Generation and Reactions of Nonstabilized Bis(α-amino carbanions)

Full text of DOI:10.1021/jo980395t

6712
J . Org. Chem. 1998, 63, 6712-6714
Sch em e 1. F or m a tion of 1,6-Bis(r-a m in o
Gen er a tion a n d Rea ction s of Non sta bilized
ca r ba n ion s)
Bis(r-a m in o ca r ba n ion s)
Alan R. Katritzky,* Ming Qi,§ and Daming Feng
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received March 2, 1998
The development of new strategies for the single-step
achievement of multiple reactions can allow the efficient
construction of complex molecules. Among available
strategies, the utility of dicarbanions has recently
emerged.1 Bis(R-amino carbanions) lacking stabilizing
groups are rare because there are only a few methodolo-
gies available for the preparation of nonstabilized R-ami-
no carbanions in general.2-4 Previously, successful prepa-
rations of such bis-derivatives have been limited to (i)
direct double lithiation of bis(dimethylamino)methane
(1a ) by t-BuLi to give 1,5-dicarbanion 1b,5 (ii) lithium-
generation of various nonstabilized bis(R-amino carban-
ions) which can be trapped with a variety of electrophiles.
Resu lts a n d Discu ssion
The bis(R-aminobenzotriazole) 5a was prepared from
1,2-anilinoethane (4a ), and 1-(hydroxymethyl)benzotria-
zole (BtCH2OH) in refluxing toluene in 94% yield. The
utilization of 5a as a formal dicarbanion synthon equiva-
lent and its subsequent reaction with electrophile 2-pen-
tanone was attempted under two different conditions:
metal exchange of organotin compound 2a to form 1,3-
dicarbanions 2b,6 and (iii) reductive C-S bond cleavage
of R-thioamine 3a to prepare 1,6-dicarbanion 3b.7 More-
over, only silyl chlorides5-7 and deuterium oxide5 were
employed as electrophiles in the reported reactions of bis-
(R-amino carbanions) 1b, 2b, and 3b.
We recently demonstrated that readily available N-(R-
aminoalkyl)benzotriazoles8 and tosylmethylamines9a are
advantageous and versatile precursors of nonstabilized
R-amino carbanions. We have now found that our
previous and other methods7,9b,10 can be extended to the
8
using (i) SmI2 and (ii) lithium naphthalene (LiNap) as
reducing reagents (Scheme 1).7 The first reaction gave
product 7a , expected from a dicarbanion intermediate
(6a ), together with a byproduct deriving from a C-N(Ph)
bond cleavage of the starting 5a due to the presence of
two C-N bonds.8 The use of LiNap as reducing reagent
for 5a resulted in a complex mixture.
To avoid the low C-N bond selectivity in the above
reaction, the bis(R-sulfonylamine) 5b was prepared from
4a , toluenesulfonic acid, and formaldehyde in 90% yield
(Scheme 1) by using a modified version of a previously
published method.11 However, reaction of 5b with 3-pen-
tanone in the presence of SmI2/THP (tetrahydropyran)-
HMPA9a gave only 31% bis(R-amino alcohol) 7a (24% of
7a was isolated when SmI2/THF-HMPA was used). A
somewhat higher yield (40%) of 7a was afforded when
bis(R-phenylthioamine) 5c was treated with lithium/
lithium bromide12 and 3-pentanone. Compound 5c was
synthesized from 4a in a fashion similar to the literature
methods.13 In all the reactions of 5b,c, 1,3-diphenylimi-
§ Current address: Trega Biosciences, Inc., 9880 Campus Point
Drive, San Diego, CA 92121.
(1) (a) Thompson, C. M. Dianion Chemistry in Organic Synthesis;
CRC Press: Boca Raton, FL, 1994. (b) Marek, I.; Normant, J .-F. Chem.
Rev. 1996, 96, 3241.
(2) For recent reviews of the generation of nonstabilized R-ami-
nocarbanions, see: (a) Katritzky, A. R.; Qi, M. Tetrahedron 1998, 54,
2647. (b) Kessar, S. V.; Singh, P. Chem. Rev. 1997, 97, 721.
(3) Representative reviews on stabilized R-amino carbanions: (a)
Beak, P.; Zajdel, W. J .; Reitz, D. B. Chem. Rev. 1984, 84, 471. (b)
Seebach, D.; Enders, D. Angew. Chem., Int. Ed. Engl. 1975, 14, 15.
(4) Representative reviews on lithium/element exchange: (a) Kauff-
mann, T. Top. Cur. Chem. 1980, 92, 109. (b) Cohen, T.; Bhupathy, M.
