Heavier group-2-element catalyzed hydroamination of carbodiimides

Article abstract of DOI:10.1002/ejic.200800613

The heteroleptic calcium amide [{ArNC(Me)CHC(Me)-NAr}Ca{N(SiMe ₃)₂}(THF)] (Ar = 2,6-diisopropylphenyl) and the homoleptic heavier alkaline earth amides, [M{N(Si-Me₃)₂} ₂(THF)2] (M = Ca, Sr and Ba) are

Full text of DOI:10.1002/ejic.200800613

FULL PAPER
DOI: 10.1002/ejic.200800613
Heavier Group-2-Element Catalyzed Hydroamination of Carbodiimides
Jennifer R. Lachs,[a] Anthony G. M. Barrett,*[a] Mark R. Crimmin,[a]
Gabriele Kociok-Köhn,[b] Michael S. Hill,*[b] Mary F. Mahon,[b] and
Panayiotis A. Procopiou[c]
Keywords: Hydroamination / Guanidine / Guanidinate / Alkaline earth amides
The heteroleptic calcium amide [{ArNC(Me)CHC(Me)-
NAr}Ca{N(SiMe3)2}(THF)] (Ar = 2,6-diisopropylphenyl) and
the homoleptic heavier alkaline earth amides, [M{N(Si-
Me3)2}2(THF)2] (M = Ca, Sr and Ba) are reported as compe-
tent pre-catalysts for the hydroamination of 1,3-carbodiim-
ides. Whilst the reaction scope is currently limited to reac-
tions of aromatic amines with 1,3-dialkylcarbodiimides, in
most cases preparations in hydrocarbon solvents proceed
rapidly at room temperature with catalyst loadings as low as
0.2 mol-% and the guanidine reaction products crystallize di-
rectly from the reaction mixture. Initial studies are consistent
with the intermediacy of heavier group-2 guanidinate com-
plexes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
heterocumulenes, we recently reported that β-diketiminato
calcium amides, [{ArNC(Me)CHC(Me)NAr}Ca{NR2}-
(THF)] (Ar = 2,6-diisopropylphenyl, NR2 = NHAr, NPh2,
NHCH2CH2OMe), readily undergo insertion reactions
with 1,3-dialkylcarbodiimides to yield the corresponding
heteroleptic calcium guanidinate complexes. Furthermore,
these latter complexes could be synthesized through a one-
pot procedure from addition of the amine and carbodiimide
to [{ArNC(Me)CHC(Me)NAr}Ca{N(SiMe3)2}(THF)] (1)
in hydrocarbon solutions.[15] We now describe the extension
of this work to the group-2 catalyzed synthesis of guani-
dines by the hydroamination of 1,3-carbodiimides.
Introduction
Over the past few years a useful reaction chemistry of
the organometallic compounds of the heavier alkaline
earths (M = Ca, Sr and Ba) has begun to emerge.[1] Studies
within our group, and elsewhere, have demonstrated the ap-
plication of heavier group-2 species to the catalytic hydro-
amination,[2] hydrophosphination,[3] hydrosilylation,[4] and
polymerization[5] of substrates containing unsaturated car-
bon–carbon bonds. In addition, a number of group-2 medi-
ated catalytic reactions have been reported that employ sub-
strates containing carbon–heteroatom multiple bonds.
These include the polymerization of lactides and lactones,[6]
the trimerisation of phenyl isocyanate,[7] the dimerisation of
aldehydes (Tischenko reaction)[8] and the hydrophosphin-
ation of 1,3-carbodiimides.[9]
Guanidines have received considerable attention not only
for use as ancillary ligands in f-block and transition-metal
chemistry,[10] but also due to their appearance as functional
groups in many natural products and synthetic pharmaceu-
ticals.[11] Despite this, catalytic syntheses of these molecules
remain limited to a handful of examples. These include the
early transition metal,[12] lanthanide[13] and group 1[14] me-
diated hydroamination of carbodiimides and group 4 imido
catalyzed transamination of guanidines.[12a] As part of a
preliminary study toward the catalytic hydroamination of
Results and Discussion
Hydroamination Catalysis
An initial NMR experiment was conducted between 2-
fluoroaniline (δ19F = –135.8 ppm), 1,3-diisopropylcarbodi-
imide and [Ca{N(SiMe3)2}2(THF)2] (2a) in [D6]benzene.
