Preparation of diarylamines by the addition of 4-(N,N-dimethylamino)phenyllithium to nitroarenes

Article abstract of DOI:10.1016/j.tetlet.2003.07.002

The addition of 4-(N,N-dimethylamino)phenyllithium to nitroarenes in THF (-78°C) affords the corresponding diarylamines in one-pot and the reaction appears to be general in scope. A 'nitroso'-based mechanism is proposed for this novel nitroreductive N-arylation reaction.

Full text of DOI:10.1016/j.tetlet.2003.07.002

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7549–7552
Preparation of diarylamines by the addition of
-(N,N-dimethylamino)phenyllithium to nitroarenes
4
Tianle Yang and Bongsup P. Cho*
Department of Biomedical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
Received 20 June 2003; revised 21 July 2003; accepted 25 July 2003
Abstract—The addition of 4-(N,N-dimethylamino)phenyllithium to nitroarenes in THF (−78°C) affords the corresponding
diarylamines in one-pot and the reaction appears to be general in scope. A ‘nitroso’-based mechanism is proposed for this novel
nitroreductive N-arylation reaction.
©
2003 Elsevier Ltd. All rights reserved.
1
We have recently developed a general method for the
afforded a 1:7 ratio of the desired 2 and a tandem
addition adduct 3, whose structures have been thor-
preparation of N-desmethylated metabolites of mala-
2
1
chite green,
a
potentially genotoxic dye. We
oughly characterized. The major product was initially
1
envisioned that an addition of 4-(N,N-dimethyl-
amino)phenyllithium (1) to 4-nitrobenzophenone
should give the didesmethyl leuco derivative 2 after the
usual acid-catalyzed dehydration and reduction
thought to be the isomeric adduct 4; however, the
3
identity of 3 was confirmed by NMR. Clearly, the
formation of the diarylamine 3 can be rationalized in
terms of simultaneous addition of 1 to both the ketone
and nitro groups of 4-nitrobenzophenone.
(
Scheme 1). Interestingly, however, the sequence
Scheme 1.
Keywords: aryllithium; diarylamine; nitroarene.
*
Corresponding author. Tel.: 401-874-5024; fax: 401-874-5048; e-mail: bcho@uri.edu
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.07.002

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T. Yang, B. P. Cho / Tetrahedron Letters 44 (2003) 7549–7552
Diarylamines belong to an important class of func-
tional groups that are accessible mostly via metal-cata-
lyzed cross-coupling reactions using aromatic amines
While the mechanisms of the nitroreductive N-arylation
with Grignard reagents have been studied, little is
known regarding the reactions with aryllithium. Reac-
tion of nitroarenes with aryl Grignard reagents is
shown to produce a coupled product diaryl hydroxyl-
amine via a nitroso intermediate. The resulting hydrox-
5
(
collectively known as Buchwald–Hartwig reaction) as
4
precursors. While the reaction of nitroarenes with
5
Grignard reagents has been studied extensively, sur-
prisingly little is known about analogous reactions with
ylamine could be further reduced to diarylamine by an
6
organolithium agents. Buck and Kobrich have
5d,e
additional Grignard reagent,
but Sapountzis and
reported that nitrobenzene, or nitrosobenzene, reacts
with excess phenyllithium to give diphenylamine and
azobenzene as well as phenol. The phenol formation
reaction, which utilizes nitrobenzene as a novel aro-
matic hydroxylating agent, has been employed for the
preparation of certain phenolic substances that are
5b
Knochel have reported that a reductive workup pro-
cedure (NaBH /FeCl or Zn) is required for its prepara-
4
2
tive application. The general validity of this mechanism
had been substantiated by isolation of the highly air
sensitive hydroxylamine intermediate and the corre-
sponding phenol.
7
otherwise difficult to obtain. However, the use of
nitroarenes as precursors for the preparation of diaryl-
amines has not been explored. We have investigated the
reactions of various nitroarenes with 1 and found that
A similar mechanism can be applied for reactions with
aryllithium. Thus, the first equivalent of 1 attacks the
oxygen atom of the nitro group via either a radical or
a polar mechanism to produce an adduct 6 (Scheme 2).
Decomposition of 6 furnishes 8 and 4-(N,N-dimethyl-
8
the corresponding diarylamines can be prepared in a
simple, one-step process.
12
amino)phenol (7). Like the Grignard case, the nitroso
intermediate 8 may react with the second equivalent of
1 to form a ‘hydroxylamine’ intermediate (9). Alterna-
tively, a novel ‘nitrenoid’ (10) intermediate can be
formed if addition occurs at the oxygen atom of the
A series of nitroarenes have been employed to give the
N,N-dimethylated diarylamines in moderate yields
9
(
Table 1). The use of excess (at least 3 equiv.) aryl-
lithium is required to complete the nitroreductive N-
arylation (Scheme 2). All the reactions were conducted
under nitrogen with exclusion of oxygen. Although
yields are generally lower than the existing Grignard-
6a,13
nitroso group of 8.
These species can then react
with the third equivalent of 1 to produce diarylamine 5
and 7 upon protonation. Support for these mechanisms
comes from the fact that the phenol 7 is isolated as a
main product and that reaction yields increase with the
use of 3 equivalents of 1 (Table 1). We have shown that
nitrosobenzene reacts with 3 equivalents of 1 to give 5a
5
b
4
based and metal-catalyzed reactions, the new reac-
tion is simple and is complementary to existing
procedures. It offers a valuable alternative of using
nitroarenes as a starting material for aromatic car-
bonꢀnitrogen bond formation.
a
Table 1. Reactions of 4-(N,N-dimethylamino)phenyllithium (1) with nitroarenes

