PEt3-mediated deoxygenative C–N coupling of nitroarenes and boronic acids

Article abstract of DOI:10.1016/j.tet.2019.03.035

A method for the preparation of aryl- and heteroarylamine products by triethylphosphine-mediated deoxygenative coupling of nitroarenes and boronic acids is reported. This method provides access to an array of functionalized (hetero)arylamine products from readily available starting materials under the action of an inexpensive commercial reagent. The developed triethylphosphine-mediated transformation highlights the capability of organophosphorus compounds to carry out this useful deoxygenative transformation without the necessity of any transition metal additives.

Full text of DOI:10.1016/j.tet.2019.03.035

Accepted Manuscript
PEt -mediated deoxygenative C –N coupling of nitroarenes and boronic acids
3
Trevor V. Nykaza, Junyu Yang, Alexander T. Radosevich
PII:
S0040-4020(19)30332-1
https://doi.org/10.1016/j.tet.2019.03.035
TET 30221
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 February 2019
Accepted Date: 22 March 2019
Please cite this article as: Nykaza TV, Yang J, Radosevich AT, PEt -mediated deoxygenative
3
C –N coupling of nitroarenes and boronic acids, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.03.035.
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ACCEPTED MANUSCRIPT
Graphical Abstract
PEt
3
-Mediated Deoxygenative C–N Coupling
Leave this area blank for abstract info.
of Nitroarenes and Boronic Acids
Trevor V. Nykaza, Junyu Yang, and Alexander T. Radosevich
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
PEt -Mediated Deoxygenative C–N Coupling of Nitroarenes and Boronic Acids
3
∗
Trevor V. Nykaza, Junyu Yang, and Alexander T. Radosevich
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method for the preparation of aryl- and heteroarylamine products by triethylphosphine-
mediated deoxygenative coupling of nitroarenes and boronic acids is reported. This method
provides access to an array of functionalized (hetero)arylamine products from readily available
starting materials under the action of an inexpensive commercial reagent. The developed
triethylphosphine-mediated transformation highlights the capability of organophosphorus
compounds to carry out this useful deoxygenative transformation without the necessity of any
transition metal additives.
Available online
Keywords:
C-N bond formation
Nitroarene
2
019 Elsevier Ltd. All rights reserved.
Boronic Acid
Phosphine
1
. Introduction
Aryl- and heteroaryl amines find many uses in pharmaceutical,
agrichemical, and organic materials chemistry; they are also
present in naturally occurring secondary metabolites and
derivatives thereof [1]. Developments in intermolecular arylation
of anilines, especially transition metal catalyzed C–N coupling
methods (Buchwald-Hartwig [2], Chan-Lam [3], Ullmann [4]),
have enabled broad access to these compounds. Recently, we
have reported that intermolecular (hetero)aryl C–N bond
formation is driven by deoxygenative amination of boronic acids
with nitroarenes [5]. Leveraging the utility of tricoordinate
phosphorus reagents as O-atom acceptors [6], this chemistry
advances a line of work from Cadogan who showed that P(III)-
mediated deoxygenation of nitroarenes can give nitrogen
containing heterocyclic products through intramolecular C-N
bond formation (Figure 1A) [7,8], Indeed, nitroarenes are
attractive substrates for aryl amination reactions because they are
readily available from both commercial and synthetic sources,
thereby comparing favorably with respect to nitrosoarenes [9], N-
alkyl hydroxylamines [10], azides [11], and tosyl triazenes [12]
substrates for boronic acid amination reactions. Knochel [13],
Kürti [14], and Niggemann [15] have all reported main group
reagent approaches for direct intermolecular C-N bond formation
with nitroarene substrates. Relatedly, Suárez� Pantiga and Sanz
reported that phosphine-mediated reductive coupling of
nitroarenes and boronic acids is catalyzed by an oxomolybdenum
compound [16]. Here, we show that an inexpensive commercial
phosphine reagent (triethylphosphine) can drive the
deoxygenative coupling of nitroarenes and boronic acids to give
Figure 1. Intra- and intermolecular C-N bond forming reactions
resulting from nitroarene deoxygenation. (A) Classical Cadogan
cyclization reactions. (B) This work: stoichiometric phosphine-
mediated deoxygenative C-N coupling of nitroarenes and boronic
acids.
di(hetero)arylamine products in a direct synthetic operation
without the need of any transition metal additives (Figure 1B).
The method serves as an operationally simple entry into valuable
C–N coupling products from readily available reaction partners.
