Batch and flow photochemical benzannulations based on the reaction of ynamides and diazo ketones. application to the synthesis of polycyclic aromatic and heteroaromatic compounds

Article

pubs.acs.org/joc

Batch and Flow Photochemical Benzannulations Based on the

Reaction of Ynamides and Diazo Ketones. Application to the

Synthesis of Polycyclic Aromatic and Heteroaromatic Compounds

Thomas P. Willumstad, Olesya Haze, Xiao Yin Mak, Tin Yiu Lam, Yu-Pu Wang, and Rick L. Danheiser*

Department of Chemistry Massachusetts Institute of Technology Cambridge, Massachusetts 02139

S

* Supporting Information

ABSTRACT: Highly substituted polycyclic aromatic and

heteroaromatic compounds are produced via a two-stage tandem

benzannulation/cyclization strategy. The initial benzannulation

step proceeds via a pericyclic cascade mechanism triggered by

thermal or photochemical Wolﬀ rearrangement of a diazo ketone.

The photochemical process can be performed using a continuous

ﬂow reactor which facilitates carrying out reactions on a large scale and minimizes the time required for photolysis. Carbomethoxy

ynamides as well as more ketenophilic bis-silyl ynamines and N-sulfonyl and N-phosphoryl ynamides serve as the reaction partner in

the benzannulation step. In the second stage of the strategy, RCM generates benzofused nitrogen heterocycles, and various

heterocyclization processes furnish highly substituted and polycyclic indoles of types that were not available by using the previous

cyclobutenone-based version of the tandem strategy.

Scheme 1. Tandem Benzannulation−Cyclization Strategies

Based on Cyclobutenones as Vinylketene Precursors

INTRODUCTION

■

The design and invention of improved methods for the

synthesis of benzofused nitrogen heterocycles continues to

command a great deal of attention from laboratories in

synthetic organic chemistry. Driving this interest are the

numerous natural products and pharmaceutical compounds

whose structures incorporate these heterocyclic systems. The

great majority of synthetic approaches to benzofused nitrogen

heterocycles involves cyclization of ortho-substituted aniline

derivatives, but the application of these strategies to the

synthesis of systems bearing a high level of substitution on the

benzenoid ring is often problematic due to the challenges

associated with the regioselective preparation of the requisite

polysubstituted anilines.

Convergent benzannulation strategies¹provide the most

attractive approach for the regiocontrolled construction of multiply

substituted benzenoid aromatic systems. Our laboratory has

developed two complementary benzannulation strategies based on

the reaction of alkynes and vinylketenes²⁻⁴and we have applied

these methods to the synthesis of a number of bioactive natural

products.^5,6Recently we extended the cyclobutenone-based

version of this benzannulation strategy to include ynamine

derivatives, demonstrating that the use of certain ynamides as

alkyne reaction partners suppresses side reactions that are

observed in reactions with simple ynamines. When employed in

conjunction with ring-closing metathesis, this version of our

benzannulation method provides an eﬃcient “tandem” strategy for

the synthesis of highly substituted dihydroquinolines, benzaze-

pines, and benzazocines, including a key intermediate in a formal

total synthesis of (+)-FR900482.⁷In the ﬁrst stage of the tandem

strategy, benzannulations using ynamine derivatives 2 (Z =

electron-withdrawing group) and cyclobutenones 1 furnish

anilines having general structure 3 (Scheme 1). Application of

ring-closing metathesis (or other cyclization methods) to 3 then

leads to benzofused heterocycles of type 4 or type 5, depending

on the substitution of the aniline derivative and the cyclization

method employed. Further research in our laboratory has focused

on the application of various heterocyclization processes in an

extension of this “tandem strategy” to the synthesis of indoles

bearing a high level of substitution on the six-membered ring.⁸

While the cyclobutenone-based benzannulation depicted in

Scheme 1 is eﬀective for the synthesis of a wide range of

substituted anilines, polycyclic systems of type 6 present a

challenge. As outlined in Scheme 2, the synthesis of polycyclic

aniline derivatives with this general structure would require

benzannulation with a cyclobutenone of type 7 as the vinyl-

ketene precursor. The synthesis of fused-ring cyclobutenones of

this type generally requires lengthy and ineﬃcient routes,⁹and

Received: September 10, 2013

Published: October 11, 2013

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synthesis of benzofused nitrogen heterocycles, the polycyclic

aniline derivatives generated in this fashion would be subjected

to various heterocyclization processes providing access to a

wide variety of heterocyclic systems that were not available via

our previous cyclobutenone-based strategy.

Scheme 2. Benzannulation Disconnection for Polycyclic

Compounds

RESULTS AND DISCUSSION

■

Synthesis of Benzannulation Reaction Partners. The

benzannulation reaction partners employed in this investigation

were easily prepared by using standard methods. For the

synthesis of ynamides,^11,12we employed the closely related

copper-promoted N-alkynylation methods previously devel-

oped in our laboratory¹³and that of Hsung.¹⁴Both methods

involve the reaction of amine derivatives with alkynyl bromides,

which are themselves readily obtained from terminal alkynes or

silyl alkynes by reaction with NBS in the presence of catalytic

silver nitrate.¹⁵The Hsung N-alkynylation protocol utilizes

catalytic CuCN or CuSO₄in conjunction with diamine ligands

and requires elevated temperatures, while our complementary

procedure employs 1 equiv of CuI but has the advantage of

proceeding at room temperature and thus being applicable to

thermally sensitive systems.¹⁶All of the ynamides required for this

study were known compounds with the exception of 15 which

was prepared by our N-alkynylation method as outlined in eq 1.

some potential substrates of interest are expected to be

prohibitively strained compounds.

In order to extend the benzannulation to include the

synthesis of polycyclic systems, we previously developed a

“second generation” variant of our strategy in which α-diazo

ketones are employed as vinylketene precursors in place of

cyclobutenones.^2bDiazo ketones of type 8 are readily available

(vide infra) by a number of straightforward routes and provide

eﬃcient access to the requisite ketenes via Wolﬀ rearrange-

ment.¹⁰In this contribution we report the application of this

“second generation” version of our strategy for the ﬁrst time to

reactions in which ynamine derivatives function as the alkyne

benzannulation partners. On the basis of our previous studies,

the proposed benzannulation was expected to proceed via the

“pericyclic cascade” mechanism outlined in Scheme 3.

Scheme 3. Pericyclic Cascade Mechanism of

Benzannulations Based on Diazo Ketones

The most popular synthetic routes to α-diazo ketones¹⁷involve

either the reaction of carboxylic acid derivatives with diazo

compounds or the reaction of ketones with sulfonyl azides (“diazo

transfer”). For the synthesis of the α,β-unsaturated diazo ketone

benzannulation partners used in this study, we employed the

detriﬂuoroacetylative diazo transfer protocol previously developed

in our laboratory.¹⁸

Initial Photochemical Benzannulation Studies. We

initially examined the reaction of the diazo ketone 16 derived

from acetylcyclohexene to determine the feasibility of employing

ynamides in the photo-Wolﬀ variant of the vinylketene-based

benzannulation strategy. Table 1 summarizes our results. Irradiation

was carried out in quartz tubes positioned ca. 20 cm from a Hanovia

450 W medium-pressure mercury lamp in a water-cooled quartz

immersion well and was continued until TLC analysis indicated

complete consumption of the diazo ketone. As we have noted in

some prior photochemical benzannulations, at that point the

reaction mixture consists of varying amounts of the desired

phenolic annulation product and the intermediate vinylcyclobu-

tenone (i.e., 10 in Scheme 3). The buildup of colored polymers on

the walls of the reaction tube apparently impedes the complete

conversion of vinylcyclobutenone to product even on prolonged

irradiation. Consequently, the crude reaction products were

generally heated to complete the conversion of vinylcyclobutenone

to phenol.

Irradiation (or thermolysis) of diazo ketones of type 8 would

generate the vinylketene 9, which would be intercepted by the

ynamide reaction partner 2 in a regioselective [2 + 2]

cycloaddition to furnish vinylcyclobutenone 10. Reversible

electrocyclic cleavage of 10 under the inﬂuence of heat or light

would then lead to the dienylketene 11, and rapid 6-π

electrocyclic ring-closure and tautomerization would ﬁnally

aﬀord the polysubstituted aniline derivative 12. In principle,

this version of the benzannulation should proceed smoothly

not only with cyclic α,β-unsaturated diazo ketones of type 8,

but also with a variety of aryl and hetaryl diazo ketones. For the

The desired benzannulation product 18 was obtained in 48%

yield when 1.0 equiv of diazo ketone was used (Table 1, entry 1).

We hypothesized that competing processes involving the

intermediate vinylketene such as dimerization were limiting the

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compared to the more reactive vinylketene derived from 16.

Consequently, the desired [2 + 2] cycloaddition with ynamide

competes more eﬃciently and the desired naphthylamine 20 is

obtained in good yield without the need for slow addition to

minimize ketene concentration.

Table 1. Optimization of the Photochemical Benzannulation

Reactivity of Ynamine Derivatives in Ketene [2 + 2]

Cycloadditions and Benzannulation. The competitive

dimerization of vinylketenes presents a particular problem in

the “second-generation” photo-Wolﬀ version of the benzannu-

lation due to the fact that the ketene intermediates are generated

more rapidly and in higher concentration as compared to

generation via thermolysis of cyclobutenones. Although this

problem can be mitigated by the use of slow addition and by

employing an excess of ketene precursor, these measures are less

than ideal, and we therefore became interested in replacing

carbomethoxy ynamides such as 17 with ynamides that would

exhibit greater ketenophilicity in the [2 + 2] cycloaddition step of

the pericyclic cascade.

Previously, it has been shown that N-carbonyl substituents

reduce the electron-donating ability of nitrogen atoms to a

greater extent than N-sulfonyl groups, a consequence of the

more signiﬁcant π-delocalization of the nitrogen lone pair

present in the carbonyl derivatives.^19,20To conﬁrm our

prediction that N-sulfonyl ynamides would therefore exhibit

increased reactivity in ketene [2 + 2] cycloadditions, we carried

out the competition experiment outlined in eq 3. Reaction of an

a

diazo ketone

(equiv)

irradiation time

(h)

yield

b

entry

solvent

CH₂Cl₂

(%)

1

2

3

4

5

1.0

2.5

1.5

2.5

8

5.5

4.5

10

9

48

67

CH₂Cl₂

c

CH₂Cl₂

65

c

CH₂Cl₂

85

c,d

ClCH₂CH₂Cl

73

a

b

c

Irradiation with a 450 W medium-pressure mercury lamp (220−600 nm).

Isolated yields of products puriﬁed by column chromatography.

A solution of diazo ketone (0.4 M) was added to the ynamide

d

solution via syringe pump (ca. 0.009 mL/min). Heated in DCE

(reﬂux, 24 h) after irradiation.

yield, so we explored employing an excess of the diazo ketone for

the reaction. In fact, when 2.5 equiv of diazo ketone was used, the

yield improved to 67% (entry 2), and the yield also increased

dramatically when the reaction was performed using slow addition

of the diazo ketone (entry 3). Finally, the desired benzannulation

product was generated in 85% yield when both slow addition was

employed and the amount of diazo ketone was increased from 1.5

to 2.5 equiv (entry 4).

Dichloromethane was found to be the optimal solvent for the

photochemical Wolﬀ rearrangement. In our standard protocol,

after irradiation for the indicated time the solution was

concentrated and the solvent replaced with toluene. Heating

at reﬂux then resulted in rapid conversion of any remaining

intermediate vinylcyclobutenone to the desired phenolic

product. For convenience, the benzannulation can be carried

out without the need for solvent exchange by employing 1,2-

dichloroethane (bp 83 °C), but in this case heating for 24 h is

required to complete the reaction (entry 5).

For most benzannulations we found that optimal yields were

obtained by employing a Hanovia 450 W medium-pressure

mercury lamp for irradiation. However, in some cases

comparable results were obtained by employing a standard

Rayonet photochemical reactor equipped with a circular array

of 16 254-nm low-pressure mercury lamps. In the case of the

prototypical benzannulation described in Table 1, irradiation

for 1 h in a Rayonet reactor using 1 equiv of diazo ketone 16

produced 18 in somewhat lower yield (40%) as compared to

reaction with the standard Hanovia protocol (entry 1).

Not unexpectedly, the optimal conditions for eﬀecting

benzannulations with aryl diazo ketones diﬀered from the

protocol described above for α,β-alkenyl derivatives. In the case

of α-diazoacetophenone (19), benzannulation proceeded in

good yield using only 1.1 equiv of the diazo ketone and without

the need for slow addition (eq 2). Wolﬀ rearrangement of 19

equimolar mixture of ynamides 21^13aand 22^14bwith excess

ketene in the presence of an internal standard indicated that the

N-sulfonyl derivative indeed reacts at a rate twice that of the

carbomethoxy ynamide.²¹

As expected, ynamide 25^14ewith the even less electron-

withdrawing phosphoryl group displays an even higher level of

ketenophilicity. In the competition experiment shown in eq 4,

we observed that the N-phosphoryl ynamide undergoes [2 + 2]

cycloaddition at a rate 5 times faster than the sulfonamide.

Finally, a third competition experiment comparing the

reactivity of the carbomethoxy ynamide and the phosphoryl

derivative indicated that the rate of reaction of the phosphoryl

ynamide is ca. 8 times that of the carbamate (eq 5).

generates phenylketene, which has less tendency to undergo

dimerization and other unproductive side reactions as

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reactions conducted in continuous ﬂow are conveniently scaled

up, a signiﬁcant problem and longstanding constraint when

conducting photochemistry using standard batch reactors.

In the case of the “second generation” photo-Wolﬀ-based

benzannulation, we anticipated that the use of a continuous-

ﬂow photochemical reactor would increase the eﬃciency of the

reaction, allow for shorter photolysis times, facilitate carrying

out large-scale reactions, and would lead to an increase in the

yield of benzannulations by minimizing side reactions involving

photoreactive aniline products. We based the design of our

single-pass continuous ﬂow reactor on the very practical and

easily assembled system described by Booker-Milburn and co-

workers.²⁶UV-transparent ﬂuorinated ethylene propylene

(FEP) tubing (0.76 mm i.d., 1.59 mm o.d.) was wound around

a standard water-jacketed quartz immersion well into which was

placed a 450 W medium pressure mercury lamp. In most cases

irradiation was conducted through a Pyrex ﬁlter as this served

to reduce polymer buildup on the walls of the tubing. A syringe

pump was employed to drive the reaction solution (ca. 0.25 M

in ynamide and diazo ketone) through the tubing at a ﬂow rate

of 0.057−0.32 mL/min (vide infra). The residence time in the

irradiated section of tubing ranged from 21 to 33 min, and the

throughput with this reactor was typically 0.9 mmol/h.²⁷

Table 2 summarizes the results of our investigation of the

photochemical benzannulation reaction performed both as a

batch process and using the continuous-ﬂow reactor. The

photochemical benzannulation of α,β-alkenyl diazo ketone 16

was examined ﬁrst. As discussed previously, as a batch process

the reaction of 16 with N-carbomethoxy ynamide 17 is best

performed using slow addition of excess diazo ketone to a

solution of the ynamide in order to maintain the vinylketene

intermediate in low concentration and thus to minimize its

dimerization. This slow addition protocol is not easily applied

in a continuous ﬂow photolysis, and so for benzannulations

using α,β-alkenyl diazo ketones, we have found that the more

ketenophilic N-phosphoryl ynamides such as 25 are the

preferred reaction partners. Using 25, benzannulation with

only 1.1 equiv of diazo ketone 16 provides the desired product

(29) in 66% yield when carried out as a batch process without

the need for slow addition. Irradiation of the same

benzannulation partners under conditions of continuous ﬂow

aﬀorded 29 in comparable yield (entry 2). Importantly, this

result established for the ﬁrst time the feasibility of conducting

the photochemical benzannulation under conditions of

continuous ﬂow. As discussed earlier, conducting photo-

chemical benzannulations under ﬂow enables the reaction to

be performed on multigram scale much more easily than would

be the case by employing conventional batch equipment.

It is worth noting with regard to the synthetic utility of N-

phosphoryl benzannulation products such as 29 that cleavage of

the protective group can be achieved either under acidic

conditions or by reaction with hydride reagents.²⁸Deprotection

of 29, for example, is readily accomplished upon heating with

Red-Al in toluene and furnishes 37 in 82% yield (eq 7).

N,N-Bis(trialkylsilyl) ynamines such as 27 were another class

of ynamine derivatives that we expected to exhibit increased

ketenophilicity compared to carbomethoxy derivatives. We

anticipated that these electron-rich alkynes would prove highly

reactive as benzannulation partners, furnishing aniline deriva-

tives that would also undergo deprotection under exceptionally

mild conditions. Of concern to us, however, was the known

sensitivity of this class of ynamines to acid and the possibility

that they might be unstable in the presence of the phenolic

products of the benzannulation.

The feasibility of employing silyl ynamines in the

benzannulation was investigated using the known ynamine 27

which we prepared by electrophilic amination of phenyl-

acetylene as described by Wurthwein.²²A stratagem for

̈

avoiding the potential destruction of the ynamine by phenolic

product was devised on the basis of our prior observation that

the electrocyclic ring-opening of vinylcyclobutenones does not

take place when irradiation is conducted through a uranium

ﬁlter. Uranium ﬁlters block wavelengths below 340 nm,

allowing photo-Wolﬀ rearrangement to take place but halting

the pericyclic cascade at the stage of intermediate 10 (Scheme 3).

Heating can then be employed to complete the benzannulation. In

the event, application of this protocol to the reaction of the

bis(silyl) ynamine 27 with 1.0 equiv of diazo ketone 19 aﬀorded

the desired aminonaphthol 28 in 61% overall yield (eq 6).

Unfortunately, attempts to extend the silyl ynamine

benzannulation to include heteroaryl or α,β-alkenyl diazo

ketones have not been fruitful, with reactions proceeding in low

(<30%) and variable yield. In view of the limited scope of this

variant of the benzannulation, the use of silyl ynamines have

not been investigated further.²³

Scope of Photochemical Benzannulations Performed

in Batch and Continuous Flow. In planning our systematic

investigation of the photo-Wolﬀ-based ynamide benzannula-

tion, we decided to examine reactions in which irradiation was

performed both in batch and under conditions of continuous

ﬂow. The advantages of continuous-ﬂow photochemical

reactors are now well established.^24,25Due to their higher

surface-to-volume ratio, ﬂow reactors allow for more uniform

and eﬃcient irradiation as compared to conventional batch

reactors where light does not penetrate a signiﬁcant distance

into the solution. Conducting photochemical reactions in ﬂow

also minimizes any secondary photo processes leading to the

decomposition of the desired products. Finally, photochemical

As shown in Table 2, benzannulations involving aryl and

hetaryl diazo ketones proceed smoothly with all three classes of

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Table 2. Photochemical Benzannulations Performed in Batch and Flow

a

b

Isolated yield of products puriﬁed by column chromatography. Batch reactions: 1.1 equiv of diazo ketone, irradiation (220−600 nm) for 3−8 h in

c

CH₂Cl₂; then reﬂux, toluene, 1.5−2.5 h. For entry 6, irradiation at >340 nm (uranium ﬁlter) for 50 h. Continuous-ﬂow reactions: 1.1 equiv of diazo

ketone, irradiation at >280 nm (Pyrex ﬁlter) in DCE, residence time = ca. 21 min; then reﬂux, DCE, 40−48 h (entries 2, 3, 6, and 7) or reﬂux,

toluene, 2 h (entries 4 and 5). For entry 6, irradiation at >340 nm (uranium ﬁlter), residence time = ca. 33 min. Slow addition of 2.5 equiv of diazo

d

e

ketone. Overall yield for 2 steps. Benzannulation product was treated with 1.2 equiv Tf₂O, 2 equiv 4-DMAP, CH₂Cl_2,0 °C to rt, 2−4 h.

ynamides when conducted using either a batch process or in

continuous ﬂow. Particularly notable are the syntheses of

indoles 31 and 33 (entries 4 and 5), demonstrating the ability

of this version of the benzannulation to provide access to

indoles bearing multiple substituents on the six-membered ring.

