Copper-Catalyzed Aerobic Oxidative Amidation of Benzyl Alcohols

Article abstract of DOI:10.1021/acs.joc.6b01686

A Cu-catalyzed synthesis of amides from alcohols and secondary amines using the oxygen in air as the terminal oxidant has been developed. The methodology is operationally simple requiring no high pressure equipment or handling of pure oxygen. The commercially available, nonprecious metal catalyst, Cu(phen)Cl₂, in conjunction with di-tert-butyl hydrazine dicarboxylate and an inorganic base provides a variety of benzamides in moderate to excellent yields. The pK_a of amine conjugate acid and electronics of alcohol were shown to impact the selection of base for optimal reactivity. A mechanism consistent with the observed reactivity trends, KIE, and Hammett study is proposed.

Full text of DOI:10.1021/acs.joc.6b01686

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Article
Copper-Catalyzed Aerobic Oxidative Amidation of Benzyl Alcohols
Scott W Krabbe, Vincent S. Chan, Thaddeus S. Franczyk, Shashank
Shekhar, José G Napolitano, Carmina A Presto, and Justin A Simanis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01686 • Publication Date (Web): 14 Oct 2016
Downloaded from http://pubs.acs.org on October 14, 2016
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CopperꢀCatalyzed Aerobic Oxidative Amidation of
Benzyl Alcohols
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Scott W. Krabbe, †*Vincent S. Chan, † Thaddeus S. Franczyk, † Shashank Shekhar, † José G.
Napolitano,‡ Carmina A. Presto, ‡ and Justin A. Simanis†
†AbbVie Inc., Process Research and Development, 1 North Waukegan Road, North Chicago, IL
60064, USA
‡AbbVie Inc., Discovery Chemistry and Technology, 1 North Waukegan Road, North Chicago,
IL 60064, USA
KEYWORDS Aerobic oxidation, amidation, nonꢀprecious metals, copper, catalysis
ABSTRACT: A Cuꢀcatalyzed synthesis of amides from alcohols and secondary amines using the
oxygen in air as the terminal oxidant has been developed. The methodology is operationally
simple requiring no high pressure equipment or handling of pure oxygen. The commercially
available, nonꢀprecious metal catalyst, Cu(phen)Cl2, in conjunction with diꢀtertꢀbutyl hydrazine
dicarboxylate and an inorganic base provides a variety of benzamides in moderate to excellent
yields. The pKa of amine conjugate acid and electronics of alcohol were shown to impact the
selection of base for optimal reactivity. A mechanism consistent with the observed reactivity
trends, KIE, and Hammett study is proposed.
Introduction
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Amides are an important structural motif found in diverse natural products, pharmaceuticals, and
agrochemicals.1,2 Due to their abundance in synthetically targeted molecules, a wide variety of
methodologies have been developed to form amides.3ꢀ7 Although effective, many of the
commonly used methods are not atom economical because of the need to use stoichiometric
coupling reagents to activate the carboxylic acid prior to reaction with the amine.8,9 Moreover,
the stoichiometric byꢀproducts from these coupling reagents can be carcinogenic,10 cytotoxic,11
and challenging to remove requiring multiple aqueous extractions or recrystallizations.9 In light
of these limitations, the ACS Green Chemistry Institute Pharmaceutical Roundtable has
identified “amide formation avoiding poor atom economy reagents” as a key area of research.12
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In recent years, the catalytic amidation of alcohols has emerged as an atomꢀ and stepꢀeconomical
alternative that circumvents the need for preꢀactivation of carboxylic acids. While direct
amidations of alcohols have been developed with secondꢀ and thirdꢀrow transition metals (e.g.
Ru, 13ꢀ21 Rh, 22ꢀ24 Re, 25 and Au26,27), far fewer methods have been reported with cheaper, more
abundant nonꢀprecious metals.28ꢀ33,34 Given the cost,35 toxicity,36 and longꢀterm supply issues37
associated with precious metal catalysts,38ꢀ40 the identification of efficient and reliable nonꢀ
precious metal alternatives is especially important with regards to sustainability. In addition,
direct amidation of alcohols necessarily rely on oxidative pathways, and the majority of methods
catalyzed by nonꢀprecious metals utilize tertꢀbutylhydroperoxide as the terminal oxidant, while
oxygen is the ideal oxidant from a green chemistry perspective.41ꢀ43 From a safety perspective,
the use of pure oxygen with organic solvents can represent an untenable risk. This risk can be
partially mitigated by using lower concentrations of oxygen.41 While air is obviously the
convenient oxygen gas blend available, its use still presents risk in the presence of flammable
vapor.41,44
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Copperꢀcatalyzed aerobic oxidations of alcohols to aldehydes are wellꢀknown and have been the
subject of numerous mechanistic studies.45ꢀ57 Only a few reports of the corresponding oxidation
of aldehydes to amides have been reported.58,59 We postulated this concept could be extended to
a oneꢀpot, doubleꢀoxidation of an alcohol to amide that proceeds through a hemiaminal
intermediate (Scheme 1).34 One of the challenges in developing this method is to identify
reaction conditions that limit formation of related byꢀproducts (i.e. esters and carboxylic acids)
and also tolerate the potentially oxidizable amine functionality. In this regard, reports by Markó
and coworkers in which alcohols were effectively converted to aldehydes by a copper species in
concert with diꢀtertꢀbutyl azodicarboxylate (DBAD) were of particular interest to us.60ꢀ67
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Scheme 1. Proposed Oxidative Amidation of Alcohols
Results and Discussion
To establish proofꢀofꢀconcept and demonstrate that a hemiaminal could be oxidized to the amide,
we evaluated the reaction of benzaldehyde (1a) and piperidine (2a) in the presence of CuCl,
1,10ꢀphenanthroline (phen), diꢀtertꢀbutyl hydrazine dicarboxylate (DBADH2), and K3PO4 in
toluene under air. Gratifyingly, after 20 h at 75 °C, 76% yield of benzamide 3a was observed
(Table 1, entry 1). The particle size of K3PO4 had a significant impact on reaction conversion;
replacing milled K3PO4 (29 ꢁm) with pelleted K3PO4 led to a drastic decrease in yield of 3a
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(entry 1 vs. 3). Other inorganic bases proved less efficient than K3PO4 (entries 4 and 5).
Alternative Cu(I) sources did not perform as well as CuCl. A Cu(II) source, CuCl2, provided only
slightly lower yield of 3a (entries 6ꢀ868). Varying the electronics of the phen ligands (entries 9
and 1068) provided similar results except when the binding site was sterically encumbered (entry
11). 4,4ʹꢀDiꢀtertꢀbutylꢀ2,2ʹꢀbipyridine was not as effective a ligand as phen (entry 12). A control
experiment performed without DBADH2 afforded 50% yield of 3a (entry 13); the observation of
an operative DBADꢀfree oxidation pathway is consistent with recent findings reported by Stahl
and coworkers.53 Performing the reaction with less than two equivalents of 2a or K3PO4 resulted
in lower yields of 3a (entries 14 and 15). Only trace amounts of 3a were observed in the absence
of CuCl (entry 16). Ligandless CuCl formed 3a in 18% yield (entry 17), indicating a Cu/phen
species is critical to the oxidative amidation. Screening of additional azenes was also conducted
but none of those investigated provided better results than DBADH2.68
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Table 1. Initial Optimization of Oxidative Amidation from Benzaldehyde Using Oxygen in Air
as the Terminal Oxidant
Entry
Change from conditions in scheme
Yield (3a)b
1
none
76
79
9
60
62
54
5
2
10% CuCl, phen, and DBADH2
Pelleted K3PO4 instead of milled K3PO4
K2CO3 instead of K3PO4
Cs2CO3 instead of K3PO4
CuI instead of CuCl
3c
4c
5c
6
7
Cu2O instead of CuCl
8
9
10
11
CuCl2 instead of CuCl
70
77
73
18
4,7ꢀdimethoxyꢀ1,10ꢀphen instead of phen
4,7ꢀdiphenylꢀ1,10ꢀphen instead of phen
2,9ꢀdimethyꢀ4,7ꢀdiphenylꢀ1,10ꢀphen instead of phen
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13c
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4,4ʹꢀdiꢀtert-butylꢀ2,2ʹꢀbipy instead of phen
No DBADH2
1.5 equiv piperidine
1.5 equiv K3PO4
No CuCl
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70
64
3
No 1,10ꢀphenanthroline
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(a) Loose cap vial refers to tightening cap ¼ turn when 1 turn is required for full closure; (b)
Assay yield (% wt/wt) determined by HPLC against a standard of 3a; (c) 10 mol% CuCl, phen
and DBADH2 (when present) were used;
Having identified effective conditions for an oxidative amidation of benzaldehyde and
piperidine that avoided the use of high pressure equipment or pure oxygen (Table 1, entry 1), we
turned our attention to the ultimate goal of starting directly from alcohols (Table 2). The
conditions optimized for amidation of benzaldehyde gave complete conversion of benzyl alcohol
to benzaldehyde, but significantly lower yield of 3a (Table 2, entry 1). Increasing the catalyst
loading from to 5 to 10 mol% provided a significant improvement in yield of 3a (entry 2). Given
the need for 2 equivalents of K3PO4 in the amide formation from benzaldehyde, it was postulated
that additional base was required now that two sequential oxidations were occurring. The use of
3 equivalents K3PO4 at 5 mol% catalyst loading also provided an improved yield (entry 3), but a
further increase to four equivalents provided no additional improvement (entry 4). The highest
yield of 3a was achieved by using 10 mol% catalyst and 3 equivalents K3PO4 (entry 5),
providing similar yield to that observed for aldehyde to amide oxidation (Table 1, entry 1).
