On the selective N-methylation of BOC-protected amino acids

Article abstract of DOI:10.1021/jo9016293

(Chemical Equation Presented) The selective N-methylation of BOC-protected valine 1a with MeI and NaH in THF (i.e., in the presence of a free carboxyl group) has been attributed to the protection of the carboxylate by chelation to Na⁺. An alternative mechanism, involving the formation of the carbene intermediate generated from MeI and its insertion into the N-H bond, has been ruled out by isotopic labeling. 2009 American Chemical Society.

Full text of DOI:10.1021/jo9016293

pubs.acs.org/joc
Thus, we have extensively used formamides derived from
N-methylvaline and other N-methylamino acids as a scaffold
in designing novel organocatalysts for asymmetric reduction
8
of imines with trichlorosilane.
On the Selective N-Methylation of BOC-Protected
Amino Acids
,
†,§
†
Andrei V. Malkov,* Kvetoslava Vrankov ꢀa ,
‡
,†
ꢁ
Miloslav Cern ꢀy , and Pavel Ko ꢁc ovsk ꢀy *
SCHEME 1. N-Methylation of Carbamate Derivatives of
Valine
†
Department of Chemistry, WestChem, University of
‡
Glasgow, Glasgow G12 8QQ, U.K., and Department of
Organic Chemistry, Charles University, 128 40, Prague 2,
Czech Republic. Present address: Department of Chemistry,
§
Loughborough University, Loughborough LE11 3TU, UK.
a.malkov@lboro.ac.uk; pavelk@chem.gla.ac.uk
Received February 24, 2009
Selective N-alkylation of amino acids is a challenging
problem that generally requires selective protection and the
use of procedures that minimize racemization. From a
number of existing methods, the N-methylation of carba-
mate derivatives of amino acids, such as N-BOC or N-Cbz
(
most simple (Scheme 1). This methodology was first deve-
1a,b), with CH I and NaH, stands as one that is potentially
3
3
loped by Benoiton and later further improved or modi-
2
,4,5
fied.
Other approaches, relying, e.g., on double-reductive
amination of the free amino group (first with PhCHO and
The selective N-methylation of BOC-protected valine 1a
with MeI and NaH in THF (i.e., in the presence of a free
carboxyl group) has been attributed to the protection of
then with CH O), have been developed for polyfunctional
2
amino acids, such as histidine, where N-methylation of the
9
+
the carboxylate by chelation to Na . An alternative
imidazole moiety must be avoided.
The original Benoiton protocol, employing CH I and
3
a
mechanism, involving the formation of the carbene inter-
mediate generated from MeI and its insertion into the
N-H bond, has been ruled out by isotopic labeling.
3
NaH, followed the traditional wisdom, i.e., initial double
deprotonation of 1 by g2 equiv of NaH to generate the
corresponding dianion, followed by treatment with MeI,
which provided the product of N,O-bismethylation. Sub-
sequent hydrolysis of the ester group, which may be accom-
panied by a certain degree of racemization, then gave the free
acid 2. In fact, the double methylation required elevated
temperature and/or addition of DMF to improve the solu-
N-Methylamino acids are valuable building blocks in
medicinal chemistry and as substitutes for “natural” amino
1-5
acids.
Their popularity stems, in particular, from various
3
a
effects they introduce to peptides, such as the restriction of
conformational mobility, conformational change, and an
bility of the dianion. A modification of this protocol in the
way that 1a was first mixed with MeI prior to the addition of
NaH resulted in a dramatic change: thus, at room tempera-
ture, with just THF as a solvent, Benoiton was able to obtain
the enantiopure N-methylated product 2a in an excellent
yield, with only trace amounts of the unreacted starting
1
-5
increased stability to proteolytic enzymes.
amino acids have also been frequently employed in the con-
The N-methyl-
6
struction of various catalysts and ligands for transition metals.
7
3
c
(
1) (a) Fairlie, D. P.; Abbenante, G.; March, D. R. Curr. Med. Chem.
