Iron(II)-Catalyzed Hydrophosphination of Isocyanates

Article abstract of DOI:10.1002/anie.201701051

The first transition metal catalyzed hydrophosphination of isocyanates is presented. The use of low-coordinate iron(II) precatalysts leads to an unprecedented catalytic double insertion of isocyanates into the P?H bond of diphenylphosphine to yield phosphinodicarboxamides [Ph₂PC(=O)N(R)C(=O)N(H)R], a new family of derivatized organophosphorus compounds. This remarkable result can be attributed to the low-coordinate nature of the iron(II) centers whose inherent electron deficiency enables a Lewis-acid mechanism in which a combination of the steric pocket of the metal center and substrate size determines the reaction products and regioselectivity.

Full text of DOI:10.1002/anie.201701051

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701051
German Edition: DOI: 10.1002/ange.201701051
Homogeneous Catalysis
Iron(II)-Catalyzed Hydrophosphination of Isocyanates
Helen R. Sharpe, Ana M. Geer, William Lewis, Alexander J. Blake, and Deborah L. Kays*
Abstract: The first transition metal catalyzed hydrophosphi-
nation of isocyanates is presented. The use of low-coordinate
iron(II) precatalysts leads to an unprecedented catalytic double
LY[N(SiMe3)2]2
C6H3]2N).[5c]
Herein, we report the first transition metal catalyzed
hydrophosphination of isocyanates, which affords phosphino-
dicarboxamides by an unprecedented catalytic double inser-
(L = [4-CH3-2-{(CH3)CH-[N(CH)2CN]}-
À
insertion of isocyanates into the P H bond of diphenylphos-
=
phine to yield phosphinodicarboxamides [Ph2PC( O)N(R)-
=
À
C( O)N(H)R], a new family of derivatized organophospho-
tion of isocyanates into the P H bond of the phosphine. The
rus compounds. This remarkable result can be attributed to the
low-coordinate nature of the iron(II) centers whose inherent
electron deficiency enables a Lewis-acid mechanism in which
a combination of the steric pocket of the metal center and
substrate size determines the reaction products and regioselec-
tivity.
reaction between organic isocyanates and diphenylphosphine
in the presence of catalytic amounts of (2,6-Mes2C6H3)2Fe[8]
(1; Mes = 2,4,6-Me3C6H2) or (2,6-Tmp2C6H3)2Fe(THF)[9] (2;
Tmp = 2,4,5-Me3C6H2) produces the mono- (3) and/or di-
insertion (4) products, where one and two isocyanate units,
À
respectively, have inserted into the P H bond (Scheme 1).
This result is remarkable since diinsertion processes are
incredibly rare.[10] Significantly, the compounds 4 are a new
family of derivatized phosphinodicarboxamides, and have
potential applications in coordination chemistry,[11] supra-
molecular and self-assembled arrays,[12] biomedicine,[13] and
enantioselective catalysis.[14]
O
rganophosphorus compounds are a vital class of chemicals
with extensive commercial applications.[1] Classic synthetic
methodologies for phosphine preparation have major draw-
backs, including poor functional-group tolerance, side-prod-
uct formation, the use of protecting groups and stoichiometric
amounts of additives, which is a significant disadvantage for
atom economy.[2] Therefore, there is growing demand to
develop atom-economical routes for the preparation of
functionalized phosphines. In particular, hydrophosphination
is an attractive synthetic route to phosphine products,
À
proceeding by P H bond addition across a C–C/X (X = O,
N, S) multiple bond.[3] However, this reaction can be syntheti-
cally challenging as a result of the coordination capability of
both the phosphine substrates and products which can poison
the metal catalyst.
The hydrophosphination of olefins and alkynes has
received much attention in the last decade,[4] but the use of
heterocumulene substrates has been less explored, with
examples of precatalysts for these reactions being limited to
rare-earth,[5] alkali-metal,[6] and group 2 complexes.[7] The
hydrophosphination of organic isocyanates, yielding phosphi-
nocarboxamide products, is limited to a few recent examples,
Scheme 1. Hydrophosphination of isocyanates with Ph2PH catalyzed by
1 and 2.