In the case of benzannulation with diazo ketone 32, puriﬁcation

was carried out after converting the air-sensitive phenolic

product to the corresponding triﬂate derivative. This measure

facilitated puriﬁcation, and in principle the triﬂate should serve

as a useful handle for the further synthetic elaboration of the

product via metal-catalyzed coupling reactions (vide infra).

Benzannulation using the N-sulfonyl ynamide 22 worked

well, but this benzannulation requires irradiation through a

uranium ﬁlter (>340 nm) in order to prevent photochemical

decomposition of the sulfonyl ynamide which most likely takes

place via a photo-Fries type process.²⁹In the case of the batch

process, irradiation at this longer wavelength necessitated an

increase in the photolysis time up to 50 h from the usual 3−8 h

employed in reactions of other ynamides. The alternative

continuous ﬂow protocol proved to be highly advantageous in

this case, as complete conversion could be achieved simply by

increasing the residence time from the usual 21 min to 33 min.

Feasibility of Triggering Benzannulations via Thermal

Wolﬀ Rearrangement. The next goal in our investigation

of the scope of the diazo ketone version of the benzannulation

was to determine the feasibility of eﬀecting the initial Wolﬀ

rearrangement step under thermal rather than photochemical

conditions.¹⁰If successful, this might allow us to extend this

version of the benzannulation to include photochemically unstable

ynamides and could also lead to improved yields in the case of

benzannulations that generate photochemically unstable products.

Initial experiments using cyclohexenyl diazo ketone 16 were

not encouraging. Once again, side reactions involving the

intermediate vinylketene competed with the desired [2 + 2]

cycloaddition with ynamide, and useful yields were only

obtained when the reaction was performed by slow addition

of a 2-fold excess of diazo ketone (eq 8).

Fortunately, both slow addition and the use of excess diazo

ketone were not necessary when the more ketenophilic

N-phosphoryl ynamide 25 was employed in the reaction. As

shown in eq 9, heating a solution of diazo ketone 16 and 25 at

reﬂux in toluene aﬀorded benzannulation product 29 in

essentially the same yield as obtained in the photochemical

process (Table 2, entry 2). The application of this thermal

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Scheme 5. Tandem Thermal Benzannulation−RCM

Wolﬀ-triggered benzannulation to reactions involving photo-

chemically unstable ynamides and aniline products is described

in the next section.

Tandem Ynamide Benzannulation−RCM Strategies.

The successful extension of our “second generation” strategy to

include ynamides as the alkyne benzannulation partners

provides access to polycyclic anilines that were not available

via the cyclobutenone-based version of the method. In

combination with ring-closing metathesis, this new variant of

benzannulation provides an attractive route to a variety of

polycyclic benzofused nitrogen heterocyclic systems. For

example, as illustrated in Scheme 4, benzannulation using

substituents on the benzenoid ring.⁸A limitation of this tandem

strategy, however, is that it cannot provide access to indoles with

certain substitution patterns and to indoles fused to additional ring

systems. As demonstrated below, the “second generation” variant

of the benzannulation strategy addresses these limitations and

extends the scope of this chemistry to include the construction of a

number of highly substituted polycyclic indoles.

Scheme 4. Tandem Photochemical Benzannulation−RCM

Table 3 illustrates one version of this tandem strategy.

Previously we have shown that benzannulations with ynamide

45⁸aﬀord products that undergo cyclization to indoles upon

exposure in one ﬂask to TBAF and then acid. As shown in

Table 3, irradiation of 45 with a variety of α,β-unsaturated diazo

ketones proceeds smoothly to aﬀord benzannulation products that

in most cases would not have been available via the cyclobutenone-

based method. Treatment in one pot with TBAF and then HCl

provides the desired indoles in good to excellent yield. Due to its

limited stability, the benzannulation product 54 (entry 4) was best

transformed to the corresponding triﬂate 55 prior to indole

formation. In this case, conversion to the indole was accomplished

in one step by brief exposure to excess TfOH at room

temperature.³³Particularly notable is the eﬃcient formation of

the indole 52, incorporating an interesting cyclobutarene system.³⁴

Due to their sensitivity to air oxidation, the indole products in

entries 2 and 3 were best isolated as their acetate or triﬂate

derivatives. The utility of the triﬂates as synthetic intermediates for

the further elaboration of the indole products is illustrated by the

Suzuki−Miyaura coupling shown in eq 10 which we found is best

accomplished by using Buchwald’s SPhos ligand.³⁵

ynamide 15 and α-diazoacetophenone (19) leads to the

formation of the highly substituted naphthol derivative 38 in

good yield. Exposure of 38 to the Grubbs II catalyst 39³⁰then

aﬀords naphthazocine derivative 40.

The advantages associated with using the thermal Wolﬀ

rearrangement to initiate the benzannulation cascade are

illustrated in the tandem benzannulation/RCM sequence

shown in Scheme 5. Prior experiments had taught us that

C-allyl ynamides such as 41 do not participate in photochemical

benzannulations in good yield due to the facile cyclization of

the o-allylphenol products that takes place on irradiation.³¹This

destructive side reaction is avoided when the benzannulation is

eﬀected thermally, and ring-closing metathesis then provides

the benzazepine 44 in excellent yield.³²

Synthesis of Indoles via Tandem Ynamide Benzannu-

lation−Cyclization Strategies. Recently, we demonstrated

that the combination of the cyclobutenone-based benzannula-

tion with various heterocyclization and annulation processes

provides an attractive route to indoles bearing multiple

N-Allyl ynamides serve as another useful building block in

our tandem benzannulation/heterocyclization strategy for the

synthesis of highly substituted indoles.⁸Oxidative cleavage of the

allyl double bond following benzannulation aﬀords an aldehyde

that undergoes cyclization to generate the desired indole upon

treatment with K₂CO₃or DBU followed by brief exposure to HCl.

Table 4 illustrates the application of this cyclization protocol

in conjunction with the “second generation” benzannulation to

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Table 3. Tandem Benzannulation/Cyclization Strategy for the Synthesis of Indoles

a

Irradiation (220−600 nm) of 45 and 2.4 equiv of diazo ketone (1.5 equiv in entry 4). In entries 1−3 diazo ketone was added over 3.5−5 h followed

b

by 1.0−6.5 h of further irradiation. In entry 4 a solution of 45 and 53 was irradiated for 2.5 h. Isolated yield of products puriﬁed by column

chromatography. Overall yield from 48 for cyclization and acetylation (1.2 equiv AcCl, 2.2 equiv Et₃N, CH₂Cl₂, 0 °C to rt, 2.5 h). In this case

reaction with HCl was conducted at rt for 41 h. Overall yield from 51 for cyclization and triﬂuoromethylsulfonylation (1.7 equiv NaH, 1.6 equiv

PhNTf₂, THF, 0 °C to rt, 1 h). Triﬂuoromethylsulfonylation of 54 by reaction with 1.4 equiv NaH, 1.4 equiv PhNTf₂, THF (0 °C to rt, 15 min).

c

d

e

provide access to very highly substituted indoles whose

synthesis would be diﬃcult to achieve by alternative methods.

In these experiments to establish the scope of the method the

benzannulations were carried out as batch reactions, but

application of the continuous ﬂow reactor with N-phosphoryl

ynamides should allow the benzannulation to be accomplished

on multigram scale since the outcome of ﬂow processes is

expected to be independent of scale.

highly reactive dienes in Diels−Alder cycloadditions is well

documented.³⁶Eq 11 and Scheme 6 illustrate the application of

the o-quinodimethanes derived from 66 in [4 + 2] cycloadditions

with N-phenylmaleimide and ethyl propiolate, respectively. Not

unexpectedly, little regioselectivity was observed in the Diels−

Alder reaction of the unsymmetrical dienophile.

CONCLUSION

■

A wide range of benzofused nitrogen heterocyclic compounds are

available via the application of our “second generation”

benzannulation strategy employed in conjunction with various

heterocyclization reactions. The triggering step for the pericyclic

cascade involved in the benzannulation is the Wolﬀ rearrangement

of an α,β-unsaturated diazo ketone that can be eﬀected photo-

chemically or by heating in reﬂuxing toluene. The photochemical

process can be performed by irradiation as a batch process or by

using a simple photochemical continuous ﬂow reactor. The benz-

annulation has also been extended to include several new classes of

ynamides that exhibit enhanced reactivity in the key [2 + 2]

cycloaddition step of the pericyclic cascade. Ring-closing metathesis

and several types of nucleophilic cyclization processes are employed

The availability of cyclobutarenes such as 66 via this

methodology is of particular interest. Thermolysis of cyclo-

butarenes provides access to o-quinodimethanes, whose utility as

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Table 4. Tandem Benzannulation−Aromatic Substitution Strategy for the Synthesis of Indoles

a

Irradiation (220−600 nm) of 58 and 2.6 equiv of diazo ketone. Diazo ketone was added over 5−7 h followed by 0.3−5 h of further irradiation.

Oxidation conditions: 2−3 mol % OsO₄, 1.3−1.5 equiv NMO, THF/H₂O (rt, 24−26 h); then 2.0−2.3 equiv NaIO₄−SiO₂, CH₂Cl₂(rt, 10−30 min).

b

c

Cyclization conditions: 1.0 equiv K₂CO₃, i-PrOH, 75−80 °C, 2.5 h (entry 1) or 10 h (entry 2), then 1 M HCl to pH 1 (entry 1) or neutralize with

d

0.6 M HCl (entry 2). Isolated yield of products puriﬁed by column chromatography.

cannula and introduced into reaction vessels through rubber septa.

Reaction product solutions and chromatography fractions were

concentrated by rotary evaporation at ca. 20 mmHg and then at ca.

0.1 mmHg (vacuum pump) unless otherwise indicated. Thin layer

chromatography was performed on precoated glass-backed silica gel 60

F-254 0.25 mm plates. Column chromatography was performed on

silica gel 60 (230−400 mesh) or basic alumina (80−325 mesh). Slow

additions were performed with a syringe pump.

Scheme 6. Tricyclic Indoles via Diels-Alder Reactions of

o-Quinodimethanes

Materials. Commercial-grade reagents and solvents were used

without further puriﬁcation except as indicated below. Dichloro-

methane, diethyl ether, and tetrahydrofuran were puriﬁed by pressure

ﬁltration through activated alumina. Toluene was puriﬁed by pressure

ﬁltration through activated alumina and Cu(II) oxide. Acetonitrile, 1,2-

dichloroethane, 1,1,1,3,3,3-hexamethyldisilazane, pyridine, triethyl-

amine, 2,2,2-triﬂuoroethyl triﬂuoroacetate (TFETFA), and p-xylene

were distilled under argon from calcium hydride. Triﬂic anhydride was

distilled under argon from P₂O₅. N-Bromosuccinimide was recrystal-

lized from boiling water. 4-DMAP was recrystallized from boiling

toluene. Copper(I) iodide was extracted with THF for 24 h in a

Soxhlet extractor and then dried under vacuum (0.1 mmHg). Sodium

periodate supported on silica gel was prepared according to the

procedure of Zhong and Shing.³⁷Methanesulfonyl azide was prepared

by reaction of methanesulfonyl chloride with sodium azide.^18a

n-Butyllithium was titrated using menthol in THF with 1,10-

phenanthroline as an indicator.³⁸Deactivated alumina was prepared

by ﬁrst generating Brockman I grade by heating 150 g of alumina at

250 °C under vacuum (0.050 mmHg) for 12−18 h and then cooling

under Ar. The alumina was then transferred to a 500-mL Erlenmeyer

with a screw cap and the requisite amount of water was added to

obtain the desired grade (Brockman grade II: 3%; grade III: 6%; grade

IV: 10%; grade V: 15% w/w water). The alumina was then vigorously

shaken for 10−15 min until a free-ﬂowing powder was obtained. The

powder was allowed to stand at rt for 24 h with occasional mixing prior

to use.

to convert the benzannulation products to benzazepines, benzacines,

and in particular, to highly substituted indoles and polycyclic indoles

that were not available by using previous versions of our tandem

benzannulation−cyclization strategy.

EXPERIMENTAL SECTION

■

General Procedures. All reactions were performed in ﬂame-dried

or oven-dried glassware under a positive pressure of argon. Reaction

mixtures were stirred magnetically unless otherwise indicated. Air- and

moisture-sensitive liquids and solutions were transferred by syringe or

Instrumentation. Melting points are uncorrected. ¹H NMR

chemical shifts are expressed in parts per million (δ) downﬁeld from

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tetramethylsilane (with the CHCl₃peak at 7.27 ppm used as a

standard). ¹³C NMR chemical shifts are expressed in parts per million

(δ) downﬁeld from tetramethylsilane (with the central peak of CHCl₃

at 77.23 ppm used as a standard). ³¹P NMR chemical shifts are

expressed in parts per million (δ) downﬁeld from an external 85%

H₃PO₄standard (0.0 ppm). High-resolution mass spectrometry

(HRMS) was performed with a Fourier transform ion cyclotron

resonance mass spectrometer.

Construction of the Continuous Flow Reactor. The con-

tinuous ﬂow reactor employed in our experiments was constructed on

the basis of the design of Booker-Milburn et al.²⁶Fluorinated ethylene

propylene (FEP) tubing, 1.59 mm o.d., 0.76 mm i.d., length = 440 cm

(Reactor A) or 1520 cm (Reactor B) was wrapped around a quartz

immersion well in tightly packed coils leaving 90 cm of tubing free at

each end. The length of tubing wrapped around the well was 260 cm

in the case of Reactor A (internal volume ca. 1.2 mL) and 1340 cm in

the case of Reactor B (internal volume ca. 6.1 mL). The ends of the

tubing were secured to the well with Teﬂon tape. The top end of the

tubing was ﬁtted with a nut, ferrule, and a thread to a female Luer

adapter for attachment of a syringe. The bottom end of the tubing was

connected through a rubber septum to a 25-mL or 50-mL pear-shaped

ﬂask equipped with an argon inlet needle and a needle vent. The ﬂask

was wrapped in aluminum foil. The immersion well was connected to

recirculating tap water via PVC tubing. A Pyrex or uranium ﬁlter and a

450 W Hanovia medium-pressure mercury lamp were placed inside

the immersion well as shown in the diagram below.

5.25 (dt, J = 1.5, 17.1 Hz, 1H), 5.11 (dt, J = 1.5, 10.4 Hz, 1H), 4.24−

4.29 (m, 1H), 2.38 (app qd, J = 6.8, 16.5 Hz, 2H), 0.91 (s, 9H), 0.10

(s, 3H), and 0.07 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 140.1,

115.0, 77.6, 72.3, 39.8, 29.7, 26.0, 18.4, −4.4, and −4.7; HRMS (ESI)

(m/z) [M + Na]⁺calcd for C₁₂H₂₁BrNaOSi, 311.0443, found:

311.0438.

N-(Methoxycarbonyl)-N-(2-propenyl)-hex-5-en-4-(tert-butyl-di-

methylsilanyloxy)-1-ynylamine (15). A 50-mL, three-necked, round-

bottomed ﬂask ﬁtted with a rubber septum, argon inlet adapter and

glass stopper was charged with allyl carbamate 13 (0.160 g, 1.39 mmol,

1.0 equiv) and 6 mL of THF. The solution was cooled to 0 °C, and a

solution of KHMDS (1.5 mL, 0.91 M in THF, 1.0 equiv) was then

added rapidly dropwise over ca. 4 min. The resulting pale-yellow slurry

was stirred at 0 °C for 15 min, and 3.8 mL of pyridine was then added,

followed by CuI (0.265 g, 1.39 mmol, 1.0 equiv) in one portion. The

reaction mixture was allowed to warm to rt over 2 h, and a solution of

the alkynyl bromide 14 (0.528 g, 1.83 mmol, 1.3 equiv) in 5 mL of

THF was then added dropwise via cannula over 25 min. The reaction

mixture was stirred at rt for 18 h, diluted with 25 mL of Et₂O, and

washed with three 20-mL portions of a 2:1 mixture of brine and concd

NH₄OH solution. The combined aqueous layers were extracted with

two 15-mL portions of Et₂O, and the combined organic phases were

washed with 30 mL of brine, dried over MgSO₄, ﬁltered, and

concentrated to aﬀord 0.871 g of red−brown oil. Puriﬁcation by

column chromatography on 35 g of silica gel (elution with 3%

EtOAc−hexanes) provided 0.222 g (49%) of 15 as a pale-yellow oil:

IR (thin ﬁlm) 3084, 2956, 2858, 2265, 1732, 1646, and 1388 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 5.81−5.94 (m, 2H), 5.2105.28 (m, 3H),

5.09 (app dt, J = 1.5, 10.4 Hz, 1H), 4.20−4.25 (m, 1H), 3.98−4.08 (m,

2H), 3.79 (s, 3H), 2.40−2.55 (app qd, J = 6.0, 16.3 Hz, 2 H), 0.90 (s,

9H), 0.08 (s, 3H), and 0.06 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

156.2, 140.4, 132.0, 118.4, 114.6, 75.2, 72.8, 66.9, 54.1, 52.8, 28.5, 26.0,

18.4, −4.4, and −4.7; HRMS (ESI) (m/z) [M + Na]⁺calcd for

C₁₇H₂₉NNaO₃Si: 346.1809, found: 346.1807.

1-(tert-Butoxycarbonyl)-3-acetylpyrrole. A 50-mL, pear-shaped

ﬂask equipped with a rubber septum and argon inlet needle was

charged with 3-acetylpyrrole⁴⁰(0.510 g, 4.67 mmol, 1.0 equiv) and

9 mL of CH₂Cl₂. The resulting solution was cooled to 0 °C, and a

solution of Boc₂O (1.05 g, 4.79 mmol, 1.1 equiv) in 7.5 mL of CH₂Cl₂

was added via cannula over 15 min. After 10 min, a solution of 4-

DMAP (0.085 g, 0.70 mmol, 0.15 equiv) and Et₃N (0.67 mL, 4.79 equiv,

1.1 equiv) in 6.5 mL of CH₂Cl₂was added dropwise via cannula over 20

min. The reaction mixture was stirred at 0 °C for 2.5 h and then washed

with two 25-mL portions of water, dried over MgSO₄, ﬁltered, and

concentrated to yield 1.07 g of a yellow oil. Column chromatography on

50 g of silica gel (elution with 7% EtOAc−hexanes) furnished 0.952 g

(97%) of 1-(tert-butoxycarbonyl)-3-acetylpyrrole as a white solid: mp 69−

1

71 °C; IR (neat) 2977, 1752, 1673, 1494, 1396, 1280, 1150 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 7.80−7.83 (m, 1H), 7.21−7.24 (m, 1H),

6.62−6.65 (m, 1H), 2.45 (s, 3H), 1.63 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 193.7, 148.4, 128.6, 124.7, 121.5, 111.1, 85.4, 28.1, 27.4; HRMS

(ESI) (m/z) [M + Na]⁺calculated for C₁₁H₁₅NNaO₃: 232.0944, found:

232.0945.

1-(tert-Butoxycarbonyl)-3-diazoacetylpyrrole (30). A 100-mL,

three-necked, round-bottomed ﬂask equipped with two rubber septa,

an argon inlet adapter, and a thermocouple was charged with a

solution of 1,1,1,3,3,3-hexamethyldisilazane (1.15 mL, 5.45 mmol, 1.2

equiv) in 12 mL of THF and then cooled at 0 °C while n-BuLi (2.64

M in hexane, 1.9 mL, 5.02 mmol, 1.1 equiv) was added dropwise over

5 min. After 10 min, the resulting solution was cooled at −78 °C while

a solution of 1-(tert-butoxycarbonyl)-3-acetylpyrrole (0.951 g, 4.55

mmol, 1.0 equiv) in 12 mL of THF was added dropwise via cannula

over 35 min (0.8 mL THF wash). After 45 min, 2,2,2-triﬂuoroethyl

triﬂuoroacetate (0.73 mL, 5.45 mmol, 1.2 equiv) was added rapidly by

syringe. After 10 min, the reaction mixture was diluted with 25 mL of

1 M aq HCl solution and 30 mL of Et₂O. The aqueous phase was

extracted with two 15-mL portions of Et₂O, and the combined organic

phases were washed with 30 mL of brine, dried over Na₂SO₄, ﬁltered,

and concentrated to give 1.62 g of an orange oil which was immediately

dissolved in 12 mL of CH₃CN and transferred to a 100-mL pear-shaped

Procedures for Preparation of Benzannulation Reaction

Partners. 1-Bromo-4-(tert-butyldimethylsilanyloxy)-hex-5-en-1-yne

(14). A 250-mL round-bottomed ﬂask equipped with a rubber septum

and argon inlet needle was charged with 4-(tert-butyldimethylsiloxy)-

hex-5-en-1-yne³⁹(2.40 g, 11.4 mmol, 1.0 equiv) and 50 mL of acetone.

