Selective cleavage of N-benzyl-protected secondary amines by triphosgene

Article abstract of DOI:10.1021/jo0263622

A series of competition experiments has revealed that selective cleavage of N-benzyl-protected secondary amines can be achieved with triphosgene, thereby providing a useful range of carbamoyl chlorides.

Full text of DOI:10.1021/jo0263622

methane at 0-4 °C. After 16 h, the reaction mixture was
analyzed by GLC so as to determine the proportions of
substrates remaining as well as the ratios of the product
carbamoyl chlorides. Authentic samples of the products
were prepared by independent reaction of the N-benzyl-
amines with triphosgene in the manner defined by
J orand-Lebrun et al.6 The collection of substrates inves-
tigated is shown below together with the structures of
the products, while the nature and outcomes of the
competition experiments are presented in Table 1.
Selective Clea va ge of N-Ben zyl-P r otected
Secon d a r y Am in es by Tr ip h osgen e
Martin G. Banwell,* Mark J . Coster,
Michael J . Harvey, and J ohn Moraes
Research School of Chemistry, Institute of Advanced
Studies, The Australian National University,
Canberra ACT 0200, Australia
mgb@rsc.anu.edu.au
Received August 28, 2002
Abstr a ct: A series of competition experiments has revealed
that selective cleavage of N-benzyl-protected secondary
amines can be achieved with triphosgene, thereby providing
a useful range of carbamoyl chlorides.
In connection with efforts to develop synthetic routes
to the marine natural product haliclonacyclamine A (1)1
and its various congeners,1,2 we sought a method that
would allow for selective mono-debenzylation of the
readily available bis-piperidine 2.3 Among the various
reagents investigated for this purpose,4 the commercially
available and easily handled triphosgene [bis(trichloro-
methyl) carbonate]5,6 proved especially efficacious in
converting, in a completely selective fashion, substrate
2 into the carbamoyl chloride 3, which could be readily
manipulated so as to give the corresponding secondary
amine or a now orthogonally protected diamine. In view
of this result, and the likely utility of regioselective
methods for the N-debenzylation of amines,4c we have
evaluated the capacity of triphosgene to effect the selec-
tive cleavage of a suite of N-benzyl-protected secondary
amines and report the outcomes here.
In undertaking the above-mentioned evaluation, a
series of competition experiments was set up wherein
equimolar quantities of various pairs of N-benzyl-
protected secondary amines were subjected to treatment
with a 0.166 molar equiv of triphosgene in dichloro-
(1) Clark, R. J .; Field, K. L.; Charan, R. D.; Garson, M. J .; Brereton,
I. M.; Willis, A. C. Tetrahedron 1998, 54, 8811.
(2) (a) J aspars, M.; Pasupathy, V.; Crews, P. J . Org. Chem. 1994,
59, 3253. (b) Harrison, B.; Talapatra, S.; Lobkovsky, E.; Clardy, J .;
Crews, P. Tetrahedron Lett. 1996, 37, 9151. (c) Torres, Y. R.; Berlinck,
R. G. S.; Magalha˜es, A.; Schefer, A. B.; Ferreira, A. G.; Hajdu, E.;
Muricy, G. J . Nat. Prod. 2000, 63, 1098.
(3) Banwell, M. G.; Coster, M. J .; Rea, A. J . Unpublished observa-
tions.
(4) (a) Kocienski, P. J . In Protecting Groups; Enders, D., Noyori, R.,
Trost, B. M., Eds.; Foundations of Organic Chemistry Series; Georg
Thieme Verlag: Stuttgart, 1994. (b) Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.; J ohn Wiley: New York,
1999. (c) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad,
R. S.; Smith, A. D. J . Chem. Soc., Perkin Trans 1 2000, 3765.
In almost every instance a very clean reaction was
observed. It is clear, as evidenced by the results presented
in entries 1, 2, and 7, that it is possible to achieve very
selective de-benzylation in cases where there is a signifi-
cant difference in electron densities at the N-benzylated
ring nitrogens in the two competing substrates. Thus, it
would seem that the more nucleophilic nitrogen centers
10.1021/jo0263622 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/06/2002
J . Org. Chem. 2003, 68, 613-616
613

TABLE 1. Ou tcom es of Com p etitive N-Deben zyla tion
Exp er im en tsa
such groups are incorporated within the one substrate.
With the developments described here, we believe the
benzyl moiety can be regarded as an especially valuable
protecting group for polyamines and that it warrants
greater attention than it has been accorded to date.
