Intermolecular Reductive C-N Cross Coupling of Nitroarenes and Boronic Acids by PIII/PV=O Catalysis

Article abstract of DOI:10.1021/jacs.8b10769

A main group-catalyzed method for the synthesis of aryl- and heteroarylamines by intermolecular C-N coupling is reported. The method employs a small-ring organophosphorus-based catalyst (1,2,2,3,4,4-hexamethylphosphetane) and a terminal hydrosilane reductant (phenylsilane) to drive reductive intermolecular coupling of nitro(hetero)arenes with boronic acids. Applications to the construction of both C_sp2-N (from arylboronic acids) and C_sp3-N bonds (from alkylboronic acids) are demonstrated; the reaction is stereospecific with respect to C_sp3-N bond formation. The method constitutes a new route from readily available building blocks to valuable nitrogen-containing products with complementarity in both scope and chemoselectivity to existing catalytic C-N coupling methods.

Full text of DOI:10.1021/jacs.8b10769

Subscriber access provided by RMIT University Library
Communication
Intermolecular Reductive C–N Cross Coupling of
Nitroarenes and Boronic Acids by PIII/PV=O Catalysis
Trevor V. Nykaza, Julian C. Cooper, Gen Li, Nolwenn Mahieu,
Antonio Ramirez, Michael R. Luzung, and Alexander T. Radosevich
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10769 • Publication Date (Web): 29 Oct 2018
Downloaded from http://pubs.acs.org on October 29, 2018
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 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 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.
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 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Intermolecular Reductive C–N Cross Coupling of Nitroarenes and
Boronic Acids by PIII/PV=O Catalysis
Trevor V. Nykaza,†§ Julian C. Cooper,†§ Gen Li,† Nolwenn Mahieu,† Antonio Ramirez,‡ Michael R.
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
Luzung,‡║* Alexander T. Radosevich†*
† Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
‡ Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey
08903, United States.
§ Authors contributed equally.
Supporting Information Placeholder
ABSTRACT: A main group-catalyzed method for the synthesis
of aryl- and heteroarylamines by intermolecular C–N coupling is
reported. The method employs a small-ring organophosphorus-
based catalyst (1,2,2,3,4,4-hexamethylphosphetane) and a termi-
nal hydrosilane reductant (phenylsilane) to drive reductive inter-
molecular coupling of nitro(hetero)arenes with boronic acids.
Applications to the construction of both Csp2–N (from arylboronic
acids) and Csp3–N bonds (from alkylboronic acids) are demon-
strated; the reaction is stereospecific with respect to Csp3–N bond
formation. The method constitutes a new route from readily avail-
able building blocks to valuable nitrogen-containing products with
complementarity in both scope and chemoselectivity to existing
catalytic C–N coupling methods.
Aryl- and heteroarylamines comprise a diverse class of organic
compounds with significant value as pharmaceuticals, agrochemi-
cals, fine chemicals, and optoelectronic materials. The prevailing
Figure 1. A) Established methods for intermolecular C–N cou-
pling. B) This work: PIII/PV=O-catalyzed reductive C–N coupling
of nitroarenes and boronic acids.
strategy for the preparation of these useful compounds—N-
arylation of the parent aniline through carbon-nitrogen (C–N)
coupling (Figure 1A)—is currently shaped by transition metal
catalyzed methods (e.g. Buchwald-Hartwig, Ullmann, Chan-Lam
couplings).1,2 Herein, we describe an alternative main group ap-
proach to catalytic intermolecular C–N bond construction that
does not rely on transition metals, enabling a complementary
route from readily accessible components to (hetero)arylamines.
Specifically, we show that a redox active organophosphorus-
based catalyst operating in the PIII/PV=O manifold drives reduc-
tive coupling of nitroarenes and boronic acids with C–N bond
formation to give (hetero)arylamine products (Figure 1B) in a
manner functionally distinct from current catalytic practice.
