Intramolecular palladium-catalyzed alkene carboalkynylation

DOI: 10.1016/j.tet.2015.06.030

Source and publish data:

Tetrahedron p. 5959 - 5964 (2015)

Update date:2022-08-28

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Authors:

Nicolai, Stefano

Swallow, Peter

Waser, Jerome

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Article abstract of DOI:10.1016/j.tet.2015.06.030

Abstract Carbocycles are essential building blocks for the synthesis of natural and synthetic bioactive compounds. Herein, we report the first example of palladium-catalyzed intramolecular carboalkynylation of non-activated olefins. Using activated carbon

Full text of DOI:10.1016/j.tet.2015.06.030

Tetrahedron 71 (2015) 5959e5964

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Intramolecular palladium-catalyzed alkene carboalkynylation

Stefano Nicolai, Peter Swallow, Jerome Waser

ꢀ ꢀ

Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Federale de Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland

a r t i c l e i n f o

a b s t r a c t

Article history:

Carbocycles are essential building blocks for the synthesis of natural and synthetic bioactive compounds.

Herein, we report the ﬁrst example of palladium-catalyzed intramolecular carboalkynylation of non-

activated oleﬁns. Using activated carbonyl compounds as nucleophiles and an alkynyl bromide as an

electrophile, the reaction gives access to cyclopentanes in 44e93% yield and one example of cyclohexane

in 31% yield with simultaneous formation of a SP³eSP CeC bond. The reaction therefore combines ring

formation with the introduction of a versatile triple bond for further functionalization.

Received 4 February 2015

Received in revised form 17 March 2015

Accepted 9 June 2015

Available online 16 June 2015

Keywords:

Catalysis

Alkynes

Alkenes

Multi-functionalization

Carbocycles

1. Introduction

Carbocycles confer a well-deﬁned tridimensional structure to

organic molecules and therefore allow more selective interactions

with biological targets (Fig. 1). This can already be achieved with

a single ﬁve-membered ring, like in prostaglandin (1), or with more

complex polycyclic frameworks, like the classical 6,6,6,5 ring sys-

tem of the steroid cholesterol (2). Although ﬁve- and six-membered

rings are most often encountered, other ring sizes can add further

structural diversity, as exempliﬁed by the diterpene ingenol (3)

featuring three-, ﬁve- and seven-membered rings.¹The importance

of the exact cyclic structure of bioactive terpenes is also apparent

from their biosynthesis via a cyclase and an oxidase phase, an ap-

proach, which has also inspired synthetic chemists.²The de-

velopment of new cyclization or annulation reactions to construct

saturated carbocycles has consequently been an intensively in-

vestigated ﬁeld of organic chemistry.

In this context, the palladium-catalyzed cyclization of carbon-

nucleophiles onto alkenes is a powerful method to construct efﬁ-

ciently ﬁve- and six-membered rings.³If ring-formation can be

accompanied by a second CeC bond formation in a domino re-

action, the efﬁciency of the process will be greatly increased.⁴

Nevertheless, the selective formation of two different CeC bonds

in a single reaction sequence is challenging, and has been realized

Fig. 1. Carbocycles in bioactive compounds.

Balme and co-workers on the cyclization of activated carbonyl

compounds combined with arylation or vinylation (Scheme 1, A).⁵

However, this method remains underdeveloped in comparison to

the oxy- or amino-carbofunctionalization reactions, which have

been intensively investigated in the last decade, in particular by

Wolfe and co-workers (Scheme 1, B).⁶

Since 2010, our group has been particularly interested in the

hetero-alkynylation of alkenes,⁷as alkynes are among the most

useful functional groups_ꢀin organic chemistry.⁸We have developed

both a Pd^II-^7aeband a Pd -catalyzed^7cedintramolecular oxy/amino-

alkynylation of oleﬁns using EBX (Ethynylbenziodoxolone) hyper-

valent iodine reagents and alkynyl bromides respectively. Herein,

we would like to report the ﬁrst use of activated carbonyls as nu-

cleophiles in a Pd^ꢀ-catalyzed carboalkynylation of oleﬁns (Scheme

ꢀ

only in few rare cases. Most impressive are the reports of Gore,

* Corresponding author. Tel.: þ41 21 693 93 88; fax: þ41 21 693 97 00; e-mail

address: jerome.waser@ep ﬂ .ch (J. Waser).

http://dx.doi.org/10.1016/j.tet.2015.06.030

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S. Nicolai et al. / Tetrahedron 71 (2015) 5959e5964

desired carboalkynylation product was obtained in 44% yield (entry

1). We then decided to systematically vary the palladium source, the

phosphine ligand, the solvent, the base and the alkynylation reagent

4 in order to improve the yield. The palladium source used had

a strong inﬂuence on the yield (entries 1e6).

Low yields were obtained with Pd(dba)₂, Pd(PPh₃)₄or Pd (OAc)₂

(entries 2e4). With PdCl₂(PPh₃)₂, the yield could be improved to

72% (entry 5). Finally, the best result (86% yield) was obtained with

[Pd(allyl)(cod)]BF₄as precursor (entry 6). When other bisphos-

phine ligands were tested (entries 7e12), only dppf, which has

a bite angle similar to DPE-Phos (99 vs 102^ꢀ) gave a substantial yield

of 6a (40%, entry 9). With the bulky monophosphine Ru-Phos, the

carboalkynylation product 6a could be obtained in 37% yield (entry

13). Up to now, no ligand superior to DPE-Phos could be found.

