Medium-sized heterocycle synthesis by the use of synergistic effects of Ni-NHC and γ-coordination in cycloisomerization

DOI: 10.1021/jo5008477

Source and publish data:

Journal of Organic Chemistry p. 11873 - 11884 (2014)

Update date:2022-09-26

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Authors:

Ho, Chun-Yu

He, Lisi

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Article abstract of DOI:10.1021/jo5008477

This paper describes a new approach in transition-metal-catalyzed unsymmetric cycloisomerization for medium-sized heterocycles. The steric and electronic effects of an NHC-NiH catalyst and γ-heteroatom chelation were used together as a basis for 1,n-diene termini differentiation and for n^γ-exo-trig (head-to-tail) product selectivity. Heterocycles bearing an exocyclic methylene such as oxepines, thiepines, siloxepines, and oxocanes were synthesized from the corresponding 1,n-dienes by a fine-tuning of the NHC properties. The implication of the underlying hypothesis was further demonstrated in a competition experiment in which strained oxepines were formed preferentially over other competing oxa-/carbocycles. Under more forcing physical conditions and the use of a suitable NHC ligand, the exocyclic methylene products were isomerized further into endocyclic olefin products regioselectively in one pot. (Chemical Equation Presented).

Full text of DOI:10.1021/jo5008477

Article

pubs.acs.org/joc

Medium-Sized Heterocycle Synthesis by the Use of Synergistic

Eﬀects of Ni-NHC and γ‑Coordination in Cycloisomerization

Chun-Yu Ho*^,†,‡and Lisi He^‡

^†Department of Chemistry, South University of Science and Technology of China (SUSTC), Shenzhen 518055, P.R. China

^‡Center of Novel Functional Molecules, Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin NT, Kong Kong

* Supporting Information

ABSTRACT: This paper describes a new approach in transition-

metal-catalyzed unsymmetric cycloisomerization for medium-sized

heterocycles. The steric and electronic eﬀects of an NHC−NiH

catalyst and γ-heteroatom chelation were used together as a basis for

1,n-diene termini diﬀerentiation and for n^γ-exo-trig (head-to-tail)

product selectivity. Heterocycles bearing an exocyclic methylene such

as oxepines, thiepines, siloxepines, and oxocanes were synthesized

from the corresponding 1,n-dienes by a ﬁne-tuning of the NHC properties. The implication of the underlying hypothesis was

further demonstrated in a competition experiment in which strained oxepines were formed preferentially over other competing

oxa-/carbocycles. Under more forcing physical conditions and the use of a suitable NHC ligand, the exocyclic methylene

products were isomerized further into endocyclic oleﬁn products regioselectively in one pot.

INTRODUCTION

■

Catalytic cycloisomerization is important in organic chemistry

as an expedient way of constructing relevant frameworks for

further applications. A commonly used C−C forming approach

involves the use of 1,n-dienes as cycloisomerization substrates.¹

The products obtained through these methods may comple-

ment ring-closing metathesis, which also uses 1,n-dienes as

substrates for chemical library synthesis and for eﬃcient

structure−activity relationship (SAR) studies (Figure 1).²

However, the full potential of this complementarity has yet

to be realized.

Current cycloisomerization technology is eﬀective for only a

subset of the possible range of 1,n-dienes. Oligomerization or

isomerization often complicates the reaction, and rings with

lower strains are the preferred outcomes. As such, the most

eﬃcient cases are those either with a 1,6-relationship, with

templates for conformational freedom reduction or with

Thorpe−Ingold acceleration.³Few protocols for medium-

sized rings (1,n > 6 dienes) with a freely rotating linear tether

have been discovered.⁴Other than in cases governed by ring

Figure 1. New approach for 1,7-oxadienes selective cycloisomeriza-

tion.

closure constraints (e.g., n = 5), systems giving n- over (n − 1)-

exo-trig cycloisomerization products from 1,n-dienes, which

require a head-to-tail over typical tail-to-tail cycloisomerization,

are rare (Figure 1, eqs 1 and 2).^5,6This is because, in an

approach based on oxidative cyclometalation in early transition

diﬀerentiation. Unlike approaches that employ two tethers with

diﬀerences in their degree of unsaturation,^7,8the progress for an

metals, n-exo-trig product formation often ﬁrst requires a

geometrically relatively more constrained diene−M coordina-

tion. In contrast, in cases based on oleﬁn insertion to M−H,

such formation generally faces strong hydrometalation

regioselective competition and also a catalyst deactivation

pathway related to γ-heteroatom chelation, which signiﬁcantly

hampers the synthesis of heterocycles (Figure 1, eq 3).^5c

Another persistent challenge in the M−H approach is tether

eﬀective diﬀerentiation of structurally and electronically similar

termini in 1,n-dienes is mostly limited to (n − 1)-exo-trig cases

on a steric basis.^9,10

Special Issue: Mechanisms in Metal-Based Organic Chemistry

Received: April 15, 2014

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In this context and as part of our continuing programs that

aim to discover new applications for N-heterocyclic carbene

(NHC) in transition-metal catalysis, we became interested in

the potential of NHC−Ni interactions with heteroatoms for

selective C−C forming reactions. In this paper, we are

interested in expanding the scope of current cycloisomerization,

particularly in the synthesis of medium-sized heterocycles

(Figure 1, eq 4). We surmise that γ-heteroatom chelation could

be used as a strong directing eﬀect for C−C forming activity if

we could mitigate its strength to an optimal level by using a

strongly electron-donating NHC ligand. Accordingly, we

believe that the formation of n-/(n − 1)-exo-trig types of

products would be less favorable than products formed via a

n^γ-/(n − 1)^γ-exo-trig (γ denoted as the cases with the help of γ-

heteroatom chelation). Furthermore, by using the strong steric

eﬀect of NHC substituents as an ancillary factor to favor a 1,2-

hydrometalation and to disfavor a secondary carbocenter on Ni

for tether insertion, this approach should as a whole be able to

provide n^γ- over a (n − 1)^γ-exo-trig product highly selectively.¹¹

supported the possibility of a positive role for a γ-heteroatom

chelation with Ni−NHC at this stage. There are several

protocols for termini-selective (n − 1)-exo-trig cycloisomeriza-

tion.^5,6,9,10Unusually, our system enabled a termini-selective n-

exo-trig cycloisomerization and favored a less sterically

demanding tether insertion (entry 7). We suggest that this

selectivity was due either to the creation by IPr of large steric

diﬀerences in n-exo-trig ring-closure barriers between the two

1,2-hydrometalated species or the relatively faster isomerization

on the less sterically demanding tether. In relation to diallyl

ethers, the most commonly observed activities reported in

previous attempts were (1) the deactivation of highly oxophilic

catalysts, (2) the decomposition of substrates by the use of

NHC−Pd(allyl) catalysts,¹⁴or (3) the successful cyclo-

isomerization at a high (n − 1)-:n-exo-trig selectivity by the

use of P−NiH.^5cIn this experiment, we were pleased to ﬁnd

that our system not only allowed C−C formation in the

absence of nucleophilic or Lewis acidic additives but also

changed its preference in terms of selectivity to favor a high n-:

(n − 1)-exo-trig selectivity (entries 8 and 9). Nevertheless, the

pyran synthesis eﬃciency was low due to nonselective iso-/

oligomerization competition, and we cannot conclude at this

stage whether the consistent termini-selectivity noted in entries

7−9 was related to the heteroatoms or was entirely based on

steric reason (see below).

RESULTS AND DISCUSSION

■

First, we studied the basic activities of NHC−NiH in

cycloisomerization by subjecting several 1,6-dienes to an in

situ generated [IPr-NiH(OTf)] used for cross-hydroalkenyla-

tion at rt in toluene.^12,13This showed that, in relation to simple

1,6-dienes without an allyl heteroatom, the sterically demanding

catalyst generally favored n- over (n − 1)-exo-trig but that this

ratio was only moderate unless a Thorpe-Ingold eﬀect was in

force (Table 1, entries 1−4). This ﬁnding suggests that the use

of steric interaction between an open-chained substrate and

NHC substituents to favor a high ratio may not be generally

applicable. In relation to diallylamines, the ratio observed was

found to be tunable according to the electron-donating ability

of the N-substituents (entries 5 and 6). This plausibly

To study the eﬀect of tether length and to obtain much less

readily accessible but strained medium-sized oxacycle targets

with an exocyclic gem-oleﬁn by an n^γ-exo-trig selective

cycloisomerization, several 1,7-oxadienes (i.e., 1,7-dienes with

a simple allyl ether terminus) were then tested (Table 2, entries

1−12). In the absence of conformational constraints, such as

Thorpe−Ingold acceleration and high-dilution conditions (run

at 0.5 M, cf. a general 0.1−6 × 10⁻³M required in 1,n < 7

dienes cycloisomerization) to combat a relatively higher

entropy stress, the same NHC catalyst as above can provide

n^γ-exo-trig-type cycloisomerization products eﬀectively. This

concurrently achieved prominent chemoselectivity (cyclo-

isomerization vs homohydroalkenylation), regioselectivity

(1,2- vs 2,1-hydrometalation), and termini selectivity (allyl vs

homoallyl ether) to give a single oxepine with an isolated yield

Table 1. IPr-NiH Eﬀect on 1,6-Diene Cycloisomerization

of 84−89% (R = nonyl, Bn, Bu, Hex) from a vast number of

other competitive outcomes. In addition, this reaction can be

achieved in a shorter reaction time (14−18 h) at 5 mol %

catalyst loading. Other than 5−10% nonselective starting

material isomerization and <5% product isomerization, no

other cyclic products that could be formed via such a pathway

were detected by H NMR from the crude mixture (∼19:1),

except in entries 6 and 7. Even the puriﬁcation of the isomeric

mixture is diﬃcult in some 1,n-diene cycloisomerization

systems, the high selectivity of our system and the higher

polarity of the n^γ-exo-trig product compared with the other

types of products made puriﬁcation easy. Strategically, the

exocyclic methylene products obtained here oﬀers an easy

channel to access related structures and complements the

endocyclic oleﬁn products obtained from 1,7-oxadiene RCM.

For instance, a 4-oxepanone was obtained by ozonolysis at a

78% yield from 7a.

Ligand screening indicated that the eﬃcient oxepine

formation was not simply a direct result of optimal tether

length and γ-oxy chelation with Ni. This ﬁnding was supported

by a control that used a P−NiH equivalent generated from

PPh₃/[(allyl)NiCl]₂/AgOTf, in which a 78% 7a precursor was

isomerized to a mixture of noncyclic products. In addition, the

See the Experimental Section for details of the procedure for

cycloisomerization. The yields of the desired products from n-exo-trig

were determined by ¹H NMR and isolation. Unless otherwise

indicated, no other cyclic products (<5%) were detected by ¹H

NMR and isolation. Other conversions of 1,n-dienes were found due

to nonselective isomerization and oligomerization. 35 °C. 36 h.

mol % of catalyst. dr of (n − 1)-exo-trig products, syn/anti = 2.1.

NMR yield. 20 mol % of catalyst. The alternative n- or (n − 1)-exo-

trig isomers via a 1,2- or 2,1-hydrometalation at a terminus without an

α-branch R was not detected by H NMR.

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Table 2. Termini and Regioselective Heterosubstituted 1,7- and 1,8-Diene Cycloisomerization

See the Experimental Section for the detailed cycloisomerization procedure. All of the 1,n-dienes are in racemic form, and the products shown are in

relative conﬁgurations. The yields of the desired products from n^γ-exo-trig were determined by H NMR and isolation. Other than 5−10%

nonselective 1,7-oxadiene isomerization and <5% product isomerization, no other cyclic products that could be formed from these substrates were

detected by ¹H NMR and isolation unless otherwise indicated. Yield of endocyclic 4-oxepine 7a′ and 7p′, respectively (see later section). Mixture

of (n − 1)-exo-trig products. By NMR, the product was not stable on the column. Attempts to recover the decomposed products failed.

reactivity was found to be sensitive to both the NHC electronic

properties and to its substituents, where using IMes resulted in

mainly nonselective isomerization and oligomerization (entry 1,

footnote b). Moreover, screening a 1,7-diene with the Thorpe−

Ingold eﬀect but without γ-oxy chelation, diethyl (homoallyl)-

allylmalonate, did not form n-exo-trig product under our

experimental conditions and provided only nonselective

oligomerization. This indicated that the oxepine formation

was not merely the direct result of optimal tether length and

NHC steric eﬀect directed 1,2-hydrometalation, but that the γ-

oxy chelation was assumed to have a substantial role. Together

with the high n^γ-:(n − 1)^γ-exo-trig selectivity observed, we

believe that the tether length, γ-oxy chelation, and NHC steric

eﬀects were intercorrelated factors that are important to the

success described above.

