Inversion or retention? Effects of acidic additives on the stereochemical course in enantiospecific suzuki-miyaura coupling of α-(acetylamino) benzylboronic esters

Article abstract of DOI:10.1021/ja210025q

The stereochemical course of the stereospecific Suzuki-Miyaura coupling of enantioenriched α-(acetylamino)benzylboronic esters with aryl bromides can be switched by the choice of acidic additives in the presence of a Pd/XPhos catalyst system. Highly enant

Full text of DOI:10.1021/ja210025q

Communication
pubs.acs.org/JACS
Inversion or Retention? Effects of Acidic Additives on the
Stereochemical Course in Enantiospecific Suzuki−Miyaura Coupling
of α-(Acetylamino)benzylboronic Esters
Tomotsugu Awano, Toshimichi Ohmura,* and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
S
* Supporting Information
chiral alkylboron compounds in Suzuki−Miyaura coupling
ABSTRACT: The stereochemical course of the stereo-
specific Suzuki−Miyaura coupling of enantioenriched α-
(acetylamino)benzylboronic esters with aryl bromides can
be switched by the choice of acidic additives in the
presence of a Pd/XPhos catalyst system. Highly
enantiospecific, invertive C−C bond formation takes
place with the use of phenol as an additive. In contrast,
high enantiospecificity for retention of configuration is
attained in the presence of Zr(Oi-Pr)4·i-PrOH as an
additive.
reactions, such a switch of stereospecificity would be highly
interesting not only from the viewpoint of synthetic
applications, but also from the mechanistic point of view. It
should be noted that a switch of stereospecificity was achieved
in Hiyama coupling of enantioenriched chiral benzylic silanes
with aryl triflates, although the enantiospecificity (es)13 was not
very high.4 In this paper, we disclose remarkable effects of
acidic additives on the stereochemical course of the Suzuki−
Miyaura coupling of enantiopure α-(acylamino)benzylboronic
esters. We have found that some acidic additives can make the
reaction highly “retentive”, while some other acids enhance the
“invertive” nature of the Suzuki−Miyaura coupling of α-
(acetylamino)benzylboronic esters.
ncreasing attention has been paid to asymmetric synthesis
through transition-metal-catalyzed cross-coupling reactions
In our previous report on the invertive Suzuki−Miyaura
coupling of α-(acylamino)benzylboronic esters,10a introduction
of a bulky acyl group, for example, a pivaloyl group, was found
to be essential to gain high es. Reaction of enantioenriched α-
(acetylamino)benzylboronic ester 1a, which showed moderate
es under the previously reported coupling conditions,10a with 4-
bromotoluene (2a, 1.2 equiv) was carried out in toluene at 80
°C in the presence of Pd(dba)2 (5 mol %), XPhos14 (10 mol
%), K2CO3 (3.0 equiv), and various protic additives (2.0 equiv)
(Table 1). Although the coupling took place smoothly even in
the absence of the additives, low es was observed (entry 1). The
es’s were improved to 53−61% when the reaction was carried
out in the presence of protic additives such as water, benzoic
acid, and acetic acid (entries 2−4). We found that phenol was
the most effective additive for the enantiospecific Suzuki−
Miyaura coupling, in which 3a was formed in 85% yield with
96% es (entry 5). The absolute configuration of the major
enantiomer of 3a was determined to be S,15 indicating that the
reaction proceeded with inversion of configuration. Use of a
larger amount of phenol induced higher es’s with a decrease in
the chemical yields (entries 10 and 11). It is interesting to note
that the reaction in the presence of i-PrOH and t-BuOH
proceeded with retention of configuration, although the es’s
were low (entries 8 and 9).
I
at stereogenic sp3 carbon centers.1 Recent remarkable progress
involves asymmetric cross-couplings of chiral secondary alkyl
halides using chiral transition metal catalysts, which proceed
through a dynamic kinetic resolution (DKR) pathway.2 Cross-
couplings using stereochemically labile chiral alkylmetal
reagents such as Grignard reagents have also been studied
with remarkable success.3 The asymmetric reactions also
proceed through facile racemization at the metal-bound
stereogenic carbon centers, being classified as DKR processes.
