Selective N-Formylation of Amines with H2 and CO2 Catalyzed by Cobalt Pincer Complexes

Article abstract of DOI:10.1021/acscatal.7b00116

N-formylation of amines utilizing CO₂ in the presence of reducing agents constitute an important methodology in organic synthesis. Presented herein is a selective N-formylation of amines with CO₂ and H₂ catalyzed by complexes of Earth-abundant cobalt. A wide range of amines were converted to their corresponding formamides under CO₂ and H₂ pressure, catalyzed by Co-PNP pincer complex, generating water as the sole byproduct.

Full text of DOI:10.1021/acscatal.7b00116

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Letter
Selective N-Formylation of Amines with H2 and
CO2 Catalyzed by Cobalt Pincer Complexes
Prosenjit Daw, Subrata Chakraborty, Gregory Leitus, Yael
Diskin-Posner, Yehoshoa Ben-David, and David Milstein
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00116 • Publication Date (Web): 01 Mar 2017
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Selective N-Formylation of Amines with H2 and CO2 Catalyzed by
Cobalt Pincer Complexes
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Prosenjit Daw,† ‡ Subrata Chakraborty,† ‡ Gregory Leitus,δ Yael Diskin-Posner, δ Yehoshoa Ben-David, † and Da-
vid Milstein*†
Department of †Organic Chemistry and δChemical Research Support, Weizmann Institute of Science, Rehovot, 76100, Israel
ABSTRACT: N-formylation of amines utilizing CO2 in the presence of reducing agents constitute an important methodology in organic syn-
thesis. Presented herein is selective N-formylation of amines with CO2 and H2 catalyzed by complexes of earth-abundant cobalt. A wide range
of amines were converted to their corresponding formamides under CO2 and H2 pressure catalyzed by Co-PNP pincer complex generating
water as the sole by product.
KEYWORDS: Cobalt, formylation, CO2, hydrogenation, pincer.
Formamides are a class of compounds widely used in organic synthesis,
including synthesis of valuable heterocycles, biological intermediates
and pharmaceuticals. Formamides are also used as Lewis base organo-
catalysts in hydrosilylation reactions and other transformations. More-
over, the formyl group is a useful protecting group of the amine func-
tionality in peptide synthesis.1-6
unactivated esters and amides with alcohol.19g We have reported ester
hydrogenation20a and nitrile hydrogenation20b catalyzed by a pyridine-
based PNNH pincer Co complex, and very recently, using this catalyst,
we have exploited the dehydrogenative coupling of diols and amines to
selectively form functionalized 1,2,5-substituted pyrroles liberating
water and hydrogen gas as the sole by-products.21 N-formylation of
secondary amines using CO2 and H2 catalyzed by complexes of base
metals (Fe and Co) was reported by Beller for the synthesis of DMF,
diethylformamide and N-formylpiperidine.22 To our knowledge,
formylation of primary amines, using CO2 and H2 catalyzed by base-
metal complexes was not reported.
Traditionally, N-formamide synthesis involves the use of stoi-
chiometric amounts of coupling reagents like chloral, formic acid, for-
maldehyde or formate, generating copious waste and resulting in poor
atom-economy.7 The direct catalytic synthesis of N-formamides from
8a
8h-j
amines and carbonyl sources like formates,7, methanol,8b-gCO2 in
the presence of a catalyst has become a field of much interest due to
high atom efficiency. In this regard an attractive green route for the N-
formylation of amines is the use of a mixture of CO2 and H2 as a
formylating agent; CO2 is a non-toxic and abundant C1 building block
and hydrogen gas is the cleanest and most atom-economical reducing
agent; water is the only by-product generated in this reaction. In addi-
tion capturing the greenhouse gas CO2 and its utilization for the pro-
duction of value-added chemicals is highly desirable.9 However, cata-
lytic N-formylation of amines using CO2 is challenging due to the sta-
bility of CO2.10 Moreover, selectivity is a crucial issue in this methodol-
ogy, since methylated amines may also form via over reduction of the
formed formamides.11 Despite this, the first homogeneously catalysed
preparation of DMF using H2 ,CO2 and dimethylamine was reported
by Haynes12 in 1970. Subsequently several other reports appeared for
the synthesis of DMF from CO2, H2 and dimethylamine.13 However,
this methodology is mostly limited to DMF synthesis. The first exam-
ple of N-formylation of a wide range of amines with CO2 and H2 was
reported by Ding using highly efficient Ru-pincer catalysts.14
Figure 1. Co-based pincer complexes explored in this study.
