Synthesis of ferrocene derivatives with planar chirality via palladium-catalyzed enantioselective C-H bond activation

Article abstract of DOI:10.1021/ol502509f

The first catalytic and enantioselective C-H direct acylation of ferrocene derivatives has been developed. A series of 2-acyl-1-dimethylaminomethylferrocenes with planar chirality were provided under highly efficient and concise one-pot conditions with up to 85% yield and 98% ee. The products obtained could be easily converted to various chiral ligands via diverse transformations.

Full text of DOI:10.1021/ol502509f

Letter
pubs.acs.org/OrgLett
Synthesis of Ferrocene Derivatives with Planar Chirality via
Palladium-Catalyzed Enantioselective C−H Bond Activation
Chao Pi,† Xiuling Cui,*,†,‡ Xiuyan Liu,† Mengxing Guo,† Hanyu Zhang,† and Yangjie Wu*,†
†Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities,
Department of Chemistry, Zhengzhou University, Zhengzhou 450052, P. R. China
‡Xiamen Key Laboratory of Ocean and Gene Drugs, School of Biomedical Sciences and Institute of Molecular Medicine of Huaqiao
University & Engineering Research Center of Molecular Medicine of Chinese Education Ministry, Xiamen 361021, P. R. China
S
* Supporting Information
ABSTRACT: The first catalytic and enantioselective C−H direct
acylation of ferrocene derivatives has been developed. A series of 2-
acyl-1-dimethylaminomethylferrocenes with planar chirality were
provided under highly efficient and concise one-pot conditions
with up to 85% yield and 98% ee. The products obtained could be
easily converted to various chiral ligands via diverse trans-
formations.
and hydrogenation reactions of CC and CN bonds.3 They
errocene derivatives with planar chirality as powerful chiral
Fligands in asymmetric reactions have attracted great could also be accessed from 2-acyl-1-dimethylaminomethyl-
attention during the past decades.1 Chiral 2-acyl-1-dimethyl-
ferrocenes. Moreover, chiral 2-acyl-1-dimethylaminomethyl-
ferrocenes can serve as useful precursors in the synthesis of
chiral ferroquine and ferrocenic mefloquine analogues, both of
which are endowed with biological activities in terms of
aminomethylferrocenes containing dual functional groups of
amino and carbonyl groups are especially valuable due to being
readily modified.2 They could be easily converted to various
useful molecules via diverse transformation, such as optically
planar ligands in the asymmetric reactions and bioactive
compounds. For instance, chiral ferrocenyl amino alcohols
were directly obtained through reduction of corresponding chiral
2-acyl-1-dimethylaminomethylferrocenes with lithium reagents,
which could promote various asymmetric catalysis, such as
enantioselective alkylation of aldehydes with diethylzinc (Figure
antimalarial (Figure 1, S-3).4 However, the enantioselective
p
synthesis of 2-acyl-1-dimethylaminomethyl ferrocenes with
planar chirality remains rare. To the best of our knowledge,
only one procedure was reported, which involved the ortho-
lithiation of N,N-dimethylaminomethylferrocene using a stoi-
chiometric amount of lithium reagent and (R,R)-tetra-methyl-
1,2-cyclohexanediamine as a chiral auxiliary, formylation,
addition reaction of R-4 with phenylithium, and sequential
p
1, R-2). Josiphos and PPFA analogs are powerful ligands in a
variety of asymmetric transformations, such as allylic alkylations
p
oxidation with manganese dioxide (Scheme 1a).4,5 This protocol
suffers from tedious procedures, low atom economy, less
efficiency, narrow substrate scope, relatively harsh reaction
conditions, and requirement of excessive organometallic reagents
and chiral auxiliaries. Therefore, the development of mild,
convenient, and efficient methods to access chiral 2-acyl-1-
dimethylaminomethylferrocenes is highly desirable.
Scheme 1. Synthesis of (pR)-2-Benzoyl-1-N,N-
dimethylaminomethylferrocene
Received: August 26, 2014
Figure 1. Synthetic method and general applications.