Indeed, with the increasing number of biologically active
polyamine natural products7 being discovered, benzyl
protection of amines would now seem to be a useful tool
in developing serviceable syntheses of these compounds
and their analogues.
first
substrate
second
substrate
major
product
minor
product
product
ratiob
entry
1
2
3
4
5
6
7
8
9
4
4
4
4
4
6
8
16
20
6
8
5
5
5
7
9
11
15
5
7
9
600:1
93:1
4:1
3:1
4:3
10
14
16
12
14
18
22
5
17
13
15
17
21
7:3
23:1
8:7
19
23
9:5c
Exp er im en ta l Section
a
Reactions conducted as defined in the Experimental Section
using 0.5 mmol of the first and second substrates as well as 0.166
General experimental procedures have been described previ-
ously.8 Unless otherwise specified, NMR spectra were recorded
using deuteriochloroform as solvent.
b
mmol of triphosgene. Unless otherwise specified, ratio deter-
mined by GLC analysis under conditions defined in the Experi-
mental Section. c Ratio determined by 1H NMR analysis at 300
MHz.
N-Ben zyl-P r otected Am in es 4, 6, 8, 10, 12, 14, 16, 18, 20,
22, 24, 26, 28, a n d 31. N-Benzylamines
8 and 18 were
purchased from commercial suppliers while compounds 4, 6, and
16 were prepared by reaction of the corresponding secondary
amine with benzyl chloride in the presence of ethanolic potas-
sium carbonate according to the method of Diouf et al.9 Com-
pound 14 was prepared by reduction of N-benzylpyridinium
chloride with sodium borohydride,10 while N-benzylamine 20 was
generated from N,N-dibenzylamine and methyl acrylate accord-
ing to the method of Bartoli et al.11 Compounds 22 and 24 were
prepared by tris-benzylation of glycine and (S)-alanine, respec-
tively, according to the procedure of Beaulieu and Wernic.12 The
remaining substrates were prepared according to the methods
defined below.
react preferentially with triphosgene and, thereby, set
in motion the debenzylation reaction. This explanation
would also account for the selective conversion of sub-
strate 2 into product 3. Such electron density arguments
presumably also account for the preferential debenzyla-
tion of the â-amino acid derivative 20 over its R-amino
acid counterpart 22 (entry 9). Further, the observation
that the N-benzyl-protected alanine derivative 24 fails
to react, even at 100 °C, with triphosgene (so as to give
compound 25) may be attributed to the increased steric
congestion (relative to the glycine congener 22) at the
R-carbon, which is likely to impede attack of triphosgene
at the nitrogen. The conversion 22 f 23 is notable for
the lack of cleavage of the benzyl ester moiety. The
observed ring cleavage of [1,3]oxazine (12) to give the
chloromethyl ether 13 is not surprising, but this result
serves to highlight one constraint (albeit a modest one)
on the applicability of this type of debenzylation protocol.
In addition to the cases just mentioned, some further
internal competition experiments were undertaken. Thus,
treatment of the bis-dibenzylamine 26 with triphosgene
gave, in 91% yield, the carbamoyl chloride 27 wherein
reaction has taken place at the nitrogen remote from the
ester moiety. The structure of product 27 follows from
the significant change in the 1H NMR chemical shift
observed (δ 2.43 f 3.27) for the triplet resonance due to
the C6 protons in the substrate and product. Reaction of
compound 28 under the usual debenzylation conditions
gave, in 87% combined yield, a ca. 5:1 mixture of the
carbamoyl chloride 29 and its doubly debenzylated
counterpart 30 (once again, structural assignments follow
from analysis of changes in chemical shifts for key proton
resonances). In contrast, the â-amino ester derivative 31
only gave a complex mixture of products on exposure to
triphosgene. Nevertheless, the results just mentioned
clearly add weight to the idea that electronic factors play
a pivotal role in determining the selectivity of these
debenzylation reactions. Such factors may be either
reinforced or counterbalanced by steric effects.
1-Ben zylp ip er id in -4-yl Aceta te (10). A magnetically stirred
solution of 1-benzyl-4-piperidone (1.89 g, 10 mmol) in MeOH (20
mL) and maintained under nitrogen was cooled to 0 °C and then
treated, portionwise over 0.25 h, with sodium borohydride (810
mg, 20 mmol). The resulting solution was stirred at 18 °C for 2
h and then diluted with H2O (10 mL). The resulting mixture
was partitioned between ethyl acetate (50 mL) and brine (50
mL), and then the separated organic phase was dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue
thus obtained was dissolved in pyridine (20 mL), and the
resulting magnetically stirred solution treated, in one portion,
with acetic anhydride (1.23 g, 12 mmol). After being stirred at
18 °C for 6 h, the reaction mixture was concentrated under
reduced pressure and the residue partitioned between dichlo-
romethane (50 mL) and brine (50 mL). The separated organic
phase was washed with water (2 × 50 mL) and brine (2 × 50
mL) and then dried (Na2SO4), filtered and concentrated under
reduced pressure to afford compound 10 (2.25 g, 97%) as a clear
yellow oil: 1H NMR (300 MHz) δ 7.32-7.27 (5H, m), 4.77 (1H,
septet, J ) 4 Hz), 3.51 (2H, s), 2.70 (2H, m), 2.25 (2H, m), 2.02
(3H, s), 1.88 (2H, m), 1.71 (2H, m); 13C NMR (75 MHz) δ 170.8
(CdO), 138.5 (C), 129.3 (CH), 128.4 (CH), 127.3 (CH), 70.8 (CH),
63.3 (CH2), 51.2 (CH2), 31.2 (CH2), 21.8 (CH3); IR (NaCl, film)
νmax 2949, 2804, 1734, 1362, 1243, 1041, 698 cm-1; MS (EI) m/z
233 (M•+, 20), 190 [(M - CH3CO•)+, 7], 174 (17), 172 (24), 156
[(M - Ph•)+, 15], 91 (100), 82 (43). Anal. Calcd for C14H19NO2:
C, 72.07; H, 8.21; N, 6.00. Found: C, 71.77, H, 8.24, N, 6.01.
