Nickel-Catalyzed Hydrophosphonylation and Hydrogenation of Aromatic Nitriles Assisted by Lewis Acid

Article abstract of DOI:10.1002/cctc.201801989

In this paper, we describe the catalytic hydrophosphonylation of several aromatic nitriles used to synthesize α-aminophosphonates (α-APs) using commercially available trialkyl phosphites (P(OR)₃, R=Et, iPr, Bu,) and simple and inexpensive nickel chloride (NiCl₂.6H₂O) as the catalytic precursor. The use of triethylborane (Et₃B) as a Lewis acid (LA) was mandatory in order to successfully perform H-phosphite moiety incorporation at the CN bond of non-activated benzonitriles (BN) derivatives. Interestingly, when a highly activated BN such as 2,3,4,5,6-pentafluorobenzonitrile (BN-g) was employed, it was possible to perform the reaction in the absence of an LA using milder reaction conditions. Also, we found that using HP(O)(OiPr)₂ as a starting material afforded the aminobisphosphonate derivative with better selectivity than using the method involving P(OiPr)₃ as the initial reagent. Remarkably, when using HP(O)(OiPr)₂ with an excess of Et₃B, the reaction's selectivity completely changed to yield N-benzyl- benzylimine (BBI) and 2,4,5-triphenylimidazole.

Full text of DOI:10.1002/cctc.201801989

Accepted Article
Title: Nickel-catalyzed hydrophosphonylation and hydrogenation of
aromatic nitriles assisted by Lewis acid
Authors: Rosa E. Islas and Juventino J Garcia
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Nickel-catalyzed hydrophosphonylation and hydrogenation of aromatic nitriles assisted
by Lewis acid
Rosa E. Islas and Juventino J. García
Facultad de Química. Universidad Nacional Autónoma de México. México D. F. 04510
México
juvent@unam.mx
Abstract
In this paper, we describe the catalytic hydrophosphonylation of several aromatic nitriles used
to synthesize -aminophosphonates (-APs) using commercially available trialkyl phosphites
(P(OR)3, R= Et, iPr, Bu,) and simple and inexpensive nickel chloride (NiCl2.6H2O) as the
catalytic precursor. The use of triethylborane (Et3B) as a Lewis acid (LA) was mandatory in
order to successfully perform H-phosphite moiety incorporation at the CN bond of non-
activated benzonitriles (BN) derivatives. Interestingly, when a highly activated BN such as
2,3,4,5,6-pentafluorobenzonitrile (BN-g) was employed, it was possible to perform the
reaction in the absence of an LA using milder reaction conditions. Also, we found that using
HP(O)(OiPr)2 as a starting material afforded the aminobisphosphonate derivative with better
selectivity than using the method involving P(OiPr)3 as the initial reagent. Remarkably, when
using HP(O)(OiPr)2 with an excess of Et3B, the reaction’s selectivity completely changed to
yield N-benzyl- benzylimine (BBI) and 2,4,5-triphenylimidazole.
Keywords: hydrophosphonylation, hydrogenation, nitriles, trialkyl phosphites, nickel,
catalysis.
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Introduction
Both aminophosphonic acids and aminophosphonate (AP) derivatives, regarded as
structural analogs of the corresponding amino acids, have drawn attention because of their
biological activities as enzyme inhibitors, anticancer agents, antibiotics, antiviral drugs, and
herbicides. [1] These compounds can be synthesized via several routes.[2] Among the routes
that are worthy of mention are the Pudovik and the Kabachnik-Fields reactions. In the
Pudovik reaction, nucleophilic addition of a dialkylphosphite HP(O)(OR)2 is performed in
compounds containing carbon–nitrogen multiple bonds in the presence of a base or a Lewis
acid LA, [3] while in the Kabachnik-Fields reaction the -APs are synthesized from an
aldehyde or ketone, an amine, and a phosphite in the presence of a Lewis or Bronsted acid
in a multicomponent reaction.[4]
Regarding the compounds used for these reactions, nitriles are simple, low cost, and
commercially available compounds that possess vast synthetic versatility and undergo
several important reactions: reductions;[5] hydrolysis;[6] alkylations;[7] and
hydrofunctionalizations.[8] However, only a small amount of research has been done using
aliphatic and aromatic nitriles as starting materials for the synthesis of aminophosphonic
acids and their derivatives, aminophosphonates (APs). A few examples include the use of
-
phosphorous halides (PX3) or phosphoric acid (H3PO4), hydrogenphosphite ion (H2PO3 ), or
hydrochloric acid (HCl) with aliphatic nitriles in moderate reaction conditions, while a
strong Lewis acid and harsher reaction conditions are necessary for aromatic nitriles.
