Catalyst Pendent-Base Effects on Cyclization of Alkynyl Amines

Article abstract of DOI:10.1002/cctc.201800713

A family of [CpRu(PP)(MeCN)]PF₆ complexes (2 a–e and 4) were prepared in which the bis-phosphine ligand contains a pendent tertiary amine in the second-coordination sphere. 2 a–e contain P^Ph₂N^R′₂ ligands with two amine groups as the pendent base. Complex 4 has the P^Ph₂N^Ph₁ ligand with only one pendent amine. The catalytic performance of 2 a–e and 4 were assessed in the cyclization of 2-ethynyl aniline and 2-ethynylbenzyl alcohol. It was revealed that the positioning of the pendent amine near the metal active site is essential for high catalyst performance. A comparison of P^Ph₂N^R′₂ catalysts (2 a–e) showed minimal difference in performance as a function of pendent amine basicity. Rather, only a threshold basicity – in which the pendent amine was more basic than the substrate – was required for high performance.

Full text of DOI:10.1002/cctc.201800713

Full Papers
DOI: 10.1002/cctc.201800713
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Catalyst Pendent-Base Effects on Cyclization of Alkynyl
Amines
James M. Stubbs,[a] Devon E. Chapple,[a] Paul D. Boyle,[a] and Johanna M. Blacquiere*[a]
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A family of [CpRu(PP)(MeCN)]PF6 complexes (2a–e and 4) were
prepared in which the bis-phosphine ligand contains a pendent
tertiary amine in the second-coordination sphere. 2a–e contain
was revealed that the positioning of the pendent amine near
the metal active site is essential for high catalyst performance. A
comparison of PPh2NR’ catalysts (2a–e) showed minimal differ-
2
PPh2NR’ ligands with two amine groups as the pendent base.
ence in performance as a function of pendent amine basicity.
Rather, only a threshold basicity – in which the pendent amine
was more basic than the substrate – was required for high
performance.
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Complex 4 has the PPh2NPh1 ligand with only one pendent amine.
The catalytic performance of 2a–e and 4 were assessed in the
cyclization of 2-ethynyl aniline and 2-ethynylbenzyl alcohol. It
19 Introduction
(PPh3)2 (A) achieves complete conversion with short reaction
times, but the solvent is limited to pyridine, which is required
as an intermolecular base to mediate proton-transfer steps.[2e]
The MLC catalyst B, with a pendent pyridyl group on the
phosphine ligand, gives Ind in more typical solvents (i.e. THF)
and with lower catalyst loadings (2 mol% B vs. 10 mol% for
A).[2f]
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21 Metal-ligand cooperative (MLC) catalysts employ ligands that
22 work in concert with the metal to convert substrate to
23 product.[1] The most common subset of these catalysts contain
24 an acidic or basic site on the ligand that shuttle protons in an
25 intramolecular fashion, allowing for high performance in a
26 variety of transformations such as hydrogenation, dehydrogen-
27 ation, dehydrogenative coupling and hydration reactions.
The mechanism for alkynyl amine cyclization is expected to
follow a similar route to the related intermolecular hydration of
alkynes.[1e,2a] The simplified mechanism for cyclization includes
reaction of the low-coordinate active catalyst (I) with the alkyne
to give a vinylidene intermediate (II) (Figure 1). Nucleophilic
28 Cyclization of alkynyl amines or alcohols gives N- and O-
29 heterocycles respectively,[2] which are important motifs in a
30 variety of natural products and pharmaceuticals.[3] Cyclization of
31 the benchmark substrate 2-ethynylaniline (EA) to indole (Ind)
32 showcases the benefit of MLC catalysts over non-cooperative
33 catalysts (Scheme 1).[2e,f] The non-cooperative catalyst CpRuCl
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Scheme 1. Cyclization of 2-ethynylaniline (EA) with a) a non-cooperative
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catalyst A (10 mol% A, pyridine, 908C, 25 min, 84% Ind)[2e] and b) a
cooperative catalyst B (2 mol% B, THF, 708C, 7 h, 87% Ind).[2f] [Please use
corrected scheme 1 (cdx file attached) in which the structure of A is
corrected]
Figure 1. Simplified probable mechanism for cyclization of 2-ethynyl aniline
(EA) based on studies[1e,2a] of catalytic alkyne hydration. The mechanism is
depicted with an exogenous base, but an internal base on the ligand would
serve the same role. The box in I indicates an open coordination site.
attack at Ca by the substrate amine, and proton shuttling by
exogenous or internal base, will give intermediate III. Proto-
nolysis of the RuÀC bond by the protonated base releases the
product and regenerates I. Experimental and computational
studies of hydration reactions indicate that the highest-barrier
steps include proton-transfer events.[1e,2a] Therefore, it is
expected that the pKa/pKb and sterics of the acidic/basic site of
cyclization catalysts will influence catalyst performance and
that these properties offer an additional dimension for ligand
tuning.
[a] J. M. Stubbs, D. E. Chapple, Dr. P. D. Boyle, Prof. J. M. Blacquiere
Department of Chemistry
University of Western Ontario
London, Ontario, Canada, N6A 5B7
E-mail: johanna.blacquiere@uwo.ca
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.201800713
This publication is part of the Young Researchers Series. More information
regarding these excellent researchers can be found on the ChemCatChem
hompage.
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Systematic studies that evaluate the effects of the second-
coordination sphere properties on catalyst performance are
scarce. Such studies are challenging since many MLC ligand
motifs have the acidic or basic site in the primary coordination
sphere, where any changes in basicity will inevitably strongly
affect the optimal steric/electronic properties for metal-medi-
ated catalytic steps. Several ligands have the acidic or basic site
in the secondary-coordination sphere (i.e. the ligand back-
bone), but in many cases extensive synthetic variation is non-
Scheme 3. Synthesis of PPh2NR’2 ligands used in this study. Conditions: (i) p-
CH2O, EtOH, 788C, 4 h; (ii) dropwise H2NR’, EtOH, 788C, 24 h. Yield 1c=15%;
1a–b, 1d–e are known.[5,7]
10 trivial. Conversely, the PR NR’ (1,5-R’-3,7-R-1,5-diaza-3,7-diphos-
2
2
11 phacyclooctane) ligand class contains a tertiary amine in the
12 secondary-coordination sphere that is readily synthetically
properties. The ligands were synthesized using modified
literature procedures starting from phenyl phosphine, p-
formaldehyde and the respective amine (Scheme 3).[5,7] Deriva-
tive 1c is a new entry into this ligand family and it was
synthesized as a white solid in a poor yield (15%). Cyclization to
give the 8-membered ligand is sensitive to the steric bulk of
the amine since a related ligand with R’=tBu was reported to
have a similarly low yield (cf. 26%).[8] X-ray quality crystals were
obtained for 1d and 1e (R’=p-CF3Ph and p-OMePh, respec-
13 varied (e.g. see ligand in C, Scheme 2).[4] In the case of [Ni(PR
2
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19
20
21
˚
tively). The P1-C1 bond lengths (1d=1.832(2) A; 1e=
Scheme 2. Cyclization of 2-ethynylbenzyl alcohol (EBA) with PR NR’2 catalyst
2
˚
22
23
1.829(1) A) are similar to that of R’=Ph ligand 1b (1.828–
C, and catalyst deactivation product D.[6a]
[9]
˚
1.833 A). This suggests that the substitution at R’ has minimal
24
25
long-range influence on the phosphine.
