Facile and Efficient Guanylation of Amines Using Thioureas and Mukaiyama's Reagent

Full text of DOI:10.1021/jo962196k

1540
J . Org. Chem. 1997, 62, 1540-1542
Mukaiyama’s reagent (4)8 proved attractive since it is
known to be compatible with amines. In the event,
treatment of N,N′-bis(tert-butoxycarbonyl)thiourea (2)
with 4 in the presence of benzylamine resulted in the
rapid and complete consumption of amine and formation
of the desired N,N′-bis(tert-butoxycarbonyl)guanidine (5)
in 91% yield (eq 2).
F a cile a n d Efficien t Gu a n yla tion of Am in es
Usin g Th iou r ea s a n d Mu k a iya m a ’s Rea gen t
Yaw Fui Yong, J ennifer A. Kowalski, and
Mark A. Lipton*
Department of Chemistry, Purdue University, West
Lafayette, Indiana 47907
Received November 25, 1996
With the growing importance of peptides and peptido-
mimetics in a variety of disciplines, the need for efficient
methods of synthesizing guanidines has increased, re-
sulting in the recent development of several new reagents
for the guanylation of amines.1-5 During a recent solid
phase synthesis of a guanidine-containing cyclic dipep-
tide,6 we were confronted with the need for an efficient
method for the guanylation of resin-bound amines.
Initial studies led to the development of 4-nitro-1H-
pyrazole-1-N,N′-bis(tert-butoxycarbonyl)carboxamidine
(1a ),7 a more electrophilic variant of the literature
reagent 1H-pyrazole-1-[N,N′-bis(tert-butoxycarbonyl)]car-
boxamidine (1b).4 Dissatisfaction with the need for
multiple equivalents of 1 to completely guanylate resin-
bound amines led to a reexamination of the fastest and
A representative sample of amines was subjected to
reaction with 2 and 4 under a variety of conditions (Table
1). From these data, several conclusions can be reached.
First, primary and unhindered secondary amines can
generally be guanylated in high (>80%) yield using a
slight excess of reagent in anhydrous DMF (entries 1-4).
Second, for hindered or unreactive amines (entries 7 and
8) the use of methylene chloride as solvent can provide a
substantial increase in yield over reactions run in DMF
(entries 5 and 6). The effect of solvent on yield most
likely results from the instability of the carbodiimide
intermediate 3: when nucleophilic attack by an amine
is slow, a competitive decomposition of the carbodiimide
leads to loss of reagent and thus lower yield. Support
for this view comes from the recovery of unreacted amine
in entries 5 and 6. When methylene chloride is used as
solvent instead, the reactions are heterogeneous owing
to the sparing solubility of 4; it is believed that this
results in a slower production of 3 and, consequently, its
more efficient consumption by less reactive amines.
The guanylation of resin-bound amines under these
conditions was also examined. The side-chain amino
functionality of two peptides, 6 and 7, bound to the
most efficient of the literature methods, treatment of
amines with a N,N′-bis(tert-butoxycarbonyl)thiourea (2)
and mercuric chloride (eq 1).5a Although, owing to the
formation of insoluble mercuric sulfide precipitate, this
reaction is not applicable to solid phase guanylation, it
provides the basis for the development of improved
reagents.
Merrifield9 and Rink10 resins, respectively, were guany-
lated using three different reagents: 1a , 1b, and our new
conditions. Reactions were monitored by the loss of
amine, as judged by qualitative and quantitative ninhy-
drin assays.11 As with other slowly reacting amines,
reactions using 2 and 4 were found to improve markedly
when methylene chloride was used as solvent. When
DMF was used, 4 had to be repeatedly added in portions
over 3 h to effect complete reaction. In contrast, guany-
lation in methylene chloride resulted in complete con-
sumption of amine in 3 h using 3 equiv of reagent.
Although the reaction was heterogeneous, washing the
resin with DMF removed the precipitate, permitting the
successful isolation of guanylated peptide. Reactions
It has been suggested that the remarkable facility of
the reaction shown in eq 1 results from the formation of
N,N′-bis(tert-butoxycarbonyl)carbodiimide (3), a highly
electrophilic intermediate.5a Operating on this assump-
tion, other reagents known to promote formation of
carbodiimides from thioureas were examined as replace-
ments for mercuric chloride. Of the various candidates,
(1) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J . Org. Chem. 1992,
57, 2497. See refs 3-6 for earlier methods.
(2) Kim, K.; Lin, Y.-T.; Mosher, H. S. Tetrahedron Lett. 1988, 29,
3183.
(3) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett.
1993, 34, 3389.
(4) Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579.
(5) (a) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677. (b) Su,
W. Synth. Commun. 1996, 26, 407.
(6) Kowalski, J . A.; Lipton, M. A. Tetrahedron Lett. 1996, 37, 5839-
5840.
