H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Enantioenriched Secondary Alcohols by N-, O-, and S-Centered Nucleophiles to Generate Heterocycles

Article abstract of DOI:10.1021/acscatal.9b03458

The direct intramolecular stereospecific substitution of the hydroxyl group in enantiomerically enriched secondary benzylic, allylic, propargylic, and alkyl alcohols was successfully accomplished by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered nucleophiles to provide enantioenriched five-membered tetrahydrofuran, pyrrolidine, and tetrahydrothiophene as well as six-membered tetrahydroquinolines and chromanes in up to a 99% yield and 100% enantiospecificity with water as the only byproduct. Mechanistic studies using both experiments and calculations have been performed for substrates generating 5-membered heterocycles. Rate studies show dependences in a catalyst, an internal nucleophile, and an electrophile, however, independence in an external nucleophile, an electrophile, or water. Kinetic isotope effect studies show an inverse KIE of k_H/k_D = 0.79. Furthermore, phosphinic acid does not promote S_N1 reactivity. Computational studies support a bifunctional role of the phosphinic acid in which activation of both nucleofuge and nucleophile occurs in a bridging S_N2-type transition state. In this transition state, the acidic hydrogen of phosphinic acid protonates the leaving hydroxyl group simultaneously as the oxo group partially deprotonates the nucleophile. Thereby, phosphinic acid promotes the substitution of the nonderivatized hydroxyl group in enantioenriched secondary alcohols by uncharged nucleophiles with conservation of the chirality from the alcohol to the heterocycle.

Full text of DOI:10.1021/acscatal.9b03458

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Article
H3PO2-Catalyzed Intramolecular Stereospecific Substitution of
the Hydroxyl Group in Enantioenriched Secondary Alcohols by
N-, O-, and S-centered Nucleophiles to Generate Heterocycles
Anon Bunrit, Pemikar Srifa, Thanya Rukkijakan, Christian Dahlstrand,
Genping Huang, Srijit Biswas, Rahul Watile, and Joseph S. M. Samec
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03458 • Publication Date (Web): 20 Dec 2019
Downloaded from pubs.acs.org on December 20, 2019
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H3PO2-Catalyzed Intramolecular Stereospecific
Substitution of the Hydroxyl Group in Enantioenriched
Secondary Alcohols by N-, O-, and S-centered
Nucleophiles to Generate Heterocycles
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Anon Bunrit,† Pemikar Srifa,† Thanya Rukkijakan,† Christian Dahlstrand,§ Genping Huang,†,⊥
Srijit Biswas,¶, Rahul A. Watile,*,† and Joseph S. M. Samec*,†
†Department of Organic Chemistry, Stockholm University, 10691 Stockholm, Sweden.
§Department of Chemistry, BMC, Uppsala University, Box 576, 75123 Uppsala, Sweden.
⊥Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. China.
¶Department of Chemistry, University College of Science, University of Calcutta, 92, A. P. C.
Road, Kolkata - 700009, West Bengal, India.
*Corresponding author. Tel.: +46705592511; Fax: +468162000
E-mail: joseph.samec@su.se (J. S. M. Samec), rahulwatile@gmail.com (R.A. Watile)
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Abstract
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The direct intramolecular stereospecific substitution of the hydroxyl group in enantiomerically
enriched secondary benzylic, allylic, propargylic, and alkyl alcohols was successfully accomplished
by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered
nucleophiles to provide enantioenriched five-membered tetrahydrofuran, pyrrolidine, and
tetrahydrothiophene as well as six-membered tetrahydroquinolines and chromanes in up to 99%
yield and 100% enantiospecificity with water as the only by-product. Mechanistic studies using both
experiments and calculations have been performed for substrates generating 5-membered
heterocycles. Rate studies show dependences in catalyst, internal nucleophile, and electrophile,
however, independence in external nucleophile, electrophile, or water. Kinetic isotope effect studies
show an inverse KIE of kH/kD = 0.79. Furthermore, phosphinic acid does not promote SN1 reactivity.
Computational studies support a bifunctional role of the phosphinic acid in which activation of both
nucleofuge and nucleophile occur in a bridging SN2-type transition state. In this transition state, the
acidic hydrogen of phosphinic acid protonates the leaving hydroxyl group simultaneously as the oxo
group partially deprotonates the nucleophile. Thereby, phosphinic acid promotes the substitution of
the non-derivatized hydroxyl group in enantioenriched secondary alcohols by uncharged
nucleophiles with conservation of the chirality from the alcohol to the heterocycle.
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Keywords: stereospecific substitution, alcohols, phosphinic acid catalysis, heterocyclic compounds,
atom economy.
