Stereoselective Cyclopropanation as a Way to 1-Aminocyclopropane-1-phosphonic Acids: Rationale for Phosphoryl Group Migration

Article abstract of DOI:10.1002/ejoc.201600111

Asymmetric cyclopropanation of vinylphosphonates by using (S)-dimethylsulfonium(p-tolylsulfinyl)methylide and subsequent highly stereoselective methylation provided substituted cyclopropylphosphonates, which are useful intermediates in the synthesis of rigid aminophosphonic acids. However, in some examples desulfinylation by iPrMgCl led to 1,2-migration of the phosphoryl group. The scope of this transformation was investigated by changing the temperature, electronegativity of the substituent α to phosphoryl group, and the configuration of the cyclopropylphosphonates. It was found that a cis relationship between the phosphoryl and sulfinyl groups led exclusively to the product of migration. It was proposed that the rearrangement occurred as an internal process in a concerted manner. The feasibility of an intramolecular mechanism was supported by DFT calculations. The products of desulfinylation with retained structure were used for the synthesis of enantiomerically pure 1-aminocyclopropane-1-phosphonic acids. Desulfinylation of cyclopropylphosphonates by reaction with iPrMgCl results in 1,2-migration of the phosphoryl group. A relationship between the structure and course of the sulfinyl-metal exchange suggests that mechanistically this transformation is an internal process. An isomerization mechanism is verified by DFT calculations.

Full text of DOI:10.1002/ejoc.201600111

DOI: 10.1002/ejoc.201600111
Full Paper
Rearrangement
Stereoselective Cyclopropanation as a Way to
1-Aminocyclopropane-1-phosphonic Acids: Rationale for
Phosphoryl Group Migration
Wanda H. Midura,*[a] Marek Cypryk,[a] Aneta Rzewnicka,[a] Jerzy A. Krysiak,[a] and
Lesław Sieroń[b]
Abstract: Asymmetric cyclopropanation of vinylphosphonates of the cyclopropylphosphonates. It was found that a cis rela-
by using (S)-dimethylsulfonium(p-tolylsulfinyl)methylide and
subsequent highly stereoselective methylation provided substi-
tuted cyclopropylphosphonates, which are useful intermediates
in the synthesis of rigid aminophosphonic acids. However, in
some examples desulfinylation by iPrMgCl led to 1,2-migration
of the phosphoryl group. The scope of this transformation was
investigated by changing the temperature, electronegativity of
the substituent α to phosphoryl group, and the configuration
tionship between the phosphoryl and sulfinyl groups led exclu-
sively to the product of migration. It was proposed that the
rearrangement occurred as an internal process in a concerted
manner. The feasibility of an intramolecular mechanism was
supported by DFT calculations. The products of desulfinylation
with retained structure were used for the synthesis of enantio-
merically pure 1-aminocyclopropane-1-phosphonic acids.
Introduction
enantiomerically pure form and their conversion into particular
amino acids. Enantiopure sulfoxides have become an important
class of chiral auxiliaries owing to their ease of preparation and
the high level of asymmetric induction exerted by the chiral
sulfinyl group. Moreover, chiral sulfur groupings that can induce
asymmetry in the reaction can usually be removed easily from
the molecule under mild conditions.[4] Recently, we designed a
new type of chiral sulfur ylide as a single enantiomer containing
a sulfinyl group bonded to the ylidic carbon atom.[5] Cycloprop-
anation of activated vinylic phosphonates by using this ylide
was an effective way to prepare appropriate phosphonocyclo-
propyl sulfoxides, which became, according to our concept,
convenient intermediates in the synthesis of conformationally
constrained analogues of aminophosphonic acids.
The extraordinary richness of organophosphorus compounds,
their tremendous structural and electronic diversity, as well as
their specific chemical behavior make them versatile reagents
that play a very important role in modern synthetic organic
chemistry. Bioisosteric phosphonic acid analogues of important
compounds such as amino acids are finding increased interest.
This is associated, among other issues, with their tetrahedral
structure and thereby their related possible action as a “transi-
tion-state analogue”.[1] Restriction of conformational flexibility
has also proven effective in drug design to improve various
properties of biologically active substances.[2] In particular, in-
troduction of the cyclopropane ring into amino acids leads to
structures selective in binding with different subtypes of recep-
tors. This is why aminocyclopropanephosphonic acids have be-
come a subject of intense investigation.[3]
Results and Discussion
It is well known that the biological activity of amino acids
and derivatives depends on the absolute configuration, so to
find an efficient way of controlling the stereochemistry around
the cyclopropane ring remains an important goal. In our recent
work, we concentrated on the synthesis of cyclopropanes in
Cyclopropanation
(S)-Dimethylsulfonium(p-tolylsulfinyl)methylide (1) was shown
to be an effective reagent for cyclopropane formation in a
Michael-initiated ring closure (MIRC)-type reaction.[6] Cyclo-
propanation was performed with different vinylic phosphon-
ates, additionally activated by a second electron-withdrawing
substituent. The ylide was generated with NaH as a base prior
to the reaction and was also formed in situ by reaction of 1 in
the presence of potassium carbonate or 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) as a base (Table 1).
[a] Centre of Molecular and Macromolecular Studies, Polish Academy of
Sciences, Department of Heteroorganic Chemistry,
90-363 Łódź, Sienkiewicza 112, Poland
E-mail: whmidura@cbmm.lodz.pl
http://www.cbmm.lodz.pl/
[b] Institute of General and Ecological Chemistry, Lodz University of
Technology,
Stereoselectivity was found to depend on the structure of
the Michael acceptor and slightly on the reaction conditions.
Żeromskiego 116, 90-924 Łódź, Poland
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600111.
1
The relative configuration was determined by H NMR spectro-
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Table 1. Cyclopropanation of vinylic phosphonates with ylide 1.
Entry
R
X
Reaction conditions
Cyclo-
propane
Total
yield [%]
Ratio of
Ratio
Facial
selectivity
a/b/c/d[a]
trans/cis[b]
1.
2.
3.
4.
5.
6.
7
8.
Me
Me
Me/D[c]
Et
Et
Et
CO2tBu
CO2tBu
CO2tBu
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
NaH/MeCN, 0 °C, 2 h
K2CO3/CH2Cl2, r.t., overnight
NaH/MeCN, 0 °C, 2 h
NaH/THF, 0 °C, 2 h
NaH/MeCN, 0–20 °C
NaH/MeCN, 0 °C
K2CO3/CH2Cl2, r.t., overnight
NaH/MeCN, –10 °C
DBU/CH2Cl2, overnight
K2CO3/CH2Cl2, r.t.
3
3
d-3
4
4
4
4
d-4
5
5
6
80
95
76
75
80
76
84
78
89
93
85
83
74
62:28:10:–
65:21:14:–
62:28:10:–
70.5:13:15:1.5
64:23:13:–
68:27:5:–
62:26:12:–
64:23:13:–
80:5:15:–
72:28
79:21
72:28
85.5:14.5
77:23
73:27
74:26
77:23
95:5
96.5:3.5
62:38
–:100
–:100
90:10
86:14
90:10
83.5:16.5
87:13
95:5
88:12
87:13
85:15
87.5:12.5
90:10
95:5
Et
Et/D[c]
Et
9.
10.
11.
12.
13.
Et
Et
Et
Et
CN
84:3.5:12.5:–
52:38:10:–
–:95:–:5
SpTol
K2CO3/CH2Cl2, r.t., overnight
K2CO3/CH2Cl2, r.t., overnight
NaH/MeCN, 0 °C
SOpTol[d]
SOpTol[d]
7
7
–:95:–:5
95:5
[a] Ratio of diastereomers was established by analysis of the crude reaction mixture by 31P NMR spectroscopy. [b] Relative to phosphonate group. [c] Me/D,
Et/D = cyclopropane with CD2 in the cyclopropane ring. [d] Enantiomerically pure (S)-(+)-(1-diethoxyphosphoryl)vinyl p-tolyl sulfoxide was used as the Michael
acceptor.
scopy, for which the coupling constant values, 3JHP, were usually in a pyramidal form and the ylide carbon atom has a configura-
conclusive for the assignment of the cis (JPH ≈ 9.0 Hz) or trans tion close to sp3 with the C-ylide and S-sulfoxide lone pairs of
(JPH ≈ 15.0 Hz) geometry in substituted cyclopropylphosphon- electrons in a gauche position. Although relatively low inversion
ates. For convenience and clarity, we give the cis–trans descrip- barriers indicate that rapid inversion may take place in solution,
tion relative to the phosphonate group, even if it is not in ac- conformation B seems to be more favorable than A owing to
cordance with the priority of substituents. Generally, steric con- steric reasons. According to this assumption, approach of the
gestion causes the phosphonate moiety to be considered as a ylide should lead to formation of a product with the 1R and 2S
trans-directing group,[7] and this was also the case in our reac- configurations on the newly formed stereogenic centers (Fig-
tions. The ratio of trans versus cis diastereomers depended on ure 1).
the relative sizes of both geminal substituents in the Michael
acceptor. The best results were observed for a relatively small
CN group; for sulfenyl and alkoxycarbonyl substituents, the di-
astereoselectivity was rather moderate, although for all sub-
strates the trans isomers dominated. The only exception was
cyclopropane 7 (Table 1, entries 12 and 13), which was formed
against the phosphonate trans-directing-group rule, because
full cis diastereoselectivity was established. We explained this
result by dipole–dipole interaction between both polar sulfinyl
substituents during cyclopropanation. Cyclopropane 7 should
be treated as a special case, as its formation occurred under
control of two sulfinyl auxiliaries. On the basis of the stereo-
chemical pathways of cyclopropanations occurring under con-
trol of each sulfinyl group, the configuration of obtained prod-
Figure 1. Preferential conformation B of ylide 1 and preferred intermediate
leading to the major isomers.
uct 7 was assigned tentatively.[8]
Facial selectivity for all performed experiments varied from
83.5:16.5 to 95:5 depending on the structure of the Michael
acceptor. The highest ratio was observed for cyclopropane 7,
for which each of the two sulfinyl auxiliaries led to the same
major isomer.[8]
Conclusive results were obtained from single-crystal X-ray
diffraction analysis of tert-butyl 1-dimethylphosphono-2-p-tolyl-
sulfinyl cyclopropanecarboxylate (3a, Figure 2), which con-
DFT calculations performed earlier to understand the stereo- firmed our earlier speculations. The configuration of the major
chemistry of epoxidation[9] indicate that the starting ylide is not diastereomer was established unambiguously by using the
planar, which implies diastereomerism of the reactant. It exists Bijvoet method to be (1R,2S,RS).[10]
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Figure 2. Single-crystal X-ray structure of 3a. Displacement ellipsoids are
drawn at the 50 % probability level.