We then directed our eﬀorts to delineating the generality and

scope of this approach with respect to the steric effect next to

the oleﬁn, such as the incorporation of α-substituents or a cyclic

template (entries 8−12). We found that our approach was

remarkably powerful in its eﬀects on an n^γ-exo-trig cyclo-

isomerization. Our system did not follow the predictions

entirely based on conventional steric rationales or the relative

oleﬁn isomerization rate (vs the trend observed in Table 1,

entries 7−9). Although the tethers involved were sterically

more challenging than the former and the desired n^γ-exo-trig

selectivity may be aﬀected according to the relative fused ring

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strains (entries 10−12),^4,11the system consistently gave n^γ-exo-

trig product as the dominant mode and allowed the

diastereoselective formation of oxepine. In other words, an

increase in steric eﬀect around the oleﬁn substituents as shown

cannot supersede the selectivity on γ-oxy chelation and an

NHC steric basis and cannot reprioritize the preference for

favoring n-exo-trig or (n − 1)^γ-exo-trig. To a limited extent, this

ﬁnding also suggests that the high n-:(n − 1)-exo-trig

cycloisomerization observed in Table 1, entries 7−9, may be

strongly related to the γ-heteroatom chelation rather than to

the eﬀect of R alone. As such, the R may be the key factor to

diﬀerentiate the two competing n^γ-exo-trig pathways on steric

and rate of isomerization basis, since both of which have a

primary (1°) carbocenter on Ni.

tional Lewis acidic cationic catalyst systems^1,5aand the fact that

our system also catalyzes the carbodiene cycloisomerization as

shown in Table 1.

Although a precise cycloisomerization mechanism awaits

further study, we believe that our initial proposal was

reasonable in that the optimal γ-heteroatom chelation with

Ni−NHC has a fundamental role in accounting for the

observations. The use of an electron-rich NHC ligand may

result in a weaker σ-heteroatom−Ni chelation than a P ligand,

and a syn 1,2-hydrometalation on an allyl ether terminus could

be favored (Figure 2). The hydrometalated species is then

Having studied the system with respect to allyl heteroatoms

below, we found that the strength of the heteroatom−Ni

chelation was tunable through the use of the electronic

properties of NHC. The use of a more electron-rich NHC

ligand SIPr led to a signiﬁcant improvement in reactivity and

functional group compatibility and solved issues related to

catalyst deactivation by a stronger γ-heteroatom chelation or

simply by σ-coordination. This expanded the scope of our

ﬁndings to other heterocycles such as siloxepine and

thiephine,¹⁵further highlighting the potential of this approach

(entries 13 and 14). However, using commercially available

ligands at this stage, the cycloisomerization system only

resulted in limited success when using 1,8-oxadiene substrates

without a cyclic backbone (entries 15 vs 16). Nevertheless, the

selective oxocane over oxepine formation showed again that the

success was related to γ-oxy chelation and the NHC eﬀect and

was not a direct result of relative ring strain or tether length.

In Scheme 1, by subjecting precursors with an extra terminus

for competition, the results further showed that our approach

Figure 2. Eﬀect of ligand and σ-oxy-Ni chelation on regioselective

hydrometalation of allyl ether.

stabilized by a γ-heteroatom−Ni chelation in the form of

heteronickelacyclopentane.^16,17Next, this stabilized intermedi-

ate allows ring closure in an n^γ-exo-trig manner. The rest of the

mechanism is expected to resemble that described in a typical

P−NiH-catalyzed 1,n-diene case, in which the Ni−H is

regenerated after a typical syn β-H elimination. The n^γ- over

(n − 1)^γ-exo-trig selectivity observed could be a result of a more

diﬃcult 2,1-hydrometalation on an homoallylether terminus or

the higher ring closure barriers in a secondary (2°) over a 1°

carbocenter on Ni−NHC.¹⁸Overall, the cycloisomerization

selectivity could be a balance between the challenges of

hydrometalation under the σ-heteroatom−Ni chelation eﬀect,

the stability of the resulted heteronickelacycles (Figure 3), and

the NHC steric eﬀect on ring closure.

Scheme 1. Competitive Oxa- and Carbocycles Synthesis

Figure 3. n^γ-Exo-trig directed by NHC steric eﬀect and γ-oxy

stabilization.

It should be noted that, in the presence of a σ-heteroatom−

Ni chelation, the allyl ether terminus could be quite diﬃcult to

adopt a desired conformation for a syn 1,2-hydrometalation

under mild conditions. Indeed, the crystallographic data of

several bulky P-ligated oxanickelacyclopentanes reported in the

literature also suggested this conjecture.^16a,bThis inspired us to

hypothesize an alternative mechanism that involves a

contrasting progression. Unlike many chelation-controlled

reactions sequences, we hypothesize that the reaction may

ﬁrst undergo a NHC steric eﬀect directed 1,2-hydrometalation

followed by γ-heteroatom stabilization. The reversible nature of

hydrometalation (Scheme 2) and the NHC steric eﬀect may

allow the system to sort out the optimal stabilization and tether

for the desired ring closure selectivity. As such, eventually, a

stabilized oxa-/thio-/siloxanickelacyclopentane intermediate

(Figure 3) as described in the above reaction mechanism can

be obtained on the allyl ether terminus after a 1,2-hydro-

metalation favored by the NHC steric eﬀect. However, we do

not have direct evidence for this new reaction sequence.

See the Experimental Section for the detailed cycloisomerization

procedure. The yields of the desired products from 7^γ-exo-trig were

determined by ¹H NMR and isolation. No other oxacycle regioisomers

and carbocycles (<5%) were detected by ¹H NMR and isolation. The

exocyclic homoallyl ether terminus was isomerized to give allyl ether

(E:Z = 19:1 by H NMR).

was exceptionally suited to directing a n^γ-exo-trig compared with

other cycloisomerization modes.

The formation of strained oxepines was preferable to all of

the other possible oxacycles (e.g., pyrans), and also out-

performed all of the other highly competitive, less strained,

smaller ordinary carbocycle formation pathways (e.g., cyclo-

pentanes/hexanes). As such, a high oxa- to carbocycle ratio was

achieved. This set of observations is notable given that both 1,5-

and 1,6-carbodienes are often regarded as more eﬃcient

substrates than their heterosubstituted counterparts in tradi-

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the steric eﬀect around the exocyclic methylene. A greater steric

hindrance closed to exocyclic methylene of the oxepine resulted

a more diﬃcult exo- to endo-isomerization of the oleﬁn (Table

2, 7h,j,m−n). Finally, it should be noted that the isomerization

was sensitive toward the electronic property of the product

substituents. It was more diﬃcult in cases having better

electron-donating heteroatoms for σ-coordination (Table 2,

7o−p), but it was easier in the isomerization of oxepines and

carbocycle such as 6c to 6c′. Overall, the above experiments

and analysis suggested that the selective formation of 7a′ was a

result of a NHC−NiH catalyzed isomerization of 7a, where the

isomerization eﬃciency and regioselectivity were related to

both the electronic and the steric properties of the catalyst and

the heterocycle. Since the 2,1-hydrometalation step required for

the isomerization is expected to be diﬃcult with a bulky NHC

ligated NiH, the optimized catalytic one-pot synthesis of the

endocyclic product required an elevated temperature or in a

longer period of reaction time than the normal cyclo-

isomerization procedure (Scheme 3, B).

Scheme 2. Labeling Experiments

The cycloisomerization procedure employed was the same as the 7a

preparation in Table 2. Products ratios were determined by NMR A

mixture of D-labeled isomers was obtained in ca. 1:1.

CONCLUSION

As noted in Table 2 entry 1, there is a regioselective

formation of a minor endocyclic methylene product 7a′ when

SIPr is used; we therefore studied the system further hoping to

understand and to develop a more eﬃcient one-pot process

after optimization (Scheme 3).¹⁹First, we conﬁrmed the

■

In summary, the γ-oxy deactivation^5awas transformed into a

valuable asset for a highly site- and regioselective C−C forming

reaction by using NHC as an optimal ligand to balance the high

oxophilicity of hydrometalation catalyst. The new reactivity

proﬁle realized from this pairing provides not only the ﬁrst 1,7-

heterodiene unsymmetric n^γ-exo-trig cycloisomerization but also

a novel means of circumventing the typical 1,n-diene

cycloisomerization preferences that normally favor a lower

ring strain product. With this method, larger heterocycles with a

higher strain can be formed preferentially over the ordinary less

strained hetero-/carbocycles observed in conventional systems.

This new approach and its implications will encourage

subsequent optimization and allow the paradigm to achieve

its full potential. The n^γ-exo-trig cycloisomerization outcomes

oﬀered in this work should complement the products obtained

from (n − 1)-exo-trig cycloisomerization and oleﬁn RCM, and

this may further facilitate SAR study in drug synthesis.

Scheme 3. One-Pot Selective Cycloisomerization to

Endocyclic Products

EXPERIMENTAL SECTION

■

General Methods. Unless otherwise indicated, all reactions were

performed under a nitrogen atmosphere from which oxygen and

moisture were rigidly excluded from the reagents and glassware. IPr

[1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene], Ni(cod)₂[bis-

(cyclooctadienyl)nickel(0)], IMes [1,3-bis(2,4,6-trimethylphenyl)-

imidazol-2-ylidene], and SIPr [1,3-bis(2,6-diisopropylphenyl)-

imidazolidin-2-ylidene] were used as received from commercial

sources and stored in a glovebox. Triethylsilyl triﬂuoromethanesulfo-

nate (TESOTf), p-anisaldehyde, and triethylamine (NEt₃) were

distilled before use. Toluene was distilled over sodium before use.

1,n-Dienes were dried with CaH₂or CaCl₂before use. Unless

otherwise indicated, they were synthesized according to the

procedures in the literature. Analytical thin-layer chromatography

(TLC) was performed with the use of silica gel 60 F254 plates. The

developed chromatogram was analyzed by UV lamp (254 nm),

ethanolic phosphomolybdic acid (PMA), or potassium permanganate

(KMnO₄). Flash liquid chromatography was performed on a coarse

fritted glass column packed with silica gel (230−400 mesh, 0.040−

0.063 mm). The cycloisomerization products were found to be

unstable to acidic aqueous conditions.²¹We therefore did not use

HCl-washed sand to pack the silica gel column, and we recommend

the use of fritted glass column. The cycloisomerization products,

except those with α-branch to the exocyclic oleﬁn, were found to be

unstable upon storage in general and will decompose or isomerize

upon heating. The preferred water bath temperature for rotavap is

See the Experimental Section for the detailed procedures. The yields

of the products were determined by ¹H NMR and isolation. No other

cycloisomerization products and other oleﬁn regioisomers (<5%) were

detected by ¹H NMR and isolation. Yield of less hindered 7a′ isomer,

assigned by comparison with related literatures.²⁰

observation is not a direct result of an acid-catalyzed

isomerization. By subjecting an isolated oxepine 7a to a

TfOH-catalyzed oleﬁn isomerization condition, we found that a

new trisubstituted oleﬁn 7a″ was formed as a major product

rather than a highly selective formation of 7a′ observed

(Scheme 3, A). Second, we found that the isomerization

eﬃciency was related to the NHC electronic properties, in

which the use of sterically similar but more electron rich NHC

ligand SIPr was signiﬁcantly more eﬃcient than IPr in the

isomerization of exo- to endocyclic oleﬁn product (Table 2,

entry 1). Third, we found that the reaction was also sensitive to

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below 40 °C. NMR spectra were recorded with a 400 NMR

J = 12.4 Hz), 3.27 (d, 1H, J = 12.4 Hz), 3.23−3.19 (m, 1H), 2.49−2.45

(m, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 1.97−1.94 (m, 1H), 1.35−1.11

(8H), 0.80 (t, 3H, J = 6.9 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 146.2,

137.9, 129.0, 128.3, 125.2, 106.5, 58.1, 57.5, 33.5, 33.4, 33.1, 32.1, 25.7,

22.7, 20.0, 19.8, 19.6, 14.0. HRMS−ESI (m/z): [M + H]⁺calcd for

C₁₉H₃₀N 272.2373, found 272.2378.

spectrometer for H NMR and 100 MHz for ¹³C NMR. Chemical

shifts in ¹H NMR spectra are reported in ppm on the δ scale from an

internal standard of residual chloroform (7.27 ppm). Chemical shifts

of ¹³C NMR spectra are reported in ppm from the central peak of

CDCl₃(77.16 ppm) on the δ scale. Cycloisomerization precursors

conversion and products ratio was determined by integration of areas

of selected peaks in crude ¹H NMR with relaxation time d₁= 10 s and

nitromethane as standard. High-resolution mass spectra (HRMS) data

were obtained by electron-impact (EI) ionization or electrospray

ionization (ESI) with the mass analyzer of magnetic sector used.

NHC−NiH Catalyst Generation. In a glovebox, Ni(cod)₂and IPr

or SIPr or IMes (0.05 mmol, 5 mol % each) were added to an oven-

dried test tube equipped with a stir bar. After being sealed with a

septum and brought out of the glovebox, the tube was connected to a

N₂line. The mixture was dissolved in 2 mL of dried degassed toluene

and stirred at rt for 1 h. 1-Octene (25 mol %), NEt₃(0.3 mmol), p-

anisaldehyde (5 mol %), and TESOTf (10 mol %) were then added

sequentially and stirred for 45 min at rt.¹²The catalyst can be

generated by using conventional methods analogous to the P systems

carefully.^9b,13aHowever, technically we strongly recommend the above

procedure for high consistency. The presence of small amounts of

catalytically active impurities, such as other NiH or its equivalent, may

consume the cycloisomerization precursors more readily than our

desired pathway with the NHC catalyst.

General Cycloisomerization Procedure in Tables 1 and 2

and Schemes 1 and 2. The 1,n-diene (1.0 mmol or indicated

amount) was added to the above catalyst at rt. After the mixture was

stirred at the temperature and time indicated, a spatula of Na₂CO₃(s)

was added, and the mixture was diluted with 4 mL of hexane and

stirred in open air for 30 min. The mixture was then ﬁltered through a

short plug of silica gel and rinsed with 75 mL of 80% ether/hexane.