Herein we present cobalt catalyzed N-formylation of a wide
range of primary- and secondary amines under relatively mild CO2 and
H2 pressure. We also describe the key intermediate of the active
catalyst.
The novel paramagnetic Co(II) chloride complex CoII(iPr-PNHP)Cl2
1 was synthesised by treating our previously reported iPr-PNHP pincer
ligand23 with one equivalent of CoCl2 at room temperature in THF in
93% yield (Figure 1, see also ESI). Single crystals of complex 1 suitable
for an X-ray diffraction study were obtained by slow diffusion of
pentane into a saturated solution of THF at -30 °C. The molecular
structure is shown in Figure 2. Complexes 2-6 were prepared according
to literature procedures.20a, 24, 25
The development of catalytic systems based on low toxicity,
earth abundant base metals is an important goal in homogeneous catal-
ysis.15 Appreciable progress has been made in recent years employing
complexes of base metals (Fe, Co, Mn, Ni) in various
(de)hydrogenation reactions.16-19 Homogeneous cobalt catalysts have
been reported in hydrogenation reactions of olefins,18a-e ketones,18a,f
imines,18a CO2,18g-i N-heterocycles18k and carboxylic acids18l; dehydro-
genation of alcohols,19a N-heterocycles,19b N-alkylation of amines with
alcohols,19c-e N-alkylation of amines with amines,19f C-alkylation of
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hi
gh yields of N-h
exylformamide
). In the absence of
(entries 6 and 7
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base, using 5 mol% NaHBEt3 and 5 mol% of 1, 73% yield of N- hexyl-
formamide was obtained (entry 8), whereas using 20 mol% NaHBEt3
and 5 mol% of 1, N- hexylformamide was obtained in 95% yield (entry
9). On the other hand, in the absence
9
Table 2. Substrate scope for the N-formylation of amines using CO2
and H2 catalyzed by complex 1.
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Figure 2. X-ray structure of complex 1. Thermal ellipsoids are drawn at
50% probability level. Selected hydrogen atoms are omitted for clarity.
For selected bond lengths and angles see SI.
Entrya Amines
Formamides
Conv.(%)b Yield
(%)c
Table 1. Optimization of the reaction conditions for the N-formylation
of hexylamine.
1
2
99
99
99
Entrya
Cat
NaHBEt3
(mol%)
5
Base
(mol%)
tBuOK (5)
Yieldb
(%)
60
95[d]
1c
2
3d
4e
5f
1
1
5
5
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
NaOEt (5)
KHMDS (5)
-
99
80
40
45
90
92
73
95
00
00
00
00
00
99
87
89
85
00
1
3
4
85
74
80
60
1
5
1
5
6
1
5
7
1
5
8
1
5
9
1
20
-
5
75
70
10
11
12
13
14
15g
16
17
18
19
1
tBuOK (5)
tBuOK (25)
-
1
1
-
25
5
6
7
8
99
95
99
96
88
90
-
tBuOK (25)
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK (5)
tBuOK(5)
CoCl2
1
2
3
4
5
5
5
5
O
5
5
N
CHO
20
21h
22h
6
tBuOK (5)
tBuOK (5)
-
00
96
93
9
99
99
99
99
92
90
CHO
N
1-Cl
1-Cl
-
5
10
11
aConditions: hexylamine (0.5 mmol), catalyst (5 mol%), NaHBEt3, base, and
dry toluene (2 mL), heated in an autoclave at 150 °C (bath temperature) for 36
N
CHO
b
c
d
e
h. Isolated yield. 120 °C. the reaction was carried out for 24 h. THF solvent.
fdioxane solvent. gthe reaction was carried out in the presence of 50 equiv. Hg. h
See mechanistic part.
