Heteroaliphatic Dimethylphosphine Oxide Building Blocks: Synthesis and Physico-Chemical Properties

Article abstract of DOI:10.1002/ejoc.202100581

Scalable synthesis of saturated heterocyclic dimethyl phosphine oxides (derivatives of azetidine, pyrrolidine, piperidine, and morpholine) is disclosed. The key steps of the synthesis relied on the reactions of HP(O)Me₂, i. e. the phospha-Mannich (the Kabachnik-Fields-type) condensation with cyclic imines or monoprotected diamines, palladium-catalyzed reactions of alkenyl halides or trifltates (generated from cyclic ketones), as well as base-mediated nucleophilic substitution, Michael addition, or oxirane ring opening. It was shown that introducing the P(O)Me₂ group into the saturated heterocyclic core had very strong impact on the compound's basicity: the corresponding α-, β-, and γ-isomeric derivatives were by ca. 4, 2, and 1.6 pK_a units less basic, respectively, as compared to the parent saturated heterocycle. Meanwhile, the P(O)Me₂-substituted compound was more basic than its SO₂i-Pr and SO₂NMe₂-containing isosteres (by ca. 1.2 and 0.4 pK_a units, respectively). It was also demonstrated that the P(O)Me₂ group typically increased the compound's hydrophilicity and aqueous solubility. In particular, the LogP values for the corresponding derivatives were by ca. 1.4–1.7 and 0.6 units lower than for the non-substituted counterpart and sulfonamide/sulfone isosteres, respectively. Finally, a potential of the synthesized building blocks to generate lead-like three-dimensional compound libraries was confirmed using the Nelson's LLAMA tool.

Full text of DOI:10.1002/ejoc.202100581

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Very Important Paper
Heteroaliphatic Dimethylphosphine Oxide Building Blocks:
Synthesis and Physico-Chemical Properties
Andrii Fedyk,[a, b] Evgeniy Y. Slobodyanyuk,[a, b] Olha Stotska,[a, c] Bohdan V. Vashchenko,[a, c]
Dmitriy M. Volochnyuk,*[a, b, c] Dmitriy A. Sibgatulin,[a] Andrey A. Tolmachev,[a, c] and
Oleksandr O. Grygorenko[a, c]
Scalable synthesis of saturated heterocyclic dimethyl phosphine
oxides (derivatives of azetidine, pyrrolidine, piperidine, and
morpholine) is disclosed. The key steps of the synthesis relied
on the reactions of HP(O)Me2, i.e. the phospha-Mannich (the
Kabachnik-Fields-type) condensation with cyclic imines or
monoprotected diamines, palladium-catalyzed reactions of
alkenyl halides or trifltates (generated from cyclic ketones), as
well as base-mediated nucleophilic substitution, Michael addi-
tion, or oxirane ring opening. It was shown that introducing the
P(O)Me2 group into the saturated heterocyclic core had very
strong impact on the compound’s basicity: the corresponding
α-, β-, and γ-isomeric derivatives were by ca. 4, 2, and 1.6 pKa
units less basic, respectively, as compared to the parent
saturated heterocycle. Meanwhile, the P(O)Me2-substituted
compound was more basic than its SO2i-Pr and SO2NMe2-
containing isosteres (by ca. 1.2 and 0.4 pKa units, respectively). It
was also demonstrated that the P(O)Me2 group typically
increased the compound’s hydrophilicity and aqueous solubil-
ity. In particular, the LogP values for the corresponding
derivatives were by ca. 1.4–1.7 and 0.6 units lower than for the
non-substituted counterpart and sulfonamide/sulfone isosteres,
respectively. Finally, a potential of the synthesized building
blocks to generate lead-like three-dimensional compound
libraries was confirmed using the Nelson’s LLAMA tool.
Introduction
Organic compounds containing phosphorus, i.e. phosphates,
phosphonates, and phosphoramides, have an outstanding roles
in life sciences varying from biomolecules having vital functions
in living organisms to numerous commercial agricultural and
pharmaceutical agents.[1–7] Meanwhile, phosphine oxides have
been largely infamous as annoying by-products in organic
synthesis (formed, for example, in Wittig, Appel, and Mitsunobu
reactions) that are challenging to separate from the target
compounds.[8] Nevertheless, this page in the R3P=O history was
turned in 2017, when the first drug containing a phosphine
oxide motif, brigatinib (used for the treatment of advanced
anaplastic lymphoma kinase (ALK)-positive metastatic non-small
cell lung cancer) was approved by FDA (Figure 1).[9,10] One of the
Figure 1. Pharmaceutically relevant dimethylphosphine oxides.
[a] A. Fedyk, Dr. E. Y. Slobodyanyuk, O. Stotska, B. V. Vashchenko,
Prof. Dr. D. M. Volochnyuk, Dr. D. A. Sibgatulin, Prof. Dr. A. A. Tolmachev,
Dr. O. O. Grygorenko
Enamine Ltd.
Chervonotkatska Street 78,
Kyiv 02094, Ukraine
E-mail: d.volochnyuk@gmail.com
https://www.enamine.net
key features in the successful design of this kinase inhibitor was
related to hydrogen bond acceptor properties of the P=O group
providing an efficient interaction with the biological target.
Further studies revealed that the uncharged phosphine oxide
moiety can be related to lower toxicities, improved cell
permeability and oral bioavailability as compared to their more
acidic organophosphorus counterparts, e.g. phosphates, phos-
phonates, or phosphinates charged at physiological pH.[11–13]
This resulted in revision of the common medicinal chemistry
filters that have been swiping out phosphine oxides. Addition-
ally, R3P=O are more polar than dialkyl phosphonates, amides,
or sulfonamides, being comparable to sulfoxides and
[b] A. Fedyk, Dr. E. Y. Slobodyanyuk, Prof. Dr. D. M. Volochnyuk
Institute of Organic Chemistry,
National Academy of Sciences of Ukraine,
Murmanska Street 5,
Kyiv 02660, Ukraine
[c] O. Stotska, B. V. Vashchenko, Prof. Dr. D. M. Volochnyuk,
Prof. Dr. A. A. Tolmachev, Dr. O. O. Grygorenko
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60,
Kyiv 01601, Ukraine
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100581
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sulfoximines.[14] Other fruitful physico-chemical features of
phosphine oxides include higher aqueous solubility, stability
upon both acidic and basic conditions, and microsomal stability
in human liver.[9,14] The aforementioned favorable properties of
phosphine oxides resulted in an increased interest of scientific
and industrial chemists towards novel building blocks contain-
ing the dimethylphosphine moiety.
Figure 2. P(O)Me2-substituted saturated heterocyclic amines – target com-
While most known compounds of this class contain the P(O)
Me2 moiety attached to the aromatic ring[15–22] or alkenes,[23–25]
some examples of sp- and sp3-hybridized derivatives have been
studied as progesterone receptor agonist and epithelial Na+
channel (ENaC) inhibitor, respectively (Figure 1).[26] Meanwhile,
introducing the dimethylphosphine oxide fragment into low-
molecular-weight saturated heterocyclic amines (such as azeti-
dine, pyrrolidine, piperidine, or morpholine) was not explored
in the literature to date. Taking into account recent interest in
sp3-enriched building blocks in early drug discovery,[27–29] in this
work, we have aimed at the efficient synthesis of saturated P(O)
Me2-containing nitrogen heterocycles (Figure 2), as well as at
evaluation of their physico-chemical properties in order to
establish the impact of the dimethylphosphine oxide moiety on
their potential to generate lead-like compound libraries.
pounds of this work.
phosphine oxide (HP(O)Me2) with trimeric imines, which was
used for the synthesis of two simplest acyclic (N-
alkylaminomethyl)dimethylphosphine oxides (i.e. N-methyl- and
N-benzyl).[30,31] Other literature methods involved reactions of
HP(O)Me2 with tetrasubstituted 2,5-dihydrooxazoles or 5,6-
dihydro-2H-1,3-oxazines,[32] aromatic imines,[33,34] or dipeptide-
derived
aldehydes,[35]
reactions
of
alkyl
meth-
ylphosphonochloridates with the Grignard reagents,[36] as well
as radical addition to the double bonds of enamides,[37] allyl
amines/amides,[37,38] etc.[39]
Firstly, we took an advantage of the phospha-Mannich
reaction that was tested with cyclic imines 1a–e (typically
existing as their trimers). Thus, refluxing of HP(O)Me2 and
trimeric 1a in toluene gave the target product 2a (ca. 50% by
1H NMR), but its isolation and purification were complicated.
Performing the same reaction with pre-mixed HP(O)Me2 and
Results and Discussion
Synthesis. The known approaches to the preparation of P(O)
Me2-containing amines relied on the phospha-Mannich (the
Kabachnik-Fields-type) reaction of the parent dimethyl
°
Et2Zn in toluene at À 15 C gave a complex mixture of products.
Further optimization showed that 1a–e reacted with HP(O)Me2
in the presence of the Lewis acid (BF3 ·H2O), and gave 2-
susbtituted pyrrolidines 2a and 2b, as well as piperidines 2c–e
in moderate to good isolated yields (44–60%, Scheme 1).
Notably, the method was suitable for the preparation of more
than 50 g of the target building blocks in one run. 2-Phenyl-
substituted derivatives 2c and 2e were isolated as free bases,
while products 2a, 2b, and 2d were obtained as hydro-
chlorides.
The phospha-Mannich strategy was also implemented to
monoprotected piperazine 3, which reacted with paraformalde-
hyde and dimethylphosphine oxide in the presence of TsOH in
°
THF at 60 C to give N-Cbz-protected piperazin-1-ylmethyl
derivative 4 in 93% yield (Scheme 2). Hydrogenolysis of 4 in the
presence of PdÀ C and HCl-1,4-dioxane in MeOH resulted in
piperazine-containing dimethylphosphine oxide 5, isolated as a
dihydrochloride in 91% yield. Notably, previously reported
Prof. Dr. Dmitriy M. Volochnyuk got his Ph.D. (2005) and Dr.Sci.
(2011) degrees from Institute of Organic Chemistry, NAS of Ukraine.
At the moment, he shares his time as Head of Biologically Active
Compounds Department at this institute, Professor at Taras
Shevchenko National University of Kyiv, and senior scientific
advisor at Enamine Ltd. Dr. Volochnyuk is an expert in organic
synthesis, organofluorine, organophosphorus, heterocyclic, combi-
natorial, and medicinal chemistry. He is a co-author of more than
155 papers and 3 monograph chapters. Prof. Volochnyuk super-
vises and consults many research groups at Enamine Ltd. and
Ukraininan academic institutions. This paper is a result of such
collaboration with Dr. Evgeniy Y. Slobodyanyuk, Dr. Oleksandr O.
Grygorenko, and their teams focusing on synthesis of advanced
building blocks for drug discovery. On the photo (from left to
right): Dr. Evgeniy Y. Slobodyanyuk, Prof. Dr. Dmitriy M. Voloch-
nyuk, Olha Stotska, Dr. Oleksandr Grygorenko, and Andrii Fedyk.
Scheme 1. The phospha-Mannich reaction of cyclic imines 1a–e.
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hydrochloride 6·HCl after work-up with HCl-1,4-dioxane (76%
yield).
Synthesis of a close analog of 6, (2,2-dimethylpyrrolidin-3-yl)
dimethylphosphine oxide (9), commenced from ketone 10 that
was transformed into the corresponding vinyl triflate 11 upon
reaction with LiHDMS and then – PhNTf2. Without additional
purification, the derivative 11 was immediately involved in the
reaction with dimethylphosphine similarly to vinyl bromide,
which provided 2,5-dihydro-1H-pyrrole 12 in 58% yield over
three steps (Scheme 5). Further reduction of the double bond in
12 was performed with H2 (10 atm) in the presence of MeONa.
N-Protected pyrrolidine 13 thus obtained was treated with HCl-
1,4-dioxane to give pyrrolidine 9·HCl, which was isolated as a
free base in 84% yield.
