Silver(I)-Catalyzed Diastereoselective Synthesis of anti-1,2-Hydroxyboronates

Article abstract of DOI:10.1002/anie.201507171

A catalytic protocol for the diastereoselective synthesis of anti-1,2-hydroxyboronates is described. The process provides access to secondary alkyl organoborons. The deborylative 1,2-addition reactions of alkyl 1,1-diborons proceed in the presence of a silver(I) salt with either KOtBu or nBuLi as an activator. The catalytic diastereoselective protocol can be extended to aryl, alkenyl, and alkyl aldehydes with up to 99:1 d.r.

Full text of DOI:10.1002/anie.201507171

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507171
German Edition: DOI: 10.1002/ange.201507171
Homogeneous Catalysis
Silver(I)-Catalyzed Diastereoselective Synthesis of anti-1,2-
Hydroxyboronates
Matthew V. Joannou, Brandon S. Moyer, Matthew J. Goldfogel, and Simon J. Meek*
Abstract: A catalytic protocol for the diastereoselective syn-
thesis of anti-1,2-hydroxyboronates is described. The process
provides access to secondary alkyl organoborons. The debor-
ylative 1,2-addition reactions of alkyl 1,1-diborons proceed in
the presence of a silver(I) salt with either KOtBu or nBuLi as
an activator. The catalytic diastereoselective protocol can be
extended to aryl, alkenyl, and alkyl aldehydes with up to 99:1
d.r.
F
unctionalized secondary alkyl boronate esters are enabling
reagents for chemical synthesis, thus catalytic stereoselective
methods for their preparation are a compelling objective.[1]
Carbon–carbon bond-forming reactions of boron-stabilized
alkyl nucleophiles provide direct approaches to functional-
3
À
ized molecules containing C(sp ) B bonds. Specifically,
alkylation of aldehydes with a-boryl nucleophiles serves to
generate secondary alcohols bearing a vicinal alkyl boron
unit.[2] Such processes form two contiguous stereogenic
3
[3,4]
À
centers with a versatile C(sp ) B bond.
Despite progress
Scheme 1. Addition of a-boryl reagents to aldehydes. Previous work:
in this area, several shortcomings preclude their synthetic
utility, the most apparent of which are the lack of catalytic
processes to afford products in high yield and stereoselectiv-
ity. Existing protocols for the stereoselective synthesis of 1,2-
hydroxyboronates are achieved through organocuprates and
deprotonations of bis(mesityl)-substituted alkyl boranes.
Miyaura and co-workers reported one example of the
addition of Knochelꢀs a-B(pin) cyanocuprate [B(pin) =
(pinacolato)boron] to benzaldehyde to afford a 1,2-hydrox-
yboronate in 6:1 d.r. (anti/syn; Scheme 1a).[2b] Pelter et al.
reported excellent levels of anti selectivity for the addition of
dimesityl-boron-stabilized carbanions to aldehydes. However,
strong lithium bases and cryogenic conditions (À1168C) are
required for carbanion generation and reaction, thus limiting
functional-group compatibility.[2c]
Bench-stable alkyl germinal diborons have emerged as
useful difunctional reagents which provide effective methods
to access a-boryl anion synthons. In the presence of an
alkoxide or hydroxide activator 1,1-diborons participate in
alkylation and cross-coupling reactions. Morken and co-
workers demonstrated that the corresponding borates decom-
pose to a-boryl-stabilized carbanions, which undergo efficient
and diastereoselective alkylation with alkyl halides to gen-
a) Diastereoselecitve cuprate 1,2-addition. b) Deprotonation/1,2-addi-
tion of alkyl borons. c) This work: Catalytic anti-selective 1,2-addition
of 1,1-diboronates. pin=pinacol, THF=tetrahydrofuran.
erate substituted quaternary carbon atoms.[5] Catalytic reac-
tions developed with difunctional alkyl organoboron reagents
have focused on Suzuki cross-couplings.[6] Shibata and co-
workers demonstrated that palladium-catalyzed cross-cou-
plings of alkyl 1,1-diborons effectively proceed under ambient
conditions to afford secondary alkyl boronates.[6a] More
recently, the groups of Morken and Hall independently
reported catalytic enantioselective variants for the stereose-
lective synthesis of secondary benzylic and allylboronates.[7]
Advances notwithstanding, catalytic diastereoselective pro-
tocols for the addition of 1,1-diborons to carbonyls remain
limited. Previously, we reported the enantio- and diastereo-
selective copper(I)-catalyzed additions of substituted alkyl
1,1-diborons to aldehydes to afford 1,2-hydroxyboronates in
high syn selectivity (Scheme 1c).[8] The reaction most likely
proceeds via a chiral a-boron copper(I)/alkyl intermediate
À
adding to the aldehyde, and simultaneously forming a new C
C bond and two vicinal stereogenic centers, one of which
comprises a secondary alkyl boron unit for further synthetic
elaboration.
