2-Chloro-1,3-dimethylimidazolinium chloride. 1. A powerful dehydrating equivalent to DCC

Article abstract of DOI:10.1021/jo990210y

2-Chloro-1,3-dimethylimidazolinium chloride (DMC) (3) can act as a powerful dehydrating agent, replacing DCC (1) under nearly neutral conditions. Its application to acylation and dehydration is described.

Full text of DOI:10.1021/jo990210y

6984
J . Org. Chem. 1999, 64, 6984-6988
2-Ch lor o-1,3-d im eth ylim id a zolin iu m Ch lor id e. 1. A P ow er fu l
Deh yd r a tin g Equ iva len t to DCC
Toshio Isobe
Central Research Laboratory, Shiratori Pharmaceutical Co. Ltd., 6-11-24 Tsudanuma, Narashino,
Chiba 275-0016, J apan
Tsutomu Ishikawa*
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, J apan
Received February 3, 1999
2-Chloro-1,3-dimethylimidazolinium chloride (DMC) (3) can act as a powerful dehydrating agent,
replacing DCC (1) under nearly neutral conditions. Its application to acylation and dehydration is
described.
Ch a r t 1
In tr od u ction
Dicyclohexylcarbodiimide (DCC)1 (1) (Chart 1) is widely
used in organic reactions as a dehydrating agent because
it is inexpensive and can be used under mild conditions.
However, it has the disadvantages of low reactivity, and
the resulting dicyclohexylurea (2) byproduct is relatively
insoluble, making the purification of products difficult.
Furthermore, it is known that 1 is a potent skin irritant
for some individuals.1a Although N-(3-dimethylamino-
propyl)-N′-ethylcarbodiimide (EDCI)2 has also been pre-
pared and is a water-soluble carbodiimide, making the
workup procedure more facile, it is expensive.3
Chloroamidinium salts such as 2-chloro-1,3-dimeth-
ylimidazolinium chloride4 (DMC)5 (3) and N,N,N′,N′-
tetramethylchloroformamidinium chloride6 have also
been used in dehydration reactions. However, not as
much attention has been paid to these reagents until
now7 despite their potential ability to act as dehydrating
agents. In our studies on the development of useful
reagents for organic synthesis, we focused on 3 as a useful
equivalent to 1 because of its low cost8 and expected
nontoxicity.9 Its synthetic utilities were systematically
studied because of its dual advantages of simple prepara-
tion from the corresponding cyclic urea, 1,3-dimethyl-2-
imidazolidinone (DMI) (4) by chlorination, and the easy
removal of regenerated 4 after the condensation reaction
by washing with water. In this paper we describe in detail
the versatility of 3 as an alternative dehydrating agent
comparable to 1.
(1) For example, see: (a) Fieser, L. F.; Fieser, M. Reagents for
Organic Synthesis; J ohn-Wiley and Sons: New York, 1967; Vol. 1, pp
231-236. (b) March, J . Advanced Organic Chemistry, 3rd ed.; Wiley-
Interscience: New York, 1985; pp 349-350.
(2) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn-
Wiley and Sons: New York, 1967; Vol. 1, p 274.
Resu lts a n d Discu ssion
(3) The price of EDCI is ¥16500/25 g (Nacalai Tesque, Inc., J apan).
This corresponds to $137.5/25 g, based on the exchange rate of ¥120/$
of J apanese yen to U.S. dollars.
(4) Fujisawa, T. Mori, T.; Fukumoto, K.; Sato, T. Chem. Lett. 1982,
1891.
(5) The CAS No is 37091-73-9. In the 9th Collective Index of
Chemical Abstracts an alternative nomenclature of 2-chloro-4, 5-di-
hydro-1, 3-dimethyl-1H-imidazolium chloride has been adopted. The
name of DMC is derived from the chloro derivative of 1, 3-dimethyl-
2-imidazolidinone (DMI) (4).
P h ysicoch em ica l P r op er ties of DMC (3). DMC (3),
C5H10Cl2N2 (169.05), was originally prepared from DMI
(4) by chlorination with phosgene.10 However, we pre-
pared 311 by treatment of 4 with trichloromethylchloro-
formate (diphosgene) or oxalyl chloride in place of
phosgene (Scheme 1; see the Supporting Information).
DMC (3) was obtained as colorless and odorless prisms,
(6) Fujisawa, T.; Tajima, K.; Sato, T. Bull. Chem. Soc. J pn. 1983,
56, 3529.
