Regio- and Diastereoselective Iron-Catalyzed [4+4]-Cycloaddition of 1,3-Dienes

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Article

C. Rose Kennedy, Hongyu Zhong, Rachel MacCauley, and Paul J. Chirik

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Page 1 of 19

Journal of the American Chemical Society

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Regio- and Diastereoselective Iron-Catalyzed

4+4]-Cycloaddition of 1,3-Dienes

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C. Rose Kennedy, Hongyu Zhong, Rachel L. Macaulay, and Paul J. Chirik*

Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States

ABSTRACT: A family of single-component iron precatalysts for the [4+4]-cyclodimerization and intermolecular cross-[4+4]-

cycloaddition of monosubstituted 1,3-dienes is described. Cyclooctadiene products were obtained with high regioselectivity, and catalyst-

controlled access to either cis- or trans-diastereomers was achieved using 4-substituted diene substrates. Reactions conducted either with

single-component precatalysts or with iron dihalide complexes activated in situ proved compatible with common organic functional groups

R

and were applied on multi-gram scale (up to >100 g). Catalytically relevant, S = 1 iron complexes bearing 2-iminopyridine ligands, ( PI)FeL

2

R

i

(

PI = [2-(2,6-R

2

-C

6

H

3

-N=CMe)-C

5

H

4

N] where R = Pr or Me, L

2

= bis-olefin) were characterized by single-crystal X-ray diffraction,

Mößbauer spectroscopy, magnetic measurements, and DFT calculations. The structural and spectroscopic parameters are consistent with an

electronic structure description comprised of a high spin iron(I) center (SFe = 3/2) engaged in antiferromagnetically coupling with a ligand

radical anion (SPI = –1/2). Mechanistic studies conducted with these single-component precatalysts—including kinetic analyses, C/ C

isotope effect measurements, and in situ Mößbauer spectroscopy— support a mechanism involving oxidative cyclization of two dienes that

determines regio- and diastereoselectivity. Topographic steric maps derived from crystallographic data provided insights into the basis for the

catalyst-control through stereoselective oxidative cyclization and subsequent, stereospecific allyl-isomerization and C–C bond-forming re-

ductive elimination.

12

13

INTRODUCTION

yond butadiene would be attractive due to the availability of

substituted 1,3-dienes from sources including biomass and pet-

rochemical feedstocks¹²as well as through synthetic methods

Medium-sized (7–11-membered) rings, by virtue of their

ring strain and distinctive conformational preferences, are im-

portant chemical substructures with applications in the synthe-

sis and properties of polymers, fuels, fragrances, and other

1

13

14

including enyne metathesis, cross-coupling, Mizoroki–Heck

15

16

2

3

4,5

olefination, Wittig olefination, and diverted aerobic Heck

17

6

reactions. However, realization of such a method poses several

challenges including: (i) the reduced coordination rate of more

sterically encumbered substituted dienes relative to butadiene,

specialty chemicals (Scheme 1A). Among these, eight-

membered cyclic olefins are particularly valuable targets as evi-

denced by ring-opening metathesis polymerization (ROMP) of

cyclooctene, 1,5-cyclooctadiene, and their derivatives to access

vinyl copolymers and, following hydrogenation, precision poly-

ethylene derivatives. While strategies have been developed for

the synthesis of eight-membered carbocycles in the context of

(

ii) the potential for competitive formation of side-products

including linear oligomers and [2+2]- and [4+2]-cycloadducts,

and (iii) the possibility for formation of multiple regio- and

stereoisomeric [4+4] products. Catalyst designs must, there-

fore, balance competing demands of reactivity and selectivity to

achieve synthetic utility.

2

7

complex molecule total syntheses, most notably through ring-

8

9

closing olefin metathesis and radical cascades, alternative

methods for the modular and convergent synthesis of these

rings with high degrees of regio- and stereocontrol remain de-

While high (10–20 mol%) loadings of nickel precatalysts

have been reported for intramolecular [4+4]-cycloadditions of

tethered dienes (Scheme 2B), attempts to apply these condi-

2

–6

18

sirable for fine-chemical applications.

The [4+4]-

cycloaddition of two 1,3-dienes would constitute an atom-

economical method to address this need, enabling synthesis of

substituted cyclooctadienes from readily accessed, and in many

cases, commodity substrates.

tions for intermolecular coupling of substituted dienes have

been met with low activity and/or low chemo- and regioselec-

19

tivity for the [4+4]-cycloadducts (Scheme 2C). Likewise, α-

diimine and related ligands used in combination with iron salts

and in situ reductants for the cyclodimerization of butadiene

have been evaluated for [4+4]- and [4+2]-coupling reactions

with other substrates.¹Promising results were obtained with

isolated examples (Scheme 2C); however, selectivity for [4+4]-

cycloaddition was variable and limited in scope. Moreover, the

identity, speciation, and oxidation states of the complexes re-

Metal-catalyzed [4+4]-cyclodimerization of butadiene to

generate 1,5-cyclooctadiene is well established and is practiced

industrially using nickel salts in combination with phosphite

1a,20

10

ligands and trialkylaluminum activators (Scheme 2A). Other

metal catalysts, most notably an iron(I) α-diimine cyclooctadi-

ene complex, have since been reported to promote this trans-

2

1

11

sponsible for C–C bond-formation remained ambiguous.

formation with high turnover numbers and frequencies. Ena-

bling metal-catalyzed [4+4]-cycloaddition for substrates be-

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Journal of the American Chemical Society

Page 2 of 19

Scheme 1. Demand, conceptual evolution, and design strategy for iron-catalyzed [4+4]-cycloaddition of substituted

1,3-dienes.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

A. Utility of 8-Membered Alicycles

O

R

O

Ph

OMe

O

n

R

G

[

M] cat.

H

G

O

Ph

2

n – 1

+

where R = H, performance-enhancing rubber additive

_V_e_s_t_e_n_e_m_e_r® (Evonik)

Violiff™ oderant (IFF)

ligands for transition metal

(pre)catalysts

green odorant

(Cognis)

G

O

Kephalis^®oderant

R ≠ H Desired for:

flexibility/processibility

[M] cat.

H

2

(Givaudan)

O

biodegradability

recyclability

R

G

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

G

Georgywood^®oderant surrogate

(Givaudan)

biorenewable jet-fuel

component

2

n – 1

mixing properties

green odorant

(Givaudan)

where R = H, polyethylene (PE)

limited by monomer availability

Polymers

Fragrances

Specialty Chemicals

B. Ligand Designs to Control Iron Metallacycles for Selective Catalysis

C. This Work: Catalyst-Controlled [4+4]-Cycloaddition

R

R′

[

Fe]^A

[Fe]^C

Ar

N

Ar

N

R′′

R′

N

R′

Fe

_R1

Fe

N

Fe

_R1

R

R¹

N

Fe

_R1

N

R

R′

R¹

_R1

R′

_R1

R

R′

R¹

Alkene–Diene

R²

R

R²

_[_F_e_]B

_[_F_e_]A

R²

R′

Diene Self- and Cross-

[4+4]-Cycloaddition

Diene [1,4]-Hydrovinylation ^c

_A_l_k_e_n_e_[₂₊₂_]_-_C_y_c_l_o_a_d_d_i_t_i_o_na

b

R

diastereoselectivity

Cross-[2+2]-Cycloaddition

Control of:

chemoselectivity

regioselectivity

Prior Work

This Work

&

mechanistic insights from well-defined, single-component precatalysts

a

b

c

Refs. 23 & 25. Refs. 23b & 24. Ref. 26.

Reduced iron complexes bearing tridentate pyridine-2,6-

diimine (PDI) ligands catalyze numerous C–C bond-forming

achieve broadly useful chemo-, regio-, and diastereoselective

[4+4]-cycloaddition of substituted dienes.

2

reactions including the [2+2]-cyclodimerization and hydrovi-

Here we describe the synthesis and electronic structure de-

termination of iminopyridine iron bis-olefin complexes that,

along with select α-diimine iron complexes, are highly active and

selective catalysts for the [4+4]-cycloaddition of monosubsti-

tuted dienes. Collectively, the single-component precatalysts

enabled the regioselective [4+4]-cyclodimerization and inter-

molecular cross-[4+4]-cycloaddition of 2- and 4-substituted

1,3-dienes (Scheme 1C) with iron loadings as low as

0.025 mol % and substrate ratios as low as 1.5:1. In the case of 4-

substituted diene substrates, catalyst-controlled access to either

cis- or trans-diastereomers was achieved. Kinetic analyses,

2

3

nylation of α-olefins as well as the cross-[2+2]-cycloaddition

2

3b,24

of unactivated alkenes and dienes.

High degrees of chemo-

and regioselectivity were observed, arising from oxidative cy-

clization of the coupling partners to form metallacyclic inter-

2

5,26

mediates,

where the divergent outcomes reflected the fate of

the metallacycle (Scheme 1B). Iron compounds bearing steri-

3

cally demanding tridentate ligands favored C(sp )–C(sp ) re-

2

3b,25

ductive elimination

while more open iron complexes un-

derwent preferential β-H elimination followed by C–H reduc-

2

3b,26

tive elimination.

12

13

These observations suggested that further catalyst evolution

could be applied to promote selective [4+4]-cycloaddition of

substituted dienes (Scheme 1B). Following oxidative coupling

of two dienes, selective [4+4]-cycloaddition would result if allyl

isomerization and C–C bond-forming reductive elimination

were accelerated relative to competitive diene insertion and β-H

elimination pathways. In light of recent mechanistic work

providing evidence for the intermediacy of metallacycles in C–

C bond-forming reactions catalyzed by α-diimine iron com-

C/ C isotope effect measurements, and in situ Mößbauer

spectroscopic studies provided support for a mechanism in

which oxidative cyclization of two dienes determined regio- and

diastereoselectivity. The conserved electronic structure of the

reduced iminopyridine iron complexes with respect to known α-

diimine and pyridine(diimine) iron bis-olefin complexes high-

lights a potential role for ligand redox activity in selective, iron-

catalyzed C–C bond-forming reactions. Thus, not only does

this method provide access to modular building blocks likely to

find broad application in the synthesis and study of precision

polyolefins, lubricants, fuels, fragrances, and other specialty

chemicals, the mechanistic insights provide a blueprint for other

methods applying metallacyclic intermediates to upgrade un-

saturated coupling partners.

26

plexes, bidentate redox-active ligands seemed well-suited for

this purpose. In addition to opening a site for allyl coordination,

these ligands could mediate access to high-oxidation-state

(

iron(III) or iron (IV)) and/or high-spin intermediates to pro-

27,28

mote C–C reductive elimination.