—
——
∗
Corresponding author. E-mail address: radosevich@mit.edu

2
Tetrahedron
ACCEPTED MANUSCRIPT
a
Table 1. Reaction Development and Optimization
b
Entry
1
PR
3
Reagent
Yield %
Triphenylphosphine (PPh
3
, 4)
4
t
2
3
4
5
6
7
8
Tri-tert-butylphosphine (P( Bu)
3
, 5)
, 6)
, 7)
, 8)
Trimethylphosphine (PMe , 9)
Triethylphosphite (P(OEt) , 10)
Tris(dimethylamino)phosphine (P(NMe)
24
46
66
81
Tricyclohexylphosphine (PCy
Tributylphosphine (PBu
Triethylphosphine (PEt
3
3
3
c
3
39
3
8
3
, 11)
10
a
0
.5 mmol scale.
b
c
Yields determined via GC vs internal standard.
PMe was introduced as a 1 M solution in THF.
3
2
. Results and Discussion
The coupling reaction of nitrobenzene (1) and phenylboronic
successfully coupled with phenylboronic acid to give product
heteroarylamine 17 in good yield.
acid (2) to give diphenylamine (3) was selected for development
and optimization studies (Table 1). Commercially available
phosphine and phosphite reagents (3 equiv relative to 1) were
assessed for their efficacy in the reductive coupling under
The coupling reaction is similarly amenable to deoxygenative
arylation of nitrobenzene by variation of the boronic acid partner
(Figure 2B). Para-substituted boronic acids containing
o
inductively withdrawing (18) and resonance donating (19)
substitutents were found to be suitable partners for the coupling
reaction. It was also found that primary (20), secondary (21), and
even tertiary (22) carbons can transferred from alkylboronic acid
partners in serviceable yields. Consequently, the deoxygenative
coupling reaction can be used to access N-alkyl arylamines. That
said, coupling with tert-butylboronic acid remains challenging,
thus presenting a direction for future development.
previously defined reaction conditions (m-xylene, 120 C). While
triphenylphosphine 4 (entry 1) was found to produce only 4% of
the desired diphenylamine product 3, trialkylphosphines tri-tert-
butylphosphine 5 (entry 2, 24%), tricyclohexylphosphine 6 (entry
3
, 46%), and tributylphosphine 7 (entry 4, 66%) demonstrated an
increase in yield from tertiary to primary alkyl substituents
t
(
Bu>Cy> Bu). Further investigation of trialkylphosphines
indicated that triethylphosphine 8 (entry 5, 81%) provided
desired product diphenylamine 2 with a yield comparable to our
previously developed catalytic system within the same time
frame of 4 hours. Trimethylphosphine 9 (entry 6, 39%) was less
effective, perhaps attributed to the low boiling point of this
To further demonstrate the synthetic utility of the developed
transformation, variations were made to both the nitro and
boronic acid components (Figure 2C). For instance, the
deoxygenative C-N coupling 3-iodo-1-nitrobenzene with 2,3-
dimethylphenylboronic acid gave diarylamine 23 in 57% yield.
The method is similarly applicable to the reductive union of 3-
nitropyridine with 2-bromophenylboronic acid to give heteroaryl
amine product 24, albeit in modest yield. The identity of the
nitroarene substrates plays a significant role in controlling the
efficiency of the deoxygenative coupling with more electron
deficient substrates performing at a higher level. Specifically,
whereas the coupling of 3,5-difluoro-1-nitrobenzene with 4-
methoxyphenylboronic acid evolves efficiently to product 25
r
e
a
g
e
n
t
(
b
p
3
8
-
4
0
°
C
f
o
r
P
M
e
v
s
1
2
7
-
1
2
8
°
C
f
o
r
P
E
t
)
.
3
3
Triethylphosphite
10
(entry
7,
8%)
and
tris(dimethylamino)phosphine (entry 8, 10%) proved to be poor
reagents for the desired coupling reaction.
With respect to variation of the nitro coupling partner, a series
of mixed diarylamine products by coupling with phenylboronic
acid were prepared in good yield (Figure 2A). Halogen- (12),
boryl- (13), and free aniline-containing (14) are all prepared in
straightforward fashion, presenting opportunities for further
functionalization, including subsequent transition metal catalyzed
cross coupling if desired. It was found that electronic-deficient
nitroarenes excel as substrates, providing the desired products in
high yield and short reaction times. Indeed, while 3,5-
bis(trifluoromethyl)aniline is considered to be a challenging
substrate for Pd-catalyzed C-N coupling [17], 1-nitro-3,5-
bis(trifluoromethyl)benzene is readily arylated under the
deoxygenative phosphine-mediated coupling protocol to give 16.
Further highlighting the variety of possible nitroarene coupling
partners, heterocyclic substrate 5-nitroisoquinoline was
(
79%), the related coupling of 4-methoxy-1-nitrobenzene with 4-
methoxyphenylboronic acid proceeded in a much reduced yield
6, 40%). To study the effects of introducing withdrawing
2
substituents on to the core structure of challenging 4-nitroanisole,
nitroanisole substrates bearing a trifluoromethyl group either
meta (27) or ortho (28) to the nitro substituent were tested. In
both cases, yields were slightly improved and nearly identical
(44% vs 45%) – emphasizing that the introduction of
withdrawing groups to the nitroarene partner can improve the
overall yield in some difficult substrates.

