A second-generation ligand for the enantioselective rhodium-catalyzed addition of arylboronic acids to alkenylazaarenes

Article abstract of DOI:10.1039/c4cc00340c

A 2,4,6-trialkylanilide-containing chiral diene has been identified as a superior ligand for the enantioselective rhodium-catalyzed arylation of alkenylazaarenes with arylboronic acids.

Full text of DOI:10.1039/c4cc00340c

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A second-generation ligand for the
enantioselective rhodium-catalyzed addition of
arylboronic acids to alkenylazaarenes†
Cite this: Chem. Commun., 2014,
50, 2865
Received 15th January 2014,
Accepted 24th January 2014
Iain D. Roy,a Alan R. Burns,ab Graham Pattison,a Boris Michel,a Alexandra J. Parkerc
and Hon Wai Lam*ab
DOI: 10.1039/c4cc00340c
www.rsc.org/chemcomm
Table 1 Ligand evaluation for arylation of 1aa
A 2,4,6-trialkylanilide-containing chiral diene has been identified as
a superior ligand for the enantioselective rhodium-catalyzed aryla-
tion of alkenylazaarenes with arylboronic acids.
As part of a program aimed at the preparation of enantioenriched
chiral azaarene-containing compounds,1 we have focused upon an
underexploited strategy in asymmetric synthesis, namely the utiliza-
tion of the CQN moiety within certain azaarenes to activate adjacent
functionality in enantioselective catalysis.2–4 In this context, we have
reported1b the enantioselective rhodium-catalyzed 1,4-arylation5–8 of
b-substituted alkenylazaarenes with arylboronic acids using a second-
ary amide-containing chiral diene9–11 ligand L1 (see Table 1, entry 1),
which builds upon early studies by the groups of Lautens12a and
Entry
1b
Ligand
X
Conversion (%)
67% yield
ee (%)
92
L1
2
3
4
5
6
7
8
9
L2
L3
L4
L5
L6
L7
L8
L9
NHCy
NCy2
NHBn
NBn2
NMe2
NHPh
NH(2,4,6-Me3C6H2)
NH[2,4,6-(i-Pr)3C6H2]
>95
28
>95
81
91
58
90
59
88
85
46
76
96
99
ˆ 12b
Genet using vinylazaarenes. Although L1 was highly effective, it
was of interest to determine whether a ligand of this complexity,
possessing stereochemical elements additional to those of the chiral
diene component, was actually necessary for optimal results.13
Herein, we report a simpler ligand that provides results superior to
those obtained using L1, along with a more comprehensive evalua-
tion of the scope of the reaction.
First, various analogues of L1 were prepared and evaluated in
the enantioselective addition of 4-methylphenylboronic acid to
2-alkenylquinoline 1a (Table 1), a reaction that gave 2a in 67% yield
33
>95
a
Reactions were conducted using 0.10 mmol of 1a (0.2 M). Conversions
were determined by 1H NMR analysis of the unpurified reaction mixtures.
b
Enantiomeric excesses were determined by chiral HPLC analysis. Ref. 1b.
and 92% ee in our original study.1b The conditions employed were L3 was noticeably inferior (entry 3). Ligands L4 and L5, which contain
identical to those we described previously.1b Ligand L2, which lacks one or two benzyl groups, respectively, provided reasonable results
the pyrrole moiety on the cyclohexane, provided 2a in high conver- (entries 4 and 5), but the enantioselectivities were lower compared
sion but the enantioselectivity was slightly lower (entry 2) compared with L1. The dimethylamide L6 gave high conversion but the reaction
with that obtained using L1 (entry 1). However, the dicyclohexylamide was poorly enantioselective (46% ee, entry 6). Next, ligands L7–L9
containing anilide groups were studied (entries 7–9), and of these, the
2,4,6-triisopropylanilide L9 provided the best results, giving 2a in
>95% conversion and 99% ee (entry 9).
a EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building,
The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK
b School of Chemistry, University of Nottingham, University Park, Nottingham,
NG7 2RD, UK. E-mail: hon.lam@nottingham.ac.uk; Tel: +44 (0)115-748-4677
c AstraZeneca Process Research and Development, Charter Way,
Further confirmation of the superior enantioselectivities imparted
by this new triisopropylanilide ligand L9 was provided by repeating
representative reactions described in our original study1b using L9 in
place of L1 (Table 2). These results indicate that while in most cases
the isolated yields of the products with both ligands are comparable,
the enantioselectivities are higher using L9 (2a, 2b, 2c, 2e, and 2f).
