New chiral diamino-bis(tert-thiophene): An effective ligand for Pd- and Zn-catalyzed asymmetric transformations

Article abstract of DOI:10.1039/b711666g

Enantiomerically pure diamino-bis(tert-thiophene) 1b proved to be a valuable and flexible chiral ligand for Pd- and Zn-catalyzed transformations, allowing for high levels of stereocontrol in asymmetric allylic alkylation (ee up to 99%) and hydrosilylation

Full text of DOI:10.1039/b711666g

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New chiral diamino-bis(tert-thiophene): an effective ligand for Pd- and
Zn-catalyzed asymmetric transformations{
Marco Bandini,* Manuela Melucci, Fabio Piccinelli, Riccardo Sinisi, Simona Tommasi and
Achille Umani-Ronchi*
Received (in Cambridge, UK) 1st August 2007, Accepted 14th August 2007
First published as an Advance Article on the web 21st August 2007
DOI: 10.1039/b711666g
The synthesis of T3-CHO 24a was accomplished by replacing the
Enantiomerically pure diamino-bis(tert-thiophene) 1b proved to
environmentally undesiderable Stille cross-coupling with a Suzuki
reaction.11 In particular, the direct coupling of commercially
available 5-bromo-2-thiophenecarboxaldehyde and 5-(4,4,5,5-
tetramethyl-1,2,3-dioxaborolan-2-yl)-2,29-bithiophene led to T3-
CHO in 55% isolated yield (Scheme 1). Ligand 1b was finally
obtained by condensing 2 with the enantiomerically pure (1R,2R)-
cyclohexanediamine followed by reduction of the imine moieties
with HCl(Et2O)–NaBH3CN (72% overall yield).
be a valuable and flexible chiral ligand for Pd- and Zn-catalyzed
transformations, allowing for high levels of stereocontrol in
asymmetric allylic alkylation (ee up to 99%) and hydrosilyla-
tions of prochiral carbonyls (ee up to 97%).
Asymmetric organometallic catalysis is a well established route to
the synthesis of stereochemically defined poly-functionalized
compounds and the discovery of new sources of inspiration for
the design of chiral catalysts is a long-sought goal for numerous
synthetic chemists.1,2
With the ligand in hand, we examined the generality in scope
of the corresponding (R,R)-1b–[Pd] complex in the asymmetric
Pd-catalyzed allylic alkylation.
In this context, we recently focused on the suitability of hybrid
metallo-organic semiconductors chemistry as a valuable guideline
in the development of new leads in asymmetric transformations.3
As initial contributions, we described diamino-bithiophene 1a
(DAT2, Fig. 1) as a ligand for Pd-4 and Cu-catalyzed5
enantioselective reactions. The ability of oligothiophenes to shuttle
charges across their skeletons enabled the modulation of the
catalytic activity of Pd–1a-type complexes through remote
molecular functionalization of the organic ligand.6
The versatility in molecular design of thiophene chemistry7
allows for the introduction of longer oligothienyl units as sidearms,
this being interesting for a variety of applications such as hybrid
dyes for optoelectronics, NLO-phores and fine-tuning chiral
organometallic catalysts.8 Therefore, we decided to examine the
properties of 1b (N,N9-bis-[2,29;59,20]tert-thiophen-5-ylmethyl-
cyclohexane-1,2-diamine) as a chiral ligand in bench-test asym-
metric organometallic transformations such as asymmetric allylic
alkylation (AAA, Pd)9 and hydrosilylations of prochiral carbonyls
(Zn).10
Hindered as well as unhindered acyclic allyl carbonates (3a–c)
were reacted with dimethyl malonates 4 as nucleophiles and the
results are collected in Table 1.12 Besides the high enantiomeric
excess already recorded with sterically hindered 1,3-diphenylallyl
carbonate 3a (99% yield, 99% ee, entry 1),4 DAT3 guaranteed
good results also with the chloro-substituted carbonate 3b (94–
97% ee, entries 3–4) and a moderate drop in optical outcome was
observed with dimethyl methylmalonate 4b in combination with 3a
(85% ee, entry 2).
Interestingly, the longer thienyl sidearms of 1b, with respect to
1a, engendered higher stereoinduction and activity with challen-
ging 1,3-dimethylallyl carbonate 3c (yield 55%, ee 91%, entry 5).4a
In this case, a brief survey of reaction conditions indicated the
use of [PdCl(p-allyl)]2, in combination with AgSbF6 as optimal
reaction parameters. It is known that the use of scavengers for
halide counterions speeds up the reaction rates of Pd-catalyzed
AAA13 and cross-couplings.14
Interestingly, the recently described X-ray structure for
C1-symmetry R,S-(1R,2R)-1b–[Pd(g3-C3H5)][PF6]15 provides
insight into the effect of the tert-thienyl ancillary pendants on
Fig. 1 Enantiomerically pure DAT ligands.
Dipartimento di Chimica ‘‘G. Ciamician’’, Universita` di Bologna, via
Selmi 2, 40126, Bologna, Italy. E-mail: marco.bandini@unibo.it;
achille.umanironchi@unibo.it; Fax: +39-051-2099456
{ Electronic supplementary information (ESI) available: Typical proce-
dures for the synthesis of unknown compounds and for the asymmetric
transformations. See DOI: 10.1039/b711666g
Scheme 1 Synthesis of 1b. Reagents and conditions: i. PdCl2(PPh3)2,
Na2CO3, EtOH, DME, 24 h, reflux; ii. MgSO4, DCM, rt; iii. HCl,
NaBH3CN, THF, 0 uC A rt.
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Chem. Commun., 2007, 4519–4521 | 4519