The solvent was removed under a vacuum. Puriﬁcation via silica gel

column chromatography (hexane/DCM 5:1, 4:1, 3:1, 2:1, 1:1) yielded

the cycloisomerization product as a colorless oil, and the 7^γ-exo-trig

cycloisomerization products were found to be more polar than the 1,7-

oxadienes and the isomerization product mixtures on TLC by using

DCM/Hex as eluent in silica gel in general. In cases where there were

minor 6-exo-trig cycloisomerization products observed, e.g., in Table 2,

R = aryl, they were found to be less polar than the starting material,

and thus, the puriﬁcation is not diﬃcult. For reactions carried out at a

higher temperature, we preheated the oil bath to the required

temperature before immersing the reaction tube.

Table 1, Entry 8, 6h. 14 mg, 30% yield. H NMR (400 MHz,

CDCl₃) δ: 7.38−7.32 (m, 4H), 7.29−7.25 (m, 1H), 4.88 (d, 1H, J =

1.5 Hz), 4.84 (s, 1H), 4.48 (dd, 1H, J = 11.2, 2.1 Hz), 4.36 (dd, 1H, J

= 12.4, 1.5 Hz), 4.17 (d, 1H, J = 12.4 Hz), 2.56−2.42 (m, 2H), 2.18−

1.97 (m, 1H), 1.81−1.71 (m, 1H). ¹³C NMR (100 MHz, CDCl₃) δ:

143.5, 142.5, 128.5, 127.6, 126.1, 109.7, 79.8, 73.0, 35.6, 32.2. HRMS−

EI (m/z): [M]⁺calcd for C₁₂H₁₄O 174.1045, found 174.1055.

Table 1, Entry 9, 6i. 24 mg, 57% yield. ¹H NMR (400 MHz,

CDCl₃) δ: 4.78 (s, 1H), 4.76 (s, 1H), 4.18 (d, 1H, J = 12.3 Hz), 3.96

(d, 1H, J = 12.3 Hz), 3.38−3.35 (m, 1H), 2.42−2.39 (m, 1H), 2.29−

2.23 (m, 1H), 1.78−1.73 (m, 1H), 1.51−1.48 (m, 8H), 0.89 (t, 3H, J =

6.7 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 144.3, 109.1, 77.6, 72.6,

36.2, 33.5, 32.1, 31.8, 25.5, 22.8, 14.2. HRMS−EI (m/z): [M + H]⁺

calcd for C₁₁H₂₁O 169.1587, found 169.1589.

Table 2, Entry 1, 7a. 202 mg, 85% yield. H NMR (400 MHz,

CDCl₃) δ: 4.78 (s, 1H), 4.71 (s, 1H), 4.05−3.95 (m, 1H), 3.50−3.40

(m, 1H), 3.40−3.33 (m, 1H), 2.49−2.41 (m, 1H), 2.41−2.35 (m, 1H),

2.35−2.28 (m, 1H), 2.28−2.21 (m, 1H), 1.85−1.73 (m, 1H), 1.73−

1.69 (m, 1H), 1.46−1.38 (m, 2H), 1.35−1.20 (m, 14H), 0.87 (t, 3H, J

= 6.6 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 148.6, 112.1, 80.3, 70.6,

44.8, 36.9, 34.8, 32.1, 30.6, 29.8, 29.8, 29.7, 29.4, 26.2, 22.8, 14.3.

HRMS−EI (m/z): [M]⁺calcd for C₁₆H₃₀O 238.2297, found 238.2296.

Table 2, Entry 2, 7b. 180 mg, 89% yield. H NMR (400 MHz,

CDCl₃) δ: 7.31−7.19 (m, 5H), 4.79 (s, 1H), 4.70 (s, 1H), 3.97 (dt,

1H, J = 12.4, 4.6 Hz), 3.70−3.63 (m, 1H), 3.44−3.37 (m, 1H), 2.87

(dd, 1H, J = 13.8, 7.4 Hz), 2.69 (dd, 1H, 13.8, 5.7 Hz), 2.50−2.45 (m,

1H), 2.42−2.26 (m, 3H), 1.91−1.73 (m, 1H), 1.71−1.64 (m, 1H). ¹³C

NMR (100 MHz, CDCl₃) δ: 159.0, 147.3, 129.6, 121.0, 114.8, 113.1,

78.0, 71.0, 70.8, 40.8, 35.0, 30.5. HRMS−ESI (m/z): [M + H]⁺calcd

for C₁₄H₁₉O 203.1430, found 203.1430.

Table 2, Entry 3, 7c. 169 mg, 87% yield. H NMR (400 MHz,

CDCl₃) δ: 4.78 (s, 1H), 4.72 (s, 1H), 4.00 (dt, 1H, J = 12.2, 4.7 Hz),

3.45−3.39 (m, 1H), 3.15−3.10 (m, 1H), 2.47−2.26 (m, 4H), 1.91 (d,

1H, J = 12.2 Hz), 1.82−1.64 (m, 6H), 1.39−0.93 (m, 6H). ¹³C NMR

(100 MHz, CDCl₃) δ: 149.2, 112.1, 84.6, 71.2, 43.8, 41.8, 34.7, 30.9,

29.5, 28.9, 26.7, 26.5, 26.4. HRMS−ESI (m/z): [M + H]⁺calcd for

C₁₃H₂₃O 195.1743, found 195.1746.

Table 1, 6a,d,e, are literature compounds, and they were obtained in

59% (70.8 mg), 27% (27.3 mg), and 43% (54.2 mg) yield,

respectively.²²

Table 2, Entry 4, 7d. 141 mg, 84% yield, H NMR (400 MHz,

CDCl₃) δ: 4.78 (s, 1H), 4.72 (s, 1H), 3.99 (dt, 1H, J = 12.3, 4.6 Hz),

3.50−3.40 (m, 2H), 2.44−2.18 (m, 4H), 1.84−1.70 (m, 3H), 1.52−

1.44 (m, 1H), 1.20−1.13 (m, 1H), 0.91 (d, 3H, J = 3.2 Hz), 0.89 (d,

3H, J = 3.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 148.7, 112.2, 78.3,

70.6, 46.0, 45.2, 34.8, 30.6, 24.8, 23.5, 22.4. HRMS−ESI (m/z): [M +

H]⁺calcd for C₁₁H₂₁O: 169.1587, found 169.1588.

Table 1, Entry 2, 6b. 132 mg, 79% yield. H NMR (400 MHz,

CDCl₃) δ: 7.34−7.24 (m, 10H), 4.66 (s, 1H), 4.59 (s, 1H), 4.49 (s,

4H), 3.41−3.33 (m, 4H), 2.12−2.09 (m, 4H), 1.58−1.53 (m, 4H). ¹³C

NMR (100 MHz, CDCl₃) δ: 146.7, 139.2, 139.0, 128.4, 128.1, 127.5,

127.4, 124.8, 109.2, 73.6, 73.3, 41.0, 39.8, 35.0, 29.5, 22.7. HRMS−ESI

(m/z): [M + Na]⁺calcd for C₂₃H₂₈O₂359.1982, found 359.1980.

Table 2, Entry 5, 7e. 170 mg, 78% yield. H NMR (400 MHz,

CDCl₃) δ: 7.30−7.27 (m, 2H), 6.96−6.91 (m, 3H), 4.86 (s, 1H), 4.79

(s, 1H), 4.09 (dt, 1H, J = 12.3, 4.5 Hz), 4.04−3.92 (m, 1H), 3.90−3.84

(m, 2H), 3.62−3.54 (m, 1H), 2.62 (dd, 1H, J = 14.4, 2.4 Hz), 2.53−

2.41 (m, 2H), 2.37−2.31 (m 1H), 1.87−1.72 (m, 2H). ¹³C NMR (100

MHz, CDCl₃) δ: 159.0, 147.3, 129.6, 121.0, 114.8, 113.1, 78.0, 71.0,

70.8, 40.8, 35.0, 30.5. HRMS−ESI (m/z): [M + Na]⁺calcd for

C₁₄H₁₈O₂Na 241.1199, found 241.1200.

Table 1, Entry 3, 6c. 204 mg, 90% yield. H NMR (400 MHz,

CDCl₃) δ: 8.04−8.02 (m, 1H), 7.46−7.42 (m, 1H), 7.31−7.29 (m,

1H), 7.27−7.20 (m, 1H), 4.79 (s, 1H), 4.67 (s, 1H), 2.98−2.87 (m,

2H), 2.55−2.51 (m, 1H), 2.31−2.28 (m, 1H), 2.18−2.15 (m, 1H),

2.10−1.96 (m, 2H), 1.87−1.74 (m, 2H), 1.70−1.04 (m, 1H), 1.62−

1.51 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ: 202.1, 145.9, 143.3,

133.2, 131.9, 128.8, 128.2, 126.7, 109.9, 46.5, 40.7, 34.6, 30.8, 29.6,

24.9, 22.8. HRMS−EI (m/z): [M]⁺calcd for C₁₆H₁₈O 226.1358,

found 226.1356.

Table 2, Entry 6, 7f. 113 mg, 60% yield. H NMR (400 MHz,

CDCl₃) δ: 7.35−7.23 (m, 5H), 4.87 (s, 1H), 4.78 (s, 1H), 4.49 (dd,

1H, J = 10.28 Hz, 3.08 Hz), 4.16−4.10 (m, 1H), 3.68−3.62 (m, 1H),

2.73−2.69 (m, 1H), 2.64−2.57 (m, 1H), 2.49−2.44 (m, 2H), 1.95−

1.79 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ: 148.0, 143.8, 128.5,

127.3, 125.8, 113.0, 82.5, 70.9, 46.9, 34.8, 30.3. HRMS−EI (m/z): [M

+ Na]⁺calcd for C₁₃H₁₆NaO 211.1093, found 211.1095

Table 1, Entry 6, 6f. 81% NMR yield, 50 mg, 47% isolated yield, it

was found to be unstable on colunm. ¹H NMR (400 MHz, CDCl₃) δ:

6.81 (s, 2H), 4.69 (s, 1H), 4.67 (s, 1H), 3.51 (s, 2H), 3.09 (t, 2H, J =

5.2 Hz), 2.28−2.25 (m, 2H), 2.26 (s, 6H), 2.23 (s, 3H), 1.75−1.71 (m,

2H). ¹³C NMR (100 MHz, CDCl₃) δ: 146.4, 146.0, 137.1, 134.5,

129.6, 107.0, 57.4, 50.8, 33.3, 28.5, 20.8, 19.6. HRMS−ESI (m/z): [M

+ H]⁺calcd for C₁₅H₂₂N 216.1747, found 216.1752.

Table 2, Entry 7, 7g. 120 mg, 55% yield. H NMR (400 MHz,

CDCl₃) δ: 7.28 (d, 2H, J = 8.5 Hz), 6.87 (d, 2H, J = 8.5 Hz), 4.86 (s,

1H), 4.78 (s, 1H), 4.44 (dd, 1H, J = 9.8, 2.8 Hz), 4.11 (dt, 1H, J =

12.4, 4.4 Hz), 3.80 (s, 3H), 3.66−3.60 (m, 1H), 2.82−2.57 (m, 2H),

2.52−2.36 (m, 2H), 2.08−1.87 (m, 1H), 1.82−1.69 (m, 1H). ¹³C

Table 1, Entry 7, 6g. 64 mg, 48% yield. H NMR (400 MHz,

CDCl₃) δ: 7.04−6.89 (m, 3H), 4.68 (s, 1H), 4.66 (s, 1H), 3.69 (d, 1H,

dx.doi.org/10.1021/jo5008477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

NMR (100 MHz, CDCl₃) δ: 158.9, 148.1, 136.1, 127.1, 113.8, 113.0,

82.1, 70.7, 55.4, 46.8, 34.7, 30.2. HRMS−ESI (m/z): [M + H]⁺calcd

for C₁₄H₁₉O₂219.1380, found 219.1382.

2.63−2.56 (m, 1H), 2.43−2.32 (m, 2H), 2.21−2.15 (m, 1H), 2.09−

1.97 (m, 1H), 1.87−1.75 (m, 1H). ¹³C NMR (100 MHz, CDCl₃) δ:

147.8, 138.3, 128.5, 127.8, 127.8, 114.4, 73.4, 73.3, 46.2, 42.6, 35.2,

32.6, 32.0. HRMS−ESI (m/z): [M + Na]⁺calcd for C₁₅H₂₀OSNa

271.1127, found 271.1126.

Table 2, Entry 8, 7h. Rac-, relative conﬁguration only, 85 mg, 68%

yield. ¹H NMR (400 MHz, CDCl₃) δ: 4.77 (s, 1H), 4.73 (s, 1H), 4.12

(d, 1H, J = 11.8 Hz), 3.37−3.30 (m, 1H), 2.97 (t, 1H, J = 9.1 Hz),

2.44−2.15 (m, 3H), 1.73−1.66 (m, 2H), 1.54−1.50 (m, 2H), 1.40−

1.22 (m, 14H), 1.00 (d, 3H, J = 6.9 Hz), 0.88 (t, 3H, J = 5.9 Hz). ¹³C

NMR (100 MHz, CDCl₃) δ: 154.9, 111.6, 87.0, 73.7, 48.2, 34.9, 33.7,

32.2, 32.1, 29.9, 29.8, 29.8, 29.5, 26.3, 22.8, 19.6, 14.3. HRMS−ESI

(m/z): [M + H]⁺calcd for C₁₇H₃₃O 253.2526, found 253.2525.