Our entry into nitroarene functionalization has centered on the
use of a redox-active small-ring phosphorus-based compound. We
have previously reported that a simple trialkylphosphine catalyst
containing a core four-membered ring, in combination with
phenylsilane as a terminal reductant, constitutes a competent sys-
tem for the catalytic transformation of nitroaromatic substrates
into azaheterocycles through intramolecular C–N bond forming
Cadogan cyclization.11,12 In this chemistry, the phosphacyclic
catalyst promotes reductive O-atom transfer from the nitroarene
substrates by cycling in the PIII/PV=O catalytic couple.13-16 We
considered whether introduction of a suitable exogenous coupling
partner to the PIII/PV=O catalytic conditions might enable the con-
struction of C–N bonds in an intermolecular manner.
Nitroarenes are common intermediates in synthesis (most typi-
cally as aniline precursors), but are relatively underutilized for
direct catalytic C–N bond forming reactions.3 Notable exceptions
include the work of Nicholas4 and Baran,5 who have reported
iron-catalyzed reductive C–N bond construction by reaction of
nitroarenes with alkynes and alkenes, respectively. Hu has report-
ed a related iron-catalyzed reductive C–N bond formation by reac-
tion of nitroarenes with alkyl6 and acyl7 electrophiles. Stoichio-
metric main group metal approaches have also been described;
Knochel,8 Kürti,9 and Niggemann10 have demonstrated reductive
conversion of nitroarenes to N-arylanilines.
The reaction of nitrobenzene (1) and phenylboronic acid (2a) to
give diphenylamine (3) was chosen for discovery and optimiza-
tion studies (Table 1). An initial attempt at reductive coupling
using conditions previously reported for Cadogan cyclization
proved promising, providing diphenylamine in an unoptimized
59% yield (Fig. S1). Using the Design of Experiments approach
to evaluate the impact of temperature, concentration, and reagent
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
equivalencies on the reaction outcome (Fig. S2), optimization
Table 1. Discovery and optimization of the organophosphorus-
catalyzed reductive C–N coupling reaction.a
studies converged on the conditions outlined in Table 1 (entry 1,
1.1 equiv of 2a, 15 mol % of 4•[O], 0.5 M in m-xylene, 120 °C).
Under these conditions, the organophosphorus-catalyzed reduc-
tive coupling of nitrobenzene and phenylboronic acid gave diphe-
nylamine in 86% GC yield, and 80% isolated yield on a one mil-
limole scale. A comparable performance is observed if the corre-
sponding tricoordinate phosphacycle 4 is employed as catalyst
(entry 2), consistent with the interconversion of PIII and PV=O
oxidation states by catalytic cycling. Relatedly, a stoichiometric
implementation of the reductive coupling of 1 and 2a employing 3
equivalents of phosphetane 4 is successful (89% yield) (Table
S2).17 Control experiments omitting either the phosphorus catalyst
(entry 3) or the terminal silane reductant (entry 4) do not give the
desired product. The reaction performed well in a variety of non-
polar solvents (entries 1,5,6), but was less efficient in a solvent of
high donicity (entry 7). The identity of the boron reagent was
found to play a significant role in the success of the reaction (Ta-
ble 1); both phenylboronic acid (2a) and phenylboroxine (2b,
entry 8) were successfully aminated by nitrobenzene to give di-
phenylamine 3 under standard catalytic conditions. However,
other common phenylboronic esters are either less productive
(catecholatoboronate 2c – entry 9) or unproductive (pinacolato-
boronate 2d – entry 10) when employed as the aryl donor in the
catalytic C–N coupling reaction, suggesting the possibility of
chemoselective differentiation of boryl moieties (vide infra).