Table 2. Optimization of Oxidative Amidation from Alcohol Oxidation State
Catalyst
Entry Loading (mol%)b (equiv) Solvent
Toluene
K3PO4
Yield (3a)c
1
5
2
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Toluene
Toluene
Toluene
Toluene
1,4ꢀdioxane
DMF
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2ꢀMeꢀTHF
DME
(a) Loose cap vial refers to tightening cap ¼ turn when 1 turn is required for full closure; (b)
Catalyst loading refers to loading of CuCl, 1,10ꢀphenanthroline, and DBADH2 unless otherwise
stated (c) Assay yield (% wt/wt) determined by HPLC with a product standard (d) Cu(phen)Cl2
and DBADH2;
Based on the similar performance of CuCl2 and CuCl in earlier optimization (Table 1), the
commercially available (phen)CuCl2 complex was subjected to the optimized conditions; the
preꢀformed complex furnished 3a in 76% yield, comparable to the in situ generated catalyst
(Table 2, entries 5 and 6). Among the other solvents evaluated (Table 2, entries 7ꢀ10), 2ꢀ
methyltetrahydrofuran (2ꢀMeTHF) and 1,2ꢀdimethoxyethane (DME) were identified as viable
alternatives. However, toluene was chosen for examination of the substrate scope due to its more
favorable safety profile (vs. DME) and higher boiling point (vs. 2ꢀMeTHF).69ꢀ71
Using the optimized conditions for the oxidative amidation of benzyl alcohol, the scope of
substituted benzylic alcohols was explored (Table 3). A variety of ortho-, meta-, and paraꢀ
substituted benzyl alcohols with diverse electronic character were wellꢀtolerated, providing the
corresponding amides (3bꢀ3o) in synthetically useful yields. In general, the remaining mass
balance can be accounted for in unreacted aldehyde, although the corresponding carboxylic acids
were observed in some cases. Representative amounts of carboxylic acid formed (3ꢀ13%) are
provided for entries 1, 9, and 11 in which carboxylic acid was extracted from the crude reaction
precipitate. In the case of 3ꢀbromobenzyl alcohol (Table 3, entry 5) 20% (by HPLC) of Nꢀ
arylation at the bromide of 3ꢀbromobenzaldehyde was observed, resulting in lower yield of 3h.
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Furthermore, a methyl ester was susceptible to hydrolysis under the current conditions resulting
in formation of 4ꢀformylbenzoic acid as a major side product (Table 3, entry 8).
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Table 3. Alcohol Substrate Scope with Piperidine
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entry
1
2
3a
3be
4a
4be
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8
9
Ar
Ph
Amide ArCHO Conv. (%)b Yieldc
96
91
71
84
42
67
76
94
72g
93
96
95
76
97
81
83d
76
3a
3b
3c
2ꢀClꢀC6H4
2ꢀNO2ꢀC6H4
43
50
3ꢀCF3ꢀC6H4
NDf
57
3d
3ꢀBrꢀC6H4
55
81
66
3e
3f
3g
3h
3i
3j
3k
3l
3ꢀMeꢀC6H4
3ꢀNMe2ꢀC6H4
4ꢀCO2MeꢀC6H4
4ꢀClꢀC6H4
51
76h
76
10
11
12
13
4ꢀFꢀC6H4
4ꢀOMeꢀC6H4
2ꢀNaphthyl
1ꢀNaphthyl
55i
83
81
3m
14
50
45
3n
3o
15a
24
70
NDf
54
15be
(a) Loose cap vial refers to tightening cap ¼ turn when 1 turn is required for full closure; (b) The
reaction progress was monitored by HPLC. Conversion refers to the ratio: [amide/(aldehyde +
amide)] based on peak area percent; In most cases, <1% alcohol remained as determined by
HPLC analysis; (c) Isolated yield following purification by column chromatography, unless
otherwise noted; (d) 8% PhCOOH extracted from crude precipitate; (e) K2CO3 as base; (f) Not
determined due to lower conversion observed by HPLC versus K2CO3 as base (g) 9% alcohol
and 19% aldehyde remained; (h) 13% 4ꢀClꢀC6H4COOH extracted from crude precipitate; (i) 3%
4ꢀMeOꢀ C6H4COOH extracted from crude precipitate.
Interestingly, several electronꢀdeficient benzyl alcohols in Table 4 gave low conversion to
amide despite achieving full oxidation of alcohol to aldehyde (entries 3a, 4a, and 15a). Because
electronꢀpoor aldehydes should form hemiaminals more readily, the lower yield of amide
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suggests the amide formation is not directly analogous to the corresponding aldehyde formation.
Because the base used is expected to impact hemiaminal formation, we reꢀexamined bases, and
found in contrast to our initial optimization, that switching to a weaker base such as K2CO3,
resulted in improved conversion and greater yield of amides 3c, 3d, and 3o.
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The results showing the amidation with electronꢀpoor alcohols was more efficient using
K2CO3, a weaker base, led us to investigate how the basicity of the amine would impact this
transformation. The coupling of morpholine (2b)72 with a variety of benzylic alcohols was
investigated (Table 4) and in the majority of cases, K2CO3 provided superior yields. Again,
exceptions were observed when the alcohols were more electronꢀrich (entry 4a vs 4b and 6a vs
6b), in which case switching to K3PO4 offered better reactivity. Collectively, these results
suggest an assessment to correlate the electronic nature of alcohol substrate and amine pKa is
required.
Table 4. Alcohol Substrate Scope with Morpholine
entry Ar
Amide ArCHO Conv. (%)b
Yieldc
84
1
3ꢀCF3ꢀC6H4
3ꢀNMe2ꢀC6H4
4ꢀClꢀC6H4
95
88
97
40
96
80
96
53
87
94
4a
4b
4c
2d
3a
3bd
4ad
4b
5
88
92
NDe
84
4ꢀOMeꢀC6H4
4ꢀSMeꢀC6H4
4d
65
91
53
4e
4f
6a
6bd
7
81
91f
4g
4h
8
73
65
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82f
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83f
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4j
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(a) Loose cap vial refers to tightening cap ¼ turn when 1 turn is required for full closure; (b) The
reaction progress was monitored by HPLC. Conversion refers to the ratio: [amide/(aldehyde +
amide)] based on peak area percent; In most cases, <1% alcohol remained as determined by
HPLC analysis; (c) Isolated yield unless otherwise noted; (d) K3PO4 as base; (e) Not determined
due to lower conversion observed by HPLC versus K2CO3 as base (f) Yield determined by
quantitative NMR; amide was not separated from phen by column chromatography.
