Pd-catalysed ortho-alkoxylation of benzamides N-protected with an iminophosphorane functionality

Article abstract of DOI:10.1039/c5nj00189g

The oxidative coupling of keto-stabilised iminophosphoranes (IPs) Ph₃P=NC(O)C₆H_xR_y with alcohols R′OH affords the alkoxylated species Ph₃P=NC(O)C₆H_x-1R_y-2-OR′. The process is catalysed by 10% PdCl₂(NCMe)₂, uses oxone as an oxidant and alcohol R′OH as a source of OR′ groups and reaction solvent. The reaction takes place at room temperature regioselectively at the ortho-position of the benzamide ring, gives only the mono-alkoxylated derivatives, and shows tolerance to a variety of functional groups and different primary and secondary alcohols. Better yields were obtained when the aryl ring contains electron-releasing substituents (OMe, Me). The iminophosphorane moiety plays a dual role as the protecting/directing group, and can be hydrolysed to give the corresponding free benzamide.

Full text of DOI:10.1039/c5nj00189g

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Journal Name
RSCPublishing
ARTICLE
Pd-catalysed ortho-alkoxylation of benzamides N-
protected with an iminophosphorane functionality
Cite this: DOI: 10.1039/x0xx00000x
Pedro Villuendas,a Elena Serranob and Esteban P. Urriolabeitia*a
The oxidative coupling of ketoꢀstabilised iminophosphoranes (IPs) Ph3P=NC(O)C6HxRy with
alcohols R'OH affords the alkoxylated species Ph3P=NC(O)C6Hxꢀ1Ryꢀ2ꢀOR'. The process is
catalysed by 10% PdCl2(NCMe)2, uses oxone® as oxidant and the alcohol R'OH as source of
OR' groups and reaction solvent. The reaction takes place at room temperature regioselectively
at the orthoꢀposition of the benzamide ring, gives only the monoꢀalkoxylated derivatives, and
shows tolerance to a variety of functional groups and different primary and secondary alcohols.
Better yields were obtained when the aryl ring contains electronꢀreleasing substituents (OMe,
Me). The iminophosphorane moiety plays a dual role as protecting/directing group, and can be
hydrolysed to give the corresponding free benzamide.
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
particular reluctance to be functionalised, and this reaction is
worth to be studied in more depth.
Introduction
One of the most interesting issues in today’s chemistry is the
functionalisation of simple organic molecules to yield more
complex, high valuable molecules. In this context, the
transformation of inert and ubiquitous C–H bonds into more
reactive and elaborated C–C or C–X bonds (X = O, N, S,
halogen) mediated by transition metals is of paramount
importance.1 While the introduction of the metal (mostly Pd,
Ru, Rh or Pt) overcomes the problem of the low reactivity of
the C–H bond, the goal of a highly selective orientation has
been achieved using several approximations. Among them, the
directed C–H activation is probably the most versatile strategy
to reach C–C and C–X couplings with good yields and
selectivities, specially for C(sp2)–H bonds.2 In this way a high
number of tranformations have been successfully developed,
although not all of them are equally represented. Therefore,
while Caryl–C couplings are now easily produced by directed
oxidative coupling of two C–H bonds, examples of Caryl–O
bond formations are less frequent,2n,2o,3 this fact being probably
related with the different metalꢀligand bond strengths, as well
as with the different electronegativities of the atoms involved.4
As a consequence, further development of Caryl–O bond
forming reactions is still desirable, because products containing
the C–O unit (aryl ethers, among others) are of high practical
importance due to their pharmacological activity or as building
blocks in fine chemistry.5 The oxidative coupling of aryl rings
and alcohols, promoted by palladium in high oxidation states,
affords alkoxylated arylꢀderivatives as showed in pionnering
works of Sanford and Yu.6 Despite notable recent progress in
this area7 not only the C–O bond formation by catalysed
alkoxylation is still challenging, but certain substrates show
Benzamides are one of the special class of molecules difficult
to functionalise through C–H bond activation, due to the strong
electronwithdrawing effect of the amide group. However,
during our current research on metalꢀmediated C–H bond
activation processes on iminophosphoranes (IPs),8 we have
found a regioselective incorporation of the Pd center to the
benzamide ring in the case of ketoꢀstabilised IPs R3P=NC(O)Ar
(R = alkyl, aryl; Ar = substituted aryl). This reaction affords
orthopalladated benzamideꢀderivatives under very mild reaction
conditions, circumventing the typical low reactivity of
benzamides.8e,8k Furthermore we have shown that is possible to
functionalise the orthopalladated benzamide ring selectively in
mild conditions, using IPs as directing/protecting groups in Pdꢀ
mediated CO insertions and in oxidative additions of iodine, as
it is shown in Scheme 1.8c
Scheme 1. Iminophosphoranes as protecting/directing groups
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In this way, the protection of the benzamide nitrogen as an IP Other oxidants used in Pdꢀcatalysed oxidative couplings, such
group ꢀN=PR3 plays several roles besides its character as Nꢀ as Cu(OAc)2, AgOAc or benzoquinone (entries 6ꢀ8), were not
directing group, being the most important the tuning of the efficient in the alkoxylation of 1a and only products derived
reactivity of the aryl ring by change of the electron density, from the decomposition of the starting IP (mainly O=PPh3)
shifting the positive charge towards the P atom, and activating were detected. We then decided to screen new catalysts, using
this ring towards the incorporation of the Pd center.8e
oxone® as oxidant, and we selected different Pd salts among
Because both the C–H bond activation and the subsequent typical complexes used as C–H activation promoters. The use
reactivity of the orthopalladated intermediate take place of Li2[PdCl4] gave only a low 24% yield of 3aa (entry 9) but,
smoothly, we hypothesize that the use of IPs as protectingꢀ fortunately, the use of PdCl2(NCMe)2 allowed the obtention of
directing groups could allow roomꢀtemperature catalytic functionalised 3aa in a good 76% isolated yield (entry 10).