N
N
CHO
Our initial attempts were focused on assessing the catalytic activ-
ity of complexes 1-6 in the presence of one equiv. of NaHBEt3 (relative
to Co) and tBuOK as a base, in the N-formylation of hexylamine by
CO2 and H2. Thus, reaction of hexylamine (0.5 mmol) in the presence
of CO2 (30 bar) and H2 (30 bar) using NaHBEt3 (5 mol%), tBuOK (5
mol%) and complex 1 (5 mol%) in toluene resulted in the formation of
N-hexylformamide in 60% yield at 120 °C and in 99% yield at 150 °C
after 36 h (Table 1, entries 1 and 2). Analysis of the crude reaction
mixture by GC revealed selective formation of the corresponding
formamide as a sole product. N- methylation of the amine via fur-
ther hydrogenation of the formamide was not observed. Changing the
solvent to THF or 1,4-dioxane resulted in poor yields under analogous
condition (Table 1, entries 4 and 5). Exploring the effect of the bases
KHMDS and NaOEt under similar reaction conditions also resulted in
12
13
99
77
93
75
14[e][f]
99
99[a][d]
aConditions: amine (0.5 mmol), catalyst (5 mol%), NaHBEt3 (5 mol%) tBuOK
(5 mol%), CO2 (30 bar), H2 (30 bar), and dry toluene (2 mL), heated in an
autoclave at 150 °C bath temperature for 36 h. bconversions determined by GC-
MS based on amine consumption. Isolated yield. GC yield. For TON calcu-
lation: dimethylamine (6 mmol, 3 mL of 2M in THF), catalyst (0.4 mol%),
NaHBEt3 (0.4 mol%) tBuOK (0.4 mol%), CO2 (30 bar), H2 (30 bar), heated in
c
d
e
f
an autoclave at 150 °C bath temperature for 36 h (Yield 18%, TON 45). same
as [e] in presence of molecular sieve (Yield 54%, TON 130).
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of NaHBEt3 no conversion was observed under the same reaction con-
Based on the aforementioned observations a plausible mechanism is pro-
posed in Scheme 1. 1-Cl is generated upon treatment of complex 1 with
one equivalent NaBEt3H (Scheme 1). A highly reactive, coordinatively
unsaturated intermediate A is expected to be formed upon reaction of 1-Cl
with tBuOK, which under H2 generates the Co(I) hydride B. CO2 inser-
tion into the Co-H bond forms the η1-formato complex C. The presence
of excess amine results in formate salt formation, likely by deprotonation
of the coordinated amine of the pincer ligand, as suggested by Beller.22c
The formate salt liberates water forming the formamide13b and regenerat-
ing the active intermediate A. Direct nucleophilic attack on the formato
complex C by amine followed by liberation of H2O from the metal centre
cannot be excluded at this stage.
ditions even upon increase of the base loading to 25 mol% (entries 10-
11). The absence of both tBuOK and NaHBEt3 also did not show any
conversion of the amine (entry 12). The aforementioned experiments
indicated that both NaHBEt3 and tBuOK play crucial roles in generat-
ing the catalytically active species. However using only NaBEt3H and
tBuOK (25 mol% each) without any Co source did not result in any
formamide formation (entry 13). Using CoCl2 as pre-catalyst in the
presence of NaBEt3H and tBuOK under the same conditions resulted
in no conversion of hexylamine (entry 14). Moreover, a reaction using
pre-catalyst 1 under same condition in the presence of 50 equivalents
of Hg gave quantitative conversion to the N-hexylformamide (Table 1,
entry 15), indicating that Co nanoparticle formation is unlikely, and
supporting the homogeneity of the reaction. Next, the catalytic activity
of our previously reported dihalo Co-PNP, Co-PNN and Co-PNNH
complexes 2-6 (Figure 1) was explored.[20a],[24,25] Indeed, the Co-
PNPiPr complex 2, Co-PNPtBu complex 3 and Co-PNNBy 4 also
catalyze the reaction in 85-89% yields (Table 1, entries 16-18) under
similar conditions. Surprisingly, Co-PNNH and Co-PNNEt, complex-
es 5 and 6, did not show any catalytic activity (Table 1, entries 19 and
20) under analogous conditions. The best performing complex 1 was
chosen for further substrate scope studies.
