Introducing Alkene Moieties via Iterative Carbenoid Insertions: Vi-

nylene Homologation of Organoboronates

Miao Chen†, Thomas Tugwell‡, Peng Liu‡* and Guangbin Dong†*
†Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
‡
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260, United States
ABSTRACT: The Matteson homologation of organoboronates has been an attractive approach for constructing aliphatic carbon
chains via iterative insertion of carbenoids. However, the corresponding homologation that can introduce alkene moieties to molecular
backbones remains elusive. Here we report the development of a stereoselective vinylene homologation of various alkyl and aryl
boronates. The reaction is enabled by diastereoselective consecutive insertion of a silyl- and an alkoxy-substituted carbenoid, followed
by a Peterson-type elimination. Diverse alkenyl boronates can be obtained in good yield and good to excellent trans selectivity.
Density functional theory (DFT) calculations revealed the origin of diastereoselectivity in carbenoid insertion and how Lewis acids
with different sulfide binding affinities affect the competing SN2- and SN1-type 1,2-boronate migration pathways with distinct levels
of stereospecificity. This protocol has been successfully applied to programmable synthesis of piperamide-family natural products by
merging with the methylene homologation. Guided by the mechanistic understanding, preliminary success has been achieved with
the cis-selective vinylene homologation enabled by oxyphilic Lewis acids.

INTRODUCTION Considering the difficulty of directly inserting an alkene moi-

Homologation reactions have been broadly useful in organic ety into C−B bonds8, we hypothesized that one approach could
synthesis, as it enables direct editing of molecular scaffolds via be to introduce two sp3-carbon units consecutively, with each
either chain elongation or ring expansion without altering the bearing a specific functional group (FG), and then allow these
original reacting group.1 In particular, the boron-based homol- FGs to react and eliminate together under a specific condition
ogation, namely the Matteson-type reactions, has become in- (without affecting the boron group) to reveal the alkene moiety.
creasingly important to the development of programmable or As such, the overall transformation furnishes the vinylene ho-
automated organic synthesis through precise control of the ad- mologation (Scheme 1D). While a number of olefination reac-
dition sequence and stereochemistry.2,3 In a typical Matteson re- tions could potentially be suitable for the proposed alkene-in-
action, carbenoids are inserted into C−B bonds of boronates in sertion strategy, our first-generation approach was inspired by
an iterative manner (Scheme 1A), which introduces sp3-hybrid- the Peterson olefination because of the relative robustness of
ized carbons into the molecular backbone. Substantial hurdles silane and ether moieties under the boron homologation (nucle-
remain for extending the Matteson homologation to construct ophilic and basic) conditions.9 We envisioned that sequential
diverse organic molecules. For instance, besides sp3-carbons, addition of silyl-10 and alkoxy-substituted11 methylene (or vice
heteroatoms and unsaturated moieties widely exist in molecular versa) into boronates, followed by in situ stereospecific elimi-
skeletons. Recently, we have developed the aza- and oxa- nation, should lead to the desired vinylene homologation prod-
Matteson reactions to allow nitrogen and oxygen, respectively, uct. However, a number of difficulties could be associated with
to be installed during the chain propagation. (4) Considering that this approach. First, in the final elimination step the E/Z selec-
sp2-carbons, in particular alkenes, frequently exist in scaffolds tivity of the olefin product would largely rely on the diastereo-
of functional organic molecules (Scheme 1B), the realization of purity of the β-alkoxysilane intermediate; but there has been
stereoselective vinylene insertion into C−B bonds would be nearly no precedent to control diastereoselectivity of consecu-
critical for introducing alkene moieties by this iterative boron tive carbenoid insertions without using enantiopure reagents.12
homologation strategy. Thus, judicious choice of the silyl- and alkoxy-substituted car-
benoid reagents would be highly important. In addition, direct
Currently, a number of efficient methods exist for preparing
homologation using oxy-bearing carbenoids has been much less
alkenyl boronates, including alkyne hydroboration, bora-Wittig,
developed than the carbon-substituted ones,11 as oxygen can
Heck reaction, cross metathesis, and others.5 However, synthe-
also serve as a good leaving group (LG) in Matteson-type reac-
sis starting from organoboronates has been rarely explored. The
tions.13 Moreover, compatibility of the boronate moiety under
use of a bifunctional building block containing a boron-protect-
the Peterson elimination conditions could be another concern.
ing group, e.g., (2-halo)-vinyl-N-methyliminodiacetic acid
In this full article, we describe the first development of stere-
boronates, could result in a formal alkene insertion via the Pd-
oselective vinylene homologation of alkyl and aryl boronates
catalyzed Suzuki coupling.6 While effective, this approach re-
via sequential and diastereoselective insertion of silyl- and
quires boron protection and deprotection, and the cross cou-
alkoxy-substituted carbenoids, which provides a “boron-to-bo-
pling with alkyl boronates is not a trivial issue. 6c On the other
ron (B-to-B)” transformation without using protecting groups
hand, Zweifel Olefination is an elegant approach to couple an
or noble metal catalysts.
