Phosphino-amine (PN) Ligands for Rapid Catalyst Discovery in Ruthenium-Catalyzed Hydrogen-Borrowing Alkylation of Anilines: A Proof of Principle

Article abstract of DOI:10.1002/adsc.201500562

A general synthetic protocol for the synthesis of simple phosphino-amine (PN) ligands is described with 19 ligands being isolated in good yields. High-throughput ligand screening uncovered the success of two of these ligands for aromatic amine alkylations via ruthenium-catalyzed hydrogen borrowing reactions. The combination of N,N'-bis(diphenylphosphino)-N,N′-dimethylpropylenediamine with a ruthenium(II) source and potassium hydroxide (15 mol%) is the optimal system for selective monobenzylations of aromatic amines (method A). Over 70% isolated yields have been achieved for the formation of 14 secondary aromatic amines under mild reaction conditions (120 C and 1.05 equivalents of benzyl alcohol). On the other hand, N,N-bis(diphenylphosphino)-isopropylamine was the ligand utilized for both selective monomethylation and monoethylation reactions of aromatic amines (method B). Here the alcohol is charged as both the reaction medium and substrate and 9 examples are disclosed with all isolated yields exceeding 70%. These methods have been applied to the synthesis of important synthetic building blocks based on aminoferrocene.

Full text of DOI:10.1002/adsc.201500562

FULL PAPERS
DOI: 10.1002/adsc.201500562
Phosphino-amine (PN) Ligands for Rapid Catalyst Discovery in
Ruthenium-Catalyzed Hydrogen-Borrowing Alkylation of
Anilines: A Proof of Principle
Lewis Marc Broomfield,a Yichen Wu,a Eddy Martin,a and Alexandr Shafira,*
a
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Spain
Fax: (+34)-977-920-222; e-mail: ashafir@iciq.es
Received: June 11, 2015; Revised: September 26, 2015; Published online: November 17, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500562.
Abstract: A general synthetic protocol for the syn- benzyl alcohol). On the other hand, N,N-bis(diphe-
thesis of simple phosphino-amine (PN) ligands is de- nylphosphino)-isopropylamine was the ligand uti-
scribed with 19 ligands being isolated in good yields. lized for both selective monomethylation and mono-
High-throughput ligand screening uncovered the suc- ethylation reactions of aromatic amines (method B).
cess of two of these ligands for aromatic amine alky- Here the alcohol is charged as both the reaction
lations via ruthenium-catalyzed hydrogen borrowing medium and substrate and 9 examples are disclosed
reactions. The combination of N,N’-bis(diphenyl- with all isolated yields exceeding 70%. These meth-
phosphino)-N,N’-dimethylpropylenediamine
with ods have been applied to the synthesis of important
a ruthenium(II) source and potassium hydroxide synthetic building blocks based on aminoferrocene.
(15 mol%) is the optimal system for selective mono-
benzylations of aromatic amines (method A). Over
70% isolated yields have been achieved for the for- Keywords: alkylation; high throughput screening;
mation of 14 secondary aromatic amines under mild hydrogen borrowing; PN ligands; ruthenium cataly-
reaction conditions (1208C and 1.05 equivalents of sis
Introduction
of the reagents applied (Scheme 1, a). Indeed this
aspect causes a bottle neck when requiring speedy
A variety of catalytic processes utilize phosphine li- structural modifications for rapid reaction discovery
gands to moderate the reactivity of catalytic metal and optimization. In this context, phosphino-amines,
centers.[1] Despite doing this job very effectively, the referred to here as PN ligands, offer a valuable scaf-
synthesis of these ligands, however, can be work con- fold for generating structural ligand diversity for pro-
suming and often delicate, due to the sensitive nature cess optimization. Contrary to their triorganophos-
phine counterparts, these PN derivatives are obtaina-
ble in a relatively simple single-step procedure by
condensing an amine with
a
chlorophosphine
(Scheme 1, b).[2] This synthetic method is versatile
and the abundance of commercial amines allows
ample ligand sets to be swiftly generated for rapid
parallel screening.[3,4]
Indeed, ligands based on the PN scaffold have been
widely used in catalytic processes, including nitrile hy-
drations,[5] transfer hydrogenations of acetophenone
derivatives[6] and cross-coupling reactions with gold.[7]
Many enantioselective catalytic processes also benefit
from the modular chiral P-N systems pioneered by
Alexakis and Feringa.[8] In bulk processes, the use of
PNP ligands is the basis for the industrial chromium-
Scheme 1. A comparison of synthetic approaches towards bi-
sphosphines with bis-phosphino-amines.[2]
3538
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3538 – 3548

FULL PAPERS
Phosphino-amine (PN) Ligands for Rapid Catalyst Discovery
based production of 1-hexene and, more recently, 1-
octene from ethene.[2a–h]
Wide-scope screening of PN ligand sets by taking
advantage of their simplistic synthesis however is
scarce. Yet, this feature has been effectively exploited
by Wasserscheid at al.[2d] in ethylene oligomerization.
This study found that the selectivity (in particular 1-
octene vs. 1-hexene) could be tuned by altering the
steric bulk on the central nitrogen atom of a PNP
ligand. Thus, we wondered to what extent the facile
generation of phosphino-amines can be used to devel-
op and optimize other catalytic processes. In light of
the structural (albeit not electronic) similarity be-
tween linear disphosphines and bis-phosphino-amines
Figure 1. Selected examples of commercial bisphosphines
used as ligands in Ru(II)-catalyzed H2-borrowing reactions.
