Intramolecular inverse electron demand Diels-Alder reactions of tryptamine with tethered heteroaromatic azadienes

TETRAHEDRON

Pergamon

Tetrahedron 56 (2000) 1165–1180

Intramolecular Inverse Electron Demand Diels–Alder Reactions

of Tryptamine with Tethered Heteroaromatic Azadienes¹

*

Scott C. Benson, Lily Lee, Lydie Yang and John K. Snyder

Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA

Received 21 September 1999; accepted 22 December 1999

Abstract—1,2,4,5-Tetrazines and 1,2,4-triazines tethered to tryptamine via the ethylamine side chain undergo intramolecular inverse

electron demand cycloadditions to produce adducts with the [ABazaCE]-ring skeleton of the Aspidosperma alkaloids. ᭧ 2000 Elsevier

Introduction

cycloaddition to complete the pentacyclic core structure.

We now report the full details and scope of this chemistry,

including the limitations.

The inverse electron demand Diels–Alder cycloadditions of

heteroaromatic azadienes have proven to be valuable,

fundamental reactions for the construction of various

heterocyclic compounds.²Indole and its derivatives have

been established as suitable dienophiles in this chemistry,³

with intramolecular cycloadditions onto the indole 2,3-

double bond allowing for the formation of a variety of poly-

cyclic compounds.⁴We recently communicated preliminary

results exploring the dienophilicity of 3-substituted indoles,

Results and Discussion

Preparation of tethered heteroaromatic azadienes 5–7

Heteroaromatic azadienes such as pyridazines, 1,2,4-tria-

zines, and 1,2,4,5-tetrazines bearing suitable leaving groups

Scheme 1.

Table 1. Tethering of 1,2,4,5-tetrazines to tryptamine and derivatives

including tryptamine, with 1,2,4-triazines and 1,2,4,5-tetra-

zines in both intermolecular and intramolecular reactions.⁵

Upon acylation of the tethering tryptamine nitrogen, the

intramolecular reactions proceeded smoothly to provide

the desired cycloadducts in good to excellent yields

(Scheme 1). Our interest in pursuing this chemistry

stemmed from the recognition that adducts 8 and 9 incorpo-

rated four of the ﬁve rings of the Aspidosperma alkaloids

with the azadiene C-ring poised for a second intramolecular

Item Indole R¹R²Tetrazine R³

LG

Conditions^aProduct^b

1

2

3

4

5

6

7

1a

1b

1c

1a

1b

H

Bn

H

2a

SCH₃SCH₃

A

B

A

C

5a (94)

5b (95)

5c (60)

5d (86)

5e (85)

5f (85)

5h (83)

Bn Ac 2a

H

Bn

H

2b

2c

2d

H

SCH₃

CH₃SCH₃

Cl Cl

^aConditions: Areﬂux in MeOH; Bn-BuLi in THF, Ϫ30ЊC; Creﬂux

^b% Isolated yield in parentheses.

in CH₂Cl₂.

Keywords: cycloaddition; indoles; tetrazines; triazines.

* Corresponding author. E-mail: jsnyder@chem.bu.edu

PII: S0040-4020(00)00003-X

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S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

Table 2. Tethering of 1,2,4-triazines and 3,6-dichloropyridazine to tryptamine and derivatives

Item

Indole

R¹

R²

Azadiene

X

LG

R³

R⁴

Conditions^a

Product^b

1

2

3

4

5

6

7

8

9

10

1a

1b

1c

1d

1a

1b

1a

H

Ac

Me

H

3a

3b

3c

3d

3e

3f

N

CH

SCH₃

OCH₃

SCH₃

OCH₃

SCH₃

Cl

CO₂Me

H

CH₃

Ph

CO₂Me

H

A

B

A

D

A

D

A

E

6a (99)

6b (99)

6c (52)

6d (89)

6e (55)

6e (49)

6f (58)

6f (54)

6g (89)

7a (35)

Bn

H

Bn

H

CH₃

Ph

H

4

Cl

H

^aConditions: Areﬂux in MeOH; Bn-BuLi in THF, Ϫ30ЊC; Dreﬂux in MeOH in presence of NaOMe (2 equiv.); Ereﬂux in DMF.

^b% Isolated yield in parentheses.

as substituents are well known to undergo S_NAr displacement

reactions with appropriate nucleophiles.⁶Heteroaromatic

azadienes, prepared from literature procedures, were tethered

to the primary amino group of tryptamine (1a) and N¹-benzyl-

tryptamine (1b) through simple S_NAr displacements (Tables

1 and 2). Thus, tryptamine-tethered tetrazines were prepared

by the displacements of methylthiolate from tetrazines in

excellent yields (Scheme 2, LGSMe) by reﬂuxing 1a and

1b with 3,6-bis-(methylthio)-1,2,4,5-tetrazine (2a)⁷and 3-

methylthio-1,2,4,5-tetrazine (2b)⁸in methanol to give 5a

and 5b (94 and 95%, Table 1, Items 1 and 2, respectively)

and 5d and 5e (86 and 85%, Items 4 and 5, respectively).⁹

Similar displacement of methylthiolate from 3-methyl-6-

methylthio-1,2,4,5-tetrazine (2c)⁸by 1b (85%, Item 6) was

equally successful. Dichlorotetrazine 2d¹⁰was very sensitive

toward displacement, and the tethering reaction had to be

performed in CH₂Cl₂(Item 7, Scheme 2, LGR³Cl); in

MeOH, displacement of chloride by the solvent occurred.

Displacements of methylthiolate from triazines were also

straightforward (Scheme 3, LGSMe, XN; Table 2).¹¹

Reﬂuxing dimethyl 3-methylthio-1,2,4-triazine-5,6-dicar-

boxylate (3a)¹²in methanol with 1a and 1b gave the

tethered triazines 6a and 6b (each 99%, Table 2, Items 1

and 2, respectively), while similar reactions of 3a with

N¹-benzyl-N¹⁰-methyltryptamine (1d, 89%, Item 4) and

5,6-diphenyl-3-methylthio-1,2,4-triazine (3f)^11awith 1b

(89%, Item 9) were also successful.

Displacement of methyl thiolate from the more electron rich

triazines 3b^11aand 3d^11arequired the presence of added

base; NaOMe (2 equiv.) was used (Table 2, Items 5 and

7), which also gave rise to small amounts of the 3-methoxy-

triazines 3c (8%) and 3e (10%), respectively. On the

assumption that the tethering of these triazines proceeded

through initial production of the methoxy triazines followed

by methoxide displacement,^11a3c and 3e were prepared

from 3b and 3d (86 and 81%, respectively)^11aand resub-

jected to the tethering reaction. The methoxyl groups were

displaced, but the yields of the tethered tryptamines 6e and

6f remained approximately the same (Table 1, Items 5–8).

Chloride displacement from 3,6-dichloropyridazine (4) by

1a, however, required more vigorous conditions (reﬂuxing

DMF), and the yield of the tethered pyridazine 7a (35%,

Item 10) was considerably less than that of the tethered

triazines and tetrazines.¹³Thus as expected, the ease of

displacements followed the series tetrazinesϾtriazines

Ͼpyridazines, matching the decrease in electron deﬁciency.

Scheme 2.

Since preliminary results had indicated that acylation of the

nitrogen linker was necessary for the cycloaddition to

proceed,⁵tetrazine 2a and triazine 3a were also tethered

to N¹-benzyl-N¹⁰-acetyltryptamine 1c following deproto-

nation of the amide with n-BuLi (60 and 52%, Table 1,

Item 3, and Table 2, Item 3, respectively; Scheme 4).¹⁴

Attempts to apply the same tethering reaction of 1c to

tetrazines 2b, 2c, and 2d (see Table 1 for tetrazine

Scheme 3.

Scheme 4.

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1167

the H9 methylene protons of the tryptamine side chain (now

appearing near d 4.0), comparable to the deshielding

observed upon N-acylation. The ¹H NMR spectrum of

tethered triazine 6a recorded at room temperature indicated

the presence of two distinct rotamers (Fig. 1) about the

tethering, amino nitrogen–triazine bond in a 2:1 ratio.

Thus, three singlets for the methyl ester protons appeared

at d 4.02, 3.98, and 3.95 in a 2:3:1 ratio, while the tethering

amino proton, both pairs of methylene protons (H8/8⁰and

H9/9⁰), and the indole H4 all appeared as two separate reso-

nances in 2:1 ratios. Upon warming to 40ЊC, the methyl

ester resonances collapsed to a single, sharp singlet (d

3.97, 6H), and the indole H4 also appeared as a single reso-

nance (d 7.59, d, J8 Hz). At this temperature, severe

broadening, but not coalescence, was observed in the

tethering amino NH and the tryptamine side chain methy-

lene resonances. Further warming of the sample was not

pursued since the coalescence observed at 40ЊC and the

broadening of the other resonances conﬁrmed the existence

of NMR-distinct rotamers at room temperature. Slowly

interconverting rotamers were not observed in the proton

spectrum at ambient temperature (270 MHz) of the corre-

sponding acetylated tethered triazine 6c, nor in the spectra

of tethered triazines 6e–6g which do not bear electron with-

drawing substituents at the triazinyl 4-, and 5-positions.

Similar rotamers were observed, however, in the proton

and carbon spectra of 6b and 6d.

Scheme 5.

Scheme 6.

structures), triazines 3b and 3d (see Table 2 for triazine

structures), as well as pyridazine 4 were all unsuccessful.

The tetrazines 2b–2d decomposed under the strongly basic

conditions,¹⁵while only starting materials were recovered

from the reactions of the triazines 3b and 3d and pyridazine

4. In order to discern whether the location of the carbonyl

group would impact upon the cycloaddition of the tethered

azadienes, N¹-benzylindoleacetamide (1e) was also

prepared and linked to 2a to give 5g (Scheme 5). Finally,

tethered tetrazine 5i was prepared from 5h by cyanide

displacement (KCN, DMF, rt) of the remaining chloro

substituent (Scheme 6).

Cycloadditions of the tethered triazines

Tethered tetrazines 5 and triazines 6 without N¹⁰-acylation

did not produce cycloadducts upon heating in 1,3,5-tri-

isopropylbenzene (TIPB, bp 232ЊC); prolonged heating at

reﬂux led only to decomposition. With the assumption that

electron donation from the tethering nitrogen lone pair of

electrons was inhibiting the cycloaddition due to the rela-

tively high LUMO level of the azadiene, 5a, 6a, and 7a were

each submitted to the in situ acetylation procedure

employed by Boger for inducing intramolecular cyclo-

additions between pyridazines and tethered alkynes.¹⁶

Under these conditions, 6a produced cycloadduct 8a in

74% yield, along with a 10% yield of N¹,N¹⁰-diacetylated

tethered triazine 6h (Scheme 7, Eq. 1). Upon reﬂuxing in

Ac₂O in the absence of added NaOAc, cycloadduct 8a was

obtained in 89% yield with no 6h detected. The cis-fused

1

In general, the tethered products were evidenced in the H

NMR spectrum by an approximate 1 ppm downﬁeld shift of

Figure 1. Rotamers observed in the NMR spectra of 6a, 6b, and 6d.

Scheme 7.

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S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

the cycloaddition was emphasized by the failure of

N¹⁰-methylated tethered triazine 6d, which cannot be

acylated on the tethering nitrogen, to react under the same

conditions (reﬂuxing Ac₂O).

None of the other tethered triazines 6e–g (see Table 2, Items

5–9, Scheme 9), which do not have strongly electron with-

drawing triazine substituents, participated in intramolecular

cycloadditions under any of the conditions that were

successful with 6a–6c. In reﬂuxing Ac₂O, only the

N¹⁰-acetylated tethered triazines were produced (96–97%),

while triﬂuoroacetic anhydride (TFAA, 8 equiv.) in reﬂux-

ing dioxane (100ЊC) yielded only the N¹⁰-triﬂuoro-ace-

tylated derivatives (92–94%). Addition of NaOAc resulted

only in further acylation of the indole nitrogen, yielding

N¹,N¹⁰-bis-acylated tethered triazines. Thus, the requisite

N¹⁰-acylation, acylating reaction medium, and electron

withdrawing triazine substituents indicated that the intramo-

lecular cycloadditions of tryptamine-tethered azadienes

required very electron-deﬁcient diene systems to react

with the indole 2,3-double bond.

Scheme 8.

1,2-dihydro tautomeric form of the dihydropyridine ring in

8a was readily assigned by NOE’s as described later. In

contrast, no cycloadducts were obtained from 5a or 7a

under these conditions (with and without NaOAc). Acetate

addition to the tetrazine ring with multiple N-acetylations

resulted in unidentiﬁed products from the reaction of 5a,

while 7a only yielded the N¹,N¹⁰-diacetylated and

N¹⁰-acetylated tethered pyridazines 7b and 7c, respectively

(Scheme 7, Eq. 2).

It was concluded that initial acetylation of the tethering

nitrogen was essential to allow the cycloaddition of tethered

triazine 6a to proceed. If competing acetylation of the indole

nitrogen (N¹), which apparently requires base (acetate)

promotion, occurs ﬁrst, no cycloaddition would result

presumably due to the lowering of the HOMO of the indole

2,3-double bond upon acetylation,¹⁷and subsequent

N¹⁰-acetylation would give only 6h. In support of this

conclusion, heating 6h to 150ЊC in diglyme (well above

the reﬂux temperature of Ac₂O: 138ЊC) produced no

reaction; 6h was recovered unchanged. Subjecting 6h to

reﬂuxing Ac₂O also did not produce any cycloadduct.

Higher temperatures led only to decomposition.