Addition of an excess of both 2-fluoroaniline and 1,3-dialk-
ylcarbodiimide to the pre-catalyst resulted in an instant
crystallization of a colorless reaction product from the
NMR tube. Whilst this event prevented the acquisition of
satisfactory multinuclear NMR spectroscopic data on the
reaction mixture, following work-up of the tube, isolation
and characterization revealed the solid to be the guanidine
[{(2-FC6H5)N}C{NHiPr}2] (δ19F = –125.1 ppm) formed in
44% isolated yield from the catalytic hydroamination of
1,3-diisopropylcarbodiimide followed by, or concominant
with, a 1,3-proton shift. The structure of the product was
confirmed by single-crystal X-ray diffraction (Figure 1). A
[a] Department of Chemistry, Imperial College London,
Exhibition Road, South Kensington, London, SW7 2AZ, UK
[b] Department of Chemistry, University of Bath,
Claverton Down, Bath, BA2 7AY, UK
E-mail: msh27@bath.ac.uk
[c] GlaxoSmithKline Medicines Research Centre,
Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
Eur. J. Inorg. Chem. 2008, 4173–4179
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A. G. M. Barrett, M. S. Hill et al.
FULL PAPER
background experiment between 2-fluoroaniline and 1,3-di- tion of stoichiometric calcium reactivity, in the current con-
isopropylcarbodiimide demonstrated no reaction after 7 d text, use of the β-diketiminato complex 1 offers no advan-
at room temperature (Scheme 1).[16]
tage over the homoleptic calcium amide 2a in terms of
either activity or ease of utility. Indeed it is likely that the
β-diketiminate ligand is protonated and effectively removed
during the early stages of catalytic turnover to provide com-
mon catalytic intermediates (viz. the homoleptic guanidin-
ate complexes 3a and 3b, vide infra). Reactions were con-
ducted using 2 mol-% catalyst and based upon initial sub-
strate concentrations of 0.15 . Although, in all cases,
crystallization of the product from solution was observed
at room temperature, the reaction yield of the isolated gua-
nidine was consistently low (37–68%). This latter limitation
could be overcome, however, by changing the conditions for
what is effectively a crystallization of the reaction product
upon mixing starting materials and catalyst. In this manner,
increasing the concentrations of the substrates to 0.3  and
changing the reaction solvent to hexane yielded the hydro-
amination product [{(2-FC6H5)N}C{NHiPr}2] in 71–84%.
Again 1 and 2a–c proved catalytically active with most reac-
tions taking less than 5 min at room temperature (Table 1,
Entries 1–4).
Figure 1. ORTEP representation (50%) of [{(2-FC6H5)N}-
C{NHiPr}2]. Selected bond lengths [Å] and angles [°]. C(1)–N(1)
1.306(2), C(1)–N(2) 1.364(3), C(1)–N(3) 1.363(3), N(1)–C(1)–N(3)
118.73(19),
N(1)–C(1)–N(2)
127.06(19),
N(3)–C(1)–N(2)
114.15(18). Disordered fluorine atoms modelled over two sites.
A number of anilines and 1,3-carbodiimides were investi-
gated under these reaction conditions and the results of this
study are presented in Table 1. The hydroamination of both
symmetric and unsymmetric carbodiimides was achieved at
room temperature using 2 mol-% of the calcium amide 2a.
Choice of pre-catalyst was dictated by its ease of synthesis
and low cost. Both electron-rich and electron-deficient ani-
Scheme 1. Group-2 catalyzed hydroamination of carbodiimides.
On the basis of this observation a series of reactions were lines react readily and, in most cases, following crystalli-
conducted in benzene solutions. The heteroleptic calcium zation the guanidine products could be isolated by a simple
amide 1 and the series of homoleptic heavier alkaline earth filtration. Catalytic hydroamination reactions employing
amides [M{N(SiMe3)2}2(THF)2] (M = Ca, 2a; Sr, 2b; Ba; sterically demanding substrates, such as 1,3-di-tert-butyl-
2c) were applied to the catalytic hydroamination of 1,3-di- carbodiimide (Table 1 Entries 8, 9) and 2,6-diisopropyl-
isopropylcarbodiimide with 2-fluoroaniline. Although it has aniline (Table 1, Entry 17, 18) however, could only be
proven to be a remarkably useful prototype for the elabora- achieved at higher reaction temperatures. These observa-
Table 1. Group 2 catalyzed hydroamination of carbodiimides.
