Regio- and stereospecific syntheses of syn- and anti-1,2- imidazolylpropylamines from the reaction of 1,1′-carbonyldiimidazole with syn- and anti-1,2-amino alcohols

Article abstract of DOI:10.1021/jo049677l

The regio- and stereospecific conversion of syn- and anti-1,2-amino alcohols to their respective syn- and anti-1,2-imidazolylpropylamines via treatment with 1,1′-carbonyldiimidazole is described. The rationale behind the regio- and stereospecific nature as well as the generality of the reaction is discussed.

Full text of DOI:10.1021/jo049677l

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SCHEME 1
Regio- a n d Ster eosp ecific Syn th eses of syn -
a n d a n ti-1,2-Im id a zolylp r op yla m in es fr om
th e Rea ction of 1,1′-Ca r bon yld iim id a zole
w ith syn - a n d a n ti-1,2-Am in o Alcoh ols
Mark J . Mulvihill,* Cara Cesario, Vanessa Smith,
Patricia Beck, and Anthony Nigro
OSI Pharmaceuticals, Inc., Broadhollow Bioscience Park,
1 Bioscience Park Drive, Farmingdale, New York 11735
mark.mulvihill@osip.com
Received February 25, 2004
Abstr a ct: The regio- and stereospecific conversion of syn-
and anti-1,2-amino alcohols to their respective syn- and anti-
1,2-imidazolylpropylamines via treatment with 1,1′-carbo-
nyldiimidazole is described. The rationale behind the regio-
and stereospecific nature as well as the generality of the
reaction is discussed.
SCHEME 2
The imidazole group is an important heteroaryl residue
found in a wide variety of biologically active and medici-
nally significant molecules, comprising several classes of
derivatives that can be found in fungicides,1 histamine
H2-receptor antagonists,2 and anticancer agents.3 Several
methods are available for the construction as well as
incorporation of an imidazole moiety,4 with one of the
more direct methods involving the reaction of a suitable
alcohol with carbonyldiimidazole.3,5 Literature reports
concerning the generality of the CDI/alcohol reaction
include the following observations: (1) the reaction
proceeds with retention of configuration via an SNi
mechanism;5c (2) the reaction proceeds via an SN2 mech-
anism with inversion of configuration;3d (3) the reaction
proceeds via an SNi or double-inversion mechanism with
retention of configuration when applied to amino alcohol
systems;3c,5d and (4) the reaction, in certain instances,
does not proceed past the imidazolyl-derived carbamate
and does not afford the alkylated imidazolyl product.5b
With the reported variability in the reaction and our
general need, in connection with other studies, to syn-
thesize compounds within this general class, we em-
barked on, to our knowledge, the first systematic model
study designed to test not only the feasibility of preparing
both syn- and anti-1,2-imidazolylpropylamines from their
respective syn- and anti-1,2-aminopropanols but also the
regio- and stereochemical implications of the reaction
based upon the presence of a neighboring tertiary amino
moiety (dialkylamino- and anilino-derived).
2-Dimethylamino-1-phenylpropan-1-ol, based on the
commercial availability of both optically pure syn- and
anti-isomers (+)-1 and (+)-6, was chosen as our model
system. With a general respect for the various plausible
routes through which the reaction could proceed,3,5 we
embarked on the chemistry by first reacting (1S,2S)-(+)-
N-methylpsuedoephedrine 1 with CDI in acetonitrile at
room temperature (Scheme 1). After 8 h, imidazolyl-
derived carbamate 2 was isolated as the sole product
(quenching the reaction with methanol afforded methyl
carbonate 4). Interestingly, under the same conditions,
(1S,2R)-(+)-N-methylephedrine 6 afforded exclusively
anti-imidazolylpropylamine (+)7 in 85% yield (Scheme
2). With such a promising result, we returned to syn-
amino alcohol (+)-1 and discovered that heating the
reaction to 80 °C for 8 h afforded exclusively syn-
imidazolylpropylamine (-)-5 in 76% yield. We also dis-
covered that heating imidazolylcarbamate 2 in acetoni-
trile at 80 °C for 8 h afforded syn-imidazolylpropylamine
(-)-5. The stereochemistry of both compounds (-)-5 and
(+)-7 was validated by X-ray crystallography analysis,
revealing that the syn-imidazolylpropylamino product
was obtained from the syn-precursor and, likewise, the
* To whom correspondence should be addressed. Phone: 631-962-
0787. Fax: 631-845-5671.
(1) (a) Rosello, A.; Bertini, S.; Lapucci, A.; Macchia, M.; Martinelli,
A.; Rapposelli, S.; Herreros, E.; Macchia, B. J . Med. Chem. 2002, 45,
4903-4912. (b) Sheehan, D. J .; Hitchcock, C. A.; Sibley, C. M. Clin.
