Nucleophilic substitution of p-stereogenic chlorophosphines: Mechanism, stereochemistry, and stereoselective conversions of diastereomeric secondary phosphine oxides to tertiary phosphines

Article abstract of DOI:10.1021/acs.orglett.7b02667

A diastereomeric mixture of secondary phosphine oxide is stereospecifically converted to chlorophosphine salt by treatment with oxalyl chloride, which stereoselectively affords P-inverted or retained tertiary phosphines, depending on the substitution with aliphatic or aromatic Grignard reagents, respectively, in high to 99% yield and 99:1 dr. The repulsion of π- electron on aryl to lone electron pair on phosphorus is proposed for the P-retained substitution.

Full text of DOI:10.1021/acs.orglett.7b02667

Letter
pubs.acs.org/OrgLett
Nucleophilic Substitution of P‑Stereogenic Chlorophosphines:
Mechanism, Stereochemistry, and Stereoselective Conversions of
Diastereomeric Secondary Phosphine Oxides to Tertiary Phosphines
Jing-Jing Ye,† Shao-Zhen Nie,† Ji-Ping Wang, Jing-Hong Wen, Yu Zhang, Mao-Ran Qiu,
and Chang-Qiu Zhao*
College of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, Shandong 252059, China
S
* Supporting Information
ABSTRACT: A diastereomeric mixture of secondary phosphine oxide is stereospecifically converted to chlorophosphine salt by
treatment with oxalyl chloride, which stereoselectively affords P-inverted or retained tertiary phosphines, depending on the
substitution with aliphatic or aromatic Grignard reagents, respectively, in high to 99% yield and 99:1 dr. The repulsion of π-
electron on aryl to lone electron pair on phosphorus is proposed for the P-retained substitution.
halogenation followed by substitution with metallic reagents,11
hiral tertiary phosphines attract extensive attention
Cbecause of their important applications in asymmetric
with good stereoselectivity. However, the optically pure SPOs
are difficult to acquire.12 Another precursor SPB (secondary
phosphine borane), usually prepared from SPO, is similarly
converted to TPB (tertiary phosphines borane) but is also
restricted by poor availability.13 Thus, the use of an accessible
racemic or epimeric SPO or SPB in the strategy is highly
valuable.
synthesis, as ligands of metallic catalysts1 and as organo-
catalysts.2 Because the stereogenic center is closer to the active
center, P-stereogenic tertiary phosphines exhibit excellent
asymmetric induction.3 Traditionally, the compounds are
generated from multistep conversions,4 tedious resolutions,5
or by asymmetric reactions.6 Several recent reviews have
documented the preparation of stereogenic phosphines.7
The stereogenic secondary phosphine oxides (SPO) can be
easily converted to tertiary phosphines oxides (TPO) via
alkylating, cross-coupling, addition (Figure 1),8−10 and
The above-obtained TPO or TPB contains oxygen or boron
that have to be removed to form TP.14 The straightforward
conversion of SPO to TP, even for the nonchiral ones, has
rarely been reported (Figure 1). In addition, the P-chirality is
probably lost during the multistep conversions from SPO to
TP.14,15 Shortening the pathway can reduce the loss.
The traditional nucleophilic substitutions of the P-
heteroatom species16 can be applied for the preparation of
stereogenic TPO11b,17 and TPB18 (Figure 1b). The strategy has
been used for the synthesis of the famous DIPAMP, as reported
by Knowles.4 Obviously, unprotected stereogenic chlorophos-
phines are more straightforward precursors of TP. However,
perhaps due to configurationally instability,18a,19 to the best of
our knowledge, their substitution, mechanism and stereo-
chemistry have rarely been reported.
Herein we disclose a stereospecific conversion of epimeric
(−)-menthyl alkylphosphine oxide 1/1′20 to a hydrochloride
salt of chlorophosphine (Figure 1). The salt was stereo-
selectively converted to P-inverted and retained TP via the
Received: August 27, 2017
Figure 1. Comparison of our work to traditional reactions.
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b02667
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Letter
substitution with aliphatic and aromatic metallic reagents,
respectively.
Table 1. Preparation of 4 or 4′ from 1/1′ via Chlorination−
Substitution
When RP-1a was chlorinated with oxalyl chloride at 0 °C14c,21
and then reacted in situ with benzyl magnesium chloride 2a, RP-
3a and SP-3a′ were detected, as evidenced by the peaks at
−16.0 and −12.7 ppm (72:28) on 31P NMR spectrum. After
protection with borane, RP-4a and SP-4a′ were formed.
