Direct Aldehyde C-H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.7b07078

A mechanism that enables direct aldehyde C-H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis. This mild, operationally simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C-H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.

Full text of DOI:10.1021/jacs.7b07078

Subscriber access provided by UNIVERSITY OF CALGARY
Communication
Direct Aldehyde C–H Arylation and Alkylation via the
Combination of Nickel, HAT, and Photoredox Catalysis
Xiaheng Zhang, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07078 • Publication Date (Web): 06 Aug 2017
Downloaded from http://pubs.acs.org on August 6, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
Direct Aldehyde C–H Arylation and Alkylation via the Combination
of Nickel, HAT, and Photoredox Catalysis
7
8
9
Xiaheng Zhang and David W. C. MacMillan*
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
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
Supporting Information Placeholder
The Synthetic Utility and Importance of Ketones
ABSTRACT: A mechanism that enables direct aldehyde C–H
functionalization has been achieved via the synergistic merger
O
Ubiquitous Motif
of photoredox, nickel, and hydrogen atom transfer (HAT)
Wittig, Grignard
catalysis. This mild, operationally simple protocol transforms
a wide variety of commercially available aldehydes, along
Pharmaceuticals
Aldol, Claisen
Photosensitizers
Photoredox
with aryl or alkyl bromides, into the corresponding ketones in
excellent yield. This C–H abstraction coupling technology has
Key Building
Organic Materials
β-Catalysis
Block
been successfully applied to the expedient synthesis of the
medicinal agent haloperidol.
Traditional Methods of Accessing Ketones
Ketones are important and ubiquitous structural motifs
found in natural products, pharmaceuticals, photosensitizers,
flavors, fragrances, and organic materials.1 Moreover, within
the field of synthetic organic chemistry, they represent a
versatile building block that can be utilized in a diverse array
of powerful bond-forming reactions. Conventional methods
for the synthesis of ketones include (i) the addition of
organometallic species to carbonyl moities that include
amides, anhydrides, and acid chlorides, (ii) aromatic
substitution protocols such as Friedel–Crafts acylations,2 and
O
O
MgBr
1. addition
(2. reoxidation)
=
R2N, Cl, H
organometallic
nucleophile
ketone
product
activated carbonyl
This work: Photoredox-Enabled Direct Aldehyde C–H Arylation
O
O
(iii) transition metal-catalyzed couplings of acid chlorides with
Br
3,4
H
aryl and alkyl stannanes and boronic esters.
Recently, an
one step
via photoredox
alternative yet equally attractive approach to ketone formation
has emerged that involves metal-catalyzed formyl C–H
functionalization, wherein aryl iodides and aldehydes were
successfully combined as coupling partners. 5 While these
transformations require the use of stoichiometric oxidants,
reductants, or directing groups, it is important to recognize
that these seminal studies were the first to employ widely
available aldehydes (enolizable and non-enolizable) in a C–H
arylation cross-coupling mechanism. Recently, we questioned
if this overall strategy might be accomplished in a general
sense using widely available aryl bromides (and for the first
time alkyl halides) via the combination of three interconnected
catalytic cycles, namely photoredox, nickel, and HAT
catalysis. Given the intrinsic utility of ketones along with the
widespread availability of both coupling partners, we
envisioned that this new C–H abstraction–arylation/alkylation
redox mechanism would be of conceptual and practical
interest to chemists in both academic and industrial settings.
The merger of photoredox and transition metal catalysis
(now termed metallaphotoredox) has enabled the invention of
a large and varied range of cross-coupling reactions,6 many of
which are now being adopted by the pharmaceutical industry.7
In this context, our laboratory has previously demonstrated a
direct sp3 C–H bond functionalization method wherein the
synergistic combination of photoredox, nickel, and hydrogen
aldehyde
aryl bromide
aryl ketone
This work: Photoredox-Enabled Direct Aldehyde C–H Alkylation
O
O
Br
H
O
O
one step
via photoredox
aldehyde
alkyl bromide
alkyl ketone
mechanism allows amines and ethers to undergo direct a-C–H
arylation and alkylation. 8 As a critical design element, the
exploitation of a polarity-matched hydrogen abstraction step
using an electrophilic quinuclidinium radical cation enables a
high degree of kinetic selectivity, in that bond dissociation
enthalpy (BDE) considerations are less important than C–H
bond polarity.9 As a result, electron-rich sp3 C–H bonds
undergo selective and efficient H-abstraction/nickel-catalyzed
arylation in the presence of weak, acidic or weak, neutral C–H
systems found in methyls, methylenes, and methines. With
this selectivity paradigm in mind, we recently questioned
whether aldehydic sp2 H–C(O) bonds might be activated
toward arylation and alkylation using this strategy, thereby
providing a new and generic pathway to ketone construction.
