P-Stereogenic β-Aminophosphines: Preparation and Applications in Enantioselective Organocatalysis

Article abstract of DOI:10.1021/acs.joc.7b00199

The synthesis of stereodefined β-aminophosphines having both carbon- and phosphorus-based chirality centers is described. The method involves resolution of a mixture of β-aminophosphine oxide diastereomers accessed by ring-opening of an amino alcohol-derived cyclic sulfamidate. A stereospecific, borane-promoted reduction of β-aminophosphine oxides, which occurs under mild conditions and with inversion of configuration at phosphorus, is a key step in this process. The products obtained are new building blocks for the synthesis of P-chiral ligands and organocatalysts. In a proof-of-concept application in organocatalysis, the diastereomeric P-chiral β-aminophosphine-based bifunctional thioureas displayed significantly different activities in the Morita-Baylis-Hillman reaction of methyl acrylate with benzaldehyde derivatives.

Full text of DOI:10.1021/acs.joc.7b00199

Article
pubs.acs.org/joc
P‑Stereogenic β‑Aminophosphines: Preparation and Applications in
Enantioselective Organocatalysis
Hsin Y. Su and Mark S. Taylor*
Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: The synthesis of stereodefined β-aminophos-
phines having both carbon- and phosphorus-based chirality
centers is described. The method involves resolution of a
mixture of β-aminophosphine oxide diastereomers accessed by
ring-opening of an amino alcohol-derived cyclic sulfamidate. A
stereospecific, borane-promoted reduction of β-aminophos-
phine oxides, which occurs under mild conditions and with
inversion of configuration at phosphorus, is a key step in this
process. The products obtained are new building blocks for the
synthesis of P-chiral ligands and organocatalysts. In a proof-of-concept application in organocatalysis, the diastereomeric P-chiral
β-aminophosphine-based bifunctional thioureas displayed significantly different activities in the Morita−Baylis−Hillman reaction
of methyl acrylate with benzaldehyde derivatives.
cyclic sulfamidates with metal diarylphosphinites (Scheme
1a).10 Using secondary phosphine oxides rather than secondary
INTRODUCTION
■
P-Stereogenic phosphines have been used extensively in
enantioselective catalysis, particularly as chiral ligands or
organocatalysts.1 Preparing these compounds in enantioen-
riched form is a challenge, and continues to inspire the
development of new synthetic methods. Approaches that have
been implemented successfully include resolution,2 the use of
chiral auxiliaries,3 kinetic and dynamic kinetic resolution,4,5
desymmetrization6 and enantioselective P-arylation7 or P-
alkylation.8 Phosphines that possess an additional element of
chirality along with the P-stereogenic center present unique
potential advantages. Opportunities exist to prepare such
compounds efficiently, taking advantage of methods for the
selective synthesis or separation of diastereomers. The ability to
vary the relative configuration of the two chirality centers, in
addition to other steric and electronic properties, may also be
useful when optimizing catalyst performance. Several types of
P-stereogenic phosphines containing one or more additional
chirality centers or other elements of chirality (e.g., chirality
axes) have been synthesized (Figure 1).9
Scheme 1. (a) Preparation of β-Aminophosphines from
Cyclic Sulfamidates and Diarylphosphinites; (b) Envisioned
Synthesis of P-Chiral Congeners
phosphines11,12 as pro-nucleophiles for ring-opening proved to
be particularly advantageous for the synthesis of derivatives
having substituted aryl groups at phosphorus, as it minimized
the purification and handling of air-sensitive phosphine
intermediates.13 β-Aminophosphines are useful precursors to
chiral ligands14−19 and organocatalysts,20−23 and access to P-
aryl-substituted derivatives creates opportunities to explore
structure−activity relationships for these types of catalytic
applications. The ability to vary the phosphine substituents also
suggested the possibility of generating P-stereogenic β-amino-
We recently developed a protocol for the synthesis of chiral
β-aminophosphines by ring-opening of amino alcohol-derived
Figure 1. Examples of reported P-stereogenic phosphines having an
additional element of chirality.
Received: January 25, 2017
© XXXX American Chemical Society
A
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phosphines from unsymmetrical phosphine oxides (Scheme
1b). The reaction of an enantiopure sulfamidate with a metal
diarylphosphinite derived from a racemic secondary phosphine
oxide would result in a mixture of diastereomers. Phosphines of
defined configuration at the two chirality centers could be
accessed by separation of the diastereomersby chromatog-
raphy or recrystallization, again taking advantage of the ease of
isolation and handling of phosphine oxide derivatives
followed by stereospecific reduction. Here, we describe the
successful realization of this strategy, and the preparation of
novel, stereodefined β-aminophosphines having both carbon-
and phosphorus-based chirality centers. In addition to the
sulfamidate/diarylphosphinite coupling mentioned above, a
stereospecific, borane-mediated reduction of β-aminophosphine
oxides was a key step in the reaction sequence. The products
were employed to synthesize the first examples of bifunctional
organocatalysts having a P-stereogenic phosphine moiety,
revealing an unexpected effect of relative configuration on
catalytic activity in the asymmetric Morita−Baylis−Hillman
reaction.
Unsymmetric phosphine oxide 2, the starting material
needed for the preparation of (o-anisyl) (phenyl)phosphines
(S,RP)-1a and (S,SP)-1b, was prepared according to reported
protocols.25 Compound 2 was then coupled with sulfamidate 3
using the procedure developed in our laboratory, yielding a
mixture of diastereomeric, tert-butoxycarbonyl- (Boc)-protected
aminophosphine oxides (Scheme 3a). Removal of the Boc
Scheme 3. (a) Preparation of Diastereomeric Hydrochloride
Salts (S,RP)-8a·HCl and (S,SP)-8b·HCl from Secondary
Phosphine Oxide 2 and Enantioenriched Sulfamidate 3; (b)
Epimerization of the Tertiary Phosphine Oxide Chirality
Center under Conditions for Deprotection of the Boc
a
Group
RESULTS AND DISCUSSION
■
Preparation and Resolution of P-Chiral β-Amino-
phosphine Oxides. The targets for our initial studies were
diastereomeric ligands (S,RP)-1a and (S,SP)-1b shown in
Scheme 2a, which combine a tert-leucinol-derived chirality
Scheme 2. (a) Structures of β-Aminophosphines (S,RP)-1a
and (S,SP)-1b Targeted in This Study; (b) Approaches to
Previously Reported β-Aminophosphines 4, (RP,R)-5a and
a
Conditions A: CF3CO2H, CH2Cl2, 23 °C. Conditions B: BF3·OEt2, 4
a
(SP,R)-5a
Å MS, CH2Cl2, 23 °C.
group was accomplished by treatment with trifluoroacetic acid
in dichloromethane, and the resulting amine was treated with
anhydrous hydrogen chloride in diethyl ether to generate a 1:1
mixture of diastereomeric ammonium salts (S,RP)-8a·HCl and
(S,SP)-8b·HCl. A 70% yield was obtained over the three-step
process of sulfamidate ring-opening, deprotection and salt
formation. It should be noted that the phosphine oxide chirality
center is subject to epimerization under the conditions for Boc
deprotection shown in Scheme 3a. This fact was established by
subjecting diasteromerically pure (S,RP)-7aobtained from the
mixture by preparative thin layer chromatography on silica gel,
using a mixture of diethyl ether, hexanes and triethylamine
(15:5:1 by volume) as the mobile phaseto trifluoroacetic acid
in dichloromethane (Scheme 3b). The product amino-
phosphine oxide (S,RP)-8a was obtained as a 9:1 mixture of
diastereomers, as assessed by 31P NMR spectroscopy.
