Simultaneous Deprotection and Purification of BOC-amines Based on Ionic Resin Capture

Full text of DOI:10.1021/jo972001o

J . Org. Chem. 1998, 63, 3471-3473
3471
Sim u lta n eou s Dep r otection a n d
Sch em e 1
P u r ifica tion of BOC-a m in es Ba sed on Ion ic
Resin Ca p tu r e
Yun-Shan Liu, Cunxiang Zhao,
David E. Bergbreiter,* and Daniel Romo*
Department of Chemistry, Texas A&M University,
College Station, Texas 77843
Received October 31, 1997
Combinatorial chemistry and the synthesis of chemical
libraries has resulted in a need to develop new strategies
to rapidly and simply purify, isolate, and manipulate
library members during each synthetic step. Two major
strategies have been used. The first uses cross-linked
polymers such as those used in Merrifield’s solid-phase
peptide synthesis.1 The second strategy uses soluble
polymer supports or biphasic syntheses.3 The recent
development of polymer-supported quenching reagents
as a rapid purification tool in solution-phase parallel
synthesis is an outgrowth of the former strategy.5 This
chemistry typically relies on molecular reactivity and/or
molecular recognition (often acid-base chemistry) as the
means by which excess reagents or byproducts are
sequestered and isolated. On the other hand, the “resin
capture” idea has also recently been introduced as an
alternative solution-phase library methodology.6 This
method uses functionalized resins to trap selectively (via
a covalent bond linkage) the desired products away from
solution-phase reagents or byproducts. The products are
then released from the resin through an appropriate
cleavage step. Herein, we disclose a new and simple ionic
equivalent of this resin capture technique as demon-
strated by the deprotection and purification of solution-
phase BOC-protected amines through the use of a
strongly acidic macroreticular ion-exchange resin, Am-
berlyst 15.
Ta ble 1. Dep r otection /P u r ifica tion of Va r iou s
BOC-Am in es Usin g Am ber lyst 15a
,2
,4
a
All reactions were carried out on 100 mg scale except entry g.
Isolated yields. c 1 g of the substrate was used.
b
by using an acid like CF
3
COOH or HCl.7 Recently, ion-
exchange chromatography was used to expedite purifica-
8
tion of libraries of amines or amine derivatives. We
reasoned that a strongly acidic ion-exchange resin should
be able to both deprotect BOC-protected amines and to
also isolate the resulting amine products. This expecta-
tion has been successfully realized.
In a typical procedure, N-BOC-(R)-R-methylbenzyl-
amine (1) was treated with cleaned Amberlyst 15 by
The tert-butyloxycarbonyl (BOC) group is widely used
in organic synthesis as an amine protecting group.
Deprotection of BOC-protected amines is usually achieved
*
To whom correspondence should be addressed. (D.B.) Tel.: (409)
45-3437. Fax: (409) 845-4719. E-mail: Bergbreiter@chemvx.tamu.edu.
D.R.) Tel.: (409) 845-9571. Fax: (409) 845-4719. E-mail: Romo@
chemvx.tamu.edu.
1) For some recent reviews, see: (a) Nefzi, A.; Ostresh, J . M.;
8
gentle agitation at 25 °C in CH
2 2
Cl . All the BOC-amine
(
1
was deprotected in 12 h (Scheme 1). The reaction was
(
readily monitored by TLC or HPLC. Complete disap-
pearance of the BOC derivative by these methods served
to indicate when complete deprotection of the BOC-amine
had occurred. The pure (R)-R-methylbenzylamine (3) was
then isolated in 93% yield in a second step by gently
shaking the amine bound resin 2 with excess ammonia
in methanol for 50 min. No additional purification steps
were required. Various other BOC-protected amines
were also deprotected satisfactorily as shown in Table 1.
The deprotection/immobilization process took place
smoothly in dichloromethane, THF, or chloroform but
was very slow in methanol.