3-Ben zyl[1,3]oxa zin a n e (12). This compound was prepared
according to the method of Booth and Lemieux13 and obtained
as a clear, colorless oil: bp 104 °C (4 mmHg); 1H NMR (300 MHz)
δ 7.34-7.22 (5H, m), 4.31 (2H, s), 3.87 (2H, t, J ) 5.6 Hz), 3.82
(7) See, for example, (a) Williams, D. E.; Craig, K. S.; Patrick, B.;
McHardy, L. M.;van Soest, R.;Roberge, M.;Andersen, R. J . J . Org. Chem.
2002, 67, 245. (b) Ovenden, S. P. B.; Cao, S.; Leong, C.; Flotow, H.;
Gupta, M. P.; Buss, A. D.; Butler, M. S. Phytochemistry 2002, 60, 175.
(8) Banwell, M. G.; Clark, G. R.; Hockless, D. C. R.; Pallich, S. Aust.
J . Chem. 2001, 54, 691.
On the basis of the foregoing, triphosgene would seem
to be a useful reagent for the selective cleavage of
N-benzyl-protected secondary amines even when several
(9) Diouf, O.; Depreux, P.; Chavatte, P.; Poupaert, J . H. Eur. J . Med.
Chem. 2000, 35, 699.
(5) Roestamadji, J .; Mobashery, S. Bis(trichloromethyl) Carbonate.
In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; J ohn Wiley and Sons Ltd: Chichester, 1995.
(6) J orand-Lebrun, C.; Valognes, D.; Halazy, S. Synth. Commun.
1998, 28, 1189.
(10) Takemura, S.; Miki, Y.; Uono, M.; Yoshimura, K.; Kuroda, M.;
Suzuki, A. Chem. Pharm. Bull. 1981, 29, 3026.
(11) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri, L.;
Torregiani, E. J . Org. Chem. 2001, 66, 9052.
(12) Beaulieu, P. L.; Wernic, D. J . Org. Chem. 1996, 61, 3635.
614 J . Org. Chem., Vol. 68, No. 2, 2003

(2H, s), 2.88 (2H, t, J ) 5.6 Hz), 1.72 (2H, p, J ) 5.6 Hz); 13C
NMR (75 MHz) δ 138.7 (C), 129.2 (CH), 128.5 (CH), 127.3 (CH),
85.0 (CH2), 68.3 (CH2), 56.2 (CH2), 49.9 (CH2), 22.8 (CH2); IR
(NaCl, film) νmax 2948, 2849, 1453, 1046, 737, 698 cm-1; MS (EI)
m/z 177 (M•+, 16), 176 [(M - H•)+, 46], 91 (100), 86 (23). Anal.
Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.55,
H, 8.47, N, 7.86.
%). The resulting solution was cooled to 0 °C, and EDCl (3.78 g,
19.68 mmol, 4.5 molar equiv) was added. The reaction mixture
was then removed from the cooling bath and allowed to stir at
18 °C for 16 h. After this time, sodium bicarbonate (40 mL of a
saturated aqueous solution) and water (20 mL) were added, and
the resulting mixture extracted with dichloromethane (3 × 20
mL). The combined organic fractions were dried (Na2SO4),
filtered, and concentrated under reduced pressure to yield a
yellow oil. Subjection of this material to flash chromatography
(silica gel, 1:9 v/v ethyl acetate/hexane elution) provided, after
concentration of the appropriate fractions (Rf 0.3), ester 31 (1.64
g, 76%) as white crystals: mp 62-64 °C; 1H NMR (300 MHz) δ
7.42-7.20 (20H, m), 4.19 (2H, t, J ) 6.0 Hz), 3.68 (4H, s), 3.64
(4H, s), 2.87 (2H, t, J ) 7.0 Hz), 2.73 (2H, t, J ) 6.0 Hz), 2.55
(2H, t, J ) 7.0 Hz); 13C NMR (75 MHz) δ 172.3 (CdO), 139.3(4)
(C), 139.3 (C), 128.8 (CH), 128.6 (CH), 128.2 (C), 127.0 (CH),
62.5 (CH2), 58.8 (CH2), 58.2 (CH2), 51.8 (CH2), 49.3 (CH2), 33.0
(CH2) (one peak obscured or overlapping); IR (KBr) νmax 3027,
2928, 2799, 1734, 1494, 1453, 1180, 1028, 745, 698 cm-1; MS
(EI) m/z 492 (M+, 10), 401 [(M - C7H7•)+, 45], 357 (13), 224 (13),
210 (66), 91 (100); HRMS calcd for C33H36N2O2 492.2777, found
492.2775.
