 (CH₃). HRMS (ESI): m /z calcd for C₃₀H₃₀N₃,

432.2440 [M + H]⁺; found, 432.2451.

1-(Isoquinolin-6-yl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2i.

1

128.3 (C_q), 128.0 (q, C−F, J_C−F= 274.4 Hz, CF₃), 126.5 (q, C−F,

3

³J_C−F= 3.5 Hz, CH), 125.0 (q, C−F, J_C−F= 3.5 Hz, CH), 121.3

(CH), 120.5 (CH), 120.2 (CH), 109.0 (CH), 100.2 (C_q), 100.0

(CH), 66.9 (CH), 52.5 (CH₂), 47.0 (CH₂), 41.8 (CH₂), 21.1 (CH₃),

+

Compound 2i was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 6-quinolinaldehyde (47

mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075 mmol) in

DCM (1.5 mL). The desired product 2i was obtained after column

chromatography on silica gel (gradient from 0 to 100% heptane/

EtOAc) as a green amorphous solid (60 mg, 0.14 mmol, 93%). IR

(neat): ν_max2919, 1738, 1450, 1357, 1312, 1265, 1116, 1010 cm⁻¹.

¹H NMR (CDCl₃, 500 MHz): δ 8.93 (dd, J = 4.1, 1.5 Hz, 1H), 8.14

(d, J = 7.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 1.3 Hz, 1H),

7.80 (dd, J = 8.7, 1.9 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.41 (dd, J =

8.3, 4.3 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H),

7.10 (t, J = 7.3 Hz, 1H), 6.84 (s, 2H), 5.80 (s, 1H), 4.87 (s, 1H), 4.17

(dt, J = 11.5, 3.9 Hz, 1H), 3.99 (td, J = 11.7, 4.5 Hz, 1H), 3.71 (d, J =

12.6 Hz, 1H), 3.45 (d, J = 12.6 Hz, 1H), 3.22 (dt, J = 12.1, 4.1 Hz,

1H), 2.85 (td, J = 11.0, 4.0 Hz, 1H), 2.28 (s, 6H), 2.27 (s, 3H).

¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 150.6 (CH), 148.5 (C_q), 140.1

(C_q), 138.5 (C_q), 138.0 (C_q), 136.9 (C_q), 136.1 (CH), 131.2 (CH),

131.1 (C_q), 129.6 (CH), 129.3 (CH), 128.3 (CH), 127.9 (C_q), 121.4

(CH), 121.1 (CH), 120.5 (CH), 120.0 (CH), 108.9 (CH), 100.1

(C_q), 100.0 (CH), 66.9 (CH), 52.5 (CH₂), 46.8 (CH₂), 41.8 (CH₂),

20.6 (CH₃). HRMS (ESI): m /z calcd for C₂₈H₂₈N₂F₃, 449.2205 [M

+ H]⁺; found, 449.2217.

1-(3-Methoxyphenyl)-2-(2,4,6-trimethylbenzyl)-1,2,3,4-

tetrahydropyrazino[1,2-a]indole 2g.

Compound 2g was synthesized following general procedure 1 using

tryptamine 5a (44 mg, 0.15 mmol, 1.0 equiv), 3-methoxybenzalde-

hyde (41 mg, 0.30 mmol, 2.0 equiv), and cat. b (5.3 mg, 0.0075

mmol) in DCM (1.5 mL). The desired product 2g was obtained after

column chromatography on silica gel (gradient from 0 to 50%

heptane/EtOAc) as a green amorphous solid (36 mg, 0.088 mmol,

59%). IR (neat): ν_max2952, 1739, 1599, 1486, 1452, 1375, 1321,

1265, 1148, 1044 cm⁻¹. ¹H NMR (CDCl₃, 500 MHz): δ 7.49 (d, J =

7.8 Hz, 1H), 7.30 −7.25 (m, 2H), 7.17 (td, J = 7.6, 0.9 Hz, 1H), 7.08

(td, J = 7.5, 0.8 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 7.03 −7.01 (m,

1H), 6.89 (ddd, J = 8.2, 2.6, 0.5 Hz, 1H), 6.84 (s, 2H), 5.83 (s, 1H),

4.64 (s, 1H), 4.13 (dt, J = 11.4, 3.8 Hz, 1H), 3.94 (ddd, J = 4.5, 10.2,

11.2 Hz, 1H), 3.78 (s, 3H), 3.71 (d, J = 12.5 Hz, 1H), 3.36 (d, J =

12.5 Hz, 1H), 3.18 (dt, J = 12.1, 4.0 Hz, 1H), 2.78 (m, 1H), 2.30 (s,

6H), 2.28 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 159.7 (C_q),

143.2 (C_q), 138.8 (C_q), 138.6 (C_q), 136.8 (C_q), 136.0 (C_q), 131.5

(Cq), 129.3 (CH), 129.1 (CH), 128.4 (C_q), 122.3 (CH), 120.9

(CH), 120.4 (CH), 119.9 (CH), 114.9 (CH), 114,0 (CH), 108.9

(CH), 100.2 (C_q), 99.7 (CH), 67.5 (CH), 55.4 (CH₂), 47.0 (CH₂),

42.0 (CH₂), 21.1 (CH₃), 20.7 (CH₃). ¹⁹F NMR (CDCl₃, 282 MHz):

+

21.1 (CH₃), 20.7 (CH₃). HRMS (ESI): m /z calcd for C₃₀H₃₀N₃,

432.2440 [M + H]⁺; found, 432.2427

C2-Iso-Pictet−Spengler Reaction. Synthesis of 2-(1H-Indol-2-

yl)-N-(2,4,6-trimethylbenzyl)ethan-1-amine 5b.

The synthesis of 2-(1 H -indol-2-yl)ethan-1-amine was performed

following procedures from the literature.^8d,23To a solution of

6412

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

indole-2-carboxylic acid (16.1 g, 1.00 equiv, 100 mmol) in THF (75

mL) was added LiAlH₄(7.9 g, 2.07 equiv, 207 mmol) at 0 °C in a 15

min period; the mixture was then allowed to warm to room

temperature slowly and stirred at room temperature for about 3 h.

The reaction was quenched with 2 M NaOH under 0 °C and

extracted with EtOAc, dried over MgSO₄, and evaporated under a

vacuum. The crude product was then puriﬁed by column

chromatography to aﬀord the corresponding (1H-indol-2-yl)methanol

in 84% yield (12.4 g, 84 mmol). To a solution of (1H-indol-2-

yl)methanol (12.4 g, 1 equiv, 84 mmol) in MeCN (360 mL) was

added MnO₂(73 g, 10 equiv, 840 mmol) at room temperature, and

the mixture was stirred for 16 h; then the mixture was ﬁltrated with

Celite and concentrated under a vacuum. The crude product was used

directly without puriﬁcation. To the solution of crude 1H-indole-2-

carbaldehyde (11.0 g, 1.00 equiv, 76.1 mmol) in MeNO₂(70 mL)

was added AcONH₄(2.3 g, 0.39 mmol, 29.7 mmol) at room

temperature. The mixture was allowed to heat to 100 °C and

following by TLC, and 30 min later, the reaction was completed and

concentrated under a vacuum. The residue was then extracted with

EtOAc, dried over MgSO₄, and evaporated under a vacuum, leading

to 2-(2-nitrovinyl)-1H-indole. It was then dissolved in THF (50 mL),

and a suspension of LiAlH₄(5.5 g, 1 equiv, 29 mmol) in THF (50

mL) was added dropwise at 0 °C. After completion, the resulting

mixture was stirred at room temperature for 3.5 h. The reaction

solution was then quenched with NH₄Cl and extracted with EtOAc;

organic layers were combined and dried over MgSO₄, concentrated

under a vacuum, and puriﬁed by column chromatography to aﬀord

the corresponding 2-(1H-indol-2-yl)ethan-1-amine (2.4 g, 15 mmol,

52%).²⁴

Compound 3a was prepared according to general procedure 2 from

5b (0.05 mmol, 1 equiv, 14.6 mg), 4-bromobenzaldehyde (0.1 mmol,

2 equiv, 18.5 mg), cat. b (5 mol %, 1.8 mg), 3 Å MS (50 mg), and

anhydrous DCM under N₂, yielding product 3a (12.7 mg, 0.028

1

mmol, 56%) as a pale yellow solid. H NMR (CDCl₃, 300 MHz): δ

7.84 (bs, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 7.9 Hz, 1H), 7.17

(d, J = 8.5 Hz, 2H), 7.11 −7.05 (m, 1H), 6.93 −6.88 (m, 1H), 6.83 −

6.79 (m, 3H), 4.64 (s, 1H), 3.77 (d, J = 12.4 Hz, 1H), 3.48 (d, J =

12.4 Hz, 1H), 3.09 −2.99 (m, 1H), 2.84 −2.69 (m, 3H), 2.27 (s, 3H),

2.19 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 142.6 (C_q), 138.6

(C_q), 136.6 (C_q), 136.1 (C_q), 133.5 (C_q), 132.5 (C_q), 131.4 (CH),

131.1 (CH), 129.2 (CH), 126.9 (C_q), 121.4 (CH), 121.0 (C_q), 119.7

(CH), 118.7 (CH), 111.0 (C_q), 110.7 (CH), 62.6 (CH), 51.2 (CH₂),

45.8 (CH₂), 22.7 (CH₂), 21.1 (CH₃), 20.4 (CH₃). HRMS (ESI): m /z

+

calcd for C₂₇H₂₈BrN₂, 459.1430 [M + H]⁺, found, 459.1437.

1-(Quinolin-4-yl)-2-(2,4,6-trimethylbenzyl)-2,3,4,5-tetrahydro-

1H-pyrido[4,3-b]indole 3b.

Compound 3b was prepared according to general procedure 2 from

5b (0.05 mmol, 1 equiv, 14.6 mg), quinoline-4-carbaldehyde (0.1

mmol, 2 equiv, 15.7 mg), cat. b (5 mol %, 1.8 mg), 3 Å MS (50 mg),

and anhydrous DCM under N₂, yielding product 3b (13.1 mg, 0.03

A mixture of 2-(1H-indol-2-yl)ethan-1-amine (481 mg, 1.00 equiv,

3.00 mmol) and mesitaldehyde (467 mg, 1.05 equiv, 3.15 mmol) in

MeOH (5 mL) under N₂was stirred at room temperature for 16 h.

Then NaBH₄was added under 0 °C; the mixture was allowed warm

to room temperature and stirred at room temperature for another 1 h,

and water was added. After the phases were separated, the aqueous

phase was extracted twice by ethyl acetate. Then the combined

organic phases were dried over MgSO₄, evaporated under a vacuum,

and extracted with EtOAc. The organic layers were combined and

dried over MgSO₄, concentrated under a vacuum, and puriﬁed by

column chromatography to aﬀord the corresponding 2-(1H-indol-2-

yl)-N-(2,4,6-trimethylbenzyl)ethan-1-amine 5b (265 mg, 0.91 mmol,

30%). ¹H NMR (CDCl₃, 500 MHz): δ 9.71 (bs, 1H), 7.51 (d, J = 7.6

Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.0 Hz, 1H), 7.04 (t, J =

7.3 Hz, 1H), 6.89 (s, 1H), 6.20 (s, 1H), 3.81 (s, 2H), 3.08 (t, J = 5.8

Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.39 (s, 6H), 2.28 (s, 3H), 1.42 (m,

1H). ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 139.6 (C_q), 137.1 (C_q),

137.1 (C_q), 136.0 (C_q), 133.4 (C_q), 129.4 (CH), 128.6 (C_q), 121.0

(CH), 119.9 (CH), 119.5 (CH), 110.7 (CH), 99.3 (CH), 49.8

(CH₂), 47.9 (CH₂), 28.1 (CH₂), 21.1 (CH₃), 19.7 (CH₃). HRMS

1

mmol, 61%) as a pale yellow solid. H NMR (CDCl₃, 500 MHz): δ

8.68 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 7.62 (t, J = 7.6

Hz, 1H), 7.55 (bs, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 (t, J = 7.6 Hz,

1H), 7.11 (t, J = 7.5 Hz, 1H), 7.03 (bs, 1H), 6.91 (s, 2H), 6.86 (t, J =

7.5 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.51 (s, 1H), 3.99 (d, J = 12.4

Hz, 1H), 3.63 (d, J = 12.5 Hz, 1H), 3.19 −3.09 (m, 2H), 2.99 −2.90

(m, 1H), 2.83 −2.74 (m, 1H), 2.34 (s, 3H), 2.14 (s, 6H). ¹³C{¹H}

NMR (CDCl₃, 125 MHz): δ 150.0 (CH), 148.8 (C_q), 148.3 (C_q),

139.1 (C_q), 137.1 (C_q), 136.1 (C_q), 133.6 (C_q), 131.9 (C_q), 131.2

(C_q), 130.4 (CH), 129.8 (CH), 129.3 (CH), 128.9 (CH), 128.0 (C_q),

125.8 (CH), 125.1 (C_q), 122.4 (CH), 121.7 (CH), 119.8 (CH),

118.4 (CH), 110.8 (CH), 50.9 (CH₂), 46.8 (CH), 45.9 (CH₂), 21.2

(CH₂), 20.5 (CH₃), 20.2 (CH₃). HRMS (ESI): m /z calcd for

+

C₃₀H₃₀N₃, 432.2434 [M + H]⁺, found, 432.2436.

1-(Pyridin-4-yl)-2-(2,4,6-trimethylbenzyl)-2,3,4,5-tetrahydro-1H-

pyrido[4,3-b]indole 3c.

+

(ESI): m/z calcd for C₂₀H₂₅N₂, 293.2012, [M + H]⁺, found,

293.2009.

General Procedure 2 for the Synthesis of Tetrahydro-1H-

pyrido[4,3-b]indole 3. A mixture of 2-(1H-indol-2-yl)-N-(2,4,6-

trimethylbenzyl)ethan-1-amine 5b (1 equiv), cat. b (5 mol %), and

3 Å molecular sieves (150 mg for 0.15 mmol of 5b, powdered) in

dichloromethane (1.5 mL of 0.15 mmol of 5a) was stirred for 5 min at

room temperature under an argon atmosphere. Subsequently,

aldehyde (2.0 equiv) was added, and the mixture stirred at −20 °C

for 16 h. Then it was ﬁltered under Celite, and silica was added. After

evaporation of the volatiles, the silica mixture was puriﬁed by

chromatography under silica gel to give the desired product 3.

1-(4-Bromophenyl)-2-(2,4,6-trimethylbenzyl)-2,3,4,5-tetrahydro-

1H-pyrido[4,3-b]indole 3a.

