One-Step Synthesis of Aliphatic Potassium Acyltrifluoroborates (KATs) from Organocuprates

Article abstract of DOI:10.1021/acs.orglett.8b00720

A one-step synthesis of aliphatic KATs from organocuprates is reported. Organolithium and organomagnesium reagents were readily transmetalated onto Cu(I) and coupled with a KAT-forming reagent to yield the respective aliphatic KAT. The protocol is suitable for primary, secondary and - for the first time - tertiary alkyl substrates. These protocols considerably expand the range of KATs that can be readily accessed in one step from commercially available starting materials.

Full text of DOI:10.1021/acs.orglett.8b00720

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Step Synthesis of Aliphatic Potassium Acyltrifluoroborates
(KATs) from Organocuprates
Sizhou M. Liu,‡ Dino Wu,‡ and Jeffrey W. Bode*
Laboratorium fur Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
̈
̈
̈
S
* Supporting Information
ABSTRACT: A one-step synthesis of aliphatic KATs from
organocuprates is reported. Organolithium and organo-
magnesium reagents were readily transmetalated onto Cu(I)
and coupled with a KAT-forming reagent to yield the
respective aliphatic KAT. The protocol is suitable for primary,
secondary andfor the first timetertiary alkyl substrates.
These protocols considerably expand the range of KATs that
can be readily accessed in one step from commercially
available starting materials.
Scheme 1. One-Step Synthesis of Potassium
Acyltrifluoroborates
cylboronates are a fascinating and underdeveloped class of
Afunctional groups for organic synthesis. While their
existence was proposed as reactive intermediates in several
transformations over the last century,1 it was not until 2007 that
the first fully characterized acyl boron species was disclosed by
Nozaki and co-workers.2 Several approaches for the synthesis of
acylboronates have since been reported. In 2010, Curran and
Laco
̂
te3 reported the synthesis of an acylborane species from an
N-heterocyclic carbene-stabilized borane. In the same year,
Molander and co-workers4 synthesized a single example of a
potassium acyltrifluoroborate. In 2012, Yudin developed a
multistep approach to N-methyliminodiacetyl (MIDA) acyl-
boronates from a vinyl boron species5 and, just recently, Ito and
Perrin independently reported the synthesis of acylboronates
by oxidation of vinyl (MIDA) boronates.6,7
As part of our group’s long-standing interest in new amide-
forming reactions, we gained interest in KATs after finding that
they undergo rapid ligation reactions with hydroxylamines in
water.8,9 In order to expand synthetic access to KATs, our
research group previously devised a route exploiting Katritzky’s
benzotriazole chemistry10 to prepare a range of KATs, albeit in
somewhat poor yields and limited substrate scope.11,12 In order
to provide direct access to aromatic KATs from the
corresponding halides, we also introduced KAT transfer reagent
(ethylthiotrifluoroborate)methane dimethyliminium (1),
(Scheme 1).13 Unfortunately, these conditions were largely
unsuccessful for the synthesis of aliphatic KATs, because of the
double addition of the more nucleophilic aliphatic organo-
lithium reagents.
In this report, we document the synthesis of aliphatic KATs
from in-situ-generated organocuprates and KAT transfer
reagent 1. This convenient protocol allows readily prepared
or commercially available organolithium and Grignard reagents
derived from primary, secondary, and tertiary alkyl halides to be
easily converted to the corresponding KATs in high yields. This
chemistry affords the first known tertiary acylboronates, and we
demonstrate that even these hindered examples undergo KAT
ligation with hydroxylamines.
At the onset of this work, we envisioned the direct
conversion of organometallic reagents to KATs through the
reaction of the desired substrate with the formerly developed
KAT transfer reagent 1 in a one-pot fashion. Our initial
attempts using n-butyllithium and n-butylmagnesium chloride
for this transformation failed to give the desired product (see
Scheme 2). Instead, double addition of the substrate to the
transfer reagent and formation of the bis-alkylated product were
observed.
