Chemoselective palladium-catalyzed α-allylation of α-boryl aldehydes

Article abstract of DOI:10.1039/c2ob26503f

Herein we report the development of an α-allylation reaction of α-boryl aldehydes that preserves the carbon-boron bond under Pd ⁰/Pd^II catalysis. A variety of α-boryl aldehydes and allylic alcohols participate in this chemoselective transformation. The α-allylated products were obtained as single regioisomers.

Full text of DOI:10.1039/c2ob26503f

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 7900
www.rsc.org/obc
PAPER
Chemoselective palladium-catalyzed α-allylation of α-boryl aldehydes†
Jeffrey D. St. Denis, Zhi He and Andrei K. Yudin*
Received 19th July 2012, Accepted 2nd August 2012
DOI: 10.1039/c2ob26503f
Herein we report the development of an α-allylation reaction of α-boryl aldehydes that preserves the
carbon–boron bond under Pd0/PdII catalysis. Avariety of α-boryl aldehydes and allylic alcohols
participate in this chemoselective transformation. The α-allylated products were obtained as single
regioisomers.
The development of chemoselective processes is an active field
of modern synthetic organic chemistry.1 Boronic acids have been
instrumental in the area of chemoselective transition metal-cata-
lyzed cross-coupling transformations and recently in the gener-
ation of stereodefined substrates through lithium boronate
intermediates.2–4 In addition to our interest in amphoteric aziri-
dine aldehydes, a novel class of bench-stable α-boryl aldehydes,
equipped with a MIDA-chelated sp3-boron centre, were recently
developed.5–7 The MIDA group attenuates the Lewis acidity of
the boron centre and is essential for the stabilization of the
α-boryl aldehyde.5,7 Amphoteric α-boryl aldehydes have been
utilized in several chemo- and stereoselective bond forming
processes,5–8 including the synthesis of a series of functionalized
vinyl boronates and their use in the three component Petasis
reaction.9
In order to explore the synthetic potential of α-boryl alde-
hydes, we were determined to selectively activate the pro-nucleo-
philic α-C–H bond in preference to the C–B bond (Fig. 1a). Our
hope was to find mild reaction conditions that would enable
functionalization of the sp3 α-carbon stereocentre while keeping
the dense array of reactive functional groups (nucleophilic C–B
bond and electrophilic aldehyde group) intact. In doing so, we
hoped to develop access to novel C,O-bis enolate intermediates
(Fig. 1b).10
amount of time. We also observed that the addition of 4 Å mole-
cular sieves was necessary to improve the reaction efficiency by
absorbing the water that was formed as a by-product.
With the appropriate reaction conditions for the α-allylation in
hand, we investigated the scope of α-MIDA boryl aldehyde reac-
tivity. Due to higher acidity of the benzylic C–H bond, α-aryl
derivatives performed better than the corresponding α-alkyl
variants under our allylation conditions. α-Boryl cyclohexyl
aldehyde did not undergo allylation (Table 2, entry 11). This
lack of reactivity can be attributed to the difficulty in forming a
quaternary centre adjacent to two β-branched substituents. A
similar outcome was recorded in the case of cyclohexene-2-ol
(Table 2, entries 4 and 8), which failed to react. Unsymmetrical
allyl alcohols were also subjected to allylation. The use of
(E)-cinnamyl alcohol (Table 3, entry 1) afforded the linear
product in 72% yield. Examination of the crude 1H NMR
showed no formation of the branched or (Z)-isomer.
Subjecting α-boryl hexanaldehyde to palladium-catalyzed