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Introduction
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Enantiomerically enriched alcohols are easily accessible naturally occurring organic compounds. In
organic synthesis, alcohols are often used as nucleophiles.1 When the opposite reactivity is desired,
i.e. if alcohols are to be used as electrophiles, derivatization of the hydroxyl (OH) group into a better
leaving group is required. This derivatization step is either performed in-situ2, e.g. in the Mitsunobu
reaction3 or in a separate reaction step, e.g. via tosylation (Scheme 1a).4 These procedures have
drawbacks in increasing the cost, the number of synthetic steps, and environmental impact of the
transformation.5 In 2005, the nucleophilic substitution of non-derivatized alcohols was voted as the
second most desired reaction that pharmaceutical companies wanted greener alternative to with a
special emphasis on stereospecific reactions (“The challenge of achieving a method of activation for
secondary alcohols that maintains control over the stereochemistry of the reaction remains.”).6
Therefore, the development of methodologies for direct activation of the OH group has emerged. 7
These include: (i) hydrogen borrowing that proceed through an initial metal-catalyzed transfer
dehydrogenation step to generate the corresponding electrophilic carbonyl, that then condensates
with a nucleophile, and then the hydrogen is transferred back from the catalyst to generate the product
(Scheme 1b);4d (ii) direct substitution of the OH group promoted by Lewis acid catalysis that proceed
through an SN1 pathway where the nucleophile attacks the intermediate carbocation to form the
product (Scheme 1c).7 A disadvantage with these methodologies is that they both proceed through
an achiral intermediate. Thereby, the inherent chirality in these easily accessible compounds cannot
be utilized.4a,4c,8 Optically pure alcohols are abundant in biomass and efficient methodologies to
substitute the OH group would enable the usage of biomass as a raw material for the production of
bulk and fine chemicals in the future. Therefore, it would be worthwhile to develop efficient
stereospecific methodologies to substitute the OH group in enantioenriched alcohols.
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OX
XCl, Base
-HCl
NuH, Base
-XOH
(a)
R1
R2
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8
9
NuH
[M] H + H
[M]
OH
R2
Nu
R2
O
(b)
(c)
R1
R1
-H2O
-[M]
R1
R2
[M] H + H
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HO [L.A.]
R1 R2
NuH
[L.A.]
-H2O
[L.A.]
Scheme 1. General substitution reactions via different modes of activation of the hydroxyl group of
alcohols: (a) preactivation, (b) catalytic hydrogen transfer, and (c) direct catalytic substitution.
To develop direct stereospecific substitution reactions of the OH group without prior
derivatization is more challenging than the SN1 reactions in which control of the C─O bond cleavage
is required for chirality transfer to the product to occur.3a Recently, Aponick, Widenhoefer, and
Uenishi successfully performed intramolecular stereospecific substitution reactions of
enantioenriched allylic alcohols using gold and palladium based catalysts (Scheme 2a).9 The
chemical transformation proceeded via an SN2′-type transition-state (TS) which was supported by
density functional theory (DFT) calculations.10 A unique bicylic transition-state was found in which
the nucleophile protonated the leaving OH group in a bicyclic transition state. However, the
methodology was substrate specific, where no reactivity was observed when the OH group of the
allylic and alcohol were juxtapositioned (Scheme 2b). In 2014, Cook and Umani-Ronchi reported
iron(III)-catalyzed intramolecular Friedel-Crafts alkylation of unactivated alcohols, where
stereospecificity was reported for two substrates (Scheme 2c).11 They recently extended this to
secondary and tertiary alcohols using a N-centered nucleophile.12 We have previously communicated
a direct stereospecific nucleophilic substitution of the OH group of non-derivatized secondary
alcohols using phosphinic acid (H3PO2) as a catalyst with water as the only byproduct (Scheme 2d).
The OH group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols was substituted by O-
, N-, and S-centered nucleophiles to generate five-membered heterocyclic compounds with
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conservation of the chirality. Limited mechanistic studies suggested that H3PO2 had a bifunctional
role and promoted an SN2-type reaction.13
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9
In this study, we expand the study of direct stereospecific intramolecular substitution of
various substrates to generate both five- and six-membered heterocyclic compounds. Mechanistic
studies using both experiments and calculations have been performed to get better insight into the
reaction mechanism.
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NuH
n
Nu = O, NR
n = 1, 2
Au or Pd-catalysis
X
OH
R
(a)
SN2' mechanism
(Allylic alcohols)
R
n
M
R
OH
H
Nu
NuH
OH
Previos work
Fe(III) cat.
(b)
(c)
(d)
no reaction
R
n
n = 1, 2
R
OH
R
X
X
X = C (63% ee)
X = NTs (-)
X = C (65% ee)
X = NTs (-)
NuH
OH
X
R
H3PO2
-H2O
R
n
n
This work
Nu = O, NR, S
R = aryl, propargyl, allyl, alkyl
n = 1, 2
Scheme 2. Current catalytic methodologies for direct intramolecular substitution of alcohols.