An array of primary and secondary amines were then examined in the
N-formylation reaction using complex 1 (5 mol%), NaHBEt3 ( 5
mol%), tBuOK (5 mol%), 30 bar CO2 and 30 bar H2 at 150 °C. As
shown in Table 2, the N-formylation reaction proceeded smoothly for
primary aliphatic and benzylic amines to selectively afford the corre-
sponding formamides in good to excellent 60-99% yields (Table 2,
entries 1-6). Cyclohexylamine gave N-cyclohexylformamide in 88%
yield (Table 2, entry 7). Cyclic secondary amines yielded the corre-
sponding N-formamides selectively in excellent yields, (Table 2, entries
8-12). The acyclic secondary amine N-methyl benzylamine yielded N-
methyl-N-benzylformamide in 75% yield (Table 2, entry 13). However
the less nucleophilic aromatic amines aniline and 3,4-dimethylaniline
were completely inactive under the optimized protocol. Finally, the
industrially important DMF was also obtained in 99% yield from dime-
thylamine, CO2 and H2 (Table 2, entry 14). Using lower catalyst load-
ing (0.4 mol% catalyst, 6 mmol dimethylamine,) the TON value was
45 (18% yield), likely because the large excess of the generated water
with respect to the catalyst hampers its activity. Addition of 500 mg of
4Å molecular sieves resulted in TON increases to 130 (54% yield).
Thus, in large scale experiments addition of molecular sieves is advan-
tageous (Table 2, entry 14e,f, and see SI)
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Figure 3. Molecular structure of complex 1-Cl. Thermal ellipsoids are
drawn at 50% probability level. Selected hydrogen atoms are omitted
for clarity. For selected bond lengths and angles see SI.
To support involvement of intermediates B and C, the Co(I) com-
plex 1-Cl was reacted with one equivalent of NaBEt3H (Scheme 1), form-
ing a paramagnetic species, probably a Co(I) hydride intermediate B. In
the IR spectrum a weak signal at 1995 cm-1 was assigned to the Co-H
stretching frequency of B. However, a crystal structure of B could not be
obtained. When B was used as catalyst in the absence of any base, quantita-
tive conversion of hexylamine to hexylformamide (93%) was observed
(Table 1, entry 22). Moreover, a sharp peak at 1595 cm,-1 which is in the
range of νC-O vibration of a formate complex,26 was noticed in the IR spec-
trum when B was treated with one bar CO2 at room temperature, support-
ing formation of intermediate C (see ESI). Treatment of 1-Cl with sodium
formate in THF at room temperature resulted in a formate complex exhib-
iting this IR stretch as well (see SI).
An alternative possibility involving the generation of free formic acid fol-
lowed by reaction with the amine can be excluded (see SI). Performing the
catalytic reaction under the conditions of Table 2, but in the absence of
amine substrate did not generate any formic acid.
Scheme 1. Proposed mechanism for the N-formylation of amines using
CO2 and H2 catalyzed by Co-PNP complex.
