Catalyst-Controlled Chemodivergent Reactions of 2-Pyrrolyl-α-diazo-β-ketoesters and Enol Ethers: Synthesis of 1,2-Dihydrofuran Acetals and Highly Substituted Indoles

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Catalyst-Controlled Chemodivergent Reactions of 2‑Pyrrolyl-α-

diazo-β-ketoesters and Enol Ethers: Synthesis of 1,2-Dihydrofuran

Acetals and Highly Substituted Indoles

Gabriel Guerra Faura, Tena Nguyen, and Stefan France*

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ABSTRACT: A catalyst-controlled, chemodivergent reaction of

pyrrolyl-α-diazo-β-ketoesters with enol ethers is reported. While

Cu(II) catalysts selectively promoted a [3 + 2] cycloaddition to

provide pyrrolyl-substituted 2,3-dihydrofuran (DHF) acetals,

dimeric Rh(II) catalysts aﬀorded 6-hydroxyindole-7-carboxylates

via an unreported [4 + 2] benzannulation. The choice of enol ether

proved to be crucial in determining both regioselectivity and yield

of the respective products (up to 91% yield for Cu(II) and 82% for

Rh(II) catalysis). Furthermore, the DHF acetals were shown to serve as precursors to 7-hydroxyindole-6-carboxylates (isomeric to

the indoles formed from Rh) and highly substituted furans in the presence of Lewis acids. Thus, from a common pyrrolyl-α-diazo-β-

ketoester, up to three unique heterocyclic scaﬀolds can be achieved based on catalyst selection.

Scheme 1. Previously Reported Reactions of α-Diazo β-

Ketoesters and Enol Ethers

INTRODUCTION

■

Catalytic transformations that selectively generate regio-,

diastereo-, or chemodivergent products from a common set

of starting materials represent a ﬂourishing ﬁeld in synthetic

chemistry that has been termed divergent catalysis.¹The ability

to control reactivity and access structurally diﬀerent com-

pounds or isomers based on the choice of catalyst, reagents,

substitution pattern, or reaction conditions is a long-standing

goal of the synthetic community when developing new

strategies, as it allows for diversity-oriented synthesis.²

Divergent catalysis is particularly relevant in the ﬁeld of

functionalized materials³and drug discovery,⁴as it facilitates

the search for molecules with diﬀerent physical, chemical, or

biological properties. Despite this synthetic potential, examples

of rationally designed divergent catalysis are still rare in the

literature.

A prime example that oﬀers great potential for divergent

catalysis is the transition metal-catalyzed reactions of α-diazo-

beta-ketoesters with enol ethers (Scheme 1).⁵These reactions

have garnered attention from the synthetic community due to

their ability to access diverse compounds (e.g., cyclopropanes,

2,3-dihydrofurans, dihydropyranones, etc.) depending on the

choice of substrates, catalyst(s), or conditions. For instance,

Reyes and Mead⁸reported the selective formation of

cyclopropanes when using vinyl acetate in the presence of

Rh(II) salts (Scheme 1), while Tan and Yoshikai⁹demon-

strated selective formation of 2,3-dihydrofuran (DHF) acetals

when utilizing Cu(II) salts and silyl enol ethers. Our group has

previously shown that alkyl vinyl ethers and α-diazo-β-

ketoesters can generate either 2,3-dihydrofuran (DHF) acetals

or β′,γ-unsaturated β-ketoesters in the presence of dimeric

Rh(II) salts.^6,7Each of these product classes serve as useful

building blocks that can be employed in subsequent trans-

formations.

While DHF acetals have been shown to be versatile

precursors toward the synthesis of 1,4-dicarbonyl compounds,

furans, and polymers, our group has been particularly

interested in utilizing DHF acetals as precursors to the

Received: April 9, 2021

Published: July 14, 2021

https://doi.org/10.1021/acs.joc.1c00826

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Intrigued by the unexpected formation of indole 3aa, we set

out to identify the conditions that would provide selective

formation of either the indole or the DHF acetal. To this end,

the framework for our study centered upon addressing several

questions crucial to harnessing this chemodivergence. First,

why does the pyrrolyl substitution on the diazo change the

reaction outcomes obtained in our previous report? Second,

how can the indole-forming reaction be optimized? Third, is

there a way to selectively form the DHF acetal by changing the

catalyst? Fourth, what are the eﬀects of employing diﬀerentially

substituted enol ethers? Herein, we describe our successful

eﬀorts toward rationally designed divergent catalysis for the

transition metal catalyst-controlled reactions of pyrrolyl-α-

diazo-β-ketoesters with enol ethers.

Scheme 2. Unexpected Formation of Indole 3aa

RESULTS AND DISCUSSION

■

Proposed Reaction Mechanism. We began our study by

investigating the unique reactivity of the C(2)-substituted

pyrrolyl-α-diazo-β-ketoester 1a and, consequently, the mech-

anism behind the formation of indole 3aa. To do that, we

turned initially to a report published by our group describing a

predictive computational model for C(sp³)−H insertions of β-

carbonyl ester α-dirhodium carbenes.¹¹According to that

report, dirhodium carbenes derived from aryl α-diazo-β-

ketoesters favor Wolﬀ rearrangement when a ketone bearing

an electron-rich aryl group is present. Thus, the electron-rich

pyrrole in 1a is believed to enable the respective dirhodium

carbene to undergo Wolﬀ rearrangement, which is further

conﬁrmed by the substitution pattern of indole 3aa, in which

the expected position of the ester group and the hydroxyl

group are exchanged. Curiously, Wolﬀ rearrangement was not

observed when utilizing pyrrolyl- or indolyl-α-diazo-β-

ketoesters substituted at the N(1) position (vs C(2) as in

1a), as shown in our previous reports. Such diazo compounds

generated either the DHF product or the β,γ-unsaturated β-

ketoester product under Rh(II)-catalyzed reaction with an enol

ether. The reactivity diﬀerence between the N(1)- and C(2)-

substituted pyrrolyl-α-diazo-β-ketoesters, however, does not

come as a surprise, since the Wolﬀ rearrangement of the

regioselective synthesis of various aromatic products through

Lewis acid-catalyzed ring-opening benzannulation (Scheme

2A).⁶When expanding our methodology to the synthesis of

indoles, a privileged and sought after pharmacophore in

medicinal chemistry, the Rh(II) catalyzed reaction of pyrrolyl-

α-diazo-β-ketoester 1a in the presence of enol ether 2a proved

an interesting case (Scheme 2B). Instead of the expected DHF

acetal 4aa, we observed direct formation of indole 3aa, without

any detectable 4aa, β,γ-unsaturated β-ketoester, or cyclo-

propane product.¹⁰Curiously, the obtained indole 3aa had a

diﬀerent substitution pattern of what would be expected from

the Lewis acid-catalyzed benzannulation reaction of 4aa (i.e.,

5aa). The two indoles are isomeric at the C(6)- and C(7)-

positions, with the hydroxyl and the carboxyl groups

exchanged. Thus, being able to access the 4aa would grant

us the opportunity to synthesize diﬀerent indole regioisomers,

an important feature in the context of further synthesis, as both

the hydroxy and the ester substituents could be utilized as

functional handles.

Scheme 3. Postulated Mechanisms for Formation of Indole 3aa and DHF 4aa

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former would require the less favored migration of the nitrogen

group over the carbon group.

Scheme 4. Probing Ester Group Eﬀects

Hence, given our experimental observation, our computa-

tional model, and other literature precedence, we have

formulated a plausible and complete mechanistic picture for

both DHF acetal and indole formation (Scheme 3). DHF

acetal formation has been previously established⁵⁻⁹and

necessitates enol ether attack on metal carbene 6a followed

by intramolecular enolate attack on the resulting oxonium 7aa.

Alternatively, a pathway involving the generation of a transient

alkoxycyclopropane 7aa′ intermediate followed by its ring

opening to 7aa and subsequent enolate attack is also plausible.

As previously discussed, the indole formation represents a

more complex cascade reaction that presumably involves an

initial Wolﬀ rearrangement¹²of the dirhodium carbene 6a to

form pyrrolyl ketene 8a. Subsequent nucleophilic attack by the

enol ether 2a forms oxonium intermediate 10aa (presumably

in equilibrium with 4-dihydropyranone 9aa), which provides

indole 3aa following intramolecular Friedel−Crafts alkylation

and concurrent MeOH elimination. The formed MeOH can

then react with ketene 8a to form diester byproduct 11a.

Ketene 8a can be classiﬁed both as a vinylketene^13,14and as

an α-oxoketene,¹⁵conferring it with unique reactivity. While

vinylketenes have been extensively explored by Danheiser in [4

+ 2] benzannulation reactions with activated alkynes, such as

alkynol ethers or ynamides,¹⁶, to the best of our knowledge, no

examples utilizing enol ethers as the two-carbon synthons have

been reported. In Danheiser’s methodology, the reactive

vinylketene undergoes a series of cycloadditions and electro-

cyclic cleavages/cyclizations. In contrast, our proposed

mechanism for indole formation, which supports the observed

regiochemistry, relies on a Friedel−Crafts attack of the pyrrole

ring on the oxonium intermediate (10aa). From literature, α-

oxoketenes in the presence of enol ethers undergo [4 + 2]

cycloadditions to form 4-dihydropyranones.^5a,bHence, we

expect oxonium intermediate 10aa to be in equilibrium with

dihydropyranone 9aa. Presumably, this process is facilitated by

the presence of the ester group that can stabilize the enolate by

conjugation. This stabilization enables the pyrrole to act as a

nucleophile, resulting in an irreversible cascade reaction to

form the indole.

In reviewing these two mechanisms, the lability of the metal-

carbene and its propensity to rearrange seem to be the key

factors in controlling the reactivity of the metal carbene 6a. In

order to optimize the indole formation and identify conditions

to generate the DHF acetal, we sought to understand the

eﬀects of (1) making the carbene more electrophilic (to

modulate its propensity to rearrange) and (2) changing the

metal catalyst to tune metal-carbene lability (to impede its

propensity to rearrange). For the indole, we looked to access

an electrophilic carbene with a labile metal-carbene bond that

would rearrange faster than undergoing nucleophilic attack by

the enol ether. In contrast, for the DHF, an electrophilic

carbene coupled with a less labile metal-carbene bond would

prevent rearrangement and facilitate nucleophilic attack.

Increasing Carbene Electrophilicity. To study the eﬀect on

increasing carbene electrophilicity, we synthesized diazoesters

1a−1d containing methyl, ethyl, 2,2,2-trichloroethyl (TCE),¹⁷

and 2,2,2-triﬂuoroethyl (TFE)¹⁸groups, respectively (Scheme

4).

and TFE esters, increased yields of 51% and 53% were

obtained, respectively. This came as no surprise since a more

electrophilic carbene would favor Wolﬀ rearrangement and

facilitate enol ether attack to the resulting ketene. Although

both TCE and TFE gave comparable yields, the TFE diazo

ester 1d was selected as the model substrate for further

optimizations toward indole formation, due to a relatively

cheaper and more convenient synthetic route.¹⁹

Optimizing Indole Formation. With TFE diazo 1d as the

model substrate along with alkyl enol ether 2a,²⁰we initiated a

catalyst screen to optimize the indole formation. Using a diazo

to enol ether ratio of 1:10, we employed several dirhodium

catalysts (at 0.5 mol %) and compared them against Rh₂(esp)₂

(Table 1, entry 1). Rh₂(OAc)₄, Rh₂(Oct)₄, and Rh₂(TFA)₄

a

Table 1. Optimizing Indole Formation

1d:2a

ratio

yield of 3da

yield of 11b

b

entry

cat (mol %)

(%)

1

2

3

4

5

6

7

8

Rh₂(esp)₂

Rh₂(OAc)₄

Rh₂(Oct)₄

Rh₂(TFA)₄

Rh₂(S-PTTL)₄

Rh₂(S-PTAD)₄

Rh₂(S-DOSP)₄

Rh₂(esp)₂

1:10

1:3

53

42

41

31

26

49

53

57

38

34

43

36

31

28

a

Reaction of 1d and 2a in CH₂Cl₂at 40 °C with indicated

stoichiometry and catalyst loading. NMR yields with dimethyl

terephthalate as internal standard.

b

provided 3da with reduced yields of 42%, 41%, and 31%,

respectively (entries 2−4). Next, we employed chiral

dirhodium catalysts in hopes that increased ligand sterics

would enhance reactivity. While Rh₂(S-PTTL)₄only gave 26%

yield (entry 5) of 3da, Rh₂(S-PTAD)₄and Rh₂(S-DOSP)₄

aﬀorded the desired product 3aa in higher yields (49% and

53%, respectively). With this information in hand, we opted to

continue the use of Rh₂(esp)₂for further optimization

screenings and began probing further conditions. Upon

lowering the amount of enol ether 2a to 3 equiv (entry 8),

the yield of 3da increased to 57%. Diﬀerent solvents,

When subjected to the initial reaction conditions, the ethyl

ester behaved similarly to the methyl ester (35% vs 38% yield).

In contrast, when employing the electron-withdrawing TCE

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a

concentrations, and temperatures were also tested, but none

positively impacted the yields of the desired indole product.²¹

In each case, the reactions were limited by concomitant

formation of diester 11b, isolated in 28% yield under the

optimized reaction conditions (and up to 43% yield with the

other catalysts). While the presence of 11b could be partially

attributed to methanol in the reaction mixture resulting from

the elimination/aromatization process, a more complex

mechanism is likely occurring as 11b was found to be the

major product in some cases. For instance, when performing

the reaction at room temperature, 11b was obtained as the

main product in 49% yield, while 3da was generated in only

26% yield. Similar side products have been observed in studies

by Lee²²and attributed to the acidity of the employed Au(I)

catalyst, which could presumably catalyze enol ether

degradation and generate MeOH. However, no MeOH

formation was observed in a control experiment where enol

ether 2a was reﬂuxed in the presence of Rh₂(esp)₂(see

Supporting Information). Similarly, when the reaction was

performed without Rh₂(esp)₂in the presence of UV light (to

form the ketene via Wolﬀ rearrangement), 11b was formed in

28% yield along with trace amounts (<3% yield) of 3da. Thus,

it is clear that other ambiguous MeOH formation pathways

exist to 11b that serve as factors impeding full conversion to

the desired indole 3da. Despite this limitation, good isolated

yields of indole 3da were accessible, allowing us to continue

forward with the study.

Interestingly, a reaction intermediate, believed to be 9aa,

was consistently observed by TLC analysis but attempts to

isolate and characterize the intermediate (via crude ¹H NMR)

were unsuccessful. Instead, the corresponding indole product

would be isolated, which we believe was a conversion of 9aa

upon exposure to silica gel during puriﬁcation. On the basis of

this observation, we found that treatment of the reaction

mixture with silica gel, after all the diazo starting material has

been consumed, would convert the intermediate to the desired

product. Hence, this step became part of the quenching

procedure for the indole formation. As a comparison, a control

reaction without the addition of silica gel aﬀorded 3da in only

35% yield (vs 58% when the silica gel was added).

Table 2. Catalyst Screen for DHF Formation

b

entry cat (mol %) 1d:2a ratio yield of 3da (%) yield of 4da (%)

c

1

2

3

4

5

6

7

8

9

Fe(acac)₂

Ag₂O

Grubbs I

Ir(cod)CI₂

Cu(tfacac)₂

Cu(acac)₂

Cu(hfacac)₂

1:10

1:5

trace

−

7

−

trace

36

49

trace

80

74

c

1:3

a

Reaction of 1d and 2a in CH₂Cl₂at 40 °C with indicated

stoichiometry and catalyst loading. NMR yields with dimethyl

terephthalate as internal standard. Reaction did not reach

b

c

completion.

9). Other Cu(I) or Cu(II) salts used did not oﬀer better

results.²¹Therefore, a 5:1 stoichiometric ratio,²³alongside

Cu(hfacac)₂as the catalyst, was used as the optimal reaction

conditions for formation of the DHF acetals.

With an eﬀective catalyst in hand for selective DHF

formation, we sought to revisit the eﬀect of the ester group

on reactivity. Since we initially employed the TFE ester to

make the metal carbene more electrophilic and help promote

Wolﬀ rearrangement, we were interested in comparing the

performance of the methyl ester 1a under the optimized

reaction conditions with Cu(hfacac)₂. Interestingly, the

reaction gave 50% yield of DHF 4da along with 9% of indole

3da (see Supporting Information). Thus, the TFE ester not

only facilitates the indole generation with Rh₂(esp)₂but also

helps to selectively form the DHF acetal with Cu(hfacac)₂.

Understanding the Metal-Dependent Selectivities. The

observed indole vs DHF selectivities can be rationalized based

on the propensity of the metal-carbene complex to undergo

Wolﬀ rearrangement. In highly electrophilic metal-carbenes,

the metal−C_carbenebond length tends to be elongated, which

makes the complex more labile and prone to undergoing

rearrangement. In a seminal computational study on metal-

carbene C(sp³)-H bond insertion,^24,25Nakamura et al.

compared the metal-carbene complexes formed from diazo-

methane with both dirhodium tetracarboxylate and Cu(acac)₂

catalysts (Figure 1).²⁴The Cu(I)-carbene was calculated to

Changing the Metal Catalyst. In all cases with the

dirhodium catalysts, no DHF product was observed in the

reaction of diazo 1d with enol ether 2a. In hopes of selectively

forming the DHF, we next explored other commonly used

catalysts based on other transition metals (each at 10 mol %

loading) for diazo decomposition and metal carbene

formation.

