Tandem Addition of Phosphite Nucleophiles Across Unsaturated Nitrogen-Containing Systems: Mechanistic Insights on Regioselectivity

Article abstract of DOI:10.1021/acs.joc.6b02340

The addition of phosphite nucleophiles across linear unsaturated imines is a powerful and atom-economical methodology for the synthesis of aminophosphonates. These products are of interest from both a biological and a synthetic point of view: they act as amino acid transition state analogs and Horner-Wadsworth-Emmons reagents, respectively. In this work the reaction between dialkyl trimethylsilyl phosphites and α,β,γ,δ-diunsaturated imines was evaluated as a continuation of our previous efforts in the field. As such, the first conjugate 1,6-addition of a phosphite nucleophile across a linear unsaturated N-containing system is reported herein. Theoretical calculations were performed to rationalize the observed regioselectivites and to shed light on the proposed mechanism.

Full text of DOI:10.1021/acs.joc.6b02340

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Article
Tandem addition of phosphite nucleophiles across unsaturated
nitrogen-containing systems: mechanistic insights on regioselectivity
Wouter Debrouwer, Dietmar Hertsen, Thomas S.A. Heugebaert, Esma Birsen
Boydas, Veronique Van Speybroeck, Saron Catak, and Christian Victor Stevens
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02340 • Publication Date (Web): 06 Dec 2016
Downloaded from http://pubs.acs.org on December 7, 2016
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Tandem addition of phosphite nucleophiles across unsaturated
nitrogen-containing systems: mechanistic insights on
regioselectivity
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†
‡
†
Wouter Debrouwer, Dietmar Hertsen, Thomas S.A. Heugebaert, Esma Birsen
§
‡
‡§
†
Boydas, Veronique Van Speybroeck, Saron Catak * and Christian V. Stevens *
†
SynBioC Research Group, Department of Sustainable Organic Chemistry and
Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
6
53, 9000 Ghent, Belgium.
E-mail: Chris.Stevens@ugent.be
‡
Center for Molecular Modeling, Ghent University, Technologiepark 903, 9052
Zwijnaarde, Belgium.
§
Bogazici University, Department of Chemistry, Bebek, Istanbul, 34342 Turkey.
E-mail: Saron.Catak@boun.edu.tr
Abstract
The addition of phosphite nucleophiles across linear unsaturated imines is a powerful
and atom-economical methodology for the synthesis of aminophosphonates. These
products are of interest from both a biological and a synthetic point of view: they act
as amino acid transition state analogs and Horner-Wadsworth-Emmons reagents,
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respectively. In this work the reaction between dialkyl trimethylsilyl phosphites and
α,β,γ,δ-diunsaturated imines was evaluated, as a continuation of our previous efforts
in the field. As such, the first conjugate 1,6-addition of a phosphite nucleophile across
a linear unsaturated N-containing system is reported herein. Theoretical calculations
were performed to rationalize the observed regioselectivites and to shed light on the
proposed mechanism.
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Introduction
The addition of phosphorus nucleophiles across unsaturated systems is a
conceptually simple yet powerful and atom-economical tool for the construction of C-
1-7
8-19
P bonds. Michael-type additions of phosphorus nucleophiles are known,
but
conjugate 1,6-additions of phosphorus nucleophiles are unprecedented to the best of
our knowledge. Conjugate 1,6-additions (vinylogous Michael reactions) are known for
carbon nucleophiles under transition-metal catalysis or organocatalysis, and
20
enantioselective variants have also been reported.
Numerous transition metals have been used, of which Cu(I) has received the most
attention. Cu-salts readily transmetalate other organometallic reagents such as
21-24
trialkylaluminiums, Grignard reagents, diethyl zinc and organolithiums.
After initial
formation of a π-complex, the organocuprate undergoes addition to the unsaturated
system. 1,3-Migration, or the lack of it, dictates the regioselectivity of the conjugate
22
addition and is influenced by electronic and steric factors. Pd, Ir and other metals
25-28
have been reported to mediate 1,6-conjugate additions as well,
and Yamamoto
26
and coworkers even succeeded in a conjugate 1,8-addition using Pd-catalysts.
The approach in organocatalytic 1,6-conjugate addition relies on lowering the LUMO
of the substrate, often by formation of an intermediate iminium ion (‘vinylogous
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iminium ion catalysis’). A pending nucleophile, activated (elevated HOMO) or not,
then attacks the conjugated system and is directed to the δ-position by both steric
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and electronic factors. Application of chiral organocatalysts, e.g. prolinol and
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cinchona derivatives, has resulted in excellent remote stereocontrol.
coworkers used triaminoiminophosphoranes,
Ooi and
a
type of phosphazene, as
organocatalysts which resulted in the regio-, stereo- and diastereoselective formation
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of 1,6- and 1,8-adducts.
35-
Selective uncatalyzed conjugate 1,6-addition has been reported in only two cases.
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In continuation of our work on tandem 1,4-1,2-phosphite additions across α,β-
8, 38-42
unsaturated imines 1,
the feasibility of a tandem 1,6-1,4-1,2-addition to suitable
α,β,γ,δ-diunsaturated imines 3 was assessed (Scheme 1). In addition to their
synthetic relevance, triadducts 4 are of potential biological interest as their
tricarboxylic analogs display micromolar activity as agonists of ionotropic glutamate
43
receptors (iGluRs). Anticipated side products were 1,4-1,2-adducts 5 or 1,6-1,2-
adducts 6.
Scheme 1. Envisaged transformation of 3 to 4 based on previous work.
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Results and Discussion
Phosphite addition: results and regioselectivity
The required α,β,γ,δ-diunsaturated imines 3 were prepared from their respective
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lower aldehyde homologues by Wittig reaction, followed by imination (see SI for
details). They were then treated with dimethyl trimethylsilyl phosphite (DMPTMS), a
45-48
reactive phosphite nucleophile,
and sulfuric acid in order to activate the
conjugated system for nucleophilic attack. The benzyl imine of 3a was selected as
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model substrate, as tandem addition to its lower homologue proceeded readily.
Upon application of our previously optimized conditions (2 equiv DMPTMS, 0.5 equiv
8
H SO , 30 minutes at room temperature), the imine 3a was completely consumed
2
4
but only a trace of double addition product was detected (Table 1, entry 1). The major
product was the corresponding α-aminophosphonate, resulting from 1,2-attack
across the imine. Prolonging the reaction time to 24 h resulted in merely 40%
conversion to a double addition product (entry 2). In order to assess whether a triple
tandem addition was feasible and to drive the reaction to completion, a large excess
of DMPTMS was added (entry 3). This resulted in 57% conversion to diastereomeric
double addition compounds. After careful separation, it became clear that two
diastereomers of the tandem 1,4-1,2-addition product 5 had been formed.
Interestingly, no products 4 or 6 resulting from 1,6-phosphite addition were present in
the crude reaction mixture. As reaction at room temperature failed to engender
complete conversion to a double addition product, it was performed at reflux
temperature (entry 4).
Gratifyingly, these conditions resulted in full transformation of the doubly unsaturated
imine to 1,4-1,2-adducts 5 after 8 hours in a good isolated yield (77%). The tandem
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addition is diastereoselective (dr 7/3, according to P-NMR integration) in favor of
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4
the diastereomers which display P- P coupling in P-NMR ( J = ca. 10 Hz). On
PP
account of the flexibility of the linear chain, the relative configuration of the products
could not be determined.
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Table 1. Tandem phosphite addition to α,β,γ,δ-diunsaturated imines.
