X. Wang et al. / Tetrahedron Letters 46 (2005) 273–276
Table 1. Copper(I) salt-promoted cyclization of 7 to 5
275
derivatives, and subsequent iodination of the derived
phosphates. This process for iodoimidazoles 2a–b from
template 9 involves eight linear steps with only three iso-
lations and an overall yield of 30%. This process has
been successfully implemented in the pilot plant to pro-
duce multikilogram quantities of LFA-1 inhibitors such
as 1a–b.
Compound 7
Reagent
Equivalent
Yield of 5a,b,c (%)
X = Br
X = Br
X = Br
X = CN
X = CN
X = CN
CuCl
CuBr
CuBr2
CuCl
CuI
2.1
2.1
2.1
2.1
2.1
2.1
85–92
65–75
45–57
89–93
60–70
<30
CuCl2
a Weight % assay by HPLC.
b i-Pr2NEt (2.2 equiv) used.
c Reactions run in a mixture of toluene/CH3CN at 80 °C for 0.5–1 h.
References and notes
1. (a) Kelly, T. A.; Jeanfavre, D. D.; McNeil, D. W.; Woska,
J. R., Jr.; Reily, P. L.; Mainolfi, E. A.; Kishimoto, K. M.;
Nabozny, G. H.; Zinter, R.; Bormann, B.-J.; Rothlein, R. J.
Immunology 1999, 163, 5173–5177; (b) Last-Barney, K.;
Davidson, W.; Cardozo, M.; Frye, L. L.; Grygon, C. A.;
Hopkins, J. L.; Jeanfavre, D. D.; Pav, S.; Qian, C.;
Stevenson, J. M.; Tong, L.; Zindell, R.; Kelly, T. A. J.
Am. Chem. Soc. 2001, 123, 5643–5650.
2. Wu, J.-P.; Kelly, T. A.; Lemieux, R.; Goldberg, D. R.;
Emeigh, J. E.; Sorcek, R. J. U.S. Patent WO-2001007440,
2001.
3. (a) Yee, N. K. Org. Lett. 2000, 2, 2781–2783; (b) Frutos, R.
P.; Stehle, S.; Nummy, L.; Yee, N. K. Tetrahedron:
Asymmetry 2001, 12, 101–104.
We were pleased to find that copper(I) salts are very
effective to promote the cyclization of thiohydantoins
7 to bicyclic guanidine 5 (Table 1). As we already ob-
served in the cyclization of N-(2-aminoaryl)thioureas
to 2-(N-substituted)-aminobenzimidazoles,7 CuCl2 and
CuBr2 were much less effective in promoting this cycliza-
tion. Although more air-sensitive copper(I) salts such as
CuI and CuBr are fairly efficient in effecting the cycliza-
tion, less air-sensitive CuCl and CuBrÆSMe2 provided
more consistent results and better yields. The optimized
result was obtained with CuCl as promoter.
4. Frutos, R. P.; Johnson, M. Tetrahedron Lett. 2003, 44,
6509–6511.
With the utilization of this CuCl-promoted cyclization
to the bicyclic guanidine derivatives, a practical synthe-
sis of LFA-1 inhibitors such as 1a–b was developed
(Scheme 3). Thus, the crude thiohydantoins 7a–b from
12a–b were subjected to 2.1 equiv of CuCl in presence
of 2.2 equiv of diisopropylethylamine in 10:1 mixture
of toluene and acetonitrile at 80 °C for 30 min.7 A por-
tion of Celite was added to the reaction mixture to facil-
itate filtration after a complete conversion. Addition of
acetonitrile was necessary to facilitate dissolution of
both copper(I) chloride and thiohydantoins 7a–b for
the cyclization process. After filtration through a pad
of active carbon, the crude bicyclic guanidines 5a–b were
obtained in >85% yield. Both bicyclic guanidines 5a–b
can be isolated by crystallization from toluene in moder-
ate yield.8 However, it was unnecessary to perform this
operation, because the crude products had a purity of
>95%. Treatment of crude 5a–b with LiN(TMS)2 in
THF at À20 to À10 °C followed by addition of diethyl
chlorophosphate gave 6a–b in >90% yield. Without
purification, iodination of the crude 6a–b was performed
with 4 equiv of TMSCl and 4 equiv of NaI in presence of
2.6 equiv of H2O in methylene chloride at 20–25 °C for
20 min.4 Crude iodoimidazoles 2a and 2b were purified
by crystallization from isopropyl alcohol with a recovery
of >40% over five steps from 11, in both cases. A one-
pot operation was developed for conversion of both iodo-
imidazoles 2a–b to LFA-1 inhibitors 1a–b.2 Treatment
of 2a–b with isopropylmagnesium chloride in THF at
À20 °C was followed immediately by addition of SO2
in THF and NCS, respectively. The resulting mixture
was then treated with piperazine in the presence of water
to give 1a–b in >85% yield after crystallization.
