Development and challenges in copper-catalyzed asymmetric Ullmann-type coupling reactions

Article abstract of DOI:10.1055/s-0032-1317866

Ullmann-type coupling is one of the most powerful methods for the formation of aryl C-C, C-N, and C-O bonds. Yet asymmetric Ullmann coupling has received little attention because of the great challenges in both ligand and reaction designs. The success of the first catalytic enantioselective intramolecular Ullmann C-N coupling reaction through an asymmetric desymmetrization strategy offers a new way to develop enantioselective variants of such reactions. This paper addresses the importance of the desymmetrization strategy in Ullmann-type couplings and outlines some future directions in this field. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317866

SYNPACTS
▌408
sDynepavctes lopment and Challenges in Copper-Catalyzed Asymmetric Ullmann-
Type Coupling Reactions
Asymmetric Intramolecular Ullmann C–N Coupling
Qian Cai,* Fengtao Zhou
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou,
510530, P. R. of China
Fax +86(20)32290606; E-mail: cai_qian@gibh.ac.cn
Received: 16.10.2012; Accepted after revision: 21.11.2012
Abstract: Ullmann-type coupling is one of the most powerful
methods for the formation of aryl C–C, C–N, and C–O bonds. Yet
asymmetric Ullmann coupling has received little attention because
of the great challenges in both ligand and reaction designs. The suc-
cess of the first catalytic enantioselective intramolecular Ullmann
C–N coupling reaction through an asymmetric desymmetrization
strategy offers a new way to develop enantioselective variants of
such reactions. This paper addresses the importance of the desym-
metrization strategy in Ullmann-type couplings and outlines some
future directions in this field.
Key words: copper catalysis, asymmetric desymmetrization,
Ullmann coupling, enantioselectivity, indolines
The copper-catalyzed Ullmann-type coupling reactions,
including Ullmann, Ullmann–Goldberg, and Ullmann–
Hurtley condensation and Ullmann diaryl ether formation,
have been known for more than a century as one of the
Qian Cai (left) is a principal investigator at the Guangzhou Institutes
of Biomedicine and Health, Chinese Academy of Sciences (GIBH).
He received his B.S. degree in chemistry from Nankai University in
2001 and PhD in organic chemistry from Shanghai Institute of Organ-
most efficient and powerful methods for the formation of
aryl C–C, C–N and C–O bonds.1 Traditional Ullmann-
type coupling reactions suffered from the harsh reaction
conditions such as high temperature, stoichiometric
amounts of copper reagents, and limited substrate scope.
However, with soluble copper salts or ligand coordinated
Cu complexes as the catalysts, research on Ullmann-type
coupling has been resurrected and many mild conditions
have been developed since the 1990s. Now such reactions
have been applied extensively in both academia and in-
dustry.1c–f
ic Chemistry in 2006 under the supervision of Prof. Dawei Ma. After
conducting postdoctoral research with Prof. Shaomeng Wang at the
University of Michigan, Ann Arbor, he joined the faculty at GIBH in
2009 and has worked as a principal investigator since 2010.
Fengtao Zhou (right) received his B.S. degree from Sichuan Univer-
sity in 2008 and is now pursuing his doctoral degree under the super-
vision of Prof. Ke Ding and Prof. Qian Cai.
significant features: it runs at the lowest reaction temper-
ature in the history of Ullmann-type coupling reactions
(–45 to –20 °C), and it is also the first catalytic asymmet-
ric Ullmann C–C coupling reaction. However, the scope
of both reactants was greatly limited; only 2-iodotrifluo-
roacetanilides and 2-methylacetoacetates were suitable
substrates for the reaction. The ortho-substituted -
NHCOCF3 group of the aryl halides is necessary for
achieving high reactivity and good enantioselectivity.
Furthermore, only 2-methylacetoacetates were suitable
carbon nucleophiles for the formation of the enantioen-
riched products bearing quaternary carbon centers. Other
carbon nucleophiles, such as ethyl acetoacetates, afforded
the products bearing tertiary carbon centers accompanied
by rapid racemization.
Despite the great progress that has been made in recent
years, achieving high enantioselectivity in Ullmann-type
coupling reactions remains a significant challenge. Until
2006, only some chiral substrate-induced asymmetric Ull-
mann reactions2 have been developed for the synthesis of
biaryl compounds, and, to the best of our knowledge, no
catalytic asymmetric Ullmann-type coupling reactions
have been reported.
In 2006, an important breakthrough was achieved by Ma
and co-workers.3 They reported the CuI and trans-4-
hydroxy-L-proline catalyzed enantioselective arylation of
2-methylacetoacetate, affording 2,2-arylmethylacetates
bearing chiral quaternary carbon centers in good yields
and high ee values (Scheme 1). This reaction has some
With such limitations, no further research was reported in
asymmetric Ullmann C–C coupling reactions since Ma’s
work in the last few years and direct asymmetric Ullmann
C–C coupling still remains a great challenge. Other
Ullmann-type coupling, such as Ullmann C–N or C–O
coupling, did not involve the direct formation of a chiral
SYNLETT 2013, 24, 0408–0411
Advanced online publication: 10.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317866; Art ID: ST-2012-P0894-SP
© Georg Thieme Verlag Stuttgart · New York