Presumably, the epimerization follows a pathway similar to
that proposed by Mislow and co-workers for the racemization
of tertiary phosphine oxides by HCl.26 Epimerization could be
suppressed by using boron trifluoride diethyl etherate27 rather
than trifluoroacetic acid as the reagent for deprotection of the
Boc group. Since the present approach involves separation of
the diastereomers after cleavage of the Boc group, the
configurational instability of the phosphine oxide in the
presence of acid is not an issue, and the deprotection was
conducted using TFA.
a
o-An denotes ortho-anisyl (2-methoxyphenyl).
center with the (o-anisyl) (phenyl)phosphine substitution
pattern characteristic of the iconic P-stereogenic phosphines
PAMP and DIPAMP.24 Related examples of stereodefined β-
aminophosphines having chirality centers at the phosphorus
atom at the α- or β-position are 4, which was prepared by
diastereoselective addition of enantioenriched, lithiated
PAMP−borane to an imine (Scheme 2b),9c and the
diastereomers (RP,R)-5a and (SP,R)-5b, which were generated
from the borane complex of enantiopure trans-1-phenyl-
phospholane-2-carboxylic acid.9d
Separation of the diastereomeric ammonium salts was
accomplished by fractional recrystallization from a mixture of
acetonitrile and diisopropyl ether (3:1 by volume, Scheme 4).
The less soluble isomer was obtained with a diasteomeric ratio
B
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Scheme 4. Separation of Diastereomeric β-Aminophosphine
Oxide Hydrochloride Salts by Fractional Recrystallization
Scheme 5. (a) Epimerization upon Reduction of Phosphine
Oxide (S,RP)-8a by Diphenylsilane; (b) Stereospecific,
Borane-Mediated Reduction of Epimeric Phosphine Oxides
a
(S,RP)-8a and (S,SP)-8b
of greater than 40:1. It was found to have the R configuration at
phosphorus, as determined by X-ray crystallography (Support-
ing Information, Figure S1). The filtrate was enriched in the
(S,SP) isomer, with a diastereomeric ratio of 3:1. The mixture of
diastereomers obtained from the filtrate was carried through
subsequent manipulations until column chromatography could
be used to obtain diastereomerically pure material (see below).
The hydrochloride salts were converted to the corresponding
free amines by treatment with Amberlite IRA-400, a basic anion
exchange resin.
Stereospecific Reduction of P-Chiral β-Aminophos-
phine Oxides. Having established that the diastereomeric β-
aminophosphines could be separated by recrystallization of
their hydrochloride salts, we turned our attention to the
stereospecific reduction of the phosphine oxide group. When
(S,RP)-8a was subjected to diphenylsilane in the absence of
solvent at 140 °C,10,28 the reduction was achieved in
quantitative yield, but the aminophosphine was obtained as a
1:1 mixture of diastereomers (Scheme 5a). Based on the
reported rate constants for racemization of (alkyl)-
diarylphosphines via pyramidal inversion, the product is
unlikely to be configurationally stable at 140 °C.29 Other
silane-derived reagents, including chlorosilane (with or without
amine additives) and phenylsilane, have been used to reduce
optically active phosphine oxides to phosphines.30 Using such
reagents, racemization at phosphorus can usually be minimized,
but not entirely eliminated, and care is often needed to avoid
oxidation of the phosphine product during the workup and
purification steps. Stereospecific reductions of phosphine oxides
have also been achieved using methyl triflate and lithium
aluminum hydride, but the former reagent would not likely be
compatible with the free amine group in the present system. On
the other hand, the mild conditions that have been employed
for stereospecific reductions of α- and β-hydroxyphosphine
oxides appeared to be particularly promising as a solution to
this problem.31 Reaction of tertiary α- and β-hydroxyphosphine
oxides with borane complexes (BH3·THF or BH3·SMe2)
resulted in the efficient formation of the corresponding
phosphine−borane complexes in THF at room temperature
or 60 °C.31c Unfunctionalized tertiary phosphine oxides were
unreactive under these conditions, and it was proposed that the
formation of a cyclic complex from BH3 and the hydrox-
yphosphine oxide served to activate the phosphorus−oxygen
bond toward reduction. On the basis of this proposal,
reductions of β-aminophosphine oxides such as 8a and 8b
under similar conditions could be envisioned, with the amino
group interacting with the boron Lewis acid in place of the OH
a
The relative configuration of (S,SP)-8b was established by conversion
to (S,SP)-9b·BH3 and structural determination by X-ray crystallog-
raphy.
group. Indeed, treatment of (S,RP)-8a with BH3·SMe2 in THF
at 70 °C resulted in the evolution of hydrogen gas and the
reduction of the phosphine oxide, leading to the formation of
phosphine−borane complex (S,RP)-1a·BH3 (Scheme 5b). In a
similar way, the mixture of aminophosphine oxide diaster-
eomers enriched in (S,SP)-8b (3:1 d.r.) was reduced under
these conditions, leading to phosphine−borane complexes that
could be separated by flash column chromatography on silica
gel. Complex (S,SP)-1b·BH3 was obtained in 20:1 d.r. The
formation of air-stable phosphine−borane complexes that can
be purified by column chromatography is an advantage of the
borane-mediated reduction protocol. As was observed
previously, unfunctionalized tertiary phosphine oxides were
unreactive under these conditions, as were N-Boc-protected β-
aminophosphine oxide derivatives (data not shown).
In contrast to the retention of configuration that has
generally been observed for silane-mediated reductions of
phosphine oxides, inversion of configuration at phosphorus has
been documented for reductions of α- and β-hydroxyphosphine
oxides with BH3 complexes.31b,c The stereochemical outcome
of the BH3-mediated reduction was rationalized in terms of a
mechanism involving SN2-type cleavage of the P−O bond by an
external hydride nucleophile. As shown in Scheme 5b,
reductions of β-aminophosphine oxides by BH3·SMe2 also
proceed with inversion of configuration. The configuration of
the phosphine−borane obtained from (S,SP)-8b was assigned
by single crystal X-ray diffraction analysis of the corresponding
para-nitrophenylurea derivative, (S,SP)-9b·BH3 (Supporting
Information, Figure S2). Thus, it appears that a similar
C
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mechanistic pathway to that proposed for hydroxyphosphine
oxide reductionnamely, formation of a cyclic borane adduct
and SN2-type attack of hydride on the activated P−O bondis
operative.
Scheme 7. Synthesis of Bifunctional Thioureas Derived from
(S,RP)-1a and (S,SP)-1b
The free aminophosphines (S,RP)-1a and (S,SP)-1b were
obtained by treatment of the phosphine−borane complexes
with an excess of 1,4-diazabicyclo[2.2.2]octane (DABCO) in
degassed toluene at 40 °C (Scheme 6). This reaction proceeds
Scheme 6. Synthesis of β-Aminophosphines (S,RP)-1a and
(S,SP)-1b by Decomplexation of Phosphine−Borane Adducts
Table 1. Influence of the Relative Configuration of the P-
Stereogenic Phosphine−Thiourea Catalyst on Yield and
Enantioselectivity for the Morita−Baylis−Hillman Reaction
a
b
entry
catalyst
% yield
% ee
1
2
3
4
(S,RP)-10a
(S,SP)-10b
(S,RP)-11a
(S,SP)-11b
57
10
53
12
76
73
73
72
with retention of configuration at phosphorus.3a Under the
relatively mild conditions of the decomplexation reaction,
epimerization of the P-stereogenic center could be largely
suppressed. The products were purified by flash chromatog-
raphy on silica gel with degassed solvents, using compressed
nitrogen gas to speed the flow of the eluent through the
column.
Preparation and Application of Bifunctional Organo-
catalysts Derived from P-Stereogenic β-Aminophos-
phines. As an initial application in asymmetric catalysis, we
explored the synthesis of bifunctional organocatalysts based on
(S,RP)-1a and (S,SP)-1b. Ureas, thioureas, amides and
sulfonamides derived from chiral β-aminophosphines are useful
catalysts for enantioselective Morita−Baylis−Hillman reactions
and for a range of related transformations.21−23 Although P-
stereogenic phosphines have been employed as chiral Lewis
base catalysts (for example, for [3 + 2] annulations,32 γ-
additions to allenoates33 and acylations of secondary
alcohols34), bifunctional hydrogen bond donor/phosphine
Lewis base catalysts having a P-stereogenic center have not
been explored previously. On the basis of reported structure−
activity relationships for Morita−Baylis−Hillman reactions
catalyzed by bifunctional phosphines,21a we prepared elec-
tron-deficient thioureas derived from the epimeric amino-
phosphines (Scheme 7).