This approach was extended to 4-oxoproline derivative 14
for the preparation of proline-derived phosphine oxides 15 and
16 (Scheme 6). The reaction sequence included enolyzation-
triflation of 14 into 17 followed by dimethylphosphine oxide
group incorporation for the synthesis of 18 (80% yield over
three steps). Further hydrogenation of 18 under mild conditions
provided protected 4-P(O)Me2-proline 19 in 91% yield. The N-
Scheme 2. Synthesis of 5·2HCl.
methods for the preparation of similar derivatives relied on the
alkylation
of
N-arylpiperazines
with
(chloromethyl)
dimethylphosphine oxide.[40]
Nevertheless, it was obvious that the phospha-Mannich-
based approach could not be easily extended for the selective
preparation of other isomeric heteroaliphatic phosphine oxides;
therefore, alternative synthetic sequences were designed. In
particular, straightforward preparation of dimethyl(pyrrolidin-3-
yl)phosphine oxide (6), an isomer of the product 2a bearing no
additional substituents, relied on the construction of the
pyrrolidine ring by 1,3-dipolar cycloaddition of azomethyne
ylides that demonstrated very good efficiency in our previous
works.[41–44] For this purpose, a robust and scalable approach to
the synthesis of dimethyl(vinyl)phosphine oxide (7) was
developed, which included treatment of vinyl bromide with the
parent dimethylphosphine oxide in the presence of Pd(PPh3)4
and Et3N in MeCN (68% yield) (Scheme 3).
It should be stressed out that the known protocols for the
synthesis of alkene 7 were based on β-elimination reactions[45,46]
and were poorly scalable. The current method allowed for the
preparation of 7 on up to 75 g scale; further studies of this
valuable reagent are ongoing in our lab. Compound 7 was
involved into 1,3-dipolar cycloaddition with in situ generated
azomethine ylide for the synthesis of N-benzyl pyrrolidine 8 in
72% yield (Scheme 4).
Scheme 5. Synthesis of 2,2-disubstituted pyrrolidine-3-ylphosphine oxide 9.
Further removal of N-protecting group of 8 required PdÀ C-
mediated hydrogenolysis in an autoclave under high pressure
°
of H2 (50 atm) at 50 C; notably, the P(O)Me2 moiety did not
interfere with these relatively harsh conditions. The target
compound was isolated from the reaction mixture as a
Scheme 3. Synthesis of dimethyl(vinyl)phosphine oxide (7).
Scheme 4. 1,3-Dipolar cycloaddition approach to pyrrolidine derivative
6·HCl.
Scheme 6. Synthesis of P(O)Me2-substitited proline derivatives 15 and 16
(relative configurations are shown).
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Boc group cleavage of 19 was used for the preparation of
followed by acylation with 2-chloroacetyl chloride in the
presence of i-Pr2NEt. The corresponding 2-chloro-N-(2-hydrox-
yethyl)acetamide 27 thus formed was immediately involved in
the t-BuONa-mediated cyclization into morpholinone 28, that
was obtained in 62% yield over three steps (Scheme 9).
Amide reduction in 28 proceeded smoothly with borane
(generated from NaBH4 and I2) in THF and gave N-benzyl
morpholine 29 in 84% yield. The debenzylation of 29 was
performed successfully under high pressure of H2 (100 atm),
and target morpholine 23 was obtained in 87% yield as a
hydrochloride after action of HCl-1,4-dioxane.
Finally, ethylene homologue of 2c, compound 30, was
obtained via the base-mediated Michael addition of dimeth-
ylphosphine oxide to 2-vinylpyridine (31), followed by catalytic
hydrogenation of dimethyl(2-(pyridin-2-yl)ethyl)phosphine
oxide (32) with H2 (50 atm) in the presence of HOAc and
treatment with HCl-1,4-dioxane, which gave piperidine 30·HCl
as a hydrochloride in 58% yield (Scheme 10).
Being inspired by the aforementioned results, we have also
tested ethenesulfonyl fluoride (a good connective hub to
explore the SuFFEx-type click chemistry[48]) was also tested as
the Michael acceptor under analogous reaction conditions. It
was successfully transformed into 2-P(O)Me2-substituted
ethane-1-sulfonyl fluoride 33 (68% yield), which reacted with
amino ester 15·HCl (59% yield), while alkaline hydrolysis in
THF-H2O media at rt provided N-Boc proline 16 (67% yield).
Notably, hydrogenation of 18 proceeded diastereoselectively;
relative configuration of the products obtained was confirmed
by NOE experiments with compounds 15·HCl and 16 (Figure 3).
Another approach towards heteroaliphatic phosphine ox-
ides was designed to obtain azetidine derivative. Since the
corresponding vinyl triflate is challenging to be obtained, our
attention turned to the reaction of alkyl halides with phosphin-
ite nucleophile.[47] Thus, iodide 20 was used directly in the
NaHMDS-mediated reaction with the HP(O)Me2, which provided
3-P(O)Me2 substituted derivative 21 in 48% yield (Scheme 7).
Typical N-deprotection of 21 proceeded smoothly to give
azetidin-3-yldimethylphosphine
oxide
(22·HCl)
as
a
hydrochloride in high yield. The product 22·HCl was obtained
on up to 25 g scale in a single run.
Next, we have aimed at the preparation of morpholine-
derived dimethylphosphine oxide 23. It was envisaged that the
three-atom CCO fragment of the morhpoline core could be
introduced via oxirane ring opening with N-nucleophiles. For
this purpose, hereto unknown dimethyl(oxiran-2-yl)phosphine
oxide (24) was obtained in two steps from 2-chloroacetalde-
hyde (25) via an addition of HP(O)Me2 to the carbonyl group
providing 2-chloro-1-hydroxyethyl derivative 26 in 52% yield
(Scheme 8).
Cyclization of 26 in the presence of MeONa in MeOH
resulted in oxirane 24 in 85% yield. Notably, this very promising
reagent was obtained on up to 70 g scale in a single run.
Further steps relied on the epoxide ring opening with BnNH2,
Figure 3. Significant NOEs observed for compounds 15·HCl and 16.
Scheme 9. Synthesis of dimethyl(morpholin-2-yl)phosphine oxide (23·HCl).
Scheme 7. An approach to azetidin-3-yldimethylphosphine oxide (22·HCl).
Scheme 10. Synthesis of phosphine oxides 30·HCl, 33, and 34 via the
Michael addition of HPOMe2.
Scheme 8. Preparation of dimethyl(oxiran-2-yl)phosphine oxide (24).
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aq ammonia in 1,4-dioxane to give the corresponding sulfona-
mide 34 in 75% yield.
42, the pKa values were by ca. 2 units lower than for piperidine,
whereas for the γ-isomer – by 1.6 units.
Physico-chemical properties. The next part of this work
was devoted to evaluation of basicity (pKa), lipophilicity (logP),
and aqueous solubility (Sw) of P(O)Me2-containing saturated
heterocyclic amines. Isosteric sulfone 35 and sulfonamide 36
bearing SO2i-Pr and SO2NMe2 groups, respectively, were also
prepared for comparison of their physico-chemical properties to
that of P(O)Me2-substituted counterparts. The compound 35
was obtained from 3-bromopyridine (37) by nucleophilic
substitution with i-PrSHÀ NaH, oxidation of sulfide 38 thus
obtained into sulfone 39 with RuCl3À NaIO4, and further PdÀ C-
catalyzed hydrogenation with H2 (45 atm) in aq HOAc
(Scheme 11). In turn, synthesis of sulfonamide 36 relied of
amination of known N-Cbz-protected sulfonyl chloride 40 into
piperidine 41 bearing SO2NMe2 moiety, which was involved in
hydrogenative cleave of Cbz-group to give 36. Finally, isomeric
piperidine derivatives 42 and 43 were also added to the series
of compounds studied.
Measuring the dissociation constants revealed that intro-
ducing the dimethylphosphine oxide group into the α-position
(2a and 2c) decreased the values by more than 4 pKa units as
compared to the parent piperidine; the size of the ring (5- or 6-
membered) showing no significant effect (Figure 4). Expectedly,
moving the PO2Me group further from the secondary amino
function diminished this effect: for β-isomeric derivatives 6 and
For azeditine and morpholine derivatives 22 and 23, the pKa
values were 8.68 and 7.13, which can be totally expected for
these heterocycles. Further comparison of 42, 35, and 36
revealed that the P(O)Me2 group has less pronounced effect on
the basicity as compared to the SO2i-Pr and SO2NMe2 moieties:
the pKa values for 35 and 36 were by 1.13 and 0.44 units,
respectively, lower than for 42.
To evaluate lipophilicity (LogP) and aqueous solubility (Sw)
of the heterocycles studied in this work, N-benzoylated
derivatives 44a–i were synthesized from the corresponding
amines 2a, 2c, 6, 23, 35, 36, 42, and 43 (Scheme 12). It was
found that for azetidine 44b, pyrrolidines 44c and 44c, and γ-
substituted piperidine 44g, negative LogP values were ob-
served. Moreover, α- and β-substituted piperidines 44e and 44f
were also quite hydrophilic (LogP=0.32 and 0.21). In all cases,
the LogP values increased within the following series: γ<β<α.
Comparison of the obtained values within the piperidine series
(including parent piperidine 44a, logP=1.71) showed that
introducing the P(O)Me2 group decreased lipophilicity by 1.4–
1.7 LogP units. This is higher than for the SO2i-Pr- and SO2NMe2-
substituted derivatives (44h and 44i, respectively) by ca.
0.7 units.
Analysis of Sw values showed that over a 10-fold increase in
aqueous solubility was observed for P(O)Me2-substituted piper-
idines 44f and 44g as compared to 44a. In this case, the
substitution pattern appeared to be the most important factor
since other isomers did not demonstrate such pronounced
effect.
Virtual library generation. To evaluate potential of the
saturated heterocyclic P(O)Me2-substituted building blocks for
exploring lead-like areas of chemical space, we have used
LLAMA, an open-access computational tool developed by
Scheme 11. Synthesis of compounds 35 and 36.
Figure 4. Dissociation constants (pKa) of cyclic amines bearing the P(O)Me2,
SO2i-Pr, or SO2NMe2 groups compared to that of parent piperidine.
Scheme 12. Lipophilicity (LogP) and aqueous solubility (Sw) of N-benzoyl
derivatives 44.
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Nelson and co-authors.[49] Their approach relies on the so-called
lead-likeness penalty (LLP), combined measure of the
a
compound compliance with the lead-likeness criteria chemical
space based on its physico-chemical properties (i.e. heavy (non-
hydrogen) atom count, AlogP, number of aromatic rings, and an
undesirable functional group filter).[50] The LLP parameter has
the lowest value of zero and increases as the compound
violates the Churcher’s lead-likeness definition.[51]
For the virtual library generation, six piperidines shown in
Figure 4 (2c, 35, 36, 42, 43, and the parent compound) were
used as the building blocks. It was found that libraries
generated from the P(O)Me2-bearing amines had somewhat
higher mean lead-likeness penalty (LLP) as compared to those
obtained from either 35 or 36; nevertheless, it was substantially
lower than for the case of parent piperidine derivatives
(Table 1). One of the reasons behind that might be a strong
penalization of library members with too low heavy (non-
hydrogen) atom count by the LLP tool. All the enumerated
library members fit perfectly the lead-like chemical space as
defined by “rule-of-four” (MW<400, LogP <4)[52] and even
partially – by far more strict Churcher’s rules (MW=200…350,
LogP=À 1…3)[51] (Figure 5, A). The three-dimensionality of all
the four library members was similar (see Table 1 for the
average Fsp3 and plane of best fit (PBF) values), and all of them
occupied similar part of the principal moment of inertia (PMI)
plot illustrating the overall molecular shape (Figure 4, B).
Expectedly, the parent piperidine derivatives lacking the C-
substituents performed somewhat worse according to the
aforementioned criteria.
Conclusions
Figure 5. LLAMA-based virtual libraries generated from P(O)Me2-containing
piperidines and their analogues: (A) MW-ALogP plot; (B) principal moment of
inertia (PMI) plot.
Despite the known biological activities, well-defined functions
and high abundance in living organisms, organophosphorous
compounds had been considered exotic for routine drug
discovery until recently, which resulted in low accessibility of
the simplest building blocks bearing the P(O)Me2 group. In this
work, we have disclosed several scalable synthetic approaches
to saturated heterocyclic dimethylphosphine oxides, i.e. azeti-
dine, pyrrolidine, piperidine, and morpholine derivatives.
with cyclic imines or monoprotected diamines in the presence
of formaldehyde, palladium-catalyzed reactions of alkenyl
halides or triflates, base-mediated nucleophilic substitution in
alkyl iodides, Michael addition, or oxirane ring-opening reaction
as the key steps. Notably, very efficient approaches to the
multigram synthesis of valuable low-molecular reagents bearing
the P(O)Me2 groups (i.e. compounds 7 and 24) were developed
as an important side result of this study, which should boost
further endeavors in this area.
