O-(Trialkylstannyl)anilines and their utility in Migita-Kosugi-Stille cross-coupling: Direct introduction of the 2-aminophenyl substituent

Article abstract of DOI:10.1016/j.tetlet.2012.06.138

We have developed shelf- and air-stable ortho-stannylated aniline reagents that can directly be coupled with alkenyl and aryl halides via Migita-Kosugi-Stille cross-coupling. We report (i) the efficient preparation of o-(tributylstannyl)aniline (2a) and o-(trimethylstannyl)aniline (2b), (ii) the comparison of the reactivities of 2a and 2b with those of related organostannanes in cross-coupling reaction with an alkenyl halide, and (iii) the cross-coupling of 2a and 2b with a series of arylhalides and triflate.

Full text of DOI:10.1016/j.tetlet.2012.06.138

Tetrahedron Letters 53 (2012) 4938–4941
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Tetrahedron Letters
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o-(Trialkylstannyl)anilines and their utility in Migita–Kosugi–Stille
cross-coupling: direct introduction of the 2-aminophenyl substituent
⇑
Enver Cagri Izgu, Thomas R. Hoye
Department of Chemistry, 207 Pleasant Street, SE, University of Minnesota, Minneapolis, MN 55455, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed shelf- and air-stable ortho-stannylated aniline reagents that can directly be coupled
with alkenyl and aryl halides via Migita–Kosugi–Stille cross-coupling. We report (i) the efficient prepa-
ration of o-(tributylstannyl)aniline (2a) and o-(trimethylstannyl)aniline (2b), (ii) the comparison of the
reactivities of 2a and 2b with those of related organostannanes in cross-coupling reaction with an alkenyl
halide, and (iii) the cross-coupling of 2a and 2b with a series of arylhalides and triflate.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 June 2012
Accepted 28 June 2012
Available online 6 July 2012
Keywords:
Cross-coupling
Ortho-metalation
Aniline
Organostannanes
The 2-aminophenyl substituent is an important structural en-
tity in organic and medicinal chemistry. The essential features of
cross-coupling partners suitable for installation of such a moiety
are shown in Figure 1. In principle, the 2-aminophenyl partner
can be either the acceptor (panel A) or donor (panel B) and the
most direct access to the desired anilino cross-coupling product
is when the nitrogen functionality in these reactants is the free
amino (–NH2) group.
Examples of molecules of medicinal relevance that contain an
embedded 2-aminoarene subunit are shown in Figure 2. In the syn-
thesis of each of these compounds, the 2-aminophenyl units were
installed by an aryl–aryl cross-coupling reaction (see arrow in each
structure).1a–d The key reagent for these transformations was either
the boronic acid 1a or its pinacolate ester 1b (Fig. 3). These are com-
halides under neutral conditions, a feature that is often advanta-
geous in complex molecule settings.
Our investigations into the synthesis of 2a are summarized in
Scheme 1. First, we explored the reduction of o-(tributylstannyl)-
nitrobenzene (2d5) with Sn(II)Cl2/EtOH, Fe(0)/EtOH, or Pd/C, H2
(1 atm)/DCM or EtOH. We recovered the starting material using
the first two conditions, and we observed only the formation of
nitrobenzene with the last. Next, we considered di-debenzylation6
of N,N-dibenzyl-2-(tributylstannyl)aniline (6). However, stannyla-
tion of the iodo-precursor 5 via lithium halogen exchange with
n-BuLi gave N,N-dibenzyl-2-butylaniline as the only identifiable
product. We then examined directed-ortho-metalation7 of the ani-
lide, 4-methoxy-N-phenylbenzamide (7). However, stannylation
occurred, instead, primarily at the 2-position of the 4-methoxy-
phenyl moiety of the starting anilide 7.