We initially looked at Fe(acac)₂and Ag₂O, which both gave

trace amounts of indole 3aa and no desired DHF 4aa (Table 2,

entries 1 and 2). In contrast, Ru-based Grubbs I catalyst (entry

3) aﬀorded DHF 4aa in trace amounts, without any detectable

formation of indole. When [Ir(cod)Cl]₂was employed, we

were pleased to see the DHF acetal 4aa was formed in 36%

yield, along with 7% of indole 3aa (entry 4). Gratifyingly, when

Cu(tfacac)₂was used, DHF acetal 4aa was obtained exclusively

in a 49% yield (entry 5). Copper ligand electronics proved an

important factor; while Cu(acac)₂generated DHF product in

trace amounts (entry 6), the more electron-withdrawing ligand

in Cu(hfacac)₂aﬀorded 4aa in 80% yield (entry 7).

Furthermore, no drop in DHF yield was observed when the

ratio of enol ether to diazo was reduced from 10:1 to 5:1

(entry 8). However, dropping the ratio to 3:1 (as in the

optimized Rh reaction) provided a reduced yield of 74% (entry

Figure 1. Comparisons of Nakamura’s calculated metal-carbene bond

lengths.

have both a smaller bond length when compared to the

dirhodium complex (1.789 vs 2.482 Å), as well as a higher

activation energy (15.6 vs 5.7 kcal/mol) toward C−H

activation, suggesting Cu(I)-carbenes are, indeed, less electro-

philic and less prone to rearranging.

While the metal catalyst plays an important role in

determining the reactivity of the metal carbene, components

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of the diazo precursor also inﬂuence the observed reactivity.

The TFE ester group, in diazo 1d, was also shown to increase

metal-carbene electrophilicity and enhance reactivity.⁷While

this increased electrophilicity was expected to enhance Wolﬀ

rearrangement for the more labile Rh-carbenes derived from

pyrrolyl diazo 1d, it had the added beneﬁt of facilitating enol

ether nucleophilic attack on the more stable (and less labile)

Cu-carbenes. Thus, a correct balance of electrophilicity and

metal-carbene lability proved necessary to favor both the

nucleophilic attack to the metal-carbene 6a under Cu(II)

catalysis and to favor the Wolﬀ rearrangement under Rh(II)

catalysis.

Table 3. Reactions with Acyclic Enol Ethers

Reaction Scope. With optimized conditions for both the

indole and the DHF acetal formation, we were interested in

evaluating how diﬀerent substituents on the enol ether would

impact the formation of the respective products. Pyrrolyl

diazoester 1d was subsequently reacted with various acyclic

and cyclic enol ethers with either Rh₂(esp)₂(0.5 mol %) or

Cu(hfacac)₂(10 mol %).

Acyclic Enol Ethers. To begin the exploration of substrate

scope, we ﬁrst looked at the reaction of pyrrolyl diazo 1d with

acyclic enol ethers (Table 3). Given the amenability of 2-

methoxypropene 2a (a 1-alkyl disubstituted enol ether) in the

reaction (57% yield of indole 3da and 80% yield of DHF 4da,

entry 1), we sought to examine 1-aryl disubstituted enol ethers

in hopes of investigating the aryl substituent eﬀects on

reactivity. A trend rapidly became apparent, in which electron-

rich enol ethers worked best in providing the corresponding

desired products. For instance, the electron-rich 1-(4-

methoxyphenyl) enol ether 2b aﬀorded indole 3db in 82%

yield and DHF acetal 4db in 91% yield (entry 2). Switching

from the methoxy to the less donating methyl group (entry 3)

provided slightly reduced yields for both the indole 3dc (78%)

and the DHF 4dc (63%). A simple phenyl substituent (as in

2d) gave yield of 65% and 64% for indole 3dd and DHF 4dd,

respectively (entry 4). Lastly, when the inductively with-

drawing chloro-containing enol ether 2e was employed, indole

3de was formed in a modest 49% yield while DHF acetal 4de

was formed in a comparatively low yield (29%, entry 5). The

observed trend is consistent with the expected enol ether

nucleophilicities²⁶and supported by established Hammett

correlations.²⁷

a

Reaction of 1d (1 equiv), 2 (3 equiv), and Rh₂(esp)₂(0.5 mol %) in

b

CH₂Cl₂at 40 °C. Reaction of 1d (1 equiv), 2 (3 equiv), and

c

Cu(hfacac)₂(10 mol %) in CH₂Cl₂at 40 °C. Percentages represent

d

isolated yields following column chromatography. A 1:1.5 ratio of 1d

e

to 2b−e was used for the Rh(II) catalysis. A 10:1 ratio of 2h to 1d

was employed.

Similar reasoning can also help explain why the less

nucleophilic 1,2-disubstituted enol ethers performed poorly

as compared to their 1,1-disubstituted counterparts. Although

a 2-alkyl disubstituted enol ether (1-ethoxypropene 2f) did

aﬀord both indole and DHF products, the yields of each were

modest at best (35% for indole 3df; 30% for DHF 4df, entry

6). In contrast, no desired products were isolated for either Rh

or Cu catalysis with β-methoxystyrene 2g (a 2-phenyl

substituted enol ether, entry 7). This lack of reactivity can

be attributed to the very low nucleophilicity of the conjugated

2-aryl disubstituted enol ether.²⁶

Finally, a simple unsubstituted enol ether was employed in

the reactions. Ethyl vinyl ether 2h provided a 67% yield of

indole 3dh²⁸using Rh₂(esp)₂while giving a 53% yield of DHF

4dh with Cu(hfacac)₂(entry 8). A 10:1 enol ether to diazo

ratio was utilized due to the volatility of 2h under the reaction

conditions.

to provide interesting products with more functionalization as

compared to the acyclic enol ethers. Particularly, the indole-

forming reactions under Rh catalysis were anticipated to give

uniquely substituted products based on our mechanistic

understanding. As previously discussed, elimination of the

ROH group from the enol ether is required for the

aromatization step to form the indole product. In the case of

the cyclic enol ethers, this elimination is expected to result in

ring-opening of the ether and generation of an indole with a

hydroxyalkyl substituent.

We began this study with the readily available cyclic enol

ethers, dihydrofuran 2i and dihydropyran 2j. Dihydrofuran

provided indole 3di, which contains a hydroxyethyl chain as a

substituent, in 51% yield and DHF product 4di, a furo[2,3-

b]furan, in 48% yield (entry 1). Similarly, dihydropyran gave

both the hydroxypropyl substituted indole 3dj and a

diastereomeric mixture (1.3:1 dr) of DHF product 4dj (a

4H-furo[2,3-b]pyran) in low yields (27% and 23%, respec-

tively, entry 2). We believe that the reduced nucleophilicity of

dihydropyran compared to dihydrofuran is responsible for the

observed outcome.²⁶

Cyclic Enol Ethers. Following the scope for the acyclic enol

ethers, we moved on to investigate cyclic enol ethers

containing an endocyclic oxygen (Table 4). We were keenly

interested in exploring cyclic enol ethers as they were expected

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Table 4. Reactions with Cyclic Enol Ethers

Figure 2. Ketene-trapped indole byproducts 11c−11f.

catalyzed reactions of ethyl vinyl ether 2h as a basis for

comparison (Table 5, entry 1). A N-benzyl protecting group

Table 5. Pyrrole Substituent Eﬀects

a

Reaction of 1d (1 equiv), 2 (3 equiv), and Rh₂(esp)₂(0.5 mol %) in

b

CH₂Cl₂at 40 °C. Reaction of 1d (1 equiv), 2 (3 equiv), and

c

Cu(hfacac)₂(10 mol %) in CH₂Cl₂at 40 °C. Percentages represent

isolated yields following column chromatography.

Next, we sought an example of a cyclic 1,1-disubstituted enol

ether and selected 2-methylenetetrahydrofuran 2k (entry 3).

Enol ether 2k aﬀorded a 47% yield of indole 3dk, which

contains a hydroxypropyl group at the C(4) position. With

Cu(II), the spirocyclic DHF 4dk (a 1,6-dioxospiro[4.4]-

nonane) was formed in 78% yield.

Lastly, a trisubstituted enol ether 2l was also evaluated under

both Rh(II) and Cu(II) catalysis conditions (entry 4). While

the desired indole product 3dl which contained the fully

substituted benzenoid ring was obtained in an unexpectedly

low 23% yield with Rh₂(esp)₂, constitutional isomeric indole

3dk was also isolated in 21% yield. This outcome suggests an

equilibrium between the exocyclic and the endocyclic enol

ethers (2l and 2k, respectively) must take place over the course

of the reaction, resulting in the observed mixture of products.

Under Cu(II) catalysis, no isomerization was observed as the

only discernible product, DHF 4dl, was isolated in 12% yield.

This reduced yield reﬂects both the reduced nucleophilicity of

the trisubstituted enol ether and the low stability of the formed

DHF acetal.

a

Reaction of 1 (1 equiv), 2g (10 equiv), and Rh₂(esp)₂(0.5 mol %)

b

in CH₂Cl₂at 40 °C. Reaction of 1 (1 equiv), 2g (10 equiv), and

c

Cu(hfacac)₂(10 mol %) in CH₂Cl₂at 40 °C. Percentages represent

d

isolated yields following column chromatography. Obtained in 10%

yield as an inseparable mixture with 12ih.

It is worth noting that byproducts 11c−11f could be

identiﬁed (in varying amounts) for all the indoles containing a

hydroxyalkyl substituent from the Rh(II)-catalyzed reaction

with cyclic enol ethers (Figure 2). These ketene-trapping side-

products presumably arise from nucleophilic attack of the

pendant alcohol group on the ketene intermediate which

supports the previous discussion regarding the deleterious

eﬀects of free ROH to the overall reaction eﬃciency.

(as in 1e) did not negatively impact indole formation,

generating 3eh in 68% yield (entry 2). However, the Cu(II)-

catalyzed reaction gave a comparatively decreased yield of

DHF product 4eh (32%). On the other hand, N-tosyl-

protected pyrrole 1f failed to provide any of the indole product

3fh (entry 3). On the basis of our mechanistic understanding,

this outcome is consistent with the expectation that an

electron-rich pyrrolyl ketone is needed for the Wolﬀ

rearrangement to occur. Conversely, pyrrole 1f gave DHF

Pyrrole Substituent Eﬀects. To complete our study of the

scope, the inﬂuence of diﬀerent pyrrole protecting groups and

substituents were evaluated using the Rh(II)- and Cu(II)-

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4fh in 65% yield but required a much longer reaction time to

reach completion.

acetals 4 could also be utilized as an eﬃcient precursor for the

synthesis of substituted 2-(2-furyl)-1H-pyrroles.

The eﬀects of substituents on C(4) of the pyrrole ring of the

diazo were next examined. Ethyl pyrrole 1g was tolerated for

both Rh(II) and Cu(II) catalysis conditions, providing indole

3gh and DHF 4gh in 45 and 33% yield (entry 4). In contrast,

the 4-phenyl pyrrole 1h generated both of its products (indole

3hh and DHF 4hh) in 68% yield (entry 5).

In a pursuit to expand our reach to other positional isomers,

the 3-acyl-substituted pyrrole diazo compound 1i was treated

under Rh(II) and Cu(II) catalysis (entry 6). Diazo 1i did not

perform well under the Rh catalysis conditions. Indole 3ih

could only be obtained as an inseparable mixture with its

isomer, isoindole 12ih in a combined yield of 10%. Isoindole

12ih most likely arises from competing Friedel−Crafts

alkylation occurring at the free nucleophilic C(4) position. In

contrast, DHF acetal 4ih was isolated in 77% yield under

Cu(II) catalysis. This outcome suggests that the 3-substituted

isomer works better than the 2-substituted pyrrole for DHF

formation.

CONCLUSIONS

■

In summary, we have developed a catalyst-dependent chemo-

divergent methodology that allows for the selective synthesis of

indoles and DHF acetals. We learned the electron-rich pyrrole

ring encourages Wolﬀ-rearrangement in the presence of

dirhodium catalysts, and the overall [4 + 2] benzannulation

was further improved by assistance of the 2,2,2-triﬂuoroethyl

ester. The TFE ester also plays a pivotal role in controlling the

chemodivergence of the system, as it allowed for selective

access to the [3 + 2] DHF acetal products under Cu(II)

catalysis.

Through exploring the scope for both reactions, the choice

of enol ether proved to be essential in determining the

stereochemistry and the yield of the corresponding products.

For instance, the more nucleophilic enol ethers aﬀorded the

corresponding products in higher yields (up to 82% yield for

the indoles and 91% yield for the DHF acetals). This trend is

observed both when comparing enol ethers from within the

same group (e.g., aryl enol ethers) or among diﬀerent groups

such as 1,1 versus 1,2-disubstituted enol ethers, with the latter

being less nucleophilic. The choice of enol ethers also

determines the regiochemistry of the obtained products,

which allows for the regioselective synthesis of indoles and

DHF acetals at the C4 and C5 positions. Besides the enol

ethers, a range of pyrrolyl-α-diazo-β-ketoesters containing

diﬀerent N1 and C4 substituents were also investigated. While

most substitutions were tolerated for both reactions, electron-

rich pyrroles proved to be essential, as expected by our

predictive model, for the Rh(II)-catalyzed [4 + 2] reaction to

take place, as both N-tosyl (1f) and 3-acyl pyrrole (1i) failed to

provide the desired indole in satisfactory yields.

Revisiting Ring-Opening Benzannulation Reactions

of Pyrrolyl DHF Acetals: Proof of Concept. Given that

DHF acetals 4 can be selectively accessed using copper(II)

catalysis, we sought to demonstrate that they can undergo

benzannulation in the presence of a Lewis acid to access

indoles regioisomeric to the ones obtained through Rh(II)

catalysis (Scheme 5). Starting with the optimized conditions

Scheme 5. DHF Benzannulation Study (A) and Molecular

Structure of Indole 5da (B) with Thermo Ellipsoids Shown

at 50% Probability

Lastly, a model DHF acetal proved to be viable precursors to

the selective synthesis of a highly substituted indole and furan,

through a Lewis acid-catalyzed benzannulation or elimination,

respectively. This two-step process from the corresponding

diazo compound oﬀers access to indoles that are regioisomeric

at the C(6) and C(7) positions to the ones obtained directly

through the Rh(II) catalysis. Hence, our methodology allows

for selective access to indoles with predictable substitutions at

every position of the benzenoid ring (i.e., C(4)−C(7)). This is

particularly useful when considering that common non-

benzannulation indole-forming strategies (e.g., Fischer, Larock,

Bartoli, etc.) require a prefunctionalized benzene ring to

achieve indole C(4)−C(7) substitution, which can be

challenging due to inherent limitations involving the

regioselectivity of aromatic substitutions. Similarly, the direct

C(4)−C(7) functionalization of unsubstituted indoles can be

diﬃcult due to the higher reactivity of the C(2) and C(3)

positions. Our methodology herein complements other

common approaches to the synthesis of C(4)−C(7)

substituted indoles.

from our previous work (Al(OTf)₃, 10 mol %, toluene, 1 drop

of H₂O, 70 °C), indole 5da was obtained in 63% yield.

Treatment of DHF acetal 4da with Sc(OTf)₃(no water

added) aﬀorded the corresponding indole 5da in 77% yield

along with 12% of the furan 13da. Furan 13da is presumably

formed from Lewis acid-mediated MeOH elimination from

DHF 4da. Finally, Ga(OTf)₃(no water added) oﬀered a bit of

chemodivergence as formation of the furan was slightly

preferred over the indole (43% vs 28%). This is particularly

interesting considering that, with further optimization, DHF

Future work involving the exploration of diazo compounds

containing other electron-withdrawing groups, the utilization

of strategic enol ethers for target synthesis, and the preliminary

evaluation of the bioactivities of the indole and DHF

derivatives are currently underway.

EXPERIMENTAL SECTION

General Information. Chromatographic puriﬁcation was per-

formed as ﬂash chromatography with Silicycle SiliaFlash P60 silica gel

■

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(40−63 μm) or preparative thin-layer chromatography (prep-TLC)

using silica gel F254 (1000 μm) plates and solvents indicated as

eluent with 0.1−0.5 bar pressure. For quantitative ﬂash chromatog-

raphy, technical grade solvents were utilized. Analytical thin-layer

chromatography (TLC) was performed on Silicycle SiliaPlate TLC

silica gel F254 (250 μm) TLC glass plates. Visualization was

accomplished with UV light. Infrared (IR) spectra were obtained via

attenuated total reﬂection (ATR) with a diamond plate using a Bruker

ALPHA Fourier-transform infrared spectrophotometer. The IR bands

are characterized as broad (br), weak (w), medium (m), and strong

(s). Proton and carbon nuclear magnetic resonance spectra (¹H NMR

and ¹³C NMR) were recorded on a Varian Mercury Vx 300 MHz

spectrometer or a Bruker 500 MHz spectrometer with solvent

resonances as the internal standard (¹H NMR: CDCl₃at 7.26 ppm or

DMSO-d₆at 2.50; ¹³C NMR: CDCl₃at 77.0 ppm or DMSO-d₆at

39.5). ¹H NMR data are reported as follows: chemical S-1 shift

(ppm), multiplicity (s = singlet, d = doublet, dd = doublet of doublets,

dt = doublet of triplets, ddd = doublet of doublet of doublets, t =

triplet, m = multiplet, br = broad), coupling constants (Hz), and

integration. Mass spectra were obtained through EI on a Micromass

AutoSpec machine or through ESI on a Thermo Orbitrap XL. The

accurate mass analyses run in EI mode were at a mass resolution of

10 000 and were calibrated using PFK (perﬂuorokerosene) as an

internal standard. The accurate mass analyses run in EI mode were at

a mass resolution of 30 000 using the calibration mixture supplied by

Thermo. Enol ethers 2a, 2g−j, and 2l were obtained from commercial

sources.