Examination of the base conﬁrmed that sodium tert-butoxide was

the best (entries 14e19). Lithium tert-butoxide gave a similar yield

(83%, entry 14), whereas 6a was obtained in 64% yield with po-

tassium tert-butoxide (entry 15). Stronger (entries 16 and 17) and

weaker (entries 18 and 19) bases gave lower yields. Interestingly,

product 6a could still be obtained in 74% yield using DBU as a base

(entry 18). The solvent effect was then examined (entries 20e26). A

comparable yield was obtained in dioxane (83%, entry 20). Mod-

erate yields were still observed in triﬂuorotoluene and toluene

(entries 21 and 22), but no desired product could be obtained in

dichloroethane, acetonitrile, NMP and DMSO (entries 23e26). It is

interesting to note that highly polar solvents such as NMP and

DMSO, which gave the best results for the related carboarylation

reaction,^5adid not work in this case. To conclude our optimization

studies, we turned to variation of the alkynylation reagent (entries

Scheme 1. Pd-catalyzed intramolecular carbofunctionalization of oleﬁns.

1, C). The method could be applied to the synthesis of ﬁve- and six-

membered rings and was also successful in the case of 5,5-, 5,6- and

5,7-bicyclic ring systems.

2. Results and discussion

We started our investigations by examining the cyclization-

alkynylation of diester 5a with triisopropylsilylethynyl bromide

(4a)⁹using the conditions developed previously for oxyalkynylation

(Pd₂(dba)₃with DPE-Phos as ligand, Table 1). Gratifyingly, the

Table 1

Optimization of the carboalkynylation reaction

Entry

Pd source

Ligand/bite angle

Base

Solvent

Yield^a

Pd₂(dba)₃

Pd(dba)₂

Pd(PPh₃)₄

Pd(OAc)₂

DPE-Phos/102^ꢀ

dppe/76^ꢀ

NaO^tBu

LiO^tBu

THF

44%

14%

25%

72%

86%

<1%

40%

<1%

14%

37%

83%

64%

27%

19%

74%

83%

57%

22%

PdCl₂(PPh₃)₂

[Pd(allyl)(cod)]BF₄

dppp/86^ꢀ

dppf/99^ꢀ

XANT-Phos/111^ꢀ

SEG-Phos/67^ꢀ

BINAP/93^ꢀ

Ru-Phos

DPE-Phos/102^ꢀ

KO^tBu

NaHMDS

NaH

DBU

THF

Cs₂CO₃

NaO^tBu

Dioxane

Triﬂuorotoluene

Toluene

Dichloroethane

Acetonitrile

DMSO

NMP

THF

<1%

67%

43%

<1%

The best conditions are indicated in bold.

Reaction conditions: 0.10 mmol 5a, 0.15 mmol 4, 4 mol % Pd source, 8 mol % ligand, 0.15 mmol base, 0.5 mL solvent, 80 ^ꢀC. Yield determined by GCeMS.

BX¼Benziodoxolone.

S. Nicolai et al. / Tetrahedron 71 (2015) 5959e5964

5961

Table 3

27e29). The use of chloro- or iodo-alkynes 4b and 4c gave lower

Scope of substituents on the diethylmalonate substrates

yields (entries 27 and 28). Finally, the use of the hypervalent iodine

reagent TIPS-EBX (4d) was not successful (entry 29).

Entry

Starting material

CO₂Et

Product

EtO₂C CO₂Et

Yield^a

On preparative scale, cyclopentane 6a was obtained in 85% yield

(Table 2, entry 1). We then investigated, which types of activated

carbonyl compounds could be used in the cyclization reaction.¹¹

Dimethylmalonate derivative 5b gave the desired product 6b in

62% yield (entry 2). The reaction was also successful in the case of

mixed malonate 5c and cyano ester 5d, although in this case mix-

tures of diastereoisomers were obtained (entries 3 and 4). No

product was observed when using nitro ester 5e (entry 5).

We then turned to further modiﬁcation of the diethyl malonate

31%

SiⁱPr₃

CO₂Et

EtO₂C CO₂Et

60%^b,c

CO₂Et

EtO₂C CO₂Et

Table 2

44%^b,c

Scope of activated carbonyl compounds

SiⁱPr₃

Entry

Starting material

Product

Yield^a

85%

EtO₂C CO₂Et

CO₂Et

EtO₂C CO₂Et

ⁱPr₃SiO

CO₂Et

78%^b

SiⁱPr₃

ⁱPr₃SiO

MeO₂C CO₂Me

CO₂Me

EtO₂C

CO₂Et

62%

60%^b,c

MeO₂C CO₂Et

CO₂Me

CO₂Et

SiⁱPr₃

53%^b

CO₂Et

NC CO₂Et

CO₂Et

86%^b

82%^b

SiⁱPr₃

O₂N CO₂Et

NO₂

CO₂Et

SiⁱPr₃

CO₂Et

93%^b

Reaction conditions: 0.40 mmol 5, 0.60 mmol 4a, 0.015 mmol [Pd(allyl)(cod)]

BF₄, 0.03 mmol DPE-Phos, 0.60 mmol NaO^tBu, 2 mL THF, 80 ^ꢀC. Isolated yields after

column chromatography are given.

SiⁱPr₃

ⁱPr₃Si

Obtained as a mixture of diastereoisomer (<2:1 dr), the diastereoselectivity

could not be determined exactly due to peaks overlap.

EtO₂C

CO₂Et

substrates (Table 3). Cyclohexane 6f could be obtained in 31% yield,

demonstrating that the synthesis of six-membered rings was also

possible, albeit in lower yield (entry 1).

EtO₂C CO₂Et

SiⁱPr₃

Substituents in

b or g positions of the malonates were well tol-

CO₂Et

erated (entries 2e4). However, a low diastereoselectivity (<2:1) was

observed. Substituted ﬁve-, six-, and seven-membered rings were

then examined in order to access important bicyclic systems (entries

5e7). The reaction proceeded in 60e93% yield and gave a mixture of

diastereoisomers at the newly formed stereocenter. Currently, the

method is limited to terminal alkenes, as no product was observed

when using cyclic or acyclic internal alkenes (entries 8 and 9). In

addition, a complex mixture of compounds was obtained when al-

iphatic or aryl alkynyl bromides were used under these conditions.

