Isoquinoline Alkenylboron ACIE 2023

15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202216961 by levent artok - Izmir Yuksek Teknoloji Enstit , Wiley Online Library on [08/03/2023].
See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Angewandte
Research Articles Chemie
www.angewandte.org
How to cite:
Synthetic Methods International Edition: doi.org/10.1002/anie.202216961
German Edition: doi.org/10.1002/ange.202216961
Diastereoselective Alkylation of Activated Nitrogen Heterocycles

with Alkenyl Boronate Complexes
James E. McGettigan, Jr. and Joseph M. Ready*
Abstract: Alkenyl boronate complexes react with acy-

lated quinolines and isoquinolines via 1,2-metalate
rearrangement to give alkylated, dearomatized hetero-
cycles in good yields, diastereoselectivities, and regiose-
lectivities. This multi-component coupling is highly
modular and can be used to access a wide scope of
heterocyclic scaffolds. Chiral boronic esters made
through this methodology possess high synthetic poten-
tial and can be transformed into various functional
groups in one step without racemization.
Introduction
Tetravalent boron-“ate” complexes have recently emerged

as versatile nucleophiles in multi-component coupling reac-
tions. For example, alkenyl boronate complexes (A,
Scheme 1) undergo 1,2-metalate shifts upon exposure to
suitable electrophilic partners.[1] This reactivity builds on the
classic studies by Zweifel, which leveraged iodine as the
electrophile, leading to olefination products after
elimination.[2] Modern approaches have shown that organo-
metallic complexes,[3] heteroatoms,[4] strained π-systems,[5]
and stabilized carbocations[4b, 6] are competent to initiate the
1,2-metalate rearrangement. Techniques that facilitate 1,2-
migration of alkenyl boronates through radical polar cross-
Scheme 1. a) Relevant N-heterocyclic scaffolds. b) 1,2-metalate shifts of
over have also been developed.[7] Notably absent, however,
alkenyl boronate complexes into different types of electrophiles. c) Acyl
are general and stereoselective methods to add alkenyl pyridinium salts promoting 1,2-metalate shifts of boronates. d) Intra-
boronate complexes to nitrogen heterocycles, despite the amolecular dearomatization of pyridines via 1,2-metalate rearrange-
potential of such a transformation to access drug-like ment. e) 1,2-metalate shifts of alkenyl boronates into acylated hetero-
molecular scaffolds. cycles. B(pin) = boronic acid pinacol ester, Ar = aryl, Ac = acetyl.
Nitrogen heterocycles such as pyridine, quinoline, and
isoquinoline and their reduced variants are common sub-
structures in both pharmaceuticals and natural products.[8] chemical complexity (Scheme 1a), making their synthesis
Molecules of interest that contain these heterocycles are challenging. An attractive starting point for these targets is
often accompanied by significant structural and stereo- the parent heteroarene. Methods for dearomatizing addition
to pyridine and related heterocycles commonly employ
[*] J. E. McGettigan, Jr., Prof. J. M. Ready alkylated or acylated heterocyclic salts owing to their
Department of Biochemistry, Division of Chemistry, UT Southwest- increased electrophilicity.[9] Good regioselectivities often
ern Medical Center require sterically or electronically biased substrates, limiting
5323 Harry Hines Blvd., Dallas, TX 75390-0938 (USA) the scope of these methods.[10] The generation and control of
E-mail: joseph.ready@utsouthwestern.edu
one or more stereocenters has been achieved with the use of
© 2023 The Authors. Angewandte Chemie International Edition chiral auxiliaries, metal catalysts, organocatalysts, and chiral
published by Wiley-VCH GmbH. This is an open access article under
nucleophiles.[11]
the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any med- Dearomatizing addition of alkenyl boronates to acylated
ium, provided the original work is properly cited, the use is non- N-heteroarenes could give access to chiral, heterocyclic
commercial and no modifications or adaptations are made. products, but this type of reactivity has not been described
Angew. Chem. Int. Ed. 2023, e202216961 (1 of 8) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202216961 by levent artok - Izmir Yuksek Teknoloji Enstit , Wiley Online Library on [08/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Angewandte
previously. While the scope of appropriate electrophiles for activate isoquinoline and initiate the addition/1,2-metalate
alkenyl boronate complexes has expanded greatly in recent rearrangement process. Boc anhydride (Boc2O) (entry 1)
years, examples of iminium-type electrophiles are still proved to be a competent activator, giving the desired
limited. The Aggarwal group has shown that simple iminium dihydroisoquinoline in 78 % yield. A superstoichiometric
salts such as Eschenmoser’s salt will react with alkenyl amount of both activator and heterocycle was required to
boronate complexes, giving the respective aminoboronic achieve optimal yields (entry 2). We were encouraged to see
ester products (Scheme 1b).[6] A related approach from the that product 2 a was obtained as a single diastereomer, with