Entry
R1
R2
Ar
Catalyst
[mol-%]
Time
[h]
Yield
[%][a]
1
2
3
4
5
6
7
8
iPr
iPr
iPr
iPr
Cy
tBu
tBu
tBu
tBu
iPr
Cy
iPr
Cy
iPr
Cy
iPr
Cy
Cy
iPr
iPr
iPr
iPr
Cy
Et
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
2-FC6H4
4-MeC6H4
4-MeC6H4
Ph
1 (2)
0.1
0.1
0.1
1
0.1
12
0.25[b]
24
24
12
4
84
77
80
67
79
91
2a (2)
2b (2)
2c (2)
2a (2)
2a (2)
2a (2)
2a (4)
2a (4)
2a (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (2)
2a (4)
2a (4)
Et
74[b]
37[c]
46[b,c]
71
tBu
tBu
iPr
Cy
iPr
Cy
iPr
Cy
iPr
Cy
Cy
9
10
11
12
13
14
15
16
17
18
81
74
81
85
1
Ph
0.1
12
12
72
2
2-MeOC6H4
2-MeOC6H4
1-naphthyl
2,6-iPrC6H3
2,6-iPrC6H3
80
57
55[c]
82[b,c]
2
1
[a] Isolated yield following crystallization of the product from hexane at 25 °C. [b] Yield determined by H NMR spectroscopy in [D6]
benzene using tetrakis(trimethylsilyl)silane as an internal standard. [c] Reaction conducted at 80 °C.
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Hydroamination of Carbodiimides
tions are consistent with those previously made in stoichio- significant degree of delocalisation of the non-coordinated
metric heavier group-2 chemistry. For example, although nitrogen lone pair across the π-framework of the ligand.
the calcium amide [{ArNC(Me)CHC(Me)NAr}Ca-
{NHAr}(THF)] reacts readily with 1,3-diisopropyl- and
1,3-dicyclohexylcarbodiimide at room temperature, this lat-
ter complex does not undergo an insertion reaction with
1,3-di-tert-butylcarbodiimide even after being heated to
60 °C for 12 h.[15] Initial attempts to extend the catalytic
methodology to primary alkylamines proved unsuccessful.
Although stoichiometric reactions using 1 in these instances
provided the expected heteroleptic calcium guanidinate
complexes,[15] these species did not undergo catalytic turn-
over.
Previous catalytic syntheses of guanidines employing
early transition metal, group 1 or f-block-based catalysts
typically require long reaction times and/or elevated reac-
tion temperatures to achieve the hydroamination of 1,3-car-
Figure 2. ORTEP representation (40%) of 3a. H-Atoms with the
exception of NH protons omitted for clarity. Selected bond lengths
bodiimides.[13–14] For instance the reaction of aniline with
[Å] and angles [°]. Ca–N(1) 2.4215(11), Ca–N(2) 2.4179(10), Ca–
N(4) 2.4202(11), Ca–N(5) 2.4291(11), Ca–O(1) 2.4106(10), Ca–
O(2) 2.4194(10); N(1)–Ca–N(2) 56.13(3), N(1)–C(9)–N(2)
1,3-diisopropylcarbodiimide to yield [(C6H5N)C{NHiPr}2]
is reported to be catalyzed by [Li{N(SiMe3)2}] (2 mol-%,
18 h, room temp., 96% yield) and [{Me2Si(C5Me4)-
NPh}Y(CH2SiMe3)(THF)2] (1 mol-%, 24 h, 50 °C, 92%
yield). Encouraged by the synthetic ease of the procedure
detailed herein, we therefore sought to investigate the limits
of this catalytic reaction. A series of reactions were con-
ducted at room temperature based upon a 60 mmol quan-
tity of 1,3-dicyclohexylcarbodiimide and aniline using 0.2–
2 mol-% of 2a. These experiments demonstrated that whilst
the reaction proceeds rapidly at catalyst loadings as small
as 0.5 mol-% (82%, 0.5 h), at even lower catalyst loadings
product yields diminish quickly and the catalyst reaches a
limit at 0.2 mol-% (56%, 48 h). In all cases, as with the
small scale reactions, the product crystallizes directly from
the reaction mixture.
115.81(11),
N(1)–C(9)–N(3)
121.53(11),
N(2)–C(9)–N(3)
122.65(11), O(1)–Ca–O(2) 89.54(4).
Table 2. Selected bond lengths [Å] and bond angles [°] in complexes
3a–b.