built with linear aliphatic diamines, we chose Ru(II)- systems were found to effectively catalyze a number
catalyzed H2-borrowing reactions, more specifically of amine alkylation reactions under relatively mild re-
the alkylations of amines by alcohols, as a possible action conditions.[14] Additionally, important pharma-
candidate for the rapid process optimization. This ceuticals have been isolated in good yields using this
choice of process was strongly influenced by the fact combination (Piribedil, 87%, Tripelennamine, 75%
that bisphosphines are commonly utilized to modulate and Chlorpheniramine, 81% are just 3 examples).[14b,c]
metal centers in these processes (vide infra). In addi- Along the same lines, Deutsch et al.[15] recently ap-
tion, such catalytic protocols are in many ways pref- plied Ru(II) complexes of DPEphos for alkylation
erable to the more classical nucleophilic substitution protocols of ammonia by alcohols. Yields of above
approaches, which typically use alkyl halides as alky- 90% to the desired primary amines were achievable
lating agents.[9] Two clear advantages of using H2-bor- in some cases. Importantly, in addition to DPEphos,
rowing catalysts to perform amine alkylation reac- several commercial bisphosphines, bridged by linear
tions are superior reaction control and the fact that alkyl chains (Figure 1), were also operative ligands
the toxicity of alcohols, employed as alkylating for this reaction. Of these, particularly effective was
agents, tends to be lower than that of the correspond- DPPB, which gave cyclohexanamine in 94% yield.
ing alkyl halide.[10–12] Therefore, amine alkylation re- Worth mentioning is that increasing this carbon back-
actions by alcohols complement perfectly the reduc- bone by one methylene unit to a pentylene bridge in-
tive amination of aldehydes, with both methods af- flicts a drastic drop in product yield to just 26%. This
fording the same product. A basic sequence of this re- difference highlights the importance of testing many
action is outlined in Scheme 2 and operates by metal- ligands with slight structural modifications in catalysis.
catalyzed dehydrogenation of an alcohol A to form Finally, Wass et al.[16] used a catalytic system compris-
an aldehyde B. Once the imine C is formed through ing of [RuCl2(p-cymene)]2/DPPM/NaOEt in the selec-
the condensation with an amine, the borrowed hydro- tive ethanol upgrade (Guebert process). An impres-
gen is then returned at the C=N bond to yield the sive 23% yield with 89% selectivity for n-butanol was
target secondary amine D.[13] Significantly, water is achieved by the in-situ system. It was suggested that
the only reaction by-product in this process.
the small bite angle (bn) of DPPM aided the superla-
Regarding effective catalytic systems for such trans- tive selectivity achieved by this homogeneous Ru(II)
formations, Williams has developed some by regulat- catalyst.
ing the activity of [RuCl2(p-cymene)]2 with bisphos-
Considering these factors we decided to acquire
phine ligands (DPPF and DPEphos are two promi- a robust synthetic procedure for PN ligands in order
nent ligands used, Figure 1). The resulting catalytic to rapidly generate an initial ligand library. With this
ligand library in hand, we have tested its aptitude in
modulating Ru(II)-catalyzed H2-borrowing alkylations
of aromatic amines. Herein, we report our findings
concerning this research.
Results and Discussion
Ligand Syntheses
At the outset, three simple families of PN ligands
would be rapidly generated, allowing us to cover
Scheme 2. Hydrogen borrowing strategy in the alkylation of
amines by alcohols.
Adv. Synth. Catal. 2015, 357, 3538 – 3548
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3539

FULL PAPERS
Lewis Marc Broomfield et al.
proved an invaluable handle for monitoring progress
of the reaction. Under these revised conditions, the
pure products are produced in good yields (66–91%)
upon extraction with toluene and a subsequent wash-
ing of the solids with acetonitrile. Alternatively, for
oily products (such as for 2c, 3b, 3e, 3f) a ligand of
sufficient purity is obtained by extraction with
hexane. For 3b, prepared from N,N’-dimethylpropy-
lenediamine, analytically pure samples were achieved
by an additional washing with degassed ethanol.
While both 1,2-ethylenediamine and 1,3-propylenedi-
amine reacted readily with 4 equivalents of diphenyl-
chlorophosphine, to afford the corresponding bis-PNP
systems (1e and 1f), in the case of the more constrain-
ed trans-1,2-cyclohexanediamine the reaction stopped
at three phosphine groups. The solid-state structure of
the resulting 2b placed the remaining NH deep within
a pocket formed by the surrounding residues; at-
tempts to activate this NH group, including the use of
n-BuLi, were futile.
For 2b, the 31P NMR spectrum contains a singlet
and two doublets, the latter for the diastereotopic
PNP phosphorus atoms.[17] Interestingly, while each of
the N-bound ring C atoms was expected to couple to
all three P atoms, the two 13C NMR resonances
appear as doublet of doublets, indicating coupling to
only two P in each case. Selective decoupling experi-
ments (see the Supporting Information) reveal that
one of the two P of the PNP unit does not couple
Scheme 3. The generated PN ligand library.
a range of complex structures. The first two families with these C nuclei, likely due to the P lone pair (lp)
would derive from primary amines that, depending on oriented nearly antiperiplanar (1688 in the solid state)
[18]
À
the number of equivalents of chlorophosphine to the N C bond in the lp-P-N-C system (Figure 2).
charged, would give either a “PNP” or a “PNH”
system (type 1 and 2). In addition, the third PNR
family is obtainable using secondary amine scaffolds Catalytic Activity
(type 3). Furthermore, within each family, both mono-
and diamines can be employed.
The PN ligands generated were then tested in the
Thus, all ligands (1–3) were synthesized by con- model Ru-catalyzed N-benzylation of aniline
densing a chlorophosphine R2PCl (R=Ph or i-Pr) (PhNH2) with benzyl alcohol (BnOH). The initial re-
with the corresponding amine in the presence of Et3N action conditions, chosen based on recent work by
(Scheme 3). Given the size of the intended ligand Williams et al.[14b,c,19] and our own preliminary tests,
pool, the published condensation procedure[2g] was re- consisted in exposing PhNH2 and a slight excess of
vised in order to minimize the quantities of chloro- BnOH (1.05 equiv.) to [RuCl2(p-cymene)]2 (at
phosphine and base required, therefore simplifying 1.25 mol% Ru) and KOH (15 mol%) in toluene at
the time-intensive purification protocol. The 31P NMR 1508C. As a benchmark, the coupling in the absence
Figure 2. “Isolation” of one of the PNP phosphorus atoms from the C1 and C2 spin systems; a section of the corresponding
13C NMR spectrum is shown.
3540
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3538 – 3548

FULL PAPERS
Phosphino-amine (PN) Ligands for Rapid Catalyst Discovery
Figure 4. Performance survey of additional propylenedia-
mine-bridged systems; conditions as in Figure 3.