H
N
H
NaHBEt3
N
PiPr2
1-Cl
P
iPr2
Co
Regarding the nature of the active cobalt catalyst, we previously re-
ported that treatment of the pincer complex Co-(PNNH)Cl2 with one
equiv of NaHBEt3 at room temperature gave the paramagnetic
(PNNH)CoICl,20a which was proposed as an active species in hydro-
genation and dehydrogenation reactions.20,21 Similarly, we prepared the
paramagnetic Co(I) complex [(iPr-PNHP)CoICl], 1-Cl (Scheme 1) by
treatment of complex 1 with one equivalent of NaHBEt3 at room tem-
perature (see ESI). Complex 1-Cl was characterized by X-ray crystal-
lography (Figure 3, and see ESI). It adopts an uncommon distorted
tetrahedral geometry and hence it is paramagnetic. Complex 1-Cl was
tested in the formylation reaction of hexylamine with a mixture of CO2
and H2. Using 5 mol% of 1-Cl and 5 mol% of tBuOK at 150 °C yielded
96% of N-hexylformamide after 36 h (Table 1, entry 21), which is compa-
rable to the results obtained using the CoII complex 1 (Table 1, entry 2), in
line with it being involved in the generation of the actual Co(I) catalyst.
PiPr2
CHO
P
Co
Cl
iPr2
R
N
H
Cl
Cl
1
tBuOK
- H2O
+ HCOO-
R
NH3
N
H2
PiPr2
P
Co
iPr2
A
R
NH2
H
N
H
N
PiPr2
P
iPr2
Co
PiPr2
P
iPr2
Co
H
B
OCHO
C
NaHBEt3
CO2
H
N
PiPr2
1-Cl
P
iPr2
Co
Cl
In conclusion, the synthesis of a wide range of N-formamides catalyzed
by a base metal complex in good to excellent yields using both primary
amines (for the first time) and secondary amines under relatively mild
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49, 9777–9780. (j) Jacquet, O.; Das, C.; Gomes, N.; Ephritikhine, M.;
Cantat, T. J. Am. Chem. Soc. 2012, 134, 2934–2937.
CO2 and H2 pressure (30 bar each) was accomplished. The reaction is
catalyzed by a complex of low-toxicity, earth-abundant cobalt. The
active Co(I) species is generated using catalytic NaHBEt3 and tBuOK.
A plausible mechanism is proposed. We believe that this environmen-
tally benign protocol is attractive, considering the wide scope, excellent
yields, earth-abundant metal, and H2O as the sole by-product.
(9) Selected recent reviews: (a) Carbon Dioxide as Chemical Feedstock
(Ed.: M. Aresta), Wiley-VCH, Weinheim, 2010. (b) A. Boddien, F. G.rtner,
C. Federsel, I. Piras, H. Junge, R. Jackstell, M. Beller in Organic Chemistry:
Breakthroughs and Perspectives (Eds.: K. Ding, L. Dai), Wiley-VCH,
Weinheim, 2012, p. 685. (c) Aresta, M.; Dibenedetto, A.; Angelini, A.
Chem. Rev. 2014, 114, 1709–1742.
(10) Liu, Q.; Wu, L.; Jackstell, R.; Beller, M. Nat. Commun. 2015, 6,
5933.
(11) Li, Y.; Cui, X.; Dong, K.; Junge, K.; Beller, M. ACS Catal. 2017, 7,
1077–1086.
(12) P. Haynes, L. H. Slaugh, J. F. Kohnle, Tetrahedron Lett. 1970, 11,
365–368.
(13) (a) Jessop, P. G.; Hsiao, Y.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc.1994, 116, 8851–8852. (b) Jessop, P. G.; Hsiao, Y.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1996, 118, 344–355. (c) Kröcher, O.; Kחppel, R. A.;
Baiker, A. Chem. Commun. 1997, 453–454.
(14) Zhang, L.; Han, Z.; Zhao, X.; Wang, Z.; Ding, K. Angew. Chem.,
Int. Ed., 2015, 54, 6186–6189.
(15)(a) Albrecht, M.; Bedford, R.; Plietker, B. Organometallics 2014,
33, 5619–5621. (b) Bullock, R. M. Catalysis without Precious Metals;
Wiley-VCH: Weinheim, 2010.
(16) Recent reviews on catalysis by Fe and Ni complexes: (a) Bauer, I.;
Knolker, H.-J. Chem. Rev. 2015, 115, 3170–3387. (b) Morris, R. H. Acc.
