The design and synthesis of novel IBiox N-heterocyclic carbene ligands derived from substituted amino-indanols

Article abstract of DOI:10.1039/c1ob06780j

A synthetic route towards a number of novel IBiox N-heterocyclic carbene (NHC) ligands has been developed. The resulting ligands have restricted flexibility and high steric demand. Preliminary studies have shown these ligands to give high levels of asymmetric induction in the copper-free allylic alkylation of cinnamyl bromide.

Full text of DOI:10.1039/c1ob06780j

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The design and synthesis of novel IBiox N-heterocyclic carbene ligands
derived from substituted amino-indanols†
Jean-Noe¨l Levy,a Christopher M. Latham,b Lo¨ıc Roisin,a Nadine Kandziora,a Paolo Di Fruscia,a
Andrew J. P. White,a Simon Woodwardb and Matthew J. Fuchter*a
Received 22nd October 2011, Accepted 14th November 2011
DOI: 10.1039/c1ob06780j
A synthetic route towards a number of novel IBiox N-
heterocyclic carbene (NHC) ligands has been developed. The
resulting ligands have restricted flexibility and high steric
demand. Preliminary studies have shown these ligands to give
high levels of asymmetric induction in the copper-free allylic
alkylation of cinnamyl bromide.
reactions of unactivated partners,1a,3b and more recently (for
IBiox[(-)-menthyl] 3) in asymmetric a-arylation reactions,3c and
asymmetric hydroarylation reactions.4 When we commenced our
work in this area, we were surprised that IBiox ligands derived from
an amino-indanol nucleus had not been significantly studied,5
despite the fact that this unit has proved an extremely successful
scaffold on which to build effective chiral NHC organocatalysts.6
Furthermore, current issues in chiral NHC ligand design include
the fact that the elements of chirality are often far from the reactive
carbenic C-2 centre, and that chiral N-substituents often are freely
rotating, defining a poor chiral space.7 We felt the structurally rigid
“wings” of the aminoindanol unit would provide a well defined
chiral space around the C-2 centre. Indeed, key to our design
was the use of substituents (R), which project directly into the
C-2 centre, defining an effective, C2-symmetric chiral pocket (see 4,
Fig. 1). We therefore decided to explore the synthesis of a selection
of amino-indanol derived IBiox ligands, with a variety of R groups,
and explore their use as chiral NHC ligands.
The use of N-heterocyclic carbenes (NHCs) in preparative chem-
istry is now ubiquitous. Indeed, NHCs have a wide range of
applications, from enabling ligands for transition metal mediated
and main group processes, to highly useful organocatalysts.1
Numerous studies have concerned the design and preparation of
chiral NHCs to mediate stereocontrol in asymmetric reactions.2,3
Despite this large body of work however, there are few such
chiral NHCs that could be termed “privileged” due to a broad
applicability to diverse reaction types. Using an alternative
“privileged” ligand class, the bisoxazolines, as inspiration, Glorius
and co-workers have pioneered the development of NHC ligands
derived from oxazolines (IBiox, Fig. 1).3 Such IBiox ligands
have shown particular applicability as ligands in cross-coupling
Rearrangement of the 4-chromanone (5) at high temperature in
the presence of AlCl3 afforded hydroxyindanone 6 (Scheme 1).8
Triflation of 6 afforded the corresponding aryltriflate in excellent
yield (99%). This was followed by either the use of dimethylzinc in
the presence of a nickel catalyst, or a palladium-mediated cross-
coupling reaction with phenylboronic acid to give the methyl
Fig. 1 Examples of IBiox ligands.
aDepartment of Chemistry, Imperial College London, London, SW7 2AZ,
United Kingdom. E-mail: m.fuchter@imperial.ac.uk
bSchool of Chemistry, The University of Nottingham, Nottingham, NG7
2RD, United Kingdom
† Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra and X-ray crystallographic data.
CCDC reference numbers 842971–842973. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1ob06780j
Scheme 1 Synthesis of aminoindanol derivatives (R = Me, Ph).
512 | Org. Biomol. Chem., 2012, 10, 512–515
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(R = Me) or phenyl (R = Ph) appended indanones 7 respectively.