To inform our understanding of these catalytic processes
a series of stoichiometric reactions were performed. Ad-
dition of 2 equiv. of aniline and 1,3-diisopropylcarbodi-
imide to 2a in [D8]toluene yielded, in addition to 2-phenyl-
1,3-diisopropylguanidine, a new calcium species, 3a, which
could also be synthesized by addition of two equivalents of
the free guanidine to the pre-catalyst 2a. Crystallization of
3a from a hexane/THF solvent mixture allowed the isola-
tion of single crystals. An X-ray diffraction experiment re-
vealed the product 3a to be a homoleptic calcium guanidin-
ate complex with coordination at the metal provided by two
unsymmetrically chelated κ2-N,N-guanidinate ligands and
In solution 3a demonstrated a level of complexity that
two molecules of tetrahydrofuran (Figure 2 and Table 2). was not consistent with the solid-state data. Variable tem-
The complex possess pseudooctahedral geometry at the six- perature NMR studies upon a [D8]toluene solution of 3a
coordinate calcium center with the two tetrahydrofuran li- showed a number of reversible changes. At 298 K four inde-
1
gands demonstrating a cisoid geometry [O(1)–Ca–O(2) pendent isopropyl signals were observed by H NMR spec-
89.54(4)°] with repect to one another. Calcium–nitrogen troscopy. In the high-temperature limit (353 K) these reso-
bond lengths [av. Ca–N 2.418 Å] and the guanidinate ligand nances coalesced to give only two isopropyl environments.
bite angles [N(1)–Ca–N(2) 56.13 and N(4)–Ca–N(5) 55.90°] Although coalescence of the apparent two sets of twin reso-
are consistent with those reported in the only previously nances occurred at two independent temperatures [TA
=
reported homoleptic calcium guanidinate complex 318 K; TB = 338 K] with two independent frequencies
[{(Me3Si)2N}C(NCy)2]2Ca(OEt2) (4) [av. Ca–N 2.381 Å; av. [kA = 34 Hz; kB = 117 Hz], these data gave a single acti-
N–Ca–N 56.39°].[17] In addition, bond lengths and bond vation energy [∆G‡ = 68 kJmol–1] characterising one flux-
angles within the two guanidinate ligands of 3a suggest a ional process. The complexity of these observations was re-
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A. G. M. Barrett, M. S. Hill et al.
FULL PAPER
solved by the synthesis of a solvent-free analogue of 3a.
Although it has previously been reported that
Reaction of two equivalents of [(PhN)C{NHiPr}2] with [{(Me3Si)2N}C(NCy)2]2Ca(OEt2) (4) is susceptible to re-
[Ca{N(SiMe3)2}2] in toluene yielded the dimeric calcium versible decomposition with reformation of a carbodiimide
guanidinate complex 3b. An X-ray crystallograpic study re- and calcium amide,[17] the attempted crossover reaction of
vealed 3b to consist, in the solid-state, of a centrosymmetric [{(2-FC6H5)N}C{NHiPr}2], 1,3-dicyclohexylcarbodiimide
dimer in which five-coordinate calcium centers are bridged and 2 mol-% 2a yielded no new reaction products after 12 h
by unsymmetric Ca–N–CaЈ interactions (Figure 3 and at room temperature as monitored by 19F NMR spec-
Table 2). The N–C–N chelate rings are disposed with and troscopy. Similarly,
a
mixture of [{(2-FC6H5)N}-
anti-configuration with respect to the dimer core giving rise C{NHiPr}2], 4-methylaniline and 2 mol-% 2a demonstrated
to an S2-symmetric tricylic ladder structure. Further coor- no signs of crossover reaction products over the same
dination at calcium is provided by terminal guanidinate li- period. These experiments suggest that, under the catalytic
gands. As with 3a the guanidinate ligands in both terminal reaction conditions, the calcium guanidinate complexes are
and bridging positions in 3b coordinate as unsymmetric κ2- kinetically stable and guanidine formation is non-reversible.
N,N-chelates. The calcium–nitrogen bond lengths of the
non-bridging interactions [av. 2.379 Å] are slightly shorter
Proposed Catalytic Cycle
than those observed in 3a due to the higher coordination
number at calcium in the former complex. The guanidinate
bite angles within 3b [N(3)–Ca–N(1) 57.45° and N(6)–Ca–
N(4) 55.08°] also differ slightly from those in the mono-
meric species with the terminal ligands demonstrating a
more obtuse bite-angle than those in the bridging positions.
