Selective hydrogenolysis of novel benzyl carbamate protecting groups

Article abstract of DOI:10.1021/ol005589l

Highly efficient and selective hydrogenolysis of the 2-naphthylmethyl carbamate group (CNAP) in the presence of the 4-trifluoromethylbenzyl carbamate group (CTFB) has been observed for a wide range of substrates.

Full text of DOI:10.1021/ol005589l

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1049-1051
Selective Hydrogenolysis of Novel
Benzyl Carbamate Protecting Groups
Edward A. Papageorgiou, Matthew J. Gaunt, Jin-quan Yu, and
Jonathan B. Spencer*
UniVersity Chemical Laboratory, Lensfield Road, Cambridge,
United Kingdom, CB2 1EW
jbs20@cam.ac.uk
Received January 27, 2000
ABSTRACT
Highly efficient and selective hydrogenolysis of the 2-naphthylmethyl carbamate group (CNAP) in the presence of the 4-trifluoromethylbenzyl
carbamate group (CTFB) has been observed for a wide range of substrates.
Benzyl-type protecting groups constitute one of the major
strategies for the protection of oxygen and nitrogen functional
groups in organic synthesis.1 Recently we have determined
that the removal of the benzyl group by hydrogenolysis is
strongly influenced by the electronic properties of the
aromatic ring and its affinity to the metal surface.2 This has
led to the introduction of the 2-naphthylmethyl (NAP) group
as a new benzyl-type protecting group for hydroxyl and
carboxyl functions that can be removed by hydrogenolysis
in the presence of a benzyl group.2,3
in peptide synthesis.4 It has found widespread application
owing to its ease of removal by hydrogenolysis. Attempts
to modify the activity of the Cbz group to achieve orthogonal
deprotection under hydrogenolysis conditions have not been
successful.5 Assuming the mechanism of hydrogenolysis of
the Cbz group is similar to that of the benzyl group, we
anticipated that this goal might be achieved using the
combination of Cbz and 2-naphthylmethyl carbarmate (CNAP)
groups.6,7
To assess the relative reactivities of these two groups,
intramolecular competition experiments using a piperazine
linker were carried out (Table 1). Attempts to remove CNAP
in the presence of Cbz from 1a gave low selectivity. This
Here we report the extension of this methodology to the
protection of the amine functional group and the development
of novel benzyl carbamate derivatives that can be sequentially
removed by hydrogenolysis (Figure 1).
Table 1. Competitive Hydrogenolysis of Benzyl Carbamates
Separated by a Symmetrical Linker
Pd-C,
mg/mmol
reaction
time
yield,
%
Figure 1. The structures of the novel benzyl carbamate groups
CNAP and CTFB.
R1
R2
1a
1b
1c
Cbz
CTFB
CTFB
CNAP
Cbz
CNAP
15.0
10.3
30.1
24 h
45 min
45 min
29
66
94
Benzyl carbamate (Cbz) protection of amines was intro-
duced as a versatile alternative to the ethoxy carbamate group
10.1021/ol005589l CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/18/2000