1
2
3
4
5
6
7
8
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
Entry
1
[B]
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
Solvent
m-xylene
m-xylene
m-xylene
m-xylene
dibutyl ether
toluene
R3P=O
4•[O]
Yield (%)
86% (80%)
82%
2
4
3
none
0%
4
4•[O]; no silane
4•[O]
0%
5
86%
6
4•[O]
80%
7
8b
DMF
4•[O]
17%
m-xylene
m-xylene
m-xylene
4•[O]
74%
9
4•[O]
54%
A qualitative assessment of the electronic demand of the reac-
tion was undertaken (Figure 2A). For a series of differentially
para-substituted nitroarenes, an empirical electronic trend is ob-
served where increasingly electron-withdrawing para substituents
lead to faster qualitative rates and higher yields of C–N coupling
(cf. 5-8). Complementarily, the inverse empirical trend with re-
spect to electron demand of the arylboronic acid moiety is ob-
served, where increasingly electron-donating para substituents
result in higher yields of C–N coupling (cf. 9-12). The conse-
quence of these two differing trends is that the organophosphorus-
catalyzed C–N coupling reaction is most productive for union of
electron deficient nitroarenes with electron rich arylboronic acids,
as illustrated in the synthesis of 15 in 88% by the coupling of
electron-deficient nitroarene 13 with electronic-rich boronic acid
14 (Figure 2A). This observed electronic preference serves as a
point of distinction with respect to palladium-catalyzed C–N cou-
pling, where the arylation of electron-deficient arylamine sub-
strates are among the most persistently challenging.18 The current
organophosphorus-catalyzed method may therefore provide a
route to construction of otherwise electronically deactivated C–N
bonds.
10
4•[O]
2%
aYields were determined through analysis by gas chromatography
(GC) with the aid of an internal standard. Yield in parenthesis
(entry 1) is for isolated material from a 1.0 mmol reaction scale.
b0.37 mmol of 2b was used. See SI for additional optimization
experiments.
deactivated following an initial reductive C–N coupling event,
such that selective mono-coupling product 28 may be isolated in
good yield. And notably, only selective C–N cross coupling prod-
uct
29
is
observed
in
the
reaction
of
4-
pinacolatoborylnitrobenzene and phenylboronic acid; the Bpin
moiety is inert to the main group-catalyzed conditions, allowing
for further functionalization by known transition metal-catalyzed
chemistry if so desired.
The reaction is not limited to Csp2–N bond formation; indeed,
the amination of nitrobenzene with Csp3 boronic acid reagents
including methyl (30), primary alkyl (31), secondary alkyl (32),
and strained cycloalkyl (33) provide serviceable yields of the
desired Csp3–N cross coupling products. As a further illustration
of the synthetic utility of the transformation, a number of het-
eroarylamine structures displaying varied substitution on both the
nitro and boronic acid components were synthesized. Carboxyes-
ters on either the nitroarene or boronic acid reaction component
were well tolerated (34, 35), and both π-deficient (37) and π-
excessive (39) heterocycles are readily employed. As a general
point, since the organophosphorus catalyst is only weakly Lewis
acidic, substrates and products with Lewis basic functionalities
(amines, pyridines, sulfides) are not inherently inhibitory under
these main group coupling conditions.
Additional synthetic examples illustrating the reaction scope
are collected in Figure 2B. The main group-catalyzed conditions
for the C–N coupling method show good functional group com-
patibility and provide complementary chemoselectivities with
respect to established transition metal coupling. Since phosphines
do not readily undergo oxidative addition to Csp2–X bonds, halo-
gen substitution is well-tolerated on both the nitroarene compo-
nent (7, 19, 20) and the boronic acid (11, 23, 24) component.