Table 2, Entry 9, 7i. Rac-, relative conﬁguration only, 153 mg, 92%

Table 2, Entry 14, 7p. 44 mg, 70% yield. H NMR (400 MHz,

CDCl₃) δ: 4.85 (s, 1H), 4.81 (s, 1H), 2.79 (dt, 1H, J = 14.6, 4.3 Hz),

2.75−2.67 (m, 2H), 2.60−2.52 (m, 1H), 2.45−2.39 (m, 1H), 2.26−

2.13 (m, 2H), 2.05−1.99 (m, 1H), 1.82−1.71 (m, 1H), 1.53−1.48 (m,

2H), 1.48−1.40 (m, 1H), 1.30−1.26 (m, 12H), 0.88 (t, 3H, J = 6.3

Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 148.8, 113.9, 47.6, 47.0, 36.3,

34.8, 32.5, 32.3, 32.0, 29.7, 29.5, 27.7, 22.8, 14.3. HRMS−EI (m/z):

[M]+ calcd for C₁₆H₃₀S 254.2063, found 254.2063.

yield. H NMR (400 MHz, CDCl₃) δ: 4.86 (s, 1H), 4.76 (s, 1H),

4.06−4.01 (m, 1H), 3.50−3.43 (m, 1H), 3.04−2.98 (m, 1H), 2.39−

2.26 (m, 2H), 2.12−2.07 (m, 1H), 1.97−1.95 (m, 1H), 1.80−1.69 (m,

5H), 1.43−1.18 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ: 154.0

111.2 84.7 71.3 52.3 34.3 34.2 32.9 31.8 26.0 25.5. HRMS−ESI (m/z):

[M + H]⁺calcd for C₁₁H₁₉O 167.1430, found 167.1432.

Table 2, Entry 15, 8a. (31 mg, 32% yield) H NMR (400 MHz,

CDCl₃) δ: 4.78 (s, 1H), 4.74 (s, 1H), 3.83−3.77 (m, 1H), 3.57−3.51

(m, 1H), 3.40−3.35 (m, 1H), 2.41−2.31 (m, 1H), 2.30−2.26 (m, 2H),

2.11−2.04 (m, 1H), 1.98−1.91 (m, 1H), 1.82−1.75 (m, 1H), 1.66−

1.62 (m, 1H), 1.61−1.51 (m, 1H), 1.47−1.38 (m, 2H), 1.36−1.24 (m,

6H), 0.88 (t, 3H, J = 6.9 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 152.0,

109.9, 78.9, 69.5, 36.6, 36.0, 34.3, 32.4, 32.1, 29.4, 25.9, 22.8, 14.2.

HRMS−EI (m/z): [M + H]⁺calcd for C₁₃H₂₅O: 197.1905, found

197.1904.

Table 2, Entry 10, 7j. Rac-, relative conﬁguration determined by

NOESY, 24 mg, 54% yield. Major diastereomer. H NMR (400 MHz,

CDCl₃) δ: 4.85 (s, 1H), 4.78 (s, 1H), 3.94 (dd, 1H, J = 12.2, 5.1 Hz),

3.08−3.00 (m, 2H), 2.29 (dd, 1H, J = 12.9, 4.0 Hz), 2.16−2.10 (m,

2H), 1.96−1.90 (m, 2H), 1.78−1.67 (m, 3H), 1.33−1.22 (m, 4H),

0.83 (d, 3H, J = 6.8 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 152.5,

112.2, 85.2, 78.4, 52.8, 42.3, 37.0, 34.1, 33.3, 26.0, 25.5, 17.5. HRMS−

ESI ( m/z): [M + H]⁺calcd for C₁₂H₂₁O 181.1587, found 181.1589.

Minor diastereomer, ∼3% yield as determined by NMR. Isolation was

not successful, and the following data was deduced from a product

Table 2, Entry 16, 8b. 61 mg, 70% yield. H NMR (400 MHz,

CDCl₃) δ: 7.21−7.14 (m, 2H), 7.07−7.01 (m, 2H), 4.82 (s, 1H), 4.68

(s, 1H), 4.15−4.12 (m, 2H), 3.50−3.41 (m, 2H), 2.32- 2.30 (m, 2H),

1.62−1.58 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ: 156.6, 150.6,

135.8, 130.2, 128.5, 125.1, 122.4, 111.9, 77.8, 39.7, 36.1, 28.7. HRMS−

ESI (m/z): [M + H]⁺calcd for C₁₂H₁₅O 175.1117, found 175.1113.

Scheme 1, 7q. 107 mg, 78% yield. ¹H NMR (400 MHz, CDCl₃) δ:

5.97−5.87 (m, 1H), 5.29−5.14 (m, 2H), 4.88 (m, 2H), 4.00−3.96 (m,

3H), 2.55−2.35 (m, 3H), 2.28−2.17 (m, 1H), 1.88−1.72 (m, 2H). ¹³C

NMR (100 MHz, CDCl₃) δ: 149.9, 135.4, 116.7, 106.6, 80.0, 70.0,

39.6, 32.2, 30.2. HRMS−ESI (m/z): [M + H]⁺calcd for C₉H₁₅O

139.1123, found 139.1120.

mixture roughly puriﬁed on a short plug of silica gel. H NMR (400

MHz, CDCl₃) δ: 4.82 (s, 1H), 4.78 (s, 1H), 3.72 (dd, 1H, J = 12.1, 2.4

Hz), 3.58 (dd, 1H, J = 12.2, 4.2 Hz), 3.46 (d, 1H, J = 11.0 Hz), 3.19

(d, 1H, J = 11.0 Hz), 2.94 (dd, 1H, J = 12.8, 9.1 Hz), 2.52 (dd, 1H, J =

12.8, 5.0 Hz), 1.96−1.67 (m, 5H), 1.33−1.22 (m, 4H), 0.97 (d, 3H, J

= 7.0 Hz). ¹³⁵DEPT NMR (100 MHz, CDCl₃) δ: 111.0, 85.8, 76.5,

52.1, 42.5, 37.0, 32.1, 31.9, 29.9, 28.5, 14.3.

Table 2, Entry 11, 7k. Rac-, relative conﬁguration only, 50 mg, 66%

yield. ¹H NMR (400 MHz, CDCl₃) δ: 4.80 (s, 1H), 4.67 (s, 1H), 4.01

(ddd, 1H, J = 12.0, 5.1, 3.3 Hz), 3.63 (dd, 1H, J = 14.9, 8.5 Hz), 3.53−

3.47 (m, 1H), 2.60−2.48 (m, 3H), 2.10−2.01 (m, 1H), 1.98−1.91 (m,

1H), 1.90−1.80 (m, 1H), 1.77−1.72 (m, 2H), 1.68−1.50 (m, 3H). ¹³C

NMR (100 MHz, CDCl₃) δ: 151.1, 108.6, 85.1, 71.6, 52.6, 36.4, 32.5,

29.6, 29.2, 21.6. HRMS−ESI (m/z): [M + H]⁺calcd for C₁₀H₁₇O

153.1274, found 153.1273.

Scheme 1, 7r. 167 mg, 78% yield. ¹H NMR (400 MHz, CDCl₃) δ:

7.42−7.20 (m, 5H), 6.59 (d, 1H, J = 16.0 Hz), 6.27−6.22 (m, 1H),

4.86 (s, 1H), 4.80 (s, 1H), 4.17−4.10 (m, 1H), 4.09−4.05 (m, 1H),

3.64−3.58 (m, 1H), 2.61 (dd, 1H, J = 14.7, 2.9 Hz), 2.48−2.34 (m,

3H), 1.89−1.81 (m, 1H), 1.80−1.70 (m, 1H). ¹³C NMR (100 MHz,

CDCl₃) δ: 147.6, 137.1, 130.9, 129.6, 128.6, 127.6, 126.6, 113.0, 80.3,

70.1, 44.7, 34.9, 30.3. HRMS−EI (m/z): [M]⁺calcd for C₁₅H₁₈O

214.1358, found 214.1346.

Scheme 1, 7s. E conﬁguration, 111 mg, 73% yield. H NMR (400

Table 2, Entry 12, 7l. Rac-, relative conﬁguration only, 55 mg, 55%

yield. H NMR (400 MHz, CDCl₃) δ: 7.21−7.19 (m, 4H), 4.99 (s,

MHz, CDCl₃) δ: 5.70−5.50 (m, 2H), 4.81 (s, 1H), 4.76 (s, 1H), 4.03−

3.98 (m, 1H), 3.92−3.86 (m, 1H), 3.56−3.50 (m, 1H), 2.51−2.47 (m,

1H), 2.42−2.30 (m, 3H), 1.84−1.76 (m, 1H), 1.74−1.69 (m, 4H). ¹³C

NMR (100 MHz, CDCl₃) δ: 147.9, 132.6, 126.3, 112.7, 80.6, 70.0,

44.8, 34.9, 30.3, 17.9. HRMS−EI (m/z): [M + H]⁺calcd for C₁₀H₁₇O

153.1279, found 153.1275.

In Scheme 2, each of those D-labeled oxepines is not separable by

column and were isolated with the 7a obtained together. The peaks

corresponding only to 7a were identiﬁed and indicated in parentheses

as shown below.

1H), 4.98 (s, 1H), 4.09 (dd, 1H, J = 11.7, 5.5 Hz), 3.95 (dd, 1H, J =

17.7, 8.5 Hz), 3.83 (d, 1H, J = 8.5 Hz), 3.56 (m, 1H), 3.20 (dd, 1H, J =

15.0, 7.5 Hz), 2.89 (dd, 1H, J = 15.0, 9.8 Hz), 2.73−2.69 (m, 1H),

2.61−2.53 (m, 1H), 2.09−1.98 (m, 1H), 1.96−1.88 (m, 1H). ¹³C

NMR (100 MHz, CDCl₃) δ: 148.6, 141.2, 141.0, 127.0, 126.6, 125.8,

124.8, 110.5, 90.4, 70.4, 56.2, 38.1, 35.5, 28.3. HRMS−EI (m/z): [M]+

calcd for C₁₄H₁₆O 200.1196, found 200.1195.

Table 2, Entry 13, 7m. Low boiling, puriﬁed in DCM/pentane. 60%

NMR yield, 54 mg, 35% isolated yield, it was found not stable on

column. H NMR (400 MHz, CDCl₃) δ: 4.67−4.66 (m, 1H), 4.57−

Scheme 2, D-Labeled 7a in eq 1. Mixed with 7a, 200 mg, 84%

yield. H NMR (700 MHz, CDCl₃) δ: 4.78 (s, 1H), 4.71 (s, 1H),

4.56 (m, 1H), 3.85−3.83 (m, 2H), 2.26−2.23 (m, 2H), 1.79−1.74 (m,

2H), 1.72 (s, 2H), 0.14 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ:

147.0, 109.0, 64.7, 38.7, 32.8, 28.9, −1.3. HRMS−ESI (m/z): [2M +

Na]⁺calcd for C₁₆H₃₂NaO₂Si₂335.1833, found 335.1835.

Table 2, Entry 13, 7n. 60% NMR yield, 17 mg, 30% isolated yield, it

was found not stable on column. ¹H NMR (400 MHz, CDCl₃) δ: 4.63

(s, 1H), 4.56 (s, 1H), 3.73−3.69 (m, 1H), 2.42−2.36 (m, 1H), 2.11−

2.01 (m, 1H), 1.76−1.66 (m, 3H), 1.58−1.18 (m, 11H), 0.88 (t, 3H, J

= 6.6 Hz), 0.14 (s, 3H), 0.12 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ:

147.3, 108.6, 74.1, 38.8, 37.9, 37.7, 31.9, 29.4, 25.8, 22.8, 14.2, −1.0,

−1.2. HRMS−EI (m/z): [M]⁺calcd for C₁₃H₂₆OSi 226.1747, found

226.1745.

4.03−3.97 (m, 1H), 3.50−3.43 (m, 1H), 3.43−3.35 (m, 1H), 2.46−

2.42 (m, 1H), 2.38−2.35 (m, 0.5H) [7a: 2.41−2.35 (m, 1H)], 2.31−

2.27 (m, 0.5H) [7a: 2.34−2.27 (m, 1H)], 2.27−2.22 (m, 1H), 1.81−

1.73 (m, 1H), 1.72−1.67 (m, 1H), 1.52−1.47 (m, 1H), 1.42−1.38 (m,

1H), 1.35−1.20 (m, 14H), 0.88 (t, 3H, J = 7.0 Hz). ¹³C NMR (100

MHz, CDCl₃) δ: 148.6, 112.1, 80.3, 70.7, 70.6, 44.8, 36.9, 34.5 (t, J =

19.3 Hz), 34.4 (t, J = 19.3 Hz) [7a: 34.8], 32.1, 30.5, 30.5 [7a: 30.6],

29.8, 29.8, 29.7, 29.4, 26.2, 22.8, 14.3. HRMS−EI (m/z): [M]⁺calcd

for C₁₆H₂₉DO 239.2354, found 239.2352.

