An expedient conversion of α-amino acids into Weinreb amides using COMU As a coupling agent

Article abstract of DOI:10.1016/j.tetlet.2010.10.169

The use of COMU, as a non-hazardous partner, in the coupling of N-protected α-amino acids to N-methoxy-N-methylamine to afford the corresponding Weinreb amides is discussed. From a practical point of view the reaction can be monitored visually by virtue of the colour change associated with the conversion of substrates (yellow) into the products (orange). As the by-products of the reaction are conveniently water-soluble the products are isolated relatively pure and with minimal racemisation. These factors coupled with the short reaction time make this a very useful procedure.

Full text of DOI:10.1016/j.tetlet.2010.10.169

Tetrahedron Letters 52 (2011) 369–372
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expedient conversion of
as a coupling agent
a
-amino acids into Weinreb amides using COMUÒ
Elizabeth Tyrrell a, , Peter Brawn a, Mark Carew a, Iain Greenwood b
⇑
a School of Chemistry and Pharmacy, Kingston University, Penrhyn Road, Kingston, Surrey KT1 2EE, United Kingdom
b St George’s, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
a r t i c l e i n f o
a b s t r a c t
The use of COMUÒ, as a non-hazardous partner, in the coupling of N-protected
a-amino acids to N-meth-
Article history:
Received 6 September 2010
Revised 12 October 2010
Accepted 29 October 2010
Available online 4 November 2010
oxy-N-methylamine to afford the corresponding Weinreb amides is discussed. From a practical point of
view the reaction can be monitored visually by virtue of the colour change associated with the conversion
of substrates (yellow) into the products (orange). As the by-products of the reaction are conveniently
water-soluble the products are isolated relatively pure and with minimal racemisation. These factors
coupled with the short reaction time make this a very useful procedure.
Keywords:
Ó 2010 Published by Elsevier Ltd.
Weinreb amides
Colorimetric changes
Amidation
Water-soluble by-products
COMUÒ
In 1981 the use of N-methoxy-N-methylamides, as effective
acylating agents, was first disclosed.1 Since then the use of Wein-
reb amides, as a strategy for the conversion of a carboxyl group di-
rectly into the corresponding ketone or aldehyde, has significantly
increased.2 Recently, applications of Weinreb amides has included
their conversion into ketones using Wittig chemistry,3 remote
Birch reductions performed in the presence of the stable Weinreb
‘intermediate’4 as well as the development of novel modified
Weinreb amides themselves.5
the N-methoxy-N-methylamine. A wide variety of suitable re-
agents have been described for this purpose including the use of
a mixed anhydride,10 DCC,7,11 DCC/HOBt,12 CBr4/PPh3,13 BOP,14
EDCI/HOBt.9c,15 CDMT16 and the fluorinating agent Deoxo-Fluor.17
Due to recent concerns about the safety of reagents such as the
triazoles HOBt18 and HOAt we focused our attention upon the
use of COMUÒ19 3 (Fig. 2) as an alternative coupling agent.
Our work on these compounds stems from an ongoing interest
in the chemistry of chiral alkynes and chiral propargyl alcohols.
With this in mind we considered the application of Weinreb
H C
R
R
3
N
OCH
H
3
BocHN
BocHN
amides 1, derived from
a-amino acids as a method for accessing
the corresponding aldehydic derivatives 2 (Fig. 1).
O
1
O
Weinreb amides are particularly useful for this conversion due
2
6
to the repression of over reduction, when using LiAlH4 or DIBAL-
H7as well as racemisation
a to the carbonyl group. These were
Figure 1.
important criteria in our investigations as we wanted minimal loss
of optical activity in the formation of aldehyde 2. A range of
methodologies have been developed for the synthesis of N-
methyl-N-methoxy carboxamide derivatives of esters/lactones8
and oxazolidinones9, however, methods that describe conversion
of an acid motif directly into a carboxamide were of more rele-
vance to our investigations. As a rule most approaches involve
the in situ formation of an active ester followed by an attack by
O
CH
N
3
+
N
H C
3
OH
-
O
PF
6
N
N
EtO C
CN
EtO2C
CN
2
3
4
⇑
Corresponding author.
E-mail address: e.tyrrell@kingston.ac.uk (E. Tyrrell).
Figure 2.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.10.169

