Hydroamination of Dihapto-Coordinated Benzene and Diene Complexes of Tungsten: Fundamental Studies and the Synthesis of γ-Lycorane

HELVETICA

chimica acta

Accepted Article

Title: Hydroamination of Dihapto-Coordinated Benzene and Diene

Complexes of Tungsten:

Fundamental Studies and the Synthesis of γ-Lycorane

Authors: W. Dean Harman, Katy B. Wilson, Hannah S. Nedzbala,

Spenser R. Simpson, Megan N. Ericson, Karl S. Westendorff,

Mahendra D. Chordia, and Diane A Dickie

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10.1002/hlca.202100103

Helvetica Chimica Acta

Hydroamination of Dihapto-Coordinated Benzene and Diene

Complexes of Tungsten:

g

Fundamental Studies and the Synthesis of -Lycorane

Katy B. Wilson, Hannah S. Nedzbala, Spenser R. Simpson, Megan N. Ericson, Karl S. Westendorff,

Mahendra D. Chordia, Diane A. Dickie, and W. Dean Harman*

Department of Chemistry, University of Virginia, Charlottesville, Virginia, 22904, U.S.A.

e-mail: wdh5z@virginia.edu

Dedicated to Prof. E. Peter Kündig on the occasion of his 75th birthday

Abstract: Reactions are described for complexes of the form WTp(NO)(PMe₃)(h²-arene) and various

amines, where the arene is benzene or benzene with an electron-withdrawing substituent (CF₃, SO₂Ph,

SO₂Me). The arene complex is first protonated to form an h²-arenium species, which then selectively adds

the amine. The resulting h²-5-amino-1,3-cyclohexadiene complexes can then be subjected to the same

sequence with a second nucleophile to form 3-aminocyclohexene complexes, where up to three

stereocenters originate from the arene carbons. Alternatively, 1,3-cyclohexadiene complexes containing

an ester group at the 5 position (also prepared from an arene) can be treated with acid followed by an

amine to form trisubstituted 3-aminocyclohexenes. When the amine is primary, ring closure can occur to

form a cis-fused bicyclic g lactam. Highly functionalized cyclohexenes can be liberated from the tungsten

through oxidative decomplexation. The potential utility of this methodology is demonstrated in the

synthesis of the alkaloid g-lycorane. An enantioenriched synthesis of a lactam precursor to g-lycorane is

also described. This compound is prepared from an enantioenriched version of the tungsten benzene

complex. Regio- and stereochemical assignments for the reported compounds are supported by detailed

2D NMR analysis and 13 molecular structure determinations (SC-XRD).

keywords: tungsten, hydroamination, lycorane, dearomatization, diene, arene, nitrosyl, cyclohexene

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NR₂

Introduction

HNR₂

I

Hydroamination is among the most powerful tools

available for the synthesis of amines (reaction I, Scheme

1).^[1-4]While numerous methods have been developed for

the addition of amines to alkenes and alkynes, such a

reaction for benzene itself (reaction II) is highly

endergonic. For more than half a century, chemists have

exploited the properties of transition metals to promote

the nucleophilic addition to benzenes.^[5-6]However, the

majority of this work has been limited to carbon

nucleophiles, typically stabilized enolates, dithianes,

Grignards or other organometallics.^[7]Amines have been

widely demonstrated to undergo nucleophilic

substitution with arene ligands containing suitable

leaving groups in complexes such as Cr(CO)₃, [Mn(CO)₃]⁺,

and [RuCp]^+-.^[8]However, examples of nitrogen

nucleophiles undergoing addition to benzene complexes

are far less common. Still, pioneering work by Birch,

Pearson and those that followed demonstrated that

cyclohexadiene complexes can be subjected to hydride

abstraction to form electrophilic cyclohexadienyl species

such as the venerable [Fe(CO)₃(C₆H₇)]⁺system,^[9-10]which

readily adds amines to form complexed aminodienes

(reaction III). Research in our laboratories has focused on

the ability of π-basic transition metal complexes to

promote addition reactions to h²-bound arenes.^[11-13]In

this case, the metal activates the aromatic ligand toward

protonation to form an h³- or h²-arenium intermediate

(reaction IV).^[14]Our previous work has demonstrated

NR₂

HNR₂

II

X

-H^-

HNR₂

M

III

M

NR₂

H⁺

HNR₂

IV

NR₂

M

Scheme 1. Hydroamination of alkenes and arenes via cyclohexadienyl

intermediates.

Hydroaminations are typically carried out through the use

of transition metal or lanthanide catalysts, or by strong

bases.^[1-4]However, if the amine is suitably protected by a

strong

withdrawing

group,

acid

catalyzed

hydroaminations can also be realized, especially

intramolecular variations.^[17-19]The main obstacle in

carrying out such a reaction is the incompatibility of the

acid and the amine, as well as the negative entropy

associated with the intermolecular reaction.^[2]In the case

of benzene dihapto-coordinated to {WTp(NO)(PMe₃)}, we

have previously demonstrated that the strong tungsten-

benzene backbonding interaction promotes the

protonation of the aromatic ligand to form an arenium

species.^[14]The question remained, however, whether the

addition of the amine could pre-empt deprotonation of

the h²-arenium (i.e. h²-cyclohexadienyl) complex at

reduced temperatures. Our study commenced by

preparing the arenium complex in situ from its benzene

precursor (1) followed by addition of an amine. Even with

benzene, several regio- and stereochemical issues come

into play. The benzene ligand is competitively protonated

at two different carbons,^[14]resulting in two different

arenium species, 2 and 3. Each of these exists as two

different conformational isomers in which two carbons

are tightly bound by the tungsten but a third is loosely

associated.^[20]Herein, we indicate this weakly bound

carbon as a carbocation in order to differentiate the two

conformations. We note however, that much like

that this intermediate reacts with carbon nucleophiles to

[15-16]

generate substituted cyclohexadienes.

Strikingly,

we found that addition of methylamine resulted in the

hydroamination of the benzene ring to form the

aminodiene (reaction IV).^[15]This result was surprising

because not only was addition of the amine competitive

with deprotonation of the arenium ligand, but the

resulting complex was kinetically stable with respect to

elimination, provided that it was kept in a basic

environment. The results outlined below are a systematic

examination of the ability of {WTp(NO)PMe₃} (Tp =

tripyrazolylborate) to promote the hydroamination of h²-

coordinated arenes and cyclohexadienes to form highly

substituted, three dimensional cyclohexenes.

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Figure 1. Key NOE interactions with a generic h²-1,3-diene complex (a),

and the WTp(NO)(PMe₃)(h²-1,3-cyclohexadiene complex) (b);

structure of the parent h²-1,3-cyclohexadiene from SC-XRD

analysis)^[14]

conformations of chiral amines that differ only by

inversion of the nitrogen (invertomers), allyl-shift isomers

can be represented by the same bond structure (i.e.,

bonds from the metal to all three allyl carbons) but they

differ in torsion and bond angles.^[14]For the h²-benzenium

system, this equilibrium in solution is approximately 10:1

(¹H NMR), favoring isomer 2 in its distal conformer (2D).

Under Curtin–Hammett conditions, addition of the amine

is not necessarily dictated by the dominant species in

solution, but in the case of methylamine, addition occurs

smoothly at the anticipated carbon providing the distal

aminodiene 4D with a >96:4 selectivity.^[15]As is typical for

these arenium species,^[13]nucleophilic addition occurs

strictly anti to the ring face bound by the metal.^[15]The

selectivity becomes even more impressive when the

arene contains an electron-withdrawing group.

Protonation of the trifluorotoluene ligand of 5 generates

the arenium in >20:1 selectivity,^[16]and subsequent

addition of methylamine generates aminodiene 6

(Scheme 3), exclusively. In this case, protonation occurs

ortho to the CF₃group, and amine addition occurs at the

adjacent carbon. Analogous reactions are achieved with

p-chlorobenzylamine, 2-(aminomethyl)pyridine, and even

with the secondary amine, morpholine. In all cases (6-9),

both regio- and stereoselectivity is >98:2. Structural

assignments were confirmed with a combination of NOE

interactions between the diene and the PMe₃and Tp

ligands of the complex (Figure 1), and when possible, SC-

XRD data (Figure 2). When the diphenylsulfone complex

10 was subjected to similar reaction conditions, the

selective formation of 5-aminodiene complexes was also

realized, this time with either morpholine (11) or

piperidine (12). In all cases, the corresponding

aminodiene complexes were found to be kinetically

stable in solution, provided that they were kept away

from acid. Even under weakly acidic conditions,

elimination to re-form the h²-arene starting materials was

rapid.

PMe₃

NO

W

Tp

H⁺

1

H⁺

PMe₃

NO

W

NO

H

W

Tp

2P

3D

H

allyl shift

PMe₃

allyl shift

PMe₃

NO

H

W

Tp

H

2D

3P

coordination diastereomers

MeNH₂

PMe₃

NO

W

NO

NHMe

W

Tp

4D

4P

NHMe

Scheme 2. Dihapto-coordinated h²-benzenium isomers and their

reaction with methylamine.

a)

b)

Me

P

Me

NO

H

N

H

N

R

H

N

W

H

N

HB

N

H

NR₂

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PMe₃

NO

PMe₃

NO

Bu₄NOH/MeOH at low temperature (–30 °C) provides

the trisubstituted cyclohexene 13.

CF₃

a

CF₃

HOTf

W

CF₃

H

Tp

[W]

Tp

CH₃CN

Significantly, in the absence of an added nucleophile, a

different outcome was observed: When 6 was allowed to

stand in a solution of acetone, an isomerization occurred

over a period of 12 hours to form a new diene complex

(14). From 2D NMR data and an SC-XRD study, the new

diene now has an amino group adjacent to the CF₃group.

This suggests that protonation from adventitious water

momentarily forms an allyl monocation (II; Scheme 4) that

can undergo intramolecular addition of the amino group

to form the azabicyclic intermediate III. We postulate

further that this species then evolved into a new allyl

intermediate, IV, which upon deprotonation delivers the

new diene (14). We note that in both 13 and 14 the CF₃

group is trans to the tungsten. This suggests that

protonation at the carbon bearing this substituent occurs

syn to the metal, similar to that seen in the protonation

of h²-arene complexes of TpW(NO)(PMe₃).^[14]Protonation

anti to the metal is disfavored owing to a steric interaction

between the CF₃group and the nitrosyl ligand.

NHMe

H

5

6

67%

d

c

b

CF₃

[W]

Cl

N

HN

N

O

37%

7

9(SC-XRD) 85%

8 (SC-XRD)

85%

SO₂Ph

PMe₃

[W]

SO₂Ph

HOTf

NO

W

SO₂Ph

H

[W]

Tp

N

X

10

H

11 X = O 67%

57%

12 X = CH₂

Scheme 3. Preparation of 5-amino-1,3-cyclohexadiene complexes

from trifluorotoluene and diphenyl sulfone precursors.

A third reactivity type for 6 was observed in an attempt to

add the silyl ketene acetal ((1-methoxy-2-methylprop-1-

en-1-yl)oxy)trimethylsilane (MMTP) to the allyl

intermediate (I, Scheme 4). The product generated (15)

did not show any incorporation of the enolate, but rather

the acetonitrile solvent appears to have acted as the

initial nucleophile (V), analogous to the Ritter reaction.

Subsequent ring closure with the pendent amine group

(exposed upon addition of triethylamine base) results in

the benzimidazolium derivative 15. Detailed 2D NMR

data and a SC-XRD study confirm the assigned structure.

When the reaction was repeated in the absence of the

MMTP, no reaction occurred. This observation suggests

that the TMS group of the MMTP plays an important role

in this reaction. We speculate that interaction of the TMS

with the nitrosyl may enhance the electrophilicity of the

allyl cation (via the tungsten), which would enhance its

reactivity with the nitrile solvent. Previously we have

Figure 2. SC-XRD molecular structures (50% ellipsoids) of 8 (left) and

9 (right): products of hydroamination of the trifluorotoluene complex

(5) using morpholine or 2-methylaminopyridine.

Our next objective was to carry out a second

hydroamination reaction with the diene derived from the

arene complexes 1 and 5. We began this phase of the

research with an exploration of the aminodiene complex

6, derived from methylamine and trifluorotoluene. While

we speculate that subjecting this compound to an excess

of strong acid first results in the protonation of the amino

group, a second protonation can occur to form the allyl

dication (I, Scheme 4).^[20]Gratifyingly, the addition of acid

followed by the addition of the methoxide source

shown

that

the

nitrosyl

ligand

of

WTp(NO)(PMe₃)(cyclohexene) can be methylated with

MeOTf,^[14]and independently the Legzdins group has

demonstrated this reactivity with similar tungsten-

nitrosyl systems and Lewis acids.^[21]In absence of the TMS

group, a purported protonation of the nitrosyl is

apparently reversed by the addition of triethylamine and

cyclization does not occur. Again, we find that the CF₃

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substituent in 15 is trans to the tungsten, as is the cis-

fused amidine ring (Figure 3).