Chem. Res. 2015, 48, 1494–1502. (c) Chirik, P. J. Acc. Chem. Res. 2015,
48, 1687–1695. (d) Chakraborty, S.; Bhattacharya, P.; Dai, H.; Guan, H.
Acc. Chem. Res. 2015, 48, 1995–2003. (e) McNeil, W.; Ritter, T. Acc.
Chem. Res. 2015, 48, 2330–2343. (f) Benito-Garagorri, D.; Kirchner, K.
Acc. Chem. Res. 2008, 41, 201–213. (g) Zell, T.; Milstein, D. Acc. Chem.
Res. 2015, 48, 1979–1994 and references therein.
(17) Mn catalyzed (de)hydrogenation: (a) Mukherjee, A.; Nerush, A.;
Leitus, G.; Shimon, L. J. W.; Ben David, Y.; Jalapa, N. A. E.; Milstein, D. J.
Am. Chem. Soc. 2016, 138, 4298–4301. (b) Elangovan, S.; Topf, C.; Fisch-
er, S.; Jiao, H.; Spannenberg, A.; Baumann, W.; Ludwig, R.; Junge, K.;
Beller, M. J. Am. Chem. Soc. 2016, 138, 8809–8814. (c) Elangovan, S.;
Garbe, M.; Jiao, H.; Spannenberg, A.; Junge, K.; Beller, M. Angew. Chem.
Int. Ed. 2016, 55, 15364–15368. (d) Espinosa-Jalapa, N. A.; Nerush, A.;
Shimon, L. J. W.; Leitus, G.; Avram, L.; Ben-David, Y.; Milstein, D. Chem.
Eur. J. 2016, 22, DOI: 10.1002/chem.201604991. (e) Kallmeier, F.; Ir-
rgang, T.; Dietel, T.; Kempe, R. Angew. Chem. Int. Ed. 2016, 55, 11806–
11809. (f) Mastalir, M.; Glatz, M.; Gorgas, N.; Stöger, B.; Pittenauer, E.;
Allmaier, G.; Veiros, L. F.; Kirchner, K. Chem. Eur. J. 2016, 22, 12316–
12320. (g) Peña-López, M.; Piehl, P.; Elangovan, S.; Neumann, H.; Beller,
M. Angew. Chem. Int. Ed. 2016, 55, 14967–14971. (h) Elangovan, S.;
Neumann, J.; Jean-Baptiste, S.; Junge, K.; Darcel, C.; Beller, M. Nat. Com-
mun. 2016, 7, 12641. (i) Andérez-Fernández, M.; Vogt, L. K.; Fischer, S.;
Zhou, W.; Jiao, H.; Garbe, M.; Elangovan, S.; Junge, K.; Junge, H.; Ludwig,
R.; Beller, M. Angew. Chem. Int. Ed. 2017, 56, 559–562.
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ASSOCIATED CONTENT
Experimental procedure, crystallographic data of 1 and 1-Cl, GC-MS,
NMR spectra of products “This material is available free of charge via
the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*E-mail: david.milstein@weizmann.ac.il.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Israel Science Foundation and by
the Kimmel Center for Molecular Design. D.M. holds the Israel Matz
Professorial Chair. P.D. is thankful to the Planning and Budgeting
Committee (PBC) for a fellowship. S.C. thanks the Swiss Friends of
the Weizmann Institute of Science for a generous postdoctoral fellow-
ship.
REFERENCES
(1) (a) Pettit, G.; Kalnins, M.; Liu, T.; Thomas, E.; Parent, K. J. Org.
Chem., 1961, 26, 2563–2566. (b) Wang, P. C.; Ran, X. H.; Chen, R.; Li, L.
C.; Xiong, S. S.; Liu, Y. Q.; Luo, H. R.; Zhou, J.; Zhao, Y. X. Tetrahedron
Lett. 2010, 51, 5451–5453.