Tandem
[
a]
2
DMPTMS
(equiv)
H
2
SO
4
Time
(h)
Temp
(°C)
Addition
Ratio
5/6
substrate
entry
R
dr
(equiv)
(isolated
yield, %)
10 (-)
1
2
3
4
5
6
7
8
9
Bn (3a1)
Bn (3a1)
Bn (3a1)
Bn (3a1)
n-Pr (3a2)
n-Pr (3a2)
i-Pr (3a3)
i-Pr (3a3)
t-Bu (3a4)
t-Bu (3a4)
t-Bu (3a4)
Bn (3b1)
Bn (3b1)
Bn (3b1)
n-Pr (3b2)
i-Pr (3b3)
i-Pr (3b3)
i-Pr (3b3)
i-Pr (3b3)
t-Bu (3b4)
i-Pr (3c)
2
2
10
2
2
2
2
2
10
2
5
2
5
5
2
2
5
2
5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
24
24
8
24
7
24
6
24
3
rt
rt
rt
Δ
rt
Δ
rt
Δ
rt
Δ
Δ
rt
rt
Δ
rt
rt
rt
Δ
Δ
rt
rt
1/0
1/0
1/0
1/0
1/0
1/0
1/0
1/0
1/0
1/0
1/0
1/1
1/1
1/1
7/3
6/4
1/1
6/4
1/1
6/4
1/0
-
-
-
40 (-)
57 (-)
100 (77)
60 (-)
100 (71)
65 (-)
100 (82)
92 (-)
100 (73)
100 (-)
100 (75)
100 (69)
100 (-)
100 (50)
100 (43)
100 (40)
100 (-)
100 (-)
100 (60)
78 (-)
7/3
-
7/3
-
7/3
-
10
11
12
13
14
15
16
17
18
19
20
21
1/1
-
3
[b]
16
24
24
5
8
3
3
3
3
24
-
-
[
b]
[b]
-
-
-
[
b]
2
2
-
-
22
i-Pr (3c)
2
0.5
1
Δ
100 (84)
1/0
[
a]
[b]
the remainder is 1,2-addition product. SeeTable 2.
Other derivatives of 3a with various R-groups were prepared and subjected to the
same reaction conditions (entries 5-11). The n-Pr and i-Pr derivatives displayed very
similar behavior: reflux temperature was required to drive the reactions to completion
and good yields were obtained. Again, only tandem 1,4-1,2-adducts were formed and
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the diastereomeric ratios were very similar to those of the Bn-derivative. For the t-Bu
derivative not even a large excess of DMPTMS could drive the reaction to completion
at room temperature (entry 9). Again, at reflux temperature full conversion to the
tandem 1,4-1,2-adduct was attained (entry 10). It is noteworthy that an excess of
phosphite did not result in any 1,6-addition whatsoever, even at reflux temperature
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(entry 11). This implies a certain regioselectivity in case of substrates 3a, possibly
due to the conservation of a conjugated stryrenyl moiety. Any 1,6-addition would
result in disruption of the conjugated system to the phenyl ring, an energetically
unfavorable event. With regard to the diastereoselectivity for the t-Bu derivative an
approximate 1/1 ratio is obtained. This is somewhat different than for the other
derivatives (entries 4, 6, 8), possibly due to the sterically demanding t-Bu substituent.
Imines 3b derived from E,E-hexadienal were also evaluated as substrates. In this
case, the benzyl imine was completely converted into diastereomeric
diphosphonylated compounds at room temperature (entry 12), contrary to the
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cinnamaldehyde derivatives. Interestingly, the crude P-NMR spectrum displayed a
number of novel peaks. Purification followed by careful spectral analysis
demonstrated that the 1,6-1,2-adduct had also been formed in this case. A 1/1 crude
of 1,6-1,2-adduct and 1,4-1,2-adduct was obtained in 75% yield. The 1,4-1,2-adducts
13
were obtained as E/Z isomers, as was apparent from the C-shifts of the vinylic
methyl group (see experimental part for details). Similar to entry 9, augmenting the
nucleophile loading had no influence on the regioselectivity, nor did performing the
reaction at reflux temperature (entries 13-14). It is noteworthy that in the 1,6-1,2-
adducts the double bond has shifted as compared to the starting material (for an
elaborate mechanistic discussion, vide infra). The n-Pr derivative displayed a larger
regioselectivity in favor of the 1,4-1,2-adducts, possibly on account of steric reasons
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(
entry 15). For R = i-Pr the nucleophile loading as well as the reaction temperature
did not seem to influence the outcome of the reaction. There was a small shift
towards more 1,6-1,2-adduct when an excess of nucleophile was employed (entries
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1
6 and 18 vs. 17 and 19). From these results it is apparent that the products derived
from 3b are much more polar than their 3a analogues, as reflected in the isolated
yields.
Table 2 shows the regioselectivities of the phosphite additions as well as the
diastereomeric ratios obtained. Similar to the Bn, n-Pr and i-Pr derivatives in entries
4
, 6 and 8 (Table 1), the dr for the 1,4-1,2-adducts is ca. 7/3, except for more
sterically hindered substrates (i-Pr and t-Bu). With respect to the 1,6-1,2-adducts, the
dr is approximately 1/1 for all derivatives (Table 2). Finally, a diunsaturated imine
derived from (1R)-(−)-myrtenal 3c was subjected to the developed reaction
conditions (Table 1, entries 21-22). Similar to 3a, reflux temperature was required to
obtain full conversion to diphosphonylated compounds. Furthermore, no 1,6-1,2-
adduct was observed, suggesting that aside from conjugation, regioselectivity of
phosphite addition is governed by steric factors at the distal end of the unsaturated
system as well.
Table 2. Diastereomeric ratios for isolated 1,4-1,2- and 1,6-1,-2 adducts of 3b.
Isolated
yield (%)
entry
Ratio 5/6
dr 5
dr 6
12
15
16
20
75
50
43
60
1/1
7/3
6/4
6/4
7/3
7/3
6/4
1/1
1/1
6/4
6/4
1/1
Besides tandem addition the regioselectivity could be steered to 1,2-addition as well,
49
furnishing the classical Kabachnik-Fields products. For most derivatives it was
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sufficient to simply lower the amount of DMPTMS to one equivalent and perform the
reaction at room temperature (Table 3, entry 1), as compared to the conditions that
result in tandem addition. For other derivatives, one equivalent of DMPTMS was
inadequate to result in full conversion (entry 2-3). Upon augmenting the amount of
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DMPTMS, more H SO was required in order to prevent any tandem addition (entry
2
4
4
, mechanistic discussion vide infra). However, as DMPTMS is labile in the presence
of large amounts of H SO , a larger excess of nucleophile was a prerequisite to
2
4
obtain full conversion (entry 5). In this manner, all substrates were converted into the
corresponding 1,2-adducts in moderate to excellent isolated yields (Table 3). As
such, by adjusting the loading of both the nucleophile and acid, the regioselectivity of
the phosphite addition can easily by governed.
Table 3. 1,2-addition of DMPTMS to dinusaturated imines.
Conversion Isolated
2
DMPTMS
H SO
2 4
(equiv)
substrate
entry
R
time
to 7
(%)
100
53
Yield
(
equiv)
(%)
82
-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Bn (7a1)
n-Pr (7a2)
n-Pr (7a2)
n-Pr (7a2)
n-Pr (7a2)
i-Pr (7a3)
i-Pr (7a3)
t-Bu (7a4)
t-Bu (7a4)
t-Bu (7a4)
Bn (7b1)
n-Pr (7b2)
n-Pr (7b2)
i-Pr (7b3)
i-Pr (7b3)
t-Bu (7b4)
t-Bu (7b4)
i-Pr (7c)
1
1
1
2
5
1
5
1
5
5
1
1
1
1
1
1
5
1
0.5
0.5
0.5
2
2
0.5
2
0.5
2
2
0.5
0.5
0.5
0.5
0.5
0.5
2
5 min
1.5 h
24 h
24 h
15 min
24 h
15 min
48 h
3 h
63
-
90
-
100
47
83
-
100
63
97
-
95
-
6 h
95
100
80
86
87
-
5 min
5 min
30 min
30 min
3 h
48 h
1 h
24 h
100
57
71
-
15
16
17
18
100
85
68
-
87
43
0.5
80
-
19
i-Pr (7c)
5
2
15 min
100
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Mechanistic considerations
In our previous communications on tandem 1,4-1,2-phosphite additions some
8, 40-42
tentative mechanisms were proposed.