Having noted the reactivity differences between morpholine and piperidine, we varied the
amine nucleophiles to elucidate the criteria for base selection. A variety of cyclic and acyclic
amines with pKa’s of the conjugate acid ranging from 6.5 to 1173 were subjected to the amidation
conditions (Table 5). Amines more acidic than morpholine (pKa = 8.97) gave excellent yields of
the corresponding benzamide products 5aꢀ5d when K2CO3 was used (entries 1ꢀ4). As the amine
pKa was increased, >90% conversion of aldehyde to amide was observed in most cases (entries
6a, 7a, and 9a) until the pKa approached 10.2 when the stronger base, K3PO4, became more
effective (entry 10b). By contrast, amines with pKa lower than 10.2 performed more poorly with
K3PO4 (Table 5, entry 7b vs 7a and Table 4, entry 3b vs 3a). Synthetically useful amide yields
were obtained with pyrrolidine and azepane (entries 12 and 15, respectively). Acyclic amines
gave poor to modest yields depending on amine pKa (Table 5, entries 9 and 14). A hindered
amine, (S)ꢀ2ꢀmethylpiperidine, provided only 16% yield of 5k with no racemization. A few
primary amines have been investigated under the current conditions and despite achieving full
oxidation of alcohol to aldehyde, little to no amide products were formed, likely due to facile
imine formation.68
Table 5. Scope of Amines and Reactivity Trends with 4ꢀChlorobenzyl Alcohol Based on
Predicted Amine pKa
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b
entry Amine
1
Predicted pKa
base
Amide ArCHO Conv. (%)c Yieldd
6.48
8.20
K2CO3
97
99
85
91
5a
5b
2
3
K2CO3
K2CO3
8.41
95
95e
5c
4
5
8.45
8.97
K2CO3
K2CO3
96
97
92
92f
5d
4c
6
9.12
K2CO3
96
96
5e
7a
7b
8a
8b
9a
9b
10a
10b
K2CO3
K3PO4
K2CO3
K3PO4
K2CO3
K3PO4
K2CO3
K3PO4
96
96g
49
69
90
92
72
97
93
76
32
59
90
83
64
82
9.62
9.77
9.78
10.20
5f
5g
5h
5i
11
12
10.45
10.50
K3PO4
K3PO4
96
78
76
65
3i
5j
13
10.63
K3PO4
46
16e
5k
14
15
11.03
11.24
K3PO4
K3PO4
65
85
32
51
5l
5m
(a) Loose cap vial refers to tightening cap ¼ turn when 1 turn is required for full closure; (b)
Predicted amine conjugate acid pKa from Scifinder®; calculated using Advanced Chemistry
Development (ACD/Labs) Software V11.02 (c) The reaction progress was monitored by HPLC.
Conversion refers to the ratio: [amide/(aldehyde + amide)] based on peak area percent; In most
cases, <1% alcohol remained as determined by HPLC analysis; (d) Isolated yield unless
otherwise noted; (e) amide obtained in 99.6% ee (f) Reaction performed on 35 mmol scale
provided identical yield (g) 13% carboxylic acid was observed.
The data for oxidative amidation of 4ꢀchlorobenzyl alcohol (Table 5) provides guidance for
selecting an inorganic base for a given secondary amine. When the conjugate ammonium pKa is
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<10.2, K2CO3 is likely to give the highest yields. By contrast, K3PO4 is optimal for amines with
ammonium pKa ≥10.2. The pKa range over which base selection changes will likely also depend
on electronics of the alcohol substrate.
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The mechanism proposed by Stahl and coworkers for alcohol oxidation to aldehyde with the
Cu/DBADH2/O2 system involves two interdependent catalytic cycles, one of which does not
require DBAD.53 Furthermore, one cycle relies on redox between Cu(I) and Cu(II) while Cu(II)
undergoes no formal oxidation state change in the other. In the presence of piperidine, benzyl
alcohol undergoes rapid oxidation to benzaldehyde prior to the formation of amide 3a,68
suggesting two distinct oxidation steps, alcohol to aldehyde followed by aldehyde to amide,
which allows for the independent study of each step. Given the significant levels of amide
formation from benzaldehyde observed in the absence of DBADH2 (Table 1, entry 12) we
postulate a bimodal mechanism for the amidation similar to the alcohol oxidation (Figure 1). The
first part of the catalytic cycle (Figure 1, left) begins with coordination of benzaldehyde to
copper providing complex I which can react with 2a to form II. Deprotonation forms Cuꢀbound
hemiaminal III which upon reaction with DBAD liberates benzamide 3a, DBADH2 and reforms
complex I. The resulting DBADH2 is reꢀoxidized in conjunction with two molecules of Cu(I) (V
to VI); these oxidations account for the net consumption of one molecule of oxygen, a four
electron oxidant. The second part of the catalytic cycle (Figure 1, right) begins with complex VI
coordinating to 1a forming intermediate VII which reacts with 2a to form intermediate III and
water. Following oxidation, III liberates benzamide 3a and two molecules of Cu(I) complex V.
A variety of results including control experiments with DBAD(H2), kinetic isotope effect, and a
Hammett study were found to be consistent with the proposed mechanism.
Figure 1. Proposed Mechanism for Oxidative Amidation of Benzaldehyde with Piperidine
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Oxygen serves as the terminal oxidant evidenced by trace formation of 3a under N2
atmosphere (<5 ppm O2, Table 6, entry 1). Also, nearly identical conversions were obtained
when the amidation was conducted with catalytic DBADH2 (Table 1, entry 1) or its oxidized
equivalent diꢀtertꢀbutyl azodicarboxylate, DBAD (Table 6, entry 2) under aerobic conditions,
suggesting an active redox interconversion between the two. The omission of DBAD or
DBADH2 results in lower conversion to 3a (Table 6, entry 12). Under a N2 atmosphere (<5 ppm
O2), 32% of benzamide 3a was formed with one equivalent of DBAD present (Table 6, entry 3),
while stoichiometric DBADH2 provided only trace conversion to product (entry 4) confirming
that DBAD does participate in the oxidation of the hemiaminal to amide. The stoichiometric
DBAD experiment was complicated due to a background reaction with 2a to form triazane 7
(Figure 1). The formation of 7 is reversible68 and the substitution of 7 for DBAD(H2) resulted in
similar yield of 3a (Table 6, entry 5).
Table 6. Control Experiments with DBADH2/DBAD
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Entry Atmosphere Additive (equiv) Yield (%)a
1
2
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5
N2
air
N2
N2
air
DBADH2 (0.1)
DBAD (0.1)
DBAD (1)
DBADH2 (1)
7 (0.1)
3
75
32
1
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(a) Assay yield (% wt/wt) as determined by HPLC against a standard of 3a.
The observation of a kinetic isotope effect (KIE) can provide useful information about the
bonds being broken or formed during the rateꢀdetermining step (RDS) of a reaction.74,75 An
experiment was performed to determine if a KIE could be observed with the aldehyde C−H(D)
(Scheme 2). By considering initial reaction rates, a kH/kD of 2.4 ± 0.2 was found. This primary
isotope effect is consistent with benzylic C−H bond cleavage in the RDS of amide formation.
Scheme 2. KIE Experiment for Cu/DBADH2 Oxidative Amidation
Having established the hemiaminal oxidation as the RDS, a Hammett study was performed to
further probe the nature of this step. Initial rates were measured for the reaction between
piperidine and a variety of benzaldehydes and it was found that electronꢀdeficient aldehydes
reacted more rapidly.76 From the resulting Hammett plot (Figure 2), the ρ value was +2.6,
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suggesting significant development of anionic character at the benzylic position during the
formal “oxidation” step. The ρ value is consistent with a deprotonation rather than hydrogen
atom or hydride abstraction, which might be expected for a Cuꢀcatalyzed benzylic oxidation
based on recent work by Stahl50 and Riisager,77 respectively. A RDS involving deprotonation is
consistent with the observation that with more basic amines, which will reduce the acidity of the
Cuꢀhemiaminal intermediate III, a stronger base like K3PO4 is necessary to achieve good yields
of amides. Furthermore, more electronꢀdeficient benzaldehydes will furnish a more acidic Cuꢀ
bound hemiaminal III, allowing the use of a weaker base (K2CO3) for deprotonation in the
formal “oxidation” step.
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Figure 2. Hammett Plot for Reaction of Piperidine with Electronically Varied Benzaldehydes
Effect of Substituent on Reaction Rate
0.6
0.4
p-F
0.2
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p-Cl
H
-0.3
-0.2
-0.1
0
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y = 2.6x - 0.1
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-0.4
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-0.8
-1
p-Me
p-OMe
-1.2
σp
In conclusion, a copperꢀcatalyzed oxidative amidation has been developed for the direct
conversion of benzylic alcohols to the corresponding tertiary benzamides with a variety of
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secondary amines. The new methodology utilizes a readily available nonꢀprecious metal catalyst
and oxygen in air as the terminal oxidant. The pKa of amine conjugate acid and electronics of
alcohol were shown to impact the selection of base for optimal reactivity. A primary KIE was
observed for the oxidative amidation which is consistent with benzylic C−H bond cleavage in the
rateꢀdetermining step. Furthermore, a Hammett study revealed the buildꢀup of anionic character
at the benzylic position, pointing to a deprotonation in the formal oxidation step. A catalytic
cycle consistent with observed reactivity trends and mechanistic experiments has been proposed.
