Copper-Catalyzed Cross-Coupling of Allylboronic Acids with α-Diazoketones

Article abstract of DOI:10.1021/acs.orglett.5b02285

Copper-catalyzed cross-coupling of substituted allylboronic acids with α-diazoketones was studied. This allylation reaction is highly regioselective, providing the branched allylic product. The process involves creation of a new C(sp³)-C(sp³) bond by retaining the keto functional group of the α-diazoketone precursor.

Full text of DOI:10.1021/acs.orglett.5b02285

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Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Cross-Coupling of Allylboronic Acids with
α‑Diazoketones
Arindam Das, Dong Wang,‡ Marie-Charlotte Belhomme,‡ and Kalman J. Szabo*
́
́
́
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Copper-catalyzed cross-coupling of substituted
allylboronic acids with α-diazoketones was studied. This allylation
reaction is highly regioselective, providing the branched allylic
product. The process involves creation of a new C(sp3)−C(sp3)
bond by retaining the keto functional group of the α-diazoketone
precursor.
llylboration is a very powerful method in selective organic
synthesis.1 The most widely used application is allylbora-
Table 1. Attempted Coupling of Cinnamyl-Bpin 1a with
a
A
α-Diazoketone 2a
tion of carbonyl compounds2 and imines,1a,2a,g,3 to obtain
homoallylic alcohols and amines. A new emerging area involves
transition metal catalyzed cross-coupling reactions involving
allylboron species. The research group of Miyaura4 and our
group5 published independently cross-coupling reactions
employing alkyl−allyl and crotyl boronates with aryl halides.
Both studies pointed out that the cross-coupling reactions
selectively gave the branched allylic product using appropriate
ligands. This is surprising, since palladium-catalyzed allylic
substitutions usually provide the corresponding linear allylic
isomer.6 Recently, the groups of Buchwald7 and Organ8 have
studied the regioselectivity of the process with particular atten-
tion on the prenylation reactions. These authors found that the
regioselectivity can be efficiently controlled by choice of the
ligands and the additives of the reaction. In a very recent study
the groups of Crudden9 and Aggarwal9b studied the regio-
and stereochemistry of this interesting reaction using chiral
allylboronate substrates. In addition Morken and co-workers
published useful palladium-catalyzed allyl−allyl cross-coupling
reactions10 and nickel-catalyzed conjugate addition to enones11
based on allylboronates.
b
b
entry
solvent
catalyst
additive
3a (%)
4 (%)
1
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
−
−
−
−
−
−
−
0
0
0
0
Pd(PP3)4
Cul
<5
<5
<5
<5
<5
<5
<5
74
69
64
61
24
82
0
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
c
5
6
7
8
9
BF3·Et2O
PhCOOH
NaOMe
a
Unless otherwise stated a mixture of 1a (0.12 mmol), 2a (0.1 mmol),
catalyst (10 mol %), and the additive (10 mol %) in CH2Cl2 (0.5 mL)
b
was stirred at rt for 4 h. The yield was determined by 1H NMR using
c
naphthalene as an internal standard. The reaction was performed at
50 °C.
dimerization of 2a, affording 4. Heating the reaction to 50 °C
or changing the solvent to toluene did not alter the results
(entries 5−6). Application of acid catalysis,2a,16 which is usually
suitable for activation of allyl-Bpin compounds, did not increase
the amount of the coupling product 3a (entries 7−8). Addition
of base was not efficient either (entry 9). These studies
suggested that cinnamyl-Bpin 1a is not reactive enough for
synthetically useful cross-coupling with diazoketones. Our
recent studies indicated that allylboronic acids are much
more reactive in allylboration of ketones and imines than allyl-
Bpin compounds.2b,c,12d,e Therefore, we decided to employ
cinnamylboronic acid 1b instead of 1a in the cross-coupling
reaction (eqs 1−4). When the reaction was performed
with cinnamylboronic acid 1b under the above mild conditions
As a part of our research program on studying the synthesis
and application of allylboronates,2a−c,5,12 we decided to extend
the synthetic scope of the cross-coupling reactions of allylboron
species. Considering the above successful Suzuki−Miyaura and
allyl−allyl coupling reactions, we focused our attention on
other types of C−C bond-forming cross-couplings involv-
ing organoboronates. Inspired by the seminal cross-coupling
reactions of aryl- and vinyl boronates with α-diazoketones by
Barluenga13 and Wang,14 we chose to investigate the coupling
of allylboronic acid derivatives.