Reaction of ligands 1a–e with [CpRu(NCMe)3]PF6 in
acetonitrile at 70 8C for 4 h produced the known complex 2a[6a]
and new derivatives 2b–e in good to excellent yields (79–98%;
Scheme 4). All of the complexes were characterized by 1H,
26 NR’ ) ]2+ electrocatalysts, tuning the properties of the pendent
2 2
27 base significantly altered the rates of H2 oxidation/produc-
28 tion.[4b,5] We have previously demonstrated that these ligands
29 can be used to give MLC catalysts of the type [CpRu(PR
2
30 NR’ )(MeCN)]PF6, where derivative C exhibits similar performance
2
31 to B in the cyclization of 2-ethynylbenzyl alcohol (Scheme 2).
32 Unfortunately, this catalyst easily deactivates at elevated
33 temperatures to give the vinyl ammonium species D.[6]
34 Deactivation occurs by nucleophilic attack of the ligand
35 pendent amine, rather than the oxygen nucleophile of the
36 substrate, on Ca of the vinylidine intermediate (i.e. II). We
37 hypothesize that a more nucleophilic substrate, such as an
38 amine, will preferentially undergo productive turnover, rather
39 than decomposition. Therefore, we have elected to employ 2-
40 ethynylaniline and related compounds as representative cycliza-
41 tion substrates to elucidate the optimal steric and electronic
42 parameters of the ligand basic site in MLC cyclization catalysts.
Scheme 4. Synthesis of Ru(PPh2NR’2) complexes 2a–e by metalation of PPh2NR’
2
ligands (1a–e). Complex 2a was previously reported.[6a]
13C{1H}, 31P{1H} NMR and IR spectroscopies and MALDI mass
spectrometry. The 31P{1H} NMR signals are all found at ca.
40 ppm for 2a–e, suggesting the phosphine environment is
not significantly influenced by the different R’ substituents of
the pendent amine.
43 Thus, we have prepared a group of [CpRu(PPh2NR’ )(MeCN)]PF6
2
44 complexes that differ in the substituent on the pendent amine
45 (R’) to systematically compare ligand structure to catalyst
46 performance.
47
Single crystals of 2b were obtained and X-ray crystallog-
raphy confirmed the expected structure (Figure 2). The RuÀP
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49 Results and Discussion
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51 Catalyst Synthesis
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53 A group of five PR NR’ ligands were synthesized that have the
2
2
54 same phosphine substituent (R=Ph), but differ in the amine
55 substituent R’ (Scheme 3). The amine substituents were
56 selected to evaluate both steric (R’: 1a=Bn, 1b=Ph, 1c=Mes)
57 and electronic (R’: 1d=p-CF3Ph, 1b=Ph, 1e=p-MeOPh)
Scheme 5. Synthesis of dynamic Ru(PPh2NPh1) complex 4. Conditions: (i) [CpRu
(MeCN)3]PF6, MeCN, RT, 4 h. Yield 4=92%. [please have Scheme 5 appear
after Figure 2 in text]
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Table 1. Catalysis of 2-Ethynylaniline (EA) using 2a.
3
4
5
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Entry
Catalyst
[mol%]
Solvent
Temp
[8C]
Time
[h]
Yield Ind[a]
[%]
8
9
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
1
0.1
1
Acetone
Dioxane
THF
EtOAc
Anisole
DMF
DMA
THF
THF
THF
THF
THF
THF
40
40
40
40
40
40
40
40
40
55
55
55
55
70
1
1
1
1
1
1
1
16
24
24
6
6
24
2
13
8
12
13
10
8
15
30
10
11
12
13
14
15
Figure 2. Displacement ellipsoid plot of 2b. Ellipsoids are at the 50%
probability level. Hydrogen atoms and PF6À were omitted for clarity.
9
73
10
11
12
13
14[b]
>99
>99
91
37
>99
˚
16 bond lengths are 2.251(2) and 2.260(2) A (RuÀP1 and RuÀP2,
17 respectively), which are very similar to the analogous values
18 found for 2a[6a] (2.2589(6) and 2.2605(6) A). The distances
Me-THF
˚
[a] All yields are in situ values, determined by 1H NMR spectroscopy by
quantification of EA and Ind relative to the internal standard, dimethyl
terephthalate. Reactions were conducted in proteo solvents, which were
removed under vacuum and the residues redissolved in CDCl3 for NMR
analysis. [b] Yield of Ind was determined by calibrated GC-FID and the yield
was determined relative to the internal standard, tetralin.
19 between ruthenium and the Cp carbon atoms are likewise
20 similar to 2a. This shows that changing the R’ substituent from
21 Bn to Ph (2a and 2b, respectively) has very little impact on the
22 solid-state bonding parameters of the primary-coordination
23 sphere.
24
While the PR NR’ ligands contain two pendent basic sites,
2 2
25 only the amine proximal to the acetonitrile ligand (i.e. the
26 metal active site) in 2a–e should participate productively in
27 cyclization catalysis. To evaluate the necessity of the second
conducted at 40 8C in a range of solvents (Table 1, Entry 1–7).
Minor amounts of side products were observed in carbonyl-
containing solvents, thus THF was selected as the optimal
solvent for ongoing studies. Extending the reaction time from 1
to 24 h increased the yield of indole (Ind) from 12 to 73%
(Entry 9). The temperature was increased to 558C and complete
conversion was observed at 6 h (Table 1, Entry 11). Lowering
the catalyst loading to 1 mol% gave 91% Ind after 6 h and
>99% conversion was reached after 24 h. Further reduction in
catalyst loading to 0.1 mol% gave a cyclization yield of 37%,
which corresponds to a turnover number of 370 (Entry 13).
Increasing the temperature further to 708C resulted in
quantitative conversion to Ind with 1 mol% 2a within 2 h
(Table 1, Entry 14).
28 pendent base, the known[10] bisphosphine ligand PPh2NPh (3),
1
29 with one backbone amine, was prepared. Metalation of 3 with
30 [CpRu(NCMe)3]PF6 gave 4 in high yield (Scheme 5). Instead of
31 the typical yellow/orange solid observed for 2a–e, complex 4 is
32 a vibrant red solid on solvent removal. This distinct color is also
33 observed following halide abstraction from CpRuCl(PR NR’ ) and
2
2
34 Cp*RuCl(PR NR’ ) complexes in non-coordinating solvent.[6b,11]
2
2
35 The color in these reactions was presumed to be a conse-
36 quence of ligand coordination in
k3-PPN mode. The
a
37 appearance of the 31P{1H} NMR spectrum of isolated 4 in non-
38 coordinating CD2Cl2 is highly dependent on the presence of
39 excess acetonitrile. Rigorous removal of CH3CN gives a spec-
40 trum with broad signals between 48.9–56.0 ppm and a minor
41 (ca. 15%) sharp singlet at 34.3 ppm. Cooling exhibited some
42 sharpening of the broad signals, but the sample precipitated
43 before the signals could be fully resolved. When 4 is dissolved
44 in CD3CN, only the sharp singlet at 34.6 ppm is observed, which
45 is similar to the analogous signals in 2a–e. Additionally,
46 dissolution in CD3CN causes a color change from red to orange
47 and all of the 1H NMR signals are sharper than in CD2Cl2
48 (Figure S20 vs. S17). Therefore, this indicates that acetonitrile
The high yield of Ind at elevated temperatures suggests
that catalyst 2a preferentially undergoes productive catalysis
rather than deactivation, such as to a vinyl ammonium complex
(i.e. an analog of D). To confirm this, cyclization of EA was
monitored by 31P{1H} NMR spectroscopy under catalytic con-
ditions (1.5 mol% of 2a in THF at 508C). Throughout the
experiment (up to 2 h), no new signal appeared in the
downfield region (55–75 ppm) where D and related vinyl
ammonium species were previously[6] observed (Figure S26). At
2 h, the reaction composition is comprised of pre-catalyst 2a
(85%) and a new minor species (ca. 10%) observed as a singlet
at 30.6 ppm. This signal is in a similar location to a known
benzylamine adduct formed with 2a that has dP =29.2.[12] With
the goal in mind of identifying the structure of this minor
resting state species, the chloro complex CpRuCl(PPh2NBn2), 5,
49 coordinates to 4 and the PPh2NPh ligand changes its coordina-
1
50 tion mode to k2-PP.
