Cyclization of β-hydroxyalkylphosphine oxides - Mechanism elucidation using experimental and DFT methods

Article abstract of DOI:10.1016/j.tet.2016.12.008

β-Hydroxyalkylphosphine oxides undergo an intramolecular electrophilic cyclization reaction in strongly acidic media. The main product in cases where rearrangement of the starting β-carbocation is possible possesses the benzophosphorinane skeleton. To gain insight into the mechanism of this transformation, both experimental methods and DFT calculations have been used. The data show a clear dependence of the selectivity of the reaction on both the amount and the concentration of the acid. NMR experiments provided some insight into the transformation of the substrate whereas DFT calculations explain the preferential formation of benzophosphorinane skeleton.

Full text of DOI:10.1016/j.tet.2016.12.008

Accepted Manuscript
Cyclization of β-hydroxyalkylphosphine oxides - mechanism elucidation using
experimental and DFT methods
Katarzyna Włodarczyk, Piotr Borowski, Mateusz Drach, Marek Stankevič
PII:
S0040-4020(16)31276-5
10.1016/j.tet.2016.12.008
TET 28300
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 September 2016
Revised Date: 19 November 2016
Accepted Date: 6 December 2016
Please cite this article as: Włodarczyk K, Borowski P, Drach M, Stankevič M, Cyclization of β-
hydroxyalkylphosphine oxides - mechanism elucidation using experimental and DFT methods,
Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.008.
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ACCEPTED MANUSCRIPT
Me
unfavored
P
H
Me
O
P
OH
Me
O
P
O
Me
Ph
Me
Ph
Me
Me
Me
favored
P
O Me

ACCEPTED MANUSCRIPT
Cyclization of β-hydroxyalkylphosphine oxides - mechanism elucidation
using experimental and DFT methods
Katarzyna Włodarczyk,[a] Piotr Borowski,[b] Mateusz Drach[c] and Marek Stankevič[a]*
[a] Department of Organic Chemistry, Faculty of Chemistry, Marie Curie-Sklodowska University,
Gliniana 33, 20-614 Lublin, Poland
[b] Department of Chromatographic Methods, Faculty of Chemistry, Marie Curie-Sklodowska
University, Marie Curie-Sklodowska sq. 3, 20-031 Lublin, Poland
[c] Department of Theoretical Chemistry, Faculty of Chemistry, Marie Curie-Sklodowska University,
Marie Curie-Sklodowska sq. 3, 20-031 Lublin, Poland
* - Corresponding author. Tel.: +48 81 537-77-52; fax: +48 81 524-22-51;
email: marek.stankevic@poczta.umcs.lublin.pl
ABSTRACT
β-Hydroxyalkylphosphine oxides undergo an intramolecular electrophilic cyclization reaction in
strongly acidic media. The main product in cases where rearrangement of the starting β-carbocation is
possible possesses the benzophosphorinane skeleton. To gain insight into the mechanism of this
transformation, both experimental methods and DFT calculations have been used. The data show a
clear dependence of the selectivity of the reaction on both the amount and the concentration of the
acid. NMR experiments provided some insight into the transformation of the substrate whereas DFT
calculations explain the preferential formation of benzophosphorinane skeleton.
KEYWORDS
β-Hydroxyalkylphosphine oxides / Phosphoric acid / Cyclization / Mechanism / DFT
1. Introduction
The intramolecular electrophilic substitution reaction is an operationally simple method for the
synthesis of fused systems incorporating both aryl and cycloalkyl moieties.1 Depending on the
structure of the substrate different final structures including bicyclic,2 tricyclic,3 polycyclic4 or
spirocyclic5 compounds could be obtained. Compounds with functional groups in the carbon skeleton
may undergo cyclization to the corresponding fused systems with preservation of these
1

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functionalities.6 Some naturally occurring compounds have been synthesized using this reaction as one
of the steps (Figure 1).7
MeO
HO
OH
OH
H
Me Me
N
H
Me
Me
N
HO
O
O
H
H
HO
O
Me
O
4
1
2
3
OMe
Figure 1. Examples of compounds synthesized using intramolecular cationic cyclization.
In organophosphorus chemistry, this reaction has found little applications so far. Only a few
examples of intramolecular cyclization of alkenylphosphine oxides under acidic conditions or in the
presence of a Lewis acid have been presented in the literature.8 In this case, formation of either
phosphaindane or benzophosphorinane oxides has been observed and the outcome of the reaction was
dependent on the structure of alkenyl fragment. Apart from alkenylphosphine oxides, there are only
two mentions regarding the cyclization of other precursors, namely β-hydroxyalkylphosphine oxides,
under acidic conditions.9 There was a suggestion that cyclization of these compounds might proceed
either through preliminary dehydration to an alkene or through the direct formation of a carbocation
but no evidence has been given to support any of these theories. Regarding the utility of this reaction
as a tool in the formation of fused bicyclic systems it would be desirable to study in detail the
mechanism of this transformation, especially in the cases where the rearrangement of the tertiary
carbocation to the less stable secondary carbocation takes place prior to the cyclization step.
2. Results and discussion
In our previous paper,10 we have described the intramolecular cyclization of β-hydroxyalkylphosphine
oxides under acidic conditions (Scheme 1).
Me
Me
Me
Me
O
P
Me
OH
R'
Me
H3PO4
170 o
H3PO4
170 o
P
R
P
C
C
O
O Me
5b (R = Et, R' = Me)
5a (R, R' = Me)
6 (54%)
5
7 (74%)
Scheme 1. Cyclization of 5a and 5b under acidic conditions.
Depending on the used substrate, either phosphaindane oxide 7 or benzophosphorinanone oxide 6
could be obtained. The formation of 6 would require the prior rearrangement of the tertiary
carbocation, obtained by OH-group removal under acidic conditions from the starting 5, to the
corresponding secondary carbocation. In general, selectivity of the reaction was strongly shifted
towards the formation of fused 6,6-system (6) unless the primary carbocation had no possibilities to
undergo rearrangement due to, for example, the length of the alkyl substituent at the carbinolic atom
2

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like in 5a. So far, the factors governing cyclization are not clear and it was therefore decided to
perform more detailed studies to gain an insight into the mechanism of this reaction.
For test reactions, diastereomeric mixture of phenylmethyl(2-hydroxy-3-methylbutyl)-phosphine
oxide 8 has been used as a model compound. We have already established that this product undergoes
predominant cyclization towards benzophosphorinane.10 What is more important, the product contains
only one stereogenic center at the phosphorus atom which simplifies the analysis of the reaction
mixture. At first, the correlation between the concentration of phosphoric acid and the selectivity of
the reaction was verified (Scheme 2, Table 1).
Me
Me Me
O
P
Me
Me
Me
+
+
Me
P
P
O
P
Me
OH
O
9
Me
O Me
6
H3PO4
Me
10
170 oC, 21 h
Me
i-Pr
O
P
Me
OH
Me
8
P
Me
Me
O
11
12
Scheme 2. Influence of the concentration of phosphoric acid on the cyclization of 8.
Table 1. Influence of the concentration of phosphoric acid on the cyclization of 8.
Products (%)b,c
H3PO4
Entry
concentrationa
9
6
10/11/12
1
2
3
4
5
6
7
99%
85%
73%
64%
57%
52%
35%
67
28
17 (12)
10 (6)
8 (8)
-/3/-
-/-/-
83 (68)
90 (68)
92 (85)
92 (90)
2
-/-/-
-/-/-
8 (8)
-/-/-
-
3/-/27
No reaction
[a] 85% (H3PO4xH2O); 73% (H3PO4x2H2O); 64% (H3PO4x3H2O); 57% (H3PO4x4H2O); 52% (H3PO4x5H2O); 35% (H3PO4x10H2O).
[b] Conversion based on 31P NMR analysis. [c] In brackets, isolated yields are given.
For these reactions, a huge excess of phosphoric acid has been used in order to assure the high
concentration of H+ ions, i.e., phosphoric acid has been used as a solvent with a specific dielectric
constant. Concentration of phosphoric acid used in the cyclization reaction has been adjusted to a
formal hydratation level of H3PO4 molecule. To achieve the high selectivity of the reaction towards
cyclization, high temperature must be applied, otherwise dehydratation is the major reaction.10 Thus,
3

