Synthesis and structure-activity relationships of 2-phenyl-1-[(pyridinyl- and piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents

Article abstract of DOI:10.1016/j.bmcl.2008.11.101

Continuous efforts on the synthesis and structure-activity relationships (SARs) studies of modified 1-benzylamino-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents, allowed identification of new 1-[(pyridinyl- and piperidinylmethyl)amino] derivatives with MIC₈₀ values ranging from 1410.0 to 23.0 ng mL^-1 on Candida albicans. These results confirmed both the importance of π-π stacking and hydrogen bonding interactions in the active site of CYP51-C. albicans.

Full text of DOI:10.1016/j.bmcl.2008.11.101

Bioorganic & Medicinal Chemistry Letters 19 (2009) 301–304
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and structure–activity relationships of 2-phenyl-1-[(pyridinyl-
and piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols
as antifungal agents
b
b
a
Francis Giraud a, Rémi Guillon a, Cédric Logé a, , Fabrice Pagniez , Carine Picot , Marc Le Borgne ,
*
Patrice Le Pape b
a Université de Nantes, Nantes Atlantique Universités, Département de Pharmacochimie, Cibles et Médicaments des Infections, de l’Immunité et du Cancer, IICIMED-EA 1155,
UFR de Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France
b Université de Nantes, Nantes Atlantique Universités, Département de Parasitologie et Mycologie Médicale, Cibles et Médicaments des Infections, de l’Immunité et du Cancer,
IICIMED-EA 1155, UFR de Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44035 Cedex 1, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Continuous efforts on the synthesis and structure–activity relationships (SARs) studies of modified 1-
benzylamino-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents, allowed identification
of new 1-[(pyridinyl- and piperidinylmethyl)amino] derivatives with MIC80 values ranging from 1410.0
Received 13 October 2008
Revised 25 November 2008
Accepted 26 November 2008
Available online 3 December 2008
to 23.0 ng mLÀ1 on Candida albicans. These results confirmed both the importance of
hydrogen bonding interactions in the active site of CYP51-C. albicans.
p–p stacking and
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Homology model
Docking
H-bond acceptor
Triazole
Candida albicans
CYP51 inhibitors
Antifungal agents
During the past two decades, the frequency of invasive and sys-
temic fungal infections has increased dramatically due mainly to
Candida species among which Candida albicans, at the origin of
the greatest number of pathologies. Because of their safety profile
and high therapeutic index, azoles are the most widely used and
studied class of antifungal agents. They target the biosynthesis of
ergosterol, a major component of fungal membranes (thereby pre-
venting fungal growth), by inhibiting the cytochrome P450-depen-
In an attempt to find potent azole antifungal agents focused on 1-
benzylamino-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols, we
previously studied compounds bearing H-bond acceptors entities
N
N
N
OH
N
*
dent lanosterol 14
a
-demethylase (CYP51), encoded by the ERG11
N
N
X
R
gene. Unfortunately, azoles are fungistatic against yeasts and the
broad usage of these compounds led to development of resistance
showing the urgent need for new and effective antifungal agents.
Recent studies showed that typical azole inhibitors were able to
fit the putative active site of CYP51 by a combination of heme coor-
N
N
OH
II
N
R
X
*
X = Cl or F
Cl
R = H or CH3
Y
N
R1 = H or Boc
N
dination, hydrogen bonding, p–p stacking and hydrophobic inter-
I
N
actions.1–3 In particular, the receptor-based pharmacophore
model published by Sheng et al.3 highlighted the importance of
Tyr118 and Ser378 residues in the stabilization of the inhibitors
within the channel 2 which is oriented to the FG loop.
OH
Cl
Y = NO2, CN, CF3
R = H or CH3
N
R
*
N
X
R1
III
X
* Corresponding author. Tel.: +33 (0) 240411108; fax: +33 (0) 240412876.
E-mail address: cedric.loge@univ-nantes.fr (C. Logé).
Scheme 1. General structures of synthesized compounds.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.101

302
F. Giraud et al. / Bioorg. Med. Chem. Lett. 19 (2009) 301–304
in para position of the benzyl group (I, Scheme 1). These compounds
showed MIC80 values ranging from 0.37 to 30.0 ng mLÀ1 4
In this letter, we describe our continued efforts in the structure–
activity relationships (SARs) studies toward the identification of
new 1-[(pyridinyl- and piperidinylmethyl)amino] derivatives (II
and III, Scheme 1).