Nonetheless, this particular work has
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resulted in several new mechanistic insights and the current hypotheses are
presented herein (Scheme 2). Without any acid present no phosphite addition to the
unsaturated system takes place, and this is clearly visible, since upon addition of
H SO to the reaction medium may even start to boil. Once imine A is suitably
2
4
activated (species B) phosphite addition can take place and result in initial 1,6, 1,4 or
1
,2-addition. Careful follow-up of the reaction revealed that 1,2-addition initially
8
proceeds (B to C), but it can be reversible depending on the amount of acid present.
+
When a stoichiometric amount of H is present in the reaction medium (0.5 equiv
H SO ), the secondary amine in C will not be protonated (C to E does not take place)
2
4
and 1,2-addition is reversible. However, C might undergo intramolecular TMS-
8
transfer to D. This TMS-shift is reversible as well and as a consequence, C can
8
again be formed.
Subsequently, this unstable intermediate will either revert to iminium B due to
expulsion of phosphite, or it will undergo S ' yielding species G or I when excess
N
phosphite is present. In the former case, iminium B will then undergo 1,6- or 1,4-
addition, which are probably irreversible. In case of 1,4-addition to B, compound I will
then equilibrate to iminium K, which will eventually undergo 1,2-addition. In case of
1
,6-addition, compound G will be protonated in the α-position before undergoing 1,2-
addition, overall resulting in a shift of the double bond. As such, no 1,4-addition can
ensue. These pathways account for the observed tandem 1,6-1,2- or 1,4-1,2-
+
phosphite addition products (Table 1). In case an excess of H is present in the
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reaction medium (> 0.5 equiv H SO , generally 2 equiv, cfr. Table 3) the initial 1,2-
2
4
addition will be rendered irreversible. Compound C will immediately be protonated
due to an excess of H SO giving rise to compound E. This would result in a doubly
2
4
0
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9
0
positively charged species which is highly unlikely. Therefore, protonation and
desilylation may take place simultaneously, assisted by one (as depicted) or more
5
2
molecule(s) of R SO , yielding species D. After aqueous work-up the 1,2-addition
4
adduct is isolated. It must be noted that 1,2-adducts may also be isolated after
reaction using 1 equiv of DMPTMS and 0.5 equiv H SO , corroborating that 1,2-
2
4
addition is kinetically favored.
Scheme 2. Proposed mechanism for tandem and mono-phosphite additions.
In summary, it is in the first place the amount of DMPTMS and H SO that will dictate
2
4
the regioselectivity of the phosphite addition. However, the intrinsic reactivity of the
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substrate will also differentiate between 1,6- or 1,4-addition. Temperature or reaction
time do not seem to exert any effect onto the regioselectivity.
Theoretical rationalization
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A computational study was performed to understand the reactivities of mono- and
diunsaturated imines towards Michael-type additions of silylated phosphites. DFT
50
calculations utilizing the M06-2X/6-31+G(d,p) level of theory implemented in the
51
G09 program package
have elucidated the underlying rationale for the
experimentally observed regioselectivity.
Reaction mechanisms have been explored in an effort to rationalize the ease of
addition of the phosphite nucleophile, P(OTMS)(OMe) , across α,β-unsaturated
2
imines 1 and α,β,γ,δ-diunsaturated imines 3 (Scheme 1). Energetics for the first
phosphite addition step are illustrated in Table 4. The difference in free energy
barriers for the 1,2-, 1,4- and 1,6- phosphite additions to iminium ions of mono-
unsaturated systems 1a, 1b and di-unsaturated systems 3a and 3b are shown. The
‡
1,2-addition is clearly the most feasible (lowest free energy of activation, ΔG )
reaction for all four systems, revealing the 1,2-adduct as the kinetic product.
However, it is also the most reversible type of addition (lowest barrier for reverse
reaction, 20-30 kJ/mol for all systems), as inferred from the relative stabilities of the
respective adducts.
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‡
Table 4. Activation (ΔG ) and reaction (ΔG ) free energies (M06-2X/6-31+G(d,p),
rxn
2
98 K, 1 atm, in kJ/mol) for initial 1,2-, 1,4- and 1,6- phosphite addition to iminium
[
a,b]
ions of mono- and di-unsaturated imines 1 and 3.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
2
3
4
5
6
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9
0
1
ΔG
,2-addition
1,4-addition
1,6-addition
1
‡
‡
‡
‡
n
0
0
1
1
R
ΔGrxn
ΔG
ΔG
ΔG
ΔGrxn
rxn
1a
1b
3a
3b
Ph
Me
Ph
Me
23.0
12.2 -21.6
33.1 10.6
28.5
0.8
23.8 -37.9
15.7 -51.2
40.8 -13.5
30.1 -27.2
42.8 -30.2
32.3 -49.2
1.6
[
a]
Barriers and reaction energies calculated from separate reactants, namely the
[b]
corresponding iminium ion and the silylated phosphite, P(OTMS)(OMe)2.
The
identity of the N-substituent was shown to have minimal effect on the relative
energetics, with similar energetics for N-t-Bu, N-Bn and N-i-Pr.
Nevertheless, the highly exergonic 1,4- and 1,6-additions are also likely since they
require only slightly higher activation energies than the 1,2-addition for the
corresponding system, but lead to remarkably more stable adducts with higher
reverse reaction barriers (in the order of ~60 and ~80 kJ/mol for the 1,4- and 1,6-
additions, respectively). For the initial phosphite addition step (Table 4), the 1,4-
adduct is clearly the thermodynamic product for systems 1. For systems 3, while the
relative stabilities of 1,4- and 1,6-adducts favor the latter due to the disruption of
conjugation ensued by 1,4-addition, their respective activation energies are quite
close. Hence, both adducts are expected to form although the 1,6-adduct is the
thermodynamic product. The final product, however, will be the most stable tandem
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1
diadduct.For mono-unsaturated system 1a (R = Ph), a slightly larger activation
1
‡
energy compared to 1b (R = Me) is observed for both 1,2- and 1,4-addition (ΔG =
23.0 and 23.8 kJ/mol, respectively). This is understandably due to the additional
conjugation brought to the system by the phenyl ring; hence, disrupting it costs more
energy. Similarly, for diunsaturated system 3a, which comprises extended
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1
conjugation with the phenyl group (R ), 1,4- and 1,6-additions disrupting the
conjugation have ~10 kJ/mol higher barriers than 3b. Figure 1 depicts transitions
state structures 1,2- 1,4- and 1,6-phosphite additions to iminium ion of 3a.
1
,2-addition TS
1,4- addition TS
1,6-addition TS
Figure 1. M06-2X/6-31+G(d,p) optimized geometries for the transition state
structures of 1,2- 1,4- and 1,6- phosphite addition to iminium ion of 3a. Critical
distances in Å.
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53-54
Natural Population Analysis (NPA) and Iterative Hirshfeld (HI)
atomic charges
depict a clear difference between the neutral imines and their ‘activated’ iminium
counterparts (Table 5). The iminium ions of 1 and 3 (Table 5) show a higher positive
charge on carbon C2 with both population schemes, indicating higher reactivity
compared to C4 and C6 (for 3).
0
1
2
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5
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7
8
9
0
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2
3
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0
Table 5. Natural Population Analysis (NPA), Iterative Hirshfeld (HI) atomic charges
and π-orbital LUMO coefficients (M06-2X/6-31+G(d,p)) for mono- and di-unsaturated
imines 1 and 3 and their iminium ions.
