N,N′,N″-Tri-Boc-guanidine (TBG): a common starting material for both N-alkyl guanidines and amidinoureas

Article abstract of DOI:10.1016/j.tetlet.2007.01.055

In this Letter, we describe the unexpected reaction pattern of N,N′N″-tri-Boc-guanidine (TBG) with amines at room temperature and under reflux conditions affording N-substituted guanidines and amidinoureas, potentially important compounds with extensive a

Full text of DOI:10.1016/j.tetlet.2007.01.055

Tetrahedron Letters 48 (2007) 1725–1727
N,N0,N00-Tri-Boc-guanidine (TBG): a common starting material
for both N-alkyl guanidines and amidinoureas
Panchami Prabhakaran and Gangadhar J. Sanjayan*
Division of Organic Synthesis, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 4 October 2006; revised 26 December 2006; accepted 10 January 2007
Available online 14 January 2007
Abstract—In this Letter, we describe the unexpected reaction pattern of N,N0N00-tri-Boc-guanidine (TBG) with amines at room tem-
perature and under reflux conditions affording N-substituted guanidines and amidinoureas, potentially important compounds with
extensive applications in medicinal chemistry. This investigation shows that TBG is an excellent, readily available common starting
material for the synthesis of various N-alkyl guanidines as well as N-alkyl-N0-substituted amidinoureas by simply manipulating the
reaction conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
Towards the end of his illustrious career,1 Murray
Goodman, a pioneer peptide chemist,2 first introduced
tri-Boc-guanidine (TBG) 1, as a versatile guanidinylat-
ing reagent for the synthesis of N-substituted guanidines
3a by its reaction with alcohols under Mitsunobu
conditions.3
A related trifluoro sulfonyl analog 2, which is found to
be one of the most powerful guanidinylating reagents
so far, was also introduced by Goodman for the efficient
synthesis of substituted guanidines, under extremely
mild conditions by its reaction with amines.4 The reac-
tion proceeds with attack of amines at the amidine car-
bon eliminating the trifluoro sulfonamide and cleanly
furnishing the protected guanidines 3b. In one of our
recent programmes directed towards the synthesis of
highly stable quadruply hydrogen-bonding systems with
degenerate prototropy,5 we required an efficient proce-
dure for the construction of 4, a self-assembling system
adorned with AADD-type quadruple hydrogen-bonding
arrays.
Di-Boc guanidine4 5 has been shown to react with
amines under an elevated temperature to afford amid-
inoureas 7.6
Keywords: N,N0,N00-Tri-Boc-guanidine; N-Alkyl guanidines; Amidino-
urea.
*
Corresponding author. Tel.: +91 20 25902982; fax: +91 20
25893153; e-mail: gj.sanjayan@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.055

1726
P. Prabhakaran, G. J. Sanjayan / Tetrahedron Letters 48 (2007) 1725–1727
In this reaction, the intermediacy of isocyanate 6, gener-
ated in situ by the elimination of t-butanol, has been
advocated, which reacts with the amines to form amidi-
noureas 7.7
ing N-substituted, N0,N00-di-Boc guanidine 12, which led
us to explore further the reaction chemistry of TBG with
various amines under different conditions. A summary
of the reactions performed under different conditions
with the isolated yields is given in Table 1, which sug-
gests that the reaction of 1 with amines can be manipul-
ated to afford either N-substituted guanidines 12 or N-
alkyl amidinoureas 13 under relatively mild reaction
conditions.
In this context we anticipated that TBG 1 would also re-
act with amines in a similar way, to eventually afford 11,
through intermediates 8 and 10, which in turn could be
subjected to cyclization to form the quadruple H-bonded
self-complimentary AADD-type self-assembling system
4 (Scheme 1). As reported in the case of di-Boc guanidine
5, we envisaged that the reaction of 1 with amines would
involve the intermediacy of an isocyanate.7
It is noteworthy that amidinoureas are of considerable
interest in medicinal chemistry;8a–c for instance in treat-
ing irritable bowel syndrome, gastrointestinal, spasmo-
lytic and cardiovascular disorders and parasitic
infestations. Furthermore, amidinourea has also been
shown to be the essential structural feature for the
potent antibacterial activity of TAN-1057A-D,9 a natu-
rally occurring potent antibiotic dipeptide-amidinourea
isolated from the bacteria Flexibacter sp. PK-74 and
PK-176. Moreover, it has been noted that long chain
N-substituted amidinoureas find industrial application
as non-toxic and non-polluting stabilizers and disper-
sants (multifunctional) for middle distillate fuels.10 The
methods so far known in the literature for the prepara-
tion of amidinoureas include, the reaction of guanidines
with isocyanates,11 the hydrogenation of 5-amino-3-
amino-l,2,4-oxadiazoles,12 the reaction of carbamic
esters with guanidine,13 the hydrolysis of cyanoguanidines
under strongly acidic conditions14 and the reaction of
acyl-S methylisothiourea with amines.15
Unexpectedly, TBG reacted with primary amines at
room temperature in an entirely different fashion afford-
The reactions of TBG 1 with amines under different con-
ditions were investigated in order to understand the
reaction pattern. Unlike the reaction of di-Boc guani-
dine 5 with an amine6 to afford substituted amidino-
ureas 7 through the isocyanate mechanism, TBG reacted
with primary amines at room temperature resulting in
the formation of the corresponding N-alkylated di-Boc
guanidines, 12 (entries 1, 5, 10, 12 and 14, Table 1) in
good yields. Enhancement in the rate of the reaction
as well as the yield was examined by carrying out the
Scheme 1. Reaction of TBG 1 with amines.
Table 1. Reaction of TBG 1 with amines under different conditions
Entry
Amine
TBG/amine (equiv)
Base/LA
Solvent, temp
12 (%)
13 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Benzyl amine
Benzyl amine
Benzyl amine
Benzyl amine
Isobutyl amine
Isobutyl amine
Isobutyl amine
Isobutyl amine
Isobutyl amine
Dodecyl amine
Dodecyl amine
Cyclohexyl amine
Cyclohexyl amine
Isopropyl amine
Isopropyl amine
Aniline
1:1
1:1
1:4
1:3
1:1
1:1
1:3
1:1
1:1
1:1
1:3
1:1
1:3
1:1
1:4
1:1
1:1
—
—
—
TMA
—
—
—
DBU
DBU
—
—
—
—
—
—
—
—
THF, rt
98
38
—
20
60
50
—
61
40
97
—
52
—
40
—
—
30
90
30
—
22
86
—
40
—
91
—
60
—
52
THF, reflux
THF, reflux
Toluene, reflux
THF, rt
THF, reflux
THF, reflux
THF, rt
DMSO, 50 °C
THF, rt
THF, reflux
THF, rt
THF, reflux
THF, rt
THF, reflux
THF, rt
a
a
—
a
—
—
a
Diethyl amine
THF, rt
—
LA: Lewis acid, TMA: trimethyl aluminium.
a An intractable mixture of products was obtained.