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the use of anhydrous phosphoric acid led to the formation of 9 as the major compound accompanied
by some isomeric product 6. The latter compound is formed from the isomeric secondary carbocation
obtained by methyl group shift in the parent carbocation. The amount of this product depended
strongly on the concentration of phosphoric acid. The use of aqueous phosphoric acid led to a decrease
in the amount of this product down to 8% in 64% H3PO4. On the other hand, the formation of 9
increased with the decrease of H3PO4 concentration and varied at 80-90% level in a wide
concentration range (57-85% H3PO4). The use of 52% H3PO4 (H3PO4x5H2O) led to a dramatic drop in
the conversion towards 9 (Table I, Entry 6). In this reaction, the main product was 12, the OH-group
migration product along with many other unidentified species and unreacted substrate which was the
main component of the mixture. Formation of this compound must involve dehydration of 8, cation
rearrangement followed by its reaction with water instead of cyclization.
According to the data presented above, cyclization of compound 8 towards 9 effectively proceeds
at relatively high H3PO4 concentrations. This might cause problems during a work-up of the reaction
mixture, especially when the whole amount of acid has to be neutralized. It was assumed that the use
of stronger acid could result in a more effective transformation of the substrate, and therefore, allow a
decrease in the amount of acid used. It was decided therefore to perform a set of the reactions in
H2SO4 and compare the results with those obtained using phosphoric acid (Scheme 3).
O
P
Me
OH
Me
Me Me
H2SO4
Me
Me
+
170 oC, 21 h
Me
P
P
O Me
9
O Me
6
8
84% H2SO4 (x H2O)
73% H2SO4 (x 2H2O)
64% H2SO4 (x 3H2O)
58% H2SO4 (x 4H2O)
52% H2SO4 (x 5H2O)
Complex mixture
97% (10%)
93% (33%)
92% (65%)
91% (65%)
3% (1%)
7% (2%)
8% (6%)
9% (7%)
In brackets, yields of the products are given.
Scheme 3. Cyclization of 8 in H2SO4.
The concentration of sulfuric acid has been adjusted to the hydration level, similarly to
phosphoric acid. Attempted cyclization in 84% H2SO4 (H2SO4-H2O) led to the formation of a complex
reaction mixture whereas dilution of sulfuric acid with water resulted in a dramatic increase of the
reaction selectivity towards the cyclization pathway. It is possible that under strongly acidic conditions
the substrate undergoes extensive decomposition in the presence of sulfuric acid which is not the case
for more diluted solutions. The higher activity of sulfuric acid is evident when comparing the
cyclization of 8 in media with lower acid concentration. With 52% H3PO4, the conversion of 8 towards
9 was only 2% whereas in 52% H2SO4 it still reached 100%.
In another set of reactions, compound 8 has been treated with an equimolar amount of phosphoric
acid but at different concentrations (Scheme 4, Table 2).
4

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O
P
Me
OH
Me Me
O
O
P
H3PO4 (1.0)
170 oC, 21 h
Me
P
Me
Me
Me
Me
+
+
Me
Me
Me
P
O
Me
8
9
10
13
Scheme 4. Attempted cyclization with equimolar amount of H3PO4 at different concentrations.
Table 2. Attempted cyclization with equimolar amount of H3PO4 at different concentrations.
Productsb
H3PO4
Entry
concentrationa
9
10
13
1
2
3
4
5
6
7
99%
85%
73%
64%
57%
52%
35%
-
58%
74%
58%
51%
67%
75%
61%
5%
7%
6%
4%
5%
5%
4%
1%
1%
3%
1%
-
-
[a] 85% (H3PO4xH2O); 73% (H3PO4x2H2O); 64% (H3PO4x3H2O); 57% (H3PO4x4H2O); 52% (H3PO4x5H2O); 35% (H3PO4x10H2O).
[b] Conversion based on 31P NMR analysis.
The most striking observation was the formation of β,γ-alkenylphosphine oxide 10 as the main
and α,β-alkenylphosphine oxide 13 as the minor reaction products. The formation of
benzophosphorinanone oxide 9 is extremely strongly inhibited, irrespectively of the concentration of
the used phosphoric acid. It appeared that the selectivity of this reaction is dependent on the amount of
acid and can be shifted from dehydration to cyclization.
Therefore, it was decided to find out the relation between the amount of an acid and the
selectivity of the reaction (Scheme 5, Table 3). The data collected in Table 3 show a clear correlation
between the reactivity of substrate and the amount of acid used. With 0.5 equiv. of 85% H3PO4 the
only products were alkenylphosphine oxides 10 and 13 (Table 3, Entry 1). However, with 2 equiv. of
acid the formation of reasonable amounts of cyclization product 9 has been observed although the
selectivity was low due to the formation of side products (see also Supporting Information). A detailed
analysis of this mixture using 31P NMR technique suggested that some signals might correspond to the
isomeric products with shifted OH-group.
5

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Me
Me Me
O
P
Me
Me
Me
+
+
Me
P
P
O
P
Me
OH
O
9
Me
O Me
6
H3PO4 (85%)
170 oC, 21 h
Me
10
Me
i-Pr
O
P
Me
Me
Me
8
+
P
Me
O
11
13
Scheme 5. Influence of the amount of acid on the selectivity of the reaction.
Table 3. Influence of the amount of acid on the selectivity of the reaction.
Products (%)a
Entry
Acid (equiv.)
9
6
-
10
52
74
22
-
11
-
13
48
7
1
-
1
2
3
4
5
6
7
8
9
0.5
1
-
1
-
-
2
20
67
64
64
77
82
85
3
-
3
20
13
15
17
17
14
1
1
8
6
1
1
4
-
-
5
-
-
10
20
50
-
-
-
-
-
-
[a] Conversions based on NMR analysis.
Selectivity of the tested reaction appeared to increase with the increase of the amount of
phosphoric acid. The use of 5 equiv. of H3PO4 was found to be enough for the selective cyclization
and only trace amounts of other products were observed in the reaction mixture. Further increase of
the amount of acid still increased the selectivity towards cyclic products but to a much lesser degree.
The experiments conducted so far were mostly directed towards the optimization of the reaction
conditions in order to achieve the best selectivity towards bicyclic product. For organophosphorus
31
compounds, P NMR spectroscopy is an ideal tool to follow the reaction course but in this case this
method is completely useless due to the presence of a large excess of phosphoric acid in the mixture.
Luckily, sulfuric acid appeared to be a good substitute to phosphoric acid. Therefore, cyclization of 8
in 52% sulfuric acid has been followed by 31P NMR. The mixture was heated for a specified time, then
cooled to rt and analyzed by NMR technique. The outcome is presented in Figure 2.
6

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Figure 2. Conversion of 8 with time followed by 31P NMR.
7