mercially available but relatively expensive (ca. $100/g). Their
2a,b
preparation via borylation with (RO)2B–B(OR)2
or (RO)2B-H2c,d
We then explored lithiation8 and stannylation of N-Boc aniline
(9). We found Stanetty’s protocol for the lithiation (t-BuLi, Et2O,
À40 °C)8b to be more serviceable9 for the efficient preparation of
the desired aniline precursor 2c,10 following quenching with
n-Bu3SnCl. We explored a number of conditions for the removal
of the Boc group in 2c. Purification of 2a on either silica gel or alu-
mina (basic or neutral) was problematic. Gratifyingly, the TMSOTf-
mediated Boc-cleavage developed by Sakaitani and Ofune11
smoothly provided o-(tributylstannyl)aniline (2a) with excellent
yields and in a high state of purity. This material (oil) has been
stored on the benchtop with no protection from light, air, or mois-
ture for over a year, and no significant deterioration is observable in
its 1H NMR spectrum. Access to 2b involves a similar protocol from
9 (Me3SnCl was used to quench the initial lithiated N-Boc aniline)
and proceeds with a similar overall yield.
uses rather exotic reagents, ligands, and/or conditions.3
Faced with the need to effect introduction of a 2-aminophenyl
substituent in the course of a natural product synthesis project,
we had occasion to explore a new class of reagents—namely the
2-aminophenylstannanes 2a and 2b (Fig. 3). We could find no re-
ports in the literature describing any 2-aminophenylstannanes.
We viewed 2a and 2b as potentially general and valuable synthons
for Migita–Kosugi–Stille, cross-coupling4 reactions. We have devel-
oped a high-yielding, multigram synthesis of each reagent. These
organostannanes have proven to be robust (shelf- and air-stable)
and, in our hands, additionally advantageous compared to the
boron-based analogs 1. They can be coupled with alkenyl and aryl
We then studied the performance of 2a and 2b vis-à-vis the
known 2-N-Boc- and 2-nitro-phenylstannanes (2c and 2d) in
⇑
Corresponding author. Tel.: +1 612 625 1891; fax: +1 612 626 7541.
E-mail address: hoye@umn.edu (T.R. Hoye).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.138

E. C. Izgu, T. R. Hoye / Tetrahedron Letters 53 (2012) 4938–4941
4939
I
SnBu3
NO2
i) n-BuLi, –110 °C
reduction
acceptor
acceptor
donor
donor
cross-coupling
product
2a
ii) n-Bu3SnCl to rt
NO2
A
B
83%
Hal
Met
Met
Hal
3
4
2d
debenzylation
N*
N
*
i) LHMDS (2 equiv)
NH2
SnBu3
NBn2
I
I
i) n-BuLi, –78 °C
–78 °C to rt
2-aminophenyl
derivative
N
*
= NH2 or NH2 surrogate (e.g., NHBoc, N3, or NO2)
Met = e.g., tin, zinc, magnesium, boron, or silicon
ii) n-Bu3SnCl
ii) BnBr
90-95 %
NH2
O
NBn2
to rt
5
6
Figure 1. Cross-coupling strategies for preparation of 2-aminophenyl derivatives.
SnBu3
O
i) n-BuLi, –78 °C
ii) n-Bu3SnCl
deacylation
N
H
N
H
1a
HO2C
to rt
OMe
OMe
7
8
S
N
H2N
O
O2
S
HN
1a
i) t-BuLi, Et2O,
–40 °C
i) TMSOTf, 2,6-lutidine
CH2Cl2, rt
N
H
SnBu3
O
2a
R
NBoc
H
NBoc
H
2c
ii) n-Bu3SnCl
–78 to 0 °C
80%
ii) MeOH
ca. 99%
endothelin antagonists1a
selectin antagonists1b
9
Scheme 1. Synthesis of o-(tributylstannyl)aniline (2a).
1b
O
consumed, and 2a was ca. 10% consumed (GC/MS integration).
