Synthesis of the hindered N,N,N′-trisubstituted guanidine moiety of martinelline and martinellic acid

Article abstract of DOI:10.1016/S0040-4039(01)00206-4

Hindered guanidines can be prepared by reaction of cyanamides with amines in hexafluoroisopropanol at 90-120°C. This sequence was used for preparing guanidinium acid 21 as a model for martinellic acid.

Full text of DOI:10.1016/S0040-4039(01)00206-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2455–2458
Synthesis of the hindered N,N,N%-trisubstituted guanidine moiety
of martinelline and martinellic acid
Barry B. Snider* and Sean M. O’Hare
Department of Chemistry, MS 015, Brandeis University, Waltham, MA 02454-9110, USA
Received 30 January 2001; revised 1 February 2001; accepted 6 February 2001
Abstract—Hindered guanidines can be prepared by reaction of cyanamides with amines in hexafluoroisopropanol at 90–120°C.
This sequence was used for preparing guanidinium acid 21 as a model for martinellic acid. © 2001 Elsevier Science Ltd. All rights
reserved.
Martinellic acid (1a) and martinelline (1b) were isolated
by Witherup, Varga and co-workers at Merck Research
Laboratories from the roots of the tropical plant Mar-
tinella iquitosensis.1 These alkaloids are the first natu-
rally occurring nonpeptide bradykinin B1 and B2
receptor antagonists. The novel tricyclic pyrrolo[3,2-
c]quinoline core has been the object of intense synthetic
effort.2 We have developed an eight-step synthesis of
the model triamine 2, which proceeds in 11% overall
yield from 2-hydroxymethylaniline.3 Construction of
the N,N%-disubstituted guanidine on the side chain of 2
could be easily achieved.4 Formation of the N,N,N%-
trisubstituted guanidine from the hindered pyrrolidine
proved to be much more challenging.
thiourea using EDC6b,m afforded none of the guani-
dine, while use of HgCl2 and Et3N in THF6i
afforded approximately 20% of the Boc-protected
guanidine.
We decided to prepare the cyanamide from the hin-
dered pyrrolidine with the expectation that this reaction
would be clean because cyanogen bromide is both less
hindered and more electrophilic than guanidinylating
agents. However, addition of prenylamine to the
cyanamide may not be straightforward. Although addi-
tions of amines to cyanamides to form guanidines have
been known since the work of Von Braun, harsh condi-
tions are usually required for this reaction.7
HN
1a, R = H
H
N
HN
NH2
NH
HN
O
N
2
1b, R =
R
O
NH2
H
N
H
N
N
H
N
H
NH
We therefore chose to carry out model studies using
2-phenylpyrrolidine (3b)5 as a model for the pyrrolidine
of 2. Guanidinylation of 3b proved to be quite challeng-
ing despite the numerous methods developed to prepare
N,N%-polysubstituted guanidines in the past decade.6
For instance, reaction of 3b with N-butyl-N%-(Boc)-
Reaction of pyrrolidine (3a) with a slight excess of
cyanogen bromide and 3 equiv. of NaHCO3 in EtOH
for 2 h afforded 96% of crude cyanamide 4a, which was
used without purification. Reaction of n-BuNH2 (5a)
with 4a was investigated in several solvents. No
guanidine was formed in THF, MeOH, CH3CN,
t-BuOH, or CH3NO2 at reflux or in DMF at 100°C.
We chose to investigate fluorinated alcohols since their
polarity should facilitate the addition, while their lack
of nucleophilicity should retard the formation of
O-fluoroalkyl isoureas. Reaction of 4a with n-BuNH2
Keywords: guanidines; alkaloids; cyanides.
* Corresponding author. Fax: 781-736-2516; e-mail: snider@
brandeis.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00206-4