Microbiol. Rev. 1999, 12, 40-79. (c) Lartey, P. A.; Moehle, C. M. In
Annual Reports in Medicinal Chemistry; Bristol, J . A., Ed.; Academic
Press: New York, 1997; Vol. 32, pp 151-169. (d) Botta, M.; Corelli,
F.; Gasparrini, F.; Messina, F.; Mugnaini, C. J . Org. Chem. 2000, 65,
4736-4739.
(2) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles;
Georg Thieme Verlag: New York, 1995; pp 172-173. (b) King, F. D.,
Ed. Medicinal Chemistry: Principles and Practice; Royal Society of
Chemistry: Cambridge, England, 1994; pp 191-202.
(3) (a) Freyne, D.; Raeymaekers, A.; Venet, M.; Sanz, G.; Wouters,
W.; De Coster, R.; Wauwe, J . V. Biorg. Med. Chem. Lett. 1998, 8, 267-
272. (b) Njar, V. C. O.; Nnane, I. P.; Brodie, A. M. H. Biorg. Med. Chem.
Lett. 2000, 10, 1905-1908. (c) Aelterman, W.; Lang, Y.; Willemsens,
B.; Vervest, I.; Leurs, S.; De Knaep, F. Org. Process Res. Dev. 2001, 5,
467-471. (d) Pouget, C.; Fagnere, C.; Basly, J . P.; Habrioux, G.; Chulia,
A. J . Biorg. Med. Chem. Lett. 2002, 12, 2859-2861.
(4) (a) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry; Potts, K. T., Ed.; Pergamon: New York, 1984; Vol. 5, Part
4A, pp 345, 373, 457. (b) Eicher, T.; Hauptmann, S. The Chemistry of
Heterocycles; Georg Thieme Verlag: New York, 1995; pp 165-173.
(5) (a) Tafi, A.; Costi, R.; Botta, M.; Di Santo, R.; Corelli, F.; Massa,
S.; Ciacci, A.; Manetti, F.; Artico, M. J . Med. Chem. 2002, 45, 2720-
2732. (b) Fischer, W. Synthesis 2002, 29-30. (c) Njar, V. C. O. Synthesis
2000, 2019-2028. (d) Totleben, M. J .; Freeman, J . P.; Szmuszkovicz,
J . J . Org. Chem. 1997, 62, 7319-7323.
10.1021/jo049677l CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/18/2004
5124
J . Org. Chem. 2004, 69, 5124-5127

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TABLE 1. Syn th esis of syn - a n d a n ti-Am in o Alcoh ols
(14) a n d Th eir Resp ective Im id a zole P r od u cts (15)
SCHEME 3
compd
NR1R2
conditionsa stereochemistry yield (%)
(()-13a N(Et)2
a
a
a
b
b
b
c
b/f
d
e/f
e/f
e/f
e
e
e/f
85
82
69
45
38
78
76
84
15
62
67
80
(()-13b morphilino
(()-13c N(Me)Ph
(()-14a N(Et)2
anti-imidazolylpropylamino product was obtained from
the anti-precursor.
syn
anti
syn
anti
syn
anti
syn
anti
syn
anti
syn
(()-14b N(Et)2
(()-14c morphilino
(()-14d morphilino
(()-14e N(Me)Ph
(()-14f N(Me)Ph
(()-15a N(Et)2
Based on the net retention of stereochemistry in each
respective reaction, we postulate a mechanism involving
double-inversion of configuration. The reaction proceeds
by the initial formation of the imidazolyl-derived car-
bamate (2 and 8) followed by displacement of the car-
bamoyl group via neighboring group participation by the
dimethylamino moiety to afford an aziridinium interme-
diate (9 and 11), which undergoes subsequent regiospe-
cific ring opening at the benzylic position by attack of
imidazolide 10 to afford the respective imidazolylpropyl-
amino product ((+)-7 and (-)-5) (Scheme 3).6,7 Upon
examining the two aziridinium species 9 and 11, trans-
aziridinium species 9 is derived from the anti-amino
alcohol (+)-6 and the more hindered cis-aziridinium
species 11 is derived from the syn-amino alcohol (+)-1.