Moreover, controlling reaction selectivity is difficult in order to obtain a mixture of the APs
and aminobisphosphonate derivatives. [9]
In order to substitute the extremely corrosive and difficult to handle PX3 compounds, a
series of methods, which make use of safer phosphorus raw materials such as phosphites, H-
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phosphites, phosphinates, and phosphine oxides, have been developed.[10] To the best of our
knowledge, only H-phosphites and phosphines such as H-P(O)(R)2 or H-P(R)2 have been
used for the hydrofunctionalization of aliphatic and aromatic nitriles in order to produce the
corresponding -APs (under basic conditions),[11] aminobisphosphonates (in acidic media
or by free radical reaction)[9a-b],[12] or the -aminophosphine oxides.[8a].
The APs can also be obtained by alkylphosphonate amination or by iminophosphonates
reduction in the presence of a transition metal catalyst such as Cu [13] or Pd. [14] However, as
far as we know, there are no previous reports of either AP or aminobisphosphonates
synthesis from nitriles in the presence of a Ni catalyst precursor even when nickel catalysts
have shown great versatility for catalyzing several important transformations.[15] With this
respect to this point, our research group has recently reported the synthesis of
vinylphosphonates from alkynes by addition of H-phosphites formed in situ from trialkyl
phosphites in the presence of inexpensive nickel chloride (NiCl2.6H2O). [16]
On the other hand, the use of Lewis acids LA (as either promoters or catalysts) in
combination with transition metal catalyst precursors have allowed efficient formation of C-
C, C-Het, or C-H. [17] Generally, B(III) and Al (III) derivatives are the most commonly used
LAs for this kind of reactions. Taking this and the fact that the synthesis of
aminophosphonates from aromatic nitriles is quite challenging into account, we propose the
use of an LA, particularly triethyl borane (Et3B) in combination with an Ni catalyst
precursor in order to obtain the AP derivatives. The combination of Et3B and a nickel
catalyst precursor has been successfully applied in the olefin hydrocyanation reaction, [18a]
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homoallylation, [18b] synthesis of cyclic structures, [18c] and reduction of nitriles (the latter in
the presence of a cobalt catalyst). [18d]
Nitrile reduction catalyzed by transition metals is of great interest because it allows the
preparation of important precursor materials such as amines [19] and imines, [20] which are
starting materials in the development of added value compounds for the pharmaceutical,
perfume, and polymer industries, among many others. Nevertheless, the use of earth
abundant transition metals in this kind of reactions have been little explored. [21] In this
regard, our group has reported the use of benzonitrile (BN) hydrogenation for the synthesis
of N-benzyl- benzylimine (BBI) by using an Ni(I) or Ni(0) catalyst precursor in the
presence of H2 or 1,4-butanediol as hydrogen sources.[22] In the current study, we
investigated the synthesis of APs and BBI from benzonitriles and trialkyl phosphites using
Et3B as a Lewis acid and air stable and inexpensive NiCl2.6H2O as a catalytic precursor.
Results and Discussion
We explored first the reactivity of a series of LAs in the hydrophosphonylation reaction
between BN and P(OiPr)3 in the presence of NiCl2.6H2O (Table 1). It was found that under
the studied conditions, Et3B promoted the formation of -AP 1 with high selectivity and
moderate conversion of BN (entry 1). Also, B(CH(CH3)(C2H5))3 was used; however,
formation of -AP 1 was not detected, which can be attributed to an increase in steric
hindrance from the substituent, thus avoiding substrate activation (entry 2). Additionally,
.
AlCl3 and BF3 OEt2, both regarded as stronger LAs than Et3B, [23] were used in different
proportions; however, in any case, compound -AP 1 was produced (entries 3–5). In the case
of AlCl3, a solubility issue in the reaction medium could explain the lack of substrate
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activation, while in the case of BF3.OEt2, it reacts with P(OiPr)3 generating side products even
at low temperatures, also inhibited the formation of compound 1. Worthy of mention is the
absence of the AP when no LA is present in the reaction media (entry 6), which denotes the
role of Et3B in promoting the -CN of BN activation to be more reactive towards a nucleophile
and eventually, giving rise to the product of interest. [18a]
Table 1. Nickel catalyzed hydrophosphonylation of BN assisted by Lewis Acidsa
Conv.