While DKR-based asymmetric cross-couplings have been
achieved with highly effective chiral ligands on transition
metal catalysts, interest has also focused on the cross-couplings
of stereochemically defined, stable α-chiral alkylmetals such as
alkylsilanes,4 alkylstannanes,5 and alkylboron compounds6 with
achiral ligands.7,8 In particular, much effort is currently being
devoted to the development of cross-coupling of sterochemi-
cally defined, chiral alkylboronates.9 Although stereochemical
retention had been accepted generally in the Suzuki−Miyaura
coupling of α-chiral alkylboron compounds,6 our recent
report10 in conjunction with reports from other groups11,12
has established that the coupling can proceed with highly
enantiospecific inversion of stereochemistry at the boron-
bound stereogenic carbon centers. In the invertive cross-
coupling system, intramolecular coordination of a carbonyl
group of an amide10a,11 or ester12 functionality to boron is
commonly involved and regarded as the key for the inversion of
stereochemistry in the transmetalation step. It would be highly
attractive if the change of the intramolecular coordination
mode leads to a switch of stereochemical course from inversion
to retention. Although there is no example for selective
production of both enantiomers from a single enantiopure α-
Suzuki−Miyaura coupling of 1a and 1b with aryl bromides
2a−2d was examined in the presence of phenol (2.5 equiv)
(Table 2). High enantiospecificities for inversion of stereo-
chemistry were generally achieved by the addition of phenol.
Received: October 25, 2011
Published: November 30, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Reaction in the Presence of Protic Additives
were much lower than for the reaction of 1a. In contrast, the
pivaloyl-substituted 6 reacted with 2a with high es with
inversion of configuration. These results indicate that metal
alkoxides can switch the stereochemical course of the reaction,
and that less bulky acyl group makes retentive coupling more
favorable.
To achieve further improvement of the stereoretentive cross-
coupling, we screened metal alkoxides (Table 3).16 Reaction of
1a with 2a in the presence of metal alkoxides is generally found
to be slower than that in the absence of them. Trialkoxyboranes
gave 3a in 60−85% yields with retention of configuration with
es’s in the range of 24−63% (entries 1−4). Because B(Oi-Pr)3
showed the best es among the four (63% es, entry 3),
isopropoxides of Group 4 and 13 elements were then screened
(entries 5−9). The reactions using Al(Oi-Pr)3, Ga(Oi-Pr)3,
In(Oi-Pr)3, and Ti(Oi-Pr)4 proceeded in good yields (55−
74%) with retention of configuration (36−75% es’s, entries 5−
8). Use of Zr(Oi-Pr)4 resulted in an unexpectedly low yield of
3a with low es (entry 9). However, we fortuitously found that
Zr(Oi-Pr)4·i-PrOH17 induced high es with retention of
configuration (entry 10). Decreasing the molar equivalents of
the zirconium complex to 1−0.5 equiv improved both the
yields of 3a and the es’s (entries 11 and 12). However, the es
dropped when the reaction was carried out in the presence of
0.1 equiv of the zirconium complex (entry 13). The es
improved to 83% in the reaction at 60 °C, although the reaction
was rather slow (entry 14).
a
1 (0.10 mmol), 2a (0.12 mmol), Pd(dba)2 (5.0 μmol), ligand (10
μmol), base (0.30 mmol), and additive (0−0.30 mmol) were stirred in
toluene (0.2 mL) at 80 °C for 12 h. The ee of 3a and absolute
configuration of major enantiomer were determined by HPLC analysis
b
c
d
with a chiral stationary phase column. Isolated yield. See ref 13. Bar
color indicates a major configuration of 3a (red: S, inversion; blue: R,
retention) and bar size is corresponding to the % es value.
The reaction of electron-rich 2b showed higher es than that of
electron-deficient 2c (entries 2 and 3). Sterically demanding 2d
reacted with 1a with slightly low es (entry 4). Enantioenriched
1b also reacted with 2a in high es with inversion of
configuration (entry 5).