Figure 3. Screening of the PN library in the Ru(II)-catalyzed
N-benzylation of PhNH2 by BnOH. %GC yields vs. mesity-
lene (average from at least two separate runs).
infra). Finally, the superior catalyst performance of 3b
appears to be strongly correlated with the presence of
the NMe linkers as replacing these with either oxygen
(L4) or CH2 units (DPPPE, Figure 6) led to systems
with lower catalytic activities.
of an additional ligand led to an 87% consumption of
Additional exploration (Table 1) showed that the
PhNH2 after 12 h and the formation of a roughly process could be further improved by lowering the
equimolar mixture of the targeted benzylaniline temperature to 1208C, whereby the use of 1.25 mol%
(49%) and the corresponding imine (34%).
of the 1:1 Ru:3b catalyst system now led to quantita-
While no benzylamide (another potential side prod- tive formation of N-benzylaniline (compare entries 1
uct) could be detected, this outcome signaled a diffi- and 2; see the Supporting Information for the GC
culty in the last imine rehydrogenation step under trace). Nevertheless, inferior results were obtained at
these “ligand-free” conditions. As seen in Figure 3, 1108C (entry 3) or at other ligand-to-metal ratios (en-
the introduction of any of the PN ligands (at 2P/Ru tries 4 and 5). Notably, none of the benzyl benzoate
loading) from the preliminary library increased the side product is formed at these lower temperatures.
selectivity towards N-benzylaniline. Nevertheless, for
The efficiency of the reaction also depended on the
the PNP and PNH ligand families (1a–f, 2a–c), this seal created by the septum, as the use of older septa
improvement came at a cost of the reaction rate. sometimes led to the appearance of the imine side-
However, competitive rates were recovered using the product. Indeed, piercing the septum or removing it
bridged PNR ligands 3a–e. In particular, to our de- altogether (open reflux) led to the formation of 42%
light the use of 3b, comprising two Ph2PN(Me) moiet- and 71% of the imine, respectively (Table 1, entries 6
ies bridged by a propylene linker, afforded N-benzyl- and 7). These observations indicate the importance of
aniline in a 94% yield, with only traces of the imine the equilibrium associated with the ruthenium dihy-
being detected by GC. The privileged size of the dride species [Eq. (1)], given its role in the [H2] drop
three-carbon tether in 3b is evidenced by the some- in non-sealed system.
what inferior catalytic performance of the two- and
four-carbon bridged analogues 3a and 3c. Moreover,
the poor performance achieved using the monophos-
phine 3e (44% yield, 57% selectivity) indicates the
importance of a tethered system.
Additional structure-activity insights were gained
by testing further modifications of the “winning” pro-
Of the bases tested, potassium hydroxide led to the
pylene-bridged system 3b (Figure 4). Replacing the most effective catalyst system (see the Supporting In-
Ph2P groups with more electron-donating (i-Pr)2P formation for base screening). In this case, the catalyt-
(L1) led to a drop in catalyst selectivity as evidenced ic activity showed a sharp dependency on KOH load-
by the formation of 25% of imine side product. Re- ing; dipping at approx. 2 mol% and then rising sharp-
placing the central CH2 group with a CMe2 unit (L2 ly at base loadings of 5–10% (Figure 5). Although 6 h
and L3) led to relatively poor catalytic performance, was sufficient to obtain full conversion, a 12-hour pro-
lending evidence to the key role played by the hydro- cess was chosen for robustness. We note that under
gens of the central propylene CH2 group in 3b (vide these optimized reaction conditions, 3b outperforms
Adv. Synth. Catal. 2015, 357, 3538 – 3548
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3541

FULL PAPERS
Lewis Marc Broomfield et al.
Table 1. Selected optimization experiments of the Ru(II)-catalyzed benzylation of aniline.
Entry
L:M
Temperature [oC]
Conveersion [%][b]
Amine [%][b]
Imine [%][b]
1
2
3
4
1:1
1:1
1:1
0.5:1
2:1
1:1
150
120
110
120
120
120
120
100
100
89
92
90
94
>99
86
89
66
1
0
0
0
24
42
71
5
6[c]
7[d]
100
100
58
29
1:1
[a]
In 15-mL closed tubes under an inert atmosphere.
Conversion [%] and yields [%] (average from at least two separate runs) by GC vs. mesitylene as internal standard.
Septum was pierced with a needle.
Open reactor under reflux.
[b]
[c]
[d]
a number of commercially available bisphosphine li-
gands (Figure 6).
Substrate Scope
Given the synthetic potential of N-alkylations of
amines using H2-autotransfer in the pharmaceutical in-
dustry,[12j,k,14b,c,20] the substrate scope for this process
Figure 5. Catalytic activity of 3b/Ru(II) vs. %KOH (cou-
pling PhNH2 +BnOH). Rest of conditions as in run 4 in
Table 1.
was explored using the propylenediamine-based
ligand 3b under the optimized conditions. Indeed, sev-
eral para- and meta-functionalized anilines were suc-
cessfully N-benzylated using BnOH. For example, N-
benzyl-4-chloroaniline was isolated in 92% yield after
12 h (Table 2, Ae). In contrast, anilines with either
CN or CF3 groups in the para position proved to be
problematic (Table 2, Af and Ag).[21] The coupling of
ortho-substituted anilines and alkylamines were also
more sluggish as exemplified by the N-benzylation of
o-toluidine (42% after 12 h) and n-pentylamine (13%
after 12 h).
In terms of the alkylating agent, a range of substi-
tuted benzyl alcohols was successfully coupled with
aniline (Table 2, products Aa and Aj–An). An inter-
esting case was found for p-bromobenzyl alcohol,
which initially afforded only a modest yield (40%) of
the target N-(4-bromobenzyl)aniline (Am). However,
a series of control experiments led to a modified pro-
tocol, under which the p-Cl- and p-Br-benzyl alcohols
were used as substrates in the presence of 10 mol% of
BnOH as a booster. The finding stems from efforts to
establish whether the poor performance of the halo-
gen-substituted benzyl alcohols is due to catalyst de-
activation by these substrates. Thus, for the control
Figure 6. Comparison of 3b with a selection of commercially
available bis-phosphines.