As such, reexamination of

the modular and inexpensive α-diimine (DI) ligands along with

the more-open, redox-active 2-iminopyridine (PI) ligands using

well-defined, single-component precatalysts was targeted to

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Journal of the American Chemical Society

minutes (Scheme 3; see Supporting Information for additional

Scheme 2. State-of-the-art methods for [4+4]-

cycloaddition of 1,3-dienes.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

details). Rapid solvent removal and work-up minimized ligand

exchange—which results in formation of the homoleptic bis-

A. Metal-Catalyzed [4+4]-Cyclodimerization of Butadiene

R

ligand complexes, ( PI)

prior efforts. While the ( PI)Fe(COD) complexes were unsta-

2

Fe, and iron black—that had frustrated

[M]

+

R

ble in hydrocarbon or ethereal solvent at ambient temperature

P(OAr)

3

=

[Fe] =

Ar

R

N

(~23 °C), undergoing decomposition to form ( PI)

2

Fe and iron

up to 96% [4+4], using:

.01 mol% Ni(COD)

0.01 mol% P(OAr)

up to >98% [4+4], using:

0.005 mol% [Fe]

–or–

0

2

black, over the span of minutes (where R = Me) or hours

P

N

Fe

Cl

^O3

3

0.01 mol% MeMgCl

_t_o_m_D_i_e_c_k_&_R_i_t_t_e_rb

i

_R_e_e_d_,_Z_i_e_g_l_e_r_&_W_i_l_k_ea

Cl

(where R = Pr), they were isolated and stored indefinitely at –

Ph

R

vi vi

3

5 °C as dark brown solids. The ( PI)Fe(M M ) complexes

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

c

B. Intramolecular Diene [4+4]-Cycloaddition

proved more robust in solution and were recrystallized as deep

red-purple needles from saturated pentane solutions at –35 °C.

Additional characterization data are discussed in the “Electronic

Structure Determination” section below.

Scheme 3. Synthesis of reduced iminopyridine iron bis-

olefin complexes.

11 mol% Ni(COD)

3 mol% PPh

2

H

3

EtO

2

C

EtO

2

C

70% [4+4]

95:5 d.r.

EtO

PhMe, 60 °C, 19 h

EtO

C

H

C. State-of-the-Art Intermolecular Diene [4+4]-Cycloaddition

[

4+4]-Cyclodimerization of Isoprene ^d

Me

[M]

+

Me

COD (3.3 equiv)

N

Fe

Cl

N

Mg(C

4

H

6

)•2THF (1.2 equiv)

Cl

0

.5 ⁱPr

Cl

ⁱPr

N

Fe

[

Fe]

Et O, cold well →

2

rt, 20 min

up to 95%

cyclic dimers using:

0.5 mol% Fe(acac)

0.5 mol% PI ligand

92% yield

up to 97% cyclic dimers

up to 64% [4+4]

0

.1 mol% Ni(acac)

.3 mol% PR

0.6 mol% AlEt

2

ⁱPr

i

R

Pr

(ⁱ^P^rPI)Fe(COD)

0

3

–or–

3

N

up to 93:7 r.r.

[(ⁱ^P^rPI)FeCl(µ-Cl)]

2

3

(all with different ligands)

N

PI ligand

3 mol% AlEt

3

Ar

Prepared Analogously:

Directed, Head-to-Head, [4+4]-Cyclodimerization of 4-Substituted-1,3-Dienes ^e

0 mol% Ni(acac)

0 mol% PPh

20 mol% Et AlOEt

1

2

N

1

3

CO

2

Me

ⁱPr

2

3 examples

N

Fe

N

Fe

N

Fe

3

0–90% yield

Si

2

CO Me

PhMe, 60 °C, 1–18 days

CO

2

O

ⁱPr

(ⁱ^P^rPI)Fe(M^vⁱM^vⁱ

Si

₄₊₄_]_-_C_y_c_l_o_a_d_d_i_t_i_o_n_o_f₂_,₃_-_D_i_m_e_t_h_y_l_-₁_,₃_-_B_u_t_a_d_i_e_n_e_w_i_t_h_P_i_p_e_r_y_l_e_n_ef

[

(^M^ePI)Fe(COD)

)

(^M^ePI)Fe(M^vⁱM^vⁱ

)

3

2

mol% (DI) Fe

15 mol% AlEt

3

+

Other Complexes Evaluated in this Study:

+

rt, 60 h

63% [4+4]

22% [4+2]

Ar

N

Fe

N

Ar

N

Fe

R

Key Limitations Include:

N

^N2

low [4+4]

chemoselectivity

unknown

active catalyst

H

9

C

5

N

Fe

AND/OR low activity AND/OR low regioselectivity

N

R

ꢀR′

a

b

c

d

e

f

(

iPrPI) Fe: R =

i

Pr,ꢀR′ = H

R = ꢀR′ = Me

Ref. 10. Ref. 11. Ref. 18. Refs. 19a & 20b. Refs. 19c,d. Ref. 20a.

2

(^C⁵^H⁹PDI)Fe(N

)

(^M^e^sDI)Fe(COD)

(^M^e^sPI)

Fe:

2

RESULTS AND DISCUSSION

Ligand Denticity and Cycloaddition Chemoselectiv-

ity. To evaluate the effect of ligand denticity on the chemose-

lectivity of iron-catalyzed diene coupling reactions, single-

component precatalysts were targeted to minimize the potential

for confounding effects arising from ill-defined speciation under

in situ activation conditions. Pyridine(diimine) iron dinitrogen

complexes have proven to be excellent precatalysts for the

With access to these well-defined, reduced iron complexes

bearing either tridentate (PDI) or bidentate (DI or PI) poten-

tially redox-active ligands, the role of ligand denticity in diene

coupling reactions was examined. Piperylene (1a) was selected

as a representative 4-substituted-1,3-diene to evaluate iron

precatalyst performance. Stirring (E)-1a with 5 mol% of iron

C5H9

complex ( PDI)Fe(N ), which bears a tridentate PDI ligand

2

3,24

[

2+2]-cycloaddition of alkenes and dienes,

and α-diimine

optimized for alkene [2+2]-cyclodimerization, resulted in selec-

tive formation of the analogous diene [2+2]-cyclodimerization

product (2a), albeit in low conversion and yield (18%; Scheme

4A). Use of iron complexes with bidentate ligands altered the

outcome of the catalytic reaction. With 1 mol% of α-diimine-

R

iron bis-olefin complexes, ( DI)Fe(COD) ( DI = [2,6-R

2

-

i

C

6

H

3

-N=CMe]

N=CMe]

lysts for olefin hydrogenation, diene [1,4]-hydrovinylation,

2

where R = Pr, Me or [2,4,6-Me

3

-C

6

H

2

where R = Mes), were introduced as suitable precata-

2

9

26

1

1b

Mes

and butadiene cyclodimerization.

While the analogous

supported precatalyst ( DI)Fe(COD), cis-3,7-dimethyl-1,5-

iron(iminopyridine) olefin complexes had been elusive previ-

cyclooctadiene (3a) was obtained in 93% yield and 95:5 dia-

stereomeric ratio (d.r.; Scheme 4A) as determined by quantita-

3

0

R

vi vi

R

ously, ( PI)Fe(COD) and ( PI)Fe(M M ) ( PI = [2-(2,6-R

2

-

i

13

C

6

H

3

-N=CMe)-C

by treating [( PI)FeCl(μ-Cl)]

bis(tetrahydrofuran)

cyclooctadiene

tetramethyldisiloxane (M M ) in thawing Et

5

H

4

N] where R = Pr or Me) were prepared

tive C NMR spectroscopy. Conversely, use of 1 mol%

R

iPr

2

with magnesium butadiene

)•2THF) and 1,5-

or 1,3-divinyl-1,1,3,3-

O over 9–20

iron(iminopyridine) precatalyst ( PI)Fe(COD) generated the

(Mg(C

(COD)

4

H

6

opposite diastereomer, trans-3,7-dimethyl-1,5-cyclooctadiene

(4a), in 87% yield and >98:2 d.r., demonstrating the influence

of the supporting ligand on the chemo-, regio- and diastereose-

vi vi

2

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Page 4 of 19

lectivity of the cycloaddition process (Scheme 4A). Further- vides selective access to the head-to-head isomer in contrast to

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

more, the high [4+4] activity of these single-component precat-

alysts stands in contrast to the low reactivity noted previously

using in situ activation protocols.

nickel catalysis, which has been reported to favor the opposite,

head-to-tail, regioisomer (8a) in the cyclodimerization of iso-

1

1a

19a,b

prene (commercially available samples are ~20:80 r.r.). Tak-

en together these results exemplified remarkable control by

ancillary ligands on iron, achieving regio- and diastereoselectivi-

ty for the [4+4]-cycloaddition of unactivated dienes without the

requirement for directing groups or electronically activating

substituents.

Scheme 4. Ligand denticity controls cycloaddition

chemoselectivity.

A. Catalyst–Controlled Cyclodimerization of Piperylene ^a

5

mol% (^C⁵^H⁹PDI)Fe(N

2

)

2a

1

8% yield

neat, rt, 24 h

52:48 d.r.

Scheme 5. Evaluation of single-component imino-

pyridine iron precatalysts for [4+4]-cyclodimerization

[

Tridentate, C2v Ligand]

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

a

of isoprene.

1

mol% (^M^e^sDI)Fe(COD)

3a

93% yield

neat, rt, 12 h

95:5 d.r.

[Bidentate, C2v Ligand]

(E)-1a

1

mol% [Fe]

+

cyclooctane (0.1 equiv)

neat, rt

₁_m_o_l_%₍iPrPI)Fe(COD)

4a

8

7% yield

5a

7a

8a

neat, rt, 12 h

>98:2 d.r.

s

[Bidentate, C Ligand]

time = 1 h:

yield ^b% [4+4] ^b

4 h:

24 h:

[Fe]

B. Catalyst–Controlled Cyclodimerization of Myrcene ^b

yield ^b% [4+4] ^b

r.r. ^c

(^M^ePI)Fe(COD)

98%

93%

<1%

96%

n.d.

94%

6%

96%

92%

96%

34%

96%

90 : 10

92 : 8

5

mol% (^C⁵^H⁹PDI)Fe(N

2

)

6b

₍Me_P_I₎_F_e₍_Mvi_Mvi

)

44% yield

neat, rt, 24 h

(^M^e^sPI)

94% [2+2]

2

Fe

≥90%

[Tridentate, C2v Ligand]

>98:2 d.r.

a

Reaction conducted on 1 mmol scale at ambient temperature (~23

°C). ^bYield and % [4+4] selectivity determined from the calibrated

relative integrals of product and cyclooctane signals measured by gas

chromatographic analysis of aliquots removed from the reaction mix-

ture at the indicated time. r.r. determined from the relative integrals of

diagnostic signals for 7a and 8a in the quantitative C NMR spectrum

of the crude reaction mixture.

5

b

_m_o_l_%₍MePI)Fe(COD)

7b

1

00% yield

98% [4+4]

96:4 r.r.

neat, rt, 3 h

[

Bidentate, C

s

Ligand]

c

1

3

denticity-controlled

chemoselectivity

symmetry-controlled

diastereoselectivity

high [4+4] activity

high regioselectivity

In Situ Catalyst Activation. Contrary to the case with

piperylene dimerization, several reductants (including

a

Reactions were conducted on 0.5 mmol scale. Yield and d.r. deter-

(0)

mined from the relative integrals of diagnostic signals for 1a, 2a, 3a,

and 4a in the quantitative ¹³C NMR spectrum of the crude reaction

mixture relative to an internal standard added at the end of the reac-

tion. Stereochemical assignment of the diastereomers was corroborat-

ed by chiral-phase gas chromatographic analysis (BETA DEX 120, 60

°

mmol scale. Yield describes the combined isolated yield of isomeric

products; r.r. determined from the relative integrals of diagnostic sig-

nals for 6b, head-to-head [4+4]-cycloadduct 7b, and head-to-tail

[4+4]-cycloadduct 8b in the quantitative ¹³C NMR spectrum of the

isolated material.