One exception was the addition of 4-methylphenylboronic acid to a
Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectroscopic data for new compounds, and crystallographic data. CCDC
976345 and 976346. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc00340c
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Table 2 Comparison of ligand L9 with L1a
Table 3 Arylation of alkenylazaarenes with 4-methylphenylboronic acida
a
Reactions were conducted using 0.50 mmol of alkenylazaarene (0.2 M).
Yields are of isolated material. Enantiomeric excesses were determined
b
c
by chiral HPLC analysis. Results taken from ref. 1b. Reaction con-
ducted using 0.30 mmol of alkenylazaarene.
a
Reactions were conducted using 0.30 mmol of alkenylazaarene (0.2 M).
substrate containing a 4,5-diphenyloxazole as the activating group,
which gave 2d in 77% ee using L9, and this result is inferior to that
obtained using ligand L1 (89% ee). Interestingly, the inferiority of L9
compared with L1 with this substrate appeared to be restricted to the
use of 4-methylphenylboronic acid; when 3-methylphenylboronic acid
was employed, L9 provided the product 2e in a higher enantioselec-
tivity. The reasons for these contrasting results are not currently
known.
Yields are of isolated material. Enantiomeric excesses were determined by
b
chiral HPLC analysis. Enantiomeric excess determined after hydrolysis to
c
the secondary amide. The stereochemistry of 2m was determined by X-ray
d
crystallography, CCDC 976346. The structure of the alkenylazaarene
substrate 1m was determined by X-ray crystallography, CCDC 976345.
To explore the scope of the process with the second generation
ligand L9 more comprehensively, a range of previously reported and
new alkenylazaarenes were reacted with 4-methylphenylboronic acid
(Table 3). While substrates containing pyrimidine or benzoxazole,
azaarenes that have already been demonstrated to be efficient
activating groups in our original study,1b underwent arylation effi-
Fig. 1 Difference in conjugation between alkenyltetrazoles 1l and 1m.
ciently with excellent enantioselectivities as expected (2g and 2k), to a greater degree of activation. With respect to the b-substituent on
further examples demonstrate that other azaarenes are also effective. the alkene, the process is tolerant of simple alkyl groups (2i and 2j), a
These examples include p-deficient azaarenes such as pyrazine (2h), a cyclopropane (2h), an ether (2g), and aryl groups (2k, 2l, 2m, and 2o).
chloropyrimidine (2i), and a 4,6-bis(aryl)-1,3,5-triazine (2j), as well as
A range of arylboronic acids are compatible with this pro-
p-excessive azaarenes such as benzothiazole (2l), a 1,3,4-oxadiazole cess, as demonstrated by the results presented in Table 4.
(2m), and a tetrazole (2o). A pyrazine-containing substrate was only Arylboronic acids containing substituents such as methyl
moderately reactive, providing product 2h in 48% yield, though in (entries 2 and 9), halogen (entries 3 and 10), or alkoxy (entries
99% ee. Although alkenyltetrazole 1l was unreactive (none of 2n was 4 and 10) groups reacted smoothly with various alkenyl-
obtained), its regioisomer 1m provided 2o in 64% yield and 95% ee. azaarenes in good yields and high enantioselectivities. Aryl-
The difference in reactivities between 1l and 1m can be understood boronic acids containing strong electron-withdrawing groups
by consideration of their conjugation patterns (Fig. 1). Whereas the such as ester, trifluoromethyl, or even nitro substituents were
alkene is conjugated only with the CQN group of the tetrazole in 1l, it also effective (entries 5–7). A sterically encumbering ortho-
is conjugated with both the CQN and NQN moieties in 1m, leading substituent on the arylboronic acid was also tolerated (entry 2).
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Table 4 Arylation of alkenylazaarenes with various arylboronic acidsa
In summary, a more in-depth evaluation of chiral diene ligands
for the enantioselective addition of arylboronic acids to alkenylazaar-
enes has resulted in the identification of a second-generation ligand
L9 containing a 2,4,6-triisopropylanilide moiety that is superior to our
first generation ligand L1. Not only does this new chiral diene result
in generally superior enantioselectivities, it is simpler in structure. A
more thorough assessment of the scope of the process demonstrated
that the effectiveness of ligand L9 is fairly general across a range
alkenylazaarenes and arylboronic acids. Further experimental and
theoretical14 investigations of anilide-containing chiral dienes in
asymmetric catalysis are planned, and will be reported in due course.