Physico-chemical properties of the saturated P(O)Me2-con-
taining heterocycles, as well as some isosteric derivatives
thereof, were evaluated by measurement of pKa, logP, and Sw
values (Figure 6). It was shown that the inductive effect of
dimethylphosphine oxide had a strong impact on the com-
pound’s basicity: introducing the P(O)Me2 group into α, β, and γ
positions of the heterocyclic core diminished the pKa values by
ca. 4, 2, and 1.6 units, respectively. Still, this effect was not so
pronounced as for the case of SO2i-Pr- and SO2NMe2-containing
isosteres that were by 1.1 and 0.4 pKa units less basic further. In
The key steps of the reaction sequences typically relied on
the reactions of HP(O)Me2 with electrophiles, namely, the
phospha-Mannich (the Kabachnik-Fields-type) condensation
Table 1. LLAMA analysis of P(O)Me2-containing saturated heterocyclic
building blocks and their analogues.
Building
block(s)
Library
size
Lead-likeness
penalty (LLP)[a]
Fsp3 a,b
Plane of best
fit (PBF), [Å] a,b
2c, 42, and 43
Piperidine
35
36
72
26
26
26
0.78
2.81
0.38
0.38
0.728
0.675
0.743
0.724
0.99
0.85
0.94
0.96
[a] Mean values over the corresponding libraries are given. [b] Fraction of
sp3-hybrid carbon atoms. [c] Plane of best fit, the mean atomic distance
from a theoretical plane that passes through the molecule, configured in
such a way as to minimize the value.
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internal standard and are referenced using residual NMR solvent
1
peaks at 7.26 and 77.16 ppm for H and 13C{1H} in CDCl3, 2.50 and
39.52 ppm for 1H and 13C{1H} in DMSO-d6. Coupling constants (J) are
given in Hz. Spectra are reported as follows: chemical shift (δ, ppm),
multiplicity, integration, coupling constants (Hz). Elemental analyses
were performed at the Laboratory of Organic Analysis, Department
of Chemistry, Taras Shevchenko National University of Kyiv. Mass
spectra were recorded on an Agilent 1100 LCMSD SL instrument
(chemical ionization (CI)) and Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)). High-resolution mass
spectra (HRMS) were recorded on Agilent Infinity 1260 UHPLC
system coupled to 6224 Accurate Mass TOF LC/MS system.
Representative procedure for the preparation of phosphine
oxides 2a–e (given for 2a). BF3 ·OEt2 (5.43 mL, 6.24 g, 44.0 mmol)
was slowly added via syringe at rt to
a solution of the
corresponding cyclic imine (15.2 g, 0.220 mol) and dimeth-
ylphosphine oxide (17.2 g, 0.220 mol) in THF (450 mL). The mixture
was stirred at rt for 12–24 h. The completion of the reaction was
Figure 6. Physico-chemical properties of P(O)Me2-containing saturated het-
erocycles and their analogues: a brief summary.
1
monitored by H NMR and TLC. Then, most of THF was evaporated
in vacuo, and the residue was diluted with CH2Cl2 (250 mL). The
resulting mixture was washed with saturated aq NaHCO3 (30 mL),
dried over Na2SO4, filtered, and evaporated in vacuo. For the
preparation of hydrochlorides, the crude residue was dissolved in
MeOH (200 mL) and 10% HCl-1,4-dioxane (150 mL) was added at rt.
The solvents were evaporated, and the crude product was purified
by crystallized from t-BuOMe (250 mL).
all cases, introducing the P(O)Me2 group into the saturated
heterocyclic amine scaffolds resulted in significantly increased
hydrophilicity (by 1.4–1.7 LogP units) that decreased in the
isomeric series: γ>β>α. In some cases, significant increase of
aqueous solubility was also observed (i.e. for the 3- and 4-
substituted piperidine derivatives). Moreover, the P(O)Me2-
substituted compounds were by ca. 0.7 LogP units more
hydrophilic than the corresponding sulfur-containing isosteres.
Generation of virtual libraries based on the P(O)Me2-
substituted piperidines using the Nelson’s LLAMA tool showed
that the title building blocks showed performance more or less
similar to their SO2i-Pr- and SO2NMe2-containing isosteres; all
three-compound series could easily access the lead-like chem-
ical space even according to the strictest Churcher’s criteria.
Taking into account all of the above, we believe that the
saturated heterocyclic dimethylphospine oxides described in
2-(Dimethylphosphoryl)pyrrolidin-1-ium chloride (2a). Yield
21.4 g (53% from imine 1a (15.2 g, 0.220 mol)). Beige solid; mp
198–201 C. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.33 (s,
°
1H), 4.11–3.19 (m, 3H), 2.26–2.12 (m, 1H), 2.02–1.84 (m, 3H), 1.65 (d,
J=13.5 Hz, 3H), 1.60 (d, J=13.5 Hz, 3H). 13C NMR (126 MHz, DMSO-
d6) δ 56.1 (d, J=67.9 Hz), 46.1 (d, J=4.5 Hz), 25.1, 23.9, 15.1 (d, J=
67.5 Hz), 14.5 (d, J=68.1 Hz). 31P NMR (202 MHz, DMSO-d6) δ 40.6.
LC/MS (CI): m/z=148 [M+HÀ HCl]+. HRMS (ESI-TOF) m/z: [M+
HÀ HCl]+ calcd. for C6H15NOP 148.0886, found 148.0884; [M+
NaÀ HCl]+ calcd. for C6H14NNaOP 170.0705, found 170.0711.
Dimethyl(2-phenylpyrrolidin-2-yl)phosphine oxide (2b). Yield
32.6 g (60% from imine 1b (35.3 g, 0.243 mol)). Yellowish solid; mp
1
°
92–93 C. H NMR (400 MHz, CDCl3) δ 7.58–7.47 (m, 2H), 7.34 (t, J=
7.6 Hz, 2H), 7.28–7.22 (m, 1H), 3.15 (ddd, J=11.1, 8.0, 5.5 Hz, 1H),
2.99–2.81 (m, 2H), 2.47 (tt, J=12.9, 8.7 Hz, 1H), 2.41–2.29 (m, 1H),
1.97–1.81 (m, 1H), 1.64 (ddt, J=13.5, 10.6, 5.2 Hz, 1H), 1.37 (d, J=
12.3 Hz, 3H), 1.29 (d, J=12.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
139.8 (d, J=3.4 Hz), 128.0 (d, J=2.7 Hz), 126.8 (d, J=3.1 Hz), 126.5
(d, J=3.9 Hz), 68.1 (d, J=77.9 Hz), 46.0 (d, J=9.1 Hz), 33.4 (d, J=
3.5 Hz), 25.2 (d, J=6.9 Hz), 12.3 (d, J=65.8 Hz), 12.1 (d, J=68.0 Hz).
31P NMR (202 MHz, CDCl3) δ 50.3. LC/MS (CI): m/z=146 [M+
HÀ HP(O)Me2]+. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C12H19NOP
224.1199, found 224.1195.
this work are very promising building blocks adding
a
significant value to the medicinal chemists’ toolbox, and they
will find their application in early drug discovery in the nearest
future.
Experimental Section
The solvents were purified according to the standard procedures.[53]
Compounds 42 and 43 were provided by Mr. Maksym Stambirskyi;
their synthesis will be published elsewhere. All other starting
materials were available from Enamine Ltd. or purchased from
other commercial sources. Melting points were measured on
MPA100 OptiMelt automated melting point system. Column
chromatography was performed using Kieselgel Merck 60 (230–
2-(Dimethylphosphoryl)piperidin-1-ium chloride (2c). Yield 18.4 g
(44% from imine 1c (17.6 g, 0.212 mol)). Yellowish solid; mp 171–
1
°
174 C. H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.41 (s, 1H), 3.64–
3.49 (m, 2H), 2.97–2.77 (m, 1H), 2.04–1.89 (m, 1H), 1.89–1.70 (m, 3H),
1.65 (d, J=6.5 Hz, 3H), 1.62 (d, J=6.5 Hz, 3H), 1.61–1.30 (m, 2H). 13
C
NMR (126 MHz, DMSO-d6) δ 54.2 (d, J=67.3 Hz), 45.5 (d, J=5.6 Hz),
22.6, 21.9 (d, J=10.5 Hz), 21.4, 15.0 (d, J=67.3 Hz), 14.0 (d, J=
67.8 Hz). 31P NMR (202 MHz, DMSO-d6) δ 43.1. LC/MS (CI): m/z=162
[M+HÀ HCl]+. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C7H17NOP
162.1042, found 162.1043; [M+NH4]+ calcd. for C7H20N2OP
179.1308, found 179.1308; [M+Na]+ calcd. for C7H16NNaOP
184.0867, found 184.0861.
1
400 mesh) as the stationary phase. H, 13C{1H}, 19F{1H}, 31P{1H} NMR
spectra were recorded on a Agilent ProPulse 600 spectrometer (at
151 MHz for 13C NMR), a Bruker 170 Avance 500 spectrometer (at
1
500 MHz for H NMR, 126 MHz for 13C{1H} NMR, 470 MHz for 19F{1H}
NMR, and 202 MHz 31P{1H} NMR) and Varian Unity Plus 400
spectrometer (at 400 MHz for 1H NMR, 101 MHz for 13C{1H} NMR,
376 MHz for 19F NMR, and 162 MHz 31P{1H} NMR). NMR chemical
shifts are reported in ppm (δ scale) downfield from TMS as an
2-(Dimethylphosphoryl)-2-methylpiperidin-1-ium chloride (2d).
Yield 21.9 g (44% from imine 1d (0.235 mol)). Beige solid; mp 163–
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1
°
°
165 C. H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.83 (s, 1H), 3.11–
2.97 (m, 2H), 1.91–1.79 (m, 1H), 1.71 (d, J=13.0 Hz, 3H), 1.69–1.62
(m, 5H), 1.59 (d, J=13.0 Hz, 3H), 1.45 (d, J=14.3 Hz, 3H). 13C NMR
(126 MHz, DMSO-d6) δ 55.1 (d, J=69.8 Hz), 39.5 (d, J=3.6 Hz), 27.2,
21.2, 16.6 (d, J=7.3 Hz), 14.7, 13.1 (d, J=65.5 Hz), 12.5 (d, J=
66.1 Hz). 31P NMR (202 MHz, DMSO-d6) δ 51.7. LC/MS (CI): m/z=98
[M+HÀ HP(O)Me2]+. HRMS (ESI-TOF) m/z: [M+HÀ HCl]+ calcd. for
C8H19NOP 176.1197, found 176.1199; [M+NaÀ HCl]+ calcd. for
C8H18NNaOP 198.1018, found 198.1014.
The crude product was purified by distillation in vacuo (76–77 C,
1 mbar). Yield 72.9 g (68%). Greyish solid; mp 50–51 C. 1H NMR
°
(400 MHz,CD3CN) δ 6.39 (ddd, J=25.5, 19.0, 12.3 Hz, 1H), 6.23–5.94
(m, 2H), 1.46 (d, J=13.3 Hz, 6H). 13C NMR (126 MHz, CD3CN) δ 134.4
(d, J=91.1 Hz), 130.3, 15.9 (d, J=72.4 Hz). 31P NMR (202 MHz,
CD3CN) δ 31.1. GC/MS (EI): m/z=104 [M]+. HRMS (ESI-TOF) m/z: [M
+H]+ calcd. for C4H10OP 105.0464, found 105.0469.
