Access to 1-Phospha-2-azanorbornenes by Phospha-aza-Diels–Alder Reactions

Article abstract of DOI:10.1002/anie.201811673

The unprecedented phospha-aza-Diels–Alder reaction between an activated electron-poor imine and 2H-phospholes yields 1-phospha-2-azanorbornenes in a highly chemoselective and moderately diastereoselective reaction. The intermediate 2H-phospholes, which ac

Full text of DOI:10.1002/anie.201811673

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Accepted Article
Title: 1-Phospha-2-azanorbornenes by Phospha-aza-Diels–Alder
Reaction
Authors: Evamarie Hey-Hawkins, Peter Wonneberger, Nils König,
Fabian B. Kraft, and Menyhárt B. Sárosi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811673
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1-Phospha-2-azanorbornenes by Phospha-aza-Diels–Alder
Reaction
Peter Wonneberger, Nils König, Fabian B. Kraft, Menyhárt B. Sárosi, and Evamarie Hey-Hawkins*[a]
Abstract: The unprecedented phospha-aza-Diels–Alder reaction
between an activated electron-poor imine and 2H-phospholes yields
between 2H-phospholes 2a–e and an electron-poor imine,
namely, N-sulfonyl -imino ester 3, resulting in unprecedented
1-phospha-2-azanorbornenes in
a
highly chemoselective and
1-phospha-2-azanorbornenes. In
a
highly chemo- and
moderately diastereoselective reaction. The intermediate 2H-
phospholes, which act as dienes, are formed in situ from the
corresponding 1H-phospholes. Theoretical calculations confirm that
the phospha-aza-Diels–Alder reaction is of normal electron demand.
The reactive P–N bond in 1-phospha-2-azanorbornenes can be
cleaved by nucleophiles with formation of 2,3-dihydrophospholes.
regioselective reaction, only the diastereomeric 1-phospha-2-
azanorbornenes endo-4a–d and exo-4b–e are formed as
racemic mixtures (Scheme 1, Table 1). Equimolar mixtures of
the corresponding 1H-phospholes 1b–e and 3 in xylene were
heated to 125 or 140 °C. 3,4-Dimethyl-1-mesitylphosphole (1e)
has not been reported up to now and was prepared from 1d and
mesityllithium according to the general procedure published by
Mathey et al. (X-ray structure in Supporting Information).[11] Due
to the bulky mesityl substituent, the sum of bond angles at the P
atom (313.1(3)°) is, as expected, relatively large.[12] For 4a, the
dimer of 2a was used as 2H-phosphole source.
Hetero-Diels–Alder reactions, especially aza-Diels–Alder
reactions, are a powerful and valuable way for obtaining
heterocycles and are often a key step in natural product
synthesis.[1] A large variety of functional groups and unsaturated
nitrogen compounds can be used as dienophiles and/or dienes
in aza-Diels–Alder reactions,[2] of which reactions involving
activated imines as dienophiles are the most important.[2a] In
contrast to their aza analogues, phospha-Diels–Alder-reactions
have been investigated to a much lesser extent.[3] Beside
The first and rate-determining step is the formation of the highly
reactive 2H-phospholes 2 by a [1,5]-sigmatropic shift reaction
(1b–e) or retro Diels–Alder reaction (2a).[8] Once formed, 2a–e
react immediately with dienophile 3. At the temperatures
employed (Table 1), no 2H-phosphole dimers (for 2b–e) or other
intermediates are detectable in the reaction mixture by 31P{1H}
inverse gated decoupling NMR spectroscopy. Time-dependent
NMR investigations of the phospha-aza-Diels–Alder reaction
showed that the exo isomers are the kinetic and the endo
isomers the thermodynamic products (shown for the reaction of
1b and 3 in Figure 1). There is a strong correlation between the
steric bulk of the substituent R in the corresponding 2H-
phospholes 2 and the endo/exo ratio. A bulky substituent leads
to exo-enriched 1-phospha-2-azanorbornenes. Thus, no exo
isomer is observed for 4a, and for 4e no endo isomer was found
in the reaction mixtures. The endo/exo ratios are only slightly
phosphaalkenes,[4]
phosphabutadienes,[5]
various
heterophospholes,[6] and phosphinines,[7] 2H-phospholes are
versatile reactants for [2+4] and [4+2] cycloadditions.[8] However,
combinations of both types of hetero Diels–Alder-reactions are
rare. Bansal et al. described a phospha-aza-Diels–Alder reaction
between a heterophosphole and an ,-unsaturated imine.[9]
Attempted Lewis acid-catalyzed phospha-aza-Diels–Alder
reactions between 2H-phospholes and aldimines by Mathey et al.