370
E. Tyrrell et al. / Tetrahedron Letters 52 (2011) 369–372
PBRX274.010.esp
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
O
BocHN
OMe
N
CH
CH
3
3
5
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
-0.5
Chemical Shift (ppm)
Figure 3. 1H NMR spectrum of the crude Weinreb amide derived from N-Boc-protected alanine 5
The evolution of 3 as a synthetic tool in the chemistry of peptide
Table 1
bond formation is derived from two important studies. The first
was that Oxyma 4 was shown to serve as an excellent alternative
to benzotriazole derivatives in coupling reactions when used in
conjunction with carbodiimide20 whilst being efficacious with
sterically demanding substrates, readily outperforming HOBt. Fur-
thermore, it was shown to be a powerful inhibitor of racemisation
during the ensuing coupling reaction. Secondly, it was shown that
when a hydrogen bond acceptor, based upon a polar morpholino
group, replaced a dimethylamino moiety present in HATU or HBTU
it provided a more soluble reagent accompanied by an enhance-
ment in its stability and reactivity.21 The combination of these
structural motifs into one molecule produced COMUÒ a third gen-
eration of uronium-type coupling agent.22
Weinreb amide derivatives of L-a-amino acids
Entry
N-Boc amino acid
% Yield
O
i. CH ONHCH ·HCl
O
3
3
DIEA, DMF, 0 ºC.
BocHN
BocHN
OMe
3
OH
N
CH
ii. Protected amino acid, COMU
R
R
1
2
Alanine
Valine
63
88
86
91
74
97
74
87
79
68
3
4
5
Phenylalanine
Typtophan
Tyrosine
6
7
Methionine
Proline
8
9
Isoleucine
Leucine
The advantages to us in the use of COMUÒ were based upon its
enhanced performance compared to HATU, the absence of a tria-
zole group that reduces any inherent dangers and the reported
minimal or zero tendency for racemisation. With regard to labora-
tory procedures it was noted that the by-products from the reac-
tion were mainly all water soluble, therefore, we anticipated that
this would lead to cleaner reaction conditions that might afford a
fairly pure and uncontaminated range of Weinreb amides.
In practice we found that addition of an N-Boc-protected amino
acid and COMUÒ, to an ice-cooled solution of N,O-dimethylhydr-
oxylamine hydrochloride and diisopropylethylamine in DMF led
to the formation of yellow-coloured solution. Formation of the
amide product was accompanied by a colour change of the reaction
mixture from yellow to orange (over 2–2.5 h). The reaction was
then quenched and product isolated from an ether/water mix-
ture.23 Colorimetric monitoring of all of the substrates shown
was possible. Confirmation that most of the residues from the reac-
tion were water soluble was evident from an inspection of the cor-
responding 1H NMR spectra of the crude product ( Fig. 3).
Compounds synthesized in this way needed no further purification,
such as column chromatography, making this a highly expedient
process.
10
Thiaproline
In order to ascertain whether the use of COMUÒ, as a coupling
agent, confers an advantage over other methods, we repeated the
amide formation from N-Boc protected alanine using 2-chloro-
4,6-dimethoxy[1,3,5]triazine (CDMT) and N-methylmorpholine
(NMM) in THF as the coupling reagents.16 We chose this method
as it uses a similar water/ether work-up procedure to afford the de-
sired products, including a-amino acids, in pure form. In our hands,
however, the product(s) always needed further purification by
chromatography on silica and the reaction times were considerably
longer.
Chiral HPLC24 was used in order to ascertain the degree of rac-
emisation that may have occurred during the COMUÒ-mediated
coupling reactions. This was established by comparison of the
chiral amides to those prepared from the corresponding racemic
amino acids (Fig. 4).
It was reassuring that we observed a significant difference in
the retention times between the
tives Analysis of these data reveals that the retention times for
the racemic amides derived from ( )-alanine were t = 14.21 min,
D- and the L-amino acid deriva-
All of the amide derivatives synthesized using COMUÒ were
isolated with very high levels of purity (Table 1).
D/L