ACCEPTED MANUSCRIPT
Figure 2. Examples of stoichiometric C-N coupling. See experimental section for specific reaction details.
®
1
on silica gel (SiliFlash Irregular Silica Gel, P60 40-63ꢀm). H,
13
19
C, and F NMR were collected with a Bruker AVANCE III
DRX 400 spectrometer and processed using MestReNova. H
NMR chemical shifts are given in ppm with respect to solvent
3
. Conclusion
1
We have demonstrated that stoichiometric reductive coupling
13
1
residual peak (CDCl , δ 7.26 ppm) and C{ H} NMR shifts are
3
of nitroarenes and boronic acids using triethylphosphine enables
the preparation of useful di(hetero)arylamine products. While
phosphines are commonly encountered as spectator ligands in
transition metal-catalyzed transformations [18], we have shown
that deoxygenative C-N coupling of nitroarenes and boronic
acids can be mediated by a phosphine alone. The phosphine-
given in ppm with respect to (CDCl δ 77.16 ppm). Multiplicities
3
are described as s = singlet, br s = broad singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublets, tt = triplet of
triplets, m = multiplet. Coupling constants are reported in Hertz
(Hz). High-resolution ESI mass spectra were obtained from the
MIT Department of Chemistry Instrumentation Facility on an
Agilent 6545 Q-TOF instrument.
mediated
transformation
showcases
the
ability
of
triethylphosphine to deoxygenate nitroarenes and expands on our
previously reported catalytic C-N cross coupling by utilizing a
commercially available phosphine reagent.
4
.1. General Procedure
A glass culture tube containing a magnetic stir bar was
charged with a nitroarene substrate and boronic acid, then fitted
with a PTFE-lined silicone septum within a phenolic screw-
thread open-top cap. The vessel was evacuated and backfilled
with nitrogen on a Schlenk line. Dry m-xylene (2 mL, 0.5 M)
was added via syringe, followed by triethylphosphine (0.44 mL,
3 equivalents) and the reaction mixture was heated 120 °C with
stirring. Upon completion, the reaction mixture was cooled to
ambient temperature then diluted with 10 mL of distilled water.
With the aid of ethyl acetate (ca. 3x10 mL), the reaction mixture
was transferred to a separatory funnel. After mixing and
separating the phases, the organic layer was washed with 10 mL
of a 1 M NaOH aqueous solution, and 10 mL of brine. Each
aqueous phase was back-extracted with one 10 mL portion of
ethyl acetate. The combined organic layers were dried over
anhydrous sodium sulfate, filtered and concentrated by rotary
evaporation. The crude residues were purified via column
chromatography to yield pure coupling products. Columns were
4
. Experimental section
All reagents (including commercial phosphorus reagents used
in optimization studies) were purchased from commercial
vendors (Sigma-Aldrich, Alfa Aesar, Acros, TCI, or Oakwood
Chemical, Combi-Blocks) and used without further purification
unless otherwise indicated. Nitrobenzene was distilled over CaH
prior to use. Anhydrous m-xylene was obtained from a Sigma-
Aldrich and used as received. All other solvents were ACS grade
or better and were used without further purification.
Manipulations were conducted under an atmosphere of dry N2
gas unless otherwise noted. The phosphine-mediated
deoxygenative C–N coupling reactions were carried out in
threaded glass culture tubes outfitted with a phenolic screw-
thread open top cap and PTFE-lined silicone septum. No special
drying of the reaction vessel components was conducted prior to
the reported reactions. Column chromatography was carried out

4
Tetrahedron
ACCEPTED MANUSCRIPT
primarily slurry packed with hexanes and mobile phase polarity
was increased gradually to the mixture indicated. Note: hexanes
Following an altered general procedure using phenylboronic
acid
(134
mg,
1.10
mmol,
1.1
equiv)
3,5-
=
Hex, dichloromethane = DCM, ethyl acetate = EA.
bis(trifluoromethyl)nitrobenzene (169 µL, 1.00 mmol, 1.0 equiv),
and distilled water (0.16 mL, 9 mmol, 9 equiv) for 2 h at 120 °C.
