The Aryne-Abramov Reaction as a 1,2-Benzdiyne Platform for the Generation and Solvent-Dependent Trapping of 3-Phosphonyl Benzynes

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The Aryne-Abramov Reaction as a 1,2-Benzdiyne Platform for the

Generation and Solvent-Dependent Trapping of 3‑Phosphonyl

Benzynes

Brianna M. Bembenek, Maya M. S. Petersen, Julia A. Lilly, Amber L. Haugen, Naomi J. Jiter,

Andrew J. Johnson, Ethan E. Ripp, Shelby A. Winchell, Alisha N. Harvat, Caitlin McNulty,

Sierra A. Thein, Abbigail M. Grieger, Brandon J. Lyle, Gabriella L. Mraz, Abigail M. Stitgen, Samuel Foss,

Merranda L. Schmid, Joseph D. Scanlon, and Patrick H. Willoughby *

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ABSTRACT: Synthetic methodology utilizing two aryne intermediates

(i.e., a formal benzdiyne) enables the rapid generation of structurally

complex molecules with diverse functionality. This report describes the

sequential generation of two ortho-benzyne intermediates for the

synthesis of 2,3-disubstituted aryl phosphonates. Aryl phosphonates

have proven useful in medicinal chemistry and materials science, and the

reported methodology provides a two-step route to functionally dense

variants by way of 3-phosphonyl benzyne intermediates. The process

begins with regioselective trapping of a 3-triﬂoxybenzyne intermediate

by an O-silyl phosphite in an Abramov-like reaction to bond the strained

Csp carbons with phosphorus and silicon. Standard aryne-generating

conditions follow to convert the resulting 2-silylphenyl triﬂate into a 3-

phosphonyl benzyne, which readily reacts with numerous aryne trapping reactants to form a variety of 2,3-difunctionalized aryl

phosphonate products. DFT computational studies shed light on important mechanistic details and revealed that 3-phosphonyl

benzynes are highly polarizable. Speciﬁcally, the distortion in the internal bond angles at each of the Csp atoms was strongly

inﬂuenced by both the electronegativity of the phosphonate ester groups as well as the dielectric of the computational solvation

model. These eﬀects were veriﬁed experimentally as the regioselectivity of benzyl azide trapping increased with more electronegative

esters and/or increasingly polar solvents. Conversely, replacing the conventional solvent, acetonitrile, with nonpolar alternatives

provided attenuated or even inverted selectivities. Overall, these studies showcase new reactivity of benzyne intermediates and

extend the aryne relay methodology to include organophosphonates. Furthermore, this work demonstrates that the regioselectivity of

aryne trapping reactions could be tuned by simply changing the solvent.

useful platform for the synthesis of aryl phosphonates,¹⁰

INTRODUCTION

■

allowing for either trialkyl^10aor dialkyl phosphites^10b,c,eto

Phosphonates have established roles in pharmaceutical,

serve as phosphonylating agents. Despite these impressive

advances, the concise preparation of densely functionalized aryl

agrochemical, and materials industries,¹where P-aryl phos-

phonates (e.g., 12, Figure 1) have proven particularly versatile.

phosphonates remains challenging and/or impractical.

Speciﬁcally, aryl phosphonates possess an array of interesting

Benzyne reactive intermediates are a versatile platform for

biological activities²and are synthetically useful where the

generating molecular complexity through the use of various

phosphonate is both a precursor to other phosphorus moieties³

“trapping” agents, often enabling ortho-difunctionalization

and a directing group for ortho C−H activation.⁴Moreover,

across the strained sp-hybridized carbon atoms.¹¹Recently,

aryl phosphonates are important monomeric building blocks

multibenzyne strategies have been reported, oﬀering new

for ﬂame-retardant polymers,⁵and their use as tunable surface-

modifying agents is beneﬁcial to myriad technologies.⁶The

Received: June 11, 2021

Published: July 8, 2021

most widely used approach for the synthesis of aryl

phosphonates includes transition-metal-catalyzed phosphony-

lation of arenes (e.g., Hirao reaction⁷).⁸More recently, several

impressive photomediated catalytic systems have been

reported, greatly expanding arene phosphonylation method-

ologies.⁹Benzyne and related aryne intermediates serve as a

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nucleophilic addition of 8, resulting in a zwitterionic

intermediate like 9. Driven by the formation of a P=O π

bond, intramolecular silyl transfer would follow to give arene

10, which is equipped with the requisite 2-silylphenyl triﬂate

moiety for generating a second, 3-phosphonyl, benzyne (cf.

11) under ﬂuoride-mediated conditions. Trapping 3-phos-

phonyl benzyne 11 with any of the multitude of possible aryne

trapping reactants would aﬀord aryl phosphonates with a range

of functionality (cf. 12). Herein, we describe our eﬀorts to

evaluate this hypothesis by developing a benzyne variant on

the classic Abramov reaction, which we term the aryne-

Abramov reaction, allowing for the concomitant formation of

arene C−P and C−Si bonds. Furthermore, we show that

application of the aryne-Abramov reaction to a 3-triﬂox-

ybenzyne enables the subsequent generation of a 3-phosphonyl

benzyne, which can engage numerous aryne trapping agents to

form structurally complex aryl phosphonates. This multi-

benzyne (i.e., formally 1,2-benzdiyne¹²) strategy represents an

extension of Hosoya’s aryne relay methodology and provides a

straightforward route to functionally dense 2,3-disubstituted

aryl phosphonates that would otherwise require lengthy

synthetic routes to prepare. Given the range of applications

for aryl phosphonates discussed above, the reported method-

ology will enable preparation of structurally complex analogues

to further enhance the utility of this versatile functional group.

Additionally, access to 3-phosphonyl benzynes reveals that

these unique intermediates engage lowly selective aryne

trapping agents with solvent-dependent regioselectivities. This

further demonstrates the utility of 3-phosphonyl benzynes by

enabling tunable access to regioisomeric mixtures of aryl

phosphonates. More broadly, these studies show that solvent

generally inﬂuences benzyne distortion as this eﬀect was

observed for other strained alkyne intermediates. Overall, this

report describes that the aryne-Abramov reaction provides (1)

a new strategy for the synthesis of structurally complex aryl

phosphonates, (2) an extension of aryne relay methodology,

and (3) the opportunity to study the properties of 3-

phosphonyl benzynes.

Figure 1. Comparison of previous studies to the work described in

this report. (a) Hosoya’s ﬁrst report of aryne methodology for the

synthesis of substituted anilines via 3-amino benzyne intermediates.

(b) A general representation of the Abramov reactions. (c) A

summary of the work described in this report. Structurally complex

aryl phosphonates are available under aryne relay methodology by

utilizing the aryne-Abramov reaction.

approaches for generating densely functionalized arenes.¹²

Aryne relay processes provide a convenient approach for

sequentially accessing two distinct aryne intermediates, which

are formed under complementary benzyne-generating con-

ditions (Figure 1a). The Hosoya lab ﬁrst reported this strategy

by generating 3-triﬂoxybenzyne (1) and trapping the highly

electrophilic intermediate with an N-silyl amine via N−Si bond

insertion to form a C-silyl aniline (cf. 2).¹³This initial aryne

process formed a 2-silylphenyl triﬂate moiety capable of readily

generating a second aryne (cf. 3) under standard (i.e.,

Kobayashi¹⁴) ﬂuoride-mediated conditions. Using a variety of

established aryne trapping agents, several structurally diverse

anilines (cf. 4) were readily prepared. Since this initial report,

the Li¹⁵and Hosoya¹⁶laboratories have independently

reported methods to extend aryne relay strategies for the

synthesis of α-aryl carbonyls,^15a,16a2-aryl pyridines,^15band aryl

sulﬁdes.^16b

We envisioned that aryne relay methodology could be

applied to the synthesis of aryl phosphonates using readily

available silyl phosphites (cf. 8). In general, O-silyl organo-

phosphorous agents (cf. 6) are best known for their role in the

Abramov reaction (Figure 1b), where the P(III) center

undergoes nucleophilic addition to an aldehyde or α,β-

unsaturated carbonyl with subsequent silyl transfer to form

α-siloxy (cf. 5) or silyl enol ether (cf. 7) products,

respectively.¹⁷⁻¹⁹With this in mind, it seemed viable that

silyl phosphites could engage aryne 1 by regioselective²⁰

RESULTS AND DISCUSSION

■

Optimization of Reaction Conditions. We chose to

evaluate the feasibility of the aryne-Abramov reaction using 3-

triﬂoxy benzyne precursor 13 (Table 1) and diethyl

trimethylsilyl phosphite (8a). Precursor 13 is readily prepared

in decagram quantities over two steps from resorcinol via

regioselective iodination followed by bis-triﬂation.²⁰O-Silyl

phosphites like 8a are readily prepared from silylation of the

corresponding dialkyl phosphite with chlorotrimethylsilane.²¹

As ﬁrst described by Hosoya and co-workers, 13 is capable of

forming 3-triﬂoxybenzyne 1 when treated with either organo-

lithium or Grignard reagents.^20,22Following guidance from

these studies, we initially used (trimethylsilyl)-

methylmagnesium chloride. Consistent with our hypothesis,

when 1 was generated in the presence of silylphosphite 8a, 3-

triﬂoxy-2-(trimethylsilyl)aryl phosphonate 10a was isolated in

52% yield (entry 1). Similar to prior reports involving 1,²⁰

phosphorus addition was highly regioselective, and the

alternative regioisomer was not detected. In our hands, other

conditions known^16b,22to promote eﬃcient generation of

aryne 1 from precursor 13 (entries 2−4) led to reduced yields.

Screening other routine alterations to the reaction conditions

(e.g., stoichiometry, solvent choice, solvent volume, reaction

time, temperature, and rate of reactant addition) did not

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Table 1. Aryne-Abramov Reaction Conditions Screen

entry

variation from initial conditions

yield

a

1

2

3

4

none

toluene solvent

CH₂Cl₂solvent

TMSCH₂Li·MgCl₂with n-hexane solvent in place of

TMSCH₂MgCl

OTs in place of OTf on 13

OSO₂(p-Cl)Ph in place of OTf on 13

substrate 13 added last

52%

44%

53%

14%

a

b

5

6

7

trace

77%

b

c

a

b

Isolated yield after ﬂash chromatography puriﬁcation. Yield

determined from ¹H NMR by adding 1-bromo-4-nitrobenzene to

the crude reaction mixture to serve as an internal standard. 13 added

c

as a solution in Et₂O to a mixture of 8a and TMSCH₂MgCl also

dissolved in Et₂O.

noticeably improve the reaction eﬃciency, and use of other

1,3-bis(sulfonates) failed to promote product formation

(entries 5−6). However, the isolated yield increased to 77%

when we changed the order of reactant addition such that a

diethyl ether solution of precursor 13 was added last to a dilute

mixture containing silyl phosphite 8a and the Grignard reagent

(entry 7), suggesting that diluting both 13 and the Grignard

reagent improves the eﬃciency of the transformation.

Evaluation of the Aryne-Abramov Reaction Substrate

Scope. With suitable reaction conditions in hand, we

evaluated the scope of iodophenyl bis(triﬂate) reactants

amenable to the aryne-Abramov reaction (Figure 2a). Parent

10a was isolated in 77% yield on a 0.2 mmol scale, and the

yield was unchanged when the reaction was scaled up to 3.0

mmol (i.e., 1.33 g of isolated product). Alkyl and aryl

substituents at C5 were well-tolerated, providing good yields

of products 10b and 10c. The yield of 5-bromo product 10d

reduced to nearly half of that observed with the parent

substrate. We saw no evidence that the additional halogen

provided a competitive site for the Grignard reagent to engage.

Rather, as reported by others,²²⁻²⁴the inductively withdrawing

bromine likely promotes a competitive thia-Fries rearrange-

ment, preventing formation of the aryne intermediate. Lower

yields were also observed in the formation of methyl ester 10e,

which is likely due to a combination of undesired thia-Fries

rearrangement along with competitive Grignard addition to the

ester carbonyl. Replacing the methyl ester with a more

electron-rich and sterically encumbered tert-butyl ester

provided 10f with an improved isolated yield. Not surprisingly,

complex mixtures were observed when trying to prepare the

corresponding methyl ketone (not shown). However, the

reaction proceeded smoothly with a cyclic ketal, which allowed

for the preparation of aryl phosphonate 10g. Iodophenyl

monotriﬂate 14 was amenable to the standard reaction

conditions to give 2-silyl aryl phosphonate 16, demonstrating

that benzyne itself (15) is able to participate in the aryne-

Abramov reaction. This example also highlights that the

reported conditions can form standard 2-silyl phosphonates,

which are valuable ligands for iridium-catalyzed ortho

borylation of arenes.²⁵Unlike symmetric 5-substituted

substrates, 4-hexyl aryne precursor 17 formed isomeric

Figure 2. Studies related to the substrate scope of the aryne-Abramov

reaction. (a) Scope of iodophenyl triﬂates found to participate in the

aryne-Abramov reaction. (b) Scope of O-silyl phosphites found to

participate in the aryne-Abramov reaction. (c) Attempted silyl

phosphorus nucleophiles that failed to eﬃciently form aryne-Abramov

products.

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benzyne intermediates 18 and 19, and each engaged phosphite

8a to give aryl phosphonates 10h and 10i in a ∼5:1 ratio.

The scope of silyl phosphorus nucleophiles was also assessed

(Figure 2b), which demonstrated that a number of O-silyl

phosphites are capable of readily forming product. Like the

parent example, dimethyl, diisopropyl, diphenyl, and dibenzyl

substrates aﬀorded good yields of 10j−10m, respectively.

Trimethylsilyl-containing product 10n was isolated in a similar

yield, providing an opportunity to probe the inﬂuence of

multiple silyl groups on ﬂuoride-mediated benzyne generation.

A slightly reduced yield was observed for triﬂuoroethyl-bearing

product 10o, which could be attributed to attenuated

nucleophilicity of the corresponding phosphite or reduced

stability of the phosphonate ester in the product. Aryl

dibenzo[c,e][1,2]oxaphosphonate 10p was readily prepared

using the reported methodology and represents a novel DOPO

derivativea class of molecules with a multitude of ﬂame-

retardant applications.²⁶Use of the O-TBS analogue of the

parent silylphosphite provided product 10q, albeit in reduced

yields, suggesting that the larger TBS group impedes silyl

transfer. Despite the ease with which numerous substrates were

utilized under the reported conditions to provide products

10a−10q, some silyl phosphorus nucleophiles proved un-

productive (Figure 2c). Nitrogen analogue 20 seemingly

participated in the aryne-Abramov reaction, but the corre-

sponding product rapidly decomposed following chromatog-

raphy puriﬁcation.²⁷Poor crude yields (0−10%) of the

corresponding aryne-Abramov products were observed with

O-silyl phosphine oxides 21 and 22 as well as O-silyl

phosphonite 23 and P-silyl phosphine 24. Benzyne P−Si

bond insertion has been observed with 24 as substrate,²⁸

suggesting alternative conditions for generating 3-triﬂoxyben-

zyne will likely enable use of P-silyl phosphines as substrates.

DFT Computations of the Aryne-Abramov Reaction

Mechanism. Computational investigation of the mechanism

for the aryne-Abramov reaction was conducted using DFT

(Figure 3) to evaluate the feasibility of the mechanism

proposed in Figure 1c. Intermediates and transition states were

located for the stepwise process in which silyl phosphite 8b

adds to 3-triﬂoxybenzyne (1) to form zwitterionic adduct 25. A

transition state corresponding to C1 addition was located

(TS1), and the corresponding energy barrier was low (8.5 kcal·

mol⁻¹), suggesting formation of 25 is rapid under the reaction

conditions. Interestingly, the carbon-to-phosphorus atom

distance was quite large (4.1 Å), indicating that the located

structure corresponds to an early transition state. Numerous

reports by Houk have demonstrated that nucleophile addition

to aryne intermediates preferentially occurs at strained Csp

atoms with internal bond angles that more closely resemble

those of the transition state.²⁹Consistent with these studies,

the internal bond angle at C1 of TS1 (136.4°) was similar to

the angle at C1 in the optimized ground-state geometry for

benzyne 1 (135.5°, see Supporting Information), whereas the

angle at C2 of 1 was substantially more acute (117.4°).

Formation of the intermediate zwitterionic adduct was

substantially exergonic (ΔG = −21.5 kcal·mol⁻¹), and the

Figure 3. DFT computational [B3LYP/6-311+G(2d,p) with

IEFPCM(Et₂O) solvation] studies of the mechanism for the aryne-

Abramov reaction support a stepwise mechanism involving a

zwitterionic intermediate.

which is aided by the longer carbanion-to-silicon atom distance

(2.7 Å).

Generation of 3-Phosphonyl Benzynes and Scope of

Trapping Reactants. To complete the aryne relay process,

we needed to demonstrate that a second benzyne could be

generated from products of the aryne-Abramov reaction. Using

the conventional Kobayashi¹⁴protocol for ﬂuoride-mediated

aryne generation, we studied the reaction of precursors 10a

and 10p with several symmetric dienes (Figure 4a). Treating a

mixture of 10a and furan with CsF in MeCN provided 1,4-

dihydro-1,4-epoxynaphthalene 12a in excellent yield. Similar

yields were observed with recently reported³⁰conditions using

a combination of 18-crown-6 and either KF or Cs₂CO₃.

Precursor 10p provided a similar outcome to give highly

complex DOPO analogue 26. N-Boc pyrrole and anthracene

also provided cycloadducts with 10a in good yields to give

bicyclic aryl phosphonates 12b and 12c, respectively. The

products observed from these diene trapping reactions strongly

support the proposed intermediacy of a 3-phosphonyl benzyne

like 11a. Furthermore, tetraphenylcyclopentadienone (TPCP),

another symmetric diene known³¹to react with arynes,

engaged 10a in the presence of CsF to form naphthalene

12d, presumably following decarbonylation of Diels−Alder

adduct 27.

Other trapping agents were evaluated to expand upon the

diversity of 2- and 3-substituted aryl phosphonates that can be

prepared under this aryne relay protocol (Figures 4b−d).

́

Using conditions described by Perez and Guitian for Pd-

catalyzed [2 + 2 + 2] cocyclization of benzyne with alkynes

(Figure 4b),³²aryne precursor 10a was converted into

naphthalene 12e when treated with dimethylacetylenedicar-

boxylate (DMAD), presumably via Pd-coordinated aryne 28.

Trapping 11a with nitrogen-containing 1,3-dipoles allowed us

to both prepare heterocycle-fused aryl phosphonates and probe

the regioselectivity of nonsymmetric trapping reactions (Figure

reaction continued downhill to form product 10j (ΔG_rxn

=

−41.8 kcal·mol⁻¹), likely driven by formation of the P=O π

bond and neutralization of the zwitterion. The transition state

for intramolecular silyl transfer (TS2) suggests the event is a

low-barrier process (ΔG^‡= 4.4 kcal·mol⁻¹) that proceeds with

a nearly planar arrangement of the ﬁve participating atoms,

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Figure 4. Scope studies of 3-phosphonyl benzyne generation and trapping reactions for the synthesis of structurally complex and functionally dense

aryl phosphonates. (a) Products resulting from reaction of 3-phosphonyl benzynes with diene reactants. (b) Palladium-catalyzed alkyne

trimerization involving a 3-phosphonyl benzyne. (c) Cycloaddition and observed regioselectivity of benzyne 11a with several 1,3-dipoles. (d)

Insertion of 3-phosphonyl benzynes into C−C σ bonds. ^aTrace amounts of regioisomeric products were observed in crude reaction mixtures but we

were not able to isolate suﬃcient quantities to conﬁrm their structure.

4c). Nitrone 29 readily reacted under the usual conditions,

providing dihydrobenzisoxazole 12f with trace amounts of

regioisomer 12g. Consistent with previous reports involving

benzynes with 3-amino,¹³3-thionyl,^16band 3-halo²⁴sub-

stitution, the reaction led to preferential C−C bond formation

at C2 of the aryne intermediate to give the seemingly more

sterically congested product. The degree of observed

regioselectivity was again large when the same aryne

intermediate was trapped by ethyl diazoacetate to give 7-

phosphonyl indazole 12h without detectable formation of C4

isomer 12i. However, reduced selectivity was observed in the

aryne click reaction³³with benzyl azide, providing triazole

regioisomers 12j and 12k with an observed regioisomer ratio

of ∼3:1 in the crude reaction mixture. 3-Phosphonyl benzynes

were also shown to engage 1,3-dicarbonyls to give products

resulting from C−C σ bond insertion (Figure 4d) where both

10a and 10p engaged ethyl benzoylacetate to form benzoylated

phenylacetates 12l and 30, respectively.

Studies Related to the Regioselectivity of 3-

Phosphonyl Benzyne Trapping Reactions. An important

feature of aryne relay processes is the opportunity to study

properties of otherwise inaccessible aryne intermediates.

Several reports have demonstrated that the regioselectivity of

azide cycloadditions with substituted benzynes is strongly

inﬂuenced by the electronic nature of the aryne substitu-

ents.^29,34Speciﬁcally, electronegative groups at C3 direct the

reaction to preferentially add the alkylated nitrogen of the

azide to C1 of the aryne. This results in the distal benzotriazole

regioisomer (e.g., 31a−c, Figure 5a), where the N-alkyl is

situated away from the C3-substituent. Conversely, reduced

distal selectivity is observed with less electronegative groups at

C3, providing an opportunity for formation of the proximal

regioisomer (e.g., 32a−c). We hypothesized that equipping the

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containing aryl phosphonate, where the distal:proximal ratio

(31b:32b = 3.1:1) was similar to that of the dimethyl (31a:32a

= 3.3:1) and diethyl (12j:12k = 3.1:1 in Figure 4c) analogues.