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B. B. Snider, S. M. O’Hare / Tetrahedron Letters 42 (2001) 2455–2458
in trifluoroethanol in a sealed tube at 90°C for 17 h
afforded a 2:1:2 mixture of the desired guanidine 6aa,
the O-trifluoroethyl isourea and recovered 4a indicating
the validity of this approach. Optimal results were
obtained with the more polar, less nucleophilic solvent,
hexafluoroisopropanol (HFIP). Reaction of 4a with 1.1
equiv. of n-BuNH2 as a 0.1 M solution in HFIP in a
sealed tube at 90°C for 12 h afforded 85% of pure
guanidine 6aa. The guanidine was easily purified by
dissolution in aqueous citric acid and extraction of the
non-basic impurities into ether. The aqueous layer was
basified with 20% aqueous KOH solution and the
guanidine was extracted into CH2Cl2 to give 6aa that
Guanidines 7a (80°C, 12 h, 91%), 7b (130°C, 18 h,
64%), and 811 (100°C, 14 h, 92%) were prepared by
heating the appropriate cyanamide and amine in HFIP.
Tricyclic pyrrolidine 11 was prepared as a better model
for 2 by condensation of 2-allyloxybenzaldehyde (9a)
with N-benzylglycine·NaCl to give 66% of 10a.4,12
Hydrogenolysis over Pd(OH)2 afforded 80% of 11.4,12c
Condensation of 11 with CNBr and NaHCO3 in EtOH
afforded 96% of cyanamide 12. Reaction of 12 with
prenylamine in HFIP at 120°C for 16 h provided 70%
of the required guanidine 13 indicating the suitability of
this method for the synthesis of the trisubstituted
guanidine of martinelline and martinellic acid.
1
was >95% pure by H NMR spectroscopy.
R1
R1
CNBr, NaHCO3
EtOH, 2 h, 25 °C
R1
(CF3)2CHOH
heat
NH
NH
R2NH2
+
N C N
N C
NHR2
6aa, R1 = H, R2 = n-Bu (85%)
6ba, R1 = Ph, R2 = n-Bu (86%)
6bb, R1 = Ph, R2 = prenyl (88%)
5a, R2 = n-Bu
5b, R2 = prenyl
3a, R1 = H
3b, R1 = Ph
4a, R1 = H (96%)
4b, R1 = Ph (98%)
R
NH
NH
N
8 (92%)
7a, R = H (91%)
7b, R = CH2OMe (64%)
O
N
N C
N
O
N
R
Bn
N
R
O
HN
HN
(1) H2, Pd(OH)2
prenylamine
(CF3)2CHOH
120 °C, 16 h
R
CH2
R
MeOH/HCl
BnNHCH2CO2H•NaCl
toluene, reflux, 14 h
N
(2) CNBr,NaHCO3
EtOH
O
O
O
9a, R = H
9b, R = Br
10a, R = H (66%)
10b, R = Br (61%)
11, R = H (80%)
12, R = CN (96%)
O
13 (70%)
Fortunately, comparable results were obtained with
more hindered 2-phenylpyrrolidine (3b). Condensation
of 3b with cyanogen bromide and NaHCO3 in EtOH
afforded 98% of cyanamide 4b.8 Reaction of 4b with
n-BuNH2 in HFIP at 90°C for 11 h gave 86% of pure
guanidine 6ba. We were initially surprised to find that
4b did not react with prenylamine (5b)9 under these
conditions. However, the allylic double bond is elec-
tron-withdrawing making allylamine 15 times less basic
than propylamine.10 Therefore prenylamine should be
less nucleophilic than n-BuNH2. Guanidine formation
was achieved by heating 4b with prenylamine in HFIP
at 130°C in a sealed tube for 18 h to give 88% of the
pure model guanidine 6bb.8 Attempted preparation of
guanidines 6ba and 6bb by reaction of the cyanamide
prepared from 5a or 5b with 3b in HFIP at 90–120°C
for 12–48 h proceeded in only 25–50% yield, indicating
that the hindered secondary amine, rather than the
primary amine, should be converted to the cyanamide.
N,N,N%,N%-tetrasubstituted guanidines can be prepared
by addition of secondary amines to cyanamides.
We investigated the preparation of guanidine 16 to
determine whether an ester was stable to the high
temperature needed for the addition of the amine to the
cyanamide. Reaction of 14 with CNBr afforded 90% of
cyanamide 15, which was treated with n-BuNH2 (90°C,
17 h) or prenylamine (105°C, 14 h) to give ester
guanidines 16a (80%) and 16b (71%), respectively. This
indicates that aminolysis of the methyl ester to give the
amide does not occur at 90–105°C.
Pyrrolidine ester 18 was prepared to complete the model
study. Condensation of 2-allyloxy-5-bromobenzalde-
hyde (9b)13 with N-benzylglycine·NaCl gave 61% of 10b.
Halogen–metal exchange with t-BuLi and trapping with
14
CO2 gave the acid, which was refluxed in HCl/MeOH
to give 53% of ester 17. Hydrogenolysis afforded 85% of
pyrrolidine 18,8 which was condensed with CNBr to
give 99% of cyanamide 19.8 Reaction of 19 with prenyl-
amine in HFIP at 120°C for 14 h afforded 84% of the
desired ester guanidine 20,8 indicating that this proce-
dure is compatible with the ester of martinelline.

