Dehydrative Nazarov-type electrocyclizations of alkenyl (hetero)aryl carbinols via calcium catalysis: Access to cyclopenta[b]thiophenes and indene derivatives

Accepted Manuscript

Dehydrative Nazarov-type electrocyclizations of alkenyl (hetero)aryl carbinols via

calcium catalysis: Access to cyclopenta[b]thiophenes and indene derivatives

M. Cynthia Martin, Matthew J. Sandridge, Corey W. Williams, Zola A. Francis, Stefan

France

PII:

S0040-4020(17)30278-8

10.1016/j.tet.2017.03.041

TET 28547

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 12 October 2016

Revised Date: 25 February 2017

Accepted Date: 14 March 2017

Please cite this article as: Martin MC, Sandridge MJ, Williams CW, Francis ZA, France S, Dehydrative

Nazarov-type electrocyclizations of alkenyl (hetero)aryl carbinols via calcium catalysis: Access to

cyclopenta[b]thiophenes and indene derivatives, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.041.

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Dehydrative Nazarov-type

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Electrocyclizations of Alkenyl (Hetero)aryl

Carbinols via Calcium Catalysis: Access to

Cyclopenta[b]thiophenes and Indenes

M. Cynthia Martin^≠, Matthew J. Sandridge^≠, Corey W. Williams, Zola A. Francis, and Stefan France

School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

1

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Dehydrative Nazarov-type Electrocyclizations of Alkenyl (Hetero)aryl Carbinols via

Calcium Catalysis: Access to Cyclopenta[b]thiophenes and Indene Derivatives

M. Cynthia Martin^a,≠, Matthew J. Sandridge^a,≠, Corey W. Williams^a, Zola A. Francis^a, and Stefan France^a,b

^aSchool of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States

^bPetit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States

^≠These authors contributed equally to this work.

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

A general approach to the understudied cyclopenta[b]thiophenes is reported. The products were

directly generated from calcium-catalyzed, dehydrative, Nazarov-type electrocyclizations of

alkenyl thienyl carbinols in up to 82% yield. The thienyl carbinols demonstrated good tolerance

for aryl and heteroaryl substituents on the alkene. Aryl carbinols were also amenable to the

calcium-catalyzed conditions and afforded indene derivatives in good yields. In most cases, the

reaction was selective for the thermodynamic alkene isomer; however, substituent effects played

a role in determining product outcomes. Mechanistically, the calcium catalyst initiated formation

of alkenyl (hetero)aryl carbinyl cations which subsequently underwent a 4π electrocyclization

and elimination that is reminiscent of the Nazarov reaction. This transformation is significant for

two main reasons: 1) it represents one of the only examples of catalysis for dehydrative,

Nazarov-type electrocyclizations in which thiophene was compatible; 2) it allowed for the direct

Available online

Keywords:

Keyword_1

Keyword_2

Keyword_3

Keyword_4

Keyword_5

formation

of

cyclopenta[b]thiophenes

while

circumventing

the

need

for

cyclopenta[b]thiophenones as precursors.

.

———

Corresponding author. Tel.: +1-404-385-1796; fax: +1-404-894-7452; e-mail: Stefan.france@chemistry.gatech. edu

2

Tetrahedron

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1. Introduction

Over the past several years, we have developed a variety of

Lewis acid-catalyzed protocols toward (hetero)aryl-fused five-,

six-, and seven-membered rings using Nazarov-like reactions.^11,12

We have further sought to establish the catalytic, formal homo-

Nazarov cyclization as a viable template for diversity-oriented

synthesis.¹³Toward that end, we recently reported a calcium-

catalyzed, dehydrative, ring-opening cyclization of (hetero)aryl

cyclopropyl carbinols to form (hetero)aryl-fused cyclohexa-1,3-

dienes in up to 97% yield (Scheme 2a).¹⁴

Cyclopenta[b]thiophenes represent a unique class of organic

molecules that are interesting isosteres of indenes (Figure 1).¹

They exist in equilibrium as mixtures of the major 4H- and 6H-

isomers and the transient 5H-isomer (isosteric with isoindene).²

The parent compounds have been primarily used as precursors to

thiophene-fused cyclopentadienyl metal complexes,³whereas, the

5,6-dihydro derivatives have been employed by materials

scientists⁴(for use in conjugated polymers, liquid crystalline

media, and organic field-effect transistors) and medicinal

chemists⁵(as anti-cancer, anti-bacterial, anti-viral, and anti-

fungal agents).

a) previous work

Ca(NTf₂)₂

(1 or 5 mol %)

cat. n-Bu₄NPF₆

(1 or 5 mol %)

R⁴

R⁴OH

CO₂Me

R³

CO₂Me

R¹

1,2-DCE

4 Å MS

84 ˚C

R³

R¹R²

R²

S

6H-cyclopenta[b]thiophene

4H-cyclopenta[b]thiophene

up to 97% yield

R³

indene

b) this work

OH

R³

CO₂Me

R²

CO₂Me

R²

S

cat. Ca(NTf₂)₂

cat. n-Bu₄NPF₆

S

R¹

S

isoindene

R¹

5H-cyclopenta[b]thiophene

or

Figure 1. Isomeric Forms of Cyclopenta[b]thiophene

OH

R⁵

R⁴

R⁵

R⁴

CO₂Me

R¹

CO₂Me

R¹

Scheme 2. Calcium-Catalyzed, Dehydrative Cyclizations of

Cyclopropyl or Alkenyl (Hetero)aryl Carbinols

Despite these rich applications, there exists a lack of general

and robust methods for the preparation of functionalized

cyclopenta[b]thiophenes. Only a handful of syntheses have been

reported to date, the majority of which start with derivatization of

a thiophene-fused cyclopentanone. For example, the most robust

method reported by Lee^3b,3cinvolves the following three-step

Inspired by this outcome, we sought to identify catalytic

conditions that were amenable for the general cyclization of

alkenyl (hetero)aryl carbinols that specifically allow for the

formation of cyclopenta[b]thiophenes. It is important to note that

thiophenes have been somewhat problematic in dehydrative,

Nazarov-type cyclizations. For instance, in 2011, Singh¹⁵

published a Nazarov-type electrocyclization initiated by a

Sc(OTf)₃-catalyzed ionization of alkenyl (hetero)aryl carbinols to

form [6,6,5,6] and [6,6,5,5] heterocyclic ring systems. While the

reaction worked for arenes and indole, the thienyl- or

benzothienyl-substituted substrates rapidly decomposed or

afforded uncharacterized products. Yamamoto¹⁶was later able to

accomplish cyclization with a benzothienyl substrate, although

the corresponding thiophene provided no discernible product.

With an eye towards overcoming these issues, we disclose an

effective, calcium-catalyzed, dehydrative, Nazarov-type 4π-

electrocyclization of alkenyl thienyl (or aryl) carbinols to form

cyclopenta[b]thiophenes and/or indenes (Scheme 2b).

sequence: 1)

a

one-pot acid-promoted Friedel-Crafts

acylation/Nazarov cyclization of thiophene with acrylic acid

derivatives to form thiophene-fused cyclopentanones; 2)

nucleophilic attack at the carbonyl to form the corresponding

alcohols; and 3) acid-promoted dehydration to form the

cyclopenta[b]thiophenes. Unfortunately, this approach affords

limited scope (only methyl or phenyl substituents) and low

functional group tolerance due to the use of strong acids.

Therefore, the design of milder and more generalized approaches

to cyclopenta[b]thiophenes represents a worthwhile synthetic

endeavor, particularly one that circumvents the formation and

derivatization of a thiophene-fused cyclopentanone.

Renewed interest in the Nazarov cyclization⁶has led to the

breakthrough of many new methods for the initiation of the 4π-

electrocyclization, central to the formation of functionalized

cyclopentyl rings. One relevant example is the direct ionization

of the C-O bond of divinyl alcohols and (hetero)aryl-substituted

allyl alcohols (Scheme 1).^7,8Explored by several groups, this

dehydrative, Nazarov-type approach⁹provides straightforward

routes to cyclopentadienes, indenes, and heteroaryl-fused

cyclopentadienes.¹⁰

2. Results and Discussion

2.1. Mechanism

In 2010, Batey and co-workers extensively investigated

substituent effects on the selectivity of the cyclizations of 1,3-

diarylallylic cations I, derived from the diallyl alcohols using

stoichiometric BF₃•OEt₂(Scheme 3).¹⁷The reactions worked

when R²= Me or CO₂Et, but failed when R²= H. Depending on

the choice of substituents, mixtures of indenes 5-II (from

cyclization onto the ring bearing R¹) and 5-IV (from cyclization

onto the ring bearing R³) were most commonly obtained. Also

observed in select cases was indene 5-I, the product resulting

from alkene isomerization. The authors argue that alkene

isomerization is most likely due to base-catalyzed process given

the increased acidity of the dibenzylic C-1 proton. A 1,5-

hydrogen shift mechanism was ruled out since the reactions were

performed at room temperature.

Nazarov cyclization:

Z

O

+ Z

4

π

electrocyclization

Dehydrative, Nazarov-type electrocyclization:

OH

+ Z

- ZOH

4

π

electrocyclization

Scheme 1. Nazarov Cyclization vs. Dehydrative, Nazarov-

type Electrocyclization

3

Given the work by Panda,¹⁵we were surprised to find that

BF₃•OEt₂

(100 mol %)

OH

ACCEPTED MANUSCRIPT

R²

R¹

Sc(OTf)₃afforded poor yield (11%) of 5aa-I and 5aa-II as a

1.2:1 mixture (entry 2). Similar isomeric ratios, but with higher

yield (43%), were obtained with TfOH and BF₃•OEt₂(entries 3

and 4). Employing stoichiometric BF₃•OEt₂(Batey’s conditions

for indene synthesis) gave 5aa-I as the only product with only a

slight improvement in yield (entry 5). No desired product was

formed with Yb(OTf)₃, La(OTf)₃, Dy(OTf)₃, or Ni(OTf)₂after 24

h (entries 6-9), and trace amounts of product were detected with

Al(OTf)₃at 20 h (entry 10). In contrast, Ga(OTf)₃and In(OTf)₃,

each gave 5aa-I as the only isomer in 47% and 51% yield,

respectively (entries 11 and 12). Bi(OTf)₃gave an increased yield

of 57%, but with 5aa-I and 5aa-II as a 2:1 mixture (entry 13).

R¹

- OH

R³

I

for R²= CO₂Et

R¹

R³

CO₂Et

R³

CO₂Et

R³

CO₂Et

R¹

CO₂Et

R¹

5-I

5-II

5-III

5-IV

Scheme 3. Batey’s Indene Synthesis Using 1,3-Diaryl Allylic

Alcohols

Regarding substituent effects, electron-withdrawing aryl

substituents disfavored cyclization and only the more electron-

rich ring engaged in ring-formation. In the case of electron-

donating groups, the selectivity was dependent upon the nature

and position of the substituent. The authors then argue that,

unlike in electrophilic aromatic substitution, no correlation of

selectivity with calculated electron densities was observed, which

is consistent with a cationic 4π conrotatory electrocyclization

mechanism.

Table 1. Selection of Acid Catalyst^a

2.2. Synthesis of Carbinols 4

Guided by the work of Batey¹⁷, we outlined a straightforward

approach to allyl (hetero)aryl-substituted carbinols 4 using a two-

step sequence starting from (hetero)aryl β-ketoesters 1 (Scheme

4). Knoevenagel condensation of 1 with aldehydes 2 afforded

alkylidene β-ketoesters 3 in up to >99% yield. Subsequent Luche

reduction¹⁸of 3 provided the desired carbinols 4 in up to 66%

yield.¹⁹With the emphasis on accessing cyclopenta[b]thiophenes,

most of the prepared substrates contained the 3-thienyl moiety,

using 4aa as the model compound selected for optimization. 3-

Benzothienyl, 2-benzofuranyl-, 2-naphthyl-, and aryl-substituted

allyl alcohols were also prepared in order to explore reaction

scope once optimized conditions were identified. When 3ak

(bearing an i-Pr substituent) was subjected to Luche conditions,

the desired product 4ak proved inseparable from the fully

reduced saturated alcohol.

^aReaction was performed with carbinol 4aa and acid catalyst

(10 mol %) in CH₂Cl₂(0.1 M) at 23 ˚C.

^bIsolated yield after column chromatography.

^cRatio determined by ¹H NMR of the product mixture.

^dPerformed using 100 mol % BF₃•OEt₂.

^eNo desired product formed.

^fNot determined.

^gReaction performed at reflux (~40 ˚C).

O

2

R

H

CeCl₃•7H₂O

NaBH₄

piperidine

HOAc

O

OH

O

CO₂Me

R

CO₂Me

R

CO₂Me

MeOH

C₆H₆

reflux

1

3

4

up to >99% yield

up to 66% yield

OH

4aa R = H

4ah R = 2-thienyl

4ai R = β-styryl

4aj R = 2-Np

Inspired by our previous work on the ring-opening

cyclizations of cyclopropyl carbinols,¹⁴the Niggemann

combination²⁰of Ca(NTf₂)₂and additive n-Bu₄NPF₆(10 mol %

each) was employed. This combination has been shown to be

effective in catalyzing the Nazarov cyclization and the reactions

of carbinols.²¹Under these conditions, 5aa-I was obtained as the

only product in 55% yield (entry 14). In an attempt to improve

the yields, the reaction was performed at reflux (~40 ˚C).

Unexpectedly, although the yield improved to 60%, a 2.6:1 ratio

was formed with 5aa-II as the major isomer (entry 15).

CO₂Me

R

CO₂Me

4ab R = 4-OMe

4ac R = 4-Me

4ad R = 4-Br

4ae R = 4-CF₃

4af R = 2-OMe

4ag R = 3-OMe

S

4ak R = i-Pr

R

OH

CO₂Me

Ph

CO₂Me

CO₂Me MeO

Ph

CO₂Me

O

2-Np

S

Ph

R

Ph

4ba

4ca

4da

4ea R = H

4fa R = OMe

Scheme 4. Synthesis of Carbinols 4

Next, the effects of time at reflux on both the yield and

product ratios were examined (Figure 2). Reactions were set up

using the conditions above and then quenched at 30 min, 1 h,

1.75 h, and 2.5 h. Both 30 min and 1 h gave ~1:3 mixtures with

5aa-II as the major component in 63% and 60% yield,

respectively. Conversely, 5aa-I was obtained in 65% yield as the

only observable product at 1.75 h. At 2.5 h, some isomerization

2.3. Reaction Optimization

3-Thienyl carbinol 4aa was subjected to an initial screening of

acid catalysts at 10 mol % loading in CH₂Cl₂(Table 1). As

expected, no reaction occurs in the absence of catalyst (entry 1).

4

Tetrahedron

is observed as the 5aa-I to 5aa-II ratio erodes to 5.5:1 along

necessary for the 2.5 mol % reaction to reach completion;

ACCEPTED MANUSCRIPT

with a minor drop in yield (58%), possibly due to product

degradation. Thus, to minimize product degradation while

optimizing for yield and product ratios, 1.75 h was targeted as the

ideal reaction time.

product degradation was observed as a result.

In hopes of replacing CH₂Cl₂, a screening of solvents was then

performed to determine the optimum solvent. The reaction

temperature was maintained at 40 ˚C to minimize product

degradation. Both 1,2-dichloroethane and toluene afforded 5aa-I

selectively, albeit with reduced yields (entries 4 and 5). In

contrast, CH₃CN proved incompatible, as no desired products

were detected (entry 6). This is most likely due to catalyst

deactivation through solvent coordination. With THF, 5aa-I was

formed in 57% yield as a 6.0:1 isomeric mixture (entry 7).

Benzene proved to be the best solvent for the reaction as 5aa-I

was selectively generated in 67% yield (entry 8). After further

exploration of the reaction concentration, an improved yield

(70%) was obtained using a more dilute reaction mixture (0.05

M, entry 9). Ultimately, these conditions (10 mol % Ca(NTf₂)₂,

10 mol % n-Bu₄NPF₆, benzene, 0.05 M, 40 ˚C, 1.75 h) were

chosen as the optimized conditions for the remainder of the

study.