The phosphine−thioureas depicted in Scheme 7 were
evaluated as catalysts for the Morita−Baylis−Hillman reaction
of methyl acrylate and benzaldehyde (Table 1). The conditions
employed for this reaction are based on those developed by Lu
and co-workers.21a The 4 Å molecular sieves (MS) were
substituted for 5 Å MS, which gave higher yields without
appreciably altering the enantioselectivity. The configuration of
the phosphorus chirality center had a significant effect on the
yield of this transformation, with the (S,RP)-configured catalysts
showing higher activity than the (S,SP)-configured variants.
Although the results of Table 1 pointed toward differences in
the behavior of the epimeric catalysts for both thiourea
substitution patterns, we sought to put this result on more solid
ground through further comparisons of the 4-nitrophenyl-
a
Yield after purification by flash column chromatography on silica gel.
Determined by high performance liquid chromatography (HPLC)
using a chiral stationary phase. The absolute configuration was
assigned by comparing the sign of the optical rotation to the literature
data.
b
substituted thiourea catalysts (S,RP)-10a and (S,SP)-10b with
(S)-10c, a variant lacking the P-stereogenic center. These
comparisons were conducted for benzaldehyde itself, using the
results from entries 1 and 2 of Table 1, and for two relatively
electron-rich, substituted variants, 4-bromobenzaldehyde and
para-tolualdehyde, which show relatively poor reactivity in
Morita−Baylis−Hillman reactions catalyzed by bifunctional
thioureas. The results are summarized in Table 2. A consistent
trend was evident across the three aldehyde substrates, with
catalyst turnover numbers decreasing in the order (S,RP)-10a >
10c > (S,SP)-10b. A small but consistent increase in
enantioselectivity for P-chiral (S,RP)-10a versus 10c was also
observed.
Stereochemical models have been proposed for Morita−
Baylis−Hillman and related reactions catalyzed by chiral β-
aminophosphines,22a,b and insight has been gained through
computational modeling.35 A rationale for the difference in
activity between the P-stereogenic aminophosphine epimers
studied here would be of interest, but the issues involved are
complex. Using diazabicyclo[2.2.2]octane (DABCO) as cata-
lyst, the aldol-type addition step and/or the elimination step
may be rate-limiting, depending on the reaction conditions.36
Experimental kinetic or isotope effect data are not available for
the bifunctional phosphine-catalyzed variant of this reaction.
Thus, it is not clear which step(s) of the catalytic cycle are
influenced by the change in configuration of the P-stereogenic
center. Nonetheless, we used density functional theory (DFT)
calculations using the B3LYP functional and the 6-31G(d,p)
basis set to model the adducts of catalysts (S,RP)-10a and
(S,SP)-10b with methyl acrylate (Figure 2). The starting
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geometries for these optimizations were based on the calculated
structures of related adducts of naphthyl acrylate with a
sulfonamide-functionalized bifunctional phosphine, from a
study conducted by Lu, Huang and co-workers.35a The
minimum-energy geometries of the adducts derived from the
thiourea-functionalized, P-chiral variants preserve the intra-
molecular NH−−O hydrogen bond that was identified in the
previously reported computational study. The calculated free
energy of the acrylate adduct of (S,SP)-10b was 1.79 kcal/mol
higher than that of (S,RP)-10a. In the structure of the higher-
energy diastereomer, the o-anisyl methoxy substituent occupies
a position close to the acrylate-derived moiety. In contrast,
these groups are oriented in opposite directions in the structure
of the lower-energy diastereomer. To the extent that this
energy difference is reflected in the relative concentrations of
kinetically relevant species derived from (S,RP)-10a and (S,SP)-
10b, the calculations may provide a plausible rationale for the
effect of configuration of the P-stereogenic center on the
activity of these bifunctional catalysts.
The results described above indicate that employing a P-
stereogenic (o-anisyl) (phenyl)phosphino group of appropriate
configuration provides an appreciable increase in catalytic
activity, along with a more modest increase in enantioselectiv-
ity, relative to the diphenylphosphino group on which the most
widely employed bifunctional organocatalysts are based. It
should be noted that the best-in-class aminophosphine-
bifunctional catalysts for Morita−Baylis−Hillman reactions
are not derived from tert-leucine, but rather from threonine
derivatives bearing bulky O-silyl substituents.21a Further
improvements upon the results shown in Table 2 may be
possible using P-chiral variants of the threonine-derived
catalysts. It will also be of interest to identify other pairs of
substituents on the P-stereogenic center that lead to more
dramatic effects on activity and enantioselectivity for this and
other organocatalytic reactions.
Table 2. Comparison of Yield and Enantioselectivity Data
for P-Chiral Catalysts (S,RP)-10a and (S,SP)-10b, and
a
Catalyst 10c Lacking the P-Stereogenic Center
catalyst
catalyst
catalyst
aldehyde
PhCHO
(S,RP)-10a
(S)-10c
(S,SP)-10b
57% yield
76% ee
33% yield
68% ee
10% yield
73% ee
4-BrC6H4CHO
4-MeC6H4CHO
80% yield
81% ee
63% yield
74% ee
<5% yield
% ee ND
<5% yield
% ee ND
41% yield
73% ee
21% yield
68% ee
a
Yields are of isolated products after purification by flash column
chromatography on silica gel. Enantiomeric excess was determined by
high performance liquid chromatography (HPLC) using a chiral
stationary phase.
CONCLUSIONS
■
Ring-opening of enantiopure cyclic sulfamidates by unsym-
metrical secondary phosphine oxide nucleophiles, followed by
resolution of the mixture of diastereomers, provides access to
new β-aminophosphines having a P-stereogenic center. The
stereospecific, borane-mediated reduction of β-aminophosphine
oxides to β-aminophosphine−boranes was important to the
successful implementation of this approach. A mechanistic link
to previously reported reductions of α- and β-hydroxyphos-
phine oxides by borane complexes is likely, with both classes of
substrates reacting with inversion of configuration at
phosphorus.
Extending this process to other combinations of phosphine
substituents will be of interest. The scope of the (symmetrical)
secondary phosphine oxide−sulfamidate coupling reaction,
which tolerates electron-deficient, electron-rich and sterically
hindered aromatic substituents at phosphorus, is encouraging
from this perspective.10 For the (o-anisyl)(phenyl)phosphine
substitution pattern, resolution of the diastereomeric phosphine
oxides was carried out by fractional recrystallization. However,
the ability to separate the epimeric phosphine−borane
complexes by column chromatography on silica gel was also
important in providing access to the more soluble diastereomer
in high purity. The possibility of achieving separation of
diastereomers by two techniques, and at different stages of the
process, may be useful in extending this approach to other
phosphine substitution patterns.
Figure 2. Calculated structures (B3LYP/6-31G(d,p)) and relative
energies of the adducts of methyl acrylate with (S,RP)-10a and (S,SP)-
10b. Ar denotes 4-nitrophenyl.
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anhydrous Na2SO4, filtered and concentrated in vacuo to give a brown
oil.
The organocatalysis experiments described here indicate that
the configuration of the P-chiral phosphine substituent can
influence the behavior of bifunctional thioureas derived from 1a
and 1b. The primary effect is on catalyst activity, with the
(S,RP)-configured diastereomer showing higher activity than
the diphenylphosphino variant and the (S,SP)-configured
diastereomer being significantly less active. A modest but
consistent beneficial effect of the RP-configured (o-anisyl)-
phenylphosphino substituent on enantioselectivity was also
observed. Evaluating other P-chiral phosphine substituents may
help to elucidate the factors responsible for this effect, and
could lead to more pronounced improvements in catalytic
properties. Given that β-aminophosphines are components of
useful classes of chiral ligands, applications of P-chiral variants
in transition metal catalysis are another potential direction for
future studies.
