Efficient synthesis of esters containing tertiary amine functionalities via active cyanomethyl ester intermediates

Article abstract of DOI:10.1016/j.tetlet.2009.05.034

Esters containing tertiary amine functionalities were successfully synthesized under mild conditions and in good yields, using a three-step process involving the activation of acids into their corresponding cyanomethyl esters, followed by transesterificat

Full text of DOI:10.1016/j.tetlet.2009.05.034

Tetrahedron Letters 50 (2009) 4346–4349
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of esters containing tertiary amine functionalities
via active cyanomethyl ester intermediates
*
Camille Bouillon, Gilles Quéléver , Ling Peng
Centre Interdisciplinaire de Nanoscience de Marseille, CNRS UPR 3118, Department of Chemistry, Faculty of Sciences of Luminy, Aix-Marseille Université,
13288 Marseille Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Esters containing tertiary amine functionalities were successfully synthesized under mild conditions and
in good yields, using a three-step process involving the activation of acids into their corresponding
cyanomethyl esters, followed by transesterification with the alcohol counterparts, and subsequent scav-
enging of the excess of alcohol to facilitate purification.
Received 8 April 2009
Revised 7 May 2009
Accepted 13 May 2009
Available online 18 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Tertiary amine-containing esters
Cyanomethyl ester
Transesterification
Scavenging
The formation of an ester bond is frequently required in or-
ganic synthesis and a large variety of methods are available to
achieve this reaction.1 One of the simplest and most popular pro-
cedures involves the activation of the acid using activating
agents such as DCC, EDC and BOP, followed by coupling with
the corresponding alcohol under mild conditions. However,
according to a recent report on the preparation of esters of
EDTA2 and our own experience,3 it is not the method of choice
for the synthesis of esters bearing tertiary amine functionalities.
Indeed, the presence of these tertiary amines in acids or alcohols
was often associated with the reaction not going to completion.
Purification of the product also proved difficult and the yields
were rather poor.2,3 The fact that tertiary amines are protonated
to form zwitterions or H-bonds in the reaction medium may ex-
plain why the presence of the tertiary amine functionalities re-
duces the reactivity for ester formation and enhances the
difficulty of purification.
step with the alcohol counterpart to achieve the corresponding
ester. This whole reaction sequence could be performed under
mild conditions, leading to the desired esters in good to excel-
lent yields. This method has previously been reported for the
synthesis of amino acid esters of peptides5 and nucleotides,6
as well as natural products.7 However, it has not yet been
widely explored and generally applied for the synthesis of es-
ters. Here, we report the use of this method in the synthesis
of tertiary amine-containing esters. The method developed for
the synthesis of this particular family of esters involves the
activation of the acid to its cyanomethyl ester, followed by
its transesterification and subsequent solution-phase scavenging
of the excess of alcohol (Scheme 1). In this way and in con-
trast to previously reported methods of synthesis, tertiary
amine-bearing esters can be readily synthesized and easily
purified.
Scheme 2 shows the synthesis of the tertiary amine contain-
ing alcohols (1–3) and acids (4–6) used in this study. Alcohols 1–
3 were obtained quantitatively via double Michael additions
starting with commercially available amino alcohols and t-butyl-
acrylate.8,9 Subsequent acylation with benzoic anhydride led to
To overcome this, we explored the possibility of synthesiz-
ing tertiary amine-bearing esters via active cyanomethyl ester
intermediates.4 The process involved firstly the conversion of
the acid into its corresponding cyanomethyl ester by the action
of chloroacetonitrile. This was followed by a transesterification
10
10-30 which were further treated with TFA to remove the t-bu-
tyl group, giving the corresponding acids 4–6 in excellent
yields.11
Starting with the amine containing alcohol 1 and acid 4, we
first attempted to synthesize ester 7 using the conventional cou-
pling system DCC/DMAP in CH2Cl2 (Scheme 3). Under these con-
ditions, 7 could neither be isolated nor identified since the
* Corresponding author. Tel.: +33 491 82 91 54; fax: +33 491 82 93 01.
E-mail address: gilles.quelever@univmed.fr (G. Quéléver).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.034

C. Bouillon et al. / Tetrahedron Letters 50 (2009) 4346–4349
4347
R1
CO2H
from 1, with both 7 and 1 migrating very closely on silica gel.
