cis- and trans-2-(isocyanomethyl)-5,5-dimethyl-2-oxo-4-phenyl-1,3,2-dioxaphosphorinane - Synthesis and structure of the first chiral isocyanomethylphosphonate synthons

Article abstract of DOI:10.1002/(SICI)1099-0690(199808)1998:8<1511::AID-EJOC1511>3.0.CO;2-G

Both cis-2-(isocyanomethyl)-5,5-dimethyl-2-oxo-4-phenyl-1,3,2-dioxaphosphorinane (1a) and the trans epimer 1b have been prepared as potentially useful chiral isocyanomethylphosphonate synthons. 2-Methoxy-1,3,2-dioxaphosphorinanes 5 and the corresponding 2-ethoxy analog 6 were prepared from 2,2-dimethyl-1-phenyl-1,3-propanediol (2) and were converted in an Arbuzov-type reaction to 2-(formamidomethyl)oxo-1,3,2-dioxaphosphorinane 7, which upon dehydration gave 1a. Thus, both (±)-1a and (2S,4S)-(-)-1a were prepared, and their molecular structures were determined by single-crystal X-ray analysis. Treatment of (2S,4S)-(-)-1a with KF gave a 1:3 equilibrium mixture of the phosphorus epimers 1a and 1b, from which the predominant trans epimer (2S,4R)-(-)-1b was isolated by column chromatography and crystallisation.

Full text of DOI:10.1002/(SICI)1099-0690(199808)1998:8<1511::AID-EJOC1511>3.0.CO;2-G

FULL PAPER
Chemistry of Phosphorylmethyl Isocyanides, 6[᭛]
cis- and trans-2-(Isocyanomethyl)-5,5-dimethyl-2-oxo-4-phenyl-1,3,2-
dioxaphosphorinane – Synthesis and Structure of the First Chiral
Isocyanomethylphosphonate Synthons
Jan-Willem Weener, Jos P. G. Versleijen, Auke Meetsma, Wolter ten Hoeve, and Albert M. van Leusen*
Department of Organic and Molecular Inorganic Chemistry, Groningen University,
Nijenborgh 4, NL-9747 AG Groningen, The Netherlands
Received January 12, 1998
Keywords: Chiral isocyanomethylphosphonates / Phosphorus heterocycles / Chiral auxiliaries
Both cis-2-(isocyanomethyl)-5,5-dimethyl-2-oxo-4-phenyl-
1,3,2-dioxaphosphorinane (1a) and the trans epimer 1b have
upon dehydration gave 1a. Thus, both (±)-1a and (2S,4S)-(Ϫ)-
1a were prepared, and their molecular structures were
been prepared as potentially useful chiral isocyano- determined by single-crystal X-ray analysis. Treatment of
methylphosphonate synthons. 2-Methoxy-1,3,2-dioxaphos-
phorinanes 5 and the corresponding 2-ethoxy analog 6 were
prepared from 2,2-dimethyl-1-phenyl-1,3-propanediol (2)
and were converted in an Arbuzov-type reaction to 2-
(formamidomethyl)oxo-1,3,2-dioxaphosphorinane 7, which
(2S,4S)-(–)-1a with KF gave a 1:3 equilibrium mixture of the
phosphorus epimers 1a and 1b, from which the predominant
trans epimer (2S,4R)-(–)-1b was isolated by column
chromatography and crystallization.
chiral chromium complexes of benzaldehyde.[6] A number
of chiral TosMIC analogs R*SO2CH2NϭC, together with
PhS*(O)(NTos)CH2NϭC have been reported, but their use
has been limited.[1i][7] The same holds for a few chiral isocy-
anoacetates R*O2CCH2NϭC, derived, for example, from
(Ϫ)-menthol and (ϩ)-borneol,[8] and the recently reported
(4R)- and (4S)-3-(isocyanoacetyl)-4-(phenylmethyl)-2-ox-
azolidinones.[9]
We wish to report the synthesis of the first chiral analogs
of PhosMIC: cis- and trans-2-(isocyanomethyl)-5,5-di-
methyl-2-oxo-4-phenyl-1,3,2-dioxaphosphorinane, 1a and
1b. Isocyanides 1a and 1b, unlike PhosMIC, are crystalline
compounds, both in the racemic as well as in the optically
active forms. Generally speaking, crystalline isocyanides are
more stable, which usually means improved storability.
