Rhodium-catalyzed asymmetric hydroboration of γ,δ-unsaturated amide derivatives: δ-borylated amides

Article abstract of DOI:10.1039/c8cc01563e

γ,δ-Unsaturated amides in which the alkene moiety bears an aryl or heteroaryl substituent undergo regioselective rhodium-catalyzed δ-borylation by pinacolborane to afford chiral secondary benzylic boronic esters. The results contrast the γ-borylation of γ,δ-unsaturated amides in which the disubstituted alkene moiety bears only alkyl substituents; the reversal in regiochemistry is coupled with a reversal in the sense of π-facial selectivity.

Full text of DOI:10.1039/c8cc01563e

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: G. L. Hoang, S.
Zhang and J. M. Takacs, Chem. Commun., 2018, DOI: 10.1039/C8CC01563E.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 5
View Article Online
DOI: 10.1039/C8CC01563E
Journal Name
COMMUNICATION
Rhodium-catalyzed asymmetric hydroboration of γ,δ-unsaturated
amide derivatives: δ-borylated amides‡
G. L. Hoang, S. Zhang and J. M. Takacs*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
R
CH2
γ,δ-Unsaturated amides in which the alkene moiety bears an aryl
or heteroaryl substituent undergo regioselective rhodium-
catalyzed δ-borylation by pinacolborane to afford chiral secondary
benzylic boronic esters. The results contrast the γ-borylation of
γ,δ-unsaturated amides in which the disubstituted alkene moiety
bears only alkyl substituents; the reversal in regioschemistry is
coupled with a reversal in the sense of π-facial selectivity.
2015
Toste,
H
2014
2016
Watson,
Morken,
B(pin)
B(pin)
Ar
N2BF4
Pd cat
B2(pin)2,
Ar
X
B2(pin)2
Ni cat
NMe3OTf
Ar
R
R
Pd cat
B(OR)2
Ar
R
pinBH
Ar
X
B(dan)
B(pin)
2013
Chiral boronic acid derivatives are useful building blocks for
the synthesis of biologically active natural products and
pharmaceutical intermediates.1 Structures in which boron is
attached to the same carbon as an aryl or heteroaryl
substituent (i.e., benzylic boronic acid derivatives) are of
particular synthetic interest. The catalytic asymmetric
hydroboration (CAHB) of styrene and related vinyl arenes to
yield benzylic boronic esters was first reported in the mid-
1980s.2,3 The observed regioselectivity is often attributed to
Ar
R
R
Pd cat
H2, Co cat
pinBH Rh cat
R4
2017
Yun,
Hall,
Lu,
2011
O
R1
Ar
N
R2 R3
This work:
• 24 examples of direct -borylation of unsaturated amides
δ
• high regioselectivity (up to >20:1 rr)
• high enantioselectivity (up to 97:3 er)
• high diastereoselectivity (dr) with chiral substrates
the formation of a π-benzyl metal intermediate en route to the
benzyl borylated product.3c,d In spite of its long history and
foundational impact on CAHB,4 the chemistry has largely been
limited to simple vinyl arenes; Rh(I)/QUINAZOLINE5 and
Cu(I)/DTBM-SEGPHOS6 are among a few catalyst systems that
Fig. 1 Recent approaches in preparation of chiral benzylic boronic esters.
aryldiazonium salt, and bis(pinacolato)diboron (B2pin2); the
enantioselectivity is controlled by a cooperative chiral anion
phase transfer catalyst in conjunction with a palladium
catalyst.10 Watson constructed the desired chiral boronic ester
derivatives via stereospecific nickel-catalyzed Miyaura
borylation of a chiral ammonium salt precursor by B2pin2.11
Most recently, Lu introduced a one-pot cobalt-catalyzed
sequential hydroboration/hydrogenation of internal alkynes.12
Other recently developed methods for the preparation of
benzylic boron derivatives include enantioselective conjugate
borylation,13 enantioselective allylic borylation14 and
asymmetric hydrogenation15 as well as functionalization16 of
vinyl boronates. Herein, we report that γ,δ-unsaturated
carbonyl compounds, in which the disubstituted alkene moiety
bears an aryl or heteroaryl substituent, undergo efficient CAHB
to yield functionalized chiral benzylic boron derivatives.
exhibit high selectivity for unfunctionalized
arenes.
