Spiro[1,2]oxaphosphetanes of nonstabilized and semistabilized phosphorus ylide derivatives: Synthesis and kinetic and computational study of their thermolysis

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Spiro[1,2]oxaphosphetanes of Nonstabilized and Semistabilized

Phosphorus Ylide Derivatives: Synthesis and Kinetic and

Computational Study of Their Thermolysis

́

Jesus Garc í a Lopez, Pablo M. Sansores Peraza, Mar í a Jose Iglesias, Laura Roces, Santiago Garc í a-Granda,

and Fernando Lopez Ortiz *

́

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ABSTRACT: A series of tri- and tetrasubstituted spiro-oxaphosphetanes

stabilized by ortho-benzamide (oBA) and N-methyl ortho-benzamide (MoBA)

ligands have been synthesized by the reaction of C_α,C_ortho-dilithiated

phosphazenes with aldehydes and ketones. They include enantiopure products

and the ﬁrst example of an isolated oxaphosphetane having a phenyl

substituent at C3 of the ring. Kinetic studies of their thermal decomposition

showed that the process takes place irreversibly through a polar transition state

(ρ = −0.22) under the inﬂuence of electronic, [1,2], [1,3] steric, and solvent

eﬀects, with C3/P-[1,2] interactions as the largest contribution to ΔG^⧧of

oleﬁnation. Inversion of the phosphorus conﬁguration through stereomutation

has been observed in a number of cases. DFT calculations showed that oBA derivatives oleﬁnated through the isolated (N, O)(Ph,

C₆H₄, C) oxaphosphetanes (Channel A), whereas MoBA compounds decomposed faster via the isomer (C₆H₄, O)(C, N, Ph)

formed by P-stereomutation involving a M_B2permutational mechanism (Channel B). The energy barrier of P-isomerization is lower

than that of oleﬁnation. Fragmentation takes place in a concerted asynchronous reaction. The thermal stability of oxaphosphetanes is

determined by strong C3/P-[1,2] interactions destabilizing the transition state of oleﬁnation. The eﬀect of charge distribution and

C3/C4-[1,2] and C4/P-[1,3] steric and solvent interactions on ΔG^⧧was also evaluated.

control involves a [2 + 2] cycloaddition to give a 1,2-

oxaphosphetane intermediate (cis-OPA/trans-OPA, Scheme

1), which decomposes via the isomer formed by phosphorus

pseudorotation to place the P−O bond in an equatorial position

(cis-OPA_eq/trans-OPA_eq,) followed by [2 + 2] cycloreversion to

yield the oleﬁn (Z-OL/E-OL), and a phosphine oxide (Scheme

1).^6,7

In the absence of inorganic salts, the stereochemical course of

the process can be explained through a combination of [1,2]-,^6,8

[1,3]-,⁶C−H···O,^4c,9and dipole−dipole⁹interactions that

control the relative energy of the transition states (cis-TS/

trans-TS) of 1,2-oxaphosphetanes formation (Scheme 1). In a

few cases, reversibility in this ﬁrst step has been observed, and

the E/Z selectivity obtained proceeds from the thermodynamic

equilibrium between the diastereomeric oxaphosphetanes. This

reversal of the cycloaddition step causes the so-called stereo-

chemical drift.^10,11

INTRODUCTION

■

In 1919, Staudinger and Meyer found that the reaction of

Ph₃PCPh₂with phenylisocyanate aﬀorded triphenylketeni-

mine and triphenylphosphine oxide and suggested the

involvement of a 1,2-oxaphosphetane as an intermediate in the

formation of the carbon−carbon double bond (Scheme 1).¹In a

seminal article published in 1953, Wittig and Geissler also

proposed the participation of a 1,2-oxaphosphetane in the

synthesis of 1,1-diphenylethylene by reacting Ph₃PCH₂with

benzophenone.²This work represents the birth of the

oleﬁnation of aldehydes and ketones by phosphorus ylides, the

Wittig reaction, which evolved into a reference synthetic method

for the regio- and stereodeﬁned construction of carbon−carbon

double bonds.^3,4Despite being intensively studied for almost 70

years, the mechanism of this fundamental transformation in

organic synthesis is still under debate. In an excellent recent

review, Gilheany and Byrne performed a detailed analysis of the

experimental and computational studies about the mechanism

of the Wittig reaction between phosphonium ylides and

aldehydes or ketones.⁵Phosphorus ylides are categorized by

the substituent(s) R attached to the ylidic carbon as non-

stabilized (R = alkyl), semistabilized (R = alkenyl, phenyl), and

stabilized (R = heteroatom-containing conjugating group, e.g.,

carbonyl, ester, nitrile, etc.). The accepted mechanism for the Li-

salt free Wittig oleﬁnation of nonstabilized ylides under kinetic

Special Issue: The New Golden Age of Organo-

phosphorus Chemistry

Received: May 27, 2020

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A

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a

Scheme 1. Mechanism of Wittig Oleﬁnation

a

Stereoelectronic interactions are highlighted in blue.

One hundred years after 1,2-oxaphosphetanes were ﬁrst

introduced,¹they remain the only intermediates isolated in the

Wittig reaction. Experimental evidence about the participation

of 1,2-oxaphosphetanes in the Wittig oleﬁnation arise mostly

from in situ NMR monitoring of the process at low temper-

atures.^10,12,13Generally, 1,2-oxaphosphetanes are highly ther-

mally labile species and are transformed into the corresponding

oleﬁn and PO byproduct upon warming the NMR sample. A

very small number of these intermediates have been isolated and

structurally characterized through X-ray diﬀraction studies.¹⁴

Representative examples are shown in Chart 1. Based on the

oxaphosphetanes 4,¹⁸5,¹⁹and 6.²⁰The Martin ligand²¹(ML)

and the ortho-benzamide ligand (oBA) proved to be very

eﬃcient scaﬀolds for OPA stabilization.^22,23So far, only 1,2-

oxaphosphetanes derived from nonstabilized ylides have been

isolated as products of the Wittig reaction. It is nevertheless

important to note that 1,2-oxaphosphetanes formally arising

from ylides stabilized by a methoxycarbonyl group have been

obtained through alkoxycarbonylation of stable precursors

unsubstituted at C-3 (i.e., proceeding from nonstabilized

ylides).²⁴

Although most oxaphosphetanes isolated undergo oleﬁnation

upon heating, the rather simple substitution pattern prevents

gaining insight into the stereoelectronic eﬀects that govern the

reaction. We have previously shown that the stabilizing eﬀect of

the oBA ligand allowed us to obtain stable tri- and

tetrasubstituted spiro-1,2-oxaphosphetanes 9 in a one-pot two-

step process (Scheme 2).^19,23First, double C_αand C_ortho

deprotonation of phosphazene 7 with ^tBuLi at −90 °C provides

dianion 8,²⁵which undergoes cyclocondensation at −35 °C by

the attack of the ortho anion to the carbonyl group of the

phosphazene moiety followed by the elimination of lithium

methoxide to give the monoanionic intermediate Li−I. Then,

the reaction of Li−I with aldehydes and ketones would aﬀord

lithiated species Li−II, which is converted into spiro-1,2-

oxaphosphetanes 9 upon aqueous workup. The thermolysis of 9

in the toluene solution aﬀorded the corresponding oleﬁns 10 in a

quantitative and stereospeciﬁc manner (Scheme 2).^19,23In

contrast to the accepted mechanism mentioned above,^5,26the

computational study of the thermal decomposition of 9 revealed

that the [2 + 2] OPA cycloreversion to the corresponding

alkenes 10 and benzoazaphospholone 1-oxide 11 is a single-step

asynchronous reaction.²⁷The positional interchange of apical

and equatorial ligands around the phosphorus atom leading to

an antiapicophilic P−O_eqOPA takes place along the reaction

coordinate via mechanisms involving two (M_B2) or three (M_B3)

and four (M_B4) Berry pseudorotations (BPR).²³These

mechanisms also explained the isomerization of OPA 9 into 9′

through inversion of the conﬁguration of the phosphorus atom

during thermal decomposition (Scheme 2).

Chart 1. Examples of 1,2-Oxaphosphetanes Characterized in

a

the Solid-State with X-ray Diﬀraction

a

Ligands ML and oBA are highlighted in blue and red, respectively.

origin of their thermal stability, they can be classiﬁed into two

groups. Group A is formed by monoheterocyclic systems

stabilized by strong electron-withdrawing substituents (e.g., 1,¹⁵

2,¹⁶and 3¹⁷). Group B includes compounds characterized by the

integration of the oxaphosphetane moiety into a polycyclic

system. Spiro-compounds with rings connected through a

pentacoordinated phosphorus atom seem to represent a

particularly stable arrangement, as shown by the spiro-

In the light of the stability of spiro-compounds 9, we reasoned

that they could be used for investigating the stereoelectronic

B

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Scheme 2. Synthesis of Spiro-1,2-oxaphosphetanes 9 and Alkenes 10

Table 1. Spiro-1,2-oxaphosphetanes 9 and 12 Synthesized and ³¹P NMR Data, δ in ppm

a

Diastereomeric ratios determined through integration of the ³¹P NMR spectra of the crude reaction mixture. The trans/cis descriptors indicate the

relative orientation of the P-phenyl ring and the higher rank substituent linked either to C3 and/or C4 carbons of the oxaphosphetane ring.

b

c

d

e

Compound described in ref 23. Compounds described in ref 25. Reaction time with the ketone of 5 h. Reaction time with the ketone of 5 h at a

temperature of −35 °C.

features controlling oleﬁn formation in the second step of Wittig

oleﬁnation. Here we report the extension of the synthesis of

oBA-stabilized spiro-oxaphosphetanes to the preparation of

compounds with a substitution pattern that allows us to unravel

the eﬀects determining the course of the oleﬁnation process via

thermolysis. New developments include the synthesis of N-

alkylated derivatives and the isolation and structural character-

ization of the ﬁrst example of a 1,2-oxaphosphetane derived from

a semistabilized ylide derivative. Kinetic and thermodynamic

parameters obtained in the oleﬁnation study revealed the

inﬂuence of electronic and solvent eﬀects as well as steric [1,2]

and [1,3] interactions in the reaction pathway.

RESULTS AND DISCUSSION

■

Synthesis of oBA-Stabilized Spiro-1,2-oxaphosphe-

tanes. Compounds 9 used in this study were prepared

according to the procedure shown in Scheme 2 (Table 1).²⁵

Oxaphosphetanes 9a−p were obtained in very high to excellent

C

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yields, except for 9p (see below). High yields of 9e and 9i were

achieved by increasing the reaction time to 5 h (entry 5) and the

reaction temperature to −35 °C (entry 9), respectively.

Compounds 9c,²³9d,²³9e,²⁵9j,²⁵and 9l²⁵reported previously

have been included here in order to complete the kinetic studies

and the analysis of the eﬀects involved in the Wittig oleﬁnation.

The reactions of phosphazenes 7b−c monosubstituted at the P-

C_αproceeded with excellent diastereoselectivity (cf. entries 12−

15), whereas C_α-disubstituted phosphazenes 7d−e provide

oxaphosphetanes 9 with moderate to low diastereoselectivity

(entries 5, 10, and 11). Diastereoisomers were separated by

precipitation from diethyl ether or by column chromatography.

All compounds were structurally characterized based on their

spectroscopic data (Supporting Information). The stereo-

chemistry was assigned through selective 1D gNOESY experi-

ments. Recrystallization of oxaphosphetane cis-9d from a

mixture of dichloromethane-hexane aﬀorded single crystals

suitable for X-ray diﬀraction analysis. The crystal structure is

shown in Figure S13 (Supporting Information). Oxaphosphe-

tanes cis/trans-9k formed in the reaction of dilithiated 7d with

(−)-mirtenal ((−)-(1S,5R)-6,6-dimethylbicyclo[3.1.1]-2-hept-

en-2-carbaldehyde) are enantiomerically pure. Their conﬁg-

uration was assigned based on the 2D gNOESY spectra. This

structural study showed that the racemic phosphazenyl

carbanion added to the carbonyl group of (−)-mirtenal

exclusively through the si face. Isomer trans-9k was recrystallized

from a mixture of dichloromethane−hexane, and the X-ray

crystal structure was measured (Figure S14).

cyclization intermediate Li-Ip is in agreement with the suggested

reduction in nucleophilic reactivity of Li-Ip toward the carbonyl

group of acetone.

Puriﬁcation through two consecutive column chromatog-

raphies provided a small amount (2.6 mg, yield 1%) of nearly

pure cis-9p, enough to achieve the structural characterization

through mass spectrometry and spectroscopic methods. The

HRMS spectrum showed the [M + H]⁺ion at m/z 390.1639 in

agreement with the molecular formula of protonated 9p

(C₂₄H₂₅NO₂P calculated exact mass: 390.1623). The ³¹P

NMR spectrum shows a resonance at δ −67.5 ppm in the

expected range for a pentacoordinated phosphorus atom (Figure

S2d). The ¹H and ¹³C NMR spectra present the same pattern of

signals of the family of compounds 9 (Figure S2a,c). The relative

conﬁguration of the P and C stereogenic centers was established

based on 1D NOE experiments (Figure S2b). To the best of our

knowledge, this is the ﬁrst example of a 1,2-oxaphosphetane

isolated from a semistabilized phosphorus ylide having a phenyl

group at the ylidic carbon. It should be noted that Vedejs and

Fleck reported the observation through ³¹P NMR of C3-vinyl

substituted OPAs stabilized by a dibenzophosphole system.^6c

Spiro-oxaphosphetanes 9 contain an N−H bond that might

participate in the oleﬁnation reaction via hydrogen bonding with

the solvent, the phosphorus byproduct, or through self-

association. To eliminate these possible contributions to the

oleﬁnation process, we sought to prepare N-methylated

derivatives of 9. Quenching the lithiated species Li−II with

methyl triﬂuoromethanesulfonate (MeOTf) at −35 °C during

30 min furnished N-methyl spiro-oxaphosphetanes 12 in

excellent yields (Table 1, entries 17−20). N-Methylation is

evidenced by the ¹H NMR spectra. Recrystallization of 12a from

hexane aﬀorded a crystal suitable for X-ray diﬀraction analysis.

The structure obtained is shown in Figure S15. A brief analysis of

the main solid-state structural features of compounds cis-9d,

trans-9k, and 12a is given in the Supporting Information. The

synthesis of 12 illustrates the wide scope of the methodology

developed for the preparation of spiro-1,2-oxaphosphetanes

making feasible the derivatization of the spiranic system in a one-

pot manner. Furthermore, the N-methylated oBA ligand

(MoBA) of 12 introduces new interactions with the substituents

at carbon C3 of the oxaphosphetane ring, which will be analyzed

below.

The reaction of benzylphosphazene 7f deserves a particular

comment (Scheme 3). The phenyl ring attached to the P-CH

Scheme 3. Synthesis of Spiro-1,2-oxaphosphetane 9p

Synthesis of Oleﬁns by Thermolysis of Spiro-1,2-

oxaphosphetanes. Spiro-1,2-oxaphosphetanes 9 undergo a

quantitative transformation into the corresponding alkenes 10

and benzazaphospholone 11 by heating in DMSO-d₆at 140 °C

overnight in an NMR tube (Table 2). E/Z isomerization was not

observed during the NMR monitoring process; i.e., the

stereochemical drift did not take place. Pure alkenes were

obtained by dissolving the DMSO solution into CH₂Cl₂,

washing with water followed by solvent elimination in vacuo.

The addition of hexane to the crude reaction mixture dissolved

the oleﬁn and induced the quantitative precipitation of 11. No

signal was detected in the ³¹P NMR spectrum of the hexane

solution. Finally, solvent evaporation aﬀorded pure tri- and

tetrasubstituted alkenes 10. The conﬁguration of the carbon−

carbon double bond was assigned based on the NOEs detected

in 1D gNOESY spectra. Changes in the phosphorus

conﬁguration²⁸could be unraveled by investigating the

oleﬁnation of enantiomerically pure compounds cis-9k and

trans-9k (Table 2). Although their thermolysis led to an alkene

devoid of geometrical isomers, the benzazaphosphole 11

generated is chiral and arises from an enantiomerically pure

carbon means that this substrate will be the precursor of a

semistabilized phosphorus ylide derivative (species Li−I in

Scheme 2). Under the reaction conditions shown in Table 1 and

using acetone as a carbonyl component, spiro-OPA cis- and

trans-9p were obtained with 17% conversion together with a

large amount of starting material (26%) and a number of

byproducts (57%) (Scheme 3). After some experimentation, we

found that the cleanest reaction leading to 9p consisted of

performing the double deprotonation in the standard manner

followed by the addition of 5 equiv of acetone at −90 °C and

allowing the temperature to rise to −35 °C for 90 min.

In this way, oxaphosphetanes cis-/trans-9p were obtained in a

conversion of 27% and a ratio of 66:34 (Table 1) together with

unreacted 7f (38%) and the phosphorylbenzamides 13 (35%,

mixture of two diastereoisomers in a ratio of 14:21) (Figure S1,

Supporting Information). The formation of signiﬁcant amounts

of byproducts 13 arising from the hydrolysis of the lithiated

D

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substituents in the compounds selected may inﬂuence the

reaction course through electronic eﬀects, [1,2]/[1,3] steric

interactions, and hydrogen bonding. Solvent eﬀects were

evaluated by measuring oleﬁnation rates in DMSO, DMF, and

toluene. These eﬀects are indicated using a color key in Chart 2.

The TS shown in Chart 2 is that considered more representative

of the oleﬁnation reaction (see computational section).^5,9,23

[1,2] Interactions may be observed between C3/C4 and C3/

P substituents. The asymmetric phosphorus atom of 9/12c

would lead to two diﬀerent C3/P-[1,2] interactions labeled as

C3/P_N-[1,2] and C3/P_Ph-[1,2]. The subscript designates the P-

group syn to a C3 substituent. Substituents in C4/P would give

rise to [1,3] interactions. A distinguishing feature of compounds

9/12c is the much higher thermal stability as compared with 1,2-

oxaphosphetanes generated in standard Wittig processes. Since

substituents in C3 and C4 of 9/12c are commonly found in

Wittig reactions, their stability, i.e., the diﬃculty of oleﬁnation,

must arise from the destabilization of the TS produced by

spiranization. Taking into account that the consensus

mechanism of oleﬁnation involves stereomutation of the

phosphorus atom, the TS of the formation of alkenes 10 will

be destabilized by three eﬀects: the presence of two electro-

negative substituents in equatorial sites of a trigonal bipyramidal

phosphorus (tbp, antiapicophilic element eﬀect), the ring

constrains arising from the ﬁve-membered ring (ring eﬀect

distortion of tbp), and the steric interaction generated by the

NR⁵moiety eclipsed with one substituent in C3. These features

make the decomposition of spiro-oxaphosphetanes 9/12c the

rate-determining step in the synthesis of alkenes 10.

Table 2. Alkenes 10 Obtained by Thermolysis of

Oxaphosphetanes 9 and 12c

a

The kinetic of oleﬁnation was monitored through ³¹P NMR

spectroscopy. A known amount of 9/12c was heated in the

selected solvent, and ³¹P NMR spectra were acquired at set time

intervals. Monitoring the integrals of the upﬁeld signal typical of

oxaphosphetanes 9/12c (δ in the range −65 to −75 ppm) and

the peak at δ 20.5 ppm corresponding to 11 (in DMSO-d₆)

aﬀorded the concentration of each species as a function of time.

The reaction showed a ﬁrst-order dependence in the

oxaphosphetane, as established by standard methods. The rate

constants measured are summarized in Table 3 (for details, see

Table S1). The error associated with the measurement of k is

considered to be ≤2%.³⁰

Rate diﬀerences will be determined by the balance of

electronic and steric eﬀects in the TS in the spiranic system.

An overview of these eﬀects is given in Chart 2. Based on atom

electronegativities, C3 and C4 atoms in 9/12c will bear a

negative and positive partial charge, respectively, in the GS.