1:3.0

1:2.6

1.0:0

5.5:1

70

60

50

40

30

20

10

0

5aa-II

5aa-I

0.5 h

1 h

1.75 h

2.5 h

Figure 2. Effect of Reaction Time at Reflux on Product Ratios

2.4. Examination of Substrate Scope

Table 2. Final Reaction Optimization^a

With working conditions, the effect of changing the alkenyl

substituent of the carbinol was examined (Table 3). First, the

existence of any stereoelectronic effects imparted by substituents

on a phenyl ring was probed using carbinols 4ab-4ae. When the

more electron-rich 4-methoxy phenyl group was employed (as in

4ab), 5ab-I was obtained in 82% yield (entry 2). 4ac, bearing a

weakly-activating 4-tolyl substituent, cyclized to form 5ac-I in

66% yield as a 6.5:1 isomeric mixture (entry 3). Products 5ad-I

and 5ae-I were respectively obtained in 69% and 67% yield for

substrates bearing a weakly electron-withdrawing 4-bromophenyl

group (4ad) and a strongly withdrawing 4-trifluoromethyl phenyl

substituent (4ae) (entries 4 and 5). These combined outcomes

suggest that due to a slight inductive effect, higher yields are

anticipated with strong donor groups on the phenyl rings.

To further probe substituent effects on the cyclization, the 2-

and 3-methoxyphenyl substrates 4af and 4ag were subjected to

the reaction conditions. In the case of 4af, the cyclization

occurred with higher yield (75%) to furnish 5af-II as an 8:1

isomeric mixture with 5af-I (entry 6). This result was unexpected

given the previous substrates and thermodynamic preference of

5af-I vs. 5af-II. The most plausible explanation is that steric

influences (imparted by the methoxy group) slow the rate of

alkene isomerization. By comparison, 4ag did not produce either

5af-I or 5af-II. Instead, 5af-IV, where cyclization has occurred

onto the aryl group, was isolated in 79% yield (entry 7). This

result is consistent with Batey’s work¹⁶in which the location of

substituent has a direct influence on product outcome, with

cyclization onto the more nucleophilic aromatic ring as the major

product.²²Ring closure is therefore expected to occur

preferentially on the phenyl ring para to the methoxy group- a

more nucleophilic position than C-2 on the thiophene ring.

^aReaction was performed with carbinol 4aa and Ca(NTf₂)₂(10

mol %), n-Bu₄NPF₆(10 mol %) in indicated solvent (0.1 M) at 40

˚C.

^bIsolated yield after column chromatography.

^cRatio determined by ¹H NMR of the product mixture.

^d5 mol % each of Ca(NTf₂)₂and n-Bu₄NPF₆were used.

^e2.5 mol % each of Ca(NTf₂)₂and n-Bu₄NPF₆were used.

^fNo desired product formed.

^gYield in parentheses represents the product yield when

performed at reflux (~80 ˚C).

^hReaction performed at a concentration of 0.05 M.

In the final phase of optimization, we examined the effects of

(1) reducing the catalyst loading, (2) changing the solvent, and

(3) changing the reaction concentration (Table 2). The reaction in

CH₂Cl₂at 40 ˚C with 10 mol % catalyst loading was used as the

benchmark (65% yield of only 5aa-I, entry 1). First, the catalyst

loadings for Ca(NTf₂)₂and n-Bu₄NPF₆were each reduced to 5

and then 2.5 mol %. With each decrease in catalyst loading, a

change in isomeric ratio is observed. At 5 mol % loading, a 4.5:1

isomeric mixture is formed, while a 1.4:1 mixture is seen with

2.5 mol %. It is likely that the reduced loading directly effects the

rate of the base-promoted alkene isomerization due to the in situ-

generated [n-Bu₄N]NTf₂. Moreover, a longer reaction time was

In contrast, only 5ah-I was generated (66% yield) with 4ah,

as no cyclization onto the 2-thienyl moiety was observed (entry

8). This outcome agrees with the greater nucleophilicity of the

thiophene C-2 vs C-3. For 4ai with a β-styryl substituent, only

22% yield of 5ai-I was isolated along with significant

degradation and uncharacterized compound mixtures (entry 9).

Given the added delocalization, multiple cationic intermediates

can be generated that may undergo competing reactions.

5

Table 3. Ca-Catalyzed Synthesis of Cyclopenta[b]thiophenes^a

Ca(NTf₂)₂

(10 mol %)

n-Bu₄NPF₆

(10 mol %)

ACCEPTED MANUSCRIPT

OH

CO₂Me

2.0

:

1

S

5aj-II/5aj-IV : 5aj-I/5aj-III

C₆H₆

40 ˚C

4aj

71%

CO₂Me

S

5aj-I

5aj-II

5aj-III

5aj-IV

Scheme 5. Complex Products Outcomes from Cyclization of

4aj

Ca(NTf₂)₂

(10 mol %)

n-Bu₄NPF₆

(10 mol %)

OH

CO₂Me

Me

CO₂Me

Me

indeterminable

mixture

S

C₆H₆

40 ˚C

Me

4ak

6ak

Scheme 6. Attempted Cyclization of 4ak Mixture

Next, the effects of replacing the thienyl group with other

(hetero)arenes were studied under the optimized conditions

(Table 4). 2-Benzothienyl carbinol 4ba cyclized to give

benzo[b]cyclopenta[d]thiophene 5ba-I in 53% yield (entry 1).

With 2-benzofuranyl carbinol 4ca, no product 5ca was obtained,

as significant decomposition was encountered (entry 2). This

outcome is consistent with the low yield (10%) observed by

Batey¹⁷for a similar 3-benzofuranyl derivative.

Table 4. Changing the (Hetero)aryl Carbinol Substituent^a

^aReaction was performed with carbinol 4 and Ca(NTf₂)₂(10

mol %), n-Bu₄NPF₆(10 mol %) in benzene (0.05 M) at 40 ˚C

over 1.45 h.

^bIsolated yield after column chromatography.

^c7.0:1 ratio of 4ac to unreduced alkylidene 3ac.

^dRatio determined by ¹H NMR of the product mixture.

When a 2-naphthyl group was employed as the alkenyl

substituent (4aj), a 20:7.0:3.5:1.0 mixture of the four possible

isomers was obtained in 71% yield (Scheme 5). Given the

complexity of the NMR spectra, we were unable to

unequivocally correlate each isomer with the observed ratios.

Despite that limitation, we were able to determine that a 2.0:1

ratio of trisubstituted alkene isomers (5aj-II and 5aj-IV) to tetra-

substituted alkene isomers (5aj-I and 5aj-III) exists.

Finally, encouraged by the outcome of 4ac (employed as a

mixture with left over starting material 3ac), we subjected the

isopropyl-substituted alkenyl substrate 4ak to the cyclization

conditions, despite it existing as a 2.0:1 mixture with the fully

reduced alcohol 6ak (Scheme 6). Disappointingly, the reaction

only gave an indeterminable mixture and neither 4ak nor 6ak

was recovered.

^aReaction was performed with carbinol 4 and Ca(NTf₂)₂(10

mol %), n-Bu₄NPF₆(10 mol %) in benzene (0.05 M) at 40 ˚C

over 1.45 h.

^bIsolated yield after column chromatography.

^cDecomposition.

6

Tetrahedron

ACCEPTED MANUSCRIPT

2-Naphthyl carbinol 4da proved a competent substrate (75%

yield) with alkylation readily occurring at C-1 to form 5da-II as

the only observable product (entry 3). This result contrasts with

what Batey¹⁷obtained for a 2-naphthyl derivative with a methyl

group in place of the ester. In that case, a 3:1 mixture of product

from C-1 alkylation and product from cyclization onto the phenyl

group was formed. Lastly, in agreement with Batey’s

observations, 3-methoxy-substituted phenyl carbinols (4ea)

expectedly gave the corresponding indene 5ea-II in 77% yield

(entry 4). A similar result was obtained with the 3,4-dimethoxy

substrate 4fa (entry 5).

Scheme 8. Plausible Mechanisms for Interconversion.

To further interrogate the effects of heat and the nature of the

interconversion we sought to plot product ratios as a function of

time using: (1) the optimized reaction conditions in benzene

starting with 4aa; (2) heating and stirring a known ratio of 5aa-I

to 5aa-II; and (3) heating and stirring a ratio of 5aa-I to 5aa-II in

the presence of a Brønsted acid (HNTf₂). The results of these

studies, along with the data from Figure 2 (yellow line) and Table

5 (red line), are shown in Figure 3.

2.5. Control Reactions and Mechanistic Studies

After establishing a good understanding of the effects of

changes in substrate, questions about the nature of product ratios

persisted. The reaction appeared to be more complicated than a

simple kinetic vs thermodynamic product argument due to the

fact that the ratios oscillated, changing in both directions. In an

attempt to gain a deeper understanding of the interconversion

between products 5aa-I and 5aa-II, a series of control reactions

were performed.

Scheme 7. Probing the Interconversion of 5aa-I and 5aa-II

In the first experiment, performed before solvent optimization,

a 1.7:1 mixture of 5aa-I:5aa-II (obtained by combining previous

products after column chromatography) was subjected to the

initial reaction conditions [Ca(NTf)₂(10 mol %), n-Bu₄NPF₆(10

mol %), CH₂Cl₂, 40 ˚C] at both room temperature and at reflux

(Table 5). No change in ratios was observed at room temperature;

however, under reflux for 0.5 h, the 5aa-I:5aa-II product ratio

improved to 15.0:1. At 1.0 h, the product ratios deteriorated to

3.5:1. In both cases, product degradation was observed and about

65-69% of the mixture was recovered. This study suggests two

things: (1) reflux time has a direct effect upon product ratios; and

(2) product degradation is likely a competing pathway that must

be considered.²³

Figure 3. Control Reactions Probing Product Ratios as a Function of Time.

Reactions were performed in indicated solvent (DCM or benzene) with

indicated starting material (4aa or 5aa) at 40 ˚C with either Lewis acid (LA =

Ca(NTf₂)₂and n-Bu₄NPF₆(10 mol % each)), Brønsted acid (BA = HNTf₂(10

mol %)), or no additive. 5aa DCM LA (red); 4aa DCM LA (yellow); 4aa

Benzene LA (blue); 5aa Benzene (green); 5aa Benzene BA (purple)

Significant fluctuations in product ratios between 60 and 120

minutes were observed for the optimized reaction starting with

4aa (Figure 3, blue line). Full conversion of 4aa to 5aa was

observed within 15 min. Isolated product yields remained

consistent for each time point (within 5%) of the optimized 67%

yield (Table 3 entry 8). Oscillation of product ratios was

observed under these conditions; however at 105 min, only 5aa-I

persists in solution. Finally, although product degradation is still

a potential issue, it does not seem to worsen over the time span of

15 minutes and 120 minutes.

Table 5. Control Experiment to Probe Interconversion

Between 5aa-I and 5aa-II Under Initial Reaction Conditions.^a

entry

time at reflux (h)

% recovery^b

5aa-I : 5aa-II^c

1.7:1

1

2

3

0.0

0.5

1.0

>95

65

15.0:1

69

3.5:1

^aReaction was performed with indicated mixture of 5aa-I and

5aa-II and Ca(NTf₂)₂and n-Bu₄NPF₆(10 mol % each) in CH₂Cl₂

(0.1 M) at 40 ˚C. Each entry was a separate, isolated reaction.

^bPercentage of 5aa-I:5aa-II mixture recovered after column

chromatography.

The next two experiments involved subjecting a 2.2:1 ratio of

5aa-I to 5aa-II to heating and stirring in benzene either with

(purple line) or without (green line) 10 mol % HNTf₂. The

reactions were set up using the same solution of 5aa in benzene

split into two flasks, both heated to 40 ˚C. If the interconversion

were the result of purely thermodynamic H-shifts, product

oscillation would be observed with simple heating and stirring

over time. If it were protonation/deprotonation instead,

oscillation should only occur with acid present. The results for

both show a minor change (~5%) in ratio within the first 15

minutes, followed by little change at all (<5%). It seems as

though interconversion is very slow or the system had reached

equilibrium. This result is distinctly different from the other data

sets involving the calcium catalyst, which seems to be

responsible for the large oscillations. One can speculate that there

may be some sort of complex involving the calcium catalyst and

the products that facilitates interconversion.

^cRatio determined by ¹H NMR of the product mixture.

Two plausible mechanisms for the interconversion exist

(Scheme 8). In the first case, two 1,5-H shifts occur in tandem

(converting from the 4H-, 5H-, and 6H-cyclopenta[b]thiophenes

and vice versa). The second mechanism involves acid/base-

mediated protonation/deprotonation. Another possibility, of

course, would be some combination of the two if they occur

concurrently.

7

3. Conclusion

In one final attempt at probing the hydride shift mechanism,

ACCEPTED MANUSCRIPT

the deuterated starting material, 4aa-d, was synthesized and

subjected to the reaction conditions (Scheme 9). 5aa-II-d was

obtained as the major product in a 40:1 ratio of 5aa-II-d:5aa-I-d.

The product was fully deuterated. This result was repeated at 30

min and 60 min reaction times as well, with effectively identical

results. Unfortunately, because of the small amounts of 5aa-I-d

formed, the extent of deuterium incorporation was not

determined. Similarly, the control reaction of 4aa in deuterated

solvent showed no deuterium incorporation, although it did show

a change in product ratio, indicating a solvent effect.

In summary, we have disclosed a calcium-catalyzed protocol

for the dehydrative, Nazarov-type electrocyclization of alkenyl

(hetero)aryl carbinols that allows access to functionalized

cyclopenta[b]thiophenes and indenes. Products are isolated in up

to 82% yield. Good tolerance for aryl and heteroaryl substituents

on the alkene was demonstrated, whereas a β-styryl substituent

gave low yield. Substituent effects play a significant role in

determining product outcomes and isomeric ratios. For systems

with competing (hetero)aryl substituents, cyclization occurs

preferentially on the most nucleophilic ring. When the relative

nucleophilicities are close, mixtures are then observed. For the 3-

thienyl series (without a competing aryl substituent), the reaction

is selective for the thermodynamic alkene isomer in all but one

case, whereas the arene series favors the kinetic alkene isomer for

the resulting indenes. This transformation represents one of the

only examples of catalytic, dehydrative, Nazarov-type

electrocyclizations in which thiophenes are compatible. Thus, it

allows for the direct formation of cyclopenta[b]thiopenes and it

circumvents the need for cyclopenta[b]thiophenones as

precursors. Future efforts will be focused in two primary

directions. Firstly, improved methods for selective 1,2-reduction

of the alkylidene β-ketoesters will be explored. Secondly, the

method will be expanded to synthesize more functionalized

cyclopenta[b]thiophenes, which can be used in organometallic

chemistry and materials science.

Scheme 9. Dehydrative Cyclization of 4aa-I-d

Some strong mechanistic conclusions can be drawn from these

deuterium studies. The consistency over time and overwhelming

prevalence of the 5aa-II-d isomer indicates that it forms first in

the reaction and the presence of the deuterium prevents

isomerization, suggesting a very large kinetic isotope effect.

Mechanistically, this means that the II isomer is the first to form

in the reaction and it subsequently isomerizes in the instances

that we see the I isomer. The same is true for the formation of the

indenes where the IV isomer would before the III isomer.

4. Experimental section

4.1. General Information

Although we cannot make definitive conclusions on how and

why the product seems to oscillate between the two isomers 5aa-

I and 5aa-II, we have learned several important details about the

reaction from our studies. (1) The reaction initially, and rapidly,

generates isomers II (or IV) and any variations in isolated

product ratios observed are the result of isomerization. (2) There

is a large KIE for isomerization. (3) Although the isomerization

does not require the calcium catalyst, it is likely the cause for the

large oscillations in product ratios. (4) There are observable

solvent effects on the isomerization rate. (5) Although some

product degradation is detected, it can be ruled out as mostly

irrelevant as a function of reaction time in our optimized

conditions.

Chromatographic purification was performed as flash

chromatography with Silicycle SiliaFlash P60 silica gel (40-

63µm) 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

chromatography, technical grades 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 using an IRAffinity-1S FTIR from

Shimadzu. The IR bands are characterized as broad (br), weak

(w), medium (m), and strong (s). Proton and carbon nuclear

magnetic resonance spectra (H¹NMR and C¹³NMR) were

recorded on a Varian Mercury Vx 300 MHz spectrometer or a

Bruker 500 MHz spectrometer with solvent resonances as the

internal standard (H¹NMR: CDCl₃at 7.26 ppm; C¹³NMR:

CDCl₃at 77.0 ppm). H¹NMR data are reported as follows:

chemical 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. Uncorrected melting points were measured with a

digital melting point apparatus (DigiMelt MPA 160).