Results and discussion
Optimization of reaction parameters
Initially, the weakly nucleophilic O-centered (S)-1-phenylbutane-1,4-diol (1a) was chosen as the
model substrate for screening the intramolecular stereospecific substitution reaction to yield (R)-2-
phenyltetrahydrofuran (2a) (Table 1). An initial catalyst screening with various Lewis acidic catalysts
(Fe(III), Au(I), and Au(III)) that previously have beeen reported to activate the OH group were
chosen.14 These catalysts showed high reactivity, however low enantiospecificity (e.s.) was observed
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(Table 1, entries 1-3). In the presence of 10 mol% of H3PO2 product 2a was obtained in excellent
yield with 91% e.s.. Similar phosphorous-based acids such as H3PO3, H3PO4, PhH2PO2, and Ph2HPO2
were also tested (Table 1, entries 5-8), however no product formation was observed under the
employed reaction conditions. Other Brønsted acids having a O═X–OH motif similar to phosphinic
acid such as trifluorometanesulfuric acid (TfOH), acetic acid (AcOH), sulfuric acid (H2SO4), and p-
toluenesulfunic acid (p-TSA) were also studied (Table 1, entries 9-12). Stronger acids than H3PO2
promoted the nucleophilic substitution to yield 2a in high yield, but gave lower e.s. (Table 1, entries
10-12). Inspired by the good result obtained using p-TSA as a catalyst in entry 12, the reaction was
carried out at 25 ⁰C. However, at this temperature a low conversion was observed (Table 1, entry
13). The pKa of the acid affected the reactivity of the reaction where weaker acids (pKa > 2) did not
promote the substitution reaction and stronger acids (pKa < 1) did. However, the correlation between
acidity and enantiospecificity of the nucleophilic substitution reaction is not clear.
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The solvent effect was also studied. Cyclohexane and toluene which have lower polarity than
1,2-DCE generated 2a in slightly lower yields (Table 1, entries 14-15). With solvents of higher
polarity than 1,2-DCE, i.e. acetonitrile and nitromethane, the reaction proceeded to give 2a in high
yields, however, with lower e.s. (Table 1, entries 16-17). Furthermore, the effect of temperature was
investigated using toluene with a wide temperature window as solvent. The conversion increases with
temperature, however, the enantiospecificity drops when the temperature was raised (Table 1, entries
18-20).
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Table 1. Optimization of the reaction conditions for the intramolecular nucleophilic substitution of
benzylic alcohol 1a.
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OH
cat. 10 mol%
OH
Ph
O
Ph
solvent, temp.,
time
1a
2a
er (S:R) = 937
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Entry
1
Catalyst
FeCl3
pKa
-
Solvent
T (°C)
t (h)
12
12
12
24
24
48
48
48
48
12
12
12
24
24
24
24
24
12
12
2
Yield (%)a
>95
90
e.s. (%)b
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
Cyclohexane
Toluene
MeCN
40
80
40
80
80
80
80
80
80
40
40
40
25
80
80
80
80
100
110
160
0
0
2
AuCl
-
3
NaAuCl4
H3PO2
H3PO3
H3PO4
PhH2PO2
Ph2HPO2
AcOH
TfOH
-
>95
>95
0
19
91
0
4
1.07
2.0
5
6
2.12
1.86
2.3
0
0
7
0
0
8
0
0
9
4.76
-12
-3
0
0
10
11
12
13
14
15
16
17
18
19
20c
>95
>95
>95
10
23
0
H2SO4
p-TSA
p-TSA
H3PO2
H3PO2
H3PO2
H3PO2
H3PO2
H3PO2
H3PO2
-2.8
-2.8
1.07
1.07
1.07
1.07
1.07
1.07
1.07
84
-
>80
>90
>95
>95
>95
>95
>95
73
91
65
60
21
9
MeNO2
Toluene
Toluene
Toluene
0
a
Reaction conditions: 1a (0.3 mmol), solvent (1.0 mL) and catalyst (10 mol%) was heated in an oil bath. NMR yield.
bEnantiospecificity was determined by chiral stationary phase HPLC analysis. cReaction performed at 160 °C in which
microwave irradiation was used (3 bar).
Water effect
The phosphinic acid used in this study was administrated as an aqueous solution (50 w/w%), while
the other catalysts used were dry. Thereby, the reaction with H3PO2 as catalyst contained water from
the beginning of the reaction. In addition, water is generated during the course of the reaction.
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Therefore, the effect of water on the reaction was studied by measuring the initial rate and the
enantiospecificity of the reaction (Table 2). The initial rates were determined at below 20%
conversion and the enantiospecificity was determined after 24 hours. Dried CaSO4 (oven dried at
250°C for 3h) was used as a neutral drying agent in the reaction where CaSO4 + H2O form
CaSO4.2H2O. The standard reaction without dried CaSO4 was performed. The observed initial rate
was 3.6×10-6 M.s-1 with 90% e.s. (Table 2, entry 1). Different amounts of dried CaSO4 were added
to reaction mixture. Increasing the amount of water did not affect either initial rate or
enantiospecificity of the reaction (Table 2, entries 2-6). To study the influence of CaSO4, mole
equivalence of water and CaSO4 were added to the reaction. However, no effect on the rate or
enantiospecificity was observed (Table 2, entry 7). Without H3PO2, CaSO4 did not promote the
reaction (Table 2, entry 8). Thereby, water does not affect the rate or the enantiospecificity of the
reaction.