These charges are expected to increase in the TS of oleﬁnation

due to the rupture of C3−P and C4−O bonds. This implies that

electron-donating substituents in C3/C4 will destabilize/

stabilize more the TS than the GS. In the reaction pathway,

the hybridization of C3/C4 changes from sp³to sp². As a result,

the C3−C4 bond distance would shorten, producing larger [1,2]

interactions in the TS. This eﬀect may be partially compensated

by the increase of bond angles undergone by C3/C4. On the

other hand, the C3−P bond is larger in the TS. Therefore, the

substituents will move away from each other, contributing to the

stabilization of the TS. However, due to phosphorus stereo-

mutation, the C3 and P substituents become eclipsed in the TS,

inducing strong [1,2] interactions. Simultaneously, the reorder-

ing of C3 and P substituents in the TS bring closer those linked

to C3 and N, which gives rise to large destabilizing [1,2]

interactions. [1,3] Steric eﬀect between C4/P substituents also

arises from two opposite contributions. Crowding will be

a

Alkenes have been labeled with the same alphabetical identiﬁer of

b

the oxaphosphetane precursor. The same alkene is formed in the

thermolysis of 12c.

oxaphosphetane with a phosphorus atom of (R) and (S)

conﬁguration, respectively.²⁹Heating cis-9k at 130 °C in DMSO

for 6 h aﬀorded 10k and 11 quantitatively. Chiral HPLC analysis

of 11 showed an enantiomeric ratio (R)-11/(S)-11 of 76:24

(Figure S3, based on the known absolute conﬁguration of (S)-

11).²³Clearly, stereomutation occurred during fragmentation of

the oxaphosphetane ring, causing partial racemization of 11.

This P-isomerization during oleﬁnation has been previously

ascertained in oBA-stabilized OPAs.²³Interestingly, the

analogous reaction of trans-9k provided enantiomerically pure

11 (Figure S3). This means that, for this isomer, the reaction

takes place stereospeciﬁcally without apparent stereomutation

of the phosphorus atom.

The thermal decomposition of the N-methylated oxaphos-

phosphetane 12c proceeded in an analogous manner to that of

compounds 9, aﬀording alkene 10c and N-methyl benzazaphos-

pholone 14 quantitatively.

Kinetic Study of the Thermolysis of Spiro-1,2-

oxaphosphetanes. To gain insight into the factors determin-

ing the energy proﬁle of the second step of the Wittig reaction,

we carried out a kinetic study of the thermolytic fragmentation

of 9/12c. The study was aimed at establishing relationships

among the factors contributing to the relative stability of the

ground state (GS) and transition state (TS) of the oleﬁnation

with kinetic and thermodynamic data of the transformation. The

E

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Chart 2. Spiro-1,2-oxaphosphetanes Selected for Thermal Decomposition Studies

a

b

c

As compared with the GS. Stabilization or destabilization of TS is indicated by a + or − sign, respectively. [1,2] Interactions. [1,3] Interactions.

d

e

f

g

h

Decrease in the TS. Increase in the TS. Distance between substituents is expected to increase. Substituents eclipsed. Distance between

substituents is expected to decrease.

relieved in the TS through the increase in the distance between

these atoms, whereas the C4/P geometrical reordering would

destabilize the TS by slightly approaching the respective

substituents. In the following, a qualitative analysis aimed at

identifying major contributions to the rate of oleﬁnation of

compounds shown in Table 3 is provided. Spiro-oxaphosphe-

tanes 9/12 can be clustered in three groups according to the

number and position of the substituents in the four-membered

ring. With the exception of cis-9p (see below), the thermal

stability increases in the series trisubstituted−C3-H (group I) ≪

trisubstituted−C4-H (group II) ≈ tetrasubstituted (group III).

The fact that trisubstituted OPAs showing one proton at carbon

C3 (entries 7, 8, and 9) oleﬁnate signiﬁcantly faster than those

with the proton at carbon C4 (entries 10, 11, and 12) indicates

that the thermal stability is primarily determined by C3/P-[1,2]

interactions. The eclipsed arrangement of the substituents on

the C3 and P atoms of the TS of oleﬁnation (TS-ol) would

produce an increase of the energy barrier of decomposition. In

agreement with this ﬁnding, 12c showed the lowest rate of

oleﬁnation (entry 14). In the TS-ol, the N-Me group would be

very close to the neighbor C3-Me substituent, leading to very

large C3/P-[1,2] steric interactions. Within OPAs of group I, the

faster oleﬁnation of cis-9o with respect to cis-9m (factor 4.4,

entries 8 and 9) may be attributed to the stabilizing charge eﬀect

of the methoxi groups in TS-ol-cis-9o.³¹The comparison with

cis-9l is less evident. The restricted mobility of the cyclohexyl

moiety would produce less C3/C4-[1,2] steric interactions than

the C4-aryl groups of the other member of the group. In

addition, the rehybridization of C4 in TS-ol-cis-9l would cause a

relief of [1,3] diaxial interactions involving the C4−O bond.

These features seem to accelerate the oleﬁnation of cis-9l slightly

when compared with cis-9o (factor 1.15 at 80 °C in DMSO,

Supporting Information). Concerning group II, the diﬀerences

in the rate of oleﬁnation of cis-9k and trans-9k reveal changes in

C4/P-[1,3] interactions (entries 11 and 12). The thermolysis of

the trans isomer proceeded 1.28 times faster than the cis

derivative, which suggests that the P-phenyl substituent gives

rise to a larger [1,3] steric hindrance than the oBA moiety, thus

destabilizing the TS of cis-9k with respect to trans-9k.

OPAs of group III that diﬀer in the substitution pattern at C3

include cis-9d, cis-9e, and trans-9e (entries 4, 5, and 6). The

oleﬁnation of trans-9e, 1.94 times faster than its C3-epimer cis-

9e (Table 3, entries 5, 6), reﬂects the larger destabilization of

TS-ol-cis-9e due to stronger C3/C4- and C3/P-[1,2] inter-

actions; i.e., [1,2] steric hindrance arising from the P-phenyl

substituent is also larger than that of oBA. cis-9d underwent the

slowest decomposition in this subgroup (2.04 times slower than

cis-9e), which points to a larger C3/C4- and C3/P-[1,2] steric

strain in TS-ol-cis-9d compared with the 9e derivatives. The

rates of oleﬁnation of OPAs of group III bearing diﬀerent

substituents at C4 increase in the series cis-9d < 9c < 9a < 9b

(entries 1−4). These results show that the change of alkyl

groups at C4 by phenyl substituents increases the energy barrier

of oleﬁnation. This implies that destabilizing steric [1,2]- and

[1,3] steric interactions in TS-ol of 9c and cis-9d outweigh the

electronic stabilization provided by the phenyl rings. Diﬀerences

between cis-9d/9c and 9a/9b can be ascribed to better charge

delocalization in TS-ol-9c and to lower steric hindrance of the

cyclohexyl ring compared with two methyl substituents (see

above), respectively.

The fastest oleﬁnation is observed for cis-9p (entry 13). The

decrease of C3/C4-[1,2] involving the C3-phenyl ring of TS-ol-

cis-9p, owing to the increase of distances with the nearby

substituents, together with the delocalization of the negative

charge developed on C3 (Chart 2), will promote a large

stabilization of the TS-ol of cis-9p. The easy decomposition of

cis-9p, an OPA derived from a semistabilized phosphorus ylide,

allows us to understand the diﬃculty in isolating this type of

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Table 3. Rate Constants for Thermal Decomposition of Oxaphosphetanes Shown in Chart 2

a

b

c

Calculated from the activation parameters in ref 23. Calculated from the activation parameters. Determined at 110 °C.

Wittig intermediates and the important stabilizing eﬀect of the

oBA ligand.

To summarize, in the absence of C3-aryl substituents, large

C3/P-[1,2] steric interactions determine the high stability of

spiro-oxaphosphetanes. The P-phenyl substituent gives rise to

larger [1,2] and [1,3] steric hindrance than the oBA moiety.

Charge delocalization at C4 stabilizes the TS of oleﬁnation,

although less eﬃciently than the destabilization caused by [1,2]

and [1,3] steric interactions. In cis-9p, the phenyl group at C3

that makes both steric and electronic eﬀects would contribute to

the stabilization of TS-ol, favoring a large decrease in the barrier

of oleﬁnation.

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The kinetic measurements for representative members of tri-

and tetrasubstituted spiro-oxaphosphetanes have been per-

formed at diﬀerent temperatures, and the graphic representation

of ln(k/T) as a function of (1/T) (Eyring plot) aﬀorded straight

lines from which the activation parameters ΔH^⧧and ΔS^⧧were

calculated (Table 4). Using these values, the Gibbs free energy

TS associated with approaching/moving away the substituent in

C3 and C4 due to the change of hybridization of these carbon

atoms must await the computational section. The contribution

to ΔG^⧧of C3/P_N-[1,2] interactions can be quantiﬁed by

comparing the values of 9a and 12c (entries 1 and 7). N-

Methylation produced an increase of 1.72 kcal mol⁻¹of the

activation energy barrier. Importantly, this larger ΔG^⧧of 12c

arises from an increase of the enthalpy of the reaction and a

change in the sign of entropic contributions. The latter is now

positive. Positive entropic eﬀects are also responsible for the

lower energy barrier of cis-9p with respect to 9a (ΔΔG^⧧= 2.3

kcal mol⁻¹).

Table 4. Activation Parameters of Selected Spiro-

oxaphosphetanes in DMSO-d₆

Solvent Eﬀects. The solvent may inﬂuence the decom-

position of 9 and 12 via polar and hydrogen-bonding

interactions. These features were analyzed by measuring the

rate of oleﬁnation of 9b, 9c, cis-9l, trans-9j, and 12c in DMSO (ε

= 46.45), DMF (ε = 36.71), and toluene (ε = 2.38) (Table 3, the

kinetic study of 9c in toluene has been previously reported²³).

Compounds 9c,²³cis-9l, and trans-9j oleﬁnated signiﬁcantly

faster in the nonpolar solvent toluene than in the most polar

solvent of the series, DMSO (entries 3, 7, and 10). A similar

trend was observed for the rate of oleﬁnation of 9b in DMF and

DMSO. The reaction in the less polar solvent DMF took place at

a slightly higher rate (factor 1.15, entry 2). The use of DMSO as

a solvent increased ΔG^⧧of the thermolysis of 9c in 1.1 kcal

mol⁻¹with respect to the reaction reported in toluene (Table 4,

entry 3).²³Both ΔH^⧧and ΔS^⧧are lower in DMSO than in

toluene. These results are consistent with a reaction whose TS is

more polar than the GS. In this situation, the TS will be less

eﬃciently solvated by toluene than by DMSO molecules (higher

ΔH^⧧) and will be less ordered (ΔS^⧧more positive). The lower

ΔG^⧧value for the reaction in toluene would reﬂect the larger

contribution of entropic factors to the process.

DMSO may aﬀect the rate of oleﬁnation via polar and

hydrogen-bonding interactions. The latter contribution will be

absent in the thermolysis of 12c lacking the NH group. In this

case, oleﬁnation in DMSO proceeded 1.19 times faster than in

DMF (Table 3, entry 14). This behavior can be explained by

considering that in the absence of hydrogen bonding, the

stabilization on the polar TS provided by the more polar solvent

(decrease of ΔH^⧧) will prevail over the entropic contributions

due to less eﬃcient solvation.

Stereomutation. Thermolysis of cis-9e and trans-9e provided

the corresponding oleﬁn together with a new spiro-oxaphos-

phetane (Figure S6). The products obtained as cis-9e″ and trans-

9e″ are shown in Chart 3. Full details about the evolution of

reaction products as a function of time are given in Table S2. A

similar ﬁnding was observed previously for compounds cis-9d

and cis-9l.²³

The new compounds were identiﬁed in situ through NMR

spectroscopic analysis as permutational isomers in which the

conﬁguration of the phosphorus atom is inverted with respect to

the starting substrate. The relative conﬁguration was established

based on 1D gNOESY spectra (Figure S7). The highest amount

of P-stereoisomers were obtained for the ratios cis-9e/cis-9e″ of

34.8:21.7 and trans-9e/trans-9e″ of 28.2:9.1 (Table S2).

Importantly, alkenes Z-10e and E-10e were obtained without

traces of products of geometrical isomerization being detected.

The retention of the C3/C4 conﬁguration during thermolysis

conﬁrms that the new oxaphosphetane formed must be an

epimer of the starting compound at the phosphorus center.

Spiro-oxaphosphetanes 9 contain a pentacoordinated phos-

phorus atom with a tbp geometry. Isomerization may occur

of activation ΔG^⧧for each reaction at a given temperature was

calculated. Interestingly, the process involves predominant

negative entropic contributions both in the tri- and tetrasub-

stituted series of OPAs and ΔG^⧧increases in the series: cis-9l <

cis-9m < cis-9p < 9b < 9a < 9c < 12c. The data collected in Table

4 allow for establishing the dominant role of C3/P_Ph-[1,2]

interactions over other steric eﬀects in the Wittig oleﬁnation of

spiranes 9/12.

The ΔG^⧧values of compounds dimethylated in C3 are 3.8−

4.4 kcal mol⁻¹larger than those of C3-monomethylated

analogues, cf. 9b/cis-9l, 9c/cis-9m (entries 2/4 and 3/5). This

ΔΔG^⧧represents roughly the contribution to the activation

energy of the oleﬁnation of a C3-methyl group cis to the oBA

ligand. The diﬀerence of 0.6 kcal mol⁻¹between the two values

can be assigned to slight diﬀerences in the steric demand (C3/

C4-[1,2] C4/P-[1,3]) of the pentamethylene moiety and the

phenyl rings linked to C4. In contrast, changes in ΔG^⧧involving

C3/C4-[1,2] and C4/P-[1,3]-interactions are in the range of

0.5−1.6 kcal mol⁻¹(cf. 9a/9b, 9a/9c, and 9b/9c).

It must be remembered that an estimation of the role of C3/

C4-[1,2] interactions in the decomposition process is

complicated by the participation of opposed eﬀects (Chart 2).

In particular, elucidating the contribution to the energy of the

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applied to all calculations.³⁴All stationary points located were

characterized by computing the harmonic vibrational frequen-

cies. In the case of the transition structures, the intrinsic reaction

coordinate (IRC) calculations were performed in order to

correlate the structures found with those of the starting reagents

and the reaction products. The computations were carried out

with the Gaussian09 program.³⁵First, we completed the study of

the thermochemistry of 9c by computing the eﬀect produced by

changing the solvent of the decomposition reaction from

toluene to DMSO. Next, the potential energy surface (PES) of

the thermolysis of 12c was investigated with the aim of

explaining the higher stability of OPAs bearing the MoBA ligand

with respect to the oBA-stabilized derivatives. Then, [1,2] and

[1,3] interactions were examined by calculating the energy

proﬁle of suitably substituted compounds 9 including 9a, 9b, 9c,

cis-9m, and 12c.

Chart 3. (a) Oxaphosphetanes Formed by Stereomutation

and (b) Mechanism of Berry Pseudorotation

through sequential Berry pseudorotations³²(MB1, MB2, MB3,

MB4).^23,33The process can be visualized in Chart 3 for a tbp

with ﬁve diﬀerent ligands. Deﬁning ligand 5 as a pivotal center,

the angle between apical positions 1 and 2 closes down with

simultaneous opening up of the angle involving ligands 3 and 4.

In this way, tbp (a) apparently rotates (pseudorotate) toward

tbp (b) via a square pyramide (sp) intermediate.

We have previously shown that the thermal transformation of

9c into alkene 10c and benzoazaphosphole 11 could take place

through two mechanisms, A and B (Scheme 4).²³Route A is the

Scheme 4. Key Computational Results of the Oleﬁnation of

9c in the Gas Phase

Stereomutation in enantiomerically pure cis-9k implies that

the byproduct 11 formed in the oleﬁnation reaction will be

partially racemized. Moreover, the rates of oleﬁnation measured

do not correspond to a single process. For the determination of

the rate constants, we have considered that both isomers

represent a single reagent. This assumption is compatible with

two premises: the two pseudorotamers decompose through a

common intermediate (Curtin−Hammett principle) or oleﬁna-

tion proceeds through diﬀerent intermediates of similar

activation energies, aﬀording average rate constants. Support

for this latter assumption is provided by the relatively low

concentration of permutational isomers detected and by the fact

that fragmentation of cis-9l (70 °C), cis-9e (115 °C), and trans-

9e (115 °C) in toluene took place without the formation of

pseudorotamers. In all cases, the representation of ln[9]_tagainst

time originates straight lines of r ≥ 0.997 (Supporting

Information). The ³¹P NMR monitoring of the oleﬁnation

reactions showed that isomerization occurred in parallel with

oleﬁn formation (Figure S6, Table S2). Considering that

stereomutation has been observed in most cases in which a

new diastereoisomer could be formed, it is reasonable to assume

that decomposition of spiro-oxaphosphetanes 9 at 130 °C

involves, most probably, small contributions of phosphorus

isomerization processes exchanging the positions of the two

equatorial ligands.

Computational Study of the Oleﬁnation of Spiro-

oxaphosphetanes. The results discussed above have revealed

that the thermal decomposition of compounds 9 is a process

characterized by a negative entropy, except for cis-9p and 12c,

and a polar transition state in which relative energy depends on a

combination of electronic, steric, and solvent eﬀects. Besides

fragmentation, the pentacoordinated phosphorus undergoes

stereomutation, causing partial racemization of the phosphorus

center of some derivatives. In order to understand the

stereoelectronic factors determining the oleﬁnation of spiro-

oxaphosphetanes, we have performed a DFT study of the

potential energy surface (PES) for the thermolysis of 9 and 12.

Three functionals were evaluated using the oleﬁnation of 9a and

12c as test reactions: B3LYP/6-31G*, M06/6-31G*, and M06-

L/6-31G* M06-2X/6-31G*. The best results including London

dispersion correction were obtained with M06-L/6-31G*

(Tables S3 and S4), and therefore, this level of theory was

direct conversion of 9c into products with an activation barrier

of 30.1 kcal mol⁻¹(recalculated from B3LYP/6-31G* to the

level of theory M06-L/6-31G*, Table S5, Figure S8) in excellent

agreement with the experimental value of 30.9 kcal mol⁻¹

determined in toluene as a solvent.²³The formation of 9c is a

highly exothermic and irreversible reaction.

Route B is also a single-step process that starts with the

permutational isomer 9c′ and proceeds to the products through

a barrier of 37.2 kcal mol⁻¹; i.e., decomposition via channel A is

highly favored (ΔΔG^⧧= 7.1 kcal mol⁻¹). The higher energy

barrier of channel B correlates with the larger distortion of the

geometry of TS-ol-9c′ from an ideal tbp, deﬁned by the

deviation of the P atom (ΔP = 0.228) from the basal plane,³⁶

with respect to TS-ol-9c (ΔP = 0.213) (Figure S8). The

antiapicophilic P−N_eqisomer 9c′ is formed by stereomutation

of 9c via an M_B2mechanism with a barrier of 23.1 kcal mol⁻¹.

This barrier is 7 kcal mol⁻¹lower than the activation energy for

oleﬁnation via channel A, which indicates that stereomutation of

9c occurs faster than fragmentation.^13,28This feature supports

the observation of stereoisomers in the oleﬁnation of

compounds 9 in which inversion of the conﬁguration of the

phosphorus atom originated a new diastereoisomer (Figure S7).