The product was purified by column chromatography with a
gradient from hexanes to 10% DCM/2% EA in hexanes on silica
4
.1.2. 2-Iodo-N-phenylaniline (12)
Following the general procedure using phenylboronic acid
(
0
7
215 mg, 0.70 mmol, 70%). R (10% DCM/2% EA in hexanes)
f
1
(134 mg, 1.10 mmol, 1.1 equiv) and 1-iodo-2-nitrobenzene (249
.28. H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.35 (m, 4H),
mg, 1.00 mmol, 1.0 equiv) for 3 h at 120 °C. The product was
purified by column chromatography with a gradient from
hexanes to 10% DCM/1% EA/89% Hex on silica (231 mg, 0.78
13
.33 (s, 1H), 7.20 – 7.08 (m, 3H), 5.98 (br s, 1H). C NMR (101
MHz, Chloroform-d) δ 145.46, 140.48, 132.85 (q, J = 33.0 Hz),
1
130.00, 123.99, 123.49 (q, J = 272.8 Hz), 120.57, 115.28 (d, J =
mmol, 78%). R (10% DCM/1% EA/89% Hex) 0.61. H NMR
f
19
3
.3 Hz), 113.11 (p, J = 3.9 Hz). F NMR (376 MHz,
(400 MHz, Chloroform-d) δ 7.66 (d, J = 7.9 Hz, 1H), 7.21 (t, J =
Chloroform-d) δ -63.21. HRMS (ESI) calculated for C H F N
1
4
9 6
7
.7 Hz, 2H), 7.14 – 7.05 (m, 2H), 7.02 (d, J = 7.9 Hz, 2H), 6.93
+
13
[M+H] : 306.0712; Found: 306.0706.
(
t, J = 7.3 Hz, 1H), 6.57 – 6.45 (m, 1H), 5.80 (br s, 1H).
NMR (101 MHz, Chloroform-d) δ 144.04, 142.11, 139.63,
29.57, 129.14, 122.66, 122.04, 120.11, 115.98, 88.93. HRMS
C
4.1.7. N-Phenylisoquinolin-5-amine (17)
1
+
Following the general procedure using phenylboronic acid
134 mg, 1.10 mmol, 1.1 equiv) and 5-nitroisoquinoline (174 mg,
(ESI) calculated for C H IN [M+H] : 295.9931; Found:
12 10
(
2
95.9927.
.1.3. N-Phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
1
.00 mmol, 1.0 equiv) for 3 h at 120 °C. The product was
4
purified by column chromatography with 20% DCM/20% EA in
yl)aniline (13)
hexanes to full EA on silica (154 mg, 0.70 mmol, 70%). R (EA)
f
1
0
.52. H NMR (400 MHz, Chloroform-d) δ 9.25 (s, 1H), 8.51 (d,
Following the general procedure using phenylboronic acid
J = 6.0 Hz, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.63 (d, J = 7.7 Hz,
(134 mg, 1.10 mmol, 1.1 equiv) and 4-nitrobenzeneboronic acid
1
7
H), 7.56 – 7.47 (m, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.05 (d, J =
.6 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.05 (br s, 1H). C NMR
pinacol ester (249 mg, 1.00 mmol, 1.0 equiv) for 5 h at 120 °C.
The product was purified by column chromatography with 10%
DCM/1% EA/89% Hex on silica (212 mg, 0.72 mmol, 72%). Rf
13
(101 MHz, Chloroform-d) δ 153.09, 143.62, 142.89, 138.55,
1
129.87, 129.82, 129.64, 127.68, 121.71, 121.56, 118.42, 117.96,
(10% DCM/1% EA/89% Hex) 0.13. H NMR (400 MHz,
+
1
14.81. HRMS (ESI) calculated for C H N [M+H] : 221.1073,
15 12 2
Chloroform-d) δ 7.73 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 8.3, 7.4 Hz,
Found: 221.1066.
2
1
1
2
2
H), 7.14 (d, J = 8.3 Hz, 2H), 7.06 – 6.97 (m, 3H), 5.88 (br s,
H), 1.35 (s, 12H). C NMR (101 MHz, Chloroform-d) δ
45.98, 141.73, 136.11, 129.17, 121.71, 118.93, 115.32, 83.25,
4.67. HRMS (ESI) calculated for C H BNO [M+H] :
13
4
.1.8. 4-Fluoro-N-phenylaniline (18)
+
Following the general procedure using 4-fluorophenylboronic
18
22
2
96.1820; Found: 296.1820.
acid (154 mg, 1.10 mmol, 1.1 equiv) and nitrobenzene (103 µL,
.00 mmol, 1.0 equiv) for 18 h at 120 °C. The product was
1
1
4
.1.4. 4-Chloro-N -phenylbenzene-1,3-diamine (14)
purified by column chromatography with a gradient from
hexanes to 10% DCM in hexanes to 20% DCM/1% EA in
Following the general procedure using phenylboronic acid
134 mg, 1.10 mmol, 1.1 equiv) and 2-chloro-5-nitroaniline (173
hexanes to 20% DCM/5% EA in hexanes on silica (116 mg, 0.62
(
1
mmol, 62%). R (10% DCM in hexanes) 0.10. H NMR (400
f
mg, 1.00 mmol, 1.0 equiv) for 7 h at 120 °C. The product was
purified by column chromatography with 20% EA in hexanes on
MHz, Chloroform-d) δ 7.28 (t, J = 7.5 Hz, 2H), 7.12 – 6.97 (m,
13
6
H), 6.93 (t, J = 7.3 Hz, 1H), 5.59 (br s, 1H). C NMR (101
silica (130 mg, 0.59 mmol, 59%). R (20% EA in hexanes) 0.27.