Mg(C

4

H

6

)•2THF, MeMgCl, and Mg powder) were identi-

Me

fied that, upon combination with [( PI)FeCl(μ-Cl)] and iso-

2

prene or myrcene, afforded the corresponding [4+4]-

cycloadduct (7a or 7b) with comparable reactivity and identi-

cal selectivity to that obtained with precatalysts

b

C isothermal method, 120 min). Reactions were conducted on 1.0

Me

vi vi

( PI)Fe(COD) or ( PI)Fe(M M ) (see Supplementary In-

formation for details).³¹In control experiments, no substrate

consumption was observed when FeCl

2

was treated with

Mg(C H )•2THF in the absence of a DI or PI ligand. While the

4

6

single-component reduced iron precatalysts required handling

under rigorously air- and moisture-free conditions, the iron(II)

A similarly striking dependence of chemoselectivity on ligand

denticity was observed using isoprene (5a) and myrcene (5b)

as model 2-substituted-1,3-diene substrates. Stirring 5b with 5

mol% ( PDI)Fe(N ) afforded [2+2]-cycloadduct 6b in 44%

isolated yield (94% [2+2] over all other isomers, >98:2 d.r.;

Scheme 4B). By contrast, with 1 mol% of iminopyridine iron

R

halide precursors (( DI)FeX

2

and [( PI)FeX(μ-X)]

2

where X =

Cl or Br) exhibited enhanced robustness, allowing for bench-

Me

C5H9

top manipulation. Using in situ activation of [( PI)FeCl(μ-

2

Cl)] , the [4+4]-cyclodimerization of isoprene was conducted

2

in batches as large as 2 mol (168 g) with iron precatalyst load-

Me

ings as low as 0.025 mol% (175 mg [( PI)FeCl(μ-Cl)] ).

2

complex ( PI)Fe(COD), 98% [4+4]-cyclodimerization selec-

[Caution: The [4+4]-cyclodimerization of 1,3-dienes is highly

exothermic. When performing the reaction on a preparative

scale, special care should be taken to ensure adequate heat

transfer. Maintaining a controlled temperature throughout the

course of the reaction is necessary to prevent a pressure build-

up.] While rigorously dried diene was required to achieve com-

plete conversion at low catalyst loadings, 7a was alternately

obtained in 90% yield using reagents measured and combined

outside of a glovebox using modestly increased precatalyst load-

tivity was observed, providing 1,6-dimethyl-1,5-cyclooctadiene

(

7b) in 99% combined isolated yield and 96:4 regioisomeric

ratio (r.r.; Scheme 4B). Similarly high selectivity was observed

using isoprene as a substrate. Nearly identical results were ob-

Me

vi vi

tained using ( PI)Fe(COD) and ( PI)Fe(M M ) as precata-

lysts (Scheme 5); however, only very low activity was observed

Mes

using the isolated, homoleptic bis-ligand complex ( PI) Fe.

2

The iron-catalyzed cycloaddition is noteworthy in that it pro-

ACS Paragon Plus Environment

Page 5 of 19

Journal of the American Chemical Society

gents. Alternatively, magnesium powder was used as a more

ing (1 mol% [Fe]). While the [4+4]-cyclodimerization was

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

routinely conducted in neat substrate, the in situ activation pro-

tocol was also adapted to dilute solutions as a strategy for con-

trolling reaction exotherms. The high chemo- and regioselectiv-

ity observed under neat reaction conditions was maintained

across reactions conducted in all of the ethereal and hydrocar-

bon solvents evaluated (Scheme 6). The apparent catalyst fideli-

ty using these in situ activation protocols holds promise for ap-

plications to the scalable synthesis of monomers for ROMP.

functional-group-tolerant activator; however the slow activation

necessitated extended reaction times and/or increased catalyst

loadings (see Supporting Information).

Scheme 7. Scope of iron-catalyzed, diastereoselective

a

[

4+4]-cyclodimerization of 4-substituted dienes.

I. 5 mol% (^M^e^sDI)Fe(COD)

neat, rt

R

–

or –

–or–

R

_I_I_.₅_m_o_l_%₍iPrPI)Fe(COD)

R

neat, rt

1

3

4

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

Scheme 6. Evaluation of solvents suitable for iron-

where R =

a

OTBDPS

catalyzed [4+4]-cyclodimerization.

Ph

R

_.₅_m_o_l_%_[₍MePI)FeCl(µ-Cl)]

Me

I. 89%, 98% [4+4]

I. 100%, 98% [4+4]

94 : 6 3c : 4c

I. 81%, 98% [4+4]

>98 : 2 3d : 4d

0

2

9

3 : 7 3b : 4b

0.6 mol% MeMgCl

I. 93%, 98% [4+4]

95 : 5 3a : 4a

II. 100%, 76% [4+4]

<1 : 99 3b : 4b

II. 92%, 85% [4+4]

<2 : 98 3c : 4c

II. 66%, 65% [4+4]

3 : 97 3d : 4d

+

solvent (X M), rt, 4 h

5

b

7b

8b

74%, 98% [4+4]

R

8

9 : 11 3a : 4a

O

b

(

5 mmol scale)

_I_I_.c 100%, 85% [4+4]

1: 99 3a : 4a

O

Ph

b

c

b

d

O

Ph

OMe

entry

solvent

X

conv

yield

% [4+4]

r.r

<

I. 20%, 98% [4+4]

8 : 2 3e : 4e

II.^d50%, 79% [4+4]

: 99 3e : 4e

I. 90%, 96% [4+4]

93 : 7 3f : 4f

I. 81%, >98% [4+4]

89 : 11 3g : 4g

II. 65%, 53% [4+4]^e

1

2

none

--

>95%

99%

97%

94:6

95:5

9

C

5

H

12

2.5 M

II. 80%, 82% [4+4]

<2 : 98 3f : 4f

1

<2 : 98 3g : 4g

3

4

5

6

7

Et

2

O

2.5 M

1.0 M

0.5 M

>95%

97%

94%

99%

93%

95%

97%

96%

97%

96%

94:6

THF

PhMe

a

Unless indicated otherwise, reactions were run on 0.5 mmol scale with

5 mol% [Fe] precatalyst. Values describe combined isolated yield of

isomeric products, the portion of this isolated mixture comprised of

ꢀ

[

4+4]-cycloadducts as determined by gas chromatographic analysis,

a

Reaction conducted on 5 mmol scale at ambient temperature (~23

C). ^bConversion and % [4+4] selectivity determined from relative

and the diastereomer ratio of the [4+4]-cycloadducts as determined by

relative integration of diagnostic resonances in the quantitative

°

13

C

integrals of starting material and product signals measured by gas

chromatographic analysis of aliquots removed from the reaction mix-

ture. ^cValues describe combined isolated yield of isomeric products ^d

r.r. determined from the relative integrals of diagnostic signals for 7b

NMR ^s^p^e^c^t^r^u^mb of the isolated material. TBDPS

=

tert-

c

butyldiphenylsilyl with 2.5 mol% [Fe] on 5 mmol scale with 5 mol%

iPr

vi vi

d

e

(

PI)Fe(M M ) at 40 °C 28% [4+2]

1

3

and 8b in the quantitative C NMR spectrum of the isolated material.

Scheme 8. Scope of iron-catalyzed, regioselective

a

[

4+4]-cyclodimerization of 2-substituted dienes.

Regio- and Diastereoselective [4+4]-

R

III. 1 mol% (^M^ePI)Fe(COD)

Cyclodimerization of Monsubstituted-1,3-Dienes.

With both isolated organometallic precatalysts and in situ acti-

vation protocols in hand, the scope of the iron-catalyzed [4+4]-

cycloaddition was evaluated with varied 4- (1a-g; Scheme 7)

and 2-substituted (5a–l; Scheme 8) 1,3-dienes. While reduced

iron complexes are often incompatible with polar functional

groups—carbon–heteroatom bond cleavage can lead to irre-

neat, rt

– or –

+

R

_I_V_.₀_.₅_m_o_l_%_[₍MePI)FeCl(µ-Cl)]

2

1

–10 mol% activator

5

R

7

R

8

neat, rt

activator = Mg(C

4

H

6

)•2THF, MeMgCl, or Mg(0) powder

where R =

III. 99%, 96% [4+4]

0 : 10 7a : 8a

Ph

III. 73%, 87% [4+4]

9

Me

3

2

IV. 90%, 97% [4+4]

1 : 9 7a : 8a

versible catalyst deactivation —the product yield and [4+4]

9

4 : 6 7c : 8c

9

_I_I_I_.d 100%, 98% [4+4]

Mes

iPr-

(0.025 mol% [Fe], 168 g scale)^b

selectivity obtained using 1–5 mol% of ( DI)Fe(COD), (

96 : 4 7b : 8b

(0.1 mol% [Fe], 1 g scale)

Cy

Me

90%, 97% [4+4]

PI)Fe(COD), or ( PI)Fe(COD) proved to be largely insensi-

tive to introduction of heteroatoms. Cyclooctadienes bearing

ester (3g, 4g, 7g, 7h), acetal (7e), amide (7i), amine (7j),

arene (7k), and heteroarene (7l) functionality were prepared

with levels of selectivity comparable to those achieved with the

pure hydrocarbon substrates. While residual water and other

protic functionality were problematic, resulting in low to no

substrate conversion, sensitive functional groups were masked

effectively with common protecting groups (e.g. benzyl ethers,

silyl ethers, carbamates).

9

1 : 9 7a : 8a

IV.

e

96%, 98% [4+4]

III. 88%, 91% [4+4]

>99 : 1 7d : 8d

(set-up outside a glovebox)^c

96 : 4 7b : 8b

MeO

EtO

TBSO

PivO

OMe

O

III. 100%, 85% [4+4]

5 : 5 7e : 8e

_I_V_.e 100%, 94% [4+4]

III. 100%, 98% [4+4]

III. 67%, 97% [4+4]

III. 78%, >98% [4+4]

9

94 : 6 7f : 8f

_I_V_.e 98%, 98% [4+4]

95 : 5 7g : 8g

_I_V_.e,f 45%, 97% [4+4]

90 : 10 7h : 8h

_I_V_.g 73%, 98% [4+4]

9

7 : 3 7e : 8e

95 : 5 7f : 8f

96 : 4 7g : 8g

90 : 10 7h : 8h

Ph

N

III. 91%, 89% [4+4]

7 : 13 7k : 8k

O

Boc

i

8

III. 90%

The conditions for in situ catalyst activation proved similarly

robust for [4+4]-cyclodimerization of many 2-substituted

dienes. However, the single-component precatalysts afforded

_I_V_.h 100%, 94% [4+4]

95 : 5 7i : 8i

IV.

e

100%, 97% [4+4]

_I_V_.e 98%, 93% [4+4]

87% [4+4]

96 : 4 7j : 8j

91 : 9 7k : 8k

94 : 6 7l : 8l

R

improved chemoselectivity over the [( PI)FeCl(μ-

a

Unless indicated otherwise, reactions were run on 0.5 mmol (Method

Cl)]

2

/activator combination for substrates bearing electrophilic

III) or 1.0 mmol (Method IV) scale with 1 mol% [Fe] precatalyst.