PhCN
(%)
Yield 1a,c
(%)
Entry
Lewis Acid
BEt3
34
76
1
B(CH(CH3)(C2H5))3
AlCl3
BF3.OEt2
BF3.OEt2
---
<1
<1
<1
<1
7
ND
ND
ND
ND
ND
2
3
4d
5b,d
6
a All reactions were carried out in a Schlenk flask (50 mL) equipped with a Rotaflo valve and
heated at 140°C. Reaction conditions: mol ratio of 1: 2: 1: 0.05 of benzonitrile, triisopropyl
phosphite, Lewis acid and NiCl2.6H2O, respectively. bReaction conditions: mol ratio of 1: 2:
0.1: 0.05 of benzonitrile, triisopropyl phosphite, Lewis acid and NiCl2.6H2O, respectively.
dTemperature= 0-20°C. cIsolated yield. ND= Not Detected. Conversions were determined by
GC/MS analysis.
In order to optimize reaction conditions, we performed several tests (Table 2). Since this
study centers in the obtention of -APs, the obtention of compound 1 will be discussed. To
consult about other products (like iminobisphosphonate 1S, aminobisphosphonate 2, N-
benzyl- benzylamine 3 y 2,4,5-triphenylimidazole 4) please refer to Table S1 in the
supporting material.
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First, the reaction time was increased and ranged from 42 to 100 h; however, there was no
significant increment in the conversion of BN (entry 1). We then investigated whether
different P(OiPr)3 and Et3B concentrations might have an impact on the formation of the
susceptible species (HP(O)(OiPr)2) to be added to the saturated -CN moiety; however, once
again, the increase in the conversion was not substantial (entries 2-3). An increase in catalyst
loading yielded a high conversion rate of the BN in lower reaction time (entry 3). An
additional experiment with a greater concentration of Et3B (3 equivalents) was also performed
and showed a high BN conversion rate but lower selectivity (entry 5). Additional solvents
were used. The best results were obtained using low polarity solvents such as toluene and
mesitylene (entries 5 and 6). A decrease in conversion and selectivity was related to an
increase in solvent polarity (entries 7–9). Additionally, we performed experiments with other
commercially available Ni(II) and Ni(0) resources (entries 10–12), and none of these provided
better conversion or selectivity values than the ones achieved with simple NiCl2.6H2O.
A control experiment (without metal catalyst precursor, entry 13) showed that the metal center
appears to be necessary for optimal conversion of BN under the scoped reaction conditions. A
mercury drop test was performed in order to elucidate the type of predominant reaction
mechanism (entry 14). This test revealed that the mechanism is homogenous as there were no
substantial differences between the conversion and selectivity values of the reaction under the
optimized reaction conditions (entry 4). When performing the experiment at 160°C it was
found that the selectivity toward compound 1 was diminished (entry 15), since an increased
number of products were obtained, compared at the optimized reaction conditions.
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Table 2. Optimization of the reaction conditions for hydrophosphonylation of BN using Et3B
as a LAa
Selectivity
1
Conv.
PhCN
(%)
Entr
y
Time
(h)
i
Et3B
Solvent
Catalyst
[mol%]
P(O Pr)3
NiCl2.6H2O
(5%)
2
3
1
1
100
Toluene
69
76
74
1
2
NiCl2.6H2O
(5%)
100
Toluene
75
NiCl2.6H2O
(5%)
3
3
3
2
2
3
100
84
Toluene
Toluene
Toluene
82
98
99
73
88 (83)e
39
3
4
5
NiCl2.6H2O
(10%)
NiCl2.6H2O
(10%)
84
NiCl2.6H2O
(10%)
3
3
3
3
3
3
2
2
2
2
2
2
84
84
84
84
84
84
Mesitilene
THF
99
89
67
<1
81
72
77
81
78
Nd
52
60
6
NiCl2.6H2O
(10%)
7
NiCl2.6H2O
(10%)
1,4-Dioxane
2-propanol
Toluene
8
NiCl2.6H2O
(10%)
9
Ni(OAc)2
(10%)
10b
11b
Ni(acac)2
(10%)
Toluene
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Ni(COD)2
(10%)
12b
3
3
3
2
2
2
84
84
84
Toluene
Toluene
Toluene
76
49
93
72
82
81
13c ----
NiCl2.6H2O
(10%)
14d
15f
NiCl2.6H2O
(10%)
3
2
84
Toluene
99
74
a All reactions were carried out in a Schlenk flask (50 mL) equipped with a Rotaflo valve and 1.5 mL of
solvent. Reaction conditions: mol ratio of 1: x: y: z of BN, triisopropyl phosphite, Et3B, and NiCl2.6H2O,
respectively. bReaction conditions: mol ratio of 1: 3: 2: 0.1 of BN, triisopropyl phosphite, Et3B, and nickel
catalyst, respectively. cControl experiment: mol ratio of 1: 3: 2 of BN, triisopropyl phosphite, and Et3B,
respectively. dHomogeneity test: mol ratio of 1: 3: 2: 0.1 of BN, triisopropyl phosphite, Et3B, and
NiCl2.6H2O, respectively. A drop of metallic mercury was added. eIsolated yield. fReaction performed at
160°C. Complete conversion percentage of benzonitrile is calculated by summing, 1, 1S, 2, 3 y 4
percentage which is presented in Table 1S in the Supporting Information. Conversions and selectivity were
determined by GC/MS analysis.