General Procedure for Optimization of the Rh(II) Catalyzed

Indole Formation. To a ﬂame-dried ﬂask equipped with a magnetic

stir, Rh(II) catalyst was added followed by dry DCM and enol ether

2a, under constant nitrogen ﬂow. After attaching a reﬂux condenser

and bringing the reaction mixture to a boil, a solution of diazo

compound 1d in dry DCM was slowly added via syringe pump. After

all the contents are added, the mixture was reﬂuxed overnight or until

all starting material was consumed (indicated by TLC analysis). The

reaction mixture was then removed from the heat, a scoop of silica gel

300−400 mesh was added and the mixture was allowed to stir for an

additional 0.5 h. The solvent was then removed under reduced

pressure and dimethyl terephthalate (DMTP) was added as an

internal standard for quantitative NMR analysis.

through a Celite plug and concentrated under reduced pressure to

aﬀord the crude carboxylic acids 15, which were subsequently used

without further puriﬁcation.

Synthesis of 2-Pyrrolyl-β-ketoesters (16). To a dry ﬂask charged

with a stir bar and the corresponding carboxylic acid 15 (1.0 equiv),

dry CH₂Cl₂was added to make a 0.5 M solution, followed by addition

of catalytic DMF (a few drops). The solution was then cooled to 0 °C

and oxalyl chloride (1.2 equiv) was slowly added over 1 min. After 15

min, the reaction was allowed to warm to room temperature with

continued stirring. After 3 h at room temperature, the reaction was

concentrated under reduced pressure and the acid chloride residue

was dissolved in dry THF to make a 1 M solution (keeping it under

inert atmosphere). The solution was added slowly to the prepared

enolate at −78 °C. The enolate was prepared by ﬁrst adding LHMDS

(1 M in THF, 2.10−3.0 equiv) to a dry ﬂask charged with a stir bar

under nitrogen and cooling to −78 °C. The corresponding acetate

(1.05 equiv) was added to the solution of LHMDS in one shot and

stirred for 45 min at −78 °C. After 30 min from the addition of the

acid chloride to the enolate solution, the reaction was quenched with

NH₄Cl (aq.) at −78 °C, extracted with EtOAc three times, dried

using MgSO₄, and ﬁltered through Celite. The combined organic

layers were concentrated under reduced pressure and puriﬁed by ﬂash

chromatography on silica gel using EtOAc/Hexanes as the mobile

phase.

Methyl 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanoate (16a). Pre-

pared following the general procedure using 1-methyl-1H-pyrrole-2-

carboxylic acid (4.0 g, 32.0 mmol), oxalyl chloride (3.3 mL, 38.4

mmol), methyl acetate (2.6 mL, 33.6 mmol), and LHMDS (1 M, 68

mL) in DCM (0.5 M, 60 mL) and THF (1 M, 30 mL). After workup

and puriﬁcation on silica gel column chromatography (10% EtOAc/

Hexanes, R_f= 0.39 in 30% Et₂O/Hexanes), desired product 16a was

1

obtained as a yellow oil (2.1 g, 36% yield). H NMR (500 MHz,

CDCl₃) δ 6.95 (dt, J = 4.3, 1.2 Hz, 1H), 6.84 (t, J = 2.1 Hz, 1H), 6.13

(ddd, J = 4.1, 2.5, 1.1 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 2H), 3.73 (s,

3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 182.1, 168.4, 132.1, 129.9,

120.6, 108.6, 52.4, 46.2, 37.7. IR (cm⁻¹) 1736 (s), 1644 (s). HRMS

(ESI) m/z [M + H]⁺calcd for C₉H₁₁NO₃182.0811, found 182.0813.

Ethyl 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanoate (16b). To a

dry round-bottom ﬂask under nitrogen, NaH (0.91 g, 22.7 mmol) is

added followed by the addition of toluene (4.0 mL, 1M) and diethyl

malonate (1.97 mL, 16.2 mmol). The reaction mixture was heated to

reﬂux and a solution of 1-(1-methyl-1H-pyrrol-2-yl)ethan-1-one (1.0

g, 8.12 mmol) in 4 mL of toluene was slowly added over the course of

30 min. Upon completion (monitored by TLC), the reaction is

cooled to 0 °C, acidiﬁed with acetic acid to pH 4 and then cold water

is added to dissolve solids. The solution was then extracted with

EtOAc (3 × 10 mL), dried with MgSO₄, ﬁltered through Celite, and

concentrated under reduced pressure. The crude oil was puriﬁed on

silica gel column chromatography (10% EtOAc/Hexanes, R_f= 0.25 in

30% Et₂O/Hexanes) and the desired product 16b was isolated as a

General Procedure for the Optimization of the DHF Acetal

Formation. To a ﬂame-dried ﬂask equipped with a magnetic stir, the

metal-catalyst was added followed by dry DCM (0.1 M), enol ether

2a and diazo 1d. A reﬂux condenser was then attached and the

reaction mixture was reﬂuxed overnight (16 h). The solvent was then

removed under reduced pressure and dimethyl terephthalate

(DMTP) was added as an internal standard for quantitative NMR

analysis.

General Procedure for the Lewis-Acid Ring-Opening

Benzannulation Optimizations. A solution of DHF acetal 4da in

toluene (0.1 M) was added to a ﬂame-dried round-bottom ﬂask

containing the desired Lewis Acid (10 mol %). The reaction mixture

was then heated to 70 °C until all 4da was consumed, monitored by

TLC. Upon completion, the reaction mixture was washed with water

(2 × 5 mL), extracted with Et₂O (3 × 5 mL), dried with MgSO₄,

ﬁltered through a Celite plug, and concentrated under reduced

pressure. To the crude oil, dimethyl terephthalate (DMTP) was

added as an internal standard for quantitative NMR analysis. The

crude mixture was then puriﬁed by silica gel column chromatography.

General Procedure for the Synthesis of 2-Pyrrolyl-β-

ketoesters (16) from Carboxylic Acids (15). Synthesis of the

Carboxylic Acids (15). To a 0.5 M solution of pyrrolyl-ester 14,

synthesized through known literature procedures,²⁹⁻³²in MeOH/

THF/H₂O (1:1:1), LiOH monohydrate (2.5 equiv) was added and

the reaction was stirred at room temperature. After 16 h, if 14 was still

present, indicated by TLC, the reaction mixture was heated to 35 °C

until SM has been fully consumed. Upon completion, the reaction

mixture was cooled to 0 °C and HCl (3 M) was slowly added until

the mixture reached a pH ∼1−2 (indicated by pH paper). The

mixture was then extracted with EtOAc, dried with MgSO₄, ﬁltered

1

yellow oil (1.34 g, 85% yield). H NMR (500 MHz, CDCl₃) δ 6.92

(dd, J = 4.2, 1.7 Hz, 1H), 6.81 (t, J = 2.1 Hz, 1H), 6.10 (dd, J = 4.2,

2.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.76 (s, 2H), 1.23

(t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 182.3,

167.9, 132.0, 129.9, 120.5, 108.5, 61.2, 46.4, 37.6, 14.1. IR (cm⁻¹)

1731 (s), 1645 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₀H₁₃NO₃

196.0968, found 196.0969.

2,2,2-Triﬂuoroethyl 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropa-

noate (16c). Prepared following the general procedure using 1-

methyl-1H-pyrrole-2-carboxylic acid (3.0 g, 24.0 mmol), oxalyl

chloride (2.4 mL, 28.8 mmol), 2,2,2-triﬂuoroethyl acetate (2.7 mL,

25.2 mmol) and LHMDS (1 M, 72 mL) in DCM (0.5 M, 48 mL) and

THF (1 M, 24 mL). After workup and puriﬁcation on silica gel

column chromatography (10% EtOAc/Hexanes, R_f= 0.57 in 30%

EtOAc/Hexanes), desired product 16c was obtained an orange oil

(4.2 g, 70% yield). ¹H NMR (500 MHz, CDCl₃) δ 6.94 (dd, J = 4.2,

1.7 Hz, 1H), 6.87 (t, J = 2.1 Hz, 1H), 6.16 (dd, J = 4.2, 2.5 Hz, 1H),

4.53 (q, J = 8.4 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 2H). ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 180.8, 166.4, 132.4, δ 122.8 (q, J_C−F= 277.2

Hz), 120.6, 119.5, 108.7, 45.5, 60.8 (q, J_C−F= 36.8 Hz) 37.7. ¹⁹F

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NMR (471 MHz, CDCl₃) δ −73.69 (t, J = 8.4 Hz). IR (cm⁻¹) 1758

(s), 1649 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₀H₁₀F₃NO₃

250.0685, found 250.0685.

5H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 181.0, 166.3, 133.7, 130.1,

129.2, 128.9, 126.6, 125.2, 124.8, 122.8 (q, J_C−F= 277.4 Hz), 117.2,

60.9 (q, J_C−F= 36.9 Hz), 45.5, 37.9. ¹⁹F NMR (471 MHz, CDCl₃) δ

−73.6 (t, J = 8.4 Hz). IR (cm⁻¹) 1761 (s), 1648 (s). HRMS (ESI) m/

z [M + H]⁺calcd for C₁₆H₁₄F₃NO₃326.0998, found 326.0999.

2,2,2-Triﬂuoroethyl 3-(1-methyl-1H-pyrrol-3-yl)-3-oxopropa-

noate (16h). Prepared by following the general procedure using 1-

methyl-1H-pyrrole-3-carboxylic acid (280 mg, 2.24 mmol), oxalyl

chloride (0.38 mL, 2.69 mmol), 2,2,2-triﬂuoroethyl acetate (0.27 mL,

2.345 mmol), and LHMDS (1 M, 6.7 mL) in DCM (0.5 M, 4.5 mL)

and THF (1 M, 2.3 mL). After workup and puriﬁcation on silica gel

column chromatography (10% EtOAc/hexanes, R_f= 0.34 in 30%

Et₂O/Hexanes), desired product 16h was obtained an orange oil (370

2,2,2-Triﬂuoroethyl 3-(1-benzyl-1H-pyrrol-2-yl)-3-oxopropa-

noate (16d). Prepared by following the general procedure using 1-

benzyl-1H-pyrrole-2-carboxylic acid (509 mg, 2.53 mmol), oxalyl

chloride (0.25 mL, 2.48 mmol), 2,2,2-triﬂuoroethyl acetate (0.29 mL,

2.61 mmol) and LHMDS (1 M, 5.7 mL) in DCM (0.5 M, 5 mL) and

THF (1 M, 2.5 mL). After workup and puriﬁcation on silica gel

column chromatography (10% EtOAc/Hexanes, R_f= 0.63 in 30%

EtOAc/Hexanes), desired product 16d was obtained a clear oil (491.7

1

mg, 60% yield). H NMR (500 MHz, CDCl₃) δ 7.34−7.22 (m, 3H),

7.15−7.07 (m, 2H), 7.01 (dd, J = 4.2, 1.7 Hz, 1H), 6.97 (dd, J = 2.5,

1.7 Hz, 1H), 6.23 (dd, J = 4.1, 2.6 Hz, 1H), 5.57 (s, 2H), 4.50 (q, J =

8.4 Hz, 2H), 3.91 (s, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

1

mg, 66% yield). H NMR (500 MHz, CDCl₃) δ 7.27 (t, J = 2.0 Hz,

1H), 6.58 (ddd, J = 11.8, 2.9, 1.9 Hz, 1H), 4.52 (q, J = 8.4 Hz, 1H),

3.85 (s, 1H), 3.69 (s, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

185.5, 166.4, 127.4, 124.5, 123.9, 122.8 (q, J_C−F= 277.2 Hz), 109.8,

60.7 (q, J_C−F= 36.8 Hz), 45.9, 36.8. ¹⁹F NMR (471 MHz, CDCl₃) δ

−73.7 (t, J = 8.6 Hz). IR (cm⁻¹) 1758 (s), 1654 (s). HRMS (ESI) m/

z [M + H]⁺calcd for C₁₀H₁₀F₃NO₃250.0685, found 250.0686.

2,2,2-Trichloroethyl 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropa-

noate (16i). To a dry round-bottom ﬂask, 3-(1-methyl-1H-pyrrol-2-

yl)-3-oxopropanoic acid (150 mg, 0.897 mmol), 2,2,2-trichloroetha-

nol (0.10 mL, 1.08 mmol) and 2 mL of DCM were added. The

reaction mixture was then cooled to 0 °C and a solution of N,N′-

dicyclohexylcarbodiimide (203 mg, 0.987 mmol) in 1.0 mL of DCM

was slowly added. Upon completion, the reaction mixture was ﬁltered

through Celite and concentrated under reduced pressure. The crude

material was then puriﬁed by silica gel column chromatography (30%

EtOAc/Hexanes, R_f= 0.63) to aﬀord 16i as a yellow oil (174.8 mg,

65% yield). ¹H NMR (500 MHz, CDCl₃) δ 6.98 (dd, J = 4.2, 1.7 Hz,

1H), 6.87 (t, J = 2.1 Hz, 1H), 6.16 (dd, J = 4.2, 2.5 Hz, 1H), 4.80 (s,

2H), 3.96 (s, 2H), 3.94 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

180.9, 166.4, 132.3, 129.7, 120.7, 108.7, 94.6, 74.4, 45.8, 37.7. IR

(cm⁻¹) 1754 (s), 1648 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₀H₁₀Cl₃NO₃297.9799, found 297.9802.

General Procedure for the Synthesis of Diazo Compounds

(1). To an ice-cold solution of β-ketoester (1.0 equiv) and 4-

acetamidobenzenesulfonyl azide (p-ABSA, 1.2 equiv) in dry MeCN

(0.2 M), NEt₃(1.1 equiv) was slowly added. The reaction was left to

warm gradually to room temperature overnight or monitored by TLC

for completion. Upon completion, the reaction mixture was vacuum-

ﬁltered through a Celite plug to remove the formed solids, and

washed three times with cold DCM. The ﬁltrate was concentrated

under a vacuum and the obtained residue was puriﬁed on silica gel

(10−20% EtOAc/Hexanes) to aﬀord diazo compound 1.

Methyl 2-diazo-3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanoate

(1a). Prepared following the general procedure using β-ketoester

16a (501 mg, 2.76 mmol), p-ABSA (860 mg, 3.59 mmol), and NEt₃

(0.42 mL, 3.04 mmol) in MeCN (14 mL). After workup and

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.13), diazo 1a was obtained as a yellow solid (429

mg, 75% yield). ¹H NMR (500 MHz, CDCl₃) δ 6.93 (dd, J = 4.2, 1.7

Hz, 1H), 6.84 (t, J = 2.1 Hz, 1H), 6.13 (dd, J = 4.2, 2.5 Hz, 1H), 3.89

(s, 3H), 3.84 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 173.7,

162.4, 131.2, 128.1, 120.0, 108.1, 73.6, 52.4, 37.1. IR (cm⁻¹) 2146 (s),

1715 (s), 1600 (m). HRMS (ESI) m/z [M + H]⁺calcd for C₉H₉N₃O₃

208.0716, found 208.0718.

Ethyl 2-diazo-3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanoate

(1b). Prepared following the general procedure using β-ketoester

16b (315 mg, 1.614 mmol), p-ABSA (390 mg, 1.629 mmol), and

NEt₃(0.24 mL, 1.721 mmol) in MeCN (7.7 mL). After workup and

puriﬁcation on silica-gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.15), diazo 1b was obtained as an orange oil (274.7

mg, 77% yield). ¹H NMR (500 MHz, CDCl₃) δ 6.94 (dd, J = 4.2, 1.6

Hz, 1H), 6.83 (t, J = 2.1 Hz, 1H), 6.13 (dd, J = 4.2, 2.5 Hz, 1H), 4.30

(q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 173.96, 161.87, 131.14, 128.17, 120.04,

108.05, 73.73, 61.50, 37.08, 14.39. IR (cm⁻¹) 2128 (s), 1717 (s),

180.6, 166.3, 137.6, 131.9, 129.1, 128.7, 127.6, 127.2, 122.8 (q, J_C−F

=

277.4 Hz), 121.4, 109.4, 60.8 (q, J_C−F= 36.8 Hz), 52.7, 45.7. ¹⁹F

NMR (471 MHz, CDCl₃) δ −73.7 (t, J = 8.2 Hz). IR (cm⁻¹) 1758

(s), 1651 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₄F₃NO₃

326.0998, found 326.0998.

2,2,2-Triﬂuoroethyl 3-oxo-3-(1-tosyl-1H-pyrrol-2-yl)propanoate

(16e). Prepared by following the general procedure using 1-tosyl-

1H-pyrrole-2-carboxylic acid (1.00 g, 3.77 mmol), oxalyl chloride

(0.38 mL, 4.52 mmol), 2,2,2-triﬂuoroethyl acetate (0.44 mL, 7.92

mmol) and LHMDS (1 M, 7.9 mL) in DCM (0.5 M, 7.5 mL) and

THF (1 M, 3.8 mL). After workup and puriﬁcation on silica gel

column chromatography (10% EtOAc/Hexanes, R_f= 0.30 in 30%

EtOAc/Hexanes), desired product 16e was obtained a beige oil (200

mg, 14% yield). Mixture of keto−enol tautomers. As 16e proved to

1

degrade easily, it was stored in a freezer at −20 °C. H NMR (500

MHz, CDCl₃) δ 9.39 (s, 6H), 7.08 (dtd, J = 9.4, 2.6, 1.2 Hz, 15.73H),

6.97 (dt, J = 4.1, 1.9 Hz, 4.87H), 6.92−6.84 (m, 3.47H), 6.34 (dt, J =

3.8, 2.6 Hz, 7.89H), 6.29 (ddt, J = 6.3, 3.7, 2.5 Hz, 2.14H), 6.19 (dd, J

= 4.2, 2.5 Hz, 2.71H), 4.55 (q, J = 8.4 Hz, 5.91H), 4.25 (q, J = 8.0 Hz,

16.28H), 4.20 (d, J = 4.3 Hz, 7.73H), 4.07 (d, J = 4.3 Hz, 7.80H),

3.96 (d, J = 0.9 Hz, 14H), 3.88 (s, 3H). ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 180.9, 166.4, 157.6, 155.7, 132.5, 129.5, 128.2, 126.0, 124.9,

123.9, 123.8, 123.5, 123.0, 121.7, 121.5, 120.7, 120.6, 120.1, 119.3,

117.9, 115.3, 111.2, 110.5, 110.2, 108.8, 66.1 (q, J

= 36.6 Hz),

C−F

60.8 (q, J _C−F= 36.8 Hz), 51.5, 45.4, 37.7, 29.7. ¹⁹F NMR (471 MHz,

−1

CDCl₃) δ −73.7 (t, J = 8.0 Hz), −73.8 (t, J = 7.9 Hz). IR (cm

)

3337 (br), 1723 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₆H₁₄F₃NO₅S 390.0617, found 390.0618.