51
52
53 Catalytic Studies
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55 The benchmark substrate 2-ethynylaniline (EA) was employed
56 to optimize catalytic cyclization conditions with 2a (Table 1).
57 Very little difference in conversion was observed for cyclization
1
was synthesized and characterized by H, 31P{1H}, 13C{1H} NMR
and IR spectroscopies, MALDI mass spectrometry and X-ray
crystallography. Complex 5 was reacted with KPF6 in THF in the
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presence of aniline (Scheme 6). Only one new product signal
was observed by 31P{1H} spectroscopy and it is a singlet at
play here and is the reason for the superior performance of PPh
2
NR’2 catalysts 2a–e over PPh2NPh1 catalyst 4.
A comparison of PPh2NR’ catalysts 2a–e with a 0.5 mol%
2
4
5
6
7
8
9
10
11
12
13
14
catalyst loading (Figure 3, orange bars) reveals that the order of
activity in EA cyclization follows 2aꢀ2bꢀ2e>2c>2d (R’=
BnꢀPhꢀp-OMePh>Mes>p-CF3Ph). The yield of Ind is ca.
15% lower with 2c relative to 2b (R’=Mes and Ph, respec-
tively). Thus, the reaction is tolerant of the increase in steric
bulk at the pendent amine despite the likely steric hindrance
during proton-transfer steps. Also notable from the perform-
ance trend is the poor conversion with 2d, which has the least
basic pendent amine. A comparison of ammonium pKa values
gives a rough guide to relative acidities of the substrates,
possible intermediates and the protonated pendent amine of
the ligand. None of ligands in 2a–e have a pendent amine that
is sufficiently basic to deprotonate aniline. Therefore, it is most
likely that the ligand deprotonates the substrate after, or in
concert with, nucleophilic attack on the vinylidene intermediate
II (see Figure 1). The pendent amine of 2d is less basic than the
substrate EA (pKa: [p-CF3C6H4NH3]+ =8.16, [PhNH3]+ =10.6).[14]
In contrast, catalysts 2a,b,e are all of similar or higher basicity
(pKa: [p-OMeC6H4NH3]+ =12.05, [BnNH3]+ =16.76, [PhNH3]+ =
10.6)[14] and these three catalysts have equivalent activity. We
hypothesize that, to achieve high activity, the basicity of the
ligand need only be above a threshold defined by the basicity
of the substrate.
Scheme 6. Stoichiometric reaction of 5 with aniline.
15 30.4 ppm. The close similarity of this shift to that of the minor
16 species observed under catalytic conditions with 2a, suggests
17 that the latter is a Ru-NH2Ar adduct. Evidence of a deactivated
18 vinyl ammonium compound (analogous to D), or other
19 deactivation species, are not observed. Rather, the catalyst
20 predominantly exists as pre-catalyst and an amine-adduct,
21 which are both off-cycle resting states.
22
With optimal conditions identified, a screen of catalysts 2a–
23 e and 4 was undertaken. Cyclization of EA was conducted in
24 THF, at 55 8C with 0.1, 0.5, 1, and 3 mol% catalyst loadings
25 (Figure 3). Conversion to Ind was quantified by GC-FID analysis
26
27
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29
30
31
32
33
34
35
36
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38
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A similar catalyst performance study for 2a–e and 4 was
conducted with EBA as the substrate (Figure 4). All of the
catalysts 2a–e showed lower performance than in cyclization of
EA; the highest yield of isochromene (IC) was 32%, which was
achieved with 3 mol% 2a. The trend in activity of the PPh2NR’
2
catalysts followed a very similar trend to that found with EA
where 2aꢀ2bꢀ2e>2d>2c (R’=BnꢀPhꢀp-OMePh>p-
CF3Ph>Mes). In all cases the pendent amine is more basic than
the substrate alcohol functionality,[15] indicating that all catalysts
should be equally competent at deprotonation of an intermedi-
ate formed after nucleophilic attack of the alcohol on the
vinylidene. We hypothesize that the low yields of IC are due to
competing formation of deactivation compounds, including
those similar to D, as was confirmed previously in the
Figure 3. Cyclization yields of 2-ethynylaniline (EA) to indole (Ind) in THF at
558C after 24 h with catalysts 2a–e and 4 at 3 mol% (blue), 1 mol% (red),
41
42
43
44
0.5 mol% (orange) and 0.1 mol% (purple).
45 of reaction solutions after a 24 h reaction time. All of the
46 complexes were active cyclization catalysts, except the PPh2NPh
1
47 complex 4. Even at 3 mol% 4 shows no conversion, while its
48 closest PR NR’ comparator 2b gives 31% Ind at only 0.1 mol%
2
2
49 loading. This corresponds to a higher activity of 2b over 4 by at
50 least an order of magnitude. Thus, the second metallacycle ring
51 and pendent amine is critical for high catalyst activity. In the
52 case of [Ni(PR NR’ ) ]2+ electrocatalysts, steric repulsions be-
2
2 2
53 tween the two metallacycle rings enforced the close position-
54 ing of one pendent base to the metal center.[4b,c] This position-
55 ing was deemed essential to achieve high catalytic rates.[13]
56 similar importance of pendent amine positioning is likely at
A
Figure 4. Cyclization yields of 2-ethynylbenzyl alcohol (EBA) to isochromene
(IC) in THF at 558C after 24 h with catalysts 2a–e and 4 at 3 mol% (blue),
1 mol% (red), 0.5 mol% (orange) and 0.1 mol% (purple).
57
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cyclization of EBA with catalyst C. To confirm that deactivation,
rather than low catalyst initiation, limits activity, cyclization of
EBA was conducted with 1 mol% 2a–e at 708C. Complexes
2a–c,e gave <5% IC with no increase in product after 1 h,
which is lower than the yields observed at 558C. Catalyst 2d
was slightly improved at the higher temperature, but the yield
of IC only reached 15%. We had previously hypothesized that a
sterically hindered or a poorly nucleophilic pendent amine
would be less susceptible to vinyl ammonium deactivation.
10 However, catalysts 2c and 2d (R’=Mes and p-CF3Ph, respec-
11 tively), which were designed with these characteristics in mind,
12 showed the lowest activity of 2a–e. Therefore, preventing
13 deactivation through steric or electronic tuning of the ligand
14 was insufficient to effectively cyclize EBA.