Scheme 1 shows the results of using a variety of BNs and dialkyl phosphites under general
reaction conditions. When P(OEt)3 and P(OBu)3 were used instead of P(OiPr)3, the selectivity
toward the formation of the APs diminished and also yielded the iminobisphosphonates 1Sa
and 1Sb (see supplementary material, Table S2). At the studied reaction conditions, the
formation of 1S can be explained by a dehydrogenation of a secondary amine (see Scheme
S1, SI information). It has been reported that amine dehydrogenation to produce imines or
even nitriles takes place in the presence of Ru, Rh, Ir and Ni catalytic precursors, this last one
being the least studied catalytic system, which further increases the interest in the future study
and application of this kind of systems. [27]
Interestingly, the use of p-trifluoromethyl benzonitrile (BN-c), which possesses a strong
electron-withdrawing substituent, yielded the corresponding -AP in shorter reaction times
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(about half of the time of the optimized conditions [Table 2, entry 4]), while the use of p-
methoxy benzonitrile (BN-f), which possesses a strong electron-donating substituent, yielded
the corresponding -AP over longer reaction times and lower selectivity. Generally, the use
of electron-withdrawing substituents at the phenyl ring of aromatic nitriles will produce a
more electrophilic -CN carbon, thus being more susceptible to reactions with a nucleophile.
When using p-fluoro benzonitrile (BN-e), which possesses a modest electron-withdrawing
substituent, the reaction proceeded in a similar time period as the one at the optimized
conditions (Table 2, entry 4) and with higher selectivity to yield the corresponding -AP.
When using 4-toluenenitrile (BN-d), similar behavior to the reaction with p-methoxy
benzonitrile was observed.
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Scheme 1. A series of substituted aromatic nitriles and dialkyl phosphites used under catalytic
conditions.
a All reactions were carried out in a Schlenk flask (50 mL) equipped with a Rotaflo valve and
2 mL of solvent. Reaction conditions: mol ratio of 1: 3: 2: 0.5 of BN, trialkyl phosphite, Et3B,
and NiCl2.6H2O, respectively. bIsolated yield. cYield determined by GC-MS using the
corresponding BN as internal standard. dReaction time: 48 h. Conversions were determined by
GC/MS analysis.
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It is noteworthy that use of BN-g in the presence of triisopropyl phosphite and NiCl2.6H2O as
catalytic precursor, the product of interest was detected with high selectivity and high
conversion rates with milder reaction conditions and without the addition of LA (Table 3).
The latter can be attributed to the higher electrophilicity of the CN in the 3,4,5,6-
pentafluorobenzonitrile compound compared to the previously studied substrates, which
makes this compound more susceptible to H-phosphite incorporation.
Table 3. Hydrophosphonylation of a highly electrophilic CN bond of BN-g
Conv.
PhCN
(%)
Yielda
1
Temperature Time
(°C) (h)
Entry Et3B
2
140
100
100
24
16
16
99
99
98
93
94
96
1
2
2
3b
--
a All reactions were carried out in a Schlenk flask (50 mL) equipped with a Rotaflo valve and
2 mL of solvent. Reaction conditions: mol ratio of 1: 3: 2: 0.1 of BN-g, trialkyl phosphite,
Et3B and NiCl2.6H2O, respectively. bReaction conditions: mol ratio of 1: 3: 0.1 of BN-g,
trialkyl phosphite, Et3B, and NiCl2.6H2O, respectively. cConversions and yields were
determined by GC-MS using BN-g as an internal standard.
In order to further optimize the reaction time (Table 2, entry 4), we decided to perform the
nitrile hydrophosphonylation in a two-step manner (Table 4). The first step was in situ
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formation of HP(O)(OiPr)2 from P(OiPr)3 in the presence of NiCl2.6H2O (Method A).[16] The
HP(O)(OiPr)2 was produced with 80% selectivity and 99% conversion of triisopropyl-
phosphite after 108 h. Alternatively, hydrolysis of P(OiPr)3 was also used to obtain
HP(O)(OiPr)2 at both 85% selectivity and full conversion of the phosphite after 18 h (Method
B). Once HP(O)(OiPr)2 was formed, BN, Et3B, and NiCl2.6H2O were then added to the
reaction mixture.