SYNPACTS
Asymmetric Intramolecular Ullmann C–N Coupling
409
selectivity was obtained in the model reaction with the as-
sistance of three types of chiral ligands (Table 1): L-
proline (L1), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-di-
amine (L2) and (R)-BINOL (L3). Further optimization of
BINOL-derived ligands and reaction conditions led to the
development of a highly enantioselective intramolecular
Ullmann C–N coupling reaction (Table 1, entry 4).
NHCOCF3
O
CuI, (2S,4R)-4-
hydroxyproline
NHCOCF3
Y
O
O
Y
+
NaOH, DMF–H2O
–20 to –45 °C
I
O
OR
RO
29–82% yields, 60–93% ee
Scheme 1 Copper-catalyzed enantioselective arylation of 2-methyl-
acetoacetates
This CuI-catalyzed asymmetric desymmetric intramolec-
ular Ullmann C–N coupling reaction7 is effective for pre-
paring a wide range of indolines bearing quaternary or
tertiary chiral carbon centers. As shown in Scheme 2, dif-
ferent substitutes on the aryl rings were well-tolerated and
the desired products were obtained in high yields (typical-
ly 64–94%) and good to excellent enantioselectivity (typ-
ically 75–99% ee). Furthermore, despite the fact that
formation of a six-membered ring is more difficult than a
five-membered ring, extending the reaction to enantiose-
lective preparation of 1,2,3,4-tetrahydroquinolines 4a–c
was also successful with the assistance of higher dosing of
CuI and ligand L5.
Based on the literature reports8 and on our experimental
observations, we proposed a preliminary model for chiral-
ity induction. As shown in Scheme 3, the CuI may coordi-
nate with the substrate and the chiral ligand to form a
tetrahedral CuI-complex in two different ways. Clearly,
TS-1 suffers less problematic steric interactions between
the aryl group of the binol moiety and the phenyl ring of
the residual 2-iodobenzyl than TS-2. Thus, one would ex-
pect the reaction through TS-1 leading to the formation of
enantiomer I to be more favorable than TS-2, which
would produce enantiomer II.
center, thus, little attention was focused on their asymmet-
ric variation.
Normally, for reactions in which the chiral center does not
participate directly at the reactive site of bond formation,
there are two ways to achieve enantioselectivity: kinetic
resolution of racemic substrates4 and asymmetric desym-
metrization reactions.5 Based on the desymmetrization
strategy, we have recently reported the ‘indirect’ forma-
tion of chiral centers through the copper-catalyzed asym-
metric desymmetric intramolecular Ullmann C–N
coupling,6 which offered a new way to achieve enantiose-
lective Ullmann-type coupling reactions.
In our research, we anticipated that the desymmetric intra-
molecular coupling reaction of compound 1a would lead
to the enantioselective formation of product 2a bearing a
chiral quaternary carbon center (Table 1). The success of
such enantioselective coupling relied on the appropriate
selection of chiral ligands and reaction conditions. In re-
cent years, many ligands have been developed for copper-
catalyzed Ullmann-type coupling reactions. By exploiting
those well-developed ligands, we found that low enantio-
Table 1 Screening of Ligands and Reaction Conditions
Although this model is in agreement with the observed
stereochemistry, a contradiction existed in this explana-
tion. Based on the data analysis of products 2j and 2m–o,
it seemed that a bulky substitute reduced the enantioselec-
tivity (recently, we further studied the reaction by putting
a bulkier alkyl group at this position, which offered lower
enantioselectivity in comparison with 2j and 2m). How-
ever, the enantioselectivity of 2a is clearly higher than that
of 2j and 2m, despite the fact that the ester group is much
bulkier than a hydrogen atom or methyl group, which im-
plied other factors may also be operative for the enantio-
selectivity. We proposed that a hydrogen bond between
the oxygen atom of the ester group and the amine group
may be formed to account for the higher enantioselectivity
of ester-substituted substrates. However, such a model is
still only a hypothesis based on current experimental ob-
servations. It is still a great challenge to fully understand
the mechanism of such reactions.
I
CO2Et
CuI, L*
NH2
base, solvent
*
CO2Et
2a
N
I
I
H
1a
R1
NHMe
NHMe
OH
OH
CO2H
N
H
R1
L3: R1 = H, (R)-BINOL
L4: R1 = 9-anthracenyl
L5: R1 = 3,5-bis(trifluoromethyl)-
phenyl
L2: (1R,2R)-N1,N2-dimethyl
cyclohexane-1,2-diamine
L1: L-proline
Entry L*
Base
Solvent
Time Yield ee
(h)
(%) (%)
With the successful development of the first copper-cata-
lyzed asymmetric intramolecular Ullmann C–N coupling
reaction, we envisioned that such an approach would offer
opportunities for developing novel asymmetric Ullmann-
type coupling and to further extend the applications of
such reactions. In the future, in our view, at least four as-
pects are worth further endeavor: (1) The modification
and optimization of the chiral ligands. Current binol-
1
2
3
4
5
L1
L2
L3
L4
L5
K3PO4
K3PO4
K3PO4
Cs2CO3
Cs2CO3
DMSO
3
20
10
10
10
95
35
51
91
95
41 (R)
DMSO
25 (S)
40 (S)
96 (S)
87 (S)
1,4-dioxane
1,4-dioxane
1,4-dioxane
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 408–411