As a consequence, the anti reaction proceeds at room
temperature while the syn reaction requires higher
temperatures to drive the reaction beyond the isolated
imidazolylcarbamate intermediate 2, therefore overcom-
ing a greater steric constraint in the cis-aziridinium
species.
With a better understanding of the regio- and ster-
eospecific nature of the reaction, a focused series of syn-
and anti-amino alcohols were synthesized in which the
dimethylamino group was replaced with diethylamino,
morpholino, and N-methylanilino groups to probe in-
creased sterics as well as the inherent nucleophilicities
of the amino moieties (Table 1). Commercially available
bromopropiophenone (()-12 was treated with the above
amines to afford R-aminoketones (()-13a -c.8-11 At-
(()-15b N(Et)2
(()-15c morphilino
(()-15d morphilino
(()-15e N(Me)Ph
(()-15f N(Me)Ph
81
no reaction
66
anti
a
Conditions: (a) HNR1R2, DIEA, NaI, CH3CN, 40 °C, 16 h; (b)
NaBH4, MeOH, 0 °C, 20 min, separation of isomers via column
chromatography; (c) H2, Pd/C, MeOH, rt, 1 h; (d) Al(i-OPr)3,
i-PrOH, 60 °C, 2 d; (e) CDI, CH3CN, reflux, 8 h; (f) compounds
(()-14e, (()-15a -c, and (()-15f were converted to their respective
bis-hydrochloride salts via treatment with 2 M HCl in ether.
tempts to reduce R-aminoketones (()-13a -c with NaBH4
to afford both syn- and anti-amino alcohols (()-14a -f
gave varying results.12 Reduction of R-diethylaminoke-
tone (()-13a with NaBH4 smoothly afforded both syn-
and anti-amino alcohols (()-14a and (()-14b in a 1:1
ratio.13 However, when R-morphilinoketone (()-13b was
treated with NaBH4, the syn-amino alcohol (()-14c14 was
the major product (10:1 syn/anti ratio), and in the case
of anilinoketone (()-13c, only the syn product (()-14e
was isolated. With our desire to explore the CDI reaction
with both syn- and anti-amino alcohols, R-aminoketones
(()-13b and (()-13c were subjected to hydrogenation
(8) Hyde, J . F.; Browning, E.; Adams, R. J . Am. Chem. Soc. 1928,
50, 2287-2292.
(9) Nadkarni, D.; Hallissey, J .; Mojica, C. J . Org. Chem. 2003, 68,
594-596.
(6) Aziridinium ions have been postulated in the reaction of amino
alcohols with mesyl chloride: (a) Dieter, R. K.; Deo, N.; Lagu, B.;
Dieter, J . W. J . Org. Chem. 1992, 57, 1663-1671. (b) O’Brien, P.;
Towers, T. D. J . Org. Chem. 2002, 67, 304-307. (c) Colman, B.; de
Sousa, S. E.; O’Brien, P.; Towers, T. D.; Watson, W. Tetrahedron:
Asymmetry 1999, 10, 4175-4182. (d) Anderson, S. R.; Ayers, J . T.;
DeVries, K. M.; Ito, F.; Mendenhall, D.; Vanderplas, B. C. Tetrahe-
dron: Asymmetry 1999, 10, 2655-2663. (e) Saravanan, P.; Singh, V.
K. Tetrahedron Lett. 1998, 39, 167-170. (f) Gmeiner, P.; J unge, D.;
Ka¨rtner, A. J . Org. Chem. 1994, 59, 6766-6776. (g) For a review on
the nucleophilic ring opening of aziridines, see: Hu, X. E. Tetrahedron
2004, 60, 2701-2743.