N-bromosuccinimide (2.23 g, 12.6 mmol, 1.1 equiv) was added, and

the mixture was stirred until all of the NBS dissolved. AgNO₃(0.194 g,

1.14 mmol, 0.1 equiv) was added, and then the reaction mixture was

stirred at rt for 16 h. The resulting gray slurry was diluted with 50 mL

of H₂O and 80 mL of Et₂O. The aqueous layer was extracted with two

50-mL portions of Et₂O, and the combined organic layers were washed

with two 50-mL portions of satd Na₂S₂O₃solution and 50 mL of brine,

dried over MgSO₄, ﬁltered, and concentrated to aﬀord ca. 3.9 g of

green oil. Column chromatography on 20 g of silica (elution with

hexanes) aﬀorded 2.60 g (81%) of alkynyl bromide 14 as a colorless

oil: IR (thin ﬁlm) 2957, 2858, 2228, 1473, 1362, 1255, and 1090 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 5.88 (ddd, J = 5.6, 10.4, 17.1 Hz, 1 H),

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ﬂask equipped with a rubber septum and argon inlet needle. Water

(0.08 mL, 4.43 mmol, 1.0 equiv) and Et₃N (0.95 mL, 6.82 mmol, 1.5 equiv)

were added, and a solution of methanesulfonyl azide (0.880 g, 7.27

mmol, 1.6 equiv) in 14 mL of CH₃CN was added dropwise via cannula

over 30 min (1 mL CH₃CN wash). The resulting solution was stirred

at room temperature for 3 h and then diluted with 50 mL of Et₂O and

washed with three 20-mL portions of 10% aq NaOH solution and

50 mL of brine, dried over Na₂SO₄, ﬁltered, and concentrated to aﬀord

1.199 g of a yellow oil. Column chromatography on 53 g of silica gel

(gradient elution with 10−20% EtOAc−hexanes) furnished 1.004 g

(94%) of diazo ketone 30 as a yellow solid: mp 58−59 °C; IR (neat)

3124, 2982, 2103, 1752, 1617, 1496, 1396, 1336, 1255, 1154 cm⁻¹; UV

yellow oil: IR (thin ﬁlm) 2929, 2857, 1751, 1602, 1455, 1384, 1351,

1270, 1020 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.37 (t, J = 7.5 Hz,

2H), 7.25−7.34 (m, 3H), 4.90 (d, J = 11.5 Hz, 2H), 3.90−4.20 (m,

4H), 3.37 (t, J = 1.5 Hz, 2H), 1.90 (t, J = 7.5 Hz, 2H), 1.29−1.39 (m,

8H), 1.18−1.29 (m, 2H), 1.04−1.18 (m, 4H), 0.84 (t, J = 7.3 Hz, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 187.1, 161.6 (d, J = 5.1 Hz), 137.4,

129.0, 127.9, 126.3, 125.6 (d, J = 9.8 Hz), 64.2 (d, J = 5.8 Hz), 52.2 (d,

J = 5.0 Hz), 49.7, 31.7, 29.5, 28.6, 23.9, 22.7, 16.2 (d, J = 6.9 Hz) 14.2;

³¹P NMR (121 MHz, CDCl₃) δ 2.17; HRMS (ESI) (m/z) [M + H]⁺

calcd for C₂₁H₃₃NO₄P, 394.2142, found 394.2141.

Ketene [2 + 2] Cycloaddition Competition Experiment: N-

Diethylphosphoryl vs N-Tosyl Ynamides. Ketene was generated by

pyrolysis of acetone over an electrically heated metal ﬁlament using the

apparatus described by Williams and Hurd. A 13 mm × 100 mm test

tube equipped with a rubber septum was charged with 3.5 mL CDCl₃

and then ﬁtted with an inlet needle connected to the ketene generator

and an outlet needle connected via tubing to a column of calcium

sulfate leading into a trap of water. Ketene was bubbled into the

solution at rt for 5 min, then a solution of ynamide 25 (0.124 g, 0.353

mmol), ynamide 22 (0.130 g, 0.352 mmol), and 1,3,5-trimethox-

ybenzene (0.059 g, 0.351 mmol) as an internal standard in 0.5 mL of

CDCl₃was added via syringe, and the addition of ketene was

continued over a period of 2 h. Aliquots (ca. 0.1 mL) of the reaction

mixture were taken at intervals, diluted with CDCl₃, and examined by

¹H NMR (500 MHz) with a relaxation time d1 = 20 s to ensure

1

(CH₃CN) λ_max, nm (ε) 294 (20642), 245 (19339), 229 (22817); H

NMR (500 MHz, CDCl₃) δ 7.70−7.72 (m, 1H), 7.23−7.25 (m, 1H),

6.51−6.52 (m, 1H), 5.63 (s, 1H), 1.62 (s, 9H); ¹³C NMR (125 MHz,

CDCl₃) δ 181.6, 148.3, 126.9, 122.0, 121.4, 110.3, 85.4, 54.2, 28.1;

HRMS (ESI) (m/z) [M + Na]⁺calculated for C₁₁H₁₃N₃NaO₃:

258.0849, found: 258.0848.

Ynamide Reactivity Comparison Study. 2-Hexyl-3-(N-benzyl-

N-(methoxycarbonyl))-2-cyclobuten-1-one (23). Ketene was gener-

ated by pyrolysis of acetone over an electrically heated metal ﬁlament

using the apparatus described by Williams and Hurd.⁴¹A 12 mm × 75 mm

test tube ﬁtted with a rubber septum was charged with ynamide 21^13a

(0.098 g, 0.358 mmol, 1.0 equiv) and 3.0 mL of toluene. The septum was

ﬁtted with an inlet needle connected to the ketene generator and an outlet

needle connected via tubing to a column of calcium sulfate leading into a

trap of water. Ketene was bubbled into the solution at rt over a period of 6

h. The reaction mixture was then concentrated to aﬀord 0.127 g of an

orange oil. Column chromatography on 12 g of silica gel (elution with 15%

EtOAc−hexane) yielded 0.051 g of unreacted ynamide 21 as a colorless oil

and 0.045 g (40%) of cyclobutenone 23 as a yellow oil: IR (thin ﬁlm)

accurate integration and auto phasing or manual phasing to ensure a

level baseline. For cyclobutenone 26 the resonance at 4.90 ppm was

integrated; for cyclobutenone 24 the resonance at 5.04 ppm was

integrated. For ynamide 25 the resonance at 4.40 ppm was integrated;

for ynamide 22 the resonance at 4.45 ppm was integrated.

Ketene [2 + 2] Cycloaddition Competition Experiment: N-Carbome-

thoxy vs N-Diethylphosphoryl Ynamides. Ketene was generated by

pyrolysis of acetone over an electrically heated metal ﬁlament using the

apparatus described by Williams and Hurd. A 12 mm × 75 mm test

tube ﬁtted with a rubber septum was charged with 3.5 mL CDCl₃then

ﬁtted with an inlet needle connected to the ketene generator and an

outlet needle connected via tubing to a column of calcium sulfate

leading into a trap of water. Ketene was bubbled into the solution at rt

for 10 min, then a solution of ynamide 21 (0.110 g, 0.404 mmol),

ynamide 25 (0.142 g, 0.404 mmol), and 1,3,5-trimethoxybenzene

(0.068 g, 0.404 mmol) as an internal standard in 0.5 mL of CDCl₃was

added via syringe, and the addition of ketene continued over a period

of 2 h. Aliquots (ca. 0.1 mL) of the reaction mixture were taken at

intervals, diluted with CDCl₃, and examined by ¹H NMR (500 MHz)

with a relaxation time d1 = 20 s to ensure accurate integration and

auto phasing or manual phasing to ensure a level baseline. For

cyclobutenone 23 the resonance at 4.96 ppm was integrated; for

cyclobutenone 26 the resonance at 4.90 ppm was integrated. For

ynamide 21 the resonance at 4.61 ppm was integrated; for ynamide 25

the resonance at 4.40 ppm was integrated.

Scope of Benzannulation Reactions. 3-[N-(Carbomethoxy)-N-

(methyl)amino]-2-hexyl-5,6,7,8-tetrahydronaphthalen-1-ol (18) by

Batch Photochemical Benzannulation. A 20-cm quartz tube (7 mm

i.d., 10 mm o.d.) equipped with a rubber septum and argon inlet

needle was charged with ynamide 17⁴²(0.106 g, 0.537 mmol, 1.0

equiv) and 1.7 mL of CH₂Cl₂. A 10-mL Pyrex tube ﬁtted with a rubber

septum and argon inlet needle was charged with diazo ketone 16^18a

(0.202 g, 1.34 mmol, 2.5 equiv) and 3.3 mL of CH₂Cl₂. Both solutions

were degassed via three cycles of freeze−pump−thaw (−196 °C, 0.05

mmHg). The solution of diazo ketone was taken up in a 5-mL glass

syringe wrapped in aluminum foil and ﬁtted with a 20-gauge, 20 cm

long steel needle. The upper portion (ca. 5−7 cm length) of the quartz

tube was wrapped in aluminum foil. The quartz tube was positioned

ca. 20 cm proximity to the Hanovia 450 W medium pressure mercury

lamp (quartz immersion well, cooled by recirculating tap water). The

diazo ketone solution was added to the reaction tube via syringe pump

during irradiation under argon at 28 °C. After the addition was

completed (ca. 6 h), the Pyrex tube was rinsed with 0.5 mL CH₂Cl₂and

added with the same syringe in one portion to the reaction mixture.

Irradiation was continued for 4 h. The resulting reaction mixture was

1

2956, 2929, 2857, 1737, 1611, 1453, 1393, 1364, 1233 cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 7.37 (t, J = 7.0 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H),

7.19 (d, J = 7.5 Hz, 2H), 4.99 (s, 2H), 3.84 (s, 3H), 3.54 (t, J = 1.5 Hz,

2H), 1.97 (t, J = 7.5 Hz, 2H), 1.30−1.38 (m, 2H), 1.20−1.30 (m, 2H),

1.10−1.20 (m, 4H), 0.84 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 188.1, 159.6, 153.7, 136.5, 129.1, 127.9, 127.7, 125.9, 54.4, 51.2,

50.9, 31.6, 29.4, 28.5, 24.0, 22.7, 14.2; HRMS (ESI) (m/z) [M + H]⁺calcd

for C₁₉H₂₆NO₃, 316.1907, found 316.1911.

Ketene [2 + 2] Cycloaddition Competition Experiment: N-

Carbomethoxy vs N-Tosyl Ynamides. Ketene was generated by

pyrolysis of acetone over an electrically heated metal ﬁlament using the

apparatus described by Williams and Hurd. A 5-mL conical vial ﬁtted

with a rubber septum was charged with ynamide 21 (0.103 g, 0.377

mmol), ynamide 22^14b(0.140 g, 0.379 mmol) and 1.5 mL of CDCl₃

containing 1,3,5-trimethoxybenzene (0.063 g, 0.375 mmol) as an

internal standard. The septum was ﬁtted with an inlet needle

connected to the ketene generator and an outlet needle connected

via tubing to a column of calcium sulfate leading into a trap of water.

Ketene was bubbled into the solution at rt over a period of 4 h.

Aliquots (ca. 0.1 mL) of the reaction mixture were taken at intervals,

1

diluted with CDCl₃, and examined by H NMR (500 MHz) with a

relaxation time d1 = 20 s to ensure accurate integration and auto

phasing or manual phasing to ensure a level baseline. For

cyclobutenone 23 the resonance at 4.96 ppm was integrated; for

cyclobutenone 24⁴²the resonance at 5.04 ppm was integrated. For

ynamide 21 the resonance at 4.61 ppm was integrated; for ynamide 22

the resonance at 4.45 ppm was integrated.

2-Hexyl-3-(N-benzyl-N-(diethylphosphoryl))-2-cyclobuten-1-one

(26). Ketene was generated by pyrolysis of acetone over an electrically

heated metal ﬁlament using the apparatus described by Williams

and Hurd. A 10 mm × 75 mm test tube ﬁtted with a rubber septum

was charged with ynamide 25^14e(0.061 g, 0.174 mmol, 1.0 equiv) and

1.5 mL of toluene. The septum was ﬁtted with an inlet needle

connected to the ketene generator and an outlet needle connected via

tubing to a column of calcium sulfate leading into a trap of water.

Ketene was bubbled into the solution at rt over a period of 40 min.

The reaction mixture was then concentrated to aﬀord 0.082 g of an

orange oil. Column chromatography on 7 g of silica gel (elution with

30% EtOAc−hexane) yielded 0.062 g (90%) of cyclobutenone 26 as a

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concentrated to 0.320 g of orange oil and transferred to a 10-ml Pyrex

tube with the aid of 3.5 mL of toluene. The solution was heated at reﬂux

for 1.5 h and then cooled to rt and concentrated to aﬀord 0.347 g of

dark-orange oil. Puriﬁcation by column chromatography on 13 g of silica

gel (elution with 10% EtOAc−hexanes) aﬀorded 0.146 g (85%) of the

aniline 18 as a viscous yellow oil: IR (thin ﬁlm) 3408, 2960, 2929, 1688,

3-[N-(Diethylphosphoryl)-N-(benzyl)amino]-2-hexyl-5,6,7,8-tetra-

hydronaphthalen-1-ol (29) − Flow Reactor. Reactor A with a Pyrex

ﬁlter was employed for this reaction. A 25-mL pear-shaped ﬂask

equipped with a rubber septum and argon inlet needle was charged

with diazo ketone 16 (0.115 g, 0.766 mmol, 1.1 equiv), ynamide 25

(0.240 g, 0.683 mmol, 1.0 equiv), and 2.9 mL of DCE, and the yellow

solution was degassed via three freeze−pump−thaw (−196 °C, 0.05

mmHg) cycles. The FEP tubing of the reactor was ﬂushed with 3 mL

of degassed DCE, the mercury lamp was turned on, and degassed DCE

was pumped through the tubing for 5 min at a rate of 0.057 mL/min

by syringe pump. The solution of 16 and 25 was transferred to a 5-mL

glass syringe and pumped through the tubing at a rate of 0.057 mL/min.

Once the addition was complete, the tubing was ﬂushed with three

portions of degassed DCE (0.4, 0.4, and then 4.0 mL). The 25-mL pear-

shaped collection ﬂask was equipped with a stir bar and coldﬁnger

condenser, and the reaction mixture was heated at reﬂux for 40 h and

then concentrated to aﬀord 0.386 g of orange oil. This material was

dissolved in 5 mL of CH₂Cl₂and concentrated onto 5 g of silica gel. The

free-ﬂowing powder was deposited on a column of 55 g of silica gel and

eluted with 35% EtOAc−hexanes to furnish 0.204 g of an orange oil

which was further puriﬁed by column chromatography on 33 g of silica

gel (gradient elution with 0−1% MeOH−CH₂Cl₂) to aﬀord 0.176 g

(53%) of phenol 29 as an orange oil with spectral data consistent with

that reported in the procedure for the batch process given above.

3-[N-(Diethylphosphoryl)-N-(benzyl)amino]-2-hexyl-5,6,7,8-tetra-

hydronaphthalen-1-ol (29) − Thermal Benzannulation. A 25-mL

round-bottomed ﬂask equipped with a rubber septum and argon inlet

needle was charged with ynamide 25 (0.154 g, 0.438 mmol, 1.0 equiv),

diazo ketone 16 (0.070 g, 0.466 mmol, 1.1 equiv), and 5.5 mL of

toluene. The septum was replaced with a condenser ﬁtted with an

argon inlet adapter, and the yellow reaction mixture was stirred at

reﬂux for 7 h. The resulting orange mixture was concentrated to yield

0.220 g of an orange oil. Column chromatography on 42 g of silica gel

(elution with 20% EtOAc−hexanes +5% Et₃N) provided 0.154 g of an

orange oil that was further puriﬁed by column chromatography on 21 g of

silica gel (elution with 20% EtOAc−hexanes) to aﬀord 0.137 g (65%)

of phenol 29 as a pale-yellow oil with spectral data consistent with that

reported in the procedure for the batch process given above.

1

1455, 1261, and 1101 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 6.53 (s,

minor rotamer), 6.49 (s, 1H), 4.95 (s, 1H), 3.79 (s, minor rotamer),

3.64 (s, 3H), 3.19 (s, 3H), 2.73−2.67 (m, 2H), 2.60 (t, J = 6.3 Hz, 2H),

2.49−2.45 (m, 2H), 1.88−1.83 (m, 2H), 1.79−1.72 (m, 2H), 1.53−1.47

(m, 2H), 1.41−1.35 (m, 2H), 1.33−1.27 (m, 4H), and 0.89 (t, J = 6.8

Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) 156.9, 152.4, 139.6, 136.6,

123.4, 122.4, 120.1, 53.1, 38.9, 31.9, 30.1, 29.4, 29.3, 25.9, 23.1, 22.8,

22.7, and 14.3; HRMS (ESI) (m/z) [M + H]⁺calcd for C₁₉H₃₀NO₃;

320.2220, found 320.2229.

3-[N-(Carbomethoxy)-N-(methyl)amino]-2-hexyl-5,6,7,8-tetrahy-

dronaphthalen-1-ol (18) by Thermal Benzannulation. A 10-mL

round-bottomed ﬂask equipped with a reﬂux condenser, rubber

septum, and argon inlet needle was charged with ynamide 17 (0.060 g,

0.306 mmol, 1.0 equiv) and 1.5 mL of toluene. A 10-mL pear-shaped

ﬂask ﬁtted with a rubber septum and argon inlet needle was charged

with diazo ketone 16 (0.092 g, 0.612 mmol, 2.0 equiv) and 3 mL of

toluene. Both solutions were degassed with a stream of argon for

15 min. The solution of diazo ketone was taken up in a 5-mL glass

syringe wrapped in aluminum foil and ﬁtted with a 20-gauge, 20-cm

long steel needle. The reaction mixture was heated at reﬂux, and the

diazo ketone solution was added through the condenser via syringe

pump. After the addition was completed (ca. 8 h), the pear-shaped

ﬂask was rinsed with 0.5 mL of toluene and added with the same

syringe in one portion to the reaction mixture. Heating was continued

for 4 h. After cooling to rt, the reaction mixture was concentrated to

aﬀord 0.148 g of orange oil. Puriﬁcation by column chromatography

on 20 g of silica gel (elution with 5% EtOAc−10% benzene−85%

hexanes) aﬀorded 0.074 g of a yellow oil that was further puriﬁed by

column chromatography on 16 g of silica gel (elution with 5%

EtOAc−10% benzene−85% hexanes) to aﬀord 0.055 g (56%) of

phenol 18 as a yellow oil with spectral data consistent with that

reported in the procedure for the batch process given above.

3-[N-(Diethylphosphoryl)-N-(benzyl)amino]-2-hexyl-5,6,7,8-tetra-

hydronaphthalen-1-ol (29) − Batch Reactor. A 20-cm quartz tube

(7 mm i.d., 10 mm o.d.) equipped with a rubber septum and argon inlet

needle was charged with diazo ketone 16 (0.073 g, 0.486 mmol, 1.1

equiv), ynamide 25¹⁴^e(0.151 g, 0.430 mmol, 1.0 equiv), and 2.0 mL of

CH₂Cl₂. The yellow solution was degassed for 10 min with a stream of

argon. The quartz tube was positioned ca. 20 cm from a Hanovia

450 W medium pressure mercury lamp (quartz immersion well, cooled

by recirculating tap water) and irradiated under argon at 25 °C for 6 h.

The reaction mixture was transferred to a 25-mL pear-shaped ﬂask

with the aid of two 4-mL portions of CH₂Cl₂and concentrated to

aﬀord 0.222 g of orange oil. This material was dissolved in 4.4 mL of

toluene, the ﬂask was equipped with a stir bar and coldﬁnger

condenser, and the reaction mixture was heated at reﬂux for 2 h. The

resulting mixture was concentrated to aﬀord 0.234 g of orange oil.

