Phosphinamide-directed ortho metalations: Application to the desymmetrization of the diphenylphosphoryl group

Article abstract of DOI:10.1055/s-2007-967976

Diphenylphosphinamides have been regioselectively ortho-lithiated under mild conditions providing a simple access to ortho-functionalized derivatives in good yields. The application of the methodology to the diastereoselective desymmetrization of the phos

Full text of DOI:10.1055/s-2007-967976

LETTER
611
Phosphinamide-Directed ortho Metalations: Application to the Desym-
metrization of the Diphenylphosphoryl Group
P
hosphin
g
amide-Direc
n
tedortho
M
a
Fernando López Ortiz*a
a
Área de Química Orgánica, Universidad de Almería, Carretera de Sacramento s/n, 04120 Almería, Spain
Fax +34(950)015478; E-mail: flortiz@ual.es
b
Departamento de Química Física y Analítica, Universidad de Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain
Received 1 November 2006
absence of coordinating cosolvents, ortho anions were
detected in low concentration. They were trapped through
reaction with benzaldehyde and D2O to give the ortho-
substituted derivates 3 in low yield.7
Abstract: Diphenylphosphinamides have been regioselectively
ortho-lithiated under mild conditions providing a simple access to
ortho-functionalized derivatives in good yields. The application of
the methodology to the diastereoselective desymmetrization of the
phosphorus atom is described for the first time.
In this report we demonstrate that the phosphinamide link-
age can be used as an efficient DoM group. The reaction
of the lithiated anions with a series of electrophiles pro-
vides access to new ortho-functionalized phosphina-
mides, which can easily be elaborated further. The process
has been applied to the desymmetrization of the diphen-
ylphosphoryl moiety of chiral derivatives, a transforma-
tion unprecedented in the chemistry of DoM reactions.2
Key words: phosphinamides, ortho lithiation, diastereoselectivity,
organotin, directed metalation
Directed ortho metalation (DoM) followed by electro-
philic trapping is a very useful method for the regioselec-
tive introduction of a great variety of substituents at the
ortho position of a phenyl ring.1 The development of new
DoM strategies2 and the investigations on the metalation
process itself3 have attracted the interest of chemists for
decades.1–3 A large number of heteroatom-directed
metalation groups (DMGs) can be used for promoting
DoM reactions. A few are based on the directing effect of
R2
O
P
O
R2
Ph
O
Ph
E
P
R3
N
R1
R3
NR1
Ph2P
N
R1
E
R3
R2
1
tetracoordinated
phosphorus-containing
functional
2
3 (byproduct)
groups.4 The double ortho lithiation of the diphenyl-
phosphoryl moiety has been reported very recently.5 The
synthetic utility of these DoM reactions generally suffer
limitations such as ineffective directing ability, reduced
scope due to the use of triaryl derivatives, and competing
side reactions, the nucleophilic attack at the phosphorus
being the most important.4e–g To overcome this limitation,
a cooperative meta-methoxy DMG effect, implemented
by Schmid and Brown, has been proposed.6 The use of
bulky tert-butyl substituents linked to the phosphorus
atom to avoid P-attack has also been exploited showing
moderate to excellent conversions to the desired ortho
products.4e–g,5
Scheme 1 Lithiation–electrophilic trapping of 1
We reasoned that the simplest way of favoring ortho lithi-
ation with respect to the competing N–Ca deprotonation
would be to use phosphinamides which do not contain N-
benzylic or N-allylic8b moieties as starting material. Con-
sidering that organolithium bases are able to deprotonate
HMPA,9 we decided to explore the viability of the ortho
lithiation of phosphinamides 4 and 5 bearing, respective-
ly, one and two isopropyl groups at the nitrogen. In both
cases, the deprotonation at the N–Ca position will lead to
dipole-stabilized carbanions.10
Phosphinamide 4 was prepared in very high yield by reac-
tion of isopropylamine with Ph2P(O)Cl in toluene in the
presence of triethylamine (Scheme 2).11a,b
We have previously reported that the lithiation of N-alkyl-
N-benzyldiarylphosphinamides in THF in the presence of
HMPA (hexamethylphosphoramide) or DMPU (N,N¢-
dimethylpropylene urea) afforded after electrophilic
quench dearomatized products 2 in high yield and with
very high regio- and stereocontrol (Scheme 1).7 The in-
vestigation of the reaction mechanism showed that the
formation of compounds 2 takes place through the conju-
gate addition of a N–Ca anion to a P-phenyl ring.8 In the
The synthesis of 5 was performed through addition of
LDA, generated in situ, to chlorodiphenylphosphine ox-
ide in THF at –35 °C (see Scheme 2).11c
After some experimentation, we found that compound 4
could be efficiently deprotonated at the ortho position by
treatment of its THF solution with 2.2 equivalents of n-
BuLi at –35 °C for 2 hours. In the case of phosphinamide
5 the ortho lithiation is best achieved with t-BuLi as base.