We then carried out a scavenging process to remove the excess
of 1 by treating the crude reaction mixture with benzoic anhy-
dride in the presence of DMAP. In this way, 1 could be quantita-
tively transformed into the less polar benzoate ester 10 leading
to its ease of separation from 7. However, the yield of the de-
sired ester 7 was a mere 40% with contamination of dicyclohex-
ylurea, DCU.12
N
R2
Activation
ClCH2CN
R1
N
CO2CH2CN
We then focused our attention on using the active cyanomethyl
ester to synthesize 7 (Scheme 3). Treating acid 4 with chloroaceto-
nitrile in the presence of Et3N, we were able to obtain the cyanom-
R2
ethyl ester 40 (Scheme 3), almost quantitatively13 using
a
procedure previously described by Wong et al.5 This cyanomethyl
ester 40 was stable enough to be isolated and characterized and
was also sufficiently reactive to undergo a transesterification with
1 in the presence of DBU in CH3CN to give 7 (Scheme 3).14 After
scavenging of the excess of alcohol 1 with benzoic anhydride, 7
could be easily purified on silica gel and isolated in 75% yield in
pure form.15 Collectively, the three-step procedure involving the
activation of the acid into its cyanomethyl ester, followed by a
transesterification step and subsequent scavenging of the excess
of alcohol appeared to be the method of choice to synthesize the
tertiary amine bearing ester 7.
R'OH excess
Transesterification
R1
CO2R'
R'OH excess
N
R2
Scavenging
Bz2O
We further applied this three-step sequence to synthesize
esters, starting with acid 4 and alcohols 2 and 3 (Scheme 4).
Compared to 1, both 2 and 3 are characterized by longer link-
ers between the terminal hydroxyl group and the tertiary amine
R1
CO2R'
R' OBz
N
R2
function, with the former having
a
non-polar linker
polar one
(–CH2CH2CH2CH2CH2–) and the latter having
a
pure
(–CH2CH2OCH2CH2–). Using the above-described three-step syn-
thesis, the two esters 8 and 9 (Scheme 4) were obtained in
yields of 63% and 70%, respectively.15 Similarly, starting with
acids 5 and 6, we quantitatively obtained the corresponding
cyanomethyl esters 50 and 60,13 which were further coupled with
alcohols 2 and 3 to give the corresponding esters 10 and 11
(Scheme 4) with yields of 68% and 70%, respectively.15 It is
noteworthy that the esters containing –CH2CH2OCH2CH2– linkers
(9 and 11) are more polar than those with –CH2CH2CH2CH2CH2–
linkers (7, 8 and 10), and consequently required more effort for
their purification.
Scheme 1. Three-step sequence involving activation, transesterification and scav-
enging for synthesizing esters containing tertiary amines.
CO2tBu
CO2tBu
X
X
N
HO
NH2
HO
In summary, we have developed a three-step sequence for
the preparation of esters containing tertiary amine functions.
The synthesis involves activation of the acid into its cyanom-
ethyl ester, subsequent transesterification with the alcohol
counterpart, and a final solution-phase scavenging of the excess
of alcohol. This procedure is particularly suitable and efficient
for the synthesis of esters containing tertiary amine functional-
ities in both acid and alcohol components. The synthesis can
be performed under very mild conditions, giving the desired
esters in good yields following an easy purification. Further
work is underway to validate this method for the synthesis
of various tertiary amine-bearing esters and other esters which
are otherwise difficult to obtain using conventional coupling
methods.
CO2tBu
1 X
:
= -CH2CH2-
2: X = -CH2CH2CH2CH2CH2-
3 X
:
= -CH2CH2OCH2CH2-
Bz2O, DMAP
CO2H
CO2tBu
TFA
X
X
N
BzO
N
. CF3CO2H
CO2H
BzO
CO2tBu
1' X
4 X
:
= -CH2CH2-
2': X = -CH2CH2CH2CH2CH2-
3' X
:
= -CH2CH2-
5: X = -CH2CH2CH2CH2CH2-
6 X
Acknowledgements
:
= -CH2CH2OCH2CH2-
:
= -CH2CH2OCH2CH2-
This work is founded by CNRS and Association Française
contre les Myopathies. CB is supported by the Ph.D fellowship
from the French Ministry of Education. We are grateful to Pro-
fessor Michiko Iwamura and Dr. Cédrik Garino for helpful dis-
cussions, Sophie Gallo and Thomas von Essen for technical
assistance and Dr Claude Niebel for critical reading of the
manuscript.