Column chromatography on 30 g of silica gel (gradient elution with

20−40% EtOAc−hexanes) furnished 0.149 g of an yellow oil which

was further puriﬁed by column chromatography on 25 g of silica gel

(elution with 1% MeOH−CH₂Cl₂) to aﬀord 0.135 g (66%) of phenol

29 as a yellow oil: IR (neat) 3296 (broad), 2929, 2858, 1572, 1439,

3-[N-(Carbomethoxy)-N-(methyl)amino]-2-hexylnaphthalen-1-ol

(20) − Batch Reactor. A 25-cm quartz tube (5 mm i.d., 7 mm o.d.)

equipped with a rubber septum and argon inlet needle was charged

with diazo ketone 19^18a(0.081 g, 0.552 mmol, 1.1 equiv), ynamide 17

(0.099 g, 0.502 mmol, 1.0 equiv), and 1.7 mL of CH₂Cl₂. The yellow

reaction mixture was degassed via three cycles of freeze−pump−thaw

(−196 °C, 0.05 mmHg). The quartz tube was positioned ca. 20 cm

proximity to the Hanovia 450 W medium pressure mercury lamp

(quartz immersion well, cooled by recirculating tap water) and

irradiated under argon at 25 °C for 2.5 h. The reaction mixture was

concentrated to 0.244 g of yellow oil, which was transferred with 2 mL

of toluene to a 10-mL reaction tube. The solution was heated at reﬂux

for 2.5 h, cooled to rt, and concentrated to give 0.262 g of an orange

oil, which was dissolved in 1 mL of CH₂Cl₂and concentrated on 0.5 g

of silica gel. The resulting free-ﬂowing powder was deposited onto a

column of 12 g of silica gel and eluted with 20% EtOAc−hexanes to

aﬀord 0.102 g (64%) of 20 as an orange wax: IR (thin ﬁlm) 3385,

1

2955, 2928, 2857, 1684, 1573, 1461, 1374, 1194, and 1164 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 8.12 (d, J = 9 Hz, 1 H), 7.95 (bs, minor

rotamer), 7.74 (d, J = 9 Hz, 1H), 7.60 (bs, minor rotamer), 7.46 (app

dt, J = 3.8, 7.0 Hz, 2H), 7.34 (bs, minor rotamer), 7.26 (s, 1H), 7.24

(s, minor rotamer), 6.19 (s, minor rotamer), 5.85 (s, 1H), 3.88 (s,

minor rotamer), 3.64 (s, 3H), 3.30 (s, 3H), 3.28 (s, minor rotamer),

2.67 (t, J = 7.1 Hz, 2H), 1.61−1.55 (m, 2H), 1.43−1.39 (m, 2H),

1.33−1.27 (m, 4H), and 0.90 (t, J = 6.3 Hz, 3H); ¹³C NMR (75 MHz,

CDCl₃) δ 157.0, 150.1, 140.6, 132.8, 127.7, 126.3, 125.8, 124.0, 121.3,

121.0, 118.8, 53.1, 39.1, 31.9, 30.0, 29.5, 26.0, 22.8, and 14.3; HRMS

(EI) (m/z) M⁺calcd for C₁₉H₂₅NO₃: 315.1829, found 315.1823.

3-[N-(Carbomethoxy)-N-(methyl)amino]-2-hexylnaphthalen-1-ol

(20) − Flow Reactor. Reactor A with a Pyrex ﬁlter was employed for

this reaction. A 25-mL pear-shaped ﬂask equipped with a rubber

septum and argon inlet needle was charged with diazo ketone 19

1

1421, 1211, 1125, 1097, 1055, 1029, 966 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 7.20−7.26 (m, 3H), 7.14−7.20 (m, 2H), 6.32 (s, 1H), 4.80

(s, 1H), 4.50−4.66 (m, 1H), 4.21−4.35 (m, 1H), 3.96−4.16 (m, 4H),

2.37−2.67 (m, 6H), 1.75−1.84 (m, 2H), 1.65−1.75 (m, 2H), 1.54−

1.65 (m, 1H), 1.22−1.38 (m, 12H), 1.06−1.21 (m, 1H), 0.90 (t, J =

7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 152.7, 138.4 (d, J = 2.5

Hz), 138.1 (d, J = 3.8 Hz), 135.7 (d, J = 1.8 Hz), 129.9, 128.2, 127.6,

125.3 (d, J = 4.0 Hz), 123.5, 122.1 (d, J = 1.8 Hz), 62.9 (d, J = 5.6 Hz),

56.0 (d, J = 5.1 Hz), 32.0, 30.5, 29.5, 29.1, 26.4, 23.2, 23.0, 22.9, 16.4

(d, J = 6.9 Hz), 14.2; ³¹P NMR (121 MHz, CDCl₃) δ 6.65; HRMS

(ESI) (m/z) [M + H]⁺calculated for C₂₇H₄₁NO₄P, 474.2768; found

474.2780.

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Article

(0.088 g, 0.602 mmol, 1.1 equiv), ynamide 17 (0.108 g, 0.548 mmol,

1.0 equiv), and 2.2 mL of DCE. The yellow solution was degassed via

three freeze−pump−thaw (−196 °C, 0.05 mmHg) cycles. The FEP

tubing of the reactor was ﬂushed with 3 mL of degassed DCE, the

mercury lamp was turned on, and degassed DCE was pumped through

the tubing for 5 min at a rate of 0.057 mL/min by syringe pump. The

solution of 19 and 17 was transferred to a 5-mL glass syringe and

pumped through the tubing at a rate of 0.057 mL/min. Once the

addition was complete, the tubing was ﬂushed with three portions of

degassed DCE (0.4, 0.4, and then 4.0 mL). The 25-mL pear-shaped

collection ﬂask was equipped with a stir bar and coldﬁnger condenser,

and the reaction mixture was heated at reﬂux for 48 h and then

concentrated to aﬀord 0.188 g of orange oil. This material was dissolved

in 3 mL of CH₂Cl₂and concentrated onto 2 g of silica gel. The free-

ﬂowing powder was deposited on a column of 25 g of silica gel and eluted

with 10% EtOAc−10% benzene−80% hexanes to furnish 0.114 g (66%)

of phenol 20 as a yellow oil with spectral data consistent with that

reported in the procedure for the batch process given above.

3-[N-(Carbomethoxy)-N-(methyl)amino]-2-hexylnaphthalen-1-ol

(20) − Large-Scale Flow Reactor. Reactor B with a Pyrex ﬁlter was

employed for this reaction. A 25-mL pear-shaped ﬂask equipped with a

rubber septum and argon inlet needle was charged with diazo ketone

19 (0.184 g, 1.26 mmol, 1.1 equiv), ynamide 17 (0.223 g, 1.13 mmol,

1.0 equiv), and 4.8 mL of DCE. and the yellow solution was degassed

via three freeze−pump−thaw (−196 °C, 0.05 mmHg) cycles. The FEP

tubing of the reactor was ﬂushed with 3 mL of degassed DCE, the

mercury lamp was turned on, and degassed DCE was pumped through

the tubing for 5 min at a rate of 0.32 mL/min by syringe pump. The

solution of 19 and 17 was transferred to a 10-mL glass syringe and

pumped through the tubing at a rate of 0.32 mL/min. Once the

addition was complete, the tubing was ﬂushed with three portions of

degassed DCE (0.6, 0.6, and then 9.0 mL). The 50-mL pear-shaped

collection ﬂask was equipped with a stir bar and coldﬁnger condenser,

and the reaction mixture was heated at reﬂux for 40 h and then

concentrated to aﬀord 0.500 g of orange oil. This material was

dissolved in 5 mL of CH₂Cl₂and concentrated onto 5 g of silica gel.

The free-ﬂowing powder was deposited on a column of 50 g of silica

gel and eluted with 10% EtOAc−10% benzene−80% hexanes to

furnish 0.220 g (63%) of phenol 20 as a yellow oil with spectral data

consistent with that reported in the procedure for the batch process

given above.

0.574 mmol, 1.1 equiv), ynamide 17 (0.103 g, 0.522 mmol, 1.0 equiv),

and 2.2 mL of CH₂Cl₂. The yellow solution was degassed for 10 min

with a stream of argon. The quartz tube was positioned ca. 20 cm from

a Hanovia 450 W medium pressure mercury lamp (quartz immersion

well, cooled by recirculating tap water) and irradiated under argon at

25 °C for 8 h. The reaction mixture was transferred to a 25-mL pear-

shaped ﬂask with the aid of two 4-mL portions of CH₂Cl₂and

concentrated to aﬀord 0.222 g of an orange oil. This material was

dissolved in 5.2 mL of toluene, the ﬂask was equipped with a stir bar

and coldﬁnger condenser, and the reaction mixture was heated at

reﬂux for 2 h. The resulting mixture was concentrated to aﬀord 0.234 g

of an orange oil. Column chromatography on 25 g of silica gel

(gradient elution with 10−20% EtOAc−hexanes) furnished 0.084 g

(40%) of phenol 31 as a yellow oil: IR (neat) 3162 (broad), 2930,

2857, 1708, 1688, 1584, 1452, 1380, 1353, 1242, 1156, 1120 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 11.13 (s, 1H), 11.09 (s, minor rotamer),

7.36−7.42 (m, 1H), 6.88 (s, minor rotamer), 6.82 (s, 1H), 6.43−6.49

(m, 1H), 3.80 (s, minor rotamer), 3.62 (s, 3H), 3.24 (s, 3H), 3.22 (s,

minor rotamers), 2.53−2.68 (m, 2H), 1.65 (s, 9H), 1.50−1.60 (m,

2H), 1.36−1.45 (m, 2H), 1.27−1.36 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 157.0, 152.7, 143.6, 139.5, 131.1,

126.7, 124.8, 123.3, 110.7, 109.4, 86.3, 53.0, 38.9, 32.0, 30.2, 29.4, 28.2,

26.6, 22.8, 14.3; HRMS (ESI) (m/z) [M + Na]⁺calculated for

C₂₂H₃₂N₂NaO₅, 427.2203; found 427.2208.

1-(tert-Butoxycarbonyl)-6-hexyl-7-hydroxy-5-[N-(methoxycar-

bonyl)-N-(methyl)amino]indole (31) − Flow Reactor. Reactor A with

a Pyrex ﬁlter was employed for this reaction. A 25-mL pear-shaped

ﬂask equipped with a rubber septum and argon inlet needle was

charged with diazo ketone 30 (0.134 g, 0.570 mmol, 1.1 equiv),

ynamide 17 (0.100 g, 0.507 mmol, 1.0 equiv), and 2.2 mL of DCE, and

the yellow solution was degassed via three freeze−pump−thaw (−196

°C, 0.05 mmHg) cycles. The FEP tubing of the reactor was ﬂushed

with 3 mL of degassed DCE, the mercury lamp was turned on, and

degassed DCE was pumped through the tubing for 5 min at a rate of

0.057 mL/min by syringe pump. The solution of 30 and 17 was

transferred to a 5-mL glass syringe and pumped through the tubing at

a rate of 0.057 mL/min. Once the addition was complete, the tubing

was ﬂushed with three portions of degassed DCE (0.4, 0.4, and then

4.0 mL). The reaction mixture was then concentrated to aﬀord 0.209 g

of orange oil. This material was dissolved in 5.0 mL of toluene in the

same 25-mL pear-shaped collection ﬂask. The ﬂask was equipped with

a stir bar and coldﬁnger condenser, and the reaction mixture was

heated at reﬂux for 2 h. The resulting mixture was concentrated to

aﬀord 0.189 g of a dark-orange oil. Column chromatography on 25 g

of silica gel (elution with 12% EtOAc−hexanes) furnished 0.075 g

(37%) of phenol 31 as a yellow oil with spectral data consistent with

that reported in the procedure for the batch process given above.

5-Hexyl-4-(triﬂuoromethylsulfonyloxy)-6-[N-(diethylphosphoryl)-

N-(benzyl)amino]indole (33) − Batch Reactor. A 20-cm quartz tube

(7 mm i.d., 10 mm o.d.) equipped with a rubber septum and argon

inlet needle was charged with diazo ketone 32^2b(0.137 g, 0.582 mmol,

1.1 equiv), ynamide 17 (0.103 g, 0.522 mmol, 1.0 equiv), and 2.2 mL

of CH₂Cl₂. The yellow reaction mixture was degassed via three freeze−

pump−thaw (−196 °C, 0.05 mmHg) cycles. The quartz tube was

positioned ca. 20 cm from a Hanovia 450 W medium pressure mercury

lamp (quartz immersion well, cooled by recirculating tap water) and

irradiated under argon at 25 °C for 5.5 h. The reaction mixture was

transferred to a 25-mL pear-shaped ﬂask with the aid of two 4-mL

portions of CH₂Cl₂and concentrated to aﬀord 0.249 g of a dark-orange

oil. This material was dissolved in 5.2 mL of toluene, the ﬂask was

equipped with a stir bar and coldﬁnger condenser, and the reaction

mixture was heated at reﬂux for 2 h. The resulting mixture was

concentrated to aﬀord 0.262 g of a dark-orange oil. Column

chromatography on 30 g of silica gel (elution with 15% EtOAc−hexanes)

furnished 0.152 g of crude benzannulation product as an orange oil.

A 25-mL pear-shaped ﬂask equipped with a rubber septum and

argon inlet needle was charged with the crude benzannulation product

(0.152 g, 1.0 equiv), 4-DMAP (0.092 g, 0.753 mmol, 2.0 equiv), and

2.7 mL of CH₂Cl₂. The orange solution was cooled to 0 °C, and triﬂic

anhydride (0.07 mL, 0.416 mmol, 1.1 equiv) was added dropwise by

3-[Bis(trimethylsilyl)amino]-2-phenylnaphthalen-1-ol (28). A 20-cm

quartz tube (7 mm i.d., 10 mm o.d.) equipped with a stir bar, rubber

septum, and argon inlet needle was charged with diazo ketone 19

(0.048 g, 0.325 mmol, 1.0 equiv), ynamine 27²²(0.65 mL, 0.5 M in

benzene, 0.325 mmol, 1.0 equiv), and 0.7 mL of toluene. The yellow

solution was degassed (three freeze−pump−thaw cycles at −196 °C,

0.05 mmHg) and backﬁlled with argon. The quartz tube was

positioned ca. 20 cm from a Hanovia 450 W medium pressure

mercury lamp equipped with a uranium ﬁlter (quartz immersion well,

cooled by recirculating tap water) and irradiated under argon with

stirring at 25 °C for 45 h. The reaction mixture was transferred to a 15-mL

threaded Pyrex tube (20 mm o.d.) with the aid of two 0.8-mL portions of

toluene. The reaction tube was sealed with a threaded Teﬂon cap, and the

reaction mixture was heated at 110 °C (bath temperature) for 2.5 h. The

resulting mixture was concentrated to aﬀord 0.116 g of a dark-yellow oil.

Column chromatography on 20 g of silica gel (elution with 94:5:1 hexanes-

EtOAc−Et₃N) furnished 0.075 g (61%) of phenol 28 as a yellow solid: mp

79−81 °C; IR (neat) 3540, 3054, 2954, 1630, 1590, 1494, 1435, 1385,

1

1251, 1127, 1075, 942, 876, 839, and 822 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 8.18 (app d, J = 8.4 Hz, 1H), 7.70 (app d, J = 8.2 Hz, 1H),

7.52−7.56 (m, 2H), 7.38−7.49 (m, 5H), 7.10 (s, 1H), 5.47 (s, 1H), and

−0.06 (s, 18H); ¹³C NMR (125 MHz, CDCl₃) δ 149.1, 145.9, 135.2,

134.0, 132.1, 129.5, 128.4, 126.8, 126.7, 124.2, 122.9, 122.6, 121.8, 119.2,

and 2.3; HRMS (ESI) (m/z) [M + H]⁺calculated for C₂₂H₃₀NOSi₂,

380.1860; found 380.1889.

1-(tert-Butoxycarbonyl)-6-hexyl-7-hydroxy-5-[N-(methoxycar-

bonyl)-N-(methyl)amino]indole (31) − Batch Reactor. A 20-cm

quartz tube (7 mm i.d., 10 mm o.d.) equipped with a rubber septum

and argon inlet needle was charged with diazo ketone 30 (0.135 g,

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The Journal of Organic Chemistry

Article

syringe over ca. 2 min. The reaction mixture was allowed to warm to

rt, stirred for 2 h, and then diluted with 20 mL of CH₂Cl₂and washed

with two 10-mL portions of 1 M HCl solution. The combined aqueous

layers were extracted with 10 mL of CH₂Cl₂, and the combined

organic layers were washed with 20 mL of satd aq NaHCO₃solution

and 20 mL of brine, dried over MgSO₄, ﬁltered, and concentrated to

aﬀord 0.187 g of orange oil. Column chromatography on 28 g of silica

gel (elution with 10% EtOAc−hexanes) aﬀorded 0.160 g (57% over

two steps from the ynamide) of triﬂate 33 as an orange oil: IR (neat)

2958, 2932, 2860, 1744, 1716, 1529, 1449, 1409, 1373, 1347, 1304,

was dissolved in 4.0 mL of toluene, the ﬂask was equipped with a stir

bar and coldﬁnger condenser, and the reaction mixture was heated at

reﬂux for 2 h. The resulting mixture was concentrated to aﬀord 0.235 g

of a dark-red oil. Column chromatography on 20 g of silica gel (elution

with 10% EtOAc−hexanes) furnished 0.125 g of crude benzannulation

product as an orange oil.

A 25-mL pear-shaped ﬂask equipped with a rubber septum and

argon inlet needle was charged with the crude benzannulation product

(0.125 g, 1.0 equiv), 4-DMAP (0.062 g, 0.753 mmol, 2.0 equiv), and

3 mL of CH₂Cl₂. The orange solution was cooled to 0 °C and triﬂic

anhydride (0.05 mL, 0.297 mmol, 1.2 equiv) was added dropwise by

syringe over ca. 2 min. The reaction mixture was allowed to warm to

rt, stirred for 4 h, and then diluted with 10 mL of CH₂Cl₂and washed

with two 6-mL portions of 1 M HCl solution. The combined aqueous

layers were extracted with 10 mL of CH₂Cl₂, and the combined

organic layers were washed with 15 mL of satd aq NaHCO₃solution

and 15 mL of brine, dried over MgSO₄, ﬁltered, and concentrated to

aﬀord 0.250 g of orange oil. Column chromatography on 16 g of silica

gel (elution with 7% EtOAc−hexanes) aﬀorded 0.117 g (52% over two

steps from the ynamide) of triﬂate 35 as an oﬀ-white solid: mp 97−

100 °C; IR (neat) 2929, 2858, 1598, 1408, 1350, 1245, 1214, 1163,

1

1249, 1215, 1154 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 8.12 (minor

rotamer), 8.06 (s, 1H), 7.57−7.67 (m, 1H), 6.65−6.72 (m, 1H), 3.81

(minor rotamer), 3.63 (s, 3H), 3.29 (s, 3H), 2.61−2.76 (m, 2H), 1.66

(s, 9H), 1.46−1.57 (m, 2H), 1.32−1.40 (m, 2H), 1.25−1.32 (m, 4H),

0.89 (t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 156.7, 149.2,

139.7, 139.5, 135.0, 129.0, 128.1, 124.0, 118.9 (q, J = 318 Hz), 115.6,

103.9, 85.0, 53.2, 39.1, 31.8, 29.8, 29.8, 28.3, 26.6, 22.7, 14.2; HRMS

(ESI) (m/z) [M + Na]⁺calculated for C₂₃H₃₁F₃N₂NaO₇S, 559.1696;

found 559.1703.