Introduction
Organic isocyano compounds have developed into an im-
portant category of synthesis reagents (synthons), covering
a large variety of synthetic applications.[1] Two events of the
last three decades have been crucial in this development: (1)
the extension of the Passerini reaction (of 1921) into the
Ugi Multi-Component Reactions (starting in 1961);[1a][2]
(2) the introduction of α-metalated isocyanides in organic
synthesis by the Schöllkopf group (from 1968 on).[3]
The scope of α-metalated isocyanides in organic synthesis
is considerably enlarged by the introduction of α-substitu-
ents X in compounds XCHRNϭC (R ϭ H, alkyl, aryl), in
particular when X is a carboxylate derivative[1b][1f][3] or one
of certain hetero substituents.[1e][1g][1h][1i] A multitude of
synthetic goals has been realized by the use of sulfonyl-sub-
stituted methyl isocyanides (X ϭ RSO2), with TosMIC as
the most prominent representative.[1h][1i] Another import-
ant group of hetero-substituted methyl isocyanides is cen-
tered around diethyl isocyanomethylphosphonate (Phos-
MIC).[1e] Nitrogen- and boron-substituted methyl isocyan-
ide, on the other hand, are still at infancy.[4]
For a group of synthons of established significance, the
application of chirality in isocyanide-based syntheses is lag-
ging behind remarkably. So far, achiral EtO2CCH2NϭC,
TosMIC, and PhosMIC have been successfully applied in
the stereoselective synthesis of chiral oxazolines and chiral
β-hydroxy amines by Hayashi, Ito, and coworkers using chi-
Synthesis of (Isocyanomethyl)dioxaphosphorinanes 1a and
ral gold or silver catalysts.[5] Similar results were achieved
1b ؊ Considerations and Reaction Scheme
´
by Solladie-Cavallo et al. in the reaction of TosMIC with
An obvious way to introduce chirality in compounds like
PhosMIC involves replacement of the achiral alkoxy groups
for a chiral alcohol. There are several reasons for selecting
[᭛] Part 5: J. Stoelwinder, A. M. van Leusen, J. Org. Chem. 1993,
58, 3687Ϫ3691.
Eur. J. Org. Chem. 1998, 1511Ϫ1516
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0808Ϫ1511 $ 17.50ϩ.50/0
1511

J.-W. Weener, J. P. G. Versleijen, A. Meetsma, W. ten Hoeve, A. M. van Leusen
FULL PAPER
chiral 2,2-dimethyl-1-phenyl-1,3-propanediol (2) for this of this mixture during distillation (at 70°C/0.4 Torr) led to
purpose. The major reasons are: (1) both enantiomers of 2 the isolation of diastereomerically pure trans-5a as the sin-
are readily available; (2) phosphoric acids 3, derived from 2, gle product in 72% yield based on 2. The same trans-5a
have been developed into commercially available resolving was obtained in 79% yield directly from 2 in one operation
agents for amines, amino acids, and amino alcohols;[10] and (avoiding the potentially explosive and highly water-sensi-
(3), above all, the use of 2 will turn the phosphorus atom tive chlorodioxaphosphorinane 4) by a transesterification
of compounds 1 into a second stereogenic center, as part of using trimethyl phosphite. The latter approach was also
a rigid and chiral dioxaphosphorinane ring. Thus, a poten- used to convert enantiomerically pure (S)-(ϩ)-2,2-dimethyl-
tially important additional chiral center will be situated 1-phenyl-1,3-propanediol
next to the main reaction site of compounds 1: the exocyclic 1,3,2-dioxaphosphorinane 5a in 88% yield. Reaction of (S)-
methylene group. (ϩ)-diol 2 with triethyl phosphite similarly gave (2S,4S)-
Our synthesis of (isocyanomethyl)dioxaphosphorinanes (ϩ)-6a in 89% yield.
2
to (2S,4S)-(ϩ)-2-methoxy-
1, as outlined in Scheme 1, is based on an adaption of the
Crude 2-chloro-1,3,2-dioxaphosphorinane 4 (not re-
Schöllkopf synthesis of PhosMIC (2),[11] in combination ported previously) gave one signal only in 31P NMR at δ ϭ
with the Wynberg preparation of enantiomerically pure 150.3, both in the racemic and in the optically active reac-
2.[10][12] We have worked out the reactions of Scheme 1 with tion series. This means that of the conceivable cis and trans
racemic diol 2 first. Subsequently, the same reactions were isomers of 4, only one (the trans isomer as depicted in
carried out with (S)-(ϩ)-diol 2. In fact, the latter reactions Scheme 1) is formed. In trans-4 the dioxaphosphorinane
are depicted in Scheme 1, which is based on the reasonable ring is fixed in the chair conformation by the equatorial 4-
assumption that the stereogenic center of 2 is unaffected phenyl ring, with the 2-chlorine in axial position, as is ex-
during the entire series of reactions. This assumption has pected on the basis of gauche[13] and anomeric[14] effects.
been substantiated by experiment. As is shown in Scheme Several other examples are known of 1,3,2-dioxaphosphori-
2, the configuration of the phosphorus stereocenter of com- nanes with axial 2-chloro substituents.[15] Also, the trans
pounds 1 can, however, be inverted in a separate reaction.
structure assigned to 4 is consistent with the stereochem-
istry of the next reactions of Scheme 1.
Scheme 1. Synthesis of isocyanomethylphosphorinane 1a
Reaction of 4 with MeOH at room temperature led pre-
dominantly to cis-dioxaphosphorinane 5b, which is as-
sumed to be the kinetically favored isomer formed by dis-
placement of chlorine in an SN2(P)-type reaction with in-
version at the phosphorus atom.[15a][16] The product mix-
ture showed two signals in 31P NMR: one at δ ϭ 134.8 for
5b and the other at δ ϭ 127.6 of 5a. The peak at δ ϭ 134.8
disappeared completely when a solution of 5b in toluene
was heated for 2 h, to only give a signal at δ ϭ 127.6 of
the thermodynamically more stable trans isomer 5a. The
assignment of the trans configuration to 5a is based on the
3JPH coupling constants of the ring protons.[17][18] The ob-
3
served JPH coupling constants (see Experimental Section)
are consistent with a 1,3,2-dioxaphosphorinane ring in a
chair conformation with the 4-phenyl group and the free
electron pair on the phosphorus atom in equatorial posi-
tions.