Methylation
To introduce an additional substituent onto the cyclopropane
ring, substitution at the α-carbon atom to the sulfinyl group
was performed. The corresponding carbanion was formed by
using lithium hexamethyldisilazane (LiHMDS) as the base, and
the carbanion was then quenched with a methylating agent
(Scheme 1).
Scheme 1. Methylation of cyclopropyl sulfoxides. mCPBA = meta-chloroper-
oxybenzoic acid.
In general, the reaction was stereoselective and only a single
diastereomer of cyclopropanes 8a, 10a, in the approach pre-
sented in part A of Scheme 1 and 8c, 10c, 11c (in part B) were
formed (see also Table 2). The relative configurations of the
obtained methylated cyclopropanes were determined by
NOESY experiments: the H-cis and H-trans protons were easily
assigned according to the P–H coupling constants. For products
8a, 10a, and 11c, we observed interaction between the methyl
group and the H-trans proton, which supports the cis configura-
tion (i.e., phosphoryl group and ꢀ-sulfinyl substituent on the
same side of the ring) of all structures mentioned above (see
the Supporting Information).
ration of both products. On the basis of our earlier established
relations, configurational assignment was extended to all inves-
tigated structures.
We determined the crystal and molecular structures of cyclo-
propane 8a by X-ray diffraction (Figure 3). This unequivocally
confirmed that the absolute configuration of the chiral center
formed at the α-carbon atom to the sulfinyl group was R; thus,
the absolute configuration of 8a is (+)-(1R,2R,Ss). Oxidation of
8a and 8c gave the corresponding sulfones; the sulfones
showed the same chemical shift in the 31P NMR spectrum (δ =
20.2 ppm) contrary to the sulfoxides, owing to the loss of chiral-
Figure 3. Single-crystal X-ray structure of 8a. Displacement ellipsoids are
drawn at the 25 % probability level.
Only for the case in which a CN group was used as an elec-
ity at sulfur. It additionally confirmed the same relative configu- tron-withdrawing substituent was a much different steric
Table 2. Methylation of cyclopropyl sulfoxides.
Entry
Cyclopropane
X
Conditions
Product(s)
Total yield
[%]
Relative configuration
[P/SOTol cis]/[P/SOTol trans]
Steric
course
1
2
3
4
5
6
7
8
3a
3b
3c
3a
5a
5a
6a
6a
6b
6b
7b
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CN
CN
SpTol
SpTol
SpTol
MeI
MeI
MeI
(MeO)2SO2
MeI
(MeO)2SO2
MeI
(MeO)2SO2
MeI
(MeO)2SO2
MeI
8a
8c
8c
93
75
86
81
88
90
86
78
81
77
72
>98:–
>98:–
>98:–
>98:–
50:50
22:78
>98:–
>98:–
>98:–
>98:–
>98:–
inversion
retention
inversion
inversion
retention/inversion
retention/inversion
inversion
inversion
retention
8a
9a/9b
9a/9b
10a
10a
10c
10c
11c
9
10
11
SpTol
S(O)pTol
retention
retention
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course of methylation observed. First, the reaction was not and strong repulsion between the CN and SO dipoles,[14] which
stereoselective with the use of methyl iodide (Table 2, entry 5), could change the conformation and configuration of the sul-
contrary to the other cyclopropylphosphonates, and two prod- finyl carbanion. Precoordination of the nitrile function, as postu-
ucts of methylation were formed. Moreover, it was the only ex- lated by the Knochel group,[15] can increase participation of
ample for which we observed the influence of the character of structure C, which would result in the lack of selectivity ob-
the methylating agent; the use of dimethyl sulfate increased served in this case. Improved stereoselectivity of methylation
the stereoselectivity to 22:78 (Table 2, entry 6). For the major by using dimethyl sulfate is the result of attack from the lithium
diastereomer formed in that case (i.e., compound 9b), an NOE side caused by chelation between the metal and the electro-
interaction of the methyl group with the H-cis proton was ob- phile.[16]
served, which evidenced that the methyl group and the phos-
phoryl substituent were on the same side of the cyclopropane
ring (see the Supporting Information).
1,2-Migration
The stereochemical result of the reaction of sulfoxide-stabi-
lized carbanions with electrophiles depends on (1) the stereo-
chemistry of the carbanion initially formed, (2) the configura-
tional interconversion of the carbanion during the reaction, and
(3) the mode in which the electrophile attacks the carbanion.[11]
To remove the sulfinyl chiral auxiliary, a metal-exchange reac-
tion was applied by using a Grignard reagent.[17,18] Our last ex-
perience showed this method to be less polluting to the envi-
ronment and in some cases more selective than the classical
In the presented case, the introduction of a methyl group in method for which amalgam or Raney nickel is used.[17c]
the trans position (relative to the phosphonate group) can be
the effect of inversion, assuming formation of a lithium deriva-
tive trans to the phosphoryl group (structure C) and subsequent
retention of configuration in the alkylation step. However,
stronger carbanion stabilization and the absence of an unfavor-
able interaction between the two bulky substituents make
structure D more favorable than structure C (Figure 4). This
proposition was supported by preliminary PM3 calculations.
However, in recent experiments we found that the reaction
of phosphonocyclopropyl sulfoxides 8a, 9a, and 10a with
iPrMgCl led to unprecedented 1,2-migration of the phosphoryl
group[19] (Scheme 2). To the best of our knowledge, migration
of the phosphoryl group in a cyclopropane ring has not been
previously reported. This phenomenon was observed by us for
the first time in the case of phosphonocyclopropanecarboxy-
lates and led to different products than expected. It was reason-
able to investigate the influence of the structure of the cyclo-
propylphosphonate and the reaction conditions on the behav-
ior of the carbanion formed after sulfinyl–metal exchange to
determine the scope and limitations of the discovered rear-
rangement.
Figure 4. Lithium derivatives with trans and cis structures.
In this way, according to our hypothesis, for all cases, regard-
less of configuration of the starting cyclopropane, a trans car-
banion (phosphoryl group and ꢀ-sulfinyl substituent on the
same side of the ring) was formed. Thus, trans lithium deriva-
tives D should be formed by retention of configuration from
trans cyclopropyl sulfoxides 3a, 4a, 6a, and trans D′ should be
formed by retention of configuration from 3c and inversion
from cis cyclopropanes 3b, 6b, and 7b. Owing to steric reasons,
the approach of the methylating agent should occur only from
the back side (inversion), which explains the high selectivity
of this step. This can be considered as common behavior of
carbanions, as inversion of configuration is established as a typi-
cal mode in the stereochemistry of electrophilic reactions in
which α-sulfinyl carbanions are not stabilized by intramolecular
chelation.[11–13]
Scheme 2. The reaction of phosphonocyclopropyl sulfoxides with iPrMgCl.
It was established that the reaction of a Grignard reagent
with cyclopropane 3a, unsubstituted in the α position to the
sulfinyl group, could be controlled by temperature. At low tem-
peratures (–50 °C), the desulfinylated cyclopropane was ob-
served as the only product, whereas increasing the temperature
and extending the reaction time caused the formation of a re-
Low selectivity during the formation of cyclopropane 9 evi- gioisomer of the rearranged structure.[19] Unfortunately, the
denced that the approach of methyl iodide can occur from both same relation did not work for methylated cyclopropyl sulfox-
sides with about the same probability. A possible explanation ides. Lowering the temperature stopped the reaction, and only
could be connected with the small size of the nitrile substituent starting materials were isolated.
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According to our hypothesis, the driving force causing 1,2- phosphoryl oxygen atom to magnesium [i.e., structure 9a(Mg)-
migration of the phosphoryl group is the instability of the 1] followed by attack of the transient carbanion on the phos-
carbanion formed after removing the sulfinyl group, whereas phorus atom with the formation of a bicyclic structure similar
there are two stabilizing substituents present at the adjacent to 9a(Mg)_ts1 (Scheme 3). The reaction pathway involves two
carbon atom. For this reason, the phosphoryl group relocates transition states, 9a(Mg)_ts1 and 9a(Mg)_ts2 (Scheme 3), which
to quench the initial carbanion, whereas the new carbanion result from rotation of the phosphoryl substituents around the
is still stabilized by the remaining X substituent. We selected phosphorus atom with an overall free-energy barrier of
cyclopropylphosphonates that were subjected to the sulfinyl– 28 kcal mol–1 in the gas phase. The first transition state involves
metal exchange reaction, with X substituents presenting dimin- breaking of the C2–Mg bond; the second transition state corre-
ishing electron-withdrawing character (CO2R > CN > SAr). In this sponds to formation of the C1–Mg bond. The driving force for
way, the newly created carbanion would be stabilized more or the isomerization is the higher thermodynamic stability of the
less effectively after rearrangement. Evidently, even the rela- structure with a negatively charged carbon atom substituted
tively weak sulfenyl group was sufficient, because the 1,2-mi- by a more electron-withdrawing group (nitrile in this case). The
gration of the phosphoryl group took place for all the used resulting product, that is, 14a(Mg)-1, is more stable than start-
cyclopropylphosphonates.
ing isomer 9a(Mg)-1 by about 7 kcal mol–1. SCRF calculations
performed by assuming THF as the solvent provided an analo-
gous picture, with a total free-energy barrier of 30 kcal mol–1
and a net free-energy gain of –11 kcal mol–1. The free-energy
profiles of the reaction in the gas phase and in THF are com-
pared in Figure 5. The calculated free-energy barrier for isomeri-
zation seems to be too high if taking into account that the
reaction proceeds smoothly at temperatures as low as 0 °C. We
believe that this is the result of specific solvation effects that
are very significant for organic magnesium compounds in ether
Another factor that should have an influence on the rear-
rangement is the configuration of the phosphonocyclopropyl
sulfoxides. Indeed, for all the obtained methylation products
with cis configuration (i.e., compounds 8a, 9a, and 10a), the
1,2-migration took place exclusively. The only example for
which we were able to avoid rearrangement of the α phos-
phoryl group on a cyclopropane ring was 9b (phosphoryl and
sulfinyl groups in trans relation), and it afforded unsulfinylated
product of retained structure 16[20] (Scheme 2). The last obser-
vations suggest that rearrangement occurs as an internal proc-
ess in a concerted manner. Given that during the sulfinyl–mag-
nesium exchange a carbanion is formed with retention of con-
figuration,[21] for cis isomers the phosphoryl group is “ready” to
migrate as it is on the same side of the cyclopropane; for the
trans structures, inversion of the magnesium derivative is re-
quired. Additional rationale for the intramolecular character of
the phosphoryl group migration is the optical activity of the
rearranged products.