alkenyl group to a C−B bond; but the original boronate group is
eliminated during this process (Scheme 1C).7
 Scheme 1. Vinylene Homologation and Strategy Design Table 1. Model Study to Access E-Alkenyl Boronatesa

aReaction conditions: Int-1a (0.1 mmol, 1.0 equiv), S-reagent

(1.1 equiv), THF (1.0 mL), −78°C, 1 h; ZnCl2 (2.0 equiv), 12 h;
H2SO4 (1.2 equiv), 3h. Yields were determined by 1H NMR with
1,1,2,2-tetrachloroethane as an internal standard.
RESULTS AND DISCUSSION
Given that consecutive insertions of heteroatom-substituted based S-reagent (S-1) was used, 91% yield and 13:1 E/Z selec-
methylenes into boronates has been rare, our initial investiga- tivity were obtained (entry 1). Other aryl-substituted reagents
tion was focused on the efficiency and diastereoselectivity of with different steric and electronic properties all gave lower
the insertion of alkoxy-substituted carbenoids into α-silylalkyl yield and/or lower diastereoselectivity (entry 2). ZnCl2 proved
boronates. At the outset, pinacol boronate Int-1a was employed be a more effective Lewis acid than HgCl2 in this case (entry 3),
as the model substrate (Table 1). It can be envisioned that nature and the ate-complex was stable and unactive when no Lewis
of the LG on the alkoxy-substituted carbenoid could have a pro- acid was added (entry 4). When warming the reaction mixture
found impact on the reaction diastereoselectivity. Inspired by to room temperature before adding ZnCl2, the reaction pro-
the earlier study of Brown,11 various lithiated alkoxy aryl sul- ceeded in high yield but low E/Z selectivity (entry 5). Finally,
fanes (S-reagent), which were readily prepared from commer- the addition of LiBr can promote both the yield and diastereose-
cially available aryl thiols and 2-(trimethylsilyl)-ethoxymethyl lectivity (entry 6), though the exact reason remains to be deter-
chloride, were used as the precursors of the oxygen-substituted mined. Comparable results were obtained using TsOH (2.5
carbenoids. After forming an ate-complex intermediate, subse- equiv) instead of H2SO4 in the elimination step (entry 7).
quent addition of a Lewis acid promoted the 1,2-metallate mi- With the optimized diastereoselective insertion and elimina-
gration and allowed insertion of the oxygen-substituted meth- tion conditions in hand, the direct vinylene homologation of al-
ylene into the C−B bond. Our further study shows that simple kyl boronates was explored (Table 2). The insertion of silyl-
one-pot treatment of the resulting α-alkoxy-β-silyl boronate in- substituted carbenoids was carried out by adding the boronates
termediate with 1.2 equivalent of H2SO4 at room temperature to freshly prepared chloro(trimethylsilyl)-methyllithium (Si-1).
afforded the desired alkenyl boronate product. Under the opti- The subsequent insertion of alkoxy-substituted carbenoids and
mized conditions, a bulky arylthiolate LG was found to give acid-mediated elimination proceeded smoothly to deliver the
high diastereoselectivity. When the 2,4,6-triisopropylphenyl-
Table 2. Substrate Scope for Alkyl Boronatesa

aAll reactions were carried out on 0.2 mmol. For primary alkyl substrates, chloro(trimethylsilyl)-methyllithium (Si-1, 1.3 equiv),
lithiated S-1 (1.3 equiv), and ZnCl2 (2.0 equiv) were used. For secondary alkyl substrates, chloro(dimethylphenylsilyl)-methyllithium
(Si-2, 1.3 equiv), lithiated S-2 (1.2 equiv), and HgCl2 (1.2 equiv) were used. For experimental details, see the Supporting Information.
Isolated yields are the overall yields of all operations starting from RBpin or RBneop. bThe number in parenthesis is the NMR yield.
The lower isolated yield is due to volatility of the products.