The single-step mechanism of decomposition of spiro-1,2-

oxaphosphetanes 9c and 9c′ implies that the process does not

involve the formation of an intermediate OPA with C3 in the

apical position.²⁷Analogous results have been found previously

in the theoretical study at the MP2 level of the Wittig reaction of

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Figure 1. Potential energy surface of the thermal decomposition of 12c at 130 °C calculated at the M06-L/6-31G(d) level of theory. Free energies (in

brackets, kcal mol⁻¹) are relative to the starting materials.

very simpliﬁed model compounds.³⁷Dynamic calculations on

similar systems showed that stereomutation takes place almost

without an energy barrier³⁸or could not be detected.³⁹

Furthermore, the TS of oleﬁnation is more polar (μ = 4.1 D)

than the starting spiro-oxaphosphetane (μ = 2.97 D), in

agreement with the results of the kinetic study.

To complete this study, the macroscopic contribution of the

solvent to the thermal decomposition of 9c was estimated by

using the SMD method of solvent interaction (Table S6).⁴⁰The

ΔG_solvvalues obtained as 30.0 and 31.6 kcal mol⁻¹for the

reaction in toluene and DMSO, respectively, are in good

agreement with those experimentally determined (Tables 3 and

4, entries 3) and support that the decomposition of 9c takes

place faster in toluene than in DMSO.

Theoretical Study of the Oleﬁnation of 12c. Thermolysis of

12c is characterized by the largest ΔH^⧧and ΔS^⧧measured, the

latter being now positive. Similar to 9c, the computational study

of the oleﬁnation of 12c at the M06-L/6-31G* level of theory

led to seven stationary points: two spiro-oxaphosphetanes

isomers, 12c and 12c′, the transition states of their stereo-

mutation, TS-s-12c, and oleﬁnation, TS-ol-12c and TS-ol-12c′,

and the reaction products 10c and 15. The energy proﬁle is

shown in Figure 1. Relative energies and thermodynamic

parameters are given in Table S7. The stationary points located

are qualitatively analogue to the corresponding structures

calculated for the fragmentation of 9c (Figures S9 and S10).

Compound 12c matches the isomer experimentally observed

and is considerably more stable than the permutational isomer

12c′ (ΔΔG_{(12c−12c′)}= 5.6 kcal mol⁻¹at 130 °C). This energy

diﬀerence indicates that the equilibrium between both isomers is

completely displaced to 12c, thus explaining that this is the only

stereoisomer experimentally observed.

the nitrogen shortens the energy gap between isomers 12c and

12c′ in 0.3 kcal mol⁻¹as compared with 9c and 9c′ (cf. Tables

S5 and S7) and increases the energy liberated in the oleﬁnation

reaction in 3.6 kcal mol⁻¹with respect to 9c. The higher

exothermicity of the decomposition of 12c is a consequence of

the destabilization of its GS with respect to 9c due to the steric

interaction of the N-Me group with the C3-methyl cis to the P-

phenyl ring, a structural feature already evidenced in the X-ray

structure of 12a (Figure S15)

Most importantly, contrary to 9c/9c′, oleﬁnation of 12c′

through channel B is energetically favored with respect to 12c

(channel A) by 2.4 kcal mol⁻¹. This energy diﬀerence implies

that 95% of the molecules will oleﬁnate via channel B. The

destabilization of TS-ol-12c arises from the steric hindrance

between the methyl groups linked to the nitrogen and to C3

(distortion of the tbp, ΔP = 0.234, Figure S9). This proximity

eﬀect is counterbalanced by a remarkable lengthening of the P−

C3 bond distance (2.497 Å, Figure 1). In contrast, the N-Me

group of TS-ol-12c′ is located in a region devoid of relevant

steric eﬀects (ΔP = 0.218, Figure S10), and the structural

parameters are very similar to those of the TS for the oleﬁnation

of 9c′. Therefore, the lower energy barrier calculated for channel

B can be assigned to the loss of torsional strain in the transition

state as compared with channel A, which correlates with the ΔP

values computed. The large positive entropy of activation found

for channel B supports this hypothesis. Furthermore, the ΔG^⧧=

34.2 kcal mol⁻¹calculated for oleﬁnation through channel B is in

good agreement with that experimentally determined in DMSO

(Table 4, entry 7). A few antiapicophilic P−O_eqOPAs have been

isolated.⁴¹However, it has been shown that they convert into the

P−O_apisomer during thermal decomposition.^22a

Analysis of Charge Eﬀects. Next, we undertook the

theoretical study of the stereoelectronic interactions involved

in the oleﬁnation reaction. Charges distribution around the 1,2-

oxaphosphetane ring in the oleﬁnation pathway were calculated

at the NBO level for derivatives 9a, 9c, and cis-9m. The P and O

heteroatoms show the expected behavior: higher charges in the

transition state than in the ground state (Tables S8). Regarding

12c/12c′ stereomutation proceeds through an M_B2mecha-

nism via the transition state TS-s-12c. Interestingly, the

activation energy barrier of this process (20.2 kcal mol⁻¹) is

2.9 kcal mol⁻¹lower than that calculated for the isomerization of

9c to 9c′ and signiﬁcantly lower than the energy required for the

oleﬁn-forming reaction. Moreover, the presence of a methyl on

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Table 5. Calculated (M06-L/6-31G*) Energies and Activation Parameters for the Transition States Found in the Study of [1,2]

a

and [1,3] Interactions and Selected Bond Distances in Å

b

c

b

entry

structure

ΔE

ΔH^⧧

ΔS^⧧

ΔG^⧧

P−C3

C4−O1

C3−C4

P−O1

403.15 K

1

2

3

4

5

TS-ol-cis-9m

TS-ol-9c

TS-ol-9a

TS-ol-9b

TS-ol-12c′

28.9

31.9

30.2

30.0

36.6

27.5

30.6

28.7

28.5

35.2

0.3

1.3

0.6

0.5

2.5

27.4

30.1

28.5

28.3

34.2

2.254 (1.838)

2.316 (1.855)

2.362 (1.863)

2.341 (1.85)

1.998 (1.430)

1.975 (1.423)

1.961 (1.438)

1.989 (1.442)

1.940 (1.424)

1.428 (1.555)

1.449 (1.576)

1.435 (1.558)

1.436 (1.558)

1.451 (1.570)

1.559 (1.777)

1.560 (1.778)

1.556 (1.763)

1.557 (1.761)

1.563 (1.786)

2.430 (1.877)

a

b

Bond distances in the corresponding OPA ground state are indicated in brackets. The reference structure is indicated by ΔE^⧧, ΔH^⧧, and ΔG^⧧= 0

c

kcal mol⁻¹. The reference structure is indicated by ΔS^⧧= 0 e.u. (cal K⁻¹mol⁻¹).

C3 and C4, the TS of oleﬁnation of compounds 9 seems to be

stabilized by dispersing the increase of negative/positive charge

on C3/C4 through the respective substituents.

The calculations provide support to previous assumptions

about the reasons for the stability of compounds 9 and the

prevailing contribution of C3/P- vs C3/C4-[1,2] interactions to

ΔG^⧧. In TS-ol, the C3 and P substituents are eclipsed. The

shortest distances are found for the C3-substituent and the NH

in a mutual cis orientation (2.003/2.007 Å for cis-9m/9c,

channel A, Table S9). They are lower than the sum of van der

Waals radii (2.18 Å); i.e., along this series, TS-ol becomes more

destabilized and ΔG^⧧oleﬁnation increases, in agreement with

the experimental observations. For the N-methyl derivative 12c,

the strong C3-Me/NMe interactions determined that oleﬁna-

tion through channel B involving the P−N_eqisomer 12′ became

the preferred pathway of decomposition. During oleﬁnation,

substituents in C3 and C4 cis to the P-phenyl group move away

from each other, whereas those cis to the benzazaphosphole

system come closer (Table S9). In any case, the changes in

interatomic distances are much smaller than those observed for

C3/P-[1,2] interactions. Hence, the stability of compounds 9/

12 can be assigned to strong C3/P-[1,2] interactions in TS-ol

with those involving the NH/NMe being the strongest.

C3/C4-[1,2] interactions are also present; however, they

produce two opposing eﬀects, and their contribution to ΔG^⧧of

oleﬁnation seems to be signiﬁcantly lower. Although the

discussion above has been centered on steric eﬀects, it must

be remembered that electron-donating groups such as Me at a

carbon, which develops a negative charge in the TS, will also

contribute to increasing ΔG^⧧by destabilizing TS-ol.

Analysis of [1,3] Interactions. The kinetic study of

substituents eﬀect in C4 on the rate of oleﬁnation suggested

that large groups in this carbon increased the energy barrier of

the reaction due to [1,3] interactions with groups linked to the

phosphorus atom. In this context, the contribution of the

cyclohexyl moiety of 9b to the rate of decomposition remains

arguable. To clarify these uncertainties, we performed a

theoretical study of the oleﬁnation of 9a, 9b, and 9c, having

diﬀerent substituents in C4 (Figures S8, S11, and S12). The

energies calculated for these transformations and some selected

bond distances are given in Table 5 (entries 2−4). The

oleﬁnation barrier increases in the series 9b < 9a < 9c, in

excellent agreement with the experimental results (Table 4).

The analysis of distances of the dissociating/forming bonds in

TS-ol of the compounds under study revealed the existence of

only very small diﬀerences, insuﬃcient to explain the changes in

Analysis of [1,2] Interactions. The calculations above have

shown that, in the transition state of the oleﬁn-forming step, the

substituents in carbon C3 and in the phosphorus atom are

eclipsed. Therefore, increasing the size of the substituents

around the P−C3 bond will destabilize the TS of the reaction.

To complement the results obtained for 9c and 12c, we have

extended the calculations to cis-9m (Figure S11). The diﬀerent

substitution patterns in C3 of these compounds will allow us to

correlate diﬀerences in the thermodynamic parameters of

oleﬁnation with steric [1,2] interactions. These may arise from

the proximity of the substituents on C3 to those bonded to the

phosphorus atom and to C4. Only the most favored pathway of

oleﬁnation of OPAs stabilized by oBA (channel A) and MoBA

(channel B) ligands was investigated. Energy parameters and

bond distances relevant for the discussion are given in Table 5.

The free energy calculated in the gas phase for the

decomposition of cis-9m is in excellent agreement with

experimental values obtained in the polar solvent DMSO (cf.

entries 1/5 of Table 5/4).

Entries 1, 2, and 5 in Table 5 show some clear trends: (i) the

reaction is highly asynchronous (in TS-ol, P−C3 and C4−O1

bond dissociations are notably more advanced than C3−C4 and

P−O1 double bond formation), (ii) P−C3/C4−O1 bond

distances increase/decrease by introducing Me groups at C3 (cf.

9c and cis-9m, Δ_P−C3/Δ_C4−O1= 0.062/−0.023 Å) and at the

nitrogen atom (cf. 12c and 9c, Δ_P−C3/Δ_C4−O1= 0.114/−0.035

Å). Therefore, the reaction reaches the TS-ol more and more

later with an increasing number of methyl groups attached to C3

and N. Accordingly, ΔH^⧧and ΔS^⧧increase in the series cis-9m <

9c < 12c (TS-ol more product like, increase of disorder).

Interestingly, this feature correlates with the increment of

distortion of the tbp from the GS to the TS for the most favored

oleﬁnation channel (ΔΔP = 0.107 (cis-9m, Figure S11), 0.119

(9c), 0.149 (12c)). The ΔG^⧧values given in Table 5 indicate

that the introduction of a methyl group at C3 produced an

increase of the energy barrier of oleﬁnation of 2.7 kcal mol⁻¹.

This value is notably smaller than the contribution to ΔG^⧧of 4.4

kcal mol⁻¹experimentally observed in the polar solvent DMSO

(entries 3 and 5, Table 4).

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activation parameters shown in Table 5. Diﬀerences between 9a

and 9b can be explained by analyzing steric eﬀects between C4/

P substituents. The C4-methyl group of cis geometry with the P-

phenyl ring in the TS-ol of 9a become much closer (Δ_{(Me19···PhP)}

= −0.423 Å) than the corresponding C4-CH₂protons of the TS-

ol of 9b (Δ_{(CH219···PhP)}= −0.136 Å) (Table S9) causing a larger

destabilization of TS-ol-9a with respect to TS-ol-9b and,

consequently, an increase of ΔG^⧧of oleﬁnation.

The replacement of methyl groups by phenyl substituents in

C4 (cf. compounds 9a and 9c) introduces electronic eﬀects

together with [1,2] and [1,3]-interactions. NBO charge

calculations indicate that the CPh₂moiety delocalizes the

positive charge developed in C4 of TS-ol more eﬃciently than

the CMe₂group (Table S8). In the same vein, when going from

GS to TS-ol of 9c, the C4-Ph and P-Ph groups move away (an

increase of the distance of 0.075 Å), leading to less C4/P_Ph-[1,3]

interactions. C3/C4-[1,2] interactions in TS-ol of 9a and 9c are

destabilizing due to the approach of the substituents (e.g.,

change of distances for 9c between substituents with a cis/trans

geometry to the P-phenyl of −0.072/−0.049 Å). These eﬀects

suggest that, contrary to calculations and experimental

observations, 9c should oleﬁnate faster than 9a via a more

activation energy supported the determining contribution of

C3/P-[1,2] interactions to ΔG^⧧and the decrease of [1,3]-

interactions in the TS of the reaction. This TS is more polar than

the starting spiro-oxaphosphetane and showed a distorted tbp

geometry with C3 and C8 in apical positions. The higher rate of

decomposition observed in solvents of low polarity was a

consequence of macroscopic solute−solvent interactions. The

stabilization of 1,2-oxaphosphetane through oBA and MoBA

ligands opens the way to the isolation of elusive intermediate

species in the Wittig reaction making feasible their structural and

thermochemical characterization. Work is underway to extend

the applications of oBA and MoBA ligands.

EXPERIMENTAL SECTION

General Information. Melting points were measured on a Bu

■

̈

chi B-

540 capillary melting point apparatus. High-resolution mass spectra

were recorded on Acquity UPLC-Xevo QtoF (Waters) equipment

using positive electrospray ionization (ESI). NMR spectra were

acquired on a Bruker Avance III HD 300 (¹H 300.13 MHz; ¹³C

75.47 MHz; ¹⁹F 282.40 MHz; ³¹P 121.49 MHz) and a Bruker Avance

III HD 500 (¹H 500.13 MHz; ¹³C 125.76 MHz; ³¹P 202.46 MHz) at

room temperature using CDCl₃as a solvent. Chemical shifts are

referred to internal tetramethylsilane for ¹H and ¹³C, internal CCl₃F for

¹⁹F, and external 85% H₃PO₄for ³¹P. The enantiomeric excesses were

determined by HPLC analysis on an HP1100 instrument using a

Chiralcel OD-H (5 μm, 150 × 4.6 mm) column and a diode array

detector.

stabilized TS-ol. The key diﬀerence proceeds from the C3/P_NH

-

[1,2] interactions. These are much stronger in TS-ol-9c due to a

reduction of the Me···HN distance of 1.157 Å (vs 0.805 Å for

TS-ol-9a, Table S9). The destabilization of TS-ol of 9c caused

by this steric eﬀect explains that it shows the largest energy

barrier of oleﬁnation on the series of compounds studied.

Reactions involving organolithium reagents were performed under

an inert atmosphere of nitrogen using Schlenk techniques. Anhydrous

solvents were obtained via elution through a solvent column drying

system. Commercial reagents were distilled prior to their use, except t-

BuLi. TLC was performed on Merck plates with aluminum backing and

silica gel 60 F₂₅₄. For column chromatography, silica gel 60 (40−63

μm) from Scharlau was used. Phosphazenes 7a,⁴²7b,⁴²7d,⁴³and 7g⁴³

(precursor of 7f) used in this study were prepared according to methods

described in the literature. The synthesis of spiro[1,2]-oxaphosphe-

tanes 9c,²³9d,²⁵9e,²⁵9j,²⁵and 9l²⁵has been reported previously.

Compounds 10a (CAS No. 563−79−1), 10d/10p (CAS No. 769−

57−3), 10l (CAS No. 1003−64−1), and 10m (CAS No. 778−66−5)

are commercial. Compounds 10b,⁴⁴10c,⁴⁵Z-10e,^19,4610d

(=10p),^23,47E-10e,^19,4810j,⁴⁹10k,⁵⁰10l,⁵¹Z-10n,⁴⁸10o,⁵²and 11¹⁹

have been described previously.

X-ray Crystallographic Studies of cis-9d, trans-9k, and 12a. A

suitable crystal of cis-9d, trans-9k, and 12a was covered in Paratone-N

(Hampton Research) and mounted onto a MiTeGenmicromount. The

crystal was transferred directly to a Nonius Kappa CCD diﬀractometer

with CuKα (λ = 1.54184 Å) for cis-9d, an Oxford Diﬀraction Xcalibur

Gemini S with MoKα (λ = 0.71073 Å) for trans-9k, and a Bruker Smart

1000 CCD diﬀractometer with MoKα (λ = 0.71073 Å) for 12a. The

intensities were measured using the oscillation method. The crystal

structures were solved by direct methods for cis-9d and trans-9k and

Patterson methods for 12a. The reﬁnement was performed using full-

matrix least-squares on F2. All non-H atoms were anisotropically

reﬁned. All H atoms were geometrically placed riding on their parent

atoms with isotropic displacement parameters set to 1.2 times the Ueq

of the atoms to which they are attached (1.5 for methyl groups).

Crystallographic calculations were carried out by the X-ray team, at

the University of Oviedo, using the following programs: Collect⁵³for

data collection and HKL Denzo and Scalepack⁵⁴for cell reﬁnement and

data reduction for cis-9d; Bruker SMART⁵⁵for data collection and cell

reﬁnement and Bruker SAINT3⁵⁵for data reduction for 12a;

CrysAlisPro CCD and RES⁵⁶for data collection, cell reﬁnement, and

data reduction for trans-9k; for structure solution SIR-92⁵⁷for cis-9d,

SIR-2004⁵⁸for trans-9k, DIRDIF-2008⁵⁹for 12a; XABS2⁶⁰for reﬁned

absorption correction; SHELXL-97⁶¹for structure reﬁnement;

WinGX⁶²publication routines and enCIFer⁶³for preparing material

for publication; PLATON⁶⁴for the geometrical calculations; ORTEP-

3⁶⁵for windows for molecular graphics. Crystal data and structure

CONCLUSIONS

■

The reaction of C_α,C_ortho-dilithiated phosphazenes with

aldehydes and ketones represents the ﬁrst general method of

accessing to a large variety of air and temperature stable C3/C4

tri- and tetrasubstituted spiro-1,2-oxaphosphetanes stabilized by

the oBA and MoBA ligands 9/12. The wide scope of the process

is supported by the synthesis of homochiral products using the

aldehyde (−)-mirtenal as an electrophile and the isolation of the

ﬁrst example of a 1,2-oxaphosphetane derived from a semi-

stabilized phosphorus ylide cis-9p. Stereoselectivities are

generally excellent. Mixtures of stereoisomers were readily

separated through column chromatography. Their thermolysis

aﬀorded the corresponding alkenes quantitatively and stereo-

speciﬁcally. In a number of cases, the permutational isomers by

P-stereomutation could be structurally characterized in situ

through NMR spectroscopy. The rates of oleﬁnation of 9/12

showed a dependence on stereoelectronic and solvent eﬀects

and decreased with an increasing number of substituents in C3/

C4 and the nitrogen atom. The reaction is characterized by a

negative ΔS^⧧, except for N-methylated derivatives, involved a

polar transition state, and proceeds faster in low polar solvents.

The computational study of the thermolysis of 9/12 showed

that OPAs 9/12 oleﬁnated via species (N, O)(Ph, C₆H₄, C)/

(C₆H₄, O)(C, N, Ph) designated as “channel A” and “channel

B”, respectively. These processes are associated with the lowest

distortion of the tbp in the respective TSs. P-Stereomutation

takes place through an M_B2mechanism, which exchanged the

apical nitrogen with the equatorial C_ipsocarbon of the oBA/

MoBA moiety. For both channels, the activation energy of

oleﬁnation is higher than that of stereomutation. In contrast with

the consensus mechanism of Wittig oleﬁnation, oxaphosphetane

ring fragmentation occurred via a concerted asynchronous

reaction (dissociation of P−C3 more advanced than that of C4−

O1). The analysis of electronic, solvent, and steric eﬀects on the

L

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reﬁnement details for all compounds are outlined in Tables S10 −S12.