Scheme 2. Preparation of alcohols (1–3) and acids (4–6).
coupling reaction did not go to completion, leaving both 1 and 4
in the reaction mixture. It was impossible for us to separate 7

4348
C. Bouillon et al. / Tetrahedron Letters 50 (2009) 4346–4349
CO2tBu
X
X
O
N
N
CO2H
O
O
1, DCC, DMAP
CO2tBu
CO2tBu
X
BzO
N
. CF3CO2H
CO2H
X
BzO N
O
CO2tBu
4 X
:
= -CH2CH2-
7: X = -CH2CH2-
1) 1, DBU
ClCH2CN, Et3N
CO2CH2CN
2) Bz2O, DMAP
X
BzO
N
CO2CH2CN
4': X = CH2CH2
Scheme 3. Synthesis of tertiary amine-containing ester 7 starting with 1 and 4.
CO2CH2CN
CO2H
ClCH2CN, Et3N
X1
X1
N
BzO
N
. CF3CO2H
CO2H
BzO
CO2CH2CN
: 1 = -CH2CH2-
4' X
4 X
:
1 = -CH2CH2-
5': X1 = -CH2CH2CH2CH2CH2-
5: X1 = -CH2CH2CH2CH2CH2-
6' X
:
6 X
:
1 = -CH2CH2OCH2CH2-
1 = -CH2CH2OCH2CH2-
CO2tBu
1) 2 or 3, DBU
X2
O
O
N
N
O
2) Bz2O, DMAP
CO2tBu
CO2tBu
BzO X1
N
O
X2
CO2tBu
8: X1 = -CH2CH2- ,
9: X1 = -CH2CH2- ,
11: X1 = -CH22CH22OC2H2C2H2- , X2 = -CH2CH2OCH2CH2-
X
2 = -CH2CH2CH2CH2CH2-
2 = -CH2CH2OCH2CH2-
X
10
:
X
X2
= -CH2CH2CH2CH2CH2-
1 = -CH CH CH CH CH2- ,
Scheme 4. Synthesis of tertiary amine-containing esters using the three-step sequence.
8. Krishna, T. R.; Jain, S.; Tatub, U. S.; Jayaramana, N. Tetrahedron 2005, 61, 4281–
References and notes
4288.
9. General procedure for the synthesis of alcohols 1–3: A mixture of an amino
alcohol and tert-butyl acrylate (2.6 equiv) in MeOH was stirred at room
temperature for 4 days. Then, excess of tert-butyl acrylate and solvent were
removed in vacuo. The crude material was purified by flash chromatography
on silica gel (eluent cyclohexane–EtOAc) to afford the product.
Compound 1 (98%): 1H NMR (CDCl3, 250 MHz) dY 1.45 (s, 18H), 2.35 (t, 4H,
3J = 6.8 Hz), 2.56 (t, 2H, 3J = 5.2 Hz), 2.74 (t, 4H, 3J = 6.8 Hz), 3.55 (t, 2H,
3J = 5.2 Hz); 13C NMR (CDCl3, 62.9 MHz) dC 27.8 (6C), 33.5 (2C), 49.0 (2C),
55.5, 58.8, 80.3 (2C), 171.8 (2C).
1. For reviews about recent methodologies for ester formation, see: Nahmany, M.;
Melman, A. Org. Biomol. Chem. 2004, 2, 1563–1572; Houston, T. A.; Levonis, S.
M.; Kiefel, M. J. Aust. J. Chem. 2007, 60, 811–815; Ishihara, K. Tetrahedron 2009,
65, 1085–1109.
2. Buschhaus, B.; Hampel, F.; Grimme, S.; Hirsch, A. Chem. Eur. J. 2005, 11, 3530–
3540.
3. Bouillon, C.; Ph.D Thesis, Aix-Marseille University, 2009.
4. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley: New York, 1999. pp 518–525, and references therein.
5. Hennen, W. J.; Sweers, H. M.; Wang, Y. F.; Wong, C.-H. J. Org. Chem. 1988, 53,
4939–4945.
6. Ellman, J.; Mendel, D.; Anthony-Cahill, S.; Noren, C. J.; Schultz, P. G. Methods
Enzymol. 1991, 202, 301–336; Robertson, S. A.; Ellman, J. A.; Schultz, P. G. J. Am.