functionalisation of benzamides. We report here our results in Further attempts to optimise the reaction conditions using
the Pdꢀcatalysed orthoꢀalkoxylation of benzamides protected as PdCl2(NCMe)2 as catalyst did not resulted in additional
ketoꢀstabilised iminophosphoranes. This process shows some improvements of the reaction yield. A control experiment using
remarkable improvements with respect to previous works, such C6H5C(O)NH2 under conditions described in entry 10 showed a
as performance at room temperature (avoiding usual harsh 10 % conversion of benzamide to give 2ꢀmethoxybenzamide.
conditions),7cꢀ7i tolerance to a variety of substituents in the Once the reaction conditions were optimised we have studied
benzamide moiety and to different primary and secondary the scope of the reaction. In a first step we have checked the
alcohols, and easy removal of the IP moiety.
reactivity of IPs 1a-1g towards methanol 2a, which acts as
methoxide source and as reaction solvent. IPs 1a-1g contain
substituents of different nature (electronꢀreleasing and electronꢀ
withdrawing groups) at different positions of the benzamide
Results and discussion
We started our studies on alkoxylation of Ph3P=NC(O)Ph 1a
with methanol 2a using Pd(OAc)2 as catalyst (10%), based on
the easy orthopalladation of 1a by Pd(OAc)2 observed in our
previous works.8e,8k The oxidant was the first parameter to be
changed and optimised. The use of PhI(OAc)2 as oxidant results
in a complete lack of reactivity (entry 1), even at 100 ºC (entry
2) while the use of oxone® allows to obtain the methoxylated
derivative 3aa in 30% isolated yield (entry 3). This yield was
not improved by a further increase of the temperature (entry 4),
neither by an increase of the amount of oxidant (entry 5).
ring (oꢀ, mꢀ, pꢀ). The obtained results are shown in Scheme 2.
Table 1. Optimization of the reaction conditions for the
catalytic synthesis of 3aaa
Entry
Catalyst
Oxidant
T
(ºC)
23
t (h)
3aa
(%)b
0
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Li2[PdCl4]
PdCl2(NCMe)2
PhI(OAc)2
18
2
PhI(OAc)2 100
0
3
oxone®c
oxone®c
oxone®d
Cu(OAc)2
AgOAce
benzoq.
oxone®c
oxone®c
oxone®c
23
40
23
23
23
23
23
23
23
18
18
68
18
18
18
18
18
18
30
8
Scheme 2. Scope of the alkoxylation of iminophosphoranes:
4
change of substrate. Standard reaction conditions: IPs 1a-g
,
5
18
0
catalyst PdCl2(NCMe)2 [Pd], and oxone® (amounts specified in
experimental) in MeOH were stirred at 23 ºC (r.t.) for 18h
6
7
0
8
0
In all studied cases the alkoxylation is Pdꢀcatalysed and takes
place with complete conversion at room temperature in 18 h.
The mild reaction conditions and the short reaction times at this
temperature are clear advantages with respect to previous
published reports, which use prolongued heating.7cꢀ7i It is
remarkable that the reaction occurs with preservation of the
9
24
76
61
10
11
f
PdCl2(NCMe)2
a) Standard reaction conditions: 1a (0.5 mmol), PdCl2(NCMe)2
[Pd] (0.05 mmol), and the oxidant (1 mmol) in MeOH were
stirred at the indicated temperature during the specified time; b)
isolated yield (%); c) 1 mmol; d) 2 mmol; e) the same result
was obtained at 100 ºC; f) 5 mol % PdCl2(NCMe)2.