β-substituted vinyl
Figure 1 highlights several alternative methods for the
preparation of chiral benzylic boron derivatives that have
attracted recent interest. Hall,7 Yun,8 and Morken9
independently reported group-selective cross-coupling of
chiral gem-diboron derivatives. The methods of Hall and Yun
exploit stereoretentive Pd-catalyzed cross-coupling of chiral
1,1-diborylalkanes. Morken uses enantiotopic group-selective
cross-coupling of achiral 1,1-diborylalkane derivatives using a
chiral palladium catalyst. Toste developed a novel three
component coupling strategy using an α-olefin, an
We have explored rhodium-catalyzed directed-CAHBs of a
range of β,γ-unsaturated substrates with varying alkene
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
View Article Online
DOI: 10.1039/C8CC01563E
COMMUNICATION
Journal Name
substitution patterns and bearing carbonyl,17 oxime ether,18 low conversion (50–80% after 12 hours), lower regioselectivity
and phosphonate19 functionalities. To expand the substrate (<4:1 rr) and consequently a low isolated yield of 4a (18–
scope, we are investigating the homologous γ,δ-unsaturated 28%).24 In addition to the N-benzyl amide 3a, the N-phenyl
substrates20 and recently reported that γ,δ-unsaturated amide 5a and the morpholine-derived tertiary amide 5b are
amides
substituents, undergo efficient regio- and enantioselective
borylation (Fig. 2). For example, benzyl amide (R = (CH2)2Ph)
affords the -borylated product (81%) in a >20:1 regioisomer reaction conditions for a series of γ,δ-unsaturated benzyl
ratio (rr) and a high enantiomer ratio (96.5:3.5 er).21 We now amides
. Using ligands B1–3, the most efficient catalyst
1
, in which the alkene moiety bears only alkyl also good substrates; CAHB affords
76%, 94:6 er) and B2: 78%, 95.5:4.5 er), respectively.
Figure 3 shows the results obtained under the standard
δ-borylated product 6 (B1:
γ
-
7 (
1
γ
2
3
report that the analogous γ,δ-unsaturated benzyl amide 3a (R system varied among the different substrates. For example,
= Ph), in which the alkene moiety instead bears an aryl although the N,N-diphenyl ligand B3 gives relatively low
substituent, behaves much differently. Using the same catalyst enantioselectivity compared to B1 and B2 for substrate 3a, it
system, CAHB proceeds with good regiocontrol (>20:1 rr) to gives the highest level of induction for 3b, a substrate bearing
give a chiral, secondary benzylic boronic ester, i.e., 4a (89%, a relatively electron poor aryl substituent (i.e., 4-CF3C6H4).
95:5 er). Unlike product
2
,
4a is the result of
δ-borylation not CAHB with B3 affords δ-borylated amide 4b (78%, 95:5 er); B1
-facial selectivity is reversed; and B2 give comparable yields but only 91:9 and 90:10 er,
γ
-borylation, and the sense of
π
pinBH adds to the opposite faces of the
substrates.22
π
-system in the two respectively. Substrates 4c and 4d, 4-fluorophenyl and 4-
chlorophenyl derivatives, undergo CAHB in good yield and
While we have not carried extensive ligand optimization enantioselectivity (75–77%, 95:5 er). Aryl derivatives bearing
studies, the series of BINOL-derived phosphoramidites B1 B5 alkoxy group(s) at the para- and/or meta-positions undergo
–
indicate that an N-phenyl substituent on the phosphoramidite efficient CAHB (71–80%, >20:1 rr) as illustrated by the 4-
ligand is needed to achieve good conversion and high levels of methoxyphenyl (4e, 96:4 er), 3 methoxyphenyl (4f, 97:3 er),
regio- and enantioselectivity (Fig. 2).23 Ligands B1 and B2 give 3,5-dimethoxyphenyl (4g, 96.5:3.5 er) and 3,4-dialkoxyphenyl
the major product 4a in high yield and enantioselectivity (87–
(4h, 92:8 er) derivatives. The product bearing a 2-
89%, 95:5 er). Ligand B3, the corresponding N,N-diphenyl methoxyphenyl-substituent (4i, 82%, >20:1 rr) is obtained in
derivative, also affords 4a in good yield (87%) and with high good yield but with lower enantioselectivity (85:15 er); the
regioselectivity (>20:1 rr), but the er is lower in this case corresponding 2-methylphenyl derivative is somewhat more
(85:15); however, B3 proves more successful with other efficient (4j, 84%, 93:7 er). A series of four heteroaromatic
substrates (vide infra). The N,N-dibenzyl ligand B4 and the substrates, although more sluggish to react, undergo CAHB
more rigid indoline- derived phosphoramidite B5 afford yielding 4k–n with good regio and enantioselectivity (69–73%
catalysts giving relatively
yield, 92:8–97:3 er, 11–>20:1 rr); three equivalents of pinBH
are employed to achieve complete conversion in 12 hours.