2-(Formamidomethyl)-5,5-dimethyl-2-oxo-4-phenyl-1,3,2-
dioxaphosphorinane (7) and rac-2-(Isocyanomethyl)-5,5-
dimethyl-2-oxo-1,3,2-dioxaphosphorinane (1a)
2-Chloro-1,3,2-dioxaphosphorinane (4) and 2-Methoxy- and
2-Ethoxy-1,3,2-dioxaphosphorinanes (5 and 6a)
The formamidomethyl group of 7 was introduced by an
Arbuzov-type reaction, analogous to the one previously
used by Schöllkopf et al. in the synthesis of PhosMIC.[11]
Thus, trans-(±)-5a (or 6a) was refluxed for 2 h with 1.5
equivalents of N-(formamidomethyl)-N,N,N-trimethylam-
monium iodide in nitromethane to give (±)-7 in 63% yield
(Scheme 1). Compound 7 gave one signal in 31P NMR at
In the racemic series, reaction of (±)-diol 2 with PCl3
(10 min, room temp.) gave the (highly) reactive tervalent
2-chloro-1,3,2-dioxaphosphorinane 4, which, without being
isolated, was converted to 5. The latter reaction with
MeOH (2 h, room temp.) gave, prior to distillation, a mix-
ture of trans- and cis-phosphites 5a and 5b,[*] respectively,
in ratios varying from ca. 1:4 to 1:6. Thermal epimerization
3
δ ϭ 22.1. The JPH coupling constants of the ring protons
of 7 are consistent with a chair conformation, as in com-
pound 5a. The positions of the formamidomethyl group
and the phosphoryl oxygen atom of 7 follow from the X-
ray structure of 1a, which is obtained as the sole product
[*] For all dioxaphosphorinanes in this report, the terms cis and
trans refer to the relative positions of the phenyl group at C4
and the single-bonded substituent at P.
1512
Eur. J. Org. Chem. 1998, 1511Ϫ1516

Chemistry of Phosphorylmethyl Isocyanides, 6
Figure 1. Single-crystal X-ray structure of (±)-1a[a]
FULL PAPER
[a] Selected torsion angles [°] of the two crystallographically independent molecules of (±)-1a: P1ϪO1ϪC1ϪC4 177.6(3), O3ϪP1ϪO1ϪC1
Ϫ77.2(3), C12ϪP1ϪO1ϪC1 158.8(3), O3ϪP1ϪC12ϪN1 Ϫ168.0(4), P2ϪO4ϪC14ϪC17 Ϫ177.1(3), O6ϪP2ϪO4ϪC14 78.3(4),
C25ϪP2ϪO4ϪC14 Ϫ158.1(4), O6ϪP2ϪC25ϪN2 172.1(4).
upon dehydration of 7. Also, the stereochemistry of 7 is at 100°C, unless KF was added. In that case equilibration
consistent with the earlier proposed mechanism of compar- into a 1:3 mixture of 1a/1b was achieved in 4 h. At room
able Arbuzov reactions.[19]
temperature, equilibration of 1a in DMSO with KF took
Dehydration of (±)-7 with POCl3 gave racemic isocyano- several weeks. The formation of 1b is marked by the appear-
methylphosphonate 1a in 69% yield when either Et3N or ance of a second 31P-NMR signal at δ ϭ 8.0, in addition
iPr2NH was used as base in CH2Cl2 at Ϫ20°C (Scheme 1). to the peak of 1a at δ ϭ 14.6. Starting with 1b, the same
In contrast to PhosMIC, 1a is a stable, odorless solid, which 1:3 ratio of 1a/1b was obtained with 0.4 equivalent of KF
crystallizes in colorless needles, melting at 145°C. The IR in 5 h in DMSO at 100°C. Isolation of pure trans epimer
stretch vibrations of NϭC and PϭO are found at 2154 and 1b from the equilibrium mixture was achieved by column
1251 cmϪ1, respectively, the only 31P-NMR peak at δ ϭ chromatograpy and repeated crystallization from hexane/
13.9.
CHCl3 (2:1). In this way, (2R, 4S)-(Ϫ)-1b (mp 155°C) was
A single-crystal X-ray structure of (±)-1a was determined obtained in 60% yield from (2S,4S)-(Ϫ)-1a.
from crystals obtained from CHCl3/hexane (1:3). The asym-
metric unit contains two crystallographically independent
molecules (Figure 1). The X-ray structure clearly shows the
chair conformation of the 1,3,2-dioxaphosphorinane ring,
the equatorial positions of the phenyl and isocyanomethyl
substituents, and the axial phosphoryl oxygen atom.
Figure 2. Single-crystal X-ray structure of (2S,4S)-(Ϫ)-1a[a]
(2S,4S)-(؊)-2-(Isocyanomethyl)-5,5-dimethyl-2-oxo-4-
phenyl-1,3,2-dioxaphosphorinane (1a) and the (2R,4S)-(؊)
Epimer 1b
In analogy to the racemic series, transesterification of
P(OEt)3 with (S)-(ϩ)-2 gave (2S,4S)-(ϩ)-6a, which was con-
verted into formamide (2S,4S)-(ϩ)-7 in 77% yield. Sub-
sequent dehydration of (2S,4S)-(ϩ)-7 gave, after column
chromatography, pure (2S,4S)-(Ϫ)-1a in 31% yield, which
melted at 133°C.