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Table 2. Water effect on initial rate and enantiospecificity of the reaction
H3PO2 10 mol%
1,2-DCE, 80 oC
OH
+
H2O
OH
Ph
O
2a
Ph
1a
er (S:R) = 937
Entry
Amount of water (%)
CaSO4 (mmol)
Initial rate (×10-6 M.s-1)
e.s. (%)a
1
2
3
4
5
6
7
8
100
0
-
3.6
3.1
4.1
3.1
4.1
3.6
3.1
N/A
91
90
91
91
91
91
90
-
0.070
0.056
0.042
0.028
0.014
0.14
20
40
60
80
100
-
0.14
Reaction conditions: 1a (0.3 mmol), 1,2-DCE (1.5 mL), H3PO2 (10 mol%), CaSO4, and H2O was heated in an oil bath at
80 °C. N/A = no reaction. aEnantiospecificity was determined by chiral stationary phase HPLC analysis.
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Stereospecific substitution to generate five-membered heterocycles from benzylic alcohols
Having optimized the reaction conditions, the substrate scope with respect to both nucleophile and
benzylic alcohols was studied (Table 3). Substrates with O-, N-, and S-centered nucleophiles
generated tetrahydrofuran 2a, pyrrolidine 2b, and tetrahyrothiophene 2c in excellent yields and high
e.s. (Table 3, entries 1-3). Substrates with electron-withdrawing p-fluoro in the benzyl group
generated heterocyclic products 2d-2f in good to excellent yield and high e.s. (Table 3, entries 4-6).
The strongly deactivating group, p-trifluoromethyl substituent, generated pyrrolidine 2g in high yield
and full e.s. (Table 3, entry 7). Lower e.s. was observed for reaction of 1h to generate product 2h
having an electron-donating p-methoxy group on the benzylic alcohol (Table 3, entry 8). However,
exchanging the N-centered nucleophile (aniline) with an electron-rich p-anisidine overcame this and
product 2j was obtained in high yield and excellent e.s. (Table 3, entry 10). With the PMP group on
the N-centered nucleophile, all products were obtained in excellent yields and e.s. (Table 3, entries
9-15). The PMP group also has synthetic advantages as it can easily be removed if desired.
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Table 3. Intramolecular substitution of benzylic alcohols to generate five-membered heterocylic
4
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compounds
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8
9
OH
H3PO2 10 mol%
H2O
+
NuH
R
Nu
2a
1,2-DCE
80 oC, 24 h
R
1
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1.
4.
7.
2.
3.
6.
Ph
2b
Ph
2c
Ph
N
S
O
Ph
, 99%
2a
, 99%
(91% e.s.)
, 95%
(96% e.s.)
(91% e.s.)
5.
4-F-
C H
6
4
C H
6
C H
6 4
N
4-F-
4-F-
4
O
S
Ph
,96%
2d
(85% e.s.)
2e
2f
, 92%
(97% e.s.)
, 92%
(98% e.s.)
8.
9.
Ph
C H
6
PMP
4-F3C-
4
N
N
N
PMP
Ph
, 91%
Ph
, 92%
b
2g
2i
, 98%
(98% e.s.)
2h
(100% e.s.)
(76% e.s.)
10.
11.
12.
4–F–C6H4
4–Cl–C6H4
PMP
N
N
N
PMP
, 97%
PMP
PMP
83%
c
2k
2l
, 96%
2j,
(99% e.s.)
(100% e.s.)
(100% e.s.)
13.
14.
15.
3–MeO–C6H4
4–Me–C6H4
3–F3CO–C6H4
N
N
N
PMP
, 96%
PMP
, 90 %
PMP
2o,
95%
(96% e.s.)
2m
(95% e.s.)
2n
(96% e.s)
Reaction conditions: 1 (0.5 mmol), 1,2-DCE (1.0 mL) and H3PO2 (10 mol %) was heated in an oil bath at 80 oC. aIsolated
yields. bReaction temp. 65 oC. cReaction temp. 50 oC.
Stereospecific substitution to generate five-membered heterocycles from non-benzylic alcohols
The substrate scope was expanded to more challenging non-benzylic alcohols (Table 4). H3PO2
catalyzed the nucleophilic substitution of stereogenic allylic alcohol 1p to yield pyrrolidine 2p in
85% yield and 93% e.s. (Table 4, entry 1). Exchanging the nucleophilic moiety from aniline to
stronger nucleophilic p-anisidine improved the enantiospecificity to 100% in product 2q (Table 4,
entry 2). Noteworthy, this direct intramolecular stereospecific nucleophilic substitution overcame the
previous limitation of allylic alcohols that only could proceed via an SN2′-reaction pathway (Scheme
2b).6,7 Intramolecular substitution of less reactive propargylic alcohol with S-centered nucleophiles
1r was also performed. The reaction generated 2r in high yield and excellent enantiospecificity
(Table 4, entry 3). The nucleophilic substitution of secondary aliphatic alcohols remains challenging
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due to the relative difficulty in activating of the OH group and the risk for dehydration reactions. To
date, the activation of the OH group of aliphatic secondary alcohols has only been reported a few
times for reactions that proceed through an SN1-pathway.3e,15 The intramolecular substitution
reaction of aliphatic alcohols 1s-1u with N-centered nucleophiles overcame this limitation. The
reaction generated pyrrolidines 2s-2u in good yields and excellent enantiospecificities (Table 4,
entries 4-6).