15
The conversion of EA to Ind was monitored over time with
16 2 mol% 2a,b,d at 558C (Figure 5). In the above studies it was
17
18
19
20
21
22
23
24
25
26
Figure 5. Cyclization of 2-ethynylaniline (EA) under optimal conditions
27
28
29
30
(2 mol% [Ru], Me-THF, 558C) monitored over time. [Ru]=2a (R’=Bn, green),
2b (R’=Ph, blue), 2d (R’=p-CF3Ph, red).
31 observed that catalysts 2a and 2b (R’=Bn and Ph) have similar
32 24 h conversion. Here it is clear that their rates are very similar
33 and that they both reach complete conversion to Ind within
34 6 h. The activity is superior to the previously reported catalysts
35 A (Scheme 1) that requires higher catalyst loading (10 mol% A)
36 and the conditions are milder than those used with catalysts A
37 and B that operate at higher temperatures (A: 908C; B:
38 708C).[2e,f] Notably, heating 1 mol% 2a to 708C gives complete
39 conversion to Ind within 2 h (Table 1, Entry 14), which is more
40 rapid than the MLC catalyst B (2 mol%). At short reaction times
41 (<2 h) catalyst 2d (R’=p-CF3Ph) also has similar performance,
42 but shows lower conversion than 2a and 2b at longer times.
Figure 6. Cyclization conversion over time with 2 mol% [Ru] in Me-THF of: a)
2-ethynyl-4-methoxyaniline (EA-OMe) at 558C with 2b (R’=Ph, blue) and 2e
(R’=p-MeOPh, orange); b) 2-ethynyl-4-fluoroaniline (EA-F) at 558C with 2b
(R’=Ph, blue) and 2d (R’=p-CF3Ph, red); and c) 2-ethynylbenzylamide (EAM)
at 708C with 2a (R’=Bn, green) and 2b (R’=Ph, blue). In all cases
conversion was quantified by 1H NMR spectroscopy.
respectively) within 48 h at 558C. The EA-F conversion curves
for 2b and 2d are nearly indistinguishable, which is in contrast
to cyclization of EA with these two catalysts where 2b was
superior to 2d (Figure 5). This supports the hypothesis that a
threshold basicity of the pendent amine is important for
catalyst performance. Cyclization of amide substrate EAM was
attempted with 2a and 2b (R’=Bn and Ph, respectively) at
558C, but <15% 1(2H)-isoquinolinone (IQO) was observed after
48 h. At 708C, 2a gave complete conversion to IQO by 48 h,
but conversion with 2b reached only 15%. The poor perform-
ance of 2b is surprising since the pendent amine in this catalyst
is significantly more basic than EAM (pKa: [PhNH3]+ =10.6,
[PhCONH3]+ =3.7).[14,16] The nucleophilicity of the amide func-
tionality in EAM is expected to be lower than that of the aniline
substrates. Thus, the lower performance of 2b may be a
consequence of competitive deactivation through a vinyl
43
We proposed above that, for amine substrates, the pendent
44 amine of the PPh2NR’2 catalysts must only be more basic than the
45 substrate to give productive turnover. To probe this hypothesis,
46 the cyclization of three additional substrates – 2-ethynyl-4-
47 methoxyaniline (EA-OMe), 2-ethynyl-4-fluoroaniline (EA-F) and
48 2-ethynylbenzamide (EAM) – was conducted (Figure 6). In all
49 cases, 2 mol% [Ru] was employed and reactions were con-
50 ducted in Me-THF at 55 or 708C. Substrate EA-OMe was
51 effectively cyclized by both catalysts 2b and 2e (R’=Ph and p-
52 OMePh, respectively) within 48 h at 558C. Catalyst 2b is
53 estimated to be similar or slightly less basic than the substrate
54 (pKa, [PhNH3]+ =10.6, [PhNMe2H]+ =12.30: [p-OMeC6H4NH3]+ =
55 12.05),[14] which could account for the slightly slower rate of 2b
56 relative to 2e. The less basic aniline substrate EA-F is cyclized
57 to ca. 85% with both 2b and 2d (R’=Ph and p-CF3Ph,
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OMe), 2-ethynyl-4-fluoroaniline (EA-F), and 2-ethynylamide (EAM)
were synthesized following literature procedures.[2d,18] Dry and
degassed tetrahydrofuran (THF), diethyl ether, toluene, dichloro-
methane (DCM), hexanes, dimethylformamide (DMF), dioxane and
acetonitrile (MeCN) were obtained from an Innovative Technology
400-5 Solvent Purification System and stored under N2. These dry
1
2
3
4
5
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9
ammonium species of type D. Alternatively, the mechanistic
pathway, and/or rate determining step, may be different for this
substrate. Further mechanistic analysis is required to fully
understand the limitations of 2b as compared to 2a when
extending the scope beyond aniline-type substrates.
˚
and degassed solvents, except for MeCN, were stored over 4 A
molecular sieves (Fluka and activated at 1508C under vacuum for
over 12 h). Acetone was dried with Cs2CO3 and degassed by
bubbling with N2. Tetrahydrofuran was distilled from CaH2 and
degassed by bubbling N2. Absolute ethanol was deoxygenated by
bubbling with N2. N,N-Dimethylacetamide and chlorofrom-d1 were
Conclusions
10 We have synthesized a group of [CpRu(PPh2NR’ )(NCMe)]PF6
2
11 complexes (2a–e) that differ in the steric and electronic
12 properties of the pendent amine. These complexes were tested
13 as catalysts in the cyclization of alkynyl amines and alcohol to
14 give N- and O-heterocycles, respectively. This class of catalyst
15 showed much higher activity toward aniline-type, as compared
16 to alcohol-type, substrates. Indeed, the optimal catalysts
17 (2a,b,e) generate indole under milder conditions and shorter
18 reaction times than previously reported catalysts. The superior
19 performance of the PPh2NR’ catalysts (2a-e) over the PPh2NPh
20 catalyst 4, suggests that a positioned pendent amine is
21 essential to achieve high performance. Catalyst comparison in
22 the cyclization of 2-ethynylaniline derivatives revealed that the
23 yield and rates are very similar for R’=Bn, Ph, p-OMePh
24 derivatives 2a, 2b and 2e, respectively. The less basic catalyst
25 2d (R’=p-CF3Ph) showed inferior performance, except with the
26 relatively low-basicity substrate 2-ethynyl-4-fluoroaniline where
27 it had comparable performance to 2b. This suggests that to
28 achieve high catalyst performance, the ligand pendent base
29 should be similar or more basic than the substrate amine of
30 aniline substrates. Proton shuttling during catalysis is somewhat
31 tolerant of steric bulk at the pendent amine since catalyst 2c
32 (R’=Mes) shows only a minor reduction in activity as compared
33 to 2b (R’=Ph) in the cyclization of 2-ethynyl aniline. Surpris-
34 ingly, only catalyst 2a was competent in the cyclization of 2-
35 ethynylamide, indicating that there are still important aspects
36 to the mechanism that are yet to be elucidated. We are
37 currently extending this investigation to study the mechanism
38 and the role of the primary-coordination sphere (i.e. the
39 phosphine substituents, R) on catalyst performance.
40
˚
dried with 4 A molecular sieves and degassed by bubbling with N2.
Benzylamine was dried with NaOH, distilled under vacuum and
stored under N2. All other chemicals were used as received.
