A novel, facile methodology for the synthesis of N,N′-bis(tert-butoxycarbonyl)-protected guanidines using polymer-supported carbodiimide

Article abstract of DOI:10.1016/S0040-4039(02)01390-4

A novel methodology for the synthesis of guanidines from amines has been developed using polymer assisted synthesis, potentially allowing the preparation of series of compounds in a high throughput manner. The methodology comprises the use of polymer-supported carbodiimide as the activating agent for N,N′-bis(tert-butoxycarbonyl) thiourea with polymer-supported trisamine as a scavenger, followed by deprotection with trifluoroacetic acid. For the first time, polymer-supported carbodiimide has been utilized as an activating agent to synthesize guanidines.

Full text of DOI:10.1016/S0040-4039(02)01390-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7105–7109
A novel, facile methodology for the synthesis of
N,N%-bis(tert-butoxycarbonyl)-protected guanidines using
polymer-supported carbodiimide
Olga Guisado, Sonia Mart´ınez and Joaqu´ın Pastor*
High Throughput Chemistry Group, Johnson & Johnson Pharmaceutical Research and Development, a division of Janssen-Cilag,
S.A., Centro de Investigacio´n Qu´ımica. C/ Jarama s/n, Toledo 45007, Spain
Received 17 June 2002; revised 8 July 2002; accepted 10 July 2002
Abstract—A novel methodology for the synthesis of guanidines from amines has been developed using polymer assisted synthesis,
potentially allowing the preparation of series of compounds in a high throughput manner. The methodology comprises the use
of polymer-supported carbodiimide as the activating agent for N,N%-bis(tert-butoxycarbonyl) thiourea with polymer-supported
trisamine as a scavenger, followed by deprotection with trifluoroacetic acid. For the first time, polymer-supported carbodiimide
has been utilized as an activating agent to synthesize guanidines. © 2002 Elsevier Science Ltd. All rights reserved.
The guanidine functional group is an important compo-
nent in many biologically active natural products,1 as
well as medicinal agents,2 for instance, with anti-
tumour, anti-hypertensive, anti-glaucoma and car-
diotonic activities, and H2 antagonism/agonism.
cleavage, in terms of purity, is desired. This is a major
issue, particularly in our case, where the amines of
interest are of high synthetic value, since they are
usually prepared in multi-step sequences. Furthermore,
in some cases, the success of the reaction is also very
substrate-dependent. Other alternatives based on solu-
tion phase approaches would need additional work-up
and purification steps to obtain the final products.8
As part of a lead discovery project, our work was
devoted to converting a diverse set of proprietary pri-
mary and secondary amines directly into their corre-
sponding terminal guanidines. To reach this goal in a
high throughput way, it was desirable to employ solid
phase methodology. Thus, a number of approaches,
where the guanidylating agent is polymer-supported,
have been reported in the literature. These include
pyrazole carboxamidine and its derivatives,3,4 and ana-
logues of N,N%-bis(tert-butoxycarbonyl) thiourea,5 S-
Herein, we report a polymer assisted synthesis (PAS)
methodology9 to obtain guanidines, which combines
advantages of traditional solution phase chemistry with
the application of polymeric reagents. This approach
led to the desired compounds in a high throughput
manner, in sufficient purity, without additional purifica-
tion steps.
alkyl
thiourea,6
N-triflyl
guanidine,7
and
N,N%-bis(tert-butoxycarbonyl) pseudourea.5d However,
there are some potential disadvantages by using such a
strategy. These reagents must be synthetically prepared,
most of them in a multi-step sequence, since they are
not commercially available. Additionally, there is the
need of using a large excess of starting amine to reach
completion of the reaction, if an efficient subsequent
Among the different guanidylation methodologies
reported in the literature, we focused our attention on
the use of N,N%-bis-BOC-thiourea and dicyclohexylcar-
bodiimide,10 since its versatility has been proven clearly
in solution phase. Thus, we decided to adapt this
method to a PAS environment using the activating
agent in solid support, while keeping the amidine donor
in solution. N,N%-Bis(tert-butoxycarbonyl) thiourea is
readily prepared in one step,11 in multigram scale and
PS-carbodiimide is commercially available.12 The use of
PS-carbodiimide is well known in several PAS applica-
tions,13 nevertheless, to the best of our knowledge, there
are no precedents where PS-carbodiimide had been
utilized for the synthesis of guanidines.