Although addition reactions similar to the formation of

the aminomethoxycyclohexene 13 from 6 were also

successful with other amine and cyanide nucleophiles,

these reactions were plagued by significant amounts of

elimination. Hence, we decided on a new tack in which a

carbon nucleophile was first employed in the preparation

of the diene, and then the amine would be incorporated

in the second step. Three diene complexes were

prepared as test cases (16-18). Two were derived from

the benzene complex 1, and the third was derived from

the trifluorotoluene analog

5 (Scheme 5). High

stereoselectivity was observed (95:5 or greater) in all

three examples, with the dominant isomer having the

carbon substituent distal to the PMe₃and trans to the

tungsten. 2D NMR data was used to assign all three

structures (16-18D) and that of 16D was confirmed

Figure 3. SC-XRD molecular structure of 15 (50% ellipsoids).

Me₃P

CF₃

H

NO

Me₃P

NO

through a SC-XRD analysis.

NO

CF₃

H

CF₃

W

HOTf

MeCN

Tp

O

W

Tp

N

H₂

-30 °C

OMe

1. DPhAT

2. TBSME

+

HN

H₂N

I

[W]

H

6

H

OMe

H

[W]

{TMS⁺

acetone

(+ H⁺)

EtCN, -60ºC

}

1. CH₃CN

2. Et₃N

PMe₃

59%

Bu₄NOMe

O

Me₃P

NO

98:2

16P

NO

W

CF₃

H

16D (SC-XRD)

Tp

W

Tp

SiMe₃

1

O

Me₃P

1. DPhAT

2. NaCN

CN

N

HN

CF₃

II

CF₃

+

H

Me₃P

W

[W]

Tp

H

MeCN, -30ºC

NO

[W]

W

61%

Tp

NHMe

CN

N

H

Me₃P

N

17P

17D

96:4

CF₃

NO

O

C

W

HN

Me

Tp

13

V

{H⁺}

O

PMe₃

III

CF₃

H

NO

OMe

H

+

1. HOTf

2. MMTP

W

CF₃

[W]

Tp

Me₃P

NH

Me₃P

NH

NO

CF₃

- H⁺

NO

H

[W]

NO

CF₃

5

CF₃

W

MeCN, -30ºC

OMe

W

Tp

W

CF₃

Tp

79%

Tp

O

18D

18P

Me

>95:5

N

IV

N

H

Me

15 (SC-XRD)

14 (SC-XRD)

16D

14

Scheme 5. Protonation and addition of carbon nucleophiles to

dihapto-coordinated arene complexes. Bottom: SC-XRD molecular

structure of 16D (50% ellipsoids). (DPhAT = diphenylammonium

Scheme 4. Rearrangement, elimination, and nucleophilic addition

reactions observed for the aminodiene complex 6. Bottom: SC-XRD

molecular structure of 14 (50% ellipsoids)

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triflate; TBSME

MMTP = ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane).

=

tert-butyl((1-methoxyvinyl)oxy)dimethylsilane;

Me₃P

CF₃

Me₃P

NO

CF₃

NO

W

OMe

O

W

Tp

W

Tp

HOTf

Tp

The addition of amines to the diene complexes 16-18

follow a general pattern. Here we will focus on the

trifluorotoluene examples, which lead to cyclohexene

complexes with three stereocenters in the ring.

Protonation of the diene occurs at the terminal position

of the h²-diene ligand, which in this case is the carbon

bearing a CF₃substituent. While we speculate that initial

protonation is trans to the metal,^[14]this process is likely

reversible and protonation ultimately occurs cis to the

tungsten in order to avoid a CF₃-nitrosyl steric interaction

(vide supra). The purported allyl intermediate exists as

four conformations, including two different distortions of

the allyl framework (19P and 19D). DFT calculations

indicate that the boat form of 19D is favored over the

chair-like form by 15.0 kcal/mol, while proximal

conformations (19P) are energetically uncompetitive.

Correspondingly, amines appear to first add to 19D to

form II (Scheme 6). Subsequent deprotonation of the

amine results in compounds of the type IV, which can be

isolated provided that they are kept in a basic

environment. In several cases (20-22), one of the isomers

spontaneously crystallized from CH₃CN solution in pure

form. However, even in the presence of an excess of

amine, the ammonium salt byproduct resulting from the

reaction of HOTf and the amine was sufficient to allow the

re-protonation of IV to form II. Rearrangement of the

latter to type I and its deprotonation to III resulted in the

species 20-22P. SC-XRD analysis was performed on three

examples, (20P, 21D, 22D; e.g., as shown in Figure 4)

confirming the structures of these 3,4,6-trisubstituted

cyclohexene complexes. Proton NMR data confirmed that

these complexes in solution were often mixtures of the D

and P isomers, even when starting with crystalline

material. However, these allyl amine ligands were much

more stable once the metal was removed. An example is

shown for 20P, which upon oxidation by [FeCp₂]PF₆yields

the organic compound, 20-O (Scheme 6).

OMe

O

19D

18

19P

HNR₂

Me₃P

CF₃

NHR₂

Me₃P

NO

CF₃

OMe

O

W

Tp

N

CF₃

OMe

NHR₂

II

I

O

base

CF₃

base

OMe

O

Me₃P

NR₂

NO

CF₃

20-O

OMe

O

W

Tp

[FeCp₂]⁺

OMe

NR₂

IV

III

O

N

O

N

CF₃

[W]

OMe

O

21P

22P

20P (SC-XRD)

CF₃

OMe

O

OMe

[W]

O

N

O

N

22D (SC-XRD)

21D (SC-XRD)

20D

Scheme 6. The stereoselective preparation of 3,4,6-trisubstituted

cyclohexene complexes.

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R²

OMe

[W]

O

R¹

OMe

1

R^{1 R}

III

I

O

II

H₂NR³

NHR³

R²

MeO

R²

[W]

O

[W]

R¹

[W]

R¹

OMe

R¹

R³N

NHR³

IV

VI

R¹

O

V

O

CF₃

[W]

H

[W]

O

X

OMe

N

O

23

O

24

X = Br: 25 (SC-XRD)

X = Cl: 26 (SC-XRD)

Scheme 7. The stereoselective preparation of cis-fused bicyclic-g-

lactams.

Given the generality of the lactam formation and the

ability to control the stereochemistry, the reaction

sequence shown in Scheme 7 provided the opportunity to

demonstrate the utility of the tungsten methodology in

natural product synthesis. The lycorines are an abundant

class of tetra- and pentacyclic molecules that are part of

the Amaryllidaceae alkaloids family.^[22]They are of

interest for their diverse biological activity including

inhibition of growth and cell division, treatment of

Alzheimer’s disease, and antitumor activity. They also are

a popular target of synthetic chemists due to their

complex structure and multiple stereocenters. Although

g-lycorane, (27) is not as pharmacologically active as some

of its more oxidized cousins, it has been a popular target

for demonstrating new synthetic methodologies. The

first asymmetric synthesis of g-lycorane was reported by

Mori in 1995,^[23]and its structure is considered

prototypical for this important class of alkaloids. In just

the past five years, well over a dozen new syntheses of

the lycorine family have appeared.^[24-37]Of these only one

uses a benzene ring as the source of the C ring, which

contains all of the stereocenters. Baudoin et al. reported

a double C-H arylation of an acetanilide derivative

followed by arene hydrogenation.^[26]Given that all the

Figure 4. SC-XRD molecular structures (50% ellipsoids) of 20P (top) and

22D (bottom): trisubstituted cyclohexene complexes derived from

piperidine and imidazole.

When the diene ester complexes (I Scheme 7) are

protonated and subsequently treated with a primary

amine, what initially is a mixture of products resolves into

one dominant compound in which the amine and ester

form a bicyclic g-lactam. This reaction appears to be

general, occurring with a wide range of amine, ester, and

arene precursors, and in all cases

a cis-fused

hexahydroindole core is formed. Four examples^[15]are

provided in Scheme 7 and two molecular structures

derived from SC-XRD studies (25, 26) are provided in the

SI. As with the case of simple amine additions, the final

stereochemistry of the CF₃group is always trans to the

tungsten, placing it in the concave side of the bicyclic

lactam core.

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carbons in a benzene ring are unsaturated and that so of a C=O stretching frequency in the IR absorption

many benzene derivatives are commercially available, spectrum to 1678 cm^-1, consistent with amide formation.

approaches that utilize a benzene precursor as the C-ring At this stage, the mild one-electron oxidant [FeCp₂]PF₆

could offer considerable diversity for medicinal chemists was added to a solution of 28. Oxidation of the tungsten

interested in exploring this scaffold. Our proposed route dramatically reduces backbonding to the cyclohexene

took advantage of the ability of benzene complex 1, ligand and induces the release of 32. Crystals of 32 were

available on a 9 g scale,^[38]and as either enantiomer,^[39]to grown from an ethyl acetate/CH₂Cl₂/ether (1:3:2)

undergo an efficient sequence of reactions leading to the solution. A SC-XRD determination (see Scheme 9)

requisite cis-fused lactam (Scheme 8). Use of the confirms the molecular structure and stereochemistry of

appropriate benzylamine in the lactamization would set the lactam 32, which was originally reported in Mori’s

the stage for a Heck coupling and hydrogenation to form landmark paper as an advanced intermediate in the

synthesis of g-lycorane.^[23]

the desired product (27).

Demetallation

Heck Coupling

Hydrogenation

H

[W]

H

Br

NH₂

H

O

H

[W]

O

[W]

Br

H

N

OMe

29

O

OMe

MeO

O

16

(+/-) γ-lycorane (27)

O

28

O

30P

30D

O

1,4-addition

1,2-addition

O

[W]

1

Br

[W]

O

[W]

Br

H

[W]

Br

H

TBSO

NH₂

+

OMe

-MeOH

OMe

FeCp₂

71%

16

29

H

O

NH

O

N

OMe

O

Scheme 8. Retrosynthetic analysis for the preparation of g-lycorane.

28

(69% from 16)

31

Our synthesis (Scheme 9) commenced with the diene

16 prepared from benzene complex 1 and the TBS-

protected enolate of methyl acetate. Treatment of the

h²-diene 16 with an acetonitrile solution of triflic acid

results in conversion to the h²-allyl complex 30P, which as

described above, exists in equilibrium with its

thermodynamically favored conformational isomer

30D.^[20]In line with our earlier results, benzylamine 29

(prepared from piperonal)^[40]purportedly reacts

selectively with 30D to form the 3-aminocyclohexene

complex 31. Addition of an excess of DBU ensures that

the allyl amine will not eliminate in the presence of

residual acid (via E1) nor isomerize to the potentially

more stable 3,6-disubstituted cyclohexene complex (via

30P). Continued stirring of the reaction mixture over

several days promoted the desired lactamization and

crystals of complex 28 precipitated out of solution (69%

from 16). A full 2D NMR analysis and SC-XRD analysis

confirms that 28 was formed from the addition of the

benzylamine anti to the metal with subsequent loss of the

methoxy group. Key spectroscopic features include the

loss of a methoxy group in the proton NMR and the shift

H

Br

H

O

N

O

32

Scheme 9. Preparation of the lactam 32, an advanced precursor to g-

lycorane (racemic).

To demonstrate the versatility of this method, we took

advantage of the stereogenic tungsten center, which

retains its configuration even through ligand exchange.

Thus, in principle any of these compounds can be

prepared enantioselectively, starting from the desired

enantiomer of the benzene complex 1. Given that the

naturally occurring form of the alkaloid ((+)-g-lycorane)

has a 3aR, 3a’S, 12bR configuration, the desired form of 1

was the S configuration. In a previous report,^[39]we have

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shown that either form of 1 is available starting from the The biggest potential advantage of the present approach

appropriate dibenzoyltartaric acid salt of to lycorane is the ability to readily exchange the benzene

dimethoxybenzene (Scheme 10), which precipitates away substrate with other arenes. To illustrate this, the

from its diastereomeric salt in 2-butanone. In this case, sequence used to prepare the key lactam 37 (Scheme 12)

D-dibenzoyl tartarate leads to (S)-1 in ee from 90-99%, was attempted, this time starting with trifluorotoluene

depending on processing time.^[39]Using the procedures complex 5. Trifluoromethyl groups in agrochemicals and

outlined above, (S)-1 was converted into (S,R)-32 in er = pharmaceuticals have been of continued interest because

of their increased hydrolytic, oxidative, and metabolic

stability, as well as their increased bioavailability.^[41]While

numerous methods are available for installing CF₃,^[42-45]

few approaches have been described that generate CF₃-

substituted cyclohexenes from aromatic precursors.^[46]As

described earlier,^[16]protonation of the trifluorotoluene

complex (5) occurs selectively at the ortho carbon to

generate the arenium complex (Scheme 12). When this

species is treated with the silyl ketene acetal TBSME,

addition occurs smoothly at C3 to generate the diene

complex 35. Thermodynamics favors protonation of the

diene such that the CF₃group is trans to the tungsten, and

addition of the benzylamine ultimately leads to lactam 37.