Herein, we describe the successful implementation of these
atom transfer catalysis in
a triple catalytic activation
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
+
Br
O
–H
triple catalytic
activation
1
Br
LnNiII
Ar
2
3
11
N
Boc
10
7
4
5
6
7
8
aryl bromide
3
N
N
Br
H
Nickel
Catalytic
Cycle
LnNi0
9
Organocatalytic
Cycle
NiIIILn
Ar
IrII (5)
12
O
reductant
Alk
O
8
9
N
⎯
Boc
HAT
SET
SET –Br
7
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
Photoredox
Catalytic
Cycle
LnNiI
Br
N
13
O
4
O
*IrIII (2)
IrIII (1)
H
oxidant
N
BocN
Boc
6
14
visible light
aldehyde
aryl ketone
Scheme 1. Proposed Mechanism for Aldehyde C–H Arylation and Alkylation via
a Triple Catalysis Mechanism.
ideals and present
a
broadly applicable protocol for
aldehyde C–H arylation,
anticipated that the desired transformation would be possible
using DMSO or CH3CN; however, the efficiency of ketone
product formation was poor (Table 1, entries 1–2, 2–8% yield).
To our surprise, we observed that a competing α-amino C–H
arylation mechanism was operating in both media.
Remarkably, by switching to 1,4-dioxane, we observed
exclusive formation of the desired ketone product (entry 3,
87% isolated yield) without any observable α-amino C–H
arylation. We surmised that solvent dielectric constant might
play an important role in stabilizing the ionic nature of the
quinuclidinium radical cation species and likely impacts the
relative roles of BDEs vs. degree of bond polarization. It is
worth noting that, under the optimized conditions, the nickel
catalyst loading could be reduced without an impact on the
efficiency of this reaction (entry 4, 80% yield). Control
experiments (entries 5–7) revealed that the photocatalyst,
nickel catalyst, quinuclidine, base, and visible light were all
essential for the success of this new aldehyde C–H arylation.
With the optimized conditions in hand, we next sought to
determine the generality of the aryl halide component in this
new ketone-forming reaction. As shown in Table 2, electron-
metallaphotoredox-mediated
vinylation, or alkylation.
The mechanistic details of our proposed transformation are
outlined in Scheme 1. Photoexcitation with visible light of
photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1) is known to
produce the strongly oxidizing complex *Ir[dF(CF3)ppy]2
(dtbbpy)+ (2) (E1/2red [*IrIII/IrII] = +1.21 V vs. the saturated
calomel electrode (SCE) in CH3CN).10 The *Ir(III) excited state
ox
2 can effect the oxidation of quinuclidine (3) (E1/2 = +1.1 V
vs. SCE in CH3CN)11 to form cationic radical 4 and the
reduced Ir(II) complex 5. At this stage, we proposed that
quinuclidinium radical cation (4) should engage in a HAT
event
with
any
given
aldehyde
(N-Boc-4-
piperidinecarboxaldehyde (6) is shown) to generate the
corresponding acyl radical 7.12 With respect to regiocontrol,
we hypothesized that the hydrogen abstraction event should be
selective for the formyl C–H bond given that it is both
hydridic and relatively weak in comparison to most other C–H
moieties. For example, the difference in the bond dissociation
enthalpies of aldehyde C–H bonds vs. α-amino C–H bonds
(both of which exhibit hydridic bond polarization) might be
sufficient to ensure exclusive formation of the acyl radical
species 7. At this stage, concurrent oxidative addition of aryl
bromide 10 to LnNi0 species 9 should deliver the aryl–NiII
species 11, which we hoped would be rapidly intercepted by
the radical 7 to form the acyl–NiIII complex 12.13 Thereafter,
reductive elimination would afford the desired ketone product
14 and NiI species 13. As a critical step, both the nickel and
photoredox catalytic cycles would simultaneously turn over
via single electron transfer from the reduced IrII species 5
(E1/2red [IrIII/IrII] = –1.37 V vs. SCE in CH3CN)10 to the NiI
complex 13 (E1/2red[NiII/Ni0] = –1.2 V vs. SCE in DMF).14
Finally, the quinuclidine catalyst would be regenerated via
deprotonation of the quinuclidinium ion 8 with inorganic base.
