Synthesis of condensed tetrahydroisoquinoline class of alkaloids by employing TfOH-mediated imide carbonyl activation

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DOI: 10.1002/ejoc.201403617

Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids by

Employing TfOH-Mediated Imide Carbonyl Activation

Jayaraman Selvakumar,^[a]Ramana Sreenivasa Rao,^[a]Vijayan Srinivasapriyan,^[a]

Srinivasan Marutheeswaran,^[a]and Chinnasamy Ramaraj Ramanathan*^[a]

Keywords: Alkaloids / Nitrogen heterocycles / Lactams / Cyclization / Regioselectivity

Isoquinoline-based polycyclic lactams such as isoindoloiso-

quinolinones, pyrroloisoquinolinones, and benzo[a]quinol-

alkaloids crispine A, trolline/oleracein E, and erythrinarbine

were successfully synthesized in racemic form. The reaction

izinones were successfully assembled from the correspond- of unsymmetrical N-phenethylphthalimides with TfOH dis-

ing imides by using a TfOH-mediated (TfOH = trifluorometh- played excellent regioselectivity, which was rationalized by

anesulfonic acid) imide carbonyl activation and cyclization

strategy. By employing this simple method, the isoquinoline

DFT calculations.

molecules drove many synthetic chemists to develop simple

methods to prepare the THIQ skeleton.^[3]Some of the exi-

sting methods are efficient, but they also have drawbacks

such as vigorous reaction conditions, a catalyst/substrate

that is not commercially available and difficult to prepare,

and specificity toward a particular skeleton. More import-

antly, the adaptability of some of these methods towards

the synthesis of natural products is very limited. With their

ease of generation and stability, condensed tetrahydroiso-

quinoline derivatives can be constructed from N-phen-

ethylimides through the formation of a C–C bond between

a phenyl carbon atom and the imide carbonyl carbon.

Bischler–Napieralski (B–N) reaction conditions have been

adopted to synthesize fused isoquinolines from N-phen-

ethylimides. For example, these conditions involve heating

N-phenethylimides at reflux with either POCl₃or PPA/P₂O₅

to furnish cyclic enamides in an uncontrolled manner.^[4]

The N-acyliminium ion and Parham-type cyclizations are

other simple and efficient methods that are utilized to con-

vert N-phenethylimides into fused tetrahydroisoquinolines

in two steps^[5](Scheme 1). The success of these two proto-

cols is attributed to the activation of either the electrophile

(N-acyliminium ion) or the nucleophile (Parham-type) that

is present in the substrate. The former method involves the

conversion of the imide into a hydroxyisoindolone prior to

the cyclization. The latter one involves the halogenation of

the aryl group by using an interhalogen compound followed

by a cyclization that is facilitated by butyllithium.

Introduction

Condensed heterocycles such as isoindoloisoquinolinone,

pyrroloisoquinoline, and benzo[a]quinolizine are found in

pharmacologically active alkaloids such as nuevamine,

trolline, crispine A, erysotramidine, and jamtine as well as

in pharmaceuticals such as tetrabenzazine (Figure 1).^[1]

These classes of molecules display a wide spectrum of bio-

logical activities. Some α-alkylated benzo[a]quinolizine mol-

ecules exhibit excellent pharmacological activity relative to

existing drug molecules.^[2]

Figure 1. Representative fused tetrahydroisoquinoline (THIQ)

alkaloids and pharmaceuticals.

The existence of a large number of biologically active

natural and unnatural polycyclic tetrahydroisoquinoline

We recently reported our initial work towards developing

a BBr₃- or TfOH-promoted imide carbonyl group acti-

vation strategy for the construction of fused isoquinolinone

and β-carboline skeletons from the corresponding imides.^[6]

These studies mainly dealt with the conversion of activated

and some selected N-phenethylphthalimides, -succinimides,

[a] Department of Chemistry, Pondicherry University,

Puducherry, 605014, India

E-mail: crrnath.che@pondiuni.edu.in

http://ww w .pondiuni.edu.in/profile/dr-crramanathan

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201403617.

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Scheme 1. Comparison of the Bischler–Napieralski reaction, the Parham-type cyclization, and the N-acyliminium ion cyclization with

the present method (TfOH = trifluoromethanesulfonic acid, TFA = trifluoroacetic acid, M = metal, LA = Lewis acid, BA = Brønsted

acid).

and -glutarimides into the corresponding fused isoquinol- dihydroxyphenyl)ethyl]phthalimide (1b) furnished the corre-

inones by using BBr₃. Later, the same reaction was success- sponding cyclized product 2b in 82% yield (Table 1, En-

fully carried out with variety of N-phenethylphthalimides try 2). The N-[2-(3-methoxy-4-hydroxyphenyl)ethyl]phthal-

by using TfOH.^[6b]To further justify the versatility of this imide (1c), which is derived from vanillin, underwent the

methodology towards the synthesis of unique fused iso- cyclization in the presence of TfOH followed by quenching

quinoline motifs, we plan to explore the cyclization of N- the reaction with a mild base (equal of NaHCO₃with re-

phenethylphthalimides, N-naphthylethylphthalimides, N- spect to TfOH) to deliver hydroxy lactam 2c in 83% yield.

phenethylsuccinimides, and N-phenethylglutarimides into The presence of the existing acidic phenolic group did not

the corresponding cyclized products. Finally, the efficiency affect the acid-sensitive hydroxy lactam unit (Table 1,

of this methodology is demonstrated by the successful short Entry 3). Upon cyclization, N-[2-(3-methoxyphenyl)ethyl]-

synthesis of alkaloids that contain the tetrahydroisoquin- phthalimide and N-[2-(3,4-dimethoxyphenyl)ethyl]phthal-

oline skeleton such as crispine A, trolline/oleracein E, and imide led to the cyclized compounds, in which the new C–

erythrinarbine.

C bond was established between the imide carbonyl carbon

and the phenyl carbon atom that is para to the methoxy

group, even though the ortho position was available. To di-

rect the cyclization at the ortho position (ortho to the direct-

ing methoxy group), N-[2-(2-bromo-4,5-dimethoxyphenyl)-

Results and Discussion

So far, the methoxy-substituted N-phenethylphthal- ethyl]phthalimide (1d) (with a bromo at the para position

imides and N-[2-(3-indolylethyl)]phthalimide, -succinimide, with respect to the directing methoxy group and thus block-

and -glutarimide derivatives have successfully generated the ing that carbon for cyclization) was prepared. Imide 1d

condensed heterocyclic skeletons under the influence of failed to furnish the cyclized product in presence of TfOH

TfOH. However, there are alkaloids such as trolline/ at room temperature, but under neat conditions at reflux in

oleracein E and erythrinarbine that have phenolic OH the presence of TfOH, 1d delivered the expected ortho-

groups. Hence, we decided to examine the compatibility of cyclized product 2d in 64% yield (Table 1, Entry 4). How-

the phenethyl moiety with a free OH group in this cycliza- ever, the methyl group of the methoxy group at C-4 was

tion reaction. The substrate N-[2-(2-methoxyphenyl)ethyl]- cleaved during the process. To further diversify the struc-

phthalimide failed to deliver the cyclized product upon tural skeletons, we decided to examine the naphthyl group

treatment with TfOH even at an elevated temperature, as the π-nucleophile in this cyclization reaction. Accord-

whereas N-[2-(3,4-dihydroxyphenyl)ethyl]phthalimide fur- ingly, the N-[2-(2-naphthyl)ethyl]phthalimide (1e) was sub-

nished the corresponding cyclized product in presence of jected to the cyclization by using TfOH at room tempera-

TfOH. This observation prompted us to examine the cycli- ture, and the aqueous workup delivered cyclized product 2e

zation reaction of N-[2-(2-hydroxyphenyl)ethyl]phthalimide in 91% yield (Table 1, Entry 5 and Figure 2). Because of

(1a) with TfOH instead of the cyclization of N-[2-(2-meth- steric reasons, cyclization occurred at the C-3 position in-

oxyphenyl)ethyl]phthalimide. Accordingly, imide 1a was stead of more reactive C-1 position of the naphthyl ring.

treated with TfOH at 70 °C under neat conditions, which Also, N-[2-(1-naphthyl)ethyl]phthalimide (1f) smoothly de-

delivered the corresponding cyclized product 2a in 30% livered the steroidal-type skeleton hydroxy lactam 2f in 87%

yield (Table 1, Entry 1). Similarly, the substrate N-[2-(2,5- yield (Table 1, Entry 6; Figure 2).

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Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids

Table 1. Synthesis of isoindoloisoquinolinones and isoindolo- quinoline alkaloids, are known to have various therapeutic

naphthaquinolinones.

uses. The wide substrate scope for the Brønsted acid as-

sisted imide carbonyl activation of N-phenethylphthal-

imides motivated us to exploit this strategy to synthesize

pyrroloisoquinolinones from N-phenethylsuccinimides.

Thus, the synthesis of pyrroloisoquinolinone began by ex-

amining the reaction of N-[2-(3,4-dimethoxyphenyl)ethyl]-

succinimide (3a) with 4 equiv. of TfOH at 0 °C to room

temperature. After 3 h, the generated fused cyclic iminium

ion (monitored by TLC) was reduced in situ by using

NaBH₄/MeOH to deliver tricyclic lactam 4a in 89% yield

(Scheme 2 and Figure 3).

Scheme 2. Cyclization and reduction of imide 3a.

Figure 3. ORTEP diagrams for the compounds 4a, 4b and 4e with

50% probability level.

Encouraged by this result, various methoxy-substituted

N-phenethylsuccinimides 3b–3g were subjected to this

cyclization/reduction sequence to generate pyrroloisoquino-

linone derivatives 4b–4g (Table 2, Entries 1–6). As expected,

all of the imides 3b–3g produced good yields of products

4b–4g. Imide 3e underwent cyclization followed by an in

situ reduction to deliver the alkaloid mescalotam 4e

(Table 2, Entry 4 and Figure 3), which was originally iso-

lated from Lophophora williamsii.^[7]The time required for

[a] (1) imide (0.5 mmol), TfOH (8 equiv.), 70 °C for 48 h;

the conversion of the imide into the fused cyclic iminium

ion depended on the positions of the methoxy groups that

are present in the benzene ring of the phenethyl moiety. For

example, the conversion of N-[2-(3,4-dimethoxyphenyl)-

ethyl]succinimide (3a) and N-[2-(2,3,4-trimethoxyphenyl)-

ethyl]succinimide (3f) into lactams 4a and 4f required 3 and

8 h respectively, whereas N-[2-(3,5-dimethoxyphenyl)ethyl]-

succinimide 3b furnished lactam 4b in 1 h (Figure 3). The

slow reactivities of 3a and 3f may result from the presence

of the 2-methoxy, 4-methoxy, or both groups on the benz-

ene ring of the phenethyl moiety, which would inductively

deactivate the aromatic carbon involved in C–C bond for-

mation. Imide 3g, which contains the benzyloxy and meth-

oxy groups also furnished cyclized product 4g in 46% yield.