A single crystal of 37 was grown from MeCN solution and

the solid-state molecular structure confirms the assigned

stereochemistry (Figure 5). Unfortunately, while the

lactam 38 could be liberated from the metal, our attempts

to close the final ring by Heck coupling proved

unsuccessful.

95:5 thereby completing the formal synthesis of (+)-g-

lycorane (Scheme 10).

PMe₃

W_S

PMe₃

W_S

Me₃P

W_S

Tp

=

H

ON

Br

H

ON

N

Tp

NO

O

(S)-1

(S)-28

O

[FeCp₂]PF₆

H

(S)

Br

(R)

er: > 95:5

O

H

N

[α]_D= 27.5

O

(S,R)-32

Scheme 10. The preparation of enantioenriched lactam 32, a g-

lycorane precursor.

From this point, a sequence of Heck coupling, alkene

hydrogenation, and reduction of the amide produced the

target g-lycorane. As a verification, we carried out the

same sequence as reported in the literature to

generate g-lycorane. Under our unoptimized conditions,

the yield of 33% fell short of expectations (cf. 86% over 3

steps), but spectral data matched that reported for 27.

Me₃P

OTBS

NO

CF₃

H

DPhAT

-60 °C

W

OMe

W

Tp

-60 °C

H

5

Me₃P

W

H

Me₃P

W

CF₃

NO

CF₃

Tp

HOTf

H

Pd(OAc)₂

PPh₃

H

Br

H

MeO

O

OMe

O

H

N

O

50%

N

35

36

O

33

-60 °C

-MeOH

32

29

Pd/C

79%

H₂

H

CF₃

H

O

[W]

LAH

84%

H

+

H

FeCp₂

O

Br

H

Br

N

H

O

H

O

N

O

27

O

34

38

(+/-) γ-lycorane

37 (SC-XRD)

(6 steps; 25% from 1)

Scheme 12. The preparation of 38, the trifluoromethylated derivative

of the g-lycorane precursor lactam 32.

Scheme 11. The preparation of g-lycorane (27) from lactam 32.

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can also be accomplished in good yield. The

hydroamination of the ester-diene complex 18 results in

two different regioisomers, but when a primary amine is

used, the addition at the adjacent ring carbon leads

cleanly to bicyclic g-lactams. In order to demonstrate the

potential of this methodology in more complex synthetic

targets, benzene was incorporated as the central ring of

the pentacyclic molecule g-lycorane.

Inspired by the chemistry pioneered by Kündig,

Semmelhack, Pearson, Sweigart, Davies, and others who

earlier demonstrated the synthetic power of transition

metal arene complexes, this tungsten system offers

complementary reaction patterns to the h⁶analogs. Here

the metal acts as an electron donor, both for the arene

ligand and diene species prepared from the arene

complex. The ability to add amines, alkoxides, protected

enolates, and cyanide under mild conditions allows the

formation of up to three stereocenters to be prepared

from carbons of the initial arene ring, with the product

being potentially accessible in enantio-enriched form.^[39]

Experimental Section

General Methods

NMR spectra were obtained on 500, 600 or 800 MHz

spectrometers. Chemical shifts are referenced to

tertramethylsilane (TMS) utilizing residual ¹H or ¹³C

signals of the deuterated solvents as internal standards.

Phosphorus NMR signals are referenced to 85% H₃PO₄(δ

0.00) using a triphenyl phosphate external standard (δ

−16.58). Chemical shifts are reported in ppm and coupling

constants (J) are reported in hertz (Hz). Infrared Spectra

(IR) were recorded on a spectrometer as a glaze on a

diamond anvil ATR assembly, with peaks reported in cm^-

¹. Electrochemical experiments were performed under a

nitrogen atmosphere. Most cyclic voltammetric data

were recorded at ambient temperature at 100 mV/s,

unless otherwise noted, with a standard three electrode

cell from +1.8 V to -1.8 V with a platinum working

electrode, N,N-dimethylacetamide (DMA) or acetonitrile

solvent, and tetrabutylammonium hexafluorophosphate

(TBAH) electrolyte (~1.0 M). All potentials are reported

versus the normal hydrogen electrode (NHE) using

cobaltocenium hexafluorophosphate (E_1/2= -0.78 V, -1.75

V) or ferrocene (E_1/2= 0.55 V) as an internal standard. Peak

separation of all reversible couples was less than 100 mV.

All synthetic reactions were performed in a glovebox

under a dry nitrogen atmosphere unless otherwise noted.

Figure 5. SC-XRD molecular structures (50% ellipsoids) of 28, an

advanced intermediate toward g-lycorane (27), and the

trifluoromethylated analog 37.

Conclusions

The coordination of the tungsten complex

WTp(NO)(PMe₃) to benzene or substituted benzenes

activates the aromatic ligand toward protonation. Much

like the venerable [Fe(CO)₃(C₆H₇)]⁺complex of Birch et

al.,^{[10, 47]}the addition of an amine nucleophile completes

the hydroamination of the benzene ligand with good

control of the regio- and stereochemistry. Carbon

nucleophiles can also be added to the arenium

intermediate to generate dihapto-coordinated diene

complexes, and hydroamination of these diene ligands

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All solvents were purged with nitrogen prior to use. was still cold, 1M tBuOK in tert-butanol (3.1 mL, 3.1

Deuterated solvents were used as received from mmol) was added, and then the reaction solution was put

Cambridge Isotopes. NMR assignments of all compounds back in the freezer at –30°C for 15 min. The reaction was

were determined using 2D NMR methods including then transferred to a filter flask and evaporated in vacuo

NOESY, COESY, HMBC, and HSQC. When possible, to ~half volume. Precipitation was then induced by adding

pyrazole (Pz) protons of the (trispyrazolyl) borate (Tp) H₂O (20 mL), and the resulting pale yellow solid was

ligand were uniquely assigned (e.g., “PzB3”) using two- collected on a 15 mL fine porosity fritted disc, washed

dimensional NMR data (see Figure 1). If unambiguous with H₂O (1 mL), acetonitrile (1 mL), and pentane (2 x 5

assignments were not possible, Tp protons were labeled mL) then desiccated overnight, yielding 6 (350 mg, 0.515

as “Pz3/5 or Pz4”. All J values for Pz protons are 2 (±0.4) mmol, 67% yield). CV (DMAc) E_p,a= +0.70 V (NHE). IR:

Hz. BH peaks (around 4-5 ppm) in the ¹H NMR spectra are ν(BH) = 2487 cm^-1, ν(NO) = 1565 cm^-1. Anal. Calc’d for

not assigned due to their quadrupole broadening; C₂₀H₂₉BF₃N₈OPW: C, 35.32; H, 4.30; N, 16.48. Found: C,

however, confirmation of the BH group is provided by IR 35.59; H, 4.21; N, 16.20. ³¹P NMR (d⁶-DMSO, δ): -11.10

1

data (around 2500 cm^-1). High resolution electrospray (J_WP= 279). H NMR (CD₃CN, δ): 8.05 (d, 1H, PzB3), 7.98

ionization mass spectrometry (ESI-MS) analyses were (d, 1H, PzA3), 7.86 (t, 2H, PzB5 & PzC5), 7.77 (d, 1H, PzA5),

taken on an Agilent 6545B Q-TOF LC/MS using purine and 7.44 (d, 1H, PzC3), 7.16-7.20 (m, 1H, H2), 6.37 (t, 1H,

hexakis(1H, 1H, 3H-tetrafluoropropoxy)phosphazine as PzB4), 6.29 (overlapping t, 2H, PzA4 & PzC4), 3.52 (dm, J

internal standards. Samples were dissolved in MeCN and = 5.3, 1H, H5), 2.75-2.83 (m, 1H, H3), 2.71 (dm, J = 16.5,

eluted with a MeCN/H₂O solution containing 0.1% formic 1H, H6x), 2.33 (buried, 1H, H6y), 2.32 (s, 3H, NMe), 1.36

acid. The enantiomer ratios of (R,S)-32 and (S,R)-32 were (dm, J = 9.7, 1H, H4), 1.22 (d, J = 8.6, 9H, PMe₃). ¹³C NMR

determined using chiral HPLC with a Chiralpak IC-3 (CD₃CN, δ): 144.5 (PzB3), 143.2 (PzA3), 141.9 (PzC3),

column. Compound 1,^[48]2,3,^[14]4,^[15]5,^[16]10,^[49]17,^[15]138.0 (PzC5), 137.4 (PzB5), 137.1 (PzA5), 136.8 (m, C2),

18,19,^[16]23, 24,^[15]and 29^[40]were reported previously.

126.8 (q, J = 268.6, CF₃), 115.8 (q, J = 29.5, C1), 107.5 (Pz4),

Ground-state structures were optimized at the M06 level 107.2 (Pz4), 106.9 (Pz4), 60.2 (C4), 58.3 (C5), 47.6 (d, J =

of theory using the 6-31G**[LANL2DZ for W] basis set in 9.6, C3), 34.7 (NMe), 26.1 (C6), 13.8 (d, J = 29.0, PMe₃).

Gaussian 16. Previous literature demonstrates that this

functional and basis set choice accurately corroborates

experimental results. Vibrational frequency analysis

verified that optimized structures were minima, and rigid- Compound 7. To a 4-dram vial charged with a stir pea

rotor-harmonic-oscillator thermochemical chemical were added 5 (100 mg, 0.154 mmol) followed by

corrections were applied at 298 K and 1 atm utilizing acetonitrile (1 mL, -30°C) and a 1M solution of HOTf in

Gaussian's default implementation. When solvent acetonitrile (0.23 mL, 0.23 mmol, -30°C), resulting in a

homogeneous golden solution, which was allowed to sit

for 20 min at –30°C. 4-Chlorobenzylamine (370 mg, 2.61

mmol, –30°C) was added with stirring, and then the

reaction solution was allowed to sit at –30°C for 19 h.

While the reaction was still cold, 1M tBuOK in tert-butanol

(0.62 mL, 0.62 mmol) was added, and then the reaction

solution was put back in the freezer at -30°C for 10 min.

The reaction was diluted with H₂O (10 mL), and extracted

with Et₂O (10 mL). The organic layer was then evaporated

in vacuo. The film was redissolved in minimal THF and

added to stirring pentane (20 mL), which resulted in an

oil. The liquid was decanted off, and the oil was

redissolved in THF and added to pentane (20 mL). The

resulting pale yellow solid was collected on a 15 mL fine

porosity fritted disc, washed with pentane (2 x 5 mL) then

desiccated overnight, yielding 7 (45 mg, 0.057 mmol, 37%

corrections were applied to estimate DG_solv, optimization

and frequency calculations were performed using the

SMD continuum solvent model with the appropriate

solvent's parameters from Gaussian.

Procedures

Compound 6. To a 4-dram vial charged with a stir pea

were added 5 (500 mg, 0.770 mmol) followed by

acetonitrile (2 mL, –30°C) and a 1M solution of HOTf in

acetonitrile (1.54 mL, 1.54 mmol, –30°C), resulting in a

homogeneous golden solution, which was allowed to sit

for 15 min at –30°C. 2M H₂NMe/THF (3.85 mL, 7.70 mmol,

–30°C) was then added to the reaction vial with stirring

and allowed to sit at –30°C for 2.5 h. While the reaction

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Helvetica Chimica Acta

yield). IR: ν(BH)= 2487 cm^-1, ν(NO) = 1561 cm^-1. Anal. 137.0 (PzA5), 136.6 (m, C2), 126.6 (q, J = 269.5, CF₃), 117.4

Calc’d for C₂₆H₃₂BClF₃N₈OPW: C, 39.50; H, 4.08; N, 14.17. (q, J = 29.0, C1), 107.3 (PzB4), 107.1 (PzC4), 106.6 (PzA4),

Found: C, 39.00; H, 3.89; N, 13.86. ¹H NMR (d⁶-acetone, 68.2 (2C, C2’ & C6’), 62.2 (C5), 52.6 (C4), 50.2 (2C, C3’ &

δ): 8.12 (d, 1H, Pz3/5), 7.97 (d, 1H, Pz3/5), 7.95 (d, 1H, C5’), 49.6 (d, J = 9.5, C3), 22.5 (C6), 13.8 (d, J = 28.6, PMe₃).