result was in sharp contrast to observations with other NAP-
Bn systems,2,3 which is probably due to the higher inherent
reactivity of benzyl carbamates. In a previous study it was
determined that the introduction of a trifluoromethyl sub-
stituent onto the aromatic ring of the benzyl group reduced
its reactivity toward hydrogenolysis.2 This prompted us to
investigate the effect the trifluoromethyl substituent would
have on the Cbz group. The result from the competition of
Cbz against 4-trifluoromethylbenzyl carbamate (CTFB) 1b,
shows that the carbamate can be substantially deactivated
by the electron-withdrawing group. This suggested that the
combination of CTFB and CNAP might give the desired
orthogonal deprotection. This was demonstrated by the
excellent selectivity observed in the hydrogenolysis of
piperazine 1c.
Table 2. Selective Hydrogenolytic Removal of CNAP in the
Presence of CTFB
To demonstrate the synthetic utility of the CNAP-CTFB
amino protection strategy, the selective removal of CNAP
in the presence of CTFB was performed on substrates 5a-
h, to afford the mono-deprotected amines8 in excellent yields
(Table 2).9,10
Of particular interest in the above table is entry 5g, as it
highlights the potential application of CNAP-CTFB amino
protection to the synthesis of peptides. The mild removal
(1) Greene, T. W.; Wutts, P. G. M. Protection for the Amino Group. In
ProtectiVe Groups in Organic Synthesis, 3rd ed.;, John Wiley & Sons Inc:
New York, 1999. Kunz, H.; Waldmann, H. In Protecting Groups.
ComprehensiVe Organic Synthesis: SelectiVity, Strategy and Efficiency in
Modern Organic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Elmsford, NY, 1991; Vol. 6, pp 631-642. Kocienski, P. J. In
Protecting Groups; Georg Thieme: Stuttgart, 1994 and references therein.
(2) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172-
4173.
(3) Gaunt, M. J.; Boschetti, C. E.; Yu, J.; Spencer, J. B. Tetrahedron.
Lett. 1999, 40, 1803-1806.
(4) Bergmann, M.; Zervas, L. Ber. Dtsch. Chem. Ges. 1932, 65, 1192-
1201.
(5) For discussions, see: Berse, C.; Boucher, R.; Piche´, L. J. Org. Chem.
1957, 22, 805-808. Carpino, L. A.; Tunga, A. J. Org. Chem. 1986, 51,
1930-1932.
(6) The CNAP and CTFB groups were introduced with excellent yields
onto the amines using the corresponding chloroformates, CNAP-Cl and
CTFB-Cl. Carbamate Preparations. CNAP: To a vigorously stirred
CHCl3-water mixture (1:1, 20 mL/mmol of amine) were added the amine,
NaHCO3 (2.0 equiv), and CNAP-Cl (1.05 equiv). The reaction was stirred
at room temperature until complete as judged by TLC (3-10 h). The
aqueous layer was extracted with DCM and washed with brine. Condensa-
tion under reduced pressure afforded crude product that was purified by
flash column chromatography (silica gel, gradient elution with EtOAc-
hexane or MeOH-DCM). CTFB: To a solution of amine in acetone-
water (9:1, 10 mL/mmol of amine) were added NaHCO3 (2.0 equiv) and
CTFB-Cl (1.2 equiv) in acetone. The reaction was stirred at room
temperature until complete by TLC (30 min to 4 h). Volatile material was
removed under reduced pressure. The solid residue was partitioned between
water and DCM. The aqueous layer was extracted with DCM and washed
with brine. Condensation under reduced pressure afforded crude product
that was purified by flash column chromatography (silica gel, gradient
elution with EtOAc-hexane or MeOH-DCM). The chloroformates were
prepared in excellent yields by treatment of the alcohols with phosgene
solution. Chloroformate Preparations. CNAP-Cl: 2-Naphthylmethanol
was added in one portion to COCl2 (1.3 equiv of a 20% solution of COCl2
in PhMe) in dry THF (1.5 mL/mmol). The reaction was stirred at room
temperature for 2 h. Volatile material was removed under reduced pressure.
The solid residue was dissolved in boiling hexane and filtered. Pure
2-naphthylmethyl chloroformate was obtained as a white solid (>95%) by
condensation of the filtrate. CTFB-Cl: Similar procedure was followed
with 2.0 equiv of COCl2 and stirring for 20 h. Condensation of volatile
material afforded 4-trifluoromethylbenzyl chloroformate as a clear colorless
oil that was purified by filtration through Florisil with 10% Et2O/hexane
as the eluent. Both chloroformates could be stored for long periods (12
months) without decomposition in a refrigerator.
conditions are ideally suited for the deprotection of the
amines in these sensitive molecules.
The observation that the aromatic nitro group in 5b is not
reduced during the removal of the CNAP group, further
(7) In the assembly of the substrates for the hydrogenolysis experiments,
both carbamates, CNAP and CTFB, were found to be resistant to acidolysis
in refluxing MeOH-HCl solution for 5 h or 15% TFA in DCM at room
t
temperature for 3 h, conditions that were used for the cleavage of Boc
groups. They were also found to be resistant to hydrolysis by aqueous base
(NaOH or LiOH), conditions used for the saponification of methyl esters.
(8) For the purposes of subsequent discussion the mono-deprotected
amines carry the designations 6a-h.
(9) General Hydrogenolysis Procedure. Pd-C (10%) was dispersed
in EtOAc-EtOH (40 mL/mmol) under argon. The mixture was degassed
and saturated with hydrogen. After 30-60 min of vigorous stirring, the
substrate was added in a single portion (solids) or as a solution in reaction
solvent (oils). The reaction was stirred at room temperature under a hydrogen
atmosphere (balloon) until complete by TLC. The catalyst was removed
by filtration through Celite with EtOAc or MeOH as the eluent. Condensa-
tion of the filtrate afforded the crude product. Purification of amines 2a-c
and 6a-e: flash column chromatography (silica gel, gradient elution with
MeOH-DCM). Purification of Amines 6f-h. The crude was dissolved
in MeOH-water (3:1 to 1:1 mixture) and extracted with hexane (5 × 20
mL). The resultant 2-naphthylmethane-free solution was condensed to afford
1
the amine, pure by H NMR.
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Org. Lett., Vol. 2, No. 8, 2000