2,2,2-Triﬂuoroethyl 3-(4-ethyl-1-methyl-1H-pyrrol-2-yl)-3-oxo-

propanoate (16f). Prepared by following the general procedure

using 4-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid (360 mg, 2.35

mmol), oxalyl chloride (0.24 mL, 2.82 mmol), 2,2,2-triﬂuoroethyl

acetate (0.28 mL, 2.47 mmol) and LHMDS (1 M, 7.1 mL) in DCM

(0.5 M, 4.7 mL) and THF (1 M, 3.4 mL). After workup and

puriﬁcation on silica gel column chromatography (10% EtOAc/

Hexanes, R_f= 0.36 in 30% Et₂O/Hexanes), desired product 16f was

obtained as a brown oil (504.3 mg, 77% yield). ¹H NMR (500 MHz,

CDCl₃) δ 6.77 (d, J = 1.7 Hz, 1H), 6.69 (d, J = 1.9 Hz, 1H), 4.53 (q, J

= 8.4 Hz, 2H), 3.89 (s, 2H), 3.88 (s, 3H), 2.46 (q, J = 7.6 Hz, 2H),

1.18 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 180.5,

166.5, 130.5, 129.1, 126.5, 122.8 (q, J_C−F= 277.3 Hz), 119.5, 60.8 (q,

J

_C−F= 36.8 Hz), 45.4, 37.5, 19.6, 15.1. ¹⁹F NMR (471 MHz, CDCl₃)

δ −73.7 (t, J = 8.3 Hz). IR (cm⁻¹) 1761 (s), 1647(s). HRMS (ESI)

m/z [M + H]⁺calcd for C₁₂H₁₄F₃NO₃278.0998, found 278.0999.

2,2,2-Triﬂuoroethyl 3-(1-methyl-4-phenyl-1H-pyrrol-2-yl)-3-oxo-

propanoate (16g). Prepared by following the general procedure

using 1-methyl-4-phenyl-1H-pyrrole-2-carboxylic acid (400 mg, 1.99

mmol), oxalyl chloride (0.20 mL, 2.385 mmol), 2,2,2-triﬂuoroethyl

acetate (0.23 mL, 2.09 mmol) and LHMDS (1 M, 6.0 mL) in DCM

(0.5 M, 4.0 mL) and THF (1 M, 2.0 mL). After workup and

puriﬁcation on silica gel column chromatography (10% EtOAc/

Hexanes, R_f= 0.26 in 30% Et₂O/hexanes), desired product 16g was

obtained a clear oil (550 mg, 85% yield). ¹H NMR (500 MHz,

CDCl₃) δ 7.53−7.47 (m, 2H), 7.39 (dd, J = 8.5, 7.0 Hz, 2H), 7.27−

7.25 (m, 1H), 7.23−7.16 (m, 2H), 4.58 (q, J = 8.4 Hz, 2H), 4.01 (s,

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1597 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₀H₁₁N₃O₃

222.0873, found 222.0873.

1731 (s), 1604 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₂H₁₂F₃N₃O₃304.0903, found 304.0903.

2,2,2-Trichloroethyl 2-diazo-3-(1-methyl-1H-pyrrol-2-yl)-3-oxo-

propanoate (1c). Prepared following the general procedure using

β-ketoester 16i (167.3 mg, 0.560 mmol), p-ABSA (142 mg, 0.588

mmol), and NEt₃(0.08 mL, 0.616 mmol) in MeCN (3 mL). After

workup and puriﬁcation on silica gel column chromatography (10%

Et₂O/Hexanes, R_f= 0.17), diazo 1c was obtained as a yellow oil

(153.6 mg, 85% yield). ¹H NMR (500 MHz, CDCl₃) δ 6.98 (dd, J =

4.3, 1.7 Hz, 1H), 6.86 (t, J = 2.1 Hz, 1H), 6.14 (dd, J = 4.2, 2.5 Hz,

1H), 4.87 (s, 2H), 3.89 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

172.9, 159.9, 131.7, 127.8, 120.7, 108.3, 94.8, 73.8, 73.7, 37.1. IR

(cm⁻¹) 2135 (s), 1725 (s), 1600 (s). HRMS (ESI) m/z [M + H]⁺

calcd for C₁₀H₈Cl₃N₃O₃323.9704, found 323.9707.

2,2,2-Triﬂuoroethyl 2-diazo-3-(1-methyl-4-phenyl-1H-pyrrol-2-

yl)-3-oxopropanoate (1h). Prepared following the general procedure

using β-ketoester 16g (520 mg, 1.60 mmol), p-ABSA (460 mg, 1.92

mmol), and NEt₃(0.27 mL, 1.92 mmol) in MeCN (8.0 mL). After

workup and puriﬁcation (15% EtOAc/Hexanes, R_f= 0.21), diazo 1h

1

was obtained as a beige solid (592 mg, 94% yield). H NMR (500

MHz, CDCl₃) δ 7.50−7.44 (m, 2H), 7.36 (dd, J = 8.4, 7.1 Hz, 2H),

7.25−7.20 (m, 2H), 7.17 (d, J = 1.9 Hz, 1H), 4.64 (q, J = 8.3 Hz,

2H), 3.94 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 172.8, 160.0,

134.0, 128.8, 128.6, 128.5, 126.4, 125.3, 124.5, 122.7 (q, J_C−F= 277.5

Hz), 117.3, 73.9, 60.5 (q, J_C−F= 37.0 Hz), 37.4. ¹⁹F NMR (471 MHz,

CDCl₃) δ −73.8 (t, J = 8.2 Hz). IR (cm⁻¹) 2146 (s), 1730 (s), 1593

(s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₂F₃N₃O₃352.0903,

found 352.0903.

2,2,2-Triﬂuoroethyl 2-diazo-3-(1-methyl-1H-pyrrol-2-yl)-3-oxo-

propanoate (1d). Prepared following the general procedure using

β-ketoester 16c (4.2 g, 16.8 mmol), p-ABSA (4.86 g, 20.2 mmol), and

NEt₃(2.6 mL, 18.5 mmol) in MeCN (84 mL). After workup and

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.19), diazo 1d was obtained as a yellow-oil (4.2 g,

2,2,2-Triﬂuoroethyl 2-diazo-3-(1-methyl-1H-pyrrol-3-yl)-3-oxo-

propanoate (1i). Prepared following the general procedure using β-

ketoester 16h (0.370 mg, 1.48 mmol), p-ABSA (393 mg, 1.63 mmol),

and NEt₃(0.25 mL, 1.78 mmol) in MeCN (15 mL). After workup

and puriﬁcation on silica gel column chromatography (20% EtOAc/

Hexanes, R_f= 0.19), diazo 1i was obtained as a light-beige solid (343

1

91% yield) which crystallized upon storage in the refrigerator. H

NMR (500 MHz, CDCl₃) δ 6.94 (dd, J = 4.2, 1.6 Hz, 1H), 6.87 (t, J =

2.1 Hz, 1H), 6.16 (dd, J = 4.2, 2.5 Hz, 1H), 4.62 (q, J = 8.3 Hz, 2H),

3.90 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 172.7, 160.1,

131.7, 127.8, 122.7 (q, J_C−F= 277.5 Hz), 120.5, 108.3, 73.4, 60.4 (q,

J_C−F= 37.1 Hz), 37.1. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.8 (t, J =

8.2 Hz). IR (cm⁻¹) 2132 (s), 1733 (s), 1604 (s). HRMS (ESI) m/z

[M + H]⁺calcd for C₁₀H₈F₃N₃O₃276.0590, found 276.0591.

2,2,2-Triﬂuoroethyl 3-(1-benzyl-1H-pyrrol-2-yl)-2-diazo-3-oxo-

propanoate (1e). Prepared following the general procedure using

β-ketoester 16d (1.02 g, 3.15 mmol), p-ABSA (0.87 g, 3.63 mmol),

and NEt₃(0.6 mL, 3.78 mmol) in MeCN (16 mL). After workup and

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.11), diazo 1e was obtained as a light-beige solid

1

mg, 84% yield). H NMR (500 MHz, CDCl₃) δ 7.54 (t, J = 1.9 Hz,

1H), 6.70 (dd, J = 3.0, 1.7 Hz, 1H), 6.57 (dd, J = 2.9, 2.1 Hz, 1H),

4.61 (q, J = 8.3 Hz, 2H), 3.69 (s, 3H). ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 177.0, 160.0, 128.7, 122.8 (q, J_C−F= 277.6 Hz), 122.7,

122.4, 111.0, 60.3 (q, J_C−F= 36.9 Hz), 36.7. ¹⁹F NMR (471 MHz,

CDCl₃) δ −73.8 (t). IR (cm⁻¹) 2142 (s), 1727 (s), 1597 (s). HRMS

(ESI) m/z [M + H]⁺calcd for C₁₀H₈F₃N₃O₃276.0590, found

276.0591.

General Procedure for the Synthesis of Aryl Enol Ethers

2b−f. Aryl enol ethers 2b−f were prepared following an adapted

procedure from literature.³³To a dry round-bottom ﬂask, Pd₂(dba)₃

(1.5 mol %) is added, followed by the addition of CsF (2.2 equiv),

aryl halide (1.0 equiv), P(t-Bu)₃(6.2 mol %), tri-butyl(1-

ethoxyvinyl)tin (1.0 equiv), and solvent (1 M). For aryl chlorides,

1,4-Dioxane was used as solvent, and for aryl bromides NMP was

used instead. The reaction was heated to 100 °C (when using aryl

chlorides) or kept at room temperature (aryl bromides). Upon

completion (monitored by TLC), the reaction mixture was diluted

with Et₂O and ﬁltered through a pad of silica-gel. The ﬁltrate was

concentrated under reduced pressure and puriﬁed by a long-plug

alumina column chromatography using 2.5% NEt₃/Hexanes as eluent

to aﬀord the corresponding aryl enol ether.

1-(1-Ethoxyvinyl)-4-methoxybenzene (2b). Prepared following

the general procedure using 4-chloroanisole (191 mg, 1.344 mmol),

Pd₂(dba)₃(14.4 mg, 1.5 mol %), CsF (349 mg, 2.297 mmol), P(t-

Bu)₃(13.1 mg, 0.083 mmol), stannane (0.37 mL, 1.05 mmol), and

1,4-dioxane (1 M, 1.3 mL). After workup and puriﬁcation on alumina

column chromatography (2.5% NEt₃/Hexanes, R_f= 0.67), desired

product 2b was obtained as a yellowish oil (203 mg, 85% yield).

Characterizations were consistent with previously reported liter-

ature.³³

1-(1-Ethoxyvinyl)-4-methylbenzene (2c). Prepared following the

general procedure using 4-chloroanisole (300 mg, 1.75 mmol),

Pd₂(dba)₃(24 mg, 1.5 mol %), CsF (560 mg, 3.69 mmol), P(t-Bu)₃

(0.03 mL, 0.108 mmol), stannane (0.59 mL, 1.75 mmol), and NMP

(1 M, 1.7 mL). After workup and puriﬁcation on alumina column

chromatography (2.5% NEt₃/Hexanes, R_f= 0.68), desired product 2c

was obtained as a clear oil (180 mg, 63% yield). ¹H NMR (300 MHz,

CDCl₃) δ 7.59−7.43 (m, 2H), 7.38−7.23 (m, 1H), 7.17 (s, 1H), 4.66

(d, J = 2.6 Hz, 1H), 4.22 (d, J = 2.6 Hz, 1H), 3.96 (q, J = 7.0 Hz, 2H),

2.41 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ

160.2, 137.6, 136.7, 129.1, 128.0, 126.1, 122.6, 82.1, 63.3, 21.5, 14.6.

IR (cm⁻¹) 2979 (w), 2925 (w), 1302 (m), 785 (s). HRMS (ESI) m/z

[M + H]⁺calcd for C₁₁H₁₄O 163.1117, found 163.1116.

1

(0.82 g, 77% yield). H NMR (500 MHz, CDCl₃) δ 7.34−7.22 (m,

3H), 7.13−7.07 (m, 2H), 7.00 (dd, J = 4.2, 1.6 Hz, 1H), 6.96 (dd, J =

2.6, 1.6 Hz, 1H), 6.23 (dd, J = 4.2, 2.6 Hz, 1H), 5.50 (s, 2H), 4.59 (q,

J = 8.3 Hz, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 172.8, 160.0,

137.8, 131.1, 128.70, 127.6, 127.6, 127.0, 122.7 (q, J_C−F= 277.5 Hz),

121.0, 108.9, 73.7, 60.4 (q, J_C−F= 37.0 Hz), 52.3. ¹⁹F NMR (471

MHz, CDCl₃) δ −73.8 (t, J = 8.2 Hz). IR (cm⁻¹) 2144 (s), 1726 (s),

1600 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₂F₃N₃O₃

352.0903, found 352.0904.

2,2,2-Triﬂuoroethyl 2-diazo-3-oxo-3-(1-tosyl-1H-pyrrol-2-yl)-

propanoate (1f). Prepared following the general procedure using β-

ketoester 16e (200 mg, 0.514 mmol), p-ABSA (142 mg, 0.591 mmol),

and NEt₃(0.08 mL, 0.616 mmol) in MeCN (2.6 mL). After workup

and puriﬁcation on silica gel column chromatography (15% EtOAc/

Hexanes, R_f= 0.14), diazo 1f was obtained as a beige solid (168 mg,

79% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J = 8.3 Hz, 2H),

7.52 (dd, J = 3.3, 1.6 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 6.75 (dd, J =

3.7, 1.6 Hz, 1H), 6.31 (t, J = 3.5 Hz, 1H), 4.57 (q, J = 8.3 Hz, 2H),

2.41 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 174.8, 159.0,

145.3, 135.8, 129.8, 129.7, 128.0, 127.8, 122.6 (q, J_C−F= 277.4 Hz),

121.3, 111.6, 65.9, 60.6 (q, J_C−F= 37.1 Hz), 21.7. ¹⁹F NMR (471

MHz, CDCl₃) δ −73.7 (t, J = 8.6 Hz). IR (cm⁻¹) 2141 (s), 1739 (s),

1630 (m). HRMS (ESI) m/z [M + H]⁺calcd for C₁₆H₁₂F₃N₃O₅S

416.0522, found 416.0523.

2,2,2-Triﬂuoroethyl 2-diazo-3-(4-ethyl-1-methyl-1H-pyrrol-2-yl)-

3-oxopropanoate (1g). Prepared following the general procedure

using β-ketoester 16f (460 mg, 1.66 mmol), p-ABSA (478 mg, 1.99

mmol), and NEt₃(0.28 mL, 1.99 mmol) in MeCN (8.3 mL). After

workup and puriﬁcation on silica gel column chromatography (10%

EtOAc/Hexanes, R_f= 0.11), diazo 1g was obtained as a brown oil

(486 mg, 96% yield). ¹H NMR (500 MHz, CDCl₃) δ 6.77 (d, J = 1.8

Hz, 1H), 6.69 (d, J = 1.8 Hz, 1H), 4.62 (q, J = 8.3 Hz, 2H), 3.84 (s,

3H), 2.46 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 172.2, 160.2, 129.9, 127.4, 126.1, 122.8

(q, J_C−F= 277.5 Hz), 119.5, 73.0, 60.4 (q, J_C−F= 37.0 Hz), 37.0, 19.6,

15.1. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.8. IR (cm⁻¹) 2128 (s),

(1-Ethoxyvinyl)benzene (2d). Prepared following the general

procedure using 4-chloroanisole (500 mg, 3.18 mmol), Pd₂(dba)₃

(44 mg, 1.5 mol %), CsF (1.06 g, 7.01 mmol), P(t-Bu)₃(39.9 mg,

0.197 mmol), stannane (1.07 mL, 3.185 mmol), and NMP (1 M, 3.1

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mL). After workup and puriﬁcation on alumina column chromatog-

raphy (2.5% NEt₃/Hexanes, R_f= 0.71), desired product 2d was

obtained as a yellow oil (409 mg, 86% yield). H NMR (500 MHz,

diazo 1c (100.0 mg, 0.308 mmol), Rh₂(esp)₂(1.2 mg, 0.05 mol %)

and methoxy propene (0.3 mL, 3.081 mmol). After puriﬁcation on

silica gel (5%−10% Et₂O/Hexanes, R_f= 0.57 in 30% Et₂O/Hexanes),

1

CDCl3) δ 7.72−7.60 (m, 2H), 7.41−7.30 (m, 3H), 4.67 (d, J = 2.6

Hz, 1H), 4.22 (d, J = 2.6 Hz, 1H), 3.95 (q, J = 7.0 Hz, 2H), 1.45 (t, J

= 6.9 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 160.0, 136.7,

128.4, 128.1, 125.4, 82.1, 63.3, 14.5. IR (cm⁻¹) 2979 (w), 2976 (w),

1285 (s), 767 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₀H₁₂O

149.0960, found 149.0959.