Ca r ba m oyl Ch lor id es 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 27,
29, a n d 30. Authentic samples of the title carbamoyl chlorides
were prepared by reaction of the corresponding N-benzylamines
with triphosgene according to the method of J orand-Lebrun et
al.6 The samples of compounds 5,18 7,18 9,6 15,19 and 1718 obtained
by such means gave spectroscopic data in complete accord with
the same derived from authentic samples or reported previously.
Data for the remaining compounds are presented below.
1-Ch lor oca r bon ylp ip er id in -4-yl Aceta te (11). Obtained in
88% yield from compound 10: 1H NMR (300 MHz) δ 4.99 (1H,
septet, J ) 3.5 Hz), 3.84 (2H, m), 3.61 (2H, m), 2.07 (3H, s),
1.92 (2H, m), 1.74 (2H, m); 13C NMR (75 MHz) δ 170.0 (C), 148.0
(C), 68.3 (CH), 45.7 (CH2), 43.2 (CH2), 30.6 (CH2), 30.1 (CH2),
21.2 (CH3) (additional signals due to slow interconversion of
rotamers); IR (NaCl, film) νmax 2961, 1738, 1407, 1366, 1239,
1194, 1044 cm-1; MS (EI) m/z 207 and 205 (M•+, each <1%), 170
[(M - Cl•)+, 16], 147 and 145 [(M - HOAc)•+, 45 and 100], 130
(26), 110 (38). Anal. Calcd for C8H12ClNO3: C, 46.73; H, 5.88;
Cl, 17.24; N, 6.81. Found: C, 46.58, H, 5.91, Cl, 17.23, N, 6.79.
N-Ben zyl-(3-ch lor om et h oxy-p r op yl)a m in e-1-ca r b on yl
Ch lor id e (13). Obtained in 74% yield from compound 12: 1H
NMR (300 MHz) δ 7.40-7.26 (5H, m), 5.46 (1H, s), 5.45 (1H, s),
4.73 (1H, s), 4.59 (1H, s), 3.70 (2H, t, J ) 5.9 Hz), 3.47 (2H, m),
1.94 (2H, m); 13C NMR (75 MHz) δ 150.3 (CdO), 149.8 (CdO),
135.8 (C), 135.7 (C), 131.2 (CH), 129.8 (CH), 129.1(4) (CH), 129.0-
(9) (CH), 128.3 (CH), 127.3 (CH), 83.2 (CH2), 83.1 (CH2), 67.8
(CH2), 67.6 (CH2), 55.1 (CH2), 53.1 (CH2), 47.9 (CH2), 47.1 (CH2),
28.1 (CH2), 27.1 (CH2) (additional signals due to slow intercon-
version of rotamers); IR (NaCl, film) νmax 2950, 1732, 1403, 1190,
1131, 702 cm-1; MS (EI) m/z 277 and 275 (M•+, each <1), 91
(100); HRMS calcd for C2H1535Cl2NO2 275.0480, found 275.0477.
2,5-Dih yd r op yr r ole-1-ca r bon yl Ch lor id e (19). Obtained
in 44% yield from compound 18: 1H NMR (300 MHz) δ 5.86 (1H,
m), 5.81 (1H, m), 4.38 (2H, m), 4.28 (2H, m); 13C NMR (75 MHz)
δ 146.8 (C), 125.3 (CH), 124.8 (CH), 56.8 (CH2), 54.8 (CH2)
(additional signals due to slow interconversion of rotamers); IR
(NaCl, film) νmax 2921, 2872, 1742, 1627, 1470, 1375, 1183, 883,
755 cm-1; MS (EI) m/z 133 and 131 (M•+, 27 and 98), 132 and
130 [(M - H•)+, 17 and 35], 96 [(M - Cl•)+, 100], 67 (26), 63
(21); HRMS calcd for C5H635ClNO 131.0138, found 131.0138.
Com p ou n d 21. Obtained in 94% yield from compound 20:
1H NMR (300 MHz) δ 7.45-7.20 (5H, m), 4.79 (1H, s), 4.63 (1H,
s), 3.72 (1H, t, J ) 7.2 Hz), 3.69 (3/2H, s), 3.67 (3/2H, s), 3.61
(1H, t, J ) 6.9 Hz), 2.65 (2H, m); 13C NMR (75 MHz) δ 171.5
(C), 171.1 (C), 149.9 (C), 149.5 (C), 135.5 (C), 135.4 (C), 128.9
(CH), 128.2 (CH), 128.1 (CH), 127.1 (CH), 55.3 (CH2), 53.0 (CH2),
Ben zyl (S)-2,6-Bis-d iben zyla m in oh exa n oa te (26). A mag-
netically stirred suspension of L-lysine hydrochloride (1.83 g, 10.0
mmol) in DMF/water (10:1 v/v mixture, 22 mL) was treated with
anhydrous potassium carbonate (11.1 g, 80.0 mmol, 8 molar
equiv) and benzyl bromide (6.5 mL, 55 mmol, 5.5 molar equiv).