alkenyl boronate products without isolation of any reaction in- products (3v and 3x) with retention of the relative stereochem-
termediates. Note that the addition of LiBr was not necessary istry.
during the insertion of alkoxy carbenoid as stoichiometric LiCl Aryl boronates are also suitable substrates for vinylene ho-
was generated after the silyl carbenoid insertion. The reaction mologation (Table 3). The use of HgCl2 as the Lewis acid gave
shows a broad scope and various alkyl boronates underwent the high diastereoselectivity during the alkoxy-carbenoid insertion
vinylene homologation with good to excellent E/Z selectivity (see Supporting Information, Table S4).15 The reaction appears
(up to 19:1).14 FGs, such as aryl fluoride (2b, 2i), aryl chloride to be quite general. First, aryl groups with various substitution
(2c, 2j, 2k), aryl bromide (2d) and thioether (2h), were tolerated. patterns, such as those containing para, ortho, or meta substitu-
When secondary alkyl boronates were used as substrates, the ents, all afforded the desired products. The electronic properties
desired E alkene products were only observed in low yield un- of the arene do not seem to have a significant effect on either
der the standard conditions likely due to increased sterics. We the reactivity or the E/Z selectivity. Unlike the cases of alkyl
hypothesized that the reactivity could be restored by reducing boronates, typically more than 20:1 E/Z selectivity were
the steric congestion around the boron. Indeed, using the corre- achieved for all the products. In addition, FGs, including trifluo-
sponding neopentyl glycol-derived boronates (Bneop), the re- romethyl ether (5b), thioether (5c), silyl ether (5d), iodide (5e),
activity was greatly improved. Meanwhile, employment of a silane (5f) and alkyl chloride (5h), were compatible. Note that
bulkier dimethylphenylsilyl-derived carbenoid afforded better alkene (5i) and alkyne (5j) moieties were also tolerated. More-
diastereoselectivity, and the use of HgCl2 further improved the over, heteroarene-derived boronates are competent substrates
E/Z selectivity to some extent (see Supporting Information, Ta- (5u-5y). This method can be used to derivatize an estrone-based
ble S3). To ease the isolation process, the alkenyl Bneop prod- substrate (5z). Finally, the reaction is scalable, and on 5 mmol
ucts were directly converted to the corresponding alkenyl io- scale alkenyl boronate product 5a was isolated in 50% overall
dides. Cycloalkyl boronates of different ring sizes all showed yield.
moderate to good efficiency and good E/Z selectivity (3p-3s).
Bridged-ring scaffolds (3t and 3u) were compatible, and the
acyclic secondary alkyl boronate (3w) also worked reasonably
well. Moreover, the substrates derived from more complex nat-
ural products could deliver the desired vinylene homologation
Table 3. Substrate Scope for Aryl Boronatesa

aAll
reactions were run on 0.2 mmol, unless noted otherwise. Isolated yields are the overall yields of all operations starting from
RBpin. bIsolated yield on 5.0 mmol scale. cThe corresponding ethylene glycol ketal was used as the substrate; H2SO4 (2.0 equiv) was
added in the elimination step to reveal the ketone moiety through deprotection.

The reaction mechanism was explored through a combined plane but opposite to the direction of the carbenoid addition,
effort between experiment and computation. The α-methoxy, β- which is analogous to both the Felkin−Anh and Cieplak models
silyl boronate intermediate (anti-7a) can be successfully iso- in carbonyl addition reactions.17 The calculated transition states
lated and characterized spectroscopically (Scheme 2). Its fur- corroborate this hypothesis. Our computation indicates that
ther treatment with acids delivered the E product 5a exclu- boronate 12a is the kinetically favored product, which is formed
sively, which confirms its intermediacy in the Peterson-type through transition state TS1a. In contrast, transition state TS1b
elimination step. To unambiguously determine the relative ste- leading to the other diastereomer 12b is 1.3 kcal/mol less stable
reochemistry, further methylene homologation of the α-meth- than TS1a, due to unfavorable gauche-like interactions between
oxy, β-silyl boronate intermediate (anti-7b) followed by oxida- the arylthiolate LG and the α-methyl group on boronate 10.18
tion and p-nosyl protection afforded sulfinate 8, which can be This stereochemical model is also consistent with the higher di-
characterized by X-ray crystallography. The X-ray structure of astereoselectivity observed with bulkier arylthiolates (e.g., S-1,
compound 8 clearly shows an anti-relationship between the si- Table 1).
lyl and the methoxy groups.
Next, we considered the ZnCl2-promoted 1,2-migration from
Density function theory (DFT) calculations were carried out boronate 12a. Conformational sampling using CREST and DFT
to investigate the diastereoselectivity of the carbenoid insertion calculations (see Supporting Information for details) suggests
step and the Lewis acid effect. One intriguing question is that ZnCl2 prefers to bind to the arylthiolate sulfur and one of
whether the use of different Lewis acids (ZnCl2 and HgCl2) the boronate oxygen atoms to form 13a (Figure 2). From 13a,
would alter the mechanism of the 1,2-boronate migration from the SN2-type pathway, where the 1,2-migration and arylthiolate
a concerted SN2-type pathway to a non-stereospecific stepwise LG dissociation occur via a concerted transition state TS2 was
SN1-type pathway. First, the transition states of the addition of found to be the most favorable with an activation free energy
alkoxy-substituted carbanion 11 to 𝛼-silylalkyl boronate 10 was (ΔG‡) of 15.6 kcal/mol. By contrast, the SN1-type pathway that
computed (Figure 1).16 We hypothesize that the bulkiest silyl involves a stepwise LG dissociation to form 14 followed by 1,2-
group should orientate nearly perpendicularly to the boronate migration via either TS3a or TS3b is less favorable because the
Scheme 2. Intermediate Isolation and Relative Stereochemistry

aThermal ellipsoids are displayed at 50% probability.

