Selective [3 + 2] huisgen cycloaddition. Synthesis of TVaws-disubstituted triazolodiazepines from asa-baylis-hillman adducts

Article abstract of DOI:10.1021/jo802533d

The 1,3-dipolar cycloaddition of linear azido alkynes derived from protected β-amino esters proceeds via diastereomeric differentiation to provide irans-disubstituted triazolodiazepines in good yields.

Full text of DOI:10.1021/jo802533d

Selective [3 + 2] Huisgen Cycloaddition. Synthesis of
Trans-Disubstituted Triazolodiazepines from Aza-Baylis-Hillman
Adducts
Vale´rie Declerck,†,‡ Loic Toupet,§ Jean Martinez,† and Fre´de´ric Lamaty*,†
Institut des Biomole´cules Max Mousseron (IBMM), UMR 5247 CNRS-UniVersite´ Montpellier 1-UniVersite´
Montpellier 2, Place Euge`ne Bataillon, 34095 Montpellier Cedex 5, France, and Institut de Physique
(IPR), UMR 6251 CNRS-UniVersite´ de Rennes 1, Baˆtiment 11A, 35042 Rennes Cedex, France
frederic.lamaty@uniV-montp2.fr
ReceiVed NoVember 14, 2008
The 1,3-dipolar cycloaddition of linear azido alkynes derived from protected ꢀ-amino esters proceeds
Via diastereomeric differentiation to provide trans-disubstituted triazolodiazepines in good yields.
Introduction
In an ongoing project dealing with the use of these R,ꢀ-
unsaturated ꢀ-amino esters as building blocks for the synthesis
of various heterocyclic structures, we reported the preparation
of pyrroles,6 pyrrolines,8 pyrrolidines,8 and benzazepines.9,10 We
describe herein the synthesis of triazolodiazepines from these
ꢀ-amino esters involving an intramolecular [3 + 2] Huisgen
cycloaddition11 as a keystep.
Triazoles are important molecules due to their unique
chemical properties. They possess a wide range of applications
in organic, organometallic, medicinal, and material chemistry.
Although no product containing the 1,2,3-triazole moiety has
been found in nature, this scaffold constitutes an interesting class
of pharmacophores since it shows a remarkable resistance to
metabolic transformations such as oxidation, reduction, basic
or acidic hydrolysis. The 1,2,3-triazole unit is present in various
compounds exhibiting interesting antibacterial,12 anti-HIV,13 and
antiallergic14 activities. As examples, cefmatilen15 exhibit
antibacterial activities and tazobactam16 is a ꢀ-lactamase inhibi-
The aza-Baylis-Hilman reaction1-3 is a powerful method
for the preparation of densely functionalized small molecules
which has attracted the attention of organic chemists. We have
recently reported a three-component aza-Baylis-Hillman reac-
tion involving a sulfonamide, an aldehyde, and an acrylate for
the preparation of highly functionalized 2-(trimethylsilyl)e-
thanesulfonyl (or SES)-protected4,5 R,ꢀ-unsaturated ꢀ-amino
esters which can be used in further transformations.6,7
* To whom correspondence should be addressed. Fax: +33 (0) 4 67 14 48
66.
† IBMM, Universite´ de Montpellier 2.
‡ Present address: Laboratoire de Synthe`se Organique et Me´thodologie,
ICMMO, Universite´ Paris-Sud 11, 15 Rue Georges Clemenceau, 91405 Orsay
Cedex, France.
§ IPR, Universite´ de Rennes 1.
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D.; Adolfsson, H. J. Org. Chem. 2002, 67, 2329–2334.
(2) Declerck, V.; Martinez, J.; Lamaty, F. Chem. ReV. 2009, 109, 1–48.
(3) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905–2916.
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(8) Declerck, V.; Allouchi, H.; Martinez, J.; Lamaty, F. J. Org. Chem. 2007,
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S. M.; Ralbovsky, J. L. ꢀ-(Trimethylsilyl)ethanesulfonyl Chloride (17 September
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2004 J. Org. Chem. 2009, 74, 2004–2007
10.1021/jo802533d CCC: $40.75 2009 American Chemical Society
Published on Web 02/06/2009

SelectiVe [3 + 2] Huisgen Cycloaddition
SCHEME 2. Conjugate Addition of HN3
TABLE 1. Yields and Stereoselectivities of Isolated Compounds 2,
3, 5, and 6
FIGURE 1. Biologically active 1,2,3-triazole containing compounds.
