Oxidative amination of heteroaromatic zinc reagents mediated by PhI(OAc)2

Article abstract of DOI:10.1021/ol902056j

The oxidative amination of functionalized heterocycles has been achieved by using readily available heterocyclic zinc reagents and lithium amides. PhI(OAc)₂ proved to be a suitable reagent for this oxidative amination

Full text of DOI:10.1021/ol902056j

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5158-5161
Oxidative Amination of Heteroaromatic
Zinc Reagents Mediated by PhI(OAc)2
Marcel Kienle, Cora Dunst, and Paul Knochel*
Department Chemie & Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse
5-13, 81377, Mu¨nchen (Germany)
paul.knochel@cup.uni-muenchen.de
Received September 4, 2009
ABSTRACT
The oxidative amination of functionalized heterocycles has been achieved by using readily available heterocyclic zinc reagents and lithium
amides. PhI(OAc)2 proved to be a suitable reagent for this oxidative amination.
Heteroaromatics belong to one of the most important classes
of compounds in medicinal chemistry.1 Especially amines
containing five-membered heteroaryl groups such as furans,
thiophenes, thiazoles, and pyrazoles are widely found in both
natural products and drugs.2 Whereas the direct amination of
six-membered heterocyclic halides proceeds even uncatalyzed
at high temperatures or high pressure,3 the amination of five-
membered heteroaromatics has been hampered for a long time.
However, due to the work of Buchwald and Hartwig and others
on Pd-catalyzed aminations,4,5 many functional five- and six-
membered heterocylic amines are nowadays available.6
Nonetheless, these protocols still have some limitations, such
as long reaction times and the use of strong bases. In addition,
some functional groups such as iodides and bromides are
not compatible with this Pd-catalyzed amination procedure.
Thus, the development of other mild and general methods
for the amination of heteroaromatics is still an important goal.
Recently, we have described an oxidative amination of
arylcopper reagents7 starting from organomagnesium re-
agents furnishing primary, secondary, and tertiary amines
using chloranil as an oxidation reagent.8 For the oxidative
(5) For recent reports: (a) Harkal, S.; Rataboul, F.; Zapf, A.; Fuhrmann,
C.; Riermeier, T.; Monsees, A.; Beller, M. AdV. Synth. Catal. 2004, 346,
1742. (b) Shekhar, S.; Ryberg, P.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 3584. (c) Tundel, R. E.; Anderson, K. W; Buchwald, S. L. J. Org.
Chem. 2006, 71, 430. (d) Anderson, K. W.; Tundel, R. E.; Ikawa, T.;
Altmann, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523.
(e) Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 925.
(f) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354. (g)
Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 13552. (h) Fors, B. P.; Davis, N. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2009, 131, 5766. (i) Schulz, T.; Torborg, C.; Enthaler, S.;
Scha¨ffner, B.; Dumrath, A.; Spannenberg, A.; Neumann, H.; Bo¨rner, A.;
Beller, M. Chem.sEur. J. 2009, 15, 4528.
(1) (a) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Hetero-
cycles in Life and Society; John Wiley & Sons: Weinheim, 1997. (b) Wipf,
P.; Wang, Z. Org. Lett. 2007, 9, 1605.
(2) (a) Metzger, J. V. Thiazole and its DeriVatiVes; John Wiley & Sons:
New York, 1979. and references therein. (b) Koike, K.; Jia, Z.; Nikaido,
T.; Liu, Y.; Zhao, Y.; Guo, D. Org. Lett. 1999, 1, 197. (c) Walcynski, K.;
Guryn, R.; Zuiderveld, O. P.; Timmermann, H. Il Farmaco 1999, 54, 684.
(3) Kosuki, H.; Sakai, H.; Shinohara, T. Synlett 2000, 1, 116.
(6) (a) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
2003, 68, 2861. (b) Hooper, M. W.; Hartwig, J. F. Organometallics 2003,
22, 3394. (c) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005,
7, 3965. (d) Reddy, C. V.; Kingston, J. V.; Verkade, J. G. J. Org. Chem.
2008, 73, 3047. (e) Shen, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109. (f)
Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586.
(7) (a) Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739. (b)
Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.; Ricci,
A.; Seconi, G. J. Org. Chem. 1993, 58, 5620. (c) Alberti, A.; Cane`, F.;
Dembech, P.; Lazzari, D.; Ricci, A.; Seconi, G. J. Org. Chem. 1996, 61,
1677. (d) Cane`, F.; Brancaleoni, D.; Dembech, P.; Ricci, A.; Seconi, G.
Synthesis 1997, 545. (e) Bernardi, P.; Dembech, P.; Fabbri, G.; Ricci, A.;
Seconi, G. J. Org. Chem. 1999, 64, 641.
(4) For selected reviews see: (a) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (c) Wolfe,
J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805. (d) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125. (e) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131. (f) Blaser, H.-U.; Indolese, A.; Naud, F.; Nettekoven, U.; Schnyder,
A. AdV. Synth. Catal. 2004, 346, 1583. (g) Surry, D. S.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 6338. (h) Hartwig, J. F. Acc. Chem. Res.
2008, 41, 1534
.
10.1021/ol902056j CCC: $40.75
Published on Web 10/20/2009
 2009 American Chemical Society