2.6. Attempted derivatizations

Inspired by Skramstad’s report demonstrating that the

transient 5H-cyclopenta[b]thiophene isomer can undergo Diels-

Alder-type cyclizations,^2cwe reacted cyclopenta[b]thiophene

product 5aa with various dienophiles as well as a diene to

explore reactivity (Scheme 10). Unfortunately, no reactivity was

observed between 5aa and maleic anhydride (to probe normal

electron demand cycloaddition), n-butyl vinyl ether (to probe

inverse electron demand cycloaddition), or 2,5-dimethylfuran (to

probe if 5aa can behave as a dienophile).

O

n-Bu

O

recovered

CO₂Me

starting

S

material

Me

O

Ph

Me

4.2. Synthesis of β-Keto Esters 1

5aa-I

Scheme 10. Attempted Diels-Alder-type Cycloaddtions of

5aa-I

General Procedure A: The starting aryl carboxylic acid (1.0

equiv) was added as a 0.5 M solution in dry CH₂Cl₂to a dry

round-bottom flask charged with a stir bar under nitrogen

atmosphere. The solution was then cooled to 0 ˚C. Catalytic DMF

8

Tetrahedron

(few drops to 1 mL) was then added. Oxalyl chloride (1.2

122.1, 52.4, 47.2 IR: 3096 (w), 2949 (w), 1736 (s), 1662 (s) cm^-1.

ACCEPTED MANUSCRIPT

equiv) was added over 1 minute with stirring at 0 ˚C using a

needle to vent into a balloon. After 15 minutes, the reaction was

allowed to warm to room temperature with continued stirring.

Upon completion, the reaction was concentrated under reduced

pressure; the generated acid chloride was re-dissolved in dry THF

to make a 1M solution, and the solution was added slowly to the

prepared enolate at -78 ˚C. The enolate was prepared by first

adding MeOAc (1.05 equiv) to a dry flask charged with a stir bar

under nitrogen. The flask was cooled down to -78 ˚C to which

LHMDS (1M in THF, 2.10 equiv) was added dropwise and

stirred for 45 min at -78 ˚C. The reaction was monitored by TLC

until complete conversion of the acid chloride was observed.

Upon completion, the reaction was quenched with NH₄Cl (aq) at

-78 ˚C, extracted with EtOAc three times, dried over Na₂SO₄, and

filtered through a celite plug. The combined organic layers were

concentrated under reduced pressure and purified by flash

chromatography on silica gel using EtOAc/Hexanes as the

mobile phase.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₂H₁₀O₃S 234.0351; Found

234.0352.

Methyl 3-(benzofuran-2-yl)-3-oxopropanoate (1c)

Prepared following general procedure A using benzofuran-2-

carboxylic acid (5 g, 30.8 mmol), oxalyl chloride (3.18 mL, 37.0

mmol) and DMF (1 mL) in CH2CL2 (50 mL) over 3 h to form

the acid chloride. The enolate was formed using LHMDS (1 M

in THF, 64.8 mL) and MeOAc (2.57 mL, 32.8 mmol) in THF (60

mL) over 45 min. The previously generated acid chloride was

added to the enolate and stirred for 30 min. After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.50), compound 1c was

afforded as a colorless oil (4.00 g, 60% yield). Keto:Enol Ratio

(4:1) Characterizations were consistent with previously reported

literature.¹⁴

Methyl 3-(naphthalen-2-yl)-3-oxopropanoate (1d)

Prepared following general procedure B using sodium hydride

(60 % dispersion in mineral oil, 1.98 g, 49.4 mmol), dimethyl

carbonate (99% pure, 2.97 mL, 35.2 mmol) and methyl β-

naphthyl ketone (3g; 17.6 mmol) in toluene (17.6 mL) over 30

min. After work up and purification, (20% EtOAc/Hexanes, R_f=

0.52), compound 1d was afforded as a light orange oil (2.98 g,

74% yield). Keto:Enol Ratio (4:1) ¹H NMR (500 MHz, CDCl₃)

δ = 12.64 (s, 0.23 H), 8.38 (d, J = 0.6 Hz, 1.01 H), 8.30 (d, J =

0.9 Hz, 0.23 H), 7.96 (dd, J = 1.8, 8.5 Hz, 1.06 H), 7.90 (d, J =

8.2 Hz, 1.07 H), 7.86 - 7.76 (m, 2.84 H), 7.72 - 7.69 (m, 0.24 H),

7.57 (ddd, J = 1.2, 6.8, 8.2 Hz, 1.05 H), 7.53 - 7.45 (m, 1.51 H),

5.78 (s, 0.23 H), 4.14 - 4.08 (m, 2.12 H), 3.79 (s, 0.73 H), 3.74 (s,

3.00 H) ¹³C NMR (126 MHz, CDCl₃) δ = 192.1, 173.3, 171.0,

167.9, 135.5, 134.4, 133.0, 132.5, 132.1, 130.4, 130.2, 129.5,

128.8, 128.7, 128.5, 128.0, 127.6, 127.4, 127.4, 126.7, 126.5,

126.5, 123.5, 122.3, 87.3, 52.2, 51.2, 45.5 IR: 3059 (w), 2951

(w), 1738 (s), 1678 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₄H₁₂O₃228.0786; Found 228.0783.

General Procedure B: A dry round-bottom flask was charged

with a stir bar, and sodium hydride (2.8 equiv) was added under

nitrogen atmosphere. Dimethyl carbonate (2.0 equiv) was then

added with toluene, and the reaction was stirred and heated to

reflux. A solution of the aryl ketone (1.0 equiv.) in toluene was

added drop-wise over 30 min using a syringe pump for an overall

reaction concentration of 1.0 M. The reaction was monitored by

TLC until complete conversion of the aryl ketone was observed.

After the evolution of hydrogen gas, the reaction was allowed to

cool to room temperature, and acetic acid (6 mL) was added

drop-wise to the reaction mixture. Ice-cold water was added to

dissolve any solid that formed, and then the solution was diluted

with EtOAc. The organic layer was extracted with EtOAc three

times, dried over Na₂SO₄, and filtered through a celite plug. 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-(3-methoxyphenyl)-3-oxopropanoate (1e)

Methyl 3-oxo-3-(thiophen-3-yl)propanoate (1a)

Prepared following general procedure A using 3-methoxy

benzoic acid (1.00 g, 6.57 mmol), oxalyl chloride (98% pure,

1.06 g, 7.88 mmol) and DMF (4 drops) in CH₂Cl₂(13 mL) over

3h to form the acid chloride. The enolate was formed using

LHMDS (1 M in THF, 14 mL) and MeOAc (0.55 mL, 6.9 mmol)

over 45 min. The previously generated acid chloride was added

to the enolate and stirred for 30 min. After work up and

purification, (25% EtOAc/Hexanes, R_f= 0.42), compound 1e was

afforded as a light yellow oil (0.99 g, 72% yield). Keto:Enol

Ratio (6:1) Characterizations were consistent with previously

reported literature.²⁵

Prepared following general procedure

A

using 3-

thiophenecarboxylic acid (99 % pure, 3g, 23.4 mmol), oxalyl

chloride (98% pure, 2.41 mL, 28.1 mmol) and DMF (1 mL) in

CH₂Cl₂(36 mL) over 3 h to form the acid chloride. The enolate

was formed using LHMDS (1 M in THF, 49 mL) and MeOAc

(99% pure, 1.95 mL, 24.6 mmol) in THF (30 mL) over 45 min.

The previously generated acid chloride was added to the enolate

and stirred for 30 min. After work up and purification, (35%

EtOAc/Hexanes, R_f= 0.60), compound 1a was afforded as a light

orange oil (3.19 g, 74% yield). Characterizations were consistent

with previously reported literature.²⁴

Methyl 3-(3,4-dimethoxyphenyl)-3-oxopropanoate (1f)

Methyl 3-(benzo[b]thiophen-3-yl)-3-oxopropanoate (1b)

Prepared following general procedure A using 3,4-dimethoxy

benzoic acid (10.5 g, 57.0 mmol) in CH₂Cl₂(114 mL), oxalyl

chloride (8.84 g, 68.4 mmol), and 4 drops of DMF stirred at room

temp for 3 hours to generate the acid chloride. The second step

used LHMDS (1M in THF, 120 mL) and MeOAc (99% pure,

4.48 g, 59.9 mmol) to generate the enolate, and the generated

acid chloride in THF (57 mL) was added at -78 ˚C and stirred for

30 minutes. After work-up and purification, compound 4a was

Prepared following general procedure

A

using 1-

benzothiophene-3-carboxylic acid (2.5 g, 14.0 mmol), oxalyl

chloride (1.45 mL, 16.8 mmol) and DMF (1 mL) in CH₂Cl₂(25

mL) over 3h to form the acid chloride. The enolate was formed

using LHMDS (1 M in THF, 30.9 mL) and MeOAc (1.16 mL,

14.7 mmol) in THF (28 mL) over 45 min. The previously

generated acid chloride was added to the enolate and stirred for

30 min. After work up and purification, (25% EtOAc/Hexanes, R_f

= 0.48), compound 1b was afforded as an orange oil (1.75 g, 53%

yield). Keto:Enol Ratio (30:1) ¹H NMR (500 MHz, CDCl₃) δ =

8.73 (td, J = 1.1, 8.2 Hz, 1 H), 8.31 (s, 1 H), 7.82 (td, J = 0.8, 8.1

Hz, 1 H), 7.47 (ddd, J = 1.1, 7.2, 8.2 Hz, 1 H), 7.42 - 7.37 (m, 1

H), 4.00 (s, 2 H), 3.74 (s, 3 H) ¹³C NMR (126 MHz, CDCl₃) δ =

186.7, 167.7, 139.5, 138.7, 136.1, 134.0, 125.9, 125.6, 125.4,

afforded as

a thick peach oil (12.32 g, 91% yield).

Characterizations were consistent with previously reported

literature.²⁶

4.3. Syntheses of Alkylidene β-Ketoesters: Knoevenagel

Condensations

9

General Procedure C: A dry round-bottom flask was charged

with a stir bar, and a solution of the β-keto ester 1x (1.0 equiv.) in

benzene (0.1 M to 0.5 M). The aldehyde (1.3 equiv.), acetic acid

Prepared following general procedure C using 1a (1.01 g,

ACCEPTED MANUSCRIPT

5.43 mmol), 4-methylbenzaldehyde (0.83 mL, 7.09 mmol),

glacial acetic acid (99.7% pure, 0.16 mL, 2.72 mmol) and

piperidine (99 % pure, 0.10 mL, 1.09 mmol) in benzene (0.16 M,

34 mL) over 18 h. After work up and purification, (20%

EtOAc/Hexanes, R_f= 0.43), compound 3ac was afforded as an

(0.5 equiv.) and piperidine (0.1 equiv.) were then added.

A

Dean-Stark trap was filled with benzene and attached to the flask.

A Liebig condenser was then attached to the top of the Dean-

Stark trap, and the reaction was heated to reflux with stirring. The

reaction was monitored by TLC until complete conversion of the

β-keto ester was observed. Upon completion, the reaction was

quenched with water and extracted three times with EtOAc. The

combined organic layers were washed with HCl and NaHCO₃,

dried over Na₂SO₄, filtered through celite, concentrated under

reduced pressure, and purified by flash chromatography on silica

gel using EtOAc/Hexanes as the mobile phase.

1

orange solid (1.44 g, 92% yield). [m.p. = 118-121 ˚C] H NMR

(500 MHz, CDCl₃) δ = 7.96 (dd, J = 1.2, 2.7 Hz, 1 H), 7.90 (s, 1

H), 7.57 (dd, J = 1.2, 5.2 Hz, 1 H), 7.29 (dd, J = 2.9, 5.0 Hz, 1

H), 7.28 - 7.25 (m, 3 H), 7.06 (d, J = 7.9 Hz, 2 H), 3.78 (s, 3 H),

2.29 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ = 189.3, 165.6,

142.5, 141.7, 141.1, 134.9, 130.3, 130.3, 129.9, 129.6, 127.0,

126.9, 100.0, 52.6, 21.4. IR: 3102 (w), 2951 (w), 1717 (s), 1653

(s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₆H₁₄O₃S 286.0664;

Found 286.0664.

Methyl (Z)-3-phenyl-2-(thiophene-3-carbonyl)acrylate (3aa)

Methyl (Z)-3-(4-bromophenyl)-2-(thiophene-3-carbonyl)acrylate

(3ad):

Prepared following general procedure C using 1a (1 g, 5.4

mmol), benzaldehyde (0.72 mL, 7.1 mmol), glacial acetic acid

(0.16 mL, 2.7 mmol) and piperidine (0.054 mL, 0.54 mmol) in

benzene (0.1 M, 54 mL) over 24 h. After work up and

purification, (25% EtOAc/Hexanes, R_f= 0.42), compound 3aa

was afforded as a powdery light yellow solid (1.23 g, 83% yield).

Prepared following general procedure C using 1a (459 mg,

2.49 mmol), 4-bromobenzaldehyde (653 mg, 3.53 mmol), glacial

acetic acid (0.08 mL, 1.36 mmol) and piperidine (0.05 mL, 0.54

mmol) in benzene (0.1 M, 27 mL) over 24 h. After work up and

purification, (25% EtOAc/Hexanes, R_f= 0.48), compound 3ad

was afforded as a yellow solid (713 mg, 81% yield). [m.p. = 77-

79 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 7.95 (dd, J = 1.2, 3.1 Hz,

1 H), 7.85 (s, 1 H), 7.55 (dd, J = 1.2, 5.2 Hz, 1 H), 7.41 - 7.37 (m,

2 H), 7.31 (dd, J = 2.9, 5.0 Hz, 1 H), 7.25 - 7.21 (m, 2 H), 3.79 (s,

3 H). ¹³C NMR (126 MHz, CDCl₃) δ = 188.6, 165.2, 141.4,

140.9, 135.1, 132.1, 131.6, 131.5, 127.2, 126.9, 125.1, 52.8. IR:

3102 (w), 2951 (w), 1715 (s), 1651 (s) cm^-1. HRMS (EI) m/z:

[M]⁺Calcd. for C₁₅H₁₁O₃SBr 349.9612; Found 349.9613.

1

[m.p. = 60-66 ˚C] H NMR (300 MHz, CDCl₃) δ = 7.93 (dd, J =

1.3, 2.9 Hz, 1 H), 7.91 (s, 1 H), 7.53 (dd, J = 1.3, 5.1 Hz, 1 H),

7.37 - 7.31 (m, 2 H), 7.28 - 7.17 (m, 4 H), 3.74 (s, 3 H) ¹³C NMR

(75 MHz, CDCl₃) δ = 188.9, 165.3, 142.3, 141.4, 134.9, 132.6,

131.3, 130.4, 130.1, 128.7, 126.9, 126.8, 52.5 IR: 3096 (w), 2949

(w), 1712 (s), 1651 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₅H₁₂O₃S 272.0507; Found 272.0499.

Methyl (Z)-3-phenyl-2-(thiophene-3-carbonyl)acrylate-d (3aa-d)

Prepared following general procedure C using 1a (0.72 g, 3.89

mmol), α-d-benzaldehyde (0.50 g, 4.67 mmol), glacial acetic acid

(0.12 g, 2 mmol) and piperidine (34 mg, 0.4 mmol) in benzene

(0.1 M, 39 mL) over 18 h. After work up and purification, (20%

EtOAc/Hexanes, R_f= 0.38), compound 3aa-d was afforded as

yellow oil in a 93% pure mixture, which was carried forward

without further purification (1.04 g). ¹H NMR (500 MHz,

CDCl₃) δ = 7.96 (dd, J = 1.2, 3.1 Hz, 1 H), 7.57 (dd, J = 1.4, 5.0

Hz, 1 H), 7.39 - 7.36 (m, 2 H), 7.30 - 7.23 (m, 4 H), 3.78 (s, 3 H)

¹³C NMR (126 MHz, CDCl₃) δ = 189.0, 165.4, 141.5, 135.0,

132.6, 131.3, 130.5, 130.2, 129.5, 128.8, 127.0, 127.0, 52.6 IR:

3098 (w), 2949 (w), 1705 (s), 1647 (s) cm^-1. HRMS (EI) m/z:

[M]⁺Calcd. for C₁₅H₁₁DO₃S 273.0570; Found 273.0562.