The construction of the benzo[a]quinolizinone skeleton

was also realized by using TfOH. Methoxy-substituted

glutarimides 5a–5d smoothly underwent cyclization at 0 °C

(2) NaBH₄(2 mmol)/TFA (1 mL), 15 min. [b] (1) imide (0.5 mmol),

TfOH (6 equiv.), 70 °C for 12 h; (2) NaBH₄(2 mmol)/TFA (1 mL),

15 min. [c] (1) imide (0.5 mmol), TfOH (2 mmol, 4 equiv.), CH₂Cl₂

(15 mL), 0 °C to room temp., 0.5 or 12 h; (2) H₂O, NaHCO₃

(2 mmol). [d] Yield of isolated product.

Figure 2. ORTEP diagrams for compounds 2e and 2f with 50%

probability level.

Synthesis of Pyrroloisoquinolinone and

Benzo[a]quinolizinone Derivatives

Pyrroloisoquinolines and benzo[a]quinolizinones, which followed by an in situ reduction at room temperature to

are fused tricyclic subunits frequently encountered in iso- deliver the benzo[a]quinolizinone derivatives 6a–6d in good

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Table 2. Synthesis of pyrroloisoquinolinone and benzo[a]quinolizinone derivatives.^[a]

[a] Reagents and conditions: (1) imide (0.5 mmol), CH₂Cl₂(15 mL), TfOH (2 mmol), 0 °C to room temp., (2) NaBH₄(2 mmol)/MeOH

(3 mL), 15 min. [b] Yield of isolated product.

yields (Table 2, Entries 7–10). The substrate N-[2-(3,4-di- Table 3. Cyclization of unactivated N-phenethylsuccinimides.^[a]

methoxyphenyl)ethyl]diglycolimide (5e) furnished the ex-

pected cyclized product 6e in 40% yield, and the ether link-

age of the imide was not affected by the reaction conditions.

On the other hand, N-[2-(3,5-dimethoxyphenyl)ethyl]di-

glycolimide (5f) gave tricyclic enamide 6fЈ exclusively in

74% yield. A change in the reduction temperature and the

use of an excess amount of reducing agent did not affect

the yield of the enamide.

To examine the electronic effect of the internal phenyl

nucleophile towards this cyclization process, the N-phen-

ethylsuccinimides that contained a methyl group (i.e., 3h),

were unsubstituted (i.e., 3i), or contained a weakly deacti-

vating bromo group (i.e., 3j) were treated with TfOH.

Imides 3h–3j failed to generate the fused cyclic iminium ion

at 0 °C to room temperature, which proved that the nucleo-

philicity of these internal phenyl nucleophiles was insuf-

ficient to undergo a reaction with the Brønsted acid acti-

vated imide carbonyl group. Instead, upon treatment with

an excess amount of TfOH at an elevated temperature un-

der neat conditions, imides 3h–3j successfully produced

70 °C, (2) CH₂Cl₂(10 mL), NaBH₄(2 mmol), MeOH (2.5 mL),

cyclized products 4h–4j (Table 3). For example, heating the 15 min. [b] Yield of isolated product.

[a] Reagents and conditions: (1) imide (0.5 mmol), TfOH, neat at

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Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids

methyl-substituted N-phenethylsuccinimide 3h with TfOH

(6 equiv.) at 70 °C for 12 h followed by a reduction using

NaBH₄/MeOH produced the expected cyclized product in

79% yield. The unsubstituted and bromo-substituted N-

phenethylsuccinimides 3i and 3j produced cyclized products

4i and 4j in 72 and 76% yield, respectively. However, the

reactions of unsubstituted and bromo-substituted sub-

strates required 8 and 10 equiv. of TfOH, respectively.

To expose the utility of this simple and single step con-

version of N-phenethylimides into fused tetrahydroiso

quinoline motifs by using a Brønsted acid, the synthesis of

alkaloids that contain either the isoindoloisoquinolinone or

the pyrroloisoquinolinone structure, two important classes

of THIQ skeletons, have been successfully performed.

Scheme 3. Synthesis of crispine A and trolline/oleracein E mixture

(THF = tetrahydrofuran).

been reported thus far. Hence, we have employed the

Brønsted acid assisted cyclization of the appropriate suc-

cinimide to synthesize erythrinarbine. First, the required

imide 3k was prepared in four simple steps from vanillin in

85% overall yield. The resulting N-[2-(3-methoxy-4-

hydroxyphenyl)ethyl]succinimide (3k) smoothly underwent

cyclization in the presence of TfOH. The reduction of the

iminium ion intermediate by treatment with NaBH₄/MeOH

delivered the alkaloid (Ϯ)-erythrinarbine (9) in 76% yield

(Scheme 4).

Synthesis of Pyrroloisoquinoline Alkaloids: (؎)-Crispine A,

(؎)-Trolline, and (؎)-Erythrinarbine

Zhao et al. isolated the pyrroloisoquinoline alkaloid (+)-

crispine A along with four other alkaloids from the leaves

of the Chinese folk medicinal plant Carduus crispus, a popu-

lar invasive plant found in Asia and Europe.^[8]This alkaloid

exhibits antitumor activity against SKOV3, KB, and HeLa

human cancer cell lines. As a result of its potent antitumor

activity, twenty nine synthetic strategies have been devel-

oped for the synthesis of racemic and optically pure

crispine A.^[9]

Wang et al. isolated the dihydroxypyrroloisoquinolinone

alkaloid (–)-trolline from the flowers of Trollius chinen-

sis.^[10a]Zhao et al. isolated the same compound from the

flowers of Salsola collina and named it salsoline A.^[10b]

Xiang et al. isolated the (+)-form of the same compound,

named R-(+)-oleracein E, from Portulaca oleracea.^[10c]Oler-

acein E is a strong antioxidant,^[11]and trolline has appreci-

able antibacterial activity and moderate antiviral ac-

tivity.^[10a]To date, there have been five synthetic strategies

reported for the synthesis of racemic and optically pure

trolline/oleracein E.^{[3x,9j,9v,12]}

Scheme 4. Synthesis of (Ϯ)-erythrinarbine.

The spectroscopic data of synthesized erythrinarbine

were in good agreement with those reported of the isolated

compound. The structure of the prepared erythrinarbine

was further confirmed by single-crystal X-ray analysis (Fig-

ure 4).

The structural features of the alkaloids crispine A and

trolline/oleracein E reveal that these molecules can be as-

sembled from the common intermediate 4a. Pyrroloiso-

quinolinone 4a was easily prepared in 89% yield from N-

phenethylsuccinimide 3a by applying the TfOH-mediated

cyclization protocol (Scheme 2). The lithium aluminum

hydride reduction of the 4a smoothly delivered the pyrrolo-

isoquinoline alkaloid (Ϯ)-crispine A in 63% yield, whereas,

under demethylation conditions, precursor 4a gave 1:1 mix-

ture of trolline and oleracein E in 82% yield (Scheme 3).

Yu et al. reported the isolation and structural elucidation

of a new pyrroloisoquinolinone alkaloid (Ϯ)-erythrinarbine

(9) from the stem of Erythrina arborescens, which belongs

to the Erythrina genus of the Papilionaceae family^[13]and is

widely found in the tropical and subtropical regions of the

world as well as in the south and southwest regions of

Figure 4. ORTEP diagram for compound 9 with 50% probability

level.

Regioselective Cyclization of Unsymmetrical

Phenethylphthalimides

After a successful cyclization step, the resulting symmet-

China. As a Chinese folk medicine, the root and stem of rical N-phenylethylphthalimides were produced as one re-

E. arborescens are used to treat rheumatism and dysentery. gioisomeric product. However, the incorporation of substit-

The synthesis of this biologically active molecule has not uents on the phthalimide moiety may potentially lead to

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Table 4. Cyclization of unsymmetrical N-phenethylphthalimides.^[a]

[a] (1) imide (0.5 mmol), TfOH (2 mmol, 4 equiv.), CH₂Cl₂(15 mL), 0 °C to room temp., 30 min, (2) H₂O, NaHCO₃(3 mmol) or NaBH₄

(2 mmol)/TFA (1 mL), 15 min. [b] Yield of isolated product.

two regioisomeric products. For example, the tetramethoxy-

Hence, we initiated our investigation of regioselective cy-

substituted phenethylphthalimide (1g) underwent cycliza- clizations that incorporate electronically complementary

tion regioselectively in the presence of TfOH to deliver the functional groups such as methoxy and nitro groups into

single isomer 2ga in 85% yield (Table 4, Entry 1). However, the phthalimide unit. These substrates were subjected to the

the nuevamine precursor 1h with a methylenedioxy unit on cyclization reaction in the presence of TfOH, and the re-

the nucleophilic aryl portion furnished the two possible sults are reported in Table 4. Imide 1i with one methoxy

regioisomers, nuevamine (2ha) and isonuevamine (2hb), in group on the phthalimide moiety (at the 5-position) dis-

equal ratio at 0 °C. When the same reaction was carried out played a similar regioselectivity to that of imide 1g and

at –78 °C, the quantity of nuevamine 2ha increased relative yielded only 2ia (Table 4, Entry 3; Figure 5). A complemen-

to isonuevamine (2hb, Table 4, Entry 2). This regioselectiv- tary regioselective cyclization was observed when imide 1j

ity difference prompted us to undertake a systematic study was treated with TfOH followed by a reduction using

of the regioselective cyclization of unsymmetrical N-phen- NaBH₄/TFA. The formation of only 2jb may occur because

ethylphthalimides. By examining how functional groups of the steric congestion in the transition state between the

and their positions affect the regioselectivity of the reaction, methoxy group on phenyl ring of phenethyl moiety and the

we could further fine-tune the cyclization conditions for the methoxy group on the phthalimide unit. Phthalimide 1k

selective synthesis of particular regioisomers.

that contained an electron-withdrawing nitro group on the

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Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids

imide portion furnished a mixture of the two regioisomers cally change the geometries. Two model systems, namely,

2ka and 2kb (2ka/2kb, 62:38) in 86% yield (Table 4, En- the nuevamine precursor 2-[2-(1,3-benzodioxol-5-yl)ethyl]-

try 5; Figure 5). Similarly, upon treatment with TfOH, pyr- 4,5-dimethoxy-1H-isoindole-1,3-(2H)dione (1h) and 2-(3,4-

idine imide 1l also delivered the two regioisomers 2la and dimethoxyphenethyl)-4,5-dimethoxyisoindoline-1,3-dione

2lb (Table 4, Entry 6).