Pelter group showed that trialkyl alkynylboronates can the relative configuration being confirmed by X-ray
participate in such reactions, giving 4-subsituted pyridine analysis.[16] Acetic anhydride (Ac2O) and acetyl chloride
exclusively after oxidation (Scheme 1c).[12] While regioselec- (AcCl) (entries 3 and 4) gave 2 b as the only product in 69 %
tivity was high, unsubstituted pyridine was the sole substrate and 58 % yields. Chloroformates such as trichloroeth-
reported. This method also suffers from the use of oxycarbonyl chloride (TrocCl) and phenyl chloroformate
pyrophoric trialkylboranes and lacks stereocontrol. A recent (PhOCOCl) (entries 5,6) were also competent; however, the
report from the Panda group utilized indole-derived boro- resulting protected amines reacted further under the
nate complexes to dearomatize acylated pyridines with oxidation conditions to give cyclic carbamate product 3.
similar regioselectivity.[13] 4-Pyridine boronic esters could Overall, all activators screened in this survey promoted the
undergo dearomative addition of alkyl lithium, magnesium, tandem addition/1,2-metalate rearrangement of alkenyl
and zinc reagents after activation through N-acylation.[14] boronate complex 1 into isoquinoline. Factors such as steric
However, those additions did not generate new stereo- bulk of the activator and counterion seemed to have little
centers (Scheme 1d). We reasoned that a similar trans- effect on diastereoselectivity, with all products being
formation would be possible with alkenyl boronate com- obtained in > 10 : 1 diastereomeric ratio.
plexes to give the alkylated, dearomatized heterocycle Next, we were interested in exploring this transformation
containing a synthetically useful and stable boronic ester with different alkenyl boronate complexes to test the
moiety (Scheme 1e). This reaction would be a net four- reactivity of other migrating groups (Scheme 2). We elected
component coupling while also generating two stereocenters to use Boc2O for these experiments, as it gave the best
in a single step. The products of this transformation possess yields, and the products were robust towards the oxidation
great synthetic potential by way of the boronic ester and conditions. The “ate” complexes were generated from
protected enamine groups. Chiral boronic esters are partic- alkenyl boronic esters and organolithium reagents (method
ularly diversifiable to many different functional groups in a A) or from in situ generated alkenyl lithiums and organo-
stereospecific fashion, making them attractive synthetic boronic esters (method B). The two organolithium-based
handles.[15] approaches to forming alkenyl boronate complexes give
access to a large scope of potential nucleophiles based on
available alkyl, alkenyl, and aryl boronic esters. An alter-
Results and Discussion native method that leverages the use of Grignard reagents
and lithium chloride to form the “ate” complex was also
Our investigations began by studying the reaction between used (method C), circumventing the need for the more
alkenyl boronate complex 1 and isoquinoline (Table 1). We hazardous organolithium reagents.[17] A range of substituted
evaluated various acylating reagents for their ability to phenyl rings participated well in the reaction. Electron-
donating substituents at the para position gave the corre-
sponding benzylic alcohols in high yields and virtually
Table 1: Alkylation of isoquinoline with alkenyl boronates using differ- complete diastereoselectivity (4, 5). Electron-withdrawing
ent acylating reagents. Boronic ester products were oxidized to the groups were also amenable, albeit with comparatively
corresponding alcohol in situ using NaOH/H2O2. Diastereomeric ratios reduced yields, likely due to the decreased nucleophilicity of
determined by 1H NMR after purification. these boronate complexes (6–9, 14). The reaction is also
suitable for migrating phenyl rings with ortho (10, 11) and
meta (12, 13) substitution. Notably, 1,2-migration of 2-
fluorophenyl (11) occurred with reduced diastereoselectivity
compared to other substituted phenyl migrants (10 : 1 d.r. vs.
> 20 : 1 d.r. for other aryl migrants). Yields and diastereose-
lectivities were comparable for the 1,2-metalate shift of aryl
migrants whether organolithiums (method A or B) or
Grignard reagents (method C) were used. Thus, selection
among the methods is largely driven by convenience. Other
aryl migrants also worked well in the multi-component
coupling, such as naphthyl (15) furan (16) thiophene (17)
[a] Isolated yields after column chromatography. [b] Reaction per-
and indole (18). Boron was a suitable migrant when used in
formed with one equivalent of isoquinoline and Boc2O. [c] Observed the form of B2(pin)2, giving the corresponding ketone after
by 1H NMR ; product not isolated. o/n = overnight, %Y = isolated oxidation of the diborylated product (19).
percent yield.
Angewandte
Scheme 2. Migrating group scope, isolated yields are reported. [a] Isolated as the boronic ester without oxidation. Ts = p-toluenesulfonyl.