(8) DMC (3) is now commercially available in J apan. The price of 3
is ¥9600/25 g (Nacalai Tesque, Inc., J apan). This corresponds to $80/
25 g, based on the exchange rate of ¥120/$ of J apanese yen to U.S.
dollars. Thus, 3 is about 2-fold cheaper than EDCI.3
(9) Although there is no report on the toxicity of DMC (3) to our
knowledge, the median lethal dose (LD50) of DMI (4) in mouse has been
reported as 2, 840 mg/kg [Lien, E. J .; Kumler, W. D. J . Med. Chem.
1968, 11, 214]. This suggests that 3 is basically nontoxic because of
easy decomposition of 3 into 4. On the other hand, cytotoxicity of
N,N,N′,N′-tetramethylurea, a synthetic precursor for a linear-type
chloroamidinium salt, has been reported [Chen, S.; Xu, J . Tetrahedron
Lett. 1992, 33, 647].
(7) Substitution reactions of 3 acting as an electrophile have been
reported: Kessler, H.; Kalinowski, H.-O. Leigibs Ann. Chem. 1971, 743,
1. Kalinowski, H.-O.; Kessler, H.; Walter, A. Tetrahedron 1974, 30,
1137. Ponti, P. P.; Baldwin, J . C.; Kaska, W. C. Inorg. Chem. 1979,
18, 873. Isolated examples of the use of 3 as a dehydrating agent can
also be found in recent literature. For example, see: Okawa, T.; Eguchi,
S. Tetrahedron Lett. 1996, 81. Hirose, M.; Kawai, R.; Hayakawa, Y.
Synlett 1997, 495. Iwata, S.; Matsuoka, H.; Tanaka, K. J . Chem. Soc.,
Perkin Trans. 1 1997, 1357. Aoyama, T.; Satoh, T.; Yonemoto, M.;
Shibata, J .; Nonoshita, K.; Arai, S.; Kawakami, K.; Iwasawa, Y.; Sano,
H.; Tanaka, K.; Monden, Y.; Kodera, T.; Arakawa, H.; Suzuki-
Takahashi, I.; Kamei, T.; Tomimoto, K. J . Med. Chem. 1998, 41, 143.
Node, M.; Fujiwara, T.; Ichihashi, S.; Nishide, K. Tetrahedron Lett.
1998, 39, 6331. Okawa, T.; Kawase, M.; Eguchi, S. Synthesis 1998,
1185.
(10) Koenig, H.-B.; Wilfried S.; Cologne, H. D.; Metzger, K. G. Ger.
Offen. DE 2104579, 1972; Chem. Abstr. 1972, 77, 140048. Koenig, H.-
B.; Schroeck, W.; Disselnkoetter, H.; Metzger, K. G. US 3959258, 1976;
Chem. Abstr. 1976, 85, 160079.
10.1021/jo990210y CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/24/1999

2-Chloro-1,3-dimethylimidazolinium Chloride
J . Org. Chem., Vol. 64, No. 19, 1999 6985
Ta ble 2. P r ep a r a tion of Ester s
Sch em e 1
Ta ble 1. Solu bilitiesa of 3 in Va r iou s Solven ts a t r t
a
b
Nonoptimized, isolated yield. The product is commercially
available.
Ta ble 3. Ester ifica tion of Cycloa r ten ol
a
b
Solvent/3 ) mL/g. Reactive solvents.
mp 95-100 °C dec. Although 3 is stable to oxygen, it is
gradually decomposed in the presence of moisture to
produce 4 and hydrochloric acid. Thus, 3 is relatively
unstable in protic solvents and the decomposition is
accelerated in the presence of a base.12 However, it is
stable at room temperature for over a year when kept
desiccated. The solubilities of 3 in various solvents at
room temperature are shown in Table 1.
a
Ap p lica tion of DMC (3) to Or ga n ic Syn th esis. (I)
Acyla tion . The first reported use10 of DMC (3) as a
condensation reagent was in 1972 in the amidation of
penicillanic acid. In our studies, we also observed that 3
acted as an effective dehydrating agent in intermolecular
condensation reactions between carboxylic acids and a
variety of nucleophiles containing an active hydrogen.
These reactions occurred under nearly neutral conditions.