The isolated guanidinate complexes 3a and 3b were also
applied to the catalytic hydroamination of 1,3-diisopro-
pylcarbodiimide with aniline. Although, both compounds
proved catalytically active the isolated yields of the guani-
dine products (3a, 1 h, 62%; 3b, 1 h, 79%) differed slightly
from those of the amide pre-catalyst [Ca{N(SiMe3)2}2-
(THF2)] (2a, 1 h, 74%), most likely due to differences in
the crystallization conditions of the reaction product. This
observation, and consideration of our previous studies on
the hydrophosphination of carbodiimides,[9] suggests that
the catalytic hydroamination chemistry proceeds via fast
catalyst initation via silylamide protonation and carbodiim-
ide insertion to form a group-2 guanidinate complex. Pro-
tonolysis of this latter species with 1 equiv. of aniline, liber-
ates the guanidine product and reforming the transient
group-2 amide complex (Scheme 2)
Figure 3. ORTEP representation (40%) of 3b. H-Atoms with the
exception of NH protons omitted for clarity. Selected bond lengths
[Å] and angles [°]. Ca–N(3) 2.3604(11), Ca–N(1) 2.3748(11), Ca–
N(6) 2.4009(11), Ca–N(4) 2.4269(11), Ca–N(4)Ј 2.5590(11), N(3)–
Ca–N(1) 57.45(4), N(6)–Ca–N(4) 55.08(4), Ca–N(4)–CaЈ 89.31(4).
Scheme 2. Proposed catalytic cycle.
Complex 3b demonstrated identical variable-temperature
1H NMR spectroscopic data to 3a in [D8]toluene solutions,
indicating that 3a also undergoes dimerisation in solution
with the exclusion of THF from the coordination sphere.
Whilst alternative fluxional modes cannot be discounted,
this behaviour may be explained by considering the equili-
bration of bridging and terminal ligands within a robust
dimeric species with the guanidinate maintaining a prefer-
ence for unsymmetrical coordination. Consistent with this
Although the calcium guanidinate complexes may be di-
meric in solution, the nuclearity of the active catalyst spe-
cies is likely to be a function of not only the substrates but
also the group-2 metal employed.
Conclusions
Homoleptic group-2 amides [M{N(SiMe3)2}2(THF)2]
hypothesis 13C NMR spectroscopic data demonstrated two (M = Ca, Sr and Ba) are reported as highly competent pre-
guanidinate ligand environments at 298 K, characterized by catalysts for the catalytic hydroamination of carbodiimides
the quaternary carbon resonances of the N3C cores [13Cquat. with anilines. Although initial attempts to extend this reac-
= 151.5, 154.9 ppm]. Further qualitative evidence for the tion chemistry to primary amines has been unsuccessful,
dimeric nature of 3 in solution was provided by the fact that the chemistry detailed herein represents a practical and
∆G‡ was found to be independent of sample concentration. scalable synthetic approach to guanidines. Coordination
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Hydroamination of Carbodiimides
found 318.2338. M.p. (hexane) 154–156 °C. C19H28FN3 (317.45):
calcd. C 71.82, H 8.82, N 13.23; found C 71.40, H 8.86, N 13.00.
chemistry studies upon the catalytic species (M = Ca) sug-
gest the involvement of homoleptric dimeric guanidinate
complexes in solution, with catalytic turnover occurring, by
analogy to our previous work,[9] with fast Brønstead acid–
Brønstead base and Lewis acid–Lewis base ligand-exchange
1,3-Dicyclohexyl-2-(2-methoxyphenyl)guanidine [{(2-MeOC6H5)N}-
C{NHCy}2]: The product crystallized as a colorless solid (414 mg,
1.26 mmol, 80%) after 12 h. 1H NMR ([D6]benzene, 400 MHz,
processes at the metal center, and carbon–nitrogen bond 298 K): δ = 0.85–0.97 (m, 6 H), 1.08–1.18 (m, 4 H), 1.36–1.39 (m,
2 H), 1.48–1.52 (m, 4 H), 3.46 (s, 3 H), 3.40–3.60 (apparent broad
s, 2 H), 3.56 (broad s, 2 H), 6.79 (d, J = 7.8 Hz, 1 H), 6.93 (ddd, J
= 7.8, 7.5, 1.8 Hz, 1 H), 6.98 (ddd, J = 7.5, 7.4, 1.5 Hz, 1 H), 7.21
(d, J = 7.4 Hz, 1 H) ppm. 13C NMR ([D6]benzene, 100 MHz,
298 K): δ = 25.3, 26.0, 34.1, 50.6, 55.6, 113.2, 122.1, 122.2, 125.2,
140.9, 149.5, 153.0; IR (DCM film) 1031, 1049, 1238, 1255, 1452,
1490, 1548, 1585, 1621, 2852, 2927, 3054, 3286 ppm. MS (ESI,
+ve): m/z (%) = 330 (100) [M + H]+. HRMS calcd. for C20H32N3O
330.2542 found 330.2545. M.p. (hexane) 113–114 °C. C20H31N3O
(329.48): calcd. C 72.91, H 9.48, N 12.75; found C 72.30, H 9.48,
N 12.50.
formation proceeding by σ-bond metathesis and insertion
reaction steps. We are continuing to investigate this reaction
and the application of heavier group-2 species in this and
related catalytic processes.