After being stirred at 18 °C for 4 days, the resulting white slurry
was diluted with water (100 mL) and extracted with diethyl
ether (3 × 50 mL). The combined organic portions were washed
with aqueous sodium chloride (50 mL of a 15 wt % solution),
dried (Na2SO4), and filtered, and the solvent was removed under
reduced pressure to yield a colorless oil. Subjection of this
material to flash chromatography (silica gel, 1:9 f 1:4 v/v ethyl
acetate/hexane elution) provided, after concentration of the
appropriate fractions (Rf 0.5 in 1:4 v/v ethyl acetate/hexane),
compound 26 (4.99 g, 84%) as a clear, colorless and highly
viscous oil: [R]D -52.5 (c 2.8, CHCl3); 1H NMR (300 MHz) δ
7.50-7.26 (25H, m), 5.33 (1H, d, J ) 12.3 Hz), 5.21 (1H, d, J )
12.3 Hz), 3.99 (2H, d, J ) 13.8 Hz), 3.59 (2H, d, J ) 13.8 Hz),
3.57 (4H, ABq, J ) 14.1 Hz), 3.43 (1H, dd, J ) 8.8 and 6.2 Hz),
2.43 (2H, t, J ) 6.9 Hz), 1.86-1.25 (6H, m); 13C NMR (75 MHz)
δ 172.8 (C), 140.0 (C), 139.7 (C), 136.1 (C), 128.8 (CH), 128.7
(CH), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH),
126.9 (CH), 126.7 (CH), 66.0 (CH2), 60.8 (CH), 58.4 (CH2), 54.5
(CH2), 53.2 (CH2), 29.5 (CH2), 26.9 (CH2), 23.9 (CH2); IR (NaCl,
film) νmax 3029, 2942, 2798, 1730, 1494, 1453, 1137, 745, 697
cm-1; MS (EI) m/z 596 (M•+, 7%), 505 [(M - C7H7•)+, 46], 461
[(M - BnOCO•)+, 67], 401 (12), 308 (20), 236 (15), 210 (41), 91
(100); HRMS calcd for C41H44N2O2 596.3403, found 596.3399.
4-Diben zyla m in obu tyl Diben zyla m in oa ceta te (28). A
magnetically stirred solution of 4-(N,N-dibenzylamino)butan-1-
ol14 (539 mg, 2.00 mmol) in dichloromethane (8 mL) was treated
with the hydrochloride salt of N,N-dibenzylglycine15 (929 mg,
3.00 mmol, 1.5 mole equiv), N,N-diisopropylethylamine (1.05 mL,
6.03 mmol, 3 molar equiv) and DMAP (37 mg, 0.30 mmol, 15
mol %). The resulting solution was cooled to 0 °C and EDCI (1.73
g, 9.00 mmol, 4.5 molar equiv) was added. The reaction mixture
was removed from the cooling bath and allowed to stir at 18 °C
for 16 h. Sodium bicarbonate (20 mL of a saturated aqueous
solution) and water (10 mL) were added, and the resulting
mixture was extracted with dichloromethane (3 × 10 mL). The
combined organic portions were then dried (Na2SO4), filtered,
and concentrated under reduced pressure to give a yellow oil.
Subjection of this material to flash chromatography (silica gel,
1:9 v/v ethyl acetate/hexane elution) provided, after concentra-
tion of the appropriate fractions (Rf 0.3), compound 28 (1.01 g,
100%) as a clear, colorless oil: 1H NMR (300 MHz) δ 7.40-7.20
(20H, m), 4.02 (2H, t, J ) 6.3 Hz), 3.80 (4H, s), 3.55 (4H, br s),
3.27 (2H, s), 2.44 (2H, br t, J ) 6.3 Hz), 1.66-1.55 (4H, m); 13
C
NMR (75 MHz) δ 171.4 (C), 139.8 (C), 139.0 (C), 128.9 (CH),
128.8 (CH), 128.3 (CH), 128.2 (CH), 127.1 (CH), 126.9 (CH), 64.3
(CH2), 58.5 (CH2), 57.9 (CH2), 53.7 (CH2), 53.0 (CH2), 26.6 (CH2),
23.8 (CH2); IR (NaCl, film) νmax 3027, 2945, 2798, 1734, 1494,
1453, 1367, 1184, 1148, 1028, 743, 698 cm-1; MS (EI) m/z 506
(M•+, 3), 415 [(M - C7H7•)+, 20], 311 (3), 252 (2), 210 (69), 181
(3), 160 (21), 118 (3), 91 (100); HRMS calcd for C34H38N2O2
506.2933, found 506.2934.