After using method A and addition of BN and LA, higher BN conversion and selectivity into
the -aminobisphosphonate 2 product was achieved (entry 1). This could be due to a higher
concentration of the HP(O)(OiPr)2 in the reaction media, which would increase the probability
of a second addition of HP(O)(OiPr)2 to the BN. This was not observed when HP(O)(OiPr)2
was slowly formed in the reaction media from P(OiPr)3 (Table 2, entry 4). As for method B,
the same conversion with slightly different selectivity was found (entry 2). However, in an
analogous experiment using an excess of Et3B, formation of a hydrogenation product, BBI,
could be detected along with the formation of an aromatic species, 2,4,5-triphenylimidazole 4,
(entry 3), in which the BBI was the main product.
Possible routes for the formation of these compounds are shown in Scheme 2. Since the
experiments were performed under controlled atmosphere, oxygen and humidity free
conditions, we propose the formation of HP(O)(OR)2 from P(OR)3 using a Ni(0) complex
formed in situ[17] (a detailed reaction mechanism is showed in Scheme S2, which is consistent
with the mechanistic proposal of Balthazor and Grabiak [24]). Once an HP(O)(OR)2 species
was formed (method A or B), a reductive reaction promoted by Ni gives rise to the formation
of the primary imine A (Scheme S3 showed a catalytic proposal for the obtention of this
imine), which can serve as the starting material for several reactions. First, an Ni-catalyzed
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Pudovik reaction with H-P(O)(OR)2 in the presence of Et3B could explain the formation of -
AP 1. Second, incorporation of a second H-P(O)(OR)2 allows the formation of the
bisaminophosphonate 2. However, imine A can also react and contribute the formation of the
BBI 3 by releasing NH3 as described in the literature. [25] Finally, the formation of imidazole
[26] could be favored by an Et3B excess via an increase in the electrophilic properties of the -
CN carbon.
According to this, it is worth to mention that the hydrophosphonylation reaction with
P(OiPr)3 as starting material (Table 2, entry 4) resulted to be an efficient strategy for the
obtention of 1. However, when HP(O)(OR)2 was used as starting material, the selectivity of
the reaction is notoriously modified, favoring the obtention of aminobisphosphonate and BBI,
which can be of interest for future venues.
Table 4. Reactivity of BN: H-Phosphite Addition versus Hydrogenation
Selectivitya
Conv.
Time
(h)
Entry
Et3B
PhCN
(%)
Hydrolysis
Method A or B
NiCl2.6H2O
3
4
1
2
Method A
Method B
Method B
---
1
1
3
24
50
24
94
98
97
27
12
28
65 ND
81 ND
ND 43
ND
ND
9
1
2
3
5%
5%
a All reactions were carried out in a Schlenk flask (50 mL) equipped with a Rotaflo valve and 2 mL of
solvent. Reaction conditions: mol ratio of 1: 3: 2: 0.1 of BN, trialkyl phosphite, Et3B, and NiCl2.6H2O,
respectively. ND= Not Detected. Conversions and selectivity were determined by GC/MS analysis.
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Scheme 2. Proposed reaction pathways for the reactivity of BN using H-phosphite as a
starting reagent.
Conclusions
Hydrophosphonylation of aromatic nitriles to yield -APs and aminobisphosphonates using
trialkyl phosphites and NiCl2.6H2O as a catalyst precursor was achieved. Through the use of
control experiments, it was determined that the hydrophosphonylation does not proceed
successfully without the addition of a Lewis acid as a reaction promoter. The
hydrophosphonylation reaction proceeds more efficiently and with lower reaction times when
using aromatic nitriles with strong electron withdrawing functional groups attached at the
aromatic ring. On the other hand, when using aromatic nitriles with electron donating
properties, more time was required in order to complete the full conversion of the starting BN.
Finally, we found that using H-P(O)(OiPr)2 as starting material, formation of
aminobisphosphonates compounds was selectively preferred, and a modified procedure using
an excess of the Lewis Acid for the reduction of the BN was performed to obtain BBI and
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benzimidazole with moderate to good selectivity. Because of the high interest and relevance
of nitrile hydrophosphonylation and hydrogenation (vide supra), current studies are underway
to further comprehend the reaction mechanism and to extend the scope of this reaction to
other aromatic and alkyl nitriles in the presence of readily available air stable catalytic
precursors such as NiCl2.6H2O.