1-[(pyridinylmethyl)amino] derivatives 2a, 2b, 3a, 3b, 4a, and
4b were synthesized from previously described key intermediates
1a or 1b4 by reductive amination with the corresponding pyridin-
ecarboxaldehydes in moderate yields (Scheme 2).5
the commercially available 4-piperidinemethanol 5 with di-tert-
butyl dicarbonate afforded 6 in quantitative yield.6 The primary
alcohol was then converted into aldehyde 7 via a Swern oxidation
using dimethyl sulfoxide, oxalyl chloride and triethylamine.7 Next,
compounds 8a and 8b were prepared from the appropriate amino-
alcohol 1a or 1b according to the procedure described in Scheme
2.8 Removal of the Boc protective group with trifluoroacetic acid
led to amines 9a and 9b.9 Finally, N-methylation was achieved
by reductive amination of 8a and 8b with formaldehyde to afford
two additional products 10a and 10b.10
.
Scheme 3 outlines the general synthesis of 1-[(piperidinylmeth-
yl)amino] derivatives 8a, 8b, 9a, 9b, 10a, and 10b. Treatment of
All these compounds were screened for their antifungal activity
against Candida albicans CA98001 and Aspergillus fumigatus
AF98003 strains. Inhibition growth was measured as previously
described.11 Fluconazole and itraconazole were used as positive
controls. The minimum inhibitory concentration (MIC80) values
(in ng mLÀ1) are presented in Table 1.
N
N
O
N
N
On C. albicans, the biological results are relatively heteroge-
neous (23.0 < MIC80 (ng mLÀ1) < 1410.0). Chlorinated compounds
bearing a pyridine moiety (2a, 3a, and 4a) exhibited significant le-
vel of activity with MIC values 5- to 8-fold lower than that of fluco-
nazole. Fluorinated analogues (2b, 3b, and 4b) are less active
(MIC80 values of 220.0, 130.0, and 83.0 ng mLÀ1, respectively).
Interestingly, replacement of the pyridine ring (4a, MIC80 = 36.0 ng
mLÀ1 and 4b, MIC80 = 83.0 ng mLÀ1) by a piperidine ring (9a, MIC80
= 120.0 ng mLÀ1 and 9b, MIC80 = 1410.0 ng mLÀ1) led to weaker
inhibitors whatever the dihalogenophenyl group. In contrast, the
corresponding N-Boc compounds 8a and 8b considerably improve
the efficacy of this series to reach high inhibitory activities (MIC80
values of 26.0 and 27.0 ng mLÀ1, respectively). Taken together,
these results seem to imply the role of both aromatic and hydrogen
bond interactions within the active site.
N
N
H
OH
OH
N
NH2
N
H
*
*
N
X
X
X
X
X = Cl 1a
X = F 1b
2-pyridine
3-pyridine
4-pyridine
X = Cl 2a (49%)
X = F 2b (30%)
X = Cl 3a (29%)
X = F 3b (30%)
X = Cl 4a (47%)
X = F 4b (25%)
Scheme 2. Preparation of targeted compounds 2a, 2b, 3a, 3b, 4a, and 4b. Reagents
and conditions: 2-pyridinecarboxaldehyde, 3-pyridinecarboxaldehyde (0.50 equiv)
or 4-pyridinecarboxaldehyde (1.00 equiv), NaBH3CN, AcOH/MeOH 2% v/v, CH2Cl2,
rt, 16 h.
OH
H
O
OH
(ii)
(i)
N
N
N
H
Boc
Boc
5
6 (100%)
7 (100%)
N
N
N
N
N
N
N
N
N
OH
OH
OH
NH2
N
N
H
7
*
*
*
H
(iii)
(iv)
X
X
N
X
NH
Boc
X
X
X
X = Cl 9a (69%)
X = F 9b (58%)
X = Cl 1a
X = F 1b
X = Cl 8a (29%)
X = F 8b (25%)
(v)
N
N
N
OH
N
*
X
CH3
N
Boc
X = Cl 10a (88%)
X = F 10b (95%)
X
Scheme 3. Preparation of targeted compounds 8a, 8b, 9a, 9b, 10a, and 10b. Reagents and conditions: (i) Boc2O, CH2Cl2, rt, 1 h 30 min; (ii) oxalyl chloride, DMSO, Et3N, CH2Cl2,
À70 °C to rt, 3 h; (iii) 7, NaBH3CN, AcOH/MeOH 2% v/v, rt, 16 h; (iv) TFA, CH2Cl2, rt, 16 h; (v) HCHO, NaBH3CN, AcOH/MeOH 2% v/v, CH2Cl2, rt, 24 h.