The feasibility of an intramolecular isomerization mechanism
was confirmed by DFT calculations. Calculations were per-
formed by using a derivative of 9a, the simplest structure
among the cyclopropyl sulfoxides investigated by us, for which
the sulfinyl group was replaced by magnesium chloride and the
ethoxy functions at the phosphorus center were changed to
methoxy groups to save computing time (Scheme 3). The re-
sults suggest that the reaction involves coordination of the
Figure 5. Gibbs free-energy profile for the isomerization of phosphonocyclo-
propyl sulfoxide (Scheme 3) in the gas phase (blue line) and in THF (red line).
Scheme 3. Mechanism of isomerization (migration of the phosphonate group) according to DFT calculations.
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Scheme 4. Crossover experiment.
solutions. These effects were not considered in the calculations propanephosphonic acid,[22] which is the first approach to this
owing to high computational costs.
Alternatively, one can consider a bimolecular exchange
mechanism (Figure 6). To establish whether the presented mi-
deuterium-labeled analogue, and a phosphonic analogue of
norcoronamic acid[20] (Scheme 5).
In the synthesis of enantiopure (+)-(1R)-1-amino-2,2-dideu-
gration reaction was occurring by an intra- or intermolecular teriocyclopropanephosphonic acid, Curtius rearrangement was
mode (Figure 6) with participation of two molecules, a cross- used to convert the ester group into an amino group. A proce-
over experiment involving two different phosphonates was de- dure involving the use of diphenylphosphoryl azide gave the
vised. Thus, a 1:1 mixture of phosphonocyclopropyl sulfoxides best results. In the synthesis of a phosphonic analogue of (–)-
8a and 9a was treated with iPrMgCl (5 equiv.) at 0 °C for 30 min. norcoronamic acid, enantiopure (–)-(1S,2R)-2-methyl-1-diethyl-
The only observed products in the crude reaction mixture were phosphonocyclopropanenitrile was converted into the appro-
rearranged phosphonates 13a, 13b, and 14a (Scheme 4). The priate amide, which was then subjected to lead tetraacetate
lack of crossover products indicates that the reaction proceeds mediated oxidative Hoffmann rearrangement.
in an intramolecular fashion.
Conclusion
It was established that the stereoselective synthesis of substi-
tuted cyclopropylphosphonates by asymmetric cyclopropan-
ation of vinylphosphonates with dimethylsulfonium(p-methyl-
sulfinyl)methylide occurs with high facial selectivity and good
to moderate diastereoselectivity. Methylation of cyclopropyl-
phosphonates, the basic structures in the performed synthesis,
occurred exclusively with the formation of diastereomers for
which the phosphoryl group and 2-sulfinyl substituent were on
the same side of the ring. Owing to the high stereoselectivity
and the presence of substituents that could be easily converted
into amino groups, such as CO2R and CN, this approach was
considered as a general method for the formation of aminocy-
clopropane-1-phosphonic acids.
Figure 6. Hypothetical intermolecular mode of isomerization.
Conversion into 1-Aminocyclopropane-1-phosphonic Acids
Elaborated procedures of desulfinylation in two cases allowed
us to avoid 1,2-migration of the α phosphoryl group on the
cyclopropane ring either by lowering the temperature or by
changing the configuration of the dominating diastereomer of
phosphonocyclopropyl sulfoxide. The cyclopropylphosphonates
However, during desulfinylation of the investigated cyclopro-
with a retained structure and configuration were used in the pylphosphonates by their reaction with iPrMgCl, 1,2-migration
synthesis of enantiopure (+)-(1R)-1-amino-2,2-dideuteriocyclo- of the phosphoryl group was discovered. This phenomenon can
Scheme 5. Synthesis of (+)-(1R)-[2,2-2H2]-1-aminocyclopropane-1-phosphonic acid and (–)-(1S,2R)-1-amino-2-methylcyclopropanephosphonic acid. Reagents
and conditions: (a) separation of diastereomers; (b) iPrMgCl (5 equiv.), THF, –50 °C, 1 h, 83 %; (c) LiOH (aq.), 96 %; (d) (PhO)2P(O)N3, Et3N tBuOH, 88 %; (e) 6
N
HCl, propylene epoxide; (f) LiHMDS, (MeO)2SO2, 63 % (g) iPrMgCl, THF, –30 °C; (h) H2O2, K2CO3, MeOH, 70 °C, 12 h, 90 %; (i) Pb(OAc)4, tBuOH, 85 °C, 5 h, 76 %.
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ture of diastereomers in 95 % yield. Separation of the diastereomers
was achieved by chromatography on silica (hexane/acetone, 2:1).
be compared to the base-induced migration of a phosphoryl
group between a heteroatom and a carbon atom,[23,24] but for
cyclopropanes, it was here observed for the first time.[19] Some
factors describing the scope and limitations of this transforma-
tion were found. One, the influence of temperature: cyclopro-
pane unsubstituted in the α-position to the sulfinyl group can
be controlled by temperature; two, the influence of configura-
tion of the cyclopropylphosphonate: a cis relationship between
the phosphoryl and sulfinyl groups leads to the product of mi-
gration, but a trans relationship affords the product of desulfin-
ylation with the retained structure; three, the influence of X
substituents with decreasing electronegativities (X: CO2R > CN
> SAr): even the relatively weak sulfenyl group is not sufficient
to avoid rearrangement.
The possibility of an intramolecular isomerization mecha-
nism was verified by DFT calculations. Nevertheless, some prod-
ucts of desulfinylation with retained structures were obtained
by fixing the temperature and by exploiting the different be-
havior of cyclopropanenitrile; these substrates were used for
the synthesis of enantiomerically pure 1-aminocyclopropane-1-
phosphonic acids.
tert-Butyl (+)-(1R,2S,RS)-1-Dimethylphosphono-2-p-tolylsulfin-
ylcyclopropanecarboxylate (3a): White solid; m.p. 93–94 °C, yield
0.4 g (55 %). [α]D20 = +109.5 (c = 6.8, acetone) 1H NMR (600 MHz,
CDCl3): δ = 1.50 [s, 9 H, COC(CH3)3], 1.71 (ddd, JHH = 5.6, 8.5 Hz,
JPH = 14.4 Hz, 1 H), 2.25 (ddd, JHH = 5.6, 6.6 Hz, JPH = 11.2 Hz, 1 H),
2.39 (s, 3 H, C6H4CH3), 2.85 [ddd, JHH = 6.6, 8.5 Hz, JPH = 15.2 Hz, 1
H, CHS(O)], 3.62 and 3.75 (2 d, JPH = 11.0 Hz, 6 H, POCH3), 7.31 and
7.59 (A2B2, 4 H, C6H4CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 12.6
(d, JCP = 2.2 Hz, CH2C), 21.4 (C6H4CH3), 27.9 [COC(CH3)3], 28.1 (d,
JCP = 179.8 Hz), 44.4 (d, JCP = 3.2 Hz, CHSO), 53.7 (d, JCP = 6.1 Hz),
53.8 (d, JCP = 5.9 Hz), 83.7 [COC(CH3)3], 124.1, 130.1, 140.9, 142.0,
164.3 (d, JCP = 4.7 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ = 22.5 ppm.
MS (CI): m/z = 389 [M + H]+. C17H25O6PS (388.41): calcd. C 52.57, H
6.49; found C 52.43, H 6.38.
tert-Butyl (–)-(1S,2S,RS)-1-Dimethylphosphono-2-p-tolylsulfinyl-
cyclopropanecarboxylate (3b): Pale-yellow oil, yield 0.12 g (16 %).
1
[α]D20 = –25.4 (c = 3.2, acetone) H NMR (500 MHz, CDCl3): δ = 1.40
[s, 9 H, COC(CH3)3], 1.99 (ddd, JHH = 5.6, 8.9 Hz, JPH = 9.0 Hz, 1 H),
2.25 (ddd, JHH = 5.6, 6.8 Hz, JPH = 12.5 Hz, 1 H), 2.39 (s, 3 H, C6H4CH3),
2.95 [ddd, JHH = 6.8, 8.9 Hz, JPH = 9.0 Hz, 1 H, CHS(O)], 3.81 and 3.83
(2 d, JPH = 11.0 Hz, 6 H, POCH3), 7.33 and 7.77 (A2B2, 4 H, C6H4CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 18.0 (d, JCP = 3.7 Hz, CH2C),
21.4 (C6H4CH3), 27.8 [COC(CH3)3], 29.2 (d, JCP = 195.6 Hz), 49.2 (d,
JCP = 2.7 Hz, CHSO), 53.1 (d, JCP = 6.2 Hz), 53.7 (d, JCP = 6.2 Hz,
Experimental Section
POCH3), 83.6 [COC(CH3)3], 124.4, 129.9, 141.6, 141.8, 166.1 (d, JCP
=
General: Unless stated otherwise, all air- and water-sensitive reac-
tions were performed under an argon atmosphere by using freshly
distilled dry solvents. Glassware was dried prior to use by heating
under vacuum. Commercial-grade reagents and solvents were used
without further purification except as indicated below. THF and di-
ethyl ether were distilled from Na/benzophenone prior to use. Thin-
layer chromatography (TLC) was conducted on Silica Gel 60 F254
TLC purchased from Merck. Column chromatography was per-
formed by using Merck silica gel (70–230 mesh). NMR spectra were
recorded with a Bruker AV 200, Bruker DRX 500, or Bruker Avance
III 600 spectrometer. 1H, 13C, and 31P chemical shifts are reported
relative to the residual proton resonance in the deuterated solvents
or referred to an 85 % aqueous solution of H3PO4. Microanalyses
were performed with an Elemental Analyzer EA 1108. HRMS were
recorded with a Finnigan MAT 95 apparatus. Optical rotations were
measured by using a Perkin–Elmer MC 241 photopolarimeter.