We next explored the reactivity of alkyl migrants. The butyl were installed in modest yield with exclusive diaster-
reaction of isoquinoline with the “ate” complex derived eocontrol (32). A highly strained bicyclopentane substrate
from methyl lithium and 2-isopropenyl Bpin gave 20 in migrated smoothly, giving dihydroisoquinoline product 33
satisfying yield. When n-butyl was used as the migrating containing a medicinally relevant phenyl bioisostere.[18]
group, product 21 was generated in high yield and modest Products obtained from tertiary migrants (32, 33) were
diastereoselectivity (7 : 1 d.r.). Other primary alkyl migrants isolated as the boronic ester, as the high level of steric
were tested, showing that the reaction is compatible with hindrance led to sluggish oxidation. Lastly, we applied this
functional groups such as olefins (22), esters (23), and azides methodology to an alkenyl boronate complex derived from
(24). Interestingly, these primary alkyl migrants all pro- the bioactive estrone ketal. The steroidal architecture
ceeded with notably lower diastereoselectivity compared to migrated in 41 % yield and high d.r. with respect to the
their aryl counterparts. Secondary alkyl substrates such as newly formed stereocenters (34).
isopropyl (27), cyclohexyl (28), Boc-piperidine (29), cyclo- Some migrating groups were incompatible with the
propyl (30) and Boc-azetidine (31) were also applicable in multi-component coupling. For example, benzylic boronate
modest to good yields. Small rings migrated with higher complex 35 failed to give any desired product. Only benzyl
diastereocontrol than larger rings or linear alkyl groups (30, addition was observed (36), similar to results seen from a
31). Even tertiary carbon-based migrants were compatible previous report by the Aggarwal group.[19] This addition is
under the reaction conditions: bulky migrants such as tert- presumably due to the relative stability of the benzylic
Angewandte
anion. Heteroaromatic migrants such as pyridine (37, 38) mixture of only two observable diastereomers out of the
and pyrimidine (39) led to complex reaction mixtures and four possible (10 : 1 d.r.). X-ray diffraction of 51 revealed the
only trace amounts of the target products. Lastly, bis- major diastereomer to be the product of syn addition of the
(alkenyl)boronates such as 40 and 41 only yielded unin- migrating group and isoquinoline across the olefin.[15] This
terpretable mixtures. syn addition process is associated with electrophiles that
Next, we investigated the alkenyl component of the react through open, asynchronous bond formation with
boronate complexes (Scheme 3). When the boronate com- alkenyl boronate complexes (see below).[3c, 4b] Chromanone-
plex derived from 2-bromo-4-phenyl-1-butene (42) was derived “ate” complex 52 also participated well, giving
utilized in the reaction, product 43 was generated in boronic ester 53 in 55 % yield and 7 : 1 d.r. between the two
comparable yield and diastereoselectivity. Styrenyl boronate observed isomers.
44 was also compatible, giving 45 in modest yield. The Various isoquinolines were also tested to gauge sub-
boronate derived from the parent vinyl-Bpin 46 gave stituent effects on heterocycle reactivity (Scheme 4). Bro-
product 47 in low yield, likely due to the decreased moisoquinolines coupled with high diastereoselectivity and
nucleophilicity of mono-substituted alkenes in this type of yields ranging from modest to good depending on the
reaction.[20] Inspired by a previous report from Aggarwal,[5] position of the bromine atom (54–57). TBS-protected
we were pleased to find that vinyl cyclopropane 48 also alcohols were compatible (58, 59), as was an O-triflate (60).
reacted favorably under the described conditions to give 49. Isoquinolines bearing carbon-based substituents such as
This 1,2-metalate rearrangement proceeds through ring vinyl and phenyl reacted smoothly to give the respective
expansion of the cyclopropane onto the alkene, giving the dihydroisoquinoline products (61, 62). We were excited to
desired cyclobutane product with an encouraging 7 : 1 find that the reaction also performed well on β-carbolines.
diastereomeric ratio, with the other two possible isomers not When 9-methylnorharmane was employed, the dihydro-β-
being observed.[21] carboline product 63 was obtained in 40 % yield as virtually
Leveraging trisubstituted alkenyl boronate complexes one diastereomer. Substituted dihydro-β-carbolines contain-
under the reaction conditions would generate complex ing 1,3-stereocenters are found in a variety of bioactive
heterocyclic scaffolds with three contiguous stereocenters in natural products, making the streamlined and modular
a single step. Indeed, when cyclohexenyl boronate complex synthesis of these molecules highly valuable.[22] 3,4-Dihydroi-
50 was exposed to Boc-activated isoquinoline, the dihydroi- soquinolines performed excellently under the optimized
soquinoline product 51 was obtained in 66 % yield as a conditions as well, providing products 64 and 65 in 86 % and
83 % yields, respectively, as single diastereomers.
Scheme 3. Scope of alkene-derived boronate complexes. The letter