amination of heterocyclic copper derivatives obtained by
transmetalation from zinc organometallics, the use of chlo-
ranil was unsatisfactory. Furthermore, the scale-up of such
aminations was difficult with this oxidation reagent. Herein,
we report an oxidative amination reaction starting from
readily available zinc reagents mediated by PhI(OAc)2.9,10
We started our investigations on the amination of function-
alized thiazoles. Thiazole derivatives containing an amino
function in position 4 or 5 can be obtained either from
R-thiocyanonitriles11 or via the Cornforth rearrangement.12
Thus, 2,4-dibromothiazole (1a) was zincated using
(TMP)2Zn·2MgCl2·2LiCl13 (2, 0.55 equiv; TMP ) 2,2,6,6-
tetramethylpiperidyl)14 furnishing the diarylzinc compound
3a. This zinc reagent was very stable and did not undergo
halogen dance reactions as is usually the case for electron-
poor heteroarylzinc compounds.15 After the addition of
CuCl·2LiCl (1.1 equiv) the corresponding copper derivative
4a was obtained. Further addition of LiN(SiMe3)2 (2.0 equiv)
afforded the amidocuprate 5a. The subsequent oxidation of
5a using PhI(OAc)2 (1.1 equiv) provided the thiazole amine
derivative 6a in 82% yield with only traces of the corre-
sponding homocoupling product as byproduct (Scheme 1;
Table 1, entry 1).
A range of thiazoles were aminated in 61-76% yield by
this procedure (Table 1). Thus, the copper derivative 4a was
also reacted with N-lithium morpholide and N-lithium N′-
methylpiperazide, leading to the tertiary amines 6b and 6c
in 70% and 61% yield, respectively (Table 1, entries 2-3).
2-Bromothiazole (1b) was aminated with various cyclic and
acyclic amines as well, furnishing the 2-bromothiazole
amines 6d-6f in 63-75% yield (Table 1, entries 4-6).
Using this method, 4-amino thiazoles are also available.
Thus, the zincation and subsequent transmetalation and
amination of 2-bromo-5-trimethylsilylthiazole (1c) furnished
the tertiary amines 6g and 6h in 73% and 75% yield and the
triarylamine 6i in 76% yield (Table 1, entries 7-9). 2-(Phe-
nylthio)thiazole (1d) was also successfully aminated, provid-
Scheme 1. Zincation of 2,4-Dibromothiazole (1a) with
(TMP)2Zn (2) Followed by an Oxidative Amination Reaction
ing the amines 6j-6k in 72-75% yield (Table 1, entries
10-11). These phenylthio thiazoles are useful intermediates
since the phenylthio group can serve as a leaving group in
cross-coupling reactions.16
We have also applied the method for the amination of other
heteroaromatics, such as benzothiazole (7a), benzofuran (7b),
and 2,5-dibromothiophene (7c). Benzothiazole (7a) was
smoothly zincated at 25 °C using TMP2Zn (2).13 Subsequent
oxidative amination with N-lithium morpholide and LiTMP
furnished the tertiary amines 8a,b in 60-73% yield (Table
2, entries 1-2).
Benzofuran (7b) as well as 2,5-dibromothiophene (7c)
were zincated using microwave irradiation (100 °C, 1 h)17
followed by an oxidative amination, yielding the correspond-
ing amines 8c-e in 60-70% yield (Table 2, entries 3-5).
Recently, we have reported a novel Mg insertion into
aromatic and heterocyclic bromides and chlorides in the
presence of LiCl and ZnCl2, leading to aromatic and
heteroaromatic zinc organometallics.18 We have applied this