However, the electronegative bis(triﬂuoroethyl) phosphonyl

benzyne showed a nearly 3-fold increase in selectivity for distal

regioisomer 31c, leading to minimal amounts of proximal

product 32c (regioisomer ratio = 7.9:1). This demonstrates

that distant inductive eﬀects can inﬂuence the reactivity of 3-

phosphonyl benzynes, which provides a straightforward

approach to improving the regioselectivity obtained with

unsymmetric trapping reactants.

We turned to DFT computations³⁵to gain deeper insight

into the inﬂuence of the phosphonyl esters on the ratios

reported in Figure 5a. Numerous reports by Garg and

Houk^29,36along with early studies by Buszek and Cramer³⁷

have demonstrated that the regioselectivity of aryne trapping

reactions can be inferred from the relative internal bond angles

of the sp-hybridized carbons within the DFT-optimized

geometries. These studies show that nucleophilic addition to

the aryne intermediate is more likely to occur at the carbon

with the greater (i.e., more obtuse) internal bond angle. Garg

and Houk have rationalized this using the distortion-

interaction model.³⁸Namely, the more obtuse Csp atom

better resembles the electrophilic site within the transition

state, which must distort to a more linear geometry upon

approaching the nucleophile. Nucleophilic addition to the Csp

atom with the smaller internal bond angle requires additional

distortion energy to reach the transition state geometry,

thereby increasing the reaction barrier and decreasing the rate

of regioisomer formation.^29,36Garg and Houk explain the role

of substituent electronegativity on benzyne distortion in the

context of Bent’s rule.³⁹Namely, increasing electronegativity at

C3 encourages greater p-character on the in-plane (i.e.,

nonaromatic) π bond at C1, resulting in a larger internal

bond angle.^29,36Given the ample precedence described above,

benzyne distortion within the dimethyl, bis-

(trimethylsilylmethyl), and bis(triﬂuoroethyl) phosphonyl

arynes (33a−c, Figure 5b) were determined from DFT-

optimized geometries. All benzynes were distorted such that

C1 was more obtuse than C2, suggesting that benzyl azide will

react with each intermediate to preferentially form the distal

regioisomer. These results are consistent with the exper-

imentally observed regioselectivities. Furthermore, the en-

hanced distal selectivity observed in the case of the more

electronegative benzyne 33c is reﬂected in a more pronounced

distortion at C1 (5.6°). The computed geometry of the

electron-rich trimethylsilyl-containing phosphonate, 33b,

showed reduced distortion (1.2°) and a less obtuse C1

internal bond angle. This suggests that we should observe a

reduced preference for distal product 31b in the reaction with

benzyl azide. However, because the experimental regioselec-

tivity was similar to that of the dimethyl and diethyl variants,

sterics likely impede nucleophilic addition to C2. A similar

steric eﬀect has been observed by Garg and Houk in the case

of the heavily C2 distorted triethylsilylbenzyne.⁴⁰

Figure 5. (a) Reactions of several 3-phosphonyl benzynes (33a−c)

with benzyl azide. Electronegative phosphonate esters greatly

inﬂuence trapping regioselectivity. Yields are isolated, and the

regioisomeric ratios (i.e., rr values) correspond to the ratio of

distal:proximal products observed in the ¹H NMR spectra of the

crude reaction mixtures. (b) DFT-optimized [B3LYP/6-311+G(2d,p)

with IEFPCM(MeCN) solvation] geometries, Csp internal bond

angles, and benzyne distortion (i.e., diﬀerence in internal bond angle

at C1 and C2) of 3-phosphonylbenzynes 33a−c. The degree of

benzyne distortion in the computed structures is dependent on the

phosphonate ester. (c) Computed [B3LYP/6-311+G(2d,p) with

IEFPCM(MeCN) at 348.15 K] transition state geometries for

formation of the distal and proximal products of benzyne 33a with

methyl azide. The distal transition state is lower in energy, suggesting

the distal product is preferentially formed, which is consistent with

experimental regioselectivities using benzyl azide. However, the

predicted regioselectivity based on the ΔΔG^‡greatly exceeds that

observed experimentally. The ΔΔG^‡values were determined from the

diﬀerence in free energies of the distal and proximal transition states.

3-phosphonyl benzynes with ester groups of varying electro-

negativities would inﬂuence the regioselectivities of azide

trapping reactions. To test this, we carried out reactions of

benzyl azide with precursors to dimethyl, bis-

(trimethylsilylmethyl), and bis(triﬂuoroethyl) phosphonyl

benzynes (33a−c, respectively). Consistent with the involve-

ment of an aryne intermediate, a mixture of distal and proximal

regioisomers was obtained in all cases. Contrary to our

proposed hypothesis, there was no substantial diﬀerence in

regioselectivity when using the seemingly electropositive silyl-

The experimental results and benzyne distortion computa-

tions suggest that the activation energy corresponding to distal

product formation should be lower than that of the proximal

isomer. DFT computations allowed us to locate geometries of

both transition states (Figure 5c) for the reaction of dimethyl

phosphonyl benzyne 33a with methyl azide, which showed that

the transition state for forming the distal product was indeed

lower in energy. However, the ΔΔG^‡of 2.9 kcal·mol⁻¹predicts

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Figure 6. Inﬂuence of including a solvation model on the distortion of DFT geometry optimized [B3LYP/6-311G+(2d,p)] strained alkyne

intermediates. Distortion is the diﬀerence in the internal bond angles at C1 and C2. (a) Comparison of DFT-optimized geometries for 3-

phosphonyl arynes 33a−c with [IEFPCM(MeCN)] and without (i.e., gas phase) inclusion of an implicit solvation model. Including MeCN implicit

solvation results in geometries with a more obtuse internal bond angle at C1 and more positive benzyne distortion. (b) A plot showing the

inﬂuence of the type of implicit solvent on the distortion of 33a−c. Use of a solvent with a greater dielectric constant increases the observed

benzyne distortion. The dielectric constants (ε) provided for each solvent refer to ambient temperature values. (c) A plot showing the inﬂuence of

the dielectric constant of the IEFPCM implicit solvent model on the distortion of several 3-substituted benzynes. Aside from the dielectric constant,

all other implicit solvent attributes are those of MeCN. (d) Comparison of distortion values of DFT-optimized geometries for several strained

alkyne intermediates with [IEFPCM(MeCN)] and without (gas phase) inclusion of an implicit solvation model. The change in distortion (i.e.,

Δdistortion) is the diﬀerence in distortion of the MeCN and gas-phase geometries. The iodinated benzynes were computed with LANL2DZ for the

iodine atoms.

a regioselectivity >60:1,⁴¹which greatly exceeds the exper-

imentally observed 3:1 distal:proximal ratio which requires

∼0.8 kcal·mol⁻¹. A similar overestimation of ΔΔG^‡values for

azide trapping reactions was observed by Garg and Houk.²⁹To

better represent the actual system, we repeated the transition

state calculations with a single conformation of benzyl azide,

but the ΔΔG^‡actually increased to 3.4 kcal·mol⁻¹, predicting

an even larger (>130:1)⁴¹preference for the distal product (cf.

the Supporting Information). Furthermore, despite consid-

erable eﬀort,⁴²we were not able to locate the distal transition

state involving the more highly regioselective bis-

(triﬂuoroethyl) phosphonyl benzyne 33c. Collectively, these

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eﬀorts suggest that structural complexities of the 3-phosphonyl

arynes preclude eﬃcient DFT transition state computations,

further demonstrating the utility of benzyne distortion analysis

to understand and predict experimental regioselectivities.

During the course of the computational studies, we noticed

an interesting trend when comparing benzyne geometry

optimizations performed with and without implicit solvation.

Many previously reported computational studies of benzyne

and aryne distortion have relied on calculations performed in

the absence of solvation modeling (i.e., gas-phase calculation-

s).^{29,34a,36,37,43}Following these reports, we initially computed

the optimal geometries of the phosphonyl benzyne inter-

mediates described above without including a solvation model

(cf. gas structures in Figure 6a). In each case, the relative

distortion was noticeably (3.4−3.6°) lower than those

observed when including an implicit solvation model of

acetonitrile (IEFPCM⁴⁴). Furthermore, the gas-phase calcu-

lations of the dimethyl and bis(trimethylsilyl)methyl phos-

phonyl benzynes gave structures with negative distortion

values. These structures not only predict that the C2 internal

bond angle of arynes 33a and 33b is more obtuse but also

suggest that the intermediates are electronically predisposed

toward formation of the proximal product in the reaction with

benzyl azide, which is inconsistent with the experimental

regioselectivities. The eﬀect was also present when we

performed the computations with alternative implicit solvation

models (e.g., CPCM⁴⁴or SMD⁴⁵) or diﬀerent DFT methods

(e.g., M06-2X⁴⁶or M06L⁴⁷), and C1 was more obtuse when

MeCN solvation was included, whereas C2 was more obtuse in

the gas-phase structures (cf. the Supporting Information).

Interestingly, the distortion measured with the MP2⁴⁸ab initio

method remained negative (−1.7° and −1.9°) both with and

without inclusion of a solvation model for MeCN. Inspection

of alternative conformations for each of the three phosphonyl

arynes showed the eﬀect was present across conformational

space (cf. the Supporting Information).

The substantial impact of including an MeCN solvation

model described above led us to consider if the degree of

benzyne distortion was solvent-dependent. We computed the

geometry of benzynes 33a−c with an IEFPCM solvation

model for a variety of common solvents (Figure 6b).

Interestingly, benzyne distortion increases with the solvent

dielectric constant where the distortion of 33a and 33b in 1,4-

dioxane and toluene was actually negativesimilar to that

observed for the gas-phase calculations. Furthermore, the

electronegativity of the ester group continued to inﬂuence the

internal bond angles as electron-rich silyl-containing benzyne

33b consistently possessed the lowest distortion value, whereas

that observed in bis(triﬂuoroethyl)-containing 33c was both

positive and gave the largest C1 distortion with all solvents.⁴⁹

Because the inﬂuence of implicit continuum solvation models

is largely due to the dielectric constant (i.e., epsilon value, ε),⁵⁰

we measured the degree of benzyne distortion in 33a as the

epsilon value was increased from 1.1 to 100, keeping all other

solvation model parameters constant for MeCN (Figure 6c).

While initially negative (i.e., C2 obtuse), the distortion sharply

increased between 1.1−10 epsilon units before plateauing with

minimal change from the MeCN distortion as epsilon

approached 100. A similar study was conducted on 3-methoxy

(R′ = OMe), 3-iodo (R′ = I), and 3-trimethylsilyl (R′ = TMS)

benzynes, all of which were similar in that the greatest change

in distortion occurred at lower epsilon values. 3-Iodobenzyne

had an overall more positive distortion than 33a but otherwise

showed a similar trend as the phosphonyl aryne. Highly

distorted 3-methoxybenzyne was minimally aﬀected by the

solvent dielectric, providing the smallest overall change in

distortion (0.9°). Negatively distorted (i.e., C2 obtuse) 3-

trimethylsilylbenzyne showed the largest dependence on

epsilon, changing by 4.2°, and in contrast to the other

benzynes, the distortion became more negative as the dielectric

constant of the solvation model increased. It is interesting to

note that while all benzyne intermediates were uniquely

aﬀected by the solvent dielectric, 33a was the only example to

cross the x-axis, providing C2 obtuse structures when ε < 3 and

C1 obtuse structures when ε ≥ 3.

Assuming the epsilon value for the gas-phase structures was

that of free space (ε = 1), the distortion values from the gas-

phase optimizations of each benzyne shown in Figure 6c

actually ﬁt the trend observed when implicit solvation is

included. This indicates that the gas-phase calculations provide

a practical lower limit of distortion, and the overall inﬂuence of

the solvent dielectric can be readily assessed by comparing the

gas-phase and MeCN-solvated DFT-optimized geometries.

With this in mind, we determined the diﬀerence in benzyne

distortion, Δdistortion, of the MeCN and gas-phase geo-

metries for a variety of strained alkynes (Figure 6d). Overall,

the Δdistortion values ranged from negligible (e.g., −0.3° for

37) to 6° (i.e., cyclohexyne 38), demonstrating that benzyne

intermediates possess variable polarizabilities that are highly

substituent-dependent. 3-Fluorobenzyne (34) exhibited a

larger distortion than the 3-OMe analogue (data in Figure

6c) and showed a much greater solvent dependence

(Δdistortion = 3.7°), similar to that of 3-iodobenzyne

(Δdistortion = 3.2°, data in Figure 6c). In contrast, the C4

substitution of iodobenzyne 35 led to a substantially reduced

Δdistortion, but of the several benzynes we studied, 35 was the

only example like the 3-phosphonyl benzynes where the

distortion in the gas-phase and MeCN-solvated structures had

opposite signs. The gas-phase structure of 3,4-pyridyne (36) is

weakly distorted, suggesting this intermediate is minimally

predisposed to favor nucleophile addition to C4. It is then

interesting to note that including an MeCN implicit solvation

model led to greater distortion, approaching the 4° threshold

considered necessary to provide highly regioselective aryne

trapping reactions.⁴³3-Substituted cyclohexynes were also

considered where, similar to 34, ﬂuoride-substituted 38 had a

large Δdistortion. However, in contrast to 3-methoxybenzyne

(R′ = OMe in Figure 6c), 3-methoxycyclohexyne (39) had a

large Δdistortion, suggesting substituted cyclohexynes are

more polarizable than their aromatic counterparts. The

unusual polarizability observed with 3-trimethylsilylbenzyne

(R′ = TMS in Figure 6c) led us to evaluate electropositive-

substituted benzynes 40 and 41. Interestingly, neither of these

structures showed as signiﬁcant solvent dependence as that of

the silylated benzyne (Δdistortion = 4.2°), and their

distortions varied by only ∼1°. Furthermore, the change in

distortion was also inconsistent, and the Δdistortion of boron-

substituted 40 increased, whereas tert-butyl benzyne 41

behaved like the silyl variant and was more strongly C2

distorted when solvent was included in the calculation.

Collectively, these data indicate that it is likely necessary to

include a solvation model when computing structures of

strained alkyne intermediates. Furthermore, as is shown in

Figure 5, the solvated structures likely serve as a better

predictor of regioselectivity for weakly selective trapping

reactions.

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The computational studies of benzyne distortion discussed

in Figures 5 and 6 suggest that the regioselectivity observed in

benzyne trapping reactions could be solvent-dependent. To

test this experimentally, we carried out benzyl azide trapping

reactions with several phosphonyl benzyne precursors in a

variety of common solvents (Figure 7). Consistent with the

CONCLUSION

■

This report provides the ﬁrst account of an Abramov-like

reaction of O-silyl phosphites with benzyne intermediates.

Under straightforward conditions, this “aryne-Abramov”

reaction proceeded with a number of benzyne precursors

and O-silyl phosphites to provide 2-silyl aryl phosphonates via

concomitant C−P and C−Si bond formation. Moreover, by

engaging a 3-triﬂoxyaryne intermediate, the resulting product

was capable of ﬂuoride-mediated formation of a second (3-

phosphonyl) benzyne intermediate. This extension of aryne

relay methodology proved useful as the 3-phosphonyl benzyne

readily engaged a number of aryne trapping agents to provide a

variety of structurally complex 2,3-disubstituted aryl phospho-

nates. The trapping reaction with benzyl azide provided a

mixture of regioisomers, and DFT computations of benzyne

distortion with MeCN implicit solvation accounted for the

observed preference for nucleophile addition at C1. Appending

electronegative ester groups onto the 3-phosphonyl benzyne

led to increased distortion in the computed structure and

enhanced regioselectivity in the reaction with benzyl azide.

Furthermore, an extensive probe of the inﬂuence of solvation

on benzyne distortion and trapping regioselectivity revealed

that 3-substituted benzynes are somewhat polarizable.

Speciﬁcally, these aryne intermediates showed variable degrees

of computed distortion and experimental regioselectivity

depending on the polarity of the solvent, and the formerly

minor isomer was favored when reactions were conducted in

nonpolar solvents. Collectively, the results summarized in this

report (1) demonstrate the versatility of the aryne-Abramov

process for the preparation of aryl phosphonates and (2)

underscore the numerous opportunities in synthesis and

physical organic chemistry available from studies into the

aryne relay methodology.

Figure 7. Plot depicting the inﬂuence of solvent on the observed

distal regioisomer excess for the reaction of several 3-phosphonyl

benzyne precursors with benzyl azide. Regioselectivity increases with

solvent polarity, and use of low dielectric solvents substantially

attenuates the distal selectivity observed in higher dielectric solvents

like acetonitrile. The dielectric constants (ε) provided for each solvent

refer to ambient temperature values.

EXPERIMENTAL SECTION

General. NMR Spectra were recorded on a 300 MHz NMR. H

■

1

computational results shown in Figure 6b,c, conducting the

reaction in solvents with a dielectric constant less than 10 (i.e.,

1,4-dioxane, toluene, and THF) gave attenuated regioselectiv-

ities for all substrates. Solvents with a larger dielectric (i.e.,

DCE, acetone, and i-PrCN) provided a preference for the

distal isomer similar to that observed with MeCN. While

experimental solvent eﬀects certainly extend far beyond

polarity, especially for substrates capable of participating in

π-stacking interactions, it is remarkable the extent to which the

observed selectivities agree with the distortion measured in the

computed geometries. Furthermore, the regioisomer prefer-

ence of all except for the CF₃-containing substrate inverted in

toluene, and the proximal product was formed as the major

regioisomer. Additionally, the inﬂuence of ester electro-

negativity emerged to a larger extent in the ethereal solvents,

where ethyl and trimethylsilylmethyl aryl phosphonates

showed the greatest preference for the proximal product.

The electronegative CF₃-containing phosphonyl benzynes had

the largest distal selectivity in all cases, but it is noteworthy that

the observed regioisomer excess in 1,4-dioxane approached

that of the dimethyl analogue. Collectively, these results clearly

demonstrate that solvent choice can greatly inﬂuence the

regioselectivity in the reaction of azides with benzynes,

providing a practical approach to tune the product ratio and

improve access to minor regioisomers. Additionally, to the best

of our knowledge, this represents the ﬁrst reported example of

solvent choice leading to inversion of regioselectivity in an

aryne trapping reaction.

NMR chemical shifts in CDCl₃are referenced to TMS (δ 0.00 ppm).

¹³C NMR data were acquired with ¹H decoupling, and chemical shifts

in CDCl₃are referenced to chloroform (δ 77.16 ppm). ¹⁹F NMR data

were acquired with ¹³C decoupling, and chemical shifts are referenced

to hexaﬂuorobenzene added (ca. 0.05% v/v) as an internal standard

(δ −163.00 ppm).⁵¹³¹P NMR data were acquired with ¹H

decoupling, and chemical shifts are referenced using a phosphoric

acid external standard (δ 0.00 ppm). High-resolution mass

spectrometry (HRMS) measurements were performed on an Agilent

6230 LC/MS accurate-mass time-of-ﬂight (TOF) instrument, using

electrospray ionization (ESI) calibrated against purine ([M+H⁺]

requires 121.0509 m/z) and hexakis(1H,1H,3H-perﬂuoropropoxy)-

phosphazene ([M+H⁺] requires 922.0098 m/z). Reactions needing

anhydrous conditions were performed in glassware that had been

dried in an oven. Reactions performed with less than 5 mmol of

starting material were carried out in screw cap vials or culture tubes

ﬁtted with a Teﬂon-lined cap.

General Procedure A: Synthesis of o-Silyl Triﬂate-Contain-

ing Aryl Phosphonates via Aryne Abramov Reaction with

(Trimethylsilyl)methyl Magnesium Chloride. A solution of 2-

iodophenyl bis(triﬂate) (e.g., 13, 0.2 mmol, 1 equiv) in Et₂O (1.0

mL) was added dropwise to a solution of silyl phosphite (0.4 mmol, 2

equiv) and (trimethylsilyl)methyl magnesium chloride (0.4 mL, 2

equiv, 1.0 M solution in Et₂O) in Et₂O (1.0 mL, excluding volume

from Grignard reagent) at 0 °C with stirring. To ensure quantitative

transfer of the 2-iodophenyl bis(triﬂate), the vial containing the 2-

iodophenyl bis(triﬂate) solution was rinsed with Et₂O (3 × 0.1 mL).

The overall reaction concentration was ∼0.07 M in 2-iodophenyl

bis(triﬂate) (i.e., 0.2 mmol in ∼2.7 mL of Et₂O). After 1 h, the

mixture was quenched with aqueous 1 M HCl and extracted with

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EtOAc. The organic extract was washed with brine, dried (MgSO₄),

and concentrated. The crude product was puriﬁed by ﬂash

chromatography.

chromatography (SiO₂, hexanes:EtOAc 7:3) gave aryl phosphonate

10b (70. mg, 0.16 mmol, 71%) as a clear, colorless oil. ¹H NMR (300

MHz, CDCl₃): δ 7.77 (d, J = 14.2 Hz, 1H), 7.26 (s, 1H), 4.03−4.24

(m, 4H), 2.42 (s, 3H), 1.35 (t, J = 7.1 Hz, 6H), and 0.49 (s, 9H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 155.7 (d, J = 29.9 Hz), 141.3 (d,

J = 17.2 Hz), 137.1 (d, J = 191.3 Hz, C_aryl-P), 134.6 (d, J = 23.1 Hz),

134.3 (d, J = 10.3 Hz), 124.5 (d, J = 3 Hz), 118.6 (q, J = 320.2 Hz,

CF₃), 62.4 (d, J = 5.8 Hz), 21.2, 16.4 (d, J = 6.9 Hz), and 2.4.

¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.9. ³¹P{¹H} NMR (121

MHz, CDCl₃): δ 18.2. IR (neat): 2985, 2907, 1602, 1421, 1247, 1216,

1143, 1098, 1054, 1024, 959, 890, 850, 812, and 765 cm⁻¹. HRMS

(ESI) m/z: [M+Na⁺] calcd for C₁₅H₂₄F₃NaO₆PSSi⁺requires

471.0645; found 471.0645.

General Procedure B: Synthesis of Silyl Phosphites.

Chlorotrimethylsilane (1.4 equiv) was added to a solution of

phosphorus substrate (1.0 equiv) and triethylamine (1.2 equiv) in

CH₂Cl₂(0.2 M) at 0 °C with stirring. After 60 min, the mixture was

concentrated under reduced pressure to remove dichloromethane and

excess chlorotrimethylsilane, and the residue was diluted with hexanes

and ﬁltered through a plug of Celite (hexanes eluent). The resulting

solution was concentrated under reduced pressure to give crude silyl

phosphite with between ∼75% and >99% purity, where the major

impurity is the starting phosphorus agent.

If the residue contained visible amounts of triethylammonium

chloride (i.e., white crystalline solids), the product was again diluted

in hexanes and ﬁltered through a cotton plug. The ﬁltrate was

concentrated to give the silyl phosphite product.

5-(Diethoxyphosphoryl)-4-(trimethylsilyl)-[1,1′-biphenyl]-3-yl

Triﬂuoromethanesulfonate (10c).

Because of the sensitivity of most silyl phosphites to convert into the

starting dialkyl phosphites, all steps in the aforementioned procedure

should be carried out in the same day. Additionally, the resulting silyl

phosphite should be used immediately or diluted in benzene and frozen for

long-term storage.

Aryl phosphonate 10c was prepared according to General Procedure

A from a solution of 4-iodo-[1,1 ′-biphenyl]-3,5-diyl bis-

(tri ﬂ uoromethanesulfonate)^15a(113 mg, 0.196 mmol) in Et₂O (1

mL) and a mixture of diethyl trimethylsilyl phosphite (8a, 83 mg, 0.40

mmol) and (trimethylsilyl)methyl magnesium chloride (0.4 mL, 0.4

mmol, 1.0 M in Et₂O) in Et₂O (1 mL). Puriﬁcation by gradient ﬂash

chromatography (SiO₂, hexanes:EtOAc 9:1 to 7:3) gave aryl

phosphonate 10c (77 mg, 0.15 mmol, 77%) as a white solid. ¹H

NMR (300 MHz, CDCl₃): δ 8.16 (dd, J = 1.9, 14.5 Hz, 1H), 7.66 (d,

J = 1.8 Hz, 1H), 7.59 (br d, J = 7 Hz, 2H), 7.41−7.53 (m, 3H), 4.07−

4.27 (m, 4H), 1.37 (t, J = 7.1 Hz, 6H), and 0.54 (s, 9H). ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 156.1 (d, J = 29.9 Hz), 143.7 (d, J = 17.2

Hz), 138.1 (d, J = 192.0 Hz, C_aryl-P), 138.0 (d, J = 1.6 Hz), 136.5 (d, J

= 23.0 Hz), 131.8 (d, J = 10.6 Hz), 129.4 (2xC), 129.0, 127.2 (2xC),

122.2 (br), 118.6 (q, J = 320.2 Hz, CF₃), 62.6 (d, J = 6.2 Hz), 16.4 (d,

J = 6.1 Hz), and 2.4. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.7.

³¹P{¹H} NMR (121 MHz, CDCl₃): δ 17.8. IR (neat): 2985, 2905,

1596, 1421, 1248, 1215, 1143, 1088, 1053, 1024, 967, 925, 851, 811,

3-(Diethoxyphosphoryl)-2-(trimethylsilyl)phenyl Triﬂuorometha-

nesulfonate (10a).

[0.1 g Scale ] Aryl phosphonate 10a was prepared according to General

Procedure A from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(109

mg, 0.218 mmol) in Et₂O (1 mL) and a mixture of diethyl

trimethylsilyl phosphite (8a, 91 mg, 0.433 mmol) and (trimethylsilyl)-

methyl magnesium chloride (0.4 mL, 0.4 mmol, 1.0 M in Et₂O) in

Et₂O (1 mL). Puriﬁcation by ﬂash chromatography (SiO₂,

hexanes:EtOAc 7:3) gave aryl phosphonate 10a (73 mg, 0.168

mmol, 77%) as a clear, colorless oil.

[1.0 g Scale] Aryl phosphonate 10a was prepared according to

General Procedure A from a solution of 2-iodophenyl bis(triﬂate) 13

(1.97 g, 3.94 mmol) in Et₂O (20 mL) and a mixture of diethyl

trimethylsilyl phosphite (8a, 1.7 g, 8.1 mmol) and (trimethylsilyl)-

methyl magnesium chloride (8.0 mL, 8.0 mmol, 1.0 M in Et₂O) in

Et₂O (20 mL). Puriﬁcation by gradient ﬂash chromatography (SiO₂,

hexanes:EtOAc 4:1 to 7:3) gave aryl phosphonate 10a (1.33 g, 3.06

mmol, 77.7%) as a clear, colorless oil. ¹H NMR (300 MHz, CDCl₃): δ

7.93 (ddd, J = 0.96, 7.0, 14 Hz, 1H), 7.43−7.55 (m, 2H), 4.04−4.24

(m, 4H), 1.35 (t, J = 7.1 Hz, 6H), and 0.52 (s, 9H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 155.6 (d, J = 28.8 Hz), 138.6 (d, J = 23.1 Hz),

137.7 (d, J = 191.9 Hz, C_aryl-P), 133.2 (d, J = 10.3 Hz), 130.4 (d, J =

16.4 Hz), 124.0 (d, J = 3 Hz), 118.6 (q, J = 320.2 Hz, CF₃), 62.5 (d, J

= 6.2 Hz), 16.3 (d, J = 6.1 Hz), and 2.4. ¹⁹F{¹³C} NMR (282 MHz,

CDCl₃): δ −74.8. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 17.6. IR

(neat): 2987, 2907, 1586, 1552, 1423, 1405, 1249, 1215, 1143, 1113,

1053, 1025, 968, 910, 850, 800, and 767 cm⁻¹. HRMS (ESI) m/z: [M

+Na⁺] calcd for C₁₄H₂₂F₃NaO₆PSSi⁺requires 457.0488; found

457.0478.

and 764 cm⁻¹

.

HRMS (ESI) m/z: [M+Na⁺] calcd for

C₂₀H₂₆F₃NaO₆PSSi⁺requires 533.0801; found 533.0811. mp: 60−

63 °C.

5-Bromo-3-(diethoxyphosphoryl)-2-(trimethylsilyl)phenyl Tri-

ﬂuoromethanesulfonate (10d).

Aryl phosphonate 10d was prepared according to General Procedure

A from a solution of 5-bromo-2-iodo-1,3-phenylene bis-

(tri ﬂ uoromethanesulfonate)^15a(111 mg, 0.192 mmol) in Et₂O (1

mL) and a mixture of diethyl trimethylsilyl phosphite (8a, 88 μL,

0.385 mmol) and (trimethylsilyl)methyl magnesium chloride (0.4

mL, 0.4 mmol, 1.0 M in Et₂O) in Et₂O (1 mL). Puriﬁcation by ﬂash

chromatography (SiO₂, hexanes:EtOAc 6:1) gave aryl phosphonate

10d (44 mg, 0.86 mmol, 44%) as a clear, colorless oil. ¹H NMR (300

MHz, CDCl₃): δ 8.05 (dd, J = 1.7, 14.2 Hz, 1H), 7.60 (d, J = 1.5 Hz,

1H), 4.06−4.26 (m, 4H), 1.36 (t, J = 7.1 Hz, 6H), and 0.50 (s, 9H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 155.1 (d, J = 30.0 Hz), 139.4 (d,

J = 191.8 Hz, C_aryl-P), 137.5 (d, J = 22.7 Hz), 136.1 (d, J = 10.5 Hz),

127.0, 123.7 (d, J = 23 Hz), 118.5 (q, J = 320.1 Hz, CF₃), 62.9 (d, J =

6.0 Hz), 16.4 (d, J = 6.6 Hz), and 2.2. ¹⁹F{¹³C} NMR (282 MHz,

CDCl₃): δ −74.7. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 15.7. IR

(neat): 2986, 2907, 1567, 1533, 1426, 1366, 1250, 1216, 1144, 1052,

1023, 969, 922, 851, 802, and 761 cm⁻¹. HRMS (ESI) m/z: [M+Na⁺]

calcd for C₁₄H₂₁BrF₃NaO₆PSSi⁺requires 534.9593; found 534.9592.

3-(Diethoxyphosphoryl)-5-methyl-2-(trimethylsilyl)phenyl Tri-

ﬂuoromethanesulfonate (10b).

Aryl phosphonate 10b was prepared according to General Procedure

A from a solution of 2-iodo-5-methyl-1,3-phenylene bis-

(tri ﬂ uoromethanesulfonate)^15a(115 mg, 0.224 mmol) in Et₂O (1

mL) and a mixture of diethyl trimethylsilyl phosphite (8a, 94 mg,

0.448 mmol) and (trimethylsilyl)methyl magnesium chloride (0.4

mL, 0.4 mmol, 1.0 M in Et₂O) in Et₂O (1 mL). Puriﬁcation by ﬂash

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Methyl 4-Iodo-3,5-bis(((triﬂuoromethyl)sulfonyl)oxy)benzoate

(E1).

∼13.5 mmol) was added to a mixture of NaHCO₃(3.4 g, 41 mol),

water (23 mL), and THF (7 mL) and cooled to 0 °C with stirring.

After 5 min, a solution of iodine (6.9 g, 27 mmol) in THF (16 mL)

was added by syringe pump over 30 min with stirring. One hour after

complete addition of the iodine solution, the resulting mixture was

diluted with diethyl ether, washed with 10% aqueous Na₂S₂O₃and

brine, dried (Na₂SO₄), and concentrated to give the crude iodo

resorcinol E2 (3.21 g, 9.55 mmol, 49% crude over three steps) as a

brown solid. The crude material was suﬃciently pure for subsequent

experiments. ¹H NMR (300 MHz, CDCl₃): δ 7.18 (s, 2H), 6.02 (br s,

2H), and 1.58 (s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 165.3,

156.0, 134.3, 107.9, 82.6, 82.2, and 28.3. IR (neat): 3424, 3207, 3183,

3001, 2973, 1672, 1603, 1586, 1422, 1375, 1288, 1258, 1211, 1157,

1126, 1040, 1023, 975, 867, 842, and 775 cm⁻¹. HRMS (ESI) m/z:

Tri ﬂ uoromethanesulfonic anhydride (1.5 mL, 8.9 mmol) was added

dropwise over 15 min to a mixture of methyl 3,5-dihydroxy-4-

iodobenzoate⁵³(1.26 g, 4.29 mmol), N,N-diisopropylethylamine (1.6

mL, 9.1 mmol), and CH₂Cl₂(10 mL) at −78 °C with stirring. After 1

h, the cooling bath was removed. The mixture was allowed to warm at

room temperature over 30 min, and water was added (3 mL). The

resulting mixture was diluted with NaHCO₃and extracted three times

with CH₂Cl₂. The organic extracts were combined, dried (MgSO₄),

and concentrated. Puriﬁcation by gradient ﬂash chromatography

(SiO₂, hexanes:EtOAc 19:1 to 9:1) gave 2-iodophenyl bis(triﬂate) E1

(1.39 g, 2.49 mmol, 58%) as a yellow oil, which partially solidiﬁed on

+

[M+Na⁺] calcd C₁₁H₁₃INaO₄requires 358.9751; found 358.9750.

mp: 148−153 °C.

tert-Butyl 4-Iodo-3,5-bis(((triﬂuoromethyl)sulfonyl)oxy)benzoate

(E3).

1

standing. H NMR (300 MHz, CDCl₃): δ 7.96 (s, 2H) and 3.99 (s,

3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 163.4, 151.8, 133.8, 122.1,

118.8 (q, J = 321.2 Hz, CF₃), 94.1, and 53.5. ¹⁹F{¹³C} NMR (282

MHz, CDCl₃): δ −74.0. IR (neat): 3103, 2961, 1720, 1428, 1301,

1251, 1217, 1142, 1135, 999, 988, 846, 796, and 768 cm⁻¹. HRMS

+

(ESI) m/z: [M+Na⁺] calcd for C₁₀H₅F₆INaO₈S₂requires 580.8267;

found 580.8280.

Tri ﬂ uoromethanesulfonic anhydride (0.85 mL, 5.0 mmol) was added

dropwise over 15 min to a mixture of the crude iodo resorcinol E2

(0.807 g, 2.40 mmol), N ,N -diisopropylethylamine (0.89 mL, 5.1

mmol), and CH₂Cl₂(8.00 mL) at −78 °C with stirring. After

complete addition of tri ﬂ uoromethanesulfonic anhydride, the cooling

bath was removed. After the mixture was stirred for an additional

hour, water was added (2.5 mL). The resulting mixture was diluted

with NaHCO₃and extracted three times with CH₂Cl₂. The organic

extracts were combined, dried (MgSO₄), and concentrated. The crude

material was dissolved in an Et₂O:hexanes solution (100 mL, 1:1);

silica gel (10 g) was added, and the mixture was set to stir. After 10

min, the mixture was ﬁ ltered through a plug of silica gel (1:1

Et₂O:hexanes eluent), and the ﬁ ltrate was concentrated to give

bis(tri ﬂ oxy)arene E3 (1.38 g, 2.30 mmol, 96%) as an o ﬀ -white

crystalline solid, which was su ﬃ ciently pure for subsequent reactions.

White crystals could be obtained by recrystallization with hexanes. On

smaller scales, the material can be puri ﬁ ed by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 39:1 to 19:1). ¹H NMR

(300 MHz, CDCl₃): δ 7.90 (s, 2H) and 1.61 (s, 9H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 161.8, 151.7, 135.8, 122.0, 118.8 (q, J = 321 Hz,

CF₃), 93.5, 84.0, and 28.1. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ

−74.1. IR (neat): 2991, 1713, 1560, 1431, 1402, 1308, 1226, 1135,

984, 842, 794, 753, 714, and 665 cm⁻¹. HRMS (ESI) m /z : [M+Na⁺]

calcd for C₁₃H₁₁F₆INaO₈S₂⁺requires 622.8736; found 622.8733. mp:

90 −94 °C.

Methyl 3-(Diethoxyphosphoryl)-5-(((triﬂuoromethyl)sulfonyl)-

oxy)-4-(trimethylsilyl)benzoate (10e).

Aryl phosphonate 10e was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) E1 (124 mg, 0.222

mmol) in Et₂O (1 mL) and a mixture of diethyl trimethylsilyl

phosphite (8a , 93 mg, 0.44 mmol) and (trimethylsilyl)methyl

magnesium chloride (0.45 mL, 0.45 mmol, 1.0 M in Et₂O) in Et₂O

(1.25 mL). Puri ﬁ cation by ﬂ ash chromatography (SiO₂, hexanes:E-

tOAc 4:1) gave aryl phosphonate 10e (45 mg, 0.091 mmol, 41%) as a

1

clear, colorless oil. H NMR (300 MHz, CDCl₃): δ 8.51 (d, J = 14.0

Hz, 1H), 8.04 (s, 1H), 4.08 −4.24 (m, 4H), 3.97 (s, 3H), 1.36 (t, J =

7.1 Hz, 6H), and 0.54 (s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃):

164.7 (d, J = 1.9 Hz), 155.4 (d, J = 28.0 Hz), 144.8 (d, J = 23.2 Hz),

138.7 (d, J = 193.5 Hz, C_aryl-P), 133.4 (d, J = 11.4 Hz), 132.4 (d, J =

17.1 Hz), 124.4 (br s), 118.6 (q, J = 320.3 Hz, CF₃), 62.8 (d, J = 6.4

Hz), 53.0, 16.4 (d, J = 6.2 Hz), and 2.2. ¹⁹F{¹³C} NMR (282 MHz,

CDCl₃): δ −74.7. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 16.4. IR

(neat): 2988, 2958, 2907, 1735, 1439, 1426, 1375, 1290, 1247, 1217,

1142, 1053, 1023, 995, 971, 930, 852, 809, and 770 cm⁻¹. HRMS

(ESI) m /z : [M+Na⁺] calcd for C₁₆H₂₄F₃NaO₈PSSi⁺requires

515.0543; found 515.0541. TLC: Rf 0.4 (SiO₂, 4:1 hexanes:EtOAc).

tert-Butyl 3,5-Dihydroxy-4-iodobenzoate (E2).

tert-Butyl 3-(Diethoxyphosphoryl)-5-(((triﬂuoromethyl)sulfonyl)-

oxy)-4-(trimethylsilyl)benzoate (10f).

Aryl phosphonate 10f was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) E3 (274 mg, 0.457

mmol) in Et₂O (2.3 mL) and a mixture of diethyl trimethylsilyl

phosphite (8a , 192 mg, 0.913 mmol) and (trimethylsilyl)methyl

magnesium chloride (0.91 mL, 0.91 mmol, 1.0 M in Et₂O) in Et₂O

(2.3 mL). Puri ﬁ cation by ﬂ ash chromatography (SiO₂, hexanes:E-

tOAc 6:1) gave aryl phosphonate 10f (134 mg, 0.251 mmol, 55%) as

a clear, colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 8.45 (dd, J = 1.5,

14.2 Hz, 1H), 7.99 (d, J = 1 Hz, 1H), 4.06 −4.26 (m, 4H), 1.60 (s,

9H), 1.36 (t, J = 7.1 Hz, 6H), and 0.53 (s, 9H). ¹³C{¹H} NMR (75

MHz, CDCl₃): δ 163.2 (d, J = 3 Hz), 155.5 (d, J = 27.8 Hz), 144.0 (d,

J = 23.2 Hz), 138.3 (d, J = 193.5 Hz, C_aryl-P), 134.4 (d, J = 17.1 Hz),

3,5-Diacetoxybenzoyl chloride⁵⁴(5.00 g, 19.5 mmol) was diluted in

dichloromethane (28 mL), set to stir at room temperature, and

sequentially treated with pyridine (1.7 mL, 21 mmol) and tert-butanol

(3.4 mL, 36 mmol). After 24 h, the mixture was diluted with

dichloromethane, washed with 1 M HCl (4×), dried (MgSO₄), and

concentrated. The crude material (5.14 g, ∼17 mmol) was dissolved

in MeOH (35 mL) and treated with K₂CO₃(12.1 g, 87 mmol) at

room temperature with stirring. After 1 h, the mixture was ﬁltered,

and the ﬁltrate was concentrated. The residue was diluted with

EtOAc, sequentially washed with 1 M HCl and brine, dried

(Na₂SO₄), and concentrated. The crude tert-butyl ester (2.84 g,

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133.2 (d, J = 11.3 Hz), 124.4, 118.6 (q, J = 320.3 Hz, CF₃), 82.8, 62.7

(d, J = 6.6 Hz), 28.2, 16.4 (d, J = 6.4 Hz), and 2.2. ¹⁹F{¹³C} NMR

(282 MHz, CDCl₃): δ −74.7. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ

16.3. IR (neat): 2984, 2928, 2853, 1723, 1428, 1370, 1297, 1247,

1215, 1144, 1053, 1023, 956, 848, 811 cm⁻¹. HRMS (ESI) m /z : [M

+Na⁺] calcd for C₁₉H₃₀F₃NaO₈PSSi⁺requires 557.1013; found

557.1012.

(s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 155.6 (d, J = 28.9 Hz),

146.9 (d, J = 15.3 Hz), 137.9 (d, J = 195.0 Hz, C_aryl-P), 138.0 (d, J =

23.5 Hz), 130.1 (d, J = 11.0 Hz), 121.1 (br s), 118.6 (q, J = 320.0 Hz,

CF₃), 107.8, 64.8, 62.6 (d, J = 6.4 Hz), 27.4, 16.4 (d, J = 6.7 Hz), and

2.3. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.8. ³¹P{¹H} NMR

(121 MHz, CDCl₃): δ 17.6. IR (neat): 2988, 2902, 1422, 1374, 1213,

1141, 1051, 1033, 1023, 941, 950, 807, and 762 cm⁻¹. HRMS (ESI)

m /z : [M+Na⁺] calcd for C₁₈H₂₈F₃NaO₈PSSi⁺requires 543.0856;

found 543.0878.

2-Iodo-5-(2-methyl-1,3-dioxolan-2-yl)-1,3-phenylene Bis-

(triﬂuoromethanesulfonate) (E4).

Diethyl (2-(Trimethylsilyl)phenyl)phosphonate (16).

Tetrabutylammonium tribromide (0.073 g, 0.16 mmol) was added to

a mixture of 3 ′,5 ′-dihydroxyacetophenone (1.01 g, 6.64 mmol),

trimethylorthoformate (1.68 mL, 15.4 mmol), and ethylene glycol

(3.7 mL, 66 mmol) at room temperature and with stirring. After 1 h,

the mixture was diluted with water and extracted with EtOAc (3 ×).

The combined organic extracts were washed with brine, dried

(Na₂SO₄), and concentrated to give the crude ketal [5-(2-methyl-1,3-

dioxolan-2-yl)benzene-1,3-diol, 1.02 g], which underwent partial

deketalization on silica gel and so was used directly in subsequent

experiments.

N-Iodosuccinimide (1.15 g, 5.10 mmol) was added to a mixture of

crude 5-(2-methyl-1,3-dioxolan-2-yl)benzene-1,3-diol (1.00 g) in

acetonitrile (12 mL) at 0 °C and with stirring. After 10 min, the

mixture was diluted with ethyl acetate and washed with 10% aqueous

Na₂S₂O₃and brine, dried (Na₂SO₄), and concentrated to give the

crude iodo resorcinol [2-iodo-5-(2-methyl-1,3-dioxolan-2-yl)benzene-

1,3-diol, 0.882 g], which underwent partial deketalization on silica gel

and so was used directly in subsequent experiments.