allylation with allyl alcohol resulted in recovery of the starting
α-boryl aldehyde (Table 1, entries 1–3).11 More forcing con-
ditions failed to produce any desired product (Table 1, entry 4).
It was evident that the active Pd0 catalyst was not being
formed under the reaction conditions. Gratifyingly, by changing
the palladium source to Pd(PPh3)4, an efficient α-allylation reac-
tion was found to take place at 5 mol% loading (Table 1, entries
5–7). When we decreased the catalyst loading, the reaction
became sluggish and failed to reach completion in an acceptable
Davenport Research Laboratories, Department of Chemistry, University
of Toronto, 80 St. George Street, Toronto, Ontario M5H 3H5, Canada.
E-mail: ayudin@chem.utoronto.ca; Fax: (+1)416-946-7676
†Electronic supplementary information (ESI) available: 1H, 13C, 11B,
HRMS. See DOI: 10.1039/c2ob26503f
Fig. 1 (a) C–B versus C–H functionalization, (b) enolization of
α-boryl aldehyde to form a C,O- bis-enolate.
7900 | Org. Biomol. Chem., 2012, 10, 7900–7902
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 1 Optimization of α-allylation conditionsa
Entry
Catalyst (mol%)
Allyl component (eq)
Additive (eq)
Base (eq)
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Allyl alcohol (1.5)
Allyl alcohol (3)
Allyl alcohol (5)
Allyl alcohol (3)
Allyl alcohol (2)
2-Methyl allyl alcohol (2)
1,4-Pentadienol (2)
Et3B (2.4)/LiCl (1.0)
Et3B (3.0)/LiCl (1.0)
Et3B (2.4)/LiCl (1.0)
Et3B (2.4)/LiCl (1.0)
Et3B (3.0)/4 Å MSb
Et3B (3.0)/4 Å MSb
Et3B (3.0)/4 Å MSb
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
50
50
50
Reflux
50
50
50
24
48
72
72
48
48
48
Trace
Trace
Trace
Trace
57
48
45
a Reaction was performed in a sealed vial under an atmosphere of nitrogen. b 2 equiv. of 4 Å MS were used (weight/weight of α-boryl aldehyde).
Table 2 Substrate scope of allylation with symmetrical allylic
Table 3 Substrate scope of allylation with unsymmetrical allylic
alcoholsa
alcoholsa
b
Entry
1
R
Starting alcohol
R1
Yieldc (%)
60
Entry
1
R
Starting alcohol
R1
Yield (%)
78
2
65
2
3
4
5
77
79
76
72
3
61
4
N/A
NR
78
5
6
70
a Reaction conditions: 5 mol% Pd(PPh3)4, 2 equiv. allylic alcohol, 1.5
equiv. Et3N, 3 equiv. 1.0 M Et3B in THF, 2 equiv. 4 Å MS, THF, 50 °C,
48 h.
7
70
8
N/A
N/A
NR
72
9
entry 3) showed exclusive formation of the linear trans-product.
Presumably, the palladium catalyst coordinates with the in situ
formed triethylborane-activated allyl alcohol to generate the elec-
trophilic η3-allyl Pd complex, which isomerizes the alkene
through the η3–η1–η3 mechanism to the most stable trans-
isomer.12–14 The allyl-Pd species undergoes nucleophilic attack
by the boryl enolate at the most sterically accessible carbon
atom. This is consistent with most Pd-catalyzed allylation reac-
tions, whereby isomerization of the allylic alcohol to the most
thermodynamically stable intermediate occurs.14
10
11
86
NR
a Reaction conditions: 5 mol% Pd(PPh3)4, 2 equiv. alcohol, 1.5 equiv.
Et3N, 3 equiv. 1.0 M Et3B in THF, 2 equiv. 4 Å MS (based on weight),
THF, 50 °C 48 h. b N/A: not applicable. c NR: no reaction.
The newly formed α-allyl α-boryl aldehydes can be used in
further transformations. The allylated boryl aldehydes have been
oxidized to the corresponding carboxylic acids under Pinnick
conditions. The reaction was slower as compared to that of non-
We also evaluated the performance of allylic alcohols contain-
ing cis-alkenes under our reaction conditions. The crude 1H
NMR of the allylation reaction using (Z)-penten-2-ol (Table 3,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7900–7902 | 7901