Figure 1. Computed energy profile of the diastereoselective carbenoid addition to 𝛼-silylalkyl boronate 10. All the boro-
nates used were pinacol boronic esters. DFT calculations were performed at the M06/6-311+G(d,p)/SMD (THF)//B3LYP-
D3(BJ)/6-31G(d)/SMD(THF) level of theory. Conformational sampling was performed with CREST at the GFN-xTB2 level of
theory.

Figure 2. Computed energy profiles of the competing SN1- and SN2-type pathways in the ZnCl2-mediated 1,2-migration of boronate
complex 13a. All the boronates used were pinacol boronic esters. DFT calculations were performed at the M06/6-
311+G(d,p)/SDD(Zn)/SMD(THF)//B3LYP-D3(BJ)/6-31G(d)/SDD(Zn)/SMD(THF) level of theory. Conformational sampling was
performed with CREST at the GFN-xTB2 level of theory.
Scheme 3. ZnCl2/HgCl2-Mediated SN1-Type 1,2-Migra- synthesized via a sequence of one-pot double methylene homol-
tion Pathwaysa ogation, vinylene homologation, and Suzuki termination with
vinyl bromide 18 (route A).22 This three-step synthesis only
needs one chromatography with 32% overall yield and 12:1 E/Z
selectivity. The piperdardine analog23 was prepared in 67%
overall yield in a similar manner via route B, involving mono
methylene homologation, vinylene homologation, and Suzuki
termination with vinyl bromide 17. To access the tri-ene natural
product retrofractamide A,24 the synthesis started with vinylene
homologation, next double methylene insertion, and then an-
other vinylene homologation before termination by the Suzuki
reaction (route C). Compared to the prior approaches to access
these compounds, this iterative synthesis strategy uses fewer
steps, gives higher overall yield, minimizes purification of re-
action intermediates, and more importantly provides program-
mability to the synthetic design.
aAll the boronates used were pinacol boronic esters. DFT calcu- Finally, preliminary success has been obtained with the Z-
lations were performed at the M06/6- selective vinylene homologation of aryl boronates (Scheme 5).
311+G(d,p)/SDD(Zn,Hg)/SMD(THF)//B3LYP-D3(BJ)/6- Based on the mechanistic understanding, it is clear that for-
31G(d)/SDD(Zn,Hg)/SMD(THF) level of theory. Conforma- mation of the ate complex (e.g., 9a) is diastereoselective and
tional sampling was performed with CREST at the GFN-xTB2 soft Lewis acids, such as zinc and mercuric salts, promote ar-
level of theory. ylthiolates as the LG during the 1,2-metallate migration. We
therefore postulated that, replacing soft Lewis acids with an ox-
LG dissociation step is endergonic by 15.5 kcal/mol. Because yphilic (i.e., “hard”) Lewis acid, the syn-oriented α-thiophe-
the stereospecific SN2-type 1,2-migration (TS2) leads to com- noxy, β-silyl boronate syn-20a could be selectively obtained by
plete stereoinversion at the alkoxy-substituted carbon center, having the alkoxy group as the LG instead (Scheme 5A). To our
this process converts 13a to the anti-diastereomer of the α- delight, the LG selectivity in the 1,2-migration step can be al-
methoxy, β-silyl boronate 15. Upon stereospecific Peterson tered simply by changing the Lewis acids to AlCl3 or CeCl3.
elimination, an E-alkene would be selectively formed, which is The α-thiophenoxy, β-silyl boronate intermediate 20a was ob-
consistent with the experimentally observed stereoselectivity tained in high diastereoselectivity (>15:1). Notably, intermedi-
when ZnCl2 is used as the Lewis acid. Considering that mercury ate 20a exhibited increased stability compared to α-methoxy
has stronger thiolate binding affinity than zinc, 19 we surmised boronate 7a, allowing for chromatography purification and
that the non-stereospecific SN1-type 1,2-migration pathway can spectroscopic characterization. To promote efficient anti-elim-
be more favorable when HgCl2 is used as the Lewis acid. In- ination, the arylthiolate (S-4) containing a para chloro group
deed, the HgCl2-promoted arylthiolate dissociation (from 16a) was found to be a better LG (Scheme 5B). Treatment of inter-
is only endergonic by 3.3 kcal/mol, which is 12.2 kcal/mol mediates 20 with 1.2 equivalent of TBAF and 1.5 equivalent of
lower in energy than the analogous ZnCl2-mediated LG disso- methyl vinyl sulfone (to sequestrate the arylthiolate LG that can
ciation process (Scheme 3). Because intermediate 14 undergoes potentially epimerize 20 through 1,2-metallate migration) af-
facile 1,2-migration via TS3a and TS3b (ΔG‡ = 1.6 and 2.5 forded the desired Z-alkenylboronates 21a-f in good yields and
kcal/mol with respect to 14, respectively), the stepwise SN1- synthetically useful diastereoselectivity (for detailed optimiza-
type pathways are much more favorable when the more thioph- tions, see Supporting Information, Table S5).25 Efforts on im-
ilic HgCl2 Lewis acid is used, leading to a diminished diastere- proving the Z selectivity and expanding to alkyl boronates are
oselectivity of the homologation product (see entry 3, Table 1). ongoing.