In a typical experiment, 1 equiv each of a carboxylic acid,
a nucleophile, and 3 in a halogenated solvent such as
dichloromethane are treated with 2 equiv of an amine
(i.e., triethylamine or pyridine) at room temperature, and
the crude products are isolated by a standard two-phase
partition method (see the Experimental Section). Esters
prepared using this procedure are reported in Table 2.13
A carboxylic acid with an unprotected guanidyl group was
esterified smoothly (run 3 in Table 2). Particularly
Nonoptimized, isolated yield.
noteworthy was that even a hindered alcohol could be
esterified in high yield (run 7 in Table 2). The method
was also applicable to the esterification of cycloartenol,
a natural triterpene alcohol, with a range of amino acids
(Table 314).
The coupling of other nucleophiles with acids also
occurred efficiently. The acylation of 2-mercapto-1,3-
thiazoline (Table 415), the preparation of acid anhydrides
(Table 516), and the acylation of 1,3-diones (Table 617)
were all carried out. In the reaction with diones an
(13) References to the products in Table 2 are as follows: (a) Run
1: Korte, W. D. J . Chromatogr. 1981, 214, 131. (b) Run 3: Muramatsu,
M.; Shiraishi, S.; Fujii, S. Biochim. Biophys. Acta 1972, 285, 224. (c)
Run 4: ref 4. (d) Run 5: Ono, N.; Yamada, T.; Saito, T.; Tanaka, K.;
Kaji, A. Bull. Chem. Soc. J pn. 1978, 51, 2401. (e) Runs 6 and 7:
Takahashi, S.; Cohen, L. A.; Miller, H. K.; Peake, E. G. J . Org. Chem.
1971, 36, 1205.
(14) References to the products in Table 3 are as follows; (a) runs
1-3: Isobe, T.; Imai, Y.; Saito, M.; Murata, S.; Nagao, T.; Tsurumi, C.
J pn. Kokai Tokkyo Koho, J P 05 239088, 1993; Chem. Abstr. 1994, 120,
134934. (b) Run 4: Kimura, G.; Hirose, Y.; Yoshida, K.; Kuzuya, F.;
Fujita, K. Eur. Patent EP 166542, 1986; Chem. Abstr. 1987, 106, 18881.
(15) References of the products in Table 4 are as follows. (a) Run 1:
Yamada, S. J . Org. Chem. 1992, 57, 1591. (b) Run 2: Izawa, T.;
Mukaiyama, T. Bull. Chem. Soc. J pn. 1979, 53, 555. (c) Run 3: Isobe,
T. J pn. Kokai Tokkyo Koho, J P 07 010853, 1995; Chem. Abstr. 1995,
123, 33057. (d) Run 4: Nagao, Y.; Seno, K.; Kawabata, K.; Miyasaka,
T.; Takao, S.; Fujita, E. Chem. Pharm. Bull. 1984, 32, 2687.
(11) Mukaiyama, T.; Isobe, T.; Kato, M.; Miyagaki, M.; Kogo, S. J pn.
Kokai Tokkyo Koho, J P 59 025375, 1984; Chem. Abstr. 1984, 101,
151844. Mukaiyama, T.; Isobe, T.; Kato, M.; Miyagaki, M.; Kogo, S.
J pn. Kokai Tokkyo Koho, J P 59 039851, 1984; Chem. Abstr. 1984, 101,
130410. Kiso and co-workers also reported the preparation of 3
according to our method (Kiso, Y.; Fujiwara, Y.; Kimura, T.; Nishitani,
A.; Akaji, K. Int. J . Peptide Protein Res. 1992, 40, 308).
(12) Time-dependent measurement of 3 in CD3OD using 1H NMR
showed 30% and 70% decomposition after 7 and 24 h, respectively,
whereas 3 was stable in CDCl3 even after 24 h (6% decomposition).
Interestingly, 3 was stable in D2O (only 3% decomposition after 24 h),
but its rapid disappearance was observed in 50% pyridine-d5 in D2O
(76% and 100% decomposition after 10 min and 3 h, respectively).

6986 J . Org. Chem., Vol. 64, No. 19, 1999
Isobe and Ishikawa
Ta ble 4. Acyla tion of 2-Mer ca p to-1,3-th ia zolin e
Sch em e 2
Ta ble 7. Deh yd r a tion of Oxim es
a
b
2,6-L ) 2,6-lutidine, TEA ) triethylamine. Nonoptimized,
isolated yield.
