Methods for the construction of new highly functionalised guanidines

Article abstract of DOI:10.1055/s-2004-829561

In this study, we present a fast and chemoselective protocol to highly functionalised guanidines. Guanidines containing a hydroxy function were constructed in the microwave by regioselective ring opening of epoxides in the presence of ammonium hydroxide giving the primary amines, which then were reacted with isothiouronium salts. Direct coupling of an unsubstituted guanidine with an epoxide in the presence of n-BuLi gave the same product.

Full text of DOI:10.1055/s-2004-829561

LETTER
1817
Methods for the Construction of New Highly Functionalised Guanidines
Methods
f
or the
r
C
onstru
i
ction o
c
f
N
ew Highly Fu
W
G
uanidinesellner, Helena Sandin,* Marie-Louise Swanstein
Active Biotech AB, Department of Drug Discovery, Box 724, 22007 Lund, Sweden
Fax +46(46)191246; E-mail: helena.sandin@activebiotech.com
Received 30 April 2004
opening of the racemic epoxides 1 in the presence of
ammonium hydroxide at 100 °C for 200 seconds in a mi-
crowave.5 Under these conditions, the formation of the
secondary alcohols 2a (93%) and 2b (95%) was favoured,
Abstract: In this study, we present a fast and chemoselective pro-
tocol to highly functionalised guanidines. Guanidines containing a
hydroxy function were constructed in the microwave by regioselec-
tive ring opening of epoxides in the presence of ammonium hydrox-
ide giving the primary amines, which then were reacted with while the generation of the regioisomeric primary alco-
isothiouronium salts. Direct coupling of an unsubstituted guanidine
with an epoxide in the presence of n-BuLi gave the same product.
hols 3a (3%) and 3b (4%) played only a minor role
(Scheme 1).
Key words: amino alcohols, epoxides, chemoselectivity, regio-
The amines were then reacted with the isothiouronium
selectivity, ring opening
salts 53 to yield the major products 6 (Scheme 2). In the
13C NMR of 6c, the signals at d = 155.2 and 65.9 ppm
could be assigned to C-2 and C-2¢ (see Scheme 2) using
Guanidines are frequently used in medicinal chemistry1
DEPT, HMBC and HMQC. From this assignment it was
due to their interesting biological and pharmacological
however not possible to determine the absolute constitu-
properties. While the access to acyclic guanidines is well
tion.
studied and documented, the synthesis of cyclic
Since it is known that both the amino group and the hy-
droxy group could function as nucleophiles,3 we wanted
to examine the chemoselectivity of the reaction to prove
the formation of 6. Therefore, the hydroxy group of 2
was protected with tert-butyldimethylsilyl chloride
(Scheme 1) to give the silyl ethers 4 in excellent yields
(4a: 95%, 4b: 99%). The coupling of the amines 4 with the
TFA salts 5 was performed in the microwave at 160 °C for
600 seconds. The excess amount of the amine was scav-
enged using methylisocyanate on resin.6 To avoid the
deacetylation of 6b and 6d, the desilylation was generally
achieved under mild conditions using MeOH–5 M HOAc
(aq) 1:2. The 1H NMR and the 13C NMR spectra of the iso-
lated products 6 generated via path A and path B were
identical proving the chemoselectivity of the reaction path
A (Scheme 2, Table 1).7
guanidines is often difficult and time consuming.1b,2 Usu-
ally, they can be obtained from isothiouronium salts and
primary amines.2 Recently, we reported a fast and easy
route to substituted and unsubstituted cyclic guanidines,
which substantially shortens the reaction time.3 In contin-
uation of our previous work in this field, we were parti-
cularly interested in expanding the scope of this
methodology towards b-hydroxy-alkyl-guanidines. An-
other objective in this study was to investigate the alkyla-
tion of N,N¢-disubstituted guanidines using epoxides as
alkylating agent.4 This would afford highly functionalised
guanidines in one step starting from commercially avail-
able epoxides.
Initially, we were interested in the construction of hydrox-
ylated primary amines. In the first step of the process, the
amine derivatives 2 were prepared by regioselective ring
NH4OH/MeOH
O
OH
NH2
O
+
H2N
O
HO
O
100 °C, 200 s
microwave
R
R
R
1
3
2
TBDMSCl
imidazole
THF
70 °C
18 h
1a, 2a, 3a, 4a: R = p-Cl
1b, 2b, 3b, 4b: R = o-NHAc
TBDMS
H2N
4
O
O
R
Scheme 1
SYNLETT 2004, No. 10, pp 1817–1819
0
9
.0
8
.2
0
0
4
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829561; Art ID: G09804ST
© Georg Thieme Verlag Stuttgart · New York