(1-Benzylpyrrolidin-3-yl)dimethylphosphine oxide (8). Azome-
thine ylide precursor (85.0 g, 0.358 mol) was added to a solution of
dimethyl(vinyl)phosphine oxide (31.2 g, 0.299 mol) in CH2Cl2
Dimethyl(2-phenylpiperidin-2-yl)phosphine oxide (2e). Yield
°
52.4 g (58% from imine 1e (0.380 mol)). Yellowish solid; mp 135–
(400 mL), and the resulting mixture was cooled to 0 C. Then, a
solution of TFA (2.30 mL, 3.42 g, 30.0 mmol) in CH2Cl2 (100 mL) was
1
°
136 C. H NMR (400 MHz, DMSO-d6) δ 7.60–7.45 (m, 2H), 7.39 (t, J=
°
7.7 Hz, 2H), 7.31–7.19 (m, 1H), 2.86–2.66 (m, 2H), 2.50–2.31 (m, 3H),
1.84 (tdd, J=13.1, 8.3, 3.6 Hz, 1H), 1.60 (d, J=13.1 Hz, 1H), 1.38 (p,
J=6.4, 4.9 Hz, 2H), 1.19 (d, J=12.3 Hz, 3H), 1.14 (d, J=12.3 Hz, 3H).
13C NMR (126 MHz, DMSO-d6) δ 137.3, 128.6 (d, J=3.9 Hz), 128.1 (d,
J=2.6 Hz), 126.4 (d, J=3.1 Hz), 60.4 (d, J=78.7 Hz), 40.3 (d, J=
11.1 Hz), 27.8, 26.1, 19.9 (d, J=9.8 Hz), 11.6 (d, J=12.9 Hz), 11.1 (d,
J=11.8 Hz). 31P NMR (202 MHz, DMSO-d6) δ 48.5. LC/MS (CI): m/z=
160 [M+HÀ HP(O)Me2]+. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C13H21NOP 238.1355, found 238.1332; [M+Na]+ calcd. for
C13H20NNaOP 260.1175, found 260.1175.
added dropwise at 0 C for 1 h (NOTE: the temperature should not
°
exceed 5 C). The resulting mixture was stirred at rt overnight, then
poured into saturated aq NaHCO3 (150 mL). Organic layer was
separated, dried over Na2SO4, filtered, and evaporated in vacuo. The
crude product was purified by column chromatography on silica
gel using CHCl3 :MeOH (10:1, v/v) as eluent; RF =0.35. Yield 51.1 g
1
(72%). H NMR (500 MHz, CDCl3) δ 7.41–7.25 (m, 4H), 7.26–7.19 (m,
1H), 3.62 (s, 2H), 2.80 (q, J=9.6 Hz, 1H), 2.74–2.53 (m, 3H), 2.40–2.33
(m, 1H), 2.16–2.04 (m, 1H), 2.02–1.91 (m, 1H), 1.44 (d, J=8.1 Hz, 3H),
1.42 (d, J=8.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 138.6, 128.6,
128.3, 127.1, 59.8, 54.0 (d, J=4.8 Hz), 53.4, 37.9 (d, J=73.3 Hz), 24.6
(d, J=1.9 Hz), 14.8 (d, J=2.2 Hz), 14.2 (d, J=2.8 Hz). 31P NMR
(202 MHz, CDCl3) δ 45.5. LC/MS (CI): m/z=238 [M+H]+. Anal. Calcd.
for C13H20NOP: C 65.80; H 8.50; N 5.90. Found: C 66.15; H 8.35; N
6.10.
Benzyl 4-((dimethylphosphoryl)methyl)piperazine-1-carboxylate
(4). Paraformaldehyde (6.80 g, 0.227 mol) and pTSA (8.06 g,
46.8 mmol) were added to a solution of benzyl piperazine-1-
carboxylate (3, 49.9 g, 0.227 mol) in THF (500 mL), and the mixture
°
was stirred at 60 C for 1 h. Then, HP(O)Me2 (17.7 g, 0.227 mol) was
°
added, and the resulting mixture was stirred at 60 C overnight. The
3-(Dimethylphosphoryl)pyrrolidin-1-ium chloride (6). A mixture of
N-benzyl amine 8 (4.90 g, 20.6 mmol) and PdÀ C (10%, 400 mg) in
MeOH (60 mL) was hydrogenated in an autoclave with H2 (50 atm)
at 50 C overnight. The completion of the reaction was monitored
by H NMR. Then, catalyst was filtered off, the filtrate was treated
with 10% HCl–1,4-dioxane (60 mL) at rt, and the resulting mixture
was evaporated in vacuo. The crude product was triturated MeCN
(ca. 20 mL), and the precipitate formed was filtered and dried in
solvent was evaporated in vacuo, the residue was dissolved in
CH2Cl2 (600 mL), washed with H2O (200 mL) and saturated aq
NaHCO3 (200 mL). The organic layer was separated, dried over
Na2SO4, filtered, and evaporated in vacuo. The compound was
purified by column chromatography using CHCl3 :MeOH (10:1, v/v);
RF =0.35. Yield 65.2 g (93%). Yellowish oil. 1H NMR (500 MHz,
DMSO-d6) δ 7.44–7.31 (m, 4H), 7.31–7.25 (m, 1H), 5.06 (s, 2H), 3.45–
3.33 (m, 4H), 2.65 (d, J=6.9 Hz, 2H), 2.55–2.47 (m, 4H), 1.37 (d, J=
12.9 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 154.8, 137.4, 128.8,
128.2, 127.9, 79.7, 66.6, 58.4 (d, J=83.0 Hz), 55.0 (d, J=7.8 Hz), 44.0,
15.4 (d, J=67.7 Hz). 31P NMR (202 MHz, DMSO-d6) δ 40.2. LC/MS (CI):
m/z=311 [M+H]+. Anal. Calcd. for C15H23N2O3P: C 58.06; H 7.47; N
9.03. Found: C 57.70; H 7.42; N 9.41.
°
1
1
°
vacuo. Yield 2.90 g (76%). Colorless solid; mp 164–167 C. H NMR
(400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.58 (s, 1H), 3.48–3.40 (m, 1H),
3.27–3.18 (m, 1H), 3.16–3.01 (m, 2H), 2.58–2.50 (m, 1H), 2.20–2.09
(m, 1H), 2.01–1.86 (m, 1H), 1.45 (d, J=13.0 Hz, 6H). 13C NMR
(126 MHz, DMSO-d6) δ 45.0 (d, J=9.3 Hz), 44.2 (d, J=2.0 Hz), 37.4
(d, J=70.9 Hz), 24.8, 15.2 (d, J=69.1 Hz), 14.9 (d, J=68.4 Hz). 31P
NMR (202 MHz, DMSO-d6) δ 41.4. LC/MS (CI): m/z=148 [M+
HÀ HCl]+. HRMS (ESI-TOF) m/z: [M+HÀ HCl]+ calcd. for C6H15NOP
148.0886, found 148.0887; [M+NH4À HCl]+ calcd. for C6H18N2OP
165.1151, found 165.1115; [M+NaÀ HCl]+ calcd. for C6H14NNaOP
170.0705, found 170.0707.
Mono(1-((dimethylphosphoryl)methyl)piperazine-1,4-diium) di-
chloride (5). PdÀ C (10%, 6.00 g) and HCl-1,4dioxane (200 mL) were
added to a solution of Cbz-protected amine 4 (65.15 g, 0.231 mol)
in MeOH (400 mL). The resulting mixture was hydrogenated with H2
(1 atm) at rt overnight. After the completion of absorption of H2,
the reaction mixture was filtered through Celite, and the filtrate
was evaporated in vacuo. The compound was purified by crystal-
tert-Butyl 3-(dimethylphosphoryl)-2,2-dimethyl-2,5-dihydro-1H-
pyrrole-1-carboxylate (12). 2.5 M n-BuLi in hexanes (214 mL,
0.535 mol) was added to a stirred solution of TMS2NH (86.3 g,
lization from MeCN (150 mL). Yield 47.5 g (91%). Beige solid; mp
1
°
°
219–222 C. H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.81 (s, 2H),
0.535 mol) in THF (600 mL) at À 30 C, and the mixture was cooled
3.69–3.46 (m, 6H), 3.46–3.37 (m, 4H), 1.63 (d, J=13.6 Hz, 6H). 13C
NMR (126 MHz, DMSO-d6) δ 54.1 (d, J=66.9 Hz), 50.5 (d, J=4.6 Hz),
40.2, 16.6 (d, J=69.4 Hz). 31P NMR (202 MHz, DMSO-d6) δ 39.1. LC/
MS (CI): m/z=177 [M+HÀ 2HCl]+. HRMS (ESI-TOF) m/z: [M+
HÀ 2HCl]+ calcd. for C7H18N2OP 177.1151, found 177.1153; [M+
NaÀ 2HCl]+ calcd. for C13H20NNaOP 199.0971, found 199.0976.
to À 78 C. A solution of ketone 10 (95.0 g, 0.445 mol) in THF
°
°
(300 mL) was slowly added at À 78 C, and the resulting mixture
°
was stirred at À 78 C for 1 h. Then, a solution of PnNTf2 (207 g,
°
0.579 mol) in THF (300 mL) at À 78 C, the mixture was stirred for
15 min and warmed up to rt overnight. Next, saturated aq NH4Cl
(350 mL) was added, organic layer was separated and evaporated
in vacuo. The residue was diluted with EtOAc (1000 mL), washed
with brine (300 mL), dried over Na2SO4, filtered, and evaporated in
vacuo. The residue was subjected to column chromatography on
silica gel using hexanes:EtOAc (12:1, v/v) as eluent (RF =0.45) to
give a ca. 1:1 mixture of alkenyl triflate 11 and PhNHTf, which was
dissolved in argon-purged MeCN (900 mL) in a sealed vial. Then,
Et3N (66.9 mL, 48.6 g, 0.480 mol), HP(O)Me2 (27.9 g, 0.357 mol), and
Pd(PPh3)4 (7.40 g, 64.0 mmol) were added. The resulting mixture
Dimethyl(vinyl)phosphine oxide (7).[45,46]
A solution of vinyl
bromide (110 g, 1.03 mol), dimethylphosphine oxide (80.0 g,
1.03 mol), and Pd(PPh3)4 (23.1 g, 20.0 mol) in argon-purged MeCN
(1500 mL) in an autoclave was treated with Et3N (215 mL, 152 g,
°
1.50 mol) and heated at 90 C for 8 h. Then, the reaction mixture
was cooled to rt and the solvent was evaporated in vacuo to a half
of volume. The residue was triturated with t-BuOMe (800 mL), the
precipitate was filtered off, and the filtrate was evaporated in vacuo.
°
was heated at 90 C for 3 h, then cooled to rt, and the solvent was
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evaporated in vacuo. The crude produce was purified by column
chromatography on silica gel using gradient CHCl3 :MeOH (19:1 to
14:1, v/v) as eluent; RF =0.20. The compound existed as a ca. 1:1
mixture of rotamers. Yield 50.2 g (58%). Colorless solid; mp 150–
compound existed as a ca. 3:2 of rotamers. Yield 33.4 g (80%).
Yellowish oil. H NMR (500 MHz, CDCl3) δ 6.48–6.37 (m, 0.6H) and
1
6.38–6.29 (m, 0.4H), 5.19–5.09 (m, 0.4H) and 5.09–5.01 (m, 0.6H),
4.43–4.28 (m, 2H), 3.70 (s, 3H), 3.42–3.37 (m, 1H), 1.62–1.53 (m, 6H),
1.43 (s, 3.6H) and 1.38 (s, 5.4H). 13C NMR (126 MHz, CDCl3) δ 168.8
and 168.6, 152.9 and 152.5, 138.7 (d, J=27.9 Hz) and 137.9 (d, J=
27.9 Hz), 135.7 (d, J=7.0 Hz) and 134.7 (d, J=7.7 Hz), 80.5, 67.3 (d,
J=11.8 Hz), 67.1 (d, J=11.6 Hz), 53.3 (d, J=16.6 Hz) and 53.2 (d, J=
17.8 Hz), 52.1 and 52.0, 27.8 and 27.7, 16.8, 16.7 (d, J=9.7 Hz), 16.5
(d, J=73.4 Hz) and 16.4 (d, J=73.4 Hz) and 16.3 (d, J=73.4 Hz). 31P
NMR (202 MHz, CDCl3) δ 27.5 and 27.2. LC/MS (CI): m/z=204
[MÀ CO2À (H3C)2C=CH2 +H]+, 304 [M+H]+. Anal. Calcd. for
C13H22NO5P: C 51.48; H 7.31; N 4.62. Found: C 51.50; H 7.09; N 4.88.