Compound 3c was prepared according to general procedure 2 from

5c (0.05 mmol, 1 equiv, 14.6 mg), isonicotinaldehyde (0.1 mmol, 2

equiv, 10.7 mg), cat. b (5 mol %, 1.8 mg), 3 Å MS (50 mg), and

anhydrous DCM under N₂, yielding product 3c (13.4 mg, 0.04 mmol,

71%) as a pale yellow solid. ¹H NMR (CDCl₃, 300 MHz): δ 8.47 (d, J

= 3.2 Hz, 2H), 8.15 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 5.5

Hz, 2H), 7.15 −7.07 (m, 1H), 6.98 −6.87 (m, 2H), 6.85 (s, 2H), 4.73

(s, 1H), 3.82 (d, J = 12.4 Hz, 1H), 3.56 (d, J = 12.5 Hz, 1H), 3.07 −

2.83 (m, 3H), 2.77 −2.66 (m, 1H), 2.28 (s, 3H), 2.20 (s, 6H).

¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 153.7 (C_q), 148.9 (CH), 138.5

(C_q), 136.8 (C_q), 136.0 (C_q), 133.6 (C_q), 132.1 (C_q), 129.3 (CH),

126.9 (C_q), 124.8 (CH), 121.6 (CH), 119.9 (CH), 118.3 (CH),

110.9 (CH), 109.2 (C_q), 60.6 (CH), 51.0 (CH₂), 45.5 (CH₂), 21.7

(CH₂), 21.1 (CH₃), 20.2 (CH₃). HRMS (ESI): m /z calcd for

+

C₂₆H₂₈N₃, 382.2278 [M + H]⁺, found, 382.2272.

6413

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

3-(2-(2,4,6-Trimethylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-

b]indol-1-yl)benzaldehyde 3d.

mixture was stirred until full destruction of lithium salts. The reaction

was ﬁ ltered over silica, concentrated under a vacuum, and triturated in

methanol. After ﬁ ltration over Celite, the pure product S6 was

obtained by ﬁ ltrate ’s concentration under a vacuum as a light brown

solid (9.10 g, 62.2 mmol, 88%). The data correspond to those found

in the literature.²⁵

Compound 3d was prepared according to general procedure 2 from

5c (0.05 mmol, 1 equiv, 14.6 mg), isophthalaldehyde (0.1 mmol, 2

equiv, 10.7 mg), cat. b (5 mol %, 1.8 mg), 3 Å MS (50 mg), and

anhydrous DCM under N₂, yielding product 3d (15.4 mg, 0.04 mmol,

75%) as a pale yellow solid. ¹H NMR (CDCl₃, 300 MHz): δ 9.95 (s,

1H), 7.90 (bs, 1H), 7.84 (t, J = 1.5 Hz, 1H), 7.77 (dt, J₁= 7.5 Hz, J₂=

1.3 Hz, 1H), 7.58 (dt, J₁= 7.7 Hz, J₂= 1.3 Hz, 1H), 7.42 (t, J = 7.5

Hz, 1H), 7.30 (dt, J₁= 8.1 Hz, J₂= 0.8 Hz, 1H), 7.11−7.04 (m, 1H),

6.90 −6.85 (m, 1H), 6.83 (s, 2H), 6.77 (d, J = 7.9 Hz, 1H), 4.77 (s,

1H), 3.76 (d, J = 12.4 Hz, 1H), 3.53 (d, J = 12.4 Hz, 1H), 3.12 −3.00

(m, 1H), 2.85 −2.73 (m, 3H), 2.27 (s, 3H), 2.18 (s, 6H). ¹³C{¹H}

NMR (CDCl₃, 75 MHz): δ 192.9 (CH), 144.9 (C_q), 138.6 (C_q),

136.6 (C_q), 136.3 (C_q), 136.2 (C_q), 136.0 (CH), 133.6 (C_q), 132.4

(C_q), 131.3 (CH), 129.2 (CH), 128.8 (CH), 128.6 (CH), 126.7 (C_q),

121.4 (CH), 119.7 (CH), 118.5 (CH), 110.8 (CH), 63.0 (CH), 51.3

(CH₂), 45.9 (CH₂), 22.9 (CH₂), 21.1 (CH₃), 20.4 (CH₃). HRMS

(ESI): m /z calcd for C₂₈H₂₉N₂O⁺, 409.2274 [M + H]⁺, found,

409.2273.

(1H-Indol-4-yl)methanamine (2.00 mg, 13.6 mmol, 1.00 equiv)

and 2-naphthaldehyde (2.02 mg, 13.0 mmol, 0.95 equiv) were stirred

in methanol (68 mL) for 4 h. Then, the reaction media was cooled to

0 °C before the addition of NaBH₄(565 mg, 15.0 mmol, 1.1 equiv in

one portion). The mixture was allowed to warm up to room

temperature. After 1 h of stirring, the volatiles were removed, and the

crude was next diluted in ethyl acetate and water. After phase

separation, the aqueous phase was extracted twice by ethyl acetate.

The combined organic phases were dried over MgSO₄and evaporated

under a vacuum. The desired product 5c was obtained after column

chromatography on silica gel (gradient from 0 to 15% DCM/MeOH)

as a brown oil (3.30 g, 11.4 mmol, 84%). IR (neat): ν_max3411, 3184,

3052, 2922, 2849, 1437, 1345, 818, 753 cm⁻¹. ¹H NMR (CDCl₃, 500

MHz): δ 8.27 (bs, 1H), 7.87−7.76 (m, 4H), 7.53 (dd, J = 8.3, 1.3 Hz,

1H), 7.50−7.42 (m, 2H), 7.33 (d, J = 8.1 Hz, 1H), 7.23−7.20 (m,

1H), 7.19 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.0 Hz, 1H), 6.23 (t, J = 2.1

Hz, 1H), 4.16 (s, 2H), 4.04 (s, 2H), 2.08 (bs, 2H). ¹³C{¹H} NMR

(CDCl₃, 75 MHz): δ 137.8 (C_q), 136.1 (C_q), 133.6 (C_q), 132.7 (C_q),

131.9 (C_q), 128.2 (CH), 127.8 (CH), 127.7 (CH), 127.1 (C_q), 126.8

(CH), 126.7 (CH), 126.1 (CH), 125.6 (CH), 124.3 (CH), 122.0

(CH), 119.3 (CH), 110.3 (CH), 100.5 (CH), 53.4 (CH₂), 51.1

(CH₂). HRMS (ESI) m/z calcd for C₂₀H₁9N₂[M + H]⁺, 287.1548;

found, 287.1542.

N-Benzyl-1-(4-(2-(2,4,6-trimethylbenzyl)-2,3,4,5-tetrahydro-1H-

pyrido[4,3-b]indol-1-yl)phenyl)methanimine oxide 3e.

Scope of the 4-Iso-Pictet−Spengler Reaction. General

Procedure 3 for the Synthesis of Tetrahydropyrrolo[4,3,2-de]-

isoquinolines 4. A mixture of tryptamine 5c (0.17 mmol), cat. b (2

mol %, 0.0034 mmol, 2.5 mg) and 3 Å molecular sieves (82 mg for

0.17 mmol of 5c, powdered) in dichloromethane (2.4 mL of 0.17

mmol of 5c) was stirred for 5 min at room temperature under an

argon atmosphere. Subsequently, aldehyde (2.0 equiv, 0.35 mmol)

was added, and the mixture stirred for 15 h. The mixture was ﬁltered

under Celite, and silica was added. After evaporation of the volatiles,

the silica mixture was puriﬁed by chromatography under silica gel to

give the desired product 4.

Compound 3e was prepared according to general procedure 2 from

5c (0.05 mmol, 1 equiv, 14.6 mg), (Z )-N -benzyl-1-(4-formylphenyl)-

methanimine oxide (0.1 mmol, 2 equiv, 23.9 mg), cat. b (5 mol %, 1.8

mg), 3 Å MS (50 mg), and anhydrous DCM under N₂. The mixture

was stirred at room temperature for 60 h, yielding product 3e (65%

conversion, 12.1 mg, 0.02 mmol, 47%) as a white solid.

Note that the background reaction performed under the same

1

conditions in the absence of a catalyst is 26% after 60 h. H NMR

3-(4-Bromophenyl)-4-(naphthalen-2-ylmethyl)-1,3,4,5-

tetrahydropyrrolo[4,3,2-de]isoquinoline 4a.

(CDCl₃, 500 MHz): δ 8.11 (d, J = 7.9 Hz, 2H), 7.88 (s, 1H), 7.47 (d,

J = 6.6 Hz, 2H), 7.42−7.33 (m, 6H), 7.25 (d, J = 7.9 Hz, 1H), 7.03 (t,

J = 7.6 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.80 (s, 2H), 6.73 (d, J = 7.6

Hz, 1H), 5.04 (s, 2H), 4.67 (s, 1H), 3.73 (d, J = 12.4 Hz, 1H), 3.47

(d, J = 12.5 Hz, 1H), 3.06−2.98 (m, 1H), 2.81−2.67 (m, 3H), 2.25

(s, 3H), 2.17 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 146.4

(C_q), 138.6 (C_q), 136.5 (C_q), 136.1 (C_q), 134.7 (CH), 133.5 (C_q),

133.4 (C_q), 132.5 (C_q), 129.9 (CH), 129.5 (CH), 129.5 (C_q) 129.2

(CH), 129.2 (CH), 129.1 (CH), 128.5 (CH), 126.7 (C_q), 121.2

(CH), 119.6 (CH), 118.7 (CH), 111.3 (C_q), 110.6 (CH), 71.3

(CH₂), 63.9 (CH), 51.5 (CH₂), 46.0 (CH₂), 23.2 (CH₂), 21.1

(CH₃), 20.5 (CH₃). HRMS (ESI): m/z calcd for C₃₅H₃₆N₃O⁺,

514.2853 [M + H]⁺, found, 514.2847.

Compound 4a was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), 4-bromobenzaldehyde

(65 mg, 0.35 mmol, 2.0 equiv), cat. b (2.5 mg, 0.0034 mmol, 2 mol

%), and 3 Å MS (82 mg) in DCM (2.4 mL). The desired product 4a

was obtained after column chromatography on silica gel (gradient

from 0 to 15% heptane/EtOAc) as a white amorphous solid (58 mg,

0.13 mmol, 75%).

1. mmol Scale Procedure. Compound 4a was synthesized

following general procedure 3 using tryptamine 5c (300 mg, 1.05

mmol, 1.0 equiv), 4-bromobenzaldehyde (387 mg, 2.10 mmol, 2.0

equiv), cat. b (15.5 mg, 0.021 mmol, 2 mol %), and 3 Å MS (503 mg)

in DCM (15.0 mL). The desired product was obtained after column

chromatography on silica gel (gradient from 0 to 15% heptane/

EtOAc) as a white amorphous solid (289 mg, 0.64 mmol, 61%). IR

(neat): ν_max3406, 3052, 2959, 2926, 2838, 1484, 1264, 1070, 1010,

C4-Iso-Pictet−Spengler Reaction. Synthesis of Tryptamine 5c.

A mixture of 1 H -indole-4-carbonitrile (10.0 g, 70.3 mmol, 1.0 equiv)

in THF (100 mL) was added dropwise to a suspension of lithium

aluminum hydride (5.70 g, 150 mmol, 2.1 equiv) in THF at 0 °C. The

reaction was re ﬂ uxed for 90 min and then allowed to cool to rt. Then,

aqueous saturated solution of Rochelle ’s salt was added, and the

1

817, 752, 735 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ 8.00 (bs, 1H),

7.85−7.77 (m, 3H), 7,72 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.50−7.44

(m, 2H), 7.43−7.40 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.25−7.21 (m,

2H), 7.18 (t, J = 7.0 Hz, 1H), 6.81 (d, J = 4.9 Hz, 1H), 6.75 (s, 1H),

6414

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

5.02 (s, 1H), 4.03 (d, J = 15.8 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H),

3.78 (d, J = 15.8 Hz, 1H), 3.69 (d, J = 13.5 Hz, 1H). ¹³C{¹H} NMR

(CDCl₃, 75 MHz): δ 141.8 (C_q), 137.3 (C_q), 133.5 (C_q), 133.5 (C_q),

132.9 (C_q), 131.4 (CH), 130.5 (CH), 128.7 (C_q), 128.1 (CH), 127.8

(CH), 127.7 (CH), 127.4 (CH), 127.3 (CH), 126.0 (CH), 125.7

(CH), 125.2 (C_q), 123.2 (CH), 121.1 (C_q), 119.3 (CH), 115.1 (CH),

113.3 (C_q), 109.0 (CH), 60.9 (CH), 58.9 (CH₂), 49.4 (CH₂) HRMS

Compound 4d was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), 2-ﬂ uorobenzaldehyde

(43 mg, 0.35 mmol, 2.0 equiv), cat. b (6.5 mg, 0.0087 mmol, 5 mol

%), and 3 Å MS (82 mg) in DCM (2.4 mL). The desired product 4d

was obtained after column chromatography on silica gel (gradient

from 0 to 15% heptane/EtOAc) as a white amorphous solid (50 mg,

0.13 mmol, 73%). IR (neat): ν_max3407, 3055, 2926, 2851, 1486,

1452, 1228, 755, 737 cm⁻¹. ¹H NMR (CDCl₃, 500 MHz): δ 8.00 (bs,

1H), 7.87 −7.79 (m, 3H), 7,77 (s, 1H), 7.59 (d, J = 8.3, 1H), 7.51 −

7.44 (m, 2H), 7.30 −7.23 (m, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.15 (t, J

= 9.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.84

(d, J = 6.7 Hz, 1H), 6.74 (s, 1H), 5.60 (s, 1H), 4.08 (d, J = 15.8 Hz,

1H), 3.91 (d, J = 13.3 Hz, 1H), 3.87 −3.79 (m, 2H). ¹³C{¹H} NMR

+

(ESI): m/z calcd for C₂₇H₂₂⁷⁹BrN₂, 453.0966 [M + H]⁺; found,

+

453.0926, calcd for C₂₇H₂₂⁸¹BrN₂, 455.0946 [M + H]⁺; found,

455.0925.

4-(Naphthalen-2-ylmethyl)-3-phenyl-1,3,4,5-tetrahydropyrrolo-

[4,3,2-de]isoquinoline 4b.

1

(CDCl₃, 75 MHz): δ 161.1 (d, C −F, J_C−F= 247 Hz, Cq), 137.2

(C_q), 133.5 (C_q), 133.4 (C_q), 132.9 (C_q), 130.4 (d, C−F, ³J_C−F= 3.8

Hz, CH), 129.7 (d, C −F, ²J_C−F= 15.1 Hz, C_q), 128.9 (d, C−F, ³J_C−F

= 8.8 Hz, CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.6 (CH),

127.5 (CH), 125.9 (CH), 125.7 (C_q), 125.6 (CH), 123.9 (d, C−F,

⁴J_C−F= 2.7 Hz, CH), 123.2 (CH), 118.8 (CH), 115.5 (d, C−F, ²J_C−F

= 22.5 Hz, CH), 115.0 (CH), 113.5 (C_q), 109.0 (CH), 59.0 (CH₂),

55.1 (CH), 49.1 (CH₂). ¹⁹F NMR (CDCl₃, 282 MHz): δ −118.0.

