Copper-catalyzed borylative coupling of vinylazaarenes and N-Boc imines

Article abstract of DOI:10.1039/c6cc00603e

Cu-catalyzed three-component couplings of vinylazaarenes, B₂(pin)₂, and N-Boc imines are described. Oxidation of the initially formed boronate gives azaarene-containing, Boc-protected amino alcohols with reasonable to good diastereoselectivities.

Full text of DOI:10.1039/c6cc00603e

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Copper-catalyzed borylative coupling of
vinylazaarenes and N-Boc imines†
Cite this:DOI: 10.1039/c6cc00603e
Joshua J. Smith,ab Daniel Bestab and Hon Wai Lam*ab
Received 21st January 2016,
Accepted 9th February 2016
DOI: 10.1039/c6cc00603e
www.rsc.org/chemcomm
Cu-catalyzed three-component couplings of vinylazaarenes, B2(pin)2,
and N-Boc imines are described. Oxidation of the initially formed
boronate gives azaarene-containing, Boc-protected amino alcohols
with reasonable to good diastereoselectivities.
Nitrogen-containing aromatic heterocycles (azaarenes) and
a-branched amines are common structures in biologically active
molecules. New catalytic reactions that can assemble compounds
containing both of these motifs in a convergent and stereocontrolled
manner are therefore highly valuable.1 In this context, we have
described enantioselective Pd-catalyzed additions of alkylazaarenes
to N-Boc imines,2 and enantioselective Cu-catalyzed reductive
couplings of vinylazaarenes with N-Boc imines.3 However, the
integration of such coupling reactions with the simultaneous
introduction of another, versatile functional group that can be
exploited in subsequent manipulations would open up additional
synthetic possibilities. Given the widely recognized utility of organo-
boron compounds,4 and in connection with our interest in the use of
Scheme 1 Catalytic borylative three-component couplings of imines.
azaarenes as activating groups in catalytic reactions,5–7 we were couplings of allenes with imines that give branched homoallylic
prompted to examine the borylative coupling of vinylazaarenes with amines containing an alkenylboronate (Scheme 1b).9b Extension
imines. Precedent for such a transformation is limited; although of these processes to other substrate classes would lead to
numerous borylative three-component coupling reactions have been important increases in reaction scope. Herein, we report the
described,8,9 none employ alkenylazaarenes, and to our knowledge, first examples of Cu-catalyzed borylative couplings of vinylazaarenes
only two examples employ imines (Scheme 1a and b).9 The Morken with N-Boc imines to give highly functionalized heterocycle-
group has reported enantioselective Pd-catalyzed diborations of containing building blocks (Scheme 1b).10,11
allenes, followed by the addition of imines to the resulting
Our investigation began with a search for effective conditions
bisboronates to give homoallylic amines (Scheme 1a).9a After for the three-component coupling of various vinylazaarenes and
acetylation of the amine and oxidation, b-acetamidoketones aldimines with bis(pinacolato)diboron. From these studies, we
were isolated in good yields and high enantioselectivities.9a found that stirring a solution of the vinylazaarene (1.0 equiv.),
Recently, Procter and co-workers described Cu-catalyzed borylative N-Boc aldimine (1.2 equiv.), and B2(pin)2 (1.2 equiv.) in TBME at
40 1C in the presence of CuF(PPh)3Á2MeOH (5.0 mol%) and dppf
a EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building,
The King’s Buildings, David Brewster Road, Edinburgh, EH9 3FJ, UK
b School of Chemistry, University of Nottingham, University Park, Nottingham,
NG7 2RD, UK. E-mail: hon.lam@nottingham.ac.uk
(5.0 mol%) successfully gave borylative coupling products with
high conversions.12–14 These products undergo decomposition
on silica gel, and were therefore oxidized to the corresponding
chromatographically stable primary alcohols with NaBO3Á4H2O.15
Under these conditions, a range of vinylazaarenes 1a–1h underwent
smooth reaction with the N-Boc imine 2a derived from benzaldehyde
to give azaarene-containing, Boc-protected amino alcohols 3a, 3b,
† Electronic supplementary information (ESI) available: Experimental procedures,
spectroscopic data for new compounds, and crystallographic data for 3b and 3h.
CCDC 1431894 and 1431895. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c6cc00603e
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Table 1 Borylative coupling of vinylazaarenes with imine 2aa
Table 2 Borylative coupling of vinylazaarenes with various iminesa
Entry Product
1
Yieldb (%) drc
6.5 : 1
(419 : 1)
4a
2
3
4
4b Ar = 3-MeC6H4 83
7.5 : 1
3:1 (5:1)
8.5 : 1
(18 : 1)
3.5 : 1
(5 : 1)
8 : 1
(11 : 1)
7.5 : 1
(419 : 1)
3 : 1
4c Ar = 3-ClC6H4
60
4d Ar = 4-MeOC6H4 58
4e Ar = 4-BrC6H4 60
4f Ar = 2-naphthyl 56
4g Ar = 2-MeC6H6 41d
4h Ar = 3-MeOC6H4 58
4i Ar = 4-MeC6H4 69
4j Ar = 4-MeOC6H4 60
5
6
7
a
Reactions were conducted using 0.50 mmol of vinylazaarene in TBME
8
9
(5 : 1)
3.5 : 1
(4 : 1)
4 : 1
(1.25 mL). Yields are of isolated single diastereomers unless otherwise
stated. Diastereomeric ratios were determined by 1H NMR analysis of
b
the unpurified reaction mixtures. Isolated as a mixture of diastereomers in
the same ratio as in the unpurified reaction mixture. c Unpurified 3c was
treated with Ac2O/pyridine to give 3ca to facilitate purification. d Reaction
performed at 60 1C. e Overlapping signals precluded accurate determination
of dr by 1H NMR analysis.
10
11
4k Ar = 4-FC6H4
64
3.5 : 1
12
4l
37
4 : 1
(419 : 1)