Herein, we outline the first catalytic protocol for the
diastereoselective synthesis of anti-1,2-hydroxyboronates
through the silver-catalyzed addition of 1,1-diboronates to
aryl and alkyl aldehydes (Scheme 1c). Reactions are pro-
moted by 10 mol% of a readily available silver(I) salt catalyst
in conjunction with an alkoxide or alkyl lithium activator. The
[*] M. V. Joannou, B. S. Moyer, M. J. Goldfogel, Prof. S. J. Meek
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
E-mail: sjmeek@unc.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507171.
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products are delivered in up to 77% yield and 99:1 d.r. The
reaction is also tolerant of several functional groups, including
silyl-ether-protected alcohols, N-Boc-protected nitrogen
atoms, esters, and acetal-protected aldehydes.
Initial studies of catalytic reaction conditions identified
silver(I) salts as effective promoters for the anti-selective
addition of 1,1-diboryl reagents to aldehydes. The data
illustrated in Table 1 summarize the optimization of the
or reaction times result in only slight increases (< 5%) in
yield.[12]
We next evaluated the scope of the silver(I)-catalyzed
protocol for the addition of 1 to aryl- and alkenyl-substituted
aldehydes (Scheme 2), and several points are noteworthy:
Table 1: Optimization of reaction conditions for the synthesis of the anti-
1,2-hydroxyboronate 2.[a]
Entry Silver salt Ligand
Base
T [8C] Conv. [%][b] d.r. (2/3)[b]
1
2
3
–
–
–
–
–
PPh3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
22
0
0
0
0
63
<2
18
47
42
33
50
47
64
84
50:50
–
AgOAc
50:50
54:46
84:16
92:8
93:7
95:5
93:7
97:3
–
4[c] AgOAc
5
6
AgOAc
AgOAc
rac-binap NaOtBu
rac-binap NaOtBu À25
7[d] AgOAc
rac-binap KOtBu
À25
À25
À25
8[c] AgOAc
PPh3
PCy3
–
KOtBu
KOtBu
9
10
11
AgOAc
AgOAc
–
Scheme 2. The anti-selective silver(I)-catalyzed 1,2-addition of the 1,1-
diboronate 1 to aryl and vinyl aldehydes. Yields of the purified
products are an average of two runs. Diastereomeric ratio (d.r.)
determined by analysis of either 400 MHz or 600 MHz 1H NMR
spectra of the unpurified reaction mixtures using hexamethyldisiloxane
as an internal standard. [a] Yield determined by 1H NMR spectroscopy.
KOtBu À25
–
KOtBu
À25 <2
[a] Reactions performed under N2 atm. [b] Conversion and diastereo-
meric ratio (d.r.) determined by analysis of either 400 MHz or 600 MHz
1H NMR spectra of unpurified reaction mixtures using an internal
standard. [c] 20 mol% PPh3. [d] Use of (R)-binap delivers 2 in 0% ee. The
reaction conditions of entry 10 represent the optimized reaction
conditions. binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl.
1) para-substituted aryl aldehydes bearing either halogens
(4a,b) or electron-donating methoxy (4c) groups undergo
diastereoselective additions to yield hydroxyboronates in
good yield (64–73%) and high selectivity (up to 97:3 anti/syn).
2) Substitution at the meta and ortho positions of the aryl
aldehyde are tolerated, as demonstrated by the formation of
4d–g in 52–75% yield and 97:3 d.r. (anti/syn). 3) Synthesis of
furyl-, pyridyl-, and Boc-indole-substituted products (4h–j)
demonstrate that heteroaryl aldehydes are effective sub-
strates with no apparent inhibition. The expected 1,2-hydrox-
yboronates were isolated in 45–77% yield and 91:9–99:1
d.r.[13] 4) Transformations with sterically unhindered alkenyl
aldehydes proceed with diminished selectivity, thus producing
the allylic alcohols 4k and 4l in 88:12 and 86:14 d.r.,
respectively. However, a-methylcinnamaldehyde-derived
4m was obtained in 64% yield and 92:8 d.r. with 10 mol%
AgOAc.
Catalytic anti-selective 1,2-additions were extended to
include substituted alkyl 1,1-diboron compounds (see 5–9;
Scheme 3). The transformations proceed effectively with
10 mol% AgOAc in up to 77% yield at À258C in 24 hours.
