Benzylic boron reagents behaving as allylic boron reagents towards aldehydes: A new asymmetric reaction leading to homoallylic alcohols with concomitant dearomatisation

Article abstract of DOI:10.1002/chem.201001174

(Figure Presented) Retention of stereochemistry: p-Meth-oxybenzylic trifluoroborate salts react with aldehydes in the presence of Lewis or Bronsted acids to give homoallylic alcohols with concomitant dearomatisation of the aromatic ring (see scheme). Using enantioenriched benzylic trifluoroborate salts leads to adducts with > 98% retention of the stereochemistry in most cases.

Full text of DOI:10.1002/chem.201001174

COMMUNICATION
DOI: 10.1002/chem.201001174
Benzylic Boron Reagents Behaving as Allylic Boron Reagents towards
Aldehydes: A New Asymmetric Reaction Leading to Homoallylic Alcohols
with Concomitant Dearomatisation
Abel Ros, Antonio Bermejo, and Varinder K. Aggarwal*[a]
Dedicated to Professor Josꢀ Barluenga on the occasion of his 70th birthday
The dearomatisation of an aromatic ring represents a
powerful synthetic strategy as the aromatic ring can be
easily carried through a number of synthetic manipulations
and, following dearomatisation, a highly functionalised six-
membered ring is created, primed for further transforma-
tions.[1] The Birch reduction is the best known example of
this and has been used extensively.[2] Other methods for
dearomatisation include metal-promoted nucleophilic and
electrophilic addition to aromatic systems,[3] oxidation, re-
duction and radical cyclisation reactions.[4]
some erosion of e.r., nevertheless, implicating that the
second mechanism was likely to be operating [Scheme 2,
Eq. (1)].
During the course of certain mechanistic studies (see
later) we have discovered a new dearomatisation reaction in
which benzylic boron substrates essentially behave as allylic
boron reagents in reactions with aldehydes leading to cyclo-
hexenones in high d.r. and e.r. In this paper we describe the
optimisation of this novel process together with its asymmet-
ric variant.
Scheme 1. Possible mechanisms for Rh-catalysed 1,2-addition of benzylic
trifluoroborate salts to aldehydes.
We recently reported the rhodium-catalysed 1,2-addition
of chiral secondary and tertiary benzyl potassium trifluoro-
borate salts to aldehydes.[5] We proposed two possible mech-
anisms for this addition reaction: i) transmetallation of B!
Rh followed by addition of the organometallic or ii) a cyclic
mechanism in which [Rh–OH] activated both the boron and
aldehyde substrates promoting the reaction (Scheme 1). In
the latter mechanism Rh was essentially acting as a Lewis
acid.[6] In order to distinguish between these two mecha-
nisms we have now tested alternative, water-stable and
However, a minor change in the substrate (p-MeOC6H4 in
place of Ph) led to
a completely different product
[Scheme 2, Eq. (2)]. Cyclohexenones (Z/E)-2bA (3:1, Z/E)
were now obtained with complete diastereoselectivity at the
new sp3 centres.[7] A possible mechanism for the formation
of the Z isomer is shown in Scheme 2. Conversion of the tri-
fluoroborate salt to the difluoroborane would lead to a
strongly electrophilic borane which could react with the al-
dehyde as if it was an allyl borane.[8] The high diastereose-
lectivity would arise from the closed six-membered ring TS
which is often associated with allyl boron reactions with al-
dehydes.[8,9] Subsequent hydrolysis of the intermediate enol
ether would give the product cyclohexenone. Presumably,
the E isomer results from reaction through the alternate
ortho position which places the substituents (Ar/Me) in
slightly different steric environments.
more standard Lewis acids. Using ScACTHNUTRGNEUNG(OTf)3 in the same sol-
vent led to the same product, albeit in lower yield and with
[a] Dr. A. Ros, A. Bermejo, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantockꢀs Close, Bristol, BS8 1TS (UK)
Fax : (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
Similar results were obtained using alternative water-
stable Lewis acids such as GdACHTUNGNERT(GUNN OTf)3, InACHUTNTRGEG(NNNU OTf)3, YACHTUNGTRENNUNG(OTf)3,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001174.
