Transition-Metal-Free Stereoselective Borylation of Allenamides

Article abstract of DOI:10.1002/chem.201803004

Complete stereocontrol on the transition-metal-free hydroboration of the distal double bond of allenamides could be achieved when allenamides contained acetyl substituents, which provided exclusively the Z-isomer. The consecutive Pd-catalyzed cross-coupli

Full text of DOI:10.1002/chem.201803004

A Journal of
Accepted Article
Title: Transition-metal-free stereoselective borylation of allenamides
Authors: Elena Ferna
́ndez, Jose Luis Vicario, Jordi Carbo, Lorena
Garcia, Jana Sendra, Nuria Miralles, and Efraim Reyes
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To be cited as: Chem. Eur. J. 10.1002/chem.201803004
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Transition-metal-free stereoselective borylation of allenamides
Lorena García,[b] Jana Sendra,[a] Núria Miralles,[a] Efraim Reyes,[b] Jorge J. Carbó,*[a] Jose L. Vicario,*[b]
Elena Fernández*[a]
Dedication ((optional))
Abstract: Complete stereocontrol on the transition-metal-free
hydroboration of the distal double bond of allenamides can be
diisopropanolaminato diboron) in the presence of
a
copper(I)catalyst, to install a boron moiety on the -position, via
hydroboration of the internal double bond (Scheme 2a).[6]
Similarly, the effect of the amide group in 2,3-disubstituted
allenamides influenced that the copper-catalyzed hydroboration
with B2pin2 took place regioselectively producing -borylated -
unsaturated enoamides via a plausible intramolecular interaction
between the carbonyl group and the organocopper intermediates
(Scheme 2b).[7] Contrarily, an efficient olefin-directed palladium-
catalyzed regioselective hydroboration of allenes containing an
allyl moiety, promotes the hydropalladation and subsequent
borylation to hydroborate the terminal double bond with B2pin2.[8]
Now, we planned to conduct in this work, the borylation of the
unexplored allenamides to identify the influence of the amine
group on the chemo- and regioselective addition of the boryl
moiety (Scheme 2d), but also to give access to stereodefined
trisubstituted alkenes.
achieved when allenamides contain acyl substituents, providing
exclusively the Z-isomer. The consecutive Pd-catalyzed cross
coupling reaction allowed the straightforward formation of tri-
substituted enamides, with total control on the stereoselectivity.
Hydroboration of allenes to afford stereodefined alkenyl
boronates represents an efficient synthetic strategy to prepare
polysubstituted olefins with total control on the
stereoselectivity.
[1] The first challenge is the regiocontrol of the
C-B and C-H formation along the allene system, which depends
on the transition metal catalyst used, the ligands involved and the
substrate itself.
From the original proof of concept by Miyaura and co-
workers,[2] the hydroboration of alkoxyallenes with HBpin
catalyzed by Pt(dba)2/PCy3 generated exclusively allylboranes,
while the hydroboration of alkyl- and aryl-substituted allenes with
HBpin catalyzed by Pt(dba)3/P(tBu)3 ocurred at the internal double
bond to selectively provide 1-alken-2-yl boronates (Scheme1).[2]
The copper-catalyzed hydroboration of allenes with
bis(pinacolato) diboron (B2pin2) forms 2-alken-2-yl or 1-alken-2-yl
boronates by applying also a ligand effect.[3-5]
Scheme 1.Synthetic approaches towards divergent transition metal catalyzed
hydroboration of allenes with HBpin and B2pin2
Alternatively, substrate directing effect to control the
regioselective hydroboration has been pursued by electrophilic
allenoates that react with PDIPA diboron (pinacolato
Scheme 2. Substrate directed transition-metal catalyzed hydroboration of
allenes with B2pin2 (a,b,c) and transition-metal-free hydroboration of
allenamides in this work (d).