With the successful cycloadditions of tethered diester tri-

azines 6a–6c, the corresponding tethered (S)-tryptophan 6i

was prepared (Scheme 10) to determine whether the amino

acid chirality could control the facial selectivity of the

cycloaddition. As with 6a, 6b, and 6d, distinct rotamers

(1:1 ratio) about the tethering nitrogen–triazinyl bond of

6i were observed in the proton and carbon spectra at

ambient temperature. Reﬂuxing 6i with TFAA (8 equiv.)

in dioxane produced adduct 8c as the sole product (Ͼ99%

de), the loss of the triﬂuoro-acetate group occurring during

chromatographic puriﬁcation. Key to the assignment of the

stereochemistry of 8c was an NOE between H5 and H12

observed in the 2D-NOE spectrum; NOE’s between H9a

and H11 protons conﬁrmed the cis ring fusion as well as

the 1,2-dihydro tautomeric form of the dihydropyridine

subunit.

In order to prevent detrimental acylation at the indole

N¹-position, N¹-benzyl derivatives 6b and 6c were prepared

(Table 2, Items 2 and 3). Reﬂuxing 6b in Ac₂O produced an

excellent yield (95%) of cycloadduct 8b (Scheme 8). Based

on this result, and the presumed necessity of N¹⁰-acylation

prior to the intramolecular cycloaddition, it was anticipated

that 6c would undergo a facile cycloaddition under thermal

conditions. Surprisingly, only starting material was recovered

when 6c was heated in TIPB (160–200ЊC), while decom-

position resulted in reﬂuxing TIPB (232ЊC). However,

reﬂuxing 6c in Ac₂O produced 8b in excellent yield

(92%). The requirement of Ac₂O to produce 8b from 6c,

while no reaction ensued at much higher temperatures but

without an acylating agent present, suggested that acetyl-

ation of both the tethering nitrogen and a triazine ring nitro-

gen may be necessary for the cycloaddition to proceed. The

importance of the acetylation of the tethering nitrogen for

Exclusive diastereoselectivity in the cycloaddition to give

8c can be hypothesized to originate from preferred con-

formation A, which would result in si-face approach of

the triazine subunit to the indole ring 2,3-double bond.

The alternative conformation B, which would lead to

cycloaddition across the re-face, suffers an additional

gauche interaction.

Cycloadditions of the tethered tetrazines

As noted, 5a did not produce a cycloadduct upon reﬂuxing

in Ac₂O, giving only complex product mixtures. When 5a

and 5d were treated with TFAA (8 equiv.) in dioxane at rt,

Scheme 9.

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1169

Scheme 10.

9a and 9b, respectively, in good yields (Scheme 11). Tetra-

zine 5e also underwent a cycloaddition under these con-

ditions, but nucleophilic addition of acetate to the

cycloadduct followed by a second acetylation, led to 10

(93%, Scheme 12, Eq. 1). Similar products resulting from

nucleophilic addition to dihydropyridazine and dihydro-

pyridine cycloadducts had been previously observed in the

intermolecular reactions of indole with both tetrazines¹⁷and

triazines.¹²When 5e was reﬂuxed in dioxane with TFAA

(8 equiv.), the desired cycloadduct 9c was obtained (83%).

Presumably, the considerably less nucleophilic triﬂuoro-

acetate anion was unable to add to this adduct. Tethered

tetrazine 5f produced only the acylated derivatives 5j and

5k upon treatment with reﬂuxing Ac₂O and TFAA/dioxane,

respectively (Scheme 12, Eq. 2); no cycloadducts were

detected.

Scheme 11.

however, a single product was formed in each reaction in

near quantitative crude yields. Both products appeared to be

cycloadducts, but were unstable to chromatography on both

silica gel and alumina, though the presence of multiple

triﬂuoroacetyl groups was apparent from the ¹³C NMR

spectra. Since the instability was thought to be due to

these triﬂuoro-acetyl groups, one of which was assumed

to be on the indole nitrogen, N¹-benzylated tryptamine

derivatives 5b and 5i were prepared and subjected to the

cycloaddition conditions.

In contrast to the N¹⁰-acetylated tethered triazine 6c, the

cycloaddition of the N-acetylated tethered tetrazine 5c

proceeded in good yield simply by heating (160ЊC, 45 min

in TIPB) to produce 9a in excellent yield (95%, Scheme 13).

Thus, further activation of the tetrazine nucleus by reﬂuxing

in an acylating medium was not necessary. Reinforcing this

point, indoleacetamide 5g also underwent a thermally

Reﬂuxing N¹-benzyl protected tethered tetrazines 5b and 5i

in Ac₂O produced the 1,2-dihydrotautomeric cycloadducts

Scheme 12.

1170

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

of 2-azadienes with enamines and vinyl ethers can be cata-

lyzed by BF₃Et₂O, though the yields of cycloadducts were

rather modest.¹⁹Boger and Panek had also sought Lewis

acid catalysis in the cycloadditions between enamines and

1,2,4-triazines, but without success.²⁰We had previously

noted a very mild catalysis of the intramolecular cyclo-

addition between indole and the tethered diethyl 1,2,4-tri-

azine-5,6-dicarboxylate 11 by the NMR shift reagent

Eu(fod)₃to produce the canthine 12 (Fig. 2),²¹a Lewis

acid used extensively by Danishefsky in catalyzing hetero

Diels–Alder reactions of aldehydes.²²Thus in reﬂuxing

diglyme, the cycloaddition of 11 was sluggish and required

8 h for completion. Addition of Eu(fod)₃enabled com-

pletion of the reaction under the otherwise same conditions

in only 2 h.^21bCatalysis of the cycloaddition of any other

tethered triazines in that series, however, was not realized

using Eu(fod)₃or any other Lewis acid, and it was specu-

lated that the presence of a chelation site offered by the

triazine ester substituents made the catalysis possible.

Scheme 13.

Scheme 14.

The tryptamine-tethered tetrazines and triazines 5 and 6

present several nitrogen lone pairs on the azadiene subunit

which could function as basic sites and allow for Lewis acid

catalysis of the cycloaddition. Thus, the possibility of catalysis

in the intramolecular cycloaddition of tethered tetrazine 5c

(see Scheme 13), which also contains a sulfur as a potential

site for Lewis acid coordination, was examined (Table 3),

with attention paid to azaphilic Lewis acids. While some did

catalyze the cycloaddition in low yields at 60ЊC or lower

temperatures (in control experiments, no reaction occurred

at 60ЊC in TIPB or DMF after 24 h), the best yield obtained

[with Ni(CN)₂, 62%, Item 2] was considerably lower than

that achieved by heating 5c to 160ЊC in TIPB (95%, Scheme

13). Nevertheless, this catalysis did enable the cycloaddition

to proceed at a considerably lower temperature. The NMR

shift reagent Eu(hfc)₃also promoted the cycloaddition to a

very limited extent at lower temperature, but the yields of

cycloadduct 9a were poor (Items 7 and 8). Attempts to apply

Ni(CN)₂catalysis to the cycloaddition of triazine 6c were

unsuccessful: no reaction was observed.

promoted cycloaddition in reﬂuxing mesitylene (bp 162–

164ЊC) to produce 9d (99%, Scheme 14).

Catalysis of the intramolecular cycloaddition

Reports of Lewis acid catalysis of inverse electron Diels–

Alder reactions are extremely rare. Conceptually, this is

understandable since Lewis acids seek electrons, and the

electron-rich dienophiles of the inverse electron demand

Diels–Alder reactions are likely to function as Lewis

bases. This acid–base interaction would lower the dieno-

phile HOMO and thereby retard the cycloaddition (and

often induce dienophile polymerization or decomposition!).

Indole itself is well known to oligomerize in the presence of

both Lewis and Bronsted acids.¹⁸Lewis acid catalysis of

such cycloadditions is feasible, however, if the Lewis acid

would preferentially coordinate with the electron deﬁcient

diene. Mariano, for example, has reported that cycloadditions

Figure 2. Mild catalysis of the cycloaddition of 11 by the NMR shift reagent Eu(fod)₃.^21b

Table 3. Lewis acid catalyzed cycloadditions of 5c to 9a

Item

Catalyst (eqiv.)

Conditions

Yield (%) 9a

Recovered (%) 5c

1

2

3

4

5

6

7

8

9

None

TIPB or DMF, 60ЊC, 24 h

DMF, 60ЊC, 3 h

CH₂Cl₂, rt, 14 h

TIPB, rt, 12 h

TIPB, 80ЊC, 4 h

CH₂Cl₂, reﬂux, 8 h

TIPB, 70ЊC, 8 h

DMF, 60ЊC, 3 h

CH₂Cl₂, rt, 10 h

0

62

40

12

Ͻ2

0

10

24

10

22

100

27

44

71

98

0

82

68

23

53

Ni(CN)₂(1.5)

Ni(acac)₂(1)

AlCl₃(1)

MeAlCl₂(1 equiv.)

Eu(hfc)₃(0.05)

CuI(1)

10

BF₃·OEt₂

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1171

Preliminary attempts to complete the Aspidosperma

alkaloidal pentacyclic skeleton

A second cycloaddition across the aza C-ring of adducts 8

and 9 with a dienophile tethered to N4 (Aspidosperma alka-

loid numbering) would complete the pentacyclic skeleton of

the Aspidosperma alkaloids. Deacetylation of 8b followed

by reacylation with pentynoyl anhydride produced 8d (96%,

2 steps, Scheme 15). Reﬂuxing 8d in TIPB gave rise to 13

(31%) with none of the desired adduct 14 detected. For-

mation of 13 arises from the desired cycloaddition, but a

subsequent retro Diels–Alder reaction to free the indole

subunit and generate the aromatic pyridine ring of 13 domi-

nates over a release of methyl cyanoformate.²³

Figure 3. Cycloadduct NMR characteristics.

Structure of the cycloadducts

The formation of cycloadducts 8 and 9 was indicated in the

NMR spectra by several key features (Fig. 3). In the

N¹-benzylated derivatives, the benzylic methylene protons,

a singlet (s, 2H) near d 5.2–5.3 in the tethered precursors 5

and 6, became an AB-system (J_ABϷ15 Hz) in the cyclo-

adducts with the two resonances appearing between 4.9

and 4.3, indicating the formation of a nearby stereogenic

center. The methylene resonances of the tryptamine side

chain, originally simple multiplets (2H each) in 5 and 6,

became distinct one proton mutliplets suggesting the for-

mation of a cyclic structure (H11/11⁰, H12/12⁰). Further-

more, the disappearance of the indole H2 resonance near

d 6.9 in the spectra of the starting materials coincided with

the appearance of a broad singlet of a methine near d

4.6–5.6 for H9a with the corresponding carbon C9a appearing

near d 65 in the triazine adducts 8, and near d 3.9–4.6 (¹³C

near d 50) in the tetrazines adducts 9. The structures were

further supported by ¹³C and HMQC spectra, with the cis

fusion of the newly formed C-ring conﬁrmed by NOE’s

between H9a and the H11 protons in DNOE or NOESY

experiments.

Similar to 8b, tethered tetrazine adduct 9b was deacetylated,

then reacylated with the pentynoic acid and DCC to give 9e

(Scheme 16). However, 9e did not undergo a cycloaddition

under any conditions examined, including reﬂuxing in TIPB

(232ЊC), which only led to decomposition.

An alternative approach to complete the pentacyclic core of

the Aspidosperma alkaloids with the second cycloaddition

of the tandem strategy forming the C- and E-rings was also

brieﬂy investigated (Scheme 17). Tetrazine 2a was tethered

to tryptamine derivative 1g to produce 5l, which underwent

a very facile cycloaddition in reﬂuxing CH₂Cl₂to produce

adduct 16a, conﬁrming the better dienophilicity of the

alkyne in comparison to the indole double bond. No con-

ditions were found which could induce 16a to undergo an

intramolecular cycloaddition to produce 17 (RSCH₃).

Reﬂuxing 16a in Ac₂O or dioxane with TFAA (8 equiv.),

with or without Ni(II), conditions which had been successful

in promoting the cycloadditions of other tethered azadienes,

all returned only starting material, similar to the results

observed with the other tethered pyridazine 7a (Scheme 7,

Scheme 15.

Scheme 16.

1172

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

Scheme 17.

Eq. 2). Reﬂuxing 16a in TIPB (232ЊC) led only to

decomposition. Oxidation of 16a to the corresponding sulf-

oxide 16b proceeded smoothly, but again, 16b would not

participate in the desired intramolecular cycloaddition.

Attempts to oxidize 16b to the sulfone were unsuccessful,

resulting in oxidation of the indole 2,3-double bond.

Infrared spectra were recorded on a Perkin–Elmer 1800

spectrometer on NaCl plates unless otherwise noted. Solid

samples were deposited on the NaCl plate as a solution in an

appropriate, volatile solvent (typically CH₂Cl₂) followed by

evaporation of the solvent. Only diagnostic bands, such as

carbonyl and triple bond stretching bands, are reported.

Mass spectra were measured on a Finnigan MAT-90 spec-

trometer as indicated.

Conclusions

Tryptamine (1a), l-(S)-tryptophan, 3-indolylacetic acid, 3,6-

dichloropyridazine (4) and pentynoic acid were purchased

from Aldrich or Lancaster and used without further puriﬁ-

cation. Tetrazines 2a,⁷2b,⁸2c,⁸2d,¹⁰and triazines 3a,¹²

3b,^11a3c,^11a3d,^11a3e,^11aand 3f^11awere prepared according

to literature procedures. All solvents were anhydrous, dried

and distilled according to standard procedures²⁴immedi-

ately before use.