Next, the synthetic utility of the vinylene homologation
method has been explored. First, due to the versatile reactivity CONCLUSIONS
of alkenylboronates, the homologation product can undergo
various facile transformations to access synthetically valuable In summary, we have developed the stereoselective vinylene
structural motifs (for details, see Supporting Information, homologation of organoboronates enabled by sequential dia-
Scheme S1). Additionally, this method can be used to generate stereoselective carbenoid insertion and the Peterson-type elim-
a masked alkene moiety, which can survive under hydrogena- ination. This strategy provides rapid access to various alkenyl
tion conditions (Scheme 4A). Moreover, besides the reactions boronates from readily available alkyl or aryl boronates, which
with alkyl boronates, mercury salts can also be avoided for the paves the way for programmable iterative synthesis of complex
homologation with aryl boronates when using 4.0 equivalent of alkene-containing molecules. The mechanistic insights gained
ZnCl2 instead (Scheme 4B).20 The synthetic potential of this on the diastereoselective carbenoid addition, the Lewis acid-de-
method was further demonstrated in the streamlined syntheses pended 1,2-migration, and divergent reactivity of lithiated
of piperamide-family natural products (Scheme 4C), which alkoxy aryl sulfanes could be valuable to understand the stere-
have been known to exhibit insecticidal, anti-cancer, and other ochemistry outcomes of similar reactions and have broad impli-
biological activities.(21) We envisioned that, through merging cations beyond this work.
the vinylene homologation and methylene homologation, the
polyene backbone of piperamides could be efficiently accessed
by a unified iterative approach. Starting from the common sub-
strate, aryl boronic ester 4r, piperdardine was efficiently
Scheme 4. Synthetic Applications
Scheme 5. Z-Vinylene Homologation of Aryl Boronatesa ACKNOWLEDGMENT
University of Chicago, ACS PRF (65249-ND1 to G.D.) and
NIGMS (R35GM128779 to P.L.) are acknowledged for research
support. We thank Dr. Qiqiang Xie (University of Chicago) for
checking the experimental procedure. Computational studies were
performed at the Center for Research Computing at the University
of Pittsburgh.

REFERENCES
(1) (a) Li, J. J. Name Reactions for Homologations, Part 1; John
Wiley & Sons, 2009. (b) Candeias, N. R.; Paterna, R.; Gois, P. M.
P. Homologation Reaction of Ketones with Diazo Compounds.
Chem. Rev. 2016, 116, 2937–2981. (c) Castoldi, L.; Monticelli, S.;
Senatore, R.; Ielo, L.; Pace, V. Homologation Chemistry with Nu-
cleophilic α-Substituted Organometallic Reagents: Chemocontrol,
New Concepts and (solved) Challenges. Chem. Commun. 2018,
54, 6692–6704. (d) Sebastian, S.; Monika; Khatana, A. K.; Yadav,
E.; Gupta, M. K. Recent Approaches towards One-carbon Homol-
ogation-functionalization of Aldehydes. Org. Biomol. Chem.
2021, 19, 3055–3074. (d) Monticelli, S.; Rui, M.; Castoldi, L.;
Missere, G.; Pace, V. A Practical Guide for Using Lithium Halo-
carbenoids in Homologation Reactions. Monatsh. Chem. 2018,
149, 1285–1291.
(2) For selected reviews: (a) Matteson, D. S. α-Halo Boronic Esters:
Intermediates for Stereodirected Synthesis. Chem. Rev. 1989, 89,
1535–1551. (b) Castoldi, L.; Monticelli, S.; Senatore, R.; Ielo, L,
Pace, V. Homologation Chemistry with Nucleophilic α-Substi-
tuted Organometallic Reagents: Chemocontrol, New Concepts
and (Solved) Challenges. Chem. Commun. 2018, 54, 6692–6704.
(c) Thomas, S. P.; French, R. M.; Jheengut, V.; Aggarwal, V. K.
Homologation and Alkylation of Boronic Esters and Boranes by
1,2‐Metallate Rearrangement of Boron Ate Complexes. Chem.