Chem. Eur. J. 2010, 16, 9741 – 9745
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9741

Scheme 3. Reactivity of o- and m-analogues of salts (ꢀ)-1c, 1d.
Further surprises emerged when we studied the reaction
of enantioenriched 1b (97:3 e.r.) with p-nitrobenzaldehyde
in the presence of ScACHTUNTRGNEUNG(OTf)3 (Scheme 4). The E and Z iso-
mers of 2bA were formed with markedly different e.r.
values: the major Z isomer was formed with 96:4 e.r. (essen-
tially complete stereoretention) whilst the minor E isomer
was formed with only 36:64 e.r. Furthermore, from single
crystal X-ray analyses of the major enantiomers of the Z-
and E-cyclohexenones 2bA[10] it was found that they both
had R,R configuration at the newly created sp3 centres. This
implies that the Z isomer of 2bA had been formed via a
closed TS and that the E isomer of 2bA had been formed
via an open TS (Scheme 5).[11] The high e.r. observed in the
formation of the Z isomer indicates that the closed TS d is
strongly favoured over the open TS b. In contrast, the low
e.r. observed for the E isomer indicates that the reaction
Scheme 2. ScIII-catalysed addition of tertiary trifluoroborate salts to p-ni-
trobenzaldehyde.
and YbACHTUNGTRENNUNG(OTf)3. (Table 1, entries 2–6). Control experiments
without Lewis acid (entry 1) or with TfOH (entry 7) showed
that the lanthanide Lewis acids were critical to the success
of the reaction. Using BF3·OEt2 or SiCl4 in anhydrous
CH2Cl2 at low temperature also led to adduct formation
with dearomatisation, although
with markedly different out-
comes. SiCl4 led to the
E
Table 1. Investigation of the effect of Lewis acid, solvent and temperature on course of reaction.
isomer (E)-2bA being the
major product instead of the Z
isomer
(entry 8)
whilst
BF3·OEt2 led to formation of
the furans 3bA/3*bA (entry 9).
Treatment of our isolated 3:1
Z/E olefin mixture of (ꢀ)-2bA
with
one
equivalent
of
BF3·OEt2 in anhydrous CH2Cl2
at ꢁ788C led to the same mix-
ture of furans 3bA/3*bA. The
reaction of the ortho- or meta-
methoxy analogues of the tri-
fluoroborate salts 1c/1d did not
show the same reactivity. The
ortho-methoxy salt 1c gave the
alkene 6 as the major product
as a result of dehydroboration,
whilst the meta-methoxy salt 1d
showed similar reactivity to the
phenyl substrate, resulting in
Entry
Catalyst (10 mol%)
none
Solvent
T [8C]
Yield [%]
Yield [%]
2bA (Z/E)[b]
3bA/3*bA[c]
1
2
3
4
5
6
7
8
9
1,4-dioxane/H2O 6:1
1,4-dioxane/H2O 6:1
1,4-dioxane/H2O 6:1
1,4-dioxane/H2O 6:1
1,4-dioxane/H2O 6:1
1,4-dioxane/H2O 6:1
1,4-dioxane/H2O 6:1
anhydrous CH2Cl2
anhydrous CH2Cl2
65
65
65
65
65
65
65
–
–
–
–
–
–
–
–
–
Sc
Gd
In(OTf)3
(OTf)3
Yb(OTf)3
T
81 (3:1)
34 (3:1)
60 (3:1)
42 (3:1)
68 (3:1)
–
N
N
Y
A
G
TfOH
SiCl4
BF3·OEt2
ꢁ78! RT
52 (1:4)
–
ꢁ78! RT
73 (3:1)
[a] A mixture of p-nitrobenzaldehyde (0.3 mmol), (ꢀ)-1b (0.45 mmol) and Lewis acid (10% mol) in deoxy-
genated 1,4-dioxane/H2O 6:1 (1.65 mL) was stirred at 658C until consumption of aldehyde by TLC. With
water-sensitive Lewis acids (SiCl4 and BF3·OEt2), anhydrous CH2Cl2 (3 mL) was used and the Lewis acid addi-
tion was carried out at ꢁ788C! RT. [b] Isolated yield. The Z/E ratio was determined by 1H NMR of the
crude. [c] Isolated yield. The 3 and 3* refer to the two diastereomers at the quaternary centre. The ratio was
predominantly
(Scheme 3).