Houghten, R. A. Chem. Rev. 1997, 97, 449-472. (b) Thompson, L. A.;
Ellman, J . A. Chem. Rev. 1996, 96, 555-600. (c) Gordon, E. M.; Gallop,
M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144-154. (d) Curran, D.
P. Chemtracts-Org. Chem. 1996, 9, 75-87. (e) Terret, N. K.; Gardner,
M.; Gordon, D. W.; Kobylecki, R. J .; Steele, J . Tetrahedron 1995, 51,
8
135-8173.
(
2) (a) Fruchtel, J . S.; J ung, G. Angew. Chem., Int. Ed. Engl. 1996,
3
1
5, 17-42. (b) Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J . Org. Chem.
996, 61, 924-928.
(
3) Gravert, D. J .; J anda, K. D. Chem. Rev. 1997, 97, 489-509.
(
4) (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; J eger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823-826. (b) Curran, D. P.;
Hadida, S. J . Am. Chem. Soc. 1996, 118, 2531-2532. (c) Carell, T.;
Wintner, E. A.; Bashir-Hashemi, A.; Rebek, J ., J r. J . Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2059-2061.
(
5) (a) Booth, R. J .; Hodges, J . C. J . Am. Chem. Soc. 1997, 119,
882-4886. (b) Flynn, D. L.; Crich, J . Z.; Devraj, R. V.; Hockerman,
S. L.; Parlow, J . J .; South, M. S.; Woodard, S. J . Am Chem. Soc. 1997,
19, 4874-4881. (c) Kaldor, S. W.; Siegel, M. G.; Fritz, J . E.; Dressman,
B. A.; Hahn, P. J . Tetrahedron Lett. 1996, 37, 7193-7196.
6) (a) Keating, T. A.; Armstrong, R. W. J . Am. Chem. Soc. 1996,
18, 2574-2583. (b) Brown, S. D.; Armstrong, R. W. J . Am. Chem.
Soc. 1996, 118, 6331-6332.
We found that both primary and secondary BOC-
protected aliphatic amines can be deprotected efficiently
4
1
(7) Greene, T. W. In Protective Groups in Organic Synthesis; J ohn
Wiley & Sons: New York, 1981; Chapter 7, pp 232-233.
(8) Siegel, M. G.; Hahn, P. J .; Dressman, B. A.; Fritz, J . E.; Grunwell,
J . R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360.
(
1
S0022-3263(97)02001-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/30/1998

3
472 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
with reaction times that ranged from 4 to 29 h at ambient
temperature. Other functional groups such as alcohols,
esters, and carboxylic acids (Table 1, entries a-c,f,h) do
not interfere with the deprotection process. However,
BOC-protected aromatic amines react slowly. For ex-
ample, it took 4 days to deprotect mono-BOC-protected
1
,5-diaminonaphthalene (Table 1, entry j). We also found
that the deprotection of BOC-aniline was not complete
even after 5 days in the presence of excess resin.
This procedure is synthetically useful on both small
and large scales. We showed that 1 g of BOC-octadecyl-
amine can be easily deprotected and purified by this
method in high yield (Table 1, entry g). In addition, this
technique is useful for the deprotection and purification
of a BOC-protected amine in a mixture of compounds as
was demonstrated in the following experiment. A mix-
ture of (R)-N-BOC-methylbenzylamine (1) with methyl
benzoate, N-phenylisopropylurethane, N-(1-phenylethyl)-
p-toluenesulfonamide, benzyl alcohol, and p-nitrophenol
2 2
in CH Cl was treated with excess Amberlyst 15 at
ambient temperature. The disappearance of N-BOC-
methylbenzylamine was monitored by HPLC analysis of
aliquots (Figure 1). Before addition of Amberlyst 15,
there are six peaks on the HPLC chromatogram corre-
sponding to each of these compounds (Figure 1A). Twelve
hours later, after addition of the resin, the peak corre-
sponding to BOC-methylbenzylamine (1) was completely
absent (Figure 1B). More importantly, the relative ratios
of the other components did not change significantly,
indicating selectivity in reaction of the BOC-amine and
in absorption of the amine. Slight decreases in peak
areas for benzyl alcohol and p-nitrophenol were ascribed
to physisorption of these components on the resin.