Aryl phosphonate 16 was prepared according to General Procedure A

from a solution of 2-iodophenyl bis(tri ﬂ ate) 14⁵⁵(103 mg, 0.292

mmol) in Et₂O (1.5 mL) and a mixture of diethyl trimethylsilyl

phosphite (8a, 132 μL, 120 mg, 0.58 mmol) and (trimethylsilyl)-

methyl magnesium chloride (0.58 mL, 0.58 mmol, 1.0 M in Et₂O) in

Et₂O (1.5 mL). The mixture was stirred for 20 h. Puriﬁcation by

gradient ﬂash chromatography (SiO₂, hexanes:EtOAc 4:1 to 7:3) gave

aryl phosphonate 16 (69 mg, 0.16 mmol, 54%) as a clear, pale brown

1

oil. H NMR (300 MHz, CDCl₃): δ 7.89 (ddd, J = 1.8, 7.4, 14 Hz,

1H), 7.74 (ddd, J = 1.6, 4.7, 6.8 Hz, 1H), 7.39−7.53 (m, 2H), 4.01−

4.21 (m, 4H), 1.33 (t, J = 7.1 Hz, 6H), and 0.41 (s, 9H). ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 145.2 (d, J = 21.5 Hz), 135.9 (d, J = 19.6

Hz), 133.5 (d, J = 188.9 Hz, C_aryl-P), 133.3 (d, J = 11.5 Hz), 131.2 (d,

J = 3.4 Hz), 128.4 (d, J = 14.2 Hz), 61.9 (d, J = 5.7 Hz), 16.4 (d, J =

6.7 Hz), and 1.0. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 20.8. IR

(neat): 2983, 2956, 2903, 1424, 1392, 1250, 1139, 1026, 963, 846,

and 755 cm⁻¹

.

HRMS (ESI) m/z: [M+Na⁺] calcd for

C₁₄H₂₂F₃NaO₆PSSi⁺requires 309.1046; found 309.1063. TLC: Rf

0.45 (SiO₂, 30% EtOAc in hexanes).

Triﬂuoromethanesulfonic anhydride (1.0 mL, 5.9 mmol) was

added dropwise over 30 min to a mixture of crude 2-iodo-5-(2-

methyl-1,3-dioxolan-2-yl)benzene-1,3-diol (0.882 g), N,N-diisopropy-

lethylamine (1.4 mL, 8.2 mmol), and CH₂Cl₂(9.1 mL) at −78 °C

with stirring. After complete addition of triﬂuoromethanesulfonic

anhydride, the cooling bath was removed and the mixture was stirred

for an additional hour; water was added (3.2 mL). The resulting

mixture was diluted with NaHCO₃and extracted three times with

CH₂Cl₂. The organic extracts were combined, dried (MgSO₄), and

concentrated. Puriﬁcation by ﬂash chromatography (SiO₂, hexane-

s:EtOAc 19:1) gave 2-iodophenyl bis(triﬂate) E4 (0.644 g, 1.10

3-(Diethoxyphosphoryl)-6-hexyl-2-(trimethylsilyl)phenyl Triﬂuor-

omethanesulfonate (10h) and 3-(Diethoxyphosphoryl)-4-hexyl-2-

(trimethylsilyl)phenyl Triﬂuoromethanesulfonate (10i).

1

A ∼4.8:1 mixture of isomeric aryl phosphonates 10h and 10i was

prepared according to General Procedure A from a solution of 2-

iodophenyl bis(tri ﬂ ate) 17 (528 mg, 0.904 mmol) in Et₂O (4.5 mL)

and a mixture of diethyl trimethylsilyl phosphite (8a , 380 mg, 1.8

mmol) and (trimethylsilyl)methyl magnesium chloride (1.8 mL, 1.8

mmol, 1.0 M in Et₂O) in Et₂O (4.5 mL). Puriﬁ cation by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 9:1 to 7:3) gave faster-eluting

aryl phosphonate 10h (240 mg, 0.46 mmol, 51%) and slower-eluting

aryl phosphonate 10i (50 mg, 0.096 mmol, 11%), each as a clear, pale-

yellow oil. Structures for 10h and 10i were assigned by comparing the

mmol, 17% over three steps) as a pale brown solid. H NMR (300

MHz, CDCl₃): δ 7.47 (s, 2H), 4.03−4.15 (m, 2H), 3.71−3.83 (m,

2H), and 1.64 (s, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 151.6,

149.0, 118.9, 118.8 (q, J = 320.3 Hz, CF₃), 107.4, 86.6, 65.0 (2C), and

27.4. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.1. IR (neat): 3090,

2995, 2898, 1709, 1564, 1433, 1415, 1400, 1377, 1277, 1247, 1217,

1139, 1038, 982, 883, 856, 796, 757, 712, and 671 cm⁻¹. HRMS (ESI)

m/z: [M+Na⁺] calcd for C₁₂H₁₀F₆INaO₈S₂⁺requires 608.8580; found

608.8592. mp: 66−69 °C.

3-(Diethoxyphosphoryl)-5-(2-methyl-1,3-dioxolan-2-yl)-2-

(trimethylsilyl)phenyl Triﬂuoromethanesulfonate (10g).

1

aromatic regions of the H NMR spectra. Speci ﬁ cally, minor isomer

10h exhibited a down ﬁ eld signal with a dd splitting (J = 7.8, 13.1 Hz)

that is characteristic of a C_aryl-H hydrogen ortho to a phosphonyl

group.

Spectral data for 10h (faster-eluting major isomer). ¹H NMR (300

MHz, CDCl₃): δ 7.24−7.37 (m, 2H), 3.94−4.20 (m, 4H), 2.92 (br t,

J = 8 Hz, 2H), 1.53−1.66 (m, 2H), 1.47−1.22 (m, 12H), 0.90 (br t, J

= 6.7 Hz, 3H), and 0.48 (s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

153.0 (d, J = 28.1 Hz), 148.4 (d, J = 11.5 Hz), 142.4 (d, J = 23.9 Hz),

136.1 (d, J = 192.3 Hz, C_aryl-P), 132.8 (d, J = 17.2 Hz), 124.0 (br s),

118.7 (q, J = 326.4 Hz, CF₃), 62.3 (d, J = 6.0 Hz), 34.8 (d, J = 3.0

Hz), 32.3, 31.9, 29.8, 22.8, 16.3 (d, J = 5.9 Hz), 14.2, and 3.6.

¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.8. ³¹P{¹H} NMR (121

MHz, CDCl₃): δ 19.0. IR (neat): 2984, 2960, 2932, 2861, 1422, 1249,

1213, 1165, 1144, 1111, 1049, 1023, 964, 919, 848, and 790 cm⁻¹.

HRMS (ESI) m/z: [M+Na⁺] calcd for C₂₀H₃₄F₃NaO₆PSSi⁺requires

541.1427; found 541.1425.

Aryl phosphonate 10g was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) E4 (62 mg, 0.11

mmol) in Et₂O (0.53 mL) and a mixture of diethyl trimethylsilyl

phosphite (8a , 44 mg, 0.21 mmol) and (trimethylsilyl)methyl

magnesium chloride (0.21 mL, 0.21 mmol, 1.0 M in Et₂O) in Et₂O

(0.53 mL). Puri ﬁ cation by gradient ﬂ ash chromatography (SiO₂,

hexanes:EtOAc 4:1 to 7:3) gave aryl phosphonate 10g (29 mg, 0.056

mmol, 51%) as a clear, colorless oil. H NMR (300 MHz, CDCl₃): δ

8.00 (dd, J = 1.1, 14.2 Hz, 1H), 7.55 (s, 1H), 4.02 −4.23 (m, 6H),

3.72 −3.79 (m, 2H), 1.64 (s, 3H), 1.36 (t, J = 7.1 Hz, 6H), and 0.51

1

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Spectral data for 10i (slower-eluting minor isomer). ¹H NMR (300

MHz, CDCl₃): δ 7.78 (dd, J = 7.9, 13.1 Hz, 1H, J^{4 31}P−¹H), 7.38 (dd,

J = 4.5, 7.7 Hz, 1H), 3.97−4.25 (m, 4H), 2.73 (br t, J = 8 Hz, 2H),

1.49−1.66 (m, 2H), 1.40−1.24 (m, 12H), 0.89 (br t, J = 6 Hz, 3H),

and 0.51 (s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 150.6 (d, J =

28.9 Hz) 141.5 (d, J = 24.3 Hz), 140.7 (d, J = 3.2 Hz), 135.5 (d, J =

194 Hz, C_aryl-P), 133.7 (d, J = 9.4 Hz), 131.7 (d, J = 17.0 Hz), 118.7

(q, J = 320.0 Hz, CF₃), 62.3 (d, J = 5.8 Hz), 31.7, 30.7, 29.8, 29.2,

22.7, 16.4 (d, J = 6.2 Hz), 14.2, and 2.9. ¹⁹F{¹³C} NMR (282 MHz,

CDCl₃): δ −74.6. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 18.7. IR

(neat): 2958, 2932, 2861, 1403, 1247, 1215, 1165, 1142, 1094, 1053,

1025, 965, 911, 872, 852, 829, 766, and 667 cm⁻¹. HRMS (ESI) m/z:

[M+Na⁺] calcd for C₂₀H₃₄F₃NaO₆PSSi⁺requires 541.1427; found

541.1427.

mmol) in Et₂O (2.1 mL) and a mixture of silyl phosphite E5 (198 mg,

0.832 mmol) and (trimethylsilyl)methyl magnesium chloride (0.83

mL, 0.83 mmol, 1.0 M in Et₂O) in Et₂O (2.1 mL). Puriﬁcation by

ﬂash chromatography (SiO₂, hexanes:EtOAc 4:1) gave aryl

phosphonate 10k (133 mg, 0.288 mmol, 69%) as a clear, colorless

1

oil. H NMR (300 MHz, CDCl₃): δ 7.90 (ddd, J = 1.3, 7.1, 13.4 Hz,

1H), 7.40−7.53 (m, 2H), 4.64−4.80 (m, 2H), 1.38 (d, J = 6.2 Hz,

6H), 1.24 (d, J = 6.2 Hz, 6H), and 0.53 (s, 9H). ¹³C{¹H} NMR (75

MHz, CDCl₃): δ 155.3 (d, J = 28.8 Hz), 139.4 (d, J = 193.4 Hz, C_aryl

-

P), 138.5 (d, J = 24.1 Hz), 133.3 (d, J = 9.4 Hz), 130.2 (d, J = 16.5

Hz), 123.8 (d, J = 1.8 Hz), 118.6 (q, J = 320.2 Hz, CF₃), 71.7 (d, J =

6.1 Hz), 24.1 (d, J = 4.4 Hz), 23.8 (d, J = 4.7 Hz), and 2.6. ¹⁹F{¹³C}

NMR (282 MHz, CDCl₃): δ −74.7. ³¹P{¹H} NMR (121 MHz,

CDCl₃): δ 15.2. IR (neat): 2982, 2937, 2904 1424, 1405, 1387, 1375,

1258, 1249, 1213, 1142, 1105, 1005, 982, 913, 882, 848, 811, 796,

766, 718, and 665 cm⁻¹. HRMS (ESI) m/z: [M+Na⁺] calcd for

C₁₆H₂₆F₃NaO₆PSSi⁺requires 485.0801; found 485.0811.

3-(Dimethoxyphosphoryl)-2-(trimethylsilyl)phenyl Triﬂuorome-

thanesulfonate (10j).

Diphenyl (Trimethylsilyl) Phosphite (E6).

Aryl phosphonate 10j was prepared according to General Procedure A

from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(228 mg, 0.456

mmol) in Et₂O (2 mL) and a mixture of dimethyl trimethylsilyl

phosphite (8b, 191 mg, 1.05 mmol) and (trimethylsilyl)methyl

magnesium chloride (0.8 mL, 0.8 mmol, 1.0 M in Et₂O) in Et₂O (2

mL). Puriﬁcation by ﬂash chromatography (SiO₂, hexanes:EtOAc

2:1) gave aryl phosphonate 10j (139 mg, 0.342 mmol, 75%) as a clear,

Silyl phosphite E6 was prepared according to General Procedure B

from diphenyl phosphite (1.0 mL, 5.2 mmol), TMSCl (0.93 mL, 7.3

mmol), Et₃N (0.87 mL, 6.3 mmol), and CH₂Cl₂(26 mL). The

resulting product (E6 , 1.1 g, 3.6 mmol, 69% crude yield) was obtained

as a clear, colorless oil with less than 25 mol % starting phosphite

contamination as determined by ¹H and ³¹P NMR. Given the

instability of related O -silyl phosphites, puri ﬁ cation was not

attempted. ¹H NMR (300 MHz, CDCl₃): δ 7.25 −7.36 (m, 4H),

7.03 −7.12 (s, 6H), and 0.23 (s, 9H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 152.0 (d, J = 3.3 Hz), 129.6, 123.8, 120.9 (d, J = 7.9 Hz),

and 1.6. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 124.6. IR (neat): 3066,

3040, 2958, 2898, 1590, 1487, 1254, 1223, 1191, 1163, 992, 839, 755,

706, and 688 cm⁻¹. HRMS (ESI) m /z : [M+H⁺] calcd for

C₁₅H₂₀O₃PSi⁺requires 307.0914; found 307.0921.

1

colorless oil. H NMR (300 MHz, CDCl₃): δ 7.90 (ddd, J = 1.4, 7,

13.5 Hz, 1H), 7.45−7.57 (m, 2H), 3.78 (d, J = 11.1, 6H), and 0.51 (s,

9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 155.6 (d, J = 28.5 Hz),

138.8 (d, J = 23.6 Hz), 136.3 (d, J = 193.4 Hz, C_aryl-P), 133.3 (d, J =

10.3 Hz), 130.6 (d, J = 16.9 Hz), 124.3 (d, J = 3 Hz), 118.5 (q, J =

320.3 Hz, CF₃), 52.9 (d, J = 6.7 Hz) and 2.1. ¹⁹F{¹³C} NMR (282

MHz, CDCl₃): δ −74.9. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 20.3.

IR (neat): 2956, 2906, 2853, 1586, 1423, 1408, 1249, 1215, 1142,

1113, 1057, 1032, 916, 850, 812, 771, and 719 cm⁻¹. HRMS (ESI) m/

z: [M+Na⁺] calcd for C₁₂H₁₈F₃NaO₆PSSi⁺requires 429.0175; found

429.0173. TLC: Rf 0.3 (SiO₂, 30% EtOAc in hexanes).

3-(Diphenoxyphosphoryl)-2-(trimethylsilyl)phenyl Triﬂuorome-

thanesulfonate (10l).

Diisopropyl (Trimethylsilyl) Phosphite (E5).

Silyl phosphite E5 was prepared according to General Procedure B

from diisopropyl phosphite (1.0 mL, 6.0 mmol), TMSCl (1.1 mL, 8.7

mmol), Et₃N (1.0 mL, 7.2 mmol), and CH₂Cl₂(30 mL). The

resulting product (E5 , 1.2 g, 5.0 mmol, 83% crude yield) was obtained

as a clear, colorless oil with starting phosphite contamination. The

ratio of product to starting phosphite was found to be 82:18 as

Aryl phosphonate 10l was prepared according to General Procedure A

from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(169 mg, 0.34

mmol) in Et₂O (1.7 mL) and a mixture of silyl phosphite E6 (207 mg,

0.68 mmol) and (trimethylsilyl)methyl magnesium chloride (0.70

mL, 0.70 mmol, 1.0 M in Et₂O) in Et₂O (1.7 mL). To remove phenol

impurities from the crude reaction mixture, the workup was modiﬁed

from the general procedure. Namely, after stirring for 1 h, the reaction

mixture was diluted in 1 M HCl (10 mL) and ethyl acetate (50 mL),

and the phases were separated. The organic phase was sequentially

washed with 1 M NaOH (3 × 25 mL) and brine, dried (MgSO₄), and

concentrated. Puriﬁcation by ﬂash chromatography (SiO₂, hexane-

s:EtOAc 19:1) gave aryl phosphonate 10l (130 mg, 0.24 mmol, 71%)

as a clear, colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 8.14 (ddd, J =

2, 6.7, 14.2 Hz, 1H), 7.52−7.62 (m, 2H), 7.27−7.35 (m, 4H), 7.11−

7.20 (m, 6H), and 0.57 (s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

155.5 (d, J = 31.1 Hz), 150.5 (d, J = 8.7 Hz), 139.5 (d, J = 25.6 Hz),

136.4 (d, J = 198.1 Hz, C_aryl-P), 133.8 (d, J = 10.3 Hz), 130.7 (d, J =

17.7 Hz), 130.0, 125.4, 124.9 (d, J = 2.4 Hz), 120.5 (d, J = 4.6 Hz),

118.6 (q, J = 320.6 Hz, CF₃), and 2.5. ¹⁹F{¹³C} NMR (282 MHz,

CDCl₃): δ −74.6. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 10.1. IR

(neat): 3071, 2958, 2906, 1592, 1491, 1424, 1405, 1280, 1251, 1213,

1187, 1161, 1142, 1113, 1072, 1049, 1025, 1006, 934, 900, 848, 811,

796, 764, 718, and 688 cm⁻¹. HRMS (ESI) m/z: [M+Na⁺] calcd for

C₂₂H₂₂F₃NaO₆PSSi⁺requires 553.0488; found 553.0487.

1

determined by H and ³¹P NMR, and this mixture was used directly

1

without further puri ﬁ cation. H NMR (300 MHz, CDCl₃): δ 4.32 −

4.49 (m, 2H), 1.21 (br d, J = 6.2 Hz, 12H), and 0.20 (s, 9H). ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 65.2 (d, J = 11.4 Hz), 24.4 (dd, J = 2.9,

3.0 Hz), and 1.60 (d, J = 2.3 Hz). ³¹P{¹H} NMR (121 MHz, CDCl₃):

δ 129.2. IR (neat): 2976, 2937, 2898, 2879, 1467, 1454, 1385, 1351,

1251, 1178, 1139, 1109, 1051, 1001, 952, 844, 759, 721, and 688

cm⁻¹. HRMS (ESI) m /z : [M+H⁺] calcd for C₉H₂₄O₃PSi⁺requires

239.1227; found 239.1231.

3-(Diisopropoxyphosphoryl)-2-(trimethylsilyl)phenyl Triﬂuoro-

methanesulfonate (10k).

Aryl phosphonate 10k was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(207 mg, 0.414

10736

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Article

Dibenzyl (Trimethylsilyl) Phosphite (E7).

Silyl phosphite E9 was prepared according to General Procedure B

from phosphite E8 (507 mg, 2.00 mmol), TMSCl (0.51 mL, 4.0

mmol), Et₃N (0.47 mL, 3.4 mmol), and CH₂Cl₂(10 mL). The

resulting product (E9 , 628 mg, 1.9 mmol, 95% crude yield) was

obtained as a clear, colorless oil with less than 5 mol % starting

phosphite contamination as determined by ¹H and ³¹P NMR. Further

puri ﬁ cation was not attempted. ¹H NMR (300 MHz, CDCl₃): δ 3.31

(ap d, J = 6.9 Hz, 4H), 0.21 (s, 9H), and 0.06 (s, 18H). ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 52.6 (d, J = 4.7 Hz), 1.68, and −2.99.

³¹P{¹H} NMR (121 MHz, CDCl₃): δ 128.9. IR (neat): 2958, 2898,

2820, 1420, 1293, 1247, 1031, 986, 960, 837, 773, 757, 742, and 697

Silyl phosphite E7 was prepared according to General Procedure B

from dibenzyl phosphite (1.0 mL, 4.5 mmol), TMSCl (0.87 mL, 6.8

mmol), Et₃N (0.94 mL, 6.8 mmol), and CH₂Cl₂(23 mL). The

resulting product (E7 , 1.3 g, 3.9 mmol, 87% crude yield) was obtained

as a clear, colorless oil with ca. 10 mol % starting phosphite

contamination as determined by ¹H and ³¹P NMR. Given the

instability of related O -silyl phosphites, puri ﬁ cation was not

+

cm⁻¹. HRMS (ESI) m /z : [M+H⁺] calcd for C₁₁H₃₂O₃PSi₃[M+H⁺]

1

attempted. H NMR (300 MHz, CDCl₃): δ 7.25 −7.37 (m, 10H),

requires 327.1391; found 327.1388.

3-(Bis((trimethylsilyl)methoxy)phosphoryl)-2-(trimethylsilyl)-

phenyl Triﬂuoromethanesulfonate (10n).

4.82 (d, J = 7.9 Hz, 4H), and 0.22 (s, 9H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 138.6 (d, J = 4.6 Hz), 128.5, 127.7, 127.6, 63.0 (d, J = 9.1

Hz), and 1.5 (d, J = 2.3 Hz). ³¹P{¹H} NMR (121 MHz, CDCl₃): δ

128.0. IR (neat): 3092, 3068, 3034, 2958, 1498, 1456, 1254, 1213,

1047, 982, 952, 848, 781, 760, 732, and 695 cm⁻¹. HRMS (ESI) m /z :

[M+H⁺] calcd for C₁₇H₂₄O₃PSi⁺requires 335.1227; found 335.1243.

3-(Bis(benzyloxy)phosphoryl)-2-(trimethylsilyl)phenyl Triﬂuoro-

methanesulfonate (10m).