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Table 4. Intramolecular substitution of non-benzylic alcohols to generate five-membered heterocylic
compounds
OH
1.
H3PO2 10 mol%
H2O
+
NuH
R
Nu
2a
1,2-DCE
80 oC, 24 h
R
1
2.
3.
N
N
S
Ph
PMP
Ph
2q
, 87%
2p
2r
, 92%
, 85%
(100% e.s.)
(93% e.s.)
(100% e.s.)
5.
4.
6.
N
N
N
PMP
PMP
Ph
2u
, 87%
(97% e.s.)
2t
, 85%
(97% e.s.)
2s
, 81%
(100% e.s.)
Reaction conditions: 1 (0.3 mmol), 1,2-DCE (1 mL) and H3PO2 (10 mol %) was heated in an oil bath at 80 oC. aIsolated
yields.
Stereospecific substitution to generate six-membered heterocycles from benzylic alcohols
We wanted to expand the substrate scope to substrates that generate six-membered heterocycles. To
our knowledge, there is only one report of a stereospecific substitution of an OH group to generate a
six-membered heterocycle (Scheme 2b), however, no reports using N- or O-centered nucleophiles.
The N-centered 1w was tested in the intramolecular substitution reaction and gratifyingly product 2w
was isolated in excellent yield and high e.s. (Table 5, entry 1). This chemical transformation has
previously only been reported in non-stereospecific substitution reaction to obtain racemic
products.16 Encouraged by the good results, the more challenging phenol was tried as nucleophile.
Phenols have, to the best of our knowledge, never been reported as nucleophiles in any substitution
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reactions of OH groups in alcohols. H3PO2 catalyzed the intramolecular substitution reaction of
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5
alcohol 1x to generate chromane 2x in 85% yield and 92% e.s. (Table 5, entry 2). The reaction
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o
required a slightly higher temperature (100 C). Alcohol with an electron-withdrawing p-fluoro
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substituent in benzylic group generate product 2y in 90% yield and 90% e.s. (Table 5, entry 3).17 In
contrast, alcohol with an electron-donating p-methoxy group 1y generated product 2y in excellent
yield, however with only 38% e.s. (Table 5, entry 4). Intramolecular substitution of less reactive
propargylic alcohol 1z generated 2z in very good yield with 75% e.s. (Table 5, entry 5).
Thus, we have showed that H3PO2 can catalyze the nucleophilic substitution of various
secondary alcohols with respect to nucleophile, electrophile, and ring-size to generate
enantiomerically enriched heterocyclic compounds with high efficiency in respect to yields and
enantiospecificities.
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Table 5. Intramolecular substitution of benzylic alcohols to generate six-membered heterocylic
compounds
OH
H3PO2 10 mol%
+
H2O
R
1,2-DCE
80-100 oC, 24 h
Nu
R
NuH
1
2a
1.
3.
2.
N
Ph
O
C6H4-4-F
O
Ph
5.
PMP
b
b
2x
,90%
2w
, 85%
2v
, 100%
(92% e.s.)
(90% e.s.)
(92% e.s.)
4.
O
C6H4-4-OMe
O
c
Ph
d
2y
,93%
2z
,87%
(38% e.s.)
(75% e.s.)
Reaction conditions: 1 (0.3 mmol), 1,2-DCE (1.0 mL) and H3PO2 (10 mol %) was heated in an oil bath. aIsolated yields.
bReaction performed in DCE + Hexane (0.5 + 0.5 mL) at 100 oC. cReaction performed in DCE + Hexane (0.5 + 1.0 mL)
at 100 oC for 40 h. dReaction performed with 20 mol% H3PO2 in DCE + Hexane (0.5 + 1.0 mL) at 90 oC for 48 h.
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Mechanistic studies
Reaction progress
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The reaction profile of the transformation of 1a to 2a was investigated (Figure 1). The reaction
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progress was monitored by H-NMR spectroscopy where consumption of 1a and formation of 2a
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were measured. It was found that the overall reaction followed first-order kinetics with a half-life of
around 10 hours.
100
90
80
Ph
O
2a
70
60
50
40
30
OH
OH
20
Ph
1a
10
0
0
10
20
30
40
reaction progress (h)
Figure 1. The substitution reaction profile of 1a with 20 mol% of H3PO2.
Reaction condition: 0.1 mmol of 1a and 20 mol% of H3PO2 in 0.5 mL of tetrachlroethane-D4 at 80 °C
Rate-order determination: Catalyst
To get a better mechanistic understanding, a rate-order determination with respect to the catalyst was
examined. The concentration of catalyst was varied in the reaction of 1a to 2a. From these results, it
appears that the reaction follows a first-order dependence in catalyst concentrations between 0-20
mol% as shown in Figure 2.
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1.2E-8
1E-8
8E-9
6E-9
4E-9
2E-9
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-1E-9
0
5
10
15
20
H3PO2 mol%
Figure 2. Rate-order determination using substrate 1a (0.2 mmol in 1 mL of 1,2-DCE)
with different concentration of H3PO2.
