Consecutive borylcupration/C-C coupling of ?-alkenyl aldehydes towards diastereoselective 2-(borylmethyl)cycloalkanols

Article abstract of DOI:10.1039/d0cc02263b

Copper(i) catalyzes the borylative cyclization of ?-alkenyl aldehydes through chemo- and regioselective addition of Cu-B to C?C and concomitant intramolecular 1,2-addition of Cu-C on C?O. The products are formed in an exclusive diastereoselective manner and computational analysis identifies the key points for the observed chemo- and diastereoselectivity.

Full text of DOI:10.1039/d0cc02263b

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DOI: 10.1039/D0CC02263B
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Consecutive borylcupration/C-C coupling of -alkenyl aldehydes
towards diastereoselective 2-(borylmethyl)cycloalkanols
Ricardo J. Maza,a Jordi Royes, a Jorge J. Carbó*a and Elena Fernández*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Copper (I) catalyzes the borylative cyclization of -alkenyl In the present work we generate new knowledge about this
aldehydes through chemo- and regioselective addition of Cu-B to challenging borylative ring closing reaction demonstrating the
C=C and concomitant intramolecular 1,2-addition of Cu-C on the viability of borylative cyclization of -alkenyl aldehydes,
C=O. The products are formed in an exclusive diastereoselective proving the favored chemoselective borylcupration of the
manner and computational analysis identify the key points for the double bond versus the carbonyl group, but also the resulting
chemo- and diastereoselectivity observed.
exclusive formation of 2-(borylmethyl)cycloalkanols with anti-
diastereoselection (Scheme 1d). Also, based on DFT
Copper-catalyzed borylative ring closing of unactivated alkenes
calculations, we are able to propose
a new reaction
bearing electrophilic sites constitutes
intramolecular 1,2-carboboration process.1 Ito and co-workers
developed the concept demonstrating that
CuCl/Xantphos/KOtBu
catalyzed the consecutive
a
strategic
mechanism identifying and evaluating the factors that control
the chemo- and diastereoselectivity.
2019
c) Lautens and co-workers,
2013
a) Ito and co-workers,
B2pin2
Ar
B2pin2
Bpin
Bpin
Ar
Cu(MeCN)4PF6
O
CuCl
Xantphos
borylcupration/C−C coupling of alkenyl halides toward the
synthesis of cyclobutanes with a pending methylboryl moiety
(Scheme 1a).2 However the loss of the leaving group (X= Br, I,
OCO2Me, OP(O)(OR)2, OMs) reduced the atom economical
properties of the transformation. The same authors extended
the concept of copper(I)-catalyzed borylative exo-cyclization to
-alkenyl aryl ketones and they found that under similar
catalytic system and reaction conditions the regioselective
borylcupration was followed by intramolecular 1,2-addition on
the carbonyl group to give 2-(borylmethyl)cycloalkanols with
excellent syn-diastereoselectivity (Scheme 1b).3 An opposite
anti-diastereselection has been found by Lautens and co-
workers, in the borylative cyclization of -alkenyl aryl/alkyl
ketones using Cu(MeCN)4PF6/BDPP as the catalytic system and
NaOtBu as the base.4 They found that isopropyl alcohol as
additive was critical to the reaction’s success together with
MTBE as solvent, achieving high levels of enantioselectivity
when (S,S)-BDPP was the chiral ligand employed.4 However,
this new methodology is limited to the use of 1,1-disubstituted
alkenes containing an aryl substituent (Scheme 1c).
(S,S)-BDPP
OH
R
X
R
K(O-t-Bu)
DME
30 C
-X
Na(O-t-Bu)
iPrOH. MTBE
r.t.
R=alkyl, aryl
(
)

anti-diastereoselective
2015
b) Ito and co-workers,
This work
d)
B2pin2
B2pin2
CuCl
Bpin
Bpin
H(Ar)
O
H
(Ar)H
O
CuCl
Xantphos
Xantphos
OH
Ar
OH
H
Ar
H
K(O-t-Bu)
THF
K(O-t-Bu)
DME
30 C
30 C
anti-diastereoselective
syn-diastereoselective
Scheme 1. Copper-catalyzed borylative ring closing reactions.