The oil was taken up in CH2Cl2 (12 mL) and cooled to 0 °C.
Trifluoroacetic acid (5.5 mL, 72 mmol) was added dropwise. The
reaction mixture was stirred at 23 °C overnight. The volatiles were
then removed on the rotary evaporator the next day. The residue was
taken up in CH2Cl2 and washed with saturated Na2CO3. The aqueous
layer was separated and extracted four times with CH2Cl2. The organic
extracts were then combined, washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated in vacuo to give a brown oil.
To a round-bottom flask equipped with a magnetic stirring bar was
added the oil. Et2O (50 mL) was added. Anhydrous HCl (2.8 mL, 1
M, 2.8 mmol) was added dropwise at 23 °C with vigorous stirring. The
white suspension was filtered over a Buchner funnel under vacuum to
give 8a·HCl + 8b·HCl (1:1 d.r., 0.71 g, 70%) as a white solid.
To a round-bottom flask equipped with a magnetic stirring bar was
added the white solid. MeCN (27 mL) was added. The white
suspension was stirred at 90 °C in an oil bath until homogeneity was
observed. The flask was then removed from the oil bath and iPr2O (9
mL) was added. The flask was sealed and allowed to cool down to 23
°C. The solvents were then removed on the rotary evaporator upon
formation of a white precipitate until very little solvent remained. The
resulting slurry was filtered over a Buchner funnel under vacuum to
give enriched 8a·HCl as a white solid. The process was repeated twice
using MeCN (36 and 45 mL) and iPr2O (12 and 15 mL) to give the
final enriched 8a·HCl (>40:1 d.r., 0.21 g) as a white solid. The filtrates
containing 8b·HCl were combined and concentrated in vacuo to give a
light brown residue (3:1 d.r., 0.49 g, 69%).
EXPERIMENTAL SECTION
■
General Procedures. Stainless steel syringes were used to transfer
air- and moisture-sensitive liquids. Flash column chromatography was
carried out using 35−75 μm particle size silica gel.
Materials. All commercially available reagents and chemicals were
used as received without purification. Benzaldehyde, p-tolualdehyde
and 4-bromobenzaldehyde were purified by passing through a short
plug of activated Al2O3 (basic, Brockmann I) immediately before use.
All solvents were dried using a solvent purification system and
degassed through three freeze−pump−thaw cycles. Deuterated
solvents were degassed through three freeze−pump−thaw cycles.
Unless otherwise stated, all reactions and purifications were carried out
under argon atmosphere using Schlenk, vacuum line, or glovebox
techniques in dry, oxygen-free solvents. Unsymmetrical secondary
phosphine oxide 225 and the tert-butyl cyclic sulfamidate 311 were
synthesized according to published protocols.
Instrumentation. 500 and 400 MHz spectrometers were
employed for recording 1H (400 MHz), 13C{1H} (125 and 100
MHz), 31P{1H} (160 MHz), 11B (128 MHz) and 19F{1H} (376 MHz)
NMR spectra at ambient temperature. 1H chemical shifts are reported
as ppm relative to tetramethylsilane, and were measured by referencing
the spectra to residual protium in the solvent. 31P chemical shifts are
reported in parts per million (ppm) relative to 85% H3PO4 as an
external reference. 19F chemical shifts are reported in ppm relative to
CFCl3 as an external reference. Coupling constants (J) are given in Hz.
1H data are reported as multiplicity (br = broad singlet, s = singlet, d =
The white solid consisting of 8a·HCl was taken up in MeOH (40
mL) in a round-bottom flask. Amberlite IRA-400 (OH) resin (5.0 g
per gram of white solid) was added and stirred vigorously at 23 °C for
30 min. The suspension was then filtered and the filtrate was
concentrated in vacuo to give product 8a with high analytical purity
(>40:1 d.r., 0.19 g, 30%) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.91 (ddd, J = 13.0, 7.6, 1.8 Hz, 1H), 7.83 (ddt, J = 11.6, 6.9,
1.5 Hz, 2H), 7.46 (ttdd, J = 8.6, 6.6, 3.3, 1.7 Hz, 4H), 7.11−7.04 (m,
1H), 6.90 (dd, J = 8.2, 5.4 Hz, 1H), 3.83 (s, 3H), 3.00 (ddd, J = 12.5,
11.2, 1.2 Hz, 1H), 2.73 (ddd, J = 15.1, 10.9, 1.2 Hz, 1H), 2.40 (s, 2H),
2.25 (ddd, J = 15.1, 13.4, 11.2 Hz, 1H), 0.91 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 159.6 (d, J = 4.0 Hz), 133.8 (d, J = 2.0 Hz), 133. Eight
(d, J = 9.0 Hz), 133.6 (d, 1JCP = 99.0 Hz), 131.3 (d, J = 3.0 Hz), 131.0
1
(d, J = 10.0 Hz), 128.2 (d, J = 12.0 Hz), 122.2 (d, JCP = 95.0 Hz),
121.3 (d, J = 11.0 Hz), 111.0 (d, J = 7.0 Hz), 55.4, 55.3 (d, 2JCP = 5.0
Hz), 35.0 (d, 3JCP = 13.0 Hz), 31.8 (d, 1JCP = 73.0 Hz), 25.9. 31P NMR
(160 MHz, CDCl3) δ 31.96. IR (neat, cm −1) 2958 (w), 1592 (m),
1579 (m), 1477 (m), 1466 (m), 1435 (m), 1240 (m), 1181 (s), 1141
doublet, t = triplet, q = quartet). Attenuated total reflectance infrared
(IR) spectra were obtained in the solid form or as neat liquid, as
indicated. High resolution mass spectroscopy (HRMS) experiments
were carried out using a time-of-flight mass spectrometer equipped
with a direct analysis in real time (DART) ion source. Melting points
were as measured and are uncorrected. Enantiomeric excesses (ee)
were determined by normal-phase HPLC analysis with a commercially
available chiral stationary phase, using a mixture of hexanes−2-
propanol as eluent and with UV detector set at 254 or 210 nm.
(R)-((S)-2-Amino-3,3-dimethylbutyl)(2-methoxyphenyl)(phenyl)-
phosphine oxide (8a). In a nitrogen-filled gloxebox, an oven-dried
screw-cap reaction tube equipped with a magnetic stirring bar was
charged with KOt-Bu (0.31 g, 2.8 mmol). THF (6 mL) was then
added outside of the glovebox. Racemic phosphine oxide 2 (0.65 g, 2.8
mmol) was dissolved in THF (6 mL) in a separate oven-dried pear-
shaped flask and transferred dropwise into the reaction mixture via a
syringe. The reaction was stirred at 23 °C for 10 min. Sulfamidate 3
(0.78 g, 2.8 mmol) was dissolved in THF (6 mL) in another oven-
dried pear-shaped flask and transferred dropwise into the reaction
mixture via a syringe. The reaction tube was then sealed and stirred at
60 °C for 17 h. The reaction was quenched with H2SO4 (80 mL, 2 M)
and stirred vigorously at 23 °C for 45 min. It was then extracted two
times with Et2O, and the combined organic extracts were washed with
saturated Na2CO3, followed by brine. The solution was dried over
(m), 1108 (m), 1078 (m), 1024 (m), 923 (br), 801 (m), 776 (s), 741
20
(s), 703 (s). Optical rotation [α] = +31.2 (c = 0.10 g mL−1, CHCl3).
589
HRMS (DART, m/z) calculated for C19H27NO2P [(M + H)+]:
332.1774. Found: 332.1779.
(S)-1-((S)-(2-Methoxyphenyl)(phenyl)phosphanylborane)-3,3-di-
methylbutan-2-amine (1b·BH3). The light brown residue consisting
of 8b·HCl was taken up in MeOH (60 mL). Amberlite IRA-400 (OH)
resin (5.0 g per gram of residue) was added and stirred vigorously at
23 °C for 30 min. The suspension was then filtered and the filtrate was
concentrated in vacuo to give crude 8b (3:1 d.r., 0.47 g) as a light
brown oil.