In the reaction of 5 with n-BuLi the metalation competes
with the attack of the organolithium to the phosphinamide
SYNLETT 2007, No. 4, pp 0611–0614
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967976; Art ID: D32106ST
© Georg Thieme Verlag Stuttgart · New York

612
I. Fernández et al.
LETTER
Table 1 Products of the ortho-Lithiation–Electrophilic-Trapping
Reaction of Arylphosphinamide 4 and 5
O
Ph2P
O
b, c
a
95%
HN
N
Ph2P
N
E+
Substrate
Product
Conversion
(%)a
85%
H2N
Entry
H
4
5
1b
2b
3b
4
MeI
4
4
4
4
5
5
5
8
82
73
77
80
85
80
84
Li
O
E
O
Me3SnCl
PhCHO
PhCHO
MeI
9
O
d
e
Ph2P
N
10/10¢c
10/10¢c
8
P
P
N
Li
N
H
Ph
Ph
4
H
8–10
70–80%
5
Li
E
6
Me3SnCl
PhCHO
11
O
O
O
P
f
e
Ph2P
N
P
7
12/12¢c
N
N
Ph
Ph
a Established based on 31P NMR.
5
b The base used was n-BuLi.
8,11–12
c Epimers in the C–OH carbon, ratio of 1:1.
75–80%
Scheme 2 Reagents and conditions: a) Ph2P(O)Cl, Et3N, THF,
–78 °C to r.t., 2 h; b) n-BuLi, THF, –35 °C, 1 h; c) Ph2P(O)Cl, –78 °C
to r.t., 2 h; d) n-BuLi, –35 °C, 2 h; e) E+ (MeI, PhCHO, Me3SnCl),
–35 °C; f) t-BuLi, –35 °C, 2 h.
Once a practical route for the ortho functionalization of
phosphinamides 4 and 5 via DoM was available, we
sought to augment the scope of the process by introducing
asymmetry. For that purpose we synthesized substrates 13
and 14 containing the readily accessible chiral auxiliary
(S)-a-methylbenzylamine. The sequence of reactions
leading to the new phosphinamides is outlined in
Scheme 3.15
linkage.12 The anionic nature of the amides generated after
the reaction with the first equivalent of base seems to
prevent the attack of the second equivalent to the P=O
moiety, favoring the abstraction of the ortho hydrogens.
The ortho anions of 4 and 5 underwent reaction with a se-
ries of electrophiles at –35 °C affording ortho-substituted
aryl phosphinamides derivatives 8–12 in very good yields
(Scheme 2, Table 1).13 The use of methyl iodide and
Me3SnCl gave similar results, adducts 8, 9 and 11 were
the only species formed. With benzaldehyde as electro-
phile, a mixture of two diastereoisomers epimers in the
hydroxylic carbon 10/10¢ or 12/12¢ were obtained (entries
3, 4 and 7). The ratio of products was 1:1, showing no
discrimination between the two faces of the prochiral
aldehyde. Pure compounds were isolated through recrys-
tallization or column chromatography (ethyl acetate and/
or hexane). To the best of our knowledge, this is the first
application of a [P(O)N–] fragment as DoM group. These
results indicate that the DoM behavior of secondary and
tertiary phosphinamides is similar to that observed for the
corresponding phenylcarboxamides.14
The ortho deprotonation of phosphinamide 14 was chal-
lenging since the lithiation of this compound with t-BuLi
in THF at –90 °C in the presence of DMPU is known to
take place at the N–Ca position providing enantiomerical-
ly pure dearomatized products.16 We were pleased to find
that in the absence of coordinating cosolvent, the same re-
action conditions directed the metalation of 14 almost ex-
clusively to the ortho position (<5% of dearomatized
products). After addition of MeI, Me3SnCl, and (n-
Bu)3SnCl the diastereomeric phosphinamides 16 and 17
were formed in very high conversions although in a disap-
pointing 1:1 ratio (Scheme 3, Table 2, entries 5–7). Using
benzaldehyde as quenching agent the diastereoselectivity
is slightly improved, i.e. three diastereoisomers 18, 18¢
and 18¢¢ (entry 8, Table 2) out of four were obtained.
Crystals of the major isomer 18¢ suitable for X-ray diffrac-
tion were grown from hexane–ethyl acetate solution at
ambient temperature.17 Figure 1 shows a view of the crys-
tal structure. The absolute configuration of 18 was deter-
mined by anomalous dispersion.