Compound 3a/3a′ was oxidized to SP-5a and RP-5a′ when
exposed to air (Scheme 1). The structures of 3a, 4a, and 5a
were confirmed on the basis of X-ray diffraction.
Scheme 1. Conversion of 1a to 3a, 4a, and 5a and Their 31P
NMR Spectral Data
When the reaction was carried out at −80 °C, the dr (5a/
5a′) improved to 82:18. Surprisingly, when RP-1a was replaced
by a mixture of 1a/1a′, similar dr was observed, indicating
either RP-1a or SP-1a′ was similarly chlorinated and substituted.
Thus, the mixture of 1/1′ was employed for the preparation of
TP and their derivatives.
As seen in Table 1, methyl- or tert-butyl-substituted benzyl
Grignard reagents with 1a afforded 4b to 4d in higher dr than
4a. Chloro-substituted 4e was formed in poorer dr than 4a.
Aliphatic 2, with primary and secondary alkyl Grignard
reagents, afforded 4f to 4m in excellent dr. Aromatic 2 usually
gave poorer dr than aliphatic compounds, except for methoxyl-
substituted 2s to 2t that formed 4s′ to 4t′ around 10:90 dr.
Similarly, 1b/1b′ (R = p-methylphenyl) or 1c/1c′ (R = benzyl)
formed 4z to 4ac′ in good to excellent dr. Most 4 could be
isolated as single stereoisomers.
a
The yield and dr (RP-4/SP-4′) were estimated by 31P{1H} NMR
spectrum. The structure of RP-4/SP-4′ was confirmed based on NMR
b
spectrum and X-ray diffraction. The structures of RP-4ab and SP-4ac′
were determined based on NMR spectrum, which were different to the
title equation (as seen in Table S2).
The structure of RP-4g was confirmed via the substitution of
menthyl phenylphosphinic chloride 6 that was obtained from
chlorination of RP-1a with NCS. Additionally, the X-ray
diffraction of 4i unambiguously confirmed its RP-configuration
(Figure 2). However, the substitution with aromatic 2 formed
SP-4′ as major products, whose structure was confirmed by the
X-ray analysis of 4r′ and 4s′. The configuration of other 4 and
4′ was determined based on their characteristic peaks on
31P{1H} NMR spectrum, which were well correlated with 4i
and 4r′.
A chlorinated intermediate was proposed to involve in the
substitution. As seen in Scheme 2, the chlorination of either 1a
or 1a/1a′ gave the broadly single peak at 103.8 ppm on 31P
NMR spectrum, which was assigned as a hydrochloride salt 7 of
chlorophosphine 8 (runs 1 and 2). The treatment of a prepared
8/8′ (75:25) with anhydrous HCl afforded 7/7′ in a similar
ratio, as evidenced by the peaks at 103.8 and 98.7 ppm (runs 4
and 5). Thus, 7 was formed as a single stereoisomer during the
chlorination of 1a/1a′, and could not be converted to 7′, as we
observed no ratio change in runs 3 and 6.
When prepared in the presence of triethylamine, or treated
with base, 7 was converted to 8/8′ around 75:25 ratio (runs 7−
9). We supposed 7 was converted to 8 that was epimerized to
8′, similar to the reported slowly racemization of P-stereogenic
Figure 2. Structure of X-ray diffraction for 4i and 4r′.
chlorophosphine.19 The chiral (−)-menthyl perhaps stabilized
the configuration of 7, and the maintained 8 was epimerized to
8′ in a 75:25 ratio, rather than thoroughly to 50:50.22
The deprotonation of 7 and the subsequent substitution of 8
with 2 afforded 3. The slow epimerization of 8 was proposed to
lead the loss of the chirality during the substitution. Active 2
reacted with 8 rapidly before the epimerization, giving excellent
dr. The sluggish reaction of less active 2 led to more
epimerization of 8 and poor dr (Scheme 3). The rough trend
of dr to the activities of 2 could be observed in Table 1.