f
1
MHz, Chloroform-d) δ 158.06 (d, J = 240.1 Hz), 143.94, 138.94
H NMR (400 MHz, Chloroform-d) δ 7.27 (t, J = 7.8 Hz, 2H),
(
2
d, J = 2.4 Hz), 129.41, 120.62, 120.55, 116.80, 115.94 (d, J =
2.5 Hz). F NMR (376 MHz, Chloroform-d) δ -122.00.
7
1
2
1
.14 – 7.02 (m, 3H), 6.95 (t, J = 7.3 Hz, 1H), 6.49 (d, J = 2.4 Hz,
H), 6.40 (dd, J = 8.5, 2.4 Hz, 1H), 5.57 (br s, 1H), 3.98 (br s,
H). C NMR (101 MHz, Chloroform-d) δ 143.63, 143.14,
19
13
4
.1.9. 4-(Benzyloxy)-N-phenylaniline (19)
42.90, 130.05, 129.49, 121.48, 118.55, 111.42, 109.19, 104.49.
+
Following
benzyloxy)phenylboronic acid (342 mg, 1.50 mmol, 1.5 equiv)
and nitrobenzene (103 µL, 1.00 mmol, 1.0 equiv) for 18 h at 120
C. The product was purified by column chromatography with a
gradient from hexanes to 8% DCM/4% EA in hexanes on silica
189 mg, 0.69 mmol, 69%). R (8% DCM/4% EA in hexanes)
the
general
procedure
using
4-
HRMS (ESI) calculated for C H ClN [M+H] : 219.0684;
Found: 219.0684.
12
11
2
(
4
.1.5. 3-Fluoro-2-methyl-N-phenylaniline (15)
°
Following the general procedure using phenylboronic acid
(
f
(134 mg, 1.10 mmol, 1.1 equiv) and 1-fluoro-2-methyl-3-
1
0
7
2
.37. H NMR (400 MHz, Chloroform-d) δ 7.51 – 7.45 (m, 2H),
.42 (t, J = 7.3 Hz, 2H), 7.39 – 7.33 (m, 1H), 7.28 – 7.21 (m,
H), 7.08 (d, J = 8.5 Hz, 2H), 6.99 – 6.92 (m, 4H), 6.87 (t, J =
nitrobenzene (122 µL, 1.00 mmol, 1.0 equiv) for 16 h at 120 °C.
The product was purified by column chromatography with 5%
EA in hexanes on silica (164 mg, 0.82 mmol, 82%). R (5% EA
in hexanes) 0.40. H NMR (400 MHz, Chloroform-d) δ 7.31 (t, J
f
13
1
7.3 Hz, 1H), 5.50 (br s, 1H), 5.07 (s, 2H). C NMR (101 MHz,
Chloroform-d) δ 154.50, 145.09, 137.31, 136.16, 129.42,
=
7.7 Hz, 2H), 7.15 – 6.96 (m, 5H), 6.73 (t, J = 8.6 Hz, 1H), 5.45
13
128.69, 128.04, 127.61, 122.01, 119.78, 115.91, 115.87,
(br s, 1H), 2.20 (s, 3H). C NMR (101 MHz, Chloroform-d) δ
+
7
0.59. HRMS (ESI) calculated for C H NO [M+H] : 276.1383;
19
17
1
1
1
62.00 (d, J = 242.3 Hz), 143.42, 143.33 (d, J = 6.5 Hz), 129.48,
26.91 (d, J = 10.2 Hz), 121.36, 118.39, 113.64 (d, J = 2.7 Hz),
08.36 (d, J = 23.1 Hz), 9.21 (d, J = 6.3 Hz). F NMR (376
Found: 276.1380.
19
4
.1.10. N-Phenethylaniline (20)
Following the general procedure on 0.5 mmol scale using
MHz, Chloroform-d) δ -115.62. HRMS (ESI) calculated for
C H FN [M+H] : 202.1027; Found: 202.1024.
+
13
12
phenethylboronic acid (83 mg, 0.55 mmol, 1.1 equiv),
nitrobenzene (51 µL, 0.50 mmol, 1.0 equiv), and 3 equivalents of
4
.1.6. N-Phenyl-3,5-bis(trifluoromethyl)aniline (16)

PEt (0.22 mL, 1.5 mmol) for 4 h at 120 °C. The product was
purified by column chromatography with hexanes to 20%
126.30, 123.90, 122.22, 116.32, 113.13. HRMS (ESI) calculated
for C H BrN [M+H] : 250.0052, Found: 250.0052.