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First, NMR analysis of the solution of 8 in 52% H2SO4 has been performed, which revealed the
presence of two peaks at 71.16 ppm and 70.87 ppm, respectively, corresponding most probably to both
o
diastereomers of protonated 8. Analysis of the reaction mixture heated at 170 C for 10 min showed
the excessive transformation of the substrate. 31P NMR spectra pointed out the presence of only traces
of substrate, whereas the main single peak appeared at 72.27 ppm. The other peaks were at 96.68,
69.61, 68.51, 68.06 and 61.89 ppm, respectively. Heating the mixture for a longer time revealed
further changes. The low intensity peak I at 96.68 ppm decreased slowly and disappeared completely
after 4 h. The peak II at 72.27 ppm appeared as major product after heating for 10 min, decreased
slowly and disappeared after 12 h. Peaks III and IV at 69.61 and 68.51 ppm, respectively, appeared
after heating the tube for 10 min and decreased slowly during 12 h. Peak V at 68.06 ppm appeared
after heating the mixture for 10 min, became the major after 30 min of heating and almost vanished
after 12 h. Finally, very low intensity peak VI at 61.89 ppm appeared after 10 min of heating. Upon
further heating, this peak became almost the sole one after 12 h.
At this moment it was clear that the transformation of 8 under acidic conditions proceeds with the
formation of several intermediate compounds of yet unknown structure. It was assumed that the
intermediate compounds might be alkenylphosphine oxides 10 and 13 or isomerized
hydroxyalkylphosphine oxide 12. Each of them has been prepared independently (Scheme 6) and then
mixed with 52% H2SO4 (Figure 3).
O
P
Me
OH
O
P
Me
O
P
Me
MsCl (1.5)
NEt3 (20.0)
Toluene, 110 o
overnight
Me
Me
Me
Me
Me
+
C
Me
8
13 (21%)
10 (48%)
O
P
Me
O
P
Me
Me
Me
Me
Me
52% H2SO4
25 oC, 4 h
OH
10
12 (63%)
Scheme 6. Synthesis of 10,12 and 13.
8

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Figure 3. 31P NMR shifts of 8, 9, 10, 12 and 13 in 52% H2SO4.
31P NMR analysis of 12 in sulfuric acid revealed the presence of two peaks. The first at 72.15
ppm corresponds to the protonated 12 whereas the peak at 95.72 ppm is most probably the cyclic
oxaphospholanium cation, which is in accordance with literature data.11 NMR analysis of
alkenylphosphine oxide 10 in 52% H2SO4 revealed the presence of three peaks, at 95.71, 72.11 and
69.42 ppm, respectively. Peaks at 95.71 ppm and 72.11 ppm correspond to cyclic oxaphospholanium
cation and protonated γ-hydroxyalkylphosphine oxide 12, respectively, and the last peak must
therefore correspond to the protonated alkenylphosphine oxide 10. It became clear from these spectra
that phosphine oxide 10 exhibits high reactivity under acidic conditions and quickly undergoes formal
water addition, most probably through the intermediate oxaphospholanium cation. 31P NMR analysis
9

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of alkenylphosphine oxide 13 in 52% H2SO4 revealed the presence of only one peak at 59.36 ppm
whereas benzophosphorinane oxide 9 mixed with sulfuric acid afforded only one peak at 61.64 ppm.
31P NMR shifts of potential intermediates shown in Figure 3 enable preliminary mechanism for
the transformation of 8 into 9 to be proposed. It seems that the first step is the formal OH-group
migration. Regarding the presence of oxaphospholanium cation I in the mixture, this process is most
likely to proceed through H+-catalyzed intramolecular oxygen addition to C=C bond by phosphoryl
oxygen as internal nucleophile and subsequent hydrolysis of oxaphospholanium cation. The second
step is most probably protonation of the isomerized γ-hydroxyalkylphosphine oxide 12 (peak II)
which in turn might undergo either water elimination and formation of alkenylphosphine oxide 10
(peak III) or cyclization to fused system 9 (peak VI). The presence of small amounts of
alkenylphosphine oxide 10 (peak III) in the reaction mixture reflects its instability under the acidic
conditions shown above. Peaks IV and V at 68.49 and 68.06 ppm, respectively, must therefore belong
to the unknown intermediates. It is evident, however, that they undergo transformation into the final
bicyclic products as can be judged from 31P NMR analysis.
Experimental data collected so far give some ideas about the mechanism of this reaction but some
questions could not be answered solely using experimental techniques. It was therefore decided to
apply computational methods to the analyzed reaction. First, the choice of the model substrate should
be considered. The use of oxide 8 would not be the best option as in this case the formation of
phosphaindane skeleton is a priori excluded. It was therefore decided to use phosphine oxide 5b for
DFT calculations as in this case the selectivity of the formation of either phosphaindane or
benzophosphorinane oxides could be discussed. In the case of 5b four isomers should be considered
due to the presence of two stereogenic centers in the molecule. However, it was decided to use only
the diastereomer possessing RP configuration at phosphorus through all simulation steps for practical
reasons.
Our main results were obtained with the aid of the density functional theory (DFT) approach.12 In
all reported cases the B3LYP hybrid functional13 in conjunction with the polarized valence triple zeta
(VDZP) basis set 6-311++G**14 was used. B3LYP is known to predict very accurate molecular
geometries and energetics; in fact, it is one of the most accurate functionals and definitely the most
frequently used at present. Due to the fact that some of the investigated systems were transition states,
in which distances between the fragments of interest were of the order of 2Å, the additional inclusion
of the diffuse functions (++) is desirable. The calculations were carried out using the PQS quantum
chemistry package.15 Default geometry convergence criteria were adopted. However, thresholds for
the integral prescreening in the SCF, gradient and hessian routines were preset to be two orders of
magnitude lower than the default values. As the reactions are carried out in solution the solvent effect
should have, in principle, been modeled. However, the intermolecular interactions in strongly acidic
conditions are mostly of the hydrogen bonding type (the so-called specific interactions) and therefore
the most commonly used conductor-like screening model (COSMO)16 cannot be reliably applied.
10

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Therefore, whenever necessary, those specific interactions were accounted for by attaching/detaching,
e.g., H3O+ to the relevant molecule/intermediate (the so-called explicit solvation model, ESM).
Besides, we did some tests using COSMO model with the dielectric constant characteristic of the
solvent. The relative energies and energy barriers were affected to minor extent, insignificant for the
final conclusions.
The geometry optimization for all the systems considered in this work followed by the frequency
calculations were performed. Type of the obtained stationary point was determined based on the
analysis of the vibrational frequencies. In the case of minima all computed frequencies were real. On
the other hand one imaginary frequency was obtained in the case of each transition state. Visual
inspection of the corresponding eigenmode allowed us to recognize species on each side of a transition
state. The obtained energies were then used to calculate energy changes and barriers. All the reported
energies were corrected for the zero point vibrational energies (ZPVE). In the case of the
rearrangement (e.g., alkyl or hydride migration) or cyclization processes which are the most important
steps in the overall mechanism ZPVE is usually (well) below 1 kcal/mol and therefore it is not
essential in our considerations. In the case of processes accompanied by the change of a number of
vibrational degrees of freedom (e.g., water association/dissociation) it was often found to be as large
as ca. 2 kcal/mol. Therefore the overall discussion will be based on the ZPE-corrected values.
It was clear, that cyclization must occur through the formation of the intermediate tertiary
carbocation from the parent 5b. The protonation mechanism of 5b has been considered which led to
the conclusion that the initial H3O+ attack occurs rather at phosphoryl oxygen and the obtained cation
might undergo either water molecule removal affording cation 14 or addition of another H+ species
leading to the corresponding dication (see Figure 3 (species IV-VI) in Supporting Information).
Figure 4. Possible transformations of 14 according to DFT calculations. Values next to the vertical
lines refer to energy differences (in kcal/mol). (*) ZPVE-uncorrected value.
11