(7) Aziridinium ions have been postulated in substitution reactions
of aminotosylates and in the Mitsunobu reaction of amino alcohols:
(a) Rosen, T.; Fesik, S. W.; Chu, D. T. W.; Pernet, A. G. Synthesis 1988,
40-44. (b) Freedman, J .; Vaal, M. J .; Huber, E. W. J . Org. Chem. 1991,
56, 670-672.
(10) Hoffman, R. V.; J ankowski, B. C.; Carr, C. S. Duesler, E. N. J .
Org. Chem. 1986, 51, 130-135.
(11) Mu¨ller, K.; Schuart, J .; Hamm, G.; Spengler, D. J . Prakt. Chem.
1973, 315, 611-619.
(12) Stereoselective reductions of R-aminoketones to syn- and anti-
amino alcohols: (a) Reiser, O.; Mengel, A. Chem. Rev. 1999, 99, 1191-
1223. (b) Tramontini, M. Synthesis 1982, 605-644. (c) Hoffman, R.
V.; Maslouh, N.; Cervantes-Lee, F. J . Org. Chem. 2002, 67, 1045-
1056. (d) Reetz, M. T. Chem. Rev. 1999, 99, 1121-1162. (e) Reetz, M.
T.; Drewes, M. W.; Lennick, K.; Schmitz, A.; Holdgru¨n, X. Tetrahe-
dron: Asymmetry 1990, 1 (6), 375-378. (f) ref 9.
(13) (a) Soai, K.; Yokoyama, S.; Hayasaka, T. J . Org. Chem. 1991,
56, 4264-4268. (b) Yu, H.; Rothman, R. B.; Dersch, C. M.; Partilla, J .
S.; Rice, K. C. Bioorg. Med. Chem. 2000, 8, 2689-2692.
(14) (a) Hamman, S.; Beguin, B. C.; Charlon, C.; Luu-Duc, C. J .
Fluorine Chem. 1987, 37, 343-356. (b) Rubin, N.; Day, A. R. J . Org.
Chem. 1940, 5, 54-60.
J . Org. Chem, Vol. 69, No. 15, 2004 5125

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with Pd/C catalyst. Under these conditions, the anti-
morpholino alcohol (()-14d 14 was successfully produced;
however, the reduction of R-anilinoketone (()-13c was
unsuccessful. To our satisfaction, we discovered that
treatment of anilinoketone (()-13c under Meerwein-
Pondorff-Verley conditions afforded a 3:1 ratio of the
syn- to anti-anilino alcohols (()-14e and (()-14f.11,15a
result, the reaction appears to be dependent upon the
participation of the neighboring amino group through
formation of an aziridinium intermediate in order to drive
the reaction past the imidazolyl-derived carbamate in-
termediate and to the 1,2-imidazolylpropylamino product.
Exp er im en ta l Section
Treatment of the anti-amino alcohols (()-14b and (()-
14d with CDI afforded the respective anti-imidazolyl
products (()-15b and (()-15d , while the syn-amino
alcohols (()-14a and (()-14c afforded the respective syn-
imidazolyl products (()-15a and (()-15c as demonstrated
previously in the N-methylephedrine cases. Interestingly,
treatment of syn-anilino alcohol (()-14e with CDI in
refluxing acetonitrile did not afford the desired imidazolyl
product(()-15e; we observed the imidazolyl-derived car-
bamate which was hydrolyzed to starting material during
aqueous workup. However, anti-anilino alcohol (()-14f
afforded anti-imidazolyl product (()-15f when refluxed
with CDI in acetonitrile. We postulate that the weakened
nucleophilicity of the anilino nitrogen in concert with the
inability of the syn-isomer to progress through the more
sterically hindered cis-aziridinium intermediate results
in the failed conversion. It is interesting to note that
without neighboring group participation by the amino
moiety to displace the imidazolylcarbamate, the reaction
fails to afford any of the imidazolylpropylanilino product,
whether via an SN1, SN2, or SNi mechanism. Conversely,
the trans-anilino-derived aziridinium intermediate is