The intramolecular inverse electron demand cycloadditions

of heteroaromatic azadienes tethered to the primary amine of

tryptamine proceed in excellent yields as long as the tethered

triazines or tetrazines are very electron deﬁcient, and the

tethering nitrogen is acylated. In the case of the triazines,

further activation by reaction in an acylating medium is

also required. Catalysis of the reaction by Ni(CN)₂was

successful with tetrazine 5c bearing the thiol substituent,

but not with triazine 6c. Attempts to convert the cycloadducts

produced in the intramolecular reactions of tethered triazines

and tetrazines to the pentacyclic core of the Aspidosperma

alkaloids have to-date been unsuccessful. We are continuing

to explore methods to achieve this ﬁnal cycloaddition.

N¹-Benzyltryptamine (1b). Di-tert-butyl dicarbonate

[(BOC)₂O, 1.5 g, 6.86 mmol] was added to a solution of

tryptamine (1.0 g, 6.24 mmol) in dioxane (10 mL) contai-

ning triethylamine (1.7 mL, 12.48 mmol), and the reaction

mixture was stirred at rt for 3 h. The solvent was removed in

vacuo, and the product puriﬁed by ﬂash chromatography

(10% EtOAc/CH₂Cl₂) to give N¹⁰-BOC-tryptamine as a

white solid (1.59 g, 6.12 mmol, 98%). Mp 94–95ЊC; IR

Experimental

General

1

(NaCl) 1692 cm^Ϫ1; H NMR (270 MHz, CDCl₃) d 8.47

(bs, NH), 7.48 (d, J7.8 Hz, 1H), 7.21 (d, J7.8 Hz, 1H),

7.07 (ddd, J7.8, 7.8, 1.0 Hz, 1H), 7.00 (ddd, J7.8, 7.8,

1.0 Hz, 1H), 6.79 (bs, 1H), 4.56 (bs, NH), 3.32 (dt, J6.8,

5.9 Hz, 2H), 2.81 (t, J6.8 Hz, 2H), 1.35 (s, 9H);

Melting points were determined in capillaries and are uncor-

rected. ¹H and ¹³C NMR spectra were recorded on a Varian

UNITY PLUS 400 (93.94 kG, ¹H 400 MHz, ¹³C 100 MHz),

a Varian Gemini 300 (70.5 kG, ¹H 300 MHz, ¹³C 75 MHz)

and a JEOL GSX-270 (63.41 kG, ¹H 270 MHz, ¹³C

67.5 MHz) in CDCl₃(0.5 mL). The d 7.24 resonance of

residual CHCl₃, and the center line of the ¹³CDCl₃triplet

(270 MHz, DMSO-d₆)

d

10.6 (bs, NH), 7.53 (d,

J7.8 Hz, 1H), 7.35 (d, J7.8 Hz, 1H), 7.11 (bs, 1H),

7.10–6.97 (m, 2H), 6.55 (bs, NH), 3.24 (dt, J7.5,

5.9 Hz, 2H), 2.84 (t, J7.5, 2H), 1.40 (s, 9H); ¹³C NMR

(67.5 MHz, DMSO-d₆, 70ЊC)²⁵d 155.2, 136.1, 127.1, 122.2,

120.5, 117.89, 117.84, 111.7, 111.0, 77.2, 40.8, 28.0 (3C),

25.3; HRMS (EI, 70 eV) m/z 260.1534 ([M]^ϩcalcd for

C₁₅H₂₀O₂N₂, 260.1525).

(d 77.0) were used as internal references for the ¹H and ¹³

C

spectra, respectively. All exchangeable protons resonances

(NH) were identiﬁed by the addition of D₂O. Relative inten-

sities of carbon resonance were determined by integration of

spectra recorded under inverse gated decoupling. Carbon

chemical shifts are reported to a single decimal place with

the exception of resolved resonances which can be distin-

guished numerically only to the second decimal position.

A solution of N¹⁰-BOC-tryptamine (1.59 g, 6.12 mmol) in

THF (10 mL) was added with stirring to a suspension of KH

(0.7 g, 6.12 mmol, 35% in mineral oil) slurried in THF

(0.5 mL) and cooled to Ϫ50ЊC. After 30 min, benzylbromide

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1173

(1.2 g, 6.73 mmol) was added, then the reaction was allowed

to warm to rt and stirring continued for an additional 3 h.

After quenching by the addition of water (10 mL), EtOAc

(20 mL) was added and the organic phase was separated,

dried over Na₂SO₄, and the solvent removed in vacuo. The

product was puriﬁed by ﬂash chromatography (2% EtOAc/

CH₂Cl₂) to give N¹-benzyl-N¹⁰-BOC-tryptamine as a pale

N¹-Benzyl-N¹⁰-methyltryptamine (1d). To a solution of

tryptamine (1a, 1.0 g, 6.24 mmol) and triethylamine

(5 mL) in CH₂Cl₂(30 mL) cooled to 0ЊC, ethyl chloro-

formate (0.75 mL, 7.8 mmol) was added dropwise over

10 min with stirring. The reaction mixture was stirred for

an additional 30 min at 0ЊC, then allowed to warm to rt and

stirred for an additional 1.5 h. The solvent was removed in

vacuo, and the residue puriﬁed by ﬂash chromatography

(CH₂Cl₂/EtOAc, 5:1) to give N¹⁰-carboethoxytryptamine

yellow oil (2.05 g, 5.87 mmol, 96%). IR (NaCl) 1695 cm^Ϫ1

;

¹H NMR (270 MHz, CDCl₃) d 7.60 (dd, J6.8, 1.0 Hz, 1H),

7.29–7.06 (m, 8H), 6.92 (s, 1H), 5.22 (s, 2H), 4.63 (bs, NH),

3.42 (bm, 2H), 2.93 (t, J6.8, 2H), 1.42 (s, 9H); ¹³C NMR

(67.5 MHz, CDCl₃) d 155.9, 137.5, 136.7, 128.7 (2C),

128.0, 127.5, 126.7 (2C), 126.1, 121.8, 119.1, 119.0,

112.3, 109.6, 79.0, 49.8, 40.9, 28.4 (3C), 25.7; HRMS (EI

70 eV) m/z 350.1975 ([M]^ϩcalcd for C₂₂H₂₆O₂N₂,

350.1994). Gram quantities of N¹-benzyl-N¹⁰-BOC-trypta-

mine were stored due to its greater stability and appropriate

amounts deprotected to 1b immediately before use in the

S_NAr reactions.

1

as a pale yellow oil (1.20 g, 84%). H NMR 400 MHz,

CDCl₃) d 8.00 (bs, NH), 7.60 (d, J8.0 Hz, 1H), 7.35 (d,

J8.0 Hz, 1H), 7.19 (ddd, J8.0, 8.0, 1.0 Hz, 1H), 7.11

(ddd, J8.0, 8.0, 1.0 Hz, 1H), 7.03 (bs, 1H), 4.68 (bs,

NH), 4.09 q, J6.8 Hz, 2H), 3.50 (dt, J6.8, 5.9 Hz, 2H),

2.95 (t, J6.8 Hz, 1H), 1.20 (t, J6.8 Hz, 3H); ¹³C NMR

(67.5 MHz, CDCl₃) d 156.7, 136.6, 127.5, 122.3, 122.0,

119.6, 118.8, 113.2, 111.2, 77.2, 60.7, 41.4, 25.9, 14.7;

HRMS (EI, 70 eV) m/z 232.1201 ([M]^ϩcalcd for

C₁₃H₁₆N₂O₂, 232.1197).

A

solution of N¹-benzyl-N¹⁰-BOC-tryptamine (2.0 g,

To a suspension of LiAlH₄(1.75 g, 46.1 mmol) in THF

(30 mL) cooled to 0ЊC under argon, a solution of

N¹⁰-carboethoxytryptamine (1.0 g, 4.2 mmol) in THF

(10 mL) was slowly added with stirring via syringe. After

the addition was complete, the reaction mixture was allowed

to warm to rt, then reﬂuxed for 3 h. After allowing to cool to

rt, the reaction was quenched by the addition of water

(5 mL) and 15% aqueous KOH (w/v, 1 mL). The precipitate

was removed by ﬁltration and washed with ether (100 mL),

then with MeOH (20 mL). The combined ﬁltrates were

dried over Na₂SO₄, then the solvent removed in vacuo and

the residues puriﬁed by ﬂash chromatography (EtOAc/

CH₂Cl₂, 1:1) to give N¹⁰-methyltryptamine (0.37 g,

5.71 mmol) in CH₂Cl₂(16 mL) at rt was treated with

triﬂuoroacetic acid (4 mL). After 1 h, the reaction was

quenched by extraction with saturated aqueous NaHCO₃

solution (3×15 mL), the organic phase was separated,

dried over Na₂SO₄, and the solvent removed in vacuo to

afford 1b as a colorless oil (1.4 g, 5.71 mmol, 99ϩ%)

which was used without further puriﬁcation. ¹H NMR

(270 MHz, CDCl₃) d 7.63 (d, J7.8 Hz, 1H), 7.27–7.07

(m, 8H), 6.93 (s, 1H), 5.21 (s, 2H), 3.00 (m, 2H), 2.91 (m,

2H), 1.4 (bs, NH₂); ¹³C NMR (67.5 MHz, CDCl₃) d 137.5,

136.6, 128.5, (2C) 128.0, 127.3, 126.62, 126.55 (2C), 121.6,

118.9, 118.8, 112.7, 109.5, 49.6, 42.2, 29.2; HRMS

(EI, 70 eV) m/z 250.1485 ([M]^ϩcalcd for C₁₇H₁₈N₂,

250.1470).

1

2.1 mmol, 50%) as a pale yellow oil. H NMR (400 MHz,

CDCl₃) d 8.11 (bs, NH), 7.62 (d, J8.0 Hz, 1H), 7.353 (d,

J8.0 Hz, 1H), 7.18 (ddd, J8.0, 8.0, 1.0 Hz, 1H), 7.10

(ddd, J8.0, 8.0, 1.0 Hz, 1H), 7.03 (bs, 1H), 3.00–2.89

(A₂B₂, J_AB6.8 Hz, 4H), 2.20 (s, 3H), 2.20 (bs, NH); ¹³C

NMR (67.5 MHz, CDCl₃) d 136.3, 127.6, 121.9 (2C),

119.2, 118.8, 113.7, 111.0, 51.7, 36.0, 25.3; HRMS (EI,

70 eV) m/z 174.1157 ([M]^ϩcalcd for C₁₁H₁₄N₂, 174.1157).

N¹-Benzyl-N¹⁰-acetyltryptamine (1c). A solution of tryp-

tamine (1a, 1.0 g, 6.24 mmol) in acetic anhydride (5 mL)

containing triethylamine (1.7 mL, 12.48 mmol) was stirred

at rt for 2 h. The solvent was then concentrated in vacuo and

the residue loaded onto a pad of silica gel in a Bu¨chner

funnel and eluted with 5% EtOAc/CH₂Cl₂to afford N¹⁰-acetyl-

tryptamine (1.26 g, 6.24 mmol, 99ϩ%) which was used in

the next step without further puriﬁcation. ¹H NMR

(270 MHz, CDCl₃) d 8.36 (bs, NH), 7.58 (d, J7.7 Hz,

1H), 7.36 (d, J7.9 Hz, 1H), 7.19 (dd, J7.9, 7.1 Hz,

1H), 7.11 (dd, 7.7, 7.1 Hz, 1H), 7.00 (d, J1.8 Hz, 1H),

5.62 (bs, NH), 3.58 (dt, J6.6, 6.8 Hz, 2H), 2.95 (t,

J6.8 Hz, 1H), 1.90 (s, 3H); ¹³C NMR (67.5 MHz,

CDCl₃) d 170.0, 136.6, 127.9, 127.5, 122.2, 119.5, 118.7,

113.1, 111.3, 39.9, 25.3, 23.3. The same benzylation pro-

cedure used to prepare 1b was followed with N¹⁰-acetyltryp-

tamine (1.26 g, 6.24 mmol) to afford 1c, puriﬁed by ﬂash

chromatography (2% EtOAc/CH₂Cl₂), as a white solid

(1.8 g, 6.16 mmol, 99%). Mp 93–94ЊC; IR (NaCl)

To a solution of N¹⁰-methyltryptamine (0.35 g, 2.0 mmol)

and triethylamine (2 mL) in dioxane (10 mL) at rt was

added BOC-ON (0.54 g, 2.2 mmol). The solution was

stirred overnight (15 h), then the solvent was removed in

vacuo, and the residue puriﬁed by ﬂash chromatography

(CH₂Cl₂/EtOAc, 5:1) to give N¹⁰-BOC-N¹⁰-methyltryp-

1

tamine (0.38 g, 1.4 mmol, 70%) as a pale yellow oil. H

NMR (400 MHz, CDCl₃) d 8.02 (s, ex, NH), 7.61 (d,

J8.0 Hz, 1H), 7.34 (d, J8.0 Hz, 1H), 7.17 (ddd, J8.0,

7.6, 1.0 Hz, 1H), 7.10 (ddd, J8.0, 7.6, 1.0 Hz, 1H), 6.99

(bs, 1H), 3.49 (t, J6.9 Hz, 2H), 2.95 (t, J6.9 Hz, 1H),

2.84 (s, 3H), 1.37 (s, 9H); ¹³C NMR (67.5 MHz, CDCl₃) d

155.8, 136.3, 127.5, 122.0, 121.9, 119.3, 118.7, 113.4,

111.1, 79.1, 49.5, 34.4, 28.4 (3C), 23.8; HRMS (EI,

70 eV) m/z 274.1664 ([M]^ϩcalcd for C₁₆H₂₂N₂O₂,

274.1681).