Recrystallization of (2S,4S)-(Ϫ)-1a from CHCl3/hexane/
MeOH (1:3:0.25) gave colorless plate-shaped crystals, from O3ϪP1ϪO1ϪC1
[a]
Selected torsion angles [°]: P1ϪO1ϪC1ϪC4 Ϫ175.4(2),
Ϫ82.6(2),
C12ϪP1ϪO1ϪC1
152.7(2),
O3ϪP1ϪC12ϪN1 60.1(3).
which a single-crystal X-ray structure was obtained (Figure
2). The asymmetric unit contains one complete molecule.
An unexpected, but interesting observation was made
during an attempt to condense 1a with tert-butyl methyl
ketone. When 1a and the ketone were heated at 100°C in
DMF with 0.4 equivalent of KF (the intended condensation
catalyst), partial epimerization of 1a to 1b was the only re-
action that was observed (Scheme 2). No epimerization was
observed when 1a (without ketone) was heated in DMSO
Table 1. Selected spectroscopic data for compounds 1a and 1b
ν(PϭO)
[cmϪ1
δ31
P
δ1H
δ13
C
]
CDCl3 [D6]DMSO
4-H
6-Hax 6-Heq C-4 C-6
1a 1253/1244 13.9
1b 1291/1278 2.3
14.6
8.0
5.52
5.68
4.56
4.71
4.01
4.24
85.2 75.8
91.9 81.7
Eur. J. Org. Chem. 1998, 1511Ϫ1516
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J.-W. Weener, J. P. G. Versleijen, A. Meetsma, W. ten Hoeve, A. M. van Leusen
FULL PAPER
solution of (±)-diol 2 (1.81 g, 10.1 mmol) and Et3N (3.5 ml, 25.0
mmol) in CH2Cl2 (30 ml) at Ϫ10°C. The solution turned yellow,
while a white precipitate was formed. After 10 min, the 31P-NMR
signal of PCl3 at δ ϭ 220.0 had disappeared and one new signal of
chlorophosphite 4 (not isolated) at δ ϭ 150.3 was present. MeOH
(1.2 ml, 30.0 mmol) was added to the mixture at room temp. After
stirring for 2 h, the 31P NMR signal of 4 had disappeared and two
new signals at δ ϭ 127.6 and 134.8 were observed corresponding
to trans- and cis-methoxydioxaphosphorinanes 5a and 5b, respec-
tively, in a trans/cis ratio of 1:6. The solvent was removed under
The spectroscopic data of the epimeric compounds 1a
and 1b (Table 1) are consistent with the previously reported
observation that 2-oxo-1,3,2-dioxaphosphorinanes with an
equatorially oriented phosphoryl oxygen atom (as in 1b)
show a higher ν(PϭO) and a lower δ31P value than the iso-
mers in which the oxygen atom is oriented axially (as in
1a).[20][21] The PϭO stretch vibration is observed as a split
peak due to rotational isomerism of the isocyanomethyl
group.
The epimerization at the phosphorus atom of 1a and 1b reduced pressure and the residue was distilled at 70°C (0.4 mbar)
is readily explained by (axial) attack of FϪ at the four-coor-
dinated phosphorus atom of 1a (or 1b) to form a 5-coordi-
yielding 1.60 g (6.7 mmol, 72%) of solid (±)-5a, m.p. 45°C. During
distillation, cis-5b is converted to trans-5a, see text. Ϫ Caution:
nated intermediate that loses FϪ after (minimal) three Berry
Phosphites react violently with oxygen or with water and an ex-
plosion may result.[24] Ϫ 1H NMR (CDCl3): δ ϭ 0.70 (s, 3 H, CH3);
pseudorotations[22] as depicted in Scheme 2.
2
3
1.04 (s, 3 H, CH3); 3.40 (dd, JAB ϭ 10.6 Hz, JPH ϭ 11.0 Hz, 1
A corresponding epimerization at the phosphorus atom
has also been effected with the (formamidomethyl)diox-
aphosphorinane 7. In this case a 1:2 equilibrium mixture
was obtained after 16 h with KF in DMSO at 100°C, again
in favour of the trans epimer.
3
2
H, 6-Heq); 3.58 (d, JPH ϭ 12.0 Hz, 3 H, OCH3); 4.32 (dd, JAB
ϭ
3
3
10.6 Hz, JPH ϭ 2.6 Hz, 1 H, 6-Hax); 5.28 (d, JPH ϭ 3.0 Hz, 1 H,
4-H); 7.32 (m, 5 H, Ar H). Ϫ 13C NMR (CDCl3): δ ϭ 17.5 (CH3);
22.7 (CH3); 36.4 (C5); 50.0 (OCH3); 70.3 (C6); 78.5 (C4); 127.4,
127.6, 137.6 (Ar C). Ϫ 31P NMR (CDCl3): δ ϭ 127.6. Ϫ HRMS:
C12H17O3P: calcd. 240.092; found 240.091.
Scheme 2. Epimerization of 1a and 1b induced by FϪ
Method 2 [by transesterification of P(OMe)3]: A solution of (±)-
diol-2 (10.02 g, 55.6 mmol), P(OMe)3 (11.8 ml, 100 mmol), and a
catalytical amount of Et3N (0.9 ml, 6.5 mmol) in toluene (60 ml)
was refluxed for 10 h. The precipitate was removed and the solution
was concentrated under reduced pressure to give 10.55 g (43.9
mmol, 79%) of solid (±)-5a, m.p. 45°C.