F. Giraud et al. / Bioorg. Med. Chem. Lett. 19 (2009) 301–304
303
Table 1
In vitro antifungal activity of pyridinyl- and piperidinylmethylamino derivatives
N
N
N
N
N
N
OH
OH
N
N
R
*
*
N
N
X
R
X
R1
8-10
2-pyridine (2)
3-pyridine (3)
4-pyridine (4)
X
X
Compound
R
X
R1
MIC80 valuesa (ng mLÀ1
)
Candida albicans CA98001
Aspergillus fumigatus AF98003
2a
2b
3a
3b
4a
4b
8a
8b
H
H
H
H
H
H
H
H
H
H
CH3
CH3
Cl
F
Cl
F
Cl
F
Cl
F
Cl
F
Cl
F
—
—
—
—
—
—
Boc
Boc
H
23.0 ( 4.00)
220.0 ( 24.0)
37.0 ( 0.40)
130.0 ( 35.0)
36.0 ( 0.40)
83.0 ( 17.0)
26.0 ( 1.00)
27.0 ( 5.00)
120.0 ( 40.0)
1410.0 ( 350.0)
39.0 ( 2.00)
153.0 ( 83.0)
190.0 ( 6.0)
—
na
na
na
na
na
na
na
na
na
na
na
na
9a
9b
10a
10b
Fluconazole
Itraconazole
H
Boc
Boc
—
420.0 ( 40.0)
a
Values are means of triplicate, standard deviation is given in parentheses (na, not active; MIC80 >30,000.0 ng mLÀ1).
To investigate the structure-activity relationships, we per-
formed the docking of one of the most active compounds, 2-(2,4-
dichlorophenyl)-1-[(pyridin-4-ylmethyl)amino]-3-(1H-1,2,4-tria-
zol-1-yl)propan-2-ol 4a, in our model of CYP51-C. albicans
(Fig. 1).12 We realized the docking with (S)-configuration since in
a precedent series, these isomers were much more active than
(R)-enantiomers.13 The pyridine ring should exploit an aromatic
stacking interaction with residue Tyr118 but the distances be-
tween the nitrogen atom and key amino acids His377 and Ser378
are too large (higher than 6.00 Å) to allow the formation of an
appropriate hydrogen bond. The reported moderate activities com-
pared to those previously observed for our benzylamine series (I,
Scheme 1),4 are consistent with that observation.
tency (Table 1) and this could be explained by the additional loss
of the interaction with the phenol group of Tyr118.
p–p
Of particular interest are piperidines bearing N-Boc groups
(compounds 8a and 8b; Table 1) compared to compounds lacking
such a substituent. Modeling of 8a suggests a hydrogen bonding
interaction between the carbonyl group and the imidazole side
chain of His377 that could be important for the antifungal activity
(Fig. 2). Even if interaction with Ser378 does not seem to occur, this
result is consistent with the recent predicted pharmacophore
model.3
Finally, all these compounds were inactive on the A. fumigatus
strain whereas an emergence of activity was observed in our pre-
vious benzylamine series (I, Scheme 1), especially for those bearing
a N-methyl group in the linker with MIC80 values ranging from
1960.0 to 2410.0 ng mLÀ1 for the best compounds (Y = NO2 and
Replacement of the pyridine moiety by non-substituted piperi-
dine derivatives 9a and 9b seems to be detrimental for high po-
Figure 1. Docking solution of compound (S)-4a in the active site of CYP51-Candida
albicans. Hip377 is the protonated form of histidine residue.
Figure 2. Docking solution of compound (S)-8a in the active site of CYP51-Candida
albicans.