Scheme 2, D-Labeled 7a in eq 2. Mixed with 7a, 199 mg, 84%

yield. H NMR (700 MHz, CDCl₃) δ: 4.77 (s, 0.43H) [7a: 4.78 (s,

0.14H)], 4.70 (s, 0.43H) [7a: 4.71 (s, 0.14H)], 3.50−3.43 (m, 1H),

3.43−3.35 (m, 1H), 2.46−2.42 (m, 1H), 2.41−2.35 (m, 1H), 2.34−

2.27 (m, 1H), 2.27−2.22 (m, 1H), 1.81−1.73 (m, 1H), 1.72−1.67 (m,

1H), 1.52−1.47 (m, 1H), 1.42−1.38 (m, 1H), 1.35−1.20 (m, 14H),

Table 2, Entry 14, 7o. 52 mg, 84% yield. H NMR (400 MHz,

CDCl₃) δ: 7.36−7.28 (m, 5H), 4.88 (s, 1H), 4.84 (s, 1H), 4.60−4.53

(m, 2H), 3.59−3.48 (m, 2H), 3.08−3.01 (m, 1H), 2.84−2.78 (m, 2H),

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0.88 (t, 3H, J = 7.0 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 148.6, 111.9

(t, J = 23.7 Hz) [7a: 112.1], 80.3, 70.6, 44.7, 36.9, 34.8, 32.1, 30.6,

29.8, 29.8, 29.7, 29.5, 26.2, 22.8, 14.3. HRMS−ESI (m/z): [M + H]⁺

calcd for C₁₆H₃₀DO 240.2432, found 240.2430.

−78 °C was sparged with ozone (O₃) until a blue color was obtained

(∼20 min). After being stirred for 1 h at −78 °C, it was sparged with

nitrogen until no trace of blue color remained (about 5 min).

Triphenylphosphine (0.75 mmol) was then added, and the reaction

was allowed to reach rt gradually by stirring overnight. Removal of

solvent in vacuum followed by ﬂash chromatography on silica gel (10%

EtOAc/hexanes) aﬀorded the desired product as colorless oil (78%

Scheme 2, D-Labeled 7a in eqs 3 and 4. Mixed with 7a, 199 mg,

84% yield. ¹H NMR (700 MHz, CDCl₃) δ: 4.78 (s, 1H), 4.71 (s, 1H),

3.50−3.43 (m, 1H), 3.43−3.35 (m, 1H), 2.46−2.42 (m, 1H), 2.41−

2.35 (m, 1H), 2.34−2.27 (m, 1H), 2.27−2.22 (m, 1H), 1.81−1.73 (m,

0.4H) [7a: 1.81−1.73 (m, 0.2H)], 1.72−1.67 (m, 0.4H) [7a: 1.72−

1.67 (m, 0.2H)], 1.52−1.47 (m, 1H), 1.42−1.38 (m, 1H), 1.35−1.20

(m, 14H), 0.88 (t, 3H, J = 7.0 Hz. ¹³C NMR (100 MHz, CDCl₃) δ:

148.7 [7a: 148.6], 112.1, 112.1, 80.3, 80.3, 70.6, 70.6 [7a: 70.6], 44.7,

36.9, 34.7 [7a: 34.8], 32.1, 30.2 (t, J = 19.6 Hz) [7a: 30.6], 29.8, 29.8,

29.7, 29.5, 26.2, 22.8, 14.3. HRMS−ESI (m/z): [M + H]⁺calcd for

C₁₆H₃₀DO 240.2432, found 240.2429.

Triﬂic Acid Catalyzed Isomerization of 7a to Endocyclic

Oleﬁns 7a′ and 7a″ in Scheme 3, Part A. Triﬂic acid (10 mol %)

was added to a toluene solution of isolated 7a and stirred at rt for the

indicated reaction time. The mixture was then added a spatula of

Na₂CO₃(s). After the solution was ﬁltered through a short plug of

silica gel and rinsed with 75 mL of 80% ether/hexane, the solvent was

removed under vacuum. Puriﬁcation via silica gel column chromatog-

raphy (hexane/DCM, 3:1, 2:1, 1:1) yielded the endocyclic oleﬁn

products. The products obtained from the NHC catalyst and from the

acid catalyzed isomerization are respectively less polar and more polar

than the original exocyclic methylene, i.e., typical polarity trend: 7a″ >

7a > 7a′.

yield, 28 mg). H NMR (400 MHz, CDCl₃) δ: 4.21−4.16 (m, 1H),

3.66−3.61 (m, 1H), 3.59−3.52 (m, 1H), 2.73−2.55 (m, 4H), 1.95−

1.80 (m, 2H), 1.57−1.27 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz). ¹³C NMR

(100 MHz, CDCl₃) δ: 211.8, 76.9, 72.5, 52.2, 43.0, 36.8, 32.0, 29.7,

29.6, 29.4, 27.0, 25.8, 22.8, 14.3. HRMS−ESI (m/z): [M + Na]⁺calcd

for C₁₅H₂₈O₂Na 263.1982, found 263.1981.

General Procedure for the 1,n-Diene (P) Syntheses. Allylation

was the last step in most of the 1,n-dienes syntheses. All the

carbodienes were prepared according to the literature procedures.

Most of the other 1,n-dienes (P), including P6(a−i) in Table 1 and

P7(a−s), P8(a,b) in Table 2 and Schemes 1−3 were prepared

according to the literature procedures or in analogy except the

following:^24,25

Allylation General Procedure. The 1,n-dienes (P) were

synthesized by adding NaH (1.5 equiv., 60% in mineral oil) to a

solution of corresponding allylic/homoallylic alcohol, thiol, or amine

(10 mmol) in DMF (20 mL) at 0 °C and stirred for 5 min. Two

equivalents of allyl bromide (or the corresponding halides, e.g., 3-

chloro-2-methyl-1-propene, 5-bromo-1-pentene, or the corresponding

2-D-labeled allyl bromide) was then added to the above mixture. After

being stirred overnight at rt, the reaction mixture was quenched with

30 mL of ice−water, extracted with diethyl ether (3 × 50 mL), washed

with brine, dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation

via silica gel column chromatography (hexane/DCM 5:1, 3:1, 2:1)

aﬀorded the corresponding 1,n-oxadiene as a colorless oil for

cycloisomerization.

General Cycloisomerization Procedure for the One-pot

Preparation of the Endocyclic Oleﬁn Product in Scheme 3,

Part B. The NHC−NiH-catalyzed reactions were performed by

following the general cycloisomerization procedure except with the use

of the indicated ligands, time, temperature, and catalyst loading.

Product structures were assigned by NMR and by comparison with

literature²⁰

Table 2, Entry 1, P7a. Allylation of the 1- tridecen-4-ol with allyl

bromide by following the allylation general procedure gave P7a (2.1 g,

Scheme 3, Part A, 3-Endocyclic Methylene Product 7a″. 79 mg,

67% yield. Obtained by acid-catalyzed isomerization, it is more polar

89% yield). H NMR (400 MHz, CDCl₃) δ: 5.97−5.78 (m, 2H),

than the below 4-endocyclic methylene product 7a′. H NMR (400

5.29−5.03 (m, 4H), 4.03 (dd, 1H, J = 12.4, 5.6 Hz), 3.97 (dd, 1H, J =

12.6, 5.7 Hz), 3.36−3.33 (m, 1H), 2.26 (m, 2H), 1.47−1.26 (m, 16H),

0.88 (t, 3H, J = 6.6 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 135.62,

135.29, 116.86, 116.62, 78.73, 70,13, 38.51, 33.97, 32.05, 29.90, 29.77,

29.73, 29.47, 25.51, 22.83, 14.27. HRMS−ESI (m/z): [M + Na]⁺calcd

for C₁₆H₃₀ONa 261.2189, found 261.2184.

MHz, CDCl₃) δ: 5.57 (dt, 1H, J = 15.5, 7.0 Hz), 5.45 (d, 1H, J = 15.5

Hz), 3.90−3.86 (m, 2H), 2.03−1.81 (m, 5H), 1.70−1.63 (m, 1H),

1.35−1.26 (m, 17H), 0.88 (t, 3H, J = 6.5 Hz). ¹³C NMR (100 MHz,

CDCl₃) δ: 135.4, 128.1, 82.2, 67.4, 37.7, 32.4, 32.1, 29.7, 29.6, 29.5,

29.5, 29.3, 26.7, 25.9, 22.8, 14.3. HRMS−ESI (m/z): [M + Na]⁺calcd

for C₁₆H₃₀ONa 261.2189, found 261.2189.

Table 2, Entry 2, P7b. Allylation of the 5-phenylpent-1-en-4-ol with

allyl bromide by following the allylation general procedure gave P7b

We found that the cycloisomerization cascade could provide two

column separable 4-endocyclic methylene product 7a′ isomers by

using SIPr.

(1.8 g, 88% yield). H NMR (400 MHz, CDCl₃) δ: 7.29−7.17 (m,

5H), 5.92−5.76 (m, 2H), 5.22−5.06 (m, 4H), 3.99−3.88 (m, 2H),

3.58 (m, 1H), 2.80 (dd, 1H, J = 30.6, 13.7 Hz), 2.78 (dd, 1H, J = 29.9,

13.7 Hz), 2.27−2.24 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ: 139.1,

135.2, 134.9, 129.6, 128.3, 126.2, 117.3, 116.7, 79.9, 70.5, 40.5, 38.3.

HRMS−ESI (m/z): [M + H]⁺calcd for C₁₄H₁₉O 203.1430, found

203.1430.

Scheme 3, Part B, 7a′. Major isomer, less polar, 98 mg, 82% yield.

¹H NMR (400 MHz, CDCl₃) δ: 5.56 (s, 1H), 4.0−3.95 (m, 1H),

3.47−3.37 (m, 2H), 2.44−2.34 (m, 2H), 2.12−2.05 (m, 1H), 1.98 (d,

1H, J = 16.1 Hz), 1.74 (s, 3H), 1.53−1.26 (m, 16H), 0.88 (t, 3H, J =

6.3 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 138.4, 124.7, 78.9, 70.0,

42.9, 37.2, 32.1, 31.4, 29.8, 29.8, 29.7, 29.5, 26.8, 26.2, 22.8, 14.3.

HRMS m/z): [M + H]⁺calcd for C₁₆H₃₁O 239.2369, found 239.2363.

Table 2, Entry 4, P7d. Allylation of the 6-methyl-1-hepten-4-ol with

allyl bromide by following the allylation general procedure gave P7d

Minor isomer, more polar, 12 mg, 10% yield. H NMR (400 MHz,

(1.5 g, 89% yield). H NMR (400 MHz, CDCl₃) δ: 6.07−5.70 (m,

CDCl₃) δ: 5.33 (s, 1H), 4.09−4.03 (m, 1H), 3.95−3.90 (m, 1H),

3.74−3.68 (m, 1H), 2.26−2.24 (m, 2H), 1.81−1.70 (m, 2H), 1.75 (s,

3H), 1.49−1.11 (m, 16H), 0.88 (t, 3H, J = 6.4 Hz). ¹³C NMR (100

MHz, CDCl₃) δ: 141.4, 129.4, 77.0, 72.3, 36.8, 32.7, 32.1, 29.8, 29.8,

29.7, 29.5, 28.2, 26.3, 25.8, 22.8, 14.3. HRMS−ESI (m/z): [M + H]⁺

calcd for C₁₆H₃₁O 239.2369, found 239.2371.

2H), 5.29−5.03 (m, 4H), 4.07 (dd, 1H, J = 12.6, 5.8 Hz), 3.94 (dd,

1H, J = 5.8, 12.6 Hz), 3.46−3.40 (m, 1H), 2.28−2.25 (m, 2H), 1.82−

1.72 (m, 1H), 1.50−1.43 (m, 1H), 1.26−1.20 (m, 1H), 0.90 (d, 3H, J

= 4.6 Hz), 0.89 (d, 3H, J = 4.6 Hz). ¹³C NMR (100 MHz, CDCl₃) δ:

135.5, 135.1, 117.0, 116.6, 76.8, 70.0, 43.6, 38.8, 24.6, 23.4, 22.5.

HRMS−ESI (m/z): [M + Na]⁺calcd for C₁₁H₂₀ONa 191.1406, found

191.1403.

Scheme 3, Part B, 6c′. 107 mg, 95% yield. H NMR (400 MHz,

CDCl₃) δ: 8.05−8.03 (m, 1H), 7.47−7.43 (m, 1H), 7.32−7.28 (m,

1H), 7.26−7.21 (m, 1H), 5.41−5.39 (m, 1H), 3.08−3.00 (m, 1H),

2.93−2.86 (m, 1H), 2.64−2.60 (m, 1H), 2.10−1.93 (m, 4H), 1.77−

1.71(m, 2H), 1.70 (s, 3H), 1.69−1.61 (m, 1H). ¹³C NMR (100 MHz,

CDCl₃) δ: 202.7, 143.3, 133.1, 132.1, 131.9, 128.8, 128.2, 126.7, 119.2,

44.0, 36.6, 30.7, 27.3, 25.4, 24.0, 22.6. HRMS−EI ( m/z): [M]⁺calcd

for C₁₆H₁₈O 226.1358, found 226.1356.

Table 2, Entry 5, P7e. Allylation of the 1-phenoxypent-4-en-2-ol

with allyl bromide by following the allylation general procedure gave

P7e (1.9 g, 86% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.35−7.31 (m,

2H), 7.02−6.96 (m, 3H), 6.18−5.84 (m, 2H), 5.55−5.02 (m, 4H),

4.44−4.32 (m, 2H), 4.26−4.11 (m, 2H), 4.07−3.80 (m, 1H), 2.55−

2.34 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ: 158.9, 135.2, 134.3,

129.5, 120.9, 117.7, 117.1, 114.7, 76.9, 71.2, 69.7, 36.4. HRMS−ESI

(m/z): [M + Na]⁺calcd for C₁₄H₁₈O₂Na 241.1199, found 241.1199.