generated readily under refluxing conditions in acetoni-
trile, as is predicted for a less hindered species, and the
reaction proceeds to give the anti-imidazolylpropylamino
product (()-15f.15b
In conclusion, we report the regio- and stereospecific
conversion of syn- and anti-amino alcohols to their
respective syn- and anti-imidazolylpropylamines via treat-
ment with CDI. The reactions proceed with net retention
of stereochemistry leading us to speculate that the
reaction is proceeding through a required aziridinium
intermediate. The anti- and syn-amino alcohols would
likely proceed through their respective trans- and more
hindered cis-aziridinium intermediates, explaining why
the CDI reaction with the syn-amino alcohols required
higher temperatures in the subsequent conversion to the
imidazolyl products. The anilino-derived systems were
generally less reactive than their dialkylamino counter-
parts, as demonstrated with syn-anilino alcohol (()-14e,
which was unable to form its respective imidazolyl
product; however, the anti-anilino alcohol (()-14f was
able to afford the imidazole product (()-15f. With this
(1S,2S)-2-(Dim eth ylam in o)-1-ph en ylpr opyl-1H-im idazole-
1-ca r boxyla te (2). An acetonitrile solution (28 mL) of (1S,2S)-
(+)-N-methylpseudoephedrine 1 (1.0 g, 5.7 mmol) was charged
with 1,1′-carbonyldiimidazole (CDI) (1.1 g, 6.8 mmol) and stirred
at rt for 8 h. The reaction mixture was concentrated in vacuo
and partitioned between water (15 mL) and diethyl ether (15
mL), and the organic layer was washed with water (3 × 15 mL)
and brine (1 × 15 mL). The organic layer was dried over Na2-
SO4, filtered, and concentrated in vacuo. The resulting residue
was recrystallized from CH2Cl2/hexanes to afford carbamate 2
as white crystals (956 mg, 61%): mp ) 81-82 °C; IR (film) cm
-1
1
2973, 1756, 1474, 1287, 1239, 1001, 753; H NMR (CDCl3) δ
0.73 (d, 3H, J ) 6.8 Hz), 2.37 (s, 6H), 3.10-3.17 (m, 1H), 5.80
(d, 1H, J ) 9.2 Hz), 7.06 (s, 1H), 7.36-7.42 (m, 5H), 7.44-7.46
(m, 1H), 8.08 (s, 1H); 13C NMR (CDCl3) δ 9.0, 40.7, 62.9, 81.4,
117.2, 127.5, 128.8, 128.9, 130.4, 137.1, 137.2, 148.1. Anal. Calcd
for C15H19N3O2: C, 65.91; H, 7.01; N, 15.37. Found: C, 65.77;
H, 7.01; N, 15.34.
(1S,2S)-2-(Dim eth yla m in o)-1-p h en ylp r op yl Meth yl Ca r -
bon a te (4). An acetonitrile solution (28 mL) of (1S,2S)-(+)-N-
methylpseudoephedrine 1 (1.0 g, 5.7 mmol) was charged with
CDI (1.1 g, 6.8 mmol) and stirred at rt for 8 h. The reaction
mixture was charged with methanol (20 mL) and stirred at rt
for 2 h. The reaction mixture was concentrated in vacuo, and
the resulting residue was purified by silica gel chromatography
eluting with EtOAc to afford methyl carbonate 4 as a white solid
(935 mg, 69%): mp ) 66-67 °C; IR (film) cm-1 1746, 1441, 1265,
1
945; H NMR (CDCl3) δ 0.68 (d, 3H, J ) 6.0 Hz), 2.35 (s, 6H),
3.03-3.10 (m, 1H), 3.72 (s, 3H), 5.48 (d, 1H, J ) 8.0 Hz), 7.30-
7.36 (m, 5H); 13C NMR (CDCl3) δ 9.5, 40.8, 54.6, 62.5, 81.1, 127.4,
128.3, 128.5, 138.5, 155.2. Anal. Calcd for C13H19NO3: C, 65.80;
H, 8.07; N, 5.90. Found: C, 65.81; H, 8.18; N, 5.74.
(1S,2S)-N-[2-(1H-Im id a zol-1-yl)-1-m eth yl-2-p h en yleth yl]-
N,N-d im eth yla m in e [(-)-5]. An acetonitrile solution (28 mL)
of (1S,2S)-(+)-N-methylpseudoephedrine 1 (1.0 g, 5.7 mmol) was
charged with CDI (1.1 g, 6.8 mmol) and stirred at reflux for 8 h.