Values describe combined isolated yield of isomeric products, the por-

functionality prone to competitive reactions with Grignard rea-

ACS Paragon Plus Environment

Journal of the American Chemical Society

Page 6 of 19

tion of this isolated mixture comprised of [4+4]-cycloadducts as de-

ucts with the indicated connectivity as determined by gas chromato-

graphic analysis, and the diastereomer ratio as determined by the rela-

tive integration of diagnostic resonances in the quantitative C NMR

spectrum of the isolated material. ^bDiene 12 was used as a mixture

(70:30 E/Z) of isomers.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

termined by gas chromatographic analysis, and the regiosomer ratio of

the [4+4]-cycloadducts as determined by relative integration of diag-

1

3

1

3

nostic resonances in the quantitative C NMR spectrum of the isolated

material. Mg(C )•2THF magnesium butadiene

4

H

6

=

b

bis(tetrahydrofuran), TBS = tert-butyldimethylsilyl with 0.0125

Me

Intermolecular Cross-[4+4]-Cycloaddition of 1,3-

Dienes. While high chemo- and regioselectivity for [4+4]-

cyclodimerization was observed across varied monosubstitued-

1,3-dienes, the relative rates of substrate consumption proved

sensitive to subtle differences in substrate substitution pattern

and sterics. This feature was leveraged to adapt the conditions

to the cross-[4+4]-cycloaddition of two differentially reactive

dienes, thereby accessing unsymmetric disubstituted cycloocta-

dienes.

mol% [( PI)FeCl(μ-Cl)] and 0.06 mol% MeMgCl (3 M in THF) at

2

₀_°_C_t_o_r_tc with 0.5 mol% [( PI)FeCl(μ-Cl)]

Me

1

2

and 2.4 mol%

d

Me

e

MeMgCl (3 M in THF) with 0.1 mol% ( PI)Fe(COD) with 1

f

mol% Mg(C

[( PI)FeCl(μ-Cl)]

4

H

6

)•2THF as activator

and 1 mol% Mg(C

mol% Mg(0) powder as activator with 1.5 mol% [( PI)FeCl(μ-Cl)]

additional 0._g5 mol%

Me

2

4

H

6

)•2THF added with 13

h

Me

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

2

i

and 33 mol% Mg(0) powder 1 M in PhMe

Despite the success of the methods developed for the [4+4]-

cyclodimerization of monosubstituted dienes, disubstituted

dienes remained challenging substrates by virtue of their in-

creased steric profiles. Subjecting representative disubstituted

dienes such as 2,3-dimethyl-1,3-butadiene (9), 3-methyl-1,3-

pentadiene (12), and 2-methyl-1,3-pentadiene to Methods I–

III outlined above resulted either in little-to-no substrate con-

sumption or in exclusive formation of linear adducts. While in

situ activation of iron dichloride and 2,2’-bipyridine (bpy) in

the presence of 2,3-dimethyl-1,3-butadiene (9) afforded prom-

ising levels of chemoselectivity for [4+4]-cyclodimerization

product 10 (Scheme 9A), attempts to prepare and isolate a

Me

Using ( PI)Fe(COD) as the precatalyst, the cross-reaction

of two different 2-substituted dienes was achieved. This was

particularly powerful using an excess of an inexpensive coupling

partner such as isoprene or myrcene. Under these conditions,

the homocoupled products obtained from the coupling partner

used in excess were removed readily under vacuum or by pas-

sage of the crude reaction mixture through a silica plug to afford

the cross-[4+4]-cycloadduct in high yield, chemo-, and regiose-

lectivity (see Supporting Information for details).

Using precatalyst ₍MesDI)Fe(COD), the cross-[4+4]-

cycloaddition of 4-substituted dienes with 2-substituted dienes

suitable, well-defined (bpy)FeL precatalyst were unsuccessful.

2

Nonetheless, this result highlights the importance of the ligand

steric profile in enabling key oxidative cyclization and reductive

elimination steps. Further underscoring the fine balance of

competing processes determining product formation in these

highly encumbered systems, hydroalkenylation products result-

ing from dimerization of 12 or nopadiene (14) could be ob-

tained in high yield and isomeric purity using iminopyridine

was also demonstrated. In this case, the negligible activity of

Mes

(

DI)Fe(COD) for the homocoupling of 2-substituted dienes

enabled use of substrate ratios as low as 1.5:1. With the portion-

wise addition of the 4-substituted diene, these fragment-

coupling conditions were employed to unite differentially sub-

stituted coupling partners through the cross-[4+4]-

cycloaddition, again in high yield, chemo-, and regioselectivity.

iPr

precatalyst ( PI)Fe(COD) (Scheme 9B). While the formation

Scheme 10. Scope of iron-catalyzed cross-[4+4]-

of these linear products illustrates the challenge of out-

competing β-H elimination in sterically encumbered metallacy-

cles, it nonetheless affords access to potentially useful building

a

cycloaddition of substituted dienes.

R′′

3

cat [Fe]

neat, rt

blocks for further synthetic manipulations.

+

–or–

R

R′

Scheme 9. Iron-catalyzed dimerization of disubstitut-

1

or 5

5

R

16

17

a

ed-1,3-dienes.

Cross-[4+4]-Cycloadducts:

A. [4+4]-Cyclodimerization of 2,3-Dimethyl-1,3-Butadiene

TBSO

PivO

20 mol% bpy

10 mol% FeCl

2

+

16ab

0%, 96% [4+4]

0:10 r.r.

b

16af

c

16ag

d

20 mol% Mg powder

9

74%, 96% [4+4]

92:8 r.r.

55%, 97% [4+4]

94:6 r.r.

PhMe (2.0 M), rt, 72 h

9

(1.4 g scale)

(1 g scale)

9

55% conversion, 84 : 16 10 : 11

10

11

B. Linear Dimerizations of 3,4-Disubstituted-1,3-Dienes ^b

N

_m_o_l_%₍iPrPI)Fe(COD)

neat, rt, 14 h

O

Boc

5

Boc

₁₆_b_kb

16ai ^d

N

57%

77%, 96% [4+4]

92% [4+4]

94:6 r.r.

9

1:9 r.r.

Ph

1

2

13

₆_b_le

1

97% (93%)

9

2%, >95% [4+4]

1

6al ^e

2%

7% [4+4]

1:9 r.r.

95:5 r.r.

7

9

_m_o_l_%₍iPrPI)Fe(COD)

neat, rt, 22 h

5

9

OMe

1

4

15

MeO

TBSO

92% (97%), 94:6 d.r.

1

7ab ^f

17ae ^f

17af ^f

52%

a

42%

49%

Unless noted otherwise, reactions were run on 1.0 mmol scale. Values

9

3% [4+4]

85% [4+4]

87:13 r.r.

93% [4+4]

85:15 r.r.

describe combined isolated yield of isomeric products, the portion of

this isolated mixture comprised of [4+4] or hydroalkenylation prod-

87:13 r.r.

ACS Paragon Plus Environment

Page 7 of 19

Journal of the American Chemical Society

ion forms. Altogether, the lengthening of the N –C and

a

See Methods I–IV in Scheme 6. Reactions were run with 1 or 5 mol%

pyr

ipso

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

[Fe] precatalyst. For the formation of 16 from two 2-substituted

dienes, 0.5 mmol of the limiting, slow-reacting diene and 5 mmol of the

fast-reacting diene were employed. For the formation of 17 from the

coupling of a 2-substituted and 4-substituted diene, the 4-substituted

diene (1; 1.5–2 equiv in total) was added portion-wise to the reaction

N

im–Cim bonds, coupled with the contraction of the Cim–Cipso

bonds relative to the lengths expected for the neutral ligand

implicate the singly reduced radical anionic form of the ligand

across all of these structures. Likewise, the bond lengths and

angles of the bis-olefin ligands (COD and M M ) exhibit mod-

erate perturbation, consistent with partial back-donation from

vi vi

b

Me

mixture.

Mg(C

MeMgCl (3 M in THF) IV: 0.5 mol% [( PI)FeCl(μ-Cl)]

IV: 0.5 mol% [( PI)FeCl(μ-Cl)]

2

and

and 2.4 mol%

and 13

mol% Mg(0) powder III: 5 mol% ( PI)Fe(COD) with 280 μL add-

1 mol%

40

c

Me

4

H

6

)•2THF. IV: 0.5 mol% [( PI)FeCl(μ-Cl)]

2

4

1

d

Me

olefin coordination and the Dewar–Chatt–Duncanson model.

2

e

Me

The solid-state magnetic moments measured at 22 °C for the

f

Mes

ed PhMe I: 5 mol% ( DI)Fe(COD)

₍RPI)Fe(bis-olefin) complexes ((iPrPI)Fe(COD): 2.9 μ

PI)Fe(M M ): 2.7 μ

sistent with a net S = 1 ground state. Taken together with the

solid-state structural information and analogy to the

iPr-

B

; (

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

vi vi

Me

vi vi

B

; ( PI)Fe(M M ): 2.6 μ ;) are all con-

B

Taken together, these methods for the intermolecular, [4+4]-

cyclodimerization and cross-[4+4]-cycloaddition of dienes af-

ford access to cyclooctadienes with diverse patterns of function-

al group incorporation. These strained, cyclic olefins constitute

useful building blocks as the sterically and electronically differ-

entiated alkenes are poised to enable diverse transformations

including alkene hydrofunctionalization and difunctionaliza-

(

DI)Fe(COD) complexes, these results support the assignment

of high-spin iron(I) (SFe = 3/2) centers engaged in antiferro-

magnetic coupling with the iminopyridine ligand radical

(SPI = −1/2). These assignments were corroborated by zero-

field Fe Mößbauer spectroscopic measurements at 80 K of

solid-state samples of the ( PI)Fe(bis-olefin) complexes. The

isomer shift (δ) and quadrupole splitting (|ΔE |) parameters

obtained from the fits to these spectra are compiled in Table 2,

57

5

b,34

35

tion,

(

allylic

functionalization,

and

cationic

R

poly)cyclization.²

0a,36

Moreover, the potential utility of these

products as (co)monomers for ring-opening metathesis was

demonstrated through the synthesis of methyl-branched oligo-

mers for investigation as industrial lubricants and plasticizers

Q

along with those measured for reference compounds including

R

see Supporting Information).³⁷As such, these products hold

(

PI) Fe complexes as well as iron complexes across varied oxi-

2

(

11b,26,38a,38c

promise for application in the synthesis and evaluation of novel

polymers, fuels, fragrances, and other fine chemicals.

dation states bearing α-diimine

or pyridine-2,6-dimine

25,42

ligands.

Importantly, the isomer shifts observed for all four

R

(

PI)Fe(bis-olefin) complexes (δ = 0.49–0.53 mm/s) were

Electronic Structure Determination. In light of the high

activity as well as the remarkable chemo-, regio-, and diastere-

oselectivity observed for the iron-catalyzed [4+4]-cycloaddition

of monosubstituted 1,3-dienes, characterization of catalytically

relevant reduced iron species was targeted. Structural and spec-

4

3

unambiguously within the range typical for high-spin iron(I).