152 C. 1H NMR (500 MHz, DMSO-d6) δ 6.35 (dd, J=27.2, 10.9 Hz,
°
1H), 4.11–4.04 (m, 2H), 1.61–1.55 (m, 9H), 1.54 (d, J=2.8 Hz, 3H),
1.42 (s, 4.5H) and 1.38 (s, 4.5H). 13C NMR (126 MHz, DMSO-d6) δ
153.1, 152.1, 144.7 (d, J=94.7 Hz), 134.3 (d, J=10.1 Hz), 134.1 (d,
J=10.3 Hz), 79.3 and 78.8, 70.0 (d, J=14.4 Hz) and 69.4 (d, J=
13.9 Hz), 54.3 (d, J=12.9 Hz) and 54.1 (d, J=12.9 Hz), 28.6, 26.3 and
25.3, 19.6 (d, J=72.4 Hz), 19.5(d, J=72.5 Hz). 31P NMR (202 MHz,
DMSO-d6) δ 29.3 and 29.1. LC/MS (CI): m/z=274 [M+H]+. Anal.
Calcd. for C13H24NO3P: C 57.13; H 8.85; N 5.12. Found: C 57.49; H
9.15; N 5.06.
(2S*,4S*)-1-tert-Butyl
2-methyl
4-(dimethylphosphoryl)
tert-Butyl 3-(dimethylphosphoryl)-2,2-dimethylpyrrolidine-1-car-
boxylate (13). A stirred solution of alkenyl dimethylphosphine
oxide 12 (66.0 g, 0.242 mol) and 10% PdÀ C (7.00 g) in MeOH
(700 mL) was hydrogenated in an autoclave with H2 (10 atm) at rt
overnight. After the completion of absorption of H2, the reaction
pyrrolidine-1,2-dicarboxylate (19). A stirred solution of alkenyl
dimethylphosphine oxide 18 (33.4 g, 0.110 mol) and 10% PdÀ C
(3.00 g) in MeOH (300 mL) was hydrogenated with H2 (1 atm) at rt
overnight. After the completion of absorption of H2, the reaction
mixture was filtered through Celite, and the filtrate was evaporated
in vacuo. The compound was purified by column chromatography
using CHCl3 :MeOH:Et3N (10:1:0.1, v/v/v). The compound existed as
mixture was filtered through Celite, and the filtrate was evaporated
1
°
in vacuo. Yield 53.5 g (81%). Colorless solid; mp 121–122 C. H NMR
1
(500 MHz, DMSO-d6) δ 3.48 (t, J=9.0 Hz, 1H), 3.15 (q, J=8.8 Hz, 1H),
2.33–2.18 (m, 1H), 1.93–1.80 (m, 2H), 1.55 (d, J=8.6 Hz, 3H), 1.46 (d,
J=12.8 Hz, 3H), 1.44–1.27 (m, 15H). 13C NMR (126 MHz, DMSO-d6) δ
152.8 and 152.0, 78.5 and 77.9, 62.3 and 61.8, 51.1 (d, J=72.9 Hz)
and 50.5 (d, J=72.9 Hz), 46.5 (d, J=15.6 Hz) and 46.3 (d, J=
15.6 Hz), 28.2, 27.9 (d, J=141 Hz), 23.3 (d, J=43.8 Hz), 23.6–21.4
(m), 17.4 (d, J=68.3 Hz), 15.9 (d, J=66.7 Hz). 31P NMR (202 MHz,
DMSO-d6) δ 39.8. LC/MS (CI): m/z=276 [M+H]+. Anal. Calcd. for
C13H26NO3P: C 56.71; H 9.52; N 5.09. Found: C 57.11; H 9.12; N 5.37.
a ca. 5:4 mixture of rotamers. Yield 30.5 g (91%). Colorless oil. H
NMR (400 MHz, CDCl3) δ 4.34 (t, J=8.5 Hz, 0.45H), 4.28 (t, J=8.5 Hz,
0.55H), 3.93–3.80 (m, 1H), 3.73 (s, 3H), 3.58–3.46 (m, 1H), 2.59–2.36
(m, 2H), 2.21–2.03 (m, 1H), 1.50 (d, J=12.7 Hz, 6H), 1.45 (s, 4H), 1.40
(s, 5H). 13C NMR (126 MHz, CDCl3) δ 172.1, 152.8, 80.3, 58.9 (d, J=
9.0 Hz), 58.6 (d, J=9.0 Hz), 51.8 and 51.7, 46.2, 38.1 (d, J=72.6 Hz),
30.4 and 29.7, 27.8 and 27.7, 15.2 (d, J=69.4 Hz) and 14.1 (d, J=
69.4 Hz). 31P NMR (202 MHz, CDCl3) δ 41.3 and 40.8. LC/MS (CI): m/
z=306 [M+H]+. Anal. Calcd. for C13H24NO5P: C 51.14; H 7.92; N 4.59.
Found: C 51.46; H 7.61; N 4.34.
(2,2-Dimethylpyrrolidin-3-yl)dimethylphosphine oxide (9). 10%
HCl-1.4-dioxane (200 mL) was added to a solution of N-Boc amine
13 (53.5 g, 0.196 mol) in 1.4-dioxane (200 mL), and the mixture was
stirred at rt overnight. Then, the solvent was evaporated in vacuo,
the residue was crystallized from MeCN (100 mL). Yield 33.7 g
(81%) as a hydrochloride, which was then diluted with CHCl3
(500 mL). K2CO3 (110 g, 0.797 mol) was added, and the resulting
mixture was stirred at rt for 1 h. The precipitate was filtered off,
washed with CHCl3 (150 mL) and MeCN (100 mL), and the filtrate
(2S*,4S*)-4-(dimethylphosphoryl)-2-(methoxycarbonyl)pyrrolidin-
1-ium chloride (15). 10% HCl-1.4-dioxane (100 mL) was added to a
solution of N-Boc amine 19 (15.5 g, 50.8 mmol) in 1.4-dioxane
(200 mL), and the mixture was stirred at rt overnight. Then, the
solvent was evaporated in vacuo, the residue was crystallized from
1
°
MeCN (30 mL). Yield 7.24 g (59%). Beige solid; mp 120–122 C. H
NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.49 (s, 1H), 4.51–4.33 (m,
1H), 3.74 (s, 3H), 3.59–3.47 (m, 1H), 3.32–3.18 (m, 1H), 2.74–2.59 (m,
1H), 2.59–2.52 (m, 1H), 2.15–2.00 (m, 1H), 1.46 (d, J=13.2 Hz, 6H).
13C NMR (126 MHz, DMSO-d6) δ 168.2, 58.8 (d, J=10.2 Hz), 53.0,
44.8, 37.3 (d, J=69.8 Hz), 28.7, 15.3 (d, J=34.2 Hz), 14.7 (d, J=
35.3 Hz). 31P NMR (202 MHz, DMSO-d6) δ 40.5. LC/MS (CI): m/z=206
[M+HÀ HCl]+. Anal. Calcd. for C8H17ClNO3P: C 39.76; H 7.09; N 5.80;
Cl 14.67. Found: C 40.11; H 6.78; N 5.94; Cl 14.38. LC/MS (CI): m/z=
176 [M+H]+. HRMS (ESI-TOF) m/z: [M+HÀ HCl]+ calcd. for
C8H17NO3P 206.0941, found 206.0939; [M+NaÀ HCl]+ calcd. for
C8H16NNaO3P 228.0760, found 228.0753.
was evaporated in vacuo. Yield 23.3 g (84%). Colorless solid; mp
1
°
94–97 C. H NMR (400 MHz, DMSO-d6) δ 2.90–2.77 (m, 2H), 2.05–
1.86 (m, 2H), 1.84–1.68 (m, 1H), 1.42 (d, J=12.5 Hz, 3H), 1.35 (d, J=
12.5 Hz, 3H), 1.25 (s, 3H), 1.13 (s, 3H). 13C NMR (126 MHz, DMSO-d6)
δ 61.7, 49.7 (d, J=68.3 Hz), 43.4 (d, J=11.5 Hz), 29.3, 27.8, 24.1, 17.4
(d, J=66.2 Hz), 16.4 (d, J=67.2 Hz). 31P NMR (202 MHz, DMSO-d6) δ
40.6. LC/MS (CI): m/z=176 [M+H]+. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C8H19NOP 176.1199, found 176.1198.
1-tert-Butyl
2-methyl
4-(dimethylphosphoryl)-1H-pyrrole-
1,2(2H,5H)-dicarboxylate (18). 1 M NaHMDS in THF (158 mL,
0.158 mol) was added dropwise to a solution of ketone 14 (35.0 g,
(2S*,4S*)-1-(tert-Butoxycarbonyl)-4-(dimethylphosphoryl)
pyrrolidine-2-carboxylic acid (16). A solution of NaOH (2.51 g,
62.9 mmol) in H2O (80 mL) was added to a stirred solution of ester
19 (16.0 g, 52.4 mmol) in THF (150 mL) at rt, and the resulting
mixture was stirred at rt overnight. Then, 10% aq NaHSO4 was
added until pH=4 was reached, solvents were evaporated in vacuo,
the residue was triturated with MeCN (50 mL), and the precipitate
was filtered off. The filtrate was evaporated in vacuo, the residue
was triturated with Et2O (30 mL) and filtered. The compound
°
0.144 mol) in THF (500 mL) at À 78 C. After 20 min, PnNTf2 (53.9 g,
°
0.151 mol) was added at À 78 C, and the reaction mixture was
°
stirred at À 78 C for 3 h, then quenched with saturated aq NaHCO3
°
(350 mL) at À 78 C. The reaction mixture was extracted with EtOAc
(2*350 mL), the organic layer was washed with brine (350 mL), dried
over Na2SO4, filtered, and evaporated in vacuo. The crude
compound was purified by flash column chromatography using
hexanes:EtOAc (9:1, v/v) as eluent (RF = 0.40) to give a ca. 1:1
mixture of alkenyl triflate 17 and PnNHTf, which was dissolved in
argon-purged MeCN (500 mL) in a sealed vial. Then, Et3N (28.5 mL,
20.7 g, 0.205 mol), HP(O)Me2 (12.0 g, 0.153 mol), and Pd(PPh3)4
(7.88 g, 6.82 mmol) were added. The resulting mixture was heated
existed as a ca. 2:1 mixture of rotamers Yield 10.2 g (67%).
1
°
Colorless solid; mp 201–202 C. H NMR (400 MHz, DMSO-d6) δ 12.74
(s, 1H), 4.10 (t, J=8.1 Hz, 1H), 3.68 (t, J=8.8 Hz, 1H), 3.34–3.19 (m,
1H), 2.49–2.37 (m, 2H), 1.99–1.75 (m, 1H), 1.61–1.35 (m, 9H), 1.34 (s,
6H). 13C NMR (151 MHz, DMSO-d6) δ 174.3 and 173.7, 153.6 and
153.3, 79.5, 59.7 (d, J=9.5 Hz) and 59.5 (d, J=9.1 Hz), 46.9 (d, J=
2.7 Hz) and 46.7 (d, J=3.4 Hz), 38.6 (d, J=71.4 Hz) and 37.9 (d, J=
71.9 Hz), 30.8 and 30.1, 28.5 and 28.3, 15.6 (d, J=67.7 Hz) and 15.4
°
at 90 C for 3 h, then cooled to rt and the solvent was evaporated in
vacuo. The crude product was purified by column chromatography
on silica gel using CHCl3 :MeOH (14:1, v/v) as eluent; RF =0.41. The
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(d, J=67.7 Hz) and 15.3 (d, J=68.3 Hz) and 15.1 (d, J=68.3 Hz). 31P
NMR (202 MHz, DMSO-d6) δ 39.6. LC/MS (CI): m/z=292 [M+H]+.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C12H23NO5P 292.1308, found
292.1309; [M+Na]+ calcd. for C12H22NNaO5P 314.1128, found
314.1129.
(85%). Colorless solid; mp 69–70 C. 1H NMR (500 MHz, CDCl3) δ
3.04–2.82 (m, 3H), 1.50 (d, J=13.2 Hz, 3H), 1.37 (d, J=13.2 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 48.0 (d, J=98.8 Hz), 44.7 (d, J=2.0 Hz),
15.0 (d, J=70.7 Hz), 12.7 (d, J=72.0 Hz). 31P NMR (202 MHz, CDCl3)
δ 39.3. GC/MS (EI): m/z=120 [M]+. Anal. Calcd. for C4H9O2P: C 40.01;
H 7.55. Found: C 39.99; H 7.25.