Exposure of the products to NaBH4 afforded the corresponding
benzylic alcohols. We found elimination of the resultant alcohol
to yield the indene rather problematic, with polymerization
of the indene readily occurring under acidic conditions. After
an extensive survey of conditions however, two equivalents of
pyridinium p-toluenesulfonate (PPTS) was found to be optimal.
Since removal of the pyridine under reduced pressure resulted in
the partial evaporation of the desired product, a modified work-
up was employed using a saturated solution of copper sulphate to
remove residual pyridine.
The crude indenes obtained were used to prepare the required
amino-indanol derivatives 10 via epoxide formation and ring
opened by sodium azide. The epoxidation reaction was performed
with the (salen)Mn catalyst 11 designed by Jacobsen and co-
workers to perform enantioselective epoxidation of indene.9
Attempts at a rapid chromatographic purification of the epoxide
failed due to conversion of the indene oxide to 2-indanone.
Regioselective opening of the crude epoxide with sodium azide
in the presence of ammonium chloride in refluxing aqueous
ethanol afforded the trans-azido alcohols in a good yield after
chromatography (Scheme 1).10 At this stage the enantiomeric
excess was determined by chiral HPLC. Pleasingly, the levels
of asymmetric induction (96% e.e.) were comparable to those
reported by Jacobsen for the epoxidation of indene. Reduction
of the azide group via hydrogenation using activated palladium on
charcoal was performed to give the desired trans-aminoindanols.
Further purification on silica gel resulted in some degradation;
therefore the crude material was directly used in the next step
(Scheme 1).
Condensation of the aminoindanol 10 with diethyl oxalate was
performed with a substoichiometric amount of amount of acetic
acid to yield 12. Chlorination of 12 was performed as described
by Glorius.3 Reflux of 12 with 5 equivalents of thionyl chloride
afforded the desired products 13 in good yield. Subsequent heating
of 13 in the presence of sodium hydroxide gave the cyclized
products. This reaction sequence could be telescoped (9 to 14)
without purification of the intermediates in good yield over the
four steps. Alternatively, formation of the bisoxazoline 14 could
be achieved in one step from the alcohol 12 using deoxofluor as
previously described by Wipf and co-workers to promote the direct
cyclization of amino alcohols to oxazoline rings.11 This method in
general proved to be a faster and more reliable strategy (Scheme 2).
The bisoxazolines were isolated as single stereoisomers due to
the small amount of the meso compound being removed during
purification.
Scheme 2 Formation of imidazolium salts 15–17.
of the pivalate group to leave led to the subsequent undesired
side reactions and we therefore sought an alternative electrophile.
Hong and co-workers have previously synthesized constrained
imidazolium salts with chloromethyl ethylether under ambient
temperature in THF.12 Indeed this was the original reagent used by
Arduengo and co-workers in their seminal work.13 These reported
conditions did not yield the desired imidazolium salt in our case. A
modified version using one equivalent of chloromethyl ethylether
and silver triflate in dichloromethane showed consumption of
the starting material after two hours at ambient temperature
and the crude NMR showed the desired compound as the main
product. Unfortunately, purification by chromatography resulted
in partial decomposition. To combat this, the triflate counterion
was immediately exchanged for an iodide or a bromide which
proved to be more stable to chromatography. To our delight
this provided the desired target salts 15–17 (41–61%, Scheme 2).
We solved crystal structures for our three novel IBiox precursor
imidazolium salts. The crystal structure of 16 is shown in Fig. 2
and 15 and 17 are shown in the ESI.† Of interest, the structure
of 17a was found to contain two crystallographically independent
cations in the asymmetric unit (see ESI†). For both of these cations
the C-2 proton is encapsulated by the phenyl substituents such that
there are a pair of C–H ◊ ◊ ◊ p interactions. For molecule 17a-A the
˚
H ◊ ◊ ◊ centroid separations are ca. 2.59 and 2.80 A with the H ◊ ◊ ◊ p
vectors inclined by ca. 89 and 80◦ to the ring plane respectively,
whilst for molecule 17a-B the H ◊ ◊ ◊ centroid separations are ca.