Substrate
phenethyl amide moiety, undergoes highly regioselective
CAHB (>20:1 rr) (Fig. 4). CAHB/oxidation of using ligand (R)-
B1 affords (5R)- (82%, 94.5:5.5 dr); the yield and
enantioselectivity are comparable to that obtained for the
parent substrate 3a CAHB using (S)-B1 generates the
diastereomer (5S)- in similar yield (80%) but with a somewhat
8, chiral by virtue of the stereodefined (R)-
8
9
.
9
diminished diastereomer ratio (91:9 dr) indicating a modest
matched/mismatched case of double stereodifferentiation.
Chiral substrate 10 also undergoes largely catalyst-controlled
diastereoselective δ-borylation. CAHB/oxidation using (R)-B1
gives predominantly (2R,5R)-11 (79%, 91:9 dr); (S)-B1 gives
predominantly (2R,5S)-11 (79%, 92:8 dr). In contrast, the anti-
β-silyloxybenzyl amide 12 undergoes CAHB/oxidation with
lower diastereoselectivity and exhibits strong
a
matched/mismatched effect. (R)-B2 affords (2S,3S,5R)- 13
(75%, 86:14 dr); the catalyst employing (S)-B2 exhibits lower
reactivity (i.e., only 85% conversion after 12 hours) and gives
the same major diastereomer of 13 but with much lower
diastereoselectivity (67:33 dr).
The question naturally arises, why do 3a and related
substrates afford
modest, but energetically significant, matched/mismatched
change in diastereoselectivity for CAHB of chiral amide (Fig.
δ-borylation while 1 gives γ-borylation? The
8
Fig. 2 Regiocontrolled CAHB of γ,δ-unsaturated amides: the effect of aliphatic
and aromatic substituents.
4) indicates that the resident stereogenic center is positioned
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 5
View Article Online
DOI: 10.1039/C8CC01563E
Journal Name
COMMUNICATION
Fig. 3 Substrate scope for CAHB of aryl-substituted γ,δ-unsaturated amides. a 3.0 equivalents of pinBH are used.
close to the rhodium-complexed alkene as one would expect in with high regioselectivity (75–77% yield, >20:1 rr), but
a carbonyl-directed CAHB. The ester moiety in 14 and more so compared to amides 3a 5a and 5b, the level of
the TIPS ether in 16 are less likely to direct the rhodium- enantioselectivity is lower, 85:15 for ester 14 and 90:10 er for
,
catalyzed reaction. Each undergoes CAHB in good yield and
TIPS ether 16. Furthermore, in the direct competition between
equivalent amounts of 3a and 16 for a limiting amount of
pinBH, 3a is consumed somewhat faster.25 The one carbon
homologue of 3a, that is, δ,ε-unsaturated amide 18, increases
the distance between directing group and the alkene; CAHB
affords the benzylic, ε-borylated product 19 (78%, >20:1 rr,
90.5:9.5 er). These results seem to indicate that the aryl
substituent directs the regiochemistry, but the nature of the
directing group is important in determining the level of
catalyst-controlled enantioselectivity.
In conclusion, we report the
δ-borylation of γ,δ-
unsaturated amides bearing an aryl/heteroaryl substituent on
the alkene. The results contrast those obtained for CAHB of
γ,δ-unsaturated amides bearing only alkyl substituents on the
alkene, which differ both in terms of regioselectivity and π-
facial selectivity. A brief ligand survey suggests that an N-aryl
substituent is a necessary feature of the BINOL-derived
phosphoramidite ligand. While chiral phosphoramidites26 and
BINOL-derived ligands27 have found extensive use in
asymmetric catalysis, phosphoramidites derived from N-aryl
amines have less commonly been used; their requirement here
is somewhat unusual.24,28 The reaction exhibits a fairly broad
scope with respect to vinyl arene moiety; the successful use of
furan and thiophene derivatives and the catalyst-controlled
Fig. 4 Diastereoselective CAHB/oxidation of chiral substrates. Unless otherwise
noted, the reaction conditions employ 1.0% [Rh(nbd)2BF4/2 B], 1.5 pinBH in THF
(40 °C, 12 h) followed by oxidation (H2O2, aq NaOH, rt, 1 h); the reported yields
are for the isolated mixture of inseparable diastereomers. 3.0% [Rh(nbd)2BF4/2
diastereoselective
δ
-borylation of certain chiral substrates are
a
B
]. b NMR yield. c ca. 85% conversion.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
View Article Online
DOI: 10.1039/C8CC01563E
COMMUNICATION
Journal Name
7
8
9
J. C. H. Lee, R. McDonald and D. G. Hall, Nat. Chem., 2011,
894–899.