E. Tyrrell et al. / Tetrahedron Letters 52 (2011) 369–372
371
Figure 4. The chiral HPLC obtained from the Weinreb amidation of D/L-N-Boc alanine. The presence of impurities are noted at a t = 6.63 min and 7.11 min.
Figure 5. The chiral HPLC obtained from the Weinreb amidation of L-N-Boc alanine, t = 16.09 min.
area 49.9% (
For the synthesis using the corresponding (
D
-derivative) and t = 16.10 min, area 50% (
L
-derivative).
starts as a yellow solution and requires an orange colour upon
completion of the reaction (Fig. 6).
L)-alanine derivative
alone there was only one peak observed at t = 16.09 min, area
>99% relative to the region where the alternative stereoform corre-
sponding to the (D)-isomer should appear (Fig. 5).
The resulting amides were isolated in very good to excellent
yields and by using an ether/aqueous work-up the presence of
by-products was kept to a minimum as most were retained in
the aqueous phase. This resulted in the production of crude Wein-
reb amides that proved to be analytically pure by NMR and chiral
HPLC analysis and with minimal observable racemisation.
To summarise our findings we have found that COMUÒ serves
as an excellent and non-hazardous reagent for the coupling of N-
protected amino acids with N,O-dimethylhydroxylamine hydro-
chloride to afford the corresponding Weinreb amides. From a prac-
tical point of view the progress of the reaction can be readily
monitored by the colour change of the reaction mixture which
Acknowledgements
The authors thank the EPSRC National Mass Spectrometry
Service Centre, University of Swansea for High Resolution Mass
Spectra. The SWAN Alliance for financial support with this project
in the form of a studentship to P.B.
References and notes
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Figure 6. Amidation using COMUÒ. (a) Addition of coupling agent. (b) Reaction
mixture after 2–2.5 h.

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E. Tyrrell et al. / Tetrahedron Letters 52 (2011) 369–372
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23. Representative procedure: (
alaninamide (5). mixture of DMF (120 mL) containing N,O-
L
)-N-tert-Butyoxycarbonyl-(N0-methoxy-N’-methyl)
A
dimethylhydroxylamine hydrochloride (1.56 g, 0.016 mol) and redistilled
diisopropylethylamine (6.16 g, 0.0477 mol) were cooled to 0 °C in an ice-bath
under
a nitrogen atmosphere. To the mixture was added alanine (3 g,
0.0159 mol) followed by COMU (0.016 mol). The solution immediately
turned yellow and the solution was left stirring in the ice-bath for a further
20 min. The ice-bath was removed and the reaction mixture was allowed to
reach ambient temperature. After about 2 h the colour of the reaction mixture
became orange and stirring was continued for a further 30 min. The solution
was diluted with H2O (200 mL) and extracted with Et2O (3 ꢀ 100 mL). The
combined organic fractions were washed with dilute HCl (1 M) (20 mL),
saturated Na2CO3 solution (3 ꢀ 20 mL) and finally a saturated brine solution
(20 mL). The organic layer was dried over anhydrous MgSO4, filtered in vacuo
and the solvent removed at the pump to afford the title compound as a white
crystalline solid 2.32 g, 63%. Mp 147.2–148.6 °C, lit. 148–153 °C;25
[a
]
D
ꢁ26, c
1, (MeOH), lit. [
a
]
D
ꢁ26, c 1, (MeOH);25 HRMS (EI, M+) calcd for C10H21O4N2
233.1496, found 233.1497; 1H NMR (CDCl3, 400 MHz) d 5.18 (1H, br s, N–H),
4.62 (1H, br s, C–H), 3.70 (3H, s, O–CH3), 3.14 (3H, s, CH3), 1.37 (9H, s, CH3), 1.24
(3H, d J = 7.03 Hz, CH3); 13C (CDCl3 101 MHz) d 18.69, 28.36, 32.16, 46.52,
61.61, 79.50. 155.12,26 173.69.27
24. HPLC was determined using a (Chiralcel-OD-H column) with a Waters 996
photodiode array diode detector. Measurements were made at 230 nm at a
flow rate of 0.5 ml/min. Solvent, hexane/IPA (98:2).
25. The product is commercially available from Aldrich.
26. This resonance was only observed using DEPT Q.
27. This resonance was observed using HMBC.