Chem. Soc. 1991, 113, 2722–2729.
Compound 2 (97%): 1H NMR (CDCl3, 250 MHz) dY 1.26–1.65 (m, 24H), 2.28–
2.39 (m, 6H), 2.68 (t, 4H, 3J = 7.2 Hz), 3.54–3.61 (m, 2H); 13C NMR (CDCl3,
62.9 MHz) dC 23.3, 26.8, 28.0 (6C), 32.4, 33.5 (2C), 49.2 (2C), 53.4, 62.5, 80.2
(2C), 172.1 (2C); HMRS m/z calcd for C19H37NO5 [M+H]+ 360.2748, found
360.2738.
Compound 3 (78%): 1H NMR (CDCl3, 250 MHz) dY 1.43 (s, 18H), 2.39 (t, 4H,
3J = 6.1 Hz), 2.65 (t, 2H, 3J = 4.5 Hz), 2.81 (t, 4H, 3J = 6.1 Hz), 3.54–3.59 (m,
7. Findlow, S.; Gaskin, P.; Harrison, P. A.; Lenton, J. R.; Penny, M.; Willis, C. L. J.
Chem. Soc., Perkin Trans. 1 1997, 751–757.

C. Bouillon et al. / Tetrahedron Letters 50 (2009) 4346–4349
4349
4H), 3.68–3.70 (m, 2H); 13C NMR (CDCl3, 62.9 MHz) dC 28.1 (6C), 33.4 (2C),
49.9 (2C), 53.6, 61.9, 69.5, 72.6, 80.5 (2C), 171.9 (2C); HMRS m/z calcd for
C18H35NO6 [M+H]+ 362.2537, found 362.2529.
3J = 5.0 Hz), 4.44 (t, 2H, 3J = 4.7 Hz), 4.67 (s, 4H), 7.43 (t, 2H, 3J = 7.5 Hz), 7.55 (t,
1H, 3J = 7.4 Hz), 8.03 (d, 2H, 3J = 7.0 Hz); 13C NMR (CDCl3, 62.9 MHz) dC 32.3
(2C), 48.1 (2C), 49.6 (2C), 53.0, 63.9, 68.9, 69.5, 114.5 (2C), 128.3 (2C), 129.5
(2C), 129.9, 133.0, 166.4, 170.7 (2C); HMRS m/z calcd for C21H25N3O7 [M+H]+
432.1765, found 432.1746.
10. General procedure for the synthesis of esters 10–30: The corresponding alcohol,
benzoic anhydride (2.0 equiv) and DMAP (4.0 equiv) in CH2Cl2 were stirred at
room temperature for 1 h. Solvent was then removed in vacuo, and the residue
was diluted with EtOAc (20 mL), washed successively with aqueous saturated
NaHCO3 (2 ꢀ 10 mL) and brine (10 mL), dried and concentrated. The resulting
crude material was purified by flash chromatography (eluent cyclohexane–
EtOAc) to afford the desired product.
14. We tried to optimize this transesterification step by varying organic bases
(DMAP, Et3N or DBU) and solvents (CH2Cl2 and CH3CN). The best results were
obtained in the presence of DBU in CH3CN, with complete consumption of the
activated ester overnight at room temperature. It is to note that no trace of the
desired ester could be detected by using either weaker bases such as DMAP and
Et3N, or in the absence of any base, whereas transesterification in CH2Cl2
required a much longer reaction time (48 h) than in CH3CN.
15. General procedure for the synthesis of esters 7–11: The corresponding
cyanomethyl ester, alcohol (2.6 equiv) and DBU (2.6 equiv) in CH3CN were
stirred at room temperature for 48 h. Solvent was then removed in vacuo, and
the residue was diluted with EtOAc (20 mL), washed successively with water
(2 ꢀ 10 mL) and brine (10 mL), dried and concentrated. The resulting crude
material, benzoic anhydride (2.0 equiv) and DMAP (4.0 equiv) in CH2Cl2 were
stirred at room temperature for 1 h. Solvent was then removed in vacuo, and
the residue was diluted with EtOAc (20 mL), washed successively with aqueous
saturated NaHCO3 (2 ꢀ 10 mL) and brine (10 mL), dried and concentrated. The
desired tert-butyl ester was obtained by flash chromatography (eluent
cyclohexane–EtOAc).