410
Q. Cai, F. Zhou
SYNPACTS
I
R1
CuI, L*
n
R2
n
R2
R2
R2
NH2
R1
Cs2CO3, 1,4-dioxane
r.t.
N
I
I
H
2a–o
4a–c
1a–o, n = 1, L* = L4
3a–c, n = 2, L* = L5
I
I
R
CO2Et
CO2R
N
H
N
R
H
2d R = F, 81% yield, 97% ee
2e R = NO2, 90% yield, > 99% ee
2f R = CO2Me, 86% yield, 98% ee
2a R = Et, 91% yield, 96% ee
2b R = i-Pr, 93% yield, 98% ee
2c R = t-Bu, 71% yield, 97% ee
I
I
4'
R
5
R
R
5'
CO2Et
H
R
6
N
N
H
H
2g R = Br, 88% yield, > 99% ee
2h R = Me, 75% yield, 99% ee
2i R = OMe, 64% yield, 96% ee
2j R = H, 94% yield, 93% ee
2k R = F (6,4'), 94% yield, 95% ee
2l R = Me (5,5'), 93% yield, 92% ee
I
I
R1
R1
R
N
N
R2
H
H
4a R1 = H, R2 = CO2Et, 96% yield, > 99% ee
4b R1 = Me, R2 = CO2Et, 85% yield, 99% ee
4c R1 = R2 = H, 83% yield, 82% ee
2m R = Me,89% yield, 83% ee
2n R = CH=CH2, 70% yield, 90% ee
2o R = CH2N3, 75% yield, 75% ee
Scheme 2 Substrate scope of the asymmetric desymmetric Ullmann C–N coupling reactions
derived ligands work well in some cases, however, as we the reaction mechanism. As observed, the ester-substitut-
pointed out earlier, the enantioselectivity for substrates ed substrates showed higher enantioselectivity in our re-
bearing bulky alkyl groups on the prochiral center is still actions, which may be explained by the formation of a
relatively low. This problem may be solved by further li- hydrogen bond. However, more evidence is needed. Other
gand optimization. (2) The exploration of substrates bear- substrates bearing special functional groups as directing
ing special functional groups and further understanding of groups should be explored to help better understand the
Ar
Ar
I
CuI
I
O
O
CuI
N
O
vs.
H2
O
N
R
H2
Ar
R
Ar
TS-1 (favorable)
I
I
TS-2 (unfavorable)
R
I
N
H
I
R
N
H
enantiomer I (major)
enantiomer II (minor)
Scheme 3 Proposed transition state
Synlett 2013, 24, 408–411
© Georg Thieme Verlag Stuttgart · New York