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EXPERIMENTAL SECTION
General Information
Reagents were used as obtained from the vendor without further purification. HPLC grade
toluene, milled K3PO4 (29 ꢁm) and K2CO3 (44 ꢁm) were used unless otherwise stated.
Analytical thin layer chromatography (TLC) was performed utilizing preꢀcoated silica gel 60 F254
plates containing a fluorescent indicator. Flash chromatography was performed using an
automated fraction collector at 254 and 280 nm with preꢀpacked silica gel columns and
EtOAc/heptane mixtures. Loose cap vial refers to tightening cap ¼ turn when 1 turn is required
for full closure.
Routine NMR experiments were recorded at room temperature (unless otherwise stated) at 400,
1
600 or 700 MHz for H NMR and 100, 150 or 175 MHz for 13C NMR. Chemical shifts are
reported in partsꢀperꢀmillion (ppm) relative to residual solvent signal of CHCl3 (δ 7.26 ppm for
1H and δ 77.1 ppm for 13C) and scalar coupling constants are reported in hertz (Hz). Highꢀ
pressure liquid chromatography (HPLC) analyses were performed with a detector at 210 nm
using CH3CN/H2O mixtures as the mobile phase. Liquid chromatography mass spectrometry
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(LCMS) was performed at 210 nm using a quadrapole APCI mass detector. Accurate mass
measurements were acquired using a QꢀTOF mass analyzer. Melting points were obtained using
a benchtop melting point apparatus equipped with digital thermometer.
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Unless otherwise stated, all reactions were performed on 1 mmol scale
General Procedure A (GP-A)
To a 1 dram vial equipped with cross stir bar was added dichloro(1,10ꢀphenanthroline)copper(II)
(31 mg, 0.1 mmol, 10 mol%), K3PO4 (637 mg, 3 equiv, 3.0 mmol), diꢀtertꢀbutyl hydrazine 1,3ꢀ
dicarboxylate (23 mg, 0.1 mmol, 10 mol%), toluene (2.0 mL, 0.5 M), alcohol (1.0 mmol, 1
equiv), and amine (2.0 mmol, 2 equiv). The cap was loosely placed on the vial, and the mixture
was heated to 75 °C with stirring at 1000 rpm. After stirring for the indicated time, the reaction
was cooled to room temperature, diluted with ethyl acetate (2 mL) and filtered through a
polyethylene fritted funnel. The precipitate was washed with ethyl acetate (10 mL). The
combined filtrate was concentrated on a rotary evaporator and purified by flash chromatography
on silica gel with the indicated solvent system.
General Procedure B (GP-B)
To a 1 dram vial equipped with cross stir bar was added dichloro(1,10ꢀphenanthroline)copper(II)
(31 mg, 0.1 mmol, 10 mol%), K2CO3 (415 mg, 3 equiv, 3.0 mmol), diꢀtertꢀbutyl hydrazine 1,3ꢀ
dicarboxylate (23 mg, 0.1 mmol, 10 mol%), toluene (2.0 mL, 0.5 M), alcohol (1.0 mmol, 1
equiv), and amine (2.0 mmol, 2 equiv). The cap was loosely placed on the vial, and the mixture
was heated to 75 °C with stirring at 1000 rpm. After stirring for the indicated time, the reaction
was cooled to room temperature, diluted with ethyl acetate (2 mL) and filtered through a
polyethylene fritted funnel. The precipitate was washed with ethyl acetate (10 mL). The
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combined filtrate was concentrated on a rotary evaporator and purified by flash chromatography
on silica gel with the indicated solvent system.
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Phenyl(piperidin-1-yl)methanone 3a. Following GPꢀA, 3a (156 mg, 0.83 mmol, 83%
yield) was prepared in 20 h and isolated as a colorless oil by flash chromatography on silica gel
(4 g column, 10% EtOAc for 4 CV, then 10ꢀ60% EtOAc over 11 CV). Analytical data for 3a was
consistent with that previously reported.59 1H NMR (400 MHz, CDCl3): δ 7.75 – 7.31 (m, 4H),
3.89 (s, 2H), 3.52 (s, 2H), 1.96ꢀ1.56 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 170.4, 136.6,
129.4, 128.5, 126.9, 48.8, 43.2, 26.6, 25.7, 24.7; LCMS (APCI): Calculated for [M+H]+
C12H16NO: 190.12, Found: 190.20.
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2-Chlorophenyl(piperidin-1-yl)methanone 3b. Following GPꢀA, 3b (170 mg, 0.76 mmol,
76% yield) was prepared in 21 h and isolated as a colorless oil by flash chromatography on silica
gel (4 g column, 20% EtOAc for 4 CV, then 20ꢀ40% EtOAc over 12 CV). Analytical data for 3b
was consistent with that previously reported.78 1H NMR (400 MHz, CDCl3): δ 7.65 – 6.84 (m,
13
4H), 3.98 – 3.50 (m, 2H), 3.39 – 3.00 (m, 2H), 1.75 – 1.53 (m, 5H), 1.50 – 1.39 (m, 1H); C
NMR (100 MHz, CDCl3) δ 166.8, 136.5, 130.4, 129.9, 129.6, 127.6, 127.1, 47.9, 42.6, 26.4,
25.6, 24.5; LCMS (APCI): Calculated for [M+H]+ C12H14ClNO: 224.08, Found: 224.10.
2-Nitrophenyl(piperidin-1-yl)methanone 3c. Following GPꢀB, 3c (117.5 mg, 0.50 mmol,
50% yield) was prepared in 20 h and isolated as a pale orange oil by flash chromatography on
silica gel (4 g column, 20% EtOAc for 4 CV, then 20ꢀ40% EtOAc over 12 CV). Analytical data
for 3c was consistent with that previously reported.79 1H NMR (400 MHz, CDCl3): δ 8.18 (dd, J
= 8.4, 1.2 Hz, 1H), 7.69 (td, J = 7.5, 1.2 Hz, 1H), 7.55 (ddd, J = 8.3, 7.5, 1.5 Hz, 1H), 7.38 (dd, J
= 7.6, 1.5 Hz, 1H), 3.84 – 3.67 (m, 2H), 3.16 (t, J = 5.6 Hz, 2H), 1.83 – 1.30 (m, 6H). 13C NMR
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(100 MHz, CDCl3) δ 166.3, 145.2, 134.5, 133.4, 129.6, 128.0, 124.7, 48.0, 42.7, 25.8, 25.2, 24.5;
LCMS (APCI): Calculated for [M+H]+ C12H15N2O3: 235.11, Found: 235.10.
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3-Trifluoromethylphenyl(piperidin-1-yl)methanone 3d. Following GPꢀB, 3d (146 mg,
0.57 mmol, 57% yield) was prepared in 24 h and isolated as a pale yellow oil by flash
chromatography on silica gel (4 g column, 10% EtOAc for 10 CV, then 10ꢀ80% EtOAc over 10
CV). Analytical data for 3d was consistent with that previously reported.80 1H NMR (400 MHz,
CDCl3): δ 7.67 – 7.56 (m, 2H), 7.56 – 7.43 (m, 2H), 3.65 (s, 2H), 3.25 (s, 2H), 1.85 – 1.18 (m,
6H). 13C NMR (100 MHz, CDCl3) δ 168.6, 137.3, 130.9 (q, J = 32.5 Hz), 130.1, 129.0, 126.1 (d,
J = 16 Hz), 123.8 (d, J = 16 Hz), 123.7 (q, J = 272.6 Hz), 48.7, 43.2, 26.4, 25.5, 24.4; LCMS
(APCI): Calculated for [M+H]+ C13H15F3NO: 258.11, Found: 258.30.