304
F. Giraud et al. / Bioorg. Med. Chem. Lett. 19 (2009) 301–304
oil) which was used without further purification. 1H NMR (DMSO-d6): d 0.99–
CN).4 Since in this study, only piperidine derivatives 10a and 10b
contain such a substituent, we can speculate that the loss of the
aromatic ring and/or the N-methyl group are sufficient to induce
negative effects within the active site of CYP51-A. fumigatus.
In conclusion, most of these compounds are more active than
fluconazole on theC. albicans strain but are less active than our pre-
viously synthesized 1-benzylamino derivatives bearing H-bond
acceptors entities in para position of the benzyl group,4 thus con-
1.07 (m, 2H), 1.42 (s, 9H), 1.81–1.88 (m, 2H), 2.87–2.97 (m, 2H), 3.79–3.86 (m,
2H), 9.62 (s, 1H). IR (NaCl cmÀ1): 1281 (
t
CAN), 1689 (t C@O), 2931 (t CHaliph.).
8. Synthesis
of
2-(2,4-dichlorophenyl)-1-{[(1-tert-butoxycarbonylpiperidin-4-
yl)methyl]amino}-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (8a). Compound 8a was
prepared from 1a according to the same protocol as described for compound
4a. The right product was obtained in a 26% yield as a brown oil. 1H NMR
(DMSO-d6): d 0.84–0.94 (m, 2H), 1.41 (s, 9H), 1.46–1.48 (m, 1H), 1.51–1.62 (m,
2H), 2.28–2.40 (m, 2H), 2.59–2.71 (m, 2H), 3.06 (d, 1H, 2J = 12.4 Hz), 3.28 (d, 1H,
2J = 12.4 Hz), 3.86–3.94 (m, 2H), 4.66 (d, 1H, 2J = 14.4 Hz), 4.92 (d, 1H,
2J = 14.4 Hz), 5.96 (s, 1H, OH), 7.33 (dd, 1H, 3J = 8.4 Hz, 4J = 2.0 Hz), 7.55 (d,
1H, 3J = 8.4 Hz), 7.56 (d, 1H, 4J = 2.0 Hz), 7.76 (s, 1H), 8.33 (s, 1H). IR (NaCl
firming both the importance of p–p stacking and hydrogen bond-
cmÀ1): 738 (
C@O), 2929, 2960 (
384.2 (MÀBoc).
t
CACl), 1274 (
t
CAN), 1470, 1511, 1600 (
t C@C and t C@N), 1681
ing interactions in the active site of CYP51-C. albicans. However,
even if azoles are known to inhibit mainly CYP51 enzymes, we
can not exclude other mechanisms and only results on CYP51 iso-
lated could confirm our hypotheses. Optimization of those series is
ongoing and will be reported subsequently.
(
t
t
CHaliph.), 3422 (
t
OAH and NAH). MS m/z 484.0 (M+H),
t
9. Synthesis of 2-(2,4-dichlorophenyl)-1-[(piperidin-4-ylmethyl)amino]-3-(1H-1,2,4-
triazol-1-yl)propan-2-ol (9a). To a solution of 8a (240 mg, 0.50 mmol) in 0.3 mL
of dichloromethane was added 0.5 mL of trifluoroacetic acid. The solution was
stirred for 16 h at room temperature. The mixture was basified with NaOH 1 M
and extracted with dichloromethane. The organic layers were combined,
washed with HCl 1 M, dried over anhydrous Na2SO4 and evaporated to get the
right product 9a (69% yield, brown oil). 1H NMR (DMSO-d6): d 0.85–1.03 (m,
2H), 1.33–1.48 (m, 1H), 1.51–1.65 (m, 2H), 2.23–2.45 (m, 4H), 2.84–2.96 (m,
2H), 3.05 (d, 1H, 2J = 12.5 Hz), 3.27 (d, 1H, 2J = 12.5 Hz), 4.65 (d, 1H,
2J = 13.4 Hz), 4.90 (d, 1H, 2J = 13.4 Hz), 5.95 (s, 1H, OH), 7.33 (dd, 1H,
3J = 8.4 Hz, 4J = 2.0 Hz), 7.55 (d, 1H, 3J = 8.4 Hz), 7.56 (d, 1H, 4J = 2.0 Hz), 7.76
References and notes
1. Xiao, L.; Madison, V.; Chau, A. S.; Loebenberg, D.; Palermo, R. E.; McNicholas, P.
M. Antimicrob. Agents Chemother. 2004, 48, 568.
2. Chen, S. H.; Sheng, C. Q.; Xu, X. H.; Zhang, W. N.; He, C. Biol. Pharm. Bull. 2007,
30, 1246.