Even very electrophilic 2-chloro and 2-bromopyridyl substrates
(26, 27), which are known to be excellent electrophiles for both
SNAr and transition metal-catalyzed substitution, are carried
through the phosphine-catalyzed reductive C–N coupling without
undesired cleavage. Protic functional groups such as anilines (18,
24) and phenols (25) are orthogonal in reactivity to the nitro group
and are therefore tolerated in the coupling chemistry without ex-
plicit protection. Even multiple distinct nitro or boryl moieties
within a single reaction pair can be differentiated in select circum-
stances. Due to the aforementioned electronic trends in C–N cou-
pling (Figure 2A), 1,4-dinitrobenzene becomes electronically
To demonstrate the potential synthetic utility of this methodol-
ogy in the context of pharmaceutical chemistry, mefenamic acid
(40) and tolfenamic acid (41) (Figure 3A)—members of the
fenamate group of nonsteroidal anti-inflammatory drugs
(NSAIDs) marketed under the tradenames Ponstel and Clotam,
respectively—were synthesized with 67% and 73% yields on 1
millimole scale in one-pot by organophosphorus-catalyzed reduc-
tive C–N cross coupling of 2-nitrobenzonitrile and either 2,3-
dimethylphenylboronic acid or 3-chloro-2-methylphenylboronic
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
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
Figure 2. Examples of catalytic reductive C–N coupling. (A) Electronic effects on C–N coupling. (B) Synthetic examples of C–N cou-
pling. See SI for full experimental details and conditions. Yields are reported for isolated material following purification on a 1 mmol
scale, except as noted. Compounds 5-12 were prepared on 2 mmol scale; compound 26 was prepared on a 3 mmol scale; and compounds
34-39 were prepared on 1 gram scale. Preparation of 22 used 1.3 equivalents of boronic acid. Compound 36 was isolated as its hydrochlo-
ride salt.
acid, followed by alkaline nitrile hydrolysis according to a known
procedure.19
The complementarity of the current main group method for C–
N coupling with respect to existing transition metal strategies is
exemplified by the diversification of 1,3,5-trisubstituted arene 44
(Figure 3C). Whereas C–N coupling under existing Cu-mediated
(Chan-Lam) or Pd-catalyzed (Buchwald-Hartwig) methods per-
mits chemoselective functionalization at the anilide (site b, 46) or
arylbromide (site c, 47) positions, respectively, catalytic arylami-
nation by the newly developed organophosphorus-catalyzed cou-
pling approach results in selective functionalization at the nitro
moiety (site a, 45) in 81% yield. These results suggest a strategic
orthogonality between the bond constructions possible with the
various C–N coupling methods. Viewed in this light, we envision
that the main group method will augment technical capacity by
providing new freedom to synthesize valuable arylamine products
from diverse and readily available building blocks.
The stereospecificity of the catalytic C–N coupling reaction
was evaluated by amination of stereochemical probe molecules
(Fig. 3B). Reductive coupling of anti-phenylcyclopropylboronic
acid (anti-42) with nitrobenzene under standard main group-
catalyzed conditions gave the N-phenyl tranylcypromine deriva-
tive anti-43 in 71% NMR yield with retention of configuration.
Relatedly, reductive coupling of the syn-cyclopropane epimer
(syn-42) with nitrobenzene furnished syn-43, in 61% NMR yield
with stereochemical retention. Consistent with related protocols
for amination of boron derivatives,20 the reductive C–N coupling
reaction is stereospecific with respect to the boronic acid compo-
nent, permitting its potential implementation in stereoselective
synthesis.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
Funding was provided by NIH NIGMS (GM114547), MIT, and
Bristol-Myers Squibb. We thank Prof. Stephen Buchwald for
valuable discussions and for access to equipment and chemicals.
1
2
3
4
REFERENCES
1 (a) Hartwig, J. F. Transition Metal Catalyzed Synthesis of Arylamines
and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism.
Angew. Chem. Int. Ed. 1998, 37, 2046. (b) Jiang, L.; Buchwald, S. L.
Palladium-Catalyzed Aromatic Carbon-Nitrogen Bond Formation, in
Metal-Catalyzed Cross-Coupling Reactions. De Meijere, A.; Diderich, F.,
Eds.; Wiley-Blackwell: Hoboken, NJ, 2008; ed. 2, pp. 699–760. (c) Jiang,
Y.; Ma, D. Copper - Catalyzed Ligand Promoted Ullmann - type Coupling
Reactions in Catalysis without Precious Metals. Bullock, R. M. Eds.; John
Wiley & Sons, Inc.: Hoboken, NJ, 2010; pp 213-233. (d) Bariwal, J.;
Eycken, E. V. der. C–N bond forming cross-coupling reactions: an over-
view. Chem. Soc. Rev. 2013, 42, 9283. (e) Corcoran, E. B.; Pirnot, M. T.;
Lin, S.; Dreher, S. D.; DiRocco, D. A.; Davies, I. W.; Buchwald, S. L.;
MacMillan, D. W. C. Aryl amination using ligand-free Ni(II) salts and
photoredox catalysis. Science 2016, 353, 279.