Ta ble 5. P r ep a r a tion of Acid An yd r id es
a
b
Nonoptimized, isolated yield. The product is commercially
available.
(DMAP) under similar conditions (Scheme 2; see run 1
in Table 6).
(II) Deh yd r a tion . DMC (3) proved to be a good
dehydrating agent. Thus, aromatic oximes gave nitriles
quantitatively (Table 7). This reaction could be effected
in one pot from a variety of aldehydes and hydroxylamine
hydrochloride (Table 819). Carboxamides were converted
into either a nitrile (run 1 in Table 920) or an acylguani-
dine (run 2 in Table 9), dependent upon the character-
istics of the starting materials used. For the formation
of the latter product, a carboxamide acted as a nucleo-
phile to 3. On the other hand, in the presence of
trifluoroacetic acid (TFA), nitriles were obtained as sole
products (runs 3-5 in Table 9). The product distribution
from these reactions appears to be dependent upon the
ratio of keto and enol tautomers present, with TFA
effectively increasing the relative concentration of the
enol form (Scheme 3).
a
b
Nonoptimized, isolated yield. The product is commercially
available.
Ta ble 6. Acyla tion of Cyclic 1,3-Dion es
Isocyanides were synthesized from formamides (Table
1021). A low yield was observed for the formamide derived
from benzylamine (run 4 in Table 10). The poor conver-
sion observed may be caused by the high reactivity of 3
(16) References to the products in Table 5 are as follows. (a) Run 2:
Gerrard, W.; Thrush, A. M. J . Chem. Soc. 1953, 2117. (b) Run 3: ref
6. (c) Run 4: Isobe, T.; Saito, M. J pn. Kokai Tokkyo Koho, J P 05
025155, 1993; Chem. Abstr. 1993, 119, 48943. (d) Run 6: Mestres, R.;
Palomo, C. Synthesis 1981, 218. (e) Run 7: Miyoshi, M. Bull. Chem.
Soc. J pn. 1970, 43, 3321. (f) Run 8: Patel, K. M.; Morrisett, J . D.;
Sparrow, J . T. J . Lipid Res. 1979, 20, 674.
(17) References to the products in Table 6 are as follows. (a) Runs
1 and 4: Isobe, T. J pn. Kokai Tokkyo Koho, J P 07 285913, 1995; Chem.
Abstr. 1996, 124, 201688. (b) Run 2: Goldblum, A.; Mechoulam, R. J .
Chem. Soc., Perkin Trans. 1 1977, 1889. (c) Run 3: Anderson, R. J .;
Grina, J .; Kuhnen, F.; Lee, S. F.; Luehr, G. W.; Schneider, H.;
Seckinger, K. Ger. Offen. DE 3902818, 1989; Chem. Abstr. 1990, 112,
215765.
(18) Tabuchi, H.; Hamamoto, T.; Ichihara, A. Synlett 1993, 651.
(19) Reference to the product in run 6 in Table 8 is as follows; Lucier,
J . J .; Tuazon, E. C.; Bentley, F. F. Spectrochim. Acta, Part A 1968, 24,
771; Chem. Abstr. 1968, 69, 14319.
a
b
2,6-L ) 2,6-lutidine, TEA ) triethylamine. sol ) solvent; DE
) 1,2-dichloroethane, DM ) dichloromethane. c Nonoptimized,
isolated yield.
O-acylation occurred under standard conditions. Inter-
estingly, a C-acylated product18 was obtained in compa-
rable yield as a single product when the reaction was
carried out in the presence of 4-(dimethylamino)pyridine
(20) Reference of the product in run 5 in Table 9 is as follows.
Mueller, E.; Huber, H. Chem. Ber. 1963, 96, 670.
(21) Reference to the products in runs 1 and 3 in Table 10 is as
follows. J ohnson, H. W., J r.; Krutzsch, H. J . Org. Chem. 1967, 32, 1939.

2-Chloro-1,3-dimethylimidazolinium Chloride
J . Org. Chem., Vol. 64, No. 19, 1999 6987
Ta ble 8. P r ep a r a tion of Nitr iles in On e-P ot Rea ction of
Ald eh yd es a n d Hyd r oxyla m in e Hyd r och lor id e
Ta ble 10. P r ep a r a tion of Isocya n id es: Deh yd r a tion of
F or m a m id es
a
b
Nonoptimized, isolated yield. The product is commercially
available.