Experimental Section
General Procedures: All manipulations were carried out using stan-
dard Schlenk line and glovebox techniques under either dinitrogen
or argon. All solvents were distilled under dinitrogen and dried
with conventional drying agents. Anilines were purchased from
Sigma–Aldrich and used without further purification, with the ex-
ception of aniline, 2-fluoroaniline, 2-methoxyaniline and 2,6-diiso-
propylaniline which were dried with calcium hydride and distilled
before use. All carbodiimides were purchased from Sigma–Aldrich
and used without further purification. The β-diketiminate ligand
3-tert-Butyl-1-ethyl-2-(2-fluorophenyl)guanidine
[{(2-FC6H5N)}-
C{NHEt}{NHtBu}]: On a Schlenk line, a solution of 2a (16 mg,
0.032 mmol, 2 mol-%) in toluene (2 mL) was added to a toluene
(2 mL) solution of 1-tert-butyl-3-ethylcarbodiimide (200 mg,
1.58 mmol) and 2-fluoroaniline (176 mg, 1.58 mmol). The reaction
mixture was stirred overnight, and then exposed to air. The solvent
was removed in vacuo and the crude dissolved in diethyl ether
(30 mL) and washed with water (3ϫ10 mL). The organic layer was
dried with magnesium sulfate, filtered and the solvent removed in
vacuo. The resultant oil was deemed pure by multinuclear NMR
spectroscopy and mass spectrometry. Further purification was
achieved by bulb-to-bulb distillation (150 °C, 3.3ϫ10–1 mbar) to
give the product as a yellow oil (340 mg, 1.43 mmol, 91%).The re-
precursor, ArNHC(Me)CHC(Me)NAr (Ar
=
2,6-diisopro-
pylphenyl),[18] heavier alkaline earth amides [M{N(SiMe3)2}2-
(THF)2] (M = Ca, Sr and Ba),[19] and the heteroleptic calcium
amide 1[6a] were prepared by literature procedures.
Preparative Scale Experiments: In
(1.584 mmol) and carbodiimide (1.584 mmol) were dissolved in
hexane (1 mL). In separate vial, [Ca{N(SiMe3)2}2THF2]
a glovebox, the aniline
a
1
action monitored by H and 19F NMR showed a 74% yield after
(0.032 mmol, 2 mol-%) was dissolved in hexane (1 mL).The catalyst
solution was then transferred to a test tube, the substrate solution
was added and the total volume made up to ca 5 mL. The reaction
mixture was mixed thoroughly and formed a homogeneous, color-
less, solution. The test tube was sealed with a septum and the reac-
tion left for the specified time. Upon crystallization of the product,
the sample was removed from the glovebox and the guanidine iso-
lated by filtration, washed with cold hexane and dried in a desicca-
tor. Literature known compounds gave satisfactory multinuclear
data (see Supporting Information).
15 min at room temperature. 1H NMR ([D6]benzene, 300 MHz,
298 K): δ = 0.65 (t, J = 7.2 Hz, 3 H), 1.31 (s, 9 H), 2.63 (q, J =
7.2 Hz, 3 H), 3.43 (broad s, 2 H), 6.68–6.72 (m, 1 H), 6.91 (ddd, J
= 7.6, 7.6, 1.4 Hz, 1 H), 7.00 (ddd, J = 10.8, 8.1, 1.6 Hz, 1 H), 7.08
(ddd, J = 8.4, 8.1, 1.7 Hz, 1 H) ppm. 19F NMR ([D6]benzene,
298 K): δ = –125.4 ppm. 13C NMR ([D6]benzene, 100 MHz,
298 K): δ = 14.9, 29.8, 37.1, 50.8, 116.3 (d, J = 20.6 Hz), 122.0 (d,
J = 7.1 Hz), 124.8 (d, J = 3.7 Hz), 126.3 (d, J = 3.2 Hz), 139.0 (d,
J = 12.8 Hz), 150.6, 156.2 (d, J = 242.5 Hz) ppm. IR (DCM film):
ν
= 749, 1214, 1361, 1450, 1489, 1526, 1599, 1632, 2923, 2970,
˜
NMR-Scale Experiments: In a glove box, accurately weighed tetra-
kis(trimethylsilyl)silane (TMSS, ca. 2 mg), aniline (0.25 mmol) and
carbodiimide (0.25 mmol) were dissolved in [D6]benzene (0.5 mL)
and transferred to a Youngs tap NMR tube. The initial concentra-
tions of reagents were measured by 1H NMR spectroscopy, follow-
ing which the catalyst (2–5 mol-%) was added and the reaction
monitored by 1H and 19F NMR spectroscopy. Yields were calcu-
lated by reference to TMSS.