Crystallographic data (excluding structure factors) for the structures

reported in this paper have been deposited in The Cambridge

Crystallographic Data Centre no. CCDC: 749832 (cis-9d), CCDC:

749831 (trans-9k), and CCDC: 846036 (12a). These data can be

obtained free of charge from the CCDC via http://www.ccdc.cam.ac.

uk/products/csd/request/.

Computational Methods. Computations were carried out on the

Alhambra supercomputer of the IT and Communications Centre

(CSIRC) of the University of Granada using the suite of programs

Gaussian 09.³⁵Geometry optimizations, vibrational frequency, and

natural bond orbital (NBO)⁶⁶calculations were performed using the

M06-L-6-31(d) functional.⁶⁷All stationary points located were

characterized by performing the harmonic frequency calculations. All

minima have zero imaginary frequency, and all transition states have

only one imaginary frequency. Intrinsic reaction coordinate (IRC)

calculations were performed to establish the connection between

ground state, transition state, and products.⁶⁸Single-point energy

calculations were carried out using the M06-L functional and basis set

6-311+G(d,p). The SMD⁴⁰solvation model was used in the single-

point energy calculations to incorporate solvent eﬀects with toluene or

DMSO as the solvents. Thermal corrections to the Gibbs free energies

and enthalpies were calculated using the harmonic oscillator

approximation at 403.15 K.

Synthesis. General Procedure for the Synthesis of Spiro-1,2-

oxaphosphetanes 9a−b, f−i, k, m−p. To a solution of the

appropriate phosphazene 7 (6.64 × 10⁻⁴mol) in THF (10 mL) was

added a solution of t-BuLi (0.86 mL of a 1.7 M solution in cyclohexane,

1.46 × 10⁻³mol) at −35 °C. After 30 min of metalation, the

corresponding carbonyl compound was added (0.66 × 10⁻³mol). The

reaction mixture was stirred at −95 °C for 2.5 h (for the reaction of

lithiated 7e/7d with acetophenone/4,4′-bis(dimethylamino)-

benzophenone, this time was increased to 5 and 15 h, respectively,

and in the latter case, the temperature used was −35 °C) and then

quenched with MeOH. The reaction mixture was poured into water

and extracted with dichloromethane (2 × 15 mL). The organic layers

were dried over Na₂SO₄and concentrated in vacuo. ¹H, ¹H{³¹P}, and

³¹P{¹H} NMR spectra of the crude reaction were always measured in

order to determine the stereoselectivity and conversion of the process.

The crude mixture was puriﬁed by ﬂash column chromatography

(eluent: a mixture of ethyl acetate/hexane) or by precipitation from

diethyl ether to give 9a−p.

P-Penthyl-P,P-(diphenyl)(N-methoxycarbonyl)phosphazene

(7c). Compound 7c has been synthesized using the same procedure

reported for 7a⁴²and was isolated by precipitation from diethyl ether in

a yield of 85%. White solid. Mp: 99−100 °C. IR (KBr): ν 1625, 1292

cm⁻¹. ¹H NMR (300.13 MHz, CDCl₃): δ 7.79 (m, 4H, H7), 7.46−7.61

(m, 6H, H8, H9), 3.64 (s, 3H, H11), 2.63 (m, 2H, H1), 1.51 (m, 2H,

3′,3′,4′,4′-Tetramethyl-1-phenyl-1H-spiro[2,1-benzazaphosp-

hole-1,2′-[1,2]oxaphosphetan]-3(2H)-one (9a). Conversion: 92%.

Yield after precipitation from diethyl ether: 85%. White solid. Mp:

195−196 °C. IR (KBr): ν 3435, 3140, 1675 cm⁻¹. ¹H NMR (300.13

MHz, CDCl₃): δ 8.20 (m, 1H, H9), 8.05 (m, 3H, H12, H14), 7.67 (m,

2H, H10, H11), 7.41 (m, 3H, H15, H16), 6.43 (d, ²J_PH= 10.5 Hz, 1H,

H5), 1.45 (d, ³J_PH= 26.8 Hz, 3H, H17), 1.33 (s, 3H, H19), 1.28 (s, 3H,

H20), 1.23 (d, ³J_PH= 26.8 Hz, 3H, H18) ppm. ¹³C{¹H} NMR (75.47

MHz, CDCl₃): δ 168.2 (d, ²J_PC= 4.2 Hz, C6), 138.2 (d, ²J_PC= 11.7 Hz,

C7), 136.8 (d, ¹J_PC= 147.8 Hz, C8), 135.5 (d, ¹J_PC= 142.4 Hz, C13),

135.5 (d, ²J_PC= 12.0 Hz, C9), 134.7 (d, ²J_PC= 12.0 Hz, C14), 132.9 (d,

⁴J_PC= 3.0 Hz, C11), 131.9 (d, ³J_PC= 15.6 Hz, C10), 131.1 (d, ⁴J_PC= 3.6

Hz, C16), 128.4 (d, J_PC= 15.0 Hz, C15), 124.4 (d, J_PC= 12.0 Hz,

C12), 72.1 (d, ²J_PC= 16.2 Hz, C4), 64.2 (d, ¹J_PC= 109.9 Hz, C3), 27.0

(d, ³J_PC= 6.6 Hz, C20), 26.0 (d, ³J_PC= 6.6 Hz, C19), 21.0 (d, ²J_PC= 6.0

Hz, C17, C18) ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −63.9

ppm. HRMS (ESI/TOF) m/z: [M + 1] calcd for C₁₉H₂₃NO₂P,

328.1466; found, 328.1469.

3

H2), 1.31 (m, 4H, H3, H4), 0.83 (t, J_HH= 6.9 Hz, 3H, H5) ppm.

¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 162.7 (d, ²J_PC= 1.7 Hz, C10),

132.9 (d, ²J_PC= 9.2 Hz, C7), 132.2 (d, ⁴J_PC= 1.9 Hz, C9), 128.4 (d, ³J_PC

= 12.1 Hz, C8), 125.8 (d, ¹J_PC= 93.8 Hz, C6), 53.5 (d, ⁴J_PC= 3.7 Hz,

C11), 29.7 (d, ³J_PC= 13.0 Hz, C3), 28.6 (d, ²J_PC= 1.6 Hz, C2), 23.0 (d,

¹J_PC= 65.2 Hz, C1), 13.8 (C5), 22.4 (C4) ppm. ³¹P{¹H} NMR (121.50

MHz, CDCl₃): δ 25.9 ppm. HRMS (ESI/TOF) m/z: [M + 1] calcd for

C₁₉H₂₅NO₂P, 330.1623; found, 330.1638.

3

Methyl (Diphenyl(1-phenylethyl)-λ⁵-phosphanylidene)-

carbamate (7f). Compound 7f has been synthesized through α-

lithiation of 7g⁴³followed by electrophilic quench with methyl iodide

using the same procedure reported in the literature for the α-alkylation

of phosphazenes.⁴³Compound 7f was isolated by precipitation from

diethyl ether in a yield of 66%. White solid. Mp: 135−136 °C. IR (KBr):

ν 1625, 1311 cm⁻¹. ¹H NMR (300.13 MHz, CDCl₃): δ 7.76 (m, 2H,

H11^#), 7.55 (m, 4H, H7^#, H9, H13), 7.48 (m, 2H, H12*), 7.38 (m, 2H,

H8*), 7.16 (m, 3H, H4, H5), 6.92 (m, 2H, H3), 4.51 (dq, ²J_PH= 15.9

Hz, ³J_HH= 7.5 Hz, 1H, H1), 3.61 (s, 3H, H16), 1.61 (dd, ³J_PH= 16.9 Hz,

³J_HH= 7.5 Hz, 3H, H14) ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ

162.8 (d, ²J_PC= 2.4 Hz, C15), 136.3 (d, ²J_PC= 5.6 Hz, C2), 133.3 (d,

²J_PC= 8.7 Hz, C11), 133.2 (d, ²J_PC= 8.7 Hz, C7), 132.4 (d, ⁴J_PC= 2.8

Hz, C13), 132.2 (d, ⁴J_PC= 2.8 Hz, C9), 128.4 (d, ³J_PC= 11.6 Hz, C12),

128.1 (d, ³J_PC= 11.6 Hz, C8), 128.1 (d, ⁴J_PC= 2.8 Hz, C4), 127.4 (d,

⁵J_PC= 3.3 Hz, C5), 125.4 (d, ¹J_PC= 95.8 Hz, C10), 125.3 (d, ¹J_PC= 94.8

Hz, C6), 52.7 (d, ⁴J_PC= 3.7 Hz, C16), 37.3 (d, ¹J_PC= 58.7 Hz, C1), 15.6

(d, ²J_PC= 1.9 Hz, C14) ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ

29.94 ppm. HRMS (ESI/TOF) m/z: [M + 1] calcd for C₂₂H₂₃NO₂P,

364.1466; found, 330,1478. *^,#Interchangeables.

3′,3′-Dimethyl-1-phenyl-1H-dispiro[2,1-benzazaphosphole-1,2′-

[1,2]oxaphosphetane-4′,1″-cyclohexan]-3(2H)-one (9b). Conver-

sion (a = axial, e = equatorial): 93%. Yield after precipitation from

diethyl ether 87%. White solid. Mp: 207−208 °C. IR (KBr): ν 3430,

1

1672 cm⁻¹. H NMR (300.13 MHz, CDCl₃): δ 8.25 (m, 1H, H9),

7.97−8.12 (m, 3H, H12, H14), 7.58−7.72 (m, 2H, H10, H11), 7.26−

7.41 (m, 3H, H15, H16), 6.23 (d, ²J_PH= 9.8 Hz, 1H, H5), 1.57−1.95

(m, 5H, H19_e, H19′_e, H20, H20′, H21_e), 1.45 (d, ³J_PH= 26.8 Hz, 3H,

3

H17), 1.19 (d, J_PH= 26.8 Hz, 3H, H18), 1.18−1.38 (m, 3H, H19_a,

H19′_a, H21_a) ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 168.5 (d,

²J_PC= 4.2 Hz, C6), 138.3 (d, ²J_PC= 10.8 Hz, C7), 137.5 (d, ¹J_PC= 147.2

Hz, C8), 135.9 (d, ¹J_PC= 142.4 Hz, C13), 135.3 (d, ²J_PC= 12.0 Hz, C9),

135.0 (d, ²J_PC= 12.0 Hz, C14), 132.7 (d, ⁴J_PC= 3.0 Hz, C11), 131.7 (d,

³J_PC= 15.0 Hz, C10), 131.0 (d, ⁴J_PC= 3.0 Hz, C16), 128.2 (d, ³J_PC

=

14.4 Hz, C15), 124.2 (d, ³J_PC= 11.4 Hz, C12), 72.8 (d, ²J_PC= 16.2 Hz,

C4), 64.7 (d, ¹J_PC= 108.7 Hz, C3), 34.9 (d, ³J_PC= 5.4 Hz, C19′), 33.9

(d, ³J_PC= 6.6 Hz, C19), 25.4 (C21), 22.7 (C20′), 22.6 (C20), 19.8 (d,

²J_PC= 6.0 Hz, C17, C18) ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ

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−64.7 ppm. HRMS (ESI/TOF) m/z: [M + 1] calcd for C₂₂H₂₇NO₂P,

368.1779; found, 368.1791.

(202.46 MHz, CDCl₃, 25 °C) δ −65.4 ppm. HRMS (ESI/TOF) m/z:

[M + 1] calcd for C₃₀H₂₉Cl₂NO₂P, 536.1313; found, 536.1328.

4′,4′-Bis(4-ﬂuorophenyl)-3′,3′-dimethyl-1-phenyl-1H-spiro[2,1-

benzazaphosphole-1,2′-[1,2]oxaphosphetan]-3(2H)-one (9f). Con-

version: 93%. Yield after precipitation from diethyl ether: 90%. White

solid. Mp: 224−227 °C. IR (KBr): ν 3435, 3155, 1672 cm⁻¹. ¹H NMR

(500.13 MHz, CDCl₃, 25 °C) δ 8.69 (dddd, ³J_PH= 12.7 Hz, ³J_HH= 7.5

Hz, ⁴J_HH= 1.2 Hz, ⁵J_HH= 0.5 Hz, 1H, H9), 8.01 (dddd, ³J_HH= 7.5 Hz,

⁴J_PH= 3.5 Hz, ⁴J_HH= 1.2 Hz, ⁵J_HH= 0.5 Hz, 1H, H12), 7.81 (tdd, H10,

4′,4′-Bis[3-(triﬂuoromethyl)phenyl]-3′,3′-dimethyl-1-phenyl-1H-

spiro[2,1-benzazaphosphole-1,2′-[1,2]oxaphosphetan]-3(2H)-one

(9h). Conversion: 97%. Yield after precipitation from diethyl ether:

89%. White solid. Mp: 214−216 °C. IR (KBr): ν 3473, 1671, 1326,

1166, 1122 cm⁻¹. ¹H NMR (300.13 MHz, CDCl₃): δ 8.78 (dd, ³J_PH

=

12.5 Hz, ³J_HH7.5 Hz, 1H, H9), 8.41 (d, ²J_PH= 10.6 Hz, 1H, H5), 7.99−

8.10 (m, 2H, H12, H20′), 7.80−7.93 (m, 3H, H10, H14), 7.68−7.79

(m, 3H, H11, H22′, H24′), 7.57−7.64 (m, 1H, H24), 7.36−7.50 (m,

2H, H20, H23′), 7.15−7.34 (m, 5H, H15, H16, H22, H23), 1.19 (d,

³J_HH= 7.5 Hz, ⁴J_PH= 5.2 Hz, ⁴J_HH= 1.2 Hz, 1H, H10), 7.69−7.78 (m,

2H, H11 and H14), 7.57 (ddd, ³J_HH= 8.9 Hz, ⁴J_FH= 5.3 Hz, ⁴J_HH= 2.7

Hz, 2H, H20′), 7.31−7.33 (ddd, ³J_HH= 8.9 Hz, ⁴J_FH= 5.4 Hz, ⁴J_HH= 2.7

Hz, 2H, H20), 7.20−7.30 (m, 4H, H5, H15, H16), 6.95 (td, ³J_HH= ³J_FH

= 8.9 Hz, ⁴J_HH= 2.7 Hz, 2H, H21′), 6.73 (td, ³J_HH= ³J_FH= 8.9 Hz, ⁴J_HH

3

³J_PH26.2 Hz, 3H, H18), 1.71 (d, J_PH= 26.8 Hz, 3H, H17) ppm.

¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 168.6 (d, ²J_PC= 6.7 Hz, C6),

146.9 (d, ³J_PC= 11.3 Hz, C19′), 145.3 (d, ³J_PC= 3.5 Hz, C19), 138.4 (d,

= 2.7 Hz, 2H, H21), 1.66 (d, ³J_PH= 26.7 Hz, 3H, H17), 1.22 (d, ³J_PH

=

²J_PC= 11.6 Hz, C7), 136.2 (d, ¹J_PC= 141.0 Hz, C13), 135.6 (d, ¹J_PC

=

26.5 Hz, 3H, H18) ppm. ¹³C{¹H} NMR (125.76 MHz, CDCl₃, 25 °C)

δ 168.1 (d, ²J_PC= 6.0 Hz, C6), 161.3 (d, ¹J_FC= 245.4 Hz, C22), 161.2

(d, ¹J_FC= 245.7 Hz, C22′), 142.1 (dd, ³J_PC= 11.5 Hz, ⁴J_FC= 2.9 Hz,

C19′), 140.3 (t, ³J_PC= ⁴J_FC= 3.1 Hz, C19), 138.4 (d, ²J_PC= 10.8 Hz,

C7), 136.9 (d, ¹J_PC= 140.8 Hz, C8), 135.8 (d, ¹J_PC= 152.8 Hz, C13),

135.4 (d, ²J_PC= 11.3 Hz, C9), 133.1 (d, ⁴J_PC= 2.9 Hz, C11), 132.2 (d

152.4 Hz, C8), 135.4 (d, ²J_PC= 11.1 Hz, C9), 133.3 (d, ⁴J_PC= 3.0 Hz,

C11), 132.4 (d, ³J_PC= 15.3 Hz, C10), 132.0 (d, ²J_PC= 11.3 Hz, C14′),

131.8 (d, ²J_PC= 11.2 Hz, C14), 130.5 (d, ⁴J_PC= 3.5 Hz, C16), 130.4 (c,

²J_FC= 32.1 Hz, C21), 130.2 (c, ⁶J_FC= 1.0 Hz, C24′), 130.0 (c, ²J_FC

=

32.1 Hz, C21), 129.4 (c, ⁶J_FC= 1.2 Hz, C24), 128.3 (s, C23′), 128.1 (d,

³J_PC= 14.8 Hz, C15), 127.7 (s, C23), 124.6 (d, ³J_PC= 12.3 Hz, C12),

124.2 (c, ¹J_FC= 272.3 Hz, C25′), 124.0 (c, ³J_FC= 4.0 Hz, C22′), 123.9

(c, ¹J_FC= 272.6 Hz, C25), 123.5 (c, ³J_FC= 3.6 Hz, C20′), 123.4 (c, ³J_FC

= 3.7 Hz, C22), 123.0 (c, ³J_FC= 3.9 Hz, C20), 79.1 (d, ²J_PC= 12.7 Hz,

C4), 68.4 (d, ¹J_PC= 113.8 Hz, C3), 23.5 (d, ²J_PC= 5.1 Hz, C17, C18)

ppm. ³¹P{¹H} NMR δ (121.50 MHz, CDCl₃): −65.1 ppm. ¹⁹F{¹H}

NMR (282.4 MHz, CDCl₃): δ −62.6, −62.5 ppm. HRMS (ESI/TOF)

m/z: [M + 1] calcd for C₃₁H₂₅F₆NO₂P, 588.1527; found, 588.1535.

³J_PC= 15.6 Hz, C10), 131.8 (d, ²J_PC= 11.0 Hz, C14), 130.2 (d, ⁴J_PC

=

3.4 Hz, C16), 128.6 (d, ³J_FC= 7.9 Hz, C20), 128.0 (d, ³J_PC= 14.6 Hz,

C15), 127.5 (d, ³J_FC= 7.9 Hz, C20′), 124.7 (d, ³J_PC= 12.2 Hz, C12),

114.7 (d, ²J_FC= 21.4 Hz, C21), 114.1 (d, ²J_FC= 21.1 Hz, C21′), 79.1 (d,

²J_PC= 13.2 Hz, C4), 68.2 (d, ¹J_PC= 112.8 Hz, C3), 23.8 (d, ²J_PC= 5.0

2

Hz, C18), 23.7 (d, J_PC= 4.5 Hz, C17) ppm. ³¹P{¹H} NMR (202.46

MHz, CDCl₃, 25 °C) δ −65.4 ppm. ¹⁹F{¹H} NMR (282.40 MHz,

CDCl₃, 25 °C) δ −117.4 and −117.1 ppm. HRMS (ESI/TOF) m/z:

[M + 1] calcd for C₂₃H₂₅F₂NO₂P, 488,1591; found, 488.1589.

4′,4′-Bis(4-methylaminophenyl)-3′,3′-dimethyl-1-phenyl-1H-

spiro[2,1-benzazaphosphole-1,2′-[1,2]oxaphosphetan]-3(2H)-one

(9i). Conversion: 85%. Yield after precipitation from diethyl ether: 73%.

White solid. Mp: 125−126 °C, decomp. IR (KBr): ν 3444, 1665 cm⁻¹.