Initially, we attempted a coupling reaction of the readily
available cinnamyl boronate12b,15 1a and α-diazoketone 2a
under mild conditions in CH2Cl2. The reaction without any
catalyst or using Pd-catalyst did not result in any product
(Table 1, entries 1−2). However, when we employed CuI
or CuTC catalysts, traces of the branched coupling product 3a
were formed (entries 3−4). The major product arose from
Received: August 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02285
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Organic Letters
Letter
Table 2. Cross-Coupling of Allylboronic Acids with
a
α-Diazoketones
(rt, 4 h in CH2Cl2) in the absence of catalyst, no reaction was
observed (eq 1). However, at 50 °C we obtained homoallyl
alcohol derivative 5, which was certainly formed by allyl-
boration of the keto group2b,c followed by hydrolysis of the
terminal diazo functional group by residual water. Using a Pd-
catalyst under mild conditions mainly led to protodeborylation
of 1b and formation of several other products, except cross-
coupling product 3a (eq 2). We could not observe any reaction
in the presence of CuI (eq 3).
We found that the desired coupling can be achieved with a
high yield using cinnamylboronic acid 1b and α-diazoketone 2a
in the presence of CuTC as a catalyst at room temperature (eq 4).
The process is highly regioselective, as only the branched
regioisomer 3a was formed. Thus, the regioslectivity is the
same as that in the analogous Suzuki−Miyaura coupling of
allylboronic acids5 and, interestingly, the same as usually found in
the reaction of allylboronates with carbonyl compounds1b,2b,c
and with imines.12d,e
The above experiments (Table 1 and eqs 1−4) suggest that
allylboronic acids (such as 1b) are more reactive than allyl-Bpin
compounds (such as 1a) for cross-coupling with α-diazoketones.
In the presence of CuTC catalyst, cinnamylboronic acid 1b
reacted under mild conditions without additives and without
formation of dimerization product 4. Thus, in further studies we
employed allylboronic acids 1b−d with various α-diazocarbonyl
compounds to explore the synthetic scope of the reaction (Table 2).
The functional group tolerance of the reaction is remarkable.
Despite the high electrophilicity of the allylboronic acids,12d,e
the keto group in all products remained unchanged. The reaction
proceeds smoothly in the presence of aromatic bromo (2b) and
methoxy (2d) substituents in the diazoketones (entries 2, 5−6).
We were able to employ even a diazoketone with an aliphatic
substituent (2c, entry 3). In this case the reaction was conducted
at lower temperature (−20 °C → 0 °C) than the above pro-
cesses to avoid formation of side products.
The successful cross-coupling of 1b with 2c, resulting in 3c,
is a remarkable reaction. This process is both acid sensitive
(decomposition of the diazo compound), base sensitive
(decomposition of the allylboronic acid and aldol condensation
of 2c), and oxidation sensitive (oxidation of the allylboronic
acid). The successful accomplishment of this cross-coupling
was probably due to the fact that, with the exception of CuTC,
the reaction does not require additives, such as a Lewis base/
acid activator and an oxidant for regeneration of the catalyst.
Similarly to cinnamylboronic acid 1b, octyl boronic acid 1c also
reacted with high branched selectivity with α-diazoketones 2a,
2b, and 2d (entries 4−6). The reactions resulted in 3d−f with
a
Unless otherwise stated a mixture of 1b−d (0.12 mmol), 2a−g
(0.1 mmol), and CuTC (10 mol %) was stirred in CH2Cl2 (0.5 mL)
b
c
at rt. Isolated yields. The reaction mixture of 1b (0.2 mmol), 2c
(0.1 mmol), and CuTC (20 mol %) was stirred at −20 °C for 3 h and
then at 0 °C for 1 h at rt. 1d (0.2 mmol), 2a (0.1 mmol), and CuTC
d
e
f
(10 mol %) were used. The reaction was performed at 0 °C. The
ratio of the diastereomers was determined from the crude product by
g
1H NMR. 1c (0.05 mmol), 2e (0.1 mmol), and CuTC (10 mol %)
h
were used. The reaction was performed at 45 °C.
high yields without allylation of the keto functional group.
Geraniol boronic acid 1d also reacted readily with 2a, affording
3g (entry 7), which is impressive, as this process involves for-
mation of a quaternary center. Formation of the linear isomer
(product with α-selectivity, which does not have a quaternary
center) could not be observed in the crude reaction mixture.