azido-ꢀ-amino
esters 2
precursors 3 SES-triazoles 5 triazoles 6
SCHEME 1. Retrosynthetic Analysis
yield
substituent (%) anti/syna
yield
3:4
(%)b trans/cisa yield (%)
a
b
c
d
e
f
98
96
99
94
99
95
83:17
81:19
83:17
83:17
78:22
71:29
96:4
90:10
95:5
96:4
93:7
96:4
77
68
70
69
69
70
>99
98:2
98:2
>99
99:1
99:1
100
100
100
100
100
100
a Determined by 1H NMR. b Yield in two steps: alkylation and
1,3-dipolar cycloaddition.
tor. Triazolobenzodiazepines17 have high affinity for the ben-
zodiazepine receptors (Figure 1).
tion product). Consequently, we have chosen to introduce first
the azide function and then the propargyl moiety. Introduction
of the azido group on the R,ꢀ-unsaturated ꢀ-amino ester was
realized according to the procedure described by Miller19 to
avoid the use of a toxic and explosive HN3 solution. This
procedure is well-adapted for the 1,4-addition of N3 to unsatur-
ated ketones, but an intramolecular amine-mediated activation
is necessary in the case of R,ꢀ-unsaturated esters. Furthermore,
to our knowledge no example of the azide addition on a 1,1-
disubstituted acrylate has been described. Thus, treatment of
the R,ꢀ-unsaturated ꢀ-amino esters 1a with an excess of TMS-
N3 in the presence of acetic acid and triethylamine at 40 °C for
24 h allowed a complete conversion and the azido-ꢀ-amino
esters 2 were obtained in high yields as a mixture of anti and
syn diastereoisomers, which could not be separated by column
chromatography. X-ray analysis of the cyclic compound 5a
obtained after the cycloaddition step confirmed that the anti
isomer was the major one (Scheme 2, Table 1).
The stereochemical outcome of this reaction was governed
by the reprotonation of the enolate intermediate formed after
the 1,4-addition (Scheme 2). According to the studies of
Perlmutter et al. on 1,4-addition of amines to 2-hydroxyalkyl-
propenoates,20 the two possible conformers A and B of the
enolate resulting from the addition of HN3 are depicted in
Scheme 3. Since the bulky SES-NH group does not accom-
modate easily an interaction with the azidomethylene moiety,
conformer A is preferred, leading to the formation of the anti
product.
Results and Discussion
As described in the retrosynthetic scheme (Scheme 1), the
triazolodiazepines can be obtained by an intramolecular 1,3-
dipolar cycloaddition of a linear precursor possessing an azide
function and a triple bond. This precursor can be obtained by
sequential Michael addition of HN3 on the R,ꢀ-unsaturated
ꢀ-amino esters and alkylation with propargyl bromide.
Starting from the SES-protected amino ester, we had the
choice to perform first either the Michael addition of HN3 or
the alkylation reaction. A disubstituted SES-sulfonamide, which
would be obtained after alkylation by propargyl bromide, owns
a leaving group character similar to that of acetate18 and is not
suitable for a 1,4-addition (it would provide mainly an elimina-
(12) Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.;
Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.;
Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford, C. W.; Zurenko, G. E.;
Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H. J. Med. Chem. 2000, 43,
953–970.
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37, 4185–4194.
(14) Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore, M. R.; Cascieri,
M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.;
MacIntyre, D. E.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg.
Med. Chem. Lett. 2000, 10, 2111–2114.
(15) (a) Kume, M.; Kubota, T.; Kimura, Y.; Nakashimizu, H.; Motokawa,
K.; Nakano, M. J. Antibiot. 1993, 46, 177–192. (b) Kume, M.; Kubota, T.;
Kimura, Y.; Nakashimizu, H.; Motokawa, K. J. Antibiot. 1993, 46, 316–330.
(c) Kume, M.; Kubota, T.; Kimura, Y.; Nakashimizu, H.; Motokawa, K. Chem.
Pharm. Bull. 1993, 41, 758–762.
The next step was the alkylation of the azido-ꢀ-amino ester
2a by propargyl bromide (Table 2). Under classical alkylation
conditions using K2CO3 in DMF for 6 h (entry 1),6 we observed
(16) Tanaka, M.; Yamazaki, T.; Kajitani, M. “Penam Derivatives” Eur. Pat.
158494, 1985; Chem. Abstr. 1986, 104, 186239d.
(17) (a) Smalley, R. K.; Teguiche, M. Synthesis 1990, 654–666. (b) Bertelli,
L.; Biagi, G.; Giorgi, I.; Livi, O.; Manera, C.; Scartoni, V.; Martini, C.;
Giannaccini, G.; Trincavelli, L.; Barili, P. L. Farmaco 1998, 53, 305–311.