Our investigation into this new HAT-metallaphotoredox-
mediated aldehyde C–H arylation began with exposure of N-
Table 1. Optimization of the Aldehyde C–H Arylation.a
O
O
Ir Ni
H
Br
H
K2CO3
solvent
r.t., 20 h
BocN
BocN
N
CF3
N
CF3
aryl ketone
aldehyde
aryl bromide
yieldb
entry
solvent
conditions
1
2
3
4
5
6
7
DMSO
CH3CN
dioxane
dioxane
dioxane
dioxane
dioxane
as shown
as shown
2%
8%
as shown
92% (87%)
80%
0%
2 mol% Ni catalyst
no photocatalyst
no Ni catalyst
no light
0%
Boc-4-piperidinecarboxaldehyde
and
5-bromo-2-
0%
(trifluoromethyl)pyridine to visible light in the presence of
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1), NiBr2·dtbbpy, quinuclidine
and K2CO3. Given the requirement of high dielectric solvents
in our previous C–H abstraction/arylation studies, we
aPhotocat 1 (1 mol%), NiBr2·dtbbpy (10 mol%), quinuclidine (10
mol%), aryl halide (1.0 equiv), aldehyde (2.0 equiv), and K2CO3 (1.5
equiv). Yield by 1H NMR analysis. bIsolated yields in parentheses.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
Table 2. From Aldehydes to Ketone Adducts: Scope of Triple Catalytic Cross-Coupling with Aryl, Alkyl Bromides and Aldehydes.a
1
2
3
4
5
6
triple catalytic combination
F3
C
1 mol% Ir photocatalyst
F
O
O
10 mol% Ni catalyst
t-Bu
t-Bu
N
Ir
Br
t-Bu
t-Bu
Br
Br
H
N
N
N
F
F
10 mol% quinuclidine
K2CO3, dioxane, r.t., 20 h
34 W blue LEDs
R
R
Ni
Ir
Ni
H
N
N
N
F
aldehyde
aryl bromide
aryl ketone
F3C
7
8
Aryl Bromide Scope
9
O
O
O
O
O
O
O
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
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
NBoc
Me
MeO
Ac
MeO2
C
NC
F3
C
MeO2S
15, 82% yield
16, 81% yield
17, 92% yield
18, 91% yield
19, 90% yield
20, 88% yield
21, 92% yield
O
O
O
O
O
CN
O
Me
O
NC
Me
NBoc
O
NBoc
O
NBoc
NBoc
NBoc
F3CO
N
O
F
O
Me
22, 82% yield
23, 93% yield
24, 81% yield
25, 88% yield
26, 90% yield
27, 92% yield
28, 85% yield
O
O
O
O
O
O
O
MeO
F
NC
N
N
N
NBoc
N
NBoc
NBoc
NBoc
N
NBoc
N
F
N
N
29, 90% yield
30, 85% yield
31, 78% yield
32, 50% yield
33, 87% yield
34, 85% yield
35, 79% yield
Vinyl and Alkyl Bromide Scope
Me
O
Me
O
O
O
Me
O
Me
O
Me
Me
Me
Me
Me
Me
Me
NC
Me
O
NBoc
Me
NBoc
NBoc
O
t-Bu
36, 72% yieldb
37, 74% yieldb
38, 56% yieldb,c
39, 55% yield
40, 56% yield
41, 56% yield
Aldehyde Scope
Aldehyde
Product
Aldehyde
Product
Aldehyde
Product
Aldehyde
Product
O
O
O
O
O
O
O
O
NHCbz
Et
n-hexyl
Et
CbzHN
2
H
H
n-hexyl
H
H
Et
2
F3
C
N
F3C
N
F3C
N
F3C
N
Et
42, 92% yield
46, 71% yield
50, 91% yield
54, 81% yield
O
O
O
O
O
O
O
O
n-propyl
2
H
H
n-propyl
H
H
2
F3C
N
F3C
N
F3
C
N
F3C
N
43, 90% yield
47, 81% yield
51, 90% yield
55, 73% yieldd
O
O
Me
O
O
O
O
Me
Me
O
Me
O
Me
Me
Me
H
H
Me
H
H
O
O
F3
C
N
F3C
N
F3C
N
F3C
N
F
F
44, 70% yield
48, 91% yield
52, 88% yield
56, 70% yieldd
O
Me
Me
O
O
O
Me
Me
O
O
O
O
OH
Me
HO
Me
Me
Me
H
3
H
H
H
3
Me
Me
F3C
N
F3C
N
F3C
N
F3C
N
OMe
MeO
45, 87% yield
49, 91% yield
53, 85% yield
57, 72% yielde
aIsolated Yields. Performed with photocat 1 (1 mol%), NiBr2·dtbbpy (10 mol%), quinuclidine (10 mol%), aryl/alkyl bromide, aldehyde, and
K2CO3. See Supporting Information. bK2CO3 (2.0 equiv). cAldehyde (3.0 equiv). dAldehyde (10.0 equiv). eAldehyde (6.0 equiv).