Keywords: polymer assisted synthesis; N,N-bis(tert-butoxycarbonyl)-
protected guanidines; N,N%-bis(tert-butoxycarbonyl) thiourea; PS-car-
bodiimide; high throughput chemistry.
* Corresponding author. Tel.: +34-925-245-750; fax: +34-925-245-771;
e-mail: jpastor@prdes.jnj.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01390-4

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O. Guisado et al. / Tetrahedron Letters 43 (2002) 7105–7109
the success of the process, since the use of
thiourea itself gave negative results under the same
protocol.16
The general strategy is outlined in Scheme 1. Thus, a
one-pot procedure where a mixture of the amine 2,
N,N%-bis(tert-butoxycarbonyl) thiourea 1 and PS-car-
bodiimide 3 with purification using PS-trisamine14
5
afforded
N,N%-bis(tert-butoxycarbonyl)
protected
Fig. 1 displays a set of representative amines chosen to
explore the scope and limitations of this process. The
results for each amine are summarized in Table 1.
guanidines 4. Subsequent deprotection under acidic
conditions gave the final compounds in high purity and
yield without further purification.
In order to test the influence of the solvent in this
protocol, a duplicate set of experiments with DMF and
CH2Cl2 were carried out. In general, the isolated yields
for N,N%-bis(tert-butoxycarbonyl)-protected guanidines
were comparable in both solvents. However, the purity
of the final compounds was slightly better when CH2Cl2
was used. The most interesting effect was on the reac-
tion rate. Thus, in DMF some guanidylation reactions
needed times of up to 72 h for completion, while in
CH2Cl2 required reaction times were not longer than 16
h.17 Therefore, CH2Cl2 was the solvent of choice, with
the additional advantage of easier removal/evaporation
compared to DMF. Regarding the diversity of the
commercial amines, it is worth noting that in all cases
the corresponding N,N%-bis(tert-butoxycarbonyl)-pro-
tected guanidines were obtained in good to excellent
yields and purities when CH2Cl2 was used as solvent.
Even deactivated anilines (2j) or sterically hindered
amines (2l) reacted efficiently, improving on or match-
ing results with other guanidylation systems.17 Further
treatment of the protected guanidines with 25% TFA in
CH2Cl2 at room temperature for 6 h, and subsequent
evaporation gave the corresponding deprotected
guanidines, with good yields and purities, as their corre-
sponding TFA salts (see Table 1).18,19
To optimize the procedure, we chose 4-benzylpiperidine
7, as a model. Experiments were carried out using
different combinations of equivalents of 1 (from 1.2 to
1.5 equiv.) and 3 (from 1.5 to 3.0 equiv.) with or
without the presence of base (di-isopropylethylamine,
2.0 equiv.) and two different solvents (DMF and
CH2Cl2).
We observed that the use of a base is not necessary and
does not produce any improvement in the process.
Also, carrying out the reaction in DMF or CH2Cl2 gave
similar results in this model experiment. It is interesting
to note that we observed the formation of small
amounts of a byproduct (tentatively assigned as bis-
(tert-butoxycarbonyl) carbodiimide)9a in the reaction
mixture. Thus, in order to remove such an impurity-
byproduct, we added PS-trisamine 5 as a scavenger,
thereby obtaining the desired N,N%-bis(tert-butoxycar-
bonyl)-protected guanidine 8 in high yield (95%, based
on mass recovery) and purity (96%/86%, based on
LC-MS-UV/1H NMR analyses).15 The final optimized
conditions are summarized in Scheme 2. Interestingly,
the presence of electron-withdrawing groups in the
thiourea derivative was shown to be important to
In summary, we have developed a novel, facile method-
ology for the synthesis of N,N%-bis(tert-butoxycar-
bonyl)-protected guanidines, in high purity and yield,
for a diverse set of amines, by using PS-carbodiimide
and N,N%-bis(tert-butoxycarbonyl)thiourea coupled
with the use of PS-trisamine. Further deprotection with
TFA afforded terminal guanidines. This represents the
first use of PS-carbodiimide as an activating agent for
the synthesis of N,N%-bis(tert-butoxycarbonyl)-pro-
tected guanidines. The whole protocol has potential use
in high throughput synthesis for this class of
compounds.