1,2-addition
1
determined by H NMR of the crude.
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Benzylic Boron Reagents
COMMUNICATION
in the E isomer. Under the same conditions cyclohexanecar-
boxaldehyde C gave the furan derivatives 3/3*bC by intra-
molecular 1,6-addition, rather than the free alcohol 2bC
(entry 3). Small amounts of the 1,6-addition adducts 3bA
and 3bB were also observed with aromatic aldehydes with/
when using longer reaction times (entries 1–2). A mixture of
products 2/3eA and 2/3eB were obtained when the salt (S)-
1e was used with aromatic aldehydes (A and B, entries 4
and 6), but treatment of the crude reaction mixtures with
20 mol% BF3·OEt2 in anhydrous CH2Cl2 (Method B, see
Supporting Information) converted them into the furans 3/
3*eA and 3/3*eB (entries 5 and 7). With cyclohexanecarbox-
aldehyde (entry 8) the furan derivatives 3/3*eC were ob-
tained exclusively and with complete stereoretention.
Scheme 4. Reaction of enantioenriched (R)-1b with p-nitrobenzaldehyde
(major enantiomers drawn).
occurs via both open and closed TSs a and c, but now with
the open TS a being marginally favoured over the closed TS
c (~2:1).
In order to enhance the e.r. of the E isomer of 2bA we
needed to shut down one of the two competing open and
closed TSs a and c and sought to eliminate the open TS a as
this would not impact negatively on the e.r. of the major Z
isomer formed. We believed that this could be achieved by
either i) converting more of the RBF3K salt into the neutral
difluoroborane to promote the closed TS or ii) using a
weaker external LA to limit the extent of the open TS, or
both. Brønsted acids were expected to fulfil both roles. We
therefore tested triflic acid and were delighted to find that it
was highly effective, leading to adducts in good yield and
without significant erosion of e.r. in both E and Z isomers
(Table 2, entry 1). These new conditions were general for a
range of aldehydes and benzyl trifluoroborate substrates
(Table 2). The reaction with the less activated aldehyde,
PhCHO B (entry 2), gave cyclohexenones (E/Z)-2bB in
good yield but with a small degree of erosion in e.r. (<5%)
Having successfully demonstrated that the reactions of
enantioenriched diarylalkyl trifluoroborate salts 1b and 1e
with aromatic and aliphatic aldehydes occurred with almost
complete transfer of stereochemical information, we consid-
ered the extension of the methodology to tertiary dialkylaryl
and secondary arylalkyl trifluoroborate salts 1 f–g. The terti-
ary trifluoroborate salt 1 f reacted with aromatic and ali-
phatic aldehydes (A–C) giving the separable furan deriva-
tives 3 fA–fC and 3*fA–fC in good yields and again with
almost complete retention of stereochemistry (entries 9–11).
When similar conditions were applied to the secondary alkyl
trifluoroborate salt 1g (entry 12), considerable erosion of
e.r. (71:29) was observed for the minor (Z)-2gA isomer.
However, by decreasing the amount of TfOH to 5 mol%
this erosion of e.r. was markedly improved (entry 13) to give
85:15 e.r. and 95:5 e.r. for (Z)-2gA and (E)-2gA (major
isomer), respectively.
Scheme 5. Proposed reaction pathways leading to the observed isomers of adducts.
Chem. Eur. J. 2010, 16, 9741 – 9745
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9743

V. K. Aggarwal et al.
Table 2. TfOH-catalysed 1,2-addition of trifluoroborate salts 1b–1g to aldehydes A–C.[a]
Entry
Salt (e.r.)