To an oven-dried round-bottom flask equipped with a magnetic
stirring bar was added crude 8b (0.47 g, 1.4 mmol). THF (15 mL) was
added and cooled down to 0 °C. BH3·SMe2 (0.48 mL, 5.1 mmol) was
then added dropwise via a syringe at 0 °C under a positive pressure of
argon. The reaction was stirred at 70 °C for 4 h. The reaction was
quenched with saturated NH4Cl (20 mL) and extracted four times
with CH2Cl2. The organic extracts were combined, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo to give the
crude product. Purification by flash chromatography on silica gel (100
g of Si2O per gram of crude product; 1% MeOH/CH2Cl2) gave 1b·
1
BH3 (80 mg, 25% over two steps) as a colorless oil. H NMR (400
MHz, CDCl3) δ 7.88 (ddd, J = 13.6, 7.6, 1.6 Hz, 1H), 7.72−7.63 (m,
2H), 7.51−7.45 (m, 1H), 7.44−7.33 (m, 3H), 7.05 (tdd, J = 7.5, 1.9,
F
DOI: 10.1021/acs.joc.7b00199
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
0.9 Hz, 1H), 6.89 (dd, J = 8.1, 3.2 Hz, 1H), 3.72 (s, 3H), 2.93 (ddd, J
= 12.3, 10.4, 1.7 Hz, 1H), 2.57 (ddd, J = 14.4, 12.6, 1.7 Hz, 1H), 2.45
(ddd, J = 14.4, 12.3, 10.4 Hz, 1H), 1.19−1.10 (m, 2H), 0.90 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 161.3 (d, J = 2.0 Hz), 135.9 (d, J =
14.0 Hz), 133.7 (d, J = 2.0 Hz), 131.9 (d, J = 9.0 Hz), 130.6 (d, J =
58.0 Hz), 130.5 (d, J = 2.0 Hz), 128.4 (d, J = 10.0 Hz), 121.4 (d, J =
12.0 Hz), 117.6 (d, J = 52.0 Hz), 111.5 (d, J = 4.0 Hz), 55.6 (d, J =
silica gel using a positive pressure of N2 and solvents presparged with
N2 (2.5% MeOH/CH2Cl2) to give the pure product.
(S)-((R)-(2-Methoxyphenyl)(phenyl)phosphanyl)-3,3-dimethylbu-
tan-2-amine (1a). This compound was synthesized according to the
general procedure using phosphine borane 1a·BH3 (39 mg, 0.12
mmol) and DABCO (20 mg, 0.18 mmol, 1.5 equiv) in toluene (1.2
mL). The crude product was purified by flash chromatography on
silica gel (2.5% MeOH/CH2Cl2) to give the pure product (27:1 d.r.,
33.0 Hz), 35.3 (d, J = 11.0 Hz), 27.9 (d, J = 38.0 Hz), 26.0. 31P NMR
1
1
(160 MHz, CDCl3) δ 14.27 (d, J1 = 83 Hz). B NMR (128 MHz,
30 mg, 79%) as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.45
BP
CDCl3) δ −38.44 (m). IR (neat, cm −1) 2958 (m), 2380 (m), 1589
(m), 1574 (m), 1477 (s), 1464 (m), 1433 (s), 1277 (s), 1248 (s),
(td, J = 7.6, 2.3 Hz, 2H), 7.37−7.28 (m, 4H), 7.18 (ddd, J = 7.6, 6.1,
1.7 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 6.86 (dd, J = 8.0, 4.0 Hz, 1H),
3.77 (s, 3H), 2.67 (ddd, J = 11.2, 9.2, 2.2 Hz, 1H), 2.59 (ddd, J = 13.9,
3.7, 2.2 Hz, 1H), 1.79 (ddd, J = 13.9, 11.2, 3.0 Hz, 1H), 0.93 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 143.0, 133.3, 132.9 (d, J = 19.0 Hz),
130.6, 128.5, 128.4 (d, J = 7.0 Hz), 121.1 (d, J = 4.0 Hz), 110.6 (d, J =
2.0 Hz), 58.6 (d, 2JCP = 14.0 Hz), 55.6, 35.1 (d, 3JCP = 7.0 Hz), 31.0 (d,
1JCP = 10.0 Hz), 26.2. 31P NMR (160 MHz, CDCl3) δ −28.50. IR
1060 (s), 1019 (s), 909 (m), 801 (m), 756 (s), 728 (s), 696 (s).
20
Optical rotation [α] = +13.4 (c = 0.04 g mL−1, CHCl3). HRMS
589
(DART, m/z) calculated for C19H28BNOP [(M + H)+]: 328.2008.
Found: 328.2002.
(S)-1-((R)-(2-Methoxyphenyl)(phenyl)phosphanylborane)-3,3-di-
methylbutan-2-amine) (1a·BH3). To an oven-dried round-bottom
flask equipped with a magnetic stirring bar was added phosphine oxide
8a (0.19 g, 0.57 mmol). THF (5 mL) was added and cooled down to 0
°C. BH3·SMe2 (0.2 mL, 2.1 mmol) was then added dropwise via a
syringe at 0 °C under a positive pressure of argon. The reaction was
stirred at 70 °C for 4 h. The reaction was quenched with saturated
NH4Cl (30 mL) and extracted four times with CH2Cl2. The organic
extracts were combined, dried over anhydrous Na2SO4, filtered and
concentrated in vacuo to give the crude product. Purification by flash
chromatography on silica gel (2% MeOH/CH2Cl2) gave 1a·BH3 (81
mg, 43%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.04 (ddd,
J = 13.8, 7.6, 1.7 Hz, 1H), 7.63−7.50 (m, 3H), 7.43−7.33 (m, 3H),
7.11 (tdd, J = 7.5, 2.1, 1.0 Hz, 1H), 6.87 (ddd, J = 8.3, 3.2, 0.9 Hz, 1H),
3.63 (s, 3H), 3.03 (ddd, J = 17.7, 14.1, 1.3 Hz, 1H), 2.55 (ddd, J =
14.2, 10.1, 1.3 Hz, 1H), 1.99 (ddd, J = 14.1, 10.1, 6.1 Hz, 1H), 1.65 (s,
2H), 0.82 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 161.2 (d, J = 2.0
Hz), 137.6 (d, J = 15.0 Hz), 134.2, (d, J = 2.0 Hz), 131.4 (d, J = 59.0
Hz), 131.2 (d, J = 9.0 Hz), 130.3 (d, J = 3.0 Hz), 128.4 (d, J = 10.0
Hz), 121.4 (d, J = 12.0 Hz), 115.2 (d, J = 53.0 Hz), 111.0 (d, J = 4.0
Hz), 55.7 (d, J = 90.0 Hz), 35.1 (d, J = 11.0 Hz), 27.7 (d, J = 38.0 Hz),
(neat, cm −1) 2960 (s), 1586 (m), 1474 (s), 1432 (s), 1273 (m), 1241
20
(s), 1070 (w), 1025 (m), 754 (s), 698 (m). Optical rotation [α]
=
589
+83.8 (c = 0.01 g mL−1, CHCl3). HRMS (DART, m/z) calculated for
C19H27NOP [(M + H)+]: 316.1835. Found: 316.1830.