Pz3/5), 7.89 (d, 1H, Pz3/5), 7.82 (d, 1H, Pz3/5), 7.61 (d, 1H, A SC-XRD study confirms the assigned structure.

Pz3/5), 7.31 (d, J = 8.4, 2H, Ar-H), 7.25 (d, J = 8.4, 2H, Ar-

H), 7.21-7.23 (m, 1H, H2), 6.40 (t, 1H, Pz4), 6.35 (t, 1H,

Pz4), 6.25 (t, 1H, Pz4), 3.82 (d, J = 13.6, 1H, H7x), 3.78 (d,

J = 13.6, 1H, H7x), 3.77 (buried, 1H, H5), 2.7-2.9 (m, 2H, Compound 9.

H3 & H6x), 2.45 (d, J = 16.5, 1H, H6y), 1.55 (d, J = 9.6, 1H,

H4), 1.30 (d, J = 8.5, 9H, PMe₃). ¹³C NMR (d⁶-acetone, δ): To a 4-dram vial charged with a stir pea were added 5 (200

144.4 (Pz3), 142.8 (Pz3), 142.0 (Pz3), 141.8 (Ar-C), 137.8 mg, 0.31 mmol) followed by acetonitrile (2 mL, -30°C) and

(Pz5), 137.2 (Pz5), 136.8 (m, C2), 136.7 (Pz5), 132.2 (Ar-C), a 1M solution of HOTf in acetonitrile (0.46 mL, 0.46 mmol,

130.6 (2C, Ar-C), 128.8 (2C, Ar-C), 126.6 (q, J = 268.7, CF₃), -30°C), resulting in a homogeneous golden solution,

115.7 (q, J = 29.6, C1), 107.3 (Pz4), 107.1 (Pz4), 106.5 which was allowed to sit for 15 min at -30°C. 2-

(Pz4), 60.5 (C4), 55.9 (C5/C5’), 51.4 (C5/C5’), 47.4 (d, J = Picolylamine (665 mg, 6.15 mmol, –30°C) was added with

9.6, C3), 26.4 (C6), 13.8 (d, J = 28.6, PMe₃).

stirring, and then the reaction solution was allowed to sit

at –30°C for 16 h. While the reaction was still cold, 1M

tBuOK in tert-butanol (1.23 mL, 1.23 mmol) was added.

Precipitation was then induced by adding H₂O (10 mL) to

Compound 8. To a 4-dram vial charged with a stir pea the reaction solution with stirring, and the resulting pale

were added 5 (200 mg, 0.308 mmol) followed by yellow solid was collected on a 15 mL fine porosity fritted

acetonitrile (2 mL, –30°C) and a 1M solution of HOTf in disc, washed with H₂O (2 x 5 mL) and pentane (2 x 5 mL)

acetonitrile (0.46 mL, 0.46 mmol, –30°C), resulting in a then desiccated overnight, yielding 9 (198 mg, 0.26 mmol,

homogeneous golden solution, which was allowed to sit 85% yield). ¹H NMR (CD₃CN, δ): 8.40 (d, J = 4.6, 1H, Ar-H),

for 20 min at –30°C. Morpholine (416 mg, 4.78 mmol) was 8.04 (d, 1H, Pz3/5), 7.86 (bs, 3H, Pz3/5), 7.75 (d, 1H,

added with stirring, and then the reaction solution was Pz3/5), 7.6-7.7 (m, 1H, Ar-H), 7.43 (d, 1H, Pz3/5), 7.29 (d,

allowed to sit at –30°C for 17 h. While the reaction was J = 7.9, 1H, Ar-H), 7.2-7.3 (m, 1H, Ar-H), 7.10-7.14 (m, 1H,

still cold, 1M tBuOK in tert-butanol (1.23 mL, 1.23 mmol) Ar-H), 6.36 (t, 1H, Pz4), 6.29 (t, 1H, Pz4), 6.21 (t, 1H, Pz4),

was added. Precipitation was then induced by adding H₂O 3.83-3.87 (m, 2H, CH₂N), 3.74 (bs, 1H, H5), 2.81-2.85 (m,

(6 mL) to the reaction solution with stirring, and the 1H, H3), 2.76 (d, J = 16.6, 1H, H6x), 2.37 (d, J = 16.6, 1H,

resulting pale yellow solid was collected on a 15 mL fine H6y), 1.36 (d, J = 9.7, 1H, H4), 1.22 (d, J = 8.6, 9H, PMe₃).

porosity fritted disc, washed with H₂O (2 x 3 mL), A SC-XRD study confirms the assigned structure.

acetonitrile (0.5 mL), and pentane (3 x 5 mL) then

desiccated overnight, yielding 8 (193 mg, 0.262 mmol,

85% yield). IR: ν(BH) = 2487 cm^-1, ν(NO) = 1559 cm^-1. Anal. Compound 11.

Calc’d for C₂₃H₃₃BF₃N₈O₂PW: C, 37.52; H, 4.52; N, 15.22. Compound 10 (0.100 g, 0.138 mmol) and MeCN were

Found: C, 37.48; H, 4.60; N, 15.17. ³¹P NMR (d⁶-acetone, combined in a test tube to form an orange heterogeneous

δ): -11.74 (J_WP= 282). ¹H NMR (d⁶-acetone, δ): 8.11 (d, 1H, solution. Morpholine (0.18 mL, 0.18 g, 2.07 mmol) was

PzB3), 8.06 (d, 1H, PzA3), 7.97 (d, 1H, PzC5), 7.95 (d, 1H, added to a second test tube. Both solutions were cooled

PzB5), 7.84 (d, 1H, PzA5), 7.71 (d, 1H, PzC3), 7.10-7.17 (m, to 0 °C for 15 min. 1M HOTf/MeCN (0.21 mL, 0.210 mmol)

1H, H2), 6.40 (t, 1H, PzB4), 6.36 (t, 1H, PzC4), 6.30 (t, 1H, was added to the reaction. Upon addition, the reaction

PzA4), 4.00 (d, J = 7.7, 1H, H5), 3.52 (t, J = 4.5, 4H, H2’ & became a dark red, homogeneous mixture. After 15

H6’), 3.00-3.10 (m, 1H, H3), 2.83 (buried, 1H, H6x), 2.75- minutes, the reaction was added to the cooled

2.85 (m, 2H, H3’/H5’), 2.51 (dt, J = 11.3, 4.5, 2H, H3’/H5’), morpholine test tube. The reaction was stirred overnight

2.37 (d, J = 17.5, 1H, H6y), 1.32 (buried, 1H, H4), 1.30 (d, J for 16 hrs. While the reaction was still in the cold probe,

= 8.5, 9H, PMe₃). ¹³C NMR (d⁶-acetone, δ): 144.5 (PzB3), 1M tBuOK in tert-butanol (0.55 mL, 0.55 mmol) was

142.3 (PzA3), 142.0 (PzC3), 137.8 (PzC5), 137.2 (PzB5), added to the reaction and allowed to stir for an hour. The

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Helvetica Chimica Acta

reaction was warmed to room temperature and removed removed from the glove box and the white solid was

from the glovebox. The reaction was diluted with 30 mL isolated on a 15 mL fine frit. The solid was washed with 5

of H₂O and washed with 40 mL DCM. The aqueous layer mL H₂O followed by hexanes (2 x 15 mL) and desiccated

was back extracted with DCM (25mL). The organic layers overnight yielding 12 (0.063 g, 0.078 mmol, 57 %). CV

were combined and dried over MgSO₄before being (MeCN) E_p,a= +0.71 V (NHE). IR: ν(BH) = 2488 cm^-1, ν(NO)

evaporated to dryness. The film was washed with hexanes = 1574 cm^-1, ν(SO) = 1406 cm^-1. Anal. Calc’d for

and then ether. The remaining film was picked up in ethyl

acetate and ran through a 30 mL basic alumina plug with

100 mL of ethyl acetate. The resulting filtrate was

evaporated to dryness, pick up in minimal DCM, and

crashed out into 50 mL of stirring pentane. The resulting

brown precipitant was collected on a 15 mL fine porosity

fritted disc, washed with ether (2 x 10 mL) and hexanes (3

x 10 mL), and desiccated to yield 11 (0.075 g, 0.093 mmol,

67%). CV (MeCN) E_p,a= +0.77 V (NHE). IR: ν(BH) = 2484

cm^-1, ν(NO) = 1573 cm^-1, ν(SO) = 1407 cm^-1. Anal. Calc’d

for C₂₈H₃₈BN₈O₄PSW: C, 41.60; H, 4.74; N, 13.86. Found:

C₂₉H₄₀BN₈O₃PSW‧H₂O: C, 42.25; H, 5.14; N, 13.59. Found:

C, 42.22; H, 4.86; N, 13.53. ¹H NMR (CD₃CN, δ): 8.00 (1H,

d, TpB3), 7.94 (1H, d, TpA3), 7.87-7.91 (2H, m, H17, H13),

7.86 (1H, d, TpC5), 7.84 (1H, d, TpB5), 7.82 (1H, dd J = 6.0,

2.7, H2), 7.76 (1H, d, TpA3), 7.55-7.59 (1H, m, H15), 7.51-

7.53 (3H, m, TpC3, H16, H14), 6.35 (1H, t, TpB4), 6.31 (1H,

t, TpC4), 6.24 (1H, t, TpA4), 3.90 (1H, d J = 8.0, H5), 3.02-

3.06 (1H, m, H3), 2.65 (1H, dd J = 17.7, 8, H6a), 2.4-2.5

(4H, m, H11, H7), 2.38 (1H, d J = 17.7, H6b), 1.26 (9H, d J

= 8.6, PMe₃), 1.2-1.3 (4H, m, H10, H8), 1.1-1.2 (3H, m, H9,

H4). ¹³C NMR (CD₃CN, δ): 146.7 (1C, C2), 144.6 (1C, TpB3),

C, 41.54; H, 4.69; N, 13.66. ¹H NMR (CD₃CN, δ): 8.00 (1H, 143.3 (1C, C12), 142.4 (1C, TpA3), 142.1 (1C, TpC3), 138.1

d, TpB3), 7.93 (1H, d, TpA3), 7.8-7.9 (2H, m, H16, H12), (1C, TpC5), 137.5 (2C, TpA5, TpB5), 133.3 (1C, C15), 129.8

7.86 (1H, d, TpC5), 7.85 (1H, d, TpB5), 7.84 (1H, dd J = 6.0, (2C, C16, C14), 138.7 (2C, C17, C13), 128.4 (1C, C1), 107.5

2.6, H2), 7.76 (1H, d, TpA5), 7.55-7.59 (1H, m, H14), 7.53 (1C, TpB4), 107.3 (1C, TpC4), 106.9 (1C, TpA4), 62.7 (1C,

(1H, d, TpC3), 7.5-7.6 (2H, m, H15, H13), 6.35 (1H, t, TpB4), C5), 53.7 (1C, C4), 51.3 (1C, C3), 50.31 (2C, C11, C7), 27.43

6.31 (1H, t, TpC4), 6.24 (1H, t, TpA4), 3.86 (1H, d J = 7.3, (2C, C10, C8), 25.62 (1C, C9), 23.8 (1C, C6) 14.0 (3C, d J =

H5), 3.30-3.35 (4H, m, H10, H8), 3.03-3.07 (1H, m, H3), 28.6, PMe₃).

2.69 (1H, dd J = 17.1, 7.7, H6a), 2.5-2.6 (2H, m, H9/H7),

2.43 (1H, d J = 17.1, H6b), 2.10-2.14 (2H, m, H9/H7), 1.25

(9H, d J = 8.5, PMe₃), 1.17 (1H, d J = 9.5, H4). ¹³C NMR Compound 13. To a 4-dram vial charged with a stir pea

(CD₃CN, δ): 146.8 (1C, C2), 144.6 (1C, TpB3), 143.3 (1C, were added 6 (30 mg, 0.044 mmol), followed by

C11), 142.5 (1C, TpA3), 142.1 (1C, TpC3), 138.2 (1C, TpC5), acetonitrile (0.6 mL, –30°C), and a 1M solution of HOTf in

137.6 (1C, TpB5), 137.5 (1C, TpA5), 133.3 (1C, C14), 129.8 acetonitrile (0.11 mL, 0.11 mmol, –30°C), resulting in a

(2C, C15, C13), 138.7 (2C, C15, C12), 128.0 (1C, C1), 107.6 homogeneous golden solution, which was allowed to sit

(1C, TpB4), 107.3 (1C, TpC4), 106.9 (1C, TpA4), 68.0 (2C, for 20 min at –30°C. 1M Bu₄NOH/MeOH (0.66 mL, 0.66

C10, C8), 62.5 (1C, C5), 53.2 (1C, C4), 51.2 (1C, C3), 50.0 mmol, –30°C) was then added to the reaction vial with

(2C, C9, C7), 24.4 (1C, C6), 14.9 (3C, d J = 29.0, PMe₃).

stirring, and the reaction was allowed to sit at –30°C for

19 h. The reaction was evaporated in vacuo to ~half

volume then diluted with H₂O (10 mL) and extracted with

Et₂O (10 mL). The organic layer was then dried over

MgSO₄and evaporated in vacuo to dryness. The film was

Compound 12.