N=P functional group (at least in examples 3aa-3ga and 3ab
,
see below); no alcoholysis of the N=P bond was observed in
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5NJ00189G
spite of the protic nature of the solvent. In addition, the reaction end of the reaction, the presence of the IP moiety is mandatory
occurs with regioselective incorporation of one methoxide for the successful functionalisation of the benzamide ring. This
group at the ortho position of the benzamide ring. Even when is clearly shown when benzamide C6H5C(O)NH2 was subjected
two positions are available, only one OMe group is added to the to identical alkoxylation conditions than IP C6H5C(O)N=PPh3
i
starting IP. The regioselectivity in the methoxide incorporation 1a [PdCl2(NCMe)2 10%, PrOH, oxone®, 80 ºC, 18 h), because
is notable in the cases of compounds 3ca
, 3ea and 3fa whose no reaction at all was observed in the case of the free
precursors 1c 1e and 1f contain a substituent in 3ꢀposition or benzamide. Therefore, species 1a undergoes the Pdꢀcatalysed
,
two substituents in 3,4ꢀpositions and, therefore, can generate incorporation of the alkoxy moiety, giving the corresponding 2ꢀ
two isomers. In the studied cases only the products resulting of ROC6H4C(O)N=PPh3 compounds, which then hydrolyse under
the C–H activation at the less sterically hindered position were the reaction conditions affording benzamides 3ac-3af
obtained, instead of the typical mixtures of isomers. The
.
isolated yields are from moderate to good when electronꢀ
donating substituents are present
(3aa-3fa), with major
differences in the cases of 3ca and 3ea due to difficulties in
purification of the crude products. However, this yield drops
notably when the IP contains an electronꢀattracting group, for
instance 1g. In this case partial conversion has been observed,
most of the starting material remains unreacted and 3ga
represents only 16% of the final mixture (see Experimental).
We assign this effect to the strong deactivating nature of the 2ꢀ
nitro substituent. Attempts carried out with other electronꢀ
withdrawing groups as aryl substituents (2ꢀCl, 4ꢀCl and 2ꢀBr)
did not resulted in the expected alkoxylated products, and this
type of groups were not further investigated.
The case of compound 3fa merits a more detailed explanation.
After usual workꢀup of the crude only Ph3P=O was obtained
from column chromatography (see Experimental). The amount
of phosphine oxide obtained was higher than in the preceding
cases, suggesting that extensive hydrolysis occurred in this
case. An increase of the solvent polarity for chromatographic
elution allowed to obtain free benzamide 3fa in 67% yield. The
analysis of the crude by 31P NMR before chromatography
showed the presence of O=PPh3 as the unique Pꢀcontaining
species, suggesting that the hydrolysis has occurred during the
reaction, and not during the purification of the product.
Once the range of IPs has been examined, we tested the scope
of alcohols amenable to give oxidative coupling. Usually the
range of alcohols used is quite limited, being methanol the only
alcohol used in many cases. The obtained results are shown in
Scheme 3. The oxidative coupling of 1a with ethanol 2b occurs
in smooth conditions to give iminophosphorane 3ab in 46%
yield, which is similar to yields of other ethoxylation processes
found in the literature.7 Compound 3ab shows the incorporation
of a single OEt unit, as described above for the incorporation of
the OMe group.However, no reaction was observed when the
Scheme 3. Scope of the alkoxylation of iminophosphoranes:
change of alcohol. Standard reaction conditions: 1a, catalyst
PdCl2(NCMe)2 [Pd], and oxone® (amounts in experimental) in
alcohol ROH were stirred at 23 (r.t.), 60 or 80 ºC (depending of
the alcohol) for 18h.
Concerning the mechanism of this process, our proposal is
presented in Scheme 4, and it is based on the following steps.
The first step is the formation of the corresponding orthoꢀ
palladated species A through C–H bod activation. This step has
been studied in depth in our group recently, and takes place
through a concerted metallationꢀdeprotonation mechanism
(CMD).8e,8i
n
i
alkoxylation of 1a was attempted with PrOH 2c, PrOH 2d
,
nBuOH 2e or BuOH 2f at room temperature. In these cases an
increase of the reaction temperature was necessary to trigger
the oxidative coupling, although this increase of temperature
promoted an unavoidable hydrolysis of the expected
alkoxylated IP intermediate. In this way, orthoꢀfunctionalised
i
Scheme 4. Proposed mechanism for the alkoxylation of ketoꢀ
stabilised iminophosphoranes
free benzamides 3acꢀ3af were obtained in moderated yields, as
shown in Scheme 3.