X. Feng, H. Jeon and J. Yun, Angew. Chem., Int. Ed., 2013, 52
3989–3992.
C. Sun, B. Potter and J. P. Morken, J. Am. Chem. Soc., 2014,
136, 6534–6537.
3
,
,
10 H. M. Nelson, B. D. Williams, J. Miró and F. D. Toste, J. Am.
Chem. Soc., 2015, 137, 3213–3216.
11 C. H. Basch, K. M. Cobb and M. P. Watson, Org. Lett., 2016,
18, 136–139.
12 J. Guo, B. Cheng, X. Shen and Z. Lu, J. Am. Chem. Soc., 2017,
139, 15316–15319.
13 J. A. Schiffner, K. Müther and M. Oestreich, Angew. Chem.,
Int. Ed., 2010, 49, 1194–1196.
14 A. Guzman-Martinez and A. H. Hoveyda, J. Am. Chem. Soc.,
2010, 132, 10634–10637.
Fig. 5 Other directing groups exhibit lower levels of enantioselectivity.
15 (a) C. Margarita and P. G. Andersson, J. Am. Chem. Soc.,
2017, 139, 1346–1356; (b) J. J. Verendel, O. Pamies, M.
Dieguez and P. G. Andersson, Chem. Rev., 2014, 114, 2130–
2169.
16 M. Silvi, C. Sanford and V. K. Aggarwal, J. Am. Chem. Soc.,
2017, 139, 5736–5739.
17 (a) S. M. Smith, G. L. Hoang, R. Pal, M. O. B. Khaled, L. S. W.
Pelter, X. C. Zeng and J. M. Takacs, Chem. Commun., 2012,
48, 12180–12182; (b) S. M. Smith, M. Uteuliyev and J. M.
Takacs, Chem. Commun., 2011, 47, 7812–7814; (c) S. M.
Smith and J. M. Takacs, Org. Lett., 2010, 12, 4612–4615; (d)
of particular note. Whether or not δ-borylation is the result of
carbonyl-directed CAHB is mechanistically interesting but does
not greatly impact the potential utility of the process.
Nonetheless, the nature of the directing group is important to
the level of enantioselectivity. Further studies on the influence
of aryl-substituents on directed-CAHBs are in progress.
Funding from the NIH National Institutes of General
Medical Sciences (R01 GM100101) is gratefully acknowledged.
We thank T. Nguyen (UNL) for some preliminary experiments.
S. M. Smith and J. M. Takacs, J. Am. Chem. Soc., 2010, 132
,
1740–1741; (e) S. M. Smith, N. C. Thacker and J. M. Takacs, J.
Am. Chem. Soc., 2008, 130, 3734–3735.
18 V. M. Shoba, N. C. Thacker, A. J. Bochat and J. M. Takacs,
Angew. Chem., Int. Ed., 2016, 55, 1465–1469.
Conflicts of interest
There are no conflicts to declare.
19 S. Chakrabarty and J. M. Takacs, J. Am. Chem. Soc., 2017,
139, 6066–6069.
20 (a) G. L. Hoang, Z.-D. Yang, S. M. Smith, R. Pal, J. L. Miska, D.
E. Pérez, L. S. W. Pelter, X. C. Zeng and J. M. Takacs, Org.
Lett., 2015, 17, 940–943; b) Z.-D. Yang, R. Pal, G. L. Hoang, X.
Notes and references
1
(a) M. A. Soriano-Ursύa, B. C. Das and J. G. Trujillo-Ferrara,
Expert Opinion on Therapeutic Patents, 2014, 24, 485–500;
(b) S. J. Baker, C. Z. Ding, T. Akama, Y.-K. Zhang, V. Hernandez
C. Zeng and J. M. Takacs, ACS Catal., 2014,
21 G. L. Hoang and J. M. Takacs, Chem. Sci., 2017,
22 For rationalization of similarly coupled changes in
regioselectivity and -facial discrimination, see 17a.
4, 763–773.
and Y. Xia, Future Med. Chem., 2009, 1, 1275–1288; (c) S. N.
Mlynarski, C. H. Schuster and J. P. Morken, Nature, 2014,
505, 386–390; (d) C. Sanford and V. K. Aggarwal, Chem.
8
, 4511–4516.
a
π
Commun., 2017, 53
therein.
K. Burgess and M. J. Ohlmeyer, J. Org. Chem., 1988, 53
5178–5179.