Compound (2S,4S)-(ϩ)-5a: A neat mixture of (S)-(ϩ)-diol 2 (2.25
g, 12.5 mmol) and P(OMe)3 (2.0 g, 16.1 mmol) was heated at 150°C
for 6 h. The solution was concentrated under reduced pressure and
the residue was distilled (100°C, 0.1 mbar) to give 2.63 g (11.0
mmol, 88%) of solid (2S,4S)-(ϩ)-5a, m.p. 90°C. Ϫ [α]57820 ϭ ϩ97.5
(c ϭ 0.5, CHCl3).
Experimental Section
(2S,4S)-(ϩ)-trans-2-Ethoxy-5,5-dimethyl-4-phenyl-1,3,2-di-
General: Melting points (uncorrected): Mettler FP1/FP51. Ϫ Op-
oxaphosphorinane (6a): A neat mixture of (S)-(ϩ)-diol 2 (4.68 g,
tical rotations: Perkin Elmer 241 polarimeter (Hg lamp, 578 nm, 26.0 mmol) and P(OEt)3 (4.5 g, 27.0 mmol) was heated at 120°C
20°C). Ϫ NMR: Varian VXR-300S (300 MHz and 75.5 MHz for for 5 d. The solution was concentrated under reduced pressure and
13 C,
1H and
respectively) or Varian Gemini-200BB (200 MHz and the solid residue was crystallized from hexane to give 5.9 g (23.2
81.0 MHz for 1H and 31P, respectively). Chemical shifts are denoted
mmol, 89%) of solid (2S,4S)-(ϩ)-6a, m.p. 52°C. Ϫ [α]578
ϭ
20
in ppm relative to TMS (1H and 13C) or external H3PO4 (31P). Ϫ ϩ135.2 (c ϭ 0.5, CHCl3). Ϫ H NMR (CDCl3): δ ϭ 0.70 (s, 3 H,
1
MS: AEI-MS-992 (acc. voltage 8 kV, voltage 70 eV). Ϫ IR: Perkin-
CH3); 1.04 (s, 3 H, CH3); 1.31 (t, J ϭ 7 Hz, CH3); 3.40 (dd, 2JAB ϭ
Elmer 841 Infrared Spectrophotometer (KBr, cmϪ1). Ϫ Elemental 10.7 Hz, JPH ϭ 11.0 Hz, 1 H, 6-Heq); 3.90 (qd, J ϭ 7 Hz, JPH
ϭ
3
3
2
analyses were performed in the Microanalytical Department of this
1.0 Hz, 2 H, CH2); 4.34 (dd, JAB ϭ 10.7 Hz, 3JPH ϭ 3.0 Hz, 1 H,
3
laboratory. Ϫ Crystallographic data (excluding structure factors) 6-Hax); 5.30 (d, JPH ϭ 3.0 Hz, 1 H, 4-H); 7.32 (m, 5 H, Ar H). Ϫ
for the structures reported in this paper have been deposited with 13C NMR (CDCl3): δ ϭ 17.1 (CH3); 17.8 (CH3); 22.9 (CH3); 36.7
the Cambridge Crystallographic Data Centre under number
CCDC-100935. Copies of the data can be obtained free of charge
(C5); 58.9 (OCH2); 70.6 (C6); 78.7 (C4); 127.5, 127.7, 137.7 (Ar C).
31P NMR (CDCl3): δ ϭ 126.0. Ϫ C13H19O3P (254): calcd. C
Ϫ
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, 61.41, H 7.53, P 12.18; found C 60.27, H 7.57, P 12.00. Ϫ HRMS:
UK [fax: int. code ϩ44(1223)336-033, e-mail: deposit@ccdc.cam.
ac.uk). Ϫ All reactions were carried out in oven-dried (120°C)
glassware under N2. Solvents were distilled prior to use: Et2O,
CH2Cl2, CHCl3, and hexane from P2O5; MeOH and EtOH from
Mg; toluene and THF from Na/benzophenone; DMF from CaH2.
Diols (±)-2[10] and (ϩ)-2[12], and N-formamidomethyl-N,N,N-tri-
methylammonium iodide[23] were synthesized according to litera-
ture procedures. All other commercial reagents were used as re-
ceived.
calcd 254.107; found 254.107.
