Development of [3]ferrocenophane-derived N/B frustrated Lewis pairs for the metal-free catalytic hydrogenation of imines

Article abstract of DOI:10.1080/00397911.2018.1555710

A series of novel [3]ferrocenophane-derived N/B frustrated Lewis pairs (FLPs) were synthesized and successfully applied to the catalytic hydrogenation of imines in 71–93% yields. This approach could be easily conducted on gram scale and provided versatile synthetic route for the key intermediate of sertraline hydrochloride without heavy metal residues.

Full text of DOI:10.1080/00397911.2018.1555710

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Development of [3]ferrocenophane-derived N/B
frustrated Lewis pairs for the metal-free catalytic
hydrogenation of imines
Zhentao Pan, Hui Wang, Fei Ling, Lian Xiao, Dingguo Song & Weihui Zhong
To cite this article: Zhentao Pan, Hui Wang, Fei Ling, Lian Xiao, Dingguo Song & Weihui
Zhong (2019): Development of [3]ferrocenophane-derived N/B frustrated Lewis pairs
for the metal-free catalytic hydrogenation of imines, Synthetic Communications, DOI:
10.1080/00397911.2018.1555710
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https://doi.org/10.1080/00397911.2018.1555710
Development of [3]ferrocenophane-derived N/B frustrated
Lewis pairs for the metal-free catalytic hydrogenation
of imines
Zhentao Pan, Hui Wang, Fei Ling, Lian Xiao, Dingguo Song, and Weihui Zhong
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of
Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
ABSTRACT
ARTICLE HISTORY
Received 10 September 2018
A series of novel [3]ferrocenophane-derived N/B frustrated Lewis
pairs (FLPs) were synthesized and successfully applied to the catalytic
hydrogenation of imines in 71–93% yields. This approach could be
easily conducted on gram scale and provided versatile synthetic
route for the key intermediate of sertraline hydrochloride without
heavy metal residues.
KEYWORDS
Ferrocenophane; frustrated
Lewis pairs; hydrogenation;
imine; metal-free
GRAPHICAL ABSTRACT
Introduction
Amines are key structural elements of many biologically active compounds, which were
widely applied in pharmaceuticals, natural products, and agrochemicals.[1] Owing to
their great importance, numerous methodologies have been developed for the access of
amines. Among them, imine reduction represents one of the most powerful and effi-
cient approaches for the obtaining of amines. Traditionally, the metal-catalyzed hydro-
genation of imines was well established, exhibiting high efficiency in many
transformations. Despite its unarguable efficiency, the use of metal catalysts limited its
further application in pharmaceuticals.[2] As a consequence, there is a continued effort
to develop practical strategies to access amines in a metal-free fashion.
FLP chemistry has attracted much attention in the past decade as a metal-free alter-
native to transition metal catalysis for the activation of dihydrogen and related transfor-
mations.[3] The FLP-catalyzed hydrogenation reaction,[4] has sparked scientific upheaval
CONTACT Weihui Zhong
weihuizhong@zjut.edu.cn
Key Laboratory for Green Pharmaceutical Technologies and
Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, 18,
Chaowang Road, Hangzhou 310014, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 Taylor & Francis Group, LLC

2
Z. PAN ET AL.
with a promise to develop metal-free hydrogenation technology. From the appearance
of the FLP hydrogenation, the catalytic procedures were overwhelmingly accomplished
with nitrogen, phosphorous or oxygen-centered LBs combined with B(C6F5)3 as a steric-
ally overcrowded LA. In contrast to the abundant phosphorous centered LBs that had
been exploited as a component of FLPs,[5] N/B FLPs involving nitrogen-centered
LBs are relatively rare. In 2008, Repo and coworkers described the FLP employing
2,2,6,6-tetramethylpiperidine (TMP) as a bulk LB and B(C6F5)3 as an LA. This FLP suc-
cessfully realized the stoichiometric reduction of benzaldehyde under hydrogenation
(Scheme 1a).[6] In 2009, Stephan and coworkers discovered the combination of 2,6-luti-
dine and B(C6F5)3 exhibit both classical Lewis acid-base and FLP reactivity. (Scheme
1b).[7] In 2012, Alcarazo and coworkers demonstrated the combination of triethylenedi-
amine (DABCO) and B(C6F5)3 could act as an FLP to realize the catalytic hydrogen-
ation of electron-poor allenes and alkenes (Scheme 1c).[8]
Inspirited by our previous work on P/B FLPs catalyzed hydrogenation of imines,[5c] we
are interested in developing new types of N/B FLPs for the access of amines. Herein, we
report a series of novel[3] ferrocenophane-derived N/B FLPs and their application in the
catalytic hydrogenation of imines (Scheme 1d). Moreover, the current developed N/B FLP
was capable of providing the key intermediate of sertraline hydrochloride on a gram scale.
Results and disscussion
The new [3]ferrocenophane-derived FLP1-6 were successfully synthesized from com-
mercially available 1,1’-diacetylferrocene 3 as the starting material (Scheme 2). Initially,
Scheme 1. Examples of N/B FLPs and their applications in hydrogenation.