Compound 10 (0.100 g, 0.138 mmol) and MeCN were redissolved in minimal THF and added to stirring pentane

combined in a test tube to form an orange heterogeneous (15 mL, –30°C), which resulted in an oil. The solution was

solution. Piperidine (0.18 mL, 0.18 g, 2.07 mmol) was again evaporated in vacuo to dryness, redissolved in THF

added to a second test tube. Both solutions were cooled and added to pentane (15 mL, –30°C). The resulting pale

to 0 °C for 15 min. 1M HOTf/MeCN (0.21 mL, 0.210 mmol) yellow solid was filtered on a 15 mL fine porosity fritted

was added to the reaction. Upon addition, the reaction disc and discarded. The filtrate was cooled to –30°C

became a dark red, homogeneous mixture. After 15 overnight, resulting in the precipitation of a crystalline

minutes, the reaction was added to the cooled piperidine solid. The solid was collected on a 15 mL fine porosity

test tube. The reaction was stirred overnight for 16 hrs. A fritted disc, rinsed with pentane (2 mL, –30°C) then

white precipitant formed overnight. The test tube was desiccated overnight, yielding 13 (10 mg, 0.014 mmol,

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32% yield). CV (DMAc) E_p,a= +0.51 V (NHE). IR: ν(BH) = vacuo to dryness. The film was re-dissolved in minimal

2493 cm^-1, ν(NO) = 1549 cm^-1. ³¹P NMR (CD₃CN, δ): -11.82 DCM and added to stirring Et₂O (25 mL). The resulting pale

(J_WP= 283). ¹H NMR (CD₃CN, δ): 8.05 (d, 1H, PzB3), 7.87 (d, solid was collected on a 15 mL fine porosity fritted disc,

1H, PzC5), 7.86 (d, 1H, PzB5), 7.77 (d, 1H, PzA5), 7.72 (d, washed with pentane (2 x 3 mL) and desiccated overnight,

1H, PzA3), 7.33 (d, 1H, PzC3), 6.36 (t, 1H, PzB4), 6.30 (t, yielding 15 (43 mg, 0.11 mmol, 66% yield). IR: ν(BH) =

1H, PzC4), 6.29 (t, 1H, PzA4), 4.00-4.02 (m, 1H, H4), 3.72- 2496 cm^-1, ν(NO) = 1548 cm^-1. ³¹P NMR (d⁶-acetone, δ): -

1

3.74 (m, 1H, H1), 3.11 (s, 3H, OMe), 3.09 (ddd, J = 12.3, 11.39 (J_WP= 277). H NMR (d⁶-acetone, δ): 9.02 (bs, 1H,

4.0, 2.6, 1H, H5), 2.73 (ddd, J = 13.6, 11.0, 2.3, 1H, H2), NH), 8.19 (d, 1H, PzB3), 8.08 (d, 1H, PzA3), 8.01 (d, 1H,

2.45 (s, 3H, NMe), 1.67 (ddd, J = 11.8, 7.4, 4.0, 1H, H6x), PzC5), 7.99 (d, 1H, PzB5), 7.88 (d, 1H, PzA5), 7.65 (d, 1H,

1.51 (q, J = 12.1, 1H, H6y), 1.30 (d, J = 11.0, 1H, H3), 1.13 PzC3), 6.45 (t, 1H, PzB4), 6.39 (t, 1H, PzC4), 6.32 (t, 1H,

(d, J = 8.5, 9H, PMe₃). ¹³C NMR (CD₃CN, δ): 145.0 (PzB3), PzA4), 5.62 (d, J = 12.5, 1H, H3a), 4.39 (dd, J = 12.5, 7.2,

144.7 (PzA3), 142.2 (PzC3), 138.0 (PzC5), 137.7 (2C, PzA5 1H, H7a), 3.47-3.53 (m, 1H, H6), 3.19 (s, 3H, NMe), 2.50-

& PzB5), 132.4 (q, J = 279.3, CF₃), 107.6 (PzB4), 107.3 2.54 (m, 2H, H5 & H7x), 2.33 (s, 3H, C2-Me), 2.16 (d, J =

(PzA4/PzC4), 107.0 (PzA4/PzC4), 81.6 (C4), 56.9 (OMe), 17.1, 1H, H7y), 1.24 (d, J = 8.5, 9H, PMe₃), 1.21 (buried,

55.9 (C3) 55.3 (C5), 43.6 (q, J = 24.0, C1), 42.9 (d, J = 12.5, 1H, H4). ¹³C NMR (d⁶-acetone, δ): 165.6 (CN), 144.5

C2), 34.0 (NMe), 26.2 (m, C6), 13.6 (d, J = 28.8, PMe₃).

(PzB3), 143.2 (PzA3), 142.1 (PzC3), 138.4 (PzC5), 137.7

(PzA5), 137.6 (PzB5), 132.0 (q, J = 281.7, CF₃), 107.6

(PzB4), 107.4 (PzC4), 107.1 (PzA4), 58.3 (C7a), 57.7 (C3a),

48.2 (C4), 44.0 (d, J = 13.0, C5), 41.6 (q, J = 25.4, C6), 30.5

Compound 14. Compound 6 (11 mg, 0.016 mmol) was (NMe), 19.0 (C7), 12.8 (d, J = 28.6, PMe₃), 12.1 (C2-Me). A

1

dissolved in d⁶-acetone (0.7 mL) and monitored by H SC-XRD study confirms the assigned structure.

NMR. Over time, the peaks for 6 decreased as a new

product grew in. After 8 d, 6 had completely converted

1

to 14, and 2D NMR data was collected. H NMR (d⁶- Compound 16D: Diphenylammonium triflate (DPhAT, 870

acetone, δ): 8.11 (overlapping d, 2H, PzA3 & PzB3), 7.98 mg, 2.72 mmol) and propionitrile (13.5 mL, –30°C) were

(d, 1H, Pz5), 7.97 (d, 1H, Pz5), 7.80 (d, 1H, Pz5), 7.70 (d, added to a screw top test tube and cooled to –60°C for 30

1H, PzC3), 6.80-6.84 (m, 1H, H3), 6.41 (t, 1H, Pz4), 6.35 (t, min. The DPhAT solution was then added to a screw top

1H, Pz4), 6.28 (t, 1H, Pz4), 4.88 (dt, J = 9.6, 1.5, 1H, H2), test tube containing 1 (1.50 g, 2.58 mmol) with stirring,

3.69 (bs, 1H, H6), 3.65-3.69 (m, 1H, H1), 2.96-3.00 (m, 1H, and the resulting orange solution was stirred at –60°C for

H5), 2.64 (s, 3H, NMe), 1.57-1.61 (m, 1H, H4), 1.33 (d, J = 20 min. 1-(tert-Butyldimethylsilyloxy)-1-methoxyethene

8.4, 9H, PMe₃). A SC-XRD study of a recovered crystal (TBSME; 4.00 g, 21.7 mmol, –60°C) was then added to

from the NMR tube confirms the assigned structure.

reaction solution with stirring. The dark golden reaction

solution was stirring at -60°C for 17 h then stirred at –50°C

Compound 15. To a 4-dram vial charged with a stir pea for 7 h. The golden reaction solution was quenched with

were added compound 6 (50 mg, 0.074 mmol), Et₃N (3 mL, 21.5 mmol). A 150 mL medium porosity fritted

acetonitrile (1 mL, –30°C), and a 1M solution of HOTf in disc was filled ¾ full of silica gel and set in Et₂O. The

acetonitrile (0.18 mL, 0.18 mmol, –30°C) with stirring, reaction solution was loaded on the column and a pale

resulting in a homogeneous golden/orange solution, yellow band was eluted with 300 mL of Et₂O. The filtrate

which was allowed to sit for 15 min at –30°C. To this was evaporated in vacuo, then re-dissolved in minimal

solution was added MMTP (107 mg, 0.614 mmol, -30°C). THF and added to 40 mL stirring pentane (–30°C). The

After 14 h at –30°C, Et₃N (72 mg, 0.71 mmol) was added resulting pale yellow solid was collected on a 30 mL fine

to the reaction solution with stirring, then the reaction porosity fritted disc, washed with pentane (2 x 5 mL) and

was left at –30°C for 6 h. The reaction was then warmed desiccated, yielding 16D (1.02 g, 1.53 mmol, 59% yield. CV

to room temperature and monitored by ³¹P NMR. After 24 (DMAc) E_p,a= +0.47 V (NHE). IR: ν(BH) = 2481 cm^-1, ν(CO)

h at room temperature, the reaction solution was = 1725 cm^-1, ν(NO) = 1548 cm^-1. ³¹P NMR (d₆-acetone, δ):

1

removed from the glove box, diluted with H₂O (20 mL) -10.65 (J_WP= 287). H NMR (d₆-acetone, δ): 8.11 (d, 1H,

and extracted with DCM (2 x 20 mL). The combined Pz3/5), 8.04 (d, 1H, Pz3/5), 7.90-7.93 (m, 2H, Pz3/5 &

organic layer was dried over MgSO₄and evaporated in Pz3/5), 7.81 (d, 1H, Pz3/5), 7.52 (d, 1H, Pz3/5), 6.42-6.46

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(m, 1H, H2), 6.38 (t, 1H, Pz4), 6.32 (t, 1H, Pz4), 6.30 (t, 1H,

Pz4), 4.84-4.88 (m, 1H, H1), 3.52 (s, 3H, OMe), 3.11-3.15

(m, 1H, H5), 2.86-3.00 (m, 1H, H3), 2.80 (dd, J = 16.5, 1H,

H6x), 2.69 (dd, J = 14.5, 8.5, 1H, H7x), 2.37 (dd, J = 14.5,

5.7, 1H, H7y), 1.75 (dd, J = 16.5, 6.5, 1H, H6y), 1.29 (d, J =

8.4, 9H, PMe₃), 1.06 (bd, J = 10.1, 1H, H4). ¹³C NMR (d₆-

acetone, δ): 174.6, 144.2, 142.5, 141.7, 137.5, 136.9,

136.5, 132.1, 116.6, 107.0, 106.8, 106.5, 60.6, 51.1, 49.5

(d, J = 10.3), 45.0, 34.7, 28.5, 23.5, 13.8 (d, J = 28.1, PMe₃).

A SC-XRD study confirms the assigned structure.

Compound 20-O.

Outside of the glovebox, 20P (100 mg, 0.120 mmol) was

dissolved in MeCN (1.5 mL) in a 4-dram vial, then

ferrocenium hexafluorophosphate (137 mg, 0.414 mmol)

was added to the vial with stirring. The reaction solution

was stirred for 5 h and then was evaporated in vacuo to a

film. The resulting film was diluted with CH₂Cl₂(30 mL)

and washed with saturated aqueous sodium carbonate

(20 mL). The aqueous layer was back extracted with

CH₂Cl₂(2 x 20 mL)_,then the combined organic layers were

dried over MgSO₄and evaporated to dryness. The

resulting oil was loaded onto a 250 μm silica preparatory

plate with MeCN (3 × 0.3 mL) and eluted with

Et₃N/MeOH/CH₂Cl₂(1%/5%/94%). A KMnO₄active band

at R_f= 0.1 was collected and sonicated in 6% MeOH in

CH₂Cl₂(HPLC grade, 30 mL) for 15 min. The silica was

filtered off on a 30 mL fine porosity fritted disc and

washed with EtOAc (HPLC grade, 2 × 20 mL). The filtrate

was evaporated in vacuo, yielding 39 (4 mg, 0.012 mmol,

10% yield). ¹H NMR (d₆-acetone, δ): 5.89 (ddd, J = 10.4,

4.5, 2.7, 1H, H3), 5.80 (bd, J = 10.4, 1H, H2), 3.65 (s, 3H,

OMe), 3.30-3.34 (m, 1H, H4), 2.69-2.72 (m, 2H, pip), 2.50-

2.53 (m, 3H, H1 and pip), 2.46-2.49 (m, 1H, H5), 1.76 (bd,

J = 12.6, 1H, H6x), 1.63 (q, J = 12.6, 1H, H6y), 1.47-1.51 (m,

4H, pip), 1.33-1.37 (m, 2H, pip), 1.19 (s, 3H, Me), 1.17 (s,

3H, Me). ¹³C NMR (d₆-acetone, δ): 177.5 (CO), 131.5 (C2),

128.7 (q, J = 278.8, CF₃), 126.4 (C3), 57.5 (C4), 53.9 (2C,

pip), 52.1 (OMe), 45.6 (C7), 44.5 (q, J = 24.4, C5), 43.9 (C1),

Compound 20P.