Aryl phosphonate 13 was prepared according to General Procedure A

from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(456 mg, 0.912

mmol) in Et₂O (4.6 mL) and a mixture of silyl phosphite E9 (0.52 g,

1.6 mmol) and (trimethylsilyl)methyl magnesium chloride (1.8 mL,

1.8 mmol, 1.0 M in Et₂O) in Et₂O (4.6 mL). Puriﬁcation by ﬂash

chromatography (SiO₂, hexanes:EtOAc 6:1) gave aryl phosphonate

10n (367 mg, 0.66 mmol, 72%) as a clear, colorless oil. ¹H NMR (300

MHz, CDCl₃): δ 7.80 (ddd, J = 1.5, 6.9, 13.0 Hz, 1H), 7.41−7.54 (m,

2H), 3.74 (dd, J = 6.6, 13.4 Hz, 2H), 3.60 (dd, J = 5.1, 13.4 Hz, 2H),

0.51 (s, 9H), and 0.09 (s, 18H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

155.6 (d, J = 27.8 Hz), 139.1 (d, J = 23.0 Hz), 137.2 (d, J = 188.2 Hz,

C_aryl-P), 133.4 (d, J = 9.4 Hz), 130.3 (d, J = 16.2 Hz), 123.9 (br d, J =

2.6 Hz), 118.6 (q, J = 320.1 Hz, CF₃), 59.5 (d, J = 9.3 Hz), 2.4, and

−3.2. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.9. ³¹P{¹H} NMR

(121 MHz, CDCl₃): δ 21.2. IR (neat): 2958, 2902, 1426, 1405, 1251,

1213, 1144, 1113, 1031, 1013, 989, 848, 818, 764, 703, and 680 cm⁻¹.

HRMS (ESI) m/z: [M+Na⁺] calcd for C₁₈H₃₄F₃NaO₆PSSi₃⁺requires

573.0966; found 573.0957.

Aryl phosphonate 10m was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(204 mg, 0.408

mmol) in Et₂O (2.0 mL) and a mixture of silyl phosphite E7 (296 mg,

0.818 mmol) and (trimethylsilyl)methyl magnesium chloride (0.82

mL, 0.82 mmol, 1.0 M in Et₂O) in Et₂O (2.0 mL). Puriﬁcation by

ﬂash chromatography (SiO₂, hexanes:EtOAc 7:3) gave aryl

phosphonate 10m (154 mg, 0.262 mmol, 64%) as a clear, colorless

oil. ¹H NMR (300 MHz, CDCl₃): δ 7.86 (ddd, J = 2.6, 6.0, 13.8 Hz,

1H), 7.38−7.45 (m, 2H), 7.28−7.38 (m, 10H), 5.06 (ddd, J = 7.5,

11.6, 11.6 Hz, 2H), 5.05 (ddd, J = 8.1, 11.7, 11.7 Hz, 2H), and 0.50

(s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 155.6 (d, J = 28.8 Hz),

138.8 (d, J = 24.1 Hz), 137.2 (d, J = 192.5 Hz, C_aryl-P), 135.7 (d, J =

6.9 Hz), 133.4 (d, J = 10.1 Hz), 130.4 (d, J = 16.9 Hz), 128.69,

128.66, 128.4, 124.2 (br s), 118.6 (q, J = 320.2 Hz, CF₃), 68.1 (d, J =

5.8 Hz), and 2.3. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.8.

³¹P{¹H} NMR (121 MHz, CDCl₃): δ 18.8. IR (neat): 3068, 3034,

2956, 2900, 1422, 1405, 1249, 1215, 1142, 1113, 1049, 992, 917, 848,

3-(Bis(2,2,2-triﬂuoroethoxy)phosphoryl)-2-(trimethylsilyl)phenyl

Triﬂuoromethanesulfonate (10o).

and 811 cm⁻¹

.

HRMS (ESI) m/z: [M+Na⁺] calcd for

C₂₄H₂₆F₃NaO₆PSSi⁺requires 581.0801; found 581.0809. TLC: Rf

0.6 (SiO₂, 30% EtOAc in hexanes).

Bis((trimethylsilyl)methyl) Phosphonate (E8).

Aryl phosphonate 10o was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(206 mg, 0.412

mmol) in Et₂O (2 mL) and a mixture of bis(2,2,2-triﬂuoroethyl)

(trimethylsilyl) phosphite⁵⁶(303 mg, 0.95 mmol) and

(trimethylsilyl)methyl magnesium chloride (0.8 mL, 0.8 mmol, 1.0

M in Et₂O) in Et₂O (2 mL). Puriﬁcation by ﬂash chromatography

(SiO₂, hexanes:EtOAc 9:1) gave aryl phosphonate 10o (128 mg,

0.238 mmol, 58%) as a clear, colorless oil, which solidiﬁed to a white

Diphenyl phosphite (400 μ L, 2.1 mmol) was added to a solution of

(trimethylsilyl)methanol (560 μ L, 4.4 mmol) in pyridine (2.10 mL)

with stirring. After 24 h, pyridine was removed by azeotropic

distillation with cyclohexane, and the resulting material was diluted in

ethyl acetate (100 mL) and sequentially washed with 1 M NaOH (3

× 100 mL) and brine. The organic phase was dried (MgSO₄) and

concentrated to give phosphite E8 (416 mg, 1.64 mmol, 78%) as a

1

solid upon standing. H NMR (300 MHz, CDCl₃): δ 7.94 (ddd, J =

1.6, 6.9, 14.2 Hz, 1H), 7.52−7.63 (m, 2H), 4.27−4.57 (m, 4H), and

0.52 (s, 9H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 155.4 (d, J = 34.3

Hz), 139.7 (d, J = 26.5 Hz), 133.8 (d, J = 199.8 Hz, C_aryl-P), 133.6 (d,

J = 10.9 Hz), 131.0 (d, J = 17.5 Hz), 125.6 (br s), 122.6 (dq, J = 9.7,

277 Hz, CF₃), 118.5 (q, J = 319.8 Hz, CF₃), 62.6 (dq, J = 5.5, 38.2

Hz, CCF₃), and 2.0. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.7 (s,

3F) and −76.0 (t, J = 8.0 Hz, 6F). ³¹P{¹H} NMR (121 MHz,

CDCl₃): δ 19.9. IR (neat): 3004, 2971, 2907, 1586, 1556, 1456, 1428,

1416, 1407, 1295, 1252, 1219, 1176, 1142, 1116, 1100, 1068, 964,

923, 878, 848, 828, 805, 790, 760, 718, and 662 cm⁻¹. HRMS (ESI)

m/z: [M+Na⁺] calcd for C₁₄H₁₆F₉NaO₆PSSi⁺requires 564.9923;

found 564.9926. mp: 68−72 °C. TLC: Rf 0.4 (SiO₂, 10% EtOAc in

hexanes).

1

clear, colorless oil. H NMR (300 MHz, CDCl₃): δ 6.69 (d, J = 684

Hz, 1H), 3.70 (d, J = 7.2 Hz, 4H), and 0.11 (s, 18H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 58.7 (d, J = 9.9 Hz) and −3.4. ³¹P{¹H} NMR

(121 MHz, CDCl₃): δ 14.3. IR (neat): 2958, 2900, 1422, 1292, 1249,

1060, 1031, 977, 837, 759, 699, and 677 cm⁻¹. HRMS (ESI) m /z : [M

+Na⁺] calcd for C₈H₂₃NaO₃PSi₂⁺requires 277.0816; found 277.0817.

Trimethylsilyl Bis((trimethylsilyl)methyl) Phosphite (E9).

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Article

6-((Trimethylsilyl)oxy)-6H-dibenzo[c,e][1,2]oxaphosphinine

(E10).

phosphite⁵⁷(120 mg, 0.48 mmol) and (trimethylsilyl)methyl

magnesium chloride (0.4 mL, 0.4 mmol, 1.0 M in Et₂O) in Et₂O

(1 mL). Puriﬁcation by ﬂash chromatography (SiO₂, hexanes:EtOAc

4:1) gave aryl phosphonate 10q (51 mg, 0.11 mmol, 47%) as a clear,

1

colorless oil. H NMR (300 MHz, CDCl₃): δ 7.98 (ddd, J = 1, 7.5,

14.0 Hz, 1H), 7.62 (br d, J = 8.3 Hz, 1H), 7.52 (ddd, J = 4.3, 7.6, 8.5

Hz, 1H), 4.04−4.29 (m, 4H), 1.36 (t, J = 7.1 Hz, 6H), 1.00 (s, 9H),

and 0.56 (s, 6H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 157.6 (d, J =

28.8 Hz), 138.2 (d, J = 192.2 Hz, C_aryl-P), 135.2 (d, J = 23.1 Hz),

132.8 (d, J = 9.4 Hz), 130.4 (d, J = 17.1 Hz), 121.6 (m), 118.8 (q, J =

321.2 Hz, CF₃), 62.5 (d, J = 6.7 Hz), 28.5, 18.5, 16.4 (d, J = 6.6 Hz),

and 0.8. ¹⁹F{¹³C} NMR (282 MHz, CDCl₃): δ −74.5. ³¹P{¹H} NMR

(121 MHz, CDCl₃): δ 17.4. IR (neat): 2982, 2933, 2906, 2861, 1426,

1403, 1366, 1258, 1249, 1215, 1142, 1115, 1053, 1023, 967, 926, 852,

826, 813, 798, 766, 719, and 688 cm⁻¹. HRMS (ESI) m/z: [M+Na⁺]

calcd for C₁₇H₂₈F₃NaO₆PSSi⁺requires 499.0958; found 499.0962.

TLC: Rf 0.6 (SiO₂, 30% EtOAc in hexanes).

Silyl phosphite E10 was prepared according to General Procedure B

from 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide (1.50 g,

6.9 mmol), TMSCl (1.2 mL, 9.7 mmol), Et₃N (1.2 mL, 8.3 mmol),

and CH₂Cl₂(35 mL). The resulting product (E10 , 1.6 g, 5.7 mmol,

82% crude yield) was obtained as a clear, colorless oil with less than 5

mol % starting phosphite contamination as determined by ¹H and ³¹

P

NMR. Given the instability of related O -silyl phosphites, puri ﬁ cation

1

was not attempted. H NMR (300 MHz, CDCl₃): δ 7.94 −8.01 (m,

2H), 7.68 (dd, J = 7.3, 11.5 Hz, 1H), 7.59 (dd, J = 7.5, 7.7 Hz, 1H),

7.45 (br t, J = 7 Hz, 1H), 7.34 (ddd, J = 1.7, 8.8, 8.8 Hz, 1H), 7.15 −

7.27 (m, 2H), and −0.04. ¹³C{¹H} NMR (75 MHz, CDCl₃): 149.2

(d, J = 9.1 Hz), 135.3 (d, J = 24.0 Hz), 131.5, 131.3, 130.6, 129.5,

127.5 (d, J = 12.9 Hz), 124.9, 123.6, 123.3, 122.9 (d, J = 6.9 Hz),

121.0, and 1.0 (d, J = 2.2 Hz). ³¹P{¹H} NMR (121 MHz, CDCl₃): δ

119.7. IR (neat): 3060, 2958, 2898, 1603, 1592, 1582, 1560, 1491,

1474, 1444, 1429, 1252, 1230, 1200, 1137, 1115, 1087, 1042, 978,

937, 919, 872, 837, 768, 751, 731, 714, 684, and 667 cm⁻¹. HRMS

(ESI) m /z : [M+H⁺] calcd for C₁₅H₁₈O₂PSi⁺requires 289.0808;

found 289.0826.

Diethyl (1,4-Dihydro-1,4-epoxynaphthalen-5-yl)phosphonate

(12a).

Cesium ﬂ uoride (320 mg, 2.1 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (314 mg,

0.72 mmol), furan (150 μ L, 2.1 mmol), and acetonitrile (3.5 mL).

Argon was blown over the headspace of the mixture; the vial was

sealed with a Te ﬂ on-lined cap, and the reaction mixture was heated at

80 °C in a sand bath. After 24 h, the mixture was cooled to rt, diluted

in ethyl acetate, sequentially washed with water and brine, dried

(MgSO₄), and concentrated. Puriﬁ cation by gradient ﬂ ash chroma-

tography (SiO₂, hexanes:EtOAc 1:2 to 0:1) gave aryl phosphonate

12a (165 mg, 0.59 mmol, 82%) as a clear, colorless oil. ¹H NMR (300

MHz, CDCl₃): δ 7.39 (ap d, J = 6.5 Hz, 1H), 7.35 (dd, J = 7.5, 12.0

Hz, 1H), 7.02 −7.10 (m, 3H), 6.19 (s, 1H), 5.76 (s, 1H), 4.00 −4.22

(m, 4H), and 1.33 (t, J = 7.1 Hz, 6H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 154.5 (d, J = 10.6 Hz), 149.9 (d, J = 12.6 Hz), 143.6,

142.8, 127.4 (d, J = 10.6 Hz), 125.1 (d, J = 12.7 Hz), 123.6 (d, J = 3.3

Hz), 121.1 (d, J = 190.0 Hz, C_aryl-P), 82.6, 82.1, 62.2 (d, J = 5.2 Hz),

62.1 (d, J = 5.5 Hz), 16.5 (d, J = 6.3 Hz), and 16.4 (d, J = 6.5 Hz).

³¹P{¹H} NMR (121 MHz, CDCl₃): δ 17.7. IR (neat): 2984, 2907,

3-(6-Oxidodibenzo[c,e][1,2]oxaphosphinin-6-yl)-2-

(trimethylsilyl)phenyl Triﬂuoromethanesulfonate (10p).

Aryl phosphonate 10p was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(200. mg, 0.400

mmol) in Et₂O (2.0 mL) and a mixture of silyl phosphite E10 (231

mg, 0.800 mmol) and (trimethylsilyl)methyl magnesium chloride (0.8

mL, 0.8 mmol, 1.0 M in Et₂O) in Et₂O (2 mL). Puriﬁcation by ﬂash

chromatography (SiO₂, 6:1 EtOAc:hexanes) gave aryl phosphonate

10p (149 mg, 0.29 mmol, 73%) as a white solid. ¹H NMR (300 MHz,

CDCl₃): δ 8.04 (dd, J = 5.1, 8.1 Hz, 1H), 7.98 (dd, J = 2.0, 8.0 Hz,

1H), 7.74 (dd, J = 7.7, 7.7 Hz, 1H), 7.66 (dd, J = 7.5, 13.6 Hz, 1H),

7.16−7.53 (m, 7H), and 0.63 (s, 9H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 155.9, 155.6, 148.8, 148.7, 139.7, 139.4, 137.8, 136.4,

136.3, 134.24, 134.20, 134.0, 133.6, 133.5, 132.7, 132.5, 131.5, 131.4,

131.3, 130.9, 130.8, 130.3, 130.1, 129.1, 128.9, 128.82, 128.78, 128.64,

128.59, 126.2, 125.3, 124.9, 124.8, 124.5, 124.1, 124.0, 123.8, 122.5,

122.3, 120.8, 120.7, 120.6, 120.5, 116.5, and 2.9. Because of complex

J_CPcoupling and overlapping multiplets, the chemical shift of each

peak is provided without further interpretation. ¹⁹F{¹³C} NMR (282

MHz, CDCl₃): δ −74.7. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 28.0.

IR (neat): 3070, 2954, 2904, 1595, 1584, 1478, 1422, 1403, 1249,

1239, 1213, 1141, 1118, 1108, 1046, 902, 848, 809, 796, 755, and 716

cm⁻¹. HRMS (ESI) m/z: [M+Na⁺] calcd for C₂₂H₂₀F₃NaO₅PSSi⁺

requires 535.0383; found 535.0386. mp: 166−168 °C. TLC: Rf 0.6

(SiO₂, 50% EtOAc in hexanes).

1771, 1249, 1234, 1159, 1044, 1016, 965, 874, 855, 818, 794, 781,

751, 714, and 665 cm⁻¹. HRMS (ESI) m /z : [M+Na⁺] calcd for

C₁₄H₁₇NaO₄P⁺requires 303.0757; found 303.0767. TLC: Rf 0.4

(SiO₂, 67% EtOAc in hexanes).

tert-Butyl 5-(Diethoxyphosphoryl)-1,4-dihydro-1,4-epimino-

naphthalene-9-carboxylate (12b).

Cesium ﬂ uoride (320 mg, 2.1 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (296 mg,

0.68 mmol), N -Boc pyrrole (346 mg, 2.1 mmol), and acetonitrile (3.5

mL). Argon was blown over the headspace of the mixture; the vial was

sealed with a Te ﬂ on-lined cap, and the reaction mixture was heated at

75 °C in a sand bath. After 15 h, the mixture was cooled to rt and

diluted in ethyl acetate and water. The phases were separated, and the

aqueous mixture was extracted twice more with ethyl acetate. The

organic phases were combined, washed with brine, dried (MgSO₄),

and concentrated. Puri ﬁ cation by gradient ﬂ ash chromatography

(SiO₂, hexanes:EtOAc 1:2 to 0:1) gave aryl phosphonate 12b (169

2-(tert-Butyldimethylsilyl)-3-(diethoxyphosphoryl)phenyl Tri-

ﬂuoromethanesulfonate (10q).

1

mg, 0.45 mmol, 65%) as a clear, colorless oil. H NMR (300 MHz,

CDCl₃): δ 7.31 −7.47 (br m, 2H), 6.97 (m, 3H), 6.00 (s, 1H), 5.53 (s,

1H), 3.99 −4.26 (m, 4H), 1.38 (s, 9H), and 1.33 (t, J = 6.9 Hz, 6H).

¹³C{¹H} NMR (75 MHz, CDCl₃, 19 °C): δ 154.9, 153.5 (d, J = 10.5

Hz), 149.4 (d, J = 13.0 Hz), 144.2 (br), 143.2 (br), 142.5 (br), 127.8

Aryl phosphonate 10q was prepared according to General Procedure

A from a solution of 2-iodophenyl bis(tri ﬂ ate) 13⁵²(117 mg, 0.234

mmol) in Et₂O (1 mL) and a mixture of tert-butyldimethylsilyl diethyl

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(br), 125.0 (d, J = 3.9 Hz), 124.4 (br), 80.9, 66.6 (br), 66.0 (br), 62.3

(d, J = 4.7 Hz), 62.1 (d, J = 5.5 Hz), 28.2, 16.52 (d, J = 6.6 Hz), and

16.48 (d, J = 6.6 Hz). ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 17.6. IR

(neat): 2980, 2933, 2907, 1709, 1392, 1366, 1331, 1254, 1161, 1092,

1051, 1021, 964, 861, 841, 787, 762, 746, and 723 cm⁻¹. HRMS (ESI)

m /z : [M+Na⁺] calcd for C₁₉H₂₆NNaO₅P⁺requires 402.1441; found

402.1447. TLC: Rf 0.3 (SiO₂, 2:1 EtOAc:hexanes).

130.9, 127.6, 126.7, 126.5 (d, J = 13.8 Hz), 126.3, 125.9, 125.41,

125.1, 124.2 (ap s), 123.9, 123.7, 61.9 (d, J = 6.7 Hz), and 16.2 (d, J =

6.9 Hz). The 124.2 (ap s) is likely part of a C_aryl-P doublet, but the

other peak was not observed because of coincidental overlap. ³¹P{¹H}

NMR (121 MHz, CDCl₃): δ 20.2. IR (neat): 3058, 3023, 2982, 2928,

2902, 1442, 1251, 1161, 1146, 1096, 1055, 1025, 965, 777, and 697

cm⁻¹. HRMS (ESI) m /z : [M+H⁺] calcd for C₃₈H₃₄O₃P⁺requires

569.2240; found 569.2243. mp: 73 −77 °C.

Diethyl (9,10-Dihydro-9,10-[1,2]benzenoanthracen-1-yl)-

phosphonate (12c).

Tetramethyl 5-(Diethoxyphosphoryl)naphthalene-1,2,3,4-tetra-

carboxylate (12e).

Cesium ﬂ uoride (315 mg, 2.1 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (305 mg,

0.70 mmol), anthracene (370 mg, 2.1 mmol), and acetonitrile (3.5

mL). Argon was blown over the headspace of the mixture; the vial was

sealed with a Te ﬂ on-lined cap, and the reaction mixture was heated at

80 °C in a sand bath. After 15 h, the mixture was cooled to rt and

diluted in ethyl acetate and saturated aqueous NH₄Cl. The phases

were separated, and the aqueous mixture was extracted twice more

with ethyl acetate. The organic phases were combined, washed with

brine, dried (MgSO₄), and concentrated. Puriﬁ cation by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 2:1 to 1:2) gave aryl

The supply of acetonitrile used in this experiment was sparged with

N₂for 20 min and used immediately. A solution of aryl phosphonate

10a (264 mg, 0.61 mmol) in acetonitrile (6.1 mL) was added to

screwcap vial containing a mixture of dimethyl acetylenedicarboxylate

(374 μ L, 3.0 mmol), CsF (185 mg, 1.2 mmol), and Pd₂(dba)₃·CHCl₃

(31 mg, 30 μ mol) in acetonitrile (6.1 mL) at room temperature with

stirring. The headspace of the mixture was exchanged with Ar, and the

vial was sealed with a Te ﬂ on-lined cap. After 15 h, the mixture was

ﬁ ltered through a plug of silica gel (EtOAc eluent) and concentrated.