(1g) were chosen for the theoretical study.

According to Mulliken atomic charge analysis, the carb-

onyl carbon atom that is proximal to methoxy side of imide

1h has more positive character than the distal carbonyl

carbon (Figure 6). Protonation of carbonyl oxygen atom (at

C-3) that is proximal to the methoxy group is 6.90 kcal/mol

more stable than the protonation of carbonyl oxygen (at C-

1) that is distal to the methoxy group. Because of the prob-

able existence of intramolecular hydrogen bonding between

Figure 5. ORTEP diagrams for the compounds 2ia and 2ka with

50% probability level.

Although imides 1g and 1i structurally differ on the

phthalimide portion, both exhibited the same regioselectiv-

ity. Under TfOH-assisted cyclization, the C–C bond was

established between the phenyl carbon atom and the imide

carbonyl carbon proximal to the methoxy group(s) of the

phthalimide portion. In the case of imide 1j, a positional

isomer of 1g, the phenyl nucleophile approaches the carb-

onyl carbon distal to methoxy group to afford the opposite

regioselectivity. The regioselectivity that was observed with

the cyclizations of imides 1g and 1i (each with a methoxy

group para to the cyclizing carbon atom) reveals that an

electron-donating group (e.g., methoxy) on the phthalimide

unit exclusively favors the nucleophile to approach the carb-

onyl carbon proximal to the methoxy group(s). However, if

there is steric congestion from a substituent, as in the case

of 1j with the methoxy group that was ortho to the position

of cyclization, this will ultimately favor the nucleophile to

approach the steric-free distal imide carbonyl carbon. Com-

paratively, a more reactive nucleophile, such as that with a

methylenedioxy-fused benzene group (i.e., 1h) or that with

an electron-withdrawing group (e.g., the nitro group) pres-

ent in the phthalimide portion, favors the formation of a

mixture of regioisomers with a slight excess amount of the

proximal regioselective product. When the reaction was

conducted below 0 °C, the nucleophile approached the

carbonyl group that was proximal to the methoxy group

on the phthalimide unit, which led to the corresponding

regioisomeric product. Hence, nuevamine was formed as a

major product relative to isonuevamine when the reaction

was carried out at –78 °C.

Figure 6. Mulliken charge distribution of imide 1g and 1h.

To understand the mechanistic reasoning behind this

regioselectivity and the effect of the functional groups dur-

ing cyclization, we carried out computational studies by

using B3LYP/6-31G(d) level of theory, which is commonly

employed for general chemical reactions. Hence, B3LYP/

6-31G(d) geometry optimizations were performed in

Gaussian 09 for the model systems in the gas phase.^[14]Fre-

quency calculations were performed to verify the nature of

all the stationary points as either minima or transition

states and to provide zero-point energy corrections. The

geometries from the gas phase calculations were used di-

Figure 7. Computed geometries and transition states of imide 1g

rectly, as it is assumed that solvation would not dramati- (top) and 1h (bottom).

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the signal of the TMS. Coupling constant (J) values are given in

Hz. The multiplicities of the NMR signals are reported as: s (sing-

let), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet),

dd (doublet of doublet), ddd (doublet of doublet of doublet), dt

(doublet of triplet), td (triplet of doublet), or br. s (broad singlet).

X-ray crystal data were collected on an Oxford Diffraction Xcali-

bur diffractometer with Mo-K_αradiation (λ = 0.71073 Å). The em-

pirical absorption correction by using spherical harmonics, im-

plemented in SCALE3 ABSPACK scaling algorithm, was applied.

The structure solution and refinement were performed with

the protonated carbonyl oxygen and the methoxy group,

the protonation of the carbonyl oxygen (at C-3) proximal

to the methoxy group is favored. Similarly, the protonation

of imide 1g also occurs at the carbonyl oxygen on the meth-

oxy side, which is 6.91 kcal/mol more stable.

The two protonated species 1hH⁺a and 1hH⁺b of imide

1h undergo the intramolecular cyclization through the

chair-like transition states TS1 and TS2, respectively. The

energy difference between TS1 and TS2 is only 0.49 kcal/

mol, and, hence, both regioisomers are formed in equal SHELX-97.^[15]All solvents that were used for the reactions were

distilled according to standard procedures.^[16]Dry dichloromethane

amounts at 0 °C (Figure 7, bottom).

Similarly, the two protonated species 1gH⁺a and 1gH⁺b

of imide 1g also undergo the intramolecular cyclization

was obtained by distillation over calcium hydride. The substituted

phenethylamines were prepared from the corresponding aldehydes

by three simple synthetic steps that involved a nitroaldol condensa-

through chair-like transition states TS1 and TS2, respec-

tion and a reduction of the double bond and nitro group.^[17]

tively. Among these two transition states, TS2 is 4.49 kcal/

mol more stable than TS1. This large energy difference

leads to the regioselective cyclization of 1g to generate only

one regioisomeric product under the same experimental

The reagents TfOH, phenethylamine, and 3,4-dimethoxyphen-

ethylamine from Aldrich were used without further purification.

Column chromatography was performed on Merck silica gel (100–

200 mesh). The developed TLC plates (Merck 60 F₂₅₄precoated

silica plates) were visualized by using phosphomolybdic acid stain,

permanganate stain, and UV light.

conditions (Figure 7, top).

General Procedure for TfOH-Mediated Cyclization at Higher Tem-

perature and Reduction at Room Temperature: An oven-dried two-

neck round-bottom flask that had a septum in the side arm was

cooled to room temperature under a steady stream of nitrogen. The

flask was charged with a stir bar, the substrate (0.5 mmol), and

TfOH. The contents were heated at 70 °C. After the stipulated time,

the contents were warmed to room temperature, and CH₂Cl₂

(10 mL) and NaBH₄(2 mmol) were added followed by TFA

(1 mL). The resulting solution was stirred until the color disap-

peared. (Additional NaBH₄and TFA were used if the color per-

sisted for a long time). The crude mixture was concentrated to dry-

ness under reduced pressure. The solid residue was dissolved in

dichloromethane (20 mL), and the insoluble material was removed

by filtration. The filtrate was dried with anhydrous Na₂SO₄and

filtered. The solvent was evaporated under vacuum, and the crude

product was purified by silica gel column chromatography (ethyl

acetate/hexane, 60:40).

Conclusions

The activation of the imide carbonyl group of the N-

phenethylimides by using TfOH facilitated the intramolec-

ular cyclization with the internal aryl nucleophile to deliver

fused tetrahydroisoquinoline derivatives such as isoindolo-

isoquinolinones, pyrroloisoquinolinones, and benzo[a]quin-

olizinones. The substrate scope of this metal-free protocol

is excellent, and, hence, both activated and unactivated N-

arylethylimides underwent cyclization in the presence of

TfOH. Fused tetrahydroisoquinoline alkaloids such as

nuevamine, crispine A, trolline, and mescalotam were suc-

cessfully synthesized by a short route using the Brønsted

acid assisted imide carbonyl group activation strategy. The

overall yields are comparatively better than those of re-

ported methods. We have also for the first time ac-

complished the total synthesis of the erythrinarbine alka-

loid by using the cyclization/reduction sequence as the key

step. The systematic investigation of the regioselective cycli-

zation of unsymmetrial N-phenethylphthalimides by both

experimental and computational methods was disclosed for

the first time.

4-Hydroxy-5,12b-dihydro-6H-isoindolo[1,2-a]isoquinolin-8-one (2a):

By following the general procedure, imide 1a (133 mg, 0.5 mmol)

furnished the cyclized product 2a (37 mg, 30% yield) as a colorless

1

solid; m.p. 94 °C. IR (KBr): ν = 3328, 1663, 1624, 1510 cm^–1. H

˜

NMR (400 MHz, CDCl₃): δ = 7.88–7.85 (m, 2 H), 7.62–7.58 (m, 1

H), 7.49 (t, J = 7.6 Hz, 1 H), 7.28–7.26 (m, 1 H), 7.16 (t, J =

7.9 Hz, 1 H), 6.72 (d, J = 7.9 Hz, 1 H), 5.69 (s, 1 H), 5.12 (s, 1 H),

4.58 (td, J = 13.0, 4.8 Hz, 1 H), 3.42 (td, J = 13.0, 7.5 Hz, 1 H),

2.91 (dd, J = 7.5, 4.8 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 167.4, 153.54, 144.42, 132.70, 131.56, 128.49, 127.12, 123.85,

123.51, 121.67, 117.77, 113.69, 59.07, 37.47, 22.94 ppm. HRMS

(ESI): calcd. for C₁₆H₁₄NO₂[M + H]⁺252.1025; found 252.1019.