Full-molecule density functional theory (DFT) calculations

iPr

were initiated from solid-state structures for ( PI)Fe(COD),

iPr

vi vi

Me

44

Me

vi vi 45

( PI)Fe(M M ), ( PI)Fe(COD), and ( PI)Fe(M M )

R

i

46,47

troscopic data for ( DI)Fe(COD) (where R = Pr, Me, or Mes)

using the B3LYP functional,

and either the unrestricted

iPr

48

49

and ( DI)Fe(COD) were reported recently; in all cases, the

Kohn–Sham (UKS) or broken-symmetry (BS) methods.

When validated against experimental spectroscopic measure-

ments, these methods have been widely applied for determina-

electronic structures of these net S = 1 complexes were best

described as high-spin iron(I) anti-ferromagnetically coupled to

1

1b,26

tion of the ground-state electronic structures of first-row transi-

a ligand-based radical anion.

As with the α-diimine ligands,

tion metals bearing redox-active ligands.³

8,42,50

Both the UKS

the potential for ligand redox activity has been documented for

transition metal complexes bearing iminopyridine ligands.³⁸

However, little was known about the electronic structures of the

reduced iron complexes relevant to this study.

and BS methods converged to broken-symmetry BS(3,1) solu-

tions. While the optimized geometries for these structures ob-

tained at the B3LYP/def2-SVP/def2-TZVP level of theory

5

1

The solid-state structures of ₍iPr_P_I₎_F_e₍_C_O_D₎_,₍iPr-

were in excellent agreement with the solid-state structures (vide

supra), the computed zero-field ⁵Fe Mößbauer isomer shifts

obtained using Neese’s calibration constants⁵exhibited a sys-

tematic perturbation from the values obtained experimentally

(i.e. the computed values were ~0.1 mm/s too large in all cases).

Such systematic deviation has been observed previously with

other specialized ligand classes.⁵However, inclusion of an

empirical relativistic correction (ZORA) for both the geome-

try optimization and spectroscopic prediction steps afforded

improved agreement between experiment and theory.

7

vi vi

iPr

Mes

PI)Fe(M M ), ( PI)

2

Fe, and ( PI) Fe were determined by

2

0d

single-crystal X-ray diffraction, confirming their identities (Fig-

ure 1; see also Supporting Information). The latter two com-

iPr

Mes

iPr-

plexes, ( PI)

2

Fe and ( PI)

2

Fe, are analogous to the (

iPr

i

PAI)

2

Fe complex ( PAI = [2,6- Pr

2

-C

6

H

3

38b

-N=CH] ) reported

2

0e,f

previously by Wieghardt and co-workers, and were included

for comparison with the heteroleptic complexes. In each case,

the coordination geometry about iron is best approximated as

52

3

9

tetrahedral.

Distortion of the metrical parameters of the iminopyridine

scaffold is an established reporter of ligand redox activity.³The

pyridine Npyr–Cipso, imine Nim–Cim, and backbone Cim–Cipso

bond lengths are particularly diagnostic of the ligand oxidation

state. The values obtained for these key bond metrics in each of

the aforementioned solid-state structures are summarized in

Table 1 along with average values characteristic of a generic

iminopyridine in its neutral, radical anion, and closed-shell dian-

8b

ACS Paragon Plus Environment

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Page 8 of 19

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

A.

B.

C.

C15

C32

C34

C13

C5

C6

N2

N4

N1

C26

Si2

N3

C27

N2

Fe1

C20

Fe1

C26

Fe1

C27

C21

O1

C21

N1

N2

C25

Si1

C13

C24

C23

C15

C20

C22

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

(

iPrPI)Fe(COD)

(

iPrPI)Fe(Mvi

M

vi

)

2

( Fe

iPrPI)

D.

E.

F.

100

9

7

9

8

6

4

2

0

9

7

4

1

94

91

8

ꢀ = 0.52 mm/s

85 ꢀ = 0.75 mm/s

|ꢀEQ| = 1.18 mm/s

ꢀ

= 0.52 mm/s

|ꢀEQ| = 0.89 mm/s

|ꢀEQ| = 1.26 mm/s

88

82

-4.0

-2.0

0.0

2.0

4.0

-4.0 -2.0 0.0

2.0

4.0

-4.0 -2.0 0.0

2.0

4.0

Velocity (mm/s)

iPr

Figure 1. Characterization of Reduced ( PI)Fe Complexes. (A–C.) Solid-state structures represented with 30% probability ellipsoids; H atoms omit-

ted for clarity. (D–F.) Zero-field ⁵⁷Fe Mößbauer spectra collected at 80 K for solid-state samples of ( PI)Fe(COD), ( PI)Fe(M M ), and (

iPr

vi vi

iPr-

PI)

2

Fe. Red lines represent the fit of the data to the quadrupolar doublets defined by the parameters shown.

iPr

a

Table 1. Select Metrical Parameters for Reduced ( PI)Fe Complexes and Related Structures.

b

Bond Lengths (Å)

Angles (°)

τ

4

Fe–Nim

Fe–Npyr

N

im–Cim

N

pyr–Cipso

C

im–Cipso

C=C

N

im–Fe–

N

im–Fe–

C=C

Npyr–Fe–

C=C

pyr

(ⁱ^P^rPI)Fe(COD) ^c

BS(3,1) ^d

1.969(6) 2.026(6) 1.341(9) 1.383(8)

2.013 2.097 1.349 1.397

1.984(2) 2.021(2) 1.340(3) 1.376(3)

2.051 2.082 1.347 1.386

1.980(3) 2.043(3) 1.339(4) 1.381(5)

1.414(8) 1.351(11)

1.374(12)

80.23(19)

79.8

0.73

0.72

0.84

0.82

0.70

134.3

123.1

114.1

1.427

1.393

.391

133.1

126.0

117.4

111.9

1

(ⁱ^P^rPI)Fe(M^vⁱM^vⁱ) ^e

BS(3,1) ^f

1.423(3) 1.410(3)

79.84(8)

79.3

123.2

111.3

118.7

109.4

1

.403(3)

1.428

1.397

.393

121.8

110.8

122.6

108.3

1

(ⁱ^P^rPI)

Fe ^g

Fe ^h^,ⁱ

1.423(5) --

1.417(5)

--

2

79.47(12)

80.09(12)

1

.988(3) 2.026(3) 1.349(4) 1.381(5)

(ⁱ^P^rPAI)

1.411(3) --

1.408(3)

--

2

1.988(2) 2.043(2) 1.342(2) 1.387(3)

.981(2) 2.046(2) 1.336(3) 1.386(3)

81.62(7)

82.02(7)

1

(^RPI⁽^o^x⁾)⁰^h^,^j

(^RPI^•)¹^–^h^,^j

(^RPI⁽^r^e^d⁾)²^–^h^,^j

--

1.28

1.34

1.46

1.35

1.39

1.40

1.47

1.41

--

1.35

--

d

a

b

c

Metrical parameters obtained through single crystal X-ray diffraction analysis. Calculated as described in Ref 39. See Figure 1A. Optimized,

broken symmetry structure for ( PI)Fe(COD) computed using the B3LYP/def2-SVP/def2-TZVP level of density functional theory with applica-

tion of the ZORA relativistic correction. See Figure 1B. Optimized, broken symmetry structure for ( PI)Fe(M M ) computed using the

B3LYP/def2-SVP/def2-TZVP level of density functional theory with application of the ZORA relativistic correction. See Figure 1C. Taken from

Ref. 38b. Values listed for one of two structurally similar complexes in the unit cell. ( PI ) represents a generic iminopyridine ligand in its neu-

tral form, ( PI ) represents a generic iminopyridine ligand in its anionic, one-electron-reduced form, and ( PI ) represents a generic imino-

pyridine ligand in its dianionic, two-electron-reduced form.

iPr

e

f

iPr

vi vi

g

h

i

j

R

(ox) 0

R

•

1–

R

(red) 2–

ACS Paragon Plus Environment

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5

7

R

a

Table 2. Select Zero-Field Fe Mößbauer Parameters for ( PI)Fe Complexes and Related Structures.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

[Fe]

δ

|ΔE

Q

|

Ox. State

[Fe]

δ

|ΔE

Q

|

Ox. State

(

mm/s) (mm/s)

(mm/s) (mm/s)

(ⁱ^P^rPI)Fe(COD) ^b

soln. ^c

BS(3,1) ^d

(^M^ePI)Fe(COD) ^e

BS(3,1) ^d

(ⁱ^P^rDI)Fe(COD) ^f

(ⁱ^P^rPI)Fe(M^vⁱM^vⁱ) ^g

BS(3,1) ^d

0.52

0.53

0.49

0.52

0.48

0.52

0.54

0.53

0.89

1.09

0.92

1.05

1.31

1.26

1.35

1.94

Fe(I), SFe = 3/2

( DI)Fe(η -C

iPr

4

H

) ^f

0.56

0.75

0.74

0.77

0.39

0.38

0.45

0.63

1.68

1.18

1.33

1.81

0.53

1.72

0.83

2.47

Fe(I), SFe = 3/2

5

8

iPr

Fe ^h

( PI)

2

Fe(II), SFe = 2

Me

Fe ^e

( PI)

2

Fe(II), SFe = 2

Fe(I), SFe = 3/2

(^M^e^sPI)

2

Fe

Fe(II), SFe = 2

iPr

Fe ⁱ

( DI)

2

Fe(II), SFe = 2

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

(ⁱ^P^rPDI)Fe(N

(ⁱ^P^r⁽^T^B⁾PDI)Fe(N

(ⁱ^P^r⁽^T^B⁾PDI)Fe

j

Fe(I), SFe = 3/2

2

)

2

Fe(0)–Fe(II) hybrid, SFe = 0

Fe(II), SFe = 1

) ^j

k

)

2 2

Fe(0)–Fe(II) hybrid, SFe = 0

Fe(I), SFe = 3/2

Me

vi vi

( PI)Fe(M M )

Fe(I), SFe = 3/2

(

CH

(ⁱ^P^r⁽^T^B⁾PDI)Fe

(CH CHCH

2

CHCH

2

)

2

NTs ^k

BS(3,1) ^d

0.53

1.17

0.73

1.87

Fe(I), SFe = 3/2

k

2

)

2

a

All measurements recorded at 80 K for solid powder samples unless noted otherwise. Complete ligand structures for all listed complexes depicted in

b

c

d

the Supporting Information. See Figure 1D. Solution state sample frozen in C

6

H

6

. Calculated using the optimized, broken symmetry structure

e

computed at the B3LYP/def2-SVP/def2-TZVP level of density functional theory with the ZORA relativistic correction. From a sample of 90%

Me

f

g

h

i

j

k

( PI)Fe(COD) and 10% ( PI)

Ref. 25.

2

Fe. Taken from Ref. 26. See Figure 1E. See Figure 1F. Taken from Ref. 38a. Taken from Ref. 42. Taken from

A.

The qualitative d-orbital splitting diagram and spin-density

plot for ( PI)Fe(COD) derived from these computational

results are depicted in Figure 2, where the spatial overlap (S =

.47) between primarily iron- and ligand-centered orbitals is

iPr

2 2

x – y

d

0

2

z

d

indicative of their antiferromagnetic coupling. These depictions

are representative of those observed for all four (PI)Fe(bis-

olefin) complexes that were examined computationally and

highlight the involvement of the iminopyridine ligand in the

electronic structure of the catalytically relevant complexes. The

computational results thus underscore the similarities in the

electronic structures of the iminopyridine, α-diimine, and pyri-

dine-2,6-dimine iron bis-olefin complexes implicated in the

mechanisms of C–C bond-formation through oxidative cycliza-

tion.²

xz

xy

yz

π*

(

S = 0.47)

5,26

–

0.03

B.