Initial experiments were conducted on the borylative
cyclization of 4-allyltetrahydro-2H-pyran-4-carbaldehyde (1) as
model substrate in the presence of CuCl/Xantphos. The
substrate was quantitatively converted to the desired
spirocyclic compound 2, when bases such as Na(O-t-Bu) or
K(O-t-Bu) were involved (Table 1, entry 1). To the best of our
knowledge, this is the first example of a borycupration
followed by intramolecular electrophilic trapping of the
alkylcopper intermediate with the aldehyde, despite the fact
that intermolecular versions are known.5 Interestingly, the
copper-catalyzed ring closing reaction of 1 resulted in exclusive
anti-diastereoselectivity. This favored diastereoselection is in
contrast to the syn-diastereoselectivity observed by Ito and co-
workers in the borylative cyclization of alkenyl aryl ketones
a. Dept Química Física I Inorgànica. Universidad Rovira i Virgili, Tarragona, Spain.
† Footnotes relating to the title and/or authors should appear here.
Electronic
Supplementary
Information
(ESI)
available:
See
where
a
dialkylcopper(III) species was postulated as
DOI: 10.1039/x0xx00000x
intermediate.3
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Table 1. Cu-catalyzed diastereoselective borylative ring closing of alkenyl aldehydesa
yield, respectively (Table 1, entries 3 and 4). TheVrieewacArttiicolenOwnlianes
also explored for 2,2-dimethylpent-4-enal (9) providing a direct
DOI: 10.1039/D0CC02263B
B2pin
2 (1.2 equiv)
CuCl (5 mol%)
Xantphos (5 mol%)
K(O-t-Bu) (1.2 equiv)
access to 2,2-dimethyl-4-(pinacolborylmethyl)cyclobutan-1-ol
(10) in moderate isolated yield (Table 1, entry 5). Alternative
diboron reagents, such as B2hex2, works similarly to B2pin2
(Table 1, entry 6). The borylative ring closing reaction was also
extended to -Ar-substituted alkenyl aldehydes with the aim to
synthesize diastereoselective polysubstituted cyclobutanols.
The inclusion of a Ph group at the internal position of the C=C
in substrates 14, 16, 18 and 20 did not change the reaction
outcome, producing the desired spiro compounds in high
conversion and yield (Table 1, entries 7 and 8). The reaction
proceeded with exclusive diastereoselectivity keeping the
borylmethyl unit in anti diposition with respect to the alcohol
functional group. When the copper (I) catalyzed the borylative
ring closing of 1-(2-(2-bromophenyl)allyl)cyclohexane-1-
carbaldehyde (22) the expected spiro[3.5]nonan-1-ol was not
observed. The unique product generated was 4'-methylene-
3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalen]-1'-ol (23)
(Table 1, entry 9). Since 23 was not formed in a blank
experiment in the absence of B2pin2, we hypothesized that the
Cu-B species might be involved in the C-Br activation with a
concomitant intramolecular attack to the aldehyde, generating
the spirocyclic product of six-membered ring with the exocyclic
double bond in opposite position to the alcohol functionality.
The use of 2-naphthyl group as internal substituent of the
alkene group in 24 was also tolerated in this ring closing
reaction obtaining the polysubstituted spirocyclic compound
25 with the expected anti-diastereoselectivity in 52% isolated
yields (Scheme 2a). However, the reaction also produced the
boracycle 26-syn-(B-OH) due to the resulting syn-
diastereoselectivity and concomitant alcohol interaction with
Bpin moiety (Scheme 3). The X-ray diffraction structures of
products 25 and 26-syn-(B-OH) are shown in Scheme 2.