Compound 4b was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), benzaldehyde (37 mg,

0.35 mmol, 2.0 equiv), cat. b (2.5 mg, 0.0034 mmol, 2 mol %), and 3

Å MS (82 mg) in DCM (2.4 mL). The desired product 4b was

obtained after column chromatography on silica gel (gradient from 0

to 15% heptane/EtOAc) as a white amorphous solid (50 mg, 0.13

mmol, 78%). ¹H NMR (DMSO-d₆, 500 MHz): δ 10.82 (s, 1H),

7.91 −7.83 (m, 3H), 7.75 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.50 −7.44

(m, 2H), 7.33 −7.28 (m, 4H), 7.27 −7.19 (m, 2H), 7.03 (t, J = 7.4 Hz,

1H), 6.92 (s, 1H), 6.68 (d, = J = 6.7 Hz, 1H), 5.07 (s, 1H), 3.85 (d, J

= 5.6 Hz, 1H), 3.78 −3.65 (m, 3H). ¹³C{¹H} NMR (DMSO-d₆, 75

MHz): δ 142.5 (C_q), 137.4 (C_q), 133.2 (C_q), 132.9 (C_q), 132.3 (C_q),

128.2 (CH), 128.1 (CH), 127.8 (C_q), 127.7 (CH), 127.6 (CH),

127.5 (CH), 126.9 (CH), 126.8 (CH), 126.7 (CH), 126.0 (CH),

125.5 (CH), 124.9 (C_q), 121.9 (CH), 119.8 (CH), 113.6 (CH),

112.2 (C_q), 109.1 (CH), 61.0 (CH), 58.0 (CH₂), 48.5 (CH₂) HRMS

+

HRMS (ESI): m /z calcd for C₂₇H₂₂FN₂, 393.1767 [M + H]⁺; found,

393.1756.

3-(4-Methoxyphenyl)-4-(naphthalen-2-ylmethyl)-1,3,4,5-

tetrahydropyrrolo[4,3,2-de]isoquinoline 4e.

Compound 4e was synthesized following general procedure 3 using

tryptamine 5c (54 mg, 0.19 mmol, 1.0 equiv), 4-methoxybenzalde-

hyde (51 mg, 0.38 mmol, 2.0 equiv), cat. b (6.9 mg, 0.0094 mmol, 5

mol %), and 3 Å MS (91 mg) in DCM (2.7 mL). The desired product

4e was obtained after column chromatography on silica gel (gradient

from 0 to 15% heptane/EtOAc) as a white amorphous solid (29 mg,

0.07 mmol, 38%). IR (neat): ν_max3402, 3055, 2930, 2836, 1607,

1508, 1451, 1248, 1172, 1031, 819, 753 cm⁻¹. ¹H NMR (CDCl₃, 500

MHz): δ 8.01 (s, 1H), 7.86 −7.78 (m, 3H), 7.75 (s, 1H), 7.60 (d, J =

8.3 Hz, 1H), 7.49 −7.43 (m, 2H), 7.30 −7.23 (m, 3H), 7.18 (t, J = 7.3

Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 7.0 Hz, 1H), 6.77 (s,

1H), 5.05 (s, 1H), 4.08 (d, J = 15.7 Hz, 1H), 3.89 (d, J = 13.6 Hz,

1H), 3.83 −3.77 (m, 1H), 3.80 (s, 3H), 3.70 (d, J = 14.0 Hz, 1H)

¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 206.3 (C_q), 158.9 (C_q), 137.7

(C_q), 134.8 (C_q), 133.6 (C_q), 133.5 (C_q), 132.9 (C_q), 129.9 (CH),

129.1 (C_q), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.5 (CH),

127.4 (CH), 126.0 (CH), 125.6 (CH), 125.5 (C_q), 123.1 (CH),

119.2 (CH), 115.0 (CH), 113.7 (CH), 108.9 (CH), 61.2 (CH), 58.7

(CH₂), 55.4 (CH₃), 49.6 (CH₂) HRMS (ESI): m /z calcd for

C₂₈H₂₅N₂O⁺, 405.1967 [M + H]⁺; found, 405.1947.

+

(ESI): m /z calcd for C₂₇H₂₃N₂, 375.1861 [M + H]⁺; found,

375.1841.

4-(Naphthalen-2-ylmethyl)-3-(3-(triﬂuoromethyl)phenyl)-

1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline 4c.

Compound 4c was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), 3-(tri ﬂ uoromethyl)-

benzaldehyde (61 mg, 0.35 mmol, 2.0 equiv), cat. b (2.5 mg, 0.0034

mmol 2 mol %), and 3 Å MS (82 mg) in DCM (2.4 mL). The desired

product 4c was obtained after column chromatography on silica gel

(gradient from 0 to 15% heptane/EtOAc) as a white amorphous solid

(58 mg, 0.13 mmol, 77%). IR (neat): ν_max3419, 3057, 2927, 1329,

1

1164, 1123, 1072, 753 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ 8.07

(brs, 1H), 7.86 −7.80 (m, 2H), 7.80 −7.76 (m, 1H), 7.73 (s, 1H), 7.69

(s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.50 (d, J =

7.8 Hz, 1H), 7.48 −7.42 (m, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.29 −7.24

(m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.84 −6.79 (m, 2H), 5.10 (s, 1H),

4.05 (d, J = 15.9 Hz, 1H), 3.86 (d, J = 13.5 Hz, 1H), 3.81 (d, J = 15.9

Hz, 1H), 3.71 (d, J = 13.6 Hz, 1H). ¹³C{¹H} NMR (CDCl₃, 75

MHz): δ 144.0 (C_q), 137.2 (C_q), 133.6 (C_q), 133.5 (C_q), 133.0 (C_q),

3-(4-(Naphthalen-2-ylmethyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-

de]isoquinolin-3-yl)benzaldehyde 4f.

2

132.1 (CH), 130.6 (q, C −F, J_C−F= 32 Hz, C_q), 128.7 (CH), 128.6

Compound 4f was synthesized following general procedure 3 using

tryptamine 5c (76 mg, 0.27 mmol, 1.0 equiv), isophthalaldehyde (71

mg, 0.53 mmol, 2.0 equiv), cat. b (3.9 mg, 0.0053 mmol, 2 mol %),

and 3 Å MS (130 mg) in DCM (3.8 mL). The desired product 4f was

obtained after column chromatography on silica gel (gradient from 0

to 15% heptane/EtOAc) as a white amorphous solid (50 mg, 0.12

mmol, 46%). IR (neat): ν_max3406, 3054, 2925, 3838, 1693, 1600,

(C_q), 128.2 (CH), 127.9 (CH), 127.8 (CH), 127.5 (CH), 127.3

(CH), 126.1 (CH), 125.7 (CH), 125.5 (q, C −F, ³J_C−F= 4 Hz, CH),

1

125.1 (C_q), 124.4 (q, C−F, J_C−F= 272 Hz, Cq), 124.1 (q, J_C−F= 4

Hz, CH), 123.3 (CH), 119.6 (CH), 115.2 (CH), 112.9 (C_q), 61.0

(CH), 58.9 (CH₂₎, 49.5 (CH₂). ¹⁹F NMR (CDCl₃, 282 MHz): δ

+

−62.3. HRMS (ESI): m /z calcd for C₂₈H₂₂F₃N₂, 443.1735 [M +

H]⁺; found, 443.1703.

1584, 1445, 1342, 1146, 819, 754, 736 cm⁻¹. H NMR (CDCl₃, 300

1

3-(2-Fluorophenyl)-4-(naphthalen-2-ylmethyl)-1,3,4,5-

tetrahydropyrrolo[4,3,2-de]isoquinoline 4d.

MHz): δ 9.97 (s, 1H), 8.12 (bs, 1H), 7.89 −7.82 (m, 3H), 7.81 −7.76

(m, 2H), 7.73 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.61 (dd, J = 8.3, 1.8

Hz, 1H), 7.50 −7.42 (m, 3H), 7.29 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.5

Hz, 1H), 6.83 −6.81 (m, 2H), 5.16 (s, H), 4.05 (d, J = 15.7 Hz, 1H),

3.87 (d, J = 13.4 Hz, 1H), 3.82 (d, J = 16.0 Hz, 1H), 3.75 (d, J = 13.3

Hz, 1H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 192.7 (CH), 144.2

6415

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(Cq), 137.2 (Cq), 136.6 (Cq), 135.0 (CH), 133.7 (Cq), 133.5 (Cq),

133.0 (Cq), 130.4 (CH), 129.1 (CH), 128.5 (CH), 128.2 (CH),

127.8 (CH), 127.6 (CH), 127.3 (CH), 126.1 (CH), 125.7 (CH),

125.1 (Cq), 123.3 (CH), 119.7 (CH), 115.2 (CH), 112.7 (Cq), 109.2

(CH), 60.8 (CH), 58.9 (CH₂), 49.3 (CH₂). HRMS (ESI): m /z calcd

for C₂₈H₂₃N₂O⁺, 403.1810 [M + H]⁺; found, 403.1797.

4-(Naphthalen-2-ylmethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-diox-

aborolan-2-yl)phenyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-de]-

isoquinoline 4g.

4 -(Naph thalen-2-y lmethy l) -3-phene thyl-1, 3, 4 , 5 -

tetrahydropyrrolo[4,3,2-de]isoquinoline 4i.

Compound 4i was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), 3-phenylpropanal (47

mg, 0.35 mmol, 2.0 equiv), cat. b (6.5 mg, 0.0087 mmol, 5 mol %),

and 3 Å MS (82 mg) in DCM (2.5 mL). The desired product 4i was

obtained after column chromatography on silica gel (gradient from 0

to 15% heptane/EtOAc) as an oil (29 mg, 0.12 mmol, 75%). IR

(neat): ν_max3057, 2928, 2852, 1602, 1495, 1452, 820, 751, 699 cm⁻¹.

¹H NMR (CDCl₃, 300 MHz): δ 7.98 (brs, 1H), 7.92 −7.80 (m, 3H),

7.72 (s, 1H), 7.62 (dd, J = 1.9, 8.5 Hz, 1H), 7.56 −7.45 (m, 2H), 7 −

35 −7.27 (m, 2H), 7.25 −7.15 (m, 5H), 6.95 (d, J = 2.1 Hz, 1H), 6.88

(d, J = 7.0 Hz, 1H), 4.39 (d, J = 16.4 Hz, 1H), 4.10 (t, J = 7.5 Hz,

1H), 3.94 (d, J = 16.6 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.71 (d, J =

13.6 Hz, 1H), 3.01 −2.82 (m, 2H), 2.39 −2.17 (m, 1H), 2.07 −1.90

(m, 1H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 142.5 (C_q), 133.7

(C_q), 133.4 (C_q), 132.8 (C_q), 128.5 (CH), 128.4 (C_q), 128.4 (C_q),

128.3 (CH), 127.8 (CH), 127.8 (CH), 127.6 (CH), 127.5 (CH),

127.4 (CH), 125.8 (CH), 125.6 (CH), 125.4 (CH), 123.0 (CH),

118.3 (C_q), 118.2 (CH), 115.2 (CH), 114.1 (C_q), 108.8 (CH), 58.1

(CH₂), 56.8 (CH), 47.6 (CH₂), 36.7 (CH₂), 32.5 (CH₂). HRMS

Compound 4g was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)benzaldehyde (80 mg, 0.35 mmol, 2.0 equiv),

cat. b (2.6 mg, 0.0034 mmol, 2 mol %), and 3 Å MS (82 mg) in DCM

(2.5 mL). The desired product 4g was obtained after column

chromatography on silica gel (gradient from 0 to 15% heptane/

EtOAc) as a white amorphous solid (46 mg, 0.09 mmol, 53%). IR

(neat): ν_max3362, 3053, 2977, 2932, 1604, 1449, 1397, 1359, 1322,

1

1143, 1087, 858, 750 cm⁻¹. H NMR (CDCl₃, 300 MHz): δ 7.99

+

(ESI): m /z calcd for C₂₉H₂₇N₂, 403.2174 [M + H]⁺; found,

(brs, 1H), 7.86 −7.73 (m, 6H), 7.57 (dd, J = 1.5; 8.4 Hz, 1H), 7.48 −

7.39 (m, 4H), 7.24 (d, J = 9.3 Hz, 1H), 7.16 (dd, J = 6.8; 8.3 Hz, 1H),

6.78 (d, J = 6.9 Hz, 1H), 6.70 (d, J = 1.2 Hz, 1H), 5.06 (s, 1H), 4.08

(d, J = 15.6 Hz, 1H), 3.92 (d, J = 13.4 Hz, 1H), 3.79 (d, J = 15.6 Hz,

1H), 3.66 (d, J = 13.4 Hz, 1H), 1.34 (s, 12H). ¹³C{¹H} NMR

(CDCl₃, 75 MHz): δ 146.1 (C_q), 137,6 (C_q), 134.9 (CH), 133.5

(C_q), 132.9 (C_q), 129.5 (C_q), 129.1 (C_q), 128.3 (2 CH), 128.0 (CH),

127.8 (CH), 127.8 (CH), 127.5 (CH), 127.4 (CH), 126.0 (C_q),

126.0 (CH), 125.6 (CH), 125.4 (C_q), 123.1 (CH), 119.2 (CH),

114.9 (CH), 114.8 (C_q), 108.9 (CH), 83.9 (C_q), 62.4 (CH), 59.0

(CH₂), 50.1 (CH₂), 25.0 (CH₃). ¹¹B NMR (CDCl₃, 160 MHz): δ

403.2174.

3-Isobutyl-4-(naphthalen-2-ylmethyl)-1,3,4,5-tetrahydropyrrolo-

[4,3,2-de]isoquinoline 4j.

Compound 4j was synthesized following general procedure 3 using

tryptamine 5c (35 mg, 0.12 mmol, 1.0 equiv), 3-methylbutanal (21

mg, 0.24 mmol, 2.0 equiv), cat. b (1.8 mg, 0.0024 mmol, 2 mol %),

and 3 Å MS (58 mg) in DCM (1.8 mL). The desired product 4j was

obtained after column chromatography on silica gel (gradient from 0

to 15% heptane/EtOAc) as an oil (30 mg, 0.08 mmol, 69%). IR

+

22.45. HRMS (ESI): m /z calcd for C₃₃H₃₄BN₂O₂, 501.2713 [M +

H]⁺; found, 501.2689.

1

(neat): ν_max3414, 3054, 2952, 2928, 2866, 1444, 821, 751 cm⁻¹. H

4-(Naphthalen-2-ylmethyl)-3-(quinolin-4-yl)-1,3,4,5-

tetrahydropyrrolo[4,3,2-de]isoquinoline 4h.

NMR (CDCl₃, 500 MHz): δ 7.93 (brs, 1H), 7.86 −7.77 (m, 3H), 7.67

(s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.48 −7.43 (m, 2H), 7.26 (d, J = 8.1

Hz, 1H), 7.20 (dd, J = 1.0, 8.0 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 6.84

(d, J = 6.9 Hz, 1H), 4.31 (d, J = 16.4 Hz, 1H), 4.14 (t, J = 7.5 Hz,

1H), 3.86 (d, J = 16.4 Hz, 1H), 3.77 (d, J = 13.4 Hz, 1H), 3.66 (d, J =

13.5 Hz, 1H), 1.98 (sept, J = 6.8 Hz, 1H), 1.85 −1.76 (m, 1H), 1.56 −

1.48 (m, 1H), 0.98 (d, J = 6.7 Hz, 1H), 0.91 (d, J = 6.6 Hz, 1H).

¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 138.0 (C_q), 133.8 (C_q), 133.5

(C_q), 132.9 (C_q), 128.4 (C_q), 127.8 (CH), 127.8 (CH), 127.6 (CH),

127.4 (CH), 125.9 (CH), 125.5 (CH), 124.9 (C_q), 123.1 (CH),

118.1 (CH), 115.2 (CH), 114.6 (C_q), 108.8 (CH), 58.3 (CH₂), 55.4

(CH), 47.5 (CH₂), 44.3 (CH₂), 24.5 (CH), 23.0 (CH₃), 22.9 (CH₃).

Compound 4h was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), quinoline-4-

carbaldehyde (55 mg, 0.35 mmol, 2.0 equiv), cat. b (2.6 mg,

0.0034 mmol, 2 mol %), and 3 Å MS (82 mg) in DCM (2.5 mL). The

desired product 4h was obtained after column chromatography on

silica gel (gradient from 0 to 15% heptane/EtOAc) as a white

amorphous solid (53 mg, 0.12 mmol, 71%). IR (neat): ν_max3054,

2839, 1590, 1508, 1445, 1345, 818, 757 cm⁻¹. ¹H NMR (CDCl₃, 500

MHz): δ 8.76 (d, J = 4.4 Hz, 1H), 8.52 (brs, 1H), 8.30 (d, J = 8.5 Hz,

1H), 8.18 (d, J = 8.4 Hz, 1H), 7.88 −7.78 (m, 3H), 7.75 −7.70 (m,

2H), 7.52 (d, J = 8.4 Hz, 1H), 7.51 −7.44 (m, 3H), 7.31 (d, J = 8.1

Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 4.3 Hz, 1H), 6.84 (d, J

= 7.0 Hz, 1H),6.75 (s, 1H), 5.79 (s, 1H), 4.05 (d, J = 16.0 Hz, 1H),

4.02 (d, J = 14.2 Hz, 1H), 3.80 (d, J = 15..9 Hz, 1H), 3.73 (d, J = 14.2

Hz, 1H), ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 150.1 (CH), 148.9

(C_q), 148.5 (C_q), 136.8 (C_q), 133.6 (C_q), 133.4 (C_q), 133.0 (C_q),

129.9 (CH), 129.2 (CH), 128.2 (C_q), 128.1 (CH), 127.9 (CH),

127.8 (CH), 127.8 (CH), 127.7 (CH), 127.3 (C_q), 126.3 (CH),

126.1 (CH), 125.8 (CH), 125.4 (CH), 125.4 (C_q), 123.4 (CH),

121.4 (CH), 119.6 (CH), 115.3 (CH), 112.0 (C_q), 109.3 (CH), 59.4

(CH₂), 59.2 (CH), 49.5 (CH₂). HRMS (ESI): m /z calcd for

+

HRMS (ESI): m /z calcd for C₂₅H₂₇N₂, 355.2174 [M + H]⁺; found,

355.2143.

3-(But-3-en-1-yl)-4-(naphthalen-2-ylmethyl)-1,3,4,5-

tetrahydropyrrolo[4,3,2-de]isoquinoline 4k.

Compound 4k was synthesized following general procedure 3 using

tryptamine 5c (50 mg, 0.17 mmol, 1.0 equiv), hex-5-enal (29 mg, 0.35

mmol, 2.0 equiv), cat. b (2.6 mg, 0.0035 mmol, 2 mol %), and 3 Å MS

(82 mg) in DCM (2.5 mL). The desired product 4k was obtained

after column chromatography on silica gel (gradient from 0 to 15%

heptane/EtOAc) as an oil (32 mg, 0.09 mmol, 53%). IR (neat): ν_max

3411, 3054, 2974, 2929, 2848, 1443, 1343, 1092, 909, 816, 750, 738

cm⁻¹. ¹H NMR (CDCl₃, 500 MHz): δ 7.94 (brs, 1H), 7.87 −7.77 (m,

3H), 7.67 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.50 −7.43 (m, 2H), 7.26

(d, J = 8.1 Hz, 1H), 7.20 (dd, J = 0.9; 7.0 Hz, 1H), 6.90 (d, J = 1.2 Hz,

+

C₃₀H₂₄N₃, 426.1970 [M + H]⁺; found, 426.1932.

6416

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1H), 6.84 (d, J = 6.8 Hz, 1H), 5.87 (tdd, J = 6.7, 10.2, 17.1 Hz, 1H),

5.05 (dd, J = 2.1, 17.2 Hz, 1H), 4.95 (d, J = 9.9 Hz, 1H), 4.33 (d, J =

16.3 Hz, 1H), 4.04 (t, J = 7.6 Hz, 1H), 3.87 (d, J = 16.5 Hz, 1H), 3.77

(d, J = 13.5 Hz, 1H), 3.68 (d, J = 14.0 Hz, 1H), 2.38 −2.24 (m, 2H),

2.07 −1.98 (m, 1H), 1.78 −1.69 (m, 1H). ¹³C{¹H} NMR (CDCl₃, 75

MHz): δ 138.9 (CH), 137.8 (C_q), 133.8 (C_q), 133.5 (C_q), 132.9

(C_q), 128.3 (C_q), 127.9 (CH), 127.9 (CH), 127.8 (CH), 127.6 (CH),

127.4 (CH), 125.9 (CH), 125.5 (CH), 124.8 (C_q), 123.1 (CH),

118.4 (CH), 115.3 (CH), 114.7 (CH₂), 114.2 (C_q), 108.9 (CH), 58.4

(CH₂), 57.0 (CH), 47.6 (CH₂), 34.2 (CH₂), 30.5 (CH₂). HRMS

dient from 20 to 50% heptane/EtOAc) as an oil (1.41 g, 2.51 mmol,

15−70% over 2 steps). The product appears as rotamers by ¹H NMR

and ¹³C NMR. IR (neat): ν_max2973, 2922, 2859, 1685, 1413, 1364,

1

1241, 1161, 1109, 748, 735 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ

7.90−7.74 (m, 3H), 7.61 (s, 1H), 7.54−7.30 (m, 4H), 7.19 (t, J = 7.8

Hz, 1H), 7.14 (d, J = 3 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.82 (s,

2H), 6.65−6.40 (m, 1H), 4.91−4.66 (m, 2H), 4.65−4.43 (m, 2H),

4.27 (t, J = 6.2 Hz, 2H), 3.74 (s, 2H), 3.13 (t, J = 6.2 Hz, 1H), 2.27 (s,

6H), 2.24 (s, 3H), 1.56 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ

137.0 (C_q), 136.7 (C_q), 136.4 (C_q), 135.9 (C_q), 133.5 (C_q), 133.3

(c_q), 132.8 (C_q), 129.9 (C_q), 129.1 (2 CH), 128.3 (CH), 128.1 (CH),

127.8 (CH), 127.8 (CH), 126.8 (C_q), 126.5 and 126.2 (CH), 126.2

(CH), 126.0 and 125.8 (CH), 125.7 (CH), 121.5 (CH), 199.9 (C_q),

119.7 and 118.4 (CH), 109.0 and 108.8 (CH), 100.3 and 99.6 (CH),

80.1 (C_q), 49.5 (CH₂), 49.0 (CH₂), 47.6 (CH₂), 47.6 (CH₂), 46.9

(CH₂), 28.7 (3 CH₃), 21.0 (CH₃), 19.6 (CH₃). HRMS (ESI): m/z

+

(ESI): m /z calcd for C₂₅H₂₅N₂, 353.2017 [M + H]⁺; found,

353.2031.

C4/N-Iso-Pictet−Spengler Reaction Cascades. Synthesis of

Tryptamine 5d.

+

calcd for C₃₇H₄₄N₃O₂, 562.3433 [M + H]⁺; found, 562.3376.

Et₃N (3.6 mL, 25.9 mmol, 5.0 equiv) was added to a mixture of

tryptamine 5c (1.50 g, 5.18 mmol, 1.0 equiv) and Boc₂O (1.70 g, 7.78

mmol, 1.5 equiv) in dichloromethane (52 mL). After 4 h, TLC

showed full completion. H₂O was added to the mixture, the layers

were separated, and the aqueous layer was extracted three times with

DCM. The organic layer was dried over MgSO₄and concentrated

under a vacuum, and the crude product was puri ﬁ ed by

chromatography under silica gel to give the desired product tert -

butyl ((1 H -indol-4-yl)methyl)(naphthalen-2-ylmethyl)carbamate

(gradient from 0 to 20% heptane/EtOAc) as an oil (1.38 g, 3.57

HCl (4 M in dioxane, 5.4 mL, 21.5 mmol, 10 equiv) was added on

S8 (1.21 g, 2.15 mmol, 1.0 equiv). The reaction mixture was then

stirred for 20 h. The product precipitate was ﬁltered, washed with 1,4-

dioxane, and dried under a vacuum. The crude product was dissolved

in EtOAc and then washed with a 1 M aqueous NaOH solution. After

the phases were separated, the aqueous phase was extracted twice by

EtOAc; then the combined organic phases were dried over MgSO₄

and evaporated under a vacuum to give the desired product 5d (as an

oil (650 mg, 1.41 mmol, 65%). ¹H NMR (CDCl₃, 500 MHz): δ

7.85−7.79 (m, 4H), 7.52 (d, J = 9.0 Hz, 1H), 7.49−7.42 (m, 2H),

7.30 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.4 Hz, 2H), 7.16−7.10 (m, 2H),

6.79 (s, 1H), 6.54 (d, J = 3.2 Hz, 1H), 4.26 (t, J = 6.2 Hz, 2H), 4.14

(s, 2H), 4.03 (s, 2H), 3.72 (s, 2H), 3.12 (t, J = 6.4 Hz, 2H), 2.25 (s,

6H), 2.23 (s, 3H), 1.84−1.34 (bs, 2H). ¹³C{¹H} NMR (CDCl₃, 75

MHz): δ 138.1 (C_q), 137.0 (C_q), 136.6 (C_q), 136.3 (C_q), 133.6 (C_q),

133.3 (C_q), 132.8 (C_q), 132.5 (C_q), 129.1 (2 CH), 128.1 (CH), 128.0

(CH), 127.9 (C_q), 127.8 (CH), 127.8 (CH), 126.9 (CH), 126.7

(CH), 126.0 (CH), 125.6 (CH), 121.7 (CH), 119.0 (CH), 108.6

(CH), 99.5 (CH), 53.5 (CH₂), 51.2 (CH₂), 49.5 (CH₂), 47.6 (CH₂),

46.9 (CH₂), 21.0 (CH₃), 19.6 (CH₃). HRMS (ESI): m/z calcd for

1

mmol, 69%). The product appears as rotamers by H NMR and ¹³C

NMR. IR (neat): ν_max3316, 2976, 2927, 1666, 1412, 1365, 1247,

1

1161, 1115, 752 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ 8.30 (brs,

1H), 7.88 −7.74 (m, 3H), 7.61 (s, 1H), 7.52 −7.33 (m, 4H), 7.21 (t, J

= 2.8 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H),

6.72 −6.50 (m, 1H), 4.86 −4.67 (m, 2H), 4.63 −4.43 (m, 2H), 1.55 (s,

9H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 136.2 (C_q), 135.9 (C_q),

133.5 (C_q), 132.9 (C_q), 129.7 (C_q), 128.4 (CH), 127.9 (CH), 127.8

(CH), 126.8 (C_q), 126.4 and 126.2 (CH), 126.2 (CH), 126.1 and

125.8 (CH), 125.8 (CH), 124.2 (CH), 122.0 (CH), 120.1 and 118.8

(CH) 119.9 (C_q), 110.7 and 110.4 (CH), 101.6 and 100.9 (CH), 80.2

(C_q), 49.0 and 49.0 (CH₂), 47.6 (CH₂), 28.7 (CH₃). HRMS (ESI):

+

m /z calcd for C₂₁H₁₉N₂O₂, 331.1447 [M-t Bu · + 2H]⁺; found,

+

331.1443, m /z calcd for C₂₇H₂₉N₃NaO₂, 450.2157 [M + Na

+CH₃CN]⁺; found, 450.2157.

+

C₃₂H₃₆N₃, 462.2909 [M + H]⁺; found, 462.2893.

Scope of the C4/N-Iso-Pictet−Spengler Reaction Cascade

with the Same Aldehyde. General Procedure 4. A mixture of

tryptamine 5d (0.17 mmol), cat. b (10 mol %, 0.017 mmol), and 3 Å

molecular sieves (82 mg for 0.17 mmol of 5d, powdered) in

dichloromethane (2.4 mL of 0.17 mmol of 5d) was stirred for 5 min

at room temperature under an argon atmosphere. Subsequently,

aldehyde (3.0 equiv, 0.17 mmol) was added, and the mixture stirred at

reﬂux for 24 h. The mixture was ﬁltered under Celite, and silica was

added. After evaporation of the volatiles, the silica mixture was

puriﬁed by chromatography under silica gel to give the desired

product 9.

Acetonitrile (11.9 mL) was added to tert-butyl ((1H-indol-4-

yl)methyl)(naphthalen-2-ylmethyl)carbamate (1.38 g, 3.57 mmol, 1.0

equiv), 2-chloroethan-1-amine hydrochloride (476 mg, 4.11 mmol,

1.15 equiv), sodium hydroxide (314 mg, 7.86 mmol, 2.2 equiv), and

tetrabutylammonium hydrogensulfate (49 mg, 0.14 mmol, 0.04

equiv). The mixture was stirred at reﬂux for 24 h, then allowed to

cool to rt, ﬁltered over Celite (wash with DCM), dried over K₂CO₃,

and concentrated under a vacuum. This methodology routinely leads

to 30−100% conversions. The crude product was dissolved in MeOH

(18 mL), and 2,4,6-trimethylbenzaldehyde (502 mg, 3.39 mmol, 0.95

equiv) was added to the reaction mixture. After 16 h, the reaction

media was cooled to 0 °C before NaBH₄(148 mg, 3.93 mmol, 1.1

equiv) was added. Then the mixture was allowed to reach room

temperature. After 1 h of stirring, the volatiles were removed, and the

crude was next diluted in ethyl acetate and water. After the phases

were separated, the aqueous phase was extracted twice by ethyl

acetate, and then the combined organic phases were dried over

MgSO₄and evaporated under a vacuum. The crude mixture was then

puriﬁed over column chromatography on silica gel to give the desired

product tert-butyl (naphthalen-2-ylmethyl)((1-(2-((2,4,6-

trimethylbenzyl)amino)ethyl)-1H-indol-4-yl)methyl)carbamate (gra-

2-(Naphthalen-2-ylmethyl)-1,11-diphenyl-10-(2,4,6-trimethyl-

benzyl)-2,3,8,9,10,11-hexahydro-1H-pyrazino[1′,2′:1,5]pyrrolo-

[4,3,2-de]isoquinoline 9a.