3. Sheng, C.; Zhang, W.; Ji, H.; Zhang, M.; Song, Y.; Xu, H.; Zhu, J.; Miao, Z.; Jiang,
Q.; Yao, J.; Zhou, Y.; Zhu, J.; Lu, J. J. Med. Chem. 2006, 49, 2512.
4. Giraud, F.; Logé, C.; Pagniez, F.; Crepin, D.; Le Pape, P.; Le Borgne, M. Bioorg.
Med. Chem. Lett. 2008, 18, 1820.
(s, 1H), 8.33 (s, 1H). IR (NaCl cmÀ1): 735 (
1589 ( C@C and C@N), 2929, 2957 ( CHaliph.), 3422 (
m/z 384.4 (M+H).
t
CACl), 1273 (
t
CAN), 1463, 1507,
NAH). MS
t
t
t
t
OAH and t
10. Synthesis of 2-(2,4-dichlorophenyl)-1-{methyl[(1-tert-butoxycarbonylpiperidin-4-
yl)methyl]amino}-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (10a). To a solution of 8a
(835 mg, 1.72 mmol) in 12 mL of methanol and 0.24 mL of acetic acid was
added formaldehyde (30% weight solution, 0.159 mL, 1.72 mmol) under argon
at room temperature. Then sodium cyanoborohydride (130 mg, 2.06 mmol)
was added and the solution was stirred for 24 h. Mixture was diluted with
water and the product was extracted with dichloromethane. Organic layers
were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified on silica gel column chromatography (dichloromethane/
ethanol, 10:1) and compound 10a was obtained in a 88% yield as a yellow
powder. Mp 53–54 °C; 1H NMR (DMSO-d6): d 0.68–0.78 (m, 2H), 1.40–1.50 (m,
12H), 2.09 (s, 3H), 2.18–2.26 (m, 2H), 2.55–2.65 (m, 2H), 2.72 (d, 1H,
2J = 13.7 Hz), 3.33 (d, 1H, 2J = 13.7 Hz), 3.80–3.90 (m, 2H), 4.64 (d, 1H,
2J = 14.3 Hz), 4.86 (d, 1H, 2J = 14.3 Hz), 5.80 (s, 1H, OH), 7.35 (dd, 1H,
3J = 8.5 Hz, 4J = 2.1 Hz), 7.57 (d, 1H, 4J = 2.1 Hz), 7.62 (d, 1H, 3J = 8.5 Hz), 7.79
5. Synthesis of 2-(2,4-dichlorophenyl)-1-[(pyridin-4-ylmethyl)amino]-3-(1H-1,2,4-
triazol-1-yl)propan-2-ol (4a): To
a solution of 1a (486 mg, 1.69 mmol) in
10 mL of methanol and 0.2 mL of acetic acid was added 4-
pyridinecarboxaldehyde (0.16 mL, 1.69 mmol) under argon at room
temperature. Then sodium cyanoborohydride (128 mg, 2.03 mmol) was
added and the solution was stirred for 16 h. Mixture was diluted with water
and product was extracted with dichloromethane. Organic layers were
combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified on silica gel column chromatography (dichloromethane/
ethanol, 10:1) and compound 4a was obtained in a 47% yield as a yellow oil. 1H
NMR (DMSO-d6): d 3.00 (d, 1H, 2J = 12.2 Hz), 3.28 (d, 1H, 2J = 12.2 Hz), 3.70 (s,
2H), 4.69 (d, 1H, 2J = 14.7 Hz), 4.92 (d, 1H, 2J = 14.7 Hz), 5.94 (s, 1H, OH), 7.28 (d,
2H, 3J = 5.8 Hz), 7.34 (dd, 1H, 3J = 8.6 Hz, 4J = 2.1 Hz), 7.54 (d, 1H, 4J = 2.1 Hz),
7.57 (d, 1H, 3J = 8.6 Hz), 7.75 (s, 1H), 8.32 (s, 1H), 8.49 (d, 2H, 3J = 5.8 Hz). IR
(s, 1H), 8.33 (s, 1H). IR (KBr cmÀ1): 803 (
1688 ( C@O), 2931 ( CHaliph.), 3429 (
11. Pagniez, F.; Le Pape, P. J. Mycol. Med. 2001, 11, 73.
t
CACl), 1277 (
t CAN), 1455 (t C@C),
(NaCl cmÀ1): 806 (
2930, 2955 ( CHaliph.), 3340 (
t
CACl), 1271 (
t CAN), 1460, 1506, 1603 (t C@C and t C@N),
OAH). MS m/z 498.0 (M+).