NPA charges
HI charges
LUMO coefficients
C2 C4 C6
C2
C4
-
.198
C6
-
C2
C4
-
0.102
C6
-
1a
0.057
0.062
0.053
0.057
0.207
0.153 0.264
0.242 0.336
0
0
0
0
-
1b
0.215 0.022
.188
-
.221 0.202
-
-
3a
0.203
0.127 0.200 0.261
0.182 0.277 0.291
0.061 0.128
-
-
3b
0.208
0.004
0.049
.215 0.191
NPA charges
HI charges
LUMO coefficients
C2
C4
-
.034
C6
-
C2
C4
C6
C2
C4
C6
1a
1b
3a
3b
0.193
0.214
0.177
0.191
0.308 0.102
0.321 0.199
0.322 0.348
0.392 0.366
0
0
0
0
-
.019
-
.075 0.060
-
0.298 0.123 0.060
0.306 0.134 0.155
0.289 0.314 0.292
0.332 0.343 0.283
-
.063 0.049
This is consistent with the lower barrier of formation for the 1,2-adduct indicated
earlier (Table 4). Nonetheless, note that all carbons are more positive compared to
their imine counterparts. For systems 3, charges on C4 and C6 are comparable,
which also correlates well with the barriers calculated for attack on these carbons.
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Meanwhile, π-orbital LUMO coefficients (Table 5) depict no difference among C2, C4
and C6, indicating the reaction is electrostatically-driven rather than orbital-controlled.
There are several possible fates for the mono-addition products of 1 and 3, as
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indicated in Scheme 2: a) a TMS shift from oxygen to the neighboring nitrogen could
occur for 1,2- (C to D) and 1,4-adducts (I to J), b) an intramolecular S ' reaction
N
could take place in the case of the 1,2-adduct (Scheme 2, C to I), c) a second
phosphite attack could occur for the 1,4- and 1,6-mono-adducts, leading to the
tandem addition products experimentally observed (Table 1). The energetic
feasibilities of all aforementioned reactions were computationally explored in order to
rationalize the experimental findings.
The O-TMS to N-TMS shift was modeled for both 1,2- and 1,4-adducts of 1 and 3
(Table 6). This shift is shown to be both kinetically and thermodynamically
unfavorable in all four systems Silicon’s propensity for oxygen is well-known as
55
evidenced in the high bond dissociation energies (BDE) previously reported
indicating high bond strength, hence this result is expected.
‡
Table 6. Activation (ΔG ) and reaction (ΔG ) free energies (M06-2X/6-31+G(d,p),
rxn
2
98 K, 1 atm, in kJ/mol) for TMS shift from oxygen to nitrogen in 1,2- and 1,4-adducts
[
a]
of mono- and di-unsaturated imines 1 and 3.
TMS-Shift for 1,2-
TMS-Shift for 1,4-
Adduct
Adduct
‡
‡
ΔG
ΔGrxn
68.8
69.0
58.7
58.5
ΔG
ΔGrxn
51.7
52.6
63.4
61.2
1a
1b
104.4
103.7
98.5
186.4
187.9
181.9
181.3
3
3
a
b
99.1
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[
a]O-TMS monoadducts are taken as reference.
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S '-TS (1,2 to 1,6)
S '-TS (1,2 to 1,4)
N
N
Figure 2. Transition state structures for the conversion of 1,2-adduct to 1,4- and 1,6-
adducts via an S ' pathway for 3a (PM3, critical distances in Å).
N
All efforts to locate the S ' transition states for the concerted conversion of 1,2-
N
adducts to 1,4- and 1,6-adducts failed at the DFT (M06-2X and B3LYP) level of
theory. However, S ' transition state geometries converting the 1,2- to a 1,4-adduct
N
(
C to I, Scheme 2) as well as the 1,2- to a 1,6-adduct (C to G) were located at the
semi-empirical level of theory (PM3, Figure 2). Thus, their existence cannot be fully
refuted. The final fate of the mono-addition products is the nucleophilic attack of a
second phosphite nucleophile, leading to a tandem addition product, as observed
experimentally (Table 1) for systems 3.
Table 7 depicts activation and reaction free energies for 1,2-phosphite attack on 1,4-
as well as 1,6-adducts. Transition state geometries for 3a are shown in Figure 3.
When compared to activation barriers for the initial step (Table 4) the second addition
step is clearly not rate determining. Hence, the product distributions will most likely
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be dictated by thermodynamic stability of the final tandem adducts rather than the
intermediates and thermodynamic equilibration will prevail. Relative product stabilities
(Table 8), depict a significant difference favoring the 1,2-1,4-adduct in the case of 3a,
consistent with experimental results. Similarly, the product stabilities are in line with
observations for 3b, which gave a 50/50 product distribution for both tandem addition
products.
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Table 7. Relative free energies (M06-2X/6-31+G(d,p), 298 K, 1atm, in kJ/mol) of the
transition states for the second phosphite attack in the formation of 1,4-1,2 and 1,6-
1
,2 tandem adducts of di-unsaturated imines 3.
ΔΔG‡ — 1,4 addition
ΔΔG‡ — 1,6 addition
3
3
a
b
0.0
0.0
31.6
40.6
TS1,4 addition
TS1,6 addition
Figure 3. Transition state structures for the second phosphite attack in the formation
of 1,4-1,2 and 1,6-1,2 tandem adducts of diunsaturated imine 3a (M06-2X/6-
31+G(d,p), critical distances in Å).
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Table 8. Relative product free energies for the tandem 1,2-1,4- and 1,2-1,6-addition
of P(OTMS)(OMe) to mono- and diunsaturated imines 1 and 3. (M06-2X/6-
2
31+G(d,p), 298 K, 1 atm, in kJ/mol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
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1
2
3
4
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8
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0
1
2
3
4
5
6
7
8
9
0
4
5
3a
3b
0.0
0.0
16.7
4.6
The combination of these experimental and theoretical results has shed new light on
the precise mechanism of tandem phosphite additions (Scheme 2). After acidic
activation of the linear unsaturated system, phosphite addition takes place in a 1,2-,
1
,4- or 1,6-fashion. The resulting phosphonium ion either readily collapses with
concomitant loss of the TMS-moiety, or it is expelled, after which a second phosphite
attack takes place. Calculations have demonstrated that an intramolecular O-to-N
TMS-shift is not feasible (C to D).In contrast, it was shown earlier that N-to-O TMS-
8
shift does take place. However, intermolecular TMS-shift is possible (C-E-D, I-J and
B-G), assisted by one or more molecules of sulfuric acid, or a TMS-derivative thereof.
In addition, calculations have shown that S ' is somewhat less likely to occur, but it
N
cannot fully be ruled out (C to I). As such, the mechanism depicted in Scheme 2 is
the most plausible stream of events in tandem phosphite additions to acyclic
unsaturated systems, taken into account the results of the computational analysis.
Conclusion
This work has expanded the scope of tandem phosphite additions to α,β,γ,δ-
diunsaturated imines. To the best of our knowledge, a 1,6-conjugate addition of a
phosphite nucleophile has been reported for the first time. Selective mono-1,2-
addition could also be obtained by controlling the stoichiometry of the reagents. The
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observed regioselectivities were dictated by both electronic and steric properties of
the substrates and were supported by theoretical calculations. These findings
suggest that the regioselectivity of the phosphite additions is rather electrostatically-
driven than orbital-controlled. In addition, with the aid of calculations the most
comprehensive mechanism up to date has been presented here, allowing to rule out
previous hypotheses.
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Experimental Section
Commercially available products were used as received without any purification
unless otherwise noted. Dry diethyl ether (Et O), tetrahydrofuran (THF) and toluene
2
were freshly distilled from sodium/benzophenone ketyl. Dry dichloromethane
(
CH Cl ) was freshly distilled over calcium hydride (CaH ). Column chromatography
2
2
2
was performed in a glass column with silica gel (particle size 70−200 μm, pore
diameter 60 Å) using mixtures of ethyl acetate (EtOAc) and hexanes. Visualisation
was performed on TLC-plates using UV irradiation and oxidation by a KMnO solution
4
or elemental iodine. NMR spectra were recorded on a 400 MHz spectrometer at room
1
13
31
temperature at 400 MHz ( H), 100 MHz ( C) and 162 MHz ( P) in CDCl unless
3
31
otherwise noted, with tetramethylsilane (TMS) as internal standard. P-spectra were
externally referenced to 85% H PO . All chemical shifts are expressed as parts per
3
4
million (ppm). HPLC and HPLC-MS analyses were performed on an liquid
chromatograph using a reversed phase column (C18 column, 50 x 4.6 mm, particle
size 3.5 μm, or C18 column, 30 x 4.6 mm, particle size 2.7 μm) connected to a UV-
VIS detector and a mass spectrometer (ESI, 70 eV) using a mass selective single
quadrupole detector. A mixture of 5 mM NH OAc in H O and CH CN was used as
4
2
3
eluent. Preparative HPLC was performed using a reversed phase column (C18
column, 150 x 21.2 mm, particle size 5 μm) that was thermostatized at 25 °C. The
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column is connected to a UV-VIS Variable Wavelength Detector (VWD). A mixture of
H O and CH CN is used as eluent, with TFA or diethylamine as additives if needed.