Compound 10 (98%): 1H NMR (CDCl3, 250 MHz) dY 1.42 (s, 18H), 2.39 (t, 4H,
3J = 7.1 Hz), 2.82–2.88 (m, 6H), 4.36 (t, 2H, 3J = 6.1 Hz), 7.43 (t, 2H, 3J = 7.5 Hz),
7.55 (t, 1H, 3J = 7.5 Hz), 8.03 (d, 2H, 3J = 8.5 Hz); 13C NMR (CDCl3, 62.9 MHz) dC
28.1 (6C), 34.1 (2C), 50.0 (2C), 52.1, 63.3, 80.4 (2C), 128.3 (2C), 129.6 (2C),
131.2, 132.9, 166.5, 171.8 (2C).
Compound 20 (98%): 1H NMR (CDCl3, 250 MHz) dY 1.24–1.60 (m, 22H), 1.71–
1.82 (m, 2H), 2.31–2.44 (m, 6H), 2.72 (t, 4H, 3J = 7.3 Hz), 4.30 (t, 2H, 3J = 6.6 Hz),
7.42 (t, 2H, 3J = 6.8 Hz), 7.54 (t, 1H, 3J = 7.3 Hz), 8.03 (d, 2H, 3J = 8.3 Hz); 13C
NMR (CDCl3, 62.9 MHz) dC 23.8, 27.0, 28.0 (6C), 28.6, 33.6 (2C), 49.3 (2C), 53.5,
64.9, 80.2 (2C), 128.2 (2C), 129.5 (2C), 130.4, 132.7, 166.6, 172.0 (2C).
Compound 30 (90%): 1H NMR (CDCl3, 250 MHz) dY 1.42 (s, 18H), 2.35–2.39 (m,
4H), 2.62–2.83 (m, 6H), 3.52–3.61 (m, 2H), 3.78 (t, 2H, 3J = 4.8 Hz), 4.45 (t, 2H,
3J = 5.0 Hz), 7.44 (t, 2H, 3J = 7.3 Hz), 7.56 (t, 1H, 3J = 7.4 Hz), 8.06 (d, 2H,
3J = 8.4 Hz); 13C NMR (CDCl3, 62.9 MHz) dC 28.1 (6C), 33.8 (2C), 50.0 (2C), 53.1,
64.1, 69.1, 69.7, 80.3 (2C), 128.3 (2C), 129.7 (2C), 130.1, 133.0, 166.5, 171.9
(2C).
Compound 7 (75%): 1H NMR (CDCl3, 250 MHz) dY 1.35 (s, 36H), 2.27 (t, 8H,
3J = 7.2 Hz), 2.40 (t, 4H, 3J = 7.1 Hz), 2.60 (t, 4H, 3J = 6.2 Hz), 2.70 (t, 8H,
3J = 7.2 Hz), 2.76–2.84 (m, 6H), 4.01 (t, 4H, 3J = 6.3 Hz), 4.28 (t, 2H, 3J = 6.0 Hz),
7.35 (t, 2H, 3J = 7.4 Hz), 7.47 (t, 1H, 3J = 7.3 Hz), 7.94 (d, 2H, 3J = 7.2 Hz); 13C
NMR (CDCl3, 62.9 MHz) dC 27.8 (12C), 32.6 (2C), 33.7 (4C), 49.5 (2C), 49.7 (4C),
51.8 (2C), 53.3, 62.3 (2C), 62.7, 80.1 (4C), 128.1 (2C), 129.3 (2C), 129.9, 132.7,
166.1, 171.4 (4C), 171.9 (2C); HMRS m/z calcd for C47H77N3O14 [M+H]+
908.5478, found 908.5476.
11. General procedure for the synthesis of acids 4–6: To a CH2Cl2 solution of the
corresponding tert-butyl ester was added TFA (20 equiv). The solution was
stirred at room temperature for 48 h. Solvent and TFA were removed in vacuo,
and the resulting residue was triturated into Et2O to afford the desired product.
Compound 4 (quantitative): 13C NMR (CD3OD, 62.9 MHz) dC 29.0 (2C), 51.7
(2C), 54.0, 60.1, 129.7 (2C), 130.5, 130.9 (2C), 134.7, 167.3, 174.3 (2C); HMRS
m/z calcd for C15H19NO6 [M+H]+ 310.1285, found 310.1284.