(18) Declerck, V.; Martinez, J.; Lamaty, F. Unpublished results.
(19) Guerin, D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett. 1999, 1, 1107–
1109.
(20) Perlmutter, P.; Tabone, M. Tetrahedron Lett. 1988, 29, 949–952.
J. Org. Chem. Vol. 74, No. 5, 2009 2005

Declerck et al.
SCHEME 4. 1,3-Dipolar Cycloaddition of Compound 3a
SCHEME 3. Transition Structure Analysis of the Addition
of HN3 on ꢀ-Amino Esters 1
ized by heating the linear precursor 3a at 80 °C in toluene for
12 h allowed the preparation of the bicyclic triazole 5a, which
was easily separated from the elimination compound 4a by silica
gel chromatography and obtained in a 45% yield. The prolonged
reaction time resulted in the degradation of the product. We
speculated on the use of the microwave heating to reduce
reaction time and probably diminish the degradation. Heating
compound 3a in toluene at 100 °C under microwave irradiation
for 30 min did not yield a complete conversion but showed
that the linear precursor anti-3a cyclized more rapidly than the
1
syn isomer. By carefully monitoring by H NMR the reaction
under classical heating conditions, we found that after 4 h in
toluene at 80 °C, only the anti diastereoisomer had fully cyclized
while the syn one did not react. The reaction gave a mixture of
bicyclic triazole trans-5a, linear precursor syn-3a, and elimina-
tion compound 4a (present in the starting material). The
triazolodiazepine trans-5a was obtained in 77% yield after
purification by chromatography on silica gel (Scheme 4). An
NOE NMR experiment performed on 5a did not show any effect
between the phenyl group protons and those of the ester group,
which implies a trans relationship between these substituents.
Furthermore, X-ray analysis of 5a showed that the two substit-
uents are in a trans configuration, thus confirming the formation
of the anti diastereoisomer during the addition of HN3. Similar
results were obtained with the other substrates which allowed
the preparation of bicyclic triazoles 5 in good yields with a
selectivity higher than 98% for the trans isomer (Table 1).
The difference of reactivity between anti-3a and syn-3a could
be explained by unfavorable interactions between substituents.
Newman projections showed that the conformer presenting
weaker interactions possess the alkyne and azido substituents
in close proximity in the diastereoisomer anti-3a, whereas these
two substituents are in opposite directions in the diastereoisomer
syn-3a (Scheme 5). Diastereomeric differentiation of the two
linear diastereomers provided only trans-5a as a cyclic product.
The last step consisted of the cleavage of the SES group to
obtain the free amine. The use of CsF at 80 °C in DMF or
n-Bu4NF,4 usually employed to deprotect the SES group, yielded
only degradation products. We turned our attention to anhydrous
HF, a nonbasic fluoride source which has proved to be a very
efficient reagent for the deprotection of the SES group in other
cyclic ꢀ-amino esters.8,10 Deprotection of the SES group by
anhydrous HF followed by neutralization of the hydrofluoride
TABLE 2. Optimization of Alkylation of 2a with Propargyl
Bromide
proportionsa
RBr
additive
(equiv)
entry (equiv) base (equiv) time (h)
2a 3a 4a
1
2
3
4
5
4
4
4
4
8
K2CO3 (10)
K2CO3 (10)
Cs2CO3, 10)
Cs2CO3 (10)
Cs2CO3 (10)
6
4
0.5
0.5
1
0
0
0
70 30
82 18
91
18-C-6 (1)
9
4
4
NaI (8)
NaI (16)
13 83
96
0
a
1
Determined by H NMR.
the formation of compound 4a resulting from elimination of
HN3. The use of a crown ether to accelerate the alkylation
decreased the elimination (entry 2). Changing K2CO3 for the
more basic Cs2CO3 decreased the elimination to 9% and the
reaction time to 30 min (entry 3). Addition of NaI slowed down
the reaction, but the elimination was decreased (entry 4). Finally,
using Cs2CO3 with NaI in the presence of an excess of propargyl
bromide in DMF was a good compromise to obtain compound
3a in 1 h at rt, along with only 4% of elimination product 4a.
For the other substrates, the linear precursors 3 were obtained
along with the elimination compounds 4 in similar proportions
except for substrates 2b and 2e bearing an electron-withdrawing
group on the aryl moiety, for which the elimination was slightly
more significant (Table 1). Compounds 3 were obtained as an
unseparable mixture of anti and syn isomers together with
compound 4.