At this early stage of research, only a very speculative proposal for

the reaction mechanism can be made based on previous works in the

ﬁeld (Scheme 2).^5e7Under the reaction conditions, a Pd^ꢀ-phosphine

complex I is probably ﬁrst generated. Oxidative addition on alkynyl

bromide 4a then gives Pd^IIintermediate II. At this point, two mech-

anisms can be envisaged for carbopalladation: anti palladation via

transition state III to give alkyl palladium complex V, or ﬁrst ligand

exchange resulting in formation of intermediate IV, followed by syn

palladation to give V. The strong dependence on base strength in-

dicates that deprotonation of malonate 5a is required for the reaction

to proceed. In our previous work on oxyalkynylation, we could

Reaction conditions: 0.40 mmol 5, 0.60 mmol 4a, 0.015 mmol [Pd(allyl)(cod)]

BF₄, 0.03 mmol DPE-Phos, 0.60 mmol NaO^tBu, 2 mL THF, 80 ^ꢀC. Isolated yields after

column chromatography are given.

Obtained as a mixture of diastereoisomer (<2:1 dr), the diastereoselectivity

could not be determined exactly due to peaks overlap.

Compound obtained in about 90% purity as determined by ¹H NMR.

demonstrate through the use of internal alkenes as substrates that

the reaction proceeded via syn palladation.^7cedOn the other hand,

ꢀ

Balme, Gore and co-workers reported strong evidence for an anti

palladation mechanism for the related carboarylation reaction.^5aAs

the reaction did not work for internal oleﬁns under our conditions,

the stereochemistry of the carbopalladation step unfortunately can-

not yet be established.¹²Nevertheless, the low diastereoselectivity

observed would be more in agreement with an anti palladation pro-

cess. Finally, reductive elimination with formation of the C(SP)eC(SP³)

bond gives product 6a and regenerates the active Pd^ꢀcomplex I.

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S. Nicolai et al. / Tetrahedron 71 (2015) 5959e5964

a MICROMASS (ESI) Q-TOF Ultima API. All starting materials were

SiⁱPr₃

synthesized using adapted reported procedures.¹¹

Pd⁰L₂

reductive

elimination

oxidative

addition

3.2. General procedure for carboalkynylation

SiⁱPr₃

anti

The starting material 5 (0.40 mmol) was introduced into

a sealed tube containing [Pd(allyl)(cod)]BF₄(5.2 mg, 0.015 mmol,

0.04 equiv), DPE-Phos (17 mg, 0.030 mmol, 0.08 equiv), NaO^tBu

(57 mg, 0.60 mmol, 1.5 equiv), dry THF (2.0 mL) and TIPS acetylene

bromide (4a) (0.17 g, 0.60 mmol, 1.5 equiv). The vial was heated to

80 ^ꢀC and the reaction stirred until complete conversion of the

starting material (analysis by TLC). The mixture was then allowed to

cool to room temperature, silica gel was added and the solvent was

removed under reduced pressure. The crude product adsorbed on

silica gel was directly put on column chromatography for puriﬁ-

cation, eluting with PET:Et₂O, 15:1.

palladation

SiⁱPr₃

EtO₂C CO₂Et

Pd^II

NaO^tBu

- NaBr

III

ⁱPr₃Si

ligand

exchange

EtO₂C

Pd^II

EtO₂C

syn palladation

Scheme 2. Speculative mechanism for the carboalkynylation reaction.

3.3. Characterization data for cyclization products

In conclusion, we have described the ﬁrst example of intra-

molecular carboalkynylation of alkenes using activated carbonyl

compounds as nucleophiles and triisopropylsilylalkynyl bromide

(4a). The reaction proceeded in good yields for the formation of

ﬁve-membered rings and tolerated a broad range of substitution

patterns on the alkyl chain between the oleﬁn and the carbonyl

compound. The formation of a six-membered ring was also possi-

ble, albeit only in moderate yields. Future investigations will focus

on increasing the diastereoselectivity of the process, extending the

scope to internal alkenes and other types of alkynylation reagents,

as well as on in-depth understanding of the reaction mechanism.

3.3.1. Diethyl

2-(3-(triisopropylsilyl)prop-2-yn-1-yl)cyclopentane-

1,1-dicarboxylate (6a). The product was isolated as a yellow oil

(0.138 g, 3.84 mmol, 85%) Rf: 0.5 (PET:Et₂O/15:1). ¹H NMR

(400 MHz, CDCl₃)

d 4.25e4.08 (m, 4H, CO₂CH₂CH₃), 2.80e2.72 (m,

1H, ring proton), 2.57 (dd, J¼16.5, 3.9 Hz, 1H, propargylic H),

2.46e2.38 (m,1H, ring proton), 2.17e2.01 (m, 2H, ring protons), 2.11

(dd, J¼16.5, 11.2 Hz, 1H, propargylic H), 1.89e1.78 (m, 1H, ring

proton), 1.70e1.56 (m, 2H, ring protons), 1.25 (t, J¼7.2 Hz, 3H,

OCH₂CH₃), 1.24 (t, J¼7.1 Hz, 3H, OCH₂CH₃), 1.07e1.03 (m, 21H, TIPS

protons). ¹³C NMR (101 MHz, CDCl₃)

d 172.0, 170.8, 107.3, 81.1, 62.8,

61.2, 61.1, 45.1, 34.4, 30.7, 22.5, 22.1, 18.6, 14.1, 14.0, 11.3. IR (neat),

2946(m), 2868(m), 2173 (w), 1731 (s), 1462 (m), 1372 (w), 1259 (s),

1200 (m), 1068 (m), 1027 (m), 881 (w). HRMS (ESI) calcd for

3. Experimental section

3.1. General methods

₂₃H₄₂O₄Si^þ[MþH]^þ409.27741; found 409.2778.