°
tert-Butyl 3-(dimethylphosphoryl)azetidine-1-carboxylate (21). A
solution of HP(O)Me2 (54.6 g, 0.700 mol) in THF (600 mL) was cooled
4-Benzyl-6-(dimethylphosphoryl)morpholin-3-one (28). Oxirane
24 (60.0 g, 0.500 mol) was dissolved in i-PrOH (300 mL), and BnNH2
(53.5 g, 0.500 mol) was added. The resulting mixture was stirred at
°
to 0 C, and NaHMDS (2 M in THF, 350 mL, 0.700 mol) was added
dropwise under Argon atmosphere. The resulting mixture was
°
°
stirred at rt for 1 h, then cooled to 0 C, and tert-butyl 3-
80 C overnight, then cooled to rt, and evaporated in vacuo. The
iodoazetidine-1-carboxylate (20, 100 g, 0.353 mol) was added. After
stirring at rt for 24 h, the reaction mixture was evaporated in vacuo,
the residue was triturated with EtOAc (800 mL), the precipitate was
filtered off, and the filtrate was evaporated in vacuo. The crude
produce was purified by column chromatography on silica gel
residue was dissolved in CH2Cl2 (1000 mL), then chloroacetyl
chloride (46.0 g, 0.407 mol) and i-PrNEt2 (59.1 g, 0.457 mol) were
°
added dropwise at 0 C. The mixture was stirred at rt overnight,
then diluted with H2O (250 ml). Organic layer was washed with
saturated aq NaHCO3 (100 mL), brine (100 ml), dried over Na2SO4,
and evaporated in vacuo. Amide 27 was dissolved in THF
using CHCl3 :MeOH (10:1, v/v) as eluent; RF =0.28. Yield 39.2 g
1
°
°
(48%). Colorless solid; mp 131–132 C. H NMR (500 MHz, CDCl3) δ
(1000 mL), the solution was cooled to 0 C, and t-BuONa (32.1 g,
4.08 (dt, J=13.1, 9.0 Hz, 2H), 4.03–3.92 (m, 2H), 2.74 (dddd, J=15.5,
9.7, 6.0, 3.9 Hz, 1H), 1.44 (d, J=12.5 Hz, 6H), 1.36 (s, 9H). 13C NMR
(126 MHz, CDCl3) δ 155.8 (d, J=2.1 Hz), 80.0, 48.7, 28.3 (d, J=
73.2 Hz), 28.2, 13.7 (d, J=69.8 Hz). 31P NMR (202 MHz, CDCl3) δ 41.8.
LC/MS (CI): m/z=178 [MÀ (H3C)2C=CH2 +H]+. Anal. Calcd. for
C10H20NO3P: C 51.49; H 8.64; N 6.01. Found: C 51.20; H 8.56; N 5.87.
0.334 mol) was added in portions. The reaction mixture was stirred
at rt overnight, the precipitate formed was filtered off and the
filtrate was evaporated in vacuo. Analytical sample was obtained by
crystallization from t-BuOMe. Yield 81.2 g (91%). Colorless solid; mp
1
°
102–103 C. H NMR (500 MHz, CDCl3) δ 7.31–7.20 (m, 5H), 4.71 (d,
J=14.5 Hz, 1H), 4.48 (d, J=14.6 Hz, 1H), 4.34 (dd, J=16.5, 2.1 Hz,
1H), 4.20 (d, J=16.4 Hz, 1H), 3.96 (ddd, J=11.6, 7.4, 4.3 Hz, 1H),
3.55–3.40 (m, 2H), 1.53 (d, J=13.3 Hz, 3H), 1.44 (d, J=13.2 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 165.1, 135.1, 128.4, 127.9, 127.5, 71.1 (d,
J=86.4 Hz), 68.2 (d, J=12.1 Hz), 49.3, 44.3 (d, J=5.6 Hz), 14.1 (d, J=
70.1 Hz), 11.2 (d, J=68.6 Hz). 31P NMR (202 MHz, CDCl3) δ 44.8. LC/
MS (CI): m/z=268 [M+H]+. Anal. Calcd. for C13H18NO3P: C 58.42; H
6.79; N 5.24. Found: C 58.75; H 6.44; N 5.45.
3-(Dimethylphosphoryl)azetidin-1-ium chloride (22). 10% HCl-1.4-
dioxane (180 mL) was added to a solution of N-Boc amine 21
(39.2 g, 0.17 mol) in Et2O (200 mL), and the mixture was stirred at rt
overnight. Then, the solvent was evaporated in vacuo and the
residue was crystallized from MeCN (50 mL). Yield 24.5 g (85%).
1
°
Colorless solid; mp 139–142 C. H NMR (400 MHz, DMSO-d6) δ 10.00
(s, 1H), 9.31 (s, 1H), 4.15–3.93 (m, 4H), 3.25 (p, J=9.3 Hz, 1H), 1.43
(d, J=13.3 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 44.4 (d, J=
4.1 Hz), 30.8 (d, J=71.1 Hz), 14.3 (d, J=68.4 Hz). 31P NMR (202 MHz,
DMSO-d6) δ 40.2. LC/MS (CI): m/z=134 [M+HÀ HCl]+. HRMS (ESI-
TOF) m/z: [M+HÀ HCl]+ calcd. for C5H13NOP 134.0729, found
134.0732; [M+NH4À HCl]+ calcd. for C5H16N2OP 151.0995, found
151.0991; [M+NaÀ HCl]+ calcd. for C5H12NNaOP 156.0554, found
156.0555.
(4-Benzylmorpholin-2-yl)dimethylphosphine oxide (29). A solu-
tion of I2 (92.5 g, 0.364 mol) in THF (150 mL) was added slowly at
°
0 C to a solution of NaBH4 (27.8 g, 0.735 mol) in THF (600 mL) The
resulting solution was stirred at rt for 1 h, and a solution of
morpholinone 28 (81.2 g, 0.304 mol) in THF (200 mL) was added
°
dropwise at 10 C. The resulting mixture was stirred at rt for 18 h,
and MeOH (150 mL) was added dropwise at rt. The solvent was
evaporated in vacuo, and the residue was diluted with saturated aq
NaHCO3 (80 mL) and CHCl3 (500 mL). The organic layer was
separated, the aqueous layer was extracted with CHCl3 (4×150 mL).
Combined organic extracts were dried over Na2SO4, filtered, and
(2-Chloro-1-hydroxyethyl)dimethylphosphine oxide (26). Chloroa-
cetaldehyde (45% in H2O, 225 mL, 1.28 mol) was added to HP(O)
°
Me2 (100 g, 1.28 mol) at 15 C. The resulting mixture was stirred at
rt for 1 h, and Et3N (8.93 mL, 6.50 g, 64.2 mmol) was added. The
reaction mixture was stirred at rt overnight, the completion of the
reaction was monitored by 1H and 31P NMR until no starting
material was observed. Then, the mixture was re-evaporated three
times in vacuo with MeCN (500 mL), the residue was dried in vacuo
and triturated with t-BuOMe (600 mL) and MeCN (100 mL), then
evaporated in vacuo. Yield 62.7 g (84%). Colorless solid; mp 124–
1
°
125 C. H NMR (500 MHz, CDCl3) δ 7.46–7.20 (m, 4H), 7.21–7.12 (m,
1H), 3.91–3.73 (m, 2H), 3.61 (td, J=11.3, 2.4 Hz, 1H), 3.49 (dd, J=
13.5, 13.0 Hz, 2H), 3.10 (dt, J=11.5, 2.2 Hz, 1H), 2.64 (dt, J=11.8,
2.0 Hz, 1H), 2.24–2.03 (m, 2H), 1.45 (d, J=13.1 Hz, 3H), 1.42 (d, J=
13.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 137.1, 129.0, 128.3, 127.3,
74.3 (d, J=89.7 Hz), 68.1 (d, J=11.5 Hz), 63.2, 52.8, 51.9 (d, J=
3.8 Hz), 14.3 (d, J=68.8 Hz), 12.2 (d, J=67.6 Hz). 31P NMR (202 MHz,
CDCl3) δ 44.1. LC/MS (CI): m/z=254 [M+H]+. Anal. Calcd. for
C13H20NO2P: C 61.65; H 7.96; N 5.53. Found: C 61.75; H 7.94; N 5.17.
filtered and dried in vacuo. Yield 105 g (52%). Colorless solid; mp
1
°
126–127 C. H NMR (500 MHz, CDCl3) δ 6.01 (s, 1H), 4.10–3.88 (m,
2H), 3.67 (ddd, J=11.5, 8.9, 5.7 Hz, 1H), 1.53 (d, J=13.0 Hz, 3H), 1.47
(d, J=13.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 70.0 (d, J=83.1 Hz),
44.6 (d, J=10.2 Hz), 13.9 (d, J=67.6 Hz), 11.6 (d, J=66.0 Hz). 31P
NMR (202 MHz, CDCl3) δ 50.0. LC/MS (CI): m/z=157/159 [M+Hl]+.
Anal. Calcd. for C4H10ClO2P: C 30.69; H 6.44; Cl 22.64. Found: C 30.63;
H 6.23; Cl 22.60.
2-(Dimethylphosphoryl)morpholin-4-ium chloride (23). A solution
of N-benzyl amine 29 (62.7 g, 0.256 mol) in EtOH (400 mL), and
PdÀ C (10%, 20.0 g) were placed in an autoclave. The mixture was
°
hydrogenated with H2 (100 atm) at 80 C for 18 h. Then, the catalyst
Dimethyl(oxiran-2-yl)phosphine oxide (24). Na (15.3 g, 0.667 mol)
was carefully added in MeOH (600 mL), and the resulting solution
was filtered off, the filtrate was evaporated in vacuo, and HCl-1,4-
dioxane (350 mL) was added to the residue. The resulting mixture
was evaporated in vacuo, the residue was diluted with MeCN
(30 mL) and t-BuOMe (300 mL). The product crystallized after
°
was cooled to 0 C. Then, a solution of hydroxyalcohol (105 g,
0.667 mol) in MeOH (300 mL) was added dropwise. The resulting
mixture was warmed up to rt, and stirred overnight. The solvent
was evaporated in vacuo, the residue was triturated with EtOAc
(100 mL). The precipitate was filtered off, washed with EtOAc
(200 mL), and the solvent was evaporated in vacuo. The crude
produce was purified by column chromatography on silica gel
using CHCl3 :MeOH (10:1, v/v) as eluent; RF =0.35. Yield 68.1 g
vigorous stirring for 2 h and filtration. Yield 43.1 g (87%). Colorless
1
°
solid, mp 165–167 C. H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H),
9.89 (s, 1H), 4.14 (ddd, J=12.3, 6.4, 2.4 Hz, 1H), 4.02 (dd, J=12.5,
3.7 Hz, 1H), 3.85 (td, J=12.3, 2.4 Hz, 1H), 3.45–3.33 (m, 1H), 3.25–
3.16 (m, 1H), 3.16–2.93 (m, 2H), 1.48 (s, 3H), 1.44 (d, J=11.4 Hz, 3H).
13C NMR (126 MHz, DMSO-d6) δ 71.3 (d, J=84.3 Hz), 64.2 (d, J=
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10.2 Hz), 42.1, 41.4 (d, J=5.6 Hz), 13.9 (d, J=68.6 Hz), 12.2 (d, J=
68.3 Hz). 31P NMR (202 MHz, DMSO-d6) δ 41.6. LC/MS (CI): m/z=164
[MÀ HCl+H]+. HRMS (ESI-TOF) m/z: [M+HÀ HCl]+ calcd. for
C6H15NO2P 164.0835, found 164.0838; [2 M+NaÀ 2HCl]+ calcd. for
C12H28N2NaO4P2 349.1422, found 349.1433.
vacuo, and the residue was crystalized from hot EtOH (20 mL). Yield
1
°
(19.2 g, 75%). Yellowish crystals; mp 213–215 C. H NMR (400 MHz,
DMSO-d6) δ 6.72 (s, 2H), 3.19–3.10 (m, 2H), 2.09 (ddt, J=12.5, 8.9,
4.5 Hz, 2H), 1.44 (d, J=13.2 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ
47.8 (d, J=1.8 Hz), 25.8 (d, J=65.0 Hz), 15.9 (d, J=68.2 Hz). 31P NMR
(202 MHz, DMSO-d6) δ 40.0. LC/MS (CI): m/z=186 [M+H]+. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C4H13NO3PS 186.0348, found
186.0348; [M+Na]+ calcd. for C4H12NNaO3PS 208.0168, found
208.0165.