3
ACCEPTED MANUSCRIPT
11 9 2
+
DCM/0.4% EA in hexanes gradient on silica (50 mg, 0.25 mmol,
1
4.1.15. 3,5-Difluoro-N-(4-methoxyphenyl)aniline (25)
Following the general procedure using
methoxyphenylboronic acid (167 mg, 1.10 mmol, 1.1 equiv) and
3,5-difluoronitrobenzene (113 µL, 1.00 mmol, 1.0 equiv) for 3 h
at 120 °C. The product was purified by column chromatography
5
1%). R (20% DCM/0.4% EA in hexanes) 0.73. H NMR (400
f
MHz, Chloroform-d) δ 7.35 (t, J = 7.3 Hz, 2H), 7.31 – 7.18 (m,
4-
5
1
H), 6.74 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 7.6 Hz, 2H), 3.70 (br s,
H), 3.43 (t, J = 7.0 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H). C NMR
13
(101 MHz, Chloroform-d) δ 148.12, 139.43, 129.40, 128.91,
1
28.72, 126.54, 117.58, 113.11, 45.15, 35.64. HRMS (ESI)
with 9% EA/1% DCM in hexanes on silica (186 mg, 0.79 mmol,
+
1
calculated for C H N [M+H] : 198.1277; Found: 198.1276.
79%). R (9% EA/1% DCM in hexanes) 0.32. H NMR (400
14
15
f
MHz, Chloroform-d) δ 7.10 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.9
Hz, 2H), 6.31 (dd, J = 9.8, 2.1 Hz, 2H), 6.22 (tt, J = 9.1, 2.3 Hz,
4
.1.11. N-Cyclopropylaniline (21)
13
Following the general procedure using cyclopropylboronic
1H), 5.63 (br s, 1H), 3.82 (s, 3H). C NMR (101 MHz,
Chloroform-d) δ 164.21 (dd, J = 244.5, 15.7 Hz), 156.75, 148.55
(t, J = 12.9 Hz), 133.61, 124.64, 114.95, 98.09 – 96.61 (m), 94.06
acid (96 mg, 1.10 mmol, 1.1 equiv) and nitrobenzene (103 µL,
.00 mmol, 1.0 equiv) for 9 h at 120 °C. The product was
1
19
purified by column chromatography with 10% DCM/0.4% EA in
hexanes on silica (73 mg, 0.55 mmol, 55%). H NMR (400 MHz,
(t, J = 26.1 Hz), 55.67. F NMR (376 MHz, Chloroform-d) δ -
1
+
110.02. HRMS (ESI) calculated for C H F NO [M+H] :
13
11 2
Chloroform-d) δ 7.22 (dd, J = 8.5, 7.4 Hz, 2H), 6.82 (d, J = 7.6
Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 4.18 (br s, 1H), 2.50 – 2.41 (m,
236.0881, Found: 236.0883.
13
4.1.16. Bis(4-methoxyphenyl)amine (26)
1
H), 0.79 – 0.72 (m, 2H), 0.57 – 0.51 (m, 2H). C NMR (101
MHz, Chloroform-d) δ 148.79, 129.22, 117.84, 113.26, 25.35,
Following
the
general
procedure
using
4-
+
7
.53. HRMS (ESI) calculated for C H N [M+H] : 134.0964;
methoxyphenylboronic acid (167 mg, 1.10 mmol, 1.1 equiv) and
4-nitroanisole (153 mg, 1.00 mmol, 1.0 equiv), for 7 h at 120 °C.
The product was purified by column chromatography with 5%
EA/5% DCM in hexanes on silica (69 mg, 0.30 mmol, 30%). R
(5% EA/5% DCM in hexanes) 0.07. H NMR (400 MHz,
9
11
Found: 134.0961.
4
.1.12. N-(tert-Butyl)aniline (22)
f
1
Following an altered general procedure on 0.5 mmol scale
using tert-butylboronic acid (112 mg, 1.1 mmol, 2.2 equiv),
nitrobenzene (51 µL, 0.50 mmol, 1.0 equiv), and 6 equivalents of
Chloroform-d) δ 6.94 (d, J = 8.9 Hz, 4H), 6.83 (d, J = 8.9 Hz,
4H), 5.29 (br s, 1H), 3.79 (s, 6H). C NMR (101 MHz,
13
PEt (0.44 mL, 3.0 mmol) in m-xylene (2 mL, 0.25 M) for 12 h at
Chloroform-d) δ 154.37, 138.07, 119.67, 114.85, 55.79. HRMS
3
+
1
20 °C. The product was purified by column chromatography
(ESI) calculated for C H NO [M+H] : 230.1176; 230.1175.