SYNPACTS
Asymmetric Intramolecular Ullmann C–N Coupling
411
Chem. Soc. 2000, 122, 5656. (e) Lipshutz, B. H.; Kayser, F.;
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H. J. Chem. Soc., Chem. Commun. 1980, 1233.
reaction mechanism, which, in return, may help further li-
gand design and extension of substrate scope. (3) The de-
velopment of asymmetric desymmetric intermolecular
Ullmann C–N coupling and other Ullmann-type cou-
plings. Similar to the intramolecular Ullmann C–N cou-
pling reaction, other enantioselective Ullmann-type
couplings may also be achieved through the same strate-
gy. (4) The kinetic resolution of racemic reactants. The
desymmetric reaction provided the optically active prod-
ucts bearing the same substituents on both of the aryl
rings, which would cause some problems in further selec-
tive transformations. The kinetic resolution of racemic
substrates may be a good way to solve this problem,
which would also provide more attractive synthetic com-
pounds.
(3) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128,
16050.
(4) For some important reviews on kinetic resolution, see:
(a) Pellissier, H. Tetrahedron 2008, 64, 1563. (b) Vedejs, E.;
Jure, M. Angew. Chem. Int. Ed. 2005, 44, 3974. (c) Huerta,
F. F.; Minidis, A. B. E.; Bäckvall, J.-E. Chem. Soc. Rev.
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(5) For some important reviews on asymmetric
desymmetrization, see: (a) García-Urdiales, E.; Alfonso, I.;
Gotor, V. Chem. Rev. 2005, 105, 313. (b) Willis, M. C.
J. Chem. Soc., Perkin Trans. 1 1999, 1765. (c) Studer, A.;
Schleth, F. Synlett 2005, 3033. (d) Rovis, T. In New
Frontiers in Asymmetric Catalysis; Mikami, K.; Lautens,
M., Eds.; John Wiley & Sons, Inc: New York, 2007, 275–
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2007, 107, 5683.
Acknowledgment
Acknowledgment is made to the 100-talent program of CAS, Natio-
nal Natural Science Foundation (Grant 21272234) and the Natural
Science Foundation of Guangdong Province
S2012010009459) for financial support. The helpful discussions
and contributions of Jiajia Guo, Jianguang Liu, Shouyun Yu, Ke
Ding, and Jinsong Liu are also gratefully acknowledged.
(Grant
(6) Zhou, F.; Guo, J.; Liu, J.; Ding, K.; Yu, S.; Cai, Q. J. Am.
Chem. Soc. 2012, 134, 14326.
(7) Typical Procedure: A mixture of 1 or 3 (0.25 mmol), ligand
(0.05 mmol), CuI (0.025 mmol) and Cs2CO3 (0.375 mmol)
in 1,4-dioxane (1.0 mL) was stirred at r.t. for 10 h. H2O (5.0
mL) and EtOAc (5.0 mL) were added and the organic phase
was separated. The aqueous phase was extracted with EtOAc
and the combined organic phase was washed with H2O and
brine, and dried over Na2SO4. The solvent was removed
under reduced pressure and the residue was loaded on a
silica column and purified by flash chromatography to afford
the desired products.
(8) For some recent important papers on the mechanism of
copper-catalyzed reactions, see: (a) Huang, Z.; Hartwig, J. F.
Angew. Chem. Int. Ed. 2012, 51, 1028. (b) Chen, B.; Hou,
X.-L.; Li, Y.-X.; Wu, Y.-D. J. Am. Chem. Soc. 2011, 133,
7668. (c) Huffmann, L. M.; Stahl, S. S. Dalton Trans. 2011,
8959. (d) Casitas, A.; King, A. E.; Parella, T.; Costas, M.;
Stahl, S. S.; Ribas, X. Chem. Sci. 2010, 1, 326. (e) Strieer, E.
R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 78. (f) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X.
Organometallics 2007, 26, 4546.
References and Notes
(1) For important reviews on copper-catalyzed coupling
reactions, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem.
Int. Ed. 2003, 42, 5400. (b) Beletskaya, I. P.; Cheprakov, A.
V. Coord. Chem. Rev. 2004, 248, 2337. (c) Evano, G.;
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(d) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009,
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13. (g) Beletskaya, I. P.; Cheprakov, A. V. Organometallics
2012, 31, 7753.
(2) For examples of biaryl compound synthesis via chiral
substrate-induced asymmetric Ullmann coupling, see:
(a) Stavrakov, G.; Keller, M.; Breit, B. Eur. J. Org. Chem.
2007, 5726. (b) Gorobets, E.; McDonald, R.; Keay, B. A.
Org. Lett. 2006, 8, 1483. (c) Meyers, A. I.; Nelson, T. D.;
Moorlag, H.; Rawon, D. J.; Meier, A. Tetrahedron 2004, 60,
4459. (d) Spring, D. R.; Krishnan, S.; Schreiber, S. L. J. Am.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 408–411

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