5-Hexyl-4-(triﬂuoromethylsulfonyloxy)-6-[N-(diethylphosphoryl)-

N-(benzyl)amino]indole (33) − Flow Reactor. Reactor A with a Pyrex

ﬁlter was employed for this reaction. A 25-mL pear-shaped ﬂask

equipped with a rubber septum and argon inlet needle was charged

with diazo ketone 32 (0.570 g, 0.134 mmol, 1.1 equiv), ynamide 17

(0.100 g, 0.507 mmol, 1.0 equiv), and 2.2 mL of DCE, and the yellow

solution was degassed via three freeze−pump−thaw (−196 °C, 0.05

mmHg) cycles. The FEP tubing of the reactor was ﬂushed with 3 mL

of degassed DCE, the mercury lamp was turned on, and degassed DCE

was pumped through the tubing for 5 min at a rate of 0.057 mL/min

by syringe pump. The solution of 32 and 17 was transferred to a

5-mL glass syringe and pumped through the tubing at a rate of

0.057 mL/min. Once the addition was complete, the tubing was ﬂushed

with three portions of degassed DCE (0.4, 0.4, and then 4.0 mL). The

reaction mixture was concentrated to aﬀord 0.202 g of orange oil. This

material was dissolved in 5.0 mL of toluene in the same 25-mL pear-

shaped collection ﬂask. The ﬂask was equipped with a stir bar and

coldﬁnger condenser, and the reaction mixture was heated at reﬂux for

2 h. The resulting mixture was concentrated to aﬀord 0.232 g of a

dark-orange oil. Column chromatography on 25 g of silica gel (elution

with 12% EtOAc−hexanes) furnished 0.113 g of ca. 85−90% pure

benzannulation product as an orange oil.

A 25-mL pear-shaped ﬂask equipped with a rubber septum and

argon inlet needle was charged with the impure benzannulation

product (0.113 g, 1.0 equiv), 4-DMAP (0.070 g, 0.573 mmol,

2.0 equiv), and 3.0 mL of CH₂Cl₂. The orange solution was cooled to

0 °C, and triﬂic anhydride (0.06 mL, 0.357 mmol, 1.3 equiv) was

added dropwise by syringe over ca. 2 min. The reaction mixture was

allowed to warm to rt, stirred for 2 h, then diluted with 20 mL of

CH₂Cl₂, and washed with two 10-mL portions of 1 M HCl solution.

The combined aqueous layers were extracted with 10 mL of CH₂Cl₂,

and the combined organic layers were washed with 20 mL of satd aq

NaHCO₃solution and 20 mL of brine, dried over MgSO₄, ﬁltered, and

concentrated to aﬀord 0.151 g of orange oil. Column chromatography

on 18 g of silica gel (elution with 10% EtOAc−hexanes) aﬀorded

0.127 g (47% over two steps from the ynamide) of triﬂate 33 as an

orange oil with spectral data consistent with that reported in the

procedure for the batch process given above.

1

1138, 939 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 7.63 (d, J = 8.0 Hz,

2H), 7.58 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 8.0

Hz, 2H), 7.26 (s, 1H), 7.18−7.26 (m, 2H), 7.09 (d, J = 6.5 Hz, 2H),

4.90 (d, J = 13.5 Hz, 1H), 4.38 (d, J = 13.5 Hz, 1H), 2.45−2.56 (m,

2H), 2.50 (s. 3H), 1.12−1.44 (m, 7H), 0.91 (t, J = 7.3 Hz, 3H), 0.72−

0.84 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 144.3, 142.1, 138.8,

136.1, 135.7, 135.0, 134.9, 134.0, 130.2, 129.9, 129.8, 128.8, 128.4,

128.3, 123.8, 120.5, 118.7 (q, J = 318 Hz), 57.1, 31.6, 30.1, 29.0, 27.1,

22.8, 21.8, 14.3; HRMS (ESI) (m/z) [M + Na]⁺calculated for

C₂₉H₃₀F₃NNaO₅S₃, 648.1130; found 648.1120.

5-Hexyl-4-(triﬂuoromethylsulfonyloxy)-6-[N-(p-tolylsulfonyl)-N-

(benzyl)amino]benzo[b]thiophene (35) − Flow Reactor. Reactor A

with a uranium ﬁlter was employed for this reaction. A 25-mL pear-

shaped ﬂask equipped with a rubber septum and argon inlet needle

was charged with diazo ketone 34 (0.062 g, 0.407 mmol, 1.1 equiv),

ynamide 22 (0.134 g, 0.363 mmol, 1.0 equiv), and 1.6 mL of DCE, and

the yellow solution was degassed via three freeze−pump−thaw (−196

°C, 0.05 mmHg) cycles. The FEP tubing of the reactor was ﬂushed

with 3 mL of degassed DCE, the mercury lamp was turned on, and

degassed DCE was pumped through the tubing for 5 min at a rate of

0.036 mL/min by syringe pump. The solution of 34 and 22 was

transferred to a 5-mL glass syringe and pumped through the tubing at

a rate of 0.036 mL/min. Once the addition was complete, the tubing

was ﬂushed with three portions of degassed DCE (0.4, 0.4, and then

4.0 mL). The 25-mL pear-shaped collection ﬂask was equipped with a

stir bar and coldﬁnger condenser, and the reaction mixture was heated

at reﬂux for 42 h and then concentrated to aﬀord 0.195 g of red oil.

Column chromatography on 20 g of silica gel (elution with 10%

EtOAc−hexanes) furnished 0.102 g of ca. 85−90% pure benzannu-

lation product as an orange oil.

A 25-mL pear-shaped ﬂask equipped with a rubber septum and

argon inlet needle was charged with the impure benzannulation

product (0.102 g, 1.0 equiv), 4-DMAP (0.050 g, 0.409 mmol,

2.0 equiv), and 1.6 mL of CH₂Cl₂. The orange solution was cooled to

0 °C and triﬂic anhydride (0.04 mL, 0.238 mmol, 1.2 equiv) was added

dropwise by syringe over ca. 2 min. The reaction mixture was allowed

to warm to rt, stirred for 4 h, and then diluted with 10 mL of CH₂Cl₂

and washed with two 5-mL portions of 1 M HCl solution. The

combined aqueous layers were extracted with 5 mL of CH₂Cl₂, and the

combined organic layers were washed with 15 mL of satd aq NaHCO₃

solution and 15 mL of brine, dried over MgSO₄, ﬁltered, and

concentrated to aﬀord 0.125 g of a red oil. Column chromatography

on 13 g of silica gel (elution with 7% EtOAc−hexanes) aﬀorded 0.106 g

(47% over two steps from the ynamide) of triﬂate 35 as an oﬀ-white

solid with spectral data consistent with that reported in the procedure

for the batch process given above.

5-Hexyl-4-(triﬂuoromethylsulfonyloxy)-6-[N-(p-tolylsulfonyl)-N-

(benzyl)amino]benzo[b]thiophene (35) − Batch Reactor. A 20-cm

quartz tube (5 mm i.d., 7 mm o.d.) equipped with a rubber septum

and argon inlet needle was charged with diazo ketone 34⁴³(0.063 g,

0.414 mmol, 1.1 equiv), ynamide 22^14b(0.134 g, 0.363 mmol,

1.0 equiv), and 1.6 mL of CH₂Cl₂. The yellow reaction mixture was degassed

via three freeze−pump−thaw (−196 °C, 0.05 mmHg) cycles. The

quartz tube was positioned ca. 20 cm from a Hanovia 450 W medium

pressure mercury lamp equipped with a uranium ﬁlter (quartz

immersion well cooled by recirculating tap water) and irradiated

under argon at 25 °C for 50 h. The reaction mixture was transferred to

a 25-mL pear-shaped ﬂask with the aid of two 4-mL portions of

CH₂Cl₂and concentrated to aﬀord 0.211 g of a red oil. This material

5-Hexyl-4-hydroxy-6-[N-(diethylphosphoryl)-N-(benzyl)amino]-

benzo[b]thiophene (36) − Batch Reactor. A 20-cm quartz tube

(5 mm i.d., 7 mm o.d.) equipped with a rubber septum and argon inlet

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needle was charged with diazo ketone 34 (0.049 g, 0.322 mmol,

1.1 equiv), ynamide 25 (0.099 g, 0.282 mmol, 1.0 equiv), and 1.3 mL

of CH₂Cl₂. The yellow reaction mixture was degassed via three

freeze−pump−thaw (−196 °C, 0.05 mmHg) cycles. The quartz tube

was positioned ca. 20 cm from a Hanovia 450 W medium pressure

mercury lamp (quartz immersion well, cooled by recirculating tap

water) and irradiated under argon at 25 °C for 5.5 h. The reaction

mixture was transferred to a 25-mL pear-shaped ﬂask with the aid of

two 4-mL portions of CH₂Cl₂and concentrated to aﬀord 0.143 g of an

orange oil. This material was dissolved in 3 mL of toluene, the ﬂask

was equipped with a stir bar and coldﬁnger condenser, and the

reaction mixture was heated at reﬂux for 1.5 h. The resulting mixture

was concentrated to aﬀord 0.159 g of a dark-orange oil. Column

chromatography on 15 g of silica gel (elution with 30% EtOAc−

hexanes) furnished 0.115 g of an orange oil which was further puriﬁed

by column chromatography on 15 g of silica gel (elution with 0.5%

MeOH−CH₂Cl₂) to aﬀord 0.105 g (78%) of phenol 36 as an orange

oil: IR (neat) 3225 (broad), 2924, 2856, 1605, 1552, 1495, 1424, 1392,

(broad), 3452 (broad) 2926, 2856, 1621, 1582, 154, 1438, 1352, 1317,

1198, 1143 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.36−7.45 (m, 4H),

7.31 (tt, J = 7.0 Hz, J = 1.5 Hz, 1H), 6.09 (s, 1H), 4.62 (s, 1H), 4.36 (s,

2H), 3.87 (s, 1H), 2.68 (t, J = 6.3 Hz, 2H), 2.52−2.60 (m, 4H), 1.83−

1.89 (m, 2H), 1.73−1.79 (m, 2H), 1.52−1.60 (m, 2H), 1.38−1.47 (m,

2H), 1.29−1.38 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 151.8, 144.5, 140.1, 136.2,128.8, 127.7, 127.3, 112.1,

110.7, 104.1, 48.9, 32.0, 30.0, 29.9, 28.8, 24.1, 23.3, 23.2, 22.9, 22.6,

14.3; HRMS (ESI) (m/z) [M + H]⁺calculated for C₂₃H₃₂NO,

338.2478; found 338.2470.

Tandem Benzannulation/Ring Closing Metathesis. 3-[N-

(Carbomethoxy)-N-(allyl)amino]-2-[but-3-en-2-(tert-butyl-

dimethylsilanyloxy)yl]naphthalen-1-ol (38). A 25-cm quartz tube

(5 mm i.d., 7 mm o.d.) equipped with a rubber septum and argon inlet

needle was charged with diazo ketone 19 (0.075 g, 0.510 mmol, 1.1

equiv), ynamide 15 (0.150 g, 0.469 mmol, 1.0 equiv), and 1.8 mL of

CH₂Cl₂. The yellow reaction mixture was degassed via three cycles of

freeze−pump−thaw (−196 °C, 0.05 mmHg). The quartz tube was

positioned ca. 20 cm from a Hanovia 450 W medium pressure mercury

lamp (quartz immersion well, cooled by recirculating tap water) and

irradiated under argon at 25 °C for 2.5 h. The reaction mixture was

concentrated to aﬀord 0.260 g of yellow oil, which was transferred with

2 mL of toluene to a 10-mL reaction tube. The solution was heated at

reﬂux for 2.5 h, allowed to cool to rt, and then concentrated to give

0.291 g orange oil. Puriﬁcation by column chromatography on 16 g of

silica gel (elution with 10% EtOAc−hexanes) aﬀorded 0.036 g (24%)

of unreacted ynamide 15 and 0.129 g (62%) of 38 as a viscous yellow

oil: IR (thin ﬁlm) 3238, 2955, 2859, 1716, 1636, 1597, 1574, 1448,

1330, 1215, 1126, 1051, 970 cm⁻¹; H NMR (500 MHz, CDCl₃) H

NMR (500 MHz, CDCl₃) δ 7.32 (dd, J = 0.8 Hz, J = 5.5 Hz, 1H)

7.18−7.24 (m, 3H), 7.10−7.14 (m, 2H), 7.09 (d, J = 5.5 Hz), 6.95−

6.97 (m, 1H), 6.74 (s, 1H), 4.59−4.67 (m, 1H), 4.02−4.32 (m, 5H),

2.58−2.68 (m, 2H), 2.45−2.55 (m, 2H), 1.57−1.70 (m, 1H), 1.21−

1.42 (m, 12H), 0.99−1.11 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 150.4, 137.9 (d, J = 1.4 Hz), 137.7 (d, J =

3.4), 137.6 (d, J = 2.9 Hz), 129.9, 129.1 (d, J = 1.1 Hz), 128.3, 127.7,

124.2, 123.4 (d, J = 4.0 Hz), 120.3, 116.3, 63.2 (m), 55.9 (d, J = 4.5

Hz), 31.9, 30.5, 29.2, 26.2, 23.0, 16.4 (m), 14.4; ³¹P NMR (121 MHz,

CDCl₃) δ 6.18; HRMS (ESI) (m/z) [M + H]⁺calculated for

C₂₅H₃₅NO₄PS, 476.2019; found 476.2034.

5-Hexyl-4-hydroxy-6-[N-(diethylphosphoryl)-N-(benzyl)amino]-

benzo[b]thiophene (36) − Flow Reactor. Reactor A with a Pyrex

ﬁlter was employed for this reaction. A 25-mL pear-shaped ﬂask

equipped with a rubber septum and argon inlet needle was charged

with diazo ketone 34 (0.069 g, 0.448 mmol, 1.1 equiv), ynamide 25

(0.143 g, 0.407 mmol, 1.0 equiv), and 1.7 mL of DCE, and the yellow

solution was degassed via three freeze−pump−thaw (−196 °C,

0.05 mmHg) cycles. The FEP tubing of the reactor was ﬂushed with

3 mL of degassed DCE, the mercury lamp was turned on, and

degassed DCE was pumped through the tubing for 5 min at a rate of

0.057 mL/min by syringe pump. The solution of 34 and 25 was

transferred to a 5-mL glass syringe and pumped through the tubing at

a rate of 0.057 mL/min. Once the addition was complete, the tubing

was ﬂushed with three portions of degassed DCE (0.4, 0.4, and then

4.0 mL). The 25-mL pear-shaped collection ﬂask was equipped with a

stir bar and coldﬁnger condenser, and the reaction mixture was heated

at reﬂux for 42 h and then concentrated to aﬀord 0.199 g of red oil.

This material was dissolved in 2 mL of CH₂Cl₂and concentrated onto

2 g of silica gel. The free-ﬂowing powder was deposited on a column of

20 g of silica gel and eluted with 30% EtOAc−hexanes to furnish

0.159 g of an orange oil which was further puriﬁed by column

chromatography on 20 g of silica gel (elution with 1% MeOH−

CH₂Cl₂) to aﬀord 0.154 g (79%) of phenol 36 as an orange oil with

spectral data consistent with that reported in the procedure for the

batch process given above.

Reductive Cleavage of N-Phosphorylaniline 29. 3-[N-(Benzyl)-

amino]-2-hexyl-5,6,7,8-tetrahydronaphthalen-1-ol (37). A 25-mL,

pear-shaped ﬂask equipped with a rubber septum and argon inlet

needle was charged with phosphoramide 29 (0.132 g, 2.79 mmol, 1.0

equiv) and 4 mL of toluene. Red-Al (≥65 wt % in toluene, 0.65 mL,

2.13 mmol, 8 equiv) was added, and the resulting solution was heated

at 85 °C for 2 h. The reaction mixture was quenched at room

temperature by the addition of 10 mL of satd aq K₂CO₃solution,

diluted with 10 mL of ether, and the organic layer was washed with

10 mL of satd aq K₂CO₃solution. The combined aqueous layers were

extracted with three 10-mL portions of Et₂O. The combined organic

layers were washed with 20 mL of brine, dried over Na₂SO₄, ﬁltered,

and concentrated to give 0.122 g of red oil. Column chromatography

on 11 g of silica gel (elution with 2% EtOAc−hexanes) provided 0.077

g (84%) of amine 37 as a red solid: mp 58−60 °C; IR (neat) 3556

1

1386, and 1256 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 9.16 (s, minor

rotamer), 9.01 (s, 1H), 8.28−8.30 (m, 1H), 7.71−7.74 (m, 1H), 7.45−

7.47 (m, 2H), 7.20−7.23 (m, 1H), 5.84−6.08 (m, 2H), 5.11−5.30 (m,

4H), 4.47−4.54 (m, 2H), 3.81−3.95 (m, 2H), 3.66 (s, 3H), 3.60 (s,

minor rotamer), 3.03−3.11 (m, 1H), 2.82−2.89 (m, 1H), 0.92 (s, 9H),

0.08 (s, minor rotamer), 0.05 (s, 3H), −0.05 (s, minor rotamer), and

−0.15 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.5, 152.9, 139.8,

139.1, 139.0, 133.5, 133.1, 127.4, 126.6, 124.6, 125.3, 122.8, 119.5,

118.7, 117.3, 115.7, 54.4, 53.0, 35.5, 35.0, 25.9, 18.2, −4.3, and −5.0,

(Peaks corresponding to the minor rotamer: δ 153.2, 133.2, 127.3,

122.9, 119.2, 118.5, 117.0, 54.4, 53.1, 26.0, 18.3, −4.2, and −4.8);

HRMS (ESI) (m/z) [M + Na]⁺calcd for C₂₅H₃₅NNaO₄Si: 464.2228,

found: 464.2217.

Methyl 5-(tert-Butyldimethylsilanyloxy)-7-hydroxy-5,6-dihydro-

2H-napthaleno[b]azocine-1-carboxylate (40). A 100-mL, round-

bottomed ﬂask ﬁtted with a rubber septum and argon inlet needle was

charged with a solution of the Grubbs catalyst 39 (0.012 g, 0.014

mmol, 0.05 equiv) in 20 mL of CH₂Cl₂. Naphthol 38 (0.124 g, 0.281

mmol, 1.0 equiv) in 8 mL of CH₂Cl₂was added to the reaction ﬂask

via cannula in one portion. The rubber septum was replaced with a

reﬂux condenser ﬁtted with an argon inlet adapter. The pale-pink

reaction mixture was heated at reﬂux for 6 h, allowed to cool to rt, and

then concentrated to aﬀord ca. 0.134 g of yellow−brown foam.

Column chromatography on 12 g of silica gel (elution with 15%

EtOAc−hexane) yielded 0.088 g (76%) of azocine 40 as an oﬀ-white

solid: mp 74−76 °C; IR (thin ﬁlm) 3351, 2955, 2857, 1709, 1684,

1572, 1450, 1388, 1250, and 1065 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)

δ 8.24−8.26 (m, 1H), 7.70 (s, 1H), 7.72−7.75 (m, 1H), 7.44 (app dd,

J = 3.1, 6.2 Hz, 2H), 7.26 (bs, 1H), 5.57 (app d, J = 11.6 Hz, 1H),

5.34−5.41 (m, 1H), 5.14 (app s, 1H), 4.44 (bs, 1H), 4.20 (dd, J = 7.9, 14.4

Hz, 1H), 3.72 (bs, 3H), 3.24 (app d, J = 2.7 Hz, 2H), 1.01 (s, 9H), 0.26 (s,

3H), and 0.19 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.3, 150.6,

140.6, 137.7, 133.1, 127.5, 127.3, 126.3, 125.3, 124.7, 122.5, 118.9, 117.7,

72.6, 53.3, 48.0, 35.9, 26.0, 18.4, −4.5, and −4.8; HRMS (EI) (m/z)

[M + Na]⁺calcd for C₂₃H₃₁NNaO₄Si, 436.1915; found: 436.1922.

N-(Methoxycarbonyl)-N-allyl-(2-allyl-4,5-dimethyl-3-

hydroxyphenyl)amine (43). A 25-mL recovery ﬂask equipped with a

condenser, rubber septum and argon inlet needle was charged with

ynamide 41⁷(0.146 g, 0.815 mmol, 1.0 equiv) and 6.0 mL of toluene.

A 25-mL pear-shaped ﬂask ﬁtted with a rubber septum and argon inlet

needle was charged with diazo ketone 42^18a(0.244 g, 1.96 mmol, 2.4 equiv)

and 8 mL of toluene. Both solutions were degassed with a stream of argon

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for 15 min. The solution of diazo ketone was taken up in a 10-mL glass

syringe wrapped in aluminum foil and ﬁtted with a 20-gauge, 20-cm long

steel needle. The reaction mixture was heated at reﬂux and the diazo

ketone solution was added through the condenser via syringe pump.