–0.04

Mechanistic Analysis. Significant insight was obtained

through analysis of the single-component iron bis-olefin precat-

alysts/model complexes achieving highly selective [4+4]-

cycloaddition of 1,3-dienes. However, attempts to isolate and

characterize the catalytically active species from the reaction

–

0.15

–

0.08

–

0.28

–0.16

3.15

+0.05

+0.03

+

–0.10

–0.17

–

0.07

mixture were unsuccessful and invariably yielded the homolep-

–

0.08

R

–0.09

tic bis-ligand complexes, ( PI)

2

Fe, or the isoprene adduct

Fe(η -isoprene) (see Supporting Information

for single crystal X-ray diffraction data). While ( PI) Fe did

exhibit low activity for the [4+4]-cyclodimerization of 2-

substituted dienes, it was not kinetically competent to be the

predominant species responsible for catalysis (vida supra;

Me

2

thereof, ( PI)

2

Me

2

iPr

Figure 2. Electronic Structure of ( PI)Fe(COD). (A.) Qualitative

molecular orbital diagram derived from the BS(3,1) DFT solution for

iPr

( PI)Fe(COD), representing the corresponding orbitals possessing

Scheme 5). This is consistent with the observation that

Me

significant d-orbital character and the singly-occupied, ligand-based

orbital. (B.) Spin-density plot for ( PI)Fe(COD)obtained from the

BS(3,1) Mulliken population analysis (red, positive spin density; yel-

low, negative spin density). DFT calculations performed at the

B3LYP/def2-SVP/def2-TZVP level of theory with the ZORA relativ-

istic correction.

( DI)

2

Fe is, likewise, not a competent catalyst for the [4+4]-

iPr

11

cyclodimerization of butadiene. Given the apparent instability

of and difficulty in isolating the active species, kinetic tech-

niques and zero-field ⁵⁷Fe Mößbauer spectroscopic measure-

ments were employed instead to gain mechanistic insight.

ACS Paragon Plus Environment

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Page 10 of 19

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

A.

B.

C.

5

4

3

.0

5.0

4.0

3.0

2.0

1.0

0.0

40

32

24

16

8

[

5b]0 = 5.0 M, [7b]0 = 0 M

5b]0 = 2.7 M, [7b]0 = 0 M

[

5b]0 = 5.0 M

[5b]0 = 2.7 M

5b]0 = 2.7 M

[5b]0 = 5.0 M

[5b]0 = 2.7 M

[7b]0 = 1.4 M

[5b]0 = 2.7 M, [7b]0 = 1.4 M

[

[7b]0 = 1.4 M

1

30 min

2.0

1

0

.0

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

0.0

0

60 120 180 240 300 360

time (min)

0

60 120 180 240 300 360

time (min)

1.0

2.0

3.0

4.0

5.0

[5b] (M)

^D^.1_.₀

E.

1.0

0.8

0.6

0.4

0.2

0.0

F.

25

20

15

10

5

[

5b]0 = 1.0 M

[5b]0 = 0.5 M

5b]0 = 0.5 M

[5b]0 = 1.0 M

[5b]0 = 0.5 M

[7b]0 = 0.25 M

[5b]0 = 1.0 M

[5b]0 = 0.5 M

0

.8

[

0.6

0.4

[7b]0 = 0.25 M

4

0 min

0

.2

.0

0

0.0

0

20

40

60

80 100 120

0

20

40

60

80 100 120

0.2

0.4

0.6

0.8

1.0

time (min)

[5b] (M)

Figure 3. Kinetic Tests for Catalyst Deactivation and Product Inhibition for Reactions Run in Neat Substrate (A–C) or Toluene Solution (D–F).

A./D.) Concentration of substrate [5b] over time measured by gas chromatographic analysis of aliquots removed from the reaction mixture. (B./E.)

Concentration of substrate [5b] over time time-shifted to illustrate overlay with standard conditions. (C./F.) Reaction rate over the course of sub-

strate consumption shown over evenly spaced intervals of Δ[5b] = 0.25 M. Open markers represent data points obtained from individual trials;

closed markers represent average values obtained from duplicate trials. [Fe]tot = [( PI)Fe(M M )]

mation for additional experimental details.

(

Me

vi vi

0

= 2.5 mM for all trials. See Supporting Infor-

To probe whether catalyst deactivation occurred on the time-

scale of the catalytic reaction, an experiment analogous to

Catalyst turnover numbers were high in both scenarios (TON =

400–2000). Consistent with these observations, dark teal reac-

tion mixtures were observed that persisted throughout the

course of product formation but faded to dark orange-brown

rapidly following consumption of the diene substrate.

5

3

Blackmond’s “same-excess” protocol was performed. Substrate

consumption was monitored over the entire reaction course by

gas chromatographic analysis of aliquots removed from the re-

action mixture for two trials in which [Fe]tot

Additional reaction-progress kinetic analysis provided insight

into the nature of the rate dependence on diene [5b] and iron

Me

vi vi

54

(

[( PI)Fe(M M )]tot = 2.5 mM) was held constant but the

t

initial myrcene concentration of one was adjusted to mimic

initiation at partial conversion. This procedure was conducted

for reactions run both in neat substrate ([5b]

and in dilute toluene solution ([5b] = 1.0 vs. 0.5 M). For the

reactions conducted in neat substrate, the resulting rate vs. con-

centration curves (or time-shifted concentration vs. time

curves) overlaid within error (Figure 3A–C; blue circles vs. red

squares). However, a small but statistically significant deviation

between the two was evident for the reactions conducted in

toluene (Figure 3D–F). In both cases, good overlay was ob-

served for reactions conducted with (red squares) and without

teal triangles) the addition of exogenous product at the outset

of the reaction (i.e. [5b] = 2.5 M, [7b] = 0 vs. 1.25 M and

5b] = 0.5 M, [7b] = 0 vs. 0.25 M). Taken together, these re-

sults demonstrate that product inhibition does not occur under

the standard reaction conditions. While slight catalyst deactiva-

tion was observed for reactions conducted in dilute toluene,

likely due to ligand exchange and the formation of the homolep-

tic bis-ligand complex (vide supra), this deactivation process

was minimized by performing the reaction in neat substrate.

catalyst [Fe]tot. Consumption of myrcene (5b) and formation

of [4+4]-cycloadduct 7b evolved smoothly over the reaction

with no change in selectivity over time (Figure 4A). However, a

non-integer-order dependence on diene concentration was

observed, with apparent zero-order dependence of reaction rate

on diene concentration at high [5b]

conversion or low [Fe] loading) and non-zero-order depend-

ence at lower [5b] (i.e. high conversion or high [Fe] loading;

Figure 4B). Given the absence of competitive catalyst deactiva-

tion over the course of the reaction, this observation suggested a

change in the catalyst resting state as a function of [5b]. The

kinetic order in iron catalyst was thus determined over the linear

regime (i.e. where the order in myrcene is zero; 10%–80% con-

= 5.0 vs. 2.7 M)⁵⁵

0

t

relative to [Fe]tot (i.e. low

t

(

0

[

0

version) from a series of reactions run at constant [5b] where-

in the catalyst concentration was varied ([( PI)Fe(COD)]tot

2.5–60 mM; 0.02–1.2 mol% [Fe]). A first-order dependence on

[Fe]tot was observed (Figure 4C).

0

Me

=

ACS Paragon Plus Environment

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Journal of the American Chemical Society

parameters comparable to those obtained for the solid-state

sample, (benzene solution: δ = 0.52 mm/s, |ΔE | = 0.89 mm/s;

A.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

5.0

Q

solid state: δ = 0.52 mm/s, |ΔE

contrast, the Mößbauer spectrum obtained after mixing (

Q

| = 0.89 mm/s, vide supra). By

4

3

2

1

0

.0

iPr-

[

Fe]tot = 2.5 mM

Fe]tot = 5.0 mM

PI)Fe(COD) with 25 equivalents of 5b at ambient temperature

(~23 °C) for 5 minutes prior to freezing with liquid N exhibited

[Fe]tot = 10. mM

[Fe]tot = 20. mM

[Fe]tot = 40. mM

[Fe]tot = 60. mM

2

features characteristic of at least two similar but distinct iron-

containing species. Fitting the data to two species (A and B)

yielded parameters (δ

A

= 0.52 mm/s, |ΔE

Q

|

A

= 1.28 mm/s

= 0.65 mm/s (45%)) consistent

corresponds to

(

55%); δ

B

= 0.52 mm/s, |ΔE

|

Q B

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

iPr

with two ( PI)Fe(L)

2

complexes where (L)

2

0

60 120 180 240 300 360

time (min)

4

2

one (η ) or two (η ) molecules of the diene, respectively. This

assignment is consistent with the observed change in kinetic

order as a function of [5b]/[Fe]tot.

B.

5.0

A.

4.0

3.0

2.0

N

5

b (25 equiv)

i_P_r

ⁱPr

I

N

Fe

N

Fe

L

neat, rt 5 min, then 80 K

COD

–

L

i_P_r

(iPrPI)Fe(COD)

(iPrPI)Fe(L)₂

B.

1

0

.0

1

00

N

ⁱPr

I

R

N

Fe

0.0

1.0

2.0

3.0

4.0

5.0

9

8

[5b] (M)

ⁱPr

R

C.

96

94

(ⁱ^P^rPI)Fe(η -5b)2

2

5

4

3

2

1

0

.0

ꢀ

d[5b]/dt = kobs [Fe]tot + b

ꢀ1

kobs = 4.0 min

b = 0.005 M min

R²= 0.99

N

ꢀ1

ⁱPr

I

9

2

0

ꢀ = 0.52, 0.52 mm/s

N

Fe

|

ꢀEQ| = 1.28, 0.65 mm/s

-2.0 0.0 2.0

ⁱPr

(iPrPI)Fe(η4-5b)

R

-4.0

4.0

Velocity (mm/s)

Figure 5. Iron Speciation under Catalytically Relevant Conditions. (A.)

Preparation of a solution sample for in situ spectroscopic analysis. (B.)

0

20

40

Fe]tot (mM)

60

80

57

Zero-field Fe Mößbauer spectrum collected at 80 K for the frozen

[

solution sample prepared in A. Red and blue lines represent the fit of

the data to the quadrupolar doublets defined by the parameters shown.

Structures in the gray box represent plausible resting state complexes

that are consistent with the kinetic and Mößbauer spectroscopic data;

however, their precise identity cannot be assigned definitively.

Figure 4. Reaction-Progress Kinetic Analysis. (A.) Concentration of

substrate [5b] over time measured by gas chromatographic analysis of

aliquots removed from reaction mixtures over varied [Fe]tot. (B.) Reac-

tion rate over the course of substrate consumption shown over evenly

spaced intervals of Δ[5b] = 0.25 M obtained from the univariate spline

fit of the concentration vs. time plots in A. (C.) The first-order de-

pendence of reaction rate on [Fe]tot illustrated by the linear regression

to rate-data obtained at [5b] = 2.5 M, with qualitatively similar de-

pendence observed over the full course of the reaction. Open markers

represent data points obtained from individual trials; closed markers

represent average values obtained from duplicate trials.