Scheme 1. One-pot synthesis–purification of deprotected
guanidines.
Scheme 2. Conditions: (1) 1.0 equiv. 4-benzylpiperidine, 1.5
equiv. N,N%-bis(tert-butoxycarbonyl) thiourea, 3.0 equiv. PS-
carbodiimide, DMF (or CH2Cl2), rt; 16 h. (2) 2.0 equiv.
PS-trisamine, DMF (or CH2Cl2), rt; 4 h.
Figure 1. Set of representative amines.

O. Guisado et al. / Tetrahedron Letters 43 (2002) 7105–7109
7107
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a
Yields from DMF experiments ranged from 70 to 95%, and are
determined based on mass recovery of crude product. b Purity given
is determined from crude material based on area of peak corre-
sponding to the correct molecular weight, monitored by UV detec-
tion, scanning from 200 to 450 nm. c Time for CH2Cl2 experiments
was set up to 16 h and was not further optimized. d Purity given is
determined based on 1H NMR analysis of crude material. e Yield
determined based on mass recovery of crude product. f The depro-
tection step was carried out from those guanidylation experiments
performed in CH2Cl2. g See Ref. 17.
For typical experimental procedures see Ref. 15.
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M. Org. Lett. 2001, 3, 1133–1136.
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Acknowledgements
The authors wish to thank their colleagues from the
Analytical Department for their support. Johnson &
Johnson Pharmaceutical Research and Development (a
division of Janssen-Cilag, S.A. Toledo, Spain) is also
gratefully acknowledged for a Ph.D. fellowship (O.G.).
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mentioned above.
12. PS-carbodiimide, 1.26 mmol/g purchased from Argonaut
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Ltd. Reversed phase HPLC was done using a Zorbax
XDB C-18 4.6×30 mm×3.5 mm with a 6 min gradient
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both in positive and negative ionization scanning from
Technologies, Ltd.
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1
100 to 1000 a.m.u. H NMR analysis was performed on
a Bruker Avance DPX, 400 MHz.
16. Starting materials were the only products detected by
LC-MS.
14. PS-trisamine, 4.2 mmol/g, purchased from Aldrich:
Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119,
4882–4886.
17. Although experiments carried out in CH2Cl2 for 16 h
with di-isopropyl amine (2l) and p-NO2-aniline (2j)
improved precedent results with other guanidylating sys-
tems,3a,4c reaction of amine 2j proceeded with 70% of
conversion. The LC-MS-UV analysis of the crude mate-
rial revealed 30% of starting amine, protected guanidine
64% and 6% of impurities. This result means a 91%
purity for expected compound, if unreacted amine is not
taken into account. Therefore, yields of guanidines from
entry 2j are not given.
18. The purity of deprotected guanidines was determined by
1H NMR, and not by LC-MS-UV, since their high
polarity gave in general remarkable peak tailing. This
issue made difficult the adequate determination of the
peak area corresponding to these compounds.
15. Typical experimental procedures:
Guanidylation of model compound 4-benzylpiperidine (7):
To a solution of N,N%-bis(tert-butoxycarbonyl) thiourea
(236 mg, 0.85 mmol, 1.5 equiv.) in CH2Cl2 (10 mL) was
added 4-benzylpiperidine (100 mg, 0.57 mmol, 1.0 equiv.)
and PS-carbodiimide (Argonaut Technologies Ltd, 1.26
mmol/g, 1.34 g, 1.70 mmol, 3.0 equiv.). The mixture was
shaken at room temperature for 16 h, then it was filtered
and the polymer washed with CH2Cl2 (2×5 mL). PS-
trisamine (4.2 mmol/g, 270 mg, 1.14 mmol, 2.0 equiv.)
was added to the resulting solution and the mixture was
shaken for 4 h. The polymer was filtered and washed with
CH2Cl2 (2×5 mL). The solvent was evaporated under
reduced pressure affording the corresponding bis-Boc
protected guanidine 8 (226 mg, 95% yield). The purity of
crude compound 8 was determined by LC-MS-UV analy-
sis (MH+=418) (96%) and confirmed by its 1H NMR
spectrum (86%). 1H NMR (400 MHz CDCl3): l 1.28–
1.41 (m, 2H), 1.41–1.54 (m, 2H), 1.46 (s, 9H), 1.50 (s,
9H), 1.64–1.70 (m, 2H), 1.70–1.82 (m, 1H), 2.55 (d,
J=7.0 Hz, 2H), 2.80–2.94 (m, 2H), 7.13 (d, J=7.2 Hz,
2H), 7.20 (t, J=7.2 Hz, 1H), 7.28 (t, J=7.2 Hz, 2H),
10.15 (broad s, 1H).