(2) (a) Chen, B. C.; Bednarz, M. S.; Zhao, R.; Sundeen, J. E.; Chen, P.;
Shen, Z.; Skoumbourdis, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41,
5453–5456. (b) Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.;
Konishi, H.; Chem. Lett. 1995, 24, 575–576. (c) Hett, R.; Fang, Q. K.; Gao,
Y.; Wald, S. A.; Senanayake, C. H. Org. Process Res. Dev. 1998, 2, 96–99.
(3) Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry, 3rd ed.,
Translated by C. R. Lindley, Wiley-VCH, Weinheim, 1997.
(4) (a) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetra-
hedron 1993, 49, 4015–4034. (b) Kobayashi, S.; Nishio, K. J. Org. Chem.
1994, 59, 6620-6628. (c) Kobayashi, S.; Yasuda, M.; Hachiya, I.; Chem.
Lett. 1996, 25, 407–408. (d) Jones, S.; Warner, C. J. A. Org. Biomol. Chem.
2012, 10, 2189–2200. (e) Jagtap, S. B.; Tsogoeva, S. B. Chem. Commun.
2006, 4747–4749.
(18) Co catalyzed hydrogenation: (a) Zhang, G.; Scott, B. L.; Hanson,
S. K. Angew. Chem.,Int. Ed. 2012, 51, 12102–12106. (b) Yu, R. P.; Dar-
mon, J. M.; Milsmann, C.; Margulieux, G. W.; Stieber, S. C. E.; DeBeer, S.;
Chirik, P. J. J. Am. Chem. Soc. 2013, 135, 13168–13184. (c) Monfette, S.;
Turner, Z. R.; Semproni, S. P.; Chirik, P. J. J. Am. Chem. Soc. 2012, 134,
4561–4564. (d) Gärtner, D.; Welther, A.; Rezaei Rad, B.; Wolf, R.; Jacobi
von Wangelin, A. Angew. Chem. Int. Ed. 2014, 53, 3722–3726. (e) Lin, T.-
(5) (a) Han, Y.; Cai, L. Tetrahedron Lett. 1997, 38, 5423–5426. (b) Fa-
raj, M.K.; U.S. Patent 5,686,645, 1997.
(6) Wuts, P. G. M. Greene's Protective Groups in Organic Synthesis,
5th ed., Wiley, Hoboken, NJ, 2014, p. 991.
(7) Gerack, C. J.; McElwee-White, L. Molecules 2014, 19, 7689–7713.
(8) (a) Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71, 6652–
6654. (b) Ortega, N.; Richter, C.; Glorius, F. Org. Lett. 2013, 15, 1776–
1779. (c) Kanga, B.; Hong, S. H. Adv. Synth. Catal. 2015, 357, 834–840.
(d) Preedasuriyachai, P.; Kitahara, H.; Chavasiri, W.; Sakurai, H. Chem.
Lett. 2010, 39, 1174–1176. (e) Ishida, T.; Haruta, M. ChemSusChem
2009, 2, 538–541. (f) Gomes, C. D. N.; Jacquet, O.; Villiers, C.; Thuery, P.;
Ephritikhine, M.; Cantat, T. Angew. Chem., Int. Ed., 2012, 51, 187–190.
(g) Kothandaraman, J.; Kar, S.; Sen, R.; Goeppert, A.; Olah, G. A.; Surya
Prakash, G. K. J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.6b11637 (h)
Tlili, A.; Blondiaux, E.; Frogneux, X.; Cantat, T. Green Chem. 2015, 17,
157–168. (i) Federsel, C.; Boddien, A.; Jackstell, R.; Jennerjahn, R.; Dyson,
P. J.; Scopelliti, R.; Laurenczy, G.; Beller, M. Angew. Chem. Int. Ed. 2010,
P.; Peters, J. C. J. Am. Chem. Soc. 2014, 136, 13672–13683. (f) Rösler, S.;
Obenauf, J.; Kempe, R. J. Am. Chem. Soc. 2015, 137, 7998–8001. (g) Jelet-
ic, S. M.; Mock, M. T.; Appel, A. M.; Linehan, J. C. J. Am. Chem. Soc. 2013,
135, 11533–11536. (h) Federsel, C.; Ziebart, C.; Jackstell, R.; Baumann,
W.; Beller, M. Chem. Eur. J. 2012, 18, 72–75. (i) Spentzos, A. Z.; Barnes, C.