˚
2.66 and 3.02 A with the H ◊ ◊ ◊ p vectors inclined by ca. 72 and
83◦ to the ring plane respectively. In support of such C–H ◊ ◊ ◊ p
interactions in this compound, the C-2 proton of salt 17 shifts
The final step of our reaction sequence consisted of the
cyclization to the desired imidazolium salts. Using the Glorius
procedure, chloromethyl pivalate was stirred with silver triflate
at ambient temperature for one hour in the dark, followed by
transfer of the resultant reagent to a solution of the bisoxazoline
14 in dichloromethane. Unfortunately, there was no formation
of the desired imidazolium salt. After 70 h at 40 ◦C, starting
material was still observed along with some decomposition.
After some experimentation, we found that degassing and drying
the dichloromethane with molecular sieves and performing the
reaction in the microwave at 90 ◦C gave the imidazolium salt
in low yield (22%). An exploration of different solvents did not
improve this low yield. We hypothesized that the high propensity
1
from around 9.8 to 4.71 ppm in the H-NMR spectra. With this
structural data in hand, we felt it would be interesting to quantify
Table 1 Calculated buried volume (%Vbur
)
a
Entry
Ligands
%Vbur
1
2
3
4
3
51.6
36.3
50.1
80.5
4 (R = H)
4 (R = Me)
4 (R = Ph)
a The calculations used SambVca15 with the following parameters: radius
˚
˚
˚
of sphere, 3.5 A; distance from sphere, 2.1 A; mesh step, 0.05 A.
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Table 2 Different conditions for asymmetric allylic alkylation reaction
a
a
Entry
Ligand precursor
Substrate
Addition rate
Additive
NMR Conv. %
g
a
% eea
1
2
3
4
5
6
7
15b
16b
17b
16c
16c
15b
16c
R = H
R = H
R = H
R = H
R = H
R = Me
R = Me
Slow
Slow
Slow
Slow
Fast
Slow
Slow
None
None
None
None
None
None
None
>99
>99
23
>99
>99
>99
74
1.0
1.0
0
1.0
1.0
1.7
1.1
1.1
2.8
1
3.4
3.3
1
74
87
/
86
86
57
56
1
a Determined by GC using a Chiracil-Dex-CB column.
magnesium species. To our delight, good levels of asymmetric
induction were observed. This is, to our knowledge, the highest ee
value that has been reported in this reaction from an NHC ligand
lacking a further potentially chelating function (OH,20–22 SO3H23),
as used in previous studies. Interestingly, the change of counterion
does not have an effect on the selectivity or the enantioselectivity
(entries 2, 4 and 5). Finally, the speed of addition of the Grignard
reagent had no discernable effect.
To further explore this reaction, another substrate, a-methyl
cinnamyl bromide 18 (R = Me) was also surveyed using our ligands.
In line with previous studies,21 a somewhat better g-selectivity was
observed at the cost of some enantioselectivity (entry 1 vs. 7).
Interestingly, although it significantly increases the %Vbur, the
additional methyl functionality in ligand 4 (R = Me) appears not
to be significantly involved in the selective transition state for this
substrate.
Fig. 2 The molecular structure 16b (counterion omitted).
the steric demand of our ligands using the buried volume metric
(%Vbur).14 The buried volume of the most commonly used NHCs
ranges from 35 to 47%. Glorius’ sterically demanding chiral NHC
ligand 3 (see Fig. 1) was reported to have the largest buried volume
ever reported for any monodentate ligand (Table 1, entry 1).1b,3c
Calculating the buried volume for our ligands15 gave a value of
36.3 for the unsubstituted ligand, which is comparable to IMes
(Table 1, entry 2). The methyl substituted ligand had a %Vbur of
50.1 which is comparable to ligand 3 (Table 1, entry 3). %Vbur for
the phenyl derivative was an incredible 80.5 (Table 1, entry 4),
which, to the best of our knowledge is the largest buried volume
ever reported for any ligand.
We next sought a suitable reaction to test the applicability of
our novel chiral ligands. While there has been much activity on
the copper-catalyzed allylic alkylation (CAAA),12,16–19 in line with
pioneering work of Hoveyda and co-workers on activation of
Grignard reagents by NHC Lewis bases,20 Alexakis and Hoveyda
have demonstrated that the allylic alkylation could be equally as
efficient without copper with NHC ligands.20,21 We felt that such
copper-free allylic alkylation would be an interesting case study
for our novel IBiox ligands.
Conclusions
We have developed an efficient route to novel amino-indanol
derived IBiox NHCs, thus extending this important family of
ligands. Our novel ligands have a very large percentage buried
volume and are effective in allylic alkylation chemistry. An in depth
exploration of their use is currently underway in our laboratories.