Guanidylation of amines 2a–l and final deprotection:
To twelve tubes of a Quest 210™ synthesizer (Argonaut
Technologies Ltd) was added PS-carbodiimide (1.26
mmol/g, 595 mg, 0.75 mmol, 3.0 equiv.) and CH2Cl2 (5.0
mL). The resin was washed/swollen for 15 min. The
solvent was filtered and the process repeated twice. The
resin was suspended again in CH2Cl2 (5.0 mL), then the
corresponding amines 2a–l (0.25 mmol, 1.0 equiv.) were
added to each tube and finally N,N%-bis(tert-butoxycar-
bonyl)thiourea (103 mg, 0.37 mmol, 1.5 equiv.). The
mixtures were shaken at room temperature under N2
atmosphere for 16 h. Then, PS-trisamine (4.2 mmol/g,
120 mg, 0.50 mmol, 2.0 equiv.) and CH2Cl2 (1.0 mL)
were added to each mixture. The shaking was continued
for 16 h at room temperature. The polymers were
removed by filtration, washed with more CH2Cl2 (2×6
mL), and the resulting solutions were evaporated under
reduced pressure. The yield were determined by mass
recovery, and the purity of each protected guanidine 4
were calculated by LC-MS-UV and 1H NMR analyses
(see Table 1). Crude protected guanidines were further
treated with a solution of trifluoroacetic acid (25% in
CH2Cl2, 5.0 mL) at room temperature for 6 h, finally,
evaporation of the solvent gave the corresponding depro-
19. 1H NMR (400 MHz CDCl3) data for protected guanidines
derived from entries: 2a: l 1.48 (s, 9H), 1.52 (s, 9H), 4.63
(d, J=5.2 Hz, 2H), 7.25–7.40 (m, 5H), 8.58 (broad s,
1H), 11.54 (broad s, 1H). 2b: l 1.51 (s, 9H), 1.54 (s, 9H),
7.11 (t, J=7.4 Hz, 1H), 7.32 (t, J=7.8 Hz, 2H), 7.60 (d,
J=7.8 Hz, 2H), 10.33 (broad s, 1H), 11.65 (broad s, 1H).
2c: l 0.88 (t, J=6.8 Hz, 3H), 1.25–1.38 (m, 14H), 1.49 (s,
9H), 1.51 (s, 9H), 1.57–1.60 (m, 2H), 3.37–3.42 (m, 2H),
8.3 (broad s, 1H), 11.5 (broad s, 1H). 2d: l 1.20 (s, 9H),
1.51 (s, 9H), 5.15 (s, 2H), 7.05–7.16 (m, 3H), 7.19–7.38
(m, 7H), 9.22 (broad s, 1H). 2e: l 1.46 (s, 9H), 1.50 (s,
9H), 2.47–2.52 (m, 4H), 3.52 (s, 2H), 3.51–3.73 (m, 4H),
7.29–7.35 (m, 5H), 10.15 (broad s, 1H). 2f: l 1.51 (broad
s, 18H), 4.55 (s, 4H), 7.10–7.15 (m, 4H), 7.20–7.42 (m,
6H), 10.13 (broad s, 1H). 2g: l 1.21 (s, 9H), 1.53 (s, 9H),
2.32 (s, 3H), 3.42 (s, 3H), 7.09 (d, J=8.1 Hz, 2H), 7.15
(d, J=8.1 Hz, 2H), 9.22 (broad, s, 1H). 2h: l 1.48 (s, 9H),
1.51 (s, 9H), 3.22–3.28 (m, 4H), 3.62–3.85 (m, 4H),
6.88–6.96 (m, 3H), 7.24–7.30 (m, 2H), 10.24 (broad s,
1H). 2i: l 1.49 (s, 9H), 1.53 (s, 9H), 3.79 (s, 3H), 6.86 (d,
J=8.9 Hz, 2H), 7.48 (d, J=8.9 Hz, 2H), 10.18 (broad s,
1H), 11.64 (broad s, 1H). 2j: l 1.53 (s, 9H), 1.55 (s, 9H),
7.85 (d, J=9.5 Hz, 2H), 8.22 (d, J=9.5 Hz, 2H), 10.77
(broad s, 1H), 11.60 (broad s, 1H). 2k: l 1.14–1.45 (m,
6H), 1.49 (s, 9H), 1.50 (s, 9H), 1.63–1.73 (m, 2H), 1.88–
1.98 (m, 2H), 3.96–4.06 (m, 1H), 8.31 (d, J=7.4 Hz, 1H),
11.53 (broad s, 1H). 2l: l 1.33 (d, J=6.6 Hz, 12H), 1.47
(broad s, 18H), 3.93 (h, J=6.6 Hz, 2H), 8.29 (broad s,
1H).