The expected 1,2-hydroxyboronates, including those that
contain functional groups such as a phenyl ring (5), an
alkene (6), a silyl ether (7), or an n-alkyl (8), or an ester (9),
were obtained in up to 77% yield and greater than 98:2 d.r.
(anti/syn) selectivity. Only in the case of a tert-butyl-ester-
reaction conditions. As entry 1 shows, there is a significant
nonselective background reaction with 130 mol% NaOtBu at
228C and it affords 2 and 3 in (63% conversion) 50:50 d.r.,
and a less than 2% conversion is observed at 08C (entry 2).[9]
Catalytic AgOAc (10 mol%) was found to promote the
addition at 08C but with no diastereoselectivity (entry 3).
Monodentate (PPh3; entry 4), and bidentate (rac-binap;
entry 5) phosphines were evaluated for their ability to deliver
2 in high diastereoselectivity and yield, and rac-binap affords
2 in 42% conversion and 84:16 d.r. (anti/syn; entry 5).
Decreasing the temperature to À258C results in lower
conversions to 2, but increases the anti selectivity (92:8 d.r.;
entry 6). Application of KOtBu in place of NaOtBu leads to
an improved yield at À258C with no significant loss in d.r.
value.[10] Monodentate aryl (entry 8) and alkyl (entry 9)
phosphines were found to deliver 2 with a conversion and
selectivity, in the presence of KOtBu, which are similar to
those obtained with rac-binap. Optimal reaction conditions
for the catalytic diastereoselective addition of 1 to benzalde-
hyde are those run in the absence of a phosphine ligand.
Treatment of benzaldehyde and 1 with 10 mol% AgOAc with
KOtBu in THF (À258C) delivers 2 in 84% yield (NMR
analysis) and 97:3 d.r. No reaction is observed in the absence
of a silver(I) salt (entry 11).[11] Increasing the catalyst loading
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AgOAc followed by cyclohexane carboxaldehyde at À258C
afforded 11 in 51% yield and 88:12 d.r. (anti/syn). A less than
5% conversion to 11 is observed in the absence of the silver(I)
salt. The nBuLi protocol proved effective for alkyl and aryl
aldehydes in combination with substituted 1,1-diboron
reagents which contain an alkene (12), phenyl ring (13),
acetal (14), or silyl ether (15; Scheme 4b). In general, the
yields and anti-selectivity of the 1,2-hydroxyboronate prod-
ucts are slightly lower than in the case of aryl aldehydes. Alkyl
aldehydes lacking a-protons do not require nBuLi as an
activator. For example, pivaldehyde undergoes diastereose-
lective (98:2 d.r., anti/syn) addition promoted by KOtBu, but
16 is isolated in only 34% yield. The acetal-containing
product 17, while derived from an aryl aldehyde, requires
Method B for formation (Method A furnishes the product in
< 5% yield).
Scheme 3. Scope with respect to substituted 1,1-diboronates in anti-
selective 1,2-hydroxy boronate synthesis. Yields of the purified prod-
ucts are an average of two runs. Diastereomeric ratio (d.r.) determined
by analysis of either 400 MHz or 600 MHz 1H NMR spectra of the
unpurified reaction mixtures using hexamethyldisiloxane as an internal
standard. G=attached group.
To investigate the mechanism of the anti-selective 1,2-
1
addition reaction, activation of 1 was monitored by H and
11B NMR spectroscopy. Addition of 1.3 equivalents of KOtBu
to 1 in [D8]-THF at 228C (Scheme 5a) leads to 86%
containing reagent was low diastereoselectivity observed. 9
was isolated in 66% yield and 47:53 d.r., (anti/syn). One
shortcoming of the method relates to the use of b-branched
1,1-diboryl alkanes, and as an example, the cyclohexyl 10 is
formed in less than 5% yield.
Addition of a-boryl nucleophiles was next extended to
alkyl aldehydes (Scheme 4a). With cyclohexane carboxalde-
hyde, under otherwise identical reaction conditions (see
Scheme 2), there was 6% conversion to 11 in 79:21 d.r.
(Method A, Scheme 4a). We reasoned that deprotonation of
the aldehyde by KOtBu was responsible for low conversion to
product.[14] To discourage enolization caused by unreacted
alkoxide in solution, we substituted nBuLi for KOtBu
(Method B, Scheme 4a), as an irreversible activation of the
1,1-diboryl alkane should minimize undesired side reactions.