1651 cm^Ϫ1

;

¹H NMR (270 MHz, CDCl₃) d 7.58 (d,

J7.8 Hz, 1H), 7.27–7.06 (m, 8H), 6.92 (s, 1H), 5.60 (bs,

NH), 5.23 (s, 2H), 3.54 (dt, J6.8, 5.9 Hz, 2H), 2.93 (t,

J6.8 Hz, 1H), 1.86 (s, 3H); ¹³C NMR (67.5 MHz,

CDCl₃) d 170.0, 137.4, 136.7, 128.7 (2C), 127.9, 127.6,

126.8 (2C), 126.0, 121.9, 119.2, 118.9, 112.2, 109.7, 49.8,

39.8, 25.2, 23.3; HRMS (EI, 70 eV) m/z 292.1588 ([M]^ϩ

calcd for C₁₉H₂₀N₂O, 292.1576).

The same benzylation procedure which produced 1b was

then followed with N¹⁰-BOC-N¹⁰-methyltryptamine

(0.23 g, 0.84 mmol) to afford N¹-benzyl-N¹⁰-BOC-N¹⁰-

methyltryptamine after ﬂash chromatography (CH₂Cl₂) as

1174

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1

a pale yellow oil (0.21 g, 0.59 mmol, 70%). Resonances in

both the ¹H and ¹³C NMR spectra were broadened due to the

presence of slowly interconverting rotamers. ¹H NMR

(270 MHz, CDCl₃) d 7.63 (d, J7.5 Hz, 1H), 7.40–7.10

(m, 8H), 6.92 (bs, 1H), 5.25 (s, 2H), 3.50 (bt, J7.0 Hz,

2H), 2.94 (bt, J7.0 Hz, 1H), 2.84 (s, 3H), 1.37 (bs, 9H);

¹³C NMR (67.5 MHz, CDCl₃) d 155.8, 137.6, 136.7, 128.7

(2C), 128.3, 127.5, 126.8 (2C), 126.0, 121.8 119.05, 118.99,

112.5, 109.6, 79.1, 49.9, 49.8, 34.5, 28.4 (3C), 24.0; HRMS

(EI, 70 eV) m/z 364.2156 ([M]^ϩcalcd for C₂₃H₂₈N₂O₂,

364.2151).

(NaCl) 1652 cm^Ϫ1; H NMR (270 MHz, CDCl₃) d 7.55

(d, J7.3 Hz, 1H), 7.28–7.07 (m, 8H), 7.03 (s, 1H), 5.60

(bs, NH), 5.57 (bs, NH), 5.25 (s, 2H), 3.68 (s, 2H); ¹³C NMR

(67.5 MHz, CDCl₃) d 174.4, 137.0, 136.7, 128.7 (2C),

127.7, 127.5, 127.4, 126.8 (2C), 122.3, 119.8, 118.9,

109.9, 108.3, 49.9, 32.9; HRMS (EI, 70 ev) m/z 264.1255

([M]^ϩcalcd for C₁₇H₁₆N₂O, 264.1263).

N¹-Benzyl-(l)-tryptophan methyl ester (1f). The same

benzylation and deprotection (removal of BOC group)

procedures used to prepare 1b were followed beginning

with

BOC-l-tryptophan

methyl

ester²⁶

(1.42 g,

The same deprotection procedure as described above for 1b

was applied to N¹-benzyl-N¹⁰-BOC-N¹⁰-methyltryptamine

(0.10 g, 0.27 mmol) to afford 1d after ﬂash chromatography

(CH₂Cl₂/MeOH, 10:1) as a pale yellow oil (63 mg,

4.61 mmol) to afford 1f as a colorless oil (1.32 g,

4.29 mmol, 93% yield) which was used without further puri-

ﬁcation. [a]²_D⁴ϩ6.0 (c 2 g/100 mL, CDCl₃); IR (NaCl)

1737 cm^Ϫ1

;

¹H NMR (270 MHz, CDCl₃) d 7.62 (d,

1

0.24 mmol, 88%). H NMR (300 MHz, CDCl₃) d 7.62 (d,

J7.8 Hz, 1H), 7.26–7.04 (m, 8H), 6.96 (s, 1H), 5.23 (s,

2H), 3.81 (m, 1H), 3.64 (s, 3H), 3.26 (m, 1H), 3.05 (m, 1H),

1.6 (bs, NH₂); ¹³C NMR (67.5 MHz, CDCl₃) d 175.4, 137.2,

136.3, 128.4 (2C), 127.9, 127.2, 126.7, 126.4 (2C), 121.6,

119.0, 118.7, 110.0, 109.4, 54.8, 51.5, 49.4, 30.5; HRMS

(EI, 70 eV) m/z 308.1516 ([M]^ϩcalcd for C₁₉H₂₀N₂O₂,

308.1525).

J7.9 Hz, 1H), 7.40–7.06 (m, 8H), 6.98 (s, 1H), 5.24 (s,

2H), 3.09–3.01 (m, 4H), 2.851 (s, 3H) (NH not observed);

¹³C NMR (67.5 MHz, CDCl₃) d 137.5, 136.7, 128.7 (2C),

127.8, 127.6, 126.8 (2C), 126.3, 121.9, 119.2, 118.9, 111.6,

109.8, 51.1, 49.9, 34.9, 24.2; HRMS (EI, 70 eV) m/z

264.1638 ([M]^ϩcalcd for C₁₈H₂₀N₂, 264.1626).

(N¹-Benzyl-3-indolyl)acetamide (1e). Thionyl chloride

(1.4 g, 11.4 mmol) was added dropwise to methanol

(10 mL) cooled to Ϫ30ЊC and stirred for 0.5 h. (3-Indolyl)-

acetic acid (1.0 g, 5.7 mmol) was added in one portion and

the reaction mixture was allowed to warm to rt and stirred

for 4 h. The reaction was quenched with water (10 mL) and

partitioned with EtOAc (20 mL). The organic phase was

separated, then dried over Na₂SO₄. After removal of the

solvent in vacuo, the residue was puriﬁed by ﬂash chroma-

tography (2% EtOAc/CH₂Cl₂) to afford methyl (3-indolyl)-

acetate as a colorless oil (1.1 g, 5.6 mmol, 98%). IR (NaCl)

N¹-Benzyl-N¹⁰-(pent-4-ynoyl)tryptamine (1g). To a solu-

tion of 1b (1.0 g, 4 mmol) and 4-pentynoic acid (0.39 g,

4 mmol) in CH₂Cl₂(10 mL) were added DCC (1.65 g,

8 mmol) and DMAP (25 mg, 0.20 mmol). After stirring

for 3 h at rt, the reaction was cooled to 0ЊC to precipitate

the N,N⁰-dicyclohexylurea, and the mixture ﬁltered through

a pad of Celite. The solvent was removed from the ﬁltrate in

vacuo, and the residue puriﬁed by ﬂash chromatography

(10% EtOAc/CH₂Cl₂) to afford 1 g as a white solid

(1.28 g, 3.88 mmol, 97%). Mp 89–90ЊC; IR (NaCl) 2115,

1641 cm^Ϫ1

;

¹H NMR (270 MHz, CDCl₃) d 7.61 (d,

1

1737 cm^Ϫ1; H NMR (270 MHz, CDCl₃) d 8.10 (bs, NH),

J7.8 Hz, 1H), 7.27–7.07 (m, 8H), 6.92 (s, 1H), 6.07 (bt,

J6.3 Hz, NH), 5.19 (s, 2H), 3.56 (dt, J6.8, 6.3 Hz, 2H),

2.95 (t, J6.8 Hz, 2H), 2.44 (dt, J7.3, 1.5 Hz, 2H), 2.27 (t,

J7.3 Hz, 2H), 1.87 (t, J1.5 Hz, 1H); ¹³C NMR

(67.5 MHz, CDCl₃) d 170.7, 137.3, 136.5, 128.5 (2C),

127.8, 127.4, 126.6 (2C), 125.9, 121.7, 119.0, 118.8,

112.0, 109.5, 82.9, 69.1, 49.6, 39.7, 35.0, 25.0, 14.6;

HRMS (EI, 70 eV) m/z 330.1762 ([M]^ϩcalcd for

C₂₂H₂₂N₂O, 330.1732).

7.62 (d, J7.9 Hz, 1H), 7.32 (d, J7.9 Hz, 1H), 7.20–7.10

(m, 2H), 7.09 (s, 1H), 3.79 (s, 2H), 3.70 (s, 3H); ¹³C NMR

(67.5 MHz, CDCl₃) d 172.6, 136.0, 127.1, 123.1, 122.1,

119.6, 118.8, 111.2, 108.3, 51.9, 31.1; HRMS (EI, 70 eV)

m/z 189.0802 ([M]^ϩcalcd for C₁₁H₁₁NO₂, 189.0790).

The same benzylation procedure used to prepare 1b was

followed with methyl (3-indolyl)acetate (2.0 g, 10.58

mmol) to afford methyl (N¹-benzyl-3-indolyl)acetate after

ﬂash chromatography (CH₂Cl₂) as a colorless oil (2.8 g,

General procedure for tethering azadienes to trypta-

mines. A solution of the tryptamine derivative 1 with the

azadiene (1 equiv.) in the appropriate solvent as listed in

Tables 1 and 2, 5 mL/g azadiene, (conditions A: MeOH,

C: CH₂Cl₂and E: DMF) was reﬂuxed for the time indicated

below for each compound. In the case of condition D, Table

2, NaOMe (2 equiv.) was also added to the MeOH solution.

After cooling to rt, the solvent was removed in vacuo and

the residue puriﬁed by ﬂash chromatography. For condition

B, see below.

1

10.16 mmol, 96% yield). IR (NaCl) 1731 cm^Ϫ1; H NMR

(270 MHz, CDCl₃) d 7.59 (d, J7.3 Hz, 1H), 7.26–7.08 (m,

9H), 5.24 (s, 2H), 3.75 (s, 2H), 3.66 (s, 3H); ¹³C NMR

(67.5 MHz, CDCl₃) d 172.4, 137.4, 136.5, 128.7 (2C),

127.9, 127.6, 127.1, 126.8 (2C), 121.9, 119.4, 119.0,

109.7, 107.5, 51.9, 50.0, 31.1; HRMS (EI, 70 eV) m/z

279.1254 ([M]^ϩcalcd for C₁₈H₁₇NO₂, 279.1259).

A mixture of NH₄OH_(aq)and MeOH (10 mL each) was

added to methyl (N¹-benzyl-3-indolyl)acetate (4.0 g,

14.34 mmol) at rt. After stirring for 12 h, additional

NH₄OH_(aq)(10 mL) was added and stirring continued for

an additional 12 h. After extraction with EtOAc (20 mL)

the organic phase was dried over Na₂SO₄and the solvent

removed in vacuo. Puriﬁcation of the residue by ﬂash chro-

matography (25% EtOAc/CH₂Cl₂) afforded 1e as a white

solid (2.87 g, 10.90 mmol, 76%). Mp 149–150ЊC; IR

N¹⁰-[6-Methylthio-3-(1,2,4,5-tetrazinyl)]-tryptamine (5a).

Prepared from tryptamine (1a, 1.0 g, 6.24 mmol) and tetra-

zine 2a (1.09 g, 6.24 mmol) according to the general pro-

cedure, condition A (2 h) to afford 5a after ﬂash

chromatography (3% EtOAc in CH₂Cl₂), as an orange

1

solid (1.70 g, 5.92 mmol, 95%). Mp 184–186ЊC; H NMR

(270 MHz, DMSO-d₆) d 10.1 (bd, J1.5 Hz, NH), 7.64 (dd,

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1175

J7.8, 1.0 Hz, 1H), 7.46 (bs, NH), 7.39 (dd, J7.8, 1.0 Hz,

1H), 7.23 (d, J1.5 Hz, 1H), 7.10 (ddd, J7.8, 6.8, 1.0 Hz,

1H), 7.02 (ddd, J7.8, 6.8, 1.0 Hz, 1H), 3.85 (dt, J6.8,

5.8 Hz, 2H), 3.17 (t, J6.8 Hz, 2H), 2.63 (s, 3H); ¹³C NMR

(270 MHz, DMSO-d₆) d 164.9, 161.0, 136.3, 127.2, 123.0,

121.0, 118.3, 118.2, 111.4 (2C), 41.4, 24.4, 13.2; ¹³C NMR

(67.5 MHz, acetone-d₆) d 167.0, 162.6, 137.8, 128.6, 123.7,

122.2, 119.6, 119.4, 113.0, 112.2, 42.5, 25.5, 13.5; HRMS

(CI, 140 eV, ammonia) m/z 287.1061 ([Mϩ1]^ϩcalcd for

C₁₃H₁₅N₆S, 287.1079).

tetrazine 2b (0.77 g, 6 mmol) according to the general

procedure, condition A (3 h) to give 5e after ﬂash chroma-

tography (CH₂Cl₂) as a red solid (1.70 g, 5.16 mmol, 85%).

Mp 146–148ЊC; ¹H NMR (270 MHz, CDCl₃) d 9.55 (s, 1H),

7.61 (d, J7.3 Hz, 1H), 7.26–7.08 (m, 8H), 6.97 (s, 1H),

6.05 (bs, NH), 5.23 (s, 2H), 3.89 (dt, J5.6, 5.4 Hz, 2H),

3.13 (t, J5.6 Hz, 2H); ¹³C NMR (67.5 MHz, CDCl₃) d

162.8, 153.2, 137.3, 136.8, 128.7 (2C), 127.7, 127.6,

126.7 (2C), 126.4, 122.1, 119.3, 118.8, 111.3. 109.8, 49.9,

41.2, 24.8; HRMS (CI, 140 eV, NH₃) m/z 330.1570 ([M]^ϩ

calcd for C₁₉H₁₈N₆, 330.1593).