View Article Online
Acknowledgements
Funding for this work was provided by Natural Science and
Engineering Research Council (NSERC). JSD would also like to
thank NSERC for PGS-D funding.
Scheme 1 Pinnick oxidation and methyl ester formation. Reaction con-
ditions: i) NaClO2, NaHPO4, t-BuOH, H2O, 50 °C overnight, ii)
TMSCHN2, DCM : MeOH RT 2 h.
Notes and references
1 (a) N. A. Afagh and A. K. Yudin, Angew. Chem., Int. Ed., 2010, 49, 262;
(b) T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75, 4657;
(c) T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc. Rev.,
2009, 38, 3010; (d) R. A. Shenvi, D. P. O’Malley and P. S. Baran, Acc.
Chem. Res., 2009, 42, 530; (e) I. S. Young and P. S. Baran, Nat. Chem.,
2009, 1, 193.
2 D. G. Hall, Boronic Acids, Wiley-VCH, Weinheim, Germany, 2005.
3 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
4 Lithium boronate organometallics: (a) R. Larouche-Gauthier, T. G. Elford
and V. K. Aggarwal, J. Am. Chem. Soc., 2011, 133, 16794;
(b) R. S. Sonawane, V. Jheengut, C. Rabalakos, R. Larouche-Gauthier,
H. K. Scott and V. K. Aggrawal, Angew. Chem., Int. Ed., 2011, 50, 3760.
5 Z. He and A. K. Yudin, J. Am. Chem. Soc., 2011, 133, 13770.
6 For amphoteric aziridine aldehydes developed in our lab: (a) R. Hili and
A. K. Yudin, J. Am. Chem. Soc., 2009, 131, 16404; (b) L. L. W. Cheung,
Z. He, S. Decker and A. K. Yudin, Angew. Chem., Int. Ed., 2011, 50,
11798; (c) R. Hili and A. K. Yudin, Angew. Chem., Int. Ed., 2008, 47,
4188; (d) X. Li and A. K. Yudin, J. Am. Chem. Soc., 2007, 129, 14152;
(e) R. Hili and A. K. Yudin, J. Am. Chem. Soc., 2006, 128, 14772. For
amphoteric aziridine ketones: (f) L. Yu, A. Kokai and A. K. Yudin,
J. Org. Chem., 2007, 72, 1737.
7 J. Li and M. D. Burke, J. Am. Chem. Soc., 2011, 133, 13774.
8 For sp3-B(Pin) coupling, see: (a) B. W. Glasspoole, K. Ghozati,
J. W. Moir and C. M. Crudden, Chem. Commun., 2012, 48, 1230;
(b) B. W. Glasspoole and C. M. Crudden, Nat. Chem., 2011, 3, 912;
(c) C. M. Crudden, B. W. Glasspoole and C. J. Lata, Chem. Commun.,
2009, 44, 6704; (d) D. Imao, B. W. Glasspoole, V. S. Laberge and
C. M. Crudden, J. Am. Chem. Soc., 2009, 131, 5024. For RBF3K coup-
ling reactions see: (e) V. Colombel, F. Rombouts, D. Oehlrich and
G. A. Molander, J. Org. Chem., 2012, 77, 2966; (f) G. A. Molander and
I. Shin, Org. Lett., 2011, 13, 3956; (g) D. L. Sandrock, L. Jean-Gerard,
C.-Y. Chen, S. D. Dreher and G. A. Molander, J. Am. Chem. Soc., 2010,
132, 17108; (h) G. A. Molander, O. A. Argintaru, I. Aron and
S. D. Dreher, Org. Lett., 2010, 12, 5783; (i) G. A. Molander and
D. E. Petrillo, Org. Lett., 2008, 10, 1795.
Scheme 2 Oxidative elaboration of the C–B bond. Reaction conditions:
i) 1,3-propanediol, MgSO4, TsOH·H2O, DCM 72 h 76%, ii) 1.0 M NaOH,
30% H2O2, THF, 15 h 92%.
allylated α-boryl aldehydes, presumably due to the steric hin-
drance brought about by the quaternary centre (Scheme 1).5
When the crude carboxylic acid was treated with TMSCHN2 in a
DCM–MeOH solvent mixture, the methyl ester was produced in
good yield (Scheme 1). In addition, α-boryl carboxylic acids
have been used to synthesize α-boryl ureas, further highlighting
the synthetic application of this novel class of compounds.15
In an attempt to form unsymmetrically substituted tertiary
alcohols, we exposed the phenyl α-boryl aldehyde 1 to standard
carbon-boron oxidation conditions (30% H2O2, 1.0 M NaOH in
THF) and obtained the proto-deborylated product exclusively. In
effort to manipulate the aldehyde functionality, we resorted to
the protection of aldehyde 1 as the 1,3-propane acetal 2. This
acetal intermediate was easily oxidized using alkaline hydrogen
peroxide to the desired benzylic alcohol 3, which was isolated as
a clear oil in 92% yield (Scheme 2).
9 (a) N. A. Petasis and I. Akriopoulou, Tetrahedron Lett., 1993, 34, 583;
(b) N. A. Petasis and I. A. Zavialov, J. Am. Chem. Soc., 1997, 119, 445;
(c) R. A. Batey, D. B. MacKay and V. Santhakumar, J. Am. Chem. Soc.,
1999, 121, 5075.
10 (a) A. Abiko, T. Inoue and S. Masamune, J. Am. Chem. Soc., 2002, 124,
10759; (b) C. J. Cowden and I. Paterson, Org. React., 1997, 51, 1;
(c) K. M. Cergol and M. J. Coster, Nat. Protoc., 2007, 2, 2568.
11 M. Kimura, Y. Horino, R. Mukai, S. Tanaka and Y. Tamaru, J. Am.
Chem. Soc., 2001, 123, 10401.
12 Initial attempts to generate optically active material using (R,R)-DACH
Naphthyl TROST ligand gave 64% ee. See ESI† for details.
13 (a) B. M. Trost, M. R. Machacek and A. Aponick, Acc. Chem. Res.,
2006, 39, 747; (b) Z. Lu and S. Ma, Angew. Chem., Int. Ed., 2008, 47,
258.
Conclusions
In summary, the pro-nucleophilic carbon–hydrogen bond can be
functionalized in the presence of a nucleophilic carbon–boron
bond in α-boryl aldehydes. This has been accomplished through
the palladium-catalyzed allylation of α-MIDA boryl aldehydes.
Under our conditions, a wide variety of allylic alcohols can be
utilized to generate the linear trans-alkenyl products (Fig. 1b).
Facile access to C,O-bis enolate intermediates should lead to
useful synthetic opportunities.
14 I. Dudovyk, D. Pichugin and A. K. Yudin, Angew. Chem., Int. Ed., 2011,
50, 5924.
15 Z. He, A. Zajdlik, J. D. St. Denis, N. Assem and A. K. Yudin, J. Am.
Chem. Soc., 2012, 134, 9926.
7902 | Org. Biomol. Chem., 2012, 10, 7900–7902
This journal is © The Royal Society of Chemistry 2012