t
t
OAH). MS m/z 378.0 (M+).
t
t
t
6. Synthesis of N-tert-butoxycarbonyl-4-hydroxymethyl piperidine (6). To a solution
of 4-piperidinemethanol 5 (1 g, 8.68 mmol) in 10 mL of dichloromethane was
added di-tert-butyl dicarbonate (2.08 g, 9.55 mmol). The solution was stirred
for 1.5 h at room temperature. Mixture was diluted with water and product
was extracted with dichloromethane. Organic layers were combined, dried
over anhydrous Na2SO4 and evaporated to get the right product 6 (quantitative
yield, white powder) which was used without further purification. Mp 74–
75 °C; 1H NMR (DMSO-d6): d 0.91–1.07 (m, 2H), 1.42 (s, 9H), 1.62–1.65 (m, 2H),
2.59–2.84 (m, 2H), 3.27 (t, 2H, 3J = 5.2 Hz), 3.94–3.99 (m, 2H), 4.50 (t, 1H,
12. Giraud, F. Ph.D. Thesis, Université de Nantes, Nantes Atlantique Universités,
October 2007. Briefly, the structure of CYP51 from Mycobacterium tuberculosis
complexed with fluconazole (PDB code, 1EA1) was used as the template for the
homology model of CYP51-C. albicans. Multiple alignment of the CYP51-
Mycobacterium tuberculosis sequence with those of CYP51-C. albicans (PIR code,
P10613) and CYP51-A. fumigatus (PIR code, Q9P8R0) was performed using
ClustalW. This alignment was further checked by comparing a secondary
structure elements prediction for CYP51-C. albicans, obtained through the
PSIPRED protein structure prediction server (UCL, Department of Computer
Science, Bioinformatics Group, London), with the experimental secondary
structure assignments for CYP51-M. tuberculosis deduced from the PDB file. The
3D model of CYP51-C. albicans was then constructed by the Nest program from
the protein structure modeling package JACKAL (Honig Lab, Columbia
University, New York). The resulting model was further subjected to an
energy minimization using Powell’s method available in Maximin2 procedure
with the MMFF94 force field and a dielectric constant of 4.0 until the gradient
value reached 0.1 kcal/mol Å. During the optimization procedure, the structure
was checked periodically by Verify-3D and Ramachandran plots. If present,
improper geometries were manually corrected and the structure minimized
again with the above procedure.
3J = 5.2 Hz, OH). IR (KBr cmÀ1): 1256 (
CHaliph.), 3472 ( OAH).
7. Synthesis of N-tert-butoxycarbonyl-4-formyl piperidine (7). To
t CAN), 1671 (t C@O), 2940, 2961 (t
t
a
solution of
dimethyl sulfoxyde (1.42 mL, Synthesis of N-tert-butoxycarbonyl-4-formyl
piperidine (7). To a solution of dimethyl sulfoxyde (1.42 mL20.05 mmol) in
10 mL of dichloromethane at À70 °C was added dropwise successively
a
solution of oxalyl chloride (0.96 mL, 11.03 mmol) in 30 mL of dichloromethane,
and a solution of 6 (2.16 g, 10.02 mmol) in 10 mL of dichloromethane. The
mixture was stirred for 15 min at À70 °C, and then triethylamine (7.27 mL,
52.12 mmol) was added. After being stirred for 1 h at À70°C, the resulting
solution was allowed to reach to room temperature. Mixture was diluted with
water and product was extracted with dichloromethane. Organic layers were
combined, washed with saturated sodium bicarbonate, dried over anhydrous
Na2SO4 and evaporated to get the right product 7 (quantitative yield, colorless
13. Lebouvier, N. Ph.D. Thesis, Université de Nantes, Nantes Atlantique Universités,
October 2004.