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The calculations performed for the cation 14 revealed the presence of several stable conformers.
Therefore further calculations were run starting from the most stable one, as depicted in Figure 4, with
torsion angle between cationic carbon atom and phosphoryl oxygen being -43o, i.e., the cationic
carbon atom is placed inbetween oxygen and phenyl. Its conversion into one of the diastereomeric
bicyclic cyclization products 20 (with the ipso hydrogen atom and phosphoryl oxygen in cis
arrangement) could be achieved through the transition state 19 which is 24.7 kcal/mol above than the
parent cation. Structural change in the parent carbocation 14 approaching the transition state 19 is
associated with change of the torsion angle between phenyl group and cationic carbon atom, i.e., this
carbon atom should reorient towards one of the ortho positions in phenyl substituent.
The structure of the transition state 19 obtained by molecular modeling is close to the structure of
the cyclic product 20 which suggests a quite small difference in the stability of these two species.
Indeed, the gain of energy passing from the transition state to 20 is only 0.3 kcal/mol. Overall, the
cyclization process appears to be endodermic – 20 is less stable than the parent tertiary carbocation by
ca. 24.4 kcal/mol. It should be pointed out, that the cyclization of 14 depicted in Figure 4 represents
only the most obvious possibility due to the proximity of the reacting centers. Also, reaction between
cationic carbon atom and distant ortho position should be considered once 14 undergoes a slight
conformational change (change of the C+-C-P-O torsion angle). This leads to a different transition
state with ipso hydrogen and phosphoryl oxygen being in trans arrangement (figure not shown). It
appeared that the activation energy needed to reach an alternative transition state is lower than that
depicted in Figure 4 (23.8 kcal/mol) along with the higher energy gain after the formation of internal
carbon-carbon bond (3.1 kcal/mol).
Attempted calculations of the benzophosphorinanone pathway led to quite interesting results
(Figure 4). Despite numerous attempts, only one stable secondary carbocation has been found, about
19 kcal/mol less stable than the parent 14 (not shown). Unfortunately, it was not possible to find the
appropriate transition state for the cation rearrangement. Instead, hydride migration seems to induce
the formation of pentacyclic oxaphospholanium cation 18 through the transition state 17. Further
transformation of these species would probably lead to the formation of isomeric γ-
hydroxyalkylphosphine oxide after a reaction with water. This process, by the way, might be
responsible for the formation of alcohol 12 in the reaction of 8 with 52% H3PO4 or even isomeric
alcohols observed in our previous work.10
The energy needed to reach the transition state 17 from 14 was found to be 14.7 kcal/mol which is
10 kcal/mol less than the energy needed to reach the transition state 19. Moreover, energy released by
passing from 17 to 18 was far higher (37.3 kcal/mol) than the energy released in the formation of
cyclization product 20 (0.3 kcal/mol). Regarding that, it is unlikely for cation 14 to undergo
cyclization towards bicyclic benzophosphorinanone and phosphaindane frameworks.
The structural analysis of cation 14 also revealed that there might be a quite easy proton shift
between the γ carbon atom and phosphoryl oxygen (Figure 4). A search for the transition state
12

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revealed that there is only slight rise in energy between 14 and transition state 15 (1.5 kcal/mol). This
value, however, is uncorrected for ZPVE as the attempted correction of the energy led to the transition
state slightly lower in energy than the starting 14. Such a result is a consequence of the approximate
character of the calculations which lead to inaccuracies in the calculated uncorrected relative energies.
In particular, the order of species may be altered upon adding ZPVE for small activation energies.
The transformation of cation 14 through the transition state 15 leads to protonated
alkenylphosphine oxide 16 with release of energy (19.8 kcal/mol). Overall, the formed product is 18.3
kcal/mol more stable than the parent 14. Due to a low activation barrier this pathway seems to be
kinetically favorable for the transformation of β-hydroxyalkylphosphine oxide 8 in the presence of
small amounts of acid. This was actually observed in the case where a stoichiometric amount of acid
has been used (see Table 2). It was therefore interesting to find, whether 16 might be reactivated for
the cyclization reaction (Figure 5).
Figure 5. Protonation of 16. Values next to the vertical lines refer to energy differences (in kcal/mol).
Two potential H3O+ approaches to 16 should be considered. The first is the attack of H3O+ at the
phosphoryl oxygen with the consecutive proton shift from oxygen to the γ carbon atom or the direct
attack of H3O+ cation on C=C bond. Both approaches have been considered and the first one appeared
to be slightly more favorable (by 1.5 kcal/mol). This reaction proceeds through the transition state 21
and is quite energy-consuming (36.2 kcal/mol). The transformation of 21 into the tertiary carbocation
22 appears to proceed with a slight stabilization of the molecule (12.7 kcal/mol). The possible
transformation of these species could involve H3O+ dissociation which should lead to the formation of
14 or dissociation of H2O molecule which would afford dication 23 (23.2 kcal/mol less stable than 22).
As follows from DFT calculations the cation 14, the most obvious candidate for cyclization,
undergoes rather C=C or C-O bond formation instead of cyclization. Therefore, it must be the dication
23 that follows the pathway leading to cyclic products. It is essential to use at least two equivalents of
acid to ensure the presence of an appropriate amount of H3O+ species which should lead to the
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ACCEPTED MANUSCRIPT
dication. It is also clear now, that the use of an equimolar amount of acid inevitably leads to the
formation of elimination products as there is simply not enough acid to form the dication in a
reasonable timescale, all the more that the formation of 23 is a non-favorable process compared to the
formation of 14. The calculations show also, that the formation of alkenylphosphine oxides like 16
might be the first process in the cyclization pathway. This process competes with the formation of
cyclic oxaphosphonium species 18, which probably leads to the formation of isomeric γ-
hydroxyalkylphosphine oxides. The formation of the latter has been observed for some β-
hydroxyalkylphosphine oxides.10
Once it became clear that dication 23 is the crucial intermediate in the cyclization pathway,
further DFT calculations have been directed towards elucidation of the cyclization mechanism. When
considering the cyclization of the dication 23 it appears clear that, in fact, four transition states and
four intermediate cyclic carbocations should be considered. This is the consequence of the two ortho
positions present in phenyl substituent (Figure 6).
Figure 6. Cyclization of 23 and rot-23 optimized by DFT calculations. Values next to the vertical lines
refer to energy differences (in kcal/mol).
For dication 23, it is possible to imagine the reaction between the cationic carbon atom and either
the proximal or distant ortho carbon atom. In the first case, the formation of cyclic cation 25a with syn
arrangement of ipso hydrogen and phosphoryl oxygen, whereas in the second – 25b with anti
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ACCEPTED MANUSCRIPT
arrangement should be expected (Figure 6). These two structures differ only in the absolute
configuration at the former ipso carbon atom and, therefore, both will collapse into the same product
upon rearomatization step. The same situation should appear for dication rot-23: two cyclic structures,
27a and 27b should be formed through transition states 26a and 26b, respectively. For all possible
transition states the activation energy varies from 15.8 kcal/mol for 26b to 17.5 kcal/mol for 26a, i.e.,
there are only slight differences in energy barriers in the formation of phosphaindane core. Similarly,
the energy gained during the formation of carbon-carbon bond lies in the range 2.6-3.0 kcal/mol.
Structures of the obtained transition states and cyclic dications are similar which explains the minor
energy release when passing from the transition state to the product.
Cyclization pathway analysis shows that the configuration of the newly formed chirality centre at
the β carbon atom depends on the mutual arrangement of ortho carbon atom and tertiary cation.
Depending on the face of carbocation approaching to the ortho carbon atom, either R or S
configuration at the β carbon atom is possible. It is seen in Figure 6 that both approaches are equally
probable. Moreover, the calculated energy scan with respect to the rotation around the Cα-Cβ bond in
the carbocation revealed only small rotational energy barrier (3.4 kcal/mol) (see Supporting Material)
which suggests that there are no virtual restrictions for the mutual interconversion of both conformers.
The rearomatization mechanism with two possible pathways has also been studied (see
Supporting Information). In the first approach, the rearomatization of the indane fragment was
supposed to proceed first whereas in the second – the proton removal from phosphoryl oxygen was the
first step. The DFT calculations strongly supports the mechanism where the rearomatization is the first
process.
The experimental data obtained so far show a great selectivity in the formation of the
benzophosphorinane systems, whenever the isomerization of the parent carbocation is possible. It was
therefore decided to calculate cyclization of carbocation rot-23 as a model intermediate towards fused
6,6 systems (Figure 7). The same analysis should be performed for dication 23 but it seems reasonable
to conclude that the energy profile for transformation of this dication should be very similar and,
therefore, DFT calculations were limited only to rot-23.
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Figure 7. Cyclization of rot-23 towards benzophosphorinane core optimized by DFT calculations.
Values next to the vertical lines refer to energy differences (in kcal/mol). (*) ZPVE-uncorrected value.
Cyclization of rot-23 towards bicyclic benzophosphorinane core must include preliminary
rearrangement of a tertiary carbocation to the corresponding secondary carbocation. Migration of
hydride from the γ to β carbon atom will induce the formation of a new chirality centre at the β carbon
atom. Due to the flat structure of the carbocation the absolute configuration of the newly formed
chirality centre will depend only on the side of hydride migration. Moreover, the presence of two
hydrogen atoms at γ carbon atom gives a possibility for different arrangement of two methyl groups
during the rearrangement step.
It was therefore decided to investigate the rearrangement of rot-23 into the secondary carbocation
by hydride migration from the side syn to the phenyl group (Figure 7) which should lead to a new
chirality centre at the β carbon atom with R configuration. Due to the presence of two γ hydrogen
atoms two transition states 28 and 32 have been found which lead to the corresponding secondary
carbocations 29 and 33, respectively. Activation energies needed to achieve transition states were
found to be 7.2 kcal/mol and 6.3 kcal/mol, respectively. Interestingly, the activation energy for
hydride transfer is lower for cis orientation of two methyl groups than for trans orientation although
the energy release when passing from 28/32 to 29/33 is higher for trans oriented carbocation (2.3
kcal/mol vs. 0.8 kcal/mol).
Carbocations 29 and 33 are formally rotamers with only slightly different energies which might
suggest rather fluent mutual interconversion of these species through rotation about Cβ-Cγ bond.
Cyclization of these conformers leads to the formation of two different products 31 and 35 through
transition states 30 and 34, respectively, with either S (for 31) or R (for 35) configuration at the γ
carbon atom. Analogously to cyclization of 23 and rot-23 to phosphaindane core, an additional
chirality centre at ipso carbon atom is formed which, in consequence, increases the number of the
possible cyclic products. Since these chirality centers disappear during the rearomatization step, it was
decided to omit the DFT calculations for these additional structures.
Regarding the favorable arrangement of the secondary carbocations 29 and 33, their cyclization into
benzophosphorinane skeleton requires far less energy for the activation compared to the energy
16