Acc. Chem. Res. 1989, 22, 152.
(5) Karsch, H. H. Chem. Ber. 1996, 129, 483.
(6) Peterson, D. J .; Ward, J . F. J . Organomet. Chem. 1974, 66, 209.
(7) Strohmann, C.; Abele, B. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 2378.
(8) Katritzky, A. R.; Qi, M.; Feng, D.; Nichols, D. A. J . Org. Chem.
1997, 62, 4121.
(9) (a) Katritzky, A. R.; Feng, D.; Qi, M. J . Org. Chem. 1997, 62,
6222. (b) Alonso, D. A.; Alonso, E.; Na´jera, C.; Ramo´n, D. J .; Yus, M.
Tetrahedron 1997, 53, 4835.
(10) (a) Broka, C. A.; Shen, T. J . Am. Chem. Soc. 1989, 111, 2981.
(b) Tsunoda, T.; Fujiwara, K.; Yamamoto, Y.-i.; Itoˆ, S. Tetrahedron
Lett. 1991, 32, 1975.
(11) Ba¨der, E.; Hermann, H. D. Chem. Ber. 1955, 88, 41.
(12) It is noteworthy to point out that the use of Li/LiBr8 instead of
10a
LiNap7,
or lithium di-tert-butylbiphenyl (LiDBB)10b avoids the
introduction of equivalent amount of aromatic hydrocarbons, which
have to be removed by chromatography, into the reaction system.
(13) (a) Grillot, G. F.; Felton, H. R.; Garrett, B. R.; Greenberg, H.;
Green, R.; Clementi, R.; Moskowitz, M. J . Am. Chem. Soc. 1954, 76,
3969. (b) Pollard, C. B.; Butler, D. E. J . Org. Chem. 1961, 26, 600.
S0022-3263(98)00395-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/02/1998

Notes
J . Org. Chem., Vol. 63, No. 19, 1998 6713
prepared.9 However, for the bifunctional nonstabilized
bis(R-amino carbanions) now studied it transpires that
bis(R-thioamines) are the best precursors. The two-step
approach now reported gives access to various multi-
functionalized organic compounds in one-pot reactions.
Sch em e 2. F or m a tion of 1,7-Bis(r-a m in o
ca r ba n ion s)
Exp er im en ta l Section
For general information, see our previous papers.8,9a
N,N ′-Bis(b en zot r ia zolylm et h yl)-N,N ′-d ip h en ylet h yl-
en ed ia m in e (5a ). A solution of 1-(hydroxymethyl)benzotriazole
(2.98 g, 20 mmol) and 1,2-dianilinoethane (2.12 g, 10 mmol) in
toluene (50 mL) was heated to reflux for 6 h, using a Dean-Stark
trap to remove the produced water. After evaporation of the
solvent, the crude product was dried under vacuum to give the
title compound in 94% yield: white solid; mp 151-154 °C; 1H
NMR (benzotriazol-1-yl (Bt1) and benzotriazol-2-yl (Bt2) isomers,
peaks corresponding to the major (90%) Bt1Bt1 isomer reported
here) δ 3.71 (s, 4H), 6.02 (s, 4H), 6.80-7.15 (m, 7H), 7.16-7.50
(m, 9H), 7.90-8.10 (m, 2H); 13C NMR δ 47.3, 66.0, 109.8, 116.7,
119.9, 121.0, 123.9, 127.5, 129.8, 132.6, 146.1, 146.4. Anal.
Calcd for C28H26N8: C, 70.87; H, 5.52; N, 23.61. Found: C,
70.97; H, 5.55; N, 23.40.
N,N ′-Di(tosylm eth yl)-1,2-d ia n ilin oeth a n e (5b). Aqueous
formaldehyde (37%, 1.5 g, 18 mmol) and a solution of the 1,2-
dianilinoethane (1.6 g, 7.5 mmol) in methanol (20 mL) were
added, in turn, to a solution of p-toluenesulfinic acid (2.52 g 16
mmol) in methanol (15 mL) at 0 °C and stirred for 3 h. The
precipitate was filtered with suction and dried in a vacuum
system to give 5b in 90% yield: white solid, mp 139-141 °C;
1H NMR δ 2.38 (s, 6H), 3.66 (s, 4H), 4.65 (s, 4H), 6.68 (d, 4H, J
) 8.1 Hz), 6.79 (t, 2H, J ) 7.1 Hz), 7.12 (t, 4H, J ) 8.0 Hz), 7.22
(d, 4H, J ) 8.0 Hz), 7.66 (d, 4H, J ) 8.2 Hz); 13C NMR δ 21.6,
48.4, 75.4, 114.2, 119.7, 128.7, 129.3, 129.9, 135.5, 145.0, 145.3.