3542
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3538 – 3548

FULL PAPERS
Phosphino-amine (PN) Ligands for Rapid Catalyst Discovery
Table 2. Ru(II)-catalyzed benzylation of amines using
method A: reaction scope.[a,b]
Figure 7. Screening of PN ligands in standard PhNH2-meth-
ylation reaction in neat MeOH. %GC yield vs. mesitylene
(average from at least two separate runs).
as solvent led to selective aniline mono-methylation,
with N-methylaniline detected in 57% yield. Encour-
aged by this result, the initial PN-ligand library was
re-examined seeking to further improve this highly se-
lective methylation reaction. Heating a MeOH solu-
tion of aniline (1 mmol in 1 mL) in the presence of
[RuCl2(p-cymene)]2 [Ru(II)=1.25 mol%] and K2CO3
(15 mol%) at 1208C for 12 h under “ligand-free” con-
ditions only afforded 35% of N-methylaniline (at
44% conversion). The addition of any bidentate PN
ligand from the ligand library resulted in improved
catalytic performance (Figure 7). Notably the addition
of either the PNP-type 1a or the cyclohexanediamine-
based 2b (at 1:1 L:M ratio, that is 2P:Ru) led to N-
methylaniline in >80% yield. In contrast, the mono-
phosphine tested (3f) proved ineffective.
[a]
In 15-mL tubes.
Yields of isolated material.
Corrected %GC yields.
%GC yield of imine.
[b]
[c]
Although the reaction tubes were heated by an Al
block kept at 1208C, a thermometer placed inside the
MeOH solution in the closed reaction tube showed
the internal temperature to be 768C, i.e., approxi-
mately 118C above the boiling point of MeOH at
[d]
[e]
At 1358C.
aniline benzylation with BnOH in the presence of p- 1 atm. This “overheating” proved crucial, as reducing
bromobenzyl alcohol, not only was the presence of the temperature of the heating block to 1008C result-
this additive well tolerated, but the latter was also ed in a drop in internal temperature to 688C and in
found to undergo efficient coupling with aniline. Thus yield to 63% (Table 3, also see the Supporting Infor-
it would appear that BnOH either prevents the cata- mation).
lyst deactivation event, or is able to restore the cata-
Considering the ease of preparation of 1a, this
lytic activity, particularly for the imine hydrogenation ligand was applied to subsequent aniline N-alkylation
step. This modification led to respectable yields of the reactions using aliphatic alcohols (method B). Indeed,
target N-benzylated products Al (74%) and Am by using 1.25 mol% of the Ru(II)/1a catalyst system
(71%). Conversely, although the coupling of non-ben- several anilines bearing electron-donating and elec-
zylic alcohols with aniline was possible, (Table 2, tron-withdrawing groups were successfully methylated
products Ao and Ap), the yields did not exceed 60%. (Table 3, Bb–Bd). For example, 4-chloro-N-methylani-
A solvent screen, conducted as part of the reaction line, Bd, is isolated in 75% yield using these condi-
optimization with 3b, revealed that the use of MeOH tions. Furthermore, the use of EtOH in place of
Adv. Synth. Catal. 2015, 357, 3538 – 3548
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3543

FULL PAPERS
Lewis Marc Broomfield et al.
Table 3. Ru(II)-catalyzed alkylations of anilines by method
Table 4. Alkylation of aminoferrocene.
B.[a,b]
[a]
In closed tubes.
Yields of isolated product.
GC yields vs. mesitylene as internal standard (average
from at least two separate runs).
External heating to 1008C.
[b]
[c]
Complex Chemistry
[d]
In light of the potent catalytic N-benzylation activity
conferred by 3b, the Ru(II) coordination chemistry of
MeOH produced the corresponding N-ethylaniline this ligand was studied. Despite the potential of 3b to
derivatives Be–Bh. act as a wide-angle bidentate ligand, exposing this bis-
As a test of catalyst utility, the 3b/Ru(II) system aminophosphine to [RuCl2(p-cymene)]2 in toluene in-
was applied to the synthesis of N-alkylaminoferro- evitably led to the formation of the 1:2 3b:Ru com-
cenes. Our interest stemmed from the promise shown plex 4. In the solid state,[25] each phosphorus is bound
by aminoferrocenes as prodrug candidates, including to a separate (cymene)RuCl2 unit (Scheme 4) thus
their toxicity in human promyelocytic leukemia (HL- completing the normal three-legged piano stool ar-
60) and human glioblastoma-astrocytoma (U373) cell rangement of an 18e Ru(II) center.[26] Indeed, while
lines.[22]
a 1:1 3b:Ru ratio led to a mixture of 4 and free 3b, at
As a first step, the parent aminoferrocene was syn- a 1:2 3b:Ru ratio the bimetallic 4 formed quantita-
thesized from iodoferrocene[23] and NH3(aq) in the tively within just 30 min (d=75.6 ppm by 31P NMR)
presence of a CuI-Fe2O3 catalyst, as described recent- and crystallized from the reaction mixture in an 83%
ly by Gasser et al.[24] While the original protocol em- yield. In fact, even a new monometallic complex 5,
ployed NaOH (2.3 equiv), in our hands omitting this obtained (along with 4) by switching to a toluene:t-
base was beneficial, leading to partial suppression of BuOH solvent mixture, was shown by both 31P NMR
the proto-deiodination side reaction and resulting in and X-ray diffraction to contain the 3b unit with only
a 77% yield of aminoferrocene on a 3.5 mmol scale one of the two phosphorus atoms bound to a (cy-
(see the Supporting Information). This primary amine mene)RuCl2 center. A glimpse into the potential of
underwent smooth coupling with both electron-rich 3b as a bidentate ligand was gained by conducting the
and electron-poor benzyl alcohols (Table 4, Ca–Cc). same reaction in MeOH. Within 15 min reaction time,
In particular, even the less reactive para-trifluorome- a yellow solution was observed and found to contain
thylbenzyl alcohol is an effective benzylating agent in two new Ru-H species, 6a and 6b. The hydridic
this case, leading to 70% yield of the target monoben- 1H NMR resonances (apparent dq) are observed at
zylation product Cc. Moreover, both the N-methyla- À5.72 and À7.11 ppm, respectively (see the Support-
tion and N-ethylation of aminoferrocene, using this ing Information). The fact that these signals were still
time the Ru(II)/1a-based system, took place with observed in CD3OD identifies 3b as the hydride
>80% yield. The high reactivity of aminoferrocene is source. For 6a, the apparent dq signals observed at
consistent with the trend observed earlier, whereby À5.72 ppm (along with a matching set of four
the N-alkylation is favored for electron-rich aromatic 31P NMR resonances) was interpreted as an octahe-
amines.