After the addition was completed (ca. 13.5 h), the pear-shaped ﬂask was

rinsed with 0.5 mL of toluene and added with the same syringe in one

portion to the reaction mixture. Heating was continued for 5 h. After

cooling to rt, the reaction mixture was concentrated to aﬀord 0.450 g of

orange oil that was diluted with 5 mL of MeOH and 3 mL of 5 M KOH

solution. After heating at 60−70 °C for 2 h, the resulting mixture was

cooled to rt, quenched with 16 mL of 1 M HCl solution, and diluted

with 20 mL of Et₂O. The aqueous layer was extracted with two 20-mL

portions of Et₂O, and the combined organic layers were washed with

40 mL of satd aq NaHCO₃solution and 40 mL of brine, dried over MgSO₄,

ﬁltered, and concentrated to provide 0.308 g of orange oil. Puriﬁcation

by column chromatography on 39 g of silica gel (gradient elution with

15−20% EtOAc−hexanes) aﬀorded 0.146 g of aniline 43 (65%) as a

yellow solid: mp 70−72 °C; IR (neat) 3412, 3078, 2925, 2857, 1686, 1575,

1455, 1389, 1320, 1257, 1196 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.58

(s, 1 H), 5.85−6.02 (m, 2 H), 5.18−5.30 (m, 3 H), 5.07−5.15 (m, 2 H),

4.21−4.32 (m, 1 H), 3.85−4.03 (m, 1 H), 3.78 (s, minor rotamer), 3.62 (s,

3 H), 3.26−3.39 (m, 2 H), 2.24 (s, 3 H), 2.15 (s, 3 H); ¹³C NMR

(125 MHz, CDCl₃) δ 156.4, 153.5, 137.8, 136.8, 135.9, 133.4, 123.4, 122.1,

120.2, 118.4, 117.3, 54.1, 53.1, 30.9, 20.2, 12.0; HRMS (ESI) (m/z)

[M + H]⁺calculated for C₁₆H₂₂NO₃, 276.1594; found 276.1598.

Methyl 6-Hydroxy-7,8-dimethyl-2,5-dihydro-benzo[b]azepine-1-

carboxylate (44). A 100-mL, round-bottomed ﬂask equipped with a

rubber septum and argon inlet needle was charged with a solution of

the Grubbs catalyst 39 (0.014 g, 0.016 mmol, 0.05 equiv) in 30 mL of

CH₂Cl₂. The aniline 43 (0.094 g, 0.341 mmol, 1.0 equiv) in 6 mL of

CH₂Cl₂was added to the reaction ﬂask via cannula in one portion, and

the rubber septum was replaced with a reﬂux condenser ﬁtted with an

argon inlet adapter. The pale-pink reaction mixture was heated at

reﬂux for 40 min, allowed to cool to rt, and then concentrated onto 2 g

of silica gel. The free-ﬂowing powder was deposited on a column of

20 g of silica gel and eluted with 25% EtOAc−hexanes to aﬀord 0.081 g

(96%) of dihydrobenzoazepine 44 as a tan wax: IR (neat) 3399, 3024,

2955, 1685, 1615, 1579, 1456, 1395, 1333, 1262, 1193, 1088 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 6.70 (s, minor rotamer), 6.64 s, 1 H),

5.75−5.84 (m, 1 H), 5.43−5.52 (m, 1 H), 4.72−5.16 (m, 1 H), 4.69 (s,

1H), 4.22 (s, minor rotamer), 3.79 (s, minor rotamer) 3.67 (s, 3 H), 3.34−

3.66 (m, 3 H), 2.26 (s, 3 H), 2.24 (s, minor rotamer), 2.15 (s, 3 H), 2.12

(s, minor rotamer); ¹³C NMR (125 MHz, CDCl₃mixture of two

rotamers) for major rotamer: δ 156.4, 150.4, 139.5, 135.8, 127.3, 126.0,

125.2, 123.8, 121.5, 53.4, 48.3, 23.3, 20.4, 12.3; additional resonances

appeared for the minor rotamer at δ: 126.9, 121.4, 48.1, 23.1; HRMS (ESI)

(m/z) [M + H]⁺calculated for C₁₄H₁₈NO₃, 248.1281; found 248.1272.

Synthesis of Indoles via Tandem Ynamide Benzannulation/

Cyclization Strategies. 2-(Trimethylsilyl)ethyl Benzyl[2-(2,2-dime-

thoxyethyl)-3-hydroxy-4,5-dimethylphenyl]carbamate (46). A sol-

ution of ynamide 45⁸(0.340 g, 0.936 mmol, 1.0 equiv) in 3.5 mL of

CH₂Cl₂was distributed evenly between two 25-cm quartz reaction

tubes (13 mm i.d., 15 mm o.d.) ﬁtted with rubber septa and argon inlet

needles. A 15-mL Pyrex tube ﬁtted with a rubber septum and argon

inlet needle was charged with a solution of diazo ketone 42 (0.310 g,

2.07 mmol, 2.4 equiv) in 7 mL of CH₂Cl₂. All solutions were purged

with argon for 10 min. The upper portions (ca. 10 cm) of the quartz

tubes were wrapped in aluminum foil and the tubes were positioned

ca. 4 cm from a Hanovia 450 W medium pressure mercury lamp

(quartz immersion well, cooled by tap water). The quartz reaction

tubes and the immersion well were partially submerged in a room-

temperature water bath contained in a 2-L beaker wrapped in

aluminum foil. The diazo ketone solution was taken up in two 5-mL

glass syringes ﬁtted with 20 gauge, 20-cm steel needles and wrapped in

aluminum foil, and the solution was added to the reaction mixture

using a syringe pump over 5 h (0.5 mL CH₂Cl₂rinse). Irradiation was

continued for 1 h, and then the reaction mixtures were combined in a

25-mL round-bottomed ﬂask and concentrated, and the residue was

diluted with 5 mL of toluene. The ﬂask was ﬁtted with a coldﬁnger

condenser with an argon inlet side arm, and the solution was heated at

reﬂux for 1 h, allowed to cool to rt, and then concentrated to give

0.625 g of an orange oil. Column chromatography on 20 g of grade

II neutral alumina (gradient elution with 0−5% EtOAc−hexanes) gave

0.292 g of a mixture of unreacted ynamide 45 and phenol 46. Mixed

fractions (0.057 g) were puriﬁed by chromatography on 5 g of neutral

alumina (gradient elution with 5−10% EtOAc−hexanes) to give

additional 0.034 g of the mixture of 45 and 46. The combined

mixtures were then further puriﬁed on 25 g of silica gel (elution with

10:10:80 Et₂O:benzene:CH₂Cl₂) to give 0.255 g (59%) of phenol 46

as a yellow oil: IR (ﬁlm) 3314, 2952, 1698, 1619, 1573, 1454, 1407,

1311, 1251, 1116, 1093, 1074, 1041 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃): δ 8.03 (br s, 1H), 7.20−7.28 (m, 5H), 6.43 (br s, minor

rotamer), 6.35 (br s, 1H), 4.68 (s, 2H), 4.00−4.36 (br m, 3H), 3.32 (s,

3H), 3.23 (s, 3H), 2.52 (d, J = 5.6 Hz, 2H), 2.13 (s, 3H), 2.12 (s, 3H),

1.08 (br m, minor rotamer), 0.86 (br m, 2H), 0.04 (s, minor rotamer),

−0.10 (s, 9H); ¹³C NMR (100 MHz, CDCl₃), (mixture of two

rotamers) for major rotamer: δ 156.6, 154.5, 138.3, 137.7, 137.1, 129.5,

128.5, 127.7 124.6, 121.8, 118.7 105.7, 64.2, 55.1, 54.8, 53.6, 30.8, 20.1,

18.1, 12.3, −1.5; additional resonances appeared for the minor rotamer

at δ 129.0; HRMS (ESI) [M + Na]⁺calcd for C₂₅H₃₇NNaO₅Si:

482.2333, found 482.2336.

N-Benzyl-N-2-(trimethylsilyl)ethoxycarbonyl-[1-hydroxy-2-(2,2-

dimethoxyethyl)-5,6,7,8-tetrahydronaphthalen-3-yl]amine (48). A

solution of ynamide 45 (0.313 g, 0.86 mmol, 1.0 equiv) in 2.8 mL of

CH₂Cl₂was distributed equally between two 25-cm quartz reaction

tubes (13 mm i.d., 15 mm o.d.) ﬁtted with rubber septa and argon inlet

needles. A 15-mL Pyrex tube ﬁtted with a rubber septum and argon

inlet needle was charged with diazo ketone 16 (0.310 g, 2.07 mmol,

2.4 equiv) and 5.8 mL of CH₂Cl₂. Both solutions were degassed by

three freeze−pump−thaw cycles at −196 °C, 0.05 mmHg. The

solution of diazo ketone was taken up in two 5-mL glass syringes

wrapped in aluminum foil and ﬁtted with 20-gauge, 20-cm steel

needles. The upper portions (ca. 18-cm length) of the quartz tubes

were wrapped in aluminum foil and the tubes were positioned ca. 3 cm

from a Hanovia 450 W medium pressure mercury lamp cooled in a

quartz immersion well. The quartz tubes and the immersion well were

partially submerged in a room temperature water bath contained in a

2-L beaker wrapped in aluminum foil. The diazo ketone solution was

added to the reaction tubes via syringe pump over ca. 5 h (0.5 mL

CH₂Cl₂wash) while the reaction mixture was irradiated, and then

irradiation was continued for 90 min. The combined reaction mixture

was concentrated to provide 0.583 g of an orange oil which was

transferred with the aid of 5 mL of toluene to a 25-mL, one-necked,

round-bottomed ﬂask equipped with a coldﬁnger condenser with

argon inlet side arm. The solution was heated at reﬂux for 1 h, allowed

to cool to room temperature, and then concentrated to give 0.550 g of

an orange oil. This material was dissolved in ca. 10 mL of CH₂Cl₂and

concentrated onto 3.5 g of silica gel. The free-ﬂowing powder was

added to the top of a column of 55 g of silica gel and eluted with 15%

EtOAc−hexanes to aﬀord 0.224 g of acetal 48 as a viscous yellow oil

and 0.059 g of a mixture of phenol 48 and unreacted ynamide 45. This

mixture was dissolved in ca. 5 mL of CH₂Cl₂and concentrated onto

0.5 g of silica gel. The free-ﬂowing powder was added to the top of a

column of 6 g of silica gel and eluted with 15% EtOAc−hexanes to

aﬀord 0.027 g of phenol 48 as a viscous yellow oil. The combined yield

of phenol 48 was 0.251 g (60%): IR (ﬁlm) 3315, 2935, 2858, 2838,

1698, 1617, 1572, 1496, 1436, 1406, 1333, 1299, 1249, 1116, and 1072

cm⁻¹; ¹H NMR (500 MHz, CDCl₃, ca. 68:32 mixture of rotamers) for

major rotamer: δ 8.13 (s, minor rotamer), 8.09 (s, 1H), 7.18−7.35 (m,

5H), 6.38 (s, minor rotamer), 6.28 (s, 1H), 4.75 (d, J = 14.4 Hz, 1H),

4.66 (d, J = 14.4 Hz, 1H), 4.05−4.47 (m, 3H), 3.40 (s, minor

rotamer), 3.37 (s, 3H), 3.31 (s, minor rotamer), 3.28 (s, 3H), 2.51−

2.71 (m, 6H), 1.68−1.84 (m, 4H), 1.05−1.19 (m, minor rotamer),

0.83−1.01 (m, 2H), 0.07 (s, minor rotamer), −0.07 (s, 9H); ¹³C NMR

(125 MHz, CDCl₃, mixture of two rotamers) for major rotamer: δ

156.5, 154.1, 138.3, 137.7, 137.6, 129.4, 128.4, 127.5, 125.3, 120.8,

117.6, 105.6, 64.1, 55.0, 54.7, 53.5, 30.9, 30.6, 29.4, 23.5, 22.8, 17.9,

and −1.5; additional resonances appeared for the minor rotamer at: δ

156.0, 139.0, 128.8, 120.4, 117.8, 55.2, 54.9, and −1.4; HRMS (ESI)

[M+Na]⁺calcd for C₂₇H₃₉NNaO₅Si: 508.2490, found 508.2497.

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2-(Trimethylsilyl)ethyl Benzyl[5-(2,2-dimethoxyethyl)-6-hydroxy-

2,3-dihydro-1H-phenalen-4-yl]carbamate (54). Two 25-cm quartz

tubes (13 mm i.d., 15 mm o.d.) were each charged with ynamide 45

(0.300 g, 0.825 mmol, 1.0 equiv) and diazo ketone 53^2b(0.231 g,

1.24 mmol, 1.5 equiv). A stir bar was added to each reaction tube, and

the tubes were ﬁtted with rubber septa and argon inlet needles and

purged with argon. Dichloromethane (8.5 mL) was then added to each

tube, and the reaction tubes were positioned ca. 3 cm from a Hanovia

450 W medium pressure mercury lamp (quartz immersion well, cooled

by tap water) in a room-temperature water bath contained in a 2-L

beaker wrapped in aluminum foil. The reaction solutions were

irradiated for 2.5 h and then combined and concentrated to give 1.129 g

of an orange oil. A solution of this material in 20 mL of toluene was

transferred to a ﬂask ﬁtted with a coldﬁnger condenser. The solution

was heated at reﬂux for 2 h, allowed to cool to rt, and concentrated to

give 1.15 g of an orange oil. Column chromatography on 50 g of grade

II neutral alumina (elution with 10% EtOAc−hexanes) gave 0.680 g

(79%) of phenol 54 as a yellow oil: IR (ﬁlm) 3291, 2949, 2835, 1698,

1620, 1583, 1496, 1398, 1357, 1318, 1250, 1208, 1184, 1141, 1115

cm⁻¹; ¹H NMR (400 MHz, CDCl₃, ca. 80:20 mixture of rotamers) for

major rotamer: δ 8.50 (s, 1H), 8.48 (s, minor rotamer), 8.14 (d, J = 8.4

Hz, 1H), 8.13 (d, J = 8.3 Hz, minor rotamer), 7.41−7.36 (m, 1H),

7.31−7.10 (m, 6H), 4.84 (d, J = 13.9 Hz, 1H), 4.58 (d, J = 13.9 Hz,

1H), 4.48 (d, J = 14.2 Hz, minor rotamer), 4.44−4.04 (m, 3H), 3.39

(s, minor rotamer), 3.37 (s, 3H), 3.28 (s, minor rotamer), 3.27 (s,

3H), 3.01 (t, J = 5.9 Hz, 2H), 2.73 (d, J = 6.9 Hz, minor rotamer), 2.69

(d, J = 6.9 Hz, 2H), 2.84−2.42 (m, 2H), 1.89 (pq, J = 6.1 Hz, minor

rotamer), 1.81 (pq, J = 6.0 Hz, 2H), 1.26−1.18 (m, minor rotamer),

0.95−0.75 (m, 2H), 0.12 (s, minor rotamer), and 0.10 (s, 9H); ¹³C

NMR (100 MHz, CDCl₃, mixture of two rotamers) for major rotamer:

δ 156.7, 150.8, 137.0, 136.3, 135.0, 130.1, 129.9, 128.5, 128.0, 125.7,

125.5, 125.2, 124.8, 120.6, 114.9, 106.0, 64.2, 55.1, 54.4, 53.0, 31.36,

31.34, 26.8, 22.8, 18.1, −1.5; additional resonances appeared for the

minor rotamer at δ: 155.7, 136.9, 135.5, 130.4, 130.2, 128.0, 125.1,

124.6, 115.4, 106.2, 64.3, 55.6, 54.3, 52.9, 31.5, 22.9, 18.2, −1.2; HRMS

(ESI) [M + Na]⁺calcd for C₃₀H₃₉NNaO₅Si: 544.2490, found 544.2502.

4-[Benzyl([2-(trimethylsilyl)ethoxy]carbonyl)amino]-5-(2,2-dime-

thoxyethyl)-2,3-dihydro-1H-phenalen-6-yl Triﬂuoromethanesulfo-

nate (55). A 25-mL recovery ﬂask was charged with phenol 54

(0.233 g, 0.447 mmol, 1 equiv) and 4 mL of THF and cooled to 0 °C.

Sodium hydride (60 wt % oil disp., 0.025 g, 0.63 mmol, 1.4 equiv) was

then added, and the reaction mixture was stirred for ca. 5 min until gas

evolution ceased. A solution of N-phenyltriﬂimide (0.224 g, 0.627

mmol, 1.4 equiv) in 2 mL of THF was added, and the resulting brown

mixture was allowed to warm to rt over 15 min. The reaction mixture

was cooled to 0 °C, and 3 mL of satd aq NaHCO₃solution was added.

The resulting mixture was diluted with 15 mL of Et₂O, and the

aqueous layer was separated and extracted with two 15-mL portions of

Et₂O. The combined organic phases were washed with two 20-mL

portions of 2.5 M NaOH solution and 20 mL of brine, dried over

MgSO₄, ﬁltered, and concentrated to give 0.329 g of a yellow oil.

Column chromatography on 15 g of silica gel (elution with 10%

EtOAc−hexanes) gave 0.219 g (75%) of triﬂuoromethanesulfonate 55

as a viscous colorless oil: IR (ﬁlm) 2953, 2835, 1703, 1597, 1403,

Methyl Allyl(2-[2-(tert-butyldimethylsilyloxy)ethyl]-3-hydroxy-4,5-

dimethylphenyl)carbamate (61). Two 25-cm quartz tubes (13 mm

i.d., 15 mm o.d.) ﬁtted with rubber septa and argon inlet needles were

charged with solutions of ynamide 58⁸(ﬂask A: 0.168 g, 0.565 mmol,

1.0 equiv; ﬂask B: 0.151 g, 0.508 mmol, 1.0 equiv, each in 2 mL of

CH₂Cl₂). A 25-mL recovery ﬂask was charged with a solution of diazo

ketone 42 (0.340 g, 2.74 mmol, 2.6 equiv) in 7 mL of CH₂Cl₂. All

solutions were purged with argon for 15 min. The upper portions (ca.

10 cm) of the quartz reaction tubes were wrapped in aluminum foil

and the tubes were positioned ca. 5 cm from a Hanovia 450 W

medium pressure mercury lamp (quartz immersion well, cooled by tap

water). The reaction tubes and the immersion well were partially

submerged in a room-temperature water bath contained in a 2-L

beaker wrapped in aluminum foil.⁴⁴The diazo ketone solution was

taken up into two 5-mL gastight syringes wrapped in aluminum foil

and ﬁtted with 20 gauge, 20-cm steel needles. The solution was then

added to the reaction tubes using a syringe pump over 7 h (1 mL

CH₂Cl₂rinse).⁴⁵Irradiation was continued for 20 min, and then the

reaction mixtures were combined and concentrated in a 25-mL round-

bottomed ﬂask. The residue was diluted with 7 mL of toluene, the ﬂask

was ﬁtted with a coldﬁnger condenser with an argon inlet side arm,

and the solution was heated at reﬂux for 3 h. The reaction mixture was

allowed to cool to rt and concentrated to give 0.7 g of a dark-orange

oil. Column chromatography on 50 g of silica gel (elution with 10%

EtOAc−hexanes) gave 0.328 g (78%) of phenol 61 as a yellow oil

which crystallized upon refrigeration: mp 48−49 °C; IR (neat) 3273,

2859, 2930, 1709, 1620, 1574, 1449, 1388, 1313, 1259, 1214, 1192,

1147, 1092, 1039 cm⁻¹; 1H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H),

6.51 (s, 1H), 5.85−5.95 (m, 1H), 5.12 (m, 2 H), 3.70−4.30 (m, 4H),

3.62 (s, 3H), 2.78 (m, 2H), 2.23 (s, 3H), 2.17 (s, 3H), 0.92 (s, 9H),

0.08 (d, J = 5.6 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 156.5, 154.7,

137.6, 136.7, 133.3, 124.7, 122.4, 121.2, 118.3, 65.3, 54.3, 53.0, 29.5,

25.9, 20.2, 18.4, 12.3, −5.5; HRMS (ESI) [M + Na]⁺calcd for

C₂₁H₃₅NNaO₄Si: 416.2228, found 416.2218.