failed, but unexpectedly led to -C2-bridged diphospholes.[10]
Herein, we describe the first phospha-aza-Diels–Alder reaction
O
S
O
N
P
P
[2 + 4]
2a-dimer
R: a = H
b = phenyl
O
O
O
S
O
S
O
O
3
c = 2-pyridyl
d = cyano
[1,5]
+
e = mesityl
N
N
P
R
60 °C THF or
125 - 140 °C xylene
R
O
O
R
P
R
P
P
O
O
2a-e
1b-e
endo-4a-d
exo-4b-e
Scheme 1. The in-situ-formed 2H-phospholes 2a–e react with imine 3 in a Diels–Alder reaction to form 1-phospha-2-azanorbornenes endo-4a–d and exo-4b–
e. Only one enantiomer of each diastereomer is shown for clarity.
[a]
M. Sc. Peter Wonneberger, B. Sc. Nils König, B. Sc. Fabian B. Kraft,
Dr. Menyhárt B. Sárosi, Prof. Dr. Evamarie Hey-Hawkins*
Universität Leipzig, Faculty of Chemistry and Mineralogy, Institute of
Inorganic Chemistry, Johannisallee 29, 04103 Leipzig (Germany)
[*] Corresponding Author, E-mail: hey@uni-leipzig.de
Supporting information and detailed crystal structure information for
this article is given via a link at the end of the document.
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influenced by the reaction temperature (see Supporting
Information). The reactivity of the phospholes decreases in the
order 2a > 1 c > 1d > 1b > 1e and reflects the dependence of
the [1,5]-sigmatropic shift reactions on the substituent at
phosphorus.[8a] The Diels–Alder reaction is fully reversible.
Heating the pure diastereomers endo-4b,c and exo-4b in xylene
for 24 h results in formation of the other isomers, exo-4b,c and
largest overlap is between C9 in the LUMO of 2b and C8 in the
HOMO of 3. Thus, the electronic structures of 2b and 3 favor the
formation of a P–N bond.
ΔE1 = ELUMO(dienophile) – EHOMO(diene) = 4.73 eV
ΔE2 = ELUMO(diene) – EHOMO(dienophile) = 8.19 eV
LUMO dienophile 3:
HOMO diene 2b
:
endo-4b, in
a thermodynamic equilibrium. The very high
regioselectivity can be understood by considering the frontier
molecular orbitals (Figure 2 for 2b and 3).
Table 1. Diels–Alder reaction between 2a dimer, 1b–e, and 3. Reaction
conditions and isolated products.
Phosphole
Reaction time and
temperature
Ratio
endo:exo
1:0
Yield[a]
endo-4
64%
Yield[a]
exo-4
-
N1: 9.1% px; C8: 8.5% px
C5: 2.4% px; C4: 1.5% px
P1: 29.5% pz; C7: 8.4% pz
C9: 13.1% pz; C10: 5.8% pz
2a dimer
24 h, 60 °C
17 h, 140 °C
LUMO diene 2b:
HOMO dienophile 3:
1b
1c
4:1
5.5:1
9:1
69%
42%
7%
-
90 min, 140 °C
3 h 45 min, 125 °C
1d
1e
73%
-
-
11 h, 140 °C
0:1
63%
[a] Yield of isolated product.
P1: 25.0% pz; C7: 13.2% pz
C9: 7.6% pz; C10: 0.9% pz
N1: 2.6% px; C8: 0.2% px
C5: 10.5% px; C4: 3.7% px
Figure 2. Frontier molecular orbitals of diene 2b and dienophile 3.
The pure diastereomers endo-4b-d and exo-4b,e were isolated
by fractional crystallization from boiling toluene or
toluene/hexane (or n-octane); endo-4a was obtained by
crystallization from THF/toluene. Column chromatography was
not suitable due to high moisture and oxygen sensitivity. The
exo isomer of 4c,d could not be isolated due to its very low
concentration [endo/exo 5.5:1 (4c), 9:1 (4d)]; furthermore, on
recrystallization of the exo isomer from boiling toluene, an
exo/endo mixture is formed by exo–endo interconversion, which
is faster for 4c and d than for 4b.