Methyl

(Z)-2-(thiophene-3-carbonyl)-3-(4-

(trifluoromethyl)phenyl)acrylate (3ae)

Prepared following general procedure C using 1a (580 mg,

3.15 mmol), 4-(trifluoromethyl)benzaldehyde (0.56 mL, 4.09

mmol), glacial acetic acid (0.09 mL, 1.57 mmol) and piperidine

(0.06 mL, 0.63 mmol) in benzene (0.16 M, 27 mL) over 24 h.

After work up and purification, (20% EtOAc/Hexanes, R_f=

0.36), compound 3ae was afforded as a yellow solid (0.783 g,

1

73% yield). [m.p. = 60-63 ˚C] H NMR (500 MHz, CDCl₃) δ =

7.96 (dd, J = 1.2, 3.1 Hz, 1 H), 7.93 (s, 1 H), 7.55 (dd, J = 1.2,

5.2 Hz, 1 H), 7.54 - 7.50 (m, 2 H), 7.50 - 7.46 (m, 2 H), 7.33 -

7.31 (m, 1 H), 3.81 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ =

188.2, 165.0, 141.3, 140.4, 136.1, 135.1, 133.9, 130.1, 127.3,

126.8, 125.8, 125.7, 125.7, 100.0, 52.9. IR: 3102 (w), 2955 (w),

1717 (s), 1655 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₆H₁₁O₃SF₃340.0381; Found 340.0376.

Methyl

(Z)-3-(4-methoxyphenyl)-2-(thiophene-3-

carbonyl)acrylate (3ab)

Prepared following general procedure C using 1a (500 mg, 2.7

mmol), 4-methoxybenzaldehyde (0.43 mL, 3.5 mmol), glacial

acetic acid (0.078 mL, 1.4 mmol) and piperidine (0.027 mL, 0.27

mmol) in benzene (0.1 M, 27 mL) over 24 h. After work up and

purification, (25% EtOAc/Hexanes, R_f= 0.38), compound 3ab

was afforded as a yellow solid (0.66 g, 80% yield). [m.p. = 97-99

˚C] ¹H NMR (500 MHz, CDCl₃) δ = 7.98 (dd, J = 1.2, 3.1 Hz, 1

H), 7.87 (s, 1 H), 7.58 (dd, J = 1.2, 5.2 Hz, 1 H), 7.35 - 7.31 (m, 2

H), 7.30 (dd, J = 2.9, 5.0 Hz, 1 H), 6.79 - 6.75 (m, 2 H), 3.77 (s, 6

H). ¹³C NMR (126 MHz, CDCl₃) δ = 189.6, 165.7, 161.4, 142.2,

141.7, 134.9, 132.3, 128.7, 127.0, 126.9, 125.3, 114.3, 55.3, 52.5.

IR: 3098 (w), 2951 (w), 2839 (w), 1703 (s), 1651 (s) cm^-1.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₆H₁₄O₄S 302.0613; Found

302.0606.

Methyl

carbonyl)acrylate (3af)

(Z)-3-(2-methoxyphenyl)-2-(thiophene-3-

Prepared following general procedure C using 1a (500 mg,

2.71 mmol), 2-methoxybenzaldehyde (0.43 mL, 3.53 mmol),

glacial acetic acid (0.08 mL, 1.36 mmol) and piperidine (0.03

mL, 0.271 mmol) in benzene (0.1M, 27 mL) overnight. After

work up and purification, (25% EtOAc/Hexanes, R_f= 0.267),

compound 3af was afforded as an off-white solid (579 mg, 71%

1

yield). [m.p. = 73-79 ˚C] H NMR (500 MHz, CDCl₃) δ = 8.27

(s, 1 H), 7.92 (dd, J = 1.2, 2.7 Hz, 1 H), 7.52 (dd, J = 1.4, 5.0 Hz,

1 H), 7.28 - 7.22 (m, 4 H), 6.82 (d, J = 7.9 Hz, 1 H), 6.77 - 6.73

(m, 1 H), 3.81 - 3.79 (m, 3 H), 3.78 (s, 3 H). ¹³C NMR (126

MHz, CDCl₃) δ = 188.9, 165.7, 157.9, 141.9, 138.4, 134.5, 131.9,

131.1, 130.4, 127.1, 126.5, 122.2, 120.5, 110.7, 55.3, 52.5. IR:

3103 (w), 2949 (w), 2839 (w), 1709 (s), 1651 (s) cm^-1. HRMS

(EI) m/z: [M]⁺Calcd. for C₁₆H₁₄O₄S 302.0613; Found 302.0609.

Methyl (Z)-2-(thiophene-3-carbonyl)-3-(p-tolyl)acrylate (3ac)

10

Tetrahedron

= 5.04, 2.90 Hz, 1 H) 3.82 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃)

Methyl

(Z)-3-(3-methoxyphenyl)-2-(thiophene-3-

ACCEPTED MANUSCRIPT

carbonyl)acrylate (3ag)

δ = 189.1, 165.5, 142.5, 141.7, 135.0, 133.9, 132.9, 131.8, 131.3,

130.3, 128.7, 128.6, 127.7, 127.6, 127.0, 126.9, 126.7, 125.9,

52.7. IR: 3103 (w), 3055 (w), 2949 (w), 1719 (s), 1653 (s) cm^-1.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₉H₁₄O₃S 322.0664; Found

322.0659.

Prepared following general procedure C using 1a (693 mg,

3.76 mmol), 3-methoxybenzaldehyde (0.60 mL, 4.89 mmol),

glacial acetic acid (0.11 mL, 1.88 mmol) and piperidine (0.04

mL, 0.376 mmol) in benzene (0.1M, 38 mL) over 18 h. After

work up and purification, (25% EtOAc/Hexanes, R_f= 0.340),

compound 3ag was afforded as a yellow oil (981 mg, 86% yield).

¹H NMR (500 MHz, CDCl₃) δ = 7.97 (dd, J = 3.05, 1.22 Hz, 1

H) 7.89 (s, 1 H) 7.56 (dd, J = 5.19, 1.22 Hz, 1 H) 7.28 - 7.31 (m,

1 H) 7.16 (t, J = 7.93 Hz, 1 H) 6.95 - 6.99 (m, 1 H) 6.87 - 6.89

(m, 1 H) 6.83 (ddd, J = 8.24, 2.59, 0.76 Hz, 1 H) 3.78 (s, 3 H)

3.64 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃) δ = 188.9, 165.3,

159.4, 142.3, 141.6, 134.9, 133.8, 131.5, 129.7, 127.0, 126.8,

122.9, 116.9, 114.4, 55.0, 52.6 IR: 3094 (w), 2949 (w), 2835 (w),

1717 (s), 1651 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₆H₁₄O₄S 302.0613; Found 302.0616.

Methyl

(Z)-4-methyl-2-(thiophene-3-carbonyl)pent-2-enoate

(3ak)

Prepared following general procedure C using 1a (750 mg,

4.07 mmol), isobutyraldehyde (0.48 mL, 5.29 mmol), glacial

acetic acid (0.12 mL, 2.04 mmol) and piperidine (0.04 mL, 0.407

mmol) in benzene (0.1 M, 41 mL) over 18 h. After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.36), compound 3ak

(Diastereomeric ratio = 6:1) was afforded as a colorless oil (860

mg, 89% yield). ¹H NMR (500 MHz, CDCl₃) δ = 7.93 - 7.97 (m,

0.92) 7.88 - 7.91 (m, 0.15) 7.51 - 7.55 (m, 0.97) 7.46 (d, J = 1.22

Hz, 0.16) 7.30 - 7.35 (m, 1.12) 6.87 - 6.93 (m, 0.97) 6.45 (d, J =

10.38 Hz, 0.16) 3.72 - 3.75 (s, 0.59) 3.67 - 3.71 (s, 3.00) 3.12 -

3.23 (m, 0.18) 2.35 - 2.47 (m, 1.01) 1.07 - 1.13 (m, 1.12) 0.96 -

1.04 (m, 6.29). ¹³C NMR (126 MHz, CDCl₃) δ = 187.8, 186.5,

165.1, 156.4, 153.7, 153.6, 142.4, 141.2, 134.5, 133.3, 132.8,

131.7, 127.7, 126.9, 126.8, 126.5, 52.2, 51.9, 29.1, 28.9, 22.0,

21.8. IR: 3102 (w), 2961 (w), 2870 (w), 1717 (s), 1656 (s) cm^-1.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₂H₁₄O₃S 238.0664; Found

238.0660.

Methyl (Z)-3-(thiophen-2-yl)-2-(thiophene-3-carbonyl)acrylate

(3ah)

Prepared following general procedure C using 1a (580 mg,

3.15 mmol), 2-thiophenealdehyde (0.38 mL, 4.09 mmol), glacial

acetic acid (0.09 mL, 1.57 mmol) and piperidine (0.06 mL, 0.63

mmol) in benzene (0.16 M, 20 mL) over 18 h. After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.36), compound 3ah

was afforded as a thick yellow oil (750 mg, 86% yield). ¹H NMR

(500 MHz, CDCl₃) δ = 8.05 (dd, J = 1.2, 2.7 Hz, 1 H), 8.01 (t, J

= 0.8 Hz, 1 H), 7.62 (dd, J = 1.2, 5.2 Hz, 1 H), 7.39 (td, J = 0.9,

5.3 Hz, 1 H), 7.34 (dd, J = 2.9, 5.0 Hz, 1 H), 7.28 - 7.26 (m, 1 H),

6.99 (dd, J = 3.7, 5.2 Hz, 1 H), 3.77 (s, 3 H). ¹³C NMR (126

MHz, CDCl₃) δ = 188.5, 165.4, 141.6, 136.0, 135.0, 134.6, 134.1,

131.7, 128.2, 127.8, 127.1, 127.0, 52.5. IR: 3098 (w), 2949 (w),

1701 (s), 1647 (s), 1607 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd.

for C₁₃H₁₀O₃S₂278.0071; Found 278.0064.

Methyl (Z)-2-(benzo[b]thiophene-3-carbonyl)-3-phenylacrylate

(3ba)

Prepared following general procedure C using 1b (1.00 g, 4.27

mmol), benzaldehyde (0.57 mL, 5.55 mmol), glacial acetic acid

(0.12 mL, 2.13 mmol) and piperidine (0.08 mL, 0.85 mmol) in

benzene (0.25 M, 17 mL) over 24 h. After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.39), compound 3ba

was afforded as an orange solid (1.38 g, >99% yield). [m.p. =

100-102 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 8.92 (d, J = 8.2 Hz,

1 H), 8.16 (s, 1 H), 7.97 (s, 1 H), 7.86 (td, J = 0.9, 8.1 Hz, 1 H),

7.57 (ddd, J = 1.1, 7.1, 8.2 Hz, 1 H), 7.47 (dt, J = 1.1, 7.6 Hz, 1

H), 7.44 - 7.39 (m, 2 H), 7.29 - 7.20 (m, 3 H), 3.78 (s, 3 H). ¹³C

NMR (126 MHz, CDCl₃) δ = 189.5, 165.6, 142.4, 140.9, 140.3,

136.2, 134.7, 132.7, 131.5, 130.5, 130.2, 128.9, 126.2, 125.8,

125.6, 122.3, 52.7. IR: 3088 (w), 3059 (w), 2949 (w), 1715 (s),

1645 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₉H₁₄O₃S

322.0664; Found 322.0652.

Methyl (2Z,4E)-5-phenyl-2-(thiophene-3-carbonyl)penta-2,4-

dienoate (3ai)

Prepared following general procedure C using 1a (502 mg,

2.72 mmol), cinnamaldehyde (0.44 mL, 3.52 mmol), glacial

acetic acid (99.7 % pure, 0.08 mL, 1.36 mmol) and piperidine (99

% pure, 0.05 mL, 0.52 mmol) in benzene (0.16 M, 17 mL) over

18 h. After work up and purification, (20% EtOAc/Hexanes, R_f=

0.36), compound 3ai was afforded as an orange oil (319 mg, 39%

yield). ¹H NMR (500 MHz, CDCl₃) δ = 8.00 (dd, J = 1.3, 3.0 Hz,

1 H), 7.66 (dd, J = 0.6, 11.7 Hz, 1 H), 7.59 (dd, J = 1.2, 5.0 Hz, 1

H), 7.39 - 7.34 (m, 3 H), 7.34 - 7.29 (m, 3 H), 7.03 (d, J = 15.4

Methyl (Z)-2-(benzofuran-2-carbonyl)-3-phenylacrylate (3ca)

Hz, 1 H), 6.79 (dd, J = 11.8, 15.3 Hz, 1 H), 3.76 (s, 3 H). ¹³

C

Prepared following general procedure C using 1c (1.0 g, 4.6

mmol), benzaldehyde (0.61 mL, 6.0 mmol), glacial acetic acid

(0.13 mL, 2.3 mmol) and piperidine (0.04 mL, 0.45 mmol) in

benzene (0.5 M, 2 mL) over 24 h. After work up and purification,

(25% EtOAc/Hexanes, R_f= 0.37), compound 3ca was afforded as

NMR (126 MHz, CDCl₃) δ = 187.7, 165.5, 143.9, 143.5, 142.5,

135.4, 134.9, 131.4, 129.7, 128.9, 128.8, 127.9, 127.7, 127.1,

126.8, 122.8, 52.3. IR: 3107 (w), 3030 (w), 2949 (w), 1711 (s),

1655 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₇H₁₄O₃S

298.0664; Found 298.0652.

1

a yellow oil (0.94 g, 67 % yield). H NMR (500 MHz, CDCl₃)

δ = 8.02 (s, 1 H), 7.63 - 7.60 (m, 1 H), 7.58 - 7.54 (m, 1 H), 7.46

(ddd, J = 1.2, 7.1, 8.5 Hz, 1 H), 7.43 - 7.40 (m, 2 H), 7.39 (d, J =

0.9 Hz, 1 H), 7.29 - 7.22 (m, 4 H), 3.78 (s, 3 H) ¹³C NMR (126

MHz, CDCl₃) δ = 184.4, 165.1, 156.3, 152.0, 144.2, 132.5, 130.7,

130.2, 129.8, 129.8, 128.9, 128.9, 128.8, 126.8, 124.0, 123.6,

116.4, 112.6, 52.7 IR: 3059 (w), 2951 (w), 1719 (s), 1657 (s) cm^-

¹. HRMS (EI) m/z: [M]⁺Calcd. for C₁₉H₁₄O₄306.0892; Found

306.0881.