method to the zincation of several heterocycles followed by
an oxidative amination. Thus, 4-bromo-1,3,5-trimethyl-1H-
pyrazole (9a) was treated with Mg turnings (2.5 equiv) in
the presence of LiCl (2.5 equiv) and ZnCl2 (1.0 equiv),
furnishing the zinc species 10a. After transmetalation with
CuCl·2LiCl (1.1 equiv) and the addition of lithium N-
diphenylamide (2.0 equiv), the amidocuprate 11a was
obtained. Oxidation of 11a using PhI(OAc)2 (1.1 equiv) led
to the desired tertiary amine 12a in 70% yield (Scheme 2;
Table 3, entry 1).19
(8) (a) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 7838. (b) Kienle, M.; Dubbaka, S. R.; del Amo,
V.; Knochel, P. Synthesis 2007, 1272
.
(9) For an excellent overview of hypervalent iodine compounds, see:
(a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2008, 108, 5299. For recent
reports, see: (b) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulisa, M.; Beck,
E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (c) Kar, A.;
Mangu, N.; Kaiser, H. M.; Tse, M. K. J. Organomet. Chem. 2009, 694,
524. (d) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 7558.
For the synthesis and application of related hypervalent iodine compounds,
see: (e) Bielawski, M.; Zhu, M.; Olofsson, B. AdV. Synth. Catal. 2007,
349, 2610. (f) Bielawski, M.; Olofsson, B. Org. Synth. 2009, 86, 308
(10) After screening various benzoquinones as well as hypervalent iodine
derivatives, PhI(OAc)2 proved to give the best results.
.
Other heterocycles such as 9b and 9c were also converted
to the corresponding zinc compounds using the previously
described Mg insertion in the presence of ZnCl2.18 These
(11) (a) Obushak, N. D.; Matiichuk, V. S.; Ganushchak, N. I.; Martyak,
R. L. Chem. Heterocycl. Compd. 1997, 33, 1000. (b) Obushak, N. D.;
Matiichuk, V. S.; Martyak, R. L.; Ganushchak, N. I. Chem. Heterocycl.
Compd. 1999, 35, 93.
(12) Corrao, S. L.; Macielag, M. J.; Turchi, I. J. J. Org. Chem. 1990,
55, 4484.
(16) (a) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801. (b) Metzger,
A.; Melzig, L.; Despotopoulou, C.; Knochel, P. Org. Lett. 2009, 11, 4228.
(17) For microwave accelerated zincations, see: Wunderlich, S.; Knochel,
P. Org. Lett. 2008, 10, 4705.
(13) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007,
46, 7685. (b) Wunderlich, S. H.; Knochel, P. Chem. Commun. 2008, 6387.
(14) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
(18) (a) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem., Int. Ed. 2008, 48, 6802. (b) Piller, F. M.;
Metzger, A.; Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel, P.
Chem.sEur. J. 2009, 15, 7192.
(15) (a) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon,
2002. (b) Mallet, M.; Que´guiner, G. Tetrahedron 1982, 38, 3035. (c) Rocca,
P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.; Godard, A.;
Que´guiner, G. J. Org. Chem. 1993, 58, 7832. (d) Arzel, E.; Rocca, P.;
Marsais, F.; Godard, A.; Que´guiner, G. Tetrahedron 1999, 55, 12149.
(19) The amination sequence of the pyrazole 9a with Li(SiMe3)2 yielded
the desired TMS-protected amine. However, standard deprotection (TBAF)
resulted in its decomposition.
Org. Lett., Vol. 11, No. 22, 2009
5159