2-Diben zylam in oeth yl 3-Diben zylam in opr opan oate (31).
A magnetically stirred solution of 2-(N,N-dibenzylamino)etha-
nol16 (1.05 g, 4.37 mmol) in dichloromethane (10 mL) was treated
with 3-(N,N-dibenzylamino)propanoic acid17 (2.00 g, 6.56 mmol,
1.5 molar equiv), N,N-diisopropylethylamine (2.30 mL, 13.11
mmol, 3 molar equiv), and DMAP (80 mg, 0.65 mmol, 15 mol
(16) Schwerdtfeger, J .; Kolczewski, S.; Weber, B.; Fro¨hlich, R.;
Hoppe, D. Synthesis 1999, 1573.
(17) Erhardt, P. W. Synth. Commun. 1983, 13, 103.
(18) These compounds can be purchased from many major chemical
supply houses.
(13) Booth, H.; Lemieux, R. U. Can. J . Chem. 1971, 49, 777.
(14) Hasegawa, T.; Ogawa, T.; Miyata, K.; Karakizawa, A.; Ko-
miyama, M.; Nishizawa, K.; Yoshioka, M. J . Chem. Soc., Perkin Trans.
1 1990, 901.
(15) Kimura, M.; Satake, K.; Morosawa, S. Chem. Lett. 1977, 1035.
(19) Yeung, J . M.; Knaus, E. E. Eur. J . Med. Chem. 1986, 21, 181.
J . Org. Chem, Vol. 68, No. 2, 2003 615

52.1 (CH3), 52.0 (CH3), 46.0 (CH2), 45.4 (CH2), 33.2 (CH2), 32.0
(CH2) (additional signals due to slow interconversion of rotam-
ers); IR (NaCl, film) νmax 3032, 2953, 1733, 1438, 1402, 1374,
(Rf 0.3 in 3:17 v/v ethyl acetate/hexane), compound 27 (518 mg,
91%) as a clear, colorless oil: [R]D -52.0 (c 2.4, CHCl3); 1H NMR
(500 MHz) δ 7.54-7.31 (20H, m), 5.37 (1H, m), 5.27 (1H, m),
4.71 (1H, m), 4.58 (1H, ABq, J ) 15 Hz), 4.00 (2H, m), 3.63 (2H,
m), 3.44 (1H, m), 3.37 (2H, m), 1.87-1.77 (2H, m), 1.56-1.49
(3H, m), 1.30 (1H, m); 13C NMR (125 MHz) δ 172.7(4) (C),
172.7(2) (C), 150.1 (C), 149.4 (C), 139.5 (C), 136.1(1) (C),
136.0(8) (C), 135.8 (C), 135.6 (C), 128.9(4) (CH), 128.8(7) (CH),
128.7 (CH), 128.6 (CH), 128.5 (CH), 128.4(4) (CH), 128.3(7) (CH),
128.1 (CH), 128.0 (CH), 127.1(5) (CH), 127.1(0) (CH), 127.0 (CH),
66.1(0) (CH2), 66.0(7) (CH2), 60.5 (CH), 54.5(7) (CH2), 54.5(2)
(CH2), 54.2 (CH2), 52.3 (CH2), 50.1 (CH2), 49.2 (CH2), 29.0 (CH2),
27.5 (CH2), 26.7 (CH2), 23.3 (CH2), 23.2 (CH2) (additional signals
due to slow interconversion of rotamers); IR (NaCl, film) νmax
3030, 2945, 2859, 1732, 1495, 1454, 1402, 1146, 969, 747, 698
cm-1; MS (EI) m/z 533 [(M - Cl•)+, <1], 505 [(M - COCl•)+, 2],
477 [(M - C7H7•)+, <1], 433 [(M - C7H7•)+, 48], 307 (14), 210
(4), 174 (6), 91 (100); HRMS calcd for C35H37N2O3 [(M - Cl•)+]
533.2804, found 533.2804; calcd for C28H30N2O335Cl ([M -
C7H7•]+) 477.1945, found 477.1942.
1323, 1207, 1174, 1048, 702 cm-1; MS (EI) m/z 257 and 255 (M•+
,
each <1), 226 and 224 [(M - CH3O•)+, each <1], 192 [(M -
ClCO•)+,76],91(100).Anal.Calcd for C12H14ClNO3: C,56.37;H,5.52;
Cl, 13.87; N, 5.48. Found: C, 56.71, H, 5.60, Cl, 13.86, N, 5.10.