Experimental Section

General Methods: Melting points were measured with an EZ Melt

(Stanford Research Systems, USA). Infrared spectra were recorded

on a Thermo Nicolet 6700 FT-IR spectrophotometer by using

potassium bromide thin films. The IR data are reported in absorp-

tion frequencies (cm^–1). Mass spectra and GC–MS, were recorded

on a Varian GC–MS (CP-3800/Saturn 2200). LDI-MS (LDI =

laser desorption/ionization) were recorded on an ABI Voyager DE-

STR mass spectrometer. HRMS were measured by micromass Q-

TOF (ESI-HRMS). The ¹H and ¹³C NMR spectroscopic data were

recorded with a Bruker AVANCE 400 spectrometer. All NMR

spectra were recorded at room temperature, and either CDCl₃or

[D₆]DMSO was used as the solvent with TMS as an internal stan-

dard. The chemical shifts are expressed in δ (ppm) downfield from

1,4-Dihydroxy-5,12b-dihydro-6H-isoindolo[1,2-a]isoquinolin-8-one

(2b): By following the general procedure, imide 1b (141 mg,

0.5 mmol) furnished the cyclized product 2b (109 mg, 82% yield)

as a colorless solid; m.p. 89 °C (dec). IR (KBr): ν = 3381, 1656,

˜

1

1610, 1528 cm^–1. H NMR (400 MHz, [D₆]DMSO): δ = 9.51 (s, 1

H), 8.81 (s, 1 H), 8.42–8.40 (m, 1 H), 7.69–7.67 (m, 1 H), 7.59–7.55

(m, 1 H), 7.49–7.45 (m, 1 H), 6.64 (d, J = 8.5 Hz, 1 H), 6.56 (d, J

= 8.5 Hz, 1 H), 5.99 (s, 1 H), 4.44–4.40 (m, 1 H), 3.07–3.00 (m, 1

H), 2.80–2.77 (m, 1 H), 2.30–2.25 (m, 1 H) ppm. ¹³C NMR

(100 MHz, [D₆]DMSO): δ = 168.30, 147.56, 147.48, 146.99, 132.09,

131.90, 128.30, 125.99, 122.94, 122.51, 121.90, 113.52, 113.21,

8

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Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids

57.95, 37.89, 24.44 ppm. HRMS (ESI): calcd. for C₁₆H₁₄NO₃[M

+ H]⁺268.0974; found 268.0970.

87% yield) as a colorless solid; m.p. 160 °C (dec). IR (KBr): ν =

˜

3281, 2936, 2830, 1661, 1614, 1435, 1326, 1414, 1116, 1029 cm^–1.

¹H NMR (400 MHz, [D₆]DMSO): δ = 8.27 (d, J = 7.68 Hz, 1 H),

8.21 (d, J = 8.76 Hz, 1 H), 8.00 (d, J = 8.16 Hz, 1 H), 7.91–7.89

(m, 1 H), 7.86 (d, J = 8.76 Hz, 1 H), 7.71–7.66 (m, 2 H), 7.59–7.51

(m, 3 H), 7.20 (s, 1 H), 4.49–4.44 (m, 1 H), 3.61–3.54 (m, 1 H),

3.35–3.29 (m, 1 H), 3.13–3.04 (m, 1 H) ppm. ¹³C NMR (100 MHz,

[D₆]DMSO): δ = 166.04, 148.58, 134.45, 132.47, 132.26, 131.26,

130.56, 130.21, 129.47, 128.21, 126.72, 126.60, 126.37, 125.53,

124.29, 124.01, 122.62, 85.74, 33.81, 25.62 ppm. HRMS (ESI):

calcd. for C₂₀H₁₅NNaO₂[M + Na]⁺324.1000; found 324.1001.

4-Bromo-2-hydroxy-1-methoxy-5,12b-dihydro-6H-isoindolo[1,2-a]-

isoquinolin-8-one (2d): By following the general procedure, imide 1d

(195 mg, 0.5 mmol) furnished the cyclized product 2d (115 mg,

64% yield) as a colorless solid; m.p. 104 °C (dec.). IR (KBr): ν =

˜

3307, 1675, 1594, 1443 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

8.33–8.31 (m, 1 H), 7.85–7.83 (m, 1 H), 7.52–7.48 (m, 1 H), 7.45–

7.42 (m, 1 H), 7.02 (s, 1 H), 6.17 (s, 1 H), 6.07 (s, 1 H), 4.70 (ddd,

J = 13.0, 5.3, 1.3 Hz, 1 H), 3.91 (s, 3 H), 3.08 (td, J = 13.0, 3.2 Hz,

1 H), 2.91–2.87 (m, 1 H), 2.72–2.64 (m, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 169.54, 145.97, 145.26, 142.78, 132.49,

12b-Hydroxy-2,3,11,12-tetramethoxy-5,12b-dihydro-6H-isoindolo-

131.96, 128.45, 127.99, 125.78, 123.31, 122.64, 114.40, 113.81, [1,2-a]isoquinolin-8-one (2ga): By following the general procedure,

57.93, 56.42, 38.53, 30.92 ppm. HRMS (ESI): calcd. for imide 1g (186 mg, 0.5 mmol) furnished the crude product mixture,

C₁₇H₁₅BrNO₃[M + H]⁺360.0235; found 360.0235.

which was purified by silica gel column chromatography (ethyl

acetate/hexane, 60:40) to give the cyclized product 2ga (158 mg,

General Procedure for TfOH-Mediated Cyclization at 0 °C: An

oven-dried two-neck round-bottom flask that had a septum in the

side arm was cooled to room temperature under a steady stream

of nitrogen. The flask was charged with a stir bar, the imide

(0.5 mmol), and dry dichloromethane (15 mL), and the resulting

solution was cooled to 0 °C (by using ice). To this solution was

added TfOH (0.2 mL, 2 mmol) with stirring. After 30 min, the re-

action mixture was quenched with water (10 mL) followed by

NaHCO₃(1 g). The organic layer was separated, and the aqueous

layer was extracted with dichloromethane (2ϫ 15 mL). The com-

bined organic extracts were washed with brine solution, dried with

anhydrous Na₂SO₄, and filtered. The solution was concentrated to

dryness by using a rotary evaporator. The dried compound was

purified by chromatography on a short silica gel column (ethyl acet-

ate/hexane, 50:50).

85% yield) as a colorless solid; m.p. 158–160 °C. IR (KBr): ν =

˜

3241, 2996, 2936, 2836, 1680, 1614, 1494, 1334, 1135, 967 cm^–1. ¹H

NMR (400 MHz, CDCl₃): δ = 8.23 (s, 1 H), 7.48 (d, J = 8.2 Hz, 1

H), 7.03 (d, J = 8.2 Hz, 1 H), 6.5 (s, 1 H), 4.22 (ddd, J = 13.0, 6.1,

2.0 Hz, 1 H), 4.12 (s, 3 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.83 (s, 3

H), 3.66 (s, 1 H), 3.44 (ddd, J = 13.0, 11.8, 4.5 Hz, 1 H), 3.00–2.92

(m, 1 H), 2.70 (ddd, J = 16.0, 4.3, 1.8 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 166.56, 157.24, 148.97, 147.79, 144.67,

140.30, 128.73, 127.09, 124.35, 119.90, 113.46, 112.00, 111.03,

87.90, 61.91, 56.40, 55.97, 55.82, 34.74, 28.71 ppm. HRMS (ESI):

calcd. for C₂₀H₂₁NNaO₆[M + Na]⁺394.1267; found 394.1266.

12b-Hydroxy-2,3,11-trimethoxy-5,12b-dihydro-6H-isoindolo[1,2-a]-

isoquinolin-8-one (2ia): By following the general procedure, imide

1i (170 mg, 0.5 mmol) furnished the cyclized product 2ia (152 mg,

89% yield) as a colorless solid; m.p. 153–154 °C (dec). IR (KBr): ν

˜

2,12b-Dihydroxy-3-methoxy-5,12b-dihydro-6H-isoindolo[1,2-a]iso-

quinolin-8-one (2c): By following the general procedure, imide 1c

(148 mg, 0.5 mmol) furnished the cyclized product 2c (123 mg, 83%

1

= 3302, 2953, 2983, 1670, 1609, 1501, 1358, 1253 cm^–1. H NMR

(400 MHz, CDCl₃): δ = 7.66 (d, J = 8.4 Hz, 1 H), 7.45 (d, J =

2.1 Hz, 1 H), 7.39 (s, 1 H), 6.98 (dd, J = 8.4, 2.1 Hz, 1 H), 6.58 (s,

1 H), 4.29 (ddd, J = 13.2, 5.9, 1.6 Hz, 1 H), 3.95 (s, 3 H), 3.91 (s,

3 H), 3.84 (s, 3 H), 3.45–3.38 (m, 1 H), 2.98–2.89 (m, 1 H), 2.69–

2.65 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.40,

163.46, 150.35, 149.28, 147.90, 127.74, 127.63, 125.00, 123.05,

115.02, 111.41, 110.17, 108.76, 85.91, 56.15, 55.89, 55.77, 35.00,

28.95 ppm. HRMS (ESI): calcd. for C₁₉H₁₉NNaO₅[M + Na]⁺

364.1161; found 364.1155.

yield) as a colorless solid; m.p. 183 °C. IR (KBr): ν = 3294, 2935,

˜

2845, 1653, 1606, 1524, 1426, 1367, 1201, 1108, 1031, 761,

682 cm^–1. ¹H NMR (400 MHz, [D₆]DMSO): δ = 8.96 (s, 1 H), 7.97

(d, J = 7.6 Hz, 1 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.64 (d, J = 7.4 Hz,

1 H), 7.51 (t, J = 7.4 Hz, 1 H), 7.34 (s, 1 H), 6.85 (s, 1 H), 6.66 (s,

1 H), 4.21–4.17 (m, 1 H), 3.71 (s, 3 H), 3.42–3.35 (m, 1 H), 2.77–

2.67 (m, 2 H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ = 165.86,

148.80, 147.50, 144.93, 132.25, 130.34, 129.25, 129.09, 125.04,

123.48, 122.43, 114.47, 111.80, 85.35, 55.50, 34.50, 28.29 ppm. Synthesis of 2ka and 2kb: By following the general procedure, imide

HRMS (ESI): calcd. for C₁₇H₁₄NO₃[M – OH] 280.0968; found

280.0970.

1k (178 mg, 0.5 mmol) furnished the cyclized products 2ka and 2kb

as a mixture (2ka/2kb, 62:38; 153 mg, 86% yield).

14b-Hydroxy-7,8-dihydrobenzo[g]isoindolo[1,2-a]isoquinolin-5-

(14bH)-one (2e): By following the general procedure, imide 1e

(150 mg, 0.5 mmol) furnished the cyclized product 2e (137 mg, 91%

12b-Hydroxy-2,3-dimethoxy-12-nitro-5,12b-dihydro-6H-isoindolo-

[1,2-a]-isoquinolin-8-one (2ka): M.p. 162–163 °C. IR (KBr): ν =

˜

3393, 3074, 3021, 3158, 1672, 1610, 1573, 1512, 1451, 1315, 1301,

1

yield) as a colorless solid; m.p. 196 °C (dec). IR (KBr): ν = 3273,

1255, 1127 cm^–1. H NMR (400 MHz, CDCl₃): δ = 8.40 (dd, J =

˜

2926, 2823, 1674, 1601, 1439, 1318, 1410, 1104, 1025 cm^–1

.