Received: March 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00720
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
organomagnesium toward CuCN for the transmetalation could
be observed. Performing the reaction with an equimolar
amount of Cu(I) to generate the neutral heteroleptic
organocopper reagent (Table 1, entry 5) failed to give the
desired product. Addition of the Grignard reagents to KAT
transfer reagent 1 at 0 °C over an hour resulted in better yield
in the case of CuCN. However, no product was formed with
CuI under these conditions, because of cuprate decomposition
(Table 1, entries 6 and 8). Exchanging organocuprates for
organozinc reagents (Table 1, entries 10 and 11) failed to give
any product.
Scheme 2. Previous Work on Thioiminium Mono-alkylation
With the optimized protocol in hand, we expanded the
substrate scope to include primary KATs bearing simple alkyl
chains, alkene, alkyne, acetal, and hydroxyl moieties (see
Scheme 3).
Scheme 3. Synthesis of Primary Aliphatic KATs with
a
Organocuprates
Selective mono-alkylation of thioiminium reagents has been
deemed challenging, with little precedence in the literature.14
Bosch and Renaud independently reported the selective mono-
alkylation of thioiminium moieties with organocuprates.15,16
Inspired by these works, we attempted the addition of
organocuprates to transfer reagent 1, and we were pleased to
observe the formation of the desired product. Encouraged by
this finding, we set out to optimize the reaction conditions for
the synthesis of aliphatic KATs (see Table 1).
Table 1. Optimized Conditions for Organocuprate Addition
a
to KAT Transfer Reagent 1
b
No.
M
conditions
yield (%)
1
2
Li
−78 °C
−78 °C
1.1 equiv CuCN, −78 °C, 1 h
1.1 equiv CuI, −78 °C, 1 h
2.2 equiv CuCN, −78 °C, 1 h
1.1 equiv CuCN, −78 to 0 °C, 1 h
1.1 equiv CuI, −78 °C, 1 h
1.1 equiv CuI, −78 to 0 °C, 1 h
1.1 equiv CuBr·SMe2, −78 °C, 1 h
1.1 equiv ZnI2, −78 °C, 1 h
1.1 equiv ZnI2, −78 °C, 1 h
0
0
MgCl
Li
3
79
86
0
4
Li
a
Reactions were conducted with 2.3 equiv organometallic species and
5
Li
1.1 equiv Cu(I) salt. In the case of organolithium species, CuI was
used and the organocuprate was preformed at −78 °C. For
organomagnesium species, CuCN was used to preform the cuprate
6
MgCl
MgCl
MgCl
MgCl
Li
81
70
0
7
8
18
b
at 0 °C. Reaction carried out in gram scale (5.4 mmol).
9
7
10
11
0
While the organocuprate formation with primary Grignard
reagents and organolithium reagents proceeded rapidly, even at
low temperatures, secondary Grignards required significantly
longer reaction times in the transmetalation step. In order to
accelerate the transmetalation and ensure complete cuprate
formation, the reaction temperature was increased to 0 °C.
However, this necessitated the use of CuCN, because of the
low thermal stability of CuI-derived organocuprates. Subse-
quent addition of the preformed organocuprate species to KAT
transfer reagent 1 at −78 °C and warming to room temperature
overnight had a favorable effect on the selectivity toward mono-
alkylation, compared to conducting the reaction at 0 °C
throughout.
MgCl
0
a
All reactions were conducted with 2.2 equiv organolithium or
organomagnesium species on a 0.28 mmol scale, unless otherwise
specified. Organocuprates were preformed at 0 °C or −78 °C.
b
Isolated yield.
In early efforts, we performed transmetalation of commer-
cially available n-butylmagnesium chloride and n-butyllithium
onto copper(I) salts to generate the corresponding organo-
cuprates. As organocuprates display high functional group
tolerance and are readily accessible from a broad range of
commercial Grignard and alkyllithium reagents,17 they
represented the ideal candidate for our transformation. We
found that the use of CuCN (Table 1, entries 3 and 6) and CuI
(Table 1, entries 4 and 7) generally provided the highest
yielding results for both organolithium and organomagnesium
species. A slight preference of organolithium toward CuI and
With these revised conditions, we were able to prepare a
broad range of secondary aliphatic KATs ranging from
branched to cyclic products in good yields (see Scheme 4).