ACCEPTED MANUSCRIPT
consumed in the cyclization towards phosphaindane. Thus, transition of the dication 29 to 31 requires
only 4.1 kcal/mol to reach the transition state 30 which then collapses into 31 with but with only slight
stabilization (1 kcal/mol). For transition of 33 to 35 these values are 3.7 kcal/mol and 0.5 kcal/mol,
respectively. The values obtained for cyclization of the secondary carbocations suggest a very good
steric adjustment of these species which facilitates cyclization step. The activation energy is most
probably needed for slight conformational change of 29/33 to assure good overlapping of the orbitals.
In the next step, DFT calculations for hydride transfer in rot-23 from the side anti to the phenyl
group have been performed (Figure 7). This hydride shift should lead to formation of a new chirality
centre at the β carbon atom with S configuration. Attempted calculations on cationic rearrangement led
to only one intermediate 37 through a transition state 36 where two methyl groups were cis-arranged.
Activation energy for this process was similar to the other two found previously (6.7 kcal/mol)
whereas the stabilization energy was found to be only 0.5 kcal/mol. The latter value was not corrected
for ZPVE for the reasons explained above. Cyclization of 37 is easily achieved with activation energy
similar to the formation of 31 and 35 (3.3 kcal/mol).
The secondary cationic conformer analogous to 37 with trans arrangement of methyl groups
could not be obtained starting from rot-23 by a direct hydride transfer. Another possibility to obtain
cation 41 is the rotation of CH3-CH group around Cβ-Cγ bond starting from 37 (Figure 7). This process
appears to proceed through transition state 40 with an activation energy equal 4.5 kcal/mol and the
conformer appeared to be slightly less stable than 37 (by 2.9 kcal/mol). Cyclization of 41 proceeds
with very low activation energy (0.9 kcal/mol) and the cyclic product appeared to be more stable than
the starting secondary cation.
An interesting conclusion can be drawn when comparing activation energies for cyclization of
23/rot-23 towards phosphaindane core 25a,b and 27a,b and cyclization towards benzophosphorinane
core 31, 35, 39 and 43. The activation energies for cyclization towards 25a,b and 27a,b (15.8-17.5
kcal/mol) are higher than the sum of energies needed to activate rearrangement-cyclization sequence
towards 31, 35, 39 and 43 (9-10 kcal/mol). This means that cyclization of 23/rot-23 towards
benzophosphorinane is kinetically favorable. DFT calculations for the final products revealed almost
identical energy values for phosphaindane and benzophosphorinane oxides (see Supporting
Information), therefore, the whole process seems to be driven by kinetic factors. It appeared also that
hydride migration can proceed equally efficiently from both sides of planar sp2 carbon atom which
makes this process completely non-stereoselective. Unrestricted rotation of terminal methyl group in
secondary dications results in completely non-stereoselective formation of new chirality centers at the
γ carbon atom in benzophosphorinane oxides. As a result, almost equimolar mixture of four
benzophosphorinane oxides should be expected in the cyclization of 5b which was confirmed
experimentally.
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Based on both experimental and computational data the overall acid-promoted cyclization of β-
hydroxyalkylphosphine oxides proceeds as shown in the Scheme 7.
Me
O
P
Me
hydrolysis
O
P
Me
Me
Ph
Me
Ph
Me
OH
18
45
minor
process
H
H
H
H
O
P
OH
Me
O
P
OH
Me
O
P
O
P
O
P
H3O+
-H2O
-H2O
H3O+
-H2O
major
process
Ph
Me
Ph
Me
Ph
Me
Me
Ph
Me
Me
Ph
Me
Me
5b
44
14
16
23
unfavored
Me
Me
Me
H
H2O
-H3O+
H2O
-H3O+
favored
P
P
P
Me
Me
Me
O
O
O
25a,b
27a,b
H
H
47
46
Me
Me
Me
H
H
Me
Me
Me
O
P
H2O
-H3O+
H2O
-H3O+
Ph
Me
Me
P
P
P
H
O Me
H O Me
H O Me
49
48
29,33,37,41
6
Scheme 7. The proposed mechanism for the acid-catalyzed cyclization of β-hydroxyalkylphosphine
oxides.
The mechanism includes protonation of the starting 5b which undergoes water removal and the
formation of the tertiary carbocation 14. Under the reaction conditions, this intermediate
predominantly rearranges into protonated alkenylphosphine oxides 16 but also another type of
rearrangement with the formation of cyclic oxaphospholanium cation 18 might take place to a limited
extent. Its hydrolysis leads to γ-hydroxyalkylphosphine oxide 45. Intermediate 16 undergoes
protonation affording the dication 23 which then preferably undergoes proton shift and the formation
of secondary carbocations 29, 33, 37 and 41 which in turn enter intramolecular cyclization with phenyl
group at phosphorus affording upon work-up the final benzophosphorinane oxide 6. The calculated
sum of energies along the whole reaction pathway exactly matches the energy difference between the
substrate and the product.
3. Conclusions
The main purpose of this research project was to discover the rules governing cyclization of β-
hydroxyalkylphosphine oxides towards benzophosphorinanone oxides and to understand the
mechanism of this process, especially an unusual preference of these compounds to undergo
cyclization towards benzophosphorinane oxides. It was found that concentration of an acid
might have influenced the selectivity of the reaction. For phosphoric acid, the lowest
18