Dimethyl(2-(pyridin-2-yl)ethyl)phosphine oxide (32). Na (10.9 g,
0.476 mol) was carefully added in EtOH (200 mL), and the resulting
solution was added dropwise to a mixture of 2-vinylpyridine (31,
50.0 g, 0.476 mol) and HP(O)Me2 (37.1 g, 0.476 mol) in EtOH
°
(400 mL). After 15 min, the mixture was warmed up to 70 C, then
3-(Isopropylthio)pyridine (38). i-PrSH (2.05 g, 26.9 mmol) was
added to a suspension of NaH (60%, 1.08 g 26.9 mmol) in DMF
(20 mL), and the resulting mixture was stirred at rt for 1 h. Then, 3-
bromopyridine (37, 2.13 g, 13.5 mmol) was added, the reaction
°
was stirred at 60 C overnight. The solvent was evaporated in vacuo,
the residue was partitioned between H2O (100 mL) and EtOAc
(400 mL). The organic layer was separated, aqueous phase was
extracted with EtOAc (4×200 mL). Combined organic layers were
dried over Na2SO4, filtered, and evaporated in vacuo. Analitical
sample was obtained by column chromatography on silica gel
using CHCl3 :MeOH (10:1, v/v) as eluent; RF =0.34. Yield 72.3 g
(83%) 1H NMR (400 MHz, DMSO-d6) δ 8.52–8.43 (m, 1H), 7.71 (td, J=
7.7, 1.7 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.26–7.18 (m, 1H), 3.02–2.85
(m, 2H), 2.17–1.99 (m, 2H), 1.37 (d, J=12.9 Hz, 6H). 13C NMR
(126 MHz, DMSO-d6) δ 160.6 (d, J=13.9 Hz), 149.0, 136.6, 122.7,
121.5, 30.6 (d, J=67.6 Hz), 29.6 (d, J=2.9 Hz), 16. 1 (d, J=67.2 Hz).
31P NMR (202 MHz, DMSO-d6) δ 40.5. LC/MS (CI): m/z=184 [M+H]+.
Anal. Calcd. for C9H14NOP: C 59.01; H 7.70; N 7.65. Found: C 58.66; H
7.82; N 8.00.
°
mixture was stirred at 50 C overnight, then cooled to rt, and
poured into saturated aq NH4Cl (25 mL). The mixture was diluted
with EtOAc (30 mL), organic phase was separated, washed with H2O
(3×15 mL), brine (10 mL), dried over Na2SO4, filtered, and evapo-
rated in vacuo. The crude produce was purified by column
chromatography on silica gel using t-BuOMe:MeOH (60:1, v/v) as
eluent; RF =0.40. Yield 1.58 g (76%); yellowish liquid. 1H NMR
(500 MHz, CDCl3) δ 8.52 (d, J=2.3 Hz, 1H), 8.36 (dd, J=4.8, 1.7 Hz,
1H), 7.60 (dt, J=8.0, 2.0 Hz, 1H), 7.12 (dd, J=7.9, 4.8 Hz, 1H), 3.26
(sept, J=6.7 Hz, 1H), 1.19 (d, J=6.8 Hz, 6H). 13C NMR (126 MHz,
CDCl3) δ 152.1, 147.3, 139.1, 131.9, 123.0, 38.0, 22.6. LC/MS (CI): m/
z=154 [M+H]+. Anal. Calcd. for C8H11NS: C 62.7; H 7.24; N 9.14; S
20.92. Found: C 63.07; H 7.20; N 9.47; S 20.99.
2-(2-(Dimethylphosphoryl)ethyl)piperidin-1-ium chloride (30). A
mixture of pyridine 32 (80.0 g, 0.437 mol) and PdÀ C (10%, 8.00 g) in
HOAc (600 mL) was placed in an autoclave. The mixture was
hydrogenated with H2 (50 atm) at 65 C for 18 h. The catalyst was
filtered off, and filtrate was evaporated in vacuo to dryness. Then,
3-(Isopropylsulfonyl)pyridine (39). Sulfide 38 (1.58 g, 10.3 mmol),
was dissolved in MeCN:H2O (1:1, v/v, 20 mL), then NaIO4 (4.62 g,
21.6 mmol) and RuCl3 (104 mg, 0.515 mmol) were added. The
reaction mixture was stirred at rt overnight, the precipitate was
filtered off and washed with EtOAc (3×15 mL). The filtrate was
washed with H2O (2×10 mL), brine (10 mL), dried over Na2SO4,
filtered, and evaporated in vacuo. The crude produce was purified
by column chromatography on silica gel using hexane:EtOAc (1:2,
°
°
5 M aq NaOH (200 mL) was carefully added at 0 C to the residue
until pH=12 was reached, and the product was extracted with
CH2Cl2 (5×300 mL). The organic layer was dried over Na2SO4,
filtered, and evaporated in vacuo. The residue was dissolved in
MeCN (200 mL), cooled to 0 C, and 10% HCl-1.4-dioxane (180 mL)
was added. The resulting mixture was stirred for 30 min, the
precipitate formed was filtered and dried in vacuo. Yield 57.0 g
(58%). Colorless solid; mp 143–144 C. H NMR (400 MHz, DMSO-d6)
δ 9.40–9.00 (m, 2H), 3.20 (d, J=12.8 Hz, 1H), 3.10–2.95 (m, 1H),
2.85–2.73 (m, 1H), 2.04–1.52 (m, 8H), 1.45 (d, J=3.8 Hz, 3H), 1.42 (d,
J=3.7 Hz, 3H), 1.41–1.22 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ
56.1, 56.0, 43.6, 27.4, 26.2 (d, J=67.5 Hz), 25.2, 21.7 (d, J=11.6 Hz),
15.3 (d, J=68.9 Hz), 15.1 (d, J=68.9 Hz). 31P NMR (202 MHz, DMSO-
d6) δ 55.1. LC/MS (CI): m/z=190 [M+HÀ HCl]+. HRMS (ESI-TOF) m/z:
[M+HÀ HCl]+ calcd. for C9H21NOP 190.1355, found 190.1355; [M+
NaÀ HCl]+ calcd. for C9H20NNaOP 212.1175, found 212.1163.
2-(Dimethylphosphoryl)ethanesulfonyl fluoride (33). Ethenesul-
fonyl fluoride (58.0 g, 0.527 mol), HP(O)Me2 (41.1 g, 0.527 mol) and
KOH (7.39 g, 0.132 mol) were dissolved in 1,4-dioxane (500 mL). The
mixture was stirred at rt for 2 h, then the solvent was evaporated in
1
°
v/v) as eluent; RF =0.30. Yield 1.29 g (67%). Yellowish oil. H NMR
(500 MHz, CD3CN) δ 8.99 (d, J=2.5 Hz, 1H), 8.85 (dd, J=4.9, 1.9 Hz,
1H), 8.20–8.13 (m, 1H), 7.58 (dd, J=8.1, 4.8 Hz, 1H), 3.31 (sept, J=
6.9 Hz, 1H), 1.21 (d, J=6.8 Hz, 6H). 13C NMR (126 MHz, CD3CN) δ
153.8, 149.0, 136.4, 133.1, 123.6, 116.9. LC/MS (CI): m/z=186 [M+
H]+. Anal. Calcd. for C8H11NO2S: C 51.87; H 5.99; N 7.56; S 17.31.
Found: C 52.23; H 5.88; N 7.43; S 17.08.
1
°
3-(Isopropylsulfonyl)piperidine (35). Pyridine 39 (1.00 g,
5.40 mmol) and PdÀ C (10%, 300 mg) were mixed HOAc (40 mL) in
an autoclave. The mixture was hydrogenated with H2 (45 atm) at
°
80 C for 48 h. The catalyst was filtered off, and filtrate was
evaporated in vacuo to dryness. The residue was diluted with
saturated aq NaHCO3 (30 mL), and extracted with CH2Cl2 (6×
10 mL). Combined organic layers were dried over Na2SO4, filtered,
and evaporated in vacuo. The crude produce was purified by
column chromatography on silica gel using CHCl3 :MeOH:Et3N
(10:1:0.1, v/v/v) as eluent; RF =0.35. Yield 537 mg (52%). Yellowish
oil. 1H NMR (500 MHz, CDCl3) δ 3.38–3.27 (m, 1H), 3.23–3.00 (m, 2H),
3.00–2.90 (m, 1H), 2.87 (t, J=11.2 Hz, 1H), 2.56 (t, J=11.6 Hz, 1H),
2.16–2.04 (m, 1H), 1.93 (s, 1H), 1.86–1.70 (m, 2H), 1.52–1.41 (m, 1H),
1.31 (d, J=6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 55.5, 50.1, 45.8,
45.1, 25.2, 23.6, 15.0, 14.9. LC/MS (CI): m/z=192 [M+H]+. Anal.
Calcd. for C8H17NO2S: C 50.23; H 8.96; N 7.32; S 16.76. Found: C
50.42; H 8.81; N 7.02; S 16.76.
vacuo, and the residue was crystalized with t-BuOMe:MeCN (1:1, v/
v, 150 mL). Yield 67.4 g (68%). Colorless solid; mp 132–133 C. H
1
°
NMR (400 MHz, CDCl3) δ 3.80–3.62 (m, 2H), 2.30 (ddt, J=11.6, 8.9,
4.4 Hz, 2H), 1.60 (d, J=12.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ
44.0 (d, J=19.7 Hz), 25.1 (d, J=63.6 Hz), 16.2 (d, J=70.5 Hz). 19F
NMR (376 MHz, CDCl3) δ 51.7. 31P NMR (202 MHz, CDCl3) δ 39.2. LC/
MS (CI): m/z=189 [M+HÀ HCl]+. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C4H11FO3PS 189.0145, found 189.0145; [M+NH4]+ calcd.
for C4H14FNO3PS 206.0411, found 206.0411; [M+Na]+ calcd. for
C4H10FNaO3PS 210.9965, found 210.9964.
3-(N,N-dimethylsulfamoyl)piperidin-1-ium chloride (36). 40% aq
°
Me2NH (1.80 mL) was added at 0 C to a solution of 40 (1.00 g,
2-(Dimethylphosphoryl)ethanesulfonamide (34). Sulfonyl fluoride
(26.0 g, 0.138 mol) was dissolved in 1,4-dioxane (300 mL), and 25%
aq NH3 ·H2O (98.0 mL, 0.691 mol) was added. The reaction mixture
3.15 mmol) in CH2CI2 (15 mL). The reaction mixture was stirred at rt
for 18 h, then washed with H2O (15 mL), dried over Na2SO4, filtered,
and evaporated in vacuo. Cbz-protected amine 41 thus obtained
was dissolved in MeOH (10 mL), then PdÀ C (10%, 100 mg), and
°
was stirred at 60 C for 4 h, then the solvent was evaporated in
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HCl-1,4-dioxane (2.0 mL) were added. The resulting mixture was
hydrogenated with H2 (1 atm) at rt overnight, then filtered through
Celite, and the filtrate was evaporated in vacuo. The residue was
(d, J=2.7 Hz), 137.7, 130.8, 129.9, 127.9, 51.0 (d, J=73.3 Hz), 47.4,
27.0, 25.7, 21.9, 16.5 (d, J=66.7 Hz), 16.3 (d, J=66.7 Hz). 31P NMR
(202 MHz, CD3CN) δ 46.2. LC/MS (CI): m/z=266 [M+H]+. Anal.