Methyl (Z)-3-(naphthalen-2-yl)-2-(thiophene-3-carbonyl)acrylate

(3aj)

Prepared following general procedure C using 1a (693 mg,

3.76 mmol), 2-naphthaldehyde (763 mg, 4.89 mmol), glacial

acetic acid (0.11 mL, 1.88 mmol) and piperidine (0.04 mL, 0.376

mmol) in benzene (0.1M, 37 mL) overnight. After work up and

purification, (25% EtOAc/Hexanes, R_f= 0.340), compound 3aj

was afforded as a yellow solid (438 mg, 36% yield). [m.p. = 150-

157 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 8.10 (s, 1 H) 7.99 (dd, J

= 2.90, 1.37 Hz, 1 H) 7.92 (d, J = 0.61 Hz, 1 H) 7.72 - 7.79 (m, 2

H) 7.67 (d, J = 8.55 Hz, 1 H) 7.61 (dd, J = 4.88, 1.22 Hz, 1 H)

7.45 - 7.51 (m, 2 H) 7.41 (dd, J = 8.85, 1.83 Hz, 1 H) 7.28 (dd, J

Methyl (Z)-2-(2-naphthoyl)-3-phenylacrylate (3da)

Prepared following general procedure C using 1d (1.00 g, 4.38

mmol), benzaldehyde (0.58 mL, 5.70 mmol), glacial acetic acid

(0.13 mL, 2.19 mmol) and piperidine (0.09 mL, 0.88 mmol) in

11

benzene (0.26 M, 17 mL) over 18 h. After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.39), compound 3da

was afforded as an off-white solid (1.24 g, 89% yield). [m.p. =

108-112 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 8.42 (d, J = 1.2 Hz,

1 H), 8.10 (dd, J = 1.7, 8.7 Hz, 1 H), 7.92 - 7.84 (m, 3 H), 7.60

(ddd, J = 1.4, 6.9, 8.2 Hz, 1 H), 7.55 - 7.50 (m, 1 H), 7.41 - 7.38

(m, 2 H), 7.27 - 7.19 (m, 4 H), 3.76 (s, 3 H). ¹³C NMR (126

MHz, CDCl₃) δ = 195.5, 165.6, 143.0, 136.1, 133.4, 132.7, 132.5,

131.9, 130.8, 130.5, 130.2, 129.8, 128.9, 128.9, 128.8, 127.8,

126.8, 124.0, 52.7. IR: 3057 (w), 2951 (w), 1717 (s), 1663 (s),

1624 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₂₁H₁₆O₃

316.1099; Found 316.1088.

was then quenched with 0.1 M HCl and CH₂Cl₂was added

ACCEPTED MANUSCRIPT

and stirred vigorously for 5 min; the mixture was extracted with

CH₂Cl₂three times. The combined organic layers were dried over

Na₂SO₄, filtered through celite, concentrated under reduced

pressure, and purified by flash chromatography on silica gel

using Et₂O/Hexanes as the mobile phase.

Methyl (Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-phenylacrylate

(4aa)

Prepared following general procedure D using 3aa (250 mg,

0.918 mmol), NaBH₄(156 mg, 4.13 mmol) and CeCl₃•7H₂O (684

mg, 1.84 mmol) in MeOH (0.1 M, 9.2 mL) After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.46), compound 4aa

Methyl (Z)-2-(3-methoxybenzoyl)-3-phenylacrylate (3ea)

1

was afforded as a white oil (78.1 mg, 31% yield). H NMR (500

MHz, CDCl₃) δ = 7.91 (s, 1 H), 7.40 - 7.33 (m, 6 H), 7.31 (dd, J

= 3.1, 4.9 Hz, 1 H), 7.18 (td, J = 1.5, 2.8 Hz, 1 H), 7.12 - 7.10 (m,

1 H), 5.84 (d, J = 11.0 Hz, 1 H), 4.24 (d, J = 11.6 Hz, 1 H), 3.80

(s, 3 H) ¹³C NMR (126 MHz, CDCl₃) δ = 168.1, 144.6, 141.2,

134.1, 132.2, 129.3, 129.2, 128.7, 126.2, 126.1, 120.7, 67.5, 52.2

IR: 3497 (br), 3102 (w), 2949 (w), 2845 (w), 1692 (s) cm^-1.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₅H₁₄O₃S 274.0664; Found

274.0667.

Prepared following the general procedure using 1e (1 g, 4.8

mmol), benzaldehyde (0.63 mL, 6.2 mmol), glacial acetic acid

(0.14 mL, 2.4 mmol) and piperidine (0.047 mL, 0.48 mmol) in

benzene (0.1 M, 48 mL) over 24 h. After work up and

purification, (25% EtOAc/Hexanes, R_f= 0.41), compound 3ea

was afforded as a white solid (1.0 g, 72 % yield). [m.p. = 50-56

1

˚C] H NMR (500 MHz, CDCl₃) δ = 7.97 (s, 1 H), 7.54 (dd, J =

1.5, 2.4 Hz, 1 H), 7.48 (td, J = 1.3, 7.8 Hz, 1 H), 7.36 - 7.33 (m, 2

H), 7.33 - 7.30 (m, 1 H), 7.29 (d, J = 3.4 Hz, 1 H), 7.27 - 7.22 (m,

3 H), 7.10 (ddd, J = 0.9, 2.7, 8.2 Hz, 1 H), 3.83 (s, 3 H), 3.77 -

3.75 (m, 3 H) ¹³C NMR (126 MHz, CDCl₃) δ = 195.3, 165.4,

160.0, 142.8, 137.2, 132.7, 130.8, 130.4, 130.2, 129.9, 128.8,

122.3, 120.8, 112.6, 55.4, 52.6 IR: 3055 (w), 3005 (w), 2951 (w),

2837 (w), 1721 (s), 1668 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd.

for C₁₈H₁₆O₄296.1049; Found 296.1045.

Methyl 3-oxo-2-(phenylmethyl-d)-3-(thiophen-3-yl)propanoate

(4aa-d)

Prepared following general procedure D using mixture 3aa-d

(1.0 g), NaBH₄(0.56 g, 14.93 mmol) and CeCl₃•7H₂O (2.78 g,

7.46 mmol) in MeOH (0.1 M, 37 mL) After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.38), compound 4aa-d

was afforded as a white oil (397 mg, 37% yield over 2 steps from

1a). ¹H NMR (300 MHz, CDCl₃) δ = 7.40 - 7.30 (m, 6 H), 7.20 -

7.16 (m, 1 H), 7.13 - 7.09 (m, 1 H), 5.85 (dd, J = 0.7, 11.6 Hz, 1

Methyl (Z)-2-(3,4-dimethoxybenzoyl)-3-phenylacrylate (3fa)

Prepared following general procedure C using 1f (1.00 g,

4.197 mmol), benzaldehyde (0.55 mL, 5.46 mmol), glacial acetic

acid (0.12 mL, 2.10 mmol) and piperidine (0.04 mL, 0.420

mmol) in benzene (42 mL) overnight. After work up and

purification, (25% EtOAc/Hexanes, R_f= 0.27), compound 3fa

H), 4.26 (dd, J = 0.9, 11.6 Hz, 1 H), 3.80 (d, J = 0.9 Hz, 3 H) ¹³

C

NMR (75 MHz, CDCl₃) δ = 168.1, 144.6, 133.9, 132.1, 129.3,

129.2, 128.7, 126.2, 126.1, 120.7, 67.5, 52.2 IR: 3497 (br), 3103

(w), 2949 (w), 2846 (w), 1686 (s) cm^-1. HRMS (EI) m/z: [M]⁺

Calcd. for C₁₅H₁₃DO₃S 275.0726; Found 275.0724

1

was afforded as a yellow solid (1.18 g, 86% yield). H NMR

(500 MHz, CDCl₃) δ = 7.95 (s, 1 H) 7.60 (d, J = 2.05 Hz, 1 H)

7.46 (dd, J = 8.36, 2.05 Hz, 1 H) 7.33 - 7.39 (m, 2 H) 7.19 - 7.29

(m, 3 H) 6.78 (d, J = 8.36 Hz, 1 H) 3.93 (s, 3 H) 3.90 (s, 3 H)

3.76 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ = 194.1, 165.6,

154.1, 149.3, 142.4, 132.8, 130.7, 130.3, 130.2, 129.1, 128.8,

125.0, 110.2, 110.1, 56.0, 55.9, 52.6. IR: 3059 (w), 3001 (w),

2951 (w), 2841 (w), 1717 (s), 1655 (s) cm^-1. HRMS (EI) m/z:

[M]⁺Calcd. for C₁₉H₁₈O₅326.1154; Found 326.1144.

Methyl

(Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-(4-

methoxyphenyl)acrylate (4ab)

Prepared following general procedure D using 3ab (830 mg,

2.75 mmol), NaBH₄(410 mg, 10.85 mmol) and CeCl₃•7H₂O

(1.31 g, 3.53 mmol) in MeOH (0.1 M, 27 mL). After work up

and purification, (20% EtOAc/Hexanes, R_f= 0.28), a mixture of

compounds 4ab and 3ab (352 mg) was isolated and re-exposed

to the reduction conditions using CeCl₃•7H₂O (560 mg, 1.50

mmol), NaBH₄(175 mg, 4.63 mmol) in MeOH (12 mL). After

workup and purification, compound 4ab was isolated as a

4.4. Syntheses of Carbinols 4: Luche Reductions

General Procedure D: To a dry round bottom flask under

nitrogen atmosphere charged with CeCl₃•7H₂O (2.0 equiv.) and a

magnetic stir bar was added alkylidene β-ketoester 3 (1.0 equiv.)

1

colorless oil (202 mg, 24% yield). H NMR (500 MHz, CDCl₃)

δ = 7.85 (s, 1 H), 7.33 - 7.28 (m, 3 H), 7.19 - 7.17 (m, 1 H), 7.13

(td, J = 1.1, 4.6 Hz, 1 H), 6.92 - 6.87 (m, 2 H), 5.90 - 5.85 (m, 1

H), 4.31 (d, J = 11.3 Hz, 1 H), 3.82 (s, 3 H), 3.79 (s, 3 H). ¹³C

NMR (126 MHz, CDCl₃) δ = 168.3, 160.6, 144.7, 141.1, 131.2,

130.2, 126.5, 126.4, 126.1, 120.8, 114.2, 67.6, 55.3, 52.0. IR:

3491 (br), 3102 (w), 2951 (w), 2837 (w), 1686 (s) cm^-1. HRMS

(EI) m/z: [M]⁺Calcd. for C₁₆H₁₆O₄S 304.0769; Found 304.0759.

°

in MeOH (0.1 M), which was stirred at 0 C for 5 min. Then,

NaBH₄(4.0 equiv.) was gradually added to the resulting mixture

°

at 0 C and allowed to stir for 2 h. The reaction was then

quenched with 0.1 M HCl and CH₂Cl₂was added and stirred

vigorously for 5 min; the mixture was extracted with CH₂Cl₂

three times. The combined organic layers were dried over

Na₂SO₄, filtered through celite, concentrated under reduced

pressure, and purified by flash chromatography on silica gel

using Et₂O/Hexanes as the mobile phase.

Methyl (Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-(p-tolyl)acrylate

(4ac)

Prepared following general procedure D using 3ac (201 mg,

0.702 mmol), NaBH₄(106 mg, 2.79 mmol) and anhydrous CeCl₃

(231 mg, 0.937 mmol) in MeOH (0.1 M, 7 mL). After work up

and purification by prep-TLC, (20% EtOAc/Hexane, R_f= 0.43),

compound 4ac was afforded as a white oil as a 4:1 mixture with

3ac (51 mg, 21% yield of 4ac). ¹H NMR (300 MHz, CDCl₃) δ =

General Procedure E: To a dry round bottom flask under

nitrogen atmosphere charged with CeCl₃•7H₂O (2.0 equiv.) and a

magnetic stir bar was added alkylidene β-ketoester 3 (1.0 equiv.)

in a 9:1 ratio of THF:MeOH (0.05 M), which was stirred at 0 ^°C

for 5 min. Then, NaBH₄(4.0 equiv.) was gradually added to the

resulting mixture at 0 ^°C and allowed to stir for 2 h. The reaction

12

Tetrahedron

ACCEPTED MANUSCRIPT

7.97 (M, 0.28 H), 7.91 (s, 0.21 H), 7.88 (s, 0.96 H), 7.59 -

Prepared following general procedure D using 3ag (255 mg,

7.50 (m, 0.39 H), 7.37 (d, J = 8.1 Hz, 0.31 H), 7.33 - 7.28 (m,

1.43 H), 7.28 - 7.21 (m, 2.78 H), 7.21 - 7.14 (m, 3.36 H), 7.14 -

7.09 (m, 1.13 H), 7.06 (d, J = 8.4 Hz, 0.68 H), 5.87 (d, J = 11.6

Hz, 1.00 H), 4.30 (dd, J = 0.4, 11.6 Hz, 0.97 H), 3.80 - 3.76 (m,

3.76 H), 2.36 (s, 3.21 H), 2.29 (s, 0.79 H), 2.18 - 2.16 (m, 0.32

H). ¹³C NMR (75 MHz, CDCl₃) δ = 168.2, 144.7, 142.4, 141.3,

141.1, 139.6, 134.9, 131.3, 131.1, 130.3, 129.8, 129.6, 129.6,

129.5, 129.4, 129.3, 127.0, 126.9, 126.3, 126.0, 120.7, 67.5, 52.5,

52.1, 21.4, 21.3 IR: 3491 (br), 3100 (w), 2949 (w), 2849 (w),

1688 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₆H₁₆O₃S

288.0820; Found 288.0822.

0.843 mmol), NaBH₄(128 mg, 3.374 mmol) and CeCl₃•7H₂O

(629 mg, 1.687 mmol) in MeOH (0.1 M, 8.4 mL). After work up

and purification, (50% Et₂O/Hexanes, R_f= 0.39), compound 4ag

1

was afforded as a colorless oil (79 mg, 31% yield). H NMR

(500 MHz, CDCl₃) δ = 7.88 (s, 1 H) 7.25 - 7.32 (m, 2 H) 7.16 -

7.20 (m, 1 H) 7.12 (d, J = 4.58 Hz, 1 H) 6.88 - 6.95 (m, 2 H) 6.86

(s, 1 H) 5.86 (d, J = 11.60 Hz, 1 H) 4.26 (d, J = 11.60 Hz, 1 H)

3.79 (s, 3 H) 3.71 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ =

167.9, 159.5, 144.5, 141.05, 135.3, 132.3, 129.6, 126.2, 126.1,

121.4, 120.8, 115.1, 114.2, 67.5,55.0, 52.1. IR: 3495 (br), 3098

(w), 2949 (w), 2835 (w), 1692 (s) cm^-1. HRMS (EI) m/z: [M]⁺

Calcd. for C₁₆H₁₆O₄S 304.0769; Found 304.0771.

Methyl

(Z)-3-(4-bromophenyl)-2-(hydroxy(thiophen-3-

yl)methyl)acrylate (4ad)

Methyl

(Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-(thiophen-2-

yl)acrylate (4ah)

Prepared following general procedure D using 3ad (250 mg,

0.712 mmol), NaBH₄(108 mg, 2.85 mmol) and CeCl₃•7H₂O (530

mg, 1.42 mmol) in MeOH (0.04 M, 18 mL). After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.38), compound 4ad

Prepared following general procedure D using 3ah (744 mg,

2.67 mmol), NaBH₄(414 mg, 10.94 mmol) and CeCl₃•7H₂O

(1.29 g, 3.48 mmol) in MeOH (0.1 M, 26 mL). The reaction

mixture was warmed to room temperature and stirred overnight.

After workup and purification (20% EtOAc/Hexanes, R_f= 0.36),

a mixture of compounds 4ah and 3ah (323 mg) was isolated and

re-exposed to the reduction conditions using CeCl₃•7H₂O (555

mg, 1.50 mmol), NaBH₄(175 mg, 4.63 mmol) in MeOH (11

mL). After workup and purification, compound 4ah was isolated

1

was afforded as a colorless oil (111 mg, 44% yield). H NMR

(500 MHz, CDCl₃) δ = 7.80 (s, 1 H), 7.53 - 7.49 (m, 2 H), 7.32

(dd, J = 3.1, 4.9 Hz, 1 H), 7.22 - 7.18 (m, 2 H), 7.16 (td, J = 1.5,

2.8 Hz, 1 H), 7.09 - 7.07 (m, 1 H), 5.76 (dd, J = 0.6, 11.6 Hz, 1

H), 4.19 (d, J = 11.6 Hz, 1 H), 3.80 (s, 3 H). ¹³C NMR (126

MHz, CDCl₃) δ = 167.8, 144.2, 139.8, 132.9, 132.9, 131.9, 130.7,

126.3, 126.1, 123.7, 120.9, 67.4, 52.3 IR: 3493 (br), 3102 (w),

2949 (w), 2845 (w), 1697 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd.

for C₁₅H₁₃O₃SBr 351.9769; Found 351.9767.

1

as a yellow solid (143 mg, 19% yield). [m.p. = 95-99 ˚C] H

NMR (500 MHz, CDCl₃) δ = 7.94 (d, J = 0.6 Hz, 1 H), 7.51 -

7.49 (m, 1 H), 7.29 (dd, J = 3.1, 4.9 Hz, 1 H), 7.27 (td, J = 1.1,

3.6 Hz, 1 H), 7.23 - 7.21 (m, 1 H), 7.14 - 7.12 (m, 1 H), 7.09 (dd,

J = 3.7, 5.2 Hz, 1 H), 6.20 (dd, J = 0.6, 11.3 Hz, 1 H), 4.53 (d, J

= 11.3 Hz, 1 H), 3.80 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ =

168.0, 143.6, 136.6, 133.2, 132.9, 130.6, 128.6, 127.8, 126.2,

126.1, 121.0, 68.0, 52.2. IR: 3470 (br), 3102 (w), 2949 (w), 1682

(s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₃H₁₂O₃S₂280.0228;

Found 280.0225.