Methyl Allyl[4-(2-[(tert-butyldimethylsilyl)oxy]ethyl)-3-hydroxy-

benzocyclobutene]-5-carbamate (64). A 25-cm quartz tube (13

mm i.d., 15 mm o.d.) equipped with two stir bars, a rubber septum,

and argon inlet needle was charged with ynamide 58 (0.310 g, 1.04

mmol, 1.0 equiv) and 3 mL of CH₂Cl₂. An 18 mm × 160 mm test tube

was charged with a solution of diazo ketone 50 (0.328 g, 2.69 mmol,

2.6 equiv) in 8 mL of CH₂Cl₂. Both solutions were purged with argon

for 15 min. The upper portion (ca. 10 cm) of the quartz reaction tube

was wrapped in aluminum foil, and the tube was positioned ca. 15 cm

from a Hanovia 450 W medium pressure mercury lamp (quartz

immersion well, cooled by tap water). The diazo ketone solution was

taken up into a 10-mL gastight syringe wrapped in aluminum foil and

ﬁtted with a 20 gauge, 20-cm steel needle and added to the reaction

tubes using a syringe pump over 5 h (1 mL CH₂Cl₂rinse). Irradiation

was continued for 5 h, and the reaction mixture was concentrated in a

50-mL round-bottomed ﬂask. The residue was diluted with 15 mL of

toluene, the ﬂask was ﬁtted with a reﬂux condenser with an argon inlet,

and the solution was heated at reﬂux for 2.5 h. The resulting red−

brown solution was allowed to cool to rt and then concentrated to give

0.74 g of a red−brown oil. Column chromatography on 15 g of silica

gel (elution with 10% EtOAc−hexanes) yielded 0.099 g (32%) of

unreacted ynamide 58 as a colorless oil and 0.251 g (62%; 91% based

on recovered ynamide) of carbamate 64 as a white solid: mp 129−130

°C; IR (KBr pellet) 3317, 2928, 1679, 1593, 1457, 1432, 1310, 1258,

1

1318, 1248, 1215, 1138, 1121, 1074, 943, and 729 cm⁻¹; H NMR

(600 MHz, CDCl₃) δ 8.00 (d, J = 8.5 Hz, 1H), 7.59−7.60 (m, 1H),

7.38−7.14 (m, 6H), 5.35 (d, J = 14.3 Hz, 1H), 5.19 (d, J = 14 Hz,

minor rotamer), 4.76−4.78 (m, 1H), 4.70−4.72 (m, minor rotamer),

4.16−4.56 (m, 3H), 3.35−3.46 (m, 3H), 3.29−3.35 (m, 3H), 2.96−

3.13 (m, 3H), 2.54−2.60 (m, 1H), 2.14−2.27(m, 1H), 1.27−1.96 (m,

4H), 0.87−1.00 (m, 2H), 0.20 (s, minor rotamer), 0.00 (s, 9H); ¹³C

NMR (150 MHz, CDCl₃, mixture of two rotamers) for major rotamer:

δ 156.4, 142.4, 137.3, 137.1, 136.6, 134.7, 130.4, 130.3, 128.6, 127.6,

127.2, 126.87, 125.7, 119.6, 103.6, 64.5, 54.5, 54.1, 53.2, 34.8, 32.1,

31.1, 27.5, 22.1, 18.2, −1.5; additional resonances appeared for the

minor rotamer at δ: 155.2, 142.5, 137.6, 137.5, 136.4, 134.9, 130.0,

128.7, 127.4, 126.93, 125.6, 104.3, 64.7, 55.2, 54.4, 52.2, 32.6, 31.7,

27.3, 22.8, 18.3, −1.3; HRMS (ESI) [M + Na]⁺calcd for

C₃₁H₃₈F₃NNaO₇SSi: 676.1983, found 676.1986.

1

1148, 1089, 982, 921, 859, 834, and 773 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 8.64 (s, 1H), 6.45 (s, 1H), 5.87−5.93 (m, 1H), 5.11−5.14

(m, 2H), 4.31 (dd, J = 19.1, 10.1 Hz, 1H), 3.59−3.91(m, 6H), 3.09−

3.15 (m, 4H), 2.74−2.85 (m, 2H), 0.92 (s, 9H), 0.10 (d, J = 4.1 Hz,

6H); ¹³C NMR (100 MHz, CDCl₃) δ 156.6, 151.0, 145.7, 133.2,

130.9, 124.2, 118.5, 118.4, 115.5, 65.3, 54.4, 53.0, 29.7, 29.2, 27.4, 26.0,

18.5, −5.4; Anal. Calcd for C₂₁H₃₃NO₄Si: C, 64.41; H, 8.49; N, 3.58.

Found: C, 64.50; H, 8.36; N, 3.53.

1-Benzyl-5,6-dimethyl-4-hydroxyindole (47). A 25-mL recovery

ﬂask ﬁtted with a rubber septum and argon inlet needle was charged

with a solution of phenol 46 (0.325 g, 0.712 mmol, 1.0 equiv) in

3.5 mL of THF. The solution was cooled at 0 °C while TBAF solution

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The Journal of Organic Chemistry

Article

(1 M in THF, 3.5 mL, 3.5 mmol, 5 equiv) was added via syringe over 3

min. The resulting brown solution was stirred at rt for 18 h, and then

cooled at 0 °C while 6 M aqueous HCl solution (3.5 mL, 21.0 mmol,

30 equiv) was added dropwise over ca. 2 min. The resulting light

yellow solution was stirred at 0 °C for 5 min, and then heated at reﬂux

for 40 min. The resulting blue-brown mixture was allowed to cool to

rt, diluted with 80 mL of Et₂O, and washed with two 30 mL portions

of satd aq NaHCO₃solution. The combined aqueous layers were

extracted with three 15 mL portions of Et₂O, and the combined

organic phases were washed with 50 mL of brine, dried over Na₂SO₄,

ﬁltered, and concentrated to give 0.184 g of a brown oil. Column

chromatography on 20 g of silica gel (elution with 10% EtOAc−

hexanes) gave 0.146 g (82%) of indole 47 as a tan solid: IR (KBr

pellet) 3592, 3054, 2986, 2924, 1570, 1491, 1454, 1442, 1297, 1265,

N-Benzyl-5,6-dihydro-1H-cyclobuta[f ]indol-4-yl Triﬂuorometha-

nesulfonate (52). A 20-cm quartz reaction tube (13 mm i.d., 15

mm o.d.) ﬁtted with a rubber septum and an argon inlet needle was

charged with ynamide 45 (0.351 g, 0.966 mmol, 1.0 equiv) and ﬂushed

with argon. Dichloromethane (3 mL) was then added, and the reaction

tube was positioned ca. 15 cm from a Hanovia 450 W medium

pressure mercury lamp (quartz immersion well, cooled by tap water).

A solution of the diazo ketone 50^2b(0.287 g, 2.35 mmol, 2.4 equiv) in

7 mL of CH₂Cl₂was added to the vigorously stirred reaction mixture

via a syringe wrapped in aluminum foil over 3.5 h. Irradiation was

continued for 6.5 h, and then the reaction mixture was concentrated to

give 0.7 g of a dark-red-orange oil. A solution of this oil in 15 mL of

toluene was transferred to a ﬂask ﬁtted with a coldﬁnger condenser

with argon inlet side arm and heated at reﬂux for 2 h. Concentration

gave 0.68 g of a red−brown oil. Column chromatography on 15 g of

silica gel (elution with 15% EtOAc−hexanes) aﬀorded 0.262 g (59%)

of phenol 51 as a yellow oil: IR (ﬁlm) 3583, 3297, 2952, 2832, 1698,

1

1236, 909, 705 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.25−7.32 (m,

3H), 7.09−7.11 (m, 2H), 6.98 (d, J = 3.2 Hz, 1H), 6.75 (s, 1H), 6.47 (dd,

J = 3.2, 0.4 Hz, 1H), 5.27 (s, 2H), 4.85 (s, 1H), 2.35 (s, 3H), 2.25 (s,

3H); ¹³C NMR (100 MHz, CDCl₃) δ 146.2, 137.9, 136.2, 132.5, 128.9,

127.6, 126.8, 126.6, 116.6, 111.6, 103.5, 97.1, 50.1, 21.4, 11.3; HRMS

(ESI) [M + H]⁺calcd for C₁₇H₁₈NO: 252.1383, found 252.1371.

1-Benzyl-5,6,7,8-tetrahydro-1H-benz[f ]indol-4-yl Acetate (49).⁴⁶

A 25-mL, two-necked, round-bottomed ﬂask ﬁtted with a rubber

septum and argon inlet adapter was charged with a solution of

carbamate 48 (0.305 g, 0.63 mmol, 1.0 equiv) in 3.2 mL of THF. The

solution was cooled at 0 °C while TBAF solution (1 M in THF, 3.2

mL, 3.2 mmol, 5 equiv) was added via syringe over 3 min. The

resulting orange solution was stirred at rt for 8 h and then cooled at 0

°C while 6 M aq HCl solution (3.2 mL, 19.2 mmol, 30 equiv) was

added dropwise over 3 min. The resulting dark-orange solution was

stirred at rt for 41 h. The resulting dark-green mixture was diluted with

50 mL of Et₂O and washed with two 25 mL portions of satd aq

NaHCO₃solution. The combined aqueous layers were extracted with

two 20 mL portions of Et₂O, and the combined organic phases were

washed with 40 mL of brine, dried over Na₂SO₄, ﬁltered, and

concentrated to give 0.207 g of a dark-brown oil. This indole was

immediately protected as the acetate derivative due to its propensity to

oxidize. The unpuriﬁed indole was transferred to a 25-mL, one-necked,

round-bottomed ﬂask equipped with a rubber septum and argon inlet

needle, and 6.3 mL of CH₂Cl₂and Et₃N (0.138 g, 0.190 mL,

1.36 mmol, 2.2 equiv) were added. The resulting brown solution was

cooled at 0 °C while acetyl chloride (0.061 g, 0.055 mL, 0.77 mmol,

1.2 equiv) was added in one portion. The resulting solution was stirred

at room temperature for 2.5 h and then diluted with 10 mL of CH₂Cl₂

and washed with 10 mL of 1 M HCl solution. The aqueous layer was

extracted with 10 mL of CH₂Cl₂, and the combined organic phases were

washed with 10 mL of satd aq NaHCO₃solution, 10 mL of H₂O, and

10 mL of brine, and then were dried over MgSO₄, ﬁltered, and concen-

trated to provide 0.240 g of a brown foam. This material was dissolved in

ca. 10 mL of CH₂Cl₂and concentrated onto 2.4 g of silica gel. The free-

ﬂowing powder was added to the top of a column of 35 g of silica gel and

eluted with 15% EtOAc−hexanes to give 0.115 g (57% over two steps) of

acetate 49 as a pale-yellow solid: mp 112−115 °C; IR (KBr pellet) 3348,

3102, 3031, 2935, 2855, 1752, 1636, 1563, 1509, 1478, 1453, 1437, 1367,

1

1671, 1594, 1431, 1251, 1116, 1073, 859, 838 cm⁻¹; H NMR (400

MHz, CDCl₃): 8.08 (s, 1H), 6.37 (s, minor rotamer), 6.28 (s, 1H),

4.14−4.84 (m, 5H), 3.29−3.37 (m, 6H), 3.03−3.11 (m, 4H), 2.60 (d,

2H), 0.89−1.60 (m, 2H), 0.08 (s, minor rotamer), −0.06 (s, 9H); ¹³C

NMR (100 MHz, CDCl₃) δ 156.5, 150.6, 145.8, 140.9, 137.5, 130.7,

129.4, 128.9, 128.4, 127.6, 120.4, 116.1, 105.7, 64.2, 55.1, 54.8, 53.5,

34.7, 30.8, 29.0, 27.2, 18.0, −1.56.

A 25-mL recovery ﬂask ﬁtted with a rubber septum and an argon

inlet needle was charged with a solution of phenol 51 (0.170 g, 0.372

mmol, 1.0 equiv) in 2 mL of THF. The solution was cooled at 0 °C

while TBAF solution (1 M in THF, 2 mL, 2 mmol, 5 equiv) was added

via syringe over 1 min. The resulting brown solution was stirred at rt

for 24 h, and then cooled to 0 °C while 6 M HCl solution (2 mL, 12

mmol, 32 equiv)⁴⁷was added dropwise over ca. 2 min. The resulting

solution was stirred at 0 °C for 5 min, and then heated at reﬂux for 1 h.

The resulting blue-brown mixture was allowed to cool to rt, diluted

with 20 mL of Et₂O, and washed with 20 mL of satd aq NaHCO₃

solution. The combined aqueous layers were extracted with Et₂O, and

the combined organic phases were washed with brine, dried over

MgSO₄containing a small amount of decolorizing carbon, ﬁltered, and

concentrated to give 0.191 g of hydroxy indole S2 as a brown oil used

1

in the next step without puriﬁcation: H NMR (400 MHz, CDCl₃) δ

7.31−7.24 (m, 3H), 7.09−7.11 (m, 2H), 6.98 (d, J = 3.2 Hz, 1H), 6.64

(m, 1H), 6.61 (s, 1H), 5.26 (s, 2H), 3.54 (s, 1H) 3.11−3.15 (m, 4H).

The hydroxy indole prepared in the previous step was transferred

into a 25-mL recovery ﬂask equipped with a rubber septum and an

argon inlet needle, dissolved in 3 mL of THF, and cooled to 0 °C.

Sodium hydride (60 wt % oil disp., 0.025 g, 0.63 mmol, 1.7 equiv) was

added, and the reaction mixture was stirred for 2 min until no more

gas evolved. A solution of N-phenyltriﬂimide (0.210 g, 0.588 mmol,

1.6 equiv) in 2 mL of THF was added, and the resulting mixture was

stirred at rt for 1 h. Satd aq NaHCO₃(3 mL), was added, and the

resulting mixture was extracted with three 20 mL-portions of Et₂O.

The combined organic phases were washed with two 20-mL portions

of 10% NaOH solution and 20 mL of brine, dried over MgSO₄,

ﬁltered, and concentrated to give 0.225 g of a brown oil. Column

chromatography on 5 g of silica gel (elution with 10% EtOAc−

hexanes) gave 0.130 g of an oily white solid. Column chromatography

on 5 g of silica gel (elution with 5% EtOAc−hexanes) gave 0.093 g of

colorless oil. The oil was taken up in 4 mL of pentane, and the solution

was cooled to −20 °C. The resulting white crystals were washed with

cold pentane and dried under vacuum. A second crop was collected by

concentrating the mother liquor and the washes to a volume of ca.

0.5 mL and cooling to −20 °C. Crystallization provided 0.089 g (63%

from 45) of indole 52 as a white solid: mp 77−78 °C; IR (KBr pellet)

2926, 1497, 1421, 1250, 1200, 1187, 998, 916, 839, 727, 617, and 603

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.31−7.34 (m, 3H), 7.14 (d, J =

3.2 Hz, 1H), 7.07−7.13 (m, 2 H), 7.00 (s, 1H), 6.62 (d, J = 3.2 Hz,

1H), 5.31 (s, 2H), 3.18−3.36 (m, 4H); ¹³C NMR (100 MHz, CDCl₃)

δ 140.5, 138.6, 137.0, 135.4, 129.1, 128.3, 128.0, 126.9, 126.0, 120.6,

119.0 (q, J = 320 Hz, CF₃), 105.3, 98.4, 50.9, 28.5, 27.1; Anal. Calcd

for C₂₁H₃₃NO₄Si: C, 64.41; H, 8.49; N, 3.58. Found: C, 64.50; H,

8.36; N, 3.53.

1

and 1203 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 7.24−7.35 (m, 3H),

7.10−7.15 (m, 2H), 7.01 (d, J = 3.2 Hz, 1H), 6.93 (s, 1H), 6.32 (dd, J =

3.2, 0.7 Hz, 1H), 5.26 (s, 2H), 2.89 (t, J = 5.6 Hz, 2H), 2.70 (t, J = 6.0 Hz,

2H), 2.42 (s, 3H), 1.75−1.86 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ

169.2, 141.1, 137.6, 136.5, 132.6, 128.8, 128.2, 127.6, 126.9, 120.5, 120.0,

107.6, 97.8, 50.1, 30.5, 23.3, 23.3, 23.1, and 20.9; Anal. Calcd for

C₂₁H₂₁NO₂: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.75; H, 6.46; N, 4.34.

In a separate experiment, an impure sample of hydroxy indole S1

was isolated and observed to have the following spectroscopic

properties: IR (ﬁlm) 3425, 2926, 2855, 1633, 1568, 1510, 1495,

1453, 1360, 1296, 1240, and 1218 cm⁻¹; ¹H NMR (500 MHz, CDCl₃)

δ 7.23−7.34 (m, 3H), 7.12 (app d, J = 6.8 Hz, 2H), 6.98 (d, J = 3.2 Hz,

1H), 6.66 (s, 1H), 6.50 (d, J = 3.2 Hz, 1H), 5.26 (s, 2H), 4.91 (s, 1H),

2.87 (t, J = 6.2 Hz, 2H), 2.78 (t, J = 6.5 Hz, 2H), 1.86−1.91 (m, 2H),

and 1.77−1.82 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 146.0, 137.9,

136.7, 133.1, 128.8, 127.6, 126.9, 126.8, 116.4, 112.2, 102.2, 97.2, 50.1,

30.8, 23.5, and 22.7.

11466

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The Journal of Organic Chemistry

Article

N-Benzyl-1,2,3,10-tetrahydronaphtho[1,8-fg]indol-7-yl Triﬂuoro-

methanesulfonate (56). A 25-mL recovery ﬂask was charged with

carbamate 55 (0.189 g, 0.289 mmol, 1 equiv) and 5 mL of CH₂Cl₂.

Triﬂuoromethanesulfonic acid (0.225 mL, 2.88 mmol, 10 equiv) was

added via syringe in one portion producing a dark-red−brown

solution. The reaction mixture was stirred vigorously at rt for 5 min,

and then 2 mL of water was added. This biphasic reaction mixture

turned light yellow within 30 s. Satd aq NaHCO₃(5 mL) was then

added,⁴⁸and the reaction mixture was diluted with 20 mL CH₂Cl₂and

separated. The organic phase was washed with 10 mL of water and

brine, dried over MgSO₄, ﬁltered, and concentrated to give 0.117 g of a

tan solid. Column chromatography on 10 g of silica gel (elution with

20% benzene−hexanes) followed by a column chromatography on 6 g

of silica gel (elution with 20% benzene−hexanes) furnished 0.098 g

(76%) of indole 56 as a white powder: mp 112−113 °C (dec); IR

(ﬁlm) 3055, 2987, 1422, 1266, 737 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃) δ 7.97 (d, J = 8.7 Hz, 1H), 7.36−7.40 (m, 1H), 7.25−7.35 (m,

4H), 7.15 (dd, J = 10.0, 3.9 Hz, 1H), 6.96 (d, J = 7.3 Hz, 2H), 6.82 (d,

J = 3.4 Hz, 1H), 5.69 (s, 2H), 3.41 (t, J = 6.2 Hz, 2H), 3.06 (t, J = 6.2

Hz, 2H), 2.02−1.99 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 139.0,

136.6, 136.1, 135.0, 134.4, 129.2, 127.8, 127.2, 125.6, 124.5, 123.9,

122.6, 121.7, 119.1 (q, J = 310 Hz), 118.6, 118.3, 98.1, 53.2, 31.4, 26.9,

22.7; HRMS (ESI) [M + H]⁺calcd for C₂₃H₁₉F₃NO₃S: 446.1032,

found 446.1020.

glass funnel with the aid of three 3-mL portions of CH₂Cl₂.