highlights the ease with which the CNAP group may be
removed under particularly mild conditions. If either the
remaining CTFB or nitro group can be preferentially reduced
it would liberate three amines in sequence from one
molecule. Indeed, it was found that the nitro group was
selectively reduced in the presence of the CTFB group
(Scheme 1).
hydrogenolysis of other susceptible functionality in its
presence. In view of our previous studies on benzyl-type
protecting groups for oxygen,2,3 we were particularly inter-
ested in investigating the removal of benzyl ethers and esters
in CTFB-containing molecules. Preliminary results from this
study (Scheme 2) demonstrate that use of the CTFB group
should be widely applicable in synthesis.
Scheme 2. Hydrogenolysis of a Benzyl Ester and a Benzyl
Ether in the Presence of CTFBa
Scheme 1. Hydrogenation of an Aromatic Nitro Group in the
Presence of CTFBa
a Reagents and conditions: (i) anhydrous EtOAc, 10% Pd-C
(8 mg/mmol), 3 h; (ii) EtOH-EtOAc (1:1), 10% Pd-C (30 mg/
mmol), 2.2 h.
a Reagents and conditions: (i) EtOH-EtOAc (1:1), 10% Pd-C
(25 mg/mmol), 1.3 h; (ii) EtOH-EtOAc (1:1), 10% Pd-C (20 mg/
mmol), 3.0 h.
Apart from opening up the possibility of an alternative
orthogonal protection strategy for amines,13 selective nitro
reduction to 7 is noteworthy because it cannot be replicated
with Cbz in place of CTFB.14 The apparent stability of the
CTFB group prompted us to consider the selective reduction/
In summary, orthogonal deprotection for amines has been
achieved. This is based on the highly efficient and selective
deprotection of the CNAP over the CTFB carbamate under
standard hydrogenolysis conditions.
(10) Hydrogenolysis of the CTFB Group. Removal of the CTFB group
is generally facile, requiring only small increases in the amount of catalyst
compared to the CNAP-CTFB competition experiments. For example,
complete (95%) N deprotection of N-CTFB leucine methyl ester, 6a, was
effected in 85 min with 60 mg/mmol Pd-C (10%). In cases where
deprotection is sluggish with Pd-C (10%) use of the more active Pearlman’s
catalyst, Pd(OH)2 (20%) is recommended. For example, complete (97%) N
deprotection of N-CTFB 3-aminobenzonitrile could be effected in 130 min
with 20 mg/mmol Pd(OH)2 (20%) without detectable reduction of the nitrile,
but not with Pd-C (10%).
Acknowledgment. The authors acknowledge The Royal
Society for the award of a Royal Society University Research
Fellowship (J.B.S), The A.G. Leventis Foundation and St
John’s College, Cambridge (E.A.P.), and The Wellcome
Trust (M.J.G.).
OL005589L
(11) For selective hydrogenolysis of CNAP over hydrogenation of the
aromatic nitro group, the reaction had to be performed in dry EtOAc.
(12) 1H NMR of the crudes showed a single product in each case. The
lower than expected isolated yields resulted from the purification procedure
that had to be employed with these compounds. Their very polar nature
excluded flash column chromatography.
(14) Attempts to selectively reduce the aromatic nitro group in N-Cbz
3-nitrophenylamine with Pd-C (10%) afforded a mixture of all possible
products (23% of desired product). Similar results have been reported with
Pd-C/diamine complexes, with which hydrogenolysis of benzyl-type groups
is generally inhibited in the presence of other reducible functionality (Sajiki,
H.; Hattori, K.; Hirota, K. J. Org. Chem. 1998, 63, 7990-7992).
(13) The generality of this approach is being investigated.
Org. Lett., Vol. 2, No. 8, 2000
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