R
Aldehyde (R1 =)
Yield (Z)-2,[b] e.r.[c]
Yield (E)-2,[b] e.r.[c]
Yield 3,[b] e.r.[c]
Yield 3*,[b] e.r.[c]
[e]
1
2
3
4
(R)-1b (97:3)
(R)-1b (97:3)
(R)-1b (97:3)
(S)-1e (97:3)
(S)-1e (97:3)
(S)-1e (97:3)
(S)-1e (97:3)
(S)-1e (97:3)
(S)-1 f (95.5:4.5)
(S)-1 f (95.5:4.5)
(S)-1 f (95.5:4.5)
(R)-1g (97:3)
(R)-1g (97:3)
p-Cl-C6H4
p-Cl-C6H4
p-Cl-C6H4
p-NO2-C6H4 (A)
Ph (B)
Cy (C)
p-NO2-C6H4 (A)
p-NO2-C6H4 (A)
Ph (B)
Ph (B)
Cy (C)
p-NO2-C6H4 (A)
Ph (B)
Cy (C)
2bA, 70,[d] 96:4
2bB, 51, 96:4
2bA, 19, 95:5
2bB, 26, 92:8
–
–
–
–
[e]
–
–
3bC, 68, 97:3
3eA, 21, 97:3
3eA, 46, 97:3
3eB, 33, 97:3
3eB, 42, 97:3
3eC, 32, 96:4
3 fA, 54, 95:5
3 fB, 40, 95:5
3 fC, 42[h]
3*bC, 19, 95:5
–
–
–
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
H
2eA, 33[f], 97:3
2eA, 16[f], 96:4
5[g]
6
–
2eA, 17, 95:5
2eB, 13, 88:12
2eB, 13, 88:12
–
2eB, 16, 97:3
–
–
–
7[g]
8
–
3*eC, 20, 96:4
3*fA, 30, 92:8
3*fB, 22, 93:7
3*fC, 19[h]
–
9
–
–
–
10
11
12
13[i]
–
–
p-NO2-C6H4 (A)
p-NO2-C6H4 (A)
2gA, 40,[f] 71:29
2gA, 37,[f] 85:15
2gA, 39,[f] 92:8
2gA, 48,[f] 95:5
–
–
H
–
[a] Method A: A mixture of aldehyde (0.3 mmol), (ꢀ)-1b–g (0.45 mmol), H2O (0.6 mmol, 11 mL) and TfOH (20% mol, 5.4 mL) in deoxygenated and an-
hydrous CH2Cl2 (3 mL) was stirred at ꢁ788C! RT until complete consumption of aldehyde was observed by TLC. [b] Isolated yield. [c] Determined by
chiral HPLC or GC (see Supporting Information). [d] Isolated yield after partial recrystallisation. [e] The 3bA–3bB adducts were formed in small
1
amounts with longer reaction times. [f] Inseparable Z/E mixture. The yield was estimated by H NMR on the isolated mixture. [g] Method A followed by
work up and treatment with BF3·OEt2 in anhydrous CH2Cl2 (see Supporting Information). Direct reaction of the salt and aldehyde with BF3·OEt2 gave
lower yields of furan adducts due to formation of side-products derived from dehydroboration. [h] The furan enantiomers were not separable by GC
using a, b, or g-DEX columns. See Supporting Information for further details. [i] The reaction was carried out with 5% mol of TfOH.
In summary, we have discovered a new reaction manifold
for benzylic trifluoroborate salts which react with aldehydes
in the presence of Lewis or Brønsted acids to give homoal-
lylic alcohols.[12] The reactions are accompanied by dearoma-
tisation of the aromatic ring which is especially synthetically
useful since it leads to more functionalised products. The re-
actions show broad substrate scope in terms of both the ben-
zylic trifluoroborate salts, which can be primary,[13] secon-
dary or tertiary, and the aldehydes employed (aromatic/ali-
phatic). The use of enantioenriched benzylic trifluoroborate
salts, which are easily accessible through the lithiation-bory-
lation reaction,[5c–f] leads to adducts with almost complete re-
tention of stereochemistry in most cases. This new reaction
manifold extends the synthetic utility of benzylic boron re-
agents and the lithiation-borylation reactions that produce
them.
