A facile method for the preparation of MOM-protected carbamates

Article abstract of DOI:10.1021/ol8022769

(Chemical Equation Presented) A novel method for the preparation of MOM-protected carbamates is described that avoids the use of MOM-Cl, a regulated carcinogen. The two-step, one-pot procedure generates a reactive N-chloromethyl carbamate that is quenched

Full text of DOI:10.1021/ol8022769

ORGANIC
LETTERS
2009
Vol. 11, No. 2
273-275
A Facile Method for the Preparation of
MOM-Protected Carbamates
David M. Barnes,* Jufang Barkalow, and Daniel J. Plata
GPRD Process Research and DeVelopment, Abbott Laboratories, Building R13/3,
1401 Sheridan Road, North Chicago, Illinois 60064
daVid.barnes@abbott.com
Received September 30, 2008
ABSTRACT
A novel method for the preparation of MOM-protected carbamates is described that avoids the use of MOM-Cl, a regulated carcinogen. The
two-step, one-pot procedure generates a reactive N-chloromethyl carbamate that is quenched with methanol to afford MOM-protected carbamates.
The process is tolerant of a variety of functionalities, including Boc, sulfonamide, and acetamide protecting groups. Mild conditions for the
removal of the MOM group are also described; selective deprotection of the MOM group in the presence of a Boc group has been demonstrated.
The methoxymethyl (MOM) group is a well-known base-
stable protecting group that can also act as a useful
formaldehyde synthon. While commonly employed for the
protection of alcohols,1 the MOM group has also been used
as a protecting group of amides2 and carbamates. A notable
example of the latter is found in the work of Kawabata, where
the MOM group functions not only as a protecting group
but also as a key design feature in the authors’ memory of
chirality chemistry (eq 1).3 In addition, it can function as a
methylene precursor in iminium ion chemistry.4
Most methods for the installation of a MOM-group onto
acylated nitrogen groups employ a base-mediated alkylation
with MOM-Cl.2,3,5 However, utilization of this strategy is
complicated by incompatibility with base-sensitive mol-
ecules, and by the fact that MOM-Cl is a regulated
(1) Green, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(2) (a) Kirby, G. W.; Robins, D. J.; Stark, W. M. J. Chem. Soc., Chem.
Commun. 1983, 812–813. (b) Schollkopf, U.; Beckhaus, H. Angew. Chem.
1976, 88, 296–297.
(3) (a) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem.,
Int. Ed. 2000, 39, 2155–2157. (b) Kawabata, T.; Kawakami, S.-p.; Shimada,
S.; Fuji, K. Tetrahedron 2003, 59, 965–974. (c) Kawabata, T.; Chen, J.;
Suzuki, H.; Fuji, K. Synthesis 2005, 1368–1377.
(4) (a) Shono, T.; Matsumura, Y.; Uchida, K.; Kobayashi, H. J. Org.
Chem. 1985, 50, 3243–3245. (b) Brands, K. M. J.; Pandit, U. K. Tetrahderon
Lett. 1989, 30, 1423–1426. (c) Esch, P. M.; Hiemstra, H.; Spekamp, W. N.
Tetrahderon Lett. 1988, 29, 367–370. (d) Mooiweer, H. H.; Hiemstra, H.;
Spekamp, W. N. Tetrahedron 1991, 47, 3451–3462. (e) See also Kawabata
et al. (Kawabata, T.; Ozturk, O.; Suzuki, H.; Fuji, K. Synthesis 2005,
505–508), where the MOM-group takes part in a Pictet-Spengler cycliza-
tion following its use in the memory of chirality alkylation.
(5) For an example of the electrochemical oxidation of trimethylsilyl-
methyl carbamates to methoxymethyl carbamates, see: Yoshida, J.; Isoe,
S. Tetrahedron Lett. 1987, 28, 6621–6624.
10.1021/ol8022769 CCC: $40.75
Published on Web 12/15/2008
2009 American Chemical Society