5
6
7
8
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
2
(a) Schlummer, B.; Scholz, U. Palladium-Catalyzed C-N and C-O
Coupling–A Practical Guide from an Industrial Vantage Point. Adv. Synth.
Catal. 2004, 346, 1599. (b) Torborg, C.; Beller, M. Recent Applications of
Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agro-
chemical, and Fine Chemical Industries. Adv. Synth. Catal. 2009, 351,
3027. (c) Yin, J. “Selected Applications of Pd- and Cu-Catalyzed Carbon–
Heteroatom Cross Coupling Reactions in the Pharmaceutical Industry.” In
Applications of Transition Metal Catalysis in Drug Discovery and Devel-
opment: An Industrial Perspective, Crawley, M. L.; Trost, B. M. Eds.;
John Wiley & Sons, Inc.: Hoboken, NJ, 2012; pp 97-163. (d) Ruiz-
Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564.
3
Lower oxygenates of nitrogen or alternative nitrogen reagents are
more common in C-N bond formation with boronic acids. Nitrosoarenes:
(a) Yu, Y.; Srogl, J.; Liebeskind, L. S. Cu(I)-Mediated Reductive Amina-
tion of Boronic Acids with Nitroso Aromatics. Org. Lett. 2004, 6, 2631.
(b) Roscales, S.; Csákÿ, A. G. Synthesis of Di(hetero)arylamines from
Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-
Free Coupling. Org. Lett. 2018, 20, 1667.; N-Alkyl hydroxylamines: (c)
Sun, H.-B.; Gong, L.; Tian, Y.-B.; Wu, J.-G.; Zhang, X.; Liu, J.; Fu, Z.;
Niu, D. Metal- and Base-Free Room-Temperature Amination of Organo-
boronic Acids with N-Alkyl Hydroxylamines. Angew. Chem. Int. Ed.
2018, 57, 9456.; Azides: (d) Ou, L.; Shao, J.; Zhang, G.; Yu, Y. Metal-
Free Carbon–nitrogen Bond-Forming Coupling Reaction between Aryl-
boronic Acids and Organic Azides. Tetrahedron Lett. 2011, 52, 1430.
Tosyl triazenes: (e) Sarma, M. J.; Phukan, P. Metal-Free Synthesis of
Secondary Amines by the Reaction of Tosyl Triazene and Aryl Boronic
Acid. Synth. Commun. 2018, 48, 656.
Figure 3. Synthetic applications of the catalytic reductive C–N
coupling reaction. (A) Synthesis of mefenamic acid and tolfenam-
ic acid. (B) Demonstration of the stereospecificity of C–N cou-
pling. Yields determined by NMR spectroscopy. (C) Selectivity
and complementarity in the functionalization of 44 by C–N cou-
pling methods. See SI for full experimental details and conditions.
The foregoing results constitute a practical, scalable, and opera-
tionally robust organophosphorus-catalyzed protocol for intermo-
lecular C–N coupling of nitroarenes and boronic acid partners.
These findings expand the biphilic reactivity of phosphetanes as
platforms for catalytic reductive O-atom transfer operating in the
PIII/PV=O redox couple, providing further precedent for the cata-
lytic potential of main group compounds in reaction classes here-
tofore dominated by transition metal catalysis.
4
Srivastava, R. S.; Nicholas, K. M. Kinetics of the Allylic Amination
of Olefins by Nitroarenes Catalyzed by [CpFe(CO)2]2. Organometallics
2005, 24, 1563.
5
Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.; Spergel, S.
ASSOCIATED CONTENT
Supporting Information
H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.; Schmidt, M. A.; Darvat-
kar, N.; Natarajan, S. R.; Baran, P. S. Practical olefin hydroamination with
nitroarenes. Science 2015, 348, 886.