Charge-transfer Matrix Assisted Laser Desorption/Ionization (MAL-
DI) mass spectrometry data were collected on an AB Sciex 5800
TOF/TOF mass spectrometer using pyrene as the matrix in a 20:1
molar ratio to metal complex. Samples were spotted on the target
plate as solutions in DCM. All NMR spectra were recorded on either
a Varian Inova 400 or 600 MHz, a Varian Mercury 400 MHz or Bruker
400 MHz NMR spectrometer. 1H and 13C{1H} spectra acquired in
CDCl3 were referenced internally against the residual solvent signal
(CHCl3) to TMS at 0 ppm. 31P spectra were referenced externally to
85% phosphoric acid at 0.00 ppm. Infrared spectra were collected
on solid samples using a PerkinElmer UATR TWO FTIR spectrometer.
Elemental analysis of 5 was performed by Canadian Microanalytical
Service Ltd. in Delta, BC. Satisfactory elemental analyses of 2b–e
and 4 were not obtained due to persistent minor, but variable,
amounts of MeCN in the samples. Quantification of catalytic
conversion of EBA or EA was achieved using an Agilent 7890a gas
chromatography with a flame ionization detector (GC-FID), fitted
with a HP-5 column. Calibration curves for EA, Ind, EBA, IC were
prepared to determine the response factors. The amount of each
species was quantified, relative to the internal standard (tetralin),
using area counts corrected with the response factors.
2
1
General Procedure for the Synthesis of PPh2NR’2 Ligands (1a–e): A
modified literature procedure[7a] was followed. These reactions
were manipulated under argon. Phenylphosphine (1.00 g,
9.08 mmol) was added to 100 mL Schlenk flask in a glovebox. On
the Schlenk line, a 2-neck 500 mL Schlenk flask containing: a stir
bar, freshly made (ꢁ1 week) p-formaldehyde (3 g, 0.1 mol), and
200 mL EtOH, was fit with a reflux condenser under argon.
Degassed EtOH (50 mL) was added via cannula to the 100 mL
Schlenk with the primary phosphine. The primary phosphine
solution was then added to the 500 mL Schlenk via cannula at
room temperature. Degassed EtOH (50 mL) was added via cannula
to the 100 mL Schlenk to rinse the flask and this was added to the
500 mL reaction flask. The reaction flask was heated to reflux for
4 h after which an aliquot was transferred to a degassed NMR tube
by syringe. The solution was analyzed by 31P{1H} NMR spectroscopy
(unlocked) to determine if any PhPH2 (d=ca. À120) remained.
Once the PhPH2 was consumed (ca. 4 h), the primary amine
(1.05 eq) was added to the solution (still heated to 708C) dropwise
by syringe at a rate of ca. 1 drop/10 seconds. Liquid amines (RNH2:
R=Bn, Ph, Mes, p-CF3Ph) were added neat and solid amines (RNH2:
R=p-OMePh) were added as solutions in EtOH (25 mM). White
precipitate was observed on addition of each drop, but did not
persist. The reaction was left to stir at 708C for 24 h and then
cooled to room temperature. Reactions giving ligands 1a–e
afforded a white precipitate, which was isolated by filtration
through a filter frit and washed with acetonitrile (3ꢁ5 mL).
Reactions to give ligands 1d–e did not give significant precipitate
on cooling to room temperature. In these cases, the ligand (1d–e)
was precipitated after addition of acetonitrile (15 mL) and cooling
41
42 Experimental Section
43
44
All air and water-sensitive reactions were manipulated under N2
using standard Schlenk or glovebox techniques unless otherwise
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stated. All glassware was oven dried prior to use. BnNH2 (>98%),
aniline (>99%), mesitylene amine (98%), and triphenylphosphine
oxide (99%) were obtained from Alfa Aesar. Phenylphosphine
(99%) was obtained from Strem. 4-Trifluoroaniline (99%), tetrahy-
dronaphthalene (99%), 2-ethynylaniline (98%), and 2-methyltetra-
hydrofuran (Me-THF) (>99% anhydrous) were obtained from
Sigma-Aldrich. 4-methoxyaniline (98%) was obtained from Oak-
wood Chemicals. Chloroform-d1 (99.8%), and dichloromethane-d2
(99.8%) were obtained from Cambridge Isotope Laboratories.
Paraformaldehyde was prepared by filtration of formaldehyde (37%
by weight solution in water with 10–15% methanol) to remove any
solids, removing methanol and water under vacuum until a white
gel is produced. [Ru(Cp)(MeCN)3]PF6,[17] PPh2NR’ (1a,b,d,e),[5,7] and
2
[Ru(Cp)(PPh2NBn2)(NCMe)]PF6 (2a)[6a] were synthesized following
literature procedures. Substrates 2-ethynyl-4-methoxyaniline (EA-
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to À358C. The ligands 1d–e were isolated through decanting the
mother liquor and washing the solid with cold acetonitrile (5-
10 mL).
washed with toluene (3 x 2 mL) and diethyl ether (5 mL). The
product was dried under vacuum to produce clean product.
Reprecipitation of 2a-e from acetonitrile gave minor by-products,
1
2
3
4
5
6
7
8
9
1
as judged by H NMR spectroscopy, that are assigned to k3-(PPN)
PPh2NBn (1a): Yield=83%. 1H and 31P{1H} NMR spectra matched
2
derivatives. To avoid mixtures, purification by reprecipitation was
avoided for 2a-e.
literature values.[7a]
PPh2NPh (1b): Yield=87%. 1H and 31P{1H} NMR spectra matched
[Ru(Cp)(PPh2NBn2)(NCMe)]PF6 (2a): 1H and 31P{1H} NMR spectra
matched literature values in CDCl3.[6a] Spectral data in CD2Cl2 is
provided here to ease comparisons between the various catalysts
2
literature values.[7b]
1
PPh2NMes (1c) Yield=15%. H NMR (600 MHz, CD2Cl2): d 7.34–7.27
2
1
2a-e. H NMR (600 MHz, CD2Cl2): d 7.69–7.60 (m Ph-H, 4H), 7.56–
(m, Ph-H, 3H), 7.27–7.15 (m, Ph-H, 7H), 6.88–6.84 (m, Ph-H, 1H),
6.84–6.82 (m, Ph-H, 2H), 6.78–6.73 (m, Ph-H, 1H), 4.54–4.46 (m,
PCH2N, 2H), 4.12–4.05 (m, PCH2N, 2H), 3.84–3.77 (m, PCH2N, 2H),
3.69–3.61 (m, PCH2N, 2H), 2.67 (s, CH3, 3H), 2.39 (s, CH3, 6H), 2.20 (m,
CH3, 9H). 31P{1H} NMR (243 MHz, CD2Cl2): d –22.4 (s, PPh2NMes2), –27.0
(s, PPh2NMes2). 13C{1H} NMR (151.5 MHz, CD2Cl2): d 150.4–150.3 (m, CAr-
N), 137.4 (CAr), 136.7 (CAr), 136.5 (CAr), 135.5 (CAr), 135.3 (CAr), 132.5-
7.48 (m, Ph-H, 6H), 7.41–7.16 (m, Ph-H, 10H), 4.78 (s, Cp-H, 5H), 3.89
(s, PhCH2N, 2H), 3.71 (s, PhCH2N, 2H), 3.29–3.17 (m, PCH2N, 4H),
3.04–2.96 (m, PCH2N, 2H), 2.77–2.70 (m, PCH2N, 2H), 2.22 (s, NCCH3,
10
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3H). 31P{1H} NMR (243 MHz, CD2Cl2): d 38.7 (s, RuP), À144.4 (sept, 1JP-
F =712 Hz, PF6À).