N¹⁰-[6-Methylthio-3-(1,2,4,5-tetrazinyl)]-N¹-benzyltrypta-

mine (5b). Prepared from N¹-benzyltryptamine (1b, 1.50 g,

6.0 mmol) and tetrazine 2a (1.04 g, 6.0 mmol) according to

the general procedure, condition A (3 h) to give 5b after

ﬂash chromatography (CH₂Cl₂) as a red oil (2.1 g,

N¹⁰-[6-Methyl-3-(1,2,4,5-tetrazinyl)]-N¹-benzyltryptamine

(5f). Prepared from N¹-benzyltryptamine (1b, 1.0 g,

4.0 mmol) and tetrazine 2c (0.57 g, 4 mmol) according to

the general procedure, condition A (3 h) to give 5f after ﬂash

chromatography (5% EtOAc/CH₂Cl₂) as a red solid (1.2 g,

3.4 mmol, 85%). Mp 148–150ЊC; ¹H NMR (270 MHz,

CDCl₃) d 7.63 (d, J7.3 Hz, 1H), 7.27–7.06 (m, 8H),

6.97 (s, 1H), 5.87 (bs, NH), 5.23 (s, 2H), 3.88 (dt, J6.9,

6.6 Hz, 2H), 3.13 (t, J6.9 Hz, 2H), 2.79 (s, 3H); ¹³C NMR

(67.5 MHz, CDCl₃) d 161.6, 137.4, 136.9, 128.9, 128.8

(2C), 127.8, 127.6, 126.8 (2C), 126.4, 122.1, 119.3, 118.9,

111.5, 109.9, 49.9, 41.4, 25.0, 20.0; HRMS (CI, 140 eV,

NH₃) m/z 344.1734 ([Mϩ1]^ϩcalcd for C₂₀H₂₀N₆, 344.1744).

1

5.59 mmol, 93%). H NMR (270 MHz, CDCl₃) d 7.61 (d,

J7.3 Hz, 1H), 7.27–7.06 (m, 8H), 6.96 (s, 1H), 5.66 (bt,

J5.9 Hz, NH), 5.24 (s, 2H), 3.85 (dt, J6.9, 5.9 Hz, 2H),

3.12 (t, J6.9 Hz, 2H), 2.62 (s, 3H); ¹³C NMR (67.5 MHz,

CDCl₃) d 166.9, 160.8, 137.3, 136.8, 128.7 (2C), 127.8,

127.6, 126.7 (2C), 126.3, 122.0, 119.3, 118.8, 111.4,

109.8, 49.8, 41.5, 24.8, 13.6; HRMS (EI, 70 eV) m/z

376.1466 ([M]^ϩcalcd for C₂₀H₂₀N₆S, 376.1470).

N¹⁰-Acetyl-N¹⁰-[6-methylthio-3-(1,2,4,5-tetrazinyl)]-N¹-ben-

zyltryptamine (5c). A solution of n-BuLi (3.0 mL, 1.0 M in

hexanes) was added dropwise with stirring to a solution of

N¹⁰-acetyl-N¹-benzyltryptamine (1c, 888 mg, 3.04 mmol)

dissolved in THF (10 mL) and cooled to Ϫ30ЊC. After

20 min, a solution of tetrazine 2a (529 mg, 3.04 mmol) in

THF (2 mL) was added via cannula and the reaction con-

tinued for 30 min. The reaction was then quenched at

Ϫ30ЊC with water (10 mL) and after warming to rt, the

mixture extracted with EtOAc (3×15 mL). The combined

organic extracts were dried over Na₂SO₄and the solvent

removed in vacuo. Flash chromatography (CH₂Cl₂) of the

residue provided 15c as a red oil (709 mg, 1.76 mmol, 58%).

{N¹-Benzyl-N¹⁰-[6-methylthio-3-(1,2,4,5-tetrazinyl)]-3-in-

dolyl}acetamide (5g). A solution of 1e (0.1 g, 0.38 mmol)

in THF (2 mL) cooled to Ϫ60ЊC was treated with n-BuLi

(2.4 mL, 1.6 M solution in hexanes) with stirring. After

20 min, a solution of tetrazine 2a (0.07 g, 0.38 mmol) in

THF (2 mL) was added via cannula. The reaction was

allowed to warm to rt, stirred for 4 h, then quenched by

the addition of water (5 mL). The mixture was partitioned

with EtOAc (10 mL), and the organic extracts dried over

Na₂SO₄. The solvent was removed in vacuo, and the residue

puriﬁed by ﬂash chromatography (20% EtOAc/CH₂Cl₂) to

give 5g as a red solid (0.08 g, 0.21 mmol, 56%). Mp 148–

150ЊC; IR (NaCl) 1700 cm^Ϫ1; ¹H NMR (270 MHz, CDCl₃)

d 8.60 (bs, ex, NH), 7.68 (d, J7.9 Hz, 1H), 7.40–7.18 (m,

9H), 5.38 (s, 2H), 4.14 (s, 2H), 2.73 (s, 3H); ¹³C NMR

(67.5 MHz, CDCl₃) d 173.0, 169.1, 158.2, 137.0, 136.8,

128.9 (2C), 128.0, 127.9, 127.4, 126.9 (2C), 122.8, 120.4,

118.7, 110.2, 106.4, 50.1, 34.6, 13.5; HRMS (EI, 70 eV) m/z

390.1228 ([M]^ϩcalcd for C₂₀H₁₈N₆OS, 390.1263).

1

IR (NaCl) 1678 cm^Ϫ1; H NMR (270 MHz, CDCl₃) d 7.56

(dd, J6.8, 1.5 Hz, 1H), 7.29–7.24 (m, 3H), 7.18–7.06 (m,

5H), 6.86 (s, 1H), 5.20 (s, 2H), 4.50 (t, J6.8 Hz, 2H), 3.13

(t, J6.8 Hz, 2H), 2.60 (s, 3H), 2.36 (s, 3H); ¹³C NMR

(67.5 MHz, CDCl₃) d 171.6, 170.7, 162.5, 137.2, 136.4, 128.7

(2C), 127.6, 127.4, 127.0, 126.9 (2C), 121.8, 119.3, 119.1,

111.4, 109.6, 49.8, 47.5, 24.7, 24.5, 13.5; HRMS (CI, 140 eV,

NH₃) m/z 403.1720 ([Mϩ1]^ϩcalcd for C₂₂H₂₂N₆S, 403.1705).

N¹⁰-[6-Chloro-3-(1,2,4,5-tetrazinyl)]-N¹-benzyltryptamine

(5h). Prepared from N¹-benzyltryptamine (1b, 1.5 g,

6 mmol) and tetrazine 2d (0.90 g, 6 mmol) according to

the general procedure, condition C (2 h) to give 5h after

ﬂash chromatography (CH₂Cl₂) as a dark red solid (1.8 g,

N¹⁰-[3-(1,2,4,5-Tetrazinyl)]-tryptamine (5d). Prepared from

tryptamine (1a, 1.0 g, 6.24 mmol) and tetrazine 2b (0.80 g,

6.25 mmol) according to the general procedure, condition A

(2 h) to give 5d after ﬂash chromatography (5% EtOAc/

CH₂Cl₂) as a red solid (1.3 g, 5.37 mmol, 86% yield). Mp

1

4.95 mmol, 83%). Mp 147–149ЊC; H NMR (270 MHz,

1

187–188ЊC; H NMR (270 MHz, DMSO-d₆) d 10.05 (bs,

CDCl₃) d 7.59 (d, J7.3 Hz, 1H), 7.30–7.06 (m, 8H),

6.96 (s, 1H), 5.86 (bs, NH), 5.24 (s, 2H), 3.88 (dt, J6.9,

6.6 Hz, 2H), 3.12 (t, J6.9 Hz, 2H); ¹³C NMR (67.5 MHz,

CDCl₃) d 161.4, 160.4, 137.3, 136.9, 128.8 (2C), 127.7

(2C), 126.8 (2C), 126.4, 122.2, 119.5, 118.8, 111.0, 109.9,

49.9, 41.7, 24.8; HRMS (EI, 70 eV) m/z 364.1203 ([M]^ϩ

calcd for C₁₉H₁₇N₆Cl, 364.1203).

NH), 9.63 (s, 1H), 7.64 (d, J7.8 Hz, 1H), 7.38 (d,

J7.8 Hz, 1H), 7.23 (s, 1H), 7.10 (dd, J7.8, 7.3 Hz, 1H),

7.01 (dd, J7.8, 7.3 Hz, 1H), 3.88 (dt, J7.8, 5.9 Hz, 2H),

3.17 (t, J7.8 Hz, 2H); ¹³C NMR (67.5 MHz, DMSO-d₆) d

162.7, 152.6, 136.2, 127.2, 122.9, 120.9, 118.3, 118.2,

111.4, 111.3, 41.1, 24.3; HRMS (CI, 140 eV, NH₃) m/z

241.1201 ([Mϩ1]^ϩcalcd for C₁₂H₁₃N₆, 241.1202).

N¹⁰-[6-Cyano-3-(1,2,4,5-tetrazinyl)]-N¹-benzyltryptamine

(5i). To a solution of 5h (0.72 g, 1.98 mmol) in DMF (8 mL)

at rt was added KCN (1.98 mmol), and the reaction was

N¹⁰-[3-(1,2,4,5-Tetrazinyl)]-N¹-benzyltryptamine (5e). Pre-

pared from N¹-benzyltryptamine (1b, 1.5 g, 6 mmol) and

1176

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

stirred under argon for 4 h. The solvent was removed by

vacuum distillation at room temperature, and the residue

puriﬁed by ﬂash chromatography (CH₂Cl₂) to give 5i red

solid (0.66 g, 1.86 mmol, 94%). Mp 170–172ЊC; IR (NaCl)

2243 cm^Ϫ1; ¹H NMR (270 MHz, CDCl₃) d 7.58 (dd, J7.6,

1.0 Hz, 1H), 7.32–7.07 (m, 8H), 6.99 (s, 1H), 6.31 (bs, ex,

NH), 5.28 (s, 2H), 4.03 (dt, J6.6, 6.4 Hz, 2H), 3.18 (t,

J6.6 Hz, 2H); ¹³C NMR (67.5 MHz, CDCl₃) d 158.7,

145.0, 137.1, 136.9, 128.8 (2C), 127.8, 127.5, 126.8 (2C),

126.6, 122.4, 119.7, 118.6, 113.7, 110.4, 110.1, 40.0, 41.8,

24.7, a better quality ¹³C spectrum was obtained in DMSO-d₆

due to improved solubility: ¹³C NMR (67.5 MHz, DMSO-d₆)

d 158.5, 143.5, 138.3, 136.0, 128.5 (2C), 127.7, 127.3,

127.03, 126.95 (2C), 121.3, 118.7, 118.6, 115.1, 110.9,

110.1, 48.9, 41.4, 23.9; HRMS (CI, 140 eV, isobutane) m/z

355.1516 ([M]^ϩcalcd for C₂₀H₁₇N₇, 355.1546).

to the general procedure, condition A (4 h) to give 6b after

ﬂash chromatography (3% EtOAc/CH₂Cl₂) as a yellow solid

(2.64 g, 5.94 mmol, 99%). Mp 128–130ЊC; IR (NaCl) 1748,

1721 cm^Ϫ1; ¹H NMR (270 MHz, CDCl₃, 50ЊC)²⁷d 7.60 (bd,

J6.9 Hz, 1H), 7.27–7.06 (m, 8H), 6.96 (s, 1H), 6.5 (bs,

0.67NH), 5.8 (bs, 0.33NH), 5.26 (s, 2H), 3.96 (bs, 6H), 3.85

(bm, 2H), 3.13 (bm, 2H); ¹³C NMR (67.5 MHz, CDCl₃,

three sp²hybridized carbons were not observed at ambient

ء

temperature presumably due to slow exchange; reso-

nance due to minor rotamer) d 163.3, 161.3, 137.4, 136.8,

128.7 (2C), 127.7, 127.6, 126.8 (2C), 126.4, 122.1, 119.3,

118.8, 111.2, 109.9, 53.3, 53.0, 49.9, 42.1,^*41.5, 24.9;

HRMS (EI, 70 eV) m/z 445.1756 ([M]^ϩcalcd for

C₂₄H₂₃N₅O₄, 445.1750).

N¹⁰-Acetyl-N¹⁰-[5,6-dicarbomethoxy-3-(1,2,4-triazinyl)]-

N¹-benzyltryptamine (6c). A solution of 1c (888 mg,

3.04 mmol) in THF (10 mL) cooled to Ϫ30ЊC was treated

with n-BuLi (3.0 mL of 1.6 M solution in hexanes) with

stirring. After 20 min, a solution of triazine 3a (739 mg,

3.04 mmol) in THF (2 mL) was added via cannula. The

reaction was stirred for 30 min at Ϫ30ЊC, then quenched

by the addition of water (5 mL). After warming to rt, the

mixture was partitioned with EtOAc (3×15 mL), and the

combined organic extracts dried over Na₂SO₄. The solvent

was removed in vacuo, and the residue puriﬁed by ﬂash

chromatography (CH₂Cl₂) to give 6c as a yellow oil

(770 mg, 1.58 mmol, 52%). IR (NaCl) 1752, 1732,

N¹-Benzyl-N¹⁰-[6-methylthio-3-(1,2,4,5-tetrazinyl)]-N¹⁰-

pent-4-ynoyltryptamine (5l). To a solution of 1g (700 mg,

2.1 mmol) in THF (15 ml) cooled to Ϫ60ЊC was added

dropwise with stirring n-BuLi (2.1 mL, 1.0 M in hexanes).