This work was supported by the EPSRC, Pfizer, and the
University of Edinburgh. The EPSRC is gratefully acknowledged
for the award of a Leadership Fellowship to H.W.L. We thank
Dr Gary S. Nichol and Stewart Franklin at the University of
Edinburgh for X-ray crystallography and technical assistance,
respectively. We thank the EPSRC National Mass Spectrometry
Facility for providing high-resolution mass spectra.
Yieldb eec
Entry Product
(%)
(%)
1
2
3
2p Ar = Ph
2q Ar = 2-MeC6H4
2r Ar = 4-FC6H4
89
>95
78
99
97
99
4
5
2s Ar = 4-MeOC6H4
2t Ar = 3-EtO2CC6H4
82
62
98
93d
6
7
2u Ar = 3,5-(F3C)2C6H3
2v Ar = 4-O2NC6H4
92
85
96e
94
Notes and references
1 (a) L. Rupnicki, A. Saxena and H. W. Lam, J. Am. Chem. Soc., 2009,
131, 10386–10387; (b) G. Pattison, G. Piraux and H. W. Lam, J. Am.
Chem. Soc., 2010, 132, 14373–14375; (c) A. Saxena, B. Choi and
H. W. Lam, J. Am. Chem. Soc., 2012, 134, 8428–8431; (d) C. Fallan and
H. W. Lam, Chem.–Eur. J., 2012, 18, 11214–11218; (e) D. Best, S. Kujawa
and H. W. Lam, J. Am. Chem. Soc., 2012, 134, 18193–18196; ( f ) A. J.
Simpson and H. W. Lam, Org. Lett., 2013, 15, 2586–2589.
2 D. Best and H. W. Lam, J. Org. Chem., 2014, 79, DOI: 10.1021/jo402414k.
3 For Ni-catalyzed additions of organometallics to 4-alkenylpyridines
with low enantioselectivities (r15% ee), see: I. N. Houpis, J. Lee,
I. Dorziotis, A. Molina, B. Reamer, R. P. Volante and P. J. Reider,
Tetrahedron, 1998, 54, 1185–1195.
8
9
2w Ar = 2-naphthyl
2x Ar = 3,5-Me2C6H3
62
85
98
99
4 For catalytic asymmetric Michael additions of nitroalkanes and
anthrone to 4-nitro-5-styrylisoxazoles, see: (a) A. Baschieri, L. Bernardi,
A. Ricci, S. Suresh and M. F. A. Adamo, Angew. Chem., Int. Ed., 2009, 48,
9342–9345; (b) H.-W. Sun, Y.-H. Liao, Z.-J. Wu, H.-Y. Wang, X.-M. Zhang
and W.-C. Yuan, Tetrahedron, 2011, 67, 3991–3996.
5 A seminal reference: M. Sakai, H. Hayashi and N. Miyaura, Organo-
metallics, 1997, 16, 4229–4231.
6 The first enantioselective example: Y. Takaya, M. Ogasawara,
T. Hayashi, M. Sakai and N. Miyaura, J. Am. Chem. Soc., 1998, 120,
5579–5580.
10
2y Ar = 3-Cl-4-i-PrOC6H3 63
99
a
Reactions were conducted using 0.30 mmol of alkenylazaarene
b
c
d
(0.2 M). Isolated yield. Determined by chiral HPLC analysis. Enan-
tiomeric excess determined on a derivative obtained after treatment of
2t with LiOH in THF/MeOH/H2O. Enantiomeric excess determined
e
after demethylation of the methoxy groups using BBr3.
7 For reviews, see: (a) T. Hayashi and K. Yamasaki, Chem. Rev., 2003,
103, 2829–2844; (b) K. Yoshida and T. Hayashi, in Modern Rhodium-
Catalyzed Organic Reactions, ed. P. A. Evans, Wiley-VCH, Weinheim,
2005, ch. 3, pp. 55–77; (c) H. J. Edwards, J. D. Hargrave, S. D. Penrose
and C. G. Frost, Chem. Soc. Rev., 2010, 39, 2093–2105; (d) P. Tian,
H.-Q. Dong and G.-Q. Lin, ACS Catal., 2011, 2, 95–119.
8 For a review of Rh-catalyzed carbon–carbon bond-forming reactions
of organometallic compounds, see: K. Fagnou and M. Lautens,
Chem. Rev., 2003, 103, 169–196.