(21) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565–598. (b)
Huisgen, R. Angew. Chem. 1963, 75, 604–637.
(22) Huisgen, R.; Knorr, R.; Mo¨bius, L.; Szeimies, G. Chem. Ber. 1965, 98,
4014–4021.
With the compounds 3 in hand, we started to explore the
thermal 1,3-dipolar cycloaddition.21,22 A first experiment real-
2006 J. Org. Chem. Vol. 74, No. 5, 2009

SelectiVe [3 + 2] Huisgen Cycloaddition
SCHEME 5. Conformational Analysis of Compound 3a
2.95-3.10 (m, 1H), 3.35-3.65 (m, 2H), 3.70 (s, 3H), 4.65-4.75
(m, 1H), 6.07 (d, 1H, J3 ) 10.0 Hz), 7.20-7.40 (m, 5H); 13C NMR
(CDCl3, Me4Si) δ -2.2, 10.2, 50.0, 50.7, 51.8, 52.6, 57.1, 126.7,
128.7, 129.2, 138.8, 172.1.
General Procedure for Alkylation of Azido-ꢀ-amino Esters
2 and 1,3-Dipolar Cycloaddition of the Intermediate 3. To a
mixture of azido-ꢀ-amino ester 2 (0.35 mmol, 1 equiv), Cs2CO3
(1.14 g, 3.5 mmol, 10 equiv), and NaI (839 mg, 5.6 mmol, 5.6
equiv) in 9.8 mL of DMF was added propargyl bromide (210 µL,
2.8 mmol, 8 equiv). The mixture was stirred at room temperature
for 1 h and then filtered through Celite. The residue was diluted in
AcOEt, washed successively with water and brine, dried over
MgSO4, and evaporated to give the alkylated azido-ꢀ-amino ester
3 as a mixture of anti and syn diastereoisomers and enyne 4. A
solution of crude azido-ꢀ-amino ester 3 in 10 mL of toluene was
heated at 80 °C for 4 h. The solvent was evaporated. Silica gel
chromatography (AcOEt/CH2Cl2) yielded the SES-triazoldiazepine
trans-5.
Methyl 6-Phenyl-5-(2-trimethylsilylethanesulfonyl)-5,6,7,8-
tetrahydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-7-carboxy-
late (trans-5a). Alkylation of azido-ꢀ-amino ester 2a with propargyl
bromide yielded 149.3 mg (quant) of the linear precursor as a yellow
oil (mixture anti/syn/4a ) 79/17/4). Cyclization of the linear
precursor 3a yielded 118.3 mg (77%, two steps) of the title
compound as a white solid (mixture trans/cis ) >99:1) after silica
gel chromatography (CH2Cl2/AcOEt ) 9/1): mp 130-133 °C; IR
salt by NaHCO3 yielded the deprotected bicyclic triazoles
quantitatively (eq 1, Table 1).
1
cm-1 2956 (m), 1742 (s), 1266 (s); H NMR (CDCl3, Me4Si) δ
-0.09 (s, 9H), 0.60-0.90 (m, 2H), 2.65-2.90 (m, 2H), 3.64 (s,
3H), 3.79 (dt, 1H, J3 ) 8.2 Hz, J3 ) 5.0 Hz), 4.47 (d, 1H, J2 )
17.6 Hz), 4.98 (d, 2H, J3 ) 5.0 Hz), 5.00 (d, 1H, J2 ) 17.6 Hz),
5.74 (d, 1H, J3 ) 8.2 Hz), 7.30-7.50 (m, 5H), 7.49 (s, 1H); 13C
NMR (CDCl3, Me4Si) δ -2.0, 10.2, 38.5, 46.8, 48.5, 50.6, 52.9,
61.3, 127.5, 129.2, 129.7, 131.4, 134.1, 136.3, 169.8; ESIMS m/z
437.2 (M + H)+, 459.1 (M + Na)+; FAB+ m/z 437 (M + H)+;
HRMS calcd for C19H29N4O4SSi 437.1679, found 437.1704.
General Protocol for the Deprotection of the SES-triazole 5
with HF. SES-triazolodiazepine 5 (0.1 mmol) was treated with 1
mL of anhydrous HF at 0 °C for 1 h in a Teflon vessel. The HF
was removed by distillation. The HF · triazolodiazepine thus
obtained was neutralized with a saturated aqueous solution of
NaHCO3, and the aqueous phase was extracted three times with
AcOEt, dried over MgSO4, filtered, and evaporated to yield the
triazolodiazepine 6. Caution! HF is a harmful chemical.