We then focused our attention on metal alkoxides as
additives. A preliminary investigation was carried out for the
reaction of 2a with α-(acylamino)benzylboronic esters 1a and
4−6 using B(Oi-Pr)3 as an additive (eq 1). We found a
remarkable change in the stereochemical course in the reaction
of 1a with 2a in the presence of B(Oi-Pr)3 (2.0 equiv). The
reaction gave the R-isomer as the major product,15 indicating
that the stereochemical course was inverted to “retention” of
configuration (63% es). Although the reaction of propionyl (4)
and benzoyl (5) derivatives also gave the corresponding
products 7 and 8 with retention of configuration, the es’s
Stereospecific Suzuki−Miyaura coupling in the presence of
Zr(Oi-Pr)4·i-PrOH (0.5 equiv) was conducted with several
combinations of 1 with 2 (Table 4). Electron-rich 2b reacted
with 1a to give 3b with retention of configuration (78% es,
entry 1). The reaction of 1a with electron-deficient 2c took
place smoothly to afford 3c with higher es (entry 2). The es of
this reaction improved to 87% when the reaction was carried
a
Table 2. Suzuki−Miyaura Coupling with Inversion of Configuration
b
c
entry
1
ArBr
% yield
% es
config
1
2
3
4
5
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
2a (Ar2 = 4-MeC6H4)
2b (Ar2 = 4-MeOC6H4)
2c (Ar2 = 4-CF3C6H4)
2d (Ar2 = 2-MeC6H4)
2a
67 [(S)-3a]
60 [(S)-3b]
83 [(S)-3c]
69 [(S)-3d]
75 [(R)-3e]
98
99
94
91
98
inv
inv
inv
inv
inv
a
1a (0.10 mmol), 2 (0.12 mmol), Pd(dba)2 (5.0 μmol), XPhos (10 μmol), K2CO3 (0.30 mmol), and PhOH (0.25 mmol) were stirred in toluene
b
c
(0.2 mL) at 80 °C for 12 h. The ee of 3 was determined by HPLC with a chiral stationary phase column. Isolated yield. See ref 13.
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Journal of the American Chemical Society
Communication
a
Table 3. Reaction in the Presence of Metal Alkoxides
Scheme 1. Possible Effects of the Acidic Additives on the
Stereochemical Course of the Transmetallation
we proposed that the intramolecular coordination of the amide
oxygen atom to the boron center (in A) allowed electrophilic
attack of the palladium species (C) on the boron-bound carbon
atom only from the opposite side of the boron atom, leading to
the formation of the open-chain transition state TS1 for
invertive transmetalation. One of the roles of the acidic
additives in the present coupling system should be cleavage of
the intramolecular coordination by competitive coordination of
the acid to the amide oxygen atom (B′). Cleavage of the
intramolecular coordination results in the formation of
tricoordinated boron species B, which is suitable for the
formation of a four-membered-ring transition state TS2, in
which the oxygen or halogen atom serves as a bridging group
(Y). Transmetalation via this cyclic transition state should
proceed with retention of configuration at the boron-bound
carbon atom through electrophilic attack of the palladium atom
from the same side as the boron atom. Another contrasting role
of acidic additives would be to enhance the intramolecular
coordination by the coordination of the acid to the oxygen
atom of the pinacol ligand (A′). Thus, the oxygen atom of the
pinacol ligand may be protonated in the presence of phenol,
a
1a (0.10 mmol), 2a (0.12 mmol), Pd(dba)2 (5.0 μmol), XPhos (10
μmol), base (0.30 mmol), and additive (0.01−0.20 mmol) were stirred
in toluene (0.2 mL) at 80 °C. The ee of 3a and absolute configuration
of major enantiomer were determined by HPLC analysis with a chiral
b
stationary phase column. A period that required for full conversion of
1a. Isolated yield of 3. See ref 13. See footnote d in Table 1. At 60
°C.
c
d
e
f
out at 60 °C (entry 3). Highly enantiospecific coupling took
place in the reaction of 1a with sterically demanding 2d, giving
3d in up to 93% es (entries 4 and 5). Enantioenriched 1b was
also reacted with 2a in high yield with retention of
configuration (entry 6). The es in the reaction of 1b (85%,
entry 6) was higher than that in the reaction of 1a (78%, entry
12 in Table 3).