Initially, Ph2PH was treated with one equivalent of
PhNCO using 5 mol% of 1 as the precatalyst (Table 1,
entry 1). After 16 hours at room temperature, the solution
underwent a color change from yellow to dark red, with
concomitant formation of two phosphorus-containing prod-
all of which are catalyzed by f-block complexes.[5a–c,e]
A
significant issue with the hydrophosphination of isocyanates is
the competing side reactions, such as the cyclotrimerization of
isocyanates to isocyanurates, and catalyst incompatibility
towards heteroatom-containing substrates. This catalyst
incompatibility has been documented for the hydro-
phosphination of aromatic isocyanate substrates using
1
ucts, as observed by H and 31P{1H} NMR spectroscopy, in
a relative ratio of 59:41 (98% conversion). Further analysis
=
revealed that the major product was [Ph2PC( O)N(H)Ph]
=
(3a), while the second product was [Ph2C( O)N(Ph)-
=
C( O)N(H)Ph] (4a), resulting from the insertion of two
À
[*] H. R. Sharpe, Dr. A. M. Geer, Dr. W. Lewis, Prof. A. J. Blake,
Dr. D. L. Kays
isocyanate molecules into the P H bond of Ph2PH. To
optimize the formation of 4a the ratio of PhNCO/Ph2PH was
changed from 1:1 to 2:1 (entry 2), resulting in an increase in
the ratio of 4a (67%) with respect to 3a (33%). The three-
coordinate complex 2 shows a higher activity than 1, and high
conversion is achieved in a significantly shorter time with
a similar product distribution (entry 3). Very similar behavior
is observed for pTolNCO (entries 4 and 5). When 3,5-
(OMe)2C6H3NCO is used the hydrophosphination proceeds
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
E-mail: Deborah.Kays@nottingham.ac.uk
Supporting information (full experimental details for the hydro-
phosphination reactions, reaction monitoring by NMR spectroscopy,
crystallographic data) and the ORCID identification number(s) for
the author(s) of this article can be found under: http://dx.doi.org/10.
1002/anie.201701051.
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Table 1: Catalytic hydrophosphination of isocyanates mediated by 1 and
2.[a]
Entry RNCO
Cat. RNCO/Ph2PH
t
[h]
Conv. 3/4/5 [%][c]
[%][b]
Scheme 2. Hydrophosphination products obtained when using either
THF (left) or NEt3·HCl in C6D6 (right) and 5 mol% of the catalyst 1.
THF=tetrahydrofuran.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ph
Ph
Ph
pTol
1
1
2
1
2
1
2
1
2
1
1
2
1
2
1
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1:1
2:1
2:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
16
15
6
16.5 95
4.8 94
12
3
15
4
15
15
15
16
8
98
95
96
59:41:0
33:67:0
35:65:0
27:72:1
36:63:1
43:57:0
46:54:0
30:70:0
27:71:2
13:26:5:56[d]
8:39:3:49[d]
12:36:7:46[d]
93:0:6[e]
95:0:5
pTol
also observed, and the reactions required heating to 608C to
obtain moderate conversions (see Table S1, entries 1–4).
To investigate the faster rates for the precatalyst 2
compared to 1, the hydrophosphination catalysis was moni-
tored using 1H and 31P{1H} NMR spectroscopy. When using 1,
an induction period of around 2 hours was observed (Figure 1;
see the Supporting Information), indicating that 1 is not the
(OMe)2C6H3
(OMe)2C6H3
4-BrC6H4
4-BrC6H4
nHex
nHex
nHex
Cy
Cy
iPr
iPr
iPr
95
99
99
99
99
99
99
90
89
55
16
1.6 89
1
16
16
91:5:4
96:0:4
97:0:3
91:0:9
1[f]
2[f]
1[f]
2[f]
92
70
77
tBu
tBu
86:0:14
[a] Reaction conditions: 10 mg cat. (5 mol%), 0.6 mL of C6D6, 258C.