B
DOI: 10.1021/acs.orglett.5b02285
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Letter
We have briefly investigated the stereoselectivity of the
process using disubstituted diazoketones 2e−g (entries 8−11).
Most of the reactions (entries 8−10) were conducted at 0 °C
to increase the diastereoselectivity. The reaction of cinnamyl-
boronic acid 1b and 2e proceeded with high diastereoselectiv-
ity, as the ratio of the stereoisomers (determined by 1H NMR)
was 9:1. The stereoselectivity was assigned on the basis of
the published structure17 of the major diastereomer 3h. This
indicates a trans stereoselectivity for the cross-coupling reac-
tion. The same stereoselectivity was observed for the allyl-
boration of aldehydes,2a ketones,2b,c and imines12d with allyl-
boronic acids. The stereoselectivity of the reaction is lower with
1c than with cinnamyl boronic acid 1b, as the ratio of the
stereoisomers was 3:1 (entry 9). An obvious explanation is that
the pentyl moiety in 1c exerts a weaker stereoinduction effect
than the phenyl group in 1b. The bromo-analog of 2e reacted
also with trans selectivity with cinnamylboronic acid 1b (entry 10).
However, the diastereoselectivity of the reaction with 2f
was somewhat lower than that with 2e. α-Keto diazoester 2g
reacted sluggishly with cinnamylboronic acid 1b. The reaction
was very slow at 0 °C or at rt; therefore, the reaction was con-
ducted at an elevated temperature (45 °C). Possibly because
of the elevated temperature, the stereoselectivity of the process
is poor. Yet, the regioselectivity and the yield of the reaction
are high.
Currently the detailed mechanism of the cross-coupling
reaction of allylboronic acids with diazoketones is unclear and
requires further investigation and modeling studies. The
mechanism is probably very different from the Pd-catalyzed
cross-coupling of vinyl- and arylboronic acid with diazo com-
pounds,14 as the above process (eq 4 and Table 2) does not
require an external oxidant, indicating that the process is redox
neutral.
In the cross-coupling reaction of 1b and 2 an additional
hydrogen is also added to the product (3). We attempted to
explore the source of this hydrogen by a deuterium labeling
experiment (eq 5). When 3 equiv of D2O were added to the
control.19,21 Therefore, we suggest that the first step of the
cross-coupling is formation of copper carbene (such as 5) from
α-diazoketone (such as 2a) and CuTC (eq 6). Formation of
dimeric product 4 (Table 1) in the nonproductive reactions
in the presence of 1a also suggests an initial Cu-carbene
formation.
The reaction may also involve formation of Cu(I)-allyl
species before or after the formation of Cu-carbenes. Formation
of Cu(I)-allyl species has also been suggested22 or observed23
from suitable Cu-sources and metal-allyl reagents. However, the
origin of the high branched selectivity of the process is still unclear.
In summary, we have presented the first catalytic cross-
coupling of allylboronic species with α-diazoketones. The
presented CuTC catalyzed process leads to formation of a new
C(sp3)−C(sp3) bond with clean γ-selectivity. The reaction
exclusively gives the branched allylic isomer, and using geraniol
boronic acid, a quaternary carbon center can be selectively
formed. The reaction has a remarkable tolerance toward the
carbonyl group of the α-diazoketone. Because of the mild,
neutral, and nonoxidative reaction conditions, both aromatic
and aliphatic diazoketones and allylboronic acids can be
employed. The stereoselectivity of the reaction is dependent
on the substrates. The reaction of cinnamyl boronic acid 1b and
2e proceeds with excellent trans stereoselectivity. The pre-
sented reaction will extend the synthetic scope of the appli-
cation of allylboron species.10,24 It also provides a new com-
plementary method for C(sp3)−C(sp3) bond formation for
synthesis of branched homoallyl carbonyl compounds.25
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02285.
Detailed experimental procedures and compound char-
acterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
reaction mixture of 1b and 3a under the usual reaction
conditions (Table 2, entry 1), we observed about 20%
deuterium uptake at the COCH2 group of 3a (eq 5). This
indicates that the reaction involves a protonation step. The
reaction is carried out under dry/inert conditions. Formation of
boroxin from 1b under dry conditions is well documented.2b
Thus, a possible proton source under the cross-coupling reac-
tion is water produced by the boroxin formation. We could not
observe any deuterium uptake, when the solvent was changed
from CH2Cl2 to CD2Cl2 under the usual reaction conditions
(Table 2, entry 1).