While the combined kinetic experiments and spectroscopic

measurements provided information about the resting state of

the iron catalyst, the observed rate law does not distinguish be-

tween oxidative cyclization, allyl isomerization, and reductive

elimination as rate-determining steps. To gain additional insight

1

2

13

into the nature of the selectivity-determining event(s), C / C

kinetic isotope effects (KIEs) at all positions were determined.

Singleton’s NMR-based technique was applied to measure per-

To examine the identity of iron complexes formed under the

5

7

reaction conditions, zero-field, solution-state Fe Mößbauer

spectra were recorded at 80 K for frozen solution samples of

12

13

turbations of the C/ C isotopic ratios obtained for product

b isolated at low conversion relative to natural abundance

7

iPr

( PI)Fe(COD) in benzene (see Supporting Information) and

material (measured from product 7b obtained after full conver-

sion of substrate 5b). Large, primary isotope effects were

myrcene (5b, Figure 5). Because of the high activity of

56

Me

( PI)Fe(COD) with myrcene, especially at the high concen-

measured at the site of initial C–C bond-formation (C4, KIE =

trations needed for spectroscopic observations, the more steri-

cally encumbered and less active iron precursor, (

PI)Fe(COD), was used for the in situ monitoring study. In ben-

zene solution, a single quadrupolar doublet was observed with

1

.019(1) averaged over two chemically equivalent sites) and at

iPr-

the vicinal olefinic carbon (C3, KIE = 1.019(4)); a modestly

attenuated primary isotope effect was also observed at the op-

ACS Paragon Plus Environment

Journal of the American Chemical Society

Page 12 of 19

posite terminus (C1, KIE = 1.010(4); Scheme 11). While com- While the KIE measurements enabled identification of the

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

parison to high-level computational models is necessary when

applying this technique to distinguish between multiple similar

regioselectivity-determining step, this step is not necessarily also

diastereoselectivity-determining. Insight could be drawn from

the relationship between the isomeric purity of the diene sub-

strate and the observed product diastereomer ratio. If the prod-

uct diastereomer ratio were entirely catalyst controlled (i.e. if

only (E)-isomer incorporation were possible), the product d.r.

would be independent of substrate E/Z ratio (Scheme 13A).

This would be possible either through an entirely stereoconver-

gent mechanism (mechanism i) or if substrate incorporation

were entirely isomer-selective (mechanism ii). Alternatively, if

incorporation of both (E)- and (Z)-diene isomers were possible

(through either stereoconvergent or stereospecific processes, as

in mechanisms iii and iv, respectively), the product d.r. would

vary as a function of substrate E/Z ratio, resulting from the rate-

averaged statistical combination of the substrate isomers

(Scheme 13B). Finally, for a mechanism in which only one of

the two diene coupling partners were incorporated in an iso-

mer-selective fashion the product d.r. would be related directly

to the substrate E/Z ratio (Scheme 13C, mechanisms v and iv).

12

13

mechanisms, natural abundance C/ C KIE measurements

have been applied successfully in the absence of computational

models to provide general information about the identity of the

first irreversible product-determining step within an accepted

57

mechanistic pathway. With these limitations in mind, the ob-

served KIEs are most consistent with irreversible and therefore

regioselectivity-determining oxidative cyclization proceeding

through [1,4]-carbometallation from an iron bis-diene complex

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

(

[

see Supporting Information for further discussion). This direct

1,4]-carbometallation also accounts for the high chemoselec-

tivity observed for the iron-catalyzed [4+4]-cycloaddition, as

the reaction mechanism bypasses a putative divinyl metallacy-

clopentane poised to undergo side reactions. A catalytic cycle

accounting for the combined kinetic analyses, Mößbauer spec-

troscopic observations, and KIE measurements is illustrated in

Scheme 12. Model reaction time-courses simulated for this

mechanistic scenario using COPASI software are consistent

with the observed saturation kinetics (see Supporting Infor-

To probe these possibilities experimentally, (E)-1b and (Z)-

b were subjected to the [4+4]-cyclodimerization conditions

5

8

mation).

1

13

12

Scheme 11. C/ C Isotope Effects.

independently. Whereas (E)-1b was converted smoothly to

1

.000

[4+4]-cycloadducts 3b and 4b with high diastereoselectivity,

(defined)

1.006(4)

(

Z)-1b underwent non-productive isomerization upon expo-

1.019(4)

sure to either iron precatalyst (Scheme 14A & B) and cyclodi-

merization products were not detected. This isomer-dependent

reactivity thus ruled out mechanisms iii and iv depicted in

Scheme 13 for both the diimine and iminopyridine iron cata-

lysts.

_.₁_m_o_l_%₍MePI)Fe(COD)

neat, rt

0

1

.010(4)

1.019(1)

5

b

7b

a

Scheme 12. Proposed Catalytic Cycle.

Subsequently, mixtures of (E)- and (Z)-1b were subjected to

the same reaction conditions (Scheme 14C). Where diimine

iron complex (MesDI)Fe(COD) was used as a precatalyst, 3b

and 4b were obtained in the same ratio as observed with pure

(E)-1b substrate. In this case, formation of the [4+4]-

cycloadducts was accompanied by the accumulation of iso-1b.

These observations suggest that isomer-selective mechanism ii

(^M^ePI)Fe(COD)

+

diene

– COD

R

N

R

N

Fe

(

Scheme 13A) is most likely operative.

In contrast to the results obtained using (^M^e^sDI)Fe(COD),

(I)

R

(IV)

both (E)- and (Z)-isomers were consumed upon exposure to

Proposed

N

iPr

Resting-State

Species

( PI)Fe(COD), resulting in the formation of cyclodimeriza-

R

N

Fe

R

tion products with moderately reduced diastereoselectivity and

chemoselectivity for the [4+4] products. This isomer-

dependent selectivity eliminates mechanisms i and ii depicted in

Scheme 13. While these results cannot distinguish between

mechanistic possibilities v and vi depicted in Scheme 13, they

do provide evidence for a mechanism in which selectivity is

determined through the combination of catalyst-controlled

diastereoselective/isomer-selective and substrate-controlled

stereospecific/isomer-unselective contributions. Moreover,

mechanisms ii and v/vi exist on a continuum, and the extent to

which isomer-selective reactivity occurs likely varies across sub-

strates. Indeed, exposure of a mixture of piperylene isomers

N

Fe

R

(II)

R.D.S.

(III)

R

N

R

N

R

N

Fe

N

Fe

N

Fe

Avoided

R

a

(I) Diene coordination. (II) Oxidative cyclization. The observed

C/ C KIEs do not distinguish between direct oxidative cyclization to

afford the σ- or π-allyl metallacycles shown. R.D.S. = rate-determining

step. (III) Allyl isomerization. (IV) Ligand-induced reductive elimina-

tion or reductive elimination followed by diene coordination.

1

3

12

Mes

(66:34 (E)-/(Z)-1a) to either precatalyst ( DI)Fe(COD) or

iPr

( PI)Fe(COD) results in reduced chemo- and diastereoselec-

tivity (vide supra; indicative of mechanisms v/vi) in both cases

ACS Paragon Plus Environment

Page 13 of 19

Journal of the American Chemical Society

a

Scheme 13. Mechanistic Hypotheses to Account for Catalyst- and Substrate-Controlled Diastereoselectivity.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

A. Mechanisms Leading to Isomer-Independent Diastereoselectivity

R^E

_RE/Z

R^E^/^Z

[Fe]

_RE/Z

[Fe]

– [Fe]

R^E^/^Z

i –

2

– or –

[Fe]

diastereoselective

& stereoconvergent

_RE/Z

R^Z

R^E

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

R^E

[

Fe]

diastereoselective &

isomer selective (×2

– [Fe]

stereospecific

R^E

_RE

ii –

2

[Fe]

where [Fe] =

(^M^e^sDI)Fe(COD)

stereospecific

_RE

)

_RE

_RZ

where [Fe] =

(ⁱ^P^rPI)Fe(COD)

B. Mechanisms Leading to Isomer-Dependent Diastereoselectivity WITHOUT Isomer-Selective Reactivity

R^E

R

Z

_RE/Z

R^E

[

Fe]

– [Fe]

2

– or –

Z

_RE/Z

iii –

R

[Fe]

diastereoselective

stereospecific

&

stereoconvergent

_RE/Z

NOT isomer selective

R^Z

_RE/Z

R^E

_RZ

_RE

R^E

_RE

[

Fe]

R^E

– [Fe]

Z

(

and R /R )

iv–

2

– or –

_RZ [Fe]

[Fe]

_RZ

diastereoselective

& stereospecific

stereospecific

_RE

stereospecific

_RZ

R

Z

NOT isomer selective

R^Z

R^E

Z

(

and R /R^E)

C. Mechanisms Leading to Isomer-Dependent Diastereoselectivity WITH Isomer-Selective Reactivity

R^E

where [Fe] =

(^M^e^sDI)Fe(COD)

_RE

[Fe]

R^E

– [Fe]

R^E

– or –

R^Z

v –

+

[Fe]

_RZ

[Fe]

diastereoselective

& stereospecific

& isomer selective

stereospecific

_RE

stereospecific

_RZ

R

E

where [Fe] =

(ⁱ^P^rPI)Fe(COD)

_RZ

R^E

_RE

where [Fe] =

₍MesDI)Fe(COD)

R^E

R

Z

_RE

[Fe]

_RE

–

[Fe]

_RE

+

R

Z

–

or –

[Fe]

vi –

diastereoselective

stereospecific

&

stereospecific

_RE

_RZ

&

isomer selective

where [Fe] =

₍iPrPI)Fe(COD)

R^Z

R^E

a

Major products depicted for the cyclodimerization of 4-substituted dienes obtained using iron precatalyst (^M^e^sDI)Fe(COD). See Supporting Infor-

mation for the analogous scheme depicting formation of the major products expected using iron precatalyst ( PI)Fe(COD).

iPr

Taken in combination with the mechanism implicated for

oxidative cyclization through [1,4]-carbometallation, this find-

ing provided support for a scenario in which the relative stereo-

chemistry of the distal metallacycle substituent and proximal

vinyl group is set through diastereoselective and isomer-

selective oxidative cyclization. A subsequent, stereospecific al-

lyl-isomerization and C–C bond-forming reductive elimination

sequence results in the relative configuration observed in the

final product. While alternative mechanisms involving stere-

oconvergent reductive elimination cannot be ruled out on the

basis of the experimental data available, the general mechanistic

picture delineated through the studies described herein provid-

ed sufficient context to generate a qualitative stereochemical

model. To aid in visualization of relevant interactions, the coor-

ACS Paragon Plus Environment

Journal of the American Chemical Society

Page 14 of 19

Mes-

dinates for the solid-state structures of precatalysts (

+y

A.

B.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

iPr

DI)Fe(COD) and ( PI)Fe(COD) were analyzed to generate

43.6%

46.3% 48.7%

34.0%

topographic steric maps of the metal-bound, redox-active DI

and PI ligands using SambVca 2.0 (Figure 6). These plots

illustrated a striking difference in the openness of the eastern

59

N

Fe

N

Fe

N

+x

(

as drawn in Figure 6) hemisphere of the iron coordination

iPr

sphere, with the C

percent buried volume (%Vbur) than the effectively C

ligand.