Puri ﬁ cation by gradient ﬂ ash chromatography (SiO₂, hexanes:EtOAc

2:1 to 1:2 to 0:1) gave aryl phosphonate 12e (134 mg, 0.27 mmol,

44%) as a clear, yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 8.33 (ddd,

J = 1.1, 7.2, 16.5 Hz, 1H), 8.16 (ddd, J = 1.3, 1.4, 8.6, 1H), 7.72 (ddd,

J = 2.4, 7.3, 8.4 Hz, 1H), 3.95 −4.22 (m, 4H), 4.02 (s, 3H), 3.95 (s,

3H), 3.93 (s, 3H), 3.92 (s, 3H), and 1.33 (t, J = 7.1 Hz, 6H). ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 167.7, 167.4, 166.7, 165.8, 138.8 (d, J =

5.7 Hz), 136.0 (d, J = 2.4 Hz), 132.5, 132.1 (d, J = 3.3 Hz), 131.5 (d, J

= 11.7 Hz), 131.2 (d, J = 3.0 Hz), 130.6 (d, J = 13.7 Hz), 127.5 (d, J =

15.0 Hz), 127.0 (d, J = 190.9 Hz, C_aryl−P), 126.2, 62.8 (d, J = 6.1 Hz),

53.5, 53.4, 53.1, 52.9, and 16.3 (d, J = 6.7 Hz). ³¹P{¹H} NMR (121

MHz, CDCl₃): δ 16.6. IR (neat): 2984, 2954, 2902, 1735, 1439, 1392,

1375, 1355, 1338, 1236, 1167, 1094, 1083, 1051, 1021, 973, 824, 796,

and 762 cm⁻¹. HRMS (ESI) m /z : [M+Na⁺] calcd for C₂₂H₂₅NaO₁₁P⁺

requires 519.1027; found 519.1032.

1

phosphonate 12c (169 mg, 0.43 mmol, 61%) as a white solid. H

NMR (300 MHz, CDCl₃): δ 7.52 −7.62 (m, 2H), 7.35 −7.48 (m, 4H),

7.08 (dd, J = 3.8, 7.6 Hz, 1H), 6.97 −7.05 (m, 4H), 6.26 (s, 1H), 5.47

(s, 1H), 3.93 −4.26 (m, 4H), 1.36 (t, J = 7.1 Hz, 6H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 149.0 (d, J = 10.6 Hz), 146.8 (d, J = 13.0 Hz),

145.2, 144.4, 129.9 (d, J = 10.8 Hz), 128.0 (d, J = 3.3 Hz), 125.5,

124.9, 124.7, 124.2, 123.7, 122.9 (d, J = 184.5 Hz, C_aryl−P), 62.2 (d, J

= 5.1 Hz), 54.1 (d, J = 1.6 Hz), 52.0 (d, J = 3.4 Hz), and 16.6 (d, J =

6.9 Hz). ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 19.5. IR (neat): 3070,

2980, 2902, 1457, 1424, 1390, 1366, 1249, 1197, 1156, 1098, 1047,

1019, 965, 837, 798, 749, and 695 cm⁻¹. HRMS (ESI) m /z : [M+Na⁺]

calcd for C₂₄H₂₃NaO₃P⁺requires 413.1277; found 413.1289. mp:

122 −127 °C. TLC: Rf 0.4 (SiO₂, 2:1 EtOAc:hexanes).

Diethyl (5,6,7,8-Tetraphenylnaphthalen-1-yl)phosphonate

(12d).

Diethyl (2-(tert-Butyl)-3-phenyl-2,3-dihydrobenzo[d]isoxazol-4-

yl)phosphonate (12f).

Cesium ﬂ uoride (315 mg, 2.1 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (285 mg,

0.66 mmol), tetraphenylcyclopentadienone (746 mg, 1.9 mmol),

dichloromethane (1.7 mL), and acetonitrile (3.5 mL). Argon was

blown over the headspace of the mixture; the vial was sealed with a

Te ﬂ on-lined cap, and the reaction mixture was heated at 75 °C in a

sand bath. After 15 h, the mixture was cooled to rt, concentrated,

diluted in dichloromethane, and loaded onto a ﬂ ash column. Elution

of the material via gradient ﬂ ash chromatography (SiO₂, hexanes:E-

tOAc 9:1 to 0:1) achieved partial separation of the desired aryl

phosphonate from the unreacted tetraphenylcyclopentadienone.

Puri ﬁ cation with a second ﬂ ash column (SiO₂, hexanes:EtOAc 9:1

to 1:2) gave aryl phosphonate 12d (227 mg, 0.40 mmol, 60%) as a

Cesium ﬂ uoride (470 mg, 3.1 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (387 mg,

0.892 mmol), nitrone 29 (260 mg, 1.5 mmol), and acetonitrile (9.0

mL). Argon was blown over the headspace of the mixture; the vial was

sealed with a Te ﬂ on-lined cap, and the reaction mixture was heated at

100 °C in a sand bath. After 24 h, the mixture was cooled to rt and

diluted in ethyl acetate and water. The phases were separated, and the

aqueous mixture was extracted twice more with ethyl acetate. The

organic phases were combined, washed with brine, dried (MgSO₄),

1

and concentrated. Inspection of the crude H NMR did not reveal

evidence for the presence of regioisomer 12g . Puri ﬁ cation by gradient

ﬂ ash chromatography (SiO₂, CH₂Cl₂:Acetone 39:1 to 29:1) gave

dihydrobenzo[d ]isoxazole 12f (194 mg, 0.498 mmol, 56%) as a clear,

colorless oil. These chromatography solvents were required as the

product partially coelutes with excess nitrone 29 . ¹H NMR analysis of

the impure chromatography fractions suggests that an additional ∼7%

yield of product (ca. 25 mg leading to ∼220 mg total) could be

obtained with subsequent puri ﬁ cations. ¹H NMR (300 MHz, CDCl₃):

δ 7.07 −7.37 (m, 8H), 5.98 (s, 1H), 3.87 −4.02 (m, 1H), 3.42 −3.80

(m, 3H), 1.17 (s, 9H), 1.11 (t, J = 7.1 Hz, 3H), and 1.02 (t, J = 7.1

Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 158.4 (d, J = 19.8 Hz),

1

white solid. H NMR (300 MHz, CDCl₃): δ 8.10 (ddd, J = 1.4, 7.1,

17.5 Hz, 1H), 7.75 (ddd, J = 1.5, 1.6, 8.5 Hz, 1H), 7.32 −7.41 (m,

1H), 7.09 −7.25 (m, 7H), 7.02 −7.09 (m, 3H), 6.77 −6.86 (m, 6H),

6.71 −6.77 (m, 2H), 6.23 −6.68 (m, 2H), 3.74 −3.90 (m, 2H), 3.47 −

3.64 (m, 2H), and 1.17 (t, J = 7.0 Hz, 6H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 142.0, 140.4 (d, J = 8.0 Hz), 140.2, 139.6, 139.5, 139.0 (d,

J = 2.2 Hz), 138.9, 138.8, 135.6 (d, J = 7.0 Hz), 134.5, 133.7 (d, J =

12.7 Hz), 133.0 (d, J = 11.4 Hz), 132.3 (d, J = 3.4 Hz), 131.4, 131.0,

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143.2, 132.7 (d, J = 11.6 Hz), 129.1 (d, J = 15.1 Hz), 128.4, 128.2,

127.3, 125.2 (d, J = 9.0 Hz), 123.9 (d, J = 188.8 Hz, C_aryl−P), 111.0

(d, J = 2.7 Hz), 66.4 (d, J = 2.2 Hz), 61.8 (d, J = 4.7 Hz), 61.7, 61.6

(d, J = 5.0 Hz), 25.5, 16.18, and 16.08. ³¹P{¹H} NMR (121 MHz,

CDCl₃): δ 16.6. IR (neat): 2978, 2937, 2907, 1577, 1497, 1478, 1437,

1392, 1366, 1256, 1206, 1172, 1098, 1053, 1025, 971, 874, 781, 721,

and 697 cm⁻¹. HRMS (ESI) m /z : [M+H⁺] calcd for C₂₁H₂₉NO₄P⁺

requires 390.1829; found 390.1816. The proposed structure of 12f

was supported by an observed HMBC correlation between the

methine C −H and C_aryl−P (cf. structure below). Furthermore, 2D

NOESY and numerous 1D NOE experiments (DPFGSE) failed to

provide evidence for NOE correlation between the methine C −H and

the C_aryl−H para to phosphorus. Rather, the methine C −H only

demonstrated NOE correlation with the tert -butyl C −H and ortho

C_phenyl−H atoms.

solution in CH₂Cl₂), and acetonitrile (8.9 mL). Argon was blown over

the headspace of the mixture; the vial was sealed with a Te ﬂ on-lined

cap, and the reaction mixture was heated at 75 °C in a sand bath.

After 15 h, the mixture was cooled to rt and diluted in ethyl acetate

and water. The phases were separated, and the aqueous mixture was

extracted twice more with ethyl acetate. The organic phases were

1

combined, washed with brine, dried (MgSO₄), and concentrated. H

NMR analysis of the crude reaction mixture indicated that the ratio of

isomers 12k and 12j was 1.0 to 3.1. Puri ﬁ cation by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 1:1 to 1:2 to 0:1) gave faster-

eluting triazole 12k (44 mg, 0.13 mmol, 15%) as a clear, colorless oil

and slower-eluting triazole 12j (145 mg, 0.42 mmol, 47%) as a clear,

colorless oil.

Structural assignment for both isomers was determined from 1D

NOE analysis of the ¹H NMR spectrum of both isomers. Speciﬁcally,

the benzylic position of both isomers (δ 6.39 ppm for 12k and δ 5.89

ppm for 12j) was irradiated. In the case of 12j, enhancement was

observed for the resonance corresponding to H_arylpara to the

phosphonyl group (multiplet at δ 7.54−7.60 ppm).

Ethyl 7-(Diethoxyphosphoryl)-1H-indazole-3-carboxylate (12h ).

1

Analytical data for 12j (slower-eluting major isomer): H NMR

(300 MHz, CDCl₃): δ 7.96 (ddd, J = 1, 6.9, 15.2 Hz, 1H), 7.54−7.60

(m, 1H), 7.47 (ddd, J = 2.8, 7.0, 8.4 Hz, 1H), 7.28−7.40 (m, 5H),

5.89 (s, 2H), 4.19−4.42 (m, 4H), and 1.37 (t, J = 7.1 Hz, 6H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ 145.6 (d, J = 8.1 Hz), 134.3,

132.9 (d, J = 12.7 Hz), 130.5 (d, J = 8.0 Hz), 129.2, 128.8, 127.8,

126.8 (d, J = 14.6 Hz), 120.5 (d, J = 190.9 Hz, C_aryl−P), 114.8 (d, J =

3.3 Hz), 63.0 (d, J = 5.6 Hz), 52.6, and 16.5 (d, J = 6.8 Hz). ³¹P{¹H}

NMR (121 MHz, CDCl₃): δ 14.7. IR (neat): 3066, 3034, 2984, 2935,

2906, 2872, 1601, 1497, 1457, 1418, 1392, 1368, 1295, 1251, 1217,

1163, 1098, 1053, 1025, 984, 971, 859, 792, 762, 729, and 699 cm⁻¹.

HRMS (ESI) m/z: [M+H⁺] calcd for C₁₇H₂₁N₃O₃P⁺requires

346.1315; found 346.1316.

Cesium ﬂ uoride (400 mg, 2.6 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (304 mg,

0.700 mmol), ethyl diazoacetate (370 μ L, 3.5 mmol), and acetonitrile

(14 mL). Argon was blown over the headspace of the mixture; the vial

was sealed with a Te ﬂ on-lined cap, and the reaction mixture was

stirred at room temperature. After 18 h, the mixture was diluted in

ethyl acetate and washed with brine. The organic phase was dried

(MgSO₄) and concentrated. Puriﬁ cation by gradient ﬂ ash chromatog-

raphy (SiO₂, hexanes:EtOAc 7:3 to 1:2) gave indazole phosphonate

12h (153 mg, 0.469 mmol, 67%) as a pale yellow solid. The ¹H NMR

spectrum of the crude (i.e., prior to ﬂ ash chromatography) mixture

structure was supported by the absence of observed NOE correlation

between N H and C_ar₁_yl−H , which would be present in the case of

indazole isomer 12i . H NMR (300 MHz, CDCl₃): δ 11.76 (br s,

1H), 8.48 (d, J = 8.1 Hz, 1H), 7.75 (ddd, J = 0.79, 7.1, 14.7 Hz, 1H),

7.39 −7.48 (m, 1H), 4.54 (q, J = 7.2 Hz, 2H), 4.01 −4.30 (m, 4H),

1.50 (t, J = 7.1 Hz, 3H), and 1.33 (t, J = 7.0 Hz, 6H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ 162.6, 141.9 (d, J = 8.0 Hz), 137.2, 131.4 (d, J =

6.8 Hz), 127.2 (d, J = 3.3 Hz), 123.0 (d, J = 13.7 Hz), 122.9 (ap s),

110.2 (d, J = 191.4 Hz, C_aryl−P), 62.9 (d, J = 5.4 Hz), 61.4, 16.4 (d, J

= 6.8 Hz), and 14.5. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 17.0. IR

(neat): 3179, 2984, 2935, 2907, 1735, 1713, 1457, 1387, 1329, 1245,

1219, 1157, 1135, 1083, 1049, 1019, 969, and 749 cm⁻¹. HRMS

(ESI) m /z : [M+H⁺] calcd for C₁₄H₂₀N₂O₅P⁺requires 327.1104;

found 327.1104. mp: 74 −76 °C.

1

Analytical data for 12k (faster-eluting minor isomer). H NMR

(300 MHz, CDCl₃): δ 8.34 (ap d, J = 8.2 Hz, 1H), 8.10 (dd, J = 7.1,

15.4 Hz, 1H), 7.47 (ddd, J = 2.9, 7.8, 7.8 Hz, 1H), 7.22−7.32 (m,

3H), 7.04 (br d, J = 6.7 Hz, 2H), 6.39 (s, 2H), 3.84−4.13 (m, 4H),

and 1.13 (t, J = 7.0 Hz, 6H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

146.9 (d, J = 8.5 Hz), 137.0, 135.1 (d, J = 7.8 Hz), 128.6, 127.7,

126.6, 125.5 (d, J = 3.4 Hz), 123.3 (d, J = 13.9 Hz), 111.6 (d, J =

193.4 Hz, C_aryl−P), 63.0 (d, J = 5.7 Hz), 52.8, and 16.2 (d, J = 6.1

Hz). One resonance was not observed. ³¹P{¹H} NMR (121 MHz,

CDCl₃): δ 15.1. IR (neat): 3064, 3034, 2979, 2906, 1457, 1418, 1389,

1251, 1163, 1096, 1046, 1019, 990, 971, 952, 861, 796, 753, 727, 695,

and 665 cm⁻¹

.

HRMS (ESI) m/z: [M+Na⁺] calcd for

C₁₇H₂₀N₃NaO₃P⁺requires 368.1134; found 368.1157.

Ethyl 2-(2-Benzoyl-3-(diethoxyphosphoryl)phenyl)acetate (12l).

Diethyl (1-Benzyl-1H-benzo[d][1,2,3]triazol-4-yl)phosphonate

(12j) and Diethyl (1-Benzyl-1H-benzo[d][1,2,3]triazol-7-yl)-

phosphonate (12k).

Cesium ﬂ uoride (300 mg, 2.0 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (310. mg,

0.714 mmol), ethyl benzoylacetate (150 μ L, 0.87 mmol), and

acetonitrile (13 mL). Argon was blown over the headspace of the

mixture; the vial was sealed with a Te ﬂ on-lined cap, and the reaction

mixture was heated at 80 °C in a sand bath. After 17 h, the mixture

was cooled to rt and diluted in ethyl acetate and water. The phases

were separated, and the aqueous mixture was extracted twice more

with ethyl acetate. The organic phases were combined, washed with

Cesium ﬂ uoride (406 mg, 2.7 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10a (387 mg,

0.89 mmol), benzyl azide (346 mg, 2.1 mmol via 0.74 mL of a 3.6 M

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brine, dried (MgSO₄), and concentrated. Puriﬁ cation by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 6:1 to 7:3 to 0:1) gave 197

mg of an inseparable mixture of 12l , the C2/C3 regioisomer, and an

isomer resulting from C2 incorporation of hydrogen instead of

benzoyl with mole fractions of 0.76, 0.14, and 0.10, respectively. From

the relative mole fractions we could assume a 76% purity by mass of

12l (150 mg, 0.37 mmol, 50%). Subsequent puri ﬁ cation by gradient

ﬂ ash chromatography (SiO₂, hexanes:EtOAc 7:3 to 1:1 to 1:2)

enabled partial resolution of 12l , providing a sample with su ﬃ cient

purity to con ﬁ rm structure assignment of 12l , which was a clear,

colorless oil. The proposed structure of 12l was supported by 1D

Ethyl 2-(2-Benzoyl-3-(6-oxidodibenzo[c,e][1,2]oxaphosphinin-6-

yl)phenyl)acetate (30).

Cesium ﬂ uoride (120 mg, 0.79 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10p (145 mg,

0.282 mmol), ethyl benzoylacetate (60 μ L, 0.35 mmol), and

acetonitrile (3.0 mL). Argon was blown over the headspace of the

mixture; the vial was sealed with a Te ﬂ on-lined cap, and the reaction

mixture was heated at 75 °C in a sand bath. After 8 h, the mixture was

cooled to rt and diluted in ethyl acetate and water. The phases were

separated, and the aqueous mixture was extracted twice more with

ethyl acetate. The organic phases were combined, washed with brine,

dried (MgSO₄), and concentrated. Puriﬁ cation by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 7:3 to 1:1) gave aryl

phosphonate 30 (52 mg, 0.11 mmol, 39%) as a clear, colorless oil.

Structural assignment for 30 was made based on comparison with

1

NOE H NMR experiments (DPFGSE), which showed a correlation

between the methylene alpha to the ester and the C_aryl−H para to

1

phosphorus. H NMR (300 MHz, CDCl₃): δ 7.96 (ddd, J = 1.7, 7.1,

13.8 Hz, 1H), 7.70 −7.86 (m, 2H), 7.50 −7.64 (m, 3H), 7.34 −7.50

(m, 2H), 3.69 −4.18 (m, 6H), 3.48 (s, 2H), 1.06 (t, J = 7.1 Hz, 3H),

and 0.80 −1.30 (m, 6H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 197.3

(d, J = 3.6 Hz), 170.4, 143.1 (d, J = 11.4 Hz), 137.5, 135.1 (d, J = 2.5

Hz), 133.6, 132.6 (d, J = 8.9 Hz), 131.9 (d, J = 15.0 Hz), 130.7 (d, J =

193.1 Hz, C_aryl−P), 130.0 (br), 128.9 (d, J = 15.0 Hz), 128.4, 62.3 (d,

J = 4.6 Hz), 61.1, 38.4, 16.0 (br), and 14.0. ³¹P{¹H} NMR (121 MHz,

CDCl₃): δ 16.5. IR (neat): 3062, 2984, 2935, 2907, 2872, 1735, 1674,

1597, 1582, 1450, 1370, 1330, 1316, 1252, 1198, 1165, 1098, 1051,

1025, 971, 926, 794, 775, 710, and 673 cm⁻¹. HRMS (ESI) m /z : [M

+Na⁺] calcd for C₂₁H₂₅NaO₆P⁺requires 427.1281; found 427.1280.

6-(1,4-Dihydro-1,4-epoxynaphthalen-5-yl)dibenzo[c,e][1,2]-

oxaphosphinine 6-oxide (26).

1

diethyl ester variant 12l . H NMR (300 MHz, CDCl₃, 20 °C): δ

7.06 −8.33 (br m, 16H), 3.89 (br q, J = 7.03 Hz, 2H), 3.44 (br s, 2H),

and 1.03 (t, J = 7.11 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

197.0, 170.3, 148.7, 143.8, 136.8, 135.89, 135.86, 135.04, 134.97,

133.6, 133.3, 133.0, 132.5, 132.3, 132.1, 131.5, 131.3, 130.7, 130.2

(br), 129.7 (br), 129.2, 129.0, 128.7, 128.4, 128.24, 128.16, 127.5,

127.2, 125.6, 125.1, 124.6, 124.5, 123.9, 123.3, 123.2, 121.3, 121.1,

120.4 (br), 61.1, 38.3, and 14.0. Because of complex J_CPcoupling,

overlapping multiplets, and peak broadening from hindered rotation,

the chemical shift of each peak is provided without further

interpretation. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 21.2. IR

(neat): 3064, 2984, 2935, 1735, 1672, 1597, 1478, 1448, 1433,

1370, 1331, 1316, 1273, 1243, 1206, 1159, 1120, 1027, 924, 759, 706,

and 671 cm⁻¹. HRMS (ESI) m /z : [M+Na⁺] calcd for C₂₉H₂₃NaO₅P⁺

requires 505.1175; found 505.1170.

Cesium ﬂ uoride (235 mg, 1.4 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10p (235 mg,

0.46 mmol), furan (170 μ L, 2.3 mmol), and acetonitrile (5.0 mL).

Argon was blown over the headspace of the mixture; the vial was

sealed with a Te ﬂ on-lined cap, and the reaction mixture was heated at

75 °C in a sand bath. After 24 h, the mixture was cooled to rt, diluted

in ethyl acetate, sequentially washed with water and brine, dried

(MgSO₄), and concentrated. Puriﬁ cation by gradient ﬂ ash chroma-

tography (SiO₂, hexanes:EtOAc 7:3 to 1:1) gave an inseparable 1:1

mixture of racemic diastereomers (i.e., four stereoisomers total) of

Dimethyl (1-Benzyl-1H-benzo[d][1,2,3]triazol-4-yl)phosphonate

(31a) and Dimethyl (1-Benzyl-1H-benzo[d][1,2,3]triazol-7-yl)-

phosphonate (32a).