Table 1. Oxidative Amination of Various Functionalized
Thiazoles after Zincation with TMP2Zn (2)
Table 2. Oxidative Amination of Various Heterocycles Leading
to Tertiary and Protected Secondary Amines
a The reaction conditions for the metalation with TMP2Zn (2) are given
in parentheses (°C, h). b Isolated yield of analytically pure product.
Scheme 2
.
Mg Insertion in the Presence of LiCl and ZnCl2 and
Subsequent Oxidative Amination
and 67% yield (Table 3, entries 2-3). Using this protocol,
we have also prepared various protected secondary amines:
after zincation of the corresponding heteroaromatics 9b and
9c and subsequent oxidative amination, the TBDMS-
protected diarylamines 12d-e were obtained in 60% and
57% yield (Table 3, entries 4-5).
a The reaction conditions for the metalation with TMP2Zn (2) are given
in parentheses (°C, h). b Isolated yield of analytically pure product.
zinc reagents were then aminated using the oxidative
amination, yielding the tertiary amines 12b and 12c in 66%
Furthermore, we have found that the previously described
zinc reagents are suitable for large-scale oxidative amination
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Org. Lett., Vol. 11, No. 22, 2009

Table 3. Oxidative Amination of Zinc Reagents Obtained by
Magnesium Insertion in the Presence of ZnCl2 and LiCl
Scheme 3. Oxidative Amination of 3,5-Dibromopyridine
Mediated by PhI(OAc)2 on a 10 mmol Scale
Table 4. Oxidative Amination of Zinc Reagents on a 10 mmol
Scale
a The reaction conditions for the metalation with TMP2Zn (2) are given
in parentheses (°C, h). b Isolated yield of analytically pure product.
reactions, regardless if the zinc reagent is formed by
metalation using TMP2Zn (2), by insertion or by addition of
a ZnCl2 solution to a preformed magnesium reagent. Thus,
the treatment of 3,5-dibromopyridine (13, 10 mmol) with
iPrMgCl·LiCl provided the corresponding magnesium reagent
14. Subsequent addition of ZnCl2 (0.55 equiv) and CuCl·2LiCl
(1.1 equiv) furnished the copper species 15. After the reaction
with lithium N-diphenylamide and PhI(OAc)2, the desired
triarylamine 16a is obtained in 88% yield (Scheme 3).
Similarly, the amination of 3,5-dibromopyridine (13) with
lithium N-morpholide furnished the tertiary amine 16b in
71% yield (Table 4, entry 1). In addition, after zincation of
2-bromothiazole (1b) with TMP2Zn (2) the corresponding
zinc species was also smoothly aminated on a 10 mmol scale,
furnishing the desired amines 6l and 6d in 73% and 80%
yield (Table 4, entries 2-3).
We found that the best results were obtained when only
0.55 equiv of ZnCl2 was used. Nonetheless, zinc reagents
obtained by magnesium insertion in the presence of ZnCl2
and LiCl,18 therefore containing 1.0 equiv of ZnCl2, are also
well suited for these larger scale reactions. Thus, the
previously described amination of 9a on a 10 mmol scale
furnished the tertiary amine 12a in 66% yield (Table 4, entry
4; compared to 70% yield on a 1 mmol scale, Scheme 2).
a Isolated yield of analytically pure product.
In conclusion, we have developed a new general method
for the amination of readily available heterocyclic zinc
reagents. This procedure for the preparation of functional
amines can be readily scaled up to 10 mmol scale.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the European Research Council (ERC), and the
Deutsche Forschungsgemeinschaft (DFG) for financial sup-
port. We also thank Evonik AG (Hanau), BASF AG
(Ludwigshafen), W. C. Heraeus GmbH (Hanau), and Che-
metall GmbH (Frankfurt) for the generous gift of chemicals.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
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