1
[Ru(Cp)(PPh2NPh2)(NCMe)]PF6 (2b): Yield=89%. H NMR (600 MHz,
2
2
CD2Cl2): d 7.93–7.87 (m, Ph-H, 4H), 7.69–7.61 (m, Ph-H, 6H), 7.29 (dd,
132.2 (CAr), 132.1 (d, JC-P =16.1 Hz, CAr), 131.6 (d, JC-P =16.1 Hz, CAr),
3
3
3
3JH-H =8.0 Hz, JH-H =8.0 Hz, Ph-H, 2H), 7.25 (dd, JH-H =8.0 Hz, JH-H
=
3
130.2 (CAr), 130.0 (CAr), 129.5 (CAr), 128.8–128.6 (CAr), 128.5 (d, JC-P
=
3
8.0 Hz, Ph-H, 2H), 7.02–6.95 (m, Ph-H, 3H), 6.88–6.83 (m, Ph-H, 3H),
4.79 (s, Cp-H, 5H), 4.25–4.13 (m, PCH2N, 4H), 4.00–3.91 (m, PCH2N,
2H), 3.63–3.57 (m, PCH2N, 2H), 2.28 (s, NCCH3, 3H). 31P{1H} NMR
6.1 Hz, CAr), 128.3 (d, JC-P =6.1 Hz, CAr), 62.3–62.0 (m, PCH2N), 58.2–
57.9 (m, PCH2N), 20.9–20.7 (CH3), 20.0 (CH3), 19.9 (CH3), 19.3 (CH3).
MALDI MS (pyrene matrix): Calc. m/z 538.3 [C34H39N2P2]+, Obs. m/z
638.3.
1
(243 MHz, CD2Cl2): d 39.7 (s, RuP), À144.4 (sept, JP-F =712 Hz, PF6À).
13C{1H} NMR (151.5 MHz, CD2Cl2): d 152.5 (t, 3JC-P =8 Hz, CAr -N), 151.2
1
PPh2NPhCF3 (1d): Yield=75%. H and 31P{1H} NMR spectra matched
3
(t, 3JC-P =6 Hz, 3JC-P =6 Hz, CAr -N), 133.6 (dd, 1JC-P =19.7 Hz, JC-P
=
2
literature values.[5] X-ray quality crystals formed from a chilled (À35
19.7 Hz, CAr -P), 132.3-132.0 (CAr), 130.3-129.8 (CAr), 128.8 (CN), 122.4
8C) solution of 1d in MeCN.
1
(CAr), 120.9 (CAr), 118.5 (CAr), 116.8 (CAr), 82.3 (CCp), 52.8 (dd, JC-P
=
17 Hz, 3JC-P =17 Hz, PCH2N), 51.1 (dd, 1JC-P =22 Hz, 3JC-P =22 Hz,
PCH2N), 4.7 (CH3). MALDI MS (pyrene matrix): Calc. m/z 621.1
[Ru(Cp)(PPh2NPh2)]+, Obs. m/z 621.1. X-ray quality crystals were
formed from a concentrated solution of 2b in DCM to which was
added toluene until the solution was slight cloudy and the solution
was chilled (À35 8C).
1
PPh2NPhOMe (1e): Yield=90%. H and 31P{1H} NMR spectra matched
2
literature values.[5] X-ray quality crystals formed from a chilled (À35
8C) solution of 1e in MeCN.
Synthesis of PPh2NPh Ligand (3): A modified procedure of the
1
literature reported method[19] was followed. The reaction was
manipulated under argon. Diphenylphosphine (1.05 g, 5.64 mmol)
was added to 100 mL Schlenk flask in a glovebox. On the Schlenk
line, a 2-neck 500 mL Schlenk flask containing: a stir bar, freshly
made (ꢁ1 week) p-formaldehyde (3.00 g, 0.100 mol, 18 equiv.), and
200 mL EtOH was fit with a reflux condenser under argon.
Degassed EtOH (50 mL) was added via cannula to the 100 mL
Schlenk with the primary phosphine. The primary phosphine
solution was then added to the 500 mL Schlenk via cannula at
room temperature. Degassed EtOH (50 mL) was added via cannula
to the 100 mL Schlenk to rinse the flask and this was added to the
500 mL reaction flask. The reaction flask was heated under reflux
for 4 h after which an aliquot was transferred to a degassed NMR
tube by syringe. The solution was analyzed by 31P{1H} NMR
spectroscopy (unlocked) to determine if any PhPH2 remained. Once
the PhPH2 was consumed (4 h), the primary amine (1.05 equiv) was
added neat dropwise by syringe at a rate of ca. 1 drop/10 seconds,
while the reaction remained at 708C. White precipitate was
observed on addition of each drop but did not persist. The reaction
was left to stir at 708C for 24 h and then cooled to room
temperature. The reaction afforded a white precipitate, which was
[Ru(Cp)(PPh2NMes2)(NCMe)]PF6 (2c): Yield= 79%. 1H NMR
(400 MHz, CD2Cl2): d 7.92–7.77 (m, CAr-H, 4H), 7.68–7.54 (m, CAr-H,
6H), 7.35–7.24 (m, CAr-H, 2H), 6.98–6.84 (m, CAr-H, 2H), 5.04 (s, Cp-
H, 5H), 4.74–4.64 (m, PCH2N, 2H), 3.80–3.63 (m, PCH2N, 4H), 3.40–
3.30 (m, PCH2N, 2H), 2.44 (s, CH3, 3H), . 31P{1H} NMR (243 MHz,
1
CD2Cl2): d 37.8 (s, RuP), À144.4 (sept, JP-F =712 Hz, PF6À). 13C{1H}
3
NMR (151.5 MHz, CD2Cl2): d 146.7 (t, JC-P =10.1 Hz, CAr-N), 145.1
3
(CAr-N), 137.0 (CAr), 135.7, (CAr), 133.6 (t, 1JC-P =34.2 Hz, JC-P
=
34.2 Hz, CAr), 132.0 (d, 3JC-P =9.8 Hz, CAr), 132.0 (d, 2JC-P = 9.8 Hz,
CAr-P), 131.8 (CAr), 130.9–130.2 (CAr), 129.6 (d, 3JC-P =8.2 Hz, CAr),
3
1
129.5 (d, JC-P = 8.2 Hz, CAr), 129.4 (CN), 83.1 (CCp), 52.6 (dd, JC-P
=
=
3
15.7 Hz, 3JC-P =15.7 Hz, PCH2N), 51.8 (dd, 1JC-P =22.2 Hz, JC-P
22.2 Hz, PCH2N), 22.5 (PhCH3), 21.3–19.8 (PhCH3), 5.4 (CH3). MALDI
MS (pyrene matrix): Calc. m/z 705.2 [Ru(Cp)(PPh2NMes2)]+, Obs. m/z
705.2.