Com p ou n d 23. Obtained in 92% yield from compound 22:
1H NMR (300 MHz) δ 7.42-7.20 (10H, m), 5.19 (1H, s), 5.17
(1H, s), 4.82 (1H, s), 4.67 (1H, s), 4.12 (1H, s), 4.06 (1H, s)
(additional signals due to slow interconversion of rotamers); 13
C
NMR (75 MHz) δ 167.6, 167.3, 150.4, 150.2, 134.9, 134.8, 134.5,
134.3, 128.9, 128.8, 128.5(2), 128.5(0), 128.4(8), 128.3(9),
128.3(3), 128.2(7), 128.2(2), 128.1(9), 128.1(4), 127.4, 67.4, 67.3,
55.1, 53.5, 51.0, 49.2 (additional signals due to slow intercon-
version of rotamers); IR (NaCl, film) νmax 3065, 3034, 2950, 1732,
1497, 1455, 1391, 1174, 1079, 991, 738, 698 cm-1; MS (EI) m/z
281 [(M - HCl)•+, 6], 253 [(M - CO - HCl)•+, 3], 91 (100). Anal.
Calcd for C17H16ClNO3: C, 64.26; H, 5.07; Cl, 11.16; N, 4.41.
Found: C, 63.24, H, 5.37, Cl, 11.19, N, 4.37.
Com p ou n d s 29 a n d 30. A magnetically stirred solution of
diamine 28 (507 mg, 1.00 mmol) in dichloromethane (3.3 mL)
maintained at 0 °C was treated, via cannula, with a solution of
triphosgene (104 mg, 0.35 mmol, 0.35 molar equiv) in dichlo-
romethane (3.5 mL). The resulting mixture was allowed to stand
at 4 °C for 16 h then the solvent was removed under reduced
pressure to yield a clear, colorless oil. Subjection of this material
to flash chromatography (silica gel, 1:2:7 v/v/v dichloromethane/
ethyl acetate/hexane elution) provided three fractions, A-C.
Concentration of fraction A (Rf 0.5) gave the starting diamine
28 (26.2 mg, 5% recovery) as a clear, colorless oil which was
identical, in all respects, with an authentic sample.
Concentration of fraction B (Rf 0.4) gave the carbamoyl
chloride 29 (351 mg, 73%) as a colorless oil: 1H NMR (300 MHz)
δ 7.43-7.24 (15H, m), 4.70 (1H, s), 4.57 (1H, s), 4.09 (2H, m),
3.83 (4H, s), 3.40 (2H, m), 3.31 (2H, s), 1.63 (4H, m); 13C NMR
(75 MHz) δ 171.3 (C), 150.0 (C), 149.5 (C), 138.9 (C), 135.6 (C),
135.4 (C), 128.8 (CH), 128.3 (CH), 128.1(5) (CH), 128.0(9) (CH),
128.0(3) (CH), 127.2 (CH), 127.0 (CH), 63.6 (CH2), 63.5 (CH2),
57.9 (CH2), 54.4 (CH2), 53.6 (CH2), 52.5 (CH2), 50.0 (CH2), 49.0
(CH2), 26.0 (CH2), 24.8 (CH2), 24.0 (CH2) (additional signals due
to slow interconversion of rotamers); IR (NaCl, film) νmax 3029,
2946, 1734, 1495, 1454, 1402, 1184, 971, 740, 699 cm-1; MS (EI)
m/z 478 (M•+, 1), 443 [(M - Cl•)+, 2], 387 [(M - C7H7•)+, 9], 351
(5), 237 (6), 210 (94), 181 (5), 91 (100); HRMS calcd for
C28H31N2O335Cl 478.2023, found 478.2018.
Gen er a l P r oced u r e Used for Com p etition Exp er im en ts.
A solution of triphosgene (49 mg, 0.166 mmol) in anhydrous
dichloromethane (1.7 mL) was added to a magnetically stirred
solution of the two N-benzylamines (0.50 mmol of each) in
anhydrous dichloromethane maintained at 0 °C under a nitrogen
atmosphere. The ensuing mixture was left to stand at 4 °C for
16 h and then analyzed by GLC to identify (by comparison with
authentic samples) products and determine their ratios. These
analyses were carried out using a Varian 3400 Gas Chromato-
graph fitted with an FID operating at 300 °C and a 15 m × 0.25
mm (i.d.) capillary column employing a 0.25 µm thick poly-
(dimethylsiloxane) (HP1) stationary phase and helium as carrier
gas (linear velocity of 35 cm/sec); generally an initial tempera-
ture of 50 °C rising at 10 °C/min to a final temperature of 300
°C was employed together with an injector temperature of 250
°C and a 50:1 splitter. Dodecane was used as an internal
standard in all experiments. The results of such studies are
presented in Table 1.