Methyl

(Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-(4-

(trifluoromethyl)phenyl)acrylate (4ae)

Prepared following general procedure D using 3ae (250 mg,

0.735 mmol), NaBH₄(111 mg, 2.94 mmol) and CeCl₃•7H₂O (547

mg, 1.47 mmol) in MeOH (0.1 M, 7.4 mL). After work up and

purification, (40% Et₂O/Hexanes, R_f= 0.36), compound 4ae was

1

afforded as a colorless oil (69.6 mg, 28% yield). H NMR (500

Methyl (2Z,4E)-2-(hydroxy(thiophen-3-yl)methyl)-5-phenylpenta-

MHz, CDCl₃) δ = 7.88 (s, 1 H), 7.64 (d, J = 8.2 Hz, 2 H), 7.45

(dd, J = 0.6, 7.9 Hz, 2 H), 7.32 (dd, J = 3.1, 4.9 Hz, 1 H), 7.19 -

7.14 (m, 1 H), 7.10 - 7.06 (m, 1 H), 5.76 - 5.69 (m, 1 H), 4.16 (d,

J = 11.6 Hz, 1 H), 3.82 (s, 3 H) ¹³C NMR (126 MHz, CDCl₃) δ =

167.6, 144.0, 139.3, 134.2, 129.3, 126.4, 126.0, 125.7, 125.7,

125.6, 125.6, 120.9, 67.4, 52.4 IR: 3497 (br), 3107 (w), 2953

(w), 2851 (w), 1701 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₆H₁₃O₃SF₃342.0583; Found 342.0536.

2,4-dienoate (4ai)

Prepared following general procedure D using 3ai (308 mg,

1.03 mmol), NaBH₄(156 mg, 4.13 mmol) and CeCl₃•7H₂O (769

mg, 2.07 mmol) in MeOH (0.1 M, 10 mL). After work up and

purification, (40% Et₂O/Hexanes, R_f= 0.35), compound 4ai was

1

afforded as an orange oil (204 mg, 66% yield). H NMR (500

MHz, CDCl₃) δ = 7.54 (d, J = 11.6 Hz, 1H), 7.51 - 7.47 (m, 2H),

7.41 - 7.25 (m, 6H), 7.24 - 7.21 (m, 1H), 7.09 (dd, J = 1.1, 5.0

Hz, 1H), 7.01 (d, J = 15.3 Hz, 1H), 6.01 (d, J = 10.1 Hz, 1H),

4.38 (d, J = 10.1 Hz, 1H), 3.79 (s, 3H). ¹³C NMR (126 MHz,

CDCl₃) δ = 167.8, 144.5, 142.3, 140.3, 135.8. 130.1, 129.3,

128.8, 127.4, 126.0, 125.9, 122.1, 120.5, 67.5, 51.9. IR: 3449

(br), 3024 (w), 2949 (w), 1682 (s) cm^-1. HRMS (EI) m/z: [M]⁺

Calcd. for C₁₇H₁₆O₃S 300.0820; Found 300.0824.

Methyl

(Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-(2-

methoxyphenyl)acrylate (4af)

Prepared following general procedure D using 3af (500 mg,

1.65 mmol), NaBH₄(250 mg, 6.62 mmol) and CeCl₃•7H₂O (1.23

g, 3.31 mmol) in MeOH (0.1 M, 17 mL). After work up and

purification, (40% Et₂O/Hexanes, R_f= 0.36), compound 4af was

afforded as a white solid (380 mg, 75% yield). [m.p. = 98-99 ˚C]

¹H NMR (500 MHz, CDCl₃) δ = 8.02 (s, 1 H), 7.37 - 7.32 (m, 1

H), 7.29 (dd, J = 2.9, 5.0 Hz, 1 H), 7.24 - 7.20 (m, 1 H), 7.18 -

7.16 (m, 1 H), 7.09 (td, J = 1.1, 4.6 Hz, 1 H), 6.93 - 6.89 (m, 2

H), 5.80 - 5.71 (m, 1 H), 4.34 - 4.17 (m, 1 H), 3.86 (s, 3 H), 3.81

- 3.78 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ = 168.2, 157.6,

145.0, 137.8, 131.8, 130.9, 129.8, 126.3, 125.9, 123.1, 120.5,

120.4, 110.6, 67.9, 55.4, 52.0. IR: 3505 (br), 3103 (w), 2949 (w),

2837 (w), 1690 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₆H₁₆O₄S 304.0769; Found 304.0763.

Methyl (Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-(naphthalen-2-

yl)acrylate (4aj)

Prepared following general procedure E using 3aj (157 mg,

0.487 mmol), NaBH₄(73.7 mg, 1.95 mmol) and CeCl₃•7H₂O

(363 mg, 0.974 mmol) in 9:1 ratio of THF:MeOH (0.05 M, 4.9

mL). After work up and purification, (40% Et₂O /Hexanes, R_f=

0.32), compound 4aj was afforded as a yellow oil (27 mg, 17%

yield). ¹H NMR (500 MHz, CDCl₃) δ = 8.06 (s, 1 H) 7.82 - 7.86

(m, 3 H) 7.79 (d, J = 7.32 Hz, 1 H) 7.48 - 7.54 (m, 2 H) 7.45 (dd,

J = 8.54, 1.22 Hz, 1 H) 7.33 (dd, J = 5.04, 2.90 Hz, 1 H) 7.23

(dd, J = 2.59, 1.37 Hz, 1 H) 7.14 (d, J = 5.19 Hz, 1 H) 5.97 (d, J

= 11.29 Hz, 1 H) 4.31 (d, J = 11.60 Hz, 1 H) 3.83 (s, 3 H). ¹³C

NMR (126 MHz, CDCl₃) δ = 168.1, 144.6, 141.3, 133.3, 132.9,

Methyl

(Z)-2-(hydroxy(thiophen-3-yl)methyl)-3-(3-

methoxyphenyl)acrylate (4ag)

13

132.4, 131.5, 129.1, 128.4, 128.4, 127.7, 127.1, 126.6, 126.3,

126.2, 120.9, 67.6, 52.2. IR: 3482 (br), 3051 (w), 2949 (w), 2849

(w), 1694 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₉H₁₆O₃S

324.0820; Found 324.0828.

(500 MHz, CDCl₃) δ = 8.08 (s, 1 H), 7.92 - 7.83 (m, 4 H),

ACCEPTED MANUSCRIPT

7.62 (dd, J = 1.7, 8.7 Hz, 1 H), 7.53 - 7.48 (m, 2 H), 7.47 - 7.43

(m, 2 H), 7.42 - 7.37 (m, 3 H), 6.09 (d, J = 11.3 Hz, 1 H), 4.30 (d,

J = 11.6 Hz, 1 H), 3.77 (s, 3 H) ¹³C NMR (126 MHz, CDCl₃) δ =

168.0, 142.0, 140.1, 134.1, 133.2, 132.7, 132.1, 129.3, 129.2,

128.7, 128.2, 128.1, 127.6, 126.1, 125.8, 124.0, 123.9, 69.9, 52.1.

IR: 3501 (br), 3055 (w), 2949 (w), 1692 (s) cm^-1. HRMS (EI)

m/z: [M]⁺Calcd. for C₂₁H₁₈O₃318.1256; Found 328.1258.

Methyl

(Z)-2-(hydroxy(thiophen-3-yl)methyl)-4-methylpent-2-

enoate (4ak)

Prepared following general procedure D using (Z)-methyl 4-

methyl-2-(thiophene-3-carbonyl)pent-2-enoate (860 mg, 3.61

mmol), NaBH₄(546 mg, 14.4 mmol) and CeCl₃•7H₂O (2.69 g,

7.22 mmol) in MeOH (0.1 M, 36 mL). After work up and

purification, (20% Et₂O/Hexanes, R_f= 0.45), compounds 4ak and

6ak (compound ratio: 2:1) were afforded as a colorless oil (383

mg, 44% yield). ¹H NMR (500 MHz, CDCl₃) δ = 7.27 - 7.31 (m,

3.04) 7.23 (dt, J=1.83, 0.92 Hz, 0.93) 7.11 - 7.14 (m, 1.78) 7.02 -

7.06 (m, 2.82) 6.75 (d, J=10.38 Hz, 1.89) 5.70 (br. s., 1.86) 5.02

(d, J=5.49 Hz, 0.95) 4.26 - 4.34 (m, 1.42) 3.73 (s, 5.72) 3.63 (s,

2.87) 2.80 - 2.89 (m, 2.99) 1.71 - 1.78 (m, 1.00) 1.40 - 1.53 (m,

2.01) 1.11 (d, J=6.71 Hz, 6.01) 1.07 (d, J=6.41 Hz, 6.00) 0.89 (d,

J=6.41 Hz, 3.02) 0.85 (d, J=6.41 Hz, 2.97). ¹³C NMR (126 MHz,

CDCl₃) δ = 175.5, 167.9, 151.1, 144.8, 143.0, 129.7, 126.0,

125.9, 125.8, 125.4, 121.3, 120.3, 71.3, 67.3, 51.8, 51.6, 50.6,

36.2, 27.5, 26.2, 23.4, 22.2, 22.1, 21.4. IR: 3451 (br), 3107 (w),

2957 (m), 2868 (w), 1694 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd.

for C₁₂H₁₆O₃S 240.0820; Found 240.0820.

Methyl

phenylacrylate (4ea)

(Z)-2-(hydroxy(3-methoxyphenyl)methyl)-3-

Prepared following general procedure D using 3ea (514 mg,

1.74 mmol), NaBH₄(263 mg, 6.94 mmol) and CeCl₃•7H₂O (1.29

g, 3.47 mmol) in MeOH (0.1 M, 17 mL). After work up and

purification, (30% Et₂O/Hexanes, R_f= 0.208), compound 4ea

1

was afforded as an off-white oil (314 mg, 61% yield). H NMR

(500 MHz, CDCl₃) δ = 7.96 (s, 1 H) 7.34 - 7.39 (m, 5 H) 7.24 -

7.28 (m, 1 H) 7.03 (d, J=1.22 Hz, 1 H) 6.95 - 6.98 (m, 1 H) 6.82

(dd, J=8.24, 2.44 Hz, 1 H) 5.84 (d, J=9.16 Hz, 1 H) 4.07 (d,

J=10.68 Hz, 1 H) 3.80 (s, 3 H) 3.76 (s, 3 H). ¹³C NMR (126

MHz, CDCl₃) δ = 168.0, 159.8, 144.5, 141.9, 134.2, 132.2, 129.4,

129.3, 129.1, 128.7, 117.7, 112.7, 111.3, 69.6, 55.2, 52.1. IR:

3507 (br), 3024 (w), 2951 (w), 2835 (w), 1694 (s) cm^-1. HRMS

(EI) m/z: [M]⁺Calcd. for C₁₈H₁₈O₄298.1205; Found 298.1205.

Methyl

(Z)-2-((3,4-dimethoxyphenyl)(hydroxy)methyl)-3-

phenylacrylate (4fa)

Methyl

(Z)-2-(benzo[b]thiophen-3-yl(hydroxy)methyl)-3-

phenylacrylate (4ba)

Prepared following general procedure D using 3fa (262 mg,

0.803 mmol), NaBH₄(121.5 mg, 3.21 mmol) and CeCl₃•7H₂O

(598 mg, 1.61 mmol) in MeOH (0.1 M, 8.0 mL). After work up

and purification, (50% Et₂O/Hexanes, R_f= 0.174), compound 4fa

Prepared following general procedure D using 3ba (500 mg,

1.55 mmol), NaBH₄(235 mg, 6.20 mmol) and CeCl₃•7H₂O (1.16

g, 3.10 mmol) in MeOH (0.1 M, 16 mL). After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.41), compound 4ba

1

was afforded as a white oil (101 mg, 39% yield). H NMR (500

1

was afforded as a colorless oil (109 mg, 22% yield). H NMR

MHz, CDCl₃) δ = 7.95 (s, 1 H), 7.40 - 7.33 (m, 5 H), 7.07 (d, J =

1.2 Hz, 1 H), 6.87 - 6.84 (m, 1 H), 6.84 - 6.81 (m, 1 H), 5.82 (dd,

J = 0.6, 11.6 Hz, 1 H), 4.11 (d, J = 11.6 Hz, 1 H), 3.88 - 3.86 (m,

6 H), 3.78 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ = 168.2,

149.1, 148.2, 141.7, 135.3, 134.2, 132.2, 129.3, 129.1, 128.8,

128.7, 117.3, 110.8, 109.1, 69.6, 55.8, 55.8, 52.1. IR: 3491 (br),

3057 (w), 2953 (w), 2835 (w), 1694 (s) cm^-1. HRMS (EI) m/z:

[M]⁺Calcd. for C₁₉H₂₀O₅328.1311; Found 328.1317.

(500 MHz, CDCl₃) δ = 7.96 - 7.92 (m, 1 H), 7.90 - 7.84 (m, 1 H),

7.40 - 7.30 (m, 6 H), 7.30 - 7.27 (m, 2 H), 6.15 - 6.09 (m, 1 H),

4.30 (d, J = 11.6 Hz, 1 H), 3.85 (s, 3 H). ¹³C NMR (126 MHz,

CDCl₃) δ = 168.3, 141.7, 140.8, 137.8, 137.3, 134.0, 131.3,

129.4, 129.3, 128.7, 124.5, 124.1, 123.3, 123.3, 122.7, 66.9, 52.3.

IR: 3501 (br), 3061 (w), 2951 (w), 2847 (w), 1694 (s) cm^-1.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₉H₁₆O₃S 324.0820; Found

324.0824.

4.5. Reaction Optimizations

Methyl (Z)-2-(benzofuran-2-yl(hydroxy)methyl)-3-phenylacrylate

(4ca)

4.5.1. Procedure for Catalyst Screening

To a round bottom flask charged with the appropriate Lewis

acid catalyst (10 mol %), and a magnetic stir bar in CH₂Cl₂(1

mL) at the appropriate temperature under nitrogen atmosphere

was added a solution of allylic alcohol 4aa (1.0 equiv.) in CH₂Cl₂

(0.1 M). The reaction was monitored via TLC and allowed to

cool to room temperature once the reaction reached completion,

concentrated under reduced pressure and purified by flash

chromatography on silica gel using EtOAc/Hexanes as the

mobile phase.

Prepared following general procedure D using 3ca (500 mg,

1.63 mmol), NaBH₄(247 mg, 6.53 mmol) and CeCl₃•7H₂O (1.22

g, 3.26 mmol) in MeOH (0.1 M, 16 mL). After work up and

purification, (20% EtOAc/Hexanes, R_f= 0.32), compound 4ca

was afforded as a pale yellow solid (307 mg, 61% yield). [m.p. =

1

99-100 ˚C] H NMR (500 MHz, CDCl₃) δ = 8.01 (s, 1 H) 7.54 -

7.57 (m, 1 H) 7.47 - 7.51 (m, 1 H) 7.37 - 7.45 (m, 5 H) 7.20 -

7.30 (m, 3 H) 6.73 (s, 1 H) 5.95 (d, J = 11.29 Hz, 1 H) 4.48 (dd,

J=11.44, 1.07 Hz, 1 H) 3.84 (s, 3 H). ¹³C NMR (75 MHz,

CDCl₃) δ = 167.9, 157.9, 154.9, 143.1, 133.7, 129.5, 129.5,

129.3, 128.6, 128.3, 124.0, 122.8, 121.0, 111.3, 103.4, 65.6, 52.3

IR: 3489 (br), 3063 (w), 2951 (w), 1694 (s) cm^-1. HRMS (EI)

m/z: [M]⁺Calcd. for C₁₉H₁₆O₄308.1049; Found 308.1048.