trifluoromethyl, sulfone, and trifluoromethoxy groups) were
rich arenes containing alkyl and methoxy groups performed
well (15 and 16, 82% and 81% yield, respectively). Moreover,
diverse array of electron-deficient bromoarenes that
incorporate a variety of substituents (ketone, ester, nitrile,
found to be competent substrates (17–22, 82–92% yield).15
Bicyclic aromatics such as phthalides and phthalimides were
also coupled with high levels of efficiency (23 and 24, 93%
and 81% yield, respectively). Notably, the efficiency of the
a
ACS Paragon Plus Environment

Journal of the American Chemical Society
reaction was not impeded by ortho substituents on the Supporting Information
Page 4 of 5
1
2
3
4
5
6
7
8
aromatic ring (25–26, 88–90% yield). With respect to hetero-
aromatic coupling partners, we have found that a range of
substituted pyridyl bromides are also effective electrophiles
(29–32, 50–90% yield). Perhaps most importantly, this
transformation is not limited to electron-deficient pyridines.
For example, quinoline, isoquinoline, and pyrimidine can be
readily employed in this HAT-metallaphotoredox-mediated
aldehyde C–H arylation (33–35, 79–87% yield).
Having demonstrated the capacity of aryl bromides to
participate in this new ketone-forming reaction, we were
delighted to find that vinyl electrophiles can also be
incorporated (36–38, 56–74% yield). Perhaps more important
was the finding that alkyl halides can also be employed to
generate non-conjugated ketones. Indeed, we have found that
this transformation can accommodate cyclic and acyclic
aliphatic bromides with useful levels of efficiency (39–41, ≥55%
yield). To our knowledge this is the first time that aldehydes
have been merged with aliphatic bromides to generate
saturated ketones in one chemical step.
We next turned our attention to the scope of the formyl
component. As shown in Table 2, an assortment of readily
available aldehydes are viable. For example, primary
aldehydes are effective coupling partners, including substrates
that incorporate carbamate, phenyl, unprotected alcohol, and
tert-butyl groups (42–48, 70–92% yield). Notably,
acetaldehyde, which is extremely volatile, can be readily
employed (44, 70% yield). Moreover, a-branched alkanals
were found to readily undergo this C–H arylation (49 and 50,
both 91% yield). Ring-bearing formyl systems were also
successful, including cyclohexyl, cyclopentyl, cyclopropyl and
tetrahydropyranyl carboxaldehyde (51–54, 81–90% yield).
Lastly, aromatic aldehydes were found to couple with aryl
halides proficiently despite the diminished hydridic nature of
these formyl C–H bonds (55–57, 70–73% yield).
The Supporting Information is available free of charge on
the ACS Publications website at DOI: (link to DOI)
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Author
*dmacmill@princeton.edu
9
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
ACKNOWLEDGMENTS
Financial support provided by the NIHGMS (R01
GM103558-05) and kind gifts from Merck, BMS, Janssen,
and Eli Lilly. X. Z. is grateful for a postdoctoral fellowship
from the Shanghai Institute of Organic Chemistry.
REFERENCES
(1) (a) McDaniel, R.; Thamchaipenet, A.; Gustafsson, C.; Fu, H.;
Betlach, M.; Betlach, M.; Ashley, G. Proc. Natl. Acad. Sci. USA 1999,
96, 1846. (b) Cuquerella, M. C.; Lhiaubet-Vallet, V.; Cadet, J.;
Miranda, M. A. Acc. Chem. Res. 2012, 45, 1558. (c) Kamat, P. V.
Chem. Rev. 1993, 93, 267.
(2) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3818. (b)
Sartori, G.; Maggi, R. Chem. Rev. 2006, 106, 1077. (c) Bechara, W.
S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4, 228.
(3) For selected reviews, see: (a) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457; (b) Willis, M. C. Chem. Rev. 2010, 110, 725. (c)
Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986.
(d) Moragas, T.; Correa, A.; Martin, R. Chem. Eur. J. 2014, 20, 8242.