cis-2-(Formamidomethyl)-5,5-dimethyl-2-oxo-4-phenyl-1,3,2-di-
oxaphosphorinane [(±)-7 and (2S,4S)-(ϩ)-7]: Compound (±)-7: A
solution of (±)-5a (10.0 g, 42.1 mmol) and N-formamidomethyl-
N,N,N-trimethylammonium iodide[23] (10.3 g, 62 mmol) in
CH3NO2 (150 ml) was refluxed for 2 h, during which a precipitate
was formed. The precipitate was removed and H2O (100 ml) was
added. The solution was extracted with CHCl3 (3 ϫ 30 ml) and
the combined extracts were washed with H2O (50 ml), dried
trans-2-Methoxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane (MgSO4), and concentrated to give 10.1 g of crude 7 as a yellow
[(±)-5a and (2S,4S)-(ϩ)-5a]: Compound (±)-5a. Ϫ Method 1 (via in oil, which crystallized on standing at room temp. Precipitation
situ formed chlorodioxaphosphorinane 4): A solution of PCl3 (0.8
from Et2O gave 7.54 g of (±)-7 (26.6 mmol, 63%), pure according
ml, 9.2 mmol) in CH2Cl2 (60 ml) was added dropwise to a stirred to 31P and 1H NMR. An analytically pure sample was obtained
1514
Eur. J. Org. Chem. 1998, 1511Ϫ1516

Chemistry of Phosphorylmethyl Isocyanides, 6
after three crystallizations from EtOH, m.p. 173°C. Ϫ 1H NMR: and 1b (1:3). The mixture was separated by column chromatogra-
FULL PAPER
δ ϭ 0.76 (s, 3 H, 5-CH3); 0.98 (s, 3 H, 5-CH3); 3.83 (dd, JAB
11.0 Hz, JPH ϭ 22.0 Hz, 1 H, 6-Heq); 3.96 (dd, J ϭ 6.0 Hz, JPH
ϭ
phy (SiO2, CHCl3/hexane, 1:2) and the first fraction (Rf ϭ 0.6)
gave, after three crystallizations from hexane/Et2O (2:1), solid
ϭ
12.6 Hz, 2 H, CH2); 4.42 (dd, JAB ϭ 11.0 Hz, JPH ϭ 2.3 Hz, 1 H,
(2R,4S)-1b (160 mg, 60%), m.p. 155°C, which was pure according
6-Hax); 5.41 (d, JPH ϭ 3.0 Hz, 4-H); 7.06 (br. s, 1 H, NH); 7.20 Ϫ to NMR. Ϫ [α]578 ϭ Ϫ38.2 (c ϭ 0.5 in CHCl3). Ϫ 1H NMR
7.35 (m, 5 H, Ar H); 8.25 (s, 1 H, CHO). Ϫ 13C NMR: δ ϭ 17.0 (CDCl3): δ ϭ 0.87 (s, 3 H, CH3); 1.16 (s, 3 H, CH3); 3.99 (AAЈX,
and 21.2 (5-CH3); 33.2 (JPC ϭ 160 Hz, CH2); 36.2 (C5); 75.4 (C6); JPH ϭ 16 Hz, JAAЈ ϭ 16.8 Hz, 2 H, CH2); 4.24 (dd, JAB ϭ 11 Hz,
20
84.5 (C4); 127.1, 127.8, 128.5, 135.0 (Ar C); 161.1 (CHO). Ϫ 31P JPH ϭ 18.8 Hz, 1 H, 6-Heq); 4.71 (d, JAB ϭ 11 Hz, 1 H, 6-Hax);
˜
NMR δ ϭ 21.9. Ϫ IR: ν ϭ 3263 cmϪ1 (NH), 1682 (CϭO), 1282 5.68 (dd, JPH ϭ 0.7 Hz, 1 H, 4-H); 7.36 (s, 5 H, Ar H). Ϫ 13C
(PϭO), 1040 (PϪO). Ϫ C13H18NO4P (283): calcd. C 55.12, H 6.40, NMR (CDCl3): δ ϭ 17.0 (CH3); 21.0 (CH3); 36.8 (C5); 37.7 (CH2);
N 4.94, P 10.93; found C 54.80, H 6.62, N 4.80, P 10.68. Ϫ HRMS: 81.7 (C6); 91.9 (C4); 127.1, 128.0, 128.8, 134.9 (Ar C); 162.0 (Nϭ
˜
calcd. 283.097; found 283.097. Ϫ The same procedure was per-
C). Ϫ 31P NMR (CDCl3): δ ϭ 2.3. Ϫ IR: ν ϭ 2153 cmϪ1 (NϭC);
formed with (±)-6a (18.1 g, 71 mmol) to give 10.2 g of (±)-7 (36 1291/1278 (PϭO).
mmol, 51%).
Compound (2S,4S)-(ϩ)-7 was prepared as described above for
[1]
[1a]
Some leading reviews are:
I. Ugi, Isonitrile Chemistry, Aca-
[1b]
(±)-7 from (2S,4S)-(ϩ)-6a (4.3 g, 17 mmol) in 77% yield (3.7 g, 13
demic Press, New York, 1971. Ϫ
D. Hoppe, Angew. Chem.
[1c]
20
1974, 86, 878; Angew. Chem. Int. Ed. Engl. 1974, 13, 789. Ϫ
C. Grundmann in Methoden Org. Chem. (Houben-Weyl) 1985,
mmol), m.p. 141Ϫ142°C. Ϫ [α]578 ϭ ϩ20 (c ϭ 0.5, CHCl3).