Compound 9a was synthesized following general procedure 4 using

tryptamine 5d (100 mg, 0.22 mmol, 1.0 equiv), benzaldehyde (69 mg,

0.65 mmol, 3.0 equiv), cat. b (16.0 mg, 0.0217 mmol, 10 mol %), and

6417

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

3 Å MS (104 mg) in DCM (3.1 mL) at 40 °C. Desired products 9a

were obtained after column chromatography on silica gel (gradient

from 0 to 10% heptane/EtOAc) as white amorphous solids (95 mg,

0.15 mmol, 68%, dr 2:1 anti /syn ). The following data is for compound

anti -9a . IR (neat): ν_max3055, 3027, 2960, 2921, 2852, 1450, 1262,

(s, 6H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 142.6 (C_q), 141.0 (C_q),

138.4 (C_q), 137.0 (C_q), 137.0 (C_q), 133 5 (C_q), 133.1 (C_q), 133.0

(C_q), 132.2 (CH), 132.2 (CH), 131.8 (C_q), 130.8 (C_q), 130.7 (C_q),

130.3 (C_q), 129.3 (CH), 128.8 (CH), 128.6 (CH), 128.3 (C_q), 128.3

(q, C −F, ¹J_C−F= 252.5 Hz, Cq), 128.1 (CH), 128.0 (q, C−F, ¹J_C−F

=

1

1076, 1028, 1016, 711; 697 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ

248.3 Hz, Cq), 127.9 (CH), 127.7 (CH), 127.1 (CH), 127.0 (CH),

3

126.5 (d, J_C−F= 3.3 Hz, CH), 126.0 (CH), 125.7 (d, C−F, J_C−F

=

7.86 −7.82 (m, 1H), 7.80 −7.74 (m, 2H), 7.57 (s, 1H), 7.51 −7.41 (m,

3H), 7.25 −7.21 (m, 3H), 7.21 −7.11 (m, 4H), 7.01 −6.91 (m, 4H),

6.82 −6.75 (m, 4H), 4.30 (s, 1H), 4.18 (td, J = 3.0, 11.5 Hz, 1H), 4.06

(dt, J = 4.0, 10.8 Hz, 1H), 3.85 (d, J = 16.0 Hz, 1H), 3.70 (s, 1H),

3.61 (d, J = 16.0 Hz, 1H), 3.56 (d, J = 14.0 Hz, 1H), 3.52 (d, J = 12.7

Hz, 1H), 3.47 (d, J = 13.9 Hz, 1H), 3.21 (d, J = 12.6 Hz, 1H), 3.12

(td, J = 3.2, 11.8 Hz, 1H), 2.74 (dt, J = 43.5, 11.3 Hz, 1H), 2.25 (s,

3H), 2.19 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 140.9 (C_q),

138.8 (C_q), 137.5 (C_q), 136.8 (C_q), 135.6 (C_q), 132.6 (C_q), 132.0

(C_q), 131.9 (C_q), 131.8 (C_q), 130.4 (C_q), 129.1 (C_q), 128.8 (CH),

128.1 (CH), 127.5 (C_q), 127.0 (CH), 126.9 (CH), 126.8 (CH),

126.7 (CH), 126.4 (CH), 126.2 (CH), 125.8 (CH), 124.8 (CH),

124.4 (CH), 120.8 (CH), 114.2 (CH), 106.5 (C_q), 105.6 (CH), 67.3

(CH), 59.1 (CH), 57.8 (CH₂), 51.2 (CH₂), 46.4 (CH₂), 46.1 (CH₂),

42.0 (CH₂), 20.0 (CH₃), 19.6 (CH₃). HRMS (ESI): m /z calcd for

3.9 Hz, CH), 125.6 (CH), 125.4 (C_q), 125.0 (d, C−F, ³J_C−F= 3.3 Hz,

CH), 123.9 (d, C −F, ³J_C−F= 3.2 Hz, CH), 122.3 (CH), 115.5 (CH),

106.9 (CH), 106.8 (C_q), 67.8 (CH), 59.3 (CH), 58.7 (CH₂), 52.4

(CH₂), 47.6 (CH₂), 47.1 (CH₂), 42.9 (CH₂), 21.0 (CH₃), 20.5

(CH₃). ¹⁹F NMR (CDCl₃, 282 MHz): δ −62.4, −62.8. HRMS (ESI):

+

m /z calcd for C₄₈H₄₂F₆N₃774.3283 [M + H]⁺; found, 774.3231.

The following data is for compound syn -9b . IR (neat): ν_max3340,

1

2973, 2924, 1327, 1163, 1119, 1092, 1071, 1047, 736, 700 cm⁻¹. H

NMR (CDCl₃, 500 MHz): δ 7.93 −7.83 (m, 3H), 7.69 (s, 1H), 7.58 −

7.50 (m, 3H), 7.28 −7.19 (m, 3H), 7.14 (s, 3H), 7.08 (d, J = 7.7 Hz,

1H), 7.05 −6.98 (m, 2H), 6.87 −6.82 (m, H), 6.79 (t, J = 7.7 Hz, 1H),

6.69 (d, J = 7.7 Hz, 1H), 4.65 (s, 1H), 4.60 (s, 1H), 4.23 (td, J = 4.3,

11.2 Hz, 1H), 4.15 (dt, J = 3.2, 10.0 Hz, 1H), 3.80 (d, J = 16.1 Hz,

1H), 3.76 (d, J = 13.0 Hz, 1H), 3.67 (d, J = 14.1 Hz, 1H), 3.53 (d, J =

13.2 Hz, 1H), 3.43 (d, J = 12.5 Hz, 1H), 3.32 (d, J = 12.4 Hz, 1H),

3.17 (td, J = 4.0, 12.1 Hz, 1H), 2.82 (ddd, J = 3.7; 10.2; 12.6 Hz, 1H),

2.28 (s, 3H), 2.20 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 141.3

(C_q), 141.0 (C_q), 138.4 (C_q), 137.0 (C_q), 136.9 (C_q), 133 6 (C_q),

133.3 (C_q), 133.1 (C_q), 132.7 (CH), 131.6 (CH), 130.8 (C_q), 130.5

(C_q), 129.8 (C_q), 129.4 (C_q), 129.3 (2CH), 128.4 (C_q), 128.3 (q, C−

+

C₄₆H₄₄N₃, 638.3535 [M + H]⁺; found, 638.3552. The following data

is for compound syn -9a . IR (neat): ν_max3056, 3027, 2921, 2853, 1451,

1

1291, 1265, 736, 696 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ 7.91 −

7.81 (m, 3H), 7.68 (s, 1H), 7.59 −7.47 (m, 3H), 7.23 −7.15 (m, 2H),

6.98 (t, J = 7.2 Hz, 1H), 6.94 −6.88 (m, 2H), 6.85 −6.74 (m, 5H),

6.62 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 4.56 (s, 1H), 4.51

(s, 1H), 4.19 (td, J = 4.2, 11.2 Hz, 1H), 4.08 (ddd, J = 4.5, 9.5, 11.3

Hz, 1H), 3.88 (d, J = 16.3 Hz, 1H), 3.83 −3.73 (m, 1H), 3.71 −3.61

(m, 1H), 3.50 (d, J = 130 Hz, 1H), 3.49 (d, J = 12.4 Hz, 1H), 3.27 (d,

J = 12.2 Hz, 1H), 3.16 (td, J = 4.3, 12.0 Hz, 1H), 2.77 (ddd, J = 3.5,

9.4, 12.1 Hz, 1H), 2.25 (s, 3H), 2.20 (s, 6H). ¹³C{¹H} NMR (CDCl₃,

125 MHz): δ 140.1 (C_q), 139.3 (C_q), 138.5 (C_q), 136.7 (C_q), 133.6

(C_q), 133.4 (C_q), 133.0 (C_q), 131.5 (C_q), 131.5 (C_q), 130.1 (C_q),

129.5 (CH), 129.1 (CH), 128.8 (CH), 128.0 (CH), 127.9 (CH),

127.8 (CH), 127.6 (CH), 127.5 (C_q), 127.4 (CH), 127.2 (CH),

126.3 (CH), 126.0 (CH), 125.7 (C_q), 125.7 (CH), 121.9 (CH),

115.4 (CH), 106.8 (C_q), 106.7 (CH), 66.7 (CH), 60.1 (CH₂), 59.1

(CH), 52.0 (CH₂), 47.8 (CH₂), 46.5 (CH₂), 42.4 (CH₂), 21.0

1

F, J_C−F= 260.0 Hz, Cq), 128.3 (CH), 128.2 (CH), 127.9 (2 CH),

127.8 (CH), 127.8 (CH), 127.5 (CH), 127.4 (q, C −F, ¹J_C−F= 276.5

3

Hz, Cq), 126.6 (CH), 126.1 (q, C −F, J_C−F= 3.3 Hz, CH), 125.8

(CH), 125.6 (C_q), 125.2 (q, C−F, ³J_C−F= 3.8 Hz, CH), 124.5 (q, C−

3

F, J_C−F= 3.3 Hz, CH), 123.6 (q, C−F, J_C−F= 3.3 Hz, CH), 122.4

(CH), 115.7 (CH), 107.0 (CH), 106.4 (C_q), 66.6 (CH), 59.6 (CH),

59.1 (CH₂), 52.3 (CH₂), 47.7 (CH₂), 46.6 (CH₂), 42.5 (CH₂), 21.0

(CH₃), 20.5 (CH₃). ¹⁹F NMR (CDCl₃, 282 MHz): δ −62.5, −62.9.

+

HRMS (ESI): m /z calcd for C₄₈H₄₂F₆N₃, 774.3283 [M + H]⁺;

found, 774.3218.

2-(4-(Naphthalen-2-ylmethyl)-3-(quinolin-4-yl)-4,5-

dihydropyrrolo[4,3,2-de]isoquinolin-1(3H)-yl)-N-(2,4,6-

trimethylbenzyl)ethan-1-amine 9c.

+

(CH₃), 20.5 (CH₃). HRMS (ESI): m /z calcd for C₄₆H₄₄N₃,

638.3535 [M + H]⁺; found, 638.3568.

2-(Naphthalen-2-ylmethyl)-1,11-bis(3-(triﬂuoromethyl)phenyl)-

10-(2,4,6-trimethylbenzyl)-2,3,8,9,10,11-hexahydro-1H-pyrazino-

[1′,2′:1,5]pyrrolo[4,3,2-de]isoquinoline 9b.

Compound 9c was synthesized following general procedure 4 using

tryptamine 5d (75 mg, 0.16 mmol, 1.0 equiv), quinoline-4-

carbaldehyde (77 mg, 0.49 mmol, 3.0 equiv), cat. b (12.0 mg,

0.0162 mmol, 10 mol %), and 3 Å MS (78 mg) in DCM (2.3 mL) at

40 °C. The desired product 9c was obtained after column

chromatography on silica gel (gradient from 40 to 60% heptane/

EtOAc) as a single diastereoisomer (84 mg, 0.14 mmol, 88%). IR

(neat): ν_max3055, 2926, 1688, 1508, 1455, 1365, 1247, 1164, 756

Compound 9b was synthesized following general procedure 4 using

tryptamine 5d (100 mg, 0.22 mmol, 1.0 equiv), 3-(tri ﬂ uoromethyl)-

benzaldehyde (113.15 mg, 0.65 mmol, 3.0 equiv), cat. b (16.0 mg,

0.0217 mmol, 10 mol %), and 3 Å MS (104 mg) in DCM (3.1 mL) at

40 °C. Desired products 9b were obtained after column

chromatography on silica gel (gradient from 0 to 10% heptane/

EtOAc) as white amorphous solids (98 mg, 0.12 mmol, 58%, dr 1:4

anti /syn ). The following data is for compound anti -9b . IR (neat): ν_max

1

cm⁻¹. H NMR (CDCl₃, 500 MHz): δ 8.70 (s, 1H), 8.49 (bs, 1H),

8.13 (d, J = 8.6 Hz, 1H), 8.08 (bs, 1H), 7.84 −7.79 (m, 1H), 7.74 −

7.64 (m, 3H), 7.56 −7.42 (m, 3H), 7.40 −7.21 (m, 6H), 7.21 −6.97

(m, 3H), 6.80 (s, 2H), 6.77 (d, J = 7.3 Hz, 1H), 6.63 (d, J = 4.4 Hz,

1H), 4.94 (s, 1H), 4.46 −4.32 (m, 2H), 3.98 (s, 1H), 3.64 −3.49 (m,

2H), 3.42 (d, J = 16.7 Hz, 1H), 3.38 −3.31 (2H), 3.31 −3.20 (m, 1H),

3.02 −2.73 (m, 2H), 2.27 (s, 3H), 2.11 (s, 6H). ¹³C{¹H} NMR

(CDCl₃, 75 MHz): δ 149.8 (CH), 149.7 (CH), 148.8 (C_q), 148.6

(C_q), 147.2 (C_q), 144.9 (C_q), 138.4 (C_q), 137.1 (C_q), 136.9 (C_q),

133.3 (C_q), 133.1 (C_q), 132.8 (C_q), 131.1 (C_q), 130.2 (C_q), 130.1

(CH), 129.7 (CH), 129.4 (CH), 129.2 (CH), 129.1 (CH), 128.8

(C_q), 127.9 (CH), 127,8 (CH), 127.7 (CH), 127.5 (C_q), 127.3 (CH),

127.1 (CH), 127.0 (C_q), 126.8 (C_q), 126.6 (CH), 125.9 (CH), 125.9

(CH), 125.6 (CH), 124.4 (CH), 123.0 (CH), 122.6 (CH), 120.9

1

3334, 2970, 2924, 1327, 1163, 1120, 1094, 1072, 746, 702 cm⁻¹. H

NMR (CDCl₃, 500 MHz): δ 7.87 −7.84 (m, 1H), 7.77 (d, J = 8.4 Hz,

2H), 7.55 −7.46 (m, 4H), 7.43 −7.33 (m, 4H), 7.25 (s, 1H), 7.22 −

7.17 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.99 −6.93 (m, 2H), 6.83 −

6.78 (m, 2H), 4.33 (s, 1H), 4.21 (td, J = 2.8, 11.3 Hz, 1H), 4.08 (dt, J

= 4.1, 11.2 Hz, 1H), 3.81 (d, J = 16.5 Hz, 1H), 3.66 (d, J = 8.2 Hz,

1H), 3.63 (s, 1H), 3.53 (d, J = 13.9 Hz, 1H), 3.48 (d, J = 14.0 Hz,

1H), 3.42 (d, J = 12.2 Hz, 1H), 3.23 (d, J = 12.3 Hz, 1H), 3.13 (td, J

= 4.2, 11.8 Hz, 1H), 2.76 (dt, J = 3.8, 11.5 Hz, 1H), 2.24 (s, 3H), 2.16

6418

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(CH), 116.2 (CH), 107.1 (CH), 104.7 (C_q), 59.0 (CH₂), 57.9 (CH),

53.0 (CH₂), 47.9 (CH₂), 45.4 (CH₂), 43.1 (CH₂), 21.0 (CH₃), 20.6

(CH₃). Note that one of the benzylic CH does not resonate well in

the ¹³C NMR spectrum; it is estimated around 67 ppm. HRMS (ESI):

were obtained after column chromatography on silica gel (gradient

from 0 to 10% heptane/EtOAc) as an oil (70 mg, 0.10 mmol, 70%, dr

1:3 anti /syn ). In the one-pot procedure, compound 11a was

synthesized following general procedure 5 using tryptamine 5d (31

mg, 0.07 mmol, 1.0 equiv), 4-bromobenzaldehyde (12 mg, 0.07

mmol, 1.0 equiv), cat. b (5.0 mg, 0.0067 mmol, 10 mol %), then

benzaldehyde (14 mg, 0.13 mmol, 2.0 equiv), and 3 Å MS (32 mg) in

DCM (1.0 mL). The desired products 11a were obtained after

column chromatography on silica gel (gradient from 0 to 10%

heptane/EtOAc) as an oil (29 mg, 0.05 mmol, 72%, dr 1:2 anti /syn ).