T. Yang, B. P. Cho / Tetrahedron Letters 44 (2003) 7549–7552
7551
Scheme 2.
as the sole product (44%). This is contrasted with the
analogous reaction with arylmagnesium chloride,
which required a reductive work up. It appears that
the hardness of aryllithium reagent is an important
factor in determining the relative propensity for phe-
nol formation. Also, it may be that the lithiated 5 is
sufficiently electron-rich to compete with 1 for reduc-
ing the hydroxylamine 9, thereby decreasing the over-
all yield. Colored reaction mixtures indicate that some
byproducts might be formed from the radical,
References
1. (a) Cho, B. P.; Yang, T.; Blankenship, L. R.; Moody, J.
D.; Churchwell, M.; Beland, F. A.; Culp, S. J. Chem. Res.
Toxicol. 2003, 16, 285–294; (b) Cho, B. P.; Blankenship,
L. R.; Moody, J. D.; Doerge, D.; Beland, F. A.; Culp, S.
J. Tetrahedron 2000, 56, 7379–7388.
2
. Culp, S. J.; Beland, F. A. J. Am. College of Toxicol. 1996,
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. 3: mp 155–156°C (ethylacetate:hexane): TLC Rf 0.31
(benzene:hexane:ether:triethylamine=10:15:3:0.5), R 0.75
CHCl :MeOH=95:5); HPLC t 23.7 min (acetonitrile in
1
3
’
f
Me NC H , produced in reactions involving single
2
6
4
(
0
3
R
electron transfers via charge transfer complexes.
.1 mM pH 4.50 ammonium acetate 10–90%, a 30 min
gradient); UV
297 nm (log 4.60), 263 nm (log 4.57):
umax
In summary, we have described a novel aryl car-
bonꢀnitrogen bond formation involving nitroarenes
and aryllithium. The reaction of aryllithium 1 with
nitroarenes provides direct access to N,N-dimethyl-
ated diarylamines in one-pot without any additional
reduction steps and appears to be general in scope.
Efforts to elucidate the reaction mechanism and to
expand nitroarenes to prepare a variety of diaryl-
amines including arylamine-nucleoside adducts are
currently underway.
1
H NMR (500 MHz, DMSO-d ) l 7.55 (s, NH, 1H, H ,
6
13
D O exchangeable), 7.26 (dd, 2H, H , J=7.53, 7.60 Hz),
2
4
7.15 (dd, 1H, H , J=7.32, 7.34 Hz), 7.08 (d, 2H, H ,
5
3
J=7.22 Hz), 6.94 (d, 2H, H , J=8.91 Hz), 6.90 (d, 2H,
8
H , J=8.71 Hz), 6.84 (d, 2H, H , J=8.59 Hz), 6.77 (d,
2
6
2
H, H , J=8.61 Hz), 6.67 (d, 2H, H , J=8.95 Hz), 6.64
7
9
(
d, 2H, H , J=8.75 Hz), 5.29 (s, 1H, H ), 2.83 (s, 6H,
1 10
13
11
H ), 2.80 (s, 6H, H ); C NMR (126 MHz, DMSO-d6)
12
l 148.74 (q), 145.86 (q), 145.27 (q), 143.89 (q), 133.64 (q),
33.03 (q), 132.11 (q), 129.47 (C6), 129.38 (C2), 128.84
C4 or C3), 128.04 (C3 or C4), 125.71 (C5), 120.87 (C8),
14.10 (C7), 113.85 (C9), 112.35 (C1), 54.40 (C10), 40.85
C11), 40.22 (C12); ESI-MS m/z 422 (M+1); HRMS calcd
for C H N , 421.2510. Found 421.2518. Anal. calcd for
1
(
1
(
Acknowledgements
29
31
3
C H N , C, 82.62; H, 7.41; N, 9.97%. Found C, 82.70;
H, 7.66; N, 9.89.
4. For reviews: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818; (b)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067
and references cited therein; (c) Hamann, B. C.; Hartwig,
29
31
3
This research was supported in part by financial sup-
port by the National Center for Research Resources,
NIH, through grant 5 P20 RR16457-02 via the
Rhode Island Biomedical Research Infrastructure
Network.