Calcd. for C14H20NO2P: C 63.38; H 7.60; N 5.28. Found: C 62.99; H
7.27; N 5.67.
crystallized from MeCN (2 mL). Yield 409 mg (57%). Colorless solid;
1
°
mp 181–183 C. H NMR (400 MHz, D2O) δ 4.66 (s, 2H), 3.71–3.50 (m,
2H), 3.27 (dt, J=12.7, 3.9 Hz, 1H), 3.19–3.07 (m, 1H), 2.91 (td, J=
12.3, 3.3 Hz, 1H), 2.83 (s, 6H), 2.20–2.06 (m, 1H), 2.06–1.92 (m, 1H),
1.88–1.56 (m, 2H). 13C NMR (126 MHz, D2O) δ 54.2, 43.5, 42.5, 37.0,
22.5, 20.3. LC/MS (CI): m/z=193 [M+HÀ HCl]+. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C7H17N2O2S 193.1005, found 193.1007.
(3-(Dimethylphosphoryl)piperidin-1-yl)(phenyl)methanone (44f).
The compound existed as a ca. 5:4 mixture of rotamers. Yield
1
°
159 mg (75%). Colorless solid; mp 100–102 C. H NMR (500 MHz,
CD3CN) δ 7.47–7.40 (m, 3H), 7.40–7.33 (m, 2H), 4.87–4.62 (m, 1H),
4.56 (s, 0.5H) and 4.06–3.74 (m, 0.4H), 3.73–3.40 (m, 1H), 3.11–2.78
(m, 2H), 2.04–1.97 (m, 1H), 1.90–1.56 (m, 3H), 1.54–1.09 (m, 7H). 13C
NMR (126 MHz, CD3CN) δ 171.0, 137.9, 130.8, 129.8, 128.1, 49.1 and
48.5, 43.5 and 42.7, 39.4 and 38.8, 26.8 and 26.4, 25.1, 15.2 (d, J=
67.7 Hz) and 14.9 (d, J=67.7 Hz). 31P NMR (202 MHz, CD3CN) δ 41.6
and 41.2. LC/MS (CI): m/z=266 [M+H]+. Anal. Calcd. for
C14H20NO2P: C 63.38; H 7.60; N 5.28. Found: C 63.28; H 7.25; N 5.38.
General procedure for benzoylation. I-PrNEt2 (1.2 mmol or
1.76 mmol for hydrochlorides of amines) and PhCOCl (123 mg,
°
0.880 mmol) were slowly added at 0 C to a stirred solution of the
corresponding amine (0.800 mmol) in CH2Cl2 (8 mL). The mixture
was stirred at rt overnight, then the solvent was evaporated in
vacuo. The crude product was purified by flash column chromatog-
raphy on silica gel using gradient CHCl3 :MeOH (14:1 to 10:1, v/v).
(4-(Dimethylphosphoryl)piperidin-1-yl)(phenyl)methanone (44g).
Phenyl(piperidin-1-yl)methanone (44a). The crude product was
purified by flash column chromatography on silica gel using
CHCl3 :MeOH (45:1, v/v). Yield 113 mg (75%). Spectral and physical
data were analogous to that of reported.[54,55] 1H NMR (400 MHz,
CD3CN) δ 7.46–7.35 (m, 5H), 3.64 (s, 2H), 3.28 (s, 2H), 1.70–1.52 (m,
4H), 1.52–1.36 (m, 2H). 13C NMR (126 MHz, CD3CN) δ 170.9, 138.5,
130.6, 129.8, 128.1, 49.7, 44.0, 27.6, 26.9, 25.8.
The compound existed as a ca. 1:1 mixture of rotamers. Yield
°
159 mg (75%). Yellowish solid; mp 141–142 C. The compound
existed as a ca 1:1 mixture of rotamers. H NMR (500 MHz, CD3CN)
1
δ 7.44–7.39 (m, 3H), 7.38–7.35 (m, 2H), 4.93–4.31 (m, 1H), 3.97–3.48
(m, 1H), 3.08–2.91 (m, 1H), 2.84–2.62 (m, 1H), 1.91–1.80 (m, 2H),
1.80–1.61 (m, 1H), 1.53–1.41 (m, 2H), 1.33 (d, J=12.5 Hz, 6H). 13C
NMR (126 MHz, CD3CN) δ 170.9, 138.1, 130.7, 129.8, 128.1, 48.9,
43.22, 38.64 (d, J=71.8 Hz), 26.34, 25.91, 14.57 (d, J=67.3 Hz). 31P
NMR (202 MHz, CD3CN) δ 42.8. LC/MS (CI): m/z=266 [M+H]+. Anal.
Calcd. for C14H20NO2P: C 63.38; H 7.60; N 5.28. Found: C 63.33; H
7.56; N 5.05.
(3-(Dimethylphosphoryl)azetidin-1-yl)(phenyl)methanone (44b).
The compound existed as a ca. 1:1 mixture of rotamers. Yield
1
°
132 mg (70%). Colorless solid; mp 121–123 C. H NMR (500 MHz,
CDCl3) δ 7.61 (d, J=7.5 Hz, 2H), 7.47 (t, J=7.2 Hz, 1H), 7.41 (t, J=
7.5 Hz, 2H), 4.59–4.37 (m, 3H), 4.36–4.23 (m, 1H), 3.01–2.90 (m, 1H),
1.66–1.40 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 170.0, 131.9, 130.9,
128.0, 127.3, 51.8, 47.8, 28.6 (d, J=72.4 Hz), 13.9 (d, J=69.9 Hz),
13.2 (d, J=69.9 Hz). 31P NMR (162 MHz, CDCl3) δ 41.2. LC/MS (CI): m/
z=238 [M+H]+. Anal. Calcd. for C12H16NO2P: C 60.75; H 6.80; N 5.90.
Found: C 60.76; H 6.54; N 6.10.
(3-(Isopropylsulfonyl)piperidin-1-yl)(phenyl)methanone
(44h).
Yield 132 mg (56%). Colorless solid; mp 130–132 C. 1H NMR
(500 MHz, CDCl3) δ 7.59–7.20 (m, 5H), 5.10–4.73 (m, 1H), 3.90–3.57
(m, 1H), 3.45–2.88 (m, 4H), 2.28 (d, J=13.2 Hz, 1H), 2.05–1.79 (m,
2H), 1.56–1.09 (m, 7H). 13C NMR (126 MHz, CDCl3) δ 170.9, 135.1,
130.1, 128.6, 127.0, 53.7, 51.1, 47.8, 42.1, 25.0, 22.3, 16.0, 14.1. LC/
MS (CI): m/z=296 [M+H]+. Anal. Calcd. for C15H21NO3S: C 60.99; H
7.17; N 4.74; S 10.85. Found: C 60.78; H 6.78; N 4.59; S 10.95.
°
(2-(Dimethylphosphoryl)pyrrolidin-1-yl)(phenyl)methanone (44c).
Yield 146 mg (73%). Yellowish solid; mp 33–34 C. 1H NMR
°
(400 MHz, CD3CN) δ 7.56–7.51 (m, 2H), 7.47–7.39 (m, 3H), 4.57 (ddd,
J=9.1, 5.6, 3.2 Hz, 1H), 3.54–3.46 (m, 1H), 3.46–3.34 (m, 1H), 2.35–
2.20 (m, 1H), 2.19–2.07 (m, 1H), 2.04–1.94 (m, 1H), 1.81–1.68 (m, 1H),
1.49 (d, J=12.6 Hz, 3H), 1.44 (d, J=12.6 Hz, 3H). 13C NMR (126 MHz,
CD3CN) δ 171.8, 138.1, 131.6, 129.6, 128.8, 57.5 (d, J=79.3 Hz), 52.2,
26.6, 25.9, 16.6 (d, J=65.4 Hz) and 15.6 (d, J=66.8 Hz). 31P NMR
(202 MHz, CD3CN) δ 45.9. LC/MS (CI): m/z=252 [M+H]+. Anal.
Calcd. for C13H18NO2P: C 62.14; H 7.22; N 5.57. Found: C 62.45; H
7.28; N 5.97.
1-Benzoyl-N,N-dimethylpiperidine-3-sulfonamide (44i). The com-
pound existed as a ca. 5:4 mixture of rotamers. Yield 166 mg
1
°
(70%). Colorless solid; mp 102–103 C. H NMR (500 MHz, CD3CN) δ
7.46–7.36 (m, 5H), 4.85–4.63 (m, 1H), 4.58–4.27 (m, 0.5H), 4.03–3.69
(m, 0.5H), 3.67–3.38 (m, 1H), 3.33–2.61 (m, 9H), 2.19–2.10 (m, 1H),
1.89–1.66 (m, 2H), 1.64–1.38 (m, 1H). 13C NMR (126 MHz, CD3CN) δ
171.3, 137.6, 131.0, 129.9, 128.1, 58.2, 57.8, 48.7, 43.2, 42.9, 38.4,
26.5, 25.7, 25.0. LC/MS (CI): m/z=297 [M+H]+. Anal. Calcd. for
C14H20N2O3S: C 56.73; H 6.80; N 9.45; S 10.82. Found: C 56.79; H 7.14;
N 9.50; S 11.16.
(3-(Dimethylphosphoryl)pyrrolidin-1-yl)(phenyl)methanone
(44d). The compound existed as a ca. 5:4 mixture of rotamers.
Yield 139 mg (69%). Colorless solid; mp 104–106 C. 1H NMR
°
(500 MHz, CD3CN) δ 7.58–7.45 (m, 2H), 7.45–7.36 (m, 3H), 3.83–3.38
(m, 4H), 2.52–2.28 (m, 1H), 2.18–1.95 (m, 2H), 1.46–1.26 (m, 6H). 13C
NMR (126 MHz, CD3CN) δ 170.2, 138.6, 131.2 and 131.2, 129.7 and
129.6, 128.4, 50.7 (d, J=9.3 Hz) and 47.6 (d, J=9.3 Hz), 49.9 and
47.0, 41.1 (d, J=72.5 Hz) and 39.0 (d, J=73.1 Hz), 27.5 and 25.7,
16.5–15.2 (m). 31P NMR (202 MHz, CD3CN) δ 41.1 and 40.3. LC/MS
(CI): m/z=252 [M+H]+. Anal. Calcd. for C13H18NO2P: C 62.14; H 7.22;
N 5.57. Found: C 62.29; H 7.34; N 5.23.
Acknowledgements
The work was funded by Enamine Ltd, National Academy of
Sciences of Ukraine (Grant No. 0119U102718) and Ministry of
Education and Science of Ukraine (Grant No. 21BF037-01M).
O.O.G. also received additional funding from Ministry of Education
and Science of Ukraine (Grant No. 19BF037-03). The authors thank
Mr. Maksym Stambirskyi for providing compounds 42 and 43, Dr.
Pavel Mykhailiuk for his vigilance during the manuscript prepara-
tion, Ms. Margarita Bolgova and Ms. Olga Kovalenko for pKa
determinations, and Mr. Artem Skreminskiy for LogP and Sw
measurements.
(2-(Dimethylphosphoryl)piperidin-1-yl)(phenyl)methanone (44e).
The compound existed as a ca. 1:1 mixture of rotamers. Yield
151 mg (71%). Colorless solid; mp 136–137 C. H NMR (400 MHz,
CD3CN) δ 7.50–7.43 (m, 5H), 4.97–4.83 (m, 1H), 3.71 (td, J=13.0,
2.9 Hz, 1H), 3.61 (dt, J=13.3, 3.2 Hz, 1H), 2.34–2.23 (m, 1H), 2.22–
2.10 (m, 1H), 1.96–1.60 (m, 3H), 1.57 (d, J=12.5 Hz, 3H), 1.51 (d, J=
12.7 Hz, 3H), 1.46–1.27 (m, 1H). 13C NMR (126 MHz, CD3CN) δ 171.4
1
°
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FULL PAPERS
Multigram synthesis of saturated het-
erocyclic dimethylphosphine oxides
(derivatives of azetidine, pyrrolidine,
piperidine, and morpholine) –
A. Fedyk, Dr. E. Y. Slobodyanyuk, O.
Stotska, B. V. Vashchenko,
Prof. Dr. D. M. Volochnyuk*, Dr. D. A.
Sibgatulin, Prof. Dr. A. A. Tolmachev,
Dr. O. O. Grygorenko
advanced building blocks for
medicinal chemistry – as well as their
physico-chemical properties (pKa,
logP, and Sw) are disclosed.
1 – 14
Heteroaliphatic Dimethylphosphine
Oxide Building Blocks: Synthesis
and Physico-Chemical Properties