1

Cesium ﬂ uoride (151 mg, 1.0 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10j (135 mg,

0.33 mmol), benzyl azide (130 mg, 1.0 mmol via 0.28 mL of a 3.6 M

solution in CH₂Cl₂), and acetonitrile (3.3 mL). Argon was blown over

the headspace of the mixture; the vial was sealed with a Te ﬂ on-lined

cap, and the reaction mixture was heated at 70 °C in a sand bath.

After 17 h, the mixture was cooled to rt and diluted in ethyl acetate

and water. The phases were separated, and the aqueous mixture was

extracted twice more with ethyl acetate. The organic phases were

aryl phosphonate 26 (106 mg, 0.30 mmol, 65%) as a white solid. H

NMR (300 MHz, CDCl₃): δ 7.97 −8.11 (m, 4H), 7.64 −7.73 (m, 2H),

7.21 −7.64 (m, 14H), 7.00 −7.11 (m, 3H), 6.93 −6.99 (m, 2H), 6.57

(d, J = 1.7, 5.5 Hz, 1H), 5.99 (br s, 1H), 5.78 (br s, 1H), 5.73 (s, 1H),

and 5.72 (s, 1H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 155.8, 155.6,

155.3, 155.2, 150.25, 150.21, 150.11, 150.06, 149.0, 148.91, 148.86,

148.75, 143.6, 143.4, 142.73, 142.64, 135.6, 135.5, 135.42, 135.35,

135.1, 133.38, 133.36, 133.24, 133.22, 131.2, 131.10, 131.05, 130.9,

130.7, 129.9, 128.7, 128.5, 128.4, 128.3, 128.1, 127.9, 127.80, 127.75,

127.69, 127.5, 126.3, 125.8, 125.35, 125.30, 125.20, 125.16, 124.9,

124.8, 124.6, 124.26, 124.24, 124.20, 124.14, 123.88, 123.84, 123.76,

123.71, 123.5, 123.3, 122.0, 121.9, 121.8, 121.6, 121.5, 121.4, 120.9,

120.8, 120.7, 120.6, 82.23, 82.21, 82.04, 82.00, 81.9, and 81.8. Because

the sample is a mixture of diastereomers with complex J_CPcoupling

and overlapping multiplets, the chemical shift of each peak is provided

without further interpretation. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ

23.3 and 22.0. IR (neat): 3068, 3021, 2958, 2932, 2868, 2240, 1595,

1582, 1560, 1478, 1448, 1431, 1405, 1347, 1279, 1236, 1204, 1157,

1118, 1083, 1044, 1008, 919, 876, 855, 814, 777, 757, 729, 718, and

688 cm⁻¹. HRMS (ESI) m /z : [M+H⁺] calcd for C₂₂H₁₆O₃P⁺requires

359.0832; found 359.0829. mp: 57 −60 °C.

1

combined, washed with brine, dried (MgSO₄), and concentrated. H

NMR analysis of the crude reaction mixture indicated that the ratio of

isomers 32a and 31a was 1.0 to 3.3. Puri ﬁ cation by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 1:1 to 1:2 to 0:1) gave faster-

eluting triazole 32a (23 mg, 0.073 mmol, 22%) as a clear, colorless oil

and slower-eluting triazole 31a (73 mg, 0.23 mmol, 70%) as a clear,

colorless oil. Structural assignment for both isomers was made based

on comparison with diethyl ester variants 12j and 12k .

Spectral data for 31a (slower-eluting major isomer). ¹H NMR (300

MHz, CDCl₃): δ 7.97 (ddd, J = 0.9, 6.9, 15.3 Hz, 1H), 7.57−7.62 (m,

1H), 7.49 (ddd, J = 2.9, 7.0, 8.5 Hz, 1H), 7.27−7.39 (m, 5H), 5.90 (s,

2H), 3.94 (s, 3H), and 3.90 (s, 3H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 145.6 (d, J = 8.1 Hz), 134.3, 132.9 (d, J = 12.8 Hz), 130.9

(d, J = 8.1 Hz), 129.2, 128.8, 127.8, 126.9 (d, J = 14.9 Hz), 119.1 (d, J

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Article

= 191.6 Hz, C_aryl−P), 114.8 (d, J = 3.4 Hz), 53.5 (d, J = 5.6 Hz), and

52.7. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ 17.9. IR (neat): 3066,

2954, 2851, 1599, 1456, 1258, 1059, and 1032 cm⁻¹. HRMS (ESI)

m/z: [M+Na⁺] calcd for C₁₅H₁₆N₃NaO₃P⁺requires 340.0821; found

340.0823.

Bis(2,2,2-triﬂuoroethyl) (1-Benzyl-1H-benzo[d][1,2,3]triazol-4-

yl)phosphonate (31c) and Bis(2,2,2-triﬂuoroethyl) (1-Benzyl-1H-

benzo[d][1,2,3]triazol-7-yl)phosphonate (32c).

Spectral data for 32a (faster-eluting minor isomer). ¹H NMR (300

MHz, CDCl₃): δ 8.36 (br d, J = 8.4 Hz, 1H), 8.08 (dd, J = 7.2, 15.4

Hz, 1H), 7.48 (ddd, J = 2.6, 7.4, 8.3 Hz, 1H), 7.22−7.33 (m, 3H),

7.01 (br d, J = 7.6 Hz, 2H), 6.35 (s, 2H), 3.57 (s, 3H), and 3.53 (s,

3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 147.0 (d, J = 9.4 Hz),

136.9, 135.4 (d, J = 7.7 Hz), 128.6, 127.6, 126.5, 125.8 (d, J = 2.7

Hz), 123.3 (d, J = 17.0 Hz), 110.2 (d, J = 194.4 Hz, C_aryl−P), 53.1 (d,

J = 5.8 Hz), and 52.7. One resonance was not observed. ³¹P{¹H}

NMR (121 MHz, CDCl₃): δ 17.8. IR (neat): 2948, 2848, 1578, 1245,

1047, and 1023 cm⁻¹. HRMS (ESI) m/z: [M+H⁺] calcd for

C₁₅H₁₇N₃O₃P⁺requires 318.1002; found 318.0991.

Cesium ﬂ uoride (360 mg, 2.4 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10o (429 mg,

0.79 mmol), benzyl azide (320 mg, 2.4 mmol via 0.66 mL of a 3.6 M

solution in CH₂Cl₂), and acetonitrile (7.9 mL). Argon was blown over

the headspace of the mixture; the vial was sealed with a Te ﬂ on-lined

cap, and the reaction mixture was heated at 70 °C in a sand bath.

After 17 h, the mixture was cooled to rt and diluted in ethyl acetate

and water. The phases were separated, and the aqueous mixture was

extracted twice more with ethyl acetate. The organic phases were

Bis((trimethylsilyl)methyl) (1-Benzyl-1H-benzo[d][1,2,3]triazol-4-

yl)phosphonate (31b) and Bis((trimethylsilyl)methyl) (1-Benzyl-1H-

benzo[d][1,2,3]triazol-7-yl)phosphonate (32b).

1

combined, washed with brine, dried (MgSO₄), and concentrated. H

NMR analysis of the crude reaction mixture indicated that the ratio of

isomers 32c and 31c was 1.0 to 7.9, respectively. Puri ﬁ cation by

gradient ﬂ ash chromatography (SiO₂, hexanes:EtOAc 4:1 to 1:1) gave

faster-eluting triazole 32c (17 mg, 0.037 mmol, 5%) as a clear,

colorless oil and slower-eluting triazole 31c (134 mg, 0.30 mmol,

38%) as a clear, colorless oil. Structural assignment for both isomers

was made based on comparison with diethyl ester variants 12j and

12k .

Cesium ﬂ uoride (146 mg, 0.96 mmol) was added to an oven-dried

screw cap vial containing a mixture of aryl phosphonate 10n (176 mg,

0.32 mmol), benzyl azide (130 mg, 0.98 mmol via 0.27 mL of a 3.6 M

solution in CH₂Cl₂), and acetonitrile (3.2 mL). Argon was blown over

the headspace of the mixture; the vial was sealed with a Te ﬂ on-lined

cap, and the reaction mixture was heated at 70 °C in a sand bath.

After 17 h, the mixture was cooled to rt and diluted in ethyl acetate

and water. The phases were separated, and the aqueous mixture was

extracted twice more with ethyl acetate. The organic phases were

Spectral data for 31c (slower-eluting major isomer). ¹H NMR (300

MHz, CDCl₃): δ 7.88 (dd, J = 7.0, 16.0 Hz, 1H), 7.63 (dd, J = 2.7, 8.3

Hz, 1H), 7.51 (ddd, J = 3.4, 6.9, 8.6 Hz, 1H), 7.23−7.40 (m, 5H),

5.90 (s, 2H), and 4.64−4.85 (m, 4H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ 145.5 (d, J = 9.3 Hz), 134.1, 133.0 (d, J = 14.0 Hz), 129.8

(d, J = 8.0 Hz), 129.3, 129.0, 127.8, 127.0 (d, J = 16.0 Hz), 122.7 (dq,

J = 9.0, 277.6 Hz, CF₃), 117.6 (d, J = 201.1 Hz, C_aryl−P), 115.7 (d, J =

3.5 Hz), 63.0 (dq, J = 4.7, 38.0), and 52.9. ¹⁹F{¹³C} NMR (282 MHz,

CDCl₃): δ −76.4 (t, J = 8.1 Hz). ³¹P{¹H} NMR (121 MHz, CDCl₃):

δ 16.7. IR (neat): 3066, 3030, 2973, 1601, 1584, 1497, 1457, 1420,

1293, 1262, 1219, 1174, 1100, 1070, 982, 964, 867, 844, 796, 760,

729, 699, and 662 cm⁻¹. HRMS (ESI) m/z: [M+Na⁺] calcd for

C₁₇H₁₄F₆N₃NaO₃P⁺requires 476.0569; found 476.0569.

1

combined, washed with brine, dried (MgSO₄), and concentrated. H

NMR analysis of the crude reaction mixture indicated that the ratio of

isomers 32b and 31b of was 1.0 to 3.1. Puri ﬁ cation by gradient ﬂ ash

chromatography (SiO₂, hexanes:EtOAc 7:3 to 1:1) gave faster-eluting

triazole 32b (25 mg, 0.055 mmol, 17%) as a clear, colorless oil and

slower-eluting triazole 31b (76 mg, 0.17 mmol, 53%) as a clear,

colorless oil. Structural assignment for both isomers was made based

on comparison with diethyl ester variants 12j and 12k .

Spectral data for 32c (faster-eluting minor isomer). ¹H NMR (300

MHz, CDCl₃): δ 8.46 (ddd, J = 1.1, 2.0, 8.3 Hz, 1H), 8.09 (ddd, J =

1.1, 7.3, 16.2 Hz, 1H), 7.54 (ddd, J = 3.0, 7.3, 8.3 Hz, 1H), 7.27−7.35

(m, 3H), 7.00 (m, 2H), 6.38 (s, 2H), 4.20−4.36 (m, 2H), and 3.88−

4.06 (m, 2H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 136.3, 135.3 (d, J

= 7.9 Hz), 128.9, 128.0, 127.3 (d, J = 3.4 Hz), 126.4, 123.5 (d, J =

15.0 Hz), 108.9 (d, J = 186.6 Hz, C_aryl−P), 62.6 (dq, J = 5.3, 38.7 Hz),

and 53.1. Because of the low amount of material that was formed,

three resonances were not observed. ¹⁹F{¹³C} NMR (282 MHz,

CDCl₃): δ −76.3 (t, J = 7.9 Hz). ³¹P{¹H} NMR (121 MHz, CDCl₃):

δ 17.9. IR (neat): 3077, 3034, 1603, 1580, 1420, 1295, 1258, 1172,

1094, 1062, 962, 865, and 801 cm⁻¹. HRMS (ESI) m/z: [M+H⁺]

calcd for C₁₇H₁₅F₆N₃O₃P⁺requires 454.0750; found 454.0747.

Computational Methods. All computed structures were

optimized using Gaussian16.³⁵Speciﬁc functionals, basis sets, and

solvation models are provided in the corresponding ﬁgure captions for

each data set. Tight convergence criteria were used for geometry

optimizations. Vibrational frequency calculations were used to

conﬁrm minima or transition state computations, where minima

had no imaginary frequencies and transition states had one imaginary

frequency. Vibrational frequency calculations also provided the

thermochemical information (i.e., Free Energy values) used to

determine relative free energies.

Spectral data for 31b (slower-eluting major isomer). ¹H NMR (300

MHz, CDCl₃): δ 7.92 (dd, J = 6.8, 14.7 Hz, 1H), 7.50−7.57 (m, 1H),

7.46 (ddd, J = 2.7, 6.8, 8.8 Hz, 1H), 7.25−7.42 (m, 5H), 5.89 (s, 2H),

3.94 (dd, J = 6.5, 13.4 Hz, 2H), 3.83 (dd, J = 6.1, 13.4 Hz, 2H), and

0.07 (s, 18H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 145.8 (d, J = 10.5

Hz), 134.5, 132.8 (d, J = 12.8 Hz), 130.6 (d, J = 7.2 Hz), 129.2, 128.7,

127.7, 126.8 (d, J = 14.0 Hz), 120.5 (d, J = 187.3 Hz, C_aryl−P), 114.1

(d, J = 3.3 Hz), 60.0 (d, J = 10.0 Hz), 52.6, and −3.2. ³¹P{¹H} NMR

(121 MHz, CDCl₃): δ 18.7. IR (neat): 2958, 2902, 1416, 1370, 1288,

1249, 1215, 1144, 1094, 1016, and 854 cm⁻¹. HRMS (ESI) m/z: [M

+

+Na⁺] calcd for C₂₁H₃₂N₃NaO₃PSi₂requires 484.1612; found

484.1616.

Spectral data for 32b (faster-eluting minor isomer). ¹H NMR (300

MHz, CDCl₃): δ 8.33 (ddd, J = 1.2, 2.0, 8.3 Hz, 1H), 7.99 (ddd, J =

1.1, 7.2, 14.8 Hz, 1H), 7.46 (ddd, J = 2.5, 7.2, 8.4 Hz, 1H), 7.23−7.32

(m, 3H), 7.11−7.16 (m, 2H), 6.40 (s, 2H), 3.67 (dd, J = 7.3, 13.5 Hz,

2H), 3.48 (dd, J = 6.2, 13.5 Hz, 2H), and 0.02 (s, 18H). ¹³C{¹H}

NMR (75 MHz, CDCl₃): δ 146.8 (d, J = 9.4 Hz), 136.8, 135.0 (d, J =

6.7 Hz), 133.1 (d, J = 7.0 Hz), 128.7, 127.8, 127.2, 125.3 (d, J = 3.1

Hz), 123.2 (d, J = 13.7 Hz), 111.1 (d, J = 190.0 Hz, C_aryl−P), 60.3 (d,

J = 9.3 Hz), 53.0, and −3.3. ³¹P{¹H} NMR (121 MHz, CDCl₃): δ

18.8. IR (neat): 2954, 2894, 1416, 1249, 1033, 1008, and 854 cm⁻¹

.

+

HRMS (ESI) m/z: [M+H⁺] calcd for C₂₁H₃₃N₃O₃PSi₂requires

462.1793; found 462.1802.

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ASSOCIATED CONTENT

ACKNOWLEDGMENTS

■

sı

Acknowledgement is made to the Donors of the American

Chemical Society Petroleum Research Fund for support of this

research. Additional funding was provided by the Ripon

College Knop and Oyster Funds. The NSF Major Research

Instrumentation Grant Program supported acquisition of both

high-resolution mass spectrometry instrumentation (CHE-

1429616) as well as the computational chemistry resources

from the Midwest Computational Chemistry Consortium

(MU3C, CHE-1039925). The authors are grateful to Jonathan

M. Ellis and Andrew R. Buller at the University of Wisconsin

Madison for helpful conversations during the later stages of

these studies.

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01382.

Expanded experimental details; expanded computational

details; raw computational data used to construct the

plots shown Figures 3, 5, and 6; coordinates of all

optimized geometries; raw NMR data used to construct

the plot shown in Figure 7; and copies of NMR spectral

data (PDF)

AUTHOR INFORMATION

■

REFERENCES

Corresponding Author

■

Patrick H. Willoughby − Chemistry Department, Ripon

College, Ripon, Wisconsin 54971, United States;

orcid.org/0000-0001-5163-0502; Email: willoughbyp@

ripon.edu

(1) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley-

Interscience: New York, 2000. (b) Savignac, P.; Iorga, B. Modern

Phosphonate Chemistry; CRC Press: New York, 2003. (c) Svara, J.;

Weferling, N.; Hofmann, T. Phosphorus Compounds, Organic. In

Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Wein-

heim, 2006. (d) Iaroshenko, V. Organophosphorus Chemistry: From

Molecules to Applications; Wiley-VCH: Weinheim, 2019.

Authors

Brianna M. Bembenek − Chemistry Department, Ripon

College, Ripon, Wisconsin 54971, United States

Maya M. S. Petersen − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Julia A. Lilly − Chemistry Department, Ripon College, Ripon,

Wisconsin 54971, United States

Amber L. Haugen − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Naomi J. Jiter − Chemistry Department, Ripon College, Ripon,

Wisconsin 54971, United States

Andrew J. Johnson − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Ethan E. Ripp − Chemistry Department, Ripon College, Ripon,

Wisconsin 54971, United States

Shelby A. Winchell − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Alisha N. Harvat − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Caitlin McNulty − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Sierra A. Thein − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Abbigail M. Grieger − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Brandon J. Lyle − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Gabriella L. Mraz − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Abigail M. Stitgen − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Samuel Foss − Chemistry Department, Ripon College, Ripon,

Wisconsin 54971, United States

Merranda L. Schmid − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

(2) For representative examples, see: (a) Yoshino, K.; Kohno, T.;

Morita, T.; Tsukamoto, G. Organic Phosphorus Compounds. 2.

Synthesis and C orona ry V asodilator Activity of

(Benzothiazolylbenzyl)Phosphonate Derivatives. J. Med. Chem.

1989, 32, 1528−1532. (b) Veale, C. A.; Damewood, J. R.;

Steelman, G. B.; Bryant, C.; Gomes, B.; Williams, J. Non-Peptidic

Inhibitors of Human Leukocyte Elastase. 4. Design, Synthesis, and in

Vitro and in Vivo Activity of a Series of β -Carbolinone-Containing

Trifluoromethyl Ketones. J. Med. Chem. 1995, 38, 86−97.

(c) Heidebrecht, R. W.; Chenard, M.; Close, J.; Dahlberg, W. K.;

Fleming, J.; Grimm, J. B.; Hamill, J. E.; Harsch, A.; Haines, B. B.;

Hughes, B.; Kral, A. M.; Middleton, R. E.; Mushti, C.; Ozerova, N.;

Szewczak, A. A.; Wang, H.; Wilson, K.; Witter, D. J.; Secrist, J. P.;

Miller, T. A. Exploring the Pharmacokinetic Properties of

Phosphorus-Containing Selective HDAC 1 and 2 Inhibitors (SHI-

1:2). Bioorg. Med. Chem. Lett. 2009, 19, 2053−2058. (d) Dang, Q.;

Brown, B. S.; Liu, Y.; Rydzewski, R. M.; Robinson, E. D.; Van Poelje,

P. D.; Reddy, M. R.; Erion, M. D. Fructose-1,6-Bisphosphatase

Inhibitors. 1. Purine Phosphonic Acids as Novel AMP Mimics. J. Med.

Chem. 2009, 52, 2880−2898. (e) Lassaux, P.; Hamel, M.; Gulea, M.;

Delbruck, H.; Mercuri, P. S.; Horsfall, L.; Dehareng, D.; Kupper, M.;

̈

̀

Frere, J. M.; Hoffmann, K.; Galleni, M.; Bebrone, C. Mercapto-

phosphonate Compounds as Broad-Spectrum Inhibitors of the

Metallo-β -Lactamases. J. Med. Chem. 2010, 53, 4862−4876.

(f) McGrath, J. W.; Chin, J. P.; Quinn, J. P. Organophosphonates

Revealed: New Insights into the Microbial Metabolism of Ancient

Molecules. Nat. Rev. Microbiol. 2013, 11, 412−419. (g) Nandre, K. P.;

Bhosale, S. V.; Bhosale, R. S.; Pombala, S.; Kumar, C. G.; Latham, K.;

Bhosale, S. V. Organogelation and Cytotoxic Evolution of

Phosphonate Ester Functionalised Hydrophobic Alkanediamide

Motifs. Supramol. Chem. 2014, 26, 873−881. (h) Németh, G.;

Greff, Z.; Sipos, A.; Varga, Z.; Székely, R.; Sebestyén, M.; Jászay, Z.;

́

Béni, S.; Nemes, Z.; Pirat, J. L.; Volle, J. N.; Virieux, D.; Gyuris, A.;

́

Kelemenics, K.; Ay, E.; Minarovits, J.; Szathmary, S.; Kéri, G.; Orfi, L.

Synthesis and Evaluation of Phosphorus Containing, Specific CDK9/

CycT1 Inhibitors. J. Med. Chem. 2014, 57, 3939−3965. (i) Kim, T.

W.; Yong, Y.; Shin, S. Y.; Jung, H.; Park, K. H.; Lee, Y. H.; Lim, Y.;

Jung, K. Y. Synthesis and Biological Evaluation of Phenyl-1H-1,2,3-

Triazole Derivatives as Anti-Inflammatory Agents. Bioorg. Chem.

2015, 59, 1−11.

Joseph D. Scanlon − Chemistry Department, Ripon College,

Ripon, Wisconsin 54971, United States

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01382

(3) For representative examples, see: (a) Kendall, A. J.; Salazar, C.

A.; Martino, P. F.; Tyler, D. R. Direct Conversion of Phosphonates to

Phosphine Oxides: An Improved Synthetic Route to Phosphines

Including the First Synthesis of Methyl JohnPhos. Organometallics

2014, 33, 6171−6178. (b) Xu, G.; Li, M.; Wang, S.; Tang, W.