B
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11 that generated P-retained SP-3′ upon chloride loss. Thus,
aromatic 2 gave poorer or reversed dr (Scheme 4).24,25
The p−π repulsion could be observed in Scheme 3. As less
active nucleophiles, 2q and lithium ethoxide 2ad did not react
with 8 at −80 °C. However, at room temperature, they
predominantly afforded P-retained 3q′ and P-inverted 3ad,
respectively. The absence of π-electron was supposed to lead to
2ad attacking at 8 opposite chloride in a P-inverted SN2-like
manner. In addition, the reported P-retained substitution of
cyclic chiral P−Cl species with ferrocene lithium also supported
the proposal of p-π repulsion.26
Scheme 2. Chlorination and Conversion of 1a or 1a/1a′
Although the mechanism for the stereospecific formation of
7 was not clear, we attempted to grasp some aspects based on
the observations. As aforementioned, 7 and 7′ did not
converted each other. Thus, the chlorination of 1a and 1a′ to
form 7 was supposed to occur via different pathways. The poor
dr for the chlorination with thionyl chloride or triphosgene
exhibited an intramolecular attack via a cyclic intermediate,
perhaps involved with the chlorination with oxalyl chloride. As
proposed in Scheme 5, the weakly bonding H or electro-
Scheme 3. Substitution of 7 at Different Temperatures
Scheme 5. Proposed Stereospecific Chlorination of 1a/1a′
At −80 °C, the epimerization was slowed down and dr was
improved. However, some less active 2 did not react with 8 at
this temperature. For example, when the reaction of 2q (R = o-
tolyl) was quenched at −80 °C, only 1a/1a′ was formed via the
hydrolysis of unreacted 8/8′. Similarly quenching the reaction
of 2g gave 3g/3g′ in 98:2 ratio. The better dr (1:99) for 2s at
−80 °C for 7 h showed that the epimerization hardly took place
(Scheme 3).
When more active lithium reagent was used, expected
improvement of dr was not observed. We supposed that the
facile solvable lithium chloride enhanced the chloride-
promoting epimerization of 8.23 In contrast, magnesium salt
released less chloride ion and gave better dr. In fact, a cloudy
mixture developed for the reaction with 2h, whereas a clear
solution was observed for n-butyllithium.
The SP-structures of 7 and 8 were confirmed via the
oxidization of 8/8′ to 6/6′. For the aliphatic Grignard reagents,
the normal SN2-like P-inverted substitution of 8 was supposed
to occur via attacking phosphorus opposite chloride, similarly
to that of P(V)−X species24 (Scheme 4).
However, the repulsion of the lone electron pair of 8 to π-
electron on a benzene ring led to aryl approaching to
phosphorus difficultly, which was different to P(V)-X species.
Some EDW-containing aryl, such as 2r to 2u, showed enhanced
activity, attacking 8 opposite the lone electron pair to evade the
p-π repulsion. The Berry pseudorotation (BPR) of 10 afforded
negative oxygen tended to locate at the apical position of a
trigonal bipyramidal structure of 12 that was generated from 1a,
and chloride attacked from another apical position.24 An
intramolecular attacking opposite proton (path a) was hindered
by isopropyl. Another chloride approached opposite oxygen
(path b) afforded 7 in a SN2-like manner. In 13, the
intramolecular attacking of chloride (path c) formed a stable
cyclic intermediate 14 that was converted to 15 via a BPR then
further to 7.
In summary, the epimeric mixture 1/1′ was successfully
converted to tertiary phosphine 3 or its borane complex 4 in
excellent stereoselectivity. The chlorination of 1a and 1a′ was
assumed as a SN2-like and an intramolecular route, respectively,
affording the same phosphonium salt 7. When reacted with
aliphatic 2, 7 was deprotonated and converted to 8 that was
substituted in a normal SN2-like manner to form P-inverted RP-
3. For aromatic 2, the p−π repulsion of aryl to phosphorus led
attacking opposite lone electron pair and formation of P-
retained SP-3′ after BPR. The epimerization of 7 resulted in
partial loss of chirality on phosphorus. This research supplied
an example of the substitution of chlorophosphine, and the
stereochemistry and mechanism were explored, which are
hoped to have extensive application in asymmetric catalysis.
Scheme 4. Proposed Mechanism of Substitution of 8
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02667.
C
DOI: 10.1021/acs.orglett.7b02667
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Experimental procedures, spectral data for products, and
Letter
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crystallographic information (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: literabc@hotmail.com.
ORCID
Chang-Qiu Zhao: 0000-0002-9016-8151
Author Contributions
†J.-J.Y. and S.-Z.N. contributed equally to this work.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We acknowledge the financial support of the Natural Science
Foundation of China (Grant No. 20772055) and the Natural
Science Foundation of Shandong Province (Grant No.
ZR2016BM18 and ZR2014BP007).
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