6
The Supporting Information is available free of charge on the
ACS Publications website.
Cheung, C. W.; Hu, X. Amine synthesis via iron-catalysed reductive
coupling of nitroarenes with alkyl halides. Nat. Commun. 2016, 7, 12494.
7
Additional optimization results and synthetic procedures (.pdf)
Cheung, C. W.; Hu, X. Nickel-Catalyzed Reductive Transamidation
1H, 13C, and 31P NMR spectra (.pdf)
of Secondary Amides with Nitroarenes. ACS Catal. 2017, 7, 7092.
8
(a) Sapountzis, I.; Knochel, P. A New General Preparation of Poly-
functional Diarylamines by the Addition of Functionalized Arylmagnesi-
um Compounds to Nitroarenes. J. Am. Chem. Soc. 2002, 124, 9390. (b)
Doyle, W.; Staubitz, A.; Knochel, P. Mild Synthesis of Polyfunctional
Benzimidazoles and Indoles by the Reduction of Functionalized Ni-
troarenes with Phenylmagnesium Chloride. Chem. Eur. J. 2003, 9, 5323.
(c) Kopp, F.; Sapountzis, I.; Knochel, P. Preparation of Polyfunctionalized
Amines by the Addition of Functionalized Organomagnesium Reagents to
Nitrosoarenes Synlett, 2003, 885. (d) Sapountzis, I.; Knochel, P. A New
Method for the Selective Amination of 1,3- and 1,4-Dinitrobenzenes and
Protected Nitroanilines Leading to Polyfunctional 1,3- and 1,4- Disubsti-
tuted Anilines. Synlett 2004, 955. (e) Dhayalan, V.; Saemann, C.;
Knochel, P. Synthesis of polyfunctional secondary amines by the addition
of functionalized zinc reagents to nitrosoarenes. Chem. Com-
mun. 2015, 51, 3239.
AUTHOR INFORMATION
Corresponding Author
*mike@kallyope.com
*radosevich@mit.edu
Present Addresses
║Kallyope, 430 E. 29th St., Suite 1050, New York, NY 10016
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
9 Gao, H.; Xu, Q.-L.; Ess, D. H.; Kürti, L. Transition-Metal-Free, Low-
16
For electrophilic phosphonium-catalyzed methods, see: (a) Caputo,
C. B.; Hounjet, L. J.; Dobrovetsky, R.; Stephan, D. W. Lewis Acidity of
Organofluorophosphonium Salts: Hydrodefluorination by a Saturated
Acceptor. Science 2013, 341, 1374. (b) Bayne, J. M.; Stephan, D. W.
Phosphorus Lewis Acids: Emerging Reactivity and Applications in Catal-
ysis. Chem. Soc. Rev. 2016, 45, 765.
1
2
3
4
5
6
7
8
Temperature Intramolecular Amination of Aromatic C-H Bonds: Rapid
Synthesis of Fused Heterocycles.” Angew. Chem. Int. Ed. 2014, 53, 2701.
10
Rauser, M.; Ascheberg, C.; Niggemann, M. Electrophilic Amination
with Nitroarenes. Angew. Chem. Int. Ed. 2017, 56, 11570.
11 (a) Nykaza, T. V.; Harrison, T. S.; Ghosh, A.; Putnik, R. A.; Radose-
vich, A. T. A Biphilic Phosphetane Catalyzes N−N Bond-Forming Ca-
dogan Heterocyclization via PIII/PV=O Redox Cycling. J. Am. Chem. Soc.
2017, 139, 6839. (b) Nykaza, T. V.; Ramirez, A.; Harrison, T. S.; Luzung,
M. R.; Radosevich, A. T. Biphilic Organophosphorus-Catalyzed Intramo-
lecular Csp2-H Amination: Evidence for a Nitrenoid in Catalytic Cadogan
Cyclizations. J. Am. Chem. Soc. 2018, 140, 3103.
17
Attempted use of other reported phosphacyclic catalysts in the
PIII/PV=O literature proved less effective (Table S3).