7.2 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ = 20.6 ppm. MS (CI): m/z =
389 [M + H]+. HRMS (EI): calcd. for C17H25O6PS [M]+ 388.1109; found
388.1096.
tert-Butyl (+)-(1R,2S,RS)-1-Dimethylphosphono-2-p-tolylsulfin-
yl-3,3-2H2-cyclopropanecarboxylate (d-3a): White solid; m.p. 92–
94 °C, yield 0.3 g (50 %). [α]D20 = +86.8 (c = 1.0, acetone). 1H NMR
(200 MHz, CDCl3): δ = 1.46 [s, 9 H, COC(CH3)3], 2.35 (s, 3 H, C6H4CH3),
2.81 [d, JPH = 15.4 Hz, 1 H, CHS(O)], 3.57 and 3.70 (2 d, JPH = 11.1 Hz,
6 H, POCH3), 7.27 and 7.75 (AB, JHH = 8.1 Hz, 4 H, C6H4CH3) ppm.
13C NMR (125 MHz, CDCl3): δ = 12.1 (quint, JCD = 25.5 Hz, CD2), 21.2
(C6H4CH3), 27.6 [(CH3)3C], 27.7 (d, JCP = 180.4 Hz), 44.0 (d, JCP
=
3.2 Hz, CHS), 53.3 (d, JCP = 6.0 Hz), 53.5 (d, JCP = 6.0 Hz), 83.6
[(CH3)3C], 124.1, 129.9, 140.6, 141.8, 164.0 (d, JCP = 4.8 Hz, C=O)
ppm. 31P NMR (81 MHz, CDCl3): δ = 22.5 ppm. MS (CI): m/z = 391 [M
+ H]+. HRMS (FAB): calcd. for C17 H232H2O6PS [M]+ 390.1235; found
1
390.1239.
Cyclopropanation
tert-Butyl (–)-(1S,2S,RS)-1-Dimethylphosphono-2-p-tolylsulfinyl-
3,3-2H2-cyclopropanecarboxylate (d-3b): Yellowish oil, yield
0.09 g (15 %). [α]D20 = –38.7 (c = 3.1, acetone). 1H NMR (500 MHz,
CDCl3): δ = 1.33 [s, 9 H, COC(CH3)3], 2.35 (s, 3 H, C6H4CH3), 2.88 [d,
Procedure 1: NaH (0.11 g, 2.2 mmol) was added to a solution
of (S)-dimethylsulfonium(p-tolylsulfinyl)methyl tetrafluoroborate
(0.6 g, 2 mmol) in dry MeCN (8–10 mL) at room temperature under
an argon atmosphere. The resulting mixture was stirred for 30 min.
Then, the precipitate was filtered off and a solution of tert-butyl 1-
dimethylphosphonoacrylate (0.44 g, 2 mmol) in dry MeCN (5 mL)
was added. After stirring at room temperature for 2 h, the reaction
was quenched with aq. NH4Cl solution (20 mL), extracted with hex-
ane (4 × 5 mL), and dried with MgSO4. After filtration, the solvent
was evaporated under reduced pressure to afford 3 in 80 % yield
as a mixture of diastereomers. Separation of the diastereomers was
achieved by chromatography on silica (hexane/acetone, 2:1).
J
HH = 9.4 Hz, 1 H, CHS(O)], 3.73–3.79 (2 d, JHH = 11.1 Hz, 6 H, POCH3),
7.27 and 7.70 (A2B2, JHH = 8.1 Hz, 4 H, C6H4CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 17.1 (quint, JCD = 25.5 Hz), 21.2, 27.6, 28.9 (d,
JCP = 196.0 Hz), 48.8 (d, JCP = 3.2 Hz), 53.0 (d, JCP = 6.1 Hz), 53.5 (d,
J
CP = 6.9 Hz), 83.45, 124.2, 129.8, 141.3, 141.4, 165.8 (d, JCP = 6.8 Hz)
ppm. 31P NMR (81 MHz, CDCl3): δ = 20.6 ppm. MS (CI): m/z = 391 [M
+ H]+. HRMS (FAB): calcd. for C17 H232H2O6PS [M]+ 390.1235; found
1
390.1230.
Procedure 2: A round-bottomed flask equipped with a magnetic
stir bar was charged with tert-butyl 1-dimethylphosphonoacrylate
Ethyl (+)-(1R,2S,RS)-1-Diethylphosphono-2-p-tolylsulfinyl-3-cy-
clopropanecarboxylate (4a): Yellowish oil, yield 0.46 g (60 %).
1
(0.44 g, 2 mmol), (S)-dimethyl sulfonium(p-tolylsulfinyl)methyl tetra- [α]D20 = +78.9 (c = 1.2, acetone). H NMR (500 MHz, CDCl3): δ = 1.23
fluoroborate (0.6 g, 2 mmol), and CH2Cl2 (20 mL). K2CO3 (0.3 g) was
added to this suspension, and the mixture was stirred vigorously
(t, JHH = 7.0 Hz, 3 H, POCH2CH3), 1.28 (t, JHH = 7.0 Hz, 3 H,
POCH2CH3), 1.32 (t, JHH = 7.1 Hz, 3 H, COCH2CH3), 1.75 (ddd, JHH
=
overnight. Filtration and evaporation of the solvent afforded a mix- 5.7, 8.5, JPH = 15.2 Hz, 1 H), 2.28 (ddd, JHH = 5.6, 6.4, JPH = 12.1 Hz,
Eur. J. Org. Chem. 2016, 2064–2074
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Full Paper
1 H), 2.42 (s, 3 H, C6H4CH3), 2.88 [ddd, JHH = 6.4, 8.5, JPH = 15.1
Hz, 1 H, CHS(O)], 3.89–3.94 (m, 1 H, POCHHCH3), 4.0–4.03 (m, 1 H,
POCHHCH3), 4.07–4.14 (m, 2 H, POCH2CH3), 4.26 (q, 2 H, COCH2CH3,
JHH = 7.1 Hz), 7.32 and 7.58 (A2B2, 4 H, C6H4CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 12.7 (m, CD2), 14.1 (CH3CH2OC), 16.3 (m,
CH3CH2OP), 21.5 (C6H4CH3), 27.5 (d, JCP = 181.0 Hz, CP), 44.6 (CHSO),
166.2 (d, JCP = 5.2 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ = 18.8 ppm.
MS (CI): m/z = 391 [M + H]+. HRMS (ES): calcd. for C17H23H2O6NaPS
[M + Na]+ 413.1133; found 413.1135.
(+)-(1R,2S,RS)-1-Diethylphosphono-2-p-tolylsulfinylcyclopro-
panenitrile (5a): Yellowish oil, yield 0.172 g (53 %). [α]D20 = +57.8
(c = 3.2, acetone). 1H NMR (500 MHz, CDCl3): δ = 1.02 [t, JHH
=
62.5 (CH3CH2OC), 63.1 (d, JCP = 6.0 Hz, CH3CH2OP), 63.4 (d, JCP
=
7.0 Hz, 3 H, (CH3CH2O)P], 1.15 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P],
1.98 (ddd, JHH = 5.8, 8.3 Hz, JPH = 14.1 Hz, 1 H), 2.30 (ddd, JHH = 5.8,
6.7 Hz, CH3CH2OP), 124.3, 130.0, 140.8, 142.1, 165.7 (d, JCP = 7.7 Hz)
ppm. 31P NMR (81 MHz, CDCl3): δ = 18.8 ppm. MS (CI): m/z = 389
[M + H]+.
6.6 Hz, JPH = 10.4 Hz, 1 H), 2.41 (s, 3 H, C6H4CH3), 2.98 [ddd, JHH
=
6.6, 8.3 Hz, JPH = 15.2 Hz, 1 H, CHS(O)], 3.71 and 3.94 (2 m, 2 H,
POCH2CH3), 4.13–4.20 (m, 2 H, POCH2CH3), 7.35 and 7.69 (A2B2, 4 H,
Ethyl (+)-(1S,2S,RS)-1-Diethylphosphono-2-p-tolylsulfinyl-3-cy-
clopropanecarboxylate (4b): Yellowish oil, yield 0.06 g (8 %). 1H
NMR (500 MHz, CDCl3): δ = 1.20 (t, JHH = 7.2 Hz, 3 H, POCH2CH3),
1.31 (t, JHH = 7.0 Hz, 3 H, POCH2CH3), 1.34 (t, JHH = 7.0 Hz, 3 H,
COCH2CH3), 2.04 (ddd, JHH = 5.6, 8.5, JPH = 9.0 Hz, 1 H), 2.28 (ddd,
JHH = 5.6, 7.0, JPH = 12.6 Hz, 1 H), 2.38 (s, 3 H, C6H4CH3), 3.00 [ddd,
JHH = 5.6, 8.5, JPH = 9.0 Hz, 1 H, CHS(O)], 4.09–4.26 (m, 6 H,
OCH2CH3), 7.29 and 7.74 (A2B2 aromatic) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.8 (CH3CH2OC), 16.3 (m, CH3CH2OP), 18.1 (m, CD2),
21.3 (C6H4CH3), 27.6 (d, JCP = 195.7 Hz), 49.7 (CHSO), 62.4
(CH3CH2OC), 62.9 (d, JCP = 6.2 Hz, CH3CH2OP), 63.4 (d, JCP = 6.5 Hz,
CH3CH2OP), 124.5, 129.9, 141.6, 142.1, 167.5 (d, JCP = 7.7 Hz) ppm.
31P NMR (81 MHz, CDCl3): δ = 17.3 ppm. MS (CI): m/z = 389 [M +
H]+.
C6H4CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 10.5 (d, JCP
=
191.1 Hz, CPCN), 16.0 and 16.1 [2 d, JCP = 6.2 Hz, (CH3CH2O)P], 21.4
(C6H4CH3), 44.0 (d, JCP = 1.9 Hz, CH2), 53.3 (CHSO), 64.0 (d, JCP
=
6.5 Hz, CH3CH2OP), 64.4 (d, JCP = 6.5 Hz, CH3CH2OP), 115.0 (CN),
124.4, 130.4, 139.8, 143.1 ppm. 31P NMR (81 MHz, CDCl3): δ =
14.7 ppm. MS (CI): m/z = 342 [M + H]+. HRMS (EI): calcd. for
C
15H20NO4PS [M]+ 341.0851; found 341.0848.