4′,4′-Bis(4-chlorophenyl)-3′,3′-dimethyl-1-phenyl-1H-spiro[2,1-

benzazaphosphole-1,2′-[1,2]oxaphosphetan]-3(2H)-one (9g). Con-

version: 95%. Yield after precipitation from diethyl ether: 88%. White

solid. Mp: 214−215 °C. IR (KBr): ν 3415, 3151, 1669 cm⁻¹. ¹H NMR

(500.13 MHz, CDCl₃, 25 °C) δ 8.67 (dddd, ³J_PH= 12.7 Hz, ³J_HH= 7.6

Hz, ⁴J_HH= 1.2 Hz, ⁵J_HH= 0.5 Hz, 1H, H9), 8.00 (dddd, ³J_HH= 7.6 Hz,

¹H NMR (300.13 MHz, CDCl₃): δ 8.72 (dddd, ³J_PH= 12.5 Hz, ³J_HH

=

7.4 Hz, ⁴J_HH= 1.1 Hz, ⁵J_HH= 0.5 Hz, 1H, H9), 7.98 (dddd, ⁴J_PH= 3.1

Hz, ³J_HH= 7.4 Hz, ⁴J_HH= 1.1 Hz, ⁵J_HH= 0.5 Hz, 1H, H12), 7.73−7.88

(m, 3H, H10, H14), 7.67 (tdd, ³J_HH= 7.4 Hz, ⁴J_HH= 1.1 Hz, ⁵J_PH= 2.0

Hz, 1H, H11), 7.47 (dd, ³J_HH= 8.7, ⁴J_HH= 2.6 Hz, 2H, H20′), 7.21−

7.33 (m, 5H, H15, H16, H20), 6.97 (d, ²J_PH= 9.9 Hz, 1H, H5), 6.63

(dd, ³J_HH= 8.7, ⁴J_HH= 2.5 Hz, 2H, H21′), 6.46 (dd, ³J_HH= 8.9 Hz, ⁴J_HH

= 2.5 Hz, 2H, H21), 2.84 (s, 6H, H23), 2.88 (s, 6H, H23′), 1.61 (d, ³J_PH

= 27.1 Hz, 3H, H17), 1.26 (d, ³J_PH= 27.0 Hz, 3H, H18) ppm. ¹³C{¹H}

⁴J_PH= 3.5 Hz, ⁴J_HH= 1.2 Hz, ⁵J_HH= 0.5 Hz, 1H, H12), 7.53 (dd, ³J_HH

=

8.6 Hz, ⁴J_HH= 2.1 Hz, 2H, H20′), 7.69−7.84 (m, 4H, H10, H11, H14),

7.21−7.37 (m, 8H, H21′, H20, H15, H16, H5), 7.01 (dd, ³J_HH= 8.7 Hz,

⁴J_HH= 2.3 Hz, 2H, H21), 1.67 (d, ³J_PH= 26.7 Hz, 3H, H17), 1.21 (d,

³J_PH= 26.6 Hz, 3H, H18) ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ

168.1 (d, ²J_PC= 6.2 Hz, C6), 144.6 (d, ³J_PC= 11.5 Hz, C19′), 142.9 (d,

2

NMR (75.47 MHz, CDCl₃): δ 168.1 (d, J_PC= 5.4 Hz, C6), 148.7

2

1

³J_PC= 3.6 Hz, C19), 138.3 (d, J_PC= 11.0 Hz, C7), 136.8 (d, J_PC

=

1

(C22′), 148.6 (C22), 138.3 (d, ²J_PC= 10.5 Hz, C7), 137.3 (d, J_PC

=

141.3 Hz, C8), 135.7 (d, ¹J_PC= 152.6 Hz, C13), 135.4 (d, ²J_PC= 11.3

141.4 Hz, C8), 136.5 (d, ¹J_PC= 151.3 Hz, C13), 135.7 (d, ²J_PC= 11.6

Hz, C9), 135.0 (d, ³J_PC= 10.5 Hz, C19′), 133.4 (d, ³J_PC= 4.7 Hz, C19),

132.7 (d, ⁴J_PC= 3.0 Hz, C11), 132.2 (d, ²J_PC= 11.1 Hz, C14), 131.9 (d,

4

Hz, C9), 133.2 (d, J_PC= 3.1 Hz, C11), 132.4 (C22), 132.3 (C22′),

132.3 (d, ³J_PC= 15.1 Hz, C10), 131.8 (d, ²J_PC= 11.0 Hz, C14), 130.3 (d,

⁴J_PC= 3.4 Hz, C16), 128.3 (C21), 128.1 (C21′), 128.0 (d, ³J_PC= 14.6

Hz, C15), 127.43 (C20), 127.3 (C20′), 124.7 (d, ³J_PC= 12.5 Hz, C12),

79.1 (d, ²J_PC= 13.0 Hz, C4), 68.2 (d, ¹J_PC= 113.2 Hz, C3), 23.7 (d, ²J_PC

³J_PC= 15.1 Hz, C10), 130.0 (d, ⁴J_PC= 3.1 Hz, C16), 127.9 (d, ³J_PC

=

14.6 Hz, C15), 127.6 (C20), 126.8 (C20′), 124.4 (d, ³J_PC= 12.0 Hz,

C12), 111.8 (C21′), 111.5 (C21), 79.7 (d, ²J_PC= 13.7 Hz, C4), 68.8 (d,

¹J_PC= 110.4 Hz, C3), 40.5 (C23), 40.5 (C23′), 24.1 (d, ²J_PC= 5.6 Hz,

= 5.3 Hz, C18), 23.7 (d, J_PC= 5.3 Hz, C17) ppm. ³¹P{¹H} NMR

2

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C17), 23.9 (d, ²J_PC= 5.4 Hz, C18) ppm. ³¹P{¹H} NMR (121.50 MHz,

CDCl₃): δ −64.2 ppm. HRMS (ESI/TOF) m/z: [M + 1] calcd for

C₃₃H₃₇N₃O₂P, 538.2623; found, 538.2625.

(1R_P*,3′S*)-3′-Methyl-1,4′,4′-triphenyl-1H-spiro[2,1-benzaza-

phosphole-1,2′-[1,2]oxaphos-phetan]-3(2H)-one (cis-9m).⁶⁹Con-

version: 86%. Yield after precipitation from diethyl ether: 80%. White

solid. Mp: 192−193 °C. IR (KBr): ν 3425, 3193, 1675 cm⁻¹. ¹H NMR

(300.13 MHz, CDCl₃): δ 8.40 (m, 1H, H9), 7.85−8.01 (m, 3H, H12,

H14), 7.79 (d, ²J_PH= 11.0 Hz, 1H, H5), 7.59−7.67 (m, 2H, H10, H11),

7.47−7.55 (m, 2H, H19′), 7.26−7.44 (m, 5H, H15, H16, H19), 7.08−

(1S_P,4′R)-4′-[(1S,5R)-6,6-Dimethyl bicycle[3.1.1]hept-2-en-2-yl]-

3′,3′-dimethyl-1-phenyl-1H-spiro[2,1-benzazaphosphole-1,2′-[1,2]-

oxaphosphetan]-3(2H)-one (trans-9k).⁶⁹Conversion: 47%. Yield

after chromatography (ethyl acetate/hexane 1:1): 39%. Slightly yellow

oil. ¹H NMR (300.13 MHz, CDCl₃): δ 8.20 (m, 1H, H9), 7.97−8.08

(m, 3H, H14, H12), 7.61−7.72 (m, 2H, H10, H11), 7.38−7.53 (m, 3H,

H15, H16), 6.00 (d, ²J_PH= 10.2 Hz, 1H, H-5), 5.64 (tq, ³J_HH= 3.0 Hz,

⁴J_HH= 1.5 Hz, 1H, H20), 4.25 (dq, ³J_PH= 5.5 Hz, J_HH= 1.5 Hz, 1H, H4),

7.25 (m, 6H, H20, H20′, H21, H21′), 4.73 (dq, ²J_PH= 24.1 Hz, ³J_HH

=

8.1 Hz, 1H, H3), 1.51 (dd, ³J_PH= 29.2 Hz, ³J_HH= 8.1 Hz, 3H, H17)

ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 167.4 (d, ²J_PC= 7.2 Hz,

C6), 148.4 (d, ³J_PC= 7.8 Hz, C18′), 143.3 (d, ³J_PC= 6.0 Hz, C18), 138.2

(d, ²J_PC= 12.0 Hz, C7), 136.3 (d, ¹J_PC= 151.3 Hz, C8), 136.1 (d, ²J_PC

=

12.6 H, C9z), 136.0 (d, ¹J_PC= 143.0 Hz, C13), 132.9 (d, ⁴J_PC= 2.9 Hz,

C11), 132.5 (d, ²J_PC= 11.4 Hz, C14), 131.8 (d, ³J_PC= 16.2 Hz, C10),

130.5 (d, ⁴J_PC= 3.6 Hz, C16), 128.1 (d, ³J_PC= 15.0 Hz, C15), 128.0

(C20), 127.6 (C20′), 126.8 (C19), 126.6 (C21), 126.4 (C21′), 125.8

(C19′), 124.3 (d, ³J_PC= 12.6 Hz, C12), 77.5 (d, ²J_PC= 15.0 Hz, C4),

2.37 (dt, ³J_HH= 5.6 Hz, ²J_HH= 8.4 Hz, 1H, H25), 2.33 (m, 2H, H21),

2.17 (t, ³J_HH= ⁴J_HH= 5.6 Hz, 1H, H24), 2.12 (m, 1H, H22), 1.39 (d,

³J_PH= 27.7 Hz, 3H, H17), 1.28 (s, 3H, H26), 1.20 (d, ²J_PH= 8.4 Hz, 1H,

3

H25), 1.19 (d, J_PH= 26.0 Hz, 3H, H18), 0.93 (s, 3H, H27) ppm.

¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 168.6 (d, ²J_PC= 3.2 Hz, C6),

147.0 (d, ³J_PC= 16.7 Hz, C19), 137.8 (d, ²J_PC= 10.7 Hz, C7), 137.1 (d,

1

2

63.8 (d, J_PC= 109.3 Hz, C3), 13.4 (d, J_PC= 9.6 Hz, C17) ppm.

³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −72.4 ppm. HRMS (ESI/

TOF) m/z: [M + 1] calcd for C₂₆H₃₁NO₂P, 438.1623; found,

438.1635.

¹J_PC= 154.9 Hz, C8), 135.5 (d, ²J_PC= 12.1 Hz, C9), 134.8 (d, ²J_PC

=

12.1 Hz, C14), 133.4 (d, ¹J_PC= 137.6 Hz, C13), 132.7 (d, ⁴J_PC= 3.0 Hz,

C11), 131.9 (d, ³J_PC= 15.8 Hz, C10), 131.4 (d, ⁴J_PC= 3.8 Hz, C16),

128.6 (d, ³J_PC= 14.3 Hz, C15), 124.2 (d, ³J_PC= 12.8 Hz, C12), 119.8

(C20), 76.4 (d, ²J_PC= 17.4 Hz, C4), 66.4 (d, ¹J_PC= 107.8 Hz, C3), 43.0

(C24), 40.7 (C22), 37.8 (C23), 31.9 (C25), 31.3 (C21), 26.3 (C26),

23.8 (d, ²J_PC= 5.3 Hz, C17), 21.9 (C27), 19.4 (d, ²J_PC= 6.0 Hz, C18)

ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −63.7 ppm. HRMS

(ESI/TOF) m/z: [M + 1] calcd for C₂₆H₃₁NO₂P, 420.2092; found,

420.2099.

(1R_P*,3′S*,4′R*)-3′-Buthyl-4′-methyl-1,4′-diphenyl-1H-spiro[2,1-

benzazaphosphole-1,2′-[1,2]oxaphosphetan]-3(2H)-one (cis-9n).⁶⁹

Conversion: 87%. Yield after precipitation from diethyl ether: 78%.

White solid. Mp: 194−195 °C. IR (KBr): ν 3425, 3235, 1678 cm⁻¹. ¹H

NMR (300.13 MHz, CDCl₃): δ 8.50−8.60 (m, 1H, H9), 8.02−8.10 (m,

1H, H12), 7.79−7.91 (m, 2H, H14), 7.69−7.79 (m, 2H, H10, H11),

0.67 (t, ³J_HH= 6.7 Hz, 3H, H20), 7.28−7.46 (m, 4H, H5, H15, H16),

7.15−7.26 (m, 5H, H22, H23, H24), 3.81 (ddd, ²J_PH= 23.4 Hz, ³J_HH

=

10.7 Hz, ³J_HH= 3.3 Hz, 1H, H3), 1.77 (s, 3H, H25), 1.47−1.68 (m, 2H,

H17), 0.93−1.28 (m, 4H, H18, H19) ppm. ¹³C{¹H} NMR (75.47

MHz, CDCl₃): δ 167.3 (d, ²J_PC= 7.2 Hz, C6), 143.6 (d, ³J_PC= 7.9 Hz,

C21), 138.3 (d, ²J_PC= 11.5 Hz, C7), 137.3 (d, ¹J_PC= 149.6 Hz, C8),

136.1 (d, ²J_PC= 12.1 Hz, C9), 136.0 (d, ¹J_PC= 144.8 Hz, C13), 133.1 (d,

(1R_P,4′R)-4′-[(1S,5R)-6,6-Dimethyl bicycle[3.1.1]hept-2-en-2-yl]-

3′,3′-dimethyl-1-phenyl-1H-spiro[2,1-benzazaphosphole-1,2′-[1,2]-

oxaphosphetan]-3(2H)-one (cis-9k). Conversion: 49%. Yield after

chromatography (ethyl acetate/hexane 1:1): 43%. Slightly yellow oil.

¹H NMR (300.13 MHz, CDCl₃): δ 8.25 (m, 1H, H9), 7.93−8.12 (m,

3H, H14, H12), 7.62−7.78 (m, 2H, H10, H11), 7.33−7.48 (m, 3H,

H15, H16), 6.52 (d, ²J_PH= 10.7 Hz, 1H, H5), 5.65 (tq, ³J_HH= 3.0 Hz,

⁴J_HH= 1.5 Hz, 1H, H20), 4.18 (dq, ³J_PH= 7.0 Hz, J_HH= 1.5 Hz, 1H, H4),

2.32−2.48 (m, 3H, H25, H21), 2.12 (m, 1H, H22), 1.99 (t, ³J_HH= ⁴J_HH

= 5.7, 1H, H24), 1.40 (d, ³J_PH= 26.4 Hz, 3H, H17), 1.16−1.31 (m, 7H,

H18, H25, H26), 0.95 (s, 3H, H27) ppm. ¹³C{¹H} NMR (75.47 MHz,

CDCl₃): δ 168.2 (d, ²J_PC= 4.2 Hz, C6), 146.9 (d, ³J_PC= 13.2 Hz, C19),

138.8 (d, ²J_PC= 10.2 Hz, C7), 135.4 (d, ¹J_PC= 147.2 Hz, C13), 135.3 (d,

⁴J_PC= 3.0 Hz, C11), 132.3 (d, ²J_PC= 12.1 Hz, C14), 132.0 (d, ³J_PC

=

15.6 Hz, C10), 130.5 (d, ⁴J_PC= 3.0 Hz, C16), 128.2 (d, ³J_PC= 15.0 Hz,

3

C15), 127.7 (C23), 126.8 (C24), 126.5 (C22), 124.5 (d, J_PC= 12.0

Hz, C12), 74.8 (d, ²J_PC= 16.8 Hz, C4), 71.2 (d, ¹J_PC= 105.7 Hz, C3),

32.0 (d, ³J_PC= 6.0 Hz, C25), 31.1 (d, ³J_PC= 20.4 Hz, C18), 26.6 (d, ²J_PC

= 8.4 Hz, C17), 22.4 (d, ⁴J_PC= 1.8 Hz, C19), 13.6 (C20) ppm. ³¹P{¹H}

NMR (121.50 MHz, CDCl₃): δ −75.9 ppm. HRMS (ESI/TOF) m/z:

[M + 1] calcd for C₂₆H₂₉NO₂P, 418.1936; found, 418.1952.

²J_PC= 12.0 Hz, C9), 134.9 (d, ¹J_PC= 143.6 Hz, C8), 134.6 (d, ²J_PC

=

12.0 Hz, C14), 133.1 (d, ⁴J_PC= 3.0 Hz, C11), 132.0 (d, ³J_PC= 15.0 Hz,

C10), 131.1 (d, ⁴J_PC= 3.6 Hz, C16), 128.2 (d, ³J_PC= 15.0 Hz, C15),

124.7 (d, ³J_PC= 11.4 Hz, C12), 119.3 (C20), 77.6 (d, ²J_PC= 17.4 Hz,

1

C4), 65.3 (d, J_PC= 109.9 Hz, C3), 43.1 (C24), 40.8 (C22), 37.7

2

(C23), 32.0 (C25), 31.3 (C21), 26.3 (C26), 24.3 (d, J_PC= 5.8 Hz,

2

C17), 21.9 (C27), 19.6 (d, J_PC= 5.8 Hz, C18) ppm. ³¹P{¹H} NMR

(121.50 MHz, CDCl₃): δ −63.6 ppm. HRMS (ESI/TOF) m/z: [M +

1] calcd for C₂₆H₃₁NO₂P, 420.2092; found, 420.2099.

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(1R_P*,3′S*)-4′,4′-Bis(4-methoxyphenyl)-3′-methyl-1-phenyl-1H-

spiro[2,1-benzazaphosphole-1,2′-[1,2]oxaphos-phetan]-3(2H)-one

(cis-9o). Conversion: 83%. Yield after precipitation from diethyl ether:

75%. White solid. Mp: 138−140 °C, decomp. IR (KBr): ν 1683 cm⁻¹.

¹H NMR (300.13 MHz, CDCl₃): δ 8.39 (m, 1H, H9), 7.96 (m, 1H,

(300.13 MHz, CDCl₃): δ 8.08−8.28 (m, 3H, H9, H14), 8.02 (m, 1H,

H12), 7.35−7.75 (m, 5H, H11, H10, H15, H16), 7.11−7.21 (m, 5H,

H21, H22, H23), 6.07 (d, ²J_PH= 11.7 Hz, H5), 1.85 (d, ³J_PH= 28.4 Hz,

3H, H18), 1.34 (s, 3H, H20*), 0.95 (s, 3H, H19*) ppm.

*Interchangables. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −68.73

ppm.

H12), 7.84 (m, 2H, H14), 7.59−7.66 (m, 2H, H10, H11), 7.32−7.44

3

4

(m, 5H, H15, H16, H19′), 7.08 (dd, J_HH= 8.8, J_HH= 2.5 Hz, 2H,

H19), 6.95 (d, ²J_PH= 11.3 Hz, 1H, H5), 6.81 (dd, ³J_HH= 8.6, ⁴J_HH= 2.5

Hz, 2H, H20′), 6.67 (dd, ³J_HH= 8.8 Hz, ⁴J_HH= 2.5 Hz, 2H, H20), 4.69

(dq, ²J_PH= 24.0 Hz, ³J_HH= 7.9 Hz, 1H, H3), 3.76 (s, 3H, H22′), 3.73 (s,

3

3H, H22), 1.47 (dd, J_PH= 29.2 Hz, J_HH= 7.9 Hz, 3H, H17) ppm.

¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 167.9 (d, ²J_PC= 7.5 Hz, C6),

158.2 (C21′), 157.9 (C21), 139.9 (d, ³J_PC= 8.3 Hz, C18′), 138.1 (d,

3

1

²J_PC= 10.9 Hz, C7), 136.3 (d, J_PC= 5.2 Hz, C18), 136.1 (d, J_PC

=

149.8 Hz, C8), 136.1 (d, ²J_PC= 12.1 Hz, C9), 135.9 (d, ¹J_PC= 141.0 Hz,

C13), 133.0 (d, ⁴J_PC= 3.1 Hz, C11), 132.3 (d, ²J_PC= 11.4 Hz, C14),

131.9 (d, ³J_PC15.3 Hz, C10), 130.5 (d, ⁴J_PC= 3.3 Hz, C16), 128.2 (d,

³J_PC= 14.9 Hz, C15), 127.9 (C19), 126.9 (C19′), 124.3 (d, ³J_PC= 12.4

Hz, C12), 113.3 (C20′), 112.9 (C20), 79.4 (d, ²J_PC= 13.7 Hz, C4), 63.7

(d, ¹J_PC= 109.0 Hz, C3), 55.1 (C22′), 55.1 (C-22), 13.5 (d, ²J_PC= 9.3

Hz, C17) ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −72.8 ppm.

