1,2-Dimethoxy-4,5-dimethylene: A new protecting group for acyclic amino acid derivatives prepared by Stevens rearrangement

Article abstract of DOI:10.1016/j.tetlet.2012.01.013

A new protecting group, 1,2-dimethoxy-4,5-dimethylene, for acyclic amino acid derivatives could be introduced by N,N-dialkylation with 1,2-bis(bromomethyl)-4,5-dimethoxybenzene (1) and removed via amine de-alkylation with acyl chlorides. The method can be used with base-induced [2,3] and [1,2] Stevens rearrangement products.

Full text of DOI:10.1016/j.tetlet.2012.01.013

Tetrahedron Letters 53 (2012) 1373–1375
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Tetrahedron Letters
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1,2-Dimethoxy-4,5-dimethylene: a new protecting group for acyclic amino
acid derivatives prepared by Stevens rearrangement
⇑
Eiji Tayama , Keisuke Takedachi, Hajime Iwamoto, Eietsu Hasegawa
Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new protecting group, 1,2-dimethoxy-4,5-dimethylene, for acyclic amino acid derivatives could be
introduced by N,N-dialkylation with 1,2-bis(bromomethyl)-4,5-dimethoxybenzene (1) and removed via
amine de-alkylation with acyl chlorides. The method can be used with base-induced [2,3] and [1,2] Ste-
vens rearrangement products.
Received 31 October 2011
Revised 21 December 2011
Accepted 5 January 2012
Available online 12 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Protection
Amino acid
Ammonium salt
Ylide
Rearrangement
As part of the study of base-induced Stevens and Sommelet–
Hauser rearrangements, we required a new protecting group for
amino acid derivatives because the rearrangements of acyclic ami-
no acid-derived tetraalkylammonium ylides produce the N,N-dial-
kyl amino acid derivatives as the products,1 and efficient methods
to remove the N,N-dialkyl substituents from nitrogen are limited.2
Two successful examples were reported by Workman3a or Ar-
boré.3b Their groups performed palladium-catalyzed de-allylation
acid methyl esters 2 with 1 afforded the corresponding isoindoline
derivatives 3 in moderate yields (Table 1, entries 1–6, 50–86%).
First, we examined the conversion of the 5,6-dimethoxyisoind-
oline derivatives 3 into the N-ethoxycarbonyl-a-amino acid methyl
esters 5 via amine de-alkylation (Table 2). Treatment of 3a–e with
ethyl chloroformate as a de-alkylation reagent in 1,2-dichloro-
methane under reflux gave the ring-opening products 4a–e in
73–92% yields (entries 1–5). The reaction of the phenylglycine
derivative 3f resulted in a lower yield (entry 6, 30%) because of
the formation of methyl 2-chlorophenylacetate (4f0) as a side prod-
of an N,N-diallyl a-amino acid derivative prepared by [2,3] Stevens
rearrangement. However, the N-allyl substituent also functions as
a reactive migrating group, which restricts the scope and limits
uct (34%, 31% ee, R) resulting from substitution at the a-position of
the rearrangement products to
a-allyl amino acid derivatives
the ester-carbonyl.7 The N-(2-chloromethyl-4,5-dimethoxy) ben-
zyl substituents, as in 4, were removed by treatment with trifluo-
roacetic acid (TFA) at room temperature to produce 5a–f in 71% to
quantitative yields with minimal racemization.8
(Scheme 1, Eq. 1). Thus, we have been looking for a new N,N-dial-
kyl-type protecting group for amino acid derivatives that can be
alkylated with alkyl halides to yield the corresponding tetraalkyl-
ammonium salts and that do not migrate under the rearrangement
conditions. Herein, we report a new protecting group, 1,2-dime-
With these results in hand, we investigated the amine de-alkyl-
ation of 3a using various types of acyl chloride to obtain N-(2-chlo-
romethyl-4,5-dimethoxy)benzyl derivatives 6a–e (Table 3). Both
N,N-substituents, as in 6a–e, were easily removable by previously
reported methods.2 Treatment of 3a with benzyl (Cbz-Cl), allyl (Al-
loc-Cl), and p-nitrophenyl chloroformate9 resulted in lower yields
of 6 (entries 1–3, 6a–c: 12–36%). Fortunately, when the reaction
was carried out with 2,2,2-trichloroethyl chloroformate (Troc-Cl),
the de-alkylated 6d was obtained in an 86% yield (entry 4). The
use of trichloroacetyl chloride did not give the corresponding prod-
uct 6e (entry 5).
thoxy-4,5-dimethylene, for acyclic
a-amino acid derivatives
(Scheme 1, Eq. 2). This group could be introduced by N,N-dialkyla-
tion with 1,2-bis(bromomethyl)-4,5-dimethoxybenzene (1), can be
removed via amine de-alkylation with acyl chlorides,4,5 and does
not affect the base-induced Stevens rearrangement.
A
protecting reagent, 1,2-bis(bromomethyl)-4,5-dimethoxy-
benzene (1), was prepared by the bisbromomethylation of 1,2-
dimethoxybenzene.6 N,N-dialkylation of representative
L-a-amino
To obtain the non-N-protected a
-amino acid ester 9 from 6d,10
we tried to remove the N-benzylic substituent, as in 6d, by treat-
ment with TFA under the same conditions as for 4a described in
⇑
Corresponding author. Tel.: +81 25 262 7740; fax: +81 25 262 7741.
E-mail address: tayama@chem.sc.niigata-u.ac.jp (E. Tayama).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.013