(–)-(1R,2S,RS)-1-Diethylphosphono-2-p-tolylsulfinylcyclopropyl
p-Tolyl Sulfide (6a): Oil, yield 0.175 g (42 %). [α]D20 = –33.3 (c = 1.8,
1
acetone). H NMR (500 MHz, CDCl3): δ = 1.16 [t, JHH = 7.1 Hz, 3 H,
(CH3CH2O)P], 1.20 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.84–1.90 (m,
2 H, CH2), 2.33 (s, 3 H, SC6H4CH3), 2.40 [s, 3 H, S(O)C6H4CH3], 3.08
[ddd, JHH = 6.7, 8.3 Hz, JPH = 12.2 Hz, 1 H, CHS(O)], 3.77–3.83 (m, 1
H, POCHHCH3), 3.91–3.99 (m, 2 H, POCH2CH3), 4.00–4.07 (m, 1 H,
POCHHCH3), 7.14 and 7.52 (A2B2, 4 H, C6H4CH3), 7.32 and 7.68 (A2B2,
Ethyl (+)-(1R,2S,RS)-1-Diethylphosphono-2-p-tolylsulfinyl-3,3-
2H2-cyclopropanecarboxylate (d-4a): Yellowish oil, yield 0.41 g
(53 %). [α]D20 = +79 (c = 3.6, acetone). 1H NMR (500 MHz, CDCl3): δ =
1.23 (t, JHH = 7.0 Hz, 3 H, POCH2CH3), 1.28 (t, JHH = 7.0 Hz, 3 H,
POCH2CH3), 1.32 (t, JHH = 7.1 Hz, 3 H, COCH2CH3), 2.42 (s, 3 H,
C6H4CH3), 2.90 [d, JPH = 15.2 Hz, 1 H, CHS(O)], 3.89–3.94 (m, 1 H,
POCHHCH3), 4.0–4.03 (m, 1 H, POCHHCH3), 4.07–4.14 (m, 2 H,
POCH2CH3), 4.26 (q, JHH = 7.1 Hz, 2 H, COCH2CH3), 7.32 and 7.58
(A2B2, 4 H, C6H4CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 12.8 (m,
CD2), 14.1 (CH3CH2OC), 16.3 (m, CH3CH2OP), 21.5 (C6H4CH3), 27.5 (d,
4 H, C6H4CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 16.3 [(d, JCP
=
2.4 Hz, CH3CH2O)P], 16.8, (CH2), 21.2 (C6H4CH3), 21.5 (C6H4CH3), 26.8
(d, JCP = 197.7 Hz, CPS), 49.7 (CHSO), 63.1 (d, JCP = 6.5 Hz), 63.4 (d,
JCP = 6.5 Hz), 124.7, 129.1, 129.5, 129.8, 133.3, 138.8, 141.4,
141.9 ppm. 31P NMR (81 MHz, CDCl3): δ = 21.0 ppm. MS (CI): m/z =
439 [M + H]+. HRMS (ES+): calcd. for C21H27O4NaPS2 [M]+ 461.0986;
found 461.0989.
J
CP = 180.2 Hz), 44.6 (CHSO), 62.5 (CH3CH2OC), 63.1 (d, JCP = 6.0 Hz,
(–)-(1S,2S,RS)-1-Diethylphosphono-2-p-tolylsulfinylcyclopropyl
p-Tolyl Sulfide (6b): Oil, yield 0.125 g (30 %). [α]D20 = –20.5 (c = 1.3,
acetone). H NMR (600 MHz, CDCl3): δ = 1.28 [t, JHH = 7.0 Hz, 3 H,
CH3CH2OP), 63.4 (d, JCP = 6.7 Hz, CH3CH2OP), 124.3, 130.0, 140.8,
142.1, 165.7 (d, JCP = 7.7 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ =
18.7 ppm. MS (CI): m/z = 391 [M + H]+. HRMS (ES): calcd. for
1
(CH3CH2O)P], 1.33 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.76–1.79 (m,
CHH), 2.27 (s, 3 H, SC6H4CH3), 2.32–2.36 (m, 1 H, CHH), 2.39 [s, 3 H,
S(O)C6H4CH3], 2.85–2.89 [m, 1 H, CHS(O)], 4.12–4.21 (m, 4 H,
POCH2CH3), 6.85 and 7.13 (A2B2, 4 H, C6H4CH3), 7.12 and 7.52 (A2B2,
C17 H232H2O6NaPS [M + Na]+ 413.1133; found 413.1128.
1
Ethyl
(–)-(1S,2S,RS)-1-Diethylphosphono-2-p-tolylsulfinyl-3,3-
2H2-cyclopropanecarboxylate (d-4b): Yellowish oil, yield 0.15 g
(20 %). [α]D20 = –32 (c = 7.4, acetone). 1H NMR (500 MHz, CDCl3): δ =
1.23 (t, JHH = 7.2 Hz, 3 H, POCH2CH3), 1.34 (t, JHH = 7.0 Hz, 3 H,
POCH2CH3), 1.37 (t, JHH = 7.0 Hz, 3 H, COCH2CH3), 2.41 (s, 3 H,
C6H4CH3), 3.02 (d, JPH = 9.0 Hz, 1 H, SCH), 4.09–4.32 (m, 6 H,
OCH2CH3), 7.32 and 7.77 (A2B2 aromatic) ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.0 (m, CH3CH2OC), 16.3 (CH3CH2OP), 18.1 (m, CD2),
21.5 (C6H4CH3), 29.1 (d, JCP = 158.0 Hz), 49.7 (CHSO), 62.5
(CH3CH2OC), 63.0 (CH3CH2OP), 63.5 (d, JCP = 6.7 Hz, CH3CH2OP),
124.5, 129.9, 141.6, 142.1, 167.5 (d, JCP = 7.7 Hz) ppm. 31P NMR
(81 MHz, CDCl3): δ = 17.3 ppm. MS (CI): m/z = 391 [M + H]+.
4 H, C6H4CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 16.3 [(d, JCP
=
2.4 Hz, CH3CH2O)P], 16.4, [(CH3CH2O)P], 21.1 (C6H4CH3), 21.5
(C6H4CH3), 22.2 (CH2), 28.5 (d, JCP = 200.4 Hz, CPS), 52.3 (CHSO), 63.0
(d, JCP = 5.5 Hz), 63.8 (d, JCP = 6.0 Hz), 124.6, 128.7, 129.5, 129.7,
133.3, 138.4, 141.2, 141.4 ppm. 31P NMR (81 MHz, CDCl3): δ =
19.9 ppm. MS (CI): m/z = 439 [M + H]+. HRMS (EI): calcd. for
C21H27O4PS2 [M]+ 438.1078; found 438.1088.
(+)-(1S,2S,Ss,RS)-1-Diethylphosphono-2-p-tolylsulfinylcyclo-
propyl p-Tolyl Sulfoxide (7b): Oil, yield 0.39 g (90 %). [α]D20
=
+170.7 (c = 0.9, acetone). 1H NMR (600 MHz, CDCl3): δ = 1.01 [t,
JHH = 7.1 Hz, 3 H, (CH3CH2O)P], 1.18 [t, JHH = 7.0 Hz, 3 H,
(CH3CH2O)P], 1.94 (ddd, JHH = 6.2, 8.8 Hz, JPH = 14.8 Hz, 1 H, CHH),
Ethyl (+)-(1S,2R,SS)-1-Diethylphosphono-2-p-tolylsulfinyl-3,3-
2H2-cyclopropanecarboxylate (d-4c): Yellowish oil, yield 0.055
(8 %). [α]D20 = +120 (c = 10.1, acetone). 1H NMR (500 MHz, CDCl3): 2.23–2.27 (m, 1 H, CHH), 2.41 [s, 3 H, S(O)C6H4CH3], 2.42 [s, 3 H,
δ = 1.33 (t, JHH = 7.0 Hz, 3 H, POCH2CH3), 1.34 (t, JHH = 7.0 Hz, 3 H,
POCH2CH3), 1.37 (t, JHH = 7.1 Hz, 3 H, COCH2CH3), 2.43 (s, 3 H,
C6H4CH3), 3.08 [d, JPH = 13.9 Hz, 1 H, CHS(O)], 4.11–4.21 (m, 4 H,
POCH2CH3), 4.26–4.42 (m, 2 H, COCH2CH3), 7.33 and 7.58 (A2B2, 4
H, C6H4CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.0 (CH3CH2OC),
14.9 (m, CD2), 16.3 (d, JCP = 5.8 Hz, CH3CH2OP); 16.4 (d, JCP = 6.7 Hz,
CH3CH2OP), 21.4 (C6H4CH3), 27.0 (d, JCP = 181.9 Hz), 48.0 (CHSO),
S(O)C6H4CH3], 3.29 [ddd, 1 H, JHH = 6.7, 8.8 Hz, JPH = 13.0 Hz,
CHS(O)], 3.78–3.85 (m, 2 H, POCH2CH3), 3.91–3.99 (m, 1 H,
POCHCH3), 4.00–4.025 (m, 1 H, POCHCH3), 7.32 and 7.62 (A2B2, 4 H,
C6H4CH3), 7.35 and 7.88 (A2B2, 4 H, C6H4CH3) ppm, 13C NMR
(150 MHz, CDCl3): δ = 12.7 (CH2), 15.8 [d, JCP = 7.4 Hz, CH3CH2O)P],
16.0, [(CH3CH2O)P], 21.5 (C6H4CH3), 21.55 (C6H4CH3), 29.7 (d, JCP
166.0 Hz, CPS), 49.0 (CHSO), 63.2 (d, JCP = 6.0 Hz), 63.6 (d, JCP
=
=
62.7 (CH3CH2OC), 63.4 (m, CH3CH2OP), 124.2, 130.1, 140.8, 142.0, 5.5 Hz), 124.1, 125.8, 129.3, 130.3, 138.0, 141.0, 141.2, 142.3 ppm.
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31P NMR (81 MHz, CDCl3): δ = 17.3 ppm. MS (CI): m/z = 455 [M + H]+.