Compounds 3ac-3af were already known, and they show
interest due to their antifungal, analgesic and antipyretic
properties.9,10 Although the free benzamide is obtained at the
The next step is the oxidation of the PdII center to a more
electrophilic PdIV center B, achieved by the use of oxone® as
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oxidant. This highly electrophilic PdIV center should able to yellow suspension thus formed was dissolved with EtOAc (150 mL)
coordinate at least one alkoxide from the alcohol. We have and washed with aqueous Na2SO3 (10%, 3×30 mL) and then with a
recently isolated and characterize PdIV derivatives containing saturated NaCl solution (2×30 mL). The organic phase was
simultaneously orthometallated iminophosphoranes and anionic separated, dried with anhydrous MgSO4, filtered and evaporated to
Oꢀdonor ligands,8a therefore this step is really likely to occur. dryness, affording a residue containing impure 3aa. Compound 3aa
Final CꢀO coupling and reductive elimination affords the was purified by column chromatography on basic alumina using
alkoxylated iminophosphorane and regenerates the active PdII ethyl acetate/ether (8:5) as eluent. The first colourless band was
species.
collected and evaporated to dryness affording pure 3aa as a white
solid. Obtained: 0.205 g, 0.498 mmol (76% yield). Further elution
afforded a second colorless band which was Ph3P=O. 1H NMR
(CDCl3): δ 3.86 (3H, s, OMe), 6.91ꢀ6.96 (2H, m, H3+H5, C6H4), 7.22
Conclusions
In summary, we have shown that the Nꢀprotection of
benzamides under the form of iminophosphoranes (IPs) is very
useful for the obtention of orthoꢀfunctionalised benzamides
otherwise not achievable or obtained less efficiently. In the
present contribution we have applied this concept to the always
difficult C–O oxidative coupling between ketoꢀstabilised IPs
and alcohols catalysed by palladium. The reaction gives the
corresponding orthoꢀalkoxylated IPs where the benzamide ring
has undergone the regioselective incorporation of the alkoxy
moiety, and takes place under very mild conditions (room
temperature). From the orthoꢀalkoxylated IPs it is possible to
obtain the corresponding orthoꢀalkoxylated free benzamides.
Further applications of IPs as protecting/directing groups in
other metalꢀcatalysed reactions are currently in progress.
3
4
(H4, td, 1H, C6H4, JHH = 7.5, JHH = 1.9), 7.36 (6H, m, Hm, PPh3),
7.44 (3H, m, Hp, PPh3), 7.76 (6H, m, Ho, PPh3), 8.02 (1H, dd, H6,
3
4
C6H4, JHH = 7.5, JHH = 1.8). 13C{1H} NMR (CDCl3): δ 56.03 (s,
OMe), 112.00 (s, C3, C6H4), 119.93 (s, C5, C6H4), 128.36 (d, Ci,
1
3
PPh3, JPC = 99.1) 128.50 (d, Cm, PPh3, JPC = 12.3), 129.77 (d, C1,
C6H4, 3JPC = 20.4), 130.60 (s, C4, C6H4), 131.67 (s, C6, C6H4), 132.11
(d, Cp, PPh3, 4JPC = 2.9), 133.32 (d, Co, PPh3, 2JPC = 10.0), 158.24 (s,
2
C2, C6H4), 177.38 (d, C=O, JPC = 8.0). 31P{1H} NMR (CDCl3): δ
19.96 (s). IR (ν, cmꢀ1): 1598 (C=O), 1339 (P=N). MS (ESI+): 412.1
(98 %) [M+H]+. Found: C, 75.80; H, 5.44; N, 3.28. Calc. for
C26H22NO2P: C, 75.90; H, 5.39; N, 3.40%.
Synthesis of 3ba. Compound 3ba was prepared using the same
method than 3aa, but starting from Ph3P=NC(O)C6H4ꢀ2ꢀMe 1b
(0.260 g, 0.657 mmol), PdCl2(NCMe)2 (17.1 mg, 0.066 mmol) and
oxone® (0.806 g, 1.31 mmol) in MeOH 2a (15 mL). 3ba was
purified by column chromatography on basic Al2O3 using ethyl
acetate/hexane (8:5) as eluent, and obtained as a white solid.