dral Ru(II)-H center bound to four non-equivalent P
atoms, likely from two chelating 3b units, one CH-ac-
3544
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3538 – 3548

FULL PAPERS
Phosphino-amine (PN) Ligands for Rapid Catalyst Discovery
Scheme 4. Synthesis of complexes 4, 5 and 7, along with the corresponding solid state structures.
tivated. Structural elucidation of 6b led to similar con- As seen in Table 5, while the Ru-H species 7 proved
clusions, and therefore we tentatively propose that to be a poor catalyst (entry 2), the performance of the
these two intermediates are isomers. Overtime, as the bimetallic 4 (entry 3, 84%) is in line with that of a 1:2
intensity of these hydridic resonances diminished and ligand-to-metal mixture previously tested (see
the solution lightens, giving rise to a new distorted oc- Table 1, entry 4) Finally, the mixture of 4 (ca. 60%)
tahedral Ru(II)-H species 7. The X-ray structure of with 5 (ca. 40%), as obtained from the reaction out-
this 18e species reveals a trans-Cl-Ru-H center sup- lined in Scheme 4, was as efficient as the 1:1 catalyst
ported by a dehydrogenated 3b unit, which now acts formed in situ (compare entry 1 and entry 4).[29]
as a three-coordinate mer ligand through the two P
Importantly, no hydridic resonances were detected
atoms and the h2-olefin moiety. A similar structure when [RuCl2(p-cymene)]2 was exposed to ligands 3a,
has already been reported by Gusev et al.[27] The coor- 3c, 3f and L3 in CD3OD. Thus, although 7 is clearly
dination sphere in 7 is completed by a P(OMe)Ph2 a catalyst decomposition product, we believe that its
[28]
À
group, likely from the P N bond methanolysis
of formation, along with that of intermediates 6a and 6b,
a second 3b molecule. The hydridic resonance in 7 is signals that CH activation of the propylene backbone
found at À13.58 ppm (apparent td), and the olefinic could play an important role in the catalytic cycle for
3
3
signals appear at d=5.38 (dd, JH,P =13.6, J=8.5 Hz) the 3b/Ru(II) system (Scheme 5). Indeed, as seen
3
and 4.91 ppm ( J=8.5, 4.7 and 1.5 Hz). Through a se- above (Figure 4) poor catalytic performance was ob-
quence of decoupling experiments, the 31P NMR reso- served for L3 featuring a CMe2 at this key position.
nances at d=35.5 and 103.7 ppm were assigned to Pa
As a final note, the ability of 3b to form wide bite
and Pb, respectively.
angle chelates was confirmed through the synthesis of
The isolated 3b/Ru(II) complexes 4 and 7 were a 3b-Cr(CO)4 complex prepared in 86% yield from
tested in the model benzylation reaction of aniline. Cr(CO)6. Its solid-state structure (Figure 8) revealed
À
À
a distorted octahedral geometry with the P Cr P
chelate angle of 1078.[1b] For this species, at 298 K the
Table 5. Testing of the isolated Ru(II) complexes of 3b in
the benzylation of PhNH2 by BnOH.[a,b]
Entry
Ru complex
Amine [%]
Imine [%]
1
2
3
4
3b/[RuCl2](cymene)]2
7
4
>99
40
84
0
35
0
4/5 mix
>99
0
[a]
In 15-mL closed tubes at 1208C.
%GC yield vs. mesitylene (average from at least two sep-
[b]
arate runs).
Scheme 5. A possible evolution of the Ru-3b system.
Adv. Synth. Catal. 2015, 357, 3538 – 3548
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3545

FULL PAPERS
Lewis Marc Broomfield et al.
Experimental Section
Synthesis of Ligand 3b
A
solution of N,N’-dimethylpropylenediamine (1.00 mL,
8.00 mmol) in toluene (30 mL) was treated with triethyl-
amine (2.50 mL, 17.92 mmol) and the flask was cooled to
08C. Chlorodiphenylphosphine (2.95 mL, 15.95 mmol) was
slowly added. Formation of a white salt was immediately ob-
served. Once the addition was completed, the cold bath was
removed. After stirring for 6 h, the mixture was concentrat-
ed to 20 mL and filtered to separate the ammonium salt. On
removal of volatiles under reduced pressure, 3b was recov-
ered as a colorless oil; yield: 2.53 g (5.38 mmol, 67%). A
higher purity was achieved by extracting the residue into
hexane (50 mL), filtering, evaporating the solvent and fur-
ther washing with degassed ethanol. 1H NMR (400 MHz,
CD2Cl2): d=7.45–7.34 (m, 20H, Ar), 3.08–3.02 (m, 4H,
NCH2), 2.49 (d, 3JH,P =6.1 Hz, 6H, NCH3), 1.73 (p, 3J=
8.0 Hz, 2H, CH2); 13C NMR (100 MHz, CDCl3): d=139.5
Figure 8. X-ray structure of 8. Selected bond lengths (Š)
À
À
À
and angles (8): Cr(1) P(1) 2.41, Cr(1) P(2) 2.41 (1); P(1)
À
Cr(1) P(2) 107.0.
lateral NCH2 groups of the propylene bridge are un-
observable in the 1H NMR spectrum due to a fluxional
process (DG° =13.3 kcalmolÀ1). At 328 K these
appear as a single broad resonance at d=3.40 ppm,
which is consistent with an average C2V symmetry. We
also note that heating two equiv. of Cr(CO)6 with 3b
in toluene (1208C for 50 h) gives the bimetallic com-
plex 9 in 51% yield.
1
2
(d, JC,P =14.7 Hz, ipso-Ar CP), 132.1 (d, JC,P =19.5 Hz, o-
Ar CH), 128.4 (p-Ar CH), 128.2 (d, 3JC,P =5.7 Hz, m-Ar
2
2
CH), 54.4 (d, JC,P =28.2 Hz, NCH2), 37.2 (d, JC,P =1.2 Hz,
NCH3), 28.6 (t, 3JC,P =5.9 Hz, CH2); 31P NMR (161 MHz,
CDCl3): d=67.33.