4.5.2. Procedure for Optimization of Catalyst

Loading

To a round bottom flask charged with x mol % Ca(NTf₂)₂, x

mol % n-Bu₄NPF₆, and a magnetic stir bar in CH₂Cl₂(1 mL) at

40 ˚C under nitrogen atmosphere was added a solution of allylic

alcohol 4aa (1.0 equiv.) in CH₂Cl₂(0.1 M). The reaction was

monitored via TLC and allowed to cool to room temperature

once the reaction reached completion, concentrated under

reduced pressure and purified by flash chromatography on silica

gel using EtOAc/Hexanes as the mobile phase.

Methyl (Z)-2-(hydroxy(naphthalen-2-yl)methyl)-3-phenylacrylate

(4da)

Prepared following general procedure D using 3da (259 mg,

0.819 mmol), NaBH₄(546 mg, 14.4 mmol) and CeCl₃•7H₂O

(2.69 g, 7.22 mmol) in MeOH (0.1 M, 8.2 mL). After work up

and purification, (40% Et₂O/Hexanes, R_f= 0.444), compound

4.5.3. Procedure for Solvent Screening

1

4da was afforded as a white oil (99.6 mg, 38% yield). H NMR

14

Tetrahedron

Methyl

6-(p-tolyl)-6H-cyclopenta[b]thiophene-5-carboxylate

To a round bottom flask charged with 10 mol % Ca(NTf₂)₂,

ACCEPTED MANUSCRIPT

(5ac-I)

10 mol % n-Bu₄NPF₆, and a magnetic stir bar in the appropriate

solvent (1 mL) at appropriate temperature under nitrogen

atmosphere was added a solution of allylic alcohol 4aa (1.0

equiv.) in appropriate solvent (0.1 M). After 1 h 45 min, the

reaction mixture was allowed to cool to room temperature,

concentrated under reduced pressure and purified by flash

chromatography on silica gel using EtOAc/Hexanes as the

mobile phase.

The general procedure was followed using a 4:1 mixture of

allylic alcohol 4ac and compound 3ac (51 mg, 0.18 mmol) in

benzene (3.6 mL), Ca(NTf₂)₂(10.7 mg, 0.018 mmol), n-Bu₄NPF₆

(6.9 mg, 0.018 mmol). After work up and purification, (20%

EtOAc/Hexanes, R_f= 0.56), compound 5ac-I was afforded as a

yellow oil (25.1 mg, 66% yield). (Isomeric Ratio = 6.5:1) Yield

calculated based on starting material NMR. ¹H NMR (300 MHz,

CDCl₃) δ = 7.70 (d, J = 1.9 Hz, 0.14 H), 7.61 - 7.55 (m, 1.95 H),

7.47 - 7.43 (m, 0.96 H), 7.36 - 7.33 (m, 0.16 H), 7.30 - 7.24 (m,

2.21 H), 7.13 (d, J = 4.8 Hz, 1.01 H), 7.10 - 7.04 (m, 0.49 H),

7.00 (s, 0.33 H), 4.88 - 4.84 (m, 0.15 H), 3.76 - 3.73 (m, 2.00 H),

3.73 - 3.71 (m, 3.04 H), 3.70 - 3.69 (m, 0.41 H), 2.42 (s, 3.05 H),

2.30 (s, 0.46 H) ¹³C NMR (75 MHz, CDCl₃) δ = 165.1, 150.3,

148.7, 147.3, 139.0, 131.1, 130.2, 129.3, 128.8, 128.7, 127.5,

122.6, 51.1, 37.1, 21.4 IR: 3076 (w), 3022 (w), 2947 (w), 1703

(s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₆H₁₄O₂S 270.0715;

Found 270.0715.

4.6. Dehydrative Nazarov-type Cyclizations

General Procedure F: To a round bottom flask charged with 10

mol % Ca(NTf₂)₂, 10 mol % n-Bu₄NPF₆, and a magnetic stir bar

in benzene (1 mL) at 40 ˚C under nitrogen atmosphere was added

a solution of allylic alcohol 4 (1.0 equiv.) in benzene (0.05 M).

After 1.75 h, the reaction mixture was allowed to cool to room

temperature, concentrated under reduced pressure and purified by

flash chromatography on silica gel using EtOAc/Hexanes as the

mobile phase.

Methyl 6-phenyl-4H-cyclopenta[b]thiophene-5-carboxylate (5aa-

I)

Methyl

carboxylate (5ad-I)

6-(4-bromophenyl)-4H-cyclopenta[b]thiophene-5-

The general procedure F was followed using allylic alcohol

4aa (72 mg, 0.263 mmol) in benzene (5.3 mL), Ca(NTf₂)₂(15.8

mg, 0.026 mmol), n-Bu₄NPF₆(10.2 mg, 0.026 mmol). After

work up and purification, (20% EtOAc/Hexanes, R_f= 0.44),

compound 5aa-I was afforded as a white solid (47.1 mg, 70%

yield). [m.p. = 82-85 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 7.65 -

7.69 (m, 2 H), 7.41 - 7.49 (m, 5 H), 7.14 (d, J = 4.88 Hz, 1 H),

3.76 (s, 2 H), 3.72 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ =

164.9, 150.2, 148.8, 147.2, 134.1, 130.3, 129.3, 128.9, 128.7,

128.0, 122.6, 51.1, 37.1. IR: 3028 (w), 2947 (w), 2841 (w), 1701

(s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₅H₁₂O₂S 256.0558;

Found 256.0561.

The general procedure F was followed using allylic alcohol 4ad

(37 mg, 0.105 mmol) in benzene (2.1 mL), Ca(NTf₂)₂(6.3 mg,

0.010 mmol), n-Bu₄NPF₆(4.1 mg, 0.010 mmol). After work up

and purification, (20% EtOAc/Hexanes, R_f= 0.57), compound

5ad-I was afforded as a white solid (24.2 mg, 69% yield). [m.p.

= 127-128 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 7.57 - 7.61 (m, 2

H), 7.51 - 7.55 (m, 2 H), 7.46 (d, J = 4.88 Hz, 1 H), 7.14 (d, J =

4.88 Hz, 1 H), 3.74 (s, 2 H), 3.72 (s, 3 H). ¹³C NMR (126 MHz,

CDCl₃) δ = 164.8, 149.1, 148.9, 146.7, 133.0, 131.3, 130.5,

130.4, 129.8, 123.2, 122.7. IR: 3103 (w), 2947 (w), 2841 (w),

1697 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₅H₁₁BrO₂S

333.9663; Found 333.9657.

Methyl 6-phenyl-6H-cyclopenta[b]thiophene-5-carboxylate-6-d

(5aa-II-d)

Methyl

6-(4-(trifluoromethyl)phenyl)-4H-

cyclopenta[b]thiophene-5-carboxylate (5ae-I)

The general procedure F was followed using allylic alcohol

4aa-d (60 mg, 0.233 mmol) in benzene (4.6 mL), Ca(NTf₂)₂

(13.5 mg, 0.023 mmol), n-Bu₄NPF₆(9.0 mg, 0.023 mmol). After

work up and purification, (20% EtOAc/Hexanes, R_f= 0.44),

compound 5aa-II-d was afforded as a white solid (41.9 mg, 70%

The general procedure F was followed using allylic alcohol

4ae (34 mg, 0.099 mmol) in benzene (2.0 mL), Ca(NTf₂)₂(6.0

mg, 0.010 mmol), n-Bu₄NPF₆(3.8 mg, 0.010 mmol). After work

up and purification, (20% EtOAc/Hexanes, R_f= 0.55), compound

5ae-I was afforded as a white solid (21.6 mg, 67% yield). [m.p. =

1

yield). [m.p. = 94-96 ˚C] H NMR (500 MHz, CDCl₃) δ = 7.74

1

133-134 ˚C] H NMR (500 MHz, CDCl₃) δ = 7.70 - 7.78 (m, 4

(s, 1 H), 7.37 (d, J = 5.2 Hz, 1 H), 7.31 - 7.21 (m, 3 H), 7.13 -

7.08 (m, 3 H), 3.70 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ =

163.9, 154.7, 145.9, 143.8, 137.9, 137.4, 129.7, 128.6, 127.7,

127.1, 119.9, 51.3. IR: 3080 (w), 3024 (w), 2947 (w), 2839 (w),

1703 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for C₁₅H₁₁DO₂S

257.0621; Found 257.0630.

H), 7.48 (d, J = 4.58 Hz, 1 H), 7.16 (d, J = 4.58 Hz, 1 H), 3.78 (s,

2 H), 3.72 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃) δ = 164.7,

149.1, 148.8, 146.6, 137.9, 130.9, 130.6, 129.1, 125.1, 125.0,

125.0, 122.8, 51.3, 37.2. IR: 3107 (w), 2951 (w), 1701 (s) cm^-1.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₆H₁₁F₃O₂S 324.0432; Found

324.0417.

Methyl

carboxylate (5ab-I)

6-(4-methoxyphenyl)-4H-cyclopenta[b]thiophene-5-

Methyl

carboxylate (5af-II)

6-(2-methoxyphenyl)-6H-cyclopenta[b]thiophene-5-

The general procedure F was followed using allylic alcohol

4ab (59 mg, 0.194 mmol) in benzene (3.9 mL), Ca(NTf₂)₂(11.6

mg, 0.019 mmol), n-Bu₄NPF₆(7.5 mg, 0.019 mmol). After work

up and purification, (20% EtOAc/Hexanes, R_f= 0.33), compound

5ab-I was afforded as an off-white solid (45.4 mg, 82% yield).

[m.p. = 117-120 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 7.65 - 7.69

(m, 2 H), 7.45 (d, J = 4.88 Hz, 1 H), 7.13 (d, J = 4.88 Hz, 1 H),

6.97 - 7.01 (m, 2 H), 3.87 (s, 3 H), 3.72 - 3.75 (m, 5 H). ¹³C

NMR (126 MHz, CDCl₃) δ = 165.1, 160.1, 150.0, 148.7, 147.3,

130.4, 130.2, 128.1, 126.3, 122.6, 113.4, 55.2, 51.1, 37.1. IR:

3105 (w), 3007 (w), 2947 (w), 2839 (w), 1701 (s) cm^-1. HRMS

(EI) m/z: [M]⁺Calcd. for C₁₆H₁₄O₃S 286.0664; Found 286.0677.

The general procedure F was followed using allylic alcohol 4af

(54 mg, 0.18 mmol) in benzene (3.6 mL), Ca(NTf₂)₂(10.7 mg,

0.018 mmol), n-Bu₄NPF₆(6.9 mg, 0.018 mmol). After work up

and purification, (20% EtOAc/Hexanes, R_f= 0.46), compound

5af-II was afforded as a white oil (38.0 mg, 75% yield).

(Isomeric Ratio = 8:1) ¹H NMR (300 MHz, CDCl₃) δ = 7.83 (dd,

J = 0.7, 2.0 Hz, 1.00 H), 7.45 - 7.35 (m, 0.37 H), 7.27 - 7.17 (m,

2.33 H), 7.12 - 7.08 (m, 0.14 H), 7.02 (dd, J = 0.6, 5.0 Hz, 1.25

H), 6.95 (d, J = 8.2 Hz, 1.09 H), 6.80 - 6.74 (m, 2.05 H), 5.34 (d,

J = 2.1 Hz, 0.97 H), 3.99 (s, 3.22 H), 3.80 (s, 0.40 H), 3.74 (d, J =

0.6 Hz, 3.49 H), 3.67 (d, J = 0.7 Hz, 0.44 H) ¹³C NMR (75 MHz,

CDCl₃) δ = 164.3, 157.1, 154.3, 144.8, 141.6, 138.9, 128.8,

128.1, 126.8, 126.5, 120.6, 119.7, 110.6, 55.4, 51.4, 47.7. IR:

15

3080 (w), 2947 (w), 2835 (w), 1703 (s) cm^-1. HRMS (EI) m/z:

(d, J = 8.2 Hz, 1.13 H), 7.66 (d, J = 8.2 Hz, 1.12 H), 7.56 -

ACCEPTED MANUSCRIPT

[M]⁺Calcd. for C₁₆H₁₄O₃S 286.0664; Found 286.0663.

7.50 (m, 1.07 H), 7.48 (d, J = 4.9 Hz, 0.40 H), 7.43 (ddd, J = 1.2,

6.7, 7.9 Hz, 1.32 H), 7.36 (ddd, J = 1.2, 6.7, 8.2 Hz, 1.20 H), 7.33

- 7.31 (m, 0.21 H), 7.18 (dd, J = 1.4, 2.9 Hz, 1.01 H), 7.13 (dd, J

= 3.1, 4.9 Hz, 1.01 H), 7.01 (dd, J = 1.8, 8.5 Hz, 0.06 H), 6.90 -

6.89 (m, 0.04 H), 6.87 (dd, J = 1.4, 5.0 Hz, 0.04 H), 6.64 (dd, J =

1.4, 5.0 Hz, 0.98 H), 5.39 (d, J = 1.8 Hz, 1.00 H), 5.06 - 5.04 (m,

0.04 H), 3.96 (s, 0.34 H), 3.81 (s, 0.73 H), 3.78 (s, 2.96 H), 3.72

(s, 0.97 H), 3.71 (s, 0.51 H), 3.66 (s, 0.13 H) ¹³C NMR (126

MHz, CDCl₃) δ = 165.0, 164.4, 150.2, 148.8, 147.4, 146.0, 142.9,

141.5, 140.9, 139.0, 138.9, 137.5, 133.5, 133.4, 133.2, 132.9,

131.8, 130.4, 129.6, 129.4, 129.1, 128.8, 128.8, 128.4, 128.2,

127.8, 127.7, 127.5, 127.1, 126.8, 126.6, 126.2, 126.2, 126.0,

125.7, 125.3, 125.2, 124.0, 123.3, 122.8, 122.7, 122.2, 121.2,

51.5, 51.3, 51.2, 50.5, 39.9, 37.2. IR: 3103 (w), 3055 (w), 2947

(w), 2843 (w), 1703 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₉H₁₄O₂S 306.0715; Found 306.0713.

Methyl

5-methoxy-1-(thiophen-3-yl)-1H-indene-2-carboxylate

(5ag-IV)

The general procedure F was followed using allylic alcohol

4ag (78 mg, 0.256 mmol) in benzene (5.1 mL), Ca(NTf₂)₂(15.4

mg, 0.026 mmol), n-Bu₄NPF₆(9.9 mg, 0.026 mmol). After work

up and purification, (20% EtOAc/Hexanes, R_f= 0.545),

compound 5ag-IV was afforded as an off-white solid (58.2 mg,

1

79% yield). [m.p. = 101-119 ˚C] H NMR (500 MHz, CDCl₃)

δ = 7.69 (d, J = 1.8 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 1 H), 7.17 (dd,

J = 2.9, 5.0 Hz, 1 H), 7.13 (dd, J = 1.1, 2.9 Hz, 1 H), 7.05 (d, J =

2.4 Hz, 1 H), 6.87 (dd, J = 2.4, 8.2 Hz, 1 H), 6.69 (dd, J = 1.4,

5.0 Hz, 1 H), 4.98 (d, J = 1.8 Hz, 1 H), 3.84 (s, 3 H), 3.74 (s, 3 H)

¹³C NMR (126 MHz, CDCl₃) δ = 164.6, 159.3, 142.2, 141.8,

141.5, 140.9, 138.1, 126.7, 125.3, 124.9, 121.8, 114.6, 108.3,

55.4, 51.5, 49.9. IR: 3103 (w), 2949 (w), 2835 (w), 1705 (s) cm^-

¹. HRMS (EI) m/z: [M]⁺Calcd. for C₁₆H₁₄O₃S 286.0664; Found

286.0662.

Methyl

carboxylate (5ba-I)

3-phenyl-1H-benzo[b]cyclopenta[d]thiophene-2-

The general procedure was followed using allylic alcohol 4ba

(54 mg, 0.167 mmol) in benzene (3.3 mL), Ca(NTf₂)₂(10 mg,

0.017 mmol), n-Bu₄NPF₆(6.5 mg, 0.017 mmol). After work up

and purification, (25% EtOAc/Hexanes, R_f= 0.673), compound

5ba-I was afforded as a yellow solid (26.8 mg, 53% yield). [m.p.