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3-Bromophenyl(piperidin-1-yl)methanone 3e. Following GPꢀA, 3e (148 mg, 0.55 mmol,
55% yield) was prepared in 21 h and isolated as white solid by flash chromatography on silica
gel (4 g column, 20% EtOAc for 11 CV, then 20ꢀ60% EtOAc over 7 CV). Analytical data for 3e
was consistent with that previously reported.81 1H NMR (400 MHz, CDCl3): δ 7.60 – 7.42 (m,
2H), 7.35 – 7.11 (m, 2H), 3.73 – 3.62 (m, 2H), 3.30 (s, 2H), 1.83 – 1.34 (m, 6H). 13C NMR (100
MHz, CDCl3) δ 168.5, 138.5, 132.4, 130.1, 129.9, 125.3, 122.6, 48.7, 43.2, 26.5, 25.6, 24.5;
LCMS (APCI): Calculated for [M+H]+ C12H15BrNO: 268.03, Found: 268.05.
3-Methylphenyl(piperidin-1-yl)methanone 3f. Following GPꢀA, 3f (165 mg, 0.81 mmol,
81% yield) was prepared in 21 h and isolated as a colorless oil by flash chromatography on silica
gel (4 g column, 20% EtOAc for 4 CV, then 20ꢀ40% EtOAc over 15 CV). Analytical data for 3f
was consistent with that previously reported.59 1H NMR (400 MHz, CDCl3): 7.20 (m, 1H), 7.16
– 7.06 (m, 3H), 3.64 (s, 2H), 3.27 (s, 2H), 2.30 (s, 3H), 1.66 – 1.40 (m, 6H). 13C NMR (100
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MHz, CDCl3) δ 170.3, 138.1, 136.4, 129.9, 128.1, 127.3, 123.5, 48.6, 42.9, 26.4, 25.5, 24.5,
21.3; LCMS (APCI): Calculated for [M+H]+ C13H18NO: 204.14, Found: 204.10.
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3-(Dimethylamino)phenyl(piperidin-1-yl)methanone 3g. Following GPꢀA, 3g (154 mg,
0.66 mmol, 66% yield) was prepared in 24 h and isolated as viscous, pale yellow oil by flash
chromatography on silica gel (4 g column, 20% EtOAc for 10 CV, then 20ꢀ80% EtOAc over 20
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CV). H NMR (400 MHz, CDCl3): δ 7.19 (td, J = 7.4, 1.4 Hz, 1H), 6.70 (dd, J = 7.3, 1.1 Hz,
2H), 6.65 (dd, J = 7.4, 1.2 Hz, 1H), 3.67 (s, 2H), 3.32 (s, 2H), 2.92 (s, 6H), 1.71 – 1.40 (m, 6H).
13C NMR (100 MHz, CDCl3) δ 171.0, 150.5, 137.3, 129.0, 114.4, 113.2, 110.6, 48.7, 43.0, 40.5,
26.6, 25.7, 24.6.; TLC (40% EtOAc/heptanes) Rf : 0.14; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+
Calculated for C14H21N2O 233.1648; Found 233.1649.
Methyl 4-(piperidine-1-carbonyl)benzoate 3h. Following GPꢀA, 3h (125 mg, 0.51 mmol,
51% yield) was prepared in 8 h and isolated as a pale yellow oil by flash chromatography on
silica gel (4 g column, 10% EtOAc for 8 CV, then 20ꢀ60% EtOAc over 28 CV). Analytical data
for 3h was consistent with that previously reported.59 1H NMR (400 MHz, CDCl3): δ 8.07 –
8.00 (m, 2H), 7.45 – 7.38 (m, 2H), 3.89 (s, 3H), 3.68 (s, 2H), 3.25 (s, 2H), 1.56 (m, 6H). 13C
NMR (100 MHz, CDCl3) δ 169.2, 166.4, 140.9, 130.9, 129.8, 126.8, 52.3, 48.7, 43.1, 26.5, 25.6,
24.5; LCMS (APCI): Calculated for [M+H]+ C14H18NO3: 248.13, Found: 248.15.
3-Chlorophenyl(piperidin-1-yl)methanone 3i. Following GPꢀA, 3i (171 mg, 0.76 mmol,
76% yield) was prepared in 18 h and isolated as a white solid by flash chromatography on silica
gel (4 g column, 20% EtOAc for 8 CV, then 20ꢀ80% EtOAc over 20 CV). Analytical data for 3i
was consistent with that previously reported.78 1H NMR (400 MHz, CDCl3): δ 7.37 – 7.28 (m,
4H), 3.66 (s, 2H), 3.30 (s, 2H), 1.97 – 1.33 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 169.3,
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135.4, 134.9, 128.7, 128.4, 48.8, 43.3, 26.6, 25.7, 24.6; LCMS (APCI): Calculated for [M+H]+
C12H15ClNO: 224.08, Found: 224.10.
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4-Fluorophenyl(piperidin-1-yl)methanone 3j. Following GPꢀA, 3j (171 mg, 0.76 mmol,
76% yield) was prepared 20 h and isolated as a colorless oil by flash chromatography on silica
gel (4 g column, 20% EtOAc for 8 CV, then 20ꢀ80% EtOAc over 20 CV). Analytical data for 3j
was consistent with that previously reported.59 1H NMR (400 MHz, CDCl3): δ 7.40 – 7.32 (m,
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2H), 7.09 – 6.98 (m, 2H), 3.64 (s, 2H), 3.31 (s, 2H), 1.73 – 1.40 (m, 6H). C NMR (100 MHz,
CDCl3) δ 169.4 , 163.2 (d, J = 249.1 Hz), 132.5 , 129.1 (d, J = 8.4 Hz), 115.4 (d, J = 21.8 Hz),
48.8 , 43.3 , 26.5 , 25.7 , 24.6; LCMS (APCI): Calculated for [M+H]+ C12H15FNO: 208.11,
Found: 208.10.
4-Methoxyphenyl(piperidin-1-yl)methanone 3k. Following GPꢀA, 3k (120 mg, 0.55
mmol, 55% yield) was prepared in 27 h and isolated as a pale yellow solid by flash
chromatography on silica gel (4 g column, 20% EtOAc for 8 CV, then 20ꢀ80% EtOAc over 20
CV). Analytical data for 3k was consistent with that previously reported.59 1H NMR (400 MHz,
CDCl3): δ 7.33 (dd, J = 8.8, 1.1 Hz, 1H), 6.86 (dd, J = 8.8, 1.1 Hz, 1H), 3.78 (s, 3H), 3.54 (m,
4H), 1.73 – 1.41 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 170.3, 160.5, 128.8, 128.6, 113.6,
55.3, 48.9, 43.5, 26.1, 24.7; LCMS (APCI): Calculated for [M+H]+ C13H18NO2: 220.13, Found:
220.30.
Naphthalen-2-yl(piperidin-1-yl)methanone 3l. Following GPꢀA, 3l (198 mg, 0.83 mmol,
83% yield) was prepared in 21 h and isolated as a white solid by flash chromatography on silica
gel (4 g column, 20% EtOAc for 4 CV, then 20ꢀ35% EtOAc over 13 CV). Analytical data for 3l
was consistent with that previously reported.59 1H NMR (400 MHz, CDCl3): δ 7.91 – 7.77 (m,
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4H), 7.54 – 7.43 (m, 3H), 3.74 (s, 2H), 3.37 (s, 2H), 1.87 – 1.30 (m, 6H). C NMR (100 MHz,
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CDCl3) δ133.9, 133.5, 132.8, 128.4, 128.2, 127.8, 127.8, 126.9, 126.6, 126.5, 124.3, 48.8, 43.2,
26.5, 25.7, 24.6; LCMS (APCI): Calculated for [M+H]+ C16H18NO: 240.14, Found: 240.30.
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Naphthalen-1-yl(piperidin-1-yl)methanone 3m. Following GPꢀA, 3m (197 mg, 0.82
mmol, 82% yield) was prepared in 18 h and isolated as a white solid by flash chromatography on
silica gel (4 g column, 5% EtOAc for 15 CV, then 5ꢀ70% EtOAc over 20 CV). Analytical data
for 3m was consistent with that previously reported.82 1H NMR (400 MHz, CDCl3): δ 7.87 –
7.79 (m, 3H), 7.54 – 7.42 (m, 3H), 7.38 (m, 1H), 3.86 (m, 2H), 3.11 (m, 2H), 1.81 – 1.58 (m,
4H), 1.37 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 169.2, 134.9, 133.5, 129.6, 128.8, 128.3,
126.8, 126.3, 125.2, 124.9, 123.4, 48.3, 42.6, 26.7, 25.8, 24.5; LCMS (APCI): Calculated for
[M+H]+ C16H18NO: 240.14, Found: 240.20.