The reaction mixture was concentrated in vacuo and partitioned
between satd NaHCO3 (15 mL) and CH2Cl2 (15 mL), and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were washed with brine (40 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. The resulting
residue was purified by silica gel chromatography eluting with
97:2:1 CH2Cl2/MeOH/7 N NH3 in MeOH to afford syn-imida-
zolylpropylamine (-)-5 as a white solid (986 mg, 76% yield). An
analytical sample was recrystallized from hot EtOAc/hexanes
to afford white crystals. Crystals were grown by slow diffusion
from methylene chloride to hexanes from which X-ray crystal-
lography data was obtained: mp ) 81-82 °C; IR (film) cm-1
2969, 2938, 2789, 1498, 1221, 1082, 907; 1H NMR (CDCl3) δ 0.79
(d, 3H, J ) 6.8 Hz), 2.22 (s, 6H), 3.39-3.47 (m, 1H), 4.97 (d, 1H,
J ) 10.4 Hz), 6.97-6.98 (m, 1H), 7.02-7.03 (m, 1H), 7.24-7.36
(m, 5H), 7.87 (s, 1H); 13C NMR (CDCl3) δ 9.1, 40.1, 61.5, 65.5,
(15) (a) The diastereomeric ratios of syn-amino alcohols (()-14a ,c,e
and anti-amino alcohols (()-14b,d ,f were determined by reported
differences in the carbinolic proton in the 1H NMR spectra. Also, direct
comparison to the chemical shifts and coupling constants observed for
N-methylpseudoephedrine and N-methylephedrine reveals that the
carbinolic proton of the anti-amino alcohols is downfield with respect
to the carbinolic proton of the syn-amino alcohols, a trend that was
observed in the anti-amino alcohols (()-14b,d ,f and syn-amino alcohols
(()-14a ,c,e, respectively. (b) In the case of syn-imidazolylpropylamine
(-)-5 and anti-imidazolylpropylamine (+)-7, the benzylic proton of the
anti-imidazolylpropylamine (+)-7 is downfield with respect to the
benzylic proton of the syn-imidazolylpropylamine (-)-5; the chemical
shifts of syn-imidazolylpropylamines (()-15a ,c and anti-imidazolyl-
propylamines (()-15b,d ,f were assigned with respect to the chemical
shifts observed in the syn-imidazolylpropylamine (-)-5 and anti-
imidazolylpropylamine (+)-7, respectively.
118.8, 127.4, 127.8, 128.8, 129.3, 136.9, 139.0; [R]27 -23.0 (c
D
0.25, CHCl3); λmax 208 (ꢀ 11 000). Anal. Calcd for C14H19N3: C,
73.33; H, 8.35; N, 18.32. Found: C, 73.41; H, 8.25; N, 18.50.
(1S,2R)-N-[2-(1H-Im id a zol-1-yl)-1-m eth yl-2-p h en yleth yl]-
N,N-d im eth yla m in e [(+)-7]. The title compound was prepared
as a white solid (1.1 g, 85% yield) according to the procedures
described for the synthesis of [(-)-5] above except for the
replacement of (1S,2S)-(+)-N-methylpseudoephedrine 1 with
(1S,2R)-(+)-N-methylephedrine 6 (1.0 g, 5.7 mmol), CDI (1.1 g,
6.8 mmol), and performing the reaction at rt: mp ) 113-114
-1
1
°C; IR (film) cm
2969, 2938, 2789, 1498, 1221, 1082, 907; H
NMR (CDCl3) δ 0.91 (d, 3H, J ) 6.8 Hz), 2.22 (s, 6H), 3.29-3.52
(m, 1H), 5.14 (d, 1H, J ) 9.2 Hz), 7.00 (s, 1H), 7.05 (s, 1H), 7.26-
5126 J . Org. Chem., Vol. 69, No. 15, 2004

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7.36 (m, 5H), 7.75 (s, 1H); 13C NMR (CDCl3) δ 8.7, 40.7, 61.2,
65.1, 118.2, 127.7, 128.4, 129.0, 129.2, 137.0, 138.5; [R]27D +67.7
(c 0.23, CHCl3); λmax 206 (ꢀ 13 200). Anal. Calcd for C14H19N3:
C, 73.33; H, 8.35; N, 18.32. Found: C, 73.34; H, 8.29; N, 18.47.