¹H 8.1, 1.0 Hz, 1 H), 8.21 (dd, J = 7.4, 1.0 Hz, 1 H), 7.79 (dd, J = 8.1,

NMR (400 MHz, [D₆]DMSO): δ = 8.46 (s, 1 H), 8.34 (d, J =

7.4 Hz, 1 H), 6.79 (s, 1 H), 6.43 (s, 1 H), 4.83 (s, 1 H), 3.92–3.89

7.7 Hz, 1 H), 8.01–7.99 (m, 1 H), 7.83–7.80 (m, 1 H), 7.77–7.73 (m, (m, 2 H), 3.88 (s, 3 H), 3.68 (s, 3 H), 3.56–3.47 (m, 1 H), 3.0 (dt, J =

2 H), 7.69 (d, J = 7.4 Hz, 1 H), 7.58–7.54 (m, 1 H), 7.51–7.46 (m, 15.2, 5.2 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 163.82,

2 H), 7.14 (s, 1 H), 4.19–4.13 (m, 1 H), 3.62–3.56 (m, 1 H), 3.24– 149.61, 147.00, 145.07, 139.06, 135.46, 131.44, 130.34, 128.94,

3.17 (m, 1 H), 3.09–3.01 (m, 1 H) ppm. ¹³C NMR (100 MHz, [D₆]-

DMSO): δ = 166.00, 148.23, 135.99, 132.69, 132.46, 132.38, 131.62,

127.97, 127.71, 112.25, 108.42, 88.81, 56.04, 37.29, 26.89 ppm.

HRMS (ESI): calcd. for C₁₈H₁₆N₂NaO₆[M + Na]⁺379.0906;

130.64, 129.38, 127.99, 126.94, 126.83, 126.66, 126.62, 125.70, found 379.0897.

124.22, 122.55, 86.32, 35.25, 28.55 ppm. HRMS (ESI): calcd. for

12b-Hydroxy-2,3-dimethoxy-9-nitro-5,12b-dihydro-6H-isoindolo-

C₂₀H₁₅NNaO₂[M + Na]⁺324.1000; found 324.1001.

[1,2-a]isoquinolin-8-one (2kb): M.p. 174–175 °C. IR (KBr): ν =

˜

12b-Hydroxy-5,6-dihydrobenzo[f]isoindolo[1,2-a]isoquinolin-8- 3346, 2989, 2925, 2812, 1667, 1608, 1548, 1483, 1336, 1130 cm^–1.

(12bH)-one (2f): By following the general procedure (but using ethyl

acetate as the extracting solvent instead of dichloromethane), imide

1f (150 mg, 0.5 mmol) furnished the cyclized product 2f (131 mg,

¹H NMR (400 MHz, CDCl₃): δ = 8.22 (dd, J = 5.7, 2.8 Hz, 1 H),

7.78–7.68 (m, 2 H), 7.35 (s, 1 H), 6.61 (s, 1 H), 4.45 (ddd, J = 13.1,

5.9, 1.4 Hz, 1 H), 3.95 (s, 3 H), 3.85 (s, 3 H), 3.53–3.46 (m, 1 H),

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C. R. Ramanathan et al.

FULL PAPER

3.25 (s, 1 H), 3.06–2.98 (m, 1 H), 2.73 (dd, J = 16.3, 2.8 Hz, 1

0.8 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.03 (s, 1 H), 6.64 (s, 1 H),

5.95 (d, J = 1.4 Hz, 1 H), 5.88 (d, J = 1.4 Hz, 1 H), 5.45 (s, 1 H),

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 161.86, 150.24, 149.82,

148.16, 146.10, 133.35, 127.99, 126.76, 126.27, 124.06, 122.55, 4.34–4.28 (m, 1 H), 4.06 (s, 3 H), 3.89 (s, 3 H), 3.42–3.35 (m, 1 H),

111.59, 110.05, 85.44, 56.29, 55.95, 35.43, 28.79 ppm. HRMS

(ESI): calcd. for C₁₈H₁₆N₂NaO₆[M + Na]⁺379.0906; found

379.0901.

3.01–2.93 (m, 1 H), 2.75 (dt, J = 15.7, 4.7 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 166.16, 152.79, 147.33, 146.78, 146.51,

137.67, 128.32, 127.88, 125.05, 118.42, 116.24, 109.06, 105.49,

101.08, 62.54, 68.01, 56.74, 38.29, 29.29 ppm.

Synthesis of 2la and 2lb: By following the general procedure above,

imide 1l (156 mg, 0.5 mmol) furnished the cyclized products 2la

and 2lb.

8,9-Dimethoxy-5,11b-dihydro-6H-1,3-dioxa-6a-aza-indeno[5,6-c]-

fluoren-7-one (2hb): M.p. 210–212 °C (dec); ref.^[19]m.p. 212 °C. IR

(KBr): ν = 2972, 2922, 2887, 2868, 1682, 1620, 1495, 1481, 1409,

˜

12b-Hydroxy-2,3-dimethoxy-5,6-dihydropyrido[2Ј,3Ј:3,4]-pyrrolo-

[2,1-a]isoquinolin-8(12bH)-one (2la): (75 mg, 48% yield), m.p. 173–

1269, 1078, 1034, 924 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.58

(d, J = 8.2 Hz, 1 H), 7.31 (s, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 6.66

(s, 1 H), 5.92 (d, J = 1.3 Hz, 1 H), 5.86 (d, J = 1.3 Hz, 1 H), 5.63

(s, 1 H), 4.07–4.01 (m, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H), 3.59–3.53

(m, 1 H), 3.05–2.98 (m, 1 H), 2.89–2.82 (m, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 167.62, 155.48, 146.77, 146.43, 144.34,

136.14, 128.81, 128.40, 126.64, 119.76, 113.21, 108.43, 107.52,

100.95, 60.52, 58.37, 56.29, 38.78, 28.91 ppm.

174 °C. IR (KBr): ν = 3338, 2953, 2838, 1702, 1674, 1517, 1412,

˜

1259, 1226, 1119, 1058 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

8.59 (dt, J = 6.2, 2.8, 1.4 Hz, 1 H), 8.31 (dd, J = 7.8, 1.4 Hz, 1H),

7.44–7.47 (m, 1 H), 7.30 (s, 1 H), 4.67 (s, 1 H), 4.35–4.30 (m, 1 H),

3.93 (s, 3 H), 3.83 (s, 3 H) 3.53 (td, J = 16.8, 4.6, 3.9 Hz, 1 H),

2.75–2.71 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 165.1,

151.4, 149.5, 148.6, 148.6, 148.0, 142.3, 131.4, 127.5, 126.7, 126.1,

111.5, 110.1, 84.5, 56.2, 55.9, 34.8, 29.0 ppm. HRMS (ESI): calcd.

for C₁₇H₁₆N₂NaO₄[M + Na]⁺335.1008; 335.1001.

1,3,11,12-Tetramethoxy-5,12b-dihydro-6H-isoindolo[1,2-a]isoquin-

olin-8-one (2jb): By following the general procedure, imide 1j

(185 mg, 0.5 mmol) furnished the cyclized product 2jb (147 mg,

12b-Hydroxy-2,3-dimethoxy-5,6-dihydropyrido[3Ј,2Ј:3,4]-pyrrolo-

[2,1-a]isoquinolin-8(12bH)-one (2lb): (72 mg, 46% yield), m.p. 128–

83% yield) as a colorless solid; m.p. 146–147 °C. IR (KBr): ν =

˜

3342, 2987, 2921, 2858, 1667, 1601, 1498, 1362, 1154 cm^{–1 1}H

.

130 °C. IR (KBr): ν = 3309, 3003, 2937, 2836, 1712, 1686, 1591,

˜

NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 8.4 Hz, 1 H), 7.04 (d,

J = 8.4 Hz, 1 H), 6.41 (s, 1 H), 6.24 (s, 1 H), 5.82 (s, 1 H), 4.63

(dd, J = 12.0, 4.7 Hz, 1 H), 4.04 (s, 3 H), 3.97 (s, 3 H), 3.85 (s, 3

H), 3.75 (s, 1 H), 3.01 (t, J = 12.0 Hz, 1 H), 2.94–2.85 (m, 1 H),

2.58 (d, J = 15.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 167.92, 159.55, 158.28, 152.43, 146.86, 140.58, 137.86, 125.11,

120.42, 116.91, 116.14, 105.42, 97.31, 62.47, 57.07, 56.86, 55.49,

55.15, 38.76, 31.25 ppm. HRMS (ESI): calcd. for C₂₀H₂₂NO₅[M

+ H]⁺356.1498; found 356.1492.

1510, 1434, 1406, 1323, 1261, 1136, 1029 cm^–^{1 1}H NMR

.

(400 MHz, CDCl₃): δ = 8.78 (dd, J = 4.9, 1.6 Hz, 1 H), 8.03 (dd,

J = 7.6, 1.5 Hz, 1 H), 7.98 (s, 1 H), 7.40 (dd, J = 7.6, 4.9 Hz, 1 H),

4.47 (ddd, J = 13.2, 6.3, 1.4 Hz, 1 H), 3.94 (s, 3 H), 3.84 (s, 3 H)

3.60–3.52 (m, 1H), 3.04–2.96 (m, 1 H), 2.78 (dd, J = 16.3, 3.3 Hz,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 165.6, 164.8, 152.9,

149.5, 147.9, 131.8, 127.0, 126.0, 124.5, 124.3, 111.0, 84.7, 56.1,

55.9, 34.3, 28.6 ppm. HRMS (ESI): calcd. for C₁₇H₁₆N₂NaO₄[M

+ Na]⁺335.1008; found 335.1012.

General Procedure for TfOH-Assisted Cyclization (0 °C to Room

Temperature) and Reduction (at Room Temperature) by Using

NaBH₄/MeOH System – Synthesis of Pyrroloisoquinolinones,

Benzoquinolizinones, and Oxa-benzoquinolizinone: An oven-dried

two-neck round-bottomed flask that had septum in the side arm

was cooled to room temperature under a steady stream of nitrogen.