under each boronate complex indicates the method used to make
them, see Scheme 2 for details. [a] Isolated as the boronic ester without Scheme 4. Scope of substituted isoquinolines. TBS = tert-butyldimeth-
oxidation. ylsilyl.
Angewandte
With the reactivity of isoquinolines thoroughly inves- ester 66 was obtained in good yield and high diastereose-
tigated, we evaluated related N-heterocycles. Quinolines are lectivity, which could then be oxidized to alcohol 67 using
heterocycles of similar structure and reactivity which are sodium hydroxide and hydrogen peroxide.[25] Regioselectiv-
also found across many natural products and medicines.[23] ity and relative configuration were confirmed through X-ray
Direct alkylation of quinoline salts can often be problematic analysis of deprotected amine 68.[15] This reaction was
due to poor selectivity between C2 and C4 products.[9a, 10a] completely regioselective, with no evidence of C4 isomer
Diastereomeric and/or regioisomeric mixtures of products formation. Both electron rich (69) and electron poor (70, 71)
can be difficult to separate. Despite these concerns, we were aryl migrants reacted under the described conditions. Meth-
pleased to find that quinoline was a suitable electrophilic oxy-substituted quinolines were also screened, giving the
partner for boronate complex 1 when acylated with 2,2,2- respective products in modest yields (72, 73). The product of
trichloroethoxycarbonyl chloride (TrocCl) (Scheme 5a). Uti- the reaction using 4-methoxyquinoline was exposed to an
lizing 2-MeTHF in place of THF led to slightly increased acidic work-up in place of oxidation, giving quinolone 74 in
yields and selectivity.[24] Under these conditions, boronic 65 % yield and high diastereoselectivity.
Pyridines were also investigated for their ability to
participate in the 1,2-metalate rearrangement (Scheme 5b).
Unfortunately, these substrates were found to be difficult to
engage efficiently, even after extensive optimization. Prod-
ucts of the reaction were often found in low conversion and
as a mixture of C2 and C4 regioisomers. Interestingly, the
ratio of C2 : C4 was affected by the identity of the acylating
reagent. For example, pyridine acylated with Boc2O led to
dihydropyridine products 75 a and 76 a as a 3 : 1 mixture of
C2 : C4 regioisomers. Using 2,4,6-trichlorophenyl benzoyl
chloride in place of Boc2O resulted in similar yield but
favored the C4 isomer 76 b over C2 isomer 75 b. Subtle
changes in the sterics and electronics of these activators may
lead to the regioselectivites observed. Interestingly, using
acetyl chloride in the reaction only led to an unselective
mixture of C2 and C4 isomers in low conversion (not
shown). This is in contrast with Pelter’s example (Sche-
me 1c), which used more reactive, but less convenient,
trialkyl alkynyl boronates, which reacted with complete
regiospecificity at the C4 position.
The highly selective nature of this multi-component
coupling process deserves comment. A mnemonic that
predicts the observed product is depicted in Scheme 6a. We
postulate that the reaction between the acylated heterocycle
and boronate complex proceeds through a preferred
coulombic pair which aligns nitrogen cation with the “ate”-
complex anion. A syn addition process of the migrating
group and the activated heterocycle across the olefin
produces the coupling product. These factors provide ration-
ale for the observed diastereoselectivity for both isoquino-
lines and quinolines. Additionally, the coulombic pair would
explain the high regioselectivity observed in the quinoline
substrates. During our investigations, we observed varying
levels of diastereoselectivity with alkyl migrants. This is in
contrast with aryl migrants, which typically formed the
desired products as exclusively one diastereomer. The trends
observed in the diastereoselectivity are subtle. Strained rings
(cyclopropyl (30), BCP (33)) and large groups (t-butyl (32))
migrate with > 20 : 1 selectivity, while other alkyl groups
only migrate with � 5 : 1 selectivity. Future efforts will aim to
reveal the factors that dictate the degree of stereocontrol in
Scheme 5. Other N-heterocycles tested in the 1,2-metalate rearrange-
ment of alkenyl boronate complexes. a) Scope of quinoline-based these couplings. Nonetheless, we note that syn-selective
substrates. b) Attempts at alkylating pyridine with this methodology. addition has emerged as a general phenomenon for electro-
[a] From 4-methoxyquinoline. Boronic ester product was exposed to an philes that react through concerted addition/migration
acidic work-up in place of oxidation. [b] Product observed by 1H NMR, mechanisms. For example, syn-addition was noted in the Ir-
not isolated. catalyzed allylation of alkenyl boronates, as well as the
Angewandte
the chiral auxiliary 79, followed by exposure to alkenyl