1H NMR (400 MHz DMSO-d6) data for deprotected
guanidines derived from entries: 2a: l 4.35 (d, J=6.0 Hz,
2H), 6.80–7.65 (m, 9H), 8.05 (t, J=6.0 Hz, 1H). 2b: l
7.24 (d, J=7.4 Hz, 2H), 7.29 (t, J=7.4 Hz, 1H), 7.45 (t,
J=7.9 Hz, 2H), 7.61 (broad s, 4H), 10.07 (broad s, 1H).

O. Guisado et al. / Tetrahedron Letters 43 (2002) 7105–7109
7109
2c: l 0.86 (t, J=6.8 Hz, 3H), 1.14–1.36 (m, 14H), 1.39–
1.52 (m, 2H), 3.08 (dt, J=6.8 Hz, J=7.5 Hz, 2H),
6.60–7.53 (broad s, 4H), 7.60 (broad s, 1H). 2d: l 4.95 (s,
2H), 7.18–7.47 (m, 10H), 7.59 (broad s, 4H). 2e: l
3.05–3.46 (m, 8H), 4.36 (s, 2H), 7.45–7.55 (m, 5H), 7.75
(broad s, 4H). 2f: l 4.60 (s, 4H), 7.20–7.27 (m, 4H),
7.31–7.37 (m, 2H), 7.37–7.44 (m, 4H), 7.65 (broad s, 4H).
2g: l 2.35 (s, 3H), 3.25 (s, 3H), 7.22–7.40 (m, 8H). 2h: l
3.18–3.28 (m, 4H), 3.54–3.64 (m, 4H), 6.83 (t, J=7.4 Hz,
1H), 6.98 (d, J=7.8 Hz, 2H), 7.24 (t, J=7.8 Hz, 2H),
7.56 (broad s, 4H). 2i: l 3.77 (s, 3H), 7.00 (d, J=8.9 Hz,
2H), 7.18 (d, J=8.9 Hz, 2H), 7.36 (broad s, 4H). 2j: l
7.46 (d, J=9.0 Hz, 2H), 8.01 (broad s, 4H), 8.28 (d,
J=9.0 Hz, 2H), 10.49 (broad s, 1H). 2k: l 1.07–1.38 (m,
5H), 1.50–1.60 (m, 1H), 1.61–1.73 (m, 2H), 1.75–1.89 (m,
2H), 3.41–3.27 (m, 1H), 6.65–7.44 (broad s, 4H), 7.58 (d,
J=8.3 Hz, 1H). 2l: l 1.24 (d, J=6.8 Hz, 12H), 3.93 (h,
J=6.8 Hz, 2H), 7.03 (broad s, 4H). 8: l 1.07–1.21 (m,
2H), 1.55–1.67 (m, 2H), 1.74–1.88 (m, 1H), 2.54 (d,
J=7.0 Hz, 2H), 2.87–2.99 (m, 2H), 3.74–3.90 (m, 2H),
7.17 (d, J=7.0 Hz, 2H), 7.20 (t, J=7.2 Hz, 1H), 7.28 (t,
J=7.2 Hz, 2H), 7.35 (broad s, 4H).