18
Pompeo, M.; Farmer, J. L.; Froese, R. D. J.; Organ, M. G. Room‐
Temperature Amination of Deactivated Aniline and Aryl Halide Partners
with Carbonate Base Using a Pd‐PEPPSI‐IPentCl_ o‐Picoline Catalyst.
Angew. Chem. Int. Ed. 2014, 126, 3287.
9
12
19
(a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle, R.
(a) Trinus, F. P.; Mokhort, N. A.; Yagupol'skii, L. M.; Fadeicheva,
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
J. G. 896. The Reactivity of Organophosphorus Compounds. Part XIX.
Reduction of Nitro-Compounds by Triethyl Phosphite: A Convenient New
Route to Carbazoles, Indoles, Indazoles, Triazoles, and Related Com-
pounds. J. Chem. Soc. 1965, 0, 4831. (b) Cadogan, J. I. G. Reduction of
Nitro- and Nitroso-Compounds by Tervalent Phosphorus Reagents. Q.
Rev. Chem. Soc. 1968, 22, 222.
A. G.; Danilenko, V. S.; Ryabukha, T. K.; Fialkov, Y. A.; Kirichek, L. M.;
Endel'man, ꢀ. S.; Get'man, G. A. Mefenamic acid—A nonsteroid anti-
inflammatory agent. Pharm. Chem. J. 1977, 11, 1706. (b) Rao, B.; Zeng,
X. Aminocyanation by the Addition of N–CN Bonds to Arynes: Chemose-
lective Synthesis of 1,2-Bifunctional Aminobenzonitriles. Org. Lett. 2014,
16, 314.
13 For a review of PIII/PV=O redox cycling, see: Marsden, S. P. Catalytic
Variants of Phosphine Oxide-Mediated Organic Transformations in Sus-
tainable Catalysis; Dunn, P. J., Hii, K. K., Krische, M. J., Williams, M.
T., Eds.; John Wiley & Sons, Inc.: New York, 2013; pp 339−361.
20 (a) Brown, H. C.; Kim, K. W.; Cole T. E.; Singaram, B. J. Am. Chem.
Soc. 1986, 108, 6761. (b)Matteson, D. S.; Kim, G. Y. Asymmetric Al-
kyldifluoroboranes and Their Use in Secondary Amine Synthesis. Org.
Lett. 2002, 4, 2153. (c) Bagutski, V.; Elford, T. G.; Aggarwal, V. K. Syn-
thesis of Highly Enantioenriched C-Tertiary Amines from Boronic Esters:
Application to the Synthesis of Igmesine. Angew. Chem. Int. Ed., 2011,
50, 1080. (d) Mlynarski, S. N.; Karns, A. S.; Morken, J. P. Direct Steros-
pecific Amination of Alkyl and Aryl Pinacol Boronates J. Am. Chem. Soc.
2012, 134, 16449.
14
For recent examples of PIII/PV=O redox cycling, see: (a) O’Brien, C.
J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter, A. L.; Kunkel, S. R.;
Przeworski, K. C.; Chass, G. A. Recycling the Waste: The Development
of a Catalytic Wittig Reaction Angew. Chem. Int. Ed. 2009, 48, 6836. (b)
O’Brien, C. J.; Lavigne, F.; Coyle, E. E.; Holohan, A. J.; Doonan, B. J.
Breaking the Ring through a Room Temperature Catalytic Wittig Reaction
Chem. Eur. J. 2013, 19, 5854. (c) O’Brien, C. J.; Nixon, Z. S.; Holohan,
A. J.; Kunkel, S. R.; Tellez, J. L.; Doonan, B. J.; Coyle, E. E.; Lavigne, F.;
Kang, L. J.; Przeworski, K. C. Part I: The Development of the Catalytic
Wittig Reaction Chem. Eur. J. 2013, 19, 15281. (d) Coyle, E. E.; Doonan,
B. J.; Holohan, A. J.; Walsh, K. A.; Lavigne, F.; Krenske, E. H.; O’Brien,
C. J. Catalytic Wittig Reactions of Semi- and Nonstabilized Ylides Ena-
bledby Ylide Tuning Angew. Chem. Int. Ed. 2014, 53, 12907. (e) van
Kalkeren, H. A.; Leenders, S. H. A. M.; Hommersom, C. R. A.; Rutjes, F.