1374
E. Tayama et al. / Tetrahedron Letters 53 (2012) 1373–1375
Table 3
Amine de-alkylation of 3a using various types of acyl chloride
Entry
R
Time (h)
52
71
63
62
60
6a (%)
1
OCH2Ph
a
b
c
d
e
12b
34c
36
86
Messy
2
3
4
5
OCH2CH@CH2
O-p-NO2-Ph
OCH2CCl3
CCl3
Scheme 1. Removal of N,N-dialkyl substituents from Stevens rearrangement
product.
a
b
c
Isolated yield.
Recovered 3a in 75% yield.
Recovered 3b in 41% yield.
Table 1
N,N-dialkylation of representative L-
a
-amino acid esters 2 with 1a
Entry
R
3b (%)
1
2
3
4
5
6
CH2Ph
Me
i-Bu
i-Pr
(S)-sec-Bu
Ph
a
b
c
d
e
f
77
50
60
67
56
86
Scheme 2. Preparation of non-N-protected
reductive elimination and oxidative cleavage.
a-amino acid ester
9
from 6d by
a
Reaction conditions: 1 (1.0 equiv), 2 (1.0–1.2 equiv), KHCO3 (3–6 equiv), MeCN
(0.1–0.2 M), rt, 12–18 h.
b
Isolated yield.
Table 2
Conversion of 3 into N-ethoxycarbonyl-a
-amino acid methyl esters 5a
Entry
R
4b,c (%)
5b (%)
ee of 5 (%)
1
2
3
4
5
6
CH2Ph
Me
i-Bu
i-Pr
(S)-sec-Bu
Ph
a
b
c
d
e
f
88
84
92
73
75
30f
91
79
89
93
Quant.
71
>99d
99e
>99e
99e
94e
Scheme 3. Preparation of non-N-protected a-amino acid esters 14 via [2,3] or [1,2]
Stevens rearrangements.
91d
a
Reaction conditions: 3 (1.0 equiv), ClCO2Et (1.2–3.0 equiv), 1,2-dichloroethane
(0.1 M), reflux, 2–3 days; 4 (1.0 equiv), TFA (0.1 M), rt, 48 h.
b
Table 2 (Scheme 2). Unfortunately, the expected de-benzylated
product 7 was obtained in only a 16% yield. Thus, we changed
the deprotection process; first, the N-Troc group, as in 6d, was re-
moved by reductive elimination with zinc11 to give 4,5-dimethoxy-
2-methylbenzyl derivative 8 with an 81% yield. The remaining N-
benzylic substituent was removed by oxidative cleavage with ceric
Isolated yield.
c
The products may contain a small amount of impurities because of the difficulty
of purification.
d
Determined by HPLC analysis using a chiral column.
Determined by the comparison of the specific rotation with that of the
e
authentic sample prepared from
L-amino acids.
f
Methyl 2-chlorophenylacetate (4f0) was obtained with 34% yield.