CuTC has been used as an efficient catalyst in coupling reac-
tions of α-diazoketones. Lacour and co-workers18 have shown
that CuTC is a particularly effective catalyst for decomposition
of diazo reagents. It is well established that copper reagents
readily form copper carbenes from diazo compounds.19
Some of the copper carbenes formed in these processes have
been isolated and fully characterized.20 It was shown that
α-diazocarbonyl compounds particularly easily undergo copper
carbene formation, as the loss of N2 is facilitated by chelation
*E-mail: kalman@organ.su.se.
Author Contributions
‡D.W. and M.-C.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the financial support of the Swedish
Research Council (VR) and the Knut och Alice Wallenbergs
Foundation.
REFERENCES
■
(1) (a) Hall, D. G. Boronic Acids; Wiley: Weinheim, 2011. (b) Hall,
D. G.; Lachance, H. Allylboration of Carbonyl Compounds; Wiley:
Hoboken, NJ, 2012.
(2) (a) Selander, N.; Kipke, A.; Sebelius, S.; Szabo,
Soc. 2007, 129, 13723. (b) Raducan, M.; Alam, R.; Szabo,
Chem., Int. Ed. 2012, 51, 13050. (c) Alam, R.; Raducan, M.; Eriksson,
́
K. J. J. Am. Chem.
K. J. Angew.
́
C
DOI: 10.1021/acs.orglett.5b02285
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
L.; Szabo,
́
K. J. Org. Lett. 2013, 15, 2546. (d) Zhao, T. S. N.; Zhao, J.;
(19) Kirmse, W. Angew. Chem., Int. Ed. 2003, 42, 1088.
Szabo, K. J. Org. Lett. 2015, 17, 2290. (e) Ding, J. Y.; Hall, D. G.
́
(20) (a) Straub, B. F.; Hofmann, P. Angew. Chem., Int. Ed. 2001, 40,
1288. (b) Hofmann, P.; Shishkov, I. V.; Rominger, F. Inorg. Chem.
2008, 47, 11755. (c) Dai, X.; Warren, T. H. J. Am. Chem. Soc. 2004,
126, 10085.
(21) Fraile, J. M.; García, J. I.; Martínez-Merino, V.; Mayoral, J. A.;
Salvatella, L. J. Am. Chem. Soc. 2001, 123, 7616.
Angew. Chem., Int. Ed. 2013, 52, 8069. (f) Carosi, L.; Hall, D. G.
Angew. Chem., Int. Ed. 2007, 46, 5913. (g) Hesse, M.; Essafi, S.;
Watson, C.; Harvey, J.; Hirst, D.; Willis, C.; Aggarwal, V. K. Angew.
Chem., Int. Ed. 2014, 53, 6145. (h) Chen, J. L. Y.; Scott, H. K.; Hesse,
M. J.; Willis, C. L.; Aggarwal, V. K. J. Am. Chem. Soc. 2013, 135, 5316.
(i) Ito, H.; Okura, T.; Matsuura, K.; Sawamura, M. Angew. Chem., Int.
(22) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8910.
(23) (a) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Smith, R. A.
J. J. Am. Chem. Soc. 1990, 112, 4404. (b) Russo, V.; Herron, J. R.; Ball,
Z. T. Org. Lett. 2010, 12, 220.
(24) (a) Leonori, D.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2015, 54,
1082. (b) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133,
8154. (c) Lu, Z.; Fu, G. C. Angew. Chem., Int. Ed. 2010, 49, 6676.
(d) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci. 2013,
4, 4022. (e) Yang, C.-T.; Zhang, Z.-Q.; Liu, Y.-C.; Liu, L. Angew.
Chem., Int. Ed. 2011, 50, 3904. (f) Ding, J.; Rybak, T.; Hall, D. G. Nat.
Commun. 2014, 5, 5474.
(25) (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.
Science 2013, 340, 1065. (b) Evans, P. A.; Leahy, D. K. J. Am. Chem.
Soc. 2003, 125, 8974.
Ed. 2010, 49, 560. (j) Bose, D.; Niesobski, P.; Lubcke, M.; Pietruszka,
J. J. Org. Chem. 2014, 79, 4699.
̈
̈
(3) (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev.
2011, 111, 2626. (b) Kobayashi, S.; Sugiura, M.; Ogawa, C. Adv. Synth.