Experimental Section
All experiments were carried out in oven-dried Schlenk tubes in a glovebox (MBraun Unilab)
under high purity argon (Praxair 99.998%) and controlled concentrations of water and oxygen
(<1 ppm). All liquid reagents were purchased from Aldrich and Merck. They were degassed
and stored in a glovebox for further use. All solvents were dried using standard techniques
and stored in the glovebox prior to use. Aromatic nitriles and phosphites P(OEt)3, P(OiPr)3,
and P(OBu)3 were purchased from Aldrich and stored in the glovebox before use. These
phosphites were stored with molecular sieves 4 Å before its usage. Column chromatography
was performed using Silica Gel 60 (particle size 63–200 m). Deuterated solvents were
purchased from Cambridge Isotope Laboratories. NMR spectra of organic products were
acquired at room temperature using a 300 MHz Bruker spectrometer. Chemical shifts in 1H
NMR spectra (, ppm) are reported according to the residual solvent peaks. 31P{1H} NMR
spectra are referred to the 0 ppm signal of external 85% H3PO4. IR spectra were recorded
using a FT-IR Perkin Elmer instrument (Spectrum Two). GC-MS determinations were
performed using an Agilent Technologies G3171A equipped with the column containing 5 %
phenylmethylsilicone and 30 m * 0.25 mm * 0.25 μm.
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BN, BN-c, BN-d, BN-e, BN-f, and triisopropylphosphite reactions catalyzed by nickel
and promoted by Et3B
A typical experiment was done according to a standard procedure: NiCl2.6H2O (23 mg, 0.097
mmol), P(OiPr)3 (605 mg, 2.91 mmol), benzonitrile (100 mg, 0.97 mmol), Et3B (190, 1.94
mmol), and toluene (1.5 mL) were placed in a Schlenk flask (50 mL) equipped with a
magnetic stir bar and fitted with Rotaflo valve. The initial solution was a dark blue color.
After the addition of the LA, the color changed to dark orange. The flask was then removed
from the glovebox and heated at 140°C with stirring (different times were used in the
experiments as indicated in Tables 1 and 2). After this time, the reaction mixture was cooled
to room temperature, exposed to air, filtered over Celite, and then analyzed by GC-MS.
After the reaction was complete, product 1 was purified by gravity column chromatography
on silica gel (particle size 63–200 m, hexane/ethyl acetate/methanol as eluent) and the
products were isolated as isolated with 83% as a pale-yellow oil.
Mercury drop test
Following the procedure described above, the same reaction was carried out, and one drop of
elemental Hg was added to the reaction mixture. At the end of the run, the reaction mixture
was cooled to room temperature, exposed to air, filtered over Celite, and then analyzed by
GC-MS.
Reaction scope with a series of BN and trialkyl phosphites
A typical experiment was done according a standard reaction: NiCl2.6H2O (23 mg, 0.012
mmol), P(OR)3 (3.6 mmol), benzonitrile derivatives (1.2 mmol), Et3B (236 mg, 2.4 mmol),
and toluene (2 mL) were placed in a Schlenk flask (50 mL) equipped with a magnetic stir bar
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and fitted with a Rotaflo valve. The initial solution was a dark blue color, and after the
addition of the LA the color changed to dark orange. The flask was then removed from the
glovebox and heated at 140°C (different times were used in the experiments as indicated in
Scheme 1). After this time, the reaction mixture was cooled to room temperature, exposed to
air, filtered over Celite, and then analyzed by GC-MS.
After completion of the reaction, the products 1a, 1c, 1d, and 1e were purified by gravity
column chromatography on silica gel (particle size 63–200 m, hexane/ethyl acetate/methanol
as eluent).
Hydrophosphonylation of BN-g
The reaction was performed in a 50 mL Schlenk flask (equipped with a magnetic stir bar and
fitted with a Rotaflo valve) typically charged with NiCl2.6H2O (12.3 mg, 0.052 mmol),
P(OiPr)3 (324 mg, 1.56 mmol), 2,3,4,5,6-pentafluorobenzonitrile (100 mg, 0.51 mmol), Et3B
(100mg, 1.02 mmol), and toluene (1.5 mL). The initial solution was a dark blue color, and
after the addition of the LA, the color changed to orange. The flask was then removed from
the glovebox and heated at the temperatures and times indicated in Table 4. After this time,
the reaction mixture was cooled to room temperature, exposed to air, filtered over Celite, and
then analyzed by GC-MS.
Use of different Ni compounds as catalytic precursors
The Ni compound (see Table 2 for details) used as catalyst precursor (0.097 mmol), P(OiPr)3
(605 mg, 2.91 mmol), BN (100 mg, 0.97 mmol), Et3B (190mg, 1.94 mmol), and toluene (1.5
mL) were placed in a Schlenk flask (50 mL) equipped with a magnetic stir bar and fitted with
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a Rotaflo valve. The flask was then removed from the glovebox and heated at 140°C for 84 h.
After this time, the reaction mixture was cooled to room temperature, exposed to air, filtered
over Celite, and then analyzed by GC-MS.