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(2-(Allyloxy)phenyl)(piperidin-1-yl)methanone 3n. Following GPꢀA, 3n (110 mg, 0.45
mmol, 45% yield) was prepared in 19 h and isolated as a colorless oil by flash chromatography
on silica gel (4 g column, 5% EtOAc for 6 CV, then 5ꢀ80% EtOAc over 15 CV). 1H NMR (400
MHz, CDCl3): δ 7.32 – 7.23 (m, 1H), 7.21 (dd, J = 7.4, 1.7 Hz, 1H), 6.95 (td, J = 7.5, 1.0 Hz,
1H), 6.86 (dd, J = 8.4, 0.9 Hz, 1H), 6.08 – 5.91 (m, 1H), 5.36 (dq, J = 17.2, 1.7 Hz, 1H), 5.23
(dq, J = 10.6, 1.4 Hz, 1H), 4.54 (ddt, J = 5.5, 3.1, 1.6 Hz, 2H), 3.81 – 3.61 (m, 2H), 3.17 (qdt, J =
10.7, 6.7, 3.8 Hz, 2H), 1.71 – 1.35 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 167.6, 154.3, 133.1,
130.0, 127.9, 127.0, 121.2, 117.2, 112.3, 69.0, 48.0, 42.6, 26.4, 25.7, 24.7; TLC (40%
EtOAc/heptanes) Rf : 0.23; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for C15H20NO2
246.1489; Found 246.1491.
Piperidin-1-yl(quinolin-6-yl)methanone 3o. Following GPꢀA, 3o (129 mg, 0.54 mmol,
54% yield) was prepared in 19 h and isolated as a pale yellow oil by flash chromatography on
silica gel (4 g column, 20% EtOAc for 15 CV, then 20ꢀ50% EtOAc over 3 CV, hold 50% EtOAc
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for 15 CV). H NMR (400 MHz, CDCl3): δ 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.16 (ddd, J = 8.4,
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1.9, 0.9 Hz, 1H), 8.13 – 8.07 (m, 1H), 7.90 – 7.83 (m, 1H), 7.69 (dd, J = 8.7, 1.9 Hz, 1H), 7.42
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(dd, J = 8.3, 4.3 Hz, 1H), 3.74 (s, 2H), 3.36 (s, 2H), 1.75 – 1.44 (m, 6H). C NMR (100 MHz,
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CDCl3) δ 169.6, 151.4, 148.4, 136.5, 134.8, 129.9, 127.9, 126.6, 121.8, 48.9, 43.4, 26.7, 25.7,
24.6; TLC (90% EtOAc/heptanes) Rf : 0.14; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for
C15H17N2O 241.1335; Found 241.1335.
Morpholino(3-(trifluoromethyl)phenyl)methanone 4a. Following GPꢀB, 4a (218 mg, 0.84
mmol, 84% yield) was prepared in 22 h and isolated as a white solid by flash chromatography on
silica gel (4 g column, 10% EtOAc for 10 CV, then 10ꢀ80% EtOAc over 10 CV). Analytical data
for 4a was consistent with that previously reported.80 1H NMR (400 MHz, CDCl3): δ 7.65 (m,
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2H), 7.58 – 7.48 (m, 2H), 3.96 – 3.15 (m, 8H). C NMR (100 MHz, CDCl3) δ 168.8 , 136.2 ,
131.2 (q, J = 32.9 Hz), 130.4 , 129.2 , 126.6 (d, J = 3.7 Hz), 124.2 (d, J = 4.0 Hz), 123.7 (q, J =
272.6 Hz), 66.8 , 48.2 , 42.7; LCMS (APCI): Calculated for [M+H]+ C12H13F3NO2: 260.09,
Found: 260.10.
(3-(Dimethylamino)phenyl)(morpholino)methanone 4b. Following GPꢀA, 4b (206 mg,
0.88 mmol, 88% yield) was prepared in 24 h and isolated as a viscous, pale yellow oil by flash
chromatography on silica gel (4 g column, 20% EtOAc for 10 CV, then 10ꢀ80% EtOAc over 20
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CV). H NMR (400 MHz, CDCl3): δ 7.25 – 7.20 (m, 1H), 6.83 – 6.61 (m, 3H), 3.96 – 3.30 (m,
8H), 2.96 (s, 3H). 13C NMR (100 MHz, CDCl3) δ169.7, 150.2, 136.4, 128.9, 114.1, 114.0, 113.1,
110.3, 66.1, 47.6, 41.9, 39.1; TLC (40% EtOAc/heptanes) Rf : 0.09; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ Calculated for C13H19N2O2 235.1441; Found 235.1443.
(4-chlorophenyl)(morpholino)methanone 4c. Following GPꢀB, 4c (208 mg, 0.92 mmol,
92% yield) was prepared in 21 h and isolated as a white solid by flash chromatography on silica
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gel (4 g column, 20% EtOAc for 12 CV, then 20ꢀ80% EtOAc over 23 CV). Analytical data for
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4c was consistent with that previously reported.83 1H NMR (400 MHz, CDCl3): δ 7.42 – 7.27 (m,
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4H), 3.89ꢀ3.15 (m, 8H). C NMR (100 MHz, CDCl3) δ 169.3, 136.0, 133.7, 128.9, 128.7, 66.8,
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48.2, 42.7; LCMS (APCI): Calculated for [M+H]+ C11H13ClNO2: 226.06, Found: 226.20.
(4-Methoxyphenyl)(morpholino)methanone 4d. Following GPꢀA, 4d (187 mg, 0.84
mmol, 84% yield) was prepared in 18 h and isolated as a colorless oil by flash chromatography
on silica gel (4 g column, 20% EtOAc for 12 CV, then 20ꢀ80% EtOAc over 23 CV). Analytical
data for 4d was consistent with that previously reported.83 1H NMR (400 MHz, CDCl3): δ 7.38 –
7.31 (m, 2H), 6.90 – 6.84 (m, 2H), 3.78 (s, 3H), 3.66ꢀ3.58 (m, 8H). 13C NMR (100 MHz,
CDCl3) δ 170.4, 160.9, 129.2, 127.3, 113.8, 66.9, 55.3, 48.1, 43.4; LCMS (APCI): Calculated for
[M+H]+ C12H16NO3: 222.11, Found: 222.20.
(4-(Methylthio)phenyl)(morpholino)methanone 4e. Following GPꢀB, 4e (215 mg, 0.91
mmol, 91% yield) was prepared in 24 h and isolated as a white solid by flash chromatography on
silica gel (4 g column, 20% EtOAc for 12 CV, then 20ꢀ80% EtOAc over 15 CV, hold at 80%
EtOAc for 10 CV). Analytical data for 4e was consistent with that previously reported.84 1H
NMR (400 MHz, CDCl3): δ 7.39 – 7.34 (m, 2H), 7.30 – 7.25 (m, 2H), 3.90ꢀ3.45 (m, 8H), 2.52
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.0, 141.4, 131.5, 127.8, 125.8, 66.9, 48.1, 42.7, 15.3;
LCMS (APCI): Calculated for [M+H]+ C12H16NO2S: 238.09, Found: 238.10.
(2-(allyloxy)phenyl)(morpholino)methanone 4f. Following GPꢀA, 4f (200 mg, 0.81
mmol, 81% yield) was prepared in 18 h and isolated as a colorless oil by flash chromatography
on silica gel (4 g column, 5% EtOAc for 7 CV, then 5ꢀ80% EtOAc over 13 CV, hold at 80%
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EtOAc for 10 CV). H NMR (400 MHz, CDCl3): δ 7.33 (dddd, J = 8.4, 7.4, 1.8, 0.9 Hz, 1H),
7.30 – 7.23 (m, 1H), 7.00 (tt, J = 7.5, 1.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.02 (ddtd, J = 16.7,
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10.4, 5.1, 0.9 Hz, 1H), 5.45 – 5.23 (m, 2H), 4.57 (m, 2H), 3.90 – 3.71 (m, 4H), 3.70 – 3.52 (m,
2H), 3.40 – 3.10 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 167.9, 154.3, 132.8, 130.6, 128.4,
125.8, 121.4, 117.8, 112.3, 69.2, 67.0, 66.9, 47.3, 42.2; TLC (40% EtOAc/heptanes) Rf : 0.14;
HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for C14H18NO3 248.1281; Found 248.1280.