The reactivity of 2a was also compared to that of the N-Boc pro-
tected derivative 2c (entry 8). Again, anilinoimide 11a/b was the
exclusive product. These results show that 2a is very effective in
this additive-free Stille cross-coupling reaction and is more reac-
tive than either 2c or 2d. Although other explanations are possi-
HN
HN
N
N
N
OHC
1b
(S)-brevicolline1c
( )-rhazinal1d
ble, these observations are consistent with
a more rapid
Figure 2. Examples of biologically relevant compounds synthesized via
aminophenylation cross-coupling reaction.
a 2-
transmetalation to the RPd(II)Br species by the amine-bearing
organostannane 2a. A similar explanation has been invoked in
an earlier study by Farina.14
We have also explored the scope of the cross-coupling of 2a
using various alkenyl and aryl halides (Table 2). Use of the Stille
cross-coupling conditions championed by Baldwin and co-work-
ers,15 namely, Pd(PPh3)4–CuI–CsF in DMF, provided significantly
higher product yields for substrates exhibiting low reactivity
(12a in entry 1, and 12e–h in entries 5–8) under typical conditions.
Coupling of 2a with the (multifunctional) bromodihydropyrrole
12a16 provided the 2-(aminophenyl)-dihydropyrrole 13a in 62%
yield (entry 1). While aryl iodides 12b–e (entries 2–5) underwent
cross-coupling reactions efficiently, aryl bromides 12f and 12g
gave 2-(aryl)anilines 13f and 13e in somewhat lower yields (ca.
65%, entries 6-7, respectively). Similar to the case of 12a, phenyl
triflate (12h) was unreactive under the Pd2(dba)3ÁCHCl3–AsPh3
(with or without CuI additive). The coupling efficiency with this
partner significantly increased, again, using Baldwin’s conditions,
which resulted in 80% isolated yield of 2-(phenyl)aniline (entry 8).
In conclusion, we have shown that the o-anilinostannanes 2a and
2b are facile participants in Stille cross-coupling reactions. Each has
been efficiently synthesized on multigram scale. Their cross-coupling
reactivity toward N-hexyl bromomaleimide (10) is greater than that
of either the N-Boc or nitro analog 2c or 2d, respectively. The efficient
preparations of 2a and 2b and their good substrate scope in Stille
cross-couplings make these organostannanes important and practical
building blocks for general use in organic synthesis.
Suzuki coupling donor
Stille coupling donor
BR2
NH2
SnR3
NH2
1a R = OH
1b R2 = pin
2a R = n-Bu
2b R = Me
Figure 3. Free anilino cross-coupling building blocks: known boron reagents2 (1)
and new tin reagents (2).
coupling reactions with N-alkyl bromomaleimide (10) as the alke-
nyl halide. To test the relative efficiency and reactivity of Stille
cross-couplings with organotin reagents containing different
nitrogen-based functional groups, we studied the reactions of
2a–d (Table 1, graphic) with N-hexyl bromomaleimide (10) as
the halide partner. Indeed, it was the cross coupling of a 2-amino-
phenyl moiety with this specific type of halide that was the moti-
vating impetus for this study. The results are presented in entries
1–6 of Table 1. The isolated yields were excellent even when
using a nearly 1:1 stoichiometric ratio. Although the nitro com-
pound 2d reacted somewhat sluggishly under our standard condi-
tions (entry 5), addition of CuI led to a significant improvement
(entry 6).12 We also performed a series of competition studies13
designed to determine the relative reactivity of 2a, 2c, and 2d
(Table 1, entries 7–9). When imide 10 was treated simultaneously
with an excess of 2a and the nitro compound 2d (10 equiv each,
entry 7), anilinoimide 11a/b (11a = 11b; 11, N⁄ = NH2) was
observed as the sole coupling product, imide 10 was fully
Acknowledgments
These studies were supported by the National Institute of Gen-
eral Medical Sciences (GM-65597) and the National Cancer Insti-
tute (CA-76497) of the United States National Institutes of Health.