47.8 (CHSO), 63.7 [d, JCP = 6.5, (CH3CH2O)P], 64.4 [d, JCP = 6.1 Hz,
HRMS (ES+): calcd. for C21H27O5PS2 [M]+ 454.1038; found 454.1031. (CH3CH2O)P], 116.6 (CN), 124.9, 129.8, 136.9, 142.4 ppm. 31P NMR
(81 MHz, CDCl3): δ = 13.8 ppm. MS (CI): m/z = 356 [M + H]+. HRMS
Methylation: LiHMDS (prepared by adding 0.55 mL of 2
M BuLi in
(CI): calcd. for C16H23NO4PS [M + H]+ 356.1083; found 356.1085.
hexane to 0.25 mL of HMDS) was added to a solution of cyclopropyl
sulfoxide 3a (0.39 mg, 1 mmol) in 10 mL of THF at –70 °C. The
mixture was stirred for 15 min and then MeI (1.2 mmol) was added
at –70 °C. The mixture was warmed slowly to 0 °C. After quenching
with NH4Cl, the water phase was extracted with CH2Cl2 (3×), and
(+)-(1S,2R,SS)-1-Diethylphosphono-2-p-tolylsulfinyl-2-methyl-
cyclopropyl p-Tolyl Sulfide (10a): Viscous oil, yield 0.39 g (86 %).
1
[α]D20 = –33.3 (c = 1.3, acetone). H NMR (500 MHz, CDCl3): δ = 1.14
(dd, JHH = 7.0 Hz, JPH = 7.6 Hz, 1 H), 1.25 [t, JHH = 7.0 Hz, 3 H,
the combined organic phase was dried with MgSO4, filtered, and (CH3CH2O)P], 1.33 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.48 [s, 3 H,
concentrated. Crude product 8a was purified by recrystallization
(Et2O).
CH3-C(SO)], 2.23 (dd, JHH = 7.0 Hz, JPH = 18.6 Hz, 1 H), 2.28 (s, 3 H,
SC6H4CH3), 2.38 [s, 3 H, S(O)C6H4CH3], 4.15–4.21 (m, 4 H, POCH2),
7.09 and 7.32 (A2B2, 4 H, C6H4CH3), 7.29 and 7.51 (A2B2, 4 H,
tert-Butyl (+)-(1R,2R,SS)-1-Dimethylphosphono-2-p-tolylsulf-
inyl-2-methylcyclopropanecarboxylate (8a): White solid; m.p.
C6H4CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 10.5, 16.2 (d, JCP
=
6.5 Hz), 16.4 (d, JCP = 6.2 Hz), 21.0, 21.4, 24.2, 32.7 (d, JCP = 190.1 Hz),
52.1, 63.3 (d, JCP = 6.5 Hz), 63.4 (d, JCP = 6.6 Hz), 124.7, 129.2, 129.5,
129.6, 130.3, 136.7, 139.6, 141.3 ppm. 31P NMR (81 MHz, CDCl3): δ =
21.9 ppm. MS (EI): m/z = 452 [M]+. HRMS (EI): calcd. for C22H29PS2O4
[M]+ 452.1245; found 452.1244.
1
133–135 °C, yield 0.37 g (93 %). [α]D20 = +28.8 (c = 3.9, acetone). H
NMR (500 MHz, CDCl3): δ = 1.17 [s, 3 H, CH3-C(SO)], 1.45 [s, 9 H,
COC(CH3)3], 1.63 (dd, JHH = 6.2 Hz, JPH = 9.1 Hz, 1 H), 1.93 (dd, JHH
6.2 Hz, JPH = 16.6 Hz, 1 H), 2.39 (s, 3 H, C6H4CH3), 3.84 (d, JPH
=
=
11.2 Hz, 3 H, POCH3), 3.96 (d, JPH = 11.4 Hz, 3 H, POCH3), 7.29 and
7.50 (A2B2, 4 H, C6H4CH3) ppm. 13C NMR (125 MHz, CDCl3): 9.15 (d,
(+)-(1R,2S,SS)-1-Diethylphosphono-2-p-tolylsulfinyl-2-methyl-
cyclopropyl p-Tolyl Sulfide (10c): Oil. [α]D20 = –20.6 (c = 0.85, acet-
one). 1H NMR (500 MHz, CDCl3): δ = 1.28 [t, JHH = 7.0 Hz, 3 H,
J
CP = 1.4 Hz), 20.1 (d, JCP = 3.0 Hz), 21.3, 27.7, 35.7 (d, JCP = 179.7 Hz),
47.8 (d, JCP = 4.4 Hz), 53.4 (d, JCP = 5.9 Hz), 53.8 (d, JCP = 6.4 Hz),
83.2, 124.7, 129.6, 138.5, 141.6, 165.2 (d, JCP = 4.3 Hz) ppm. 31P NMR
(81 MHz, CDCl3): δ = 22.2 ppm. MS (CI): m/z = 403 [M + H]+.
C18H27O6PS (402.44): calcd. C 53.72, H 6.76; found C 53.84, H 6.87.
(CH3CH2O)P], 1.31 [s, 3 H, CH3-C(SO)], 1.34 (dd, JHH = 6.4 Hz, JPH
7.8 Hz, 1 H), 1.38 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 2.29 (s, 3 H,
SC6H4CH3), 2.43 [s, 3 H, S(O)C6H4CH3], 2.52 (dd, JHH = 6.4 Hz, JPH
=
=
17.3 Hz, 1 H), 4.18–4.28 (m, 4 H, POCH2), 6.96 and 7.20 (A2B2, 4 H,
tert-Butyl (–)-(1S,2S,SS)-1-Dimethylphosphono-2-p-tolylsulfinyl-
C6H4CH3), 7.30 and 7.82 (A2B2, 4 H, C6H4CH3) ppm. 13C NMR
2-methylcyclopropanecarboxylate (8c): Pale-yellow oil. [α]D20
=
(125 MHz, CDCl3): δ = 13.0, 16.4, 21.1, 21.4, 27.0, 33.7 (d, JCP
=
1
–36.4 (c = 0.8, acetone). H NMR (500 MHz, CDCl3): δ = 0.96 [s, 3 H,
CH3-C(SO)], 1.44 [s, 9 H, COC(CH3)3], 1.78 (dd, 1 H, J = 6.3, 9.5 Hz),
2.27 (dd, 1 H, J = 6.2, 17.0 Hz), 2.40 (s, 3 H, C6H4CH3), 3.82 (d, 6 H,
POCH3, J = 10.9 Hz), 7.32 and 7.89 (A2B2, 4 H, C6H4CH3) ppm. 13C
197.4 Hz), 52.8, 63.0 (d, JCP = 6.5 Hz), 63.3, 125.6, 129.4, 129.9, 130.4,
137.2, 137.9, 141.1 ppm. 31P NMR (81 MHz, CDCl3): δ = 19.9 ppm.
MS (EI): m/z = 452 [M]+. HRMS (EI): calcd. for C22H29NPS2O4 [M]+
452.1245; found 452.1241.
NMR (125 MHz, CDCl3): δ = 9.15 (d, JCP = 1.4 Hz), 21.3, 22.7 (d, JCP
=
3.8 Hz), 27.7, 35.9 (d, JCP = 185.7 Hz), 46.6 (d, JCP = 4.3 Hz), 53.5 (d,
JCP = 6.1 Hz), 53.6 (d, JCP = 6.4 Hz), 83.2, 125.4, 129.5, 137.9, 140.9,
164.5 (d, JCP = 4.5 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ = 20.7 ppm.
MS (CI): m/z = 403 [M + H]+. HRMS (FAB): calcd. for C18H27O6PS [M
+ H]+ 403.1344; found 403.1352.
(+)-(1S,2R,Ss,SS)-1-Diethylphosphono-2-p-tolylsulfinyl-2-meth-
ylcyclopropyl p-Tolyl Sulfoxide (11c): Viscous oil, yield 0.34 g
(72 %). [α]D20 = –114.2 (c = 0.99, acetone). 1H NMR (500 MHz, CDCl3):
δ = 1.11 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.36 [t, JHH = 7.0 Hz, 3
H, (CH3CH2O)P], 1.48 [s, 3 H, CH3-C(SO)], 2.13 (dd, JHH = 6.8 Hz, JPH
=
8.8 Hz, 1 H), 2.46 (s, 3 H, SC6H4CH3), 2.47 [s, 3 H, S(O)C6H4CH3], 2.76
(dd, JHH = 6.8 Hz, JPH = 17.3 Hz, 1 H), 3.85–3.95 (m, 2 H, POCH2),
4.17–4.21 (m, 2 H, POCH2), 7.29 and 7.34 (A2B2, 4 H, C6H4CH3), 7.30
and 7.74 (A2B2, 4 H, C6H4CH3) ppm. 13C NMR (125 MHz, CDCl3): δ =
14.0, 15.8 (d, JCP = 6.7 Hz, CH3CH2OP), 16.2 (d, JCP = 6.7 Hz,
CH3CH2OP), 21.5 (C6H4CH3), 24.8, 47.9 (d, JCP = 169.6 Hz, CP), 49.9
(CHSO), 63.1 (d, JCP = 6.6 Hz, CH3CH2OP), 63.8 (d, JCP = 5.8 Hz,
CH3CH2OP), 125.4, 125.6, 129.2, 129.5, 137.5, 137.8, 141.5,
141.7 ppm. 31P NMR (81 MHz, CDCl3): δ = 15.3 ppm. HRMS (FAB):
calcd. for C22H30PS2O5 [M + 1]+ 469.1260; found 469.1272.
(+)-(1R,2R,SS)-1-Diethylphosphono-2-p-tolylsulfinyl-2-methylcy-
clopropanenitrile (9a): Yellowish oil, yield 0.1 g (28 %) [when
(MeO)2SO2 was used]. [α]D20 = +22.1 (c = 0.7, acetone). 1H NMR
(500 MHz, CDCl3): δ = 1.46 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.48
[t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.49 (s, 3 H, CH3), 1.66 (dd, JHH
=
6.1 Hz, JPH = 7.7 Hz, 1 H, CHcis), 2.25 (dd, JHH = 6.1 Hz, JPH = 16.1 Hz,
1 H, CHtrans), 2.43 (s, 3 H, C6H4CH3), 4.29–4.40 [m, 2 H, (CH3CH2O)P],
4.41–4.44 [m, 2 H, (CH3CH2O)P], 7.32 and 7.51 (A2B2, 4 H, C6H4CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 11.9 (CH3), 16.3 [(CH3CH2O)P],
20.0 [d, JCP = 190.4 Hz, CP(O)], 21.4 (C6H4CH3), 24.1, 50.0 (CHSO),
64.2 [d, JCP = 6.2 Hz, (CH3CH2O)P], 64.9 [d, JCP = 6.5 Hz, (CH3CH2O)P],
Oxidation to Sulfone: Oxidation was performed by adding meta-
116.5 (CN), 124.5, 129.9, 138.0, 142.2 ppm. 31P NMR (81 MHz, CDCl3): chloroperbenzoic acid (0.46 g, 0.26 mmol) to a solution of sulfoxide
δ = 14.0 ppm. MS (CI): m/z = 356 [M + H]+. HRMS (EI): calcd. for 8a or 8c (0.8 g, 0.2 mmol) in CH2Cl2 (10 mL). The mixture was
C16H22NPSO4 [M]+ 355.1007; found 355.1005.
stirred vigorously overnight. Then, the mixture was washed with a
saturated aqueous solution of NaHCO3, and the organic solvent was
evaporated. The crude product was purified on silica gel (acetone/
diethyl ether).