(7) Yong, Y. F.; Kowalski, J . A.; Lipton, M. A. Tetrahedron Lett. 1997,
in press.
(8) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett. 1977,
575.
(9) Merrifield, R. B. J . Am. Chem. Soc. 1963, 85, 2149-2154.
(10) Rink, H. Tetrahedron Lett.. 1987, 28, 3787-3790.
(11) Sarin, V. K.; Kent, S. B. H.; Tam, J . P.; Merrifield, R. B. Anal.
Biochem. 1981, 117, 147.
S0022-3263(96)02196-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 5, 1997 1541
Ta ble 1. Con ver sion of Va r iou s Am in es to Gu a n id in es Usin g Mu k a iya m a ’s Rea gen t
at 25 °C. When the reaction had reached completion as judged
by TLC, the reaction was diluted with water (360 µL) and
extracted with diethyl ether (3 × 360 µL). The combined organic
layers were dried (Na2SO4) and evaporated to afford the crude
guanidine. The guanidines were purified by flash chromatog-
raphy.
using 1a and 1b were substantially less efficient, 1a
requiring 4 equiv of reagent and 24 h to completely
consume amine, and 1b failing to completely guanylate
the amine after 3 days even when 8 equiv were used.
In conclusion, the use of thioureas and 4 to for the
guanylation of amines would appear to have several
advantages over existing methods. Like methods em-
ploying mercuric chloride,5 these new conditions afford
high yields of guanidines, even relatively unreactive ones.
In addition, we believe that this new guanylation reaction
represents the best method for guanylating resin-bound
amines. Moreover, the use of 4 instead of mercuric
chloride eliminates the environmental hazard of heavy
metal waste without appreciable loss of yield or reactiv-
ity. It is anticipated that this new method will find wide
application in the synthesis of protected guanidines.
Gu a n yla tion of Hin d er ed a n d Un r ea ctive Am in es (Gen -
er a l P r oced u r e). To a solution of amine (12 µL, 0.132 mmol,
1 equiv), N,N′-bis(tert-butoxycarbonyl)thiourea (44 mg, 0.158
mmol, 1.2 equiv), and triethylamine (41 µL, 0.290 mmol, 2.2
equiv) in CH2Cl2 (1.3 mL) was added Mukaiyama’s reagent (40
mg, 0.158 mmol, 1.2 equiv). The reaction was allowed to stir at
25 °C until completion, as judged by TLC. Upon completion,
the reaction was evaporated, and the residue redissolved in
diethyl ether (2 mL) and washed with water (2 mL). The organic
layer was dried (MgSO4), the solvent removed in vacuo, and the
product purified by flash chromatography.
N,N′-Bis(ter t-bu toxyca r bon yl)-N′′-ben zylgu a n id in e (5):4
o
1
mp ) 126-127 C; H-NMR(CDCl3, 200 Hz): δ 8.61 (br s, 1H),
7.32 (m, 5H), 4.64 (d, J ) 5.1, 2H), 1.52 (s, 9H), 1.48 (s, 9H);
13C-NMR(CDCl3, 50 MHz): δ 163.9, 156.5, 153.6, 137.6, 129.2,
128.3, 128.1, 83.7, 80.0, 45.6, 28.8, 28.5; IR (KBr): 1741.4,
Exp er im en ta l Section
Gu a n yla tion of P r im a r y a n d Un h in d er ed Secon d a r y
Am in es (Gen er a l P r oced u r e). To a solution of amine (40 µL,
0.366 mmol, 1 equiv) in anhydrous DMF (120 µL) were added
N,N′-bis(tert-butoxycarbonyl)thiourea (121 mg, 0.439 mmol, 1.2
1654.0, 1625.7, 1559.8 cm-1
.
N,N′-Bis(ter t-bu toxycar bon yl)-N′′,N′′-diallylgu an idin e (6):
mp ) 74-75 °C; 1H-NMR(CDCl3, 200 Hz): δ 5.71-5.87 (m, 2H),
5.16-5.18 (m, 2H), 5.22-5.26 (m, 2H), 4.03 (d, J ) 5.9, 4H),
1.48 (s, 18H); 13C-NMR(CDCl3, 50 MHz): δ 163.0, 155.5, 151.3,
133.3, 119.0, 82.3, 79.9, 50.9, 28.6; IR (KBr): 1746.4, 1683.3,
equiv) and triethylamine (113 µL, 0.806 mmol, 2.2 equiv).
A
suspension of Mukaiyama’s reagent (112 mg, 0.439 mmol, 1.2
equiv) in anhydrous DMF (240 µL) was added dropwise via
syringe to the reaction mixture and the reaction allowed to stir

1542 J . Org. Chem., Vol. 62, No. 5, 1997
1642.4, 1581.5, 1500.0 cm-1
Notes
.