Rate dependencies of the substrate
Due to the nature of the substrate with both electrophile and nucleophile present, rate-order
determination of these reactive centers is not possible. However, especially the rate dependency in
especially the nucleophile is important in order to determine the reaction mechanism. Therefore, we
synthesized substrate 3-(hydroxymethyl)-1-phenylbutane-1,4-diol (1aa) which has two terminal O-
centered nucleophiles. In this experiment, we monitored the initial rate differences between substrate
1a and 1aa using 20 mol% of H3PO2. Substrate 1a substituted the OH group to generate product 2a
with an observed rate of 7.9×10-7 M.s-1 (Scheme 3a). Under the same reaction conditions, substrate
1aa generated tetrahydrofuran 2aa with an observed rate of 16.5×10-7 M.s-1 (Scheme 3b). This
discloses that the reaction rate is dependent on the nucleophile.
Next, we wanted to confirm the rate dependency in electrophile. We prepared 2-
(hydroxy(phenyl)methyl)-1-phenylbutane-1,4-diol (1ab) which has two benzylic electrophiles.
Employing the same reaction conditions, substrate 1ab generated tetrahydrofuran 2ab with an
observed rate of 16.7×10-7 M.s-1 (Scheme 3c).
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H3PO2 20 mol%
OH
(a)
(b)
(c)
+
H2O
H2O
H2O
OH
Ph
O
80 oC, 8h
Ph
Ph
, 7.9±0.1 10-7 M.s-1
2a
×
1a
OH
+
OH
OH
H3PO2 20 mol%
80 oC, 8h
OH
Ph
O
, 16.5±0.2 10-7 M.s-1
2aa
×
1aa
OH OH
Ph
Ph
H3PO2 20 mol%
80 oC, 8h
HO
+
Ph
HO
Ph
2ab
O
, 16.7±0.6 10-7 M.s-1
1ab
×
Scheme 3. Rate dependency in nucleophilic and electrophilic centers.
Reaction conditions: substrate (0.12 mmol), 1,2-DCE (1 mL) and H3PO2 (20 mol %) was heated in an oil bath at 80 °C.
Rates of the reaction at 8 h were determined by 1H-NMR spectroscopy.
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Deuterium kinetic isotope effect measurement
Moreover, deuterium kinetic isotope effect (KIE) was measured by comparing the rate of substitution
of 1a and 1a-[D]. A deuterium kinetic isotope effect (KIE = kH/kD = 0.790.04) was observed
(Scheme 4) (see the Supporting Information for details). This inverse KIE also support an SN2-like
pathway.
H3PO2 10 mol%
OH
D/H
Ph
D/H
Ph
+
H2O
OH
O
80 oC, 8h
2a 2a
or -[D]
1a 1a
or -[D]
kH/kD = 0.79±0.04
Scheme 4. Kinetic Isotope Effect of nucleophilic substitution.
Reaction conditions: substrate (0.3 mmol), 1,2-DCE (1.5 mL) and H3PO2 (10 mol %) was heated in an oil bath at 80 °C.
Rates of the reaction at 8 h were determined by 1H-NMR spectroscopy.
Competition experiments
Competition experiments between substrate 1i and external electrophile or nucleophile were
performed (Table 6). We wanted to study the effect on both the initial rate of the reaction as well as
the enantiospecificity. The substitution reaction of 1i catalyzed by H3PO2 generated product 2i with
an observed rate of 5.1×10-7 M.s-1 and 96% e.s. after 8 hours reaction time (Table 6, entry 1). Addition
of 1-phenylethanol (1ac) as an external electrophile to the reaction mixture only marginally affected
the rate but not the enantiospecificity (Table 6, entry 2). Similarly, addition of external N-
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methylaniline (1ad) did not inhibit the reaction (Table 6, entry 3). Instead a small increase of the rate
was observed. Interestingly, no side-reactions from intermolecular substitution reactions where
external nucleophile or electrophile were involved were observed. These experiments show that the
catalyst is very selective towards the intramolecular substitution reaction.
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Table 6. Competition experiments of 1i with external electrophile and nucleophile.
H3PO2 10 mol%
OH
H
Ph
+
H2O
N
N
Ph
PMP
additive
80 oC, 8 h
PMP
2i
1i
Entry
Additive
-
Initial rate (×10-7 M.s-1)a
e.s. (%)
1
2
3
5.1
4.4
5.9
96
98
98
1-phenylethanol (1ac)
N-methylaniline (1ad)
Reaction conditions: 1i (0.08 mmol), additive (0.08 mmol), 1,2-DCE (1 mL) and H3PO2 (10 mol %) was heated in an oil
bath at 80 °C. aInitial rates of the reaction at 8 h were determined by 1H-NMR spectroscopy.