1-Chloro-4-(1-ethoxyvinyl)benzene (2e). Prepared following the

general procedure using 1-bromo-4-chlorobenzene (400 mg, 2.09

mmol), Pd₂(dba)₃(28.7 mg, 1.5 mol %), CsF (666 mg, 4.39 mmol),

P(t-Bu)₃(25.3 mg, 0.125 mmol), stannane (0.70 mL, 2.09 mmol),

and NMP (1 M, 2.0 mL). After workup and puriﬁcation on alumina

column chromatography (2.5% NEt₃/Hexanes, Rf = 0.52), desired

product 2e was obtained as a clear oil (172 mg, 45% yield). ¹H NMR

(300 MHz, CDCl₃) δ 7.64−7.50 (m, 2H), 7.35−7.27 (m, 2H), 4.62

(d, J = 2.8 Hz, 1H), 4.21 (d, J = 2.8 Hz, 1H), 3.91 (q, J = 7.0 Hz, 2H),

1.42 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 158.9,

135.1, 134.1, 128.2, 126.7, 126.7, 126.6, 63.4, 14.5. IR (cm⁻¹) 2981

(w), 2883 (w), 1491 (m), 1130 (s). HRMS (ESI) m/z [M + H]⁺

calcd for C₁₀H₁₁ClO 183.0571, found 183.0573.

2-Methylenetetrahydrofuran (2k). Prepared following a reported

literature procedure.³⁴To a dry round-bottom ﬂask, 2-

(chloromethyl)tetrahydrofuran was added (11 g, 91.226 mmol)

followed by ground KOH (10.4 g, 182.4 mmol). A reﬂux condenser

was attached and the reaction was heated to reﬂux for 3 h. After that, a

distillation head was added to the round-bottom ﬂask and the desired

product was collected while temperature was between 80 and 90 °C,

which aﬀorded the desired product as a clear liquid (4.6 g, 60% yield).

Characterizations were consistent with previously reported liter-

ature,³⁴copies of the NMR data are provided.

indole 1i was obtained as a light-brown oil (53.0 mg, 51% yield). H

NMR (500 MHz, CDCl₃) δ 10.05 (s, 1H), 6.93 (d, J = 3.2 Hz, 1H),

6.64 (d, J = 0.9 Hz, 1H), 6.51 (d, J = 3.2 Hz, 1H), 5.14 (s, 2H), 3.85

(s, 3H), 2.51 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.3,

160.0, 140.7, 133.9, 130.1, 124.1, 111.0, 101.2, 95.4, 94.6, 74.2, 38.5,

19.2. IR (cm⁻¹) 2978 (w), 1719 (m), 1593 (m), 1270 (s), 1090 (s).

HRMS (ESI) m/z [M + H]⁺calcd for C₁₃H₁₂Cl₃NO₃335.9955,

found 335.9956.

2,2,2-Triﬂuoroethyl 6-hydroxy-1,4-dimethyl-1H-indole-7-carbox-

ylate (3da). Prepared by following the general procedure using diazo

1d (100 mg, 0.363 mmol), Rh₂(esp)₂(1.4 mg, 0.05 mol %) and 2a

(0.1 mL, 1.09 mmol). After puriﬁcation on silica gel (5%−10% Et₂O/

Hexanes, R_f= 0.52 in 30% Et₂O/Hexanes), indole 3da was obtained

1

as an oﬀ-white solid (59.4 mg, 57% yield). H NMR (500 MHz,

CDCl₃) δ 10.28 (s, 1H), 6.92 (d, J = 3.2 Hz, 1H), 6.64 (d, J = 1.0 Hz,

1H), 6.52 (d, J = 3.2 Hz, 1H), 4.80 (q, J = 8.5 Hz, 2H), 3.76 (s, 3H),

2.51 (d, J = 0.9 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.9,

160.5, 141.0, 133.6, 130.1, 124.0, 123.0 (q, J = 277.4 Hz), 110.9,

101.4, 94.9, 60.7 (q, J_C−F= 37.1 Hz), 38.1 (d, J_C−F= 1.8 Hz), 19.2.

¹⁹F NMR (471 MHz, CDCl₃) δ −72.5 (t, J = 8.7 Hz). IR (cm⁻¹)

2962 (w), 1644 (s), 1152 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₃H₁₂F₃NO₃288.0842, found 288.0842.

1-Methyl 3-(2,2,2-triﬂuoroethyl) 2-(1-methyl-1H-pyrrol-2-yl)-

malonate (11b). Isolated from the same reaction mixture of 3da,

by following the general procedure using diazo 1d (100 mg, 0.363

mmol), Rh₂(esp)₂(1.4 mg, 0.05 mol %) and 2a (0.1 mL, 1.09 mmol).

After puriﬁcation on silica gel (10% EtOAc/Hexanes, R_f= 0.48),

diester 11b was obtained as a clear yellowish oil (27.3 mg, 27% yield).

¹H NMR (500 MHz, CDCl₃) δ 6.64 (dd, J = 2.8, 1.8 Hz, 1H), 6.24

General Procedure for the Synthesis of Indoles 3aa−3ih. To

a ﬂame-dried ﬂask equipped with a magnetic stir, Rh₂(esp)₂(0.5 mol

%) is added followed by dry DCM (0.2 M) and desired enol ether 2

(1.5 to 10 equiv) under constant nitrogen ﬂow. After attaching a

reﬂux condenser and bringing the reaction mixture to a boil, a 0.2 M

solution of diazo compound 1 in dry DCM is slowly added over 1 h

via syringe pump. After all the contents are added, let mixture reﬂux

for further 15 min or until all starting material has been consumed

(indicated by TLC analysis). Remove reaction mixture from heat and

add a scoop of silica gel 300−400 mesh and let it stir for an additional

0.5−2 h. The solvent is then removed under pressure and the crude

silica dispersion is puriﬁed on silica gel supported column

chromatography.

Methyl 6-hydroxy-1,4-dimethyl-1H-indole-7-carboxylate (3aa).

Prepared by following the general procedure using diazo 1a (206.6

mg, 0.997 mmol), Rh₂(esp)₂(3.7 mg, 0.05 mol %) and 2a (0.94 mL,

9.815 mmol). After puriﬁcation on silica gel (5%−10% Et₂O/hexanes,

R_f= 0.38 in 30% Et₂O/Hexanes), indole 3aa was obtained as a light-

brown oil (83.1 mg, 38% yield). ¹H NMR (500 MHz, CDCl₃) δ 10.52

(s, 1H), 6.90 (d, J = 3.2 Hz, 1H), 6.62 (d, J = 0.8 Hz, 1H), 6.48 (d, J =

3.2 Hz, 1H), 4.00 (s, 3H), 3.74 (s, 3H), 2.49 (s, 3H). ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 170.0, 159.6, 139.4, 134.0, 129.9, 123.8, 110.8,

101.0, 96.4, 51.6, 38.4, 19.2. IR (cm⁻¹) 3102 (w), 1651 (s). HRMS

(ESI) m/z [M + H]⁺calcd for C₁₂H₁₃NO₃220.0968, found 220.0970.

Ethyl 6-hydroxy-1,4-dimethyl-1H-indole-7-carboxylate (3ba).

Prepared by following the general procedure using diazo 1b (81.4

mg, 0.368 mmol), Rh₂(esp)₂(1.3 mg, 0.05 mol %) and 2a (0.35 mL,

3.67 mmol). After puriﬁcation on silica gel (5%−10% Et₂O/Hexanes,

R_f= 0.41 in 30% Et₂O/Hexanes), indole 3ba was obtained as a light-

brown oil (30.3 mg, 35% yield). ¹H NMR (500 MHz, CDCl₃) δ 10.60

(s, 1H), 6.90 (d, J = 3.2 Hz, 1H), 6.61 (d, J = 0.9 Hz, 1H), 6.48 (d, J =

3.2 Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 2.49 (d, J = 0.9

Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃)

δ 169.7, 159.7, 139.2, 134.0, 129.8, 123.8, 110.9, 101.0, 96.8, 61.2,

38.6, 19.1, 14.4. IR (cm⁻¹) 2981 (w), 1649 (s). HRMS (ESI) m/z [M

+ H]⁺calcd for C₁₃H₁₅NO₃234.1124, found 234.1127.

(dd, J = 3.8, 1.8 Hz, 1H), 6.12 (dd, J = 3.7, 2.7 Hz, 1H), 4.85 (s, 1H),

4.56 (qd, J = 8.3, 1.4 Hz, 2H), 3.80 (s, 3H), 3.59 (s, 3H). ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 167.12, 165.91, 124.14, 122.64 (q, J_C−F

=

277.2 Hz), 121.86, 110.33, 107.54, 61.18 (q, J_C−F= 37.2 Hz), 53.18,

49.80, 34.21. IR (cm⁻¹) 2958 (w), 1757 (s), 1740 (s), 1274 (s).

HRMS (ESI) m/z [M + H]⁺calcd for C₁₁H₁₂F₃NO₄208.0791, found

208.0789.

2,2,2-Triﬂuoroethyl 6-hydroxy-4-(4-methoxyphenyl)-1-methyl-

1H-indole-7-carboxylate (3db). Prepared by following the general

procedure using diazo 1d (69.9 mg, 0.254 mmol), Rh₂(esp)₂(1.0 mg,

0.05 mol %) and enol ether 2b (70 mg, 0.392 mmol). After

puriﬁcation on silica gel (10% Et₂O/Hexanes R_f= 0.26 in 30% Et₂O/

Hexanes) and preparative TLC (15% Et₂O/2% NEt₃/Hexanes −3%

AcOH/Hexanes), indole 3db was obtained as a beige solid (79.0 mg,

82% yield). ¹H NMR (500 MHz, CDCl₃) δ 10.20 (s, 1H), 7.63−7.56

(m, 2H), 7.06−6.99 (m, 2H), 6.96 (d, J = 3.3 Hz, 1H), 6.84 (s, 1H),

6.60 (d, J = 3.3 Hz, 1H), 4.82 (q, J = 8.5 Hz, 2H), 3.88 (s, 3H), 3.78

(s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.7, 160.2, 159.8,

143.3, 134.7, 131.8, 130.7, 130.0, 123.0 (q, J_C−F= 277.3 Hz), 122.4,

114.1, 109.8, 102.9, 95.4, 60.8 (q, J_C−F= 37.1 Hz), 55.4, 38.1. ¹⁹F

NMR (471 MHz, CDCl₃) δ −72.4 (t, J = 8.5 Hz). IR (cm⁻¹) 3010

(w), 1664(s), 1171 (s). HRMS (ESI) m/z [M + Na]⁺calcd for

C₁₉H₁₆O₄NF₃Na 402.0929, found 402.0924.

2,2,2-Triﬂuoroethyl 6-hydroxy-1-methyl-4-(p-tolyl)-1H-indole-7-

carboxylate (3dc). Prepared by following the general procedure using

diazo 1d (91.1 mg, 0.331 mmol), Rh₂(esp)₂(1.2 mg, 0.05 mol %) and

enol ether 2c (83.4 mg, 0.514 mmol). After puriﬁcation on silica gel

(10% Et₂O/hexanes, R_f= 0.44 in 30% Et₂O/Hexanes) and

preparative TLC (15% Et₂O/2% NEt₃/Hexanes −3% AcOH/

Hexanes), indole 3dc was obtained as a beige solid (94.2 mg, 78%

1

yield). H NMR (500 MHz, CDCl₃) δ 10.20 (s, 1H), 7.59−7.53 (m,

2H), 7.34−7.28 (m, 2H), 6.96 (d, J = 3.3 Hz, 1H), 6.88 (s, 1H), 6.61

(d, J = 3.3 Hz, 1H), 4.83 (q, J = 8.5 Hz, 2H), 3.79 (s, 3H), 2.45 (s,

3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.8, 160.2, 143.6, 138.2,

136.5, 134.7, 130.7, 129.3, 128.7, 123.0 (q, J = 277.3 Hz), 122.5,

110.0, 102.9, 95.7, 60.8 (q, J_C−F= 36.9 Hz), 38.1 (d, J_C−F= 2.0 Hz),

21.3. ¹⁹F NMR (471 MHz, CDCl₃) δ −72.4 (t, J = 8.7 Hz). IR (cm⁻¹)

2,2,2-Trichloroethyl 6-hydroxy-1,4-dimethyl-1H-indole-7-car-

boxylate (3ca). Prepared by following the general procedure using

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3023 (w), 1662 (s), 1154 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₉H₁₆F₃NO₃364.1155, found 364.1156.

Hexanes), indole 3dh was obtained as a white-crystalline solid (0.91 g,

67% yield).

2,2,2-Triﬂuoroethyl 6-hydroxy-5-(2-hydroxyethyl)-1-methyl-1H-

indole-7-carboxylate (3di). Prepared by following the general

procedure using diazo 1d (100.9 mg, 0.367 mmol), Rh₂(esp)₂(1.3

mg, 0.05 mol %) and 2i (0.08 mL, 1.10 mmol). After puriﬁcation on

silica gel (5−15% EtOAc/Hexanes, R_f= 0.20 in 30% EtOAc/

Hexanes), indole 3di was obtained as a green-tinted oil (61.9 mg, 51%

2,2,2-Triﬂuoroethyl 6-hydroxy-1-methyl-4-phenyl-1H-indole-7-

carboxylate (3dd). Prepared by following the general procedure

using diazo 1d (31.3 mg, 0.109 mmol), Rh₂(esp)₂(0.5 mg, 0.05 mol

%) and enol ether 2d (25 mg, 0.171 mmol). After initial puriﬁcation

on silica gel (5−10% Et₂O/Hexanes, R_f= 0.41 in 30% Et₂O/

Hexanes), the product was left on a vacuum pump overnight over

heat (oil bath, 40 °C) to eliminate residual acetophenone (formed

from the hydrolysis of the corresponding enol ether). Indole 3dd was

obtained as a brown solid (25.8 mg, 65% yield). ¹H NMR (500 MHz,

CDCl₃) δ 10.17 (s, 1H), 7.69−7.63 (m, 2H), 7.54−7.47 (m, 2H),

7.47−7.38 (m, 1H), 6.97 (d, J = 3.2 Hz, 1H), 6.88 (s, 1H), 6.59 (d, J

= 3.4 Hz, 1H), 4.83 (q, J = 8.5 Hz, 2H), 3.79 (s, 3H). ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 167.8, 160.1, 134.8, 134.3, 128.8, 128.7, 128.1,

127.9, 126.4, 123.0 (q, J_C−F= 277.5 Hz), 121.8, 118.7, 110.8, 97.1,

60.9 (q, J_C−F= 37.0 Hz), 38.1. ¹⁹F NMR (471 MHz, CDCl₃) δ −72.4

(t, J = 8.7 Hz). IR (cm⁻¹) 3053 (w), 1641 (s), 1164 (s). HRMS (ESI)

m/z [M + H]⁺calcd for C₁₈H₁₄F₃NO₃350.0998, found 350.1001.

2,2,2-Triﬂuoroethyl 4-(4-chlorophenyl)-6-hydroxy-1-methyl-1H-

indole-7-carboxylate (3de). Prepared by following the general

procedure using diazo 1d (100 mg, 0.365 mmol), Rh₂(esp)₂(1.4

mg, 0.05 mol %) and enol ether 2e (100 mg, 0.551 mmol). The crude

product was puriﬁed initially on silica gel (5−10% Et₂O/Hexanes, R_f

= 0.33 in 30% Et₂O/Hexanes), followed by preparative TLC (15%

Et₂O/2% NEt₃/Hexanes −3% AcOH/Hexanes) to aﬀorded 3de as a

pale-yellow solid (68.8 mg, 49% yield). ¹H NMR (500 MHz, CDCl₃)

δ 10.14 (s, 1H), 7.60−7.54 (m, 2H), 7.49−7.42 (m, 2H), 6.98 (d, J =

3.3 Hz, 1H), 6.84 (s, 1H), 6.53 (d, J = 3.2 Hz, 1H), 4.83 (q, J = 8.5

Hz, 2H), 3.79 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.7,

1

yield). H NMR (500 MHz, CDCl₃) δ 10.40 (s, 1H), 7.62 (s, 1H),

6.91 (d, J = 3.2 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 4.81 (q, J = 8.5 Hz,

2H), 3.91 (t, J = 6.2 Hz, 2H), 3.75 (s, 3H), 3.00 (t, J = 6.2 Hz, 2H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 168.2, 157.5, 133.1, 130.7,

130.2, 123.6, 123.0 (q, J_C−F= 277.2 Hz), 119.4, 102.6, 97.7, 63.1, 60.9

(q, J_C−F= 37.0 Hz), 37.7, 34.2. ¹⁹F NMR (471 MHz, CDCl₃) δ −72.5

(t, J = 8.6 Hz). IR (cm⁻¹) 3254 (br), 1739 (m), 1165 (s). HRMS

(ESI) m/z [M + H]⁺calcd for C₁₄H₁₄F₃NO₄318.0948, found

318.0947.