Rec., 2009, 9, 24–39. (d) Matteson, D. S.; Collins, B. S. L.; Ag-
garwal, V. K.; Ciganek, E. The Matteson reaction. Org. React.
aAll reactions were run on 0.2 mmol, unless noted otherwise.
2021, 105, 427–860.
(3) (a) Blakemore, P. R.; Burge, M. S. Iterative Stereospecific Rea-
Isolated yields are the overall yields of all operations starting gent-Controlled Homologation of Pinacol Boronates by Enanti-
from RBpin. oenriched α-Chloroalkyllithium Reagents. J. Am. Chem. Soc.
2007, 129, 3068–3069. (b) Emerson, C. R.; Zakharov, L. N.;
ASSOCIATED CONTENT Blakemore, P. R. Iterative Stereospecific Reagent-Controlled Ho-
The Supporting Information is available free of charge via the In- mologation Using a Functionalized α-Chloroalkyllithium: Syn-
ternet at http://pubs.acs.org.” thesis of Cyclic Targets Related to Epibatidine. Org. Lett. 2011,
Experimental procedures and spectral data (PDF) 13, 1318–1321. (c) Sun, X.; Blakemore, P. R. Programmed Syn-
thesis of a Contiguous Stereotriad Motif by Triple Stereospecific
AUTHOR INFORMATION Reagent-Controlled Homologation. Org. Lett. 2013, 15, 4500–
4503. (d) Blair, D. J.; Chitti, S.; Trobe, M.; Kostyra, D. M.; Haley,
Corresponding Author H. M. S.; Hansen, R. L.; Ballmer, S. G.; Woods, T. J.; Wang, W.;
Guangbin Dong−Department of Chemistry, University of Chi- Mubayi, V.; Schmidt, M. J.; Pipal, R. W.; Morehouse, G. F.;
cago, Chicago, Illinois 60637, United States; orcid.org/0000- Palazzolo Ray, A. M. E.; Gray, D. L.; Gill, A. L.; Burke, M. D.
0003-1331-6015; Email: [email protected] Automated Iterative Csp3–C Bond Formation. Nature 2022, 604,
92–97.
Peng Liu − Department of Chemistry, University of Pittsburgh, (4) (a) Xie, Q.; Dong, G. Aza-Matteson Reactions via Controlled
Pittsburgh, Pennsylvania 15260, United States; or- Mono- and Double-Methylene Insertions into Nitrogen–Boron
cid.org/0000-0002-8188-632X; Email: [email protected] Bonds. J. Am. Chem. Soc. 2021, 143, 14422–14427. (b) Xie, Q.;
Dong, G. Programmable Ether Synthesis Enabled by Oxa-
Matteson Reaction. J. Am. Chem. Soc. 2022, 144, 8498–8503.
Notes (5) For selected reviews and examples of alkenyl boronate synthesis,
The authors declare no competing financial interest. see: (a) Carreras, J.; Caballero, A.; Pérez, P. J. Alkenyl Boronates:
Synthesis and Applications. Chem. Asian J. 2019. 14, 329–343.
Accession Codes (b) Coombs, J. R., Zhang, L., Morken, J. P. Synthesis of Vinyl
CCDC 2260049 contains the supplementary crystallographic data Boronates from Aldehydes by a Practical Boron–Wittig Reaction.
for this paper. This data can be obtained. free of charge via Org. Lett. 2015, 17, 1708–1711. (c) Liu, Z.; Wei, W.; Xiong, L.;
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_re- Feng, Q.; Shi, Y.; Wang, N.; Yu, L. Selective and efficient synthe-
[email protected], or by contacting The Cambridge Crystal- sis of trans-arylvinylboronates and trans-hetarylvinylboronates
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; using palladium catalyzed cross-coupling. New. J. Chem. 2017,
fax: +44 1223 336033. 41, 3172–3176. (d) Cuenca, A. B.; Fernández, E. Boron-Wittig
olefination with gem-bis(boryl)alkanes. Chem. Soc. Rev. 2021, 50,
 72–86. (e) Hemelaere, R.; Carreaux, F.; Carboni, B. Synthesis of Total Synthesis of Tatanan A and 3‐epi‐Tatanan A Using Assem-
Alkenyl Boronates from Allyl-Substituted Aromatics Using an bly‐Line Synthesis. Angew. Chem. Int. Ed. 2016, 55, 15920–
Olefin Cross-Metathesis Protocol. J. Org. Chem. 2013, 78, 6786– 15924.