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502509f | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Very recently, You, Gu, and our group independently accessed
ferrocene derivatives with planar chirality based on Pd-catalyzed
C−H bond activation using an amino acid or BINAP as ligands.6
Shibata and co-workers reported an iridium-catalyzed enantio-
selective alkylation of ferrocenes with alkenes using chiral diene
as ligands.7 Encouraged by these results obtained, we envisaged
that 2-acyl-1-dimethylaminomethylferrocenes with planar chir-
ality could be directly accessed by transition-metal-catalyzed
asymmetric C−H acylation (Scheme 1b).
product was observed when the boc group was replaced by a
larger protecting group [fmoc, (9H-fluoren-9-yl) acetate] (Table
1, entry 9). Reducing the bulk of the protecting group from boc
to acetyl resulted in a higher yield and enantioselectivity (Table
1, entries 10 and 11). Ac-L-Phe-OH proved to be the most
efficient chiral ligand in term of enantioselectivity and reactivity,
providing the desired product in 62% yield with 90% ee (Table 1,
entry 10). By elevating and reducing the reaction temperature,
the yield was reduced to 45% and 36% respectively (Table 1,
entries 12 and 13). The yield was reduced to 54% prolonging the
reaction time to 20 h. According to our previous work,6a it was
envisioned that benzoic acid might be produced in the reaction
process and participated in competition with the chiral amino
acid, which would affect the enantioselective C−H bond
activation of the ferrocene ring. With this motivation in mind,
the base was increased to 1.0 equiv. To our great delight, the
reaction proceeded smoothly and afforded the desired product in
79% yield with 96% ee (Table 1, entry 15). The yield slightly
decreased by adding 1.5 equiv of K2CO3 (Table 1, entry 16) and
dramatically decreased to 45% when reducing the catalyst
loading to 5 mol % (Table 1, entry 17). The optimized reaction
conditions were identified as follows: Pd(OAc)2 (10 mol %), Ac-
L-Phe-OH (20 mol %), 1.0 equiv of K2CO3, 50 mol % TBAB, and
3 equiv of TBHP in THF at 80 °C under air for 12 h (Table 1,
entry 15).
Under the optimized reaction conditions, the scope of
substrates for this asymmetric transformation was investigated.
The results were summarized in Scheme 2. Generally, various
diaryl diketones bearing either electron-donating or -with-
drawing groups were well-tolerated and converted into the
corresponding products in moderate to good yields with
excellent enantioselectivity. Moreover, the enantioselectivity
was not affected significantly by the steric hindrance and
electronic effect of substrates 2. Diaryl diketones with electron-
donating groups afforded the acylated products 3b−3g in 70−
85% yields with 89−98% ee’s. Meanwhile, diaryl diketones
bearing electron-withdrawing substituents, such as F, Cl, Br, and
CF3, also led to the corresponding products 3h−3n in 42−69%
yields and 76−90% ee’s. It is noteworthy that furil also reacted
smoothly with N,N-dimethylaminomethylferrocene (1), giving
the product 3o in 43% yield and 90% ee. In addition, we were
delighted to find that dialiphatic diketones also proceeded
smoothly. For example, 2,3-butanedione and 3,4-hexanedione
offered acceptable yields of the corresponding products 3p and
3q, which provided an efficient route to introduce an aliphatic
carbonyl group to the ferrocene ring. As expected, the
enantiomer 3r was obtained in good yield (76%) and excellent
enantioselectivity (98%) when Ac-L-Phe-OH was replaced by
Ac-D-Phe-OH.
a
Table 1. Screening of Protected Amino Acids
b
c
entry
ligand
yield (%)
ee (%)
1
Boc-L-Phe-OH
Boc-L-Ala-OH
Boc-L-Val-OH
Boc-L-Leu-OH·H2O
Boc-L-Ile-OH·0.5H2O
Boc-L-tLeu-OH
Boc-L-Abu-OH
Boc-L-Cys(Trt)-OH
Fmoc-L-Phe-OH
Ac-L-Phe-OH
43
50
49
52
52
48
41
23
86
71
81
79
80
79
74
77
−
90
87
91
88
90
96
97
95
2
3
4
5
6
7
8
d
9
n.r.