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3
Scheme 2. Preparation of [3]Ferrocenophane-derived Lewis LB1–6.
the intramolecular aldol condensation of 3 promoted by HNMe2/TiCl4 system afforded
1,1’-(1-Methyl-3-oxo-1,3-allyl)ferrocene 4 in 88% yield. Compound 4 was subsequently
reduced by Pd/C catalytic hydrogenation and NaBH4 to form the corresponding 1,1’-(1-
Methyl-3-hydroxy-1,3-propanediyl)ferrocene 5 in 93% yield. Then the key intermediate
6 was furnished from 5 by acetylation in 96% yield, followed by reacting with various
secondary amines to provide the corresponding [3]ferrocenophane-derived bulk Lewis
bases LB1-6 in 71–90% yields. Notably, FLP1-6 could be generated by mixing LB1-6
with one equivalent of B(C6F5)3.
In order to test the performance of the catalysts FLP1-6 in the hydrogenation of
imines, N-(1-phenylethylidene)aniline (1a) was chosen as a model substrate (Table 1).
Employing 20 mol% of FLP1 as the catalyst, the reduction of imine 1a successfully took
place and afforded the desired amine 2a in 43% yield (Table 1, entry 1). Nevertheless,
FLP2 showed no catalytic activity in this hydrogenation reaction (Table 1, entry 2),
which might be explained that B(C6F5)3 was trapped by the secondary amine of LB2.
Tertiary amine LB3 instead of LB2 could promote the reduction going on smoothly
and resulted in a slightly higher yield of 2a (52%) (Table 1, entry 3). These outcomes
indicated that increasing the steric hindrance of Lewis base might be beneficial to the
catalyst activity in hydrogenation. Therefore, more bulk Lewis bases were tested and
FLP6 showed the best activity among the screened catalysts FLP1-6 (Table 1, entries
4-6). Next, optimization of reaction conditions was conducted. Decreasing the pres-
sure of hydrogen from 5.0 MPa to 2.0 MPa extended the reaction time from 18 h to
24 h but did not affect the reaction yield (Table 1, entries 6 and 7). However, further
reducing the pressure to 1.0 MPa led to a little drop in yield of 2a to 72% (Table 1,
entry 8). Moreover, the reaction temperature had an influence on the reaction out-
comes and 80 ꢀC turned out to be the optimal temperature (Table 1, entries 9 and 10).
Notably, the catalyst loading could be reduced to 10 mol % at the price of longer