(a) T. Hayashi, Y. Matsumoto and Y. Ito, J. Am. Chem. Soc.,
1989, 111, 3426–3428; (b) T. Hayashi, Y. Matsumoto and Y.
Ito, Tetrahedron: Asymmetry, 1991, 2, 601–612; (c) D. R.
, 5481–5494, and references cited
23 (a) Unless otherwise noted, the isolated yield of the major
boronic ester is reported. Enantiomer ratios (er) are
determined by chiral HPLC analysis of the corresponding
alcohols after oxidation or by 19F NMR analysis of their
Mosher esters. Diastereomer ratios are determined by NMR
analysis; see the ESI for details. (b) A 2:1 ligand-to-metal
ratio is employed in this study. A more active catalyst is
formed using a 1:1 ratio, but the yield and enantioselectivity
are generally diminished by 5–10%.
2
3
,
Edwards, Y. B. Hleba, C. J. Lata, L. A. Calhoun and C. M.
Crudden, Angew. Chem., Int. Ed., 2007, 46, 7799–7802; (d) J.
Huang, W. Yan, C. Tan, W. Wu and H. Jiang, Chem. Commun.,
2018, 54, 1770–1773.
24 For a similar effect in an iridium-catalyzed reaction, see: C.-X.
Zhuo, Q. Cheng, W.-B. Liu, Q. Zhao and S.-L. You, Angew.
Chem., Int. Ed., 2015, 54, 8475–8479.
25 Using half an equivalent of pinBH relative to total amount of
alkene present leaves 38% of unreacted amide 3a and 68%
4
5
6
(a) J. M. Brown and B. N. Nguyen, Stereoselective
hydroboration and diboration of carbon-carbon double
bonds; Georg Thieme Verlag: 2011, 1, 295; (b) A.-M. Carroll,
T. P. O’Sullivan and P. J Guiry, Adv. Synth. Catal., 2005, 347
,
of unreacted TIPS ether 16
.
609–631; (c) C. M. Crudden and D. Edwards, Eur. J. Org.
Chem., 2003, 4695–4712; (d) K. Burgess and M. J. Ohlmeyer,
Chem. Rev., 1991, 91, 1179–1191.
(a) M. McCarthy and P. J. Guiry, Polyhedron, 2000, 19, 541–
543; (b) M. McCarthy, R. Goddard and P. J. Guiry,
Tetrahedron: Asymmetry, 1999, 10, 2797–2807; (c) P. M.
Lacey, C. M McDonnell and P. J. Guiry, Tetrahedron Lett.,
2000, 41, 2475–2478; (d) D. J. Connolly, P. M. Lacey, M.
McCarthy, C. P. Saunders, A.-M. Carroll, R. Goddard and P. J.
Guiry, J. Org. Chem., 2004, 69, 6572–6589.
26 J. F. Teichert and B. L. Feringa, Angew. Chem., Int. Ed., 2010,
49, 2486–2528.
27 (a) J. Qu and G. Helmchen, Acc. Chem. Res., 2017, 50, 2539–
2555; (b) R. B. Sunoj, Acc. Chem. Res., 2016, 49, 1019–1028);
(c) W. Fu and W. Tang, ACS Catal., 2016, 6, 4814–4858; (d) L.
Eberhardt, D. Armspach, J. Harrowfield and D. Matt., Chem.
Soc. Rev., 2008, 37, 839–864.
28 W.-B. Liu, C. Zheng, C.-X. Zhuo and S.-L. You, J. Am. Chem.
Soc., 2012, 134, 4812–4821; (c) X. Zhang, W.-B. Liu, Q. Cheng
and S.-L. You, Organometallics, 2016, 35, 2467–2472.
D. Noh, S. K. Yoon, J. Won, J. Y. Lee and J. Yun, Chem. Asian.
J., 2011, 6, 1967–1969.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C8CC01563E
A simple rhodium catalyst system promotes the regio- and enantioselective δ-borylation of γ,δ-
unsaturated amide derivatives by pinacolborane to afford chiral benzylic boronic esters.
Rh(nbd)2BF4 (0.5%)
O
R
P
N
Ph
O
O
R4
O
R4 Bpin
Ar
(1.0%)
R1
R1
N
Ar
N
pinacolborane (1.5 equiv)
THF, 40 oC
R2 R3
R2 R3
24 examples of direct -borylation of unsaturated amides
aryl and heteroaryl substituents tolerated
high regioselectivity (up to >20:1 rr)
high enantioselectivity (up to 97:3 er)
high diastereoselectivity (dr) with chiral substrates