After 20 min, tetrazine 2a (0.37 g, 2.1 mmol) in THF

(2 mL) was added via cannula, and stirring continued for

30 min, then the reaction mixture allowed to warm to rt. The

reaction was quenched with water (5 mL), extracted with

EtOAc (3×10 mL), and the organic extracts were dried over

Na₂SO₄. The solvent was removed in vacuo and the residue

puriﬁed by ﬂash chromatography (CH₂Cl₂) to give 5l as a

red oil (530 mg, 1.16 mmol, 55%). IR (NaCl) 2120,

1694 cm^Ϫ1

;

¹H NMR (270 MHz, CDCl₃) d 7.67 (d,

1684 cm^Ϫ1

;

¹H NMR (270 MHz, CDCl₃) d 7.54 (dd,

J6.8 Hz, 1H), 7.29–7.05 (m, 8H), 6.92 (s, 1H), 5.22 (s,

2H), 4.50 (t, J7.5 Hz, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.12

(t, J7.5 Hz, 2H), 2.55 (s, 3H); ¹³C NMR (67.5 MHz,

CDCl₃) d 172.0, 163.0, 162.6, 137.5, 136.4, 128.7 (2C),

127.8, 127.5, 126.9, 126.81 (2C), 126.76, 126.73, 121.8,

119.3, 119.2, 111.8, 109.6, 53.8, 53.6, 49.8, 47.1, 26.9,

24.1; HRMS (EI, 70 eV) m/z 487.1814 ([M]^ϩcalcd for

C₂₆H₂₅N₅O₅, 487.1856).

J6.8, 1.4 Hz, 1H), 7.28–7.23 (m, 3H), 7.14–7.05 (m,

5H), 6.84 (s, 1H), 5.18 (s, 2H), 4.49 (t, J7.3 Hz, 2H),

3.13 (t, J7.3 Hz, 2H), 2.87 (t, J6.8 Hz, 2H), 2.60 (s,

3H), 2.57 (td, J6.8, 2.7 Hz, 2H), 1.90 (t, J2.7 Hz, 1H);

¹³C NMR (67.5 MHz, CDCl₃) d 171.7, 171.6, 162.1, 137.1,

136.3, 128.7 (2C), 127.6, 127.3, 127.0, 126.90 (2C), 121.8,

119.3, 119.1, 111.3, 109.6, 82.8, 68.9, 49.8, 47.7, 35.6, 24.5,

14.7, 13.5; HRMS (EI, 70 eV) m/z 456 1778 ([M]^ϩcalcd for

C₂₅H₂₄N₆OS, 456.1735).

N¹⁰-[5,6-Dicarbomethoxy-3-(1,2,4-triazinyl)]-N¹⁰-methyl-

N¹-benzyltryptamine (6d). Prepared from N¹-benzyl-N¹⁰-

methyltryptamine (1d, 50 mg, 0.19 mmol) and triazine 3a

(46 mg, 0.19 mmol) according to the general procedure,

condition A (4 h) to give 6d after ﬂash chromatography

(3% EtOAc/CH₂Cl₂) as a yellow oil (0.08 g, 0.17 mmol,

N¹⁰-[5,6-Dicarbomethoxy-3-(1,2,4-triazinyl)]tryptamine

(6a). Prepared from tryptamine (1a, 1.0 g, 6.24 mmol) and

triazine 3a (1.0 g, 4.16 mmol) according to the general

procedure, condition A (3 h) to give 6a after ﬂash chromato-

graphy (10% EtOAc/CH₂Cl₂) as a yellow solid (1.45 g,

4.1 mmol, 99% yield based on 3a). Mp 149–151ЊC; IR

1

89%). IR (NaCl) 1747, 1720 cm^Ϫ1; H NMR (270 MHz,

CDCl₃) d 7.70 (m, 1H), 7.30–7.04 (m, 8H), 6.96 (s,

0.5H), 6.91 (s, 0.5H), 5.24 (s, 2H), 4.19 (t, J7.8 Hz, 1H),

3.99 (bs, 6H), 3.94 (t, J7.8 Hz, 1H), 3.39 (s, 1.5H), 3.16 (s,

1.5H), 3.16 (m, 1H), 3.04 (t, J7.8 Hz, 1H) (doubled and

broadened resonances were observed for many protons due

to the presence of slowly equilibrating rotamers); ¹³C NMR

(67.5 MHz, CDCl₃) d 164.6, 163.5, 159.4, 159.2, 137.5,

136.6, 135.5, 128.8, 128.7, 127.9, 127.6, 126.8, 126.7,

126.3, 126.2, 121.9, 119.3, 119.2, 119.1, 119.0, 118.9,

111.5, 111.4, 109.7, 53.3, 52.9, 51.1, 50.4, 49.87, 49.83,

36.2, 36.0, 22.84, 22.75 (doubled resonances were observed

for many carbons due to the presence of slowly equilibrating

rotamers); HRMS (CI, 140 eV, NH₃) m/z 460.1980

([Mϩ1]^ϩcalcd for C₂₆H₂₆N₅O₄, 460.1985).

1

(KBr) 1750, 1715 cm^Ϫ1; H NMR (400 MHz, CDCl₃) d

8.16 (bs, ex, NH), 7.62 (d, J8.0 Hz, 0.33H), 7.60 (d,

J8.0 Hz, 0.67H), 7.36 (d, J8.0 Hz, 1H), 7.20 (dd,

J8.0, 6.8 Hz, 1H), 7.12 (dd, J8.0, 6.8 Hz 1H), 7.03 (bs,

1H), 6.63 (bs, ex, 0.67NH), 5.87 (bs, ex, 0.33NH), 4.05 (dt,

J6.4, 6.4 Hz, 0.66H), 4.01 (s, 2H), 3.98 (s, 3H), 3.96 (s,

1H), 3.82 (dt, J6.4, 6.4 Hz, 1.34H), 3.14 (t, J6.4 Hz,

0.66H), 3.06 (t, J6.4 Hz, 1.34H); ¹³C NMR (100 MHz,

ء

CDCl₃, resonances from minor rotamer) d 164.4,

164.1,^ء163.2, 161.2, 159.5,^ء152.8, 152.4,^ء138.0,^ء136.4,

136.3, 127.0, 122.4, 122.1, 119.4,^ء119.3, 118.5, 111.8,

111.3, 53.4, 52.9, 42.0,^ء41.3, 24.8; HRMS (EI, 70 eV)

m/z 355.1285 ([M]^ϩcalcd for C₁₇H₁₇N₅O₄, 355.1281).

N¹⁰-[5,6-Dicarbomethoxy-3-(1,2,4-triazinyl)]-N¹-benzyl-

tryptamine (6b). Prepared from N¹-benzyltryptamine (1b,

1.50 g, 6 mmol) and triazine 3a (1.46 g, 6 mmol) according

N¹-Benzyl-N¹⁰-[5,6-dicarbomethoxy-3-(1,2,4-triazinyl)]-

(l)-tryptophan methyl ester (6i). Prepared from N-benzyl-

tryptophan methyl ester (1e, 0.05 g, 0.16 mmol) and triazine

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1177

3a (0.04 g, 0.16 mmol) according to the general procedure,

condition A (3 h) to give 6i after ﬂash chromatography (3%

EtOAc/CH₂Cl₂) as a yellow solid (0.08 g, 0.15 mmol, 94%).

Mp 56–58ЊC; [a]²_D⁴ϩ35.7 (c 3 g/100 mL, CDCl₃); IR

Cycloaddition of 6i; cycloadduct 8c. A solution of 6i

(0.10 g, 0.20 mmol) and triﬂuoroacetic anhydride (TFAA,

0.25 mL, 1.8 mmol) in dioxane (3 mL) was reﬂuxed for 1 h.

The reaction mixture was evaporated to dryness and the

residue puriﬁed by ﬂash chromatography (2% MeOH/

CH₂Cl₂) to give 8c as a yellow oil (0.80 g, 0.17 mmol,

85%). [a]²_D⁴ϩ94.0 (c 0.2g/100mL, CDCl₃); IR (NaCl)

1

(NaCl) 1748, 1721 cm^Ϫ1; H NMR (270 MHz, CDCl₃, two

rotamers observed, 1:1 ratio) d 7.50 (d, J7.3 Hz, 1H),

7.28–7.02 (m, 8H), 6.93 (s, 1H), 6.87 (bd, J8.8 Hz,

0.5NH), 6.23 (bd, J7.3, 0.5NH), 5.28 (m, 0.5H), 5.25 (s,

2H), 5.02 (m, 0.5H), 3.98 (s, 3H), 3.97 (s, 3H), 3.64 (s, 3H),

3.48 (m, 1H), 3.40 (m, 1H); ¹³C NMR (67.5 MHz,

DMSO-d₆, 75ЊC, three sp²hybridized carbons were not

observed presumably due to slow exchange) d 171.0,

163.2, 162.5, 137.8, 135.8, 128.0 (2C), 127.4, 127.3,

126.8, 126.5 (2C), 121.0, 118.5, 118.0, 109.7, 109.1, 54.8,

52.8, 52.3, 51.6, 48.7, 26.4; HRMS (CI, 140 eV, ammonia)

m/z 503.1835 ([Mϩ1]^ϩcalcd for C₂₆H₂₅N₅O₆, 503.1805).

1

1741, 1718 cm^Ϫ1; H NMR (400 MHz, CDCl₃) d 7.27–

7.17 (m, 5H), 7.16 (ddd, J7.8, 7.3, 1.0 Hz, 1H), 6.85

(dd, J7.3, 1.0 Hz, 1H), 6.70 (dd, J7.3, 7.3 Hz, 1H),

6.58 (d, J7.8 Hz, 1H), 4.67 (s, 1H), 4.57 (d,

J_AB15.6 Hz, 1H), 4.51 (dd, J10.3, 6.2 Hz, 1H), 4.35 (d,

J_AB15.6 Hz, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H),

2.01 (dd, J_AB12.2, J6.2 Hz, 1H), 1.94 (dd, J_AB12.2,

J10.3 Hz, 1H) (NH not observed); ¹³C NMR (270 MHz,

CDCl₃) d 172.4, 167.9, 166.5, 164.4, 148.3, 138.0, 130.9,

129.8, 128.6 (2C), 127.7 (2C), 127.5, 121.9, 119.2, 112.8,

111.0, 67.3, 61.4, 56.0, 53.0, 52.8, 52.5, 52.1, 43.4; HRMS

(CI, 140 eV, NH₃) m/z 475.1757 ([M]^ϩcalcd for

C₂₆H₂₅O₆N₃, 475.1743).

Cycloaddition of 6a; cycloadduct 8a. A suspension of 6a

(0.3 g, 0.85 mmol) and NaOAc (0.69 g, 8.4 mmol) in

freshly distilled Ac₂O (4 mL) was reﬂuxed until TLC indi-

cated no starting material remained (5 h). After evaporating

the mixture to dryness in vacuo, the residue was puriﬁed by

ﬂash chromatography (5% MeOH/CH₂Cl₂) to give 8a as a

white solid (0.231 g, 0.63 mmol, 74%), and 6h as a yellow

solid (0.037 g, 0.085 mmol, 10%). The same reaction in the

absence of NaOAc gave only 6a (89%). Cycloadduct 8a:

Cycloaddition of 5b and of 5c; cycloadduct 9a. A solution

of 5b (0.05 g, 0.133 mmol) was reﬂuxed in Ac₂O (2 mL) for

2 h. After evaporating the mixture to dryness in vacuo, the

residue was puriﬁed by ﬂash chromatography (5% pet ether/

CH₂Cl₂) to give 9a (0.041 g, 0.106 mmol, 80%) as a color-

less oil. Alternatively, a solution of 5c (0.05 g, 0.13 mmol)

was heated in TIPB (2 mL) to 160ЊC for 45 min. After

evaporating the mixture to dryness in vacuo, the residue

was puriﬁed as described above to give 9a (0.048 g,

Mp 270–272ЊC; IR (KBr) 1710, 1668 cm^Ϫ^{1 1}H NMR

;

(400 MHz, DMSO–d₆, 50ЊC) d 9.36 (bs, ex, NH), 7.77

(bs), 7.27 (ddd, J7.6, 6.4, 2.8 Hz), 7.11–7.06 (m, 2H),

5.63 (s, 1H), 3.59 (s, 3H), 3.52 (s, 3H), 3.60–3.50 (m,

2H), 2.59 (ddd, 12.0, 9.0, 9.0 Hz), 2.35 (s, 3H), 1.94 (dd,

12.0, 3.2 Hz); ¹³C NMR (100 MHz, DMSO–d₆) d 170.9,

169.5, 167.3, 166.1, 152.9, 140.9, 133.8, 128.7, 124.5,

121.8, 118.7, 102.2, 65.9, 52.1, 51.8, 51.2, 41.9, 36.1,

23.4; HRMS (EI, 70 eV) m/z 369.1319 ([M]^ϩcalcd for

C₁₉H₁₉N₃O₅, 369.1325). N¹,N¹⁰-Diacetyl-N¹⁰-[5,6-dicarbo-

methoxy-3-(1,2,4-triazinyl)]tryptamine (6h). Mp 165–

;

0.124 mmol, 95%). IR (NaCl) 1677 cm^Ϫ^{1 1}H NMR

(270 MHz, CDCl₃) d 7.28 (m, 5H), 7.18 (ddd, J7.8, 7.3,

1.0 Hz, 1H), 6.84 (dd, J7.8, 1.0 Hz, 1H), 6.74 (ddd, J7.3,

7.8, 1.0 Hz, 1H), 6.71 (d, J7.8 Hz, 1H), 4.80 (d,

J_AB14.9 Hz, 1H), 4.54 (d, J_AB14.9 Hz, 1H), 3.99 (s,

1H), 3.91 (m, 1H), 3.61 (m, 1H), 2.67 (s, 3H), 2.40 (s,

3H), 1.76–1.70 (m, 2H); ¹³C NMR (67.5 MHz, CDCl₃) d

171.0, 164.1, 156.5, 147.3, 137.2, 130.5, 129.9, 128.8 (2C),

128.2 (2C), 128.1, 122.2, 119.8, 110.6, 66.8, 53.5, 50.4,

42.7, 35.4, 26.2, 13.6; HRMS (CI, 140 eV, NH₃) m/z

391.1610 ([Mϩ1]^ϩcalcd for C₂₂H₂₃N₄OS, 391.1593).