[b] Determined by 1H NMR and 31P{1H} NMR spectroscopy. [c] Ratio by
1H NMR and 31P{1H} NMR spectroscopy. [d] Cyclotrimer ratio. [e] 1%
unidentified 31P{1H} peak. [f] Catalysis performed at 608C.
with a higher reaction rate and a small decrease in the amount
of the diinsertion product (entries 6 and 7). Reactions with
isocyanates featuring functional groups proceed in a similar
manner, with excellent conversions for substrates which bear
either electron-donating or electron-withdrawing groups
(entries 6–9).
Figure 1. Conversion [%] versus time [h] for the hydrophosphination of
*
CyNCO with 5 mol% cat. 1 (+) and 2 ( ) in C6D6 at 258C.
To explore the scope of the reaction, aliphatic isocyanates
were tested. When the reaction was performed with
nHexNCO, the hydrophosphination competed with the cyclo-
trimerization reaction, leading to a mixture of [nHexNCO]3,[9]
true catalyst and that a transformation takes place before the
catalysis begins. No induction period is observed for 2, where
the catalysis starts immediately after substrate addition. It is
likely that the same initial reaction takes place for 2 but the
labile THF ligand is easily displaced, thus making this step
considerably faster. Surprisingly, when 1 was reacted sepa-
rately with either Ph2PH or CyNCO no reaction was observed
after 48 hours at room temperature, either by NMR or IR
spectroscopy. As soon as the other substrate is added the
formation of 3 f is observed. Stoichiometric studies were not
conclusive as IR spectroscopy shows several peaks in the
amide region, but indicate that the active catalyst is an iron
amidate complex (A; Scheme 3). The formation of this
species could be in equilibrium, therefore both Ph2PH and
CyNCO are needed to drive the reaction to A. However, the
possibility that both substrates are required for precatalyst
activation cannot be ruled out.
Sigmoidal reaction kinetics have been used as evidence
for a heterogeneous mechanism where the catalyst may be
bulk iron metal or trace iron nanoclusters.[15] To distinguish
the true nature of the catalyst, poisoning experiments with Hg
and CS2 were performed (see the Supporting Information).
No change was observed in either the reaction rate or catalyst
selectivity, suggesting that the reaction most likely occurs
=
=
[Ph2PC( O)N(H)nHex] (3e), and [Ph2PC( O)N(nHex)-
=
C( O)N(H)nHex] (4e) (Table 1, entries 10–12). Meanwhile,
reactions with more sterically encumbered secondary and
tertiary isocyanates (CyNCO, iPrNCO, and tBuNCO)
afforded, almost exclusively, the monoinsertion products
(3 f–h; entries 13–19). For iPrNCO and tBuNCO the temper-
ature was raised to 608C to reach reasonable conversions,
within 16 hours (entries 15–19), of around 90% for 3g and
greater than 70% for 3h. Previous attempts by others to
catalyze the hydrophosphination of tBuNCO with Ph2PH
were low yielding (< 20%).[5e] Collectively, these results
indicate that the observed selectivity between the catalysis
of the mono- and diinsertion of isocyanates into Ph2PH may
be governed by steric factors, preferentially obtaining the
diinsertion product for less bulky isocyanates and the mono-
insertion product for secondary and tertiary aliphatic isocya-
nates.
Changing the solvent from C6D6 to THF resulted in
a significant change in the selectivity (Scheme 2; see Table S1
in the Supporting Information), affording the monoinsertion
product almost exclusively. A decrease in catalyst activity was
2
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=
attack of [Ph2PC( O)N(H)Ph] (3a), and is in agreement with
our proposed mechanism.
An alternate mechanism, similar to those reported for
rare-earth precatalysts[5a,b,e] where the Ph2PH attacks the
metal center first, through protolytic cleavage of the amide
ligand, has been dismissed because of the lack of evidence for
=
the formation of (2,6-MesC6H3)C( O)NH(R) as determined
1
by either H NMR or IR spectroscopy.