Anal. Calcd for C30H32N2O4S2: C, 65.67; H, 5.88; N, 5.11.
Found: C, 66.00; H, 5.99; N, 5.18.
dazolidine (8) was a major byproduct. The formation of
compound 8 probably involved an intramolecular cycliza-
tion of 5b,c to form an ammonium salt 9, which was
hydrolyzed to give imidazolidine 8 (eq 1).
N,N ′-Dim eth yl-N,N ′-bis[(th iop h en yl)m eth yl]eth ylen e-
d ia m in e (5d ). Aqueous formaldehyde (37%, 4.87 g, 60 mmol)
and thiophenol (4.45 g, 40 mmol) were added, in turn, to a
solution of the N,N′-dimethylethylenediamine (1.78 g, 20 mmol)
in methanol (35 mL) at 0 °C and stirred for 1 h and then heated
to reflux for 5 h. The precipitate was filtered off with suction,
washed with cold EtOH, and dried under vacuum to give 5d in
(1)
We believe that the low yields of the above reactions
are due to the low stability of the expected dicarbanion
intermediate 6a . As alkyl-substituted R-amino carban-
ions are more stable than their aryl-substituted coun-
terparts,14 we prepared bis(R-thioamine) 5d . We found
that 5d reacted easily with electrophiles, either in the
presence of Li/LiBr or using a two-step procedure, to give
7b-f in good yields (Scheme 1, method G).
We successfully extended this reaction to the genera-
tion of nonstabilized R-amino 1,7-dicarbanion 12 from bis-
(R-thioamine) 11 (Scheme 2). Preformation of the non-
stabilized R-amino dicarbanion 12 significantly expanded
the scope of the electrophiles that could be utilized in this
reaction to include carbonyl compounds, isocyanates, and
chlorotrimethylsilane. Thus, bis(â-hydroxyamines) 13,
bis(â-aminoamide) 14, and bis(â-aminosilane) 15 were
synthesized in 54-66% yields. For the N-alkyl-substi-
tuted R-amino dicarbanion, bis(R-aminobenzotriazole) 16
can also be used as the precursor; compound 13a was
prepared from 16 in 32% yield.
1
86% yield: mp 48-50 °C; H NMR δ 2.28 (s, 6H), 2.52 (s, 4H),
4.48 (s, 4H), 7.13-7.29 (m, 6H), 7.74 (d, 4H, J ) 7.2 Hz); 13C
NMR δ 40.8, 51.4, 67.5, 126.4, 128.8, 132.0, 137.7. Anal. Calcd
for C18H24N2S2: C, 65.02; H, 7.27; N, 8.42. Found: C, 64.90; H,
7.34; N, 8.35.
N,N ′-Bis(2-et h yl-2-h yd r oxyb u t yl)-1,2-d ia n ilin oet h a n e
(7a ). Meth od A or C. A solution of compound 5a or 5b (1.0
mmol) and 3-pentanone (0.22 g, 2.5 mmol) was added to SmI2
(0.1 N, 5 mmol) in THF/HMPA (20:1) at 0 °C under nitrogen
and stirred for 6 h. The reaction was quenched with water and
extracted with ether. The organic phase was dried and concen-
trated to give a residue, which was purified by column chroma-
tography (eluent: hexane/EtOAc/Et3N) to afford 7a : white solid,
1
mp 89-90 °C; H NMR δ 0.76 (t, 12H, J ) 7.2 Hz), 1.30-1.53
(m, 8H), 1.65 (s, 2H), 3.12 (s, 4H), 3.52 (s, 4H), 6.66 (t, 2H, J )
7.1 Hz), 6.83 (d, 4H, J ) 8.3 Hz), 7.15 (t, 4H, J ) 7.3 Hz); 13C
NMR δ 7.8, 29.1, 48.3, 58.6, 76.4, 113.9, 117.4, 129.2, 149.5. Anal.
Calcd for C26H40N2O2: C, 75.68; H, 9.77; N, 6.79. Found: C,
76.13; H, 9.57; N, 7.13.
Gen er a l P r oced u r e for th e P r ep a r a tion of 7b-f, 13-15.
Meth od G. Lithium (30% in mineral oil, 0.46 g, 20 mmol) was
washed twice with THF under argon and treated with 1,2-
dibromoethane (2.3 mmol) in THF (30 mL) for 30 min to form
the Li/LiBr suspension. The mixture was cooled to -78 °C, and
a THF solution of the diamine derivative (5d or 11, 2 mmol)
was added. The reaction mixture was stirred for 2 h, and then
an electrophile was added. After 1 h, the mixture was quenched
with water at the same temperature and extracted with ethyl
acetate. The solvent was removed to give a residue, which was
purified by column chromatography on silica gel (eluent: hexane/
EtOAc/Et3N) to afford the desired product.