MgSO4 (anh.). Concentration and purification through silica gel column
chromatography (petroleum ether 40–60/EtOAc 6:1! 1:1) gave
(1R,3S,3aS)-3*fA (first fraction, 27 mg, 30%) and (1R,3R,3aR)-3 fA
(second fraction, 49 mg, 54%) as yellow viscous oils. (1R,3S,3aS)-3*fA:
[a]2D0 = +87 (c = 0.7, CHCl3) (e.r. 92:8); 1H NMR (400 MHz, CDCl3): d
= 8.23 (d, 2H, J=8.8 Hz, CHArom.), 7.54 (d, 2H, J=8.8 Hz, CHArom.), 5.62
(dt, 1H, J=4.4, 2.8 Hz, CH-1), 4.64 (d, 1H, J=9.5 Hz, CH-5), 3.02 (ddd,
1H, J=22.0, 4.4, 2.4 Hz, CH-2a), 2.91 (m, 1H, CH-4), 2.85 (dt, 1H, J=
22.2, 2.8 Hz, CH-2b), 2.57 (dd, 1H, J=14.3, 5.5 Hz, CH-3a), 2.39 (dd,
1H, J=14.3, 12.1 Hz, CH-3b), 1.88–1.75 (m, 2H, CH2CH3), 1.47 (s, 3H,
Me), 1.03 ppm (t, 3H, J=7.5 Hz, CH2CH3); 13C NMR (100 MHz,
CDCl3): d = 207.9 (C=O), 148.7 (Cquat), 147.9 (Cquat-Arom), 147.7 (Cquat
-
Arom), 126.6 (CH-Arom), 123.9 (CH-Arom), 113.4 (C1), 84.7 (C6), 84.4
(C5), 48.6 (C4), 41.0 (C3), 38.4 (C2), 33.0 (CH2CH3), 27.7 (Me), 8.6 ppm
(CH2CH3); IR (neat): n˜ =2970, 2925, 1716, 1603, 1518, 1350 cmꢁ1
;
HRMS (CI): m/z: calcd for C17H20NO4: 302.1392; found: 302.1396
[M+H]+; HPLC: Chiralpak IA column with guard, 10% isopropanol in
hexane, 0.35 mLminꢁ1
, T=08C, tR 37.3 min (major) and 41.1 min
(minor). (1R,3R,3aR)-3 fA: [a]2D0 =ꢁ34 (c
= 1.8, CHCl3) (e.r. 95:5);
1H NMR (400 MHz, CDCl3): d = 8.24 (d, 2H, J=8.8 Hz, CHArom.), 7.57
(d, 2H, J=8.8 Hz, CHArom.), 5.63 (dt, 1H, J=4.4, 2.7 Hz, CH-1), 4.66 (d,
1H, J=9.5 Hz, CH-5), 3.01 (ddd, 1H, J=22.5, 4.4, 2.5 Hz, CH-2a), 2.87
(dt, 1H, J=22.5, 2.9 Hz, CH-2b), 2.80 (m, 1H, CH-4), 2.56 (dd, 1H, J=
14.2, 5.2 Hz, CH-3a), 2.40 (dd, 1H, J=14.2, 12.0 Hz, CH-3b), 1.84 (m,
1H, CH2CH3), 1.77 (m, 1H, CH2CH3), 1.45 (s, 3H, Me), 1.02 ppm (t, 3H,
J=7.3 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3): d = 207.9 (C=O),
148.7 (Cquat), 147.8 (Cquat-Arom), 147.4 (Cquat-Arom), 126.6 (CH-Arom),
123.9 (CH-Arom), 114.0 (C1), 84.9 (C6), 83.1 (C5), 49.7 (C4), 41.3 (C3),
38.3 (C2), 34.7 (CH2CH3), 26.0 (Me), 8.8 ppm (CH2CH3); IR (neat): n˜ =
2970, 2926, 1714, 1603, 1519, 1360 cmꢁ1; HRMS (CI): m/z: calcd for
C17H20NO4: 302.1392; found: 302.1394 [M+H]+; HPLC: Chiralpak IA
column with guard, 10% isopropanol in hexane, 0.5 mLminꢁ1, T=RT, tR
= 27.4 (minor) and 30.1 min (major).