Separate experiments showed that the physisorbed p-
nitrophenol and benzyl alcohol could both be completely
recovered by soaking the resin in a fresh polar solvent
like methanol prior to release of the pure amine. A small
extra peak at 2.53 min present in the HPLC (a, Figure
F igu r e 1. HPLC traces of an Amberlyst 15-promoted depro-
tection of a BOC-amine in a mixture of compounds with diverse
functionality. (A) HPLC trace (MICROSRB-MV column, 5 µm
1
B) reflected an impurity occasionally seen if the resin
9
2
SiO , 100 Å, 10:90 ethyl acetate/hexane) of reaction mixture
was not thoroughly washed before reaction. The amine-
bound resin was then filtered, rinsed with methanol, and
before addition of the resin: (1) methylbenzoate; (2) N-phen-
ylisopropylurethane; (3) N-BOC-R-methylbenzylamine; (4) ben-
zyl alcohol; (5) N-(phenylethyl)-p-toluenesulfonamide; (6) p-
nitrophenol. (B) Twelve hours after resin was added, BOC-
amine 1 had been deprotected and absorbed while other
components remained in solution. Peak a is an impurity from
3
treated with NH /MeOH to afford the free amine in 93%
yield. RP-HPLC analysis (Figure 1C) showed the purity
of the deprotected amine to be ∼97%. The extra peak at
4
.2 min (b, Figure 1C) was identified as an UV-active
the resin. (C) HPLC trace (reversed-phase C18-SiO
2
, 80:20
impurity in the solvent.
MeOH/H
with NH
2
O) of the free amine 3 isolated by washing the resin
/MeOH. Peak b is an impurity from the solvent.
To further demonstrate the utility of this chemistry,
we carried out two reactions that mimic a solution-phase,
parallel synthesis. In the first example, N-BOC-ethanol-
amine 8 was treated with excess phenyl isocyanate in
the presence of a catalytic amount of triethylamine in
3
Sch em e 2
2 2
CH Cl at 25 °C for 8 h (Scheme 2). Any unreacted
isocyanate was then quenched with methanol. The
mixture, which presumably consisted of two urethane
compounds 13 and 14, was treated with Amberlyst 15
2 2
in CH Cl for 8 h at ambient temperature, and the amine-
bound resin was collected and rinsed with THF and
MeOH in order to remove any physically absorbed
urethane 14. Pure N-phenyl-2-aminoethylurethane (15)
was isolated in 83% yield after the resin was treated with
4
M ammonia in methanol (Scheme 2).
In the second case, we obtained an 89% yield of
N-phenyl-N′-[4-(aminomethyl)phenyl]urea (19) when we
carried out this same chemistry in the presence of excess
diamine (Scheme 3). Thus, 2 mmol of 4-(BOC-amino-
methyl)aniline (16) and 1 mmol of 4-aminobenzylamine
were allowed to react with 5 mmol of phenyl isocyanate
(9) MacDonald, A. A.; Dewitt, S. H.; Ghosh, S.; Hogan, E. M.; Kieras,
L.; Czarnik, A. W.; Ramage, R. Mol. Diversity 1996, 1, 183-186.

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3473
Sch em e 3
Gen er a l P r oced u r e for Dep r otection /P u r ifica tion w ith
Am ber lyst 15 As Descr ibed for N-(ter t-Bu tyloxyca r bon yl)-
octa d ecyla m in e (9). A 1.0 g portion of N-tert-(butyloxycarbo-
nyl)octadecylamine was dissolved in 20 mL of dichloromethane
at ambient temperature. Then 2.5 g of cleaned resin was added,
and the mixture was gently shaken. After 14 h, TLC (hexane)
showed the complete disappearance of BOC-octadecylamine. The
resin was then separated by filtration and washed with hexane,
THF, and MeOH successively. This amine-bound resin was
transferred to 10 mL of 4 M ammonia methanolic solution and
was gently shaken for 50 min. To this mixture was added 20
mL of THF in order to dissolve all of the deprotected octadecyl-
amine. The resin was then removed by filtration, and the
solution was evaporated, yielding 0.70 g (96%) of octadecylamine
1
13
that was identical ( H NMR, C NMR) with authentic octadec-
ylamine.