All the new products synthesized were characterized
based on their 1D and 2D NMR data. Simple inspection of
the aromatic region of the 1H spectra allowed us to estab-
lish the position of substitution, i.e. 2:1 integral ratio for
the ortho protons of the P-phenyl rings. Moreover, the
ortho substitution renders the isopropyl groups diaste-
reotopic. No evidence of isopropyl substitution was ob-
served, validating the substrate design. Interestingly, the
stannylated derivatives exhibited a low field 31P signal
with respect to the starting material (Dd = +5.7 ppm for 9
and Dd = +2.7 ppm for 11), an effect ascribed to the coor-
dination of the oxygen atom of the PO linkage to the
metal. As far as we are aware, this is the first regioselec-
tive synthesis of o-stannylphosphinamides reported so far.
The ortho deprotonation of phosphinamide 13 proved to
be a much more efficient process. Firstly, the metalation
could be carried out at –35 °C using n-BuLi as a base
without observing the appearance of byproducts arising
from the competing N–Ca lithiation (Scheme 3). Second-
ly, and more importantly, the reaction of the dianions with
a series of chlorostannanes furnished the expected ortho-
stannyl derivatives in high conversion and in unequal pro-
portion. The ratio of enantiomerically pure epimers 15:15¢
Synlett 2007, No. 4, 611–614 © Thieme Stuttgart · New York

LETTER
Phosphinamide-Directed ortho Metalations
613
Me
Me
N
O
O
Me
b, c
a
Ph
Ph
Ph2P
N
H
Ph2P
Ph
H2N
Me
14
13
Me
Li
Ph
E
O
Ph2P
O
P
Me
d
Ph
N
H
N
Li
Ph
13
e
O
Me
O
Me
Ph
E
P
N
H
Ph
+
P
N
H
Ph
15
Ph
15'
Figure 1 ORTEP view of 18¢ showing 50% probability displace-
ment ellipsoids and atom labeling scheme
Me
N
Li
O
together with X-ray crystallography. A detailed structural
study will be published elsewhere. These results provide
the first examples of the desymmetrization of a diphen-
ylphosphoryl moiety using the DoM methodology. A re-
lated process consisting of the diastereoselective ortho
deprotonation of ferrocenyl derivatives directed by ste-
reogenic phosphorus-containing functional groups has
been described.18
O
Me
f
Ph
Ph2P
14
P
N
Ph
Me
Ph
Me
e
O
P
Me
E
Ph
O
Me
E
N
Ph
+
P
N
Ph
Me
Ph
Me
In summary, we have demonstrated that the phosphin-
amide moiety can efficiently direct the ortho-deprotona-
tion reaction of a phenyl ring linked to the phosphorus
under mild conditions providing simple access to ortho-
functionalized phosphorus-based compounds in good
yields. Preliminary results on the asymmetric DoM
reactions in chiral diphenylphosphinamides are promis-
ing. For N-alkylphosphinamides, enantiomerically pure
epimers were obtained in a ratio ranging from 1:2 to 1:5.
The ortho-stannylated compounds isolated contain two
reactive centers, the phosphorus and tin atoms, thus
opening new possibilities for further transformations.
Additional work is in progress to improve the diastereo-
selectivity of the process and to explore new applications.
16'–18'
16–18, 18''
Scheme 3 Reagents and conditions: a) Ph2P(O)Cl, Et3N, THF,
–78 °C to r.t., 2 h; b) NaH, THF, 0 °C, 1 h; c) MeI, 0 °C to r.t., 2 h;
d) n-BuLi, –35 °C, 2 h; e) E+ [MeI, PhCHO, Me3SnCl, (n-Bu)3SnCl,
Ph3SnCl], –90 °C; f) t-BuLi, –90 °C, 2 h.
varied from 1:2 for Me3SnCl, and (n-Bu)3SnCl to 1:5 for
Ph3SnCl (Table 2, entries 1, 3 and 4).
The pairs of enantiomerically pure epimers were separat-
ed through flash column chromatography and character-
ized by NMR. The assignment of the configuration was
based on the analysis of the 1D and 2D NOESY spectra
Table 2 Product Distribution in the ortho-Lithiation–Electrophilic Trapping Reaction of Phosphinamides 13 and 14
Entry
Electrophile
Me3SnCl
Me3SnCl
(n-Bu)3SnCl
Ph3SnCl
Temp (°C)
–35
Time (h)
Substrate
Product
Conversion (%)a Ratioa
1
2b
3
4
5
6
7
8
2
13
13
13
13
14
14
14
14
15a/15a¢
15a/15a¢
15b/15b¢
15c/15c¢
16/16¢
83
85
82
85
92
97
96
95
1:2
–35
2
1:2
–35
2
1:2
–35
2
1:5
MeI
–90
0.5
0.5
0.5
0.5
1:1
Me3SnCl
(n-Bu)3SnCl
PhCHO
–90
17a/17a¢
17b/17b¢
18/18¢/18¢¢
1:1
–90
1:1
–90
0.5:0.5:1
a Established based on 31P NMR.
b The base used was n-BuLi.