Synthesis of 4-Oxepanone.²³The ozonolysis followed a typical

procedure. A solution of 7a (36 mg, 0.15 mmol) in CH₂Cl₂(6 mL) at

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Table 2, Entry 8, P7h. Allylation of the alcohol (1.1 g, 5 mmol) with

allyl bromide by following the allylation general procedure gave P7h

(1.1 g, 88% yield). H NMR (400 MHz, CDCl₃) δ: 6.01−5.73 (m,

2H), 5.28−4.99 (m, 4H), 4.04−3.96 (m, 2H), 3.19−3.13 (m, 1H),

2.44−2.38 (m, 1H), 1.43−1.35 (m, 2H), 1.34−1.16 (m, 14H), 1.02−

0.99 (m, 3H), 0.88 (t, 3H, J = 6.8 Hz). ¹³C NMR (100 MHz, CDCl₃)

δ: 141.2, 135.7, 116.5, 114.5, 83.1, 71.2, 40.7, 32.1, 31.0, 30.0, 29.8,

29.8, 29.5, 26.1, 22.8, 15.1, 14.3. HRMS−ESI (m/z): [M + Na]⁺calcd

for C₁₇H₃₂ONa 275.2345, found 275.2345.

thioglycolate (20 mmol) in THF (60 mL) at 0 °C, and the reaction

was then stirred at rt overnight. After being quenched with water, the

mixture was extracted with diethyl ether. The combined organic layer

was washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure and then puriﬁed over silica gel column

chromatography with 10% EtOAc/n-hexane as the eluent. After a

typical ester reduction with LiAlH₄(1.2 equiv) in THF (50 mL) at 0

°C and stirring at rt for 5 h, the puriﬁed alcohol was protected with

benzyl bromide (1.5 equiv) and NaH (2 equiv) in THF (50 mL) at 0

°C and stirred at rt for overnight. After a normal aqueous workup, the

mixture was puriﬁed over silica gel column chromatography by using

10% EtOAc/n-hexane as the eluent and aﬀorded the title 1,7-thiodiene

P7o (2.6 g, 53% isolated yield over three steps). ¹H NMR (400 MHz,

CDCl₃) δ: 7.37−7.25 (m, 5H), 5.88−5.75 (m, 2H), 5.11−5.05 (m,

4H), 4.53 (s, 2H), 3.60−3.57 (m, 1H), 3.52−3.48 (m, 1H), 3.24−3.14

(m, 2H), 2.91−2.85 (m, 1H), 2.55−2.48 (m, 1H), 2.36−2.29 (m, 1H).

¹³C NMR (100 MHz, CDCl₃) δ: 138.2, 135.2, 134.7, 128.4, 127.6,

Table 2, Entry 10, P7j. Allylation of the trans-2-vinylcyclohexanol

with 3-chloro-2-methyl-1-propene by following the allylation general

procedure gave P7j (1.5 g, 85% yield). H NMR (400 MHz, CDCl₃)

δ: 5.94−5.85 (m, 1H), 5.08−4.99 (m, 2H), 4.96 (s, 1H), 4.84 (s, 1H),

3.97 (d, 1H, J = 12.3 Hz), 3.82 (d, 1H, J = 12.3 Hz), 3.01−2.97 (m,

1H), 2.09−2.08 (m, 2H), 1.73 (s, 3H), 1.73−1.68 (m, 3H), 1.22−1.17

(m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ: 143.1, 141.9, 114.1, 112.0,

81.2, 72.9, 47.9, 31.3, 31.2, 25.2, 24.7, 19.8. HRMS−ESI (m/z): [M +

Na]⁺calcd for C₁₂H₂₀ONa: 203.1406, found 203.1405.

117.2, 117.0, 73.0, 72.7, 43.3, 36.2, 34.4. HRMS−ESI (m/z): [M +

Na]⁺calcd for C₁₅H₂₀OSNa 271.1127, found 271.1127.

Table 2, Entry 11, P7k. Allylation of the trans-2-vinylcyclopentanol

with allyl bromide by following the allylation general procedure gave

Table 2, Entry 14, P7p. Diisopropyl azodicarboxylate (20 mmol, 2

equiv) was added to a solution of triphenylphosphine (20 mmol, 2

equiv) in THF (50 mL) at 0 °C. After 0.5 h, a solution of 1-tridecen-4-

ol (10 mmol, 1 equiv) and thioacetic acid (20 mmol, 2 equiv) in THF

(10 mL) was added, and the reaction mixture was stirred at rt

overnight. After the volatiles were removed under vacuum, trituration

of the residue in hexane, ﬁltration, concentration of the ﬁltrate, and

chromatography of the residue aﬀorded the thioester (6 mmol, 60%

isolated yield) by using DCM/n-hexane (1:2) as the eluent. After a

typical ester reduction with LiAlH₄(12 mmol, 2 equiv) in THF (30

mL) from 0 °C to rt, the roughly puriﬁed 1-tridecen-4-thiol was

treated with allyl bromide (9 mmol, 1.5 equiv) and NaH (12 mmol, 2

equiv) in DMF (15 mL) from 0 °C to rt for overnight. After aqueous

workup as described in Allylation General Procedure, the mixture was

puriﬁed over silica gel column chromatography with DCM/n-hexane

(1:4) as the eluent and aﬀorded the title 1,7-thiodiene P7p (0.9 g, 35%

yield over three steps). ¹H NMR (400 MHz, CDCl₃) δ: 5.89−5.76 (m,

2H), 5.12−5.05 (m, 4H), 3.15 (dd, 2H, J = 7.1, 0.9 Hz), 2.68−2.62

(m, 1H), 2.38−2.30 (m, 2H), 1.61−1.26 (m, 16H), 0.88 (t, 3H, J = 6.7

Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 135.9, 135.1, 116.8, 116.7, 43.9,

39.1, 34.1, 33.9, 32.0, 29.7, 29.7, 29.4, 26.7, 22.8, 14.2. HRMS−EI (m/

z): [M]+ calcd for C₁₆H₃₀S: 254.2063, found 254.2062.

P7k (1.3 g, 85% yield). H NMR (400 MHz, CDCl₃) δ: 6.04−5.74

(m, 2H), 5.29−4.96 (m, 4H), 3.99 (d, 2H, J = 5.5 Hz), 3.66 (dd, 1H, J

= 11.1, 5.5 Hz), 2.57−2.49 (m, 1H), 1.94−1.83 (m, 2H), 1.78−1.60

(m, 3H), 1.45−1.36 (m, 1H). ¹³C NMR (100 MHz, CDCl₃) δ: 141.4,

135.5, 116.7, 114.1, 85.6, 70.5, 50.1, 31.7, 30.4, 22.5. HRMS−ESI (m/

z): [M + H]⁺calcd for C₁₀H₁₇O 153.1274, found 153.1273.

Table 2, Entry 12, P7l. Allylation of the trans-1-vinyl-2,3-dihydro-

1H-inden-2-ol with allyl bromide by following the allylation general

procedure gave P7l (1.7 g, 85% yield). H NMR (400 MHz, CDCl₃)

δ: 7.18−7.09 (m, 4H), 5.99−5.83 (m, 2H), 5.33−5.17 (m, 4H), 4.17−

4.11 (m, 3H), 3.81−3.77 (m, 1H), 3.23 (dd, 1H, J = 15.6, 7.0 Hz),

2.91 (dd, 1H, J = 15.6, 7.0 Hz). ¹³C NMR (100 MHz, CDCl₃) δ:

142.8, 140.1, 139.0, 135.1, 127.3, 126.9, 124.8, 124.7, 117.2, 117.1,

85.8, 70.9, 56.0, 38.1. HRMS−EI (m/z): [M]+ calcd for C ₁₄H₁₆O

200.1196, found 200.1199.

Table 2, Entry 15, P8a. Alkylation of 1-octen-3-ol with 5-bromo-1-

pentene by following the allylation general procedure gave P8a (1.5 g,

80% yield). ¹H NMR (400 MHz, CDCl₃) δ: 5.87−5.62 (m, 2H),

5.17−5.10 (m, 2H), 5.04−4.94 (m, 2H), 3.60−3.47 (m, 2H), 3.29−

3.23 (m, 1H), 2.15−2.09 (m, 2H), 1.69−1.62 (m, 2H), 1.59−1.56 (m,

1H), 1.47−1.37 (m, 2H), 1.35−1.28 (m, 5H), 0.88 (t, 3H, J = 6.7 Hz).

¹³C NMR (100 MHz, CDCl₃) δ: 139.8, 138.6, 116.3, 114.7, 81.5, 67.9,

Procedure for the Preparation of 1,n-Azadienes.²⁸Table 1,

Entry 7, P6g. By following the standard Buchwald amination

procedure, 3-aminooct-1-ene (5 mmol, 1 equiv), 2,6-dimethylbromo-

benzene (5 mmol, 1 equiv), ( )-2,2′-bis(diphenylphosphino)-1,1′-

binaphthyl (0.25 mmol, 0.05 equiv), and sodium tert-butoxide (15

mmol, 3 equiv) were mixed in a sealed tube with 10 mL of toluene,

and the mixture was stirred at 90 °C for 24 h. The crude reaction

mixture was ﬁltered through Celite, washed with CH₂Cl₂, concen-

trated, and puriﬁed by column chromatography (30% DCM/n-

hexane) the product obtained was then followed by typical allylation

conditions as described in the Allylation General Procedure and

aﬀorded the branched 1,6-azadiene P6g (0.9 g, 70% isolated yield over

two steps). ¹H NMR (400 MHz, CDCl₃) δ: 6.99−6.92 (m, 3H),

5.80−5.70 (m, 1H), 5.68−5.59 (m, 1H), 5.09−5.04 (m, 2H), 4.94−

4.81 (m, 2H), 3.71 (dd, 1H, J = 14.3, 6.1 Hz), 3.59 (dd, 1H, J = 14.3,

7.4 Hz), 3.55−3.50 (m, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 1.39−1.11 (m,

8H), 0.82 (t, 3H, J = 6.9 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 146.1,

141.6, 139.7, 139.0, 137.7, 128.7, 128.3, 125.5, 115.9, 115.1, 66.5, 55.0,

33.1, 32.0, 26.2, 22.8, 20.1, 14.2. HRMS−ESI (m/z): [M + H]⁺calcd

for C₁₉H₃₀N: 272.2373, found 272.2378.

35.6, 31.9, 30.6, 29.3, 25.2, 22.8, 14.2. HRMS−EI (m/z): [M + H]⁺

calcd for C₁₃H₂₅O 197.1905, found 197.1898.

Scheme 1, P7s. Allylation of 1,6-heptadien-4-ol with allyl bromide

by following the allylation general procedure gave P7s (1.3 g, 88%

yield). ¹H NMR (400 MHz, CDCl₃) δ: 5.96−5.78 (m, 3H), 5.30−5.25

(m, 1H), 5.16−5.05 (m, 5H), 4.02 (d, 2H, J = 5.6 Hz), 3.43 (quin, 1H,

J = 5.9 Hz), 2.30−2.27 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ:

135.4, 134.9, 117.1, 116.7, 78.1, 70.2, 38.2. HRMS−EI (m/z): [M +

H]⁺calcd for C₁₀H₁₇O 153.1279, found 153.1275.

Procedure for the Preparation of 1,7-Siloxadiene.²⁶Table 2,

Entry 13, P7n. Allylchlorodimethylsilane (10.5 mmol) was added to a

solution of 1-octen-3-ol (10 mmol), triethylamine (12 mmol), and 4-

(dimethylamino)pyridine (0.6 mmol) in 50 mL of dry CH₂Cl₂at rt.

The reaction was stirred overnight and then quenched with 50 mL of

water, the organic layer was removed, and the aqueous layer was

extracted with ether (3 × 50 mL). The organic layers were combined,

washed with brine, dried over Na₂SO₄, and concentrated. Puriﬁcation

via a NEt₃buﬀered silica gel column chromatography (10% Et₂O/n-

pentane) aﬀorded the title 1,7-siloxadiene P7n (1.8 g, 80% yield). H

NMR (400 MHz, CDCl₃) δ: 5.85−5.74 (m, 2H), 5.16−4.84 (m, 4H),

4.07 (dd, 1H, J = 12.5, 6.1 Hz), 1.63 (d, 2H, J = 18.1 Hz), 1.48−1.40

(m, 2H), 1.38−1.27 (m, 6H), 0.88 (t, 3H, J = 6.5 Hz), 0.12 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ: 141.7, 134.4, 113.9, 113.7, 74.3, 38.0,

Scheme 2, Procedures for the Preparation of D-Labeled 1,7-

Oxadiene. 1,7-Oxadienes Labeled with a D at the Alkene Terminal

Position in eqs 1 and 2 (Scheme 2). were prepared from the

corresponding enynes (4-(prop-2-yn − 1-yloxy)tridec-1-ene for eq 1,

Scheme 2, 4-(allyloxy)tridec-1-yne for eq 2, Scheme 2) by a typical

deprotonation with n-BuLi, followed by quenching with D₂O, and

ﬁnally a partial hydrogenation (Lindlar catalyst).²⁹n-BuLi (1.6 M in

hexane, 1.2 equiv) was added dropwise to a solution of the

corresponding 1,7-oxaenyne (6 mmol) in dry THF (30 mL) at −78

31.9, 25.2, 25.2, 22.8, 14.2, −1.7, −1.8. HRMS−EI (m/z): [M]⁺calcd

for C₁₃H₂₆OSi 226.1747, found 226.1743.