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Morpholino(quinolin-6-yl)methanone 4g. Following GPꢀB, 4g was prepared in 18 h and
purified by flash chromatography on silica gel (4 g column, 60% EtOAc for 12 CV, then 60ꢀ
100% EtOAc over 18 CV, hold 100% EtOAc for 10 CV). The material isolated from the column
(230 mg) was analyzed by QꢀNMR and shown to contain 4 wt% 1,10ꢀphenanthroine. Yield of 4g
(220 mg, 0.91 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): δ 8.93 (dd, J = 4.2, 1.8 Hz, 1H),
8.18 – 8.09 (m, 2H), 7.88 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 8.6, 1.9 Hz, 1H), 7.42 (dd, J = 8.3,
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4.2 Hz, 1H), 4.06 – 3.25 (m, 8H). C NMR (100 MHz, CDCl3) δ 169.7, 151.7, 148.4, 136.5,
133.5, 130.1, 127.8, 127.8, 127.1, 122.0, 121.9, 66.9, 48.3, 42.7; TLC (85% EtOAc, 14%
heptanes, 1% Et3N) Rf : 0.12; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for C14H15N2O2
243.1128; Found 243.1133.
Morpholino(pyridin-2-yl)methanone 4h. Following GPꢀB, 4h (124 mg, 0.65 mmol, 65%
yield) was prepared in 24 h and purified by flash chromatography on silica gel (4 g column,
heptanes contained 5% Et3N, 30% EtOAc for 10 CV, then 30ꢀ50% EtOAc over 16 CV).
Analytical data for 4h was consistent with that previously reported.85 1H NMR (400 MHz,
CDCl3): δ 8.50 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.73 (td, J = 7.7, 1.7 Hz, 1H), 7.59 (dt, J = 7.8,
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1.1 Hz, 1H), 7.27 (ddd, J = 7.6, 4.9, 1.3 Hz, 1H), 3.82ꢀ3.65 (m, 4H), 3.64 – 3.52 (m, 4H). C
NMR (100 MHz, CDCl3) δ 167.4, 153.6, 148.2, 137.1, 124.6, 124.1, 67.0, 66.7, 47.7, 42.7;
LCMS (APCI): Calculated for [M+H]+ C10H13N2O2: 193.10, Found: 193.10.
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Morpholino(pyridin-3-yl)methanone 4i. Following GPꢀB, 4i was prepared in 18 h and
purified by flash chromatography on silica gel (4 g column, heptanes contained 5% Et3N, 20%
EtOAc for 5 CV, then 20ꢀ80% EtOAc over 15 CV, hold 80% EtOAc for 20 CV). The material
isolated from the column (168 mg) was analyzed by QꢀNMR and shown to contain 6 wt% 1,10ꢀ
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phenanthroline. Yield of 4i (158 mg, 0.82 mmol, 82% yield). H NMR (400 MHz, CDCl3): δ
8.69 – 8.64 (m, 2H), 7.76 (dt, J = 7.8, 2.0 Hz, 1H), 7.37 (ddd, J = 7.9, 4.9, 1.0 Hz, 1H), 4.11 –
3.11 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 167.8, 151.0, 148.0, 135.1, 131.2, 123.6, 66.8,
48.2, 42.7; TLC (85% EtOAc, 14% heptanes, 1% Et3N) Rf : 0.11; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ Calculated for C10H13N2O2: 193.0972; Found 193.0971.
Morpholino(pyridin-4-yl)methanone 4j. Following GPꢀB, 4j was prepared in 24 h and
purified by flash chromatography on silica gel (4 g column, heptanes contained 5% Et3N, 30%
EtOAc for 10 CV, then 30ꢀ90% EtOAc over 15 CV, hold 90% EtOAc for 10 CV). The material
isolated from the column (167 mg) was analyzed by QꢀNMR and shown to contain 5 wt% 1,10ꢀ
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phenanthroline. Yield of 4j (159 mg, 0.83 mmol, 83% yield). H NMR (400 MHz, CDCl3): δ
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8.74 – 8.66 (m, 2H), 7.32 – 7.22 (m, 2H), 3.79 (br s, 4H), 3.62 (s, 2H), 3.37 (s, 2H). C NMR
(100 MHz, CDCl3) δ 167.7, 150.3, 142.9, 121.2, 66.7, 47.8, 42.3; TLC (85% EtOAc, 14%
heptanes, 1% Et3N) Rf : 0.10; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for C10H13N2O2:
193.0972; Found 193.0970.
Morpholino(thiophen-2-yl)methanone 4k. Following GPꢀB, 4k (215 mg, 0.91 mmol, 91%
yield) was prepared in 24 h and isolated as a pale yellow oil by flash chromatography on silica
gel (4 g column, 20% EtOAc for 12 CV, then 20ꢀ80% EtOAc over 15 CV, hold at 80% EtOAc
for 10 CV). Analytical data for 4k was consistent with that previously reported.83 1H NMR (400
MHz, CDCl3): δ 7.49 (dd, J = 3.0, 1.3 Hz, 1H), 7.31 (dd, J = 5.0, 2.9 Hz, 1H), 7.14 (dd, J = 5.0,
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1.3 Hz, 1H), 3.86ꢀ3.30 (s, 8H). 13C NMR (100 MHz, CDCl3) δ 165.8, 135.9, 127.0, 126.7, 126.2,
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66.9, 47.8, 42.9; LCMS (APCI): Calculated for [M+H]+ C9H12NO2S: 198.06, Found: 198.10.
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(4-Chlorophenyl)(1,1-dioxidothiomorpholino)methanone 5a. Following GPꢀB, 5a (233
mg, 0.85 mmol, 85% yield) was prepared in 20 h and isolated as a white solid by flash
chromatography on silica gel (4 g column, 20% EtOAc for 10 CV, then 20ꢀ80% EtOAc over 20
CV). 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 4.08 (s,
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4H), 3.06 (s, 4H). C NMR (100 MHz, CDCl3) δ 170.0, 137.0, 132.4, 129.3, 128.6, 52.0, 45.9,
41.2; m.p. 163ꢀ165 °C; TLC (40% EtOAc/heptanes) Rf : 0.13; LCMS (APCI): Calculated for
[M+H]+ C11H13ClNO3S: 274.03, Found: 274.10. We were unable to obtain an accurate mass
measurement for compound 5a because it did not ionize with ESI. Elemental Analysis (average
of 4 runs): Calculated for C11H12ClNO3S: C, 48.27; H, 4.42; N, 5.12. Found: C, 48.53; H, 4.40;
N, 5.00.
(4-Chlorophenyl)(4,4-difluoropiperidin-1-yl)methanone 5b. Following GPꢀB, 5b (237
mg, 0.91 mmol, 91% yield) was prepared in 21 h and isolated as a white solid by flash
chromatography on silica gel (4 g column, 5% EtOAc for 10 CV, then 10ꢀ50% EtOAc over 20
CV). 1H NMR (400 MHz, CDCl3): δ 7.40 – 7.30 (m, 4H), 3.90ꢀ3.41 (m, 4H), 2.14ꢀ1.84 (m, 4H).
13C NMR (100 MHz, CDCl3) δ 169.5 , 136.2 , 133.6 , 129.0 , 128.5 , 121.4 (t, J = 242.3 Hz),
44.4 , 39.3 , 34.1; m.p. 69ꢀ71 °C; TLC (40% EtOAc/heptanes) Rf :0.43; HRMS (ESIꢀQꢀTOF)
m/z: [M+H]+ Calculated for C12H13ClF2NO 260.0648; Found 260.0641.
tert-Butyl (R)-4-(4-chlorobenzoyl)-2-isopropylpiperazine-1-carboxylate 5c. Following
GPꢀB, 5c (349 mg, 0.95 mmol, 95% yield) was prepared in 18 h and isolated as a viscous,
colorless oil by flash chromatography on silica gel (4 g column, 5% EtOAc for 15 CV, then 5ꢀ
40% EtOAc over 20 CV). Chiral purity (99.6 %ee) was measured by HPLC with a ChiralPak IC
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250 x 4.6 mm column (80:20 hexanes:ethanol, 25 min, 1.0 mL/min, 210 nm). H NMR (600
MHz, DMSOꢀD6, 90 °C): δ 7.49 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.14 (br s, 1H),
3.90ꢀ3.83 (m, 2H), 3.76 – 3.60 (m, 1H), 3.12 – 2.96 (m, 2H), 2.90 (ddd, J = 13.4, 12.1, 3.6 Hz,
1H), 1.95 (dq, J = 10.3, 6.6 Hz, 1H), 1.43 (s, 9H), 0.82 (d, J = 6.8 Hz, 6H).13C NMR (150 MHz,
DMSOꢀD6, 90 °C) δ 168.2, 153.6, 134.2, 133.8, 128.3, 127.9, 78.6, 56.6, 38.2, 27.6, 25.3, 19.2,
17.9; TLC (40% EtOAc/heptanes) Rf : 0.36; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ – [C5H8O2]
Calculated for C14H20ClN2O 267.1259; Found 267.1255. HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ –
[C4H8] Calculated for C15H20ClN2O3 311.1157; Found 311.1153.