S

symmetric PI resulting in a lower local

Mes

2

DI

60,61

To the extent that the transition structures for oxida-

47.7%

43.0% 46.9%

33.1%

tive cyclization resemble the incipient metallacycles, the ligand-

dependent diastereoselectivity observed with 4-substituted

diene coupling partners can be justified on the basis of compet-

ing repulsive steric interactions between proximal metallacycle

substituents and the steric environment of the DI or PI ligand in

this hemisphere. Namely the metallacycle en route to trans-

diastereomer 4 avoids repulsive gauche-butane interactions but

is only accessible when one hemisphere of the iron coordination

sphere is open. This arrangement also allows for potential stabi-

lizing π-stacking interactions with the ligand pyridine back-

₍MesDI)Fe

iPrPI)Fe

(

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

–3.0 –1.5 0.0 +1.5 +3.0 Å

C.

diastereoselective

[

Fe] + 2 (E/Z)-1

E

_RE

R

H

R^Z

R

Z

_RE

R

E

H

R^E

H

[

Fe]

=

_RZ [Fe]

H

=

R^Z

vs.

[Fe]

_RE

[Fe]

R^E

62

bone. In contrast, the more symmetrically shielded environ-

_a_v_o_i_d_s_p_r_o_j_e_c_t_i_n_g_RE_/_RZ toward

_p_r_o_j_e_c_t_s_RE_/_RZ into open quadrant

Mes

flanking ligand substituents

gauche-butane incurred

opportunity for π-stacking

gauche-butane avoided

ment enforced by DI favors the metallacycle en route to cis-

diastereomer 3.

favored where [Fe] = (MesDI)Fe

favored where [Fe] = (iPrPI)Fe

stereospecific

Scheme 14. Effect of Diene Geometry on Diastereose-

a

lectivity.

3

(cis)

4 (trans)

Figure 6. Rational for Diastereoselectivity. (A/B.) Topographic

A.

Mes

iPr

steric maps of ( DI)Fe and ( PI)Fe generated from the solid-

state structures for the corresponding COD complexes. The Fe

atom defines the center of the xyz coordinate system, the N–

Fe–N plane defines the xz-plane, and the z-axis bisects the N–

Fe–N angle. Colors indicate occupied space toward (–z, blue)

or away from (+z, red) the DI or PI ligand. Local percent buried

volume (%Vbur) listed for each quadrant of a sphere of radius, r

= 3 Å. (C.) Stereochemical rational for ligand-controlled, dia-

stereoselectivity.

H11C5

5

mol% [Fe]

neat, rt

+

C5H11

(E)-1b

3b (cis)

92

4b (trans)

_w_h_e_r_e_[_F_e_]₌₍Mes_D_I₎_F_e₍_C_O_D₎_:b

:

8

(ⁱ^P^rPI)Fe(COD):^c

<1

99

B.

C4H9

H₁₁C₅

C5H11

5 mol% [Fe]

neat, rt

NOT

5 11

C H

(Z)-1b

iso-1b

3b/4b

where [Fe] = (^M^e^sDI)Fe(COD)^dor (ⁱ^P^rPI)Fe(COD)^e

CONCLUDING REMARKS

C.

In summary, a family of iron complexes bearing bidentate

ligands enabled the [4+4]-cycloaddition of substituted 1,3-

dienes with control of chemo- and regioselectivity to afford

disubstituted 1,5-cyclooctadienes. Methods to access either of

two diastereomeric products selectively were defined. The re-

sultant cyclooctadienes hold promise as modular building

blocks in the synthesis of precision polyolefins, lubricants, fuels,

and fine chemicals. Determination of the electronic structures

of the precatalysts and comparison to in situ spectroscopic

measurements implicated catalytically active species in which an

iminopyridine ligand radical anion is antiferromagnetically cou-

pled with a high-spin iron(I) center. Mechanistic studies sup-

port a mechanism in which stereoselective oxidative cyclization

of two dienes from the resting state complex is followed by a

stereospecific allyl-isomerization/C–C bond-forming reductive

elimination sequence. These insights shed further light on strat-

egies for ligand development to enable selective chemistry that

leverages metallacyclic intermediates to upgrade unsaturated

coupling partners.

C5H11

(E)-1b

5 mol% [Fe]

neat, rt

H11C5

+

C5H11

3

b (cis)

90

4b (trans)

where [Fe] = (^M^e^sDI)Fe(COD):^f

(ⁱ^P^rPI)Fe(COD):^g

:

10

82

(Z)-1b

18

a

Compare with Scheme 6. Reactions were run on 0.4 mmol scale

with 5 mol% [Fe] precatalyst. Product ratios determined by gas

chromatographic analysis and corroborated by relative integration

1

3

of diagnostic resonances in the quantitative C NMR spectrum of

b

c

the isolated material. 98% [4+4] selectivity 77% [4+4] selectivity

d

e

no 3b or 4b detected <10% combined yield of dimeric products

with 65% [4+4] selectivity, 74:26 3b : 4b 30% combined yield

dimeric products with 98% [4+4] selectivity; 44% yield iso-1b

d

e

6

2% combined yield of dimeric products with 60% [4+4] selectivi-

ty; 38% yield iso-1b

ACS Paragon Plus Environment

Page 15 of 19

ASSOCIATED CONTENT

Journal of the American Chemical Society

Klankermayer, J.; Pischinger, S.; Pitsch, H.; Kohse-Höinghaus, K.

1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

Advanced Biofuels and Beyond: Chemistry Solutions for Propulsion

and Production. Angew. Chem. Int. Ed. 2017, 56, 5412–5452.

(a) Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Fráter, G. Odds and Trends:

Recent Developments in the Chemistry of Odorants. Angew. Chem.

Int. Ed. 2000, 39, 2980–3010. (b) Birkbeck, A. A. Challenges in the

Synthesis of Natural and Non-Natural Volatiles. In The Chemistry

and Biology of Volatiles; Herrmann, A., Ed.; John Wiley & Sons, Ltd.,

Supporting Information

4

5

.

The Supporting Information is available free of charge via the internet

at http://pubs.acs.org.

Mes

iPr

iPr-

Crystallographic information for ( DI)Fe(COD), ( PI)Fe(COD), (

vi vi

iPr

Mes

PI)Fe(M M ), ( PI)

2

Fe, ( PI)

2

Fe, and ( PI) Fe(isoprene). (CIF) This

2

metrical parameters and CIFs can also be obtained free of charge from the

2

010; pp 173–193.

Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk) under

identifiers CCDC 1862087, 1862086, 1877016, 1862088, 1862089, and

(a) Vesley, J. A.; Massie, S. N. Acetal Derivatives of Cyclooctyl

Carboxaldehydes. US 3,985,769, 1976. (b) Markert, T. Utilization of

Monocyclic Aldehydes as Odoriferous Agents. WO 99/54430 A1,

1998. (c) Fráter, G.; Bajgrowicz, J. A.; Kraft, P. Fragrance Chemistry.

Tetrahedron, 1998, 54, 7633–7703. (d) Granier, T.; Bajgrowicz, J.

A.; Hanhart, A. Cyclooct-(En)-Yl Derivatives for Use as Fragrances.

US 7,888,309 B2, 2011.

1

877015.

0

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1

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8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

Experimental details; characterization data including NMR spectra of

novel compounds; Mößbauer spectroscopic data; kinetic data; compu-

tational methods and results (PDF)

6

7

.

(a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J.

Med. Chem. 2014, 57, 5845–5859. (b) Aldeghi, M.; Malhotra, S.;

Selwood, D. L.; Chan, A. W. E. Two- and Three-Dimensional Rings

in Drugs. Chem. Biol. Drug Des. 2014, 83, 450–461. (c) Bauer, R.

A.; Wenderski, T. A.; Tan, D. S. Biomimetic Diversity-Oriented

Synthesis of Benzannulated Medium Rings via Ring Expansion. Nat.

Chem. Biol. 2012, 9, 21.

(a) Yet, L. Metal-Mediated Synthesis of Medium-Sized Rings. Chem.

Rev. 2000, 100, 2963–3008. (b) Yu, Z.-X.; Wang, Y.; Wang, Y.

Transition-Metal-Catalyzed Cycloadditions for the Synthesis of

Eight-Membered Carbocycles. Chem. Asian J. 2010, 5, 1072–1088.

AUTHOR INFORMATION

Corresponding Author

*

pchirik@princeton.edu

ORCID

Paul J. Chirik: 0000-0001-8473-2898

C. Rose Kennedy: 0000-0003-3681-819X

Hongyu Zhong: 0000-0002-6892-482X

Rachel L. Macaulay: 0000-0002-7110-8110

Author Contributions

8. (a) Blanchard, N.; Eustache, J. Synthesis of Natural Products

Containing Medium-Size Carbocycles by Ring-Closing Alkene

Metathesis. In Metathesis in Natural Product Synthesis; Cossy, J.,

Arseniyadis, S., Meyer, C., Eds.; John Wiley & Sons, Ltd, 2010; pp 1–

C.R.K. and P.J.C. conceived the work, C.R.K. and R.L.M. conducted

the experiments, H.Z. collected and solved the X-ray structural data,

P.J.C. directed the research, and C.R.K. and P.J.C. prepared the manu-

script. All authors have given approval to the final version of the manu-

script.

4

3. (b) Yet, L. Olefin Ring-Closing Metathesis. In Organic Reactions;

Wiley, 2016; pp 1–1304. (c) Fürstner, A. Catalysis for Total

Synthesis: A Personal Account. Angew. Chem. Int. Ed. 2014, 53,

8587–8598.

(a) Brill, Z. G.; Grover, H. K.; Maimone, T. J. Enantioselective

Synthesis of an Ophiobolin Sesterterpene via a Programmed Radical

Cascade. Science, 2016, 352, 1078–1082. (b) Farney, E. P.; Feng, S.

S.; Schäfers, F.; Reisman, S. E. Total Synthesis of (+)-Pleuromutilin.

J. Am. Chem. Soc. 2018, 140, 1267–1270.

Notes

The authors declare no competing financial interest.

9

.

ACKNOWLEDGMENT

C.R.K. thanks the NIH for a Ruth L. Kirschstein National Research

Service Award (F32 GM126640). Financial support and a gift of

piperylene were provided by Firmenich. We thank Dr. István Pelczer

10. (a) Oenbrink, G.; Schiffer, T. Cyclododecatriene, Cyclooctadiene,

and 4-Vinylcyclohexene. Ullmann’s Encyclopedia of Industrial

Chemistry; Wiley-VCH: Weinheim, 2009; pp 37–40. (b) Reed, H.

W. B. The catalytic cyclic polymerization of butadiene. J. Chem. Soc.

(

Princeton University) for assistance with NMR experiments, and Dr.

C5H9

Stephan Rummelt for a gift of [( PDI)Fe(N )].

2

1

954, 1931–1941. (c) Brenner, W.; Heimbach, P.; Hey, H.; Müller,

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Article Doi

Regio- and Diastereoselective Iron-Catalyzed [4+4]-Cycloaddition of 1,3-Dienes

DOI: 10.1021/jacs.9b02443

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jacs.9b02443

Full text of DOI:10.1021/jacs.9b02443

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