7
552
T. Yang, B. P. Cho / Tetrahedron Letters 44 (2003) 7549–7552
J. F. J. Am. Chem. Soc. 1998, 120, 3694–3703; (d) Zhang,
X.-X.; Harris, M. C.; Sadighi, J. P.; Buchwald, S. L. Can.
J. Chem. 2001, 79, 1799–1805; (e) Ali, M. H.; Buchwald,
S. L. J. Org. Chem. 2001, 66, 2560–2565.
134.08, 129.93, 123.35, 118.96, 115.57, 114.91, 41.42;
+
LRMS (70 eV) m/z (%) 212.1 (100, M ), 197.1 (41), 167.1
11 1
(14). 5b: mp 91–92°C; H NMR (300 MHz, DMSO-d6),
l 7.50 (s, 1H, D O exchangeable), 6.94 (d, J=8.83 Hz,
2
5
. (a) Ricci, A.; Fochi, M. Angew. Chem., Int. Ed. 2003, 42,
4H), 6.77 (d, J=8.09 Hz, 2H), 6.70 (d, J=8.83 Hz, 2H),
13
1
444–1446; (b) Sapountzis, I.; Knochel, P. J. Am. Chem.
2.81 (s, 6H), 2.17 (s, 3H); C NMR (75.5 MHz, acetone-
d6) l 147.71, 145.06, 135.06, 130.43, 128.19, 122.46,
116.33, 115.10, 41.55, 20.66; LRMS (70 eV) m/z (%)
Soc. 2002, 124, 9390–9391; (c) Bartoli, G. Acc. Chem.
Res. 1984, 17, 109–115; (d) Bartoli, G.; Bosco, M.; Can-
tagalli, G.; Daipozzo, R.; Ciminale, F. J. Chem. Soc.,
Perkin Trans. 2 1985, 773–779; (e) Yost, Y.; Gutmann, H.
R.; Muscoplat, C. C. J. Chem. Soc. 1971, 2119–2122.
. (a) Buck, P.; Kobrich, G. Tetrahedron Lett. 1967, 8,
+
226.2 (100, M ), 211.1 (39), 112.9 (12), 83.9 (13). 5c: mp
1
105–107°C, H NMR (300 MHz, acetone-d with D O): l
6
2
6.98 (d, J=8.45 Hz, 1H), 6.88 (m, 4H), 6.72 (d, J=8.46
13
6
Hz, 2H), 2.80 (s, 6H); C NMR (75.5 MHz, acetone-d6):
1
1
563–1565; (b) Kobrich, G.; Buck, P. Angew. Chem., Int.
l 157.21 (d, JC-F=234.4 Hz), 148.06, 144.15, 134.65,
3
2
Ed. 1966, 5, 1044–1045; (c) Kobrich, G.; Buck, P. Chem.
Ber. 1970, 103, 1412–1419.
. (a) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91,
122.91, 117.12 (d, JC-F=7.32 Hz), 116.33 (d, JC-F=
21.97 Hz), 115.05, 41.46; LRMS (70 eV) m/z (%) 230.1
+
7
(100, M ), 215.1 (41), 185.1 (13), 114.8 (16); HRMS calcd
3
527–3533; (b) Sheehan, M.; Cram, D. J. J. Am. Chem.
for C H N F: 230.1219. Found: 230.1219; Anal. calcd
14
15
2
Soc. 1969, 91, 3544–3552; (c) Wiriyachitra, P.; Cava, M.
P. J. Org. Chem. 1977, 42, 2274–2277; (d) Sinhababu, A.
K.; Borchardt, R. T. J. Med. Chem. 1983, 48, 1941–1951;
for C H N F C, 73.02; H, 6.57; N, 12.16; F, 8.25.
14 15 2
Found: C, 73.26; H, 6.53; N, 11.91; F, 8.03. 5d: mp
10 1
120.7–121.4°C; H NMR (300 MHz, DMSO-d
) l 7.18
6
(
e) Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem.
(s, 1H), 6.84 (d, J=8.83 Hz, 4H), 6.66 (d, J=8.82 Hz,
4H), 2.77 (s, 12H); C NMR (75.5 MHz, acetone-d ) l
6
13
Soc. 2002, 124, 9812–9824.
8
. For examples containing N,N-dimethylanilino group, see:
146.69, 137.56, 119.89, 115.57, 41.86; LRMS (70 eV) m/z
+
(a) Sanchez, E.; del Campo, C.; Avendano, C.; Llama, E.
(%) 255.1 (100, M ), 240.1 (35), 126.8 (23). 5e: mp
1
Heterocycles 1990, 31, 2003–2010; (b) Kelley, J. L.; Linn,
J. A.; Selway, W. T. J. Med. Chem. 1990, 33, 1360–1363;
