B-Alkyl sp3-sp2 Suzuki-Miyaura Couplings under Mild Aqueous Micellar Conditions

Article abstract of DOI:10.1021/acs.orglett.8b00961

Use of B-sp³-alkyl reagents for Suzuki-Miyaura couplings under aqueous micellar catalysis conditions is reported. Studies as to substrate scope, use in a four-step one-pot sequence, and reaction medium recycling exemplify the synthetic utility of this technology. OBBD (B-alkyl-9-oxa-10-borabicyclo[3.3.2]decane) derivatives are easily made and utilized for couplings under mild conditions. Comparisons were also made between OBBD and 9-BBN (B-alkyl-9-borabicyclo[3.3.1]nonane) derivatives as reaction partners.

Full text of DOI:10.1021/acs.orglett.8b00961

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
B‑Alkyl sp3−sp2 Suzuki−Miyaura Couplings under Mild Aqueous
Micellar Conditions
Nicholas R. Lee,† Roscoe T. H. Linstadt,‡ Danielle J. Gloisten,† Fabrice Gallou,§
and Bruce H. Lipshutz*,†
†Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
‡ACatechol, Inc., Santa Barbara, California 93103, United States
§Novartis Pharma AG, CH-4057 Basel, Switzerland
S
* Supporting Information
ABSTRACT: Use of B-sp3-alkyl reagents for Suzuki−Miyaura
couplings under aqueous micellar catalysis conditions is
reported. Studies as to substrate scope, use in a four-step
one-pot sequence, and reaction medium recycling exemplify
the synthetic utility of this technology. OBBD (B-alkyl-9-oxa-
10-borabicyclo[3.3.2]decane) derivatives are easily made and
utilized for couplings under mild conditions. Comparisons
were also made between OBBD and 9-BBN (B-alkyl-9-
borabicyclo[3.3.1]nonane) derivatives as reaction partners.
uzuki−Miyaura cross-coupling reactions have been broadly
applied to numerous C−C bond formations due, in part, to
Scheme 1. Preparation of OBBD Derivatives
S
their ability to make connections that may be difficult by other
means.1 Couplings using 9-BBN derivatives are common;2
however, notable variations including BF3K3 and MeO-9-
BBN2b reagents have found widespread use by broadening the
scope and flexibility of this synthetic strategy. In the search for a
boron species suitable for use in aqueous media, the OBBD (B-
alkyl-9-oxa-10-borabicyclo[3.3.2]decane) framework, a deriva-
tive of 9-BBN, appeared to be one potentially attractive option.
Practical applications associated with use of 9-BBN and other
trialkylboranes are limited due to their sensitivity to air, as well
as their pyrophoric nature and modest shelf life, leading to their
typical formation and use in situ.4 By contrast, OBBD reagents
exhibit relatively good air stability and, therefore, are easily
isolated and storable for future use. These reagents were
developed primarily by Soderquist.5 Several publications have
since utilized these reagents in applications as diverse as
reactions with allenes,6a installation of OBBDs onto a
carbohydrate framework,6b and for attachment of an OBBD
to a chromium complex,6c among others. Their potential for
use as B-sp3-alkyl partners in Suzuki−Miyaura (SM) couplings,
however, has not been explored outside of Soderquist’s original
reports with the exception of a methylation in a total
synthesis6d and an example of coupling of a vinyl OBBD
derivative to an aryl halide.6e Our group has focused mainly on
sp2−sp2 SM reactions in aqueous surfactant media,7 with
TPGS-750-M being the preferred amphiphile; none to date
forms sp2−sp3 bonds. These reagents have now been examined
for their potential as coupling partners under micellar catalysis
conditions. We have found that, in addition to their preparation
being straightforward (Scheme 1), their reactivity is comparable
to that of 9-BBN derivatives. However, their relatively greater
stability and their isolable nature make them especially suitable
for these highly valued C−C bond constructions using
environmentally responsible reaction conditions, as described
herein.
A library of OBBD derivatives was synthesized (Figure 1; see
Supporting Information for details) with which the scope of the
newly developed technology could be evaluated based on the
Figure 1. Representative OBBD derivatives prepared for cross-
couplings in water.