[Ru(Cp)(PPh2NPhCF32)(NCMe)]PF6 (2d): Yield=98%. 1H NMR
(600 MHz, CD2Cl2): d 8.04–7.90 (m, CAr-H, 4H), 7.81–7.66 (m, CAr-H,
6H), 7.58 (d, 3JH-F =7.6 Hz, CAr-H, 2H), 7.50 (d, 3JH-F =7.5 Hz, CAr-H,
2H), 7.08 (d, 3JH-F =7.1 Hz, CAr-H, 2H), 6.86 (d, 3JH-F =6.9 Hz, CAr-H,
2H), 4.79 (s, Cp-H, 5H), 4.42–4.32 (m, PCH2N, 2H), 4.26–4.12 (m,
PCH2N, 4H), 3.80–3.69 (m, PCH2N, 2H), 2.33 (s, CH3, 3H). 31P{1H} NMR
isolated by filtration through
a filter frit and washed with
acetonitrile (3ꢁ5 mL). Yield=95%. 1H and 31P{1H} NMR spectra
(243 MHz, CD2Cl2): d 40.6 (s, RuP), À144.4 (sept, JP-F =712 Hz, PF6À).
matched literature values.
1
19F{1H} NMR (376.3 MHz, CD2Cl2): d À61.9 (s, CF3), À62.0 (s, CF3),
General Procedure for the Synthesis of Ru(PPh2NR’2) (2a-e) and
À72.3 (d, 1JF-P =712 Hz, PF6À). 13C{1H} NMR (151.5 MHz, CD2Cl2): d
Ru(PPh2NPh1) (4) Complexes: To a 100 mL Schlenk flask with a stir
1
bar, [CpRu(NCMe)3]PF6 (0.100-0.120 mmol), ligand PPh2NR’2 or PPh2NR’
154.4-154.2 (m, CAr-N), 152.8–152.6, (m, CAr-N), 132.9 (d, JC-P
=
1
19.2 Hz, 3JC-P =19.2 Hz, CAr-P), 132.7 (d, 1JC-P =19.2 Hz, CAr-P), 132.5
(CAr), 132.2 (d, 2JC-P =6.1 Hz, CAr), 132.1 (d, 2JC-P =6.1 Hz, CAr), 130.2 (d,
3JC-P =5.1 Hz, CAr), 130.1 (d, 3JC-P =5.1 Hz, CAr), 129.5 (CN), 127.6
(0.105-1.26 mmol, 1.05 equiv.) and acetonitrile (20 mL) was added.
The flask was heated to 658C for 4 hours with stirring. The solvent
was removed under vacuum and the remaining solid was triturated
with pentane (3 ꢁ 2 mL). Acetonitrile (2 mL) was added and the
resulting suspension was filtered. The solid was washed with
acetonitrile until the washings were colourless. The solvent of the
filtrate was removed under vacuum to produce a solid that was
3
3
(quartet, JC-F =4.7 Hz, C ), 127.4 (quartet, JC-F =4.0 Hz, C ), 123.1
˚
Ar
˚
Ar
(found through correlation, CCF3), 121.4 (found through correlation,
CCF3), 117.9 (m, CF3), 116.9 (CAr), 116.2 (m, CF3), 114.8 (CAr), 82.4 (CCp),
1
51.6 (dd, 1JC-P =16.2 Hz, 3JC-P =16.2 Hz, PCH2N), 49.9 (dd, JC-P
=
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Full Papers
21.7 Hz, 3JC-P =21.7 Hz, PCH2N), 4.7 (CH3). MALDI MS (pyrene matrix):
0.011 mmol, 6 mM) in THF (1.77 mL); 2e (10 mg, 0.012 mmol,
6 mM) in THF (1.92 mL). Five sets (A–E) of five 4 mL vials (25 vials
total) containing stir bars were charged with the EA/tetralin stock
solution (250 mL) and additional THF (125 mL). To each vial was
added catalyst stock solution (125 mL, set A=2a, B=2b, C=2c,
1
2
3
4
5
6
7
8
9
Calc. m/z 757.1 [Ru(Cp)(PPh2NPhCF32)]+, Obs. m/z 757.1.
[Ru(Cp)(PPh2NPhOMe2)(NCMe)]PF6 (2e): Yield=95%. 1H NMR
(600 MHz, CD2Cl2): d 7.92–7.82 (m, CAr-H, 4H), 7.65–7.58 (m, CAr-H,
6H), 7.04–6.99 (m, CAr-H, 2H), 6.96–6.91 (m, CAr-H, 2H), 6.87–6.82 (m,
CAr-H, 4H), 4.88 (s, Cp-H, 5H), 4.18–4.12 (m, PCH2N, 2H), 3.96–3.91
(m, PCH2N, 2H), 3.77–3.66 (m, PCH2N and OCH3, 8H), 3.53–3.46 (m,
PCH2N, 2H), 2.37 (s, NCCH3, 3H). 31P{1H} NMR (243 MHz, CD2Cl2): d
39.9 (s, RuP), À144.4 (sept, 1JP-F =712 Hz, PF6À). 13C{1H} NMR
D=2d, E=2e) giving
a final volume of 500 mL. The final
concentrations for all vials were 0.150 M in substrate and 1.5 mM in
catalyst. A final vial was charged with substrate/internal standard
stock solution (100 mL) for use as the time=0 sample, required for
accurate quantification of substrate and product. The vials were
capped and removed from the glove box and heated to 558C (sets
AÀE) with stirring. After 0.167, 0.5, 1, 6, and 24 hours one vial from
each of the sets was removed from heat, cooled, and exposed to
air to quench. A 20 mL aliquot was diluted to 3 mM (0.980 mL) in
acetonitrile and analyzed by GC-FID. A 10 mL aliquot of the T0
sample was diluted with acetonitrile (990 mL) and analyzed by GC-
FID.
(151.5 MHz, CD2Cl2): d 156.2 (COCH3), 155.2 (COCH3), 147.0–146.7
3
(m, CAr-N), 146.3–145.8, (m, CAr-N), 133.8 (t, 1JC-P =18.2 Hz, JC-P
=
10
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13
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16
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18
19
20
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18.2 Hz, CAr-P), 132.8–131.5 (CAr), 130.1–129.4 (CAr), 128.8 (CN), 121.6
(CAr), 120.3 (CAr), 115.8–114.4 (m, CAr), 82.1 (CCp), 55.9 (OCH3), 54.0
(found through correlation due to overlap with CD2Cl2, PCH2N),
52.7(dd, 1JC-P =21 Hz, 3JC-P =21 Hz, PCH2N), 4.8 (CH3). MALDI MS
(pyrene matrix): Calc. m/z 681.1 [Ru(Cp)(PPh2NPhOMe2)]+, Obs. m/z
681.2.
High Throughput Catalytic Procedure: A representative procedure
is given for EA. In a glovebox, the following stock solutions were
prepared: EA (435 mg, 3.72 mmol, 0.300 M) and tetralin (328 mg,
2.48 mmol, 0.200 M) in THF (12.390 mL). Stock solutions of catalysts
(9 mM and 1.5 mM) were prepared as above. Reaction components
were added to a cooled (08C) 8ꢁ12 reaction plate in the following
order: catalyst, solvent, then substrate. Stock solutions of catalysts
were robotically dispensed to their appropriate concentration
amounts: 0.15, 0.75, 1.50, and 3.00 mM (0.1, 0.5, 1, 3 mol%). Solvent
and substrate were added by Eppendorf pipette to the well plate
and to a T0 sample. Final conditions: 150 mM Substrate, 0.1/0.5/1/
3 mol% catalyst, 100 mL reaction volume in THF. The 96 well plate
was sealed with a Teflon sheet, a rubber sheet and an aluminium
cover, to minimize evaporation, and the plate was heated to 558C
for 24 h. After the plate had cooled, the solutions were daughtered
into a second plate and diluted to 2.5 mM (based on the starting
concentration of 2-ethynylaniline) in acetonitrile for GC-FID analysis.