2,2,2-Triﬂuoroethyl 6-hydroxy-5-(3-hydroxypropyl)-1-methyl-

1H-indole-7-carboxylate (3dj). Prepared by following the general

procedure using diazo 1d (97.0 mg, 0.352 mmol), Rh₂(esp)₂(1.4 mg,

0.05 mol %) and 2j (0.1 mL, 1.08 mmol). After puriﬁcation on

preparative TLC silica gel (5−20% EtOAc/Hexanes, R_f= 0.19 in 30%

EtOAc/Hexanes), indole 3dj was obtained as an oﬀ-white solid (31.6

1

mg, 27% yield). H NMR (500 MHz, CDCl₃) δ 10.55 (s, 1H), 7.61

(s, 1H), 6.91 (d, J = 3.2 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 4.81 (q, J =

8.5 Hz, 2H), 3.75 (s, 3H), 3.64 (t, J = 6.2 Hz, 2H), 2.83 (t, J = 7.3 Hz,

2H), 1.95−1.85 (m, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 168.4,

157.9, 132.9, 130.7, 129.9, 123.6, 123.0 (q, J_C−F= 277.4 Hz), 122.1,

102.6, 96.9, 61.8, 60.9 (q, J_C−F= 37.0 Hz), 37.9, 33.0, 26.0. ¹⁹F NMR

(471 MHz, CDCl₃) δ −72.4 (t, J = 8.6 Hz). IR (cm⁻¹) 3346 (br),

2941 (m), 1165 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₅H₁₆F₃NO₄332.1104, found 332.1102.

160.0, 142.0, 137.8, 134.7, 134.3, 131.1, 130.0, 128.8, 123.0 (q, J_C−F

=

277.4 Hz), 122.3, 110.1, 102.5, 96.1, 60.9 (q, J_C−F= 37.0 Hz), 38.1.

2,2,2-Triﬂuoroethyl 6-hydroxy-4-(3-hydroxypropyl)-1-methyl-

1H-indole-7-carboxylate (3dk). Prepared by following the general

procedure using diazo 1d (99.9 mg, 0.363 mmol), Rh₂(esp)₂(1.2 mg,

0.05 mol %) and enol ether 2k (93 mg, 1.08 mmol). After puriﬁcation

on preparative TLC silica gel (5−20% EtOAc/Hexanes, R_f= 0.10 in

30% EtOAc/Hexanes), indole 3dk was obtained as an oﬀ-white solid

(57.3 mg, 47% yield). ¹H NMR (500 MHz, CDCl₃) δ 10.22 (s, 1H),

6.92 (d, J = 3.2 Hz, 1H), 6.66 (s, 1H), 6.55 (d, J = 3.2 Hz, 1H), 4.79

(q, J = 8.6 Hz, 2H), 3.75 (s, 3H), 3.70 (t, J = 6.3 Hz, 2H), 2.93 (dd, J

= 8.4, 6.9 Hz, 2H), 2.03−1.94 (m, 2H), 1.70 (s, 1H). ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 167.8, 160.4, 144.6, 134.0, 130.2, 123.5, 123.0

(q, J_C−F= 277.4 Hz), 109.9, 101.2, 95.2, 62.2, 60.7 (q, J_C−F= 36.9

Hz), 38.1 (d, J_C−F= 1.8 Hz), 32.7, 29.6. ¹⁹F NMR (471 MHz, CDCl₃)

δ −72.5 (t). IR (cm⁻¹) 3432 (br), 1733 (m), 1147 (s). HRMS (ESI)

m/z [M + H]⁺calcd for C₁₅H₁₆F₃NO₄332.1104, found 332.1104.

2,2,2-Triﬂuoroethyl 6-hydroxy-5-(2-hydroxyethyl)-1,4-dimethyl-

1H-indole-7-carboxylate (3dl). Prepared by following the general

procedure using diazo 1d (99.1 mg, 0.360 mmol), Rh₂(esp)₂(1.4 mg,

0.05 mol %) and 2l (0.1 mL, 1.08 mmol). After puriﬁcation on

preparative TLC silica gel (5−20% EtOAc/Hexanes, R_f= 0.20 in 30%

EtOAc/Hexanes), indole 3dl was obtained as an oﬀ-white solid (27.9

¹⁹F NMR (471 MHz, CDCl₃) δ −72.4 (t, J = 8.6 Hz). IR (cm⁻¹)

2952 (w), 1656 (s), 1101 (s). HRMS (ESI) m/z [M + Na]⁺calcd for

C₁₈H₁₃O₃NClF₃Na 406.0433, found 406.0428.

2,2,2-Triﬂuoroethyl 6-hydroxy-1,5-dimethyl-1H-indole-7-carbox-

ylate (3df). Prepared by following the general procedure using diazo

1d (98.8 mg, 0.359 mmol), Rh₂(esp)₂(1.4 mg, 0.05 mol %) and 2f

(0.12 mL, 1.09 mmol). After starting material was fully consumed,

silica was added to the reaction mixture and reﬂuxed for 1 h. After

puriﬁcation on silica gel (5%−10% Et₂O/hexanes, Rf = 0.55 in 30%

Et₂O/hexanes), indole 3df was obtained as an oﬀ-white solid (35.8

1

mg, 35% yield). H NMR (500 MHz, CDCl₃) δ 10.48 (s, 1H), 7.59

(t, J = 0.8 Hz, 1H), 6.89 (d, J = 3.1 Hz, 1H), 6.43 (d, J = 3.1 Hz, 1H),

4.81 (q, J = 8.5 Hz, 2H), 3.75 (s, 3H), 2.31 (s, 3H). ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 168.40, 158.63, 132.74, 130.34, 123.23, 122.97

(q, J = 277.3 Hz), 118.80, 102.44, 96.57, 60.80 (q, J_C−F= 37.0 Hz),

37.98 (d, J_C−F= 1.8 Hz), 29.73, 16.37. ¹⁹F NMR (471 MHz, CDCl₃)

δ −72.44 (t, J = 8.7 Hz). IR (cm⁻¹) 2925 (m), 1665 (s), 1144 (s).

HRMS (ESI) m/z [M + H]⁺calcd for C₁₃H₁₂F₃NO₃288.0842, found

288.0843.

2,2,2-Triﬂuoroethyl 6-hydroxy-1-methyl-1H-indole-7-carboxy-

late (3dh). Prepared by following the general procedure using diazo

1d (99.1 mg, 0.360 mmol), Rh₂(esp)₂(1.4 mg, 0.05 mol %) and ethyl

vinyl ether (0.35 mL, 3.633 mmol). After puriﬁcation on silica gel (5%

Et₂O/Hexanes, R_f= 0.38 in 30% Et₂O/Hexanes), indole 3dh was

1

mg, 23% yield). H NMR (500 MHz, CDCl₃) δ 10.71 (s, 1H), 6.94

(d, J = 3.3 Hz, 1H), 6.55 (d, J = 3.2 Hz, 1H), 4.82 (q, J = 8.5 Hz, 2H),

3.87 (t, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.11 (t, J = 6.6 Hz, 2H), 2.56 (s,

3H), 1.69 (s, 1H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 168.4, 158.6,

139.3, 132.3, 129. 9, 124.2, 123.0 (q, J_C−F= 277.4 Hz), 117.4, 101.5,

95.1, 62.7, 60.8 (q, J_C−F= 36.9 Hz), 38.0, 29.6, 16.4. ¹⁹F NMR (471

MHz, CDCl₃) δ −72.5 (t, J = 8.3 Hz). IR (cm⁻¹) 2966 (w), 1661 (s),

1158 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₁₆F₃NO₄

332.1104, found 332.1104.

1

obtained as a white-crystalline solid (66.4 mg, 67% yield). H NMR

(500 MHz, CDCl₃) δ 10.13 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 6.93 (d,

J = 3.2 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H),

4.82 (q, J = 8.5 Hz, 2H), 3.77 (s, 3H). ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 167.9, 160.0, 134.0, 130.7, 129.8, 124.0, 123.0 (q, J_C−F

=

277.4 Hz), 110.4, 103.1, 97.1, 60.8 (q, J_C−F= 37.0 Hz), 38.0. ¹⁹F

NMR (471 MHz, CDCl₃) δ −72.5 (t, J = 8.6 Hz). IR (cm⁻¹) 3044

(w), 1651 (s), 1155 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₂H₁₀NO₃F₃274.0685, found 274.0686.

2,2,2-Triﬂuoroethyl 1-benzyl-6-hydroxy-1H-indole-7-carboxylate

(3eh). Prepared by following the general procedure using diazo 1e

(116.7 mg, 0.332 mmol), Rh₂(esp)₂(1.3 mg, 0.05 mol %) and 2h

(0.28 mL, 2.847 mmol). After puriﬁcation on silica gel (5%−10%

Et₂O/Hexanes, R_f= 0.51 in 30% Et₂O/Hexanes), indole 3eh was

Larger Scale Synthesis of 3dh. Prepared by following the general

procedure using diazo 1d (1.5 g, 5.451 mmol), Rh₂(esp)₂(21.5 mg,

0.05 mol %) and ethyl vinyl ether (5.2 mL, 54.51 mmol). After

puriﬁcation on silica gel (5% Et₂O/Hexanes, R_f= 0.38 in 30% Et₂O/

1

obtained as a light amber oil (79.5 mg, 68% yield). H NMR (500

MHz, CDCl₃) δ 9.61 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.30−7.23 (m,

3H), 7.00 (d, J = 3.3 Hz, 1H), 6.87 (dd, J = 7.7, 1.8 Hz, 2H), 6.83 (d,

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J = 8.6 Hz, 1H), 6.58 (d, J = 3.2 Hz, 1H), 5.42 (s, 2H), 4.56 (q, J =

8.4 Hz, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.2, 159.0,

HRMS (ESI) m/z [M + H]⁺calcd for C₁₄H₁₆F₃NO₄320.1104, found

320.1101.

2,2,2-Triﬂuoroethyl 5-ethoxy-5-(4-methoxyphenyl)-2-(1-methyl-

1H-pyrrol-2-yl)-4,5-dihydrofuran-3-carboxylate (4db). Prepared by

following the general procedure using diazo 1d (70.3 mg, 0.255

mmol), Cu(hacac)₂(12 mg, 10 mol %), and 2b (133 mg, 0.746

mmol). After puriﬁcation on alumina column chromatography (10%

EtOAc/Hexanes, R_f= 0.12 in 30% Et₂O/Hexanes), desired product

137.1, 133.4, 130.5, 129.6, 128.7, 127.6, 126.4, 124.5, 122.8 (q, J_C−F

=

277.6 Hz), 110.9, 103.7, 98.3, 60.8 (q, J_C−F= 37.1 Hz), 53.5. ¹⁹F

NMR (471 MHz, CDCl₃) δ −72.55 (t, J = 8.6 Hz). IR (cm⁻¹) 3064

(w), 1604 (m), 1676 (s), 1165 (s). HRMS (ESI) m/z [M + H]⁺calcd

for C₁₈H₁₅F₃NO₃350.0998, found 350.0998.

2,2,2-Triﬂuoroethyl 3-ethyl-6-hydroxy-1-methyl-1H-indole-7-

carboxylate (3gh). Prepared by following the general procedure

using diazo 1g (239.9 mg, 0.791 mmol), Rh₂(esp)₂(3.1 mg, 0.05 mol

%) and 2h (0.8 mL, 8.244 mmol). After puriﬁcation on silica gel

(5%−10% Et₂O/Hexanes, R_f= 0.52 in 30% Et₂O/Hexanes), indole

1

4db was obtained as colorless oil (99.3 mg, 91% yield). H NMR

(500 MHz, CDCl₃) δ 8.04−7.91 (m, 2H), 7.21 (dd, J = 4.3, 1.7 Hz,

1H), 7.03−6.91 (m, 2H), 6.89 (t, J = 2.1 Hz, 1H), 6.19 (dd, J = 4.2,

2.4 Hz, 1H), 4.93 (dd, J = 7.9, 6.0 Hz, 1H), 4.50 (qd, J = 8.4, 0.8 Hz,

2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.75 (dd, J = 18.0, 7.9 Hz, 1H), 3.60

(dd, J = 18.0, 6.0 Hz, 1H), 3.48 (q, J = 7.0 Hz, 1H), 1.30−1.18 (m,

3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 195.1, 183.1, 168.6, 163.9,

132.8, 130.5, 129.3, 129.1, 123.8, 121.4, 113.8, 108.9, 65.9, 61.0 (d,

J_C−F= 36.8 Hz), 55.5, 49.5, 37.9, 37.8, 15.3. ¹⁹F NMR (471 MHz,

CDCl₃) δ −73.6 (t, J = 8.4 Hz). IR (cm⁻¹) 2962 (w), 1757 (m), 1651

(s), 1600 (s), 1165 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₂₁H₂₂F₃NO₅426.1522, found 426.1522.

2,2,2-Triﬂuoroethyl 5-ethoxy-2-(1-methyl-1H-pyrrol-2-yl)-5-(p-

tolyl)-4,5-dihydrofuran-3-carboxylate (4dc). Prepared by following

the general procedure using diazo 1d (66.1 mg, 0.240 mmol),

Cu(hacac)₂(11.3 mg, 10 mol %), and 2c (118 mg, 0.727 mmol).

After puriﬁcation on alumina column chromatography (10% EtOAc/

Hexanes, R_f= 0.21 in 30% Et₂O/Hexanes), desired product 4dc was

obtained as colorless oil (62.0 mg, 63%). ¹H NMR (500 MHz,

CDCl₃) δ 7.46−7.33 (m, 2H), 7.24 (dd, J = 4.0, 1.8 Hz, 1H), 7.23−

7.14 (m, 2H), 6.79−6.72 (m, 1H), 6.23 (dd, J = 4.0, 2.5 Hz, 1H), 4.47

(q, J = 8.5 Hz, 2H), 3.84 (s, 3H), 3.61 (dq, J = 9.3, 7.0 Hz, 1H), 3.44

(d, J = 16.2 Hz, 1H), 3.38 (dq, J = 9.3, 7.0 Hz, 1H), 3.20 (d, J = 16.3

Hz, 1H), 2.37 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 162.6, 158.3, 138.3, 137.6, 129.3, 127.6, 125.5, 123.3

1

3gh was obtained as a dark amber oil (108.2 mg, 45% yield). H

NMR (500 MHz, CDCl₃) δ 10.12 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H),

6.78 (d, J = 8.6 Hz, 1H), 6.70 (s, 1H), 4.80 (q, J = 8.5 Hz, 2H), 3.70

(s, 3H), 2.71 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H). ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 168.0, 160.0, 134.6, 127.8, 127.3, 123.5,

123.0 (q, J_C−F= 277.4 Hz), 119.1, 109.4, 96.9, 60.8 (q, J_C−F= 37.0

Hz), 37.7, 17.7, 14.4. ¹⁹F NMR (471 MHz, CDCl₃) δ −72.5 (t, J = 8.2

Hz). IR (cm⁻¹) 2963 (m), 1672 (s), 1170 (s). HRMS (ESI) m/z [M

+ H]⁺calcd for C₁₄H₁₄F₃NO₃302.0998, found 302.0996.

2,2,2-Triﬂuoroethyl 6-hydroxy-1-methyl-3-phenyl-1H-indole-7-

carboxylate (3hh). Prepared by following the general procedure

using diazo 1h (248.2 mg, 0.706 mmol), Rh₂(esp)₂(2.8 mg, 0.05 mol

%) and 2h (0.68 mL, 7.117 mmol). After puriﬁcation on silica gel

(5%−10% Et₂O/Hexanes, R_f= 0.33 in 30% Et₂O/Hexanes), indole

1

3gh was obtained as a white solid (167 mg, 68% yield). H NMR

(500 MHz, CDCl₃) δ 10.11 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.59−

7.52 (m, 2H), 7.45 (dd, J = 8.3, 7.2 Hz, 2H), 7.36−7.29 (m, 1H), 7.07

(s, 1H), 6.86 (d, J = 8.7 Hz, 1H), 4.84 (q, J = 8.5 Hz, 2H), 3.80 (s,

3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.8, 160.2, 134.8, 134.3,

128.9, 128.7, 128.1, 127.9, 126.5, 123.0 (q, J_C−F= 277.5 Hz), 121.9,

118.8, 110.8, 97.2, 60.9 (q, J_C−F= 37.0 Hz), 38.1. ¹⁹F NMR (471

MHz, CDCl₃) δ −72.4 (t, J = 8.4 Hz). IR (cm⁻¹) 1672 (m), 1162 (s),

1098 (s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₈H₁₄F₃NO₃

350.0998, found 350.0998.

(d, J_C−F= 277.0 Hz), 121.7, 118.4, 111.6, 108.4, 98.9, 59.7 (q, J_C−F

=

36.3 Hz), 59.5, 44.6, 37.0, 21.2, 15.3. ¹⁹F NMR (471 MHz, CDCl₃) δ

−73.6 (t, J = 8.2 Hz). IR (cm⁻¹) 2966 (w), 1752 (m), 1651 (s), 1159

(s). HRMS (ESI) m/z [M + H]⁺calcd for C₂₁H₂₂F₃NO₄410.1573,

found 410.1572.

Mixture of 2,2,2-Triﬂuoroethyl 5-hydroxy-1-methyl-1H-indole-4-

carboxylate (3ih) and 2,2,2-Triﬂuoroethyl 5-hydroxy-2-methyl-2H-

isoindole-4-carboxylate (12ih). Prepared by following the general

procedure using diazo 1i (100.0 mg, 0.308 mmol), Rh₂(esp)₂(1.4 mg,

0.05 mol %) and 2h (0.3 mL, 3.081 mmol). After puriﬁcation on silica

gel (5%−10% Et₂O/Hexanes, R_f= 0.35 in 30% Et₂O/Hexanes), a

mixture of isomers 3ih and 12ih was obtained (10.2 mg, 10% yield).