Procedure for the Preparation of 1,7-Thiodienes.²⁷Table 2,

Entry 14, P7o. The allylation was performed by adding NaH (2.4

equiv) followed by allyl bromide (2.5 equiv) to a solution of ethyl

dx.doi.org/10.1021/jo5008477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

°C. The reaction mixture was allowed to warm slowly and to reach 0

°C, followed by D₂O quenching (1 mL). After being stirred overnight

at rt, the reaction mixture was diluted with 20 mL of Et₂O, dried over

Na₂SO₄, ﬁltered through a short pad of silica gel, and washed

thoroughly with Et₂O. The ﬁltrate was concentrated under reduced

pressure to aﬀord the corresponding deuterated 1,7-oxaenyne and

used directly in the next step without further puriﬁcation. The

deuterated 1,7-oxaenyne above was treated with quinoline (6 mmol)

and Lindlar catalyst (palladium 5 wt % on calcium carbonate poisoned

with lead, 2 mol % Pd, 255 mg) in 30 mL of ethyl acetate. The

reaction ﬂask was then degassed and backﬁlled with H₂. A H₂balloon

was then attached, and the reaction mixture was allowed to stirred at rt

for 15 min. The reaction progress was closely monitored by NMR to

avoid over-reduction. The reaction was stopped by remove the H₂

balloon and vacuum for 5 min. The reaction mixture was ﬁltered

through a short pad of silica gel, washed with Et₂O, and the ﬁltrate was

concentrated under reduced pressure. Puriﬁcation via silica gel column

chromatography (20% DCM/hexane) aﬀorded the corresponding

deuterated 1,7-oxadiene in 58% (0.83 g) and 50% (0.72 g) isolated

yield over two steps in eqs 1 and 2 (Scheme 2), respectively.

29.5, 25.5, 22.8, 14.2. HRMS−ESI (m/z): [M + Na]⁺calcd for

C₁₆H₂₉DONa 262.2252, found 262.2254.

1,7-Oxadienes Labeled with a D at the Alkene Internal Position

in eq 4 (Scheme 2). was prepared by allylation of 1-tridecen-2-

deuterio-4-ol (3.2 mmol) with allyl bromide following the Allylation

General Procedure (0.65 g, 85% yield). H NMR (400 MHz, CDCl₃)

δ: 5.97−5.87 (m, 1H), 5.28−5.04 (m, 4H), 4.05−3.94 (m, 2H), 3.38−

3.32 (m, 1H), 2.31−2.22 (m, 2H), 1.49−1.39 (m, 2H), 1.39−1.26 (m,

14 H), 0.88 (t, 3H, J = 6.6 Hz). ¹³C NMR (100 MHz, CDCl₃) δ:

135.6, 134.8 (t, J = 23.3 Hz), 116.6, 116.1, 78.6, 70.0, 38.4, 33.9, 32.0,

29.8, 29.7, 29.6, 29.4, 25.4, 22.7, 14.1. HRMS−ESI (m/z): [M + Na]⁺

calcd for C₁₆H₂₉DONa 262.2252, found 262.2256.

Procedure for the D-Labeled Alcohol, 1-Tridecen-2-deuter-

io-4-ol.^25cDecyl aldehyde (8 mmol), the 2-D-labeled allyl bromide

above (∼0.3 M in Et₂O, 35 mL), tin powder (10 mmol) in HCl (60

mL, 0.6 mol L⁻¹), and 15 mL of THF were stirred at 35 °C for

overnight and then extracted with Et₂O (3 × 50 mL). The combined

organic layers were washed with brine, dried over Na₂SO₄, and

concentrated under reduced pressure. Puriﬁcation via silica gel column

chromatography (10% EA/Hexane) aﬀorded the 2-D-labeled 1-

tridecen-4-ol (0.64 g, 40% isolated yield). ¹H NMR (400 MHz,

CDCl₃) δ: 5.12 (s, 2H), 3.61−3.69 (m, 1H), 2.32−2.28 (m, 1H),

2.16−2.11 (m, 1H), 1.49−1.45 (m, 2H), 1.43−1.26 (m, 14H), 0.88 (t,

3H, J = 6.6 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 134.7 (t, J = 23.2

Hz), 117.7, 70.8, 41.9, 36.9, 32.0, 29.8, 29.7, 29.7, 29.4, 25.8, 22.7, 14.2.

HRMS−ESI (m/z): [M + Na]⁺calcd for C₁₃H₂₅DONa 222.1939,

found 222.1943.

1,7-Oxadienes Labeled with a D at the Alkene Terminal Position

in eq 1 (Scheme 2). H NMR (400 MHz, CDCl₃) δ: 5.95−5.78 (m,

2H), 5.14−5.03 (m, 3H), 4.06−3.94 (m, 2H), 3.38−3.32 (m, 1H),

2.32−2.21 (m, 2H), 1.49−1.46 (m, 2H), 1.43−1.26 (m, 14H), 0.88 (t,

3H, J = 6.8 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 135.4, 135.0, 116.6,

115.8 (t, J = 23.8 Hz), 78.5, 69.9, 38.4, 33.9, 32.0, 29.8, 29.7, 29.6, 29.4,

25.4, 22.8, 14.1. HRMS−ESI (m/z): [M + Na]⁺calcd for

C₁₆H₂₉DONa 262.2252, found 262.2256.

Additional Experiments with 1,n-Azadienes (Employed in

ref 15). Most of the cycloisomerization products and precursors are

literature compounds except the following:^31,32

1,7-Oxadienes Labeled with a D at the Alkene Terminal Position

in eq 2 (Scheme 2). H NMR (400 MHz, CDCl₃) δ: 5.97−5.81 (m,

6-Exo-Trig Product from N,N-Diallyl-2,6-diisopropylaniline.

2H), 5.29−5.01 (m, 3H), 4.05−3.94 (m, 2H), 3.38−3.32 (m, 1H),

2.30−2.23 (m, 2H), 1.49−1.26 (m, 16H), 0.88 (t, 3H, J = 6.7 Hz). ¹³C

NMR (100 MHz, CDCl₃) δ: 135.5, 134.9, 116.3 (t, J = 23.5 Hz),

116.1, 78.6, 70.0, 38.4, 33.9, 32.0, 29.8, 29.7, 29.6, 29.4, 25.4, 22.7,

14.1. HRMS−ESI (m/z): [M + Na]⁺calcd for C₁₆H₂₉DONa

262.2252, found 262.2254.

131 mg, 51% yield. H NMR (400 MHz, CDCl₃) δ: 7.18−7.14 (m,

1H), 7.10−7.08 (m, 2H), 4.70 (s, 1H), 4.66 (s, 1H), 3.54 (s, 2H), 3.43

(hept, 2H, J = 6.9 Hz), 3.14 (t, 2H, J = 5.2 Hz), 2.29 (t, 2H, J = 6.2

Hz), 1,77−1.71 (m, 2H), 1.19 (d, 6H, J = 6.9 Hz), 1.19 (d, 6H, J = 6.9

Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 149.4, 146.5, 145.7, 126.5,

124.0, 107.0, 58.6, 51.8, 33.2, 28.4, 28.2, 24.5, 24.4. HRMS−ESI (m/

z): [M + H]⁺calcd for C₁₈H₂₈N 258.2216, found 258.2212.

Procedure for the Enyne 4-(Prop-2-yn − 1-yloxy)tridec-1-

ene. NaH (1.5 equiv, 60% in mineral oil) was added to a solution of 1-

tridecen-4-ol (15 mmol) in DMF (30 mL) at 0 °C and stirred for 15

min. Propargyl chloride (2 equiv) was then added to the above

mixture. After being stirred overnight at rt, the mixture was quenched

with 30 mL of ice−water, extracted with diethyl ether (3 × 50 mL),

washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated.

Puriﬁcation via silica gel column chromatography (20% DCM/

Hexane) aﬀorded the 1,7-oxaenyne (1.8 g, 50% yield). ¹H NMR (400

MHz, CDCl₃) δ: 5.89−5.78 (m, 1H), 5.11−5.05 (m, 2H), 4.22 (s,

2H), 3.56−3.51 (m, 1H), 2.39 (t, 1H, J = 2.3 Hz), 2.29 (t, 2H, J = 6.3

Hz), 1.50−1.46 (m, 2H), 1.44−1.26 (m, 14H), 0.88 (t, 3H, J = 6.7

Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 134.9, 117.2, 80.6, 78.4, 73.8,

56.3, 38.1, 33.7, 32.1, 29.9, 29.7, 29.7, 29.5, 25.3, 22.8, 14.3. HRMS−

ESI (m/z): [M + Na]⁺calcd for C₁₆H₂₈ONa 259.2032, found

259.2035.

Procedure for the Enyne 4-(Allyloxy)tridec-1-yne. Allylation

of 1-tridecyn-4-ol (9 mmol) with allyl bromide by following the

Allylation General Procedure aﬀorded the title 1,7-oxaenyne (1.7 g,

80% yield). ¹H NMR (400 MHz, CDCl₃) δ: 5.97−5.87 (m, 1H),

5.31−5.15 (m, 2H), 4.13−4.08 (m, 1H), 4.02−3.96 (m, 1H), 3.45−

3.43 (m, 1H), 2.46−2.33 (m, 2H), 1.99 (t, 1H, J = 2.7 Hz), 1.63−1.59

(m, 2H), 1.42−1.27 (m, 14H), 0.88 (t, 3H, J = 6.7 Hz). ¹³C NMR

(100 MHz, CDCl₃) δ: 135.3, 117.0, 81.5, 77.3, 70.6, 69.9, 34.1, 32.0,

29.8, 29.7, 29.7, 29.5, 25.4, 24.0, 22.8, 14.3. HRMS−ESI (m/z): [M +

Na]⁺calcd for C₁₆H₂₈ONa 259.2032, found 259.2037.

6-Exo-Trig Product from N-Allyl-N-homoallyltosylamine. 42

mg, 16% yield. H NMR (400 MHz, CDCl₃) δ: 7.62 (d, 2H, J = 8.0

Hz), 7.31 (d, 2H, J = 7.8 Hz), 4.71 (s, 1H), 4.67 (s, 1H), 3.51−3.49

(m, 2H), 2.60−2.53 (m, 1H), 2.45−2.40 (m, 1H), 2.42 (s, 3H), 2.39−

2.31 (m, 2H), 2.24−2.18 (m, 1H), 1.06 (d, 3H, J = 6.6 Hz). ¹³C NMR

(100 MHz, CDCl₃) δ: 148.1, 143.6, 133.4, 129.7, 127.7, 107.9, 53.8,

48.0, 36.4, 34.0, 21.6, 15.6. HRMS−ESI (m/z): [M + Na]⁺calcd for

C₁₄H₁₉NO₂SNa 288.1029, found 288.1025.

7^γ-Exo-Trig and 6^γ-Exo-Trig Products from N-Allyl-N-homo-

allyltosylamine. Inseparable mixture, yield was determined by NMR

ratio. 6^γ-exo-trig ¹H NMR (400 MHz, CDCl₃) δ: 7.66 (d, 2H, J = 8.2

Hz), 7.33 (d, 2H, J = 7.6 Hz), 4.96 (s, 1H), 4.81 (s, 1H), 4.07 (d, 1H, J

= 12.1 Hz), 3.70−3.67 (m, 1H), 2.96 (d, 1H, J = 12.1 Hz), 2.56−2.49

(m, 1H), 2.44 (s, 3H), 1.99−1.97 (m, 1H), 1.84−1.73 (m, 1H), 1.43−

1.30 (m, 1H), 1.04 (d, 3H, J = 6.6 Hz). 7^γ-exo-trig H NMR (400

MHz, CDCl₃) δ: 7.66 (d, 2H, J = 8.2 Hz), 7.33 (d, 2H, J = 7.7 Hz),

4.78 (s, 1H), 4.73 (s, 1H), 3.28−3.24 (m, 4H), 2.44−2.40 (m, 2H),

2.42 (s, 3H), 2.30−2.27 (m, 2H), 1.82−1.74 (m, 2H). HRMS−ESI

(m/z): [M + Na]⁺calcd for C₁₄H₁₉NO₂SNa 288.1029, found

288.1024.

N,N-Diallyl-2,6-diisopropylaniline. The compound was pre-

pared in one step from 2,6-diisopropylaniline (NH₂-DIPP, 10

mmol), NaH (23 mmol, 2.3 equiv), and allyl bromide (23 mmol,

2.3 equiv) by following the Allylation General Procedure (0.8 g, 30%

yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.17−7.14 (m, 1H), 7.08−7.06

(m, 2H), 5.92−5.82 (m, 2H), 5.09−5.00 (m, 4H), 3.64 (d, 4H, J = 6.4

Hz), 3.44 (sept, 2H, J = 6.9 Hz), 1.19 (d, 12H, J = 6.9 Hz). ¹³C NMR

(100 MHz, CDCl₃) δ: 149.2, 145.7, 137.3, 126.6, 124.1, 116.2, 58.1,

28.2, 24.6. HRMS−ESI (m/z): [M + H]⁺calcd for C₁₈H₂₈N 258.2216,

found 258.2218.