ACCEPTED MANUSCRIPT
acceptable concentration for cyclization was found to be 57%, whereas for sulfuric acid even
more diluted media still mediate effective cyclization. The use of equimolar amount of acid led
only to dehydration of substrates. A detailed optimization of the reaction revealed that 3-fold
excess of the acid is sufficient to promote effectively the cyclization of β-
31
hydroxyalkylphosphine oxides. The transformation of
8
, followed by P NMR spectroscopy,
revealed the fast rearrangement of substrate into the more substituted γ-hydroxyalkylphosphine
oxide 12, most probably through an intermediate formation of dehydration product and
intramolecular cyclization catalyzed by the acid. DFT calculation performed on 5b revealed
that equimolar amount of acid leads mostly to dehydration of substrate, or to OH-group
migration from β to γ carbon atom. In the presence of an excess of acid, protonation of
phosphoryl oxygen is followed by OH-group protonation and subsequent water removal
leading to tertiary dication. According to DFT calculations, activation energy needed for
cyclization of this species towards phosphaindane core is higher than the sum of energies
needed for cationic rearrangement and subsequent cyclization towards benzophosphorinane
core. A comparison of relative energies of phosphaindane and benzophosphorinane oxides
revealed almost equal stability of these compounds and, therefore, cyclization of β-
hydroxyalkylphosphine oxides seems to be ruled by kinetic factors.
4. Experimental section
4.1. General information
All reactions were performed under an argon atmosphere using Schlenk techniques. Only dry solvents
were used, and the glassware was heated under vacuum prior to use. Solvents for chromatography
were distilled once before use, and solvents for extraction were used as received. Tetrahydrofurane
was dried over sodium/benzophenone ketyl. n-BuLi was commercially available and used as received.
Analytics and Instruments. The NMR spectra was recorded with Bruker Ascend (500 MHz)
spectrometer in CDCl3 as a solvent at room temperature unless otherwise noted. Chemical shifts (δ)
are reported in ppm relative to residual solvent peak and to internal (H3PO4) standard in case of 31P
NMR spectra. Mass spectra were recorded with Shimadzu GC-MS QP2010S spectrometer working in
electron ionization (EI) mode with Phenomenex Zebron ZB-20HT INFERNO column using following
parameters: pressure 65 kPa, total flow 33.9 mL/min, column flow 1.0 mL/min, linear velocity 36.8
cm/s, split 30, temperature program (80 °C hold 0.5 min, 80−300 °C/19 °C/min, hold 2 min, 300−340
°C/15 °C/min, hold 3.26 min, total ca. 20 min). Thin layer chromatography (TLC) was performed with
precoated silica gel plates and visualized by UV light or iodide on silica gel. The reaction mixtures
were purified by column chromatography over silica gel (60−240 mesh). Melting points were
determined in a capillary tube.
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4.2. (2-Hydroxy-3-methylbutyl)methylphenylphosphine oxide (8). In a flame-dried Schlenk tube (50
mL) equipped with magnetic stirrer and inert gas inlet was placed dimethylphenylphosphine oxide
(0.326 g, 2.1 mmol) in THF (20 mL). The mixture was cooled to −78 °C (dry ice-acetone) and n-BuLi
(2.1 mmol, 1.6 M in hexane) was added. After the orange mixture was stirred for 50 min at −78 °C,
isobutyraldehyde (0.228 g, 3.17 mmol) was added until no colour remained. Reaction was allowed to
warm to room temperature and was stirred for 1 hour. The reaction was quenched by addition of
saturated NH4Cl solution (10 mL) and extracted with DCM (3×20 mL). The combined organic phases
were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by
flash column chromatography using hexane/CHCl3/i-PrOH (v/v = 5:1:1) as eluent yielding of two
diastereomers 0.395 g, (83%), (dr = 52.5:47.5).
Major diastereomer: Yield 45% (0.182 g, 38% isolated as a pure compound); white solid; mp 90.3–
92.1 °C; Rf= 0.52 (Hexane/CHCl3/i-PrOH 5:1:1); [Found: C, 63.89; H, 8.67. C12H19O2P requires C,
63.70; H, 8.46%]; ν max (ATR) 3236, 2948, 2910, 2866, 1436, 1382, 1326, 1286, 1221, 1169, 1114,
1093, 1036, 887, 694, 689, 553, 507, 477, 418; δH (500 MHz, CDCl3) 0.86 (d, J = 6.6 Hz, 3H), 0.87
(d, J = 3.8 Hz, 6H), 1.59−1.70 (m, 1H), 1.78 (d, J = 13.6 Hz, 3H), 1.88−1.97 (m, 1H), 2.00−2.11 (m,
1H), 3.75−3.83 (m, 1H), 4.52 (bs, 1H), 7.43−7.53 (m, 3H), 7.66−7.73 (m, 2H); δC (126 MHz, CDCl3)
17.3, 17.6 (d, J = 69.9 Hz), 17.8, 34.6 (d, J = 11.8 Hz), 34.9 (d, J = 70.8 Hz), 70.8 (d, J = 5.4 Hz),
128.6 (d, J = 11.8 Hz), 129.7 (d, J = 9.1 Hz), 131.6 (d, J = 2.7 Hz), 133.5 (d, J = 96.3 Hz); δP (202
MHz, CDCl3) 40.27; GC tR = 9.89 min; GC−MS (EI, 70 eV): m/z (%) = 208 (M+−H2O) (3), 183 (72),
154 (12), 140 (37), 139 (100), 125 (18), 91 (29), 77 (26), 47 (16).
Minor diastereomer: Yield 37% (0.140 g, 29% isolated as a pure compound); colorless oil; Rf= 0.42
(Hexane/CHCl3/i-PrOH 5:1:1); [Found: C 63.92; H 8.71. C12H19O2P requires C 63.70; H 8.46%]; ν
max (ATR) 3308, 2969, 2902, 2859,1437, 1359, 1291, 1237, 1158, 1118, 1071, 1019, 965, 890, 740,
693, 668, 519, 490, 460, 437; δH (500 MHz, CDCl3) 0.90 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.9 Hz,
6H), 1.69−1.76 (m, 1H), 1.78 (d, 3H, J = 12.9 Hz), 1.94−2.12 (m, 2H), 3.87−3.96 (m, 1H), 4.06 (bs,
1H), 7.46−7.56 (m, 3H), 7.67−7.75 (m, 2H); δC (126 MHz, CDCl3) 16.1 (d, J = 69.9 Hz), 17.5, 17.9,
34.6 (d, J = 11.8 Hz), 34.9 (d, J = 69.9 Hz), 71.6 (d, J = 5.4 Hz), 128.7 (d, J = 11.8 Hz), 129.6 (d, J =
10.0 Hz), 131.8 (d, J = 2.7 Hz), 133.8 (d, J = 97.2 Hz); δP (202 MHz, CDCl3) 40.14; GC tR = 10.04
min; GC−MS (EI, 70 eV): m/z (%) = 208 (M+−H2O) (4), 183 (75), 154 (12), 140 (32), 139 (100), 125
(14), 91 (28), 77 (23), 47 (14). Analytical data are in accordance with those reported in the literature.9
4.3.
1,4,4-Trimethyl-1,2,3,4-tetrahydrophosphinoline
1-oxide
(9).
(2-Hydroxy-3-
o
methylbutyl)methylphenylphosphine oxide (8) (0.105 g, 0.46 mmol) was stirred at 170 C with 57%
o
H3PO4 (2.803 g, 16.30 mmol) for 21 h. The mixture was cooled below 100 C and poured on to ice-
water (10 mL). The dark brown mixture was extracted with dichloromethane or chloroform (4 x 20
ml). The aqueous solution was washed with sodium hydrogen carbonate solution (10 mL) and water
20