Conclusions
Catalysis by Ru(II)-3b: Synthesis of N-Benzylaniline
In summary, by screening our PN ligand library in
Ru(II) catalyzed H2-borrowing alkylation reactions of
aromatic amines, we were able to discover and opti-
mize two new high-yielding methods for synthesizing
secondary aromatic amines.
Method A utilizes bidentate PN ligands from the
PNR family with 3b giving the superlative selectivity
and product yields for this process. Indeed the opti-
mal combination of [RuCl2(p-cymene)]2/3b/KOH suc-
cessfully catalyzes benzylations of a variety of aromat-
ic amines, including aminoferrocene. Nonetheless, this
method does have its limitations and in fact only
works effectively for benzylation reactions. Thus
a second method (method B) was developed to over-
come this initial restriction.
Method B takes advantage of ligands from a differ-
ent subfamily with the PNP derivatives giving the
best performances. More specifically ligands 1a and
2b produce the highest yields of the desired secondary
amines. Moreover, the alcohol serves not only as the
alkylating agent but also as the reaction solvent in
this methodology.
In an argon-filled glovebox, an oven-dried screw-top reac-
tion tube was charged with [RuCl2(p-cymene)]2 (3.8 mg,
6.3 mmol, 1.25 mol% Ru), the ligand 3b (5.9 mg, 12.5 mmol,
1.25 mol%), potassium hydroxide (8.4 mg, 0.15 mmol,
15 mol%) and toluene (1 mL). Benzyl alcohol (109 mL,
1.05 mmol) and aniline (92 mL, 1.0 mmol) were then added,
the tube was sealed with a screw-cap septum and heated at
1208C for 12 h with agitation. Column chromatography on
silica gel, Rf =0.45 Hex:EtOAc, 9:1, afforded a colorless oil
(solidifies); yield: 169 mg (0.92 mmol, 92%). 1H NMR
(400 MHz, CDCl3): d=7.47–7.24 (m, 7H, Ar), 6.83–6.70 (m,
3H, Ar), 4.40 (s, 2H, CH2), 4.08 (s, 1H, NH).
Catalysis by Ru(II)-3b: Synthesis of N-(4-Trifluoro-
methyl)benzylaminoferrocene
Noteworthy is that the two methods profit from dif-
ferent ligand structures. This fact demonstrates the
importance of rapid ligand synthesis for such screen-
ing methodologies. In a more general sense taking ad-
vantage of facile PN bond formations for parallel
screening of ligand sets is a powerful tool for the
quick discovery and optimization of new reaction
methodologies. In this context we are currently study-
ing other processes in which this simplistic connection
can be an asset.
The compound was prepared following the procedure de-
scribed for aniline. Here, a mixture of aminoferrocene
(100 mg, 0.5 mmol), p-trifluoromethylbenzyl alcohol (92 mg,
0.525) was exposed to [RuCl2(p-cymene)]2 (1.9 mg, 3.2 mmol,
1.25 mol% Ru), the ligand 3b (3.0 mg, 6.3 mmol,
1.25 mol%), potassium hydroxide (4.2 mg, 0.08 mmol,
3546
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3538 – 3548

FULL PAPERS
Phosphino-amine (PN) Ligands for Rapid Catalyst Discovery
15 mol%) and toluene (0.5 mL). Column chromatography
2000, 112, 3772–3775; Angew. Chem. Int. Ed. 2000, 39,
3626–3629.
on silica gel, Rf =0.44 for Hex:EtOAc, 10:1, afforded a red
1
solid; yield: 124 mg (0.35 mmol, 70%). H NMR (400 MHz,
[4] a) S. M. Aucott, M. L. Clarke, A. M. Z. Slawina, J. D.
Woollins, J. Chem. Soc. Dalton Trans. 2001, 972–976;
b) for a recent review on aminophosphines as synthons
and ligands, see: J. Gopalakrishnan, Appl. Organomet.
Chem. 2009, 23, 291–318.
[5] a) E. Tomµs-Mendivil, R. García-Alvarez, C. Vidal, P.
Crochet, V. Cadierno, ACS Catal. 2014, 4, 1901–1910;
b) R. García-Alvarez, P. Crochet, V. Cadierno, Green
Chem. 2013, 15, 46–66; c) R. García-Alvarez, J. Díez, P.
Crochet, V. Cadierno, Organometallics 2011, 30, 3908–
3910.
CDCl3): d=7.62–7.59 (m, 2H, Ar), 7.53–7.50 (m, 2H, Ar),
3
4.23 (d, J=5.8 Hz, 2H, CH2), 4.17 (s, 5H, C5H5), 3.88 (s,
4H, Cp CH), 2.73 (t, 3J=5.0 Hz, 1H, NH); 13C NMR
(101 MHz, CDCl3): d=144.1 (Ar, ipso-CCH2), 129.6 (q,
3
2JC,F =32.4 Hz, ipso-CF3), 128.0 (Ar CH), 125.6 (q, JC,F
=
3.8 Hz, Ar CH), 124.3 (q, JC,F =272 Hz, CF3), 110.5 (ipso-
CpN), 68.2 (Cp, C5H5), 63.3 (Cp CH), 56.2 (Cp CH), 51.7
(CH2); HR-MS (ESI+): m/z=359.0582, calcd, for
C18H16F3FeN [M]+: 359.0579.
[6] M. Aydemir, A. Baysal, Polyhedron 2010, 29, 1219–
1224.
Acknowledgements
[7] M. D. Levin, F. D. Toste, Angew. Chem. 2014, 126,
6325–6329; Angew. Chem. Int. Ed. 2014, 53, 6211–6215.
[8] a) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J.
Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824–
2852; b) A. Alexakis, J. E. Bäckvall, N. Krause, O.
Pàmies, M. DiØguez, Chem. Rev. 2008, 108, 2796–2823.