The flask was charged with a stir bar, the imide (0.5 mmol), and dry

dichloromethane (15 mL), and the resulting solution was cooled to

0 °C. To this solution was added TfOH (0.2 mL, 2 mmol) with stir-

ring. After the stipulated time, the contents were warmed to room

temperature, and NaBH₄(2 mmol) was added followed by meth-

anol (2.5 mL). The solution was stirred until the color disappeared.

(Additional NaBH₄and MeOH were used if the color persisted for

a long time). To this mixture was added acetone, and the solution

was evaporated to dryness under reduced pressure. The solid resi-

due was dissolved in dichloromethane (20 mL), and the insoluble

material was removed by filtration. The filtrate was dried with an-

hydrous Na₂SO₄and filtered. The solvent was evaporated under

vacuum, and the crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 50:50).

General Procedure for TfOH-Mediated Cyclization at 0 °C and Re-

duction at Room Temperature: An oven-dried two-neck round-bot-

tom flask that had septum in the side arm was cooled to room

temperature under a steady stream of nitrogen. The flask was

charged with a stir bar, the imide (0.5 mmol), and dry dichloro-

methane (15 mL), and the resulting solution was cooled to 0 °C.

To this solution was added TfOH (0.2 mL, 2 mmol) with stirring.

After the stipulated time, the contents were warmed to room tem-

perature, and NaBH₄(2 mmol) was added followed by TFA

(1 mL). The resulting solution was stirred until the color disap-

peared. (Additional NaBH₄and TFA were used if the color per-

sisted for a long time). The reaction mixture was evaporated to

dryness under reduced pressure. The solid residue was dissolved in

dichloromethane (20 mL), and the insoluble material was removed

by filtration. The filtrate was dried with anhydrous Na₂SO₄and

filtered. The solvent was evaporated under vacuum, and the crude

product was purified by silica gel column chromatography (ethyl

acetate/hexane, 50:50).

Synthesis of Nuevamine (2ha) and Isonuevamine (2hb): By following

the general procedure, imide 1h (71 mg, 0.2 mmol) with TfOH

(0.1 mL, 1 mmol) furnished the cyclized products 2ha and 2hb as a

mixture. The procedure was carried out at two temperatures: (1) at

0 °C for 30 min to deliver the cyclized products 2ha and 2hb (59 mg,

86% yield) and (2) at –78 °C for 36 h to deliver the cyclized prod-

ucts 2ha and 2hb (63 mg, 92% yield).

8,9-Dimethoxy-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-

one (4a): By following the general procedure, imide 3a (131 mg,

0.5 mmol) furnished the cyclized product 4a (110 mg, 89% yield)

as a colorless solid, m.p. 106–108 °C; ref.^[20]m.p. 97–99 °C. IR

(KBr): ν = 2934, 2835, 1708, 1609, 1519, 1420, 1250, 1115, 1006,

˜

862, 764 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.61 (s, 1 H), 6.57

(s, 1 H), 4.72 (t, J = 8.0 Hz, 1 H), 4.32 (ddd, J = 12.7, 6.0, 2.0 Hz,

1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.05–2.98 (m, 1 H), 2.93–2.85

10,11-Dimethoxy-5,11b-dihydro-6H-1,3-dioxa-6a-aza-indeno[5,6-c]-

fluoren-7-one (2ha): M.p. 190–192; ref.^[18]m.p. 194–196 °C. IR

(KBr): ν = 2970, 2940, 2841, 1688, 1620, 1446, 1408, 1273, 1220, (m, 1 H), 2.70–2.44 (m, 4 H), 1.89–1.81 (m, 1 H) ppm. ¹³C NMR

˜

1035 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.42 (dd, J = 8.2,

(100 MHz, CDCl₃): δ = 173.14, 148.19, 148.01, 129.40, 125.61,

10

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Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids

111.79, 107.76, 56.57, 56.09, 55.94, 37.07, 31.77, 28.09, 27.76 ppm.

56.43, 56.25, 36.81, 31.91, 27.72, 22.39 ppm. HRMS (ESI): calcd.

for C₁₅H₁₉NNaO₄[M + Na]⁺300.1212; found 300.1210.

8,10-Dimethoxy-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3-

(10bH)-one (4b): By following the general procedure, imide 3b

(131 mg, 0.5 mmol) furnished the cyclized product 4b (107 mg,

8-Benzyloxy-9-methoxy-1,2,5,6-tetrahydropyrrolo[2,1-a]-isoquinolin-

3(10bH)-one (4g): By following the general procedure, imide 3g

(170 mg, 0.5 mmol) furnished the crude product mixture, which

was purified by silica gel column chromatography (ethyl acetate/

hexane, 40:60) to give the cyclized product 4g (74 mg, 46% yield)

87% yield) as a colorless solid; m.p. 121–122 °C. IR (KBr): ν =

˜

2974, 1689, 1586, 1442 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

6.33 (d, J = 2.4 Hz, 1 H), 6.24 (d, J = 2.4 Hz, 1 H), 4.75–4.71 (m,

1 H), 4.40–4.35 (m, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 2.87–2.78 (m,

3 H), 2.66–2.62 (m, 1 H), 2.53–2.47 (m, 1 H), 2.40–2.33 (m, 1 H),

1.69–1.60 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.49,

159.28, 157.70, 135.81, 118.60, 104.65, 96.93, 55.33, 55.21, 54.93,

36.63, 31.69, 29.70, 28.11 ppm. MS (LDI): calcd. for C₁₄H₁₇NO₃

[M + H]⁺248.1287; found 248.1300.

as a colorless solid; m.p. 185–187 °C. IR (KBr): ν = 2925, 2843,

˜

1678, 1491, 1442, 1363, 1318, 1277, 1238, 1188, 1154, 1122, 1076,

943, 735, 698 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.25–7.23

(m, 2 H), 7.18–7.15 (m, 1 H), 7.09–7.07 (m, 2 H), 6.58 (s, 1 H),

5.66 (s, 1 H), 4.79–4.75 (m, 1 H), 4.39–4.34 (m, 1 H), 4.11 (s, 2 H),

3.89 (s, 3 H), 2.90–2.85 (m, 1 H), 2.82–2.75 (m, 1 H), 2.64–2.60 (m,

1 H), 2.52–2.41 (m, 2 H), 2.36–2.28 (m, 1 H), 1.56–1.51 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.18, 145.07, 143.23,

139.65, 128.79, 128.39, 127.70, 125.93, 125.52, 122.47, 109.93,

56.52, 55.93, 37.04, 31.76, 31.53, 30.12, 29.33 ppm. HRMS (ESI):

calcd. for C₂₀H₂₁NNaO₃[M + Na]⁺346.1419; found 346.1422.

8-Methoxy-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-one

(4c): By following the general procedure, imide 3c (116 mg,

0.5 mmol) furnished the cyclized product 4c (97 mg, 89% yield) as

a colorless semisolid that changed to a pale yellow color; m.p. 121–

122 °C. IR (KBr): ν = 2933, 1682, 1611, 1502, 1449 cm^–1. ¹H NMR

˜

9,11-Dimethoxy-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]-isoquinolin-4-

(11bH)-one (6a): By following the general procedure, imide 5a

(139 mg, 0.5 mmol) furnished the cyclized product 6a (110 mg,

(400 MHz, CDCl₃): δ = 7.03 (d, J = 8.4 Hz, 1 H), 6.80 (dd, J =

8.4, 2.8 Hz, 1 H), 6.67 (d, J = 2.8 Hz, 1 H), 4.73 (t, J = 8.0 Hz, 1

H), 4.25 (ddd, J = 12.8, 6.0, 2.8 Hz, 1 H), 3.79 (s, 3 H), 3.09–3.02

(m, 1 H), 2.98–2.88 (m, 1 H), 2.77–2.72 (m, 1 H), 2.67–2.60 (m, 1

H), 2.59–2.52 (m, 1 H), 2.48–2.42 (m, 1 H), 1.88–1.79 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.51, 158.32, 134.88,

129.75, 125.86, 113.61, 113.17, 56.51, 55.30, 37.05, 31.78, 28.81,

27.66 ppm. MS (LDI): calcd. for C₁₃H₁₅NO₂[M + H]⁺218.1181;

found 218.1183.

84% yield) as a colorless solid; m.p. 124 °C. IR (KBr): ν = 2944,

˜

1

1629, 1454, 1343 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.27 (d,

J = 2.4 Hz, 1 H), 6.20 (d, J = 2.0 Hz, 1 H), 4.86 (ddd, J = 12.0,

4.4, 1.6 Hz, 1 H), 4.62 (dd, J = 10.8, 2.8 Hz, 1 H), 3.73 (s, 3 H),

3.71 (s, 3 H), 2.80–2.72 (m, 1 H), 2.68–2.62 (m, 1 H), 2.56–2.45 (m,

3 H), 2.40–2.33 (m, 1 H), 1.80–1.74 (m, 2 H), 1.21–1.18 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.25, 159.03, 157.48,

137.99, 117.95, 104.54, 97.08, 55.31, 55.20, 54.23, 38.55, 31.80,

30.43, 29.71, 19.52 ppm. MS (LDI): calcd. for C₁₅H₁₉NO₃[M +

H]⁺262.1443; found 262.1430.

7,8-Dimethoxy-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-

one (4d): By following the general procedure, imide 3d (131 mg,

0.5 mmol) furnished the cyclized product 4d (80 mg, 65% yield) as

a colorless solid; m.p. 121–122 °C. IR (KBr): ν = 2941, 2836, 1690,

˜

9-Methoxy-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-

one (6b): By following the general procedure, imide 5b (123 mg,

0.5 mmol) furnished the cyclized product 6b (94 mg, 82% yield) as

1605, 1493, 1461, 1427, 1365, 1275, 1222, 1092, 1065, 1008,

1

811 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.84 (s, 1 H), 6.83 (s,

1 H), 4.71 (t, J = 7.9 Hz, 1 H), 4.30–4.25 (m, 1 H), 3.86 (s, 3 H),

3.80 (s, 3 H), 3.06–2.94 (m, 2 H), 2.80–2.74 (m, 1 H), 2.65–2.60 (m,

1 H), 2.58–2.52 (m, 1 H), 2.49–2.42 (m, 1 H), 1.89–1.79 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.21, 151.25, 146.49,

130.91, 128.28, 120.19, 111.12, 60.24, 56.31, 55.89, 36.67, 31.83,

27.69, 22.67 ppm. HRMS (ESI): calcd. for C₁₄H₁₇NNaO₃[M +

Na]⁺270.1106; found 270.1107.

a colorless semisolid. IR (KBr): ν = 1685, 1609, 1461 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃): δ = 7.10 (d, J = 8.8 Hz, 1 H), 6.78 (dd,

J = 8.8, 2.8 Hz, 1 H), 6.66 (d, J = 2.8 Hz, 1 H), 4.79–4.75 (m, 1

H), 4.61 (dd, J = 10.4, 4.8 Hz, 1 H), 3.81 (s, 3 H), 2.99–2.86 (m, 2

H), 2.73–2.69 (m, 1 H), 2.58–2.48 (m, 2 H), 2.41–2.32 (m, 1 H),

1.86–1.82 (m, 2 H), 1.73–1.63 (m, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 169.61, 158.17, 136.42, 129.56, 125.96, 113.39, 112.79,

56.52, 55.27, 39.77, 32.18, 30.56, 29.16, 19.51 ppm. MS (LDI):

calcd. for C₁₄H₁₇NO₂[M + H]⁺232.1338; found 232.1354.

8,9,10-Trimethoxy-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3-

(10bH)-one (4e): By following the general procedure, imide 3e

(146 mg, 0.5 mmol) furnished the cyclized product 4e (112 mg, 81%

9,10-Dimethoxy-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-

4(11bH)-one (6c): By following the general procedure, imide 5c

(139 mg, 0.5 mmol) furnished the cyclized product 6c (113 mg, 87%

yield) as a colorless solid, m.p. 80–81 °C; ref.^[20]m.p. 88–89 °C. IR

yield) as a colorless solid;^[3g]m.p. 71–72 °C. IR (KBr): ν = 2938,

˜

2838, 2361, 1689, 1602, 1494, 1459, 1417, 1355, 1313, 1276, 1121,

1

1096, 1039, 858 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.40 (s, 1

H), 4.78–4.74 (m, 1 H), 4.41–4.32 (m, 1 H), 3.93 (s, 3 H), 3.83 (s,

6 H), 2.88–2.80 (m, 3 H), 2.67–2.51 (m, 2 H), 2.41 (dd, J = 16.6,

9.5 Hz, 1 H), 1.75–1.65 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 173.42, 152.47, 150.68, 140.44, 129.38, 123.14, 107.44,

60.75, 60.47, 55.96, 55.04, 36.72, 31.74, 29.21, 28.51 ppm.

(KBr): ν = 2943, 2838, 1683, 1619, 1516, 1459, 1358, 1268, 1220,

˜

1024, 869 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.67 (s, 1 H),

6.62 (s, 1 H), 4.87 (ddd, J = 11.9, 4.3, 2.0 Hz, 1 H), 4.61 (dd, J =

10.6, 4.5 Hz, 1 H), 3.86 (s, 6 H), 2.94–2.77 (m, 2 H), 2.65–2.51 (m,

3 H), 2.42–2.33 (m, 1 H), 1.98–1.80 (m, 2 H), 1.72–1.62 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 169.61, 147.91, 147.79,

129.17, 127.34, 111.63, 108.32, 56.83, 56.21, 55.99, 39.83, 32.24,

31.02, 28.57, 19.65 ppm.

7,8,9-Trimethoxy-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3-

(10bH)-one (4f): By following the general procedure, imide 3f

(146 mg, 0.5 mmol) furnished the cyclized product 4f (101 mg, 73%

yield) as a colorless solid; m.p. 80–81 °C. IR (KBr): ν = 2944, 2831,

8,9-Dimethoxy-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4-

˜

1

1686, 1602, 1458, 1364, 1310, 1268, 1106, 1026, 836, 639 cm^–1. H (11bH)-one (6d): By following the general procedure, imide 5d

NMR (400 MHz, CDCl₃): δ = 6.39 (s, 1 H), 4.70 (t, J = 8.0 Hz, 1 (139 mg, 0.5 mmol) furnished the cyclized product 6d (108 mg,

H), 4.32 (ddd, J = 13.2, 6.4, 2.0 Hz, 1 H), 3.86 (s, 6 H), 3.85 (s, 3

H), 2.98–2.83 (m, 2 H), 2.69–2.44 (m, 4 H), 1.90–1.80 (m, 1 2833, 1693, 1493, 1464, 1417, 1331, 1276, 1223, 1080, 1046, 1003,

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.11, 152.65, 151.37, 861, 634 cm^{–1 1}H NMR (400 MHz, CDCl₃): δ = 6.91 (d, J =

141.09, 133.14, 120.25, 103.68, 60.99, 60.71, 60.39, 56.71, 56.63, 8.6 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 4.84–4.80 (m, 1 H), 4.60

83% yield) as a colorless solid; m.p. 95–96 °C. IR (KBr): ν = 2952,

˜

.

Eur. J. Org. Chem. 0000, 0–0

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C. R. Ramanathan et al.

FULL PAPER

(dd, J = 10.4, 4.7 Hz, 1 H), 3.85 (s, 3 H), 3.79 (s, 3 H), 2.92–2.73

173.42, 136.69, 134.75, 133.56, 129.76, 127.75, 124.83, 56.80, 37.23,

31.95, 28.64, 27.75, 21.16 ppm. HRMS (ESI): calcd. for

(m, 3 H), 2.56–2.48 (m, 2 H), 2.39–2.30 (m, 1 H), 1.97–1.77 (m, 2

H), 1.73–1.63 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = C₁₃H₁₅NNaO [M + Na]⁺224.1051; found 224.1049.

169.44, 151.11, 146.30, 130.88, 129.83, 120.42, 110.73, 60.41, 56.51,

1,2,5,6-Tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-one (4i): By fol-

55.95, 39.54, 32.40, 30.77, 23.15, 19.71 ppm. HRMS (ESI): calcd.

lowing the general procedure, imide 3i (101 mg, 0.5 mmol) fur-

for C₁₅H₁₉NNaO₃[M + Na]⁺284.1263; found 284.1261.

nished the cyclized product 4i (67 mg, 72% yield) as a colorless

9,10-Dimethoxy-1,6,7,11b-tetrahydro-[1,4]oxazino[3,4-a]isoquinolin- semisolid.^[3k]IR (KBr): ν = 2978, 2921, 2851, 1687, 1421, 1360,

˜

4(3H)-one (6e): By following the general procedure, imide 5e

(140 mg, 0.5 mmol) furnished the crude product mixture, which

was purified by silica gel column chromatography (ethyl acetate/

1307, 1266, 1168, 755 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.24–

7.18 (m, 2 H), 7.15–7.11 (m, 2 H), 4.78 (t, J = 8.0 Hz, 1 H), 4.27

(ddd, J = 12.8, 6.0, 2.8 Hz, 1 H), 3.11–3.04 (m, 1 H), 2.99–2.91 (m,

hexane, 30:70) to give the cyclized product 6e (53 mg, 40% yield) 1 H), 2.81–2.75 (m, 1 H), 2.71–2.63 (m, 1 H), 2.60–2.54 (m, 1 H),

as a colorless solid; m.p. 120–122 °C. IR (KBr): ν = 3002, 2960,

2.50–2.43 (m, 1 H), 1.93–1.83 (m, 1 H) ppm. ¹³C NMR (100 MHz,

˜

2857, 2831, 1741, 1688, 1591, 1517, 1389, 1347, 1272, 1234, 1177,

CDCl₃): δ = 173.22, 137.54, 133.58, 129.11, 126.88, 126.80, 124.80,

1025, 967 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.65 (s, 1 H), 56.76, 37.04, 31.77, 28.53, 27.49 ppm.

6.53 (s, 1 H), 4.93–4.88 (m, 2 H), 4.42 (dd, J = 8.0, 4.8 Hz, 1 H),

8-Bromo-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-one

(4j): By following the general procedure, imide 3j (141 mg,

0.5 mmol) furnished the cyclized product 4j (101 mg, 76% yield) as

4.36 (d, J = 16.4 Hz, 1 H), 4.17 (d, J = 16.4 Hz, 1 H), 3.87 (s, 3

H), 3.86 (s, 3 H), 3.53–3.47 (m, 1 H), 2.96–2.88 (m, 1 H), 2.80 (td,

J = 12.0, 3.2 Hz, 1 H), 2.66 (d, J = 16.0 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 166.06, 148.31, 147.94, 127.27, 123.20,

112.04, 107.74, 69.85, 67.98, 56.13, 55.90, 54.70, 38.05, 28.33 ppm.

HRMS (ESI): calcd. for C₁₄H₁₇NO₄[M + H]⁺264.1236; found

264.1235.

a colorless solid; m.p. 91–92 °C. IR (KBr): ν = 2934, 2839, 1692,

˜

1426, 1309, 1171, 1076, 1022, 964, 817, 654 cm^–1. ¹H NMR

(400 MHz, CDCl₃): δ = 7.36 (d, J = 8.2 Hz, 1 H), 7.30 (s, 1 H),

6.99 (d, J = 8.2 Hz, 1 H), 4.70 (t, J = 7.8 Hz, 1 H), 4.29–4.24 (m,

1 H), 3.03 (td, J = 11.6, 4.0 Hz, 1 H), 2.95–2.87 (m, 1 H), 2.77–

2.62 (m, 2 H), 2.59–2.42 (m, 2 H), 1.83–1.78 (m, 1 H) ppm. ¹³C

9,11-Dimethoxy-6,7-dihydro-[1,4]oxazino[3,4-a]isoquinolin-4(3H)-

one (6fЈ): By following the general procedure, imide 5f (140 mg, NMR (100 MHz, CDCl₃): δ = 173.16, 136.53, 135.89, 131.93,

0.5 mmol) furnished the cyclized product 6fЈ (97 mg, 74% yield) as

129.97, 126.55, 120.63, 56.44, 36.71, 31.68, 28.35, 27.42 ppm.

HRMS (ESI): calcd. for C₁₂H₁₂NOBrNa [M + Na]⁺288.0000;

found 288.0000.

a colorless solid; m.p. 121–123 °C. IR (KBr): ν = 2998, 2945, 2900,

˜

2835, 1674, 1592, 1474, 1412, 1310, 1208, 1155, 1106, 971, 832,

734, 644 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.33 (s, 1 H), 6.40

(s, 1 H), 6.32 (s, 1 H), 4.46 (s, 2 H), 3.83–3.81 (m, 8 H), 2.83 (t, J

= 6.0 Hz, 2 H) ppm. ¹³C NMR(100 MHz, CDCl₃): δ = 163.23,

159.10, 157.36, 136.66, 131.98, 116.41, 109.67, 104.91, 97.79, 67.20,

55.61, 55.50, 37.66, 30.25 ppm. HRMS (ESI): calcd. for

C₁₄H₁₅NNaO₄[M + Na]⁺284.0899; found 284.0899.