Concentration of the ﬁltrate gave 0.316 g (97%) of aldehyde 62 as

a pale-yellow oil: IR (neat) 3259, 2955, 2931, 2885, 2859, 1706, 1619,

1574, 1451, 1387, 1331, 1260, 1136, 1093, 1053, 1038, 899, 839, 782

1

cm⁻¹; H NMR (600 MHz, CDCl₃) δ 9.71 (s, 1H), 8.65 (s, minor

rotamer), 8.59 (s, 1H), 6.61 (s, 1H), 4.43 (d, J = 18 Hz, 1H), 4.34 (d, J

= 18, minor rotamer), 4.03 (d, J = 18 Hz, 1H), 3.87 (m, 2H), 3.75 (s,

minor rotamer), 3.68 (s, 3H), 2.88 (m, 2H), 2.23 (s, 3H), 2.17 (s,

3H), 0.92 (s, 9H), 0.09 (d, J = 6 Hz, 6H); ¹³C NMR (100 MHz,

CDCl3) δ 197.3, 156.9, 154.9, 137.8, 137.2, 125.3, 122.2, 120.6, 65.2,

61.1, 53.5, 29.3, 25.9, 20.1, 18.4, 12.2, −5.5; additional resonance

appeared for the minor rotamer at δ 120.4; HRMS (ESI) [M + H]⁺

calcd for C₂₀H₃₄NO₅Si: 396.2201, found 396.2216.

4,5-Dimethyl-6-hydroxy-7-(2-hydroxyethyl)-1-methoxycarbony-

lindole (63). A 50-mL recovery ﬂask equipped with a coldﬁnger

condenser with an argon inlet side arm was charged with aldehyde 62

(0.316 g, 0.800 mmol, 1.0 equiv), 40 mL of isopropanol, and K₂CO₃

(0.11 g, 0.80 mmol, 1.0 equiv). The pale-yellow reaction mixture was

heated at 75 °C for 2.5 h. The oil bath was removed, and the warm

mixture was diluted with 15 mL of H₂O and then treated with 5 mL of

aq 1 M HCl to adjust the pH to 1. The resulting mixture was allowed

to stir at rt for 0.5 h and then was concentrated to a volume of ca. 10

mL. The resulting heterogeneous mixture was diluted with 200 mL of

Et₂O and washed with two 40-mL portions of H₂O and 40 mL of

brine. The aqueous layers were extracted with two 20-mL portions of

Et₂O, and the combined organic phases were dried over MgSO₄,

ﬁltered, and concentrated to aﬀord 0.209 g of a brown oil. Column

chromatography on 7 g of silica gel (elution with 50% EtOAc−

hexanes) aﬀorded 0.130 g (62%) of indole 63 as a white solid: mp

116−117 °C; IR (KBr pellet) 3472, 3311, 3153, 3113, 2994, 2952,

N-Benzyl-7-ethyl-1,2,3,10-tetrahydronaphtho[1,8-fg]indole (57).

A 25-mL pear-shaped ﬂask was charged with Pd(OAc)₂(2.5 mg,

0.011 mmol, 5 mol %), SPhos (6.6 mg, 0.016 mmol, 7.5 mol %), and

Cs₂CO₃(0.208 g, 0.638 mmol, 3 equiv). The ﬂask was equipped with a

rubber septum ﬁtted with an argon inlet needle and ﬂushed with

argon. A solution of triﬂate 56 (0.095 g, 0.213 mmol, 1 equiv) in

4.5 mL of THF and a solution of Et₃B (1 M in THF, 0.533 mL,

0.533 mmol, 2.5 equiv) were added. The orange-yellow reaction

mixture was stirred at rt for 1 h, diluted with 15 mL of Et₂O, and

ﬁltered through 5 g of silica gel with the aid of two 20-mL portions of

Et₂O. The resulting yellow solution was concentrated to give 0.061 g

of an oﬀ-white solid. This material was dissolved in 50 mL of hot

pentane and crystallized at −78 °C to give 0.055 g (79%) of indole 57

as an oﬀ-white powder: mp 114−115 °C; IR (ﬁlm) 3054, 2936, 1453,

1

2891, 1719, 1560, 1450, 1351, 1294, 1252, 1156, 1041, 930 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 7.42 (d, J = 4.0 Hz, 1H),

6.56 (d, J = 4.0 Hz, 1H), 4.36 (m, 2H), 3.93 (s, 3H), 3.13 (t, J = 4.8

Hz, 2H), 2.43 (br s, 1H), 2.41 (s, 3H), 2.30 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 153.0, 152.4, 133.7, 127.8, 125.6, 125.4, 121.5, 111.9,

107.4, 66.3, 54.0, 31.1, 15.8, 12.6; HRMS (ESI) [M + H]⁺calcd for

C₁₄H₁₈NO₄: 264.1230, found 264.1231.

Methyl 2-Oxoethyl[4-(2-[(tert-butyldimethylsilyl)oxy]ethyl)-3-hy-

droxybenzocyclobutene]-5-carbamate (65). A 100-mL recovery

ﬂask ﬁtted with a rubber septum and argon inlet needle was charged

with alkene 64 (1.22 g, 3.12 mmol, 1.0 equiv), 22.5 mL of THF, 7.5

mL of H₂O, OsO₄(4 wt % in H₂O, 0.5 mL, 0.08 mmol, 0.03 equiv),

and NMO (0.552 g, 4.71 mmol, 1.5 equiv). The resulting yellow

mixture was stirred at rt for 26 h. Aqueous NaHSO₃solution (2.0 M,

9.0 mL, 9.0 mmol, 9 equiv) was added, and the reaction mixture was

stirred at rt for 10 min. The resulting mixture was transferred to a

separatory funnel containing 60 mL of brine and extracted with three

40-mL portions of Et₂O. The combined organic phases were dried

over MgSO₄, ﬁltered, and concentrated to give 1.4 g of diol S4 as an

oﬀ-white foam used in the next step without puriﬁcation: IR (neat)

3345, 2939, 2858, 1680, 1595, 1455, 1391, 1254, 1084, 914, 836, and

777 cm⁻¹; ¹H NMR (400 MHz, CDCl₃), (ca. 50:50 mixture of

rotamers): δ 8.75 (s, 1H), 8.63 (s, minor rotamer), 6.55 (s, 1H), 6.38

(s, minor rotamer), 3.55−3.91 (m, 9H), 3.35−3.50 (m, 3H), 3.05−

3.15 (m, 4H), 2.61−2.85 (m, 2H), 0.90 (s, 9H), 0.09 (m, 6H).

A 100-mL recovery ﬂask was charged with NaIO₄supported on

silica gel (0.68 mmol/g, 10.6 g, 7.2 mmol, 2.3 equiv) and 20 mL of

CH₂Cl₂. A solution of the diol prepared above in 15 mL of CH₂Cl₂

was added to the stirring suspension via pipet (two 5 mL CH₂Cl₂

rinses). The reaction mixture was stirred at rt for 20 min and then

ﬁltered through 1 g of silica gel with the aid of CH₂Cl₂. Concentration

of the ﬁltrate gave 1.08 g (88%) of aldehyde 65 as a white powder: mp

134−135 °C; IR (KBr pellet) 3275, 3055, 2932, 1737, 1703, 1592,

1451, 1382, 1265, 1057, 914, 839, and 738 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 9.69 (s, 1H), 8.71 (s, minor rotamer), 8.65 (s, 1H), 6.58 (s,

1H), 3.75−4.51 (m, 4H), 3.68 (s, 3H), 3.35 (s, minor rotamer), 3.05−

3.14 (m, 4H), 2.87−2.90 (m, 2H), 0.92 (s, 9H), 0.10 (d, J = 2.8 Hz,

6H); ¹³C NMR (100 MHz, CDCl3) δ 197.1, 156.9, 151.2, 146.2,

140.5, 131.4, 124.0, 115.1, 65.2, 61.2, 53.5, 29.6, 29.1, 27.4, 26.0, 18.5,

1

1386, 1355, 1265, 739 cm⁻¹; H NMR (600 MHz, CDCl₃) δ 8.07 (d,

J = 9 Hz, 1H), 7.27−7.34 (m, 5H), 7.13 (d, J = 3.6 Hz, 1H), 7.01

(d, J = 7.2 Hz, 2H), 6.81 (d, J = 3.0 Hz, 1H), 5.70 (s, 2H), 3.45−3.48

(m, 4H), 3.11 (t, J = 6 Hz, 2H), 2.02−2.06 (m, 2H), 1.49 (t, J =

7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 140.0, 136.3, 134.5,

134.1, 129.9, 129.3, 129.0, 127.5, 127.4, 126.2, 125.8, 122.2, 114.8,

100.1, 53.2, 32.1, 27.2, 23.1, 22.9, 15.5; HRMS (ESI) [M + H]⁺calcd

for C₂₄H₂₄N: 326.1903, found 326.1900.

Methyl 2-(2-[(tert-Butyldimethylsilyl)oxy]ethyl)-3-hydroxy-4,5-

dimethylphenyl(2-oxoethyl)carbamate (62). A 50-mL recovery

ﬂask ﬁtted with a rubber septum and argon inlet needle was charged

with alkene 61 (0.325 g, 0.826 mmol, 1.0 equiv), 6 mL of THF, 2 mL

of H₂O, and OsO₄(4 wt % in H₂O, 0.11 mL, 0.11 g, 0.018 mmol, 0.02

equiv). The solution was stirred at rt for 10 min, and then NMO

(0.130 g, 1.11 mmol, 1.3 equiv) was added. The resulting cloudy tan

mixture was stirred at rt for 24 h. Aqueous NaHSO₃solution (1.0 M,

9.0 mL, 9.0 mmol, 11 equiv) was added, and the reaction mixture was

stirred at rt for 10 min, diluted with 15 mL of brine, and extracted with

three 20-mL portions of EtOAc. The combined organic phases were

dried over MgSO₄, ﬁltered, and concentrated to give 0.401 g of diol S3

as a pale-yellow oil used in the next step without puriﬁcation: IR

(neat) 3281, 2955, 2931, 2884, 2860, 1685, 1619, 1573, 1455, 1391,

1

1321, 1260, 1197, 1164, 1092, 1039, 900, 839, 781, 732 cm⁻¹; H

NMR (400 MHz, CDCl₃), (ca. 50:50 mixture of rotamers) δ 8.69 and

8.60 (s, 1H), 6.60 and 6.42 (s, 1H), 3.81−3.73 (m, 2H), 3.73−3.59

(m, 6H), 2.94−2.70 (m, 3H), 2.22 (d, J = 8.9 Hz, 3H), 2.17 (s, 3H),

0.92 (s, 9H), 0.10−0.08 (m, 6H).

A 25-mL recovery ﬂask was charged with NaIO₄supported on silica

gel (0.68 mmol/g, 2.5 g, 1.7 mmol, 2.0 equiv) and 5 mL of CH₂Cl₂. A

solution of the diol prepared above in 5 mL of CH₂Cl₂was added to

the stirring suspension via pipet (0.5 mL CH₂Cl₂rinse). The reaction

mixture was stirred at rt for 0.5 h and then ﬁltered through a sintered

11467

dx.doi.org/10.1021/jo402010b | J. Org. Chem. 2013, 78, 11450−11469

The Journal of Organic Chemistry

Article

−5.45; Anal. Calcd for C₂₀H₃₁NO₅Si: C, 61.04; H, 7.94; N, 3.56.

Found: C, 60.77; H, 7.96; N, 3.52.

(m, 4H), 4.02 (s, 3H), 3.72−3.82 (m, 2H), 3.67−3.71(m, 2H), 3.22−

3.24 (m, 2H), 1.43−1.45 (m, 3H), 1.0 (s, 9H), 0.21 (s, 6H); ¹³C NMR

(100 MHz, CDCl3) δ153.0, 152.6, 152.2, 137.2, 134.9, 134.1, 129.0,

127.0, 125.8, 124.7, 123.8, 123.3, 123.1, 119.1, 117.6, 112.5, 112.4,

106.5, 106.3, 67.3, 60.7, 60.6, 54.1, 31.7, 31.7, 28.4, 26.7, 26.3, 26.1,

26.0, 24.4, 18.5, 18.4, 14.6, −5.3, −5.4; HRMS (ESI) [M + H]⁺calcd

for C₂₅H₃₆NO₆Si: 474.2306, found 474.2312.

N-Carbomethoxy-4-(2-[(tert-butyldimethylsilyl)oxy]ethyl)-5-hy-

droxy-6,7-dihydro-3H-cyclobuta[e]indole (66). A 300-mL round-

bottom ﬂask was charged with aldehyde 65 (0.735 g, 1.87 mmol, 1.0

equiv), 100 mL of isopropanol, and K₂CO₃(0.260 g, 1.89 mmol, 1.0

equiv). The reaction ﬂask was equipped with a reﬂux condenser ﬁtted

with an argon inlet adapter, and the mixture was heated at 80 °C for 10

h. The resulting black mixture was allowed to cool to rt and was

neutralized with 3.3 mL of aq 0.6 M HCl and concentrated to a

volume of ca. 20 mL. This mixture was extracted with three 50 mL-

portions of Et₂O, and the combined organic phases were washed with

brine, dried over MgSO₄, and concentrated to aﬀord 0.82 g of a brown

oil. This oil was taken up in 200 mL of hexanes and ﬁltered, and the

ﬁltrate was concentrated to give 0.577 g of a light brown oil. Column

chromatography on 25 g of silica gel (elution with 5% EtOAc−

hexanes) aﬀorded 0.337 g (48%) of indole 66 as a white powder: mp

90−91 °C; IR (KBr pellet) 3248, 2928, 2857, 1751, 1608, 1548, 1465,

1440, 1371, 1336, 1273, 1256, 1174, 1145, 1041, 901, 786, and 719

ASSOCIATED CONTENT

■

S

* Supporting Information

¹H and ¹³C NMR spectra for all new compounds. This material

is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: danheisr@mit.edu

■

Notes

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 7.45 (d, J = 4.0

The authors declare no competing ﬁnancial interest.

Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H), 4.30 (m, 2H), 3.94 (s, 3H), 3.24−

3.30 (m, 4H), 3.08 (t, J = 4.4 Hz, 2H), 0.98 (s, 9H), 0.18 (s, 6H); ¹³C

NMR (100 MHz, CDCl₃) δ 152.4, 149.2, 136.9, 136.7, 128.0, 127.1,

121.4, 114.2, 105.6, 67.2, 54.0, 32.3, 28.6, 28.0, 26.1, 18.5, −5.31;

HRMS (ESI) [M + H]⁺calcd for C₁₄H₁₈NO₄: 264.1230, found

264.1231; Anal. Calcd for C₂₀H₂₉NO₄Si: C, 63.97; H, 7.78; N, 3.73.

Found: C, 64.20; H, 7.50; N, 3.46.

ACKNOWLEDGMENTS

■

We thank the National Science Foundation (CHE-1111567),

the National Institutes of Health (GM 28273), Merck Research

Laboratories, and Boehringer Ingelheim Pharmaceuticals for

generous ﬁnancial support. T.P.W. was supported in part by an

AstraZeneca Graduate Fellowship and David A. Johnson,

Methyl 4-(2-[(tert-Butyldimethylsilyl)oxy]ethyl)-5-hydroxy-7,9-

dioxo-8-phenyl-6a,7,8,9,9a,10-hexahydroisoindolo[5,6-e]indole-

3(6H)-carboxylate (67). A 10-cm threaded Pyrex tube (14 mm i.d., 25

mm o.d.) equipped with a rubber septum and argon inlet needle was

charged with N-phenylmaleimide (0.183 g, 1.06 mmol, 3.6 equiv) and

ﬂushed with argon. A solution of indole 66 (0.110 g, 0.293 mmol, 1

equiv) in 12 mL of p-xylene was added, the septum was replaced with

a threaded Teﬂon cap, and the reaction mixture was heated at 180 °C

(bath temperature) for 40 h. The reaction mixture was allowed to cool

to rt and concentrated to give 0.376 g of a dark-orange oil. Column

chromatography on 15 g of silica gel (elution with 20% EtOAc−hexanes)

gave 0.070 g (44%) of indole 67 as a white powder: mp 172−174 °C; IR

(KBr pellet) 3449, 2926, 1625, 1569, 1497, 1455, 1438, 1380, 1320, 1287,

Merck, and George Buchi Summer Fellowships. T.Y.L. was

̈

supported in part by a fellowship from the C. P. Chu and Y. Lai

Fund. Y.-P.W. was supported in part by an Eli Lilly Graduate

Fellowship.

REFERENCES

■

(1) Reviews: (a) Kotha, S.; Misra, S.; Halder, S. Tetrahedron 2008,

64, 10775−10790. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100,

2901−2915.

(2) (a) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1672−

1674. (b) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R.

F. J. Am. Chem. Soc. 1990, 112, 3093−3100.

1

1250, 1220, 1140, 998, 916, 840, and 727 cm⁻¹; H NMR (400 MHz,

(3) For reviews of the chemistry of vinylketenes, see (a) Danheiser,

R. L.; Dudley, G. B.; Austin, W. F. “Alkenylketenes”, In Science of

Synthesis; Danheiser, R. L., Ed.; Thieme: Stuttgart, 2006; Vol. 23; pp

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(4) A related, complementary strategy has been reported by

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3067−3068.

(5) For examples, see Dudley, G. B.; Takaki, K. S.; Cha, D. D.;

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5937.

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CDCl₃) δ 9.24 (s, 1H), 7.19−7.50 (m, 4H), 6.97 (d, J = 7.2 Hz, 2H), 6.59

(d, J = 3.6 Hz, 1H), 4.227−4.28 (m, 2H), 3.94 (s, 3H), 2.85−3.80 (m,

8H), 0.92 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); ¹³C NMR (100 MHz,

CDCl₃) δ 179.0, 178.8, 152.22, 152.17, 134.6, 132.1, 129.4, 129.1, 128.5,

126.7, 126.5, 123.8, 119.8, 113.6, 106.2, 67.2, 54.1, 40.29, 40.26, 31.8, 26.2,

26.0, 22.7, 18.4, −5.42, −5.46; HRMS (ESI) [M + H]⁺calcd for

C₃₀H₃₇N₂O₆Si: 549.2415, found 549.2419.

7-Ethyl 3-Methyl 4-(2-[(tert-Butyldimethylsilyl)oxy]ethyl)-5-hy-

droxy-3H-benzo[e]indole-3,7(6H,9H)-dicarboxylate (69) and 8-

Ethyl 3-Methyl 4-(2-[(tert-Butyldimethylsilyl)oxy]ethyl)-5-hydroxy-

3H-benzo[e]indole-3,8(6H,9H)-dicarboxylate (70). A 10-cm threaded

Pyrex tube (14 mm i.d., 25 mm o.d.) equipped with a rubber septum

and argon inlet needle was charged with a solution of indole 66 (0.109 g,

0.290 mmol, 1 equiv) in 10 mL of p-xylene followed by ethyl

propiolate (0.108 mL, 1.07 mmol, 3.7 equiv). The septum was

replaced with a threaded Teﬂon cap, and the reaction mixture was

heated at 180 °C (bath temperature) for 40 h. The reaction mixture

was allowed to cool to rt and concentrated to give 0.159 g of an orange

solid. Column chromatography on 15 g of silica gel (elution with 10%

EtOAc−hexanes) gave 0.085 g (62%) of an inseparable ca. 60:40

mixture of isomers 69 and 70 as a white powder: IR (KBr pellet) 3250,

2956, 2931, 2884, 2858, 1750, 1714, 1667, 1440, 1337, 1292, 1257,

1230, 1144, 1038, 918, 838, 781, and 719 cm⁻¹; ¹H NMR (600 MHz,

CDCl₃), (ca. 60:40 mixture of regioisomers) for major isomer: δ 9.24

(s, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.34−7.35 (m, 1H), 6.67 (d, J = 2.4

Hz, 1H), 4.35−4.39 (m, 4H), 4.02 (s, 3H), 3.72−3.82 (m, 2H), 3.67−

3.71(m, 2H), 3.22−3.24 (m, 2H), 1.43−1.45 (m, 3H), 1.03 (s, 9H),

0.21 (s, 6H); for the minor isomer: δ 9,23 (s, 1H), 7.52 (d, J = 2.4 Hz,

1H), 7.24−7.35 (m, 1H), 6.56 (d, J = 2.4 Hz, 1H), 4.35−4.39

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11468

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The Journal of Organic Chemistry

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11469

dx.doi.org/10.1021/jo402010b | J. Org. Chem. 2013, 78, 11450−11469

Article Doi

Batch and flow photochemical benzannulations based on the reaction of ynamides and diazo ketones. application to the synthesis of polycyclic aromatic and heteroaromatic compounds

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