Received: March 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00961
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
variety of resulting coupled products. Of note, was the facility
with which the OBBD moiety could be installed notwithstand-
ing the presence of other sensitive groups, including α,β-
unsaturated ketones, amines, N-heterocycles, aryl halides, and
protecting groups. Both primary and secondary OBBDs were
readily prepared. In agreement with previous reports,2b
hydroboration was slowed by increasing degrees of substitution
on the precursor alkene.
Although these reagents have been described as “air
stable”;5a,e we found that they remain intact for 1−2 days
when left open to air, after which significant deterioration does
occur. However, their shelf life when stored under argon using
refrigerated conditions was found to be good. For example,
OBBD derivatives 1 and 3 have been stored by us for over one
year with minimal degradation. The literature procedures by
Soderquist involved distillation to purify OBBD-containing
compounds.5c,f While this is suitable for lower molecular weight
cases, it is not practical for high molecular weight or heat
sensitive compounds. We found that upon completion of 9-
BBN hydroboration/monooxidation, the solvent could instead
be removed in vacuo and the crude OBBD product filtered
through a short pad of silica gel to arrive at material useful for
coupling reactions. Most of these compounds appeared to be
stable to silica gel, although OBBD derivative 9 was found to
rapidly decompose on SiO2 at rt.
based sp2−sp3 couplings. These trials revealed that Pd(dtbpf)-
Cl2 is superior to Pd(dppf)Cl2, and (SPhos)2Pd. Indeed, using
dtbpf as the supporting ligand, a model reaction could be run
successfully at a catalyst loading as low as 0.25 mol % (i.e., 2500
ppm).
Initially, Et3N was used as a base for this model study, and
while it helped to solubilize educts and leads to a much more
uniform reaction appearance, better yields and shorter reaction
times were noted by switching to K3PO4 (Scheme 3). Although
Scheme 3. Substrate Scope Using 0.5 mol % Pd
While “discovery conditions” involved use of (HandaPhos)-
Pd7d as a catalyst at 1% loading, further reductions in the
amount of catalyst resulted in decreased yields. Among several
catalysts evaluated, Pd(dtbpf)Cl2 was selected as the most
suitable. Couplings were initially screened at the 2 mol % level
to assess the substrates scope, the results from which are shown
in Scheme 2.
Following this preliminary assessment suggesting broad
substrate compatibility, we returned to catalyst screening and
reaction optimization. Our investigation centered on the choice
of ligand alternatives to that found in Pd(dtbpf)Cl2, such as
4a,5b
SPhos, and Pd(dppf)Cl2
given its frequent use in 9-BBN-
Scheme 2. Preliminary Substrate Scope Using 2 mol % Pd
a
Et3N (3 equiv) as base.
traditional 9-BBN/OBBD couplings call for KOH or NaOH as
the base,4a,5b,c several byproducts were formed under these
conditions. Reactions run at room temperature gave acceptable
yields, although these required much longer reaction times.
Attempts to use a 0.25 mol % catalyst loading, under ambient
conditions, resulted in little-to-no conversion, especially in
more challenging substrates. Therefore, further evaluation of
substrate scope was conducted at 45 °C. Interestingly, reaction
appearance seemed better at room temperature, producing
“milky” reaction mixtures, while an increase to 45 °C led to
B
DOI: 10.1021/acs.orglett.8b00961
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Letter
“oiling out”, despite improving the extent of conversion.
Product isolation followed simple extraction of the aqueous
mixtures with EtOAc.
Table 1. Impact of Exposure of Reagent to Air for 1 h Prior
to Use
organoboron reagent
yield after 1 h exposure to air
While many substrate combinations proved viable at catalyst
loadings of 0.25% Pd, those rich in nitrogen were more
challenging and required an increase to 0.5 mol % Pd to go to
completion (Scheme 3). In addition to slowing reactions, most
substrates containing nitrogen were very challenging to purify
by column chromatography, as the OBBD residue remained
present, though column fractions appeared clean by TLC.
Workup with hydrogen peroxide to remove boron-containing
residues, prior to extraction, alleviated this issue.
9-BBN (1.1 equiv)
OBBD (1.1 equiv)
49%
92%
led to essentially equivalent yields (ca. 94%). However, while
the OBBD derivative did not suffer from pre-exposure to air for
an hour and gave a similar yield of coupling product (92%), the
9-BBN analog suffered significant degradation, resulting in a
dramatic decrease in yield (49%; Scheme 5). Running both
As for limitations, OBBD-containing substrates bearing steric
hindrance near the boronate led to significantly slower
couplings. In addition, neither secondary OBBD nor 9-BBN
derivatives were capable of coupling under these standard
conditions; variations such as higher temperatures, catalyst
loadings, or changes in base also had no effect.