The following data is for compound anti -11a . IR (neat): ν_max3054,

+

m /z calcd for C₅₂H₄₆N₅, 740.3753 [M + H]⁺; found, 740.3784.

2-(3-(4-Bromophenyl)-4-(naphthalen-2-ylmethyl)-4,5-

dihydropyrrolo[4,3,2-de]isoquinolin-1(3H)-yl)-N-(2,4,6-

trimethylbenzyl)ethan-1-amine 10a.

1

2922, 2852, 1484, 1451, 1289, 1263, 1010, 736, 698 cm⁻¹. H NMR

(CDCl₃, 500 MHz): δ 7.86 −7.82 (m, 1H), 7.79 −7.74 (m, 2H), 7.53

(s, 1H), 7.50 −7.44 (m, 2H), 7.41 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 7.8

Hz, 2H), 7.21 −7.12 (m, 4H), 6.96 (t, J = 7.5 Hz, 2H), 6.83 −6.78 (m,

5H), 6.76 (d, J = 6.7 Hz, 1H), 4.27 (s, 1H), 4.18 (td, J = 3.0, 11.1 Hz,

1H), 4.06 (dt, J = 4.2, 11.2 Hz, 1H), 3.78 (d, J = 16.2 Hz, 1H), 3.59

(d, J = 15.9 Hz, 1H), 3.59 (s, 1H), 3.55 −3.50 (m, 2H), 3.44 (d, J =

13.8 Hz, 1H), 3.20 (d, J = 12.5 Hz, 1H), 3.12 (td, J = 2.9, 11.6 Hz,

1H), 2.73 (dt, J = 3.6, 11.3 Hz, 1H), 2.25 (s, 3H), 2.19 (s, 6H).

¹³C{¹H} NMR (CDCl₃, 125 MHz): δ 141.2 (C_q), 139.7 (C_q), 138.5

(C_q), 137.5 (C_q), 136.7 (C_q), 133.6 (C_q), 133.0 (C_q), 133.0 (C_q),

131.3 (C_q), 131.0 (2 CH), 130.9 (CH), 129.8 (CH), 129.3 (C_q),

129.2 (CH), 128.2 (C_q), 128.0 (CH), 127.9 (CH), 127.7 (CH),

127.2 (CH), 127.2 (CH), 127.1 (C_q), 125.9 (CH), 125.5 (CH),

121.9 (CH), 120.7 (C_q), 115.3 (CH), 106.8 (C_q), 106.7 (CH), 68.4

(CH), 59.5 (CH), 58.8 (CH₂), 52.3 (CH₂), 47.3 (CH₂), 43.1 (2

CH₂), 21.0 (CH₃), 20.6 (CH₃). HRMS (ESI): m /z calcd for

A mixture of tryptamine 5d (84 mg, 0.18 mmol, 1.0 equiv), cat. b

(13.4 mg, 0.0182 mmol, 10 mol %), and 3 Å MS (87 mg) in DCM

(2.6 mL) was stirred for 5 min at room temperature under an argon

atmosphere. Subsequently, 4-bromobenzaldehyde (34 mg, 0.18 mmol,

1.0 equiv) was added, and the mixture was stirred at re ﬂ ux for 24 h.

The mixture was ﬁ ltered under Celite, and silica was added. After

evaporation of the volatiles, the silica residue was puri ﬁ ed by

chromatography under silica gel gradient from 0 to 50% heptane/

EtOAc) to give product 10a as an oil (81 mg, 0.13 mmol, 71%). IR

(neat): ν_max3315, 3051, 2922, 2852, 1459, 1263, 1010, 734 cm⁻¹. ¹H

NMR (CDCl₃, 300 MHz): δ 7.89 −7.76 (m, 3H), 7.71 (s, 1H), 7.58

(d, J = 9.0 Hz, 1H), 7.52 −7.45 (m, 2H), 7,44 −7.37 (m, 2H), 7.26 −

7.14 (m, 4H), 6.83 (s, 2H), 6.79 (d, J = 6.6 Hz, 1H), 6.71 (s, 1H),

4.98 (s, 1H), 4.27 (t, J = 6.1 Hz, 2H), 4.05 (d, J = 15.8 Hz, 1H), 3.86

(d, J = 13.4 Hz, 1H), 3.79 (d, J = 16.2 Hz, 1H), 3.74 (s, 2H), 3.69 (d,

J = 13.6 Hz, 1H), 3.16 (t, J = 5.8 Hz, 1H), 2.30 −2.20 (m, 9H).

¹³C{¹H} NMR (CDCl₃, 75 MHz): δ 142.0 (C_q), 137.4 (C_q), 136.9

(C_q), 136.7 (C_q), 134.1 (C_q), 133.5 (C_q), 133.4 (C_q), 133.0 (C_q),

131.2 (CH), 130.5 (CH), 129.2 (CH), 129.0 (C_q), 128.1 (CH),

127.8 (CH), 127.8 (CH), 127.4 (CH), 127.4 (CH), 126.0 (CH),

125.7 (C_q), 125.7 (CH), 123.3 (CH), 122.8 (CH), 121.0 (C_q), 114.7

(CH), 112.5 (C_q), 107.6 (CH), 61.0 (CH₂), 58.9 (CH), 49.9 (CH₂),

49.6 (CH₂), 47.7 (CH₂), 47.1 (CH₂), 21.0 (CH₃), 19.6 (CH₃).

+

C₄₆H₄₃⁷⁹BrN₃₊716.2640 [M + H]⁺; found, 716.2622, calcd for

C₃₉H₃₉⁸¹BrN₃718.2620 [M + H]⁺; found, 718.2652. The following

data is for compound syn -11a . IR (neat): ν_max3054, 2958, 2924, 2871,

1485, 1451, 1364, 1290, 1010, 750, 698 cm⁻¹. ¹H NMR (CDCl₃, 500

MHz): δ 7.88 −7.82 (m, 3H), 7.66 (s, 1H), 7.53 −7.46 (m, 3H),

7.22 −7.14 (m, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.86 −6.77 (m, 6H),

6.68 (t, J = 7.5, 2H), 6.40 (d, J = 8.5 Hz, 2H), 4.55 (s, 1H), 4.46 (s,

1H), 4.21 −4.15 (m, 1H), 4.08 (dt, J = 4.2, 10.4 Hz, 1H), 3.81 (d, J =

16.3 Hz, 1H), 3.73 (d, J = 13.0 Hz, 1H), 3.65 (d, J = 16.1 Hz, 1H),

3.48 (d, J = 13.0 Hz, 1H), 3.48 (d, J = 12.6 Hz, 1H), 3.27 (d, J = 12.4

Hz, 2H), 3.20 −3.11 (m, 1H), 2.76 (ddd, J = 3.5, 9.4, 12.0 Hz, 1H),

2.25 (s, 3H), 2.19 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 125 MHz): δ

139.5 (C_q), 139.5 (C_q), 138.5 (C_q), 137.3 (C_q) 136.7 (C_q), 133.6

(C_q), 133.4 (C_q), 133.0 (C_q), 131.7 (C_q), 131.4 (C_q), 130.5 (CH),

130.3 (CH), 129.6 (CH), 129.1 (CH), 128.4 (C_q), 128.1 (CH),

127.8 (CH), 127.8 (CH), 127.7 (CH), 127.7 (CH), 127.6 (CH),

126.1 (CH), 125.7 (CH), 125.7 (C_q), 122.0 (C_q), 122.0 (CH), 120.2

(C_q), 115.4 (CH), 106.8 (CH), 108,7 (C_q), 66.9 (CH), 59.5 (CH₂),

59.1 (CH), 52.1 (CH₂), 47.8 (CH₂), 46.5 (CH₂), 42.6 (CH₂), 21.0

+

HRMS (ESI): m /z calcd for C₃₉H₃₉⁷⁹BrN₃, 628.2327 [M + H]⁺;

+

found, 628.2301. HRMS (ESI): m /z calcd for C₃₉H₃₉⁸¹BrN₃,

630.2327 [M + H]⁺; found, 630.2307.

Scope of the C4/N-Iso-Pictet−Spengler Reaction Cascade

with Two Diﬀerent Aldehydes. General Procedure 5. A mixture

of tryptamine 5d (0.17 mmol), cat. b (10 mol %, 0.017 mmol), and 3

Å molecular sieves (82 mg for 0.17 mmol of 5d, powdered) in

dichloromethane (2.4 mL of 0.17 mmol of 5d) was stirred for 5 min

at room temperature under an argon atmosphere. Subsequently,

aldehyde a (1.0 equiv, 0.17 mmol) was added, and the mixture was

stirred for 15 h. Then aldehyde b (2.0 equiv, 0.35 mmol) was added,

and the mixture was stirred at reﬂux for 24 h. The mixture was ﬁltered

under Celite, and silica was added. After evaporation of the volatiles,

the silica mixture was puriﬁed by chromatography under silica gel to

give the desired product 11.

+

(CH₃), 20.5 (CH₃). HRMS (ESI): m /z calcd for C₄₆H₄₃⁷⁹BrN₃₊,

716.2640 [M + H]⁺; found, 716.2679, calcd for C₃₉H₃₉⁸¹BrN₃,

718.2620 [M + H]⁺; found, 718.2668.

2-(Naphthalen-2-ylmethyl)-11-phenyl-1-(3-(triﬂuoromethyl)-

phenyl)-10-(2,4,6-trimethylbenzyl)-2,3,8,9,10,11-hexahydro-1H-

pyrazino[1′,2′:1,5]pyrrolo[4,3,2-de]isoquinoline 11b.

1-(4-Bromophenyl)-2-(naphthalen-2-ylmethyl)-11-phenyl-10-

(2,4,6-trimethylbenzyl)-2,3,8,9,10,11-hexahydro-1H-pyrazino-

[1′,2′:1,5]pyrrolo[4,3,2-de]isoquinoline 11a.

Compound 11b was synthesized following general procedure 5 using

tryptamine 5d (100 mg, 0.22 mmol, 1.0 equiv), 3-(tri ﬂ uoromethyl)-

benzaldehyde (38 mg, 0.22 mmol, 1.0 equiv), cat. b (16.0 mg, 0.0217

mmol, 10 mol %), 3 Å MS (104 mg), and then benzaldehyde (46 mg,

0.43 mmol, 2.0 equiv) in DCM (3.0 mL). The desired products 11b

were obtained after column chromatography on silica gel (gradient

from 0 to 10% heptane/EtOAc) as an oil (98 mg, 0.12 mmol, 58%, dr

1:4 anti /syn ). The following data is for compound anti -11b . IR

(neat): ν_max3057, 2926, 2852, 1451, 1329, 1163, 1124, 747, 704

In the sequential procedure, a mixture of tryptamine 10a (65 mg, 0.14

mmol, 1.0 equiv), cat. b (10.4 mg, 0.014 mmol, 10 mol %), and 3 Å

molecular sieves (68 mg) in dichloromethane (2.0 mL) was stirred for

5 min at room temperature under an argon atmosphere.

Subsequently, benzaldehyde (30 mg, 0.28 mmol, 2.0 equiv) was

added, and the mixture was stirred at 40 °C for 24 h. The mixture was

ﬁ ltered under Celite, and silica was added. The desired products 11a

6419

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

cm⁻¹. ¹H NMR (CDCl₃, 500 MHz): δ 7.88 −7.84 (m, 1H), 7.78 (d, J

= 8.0 Hz, 2H), 7.56 (s, 1H), 7.52 −7.45 (m, 3H), 7.42 (d, J = 8.7 Hz,

1H), 7.33 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.24 −7.08 (m, 5H), 6.92

(t, J = 7.4 Hz, 2H), 6.81 −6.77 (m, 3H), 6.72 (t, J = 7.3 Hz, 1H), 4.25

(s, 1H), 4.19 (td, J = 2.8, 11.1 Hz, 1H), 4.05 (dt, J = 4.3, 11.5 Hz,

1H), 3.82 (d, J = 16.1 Hz, 1H), 3.68 −3.61 (m, 2H), 3.56 −3.46 (m,

3H), 3.19 (d, J = 12.5 Hz, 1H), 3.15 −3.10 (m, 1H), 2.73 (dt, J = 3.5,

11.5 Hz, 1H), 2.25 (s, 3H), 2.19 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 125

MHz): δ 143.1 (C_q), 139.5 (C_q), 138.5 (C_q), 137.3 (C_q), 136.7 (C_q),

133.6 (C_q), 133.1 (C_q), 133.0 (C_q), 133.0 (C_q), 132.2 (C_q), 131.3

(C_q), 137.5 (C_q), 136.3 (C_q), 135.7 (C_q), 132.6 (C_q), 132.4 (C_q),

132.0 (C_q), 131.9 (C_q), 130.1 (C_q), 128.8 (CH), 128.6 (CH), 128.2

(CH), 128.1 (CH), 127.5 (CH), 127.3 (CH), 126.9 (CH), 126.9

(CH), 126.7 (CH), 126.5 (CH), 126.3 (C_q), 125.0 (CH), 125.0

(CH), 124.7 (CH), 124.6 (CH), 121.2 (CH), 120.3 (CH), 114.9

(CH), 106.0 (CH), 103.7 (C_q), 81.7 (C_q), 67.8 (CH), 58.4 (CH₂),

56.9 (CH), 51.4 (CH₂), 46.5 (CH₂), 44.6 (CH₂), 42.3 (CH₂), 20.0

+

(CH₃), 19.6 (CH₃). HRMS (ESI): m /z calcd for C₄₉H₄₅N₄,

689.3644 [M + H]⁺; found, 689.3622. The following data is for

compound syn -11c . IR (neat): ν_max3058, 2924, 2851, 1694, 1612,

1

1508, 1451, 1345, 1275, 758 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ

1

(C_q), 130.2 (CH), 129.8 (CH), 129.2 (q, C−F, J_C−F= 251.9 Hz,

8.38 (d, J = 4.2 Hz, 1H), 8.00 −7.86 (m, 4H), 7.74 (s, 1H), 7.57 −7.50

(m, 4H), 7.33 −7.26 (m, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.6

Hz, 1H), 6.94 −6.87 (m, 2H), 6.83 (d, J = 6.7 Hz, 1H), 6.81 (s, 2H),

6.36 (bs, 1H), 6.22 (t, J = 7.8 Hz, 2H), 6.08 (t, J = 7.3 Hz, 1H), 5.31

(s, 1H), 4.65 (s, 1H), 4.28 −4.22 (m, 1H), 4.15 (dt, J = 4.0, 10.9 Hz,

1H), 3.88 (d, J = 16.2 Hz, 1H), 3.78 (d, J = 12.7 Hz, 1H), 3.71 (d, J =

12.3 Hz, 1H), 3.63 (d, J = 16.5 Hz, 1H), 3.45 (d, J = 12.4 Hz, 1H),

3.25 (d, J = 12.1 Hz, 1H), 3.18 (td, J = 3.2, 11.5 Hz, 1H), 2.83 (dt, J =

3.8, 11.3 Hz, 1H), 2.25 (s, 3H), 2.20 (6H). ¹³C{¹H} NMR (CDCl₃,

125 MHz): δ 150.6 (C_q), 149.1 (CH), 148.4 (C_q), 146.3 (C_q), 139.3

(C_q), 138.5 (C_q), 136.9 (C_q), 136.8 (C_q), 133.5 (C_q), 133.1 (C_q),

133.0 (C_q), 131.1 (C_q), 130.4 (C_q), 129.5 (CH), 129.2 (CH), 129.2

(CH), 128.7 (CH), 128.4 (CH), 128.1 (CH), 127.9 (CH), 127.9

(CH), 127.5 (CH), 127.0 (CH), 127.0 (C_q), 126.3 (CH), 126.0

(CH), 125.9 (C_q), 125.7 (CH), 124.5 (CH), 122.3 (CH), 121.4

(CH), 116.1 (CH), 107.0 (CH), 104.0 (C_q), 68.9 (CH), 59.5 (CH₂),

54.7 (CH), 52.6 (CH₂), 47.8 (CH₂), 47.4 (CH₂), 43.3 (CH₂), 21.0

Cq), 129.2 (CH), 128.3 (CH), 128.2 (C_q), 128.1 (CH), 128.1 (CH),

127.9 (CH), 127.9 (CH), 127.7 (CH), 127.2 (CH), 127.2 (CH),

126.1 (q, C −F, ³J_C−F= 3.7 Hz, CH), 125.9 (CH), 125.5 (CH), 125.5

(C_q), 123.6 (q, C−F, ³J_C−F= 3.7 Hz, CH), 122.0 (CH), 115.4 (CH),

106.8 (CH), 106.8 (C_q), 68.6 (CH), 59.4 (CH), 58.8 (CH₂), 52.3

(CH₂), 47.3 (CH₂), 47.3 (CH₂), 43.1 (CH₂), 21.0 (CH₃), 20.6

(CH₃). ¹⁹F NMR (CDCl₃, 282 MHz): δ −62.3. HRMS (ESI): m /z

+

calcd for C₄₇H₄₃F₃N₃, 706.3409 [M + H]⁺; found, 706.3380. The

following data is for compound syn -11b . IR (neat): ν_max3055, 2924,

2851, 1451, 1329, 1162, 1122, 1073, 748, 699 cm⁻¹. ¹H NMR

(CDCl₃, 500 MHz): δ 7.90 −7.81 (m, 3H), 7.66 (s, 1H), 7.54 −7.47

(m, 3H), 7.25 −7.14 (m, 3H), 7.00 (t, J = 8.6 Hz, 1H), 6.85 (d, J = 7.9

Hz, 2H), 6.82 −6.78 (m, 3H), 6.76 (s, 1H), 6.74 −6.69 (m, 2H), 6.61

(t, J = 7.6 Hz, 2H), 4.55 (s, 1H), 4.54 (s, 1H), 4.23 −4.16 (m, 1H),

4.10 (dt, J = 3.6, 10.5 Hz, 1H), 3.77 (d, J = 16.5 Hz, 1H), 3.72 (d, J =

12.4 Hz, 1H), 3.63 (d, J = 16.4 Hz, 1H)., 3.52 −3.43 (m, 2H), 3.24 (d,

J = 12.5 Hz, 1H), 3.18 −3.11 (m, 1H), 2.76 (ddd, J = 3.9, 10.1, 11.9

Hz, 1H), 2.25 (s, 3H), 2.18 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 125

MHz): δ 141.3 (C_q), 139.5 (C_q), 138.5 (C_q), 137.2 (C_q), 136.7 (C_q),

+

(CH₃), 20.7 (CH₃). HRMS (ESI): m /z calcd for C₄₉H₄₅N₄,

689.3644 [M + H]⁺; found, 689.3593.

133.6 (C_q), 133.2 (C_q), 133.0 (C_q), 132.0 (C_q), 131.8 (C_q), 131.3

1

(C_q), 129.5 (CH), 129.2 (CH), 128.3 (C_q), 128.1 (q, C−F, J_C−F

=

ASSOCIATED CONTENT

■

275.8 Hz, C_q), 128.1 (CH), 127.8 (CH), 127.8 (3 CH), 127.6 (CH),

127.6 (CH), 127.5 (CH), 126.1 (CH), 125.7 (CH), 125.7 (CH),

125.5 (q, C −F, ³J_C−F= 3.5 Hz, CH), 123.3 (q, C−F, ³J_C−F= 3.8 Hz,

CH), 122.0 (CH), 115.5 (CH), 106.9 (CH), 106.0 (C_q), 67.5 (CH),

59.6 (CH), 59.1 (CH₂), 52.2 (CH₂), 47.5 (CH₂), 46.8 (CH₂), 42.7

(CH₂), 21.0 (CH₃), 20.6 (CH₃). ¹⁹F NMR (CDCl₃, 282 MHz): δ

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00270.

Details about optimization of the reactions, blank tests,

NMR spectra, X-ray crystallography data, and mecha-

nistic hypotheses (PDF)

+

−62.3. HRMS (ESI): m /z calcd for C₄₇H₄₃F₃N₃, 706.3409 [M +

H]⁺; found, 706.3414.

2-(Naphthalen-2-ylmethyl)-11-phenyl-1-(quinolin-4-yl)-10-

(2,4,6-trimethylbenzyl)-2,3,8,9,10,11-hexahydro-1H-pyrazino-

[1′,2′:1,5]pyrrolo[4,3,2-de]isoquinoline 11c.

Accession Codes

CCDC 2046851 and 2046871 contain the supplementary

crystallographic data for this paper. These data can be obtained

free of charge 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.

AUTHOR INFORMATION

■

Compound 11c was synthesized following general procedure 5 using

tryptamine 5d (60 mg, 0.13 mmol, 1.0 equiv), quinoline-4-

carbaldehyde (20 mg, 0.13 mmol, 1.0 equiv), cat. b (9.6 mg,

0.0130 mmol, 10 mol %), 3 Å MS (62 mg), at 40 °C, and then

benzaldehyde (28 mg, 0.26 mmol, 2.0 equiv) in DCM (1.9 mL). The

desired products 11c were obtained after column chromatography on

silica gel (gradient from 0 to 35% heptane/EtOAc) as an oil (64 mg,

0.09 mmol, 71%, dr 2:1 anti /syn ). The following data is for compound

anti -11c . IR (neat): ν_ma1x3056, 2924, 2850, 1688, 1591, 1508, 1450,

1326, 1274, 758 cm⁻¹. H NMR (CDCl₃, 500 MHz): δ 8.70 (d, J =

4.5 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.85 −7.81 (m, 1H), 7.77 −7.70

(m, 3H), 7.65 (d, J = 9.3 Hz, 1H), 7.55 (s, 1H), 7.49 −7.44 (m, 2H),

7.44 −7.37 (m, 2H), 7.27 (d, J = 8.5 Hz, 1H), 7.22 −7.13 (m, 4H),

7.04 (t, J = 7.4 Hz, 2H), 6.82 (s, 1H), 6.74 (d, J = 6.9 Hz, 1H), 6.62

(d, J = 4.4 Hz, 1H), 4.33 (s, 1H), 4.30 −4.23 (m, 2H), 4.15 (dt, J =

4.2, 11.0 Hz, 1H), 3.62 (d, J = 18.3 Hz, 1H), 3.60 (s, 2H), 3.56 (d, J =

12.5 Hz, 1H), 3.47 (d, J = 16.5 Hz, 1H), 3.23 −3.16 (m, 2H), 2.81 (dt,

J = 3.1, 11.3 Hz, 1H), 2.27 (s, 3H), 2.24 (s, 6H). ¹³C{¹H} NMR

(CDCl₃, 125 MHz): δ 148.8 (CH), 147.7 (C_q), 147.1 (C_q), 138.9

Corresponding Author

Xavier Guinchard − Université Paris-Saclay, CNRS, Institut

de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-

sur-Yvette, France; orcid.org/0000-0003-2353-8236;

Email: xavier.guinchard@cnrs.fr

Authors

Pierre Milcendeau − Université Paris-Saclay, CNRS, Institut

de Chimie des Substances Naturelles, UPR 2301, 91198 Gif-

sur-Yvette, France

Zhenhao Zhang − Université Paris-Saclay, CNRS, Institut de

Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-

Yvette, France; LCM, CNRS, Ecole Polytechnique, Institut

Polytechnique de Paris, 91128 Palaiseau, France

Nicolas Glinsky-Olivier − Université Paris-Saclay, CNRS,

Institut de Chimie des Substances Naturelles, UPR 2301,

91198 Gif-sur-Yvette, France

6420

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

for the Synthesis of Heterocycles. Adv. Heterocycl. Chem. 2019, 127,

153−226.

Elsa van Elslande − Université Paris-Saclay, CNRS, Institut de

Chimie des Substances Naturelles, UPR 2301, 91198 Gif-sur-

Yvette, France

(5) (a) Zheng, C.; You, S.-L. Exploring the Chemistry of

Spiroindolenines by Mechanistically-Driven Reaction Development:

Asymmetric Pictet −Spengler-type Reactions and Beyond. Acc. Chem.

Res. 2020, 53, 974−987. (b) Zheng, C.; Xia, Z.-L.; You, S.-L. Unified

Mechanistic Understandings of Pictet −Spengler Reactions. Chem.

2018, 4, 1952−1966. (c) Unsworth, W. P. Understanding the Role of

Spiroindolenines in Pictet −Spengler Reactions. Chem. 2018, 4,

1767−1770. (d) Kowalski, P.; Mokrosz, J. L. Structure and spectral

properties of beta-carbolines. 9. New arguments against direct

rearrangement of the spiroindolenine intermediate into beta-carboline

system in the Pictet−Spengler cyclization. An MNDO approach. Bull.

Chem. Soc. Belg. 1997, 106, 147−149. (e) Kowalski, P.; Bojarski, A. J.;

Mokrosz, J. L. Structure and spectral properties of β -carbolines. 8.

Mechanism of the Pictet −Spengler cyclization: An MNDO approach.

Tetrahedron 1995, 51, 2737−2742. (f) Bailey, P. D. Direct proof of

the involvement of a spiro intermediate in the Pictet−Spengler

reaction. J. Chem. Res. 1987, 202−203. (g) Bailey, P. D. On the

stereochemistry of the Pictet −Spengler reaction. Tetrahedron Lett.

1987, 28, 5181−5184. (h) Soerens, D.; Sandrin, J.; Ungemach, F.;

Mokry, P.; Wu, G. S.; Yamanaka, E.; Hutchins, L.; Dipierro, M.;

Cook, J. M. Study of the Pictet −Spengler reaction in aprotic media -

Synthesis of the beta-galactosidase inhibitor, Pyridinindolol. J. Org.

Chem. 1979, 44, 535−545. (i) Gobé, V.; Gandon, V.; Guinchard, X.

Reactions Involving Tryptamines and δ -Allenyl Aldehydes: Competi-

tion between Pictet −Spengler Reaction and Cyclization to 1-

Aminotetralins. Adv. Synth. Catal. 2018, 360, 1280−1288.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00270

Author Contributions

All authors have given approval to the ﬁnal version of the

manuscript.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

P.M. and N.G.-O. thank MESRI (Paris-Saclay University) for a

Ph.D. fellowship and the CHARMMMAT Laboratory of

Excellence (ANR-11-LABX0039) for ﬁnancial support. Z.Z.

thanks the China Scholarship Council for Ph.D. funding.

REFERENCES

■

(1) See, for example: (a) Rahman, A.; Basha, A. Indole Alkaloids;

Harwood Academic Publishers: Reading, Berks, 1999. (b) Kawasaki,

T.; Higuchi, K. Simple indole alkaloids and those with a non-

rearranged monoterpenoid unit. Nat. Prod. Rep. 2005, 22, 761−793.

(c) Gul, W.; Hamann, M. T. Indole alkaloid marine natural products:

An established source of cancer drug leads with considerable promise

for the control of parasitic, neurological and other diseases. Life Sci.

2005, 78, 442−453. (d) O’Connor, S. E.; Maresh, J. J. Chemistry and

biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep.

2006, 23, 532−547.

(6) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;

Boubaker, T.; Ofial, A. R.; Mayr, H. Nucleophilic Reactivities of

Indoles. J. Org. Chem. 2006, 71, 9088−9095.

(7) (a) Wu, F.; Zhu, H.; Sun, L.; Rajendran, C.; Wang, M.; Ren, X.;

Panjikar, S.; Cherkasov, A.; Zou, H.; Stöckigt, J. Scaffold Tailoring by

a Newly Detected Pictet −Spenglerase Activity of Strictosidine

Synthase: From the Common Tryptoline Skeleton to the Rare

Piperazino-indole Framework. J. Am. Chem. Soc. 2012, 134, 1498−

1500. (b) Schönherr, H.; Leighton, J. L. Direct and Highly

Enantioselective Iso-Pictet −Spengler Reactions with α -Ketoamides:

Access to Underexplored Indole Core Structures. Org. Lett. 2012, 14,

2610−2613. (c) Tiwari, R. K.; Verma, A. K.; Chhillar, A. K.; Singh,

D.; Singh, J.; Kasi Sankar, V.; Yadav, V.; Sharma, G. L.; Chandra, R.

Synthesis and antifungal activity of substituted-10-methyl-1,2,3,4-

tetrahydropyrazino[1,2-a]indoles. Bioorg. Med. Chem. 2006, 14,

2747−2752. (d) Tiwari, R. K.; Singh, J.; Singh, D.; Verma, A. K.;

Chandra, R. Highly efficient one-pot synthesis of 1-substituted-

1,2,3,4-tetrahydropyrazino[1,2-a]indoles. Tetrahedron 2005, 61,

9513−9518. (e) Katritzky, A. R.; Verma, A. K.; He, H.-Y.; Chandra,

R. Novel Synthesis of 1,2,3,4-Tetrahydropyrazino[1,2-a]indoles. J.

Org. Chem. 2003, 68, 4938−4940. (f) Huo, H.-r.; Tang, X.-Y.; Gong,

Y.-f. Metal-Free Synthesis of Pyrrolo[1,2-a]quinoxalines Mediated by

TEMPO Oxoammonium Salts. Synthesis 2018, 50, 2727−2740.