vol. E5, part 2, p. 1611Ϫ1658. Ϫ [1d] S. Marcaccini, T. Torroba,
cis-2-(Isocyanomethyl)-5,5-dimethyl-2-oxo-4-phenyl-1,3,2-di-
oxaphosphorinane [(±)-1a and (2S,4S)-(Ϫ) 1a]: Compound (±)-1a: A
solution of POCl3 (2.4 ml, 26.0 mmol) in CH2Cl2 (10 ml) was added
dropwise to a stirred solution of (±)-7 (6.38 g, 22.5 mmol) and
iPr2NH (9.5 ml, 67.5 mmol) in CH2Cl2 (130 ml) at Ϫ20°C and the
reaction mixture was stirred for 2.5 h at 0°C. Aqueous NaHCO3
(20 g in 150 ml of H2O) was added carefully (evolution of CO2)
and the mixture was stirred for 20 min. The two layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3 ϫ 30
ml). The combined organic layers were dried (MgSO4) and concen-
trated under reduced pressure to give 5.8 g of crude (±)-1a, as a
yellow solid. Column chromatography (SiO2, AcOEt/hexane, 2:1)
gave 4.52 g (17.0 mmol, 69%) of analytically pure (±)-1a, as
transparant needles, m.p. 145°C. Ϫ 1H NMR (CDCl3): δ ϭ 0.82
[1e]
Org. Prep. Proced. Int. 1993, 25, 141. Ϫ
(C2H5O)2-
P(O)CH2NϭC: A. M. van Leusen, D. van Leusen in Encyclo-
pedia of Reagents for Organic Synthesis (Ed.: L. A. Paquette),
vol. 3, Wiley, New York, 1995, p. 1820. Ϫ [1f] C2H5O2CCH2Nϭ
C: K. Matsumoto, M. Suzuki in Encyclopedia of Reagents for
Organic Synthesis (Ed.: L. A. Paquette), vol. 4, Wiley, New
[1g]
York, 1995, p. 2474. Ϫ
4-CH3C6H4SCH2NϭC: A. M. van
Leusen, D. van Leusen in Encyclopedia of Reagents for Organic
Synthesis (Ed.: L. A. Paquette), vol. 7, Wiley, New York, 1995,
[1h]
p.4979. Ϫ
4-CH3C6H4SO2CH2NϭC: A. M. van Leusen, D.
van Leusen in Encyclopedia of Reagents for Organic Synthesis
(Ed.: L. A. Paquette), vol. 7, Wiley, New York, 1995, p.4973. Ϫ
[1i]
D. van Leusen, A. M. van Leusen, Org. React., in press.
[2]
I. Ugi, Angew. Chem. 1982, 94, 826Ϫ835; Angew. Chem. Int Ed.
Engl. 1982, 21, 810Ϫ819.
[3]
[4]
U. Schöllkopf, Pure Appl. Chem. 1979, 51, 1347.
[4a] J. P. G. Versleijen, P. M. Faber, H. H. Bodewes, A. H. Braker,
(s, 3 H, CH3); 1.15 (s, 3 H, CH3); 3.99 (dd, JAB ϭ 11 Hz, JPH
ϭ
D. van Leusen, A. M. van Leusen, Tetrahedron Lett. 1995, 36,
23 Hz, 1 H, 6-Heq); 4.01 (d, JPH ϭ 16 Hz, 2 H, CH2); 4.56 (dd,
JAB ϭ 11 Hz, JPH ϭ 1.2 Hz, 1 H, 6-Hax); 5.52 (d, JPH ϭ 1.4 Hz, 1
H, 4-H); 7.36 (s, 5 H, Ar H). Ϫ 13C NMR: δ ϭ 17.2 and 21.3 (5-
CH3); 36.3 (C5); 37.3 (JPC ϭ 157 Hz, CH2); 75.8 (C6); 85.2 (C4);
[4b]
2109Ϫ2112. Ϫ
A. R. Katritzky, D. Cheng, R. P. Musgrave,
Heterocycles 1997, 44, 67Ϫ70.
[5]
[6]
M. Sawamura, Y. Ito, Chem. Rev. 1992, 92, 857Ϫ871.
´
A. Solladie-Cavallo, S. Quazzotti, S. Colonna, A. Manfredi, J.
Fischer, A. DeCian, Tetrahedron: Asymmetry 1992, 3, 287.
127.1, 127.8, 128.5, 135.0 (Ar C); 161.2 (NϭC). Ϫ 31P NMR
[7] [7a]
D. van Leusen, P. H. F. M. Rouwette, A. M. van Leusen,.
˜
(CDCl3): δ ϭ 13.9. Ϫ IR: ν ϭ 2156 cmϪ1 (NϭC); 1253/1244 (Pϭ
[7b]
J. Org. Chem. 1981, 46, 5159Ϫ5163. Ϫ
F. J. A. Hundscheid,
V. K. Tandon, P. H. F. M. Rouwette, A. M. van Leusen, Tetra-
hedron 1987, 21, 5073Ϫ5088.
O); 1044 (PϪO). Ϫ C13H16NO3P (265): calcd. C 58.87, H 6.08, N
5.28, P 11.68; found C 58.65, H 6.18, N 5.26, P 11.62. Ϫ HRMS:
calcd. 265.950; found 265.951. Ϫ X-ray structure (Figure 1): Mr ϭ
265.25, monoclinic, P21/c, a ϭ 7.687(1), b ϭ 34.798(2), c ϭ
[8] [8a]
B. Langström, B. Stridsberg, G. Bergson, Chem. Scr.
[8b]
1978؊9, 13, 49Ϫ51. Ϫ
1991, 3, 331Ϫ340.
A. Togni, S. D. Pastor, Chirality
˚
˚
[9]
10.725(1) A, β ϭ 105.409(4)°, V ϭ 2765.7(4) A3, Z ϭ 8, Dx ϭ 1.274
J. S. Tang, J. G. Verkade, J. Org. Chem. 1996, 61, 8750Ϫ8754.
W. ten Hoeve, H. Wynberg, J. Org. Chem. 1985, 50, 4508Ϫ4514.
U. Schöllkopf, R. Schröder, D. Stafforst, Justus Liebigs Ann.
Chem. 1974, 44Ϫ53.