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The versatility of 1b in asymmetric synthesis was also high-
lighted in zinc-catalyzed stereoselective hydrosilylations of pro-
chiral arylketones by using PMHS as an environmentally benign
reducing agent (Table 2).{ This ligand accelerated protocol,
introduced earlier by Mimoun,20 is of great interest also for large
scale production and involves chiral diamine–zinc complexes as
active catalytic species.21 Gratifyingly, the in situ formed (R,R)-1b–
ZnEt2 complex (5 mol%) proved to be better performing with
respect to the analogous (R,R)-1b–ZnMe2 in the reduction of 6a
(entries 1 and 2).
Table 1 Use of 1b as the ligand in Pd-catalyzed asymmetric allylic
alkylationa
Entry
Cond.
3/4
5
Yield [%]b
Ee [%]c
To determine functional group compatibility, a series of aryl
alkyl ketones 6 were subjected to reduction. Substituents on the
aryl ring as well as in the aliphatic chain were tolerated with ee up
to 83%. Remarkably, the present level of stereoinduction is among
the highest recorded to date in zinc-catalyzed PMHS-based
reductions.22
1
2
3
4
5
a
A
A
A
A
B
3a/4a
3a/4b
3b/4a
3b/4b
3c/4a
5aa
5ab
5ba
5bb
5ca
99
95
82
85
55
99 (S)
85 (S)
94 (–)
97 (–)
91 (S)d
A: [Pd2(dba)3]?CHCl3 (5 mol%), BSA, AcOK, THF, rt. B:
b
[PdCl(p-allyl)]2 (5 mol%), AgSbF6, NaH, THF, 0 uC. Isolated
yields after flash chromatography. Determined by HPLC with
c
Prompted by these promising results, 1b was efficiently
employed also in the hydrosilylation of the challenging phosphoi-
mine 8 (model substrate) in the presence of a catalytic amount of
ZnEt2 (5 mol%). Here, (S)-(2)-9 was isolated in 70% yield and ee
= 97% after 3 h reaction time (0 uC, THF, MeOH, Scheme 2).
Worthy of note is the short reaction time required for
completion at 0 uC (3 h) which markedly distinguishes our catalyst
from previously described bis-amino Zn-based chiral catalysts.23
In conclusion, we have reported on the versatility of readily
accessible chiral diamino-bis(tert-thiophene) 1b which has found
successful applications as a chiral ligand in Pd- and Zn-catalyzed
stereoselective processes. Good yields and high levels of enantio-
selectivity were obtained in asymmetric allylic alkylation and
hydrosilylation of prochiral ketones and phosphinyl imines.
Studies addressing functional chiral diamino compounds bearing
longer and variously functionalized oligothiophene pendants are
under way.
d
chiral column (OD, AD). Determined by GC (crosslinked 5% PH
ME Siloxane, Megadex 5).
the stereochemical outcome of the reactions (Fig. 2). In particular,
1b–[Pd(g3-C3H5)][PF6] displayed a similar conformation to the
corresponding 1a–[Pd(g3-C3H5)][BF4],4a in which the tert-thienyl
substituents at the nitrogen atoms showed both pseudo equatorial
and pseudo axial configuration.16
It is noteworthy that the long and electron-rich oligoaryl
sidearms of 1b concur in tightening the intramolecular sulfur–
˚
palladium contact (S(4)…Pd(1): 3.306(2) A), with a consequent
enhancement in enantiodifferentiation during the nucleophilic
attack.6
Moreover, the known tendency of electron-rich ancillary ligands
to accelerate oxidative additions of Pd(0) species could account for
the observed improvement in overall reaction rate with ligand 1b.17
The precatalytic 1b–[Pd(g3-Ph2C3H3)][PF6] complex was synthe-
sized in 87% yield through a variation of a known procedure (see
ESI for details).4a