With this we can conclude that the rate of the reaction is dependent on catalyst and substrate
having both internal nucleophile and electrophile, however independent on external nucleophile and
electrophile. Therefore, the overall reaction shows a rate-order of second order according to the
equation depicted in equation 1
[product]
d
= k[H3PO2][substrate]
(eq 1)
t
Excluding SN1 reactivity for H3PO2 catalysis
Rate-order determination studies showed that the rate is dependent on both internal nucleophile and
electrophile. This is in agreement with a bimolecular reaction mechanism and supports an SN2
pathway. Therefore, we wanted to furthermore exclude the SN1 pathway. One way to do this is to
study the etherification reaction of enantioenriched 1-phenylethanol ((S)-1ac) that proceed through
an SN1 pathway to generate racemic ether 2ac (Scheme 5). In an SN1 reaction, the rate determining
step is the C─O bond cleavage to generate the carbocation. Once the carbocation is formed, the
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nucleophilic attack by another molecule of (S)-1ac occurs in a fast step. Thereby, substrate (S)-1ac
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act as both electrophile and nucleophile in this experiment.
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[cat]
Ph
OH
OH
1ac
[cat]
+
H2O
Ph
O
Ph
Ph
-H2O
1ac
S/R = 98:2
2ac
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Scheme 5. An SN1 reaction using 1-phenylethanol 1ac.
Interestingly, no reaction of substrate 1ac was observed when H3PO2 was employed as catalyst.
Only 1ac was recovered after the reaction where a negligible racemization had occurred (Table 7,
entry 1). In contrast, other catalysts that gave either low or good enantiospecificity in the catalyst
screening (Table 1) promoted the formation of racemic 2ac. For example, p-TSA that showed high
enantiospecificity, gave racemic ether in a quantitative yield (Table 7, entry 3). These reactions
clearly show that H3PO2 does not promote SN1 reactivity under the employed reaction conditions.
Table 7. Racemization experiment of 1ac
OH
cat. 10 mol%
1,2-DCE, 24h
+
H2O
Ph
O
Ph
Ph
1ac
S/R = 98:2
2ac
Entry
Catalyst
2aca
T (°C)
Recovered 1ac
1
2
3
4
5
-
-
80
80
40
40
40
> 99% (S/R = 98:2)
H3PO2
p-TSA
TfOH
FeCl3
< 5%
> 95%
> 20%
> 95%
> 95% (S/R = 96:4)
0%
0%
0%
Reaction Condition: 1ac (1 mmol), 1,2-DCE (1.5 mL) and catalyst (10 mol %) was heated in an oil bath. aNMR yield.
To conclude the results from the experiments, the H3PO2 gives rise to a unique reactivity that
promotes an SN2 pathway for substrates that have an internal nucleophile. Interestingly, H3PO2 does
not promote C─O bond cleavage in the absence of an internal nucleophile. To shed more light on the
reaction mechanism and the transition state, DFT studies were performed.
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Density Functional Theory calculations
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The phosphinic acid catalyst has a Brønsted acid site that presumably protonates the OH group of the
electrophile in the transition state. However, this activation is not sufficient to promote C─O bond
cleavage as showed in the etherification reaction of 1ad (Table 7). Thereby, H3PO2 might have an
additional role in the reaction. Plausibly, H3PO2 acts as a bifunctional catalyst. Previous reports
support that the oxo group in phosphorous acids may act as a Brønsted base. 18 In this case, H3PO2
may act as a bifunctional catalyst that simultaneously activates both the nucleophile and the
nucleofuge in an SN2-type reaction. DFT calculations were performed to study the transformations
from 1a-1c to 2a-2c using the B3LYP functional as implemented in the Gaussian 09 package (see
the Supporting Information for details).11 Early on, low TS was located in which H3PO2 showed a
bifunctional role. In this TS, the acidic hydrogen protonates the leaving OH group of the electrophile
to promote C–O bond cleavage, simultaneously as the oxo-group of the catalyst partially deprotonates
the nucleophile. As shown in Figure 3, this bridging TS between substrate and catalyst results in an
SN2-type reaction mechanism. The energy barriers for the calculated transition states for O-, N-, and
S-centered nucleophiles (1a → 2a, 1b → 2b and 1c → 2c) were found and calculated to be 27.3, 23.1
and 26.8 kcal/mol, respectively. These values are in accordance with experimental results where N-
centered nucleophiles were reactive at a lower reaction temperature (60 C), than O- and S-centered
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nucleophiles (80 C).
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H
H
H
H
H
P
O
H
O
H
P
O
H
O
P
O
H
O
O
H
O
O
H
S
H
O
H
H
H
N
Ph
Ph
Ph
Ph
TS2a-2b
TS3a-3b
TS1a-1b
9
27.3
26.8
23.1
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OH
NuH
Ph
1a-1c
0.0
+
1a
Nu = O,
Nu = NPh,
Nu = S,
H2O
Ph
1b
Nu
2a-2c
1c
2a
-10.9, Nu = O,
2b
-13.4, Nu = NPh,
c
-19.1, Nu = S, 2
Figure 3. Calculated transition state structures with H3PO2 and their calculated energies (kcal/mol)
for transformations from 1a-1c to 2a-2c.