Reactions were scaled up successfully, leading to good
yields of isolated products for the diinsertion products (4a–d)
and for monoinsertion products (3a,c–d,f–h; see the Support-
ing Information for full procedures).
In summary, the catalytic hydrophosphination of isocya-
nates under mild reaction conditions has been demonstrated
using the iron precatalysts 1 and 2, which display remarkable
reactivity because of their low coordination number and the
unique steric pocket created by the bulky m-terphenyl
ligands. Simple modification of the reaction conditions can
control the synthetic outcome yielding either mono- or
diinsertion products with high selectivity.
Scheme 3. Proposed mechanism for the mono- and diinsertion of
À
isocyanates into the P H bond of Ph2PH.
through a homogenous mechanism. Moreover, the reaction
does not appear to be catalyzed by radicals since the presence
of excess cumene does not affect the rate of the reaction (see
the Supporting Information).[16] No significant changes were
observed when triethylamine was added to the reaction
mixture (see Table S2, entry 1). The addition of a weak acid
(NEt3·HCl) favors the double insertion product, affording 4a
and 4c almost exclusively (see Table S2, entries 2 and 4;
Scheme 2), and highlights the mechanistic differences
between our catalytic system and traditional palladium
catalysts.[17]
With these mechanistic considerations in mind the
proposed catalytic cycle is shown in Scheme 3. Because of
the relatively high oxidation state of the iron(II) and its
coordinative unsaturation, it is conceivable to envisage the
metal center acting as a Lewis acid.[4e,18] Therefore, a likely
first step is the coordination of an isocyanate molecule leading
to the intermediate B. Nucleophilic attack of free Ph2PH on
Acknowledgments
We gratefully acknowledge the support of the University of
Nottingham, the EPSRC and Leverhulme Trust. We also
thank Dr. Ross Denton, University of Nottingham for
mechanistic discussions, Dr. Huw Williams, University of
Nottingham for helpful NMR discussions, Dr. Mick Cooper at
the University of Nottingham for mass spectrometry and
Stephen Boyer (London Metropolitan University) for ele-
mental analyses.
Conflict of interest
The authors declare no conflict of interest.
À
the coordinated isocyanate leads to P C bond formation and
the transient species C. Similar substrate coordination
followed by outer-sphere attack of a phosphine have been
proposed.[4e,19] A 1,3-proton shift, followed by addition of
a new molecule of isocyanate regenerates the active species B
with displacement of 3. When the phosphinocarboxamide (3)
produced in Cycle 1 contains a smaller R group it is also
possible to proceed into Cycle 2 by a nucleophilic attack on B
with the subsequent formation of D. Proton transfer followed
by displacement of the phosphinodicarboxamide (4) by an
incoming isocyanate molecule results in the regeneration of B.
When coordinating solvents such as THF are used, solvation
of B can occur, thus blocking the approach of a phosphino-
carboxamide molecule, and enforcing the monoinsertion
pathway. The weak acid will likely aid the protonolysis step
in Cycle 2, a rate-limiting step for hydroamination reac-
tions.[20] Indeed, when a mixture of PhNCO and CyNCO is
reacted with diphenylphosphine (1:1:1) a combination of four
products 3a/3 f/4a/4i is obtained (see Scheme S1). The
Keywords: homogeneous catalysis · hydrophosphination · iron ·
ligand design · reaction mechanisms
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Final Article published: && &&, &&&&
4
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Communications
Homogeneous Catalysis
H. R. Sharpe, A. M. Geer, W. Lewis,
A. J. Blake, D. L. Kays*
&&&& — &&&&
Iron(II)-Catalyzed Hydrophosphination of
Isocyanates
Seeing double: Low-coordinate iron(II)
complexes have been used in the hydro-
phosphination of isocyanates to produce
mono- and/or diinsertion products yield-
ing phosphinodicarboxamides, a new
family of derivatized organophosphorus
compounds. Small changes in reaction
conditions drastically alter the product
selectivity.
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