;

166ЊC; IR (KBr) 1740, 1718, 1682 cm^Ϫ^{1 1}H NMR

(400 MHz, CDCl₃)

d

8.36 (d, J7.2 Hz), 7.68 (d,

J7.2 Hz), 7.35–7.26 (m, 3H), 4.51 (t, J7.6 Hz), 4.07 (s,

3H), 4.03 (s, 3H), 3.10 (t, J7.6 Hz), 2.62 (s, 3H), 2.60 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) d 172.0, 168.4, 163.0,

162.4, 160.9, 150.2, 142.2, 135.8, 130.1, 125.4, 123.6,

123.2, 119.1, 118.9, 116.6, 53.9, 53.8, 46.2, 27.0, 24.0

(2C); HRMS (EI, 70 eV) m/z 439.1498 ([M]^ϩcalcd for

C₂₁H₂₁N₅O₆, 439.1491).

Cycloaddition of 5i; cycloadduct 9b. A solution of 5i

(1.0 g, 2.8 mmol) was reﬂuxed in Ac₂O (2 mL) for 3 h.

After evaporating the mixture to dryness, the residue was

puriﬁed by ﬂash chromatography (3% EtOAc/CH₂Cl₂) to

give 9b (0.90 g, 2.45 mmol, 87%) as a yellow solid. Mp

Cycloadditions of 6b and 6c; cycloadduct 8b. A solution

of 6b (0.05 g, 0.11 mmol) or 6c (0.07 g, 0.15 mmol) was

reﬂuxed in freshly distilled Ac₂O (2 mL) for 1 h. After

evaporating the mixture to dryness in vacuo, the residue

was puriﬁed by ﬂash chromatography (3% EtOAc/

CH₂Cl₂) to give 8b as a yellow oil (0.047 g, 0.105 mmol,

95% from 6b). IR (NaCl) 1740, 1718, 1700 cm^Ϫ1; ¹H NMR

(270 MHz, CDCl₃) d 7.27–7.15 (m, 6H), 6.75–6.65 (m,

3H), 4.82 (s, 1H), 4.63 (d, J_AB15.4 Hz, 1H), 4.39 (d,

J_AB15.4 Hz, 1H), 3.86 (m, 1H), 3.75 (s, 3H), 3.71 (s,

3H), 3.62 (m, 1H), 2.63 (s, 3H), 1.60 (m, 1H), 1.46 (m,

1H); ¹³C NMR (67.5 MHz, CDCl₃) d 171.3, 167.6, 166.8,

164.5, 148.2, 142.4, 137.8, 131.7, 129.8, 128.5 (2C), 127.9

(2C), 127.7, 121.9, 119.3, 115.9, 111.6, 67.1, 53.55, 53.48,

52.4, 52.1, 43.1, 34.4, 26.1; HRMS (EI, 70 eV) m/z

459.1797 ([M]^ϩcalcd for C₂₆H₂₅N₃O₅, 459.1794).

Ͼ230ЊC (dec); IR (NaCl) 2225, 1690 cm^Ϫ^{1 1}H NMR

;

(270 MHz, CDCl₃) d 7.33–7.21 (m, 6H), 6.83–6.75 (m,

3H), 4.87 (d, J_AB15.4 Hz, 1H), 4.65 (d, J_AB15.4 Hz,

1H), 4.11 (s, 1H), 4.00 (ddd, J12.0, 8.3, 1.5 Hz, 1H),

3.68 (ddd, J12.0, 11.2, 6.3 Hz, 1H), 2.69 (s, 3H), 1.86–

1.81 (m, 2H); ¹³C NMR (67.5 MHz, CDCl₃) d 170.9, 157.2,

147.3, 139.6, 136.3, 130.6, 129.0 (3C), 128.3, 128.1 (2C),

122.1, 120.2, 115.7, 110.7, 64.0, 51.7, 49.5, 43.2, 35.1, 26.6;

HRMS (CI, 140 eV, isobutane) m/z 370.1639 ([Mϩ1]^ϩ

calcd for C₂₂H₁₉N₅O, 370.1663).

Cycloaddition of 5e; cycloadduct 9c. A solution of 5e

(0.05 g, 0.15 mmol) and TFAA (0.17, 1.2 mmol, 8 equiv.)

in dioxane (2.3 mL) was reﬂuxed for 45 min. After evapo-

rating the mixture to dryness, the residue was puriﬁed by

ﬂash chromatography (2% MeOH/CH₂Cl₂) to give 9c as a

1178

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

colorless oil (0.05 g, 0.13 mmol, 83%). IR (NaCl)

A solution of dimethyl N-benzylindolino[2,3-d]pyrroli-

dino[2,3-e]-4,5-dihydropyridine-2,3-dicarboxylate (0.05 g,

0.12 mmol) was treated with pentynoyl anhydride²⁸

(0.5 mL) at rt for 18 h. The anhydride was removed in

vacuo and the residue puriﬁed by ﬂash chromatography

(2% EtOAc/CH₂Cl₂) to afford 8d as a yellow oil (0.058 g,

1

1728 cm^Ϫ1; H NMR (270 MHz, CDCl₃) d 7.34–7.22 (m,

5H), 7.03 (dd, J7.3, 7.3 Hz, 1H), 6.92 (d, J7.3 Hz, 1H),

6.58 (dd, J7.3 Hz, 1H), 6.35 (d, J7.3 Hz, 1H), 6.01 (s,

1H), 4.60 (d, J_AB16.1 Hz, 1H), 4.34 (d, J_AB16.1 Hz, 1H),

3.91 (s, 1H), 3.65 (m, 1H), 3.44 (m, 1H), 2.27 (m, 1H), 2.16

(m, 1H); ¹³C NMR (67.5 MHz, CDCl₃) d 170.4, 154.6 (q,

²J_C,F36.8 Hz), 149.5, 137.1, 129.7, 128.9, 128.8, 128.7

(2C), 127.43, 127.3 (2C), 122.5, 117.8, 116.2 (q,

¹J_C,F287.2 Hz) 106.8, 76.5, 49.9, 49.2, 42.6, 39.3;

HRMS (EI, 70 eV) m/z 397.1260 ([M]^ϩcalcd for

C₂₁H₁₆N₄OF₃, 397.1276).

1

0.12 mmol, 98%). IR (NaCl) 1743, 1720, 1692 cm^Ϫ1; H

NMR (270 MHz, CDCl₃) d 7.28–7.12 (m, 5H), 6.76–6.65

(m, 4H), 4.82 (s, 1H), 4.63 (d, J_AB15.6 Hz, 1H), 4.38 (d,

J_AB15.6 Hz, 1H), 3.88 (m, 1H), 3.76 (s, 3H), 3.72 (s, 3H),

3.65 (m, 1H), 3.28 (t, J6.8 Hz, 2H), 2.57 (td, J6.8,

2.0 Hz, 2H), 1.95 (t, J2.0 Hz, 1H), 1.60 (m, 1H), 1.45

(m, 1H); ¹³C NMR (67.5 MHz, CDCl₃) d 172.2, 167.6,

166.6, 164.2, 148.3, 142.1, 137.8, 131.6, 129.9, 128.6

(2C), 128.0 (2C), 127.7, 121.9, 119.4, 116.3, 111.6, 83.1,

68.6, 67.1, 53.53, 53.48, 52.5, 52.2, 43.3, 37.1, 34.4, 13.7;

HRMS (EI, 70 eV) m/z 497.1985 ([M]^ϩcalcd for

C₂₉H₂₇N₃O₅, 497.1951).

Cycloaddition of 5e; cycloadduct 10. A solution of 5e

(0.05 g, 0.15 mmol) in Ac₂O (2 mL) was reﬂuxed for 1 h.

After evaporating the mixture to dryness, the residue was

puriﬁed by ﬂash chromatography (5% EtOAc/CH₂Cl₂) to

give 10 as a colorless oil (0.06 g, 0.14 mmol, 93%). IR

1

(NaCl) 1740, 1680 cm^Ϫ1; H NMR (270 MHz, CDCl₃) d

7.32–7.23 (m, 5H), 7.09 (dd, J6.8, 6.8 Hz, 1H), 7.02 (s,

1H), 6.87 (d, J6.8 Hz, 1H), 6.64 (dd, J7.8, 6.8 Hz, 1H),

6.45 (d, J7.8 Hz, 1H), 4.74 (d, J_AB16.1 Hz, 1H), 4.51 (d,

J_AB16.1 Hz, 1H), 4.12 (s, 1H), 4.02–3.96 (m, 2H), 2.53 (s,

3H), 2.25 (m, 1H), 2.15 (s, 3H), 2.04 (s, 3H), 1.92 (m, 1H);

¹³C NMR (67.5 MHz, CDCl₃) d 172.6, 170.2, 169.7, 157.5,

149.9, 137.1, 130.1, 129.2, 128.7 (2C), 127.45, 127.38 (2C),

122.5, 118.1, 107.6, 71.8, 70.8, 49.4, 48.6, 44.3, 35.5, 25.4,

21.8, 20.9; HRMS (EI, 70 eV), m/z 447.2002 ([Mϩ1]^ϩ

calcd for C₂₅H₂₇N₄O₄, 447.2032).

Cycloaddition of 8d; cycloadduct 13. A solution of 8d

(0.05 g, 0.10 mmol) in TIPB (2 mL) was reﬂuxed for 12 h.

The reaction mixture was transferred directly to a silica gel

column and puriﬁed by ﬂash chromatography (5% EtOAc/

CH₂Cl₂) to afford 13 as a colorless oil (16 mg, 0.03 mmol,

31%). IR (NaCl) 1744, 1724, 1693 cm^Ϫ1

;

¹H NMR

(270 MHz, CDCl₃) d 7.96 (s, 1H), 7.79 (d, J8.8 Hz,

1H), 7.29–7.07 (m, 7H), 6.99 (s, 1H), 5.24 (s, 2H), 4.40

(m, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.08 (m, 2H), 2.86 (t,

J7.3 Hz, 2H), 2.68 (t, J7.3 Hz, 2H); ¹³C NMR

(67.5 MHz, CDCl₃) d 170.0, 167.0, 164.9, 154.1, 150.0,

137.7, 137.0, 136.6, 128.7 (2C), 128.4, 127.5, 126.8 (2C),

126.4, 121.7, 121.5, 119.5, 119.0, 118.4, 112.2, 109.5, 53.0,

52.7, 49.9, 42.0, 30.8, 23.51, 23.45; HRMS (EI, 70 eV) m/z

497.1973 ([M]^ϩcalcd for C₂₉H₂₇N₃O₅, 497.1951).

Cycloaddition of 5g; cycloadduct 9d. A solution of 5g

(0.5 g, 1.28 mmol) was reﬂuxed in mesitylene (3 mL) for

10 min. After cooling, the mixture was puriﬁed by passing

through a short SiO₂column (4% MeOH/CH₂Cl₂), affording

9d as a yellow solid (0.46 g, 1.28 mmol, 99%). Mp 126–

128ЊC; IR (NaCl) 1737 cm^Ϫ1; ¹H NMR (270 MHz, CDCl₃)

d 7.30–7.19 (m, 6H), 6.97 (d, J6.8 Hz, 1H), 6.79 (m, 2H),

4.77 (d, J_AB14.6 Hz, 1H), 4.46 (d, J_AB14.6 Hz, 1H), 4.04

(s, 1H), 2.33 (s, 3H), 2.30 (d, J_AB16.6 Hz, 1H), 2.12 (d,

J_AB16.6 Hz, 1H) (NH was not observed); ¹³C NMR

(67.5 MHz, CDCl₃) d 179.3, 166.4, 164.2, 147.2, 137.0,

131.1, 130.0, 128.7 (2C), 128.2, 128.1 (2C), 121.8, 120.9,

111.0, 65.7, 54.0, 49.6, 46.4, 13.4; HRMS (EI, 70 eV) m/z

362.1223 ([M]^ϩcalcd for C₂₀H₁₈N₄OS, 362.1201).

Deacetylation and reacylation of 9b; cycloadduct 9e. A

solution of 9b (0.50 g, 1.36 mmol) in MeOH (3 mL) was

stirred with K₂CO₃(0.38 g, 2.72 mmol) for 4 h. The mixture

was ﬁltered, and the ﬁltrate partitioned between EtOAc

(10 mL) and H₂O (5 mL). The organic phase was separated,

dried over Na₂SO₄, then the solvent removed in vacuo to

afford N-benzylindolino[2,3-d]pyrrolidino[2,3-e]-3-cyano-

4,5-dihydropyridine as a yellow solid (0.43 g, 1.33 mmol,

1

98% yield, 99% pure by H NMR), which was used in the

next step without further puriﬁcation. Mp Ͼ250ЊC (dec); IR

1

Cycloadduct 8d. A solution of 8b (0.50 g, 1.09 mmol) in

MeOH (3 mL) was stirred with K₂CO₃(0.30 g, 2.2 mmol)

for 4 h. The mixture was ﬁltered, and the ﬁltrate concen-

trated in vacuo to afford dimethyl N-benzylindolino[2,3-

d]pyrrolidino[2,3-e]-4,5-dihydropyridine-2,3-dicarboxylate

as a pale yellow oil (0.45 g, 1.08 mmol, 98% yield, 99%

pure by ¹H NMR), which was used in the next step without

(neat) 2223 cm^Ϫ1; H NMR (270 MHz, CD₃OD) d 7.32–

7.25 (m, 5H), 7.13 (dd, J7.3, 7.3 Hz, 1H), 6.79–6.75 (m,

2H), 6.68 (dd, J7.3, 7.3 1H), 4.81 (d, J_AB15.1 Hz, 1H),

4.67 (s, 1H), 4.55 (d, J_AB15.1 Hz, 1H), 3.58 (m, 2H), 2.08

(m, 1H), 1.61 (bdd, J12.5, 4.6 Hz, 1H); ¹³C NMR

(67.5 MHz, CD₃OD) d 158.8, 147.6, 137.7, 131.1, 129.4,

128.5 (2C), 127.9 (2C), 127.8, 127.5, 122.1, 119.3, 117.2,

110.8, 66.2, 54.3, 51.5, 51.1, 40.0; HRMS (CI, 140 eV,

NH₃) m/z 327.1515 ([Mϩ1]^ϩcalcd for C₂₀H₁₇N₅,

327.1484).