[a]
[b]
Dr. E. Fernández, Dr. J. J. Carbó, Dr. N. Miralles, Ms. J. Sendra,
Author(s)
Department Química Física I Inorgànica
University Rovira i Virgili
In order to explore this new piece of chemistry we avoided the
use of any transition-metal complexes as catalysts and instead
we selected the alkoxide activation of B2pin2 to form the
nucleophilic boryl moiety in the acid-base Lewis adduct [MeO-
Bpin-Bpin]-[Hbase]+.[9] This system has already shown to be
efficient in the borylation of C=C bonds,[10] C=N bonds,[11]
electron deficient C=C bonds[12] and tertiary allylic or propargylic
alcohols.[13] The addition of the acid-base Lewis adduct [MeO-
Bpin-Bpin]-[Hbase]+ to aliphatic allenes was previously explored
C/ Marcel·lí Domingo s/n
E-mail: mariaelena.fernandez@urv.cat
Dr. J. L. Vicario, Dr. E. Reyes, Ms. L. García
Department of Organic Chemistry II
University of the Basque Country (UPV/EHU)
P.O. Box 644, 48080 Bilbao (Spain)
joseluis.vicario@ehu.es
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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giving access to the 1,2-diboration of the terminal double bond.[10]
Since replacing the aliphatic group in allenes by the amine group,
renders the allenamine more electronically enriched and
consequently very reactive and sensitive towards hydrolysis and
polymerization, we focussed the study on the electronic deficient
variants of allenamides, diminishing therefore the electron-
donating ability of the nitrogen atom, providing superior stability
as substrates.[14] Therefore we prepared N-(4-methoxyphenyl)-4-
methyl-N-(propa-1,2-dien-1-yl)benzenesulfonamide (1)[15] as the
model substrate to test the transition-metal-free borylation with
B2pin2 and MeOH/base. We selected KOtBu as the most efficient
base versus Cs2CO3 and NaOtBu, with an optimized 30 mol%
loading. The reaction temperature was explored in a range from
70ºC to 110ºC and we found that the highest temperature
favoured the major conversion towards a mixture of two
hydroborated products that have in common that the boryl moiety
is located at the central carbon of the allenamide but with a 2/1
ratio in favour of the hydroboration along the terminal double bond
(Table 1, entry 1). Similar effect was observed for a series of N-
Ts substituted amines, with electron donating or electron
withdrawing aryl substituents, but no significant differences were
detected in the reaction outcome or in the regioselectivity (Table
1, entries 1-3). When the aryl substituent was replaced by a
methyl group in the amine moiety (allenamide 4), the reaction was
less efficient (60% NMR Yield) but the ratio between the 2-
pinacolboryl prop-1-en-1-amine keeps being double than the 2-
pinacolboryl prop-2-en-1-amine (Table 1, entry 4). The
replacement of Ts by Boc in the amine functional group, showed
that the electron withdrawing substituents on the phenyl group of
the substrate might favour the borylation reaction (90% NMR
yield, Table 1, entry 6) versus the electron donating substituents
in the substrate (75% NMR yield, Table 1, entry 5). However, the
regioselectivity was again a mixture of the two hydroborated
products with a 2/1 ratio in favour of the hydroboration along the
terminal double bond. Interestingly, when the acyl group was
introduced as the electron withdrawing group in the allenamide,
substrate 7, we were able to perform the reaction with total
conversion and exclusive formation of the 2-pinacolboryl prop-1-
en-1-amine 7A, even at 70ºC (Table 1, entry 7).
Table 1. Transition-metal-free borylation of electronic deficient variants of
allenamides[a]
Entry
1
Substrate
T
(ºC)
%NMRYield[b]
[%IY][c]
np
1A[34%]
1A[53%]
A
[%IY][c]
B
(A/B)
70
90
110
16%
53%(2/1)
82%(2/1)
np
O
S
1B[22%]
1B[28%][d]
N
O
OMe
1
O
N
2
3
110
86%(2/1)
2A[48%]
2B[9%][d]
S
O
2
O
S
110
110
110
110
70
84%(2/1)
60%(2/1)
75%(2/1)
90%(2/1)
98%(1/-)
3A[47%][d]
4A[20%][d]
5A[41%]
6A[51%]
7A[71%]
3B[28%][d]
4B[11%][d]
5B[12%][d]
6B[25%][d]
7B----
N
O
Br
3
4
5
6
7
The complete regioselectivity observed requires a deep
understanding of the factors that might control it, particularly as
no transition-metal catalysts or ligands are involved in such
control. But also, in terms of chemical behaviour, we observe an
umpolung on the natural reactivity trend of the allenamide
reagent. Allenamides with electron withdrawing groups are known
to conduct electrophilic activation[16] assisted by transition-metal
[a]Conditions: allenamide (0.2 mmol), KOtBu (30 mol%), B2pin2 (1.2 equiv),
MeOH (0.4 M), 70-110ºC, 16h. [b]NMR Yields calculated in 1H NMR spectra
with naphthalene as internal standard from consumption of substrate. [c]%IY=
isolated yield. [d]% enriched purified product
complexes or Brønsted acids, to generate
a stabilized
carbocation that eventually reacts with nucleophilic reagents
either at the  or  position, involving the proximal or distal C=C
bond, respectively (Scheme 3, top).[17] Interestingly, the products
formed in all these cases are allylic systems. However, in our
transition-metal free hydroboration of the same allenamides, we
realized that the in situ generated nucleophilic Bpin moiety exerts
a nucleophilic attack on the C=C=C  system forming the C-B
bond on the central carbon and generating the corresponding
carbanion with a relative stabilized energy (Scheme 3, bottom).
Furthermore, the carbanion can be protonated both at the  or 
position, and therefore in order to control the regioselective
outcome of the reaction, a systematic study on the influence of
the N substituents is required.
Scheme 3. Umpolung reactivity of allenamides via electrophilic or nucleophilic
activation
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Previous DFT studies had characterized the mechanisms for
transition-metal-free diboration and borylation of alkenes by
diboron reagents activated with Lewis bases.[10,18] Those studies
proposed that the nucleophilic attack of the adduct [MeO-Bpin-
Bpin]- to double bond yields an anionic, 3-membered boracycle
intermediate (see Scheme 4, top) an the release of Bpin-OMe.
Subsequent protonation leads to the hydroborated product. For
allenamides, we propose that the formation of this anionic
intermediate is favoured because conjugation with the exocyclic
C=C bond stabilizes the negative charge. However, in these
allenamides, the boracycle intermediate can open to form a more
stable allylic anion that can be then protonated to give the final
product. To evaluate this mechanistic proposal and to rationalize
the observed stereoselective, we have performed DFT
calculations[19] on the key intermediates, using substrates 1 and 7
as representative examples.
of the process. Moreover, in the structures of the more stable
allylic anion, the amine substituent has an anti-configuration (see
Scheme 4) that should yield a trans configuration between the
amine and the Bpin substitutens in the major alkene product A.
To understand the difference in reactivity between the C and C,
we performed an analysis of charge distribution in the allylic
intermediates 1al and 7al (Scheme 4). Our calculations show that
the C is more negatively charged than the C, and consequently,
more reactive towards electrophiles in full agreement with
experimental selectivity. The protonation at the Cresults in
products (1A and 7A) which are more stable than that resulting
from protonation at C (1B and 7B) by 7.0 and 2.6 kcal·mol-1,
respectively. Nevertheless, we assume that the selectivity is not
thermodynamically but kinetically controlled in the irreversible
protonation step. Accordantly, in the allylic intermediate 7al, the
difference in atomic charges is larger than that computed for 1al,
which could explain the higher selectivity observed in the
hydroboration of allenamide 7.
R= tosyl (1), acyl (7)
boracycle intermediates
allyl
vinylic systems
H
H
R
R
N
N
Bpin
Bpin
1p: -19.6
7p: -16.2
1B
7B
q(C) = -.63
MeO
(-.64)
OMe
H+
Bpin
MeOBpin
R
R
N
N
·
G1 = - 7.0
G7 = -2.6
q(C) = -.83
+ [MeO-B2pin2]-
(-.93)
OMe
OMe
Figure 1. X-ray diffraction structure of stereocontrolled borylated product 14A
MeOBpin
H+
1al: -35.0
7al
1: 0.0
7: 0.0
: -30.0
G1d = 1.7
G7d = 5.1
R
R
Bpin
Bpin
N
N
Taking advantage of the exclusive regioselectivity observed by
the acyl substituted allenamide 7, we conducted a series of
reactivity to stablish the substrate scope but also the limitations in
the methodology. Changing the electron properties of the para-
substituents of the aryl group in the allenamide substrates, it was
proved that electron releasing para-substituents contributed to
quantitative conversions with complete stereoselectivity towards
the formation of the Z-isomer (Table 2, entries 1-3). However, a
trend that diminished conversions was observed when electron
withdrawing para-substituents on the aryl group were involved,
(Table 1, entries 4 and 5), but fortunately without effecting the
exclusive regioselective product formation. Replacement of the
Me group by t-Bu group at the acyl moiety, did not influenced in
the reaction outcome, since product 12A was obtained in
H
H
H
1d
7d: -20.4
1A
7A
: -20.0
OMe
OMe
Scheme 4.Proposed mechanism for the hydroboration of allenamides1 and 7.
Relative Gibbs free-energies and barriers (G‡) in kcal·mol-1. Electrostatic-
based atomic charges for the  and  carbons of allyl species in a.u.
Scheme 4 summarizes the results of our computational study for
allenamides 1 and 7. Initially, we characterized the formation of
the two boracycle intermediates corresponding to the borylation
of the proximal (1p and 7p) and distal (1d and 7d) double bonds.
The functionalization of the distal C=C bond is thermodynamically
preferred, although in the case of the tosyl substituent (1), both
regioisomers are almost isoenergetic. Nevertheless, for both
substituents the open allylic species 1al and 7al with the Bpin
moiety attached to central carbon are thermodynamically
favoured, the overall process for boryl addition to allene being
highly exergonic, -35.0 and -30.0 kcal·mol-1 for 1al and 7al,
respectively. In addition, the formation of the allylic intermediate
from boracycle has a low free-energy barrier (1.7 and 5.1
kcal·mol-1, respectively, from the lowest energy distal isomers 1d
and 7d), indicating that the process is a very fast transformation
at the high reaction temperature. Thus, it is likely that protonation
to yield the hydroborated product occurs at the allylic intermediate
and that this irreversible reaction step determines the selectivity
quantitatively yield as
a
single Z-isomer from N-(4-
methoxyphenyl)-N-(propa-1,2-dien-1-yl)pivalamide (12), (Table
2, entry 6).The reaction was also generalized for N-(4-
methoxyphenyl)-N-(propa-1,2-dien-1-yl)benzamide
(14)
demonstrating that the nature of the aryl substituents in the acyl
group contributed similarly to the borylation reaction (Table 2,
entry 8). The exclusive product (14A) formed from the transition-
metal-free borylation of 14, could be fully characterized with the
X-ray diffraction structure. Figure
1 illustrates the trans-
stereoselectivity of the amine and boryl moieties along the
trisubstituted alkene. Moreover, the electron releasing
substituents in the phenyl group favoured the reaction in contrast
to the electron withdrawing substituents (Table 2, entries 8 and 9
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for comparison). The reaction, however, showed a limitation for
the alpha and gamma substituted allenamides (N-(buta-2,3-dien-
2-yl)-N-(4-methoxyphenyl)benzamide and N-(4-methoxyphenyl)-
N-(penta-1,2-dien-1-yl)benzamide respectively) probably due to
the steric hindrance offered by the substrates to the nucleophilic
attack of the Bpin moiety.
pot metal-free borylation of the allenamide followed by a Pd-
catalyzed Suzuki-Miyaura cross-coupling reaction with 1-iodo-4-
methylbenzene. The consecutive reaction allowed the
straightforward formation of the tri-substituted olefin, with total
control on the stereoselectivity, (Scheme 5). The methodology
seems to be general since it is tolerant to alkyl and aryl
substituents on the acyl moiety.
Table 2. Transition-metal-free borylation of acyl substituted allenamides[a]
1) no metal
B2pin2 (1.2 eq)
KOtBu (30mol%)
O
O
MeOH (0.4M), 70ºC, 16h
R1
R1
N
R2
N
R2
[Pd(PPh3)4] (3 mol%)
2)
(3 eq)
I
Entry
1
Substrate
Product
%NMR Yield[b]
[%IY][c]
71%
KOH (6 eq) 90ºC, 16h
O
N
O
O
Me
N
N
98%
OMe
OMe
OMe
18, 99% [94%]
17, 98% [26%]
16, 99% [72%]
2
3
4
96%
99%
52%
62%
78%
24%
O
O
Me
N
N
NMe2
19, 99% [74%]
OMe
20, 99% [65%]
Scheme 5.Sequential transition-metal-free borylation of acyl substituted
allenamides with concomitant Pd-catalyzed Suzuki-Miyaura cross-coupling.
To conclude, we have described a transition metal-free borylation
of electronic deficient variants of allenamides, with high yields and
complete stereocontrol on the hydroboration of the distal double
bond, providing exclusively the Z-isomers. The acyl groups on the
amine moiety are crucial to obtain the complete stereoselective
as a consequence of the formation of a stable allylic anion
intermediate that is further regioselectively protonated to give the
final product. The transition-metal freee borylation can be
followed by Pd-catalyzed cross coupling with aryl iodides
generating stereoselective trisubstitutd olefins.
5
6
7
8
9
25%
94%
99%
90%
16%
--
65%
74%
72%
--
Acknowledgements
The present research was supported by the Spanish Ministerio de
Economia y competitividad (MINECO) through projects FEDER-
CTQ2016-80328-P and FEDER-CTQ2017-83633-P and by the
Basque Government (Project IT908-16). L. G. and N. M. also
acknowledges Spanish MINECO for a FPI fellowship. We thank
AllyChem for the gift of diboranes.
O
N
Bpin
14A
OMe
Keywords:allenamines • borylation • transition-metal-free • DFT
calculations • stereoselectivity
[a]Conditions: allenamide(0.2 mmol), KOtBu (30 mol%), B2pin2 (1.2 equiv),
MeOH (0.4 M), 70ºC, 16h. [b]NMR Yields calculated in 1H NMR spectra with
naphthalene as internal standard. [c]%IY= isolated yield
[1]
[2]
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[19] Calculations were performed using Gaussian09 (M06-2X functional) and
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L. García, J. Sendra, N. Miralles, E.
Reyes, J. J. Carbó,* J. L. Vicario,* E.
Fernández*
Page No. – Page No.
Title
Complete stereocontrol on the transition-metal-free hydroboration of the distal
double bond of allenamides can be achieved when allenamides contain acyl
substituents, providing exclusively the Z-isomer. The consecutive Pd-catalyzed
cross coupling reaction allowed the straightforward formation of tri-substituted
enamides, with total control on the stereoselectivity.
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