1818
E. Wellner et al.
LETTER
R
1
5
R´
Cl
O
2, MeCN
R´
Cl
O
NH
NH
1´
2´
160 °C, 600 s
Path A
N
S
2
N
N
O
H
H
H
OH
CF3COO
5
CF3COO
6
160 °C,
600 s
70 °C
4, MeCN
MeOH /5M HOAcaq
(1:2)
R
R´
Cl
O
NH
Path B
N
N
O
H
H
O
TBDMS
CF3COO
7
Scheme 2
Table 1 Reaction of Isothiuronium Salts 5 with Primary Amines 2
and 4 and Yield of 6 (%)
In conclusion, we have developed two fast pathways for
the preparation of highly functionalised guanidines.
While the chemoselective pathway A using amino-alco-
hols is more straightforward, the yields substantially in-
creased applying silyl ethers as staring material (path B).
Both approaches are expected to be readily adaptable to
the synthesis of other b-hydroxy-alkyl-guanidines. Fur-
ther, we have presented a fast and regioselective ring
opening of epoxides using microwave-assisted chemistry.
TFA salt
2a
2b
4a
4b
(R = p-Cl) (R = o-NHAc) (R = p-Cl) (R = o-NHAc)
5a (R¢ = H) 6a (56)
5b (R¢ = Cl) 6c (43)
6b (31)
6d (39)
6a (70)a
6c (54)a
6b (65)a
6d (63)a
a Over two steps with 7 as intermediate.
Next, we focused our efforts on the direct coupling8 of the
unsubstituted guanidine 83 and the epoxide 1a avoiding
the construction of the primary amines 2. Heating the mix-
ture of compound 8 and 1a with EtOH as solvent in the
microwave at 120 °C for 300 seconds failed to produce
the alcohol 9 in an epoxide opening reaction. At higher
temperatures (160 °C) decomposition of the building
blocks occurred. These results demonstrated the low reac-
tivity of guanidines towards electrophilic reagents. To in-
crease the nucleophilicity, n-BuLi was added to a solution
of compound 8 in THF at –78 °C (Scheme 3). A stabilisa-
tion of the guanidine moiety with electron withdrawing
groups to support the delocalisation of the negative charge
was not necessary.9 The crude product of this reaction re-
vealed a complex mixture of starting materials, compound
9 and by-products.10 After flash column chromatography
the guanidine 9 could be isolated in 19% yield. The poor
yield of this reaction makes this method less efficient than
the guanylation of the isothiouronium salts.
Compound 5 was synthesised3 in 3 steps from 2-hydroxy-1,3-di-
amino-propane and the appropriate fluorobenzene with an overall
yield of 40%.
General Procedure for the Preparation of 2: A solution of ep-
oxide 1 (1 mmol) in MeOH (3 mL) and NH4OH (1 mL) was heated
in the microwave at 100 °C for 200 s. The solvent was removed in
vacuo and the residue was submitted to flash column chromatogra-
phy (CH2Cl2:MeOH:NH4OH, 9:1:0.1) to give the pure isolated
product 2.
1
Selected Data for Compound 2a: H NMR (400 MHz, CDCl3):
d = 7.20 (2 H, d, J = 9.0 Hz, H-Arom.), 6.81 (2 H, d, J = 9.0 Hz, H-
Arom.), 3.93–3.88 (3 H, m, CH-OH, CH2-O), 2.93–2.77 (2 H, m,
CH2N). ESI-MS: m/z (%) = 202 (100) [M + H+].
General Procedure for the Preparation of 4: To a solution of
amine 2 (0.32 mmol) in THF (3 mL) tert-butyldimethylsilylchloride
(57 mg, 0.38 mmol) and imidazole (31 mg, 0.45 mmol) were added
and the reaction mixture was stirred overnight at r.t. The solvent
was removed in vacuo, CHCl3 was added and washed with 1 M aq
NaOH. The solvent was removed under reduced pressure and the
residue submitted to flash column chromatography (CH2Cl2:
MeOH:Et3N, 10:1:0.1%) to give the pure isolated product 4.
1
Selected Data for Compound 4a: H NMR (400 MHz, CDCl3):
Cl
R´´
d = 7.23 (2 H, d, J = 9.0 Hz, H-Arom.), 6.83 (2 H, d, J = 9.0 Hz, H-
Arom.), 4.02 (1 H, mc, CHOH), 3.90 (2H, mc, CH2O), 2.94–2.81 (2
H, m, CH2N), 0.92 [9 H, s, C(CH3)3], 0.14 (3 H, s, CH3), 0.11 (3 H,
s, CH3). ESI-MS: m/z (%) = 317 (100) [M + H+].
BuLi, 1a
N
R´´
N
O
N
NH2
–78 °C, THF
H
N
N
H
H
OH
General Preparation for the Compounds 6 and 7: To a solution
of the amine 2 (or 4) (0.12 mmol) in MeCN (600 mL) 5 (0.1 mmol)
was added and the mixture was heated at 160 °C for 600 s in the mi-
crowave. THF–MeCN (3:1, 2 mL) and Wang resin11 (2.5 equiv)
were added and the mixture was heated for additional 1000 s at
150 °C in the microwave. To remove the excess amine methyliso-
cyanate on resin (3 equiv) were added and the mixture was agitated
8
9
R´´ = p-ClC6H4O
Scheme 3
Synlett 2004, No. 10, 1817–1819 © Thieme Stuttgart · New York