A 10 mL aliquot of the T0 sample was diluted with acetonitrile
(990 mL) and analyzed by GC-FID.
1
[Ru(Cp)(PPh2NPh1)]PF6 (4): Yield=92%. H NMR (400 MHz, CD2Cl2): d
8.17–6.87 (br, CAr-H, 23H), 6.72–6.37 (br, CAr-H, 2H), 5.81–5.17 (br, CAr-
H, 2H), 4.97–4.37 (br, Cp-H and PCH2N, 7H), 4.03–3.57 (br, PCH2N,
2H). 31P{1H} NMR (243 MHz, CD2Cl2): d 48.9-56.0 (br, RuP, 85% rel.
1
integration), 34.6 (s, RuP, 15% rel. integration), À144.5 (sept, JP-F
=
712 Hz, PF6À). 1H NMR (400 MHz, CD3CN): d 7.80–7.26 (br, CAr-H,
19H), 7.22–7.10 (br, CAr-H, 2H), 7.00–6.85 (br, CAr-H, 1H), 6.69–6.46
(br, CAr-H, 3H), 4.78–4.68 (m, Cp-H, 5H), 4.68–4.51 (m, PCH2N, 2H),
3.96–3.78 (m, PCH2N, 2H), 2.34 (br, CH3). 31P{1H} NMR (243 MHz,
CD3CN): 34.6 (s, RuP), À144.6 (sept, 1JP-F =706 Hz, PF6À). 13C{1H} NMR
(151.5 MHz, CD3CN): d 152.7 (through 1H-13C HMBC, CAr-N), 137.8
1
(through H-13C HMBC, CAr-P), 133.9–133.5 (m, CAr), 131.6 (CAr), 131.4
2
2
(CAr ), 130.3 (CAr), 129.3 (d, JC-P =5.1 Hz, CAr), 129.2 (d, JC-P =5.1 Hz,
1
3
CAr), 123.2 (CAr), 120.2 (CAr), 83.7 (CCp), 56.3 (dd, JC-P =21.2 Hz, JC-P
=
21.2 Hz, PCH2N),. MALDI MS (pyrene matrix): Calc. m/z 656.1
[Ru(Cp)(PPh2NPh1)]+, Obs. m/z 656.1.
Ru(Cl)(Cp)(PPh2NBn2) (5): RuCl(Cp)(PPh3)2 (300 mg, 0.412 mmol)
and PPh2NBn (200 mg, 0.415 mmol) were combined under N2 in a
2
100 mL Schlenk flask. Toluene (50 mL) was added via cannula.
The reaction was heated to reflux and stirred for 42 h. The
reaction was cooled, and the toluene was removed under
vacuum. The resulting solid was triturated with hexanes (3ꢁ
30 mL). Hexanes were added (30 mL) and the suspension was
Stoichiometric Reactions with Complex 5 and Aniline: In a
glovebox Ru(Cp)(Cl)(PPh2NBn2) (7 mg, 0.01 mmol) was dissolved with
OPPh3 (3 mg, 0.01 mmol) in THF. An initial time=0 (T0) spectrum
was acquired by externally referenced 31P{1H} NMR spectroscopy.
KPF6 (10 mg, 0.05, 5 eq) and aniline (20 mg, 0.21 mmol, 20 eq) were
added to the NMR tube, which was then heated at 558C in an oil
bath. After times of 3 and 24 h, the tube was removed from the
bath, cooled and 31P{1H} NMR spectra were acquired.
1
filtered under air to give an orange solid. Yield: 299 mg (87%). H
NMR (400 MHz, CD2Cl2): d 7.82–7.76 (m, Ph-H, 4H), 7.45–7.38 (m,
Ph-H, 6H), 7.36–7.22 (m, Ph-H, 10H), 4.53 (s, Cp-H, 5H), 3.87 (s,
PhCH2N, 2H), 3.59 (s, PhCH2N), 3.53-3.49 (m, PCH2N, 2H), 3.19-3.11
(m, PCH2N, 4H), 2.63-2.56 (m, PCH2N, 2H). 31P{1H} (162 MHz,
CD2Cl2): d 39.3 (s, RuP). 13C{1H} NMR (101 MHz, CD2Cl2): 138.0 (s,
1
1
CAr), 137.9 (s, CAr), 136.9 (d, JC-P =12.1 ppm, CAr), 136.8 (d, JC-P
=
=
Acknowledgements
12.1 ppm, CAr), 131.5 (d, 3JC-P =4.0 ppm, CAr), 131.5 (d, JC-P
3
4.0 ppm, CAr), 129.9 (s, CAr), 128.4–128.2 (CAr), 127.5 (s, CAr), 127.3
3
3
´
Roxanne Clement of the Centre for Catalysis Research and
(s, CAr), 79.5 (s, Cp), 66.1 (t, JC-P = 8.1 Hz, NCH2Ph), 65.5 (t, JC-P
=
9.1 Hz, NCH2Ph), 52.1 (t, 1JC-P = 16.2 Hz, PCH2N), 50.7 (t, 1JC-P =14.1,
PCH2N). Anal. Calc. for C41H48F6N3P3Ru 0.1(CH2Cl2): C, 60.86; H,
Innovation (CCRI) at the University of Ottawa is thanked for her
assistance with high-throughput experiments. This work was
financially supported by a Natural Sciences and Engineering
Research Council (NSERC) of Canada Discovery Grant and The
University of Western Ontario. JMS thanks the Ontario Graduate
Scholarship program for funding.
*
5.41; N, 4.04. Found: C, 60.78; H, 5.80; N, 3.85. MALDI MS (pyrene
matrix): Calc. m/z 684.1 [RuCp(PPh2NBn2)Cl]+, 649.1 [RuCp(PPh
2
NBn2)]+, Obs. m/z 684.1, 649.1. Anal. Calc. for C41H48F6N3P3Ru: C,
61.45; H, 5.45; N, 4.09. Found: C, 60.78; H, 5.80; C, 3.85. Orange X-
ray quality crystals formed following vapor diffusion of hexanes
into a concentrated solution of 5 in DCM.
General Procedure for the Catalytic Cyclization of Substrates: In
a glovebox, the following stock solutions were prepared: EA
(246 mg, 2.10 mmol, 0.300 M) and tetralin (185 mg, 1.4 mmol,
0.2 M) in THF (14.00 mL); 2a (10 mg, 0.012 mmol, 6 mM) in THF
(2.00 mL); 2b (10 mg, 0.012 mmol, 6 mM) in THF (2.07 mL); 2c
(10 mg, 0.011 mmol, 6 mM) in THF (1.87 mL); 2d (10 mg,
Conflict of Interest
The authors declare no conflict of interest.
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ÞÞ
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Keywords: cooperative effects · cyclization · homogeneous
catalysis · phosphane ligands · ruthenium
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Manuscript received: April 30, 2018
Accepted Article published: June 15, 2018
Version of record online: &&&, &&&&
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FULL PAPERS
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J. M. Stubbs, D. E. Chapple, Dr. P. D.
Boyle, Prof. J. M. Blacquiere*
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Catalyst Pendent-Base Effects on
Cyclization of Alkynyl Amines
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Working together: A family of coop-
erative catalysts were prepared that
differ systematically in the structural
properties of the pendent base on the
ligand framework. Optimal steric and
electronic properties of the base were
elucidated for the catalytic cyclization
of alkynyl aniline substrates.