2,2,2-Triﬂuoroethyl 5-ethoxy-2-(1-methyl-1H-pyrrol-2-yl)-5-phe-

nyl-4,5-dihydrofuran-3-carboxylate (4dd). Prepared by following

the general procedure using diazo 1d (83.0 mg, 0.301 mmol),

Cu(hacac)₂(14.0 mg, 10 mol %), and 2d (200 mg, 1.09 mmol). After

puriﬁcation on alumina column chromatography (10% EtOAc/

Hexanes, R_f= 0.18 in 30% Et₂O/Hexanes), desired product 4dd

1

Ratio of 3.9:1. H NMR (500 MHz, CDCl₃) δ 10.74 (s, 1H), 10.12

1

was obtained as clear oil (75.8 mg, 64% yield). H NMR (500 MHz,

(s, 0.26H), 7.70 (dd, J = 8.5, 1.8 Hz, 0.27H), 7.49 (d, J = 8.9 Hz, 1H),

7.14 (s, 1H), 6.95−6.91 (m, 0.26H), 6.88 (dd, J = 8.9, 1.8 Hz, 1H),

6.82−6.77 (m, 1.28H), 6.49 (s, 0.26H), 4.97−4.49 (m, 2.69H), 3.80

(s, 3H), 3.76 (s, 0.81H).

General Procedure for the Synthesis of DHF Acetals (4). To

a ﬂame-dried ﬂask equipped with a magnetic stir, Cu(hacac)₂(10 mol

%) is added followed by dry DCM (0.1 M), enol ether 2 (3 to 10

equiv) and diazo 1 (1 equiv). A reﬂux condenser is attached and the

reaction mixture is reﬂuxed overnight (16 h). The solvent is then

removed under reduced pressure and the residue is puriﬁed by

column chromatography in silica gel or alumina.

CDCl₃) δ 7.55−7.48 (m, 2H), 7.45−7.34 (m, 3H), 7.30−7.21 (m,

1H), 6.78 (t, J = 2.2 Hz, 1H), 6.24 (dd, J = 4.0, 2.6 Hz, 1H), 4.48 (q, J

= 8.6 Hz, 2H), 3.85 (s, 3H), 3.64 (dq, J = 9.4, 7.0 Hz, 1H), 3.47 (d, J

= 16.3 Hz, 1H), 3.39 (dq, J = 9.4, 7.1 Hz, 1H), 3.23 (d, J = 16.3 Hz,

1H), 1.19 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

162.6, 158.3, 140.6, 128.6, 128.5, 127.7, 125.6, 123.3 (q, J_C−F= 277.4

Hz), 121.7, 118.4, 111.4, 108.5, 98.9, 59.8 (q, J_C−F= 35.0 Hz), 59.6,

44.6, 37.0, 15.3. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.6 (t, J = 8.6 Hz).

IR (cm⁻¹) 2981 (w), 1760 (m), 1162 (s), 1097 (s). HRMS (ESI) m/

z [M + H]⁺calcd for C₂₀H₂₀F₃NO₄396.1417, found 396.1417.

2,2,2-Triﬂuoroethyl 5-(4-chlorophenyl)-5-ethoxy-2-(1-methyl-

1H-pyrrol-2-yl)-4,5-dihydrofuran-3-carboxylate (4de). Prepared by

following the general procedure using diazo 1d (98.1 mg, 0.253

mmol), Cu(hacac)₂(17.3 mg, 10 mol %), and 2e (200 mg, 1.090

mmol). After puriﬁcation on alumina column chromatography (10%

Et₂O/Hexanes, R_f= 0.21 in 30% Et₂O/Hexanes), desired product 4de

2,2,2-Triﬂuoroethyl 5-methoxy-5-methyl-2-(1-methyl-1H-pyrrol-

2-yl)-4,5-dihydrofuran-3-carboxylate (4da). Prepared by following

the general procedure using diazo 1d (100.3 mg, 0.364 mmol),

Cu(hacac)₂(17.3 mg, 10 mol %), and 2a (131 mg, 1.817 mmol).

After puriﬁcation on alumina column chromatography (10% Et₂O/

Hexanes, R_f= 0.43 in 30% Et₂O/Hexanes), desired product 4da was

1

was obtained as colorless oil (42.7 mg, 29% yield). H NMR (500

1

obtained as colorless oil (92.6 mg, 80% yield). H NMR (500 MHz,

MHz, CDCl₃) δ 7.47−7.41 (m, 2H), 7.39−7.32 (m, 2H), 7.22 (dd, J

= 4.0, 1.8 Hz, 1H), 6.78 (t, J = 2.2 Hz, 1H), 6.23 (dd, J = 4.0, 2.6 Hz,

1H), 4.47 (q, J = 8.6 Hz, 2H), 3.82 (s, 3H), 3.62 (dq, J = 9.3, 7.1 Hz,

1H), 3.45 (d, J = 16.4 Hz, 1H), 3.36 (dq, J = 9.3, 7.1 Hz, 1H), 3.18

(d, J = 16.3 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 162.4, 158.1, 139.2, 134.5, 128.8, 127.8, 127.1, 123.3

CDCl₃) δ 7.13 (td, J = 3.8, 1.7 Hz, 1H), 6.73 (t, J = 2.2 Hz, 1H),

6.21−6.09 (m, 1H), 4.48 (ddd, J = 8.5, 5.8, 2.8 Hz, 2H), 3.76 (s, 3H),

3.37 (s, 3H), 3.25−2.94 (m, 2H), 1.66 (s, 3H). ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 162.6, 158.6, 127.6, 123.3 (q, J_C−F= 277.0 Hz),

121.4, 118.2, 111.0, 108.3, 98.2, 59.6 (q, J_C−F= 36.1 Hz), 50.32,

39.80, 36.79, 24.93. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.6 (t, J = 8.7

Hz). IR (cm⁻¹) 2993 (w), 1715 (m), 1601 (m), 1100 (s), 1045 (s).

(q, J_C−F= 277.4 Hz), 121.5, 118.5, 110.8, 108.5, 98.8, 59.7 (q, J_C−F

=

36.4 Hz), 59.6, 44.4, 37.0, 15.3. ¹⁹F NMR (471 MHz, CDCl₃) δ

10100

https://doi.org/10.1021/acs.joc.1c00826

J. Org. Chem. 2021, 86, 10088−10104

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

−73.6 (t, J = 8.7 Hz). IR (cm⁻¹) 2986 (w), 1717 (m), 1600 (m),

1165 (s), 1091 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₂₀H₁₉ClF₃NO₄430.1027, found 430.1023.

Hexanes, R_f= 0.37 in 30% Et₂O/Hexanes), desired product 4dj

was obtained as colorless oil (28.0 mg, 23% yield); Diastereomeric

1

ratio (1.3:1). H NMR (500 MHz, CDCl₃) δ 7.08 (dd, J = 4.0, 1.7

2,2,2-Triﬂuoroethyl 5-ethoxy-4-methyl-2-(1-methyl-1H-pyrrol-2-

yl)-4,5-dihydrofuran-3-carboxylate (4df). Prepared by following the

general procedure using diazo 1d (69.8 mg, 0.253 mmol), Cu(hacac)₂

(13 mg, 10 mol %), and 2f (0.14 mL, 1.09 mmol). After puriﬁcation

on silica-gel column chromatography (10% Et₂O/hexanes, R_f= 0.60

in 30% Et₂O/Hexanes), desired product 4df was obtained as colorless

oil (24.9 mg, 30% yield). Diastereomeric ratio (2.8:1). ¹H NMR (500

MHz, CDCl₃) δ 7.06 (dd, J = 4.0, 1.7 Hz, 2.84H), 6.93 (dd, J = 4.0,

1.8 Hz, 1H), 6.72 (ddd, J = 7.8, 2.6, 1.8 Hz, 3.90H), 6.17 (ddd, J =

10.1, 4.0, 2.6 Hz, 4H), 5.69 (d, J = 7.3 Hz, 1H), 5.26 (d, J = 1.8 Hz,

3H), 4.65−4.47 (m, 4.40H), 4.45−4.28 (m, 4.22H), 4.01−3.85 (m,

4.54H), 3.73 (s, 8.61H), 3.72−3.63 (m, 7.21H), 3.26 (ddd, J = 8.8,

7.3, 3.6 Hz, 1H), 3.11 (ddd, J = 8.5, 3.9, 1.8 Hz, 3H), 1.82−1.71 (m,

4H), 1.61−1.49 (m, 4.53H), 1.27 (t, J = 7.1 Hz, 15.28H), 1.02−0.84

(m, 12.80H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 163.0, 162. 7,

158.7, 158.7, 127.4, 127.1, 123.4 (q, J_C−F= 277.4 Hz), 121.9, 121.8,

118.1, 117.2, 109.0, 108.3, 108.2, 107.7, 103.4, 103.0, 65.9, 64.5, 59.6

(q, J_C−F= 36.2 Hz), 59.5 (q, J_C−F= 36.1 Hz), 50.1, 46.7, 36.5, 36.3,

24.5, 20.0, 15.1, 12.2, 10.4. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.5 (t, J

= 8.7 Hz), −73.56 (t, J = 8.6 Hz). IR (cm⁻¹) 2965 (w), 1712 (m),

1603 (m), 1158 (s), 1076 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₅H₁₈F₃NO₄334.1260, found 334.1261.

Hz, 1H), 6.97 (dd, J = 3.9, 1.7 Hz, 1.36H), 6.78−6.68 (m, 2.32H),

6.17 (ddd, J = 9.3, 4.0, 2.6 Hz, 2.37H), 5.65 (d, J = 7.4 Hz, 1.37H),

5.18 (d, J = 1.8 Hz, 1H), 4.55 (tq, J = 12.6, 8.6 Hz, 2.61H), 4.40 (ddq,

J = 15.2, 12.7, 8.6 Hz, 2.50H), 3.91 (ddq, J = 12.2, 9.4, 7.1 Hz,

2.78H), 3.74 (s, 3H), 3.71 (s, 3.87H), 3.66 (dddd, J = 9.3, 7.0, 4.8, 2.3

Hz, 2.45H), 3.39 (p, J = 7.1 Hz, 1.47H), 3.19 (qd, J = 7.1, 1.7 Hz,

1H), 1.31−1.22 (m, 16.59H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

162.9, 162.6, 158.5, 158.4, 127.4, 127.2, 124.1 (q, J_C−F= 349.7 Hz),

123.4 (q, J_C−F= 277.4 Hz), 121.9, 121.8, 118.1, 117.5, 110.9, 108.3,

108.2, 107.7, 104.8, 65.9, 64.6, 59.6 (q, J_C−F= 36.2 Hz), 59.5 (q, J_C−F

= 36.2 Hz), 43.8, 40.5, 36.6, 36.4, 30.33, 17.9, 15.1, 15.0, 12.2. ¹⁹F

NMR (471 MHz, CDCl₃) δ −73.5 (t, J = 8.7 Hz), −73.56 (t, J = 8.5

Hz). IR (cm⁻¹) 2979 (w), 1720 (m), 1654 (m), 1165 (s), 1084 (s).

HRMS (ESI) m/z [M + H]⁺calcd for C₁₅H₁₆F₃NO₄332.1104;

desired peak was not found.

2,2,2-Triﬂuoroethyl 2-(1-methyl-1H-pyrrol-2-yl)-1,6-dioxaspiro-

[4.4]non-2-ene-3-carboxylate (4dk). Prepared by following the

general procedure using diazo 1d (97.0 mg, 0.352 mmol), Cu(hacac)₂

(18 mg, 10 mol %), and enol ether 2k (92 mg, 1.09 mmol). After

puriﬁcation on silica-gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.53 in 30% Et₂O/Hexanes), desired product 4dk

1

was obtained as colorless oil (91.6 mg, 78% yield). H NMR (500

2,2,2-Triﬂuoroethyl 5-ethoxy-2-(1-methyl-1H-pyrrol-2-yl)-4,5-di-

hydrofuran-3-carboxylate (4dh). Prepared by following the general

procedure using diazo 1d (140.7 mg, 0.511 mmol), Cu(hacac)₂(14.4

mg, 10 mol %), and enol ether 2h (0.52 mL, 5.450 mmol). After

puriﬁcation on silica-gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.55 in 30% Et₂O/Hexanes) desired product 4dh

MHz, CDCl₃) δ 7.18 (dd, J = 4.0, 1.7 Hz, 1H), 6.72 (t, J = 2.2 Hz,

1H), 6.17 (dd, J = 4.0, 2.5 Hz, 1H), 4.60 (dq, J = 12.7, 8.6 Hz, 1H),

4.42 (dq, J = 12.7, 8.5 Hz, 1H), 4.14−4.03 (m, 1H), 3.85−3.76 (m,

1H), 3.74 (s, 3H), 3.57 (dd, J = 8.6, 1.1 Hz, 1H), 2.31−2.19 (m, 1H),

2.08 (dd, J = 12.8, 5.0 Hz, 1H), 1.70 (s, 3H). ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 162.5, 160.4, 128.0, 123.4 (q, J_C−F= 277.3 Hz),

121.0, 118.7, 118.6, 108.3, 100.0, 67.7, 59.6 (q, J_C−F= 36.2 Hz), 50.9,

37.1, 33.2, 23.9. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.6 (t, J = 8.7 Hz).

IR (cm⁻¹) 2928 (m), 1758 (m), 1649 (s), 1161 (s). HRMS (ESI) m/

z [M + H]⁺calcd for C₁₅H₁₆F₃NO₄332.1104, found 332.1107.

2,2,2-Triﬂuoroethyl 6a-methyl-2-(1-methyl-1H-pyrrol-2-yl)-

3a,4,5,6a-tetrahydrofuro[2,3-b]furan-3-carboxylate (4dl). Prepared

by following the general procedure using diazo 1d (80.0 mg, 0.290

mmol), Cu(hacac)₂(14.4 mg, 10 mol %), and enol ether 2l (0.08 mL,

0.872 mmol). After puriﬁcation on silica gel column chromatography

(10% Et₂O/Hexanes, R_f= 0.33 in 30% Et₂O/Hexanes), desired

1

was obtained as colorless oil (86.5 mg, 53% yield). H NMR (500

MHz, CDCl₃) δ 7.11 (dd, J = 4.0, 1.7 Hz, 1H), 6.72 (t, J = 2.2 Hz,

1H), 6.18 (dd, J = 4.0, 2.5 Hz, 1H), 5.66 (dd, J = 7.4, 2.8 Hz, 1H),

4.48 (q, J = 8.6 Hz, 2H), 3.91 (dq, J = 9.5, 7.0 Hz, 1H), 3.74 (s, 3H),

3.67 (dq, J = 9.5, 7.0 Hz, 1H), 3.24 (dd, J = 16.3, 7.5 Hz, 1H), 2.96

(dd, J = 16.4, 2.8 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 162.6, 158.5, 127.4, 123.3 (q, J_C−F= 277.5 Hz),

121.6, 118.1, 108.3, 104.8, 98.3, 64.6, 59.6 (q, J_C−F= 36.1 Hz), 37.0,

36.7, 15.1. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.6 (t, J = 8.7 Hz). IR

(cm⁻¹) 2940 (w), 1709 (m), 1604 (s), 1074 (s). HRMS (ESI) m/z

[M + H]⁺calcd for C₁₄H₁₆F₃NO₄320.1104, found 320.1105.

Larger Scale Synthesis of 4dh. Prepared by following the general

procedure using diazo 1d (355.3 mg, 1.291 mmol), Cu(hacac)₂(62.7

mg, 10 mol %), and enol ether 2h (1.22 mL, 12.718 mmol). After

puriﬁcation on silica-gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.55 in 30% Et₂O/Hexanes) desired product 4dh

was obtained as colorless oil (213.7 mg, 52% yield).

1

product 4dl was obtained as colorless oil (11.2 mg, 12% yield). H

NMR (500 MHz, CDCl₃) δ 7.18 (dd, J = 4.0, 1.8 Hz, 1H), 6.72 (t, J =

2.2 Hz, 1H), 6.17 (dd, J = 4.0, 2.6 Hz, 1H), 4.60 (dq, J = 12.7, 8.7 Hz,

1H), 4.42 (dq, J = 12.7, 8.6 Hz, 1H), 4.09 (ddd, J = 8.6, 7.6, 0.8 Hz,

1H), 3.81 (ddd, J = 12.1, 8.9, 5.0 Hz, 1H), 3.75 (s, 3H), 3.58 (dd, J =

8.5, 1.1 Hz, 1H), 2.43−2.18 (m, 1H), 2.08 (ddt, J = 12.8, 5.1, 1.0 Hz,

1H), 1.70 (s, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 162.5, 160.3,

127.9, 123.4 (q, J_C−F= 277.2 Hz), 121.0, 118.7, 108.3, 100.1, 67.7,

59.6 (q, J_C−F= 36.2 Hz), 51.0, 37.0, 33.2, 30.3, 23.9. ¹⁹F NMR (471

MHz, CDCl₃) δ −73.6 (t, J = 8.6 Hz). IR (cm⁻¹) 2986 (w), 1713

(m), 1600 (m), 1159 (s), 1104 (s). HRMS (ESI) m/z [M + H]⁺

calcd for C₁₅H₁₆F₃NO₄332.1104, found 332.1105.