10
11
62
60
45
36
54
79
70
45
Ac-L-Ile-OH
e
12
Ac-L-Phe-OH
f
13
Ac-L-Phe-OH
g
14
Ac-L-Phe-OH
h
15
Ac-L-Phe-OH
i
16
Ac-L-Phe-OH
hj
,
17
Ac-L-Phe-OH
a
Reaction conditions: 1 (0.5 mmol), 2a (1.5 mmol), Pd(OAc)2 (10
mol %), ligand (20 mol %), TBHP (70% aqueous solution) (3 equiv),
K2CO3 (0.3 equiv), and TBAB (0.5 equiv) in THF (2.0 mL) at 80 °C
b
c
(oil bath) under air. Isolated yields based on 1. Determined by
d
e
f
g
h
HPLC analysis. n.r. = No reaction. 60 °C. 100 °C. 20 h. K2CO3,
1.0 equiv. K2CO3, 1.5 equiv. Pd(OAc)2, 5 mol %.
i
j
To achieve this goal, a variety of carbonyl sources, including
benzaldehyde, benzyl alcohol, benzoylformic acid, benzoic acid,
benzyl amine, and diphenyl diketone, were initially tested. The
results indicated that diphenyl diketone was an effective starting
material (see Table S1 in the SI). Then the reaction of N,N-
dimethylaminomethylferrocene (1) with diphenyl diketone (2a)
was chosen as a model reaction. The desired product 3a was
afforded in 43% isolated yield with 86% ee in the presence of 10
mol % Pd(OAc)2, 20 mol % Boc-L-Phe-OH, 30 mol % K2CO3, 50
mol % TBAB, and 3 equiv TBHP in THF at 80 °C under air for
12 h. The absolute configuration of product was assigned from
the cyclopalladated complex described in the literature.8 Further,
the reaction parameters, including the catalyst, oxidant, and
solvent, were examined (for details, see Table S2 in the
Supporting Information).
The planar-chiral N,O-ligand L1 has been applied successfully
in the catalytic asymmetric ethylation of benzaldehyde by
Et2Zn.3a,9 Starting from compound 3a obtained in our
methodology, L1 was prepared by treatment with phenyllithium
in 82% yield (Scheme 3). In comparison, the current study
provided a more simple and efficient entry to various N,O-ligand
analogues, which could also be modified further into other kinds
of useful ligands in asymmetric reactions.
To gain insight into the mechanism of this transformation, the
reaction was performed in the presence of a radical scavenger
(TEMPO).10 The target product was not detected, which
indicates that the reaction proceeds via a radical pathway. Based
on the result obtained above and previous literature,6a,8,11 the
reaction mechanism was proposed and shown in Figure 2. First,
Finally, commercially available N-Boc-protected L-amino acids
as ligands were systematically examined. The results were
summarized in Table 1. The desired product was obtained in
yields ranging from 23% to 52% with enantioselectivity ranging
from 71% ee to 86% ee (Table 1, entries 1−8). No desired
B
dx.doi.org/10.1021/ol502509f | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope
Figure 2. Proposed reaction mechanism.
the cyclopalladated complex B was formed through bicycle-
intermediate A, which was formed from the coordination of the
palladium atom to the N-atom and subsequent enantioselective
electrophilic attack at the 2-position C-atom. Then, the reaction
of the cyclopalladated complex B with a benzoyl radical provided
PdIII or PdIV intermediate C.12 The benzoyl radical was generated
by the reaction of diphenyl diketone with TBHP.13 Finally a
carbon−carbon bond was formed via reductive elimination of C,
delivering the acylated product and regenerating the PdII species
for the next cycle.
In summary, we have developed a novel and convenient
protocol to achieve the 2-acyl-1-dimethylaminomethylferrocene
with planar chirality. Various 2-acyl-1-dimethylaminomethyl-
ferrocene derivatives were prepared in moderate to good yields
with excellent enantioselectivities via Pd-catalyzed asymmetric
C−H bond activation using commercially available and cheap
monoprotected amino acids as a chiral ligand under mild reaction
conditions. Further mechanistic investigations and applications
of the chiral products as ligands in organic synthesis are currently
underway in our laboratory.
a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectra copies. This material is
available free of charge via the Internet at http://pubs.acs.org.
Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), Pd(OAc)2 (10
mol %), Ac-L-Phe-OH (20 mol %), TBHP (70% aqueous solution) (3
equiv), K2CO3 (1.0 equiv), and TBAB (0.5 equiv) in THF (2.0 mL) at
80 °C (oil bath) under air. Isolated yields based on 1. b Boc-L-Phe-OH
as the ligand.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 3. Transformation of Acylated Product
*E-mail: cuixl@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the NSF of China (Nos. 21102133
and 21172200) and the NSF of Henan (082300423201).