995, 2, 654. (b) Deska, J.; Kazmaier, U. Curr. Org. Chem. 2008, 12, 355.
2) (a) Aurelio, R.; Brownlee, R. T. C.; Hughes, A. B. Chem. Rev. 2004,
04, 5823. (b) Perdih, A.; Dolenc, M. S. Curr. Org. Chem. 2007, 11, 801.
3) (a) Coggins, J. R.; Benoiton, N. L. Can. J. Chem. 1971, 49, 1968. (b)
material and the bismethylated product.
1
(
1
(8) (a) Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Ko ꢁc ovsk ꢀy , P.
Org. Lett. 2004, 6, 2253. (b) Malkov, A. V.; Ston ꢁc ius, S.; MacDougall, K. N.;
Mariani, A.; McGeoch, G. D.; Ko ꢁc ovsk ꢀy , P. Tetrahedron 2006, 62, 264. (c)
Malkov, A. V.; Figlus, M.; Ston ꢁc ius, S.; Ko ꢁc ovsk ꢀy , P. J. Org. Chem. 2007, 72,
1315. (d) Malkov, A. V.; Ston ꢁc ius, S.; Ko ꢁc ovsk ꢀy , P. Angew. Chem., Int. Ed.
2007, 46, 3722. (e) Malkov, A. V.; Figlus, M.; Ko ꢁc ovsk ꢀy , P. J. Org. Chem.
2008, 73, 3985. (f) Malkov, A. V.; Ston ꢁc ius, S.; Vrankov ꢀa , K.; Arndt, M.;
Ko ꢁc ovsk ꢀy , P. Chem.;Eur. J. 2008, 14, 8082. (g) Malkov, A. V.; Vrankov ꢀa ,
K.; Ston ꢁc ius, S.; Ko ꢁc ovsk ꢀy , P. J. Org. Chem. 2009, 74, 5839. (h) Malkov, A. V.;
Figlus, M.; Prestly, M. R.; Rabani, G.; Cooke, G.; Ko ꢁc ovsk yꢀ , P. Chem.;Eur. J.
2009, 15, 9651. (i) Malkov, A. V.; Figlus, M.; Cooke, G.; Caldwell, S. T.; Rabani,
G.; Prestly, M. R.; Ko ꢁc ovsk yꢀ , P. Org. Biomol. Chem. 2009, 1878. (j) Malkov,
A. V.; Vrankov ꢀa , K.; Sigerson, R.; Ston ꢁc ius, S.; Ko ꢁc ovsk ꢀy , P. Tetrahedron 2009,
65, 9481. (k) Figlus, M.; Caldwell, S. T.; Walas, D.; Sanyal, A.; Yesilbag, G.;
Cooke, G.; Ko ꢁc ovsk ꢀy , P.; Malkov, A. V. Org. Biol. Chem. 2009, in press
(manuscript no. B916601G).
(
McDeromott, J. R.; Benoiton, N. L. Can. J. Chem. 1973, 51, 1915. (c)
Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 906. (d) Cheung, S. T.;
Benoiton, N. L. Can. J. Chem. 1977, 55, 911. (e) Cheung, S. T.; Benoiton,
N. L. Can. J. Chem. 1977, 55, 916.
(4) (a) Pitzele, B. S.; Hamilton, R. W.; Kudla, K. D.; Tsymbalov, S.;
Stapelfeld, A.; Savage, M. A.; Clare, M.; Hammond, D. L.; Hansen, D. W.
J. Med. Chem. 1994, 37, 888. (b) Andrus, M. B.; Li, W.; Keyes, R. F. J. Org.
Chem. 1997, 62, 5542.
(5) (a) Stodulski, M.; Mlynarski, J. Tetrahedron: Asymmetry 2008, 19, 970.
See also: (b) Macleod, C.; McKiernan, G. J.; Guthrie, E. J.; Farrugia, L. J.;
Hamprecht, D. W.; Macritchie, J.; Hartley, R. C. J. Org. Chem. 2003, 68, 387.
(
6) Ko ꢁc ovsk ꢀy , P.; Malkov, A. V. Chiral Lewis Bases as Catalysts. In
Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
007; p 255.