This work was supported by M.I.U.R. (Rome), National
project ‘‘Sintesi e stereocontrollo di molecole organiche per lo
sviluppo di metodologie innovative di interesse applicativo’’, FIRB
Project (Progettazione, preparazione e valutazione biologica e
farmacologica di nuove molecole organiche quali potenziali
farmaci innovativi), Consorzio C.I.N.M.P.I.S. and the University
Although all attempts to obtain crystallographic information on
1
1b–[Pd(g3-Ph2C3H3)][PF6] were unfruitful, a H-NMR investiga-
tion (CD2Cl2, VT) revealed the presence of two C-1 symmetrical
species (65 : 35 ratio at rt)18 carrying syn–syn allyl units exclusively
(J = 11–13 Hz).19 The similarity of this spectrum with that of 1a–
[Pd(g3-Ph2C3H3)] [4.64 (d, J = 9.2 Hz, 1Hanti), 5.46 (d, J = 9.2 Hz,
1Hsyn), 6.64–6.71 (m, 1Hcentral)]6 calls for an analogous five-
membered N,N-palladacycle motif to be present in solution for 1b,
as well.
Table 2 Enantioselective reduction of arylketones with PMHS
catalyzed by 1b–Zn complexa
Entry
ZnR2
6
7
Yield [%]b
Ee [%]c
1
2
3
4
5
6
a
ZnMe2
ZnEt2
’’
’’
’’
’’
6a
6a
6b
6c
6d
6e
7a
7a
7b
7c
7d
7e
70
73
75
55
60
52
80 (S)
83 (S)
82 (S)
72 (R)
80 (S)d
80 (S)d
b
All reactions were carried out at rt for 16 h. Isolated yields.
Determined by chiral HPLC (OD). Absolute configurations were
c
d
assigned by comparison with known products. Determined by
chiral GC (crosslinked 5% PH ME Siloxane, Megadex 5).
Fig. 2 X-ray molecular structure of 1b–[Pd(g3-C3H5)]+ as a [PF6]2 salt.
4520 | Chem. Commun., 2007, 4519–4521
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6 V. G. Albano, M. Bandini, G. Barbarella, M. Melucci, M. Monari,
F. Piccinelli, S. Tommasi and A. Umani-Ronchi, Chem.–Eur. J., 2006,
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Scheme 2 Enantioselective hydrosilylation of diphenylphosphinyl
ketoimine 8.
12 Cyclic allylic carbonates reacted smoothly under the optimum reaction
conditions but only racemic products were obtained.
of Bologna. Prof. G. Gigli and Dr M. Mazzeo are kindly
13 T. P. Clark and C. R. Landis, J. Am. Chem. Soc., 2003, 125, 11792.
14 L.-C. Campeau and K. Fagnou, Chem. Commun., 2006, 1253.
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26, 4373.
acknowledged for the spectroscopic characterization of 1b.
Notes and references
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18 Diagnostic signals relative to the diphenylallyl units: d: 4.55 (d, J =
12.6 Hz, Hanti), 5.49 (d, J = 12.3 Hz, Hsyn), 6.72 (t, J = 12.9, Hcentral);
minor species d: 4.05 (d, J = 11.4 Hz, Hanti), 4.70 (d, J = 11.7 Hz, Hanti),
6.41 (t, J = 10.8 Hz, Hcentral).
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{ Typical procedure for stereoselective hydrosilylation of ketones: a flamed
25 mL two-necked flask was charged with diamine 1b (6.2 mg, 0.01 mmol),
1 mL of anhydrous toluene and 9.1 mL of Et2Zn (1.1 M, toluene). The
mixture was stirred at rt for 30 min, then 6a (0.2 mmol) and PMHS (65 mL,
1 mmol) were sequentially added. The reaction was stirred at rt and after
16 h judged complete by GC-MS. After quenching (3 ml of KOH, 45%,
wt., 1 h), the two phases were separated and the aqueous layer extracted
with Et2O (3 6 5 mL). Finally, the collected organic phases were dried over
Na2SO4 and concentrated under vacuum. The desired product 7a was
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Chem. Commun., 2007, 4519–4521 | 4521