14
15
2
with hexanes to 25% EA in hexanes gradient on silica (24 mg,
1
For the catalytic reaction on the same scale (1 mmol), an
altered general procedure was followed in which 1,2,2,3,4,4-
hexamethylphosphetane 1-oxide (26 mg, 0.15 mmol, 15 mol%)
was introduced prior to evacuation and phenylsilane (0.25 mL,
2.00 mmol, 2.0 equiv) was added via syringe instead of
triethylphosphine. After heating at 120 °C for 16 h, the product
was purified by column chromatography with a gradient of 5%
EA/5% DCM in hexanes to 10% EA/10% DCM in hexanes on
0
.16 mmol, 32%). H NMR (400 MHz, Chloroform-d) δ 7.18 (t,
J = 8.1, 7.6 Hz, 2H), 6.83 – 6.71 (m, 3H), 3.42 (br s, 1H), 1.36 (s,
1
3
9
1
H). C NMR (101 MHz, Chloroform-d) δ 146.99, 129.01,
18.43, 117.60, 51.60, 30.23. HRMS (ESI) calculated for
+
C H N [M+H] : 150.1277; Found: 150.1273. Tert-butylboronic
10
15
acid was prepared using tert-butylmagnesium chloride and
trimethylborate according to a known procedure [19Error!
Reference source not found.].
1
silica (98 mg, 0.43 mmol, 43%). H NMR (400 MHz,
4
.1.13. N-(3-Iodophenyl)-2,3-dimethylaniline (23)
Following the general procedure
Chloroform-d) δ 6.95 (d, J = 8.7 Hz, 4H), 6.83 (d, J = 8.7 Hz,
13
4
H), 5.29 (br s, 1H), 3.79 (s, 6H). C NMR (101 MHz,
using
2,3-
Chloroform-d) δ 154.37, 138.07, 119.67, 114.85, 55.79.
dimethylphenylboronic acid (165 mg, 1.10 mmol, 1.1 equiv) and
1
1
-iodo-3-nitrobenene (249 mg, 1.00 mmol, 1.0 equiv), for 18 h at
20 °C. The product was purified by column chromatography
4.1.17. 4-Methoxy-N-(4-methoxyphenyl)-3-(trifluoromethyl)-
aniline (27)
with hexanes to 10% EA in hexanes gradient on silica (185 mg,
1
Following
methoxyphenylboronic acid (167 mg, 1.10 mmol, 1.1 equiv) and
-methoxy-4-nitro-2-(trifluoromethyl)benzene (221 mg, 1.00
mmol, 1.0 equiv), for 16 h at 120 °C. The product was purified
by column chromatography with a gradient of 10% EA in
the
general
procedure
using
4-
0
.57 mmol, 57%). R (10% EA in hexanes) 0.63. H NMR (400
f
MHz, Chloroform-d) δ 7.18 – 7.13 (m, 2H), 7.11 – 7.06 (m, 2H),
1
7
1
.01 – 6.96 (m, 1H), 6.91 (t, J = 8.1 Hz, 1H), 6.75 (d, J = 8.1 Hz,
H), 5.36 (br s, 1H), 2.34 (s, 3H), 2.16 (s, 3H). C NMR (101
13
MHz, Chloroform-d) δ 146.85, 139.67, 138.27, 130.80, 130.11,
hexanes on silica to 25% EA in hexanes (131 mg, 0.44 mmol,
1
1
28.32, 126.25, 125.95, 124.38, 120.43, 115.01, 95.12, 20.78,
1
+
44%). R
f
(10% EA in hexanes) 0.17. H NMR (400 MHz,
3.93. HRMS (ESI) calculated for C H IN [M+H] : 324.0244;
14
14
Chloroform-d) δ 7.17 (d, J = 2.7 Hz, 1H), 7.07 (dd, J = 8.8, 2.6
Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.93 – 6.83 (m, 3H), 5.36 (br s,
Found: 324.0242.
13
4
.1.14. N-(2-Bromophenyl)pyridin-3-amine (24)
Following an altered general procedure using 2-
1H), 3.86 (s, 3H), 3.80 (s, 3H). C NMR (101 MHz,
Chloroform-d) δ 155.18, 151.57, 138.23, 136.59, 123.72 (q, J =
2
1
6
2
72.3 Hz), 121.50, 120.97, 116.31 (q, J = 5.3 Hz), 114.99,
bromophenylboronic acid (221 mg, 1.10 mmol, 1.1 equiv) and 3-
nitropyridine (124 mg, 1.00 mmol, 1.0 equiv), for 12 h at 80 °C.
The product was purified by column chromatography with 75%
19
13.87, 56.71, 55.75. F NMR (376 MHz, Chloroform-d) δ -
+
2.30. HRMS (ESI) calculated for C H F NO [M+H] :
15
14
3
2
98.1049, Found: 298.1048.