92.5–93.5°C; H NMR (300 MHz, acetone-d
6
with D
O)
2
l 6.99 (m, 3H), 6.71 (m, 4H), 6.48 (d, J=6.98 Hz, 1H),
13
(
c) Sessler, J. L.; Sathiosatham, M.; Doerr, K.; Lynch, V.;
Abboud, K. A. Angew. Chem., Int. Ed. 2000, 39, 1300–
303
. Typical procedure for the synthesis of 5a–f: Butyllithium
5.6 mL, 1.6 M in hexane, 9.0 mmol) was added via a
syringe to a solution of N,N-dimethyl-4-bromoaniline
1.8 g, 9.0 mmol) in dry THF (50 mL) at −78°C under a
2.83 (s, 6H), 2.17 (s, 3H); C NMR (75.5 Hz, acetone-d )
6
l 148.01, 147.67, 139.38, 134.28, 129.82, 123.36, 119.94,
116.35, 114.93, 112.94, 41.46, 21.78; LRMS (70 eV) m/z
1
+
9
(%) 226.2 (100, M ), 211.1 (44); HRMS calcd for
(
C
C
15
H
H
18
N
N
2
: 226.1470. Found: 226.1467; Anal. calcd for
C, 79.61; H, 8.02; N, 12.38; F, 8.25. Found: C,
15
18
2
11 1
(
79.76; H, 7.91; N, 12.41. 5f: mp 124–126°C; H NMR
(300 MHz, acetone-d with D O) l 7.55 (dd, J=7.36 Hz,
nitrogen atmosphere. The resulting turbid solution was
stirred at the same temperature for 2 h. A solution of
nitroarene (2.5 mmol, Table 1) in dry THF (50 mL) was
added dropwise to the mixture, which turned to orange
initially and then dark brown. The reaction mixture was
warmed slowly to room temperature and stirred
overnight. The reaction was quenched by addition of
6
2
2H), 7.44 (d, J=8.46 Hz, 2H), 7.36 (dd, J=7.91 Hz, 2H),
7.22 (dd, J=7.36 Hz, 1H), 7.06 (d, J=8.82 Hz, 2H), 6.98
3
(d, J=8.83 Hz, 2H), 6.76 (d, J=9.19 Hz, 2H), 2.84 (s,
13
6H); C NMR (75.5 MHz, acetone-d ) l 148.27, 147.34,
6
142.24, 133.74, 131.58, 129.67, 128.46, 126.96, 126.89,
123.66, 115.81, 114.91, 41.41. LRMS (70 eV) m/z (%)
+
H O and the residual THF was evaporated. The aqueous
2
288.2 (100, M ), 273.2 (30), 143.9 (17).
residue was then extracted with ether and the combined
10. Pratt, D. A.; DiLabio, G. A.; Valgimigli, L.; Pedulli, G.
F.; Ingold, K. U. J. Am. Chem. Soc. 2002, 124, 11085–
11092.
ether extracts were washed with H O and dried over
2
anhydrous MgSO . The purification by column chro-
4
matography on silica (ethyl acetate and hexane), followed
by recrystallization from ethyl acetate and hexane,
afforded pure products (5a–f, Table 1). 5a: mp 130–
11. Helmick, J. S.; Martin, K. A.; Heinrich, J. L.; Novak, M.
J. Am. Chem. Soc. 1991, 113, 3459–3466.
12. Sekiya, M.; Tomie, M.; Leonard, N. J. J. Org. Chem.
4c 1
1
31°C; H NMR (300 MHz, DMSO-d ) l 7.65 (s, 1H,
1968, 33, 318–322: HRMS calcd 137.0841. Found.
6
1
D O exchangeable), 7.11 (dd, J=7.91 Hz, 2H), 6.99 (d,
2
133.0842; H NMR (300 MHz, acetone-d
) 2.72 (s, 6H,
6
J=8.83 Hz, 2H), 6.84 (d, J=7.72 Hz, 2H), 6.72 (d,
J=9.19 Hz, 2H), 6.64 (dd, J=7.54 Hz, 1H), 2.82 (s, 6H);
-N(CH ) ), 6.64–6.75 (4H, aromatic), 7.65 (bs, OH).
13. Boche, G.; Lohrenz, J. C. W. Chem. Rev. 2001, 101,
697–756.
3 2
13
C NMR (75.5 MHz, acetone-d ) l 148.06, 147.71,
6