Compound 8 (63%): 1H NMR (CDCl3, 250 MHz) dY 1.15–1.33 (m, 8H), 1.41 (s,
36H), 1.55–1.66 (m, 4H), 2.29–2.48 (m, 16H), 2.67–2.73 (m, 8H), 2.82–2.90 (m,
6H), 3.99 (t, 4H, 3J = 6.6 Hz), 4.34 (t, 2H, 3J = 6.0 Hz), 7.41 (t, 2H, 3J = 7.5 Hz),
7.53 (t, 1H, 3J = 7.3 Hz), 8.00 (d, 2H, 3J = 8.0 Hz); 13C NMR (CDCl3, 62.9 MHz) dC
23.6 (2C), 26.8 (2C), 28.0 (12C), 28.4 (2C), 32.9 (2C), 33.5 (4C), 49.2 (4C), 49.7
(2C), 52.1, 53.4 (2C), 63.0, 64.4 (2C), 80.2 (4C), 128.3 (2C), 129.5 (2C), 130.1,
132.8, 166.4, 171.9 (4C), 172.3 (2C); HMRS m/z calcd for C53H89N3O14 [M+H]+
992.6417, found 992.6436.
Compound 5 (70%): 13C NMR (CD3OD, 62.9 MHz) dC 24.2, 24.4, 29.3 (3C), 50.6
(2C), 54.5, 65.7, 129.6 (2C), 130.5 (2C), 131.4, 134.3, 168.0, 173.6 (2C); HMRS
m/z calcd for C18H25NO6 [M+H]+ 352.1755, found 352.1746.
Compound 6 (93%): 13C NMR (CD3OD, 62.9 MHz) dC 29.2 (2C), 51.6 (2C), 54.8,
65.0, 65.6, 70.3, 129.6 (2C), 130.6 (2C), 131.1, 134.4, 167.9, 174.1 (2C).
12. Unfortunately, DCU could not be completely removed from 7 in our hands.
Further attempts to replace DCC/DMAP by BOP or Mukaiyama’s reagent were
unsuccessful, since no desired product could be identified.
Compound 9 (70%): 1H NMR (CDCl3, 250 MHz) dY 1.38 (s, 36H), 2.33 (t, 8H,
3J = 7.3 Hz), 2.47 (t, 4H, 3J = 7.1 Hz), 2.63 (t, 4H, 3J = 6.3 Hz), 2.76 (t, 8H,
3J = 7.3 Hz), 2.82–2.88 (m, 6H), 3.49 (t, 4H, 3J = 6.1 Hz), 3.57 (t, 4H, 3J = 4.9 Hz),
4.13 (t, 4H, 3J = 4.8 Hz), 4.32 (t, 2H, 3J = 6.0 Hz), 7.39 (t, 2H, 3J = 7.4 Hz), 7.51 (t,
1H, 3J = 7.4 Hz), 7.98 (d, 2H, 3J = 7.0 Hz); 13C NMR (CDCl3, 62.9 MHz) dC 27.9
(12C), 32.6 (2C), 33.4 (4C), 49.6 (2C), 49.7 (4C), 51.9, 52.9 (2C), 62.8, 63.4 (2C),
68.7 (2C), 69.3 (2C), 80.2 (4C), 128.2 (2C), 129.4 (2C), 130.0, 132.8, 166.3, 171.7
(4C), 172.1 (2C).
13. General procedure for the synthesis of activated cyanomethyl esters 40–60: To a
solution of acid in CH2Cl2, were added slowly Et3N (4.0 equiv) and
chloroacetonitrile (6.0 equiv). The solution was stirred overnight at room
temperature. Solvents were removed in vacuo, and the residue was diluted
with EtOAc (20 mL), washed successively with water (2 ꢀ 10 mL) and brine
(10 mL), dried and concentrated. The resulting crude material was purified by
flash chromatography (eluent cyclohexane–EtOAc) to afford the corresponding
activated cyanomethyl ester.