Ta ble 11. P r ep a r a tion of Isoth iocya n a tes fr om
Dith ioca r ba m a tes
a
b
Nonoptimized, isolated yield. The product is commercially
available.
Ta ble 9. Rea ction of Ca r boxa m id es
a
b
Nonoptimized, isolated yield. The product is commercially
available.
Ta ble 12. P r ep a r a tion of Ca r bod iim id es fr om Th iou r ea s
a
b
Nonoptimized, isolated yield. The product is commercially
available.
a
Nonoptimized, isolated yield.
Sch em e 3
thiourea resulted in a low conversion to product (run 4
in Table 12).
Con clu sion s
The versatility of DMC (3) as a dehydrating agent has
been clearly demonstrated. It is noteworthy to point out
that even nonacidic compounds such as carboxamides or
thioureas can be activated by 3. Thus, DMC (3) should
(22) References to the products in Table 12 are as follows. (a) Run
1: Huenig, S.; Lehman, H.; Grimmer, G. Leibigs Ann. Chem. 1953,
579, 77. (b) Run 2: Fell, J . B.; Coppola, G. M. Synth. Commun. 1995,
25, 43. (c) Run 3: Petersen, H. J . Ger. Offen. DE 2557438, 1976; Chem.
Abstr. 1976, 85, 142993. (d) Run 4: Anglada, J . M.; Campos, T.;
Campos, F.; Moreto, J . M.; Pages, L. I. J . Heterocycl. Chem. 1996, 33,
1259.
with the benzyl isocyanide product thus formed with 3.
Isothiocyanates (Table 11) and carbodiimides (Table 1222)
were also prepared from dithiocarbamates and thioureas,
respectively. In the latter reactions the use of an aliphatic

6988 J . Org. Chem., Vol. 64, No. 19, 1999
Isobe and Ishikawa
successively washed with 5% HCl, aqueous saturated NaHCO3,
and water. It was dried (MgSO4) and evaporated to dryness.
The residue was purified by short column chromatography
(SiO2) to give the acylated product.
act as a more useful dehydrating agent than DCC (1) in
organic synthesis because of both its reactivity profile and
the ease of product purification. In the following paper
in this issue we discuss some additional uses of DMC (3)
as a dehydrating agent for the construction of hetero-
cycles.
Gen er a l P r oced u r e for Deh yd r a tion (Ta bles 7-12). To
a solution of a reactant (or reactants) [1 equiv (or each 1 equiv)]
and 323 [1 equiv (or 2 equiv)] in an appropriate solvent was
added dropwise an amine [2 equiv (or 4 equiv)] at room
temperature. The reaction mixture was stirred at room tem-
perature (under reflux in some cases) and then worked up as
previously described.
Exp er im en ta l Section
Commercially available products were directly compared
with authentic samples. The physicochemical data of known
products were compared with the literature values and those
of new products referenced to published values cited in our
patents.
Gen er a l P r oced u r e for Acyla tion (Ta bles 2-6). To a
solution of a carboxylic acid (1 equiv), a nucleophile (1 equiv),
and 323 (1 equiv) in a halogenated solvent was added dropwise
an amine (2 equiv) at room temperature. The mixture was
stirred at room temperature (in some cases reflux was needed
for the completion of the reaction), poured into water, and
extracted with dichloromethane. The organic solution was
2-Ben zoylim in o-1,3-d im eth ylim id a zolid in e (Ru n 2 in
Ta ble 9). Colorless prisms (from hexane-dichloromethane);
mp 85-86 °C. Anal. Calcd for C12H15N3O: C, 66.34; H, 6.96;
N, 19.34. Found: C, 66.20; H, 7.04; N, 19.44. FABMS m/z 218
(MH+); 1H NMR (300 MHz, CDCl3) δ 2.93 (s, 6H), 3.60 (s, 4H),
7.36-7.46 (m, 3H), 8.17 (d, J ) 5.9 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 33.6, 47.5, 127.7, 129.0, 130.5, 138.3, 164.5, 170.8;
IR(KBr) 1560 cm-1 (CdO).
Su p p or tin g In for m a tion Ava ila ble: The preparation
method of DMC (3) and selected spectroscopic data for
compounds described in our patents. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) DMC (3) is essentially stable in dichloromethane.12 Thus, one
can use a pre-prepared solution of 3 in dichloromethane in place of 3
itself as a more convenient method of handling this moisture-sensitive
reagent.
J O990210Y