Tandem reaction with HP(O)(OiPr)3 obtained from Method A
A Schlenk flask (50 mL) fitted with a Rotaflo valve was charged with NiCl2.6H2O (17 mg,
0.073 mmol) and (303 mg, 1.45 mmol) of P(OiPr)3. The flask was heated at 140°C for 108 h.
After this time, the reaction mixture was cooled to room temperature and introduced into the
glovebox. A sample was taken in order to be analyzed by GC-MS and to verify the formation
of H-P(O)(OiPr)2. BN (50 mg, 0.49 mmol), Et3B (48 mg, 0.49 mmol), and toluene (1 mL)
were then added to the reaction mixture, and once again the flask was fitted with a Rotaflo
valve. The flask was then taken out from the glovebox and heated at 140°C for 24 h. After
this time, the reaction mixture was cooled to room temperature, exposed to air, filtered over
Celite, and finally analyzed by GC-MS.
Tandem reaction with HP(O)(OiPr)3 obtained from Method B
A Schlenk flask (50 mL) fitted with a Rotaflo valve was charged with P(OiPr)3 (303 mg, 1.45
mmol), H2O (18 mg, 1 mmol), and toluene (0.5 mL). The flask was heated at 140°C for 18 h.
After this time, the reaction mixture was cooled to room temperature and introduced into the
glovebox. A sample was taken in order to be analyzed by GC-MS and verify H-P(O)(OiPr)2
formation. Molecular sieves were then added in order to remove the water residue. After 10 h,
BN (50 mg, 0.49 mmol), Et3B (48 mg, 0.49 mmol), and toluene (1 mL) were added to the
reaction mixture and once again, the flask was fitted with a Rotaflo valve. The flask was then
removed from the glovebox and heated at 140°C for 24 h. After this time, the reaction mixture
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10.1002/cctc.201801989
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was cooled to room temperature, exposed to air, filtered over Celite, and finally analyzed by
GC-MS.
Tandem reaction with HP(O)(OiPr)3 obtained from Method B (LA excess)
A Schlenk flask (50 mL) fitted with a Rotaflo valve was charged with P(OiPr)3 (303 mg, 1.45
mmol), H2O (18 mg, 1 mmol), and toluene (0.5 mL). The flask was heated at 140°C for 18 h.
After this time, the reaction mixture was cooled to room temperature and was introduced into
the glovebox. A sample was taken for GC-MS analysis and verification of H-P(O)(OiPr)2
formation. Molecular sieves were then added in order to remove the remnant water. After 10
h, BN (50 mg, 0.49 mmol), Et3B (48 mg, 1.47 mmol) and toluene (1 mL) were added to the
reaction mixture and once again, the flask was fitted with a Rotaflo valve. The flask was
removed from the glovebox and heated at 140°C for 24 h. After this time, the reaction mixture
was cooled to room temperature, exposed to air, filtered over Celite, and then analyzed by
GC-MS.
1 Diisopropyl -amino--phenylmethanephosphonate. Pale yellow oil (82% yield)
1H NMR (300.52 MHz, CDCl3): δ=0.96 (d, JH,H= 6.0 Hz, 3H), 1.12-1.25 (m, 9H), 1.81 (s,
2H), 4.1 (d, JH,P= 17.1 Hz 1H), 4.44(m, 1H), 4.55(m, 1H) 7.13-7.32 (m, 3H), 7.32-7.43 (m,
2H); 13C{1H } NMR (75 MHz, CDCl3): δ= 23.48, 23.88, 24.15, 24.20, 54.46 (d, JP,C=
150.5Hz), 71.02 (d, JP,C= 7.6 Hz), 71.34 (d, JP,C= 7.6 Hz), 127.71, 127.88, 127.96, 128.29,
128.32, 137.88 (d, JP,C= 3.2Hz); 31P{1H } NMR (121.44 MHz, CDCl3): δ= 22.85. Selected
IR: andcm-1, (C-N) 1250 cm-1, P=O)cm-1.
1a Diethyl -amino--phenylmethanephosphonate. Pale yellow oil (53% yield) 1H NMR
(300.52 MHz, CDCl3): δ=1.08 (t, JH,H= 7.1 Hz, 3H), 1.15 (t, JH,H= 7.1 Hz, 3H), 1.81 (s, 2H),
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3.78 (m, 2H), 4.93 (m, 2H), 4.16 (d, JH,P= 17.2Hz, 1H), 7.19-7.30 (m, 3H), 7.33-7.39 (m, 2H);
13C{1H } NMR (75 MHz, CDCl3): δ= 16.23, 16.36, 54.01 (d, JP,C= 149.5Hz), 62.60 (d, JP,C=
7.2 Hz), 62.74 (d, JP,C= 7.3 Hz), 127.59, 127.67, 127.77, 128.34, 128.37, 137.61 (d, JP,C=
3.6Hz); 31P{1H } NMR (121.44 MHz, CDCl3): δ= 24.86. Selected IR: (N-H) 3340 and
3380cm-1, (C-N) 1237 cm-1,(P=O) 1019cm-1.