(+)-(1R,2S,SS)-1-Diethylphosphono-2-p-tolylsulfinyl-2-methylcy-
clopropanenitrile (9b): Yellowish oil, yield 0.22 g (63 %) [when
(MeO)2SO2 was used]. [α]D20 = + 52.5, (c = 0.9, acetone). 1H NMR
(500 MHz, CDCl3): δ = 1.17 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.38
tert-Butyl (+)-(1R,2R)-1-Dimethylphosphono-2-p-tolylsulfonyl-
2-methylcyclopropanecarboxylate (12a): Oil. [α]D20 = +12.3 (c =
2.1, acetone), yield 0.8 g (95 %). 1H NMR (500 MHz, CDCl3): δ = 1.25
[s, 3 H, CH3-C(SO)], 1.44 [s, 9 H, COC(CH3)3], 1.71 (dd, JHH = 5.5 Hz,
JPH = 9.5 Hz, 1 H), 2.35 (dd, JHH = 5.5 Hz, JPH = 18.0 Hz, 1 H), 2.44
(s, 3 H, CH3), 1.42 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 2.06 (dd, JHH
5.8 Hz, JPH = 14.0 Hz, 1 H, CHcis), 2.40 [dd, JHH = 5.8 Hz, JPH
=
=
8.9 Hz, 1 H, CHtrans CHS(O)], 2.43 (s, 3 H, C6H4CH3), 3.96–3.99 [m, 1
H, (CH3CH2O)P], 4.01–4.05 [m, 1 H, (CH3CH2O)P], 4.23–4.27 [m, 2 H,
(CH3CH2O)P], 7.36 and 7.73 (A2B2, 4 H, C6H4CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 9.1 (CH2), 14.5 (d, JCP = 180.3 Hz), 16.1
[(CH3CH2O)P], 16.2 (d, JCP = 6.0 Hz, CH3CH2OP), 21.5 (C6H4CH3), 25.6,
(s, 3 H, C6H4CH3), 3.84 (d, JPH = 11.0 Hz, 3 H, POCH3), 3.88 (d, JPH
11.5 Hz, 3 H, POCH3), 7.36 and 8.04 (A2B2, 4 H, C6H4CH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 17.3, 21.7, 21.8, 27.7, 37.9 (d, JCP
=
=
Eur. J. Org. Chem. 2016, 2064–2074
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183.7 Hz), 47.8 (d, JCP = 5.5 Hz), 53.8 (d, JCP = 7.0 Hz), 54.5 (d, JCP
=
63.3 [d, JCP = 6.5 Hz, (CH3CH2O)P], 63.6 [d, JCP = 6.0 Hz, (CH3CH2O)P],
119.9 (CN) ppm. 31P NMR (81 MHz, CDCl3): δ = 18.0 ppm. MS (CI):
6.2 Hz), 85.1, 129.3, 129.8, 134.9, 144.8, 165.1 (d, JCP = 3.4 Hz) ppm.
31P NMR (81 MHz, CDCl3): δ = 20.2 ppm. MS (EI): m/z = 418 [M]+. m/z = 218 [M + H]+. HRMS (CI): calcd. for C9H17NPO3 [M + H]+
HRMS (FAB): calcd. for C18H28O7PS [M + 1]+ 419.1295; found 218.0950; found 218.0946.
419.1293.
Computational Methods: Calculations were performed with the
Gaussian 09 package[25] by using density functional theory (DFT)
methods, namely, the B3LYP hybrid functional with the 6-31+G(d)
basis set, which combines high accuracy with moderate computa-
tional cost. The B3LYP functional has proven its applicability in a
wide range of chemical problems. All stationary points were identi-
fied by vibrational analysis, which also provided thermochemical
corrections to the electronic energy. Thermochemical corrections
were scaled by a factor of 0.98.[26] Final electronic accurate energies
on the B3LYP/6-31+G(d) optimized geometries were calculated by
using the wB97XD functional including empirical dispersion and
long-range corrections[27] with triple-ꢁ 6-311+G(2d,p) basis set. Cal-
culations in solution were performed by using the default SCRF-
PCM continuum solvation model in Gaussian with an UFF cavity
definition by assuming THF as the implicit solvent. Ultrafine integra-
tion grid was applied for PCM calculations.
Metal–Sulfinyl Exchange: iPrMgCl (2.0
M in THF, 1 mmol, 0.5 mL)
was added to a stirred solution of diethyl 1-cyano-2-p-tolylsulfinyl-
2-methylcyclopropylphoshonate (9, 0.2 mmol) in anhydrous THF
(5.0 mL) at –50 °C, and the mixture was stirred at this temperature
for 1 h. The reaction was quenched by adding NH4Cl, and the mix-
ture was extracted with chloroform (5 × 5 mL). The combined ex-
tract was dried with anhydrous MgSO4, filtered, and concentrated.
Purification was performed by plate chromatography (hexane/acet-
one, 4:1).
tert-Butyl (+)-(1S,2R)-2-Methyl-2-dimethylphosphonocyclopro-
panecarboxylate (13a): Oil. [α]D20 = +19.4 (c = 1.2, acetone). 1H
NMR (500 MHz, CDCl3): δ = 0.94 (ddd, J = 4.5, 7.75 Hz, JPH = 9.37 Hz,
1 H), 1.30 (d, JPH = 12.45 Hz, 3 H, CH3-CP), 1.47 [s, 9 H, COC(CH3)3],
1.67 (ddd, JHH = 4.5, 6.6 Hz, JPH = 16.75 Hz, 1 H), 1.72 (ddd, JHH
=
6.6, 7.75 Hz, JPH = 9.33 Hz, 1 H), 3.74 (d, J = 10.7 Hz, 3 H, POCH3),
3.76 (d, JPH = 10.7 Hz, 3 H, POCH3) ppm. 13C NMR (125 MHz, CDCl3):
δ = 18.3 (CH2C), 19.0 (d, JCP = 194.0 Hz, CP), 21.8 (d, JCP = 4.7 Hz),
27.9 [COC(CH3)3], 29.4 (d, JCP = 2.9 Hz), 52.5 (d, JCP = 6.3 Hz), 52.9
(d, JCP = 6.2 Hz, POCH3), 81.0 [COC(CH3)3], 168.4 (d, JCP = 7.1 Hz)
ppm. 31P NMR (81 MHz, CDCl3): δ = 30.6 ppm. MS (CI): m/z = 265
[M + H]+. HRMS (FAB): calcd. for C11H22O5P [M + H]+ 265.1205; found
265.1211.
X-ray Diffraction: X-ray diffraction data were collected for com-
pound 3a at room temperature and for compound 8a at 100 K by
the ω-scan technique by using a Bruker AXS Smart APEX-II CCD[28]
diffractometer with MonoCap capillary and 30W Incoatec Microfo-
cus Source IμS with Montel optics and Cu-Kα radiation (λ =
1.54178 Å). The crystal structure was solved by using a direct
method with the SHELXS-2013 program. Atomic scattering factors
were taken from the International Tables for X-ray Crystallography.
Positional parameters of non-hydrogen atoms were refined by a
full-matrix least-squares method with anisotropic thermal parame-
ters by using the SHELXL-2014/7 program.[29] The crystal and struc-
ture refinement data are summarized in Table S1 (Supporting Infor-
mation).
(+)-(1S,2R)-2-Methyl-2-diethylphosphonocyclopropanenitrile
1
(14a): Oil, yield 0.032 g (74 %). [α]D20 = –38.8 (c = 0.25, acetone). H
NMR (500 MHz, CDCl3): δ = 1.11 (ddd, JHH = 5.0, 5.5, JPH = 13.5 Hz,
1 H), 1.39 (t, JHH = 7.0 Hz, 3 H), 1.40 (t, JHH = 7.0 Hz, 3 H), 1.47 (d,
JPH = 13.0 Hz, 3 H, CH3-CP), 1.62 (ddd, JHH = 5.0, 9.0 Hz, JPH
=
14.0 Hz, 1 H), 2.04 (ddd, JHH = 5.5, 9.0 Hz, JPH = 14.3 Hz, 1 H), 4.13
(m, 4 H, POCH2) ppm. 13C NMR (125 MHz, CDCl3): δ = 15.9 (CH2),
CCDC 1433286 (for 3a) and 1433185 (for 8a) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre.
16.4 (d, JCP = 5.7 Hz), 17.1 (d, JCP = 194.0 Hz, CP), 18.2, 29.7 (d, JCP
=
2.9 Hz), 62.8 (d, JCP = 6.2 Hz, POCH2), 127.1 (CN) ppm. 31P NMR
(81 MHz, CDCl3): δ = 26.1 ppm. MS (CI): m/z = 218 [M + H]+. HRMS
(FAB): calcd. for C9H16NPO3[M]+ 217.0872; found 217.0868.