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Transition states for other acids (p-TSA, Ph2HPO2 and AcOH) seemingly similar to H3PO2 were also
calculated. We used O-centered nucleophile 1a as a model substrate (Table 1, Figures 1 and 2). As
can be seen in Figure 4, the TS calculated for p-TSA was 21.1 kcal/mol. This result corresponds to
the experimental outcome in which the stronger acid promotes the reaction at a lower temperature
(40 C). On the other hand, weaker acids did not promote reactivity under the employed reaction
conditions (80 C). For example, acetic acid did not promote reactivity in the intramolecular
substitution. The transition state was calculated to 36.6 kcal/mol. The seemingly similar Ph2HPO2
gave a calculated transition state of 27.6 kcal/mole which is very close to H3PO2. We performed the
reaction of 1a to 2a using a slightly higher reaction temperature. Interestingly, and in accordance to
the calculations, Ph2HPO2 became reactive when the temperature was raised (reflux, toluene).
Thereby, the calculations correlate with experimental data for the transformations and support an SN2
TS for the intramolecular substitution reaction catalyzed by H3PO2.
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H
P
Me
P
O
O
H
S
O
O
O
O
H
H
O
H
O
H
O
H
H
H
O
H
H
O
O
O
O
H
O
H
H
Ph
O
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O
Ph
Ph
Ph
9
36.6
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27.6
27.3
21.1
OH
OH
Ph
1a
0.0
+ H2O
Ph
O
2a
-10.9
Figure 4. Calculated transition state structures with H3PO2, p-TSA, AcOH, and Ph2HPO2 and their
calculated energies (kcal/mol) for transformations from 1a to 2a.
Conclusions
The direct intramolecular stereospecific substitution of the OH group of enantioenriched secondary
alcohols catalyzed by phosphinic acid has been developed. The OH group of aryl, allyl, propargyl,
and alkyl alcohols was substituted by O-, S-, and N-centered nucleophiles to generate five- and six-
membered heterocycles in good to excellent yield with high enantiospecificity. Experimental studies
show that phosphinic acid does not promote SN1 reactivity. Studies of rate dependencies show
dependency in catalyst and both nucleophilic and electrophilic center. Kinetic isotope effect studies
disclose an inverse KIE. DFT calculations corroborate a reaction pathway in which the phosphinic
acid operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the
nucleophile and nucleofuge in an SN2-type transition state. The acidic proton of the phosphinic acid
protonates the hydroxyl group enhancing the leaving group ability simultaneously as the oxo group
of phosphinic acid partially deprotonate the nucleophile enhancing the nucleophilicity in a bridging
transition state to promote the reactivity. Thereby, a broad range of easily accessible enantioenriched
secondary alcohols can be used as substrates in intramolecular substitutions by various nucleophiles
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to generate heterocyclic compounds in which the chirality from the starting material has been
conserved to the product.
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General procedure for H3PO2-catalyzed intramolecular stereospecific substitution
A glass vial was charged with alcohol 1a (50 mg, 0.30 mmol) in 1.0 mL of 1,2-DCE, was added 50%
(v/v) aqueous solution of H3PO2 (7.5 µL, 0.1 mmol). The reaction vial was capped and the mixture
o
was heated up to 80 C for 24 hours. After completion (TLC), the crude was concentrated under
reduced pressure (without work-up) and a fast column chromatographic purification was performed
using silica gel (mess 100-200) and 10% ethyl acetate/n-pentane to obtain pure 2a (48 mg, 0.29
mmol, 99% yield) as colourless oil. 1H NMR (400 MHz, CDCl3) δ = 7.34–7.31 (m, 4 H, H-arom),
7.27–7.24 (m, 1 H, H-arom), 4.91–4.88 (m, 1 H, H-2), 4.13–4.07 (m, 1 H, H-5), 3.97–3.91 (m, 1 H,
13
H-5), 2.37–2.29 (m, 1 H, H-3), 2.05–1.97 (m, 1 H, H-4), 1.86–1.79 (m, 1 H, H-3) ppm. C NMR
(100 MHz, CDCl3) δ = 144.1, 128.7, 127.9, 125.7, 73.9, 68.0, 34.7, 24.6 ppm. The enantiomeric ratio
of 2a was determined by HPLC analysis using Daicel Chiralcel AD column: n-hexane : isopropanol
= 99.8:0.2, flow rate 0.5 mL/min, λ = 254 nm (channel 1): t1 (minor) = 10.2 min, t2 (major) = 11.6
min.
Associated Content
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX.
Experimental details, computational details, spectroscopy data and HPLC chromatograms (PDF).
Author Information
Corresponding Author
*E-mail: joseph.samec@su.se (J. S. M. Samec), rahulwatile@gmail.com (R.A. Watile)
ORCID
Anon Bunrit: 0000-0003-0203-8478
Pemikar Srifa: 0000-0002-4233-9075
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Christian Dahlstrand: 0000-0003-2485-8661
Thanya Rukkijakan: 0000-0003-3020-631X
Genping Huang: 0000-0002-2249-1248
Srijit Biswas: 0000-0003-2363-7381
Rahul A. Watile: 0000-0002-5890-0867
Joseph S. M. Samec: 0000-0001-8735-5397
Notes
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The authors declare no competing financial interest.
Acknowledgements
J.S.M.S. thanks the Swedish Research Council (FORMAS), Olle Engkvist Byggmästare, and
Wenner-Gren for financial support. Computer time was generously granted by the Swedish National
Infrastructure for Computing.
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