■
C
dx.doi.org/10.1021/ol502509f | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) (a) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.;
Wang, H.; Kwong, F. Y.; Lei, A.-W. J. Am. Chem. Soc. 2010, 132, 16737.
(b) Warren, J. J.; Mayer, J. M. J. Am. Chem. Soc. 2010, 132, 7784.
(c) Chan, C.-W.; Zhou, Z.; Chan, A. S. C.; Yu, W. Y. Org. Lett. 2010, 12,
3926.
REFERENCES
■
(1) (a) Chiral Ferrocenes in Asymmetric Catalysis; Dai, L.-X., Hou, X.-L.,
Eds.; Wiley-VCH: Weinheim, 2010. (b) Halterman, R. L. Chem. Rev.
1992, 92, 965. (c) Fu, G. C. Acc. Chem. Res. 2000, 33, 412. (d) Dai, L.-X.;
Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res. 2003, 36, 659.
(e) Colacot, T. J. Chem. Rev. 2003, 103, 3101. (f) Fu, G. C. Acc. Chem.
Res. 2004, 37, 542. (g) Fu, G. C. Acc. Chem. Res. 2006, 39, 853.
(h) Togni, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 1475. (i) Arae, S.;
Ogasawara, M. J. Synth. Org. Chem. 2012, 70, 593. (j) Richards, C. J.;
Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377. (k) Duan, Z.-C.; Hu,
X. P.; Zhang, C.; Wang, D. Y.; Yu, S. B.; Zheng, Z. J. Org. Chem. 2009, 74,
9191. (l) Thiesen, K. E.; Maitra, K.; Olmstead, M. M.; Attar, S.
Organometallics 2010, 29, 6334. (m) Chang, M.-X.; Li, W.; Hou, G.-H.;
Zhang, X.-M. Adv. Synth. Catal. 2010, 352, 3121. (n) Weiss, M.; Frey,
W.; Peters, R. Organometallics 2012, 31, 6362. (o) Xu, Q.-L.; Dai, L.-X.;
You, S.-L. Chem. Sci. 2013, 4, 97. (p) Hokoshi, R. Coord. Chem. Rev.
2013, 257, 621.
(11) Sokolov, V. I.; Troitskaya, L. L.; Khrushchova, N. S. J. Organomet.
Chem. 1983, 250, 439.
(12) (a) Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 10974. (b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 11234. (c) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.;
Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945. (d) Rosewall, C. F.;
Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131,
9488. (e) Basle, O.; Bidange, J.; Shuai, Q.; Li, C. J. Adv. Synth. Catal.
2010, 352, 1145. (f) Li, C. L.; Wang, L.; Li, P.-H.; Zhou, W. Chem.Eur.
J. 2011, 17, 1020.
(13) (a) Bentrude, W. G.; Darnall, K. R. J. Am. Chem. Soc. 1968, 90,
3588. (b) Adam, W.; Oestrich, R. S. J. Am. Chem. Soc. 1993, 115, 3455.
(c) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999,
99, 1991. (d) Zhou, W.; Li, H.; Wang, L. Org. Lett. 2012, 14, 4594.
(2) (a) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E.
Org. Lett. 2002, 4, 2421. (b) Sturm, T.; Weissensteiner, W.; Spindler, F.
Adv. Synth. Catal. 2003, 345, 160. (c) Togni, A.; Breutel, C.; Schnyder,
A.; Spindler, F.; Landert, H.; Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062.
(d) Naud, F.; Malan, C.; Spindler, F.; Ruggeberg, C.; Schimidt, A. T.;
́
Blase, H.-U. Adv. Synth. Catal. 2006, 348, 47. (e) Enders, D.; Peters, R.;
Lochtman, R.; Raabe, G. Angew. Chem., Int. Ed. 1999, 38, 2421.
(f) Ierland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P.
Angew. Chem., Int. Ed. 1999, 38, 3212.
(3) (a) Ferrocenes; Togni, A., Hayashi, T., Eds.; Wiley-VCH:
Weinheim, 1995; p 105. (b) Trivalent Phosphorus Compounds in
Asymmetric Catalysis: Synthesis and Applications; Borner, A., Ed.; Wiley-
VCH: Weinheim, 2008; pp 345 and 359. (c) Delacroix, O.; Picart-
Goetgheluck, S.; Maciejewski, L.; Brocard, J. Tetrahedron: Asymmetry
1999, 10, 4417. (d) Bolm, C.; Muniz, K.; Hildebrand, J. P. Org. Lett.