Compound 10 (68%): 1H NMR (CDCl3, 250 MHz) dY 1.13–1.71 (m, 54H), 2.22–
2.37 (m, 18H), 2.59–2.71 (m, 12H), 3.92–4.02 (m, 4H), 4.22 (t, 2H, 3J = 6.4 Hz),
7.35 (t, 2H, 3J = 7.0 Hz), 7.46 (t, 1H, 3J = 6.6 Hz), 7.95 (d, 2H, 3J = 8.0 Hz); 13C
NMR (CDCl3, 62.9 MHz) dC 23.4 (2C), 23.5, 26.7 (2C), 27.8 (12C), 28.3, 28.4 (2C),
29.9, 32.3 (2C), 33.4 (4C), 48.9 (2C), 49.0 (4C), 53.3 (3C), 64.2 (2C), 64.7, 79.9
(4C), 128.1 (2C), 129.3 (2C), 130.1, 132.6, 166.3, 171.7 (4C), 172.4 (2C); HMRS
m/z calcd for C56H95N3O14 [M+H]+ 1034.6887, found 1034.6853.
Compound 40 (84%): 1H NMR (CDCl3, 250 MHz) dY 2.50 (t, 4H, 3J = 6.7 Hz), 2.77–
2.85 (m, 6H), 4.30 (t, 2H, 3J = 5.8 Hz), 4.59 (s, 4H), 7.40 (t, 2H, 3J = 7.5 Hz), 7.52
(t, 1H, 3J = 7.3 Hz), 7.96 (d, 2H, 3J = 7.0 Hz); 13C NMR (CDCl3, 62.9 MHz) dC 32.2
(2C), 48.0 (2C), 49.2 (2C), 51.8, 62.3, 114.4 (2C), 128.1 (2C), 129.2 (2C), 129.7,
132.8, 166.0, 170.4 (2C); HMRS m/z calcd for C19H21N3O6 [M+H]+ 388.1503,
found 388.1502.
Compound 11 (70%): 1H NMR (CDCl3, 250 MHz) dY 1.42 (s, 36H), 2.35 (t, 8H,
3J = 7.2 Hz), 2.47 (t, 4H, 3J = 7.2 Hz), 2.62–2.70 (m, 6H), 2.74–2.86 (m, 12H), 3.51
(t, 4H, 3J = 6.2 Hz), 3.55–3.62 (m, 6H), 3.76 (t, 2H, 3J = 4.7 Hz), 4.16 (t, 4H,
3J = 4.9 Hz), 4.44 (t, 2H, 3J = 4.9 Hz), 7.43 (t, 2H, 3J = 7.4 Hz), 7.55 (t, 1H,
3J = 7.4 Hz), 8.04 (d, 2H, 3J = 8.0 Hz); 13C NMR (CDCl3, 62.9 MHz) dC 27.9 (12C),
32.3 (2C), 33.6 (4C), 49.5 (2C), 49.8 (4C), 52.9 (3C), 63.3 (2C), 63.9, 68.7 (2C),
68.8, 69.4 (2C), 69.5, 80.1 (4C), 128.2 (2C), 129.5 (2C), 129.9, 132.8, 166.3, 171.7
(4C), 172.3 (2C); HMRS m/z calcd for C53H89N3O17 [M+H]+ 1040.6265, found
1040.6269.
Compound 50 (crude material): 1H NMR (CDCl3, 250 MHz) dY 1.31–1.58 (m,
4H), 1.74 (q, 2H, 3J = 6.7 Hz), 2.38–2.53 (m, 6H), 2.74 (t, 4H, 3J = 6.6 Hz), 4.28 (t,
2H, 3J = 6.5 Hz), 4.67 (s, 4H), 7.41 (t, 2H, 3J = 7.5 Hz), 7.53 (t, 1H, 3J = 7.8 Hz),
8.00 (d, 2H, 3J = 8.0 Hz); 13C NMR (CDCl3, 62.9 MHz) dC 23.4, 26.3, 28.4, 32.0
(2C), 48.1 (2C), 48.8 (2C), 53.3, 64.7, 114.4 (2C), 128.1 (2C), 129.3 (2C), 130.1,
132.7, 166.4, 170.7 (2C); HMRS m/z calcd for C22H27N3O6 [M+H]+ 430.1973,
found 430.1964.
Compound 60 (60%): 1H NMR (CDCl3, 250 MHz) dY 2.50 (t, 4H, 3J = 6.6 Hz), 2.67
(t, 2H, 3J = 5.8 Hz), 2.82 (t, 4H, 3J = 6.6 Hz), 3.56 (t, 2H, 3J = 5.6 Hz), 3.75 (t, 2H,