= 104-113 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 7.81 - 7.86 (m, 2

H), 7.71 (dd, J = 7.93, 1.53 Hz, 2 H), 7.40 - 7.52 (m, 4 H), 7.31 -

7.36 (m, 1 H), 3.96 (s, 2 H), 3.76 (s, 3 H). ¹³C NMR (126 MHz,

CDCl₃) δ = 164.7, 150.8, 146.9, 144.6, 143.7, 134.4, 133.8,

130.0, 129.0, 128.8, 128.0, 124.9, 124.5, 123.8, 121.8, 51.3, 36.9.

IR: 3057 (w), 2949 (w), 2845 (w), 1701 (s) cm^-1. HRMS (EI)

m/z: [M]⁺Calcd. for C₁₉H₁₄O₂S 306.0715; Found 306.0708.

Methyl

carboxylate (5ah-I)

6-(thiophen-2-yl)-4H-cyclopenta[b]thiophene-5-

The general procedure F was followed using allylic alcohol

4ah (71 mg, 0.255 mmol) in benzene (5.1 mL), Ca(NTf₂)₂(15.3

mg, 0.026 mmol), n-Bu₄NPF₆(9.9 mg, 0.026 mmol). After work

up and purification, (20% EtOAc/Hexanes, R_f= 0.692),

compound 5ah-I was afforded as a reddish-brown oil (44.2 mg,

1

66% yield). H NMR (500 MHz, CDCl₃) δ = 7.99 (d, J = 3.66

Hz, 1 H) 7.51 (d, J = 5.19 Hz, 1 H), 7.47 (dd, J = 4.88, 0.61 Hz, 1

H), 7.15 - 7.19 (m, 1 H), 7.11 (d, J = 4.88 Hz, 1 H), 3.82 (d, J =

0.61 Hz, 3 H), 3.75 (s, 2 H). ¹³C NMR (126 MHz, CDCl₃) δ =

164.9, 148.7, 146.0, 142.1, 134.9, 131.0, 130.4, 128.6, 127.3,

126.9, 122.3, 51.3, 37.3. IR: 3099 (w), 2945 (w), 1692 (s) cm^-1.

HRMS (EI) m/z: [M]⁺Calcd. for C₁₃H₁₀O₂S₂262.0122; Found

262.0127.

Methyl

1-phenyl-1H-cyclopenta[b]naphthalene-2-carboxylate

(5da-II)

The general procedure F was followed using allylic alcohol

4da (99 mg, 0.311 mmol) in benzene (6.2 mL), Ca(NTf₂)₂(18.7

mg, 0.031 mmol), n-Bu₄NPF₆(12.0 mg, 0.031 mmol). After

work up and purification, (15% EtOAc/Hexanes, R_f= 0.404),

compound 5da-II was afforded as a white solid (69.6 mg, 75%

yield). [m.p. = 145-147 ˚C] ¹H NMR (500 MHz, CDCl₃) δ = 7.90

(d, J = 8.24 Hz, 2 H) 7.88 (d, J = 1.83 Hz, 1 H) 7.70 (d, J = 8.54

Hz, 2 H) 7.43 (ddd, J = 8.16, 6.79, 1.22 Hz, 1 H) 7.35 (ddd, J =

8.32, 6.94, 1.22 Hz, 1 H) 7.21 - 7.30 (m, 3 H) 7.16 - 7.19 (m, 2

H) 5.22 (d, J = 1.83 Hz, 1 H) 3.77 (s, 3 H). ¹³C NMR (126 MHz,

CDCl₃) δ = 164.3, 146.9, 142.7, 141.1, 139.4, 138.1, 133.5,

129.3, 128.8, 128.7, 128.5, 128.4, 126.8, 126.6, 125.9, 123.9,

121.1, 55.6, 51.4. IR: 3055 (w), 3026 (w), 2949 (w), 1705 (s) cm^-

¹. HRMS (EI) m/z: [M]⁺Calcd. for C₂₁H₁₆O₂300.1150; Found

300.1148.

Methyl

(5ai-I)

(E)-6-styryl-4H-cyclopenta[b]thiophene-5-carboxylate

The general procedure F was followed using allylic alcohol

4ai (45.8 mg, 0.153 mmol) in benzene (3.1 mL), Ca(NTf₂)₂(9.2

mg, 0.015 mmol), n-Bu₄NPF₆(5.9 mg, 0.015 mmol). After work

up and purification, (15% EtOAc/Hexanes, R_f= 0.411),

compound 5ai-I was afforded as a yellow solid (9.4 mg, 22%

1

yield). [m.p. = 96-101 ˚C] H NMR (500 MHz, CDCl₃) δ = 8.29

(d, J = 16.48 Hz, 1 H) 7.65 (d, J = 7.63 Hz, 2 H) 7.50 (d, J = 4.88

Hz, 1 H) 7.37 - 7.42 (m, 3 H) 7.33 - 7.35 (m, 1 H) 7.13 (d, J =

4.88 Hz, 1 H) 3.86 (s, 3 H) 3.68 (s, 2 H). ¹³C NMR (126 MHz,

CDCl₃) δ = 165.5, 149.2, 147.4, 142.2, 136.6, 136.5, 130.2,

130.1, 128.9, 128.8, 127.4, 122.1, 121.3, 51.3, 36.5. IR: 3059

(w), 3024 (w), 2949 (w), 2845 (w), 1690 (s) cm^-1. HRMS (EI)

m/z: [M]⁺Calcd. for C₁₇H₁₄O₂S 282.0715; Found 282.0718.

Methyl 5-methoxy-1-phenyl-1H-indene-2-carboxylate (5ea-II)

The general procedure F was followed using allylic alcohol

4ea (73 mg, 0.245 mmol) in benzene (4.9 mL), Ca(NTf₂)₂(14.7

mg, 0.024 mmol), n-Bu₄NPF₆(9.5 mg, 0.024 mmol). After work

up and purification, (15% EtOAc/Hexanes, R_f= 0.320),

compound 5ea-II was afforded as an off-white solid (52.6 mg,

Methyl

carboxylate (5aj)

6-(naphthalen-2-yl)-6H-cyclopenta[b]thiophene-5-

The general procedure F was followed using allylic alcohol

4aj (27.4 mg, 0.085 mmol) in benzene (1.7 mL), Ca(NTf₂)₂(5.1

mg, 0.008 mmol), n-Bu₄NPF₆(3.3 mg, 0.008 mmol). After work

up and purification, (20% EtOAc/Hexanes, R_f= 0.48), a four

compound isomeric mixture was afforded as a reddish-brown oil

(18.4 mg, 71% yield). (Isomeric Ratio = 20 : 7.0 : 3.5: 1; Alkene

ratio = 2.0:1 trisubstituted (5aj-II/5aj-IV) to tetrasubstituted

(5aj-I/5aj-III)) H NMR (500 MHz, CDCl₃) δ = 8.17 (s, .36 H),

7.94 - 7.89 (m, 1.21 H), 7.87 (dd, J = 4.9, 8.2 Hz, 2.56 H), 7.80

(d, J = 1.8 Hz, 1.02 H), 7.75 (dd, J = 1.8, 8.5 Hz, 0.49 H), 7.71

1

77% yield). [m.p. = 131-137 ˚C] H NMR (500 MHz, CDCl₃) δ

= 7.77 (d, J = 1.8 Hz, 1 H), 7.30 - 7.23 (m, 3 H), 7.15 - 7.08 (m, 4

H), 6.87 (dd, J = 2.4, 8.2 Hz, 1 H), 4.84 (d, J = 1.8 Hz, 1 H), 3.86

(s, 3 H), 3.73 (s, 3 H) ¹³C NMR (126 MHz, CDCl₃) δ = 164.6,

159.3, 142.8, 142.6, 142.4, 141.4, 138.6, 128.5, 127.8, 126.8,

125.0, 114.7, 108.2, 55.5, 54.9, 51.5. IR: 3028 (w), 2953 (w),

2835 (w), 1707 (s) cm^-1. HRMS (EI) m/z: [M]⁺Calcd. for

C₁₈H₁₆O₃280.1099; Found 280.1098.

1

16

Methyl

(5fa-II)

Tetrahedron

Skramstad, J.; Sletten, T.; Nordenson, S. Chem. Scr. 1982, 20, 74-

5,6-dimethoxy-1-phenyl-1H-indene-2-carboxylate

ACCEPTED MANUSCRIPT

7.

3. For literature on the synthesis and use of thiophene-fused

cyclopentadienyl metal complexes, see: (a) Dieckmann, M.; Jang,

Y.-S.; Cramer, N. Angew. Chem., Int. Ed. 2015, 54, 12149-12152;

(b) Kim, S. H.; Park, J. H.; Song, B. G.; Yoon, S.-W.; Go, M. J.;

Lee, J.; Lee, B. Y. Catalysts 2013, 3, 104-124; (c) Park, J. H.; Do,

S. H.; Cyriac, A.; Yun, H.; Lee, B. Y. Dalton Trans. 2010, 39,

9994-10002; (d) Senda, T.; Hanaoka, H.; Okado, Y.; Oda, Y.;

Tsurugi, H.; Mashima, K. Organometallics 2009, 28, 6915-6926;

(e) Resconi, L.; Camurati, I.; Malizia, F. Macromol. Chem. Phys.

2006, 207, 2257-2279; (f) Landman, M.; van Staden, M.; Goerls,

H.; Lotz, S. Inorg. Chim. Acta 2005, 358, 2602-2608; (g) Ryabov,

A. N.; Voskoboynikov, A. Z. J. Organomet. Chem. 2005, 690,

4213-4221; (h) Kisun'ko, D. A.; Zabalov, M. V.; Oprunenko, Y.

F.; Lemenovskii, D. A. Russ. J. Gen. Chem. 2004, 74, 105-109; (i)

Ryabov, A. N.; Gribkov, D. V.; Izmer, V. V.; Voskoboynikov, A.

Z. Organometallics 2002, 21, 2842-2855; (j) Kissounko, D. A.;

Zabalov, M. V.; Oprunenko, Y. F.; Lemenovskii, D. A. Russ.

Chem. Bull. 2000, 49, 1282-1286; (k) Ewen, J. A.; Jones, R. L.;

Elder, M. J.; Rheingold, A. L.; Liable-Sands, L. M. J. Am. Chem.

Soc. 1998, 120, 10786-10787.

The general procedure F was followed using allylic alcohol

4fa (50 mg, 0.152 mmol) in benzene (3.1 mL), Ca(NTf₂)₂(9.1

mg, 0.015 mmol), n-Bu₄NPF₆(5.9 mg, 0.015 mmol). After work

up and purification, (20% EtOAc/Hexanes, R_f= 0.24), compound

1

5fa-II was afforded as a colorless oil (32.3 mg, 68% yield). H

NMR (500 MHz, CDCl₃) δ = 7.73 (d, J = 1.53 Hz, 1 H) 7.22 -

7.30 (m, 3 H) 7.10 (d, J = 6.71 Hz, 2 H) 7.06 (s, 1 H) 6.77 (s, 1

H) 4.79 (d, J = 1.22 Hz, 1 H) 3.95 (s, 3 H) 3.82 (s, 3 H) 3.70 (s, 3

H). ¹³C NMR (126 MHz, CDCl₃) δ = 164.6, 150.2, 148.9, 144.1,

141.7, 140.1, 138.7, 133.5, 128.5, 127.9, 126.8, 107.5, 105.9,

56.1, 55.6, 51.3. IR: 2949 (w), 2833 (w), 1701 (s) cm^-1. HRMS

(EI) m/z: [M]⁺Calcd. for C₁₉H₁₈O₄310.1205; Found 310.1201.

4.7. Attempted [4+2] cycloadditions.

General Procedure G: To a round bottom flask charged with a

magnetic stir bar under nitrogen atmosphere was added a solution

of 5aa-I (1.0 equiv.) in solvent (0.2 to 0.5 M) at room

temperature. Alkene or diene (1 to 1.8 equiv.) was then added.

The reaction stirred at reflux for 18 h and was allowed to cool to

room temperature. An aliquot of the reaction was taken and

concentrated under reduced pressure. A crude NMR was obtained

of the reaction mixture.

4. For examples of cyclopenta[b]thiophenes in various materials

applications, see: (a) Scaria, R.; Ali, F.; Dhawan, S. K.; Chand, S.

J. Mater. Sci. 2015, 50, 555-562; (b) Zhong, H.; Han, Y.; Shaw,

J.; Anthopoulos, T. D.; Heeney, M. Macromolecules 2015, 48,

5605-5613; (c) Salzner, U. J. Chem. Theory Comput. 2014, 10,

4921-4937; (d) Ie, Y.; Nishida, K.; Karakawa, M.; Tada, H.;

Asano, A.; Saeki, A.; Seki, S.; Aso, Y. Chem. Eur. J. 2011, 17,

4750-4758; (e) Ie, Y.; Nishida, K.; Karakawa, M.; Tada, H.; Aso,

Y. J. Org. Chem. 2011, 76, 6604-6610; (f) Garreau, R.; Roncali,

J.; Garnier, F.; Lemaire, M. J. Chim. Phys. Phys.-Chim. Biol.

1989, 86, 93-8.

5. For representative examples that demonstrate the biological

relevance of cyclopenta[b]thiophene derivatives, see: (a) Fortes,

A. C.; Almeida, A. A. C.; Mendonca-Junior, F. J. B.; Freitas, R.

M.; Soares-Sobrinho, J. L.; de La Roca Soares, M. F. Neurochem.

Res. 2013, 38, 726-731; (b) Fortes, A. C.; Almeida, A. A. C.;

Oliveira, G. A. L.; Santos, P. S.; De Lucca, W., Jr.; Mendonca, F.

J. B., Jr.; Freitas, R. M.; Soares-Sobrinho, J. L.; Soares, M. F. R.

Oxid. Med. Cell. Longevity 2013, 194192, 8 pp; (c) Katane, M.;

Osaka, N.; Matsuda, S.; Maeda, K.; Kawata, T.; Saitoh, Y.;

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6. For pertinent reviews on Nazarov and Nazarov-like cyclization,

see: (a) Wenz, D. R.; Read de Alaniz, J. Eur. J. Org. Chem. 2015,

2015, 23-37; (b) Atesin, T. A. Org. Chem.: Curr. Res. 2014, 3, 1-

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7. For recent and other pertinent examples, see: (a) Wang, Z.; Xu,

X.; Gu, Z.; Feng, W.; Qian, H.; Li, Z.; Sun, X.; Kwon, O. Chem.

Commun. 2016, 52, 2811-2814; (b) Lempenauer, L.; Dunach, E.;

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Rxn 1: General procedure G was followed using 5aa-I (1.0

equiv., 73 mg), maleic anhydride (1.8 equiv., 54 mg), and toluene

(0.5 M, 0.55 mL). No product formed.

Rxn 2: General procedure G was followed using 5aa-I (1.0

equiv., 108 mg), n-butyl vinyl ether (1.0 equiv., 0.6 mL), and

benzene (0.2 M, 2.1 mL). No product formed.

Rxn 3: General procedure G was followed using 5aa-I (1.0

equiv., 73 mg), 2,5-dimethylfuran (1.8 equiv., 0.6 mL), and

toluene (0.2 M, 1.5 mL). No product formed.

4.8. Isomerization probing.

Procedure: Two flasks (5 mL) containing stir bars were put

under a nitrogen atmosphere. To one was added 10 mol % HNTf₂

and to each 1 mL of benzene was added. They were then heated

to 40 ˚C with stirring. To each was added a 2.2:1 ratio of 5aa-I to

5aa-II dissolved in benzene, enough to make two 3 mL, 0.1 M

solutions when added to their flasks. The reactions were allowed

to stir for two hours, with aliquots of 0.15 mL being taken every

15 minutes. Each aliquot was immediately cooled to room

temperature while being concentrated under reduced pressure.

Once all aliquots had been taken, each was dissolved in CDCl₃

and an NMR was taken immediately without further purification.

Ratios of products were determined by NMR.

Acknowledgments

S.F. gratefully acknowledges financial support from the

National Science Foundation (CHE-1056687 and CHE-

1566086). M.S. thanks Georgia Tech for a GAANN graduate

fellowship. Z.A.F. thanks Georgia Tech for a College of Sciences

URSA award.

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17

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ACCEPTED MANUSCRIPT

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Article Doi

Dehydrative Nazarov-type electrocyclizations of alkenyl (hetero)aryl carbinols via calcium catalysis: Access to cyclopenta[b]thiophenes and indene derivatives

DOI: 10.1016/j.tet.2017.03.041

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