(S)-1-((S)-(2-Methoxyphenyl)(phenyl)phosphanyl)-3,3-dimethyl-
butan-2-amine (1b). This compound was synthesized according to
the general procedure using phosphine borane 1b·BH3 (50 mg, 0.15
mmol) and DABCO (26 mg, 0.23 mmol, 1.5 equiv) in toluene (1.5
mL). The crude product was purified by flash chromatography on
silica gel (2.5% MeOH/CH2Cl2) to give the pure product (20:1 d.r.,
1
31 mg, 66%) as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.57−
7.49 (m, 2H), 7.37 (dp, J = 5.1, 1.7 Hz, 3H), 7.29 (ddd, J = 8.8, 7.8, 1.7
Hz, 1H), 7.01 (ddd, J = 6.6, 4.8, 1.7 Hz, 1H), 6.89 (tt, J = 7.4, 0.9 Hz,
1H), 6.84 (ddd, J = 8.0, 4.4, 0.8 Hz, 1H), 3.80 (s, 3H), 2.43 (ddd, J =
11.4, 9.7, 1.7 Hz, 1H), 2.36 (ddd, J = 13.7, 5.7, 1.7 Hz, 1H), 1.90 (br,
2H), 1.89 (ddd, J = 13.6, 11.5, 4.6 Hz, 1H), 0.87 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ 160.8 (d, J = 13.3 Hz), 136.7 (d, J = 12.1 Hz),
134.1 (d, J = 19.8 Hz), 132.2 (d, J = 3.0 Hz), 129.9, 129.2, 128.5 (d, J
= 8.1 Hz), 127.7 (d, J = 14.0 Hz), 121.0 (d, J = 2.2 Hz), 110.5 (d, J =
1.4 Hz), 100.1, 57.7 (d, 2JCP = 13.0 Hz), 55.7, 35.0 (d, 3JCP = 6.0 Hz),
30.4 (d, 1JCP = 10.2 Hz), 26.1. 31P NMR (160 MHz, CDCl3) δ −29.94.
IR (neat, cm −1) 2954 (m), 1584 (m), 1573 (m), 1463 (s), 1431 (s),
25.9. 31P NMR (160 MHz, CDCl3) δ 15.27 (d, J1 = 69 Hz). 11B
BP
NMR (128 MHz, CDCl3) δ −37.35 (m). IR (neat, cm −1) 2959 (m),
2371 (s), 1589 (m), 1574 (m), 1477 (s), 1463 (s), 1431 (s), 1278 (s),
1362 (w), 1271 (w), 1239 (s), 1069 (w), 1024 (s), 793 (w), 745 (s),
1249 (s), 1061 (s), 1020 (s), 756 (s), 735 (s), 726 (s), 697 (s), 689
20
727 (m), 696 (s). Optical rotation [α] = +10.3 (c = 0.01 g mL−1,
589
20
(s). Optical rotation [α] = +5.4 (c = 0.04 g mL−1, CHCl3). HRMS
589
CHCl3). HRMS (DART, m/z) calculated for C19H27NOP [(M +
(DART, m/z) calculated for C19H28BNOP [(M + H)+]: 328.2016.
Found: 328.2002.
H)+]: 316.1836. Found: 316.1830.
General Procedure for the Synthesis of Phosphinothiour-
eas. To an oven-dried 2-dram vial equipped with a magnetic stirring
bar was added the P-chiral aminophosphine. CH2Cl2 (0.03 M) was
added, followed by isothiocyanate (1.1 equiv). The vial was sealed and
stirred at 23 °C overnight. The crude product was purified by flash
chromatography on silica gel using a positive pressure of N2 and
solvents presparged with N2 to give the pure product.
Formation of X-ray Quality Crystal for 8a·HCl. To a 2-dram
vial was charged the filter cake consisting of 8a·HCl from the
recrystallization experiment (>40:1 d.r., 10 mg). CH2Cl2 was added to
dissolve the solid. Et2O was then carefully layered on top of the
solution and left aside undisturbed at 23 °C for a day to give a
colorless crystal that was subjected to X-ray crystallographic analysis.
mp (°C) 131−132.
Synthesis and X-ray Crystallographic Analysis of Phosphine
Borane 9b·BH3. To an oven-dried round-bottom flask equipped with
a magnetic stirring bar was added phosphine borane 1b·BH3 (47 mg,
0.14 mmol). CH2Cl2 (3 mL) was added and cooled down to 0 °C. 4-
Nitrophenyl isocyanate (26 mg, 0.16 mmol) was added in one portion.
The reaction was stirred at 23 °C overnight. The volatiles were
concentrated in vacuo and the crude product was purified by flash
chromatography on silica gel (1.7% MeOH/CH2Cl2) to give 9b·BH3
(57 mg, 83%) as a light yellow solid.To a 2-dram vial was charged 9b·
BH3. CH2Cl2 was added to dissolve the solid. MeOH was then layered
carefully on top of the solution and left aside undisturbed at 23 °C for
10 days to give a yellow crystal that was subjected to X-ray
crystallographic analysis. mp (°C) 167−169.
1-((S)-1-((R)-(2-Methoxyphenyl)(phenyl)phosphanyl)-3,3-dime-
thylbutan-2-yl)-3-(4-nitrophenyl)thiourea (10a). This compound
was synthesized according to the general procedure using amino-
phosphine 1a (46 mg, 0.14 mmol) and 4-nitrophenyl isothiocyanate
(29 mg, 0.16 mmol) in CH2Cl2 (5 mL). The crude product was
purified by flash chromatography on silica gel using a positive pressure
of N2 and solvents presparged with N2 (17−20% EtOAc/hexanes) to
1
give the pure product (37 mg, 53%) as a yellow amorphous solid. H
NMR (400 MHz, Methanol-d4) δ 8.16 (d, J = 9.2 Hz, 2H), 7.81 (d, J =
9.1 Hz, 2H), 7.49 (ddd, J = 9.3, 6.1, 2.3 Hz, 2H), 7.34 (td, J = 7.7, 1.4
Hz, 1H), 7.27−7.26 (m, 3H), 7.18 (td, J = 7.2, 1.4 Hz, 1H), 6.98−6.89
(m, 2H), 3.74 (s, 3H), 3.13 (d, J = 0.7 Hz, 1H), 2.81 (dt, J = 15.0, 2.4
Hz, 1H), 2.09 (dt, J = 25.7, 15.2 Hz, 1H), 1.04 (s, 9H). 13C NMR (125
MHz, Methanol-d4) δ 182.2, 162.6 (d, J = 10.0 Hz), 147.6, 144.0,
134.3 (d, J = 20.0 Hz), 134.2 (d, J = 11.0 Hz), 131.4, 129.5, 129.3 (d, J
General Procedure for the DABCO-Mediated Deprotection
of Phosphine Borane. To an oven-dried 2-dram vial equipped with a
magnetic stirring bar was added the phosphine borane. Toluene (0.1
M) was added, followed by DABCO (1.5 equiv). The vial was sealed
and stirred at 40 °C for 17 h. The volatiles were then concentrated in
vacuo. The crude residue was purified by flash chromatography on
2
= 7.0 Hz), 125.1, 121.8, 121.8 (d, J = 4.0 Hz), 111.8, 61.2 (d, JCP
=
15.0 Hz), 55.9, 52.5, 37.5 (d, 3JCP = 8.0 Hz), 30.1 (d, 1JCP = 13.0 Hz),
26.9. 31P NMR (160 MHz, Methanol-d4) δ −26.38. IR (neat, cm
)
−1
2962 (w), 1595 (m), 1499 (m), 1432 (s), 1329 (s), 1273 (s), 1237 (s),
1177 (m), 1110 (m), 1021 (m), 850 (m), 749 (s), 696 (s). Optical
G
DOI: 10.1021/acs.joc.7b00199
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
20
rotation [α] = −44.3 (c = 0.01 g mL−1, CHCl3). HRMS (DART, m/
d4) δ −30.28. 19F NMR (376 MHz, Methanol-d4) δ −64.42. IR (neat,
589
z) calculated for C26H31N3O3PS [(M + H)+]: 496.1821. Found:
496.1824.
cm −1) 3357 (w), 2961 (w), 1588 (w), 1508 (m), 1473 (m), 1384 (s),
1274 (s), 1165 (s), 1127 (s), 744 (m), 882 (m). Optical rotation
20
1-(3,5-Bis(trifluoromethy)phenyl)-3-((S)-1-((R)-(2-
methoxyphenyl)(phenyl)phosphanyl)-3,3-dimethylbutan-2-yl)-
thiourea (11a). This compound was synthesized according to the
general procedure using aminophosphine 1a (46 mg, 0.14 mmol) and
3,5-bis(trifluoromethyl)phenyl isothiocyanate (43 mg, 0.16 mmol) in
CH2Cl2 (5 mL). The crude product was purified by flash
chromatography on silica gel using a positive pressure of N2 and
solvents presparged with N2 (14−20% EtOAc/hexanes) to give the
[α] = +50.8 (c = 0.01 g mL−1, CHCl3). HRMS (DART, m/z)
589
calculated for C28H30F6N2OPS [(M + H)+]: 587.1726. Found:
587.1721.