syn -N,N-Dieth yl-N-[2-(1H-im idazol-1-yl)-1-m eth yl-2-ph en -
yleth yl]a m in e [(()-15a ]‚Bis-h yd r och lor id e Sa lt. syn-Imida-
zolylpropylamine (()-15a was prepared according to the proce-
dure for (-)-5; tan oil (62%). An EtOAc solution of syn-imi-
dazolylpropylamine (()-15a (300 mg, 1.2 mmol) was added to 2
M HCl in diethyl ether. The resulting precipitate was filtered
and washed with diethyl ether to afford (()-15a ‚bis-HCl salt as
a tan solid (315 mg, 96%), from which all analytical data was
obtained: mp ) 194-196 °C; IR (film) cm-1 2968, 1492, 1454,
1382, 1223, 1074; 1H NMR (D2O) δ 1.23 (d, 3H, J ) 6.8 Hz),
1.34 (t, 6H, J ) 7.2 Hz), 3.15-3.27 (m, 2H), 3.53-3.61 (m, 2H),
4.72-4.77 (m, 1H), 5.92 (d, 1H, J ) 11.2 Hz), 7.48-7.50 (m, 3H),
7.54-7.55 (m, 1H), 7.57-7.60 (m, 2H), 7.97-7.98 (m, 1H), 9.16
(bs, 1H); 13C NMR (D2O) δ 10.1, 10.3, 10.7, 46.3, 48.8, 59.5, 63.9,
120.7, 122.6, 128.4, 130.4, 131.0, 134.2, 135.4. Anal. Calcd for
C16H25N3Cl2‚0.5H2O: C, 56.64; H, 7.72; N, 12.38. Found: C,
57.04; H, 7.78; N, 12.28.
a n ti-N,N-Dieth yl-N-[2-(1H-im idazol-1-yl)-1-m eth yl-2-ph en -
yleth yl]a m in e [(()-15b]‚Bis-h yd r och lor id e Sa lt. anti-Imi-
dazolylpropylamine (()-15b (tan oil, 67%) was prepared accord-
ing to the procedure for (-)-5; the salt, (()-15b‚bis-HCl (tan
solid, 309 mg, 94%), was prepared as described for (()-15a from
which all analytical data was obtained: mp ) 187-189 °C; IR
(film) cm-1 2968, 2809, 1492, 1454, 1382, 1223, 1074, 905; 1H
NMR (D2O) δ 1.11-1.21 (m, 6H), 1.26 (d, 3H, J ) 12.4 Hz), 3.12-
3.16 (m, 2H), 3.39-3.42 (m, 2H), 4.63-4.66 (m, 1H), 6.00 (d, 1H,
J ) 6.4 Hz), 7.45-7.50 (m, 4H), 7.63-7.67 (m, 2H), 7.78 (bs,
1H), 8.97 (bs, 1H); 13C NMR (D2O) δ 9.7, 10.0, 47.0, 48.7, 58.3,
64.5, 120.7, 122.1, 128.9, 131.3, 132.0, 132.2, 135.6. Anal. Calcd
for C16H25N3Cl2‚0.5H2O: C, 56.64; H, 7.72; N, 12.38. Found: C,
56.84; H, 7.69; N, 12.20.
135.5. Anal. Calcd for C16H23N3OCl2: C, 55.82; H, 6.73; N, 12.20.
Found: C, 55.62; H, 6.76; N, 12.06.
a n ti-4-[2-(1H-Im idazol-1-yl)-1-m eth yl-2-ph en yleth yl]m or -
p h olin e [(()-15d ]. anti-Imidazolylpropylamine (()-15d (white
solid, 81%) was prepared according to the procedure for (-)-5.