boronate complex 1 yielded the desired product 80 as a 10 : 1
mixture of diastereomers.[11a, 26] Sequential reductions then
gave tertiary amine 81 in reasonably high enantiomeric ratio
(92 : 8 e.r.). The absolute configuration of the product was
determined through X-ray diffraction of the HCl salt 82,
revealing alkenyl boronate addition primarily from the
bottom face of isoquinoline as drawn.[15] Employing auxiliary
79 in place of Boc2O thereby enables general access to
enantioenriched products.
The protected aminoboronic ester products obtained
from this methodology possess great synthetic potential. To
demonstrate their utility, boronic ester 83 was prepared on
gram scale in 85 % yield and > 20 : 1 d.r. (Scheme 7). 83 was
then subjected to various transformations. Hydrogenation
with palladium on carbon gave tetrahydroisoquinoline 84 in
94 % yield. Reduction/deprotection of 83 with triethylsilane
and trifluoroacetic acid occurred in high yield without
harming the boronic ester. Transformations that target the
boronic ester were then evaluated. Synthesis of the versatile
BF3K salt 86 using aqueous KHF2 and methanol proceeded
smoothly in 93 % yield. Stereospecific proto-deborylation
with (nBu)4NF·3H2O gave product 87 in almost quantitative
yield.[27] Arylation methodology developed by Aggarwal was
also applied, giving furan 88 in 62 % yield and pyridine 89 in
34 % yield.[14b, 28] Lastly, we subjected 84 to Zweifel olefina-
tion conditions using in situ generated vinyl lithium. Under
this protocol, lactam 90 was unexpectedly obtained in 89 %
yield as a mixture of diastereomers (3 : 1 d.r.). Formation of
the desired terminal alkene was not observed. Presumably,
product 91 arises from the equilibrium between the
boronate complex and the stabilized benzyl anion. The
benzyl anion then reacts with the nearby Boc group to form
Scheme 6. a) Mechanistic proposal for the observed selectivity in the
lactam 91. Cyclization via benzyl anion also explains the
alkylation of quinolines and isoquinolines with alkenyl boronates.
b) Selective access to each diastereomer by swapping alkenyl sub- erosion of stereochemical purity that was observed. Believ-
stituent and migrating group. c) Synthesis of enantioenriched tetrahy- ing tertiary benzylic boronic esters to be incompatible for
droisoquinoline products through the use of a chiral auxiliary. Absolute this reason, we performed the olefination with tertiary alkyl
configuration was confirmed through X-ray diffraction of 82. boronic ester 90 instead. Additionally, we used excess vinyl
magnesium bromide to generate the vinyl boronate complex
in place of vinyl lithium.[29] Reaction under these conditions
fluorination with Selectfluor®.[3c, 4b] By contrast, reactions led to the desired Zweifel product 92 in modest yield.
proceeding through stepwise addition/migration mechanisms Notably, arylation products 88 and 89 and Zweifel products
appear to favor anti-products, including allylation of indole 91 and 92 are all examples of generating all-carbon
boronates[3d, e] and reactions with S and Se electrophiles.[4] quaternary centers. All transformations proceeded with
Morken’s conjunctive coupling features an anti-addition, retention of the boronic ester stereocenter with no racemi-
consistent with the proposed step-wise process involving zation observed.[30]
coordination of ArPd + to the vinyl boronate followed by
1,2-metallate shift.[3a]
The modular nature of synthesizing alkenyl boronate Conclusion
complexes allows for simple access to each diastereomer
(Scheme 6b). In Scheme 2, we showed that boronate com- In summary, quinoline and isoquinoline are competent
plex 1 reacts with isoquinoline and Boc2O to give 2 a in high electrophiles for inducing 1,2-metalate rearrangements of
yield and d.r. Swapping the alkenyl substituent (methyl) and alkenyl boronate complexes. When paired with Boc2O,
migrating group (phenyl) gave the opposite diastereomeric isoquinolines react with a variety aryl and alkyl-derived
product 77 exclusively. This process can also be used with alkenyl boronates to give the alkylated, dearomatized multi-
alkyl-based migrants such as n-butyl. component coupling products in modest to high yields and
This methodology can be adapted for the synthesis of diastereoselectivities. Quinolines react with similar effi-
enantioenriched material via a chiral auxiliary (Scheme 6c). ciency when acylated with TrocCl, giving the respective
Inspired by the work of Comins, acylating isoquinoline with products with notably high diastereoselectivites and regiose-
Angewandte
Scheme 7. Synthetic transformations of tertiary boronic ester products. CyH = cyclohexane, NBS = N-bromosuccinimide, LDA = lithium diisopropyl
amide.
lectivities. The products from this study provide syntheti- Data Availability Statement
cally valuable dearomatized heterocycles containing diversi-
fiable boronic ester moieties. The modularity of this process The data that support the findings of this study are available
provides a streamlined route towards numerous heterocyclic in the Supporting Information of this article.
scaffolds in one step from simple starting materials. Studies
involving other iminium-type electrophiles in tandem with Keywords: Alkenyl Boronate · Isoquinolines · Multicomponent
1,2-metalate rearrangements from alkenyl boronate com- Coupling · Quinolines
plexes are currently ongoing.
Acknowledgements [1] a) H. Wang, C. Jing, A. Noble, V. K. Aggarwal, Angew. Chem.