4
Z. PAN ET AL.
Table 1. Optimization of reaction conditions[a].
Entry
Cat
Press (MPa)
Solvent
Time (h)
Yield[b] (%)
1
2
3
4
5
6
7
8
FLP1
FLP2
FLP3
FLP4
FLP5
FLP6
FLP6
FLP6
FLP6
FLP6
FLP6
FLP6
FLP6
FLP6
B(C6F5)3
5.0
5.0
5.0
5.0
5.0
5.0
2.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
30
30
30
30
22
18
24
48
30
48
36
48
36
48
48
43
Trace
52
65
81
84
83
72
84
79
84
73
71
26
13
9[c]
10[d]
11[c,e]
12[c,f]
13[c,e]
14[c,e]
15[c,e]
dioxane
toluene
[a]Reactions were carried out with 1a (1 mmol), FLP (0.2 mmol) in dry solvent under hydrogen at 100 ꢀC.
[b]Isolated yield.
[c]Reaction was performed at 80 ꢀC.
[d]Reaction was performed at 60 ꢀC.
[e]0.1 mmol FLP was used.
[f]0.05 mmol FLP was used.
reaction time (Table 1, entries 11 and 12). Furthermore, the reaction solvents were
also examined and toluene was chosen as the best medium for this transformation
(Table 1, entries 13 and 14). In contrast, a dramatic drop in yield was observed in the
absence of LB even after 48 h, which showed that [3]ferrocenophane-derived
Lewis bases played a crucial role in this reduction process. Thus, the optimal reaction
conditions are as follows: substrates (1.0 equiv.), hydrogen (2.0 MPa), FLP6 (10 mol%)
in toluene at 80 ꢀC.
With the optimal reaction conditions in hand, the scope of substrates of this protocol
was investigated and the results are shown in Table 2. The corresponding secondary
amines 2a–r were obtained in moderate to good yields. It was noteworthy that aldi-
mines (1b–d) had better reactivity, affording the corresponding amines in shorter reac-
tion time. Moreover, ketimines with electron-donating groups on the benzene rings (1c,
1e, 1 g, 1 h, 1j–l, 1n, 1p, and 1r) gave the corresponding products in higher yields than
those with electron-withdrawing groups (1d and 1f). The reduction of imines with ster-
ically hindered groups (1q and 1r) was difficult and provided the corresponding prod-
ucts (2q and 2r) with only moderate yields. To our delight, most of the substituted
groups such as nitro (1d), chloro (1f), and bromo (1l–o) could be tolerated during the
catalytic hydrogenation of imines.
Interestingly, current developed metal-free catalytic systems could be applied in
the synthesis of a key intermediate of antidepressant drug sertraline hydrochloride
on gram scale (Scheme 3). Initially, the condensation of 4-(3,4-dichlorophenyl)-3,4-
dihydronaphthalen-1(2H)-one 7 with methylamine in the presence of formic acid

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5
Table 2. Hydrogenations of various imines catalyzed by FLP6[a].
Entry
R1
R2
R3
Time (h)
Yield[b] (%)
1
2
3
4
5
6
7
8
H
H
Me
H
H
H
H
H
36
18
16
25
34
36
36
32
32
28
27
28
36
34
36
36
42
48
2a, 84
2b, 82
2c, 86
2d, 71
2e, 86
2f, 82
2g, 87
2h, 90
2i, 87
2j, 92,
2k, 93
2l, 91
2m, 83
2n, 79
2o, 81
2p, 80
2q, 75
2r, 71
4-OMe
4-NO2
H
H
H
4-Me
4-Me
4-OMe
4-OMe
4-OMe
4-Br
4-Br
4-Br
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2-Me
4-Cl
4-OMe
4-OMe
H
9
10
11
12
13
14
15
16
17
18
H
4-OMe
4-Br
H
2-OMe
4-Br
2-OMe
H
H
H
Ph
Ph
2-OMe
[a]Reactions were carried out with 1a (1 mmol), FLP6 (0.1 mmol) in toluene under hydrogen (2.0 MPa) at 80 ꢀC.
[b]Isolated yield.
Scheme 3. The preparation of the key intermediate for sertraline hydrochloride.
could obtain the imine 8 in 95% yield, followed by the FLP6-catalyzed hydrogenation of
8 to produce the key intermediate 9 in 83% yield. Finally, the key intermediate 9 could
be converted to sertraline hydrochloride 10 according to the reference.[9]
Conclusion
In summary, a series of novel [3]ferrocenophane-derived N/B FLPs had been developed
and were applied to the hydrogenation of imines under mild conditions to provide the