3420. MS (ESI, +ve): m/z (%) = 238 (100) [M + H]+. HRMS calcd.
for C13H21FN3 238.1719 found 238.1704.
1,3-Di-tert-butyl-2-(2-fluorophenyl)guanidine
C{NHtBu}2]: On Schlenk line, solution of 2a (32 mg,
0.064 mmol, 4 mol-%) in toluene (2 mL) was added to a toluene
(2 mL) solution of 1,3-tert-butylethylcarbodiimide (246 mg,
1.58 mmol) and 2-fluoroaniline (176 mg, 1.58 mmol). The Schlenk
[{(2-FC6H5N)}-
a
a
1,3-Dicyclohexyl-2-(2-fluorophenyl)guanidine
{NHCy}2]: The product crystallized as a colorless solid (397 mg,
[{(2-FC6H5)N}C- tube was sealed, removed from the glovebox and heated to 80 °C
for 24 h, after which point the reaction product was treated as
1.25 mmol, 79%) after 5 min. 1H NMR ([D6]benzene, 400 MHz, moisture stable and the volatiles removed. Purification was
298 K): δ = 0.78–0.95 (m, 6 H), 1.04–1.14 (m, 4 H), 1.33–1.38 (m, achieved by bulb-to-bulb distillation (175 °C, 3.0ϫ10–1 mbar) to
2 H), 1.44–1.50 (m, 4 H), 1.91–1.94 (m, 4 H), 3.40–3.52 (broad m, give the product as a yellow oil (156 mg, 37%). Monitoring of the
2 H), 3.56–3.58 (broad m, 2 H), 6.68–6.73 (m, 1 H), 6.93 (ddd, J reaction by 1H and 19F NMR showed a 46% yield after 24 h at
= 7.7, 7.6, 1.3 Hz, 1 H), 7.03 (ddd, J = 10.8, 8.1, 1.3 Hz, 1 H), 7.15–
7.20 (m, 1 H) ppm. 13C NMR ([D6]benzene, 100 MHz, 298 K): δ
= 25.2. 25.9, 33.9, 50.5, 116.3 (d, J = 20.6 Hz), 122.1 (d, J =
80 °C. 1H NMR ([D6]benzene, 300 MHz, 298 K): δ = 1.20 (s, 18
H), 3.66 (broad s, 2 H), 6.65–6.72 (m, 1 H), 6.88 (ddd, J = 7.6, 7.6,
1.4 Hz, 1 H), 6.95–7.03 (m, 2 H) ppm. 19F NMR ([D6]benzene,
7.1 Hz), 124.9 (d, J = 3.4 Hz), 126.5 (d, J = 2.6 Hz), 139.2 (d, J = 298 K): δ = –125.1 ppm. 13C NMR ([D6]benzene, 75 MHz, 298 K):
12.7 Hz), 150.1, 156.3 (d, J = 242.6 Hz) ppm. 19F NMR ([D6]ben- δ = 30.0, 50.8, 116.3 (d, J = 20.6 Hz), 122.1 (d, J = 7.1 Hz), 124.7
zene, 298 K): δ = –124.9 ppm. IR (DCM film) 1265, 1490, 1517,
1598, 1625, 2856, 2933, 2985, 3054, 3442 ppm. MS (ESI, +ve): m/z
(d, J = 3.7 Hz), 126.1 (d, J = 3.1 Hz), 139.0 (d, J = 12.9 Hz), 150.7,
156.0 (d, J = 242.2 Hz) ppm. IR (DCM film): ν = 749, 1210, 1436,
˜
(%) = 318 (100) [M + H]+. HRMS calcd. for C19H29FN3 318.2346 1490, 1520, 1600, 1635, 2962, 3472 cm–1. MS (ESI, +ve): m/z (%) =
Eur. J. Inorg. Chem. 2008, 4173–4179
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
4177

A. G. M. Barrett, M. S. Hill et al.
266 (100) [M + H]+. HRMS calcd. for C15H24FN3 266.2033 found Supporting Information (see also the footnote on the first page of
FULL PAPER
266.2045.
this article): Complete experimental details and spectra of all iso-
lated compounds and 1H and 13C{1H} NMR spectra of isolated
guanidine compounds.