HRMS (ESI/TOF) m/z: [M + 1] calcd for C₃₀H₂₉NO₄P, 418.1834;

found, 418.1849.

2-(Phenyl(1-phenylethyl)phosphoryl)benzamide (13). Con-

version: 35%. Yield after chromatography (ethyl acetate/hexane 2:3):

18%. White solid. Mp: 277−278 °C. IR (KBr): ν 3452, 3130, 1667,

1

1619, 1166 cm⁻¹. H NMR (300.13 MHz, CD₃OD): δ 7.80 (m, 3H,

H6, H9), 7.53 (m, 3H, H10, H11), 7.42 (m, 2H, H4, H3), 7.35 (m, 3H,

H5, H14), 7.08 (m, 3H, H15, H16), 4.76 (m, 1H, H12), 1.75 (dd, ³J_PH

= 16.8 Hz, ³J_HH= 7.4 Hz, 3H, H17) ppm. ¹³C{¹H} NMR (75.47 MHz,

CD₃OD): δ 171.7 (d, ³J_PC= 3.6 Hz, C1), 138.5 (d, ²J_PC= 8.8 Hz, C2),

138.1 (d, ²J_PC= 6.5 Hz, C13), 133.5 (d, ²J_PC= 5.8 Hz, C6), 131.8 (d,

²J_PC= 9.2 Hz, C9), 131.4 (d, ¹J_PC= 96.3 Hz, C8), 131.4 (d, ⁴J_PC= 2.8

Hz, C11), 131.1 (d, ⁴J_PC= 2.6 Hz, C4), 130.6 (d, ¹J_PC= 96.0 Hz, C7),

129.0 (d, ³J_PC= 10.4 Hz, C5), 128.7 (d, ³J_PC= 5.7 Hz, C14), 127.9 (d,

³J_PC= 11.6 Hz, C10), 127.5 (d, ⁴J_PC= 2.5 Hz, C15), 127.2 (d, ³J_PC= 9.7

Hz, C3), 126.4 (d, ⁵J_PC= 3.1 Hz, C16), 38.0 (d, ¹J_PC= 68.4 Hz, C12),

2

14.4 (d, J_PC= 3.8 Hz, C17) ppm. ³¹P{¹H} NMR (121.50 MHz,

CD₃OD): δ 41.48 ppm. HRMS (ESI/TOF) m/z: [M + 1] calcd for

C₂₁H₂₁NO₂P, 350.1310; found, 350.1316.

(1R_P*,3′R*)-3′,4′,4′-Trimethyl-1,3′-diphenyl-1,2-dihydro-3H-1λ⁵-

spiro[benzo[c][1,2]aza-phosphole-1,2′-[1,2]oxaphosphetan]-3-one

(cis-9p). Conversion: 18%. Yield after two successive chromatographic

puriﬁcations (ethyl acetate/hexane 2:3): 1%. White solid. Mp: 168−

1

170 °C, decomp. IR (KBr): ν 1668 cm⁻¹. H NMR (300.13 MHz,

CDCl₃): δ 8.33 (m, 2H, H14), 8.13 (m, 1H, H9), 8.02 (m, 1H, H12),

7.65 (m, 1H, H10), 7.62 (m, 1H, H11), 7.5 (m, 1H, H16), 7.47 (m, 2H,

H15), 7.25 (m, 5H, H21, H22, H23), 6.19 (d, ²J_PH= 11.8 Hz, H5), 1.76

General Procedure for the Synthesis of Spiro-1,2-oxaphos-

phetanes 12a−d. To a solution of the appropriate phosphazene 7

(6.64 × 10⁻⁴mol) in THF (10 mL) was added a solution of t-BuLi

(0.86 mL of a 1.7 M solution in cyclohexane, 1.46 × 10⁻³mol) at −35

°C. After 30 min of metalation, the corresponding electrophile was

added (0.66 × 10⁻³mol) at −90 °C, and the mixture was stirred for 2.5

h. Then, the reaction was quenched with methyl triﬂuoromethanesul-

fonate (MeOTf, 0.09 mL, 7.97 × 10⁻⁴mol) and stirred for 30 min at

−35 °C. The reaction mixture was poured into water and extracted with

dichloromethane (2 × 15 mL). The organic layers were dried over

Na₂SO₄and concentrated in vacuo, aﬀording a white solid. ¹H, ¹H{³¹P},

and ³¹P{¹H} NMR spectra of the crude reaction were always measured

in order to determine the conversion of the process. The crude mixture

was puriﬁed by precipitation from diethyl ether, aﬀording 12a−d.

2,3′,3′,4′,4′-Pentamethyl-1-phenyl-1H-spiro[2,1-benzazaphosp-

hole-1,2′-[1,2]oxaphosphetan]-3(2H)-one (12a). Conversion: 95%.

Yield after precipitation from diethyl ether: 88%. White solid. Mp:

163−164 °C. IR (KBr): ν 1635 cm⁻¹. ¹H NMR (300.13 MHz, CDCl₃):

δ 8.03−8.14 (m, 2H, H9, H12), 7.62−7.73 (m, 3H, H11, H14), 7.58

(ddt, ³J_HH= 7.5 Hz, ⁴J_PH= 4.9 Hz, ⁴J_HH= 1.4 Hz, 1H, H10), 7.28−7.45

3

(d, J_PH= 27.1 Hz, 3H, H18), 1.47 (s, 3H, H20), 1.10 (s, 3H, H19)

ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 168.8 (d, ²J_PC= 4.7 Hz,

2

1

C6), 141.1 (d, J_PC= 7.7 Hz, C17), 139.2 (d, J_PC= 152.3 Hz, C8),

137.8 (d, ²J_PC= 10.5 Hz, C7), 134.6 (d, ²J_PC= 11.7 Hz, C9), 136.6 (d,

²J_PC= 13.0 Hz, C14), 136.4 (d, ¹J_PC= 134.4 Hz, C13), 132.8 (d, ⁴J_PC

=

3.0 Hz, C11), 132.3 (d, ³J_PC= 15.6 Hz, C10), 132.0 (d, ⁴J_PC= 3.6 Hz,

C16), 129.1 (d, ³J_PC= 14.6 Hz, C15), 127.6 (d, ³J_PC= 15.1 Hz, C21),

128.9 (C22), 124.7 (d, ³J_PC= 12.3 Hz, C12), 127.4 (C23), 75.2 (d, ¹J_PC

= 115.4 Hz, C3), 73.4 (d, ²J_PC= 16.1 Hz, C4), 29.7 (d, ³J_PC= 2.7 Hz,

C19), 26.7 (d, ³J_PC= 11.5 Hz, C20), 21.2 (d, ²J_PC= 6.9 Hz, C18) ppm.

³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −67.5 ppm. HRMS (ESI/

TOF) m/z: [M + 1] calcd for C₂₄H₂₅NO₂P, 390.1623; found,

390.1639.

(m, 2H, H15, H16), 2.62 (d, ³J_PH= 3.0 Hz, 3H, H21), 1.68 (d, ³J_PH

25.2 Hz, 3H, H17), 1.18 (s, 3H, H20), 1.51 (s, 3H, H19), 1.00 (d, ³J_PH

=

27.7 Hz, 3H, H18) ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 166.8

(d, ²J_PC= 6.5 Hz, C6), 139.5 (d, ²J_PC= 10.2 Hz, C7), 135.8 (d, ²J_PC

=

(1R_P*,3′S*)-3′,4′,4′-Trimethyl-1,3′-diphenyl-1,2-dihydro-3H-1λ⁵-

spiro[benzo[c][1,2]aza-phosphole-1,2′-[1,2]oxaphosphetan]-3-one

(trans-9p). Identiﬁed from a mixture of cis-9p/trans-9p in a ratio of

76:24 obtained after puriﬁcation of a crude reaction mixture through

two successive column chromatography separations using ethyl

acetate/hexane 2:3 as an eluent. Conversion: 9%. Yield: 0.3%. The

amount obtained was too small to achieve the characterization of the

11.7 Hz, C9), 134.6 (d, ²J_PC= 12.2 Hz, C14), 134.2 (d, ¹J_PC= 139.4 Hz,

C13), 133.0 (d, ⁴J_PC= 3.2 Hz, C11), 132.9 (d, ¹J_PC= 144.4 Hz, C8),

131.3 (d, ⁴J_PC= 2.9 Hz, C16), 131.2 (d, ³J_PC= 15.6 Hz, C10), 128.6 (d,

³J_PC= 15.0 Hz, C15), 124.2 (d, ³J_PC= 11.4 Hz, C12), 73.7 (d, ²J_PC

16.1 Hz, C4), 66.0 (d, ¹J_PC= 106.9 Hz, C3), 29.7 (C21), 27.1 (d, ³J_PC

=

3

2

1.7 Hz, C19), 25.7 (d, J_PC= 11.0 Hz, C20), 21.7 (d, J_PC= 6.6 Hz,

1

mixture. Only the H and ³¹P NMR data are provided. H NMR

C18), 20.5 (d, ²J_PC= 5.2 Hz, C17) ppm. ³¹P{¹H} NMR (121.50 MHz,

P

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CDCl₃): δ −53.4 ppm. HRMS (ESI/TOF) m/z: [M + 1] calcd for

C₂₀H₂₅NO₂P, 342.1623; found, 342.1641.

4′,4′-Bis(4-methoxyphenyl)-2,3′,3′-trimethyl-1-phenyl-1H-spiro-

[2,1-benzazaphosphole-1,2′-[1,2]oxaphosphetan]-3(2H)-one

(12d). Conversion: 91%. Yield after precipitation from diethyl ether:

87%. White solid. Mp: 183−184 °C. IR (KBr): ν 1685 cm⁻¹. ¹H NMR

(300.13 MHz, CDCl₃): δ 8.39 (dddd, ³J_PH= 13.0 Hz, ³J_HH= 7.5 Hz,

(2′R_P*,3′S*)-2,3′-Dimethyl-1,4′,4′-triphenyl-1H-spiro[2,1-benza-

zaphosphole-1,2′-[1,2]oxaphosphetan]-3(2H)-one (cis-12b). Con-

version: 87%. Yield after precipitation from diethyl ether: 80%. White

1

solid. Mp: 163−165 °C. IR (KBr): ν 1665 cm⁻¹. H NMR (300.13

⁴J_HH= 1.2 Hz, ⁵J_HH= 0.5 Hz, 1H, H9), 8.06 (dddd, ⁴J_PH= 3.5 Hz, ³J_HH

=

7.5 Hz, ⁴J_HH= 1.2 Hz, ⁵J_HH= 0.5 Hz, 1H, H12), 7.66 (tdd, ³J_HH= 7.4

MHz, CDCl₃): δ 8.02 (dd, ⁴J_PH= 3.1 Hz, ³J_HH= 7.5 Hz, 1H, H12), 7.90

(dd, ³J_PH= 13.3 Hz, ³J_HH= 7.5 Hz, 1H, H9), 7.64 (m, 2H, H14), 7.50−

7.58 (m, 3H, H11, H19), 7.37−7.49 (m, 5H, H15, H16, H20), 7.23−

7.36 (m, 4H, H19′, H21, H10), 7.12−7.19 (m, 2H, H20′), 7.01−7.10

(m, 1H, H21′), 4,70 (dq, ²J_PH= 19.7 Hz, ³J_HH= 8.0 Hz, 1H, H3), 2.64

(d, ³J_PH= 2.6 Hz, 3H, H22), 1.64 (d, ³J_HH= 8.0 Hz, ³J_PH= 28.2 Hz, 3H,

H17) ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 166.1 (d, ²J_PC= 8.4

Hz, C6), 147.2 (d, ³J_PC= 4.2 Hz, C18′), 143.9 (d, ³J_PC= 10.2 Hz, C18),

138.9 (d, ²J_PC= 12.0 Hz, C7), 136.4 (d, ²J_PC= 12.0 Hz, C9), 133.3 (d,

Hz, ⁴J_HH= 1.2 Hz, ⁵J_PH= 2.0 Hz, 1H, H11), 7.38−7.62 (m, 8H, H16,

3

4

H20, H20′, H14, H10), 6.89 (dd, J_HH= 8.9 Hz, J_HH= 2.5 Hz, 2H,

H21), 7.33 (m, 2H, H15), 6.72 (dd, ³J_HH= 8.9 Hz, ⁴J_HH= 2.5 Hz, 2H,

H21′), 3.83 (s, 3H, H23), 3.71 (s, 3H, H23′), 2.53 (d, ³J_PH= 2.9 Hz,

3H, H24), 1.76 (d, ³J_PH= 25.4 Hz, 3H, H17), 1.32 (d, ³J_PH= 28.3 Hz,

3H, H18) ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 167 (d, ²J_PC

=

6.4 Hz, C6), 157.9 (C22′), 157.7 (C22), 139.5 (d, ²J_PC= 10.2 Hz, C7),

138.8 (d, ³J_PC= 6.1 Hz, C19′), 138.6 (d, ³J_PC= 8.8 Hz, C19), 135.9 (d,

²J_PC= 12.1 Hz, C9), 134.7 (d, ¹J_PC= 146.1 Hz, C13), 133 (d, ⁴J_PC= 2.9

1

2

¹J_PC= 146.6 Hz, C13), 132.8 (d, ⁴J_PC= 3.0 Hz, C11), 132.7 (d, ¹J_PC

=

Hz, C11), 132.5 (d, J_PC= 143.2 Hz, C8), 131.8 (d, J_PC= 12.3 Hz,

C14), 131.1 (d, ³J_PC= 15.1 Hz, C10), 130.4 (d, ⁴J_PC= 3.5 Hz, C16),

128.3 (d, ³J_PC= 15.3 Hz, C15), 127.5 (C20), 127.4 (C20′), 124 (d, ³J_PC

= 11.6 Hz, C12), 113.2 (C21′), 112.8 (C21), 80.7 (d, ²J_PC= 12.9 Hz,

C4), 70.4 (d, ¹J_PC= 107.9 Hz, C3), 55.2 (C23′), 55 (C23), 30.4 (C24),

24.7 (d, ²J_PC= 6.9 Hz, C18), 24 (d, ²J_PC= 4.6 Hz, C17) ppm. ³¹P{¹H}

NMR (121.50 MHz, CDCl₃): δ −48.7 ppm. HRMS (ESI/TOF) m/z:

[M + 1] calcd for C₃₂H₃₃NO₄P, 526.2147; found, 526.2156.

144.8 Hz, C8), 132.3 (d, ²J_PC= 12.6 Hz, C14), 130.9 (d, ⁴J_PC= 3.6 Hz,

C16), 130.7 (d, ³J_PC= 15.0 Hz, C10), 128.6 (d, ³J_PC= 15.7 Hz, C15),

128.1 (C20), 127.8 (C20′), 126.6 (C19), 126.6 (C21), 126.5 (C21′),

126.2 (C19′), 123.9 (d, ³J_PC= 12.0 Hz, C12), 78.2 (d, ²J_PC= 15.0 Hz,

C4), 63.7 (d, ¹J_PC= 108.7 Hz, C3), 29.7 (C22), 14.0 (d, ²J_PC= 10.0 Hz,

C17) ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −59.8 ppm.

HRMS (ESI/TOF) m/z: [M + 1] calcd for C₂₉H₂₇NO₂P, 452.1779;

found, 452.1793.

General Procedure for the Synthesis of Oleﬁns 10 and

Benzoazaphospholes 11 and 14. A solution of the appropriate 1,2-

oxaphosphetane 9/12c (1.3 × 10⁻⁴mol) in DMSO-d₆(0.5 mL) was

heated at 140 °C. After 14 h, 15 mL of water was added, and the

reaction mixture was extracted with CH₂Cl₂(2 × 20 mL). Then the

organic layers were dried over Na₂SO₄and concentrated in vacuo.

Oleﬁn 10 was extracted with hexane (2 × 5 mL), and the insoluble

residue was washed with diethyl ether and identiﬁed as the

benzoazaphosphol 11/14. All oleﬁns obtained have been described in

the literature.

2,3-Dimethyl-2-butene (10a). Conversion: >97%. Identiﬁed from

the crude reaction mixture. ¹H NMR (300.13 MHz, DMSO-d₆): δ 1.85

(s, 12H, H2) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ 124.5 (C1), 20.4

(C2) ppm.

2,3′,3′-Trimethyl-1,4′,4′-triphenyl-1H-spiro[2,1-benzazaphosp-

hole-1,2′-[1,2]oxa-phosphetan]-3(2H)-one (12c). Conversion: 95%.

Yield after precipitation from diethyl ether: 90%. White solid. Mp:

179−180 °C. IR (KBr): ν 1653 cm⁻¹. ¹H NMR (300.13 MHz, CDCl₃):

δ 8.42 (dd, ³J_PH= 12.6 Hz, ³J_HH= 7.5 Hz, 1H, H9), 8.07 (ddd, ⁴J_PH= 3.5

Hz, ³J_HH= 7.3 Hz, ⁴J_HH= 0.9 Hz, 1H, H12), 7.66−7.71 (m, 2H, H20′),

7.60−7.65 (m, 3H, H10, H14), 7.54−7.59 (m, 1H, H11), 7.29−7.53

(m, 6H, H15, H16, H20, H21′), 7.15−7.27 (m, 3H, H2, H22′), 7.01−

7.10 (m, 1H, H22), 2.54 (d, ³J_PH= 28.3 Hz, 3H, H23), 1.79 (d, ³J_PH

=

25.2 Hz, 3H, H17), 1.36 (d, ³J_PH= 28.3 Hz, 3H, H18) ppm. ¹³C{¹H}

NMR (75.47 MHz, CDCl₃): δ 166.8 (d, ²J_PC= 7.2 Hz, C6), 145.1 (d,

³J_PC= 7.6 Hz, C19′), 145.1 (d, ³J_PC= 7.2 Hz, C19), 139.0 (d, ²J_PC= 11.3

Hz, C7), 136.0 (d, ²J_PC= 12.1 Hz, C9), 134.0 (d, ¹J_PC= 137.3 Hz, C8),

133.1 (d, ¹J_PC= 155.4 Hz, C13), 133.0 (d, ⁴J_PC= 3.0 Hz, C11), 131.9 (d,

(1-Methylethylidene)cyclohexane (10b). Conversion: >97%. Col-

orless oil. Yield: 90%. ¹H NMR (300.13 MHz, CDCl₃): δ 2.06 (m, 4H,

H2), 1.55 (m, 6H, H6), 1.47 (m, 6H, H3 and H4) ppm.

²J_PC= 12.2 Hz, C14), 131.1 (d, ³J_PC= 15.0 Hz, C10), 130.5 (d, ⁴J_PC

=

3

3.4 Hz, C16), 128.3 (d, J_PC= 15.5 Hz, C15), 127.9 (C21), 127.5

(C21′), 126.5 (C20 and C20′), 126.3 (C22), 126.2 (C22′), 124.0 (d,

³J_PC= 11.6 Hz, C12), 80.4 (d, ²J_PC= 13.5 Hz, C4), 68.1 (d, ¹J_PC= 110.8

Hz, C3), 24.7 (d, ²J_PC= 7.0 Hz, C18), 30.5 (C23), 24 (d, ²J_PC= 4.7 Hz,

C17) ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ −48.9 ppm.

HRMS (ESI/TOF) m/z: [M + 1] calcd for C₃₀H₂₉NO₂P, 466.1936;

found, 466.1952.