ACCEPTED MANUSCRIPT
(10 mL). The extracts were dried over MgSO4, filtered, and evaporated under reduced pressure. The
residue was purified by column chromatography using AcOEt /MeOH (v/v = 9:1) as eluent yielding a
pale yellow oil; yield 0.095 g (90%, isolated as a mixture with 8% of 6); Rf= 0.26 (AcOEt/MeOH 9:1);
δH (500 MHz, CDCl3) 1.31 (s, 3H), 1.32 (s, 3H), 1.65 (d, J = 12.6 Hz, 3H), 1.87 - 1.98 (m, 1H), 2.04 -
2.15 (m, 2H), 2.22 - 2.32 (m, 1H), 7.27 - 7.31 (m, 1H), 7.36 - 7.44 (m, 2H), 7.76 - 7.82 (m, 1H); δC
(126 MHz, CDCl3) 17.4 (d, J = 71.8 Hz), 23.5 (d, J = 67.2 Hz), 30.9, 31.0, 34.9 (d, J = 3.6 Hz), 35.5
(d, J = 4.5 Hz), 126.6 (d, J = 10.9 Hz), 126.6 (d, J = 9.1 Hz), 129.1 (d, J = 93.5 Hz), 130.5 (d, J = 6.4
Hz), 131.9 (d, J = 2.7 Hz), 150.7 (d, J = 7.3 Hz); δP (202 MHz, CDCl3) 29.14; GC tR = 10.66 min;
GC−MS (EI, 70 eV): m/z (%) = 208 (M+) (29), 207 (14), 194 (12), 193 (100), 179 (13), 178 (20), 165
(23), 131 (15), 130 (24), 129 (21), 128 (13), 116 (12), 115 (22), 91 (16), 78 (30), 77 (13), 63 (11).
Analytical data are in accordance with those reported in the literature.9b
4.4.
1,3,4-Trimethyl-1,2,3,4-tetrahydrophosphinoline
1-oxide
(6).
(2-Hydroxy-3-
o
methylbutyl)methylphenylphosphine oxide (8) (0.113 g, 0.50 mmol) was stirred at 170 C with 73%
o
H3PO4 (3.285 g, 24.47 mmol) for 21 h. The mixture was cooled below 100 C and poured on to ice-
water (10 mL). The dark brown mixture was extracted with dichloromethane or chloroform (4 x 20
mL). The aqueous solution was washed with sodium hydrogen carbonate solution (10 mL) and water
(10 mL). The extracts were dried over MgSO4, filtered, and evaporated under reduced pressure. The
residue was purified by column chromatography using AcOEt /MeOH (v/v = 9:1) as eluent yielding a
pale yellow oil; yield 0.077 g (6%, isolated as a mixture with 68% of 9); Rf= 0.26 (AcOEt/MeOH 9:1);
δH (500 MHz, CDCl3) (due to overlapping only the selected peaks of epimers are described) 1.07 (d, J
= 7.3 Hz, 3H) and 1.14 (d, J = 6.9 Hz, 3H) and 1.18 (d, J = 7.3 Hz, 3H) and 1.21 (d, J = 6.9 Hz, 3H)
and 1.27 (d, J = 6.9 Hz, 3H) and 1.40 (d, J = 6.9 Hz, 3H), 1.64 (d, J = 12.8 Hz, 3H) and 1.67 (d, J =
12.8 Hz, 3H) and 1.71 (d, J = 12.8 Hz, 3H), 1.76 - 1.80 (m, 2H), 2.39 - 2.46 (m, 1H), 2.58 - 2.66 (m,
1H), 2.67 - 2.72 (m, 1H), 2.79 - 2.88 (m, 2H), 2.90 - 2.95 (m, 1H); δP (202 MHz, CDCl3) 24.40 and
25.57 and 27.43 and 31.07; GC peak 1; tR = 10.45 min; GC−MS (EI, 70 eV): m/z (%) = 208 (M+)
(21), 194 (12), 193 (100), 165 (22), 151 (11), 133 (23), 129 (14), 115 (14), 91 (10); GC peak 2; tR =
10.64 min; GC−MS (EI, 70 eV): m/z (%) = 208 (M+) (42), 207 (12), 194 (12), 193 (100), 179 (27),
178 (15), 166 (25); 165 (72), 151 (17), 147 (15); 133 (35), 131 (17), 130 (20), 129 (25), 128 (17), 116
(14), 115 (28), 91 (21); GC peak 3; tR = 10.69 min; GC−MS (EI, 70 eV): m/z (%) = 208 (M+) (38),
194 (12), 193 (100), 179 (26), 178 (10), 166 (35); 165 (90), 151 (20), 147 (13); 133 (41), 131 (14), 130
(20), 129 (25), 128 (16), 116 (10), 115 (23), 91 (18); GC peak 4; tR = 10.77 min; GC−MS (EI, 70 eV):
m/z (%) = 208 (M+) (19), 194 (12), 193 (100), 165 (18), 133 (19), 129 (14), 115 (12).
4.5. (3-methylbut-2-enyl)(methylphenyl)phosphine oxide (10). To a solution of (2-hydroxy-3-
methylbutyl)methylphenylphosphine oxide (8) (0.209 g, 0.92 mmol) in dry toluene containing Et3N
(1.876 g, 18.48 mmol) at 0 oC was added mesyl chloride (0.159 g, 1.39 mmol) dropwise. The reaction
21

