Tathagata Mukherjee

tathagata93@gmail.com 6980 NE Ronler Way, Apt-3528, Hillsboro, OR 97124 Ph- (979)-571-3326

Second Coordination Sphere Promoted Catalysis: Organometallic Hydrogen Bond Donors for
Enantioselective Organic Transformations

Introduction: From an application standpoint, hydrogen bonding has been explored as an architectural unit for
supramolecular assembly and host-guest interactions.1-5 Macromolecules that mimic enzyme binding sites have shown
the capability to catalyze numerous organic transformations aided by hydrogen bonding from peptidic NH or OH
linkages.6 Recently, organic molecules bearing NH or OH moieties has been explored and applied in hydrogen
bonding induced catalysis.7 Examples of hydrogen bonding also exist in inorganic molecules but less explored and
lack practical applications. The research detailed below bridged this gap by synthesizing and applying chiral inorganic
hydrogen bond donors as catalysts for enantioselective organic transformations and thereby leading to the discovery
of a new concept second coordination sphere promoted catalysis (SCSPC).

Results and Discussions: Commonly, synperiplanar hydrogen bond acceptor (A) and donor (D) sites are indicated
by a linear sequence of letters (e.g. DDADA). Similar DD motif is also seen in (thio)ureas and is considered as the
prime reason for their success in hydrogen bond donor catalysis (Figure 1, structure I).7d Likewise, 2-
guanidinobenzimidazole (GBI, Figure 1, II), an inexpensive and readily available nitrogen heterocycle, with five N-
H bonds, is capable of attaining a plethora of synperiplanar acceptor A/D arrangements. Free GBI and metal-GBI
complexes (Figure 1, III) both exhibit intermolecular hydrogen bonding in the solid state. Interestingly, in most metal
complexes, the GBI ligand features a DDD triad, which is rare in studies of the free ligand. 8 This DDD arrangement
is similar to the DD motif of (thio)ureas and can potentially act as hydrogen bond donor catalysts. 9,10
Moreover, with proper arrangement of ligands around the metal, the metal-GBI complexes can be
transformed into chiral molecules, with metal being the only source of chirality (Figure 1, green box). Finally, after
resolution these can be applied to enantioselective organic transformations. Towards this, a series of compounds
(Figure 1, 1-3) were prepared and after numerous attempts, one of them was successfully resolved (3b).8

In ruthenium-GBI complexes all of the hydrogen bond donor sites are remote from the metal center and they
feature a DDD triad. Initial NMR studies have shown that complexes 1-3 involve in hydrogen bonding interactions
with trans--nitrostyrene (4), acetylacetone, and few other common hydrogen bond acceptors.8-10 Reactions involving
atoms directly connected to the metal center represent first coordination sphere interactions. Participating atoms
remote from the metal center constitute second coordination sphere interactions. To establish a second coordination
sphere hydrogen bonding interaction with the substrate and its application in catalysis, ruthenium-GBI complexes (1-
3) were applied as catalysts in Friedel-Crafts reactions between 1-methylindole (5) and 4 to generate 6, as shown in
Table 1. It is evident from entry 1 and 2 that neither the reaction proceeds by itself nor GBI is an active catalyst for

1
 Tathagata Mukherjee
tathagata93@gmail.com 6980 NE Ronler Way, Apt-3528, Hillsboro, OR 97124 Ph- (979)-571-3326

this reaction. Whereas, each of the ruthenium complexes are active catalyst and they promote the reaction smoothly.
In accordance with the activation of the substrate through hydrogen bonding theory, a drastic anion effect was evident
(Table 1, entries 3-8). Between the two anions applied here (PF6 or BArf), BArf is the most weekly coordinating
anion11 with least hydrogen bonding capabilities12 and so, generates the most active catalyst. With PF6 anion, the
substrate has to compete for the hydrogen bonding interactions and thereby leading to a less active catalyst. Hydrogen
bonding between PF6 and the cation in 3a is evident in its crystal structure (Figure 2).8,9

After successful resolution of (SRu/RRu)-3b, one of the enantiomer ((SRu)-3b) was used as a catalyst for the
Michael addition reaction between trans-3-cinnamoyloxazolidin-2-one (7) and thiophenol (8) to produce 9. Indeed,
the catalyst was both active and extremely enantioselective, as shown in Table 2. With only 10 mol% catalyst loading
at 78 C it provided 9 (yield 25%; 12 h or 60%; 48 h) with >99% enansioselectivities (ee).
Further, via a multistep synthesis strategy as described in the published article10 a series of chiral/achiral
derivatives of GBI ligands (10a-d) was prepared. These amines were then reacted with 11 to provide the
corresponding diastereomeric salts 12a-d in good to moderate yields, as shown in Scheme 1. Later, one of the salts,
12c, was separated into its diastereomers ((SRuRCRC)-3b and (RRuRCRC)-3b) by the procedure shown in Scheme 2.
As expected, salts 12a-d were all active catalysts for the Michael addition reaction between dialkyl malonate and
trans--nitrostyrene. Interestingly, the free ligands 10c-d with an attached basic moiety NR2 by itself were active
catalysts, but when compared to the chelate complexes, as shown in Table 3, the free amine lagged far behind in
reactivity as well as enantioselectivity (yield: 1-2 d, 83-97% vs. 5 d, 30-65%; ee: 88-99% vs. 10-67%) demonstrating
the power of the ruthenium core remote from the reaction center.

2
 Tathagata Mukherjee
tathagata93@gmail.com 6980 NE Ronler Way, Apt-3528, Hillsboro, OR 97124 Ph- (979)-571-3326

Conclusion: This research for the first time describes the development of new chiral-at-metal ruthenium based
organometallic hydrogen bond donors derived from 2-guanidinobenzimidazole (GBI) and their application in second
coordination sphere promoted catalysis (SCSPC). Further, application of enantiopure ruthenium complexes in SCSPC
establishes the viability of using these transition metal complexes containing ligand based NH hydrogen bond donors
to catalyze enantioselective organic transformations in high yields and enantioselectivities. Unlike most transition
metal catalyzed reactions, there is no direct interaction of the substrate with the ruthenium; rather, association involves
hydrogen bonding derived from NH groups which are remote from the metal center (Figure 3).

These hydrogen bonding interactions and the activation of the substrates occurs solely through second
coordination sphere, and thereby promote the reactions (Figure 3). Thus, these systems successfully developed a new
hydrogen bond promoted catalytic process called second coordination sphere promoted catalysis (SCSPC).

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