LETTER
Methods for the Construction of New Highly Functionalised Guanidines
1819
for 3 h at r.t. The resins were filtered off, washed with MeOH and
CH2Cl2 and the filtrate was concentrated in vacuo to give 6 and 7.
The silyl ether 7 was deprotected in a mixture of MeOH (1 mL) and
5 M aq HOAc (2 mL) at 70 °C overnight. The solvent was removed
and the residue triturated in Et2O to give the desilylated product 6.
Selected Data for Compound 6a: 1H NMR (500 MHz, DMSO-d6):
d = 9.27 (1 H, br s, NH), 7.26–7.21 (4 H, m), 6.83–6.81 (4 H, m),
4.63 (1 H, br s, H-5), 4.19 (1 H, br s, H-2¢), 3.94 (2 H, d, J = 5.5 Hz,
H-3¢), 3.55–3.36 (6 H, m, H-4,6, H-1¢). 13C NMR (125 MHz,
CDCl3): d = 156.6, 155.1, 154.4, 129.9, 129.5, 126.6, 118.2, 117.9,
115.8, 70.2, 69.3, 65.9, 44.7, 42.0. ESI-MS: m/z (%) = 411 (100)
[M + H+].
Selected Data for Compound 6b: 1H NMR (400 MHz, DMSO-d6):
d = 7.74 (1 H, d, J = 6.7 Hz, H-Arom.), 7.30 (2 H, d, J = 9.0 Hz,
H-Arom.), 7.10–6.94 (3 H, m, H-Arom.), 6.98 (2 H, d, J = 9.0 Hz,
H-Arom.), 4.90 (1 H, mc, H-5), 4.14 (1 H, mc, H-2¢), 4.05 (2 H, mc,
H-3¢), 3.53–3.43 (6 H, m, H-4,6, H-1¢), 2.17 (3 H, s, CH3). ESI-MS:
m/z (%) = 434 (100) [M + H+].
References
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1
Selected Data for Compound 6c: H NMR (500 MHz, CDCl3):
d = 7.35 (1 H, d, J = 8.8 Hz, H-Arom.), 7.23 (2 H, d, J = 8.9 Hz, H-
Arom.), 7.00 (1 H, d, J = 2.8 Hz, H-Arom.), 6.82 (2 H, d, J = 8.9 Hz,
H-Arom.), 6.75 (1 H, dd, J = 8.8, 2.8 Hz, H-Arom.), 4.66 (1 H, mc,
H-5), 4.20 (1 H, br s, H-2¢), 3.94 (2 H, mc, H-3¢), 3.57–3.47 (5 H, m,
H-4,6, H-1¢), 3.39–3.34 (1 H, m, H-1¢). 13C NMR (125 MHz,
CDCl3): d = 156.6, 155.2, 154.8, 133.5, 131.2, 129.6, 126.7, 118.4,
116.1, 115.8, 70.4, 69.3, 65.9, 44.6, 42.0. ESI-MS: m/z (%) = 446
(100) [M + H+].
Procedure for the Preparation of 9: To a solution of 83 (0.2 mmol,
45 mg) in THF (dry, 3 mL) n-BuLi (100 mL, 2 M in hexane) was
added at –78 °C. After 30 min, the epoxide 1a (0.2 mmol, 37 mg)
was added and the mixture was allowed to attain r.t. overnight. After
concentration in vacuo and flash column chromatography (CH2Cl2:
MeOH:NH4OH, 90:10:1) the guanidine 9 was obtained in 19%
yield. Protonation of 9 in CH2Cl2–THF (1:1) gave the TFA salt. 1H
NMR, 13C NMR spectra as well as the mol peak in mass spectrom-
etry are identical to 6a.
(7) Using protected building blocks (path B), the reaction
performed less sluggishly leading to a substantially increase
in yield.
(8) Fahmy, H. H.; Soliman, G. A. Arch. Pharmacal. Res. 2001,
24, 180.
(9) Chen, B.-C.; Quinlan, S. L.; Reid, J. G.; Jass, P. A.;
Robinson, T. P.; Early, W. A.; Delaney, E. J.; Humora, M. J.
M. Tetrahedron: Asymmetry 1998, 9, 1337.
(10) NMR spectroscopy indicates also the formation of a by-
product with unsymmetrical ring substitution. Attempts to
isolate this compound failed.
(11) The addition of Wang resin ensures the removal of the
unreacted isothiouronium salt. This underlines the
ambivalent reactivity of the starting material 5 towards
alcohols3 and amines under microwave conditions.
Synlett 2004, No. 10, 1817–1819 © Thieme Stuttgart · New York