7) Malkov, A. V.; Hand, J. B.; Ko ꢁc ovsk ꢀy , P. Chem. Commun. 2003, 1948.
2
(
(9) White, K. N.; Konopelski, J. P. Org. Lett. 2005, 7, 4111.
DOI: 10.1021/jo9016293
r 2009 American Chemical Society
Published on Web 10/07/2009
J. Org. Chem. 2009, 74, 8425–8427 8425

Malkov et al.
SCHEME 3. Methylation of BOC- and Cbz-valine
JOCNote
SCHEME 2. Possible Pathways for the N-Methylation of
BOC-valine
8
b
According to our experience, when 1a was first depro-
tonated by NaH in THF before methyl iodide was added,
this procedure resulted in an incomplete conversion of the
BOC derivative 1a, affording a ∼1:1 mixture of the unreacted
and nitrogen atoms. This species can be expected to be
preferentially methylated on the nitrogen to produce 7.
However, the reaction requires an excess of MeI to reach
completion, which raises the question as to the possible
subsequent methylation of the carboxyl in 7 to produce the
corresponding methyl ester 8. In fact, methylation of the Cbz
derivative 1b, carried out in the presence of Cs CO instead
1
a and the N-methylated product 2a, even when 10 equiv of
NaH and long reaction time were used (at room
temperature). This behavior is in line with the previous and
parallel observations reported by other groups for the analo-
2
-5
gous Cbz derivatives. On the other hand, when 1a was
first mixed with MeI and NaH was added after that in several
portions, the yield of the desired N-methyl derivative 2a was
2
3
of NaH, is known to produce the corresponding methyl ester
5
,11
9.
able, as Cs CO is too weak a base to deprotonate the NH
The lack of N-methylation in this case is understand-
3c
practically quantitative in accord with Benoiton’s second
protocol; notably, the carboxyl was not methylated under
these conditions, and the product obtained was enantiomeri-
2
3
group. However, the observed clean methylation of the
carboxyl (1b f 9) stays in stark contrast to the lack of
O-methylation of the sodium salt 6/7, suggesting that Na
3
c,4b,5,8b
+
cally pure.
The former experiment clearly suffers
from the poor solubility of the corresponding dianion salt
which, being in fact a precipitate, is not readily available for
protects the carboxyl, presumably by coordination, as in 6/7
or rather in an analogous higher order complex. To shed
light on this issue, another experiment was performed in the
1
0
methylation. On the other hand, if the deprotonation
occurs in the presence of MeI, as in the latter experiment,
concentration of the dianion is kept relatively low at any
time as it gradually reacts with MeI, which apparently
prevents the precipitation.
The methylation can be expected to proceed via an SN2
mechanism (Scheme 2, eq 1). However, in view of the high
N-selectivity, another mechanism can be conjectured,
according to which NaH would react with MeI to generate
the corresponding carbene via a 1,1-elimination (eq 2).
Insertion of the carbene into the N-H bond would then
afford the same N-methylated product. To address this
mechanistic issue, deuterated methyl iodide was employed.
+
presence of 15-crown-5-ether that should sequester the Na
ions. Here, the crown ether was added to a mixture of 1a and
MeI, followed by a slow addition of NaH. Under these
conditions, clean formation of the N,O-bismethylated pro-
duct 8 was observed at room temperature (in THF), clearly
+
demonstrating the protecting role of Na in the previous
1
2
experiments. It is pertinent to note that no racemization
has occurred during this double methylation, as revealed by
the optical rotation of the product.