6792. (f) Hemelaere, R.; Caijo, F.; Mauduit, M.; Carreaux, F.; Car- (13) (a) Carmes, L.; Carreaux, F.; Carboni, B. Homologation of Bo-
boni, B. Ruthenium-Catalyzed One-Pot Synthesis of (E)-(2-Aryl- ronic Esters with (Dialkoxymethyl)lithiums. Asymmetric Synthe-
vinyl)boronates through an Isomerization/Cross-Metathesis Se- sis of α-Alkoxy Boronic Esters. J. Org. Chem. 2000, 65, 5403–
quence from Allyl-Substituted Aromatics. Eur. J. Org. Chem. 5408. (b) Mlynarski, S. N.; Karns, A. S.; Morken, J. P. Direct Ste-
2014, 3328–3333. (g) Mkhalid, I. A. I.; Coapes, R. B.; Edes, S. N.; reospecific Amination of Alkyl and Aryl Pinacol Boronates. J. Am.
Coventry, D. N.; Souza, F. E. S.; Thomas, R. L.; Hall, J. J.; Bi, S. Chem. Soc. 2012, 134, 16449–16451. (c) Edelstein, E. K.; Grote,
W.; Lin, Z.; Marder, T. B. Rhodium catalysed dehydrogenative A. C.; Palkowitz, M. D.; Morken, J. P. A Protocol for Direct Ste-
borylation of alkenes: Vinylboronates via C–H activation. Dalton reospecific Amination of Primary, Secondary, and Tertiary Alkyl-
Trans. 2008, 1055–1064. (h) Coapes, R. B.; Souza, F. E. S.; boronic Esters. Synlett 2018, 29, 1749–1752.
Thomas, R. L.; Hall, J. J.; Marder, T. B. Rhodium catalysed dehy- (14) Our initial attempts to prepare tri-substituted alkenes by replacing
drogenative borylation of vinylarenes and 1,1-disubstituted al- the second carbenoid reagent with 1-methoxyethyl phenylsulfane
kenes without sacrificial hydrogenation—a route to 1,1-disubsti- were unfruitful at this stage. The reactions gave poor conversion
tuted vinylboronates. Chem. Commun. 2003, 614–615. (i) Geier, (<10%) to the ate-complex presumably likely due to the increased
S. J.; Vogels, C. M.; Melanson, J. A.; Westcott, S. A. The transition sterics.
metal-catalysed hydroboration reaction. Chem. Soc. Rev. 2022, 51, (15) ZnCl2 gave poor diastereoselectivity (d.r. = 1:1) in this case, and
8877–8922. (j) Brown, J. M.; Lloyd-Jones, G. C. Vinylborane for- the exact reason remains unclear.
mation in rhodium-catalysed hydroborations; ligand-free homo- (16) The computed model is based on consecutive insertion with alkyl
geneous catalysis. J. Chem. Soc., Chem. Commun. 1992, 710–712. boronate substrates. The situation with aryl boronate substrates is
(k) Brown, J. M.; Lloyd-Jones, G. C. Vinylborane Formation in much more complicated, which remains to be fully understood.
Rhodium-Catalyzed Hydroboration of Vinylarenes. Mechanism (17) (a) Rondan, N. G.; Houk, K. N. Staggered Models for Asymmet-
versus Borane Structure and Relationship to Silation. J. Am. Chem. ric Induction: Attack Trajectories and Conformations of Allylic
Soc. 1994, 116, 866–878. Bonds from ab Initio Transition Structures of Addition Reactions.
(6) (a) Uno B. E.; Gillis, E. P.; Burke, M. D. Vinyl MIDA Boronate: J. Am. Chem. Soc. 1982, 104, 7162–7166. (b) Lodge, E. P.; Heath-
A Readily Accessible and Highly Versatile Building Block for cock, C. H. Acyclic Stereoselection. 40. Steric Effects, as well as
Small Molecule Synthesis. Tetrahedron 2009, 16, 3130–3138. (b) sigma*-Orbital Energies, are Important in Diastereoface Differ-
Woerly, E. M.; Struble, J. R.; Palyam, N.; O’Hara, S. P.; Burke, entiation in Additions to Chiral Aldehydes. J. Am. Chem. Soc.
M. D. (Z)-(2-Bromovinyl)-MIDA Boronate: A Readily Accessi- 1987, 109, 3353–3361. (c) Cieplak, A. S. Stereochemistry of nu-
ble and Highly Versatile Building Block for Small Molecule Syn- cleophilic addition to cyclohexanone. The importance of Two-
thesis. Tetrahedron 2011, 67, 4333–4343. Eelectron Stabilizing Interactions. J. Am. Chem. Soc. 1981, 103,
(7) (a) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. A Convenient 4540.
Stereoselective Synthesis of Substituted Alkenes via Hydrobora- (18) The ate complex generated after addition of the alkoxy-substi-
tion-iodination of Alkynes. J. Am. Chem. Soc. 1967, 89, 3652– tuted carbenoid was found to be stable at room temperature and
insensitive to water, suggesting that its formation is unlikely re-
3653. (b) Armstrong, R. J.; Aggarwal, V. K. 50 Years of Zweifel
versible. For details, see the Supporting Information.