2
3
Low-resolution mass spectra were obtained with an LC/MSD type SL mass
spectrometer (ESI, 70 eV) using a mass selective single quadrupole detector. High-
resolution mass spectra were obtained with a Time-Of-Flight (TOF) mass
spectrometer (ESI or APCI).
0
1
2
3
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9
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2
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7
8
9
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1
2
3
4
5
6
7
8
9
0
44
Synthesis of α,β,γ,δ-diunsaturated aldehydes S1
In a flame-dried round-bottom flask equipped with a stirring bar a suitable α,β-
unsaturated aldehyde was dissolved in dry THF under an inert atmosphere. Next,
(1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (1.5 equiv) and LiOMe (2.2
equiv) were added and the reaction mixture was heated to reflux temperature for 16
h. A solution of 2 M HCl with a volume equal to the reaction solvent was then added
to the reaction mixture at room temperature and was left to stir for 1 hour. Afterwards
the THF was evaporated in vacuo until only the aqueous phase remained. Ethyl
acetate was added and the mixture was extracted 3x using ethyl acetate. The
combined organic layers were washed once using NaHCO , dried over MgSO ,
3
4
44
filtered and concentrated in vacuo. The crude product was then triturated using a
9
/1 mixture of hexanes/EtOAc and filtered: the desired α,β,γ,δ,-diunsaturated
aldehyde S1 was present in the filtrate while the residue consisted of
triphenylphosphine oxide. The filtrate was concentrated in vacuo and purified using
column chromatography.
44
(2E,4E)-5-phenylpenta-2,4-dienal S1a
Cinnamaldehyde (2.04 g, 15.4 mmol) was transformed into S1a. After column
chromatography, 2.15 g was obtained (13.6 mmol, 88% yield, yellow solid). Spectral
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data are in accordance with reported values. R = 0.25. (hexanes/EtOAc 95/5). H-
f
NMR (400 MHz, CDCl )  6.28 (1H, dd, J = 15.1 Hz, J = 7.9 Hz), 7.00-7.03 (2H, m),
3
7
.24-7.31 (1H, m), 7.33-7.41 (3H, m), 7.49-7.53 (2H, m), 9.63 (1H, d, J = 7.9 Hz).
E)-3-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acrylaldehyde S1c
1R)-(−)-Myrtenal (1.74 g, 11.6 mmol) was transformed into S1c. After column
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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5
6
0
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7
8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
chromatography, 1.23 g was obtained as an E/Z mixture in a 93/7 ratio (6.97 mmol,
6
0% yield, yellow oil). Spectral data are given for the major isomer. R = 0.34
f
1
(hexanes/EtOAc 95/5). H-NMR (400 MHz, CDCl )  0.78 (3H, s), 1.16 (1H, d, J = 9.0
3
Hz), 1.35 (3H, s), 2.15-2.20 (1H, m), 2.46-2.53 (3H, m), 2.57 (1H, m), 6.06 (1H, dd, J
=
7
1
15.6 Hz, J = 7.8 Hz), 6.17-6.20 (1H, m), 7.10 (1H, d, J = 15.6 Hz), 9.58 (1H, d, J =
13
.8 Hz). C-NMR (100 MHz, CDCl )  20.8, 26.0, 31.1, 33.0, 37.8, 40.5, 41.4, 125.6,
3
-1
36.9, 146.3, 153.2, 194.3. IR (ATR, cm ) νmax: 1121, 1609, 1678, 2921. MS (ESI,
+
pos): m/z (%) 177.1/178.1 (M+H , 100/12).
Synthesis of dimethyl trimethylsilyl phosphite (DMPTMS)
In a flame-dried round-bottom flask equipped with a magnetic stirring bar dimethyl
phosphite (DMP) was dissolved in dry dichloromethane (0.2M) under a N2-
atmosphere. Next the flask was cooled to 0 °C using an ice bath before Et N (1.2
3
equiv) was added. Then TMSCl (1.1 equiv) was added in a dropwise fashion and the
reaction mixture was kept at 0 °C for 30 minutes. Afterwards the resulting suspension
was filtered using an oven-dried filter and flame-dried glassware (which was allowed
to cool in a dessicator prior to use). The residue was washed using dry diethyl ether
and the filtrate was concentrated in vacuo. The resulting suspension was again
filtered using an oven-dried filter and flame-dried glassware and was washed using
dry diethyl ether. The filtrate was concentrated in vacuo. This filtration/concentration
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2
2
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2
2
2
2
3
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3
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4
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5
5
5
5
5
5
5
5
5
5
6
procedure was repeated until no more salt was visibly present (typically 3x) and a
clear colorless solution was obtained, typically in 75% yield. The resulting DMPTMS
was stored in a flame-dried flask under a N -atmosphere in the freezer at -18 °C and
2
0
1
2
3
4
5
6
7
8
9
0
1
2
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
could be kept as such without significant hydrolysis for several months. Prior to use,
1
31
the exact concentration was determined using H- and P-NMR spectroscopy
1
3
(
relevant signals: DMPTMS: H-NMR (400 MHz, CDCl )  3.40 (6H, d, J = 10.4
3
HP
31
1
Hz) and P-NMR (162 MHz, CDCl )  128.1. DMP: H-NMR (400 MHz, CDCl ) 
3
3
3
31
3
.72 (6H, d, J = 11.9 Hz) and P-NMR (162 MHz, CDCl )  10.4.)
HP
3
Synthesis of α,β,γ,δ-diunsaturated imines 3
In a round-bottom flask equipped with a magnetic stirring bar, a diunsaturated
aldehyde was dissolved in dichloromethane (0.2 M). Then 2 equivalents of MgSO4
and 1 equivalent of a suitable amine were added to the flask. The mixture was
1
heated to reflux temperature and the reaction progress was monitored using H-NMR
spectroscopy. After consumption of all starting material, the MgSO was filtered off
4
and washed three times using dichloromethane. The filtrate was concentrated in
1
vacuo and the resulting crude was used as such in the next step if, according to H-
NMR spectroscopy ,no hydrolysis had taken place during work-up.
Synthesis of phosphonylated α-aminophosphonates 5 and 6
In a flame-dried round-bottom flask equipped with a magnetic stirring bar α,β,γ,δ-
diunsaturated imines 3 were dissolved in dry dichloromethane under a N2-
atmosphere. Next, an appropriate amount of DMPTMS was added using a syringe
and the reaction mixture was heated to reflux temperature. H SO was then added
2
4
via a syringe in a dropwise fashion. The reaction progress was monitored using
HPLC-MS and after complete consumption of the starting material, the reaction
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mixture was poured into 10 mL of a 2 M HCl-solution. Diethyl ether was added and
the mixture was extracted thrice using diethyl ether. The resulting aqueous layer was
then rendered alkaline to a pH of 14 using a 2 M NaOH solution. Next, the alkaline
aqueous phase was extracted thrice using ethyl acetate (3x 10 mL). The combined
10
11
12
13
14
15
16
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26
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28
29
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34
35
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl acetate fractions were dried over MgSO , filtered and concentrated in vacuo,
4
yielding the crude desired phosphonylated α-aminophosphonates. The regio- and
diastereomers were separated using HPLC in order to obtain analytically pure
samples.