The roles of the acidic additives in the stereospecific Suzuki−
Miyaura coupling of 1 can be assumed on the basis of the
mechanism that we proposed for the original invertive cross-
coupling (Scheme 1).10a In the invertive cross-coupling system,
a
Table 4. Suzuki−Miyaura Coupling with Retention of Configuration
b
c
entry
1
Ar2Br
temp (°C)
% yield
% es
config
1
2
3
4
5
6
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
2b (Ar2 = 4-MeOC6H4)
2c (Ar2 = 4-CF3C6H4)
2c
80
80
60
80
60
80
67 [(R)-3b]
96 [(R)-3c]
54 [(R)-3c]
73 [(R)-3d]
56 [(R)-3d]
71 [(S)-3e]
78
83
87
86
93
85
ret
ret
ret
ret
ret
ret
2d (Ar2 = 2-MeC6H4)
2d
2a (Ar2 = 4-MeC6H4)
a
1 (0.10 mmol), 2 (0.12 mmol), Pd(dba)2 (5.0 μmol), XPhos (10 μmol), K2CO3 (0.30 mmol), and additive (0.050 mmol) were stirred in toluene
b
c
(0.2 mL) at 80 °C for 18 h or at 60 °C for 96 h. The ee of 3 was determined by HPLC with a chiral stationary phase column. Isolated yield. See ref
13.
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Journal of the American Chemical Society
Communication
2809. (g) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc.
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Soc. 2011, 133, 4758.
making the boron atom more electropositive to strengthen the
intramolecular O−B coordination.18 This may be the major
reason for the enhanced enantiospecificity in the invertive
coupling reaction.
In conclusion, we have achieved a switch of stereochemical
course in enantiospecific cross-coupling at the boron-bound
stereogenic carbon center with high efficiency. The stereo-
specificity largely depends on the acidic additives: Zr(Oi-Pr)4·i-
PrOH made the reaction retentive, while PhOH resulted in the
invertive coupling with higher enantiospecificity than the
original reaction system in which no acidic additive was used.
Mechanistic details, as well as synthetic applications, of this
reaction are under investigation in our laboratory.
(7) For stereospecific cross-coupling of enantioenriched, α-chiral
alkylmagnesium and alkylzinc reagents generated in situ, see:
(a) Holzer, B.; Hoffmann, R. W. Chem. Commun. 2003, 732.
̈
(b) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C. J. Am. Chem. Soc. 2006, 128, 3538.
(8) An alternative stereospecific cross-coupling of enantioenriched,α-
chiral alkyl electrophiles has also been reported. See (a) He, A.; Falck,
J. R. J. Am. Chem. Soc. 2010, 132, 2524. (b) Taylor, B. L. H.; Swift, E.
C.; Waetzig, J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389.
(9) For well-established synthetic routes to enantioenriched, α-chiral
alkylboronates, see (a) Matteson, D. S. In Boronic Acids; Hall, D. G.,
Ed.; Wiley-VCH; Weinheim, 2005; p 305. (b) Hayashi, T.;
Matsumoto, Y.; Ito, Y. Tetrahedron: Asymmetry 1991, 2, 601.
(c) Chea, H.; Sim, H.-S.; Yun, J. Adv. Synth. Catal. 2009, 351, 855.
(d) Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew.
Chem., Int. Ed. 2007, 46, 7491.
(10) (a) Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc.
2010, 132, 13191. For a precedent report on the cross-coupling of
racemic α-(acylamino)benzylboronic esters, see (b) Ohmura, T.;
Awano, T.; Suginome, M. Chem. Lett. 2009, 38, 664.
́
(11) Sandrock, D. L.; Jean-Gerard, L.; Chen, C.; Dreher, S. D.;
Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
ohmura@sbchem.kyoto-u.ac.jp: suginome@sbchem.kyoto-u.ac.
jp
ACKNOWLEDGMENTS
■
This work is supported by Grant-in-Aid for Challenging
Exploratory Research (No. 23655082) from JSPS. T.A.
acknowledges JSPS for fellowship support.
(12) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3,
894.
(13) The term enantiospecificity [% es = (product ee/starting
material ee) × 100] has been used to describe the conservation of
optical purity over the course of stereospecific reactions: (a) Denmark,
S. E.; Vogler, T. Chem.Eur. J. 2009, 15, 11737. (b) Denmark, S. E.;
Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232.
(14) 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl.
Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(15) Absolute configuration was determined by comparison with the
specific rotation of the authentic samples. For details, see Supporting
Information.
(16) Use of BF3·OEt2, AlCl3, and TiCl4 resulted in decomposition of
1a and no formation of 3a.
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