Supporting Information (see footnote on the first page of this
article): Experimental and computational details as well as spectro-
scopic and analytical data for new compounds.
p-Tolyl (+)-(1R,2R)-2-Methyl-2-diethylphosphonocyclopropyl
Sulfide (15a): Oil, yield 0.26 g (78 %). [α]D20 = +62.6 (c = 0.8, acet-
one). 1H NMR (500 MHz, CDCl3): δ = 0.71 (ddd, JHH = 5.2, 5.5 Hz,
JPH = 12.9 Hz, 1 H), 1.31 (t, JHH = 7.0 Hz, 3 H), 1.35 (t, JHH = 7.0 Hz,
3 H), 1.37 (d, JPH = 13.6 Hz, 3 H, CH3-CP),1.62 (ddd, JHH = 5.0, 9.0 Hz,
JPH = 14.0 Hz, 1 H), 1.64 (ddd, JHH = 5.2, 8.9 Hz, JPH = 16.8 Hz, 1 H),
2.31, 2.86 (ddd, JHH = 5.5, 8.9 Hz, JPH = 13.9 Hz, 1 H), 4.03–4.15 (m,
4 H, POCH2), 7.09 and 7.30 (A2B2, 4 H, C6H4CH3) ppm. 13C NMR
Acknowledgments
This research was supported by the Polish National Science
Centre through National Science Grant DEC-2013/11/B/ST5/
01589. DFT calculations were supported by PL-Grid Infrastruc-
ture.
(125 MHz, CDCl3): δ = 13.2 (CH3), 16.4 (d, JCP = 4.5 Hz), 16.5 (d, JCP
=
6.0 Hz), 17.8 (CH2), 17.9 (d, JCP = 186.5 Hz, CP), 21.0, 24.4, 62.0 (d,
JCP = 6.1 Hz, POCH2), 62.2 (d, JCP = 6.0 Hz, POCH2), 127.7, 129.6,
133.2, 135.5 ppm. 31P NMR (81 MHz, CDCl3): δ = 26.1 ppm. MS (CI):
m/z = 315 [M + H]+. HRMS (FAB): calcd. for C15H23PSO3 [M]+
314.1105; found 314.1111.
Keywords: Reaction mechanisms · Rearrangement ·
Isomerization · Phosphorus · Ylides
(–)-(1S,2R)-2-Methyl-1-diethylphosphonocyclopropanenitrile
(16): Yellowish oil, yield 0.137 g (63 %). [α]D20 = –14.3 (c = 6.7, acet-
one). 1H NMR (500 MHz, CDCl3): δ = 1.40 [t, JHH = 7.0 Hz, 3 H,
[1] For a recent review, see: a) M. Ordóñez, J. L. Viveros-Ceballos, C. Cativiela,
F. J. Sayago, Tetrahedron 2015, 71, 1745–1784; b) A. Mucha, P. Kafarski,
Ł. Berlicki, J. Med. Chem. 2011, 54, 5955–5980; c) F. Orsini, G. Sello, M.
Sisti, Curr. Med. Chem. 2010, 17, 264–289; d) Z. H. Kudzin, M. H. Kudzin,
J. Drabowicz, C. V. Stevens, Curr. Org. Chem. 2011, 15, 2015–2071; e) M.
Ordonez, H. Rojas-Cabrera, C. Cativiela, Tetrahedron 2009, 65, 17–49; f)
Ł. Berlicki, P. Kafarski, Curr. Org. Chem. 2005, 9, 1829–1850; g) V. Kukhar,
H. Hudson (Eds.), Aminophosphonic and Aminophosphinic Acids: Chemis-
try and Biological Activity, Wiley, Chichester, UK, 2000.
(CH3CH2O)P], 1.42 [t, JHH = 7.0 Hz, 3 H, (CH3CH2O)P], 1.44 (d, JHH
=
6.7 Hz, 3 H, CH3) 1.55 (ddd, JHH = 4.8, 7.1 Hz, JPH = 14.2 Hz, 1 H,
CHcis), 1.70 (ddd, JHH = 4.8, 8.9 Hz, JPH = 7.3 Hz, 1 H, CHtrans), 1.90
(m, CH-CH3), 4.24 [m, 4 H, (CH3CH2O)P] ppm. 13C NMR (125 MHz,
CDCl3): δ = 8.6 (d, JCP = 198.8 Hz, C1), 13.0 (d, JCP = 3.4 Hz, CH3)
16.3 [d, JCP = 6.0 Hz, (CH3CH2O)P], 16.4 [(CH3CH2O)P], 21.9, 24.4,
Eur. J. Org. Chem. 2016, 2064–2074
www.eurjoc.org
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Full Paper
[2] a) R. Pellicciari, M. Marinozzi, E. Camaioni, M. Nunez, G. Costantino, F.
Gasparini, G. Giorgi, A. Macchiarulo, N. Subramanian, J. Org. Chem. 2002,
67, 5497–5507; b) H. B. Kroona, N. L. Peterson, J. F. Koerner, R. L. Johnson,
J. Med. Chem. 1991, 34, 1692–1699.
[3] a) M. Ordóñez, F. J. Sayago, C. Cativiela, Tetrahedron 2012, 68, 6369–
6412; b) L. Brisson, N. E. Bakkali-Taheri, M. Giorgi, A. Fadel, J. Kaizer, M.
Reglier, T. Tron, E. H. Ajandouz, A. J. Simaan, J. Inorg. Biochem. 2012, 17,
939–949; c) N. S. Gulyukina, N. N. Makukhin, I. P. Beletskaya, Russ. J. Org.
Chem. 2011, 47, 633–649.
[18] P. Knochel, A. Gavriushin, K. Brade, Organomagnesium Compounds, Part 1,
(Ed.: Z. Rappoport, I. Marek), Wiley, Chichester, UK, 2008, p. 503–574.
[19] W. H. Midura, A. Sobczak, P. Paluch, Tetrahedron Lett. 2013, 54, 223–226.
[20] For all details related to the synthesis and structure determination of 16
as well as its further application, see: W. H. Midura, A. Rzewnicka, Synlett
2014, 25, 2213–2216.
[21] R. W. Hoffmann, P. G. Nell, Angew. Chem. Int. Ed. 1999, 38, 338–339;
Angew. Chem. 1999, 111, 354–355.
[22] W. H. Midura, A. Rzewnicka, Tetrahedron: Asymmetry 2013, 24, 937–941.
[23] a) D. M. Hodgson, P. G. Humphreys, S. M. Miles, C. A. J. Brierley, J. G.
Ward, J. Org. Chem. 2007, 72, 10009–10021; b) D. M. Hodgson, P. G.
Humphreys, Z. Xu, J. G. Ward, Angew. Chem. Int. Ed. 2007, 46, 2245;
Angew. Chem. 2007, 119, 2295–2298.
[24] a) D. Hellwinkel, G. Hofmann, F. Lämmerzahl, Tetrahedron Lett. 1977, 18,
3241–3244; b) W. B. Jang, K. Lee, C. W. Lee, D. Y. Oh, Chem. Commun.
1998, 60; c) F. Hammerschmidt, M. Hanbauer, J. Org. Chem. 2000, 65,
6121–6131; d) T.-L. Au-Yeung, K.-Y. Chan, R. K. Haynes, I. D. Williams, L. L.
Yeung, Tetrahedron Lett. 2001, 42, 457–460.
[25] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nak-
atsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Mont-
gomery Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, revision D.01,
Gaussian, Inc., Wallingford, CT, 2009.
[4] H. Pellissier, Tetrahedron 2006, 62, 5559–5601.
[5] W. H. Midura, Synlett 2006, 733–736.
[6] a) B. Zwanenburg, N. de Kimpe, Houben-Weyl (Ed.: A. de Meijere), Thieme,
Stuttgart, Germany, 1997, vol. E 17a, p. 69–105; b) H. Pellissier, Tetrahe-
dron 2008, 64, 7041–7095; c) D. Caine, Tetrahedron 2001, 57, 2643–2684;
d) G. Bartoli, G. Bencivenni, R. R. Dalpozzo, Synthesis 2014, 46, 979–1029.
[7] V. N. G. Lindsay, D. Fiset, P. J. Gritsch, S. Azzi, A. B. Charette, J. Am. Chem.
Soc. 2013, 135, 1463–1470.
[8] For more details, see: W. H. Midura, J. Krysiak, Chirality 2015, 27, 816–
819 and references cited therein.
[9] W. H. Midura, M. Cypryk, Tetrahedron: Asymmetry 2010, 21, 177–186.
[10] Stereogenic center on sulfur remains unchanged as in starting ylide 1,
and only its description is amended owing to the change in the order
of the substituents, which was incorrectly not taken into account in our
former papers (ref.[7,18,20]).
[11] R. Tanikaga, T. Murashima, J. Chem. Soc. Perkin Trans. 1 1989, 2142–2144.
[12] K. Nakamura, M. Higaki, S. Adachi, S. Oka, A. Ohno, J. Org. Chem. 1987,
52, 1414–1417.
[13] a) A. Volonterio, M. Zanda, in: Organosulfur Chemistry in Asymmetric Syn-
thesis (Ed.: T. Toru, C. Bolm), Wiley-VCH, Weinheim, Germany, 2008, p.
351–374.
[14] a) J. L. Garcıa Ruano, C. Alemparte, A. M. Martın Castro, H. Adams, J. H.
Rodrıguez Ramos, J. Org. Chem. 2000, 65, 7938–7943; b) J. L. Garcıa Ru-
ano, A. E. Gamboa, A. M. Martın Castro, J. H. Rodrıguez, J. Org. Chem.
1998, 63, 3324–3332.
[26] J. P. Merrick, D. Moran, L. Radom, J. Phys. Chem. A 2007, 111, 11683–
11700.
[27] J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 2008, 10, 6615–
6620.
[15] F. Koppe, G. Sklute, K. Polborn, I. Marek, P. Knochel, Org. Lett. 2005, 7,
3789–3791.
[28] Bruker, APEX2, SAINT, and SADABS, Bruker AXS, Inc., Madison, WI, USA,
2008.
[29] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[16] a) J. F. Biellmann, J. J. Vicens, Tetrahedron Lett. 1978, 19, 467–470; b) G.
Chassaing, P. Lett, A. Marquet, Tetrahedron Lett. 1978, 19, 471–474.
[17] a) T. Satoh, K. Takano, Tetrahedron 1996, 52, 2349–2358; b) Tetrahedron:
Asymmetry 2010; c) P. B. Hitchcock, G. J. Rowlands, R. Parmar, Chem.
Commun. 2005, 4219–4221; d) J. Krysiak, W. H. Midura, W. Wieczorek, L.
Sieroń, M. Mikołajczyk, Tetrahedron: Asymmetry 2010, 21, 1486–149.
Received: January 31, 2016
Published Online: March 24, 2016
Eur. J. Org. Chem. 2016, 2064–2074
www.eurjoc.org
2074
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim