Complex Boron-Containing Molecules through a 1,2-Metalate Rearrangement/anti-SN2′ Elimination/Cycloaddition Reaction Sequence

Article abstract of DOI:10.1055/s-0037-1610389

The three-component coupling of benzylamines, boronic esters, and 4-phenyl-3 H -1,2,4-triazole-3,5(4 H)-dione (PTAD) is reported. The boronate complex formed from an ortho -lithiated benzylamine and a boronic ester undergoes a stereospecific 1,2-metalate rearrangement/ anti -S _N 2′ elimination in the presence of an N-activator to provide a dearomatized tertiary boronic ester. Interception of this dearomatized intermediate with a dienophile leads to stereopredictable cycloaddition reactions to generate highly complex three-dimensional boron-containing molecular structures. When enantioenriched α-methyl-substituted benzylamines are employed, the corresponding cycloaddition adducts are formed with excellent enantiospecificities.

Full text of DOI:10.1055/s-0037-1610389

SYNLETT
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5
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1
4
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2
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9
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Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
C. Tillin et al.
Letter
Synlett
Complex Boron-Containing Molecules through a 1,2-Metalate
Rearrangement/anti-SN2′ Elimination/Cycloaddition Reaction
Sequence
Me
Chloe Tillin
Me
O
B
Raphael Bigler
NMe2
+
R
Renata Calo-Lapido
Beatrice S. L. Collins
Adam Noble
O
Bpin
R
Li
O
N
R
N
N
Varinder K. Aggarwal*
0
0
0
0-0
0
0
3-0
3
4
4-
6
4
3
0
O
Ph
O
O
B
O
N
O
O
R
N
N
O
O
complex
boron-containing
molecules
School of Chemistry, University of Bristol, Cantock’s Close, Bristol
BS8 1TS, UK
v.aggarwal@bristol.ac.uk
B
Me
N
Me
N
N
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
R
O
Received: 30.09.2018
Accepted after revision: 25.10.2018
Published online: 20.11.2018
functionalized organoboron molecules, rich in orthogonal
functionality that could be used for subsequent synthetic
elaboration. Here, we detail a simple one-pot procedure
that generates complex three-dimensional boron-contain-
ing architectures that bear multiple sites of orthogonal re-
activity.
DOI: 10.1055/s-0037-1610389; Art ID: st-2018-b0627-l
License terms:
Abstract The three-component coupling of benzylamines, boronic es-
ters, and 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD) is reported.
The boronate complex formed from an ortho-lithiated benzylamine and
a boronic ester undergoes a stereospecific 1,2-metalate rearrange-
ment/anti-SN2′ elimination in the presence of an N-activator to provide
a dearomatized tertiary boronic ester. Interception of this dearomatized
intermediate with a dienophile leads to stereopredictable cycloaddition
reactions to generate highly complex three-dimensional boron-con-
taining molecular structures. When enantioenriched -methyl-substi-
tuted benzylamines are employed, the corresponding cycloaddition ad-
ducts are formed with excellent enantiospecificities.
We recently reported a method for the enantiospecific
synthesis of ortho-substituted benzylic boronic esters by a
1,2-metalate rearrangement/anti-SN2′ elimination/1,3-
borotropic shift reaction sequence starting from enantioen-
riched -substituted benzylamines [Scheme 1(A)].5 This re-
action sequence passes through a key dearomatized tertiary
boronic ester intermediate Int-I, with the subsequent 1,3-
borotropic shift driven by the favorable rearomatization.
We have also shown that this key enantioenriched dearo-
matized intermediate can participate in allylboration and
allylic Suzuki–Miyaura cross-coupling reactions to provide
complex enantioenriched products [Scheme 1(B)].5,6 Impor-
tantly, all of these transformations use rearomatization as a
driving forcing. We were, however, interested in diverting
reactivity along an alternative pathway, avoiding rearoma-
tization and thereby retaining valuable functionality. In this
way, we postulated that we might be able to intercept the
dearomatized intermediate Int-I through a Diels–Alder cy-
cloaddition reaction with an appropriate dienophile. As de-
picted in Scheme 1(C), this should give rise to complex
three-dimensional architectures that possess not only a ter-
tiary boronic ester moiety, but also two electronically dif-
ferentiated alkene moieties (an allyl boronic ester and an
isolated alkene), along with the functionalities associated
with the boronic ester component and the dienophile. In-
terception of dearomatized intermediates has a significant
history in organic synthesis, and it has been used in total
syntheses7 and, more recently, as a powerful method in
transition metal-catalyzed transformations.8 A number of
issues were expected to arise in the realization of this pro-
Key words cycloaddition, 1,2-metalate rearrangement, phenyltri-
azoledione, benzylamines, boronic esters, multicomponent reaction
Boronic esters are highly versatile molecules in organic
synthesis due to the wealth of stereospecific transforma-
tions that they have been shown to undergo. Transforma-
tion into alcohols, amines, halogens, or unsaturated carbon
moieties (alkenes or alkynes) can occur through stereore-
tentive or stereoinvertive pathways, whereas homologation
reactions can be used to build up complex carbon skele-
tons.1,2 Furthermore, -amino boronic acids have been
shown to act as potent inhibitors of serine protease, leading
to the development of, for example, bortezomib, a treat-
ment for relapsed and refractory multiple myeloma.3 Thus,
the development of novel methods for the synthesis of alkyl
boronic esters with high enantiopurity is of utmost impor-
tance. Although recent years have seen a huge growth in
the development of such methods,4 access to structurally
complex alkyl boronic esters possessing an array of useful
functionalities remains a challenge. We were interested in
the development of a method for the synthesis of densely
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
C. Tillin et al.
Letter
Synlett
A: ortho-Substituted secondary benzylic boronic esters, Aggarwal, 2017
O
R''
O
R''
R''
R
R'''
Cl
R''
N
R'''
Bpin
R'
Me2
NMe2
Bpin
R'
Bpin
N-activation
1,2-migration
and
1,3-borotropic
shift
Bpin
R'
R
R
R'
anti-SN2'-elimination
R
Int-I
B: Rearomatizing C–C bond-forming processes from Int-I
Me
PhCHO
Pd (cat.), PhI
Me
Me
Bpin
allylboration
Suzuki–Miyaura
Int-I
OH
C: Proposed interception of Int-I through a cycloaddition reaction
EWG
R''
EWG
X
X
R'
O
B
X
X
EWG
Bpin
R''
Bpin
O
X
R
R''
Bpin
X
X
R''
R'
dienophile
R'
X
R
R'
cycloaddition
R
R
EWG
Scheme 1 Rearomatizing transformations of Int-I and proposed cycloaddition pathway
cess, including (i) the well-known limited reactivity of cy-
clohexadienes, further compounded by the presence of a
sterically demanding tertiary boronic ester; (ii) the facial
selectivity in the Diels–Alder cycloaddition, which should
give rise to diastereomeric mixtures; and (iii) the potential
O
B
i) CyBpin 2a, THF, –78 °C to rt
ii) ClCO2CMe2CCl3, –78 °C to rt
O
O
NMe2
N
iii)
O
N
Li
rt, 1 h
PTAD
N
N
O
N
Li-1a
N
for matched/mismatched reactivities when both chiral ben-
zylamines and boronic esters are used.
O
3aa, 51%, 17:1 d.r.
We began our studies by preparing the key dearoma-
Scheme 2 Cycloaddition of Int-I with PTAD
tized intermediate through treatment of lithiated benzyl-
amine Li-1a with 2-cyclohexyl-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (CyBpin; 2a), followed by activation of the
amine moiety with ClCO2CMe2CCl3 (Me2Troc–Cl), in line
with our previous reports (Scheme 2). To our delight, the
We then went on to assess the scope of the boronic ester
component by using the lithiated benzylamine Li-1a
(Scheme 3). The Boc-protected piperidine boronic ester 2b
provided the cycloaddition product 3ab in 67% yield and an
excellent dr (>20:1), as did the 1-adamantyl boronic ester
2c (3ac; 42% yield, >20:1 dr). Interestingly, when the phen-
ylboronic ester 2d was used, the syn-isomer was still fa-
vored, but diastereoselectivity was poor (1.5:1). Further-
more, where less sterically bulky boronic esters, such as the
cyclopropyl boronic ester 2e or the primary boronic esters
2f–j were used, the diastereoselectivity was inverted to fa-
vor the anti-isomer. The entries shown in Scheme 3 also
highlight the range of functionalities tolerated by the reac-
tion, including protected alcohols (3ah) or aldehydes (3aj),
along with azides (3ai) or carbamates (3ab).
addition
of
4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione
(PTAD; 1.1 equivalents) to the reaction mixture at room
temperature, followed by stirring for one hour, provided cy-
cloaddition product 3aa in 51% isolated yield and a remark-
able dr of 17:1 (determined by 1H NMR analysis of both the
crude and purified product); the product was obtained as
the syn-isomer (here, syn designates the relationship be-
tween the Bpin moiety and the triazolidine group). We
chose PTAD as the dienophile on the basis of reports in the
literature that addressed the poor reactivity of cyclohexa-
dienes towards cycloaddition reactions due to the high dis-
tortion energies associated with accessing the transition-
state geometry.9 Studies by Houk and co-workers investi-
gated the superior reactivity of PTAD as a dienophile for
such systems.10 Indeed, other dienophiles tested (e.g., male-
ic anhydride, diethyl acetylenedicarboxylate, and diethyl
fumarate) were all unreactive.11
We rationalize the selectivities observed in Scheme 3 as
follows [Scheme 4(A)]. When the R group on the boronic es-
ter is large (e.g., 3aa–ac in Scheme 3), the dienophile ap-
proaches the diene of Int-I past the smaller Bpin moiety,
leading to the syn-isomer with high diastereoselectivity.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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C. Tillin et al.
Letter
Synlett
O
B
O
B
R
R
i) THF, –78 °C to rt
ii) ClCO2CMe2CCl3, –78 °C to rt
O
O
O
B
NMe2
O
O
+
+
N
N
O
iii) PTAD, rt, 1 h
R
Li
N
N
N
N
Li-1a
2x
O
O
syn-3ax
anti-3ax
O
O
O
N
O
B
O
B
O
B
O
B
B
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
O
N
N
N
N
N
N
N
N
N
N
O
O
O
O
3aa, 51%, 17:1 d.r.
3ab, 67%, >20:1, d.r.
3ac, 42%, >20:1, d.r.
3ad, 50%, 1.5:1 d.r.
3ae, 60%, 1:1.6 d.r.
O
B
O
O
O
O
O
O
B
B
Si
B
B
O
O
O
O
O
O
O
N3
O
O
N
O
O
N
N
O
N
O
N
O
N
N
N
N
N
N
N
N
N
N
O
O
3af, 59%, 1:2.7 d.r.
3ag, 56%, 1:3.0 d.r.
3ah, 43%, 1:2.4 d.r.
3ai, 35%, 1:2.8 d.r
3aj, 54%, 1:2.3 d.r.
Scheme 3 Scope of the boronic ester component. The dr was determined by 1H NMR analysis of the crude and purified products.
The remarkable diastereoselectivities observed in these
cases indicate that the Bpin group, which is widely regarded
as bulky, is considerably less sterically demanding than
simple -branched alkyl groups.12 When R is small, for ex-
ample a cyclopropyl or primary alkyl group, the dienophile
approaches past this group, avoiding the Bpin moiety,
thereby providing the anti-isomer. In these cases, the steric
difference between the smaller R group and the relatively
small Bpin moiety is less, and the diastereoselectivity is
correspondingly reduced. For the phenylboronic ester 2d,
approach past the Bpin moiety is still favored, but with
much lower selectivity.
Scheme 4 Cycloaddition facial selectivity considerations and diastereomer assignments
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
C. Tillin et al.
Letter
Synlett
The cycloaddition products were usually isolated as
mixtures of diastereoisomers, and their relative configura-
tions were assigned through analysis of the 13C NMR chemi-
cal shifts. For the anti-isomers, diagnostic downfield shifts
are observed for one of the alkene signals, due to donation
of electron density from the alkene into the proximal emp-
ty p-orbital on boron. These 13C NMR assignments were
further supported by the separation of the syn- and anti-
isomers for the cyclopropyl product 3ae; single-crystal X-
ray diffraction analyses of the two isomers confirmed our
assignments [Scheme 4(B)].
We then assessed the scope of the benzylamine compo-
nent (Scheme 5). Methyl substituents were accommodated
in both the meta- and ortho-positions (3ba and 3ca), and
fluorine substituents were also tolerated (3da and 3ea). In-
terestingly, whereas putative cycloaddition adducts could
be identified in the crude 1H NMR spectra for electron-rich
benzylamines, such as those bearing methoxy substituents,
attempts to isolate these products by chromatography were
frustrating, as despite extensive assessment of the chro-
matographic medium, no product could be isolated. We
postulate that the enol ether present in such cycloadducts
might be activated by the silica during chromatography, fa-
cilitating a series of deleterious side reactions.
proceeds with excellent enantiospecificity for secondary
boronic esters due to a selective N-acylation of a low-ener-
gy conformation of the boronate complex, in which the hy-
drogen atom of the benzylic position lies in the plane of the
aromatic ring towards the boronate.5 This leads to the gen-
eration of the tertiary boronic ester dearomatized interme-
diate Int-I in excellent levels of enantiospecificity. We ex-
pected this enantioenrichment to be transferred directly
through the cycloaddition process, and this was borne out
by the generation of cycloadduct 3fa from the -methyl-
substituted benzylamine 1f (97:3 er) in 69% yield, 95:5 er,
and >20:1 dr (Scheme 6). Primary alkyl boronic ester 2g
provided cycloadduct 3fg in 30% yield, 91:9 er, and 1:2.2 dr
in favor of the anti-isomer (the er refers to the major anti-
diastereoisomer, but this is expected to be the same for the
minor syn-diastereoisomer). When we used both enantio-
enriched chiral amine 1f and enantioenriched boronic ester
2k (95:5 er), cycloadduct 3fk was formed in 9:1 dr with re-
spect to all other isomers. The use of the opposite enantio-
mer of the benzylamine 1g (1:99 er) provided cycloadduct
3gk in similar yield and diastereoselectivity, indicating no
matched/mismatched behavior. Such behavior was also ob-
served when the menthol-derived boronic ester 2l reacted
with the two enantiomers of the -methyl-substituted ben-
zylamine to provide 3fl (17:1 dr) and 3gl (>20:1 dr).
In summary, we have developed an enantiospecific,
one-pot, 1,2-metalate rearrangement/anti-SN2′ elimina-
tion/cycloaddition reaction sequence that generates com-
plex three-dimensional structures with exquisite enanti-
oselectivity and predictable diastereoselectivities. The con-
vergent three-component nature of this process leads to
structures bearing diverse orthogonal functionalities. Stud-
ies are ongoing to exploit this functionality in subsequent
transformations, so as to permit access to valuable, densely
functionalized, chiral building blocks.
O
i) THF, –78 °C to rt
ii) ClCO2CMe2CCl3
–78 °C to rt
Cy
B
O
O
B
NMe2
O
+
R
N
O
Cy
iii) PTAD, rt, 1 h
R
Li
N
N
Li-1x
2a
3xa
O
O
B
O
B
O
O
O
O
N
N
N
N
N
N
Funding Information
O
O
This work was financially supported by the EPSRC (EP/I038071/1),
H2020 ERC (670668), and the University of Bristol. R.B. thanks the
3ba, 83%, 15:1 d.r.
3ca, 74%, >20:1 d.r.
Swiss
National
Science
Foundation
fellowship
program
O
B
O
(P2EZP2_165268). R.C.L. was funded by Xunta de Galicia and Europe-
an Social Fund.
B
O
N
O
N
E
n
g
i
n
e
eri
n
g
a
n
d
P
h
ysi
c
a
lS
c
i
e
n
c
es
R
esearc
h
C
o
u
n
c
i
l (EP/I
0
3
8
0
7
1/1)S
w
i
s
N
ati
o
n
a
lS
c
i
e
n
c
e
F
o
u
n
d
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o
n
f
el
o
wsh
i
p
progra
m
(P
2
E
Z
P
2
_
1
6
5
2
6
8)
O
O
N
N
N
N
F
F
Acknowledgment
O
O
3da, 34%, >20:1 d.r.
3ea, 57%, >20:1 d.r.
We thank Dr. Hazel A. Sparkes for assistance with X-ray crystallogra-
phy. We thank Stefan Aichhorn for useful discussions and Belén
Rubial for assistance with HPLC analysis.
Scheme 5 Scope of the benzylamine component. The dr was deter-
mined by 1H NMR analysis of the crude and purified products.
We then addressed enantioenriched -methyl-substi-
tuted benzylamines. We have previously reported that the
1,2-metalate rearrangement/anti-SN2′ elimination sequence
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610389.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
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n
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
C. Tillin et al.
Letter
Synlett
O
B
Me
R
i) THF, –78 °C to rt
ii) ClCO2CMe2CCl3, –78 °C to rt
O
B
O
NMe2
O
+
N
O
O
Me
iii) PTAD, rt, 1 h
R
Li
N
N
Li-1f (or Li-1g)
2x
3fx (or 3gx)
O
B
O
B
O
O
B
B
O
O
O
O
O
O
O
O
N
N
O
N
N
Me
Me
Me
Me
O
O
N
N
N
N
N
N
N
N
O
O
O
3fa, 69%
>20:1 d.r., 95:5 e.r.
3fg, 30%
1:2.2 d.r., 91:9 e.r.
3fk, 76%, 9:1 d.r.
3gk, 67%, 10:1 d.r.
i-Pr
i-Pr
O
B
O
B
O
O
O
O
N
O
N
Me
Me
N
N
N
N
O
3fl, 85%, 17:1 d.r.
3gl, 75%, >20:1 d.r.
Scheme 6 Reactivity of enantioenriched -methyl benzylamines. The dr was determined by 1H NMR analysis of the crude and purified products.
References and Notes
Boronic ester 2a (500 mol) was added to the ortho-lithiated ben-
zylamine Li–1a (525 mol, 1.05 equiv; prepared from 1a) in THF (2
mL) at –78 °C, and the solution was stirred at –78 °C for 15 min,
after which the cooling bath was removed, and the mixture was
stirred for a further 15 min. ClCO2CMe2CCl3 (132.0 mg, 550 mol,
1.10 equiv) was added at –78 °C, and the solution was stirred for 15
min at –78 °C, after which the cooling bath was removed and the
mixture was stirred for a further 5 min. PTAD (96.3 mg, 550 mol,
1.10 equiv) was added, and the solution was stirred for 1 h at r.t.
CHCl3 (50 mL) was added and the solution was washed with H2O
(25 mL) and sat. aq NaCl (25 mL), then dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification by flash column
chromatography [silica gel. EtOAc–pentane (15:85)] gave a white
solid; yield: 121 mg (50%), dr = 17:1; mp 86 °C, Rf = 0.47 (EtOAc–
pentane, 15:85).IR (liquid film): 2927, 1771, 1710, 1397, 1138, 908,
(1) Sandford, C.; Aggarwal, V. K. Chem. Commun. 2017, 53, 5481.
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Rubinstein, A.; Dembitsky, V. M.; Srebnik, M. Chem. Rev. 2012,
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(4) Collins, B. S. L.; Wilson, C. M.; Myers, E. L.; Aggarwal, V. K.
Angew. Chem. Int. Ed. 2017, 56, 11700.
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Soc. 2017, 139, 9519.
(6) Rubial, B.; Collins, B. S. L.; Bigler, R.; Aichhorn, S.; Noble, A.;
Aggarwal,
V.
K.
Angew.
Chem.
Int.
Ed.
2018,
DOI: 10.1002/anie.201811343.
(7) Roche, S. P.; Porco, J. A. Jr Angew. Chem. Int. Ed. 2011, 50, 4068.
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D. J. Am. Chem. Soc. 2018, 140, 4503.
(9) Paton, R. S.; Kim, S.; Ross, A. G.; Danishefsky, S. J.; Houk, K. N.
Angew. Chem. Int. Ed. 2011, 50, 10366.
(10) (a) Chen, J. S.; Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1998,
120, 12303. (b) Levandowski, B. J.; Houk, K. N. J. Org. Chem.
2015, 80, 3530.
.
727, 644 cm–1 1H NMR (400 MHz, CDCl3):  = 7.48–7.36 (m, 4 H,
Ar-H), 7.34–7.28 (m, 1 H, Ar-H), 6.50 (ddd, 3JH,H′ = 7.7, 5.5 Hz, 4JH,H′
=
1.8 Hz, 1 H, =CH), 6.43 (ddd, 3JH,H′ = 7.7, 5.4 Hz, 4JH,H′ = 1.7 Hz, 1 H,
=CH), 5.39 (s, 1 H, =CHH), 5.26–5.21 [m, 2 H, =CHH (1 H) + CHN (1
H)], 5.11 (dd, 3JH,H′ = 5.5 Hz, 4JH,H′ = 1.7 Hz, 1 H, CHN), 2.08–2.00 (m, 1
H, CHH), 1.79–1.61 (m, 4 H, CHH), 1.26 [s, 6 H, CH3 (pin)], 1.24 [s, 6
H, CH3 (pin)], 1.23–1.02 [m, 6 H, CH (1 H) + CHH (5 H)]. 13C{1H} NMR
(101 MHz, CDCl3):  = 155.8 (CO), 155.3 (CO), 142.9 (=C), 131.8
(arom.), 129.9 (=CH), 129.0 (2 C, arom.), 128.6 (=CH), 128.0 (arom.),
125.4 (2C, arom.), 113.9 (=CH2), 84.2 [2 C, OC(CH3)2], 59.0 (CHN),
57.0 (CHN), 44.4 (CH), 31.0 (CH2), 29.8 (CH2), 27.3 (CH2), 27.1 (CH2),
26.4 (CH2), 25.1 [2 C, CH3 (pin)], 24.4 [2 C, CH3 (pin)]. Carbons
attached to boron were not observed due to quadrupolar relax-
ation. 11B{1H} NMR (128 MHz, CDCl3):  = 33.5 (br s). HRMS (ESI):
m/z [M + Na]+ calcd for C27H34BN3NaO4: 498.2535; found: 498.2554.
(11) See Supporting Information for details.
(12) Huang, Q.; Zard, S. Z. Org. Lett. 2018, 20, 5304.
(13) (±)-(5S,8R,11S)-11-Cyclohexyl-10-methylene-2-phenyl-11-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,8-dihydro-
1H-5,8-ethano[1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-
dione (3aa)
Typical Procedure
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E