Scheme 5. 9-BBN vs OBBD Air Sensitivity Testing
To showcase the utility of OBBD reagents in the
construction of a complex framework, a four-step one-pot
sequence (A to D, Scheme 4) was conducted. The reaction
Scheme 4. Tandem Four-Step One-Pot Sequence in
Aqueous Media
reactions fully open to air resulted in similar decreases in yields
(Table 2). Even at 2 mol % Pd, the presence of oxygen is
Table 2. Coupling Run Fully Open to Air
organoboron reagent
yield of reaction exposed to air
9-BBN (1.1 equiv)
OBBD (1.1 equiv)
50%
51%
extremely detrimental to reaction outcome, and this effect is of
even greater consequence at lower catalyst loadings. Therefore,
while the OBBD reagent is stable to air for short periods of
time, both boron species require inert conditions for effective
coupling. Such observations have important implications for
use of these reagents, especially in industrial settings. That is,
aside from their responsiveness to aqueous micellar catalysis
conditions, tolerance of OBBDs to air allows for their ease of
handling without concern over degradation or potential
pyrophoric complications.
Examples in the literature of couplings with 9-BBN or OBBD
are typically run in THF, dioxane, or mixtures with water, e.g.,
20:1 THF/water. The reaction in Table 3 was found to proceed
much faster in TPGS-750-M than in traditional solvent systems.
Reuse of an aqueous TPGS-750-M solution was practical for
up to three recycles, after which the reaction medium becomes
too viscous to stir and difficult to extract (Table 4). Efforts to
recycle the catalyst as well were not successful, as extraction
with EtOAc removes nearly all the Pd(dtbpf)Cl2, while use of
Et2O or MTBE leaves enough for only partial conversion in a
subsequent reaction.
In summary, both alkyl-9-BBN and the corresponding
OBBD reagents have been studied in Suzuki−Miyaura
reactions run in water under mild conditions. The latter
derivatives were found to be particularly useful for sp3−sp2
couplings. Due to their relatively good air stability, non-
pyrophoric nature, and ease of preparation, OBBD derivatives
are attractive coupling partners in B-alkyl Suzuki−Miyaura
involving an OBBD derivative was used in the second step (B),
following an initial SNAr reaction (A),8 and was selected to
illustrate that it can tolerate species in the pot that are unrelated
to its couplings. The product from step B containing an
aromatic nitro group was then reduced using our procedure
based on carbonyl iron powder (CIP)9 and then acylated to
afford the final product in very good overall yield. An
alternative sequence utilizing a more complex amine for the
SNAr was attempted, but resulted in very insoluble material.
Moreover, the residual amines present hindered the subsequent
OBBD coupling such that no conversion was seen.
The effect of brief (1 h) exposure of OBBD and 9-BBN
derivatives to air was tested (Table 1). When both were kept
under an inert atmosphere before and during the reaction, they
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Organic Letters
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Reaction Medium after 6 h
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solvent/medium
isolated yield (%)
TPGS-750-M (2 wt % in water)
THF/H2O (20:1)
94
44
56
dioxane/H2O (20:1)
Table 4. Recycling of TPGS-750-M and E Factor
Calculations
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first
second
recycle
third
reaction
recycle
recycle
isolated yield (%)
81
85
86
88
E factor (organic solvent)
3.2
7.8
3.1
5.1
3.0
3.0
3.9
6.0
E factor (including
aqueous)
couplings under aqueous micellar conditions, akin to our sp2−
sp2 SM couplings previously described.7
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00961.
(9) Lee, N. R.; Bikovtseva, A. A.; Cortes-Clerget, M.; Gallou, F.;
Lipshutz, B. H. Org. Lett. 2017, 19, 6518.
Reaction optimization, details of control-experiments,
analytical data of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
ORCID
Bruce H. Lipshutz: 0000-0001-9116-7049
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We warmly acknowledge Novartis and the NSF (GOALI
SusChEM 1566212) for financial support.
■
REFERENCES
■
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DOI: 10.1021/acs.orglett.8b00961
Org. Lett. XXXX, XXX, XXX−XXX