4940
E. C. Izgu, T. R. Hoye / Tetrahedron Letters 53 (2012) 4938–4941
Table 1
Stille cross-couplings of 2a–d with imide 10a
a
b
c
d
R = n-Bu, N
*
= NH2
SnR3
2a/b
2c
2d
O
increasing
transmetallation
rate
R = Me, N
*
= NH2
O
N
*
R = n-Bu, N
R = n-Bu, N
*
*
= NHBoc
= NO2
N
C6H13
2a-d
N
C6H13
Br
O
Pd2(dba)3 CHCl3, AsPh3, DMF, rt
O
N
*
0.1 M based on 10
10 (1.0 equiv)
11
Entryb
Aryl stannane
Equiv
Time (h)
Conversion of 10 (%)
11, Yieldc
1
2
3
2a
2b
2a
2c
2d
2d
2a + 2d
2a + 2c
2c + 2d
1.1
1.1
1.1
1.1
1.1
12.0
12.0
0.5
12.0
24.0
24.0
0.5
90
90
>99
>99
20
>99
>99
>99
>99
11a/b, 82%
11a/b, 85%
11a/b, 94%
11c, 91%
11d, 13%
11d, 85%
11a/be
4
5
6d
7
1.1
10.0
10.0
10.0
8
9
0.5
12.0
11a/be
11ce
a
b
c
One-hundred mg of 10 was used in the experiments reported in entries 1–6; 10 mg in entries 7–9.
Pd2(dba)3ÁCHCl3 (1 mol %),17 AsPh3 (4 mol %) in entries 1–2, Pd2(dba)3ÁCHCl3 (5 mol %), AsPh3 (20 mol %) in entries 3–9.
Isolated yields for entries 1-6.
CuI (10 mol %) was added.
Only product that was observed by GC–MS analysis; yield was not determined.
d
e
Table 2
Stille cross-couplings of 2a with alkenyl and aryl halides 12a
R
SnBu3
NH2
12, alkenyl or aryl halide
(1 equiv)
NH2
Stille cross-coupling
conditions
2a (1.1 equiv)
13
Entry
1
12
Catalyst (mol %)
Additives (equiv)
13
Yield (%)
62
Br
O
OtBu
NBoc
O
N
Pd(PPh3)4 (5)
CuI (0.1); CsF (2.0)
Boc Ot Bu
12a
NH2 13a
NO2
NO2
2
3
4
Pd2(dba)3ÁCH3Cl3 (5)
Pd2(dba)3ÁCH3Cl3 (5)
Pd2(dba)3ÁCH3Cl3 (5)
AsPh3 (0.2)
AsPh3 (0.2)
AsPh3 (0.2)
86
84
73
I
I
12b
NH2
13b
CN
CN
12c
NH2 13c
C(O)Me
C(O)Me
I
I
12d
13d
NH2
NH2
NH2
5
6
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
CuI (0.2); CsF (2.0)
CuI (0.2); CsF (2.0)
82
66
12e
13e
N
N
Br
12f
13f
7
8
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
CuI (0.2); CsF (2.0)
CuI (0.2); CsF (2.0)
13e
13e
83
80
Br
12g
TfO
12h
a
All reactions were performed in DMF (purged with Ar for ca. 10 min prior to addition of the catalyst and additives) at room temperature and were quenched with
saturated aqueous NaCl solution after 24 h.

E. C. Izgu, T. R. Hoye / Tetrahedron Letters 53 (2012) 4938–4941
4941
Theodora, W.; Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd Ed.; J. Wiley & Sons Inc.: NY, 1999. p 579.
7. (a) Snieckus, V. Heterocycles 1980, 14, 1649–1676; (b) Snieckus, V. Chem. Rev.
1990, 90, 879–933 and references cited therein
8. (a) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798–4801; (b)
Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833–
6837.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic characterization data for all new compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.06.138.
9. In our hands performing the lithiation and quenching sequence in THF at
À78 °C8a,10 resulted in variable yields (ca. 20–55%).
10. (a) Salituro, F. G.; McDonald, I. A. J. Org. Chem. 1988, 53, 6138–6139; (b) Iwao,
M.; Takehara, H.; Furukawa, S.; Watanabe, M. Heterocycles 1993, 36, 1483–
1488.
