Abstract
A novel N ,N -diisopropylformamidine
(DIFA) protecting group for anilines was studied. Metalation is
often metal-directed by this weakly coordinating and bulky group,
making it complementary to ortho -metalation
directed by tert -butylcarbamate and pivaloylamide
groups and to regular electrophilic reactions of anilines. Importantly,
DIFA is removed under nucleophilic conditions and is stable toward
acids, thus being orthogonal to tert -butylcarbamate, N -tert -butylamide,
and other acid-labile protecting groups.
Key words
protecting groups - regioselectivity - metalation - formamidine
References and Notes
1a Chevallier F.
Mongin F.
Chem.
Soc. Rev.
2008,
37:
595
1b Schlosser M.
Mongin F.
Chem. Soc. Rev.
2007,
36:
1161
1c Majewski M.
Snieckus V.
Science
of Synthesis
Vol. 8a:
Thieme;
Stuttgart:
2006.
p.5
1d Schlosser M.
Angew.
Chem. Int. Ed.
2005,
44:
376
1e Anctil EJ.-G.
Snieckus V.
Metal-Catalyzed Cross-Coupling Reactions
2nd
ed., Vol. 2:
Wiley-VCH;
Weinheim:
2004.
p.761
2a Takagishi S.
Katsoulos G.
Schlosser M.
Synlett
1992,
360
2b Baston E.
Maggi R.
Friedrich K.
Schlosser M.
Eur. J. Org. Chem.
2001,
3985
2c Leroux F.
Castagnetti E.
Schlosser M.
J.
Org. Chem.
2003,
68:
4693
3a Schlecker W.
Huth A.
Ottow E.
3b Carroll W.
Zhang X.
Tetrahedron Lett.
1997,
38:
2637
N ,N -dimethylformamidine protection,
see:
4a Hanaya T.
Toyota H.
Yamamoto H.
Synlett
2006,
2075
4b Saneyoshi H.
Seio K.
Sekine M.
J.
Org. Chem.
2005,
70:
10453
4c Hikishima S.
Minakawa N.
Kuramoto K.
Fujisawa Y.
Ogawa M.
Matsuda A.
Angew. Chem. Int. Ed.
2005,
44:
596
4d Gudmundsson KJ.
Johns BA.
Org.
Lett.
2003,
5:
1369
4e Wuts PGM.
Greene TW.
Greene’s Protective Groups in Organic
Synthesis
4th ed.:
Wiley-Interscience;
Hoboken:
2007.
p.830
5 Varchi G.
Jensen AE.
Dohle W.
Ricci A.
Cahiez G.
Knochel P.
Synlett
2001,
477
6 Meyers A.
Aldrichimica
Acta
1985,
18:
59
7 Zhichkin P.
Peterson L.
Beer C.
Rennells M.
J. Org. Chem.
2008,
73:
8954
8a Yang X.
Knochel P.
Synthesis
2006,
2618
8b Staubitz A.
Dohle W.
Knochel P.
Synthesis
2003,
233
8c Lindsay DM.
Dohle W.
Jensen AE.
Kopp F.
Knochel P.
Org.
Lett.
2002,
4:
1819
9 Gall M.
McCall JM.
TenBrink RE.
VonVoigtlander PF.
Mohrland JS.
J. Med. Chem.
1988,
31:
1816
10 An aliquot of the reaction mixture
was quenched with 5% AcOH in H2 O, and the HPLC
areas of des-Br 2a or des-Br 2b were compared with those for decomposition
products.
11 The anion of 2b obtained
using n -BuLi had a half-life of only 1
h at -30 ˚C due to its reaction with
1-bromobutane, a side product of the metal-halogen exchange.
After warming to r.t., N ′-(4-butylphenyl)-N ,N -diisopropylformamidine
could be isolated in 90% yield (see Supporting Information
for details).
12 Li W.
Nelson DP.
Jensen MS.
Hoerrner RS.
Cai D.
Larsen RD.
Reider PJ.
J. Org. Chem.
2002,
67:
5394
13 See Supporting Information for detailed
procedures.
14a Reich HJ.
Green DP.
Medina MA.
Goldenberg WS.
Gudmundson B.
Dykstra RR.
Phillips NH.
J.
Am. Chem. Soc.
1998,
120:
7201
14b 2 O s -BuLi/PMDTA is less reactive
than s -BuLi/TMEDA, see: McGrath MJ.
Bilke JL.
O’Brien P.
Chem. Commun.
2006,
2607
14c Remenar JF.
Collum DB.
J.
Am. Chem. Soc.
1998,
120:
4081
15 No literature on DOM of derivatives
of aminobenzoic acids could be found, and only two papers (see ref.
3) dealt with the lithiation of derivatives of aminoheteroarylcarboxylic acids.
16 Maggi R.
Schlosser M.
J. Org. Chem.
1996,
61:
5430
17 Confirmed through NOE experiments
with 9b and 9c (see Supporting
Information).
18 2 base,
see: Hawad H.
Bayh O.
Hoarau C.
Trécourt F.
Quéguiner G.
Marsais F.
Tetrahedron
2008,
64:
3236
19 Huang CQ.
Wilcoxen K.
McCarthy JR.
Haddach M.
Webb TR.
Gu J.
Xie Y.-F.
Grigoriadis DE.
Chen C.
Bioorg.
Med. Chem. Lett.
2003,
13:
3375