1,1′-(2-Methylprop-1-ene-1,1-diyl)dibenzene (10c). Conversion:

1

>97%. Colorless oil. Yield: 94%. H NMR (300.13 MHz, CDCl₃): δ

7.30 (m, 2H, H5), 7.21 (m, 1H, H7), 7.16 (m, 2H, H6), 1.83 (s, 3H,

Q

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H3) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ 143.3 (C4), 137.1 (C1),

131.0 (C2), 129.8 (C5), 127.8 (C6), 126.0 (C7), 24.4 (C3) ppm.

Ethylidenecyclohexane (10l). Conversion: >97%. Colorless oil.

Yield: 92%. ¹H NMR (300.13 MHz, CDCl₃): δ 5.06 (q, ³J_HH= 6.7 Hz,

1H, H5), 2.06 (m, 2H, H2), 2.00 (m, 2H, H2), 1.51 (d, ³J_HH= 6.7 Hz,

3H, H6), 1.47 (m, 6H, H3, H4) ppm.

(1,2-Dimethyl-1-propen-1-yl)-benzene (10d). Conversion: >97%.

Colorless oil. Yield: 92%. ¹H NMR (300.13 MHz, CDCl₃): δ 7.29 (m,

2H, H7), 7.17 (m, 1H, H8), 7.09 (m, 2H, H6), 1.90 (s, 3H, H9), 1.76

(s, 3H, H4), 1.53 (s, 3H, H1) ppm.

1,1′-Prop-1-ene-1,1-diyldibenzene (10m). Conversion: >97%.

1

Colorless oil. Yield: 94%. H NMR (300.13 MHz, CDCl₃): δ 7.22−

7.38 (m, 4H, H6), 7.05−7.21 (m, 6H, H5, H7), 6.21 (q, ³J_HH= 7.0 Hz,

1H, H2), 1.69 (d, ³J_HH= 7.0 Hz, 3H, H3) ppm.

(Z)-(3-Methylhept-2-en-2-yl)benzene (Z-10e). Conversion: >97%.

Colorless oil. Yield: 95%. ¹H NMR (300.13 MHz, CDCl₃): δ 7.30 (m,

2H, H10), 7.19 (m, 1H, H11), 7.07 (d, ³J_HH= 7.5 Hz, 2H, H9), 2.00 (t,

³J_HH= 7.5 Hz, 2H, H4), 1.95 (s, 3H, H12), 1.74 (s, 3H, H1), 1.10−1.35

(m, 4H, H5, H6), 0.80 (t, ³J_HH= 7.4 Hz, 3H, H7) ppm.

(Z)-Hept-2-en-2-ylbenzene (10n). Conversion: >97%. Colorless oil.

Yield: 94%. ¹H NMR (300.13 MHz, CDCl₃): δ 7.28 (m, 2H, H10), 7.21

(m, 1H, H11), 7.12 (m, 2H, H9), 5.47 (t, ³J_HH= 6.9 Hz, 3H, H3), 2.51

(m, 2H, H4), 2.03 (s, 3H, H1), 1.07−1.37 (m, 4H, H5, H6), 0.83 (t,

³J_HH= 7.2 Hz, 3H, H7) ppm.

(E)-(3-Methylhept-2-en-2-yl)benzene (E-10e). Conversion: >97%.

Colorless oil. Yield: 96%. ¹H NMR (300.13 MHz, CDCl₃): δ 7.32 (m,

2H, H10), 7.19 (m, 1H, H11), 7.12 (d, ³J_HH= 7.7 Hz, 2H, H9), 2.19 (t,

³J_HH= 7.5 Hz, 2H, H4), 1.58 (s, 3H, H1), 1.98 (s, 3H, H12), 1.45 (m,

4H, H5, H6), 0.98 (t, ³J_HH= 7.2 Hz, 3H, H7) ppm.

1,1′-Prop-1-ene-1,1-diylbis(4-methoxybenzene) (10o). Conver-

sion: >97%. Colorless oil. Yield: 94%. ¹H NMR (300.13 MHz,

CDCl₃): δ 6.81 (dd, ³J_HH= 8.8 Hz, ⁴J_HH= 2.6 Hz, 2H, H5′), 7.12 (dd,

³J_HH= 8.8 Hz, ⁴J_HH= 2.6 Hz, 2H, H5), 6.92 (dd, ³J_HH= 8.8 Hz, ⁴J_HH

=

2.6 Hz, 2H, H6′), 6.81 (dd, ³J_HH= 8.8 Hz, ⁴J_HH= 2.6 Hz, 2H, H6), 6.04

(q, ³J_HH= 7.0 Hz, 1H, H2), 3.86 (s, 3H, H8′), 3.81 (s, 3H, H8), 1.77 (d,

³J_HH= 7.0 Hz, 3H, H3) ppm.

1-Methoxy-4-(2-dimethyl-1-propen-1-yl)-benzene (10j). Conver-

sion: >97%. Colorless oil. Yield: 95%. ¹H NMR (300.13 MHz, CDCl₃):

δ 7.19 (d, ³J_HH= 8.9 Hz, 2H, H6), 6.88 (d, ³J_HH= 8.9 Hz, 2H, H7), 6.25

(s, 1H, H1), 3.83 (s, 3H, H9), 1.92 (s, 3H, H3), 1.88 (s, 3H, H4) ppm.

(S)-1-Phenyl-2-hydrobenzo[c][1,2]azaphosphol-3-one 1-oxide,

(S)-11. The byproduct obtained from the oleﬁnation of 9k. The R_P

and S_Pisomers have been previously characterized.²³The conditions

used for chiral HPLC separation of the enantiomers were as follows:

Daicel Chiralcel OD−H-H column, hexane/i-PrOH = 7:3, ﬂow rate =

0.5 mL/min, t_R= 8.8 min (R_P), t_R= 14.6 min (S_P).

(1R,5S)-6,6-Dimethyl-2-(2-methylprop-1-enyl)bicyclo[3.1.1]hept-

2-ene (Dimethylnopadiene, 10k). Conversion: >97%. Colorless oil.

Yield: 95%. ¹H NMR (300.13 MHz, CDCl₃): δ 5.56 (m, 1H, H8), 5.38

(m, 1H, H3), 2.39 (dt, ⁴J_HH= 5.6 Hz, ²J_HH= 8.5 Hz, 1H, H7), 2.35 (m,

2H, H4), 2.21 (td, ³J_HH= ⁴J_HH= 5.6 Hz, ⁴J_HH= 1.6 Hz, 1H, H1), 2.10

(m, 1H, H5), 1.79 (bs, 3H, H10 or H11), 1.78 (bs, 3H, H10 or H11),

1.30 (s, 3H, H12 or H13), 1.22 (d, 1H, ³J_HH= 8.5 Hz, H7), 0.90 (s, 3H,

H12 or H13) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ 145.5 (C, C2),

132.7 (C, C9), 126.1 (CH, C8), 120.4 (CH, C3), 46.7 (CH, C1), 40.5

(CH, C5), 37.7 (C, C6), 31.7 (CH₂, C4), 31.5 (CH₂, C7), 26.7 (CH₃,

C10 or C11), 26.3 (CH₃, C12 or C13), 21.1 (CH₃, C12 or C13), 19.9

(CH₃, C10 or C11) ppm.

2-Methyl-1-phenyl-2-hydrobenzo[c][1,2]azaphosphol-3-one 1-

oxide (14). The byproduct obtained in the oleﬁnation of

oxaphosphetane 12c. Yield after precipitation from hexane: 99%.

1

Slightly yellow oil. IR (KBr): ν 1703, 1237 cm⁻¹. H NMR (300.13

MHz, CDCl₃): δ 8.11 (m, 1H, H5), 7.66−7.82 (m, 5H, H6, H7, H8,

R

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H11), 7.64 (m, 1H, H13), 7.52 (m, 2H, H12), 3.02 (d, ³J_PH7.3 Hz, 3H,

Notes

2

H14) ppm. ¹³C{¹H} NMR (75.47 MHz, CDCl₃): δ 166.3 (d, J_PC

=

The authors declare no competing ﬁnancial interest.

22.2 Hz, C3), 135.2 (d, ²J_PC= 8.6 Hz, C4), 133.6 (d, ³J_PC= 13.2 Hz,

C7), 133.4 (d, ⁴J_PC= 2.4 Hz, C6), 133.4 (d, ⁴J_PC= 3.1 Hz, C13), 132.2

(d, ²J_PC= 11.6 Hz, C11), 131.9 (d, ¹J_PC= 118.3 Hz, C9), 129.2 (d, ³J_PC

= 14.0 Hz, C12), 127.9 (d, ²J_PC= 10.2 Hz, C8), 126.6 (d, ¹J_PC= 129.8

Hz, C10), 124.9 (d, ³J_PC= 10.3 Hz, C5), 24.4 (d, ³J_PC= 3.8 Hz, C14)

ppm. ³¹P{¹H} NMR (121.50 MHz, CDCl₃): δ 26.92 ppm. HRMS

(ESI/TOF) m/z: [M + 1] calcd for C₁₄H₁₃NO₂P, 258.0684; found,

258.0675.

ACKNOWLEDGMENTS

■

́

Financial support by the Ministerio de Ciencia e Innovacion and

FEDER program (projects CTQ2008-117BQU, MAT2006-

01997, MAT2010-15094, PTA-2009-2346-I, and CSD2006-

́

015, Consolider Ingenio 2010, “Factorıa de Crystalizacion”) is

gratefully acknowledged.

REFERENCES

■

(1) Staudinger, H.; Meyer, J. Ueber neue organische Phosphorver-

bindungen III. Phosphinmethylenderivate und Phosphinimine. Helv.

Chim. Acta 1919, 2, 635−646.

(2) Wittig, G.; Geissler, G. Zur Reaktionsweise des Pentaphenyl-

phosphors und einiger Derivate. Liebigs Ann. Chem. 1953, 580, 44−57.

(3) (a) Kolodiazhnyi, O. I. Phosphorus Ylides: Chemistry and

Applications in Organic Chemistry; Wiley-VCH: New York, 1999.

General Procedure for the Determination of Rate Constants

of Oleﬁnation. The kinetics of the decomposition reaction was

monitored by ³¹P NMR. Samples were prepared by dissolving 10−40

mg of the appropriate spiro-1,2-oxaphosphetane 9/12c in 0.40−0.45

mL of DMSO-d₆and heated to 70−160 °C. Inverse-gated NMR

spectra (pulse width of 15°, relaxation delay of 7 s) were acquired at

speciﬁc time intervals (see tables in the Supporting Information).

Integration of the spectra aﬀorded the relative concentration of 9, 11,

and 14.

́

(b) Soto, A. P.; García-Alvarez, J. Phosphorus Ylides and Related

Compounds. In Organophosphorus Chemistry: From Molecules to

Applications; Iaroshenko, V., Ed.; Wiley-VCH: Weinheim, 2019; pp

113−162.

(4) For recent reviews, see: (a) Rocha, D. H. A.; Pinto, D. C. G. A.;

Silva, A. M. S. Applications of the Wittig Reaction on the Synthesis of

Natural and Natural- Analogue Heterocyclic Compounds. Eur. J. Org.

Chem. 2018, 2018, 2443−2457. (b) Karanam, P.; Reddy, G. M.; Lin, W.

Strategic Exploitation of the Wittig Reaction: Facile Synthesis of

Heteroaromatics and Multifunctional Olefins. Synlett 2018, 29, 2608−

2622. (c) Vik, A.; Hansen, T. V. Synthetic Manipulations of

Polyunsaturated Fatty Acids as a Convenient Strategy for the Synthesis

of Bioactive Compounds. Org. Biomol. Chem. 2018, 16, 9319−9333.

(d) Longwitz, L.; Werner, T. Recent Advances in Catalytic Wittig- type

Reactions Based on P(III) /P(V) Redox Cycling. Pure Appl. Chem.

2019, 91, 95−102. (e) Heravi, M. M.; Ghanbarian, M.; Zadsirjan, V.;

Alimadadi-Jani, B. Recent Advances in the Applications of Wittig

Reaction in the Total Synthesis of Natural Products Containing

Lactone, Pyrone, and Lactam as a Scaffold. Monatsh. Chem. 2019, 150,

1365−1407. (f) Eschliman, K.; Bossmann, S. H. Synthesis of

Isothiocyanates: An Update. Synthesis 2019, 51, 1746−1752.

(g) Zhang, K.; Lu, L.-Q.; Xiao, W.-J. Recent Advances in the Catalytic

Asymmetric Alkylation of Stabilized Phosphorous Ylides. Chem.

Commun. 2019, 55, 8716−8721.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c01270.

■

sı

Experimental and computational details, characterization

data of starting phosphazenes 7c and 7f and known

compounds 10 and 11, rate constants measured,

determination of ρ for compounds 9c,f,g,h, Cartesian

coordinates and energies of the stationary points located,

NBO charges of selected atoms and groups of atoms, and

crystallographic data for cis-9d, trans-9k, and 12a (PDF)

NMR spectra (PDF)

Crystal structure (CIF)

AUTHOR INFORMATION

■

(5) Byrne, P. A.; Gilheany, D. G. The Modern Interpretation of the

Wittig Reaction Mechanism. Chem. Soc. Rev. 2013, 42, 6670−6696.

(6) (a) Schlosser, M.; Schaub, B. Cis Selectivity of Salt-Free Wittig

Reactions: a ″Leeward Approach ″ of the Aldehyde at the Origin? J. Am.

Chem. Soc. 1982, 104, 5821−5823. (b) Vedejs, E.; Marth, C. F.

Mechanism of the Wittig Reaction: the Role of Substituents at

Phosphorus. J. Am. Chem. Soc. 1988, 110, 3948−3958. (c) Vedejs, E.;

Fleck, T. J. Kinetic (not Equilibrium) Factors are Dominant in Wittig

Reactions of Conjugated Ylides. J. Am. Chem. Soc. 1989, 111, 5861−

5871. (d) Robiette, R.; Richardson, J.; Aggarwal, V. K.; Harvey, J. N. On

the Origin of High E Selectivity in the Wittig Reaction of Stabilized

Ylides: Importance of Dipole −Dipole Interactions. J. Am. Chem. Soc.

2005, 127, 13468−13469.

Corresponding Author

́

Fernando Lopez Ortiz − Area de Quımica Organica, Centro de

́

Investigacion CIAIMBITAL, Universidad de Almerıa, 04120,

Spain; orcid.org/0000-0003-1786-0157;

Phone: +34950015478; Email: ﬂ ortiz@ual.es

Authors

́

Jesus García Lopez − Area de Quımica Organica, Centro de

́

Investigacion CIAIMBITAL, Universidad de Almerıa, 04120,

Spain

́

Pablo M. Sansores Peraza − Area de Quımica Organica, Centro

́

de Investigacion CIAIMBITAL, Universidad de Almerıa, 04120,

(7) (a) Vedejs, E.; Peterson, M. J. Stereochemistry and Mechanism in

the Wittig Reaction. Top. Stereochem. 1994, 21, 1−157. (b) Vedejs, E.;

Peterson, M. J. The Wittig Reaction: Stereoselectivity and a History of

Mechanistic Ideas (1953 −1995). Adv. Carbanion Chem. 1996, 2, 1−85.

Spain

́

María Jose Iglesias − Area de Quımica Organica, Centro de

́

Investigacion CIAIMBITAL, Universidad de Almerıa, 04120,

Spain

́

(8) Step̧ ien, M. Anomalous Stereoselectivity in the Wittig Reaction:

́

Laura Roces − Departamento de Quımica Fısica y Analıtica,

The Role of Steric Interactions. J. Org. Chem. 2013, 78, 9512−9516.

(9) Robiette, R.; Richardson, J.; Aggarwal, V. K.; Harvey, J. N.

Reactivity and Selectivity in the Wittig Reaction: A Computational

Study. J. Am. Chem. Soc. 2006, 128, 2394−2409.

Universidad de Oviedo-CINN, 33006 Oviedo, Spain; Servicios

́

Cientıﬁco Tecnicos, Universidad de Oviedo, 33006 Oviedo, Spain

́

Santiago García-Granda − Departamento de Quımica Fısica y

(10) (a) Reitz, A. B.; Mutter, M. S.; Maryanoff, B. E. Observation of

Cis and Trans Oxaphosphetanes in the Wittig Reaction by High-Field

Phosphorus-31 NMR Spectroscopy. J. Am. Chem. Soc. 1984, 106,

1873−1875. (b) Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Inners, R.

́

Analıtica, Universidad de Oviedo-CINN, 33006 Oviedo, Spain

Complete contact information is available at:

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

R.; Almond, H. R., Jr. Detailed Rate Studies on the Wittig Reaction of

Nonstabilized Phosphorus Ylides via Phosphorus-31, Proton, Carbon-

13 NMR Spectroscopy. Insight into Kinetic vs. Thermodynamic

Control of Stereochemistry. J. Am. Chem. Soc. 1985, 107, 1068−1070.

(c) Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Whittle, R. R.; Olofson,

R. A. Stereochemistry and Mechanism of the Wittig Reaction.

Diasteromeric Reaction Intermediates and Analysis of the Reaction

Course. J. Am. Chem. Soc. 1986, 108, 7664−7678.

4618−4622. (b) Perozzi, E. F.; Michalak, R. S.; Figuly, G. D.;

Stevenson, W. H., III; Dess, D. B.; Ross, M. R.; Martin, J. C. Directed

Dilithiation of Hexafluorocumyl Alcohol - Formation of a Reagent for

the Facile Introduction of a Stabilizing Bidentate Ligand in Compounds

of Hypervalent Sulfur (10-S-4), Phosphorus (10-P-5), Silicon (10-Si-

5), and Iodine (10-I-3). J. Org. Chem. 1981, 46, 1049−1053.

(22) (a) Kojima, S.; Sugino, M.; Matsukawa, S.; Nakamoto, M.; Akiba,

K.-Y. First Isolation and Characterization of an Anti-Apicophilic

Spirophosphorane Bearing an Oxaphosphetane Ring: A Model for the

Possible Reactive Intermediate in the Wittig Reaction. J. Am. Chem. Soc.

2002, 124, 7674−7675. (b) Uchiyama, Y.; Kano, N.; Kawashima, T.

Syntheses, Structures, and Thermolyses of Pentacoordinate 1,2-

Oxastibetanes: Potential Intermediates in the Reactions of Stibonium

Ylides with Carbonyl Compounds. J. Org. Chem. 2006, 71, 659−670.

(11) For recent examples, see: (a) Byrne, P. A.; Muldoon, J.; Ortin, Y.;

Muller-Bunz, H.; Gilheany, D. G. Investigations on the Operation of

̈

Stereochemical Drift in the Wittig Reaction by NMR and Variable-

Temperature NMR Spectroscopy of Oxaphosphetane Intermediates

and Their Quench Products. Eur. J. Org. Chem. 2014, 2014, 86−98.

(b) Uchiyama, Y.; Ohtsuki, T.; Murakami, R.; Shibata, M.; Sugimoto, J.

(E )-Selective Wittig Reactions between a Nonstabilized Phosphonium

Ylide Bearing a Phosphastibatriptycene Skeleton and Benzaldehydes.

Eur. J. Org. Chem. 2017, 2017, 159−174. (c) Uchiyama, Y.; Kuniya, S.;

Watanabe, R.; Ohtsuki, T. Heteroatom Effects toward Isomerization of

Intermediates in Wittig Reactions of Non-Stabilized Phosphonium

Ylides Bearing a Phosphaheteratriptycene Skeleton with Benzaldehyde.

Heteroat. Chem. 2018, 29, e21473. (d) Uchiyama, Y.; Kuniya, S.;

Watanabe, R.; Ohtsuki, T. Observation of Intermediates in Wittig

Reactions of Non- Stabilized Phosphonium Ylides Bearing a

Phosphaheteratriptycene Skeleton Containing Group 15 Elements

with Benzaldehyde. Phosphorus, Sulfur Silicon Relat. Elem. 2019, 194,

281−284.