E. Tayama et al. / Tetrahedron Letters 53 (2012) 1373–1375
1375
Acknowledgment
This work was supported by KAKENHI (Grant-in-Aid for Young
Scientists (B), 23750037).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.013.
References and notes
1. For reviews: (a) Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027–1038; (b)Nitrogen,
Oxygen, and Sulfur Ylide Chemistry; Clark, J. S., Ed.; Oxford University Press: New
York, 2002; (c) Markó, I. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, Chapter 3.10.
2. For a review: Wuts, P. G. M.; Greene, T. W. Green’s Protective Groups in Organic
Synthesis, 4th ed.; Wiley: Hoboken, 2006; Chapter 7.
3. (a) Workman, J. A.; Garrido, N. P.; Sançon, J.; Roberts, E.; Wessel, H. P.; Sweeney,
J. B. J. Am. Chem. Soc 2005, 127, 1066–1067; (b) Arboré, A. P. A.; Cane-Honeysett,
D. J.; Coldham, I.; Middleton, M. L. Synlett 2000, 236–238.
4. For a review: Cooley, J. H.; Evain, E. J. Synthesis 1989, 1–7.
5. Representative studies about de-alkylation of amines using acyl halide
derivatives: (a) Bhat, R. G.; Ghosh, Y.; Chandrasekaran, S. Tetrahedron Lett.
2004, 45, 7983–7985; (b) Dave, P. R.; Kumar, K. A.; Duddu, R.; Axenrod, T.; Dai,
R.; Das, K. K.; Guan, X.-P.; Sun, J.; Trivedi, N. J.; Gilardi, R. D. J. Org. Chem 2000,
65, 1207–1209; (c) Miller, M. W.; Vice, S. F.; McCombie, S. W. Tetrahedron Lett.
1998, 39, 3429–3432; (d) Ferguson, J. R.; Lumbard, K. W.; Scheinmann, F.;
Stachulski, A. V.; Stjernlöf, P.; Sundell, S. Tetrahedron Lett. 1995, 36, 8867–8870;
(e) Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195–196.
Scheme 4. Preparation of non-N-protected
metric [2,3] Stevens rearrangement of 15.
a-amino acid ester 19 via the asym-
ammonium nitrate (CAN)12 to afford 9 in a 91% yield. The enantio-
purity of 9 thus obtained was 99% ee. Racemization was not ob-
served during this process (2a–9).
6. Diederich, F.; Jonas, U.; Gramlich, V.; Herrmann, A.; Ringsdorf, H.; Thilgen, C.
Helv. Chim. Acta 1993, 76, 2445–2453.
We applied this synthetic method to prepare non-N-protected
7. The
a-position of the ester-carbonyl, as in 3f, was reactive for substitution
unnatural
a-amino acid esters 14 via the base-induced [2,3] or
because of benzylic. We found that 4f0 is easily racemized under various
[1,2] Stevens rearrangements (Scheme 3). Treatment of ammo-
nium salts 10 (10a: R = CH@CH2, 10b: R = 4-Me–Ph) with potas-
sium tert-butoxide in THF at 0 °C afforded 11 as rearrangement
products (11a: 85%, 11b: 58%). The 1,2-dimethoxy-4,5-dimethyl-
ene group, as in 11, was removed to afford the desired products
14 (14a: 72%, 14b: 85%)by the procedures described in Table 3
and Scheme 2.
conditions.
Similarly, this method was applied to the asymmetric [2,3] Ste-
vens rearrangement developed by Workman et al. (Scheme 4).3a
When the reaction of ammonium salt 15 with potassium tert-
butoxide was carried out in THF at ꢀ40 °C for 17 h, the correspond-
8. The formation of N-acylammonium intermediate derived from 3f might cause
racemization because of high acidity of the a-proton.
9. (a) Examples of amine de-alkylation using p-nitrophenyl chloroformate: Jones,
A. D., Zelle, R. E., Silverman, I. R. PCT Int. Appl. WO 2009035652 2009.; (b)
Kopach, M. E.; Fray, A. H.; Meyers, A. I. J. Am. Chem. Soc. 1996, 118, 9876–9883.
10. We attempted to prepare 9 by hydrogenolysis of 3a (Pd–C, H2, EtOAc, rt, 5.5 h),
however, the reaction did not proceed with the recovery of 3a in
quantitatively.
ing
a-allylglycine derivative 16 was obtained in a 73% yield (S/
R = 92/8).13,14 The removal of the N,N-substituents, as in 16, by
the same procedures described in Scheme 3, gave 19 in a 52% over-
all yield without epimerization.
11. Just, G.; Grozinger, K. Synthesis 1976, 457–458.
In conclusion, we have reported a new protecting group, 1,2-
dimethoxy-4,5-dimethylene, for acyclic amino acid esters. This
group could be introduced via N,N-dialkylation with 1,2-bis(bro-
momethyl)-4,5-dimethoxybenzene (1) and removed via amine
de-alkylation with acyl chlorides, reductive elimination, and oxida-
tive cleavage. The method can be used with base-induced [2,3] and
[1,2] Stevens rearrangement products.
12. Bull, S. D.; Davies, S. G.; Kelly, P. M.; Gianotti, M.; Smith, A. D. J. Chem. Soc.,
Perkin Trans. 1 2001, 3106–3111. Removal of 4,5-dimethoxy-2-methylbenzyl
substituent as in 8 with TFA did not proceed at all. Hydrogenolysis of 8
(5 mol % Pd–C, 0.3 MPa H2, EtOAc, rt, 41 h) gave 9 in 23% yield (99% ee) with
the recovery of 8 in 65% yield..
13. The S/R configuration was assigned tentatively by the analogy with Ref. 3a.
14. We attempted the [1,2] Stevens rearrangement of N-(4-methylbenzyl)-
ammonium salt; however, the stereoselectivity was lower (dr = 6/4 to 8/2).