3.3.2. Dimethyl 2-(3-(triisopropylsilyl)prop-2-yn-1-yl)cyclopentane-

1,1-dicarboxylate (6b). The product was isolated as a yellow oil

(93.4 mg, 0.246 mmol, 62%) Rf: 0.42 (PET:Et₂O/15:1). ¹H NMR

All reactions were carried out in oven dried glassware under an

atmosphere of nitrogen, unless stated otherwise. For quantitative

ﬂash chromatography technical grade solvents were used. For ﬂash

chromatography for analysis, HPLC grade solvents from Sigma-

eAldrich were used. THF, Et₂O, CH₃CN, toluene, hexane and CH₂Cl₂

were dried by passage over activated alumina under nitrogen at-

mosphere (H₂O content <10 ppm, Karl-Fischer titration). All

chemicals were purchased from Acros, Aldrich, Fluka, VWR, Apli-

chem or Merck and used as such unless stated otherwise. Chro-

matographic puriﬁcation was performed as ﬂash chromatography

(400 MHz, CDCl₃)

d 3.72 (s, 3H, CO₂Me), 3.70 (s, 3H, CO₂Me),

2.81e2.73 (m, 1H, ring proton), 2.55 (dd, J¼16.5 Hz, 4.0 Hz, 1H,

propargylic H), 2.47e2.39 (m, 1H, ring proton), 2.16e2.03 (m, 3H,

ring protons and propargylic H), 1.88e1.80 (m, 1H, ring protons),

1.71e1.58 (m, 2H, ring protons), 1.09e1.00 (m, 21H, TIPS). ¹³C NMR

(101 MHz, CDCl₃)

d 172.5, 171.2, 107.0, 81.3, 62.8, 52.6, 52.3, 45.2,

34.4, 30.6, 22.5, 22.1, 18.6, 11.3. IR (neat), 2943 (m), 2865 (m). 2173

(m), 1732 (s), 1464 (m), 1463 (m), 1260 (s), 1205 (m), 1155 (m), 883

(s). HRMS (ESI) calcd for C₂₁H₃₆NaO₄Si^þ[MþNa]^þ403.2275; found

403.2274.

ꢁ

using Macherey-Nagel silica 40e63, 60 A, using the solvents in-

dicated as eluent with 0.1e0.5 bar reduced pressure. TLC was per-

formed on Merck silica gel 60 F254 TLC glass plates or aluminium

plates and visualized with UV light, permanganate stain or ani-

saldehyde stain. ¹H NMR spectra were recorded on a Brucker DPX-

400 400 MHz spectrometer in chloroform-d and all signals are

reported in ppm with the internal chloroform signal at 7.26 ppm

The data is being reported as (s¼singlet, d¼doublet, t¼triplet,

q¼quadruplet, qi¼quintet, m¼multiplet or unresolved, br¼broad

signal, app¼apparent, coupling constant(s) in Hz, integration, in-

terpretation). ¹³C NMR spectra were recorded with ¹H-decoupling

on a Brucker DPX-400 100 MHz spectrometer in chloroform-d, all

signals are reported in ppm with the internal chloroform signal at

77.0 ppm. Infrared spectra were recorded on a JASCO FTIR B4100

spectrophotometer with an ATR PRO410-S and a ZnSe prism and

are reported as cm^ꢁ1(w¼weak, m¼medium, s¼strong, br¼broad).

High resolution mass spectrometric measurements were per-

formed by the mass spectrometry service of ISIC at the EPFL on

3.3.3. 1-Ethyl 1-methyl 2-(3-(triisopropylsilyl)prop-2-yn-1-yl)cyclo-

pentane-1,1-dicarboxylate (6c). The product was isolated as a yel-

low oil as a mixture of inseparable diastereoisomers (dr <2:1,

83.6 mg, 0.212 mmol, 53%). Rf: 0.48 (PET:Et₂O/15:1). ¹H NMR

(400 MHz CDCl₃)

d 4.23e4.08 (m, 4H, CO₂CH₂CH₃), 3.71 (s, 3H,

CO₂CH₃), 3.69 (s, 3H, CO₂CH₃), 2.81e2.72 (m, 2H, ring protons),

2.59e2.51 (m, 2H, propargylic H), 2.46e2.39 (m, 2H, ring protons),

2.14e2.01 (m, 6H, ring protons and propargylic H), 1.88e1.79 (m,

2H, ring protons), 1.71e1.55 (m, 4H, ring protons), 1.26e1.21 (m, 6H,

CO₂CH₂CH₃), 1.09e1.02 (m, 42H, TIPS). ¹³C NMR (101 MHz, CDCl₃)

172.6, 171.9, 171.3, 170.7, 107.2, 107.1, 81.1, 62.9, 62.8, 61.3, 61.2,

52.5, 52.2, 45.2, 45.0, 34.3, 30.7, 30.6, 22.5, 22.2, 22.118.6, 14.2, 14.1,

11.3. Not all signals for each diastereoisomer could be resolved. IR

(neat), 2941 (m), 2865 (m), 2173 (m), 1731 (s), 1464 (m), 1367 (w),

1258 (s), 1202 (m), 1153 (m), 1075 (m), 1029 (m), 996 (m), 883 (m).

S. Nicolai et al. / Tetrahedron 71 (2015) 5959e5964

5963

HRMS (ESI) calcd for C₂₂H₃₈NaO₄Si^þ[MþNa]^þ417.2432; found

as a yellow oil as a mixture of inseparable diastereoisomers (dr

417.2413.