Treatment of 1 with 1 equivalent of nBuLi in the presence of
Scheme 5. Investigation into the activation of 1 with KOtBu and the
role of AgOAc in the 1,2-addition reaction. In all cases, 1 was
completely consumed. 11B NMR spectroscopy for both reactions shows
three signals: d=34.0, d=7.8, and d=4.9 ppm. The latter signal
corresponds to potassium bis(tert-butoxypinacolborate). See the Sup-
porting Information for details.[16]
conversion into the tBuO-activated borate species 18.[15] If
left at room temperature, 18 slowly decomposes to 19, (14%
conv. in 15 min, and 75% conv. after 18 h). Morken and co-
workers have shown that borates such as 18 will deborylate at
room temperature to form a-boryl-stabilized carbanions,[5a]
however, we could not confirm the presence of the carbanion
1
in concentrations of greater than 5% conversion by H or
11B NMR spectroscopy.
To determine the role of AgOAc in the reaction,
activation of 1 with KOtBu in the presence of 1 equivalent
1
of AgOAc was monitored by H and 11B NMR spectroscopy
(Scheme 5b). Complete consumption of 1 and borate for-
mation were observed, but the presence of an a-boryl
carbanion could not be confirmed (Scheme 5a). Another
species forms after 5 minutes at 228C, and can be assigned to
the homocoupled product 20. Signals for the diastereotopic
protons at the base of the B(pin) groups produce a multiplet
at d = 0.45 ppm. Homocoupling of Grignard and organo-
boron species can be promoted by stoichiometric and
catalytic amounts of various silver(I) salts.[17] Whitesides and
Scheme 4. Silver(I)-catalyzed additions of 1,1-diboryl alkanes to alkyl
aldehydes. Yields of the purified products are an average of two runs.
Diastereomeric ratio (d.r.) determined by analysis of either 400 MHz
or 600 MHz 1H NMR spectra of unpurified reaction mixtures using
hexamethyldisiloxane as an internal standard. TBS=tert-butyldimethyl-
silyl.
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co-workers demonstrated that these reactions proceed by
reductive dimerization of alkyl silver compounds to form
silver metal.[18] Bis(alkyl) boryl compounds are known to
cyclize in the presence of KOH/MeOH/AgNO3, thus indicat-
ing organoboron compounds can be transmetalated to
silver.[19] The presence of 20 suggests that an a-boryl alkyl
silver(I) species is forming in the 1H NMR reaction, but
homocouples too quickly to be observed at 228C.
To identify the presence of an alkyl silver intermediate
under the reaction conditions, the n-butyllithium-activated
diboryl ethane 21[20] was treated with 1 equivalent of AgOAc
Scheme 7. Proposed mechanism of the silver(I)-catalyzed reaction of
1,1-diborons with carbonyls. OR=OAc or OtBu.
1
at À808C in [D8]-THF and monitored by H and 11B NMR
spectroscopy as it warmed to À208C (Scheme 6).[21] A new
that observed by the groups of Miyaura[2b] and Pelter[2c] in the
1,2-addition reactions of cyanocuprates, and can be rational-
ized by the anti- or synclinal stereochemical model A or B,
respectively, in Scheme 7. The role of silver(I) as a Lewis acid
activator for the aldehyde cannot be completely ruled out.[23]
To showcase the synthetic utility of anti-1,2-hydroxybor-
onates, the TBS-protected hydroxyboronate 23 (isolated in
77% yield from the parent hydroxyboronate) was subjected
to stereospecific aryl coupling (Scheme 8). The boronate 23
Scheme 6. Low-temperature 1H NMR detection (À80 to À208C) of
a putative a-boryl alkyl silver species.
Scheme 8. Stereospecific heteroarylation of 1,2-hydroxyboronate prod-
ucts. Boc=tert-butoxycarbonyl.
signal grew in as the reaction warmed (d = À0.46 ppm, q, J =
8.0 Hz) and is tentatively assigned as the a-boryl alkyl
silver(I) species 22 (with a maximum conversion of 13% at
À208C). The homocoupled product 20 was also detected, thus
further supporting the theory that an alkyl silver species is
present and slowly undergoing reductive dimerization. It is
unlikely that the resonance corresponds to the a-boryl-
stabilized carbanion, as Morken and co-workers have shown
that this species is only generated after several hours at
ambient temperature.[5a,22]
With these data, we propose a mechanism of how the anti-
selective 1,2-addition reaction proceeds: Interaction of
AgOAc with either 18 or 21 produces an a-boryl alkyl silver
species. The rate of homocoupling of 22 is likely reduced
under the reaction conditions and is slower than the
productive carbonyl 1,2-addition as only catalytic AgOAc is
used (22 is only formed in 13% conversion with stoichio-
metric AgOAc; Scheme 6). Catalytic quantities of an alkyl
silver intermediate would react faster with a large excess of
aldehyde, rather than dimerizing to form 20. A catalytic cycle
for the diastereoselective reaction is illustrated in Scheme 7.