P. Prabhakaran, G. J. Sanjayan / Tetrahedron Letters 48 (2007) 1725–1727
1727
and amidinoureas in good yields by reaction with pri-
mary aliphatic amines under various reaction condi-
tions. Further work is in progress to evaluate the
synthetic potential of TBG.
Acknowledgements
Scheme 2. Proposed mechanism of reaction of TBG 1 with amines.
P.P. is thankful to the CSIR, New Delhi, for a Research
Fellowship. This work was funded partly by a research
grant from the Department of Biotechnology, New
Delhi.
reaction at elevated temperature and also by the addi-
tion of an external base (DBU). When primary amines
were reacted with TBG 1 under reflux in a 1:1 ratio,
both N-substituted guanidines 12 and amidinoureas 13
were obtained (entries 2 and 6, Table 1). It is noteworthy
that the use of excess amine under reflux dramatically
increased the yield of 13 and amidinoureas were the only
products isolated under these conditions (entries 3, 7, 11,
13 and 15, Table 1). These observations suggest that N-
substituted guanidines 12 are formed first by nucleo-
philic attack of the amines at the highly electrophilic
quaternary carbon of TBG flanked by the three carba-
mate groups. Further reaction of 12, presumably pro-
ceeding through the isocyanate intermediate 14, affords
N-substituted amidinoureas 13 (Scheme 2).
Supplementary data
1
General experimental procedures, H, 13C, DEPT-135
NMR spectra and ESI mass spectra of 12a–e and 13a–e
can be found, in the online version, at doi:10.1016/
j.tetlet.2007.01.055.
References and notes
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In the presence of the strong base DBU, the reaction of
TBG with isobutylamine in an equimolar ratio under
ambient conditions proceeded with no significant differ-
ence in the yield of substituted guanidine 12 (compare
entries 5 and 8, Table 1). However, raising the reaction
temperature had a minor effect on the product distribu-
tion (compare entries 6 and 9, Table 1). These results
also suggest that the formation of 12 precedes 13 and
that even strong bases like DBU fail to promote TBG
to form isocyanate intermediate 8, which would have
led to the formation of 9 (Scheme 1). The difference in
the reaction when compared with di-Boc guanidine
may be due to the increased electrophilicity at the qua-
ternary carbon of the guanidine moiety due to the addi-
tional Boc group. In order to understand the reaction
pattern of aromatic amines, TBG was reacted with ani-
line (entry 16, Table 1). However, this reaction led to the
formation of an intractable mixture of products. A
similar outcome also occurred using a secondary amine
(entry 17, Table 1). Finally, in an effort to react TBG
with amines to afford 11, which could have been cyclo-
condensed to furnish the self-assembling system 4,
TBG was reacted with excess benzylamine in the pres-
ence of trimethyl aluminium (TMA). However, this
reaction led to the formation of a mixture N-substituted
guanidine and amidinourea (entry 4, Table 1).
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In conclusion, this work demonstrates that TBG reacts
in an unusual manner with amines under various condi-
tions, in stark contrast to the manner by which di-Boc
guanidine 5 reacts. Our finding suggest that TBG can
act as an excellent, readily available starting material
for the selective synthesis of both N-alkyl guanidines
13. Torok, S.; Nagy, B.; Pribek, F.; Balogh, S. Appl. WO
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