Int. Ed. 2020, 59, 16859–16872; Angew. Chem. 2020, 132,
Financial Support provided by the Welch Foundation (I- 17005–17018; b) S. Namirembe, J. P. Morken, Chem. Soc. Rev.
1612) and NIH (RM1GM142002). X-ray Crystallography 2019, 48, 3464–3474.
performed by Dr. Vincent Lynch (UT Austin) and Dr. Allen [2] G. Zweifel, H. Arzoumanian, C. C. Whitney, J. Am. Chem.
Soc. 1967, 89, 3652–3653.
Oliver (Notre Dame). We thank Dr. Feng Lin (UT South-
[3] a) L. Zhang, G. J. Lovinger, E. K. Edelstein, A. A. Szymaniak,
western) for help with VT NMR experiments. M. P. Chierchia, J. P. Morken, Science 2016, 351, 70–74; b) M.
Chierchia, C. Law, J. P. Morken, Angew. Chem. Int. Ed. 2017,
56, 11870–11874; Angew. Chem. 2017, 129, 12032–12036;
Conflict of Interest c) C. R. Davis, I. K. Luvaga, J. M. Ready, J. Am. Chem. Soc.
2021, 143, 4921–4927; d) S. Panda, J. M. Ready, J. Am. Chem.
The authors declare no conflict of interest. Soc. 2017, 139, 6038–6041; e) S. Panda, J. M. Ready, J. Am.
Chem. Soc. 2018, 140, 13242–13252.
[4] a) Z. Tao, K. A. Robb, J. L. Panger, S. E. Denmark, J. Am.
Chem. Soc. 2018, 140, 15621–15625; b) R. J. Armstrong, C.
Sandford, C. Garcia-Ruiz, V. K. Aggarwal, Chem. Commun.
2017, 53, 4922–4925.
Angewandte
[5] D. P. Hari, J. C. Abell, V. Fasano, V. K. Aggarwal, J. Am. supplementary crystallographic data for this paper. These data
Chem. Soc. 2020, 142, 5515–5520. are provided free of charge by the joint Cambridge Crystallo-
[6] a) S. Yu, C. Jing, A. Noble, V. K. Aggarwal, Angew. Chem. Int. graphic Data Centre and Fachinformationszentrum Karlsruhe
Ed. 2020, 59, 3917–3921; Angew. Chem. 2020, 132, 3945–3949; Access Structures service.
b) M. E. Fairchild, A. Noble, V. K. Aggarwal, Angew. Chem. [17] G. J. Lovinger, M. D. Aparece, J. P. Morken, J. Am. Chem.
Int. Ed. 2022, 61, e202205816; Angew. Chem. 2022, 134, Soc. 2017, 139, 3153–3160.
e202205816. [18] T. T. Talele, J. Med. Chem. 2020, 63, 13291–13315.
[7] a) M. Kischkewitz, K. Okamoto, C. Muck-Lichtenfeld, A. [19] M. Mohiti, C. Rampalakos, K. Feeney, D. Leonori, V. K.
Studer, Science 2017, 355, 936–938; b) M. Silvi, C. Sandford, Aggarwal, Chem. Sci. 2014, 5, 602–607.
V. K. Aggarwal, J. Am. Chem. Soc. 2017, 139, 5736–5739; c) C. [20] J. A. Myhill, L. Zhang, G. J. Lovinger, J. P. Morken, Angew.
You, A. Studer, Chem. Sci. 2021, 12, 15765–15769; d) G. J. Chem. Int. Ed. 2018, 57, 12799–12803; Angew. Chem. 2018, 130,
Lovinger, J. P. Morken, J. Am. Chem. Soc. 2017, 139, 17293– 12981–12985.
17296. [21] Relative configuration of 49 was assigned from X-ray diffrac-
[8] a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. tion of related compound S5. See Supporting Information for