<2:1, 81.2 mg, 0.180 mmol, 44%, >90% purity by ¹H NMR). Rf: 0.50

(PET:Et₂O/15:1). ¹H NMR (400 MHz, CDCl₃)

d 5.84e5.72 (m, 1H,

3.3.4. Ethyl

1-cyano-2-(3-(triisopropylsilyl)prop-2-yn-1-yl)cyclo-

CH₂CH]CH₂), 5.03e4.93 (m, 2H, CH₂CH]CH₂), 4.28e4.08 (m, 4H,

CO₂CH₂CH₃), 2.92e2.76 (m, 1H), 2.71e1.80 (m, 7H), 1.72e1.60 (m,

1H),1.38e1.24 (m, 9H),1.11e1.00 (m, 21H, TIPS). ¹³C NMR (101 MHz,

pentanecarboxylate (6d). The product was isolated as a yellow oil as

a mixture of inseparable diastereoisomers (dr: <2:1, 0.123 g,

0.339 mmol, 82%). Rf: 0.40 (PET:Et₂O/15:1). ¹H NMR (400 MHz

CDCl₃) d 171.5, 171.0, 170.9, 170.4, 138.5 (2C), 114.6. 114.5, 106.9, 81.2,

CDCl₃)

4.24 (q, J¼7.0 Hz, 2H, CO₂CH₂CH₃), 2.74e2.44 (m, 3H, ring

66.6, 66.5, 61.0, 60.9, 47.2, 44.6, 44.0, 32.5, 32.3, 31.3, 30.8, 29.2,

29.0, 28.9, 28.2, 23.2, 18.6, 18.0, 14.2, 14.1, 11.3. Not all peaks of the

minor diastereoisomer could be resolved. IR (neat), 2969 (br, s),

2173 (w), 1726 (s), 1464 (m), 1394 (m), 1252 (m), 1190 (m), 1067 (s),

883(m). HRMS (ESI) calcd for C₂₇H₄₇O₄Si^þ[MþH]^þ463.3238; found

463.3243.

protons and propargylic H), 2.36e2.14 (m, 3H, ring protons and

propargylic H), 2.04e1.65 (m, 3H, ring protons), 1.37e1.31 (m, 3H,

CO₂CH₂CH₃) 1.08e0.97 (m, 21H, TIPS). ¹³C NMR (101 MHz, CDCl₃)

168.9, 167.8, 120.7, 118.1, 105.3, 104.9, 82.6, 82.0, 62.8, 62.6, 52.6,

50.5, 50.2, 47.9, 37.9, 36.7, 30.7, 30.6, 23.2, 22.6, 22.4, 21.4, 18.5, 18.4,

14.1, 14.0, 11.3, 11.2. IR (neat), 2943 (s), 2866 (s), 2243(w), 2176 (m),

2121 (m), 2062 (w), 1742 (s), 1464 (s), 1384 (w), 1369 (m), 1257 (s),

1222 (s), 1020 (s), 921 (m), 883 (s). HRMS (ESI) calcd C₂₁H₃₆NO₂Si^þ

[MþH]^þ362.2515; found 362.2516.

3.3.8. Diethyl

pylsilyl)prop-2-yn-1-yl)cyclopentane-1,1-dicarboxylate

4-(((triisopropylsilyl)oxy)methyl)-2-(3-(triisopro-

(6i). The

product was isolated as a yellow oil as a mixture of inseparable

diastereoisomers (dr <2:1, 0.186 g, 0.313 mmol, 78%). Rf: 0.51

3.3.5. Diethyl

2-(3-(triisopropylsilyl)prop-2-yn-1-yl)cyclohexane-

(PET:Et₂O/15:1). ¹H NMR (400 MHz, CDCl₃)

d 4.23e4.09 (m, 4H,

1,1-dicarboxylate (6f). The product was isolated as a yellow oil

CO₂CH₂CH₃), 3.71e3.54 (m, 2H, OCH₂), 2.90e2.72 (m, 1H), 2.63 (dd,

J¼16.5, 3.8 Hz, 0.4H, propargylic H, minor diastereoisomer),

2.56e2.52 (m, 1.6H), 2.30e1.96 (m, 4H), 1.87e1.78 (m, 1H),

1.46e1.36 (m, 1H), 1.26e1.22 (m, 6H, CO₂CH₂CH₃), 1.08e1.02 (m,

(52.2 mg, 0.124 mmol, 31%). Rf: 0.49 (PET:Et₂O/15:1). ¹H NMR

(400 MHz, CDCl₃),

d 4.21e4.15 (m, 4H, CO₂CH₂CH₃), 2.54e2.49 (m,

1H, propargylic H), 2.31e2.24 (m, 2H, ring protons and propargylic

H), 2.17e2.10 (m, 1H, ring proton), 2.07e2.00 (m, 1H, ring proton),

1.88e1.81 (m, 1H, ring proton), 1.63e1.58 (m, 1H, ring proton),

1.52e1.30 (m, 4H, ring protons), 1.26e1.23 (m, 6H, CO₂CH₂CH₃),

42H, TIPS). ¹³C NMR (101 MHz, CDCl₃)

d 172.1, 171.8, 170.9, 170.8,

107.3, 107.2, 81.2, 81.0, 66.8, 66.6, 63.0, 62.5, 61.4, 61.3, 61.1, 44.6,

44.5, 39.9, 38.4, 37.1, 36.9, 34.6, 33.3, 22.5, 21.9, 18.7, 18.1, 14.1, 14.0,

12.0, 11.3. Not all signals for each diastereoisomer could be re-

solved. IR (neat), 1942 (m), 2892 (m), 2865 (s), 2173 (w), 1731 (s),

1464 (m), 1367 (m), 1254 (m), 1195 (m), 1098 (m), 1015 (m), 883 (s).

1.07e1.02 (m, 21H, TIPS). ¹³C NMR (101 MHz, CDCl₃)

d 171.7, 170.5,

108.9, 81.1, 61.2, 60.9, 58.4, 41.0, 31.2, 26.4, 23.4, 22.6, 22.1, 18.6, 14.1,

11.3 (2C). IR (neat), 2942 (m), 2865 (m), 2172 (m),1730 (s),1261 (m),

1368 (m), 1245 (s), 1197 (m), 1142 (m), 1022 (m), 883 (m). HRMS

(ESI) calcd for C₂₄H₄₃O₄Si^þ[MþH]^þ423.2925; found 423.2938.