Notes

The authors declare no competing ﬁnancial interest.

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Article

Efficient Synthesis of P-Chiral Biaryl Phosphonates by Stereoselective

Intramolecular Cyclization. Org. Chem. Front. 2015, 2, 1342−1345.

(c) Szabó-Szentjóbi, H.; Majoros, I.; Márton, A.; Leveles, I.; Vértessy,

B. G.; Dékány, M.; Tóth, T.; Huszthy, P. Synthesis of New Chiral

Crown Ethers Containing Phosphine or Secondary Phosphine Oxide

Units. Synthesis 2020, 52, 2870−2882.

(4) Xu, F.; Duke, O. M.; Rojas, D.; Eichelberger, H. M.; Kim, R. S.;

Clark, T. B.; Watson, D. A. Arylphosphonate-Directed Ortho C-H

Borylation: Rapid Entry into Highly-Substituted Phosphoarenes. J.

Am. Chem. Soc. 2020, 142, 11988−11992.

(5) Chen, L.; Wang, Y.-Z. Aryl Polyphosphonates: Useful Halogen-

Free Flame Retardants for Polymers. Materials 2010, 3, 4746−4760.

(6) Queffélec, C.; Petit, M.; Janvier, P.; Knight, D. A.; Bujoli, B.

Surface Modification Using Phosphonic Acids and Esters. Chem. Rev.

2012, 112, 3777−3807.

(7) (a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. A Novel

Synthesis of Dialkyl Arenephosphonates. Synthesis 1981, 1981, 56−

57. (b) Belabassi, Y.; Alzghari, S.; Montchamp, J. L. Revisiting the

Hirao Cross-Coupling: Improved Synthesis of Aryl and Heteroaryl

Phosphonates. J. Organomet. Chem. 2008, 693, 3171−3178.

(c) Jablonkai, E.; Keglevich, G. Advances and New Variations of

the Hirao Reaction. Org. Prep. Proced. Int. 2014, 46, 281−316.

(8) Demmer, C. S.; Krogsgaard-Larsen, N.; Bunch, L. Review on

Modern Advances of Chemical Methods for the Introduction of a

Phosphonic Acid Group. Chem. Rev. 2011, 111, 7981−8006.

(9) For recent reviews see: (a) Cai, B. G.; Xuan, J.; Xiao, W. J.

Visible Light-Mediated C −P Bond Formation Reactions. Sci. Bull.

2019, 64, 337−350. (b) Ung, S. P. M.; Mechrouk, V. A.; Li, C. J.

Shining Light on the Light-Bearing Element: A Brief Review of

Photomediated C-H Phosphorylation Reactions. Synthesis 2021, 53,

1003−1022. (c) Rout, L.; Punniyamurthy, T. Recent Advances in

Transition-Metal-Mediated C_sp2-B and C_sp2-P Cross-Coupling Re-

actions. Coord. Chem. Rev. 2021, 431, 213675.

Aminoaryne Precursors via Regioselective Silylamination of 3-

(Triflyloxy)Arynes. Org. Lett. 2016, 18, 6212−6215.

(14) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-Induced

1,2-Elimination of O -Trimethylsilylphenyl Triflate to Benzyne Under

Mild Conditions. Chem. Lett. 1983, 12, 1211−1214.

(15) (a) Shi, J.; Xu, H.; Qiu, D.; He, J.; Li, Y. Selective Aryne

Formation via Grob Fragmentation from the [2 + 2] Cycloadducts of

3-Triflyloxyarynes. J. Am. Chem. Soc. 2017, 139, 623−626. (b) Lv, C.;

Wan, C.; Liu, S.; Lan, Y.; Li, Y. Aryne Trifunctionalization Enabled by

3-Silylaryne as a 1,2-Benzdiyne Equivalent. Org. Lett. 2018, 20, 1919−

1923.

(16) (a) Uchida, K.; Yoshida, S.; Hosoya, T. Three-Component

Coupling of Triflyloxy-Substituted Benzocyclobutenones, Organo-

lithium Reagents, and Arynophiles Promoted by Generation of Aryne

via Carbon-Carbon Bond Cleavage. Org. Lett. 2017, 19, 1184−1187.

(b) Nakamura, Y.; Miyata, Y.; Uchida, K.; Yoshida, S.; Hosoya, T. 3-

Thioaryne Intermediates for the Synthesis of Diverse Thioarenes. Org.

Lett. 2019, 21, 5252−5258.

(17) (a) Abramov, V. S. O reaktsii al’degidov s fosforistykh efirov

[Reaction of Aldehydes with Phosphite Esters]. Dokl. Akad. Nauk

SSSR 1954, 95, 991−992. (b) Woźniak, L.; Chojnowski, J. Silyl Esters

of Phosphorous-Common Intermediates in Synthesis. Tetrahedron

1989, 45, 2465−2524.

(18) Sekine, M.; Yamamoto, I.; Hashizume, A.; Hata, T. Silyl

Phosphites V. the Reactions of Tris(Trimethylsilyl) Phosphite With

Carbonyl Compounds. Chem. Lett. 1977, 6, 485−488.

(19) For recent reports related to the Abramov reaction, see:

(a) Guin, J.; Wang, Q.; Van Gemmeren, M.; List, B. The Catalytic

Asymmetric Abramov Reaction. Angew. Chem., Int. Ed. 2015, 54,

355−358. (b) Dussart, J.; Deschamp, J.; Migianu-Griffoni, E.;

Lecouvey, M. From Industrial Method to the Use of Silylated P(III)

Reagents for the Synthesis of Relevant Phosphonylated Molecules.

Org. Process Res. Dev. 2020, 24, 637−651.

(10) (a) Dhokale, R. A.; Mhaske, S. B. P-Arylation: Arynes to Aryl-

Phosphonates, -Phosphinates, and -Phosphine Oxides. Org. Lett.

2013, 15, 2218−2221. (b) Chen, Q.; Yan, X.; Du, Z.; Zhang, K.; Wen,

C. P-Arylation of Dialkyl Phosphites and Secondary Phosphine

Oxides with Arynes. J. Org. Chem. 2016, 81, 276−281. (c) Yang, G.;

Shen, C.; Quan, M.; Zhang, W. Preparation of Organophosphorus

Compounds from P-H Compounds Using o-(Trimethylsilyl)Aryl

Triflates as Aryne Precursors. Tetrahedron 2016, 72, 333−337.

(d) Chen, J.; Fan, R.; Liu, Z.; Tan, J. Reactions of Organophosphorus

Compounds with Arynes: Reactivity and Mechanism. Adv. Synth.

Catal. 2021, 363, 657−667. (e) Huang, Y.; Hu, Y.; Han, Y.; Ou, Y.;

Huo, Y.; Li, X.; Chen, Q. Direct Synthesis of ortho -Halogenated

Arylphosphonates via a Three-Component Reaction Involving

Arynes. J. Org. Chem. 2021, 86, 7010−7018. (f) Yoshida, S.;

Hosoya, T. Synthesis of Diverse Aromatic Oxophosphorus Com-

pounds by the Michaelis-Arbuzov-Type Reaction of Arynes. Chem.

Lett. 2013, 42, 583−585.

(11) (a) Wenk, H. H.; Winkler, M.; Sander, W. One Century of

Aryne Chemistry. Angew. Chem., Int. Ed. 2003, 42, 502−528.

(b) Gampe, C. M.; Carreira, E. M. Arynes and Cyclohexyne in

Natural Product Synthesis. Angew. Chem., Int. Ed. 2012, 51, 3766−

3778. (c) Tadross, P. M.; Stoltz, B. M. A Comprehensive History of

Arynes in Natural Product Total Synthesis. Chem. Rev. 2012, 112,

3550−3577. (d) Takikawa, H.; Nishii, A.; Sakai, T.; Suzuki, K. Aryne-

Based Strategy in the Total Synthesis of Naturally Occurring

Polycyclic Compounds. Chem. Soc. Rev. 2018, 47, 8030−8056.

(e) Fluegel, L. L.; Hoye, T. R. Hexadehydro-Diels-Alder Reaction:

Benzyne Generation via Cycloisomerization of Tethered Triynes.

Chem. Rev. 2021, 121, 2413−2444.

(20) Yoshida, S.; Uchida, K.; Igawa, K.; Tomooka, K.; Hosoya, T.

An Efficient Generation Method and Remarkable Reactivities of 3-

Triflyloxybenzyne. Chem. Commun. 2014, 50, 15059−15062.

(21) Debrouwer, W.; Hertsen, D.; Heugebaert, T. S. A.; Boydas, E.

B.; Van Speybroeck, V.; Catak, S.; Stevens, C. V. Tandem Addition of

Phosphite Nucleophiles Across Unsaturated Nitrogen-Containing

Systems: Mechanistic Insights on Regioselectivity. J. Org. Chem. 2017,

82, 188−201.

(22) Uchida, K.; Yoshida, S.; Hosoya, T. Controlled Generation of

3-Triflyloxyarynes. Synthesis 2016, 48, 4099−4109.

(23) Hall, C.; Henderson, J. L.; Ernouf, G.; Greaney, M. F. Tandem

Thia-Fries Rearrangement − Cyclisation of 2-(Trimethylsilyl)Phenyl

Trifluoromethanesulfonate Benzyne Precursors. Chem. Commun.

2013, 49, 7602−7604.

(24) Yoshioka, E.; Kakigi, K.; Miyoshi, S.; Kawasaki, Y.; Miyabe, H.

Aryne Precursors for Selective Generation of 3-Haloarynes:

Preparation and Application to Synthetic Reactions. J. Org. Chem.

2020, 85, 13544−13556.

(25) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.;

Maligres, P. E.; Krska, S. W.; Maleczka, R. E.; Smith, M. R. Silyl

Phosphorus and Nitrogen Donor Chelates for Homogeneous Ortho

Borylation Catalysis. J. Am. Chem. Soc. 2014, 136, 14345−14348.

(26) (a) Salmeia, K. A.; Gaan, S. An Overview of Some Recent

Advances in DOPO-Derivatives: Chemistry and Flame Retardant

Applications. Polym. Degrad. Stab. 2015, 113, 119−134. (b) Kim, W.;

Hoang, D.; Vothi, H.; Nguyen, C.; Giang, T.; An, H.; Kim, J.

Synthesis, Flame Retardancy, and Thermal Degradation Behaviors of

Novel Organo-Phosphorus Compounds Derived from 9,10-Dihydro-

9-oxa-10-phosphaphenanthrene-10-oxide (DOPO). Macromol. Res.

2016, 24, 66−73. (c) Min, Y.; Li, P.; Yin, X.-G.; Ban, D.-M. Synthesis

and Characterization of an Novel Flame Retardant Based on

Phosphaphenanthrene for Epoxy Resin. Polym. Bull. 2017, 74, 1−10.

(27) Several attempts were made to characterize the corresponding

diazaphospholidine, which rapidly decomposed (t_1/2= 4 h) to an

unknown product. Despite our several attempts (1 h aryne-Abramov

reaction, 1 h workup and ﬂash chromatography), substantial amounts

(12) Two recent reviews include: (a) Shi, J.; Li, Y.; Li, Y. Aryne

Multifunctionalization with Benzdiyne and Benztriyne Equivalents.

Chem. Soc. Rev. 2017, 46, 1707−1719. (b) He, J.; Qiu, D.; Li, Y.

Strategies toward Aryne Multifunctionalization via 1,2-Benzdiyne and

Benzyne. Acc. Chem. Res. 2020, 53, 508−519.

(13) Yoshida, S.; Nakamura, Y.; Uchida, K.; Hazama, Y.; Hosoya, T.

Aryne Relay Chemistry En Route to Aminoarenes: Synthesis of 3-

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Article

of decomposition were present in the “puriﬁed” product. Future

studies will probe the fate of these types of products in hopes of

preventing unwanted loss of product.

Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne

Cycloadditions. Org. Lett. 2010, 12, 96−99.

(38) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with

the Distortion/Interaction-Activation Strain Model. Angew. Chem., Int.

Ed. 2017, 56, 10070−10086.

(28) (a) Li, Y.; Chakrabarty, S.; Muck-Lichtenfeld, C.; Studer, A.

̈

Ortho -Trialkylstannyl Arylphosphanes by C-P and C-Sn Bond

Formation in Arynes. Angew. Chem., Int. Ed. 2016, 55, 802−806.

(b) Mesgar, M.; Nguyen-Le, J.; Daugulis, O. New Hindered Amide

Base for Aryne Insertion into Si-P, Si-S, Si-N, and C-C Bonds. J. Am.

Chem. Soc. 2018, 140, 13703−13710.

(39) Bent, H. A. An Appraisal of Valence-bond Structures and

Hybridization in Compounds of the First-row elements. Chem. Rev.

1961, 61, 275−311.

(40) Bronner, S. M.; MacKey, J. L.; Houk, K. N.; Garg, N. K. Steric

Effects Compete with Aryne Distortion to Control Regioselectivities

of Nucleophilic Additions to 3-Silylarynes. J. Am. Chem. Soc. 2012,

134, 13966−13969.

(29) Medina, J. M.; MacKey, J. L.; Garg, N. K.; Houk, K. N. The

Role of Aryne Distortions, Steric Effects, and Charges in

Regioselectivities of Aryne Reactions. J. Am. Chem. Soc. 2014, 136,

15798−15805.

(41) Using the Boltzmann equation at 75 °C, a ΔΔG^‡of 2.88 and

3.38 kcal·mol⁻¹provides distal Boltzmann factors of 0.985 and 0.993,

respectively.

(30) Yoshida, S.; Hazama, Y.; Sumida, Y.; Yano, T.; Hosoya, T. An

Alternative Method for Generating Arynes from ortho -Silylaryl

Triflates: Activation by Cesium Carbonate in the Presence of a

Crown Ether. Molecules 2015, 20, 10131−10140.

(42) In addition to routine techniques for computing transition state

structures (e.g., gas-phase calculations and multiple phosphonate

conformations), numerous attempts to locate the distal transition

state involving the bis(triﬂuoroethyl) phosphonyl benzyne by

scanning relevant nitrogen to carbon bond distances failed.

(43) Goetz, A. E.; Garg, N. K. Regioselective Reactions of 3,4-

Pyridynes Enabled by the Aryne Distortion Model. Nat. Chem. 2013,

5, 54−60.

(44) Tomasi, J.; Mennucci, B.; Cammi, R. Quantum Mechanical

Continuum Solvation Models. Chem. Rev. 2005, 105, 2999−3093.

(45) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal

Solvation Model Based on Solute Electron Density and on a

Continuum Model of the Solvent Defined by the Bulk Dielectric

Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113,

6378−6396.

(46) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals

for Main Group Thermochemistry, Thermochemical Kinetics,

Noncovalent Interactions, Excited States, and Transition Elements:

Two New Functionals and Systematic Testing of Four M06-Class

Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120,

215−241.

(47) Wang, Y.; Jin, X.; Yu, H. S.; Truhlar, D. G.; He, X. Revised

M06-L Functional for Improved Accuracy on Chemical Reaction

Barrier Heights, Noncovalent Interactions, and Solid-State Physics.

Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 8487−8492.

(48) Head-Gordon, M.; Head-Gordon, T. Analytic MP2 Frequen-

cies without Fifth-Order Storage. Theory and Application to

Bifurcated Hydrogen Bonds in the Water Hexamer. Chem. Phys.

Lett. 1994, 220, 122−128.

(49) Unlike benzynes 33a and 33b, the relative energy of the lowest-

energy conformers of 33c was diﬀerent when solvation was omitted.

With this in mind, the lowest-energy conformation from both the gas-

phase and MeCN-solvated computations were used as the starting

geometry for the optimizations of 33c in various solvents. The

distortion of the lower-energy conformer was used to prepare the plot

in Figure 6b. Additional details are provided in the Supporting

Information.

(50) Zhang, J.; Zhang, H.; Wu, T.; Wang, Q.; Van Der Spoel, D.

Comparison of Implicit and Explicit Solvent Models for the

Calculation of Solvation Free Energy in Organic Solvents. J. Chem.

Theory Comput. 2017, 13, 1034−1043.

(51) Shirman, T.; Arad, T.; van der Boom, M. E. Halogen Bonding:

A Supramolecular Entry for Assembling Nanoparticles. Angew. Chem.,

Int. Ed. 2010, 49, 926−929.

(31) For recent examples, see: (a) Pozo, I.; Cobas, A.; Pena, D.;

̃

Guitián, E.; Pérez, D. 1,7-Naphthodiyne: A New Platform for the

Synthesis of Novel, Sterically Congested PAHs. Chem. Commun.

2016, 52, 5534−5537. (b) Xu, F.; Hershey, K. W.; Holmes, R. J.;

Hoye, T. R. Blue-Emitting Arylalkynyl Naphthalene Derivatives via a

Hexadehydro-Diels −Alder Cascade Reaction. J. Am. Chem. Soc. 2016,

138, 12739−12742.

(32) Pena, D.; Pérez, D.; Guitián, E.; Castedo, L. Palladium-

Catalyzed Cocyclization of Arynes with Alkynes: Selective Synthesis

of Phenanthrenes and Naphthalenes. J. Am. Chem. Soc. 1999, 121,

5827−5828.

(33) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Benzyne Click

Chemistry: Synthesis of Benzotriazoles from Benzynes and Azides.

Org. Lett. 2008, 10, 2409−2412.

(34) (a) Ikawa, T.; Takagi, A.; Goto, M.; Aoyama, Y.; Ishikawa, Y.;

Itoh, Y.; Fujii, S.; Tokiwa, H.; Akai, S. Regiocomplementary

Cycloaddition Reactions of Boryl- and Silylbenzynes with 1,3-Dipoles:

Selective Synthesis of Benzo-Fused Azole Derivatives. J. Org. Chem.

2013, 78, 2965−2983. (b) Ikawa, T.; Kaneko, H.; Masuda, S.;

Ishitsubo, E.; Tokiwa, H.; Akai, S. Trifluoromethanesulfonyloxy-

Group-Directed Regioselective (3 + 2) Cycloadditions of Benzynes

for the Synthesis of Functionalized Benzo-Fused Heterocycles. Org.

Biomol. Chem. 2015, 13, 520−526.

(35) Gaussian16 was used for all computations: Frisch, M. J.;

Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;

Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.;

Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.;

Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.

V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.;

Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson,

T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;

Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;

Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;

Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;

Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov,

V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;

Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;

Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.;

Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.

Gaussian 16, rev. B.01; Gaussian, Inc.: Wallingford, CT, 2016.

(36) (a) Cheong, P. H. Y.; Paton, R. S.; Bronner, S. M.; Im, G.-Y. J.;

Garg, N. K.; Houk, K. N. Indolyne and Aryne Distortions and

Nucleophilic Regioselectivites. J. Am. Chem. Soc. 2010, 132, 1267−

1269. (b) Goetz, A. E.; Bronner, S. M.; Cisneros, J. D.; Melamed, J.

M.; Paton, R. S.; Houk, K. N.; Garg, N. K. An Efficient

Computational Model to Predict the Synthetic Utility of Heterocyclic

Arynes. Angew. Chem., Int. Ed. 2012, 51, 2758−2762. (c) Picazo, E.;

Houk, K. N.; Garg, N. K. Computational Predictions of Substituted

Benzyne and Indolyne Regioselectivities. Tetrahedron Lett. 2015, 56,

3511−3514.

(52) Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama, Y.; Tanabe,

M.; Miyamoto, M.; Yasui, Y.; Matsumoto, T.; Suzuki, K. Facile Access

to Versatile Polyaromatic Building Blocks: Selectively Protected

Benzocyclobutenedione Derivatives via Regioselective [2 + 2]

Cycloaddition of α -Alkoxybenzyne and Ketene Silyl Acetal. Helv.

Chim. Acta 2002, 85, 3589−3604.

(53) Gao, L.; Han, J.; Lei, X. Enantioselective Total Syntheses of

Kuwanon X, Kuwanon Y, and Kuwanol A. Org. Lett. 2016, 18, 360−

363.

(37) Garr, A. N.; Luo, D.; Brown, N.; Cramer, C. J.; Buszek, K. R.;

VanderVelde, D. Experimental and Theoretical Investigations into the

10745

https://doi.org/10.1021/acs.joc.1c01382

J. Org. Chem. 2021, 86, 10724−10746

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(54) Andrus, M. B.; Liu, J. Synthesis of Polyhydroxylated Ester

Analogs of the Stilbene Resveratrol Using Decarbonylative Heck

Couplings. Tetrahedron Lett. 2006, 47, 5811−5814.

(55) Huang, Z.; Yang, Y.; Xiao, Q.; Zhang, Y.; Wang, J. Auto-

Tandem Catalysis: Synthesis of Acridines by Pd-Catalyzed C = C

Bond Formation and C(sp²)-N Cross-Coupling. Eur. J. Org. Chem.

2012, 6586−6593.

(56) Imai, K.; Ito, T.; Kondo, S.; Takaku, H. A New Phosphorylating

Agent, Di(2,2,2-Trifluoroethyl) Trimethylsilyl Phosphite. Its Appli-

cation in DNA Synthesis by the Phosphotriester Approach.

Nucleosides Nucleotides 1985, 4, 669−679.

(57) Kondoh, A.; Aoki, T.; Terada, M. Organocatalytic Arylation of

α -Ketoesters Based on Umpolung Strategy: Phosphazene-Catalyzed

SNAr Reaction Utilizing [1,2]-Phospha-Brook Rearrangement. Chem.

- Eur. J. 2018, 24, 13110−13113.

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The Aryne-Abramov Reaction as a 1,2-Benzdiyne Platform for the Generation and Solvent-Dependent Trapping of 3-Phosphonyl Benzynes

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