Bpin
Bpin
H(Ar)
O
Ar
R
or
OH
OH
H
THF, 30ºC, 16h
R
R
R
R
R
Entry
Substrate
Product
NMR Yield %
Isolated Yield [%]
Bpin
OH
O
H
99% [71%]
99% [70%]b
1
2
O
O
2
1
Bpin
O
H
H
OH
90% [45%]
O
O
4
Bpin
3
O
OH
3
4
5
85% [67%]
53% [50%]
64% [59%]
N
N
Ts
Ts
6
5
O
Bpin
H
H
OH
7
8
Bpin
O
OH
9
10
O
B
O
O
OH
6
7
12, 72% [34%]
13, 81% [51%]
H
11
12 Bpin
R
13 Bhex
O
X
H
Bpin
OH
15, 80% [76%]
17, 73% [24%]
19, 70% [25%]
R
14
16
, R=H, X=CH2
, R=H, X=O
, R= Bu, X=CH2
X
a)
t
18
15
17
19
, R=H, X=CH2
, R=H, X=O
, R= Bu, X=CH2
OH
B2pin2
CuCl
B
Bpin
O
t
H
O
Xantphos
K(O-t-Bu)
OH
+
Bpin
OH
O
THF
8
9
H
30ºC, 16h
24
[52%]
25
26
-syn-(B-OH) [39%]
78% [27%]
[34%]
20
21
NMR Yield: 91%
O
Br
H
OH
22
23
aReaction conditions: substrate (0.5 mmol), B2pin2 or B2hex2 (1.2 equiv), CuCl (5
mol%), Xantphos (5 mol%), K(O-t-Bu) (1.2 equiv), THF (2 mL), 30ºC, 16h. bNa(O-t-
Bu) used as base.
25
26-syn-(B-OH)
b)
B2pin2
O
OCuL
Bpin
OH
Bpin
CuCl
Xantphos
H
K(O-t-Bu)
THF
30 C
Next, we demonstrated the efficiency of this reaction by
forming the 5-membered ring spirocyclic compound 4 from -
alkenyl aldehyde 3, (Table 1, entry 2). This result contrasts with
the unsuccessful five-membered ring formation from the
analogue ketone carried out by other groups.4
27
28
29
, 43% [32%]
Scheme 2. Influence on diastereo- and chemoselectivity. X-ray diffraction structures for
25 and 26-syn-(B-OH).
It is remarkable that the copper catalyzed ring closing takes
place chemoselectively through borylcupration on the C=C
versus C=O. It brings added value to the borylative ring closing
method since it is known that copper-boryl complexes can
The proof of concept was also applied in the transformation of
4-allyl-1-(phenylsulfonyl)piperidine-4-carbaldehyde (5) and 1-
allylcyclohexane-1-carbaldehyde
(7)
towards
the
corresponding spirocyclic compounds 6 and 8 in 65% and 50%
2 | J. Name., 2012, 00, 1-3
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efficiently catalyze the borylation of aldehydes, even at room previously for borylative ring closing of alkenyl halides by
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temperature.6 However -methyl-substituted alkenyl aldehyde diphosphine-Cu(I) complexes.9
DOI: 10.1039/D0CC02263B
substrates drive preferentially the borylcupration on the C=O The reaction starts with the formation of Cu(O-t-Bu) (I1),
bond versus the C=C bond. This is the case of substrate 27 that resulting from mixing CuCl, K(O-t-Bu) and Xantphos ligand.
suffers a borylcupration on the aldehyde functional group Then, the active Cu-boryl species I2 is generated by -bond
generating the corresponding -borylhydroxyl prouct 29 metathesis between I1 with B2pin2. The next step is postulated
discarding the ring closing step (Scheme 2b).
as the coordination of Cu-Bpin to the substrate 1 through
The oxidation of the spirocyclic compounds with NaBO3·H2O, alkene moiety (I3), and subsequent insertion of the C=C double
allowed the isolation of the corresponding dihydroxylated bond into the Cu-B bond to yield the alkyl-copper(I) complex
cyclobutane products 30-35 contributing to increase the I4. This process occurs via transition state TS1 with a moderate
demand of four- and five-membered ring spirocycles.7 Single free-energy barrier of 10.7 kcal·mol-1 (I2 → TS1 in Figure 2).
crystal X-ray diffraction of products 33 and 34 confirmed the In our previous contribution,9 it was possible to optimize the
anti-diastereoselection (Figure 1).
dialkylcopper(III) intermediate proposed by Ito and co-
workers2,3 resulting from the intramolecular attack of Cu(I) to
the C-X with the concomitant elimination of the halide.
Nevertheless, Cu(III) species corresponded to a shallow well
that could not be characterized for all the studied systems.
Here, the absence of the halide leaving group makes the
formation of Cu(III) complex less likely. Thus, all attempts to
localize the Cu(III) intermediate where unsuccessful, including
more sophisticated molecular models such as tBuO- base
coordinated to Cu, the K+ counter cation interacting with the
alkoxy moiety, and two specific THF solvent molecules.