Acknowledgements
We would like to thank Imperial College and Cancer Research
UK (studentship to PDF, grant C21484A6944) for funding.
Notes and references
1 (a) S. Wurtz and F. Glorius, Acc. Chem. Res., 2008, 41, 1523; (b) T.
Droge and F. Glorius, Angew. Chem., Int. Ed., 2010, 49, 6940; (c) C. A.
Dyker and G. Bertrand, Science, 2008, 321, 1050; (d) E. A. B. Kantchev,
C. J. O’Brien and M. G. Organ, Angew. Chem., Int. Ed., 2007, 46, 2768;
(e) N. E. Kamber, W. Jeong, R. M. Waymouth, R. C. Pratt, B. G. G.
Lohmeijer and J. L. Hedrick, Chem. Rev., 2007, 107, 5813; (f) S. Diez-
Gonzalez, N. Marion and S. P. Nolan, Chem. Rev., 2009, 109, 3612;
(g) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007, 107,
5606; (h) B. T. Hahn, R. Frohlich, K. Harms and F. Glorius, Angew.
Chem., Int. Ed., 2008, 47, 9985; (i) F. E. Hahn and M. C. Jahnke,
Angew. Chem., Int. Ed., 2008, 47, 3122; (j) M. Poyatos, J. A. Mata
and E. Peris, Chem. Rev., 2009, 109, 3677; (k) Topics in Organometallic
Chemistry 21: N-Heterocyclic Carbenes in Transition Metal Catalysis,
Following slow addition of the Grignard reagent to a solution
of cinnamyl bromide 18 (R = H) and the ligand at -15 ◦C, the
◦
reaction was stirred for 19 h at -15 C. The results are shown in
Table 2. For reactions employing ligands bearing an unsubstituted
indanol unit 4 (R = H) or a methylated unit 4 (R = Me, entries
1 and 2), full conversion to the products was observed. For
our phenyl-substituted derivative 4 (R = Ph) however, only low
conversion was observed (entry 3). This lack of activity is most
likely due to the large steric bulk of this ligand, as demonstrated
by the calculated buried volume, hindering coordination to the
514 | Org. Biomol. Chem., 2012, 10, 512–515
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(Ed.: F. Glorius), Springer, Berlin, 2007; (l) A. C. Hillier, G. Grasa, M.
S. Viciu, H. M. Lee, C. Yang and S. P. Nolan, J. Organomet. Chem.,
2002, 653, 69.
11 A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno and D. R. Williams, Org.
Lett., 2000, 2, 1165.
12 H. Seo, D. Hirsch-Weil, K. A. Abboud and S. Hong, J. Org. Chem.,
2008, 73, 1983.
13 A. J. Arduengo, R. Krafczyk, R. Schmutzler, H. A. Craig, J. R.
Goerlich, W. J. Marshall and M. Unverzagt, Tetrahedron, 1999, 55,
14523.
14 A. C. Hillier, W. J. Sommer, B. S. Yong, J. L. Petersen, L. Cavallo and
S. P. Nolan, Organometallics, 2003, 22, 4322.
15 (a) A. Poater, B. Cosenza, A. Correa, S. Giudice, F. Ragone, V.
Scarano and L. Cavallo, Eur. J. Inorg. Chem., 2009, 2009, 1759;
(b) http://www.molnac.unisa.it/OMtools.php.
16 (a) S. Okamoto, S. Tominaga, N. Saino, K. Kase and K. Shimoda, J.
Organomet. Chem., 2005, 690, 6001; (b) S. Tominaga, Y. Oi, T. Kato,
D. K. An and S. Okamoto, Tetrahedron Lett., 2004, 45, 5585.
17 D. Hirsch-Weil, D. R. Snead, S. Inagaki, H. Seo, K. A. Abboud and S.
Hong, Chem. Commun., 2009, 2475.
2 (a) Y.-X. Jia, J. M. Hillgren, E. L. Watson, S. P. Marsden and E.
P. Kundig, Chem. Commun., 2008, 4040; (b) X. Luan, R. Mariz, C.
Robert, M. Gatti, S. Blumentritt, A. Linden and R. Dorta, Org. Lett.,
2008, 5569; (c) Y. Ma, C. Song, C. Ma, Z. Sun, Q. Chai and M. B.