An analytical sample was recrystallized from EtOAc/hexanes:
mp ) 114-115 °C; IR (film) cm-1 1586, 1569, 1496, 735, 701;
1H NMR (400 MHz, CDCl3) δ 1.00 (d, 3H, J ) 6.8 Hz), 2.43-
2.52 (m, 4H), 3.42-3.47 (m, 1H), 3.50-3.58 (m, 4H), 5.03 (d, 1H,
J ) 8.8 Hz), 7.04-7.07 (m, 2H), 7.29-7.37 (m, 5H), 7.70 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 11.1, 49.8, 62.7, 65.7, 67.8, 118.5,
128.2, 128.6, 129.1, 130.1, 137.4, 139.1. Anal. Calcd for C16H21N3O‚
0.3H2O: C, 69.29; H, 7.87; N, 15.15. Found: C, 68.99; H, 7.67;
N, 15.21.
a n ti-N-[2-(1H-Im id a zol-1-yl)-1-m eth yl-2-p h en yleth yl]-N-
m eth yl-N-p h en yla m in e [(()-15f]‚Bis-h yd r och lor id e Sa lt.
anti-Imidazolylpropylamine (()-15f (white solid, 66%) was
prepared according to the procedure for (-)-5; the salt, (-)-15f‚
bis-HCl (tan solid, 210 mg, 85%), was prepared as described for
(()-15a from which all analytical data was obtained: mp ) 115-
116 °C dec; IR (film) 2927, 1596, 1503, 1289, 1116, 749, 721; 1H
NMR (400 MHz, D2O) δ 1.15 (d, 3H, J ) 6.8 Hz), 2.71 (s, 3H),
4.97-5.01 (m, 1H), 5.84 (d, 1H, J ) 2.8 Hz), 6.80-6.84 (m, 1H),
6.89 (d, 2H, J ) 8.4 Hz), 7.24-7.26 (m, 2H), 7.36-7.38 (m, 3H),
7.50-7.51 (m, 1H), 7.57-7.59 (m, 2H), 7.83-7.84 (m, 1H), 9.03-
9.04 (m, 1H); 13C NMR (100 MHz, D2O) δ 13.1, 31.1, 57.5, 67.5,
115.6, 119.5, 121.0, 128.4, 129.8, 130.0, 130.1, 134.7, 136.1, 149.9;
HRMS m/z calcd for C19H21N3 292.1814, found 292.1824.
Ack n ow led gm en t. We thank OSI Pharmaceuticals
for support of this work. We also thank Dr. Arlindo L.
Castelhano, as well as Professors Bernard Golding,
Marvin J . Miller, Iwao Ojima, and Scott Sieburth, for
many fruitful discussions. We also thank Drs. Victor G.
Young, J r., and Yongsheng Che for assistance in obtain-
ing X-ray crystallographic analyses and Dr. Minghui
Wang for 13C NMR analyses.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and IR spectra of 2, 4, (-)-5, (+)-7, (()-14a -f, (()-15a -d , and
(()-15f, elemental analysis of 2, 4, (-)-5, (+)-7, (()-14c, (()-
14e, and (()-15a -d , HRMS of (()-14f and (()-15f, and X-ray
crystallography data of (-)-5 and (+)-7. This material is
available free of charge via the Internet at http://pubs.acs.org.
syn -4-[2-(1H-Im id a zol-1-yl)-1-m eth yl-2-p h en yleth yl]m or -
p h olin e [(()-15c]‚Bis-h yd r och lor id e Sa lt. syn-Imidazolyl-
propylamine (()-15c (white solid, 80%) was prepared according
to the procedure for (-)-5; the salt, (()-15c‚bis-HCl (white solid,
352 mg, 93%), was prepared as described for (()-15a from which
all analytical data was obtained: mp ) 148-150 °C dec; IR (film)
1
cm-1 1586, 1569, 1496, 735, 701; H NMR (D2O) δ 1.20 (d, 3H,
J ) 6.4 Hz), 3.08-3.11 (m, 2H), 3.28-3.34 (m, 2H), 3.80-3.91
(m, 4H), 4.39-4.41 (m, 1H), 5.90 (d, 1H, J ) 10.8 Hz), 7.48-
7.53 (m, 6H), 7.58 (bs, 1H), 9.07 (bs, 1H); 13C NMR (D2O) δ 11.7,
49.4, 63.5, 64.1, 64.2, 121.1, 121.9, 128.5, 130.5, 131.0, 134.4,
J O049677L
J . Org. Chem, Vol. 69, No. 15, 2004 5127