N-(ter t-Bu tyloxyca r bon yl)octa d ecyla m in e (9): colorless
crystals; mp 56-58 °C (EtOAc); IR (KBr) 3382, 2935, 2866, 1699
-
1
1
cm ; H NMR (CDCl
3
) δ 0.89 (t, 3H), 1.27 (m, 30H), 1.44 (m,
1
3
1
2
3
3
1H), 3.10 (dd, 2H), 4.50 (s, 1H); C NMR (CDCl ) δ 14.115,
2.680, 26.793, 28.402, 29.290, 29.350, 29.551, 29.677, 30.045,
1.907, 40.613, 78.950, 155.936. A satisfactory high-resolution
mass spectrum of the parent ion could not be obtained for this
compound.
1
-[N-(ter t-Bu t yloxyca r b on yl)a m in o]-5-a m in on a p h t h a -
-1 1
len e (12): white solid; IR (KBr) 3304, 3042, 1662 cm ; H NMR
(
1
CDCl3) δ 1.55 (s, 9H), 3.90-4.35 (broad, 2H), 6.71-6.81 (m,
1
3
H), 6.81-6.96 (broad, 1H), 7.28-7.63 (m, 4H), 7.92 (d, 1H);
) δ 28.4, 80.6, 80.8, 109.8, 110.9, 116.5, 116.8, 118.3,
18.5, 124.1, 124.7, 125.9, 126.5, 127.2, 133.4, 133.6, 142.8, 153.4;
C
NMR(CDCl
1
3
+
exact mass (M ) 258.1368 (calcd for C15
-[[(ter t-Bu t yloxyca r bon yl)a m in o]m et h yl]a n ilin e (16):
colorless crystal; mp 87-88 °C (EtOAc/hexane 1:3); IR (KBr)
18 2 2
H N O 258.1381).
4
in THF for 8 h. The unreacted isocyanate was then
quenched with MeOH. The reaction mixture at this point
presumably has three compounds (BOC-containing urea
-
1 1
3
359, 3011, 1693 cm ; H NMR (CDCl
3
) δ 1.444 (s, 9H), 1.503
(
s, 1H), 4.175 (d, 2H), 4.70 (s, 1H), 6.635 (d, 2H), 7.064 (d, 2H);
13
C NMR (CDCl
145.647, 155.795; exact mass (M + H) 223.1446 (calcd for
223.1436).
N-P h en yl-(2-a m in oeth yl)u r eth a n e (15): colorless liquid; IR
3
) δ 28.396, 44.312, 79.237, 115.122, 128.856,
1
7, diurea 18, and urethane 14). Among these three
compounds, only BOC-containing urea 17 is sequestrable
with Amberlyst 15. Thus, using similar conditions
described above, the free amine-containing urea 19 was
12 19 2 2
C H N O
-
1 1
(
KBr) 3444, 3010, 2940, 1739 cm ; H NMR (CDCl
3
) δ 1.449 (s,
2
5
1
H), 2.978 (t, 2H), 4.186 (t, 2H), 7.074 (m, 1H), 7.257-7.391 (m,
1
easily obtained in high purity as confirmed by H NMR
13
H); C NMR (CDCl
3
) δ 41.141, 67.232, 118.614, 123.368,
analysis. In these two examples, the products were
successfully deprotected and purified in a very simple
manner that reverse differentiated the functional group’s
nucleophilicity.
In summary, the strongly acidic ion-exchange resin,
Amberlyst 15, effectively deprotects, purifies, and isolates
BOC-protected amine containing compounds. This method
tolerates a variety of substrates and can be used for
solution-phase parallel synthesis, which is widely em-
ployed in combinatorial chemistry.