Experimental
General methods
1
Solvents were dried and distilled using standard procedures
before use. All reactions were carried out under Ar atmosphere
using standard Schlenck techniques. Flash column liquid
chromatographies were performed on basic Al2O3 of 90 neutral
(50ꢀ200 µm) grade. Elemental analyses were performed on a
PerkinElmer 2400 Series II microanalyser. Infrared spectra
(4000ꢀ380 cmꢀ1) were recorded on a PerkinꢀElmer Spectrum
One IR spectrophotometer. 1H, 13C{1H} and 31P{1H} NMR
spectra were recorded in CDCl3 solutions at 25 ºC on a Bruker
Obtained: 0.171 g, 0.400 mmol (61% yield). H NMR (CDCl3): δ
2.30 (3H, s, Meꢀ6) 3.83 (3H, s, OMeꢀ2), 6.71ꢀ6.74 (2H, m, H3+H5,
3
C6H3), 7.08 (1H, t, H4, C6H3, JHH = 7.9), 7.47 (6H, m, Hm, PPh3),
7.56 (3H, m, Hp, PPh3), 7.86 (6H, m, Ho, PPh3). 13C{1H} NMR
(CDCl3): δ 19.29 (s, Meꢀ6), 56.01 (s, OMeꢀ2), 108.68 (s, C3, C6H3),
122.43 (s, C5, C6H3), 127.43 (s, C4, C6H3), 128.28 (d, Ci, PPh3, 1JPC
=
=
=
3
4
98.5), 128.50 (d, Cm, PPh3, JPC = 12.3), 132.13 (d, Cp, PPh3, JPC
3
2
2.9), 132.62 (d, C1, C6H3, JPC = 8.8) 133.38 (d, Co, PPh3, JPC
10.0), 135.0 (s, C6, C6H3), 155.78 (s, C2, C6H3), 179.08 (d, C=O, 2JPC
= 8.8). 31P{1H} NMR (CDCl3): δ 19.48 (s). IR (ν, cmꢀ1): 1577
(C=O), 1332 (P=N). MS (ESI+): 426.1 (97 %) [M+H]+. Found: C,
76.37; H, 5.39; N, 3.11. Calc. for C27H24NO2P: C, 76.22; H, 5.69; N,
3.29%.
AV400 spectrometer (δ in ppm,
J
in Hz) at 1H operating
frequency of 400.13 MHz. H and 13C{1H} NMR spectra were
referenced using the solvent signal as internal standard, while
31P{1H} NMR spectra were referenced to H3PO4 (85%). ESI
(ESI+) mass spectra were recorded using an Esquire 3000 ionꢀ
trap mass spectrometer (Bruker Daltonic GmbH) equipped with
a standard ESI/APCI source. Samples were introduced by direct
infusion with a syringe pump. Nitrogen served both as the
nebulizer gas and the dry gas. Compound PdCl2(NCMe)2 was
prepared as previously reported.11 Iminophosphoranes 1a-1g
were prepared following methods previously reported.8b,8e,8k,12
1
Synthesis of 3ca. Compound 3ca was prepared using the same
method than 3aa, but starting from Ph3P=NC(O)C6H4ꢀ3ꢀMe 1c
(0.202 g, 0.511 mmol), PdCl2(NCMe)2 (13.2 mg, 0.051 mmol) and
oxone® (0.620 g, 1.01 mmol) in MeOH 2a (15 mL). 3ca was
purified by column chromatography on basic Al2O3 using ethyl
acetate/hexane (8:5) as eluent, and obtained as a white solid.
1
Obtained: 0.091 g, 0.213 mmol (42% yield). H NMR (CDCl3): δ
2.29 (3H, s, Meꢀ5) 3.84 (3H, s, OMeꢀ2), 6.82 (1H, d, H3, C6H3, 3JHH
Synthesis of ortho-alkoxylated iminophosphoranes
4
= 8.3), 7.11 (1H, dd, H4, C6H3, 3JHH = 8.3, JHH = 2.4), 7.46 (6H, m,
Synthesis of 3aa. To a suspension of Ph3P=NC(O)Ph 1a (0.250 g,
0.655 mmol) in MeOH 2a (15 mL), PdCl2(NCMe)2 (16.8 mg, 0.065
mmol) and oxone® (0.806 g, 1.31 mmol) were added, and the
resulting mixture was stirred for 18 h at room temperature. The
4
Hm, PPh3), 7.54 (3H, m, Hp, PPh3), 7.79 (1H, d, H6, C6H3, JHH
=
2.4), 7.86 (6H, m, Ho, PPh3). 13C{1H} NMR (CDCl3): δ 20.50 (s,
Meꢀ5), 56.34 (s, OMeꢀ4), 112.26 (s, C3, C6H3), 128.37 (d, Ci, PPh3,
1JPC = 99.0), 128.60 (d, Cm, PPh3, 3JPC = 12.3), 129.10 (s, C5, C6H3),
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DOI: 10.1039/C5NJ00189G
129.48 (d, C1, C6H3, 3JPC = 20.2), 130.95 (s, C4, C6H3), 131.66 (s, C6, Synthesis of 3ab. Compound 3ab was prepared using the same
4
2
C6H3), 132.10 (d, Cp, PPh3, JPC = 2.8), 133.34 (d, Co, PPh3, JPC
=
method than 3aa, but starting from Ph3P=NC(O)C6H5 1a (0.138 g,
9.9), 156.20 (s, C2, C6H3), 177.61 (d, CO, 2JPC = 5.1). 31P{1H} NMR 0.362 mmol), PdCl2(NCMe)2 (9.4 mg, 0.036 mmol) and oxone®
(CDCl3): δ 20.21 (s). IR (ν, cmꢀ1): 1614 (C=O), 1339 (P=N). MS (0.445 g, 0.724 mmol) in EtOH 2b (15 mL). 3ab was purified by
(ESI+): 426.1 (100 %) [M+H]+. Found: C, 76.08; H, 5.51; N, 3.34. column chromatography on basic Al2O3 using ethyl acetate/hexane
Calc. for C27H24NO2P: C, 76.22; H, 5.69; N, 3.29%.