(S)-1-(1-(Diphenylphosphanyl)-3,3-dimethylbutan-2-yl)-3-(4-
nitrophenyl)thiourea (10c). This compound was synthesized
according to the general procedure using (S)-1-(diphenylphosphan-
yl)-3,3-dimethylbutan-2-amine11 (73 mg, 0.26 mmol) and 4-nitro-
phenyl isothiocyanate (52 mg, 0.29 mmol) in CH2Cl2 (9 mL). The
crude product was purified by flash chromatography on silica gel using
a positive pressure of N2 and solvents presparged with N2 (14−20%
EtOAc/hexanes) to give the pure product (76 mg, 63%) as a white
amorphous solid. 1H NMR (300 MHz, Methanol-d4) δ 8.21−8.12 (m,
2H), 7.87 (d, J = 9.1 Hz, 2H), 7.57−7.40 (m, 4H), 7.37−7.20 (m,
6H), 4.72 (ddd, J = 11.8, 9.6, 2.1 Hz, 1H), 2.57 (dt, J = 14.2, 2.7 Hz,
1H), 2.15 (ddd, J = 13.9, 11.7, 2.0 Hz, 1H), 0.99 (s, 9H). 13C NMR
1
pure product (50 mg, 61%) as a white amorphous solid. H NMR
(400 MHz, Methanol-d4) δ 8.10 (s, 2H), 7.59 (s, 1H), 7.50 (td, J = 8.0,
1.6 Hz, 2H), 7.37−7.21 (m, 4H), 7.14 (td, J = 6.8, 1.6 Hz, 1H), 6.97−
6.86 (m, 2H), 3.75 (s, 3H), 2.79 (dt, J = 14.4, 2.0 Hz, 1H), 2.12 (dd, J
= 14.3, 11.4 Hz, 1H), 1.04 (s, 9H). 13C NMR (125 MHz, Methanol-
d4) δ 182.7, 162.6 (d, J = 11.3 Hz), 143.2, 139.6, (d, J = 12.5 Hz),
134.5 (d, J = 20.0 Hz), 134.1 (d, J = 11.3 Hz), 132.4 (d, J = 33.8 Hz),
131.4, 129.5, 129.2 (d, J = 7.5 Hz), 127.7 (d, J = 15.0 Hz), 124.8 (d, J
= 270.0 Hz), 123.3 (m), 121.8 (d, J = 3.8 Hz), 117.3 (m), 111.8, 61.4
1
(125 MHz, Methanol-d4) δ 182.6, 147.7, 144.1, 140.6 (d, JCP = 12.5
1
2
Hz), 140.3 (d, JCP = 13.8 Hz), 134.3 (d, JCP = 18.8 Hz), 133.8 (d,
(d, 2JCP = 16.3 Hz), 55.9, 37.4 (d, JCP = 8.8 Hz), 29.9 (d, JCP = 13.8
Hz), 26.9. 31P NMR (160 MHz, Methanol-d4) δ −22.48. 19F NMR
(376 MHz, Methanol-d4) δ −60.53. IR (neat, cm −1) 2969 (w), 2938
(w), 1533 (m), 1469 (m), 1340 (w), 1276 (s), 1237 (m), 1173 (s),
3
1
2JCP = 20.0 Hz), 129.8, 129.5, 129.4 (d, 3JCP = 6.3 Hz), 129.3 (d, 3JCP
=
7.5 Hz), 125.2, 122.0, 60.4 (d, 2JCP = 15.0 Hz), 37.4 (d, 3JCP = 7.5 Hz),
32.4 (d, JCP = 13.8 Hz), 26.9. 31P NMR (120 MHz, Methanol-d4) δ
1
−22.06. IR (neat, cm −1) 2962 (w), 1596 (w), 1506 (s), 1434 (w),
1129 (s), 1023 (m), 954 (m), 884 (m), 749 (m), 697 (m). Optical
1325 (s), 1302 (s), 1258 (m), 1245 (m), 1175 (m), 1110 (m), 849
20
rotation [α] = +16.3 (c = 0.01 g mL−1, CHCl3). HRMS (DART, m/
20
589
(m), 740 (s), 693 (s). Optical rotation [α] = +51.4 (c = 0.03 g
589
z) calculated for C28H30F6N2OPS [(M + H)+]: 587.1713. Found:
587.1721.
mL−1, CHCl3). HRMS (DART, m/z) calculated for C25H29N3O2PS
[(M + H)+]: 466.1716. Found: 466.1718.
1-((S)-1-((S)-(2-Methoxyphenyl)(phenyl)phosphanyl)-3,3-dime-
thylbutan-2-yl)-3-(4-nitrophenyl)thiourea (10b). This compound
was synthesized according to the general procedure using amino-
phosphine 1b (53 mg, 0.17 mmol) and 4-nitrophenyl isothiocyanate
(35 mg, 0.19 mmol) in CH2Cl2 (6 mL). The crude product was
purified by flash chromatography on silica gel using a positive pressure
of N2 and solvents presparged with N2 (17−20% EtOAc/hexanes) to
General Procedure for the Morita−Baylis−Hillman Reaction.
Methyl (R)-2-(Hydroxyl(phenyl)methyl)acrylate (12). To an oven-
dried 2-dram vial equipped with a magnetic stirring bar was added
thiourea catalyst 10a (5.0 mg, 0.01 mmol) in the glovebox. Five Å
molecular sieves (50 mg) and methyl acrylate (13 mg, 0.15 mmol)
were added. THF (0.3 mL) was then added. Benzaldehyde (5.2 mg,
0.05 mmol) was added and the vial was sealed. The reaction was
stirred at 23 °C for 72 h and then filtered over a short plug of Celite.
The filtrate was concentrated in vacuo to give the crude product that
was purified by flash chromatography on silica gel (13−17% EtOAc/
hexanes) to give the pure product (5.0 mg, 57%) as a colorless oil. The
enantiomeric excess was 76%, as judged by HPLC with a chiral
stationary phase. Characterization data were consistent with those
reported previously.21a 1H NMR (400 MHz, CDCl3) δ 7.40−7.31 (m,
4H), 7.31−7.25 (m, 1H), 6.33 (s, 1H), 5.84 (s, 1H), 5.56 (d, J = 4.9
Hz, 1H), 3.71 (s, 3H), 3.14 (d, J = 5.5 Hz, 1H). 13C NMR (100 MHz,
1
give the pure product (46 mg, 55%) as a yellow amorphous solid. H
NMR (400 MHz, Methanol-d4) δ 8.22−8.15 (m, 2H), 7.89 (d, J = 9.2
Hz, 2H), 7.55 (tq, J = 6.2, 2.7, 2.1 Hz, 3H), 7.35−7.27 (m, 4H), 7.21
(ddd, J = 7.6, 5.6, 1.4 Hz, 1H), 6.96−6.87 (m, 2H), 4.62 (td, J = 10.0,
2.0 Hz, 1H), 3.71 (s, 3H), 2.47 (dt, J = 13.9, 2.7 Hz, 1H), 2.29 (ddd, J
= 14.1, 11.5, 2.8 Hz, 1H), 0.98 (s, 9H). 13C NMR (125 MHz,
Methanol-d4) δ 182.6, 162.4 (d, J = 11.0 Hz), 147.7, 134.6 (d, J = 20.0
Hz), 133.8 (d, J = 10.0 Hz), 131.3, 129.7, 129.1 (d, J = 8.0 Hz), 125.2,
122.0, 121.9 (d, J = 3.0 Hz), 111.9 (d, J = 2.0 Hz), 60.1 (d, 2JCP = 14.0
3
1
Hz), 56.0, 37.4 (d, JCP = 7.0 Hz), 30.2 (d, JCP = 12.0 Hz), 26.9. 31P
NMR (160 MHz, Methanol-d4) δ −30.67. IR (neat, cm −1) 2962 (w),
1596 (m), 1509 (m), 1431 (w), 1336 (s), 1309 (s), 1293 (s), 1243
CDCl3) δ 166.9, 142.1, 141.4, 128.6, 128.0, 126.7, 126.2, 73.4, 52.1.