1c Diisopropyl -amino--[4-(trifluoromethyl)phenyl]methanephosphonate White solid
(86% yield).1H NMR (300.52 MHz, CDCl3): δ=1.00 (d, JH,H= 6.2 Hz, 3H), 1.21 (d, JH,H= 6.0
Hz, 3H), 1.25 (d, JH,H= 6.0 Hz, 3H), 1.26 (d, JH,H= 6.0 Hz, 3H), 1.85 (s, 2H), 4.25 (d, JH,P= 18
Hz, 1H), 4.59 (m, 2H), 7.57 (m, 4H); 13C{1H } NMR (75 MHz, CDCl3): δ= 23.51, 23.77,
23.98, 24.03, 54.16 (JP,C= 150.1 Hz), 122.25, 125.05 (m), 125.88, 128.10, 128.19, 129.44,
129.97; 31P{1H } NMR (121.44 MHz, CDCl3): δ= 21.95. 19F NMR (282 MHz, CDCl3) δ=-
62.55 (s, CF3-aromatic). Selected IR:  (N-H) 3290 and 3430 cm-1, (C-F) 1328 and 1106 cm-1,
(C-N) 1221 cm-1, (P=O) 980 cm-1,
1d Diisopropyl -amino--[4-methylphenyl] methanephosphonate Pale yellow oil (61%
yield). 1H NMR (300 MHz, CDCl3): δ=1.00 (d, JH,H= 6.0 Hz, 3H), 1.20 (m, 9H), 1.89 (br s),
2.27 (s, 3H), 4.07 (d, JH,P= 18 Hz, 1H), 4.44 (m, 1H), 4.55 (m, 1H), 7.07-7.09 (m, 2H), 7.26-
7.29 (m, 2H); 13C{1H } NMR (75 MHz, CDCl3): δ= 23.52, 23.91, 24.11, 24.21, 54.7 (JP,C=
151.0 Hz), 70.95, 71.30, 127.74, 127.82, 128.99, 129.02, 134.76, 137.4; 31P{1H } NMR
(121.44 MHz, CDCl3): δ= 23.48.
1e Diisopropyl -amino--[4-fluorophenyl]methanephosphonate 1H NMR (300 MHz,
CDCl3): Pale yellow oil (86% yield).1H NMR (300.52 MHz, CDCl3): δ=1.01 (d, JH,H= 6.2 Hz,
3H), 1.11-1.20 (m, 9H), 1.81 (br s, 2H), 4.10 (d, JH,P= 16.7 Hz, 1H), 4.03-4.60 (m, 2H), 6.93-
6.99 (m, 2H), 7.34-7.40(m, 2H); 13C{1H } NMR (75 MHz, CDCl3): δ= 23.57, 23.89, 24.07,
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24.17, 53.71 (JP,C= 151.4 Hz), 71.13, 71.40, 115.17 (d, JC,F= 21.4 Hz), 129.53 (d, JC,F= 8.1
Hz), 133.62, 162.35 (d, JC,F= 242.7 Hz); 31P{1H } NMR (121.44 MHz, CDCl3): δ= 22.86. 19F
-1
NMR (282 MHz, CDCl3) δ=-114.8 (s, F-aromatic). Selected IR (N-
,
(C-F) 1105 cm-1, (C-N) 1224 cm-1, (P=O) 981 cm-1.
ASSOCIATED CONTENT
 Supporting information available. Includes experimental details and relevant MS, and
NMR determinations.
AUTHOR INFORMATION
Corresponding author
E-mail: juvent@unam.mx
Conflicts of Interest
There are not conflicts of interest.
Acknowledgements
We thank CONACYT A1-S-7657 and PAPIIT-DGAPA-UNAM 200119 for their financial
support of this work. R. E. I. thanks CONACYT (245557) for graduate studies grant. We also
thank Dr. Alma Arévalo for her technical assistance.
Author Titles: Miss Rosa E. Islas; Prof. Dr. Juventino J. García
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TOC entry
The straightforward synthesis of -aminophosphonates starting from a series of available
aromatic nitriles and trialkyl phosphites was achieved using simple NiCl2.6H2O as the
catalyst precursor. The use of Et3B as Lewis acid (LA) was mandatory to activate the CN
bond of moderate to non activated aromatic nitriles. Using HP(O)(OiPr)2 as starting
material with an excess of LA, the reaction’s selectivity completely changed to yield an
imine as a major hydrogenation product.
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