Catal. 2004, 346, 1023. (c) Friestad, G. K. Eur. J. Org. Chem. 2005,
2005, 3157. (d) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687. (e) Lou,
S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
(f) Silverio, D. L.; Torker, S.; Pilyugina, T.; Vieira, E. M.; Snapper, M.
L.; Haeffner, F.; Hoveyda, A. H. Nature 2013, 494, 216. (g) Kliman, L.
T.; Mlynarski, S. N.; Ferris, G. E.; Morken, J. P. Angew. Chem., Int. Ed.
2012, 51, 521. (h) Chen, M.; Roush, W. R. J. Org. Chem. 2013, 78, 3.
(i) Nowrouzi, F.; Batey, R. A. Angew. Chem., Int. Ed. 2013, 52, 892.
(j) Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Chem. Commun. 2005,
5551.
(4) (a) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem. Lett. 2006, 35,
704. (b) Yamamoto, Y.; Takada, S.; Miyaura, N. Chem. Lett. 2006, 35,
1368.
(5) Sebelius, S.; Olsson, V. J.; Wallner, O. A.; Szabo,
Chem. Soc. 2006, 128, 8150.
(6) (a) Tsuji, J. Palladium Reagents and Catalysts. New Perspectives for
the 21st Century; Wiley: Chichester, U.K., 2004. (b) Szabo, K. J. Chem.
Soc. Rev. 2001, 30, 136.
́
K. J. J. Am.
́
(7) Yang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 10642.
(8) Farmer, J. L.; Hunter, H. N.; Organ, M. G. J. Am. Chem. Soc.
2012, 134, 17470.
(9) (a) Glasspoole, B. W.; Ghozati, K.; Moir, J. W.; Crudden, C. M.
Chem. Commun. 2012, 48, 1230. (b) Chausset-Boissarie, L.; Ghozati,
K.; LaBine, E.; Chen, J. L. Y.; Aggarwal, V. K.; Crudden, C. M. Chem. -
Eur. J. 2013, 19, 17698.
(10) Brozek, L. A.; Ardolino, M. J.; Morken, J. P. J. Am. Chem. Soc.
2011, 133, 16778.
(11) (a) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130,
4978. (b) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007,
129, 2214.
(12) (a) Dutheuil, G.; Selander, N.; Szabo,
Synthesis 2008, 2008, 2293. (b) Selander, N.; Paasch, J. R.; Szabo,
J. Am. Chem. Soc. 2011, 133, 409. (c) Larsson, J. M.; Szabo, K. J. J. Am.
Chem. Soc. 2013, 135, 443. (d) Alam, R.; Das, A.; Huang, G.; Eriksson,
L.; Himo, F.; Szabo, K. J. Chem. Sci. 2014, 5, 2732. (e) Das, A.; Alam,
R.; Eriksson, L.; Szabo, K. J. Org. Lett. 2014, 16, 3808. (f) Zhao, T. S.
N.; Yang, Y.; Lessing, T.; Szabo,
7563.
(13) (a) Barluenga, J.; Valdes
7486. (b) Barluenga, J.; Tomas
Chem. 2009, 1, 494.
́
K. J.; Aggarwal, V. K.
́
K. J.
́
́
́
́
K. J. J. Am. Chem. Soc. 2014, 136,
́
, C. Angew. Chem., Int. Ed. 2011, 50,
-Gamasa, M.; Aznar, F.; Valdes, C. Nat.
́
́
(14) (a) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236.
(b) Peng, C.; Wang, Y.; Wang, J. J. Am. Chem. Soc. 2008, 130, 1566.
(c) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun.
2010, 46, 1724. (d) Xia, Y.; Xia, Y.; Liu, Z.; Zhang, Y.; Wang, J. J. Org.
Chem. 2014, 79, 7711.
(15) Zhang, P.; Roundtree, I. A.; Morken, J. P. Org. Lett. 2012, 14,
1416.
(16) (a) Kennedy, J. W.; Hall, D. G. J. Am. Chem. Soc. 2002, 124,
11586. (b) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem.
Soc. 2003, 125, 10160. (c) Elford, T. G.; Arimura, Y.; Yu, S. H.; Hall,
D. G. J. Org. Chem. 2007, 72, 1276.
(17) Ketcham, J. M.; Biannic, B.; Aponick, A. Chem. Commun. 2013,
49, 4157.
(18) Sharma, A.; Besnard, C.; Guenee, L.; Lacour, J. Org. Biomol.
Chem. 2012, 10, 966.
D
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