For the synthesis of the saturated heterocyclic KATs (16, 17),
we observed fast decomposition of the organocuprate at 0 °C,
B
DOI: 10.1021/acs.orglett.8b00720
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Scheme 4. Synthesized Secondary and Tertiary Aliphatic
KATs
Scheme 5. Reactivity Studies of Aliphatic KATs
a
a
Reactions were conducted with 2.4 equiv organometallic species and
1.1 equiv Cu(I) salt. In the case of organolithium species, CuI was
used and the organocuprate was preformed at −78 °C. For
organomagnesium species, CuCN was used to preform the cuprate
b
at 0 °C. Reaction carried out in gram scale (5.4 mmol).
even with CuCN. By forming the organocuprate at −78 °C
under sonication, we were able to circumvent this problem and
were able to obtain KATs 16 and 17 in good yields. With these
promising results in hand, we investigated if this method
allowed for the synthesis of previously inaccessible tertiary
KATs. Upon conversion to the respective organocuprates,
bulky reagents such as t-butyllithium and 1,1-dimethyl-
propylmagnesium chloride reacted readily with KAT transfer
reagent 1 to give the first isolated examples of tertiary KATs 18
and 19 in satisfying yields. To probe the scalability of the
reaction, we repeated the reaction on gram scale (5.4 mmol)
for selected substrates (compounds 4, 10, 18). The scaleup
proved to be successful, with yields comparable to those
observed in small-scale reactions.
than the two-step benzotriazole route requiring demanding
reaction conditions and purification steps. This method also
allowed access to the first tertiary potassium acyltrifluorobo-
rates. Furthermore, ligation experiments of aliphatic KATs with
O-carbamoyl hydroxylamine were performed to determine the
relative reactivity for primary, secondary, and tertiary alkyl
KATs. We found that sterics influenced the reaction with the
expected correlation between steric bulk and conversion.
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.8b00720.
Having primary, secondary, and tertiary alkyl KATs in hand,
we probed the degree to which sterics influence the ligation rate
of KATs with O-carbamoyl hydroxylamine 20 (see Scheme 5).
In competition experiments, the ligation of unbranched alkyl
KAT 4 and secondary KAT 10 gave a 2:1 product ratio in favor
of the less-hindered substrate. This indicates that the ligation of
secondary KATs is still relatively fast. In comparison, the
competition between the primary KAT 4 and tertiary KAT 18
showed a clear selectivity of 99:1 toward the unbranched
product. The ligation of tert-butyl KAT (18) with hydroxyl-
amine (20) can proceed to full conversion with increased
reaction time (24 h) to give the desired amide in 92% yield.
These findings indicated that sterics are significant components
of reaction rate in the KAT ligation.
In summary, we have developed a convenient and robust
protocol for the preparation of aliphatic KATs from readily
available Grignards and commercially available KAT transfer
reagent 1 in a one-pot fashion. We demonstrated the scalability
of this new procedure and prepared 18 new KATs bearing a
variety of functional groups. This route is significantly simpler
Experimental procedures and characterization of aliphatic
acyltrifluoroborates (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bode@org.chem.ethz.ch.
ORCID
Jeffrey W. Bode: 0000-0001-8394-8910
Author Contributions
‡These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by an ETH Research Grant (No.
ETH-43 13-2). We thank Alberto Osuna Galvez (ETH) for
compound 8. Furthermore, we thank the LOC Mass
C
DOI: 10.1021/acs.orglett.8b00720
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Spectrometry Service and the LOC NMR Service for analysis
and helpful discussions.
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D
DOI: 10.1021/acs.orglett.8b00720
Org. Lett. XXXX, XXX, XXX−XXX