20
Optical rotation [α] = −7.2 (c = 0.003 g mL−1, CHCl3). Lit. (S
589
enantiomer, 75% ee): + 47.3 (c = 0.1, CHCl3).37 HPLC conditions
Chiralpak IB, 2.0% isopropanol/hexanes, 0.75 mL/min, 254 nm, tr:
23.75 and 25.66 min.
(m), 1179 (w), 1111 (w), 1023 (w), 851 (w), 752 (m). Optical
20
rotation [α] = +5.5 (c = 0.01 g mL−1, CHCl3). HRMS (DART, m/
589
z) calculated for C26H31N3O3PS [(M + H)+]: 496.1816. Found:
496.1824.
Methyl (R)-2-((4-Bromophenyl)(hydroxyl)methyl)acrylate (13).
This compound was synthesized according to the general procedure
using catalyst 10a (5.0 mg, 0.01 mmol), methyl acrylate (13 mg, 0.15
mmol), and 4-bromobenzaldehyde (9.3 mg, 0.05 mmol) in THF (0.3
mL). The crude product was purified by chromatography on silica gel
(10−17% EtOAc/hexanes) to give the pure product (11 mg, 80%) as a
colorless oil. The enantiomeric excess was 81%, as judged by HPLC
with a chiral stationary phase. Characterization data were consistent
with those reported previously.21a 1H NMR (400 MHz, CDCl3) δ
7.50−7.42 (m, 2H), 7.27−7.21 (m, 2H), 6.33 (s, 1H), 5.83 (s, 1H),
5.49 (d, J = 5.2 Hz, 1H), 3.72 (s, 3H), 3.18 (d, J = 5.6 Hz, 1H). 13C
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-1-((S)-(2-
methoxyphenyl)(phenyl)phosphany)-3,3-dimethylbutan-2-yl)-
thiourea (11b). This compound was synthesized according to the
general procedure using aminophosphine 1b (53 mg, 0.17 mmol) and
3,5-bis(trifluoromethyl)phenyl isothiocyanate (52 mg, 0.19 mmol) in
CH2Cl2 (6 mL). The crude product was purified by flash
chromatography on silica gel using a positive pressure of N2 and
solvents presparged with N2 (14−20% EtOAc/hexanes) to give the
1
pure product (65 mg, 65%) as a white amorphous solid. H NMR
(400 MHz, Methanol-d4) δ 8.20 (s, 2H), 7.61 (s, 1H), 7.54 (m, 2H),
7.37−7.27 (m, 4H), 7.23 (t, J = 6.8 Hz, 1H), 6.96−6.85 (m, 2H), 4.65
(td, J = 10.5, 2.2 Hz, 1H), 3.71 (s, 3H), 2.47 (dt, J = 13.8, 2.7 Hz, 1H),
2.33 (ddd, J = 13.8, 11.4, 2.1 Hz, 1H), 0.99 (s, 9H). 13C NMR (125
MHz, Methanol-d4) δ 183.2, 162.5 (d, J = 10.0 Hz), 143.4, 139.4 (d, J
= 11.3 Hz), 134.5 (d, J = 18.8 Hz), 133.9 (d, J = 10.0 Hz), 132.4 (q,
2JCF = 32.5 Hz), 131.3, 129.6, 129.1 (d, J = 7.5 Hz), 127.9 (d, J = 13.8
NMR (100 MHz, CDCl3) δ 166.7, 141.7, 140.5, 131.6, 128.4, 126.5,
20
121.9, 72.8, 52.2. . Optical rotation [α] = +2.9 (c = 0.006 g mL−1,
589
CHCl3). Lit. (83% ee): + 7.9 (c = 1.0, CHCl3).21a HPLC conditions
Chiralcel OD-H, 0.8% isopropanol/hexanes, 210 nm, 1.0 mL/min, tr:
44.45 and 49.92 min.
Methyl (R)-2-(Hydroxy(p-tolyl)methyl)acrylate (14). This com-
pound was synthesized according to the general procedure using
catalyst 10a (5.0 mg, 0.01 mmol), methyl acrylate (13 mg, 0.15
mmol), and p-tolualdehyde (6.0 mg, 0.05 mmol) in THF (0.3 mL).
The crude product was purified by chromatography on silica gel (10−
1
Hz), 124.8 (q, JCF = 270.0 Hz), 123.4 (m), 121.9 (d, J = 3.8 Hz),
2
3
117.3 (m), 111.9, 60.2 (d, JCP = 13.8 Hz), 55.9, 37.4 (d, JCP = 7.5
Hz), 30.0 (d, JCP = 11.2 Hz), 26.9. 31P NMR (160 MHz, Methanol-
1
H
DOI: 10.1021/acs.joc.7b00199
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
17% EtOAc/hexanes) to give the pure product (4.2 mg, 41%) as a
colorless oil. The enantiomeric excess was 73%, as judged by HPLC
with a chiral stationary phase. Characterization data were consistent
with those reported previously.21a 1H NMR (400 MHz, CDCl3) δ 7.26
(d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 6.33 (s, 1H), 5.85 (s,
1H), 5.53 (s, 1H), 3.72 (s, 3H), 2.95 (s, 1H), 2.34 (s, 3H). 13C NMR
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(100 MHz, CDCl3) δ 166.9, 142.2, 138.5, 137.7, 129.3, 126.6, 126.0,
20
73.3, 52.0, 21.3. Optical rotation [α] = −13.4 (c = 0.002 g mL−1,
589
CHCl3). Lit (83% ee) −57.4 (c = 0.54, CHCl3).21a HPLC conditions
Chiralpak IB, 2.0% isopropanol/hexanes, 0.5 mL/min, 254 nm, tr:
29.84 and 32.29 min.
Computational Methods. DFT calculations were carried out
using the Gaussian 09 suite of programs,38 at the B3LYP/6-31G(d,p)
level of theory.39 Vibrational frequency calculations were carried out to
ensure that the obtained structures are minima on the potential energy
surface (no imaginary frequencies). Frequency calculations were
carried out at 1 atm and 298.15 K. Structures were visualized using
Avogadro 1.2.0.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00199.
1
Copies of H, 13C and 31P NMR spectra; Cartesian
coordinates and energies of calculated structures (PDF)
(7) (a) Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S. J. Am. Chem.
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N.; Golen, J. A.; Incarvito, C. D.; Rheingold, A. L. J. Am. Chem. Soc.
2007, 129, 6847−6858. (e) Chan, V. S.; Bergman, R. G.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 15122−15123. (f) Zhang, Y.; He, H.;
Wang, Q.; Cai, Q. Tetrahedron Lett. 2016, 57, 5308−5311.
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Crystallographic information file for (S,RP)-8a·HCl
(CIF)
Crystallographic information file for (S,SP)-9b·BH3
(CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: mtaylor@chem.utoronto.ca.
ORCID
■
Mark S. Taylor: 0000-0003-3424-4380
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dr. Alan K. Lough (University of Toronto) is gratefully
acknowledged for carrying out the single crystal X-ray
diffraction experiments and solving the structures of (S,RP)-
8a·HCl and (S,SP)-9b·BH3. Graham Garrett is acknowledged
for assistance and advice related to the computational
modeling. Acknowledgement is made to the donors of the
American Chemical Society Petroleum Research Fund for
partial support of this research. Funding was also provided by
NSERC (Discovery Grants and Canada Research Chairs
Programs) and the Canada Foundation for Innovation
(Projects #17545 and 19119). The DFT calculations were
carried out at the Centre for Advanced Computing (http://cac.
queensu.ca).
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