Figure 1. Time-dependent reaction of 1b and 3 monitored by 31P{1H} inverse
gated decoupled NMR spectroscopy.
Structures of all isolated 1-phospha-2-azanorbornenes (endo-
4a–d and exo-4b,e) were determined by 2D NMR experiments
and X-ray structure analysis (Figures 3, 4 and Supporting
Information); the isomers exo-4c,d were only verified by 1H NMR
and 31P NMR spectroscopy in the reaction mixtures. The 31P
NMR chemical shifts (in CDCl3) of the 1-phospha-2-
azanorbornenes are in the range of 48.4 to 59.0 ppm. In the
endo isomers (endo-4a–d), one of the diastereotopic hydrogen
atoms at C18 (Figures 3 and 4) exhibits a strong anisotropic
effect, which is not observed in exo-4b,e. For example, in endo-
4b, the chemical shifts of the hydrogen atoms at C18 are 2.67
(dd, J = 11.5, 6.4 Hz) and 1.83 – 1.74 ppm (m), and those of
exo-4b are 1.67–1.58 (m) and 1.52–1.44 ppm (m). The
coordination geometry of phosphorus is distorted trigonal
Theoretical calculations (RI-B2PLYP-D3BJ/def2-TZVP,[13,14] gas
phase) of the reaction between 2b and 3 indicate clearly that this
Diels–Alder reaction is of normal electron demand (ΔE1
<
ΔE2).[15] During the Diels–Alder reaction, electron density is
transferred from the HOMO of diene 2b into the LUMO of
dienophile 3. The HOMO of 2b has π(P1-C7) and π(C9-C10)
character with the largest contributions coming from the P1 and
C9 atomic orbitals. The LUMO of 3 has π*(N1-C8) character
with the largest contributions coming from the atomic orbitals at
N1 and C8. The greatest orbital overlap is observed between P1
in the LUMO of 2b and N1 in the HOMO of 3, and the second
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pyramidal. The P-N bond lengths in endo-4a-d and exo-4b,e
(176.8 to 179.4 pm) correspond to a P-N single bond.[16] The P-
C bonds have similar lengths. This is a clear difference to 1-
phosphanorbornenes, in which the bond between
P and the sp2-hybridized C atom is shorter than the other P-C
bonds.[17]
phospholes 1b and 2a dimer, are much more easily obtained on
a larger scale than phospholes 1c–e. Reactions with water and
hydrogen sulfide lead to 2,3-dihydrophospholes 7a,b and 8b; the
postulated initially formed intermediates 5a,b and 6b were not
observed (Scheme 2; molecular structure of 7b in Figure 5).
Figure 3. Molecular structure of exo-4b. Ellipsoids at 50% probability.
Selected bond lengths [pm] and angles [°]:P1-N1 177.9(1), P1-C18 183.3(1),
P1-C1 183.6(1), C1-C2 134.6(2), N1-C4 149.2(1); N1-P1-C1 94.95(5), N1-
P1-C18 88.13(5), C1-P1-C18 88.49(6), S1-N1-P1 117.23(6).
Scheme 2. Cleavage of the P-N bond in endo-4a,b by water and hydrogen
sulfide. The reactions are quantitative and highly selective. Back reaction
takes place only for 7a,b.
Figure 4. Molecular structure of endo-4b. Ellipsoids at 50% probability.
Selected bond lengths [pm] and angles [°]: P1-N1 179.4(2), P1-C18 183.2(2),
P1-C1 184.1(2), C1-C2 135.1(2), N1-C4 149.8(2); N1-P1-C1 96.39(7), N1-P1-
C5 85.96(7), C1-P1-C18 88.43(8) S1-N1-P1 118.58(7).
The basicity of the endo isomers of 1-phospha-2-
azanorbornenes was probed by treating solutions of endo-4b
and endo-4c in toluene with an excess of gray selenium at 60 °C
(endo-4c) or 80 °C (endo-4b). The very large 31P-77Se coupling
constants of the resulting phosphine selenides (endo-4b-Se:
918.0 Hz; endo-4c-Se: 919.1 Hz)[18] indicate that 1-phospha-2-
azanorbornenes are only weak bases. Reaction of endo-4a with
tungsten pentacarbonyl complex [W(CO)5(THF)] proceeded
smoothly at room temperature with formation of 10a [31P{1H}
NMR: 66.2 ppm (s with 183W satellites, 1JP-W 282.4 Hz)].