L.; Bernskoetter, W. H. Inorg. Chem. 2016, 55, 8225–8233. (j) Zhang, G.;
Vasudevan, K. V.; B. L. Scott, B. L.; Hanson, S. K. J. Am. Chem. Soc. 2013,
135, 8668–8681. (k) Adam, R.; Cabrero-Antonino, J. R.; Spannenberg, A.;
Junge, K.; Jackstell, R.; Beller, M. Angew. Chem. Int. Ed. 2017, DOI:
10.1002/anie.201612290. (l) Korstanje, T. J.; van der Vlugt, J. I.; Elsevier,
C. J.; de Bruin, B. Science 2015, 350, 298–302.
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2
3
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6
7
8
9
(19) Co-catalyzed dehydrogenation: (a) Zhang, G.; Hanson, S. K. Org.
Lett. 2013, 15, 650–653. (b) Xu, R.; Chakraborty, S.; Yuan, H.; Jones, W.
D. ACS Catal. 2015, 5, 6350–6354. (c) Rösler, S.; Ertl, M.; Irrgang, T.;
Kempe, R. Angew. Chem., Int. Ed. 2015, 54, 15046–15050. (d) Zhang, G.;
Yin, Z.; Zheng, S. Org. Lett. 2016, 18, 300–303. (e) Mastalir, M.; Tomsu,
G.; Pittenauer, E.; Allmaier, G.; Kirchner, K. Org. Lett. 2016, 18, 3462–
3465. (f) Yin, Z.; Zeng, H.; Wu, J.; Zheng, S.; Zhang, G. ACS Catal. 2016,
6, 6546–6550. (g) Deibl, N.; Kempe R. J. Am. Chem. Soc. 2016, 138,
10786–10789.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(20) (a) Srimani, D.; Mukherjee, A.; Goldberg, A. F.; Leitus, G.; Diskin
Posner, Y.; Shimon, L. J. W.; Ben-David, Y.; Milstein, D. Angew. Chem.,
Int. Ed. 2015, 54, 12357–12360. (b) Mukherjee, A.; Srimani, D.;
Chakraborty, S.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2015, 137,
8888–8891.
(21) Daw, P.; Chakraborty, S.; Garg, J. A.; Ben-David, Y.; Milstein, D.
Angew. Chem. Int. Ed. 2016, 55, 14373–14377.
(22) (a) C. Federsel, A. Boddien, R. Jackstell, R. Jennerjahn, P. J. Dyson,
R. Scopelliti, G. Laurenczy, M. Beller, Angew. Chem. Int. Ed. 2010, 49,
9777–9780. (b) C. Federsel, C. Ziebart, R. Jackstell, W. Baumann, M.
Beller, Chem. Eur. J. 2012, 18, 72–75. (c) C. Ziebart, C. Federsel, P. Anba-
rasan, R. Jackstell, W. Baumann, A. Spannenberg, M. Beller, J. Am. Chem.
Soc. 2012, 134, 20701–20704.
(23) Chakraborty, S.; Leitus, G.; Milstein, D. Angew. Chem. Int. Ed.
2017, 56, 2074–2078.
(24) Khaskin, E.; Diskin-Posner, Y.; Weiner, L.; Leitus, G.; Milstein, D.
Chem Commun. 2013, 49, 2771–2773.
(25) Zhang, L.; Zuo, Z.; Leng, X.; Huang, Z. Angew. Chem. Int. Ed.
2014, 53, 2696–2700.
(26) Li, J.; Zheng, T.; Suna, H.; Li, X. Dalton Trans. 2013, 42, 13048–
13053.
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