Calcium Guanidinate 3a: To a solution of 2a (0.253 g, 0.5 mmol) in
THF (15 mL) was added a solution of 1,3-diisopropyl-2-phenyl-
guanidine (0.219 g, 1.0 mmol) in THF (10 mL). After 12 h at room
temperature the solvent was evaporated and the compound was
recrystallized from hexane/THF (10 mL/1 mL) at –20 °C yielding
colorless crystals of 3a (0.174 g, mmol, 60%). M.p. (10:1 hexane/
THF) 158–159 °C. Multinuclear NMR spectroscopic data as below
with additional resonances attributed to non-coordinated THF.
C34H56CaN6O2 (620.41): calcd. C 65.77, H 9.09, N 13.53; found C
65.69, H 8.97, N 13.62. M.p. (hexane/THF, 10:1) 158–159 °C.
Acknowledgments
We thank GlaxoSmithKline for the generous financial support (to
A. G. M. B.), the Royal Society of Chemistry for a University Re-
search Fellowship (M. S. H.) and Royal Society Wolfson Research
Merit Award (A. G. M. B.) and the Engineering and Physical Sci-
ences Research Council and GlaxoSmithKline for generous sup-
port of our studies.
Calcium Guanidinate 3b: Toluene (10 mL) was added to a solid mix-
ture of [Ca{N(SiMe3)2}2]2 (164 mg, 0.46 mmol) and 1,3-diisopro-
pyl-2-phenylguanidine (200 mg, 0.92 mmol). The mixture was
stirred for 30 min, filtered and the solvent volume reduced to in-
duce crystallization. The product 3b was isolated as a colorless
crystalline solid (127 mg, 0.133 mmol, 58%) by slow cooling of a
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1
hot toluene solution to 5 °C. M.p. (toluene) 153–158 °C. H NMR
([D8]toluene, 298 K, 400 MHz): δ = 0.71 (d, J = 6.8 Hz, 12 H), 0.91
(apparent s, 12 H), 1.13 (d, J = 6.2 Hz, 12 H), 1.18 (d, J = 6.3 Hz,
12 H), 3.15 (hept, J = 6.3 Hz, 2 H), 3.27 (hept, J = 6.2 Hz, 2 H),
3.37 (hept, J = 6.8 Hz, 2 H), 3.41 (broad s, 4 H, NH), 3.58 (mul-
tiplet, 2 H), 6.75–6.79 (m, 2 H), 6.77–6.81 (m, 2 H), 7.07–7.14 (m,
8 H), 7.15–7.23 (m, 8 H) ppm. 1H NMR ([D8]toluene, 353 K,
400 MHz): δ = 0.82 (apparent broad s, 12 H), 1.14 (d, J = 6.0 Hz,
12 H), 3.25 (multiplet, 2 H), 3.44 (multiplet, 2 H), 3.57 (broad s, 4
H, NH), 6.72 (broad t, 4 H), 6.96–7.01 (m, 8 H), 7.06–7.13 (m, 8
H) ppm. 13C NMR ([D8]toluene, 298 K, 100 MHz): δ = 24.4, 24.5,
26.3, 27.2, 115.9, 118.4, 121.6, 122.7, 123.7, 130.4, 151.5, 154.9,
163.3, 164.9 ppm. C52H80Ca2N12 (952.59): calcd. C 65.45, H 8.39,
N 17.62; found C 65.53, H 8.33, N 17.57. M.p. (toluene) 155–
158 °C.
Xray Diffraction Data:[20] Data for [{(2-FC6H5)N}C{NHiPr}2] and
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[{(2-FC6H5)N}C{NHiPr}2]: C13H20FN3, M = 237.32, monoclinic,
P21/a, a = 8.5380(5) Å, b = 11.2920(7) Å, c = 14.0080(10) Å, β =
94.402(3), V = 1346.54(15) Å3, Z = 4, ρ = 1.171 gcm–3, R1
[IϾ2σ(I)] = 0.0498, wR2 [IϾ2σ(I)] = 0.115, R1 [all data] = 0.0913,
wR2 [all data] = 0.1358, measured reflections = 12160, unique re-
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¯
3a: C34H56CaN6O2, M = 620.93, triclinic, P1, a = 8.2890(1) Å, b
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= 77.981(1), V = 1786.72(5) Å3, Z = 2, ρ = 0.213 gcm–3, R1
[IϾ2σ(I)] = 0.0432, wR2 [IϾ2σ(I)] = 0.0988, R1 [all data] = 0.0653,
wR2 [all data] = 0.1097, measured reflections: 38968, unique reflec-
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Received: June 17, 2008
Published Online: August 5, 2008
Eur. J. Inorg. Chem. 2008, 4173–4179
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
4179