(8:5) as eluent, and obtained as a white solid. Obtained: 0.070 g,
0.165 mmol (46% yield). 1H NMR (CDCl3): δ 1.32 (3H, t, CH3, OEt,
Synthesis of 3da. Compound 3da was prepared using the same 3JHH = 7.0), 4.02 (2H, q, CH2, OEt), 6.82ꢀ6.86 (2H, m, H3 + H5,
method than 3aa, but starting from Ph3P=NC(O)C6H4ꢀ4ꢀOMe 1d C6H4), 7.18 (1H, td, H4, C6H4, JHH = 7.8, JHH = 1.8), 7.39 (6H, m,
3
4
3
(0.250 g, 0.608 mmol), PdCl2(NCMe)2 (15.5 mg, 0.060 mmol) and Hm, PPh3), 7.48 (3H, m, Hp, PPh3), 7.69 (1H, dd, H6, C6H4, JHH
=
oxone® (0.75 g, 1.22 mmol) in MeOH 2a (15 mL). 3da was purified 7.8, JHH = 1.9), 7.79 (6H, m, Ho, PPh3). 13C{1H} NMR (CDCl3): δ
by column chromatography on basic Al2O3 using ethyl 15.15 (s, OCH2CH3), 64.46 (s, OCH2CH3), 113.38 (s, C3, C6H4),
acetate/hexane (8:5) as eluent, and obtained as a white solid. 120.10 (s, C5, C6H4), 128.34 (d, Ci, PPh3, 1JPC = 98.9), 128.56 (d, Cm,
4
1
Obtained: 0.183 g, 0.414 mmol (68% yield). H NMR (CDCl3): δ PPh3, 3JPC = 13.0), 129.96 (s, C4, C6H4), 130.25 (s, C6, C6H4), 132.09
3.82 (3H, s, OMe), 3.86 (3H, s, OMe), 6.46ꢀ6.50 (2H, m, H3 + H5, (d, Cp, PPh3, 4JPC = 2.9), 133.33 (d, Co, PPh3, 2JPC = 10.0), 157.00 (s,
C6H3), 7.45 (6H, m, Hm, PPh3), 7.53 (3H, m, Hp, PPh3), 7.84 (6H, m, C2, C6H4). The signals attributed to C1 (C6H4) and C=O were not
3
Ho, PPh3), 8.20 (1H, d, H6, C6H3, JHH = 8.3). 13C{1H} NMR observed, in spite of the use of long accumulation trials. 31P{1H}
(CDCl3): δ 55.35 (s, OMe), 56.04 (s, OMe), 99.25 (s, C3, C6H3), NMR (CDCl3): δ 19.87 (s). IR (ν, cmꢀ1): 1600 (C=O), 1330 (P=N).
3
103.93 (s, C5, C6H3), 121.97 (d, C1, C6H3, JPC = 20.7), 128.52 (d, MS (ESI+): 426.1 (100 %) [M+H]+. Found: C, 76.09; H, 5.31; N,
3
1
Cm, PPh3, JPC = 12.3), 128.76 (d, Ci, PPh3, JPC = 99.2), 131.95 (d, 3.06. Calc. for C27H24NO2P: C, 76.22; H, 5.69; N, 3.29%.
Cp, PPh3, 4JPC = 2.9), 133.31 (d, Co, PPh3, 2JPC = 9.9), 133.88 (d, C6,
C6H3, 4JPC = 1.9), 160.48, 162.24 (C2, C4, C6H3), 176.34 (d, CO, 2JPC
Synthesis of ortho-alkoxylated benzamides
= 4.5). 31P{1H} NMR (CDCl3): δ 19.58 (s). IR (ν, cmꢀ1): 1599
Synthesis of 3fa. Compound 3fa was prepared using the same
method than 3aa, but starting from Ph3P=NC(O)C6H3ꢀ3,4ꢀ(OMe)2 1f
(0.150 g, 0.340 mmol), PdCl2(NCMe)2 (8.8 mg, 0.034 mmol) and
oxone® (0.418 g, 0.68 mmol) in MeOH 2a (15 mL). However, the
(C=O), 1333 (P=N). MS (ESI+): 442.1 (100%) [M+H]+. Found: C,
73.71; H, 5.56; N, 3.18. Calc. for C27H24NO3P: C, 73.46; H, 5.48; N,
3.17%.