+
28.983, 137.862, 153.572; exact mass (M ) 180.0899 (calcd for
C H N O 180.0907).
N-p h en yl-N′-[4-(a m in om eth yl)p h en yl]u r ea (19): IR (KBr)
9
12
2
2
-
1
1
3
2
428, 3012, 1647, 1607 cm ; H NMR (DMSO-d
H), 6.948 (m, 1H), 7.207-7.464 (m, 7H), 8.752 (d, 2H); C NMR
) δ 45.135, 118.144, 121.696, 127.518, 128.780, 137.280,
38.014, 139.877, 152.656; exact mass (M + H) 242.1293 (calcd
O 242.1292).
6
) δ 3.650 (s,
13
(DMSO-d
6
1
for C14
16 3
H N
Ack n ow led gm en t. We thank Dr. Youfen Zhou for
performing some preliminary studies of this method.
Financial support from the Robert A. Welch Foundation
(D.E.B., A-0639; D.R., A-1280), the Petroleum Research
Fund (D.E.B.), and the National Institutes of Health
(D.R.; GM 52964-01) is greatly appreciated.
Exp er im en ta l Section
1
Gen er a l Meth od s. H NMR spectra were recorded at 200
1
3
or 300 MHz with TMS as the internal reference.
spectra were recorded at 75 MHz with CDCl or DMSO-d
the internal reference. THF was distilled from sodium-ben-
zophenone ketyl, and CH Cl was distilled from calcium hydride.
C NMR
3
6
as
1
Su p p or tin g In for m a tion Ava ila ble: The H NMR (200
2
2
or 300 MHz) spectra of the BOC-amines employed in these
studies (5 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.
All other reagents and solvents used were reagent grade. HPLC
was performed using a Ranin SD-200 HPLC system equipped
with a Dynamax UV-C detector (at 250 nm). Either a MI-
CROSORB-MV column (5 µm SiO , 100 Å) or a MICROSORB-
2
MV C18 column (5 µm, 100 Å) was used.
Clea n in g of Am ber lyst 15 Resin . Amberlyst 15 was
obtained from Aldrich and was cleaned by the following proce-
dure. It was first soaked in MeOH for 24 h, washed with MeOH,
and then neutralized with 4 M ammonia in MeOH. The
neutralized resin was acidified with 3 M HCl in 50% MeOH and
J O972001O
(10) (a) Anderson, G. W.; McGregor, A. C. J . Am. Chem. Soc. 1957,
79, 6180-6183. (b) Tesser, G. I.; Fisch, H.-U.; Schwyzer, R. Helv. Chim.
Acta 1974, 57, 1718-1730. (c) Benalil, A.; Carboni, B.; Vaultier, M.
Tetrahedron 1991, 47, 8177-8194. (d) Benalil, A.; Roby, P.; Carboni,
B.; Vaultier, M. Synthesis 1991, 787-788. (e) Breuer, E.; Berger, T.;
Sarel, S. J . Chem. Soc., Chem. Commun. 1968, 1596-1597. (f) Carpino,
L. A. Acc. Chem. Res. 1973, 6, 191. (g) Goodall, K.; Parsons, A. F.
Tetrahedron Lett. 1995, 36, 3259-3260. (h) Kita, Y.; Haruta, J .;
Yasuda, H.; Fukunaga, K.; Shirouchi, Y.; Tamura, Y. J . Org. Chem.
1982, 47, 2697-2700.
rinsed with MeOH, THF, and CH
2 2
Cl successively. The acidic
capacity of the resin was determined to be 3.5 mequiv/g by
1
0d
10a
10b
10c
10e
10f
titration. BOC-protected amines 1,
9
4, 5, 6, 7, 8,
1
0g
10h
, 10, 11, and 12 were prepared according to the literature
method from di-tert-butyl carbonate using triethylamine or
7
sodium carbonate as the base.