Alternatively, an intramolecular attack of the Cu-alkyl moiety
to the carbonyl carbon in complex I4 would then occur to lead
the ring closing C-C coupling and the resulting alkoxy-copper(I)
complex I5. The process needs to overcome a low energy
barrier (14.4 kcal·mol-1) and is exergonic by 13.0 kcal·mol-1. In
the corresponding transition state, TS2anti, a negative charge
develops at the carbonyl oxygen, which interacts with the Cu
center in order to stabilize the partial negative charge. Next,
intermediate I5anti can undergo another -bond metathesis
with the diboron reagent to recover the active Cu-boryl
species I2 and yield a 4-membered ring containing the O-Bpin
O
TsN
OH
OH
OH
OH
OH
OH
OH
32
OH
[75%]
33
30
31
[90%]
[61%]
[81%]
O
OH
HO
35
OH
OH
34
[76%]
[70%]
Figure 1. Dihydroxylated products 30-35 obtained from the oxidation of the
organoboron spirocyclic compounds with NaBO3·H2O. X-Ray diffraction structures for
33 and 34.
To propose a plausible mechanism and to understand the
factors governing the chemo- and diastereoselectivity, we
performed DFT calculations (ωB97X-D functional) in solution
(THF).8 Initially we characterized computationally the
mechanism for the Cu(I)-catalyzed borylative ring closing
reaction on substrate
1 yielding the 4-membered ring
spirocyclic product 2 with anti diastereoselectivity. Figure 2
depicts the computed potential free-energy profile, as well as
alternative pathways (dashed lines). Figure 2 and S5 show the
molecular structures of the key transition states. The initial
steps of the mechanism are analogous to those characterized
moiety (I6anti) with syn-diatereoselectivity. Finally, the
spirocyclic product 2 can be generated from species I6 though
the hydrolysis of O-B bond by the alcohol solvent or during the
isolation of the product via column chromatography.
Figure 2. a) Computed free-energy profile (kcal·mol-1) for the formation of 2. Dashed lines represent alternative paths related to chemoselectivity (red lines) and
diastereoselectivity (blue lines). P-P= Xantphos. b) Molecular structures and main geometric parameters (Å) of the key transition states (TS2anti and TS2syn).
We also evaluated the chemoselective pathway for boryl dashed lines in Figure 2. The Cu centre in I2 can coordinate the
addition to aldehyde, as illustrated for substrate 1 by red substrate through the carbonyl moiety (I3’), undergoing the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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1,2-addition of Cu-Bpin to the C=O via transition state TS1’. between the two corresponding transition states,ViewGArt‡i(cTleSO2nsliynne-
-1
The overall process has a low free energy barrier (15.9 24-TS2anti-24), is reduced to only 0.3 kcal·mDoOlI: 1(0s.e10e39F/iDgu0CreC0S262)6.3InB
kcal·mol-1) and it results in the thermodynamically stable, this case the bulky naphthyl substituent leads to 1,2 repulsive
intermediate I4’. Nevertheless, the pathway for C=C interactions with the carbonyl group in the anti path, which
borylcupration is kinetically preferred by 5.2 kcal·mol-1 (TS1 are similar to those between the carbonyl group and the -
versus TS1’in Figure 2), in agreement with the experimental CH2Bpin moiety in the syn isomer. Consequently, no
results. Table 2 compares the free-energy barriers for the two preference for any of the two diastereoisomers is observed.
competitive borylation processes in representative - In conclusion, borycupration of alkenyl aldehydes takes place
substituted alkenyl aldehydes 1, 7, 14, 24, and 27. chemoselectively on the C=C followed by intramolecular
Replacement of tetrahydropyran group in 1 by cyclohexane in electrophilic trapping of the aldehyde, with complete anti-
7 has a minor effect on the barriers. Then, incorporating diastereoselectivity. Disubstitution on the alpha-position to
aromatic substituents in the alkene moiety (substrates 14 and the aldehyde favours the cyclation but current work to extend
24) decreases the energy barrier for the borylation on C=C the reactivity to non-substituted substrates is ongoing.
bond providing the kinetic preference for ring closing Computational studies identify the key steps of the catalytic
products. Since boryl-copper complexes behave as cycle that govern the chemo- and the diastereoselectivity.
nucleophiles,10
the
electron-withdrawing
aromatic This research was supported by MINECO through projects
substituents enhance the reactivity of the double bond. On the CTQ2016-80328-P and PGC2018-100780-B-l00, and by and the
other hand, the methyl substituent in substrate 27 makes the Generalitat de Catalunya (2017-SGR629).
alkene fragment more electron rich, increasing the borylation
energy barrier and switching the chemoselectivity towards the
addition on the aldehyde moiety (product 29).