workup of the reaction was different, because purification of 3fa
proved to be more difficult than in previous cases. Thus, after
extensive elution of the chromatographic column (Al2O3) with ethyl
acetate/hexane (8:5) as eluent, only O=PPh3 was obtained. The
Synthesis of 3ea. Compound 3ea was prepared using the same
method than 3aa, but starting from Ph3P=NC(O)C6H4ꢀ3ꢀOMe 1e
(0.252 g, 0.612 mmol), PdCl2(NCMe)2 (15.9 mg, 0.061 mmol) and
oxone® (0.75 g, 1.22 mmol) in MeOH 2a (15 mL). 3ea was purified
change of the solvents ratio to ethyl acetate/hexane (4:1) developed a
by column chromatography on basic Al2O3 using ethyl
new colourless band from which, after evaporation, 3fa was obtained
acetate/hexane (8:5) as eluent, and obtained as a white solid.
as a white solid. Obtained: 0.048 g, 0.228 mmol (67.0% yield).
1
Obtained: 0.120 g, 0.272 mmol (44.5% yield). H NMR (CDCl3): δ
Characterization of 3fa has been performed by comparison of its
3.78 (3H, s, OMe), 3.83 (3H, s, OMe), 6.86ꢀ6.87 (2H, m, H3 + H4,
spectral data with those recently published.13
C6H3), 7.46 (6H, m, Hm, PPh3), 7.52ꢀ7.56 (4H, m, H6 (C6H3) + Hp
(PPh3)), 7.85 (6H, m, Ho, PPh3). 13C{1H} NMR (CDCl3): δ 55.89 (s,
Synthesis of 3ac. Compound 3ac was prepared using the same
method than 3aa, but starting from Ph3P=NC(O)C6H5 1a (0.250 g,
OMe), 57.17 (s, OMe), 114.14, 116.11 (C3, C4, C6H3), 116.27 (d, C6,
4
1
C6H3, JPC = 1.4), 128.26 (d, Ci, PPh3, JPC = 99.2), 128.60 (d, Cm,
0.655 mmol), PdCl2(NCMe)2 (16.8 mg, 0.065 mmol) and oxone®
(0.806 g, 1.31 mmol) in nPrOH 2c (15 mL) at 60 ºC. After the
reaction time (18 h) the solvent was evaporated to dryness and the
residue purified by column chromatography using silica as support
and ethyl acetate as eluent. Compound 3ac was obtained as a white
solid. Obtained: 0.072 g, 0.4 mmol (61.2% yield). Characterization
of 3ac has been performed by comparison of its spectral data with
those previously published.14
3
3
PPh3, JPC = 12.3), 130.78 (d, C1, C6H3, JPC = 20.4), 132.16 (d, Cp,
4
2
PPh3, JPC = 2.9), 133.32 (d, Co, PPh3, JPC = 10.0), 152.64, 153.13
(C2, C5, C6H3), 176.93 (d, CO, 2JPC = 8.1). 31P{1H} NMR (CDCl3): δ
20.08 (s). IR (ν, cmꢀ1): 1599 (C=O), 1333 (P=N) cmꢀ1. MS (ESI+):
442.1 (100 %) [M+H]+. Found: C, 72.98; H, 5.33; N, 3.27. Calc for
C27H24NO3P: C, 73.46; H, 5.48; N, 3.17%.
Synthesis of 3ga. The reaction between Ph3P=NC(O)C6H4ꢀ2ꢀNO2
1g (0.157 g, 0.368 mmol), PdCl2(NCMe)2 (9.5 mg, 0.037 mmol) and
oxone® (0.453 g, 0.736 mmol) in MeOH 2a (15 mL) was carried
following the same procedure than that described for 3aa. After 18 h
stirring at room temperature, the analysis of the crude showed a
mixture of 3ga (16%), 1a and O=PPh3 (84% together). Despite
repeated attempts, 3ga could not be obtained as an analytically pure
product due to contamination with 1a. It could be characterized by
31P NMR spectroscopy (δ (CDCl3) = 19.85 ppm (s)).
Synthesis of 3ad. Compound 3ad was prepared using the same
method than 3ac, but starting from Ph3P=NC(O)C6H5 1a (0.250 g,
0.655 mmol), PdCl2(NCMe)2 (16.8 mg, 0.065 mmol) and oxone®
(0.806 g, 1.31 mmol) in iPrOH 2d (15 mL) at 80 ºC. Compound 3ad
was purified by column chromatography using silica as support and
a mixture ethyl acetate/diethyl ether (4/1) as eluent, and obtained as
a pale yellow solid. Obtained: 0.045 g, 0.25 mmol (38.1% yield).