2014, 57, 10257–10274; b) C. T. Walsh, Tetrahedron Lett. 2015, details.
56, 3075–3081; c) J. P. Michael, Nat. Prod. Rep. 2008, 25, 166– [22] T. Szabó, B. Volk, M. Milen, Molecules 2021, 26, 663.
187; d) X. F. Shang, C. J. Yang, S. L. Morris-Natschke, J. C. Li, [23] O. O. Ajani, K. T. Iyaye, O. T. Ademosun, RSC Adv. 2022, 12,
X. D. Yin, Y. Q. Liu, X. Guo, J. W. Peng, M. Goto, J. Y. 18594–18614.
Zhang, K. H. Lee, Med. Res. Rev. 2020, 40, 2212–2289. [24] See Supporting Information for optimization details.
[9] a) J. A. Bull, J. J. Mousseau, G. Pelletier, A. B. Charette, [25] Isoquinoline products activated with TrocCl showed partial
Chem. Rev. 2012, 112, 2642–2713; b) G. Bertuzzi, L. Bernardi, cyclization to the cyclic carbamate under the described
M. Fochi, Catalysts 2018, 8, 632. oxidation conditions (Table ). Interestingly, quinoline variants
[10] a) R. S. J. Proctor, R. J. Phipps, Angew. Chem. Int. Ed. 2019, only cyclized after prolonged exposure. See Supporting
58, 13666–13699; Angew. Chem. 2019, 131, 13802–13837; Information for details.
b) D. M. Stout, A. I. Meyers, Chem. Rev. 1982, 82, 223–243. [26] D. L. Comins, L. Guerra-Weltzein, Tetrahedron Lett. 1996, 37,
[11] a) D. L. Comins, S. P. Joseph, R. R. Goehring, J. Am. Chem. 3807–3810.
Soc. 1994, 116, 4719–4728; b) M. Ahamed, M. H. Todd, Eur. J. [27] S. Nave, R. P. Sonawane, T. G. Elford, V. K. Aggarwal, J. Am.
Org. Chem. 2010, 5935–5942; c) M. Chrzanowska, M. D. Chem. Soc. 2010, 132, 17096–17098.
Rozwadowska, Chem. Rev. 2004, 104, 3341–3370. [28] A. Bonet, M. Odachowski, D. Leonori, S. Essafi, V. K.
[12] A. Pelter, K. J. Gould, J. Chem. Soc. Chem. Commun. 1974, Aggarwal, Nat. Chem. 2014, 6, 584–589.
347–348. [29] R. J. Armstrong, V. K. Aggarwal, Synthesis 2017, 49, 3323–
[13] K. K. Das, S. Panda, Org. Lett. 2023, 25, 314–319. 3336.
[14] a) S. Panda, A. Coffin, Q. N. Nguyen, D. J. Tantillo, J. M. [30] Diastereospecificity (d.s.) = [d.e. of product]/[d.e. of starting
Ready, Angew. Chem. Int. Ed. 2016, 55, 2205–2209; Angew. material] × 100 %. d.e. = diastereomeric excess.
Chem. 2016, 128, 2245–2249; b) J. Llaveria, D. Leonori, V. K.
Aggarwal, J. Am. Chem. Soc. 2015, 137, 10958–10961.
[15] C. Sandford, V. K. Aggarwal, Chem. Commun. 2017, 53, 5481–
5494. Manuscript received: November 18, 2022
[16] Deposition Numbers 2218021 (for (�)-2 a), 2218023 (for (�)- Accepted manuscript online: February 13, 2023
51), 2218025 (for (�)-68), 2218027 (for 82) contain the Version of record online: February 13, 2023
Angewandte
Research Articles
Synthetic Methods
J. E. McGettiganJr.,
J. M. Ready* e202216961
Diastereoselective Alkylation of Activated