B. B. Snider, S. M. O’Hare / Tetrahedron Letters 42 (2001) 2455–2458
2457
MeO2C
MeO2C
CNBr, NaHCO3
MeO2C
(CF3)2CHOH
heat
H
N
H
N
NHR
NH
RNH2
+
NH2
Bn
C
EtOH, 2 h, 25 °C
5a, R = n-Bu
N
5b, R = prenyl
15 (90%)
16a, R = n-Bu (80%)
16b, R = prenyl (71%)
14
R
(1a) t-BuLi, then CO2
N
C
N
N
(1b) MeOH/HCl
(2) H2, Pd(OH)2
MeOH/HCl
N
CNBr
NaHCO3
EtOH
MeO2C
Br
MeO2C
O
O
O
17, R = Bn (53%)
18, R = H (85%)
10b
19 (99%)
prenylamine
(CF3)2CHOH
120 °C, 14 h
OTFA
HN
H2N
HN
HN
DOWEX 550A (HO-)
MeOH 60 °C, 12 h
then TFA
N
N
HO2C
MeO2C
20 (84%)
21 (73%)
O
O
We needed to hydrolyze the ester of 20 to complete the
model study. Since guanidines are stable in acid, but
hydrolyze to ureas in base we initially investigated acid
cleavage of the methyl ester. Unfortunately, no hydro-
lysis occurred after 2.5 h in 1:1 CH2Cl2/TFA at reflux,
but the double bond was partially decomposed. Heat-
ing a solution of 20 in 9:1 1 M HCl/MeOH at 60°C for
2 h completely decomposed the double bond without
hydrolyzing the ester. Basic hydrolysis of the ester is
complicated by the problem of separation of a guani-
dino acid from inorganic salts. We therefore hydrolyzed
20 by heating with Dowex 550A resin in the hydroxide
form15 in MeOH at 60°C for 12 h. The MeOH was
discarded and the resin, to which was complexed the
carboxylate salt of 21, was suspended in D2O. The
solution was acidified with TFA, stirred for 45 min,
filtered and concentrated to afford 73% of pure acid
guanidinium salt 218 with spectral data similar to those
of martinellic acid.
son, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem.
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In conclusion, we have developed a general new
method for the synthesis of hindered guanidines by
reaction of cyanamides with amines in HFIP at 90–
120°C and shown that this procedure can be used to
prepare the hindered N,N,N%-trisubstituted guanidine of
martinellic acid and martinelline.
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Acknowledgements
We are grateful to the National Institute of General
Medical Sciences, National Institutes of Health for
financial support.
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2.16–2.05 (m, 1), 1.79 (s, 3), 1.75 (s, 3); 13C NMR: 157.8,
154.8, 131.4, 131.2, 120.6, 120.1, 117.7, 117.5, 65.1, 54.4,
46.6, 40.1, 36.2, 24.9, 23.9, 17.3 (2 quaternary carbons
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1
8. 4b: H NMR: 7.38 (dd, 2, J=7.2, 7.2), 7.33–7.29 (m, 3),
4.66 (dd, 1, J=7.3, 7.3), 3.72 (ddd, 1, J=7.2, 7.2, 6.8),
3.62–3.57 (m, 1), 2.38–2.30 (m, 1), 2.10–1.95 (m, 2),
1.92–1.83 (m, 1); 13C NMR: 139.7, 128.8 (2 C), 128.2,
126.3 (2 C), 116.9, 65.9, 51.4, 35.5, 24.8; IR 2211. 6bb: 1H
NMR: 7.35–7.31 (m, 2), 7.27–7.23 (m, 3), 5.07 (br t, 1,
J=6.7), 4.75 (dd, 1, J=7.9, 3.2), 3.68–3.55 (m, 2), 3.61
(br d, 2, J=6.7), 2.40–2.31 (m, 1), 2.00–1.81 (m, 3), 1.64
(s, 3), 1.52 (s, 3); 13C NMR: 157.9, 144.0, 135.4, 128.7 (2
C), 127.2, 125.6 (2 C), 121.2, 61.2, 47.8, 40.2, 36.3, 25.5,
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1
(M+) 257.1892, found 257.1889. 18: mp 77.5–78.5°C; H
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J=8.5), 4.16 (dd, 1, J=11, 4.3), 4.00 (d, 1, J=6.1), 3.87
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5), 2.97 (ddd, 1, J=9, 9, 9), 2.56–2.47 (m, 1), 2.19–2.07
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15. A column of Dowex 550A resin was pretreated with 20
volumes of 20% NaOH followed by 5 volumes of H2O
and 5 volumes of MeOH. The resin was dried under a
flow of air for 1 h.
1
51.8, 44.9, 35.4, 27.9; IR 1714. 19: H NMR: 8.16 (d, 1,
J=2.4), 7.95 (dd, 1, J=8.5, 2.4), 6.94 (d, 1, J=8.5), 4.55
(d, 1, J=6.1), 4.20 (dd, 1, J=11.0, 4.2), 3.89 (s, 3), 3.85
(dd, 1, J=11.0, 9.8), 3.57 (apparent t, 2, J=6.7), 2.72–
2.62 (m, 1), 2.32–2.23 (m, 1), 1.95–1.87 (m, 1); 13C NMR:
166.3, 158.0, 132.9, 131.8, 123.5, 118.4, 117.3, 116.4, 65.1,
1
57.5, 52.1, 48.5, 35.3, 26.0; IR 2208, 1714. 20: H NMR:
8.50 (br s, 1, J=8.5), 7.80 (dd, 1, J=8.5, 1.8), 6.79 (d, 1,
J=8.5), 5.49 (d, 1, J=7.3), 5.30 (br t, 1, J=6.7), 4.29
(dd, 1, J=11.6, 2.4), 4.24 (dd, 1, J=11.6, 2.4), 3.89 (s, 3),
3.77 (d, 2, J=6.7), 3.43 (ddd, 1, J=8.5, 8.5, 8.5), 3.36–
3.31 (m, 1), 2.62–2.55 (m, 1), 2.14–2.07 (m, 2), 1.76 (s, 3),
1.73 (s, 3); 13C NMR: 166.9, 157.5, 132.9, 129.9, 123.4,
.
.