3ad has been previously published, but its spectroscopic data were
This journal is © The Royal Society of Chemistry 2012
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New Journal of Chemistry
Page 6 of 9
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5NJ00189G
1
not reported.15 Due to this reason they are here included. H NMR
(CDCl3): δ 1.41 (6H, d, CH3, 3JHH = 6.1), 4.65 (1H, heptuplet, OCH,
3JHH = 6.1), 5.90 (2H, br s, NH2), 6.98 (2H, m, H4+H5, C6H4), 7.50
N. Schröder and F. Glorius, Adv. Synth. Catal., 2014, 356, 1443; (d)
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M. N. Hopkinson, J. WencelꢀDelord and F. Glorius, Angew. Chem.,
Int. Ed., 2012, 51, 10236; (k) S. R. Neufeldt and M. S. Sanford, Acc.
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3
4
3
(1H, dd, C6H4, JHH = 8.4, JHH = 2.4), 7.56 (1H, dd, C6H4, JHH
=
7.9, JHH = 2.0). 13C{1H} NMR (CDCl3): δ 21.84 (s, CH3), 71.84 (s,
OCH), 113.71, 116.83, 120.47, 133.92, 134.13, 159.96 (C6H4). The
signal due to C=O was not observed, in spite of long accumulation
times. IR (ν, cmꢀ1) = 1595 (C=O), 3062 (NꢀH).
4
Synthesis of 3ae. Compound 3ae was prepared using the same
method than 3ac, but starting from Ph3P=NC(O)C6H5 1a (0.250 g,
0.655 mmol), PdCl2(NCMe)2 (16.8 mg, 0.065 mmol) and oxone®
(0.806 g, 1.31 mmol) in nBuOH 2e (15 mL) at 60 ºC. Compound 3ae
was purified by column chromatography using silica as support and
a mixture ethyl acetate/diethyl ether (4/1) as eluent, and obtained as
a pale yellow solid. Obtained: 0.065 g, 0.34 mmol (51.9% yield).
3ae has been previously published, but its spectral data were not
reported.9 Due to this reason they are here included. 1H NMR
(CDCl3): δ 0.91 (3H, t, CH3, JHH = 6.4), 1.46 (2H, m, CH2), 1.75
(2H, m, CH2), 3.99 (2H, t, OCH2, JHH = 6.2), 5.92 (2H, br s, NH2),
6.89 (2H, m, H4+H5, C6H4), 7.45 (2H, m, H3+H6, C6H4). 13C{1H}
NMR (CDCl3): δ 13.80 (s, CH3), 19.15 (s, CH2), 30.95 (s, CH2),
68.75 (s, OCH2), 112.22, 116.57, 120.53, 133.74, 134.31, 160.87
(C6H4), 172.65 (CO). IR (ν, cmꢀ1) = 1597 (C=O), 3070 (NꢀH).
2
(a) A. McNally, B. Haffemayer, B. S. L. Collins and M. J. Gaunt,
Nature, 2014, 510, 129; (b) L. Ackermann, Acc. Chem. Res., 2014,
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2799; (e) S. de Sarkar, W. Liu, S.I. Kozhushkov and L. Ackermann,
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3
Synthesis of 3af. Compound 3af was prepared using the same
method than 3ac, but starting from Ph3P=NC(O)C6H5 1a (0.250 g,
0.655 mmol), PdCl2(NCMe)2 (16.8 mg, 0.065 mmol) and oxone®
i
(0.806 g, 1.31 mmol) in BuOH 2f (15 mL) at 60 ºC. Compound 3af
was purified by column chromatography using silica as support and
a mixture ethyl acetate/diethyl ether (4/1) as eluent, and obtained as
a pale yellow solid. Obtained: 0.048 g, 0.245 mmol (37.4% yield).
3af has been previously published, but its spectral data were not
reported.10 Due to this reason they are here included. 1H NMR
(CDCl3): δ 0.99 (6H, d, CH3, JHH = 6.8), 2.09 (1H, m, CH), 3.75
(2H, d, OCH2, JHH = 6.4), 6.85ꢀ6.90 (2H, m, C6H4), 7.42ꢀ7.47 (2H,
m, C6H4). 13C{1H} NMR (CDCl3): δ 19.13 (s, CH3), 28.19 (s, CH),
75.20 (s, OCH2), 112.25, 116.15, 120.54, 133.73, 134.29, 160.93
(C6H4). The signal due to C=O was not observed, in spite of long
accumulation times. IR (ν, cmꢀ1) = 1597 (C=O), 3080 (NꢀH).
3
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Funding by the Ministerio de Economia y Competitividad
(MINECO) (Spain, Project CTQ2011ꢀ22589) and Gobierno de
Aragón (Spain, group E97) is gratefully acknowledged. P. V.
thanks CSIC for a Juan de la Cierva contract.
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Notes and references
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DOI: 10.1039/C5NJ00189G
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ARTICLE
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New Journal of Chemistry
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DOI: 10.1039/C5NJ00189G
Text (for Table of Contents)
The mild Pd-catalysed ortho-alkoxylation of benzamides, protected as keto-stabilised
iminophosphoranes, with alcohols, is regioselective and tolerates different substituents
and alcohols
Graphical Abstract (for Table of Contents)