[9] a) Y. Ju, R. S. Varma, Green Chem. 2004, 6, 219–221;
b) J. Clayden, N. Greeves, S. Warren, P. Wothers, Or-
ganic Chemistry, Oxford University Press, USA, 2001;
c) R. N. Salvatore, C. H. Yoon, K. W. Jung, Tetrahedron
2001, 57, 7785–7811; d) C. Grimm, O. Hamed, T. L.
Vigo, N. R. Bertoniere, J. Org. Chem. 2000, 65, 9234–
9237; e) K. Mohri, K. Suzuki, M. Usui, K. Isobe, Y.
Tsuda, Chem. Pharm. Bull. 1995, 43, 159–161; f) A.
Pelter, K. Smith, H. C. Brown, Borane Reagents, Aca-
demic Press, London, 1988; g) H. Yamamoto, K. Mar-
uoka, J. Org. Chem. 1980, 45, 2739–2740.
We thank Dr. Andrew Chapman for his generous help at the
early stages of this project. L. M. Broomfield thanks the
CELLEX Foundation for a post-doctoral contract. This
work was financed through grants from ICIQ, MINECO
(CTQ2013-46705-R and 2014–2018 Severo Ochoa Excellence
Accreditation SEV-2013-0319) and the Generalitat de Catalu-
nya (2014 SGR 1192). Financial support from CELLEX
Foundation through the CELLEX-ICIQ High Throughput
Experimentation platform is gratefully acknowledged.
References
[1] See the following list for some examples: a) M. E. van
der Boom, D. Milstein, Chem. Rev. 2003, 103, 1759–
1792; b) P. W. N. M. van Leeuwen, P. C. J. Kamer,
J. N. H. Reek, P. Dierkes, Chem. Rev. 2000, 100, 2741–
2769; c) K. H. Shaughnessy, P. Kim, J. F. Hartwig, J.
Am. Chem. Soc. 1999, 121, 2123–2132 d) C. A. Tollman,
Chem. Rev. 1977, 77, 313–348.
[10] a) F. Valot, F. Fache, R. Jacquot, M. Spagnol, M. Lem-
aire, Tetrahedron Lett. 1999, 40, 3689–3692; b) S. Nar-
ayanan, B. P. Prasad, J. Chem. Soc. Chem. Commun.
1992, 1204–1205; c) H. Matsuhashi, K. Arata, Bull.
Chem. Soc. Jpn. 1991, 64, 2605–2606.
[2] a) A. Carter, S. A. Cohen, N. A. Cooley, A. Murphy, J.
Scutt, D. F. Wass, Chem. Commun. 2002, 858–859;
b) D. F. Wass (BP Chemicals Ltd.), WO Patent 02/
04119, 2002; c) A. Bollmann, K. Blann, J. T. Dixon,
F. M. Hess, E. Killian, H. Maumela, D. S. McGuinness,
D. H. Morgon, A. Neveling, S. Otto, M. Overett,
A. M. Z. Slawin, P. Wassercheid, S. Kuhlmann, J. Am.
Chem. Soc. 2004, 126, 14712–14713; d) S. Kuhlmann, K.
Blann, A. Bollmann, J. T. Dixon, E. Killian, M. C. Mau-
mela, H. Maumela, D. H. Morgan, M. Pretorius, N. Tac-
cardi, P. Wasserscheid, J. Catal. 2007, 245, 279–284;
e) T. Agapie, Coord. Chem. Rev. 2011, 255, 861–880,
and references cited therein; f) D. S. McGuinness,
Chem. Rev. 2011, 111, 2321–2341, and references cited
therein; g) Y. Shaikh, K. Albahily, M. Sutcliffe, V. Fo-
mitcheva, S. Gambarotta, I. Korobkov, R. Duchateau,
Angew. Chem. 2012, 124, 1395–1398; Angew. Chem.
Int. Ed. 2012, 51, 1366–1369.
[3] a) D. J. Jones, V. C. Gibson, S. M. Green, P. J. Maddox,
A. J. P. White, D. J. Williams, J. Am. Chem. Soc. 2005,
127, 11037–11046; b) T. R. Boussie, G. M. Diamond, C.
Goh, K. A. Hall, A. M. Lapointe, M. K. Leclerc, C.
Lund, V. Murphy, (Symyx Technologies, Inc., USA),
Patent W2002038628, 2002; c) D. J. Jones, V. C. Gibson,
S. M. Green, P. J. Maddox, Chem. Commun. 2002,
1038–1039; d) J. Tian, G. W. Coates, Angew. Chem.
[11] a) C. Chiappe, D. Pieraccini, Green Chem. 2003, 5, 193–
197; b) R. N. Salvatore, A. S. Nagle, K. W. Jung, J. Org.
Chem. 2002, 67, 674–683.
[12] a) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010,
110, 681–703; b) G. Guillena, D. J. Ramon, M. Yus,
Chem. Rev. 2010, 110, 1611–1641; c) T. D. Nixon, M. K.
Whittlesey, J. M. J. Williams, Dalton Trans. 2009, 753–
762; d) S. Bähn, A. Tillack, S. Imm, K. Mevius, D. Mi-
chalik, D. Hollmann, L. Neubert, M. Beller, ChemSu-
sChem 2009, 2, 551–557; e) B. Blank, S. Michlik, R.
Kempe, Adv. Synth. Catal. 2009, 351, 2903–2911; f) S.
Liu, M. Rebros, G. Stephens, A. C. Marr, Chem.
Commun. 2009, 2308–2310; g) B. Blank, M. Madalska,
R. Kempe, Adv. Synth. Catal. 2008, 350, 749–758;
h) K.-I. Fujita, Y. Enoki, R. Yamaguchi, Tetrahedron
2008, 64, 1943–1954; i) M. H. S. A. Hamid, P. A. Slat-
ford, J. M. J. Williams, Adv. Synth. Catal. 2007, 349,
1555–1575; j) A. Tillack, D. Hollmann, D. Michalik, M.
Beller, Tetrahedron Lett. 2006, 47, 8881–8885; k) K-I.
Fujita, T. Fujii, R. Yamaguchi, Org. Lett. 2004, 6, 3525–
3528; l) C. Gunanathan, D. Milstein, Science 2013, 341,
249–260.
[13] a) W. M. J. Ma, T. D. James, J. M. J. Williams, Org. Lett.