Olefination: A Transition-Metal-Free Coupling. Synthesis 2017,
(19) Tai, H. C.; Lim, C. Computational Studies of the Coordination
49, 3323–3336. Stereochemistry, Bonding, and Metal Selectivity of Mercury. J.
(8) For insertion of single C(sp2) into molecular backbones via boron Phys. Chem. A 2005, 110, 452–462.
homologation, see: a) Fordham, J. M.; Grayson, M. N.; Aggarwal,
(20) While the α-methoxy, β-silyl boronate intermediate was formed
V. K. Vinylidene Homologation of Boronic Esters and its Appli-
as a ca. 1:1 diastereomeric mixture in this case, the following
cation to the Synthesis of the Proposed Structure of Machillene.
elimination gave exclusively the E-isomer. This outcome suggests
Angew. Chem. Int. Ed. 2019, 58, 15268–15272. b) Aparece, M. that the syn isomer likely underwent epimerization or E1-type
D.; Gao, C.; Lovinger, G. J.; Morken, J. P. Vinylidenation of Or- elimination under the elimination conditions.
ganoboronic Esters Enabled by a Pd-Catalyzed Metallate Shift. (21) Jeon, H.J.; Kim, K.; Kim, Y.D.; Lee, S.F. Naturally Occurring
Angew. Chem. Int. Ed. 2019, 58, 592–595. Piper Plant Amides in Agriculture and Pharmacutical Industries:
(9) (a) Staden, L. F. V.; Gravestock, D.; Ager, D. J. New Develop- Perspectives of Piperine and Piperlongumine. Appl. Biol. Chem.
ments in the Peterson Olefination Reaction. Chem. Soc. Rev. 2002, 2019, 62 (63), 1–7.
31, 195–200. (b) Hudrlik, P. F.; Peterson, D. Stereospecific Ole- (22) (a) Schwarz I.; Braun M. Synthesis of Naturally Occurring Dien-
fin-forming Elimination Reactions of β-Hydroxyalkylsilanes. J. amides by Palladium-Catalyzed Carbonyl Alkenylation. J. Prakt.
Am. Chem. Soc., 1975, 97, 6285–6289. Chem. 1999, 341, 72–74. (b) De Araújo-Júnior, J. X.; de M. Du-
(10) (a) Matteson, D. S.; Majumdar, Homologation of Boronic Esters arte, C.; de O. Chaves, M. C.; Parente, J. P.; Fraga, C. A. M.; Bar-
with Trimethylsilylchloromethyl-lithium J. Organomet. Chem. reiro, E. J. Synthesis of Natural Amide Alkaloid Piperdardine and
1980, 2, C41–C43 (b) Matteson, D. S.; Majumdar, D. α-Trime- A New Bioactive Analogue. Synth. Commun. 2001, 31, 117–123.
thylsilyl Boronic Esters. Pinacol Lithio(trimethylsilyl) methane- (23) Elliott, M.; Farnham, A. W.; Janes, N. F.; Johnson, D. M.; Pulman,
boronate, Homologation of Boronic Esters with [Chloro(trime- D. A. Synthesis and Insecticidal Activity of Lipophilic Amides.
thylsilyl)methyl]lithium, and Comparisons with Some Phospho- Part 6: 6-(Disubstituted-phenyl)hexa-2,4-dienamides. Pestic. Sci.
rus and Sulfur Analogues. Organometallics 1983, 2, 230–236. 1987, 18, 239–244.
(11) (a) Brown, H. C.; Imai, T. Homologation of Alkylboronic Esters (24) (a) Banerji, A.; Bandyopadhyay, D; Siddhanta, A. K. Synthesis of
with Methoxy(phenylthio)methyl-lithium: Regio- and Stereocon- Retrofractamide A. Phytochemistry, 1987, 26, 3345-3346. (b) Ma,
trolled Aldehyde Synthesis from Olefins via Hydroboration. J. Am. D.; Lu, X. A New Methodology to Key Intermediates for Synthe-
Chem. Soc. 1983, 105, 6285–6289. (b) Brown, H. C.; Imai, T.; sizing Polyene Compounds. Tetrahedron 1990, 46, 6319–6330.
Desai, M. C.; Singaraml, B. Chiral Synthesis via Organoboranes. (25) The erosion of diastereoselectivity in the Z-alkene boronate prod-
3. Conversion of Boronic Esters of Essentially 100% Optical Pu- ucts was likely due to the epimerization caused by the arylthiolate
rity to Aldehydes, Acids, and Homologated Alcohols of Very High LG during the elimination step.
Enantiomeric Purities. J. Am. Chem. Soc. 1985, 107, 4980–4983.
(12) Noble A.; Roesner, S.; Aggarwal, V. K. Short Enantioselective
10