3
28 mg (1.33 mmol) of 3a1 was converted into 5a1 and using 2 equiv of DMPTMS
and 0.5 equiv of H SO at reflux temperature. After work-up, 478 mg of crude product
2
4
was obtained as diastereomers in a 3/7 ratio (1.02 mmol, 77% yield, yellow oil). The
,4-1,2-adducts were separated using preparative HPLC (reversed-phase C18-
1
column, water/acetonitrile eluent). Two fractions were isolated for characterization.
tetramethyl (1-(benzylamino)-5-phenylpent-4-ene-1,3-diyl)(E)-bis(phosphonate)
5
a1 (diastereomer 1)
1
H-NMR (400 MHz, CDCl ) 1.89-2.05 (1H, m), 2.29-2.41 (1H, m), 3.12 (1H, ddd,
3
2
2
JHP = 13.7 Hz, J = 6.9 Hz, J = 6.9 Hz), 3.22 (1H, dddd, J = 21.9 Hz, J = 9.4 Hz, J
HP
3
3
=
9.4 Hz, J = 5.1 Hz), 3.73 (3H, d, JHP = 10.6 Hz), 3.74 (3H, d, J = 10.7 Hz), 3.76
HP
3
3
(
3H, d, J = 10.5 Hz), 3.81 (3H, d, J = 10.4 Hz), 3.88 (2H, br s), 6.04 (1H, ddd, J
HP HP
3
4
= 15.8 Hz, J = 9.3 Hz, JHP = 6.4 Hz), 6.53 (1H, dd, J = 15.8 Hz, J = 5.0 Hz), 7.16-
HP
13
2
2
7
.32 (10H, m). C-NMR (100 MHz, CDCl )  29.8 (dd, J = 3.9 Hz, J = 3.9 Hz),
3
CP
CP
1
3
1
3
38.5 (dd, J = 138.7 Hz, J = 6.6 Hz), 51.4 (dd, J = 149.0 Hz, J = 13.3 Hz),
CP
CP
CP
CP
3
2
2
2
5
7
1.7 (d, J = 7.2 Hz), 52.8 (d, J = 7.2 Hz), 53.2 (d, J = 7.1 Hz), 53.4 (d, J
=
CP
CP
CP
CP
2
.2 Hz), 123.8 (d, J = 10.7 Hz), 126.41, 126.42, 127.1, 127.8, 128.35 (2x CHar),
CP
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2
2
2
3
3
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3
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3
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4
4
4
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5
5
5
5
5
5
5
5
5
6
3
4
1
28.39 (2x CH ), 128.6 (2x CH ), 134.6 (d, J = 13.8 Hz), 136.5 (d, J = 3.5 Hz),
ar
ar
CP
CP
31
-1
1
39.5. P-NMR (162 MHz, CDCl )  29.91, 30.47. IR (ATR, cm ) νmax: 1024, 1223,
3
-
1
452, 3395. MS (ESI, pos): m/z (%) 358.3/359.3 (M-[P(O)(OMe) ] , 60/10),
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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0
1
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2
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8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
4
68.3/469.3 (M+H , 100/20). HRMS: m/z calcd for C H NO P +H 468.1699, found
22 31 6 2
468.1711.
tetramethyl (1-(benzylamino)-5-phenylpent-4-ene-1,3-diyl)(E)-bis(phosphonate)
5
a1 (diastereomer 2)
1
2
H-NMR (400 MHz, CDCl ) 1.88 (1H, br s), 1.94-2.10 (2H, m), 2.91 (1H, ddd, J
=
HP
3
2
1
1.5 Hz, J = 11.5 Hz, J = 3.2 Hz), 3.24 (dddd, J = 20.8 Hz, J = 10.4 Hz, J = 10.4
HP
3
3
Hz, J = 3.0 Hz), 3.74 (3H, d, JHP = 10.5 Hz), 3.75 (3H, d, J = 10.6 Hz), 3.77 (1H,
HP
4
3
3
dd, J = 13.1 Hz, J = 1.3 Hz) 3.78 (3H, d, J = 10.4 Hz), 3.79 (3H, d, J = 10.4
HP
HP
HP
4
Hz), 4.05 (1H, dd, J = 13.1 Hz, JHP = 1.4 Hz), 5.91 (1H, ddd, J = 15.8 Hz, J = 9.8 Hz,
3
4
13
JHP = 6.2 Hz), 6.2 (1H, dd, J = 15.8 Hz, J = 4.8 Hz), 7.20-7.36 (10H, m). C-NMR
HP
2
2
1
(
100 MHz, CDCl )  29.7 (dd, J = 8.0 Hz, J = 2.7 Hz), 37.7 (dd, J = 140.5 Hz,
3
CP
CP
CP
3
1
3
2
JCP = 14.7 Hz), 50.6 (dd, J = 141.6 Hz, J = 16.6 Hz), 51.9, 52.6 (d, J = 7.3
CP
CP
CP
2
2
2
Hz), 52.8 (d, J = 7.3 Hz), 53.3 (d, J = 7.1 Hz), 122.9 (d, J = 10.2 Hz), 126.40,
CP
CP
CP
3
4
1
3
=
3
26.42, 127.3, 127.8, 128.4, 128.5, 128.6, 135.5 (d, JCP = 14.1 Hz), 136.4 (d, J
=
CP
4
31
4
.5 Hz), 140.1. P-NMR (162 MHz, CDCl )  30.92 (d, J = 10.2 Hz), 31.50 (d, J
3
PP
PP
-1
10.2 Hz). IR (ATR, cm ) νmax: 1024, 1223, 1641, 3394. MS (ESI, pos): m/z (%)
-
+
58.3/359.3 (M-[P(O)(OMe) ] , 90/20), 468.3/469.3 (M+H , 100/20). HRMS: m/z calcd
2
+
for C H NO P +H 468.1699, found 468.1726.
22
31
6 2
2
0
33 mg (1.17 mmol) of 3a2 was converted into 5a2 using 2 equiv of DMPTMS and
.5 equiv of H SO at reflux temperature. After work-up, 347 mg of crude product
2
4
was obtained as diastereomers in a 3/7 ratio (0.83 mmol, 71% yield, yellow oil). The
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,4-1,2-adducts were separated using preparative HPLC (reversed-phase C18-
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
column, water/acetonitrile eluent). Two fractions were isolated for characterization.
tetramethyl (5-phenyl-1-(propylamino)pent-4-ene-1,3-diyl)(E)-bis(phosphonate)
0
1
2
3
4
5
6
7
8
9
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1
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3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
a2 (diastereomer 1)
1
H-NMR (400 MHz, CDCl ) 0.87 (3H, t, J = 7.3 Hz), 1.12 (1H, br ), 1.42 (2H, sextet,
3
J = 7.3 Hz), 1.85-2.01 (1H, m), 2.25-2.39 (1H, m), 2.64 (2H, t, J = 7.3 Hz), 3.07 (1H,
2
2
ddd, J = 13.2 Hz, J = 6.9 Hz, J = 6.9 Hz), 3.24 (dddd, J = 21.9 Hz, J = 9.4 Hz, J
HP
HP
3
3
=
9.4 Hz, J = 5.2 Hz), 3.75 (3H, d, JHP = 10.6 Hz), 3.76 (3H, d, J = 10.7 Hz), 3.78
HP
3
3
(
3H, d, J = 10.6 Hz), 3.81 (3H, d, J = 10.4 Hz), 6.11 (1H, ddd, J = 15.9 Hz, J =
HP HP
3
4
9
.5 Hz, J = 6.4 Hz), 6.60 (1H, dd, J = 15.9 Hz, J = 5.0 Hz), 7.25 (1H, dd, J = 7.4
HP HP
13
Hz, J = 7.4 Hz), 7.32 (2H, dd, J = 7.4 Hz, J = 7.4 Hz), 7.38 (2H, d, J = 7.4 Hz). C-
2
2
NMR (100 MHz, CDCl )  11.6, 23.4, 29.8 (dd, J = 4.3 Hz, J = 4.3 Hz), 38.5
3
CP
CP
1
3
3
1
(
dd, J = 138.6 Hz, J = 6.9 Hz), 49.9 (d, J = 7.2 Hz), 52.5 (dd, J = 149.8
CP CP CP CP
3
2
2
2
Hz, J = 12.0 Hz), 52.6 (d, J = 7.3 Hz), 52.8 (d, J = 7.2 Hz), 53.2 (d, J =
CP
CP
CP
CP
2
2
7
.2 Hz), 53.4 (d, J = 7.0 Hz), 123.9 (d, J = 10.7 Hz), 126.35, 126.37, 127.8,
CP CP
3
4
-1
128.6 (2x CH ), 134.5 (d, J = 13.9 Hz), 136.6 (d, J = 3.2 Hz). IR (ATR, cm )
ar
CP
CP
31
νmax: 1016, 1230, 1647, 2955. P-NMR (162 MHz, CDCl )  30.09, 30.53. MS (ESI,
3
-
+
pos): m/z (%) 310.3/311.3 (M-[P(O)(OMe) ] , 100/20), 420.3/421.3 (M+H , 90/20).