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tert-Butyl 4-(4-chlorobenzoyl)piperazine-1-carboxylate 5d. Following GPꢀB, 5d (298
mg, 0.92 mmol, 92% yield) was prepared in 19 h and isolated as a white solid by flash
chromatography on silica gel (4 g column, 10% EtOAc for 10 CV, then 10ꢀ80% EtOAc over 20
CV). Analytical data for 5d was consistent with that previously reported.86 1H NMR (700 MHz,
CDCl3): δ 7.33 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 3.65 (br s, 2H), 3.48 – 3.26 (m, 4H),
1.40 (s, 9H). 13C NMR (175 MHz, CDCl3) δ 169.4, 154.4, 135.9, 133.8, 128.8, 128.6, 80.3, 47.5,
43.8, 43.4, 42.1, 28.3; LCMS (APCI, acidic mobile phase): Calculated for [M+2HꢀtBu]+
C12H14ClN2O3: 269.07, Found 269.25; Calculated for [M+2HꢀBoc]+ C11H14ClN2O: 225.08,
Found: 225.20.
(4-Chlorophenyl)(2,2,6,6-tetramethylmorpholino)methanone 5e. Following GPꢀB, 5e
(271 mg, 0.96 mmol, 96% yield) was prepared in 18 h and isolated as a viscous, colorless oil by
flash chromatography on silica gel (4 g column, 10% EtOAc for 10 CV, then 10ꢀ50% EtOAc
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over 20 CV). H NMR (400 MHz, CDCl3): δ 7.42 – 7.30 (m, 4H), 3.54 (br s, 2H), 3.18 (br s,
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2H), 1.37 – 0.98 (m, 12H). C NMR (100 MHz, CDCl3) δ 169.9, 135.8, 134.2, 128.9, 128.7,
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71.5, 56.4, 51.1, 28.2; m.p. 74ꢀ75 °C; TLC (40% EtOAc/heptanes) Rf : 0.40; HRMS (ESIꢀQꢀ
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TOF) m/z: [M+H]+ Calculated for C15H21ClNO2 282.1255; Found 282.1251.
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(4-Chlorophenyl)(4-(trifluoromethyl)piperidin-1-yl)methanone 5f Following GPꢀB, 5f
(271 mg, 0.93 mmol, 93% yield) was prepared in 20 h and isolated as a white solid by flash
chromatography on silica gel (4 g column, 10% EtOAc for 10 CV, then 10ꢀ80% EtOAc over 20
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CV). H NMR (600 MHz, 120 °C, DMSOꢀd6) δ 7.48 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz,
2H), 4.08 (d, J = 13.3 Hz, 2H), 3.03 – 2.98 (m, 2H), 2.63ꢀ2.54 (m, 1H), 1.88 (dd, J = 12.6, 3.2
Hz, 2H), 1.51 – 1.44 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 169.4, 136.0, 134.0, 128.9, 128.5,
126.9 (q, J = 278.2 Hz), 46.5, 41.3 40.6 (q, J = 27.7 Hz), 24.8; m.p. 103ꢀ105 °C; TLC (40%
EtOAc/heptanes) Rf :0.33; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for C13H14ClF3NO
292.0711; Found 292.0705.
N-benzyl-4-chloro-N-ethylbenzamide 5g. Following GPꢀA, 5g (161 mg, 0.59 mmol, 59%
yield) was prepared in 24 h and isolated as a pale yellow oil by flash chromatography on silica
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gel (4 g column, 5% EtOAc for 10 CV, then 5ꢀ30% EtOAc over 20 CV). H NMR (600 MHz,
DMSOꢀD6, 90 °C): δ 7.49 – 7.40 (m, 4H), 7.35 (t, J = 7.6 Hz, 2H), 7.32 – 7.24 (m, 3H), 4.61 (s,
2H), 3.30 (q, J = 7.1 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, DMSOꢀD6, 90 °C)
δ 169.1, 137.1, 135.3, 133.5, 127.9, 127.9, 127.7, 126.8, 126.5, 125.7, 48.5, 41.1, 12.4; HRMS
(ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for C16H17ClNO 274.0993; Found 274.0991.
tert-Butyl 1-(4-chlorobenzoyl)piperidine-4-carboxylate 5h. Following GPꢀB, 5h (291 mg,
0.90 mmol, 90% yield) was prepared in 18 h and isolated as viscous, colorless oil by flash
chromatography on silica gel (4 g column, 5% EtOAc for 10 CV, then 5ꢀ40% EtOAc over 25
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CV). H NMR (400 MHz, CDCl3): δ 7.40 – 7.30 (m, 4H), 4.46 (br s, 1H), 3.69 (br s, 1H), 3.03
(br s, 2H), 2.47 (tt, J = 10.6, 4.1 Hz, 1H), 2.02 – 1.55 (m, 4H), 1.44 (s, 9H). 13C NMR (100
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MHz, CDCl3) δ 173.5, 169.4, 135.7, 134.5, 128.8, 128.7, 128.5, 80.8, 47.1, 41.9, 28.1; TLC
(40% EtOAc/heptanes) Rf : 0.33; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for
C17H23ClNO3 324.1361; Found 324.1358.
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(4-Chlorophenyl)(4-phenylpiperidin-1-yl)methanone 5i. Following GPꢀA, 5i (247 mg,
0.82 mmol, 92% yield) was prepared in 20 h and isolated as a white solid by flash
chromatography on silica gel (4 g column, 10% EtOAc for 10 CV, then 10ꢀ80% EtOAc over 20
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CV). H NMR (400 MHz, CDCl3): δ 7.44ꢀ7.38 (m, 4H), 7.36 – 7.28 (m, 2H), 7.28 – 7.18 (m,
3H), 4.86 (br s, 1H), 3.85 (br s, 1H), 3.13 (br s, 1H), 2.99 – 2.67 (m, 2H), 2.11 – 1.57 (m, 4H).
13C NMR (175 MHz, CDCl3) δ 169.3, 145.0, 135.6, 134.6, 128.8, 128.6, 128.5, 126.7, 126.6,
48.4, 43.0, 42.8, 42.7, 33.9, 32.9, 32.8; m.p. 75ꢀ77 °C; TLC (40% EtOAc/heptanes) Rf : 0.38;
HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ Calculated for C18H19ClNO 300.1150; Found 300.1144.
(4-Chlorophenyl)(pyrrolidin-1-yl)methanone 5j. Following GPꢀA, 5j (137 mg, 0.65
mmol, 65% yield) was prepared in 24 h and isolated as a pale yellow oil by flash
chromatography on silica gel (4 g column, 20% EtOAc for 10 CV, then 20ꢀ80% EtOAc over 20
CV). Analytical data for 5j was consistent with that previously reported.80 1H NMR (400 MHz,
CDCl3): δ 7.49 – 7.42 (m, 2H), 7.40 – 7.32 (m, 2H), 3.71ꢀ3.55 (m, 2H), 3.49 ꢀ 3.29 (m, 2H), 2.02
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– 1.79 (m, 4H). C NMR (100 MHz, CDCl3) δ 168.5, 135.8, 135.6, 128.7, 128.5, 49.6, 46.3,
26.4, 24.4; LCMS (APCI): Calculated for [M+H]+ C11H13ClNO: 210.07, Found: 210.20.
(S)-(4-chlorophenyl)(2-methylpiperidin-1-yl)methanone 5k. Following GPꢀA, 5k (38 mg,
0.16 mmol, 16% yield) was prepared in 29 h and isolated as a pale yellow oil by flash
chromatography on silica gel (4 g column, 10% EtOAc for 15 CV, then 10ꢀ0% EtOAc over 25
CV). Chiral purity (99.6 %ee) was measured by HPLC with a Regis Whelk O (S,S) IC 250 x 4.6
mm column (80:15 hexanes:ethanol, 25 min, 1.0 mL/min, 210 nm). 1H NMR (400 MHz,
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