2013, 15, 4850–4853; b) A. J. A. Watson, J. M. J. Wil-
liams, Science 2010, 329, 635–636.
Adv. Synth. Catal. 2015, 357, 3538 – 3548
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3547

FULL PAPERS
Lewis Marc Broomfield et al.
[14] a) A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, J.
Org. Chem. 2011, 76, 2328–2331; b) M. H. S. A. Hamid,
C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C.
Maytum, A. J. A. Watson, J. M. J. Williams, J. Am.
Chem. Soc. 2009, 131, 1766–1774; c) M. H. S. A.
Hamid, J. M. J. Williams, Chem. Commun. 2007, 725–
727.
[15] W. Baumann, A. Spannenberg, J. Pfeffer, T. Haas, A.
Kçckritz, A. Martin, J. Deutsch, Chem. Eur. J. 2013, 19,
17702–17706.
[16] G. R. M. Dowson, M. F. Haddow, J. Lee, R. L. Wingad,
D. F. Wass, Angew. Chem. 2013, 125, 9175–9178;
Angew. Chem. Int. Ed. 2013, 52, 9005–9008.
[17] a) R. H. Contreras, J. E. Peralta, Prog. Nucl. Magn.
Reson. Spectrosc. 2000, 37, 321–425; b) R. J. Cross,
T. H. Green, R. Keat, J. Chem. Soc. Dalton Trans. 1976,
1424–1428.
[18] a) W. H. Hersh, S. T. Lam, D. J. Moskovic, A. J. Pana-
giotakis, J. Org. Chem. 2012, 77, 4968–4979; b) R. Bal-
lesteros-Garrido, L. Bonnafoux, F. Blanco, R. Balles-
teros, F. R. Lerroux, B. Abarca, F. Colobert, I. Alkorta,
J. Elguero, Dalton Trans. 2011, 40, 1387–1395; c) L. D.
Quin, K. C. Caster, J. C. Kisalus, K. A. Mesch, J. Am.
Chem. Soc. 1984, 106, 7021–7032; d) L. D. Quin, M. J.
Gallagher, G. T. Cunkle, D. B. Chesnut, J. Am. Chem.
Soc. 1980, 102, 3136–3143.
Goeltz, C. P. Kubiak, Organometallics 2011, 30, 3908–
3910.
[24] a) A. Leonidova, T. Joshi, D. Nipkow, A. Frei, J.-E.
Penner, S. Konatschnig, M. Patra, G. Gasser, Organo-
metallics 2013, 32, 2037–2040.
[25] CCDC 1428556, CCDC 1428557, CCDC 1428558,
CCDC 1428559 and CCDC 1428560 contain the supple-
mentary crystallographic data for this paper. These
data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[26] a) J. H. Nelson, H. D. Hansen, Organometallics 2000,
19, 4740–4755; b) C. Moise, P. Le Gendre, P. J. Richard,
J. Organomet. Chem. 2000, 605, 151–156; c) I. Moldes,
E. Encarnación, J. Ros, A. Alvarez-Larena, J. F. Piniel-
la, J. Organomet. Chem. 1998, 566, 165–174; d) M. R. J.
Elsegood, D. A. Tocher, Polyhedron 1995, 14, 3147–
3156.
[27] a) V. F. Kuznetsov, A. R. Kamaluddin, A. J. Lough,
D. G. Gusev, J. Am. Chem. Soc. 2006, 128, 14388–
14396; b) D. G. Gusev, A. J. Lough, Organometallics
2002, 21, 5091–5099; c) D. G. Gusev, A. J. Lough, Orga-
nometallics 2002, 21, 2601–2603.
[28] a) K. G. Gaw, M. B. Smith, J. B. Wright, A. M. Z.
Slawin, S. J. Coles, M. B. Hursthouse, G. J. Tizzard, J.
Organomet. Chem. 2012, 699, 39–47; b) J. Gopalak-
rishnan, Appl. Organomet. Chem. 2009, 23, 291–318;
c) W. Ong, A. B. Beeler, S. Kesavan, J. S. Panek, J. A.
Porco, Angew. Chem. 2007, 119, 7614–7616; Angew.
Chem. Int. Ed. 2007, 46, 7470–7472; d) S. Priya, M. S.
Balakrishna, J. T. Mague, S. M. Mobin, Inorg. Chem.
2003, 42, 1272–1281; e) P. W. Dyer, J. Fawcett, M. J.
Hanton, R. D. W. Kemmitt, R. Padda, N. Singh, Dalton
Trans. 2003, 104–113; f) V. Chandrasekhar, S. Kingsley,
A. Vij, K. C. Lam, A. L. Rheingold, Inorg. Chem. 2000,
39, 3238–3242; g) S. Kingsley, A. Vij, V. Chandrasekhar,
Inorg. Chem. 2001, 40, 6057–6060.
[19] S. Agrawal, M. Lenormand, B. Martín-Matute, Org.
Lett. 2012, 14, 1456–1459.
[20] K. Fujita, Z. Z. Li, N. Ozeki, R. Yamaguchi, Tetrahe-
dron Lett. 2003, 44, 2687–2690.
[21] Interestingly para-CN does not deactivate the catalyst
and total product yields formed from the standard ani-
line are high (>90%). Nonetheless, the reduction of
the cyano group and its subsequent alkylation reduce
the efficiency of the rehydrogenation processes. On the
other hand, 4-trifluoromethylaniline does deactivate
the catalyst.
[22] a) P. Marzenell, H. Hagen, L. Sellner, T. Zenz, R. Gri-
nyte, V. Pavlov, S. Daum, A. Mokhir, J. Med. Chem.
2013, 56, 6935–6944; b) H. Hagen, P. Marzenell, E.
Jentzsch, F. Wenz, M. R. Veldwijk, A. Mokhir, J. Med.
Chem. 2012, 55, 924–934.
[29] As suggested by a referee, an attempt was made to
carry out the reaction using a mixture 6a+6b. Some ac-
tivity was observed, but the results have been inconclu-
sive, giving a reasonable activity (80%) but a selectivity
only slightly better than for complex 7.
[23] a) M. S. Inkpen, S. Du, M. Driver, T. Albrecht, N. J.
Long, Dalton Trans. 2013, 42, 2813–2816; b) J. C.
3548
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3538 – 3548