(4) For selected examples, see: (a) Takemiya, A; Hartwig,. J. F. J.
Am. Chem. Soc. 2006, 128, 14800. (b) Gooßen, L. J.; Rudolphi, F.;
Oppel, C.; Rodríguez, N. Angew. Chem., Int. Ed. 2008, 47, 3043. (c)
Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8, 75. (d)
Amani, J.; Molander, G. A. J. Org. Chem. 2017, 82, 1856.
(5) (a) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J. Org. Chem.
2002, 67, 1682. (b) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am.
Chem. Soc. 2004, 126, 15356. (c) Ko, S.; Kang, B.; Chang, S. Angew.
Chem. Int. Ed. 2005, 44, 455. (d) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao,
J. J. Am. Chem. Soc. 2008, 130, 10510. (e) Suchand, B.;
Satyanarayana, G. J. Org. Chem. 2016, 81, 6409.
(6) (a) Kalyani, D.; McMurtrey, K. B.; Neufeldt, S. R.; Sanford, M.
S. J. Am. Chem. Soc. 2011, 133, 18566. (b) Sahoo, B.; Hopkinson, M.
N.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 5505. (c) Shu, X.-z.;
Zhang, M.; He, Y.; Frei, H.; Toste, F. D. J. Am. Chem. Soc. 2014, 136,
5844. (d) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A.
G.; MacMillan, D. W. C. Science 2014, 345, 437. (e) Tellis, J. C.;
Primer, D. N.; Molander, G. A. Science 2014, 345, 433.
(7) (a) Corcoran, E. B.; Pirnot, M. T.; Lin, S.; Dreher, S. D.;
DiRocco, D. A.; Davies, I. W.; Buchwald, S. L.; MacMillan, D. W. C.
Science 2016, 353, 279. (b) Oderinde, M. S.; Frenette, M.; Robbins,
D. W.; Aquila, B.; Johannes, J. W. J. Am. Chem. Soc. 2016, 138, 1760.
(c) Oderinde, M. S.; Jones, N. H.; Juneau, A.; Frenette, M.; Aquila, B;
Tentarelli, S; Robbins, D. W.; Johannes, J. W. Angew. Chem. Int. Ed.
2016, 55, 13219.
O
Ir Ni
H
Br
Cl
O
Cl
H
F
F
K2CO3
58
59
60, 77% yield
via subsequent
Cl
coupling with
OH
O
Cl
N
OH
F
HN
haloperidol
antipsychotic medication
61
commercially available
79% yield (61% yield over two steps)
(8) (a) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J.
D.; MacMillan, D. W. C. Science 2016, 352, 1304. (b) Le, C.; Liang,
Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C. Nature 2017, 547, 79.
(9) Roberts, B.P. Chem. Soc. Rev. 1999, 28, 25.
(10) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal,
R. A., Jr.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17,
5712.
(11) Jeffrey, J. L.; Terrett, J. A.; MacMillan, D. W. C. Science 2015,
349, 1532.
(12) (a) Fontana, F.; Minisci, F.; Barbosa, M. C. N.; Vismara, E. J.
Org. Chem. 1991, 56, 2866. (b) Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
Figure 1. Two-Step Synthesis of Haloperidol.
To highlight the synthetic utility of this triple catalytic
mechanism and its potential application to drug-like molecules,
we have accomplished a two-step synthesis of haloperidol, a
well-established antipsychotic medication.16 As shown in
Figure 1, 4-chlorobutanal 58 and 1-bromo-4-fluorobenzene 59
were successfully combined using our aldehyde coupling
protocol to forge ketone 60 in good yield (77%). Exposure of
this g-chloroarylketone to the piperidine nucleophile 61
subsequently delivered haloperidol in relatively short order.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
(13) Chu, L.; Lipshultz, J. M.; MacMillan, D. W. C. Angew. Chem.
Int. Ed. 2015, 54, 7929.
(14) Durandetti, M.; Devaud, M.; Périchon, J. New J. Chem. 1996,
20, 659.
(15) Electron-deficient aryl chlorides are also competent substrates
for this arylation protocol, albeit with reduced levels of efficiency.
(16) Kook, C. S.; Reed, M. F.; Digenis, G. A. J. Med. Chem. 1975,
18, 533.
1
2
3
4
5
6
7
8
9
TOC Graphic
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
O
Br
Ir Ni
H
O
organic
bromide
H
BocN
BocN
Br
Br
ketone product
one step
via photoredox
aldehyde
44 examples
ACS Paragon Plus Environment