Notes and references
1
K. Kubota, H. Ito, in Advances in Organoboron Chemisty
toward Organic Synthesis, Chapter 8, Science of Synthesis,
Fernández, E. Ed. Thieme. 2019
K. Kubota, E. Yamamoto, H. Ito, J. Am. Chem. Soc. 2013, 135,
2635.
E. Yamamoto, R. Kojima, K. Kubota, H. Ito, Synlett, 2015, 26,
272.
A. Whyte, B. Mirabi, A. Torelli, L. Prieto, J. Bajohr, M.
Lautens, ACS Catal, 2019, 9, 9253.
J. C. Green, M. V. Joannou, S. A. Murray, J. M. Zanghi, S. J.
Meek, ACS Catal. 2017, 7, 4441.
a) D. S. Laitar, E. Y. Tsui, J. P. Sadighi J. Am. Chem. Soc., 2006,
128, 11036; b) C. M. Moore, C. R. Medina, P. C. Cannamela,
M. L. McIntosh, C. J. Ferber, A. Roering, T. B. Clark, T. B. Org.
Lett., 2014, 16, 6056.
E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257.
See Supporting Information for full computational details
J. Royes, S. Ni, A. Farre, E. La Cascia, J. J. Carbo, A. B. Cuenca,
F. Maseras, E. Fernández ACS Catal, 2018, 8, 2833.
Table 2. Calculated free-energy barriers and differences in kcal·mol-1 for the
borylcupration of C=C versus C=O bond, G‡(TS1-TS1’), and for the ring closing of
the diastereoselective anti versus syn paths, G‡(TS2anti-TS2syn).a
2
3
4
5
6
substrate
C=C:C=O (exp.)
100:0
G‡
10.7
12.6
9.3
G‡
15.9
16.9
15.9
11.7
13.1
G‡
17.6
18.7
10.1
G‡
+5.2
+4.3
+6.6
+9.0
-2.9
C=C
C=O
1
7
100:0
14
100:0
24
100:0
7.2
27
0:100
16.1
G‡
13.7
15.5
10.4
substrate
anti:syn (exp.)
100:0
G‡
+5.1
+3.2
+0.3
anti
syn
1
3
100:0
7
8
9
24
50:50
a
Free-energy barriers G‡
and G‡syn (I4→TS1syn).
(I2→TS1), G‡
(I2→TS1’), G‡ (I4→TS1anti),
C=O anti
C=C
10 a) J. Cid, J. J. Carbó, E. Fernández, Chem. Eur. J. 2012, 18,
12794; b) D. García-López, J. Cid, R. Marqués, E. Fernández,
J. J. Carbó, Chem. Eur. J., 2017, 23, 5066.
The diastereoselectivity is decided at the C-C coupling step
where the aldehyde functional group can adopt an anti or a
syn disposition with respect to the borylmethyl unit (TS2anti
and TS2syn). In substrate 1, the anti-configuration minimizes
the 1,2 repulsion between the substituents of cyclobutane,
resulting in a significantly lower free energy barrier (13.7
versus 17.6 kcal·mol- for I4 → TS2anti and I4 → TS2syn
,
respectively). Additional calculations were performed in model
systems replacing each phenyl substituent of Xantphos ligand
by hydrogen and maintained the backbone (PH2 model) sets
off ligand-substrate interactions. The results show that a free-
energy difference between the two diastereoselective paths is
very similar to the real-world ligands, G‡ = +4.2 kcal·mol-1,
indicating that intramolecular interactions within the substrate
(-CH2Bpin···C=O) are responsible of the diastereoselectivity.
Interestingly, introducing a 2-naphthyl group on the alkene
moiety (substrate 24) produced a mixture of anti and syn
diastereoisomers. The computed free-energy difference
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC02263B
B2pin2
Bpin
H(Ar)
O
(Ar)H
CuCl
Xantphos
OH
H
H
K(O-t-Bu)
THF
30 C