Anal. Calcd for C17H29N3O4: C,
(m, 2H), 7.26-7.36 (m, 2H), 7.07-7.15 (m, 1H), 1.54 (s, 9H), 1.51
(s, 9H); 13C-NMR (CDCl3, 50 MHz): δ 164.1, 154.0, 153.8, 137.3,
128.4, 125.2, 122.6, 84.2, 80.1, 28.7, 28.6; IR (KBr): 1727.1,
60.15; H, 8.61; N, 12.38. Found: C, 60.47; H, 8.90; N, 12.42.
1-[N ,N ′-B i s (t er t -b u t o x y c a r b o n y l)c a r b o x a m i d i n o ]-
o
p ip er id in e (7): mp ) 111-113 C; 1H-NMR(CDCl3, 200Hz): δ
1637.7, 1597.9, 1562.1 cm-1
.
3.49 (br s, 4H), 1.61 (br s, 6H), 1.47 (s, 18H); 13C-NMR(CDCl3,
2-Nitr op yr a zole-1-N,N′-bis(ter t-bu toxyca r bon yl)ca r box-
a m id in e (11): mp ) 51-53 °C; 1H-NMR (CDCl3, 200 Hz): δ
9.04 (s, 1H), 8.17 (s, 1H), 1.45-1.55 (m, 18H); 13C-NMR (CDCl3,
50 MHz): δ 156.6, 149.3, 138.5, 137.6, 128.0, 84.9, 83.0, 77.7,
50 MHz): δ 155.5, 46.5, 28.6, 28.5, 26.2, 24.8; IR (NaCl): 1744.7,
1653.0, 1628.5, 1611.5 cm-1
. Anal. Calcd for C16H29N3O4: C,
58.69; H, 8.93; N, 12.83. Found: C, 58.89; H, 9.14; N, 12.66.
Meth yl (S)-2-[N,N′-Bis(ter t-bu toxyca r bon yl)gu a n id in o]-
3-p h en ylp r op ion a te (8): 1H-NMR (CDCl3, 200 Hz): δ 8.77 (br
d, J ) 7.4, 1H), 7.13-7.33 (m, 5H), 5.03-5.13 (m, 1H), 3.70 (s,
3H), 3.15 (dd, J ) 7.41, 6.22, 1H), 3.25 (dd, J ) 8.06, 5.78, 1H),
1.48 (s, 9H), 1.49 (s, 9H); 13C-NMR(CDCl3, 50 MHz): δ 172.1,
163.8, 155.9, 153.2, 136.3, 129.9, 129.0, 127.6, 83.7, 79.8, 55.1,
52.8, 38.5, 28.8, 28.5; IR (KBr): 1746.8, 1725.5, 1639.7, 1617.1
28.5; IR (NaCl): 1774.9, 1717.7, 1686.6, 1553.5, 1505.9 cm-1
.
Anal. Calcd for C14H21N5O6: C, 47.32; H, 5.96; N, 19.71.
Found: C, 47.51; H, 6.15; N, 19.86.
Gu a n yla tion of Resin -Bou n d Am in es (Gen er a l P r oce-
d u r e). A suspension of resin (50 mg, 23 µmol of amine, 1 equiv)
in CH2Cl2 (0.75 mL) was treated with triethylamine (13 µL, 92
µmol, 4.0 equiv) and N,N′-bis(tert-butoxycarbonyl)thiourea (19
mg, 69 µmol, 3.0 equiv) and the resulting mixture shaken. After
15 min, Mukaiyama’s reagent (18 mg, 69 µmol, 3.0 equiv) was
added and the reaction allowed to shake for 3 h. The reaction
was judged complete by ninhydrin assay.11
cm-1
.
[R]25 +35.7° (c 0.5, CHCl3). Anal. Calcd for
D
C
21H31N3O6: C, 59.84; H, 7.41; N, 9.97. Found: C, 60.05; H,
7.65; N, 10.22.
N,N′-Bis(ter t-bu toxyca r bon yl)-N′′,N′′-d iisop r op ylgu a n i-
d in e (9):5a,b mp ) 104-105 oC; 1H-NMR (CDCl3, 200 Hz): δ 8.28
(br s, 1H), 3.85-3.90 (m, 2H), 1.47 (s, 18H), 1.34 (s, 6H), 1.30
(s, 6H); 13C-NMR (CDCl3, 50 MHz): δ 162.3, 152.1, 151.9, 81.8,
78.1, 48.9, 28.8, 28.6, 21.3; IR (KBr): 1743.8, 1654.9, 1602.8
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 53091) for support of this research.
cm-1
.
N,N′-Bis(ter t-bu toxyca r bon yl)-N′′-p h en ylgu a n id in e (10):
3,4
mp ) 134-136 °C; 1H-NMR (CDCl3, 200 Hz): δ 7.59-7.63
J O962196K