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o
was stirred at this temperature for 0.5 hour and then heated to 110 C and stirred overnight. The
reaction mixture was diluted with 1M HCl and extracted with DCM (3×20 mL). The combined
organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue
was purified by column chromatography using hexane/AcOEt/i-PrOH (v/v = 5:1:1) as eluent yielding
0.092 g (48%) of title compound as a pale yellow oil: Rf= 0.55 (hexane/AcOEt/i-PrOH 5:1:1); [Found:
C, 69.48; H, 8.51. C12H17OP requires C, 69.21; H, 8.23%]; ν max (ATR) 3420, 3054, 2970, 2913,
1438, 1295, 1191, 1115, 902, 747, 698, 502, 432; δH (500 MHz, CDCl3) 1.45 (d, J = 3.8 Hz, 3H), 1.67
(d, J = 12.6 Hz, 3H), 1.68 (d, J = 5.0 Hz, 3H), 2.69 (dd, J = 15.8, 7.9 Hz, 2H), 5.09 - 5.17 (m, 1H),
7.41 - 7.47 (m, 2H), 7.47 - 7.53 (m, 1H), 7.64 - 7.71 (m, 2H); δC (126 MHz, CDCl3) 14.7 (d, J = 69.9
Hz), 17.8 (d, J = 1.8 Hz), 25.7 (d, J = 2.7 Hz), 32.7 (d, J = 68.1 Hz), 112.7 (d, J = 9.1 Hz), 128.4 (d, J
= 10.9 Hz), 130.0 (d, J = 9.1 Hz), 131.5 (d, J = 2.7 Hz), 133.5 (d, J = 95.4 Hz), 137.2 (d, J = 11.8
Hz); δP (202 MHz, CDCl3) 36.63; GC tR = 9.61 min; GC-MS (EI, 70 eV) m/z (%) = 208 (M+) (17),
140 (100), 139 (30), 125 (68), 77 (22), 51 (12), 47 (22).
4.6.
3-i-propyl-1-methylphosphindoline
1-oxide
(11).
(2-Hydroxy-3-
o
methylbutyl)methylphenylphosphine oxide (8) (0.115 g 0.51 mmol) was stirred at 170 C with 99%
o
H3PO4 (3.091 g, 31.54 mmol) for 21 h. The mixture was cooled below 100 C and poured on to ice-
water (10 mL). The solution was extracted with dichloromethane or chloroform (4 x 20 ml). The
aqueous solution was washed with sodium hydrogen carbonate solution (10 mL) and water (10 mL).
The extracts were dried over MgSO4, filtered, and evaporated under reduced pressure; conversion 3%
based on 31P NMR spectra as a mixture with 9 and 6; δP (202 MHz, CDCl3) 53.55 and 53.91; peak 1:
GC tR = 10.03 min; GC-MS (EI, 70 eV) m/z (%) = 208 (M+) (11), 193 (58), 180 (42), 179 (100), 165
(19), 149 (24), 133 (12), 117 (11), 116 (13), 115 (34), 91 (15); peak 2: GC tR = 10.15 min; GC-MS
(EI, 70 eV) m/z (%) = 208 (18), 193 (75), 180 (11), 179 (100), 133 (12), 116 (13), 115 (31), 91 (14).
4.7.
(3-Hydroxy-3-methylbutyl)methylphenylphosphine
oxide
(12).
(3-methylbut-2-
enyl)(methylphenyl)phosphine oxide (10) (0.059 g, 0.28 mmol) was stirred at 25 oC with 52% H2SO4
(3.38 g, 17.85 mmol) for 4 hours. The pale yellow mixture was poured on to ice water (10 mL). The
solution was extracted with dichloromethane or chloroform (4x20 ml). The extracts were dried over
MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column
chromatography using AcOEt/MeOH (v/v = 9:1) as eluent yielding 0.040 g (63%) of title compound
as a colorless oil: Rf= 0.37 (AcOEt/MeOH 9:1); [Found: C, 63.94; H, 8.69. C12H19O2P requires C,
63.70; H, 8.46%]; ν max (ATR) 3320, 2964, 1437, 1296, 1262, 1170, 1152, 1029, 917, 877, 808, 740,
697, 502; δH (500 MHz, CDCl3) 1.19 (d, J = 1.6 Hz, 6H), 1.58 - 1.69 (m, 1H), 1.71 (d, J = 12.9 Hz,
3H), 1.73 - 1.83 (m, 1H), 1.96 - 2.16 (m, 2H), 3.32 (bs., 1H), 7.43 - 7.55 (m, 3H), 7.65 - 7.74 (m, 2H);
δC (126 MHz, CDCl3) 16.0 (d, J = 70.8 Hz), 26.4 (d, J = 70.8 Hz), 28.9, 29.1, 35.1 (d, J = 3.6 Hz),
69.5 (d, J = 10.9 Hz), 128.6 (d, J = 10.9 Hz), 130.0 (d, J = 9.1 Hz), 131.6 (d, J = 2.7 Hz), 133.1 (d, J
22

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= 96.3 Hz); δP (202 MHz, CDCl3) 39.88; GC tR = 10.29 min; GC-MS (EI, 70 eV) m/z (%) = 211
(M+- CH3) (30), 208 (M+- H2O) (3), 168 (11), 141 (29), 140 (100), 139 (14), 125 (36), 77 (18), 59
(19), 47 (22). Analytical data are in accordance with those reported in the literature.9
4.8. (3-methylbut-1-enyl)(methylphenyl)phosphine oxide (13). To a solution of (2-hydroxy-3-
methylbutyl)methylphenylphosphine oxide (8) (0.209 g, 0.92 mmol) in dry toluene containing Et3N
(1.876 g, 18.48 mmol) at 0 oC was added mesyl chloride (0.159 g, 1.39 mmol) dropwise. The reaction
o
was stirred at this temperature for 0.5 hour and then heated to 110 C and stirred overnight. The
reaction mixture was diluted with 1M HCl and extracted with DCM (3×20 mL). The combined
organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue
was purified by column chromatography using hexane/AcOEt/i-PrOH (v/v = 5:1:1) as eluent yielding
0.040 g (21%) of title compound as a pale yellow oil: Rf= 0.64 (hexane/AcOEt/i-PrOH 5:1:1); [Found:
C, 69.38; H, 8.42. C12H17OP requires C, 69.21; H, 8.23%]; ν max (ATR) 3425, 2961, 2926, 2869,
1627, 1437, 1295, 1195, 1116, 990, 900, 744, 698, 509; δH (500 MHz, CDCl3) 1.02 - 1.06 (m, 6H),
1.73 (d, J = 13.2 Hz, 3H), 2.41 - 2.50 (m, 1H), 5.86 - 5.96 (m, 1H), 6.61 - 6.71 (m, 1H), 7.43 - 7.52
(m, 3H), 7.67 - 7.73 (m, 2H); δC (126 MHz, CDCl3) 16.9 (d, J = 74.5 Hz), 21.0, 32.6 (d, J = 16.3 Hz),
120.1 (d, J = 99.9 Hz), 128.5 (d, J = 11.8 Hz), 130.0 (d, J = 9.1 Hz), 131.4 (d, J = 2.7 Hz), 134.2 (d, J
= 101.7 Hz), 156.8; δP (202 MHz, CDCl3) 26.67; GC tR = 9.42 min; GC-MS (EI, 70 eV) m/z (%) =
208 (M+) (25), 207 (14), 193 (13), 165 (28), 140 (100), 139 (25), 131 (14), 125 (76), 91 (17).
Supplementary data
Supplementary data (1H, 13C and 31P NMR spectras of the products) associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/....
Acknowledgments
Financial support from National Science Centre (SONATA-BIS funding scheme, grant no.
2012/07/E/ST5/00544) is kindly acknowledged.
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