We previously found that N-(R-aminoalkyl)benzo-
triazoles, due to their ready availability, moderate reac-
tion conditions, and easy workup, are better precursors
for the nonstabilized R-amino carbanions8 than either
R-thioamines, for which stronger reducing reagents (e.g.
LiNap) have to be used,7,10 or R-sulfonylamines, for which
only N-phenyl-substituted R-amino carbanions can be
N,N ′-Dim eth yl-N,N ′-bis(2-eth yl-2-h yd r oxybu tyl)eth yl-
1
(14) Peterson, D. J . J . Am. Chem. Soc. 1971, 93, 4027.
en ed ia m in e (7b). 53% yield; colorless oil; H NMR δ 0.86 (t,

6714 J . Org. Chem., Vol. 63, No. 19, 1998
Notes
12H, J ) 7.4 Hz), 1.33-1.62 (m, 8H), 2.37 (s, 6H), 2.39 (s, 4H),
2.54 (s, 4H), 4.97 (br s, 2H); 13C NMR δ 7.8, 28.9, 47.1, 57.7,
63.2, 74.0. Anal. Calcd for C16H36N2O2: C, 66.62; H, 12.58; N,
9.71. Found: C, 66.53; H, 13.04; N, 9.88.
N ,N ′-D ie t h y l-N ,N ′-b is ((t r im e t h y ls ily l)m e t h y l)-1,3-
p r op ylen ed ia m in e (15): 54% yield; colorless oil; 1H NMR δ
-0.09 (s, 18H), 0.84 (t, 6H, J ) 7.1 Hz), 1.41 (m, 2H), 1.78 (s,
4H), 2.22 (t, 4H, J ) 7.3 Hz), 2.31 (q, 4H, J ) 6.9 Hz); 13C NMR
δ -1.2, 11.5, 24.2, 45.4, 50.7, 55.1; HRMS (FAB) (m/e) calcd for
C15H38N2Si2 + H 303.2652, found 303.2653.
N ,N ′-Die t h yl-N ,N ′-b is(2-e t h yl-2-h yd r oxyb u t yl)-1,3-
1
p r op ylen ed ia m in e (13a ). 61% yield; colorless oil; H NMR δ
0.85 (t, 12H, J ) 7.5 Hz), 1.01 (t, 6H, J ) 7.1 Hz), 1.32-1.52
(m, 8H), 1.53-1.68 (m, 2H), 2.36 (s, 4H), 2.45-2.66 (m, 8H), 3.53
(br s, 2H); 13C NMR δ 7.9, 11.8, 25.5, 29.8, 49.5, 53.7, 61.0, 72.5.
Anal. Calcd for C19H42N2O2: C, 69.04; H, 12.81; N, 8.47.
Found: C, 69.27; H, 13.29; N, 8.70.
Ack n ow led gm en t. This work was supported in part
by the National Science Foundation (Grant CHE-
9629854).
N,N ′-Diet h yl-N,N ′-b is((isop r op ylca r b a m oyl)m et h yl)-
1
1,3-p r op ylen ed ia m in e (14): 58% yield; colorless oil; H NMR
Su p p or tin g In for m a tion Ava ila ble: Text providing fully
detailed analytical data (1H and 13C NMR and microanalysis)
for compounds 5c, 7c-f, 8, 11, 13b, and 16 (3 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
δ 1.03 (t, J ) 7.1 Hz) and 1.20 (t, J ) 6.6 Hz) (total 6H), 1.02 (d,
J ) 6.4 Hz) and 1.37 (d, J ) 6.5 Hz) (total 12H), 1.50-1.67 (m,
2H), 2.36-2.70 (m, 8H), 2.99 (s) and 3.36 (s) (total 4H), 3.90-
4.17 (m) and 4.40-4.55 (m) (total 2H), 7.10 (d, J ) 7.8 Hz) and
8.19 (d, J ) 6.0 Hz) (total 2H); 13C NMR δ 12.0 (11.0), 22.6 (22.2),
25.2 (24.1), 40.4 (42.5), 49.0 (47.6), 48.9 (47.2), 52.9 (50.4), 57.9
(58.4), 170.3 (153.8). Anal. Calcd for C17H36N4O2: C, 62.16; H,
11.05; N, 17.06. Found: C, 61.61; H, 11.08; N, 16.80.
J O980395T