EA in hexanes on silica (100 mg, 0.40 mmol, 40%). R (75% EA
f
1
in hexanes) 0.34. H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J
4.1.18. 4-Methoxy-N-(4-methoxyphenyl)-2-(trifluoromethyl)-
=
2.6 Hz, 1H), 8.27 (dd, J = 4.7, 1.4 Hz, 1H), 7.55 (d, J = 7.6 Hz,
aniline (28)
1
8
H), 7.47 (d, J = 8.2 Hz, 1H), 7.25 – 7.18 (m, 3H), 6.81 (ddd, J =
.0, 5.6, 3.2 Hz, 1H), 6.08 (br s, 1H). C NMR (101 MHz,
Following
the
general
procedure
using
4-
13
methoxyphenylboronic acid (167 mg, 1.10 mmol, 1.1 equiv) and
4-methoxy-1-nitro-2-(trifluoromethyl)benzene (221 mg, 1.00
Chloroform-d) δ 143.73, 142.30, 140.51, 138.46, 133.35, 128.40,

6
Tetrahedron
ACCEPTED MANUSCRIPT
7
.
(a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.; Searle,
R. J. G. J. Chem. Soc. 1965, 0, 4831-4837. (b) Cadogan, J. I. G. Q.
Rev. Chem. Soc. 1968, 22, 222-251.
For Cadogan cyclization reactions catalytic in phosphorus see: (a)
Nykaza, T. V.; Harrison, T. S.; Ghosh, A.; Putnik, R. A.;
Radosevich, A. T. J. Am. Chem. Soc. 2017, 139, 6839–6842. (b)
Nykaza, T. V.; Ramirez, A.; Harrison, T. S.; Luzung, M. R.;
Radosevich, A. T. J. Am. Chem. Soc. 2018, 140, 3103–3113.
(a) Yu, Y.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631-
mmol, 1.0 equiv), for 16 h at 120 °C. The product was purified
by column chromatography with a 5% DCM/1% EA in hexanes
(
0
6
133 mg, 0.45 mmol, 45%). R (5% DCM/1% EA in hexanes)
f
1
8
.
.17. H NMR (400 MHz, Chloroform-d) δ 7.12 – 7.05 (m, 2H),
.99 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 8.6
1
3
Hz, 2H), 5.61 (br s, 1H), 3.80 (s, 6H). C NMR (101 MHz,
Chloroform-d) δ 155.58, 153.01, 137.14, 136.17, 124.61 (q, J =
9
.
2
72.8 Hz), 122.33, 120.12, 119.07, 114.93, 111.79 (q, J = 5.7
2
1
634. (b) Roscales, S.; Csákÿ, A. G. Org. Lett. 2018, 20, 1667-
671.
19
Hz), 55.97, 55.73. F NMR (376 MHz, Chloroform-d) δ -61.81.
HRMS (ESI) calculated for C H F NO [M+H] : 298.1049,
Found: 298.1047.
+
15
14
3
2
10. Sun, H.-B.; Gong, L.; Tian, Y.-B.; Wu, J.-G.; Zhang, X.; Liu, J.;
Fu, Z.; Niu, D. Angew. Chem. Int. Ed. 2018, 57, 9456-9460.
1
1. Ou, L.; Shao, J.; Zhang, G.; Yu, Y. Tetrahedron Lett. 2011, 52,
430-1431.
1
Acknowledgments
1
1
2. Sarma, M. J.; Phukan, P. Synth. Commun. 2018, 48, 656-662.
3. (a) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124, 9390-
9391. (b) Doyle, W.; Staubitz, A.; Knochel, P. Chem. Eur.
J. 2003, 9, 5323-5331. (c) Kopp, F.; Sapountzis, I.; Knochel, P.
Synlett, 2003, 885-887. (d) Sapountzis, I.; Knochel,
P. Synlett 2004, 955-958. (e) Dhayalan, V.; Saemann, C.;
Knochel, P. Chem. Commun. 2015, 51, 3239-3242.
Funding was provided by NIH NIGMS (GM114547) and
MIT. J.Y. thanks the MIT Undergraduate Research Opportunities
Program. T.V.N. thanks Dr. Jeffrey Lipshultz and Connor
Gilhula for HRMS data collection.
1
1
1
4. Gao, H.; Xu, Q.-L.; Ess, D. H.; Kürti, L. Angew. Chem. Int.
Ed. 2014, 53, 2701-2705.
5. Rauser, M.; Ascheberg, C.; Niggemann, M. Angew. Chem. Int. Ed.
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Supplementary Material
Nykaza, T. V.; Cooper, J. C.; Li, G.; Mahieu, N.; Ramirez, A.;
Luzung, M. R.; Radosevich, A. T. J. Am. Chem. Soc. 2018, 140,
1
13
Supplementary data (including H and C NMR spectra) for
this article can be found online.
1
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