HRMS (ESI) calcd for

595.4217.

₃₃H₆₃O₅Si^þ₂[MþH]^þ595.4209; found

3.3.6. Diethyl 2-phenyl-5-(3-(triisopropylsilyl)prop-2-yn-1-yl)cyclo-

pentane-1,1-dicarboxylate (6g). The product was isolated as a yel-

low oil as a mixture of inseparable diastereoisomers (dr: 2:1,

0.116 g, 0.250 mmol, 60%, >90% pure). The dr was calculated by

integrating the peaks at 3.92 and 3.76 ppm in the ¹H NMR. Rf: 0.44

3.3.9. Diethyl

2-(3-(triisopropylsilyl)prop-2-yn-1-yl)hexahy-

dropentalene-1,1(2H)-dicarboxylate (6j). The product was isolated

as a yellow oil as a mixture of inseparable diastereoisomers (dr

<2:1, 0.106 g, 0.237 mmol, 60%, >90% purity). Rf: 0.53 (PET:Et₂O/

15:1). ¹H NMR (400 MHz, CDCl₃)

d 4.22e4.07 (m, 4H, CO₂CH₂CH₃),

(PET:Et₂O/15:1). ¹H NMR (400 MHz, CDCl₃)

7.34e7.32 (m, 1H,

3.19e3.12 (m, 0.5H), 3.04e2.95 (m, 0.3H), 2.91e2.75 (m, 1H),

2.71e2.20 (m, 3.2H), 2.17e1.87 (m, 1H), 1.85e1.40 (m, 6H),

1.26e1.22 (m, 7H, ring proton and CO₂CH₂CH₃), 1.06e1.02 (m, 21H,

AreH, both diastereoisomers), 7.23e7.17 (m, 6.5H, AreH, both di-

astereoisomer), 4.30e4.07 (m, 4H, CO₂CH₂CH₃both di-

astereoisomer and benzylic CH major diastereoisomer), 3.98e3.87

(m, 1H, benzylic H, minor diastereoisomer and 1H, CO₂CH₂CH₃,

minor diastereoisomer), 3.76 (dq, J¼10.7, 7.1, Hz, 1H, CO₂CH₂CH₃,

major diastereoisomer), 3.65 (dq, J¼10.7, 7.2 Hz, 0.5H, CO₂CH₂CH₃,

minor diastereoisomer), 3.36 (dq, J¼10.7, 7.2 Hz, 1H, CO₂CH₂CH₃,

major diastereoisomer), 3.16e3.08 (m, 1H, ring proton), 2.77 (dd,

J¼15.6, 2.5 Hz, 0.5H, propargyl CH₂, minor diastereoisomer),

2.67e2.50 (m, 2H, propargyl CH₂, major diastereoisomer and ring

proton), 2.38e2.52 (m, 3H, ring protons), 2.18e2.05 (m, 1H, ring

proton), 2.10 (dd, J¼16.5, 10.3 Hz, 1H, propargyl CH₂, major di-

astereoisomer), 2.02e1.91 (m, 1H, ring proton), 1.75e1.62 (m, 1H,

ring proton),1.24 (t, J¼7.1 Hz, 3H, OCH₂CH₃, major diastereoisomer),

1.21 (t, J¼7.1 Hz, 1.5H, OCH₂CH₃, minor diastereoisomer), 1.09e1.05

(m, 31.5H, TIPS), 0.88 (t, J¼7.2 Hz, 1.5H, OCH₂CH₃, minor di-

astereoisomer), 0.77 (t, J¼7.2 Hz, 3H, OCH₂CH₃, major di-

TIPS). ¹³C NMR (101 MHz, CDCl₃)

d 172.3, 170.7, 170.0, 108.1, 107.7,

80.9, 80.3, 66.1, 65.4, 61.1, 61.0, 60.7, 60.5, 51.9, 50.3, 50.2, 42.4,

42.3, 40.4, 37.9, 36.5, 35.5, 32.6, 30.7, 29.3, 28.1, 27.4, 21.8, 21.3,18.6,

14.2, 14.0, 11.3. Not all signals for each diastereoisomer could be

resolved. IR (neat), 2943 (m), 2865 (m), 2173 (w), 1728 (s), 1464

(m), 1368 (m), 1252 (s), 1203 (m), 1098 (m), 1021 (m), 884 (m).

HRMS (ESI) calcd for C₂₂H₄₄NaO₄Si^þ[MþNa]^þ423.2901; found

423.2922.

3.3.10. Diethyl 2-(3-(triisopropylsilyl)prop-2-yn-1-yl)octahydro-1H-

indene-1,1-dicarboxylate (6k). Reaction done using 0.0810

(0.290 mmol) of the starting malonate. The product was isolated as

a yellow oil as a mixture of inseparable diastereoisomers (dr <2:1,

0.111 g, 0.240 mmol, 86%). Rf: 0.53 (PET:Et₂O/15:1). ¹H NMR

(400 MHz, CDCl₃)

d 4.27e4.06 (m, 4H, CO₂CH₂CH₃), 3.08e3.01 (m,

astereoisomer). ¹³C NMR (101 MHz, CDCl₃),

170.6, 170.1, 142.0,

0.6H), 2.60e2.50 (m, 1H), 2.42 (dd, J¼16.4, 4.3 Hz, 0.6H, propargylic

H, major diastereoisomer), 2.17 (dd, J¼16.3, 9.8 Hz, 0.6H, prop-

argylic H, major diastereoisomer), 2.25e2.12 (m, 0.6H), 2.08e1.60

(m, 6H), 1.35e1.20 (m, 9H, ring protons and CO₂CH₂CH₃), 1.07e1.02

(m, 23H, TIPS and ring protons), 0.87e0.77 (m, 0.6H). ¹³C NMR

139.8, 128.9, 128.7, 127.9, 127.7, 127.0, 126.8, 106.9, 81.3, 68.0, 67.6,

61.2, 61.1, 60.7, 60.5, 52.3, 51.7, 48.5, 45.1, 31.6, 30.4, 29.6, 29.0, 22.6,

21.8, 18.6, 14.1, 14.0, 13.6, 13.3, 11.4, 11.3. Not all peaks of the minor

diastereoisomer could be resolved for the alkyne and the TIPS. IR

(neat), 2961 (broad, s), 2172 (w), 1724 (s), 1462 (m), 1377 (m), 1252

(s), 1057 (s), 881 (m). HRMS (ESI) calcd for C₂₉H₄₅O₄Si [MþH]^þ

485.3082; found 485.3062.