Figure 5. Molecular structure of 7b. Ellipsoids at 50% probability. Selected
bond lengths [pm] and angles [°]: P1-C1 178.0(2), P1-C4 179.5(3), P1-O1
149.1(2) C1-C2 134.1(3), N1-C13 146.1(3); C1-P1-C4 95.1(1), C1-P1-O1
115.6(1), C4-P1-O1118.2(1).
The hydrolysis reaction was quantitative and only 7a,b were
formed. The reaction is reversible; water is eliminated with
formation of endo-4a,b in high vacuum at 60 °C or by adding
molecular sieves (3 Å) to a THF solution. With hydrogen sulfide,
a small amount of an unspecified byproduct [31P{1H} NMR: 27.5
ppm (s)] was observed besides the main product 8a. For 7b and
8b, yields could not be determined, as the products contain
residual THF, which was difficult to remove. In the 31P NMR
The reactivity of the P-N bond in 1-phospha-2-azanorbornenes
towards nucleophiles gives access to novel dihydrophospholes,
such as 7a,b and 8b. Selected reactions were conducted only
with endo-4a and endo-4b, because the starting materials,
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spectra of 7a,b and 8b, doublets (7a: 38.1, 7b: 41.2, 8b: 33.9
ppm) with large 31P-1H coupling constants are observed (7a: 1JP-
and can be cleaved by nucleophiles with formation of 2,3-
dihydrophospholes, which are potential starting materials for a
new type of P,N ligands. Further investigations in this area are
underway.
1
1
= 493.6 Hz; 7b: JP-H = 497.5 Hz; 8b: JP-H = 475.5 Hz). D2O
reacts with endo-4b to form the corresponding deuterated
product characterized by a triplet at 40.7 ppm (1JP-D = 76.3 Hz)
H
in the 31P{1H} NMR spectrum.
Acknowledgement
We thank the DFG for financial support and Dr. Peter Lönnecke
for support with X-ray crystallography.
Using a Grignard reagent, namely, ethylmagnesium bromide, as
nucleophile in the reaction with endo-4b also leads to P-N bond
cleavage. Hydrolytic workup followed by sulfur protection and
recrystallization from boiling propan-2-ol gave 9b in 70 % yield
Keywords: cycloaddition • imines • nitrogen heterocycles•
phospholes • phosphorus heterocycles
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Scheme 3. Alkylation of endo-4b with a Grignard reagent.
[3]
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Figure 6. Molecular structure of 9b. Ellipsoid level at 50%. Selected bond
lengths [pm] and angles [°]: P1-C1 179.2(2), P1-C4 181.5(2), P1-C13
180.4(2), P1-S1 195.82(7), C1-C2 134.5(2), N1-C15 146.1(2); C1-P1-C13
109.80(8), C1-P1-C4 93.17(8), C4-P1-C13 107.22(9), S1-P1-C13 112.27(7).
(Scheme 3, Figure 6).
In conclusion, the phospha-aza-Diels–Alder reaction between
2H-phospholes and electron-poor imine 3 are an innovative and
efficient route to the new compound class of 1-phospha-2-
azanorbornenes. The Diels–Alder reaction itself is of normal
electron demand, highly chemoselective, and moderately endo
selective. The isolated 1-phospha-2-azanorbornenes were
characterized by the common analytical methods, including X-
ray structure analysis. The formed P-N bond is highly reactive
[13] Grimme, S. J. Phys. Chem. 2006, 124 (3), 34108.
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[15] W. W. Schoeller, J. Chem. Soc., Chem. Commun. 1985, 334.
[16] H. R. Allcock, Phosphorus–Nitrogen Compounds, Academic Press,
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Elem., 2011, 186, 2061.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
2H-phospholes react in a highly
chemoselective phospha-aza-Diels–
Alder reaction with an activated,
electron-poor imine to give a new
class of compounds, namely, 1-
phospha-2-azanorbornenes.
Peter Wonneberger, Nils König,
Fabian B. Kraft, Menyhárt B. Sárosi
and Evamarie Hey-Hawkins*
1-Phospha-2-azanorbornenes by
Phospha-aza-Diels–Alder Reaction
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