carcinogen. In this paper, we describe an alternate approach
to the preparation of MOM-protected carbamates, which
proceeds via the N-chloromethyl derivative. This methodol-
ogy avoids the use of MOM-Cl and employs mildly acidic
conditions that are tolerant of a range of functionalities.
The reaction of carbamates with TMS-Cl and paraform-
aldehyde in the presence of MgSO4 in toluene have been
reported to afford the corresponding N-chloromethyl car-
bamates.6 Treatment of Cbz-phenethylamine (4a) with TMS-
Cl and paraformaldehyde in dichloromethane7 led to a new
peak by HPLC when samples were diluted with Et3N in
MeCN (Scheme 1). LC-MS analysis suggested that this new
Table 1. Scope of the Alkoxymethylation of Carbamates
Scheme 1
.
Preparation and Reactions of N-Chloromethyl
Carbamate 2
peak was the quaternary salt 3 (ESI+: M ) 369; M - Et3N
) 268). The facility with which the putative N-chloromethyl
carbamate alkylated a tertiary amine encouraged us to
investigate its reactivity toward other nucleophiles, and we
were pleased to find that on addition of methanol to the
reaction mixture, N-methoxymethyl (MOM) carbamate 5a
was obtained cleanly. After an aqueous workup and chro-
matography the product was obtained in 88% yield.
a The reaction was run at 0 °C. b The reaction was quenched into
Et3N/MeOH. c The reaction was quenched into DIPEA/BnOH.
The scope of the reaction is illustrated in Table 1.8 In
general, N-MOM carbamates are obtained in good yield with
95-98% consumption of starting material as determined by
HPLC analysis. A variety of carbamate protecting groups
are tolerated (entries 1-3), though due to the acid lability
of the Boc group, reactions of substrates containing that
functionality need to be quenched with a methanol/triethy-
lamine mixture (entries 3 and 5). Other aliphatic amine
derivatives are also good substrates, such as benzylamine
(entry 4) and branched derivatives (entries 5 and 6). Of
particular note is entry 5 in which the product (5e) is one
employed in the Kawabata chiral-memory-effect alkylations
(eq 1).3 The ability of an acetate group to survive the reaction
(entry 6) attests to the mildness of the conditions, though
primary TBS ether 6 underwent significant deprotection
under the reaction conditions at 0 °C. The reaction also works
well with a protected aniline derivative (entry 7). Finally,
the intermediate chloromethyl carbamate can react with other
alcohols. Trapping with ethanol affords the ethoxymethyl
(6) (a) Ortiz, J.; Guijarro, A.; Yus, M. Tetrahedron 1999, 55, 4831–
4842. (b) Smith, M. B.; Dembofsky, B. T.; Son, Y. C. J. Org. Chem. 1994,
59, 1719–1725.
(7) The conditions described in ref 6a additionally employed MgSO4 in
toluene. In our experience, the MgSO4 has little effect on the outcome of
the reaction. We observed differences in reaction rates when reactions in
toluene were stirred magnetically or mechanically; these differences were
not seen when the reaction was run in dichloromethane.
(8) General experimental: A flask was charge with N-benzyloxycarbonyl
phenethylamine (4a, 1 g, 3.9 mmol), paraformaldehyde (0.18 g, 6.0 mmol,
1.5 equiv), and 10 mL of CH2Cl2. TMSCl (1.28 g, 11.7 mmol, 3 equiv)
was charged and the reaction was stirred at room temperature for 2 h, at
which point HPLC analysis indicated that the reaction was complete. To
the flask was charged 3 mL of MeOH, and the reaction was stirred for 1 h.
The reaction mixture was quenched into 15 mL of saturated aqueous
NaHCO3 solution, mixed, and separated. The aqueous phase was extracted
with 10 mL of CH2Cl2 and the combined organic phases were washed with
10 mL of brine, dried over Na2SO4, and concentrated. Purification by column
chromatography afforded 1.03 g (88% yield) of benzyl N-methoxymeth-
yl(phenethyl)carbamate 5a.
274
Org. Lett., Vol. 11, No. 2, 2009