5. (a) Watanabe, M.; Okada, H.; Teshima, T.; Noguchi, M.;
Kakehi, A. Tetrahedron 1996, 52, 2827–2838; (b) Kosasay-
ama, A.; Konno, T.; Higashi, K.; Ishikawa, F. Chem.
Pharm. Bull. 1979, 27, 848–857; (c) Guinamant, J. L.;
Robert, A. Tetrahedron 1986, 42, 1169–1177.
6. (a) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157–160;
(b) Corey, E. J.; Ohtani, M. Tetrahedron Lett. 1989, 30,
5227–5230; (c) Ostresh, J. M.; Schoner, C. C.; Hamashin,
V. T.; Nefzi, A.; Meyer, J.-P.; Houghten, R. A. J. Org.
Chem. 1998, 63, 6509–6511.
7. Wang, X.-j.; Zhang, L.; Xu, Y.; Krishnamurthy, D.;
Senanayake, C. Tetrahedron Lett. 2004, 45, 7167–7170.
8. A typical experimental procedure for CuCl-promoted
cyclization of thiohydantoins 7a–b to bicyclic guanidines
5a–b: To a solution of 5a (175.0 g, 0.35 mol) in a 10:1
mixture of toluene and acetonitrile (800 mL) were added
Celite (120 g) and diisopropylethylamine (138.0 mL,
0.80 mol) followed by CuCl (77.2 g, 0.78 mol). The result-
ing mixture was heated to 80 °C and kept at this temper-
ature for 30 min. After being cooled to 45 °C, the mixture
was filtered. The filtrate was treated with active carbon
(58 g) at 80 °C for 10 min and filtered through a pad of
Celite (30 g). The filtrate was concentrated to a low volume
and the residue was dissolved in THF for the next reaction
without purification. The weight % assay by HPLC
indicated 149.1 g (91%) of 5a in the solution. An analytical
sample of 5a was obtained by crystallization of the crude
1
from toluene: mp 82–84 °C. H NMR (400 MHz, CDCl3):
d7.56 (ABq, J = 9.4 Hz, 2H, ArH), 7.34 (s, 1H, ArH), 7.30
(s, 2H, ArH), 6.96 (ABq, J = 9.4 Hz, 2H, ArH), 4.30 (ABq,
J = 21.9 Hz, 1H, CH2CO), 4.19 (ABq, J = 21.9 Hz, 1H,
CH2CO), 3.43 (ABq, J = 13.9 Hz, 1H, ArCH2), 3.25 (ABq,
J = 13.9 Hz, 1H, ArCH2), 1.85 (s, 3H, CH3). 13C NMR
(400 MHz, CDCl3): d 175.0, 174.3, 154.7, 135.6, 132.8,
132.6, 132.1, 131.0, 128.6, 122.7, 122.4, 65.2, 61.4, 40.8,
21.6. MS: m/z 465 (M+). Anal. Calcd for C19H14BrCl2N3O2:
C, 48.85; H, 3.02; Cl, 15.18; N, 9.00. Found: C, 48.75; H,
3.06; Cl, 15.10; N, 8.87. Compound 5b: mp 79-80 °C. 1H
NMR (400 MHz, CDCl3): d 7.56 (ABq, J = 9.5 Hz, 2H,
ArH), 7.37 (s, 2H, ArH), 7.25 (ABq, J = 9.5 Hz, 2H, ArH),
7.22 (s, 1H, ArH), 4.33 (ABq, J = 22.0 Hz, 1H, CH2CO),
In summary, the first practical synthesis of a new class of
LFA-1 inhibitors has been developed. The key transfor-
mations include the CuCl-promoted intramolecular
cyclization of thiohydantoins to bicyclic guanidine