1,7-Oxadienes Labeled with a D at the Alkene Internal Position

in eq 3 (Scheme 2). was prepared by allylation of 1-tridecen-4-ol with

2-D-labeled allyl bromide³⁰following the Allylation General Procedure

(0.8 g, 35% yield). H NMR (400 MHz, CDCl₃) δ: 5.89−5.77 (m,

1H), 5.25−5.02 (m, 4H), 4.04−3.94 (m, 2H), 3.37−3.32 (m, 1H),

2.32−2.21 (m, 2H), 1.49−1.39 (m, 2H), 1.39−1.23 (m, 14H), 0.88 (t,

3H, J = 6.6 Hz). ¹³C NMR (100 MHz, CDCl₃) δ: 135.3 (t, J = 23.6

Hz), 135.2, 116.8, 116.4, 78.7, 70.0, 38.5, 34.0, 32.0, 29.9, 29.8, 29.7,

N-Allyl-N-homoallyl-2,4,6-trimethylaniline. The compound

was prepared in two steps by allylation of 2,4,6-trimethylaniline (10

dx.doi.org/10.1021/jo5008477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

mmol) with allyl bromide (12 mmol) following the Allylation General

Procedure and followed by homoallylation of the obtained N-allyl-

2,4,6-trimethylaniline with 4-bromopentene (15 mmol) reﬂuxing in

MeCN in the presence of K₂CO₃(20 mmol) in 50% yield over two

steps (1.1 g). ¹H NMR (400 MHz, CDCl₃) δ: 6.80 (s, 2H), 5.92−5.82

(m, 1H), 5.79−5.68 (m, 1H), 5.15−5.10 (m, 1H), 5.02−4.92 (m, 3H),

3.60 (d, 2H, J = 6.5 Hz), 3.06 (t, 2H, J = 7.7 Hz), 2.25 (s, 6H), 2.22 (s,

3H), 2.17−2.11 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ: 145.6,

137.6, 137.5, 137.1, 134.5, 129.6, 115.8, 115.6, 57.7, 52.7, 34.2, 20.9,

19.7. HRMS−ESI (m/z): [M + H]⁺calcd for C₁₆H₂₄N 230.1903,

found 230.1908.

(8) Recent 1,n-enyne cycloisomerization reviews based on Cu, Ag,

and Au: (a) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200.

(b) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075. (c) Fehr, C.

Synlett 2012, 23, 990. Ru: (d) Schmidt, B. Angew. Chem., Int. Ed. 2003,

42, 4996. Recent advances by Rh: (e) Ota, K.; Lee, S. I.; Tang, J.-M.;

Takachi, M.; Nakai, H.; Morimoto, T.; Sakurai, H.; Kataoka, K.;

Chatani, N. J. Am. Chem. Soc. 2009, 131, 15203. 7-membered

azacycles by Au(I)-catalyzed 1,7-diyne benzoate cycloisomerization:

(f) Rao, W.; Koh, M. J.; Kothandaraman, P.; Chan, P. W. H. J. Am.

Chem. Soc. 2012, 134, 10811.

(9) By Ni: (a) Reference 5c. (b) Boeing, C.; Hahne, J.; Francio, G.;

Leitner, W. Adv. Synth. Catal. 2008, 350, 1073. By Pd:

P.; Widenhoefer, R. A. J. Am. Chem. Soc. 2000, 122, 10017.

(10) By Ru: (a) Yamamoto, Y.; Ohkoshi, N.; Kameda, M.; Itoh, K. J.

Org. Chem. 1999, 64, 2178. (b) Yamamoto, Y.; Nakagai, Y.; Ohkoshi,

N.; Itoh, K. J. Am. Chem. Soc. 2001, 123, 6372. By NHC−Ru:

43, 4063. (d) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;

Nishida, A. J. Org. Chem. 2006, 71, 4255.

ASSOCIATED CONTENT

* Supporting Information

■

Additional experiments as described in ref 15 and NMR spectra

of all new compounds. This material is available free of charge

via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: jasonhcy@sustc.edu.cn, jasonhcy@cuhk.edu.hk.

■

(11) Recent reviews on medium oxacycle preparation: (a) Kadota, I.;

Yamamoto, Y. Acc. Chem. Res. 2005, 38, 423. (b) Kleinke, A. S.; Webb,

D.; Jamison, T. F. Tetrahedron 2012, 68, 6999.

(12) (a) Ho, C.-Y.; He, L. Angew. Chem., Int. Ed. 2010, 49, 9182.

(b) Ho, C.-Y.; He, L. Chem. Commun. 2012, 48, 1481.

Notes

The authors declare no competing ﬁnancial interest.

(13) Recent hydrovinylation review: (a) RajanBabu, T. V. Chem. Rev.

2003, 103, 2845. (b) RajanBabu, T. V. Synlett 2009, 853. (c) Vogt, D.

Angew. Chem., Int. Ed. 2010, 49, 7166. (d) Ho, C.-Y.; He, L.; Chan, C.-

W. Synlett 2011, 1649. (e) Hilt, G. Eur. J. Org. Chem. 2012, 4441.

(14) NHC−Pd catalyzed 1,n-dienes cycloisomerization: (a) Song, Y.-

J.; Jung, I. G.; Lee, H.; Lee, Y. T.; Chung, Y. K.; Jang, H.-Y.

Tetrahedron Lett. 2007, 48, 6142. Enynes: (b) Sato, Y.; Imakuni, N.;

Mori, M. Adv. Synth. Catal. 2003, 345, 488.

(15) The system achieved only limited success in 1,7-azadiene

cycloisomeriation; see the Supporting Information for additional

experiments with 1,n-azadienes.

(16) Oxanickellacyclopentane: (a) Ogoshi, S.; Oka, M.; Kurosawa, H.

J. Am. Chem. Soc. 2004, 126, 11802. (b) Ogoshi, S.; Ueta, M.; Arai, T.;

Kurosawa, H. J. Am. Chem. Soc. 2005, 127, 12810. Review on

cyclization via oxametallacycle: (c) Tanaka, K.; Tajima, Y. Eur. J. Org.

Chem. 2012, 3715.

ACKNOWLEDGMENTS

■

C.Y.H. thanks the Thousand Young Talents Program (Na-

tional). L.H. thanks the HK Ph.D. Fellowship. Support for this

work was provided by NSFC Project Nos. 21102122, SUSTC,

CUHK SZRI, and GJHS20120702105523302 and a special

equipment grant (Project No. SEG/CUHK09) from the

University Grants Committee of Hong Kong.

REFERENCES

■

(1) (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1. (b) Lloyd-Jones,

G. C. Org. Biomol. Chem. 2003, 1, 215. (c) Nakamura, I.; Yamamoto,

Y. Chem. Rev. 2004, 104, 2127. (d) Michelet, V.; Toullec, P. Y.; Genet,

J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268. Recent advances in

catalytic asymmetric cycloisomerization: (e) Marinetti, A.; Jullien, H.;

Voituriez, A. Chem. Soc. Rev. 2012, 41, 4884. (f) Watson, I. D. G.;

Toste, F. D. Chem. Sci. 2012, 3, 2899. Dienes: (g) Yamamoto, Y.

Chem. Rev. 2012, 112, 4736.

(17) (a) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem.

Commun. 2007, 4441. (b) Liu, P.; McCarren, P.; Cheong, P. H.-Y.;

Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050.

Soc. 2011, 133, 20712.

(2) Grubbs, R. H. Tetrahedron 2004, 60, 7117.

(3) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,

107, 1080.

(18) Similar to the selective formation of n- over (n − 1)^γ-exo-trig, the

secondary carbocenter steric eﬀect on Ni made trans-/cis-disubstituted

allyl ethers much less eﬃcient as a directing terminus than un-/2-/3-

substituted allyl ethers for the desired cycloisomerization. Each yielded

an inseparable mixture, ca. 10% by weight, under standard conditions.

(19) For a metathesis-isomerization tandem, see: Sutton, A. E.;

Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002,

124, 13390.

(4) Review on the role of ring strain in ring closure of bifunctional

chain molecules: Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117.

(5) n-Exo-trig cycloisomerization of 1,5- and 1,6-carbo/aza-dienes.

Sc: (a) Piers, W. E.; Shapiro, P. J.; Bunel, E. E.; Bercaw, J. E. Synlett

1990, 74. Zr: (b) Thiele, S.; Erker, G. Chem. Ber. 1997, 130, 201. Pd:

(d) Nelson, B.; Herres-Pawlis, S.; Hiller, W.; Preut, H.; Strohmann, C.;

Hiersemann, M. J. Org. Chem. 2012, 77, 4980. Ti: (e) Okamoto, S.;

Livinghouse, T. Organometallics 2000, 19, 1449.

(6) Yttrium-catalyzed reductive or silylative cycloisomerization:

(a) Molander, G. A.; Hoberg, J. O. J. Am. Chem. Soc. 1992, 114,

3123. (b) Molander, G. A.; Romero, J. A. C. Tetrahedron 2005, 61,

2631.

(20) (a) Yadav, V. K.; Balamurugan, R. Chem. Commun. 2002, 514.

(b) Jadhav, V. H.; Bande, O. P.; Pinjari, R. V.; Gejji, S. P.; Puranik, V.

G.; Dhavale, D. D. J. Org. Chem. 2009, 74, 6486.

(21) (a) Necas, D.; Tursky, M.; Tislerova, I.; Kotora, M. New J.

Chem. 2006, 30, 671. (b) For a Et₂AlCl-directed deallylation, see:

Necas, D.; Kotora. M. Org. Lett. 2008, 10, 5261.

(22) (a) Jahn, U.; Hartmann, P.; Kaasalainen, E. Org. Lett. 2004, 6,

257. (b) Chen, C.; Mariano, P. S. J. Org. Chem. 2000, 65, 3252.

(23) Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077.

(24) Preparation of carbo-dienes: (a) Kotha, S.; Mandal, K.; Tiwari,

A.; Mobin, S. M. Chem.Eur. J. 2006, 12, 8024. (b) Necas, D.;

Tursky, M.; Tislerova, I.; Kotora, M. New J. Chem. 2006, 30, 671.

1992, 33, 5655.

(7) Ni-catalyzed 1,n-enyne cycloisomerization and cycloadditions:

(a) Montgomery, J. Acc. Chem. Res. 2000, 33, 467. (b) Shin, S.;

RajanBabu, T. V. J. Am. Chem. Soc. 2001, 123, 8416. (c) Tekavec, T.

N.; Louie, J. Tetrahedron 2008, 64, 6870. (d) Chen, M.; Weng, Y.;

Guo, M.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2008, 47, 2279.

Diynes for 8-membered heterocycles: (e) Kumar, P.; Zhang, K.; Louie,

J. Angew. Chem., Int. Ed. 2012, 51, 8602. 1,3-Diene: (f) Sato, Y.;

Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M. J. Am.

Chem. Soc. 1994, 116, 9771.

dx.doi.org/10.1021/jo5008477 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(25) Preparation of 1,n-oxa-dienes: (a) Tan, K.-T.; Chng, S.-S.;

Cheng, H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 2958.

(b) Schmidt, B.; Wildemann, H. Eur. J. Org. Chem. 2000, 3145.

Schmidt, B. Eur. J. Org. Chem. 2003, 816. (c) Guimaraes, R. L.; Lima,

D. J. P.; Barros, M. E. S. B.; Cavalcanti, L. N.; Hallwass, F.; Navarro,

M.; Bieber, L. W.; Malvestiti, I. Molecules 2007, 12, 2089. (d) Alam,

M.; Wise, C.; Baxter, C. A.; Cleator, E.; Walkinshaw, A. Org. Pro. Res.

Dev. 2012, 16, 435. (e) Ghosh, S.; Raychaudhuri, S. R.; Salomon, R. G.

J. Org. Chem. 1987, 52, 83. (f) Schmidt, B. J. Org. Chem. 2004, 69,

7672.

(26) Khabashesku, V. N.; Kerzina, Z. A.; Mal’tsev, A. K.; Nefedov, O.

M. J. Organomet. Chem. 1989, 364, 301.

(27) (a) Bergbreiter, D. E.; Morvant, M.; Chen, B. Tetrahedron Lett.

1991, 32, 2731. (b) Briggs, M. S. J.; Helliwell, M.; Moorcroft, D.;

Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1992, 2223.

(28) Sawadjoon, S.; Samec, J. S. M. Org. Biomol. Chem. 2011, 9, 2548.

(29) (a) Schmidt, B.; Staude, L. J. Org. Chem. 2009, 74, 9237.

(b) Gryparis, C.; Efe, C.; Raptis, C.; Lykakis, I. N.; Stratakis, M. Org.

Lett. 2012, 14, 2956. (c) Lindlar, H.; Dubois, R. Org. Synth. 1966, 46,

89. (d) Munoz-Bascon, J.; Sancho-Sanz, I.; Alvarez-Manzaneda, E.;

Rosales, A.; Oltra, J. E. Chem.Eur. J. 2012, 18, 14479.

(30) Paderes, M. C.; Belding, L.; Fanovic, B.; Dudding, T.; Keister, J.

B.; Chemler, S. R. Chem.Eur. J. 2012, 18, 1711.

(31) Selective publications in P ligated Group 10 metal hydride

catalyzed 1,n-diene cycloisomerization: (a) Reference 5c. (b)

Reference 9b. (c) Reference 9c.

(32) Hirashita, T.; Hayashi, A.; Tsuji, M.; Tanaka, J.; Araki, S.

Tetrahedron 2008, 64, 2642.

dx.doi.org/10.1021/jo5008477 | J. Org. Chem. XXXX, XXX, XXX−XXX

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