˚
[10]
[11]
g cmϪ3, (Mo-Kα) ϭ 0.71073 A, µ ϭ 1.99 cmϪ1, F(000) ϭ 1120,
T ϭ 295 K, RF ϭ 0.059 for 3714 unique observed reflections with
I Ն 2.5 σ(I) and 453 parameters. Two crystallographically indepen-
dent molecules are present in the asymmetric unit.
[12]
R. Ebens, R. M. Kellogg, Recl. Trav. Chim. Pays-Bas 1990,
109, 552Ϫ560.
[13] [13a]
W. G. Bentrude, H.-W. Tan, K. C. Yee, J. Am. Chem. Soc.
[13b]
Compound (2S,4S)-(Ϫ)-1a was prepared as described above for
(±)-1a from (2S,4S)-(ϩ)-7 (3.5 g, 12.4 mmol) in 31% yield (1.0 g,
1975, 97, 573Ϫ582. Ϫ
3193Ϫ3202.
N. S. Zefirov, Tetrahedron 1977, 33,
[14]
D. W. White, R. D. Bertrand, G. K. McEwen, J. G. Verkade, J.
Am. Chem. Soc. 1970, 92, 7125Ϫ7135.
20
4.0 mmol), m.p. 133°C. Ϫ [α]578 ϭ Ϫ46.4 (c ϭ 0.5, CHCl3). Ϫ
[15] [15a]
X-ray structure (Figure 2): Mr ϭ 265.25, monoclinic, P212121, a ϭ
R. S. Edmundson, O. Johnson, D. W. Jones, J. Chem Soc.,
˚
˚
5.646(1), b ϭ 9.354(1), c ϭ 25.105(1) A, V ϭ 1325.9(3) A3, Z ϭ 4,
[15b]
Perkin Trans. 2 1985, 69Ϫ75. Ϫ
C. L. Bodkin, P. Simpson,
˚
J. Chem. Soc. B 1971, 1136Ϫ1141. Ϫ [15c] W. G. Bentrude, J. H.
Hargis, J. Am. Chem. Soc. 1970, 92, 7136Ϫ7144.
C. L. Bodkin, P. Simpson, J. Chem. Soc., Perkin Trans. 2 1973,
2, 676Ϫ681.
Dx ϭ 1.329 g cmϪ3, (Mo-Kα) ϭ 0.71073 A, µ ϭ 2.07 cmϪ1
,
F(000) ϭ 560, T ϭ 130 K, RF ϭ 0.031 for 1611 unique observed
reflections with I Ն 2.5 σ(I) and 229 parameters. The absolute con-
figuration is determined by refinement of the Flack parameter.
[16]
[17] [17a] W. G. Bentrude, W. N. Setzer in Phosphorus-31 NMR Spec-
troscopy in Stereochemical Analysis, (Eds.: J. G. Verkade, L. D.
[17b]
trans-2-(Isocyanomethyl)-5,5-dimethyl-2-oxo-4-phenyl-1,3,2-di-
oxaphosphorinane [(2R,4S)-(Ϫ)-1b]: A solution of (2S,4S)-(Ϫ)-1a
(265 mg, 1.00 mmol) and KF (25 mg, 0.4 mmol) in DMSO (4 ml)
was heated at 100°C for 4 h. After cooling to room temp., H2O (20
ml) was added and the mixture was cooled in ice. The solid was
collected and dried to give 250 mg (94%) of a solid mixture of 1a
Quin), VCH, New York, 1987, p. 365Ϫ389. Ϫ
W. G. Ben-
trude in Phosphorus-31 NMR Spectral Properties in Compound
Characterization and Structural Analysis (Eds.: L. D. Quin, J.
G. Verkade), VCH, New York, 1994, p.41.
[18]
B. E. Maryanoff, R. O. Hutchins, C. A. Maryanoff, Top. Stereo-
chem. 1979, 11, 187Ϫ318.
[19] [19a]
A. F. Torralba, T. C. Meyers, J. Org. Chem. 1957, 22,
Eur. J. Org. Chem. 1998, 1511Ϫ1516
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FULL PAPER
[19b]
[23]
972Ϫ975. Ϫ
T. C. Meyers, R. G. Harvey, E. V. Jensen, J.
H. Böhme, G. Fuchs, Chem. Ber. 1970, 103, 2775Ϫ2779.
H. J. Lucas, F. W. Mitchell, Jr., C. N. Scully, J. Am. Chem. Soc.
1950, 72, 5491Ϫ5497.
[24]
Am. Chem. Soc. 1955, 77, 3101.
[20]
J. A. Mosbo, J. G. Verkade, J. Org. Chem. 1977, 42, 1549Ϫ1555.
D. B. Cooper, T. D. Inch, G. J. Lewis, J. Chem.Soc., Perkin
[21]
[98007]
Trans. 1 1974, 1043Ϫ1048.
[22] [22a] P. S. Berry, J. Chem. Phys. 1960, 32, 933. Ϫ [22b] F. H. West-
heimer, Acc. Chem. Res. 1968, 1, 70Ϫ78.
1516
Eur. J. Org. Chem. 1998, 1511Ϫ1516