Experimental Section
Typical procedure for (1R,3S,3aS)-3*fA and (1R,3R,3aR)-3 fA (Table 2,
entry 9): A dried Schlenk tube was charged with the potassium trifluoro-
borate salt (S)-1 f (122 mg, 0.45 mmol) and the corresponding aldehyde
(45 mg, 0.3 mmol). After cycles of vacuum/N2 (three cycles), deoxygenat-
ed dry CH2Cl2 (3 mL) and H2O (0.6 mmol, 11 mL) were added. The reac-
tion mixture was cooled to ꢁ788C and TfOH (20% mol, 5.4 mL) was
added. The dry ice/acetone bath was removed and the reaction mixture
was stirred at room temperature until starting aldehyde is consumed by
TLC (6 h). Saturated NH4Cl solution was then added and the mixture
was extracted with EtOAc. The combined organic layers were dried over
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Chem. Eur. J. 2010, 16, 9741 – 9745

Benzylic Boron Reagents
COMMUNICATION
and the secondary boronic esters were prepared by the lithiation-
borylation reaction of primary carabamates: d) J. L. Stymiest, G.
Dutheuil, A. Mahmood, V. K. Aggarwal, Angew. Chem. 2007, 119,
7635; Angew. Chem. Int. Ed. 2007, 46, 7491; e) G. Dutheuil, M. P.
Webster, P. A. Worthington, V. K. Aggarwal, Angew. Chem. 2009,
121, 6435; Angew. Chem. Int. Ed. 2009, 48, 6317. For a review, see:
f) S. P. Thomas, R. M. French, V. Jheengut, V. K. Aggarwal, Chem.
Rec. 2009, 9, 24.
Acknowledgements
A.R. thanks the European Union for a Marie Curie Intra-European Post-
doctoral Fellowship 7th European Community Framework Programme.
A.B. thanks the Junta de Andalucꢂa for a predoctoral fellowship. V.K.A.
thanks the EPSRC for a Senior Research Fellowship, Merck for research
support and Frontier Scientific for generous donation of boronic esters.
We thank Dr. Mairi Haddow for X-ray analysis.
[6] For RhI acting as a weak Lewis acid, see: G. Adames, C. Bibby, R.
Grigg, Chem. Commun. 1972, 491.
[7] Oxidation of the 3:1 mixture of isomers gave a 3:1 mixture of ke-
tones indicating that the diastereomeric mixture was due to E and Z
alkene isomers. NOE studies confirmed the Z/E products.
Keywords: allylboration · asymmetric catalysis · borylation ·
dearomatization · lithiation
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the E benzaldehyde adducts which were more readily separable. See
the Supporting Information.
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65, 9956. The tertiary boronic esters were prepared by the lithia-
tion–borylation reaction of a secondary carbamate: c) J. L. Stymiest,
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[11] A similar reactivity through an open TS was invoked in the reac-
tions of lithium allylic borate complexes with aldehydes. See: Y. Ya-
mamoto, H. Yatagai, K. Maruyama, J. Am. Chem. Soc. 1981, 103,
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[12] A primary 4-methoxybenzyl Grignard reagent has also been report-
ed to react with certain aldehydes through the aromatic ring with
concomitant dearomatisation. See: a) G. A. Kraus, I. Kim, S. Kesa-
van, Tetrahedron Lett. 2004, 45, 6839; b) For Pd-catalysed allylative
dearomatisation of benzylic chlorides see reference [3i]; c) Hoppe
observed that hindered benzyllithiums react with CO2 through the
aromatic ring followed by rapid rearomatisation. See: J. G. Peters,
M. Seppi, R. Frçhlich, B. Wibbeling, D. Hoppe, Synthesis 2002, 381.
[13] The primary p-methoxybenzyl trifluoroborate salt was also tested
and gave the corresponding homoallylic alcohol related to 2 in 36%
yield (unoptimized). See the Supporting Information for details.
Received: May 2, 2010
Published online: June 29, 2010
Chem. Eur. J. 2010, 16, 9741 – 9745
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9745