P. J. T.; van Delft, F. L. In Situ Phosphine Oxide Reduction: A Catalytic
Appel Reaction Chem. Eur. J. 2011, 17, 11290. (f) van Kalkeren, H. A.;
Bruins, J. J.; Rutjes, F. P. J. T.; van Delft, F. L. Organophosphorus-
Catalysed Staudinger Reduction Adv. Synth. Catal. 2012, 354, 1417. (g)
Zhao, W.; Yan, P. K.; Radosevich, A. T. Phosphetane catalyzes deoxy-
genative condensation of α-keto esters and carboxylic acids via PIII/PV=O
redox cycling. J. Am. Chem. Soc. 2015, 137, 616. (h) Lee, C.; Chang, T.;
Yu, J.; Reddy, G. M.; Hsiao, M.; Lin, W. Synthesis of functionalized
furans via chemoselective reduction/Wittig reaction using catalytic tri-
ethylamine and phosphine. Org. Lett. 2016, 18, 3758. (i) Saleh, N.; Voi-
turiez, A. Synthesis of 9H-pyrrolo[1,2-a]indole and 3H-pyrrolizine deriva-
tives via a phosphine-catalyzed umpolung addition/intramolecular Wittig
reaction. J. Org. Chem. 2016, 81, 4371. (j) Saleh, N.; Blanchard, F.; Voi-
turiez, A. Synthesis of nitrogen containing heterocycles and cyclopente-
none derivatives via phosphine catalyzed Michael addition/intramolecular
Wittig reaction. Adv. Synth. Catal. 2017, 359, 2304. (k) Zhang, K.; Cai,
L.; Yang, Z.; Houk, K. N.; Kwon, O. Bridged [2.2.1] bicyclic phosphine
oxide facilitates catalytic γ-umpolung addition−Wittig olefination. Chem.
Sci. 2018, 9, 1867.
15
For redox-neutral phosphine oxide organophosphorus-catalyzed
methods: Aza-Wittig (a) Campbell, T.W.; Monagle, J.J. A New Synthesis
of Mono- and Polycarbodiimides. J. Am. Chem. Soc. 1962, 84, 1493. (b)
Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Catalytic aza-
Wittig Cyclizations for Heteroaromatic Synthesis. Org. Lett. 2008, 10,
2589. (c) Wang, L.; Qin, R.-Q.; Yan, H.-Y.; Ding, M.-W. New Efficient
Synthesis of 1,4-Benzodiazepin-5-Ones by Catalytic Aza-Wittig Reaction.
Synthesis 2015, 47, 3522. Appel: (d) Denton, R. M.; An, J.; Adeniran, B.
Phosphine Oxide-Catalysed Chlorination Reactions of Alcohols under
Appel Conditions. Chem. Commun. 2010, 46, 3025. (e) Denton, R. M.;
An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.; Poulton, A. M. Catalytic
Phosphorus(V)-Mediated Nucleophilic Substitution Reactions: Develop-
ment of a Catalytic Appel Reaction. J. Org. Chem. 2011, 76, 6749. (f) An,
J.; Tang, X.; Moore, J.; Lewis, W.; Denton, R. M. Phosphorus(V)-
Catalyzed Deoxydichlorination Reactions of Aldehydes. Tetrahedron
2013, 69, 8769. (g) Yu, T.-Y.; Wang, Y.; Xu, P.-F. An Unusual Tri-
phenylphosphine Oxide Catalyzed Stereoselective 1,3-Dichlorination of
Unsaturated Ketoesters. Chem. Eur. J. 2014, 20, 98.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
TOC graphic
1
2
3
4
5
6
7
8
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
6
ACS Paragon Plus Environment