(101 MHz, CDCl₃)

d 171.5, 171.4, 170.2, 169.2, 108.5, 106.5, 81.6, 80.1,

65.3, 65.0, 61.0, 60.9, 60.8, 60.5, 53.3, 51.1, 45.1, 41.4, 41.2, 41.1, 37.8,

35.6, 32.7, 32.2, 28.9, 28.1, 26.3, 26.2, 26.1, 25.8, 23.5, 22.5, 18.6, 14.2,

14.1, 14.1, 14.0, 11.3, 11.3. The methyl peaks at 18.6 ppm for the TIPS

groups of both isomers were overlapping. IR (neat), 2928 (m), 2864

(m), 2173 (w), 1726 (s), 1464 (m), 1367 (w), 1250 (s), 1193 (s), 1088

3.3.7. Diethyl 2-(but-3-en-1-yl)-5-(3-(triisopropylsilyl)prop-2-yn-1-

yl)cyclopentane-1,1-dicarboxylate (6h). The product was isolated

5964

S. Nicolai et al. / Tetrahedron 71 (2015) 5959e5964

(w), 1017 (m), 883 (m). HRMS (ESI) calcd for C₂₇H₄₇O₄Si^þ[MþH]^þ

3. Denes, F.; Perez-Luna, A.; Chemla, F. Chem. Rev. 2010 , 1 10 , 2366.

4. Tietze, L. F. Chem. Rev. 1996 , 96 , 1 15.

463.3238; found 463.3239.

5. (a) Bouyssi, D.; Balme, G.; Fournet, G.; Monteiro, N.; Gore, J. Tetrahedron Lett.

1991 , 32 , 1641; (b) Bouyssi, D.; Coudanne, I.; Uriot, H.; Gore, J.; Balme, G. Tet-

rahedron Lett. 1995 , 36 , 8019; (c) Bruyere, D.; Gaignard, G.; Bouyssi, D.; Balme,

G.; Lancelin, J. M. Tetrahedron Lett. 1997 , 38 , 827; (d) Cavicchioli, M.; Sixdenier,

E.; Derrey, A.; Bouyssi, D.; Balme, G. Tetrahedron Lett. 1997 , 38 , 1 763; (e) Lom-

berget, T.; Bouyssi, D.; Balme, G. Synlett 2002 , 1439; (f) Balme, G.; Bouyssi, D.;

Lomberget, T.; Monteiro, N. Synthesis 2003 , 2115; (g) Bruyere, D.; Bouyssi, D.;

Balme, G. Tetrahedron 2004 , 60 , 4007; (h) Martinon, L.; Azoulay, S.; Monteiro,

3.3.11. Diethyl

2-(3-(triisopropylsilyl)prop-2-yn-1-yl)octahy-

droazulene-1,1(2H)-dicarboxylate (6l). The product was isolated as

a yellow oil as a mixture of inseparable diastereoisomers (dr <2:1,

0.176 g, 0.370 mmol, 93%). Rf: 0.54 (PET:Et₂O/15:1). ¹H NMR

(400 MHz, CDCl₃),

d 4.28e4.07 (m, 4H, CO₂CH₂), 2.94e2.86 (m,

€

N.; Kundig, E. P.; Balme, G. J. Organomet. Chem. 2004 , 689 , 3831; For a single

0.4H), 2.82 (dd, J¼16.4, 3.3 Hz, 0.6H, propargylic H, major di-

astereoisomer), 2.76e2.68 (m, 0.4H), 2.68e2.60 (m, 0.6H),

2.54e2.44 (m, 1H), 2.41 (dd, J¼16.7, 3.9 Hz, 0.4H, propargylic H,

minor diastereoisomer), 2.36e2.20 (m, 1.4H), 2.09 (dd, J¼16.4,

5.2 Hz, 0.6H, propargylic H, major diastereoisomer), 2.20e1.74 (m,

4.6H), 1.66e1.45 (m, 3H), 1.29e1.13 (m, 10H, ring protons and

CO₂CH₂CH₃), 1.07e1.02 (m, 21H, TIPS). ¹³C NMR (101 MHz, CDCl₃)

example of cyclization of a silyl enol ether followed by a Heck reaction, see: (i)

Ito, Y.; Aoyama, H.; Saegusa, T. J. Am. Chem. Soc. 1980 , 102 , 4519; For a recent

report involving a -bromoesters and arenes, see: (j) Fan, J.-H.; Wei, W.-T.; Zhou,

M.-B.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed. 2014 , 53 , 6650.

6. (a) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem. Soc. 1980 , 102 , 3583; (b)

Semmelhack, M. F.; Zhang, N. J. Org. Chem. 1989 , 54 , 4483; (c) Semmelhack, M.

F.; Epa, W. R. Tetrahedron Lett. 1993 , 34 , 7205; (d) Lira, R.; Wolfe, J. P. J. Am. Chem.

Soc. 2004 , 126 , 13906; (e) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004 , 43 ,

3605; (f) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004 , 126 , 1620; (g) Hay, M.

B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005 , 70 , 3099; (h) Ney, J. E.; Hay, M.