6
Z. PAN ET AL.
corresponding amines in good to excellent yield. Moreover, this protocol could be directly
used for the preparation of the key intermediate for sertraline hydrochloride on gram–scale.
Experimental
General procedure for synthesis LB1-6
To a solution of 6 (5 mmol) in MeOH (10 mL) corresponding secondary amines
(7.5 mmol) were added and the reaction mixture was stirred at 25 ꢀC for 24 h. After the
completion of the reaction, the solvent MeOH was evaporated in vacuo. The aqueous
phase was extracted with EtOAc (3 ꢁ 15 mL) and the organics were combined, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chro-
matography to afford the product LB1-6.
1,1’-(1-Methyl-3-dimethylamine-1,3-propanediyl)ferrocene (LB1)
1
Yellow solid; 71% yield; mp 93.0–94.5 ꢀC. H NMR (400 MHz, Chloroform-d) d 1.24 (d,
J ¼ 5.6 Hz, 3H), 2.07–2.11 (m, 1H), 2.23 (s, 6H), 2.35–2.41 (m, 1H), 2.71–2.76 (m, 1H),
3.04–3.06 (dd, J ¼ 7.2, 1.6 Hz, 1H), 3.96–3.95 (m, 1H), 3.99–4.00 (m, 1H), 4.03–4.06 (m,
2H), 4.09–4.11 (m, 2H), 4.15–4.16 (m, 1H), 4.21–4.22 (m, 1H). 13C NMR (100 MHz,
Chloroform-d) d 17.7, 27.8, 29.9, 43.3, 47.1, 58.4, 67.3, 67.5, 68.1, 68.2, 68.6, 69.0, 69.3,
71.4, 81.8, 91.5 (in accordance with the literature).[10] MS (ESI): m/e (%) ¼ 284.1 (100)
[M þ H]þ. HRMS (ESI): calcd for C16H22FeN [M þ H]þ: 284.1096. Found: 284.1109.
General procedure for synthesis 2a-r
FLP6 (8.6 mg, 0.01 mmol) was placed in a glass vial in the glovebox, then imine 1
(0.1 mmol) dissolved in dry toluene (2.0 ml) was added to the vial, and the vial was placed
in a stainless steel autoclave. The reactions took place under 2.0 MPa H2 pressure at 80 ꢀC
for 16–38 h. After the completion of the reaction, the solvent was evaporated in vacuo and
the residue was purified by silica gel flash chromatography to afford the product 2a–r.
N-(1-phenylethyl)-aniline (2a)
1
Colorless oil; 84% yield. H NMR (400 MHz, Chloroform-d) d 1.49 (d, J ¼ 6.8 Hz, 3H),
3.99 (s, 1H), 4.43–4.48 (dd, J ¼ 6.4 Hz, 6.8 Hz, 1H), 6.47–6.49 (t, 2H), 6.60–6.63 (m,
1H), 7.04–7.08 (m, 2H), 7.17–7.20 (m, 1H), 7.28–7.34 (m, 4H) (in accordance with the
literature[5c]). MS (ESI): m/e (%) ¼ 198.2 (100) [M þ H]þ.
Funding
We thank the National Natural Science Foundation of China (No. 21676253 and 21706234) for
financial support.
References
€
[1] (a) Blaser, H. U.; Burkhardt, S.; Kirner, H. J.; Mossner, T.; Studer, M.; Ethyl 2,4-Dioxo-4-
phenylbutyrate: Versatile Intermediate for the Large-Scale Preparation of
A