9 For seminal references describing chiral dienes in asymmetric cata-
lysis, see: (a) T. Hayashi, K. Ueyama, N. Tokunaga and K. Yoshida,
J. Am. Chem. Soc., 2003, 125, 11508–11509; (b) C. Fischer, C. Defieber,
T. Suzuki and E. M. Carreira, J. Am. Chem. Soc., 2004, 126, 1628–1629.
10 For reviews of chiral diene ligands, see: (a) R. Shintani and
T. Hayashi, Aldrichimica Acta, 2009, 42, 31–38; (b) J. B. Johnson and
T. Rovis, Angew. Chem., Int. Ed., 2008, 47, 840–871; (c) C. Defieber,
H. Grutzmacher and E. M. Carreira, Angew. Chem., Int. Ed., 2008, 47,
4482–4502.
This process can also be conducted on a larger scale using
lower loadings of the arylboronic acid and catalyst. For exam-
ple, arylation of alkenylpyrimidine 1h on a 5.0 mmol scale
with 4-methoxyphenylboronic acid (1.5 equiv.), using thermal
heating at 70 1C in the presence of 2.0 mol% of the rhodium–
chiral diene complex, provided 2s in 75% yield (1.27 g) and
96% ee (eqn (1)).
11 For selected, recent examples of chiral dienes in catalytic asymmetric 1,4-
and 1,6-addition reactions, see: (a) C. Shao, H.-J. Yu, N.-Y. Wu, P. Tian,
R. Wang, C.-G. Feng and G.-Q. Lin, Org. Lett., 2011, 13, 788–791;
(b) K. Sasaki and T. Hayashi, Tetrahedron: Asymmetry, 2012, 23,
373–380; (c) T. Nishimura, A. Noishiki and T. Hayashi, Chem. Commun.,
2012, 48, 973–975; (d) Y.-C. Chung, D. Janmanchi and H.-L. Wu, Org.
Lett., 2012, 14, 2766–2769; (e) K. Sasaki, T. Nishimura, R. Shintani,
(1)
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ˆ
E. A. B. Kantchev and T. Hayashi, Chem. Sci., 2012, 3, 1278–1283;
( f ) T. Nishimura, Y. Takiguchi and T. Hayashi, J. Am. Chem. Soc.,
2001, 123, 5358–5359; (b) R. Amengual, V. Michelet and J.-P. Genet,
Tetrahedron Lett., 2002, 43, 5905–5908.
2012, 134, 9086–9089; (g) Z.-T. He, Y.-B. Wei, H.-J. Yu, C.-Y. Sun, C.-G. 13 For application of a simpler amide-containing chiral diene L5 in
Feng, P. Tian and G.-Q. Lin, Tetrahedron, 2012, 68, 9186–9191; (h) H.-J.
Yu, C. Shao, Z. Cui, C.-G. Feng and G.-Q. Lin, Chem.–Eur. J., 2012, 18,
13274–13278; (i) J. Keilitz, S. G. Newman and M. Lautens, Org. Lett., 2013,
enantioselective rhodium-catalyzed arylations of electron-deficient
alkenylarenes, including a 5-nitro-2-alkenylpyridine, see: A. Saxena
and H. W. Lam, Chem. Sci., 2011, 2, 2326–2331.
15, 1148–1151; ( j) M. M. Hansmann, A. S. K. Hashmi and M. Lautens, 14 For computational studies of chiral diene ligands, see ref. 11e and:
Org. Lett., 2013, 15, 3226–3229; (k) A. A. Friedman, J. Panteleev, J. Tsoung,
V. Huynh and M. Lautens, Angew. Chem., Int. Ed., 2013, 52, 9755–9758.
12 For Rh-catalyzed additions of arylboronic acids to vinylazaarenes
resulting in achiral products, see: (a) M. Lautens, A. Roy,
(a) E. A. B. Kantchev, Chem. Commun., 2011, 47, 10969–10971;
(b) S. Gosiewska, J. A. Raskatov, R. Shintani, T. Hayashi and
J. M. Brown, Chem.–Eur. J., 2012, 18, 80–84; (c) Y. Luo, N. G. Berry
and A. J. Carnell, Chem. Commun., 2012, 48, 3279–3281; (d) E. A. B.
Kantchev, Chem. Sci., 2013, 4, 1864–1875.
´
K. Fukuoka, K. Fagnou and B. Martın-Matute, J. Am. Chem. Soc.,
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