200 mg of compound 18 was dissolved in 2.0 mL of CH₃CN

and the solution was brought to –30 °C. An excess of HOTf

dissolved in CH₃CN was added (0.66 mL; 1M) followed

after 15 minutes by 347 mg of piperidine. A light yellow

ppt formed. The reaction mixture was quenched with the

t

addition of 1.1 mL of BuOK (1M in tBuOH) then treated

with 4.5 mL of water. The resulting ppt was collected and

washed with water and then with pentane. Yield: 173 mg,

78% as a mixture of two isomers. Crystals of compound

20P were grown from the reaction mixture dissolved in

CD₃CN and subjected to SC-XRD analysis.

¹H NMR (d³-acetonitrile, δ): 8.00 (d, 1H, Pz), 7.85 (d, 1H,

Pz), 7.83 (d, 1H, Pz), 7.82 (d, 1H, Pz), 7.76 (d, 1H, Pz), 7.31

(d, 1H, Pz3), 6.33 (t, 1H, Pz4), 6.29 (t, 1H, Pz4), 6.27 (t, 1H,

Pz4), 3.65 (s, 3H, OMe), 3.6 - 3.7 (m, 2H, H4, H5), 2.85 (t, J

= 12, 1H, H3), 2.2-2.1 (m, 3H, H1, pip), 1.96 (q, J = 13, 1H,

H6a), 1.70-1.73 (m, 1H, H6b), 1.4-1.3 (m, 8H, pip), 1.32 27.7 (2C, pip), 25.3 (pip), 22.6 (Me), 22.2 (Me), 20.9 (C6).

(3H, Me), 1.30 (3H, Me), 1.13 (d, J = 8.5, 9H, PMe₃), 1.05

(d, J =12, 1H, H2).

Compound 21D. 102 mg of compound 18 was dissolved

in 1.5 mL of CH₃CN and the solution was brought to –30

°C. An excess of HOTf dissolved in CH₃CN was added (0.3

mL; 1M) followed after 10 minutes by 174 mg of

morpholine (~15 eq). A light yellow ppt formed. The

reaction mixture was quenched with the addition of 0.53

mL of ^tBuOK (1M in tBuOH) and the ppt was collected and

washed with water and then with pentane. Yield: 38 mg,

Compound 20D. This isomer was prepared as part of a

mixture with compound 20P. See synthetic procedure

above. ¹H NMR (d³-acetonitrile, δ): 7.94 (d, 1H, Pz), 7.93

(d, 1H, Pz), 7.87 (d, 1H, Pz), 7.81 (d, 1H, Pz), 7.80 (d, 1H,

Pz), 7.38 (d, 1H, Pz3), 6.31 (t, 1H, Pz4), 6.30 (t, 1H, Pz4),

6.26 (t, 1H, Pz4), 4.11 (d, J =4.6 1H, H5), 3.48 (s, 3H, OMe),

3.23-3.29 (m, 1H, H2), 2.90-2.94 (m, 1H, H1), 2.85 (t, J =

12, 1H, H4), 2.9 - 3.1 (4H, pip), 1.66 (q, J = 13, 1H, H6a),

1.45-1.55 (6H, pip), 1.38-1.42 (m, J= 13,7, 1H, H6_b), 1.21

(d, J = 8.5, 9H, PMe₃), 1.01 (d, J =12, 1H, H3), 0.77 (3H,

Me), 0.68 (3H, Me).

1

34%. H NMR analysis found this to be roughly a 1:1

mixture of isomers. The filtrate was concentrated under

vacuum, then treated with 4 mL water, upon which a

second precipitate formed (37 mg; 33%). The recovered

solid was found by proton NMR to be roughly a 4:1

mixture of isomers, favoring compound 21D. A crystal was

recovered from the first precipitate and subjected to SC-

XRD analysis. In solution, both isomers are unstable with

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respect to isomerization and elimination, but partial Compound 22P. The filtrate from the above procedure

characterization of 21D follows: was treated with 2 mL water, upon which a second

¹H NMR (CD₂Cl₂, δ): 8.02 (d, 1H, Pz), 7.93 (d, 1H, Pz), 7.78 precipitate formed (12 mg; 11%). The recovered solid was

(d, 1H, Pz), 7.73 (d, 1H, Pz), 7.71 (d, 1H, Pz), 7.28 (d, 1H, found by proton NMR to be roughly 80% pure. Partial

Pz3), 6.28 (t, 2H, Pz4), 6.26 (t, 1H, Pz4), 4.07 (d, J =4.6 1H, characterization follows: ¹H NMR (CD₃CN, δ): 7.99 (d, 1H,

H5), 3.67 (b,4H, morph), 3.49 (s, 3H, OMe), 3.33-3.39 (m, Pz), 7.98 (d, 1H, Pz), 7.86 (d, 1H, Pz), 7.85 (d, 1H, Pz), 7.85

1H, H2), 3.0-3.1 (4H, morph), 2.83-2.87 (m, 1H, H1), 2.81 (b, 1H, Im), 7.83 (d, 1H, Pz), , 7.44 (b, 1H, Im), 7.31 (d, 1H,

(t, J = 12, 1H, H4), 1.65 (q, J = 13, 1H, H6a), 1.42-1.46 (m, Pz), 7.00 (b, 1H, Im), 6.34 (t, 1H, Pz4) 6.30 (t, 1H, Pz4) 6.27

J= 13,7, 1H, H6_b), 1.23 (d, J = 8, 9H, PMe₃), 1.02 (d, J =12, (t, 1H, Pz4), 5.49 (b, 1H,H4), 3.51 (3H, OMe), 3.35 (ddd J =

1H, H3). 0.84 (3H, Me), 0.64 (3H, Me).

2.5, 6.4, 13, H1) 3.29-3.33 (m, 1H, H5), 2.82 (dd, J = 13, 11

1H, H3), 1.71 (q, J = 13, 1H, H6_a), 1.64 (ddd, J= 13,7, 1H,

H6_b), 1.10 (d, J = 8, 9H, PMe₃), 1.09 (d, J =12.5, 1H, H3),

Compound 21P. Partial characterization. See above 0.85 (3H, Me), 0.78 (3H, Me). NOESY and COSY data

synthetic procedure. ¹H NMR (CD₂Cl₂, δ): 8.01 (d, 1H, Pz), confirm the regiochemical assignment above.

7.82 (d, 1H, Pz), 7.77 (d, 1H, Pz), 7.74 (d, 1H, Pz), 7.67 (d,

1H, Pz), 7.22 (d, 1H, Pz3), 6.29 (t, 1H, Pz4), 6.26 (t, 1H,

Pz4), 6.21 (t, 1H, Pz4), ~3.7 (b,4H, morph), 3.68 (s, 3H, Compound 25.

OMe), 3.65 (b, H4), 3.43 (m, 1H, H5), 3.10 (b, 2H, morph), To a 4-dram vial charged with a stir pea were added 18

3.03 (b, 2H, morph) 2.81 (m, 1H, H3), 2.16 (dt, 1H, H1), (200 mg, 0.27 mmol) followed by MeCN (1.2 mL, –30°C)

1.92 (q, J = 13, 1H, H6a), 1.76 (m, H6_b), 1.35 (6H, Me), 1.23 and a 1M solution of HOTf in acetonitrile (0.53 mL, 0.53

(d, J = 8, 9H, PMe₃), 1.03 (d, J =11, 1H, H2).

mmol, –30°C), resulting in a homogeneous golden

solution, which was allowed to sit for 15 min at –30°C. 4-

bromobenzylamine (690 mg, 3.71 mmol) was then added

Compound 22D. WTp(NO)(PMe3)(L), where L = methyl 2- to reaction solution with stirring. The dark golden

(2-(1H-imidazol-1-yl)-5-(trifluoromethyl)cyclohex-3-en-1- reaction solution was left at –30°C overnight then the

yl)-2-methylpropanoate. 100 mg of compound 18 was reaction solution was warmed to room temperature and

1

dissolved in 0.7 mL of CH₃CN and the solution was brought monitored by H NMR and H NMR until reaction was

to –30 °C. An excess of HOTf dissolved in CH₃CN was complete. The reaction was then removed from the

added (0.2 mL; 1M) followed after 30 minutes by 136 mg glovebox, diluted with CH₂Cl₂(40 mL), and washed with

of imidazole (15 eq). A yellow ppt formed. The reaction H₂O (2x 30 mL). The aqueous layer was back extracted

mixture was quenched with the addition of 0.5 mL of with CH₂Cl₂(2 x 20 mL)_,then the combined organic layers

^tBuOK (1M in tBuOH) and the ppt was collected and were dried over MgSO₄and evaporated to dryness. The

washed with water and finally with pentane. Yield: 86 mg, resulting film was redissolved in minimal CH₂Cl₂and

79%. In solution, this compound is unstable with respect added to 15 mL stirring pentane. The resulting solid was

to formation of compound 22D. A small crystal was collected on a 15 mL fine porosity fritted disc, washed

recovered and subjected to SC-XRD in order to confirm with pentane (2 x 5 mL) and desiccated, yielding 25 (199

the structure. Partial characterization follows:

mg, 0.22 mmol, 81% yield. ¹H NMR (d₆-acetone, δ): 8.09

¹H NMR (CD₂Cl₂, δ): 8.14 (d, 1H, Pz), 8.07 (d, 1H, Pz), 7.77 (d, 1H, Pz3/5), 8.03 (d, 1H, Pz3/5), 7.90 (d, 1H, Pz3/5), 7.75

(d, 1H, Pz), 7.73 (d, 1H, Pz), 7.68 (d, 1H, Pz), 7.48 (b, 1H, (d, 1H, Pz3/5), 7.47 (d, 1H, Pz3/5), 7.36 (d, 1H, Pz3/5), 6.9-

Im), 7.23 (b, 1H, Im), 7.11 (d, 1H, Pz), 6.87 (b, 1H, Im), 6.34 7.0 (m, 2H, Ar-H), 6.48 (t, 1H, Pz4), 6.41-6.45 (m, 2H, Ar-

(t, 1H, Pz4) 6.31 (t, 1H, Pz4) 6.20 (t, 1H, Pz4), 5.25(bs, H), 6.34 (t, 1H, Pz4), 6.03 (t, 1H, Pz4), 4.72 (d, J = 14.6, 1H,

1H,H2), 3.90-3.94 (m, 1H, H5) 3.76 (s, 3H, OMe), 2.88 CH₂N), 4.41 (bs, 1H, H7a), 3.77 (d, J = 14.6, 1H, CH₂N),

(ddd, J = 13,11,2.5, 1H, H4), 2.76 (dt, J = 14, 1H, H1) 1.82 3.50-3.55 (m, 1H, H5), 2.83-2.87 (m, 1H, H6), 2.05-2.09

(q, J = 13, 1H, H6_a), 1.74 (ddd, J= 13,7, 1H, H_b) 1.24 (3H, (m, 1H, H3a), 1.68 (dt, J = 12.6, 4.7, 1H, H4x), 1.23-1.27

Me), 1.20 (d, J = 8, 9H, PMe₃), 0.96 (d, J =12.5, 1H, H3), (m, 1H, H4y), 1.22 (d, J = 8.5, 9H, PMe₃), 1.14 (s, 3H, Me),

0.58 (3H, Me).

1.10 (s, 3H, Me), 1.09 (buried, 1H, H7).

A SC-XRD study confirms the assigned structure.