derivative in good yield (entry 8); likewise, benzyl alcohol
delivers the BOM-protected carbamate in 91% yield (entry
9).
found that chemoselective cleavage of a MOM group from
carbamates can be achieved under relatively mild conditions,
employing toluenesulfinic acid as a formaldehyde scaven-
ger.13 For example, deprotection of Cbz-derivative 5d (2
equiv of p-MePhSO2Na, 2.5 equiv of HCl in MeCN) afforded
the deprotected carbamate 4d in 92% yield (eq 5).
In addition to carbamates, we have found that the
reaction works with other nitrogen protecting groups. The
protection of a methanesulfonamide proceeded in 66%
isolated yield (eq 2). The reaction with the corresponding
acetamide stalled at about 75% conversion. After workup
and isolation, MOM-protected acetamide 8 was isolated
in 46% yield (eq 3).9
Deprotection of Boc-derivative 5g under these conditions
led to some loss of the tert-butyl carbamate. However, the
deprotected carbamate 4g was still isolated in 76% yield (eq
66). In conclusion, we have described new conditions for
the N-methoxymethylation of carbamates which avoid the
use of MOM-Cl.14 The mild nature of these reaction
conditions grants the methodology a wide breadth of
substrate scope; acetate and Boc groups are not affected
during the protecting group installation. We have also
developed mild deprotection conditions which are compatible
with acid-sensitive functionality. Thus the MOM-group can
be considered an orthogonal protecting group to carbamates.
The reactivity of the putative chloromethyl intermediate10
toward poorly nucleophilic reagents such as triethylamine
and methanol suggests that the iminium ion formed by
chloride ionization is an intermediate in the displacement
process. Thus, a notable limitation of this methodology
includes substrates which contain nucleophilic functionality
that can undergo intramolecular trapping of the N-acyl
iminium species. For example, treatment of Cbz-protected
dimethoxyphenethylamine 9 under the reaction conditions
led to Cbz-protected tetrahydroisoquinoline 10 in 96% yield
via a Pictet-Spengler reaction (eq 4).11
Acknowledgment. The authors thank Prof. David Mac-
Millan and Dr. Tony Haight for helpful discussions.
Supporting Information Available: Experimental and
characterization data for compounds 4f, 5a-g, 7, 8, and 10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8022769
(11) This transformation has previously been accomplished in two steps
in 14% overall yield. Kim, H. J.; Yoon, U. C.; Jung, Y.-S.; Park,
N. S.;Cederstrom, E. M.; Mariano, P. S. J. Org. Chem. 1998, 63, 860–863.
(12) Reference 2a (BBr3): (a) Madin, A.; O’Donnell, C. J.; Oh, T.; Old,
D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem., Int. Ed. 1999, 38,
2934–2936 (conc. HCl). (b) Yokoshima, S.; Tokuyama, H.; Fukuyama, T.
Angew. Chem., Int. Ed. 2000, 39, 4073–4075 (TMS-Cl, NaI). (c) Sotelo,
E.; Coelho, A.; Ravina, E. Tetrahedron Lett. 2001, 42, 8633–8636 (AlCl3
or BBr3). (d) Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.; Ambhaikar,
N. B. Angew. Chem., Int. Ed. 2005, 44, 3892–3895 (bromocatecholbo-
rane).
Deprotection of N-MOM protected amides has been
accomplished by using strong acids.12 However, we have
(13) For the reaction of toluene sulfinic acid with formaldehyde, see:
Brederek, H.; Bader, E. Chem. Ber. 1954, 87, 129–139.
(9) These reactions were not further optimized.
(10) NMR analysis of a reaction run in CD2Cl2 on carbamate 4a
supported the N-chloromethyl structure shown in Scheme 1 relative to that
of the imminium ion. See the Supporting Information.
(14) Although the conditions described in this paper do not employ
MOM-Cl as a reagent, it is possible that upon MeOH quench some MOM-
Cl is in fact generated from the activated formaldehyde.
Org. Lett., Vol. 11, No. 2, 2009
275