References and notes
1. (a) Murugesan, N.; Gu, Z.; Stein, P. D.; Bisaha, S.; Spergel, S.; Girotra, R.; Lee, V.
G.; Lloyd, J.; Misra, N. R.; Schmidt, J.; Mathur, A.; Stratton, L.; Kelly, Y. F.; Bird,
E.; Waldron, T.; Liu, E. C.-K.; Zhang, R.; Lee, H.; Serafino, R.; Abboa-Offei, B.;
Mathers, P.; Giancarli, M.; Seymour, A. A.; Webb, M. L.; Moreland, S.; Barrish, J.
C.; Hunt, J. T. J. Med. Chem. 1998, 41, 5198–5218; (b) Kranich, R.; Busemann, A.
S.; Bock, D.; Schroeter-Maas, S.; Beyer, D.; Heinemann, B.; Meyer, M.;
Schierhorn, K.; Zahlten, R.; Wolff, G.; Aydt, E. M. J. Med. Chem. 2007, 50,
1101–1115; (c) Wagner, F. F.; Comins, D. L. Org. Lett. 2006, 8, 3549–3552; (d)
Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.; Hamel, E.; Verdier-
Pinard, P. Org. Biomol. Chem. 2003, 1, 296–305.
2. (a) Appukkuttan, P.; Van der Eycken, E.; Dehae, W. Synlett 2003, 1204–1206; (b)
Yamamoto, T.; Morita, T.; Takagi, J.; Yamakawa, T. Org. Lett. 2011, 13, 5766–
5769; (c) Baudoin, O.; Guénard, D.; Guéritte, F. J. Org. Chem. 2000, 65, 9268–
9271; (d) Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F. J. Org. Chem. 2002,
67, 1199–1207.
3. Earlier reports for the synthesis of 1a involved nitration of phenylboronic acid
followed by catalytic hydrogenation (a) Verbit, L.; Levy, J. S.; Rabitz, H.;
Kwalwasser, W. Tetrahedron Lett. 1966, 10, 1053–1055; (b) Groziak, M. P.;
Ganguly, A. D.; Robinson, P. D. J. Am. Chem. Soc. 1994, 116, 7597–7605.
4. Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis;
Elsevier Academic Press, London, UK, 2005, pp 438–439.
5. Kosugi, M.; Ohya, T.; Migita, T. Bull. Chem. Soc. Jpn. 1983, 56, 3855–3856.
6. (a) Gonzáles-Morales, A.; Díaz-Countiño, D.; Fernandez-Zertuche, M.; García-
Barradas, O.; Ordóñez, M. Tetrahedron: Asymmetry 2004, 15, 457–463; (b)
11. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870–876.
12. Initial screening of catalysts and additives for the coupling of 2a or 2b with
imide 10 showed that Pd2(dba)3ÁCHCl3/AsPh3 was superior to Pd(PPh3)4,
Pd(PPh3)2Cl2/LiCl, or Pd2(dba)3ÁCHCl3/PPh3.
13. Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem.
1994, 59, 5905–5911.
14. Anslyn, E. V.; Dougherty, D. A. University Science Books; Modern Physical
Organic Chemistry: Sausalito, CA, 2006. pp 473–474.
15. Farina, V. Pure. Appl. Chem. 1996, 68, 73–78.
16. Mee, S. P.; Lee, V.; Baldwin, J. E. Angew. Chem. Int. Ed. 2004, 43, 1132–
1136.
17. Compound 12a was prepared by a one-pot bromination-elimination procedure
from the enecarbamate precursor 16 (see the Supplementary data for further
details).
i. Br2
ii. DIPEA
Br
O
O
N
Boc OtBu
N
CH2Cl2, –78 °C
Boc OtBu
48%
16
12a
Enecarbamate 16 was obtained in 54% yield over three steps from
commercially available
L-pyroglutamic acid following the pathway reported
by Gross, U.; Nieger, M.; Brase, S. Org. Lett. 2009, 11, 4740–4742.