́

(23) Garcıa Lopez, J.; Moran Ramallal, A.; Gonzalez, J.; Roces, L.;

́

a-Burgos, P.; Lopez Ortiz, F.

Garcıa-Granda, S.; Iglesias, M. J.; On

̃

Mechanisms of Stereomutation and Thermolysis of Spiro -1,2-

oxaphosphetanes: New Insights into the Second Step of the Wittig

Reaction. J. Am. Chem. Soc. 2012, 134, 19504−19507.

(24) Kawashima, T.; Kato, K.; Okazaki, R. Synthesis, Structure, and

Thermolysis of a 3-Methoxycarbonyl-1, 2 λ⁵-oxaphosphetane. Angew.

Chem., Int. Ed. Engl. 1993, 32, 869−870.

́

(25) García-Lopez, J.; Fernandez, I.; Serrano-Ruiz, M.; Lopez-Ortiz,

F. C_α,C_ortho-Dimetalated Phosphazene Complexes. Chem. Commun.

2007, 4674−4676.

(26) For recent computational work, see: (a) Jarwal, N.; Thankachan,

P. P. Theoretical Study of the Wittig Reaction of Cyclic Ketones with

Phosphorus Ylide. J. Mol. Model. 2015, 21, 87. (b) Ayub, K.; Ludwig, R.

Gas Hydrates Model for the Mechanistic Investigation of the Wittig

Reaction “on Water ”. RSC Adv. 2016, 6, 23448−23458. (c) Jarwal, N.;

Meena, J. S.; Thankachan, P. P. The E /Z Selectivity in Gas Phase Wittig

Reaction of Non-Stabilized, Semi-Stabilized and Stabilized Me₃P and

Ph₃P Phosphorus Ylides with Monocyclic Ketone: A Computational

Study. Comput. Theor. Chem. 2016, 1093, 29−39. (d) Firaha, D. S.;

Gibalova, A. V.; Holloczki, O. Basic Phosphonium Ionic Liquids as

Wittig Reagents. ACS Omega 2017, 2, 2901−2911. (e) Adda, A.;

Hadjadj-Aoul, R.; Lebsir, F.; Krallafa, A. M. Ab initio Static and

Metadynamics Investigations of the Wittig Reaction. Theor. Chem. Acc.

(12) Vedejs, E.; Snoble, K. A. J. Direct Observation of

Oxaphosphetanes from Typical Wittig Reactions. J. Am. Chem. Soc.

1973, 95, 5778−5780.

(13) (a) Vedejs, E.; Meier, G. P.; Snoble, K. A. J. Low-Temperature

Characterization of the Intermediates in the Wittig Reaction. J. Am.

Chem. Soc. 1981, 103, 2823−2831. (b) Vedejs, E.; Marth, C. F.

Mechanism of Wittig Reaction: Evidence against Betaine Intermedi-

ates. J. Am. Chem. Soc. 1990, 112, 3905−3909. (c) Vedejs, E.; Marth, C.

F.; Ruggeri, R. Substituent Effects and the Wittig Mechanism: the Case

of Stereospecific Oxaphosphetane Decomposition. J. Am. Chem. Soc.

1988, 110, 3940−3948.

́

(14) (a) Lopez-Ortiz, F.; Lopez, J.; Manzaneda, R.; Alvarez, I. Isolable

1,2-Oxaphosphetanes. From Curiosities to Starting Materials for the

Synthesis of Olefins. Mini-Rev. Org. Chem. 2004, 1, 65−70.

(b) Kolodiazhna, A. O.; Kolodiazhnyi, O. I. Synthesis, Properties and

Stereochemistry of 2- Halo- 1, 2 λ⁵- oxaphosphetanes. Molecules 2016,

21, 1371.

́

2018, 137, 94. (f) Farfan, P.; Gomez, S.; Restrepo, A. On the Origins of

Stereoselectivity in the Wittig Reaction. Chem. Phys. Lett. 2019, 728,

́

153−155. (g) Farfan, P.; Gomez, S.; Restrepo, A. Dissection of the

Mechanism of the Wittig Reaction. J. Org. Chem. 2019, 84, 14644−

14658.

(27) For recent calculations support this ﬁnding, see: (a) Kyri, A. W.;

Gleim, F.; García Alcaraz, A.; Schnakenburg, G.; Espinosa Ferao, A.;

Streubel, R. ‘‘Low-Coordinate ’’ 1,2-Oxaphosphetanes − a new

Opportunity in Coordination and Main Group Chemistry. Chem.

Commun. 2018, 54, 7123−7126. (b) Espinosa Ferao, A. On the

Mechanism of Trimethylphosphine-Mediated Reductive Dimerization

of Ketones. Inorg. Chem. 2018, 57, 8058−8064. (c) Chamorro, E.;

(15) Birum, G. H.; Matthews, C. N. Reactions of Triphenyl-2,2-

bis(trifluoromethyl)vinyl-idenephosphorane, Synthesized from a Cy-

clic Ylide-Ketone Adduct. J. Org. Chem. 1967, 32, 3554−3559.

(16) Ul-Haque, M.; Caughlan, C. N.; Ramirez, F.; Pilot, J. F.; Smith, C.

P. Crystal and Molecular Structure of a Four-Membered Cyclic

Oxyphosphorane with Pentavalent Phosphorus, PO₂(C₆H₅)₂(CF₃)₄-

C₃H₂. J. Am. Chem. Soc. 1971, 93, 5229−5235.

(17) Appel, M.; Blaurock, S.; Berger, S. A Wittig Reaction with 2-Furyl

Substituents at the Phosphorus Atom: Improved (Z) Selectivity and

Isolation of a Stable Oxaphosphetane Intermediate. Eur. J. Org. Chem.

2002, 2002, 1143−1148.

́ ́ ́

Duque-Norena, M.; Gutierrez-Sanchez, N.; Rincon, E.; Domingo, L. R.

̃

A Close Look to the Oxaphosphetane Formation along the Wittig

Reaction: A [2 + 2] Cycloaddition? J. Org. Chem. 2020, 85, 6675−6686.

(28) Vedejs, E.; Marth, C. F. Oxaphosphetane Pseudorotation: Rates

and Mechanistic Significance in the Wittig Reaction. J. Am. Chem. Soc.

1989, 111, 1519−1520.

(29) For assigning the absolute conﬁguration of a pentacoordinated

stereogenic center with a tbp geometry, see: Martin, J. C.; Balthazor, T.

M. Sulfuranes. 22. Stereochemical Course of an Associative Displace-

ment at Tetracoordinate Sulfur(IV) in a Sulfurane of Known Absolute

Configuration. A Proposed System of Nomenclature for Optically

Active Pentacoordinate Species. J. Am. Chem. Soc. 1977, 99, 152−162.

(30) Repeating three times the decomposition of 9a at temperatures of

120, 130, 140, and 160 °C aﬀorded k values with average deviations of 2,

1, 1, and 1%, respectively. Throughout this study, it was assumed that

the maximum error of the k obtained does not exceed 2%.

(18) Kawashima, T.; Kato, K.; Okazaki, R. A Novel Synthetic Route to

Isolable Pentacoordinate 1,2-Oxaphosphetanes and Mechanism of

their Thermolysis, the Second Step of the Wittig Reaction. J. Am. Chem.

Soc. 1992, 114, 4008−4010.

́

(19) García-Lopez, J.; Peralta-Perez, E.; Forcen-Acebal, A.; García-

́

Granda, S.; Lopez-Ortiz, F. Dilithiated Phosphazenes: Scaffolds for the

Synthesis of Olefins through a New Class of Bicyclic 1,2-

Oxaphosphetanes. Chem. Commun. 2003, 856−857.

́

(20) Dellus, N.; Kato, T.; Bagan, X.; Saffron-Merceron, N.;

Branchadell, V.; Baceiredo, A. An Isolable Mixed P,S-Bis(ylide) as an

Asymmetric Carbon Atom Source. Angew. Chem., Int. Ed. 2010, 49,

6798−6801.

(21) (a) Granoth, I.; Martin, J. C. Hydroxyphosphoranes and

Phosphoranoxide Anions - Synthesis, Reactivity, and Acidity of

Pentacoordinate Phosphorus acids. J. Am. Chem. Soc. 1979, 101,

(31) Further support to the appearance of a partial positive charge on

carbon C4 during oleﬁnation was obtained by negative ρ = −0.22 (r =

0.998) obtained from a Hammett plot for the decomposition of 9c,f,g,h

T

https://dx.doi.org/10.1021/acs.joc.0c01270

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

́

(Table 1, Figure S5). Hansch, C.; Leo, A.; Taft, R. W. A Survey of

Hammett Substituent Constants and Resonance and Field Parameters.

Chem. Rev. 1991, 91, 165−195.

(42) (a) Barluenga, J.; Ferrero, M.; Lopez, F.; Palacios, F. Reaction of

α -Metallated N -Acyl-λ⁵-phosphazenes with Aryl Cyanides. J. Chem.

́

Soc., Perkin Trans. 1 1989, 615−618. (b) Barluenga, J.; Lopez, F.;

Palacios, F. Reactions of N -Alkoxycarbonyl Alkyldiphenyl-λ⁵-phospha-

zenes with Acetylene Esters. Synthesis of 1-Aza-2-oxo-4 λ⁵-phosphi-

nines. J. Organomet. Chem. 1990, 382, 61−67.

(32) Berry, R. S. Correlation of Rates of Intramolecular Tunneling

Processes, with Application to Some Group V Compounds. J. Chem.

Phys. 1960, 32, 933−938.

́

(33) Couzijn, E. P. A.; Slootweg, J. C.; Ehlers, A. W.; Lammertsma, K.

Stereomutation of Pentavalent Compounds: Validating the Berry

Pseudorotation, Redressing Ugi ’s Turnstile Rotation, and Revealing the

Two- and Three-Arm Turnstiles. J. Am. Chem. Soc. 2010, 132, 18127−

18140.

(34) Alternatives exist for improving the accuracy of the results by

more extensive consideration of dispersive forces in the calculations.

(a) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for

Main Group Thermochemistry, Thermochemical Kinetics, Non-

covalent Interactions, Excited States, and Transition Elements: Two

New Functionals and Systematic Testing of Four M06-Class Func-

tionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215−

241. (b) Grimme, S. Density Functional Theory with London

Dispersion Corrections. Wiley Interdiscip. Rev.: Comput. Mol. Sci.

2011, 1, 211−228.

́

(43) Alvarez-Gutierrez, J. M.; Peralta-Perez, E.; Perez-Alvarez, I.;

Lopez-Ortiz, F. Reactions of Lithiated P-Diphenyl(alkyl)(N -

́

methoxycarbonyl)phosphazenes with Michael Acceptors and Alde-

hydes. Synthesis of 1 H -1,2-Azaphosphinin-6-ones, β -Hydroxy(N -

methoxycarbonyl)phos-phazenes and 5,6-Dihydro-1,3,4-oxazaphos-

phinin-2-ones. Tetrahedron 2001, 57, 3075−3086.

(44) Bernard, M.; St. Jacques, M. Etude par Resonance Magnetique

Nucleaire a Temperature Variable de Composes Apparentes au

Methylenecyclohexane. Can. J. Chem. 1970, 48, 3039−3044.

(45) Van der Linde, R.; Korver, O.; Korver, P. K.; van der Haak, P. J.;

Veenland, J. U.; de Boer, Th. J. Proton Magnetic Resonance Spectra of

Some 1,1-Diarylalkenes. Spectrochim. Acta 1965, 21, 1893−1898.

(46) Satoh, M.; Miyaura, N.; Suzuki, A. Stereo- and Regiospecific

Synthesis of Trisubstituted Alkenes via the Palladium-catalyzed Cross-

coupling Reaction of Diisopropyl (E )-(1-Alkyl-1-alkenyl)boronates

with Organic Halides. Chem. Lett. 1986, 15, 1329−1332.

(47) Glattfeld, J. W. E.; Milligan, C. H. The Preparation of Optically

Active Hydrazines. I. The Preparation of DL-p -Trimethylethyl-

phenylhydrazine. The Isolation of Pure D-p -Trimethylethyl-aniline. J.

Am. Chem. Soc. 1920, 42, 2322−2328.

(48) Boudier, A.; Darcel, C.; Flachsmann, F.; Micouin, L.; Oestreich,

M.; Knochel, P. Stereoselective Preparation and Reactions of

Configurationally Defined Dialkylzinc Compounds. Chem. - Eur. J.

2000, 6, 2748−2761.

(49) Rappoport, Z.; Gal, A. Vinylic Cations from Solvolysis. Part XIII.

S_N1 and Electrophilic Addition−Elimination Routes in the Solvolysis of

α -Bromo- and α -Chloro-4-methoxystyrenes. J. Chem. Soc., Perkin Trans.

2 1973, 301−310.

(50) Bosch, H. W.; Hung, H. U.; Nietlispach, D.; Salzer, A. General

Route to the Half-Open Ruthenium Metallocenes C₅Me₅Ru-

(pentadienyl) and C₅Me₅Ru(diene)Cl. X-ray Structures of an Optically

Active Half-Open Metallocene and of a Dimetallic Ruthenabenzene

Complex. Organometallics 1992, 11, 2087−2098.

(51) Danheiser, R. L.; Nowick, J. S. A Practical and Efficient Method

for the Synthesis of.beta.-Lactones. J. Org. Chem. 1991, 56, 1176−1185.

(52) Wolf, J.; Brandt, L.; Fries, A.; Werner, H. Rhodium-Catalyzed

Synthesis of Trisubstituted Olefins from Ethene Derivatives and

Diazoalkanes. Angew. Chem., Int. Ed. Engl. 1990, 29, 510−512.

(53) Hooft, R. W. W. COLLECT; Nonius BV: Delft, The Netherlands,

1998.

(35) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;

Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;

Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;

Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;

Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,

T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;

Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,

K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;

Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;

Millam, M. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo,

C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.

J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma,

K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;

̈

Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;

Cioslowski, J.; Fox, D. J. Gaussian 09, Revision B.01; Gaussian, Inc.:

Wallingford, CT, 2010.

(36) Jastrzebski, J. T. H.; Boersma, J.; Esch, P. M.; van Koten, G.

Intramolecular Penta- and Hexacoordlnate Tetraorganotin Com-

pounds Containing the 8-(Dimethylamino)-1-naphthyl Ligand. Orga-

nometallics 1991, 10, 930−935.

(37) (a) Mari, F.; Lahti, P. M.; McEwen, W. E. Molecular Modeling of

Oxaphosphetane Intermediates of Wittig Olefination Reactions.

Heteroat. Chem. 1990, 1, 255−259. (b) Yamataka, H.; Nagase, S.

Theoretical Calculations on the Wittig Reaction Revisited. J. Am. Chem.

Soc. 1998, 120, 7530−7536.

(38) Restrepo-Cossio, A. A.; Gonzalez, C. A.; Mari, F. Comparative ab

Initio Treatment (Hartree −Fock, Density Functional Theory, MP2,

and Quadratic Configuration Interactions) of the Cycloaddition of

Phosphorus Ylides with Formaldehyde in the Gas Phase. J. Phys. Chem.

A 1998, 102, 6993−7000.

(39) (a) Alagona, G.; Ghio, C. Stepwise versus Concerted

Mechanisms in the Wittig Reaction in Vacuo and in THF: The Case

of 2,4-Dimethyl-3-pyrrol-1-yl-pentanal and Triphenylphosphonium

Ylide. Theor. Chem. Acc. 2009, 123, 337−346. (b) Alagona, G.; Ghio,

C. Free Energy Landscapes in THF for the Wittig Reaction of

Acetaldehyde and Triphenylphosphonium Ylide. Int. J. Quantum Chem.

2010, 110, 2509−2521.

(40) 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.

(41) (a) Vollbrecht, S.; Vollbrecht, A.; Jeske, J.; Jones, P. G.;

Schmutzler, R.; du Mont, W.-W. Unusual Ring-Closure Reactions

During the Oxidation of 1,1 ′-Bi(3-methyl- phosphol-2-ene) with

Hexafluoroacetone - Formation of a Tricyclic Fluorine-Containing

Phosphorane. Chem. Ber. 1997, 130, 819−822. (b) Kobayashi, J.;

Kawashima, T. Chemistry of Pentacoordinated Anti-Apicophilic

Phosphorus Compounds. C. R. Chim. 2010, 13, 1249−1259.

(54) Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data

Collected in Oscillation Mode. Methods Enzymol. 1997, 276, 307−326.

(55) Area-Detector Software Package. SMART & SAINT; Bruker,

2007.

(56) Oxford Diﬀraction. CrysAlis CCD and CrysAlis RED; Oxford

Diﬀraction Ltd: Abingdon, England, 2006.

(57) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;

Burla, M. C.; Polidori, G.; Camalli, M. SIR92 - a Program for Automatic

Solution of Crystal Structures by Direct Methods. J. Appl. Crystallogr.

1994, 27, 435.

(58) Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.;

Cascarano, G. L.; De Caro, L.; Giacovazzo, C.; Polidori, G.; Spagna, R.

SIR2004: an Improved Tool for Crystal Structure Determination and

Refinement. J. Appl. Crystallogr. 2005, 38, 381−388.

(59) Beurskens, P. T.; Beurskens, G.; de Gelder, R.; García-Granda, S.;

Gould, R. O.; Smits, J. M. M. The DIRDIF-99 Program System;

Technical Report of the Crystallography Laboratory, University of

Nijmegen: The Netherlands, 2008.

(60) Parkin, S.; Moezzi, B.; Hope, H. XABS2: an Empirical

Absorption Correction Program. J. Appl. Crystallogr. 1995, 28, 53−56.

(61) Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr.,

Sect. A: Found. Crystallogr. 2008, 64, 112−122.

U

https://dx.doi.org/10.1021/acs.joc.0c01270

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(62) Farrugia, L. J. WinGX Suite for Small-Molecule Single-Crystal

Crystallography. J. Appl. Crystallogr. 1999, 32, 837−838.

(63) Allen, F. H.; Johnson, O.; Shields, G. P.; Smith, B. R.; Towler, M.

CIF Applications. XV. enCIFer: a Program for Viewing, Editing and

Visualizing CIFs. J. Appl. Crystallogr. 2004, 37, 335−338.

(64) (a) Spek, A. L. PLATON, An Integrated Tool for the Analysis of

the Results of a Single Crystal Structure Determination. Acta

Crystallogr. A 1990, 46, C34. (b) Spek, A. L. PLATON, A Multipurpose

Crystallographic Tool; Utrecht University: Utrecht, The Netherlands,

1998.

(65) Farrugia, L. J. ORTEP-3 for Windows - a Version of ORTEP-III

with a Graphical User Interface (GUI). J. Appl. Crystallogr. 1997, 30,

565.

(66) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F.

NBO, Version 3.1.

(67) (a) Rassolov, V. A.; Ratner, M. A.; Pople, J. A.; Redfern, P. C.;

Curtiss, L. A. 6-31G * Basis Set for Third-Row Atoms. J. Comput. Chem.

2001, 22, 976−984. (b) Zhao, Y.; Truhlar, D. G. A New Local Density

Functional for Main-Group Thermochemistry, Transition Metal

Bonding, Thermochemical Kinetics, and Noncovalent Interactions. J.

Chem. Phys. 2006, 125, 194101.

́

(68) (a) Gonzalez, C.; Schlegel, H. B. An Improved Algorithm for

Reaction Path Following. J. Chem. Phys. 1989, 90, 2154−2161.

́

(b) Gonzalez, C.; Schlegel, H. B. Reaction Path Following in Mass-

Weighted Internal Coordinates. J. Phys. Chem. 1990, 94, 5523−5527.

(69) The trans/cis descriptors indicate the relative orientation of the

methyl group and P-phenyl groups.

V

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Spiro[1,2]oxaphosphetanes of nonstabilized and semistabilized phosphorus ylide derivatives: Synthesis and kinetic and computational study of their thermolysis

DOI: 10.1021/acs.joc.0c01270

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