R
SYNTHETIC COMMUNICATIONSV
7
EnantiomericallyPure a-Hydroxy and a-Amino Acid Esters. Synthesis. 2003, 2003,
1679–1682.; (b) Blaser, H. U.; Schmidt, E.; Wiley, V. C. H. Weinheim. 2004, 91–103.;
(c) Nugent, T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty, R. R. Asymmetric Reductive
Amination: Convenient Access to Enantioenriched Alkyl-Alkyl or Aryl-Alkyl Substituted
a-Chiral Primary Amines. Adv. Synth. Catal. 2006, 348, 1289–1299.
[2] Szeto, K. C.; Sahyoun, W.; Merle, N.; Castelbou, J. L.; Popoff, N.; Lefebvre, F.; Raynaud, J.;
Godard, C.; Claver, C.; Delevoye, L.; et al. Development of Silica-supported Frustrated
Lewis Pairs: Highly Active Transition Metal-free Catalysts for the Z-selective Reduction of
Alkynes. Catal. Sci. Technol. 2016, 6, 882–889.
[3] (a) Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W.; Reversible, Metal-Free
Hydrogen Activation. Science. 2006, 314, 1124–1126.; (b) Stephan, D. W.; Science. 2016, 3.
1248–1256.; (c)Yin, Q.; Klare, H. F. T.; Oestreich, M.; Catalytic Friedel–Crafts C–H
Borylation of Electron-Rich Arenes: Dramatic Rate Acceleration by Added Alkenes.
Angew. Chem., Int. Ed. 2017, 56, 3712–3717.; (d) Willms, A.; Schumacher, H.; Tabassum,
H.; Qi, L.; Scott, S. L.; Hausoul, P. J. C.; Rose, M. Solid Molecular Frustrated Lewis Pairs
in a Polyamine Organic Framework for the Catalytic Metal-free Hydrogenation of
Alkenes. ChemCatChem. 2018, 10, 1835–1843.; (e) Meng, W.; Feng, X.; Du, H. Frustrated
Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations. Acc.
Chem. Res. 2018, 51, 191–201.
[4] (a) Stephan, D. W.; Greenberg, S.; Graham, T. W.; Chase, P.; Hastie, J. J.; Geier, S. J.;
Farrell, J. M.; Brown, C. C.; Heiden, Z. M.; Welch, G. C.; et al. Metal-Free Catalytic
Hydrogenation of Polar Substrates by Frustrated Lewis Pairs. Inorg. Chem. 2011, 50,
12338–12348.; (b) Stephan, D. W. Frustrated Lewis Pair” Hydrogenations. Org. Biomol.
ꢀ
Chem. 2012, 10, 5740–5746.; (c) Soos, T. Design of Frustrated Lewis Pair Catalysts
for Metal-free and Selective Hydrogenation. Pure Appl. Chem. 2011, 83, 667–675.;
(d) Paradies, J. Frustrated Lewis Pair Catalyzed Hydrogenations. Synlett. 2013, 24,
777–780.; (e) Hounjet, L. J.; Stephan, D. W. Hydrogenation by Frustrated Lewis Pairs:
Main Group Alternatives to Transition Metal Catalysts? Org. Process Res. Dev 2014, 18,
385–391.; (f) Shi, L.; Zhou, Y.-G. Enantioselective Metal-Free Hydrogenation Catalyzed by
Chiral Frustrated Lewis Pairs. ChemCatChem. 2015, 7, 54–56.
[5] (a) Welch, G. C.; Stephan, D. W. Facile Heterolytic Cleavage of Dihydrogen by
Phosphines and Boranes. J. Am. Chem. Soc. 2007, 129, 1880–1881.; (b) Wang, H.;
€
Frohlich, R.; Kehr, G.; Erker, G. Chem. Commun. 2008, 45, 5966–5968.; (c) Wang, G.;
Chen, C.; Du, T.; Zhong, W. Metal-Free Catalytic Hydrogenation of Imines with
Recyclable [2.2]Paracyclophane-Derived Frustrated Lewis Pairs Catalysts. Adv. Synth.
ꢁ
Catal. 2014, 356, 1747–1752.; (d) Jian, Z.; Krupski, S.; Skoch, K.; Kehr, G.; Daniliuc,
ꢁ
ꢀ ꢁ
ꢀ
ꢁ
ꢁ
C. G.; Cısarova, I.; Stepnicka, P.; Erker, G. Phosphine–Borane Frustrated Lewis Pairs
Derived from a 1,10-Disubstituted Ferrocene Scaffold: Synthesis and Hydrogenation
Catalysis. Organometallics 2017, 36, 2940–2946.
€
[6] Sumerin, V.; Schulz, F.; Nieger, M.; Leskela, M.; Repo, T.; Rieger, B. Facile Heterolytic H2
Activation by Amines and B(C6F5)3. Angew. Chem. Int. Ed. Engl. 2008, 47, 6001–6003.
[7] Geier, S. J.; Stephan, D. W. Lutidine/B(C6F5)3: At the Boundary of Classical and
Frustrated Lewis Pair Reactivity. J. Am. Chem. Soc. 2009, 131, 3476–3477.
ꢀ
[8] Ines, B.; Palomas, D.; Holle, S.; Steinberg, S.; Nicasio, J. A.; Alcarazo, M. Metal-free
Hydrogenation of Electron-poor Allenes and Alkenes. Angew. Chem. Int. Ed. Engl. 2012,
51, 12367–12369.
[9] Rajappa, M.; Shashikala, K. N.; Achanath, R.; Chheda, A. Process for the preparation of
sertraline hydrochloride form ii. WO Patent 2006027658, 2006.
€
[10] Chen, C.; Frohlich, R.; Kehr, G.; Erker, G. Structural Features of Lithio[3]ferrocenophane
Systems Bearing Stabilizing Dimethylamino Substituents. Organometallics 2008, 27,
3248–3253.