2,2,2-Triﬂuoroethyl 2-(1-methyl-1H-pyrrol-2-yl)-3a,4,5,6a-

tetrahydrofuro[2,3-b]furan-3-carboxylate (4di). Prepared by follow-

ing the general procedure using diazo 1d (100.2 mg, 0.364 mmol),

Cu(hacac)₂(17.6 mg, 10 mol %), and 2i (0.08 mL, 1.09 mmol). After

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= in 30% Et₂O/Hexanes), desired product 4di was

1

2,2,2-Triﬂuoroethyl 2-(1-benzyl-1H-pyrrol-2-yl)-5-ethoxy-4,5-di-

hydrofuran-3-carboxylate (4eh). Prepared by following the general

procedure using diazo 1e (101.0 mg, 0.299 mmol), Cu(hacac)₂(14.1

mg, 10 mol %), and enol ether 2h (0.28 mL, 2.965 mmol). After

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.63 in 30% Et₂O/Hexanes), desired product 4eh

obtained as colorless oil (55.3 mg, 48% yield). H NMR (500 MHz,

CDCl₃) δ 7.19 (dd, J = 4.0, 1.8 Hz, 1H), 6.73 (t, J = 2.1 Hz, 1H), 6.25

(d, J = 6.3 Hz, 1H), 6.18 (dd, J = 4.0, 2.5 Hz, 1H), 4.62 (dq, J = 12.7,

8.6 Hz, 1H), 4.42 (dq, J = 12.7, 8.5 Hz, 1H), 4.11 (ddd, J = 8.7, 7.0,

1.6 Hz, 1H), 3.96 (ddd, J = 7.7, 6.2, 1.5 Hz, 1H), 3.82−3.76 (m, 1H),

3.75 (s, 3H), 2.25−2.09 (m, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃)

δ 162.4, 160.9, 128.1, 123.4 (d, J_C−F= 277.5 Hz), 120.9, 118.9, 109.5,

108.4, 99.7, 67.0, 59.6 (q, J_C−F= 36.2 Hz), 47.4, 37.1, 32.3. ¹⁹F NMR

(471 MHz, CDCl₃) δ −73.6 (t, J = 8.7 Hz). IR (cm⁻¹) 2966 (w),

1720 (m), 1651 (m), 1152 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₄H₁₄F₃NO₄318.0947, found 318.0949.

2,2,2-Triﬂuoroethyl-2-(1-methyl-1H-pyrrol-2-yl)-3a,5,6,7a-tetra-

hydro-4H-furo[2,3-b]pyran-3carboxylate (4dj). Prepared by follow-

ing the general procedure using diazo 1d (101.2 mg, 0.367 mmol),

Cu(hacac)₂(18 mg, 10 mol %), and 2j (0.10 mL, 1.09 mmol). After

puriﬁcation on silica gel column chromatography (10% Et₂O/

1

was obtained as colorless oil (38.0 mg, 32% yield). H NMR (500

MHz, CDCl₃) δ 7.35−7.22 (m, 3H), 7.13 (dd, J = 3.9, 1.8 Hz, 1H),

7.09−6.97 (m, 2H), 6.81 (dd, J = 2.7, 1.8 Hz, 1H), 6.28 (dd, J = 4.0,

2.6 Hz, 1H), 5.56 (dd, J = 7.4, 3.0 Hz, 1H), 5.40−5.16 (m, 2H), 4.48

(q, J = 8.6 Hz, 2H), 3.74−3.58 (m, 1H), 3.55−3.42 (m, 1H), 3.18

(dd, J = 16.3, 7.5 Hz, 1H), 2.92 (dd, J = 16.3, 2.9 Hz, 1H), 1.15 (t, J =

7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 162.6, 158.3,

138.5, 128.6, 127.3, 126.7, 126.4, 123.3 (q, J_C−F= 277.5 Hz), 121.7,

118.0, 109.0, 104.8, 99.1, 64.4, 59.7 (q, J_C−F= 36.1 Hz), 52.5, 36.9,

14.9. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.6 (t, J = 8.7 Hz). IR (cm⁻¹)

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2978 (w), 1716 (m), 1603 (m), 1159 (s), 1074 (s). HRMS (ESI) m/

z [M + H]⁺calcd for C₂₀H₂₀F₃NO₄396.1417, found 396.1419.

2,2,2-Triﬂuoroethyl 5-ethoxy-2-(1-tosyl-1H-pyrrol-2-yl)-4,5-dihy-

drofuran-3-carboxylate (4fh). Prepared by following the general

procedure using diazo 1f (61.2 mg, 0.147 mmol), Cu(hacac)₂(6.9

mg, 10 mol %), and enol ether 2h (0.14 mL, 1.445 mmol). After

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.39 in 30% Et₂O/Hexanes), desired product 4fh

59.5 (q, J = 36.1 Hz), 37.4, 36.6, 15.2. ¹⁹F NMR (471 MHz, CDCl₃) δ

−73.7 (t, J = 8.7 Hz). IR (cm⁻¹) 2955(w), 1717 (m), 1651 (s), 1158

(s). HRMS (ESI) m/z [M + H]⁺calcd for C₁₄H₁₆F₃NO₄320.1104,

found 320.1105.

2,2,2-Triﬂuoroethyl 7-hydroxy-1,4-dimethyl-1H-indole-6-carbox-

ylate (5da). A solution of DHF acetal 4da (71.9 mg, 0.225 mmol) in

toluene (2.2 mL, 0.1 M) was added to a ﬂame-dried round-bottom

ﬂask containing Sc(OTf)₃(10.8 mg, 0.021 mmol). The reaction

mixture was then heated to 70 °C until completion monitored by

TLC. Upon completion, the reaction mixture is washed with water (2

× 5 mL), extracted with Et₂O (3 × 5 mL), dried with MgSO₄, ﬁltered

through a Celite plug and concentrated under reduced pressure. The

crude oil was then puriﬁed by column chromatography (10% Et₂O/

Hexanes, R_f= 0.57 in 30% Et₂O/hexanes) to aﬀord 5da as white-

crystalline solid (49.3 mg, 77% yield). ¹H NMR (500 MHz, CDCl₃) δ

11.05 (s, 1H), 7.24 (q, J = 1.0 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 6.41

(d, J = 2.9 Hz, 1H), 4.72 (q, J = 8.4 Hz, 2H), 4.14 (s, 3H), 2.42 (s,

3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 169.9, 151.2, 136.0, 133.0,

124.1, 123.1 (q, J = 277.4 Hz), 121.3, 118.5, 102.0, 100.7, 60.4 (q, J =

36.7 Hz), 36.6, 17.9. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.5 (t, J = 8.3

Hz). IR (cm⁻¹) 2956 (w), 1661 (m), 1098 (s). HRMS (ESI) m/z [M

+ H]⁺calcd for C₁₃H₁₂F₃NO₃288.0842, found 288.0836.

2,2,2-Triﬂuoroethyl 5-methyl-2-(1-methyl-1H-pyrrol-2-yl)furan-

3-carboxylate (13da). A solution of DHF acetal 4da (77.0 mg,

0.241 mmol) in toluene (2.4 mL, 0.1 M) was added to a ﬂame-dried

round-bottom ﬂask containing Ga(OTf)₃(12.1 mg, 0.023 mmol).

The reaction mixture was then heated to 70 °C until completion

monitored by TLC. Upon completion, the reaction mixture is washed

with water (2 × 5 mL), extracted with Et₂O (3 × 5 mL), dried with

MgSO₄, ﬁltered through a Celite plug and concentrated under

reduced pressure. The crude oil was then puriﬁed by column

chromatography (10% Et₂O/Hexanes, R_f= 0.51 in 30% Et₂O/

Hexanes) to aﬀord 13da as white crystalline solid (29.8 mg, 43%

yield). ¹H NMR (500 MHz, CDCl₃) δ 6.83 (dd, J = 3.8, 1.8 Hz, 1H),

6.74 (dd, J = 2.6, 1.7 Hz, 1H), 6.44 (q, J = 1.1 Hz, 1H), 6.20 (dd, J =

3.8, 2.6 Hz, 1H), 4.57 (q, J = 8.5 Hz, 2H), 3.71 (s, 3H), 2.34 (d, J =

1.1 Hz, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 161.3, 151.4,

151.0, 125.9, 123.2 (d, J_C−F= 277.5 Hz), 122.0, 114.6, 112.4, 108.1,

107.5, 60.0 (q, J_C−F= 36.8 Hz), 35.9, 13.4. ¹⁹F NMR (471 MHz,

CDCl₃) δ −73.6 (t, J = 8.7 Hz). IR (cm⁻¹) 2930 (w), 1733 (m), 1165

(s), 1097 (s). HRMS (ESI) m/z [M + H]⁺calcd for

C₁₃H₁₂F₃NO₃288.0842, found 288.0839.

1

was obtained as colorless oil (43.8 mg, 65% yield). H NMR (500

MHz, CDCl₃) δ 7.76−7.63 (m, 2H), 7.40 (dd, J = 3.4, 1.7 Hz, 1H),

7.24 (dd, J = 8.6, 0.7 Hz, 1H), 6.56 (dd, J = 3.5, 1.7 Hz, 1H), 6.32 (t, J

= 3.4 Hz, 1H), 5.70 (dd, J = 7.6, 3.3 Hz, 1H), 4.34−4.07 (m, 1H),

3.84 (dq, J = 9.3, 7.1 Hz, 1H), 3.56 (dq, J = 9.5, 7.1 Hz, 1H), 3.22

(dd, J = 16.5, 7.5 Hz, 1H), 2.92 (dd, J = 16.5, 3.4 Hz, 1H), 2.38 (s,

3H), 1.24 (t, J = 7.1 Hz, 2H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

162.0, 156.5, 144.9, 136.0, 129.5, 127.3, 125.4, 122.9 (q, J_C−F= 277.0

Hz), 122.4, 120.1, 112.2, 105.6, 105.5, 64.7, 59.7 (q, J_C−F= 36.6 Hz),

36.8, 21.6, 14.9. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.7 (t, J = 8.7 Hz).

IR (cm⁻¹) 2982 (w), 1709 (m), 1373 (m), 1152 (s), 1079 (s). HRMS

(ESI) m/z [M + H]⁺calcd for C₂₀H₂₀F₃NO₆S 460.1036, found

460.1041.

2,2,2-Triﬂuoroethyl 5-ethoxy-2-(4-ethyl-1-methyl-1H-pyrrol-2-

yl)-4,5-dihydrofuran-3-carboxylate (4gh). Prepared by following

the general procedure using diazo 1g (107.4 mg, 0.354 mmol),

Cu(hacac)₂(16.0 mg, 10 mol %), and enol ether 2h (0.32 mL, 3.298

mmol). After puriﬁcation on silica gel column chromatography (10%

Et₂O/Hexanes, R_f= 0.15 in 30% Et₂O/Hexanes), desired product 4gh

1

was obtained as colorless oil (33.4 mg, 33% yield). H NMR (500

MHz, CDCl₃) δ 7.00 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 2.1 Hz, 1H),

5.64 (dd, J = 7.4, 2.8 Hz, 1H), 4.48 (qd, J = 8.6, 2.8 Hz, 2H), 3.94−

3.84 (m, 1H), 3.69 (s, 4H), 3.67−3.60 (m, 1H), 3.27−3.19 (m, 1H),

3.01−2.90 (m, 1H), 2.57−2.38 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H),

1.18 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 162.7,

158.6, 126.1, 125.2, 123.4 (q, J_C−F= 277.5 Hz), 121.2, 117.59, 104.6,

97.5, 64.5, 59.6 (q, J_C−F= 36.1 Hz), 37.0, 36.6, 19.8, 15.2, 15.0. ¹⁹F

NMR (471 MHz, CDCl₃) δ −73.6 (t, J = 8.2 Hz). IR (cm⁻¹) 2968

(w), 1756 (m), 1645 (s), 1154 (s). HRMS (ESI) m/z [M + H]⁺calcd

for C₁₆H₂₀NO₄F₃348.1417, found 348.1417.

2,2,2-Triﬂuoroethyl 5-ethoxy-2-(1-methyl-4-phenyl-1H-pyrrol-2-

yl)-4,5-dihydrofuran-3-carboxylate (4hh). Prepared by following the

general procedure using diazo 1h (112 mg, 0.318 mmol), Cu(hacac)₂

(15 mg, 10 mol %), and enol ether 2h (0.3 mL, 3.131 mmol). After

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.18 in 30% Et₂O/Hexanes), desired product 4hh

ASSOCIATED CONTENT

■

1

was obtained as colorless oil (75.3 mg, 68% yield). H NMR (500

sı

* Supporting Information

MHz, CDCl₃) δ 7.58−7.51 (m, 2H), 7.45 (t, J = 2.1 Hz, 1H), 7.37

(td, J = 7.9, 2.0 Hz, 2H), 7.26−7.18 (m, 1H), 7.05 (t, J = 2.1 Hz, 1H),

5.70 (dt, J = 7.5, 2.5 Hz, 1H), 4.64−4.45 (m, 1H), 3.95 (dqd, J = 9.3,

7.1, 2.1 Hz, 1H), 3.80 (s, 3H), 3.71 (dqd, J = 9.3, 7.0, 2.1 Hz, 1H),

3.30 (ddd, J = 16.3, 7.5, 2.0 Hz, 1H), 3.02 (dt, J = 16.3, 2.4 Hz, 1H),

1.31 (t, J = 7.0, 2.0 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00826.

Optimization tables, ¹H NMR spectra for known

compounds, and NMR (¹H, ¹³C, and ¹⁹F, where

applicable) spectra for all new compounds (PDF)

162.6, 158.0, 134.8, 128.6, 125.8, 125.2, 124.6, 124.3, 123.4 (q, J_C−F

=

277.5 Hz), 122.6, 115.3, 104.9, 98.8, 64.7, 59.7 (q, J_C−F= 36.3 Hz),

37.1, 36.9, 15.1. ¹⁹F NMR (471 MHz, CDCl₃) δ −73.6 (t, J = 8.7 Hz).

IR (cm⁻¹) 2976 (w), 2866 (w), 1761 (w), 1654 (m), 1114 (s).

HRMS (ESI) m/z [M + H]⁺calcd for C₂₀H₂₀F₃NO₄396.1417, found

396.1418.

Accession Codes

CCDC 2075486 and 2075655 contain the supplementary

crystallographic data for this paper. These data can be obtained

free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

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

Cambridge Crystallographic Data Centre, 12 Union Road,

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

2,2,2-Triﬂuoroethyl 5-ethoxy-2-(1-methyl-1H-pyrrol-3-yl)-4,5-di-

hydrofuran-3-carboxylate (4ih). Prepared by following the general

procedure using diazo 1i (98.9 mg, 0.359 mmol), Cu(hacac)₂(18 mg,

10 mol %), and enol ether 2h (0.08 mL, 0.872 mmol). After

puriﬁcation on silica gel column chromatography (10% Et₂O/

Hexanes, R_f= 0.37 in 30% Et₂O/Hexanes), desired product 4ih

AUTHOR INFORMATION

■

1

was obtained as colorless oil (87.9 mg, 77% yield). H NMR (500

Corresponding Author

MHz, CDCl₃) δ 7.92 (t, J = 2.0 Hz, 1H), 6.75 (dd, J = 2.9, 1.7 Hz,

1H), 6.64−6.50 (m, 1H), 5.62 (dd, J = 7.3, 2.6 Hz, 1H), 4.51 (qd, J =

8.7, 1.8 Hz, 2H), 3.93 (dq, J = 9.6, 7.1 Hz, 1H), 3.70−3.60 (m, 4H),

3.22 (dd, J = 16.0, 7.3 Hz, 1H), 2.94 (dd, J = 16.0, 2.6 Hz, 1H), 1.25

(t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 163.5,

162.7, 127.8, 123.5 (q, J = 277.5 Hz), 122.0, 113.4, 104.1, 94.4, 64.1,

Stefan France − School of Chemistry and Biochemistry and

Petit Institute for Bioengineering and Bioscience, Georgia

Institute of Technology, Atlanta, Georgia 30332, United

States; orcid.org/0000-0001-5998-6167;

Email: stefan.france@chemistry.gatech.edu

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(b) Wenkert, E.; Ananthanarayan, T. P.; Ferreira, V. F.; Hoffmann, M.

G.; Kim, H. S. Simple syntheses of.beta.-furoic esters and.gamma.-

pyrone. J. Org. Chem. 1990, 55, 4975−4976. (c) Lund, E. A.;

Kennedy, I. A.; Fallis, A. G. Dihydrofurans from L-diazoketones due

to facile ring opening cyclization of donor acceptor cyclopropane

intermediates. Can. J. Chem. 1996, 74, 2401−2412. (d) Xia, L.; Lee, Y.

R. Efficient One-Pot Synthesis of Multi-Substituted Dihydrofurans by

Ruthenium(II)-Catalyzed [3 + 2] Cycloaddition of Cyclic or Acyclic

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355, 2361−2374.

(6) Aponte-Guzman, J.; Phun, L. H.; Cavitt, M. A.; Taylor, J. E.;

Davy, J. C.; France, S. France, S. Catalytic, Cascade Ring-Opening

Benzannulations of 2,3-Dihydrofuran O,O- and N,O-Acetals. Chem. -

Eur. J. 2016, 22, 10405−10409.

(7) McLarney, B. D.; Cavitt, M. A.; Donnell, T. D.; Musaev, D. G.;

France, S. Rh(II)-Catalyzed,-C(sp²)-H Alkylation of Enol Ethers,

Enamides, and Enecarbamates with)-Diazo Dicarbonyl. Chem. - Eur. J.

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Dicarbonyls as Stable Donor-Acceptor-Acceptor Cyclopropanes.

Synthesis 2015, 47, 3020−3026.

Authors

Gabriel Guerra Faura − School of Chemistry and

Biochemistry, Georgia Institute of Technology, Atlanta,

Georgia 30332, United States

Tena Nguyen − School of Biological Sciences, Georgia Institute

of Technology, Atlanta, Georgia 30332, United States

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00826

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors gratefully acknowledge ﬁnancial and analytical

support from both Georgia Tech. T.N. speciﬁcally acknowl-

edges Georgia Tech for a President’s Undergraduate Research

Award. Single-crystal diﬀraction experiments were performed

at the Georgia Tech SCXRD facility directed by Dr. John

Bacsa.

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Article Doi

Catalyst-Controlled Chemodivergent Reactions of 2-Pyrrolyl-α-diazo-β-ketoesters and Enol Ethers: Synthesis of 1,2-Dihydrofuran Acetals and Highly Substituted Indoles

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