and 3d–3h (Table 1). Products containing pyridine (3a), quinoline
(3b), one of two different dimethoxypyrimidines (3d and 3e),
5-phenylthiazole (3f), benzoxazole (3g), or benzothiazole (3h)
groups were prepared in reasonable to good yields and diastereo-
selectivities (up to 73% yield over two steps and up to 7 : 1 dr).
The relative configurations of the products were assigned by
analogy with those of 3b and 3h, which were determined by X-ray
crystallography to be the anti-diastereomers.16 When 2-vinylquin-
oxaline was employed as the substrate, acetylation of the primary
alcohol 3c was performed to give 3ca to facilitate separation from
pinacol, a byproduct of the boronate oxidation.15
a
Reactions were conducted using 0.50 mmol of vinylazaarene in TBME
b
c
(1.25 mL). Yield of isolated products. Diastereomeric ratios were
determined by 1H NMR analysis of the unpurified reaction mixtures.
Ratios in parentheses are those of the isolated product. Where ratios in
parentheses are absent, the products were isolated in the same ratio as
d
in unpurified reaction mixture. A second fraction consisting of a 2 : 1
mixture of diastereomers was also obtained in 17% yield.
Table 2 presents the results of borylative coupling of various
vinylazaarenes with a range of N-Boc aldimines, which gave
products with diastereoselectivities ranging from 3 : 1 dr (entry 8) to
8.5 : 1 dr (entry 4). Imines derived from benzaldehydes containing
methyl (entries 2, 7, and 9), fluoro (entries 1 and 11), chloro (entry 3),
bromo (entry 5), or methoxy substituents (entries 4 and 8) at various
positions of the aromatic ring are compatible with this process.
The N-Boc imine derived from cyclohexane carboxaldehyde also
successfully underwent borylative coupling, although with moderate
conversion and diastereoselectivity (entry 12).
Fig. 1 Possible stereochemical model.
A tentative stereochemical model that could account for the
anti-selectivity of these reactions involves the addition of an
E-azaallylcopper species to the imine in a chair-like transition
state (Fig. 1). However, we cannot exclude alternative models
involving boat-like structures or open transition states.
To further demonstrate the synthetic utility of the borylative
coupling products, the reaction of vinylpyrimidine 1e and N-Boc Scheme 2 Sequential borylative coupling and Suzuki reaction.
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imine 2a was repeated to give alkylboronate 5. Without isolation,
5 was reacted with bromobenzene under Suzuki–Miyaura cross-
coupling conditions described previously17 using RuPhos18 as the
ligand, to give the phenylated product 6 in 47% yield over two steps
as a single diastereoisomer (crude dr 6 : 1) (Scheme 2).19,20
The Boc group of the products may be removed under acidic
conditions, as demonstrated by the deprotection of 3b using
TMSCl in MeOH,2,3 which provided the bishydrochloride salt
7 in 499% yield (eqn (1)).
(1)
In conclusion, we have demonstrated the utility of vinyl-
azaarenes as substrates for copper-catalyzed borylative couplings
with N-Boc imines. The reactions provide, after oxidation of the
initially formed alkylboronates, azaarene-containing, Boc-protected
amino alcohols with moderate-to-good diastereoselectivities. Future
work will be focused on the development of enantioselective
variants of this process.21
9 For borylative three-component coupling reactions of allenes and
imines, see: (a) J. D. Sieber and J. P. Morken, J. Am. Chem. Soc., 2006,
128, 74–75; (b) J. Rae, K. Yeung, J. J. W. McDouall and D. J. Procter,
Angew. Chem., Int. Ed., 2016, 55, 1102–1107.
10 For Cu-catalyzed three-component borylative aldol reactions of
a,b-unsaturated carbonyl compounds with carbonyl compounds,
see ref. 8e.
We thank the EPSRC (Industrial CASE studentship to J. J. S.
and Leadership Fellowship to H. W. L, grant no. EP/I004769/1
and EP/I004769/2), GlaxoSmithKline, and the ERC (Starting
Grant No. 258580) for financial support. We thank Dr. William
Lewis at the University of Nottingham for X-ray crystallography,
and Dr. Alan Nadin (GlaxoSmithKline) for helpful discussions.
11 For examples of biologically active compounds containing a 2-(amino-
alkyl)azaarene substructure, which are produced using the methodology
described herein, see references cited within ref. 2.
12 In several cases, increasing the temperature significantly above
40 1C led to appreciable quantities of the products resulting from
1,4-boration of the vinylazaarene without coupling to the imine.
Attempts to decrease the reaction times by increasing the concen-
tration led to solubility problems.
13 Other bidentate ligands examined included DPEphos, dppe, dppbz,
and bipy. No significant impact on the rate of the reaction was
observed, but compared with dppf, these ligands gave products in
poorer diastereomeric ratios. Using CuF(PPh)3Á2MeOH without an
additional bidentate ligand gave low yields of borylative coupling
products in poor diastereomeric ratios, along with significant
quantities of products resulting from 1,4-boration of the vinylazaarene
without coupling to the imine.
Notes and references
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2 D. Best, S. Kujawa and H. W. Lam, J. Am. Chem. Soc., 2012, 134,
18193–18196.
PPh3 (15.0 mol%) or dppf (5.0 mol%), with or without MeOH (10.0 mol%
or 5.0 equiv.), did not provide any products. For PPh3- or dppf-catalyzed
´
1,4-boration of a,b-unsaturated ketones, see: A. Bonet, H. Gulyas and
´
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