1999, 1, 491. (e) Schuecker, R.; Weissensteiner, W. Organometallics
2010, 29, 6443. (f) Hayashi, T.; Konishi, M.; Fukushima, M.; Mise, T.;
Kagotani, M.; Tajika, M.; Kumada, M. J. Am. Chem. Soc. 1982, 104, 180.
(g) Babaro, P.; Bianchini, C.; Giambastiani, G.; Parisel, S. L. Coord.
Chem. Rev. 2004, 248, 2131. (h) Jia, X.; Li, X. L.; Lam, W. S.; S. Kok, H.
L.; Xu, L.; Lu, G.; Yeung, C. H.; Chan, A. S. C. Tetrahedron: Asymmetry
2004, 15, 2273. (i) Tang, Z. Y.; Lu, Y.; Hu, Q. S. Org. Lett. 2003, 5, 297.
(j) Tappe, K.; Knochel, P. Tetrahedron: Asymmetry 2004, 15, 91.
(4) (a) Biot, C.; Chavain, N.; Dubar, F.; Pradines, B.; Trivelli, X.;
Brocard, J.; Forfar, I.; Dive, D. J. Organomet. Chem. 2009, 694, 845.
(b) Biot, C.; Delhaes, L.; Maciejewski, L. A.; Mortuaire, M.; Camus, D.;
Dive, D.; Brocard, J. S. Eur. J. Med. Chem. 2000, 35, 707. (c) Maguene, G.
M.; Jakhlal, J.; Ladyman, M.; Vallin, A.; Ralambomanana, D. A.;
Bousquet, T.; Maugein, J.; Lebibi, J.; Pelinski, L. Eur. J. Med. Chem. 2011,
46, 31. (d) Domarle, O.; Blampain, G.; Agnaniet, H.; Nzadiyabi, T.;
Lebibi, J.; Brocard, J.; Maciejewski, L.; Biot, C.; Georges, A. J.; Millet, P.
Antimicrob. Agents Chemother. 1998, 42, 540.
(5) (a) Nishibayashi, Y.; Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem.
1996, 61, 1172. (b) Delacroix, O.; Picart-Goetgheluck, S.; Maciejewski,
L.; Brocard, J. Tetrahedron: Asymmetry 1999, 10, 4417. (c) Delacroix, O.;
Andriamihaja, B.; Picart-Goetgheluck, S.; Brocard, J. Tetrahedron 2004,
60, 1549. (d) Malfait, S.; Pelinski, L.; Brocard, J. Tetrahedron: Asymmetry
1998, 9, 2207. (e) Picart- Goetgheluck, S.; Delacroix, O.; Maciejewski,
L.; Brocard, J. Synthesis 2000, 10, 1421.
(6) (a) Pi, C.; Li, Y.; Cui, X.-L.; Zhang, H.; Han, Y.-B.; Wu, Y.-J. Chem.
Sci. 2013, 4, 2675. (b) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You,
S.-L. J. Am. Chem. Soc. 2013, 135, 86. (c) Shi, Y.-C.; Yang, R.-F.; Gao, D.-
W.; You, S.-L. Beilstein J. Org. Chem. 2013, 9, 1891. (d) Deng, R.-X.;
Huang, Y.-Z.; Ma, X.-N.; Li, G.-C.; Zhu, R.; Wang, B.; Kang, Y.-B.; Gu,
Z.-H. J. Am. Chem. Soc. 2014, 136, 4472. (e) Gao, D.-W.; Yin, Q.; Gu, Q.;
You, S.-L. J. Am. Chem. Soc. 2014, 136, 4841.
(7) Shibata, T.; Shizuno, T. Angew. Chem., Int. Ed. 2014, 53, 5410.
(8) (a) Dendele, N.; Bisaro, F.; Gaumont, A. C.; Perriob, S.; Richards,
C. J. Chem. Commun. 2012, 48, 1991. (b) Gunay, M. E.; Richards, C. J.
Organometallics 2009, 28, 5833.
(9) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30,
49. (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
D
dx.doi.org/10.1021/ol502509f | Org. Lett. XXXX, XXX, XXX−XXX