2
+
HRMS: m/z calcd for C H NO P +H 420.1699, found 420.1698.
18
31
6 2
tetramethyl (5-phenyl-1-(propylamino)pent-4-ene-1,3-diyl)(E)-bis(phosphonate)
5
a2 (diastereomer 2)
1
H-NMR (400 MHz, CDCl ) 0.94 (3H, t, J = 7.4 Hz), 1.45 (2H, dqd, J = 9.0 Hz, J =
3
7
.4 Hz, J = 7.1 Hz), 1.93-2.10 (2H, m), 2.47 (1H, dtd, J = 11.0 Hz, J = 7.1 Hz, J = 1.3
2
Hz), 2.82-2.90 (2H, m), 3.35 (1H, dddd, JHP = 20.6 Hz, J = 10.6 Hz, J = 10.2 Hz, J =
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6
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.6 Hz), 3.74-3.75 (6H, m), 3.76-3.77 (6H, m), 6.01 (1H, ddd, J = 15.7 Hz, J = 9.8 Hz,
3
4
JHP = 6.1 Hz), 6.56 (1H, dd, J = 15.7 Hz, J = 4.9 Hz), 7.25 (1H, dd, J = 7.4 Hz, J =
HP
13
7.4 Hz), 7.32 (2H, dd, J = 7.4 Hz, J = 7.4 Hz), 7.38 (2H, d, J = 7.4 Hz). C-NMR (100
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
1
MHz, CDCl )  11.8, 23.9, 29.3 (dd, J = 8.7 Hz, J = 1.9 Hz), 37.8 (dd, J
=
CP
3
CP
CP
3
1
3
138.0 Hz, J = 16.8 Hz), 50.1, 51.5 (dd, J = 139.6 Hz, J = 18.3 Hz), 52.59 (d,
CP
CP
CP
2
2
2
2
JCP = 7.5 Hz), 52.60 (d, J = 7.4 Hz), 52.8 (d, J = 7.0 Hz), 53.3 (d, J = 6.8
CP
CP
CP
2
3
Hz), 123.1 (d, J = 10.3 Hz), 126.37, 126.39, 127.9, 128.6 (2x CH ), 135.6 (d, J
CP
CP
ar
4
31
4
=
9
14.0 Hz), 136.5 (d, J = 3.1 Hz). P-NMR (162 MHz, CDCl )  31.22 (d, J
=
PP
CP
3
4
-1
.8 Hz), 31.64 (d, J = 9.8 Hz). ). IR (ATR, cm ) νmax: 1016, 1231, 1449, 2955. MS
PP
-
+
(ESI, pos): m/z (%) 310.3/311.3 (M-[P(O)(OMe) ] , 100/20), 420.3/421.3 (M+H ,
2
+
7
1
0/10). HRMS: m/z calcd for C H NO P +H 420.1699, found 420.1733.
18
31
6 2
23 mg (0.62 mmol) of 3a3 was converted into 5a3 using 2 equiv of DMPTMS and
0.5 equiv of H SO at reflux temperature. After work-up, 214 mg of crude product
2
4
was obtained as diastereomers in a 3/7 ratio (0.51 mmol, 82% yield, yellow oil). The
,4-1,2-adducts were separated using preparative HPLC (reversed-phase C18-
column, water/acetonitrile eluent). Two fractions were isolated for characterization.
1
tetramethyl
(1-(isopropylamino)-5-phenylpent-4-ene-1,3-diyl)(E)-
bis(phosphonate) 5a3 (diastereomer 1)
1
H-NMR (400 MHz, CDCl ) 0.96 (3H, d, J = 6.2 Hz), 1.02 (3H, d, J = 6.2 Hz), 1.80-
3
2
1
1
.97 (1H, m), 2.25-2.38 (1H, m), 3.00 (1H, septet, J = 6.2 Hz), 3.13 (1H, ddd, J
=
HP
2
5.1 Hz, J = 8.5 Hz, J = 5.4 Hz), 3.25 (1H, dddd, J = 22.0 Hz, J = 9.5 Hz, J = 9.5
HP
3
3
Hz, J = 4.7 Hz), 3.75 (3H, d, JHP = 10.7 Hz), 3.76 (3H, d, J = 10.7 Hz), 3.78 (3H,
HP
3
3
d, J = 10.6 Hz), 3.81 (3H, d, JHP = 10.3 Hz), 6.09 (1H, ddd, J = 15.8 Hz, J = 9.5
HP
3
4
Hz, J = 6.4 Hz), 6.60 (1H, dd, J = 15.9 Hz, J = 5.1 Hz), 7.25 (1H, dd, J = 7.8 Hz,
HP
HP
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5
13
J = 7.8 Hz), 7.32 (2H, dd, J = 7.4 Hz, J = 7.4 Hz), 7.38 (2H, d, J = 7.5 Hz). C-NMR
2
2
1
(
100 MHz, CDCl )  22.8, 23.1, 30.3 (dd, J = 4.3 Hz, J = 4.3 Hz), 38.4 (dd, J
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
CP
CP
CP
3
3
1
3
=
1
138.7 Hz, J = 5.3 Hz), 46.4 (d, J = 9.1 Hz), 49.5 (dd, J = 152.2 Hz, J
CP
=
CP
CP
CP
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
3.7 Hz), 52.7 (d, J = 7.3 Hz), 52.8 (d, J = 7.1 Hz), 53.4 (d, J = 7.1 Hz), 53.5
CP
CP
CP
2
2
(d, J = 7.1 Hz), 123.8 (d, JCP = 10.8 Hz), 126.3, 126.4, 127.8, 128.6 (2x CHar),
CP
3
4
31
1
3
3
34.9 (d, J = 13.9 Hz), 136.6 (d, J = 3.1 Hz). P-NMR (162 MHz, CDCl ) 
CP
CP
3
-1
0.16, 30.54. IR (ATR, cm ) νmax: 1016, 1233, 2957, 3458. MS (ESI, pos): m/z (%)
-
+
10.3/311.3 (M-[P(O)(OMe) ] , 100/20), 420.3/421.3 (M+H , 85/20). HRMS: m/z calcd
2
+
for C H NO P +H 420.1699, found 420.1693.