Synthesis of (؎)-Crispine A (7): An oven-dried two-neck round-

bottom flask that had a septum in the side arm was cooled to

room temperature under a steady stream of nitrogen. The flask was

charged with a stir bar, LiAlH₄(4 mmol), and dry THF (10 mL),

and the resulting mixture was cooled to 0 °C. To this mixture was

added a solution of 4a (124 mg, 0.5 mmol) in dry THF (10 mL)

with stirring. The contents were heated at 60 °C for 6 h and cooled

General Procedure for TfOH-Assisted Cyclization at Elevated Tem-

perature (70 °C) and Reduction (at Room Temperature) by Using to room temperature, and then diethyl ether (20 mL) was added.

NaBH₄/MeOH System: An oven-dried two-neck round-bottom

flask that had a septum in the side arm was cooled to room tem-

perature under a steady stream of nitrogen. The flask was charged

with a stir bar, the substrate (0.5 mmol), and TfOH (for equiva-

lents, see Table 3), and the resulting mixture was stirred and heated

at 70 °C. After the stipulated time, the contents were cooled to

room temperature under nitrogen, and dry CH₂Cl₂(10 mL) was

added followed by the addition of NaBH₄(2 mmol) and methanol

(2.5 mL). The solution was stirred until the color disappeared. (Ad-

ditional NaBH₄and MeOH were used if the color persisted for a

long time). To this mixture was added acetone, and the solution

was concentrated to dryness under reduced pressure. The solid resi-

due was dissolved in dichloromethane (20 mL), and the insoluble

material was removed by filtration. The filtrate was dried with an-

hydrous Na₂SO₄and filtered. The solvent was evaporated under

vacuum, and the crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 50:50).

The reaction was quenched by the careful addition of saturated

sodium potassium tartrate. The mixture was stirred for an ad-

ditional 1 h followed by the addition of anhydrous MgSO₄. The

mixture was filtered through a pad of Celite. The filtrate was evapo-

rated under reduced pressure, and the resultant crude material was

purified by chromatography on a silica gel column (chloroform/

methanol, 95:5) to afford crispine A [8,9-dimethoxy-1,2,3,5,6,10b-

hexahydropyrrolo[2,1-a]isoquinoline (7), 74 mg, 63% yield] as a

colorless solid, m.p. 85–86 °C; ref.^[8]m.p. 87–89 °C. IR (KBr): ν =

˜

2934, 2835, 1708, 1609, 1519, 1420, 1250, 1115, 1006, 862,

1

764 cm^–1. H NMR (400 MHz, CDCl₃): δ = 6.60 (s, 1 H), 6.56 (s,

1 H), 3.845 (s, 3 H), 3.842 (s, 3 H), 3.46 (t, J = 8.4 Hz, 1 H), 3.17

(ddd, J = 10.8, 5.6, 2.8 Hz, 1 H), 3.09–2.97 (m, 2 H), 2.76–2.56 (m,

3 H), 2.36–2.28 (m, 1 H), 1.97–1.86 (m, 2 H), 1.77–1.67 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 147.41, 147.31, 130.70,

126.14, 111.36, 108.91, 62.83, 56.02, 55.91, 53.12, 48.26, 30.59,

27.90, 22.26 ppm.

8-Methyl-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-one Synthesis of Mixture of Trolline/Oleracein E (8): To a solution of

(4h): By following the general procedure, imide 3h (108 mg,

0.5 mmol) furnished the cyclized product 4h (79 mg, 79% yield) as

4a (123 mg, 0.5 mmol) in dichloromethane (15 mL) was added

BBr₃(1 m in dichloromethane, 2 mL, 2.0 mmol) at –20 °C. After

stirring for 5 h at –20 °C, the reaction mixture was quenched with

a colorless semisolid. IR (KBr): ν = 2930, 2847, 1682, 1429, 1364,

˜

1

1307, 1171, 1035, 810, 659 cm^–1. H NMR (400 MHz, CDCl₃): δ = MeOH (5.0 mL), and the solvent was evaporated under the reduced

7.05 (d, J = 7.9 Hz, 1 H), 7.01 (d, J = 7.9 Hz, 1 H), 6.96 (s, 1 H),

pressure. The MeOH addition and evaporation process was re-

4.74 (t, J = 7.9 Hz, 1 H), 4.25 (ddd, J = 12.8, 6.0, 2.6 Hz, 1 H), peated (5ϫ).^[3h]The residue was washed with a small portion of

3.09–3.01 (m, 1 H), 2.94–2.86 (m, 1 H), 2.76–2.70 (m, 1 H), 2.68–

2.61 (m, 1 H), 2.59–2.52 (m, 1 H), 2.48–2.42 (m, 1 H), 2.31 (s, 3

MeOH (1 mL) to give a mixture of trolline and oleracein E [8,9-

dihydroxy-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-one

H), 1.89–1.79 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = (8), 90 mg, 82% yield] as a colorless solid, m.p. 253–254 °C; ref.^[3h]

12

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Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids

m.p. 252 °C. IR (KBr): ν = 3328, 3119, 2975, 2928, 2899, 1653,

˜

1615, 1524, 1471, 1442, 1353, 1306, 1274, 1206, 1188, 1159, 1138,

870, 779, 656, 614 cm^–1. ¹H NMR (400 MHz, [D₆]DMSO): δ = 8.85

(s, 1 H), 8.80 (s, 1 H), 6.50 (s, 1 H), 6.49 (s, 1 H), 4.57 (t, J =

8.0 Hz, 1 H), 3.96 (ddd, J = 12.7, 5.4, 3.1 Hz, 1 H), 2.94–2.87 (m,

1 H), 2.59–2.51 (m, 3 H), 2.45–2.36 (m, 1 H), 2.25–2.18 (m, 1 H),

1.64–1.54 (m, 1 H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ =

171.97, 144.11, 143.95, 128.34, 123.64, 115.32, 111.60, 55.51, 36.57,

31.19, 27.32, 27.25 ppm.

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chromatography (ethyl acetate/hexane, 50:50) to afford (Ϯ)-

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erythrinarbine

[8-methoxy-9-hydroxy-1,2,5,6-tetrahydropyrrolo-

[2,1-a]isoquinolin-3(10bH)-one (9), 177 mg, 76% yield] as a color-

less solid, m.p. 206–207 °C; ref.^[13]m.p. 193–194 °C. IR (KBr): ν =

˜

3113, 3020, 2986, 2844, 1670, 1585, 1511, 1465, 1446, 1360, 1298,

1

1264, 1220, 1118, 1030, 870 cm^–1. H NMR (400 MHz, CDCl₃): δ

= 6.66 (s, 1 H), 6.59 (s, 1 H), 5.73 (s, 1 H), 4.67 (t, J = 7.6 Hz, 1

H), 4.27 (dd, J = 12.8, 4.4 Hz, 1 H), 3.86 (s, 3 H), 3.01 (td, J =

11.6, 4.0 Hz, 1 H), 2.90–2.82 (m, 1 H), 2.68–2.41 (m, 4 H), 1.82–

1.78 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 173.42,

145.69, 144.80, 130.29, 124.97, 111.12, 110.75, 56.62, 56.12, 37.29,

31.94, 28.30, 27.80 ppm. HRMS (ESI): calcd. for C₁₃H₁₅NNaO₃

[M + Na]⁺256.0950; found 256.0945.

CCDC-1028844 (for 2e), -1028843 (for 2f), -828127 (for 4a),

-1028840 (for 4b), -877454 (for 4e), -877455 (for 9), -1028842 (for

2ia), and -1028841 (for 2ka) contain the supplementary crystallo-

graphic data for this paper. These data can be obtained free of

charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

Supporting Information (see footnote on the first page of this arti-

cle): ORTEP diagrams, preparations of the starting materials, and

1

copies of H and ¹³C NMR spectra of all cyclized compounds.

Acknowledgments

The authors thank the Council of Scientific and Industrial Re-

search (CSIR) and the Department of Science and Technology

(DST), New Delhi for their financial support. J. S. thanks the CSIR

for the Senior Research Fellowship (SRF). R. S. R thanks the Uni-

versity Grants Commission (UGC), New Delhi for the SRF. The

authors gratefully acknowledge Prof. K. R. Prasad, IISc, Bengal-

uru and Prof. D. B. Ramachary, University of Hyderabad for the

HRMS analysis. The Central Instrumentation Facility (CIF), Pon-

dicherry University is thanked for the NMR/IR data and the DST-

FIST for sponsoring the single-crystal XRD facility. The authors

thank Dr. M. M. Balakrishnarajan for his support with the theoret-

ical calculations.

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Published Online: ᭿

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Job/Unit: O43617

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Date: 18-02-15 15:36:18

Pages: 15

Synthesis of Condensed Tetrahydroisoquinoline Class of Alkaloids

Alkaloid Synthesis

J. Selvakumar, R. S. Rao,

V. Srinivasapriyan, S. Marutheeswaran,

C. R. Ramanathan* ......................... 1–15

The isoquinoline-based polycyclic lactams

and simple isoquinoline alkaloids were suc-

cessfully assembled from the corresponding

imides by using a TfOH-mediated (TfOH

carbonyl activation and cyclization strat-

egy. The regioselective cyclization of un-

symmetrical phenethylimides with TfOH

was studied by experimental and compu-

tational methods.

Synthesis of Condensed Tetrahydroiso-

quinoline Class of Alkaloids by Employing

TfOH-Mediated Imide Carbonyl Acti-

vation

=

trifluoromethanesulfonic acid) imide

Keywords: Alkaloids / Nitrogen hetero-

cycles / Lactams / Cyclization / Regioselec-

tivity

Eur. J. Org. Chem. 0000, 0–0

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15

Article Doi

Synthesis of condensed tetrahydroisoquinoline class of alkaloids by employing TfOH-mediated imide carbonyl activation

DOI: 10.1002/ejoc.201403617

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Full text of DOI:10.1002/ejoc.201403617

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