1

further puriﬁcation. IR (neat) 1734, 1692 cm^Ϫ1; H NMR

(270 MHz, CDCl₃) d 7.26–7.19 (m, 5H), 7.11 (ddd, J7.8,

7.3, 1.0 Hz, 1H), 6.89 (dd, J7.3, 1.0 Hz, 1H), 6.67 (ddd,

J7.8, 7.3, 1.0 1H), 6.62 (dd, J7.8, 1.0 Hz, 1H), 4.70 (s,

1H), 4.65 (d, J_AB15.4 Hz, 1H), 4.49 (d, J_AB15.4 Hz, 1H),

3.72 (s, 3H), 3.63 (s, 3H), 3.46 (m, 1H), 3.34 (m, 1H), 1.77

(m, 1H), 1.51 (m, 1H); ¹³C NMR (67.5 MHz, CDCl₃) d

171.8, 168.0, 148.6, 147.1, 138.6, 131.9, 129.4, 128.4 (2C),

128.0, 127.9 (2C), 127.3, 122.0, 118.8, 111.3, 108.6, 67.0,

53.7, 53.5, 52.3, 51.6, 42.2, 38.7; HRMS (CI, 140 eV, NH₃)

m/z 418.1717 ([Mϩ1]^ϩcalcd for C₂₄H₂₄N₃O₄, 418.1767).

To a solution of (0.05 g, 0.12 mmol) N-benzylindolino-

[2,3-d]pyrrolidino[2,3-e]-3-cyano-4,5-dihydropyridine (0.1 g,

0.30 mmol) and 4-pentynoic acid (0.03g, 0.30 mmol) in

CH₂Cl₂(2 mL) was added DCC (0.07g, 0.33 mmol) and

DMAP (15 mg, 0.13 mmol), and the mixture was stirred

at rt for 3 h. The reaction mixture then was cooled to 0ЊC

to precipitate the N,N⁰-dicyclohexylurea, and the mixture

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

1179

2. Reviews and overviews: (a) Boger, D. L. Tetrahedron 1983, 39,

2869–2939. (b) Boger, D. L. Chem. Rev. 1986, 86, 781–793. (c)

Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in

Organic Synthesis; Organic Chemistry Monograph Series; Vol. 47;

Academic: New York, 1987; (especially Chapter 10). (d)

Kametani, T.; Hibino, S. In Advances in Heterocyclic Chemistry;

Katritzky, A. R., Ed.; Academic: New York, 1987; Vol. 42, pp

245–333. (e) Boger, D. L.; Patel, M. Prog. Heterocycl. Chem.

1989, 1, 30–64. (f) Boger, D. L. Bull. Soc. Chim. Belg. 1990, 99,

599–615. (g) Boger, D. L. Chemtracts: Org. Chem. 1996, 9, 149–

189. (h) Boger, D. L. J. Heterocycl. Chem. 1996, 33, 1519–1531.

3. Review: Lee, L.; Snyder, J. K. In Advances in Cycloadditions;

Harmata, M., Ed., JAI Press: Stamford, CT, 1999; Vol. 6; pp 119–

171.

4. (a) Kraus, G. A.; Raggon, J.; Thomas, P. J.; Bougie, D.

Tetrahedron Lett. 1988, 29, 5605–5608. (b) Kraus, G. A.; Bougie,

D.; Jacobson, R. A.; Su, Y. J. Org. Chem. 1989, 54, 2425–2428. (c)

Benson, S. C.; Li, J.-H.; Snyder, J. K. J. Org. Chem. 1992, 57,

5285–5287. (d) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60,

6258–6259. (e) Fan, W.-H.; Parikh, M.; Snyder, J. K. Tetrahedron

Lett. 1995, 36, 6591–6594. (f) Padwa, A.; Semones, M. A.

Tetrahedron Lett. 1996, 37, 335–338. (g) Padwa, A.; Harring, S.

R.; Semones, M. A. J. Org. Chem. 1998, 63, 44–54. (h) Padwa, A.;

Price, A. T. J. Org. Chem. 1998, 63, 556–565. (i) Padwa, A.;

Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998, 63, 5304–

5305. (j) Wan, Z.-K.; Snyder, J. K. Tetrahedron Lett. 1998, 39,

2487–2490.

ﬁltered through a pad of Celite. The solvent was removed

from the ﬁltrate in vacuo and the residue puriﬁed by ﬂash

chromatography (3% EtOAc/CH₂Cl₂) to afford 9e as a

yellow solid (0.12 g, 0.29 mmol, 99%). Mp 76–78ЊC; IR

(NaCl) 2230, 2120, 1693 cm^Ϫ^{1 1}H NMR (270 MHz,

;

CDCl₃) d 7.33–7.21 (m, 5H), 6.83–6.75 (m, 4H), 4.87 (d,

J_AB15.1 Hz, 1H), 4.65 (d, J_AB15.1 Hz, 1H), 4.21 (s, 1H),

4.03 (ddd, J9.8, 7.8, 2.0 Hz, 1H), 3.71 (m, 1H), 3.36 (t,

J7.3 Hz, 1H), 2.59 (td, J7.3, 2.9 Hz, 1H), 1.96 (t,

J2.9 Hz, 2H), 1.83 (m, 2H); ¹³C NMR (67.5 MHz,

CDCl₃) d 171.9, 157.1, 147.3, 139.7, 136.3, 130.7, 129.0

(2C), 128.9 128.3, 128.1 (2C), 122.2, 120.2, 115.7, 110.8,

82.7, 69.0, 64.0, 51.7, 49.5, 43.3, 37.6, 35.2, 13.8; HRMS

(EI, 70 eV) m/z 407.1747 ([M]^ϩcalcd for C₂₅H₂₁N₅O,

407.1746).

Cycloaddition of 5l; cycloadduct 16a. A solution of 5l

(0.50 g, 1.10 mmol) in CH₂Cl₂(5 mL) was reﬂuxed for

1 h. The solvent was removed in vacuo and the residue

puriﬁed by ﬂash chromatography (3% EtOAc/CH₂Cl₂) to

afford 16a as a white solid (0.47 g, 1.10 mmol, 99%). Mp

1

179–180ЊC; IR (NaCl) 1682 cm^Ϫ1; H NMR (270 MHz,

CDCl₃) d 7.74 (dd, J6.9, 1.0 Hz, 1H), 7.30–7.05 (m,

8H), 7.01 (s, 1H), 7.00 (s, 1H), 5.22 (s, 2H), 4.54 (t,

J7.8 Hz, 2H), 3.17 (t, J7.8 Hz, 2H), 2.67 (s, 3H), 2.63

(m, 2H), 2.59 (m, 2H); ¹³C NMR (67.5 MHz, CDCl₃) d

169.1, 157.5, 152.9, 137.7, 136.4, 128.7 (2C), 128.4,

127.5, 126.9, 126.8 (2C), 126.3, 124.5, 121.6, 119.4,

119.0, 112.1, 109.4, 49.8, 41.7, 30.2, 23.4, 23.1, 13.4;

HRMS (EI, 70 eV) m/z 428.1628 ([M]^ϩcalcd for

C₂₅H₂₄N₄OS, 428.1671).

5. Benson, S. C.; Lee, L.; Snyder, J. K. Tetrahedron Lett. 1996, 37,

5061–5064.

6. S_NAr reactions of 1,2,4,5-tetrazines: (a) Wiley, P. F. In

Chemistry of 1,2,3-Triazines, 1,2,4-Triazines, Tetrazines, and

Pentazines; Weissberger, A., Taylor, E. C., Eds.; The Chemistry

of Heterocyclic Compounds Monograph Series; Vol. 33; John

Oxidation of 16a; sulfoxide 16b. To a solution of 16a

(0.25 g, 0.58 mmol) in CH₂Cl₂(2 mL) cooled to Ϫ78ЊC

was added with stirring m-CPBA (0.20 g, 0.58 mmol).

After 3 h the reaction was quenched by the addition of

Na₂SO₃(0.10 g) and the solid residue ﬁltered after allowing

to warm to rt. The ﬁltrate was evaporated in vacuo and the

residue puriﬁed by ﬂash chromatography to afford 16b as a

white solid (0.24 g, 0.54 mmol, 92%). Mp 193–194ЊC; IR

¨

Wiley & Sons: New York, 1978; pp 1089–1111. (b) Neunhoffer,

H. In Comprehensive Heterocyclic Chemistry; Boulton, A. J.;

McKillop, A., Eds.; Pergamon: New York, 1984; Vol. 3, Part

¨

2B, pp 399–429. S_NAr reactions of 1,2,4-triazines: (c) Neunhoffer,

H. In Chemistry of 1,2,3-Triazines, 1,2,4-Triazines, Tetrazines, and

Pentazines; Weissberger, A., Taylor, E. C., Eds.; The Chemistry of

Heterocyclic Compounds Monograph Series; Vol. 33; John Wiley

& Sons: New York, 1978; pp 189–1072. S_NAr reactions of

pyridazines: (d) Aldous, D. L.; Castle, R. N. In Pyridazines;

Weissberger, A., Taylor, E. C., Eds.; The Chemistry of Hetero-

cyclic Compounds Monograph Series; Vol. 28, Chapter 3; John

Wiley & Sons: New York, 1973; pp 248–274. (e) Tisler, M.;

Stanovnik, B. In Comprehensive Heterocyclic Chemistry; Boulton,

A. J., McKillop, A., Eds.; Pergamon: New York, 1984; Vol. 3, Part

2B; pp 23–29.

7. Preparation of 2a, see Supplementary Material from: Boger,

D. L.; Sakya, S. M. J. Org. Chem. 1988, 53, 1415–1423.

8. Preparation of 2b and 2c: Fields, S. C.; Parker, M. H.; Erickson,

W. R. J. Org. Chem., 1994, 59, 8284–8287. For ¹H NMR data of

2b, see Ref. [9a].

1

(NaCl) 1700, 1056 cm^Ϫ1; H NMR (270 MHz, CDCl₃) d

7.83 (s, 1H), 7.70 (d, J7.3 Hz, 1H), 7.30–7.06 (m, 8H),

6.99 (s, 1H), 5.21 (s, 2H), 4.58 (t, J7.3 Hz, 2H), 3.16 (t,

J7.3 Hz, 2H), 2.96 (s, 3H), 2.87 (t, J8.3 Hz, 2H), 2.66 (t,

J8.3 Hz, 2H); ¹³C NMR (67.5 MHz, CDCl₃) d 169.0,

164.6, 155.8, 137.5, 136.4, 128.96, 128.7 (2C), 128.2,

127.5, 126.8 (2C), 126.3, 121.7, 121.4, 119.2, 119.0,

111.8, 109.5, 49.8, 42.3, 41.9, 29.8, 23.6, 23.1; HRMS

(EI, 70 eV) m/z 443.9765 ([M]^ϩcalcd for C₂₅H₂₄N₄O₂S,

443.9949).

Acknowledgements

9. Other examples of S_NAr displacements of methylthiolate from

1,2,4,5-tetrazines: (a) Mangia, A.; Bortesi, F.; Amendola, U.

J. Heterocycl. Chem. 1977, 14, 587–593. (b) Seitz, G.; Go¨rge, L.;

Dietrich, S. Tetrahedron Lett. 1985, 26, 4355–4358. (c) Panek,

J. S.; Zhu, B. Tetrahedron Lett. 1996, 37, 8151–8154. (d) Sakya,

S. M.; Groskopf, K. K.; Boger, D. L. Tetrahedron Lett. 1997, 38,

3805–3808. (e) Boger, D. L.; Schaum, R. P.; Garbaccio, R. M.

J. Org. Chem. 1998, 63, 6329–6337.

We are grateful to the National Science Foundation (CHE-

9501069) and the Boston University Undergraduate Research

Opportunity Program for ﬁnancial support (to L. Y.).

References

1. From: Lee, L. PhD dissertation, Boston University, Boston,

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1180

S. C. Benson et al. / Tetrahedron 56 (2000) 1165–1180

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¨

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converting rotamers about the carbamate.

26. N-BOC-(l)-tryptophan methyl ester was prepared from l-tryp-

tophan (1 g, 4.9 mmol) by standard procedures: esteriﬁcation of

l-tryptophan by MeOH/SOCl₂(96%) as described in the prepa-

ration of 1d, followed by BOC-protection (98%) as described in

the preparation of 1b.

27. Resonances were severely broadened in the spectra recorded at

ambient temperature due to inconverting rotamers.

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Article Doi

Intramolecular inverse electron demand Diels-Alder reactions of tryptamine with tethered heteroaromatic azadienes

DOI: 10.1016/S0040-4020(00)00003-X

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