18
31
6 2
tetramethyl
(1-(isopropylamino)-5-phenylpent-4-ene-1,3-diyl)(E)-
bis(phosphonate) 5a3 (diastereomer 2)
1
H-NMR (400 MHz, CDCl ) 0.92 (3H, d, J = 6.0 Hz), 1.04 (3H, d, J = 6.0 Hz), 1.85-
3
2
1.95 (1H, m), 2.05-2.15 (1H, m), 2.94 (1H, ddd, JHP = 11.6 Hz, J = 11.6 Hz, J = 2.5
3
Hz), 3.14 (1H, septet x d, J = 6.1 Hz, JHP = 2.7 Hz), 3.32-3.43 (1H, m), 3.74-3.78
3
(
12H, m), 6.00 (1H, ddd, J = 15.6 Hz, J = 9.9 Hz, JHP = 5.8 Hz), 6.58 (1H, dd, J =
4
15.9 Hz, J = 5.0 Hz), 7.25 (1H, dd, J = 7.1 Hz, J = 7.1 Hz), 7.32 (2H, dd, J = 7.4
HP
13
Hz, J = 7.4 Hz), 7.38 (2H, d, J = 7.4 Hz). C-NMR (100 MHz, CDCl )  22.4, 24.1,
3
2
2
1
3
30.0 (dd, J = 7.6 Hz, J = 2.5 Hz), 37.6 (dd, J = 141.6 Hz, J = 12.3 Hz),
CP
CP
CP
CP
1
3
2
2
4
6.5, 48.7 (dd, J = 143.5 Hz, J = 14.5 Hz), 52.6 (d, J = 7.3 Hz), 52.7 (d, J
CP CP CP CP
2
2
2
=
7.4 Hz), 52.8 (d, J = 7.2 Hz), 53.3 (d, J = 7.0 Hz), 123.2 (d, J = 10.7 Hz),
CP
CP
CP
3
4
126.34, 126.36, 127.8, 128.6 (2x CH ), 135.6 (d, J = 13.4 Hz), 136.5 (d, J = 3.5
ar
CP
CP
31
4
4
Hz). P-NMR (162 MHz, CDCl )  31.22 (d, J = 10.3 Hz), 31.45 (d, J = 10.3
3
PP
PP
-1
Hz). IR (ATR, cm ) νmax: 1016, 1232, 2956, 3458. MS (ESI, pos): m/z (%)
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2
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
+
3
10.3/311.3 (M-[P(O)(OMe) ] , 100/15), 420.3/421.3 (M+H , 60/10). HRMS: m/z calcd
2
+
for C H NO P +H 420.1699, found 420.1693.
18 31
6 2
142 mg (0.67 mmol) of 3a4 was converted into 5a4 using 2 equiv of DMPTMS and
.5 equiv of H SO at reflux temperature. After work-up, 211 mg of crude product
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
2
4
was obtained as diastereomers in a 1/1 ratio (0.49 mmol, 73% yield, yellow oil). The
1,4-1,2-adducts were separated using preparative HPLC (reversed-phase C18-
column, water/acetonitrile eluent). Two fractions were isolated for characterization.
tetramethyl
(1-(tert-butylamino)-5-phenylpent-4-ene-1,3-diyl)(E)-
bis(phosphonate) 5a4 (diastereomer 1)
1
H-NMR (400 MHz, CDCl ) 1.05 (9H), 1.81-1.99 (1H, m), 2.30-2.43 (1H, m), 3.08
3
2
2
(
1H, ddd, J = 17.0 Hz, J = 11.1 Hz, J = 3.2 Hz), 3.31 (1H, dddd, J = 21.7 Hz, J =
HP HP
3
3
12.2 Hz, J = 9.6 Hz, J = 2.6 Hz), 3.74 (3H, d, JHP = 10.6 Hz), 3.77 (6H, d, J = 10.7
HP
3
3
Hz), 3.84 (3H, d, J = 10.2 Hz), 6.09 (1H, ddd, J = 15.9 Hz, J = 9.7 Hz, JHP = 6.5
HP
4
Hz), 6.64 (1H, dd, J = 15.9 Hz, JHP = 4.9 Hz), 7.26 (1H, dd, J = 7.1 Hz, J = 7.1 Hz),
13
7
.33 (2H, dd, J = 7.4 Hz, J = 7.4 Hz), 7.40 (1H, d, J = 7.4 Hz). C-NMR (100 MHz,
2
2
1
CDCl ) 29.6, 33.5 (dd, J = 4.7 Hz, J = 3.8 Hz), 38.9 (d, J = 139.1 Hz), 46.7
3
CP
CP
CP
1
3
3
2
(dd, J = 160.6 Hz, J = 17.5 Hz), 52.0 (d, J = 10.1 Hz), 52.6 (d, J = 7.5
CP
CP
CP
CP
2
2
2
Hz), 52.8 (d, J = 7.3 Hz), 53.4 (d, J = 6.9 Hz), 54.3 (d, J = 7.4 Hz), 123.3 (d,
CP
CP
CP
2
3
JCP = 10.8 Hz), 126.37, 126.39, 127.8, 128.6 (2x CH ), 135.7 (d, J = 14.5 Hz),
ar
CP
4
31
-1
1
36.5 (d, J = 3.5 Hz). P-NMR (162 MHz, CDCl ) 30.10, 30.38. IR (ATR, cm )
CP
3
-
νmax: 1015, 1221, 1450, 2957. MS (ESI, pos): m/z (%) 324.3/325.3 (M-[P(O)(OMe) ] ,
2
+
+
70/10), 434.3/435.3 (M+H , 100/20). HRMS: m/z calcd for C H NO P +H
19
33
6 2
4
34.1856, found 434.1850.
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tetramethyl
(1-(tert-butylamino)-5-phenylpent-4-ene-1,3-diyl)(E)-
bis(phosphonate) 5a4 (diastereomer 2)
1
H-NMR (400 MHz, CDCl ) 1.09 (9H), 1.86 (1H, br s), 1.95-2.06 (1H, m), 2.11-2.22
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
(
1H, m), 3.16-3.23 (1H, m), 3.36 (1H, dddd, JHP = 23.0 Hz, J = 9.3 Hz, J = 9.0 Hz, J
3
3
3
=
=
5
4.0 Hz), 3.75 (3H, d, J = 10.4 Hz), 3.76 (3H, d, J = 10.9 Hz), 3.77 (3H, d, J
HP HP HP
3
3
9.8 Hz), 3.79 (3H, d, J = 10.6 Hz), 6.07 (1H, ddd, J = 15.8 Hz, J = 9.0 Hz, J
=
HP
HP
4
.9 Hz), 6.59 (1H, dd, J = 16.0 Hz, J = 5.4 Hz), 7.25 (1H, dd, J = 7.5 Hz, J = 7.5
HP
13
Hz), 7.32 (2H, dd, J = 7.6 Hz, J = 7.6 Hz), 7.38 (1H, d, J = 7.4 Hz). C-NMR (100
2
2
1
MHz, CDCl ) 30.3, 32.2 (dd, J = 7.3 Hz, J = 3.0 Hz), 37.4 (dd, J = 138.0
3
CP
CP
CP
3
1
3
2
Hz, J = 10.2 Hz), 47.3 (dd, J = 151.4 Hz, J = 14.5 Hz), 51.3, 52.8 (d, J =
CP
CP
CP
CP
2
2
2
7
.5 Hz), 52.9 (d, J = 7.1 Hz), 53.3 (d, J = 6.9 Hz), 53.4 (d, J = 7.5 Hz), 124.1
CP CP CP
2
3
(
d, J = 11.4 Hz), 126.34 , 126.35, 127.8, 128.6 (2x CH ), 134.7 (d, J = 13.3
CP ar CP
4
31
4
Hz), 136.6 (d, J = 3.7 Hz). P-NMR (162 MHz, CDCl ) 30.60 (d, J = 6.5 Hz),
CP
3
PP
4
-1
3
1.09 (d, J = 6.5 Hz). IR (ATR, cm ) νmax: 1014, 1220, 1450, 2956. MS (ESI, pos):
PP
-
+
m/z (%) 324.3/325.3 (M-[P(O)(OMe) ] , 100/20), 434.3/435.3 (M+H , 60/10). HRMS:
2
+
m/z calcd for C H NO P +H 434.1856, found 434.1852.
19
33
6 2
1
55 mg (0.84 mmol) of 3b1 was converted into 5b1 and 6b1 using 2 equiv of
DMPTMS and 0.5 equiv of H SO . After work-up, 255 mg of crude product was
2
4
obtained as diastereomers (0.63 mmol, 75% yield, yellow oil, ratio 5/6 = 1/1). The
,6-1,2-adducts and 1,4-1,2-adducts were separated using preparative HPLC
reversed-phase C18-column, water/acetonitrile eluent). Three fractions were isolated
for characterization.
1
(
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