B.; Yang, Q. F.; Wolfe, J. P. Adv. Synth. Catal. 2005 , 347 , 1614; (i) Neukom, J. D.;

Perch, N. S.; Wolfe, J. P. J. Am. Chem. Soc. 2010 , 132 , 6276; (j) Mai, D. N.; Wolfe, J.

P. J. Am. Chem. Soc. 2010 , 132 , 12157; (k) Babij, N. R.; Wolfe, J. P. Angew. Chem., Int.

Ed. 2012 , 51 , 4128; (l) Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker, F.

Angew. Chem., Int. Ed. 2005 , 44 , 257; (m) Hayashi, S.; Yorimitsu, H.; Oshima, K. J.

Am. Chem. Soc. 2009 , 131 , 2052; (n) Cernak, T. A.; Lambert, T. H. J. Am. Chem. Soc.

2009 , 131 , 3124; (o) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J.

Am. Chem. Soc. 2009 , 131 , 15945; (p) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.;

Sigman, M. S. J. Am. Chem. Soc. 2010 , 132 , 7870; (q) Hewitt, J. F. M.; Williams, L.;

Aggarwal, P.; Smith, C. D.; France, D. J. Chem. Sci. 2013 , 4 , 3538.

171.9, 171.0, 170.6, 169.6, 107.8, 107.3, 81.2, 80.5, 68.4, 66.5, 61.0,

60.9, 60.6, 60.5, 51.7, 48.5, 46.5, 43.8, 41.7, 40.8, 39.0, 38.1, 33.4, 32.0,

31.4, 31.2, 30.6, 29.7, 29.6, 29.2, 28.0, 27.8, 22.1, 21.5, 18.6, 14.2, 14.1,

13.9, 11.3. The signals for the TIPS and for one methyl group on the

esters for each diastereoisomer could not be resolved. IR (neat),

2921 (m), 2865 (m), 2173 (m), 1726 (s), 1464 (m), 1367 (m), 1252 (s),

1204 (m), 1182 (s), 1101 (m), 1076 (m), 1019 (s), 883 (s). HRMS (ESI)

calcd for C₂₈H₄₉O₄Si^þ[MþH]^þ477.3395; found 477.3411.

7. (a) Nicolai, S.; Erard, S.; Fernandez Gonzalez, D.; Waser, J. Org. Lett. 2010 , 12 ,

384; (b) Nicolai, S.; Piemontesi, C.; Waser, J. Angew. Chem., Int. Ed. 20 1 1 , 50 ,

4680; (c) Nicolai, S.; Waser, J. Org. Lett. 2011 , 13 , 6324; (d) Nicolai, S.; Sedigh-

Zadeh, R.; Waser, J. J. Org. Chem. 2013 , 78 , 3783.

8. Diederich, F.; Stang, P. J.; Tykwinski, R. R. Acetylene Chemistry: Chemistry, Biology

and Material Science ; Wiley-VCH, 2005.

9. Synthesized following a reported procedure Jiang, M. X.-W.; Rawat, M.; Wulff,

W. D. J. Am. Chem. Soc. 2004 , 126 , 5970.

10. This precursor is easily obtained in one step from [Pd(allyl)Cl]₂White, D. A.;

Doyle, J. R.; Lewis, H. In Inorganic Syntheses ; Cotton, F. A., Ed.; John Wiley &

Sons,: Hoboken, NJ, USA, 2007; Vol. 13, p 55.

Acknowledgements

EPFL, F. Hoffmann-La Roche Ltd and SNF (grant number

200021_119810) are acknowledged for ﬁnancial support. The In-

stitute of Chemical Sciences and Engineering (ISIC) at EPFL is ac-

knowledged for the support of the master thesis of P. S.

Supplementary data

11. The starting materials used in this study were obtained via alkylation of the

corresponding unsubstituted activated carbonyl compounds, based on adapted

reported procedures: (a) Salomon, R. G.; Coughlin, D. J.; Ghosh, S.; Zagorski, M.

G. J. Am. Chem. Soc. 1982 , 104 , 998; (b) Hegedus, L. S.; McKearin, J. M. J. Am.

Chem. Soc. 1982 , 104 , 2444; (c) Ma, D.; Yang, J. J. Am. Chem. Soc. 2001 , 123 , 9706;

Supplementary data (Detailed synthesis procedures, character-

ization data for starting materials and copies of NMR and IR spectra

for new compounds.) related to this article can be found at http://

dx.doi.org/10.1016/j.tet.2015.06.030.

€

(d) Fu, Y.; Hammarstrom, L. G. J.; Miller, T. J.; Fronczek, F. R.; McLaughlin, M. L.;

€

Hammer, R. P. J. Org. Chem. 2001 , 66 , 7118; (e) Seemann, M.; Scholler, M.; Kudis,

S.; Helmchen, G. Eur. J. Org. Chem. 2003 , 2003 , 2122; (f) Marsilje, T. H.; Hedrick,

M. P.; Desharnais, J.; Tavassoli, A.; Zhang, Y.; Wilson, I. A.; Benkovic, S. J.; Boger,

D. L. Bioorg. Med. Chem. 2003 , 1 1 , 4487; (g) Kammerer, C.; Prestat, G.; Gaillard, T.;

References and notes

ꢂ

Madec, D.; Poli, G. Org. Lett. 2008 , 10 , 405; (h) Lemiere, G.; Gandon, V.; Cariou,

1. Jorgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P.

S. Science 2013 , 341 , 878.

2. (a) Maimone, T. J.; Baran, P. S. Nat. Chem. Biol. 200 7 , 3 , 396; (b) Chen, K.; Baran,

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Mendoza, A.; Baran, P. S. Tetrahedron 2013 , 69 , 5685.

K.; Hours, A.; Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am.

Chem. Soc. 2009, 131, 2993 See Supplementary data for synthesis procedures

and characterization data.

12. Future work will focus on the use of deuterated alkenes to investigate the

stereochemistry of the carbopalladation step.

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