In conclusion, we have described an efficient synthesis of
new bicyclic triazoles by sequential azidation/alkylation/1,3-
dipolar cycloaddition/deprotection starting from SES-protected
aza-Baylis-Hillman ꢀ-amino esters. To our knowledge, we have
reported the first example of selective Huisgen cycloaddition,
starting from a mixture of diasteroisomers. The bicyclic triazoles
are obtained in their trans form in good yields and very high
diastereomeric ratios.
Methyl 6-Phenyl-5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[1,5-a]-
[1,4]diazepine-7-carboxylate (trans-6a). Deprotection of the com-
pound trans-5a according to the general procedure yield 27.2 mg
(100%) of the title compound as a white solid (mixture trans/cis
) >99:1): mp >230 °C; IR cm-1 2982 (m), 1732 (s), 1372 (s); 1H
NMR (CDCl3, Me4Si) δ 1.89 (sl, 1H), 3.00 (ddd, 1H, J3 ) 10.4
Hz, J3 ) 9.1 Hz, J3 ) 2.1 Hz), 3.36 (s, 3H), 3.95 (d, 1H, J2 ) 15.6
Hz), 4.23 (d, 1H, J3 ) 9.1 Hz), 4.33 (d, 1H, J2 ) 15.6 Hz), 4.57
(dd, 1H, J2 ) 14.6 Hz, J3 ) 10.4 Hz), 5.09 (dd, 1H, J2 ) 14.6 Hz,
J3 ) 2.1 Hz), 7.20-7.40 (m, 5H), 7.52 (s, 1H); 13C NMR (CDCl3,
Me4Si) δ 41.8, 50.4, 51.7, 52.0, 69.0, 127.2, 128.6, 128.9, 132.0,
137.7, 141.0, 171.2; ESIMS m/z 273.1 (M + H)+; FAB+ m/z 273
(M + H)+; HRMS calcd for C14H17N4O2 273.1352, found 273.1360.
Experimental Section
General Procedure for HN3 Addition on ꢀ-Amino Esters
1. To a solution of ꢀ-amino ester 2 (0.4 mmol, 1 equiv) in toluene
were added azidotrimethylsilane (1.06 mL, 8 mmol, 20 equiv),
acetic acid (137 µL, 2.4 mmol, 6 equiv), and triethylamine (45 µL,
0.32 mmol, 0.8 equiv). The solution was heated for 24 h at 40 °C,
and the solvent was evaporated. Silica gel chromatography (Et2O/
cyclohexane) yielded the corresponding azido-ꢀ-amino ester 2 as
a mixture of anti and syn diastereoisomers.
Methyl 2-(Azidomethyl)-3-phenyl-3-(2-trimethylsilylethane-
sulfonylamino)propanoate (2a). Addition of HN3 on the ꢀ-amino
ester 1a yielded 156.1 mg (98%) of the title compound as a white
solid (mixture anti:syn ) 81:19) after silica gel chromatography
(Et2O/cyclohexane ) 3/7): IR cm-1 2955 (m), 2108 (s), 1740 (s),
1265 (s); ESIMS m/z 399.0 (M + H)+, 421.2 (M + Na)+; FAB+
m/z 398 (M + H)+; HRMS calcd for C16H27N4O4SSi 399.1522,
Acknowledgment. We thank the MENRT and the CNRS for
financial support.
1
Supporting Information Available: Experimental details,
found 399.1518. Anti isomer: H NMR (CDCl3, Me4Si) δ -0.21
1
spectral data, and copies of H and 13C NMR spectra for all
(s, 9H), 0.45-0.85 (m, 2H), 2.40-2.75 (m, 2H), 3.00-3.15 (m,
1H), 3.53 (s, 3H), 3.60-3.75 (m, 2H), 4.70 (dd, 1H, J3 ) 9.8 Hz,
J3 ) 8.3 Hz), 6.03 (d, 1H, J3 ) 9.9 Hz), 7.20-7.40 (m, 5H); 13C
NMR (CDCl3, Me4Si) δ –2.2, 10.1, 49.9, 50.2, 51.8, 52.3, 57.4,
new compounds and X-ray structure and crystal data for
compound 5a. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
127.0, 128.7, 129.1, 138.4, 171.1. Syn isomer: H NMR (CDCl3,
Me4Si) δ -0.20 (s, 9H), 0.45-0.85 (m, 2H), 2.40-2.75 (m, 2H),
JO802533D
J. Org. Chem. Vol. 74, No. 5, 2009 2007