1-Ben zyl-4-oxo-1,2,3,4,5,6,3′,6′-octa h yd r o-2′H-[3,4′]bip y-
r id in yl-1′-ca r bon yl Ch lor id e (3). A magnetically stirred solu-
tion of triphosgene (38 mg, 0.128 mmol) in dry dichloromethane
(1.3 mL) maintained at 0 °C under nitrogen was treated with a
solution of compound 23 (131 mg, 0.362 mmol) in dry dichloro-
methane (1.2 mL). The resulting mixture was allowed to stir at
4 °C for 22 h and then concentrated under reduced pressure to
give a colorless oil. Subjection of this material to flash chroma-
tography [silica, 1:4 f 3:2 v/v ethyl acetate (containing ca. 1%
ammonia)/hexane elution] provided, after concentration of the
appropriate fractions (Rf 0.6 in 1% v/v ammonia/ethyl acetate),
compound 3 (93 mg, 77%) as a clear, colorless oil: 1H NMR (500
MHz, 55 °C) δ 7.34-7.25 (5H, m), 5.52 (1H, br s), 4.13-4.08
(2H, br m), 3.75-3.63 (2H, br m), 3.62 (2H, s), 3.17 (1H, br dd,
J ) 8.7, 5.8 Hz), 3.01-2.98 (2H, br m), 2.62-2.52 (3H, br m),
2.45-2.39 (1H, m), 2.16-2.11 (2H, m); 13C NMR (125 MHz, 25
°C) δ 208.1 (C), 208.0 (C), 148.8 (C), 148.3 (C), 137.9 (C), 133.8
(C), 133.7 (C), 129.0 (CH), 128.5 (CH), 127.5 (CH), 120.8 (CH),
120.5 (CH), 62.0 (CH2), 56.9 (CH2), 56.7 (CH), 56.6 (CH), 53.4
(CH2), 47.5 (CH2), 45.8 (CH2), 45.5 (CH2), 43.1 (CH2), 40.9(3)
(CH2), 40.9(1) (CH2), 27.7 (CH2), 27.2 (CH2) (additional signals
due to slow interconversion of rotamers); IR (NaCl, film) νmax
3027, 2908, 2806, 1739, 1716, 1494, 1453, 1405, 1363, 1352,
Concentration of fraction C (Rf 0.2) gave the bis-carbamoyl
chloride 30 (64.0 mg, 14%) as a colorless oil: 1H NMR (300 MHz)
δ 7.42-7.25 (10H, m), 4.82 (1H, s), 4.72 (1H, s), 4.66 (1H, s),
4.58 (1H, s), 4.13 (2H, m), 4.07 (1H, s), 3.99 (1H, s), 3.38 (2H,
m), 1.62 (4H, m); 13C NMR (75 MHz) δ 167.8 (C), 167.5 (C), 150.5
(C), 150.3 (C), 149.9 (C), 149.5 (C), 135.5 (C), 135.4 (C), 134.6
(C), 134.5 (C), 129.0(2) (CH), 128.9(6) (CH), 128.9(1) (CH), 128.5
(CH), 128.1(2) (CH), 128.0(8) (CH), 128.0(2) (CH), 127.6 (CH),
127.0(9) (CH), 127.0(5) (CH), 65.0 (CH2), 64.9 (CH2), 55.4 (CH2),
54.4(2) (CH2), 54.3(7) (CH2), 53.7 (CH2), 52.5 (CH2), 51.0 (CH2),
49.9 (CH2), 49.3 (CH2), 48.8 (CH2), 25.8 (CH2), 24.6 (CH2), 23.7-
(2) (CH2), 23.6(8) (CH2) (additional signals due to slow inter-
conversion of rotamers); IR (NaCl, film) νmax 3033, 2952, 1733,
1496, 1455, 1400, 1186, 989, 701 cm-1; MS (EI) m/z 454, 452,
450 (M•+, each <1), 389 and 387 [(M - COCl•)+, 1 and 5], 325
1317, 1261, 1220, 1187, 1126, 1049, 851, 741, 700, 660 cm-1
;
and 323 [(M - C7H7 - HCl)+, 3 and 11], 287 [(M - C7H7
2HCl)+, 6], 261 (4), 224 (7), 125 (22), 91 (100); HRMS calcd for
-
•
•
MS (EI) m/z 334 and 332 (M•+, 17 and 45), 297 [(M - Cl•)+, 20],
278 and 276 (4 and 11), 133 (62), 91 (100); HRMS calcd for
C18H2135ClN2O2 332.1292, found 332.1290.
C
22H24N2O4Cl2 450.1113, found 450.1121.
Ack n ow led gm en t. We thank the Institute of Ad-
Com p ou n d 27. A magnetically stirred solution of diamine
26 (597 mg, 1.00 mmol) in dichloromethane (3.3 mL) maintained
at 0 °C was treated, via cannula, with a solution of triphosgene
(104 mg, 0.35 mmol, 0.35 molar equiv) in dichloromethane (3.5
mL). The ensuing reaction mixture was allowed to stand at 4
°C for 16 h then the solvent was removed under reduced pressure
to yield a colorless oil. Subjection of this material to flash
chromatography (silica gel, 1:9 f 3:17 v/v ethyl acetate/hexane
elution) provided, after concentration of the appropriate fractions
vanced Studies for financial support including the
provision of a Postdoctoral Fellowship to M.J .C. and a
Summer Research Scholarship to J .M.
Su p p or tin g In for m a tion Ava ila ble: Selected NMR spec-
tra for compounds 3, 10-13, 19, 21, 23, and 26-31. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0263622
616 J . Org. Chem., Vol. 68, No. 2, 2003