In conclusion, the selective N-methylation of BOC-pro-
tected amino acids, such as 1a, by CH I and NaH in THF at
3
room temperature appears to originate from the chelation of
the carboxylate group by the sodium cation, which drama-
tically decelerates its methylation at room temperature; the
carbamate nitrogen is thus methylated preferentially to
produce 2a. In the presence of 15-crown-5 ether, the chelate
is disrupted, which results in the clean N,O-bis-methylation
If the methylation occurred via the S 2 mechanism, the
N
product should contain the N-CD group (eq 1). On the
3
other hand, the carbene insertion would give the product
with the N-CHD group instead (eq 2). Methylation of 1a
2
was therefore carried out with CD I under the same condi-
3
1
tions as those employed for CH I. The H NMR spectrum of
13
3
to afford 8. An alternative mechanism, involving a carbene
insertion into the N-H bond, has been ruled out by isotopic
labeling.
the product thus obtained revealed no trace of a signal
corresponding to the N-CHD group (3), demonstrating
2
that the product must contain the N-CD group (4), which
3
rules out the carbene mechanism (eq 2).
(11) N,O-Bis-methylation with the NaH/MeI system was observed at
8
other amino acids.
0 °C (in THF/DMF) for the corresponding Cbz-protected valine 1b and
It can be assumed that the deprotonation of 1a first
generates the carboxylate salt 5, where the remaining
N-proton may be bonded between the nitrogen and the
carboxylate (Scheme 3). Deprotonation with the second
equivalent of NaH would then give rise to dianion 6 with
3a,5
3a,5
(12) Note that in the methylation carried in with Cs
2
CO
3
(1b f 9),
Cs ion is not capable of coordinating the carboxylate ion and the
the
+
O-methylation occurs readily. Furthermore, elevated temperature and/or
the presence of DMF as an additive solvent are also likely to disrupt the Na -
+
chelate, which is in agreement of the experimental observation of the
N,O-bis-methylation when DMF is used as solvent.
+
3a,5,11
the second Na presumably chelated between the oxygen
(13) A similar behavior was observed by Berkessel on the attempted bis
methylation (with MeI) of the dianions generated from β-keto esters and
NaH in THF (A. Berkessel, personal communication).
5
(
10) The solubility can be improved by heating the mixture at 60 °C.
8
426 J. Org. Chem. Vol. 74, No. 21, 2009

Malkov et al.
JOCNote
Experimental Section
mmol, 10 equiv) in THF (1 mL) under an argon atmosphere.
The mixture was allowed to warm to room temperature, and
then neat iodomethane (0.62 mL, 1.42 g, 10 mmol, 10 equiv) was
added dropwise with stirring. The reaction mixture was stirred
at room temperature for 24 h and then worked up as in method
A. The crude material was composed of ca. 1:1 mixture of the
starting material 1a and product 2a.
General Procedure for N-Methylation of N-BOC-valine.
Method A. Neat sodium hydride (160 mg, 6.67 mmol, 10 equiv)
was added slowly in portions over a period of 2 h to a cooled
(
0 °C) solution of N-BOC-valine (1a) (145 mg, 0.67 mmol,
1
1
1
equiv) and iodomethane (0.42 mL, 947 mg, 6.67 mmol,
0 equiv) or iodomethane-d (0.42 mL, 967 mg, 6.67 mmol,
0 equiv) in anhydrous THF (2 mL) under a stream of argon.