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mL), and pentane (3 x 5 mL, –30°C) then desiccated,

Compound 26.

yielding 28 (270 mg, 0.316 mmol, 69% yield). CV (DMAc)

To a 4-dram vial charged with a stir pea were added 18 E_p,a= +0.52 V (NHE). IR: ν(BH) = 2481 cm^-1, ν(CO) = 1669

(100 mg, 0.13 mmol) followed by CD₃CN (0.8 mL, –30°C) cm^-1, ν(NO) = 1538 cm^-1. ³¹P NMR (CD₂Cl₂, δ): -10.06 (J_WP

=

and a 1M solution of HOTf in acetonitrile (0.2 mL, 0.2 288). ¹H NMR (CD₂Cl₂, δ): 7.98 (d, 1H, Pz3/5), 7.77 (d, 1H,

mmol, –30°C), resulting in a homogeneous golden Pz3/5), 7.70-7.74 (m, 2H, Pz3/5), 7.56 (d, 1H, Pz3/5), 7.18

solution, which was allowed to sit for 10 min at –30°C. 4- (d, 1H, Pz3/5), 6.66 (s, 1H, Ar-H), 6.61 (s, 1H, Ar-H), 6.30

chlorobenzylamine (200 mg, 1.41 mmol, –30°C) was then (t, 1H, Pz4), 6.19 (t, 1H, Pz4), 5.95 (t, 1H, Pz4), 5.92-5.96

added to reaction solution with stirring. The dark golden (m, 2H, OCH₂O), 4.78 (d, J = 4.9, 1H, H7a), 4.36 (d, J = 15.8,

reaction solution was left at –30°C for 3.5 h then the 1H, H9x), 4.11 (d, J = 15.8, 1H, H9y), 2.92-2.96 (m, 1H,

reaction solution was warmed to room temperature and H5x), 2.59-2.62 (m, 2H, H3x & H6), 2.49-2.52 (m, 2H, H3a

monitored by ¹H NMR. After stirring overnight, the & H5y), 2.24 (dd, J = 16.4, 2.4, 1H, H3y), 1.62-1.66 (m, 1H,

reaction diluted with CH₂Cl₂(20 mL) and washed with H₂O H4x), 1.37-1.41 (m, 1H, H4y), 1.15 (d, J = 8.3, 9H, PMe₃),

(20 mL). The aqueous layer was back extracted with 1.14 (buried, 1H, H7). ¹³C NMR (CD₂Cl₂, δ): 176.1 (C2),

CH₂Cl₂(20 mL)_,then the combined organic layers were 148.1 (Ar-C), 147.5 (Ar-C), 143.7 (Pz3/5), 141.9 (Pz3/5),

dried over MgSO₄and evaporated to dryness. The 140.8 (PzC3/5), 137.0 (PzC3/5), 136.5 (Pz3/5), 136.4

resulting film was redissolved in minimal CH₂Cl₂and (Pz3/5), 131.3 (Ar-C), 113.1 (Ar-C), 112.9 (Ar-C), 109.1 (Ar-

added to 15 mL stirring pentane. The resulting solid was C), 106.8 (Pz4), 106.3 (Pz4), 106.1 (Pz4), 102.3 (OCH₂O),

collected on a 15 mL fine porosity fritted disc, washed 62.3 (C7a), 51.0 (d, J = 11.9, C6), 49.3 (C7), 44.0 (C9), 38.8

with pentane (2 x 5 mL) and desiccated, yielding 26 (88 (C3), 32.7 (C3a), 27.6 (2C, C4 & C5), 14.0 (d, J = 27.9,

mg, 0.102 mmol, 79% yield. IR: ν(BH) = 2486 cm^-1, ν(CO) = PMe₃). A SC-XRD study confirms the assigned structure.

1677 cm^-1,ν(NO) = 1558 cm^-1.¹H NMR (d₆-acetone, δ): 8.09

(d, 1H, Pz3/5), 8.03 (d, 1H, Pz3/5), 7.90 (d, 1H, Pz3/5), 7.73

(d, 1H, Pz3/5), 7.47 (d, 1H, Pz3/5), 7.36 (d, 1H, Pz3/5), Partial Characterization of intermediate 30P/30D.

6.82-6.86 (m, 2H, Ar-H), 6.47-6.51 (m, 3H, Ar-H, and Pz4), (d³-acetonitrile, δ): 8.45 (d, 1H, Pz), 8.40 (d, 1H, Pz), 8.00

6.34 (t, 1H, Pz4), 6.02 (t, 1H, Pz4), 4.73 (d, J = 14.6, 1H, (d, 1H, Pz), 7.95 (d, 1H, Pz), 7.92 (d, 1H, Pz), 7.79 (d, 1H,

CH₂N), 4.40 (d, J = 4.2, 1H, H7a), 3.78 (d, J = 14.6, 1H, Pz), 6.53 (t, 1H, Pz4), 6.51 (t, 1H, Pz4), 6.33 (t, 1H, Pz4),

CH₂N), 3.54-3.58 (m, 1H, H5), 2.83-2.86 (m, 1H, H6), 2.07 6.27 (bd, J = 7, 1H, H1), 5.14 (bt, J = 7, 1H, H2), 4.38-4.42

(buried, 1H, H3a), 1.68 (dt, J = 12.5, 4.7, 1H, H4x), 1.23- (m, 1H, H3), 3.73 (s, 3H, OMe), 3.67-3.71 (m, 1H), 3.08-

1.26 (m, 1H, H4y), 1.22 (d, J = 8.5, 9H, PMe₃), 1.14 (s, 3H, 3.12 (m, 1H), 2.78 (dd, J= 17,5, 1H), 2.60 (dd, J = 17,10,

Me), 1.10 (s, 4H, Me and H7).

A SC-XRD study confirms the assigned structure.

1H), 2.40-2.44 (m, 1H), 1.62-1.66 (m, 1H), 1.16 (d, J = 10,

9H, PMe₃).

Compound 28. Compound 29 (281 mg, 1.22 mmol) and Compound 32. Outside of the glovebox, 28 (250 mg,

propionitrile (0.5 mL) were combined in a test tube and 0.293 mmol) was dissolved in CH₂Cl₂(3.75 mL) in a 4-dram

chilled to –60°C). To a screw-top test tube, charged with vial, then ferrocenium hexafluorophosphate (137 mg,

a stir pea were added 16 (300 mg, 0.458 mmol) followed 0.414 mmol) was added to the vial with stirring. The

by propionitrile (1.5 mL, –30°C) and a 1M solution of HOTf reaction solution was stirred for 2 h and then diluted with

in acetonitrile (0.55 mL, 0.55 mmol, –30°C), resulting in a CH₂Cl₂(60 mL) and washed with H₂O (50 mL). The aqueous

homogeneous golden solution, which was stirred at –60°C layer was back extracted with CH₂Cl₂(2 x 50 mL)_,then the

for 30 min. The solution of 29 was added to the reaction combined organic layers were dried over Na₂SO₄and

solution with stirring, then the reaction was stirred at - evaporated to dryness. The film was redissolved in

60°C for 5 h. DBU (124 mg, 0.815 mmol, –30°C) was added minimal CH₂Cl₂and added to Et₂O (50 mL) with stirring.

to the reaction solution while cold, and then the reaction The resulting precipitate was collected on a 15 mL fine

was stirred at room temperature for 4 days. While stirring porosity fritted disc and washed with Et₂O (2 x 10 mL), and

at room temperature, a solid precipitated from solution. hexanes (10 mL). The precipitate was discarded, and the

The solid was collected on a 15 mL fine porosity fritted filtrate was evaporated in vacuo to a film. The film was dry

loaded on silica then purified on the Combiflash^âwith a

disc, washed with MeCN (2 x 0.5 mL, –30°C), H₂O (2 x 7

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12 g silica column using a gradient solvent system starting bath. After 7 h the reaction was removed from the heat,

1

at 100% hexanes and going to 100% EtOAc (Rf=0.59, 5:1 and the reaction was observed to be complete by H

EtOAc/Hex). The combined fractions were evaporated in NMR. Outside of the glove-box, H₂O (3 mL) was added to

vacuo, yielding 32 (73 mg, 0.208 mmol, 71% yield). *Note: the reaction, and then the aqueous layer was extracted

using CH₂Cl₂as solvent results in minor side product that with EtOAc (5 x 5 mL). The combined organic layers were

can be separated via chromatography- side product can washed with brine, then dried over Na₂SO₄and

be avoided if acetone is used as reaction solvent. IR: ν(CO) evaporated down. The resulting oil was loaded onto a 250

= 1680 cm^-1. HRMS (ESI-TOF) m/z: [M+Na]⁺Calcd for μm silica preparatory plate with DCM (3 × 0.3 mL) and

C₁₆H₁₆BrNO₃Na 372.0211; Found 372.0209. ¹H NMR eluted with 85% EtOAc/hexanes (HPLC grade, 200 mL). A

(CDCl₃, δ): 6.96 (s, 1H, Ar-H), 6.74 (s, 1H, Ar-H), 5.92-5.96 KMnO₄active band at R_f= 0.20−0.30 was collected and

(m, 3H, H6 and OCH₂), 5.74 (bd, J = 10.2, 1H, H7), 4.75 (d, sonicated in 1% Et₃N in EtOAc (HPLC grade, 30 mL) for 20

J = 15.6, 1H, H8x), 4.25 (d, J = 15.6, 1H, H8y), 3.83-3.87 min. The silica was filtered off on a 30 mL fine porosity

(m, 1H, H7a), 2.52 (dd, J = 16.3, 8.3, 1H, H3x), 2.45-2.49 fritted disc and washed with EtOAc (HPLC grade, 2 × 20

(m, 1H, H3a), 2.27 (dd, J = 16.3, 5.8, 1H, H3y), 2.07-2.10 mL). The filtrate was evaporated in vacuo, yielding 33 (15

(m, 1H, H5x), 1.97-2.01 (m, 1H, H5y), 1.68-1.72 (m, 1H, mg, 0.056 mmol, 50% yield).

H4x), 1.55-1.59 (m, 1H, H4y). ¹³C NMR (CDCl₃, δ): 174.8 HRMS (ESI-TOF) m/z: [M+H]⁺Calcd for C₁₆H₁₆NO₃

(C2), 148.0 (2C, Ar-C), 132.1 (C6), 129.4 (Ar-C), 123.4 (C7), 270.1130; Found 270.1124. ¹H NMR (CDCl₃, δ): 6.66 (s,

113.7 (Ar-C), 112.8 (Ar-C), 109.5 (Ar-C), 102.0 (OCH₂O), 1H), 6.57 (s, 1H), 5.91-5.95 (m, 2H), 5.86-5.90 (m, 1H),

55.0 (C7a), 44.2 (C8), 35.9 (C3), 31.2 (C3a), 24.3 (C4), 22.4 5.64 (bd, J = 9.5, 1H), 4.78 (d, J = 17.0, 1H), 4.10 (d, J =

(C5).

17.0, 1H), 4.04 (dd, J = 8.0, 5.1, 1H), 3.26-3.30 (m, 1H),

2.85-2.88 (m, 1H), 2.66 (ddd, J = 17.0, 9.6, 1.2, 1H), 2.17-

Crystals of racemic compound 32 were isolated from ethyl 2.21 (m, 1H), 2.08-2.12 (m, 2H). ¹³C NMR (CDCl₃, δ): 174.5,

acetate:methylene chloride:ether mixture (1:3:2). The 147.1, 147.0, 132.7, 129.9, 126.9, 124.4, 109.0, 106.3,

racemic mixture was resolved by analytical chiral HPLC 101.3, 56.7, 42.3, 39.0, 38.6, 29.3, 27.5.

(Agilent 1269 Infinity II system equipped with vial

sampler, flexible pumps and DAD detector) as follows:

Using isocratic elution of 1:1 hexanes ethyl acetate at flow Compound 34. The following closely follows the

rate of 1.0mL/min of sample (0.1mg/mL dissolved in ethyl previously published procedures.^{[23, 40]}33 (14 mg. 0.052

mmol) was dissolved in MeOH (1.9 mL) in 2-neck round

bottom flask with stir pea, then 5% Pd/C (14 mg) was

added. The reaction mixture was stirred under H₂(1 atm)

for 2 h, and the reaction was checked for completion by

TLC. The catalyst was filtered off on a celite pad in a 15 mL

medium porosity fritted disc, and rinsed with MeOH. The

filtrate was evaporated in vacuo to give the crude product

as a film, which was dry loaded on silica then purified on

the Combiflash^âwith a 4 g silica column using a gradient

solvent system starting at 100% hexanes and going to

100% EtOAc (HPLC grade). The fractions containing 34

were combined and concentrated in vacuo to yield 34 as

a white solid (11 mg, 0.041 mmol, 79% yield). HRMS (ESI-

TOF) m/z: [M+H]⁺Calcd for C₁₆H₁₈NO₃272.1287; Found

acetate, 5.0µL per injection) with CHIRALPAK® IC-3

µ

column (250mm L X 4.6 mm ID, particle size 3 M, lot#

IC30CE-WE008, Daicel Corporation, Japan), monitoring

signal at 254nm, a good separation of two enantiomers

(Rt = 11.77min; 50.03%, and 13.25min; 49.97%) was

observed. The enantioenriched synthesis of compound 32

was realized following similar sequence of reactions

derived from chiral complex (S)-1. The enantiomeric ratio

was found to be >95:5 with major isomer (Rt=11.78min.),

[40, 50]

a

[ ]_D=27.5.