Andrus, Angew. Chem., Int. Ed., 2003, 42, 5871; (d) M. C. Perry, X.
Cui, M. T. Powell, D.-R. Hou, J. H. Reibenspies and K. Burgess, J. Am.
Chem. Soc., 2003, 125, 113; (e) J. J. van Veldhuizen, J. E. Campbell, R.
E. Giudici and A. H. Hoveyda, J. Am. Chem. Soc., 2005, 127, 6877;
(f) W. L. Duan, M. Shia and G. B. Rong, Chem. Commun., 2003,
2916.
3 (a) G. Altenhoff, R. Goddard, C. W. Lehmann and F. Glorius, Angew.
Chem., Int. Ed., 2003, 42, 3690; (b) G. Altenhoff, R. Goddard, C. W.
Lehmann and F. Glorius, J. Am. Chem. Soc., 2004, 126, 15195; (c) S.
Wurtz, C. Lohre, R. Frohlich, K. Bergander and F. Glorius, J. Am.
Chem. Soc., 2009, 131, 8344; (d) F. Glorius, G. Altenhoff, R. Goddard
and C. Lehmann, Chem. Commun., 2002, 2704.
18 K. B. Selim, Y. Matsumoto, K. Yamada and K. Tomioka, Angew.
Chem., Int. Ed., 2009, 48, 8733.
4 J. Bexrud and M. Lautens, Org. Lett., 2010, 12, 3160.
19 (a) D. G. Gillingham and A. H. Hoveyda, Angew. Chem., Int. Ed., 2007,
46, 3860; (b) M. A. Kacprzynski, T. L. May, S. A. Kazane and A. H.
Hoveyda, Angew. Chem., Int. Ed., 2007, 46, 4554; (c) A. O. Larsen, W.
Leu, C. N. Oberhuber, J. E. Campbell and A. H. Hoveyda, J. Am. Chem.
Soc., 2004, 126, 11130; (d) Y. Lee, K. Akiyama, D. G. Gillingham, M.
K. Brown and A. H. Hoveyda, J. Am. Chem. Soc., 2008, 130, 446.
20 (a) Y. Lee and A. H. Hoveyda, J. Am. Chem. Soc., 2006, 128, 15604;
(b) Y. Lee, B. Li and A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131,
11625.
21 (a) D. Martin, S. Kehrli, M. d’Augustin, H. Clavier, M. Mauduit and
A. Alexakis, J. Am. Chem. Soc., 2006, 128, 8416; (b) O. Jackowski and
A. Alexakis, Angew. Chem., Int. Ed., 2010, 49, 3346.
22 H. Henon, M. Mauduit and A. Alexakis, Angew. Chem., Int. Ed., 2008,
47, 9122.
5 (a) F. Glorius, PCT Int. Appl. 2004, 35 pp. WO 2004/007465 A1; (b) D.
M. Lindsay and D. McArthur, Chem. Commun., 2010, 46, 2474.
6 (a) S. C. Cullen and T. Rovis, Org. Lett., 2008, 10, 3141; (b) J. Read de
Alaniz, M. S. Kerr, J. L. Moore and T. Rovis, J. Org. Chem., 2008, 73,
2033; (c) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2010, 132, 2860;
(d) J. Read de Alaniz and T. Rovis, Syn. lett., 2009, 1189.
7 (a) D. Baskakov, W. A. Herrmann, E. Herdtweck and S. D. Hoffmann,
Organometallics, 2007, 26, 626; For a related rigid ligand system see:
(b) L. Liu, N. Ishida, S. Ashida and M. Murakami, Org. Lett., 2011,
13, 1666.
8 J. D. Loudon and R. K. Razdan, J. Chem. Soc., 1954, 4299.
9 M. Palucki, N. S. Finney, P. J. Pospisil, M. L. Gu¨ler, T. Ishida and E.
N. Jacobsen, J. Am. Chem. Soc., 1998, 120, 948.
10 M. J. Palmer, J. A. Kenny, T. Walsgrove, A. M. Kawamoto and M.
Wills, J. Chem. Soc., 2002, 416.
23 M. K. Brown, T. L. May, C. A. Baxter and A. H. Hoveyda, Angew.
Chem., Int. Ed., 2007, 46, 1097.
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