Activation of 1 with KOtBu or nBuLi forms a borate (I),
which interacts with AgOR (OR = OAc, OtBu) to form an a-
boryl alkyl silver species (II), which then undergoes addition
to the aldehyde to form the 1,2-hydroxyboronate III. The
compound III subsequently undergoes a salt metathesis to
regenerate the silver(I) salt and release the product. The
anti selectivity of the silver-catalyzed reaction is the same as
was treated with 1.2 equivalents of the lithiated furan 25 at
À788C, followed by N-bromosuccinimide, and finally a satu-
rated solution of Na2S2O3 to furnish 1,2-diarylated product 24
in 67% yield and 99:1 d.r.[24] As we demonstrated previously,
these compounds are amenable to oxidation, amination, and
carbon homologation.[9]
In summary, we have developed the first catalytic anti-
selective addition of various 1,1-diboryl alkanes to a range of
aryl-, alkenyl-, and alkyl-substituted aldehydes. Through
1H NMR experiments, we have determined that an a-boryl
alkyl silver compound is likely the active species in the
reaction. Functionalization of the hydroxyboronates is dem-
onstrated by a stereospecific aryl coupling with furan.
Investigations regarding scope, enantioselective variants of
the current diastereoselective protocol, and applications to
stereoselective chemical synthesis are underway.
Acknowledgements
Financial support was provided by the University of North
Carolina at Chapel Hill and an Eli Lilly New Faculty award.
Keywords: alcohols · asymmetric catalysis · boron ·
diastereoselectivity · silver
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How to cite: Angew. Chem. Int. Ed. 2015, 54, 14141–14145
Angew. Chem. 2015, 127, 14347–14351
[11] Use of silver(I) salts with more dissociating counter ions [e.g.,
AgOTf, AgBF4, AgSbF6, AgClO4, Ag(TFA)] afford < 10%
conversion.
[12] Further optimization demonstrates that increasing the number
of equivalents of KOtBu or the boron reagent results in lower
conversion and decreased anti/syn selectivity. For example,
200 mol% KOtBu or 2.0 equivalents 1 affords 2/3 in 13%
conv. in 86:14 d.r., and 48% conv. in 85:15 d.r., respectively.
[13] The lower yield of the pyridyl alcohol is attributed to slight
decomposition during purification.
[14] The presence of significant unreacted aldehyde upon aqueous
workup supports this hypothesis.
[15] This reactivity is in sharp contrast to the previously reported
activation of 1 by LiOtBu, where only 21% conversion to the
borate species is observed.
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[20] See the Supporting Information for the synthesis of 21.
[21] The boroate 21 was chosen because of its stability and the
irreversible activation of boron, which limits side reactions and
protodeborylation products.
[22] 11B NMR analysis proved inconclusive as the products were
generated in low quantities, and the line broadening of 11B NMR
signals is large.
[23] Monitoring a mixture of AgOAc (or the more soluble [(bina-
p)AgOAc]) and benzaldehyde at 228C by 1H and 13C NMR
spectroscopy shows no change in the chemical shift for the
aldehyde signals. This indicates that there is unlikely to be
a significant interaction between the silver(I) salt and the
aldehyde at À258C.
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Aggarwal, Nat. Chem. 2014, 6, 584 – 589. For an additional
example of diastereoselective cross-couplings of secondary alkyl
trifluoroborates, see: b) D. N. Primer, I. Karakaya, J. C. Tellis,
G. A. Molander, J. Am. Chem. Soc. 2015, 137, 2195 – 2198.
[9] Catalytic NaOtBu does not promote the addition of 1 to
benzaldehyde.
[10] Preliminary enantioselective results have been obtained with
chiral phosphine/AgI complexes employing the optimal reaction
conditions in Table 1: (a) 10 mol% AgOAc, 10 mol% (R)-
Monophos, À258C; 61% conv., 90:10 d.r., 61:39 e.r;
(b) 10 mol% AgOAc, 10 mol% (R)-(+)-1-[(R)-2-(2’-dicyclo-
hexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluorome-
thylphenyl)phosphine, À408C; 11% conv., 95:5 d.r., 77.5:22.5
e.r.
Received: August 1, 2015
Published online: September 25, 2015
Angew. Chem. Int. Ed. 2015, 54, 14141 –14145
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 14145