(g) Xu, H.; Fan, L.-l. Synthesis and antifungal activities of novel

5,6-dihydro-indolo[1,2-a]quinoxaline derivatives. Eur. J. Med. Chem.

2011, 46, 1919−1925. (h) Preetam, A.; Nath, M. An eco-friendly

Pictet −Spengler approach to pyrrolo- and indolo[1,2-a]quinoxalines

using p-dodecylbenzenesulfonic acid as an efficient Brønsted acid

catalyst. RSC Adv. 2015, 5, 21843−21853.

(2) For reviews, see: (a) Maity, P.; Adhikari, D.; Jana, A. K. An

overview on synthetic entries to tetrahydro-β -carbolines. Tetrahedron

2019, 75, 965−1028. (b) Glinsky-Olivier, N.; Guinchard, X.

Enantioselective Catalytic Methods for the Elaboration of Chiral

Tetrahydro-β -carbolines and Related Scaffolds. Synthesis 2017, 49,

2605−2620. (c) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Beta-Carboline

alkaloids: biochemical and pharmacological functions. Curr. Med.

Chem. 2007, 14, 479−500.

(3) (a) Pictet, A.; Spengler, T. On the formation of isochinolin-

derivatives through the development of methylial on phenyl-aether,

phenyl-alanin and tyrosin. Ber. Dtsch. Chem. Ges. 1911, 44, 2030−

̈

2036. (b) Tatsui, G. Uber die Synthese von Carbolinderivaten.

Yakugaku Zasshi 1928, 48, 453−459.

(4) For reviews, see: (a) 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. (c) Rao, R. N.; Maiti, B.;

Chanda, K. Application of Pictet −Spengler Reaction to Indole-Based

Alkaloids Containing Tetrahydro-β -carboline Scaffold in Combinato-

rial Chemistry. ACS Comb. Sci. 2017, 19, 199−228. (d) Ingallina, C.;

D’Acquarica, I.; Delle Monache, G.; Ghirga, F.; Quaglio, D.; Ghirga,

P.; Berardozzi, S.; Markovic, V.; Botta, B. The Pictet −Spengler

Reaction Still on Stage. Curr. Pharm. Des. 2016, 22, 1808−1850.

(e) Dalpozzo, R. The Chiral Pool in the Pictet −Spengler Reaction for

the Synthesis of β -Carbolines. Molecules 2016, 21, 699. (f) Kundu, B.;

K. Agarwal, P.; K. Sharma, S.; Sawant, D.; K. Mandadapu, A.;

Saifuddin, M.; Gupta, S. Pictet −Spengler Reaction Revisited:

Engineering of Tetherd Biheterocycles into Annulated Polyhetero-

cycles. Curr. Org. Synth. 2012, 9, 357−376. (g) Stockigt, J.;

Antonchick, A. P.; Wu, F. R.; Waldmann, H. The Pictet −Spengler

Reaction in Nature and in Organic Chemistry. Angew. Chem., Int. Ed.

2011, 50, 8538−8564. (h) Lorenz, M.; Van Linn, M. L.; Cook, J. M.

The Asymmetric Pictet −Spengler Reaction. Curr. Org. Synth. 2010, 7,

189−223. (i) Cox, E. D.; Cook, J. M. The Pictet −Spengler

condensation - a new direction for an old reaction. Chem. Rev.

1995, 95, 1797−1842. (b) Gholamzadeh, P.; Scriven, E. F. V.;

Ramsden, C. A. The Pictet −Spengler Reaction: A Powerful Strategy

(8) (a) Voznesenskaia, N. G.; Shmatova, O. I.; Nenajdenko, V. G.

Pictet −Spengler Synthesis of Perfluoroalkylated Tetrahydro-γ -carbo-

lines and Tetrahydropyrrolopyrazines. Synthesis 2020, 52, 263−272.

(b) Zhai, F.; Jordan, R. F. Complexation of an indole-based α -

aminoimine ligand to Pd(II). Inorg. Chim. Acta 2018, 482, 491−496.

(c) Urmode, T. D.; Dawange, M. A.; Shinde, V. S.; Kusurkar, R. S.

Synthesis of spiroindolone scaffolds by Pictet −Spengler spirocyclisa-

tion using β -cyclodextrin-SO3H as a recyclable catalyst. Tetrahedron

2017, 73, 4348−4354. (d) Riesco-Domínguez, A.; van der Zwaluw,

N.; Blanco-Ania, D.; Rutjes, F. P. J. T. An Enantio- and

Diastereoselective Mannich/Pictet −Spengler Sequence To Form

Spiro[piperidine-pyridoindoles] and Application to Library Synthesis.

6421

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Eur. J. Org. Chem. 2017, 2017, 662−670. (e) Huang, L.; Dai, L.-X.;

You, S.-L. Enantioselective Synthesis of Indole-Annulated Medium-

Sized Rings. J. Am. Chem. Soc. 2016, 138, 5793−5796. (f) Li, X.;

Chen, D.; Gu, H.; Lin, X. Enantioselective synthesis of benzazepi-

noindoles bearing trifluoromethylated quaternary stereocenters

catalyzed by chiral spirocyclic phosphoric acids. Chem. Commun.

2014, 50, 7538−7541. (g) Lee, Y.; Klausen, R. S.; Jacobsen, E. N.

Thiourea-Catalyzed Enantioselective Iso-Pictet −Spengler Reactions.

Org. Lett. 2011, 13, 5564−5567. (h) Grigg, R.; Sridharan, V.; Sykes,

D. A. Sonogashira/N-acyliminium ion aromatic π -cyclisation

processes: access to tetra- and pentacyclic lactams. Tetrahedron

2008, 64, 8952−8962.

(17) Mézailles, N.; Ricard, L.; Gagosz, F. Phosphine Gold(I) Bis-

(trifluoromethanesulfonyl)imidate Complexes as New Highly Effi-

cient and Air-Stable Catalysts for the Cycloisomerization of Enynes.

Org. Lett. 2005, 7, 4133−4136.

(18) (a) Jónsson, H. F.; Fiksdahl, A. Studies on gold-nitrone

systems. Dalton Trans. 2019, 48, 142−149. (b) Jónsson, H. F.; Evjen,

S.; Fiksdahl, A. Gold(I)-Catalyzed [2 + 2 + 2] Cyclotrimerization of

1,3-Diarylpropargyl Acetals. Org. Lett. 2017, 19, 2202. (c) Evjen, S.;

Fiksdahl, A. Gold(I)-catalysed [3 + 3] cycloaddition of propargyl

acetals and nitrones. Tetrahedron 2016, 72, 3270−3276.

(19) The conversion rate was 65%. The same reaction without a

catalyst led to a lower 25% conversion over 60 h.

(20) Both syn and anti diastereomers of the series have a typical

footprint in ¹H NMR spectra. NOESY experiments and X-ray

obtained in other compounds of the series allowed the determination

of the relative conﬁgurations of all of the products by analogy.

(21) (a) Martinez, C. R.; Iverson, B. L. Rethinking the term “pi-

stacking. Chem. Sci. 2012, 3, 2191−2201. (b) Cozzi, F.; Ponzini, F.;

Annunziata, R.; Cinquini, M.; Siegel, J. S. Polar Interactions between

Stacked π Systems in Fluorinated 1,8-Diarylnaphthalenes: Importance

of Quadrupole Moments in Molecular Recognition. Angew. Chem., Int.

Ed. Engl. 1995, 34, 1019−1020. (c) Hunter, C. A.; Sanders, J. K. M.

The nature of. pi.-.pi. interactions. J. Am. Chem. Soc. 1990, 112, 5525−

5534. (d) Wheeler, S. E.; Houk, K. N. Substituent Effects in the

Benzene Dimer are Due to Direct Interactions of the Substituents

with the Unsubstituted Benzene. J. Am. Chem. Soc. 2008, 130, 10854−

10855.

(22) Previous papers have hypothesized the potential involvement of

Au(I) complexes and/or acidic protons in the formation of iminium

from hemiaminal in related Au(I)-catalyzed reactions. However, our

own results (see ref 14a) ruled out the possibility that protons were

involved in that type of elementary step because reactions were

enantioselective. For these reports, see ref 9 and the following ref:

(a) Qiao, J.; Jia, X.; Li, P.; Liu, X.; Zhao, J.; Zhou, Y.; Wang, J.; Liu,

H.; Zhao, F. Adv. Synth. Catal. 2019, 361, 1419. (b) Patil, N. T.;

Mutyala, A. K.; Lakshmi, P. G.; Gajula, B.; Sridhar, B.; Pottireddygari,

G. R.; Rao, T. P. J. Org. Chem. 2010, 75, 5963. (c) Yang, T.;

Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129, 12070.

(23) Schlegel, M.; Coburger, P.; Schneider, C. A Novel Sc(OTf)₃-

Catalyzed (2 + 2+1)-Cycloannulation/Aza-Friedel-Crafts Alkylation

Sequence toward Multicyclic 2-Pyrrolines. Chem. - Eur. J. 2018, 24,

14207−14212.

(9) Patil, N. T.; Shinde, V. S.; Sridhar, B. Relay Catalytic Branching

Cascade: A Technique to Access Diverse Molecular Scaffolds. Angew.

Chem., Int. Ed. 2013, 52, 2251−2255.

(10) For other C4-iso-Pictet−Spengler reactions, see: (a) Abe, T.;

Yamada, K. Concise Syntheses of Hyrtioreticulins C and D via a C-4

Pictet −Spengler Reaction: Revised Signs of Specific Rotations. J. Nat.

Prod. 2017, 80, 241−245. (b) Abe, T.; Haruyama, T.; Yamada, K. C4

Pictet −Spengler Reactions for the Synthesis of Core Structures in

Hyrtiazepine Alkaloids. Synthesis 2017, 49, 4141−4150.

(11) (a) Cera, G.; Bandini, M. Enantioselective Gold(I) Catalysis

with Chiral Monodentate Ligands. Isr. J. Chem. 2013, 53, 848−855.

(b) Obradors, C.; Echavarren, A. M. Gold-Catalyzed Rearrangements

and Beyond. Acc. Chem. Res. 2014, 47, 902−912. (c) Zi, W.; Dean

Toste, F. Recent advances in enantioselective gold catalysis. Chem.

Soc. Rev. 2016, 45, 4567−4589. (d) Ranieri, B.; Escofet, I.;

Echavarren, A. M. Anatomy of gold catalysts: facts and myths. Org.

Biomol. Chem. 2015, 13, 7103−7118. (e) Dorel, R.; Echavarren, A. M.

Gold(I)-Catalyzed Activation of Alkynes for the Construction of

Molecular Complexity. Chem. Rev. 2015, 115, 9028−9072.

(f) Mascarenas, J. L.; Varela, I.; López, F. Allenes and Derivatives

̃

in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions. Acc.

Chem. Res. 2019, 52, 465−479.

(12) (a) Pirovano, V. Gold-Catalyzed Functionalization Reactions of

Indole. Eur. J. Org. Chem. 2018, 2018, 1925−1945. (b) Milcendeau,

P.; Sabat, N.; Ferry, A.; Guinchard, X. Gold-catalyzed enantioselective

functionalization of indoles. Org. Biomol. Chem. 2020, 18, 6006−6017.

(13) (a) Zhang, Z.; Smal, V.; Retailleau, P.; Voituriez, A.; Frison, G.;

Marinetti, A.; Guinchard, X. Tethered Counterion-Directed Catalysis:

Merging the Chiral Ion-Pairing and Bifunctional Ligand Strategies in

Enantioselective Gold(I) Catalysis. J. Am. Chem. Soc. 2020, 142,

3797−3805. (b) Sabat, N.; Soualmia, F.; Retailleau, P.; Benjdia, A.;

Berteau, O.; Guinchard, X. Gold-Catalyzed Spirocyclization Reactions

of N -Propargyl Tryptamines and Tryptophans in Aqueous Media.

Org. Lett. 2020, 22, 4344−4349. (c) Magné, V.; Sanogo, Y.; Demmer,

C. S.; Retailleau, P.; Marinetti, A.; Guinchard, X.; Voituriez, A. Chiral

Phosphathiahelicenes: Improved Synthetic Approach and Uses in

Enantioselective Gold(I)-Catalyzed [2 + 2] Cycloadditions of N -

Homoallenyl Tryptamines. ACS Catal. 2020, 10, 8141−8148.

(14) (a) Glinsky-Olivier, N.; Yang, S.; Retailleau, P.; Gandon, V.;

Guinchard, X. Enantioselective Gold-Catalyzed Pictet −Spengler

Reaction. Org. Lett. 2019, 21, 9446−9451. (b) Gobé, V.; Retailleau,

P.; Guinchard, X. Self-Relay Gold(I)-Catalyzed Pictet −Spengler/

Cyclization Cascade Reaction for the Rapid Elaboration of

Pentacyclic Indole Derivatives. Chem. - Eur. J. 2015, 21, 17587−

17590.

(24) Enders, D.; Wang, C.; Yang, X.; Raabe, G. One-Pot

Organocatalytic Asymmetric Synthesis of 1 H -Pyrrolo[1,2a]indol-

3(2 H )-ones via a Michael-Hemiaminalization-Oxidation Sequence.

Synlett 2011, 2011, 469−472.

(25) Robaa, D.; Enzensperger, C.; Abul Azm, S. E. D.; El Khawass,

E. S.; El Sayed, O.; Lehmann, J. Dopamine Receptor Ligands. Part 18:

Modification of the Structural Skeleton of Indolobenzazecine-Type

Dopamine Receptor Antagonists. J. Med. Chem. 2010, 53, 2646−

2650.

(15) For previous gold-catalyzed Pictet−Spengler reactions, see:

(a) Youn, S. W. Development of the Pictet −Spengler Reaction

Catalyzed by AuCl₃/AgOTf. J. Org. Chem. 2006, 71, 2521−2523.

(b) Subba Reddy, B. V.; Swain, M.; Reddy, S. M.; Yadav, J. S.; Sridhar,

B. Gold-Catalyzed Domino Cycloisomerization/Pictet −Spengler

Reaction of 2-(4-Aminobut-1-yn-1-yl)anilines with Aldehydes: Syn-

thesis of Tetrahydropyrido[4,3-b ]indole Scaffolds. J. Org. Chem. 2012,

77, 11355−11361.

(16) Milcendeau, P.; Zhang, Z.; Glinsky-Olivier, N.; Van Elslande,

E.; Guinchard, X., Au(I)-Catalyzed Pictet −Spengler Reactions: a

Journey Around the Indole Ring. ChemRxiv 2020, .

6422

https://doi.org/10.1021/acs.joc.1c00270

J. Org. Chem. 2021, 86, 6406−6422

Article Doi

Au(I)-Catalyzed Pictet-Spengler Reactions All around the Indole Ring

DOI: 10.1021/acs.joc.1c00270

Source and publish data:

Authors:

Article abstract of DOI:10.1021/acs.joc.1c00270

Full text of DOI:10.1021/acs.joc.1c00270

Products guided by the article

R&D Labs maybe for 14255-18-6

Relevant to this article

Hot Product