3
Method C. Neat sodium hydride (240 mg, 10 mmol, 10 equiv)
was added slowly in portions over a period of 2 h to a cooled
The reaction mixture was stirred at room temperature for 24 h
under an argon atmosphere and then diluted with ether (20 mL)
and quenched with water (30 mL). The layers were separated,
and the aqueous layer was extracted with ether (2 Â 15 mL),
acidified to pH 3 with a 20% aqueous solution of citric acid, and
extracted with AcOEt (3 Â 20 mL). The combined organic phase
(
1
0 °C) solution of N-BOC-valine (1a) (217 mg, 1.0 mmol,
equiv), 15-crown-5-ether (1.98 mL, 2.20 g, 10 mmol, 10 equiv),
and iodomethane (0.62 mL, 1.42 g, 10 mmol, 10 equiv) in
anhydrous THF (3 mL) under a stream of argon. The reaction
mixture was stirred at room temperature for 24 h under an argon
atmosphere and then diluted with ether (20 mL) and quenched
with water (30 mL). The layers were separated, the aqueous
layer (basic) was extracted with ether (2 Â 15 mL), acidified to
pH 3 with a 20% aqueous solution of citric acid, and extracted
with AcOEt (3 Â 20 mL). The original organic phase was
combined with the extract of the basic aqueous layer, dried over
MgSO , and evaporated to afford the N,O-bismethylated pro-
4
duct 8 (252 mg, 0.943 mmol, 94%) as a colorless oil: [R]
(
3
MHz, CDCl , a mixture of rotamers) δ 4.44 (d, J=10.5 Hz,
0
4
was dried over MgSO and evaporated to afford the correspond-
ing N-methylated product 2a (152 mg, 0.653 mmol, 98%) as a
thick colorless oil that solidified upon standing in a refrigerator:
3
c
mp 69-71 °C (by evaporation from AcOEt) [lit. mp 58-59 °C
1
4
15 1
or lit. mp 86 °C]; H NMR (400 MHz, CDCl
3
) δ 4.10 (d, J=
0.4 Hz, 1H), 2.87 (s, 3H), 2.20-2.36 (m, 1H), 1.47 (s, 9H), 1.03
t, J=6.6 Hz, 3H), 0.92 (t, J=6.7 Hz, 3H) in accordance with the
1
(
25
-89.2
4
b,8b
D
literature and with an authentic sample.
(
4: thick colorless oil
, a
4b
25
D
1
c 0.1, CHCl ) [lit. [R]
-87.3 (c 0.1, CHCl )]; H NMR (400
1
151 mg, 0.640 mmol, 96%); H NMR (400 MHz, CDCl
3
3
3
mixture of rotamers) δ 4.14 (d, J=10.9 Hz) and 4.09 (d, J=9.8
Hz) (together 1H), 2.16-2.33 (m, 1H), 1.45 (s) and 1.47 (s)
.55H) and 4.08 (d, J=10.6 Hz, 0.45H), 3.69 (s, 3H), 2.83 (s) and
.80 (s) (together 3H), 2.11-2.22 (m, 1H), 1.45 (s, 9H), 0.95 (t,
2
J=6.5 Hz, 3H), 0.88 (t, J=6.3 Hz, 3H) in accordance with the
(
together 9H), 1.02 (t, J=6.6 Hz, 3H), 0.91 (t, J=6.7 Hz, 3H);
C NMR δ 176.3 and 175.3 (C), 157.0 and 155.7 (C), 80.9 and
1
3
3,5
literature. The extract of the acidified aqueous layer only
8
2
0.7 (C), 65.4 and 65.1 (CH), 28.4 (3 Â CH ), 27.8 and 27.5 (CH),
3
afforded ethylene glycol (a degradation product of the crown
ether), while no trace of the N-monomethylated 2a was detected.
3 3
0.1 and 19.8 (CH ), 19.1 and 19.0 (CH ); MS (CI, isobutane)
+
m/z 235 ([M + H] , 10), 179 (100), 135 (15), 133 (10); MS (EI)
m/z 133 ([(M ) - BOC], 100), 91 (45), 89 (60), 84 (28), 57 (93);
HRMS (EI) 133.1059 (C H D NO requires 133.1055).
+
•
Acknowledgment. We thank the EPSRC for Grant No.
GR/S87294/01 and the WestChem for a graduate fellowship
to K.V.
6
9
3
2
Method B. A solution of N-BOC-valine (1a) (217 mg, 1.0
mmol, 1 equiv) in anhydrous THF (2 mL) was added dropwise
to a cooled (0 °C) suspension of neat sodium hydride (240 mg, 10
Supporting Information Available: General experimental
(
(
14) Schnabel, E. Liebigs Ann. Chem. 1967, 702, 188.
15) In fact, Benoiton attained the crystalline material after 2 years,
1
13
3
c
methods and H and C NMR spectra for 2a, 4, and 8. This
material is available free of charge via the Internet at http://
pubs.acs.org.
showing the difficulties associated with the crystallization of 2a, which is
apparently reflected in the variation of the melting point.
J. Org. Chem. Vol. 74, No. 21, 2009 8427