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614
I. Fernández et al.
LETTER
(9) (a) Fernández, I.; Forcén-Acebal, A.; López-Ortiz, F.;
Acknowledgment
García-Granda, S. J. Org. Chem. 2003, 68, 4472.
(b) Fernández, I.; González, J.; López-Ortiz, F. J. Am. Chem.
Soc. 2004, 126, 12551.
This research was supported by the Ministerio de Educación y
Ciencia (MEC) (project: CTQ2005-1792BQU and 05093BQU to
SGG). I.F. thanks the Ramon y Cajal program for financial support.
GRG thanks the Ministerio de Ciencia y Tecnología for a doctoral
fellowship.
(10) (a) Abatjoglou, A. G.; Eliel, E. L. J. Org. Chem. 1974, 39,
3042. (b) Magnus, P.; Roy, G. Synthesis 1980, 575.
(11) (a) Gutmann, V.; Mörtl, G.; Utvary, K. Monatsh. Chem.
1962, 93, 1114. (b) For spectroscopic data of 4, see: Cristau,
H.-J.; Jouanin, I.; Taillefer, M. J. Organomet. Chem. 1999,
584, 68. (c) Substrate 5 was synthesized according to the
procedure used by Wills et al.15
(12) The analogous reaction of N,N-dialkylthiophosphinamides
produced the quantitative displacement of the amino moiety.
See reference 4h.
(13) Typical Procedure for the Synthesis of 15a¢
To a solution of the phosphinamide 13 (3.11·10–4 mol) in
THF (30 mL) was added a solution of n-BuLi (0.7 mL of a
1.6 M solution in cyclohexane, 10.9·10–4 mol) at –35 °C.
After 2 h of metalation was added chlorotrimethyltin
(10.9·10–4 mol). The reaction mixture was stirred at the same
temperature for 30 min and then was poured into ice water
and extracted with EtOAc (3 × 15 mL). The organic layers
were dried over Na2SO4 and concentrated in vacuo. 1H
NMR, 1H{31P} NMR, and 31P NMR spectra of the crude
reaction were measured in order to determine the
stereoselectivity of the process. The reaction mixture was
then purified by flash column chromatography using a
mixture of EtOAc–hexane (1:5) as eluent.
References and Notes
(1) For some recent reviews on the DoM reaction of arenes, see:
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Angew. Chem. Int. Ed. 2004, 43, 888. (c) Macklin, T. K.;
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(c) Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman, G. W.;
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Spectroscopic Data of 15a¢
1H NMR (300 MHz, THF-d8): d = 0.32 (s, 9 H), 1.57 (d, 3 H,
JPH = 6.8 Hz), 4.19 (m, 1 H), 5.10 (1 H, JPH = 5.4, 10.1 Hz,
NH), 7.16–7.50 (10 H), 7.80 (m, 2 H), 7.99 (m, JPH = 11.4,
7.5 Hz). 13C NMR: d = –5.32 (CH3, JPC = 1.2 Hz), 50.82
(CH), 125.92 (HCAr), 126.27 (HCAr), 127.50 (HCAr, JPC
12.2 Hz), 127.87 (HCAr), 127.93 (HCAr, JPC = 11.9 Hz),
130.02 (HCAr, JPC = 3.8 Hz), 131.12 (HCAr, JPC = 2.6 Hz),
132.12 (HCAr, JPC = 9.0 Hz), 132.17 (HCAr, JPC = 12.8 Hz),
134.39 (Cipso, JPC = 127.4 Hz), 136.25 (HCAr, JPC = 17.4
Hz), 137.74 (ipso, JPC = 133.2 Hz), 145.69 (Cipso, JPC = 7.4
Hz), 151.17 (Cipso, JPC = 18.2 Hz). 31P NMR: d = 23.58. Oil.
MS (API-ES): m/z (%) = 508 (5) [M + Na], 470.1 (1009
[M – 15]. Anal. Calcd (%) for C23H28NOPSn: C, 57.06; H,
5.83; N, 2.89. Found: C, 57.0; H, 5.70; N, 2.97.
=
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(17) The crystal data of 18¢ has been deposited in CCDC with
number 625923.
(7) (a) Fernández, I.; López-Ortiz, F.; Tejerina, B.; García-
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Synlett 2007, No. 4, 611–614 © Thieme Stuttgart · New York