Compound 33. The following is a modification of

40]

previously published procedures.^[23,

In a glove-box

compound 32 (43 mg, 0.12 mmol) was dissolved in DMF

(1.5 mL) in a 4-dram vial with a stir pea, then Hunig’s base

was added (0.05 mL). In a separate 4-dram vial Pd(OAc)₂

(1.5 mg, 0.0067 mmol) and P(Ph)₃(6.7 mg, 0.026 mmol)

were dissolved in DMF (0.5 mL). The catalyst solution was

added to the solution of 32 with stirring, and then the

reaction solution was slowly heated up to 100°C in an oil

1

272.1280. H NMR (CDCl₃, δ): 6.60 (s, 1H), 6.58 (s, 1H),

5.90-5.94 (m, 2H), 4.53 (d, J = 17.3, 1H), 4.32 (d, J = 17.3,

1H), 3.75 (t, J = 4.5, 1H), 2.74 (dt, J = 12.6, 4.5, 1H), 2.57

(dd, J = 16.1, 6.8, 1H), 2.39-2.42 (m, 1H), 2.08 (d, J = 16.1,

1H), 1.69-1.76 (m, 3H), 1.33-1.36 (m, 1H), 1.15-1.19 (m,

2H). ¹³C NMR (CDCl₃, δ): 175.9, 146.9, 146.8, 131.8, 123.5,

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108.7, 106.9, 101.2, 55.9, 42.9, 40.5, 40.0, 33.2, 30.5, (m, 2H, H3 and H6x), 2.60 (dd, J = 14.9, 8.3, 1H, H7x), 2.37

28.1, 23.8. Proton NMR data match that of title (dd, J = 14.9, 5.9, 1H, H7y), 1.95 (d, J = 16.5, 1H, H6y), 1.31

compound 34.

(d, J = 8.5, 9H, PMe₃), 1.18-1.22 (m, 1H, H4). ¹³C NMR (d₆-

acetone, δ): 174.1, 144.3, 142.6, 141.8, 137.8, 137.2,

136.8, 136.6 (m), 126.5 (q, J = 268.9), 115.8 (m), 107.3,

Compound 27. LiAlH₄(20 mg, 0.53 mmol) and THF (0.7 107.1, 106.7, 61.2, 51.2, 46.6 (d, J = 9.6), 44.8, 34.1, 26.2,

mL) were added to a 2-neck round bottom flask with a stir 13.8 (d, J = 28.6, PMe₃).

pea, then cooled to 0°C under N₂. 34 (10 mg. 0.037 mmol)

was dissolved in THF (1.9 mL, 0°C) then added to the

reaction flask under N₂. The reaction was refluxed for 2 h, Compound 37.

then checked for completion by TLC. After the reaction Compound 29 (126 mg, 0.548 mmol) and MeCN (0.4 mL)

was complete, a saturated solution of Na₂SO₄(2 mL) was were combined and chilled to –30°C). To a 4-dram vial

added at 0°C, then stirred for 2 h. A 1 M NaOH solution (2 charged with a stir pea were added 35 (99 mg, 0.137

mL) was added, then we two layers were separated and mmol) followed by MeCN (0.6 mL, –30°C) and a 1M

the aqueous layer was extracted with EtOAc (3 x 10 mL). solution of HOTf in acetonitrile (0.55 mL, 0.55 mmol, -

The combined organic layers were washed with brine, 30°C), resulting in a homogeneous golden solution, which

then dried over Na₂SO₄, filtered and evaporated in vacuo was stirred at room temperature for 10 min, then chilled

to give the crude product. The product was purified by at –30°C for 30 min. The chilled solution of 29 was added

flash chromatography on silica gel, eluting with EtOAc, to the reaction solution with stirring, then the reaction

then 1% Et₃N in EtOAc, yielding 27 (8 mg, 0.031, 84% was stirred at –30°C for 15 h. Precipitation occurs

yield) as an oil. Proton NMR data match that of title overnight. DBU (50 mg, 0.328 mmol, -30°C) was added to

compound 27. ^[24-37]

the reaction mixture while cold, and then the reaction

mixture was stirred at room temperature for 10 days. The

solid was collected on a 15 mL fine porosity fritted disc,

washed with H₂O (2 x 7 mL), and pentane (2 x 5 mL) then

Compound 35.

To a 4-dram vial charged with a stir pea were added 5 (1.0 desiccated, yielding 37 (102 mg, 0.111 mmol, 81% yield).

g, 1.54 mmol) followed by acetonitrile (7.5 mL, –30°C) and ¹H NMR (CD₂Cl₂, δ): 7.97 (d, 1H, Pz3), 7.77 (d, 1H, Pz5),

a 1M solution of HOTf in acetonitrile (2.3 mL, 2.3 mmol, - 7.72 (m, 1H, Pz5), 7.59 (d, 1H, Pz5), 7.55 (d, 1H, Pz3), 7.19

30°C), resulting in a homogeneous golden solution, which (d, 1H, Pz3), 6.52 (s, 1H, Ar-H), 6.51 (s, 1H, Ar-H), 6.29 (t,

was allowed to sit for 15 min at –30°C. 1-(tert- 1H, Pz4), 6.26 (t, 1H, Pz4), 5.99 (t, 1H, Pz4), 5.90-5.94 (m,

Butyldimethylsilyloxy)-1-methoxyethene (TBSME; 1.43 g, 2H, OCH₂O), 4.56 (d, J = 5.7, 1H, H7a), 4.51 (d, J = 15.3, 1H,

7.76 mmol, –30°C) was then added to reaction solution NCH₂), 4.14 (d, J = 15.3, 1H, NCH₂), 3.41-3.43 (m, 1H, H5),

with stirring. The dark golden reaction solution was left at 2.73 (dd, J = 16.7, 8.2, 1H, H3x), 2.56-2.60 (m, 1H, H3a),

–30°C for 21 h then the reaction solution was quenched 2.52-2.56 (m, 1H, H6), 2.14 (d, J = 16.7, 1H, H3y), 1.91-1.94

with Et₃N (2 mL, 14.34 mmol). A 150 mL medium porosity (m, 1H, H4x), 1.49 (m, 1H, H4y), 1.21 (d, J = 11.0, 1H, H7),

fritted disc was filled ¾ full of silica gel and set in Et₂O. The 1.13 (d, J = 8.3, 9H, PMe₃). ¹³C NMR (CD₂Cl₂, δ): 175.3 (C2),

reaction solution was loaded on the column and a pale 147.7 (Ar-C), 147.4 (Ar-C), 144.0 (Pz3/5), 142.8 (Pz3/5),

yellow band was eluted with Et₂O (~160 mL). The filtrate 141.0 (PzC3/5), 137.1 (PzC3/5), 136.7 (Pz3/5), 136.6

was removed from the glovebox and evaporated in vacuo, (Pz3/5), 131.2 (q, J = 280.2, CF₃), 130.2 (Ar-C), 113.1 (Ar-

then redissolved in minimal CH₂Cl₂and added to 40 mL C), 112.6 (Ar-C), 109.6 (Ar-C), 106.7 (Pz4), 106.4 (Pz4),

stirring pentane. The resulting pale yellow solid was 106.0 (Pz4), 102.1 (OCH₂O), 59.9 (C7a), 48.8 (C7), 43.6

collected on a 30 mL fine porosity fritted disc, washed (CH₂N), 43.0 (d, J = 12.7, C6), 41.7 (q, J = 24.5, C5), 40.9

with pentane (2 x 7 mL) and desiccated, yielding 35 (927 (C3), 27.6 (C3a), 26.2 (C4), 13.7 (d, J = 28.7, PMe₃). A SC-

1

mg, 1.28 mmol, 83% yield. H NMR (d₆-acetone, δ): 8.12 XRD study confirms the assigned structure.

(d, 1H, Pz3/5), 8.04 (d, 1H, Pz3/5), 7.94-7.98 (m, 2H, Pz3/5

& Pz3/5), 7.84 (d, 1H, Pz3/5), 7.59 (d, 1H, Pz3/5), 7.19 (bs,

1H, H2), 6.40 (t, 1H, Pz4), 6.35 (t, 1H, Pz4), 6.34 (t, 1H, Compound 38.

Pz4), 3.53 (s, 3H, OMe), 3.27-3.31 (m, 1H, H5), 2.84-2.88

10.1002/hlca.202100103

Helvetica Chimica Acta

not necessarily represent the official views of the National

Institutes of Health or the University of Virginia.

Outside of the glovebox, 37 (98 mg, 0.106 mmol) was

dissolved in acetone (0.5 mL) and MeCN (1.5 mL) in a 4-

dram vial, then ferrocenium hexafluorophosphate (137

mg, 0.414 mmol) was added to the vial with stirring. The

brown reaction solution was stirred for 1 h and then

evaporated in vacuo to a film. The resulting film was

dissolved in CH₂Cl₂(40 mL) and washed with H₂O (30

mL). The aqueous layer was back extracted with CH₂Cl₂

(2 x 30 mL)_,then the combined organic layers were dried

over Na₂SO₄and evaporated to dryness. The film was

redissolved in minimal CH₂Cl₂and added to Et₂O (35 mL)

with stirring. The resulting precipitate was collected on a

15 mL fine porosity fritted disc and washed with Et₂O (2

x 5 mL), and pentanes (5 mL). The precipitate was

Author Contribution Statement

KBW, HSN, MDC, and SRS designed and performed the

experiments, KSW and MNE performed the calculations,

DAD carried out the crystallographic work, and WDH

supervised the work and wrote this manuscript.

References

[1]

[2]

[3]

[4]

[5]

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Transition Metal-Catalyzed Hydroamination and

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Mediated Dearomatization Reactions’, Chem Rev. 2000, 100,

2917-2940.

discarded, and the filtrate was evaporated in vacuo to a

film. The film was dry loaded on silica then purified on

the Combiflash^âwith a 4 g silica column using a gradient

solvent system starting at 100% hexanes and going to

100% EtOAc. The combined fractions were evaporated in

1

vacuo, yielding 38 (25 mg, 0.060 mmol, 57% yield). H

NMR (CDCl₃, δ): 6.97 (s, 1H, Ar-H), 6.69 (s, 1H, Ar-H), 6.01

(dt, J = 10.3, 2.7, 1H, H7), 5.96 (buried, 1H, H6), 5.93-5.97

(m, 2H, OCH₂), 4.73 (d, J = 15.7, 1H, H8x), 4.34 (d, J =

15.7, 1H, H8y), 3.89 (bs, 1H, H7a), 2.84-2.88 (m, 1H, H5),

2.81 (dd, J = 17.0, 8.1, 1H, H3x), 2.42-2.46 (m, 1H, H3a),

2.24 (d, J = 17.0, 1H, H3y), 1.93 (bd, J = 12.8, 1H, H4x),

1.50 (q, J = 12.8, 1H, H4y). ¹³C NMR (CDCl₃, δ): 173.8 (C2),

148.0 (2C, Ar-C), 128.8 (Ar-C), 127.0 (2C, C6 and C7),

126.2 (q, J = 279.6, CF₃), 113.3 (Ar-C), 112.8 (Ar-C), 109.2

(Ar-C), 102.0 (OCH₂O), 54.0 (C7a), 44.1 (C8), 40.4 (q, J =

28.0, C5), 38.1 (C3), 29.6 (C3a), 24.9 (C4).

[6]

[7]

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Synthesis and Catalysis, Vol. 7, Springer, Berlin, 2004.

M. F. Semmelhack, in Comprehensive Organometallic

Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A. Stone, G.

Wilkinson), Pergammon, Oxford, 1995, pp. 979-1015.

M.F. Semmelhack, A. Chlenov, in Transition Metal Arene π-

Complexes in Organic Synthesis and Catalysis, Vol. 7 (Ed.: E. P.

Kündig), Springer, Berlin, 2004.

[8]

[9]

A. J. Pearson, ‘Tricarbonyl (diene) iron complexes:

synthetically useful properties’, Accounts of Chemical

Research 1980, 13, 463-469.

Supplementary Material

[10] L. A. P. Kane-Maguire, E. D. Honig, D. A. Sweigart,

‘Nucleophillic Addition to Coordinated Cyclic p-Hydrocarbons:

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NIGMS of the National Institutes of Health under award

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Article Doi

Hydroamination of Dihapto-Coordinated Benzene and Diene Complexes of Tungsten: Fundamental Studies and the Synthesis of γ-Lycorane

DOI: 10.1002/hlca.202100103

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