Nitrogen Heterocycles with Alkenyl Boro-
Alkylation of acylated quinolines and component coupling allows for facile
nate Complexes
isoquinolines with alkenyl boron-“ate” access to a range of valuable nitrogen-
complexes via 1,2-metalate rearrange- containing scaffolds. This one-pot proto-
ment gives substituted, dearomatized col installs a chiral boronic ester moiety
nitrogen heterocycles with high diaster- which can be used in further stereo-
eocontrol. The modularity of this multi- specific transformations.
Angew. Chem. Int. Ed. 2023, e202216961 © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH

Isoquinoline Alkenylboron ACIE 2023

Uploaded by

Copyright:

Available Formats

You might also like

Isoquinoline Alkenylboron ACIE 2023

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Isoquinoline Alkenylboron ACIE 2023

Uploaded by

Copyright:

Available Formats

15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202216961 by levent artok - Izmir Yuksek Teknoloji Enstit , Wiley Online Library on [08/03/2023].

Diastereoselective Alkylation of Activated Nitrogen Heterocycles

Abstract: Alkenyl boronate complexes react with acy-

Tetravalent boron-“ate” complexes have recently emerged

Scheme 3. Scope of alkene-derived boronate complexes. The letter

the chiral auxiliary 79, followed by exposure to alkenyl

Acknowledgements [1] a) H. Wang, C. Jing, A. Noble, V. K. Aggarwal, Angew. Chem.

Diastereoselective Alkylation of Activated

You might also like