A new catalytic cross-coupling approach for the synthesis of protected aryl and heteroaryl amidines

Article abstract of DOI:10.1021/ol025547s

(equation presented) A new method for the synthesis of protected benzamidines is described. The commercially available 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea guanidylation reagent, after SEM-protection, functions as an amidine-forming cros

Full text of DOI:10.1021/ol025547s

ORGANIC
LETTERS
2002
Vol. 4, No. 6
983-985
A New Catalytic Cross-Coupling
Approach for the Synthesis of Protected
Aryl and Heteroaryl Amidines
,‡
,†
Carrie L. Kusturin,† Lanny S. Liebeskind,* and William L. Neumann*
Chemistry and Process Technology, Pharmacia Corporation, 800 North Lindbergh,
St. Louis, Missouri, and Department of Chemistry, Emory UniVersity,
1515 Pierce DriVe, Atlanta, Georgia 30322
william.l.neumann@pharmacia.com
Received January 11, 2002
ABSTRACT
A new method for the synthesis of protected benzamidines is described. The commercially available 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-
thiopseudourea guanidylation reagent, after SEM-protection, functions as an amidine-forming cross-coupling partner under Liebeskind−Srogl
conditions. In the presence of copper(I) thiophenecarboxylate (CuTC), the palladium-catalyzed cross-coupling of the SEM-protected thiopseudourea
reagent with boronic acids affords fully protected benzamidines in good to excellent yield (40−91%).
The amidine functional group is found in many biological
molecules,1 and the benzamidine variant is often employed
as an excellent guanidine surrogate in medicinal chemistry.2
Consequently, a number of synthetic methods have been
developed for the preparation of amidines.3 Most of these
methods rely on the nucleophilic addition of amines or
ammonia equivalents to nitriles under forcing conditions, or
to suitably activated carboxylate equivalents, such as imidoyl
chlorides, imidates, and thioimidates. As a complement to
these procedures, we report herein a new and mild method
of substituted benzamidine synthesis that involves the cross-
coupling of boronic acids with the protected methyl thio-
pseudourea, 2 (Scheme 1). This new, nonbasic, and general
methodology is an extension of the previously described
Liebeskind-Srogl thioether cross-coupling protocol.4 As
Scheme 1
† Pharmacia Corporation.
‡ Emory University.
(1) Patai, S.; Rappoport, Z. The Chemistry of Amidines and Imidates,
Wiley: New York, 1991; Vol. 27.
(2) Zablocki, J. A.; Miyano, M.; Garland, R.; Pireh, D.; Schretzman, L.;
Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite,
B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. J. Med.
Chem. 1993, 36, 1811. Greenhill, J. V. ; Lue, P. In Amidines and Guanidines
in Medicinal Chemistry, Progress in Medicinal Chemistry; Ellis, G. P.,
Luscombe, D. K., Eds.; Elsevier: New York, 1993; Vol. 30, Chapter 5, pp
203-326.
(3) For an excellent review, see: Yet, L. A Survey of Amidine Synthesis.
Technical Report No. 3, Vol. 4, 2000; Albany Molecular Research, Inc.,
New York.
10.1021/ol025547s CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/19/2002

such, it offers a strategic alternative to the aforementioned
nucleophilic addition chemistry for the preparation of fully
protected aryl and heteroaryl amidines in the presence of a
variety of sensitive functionalities.
Table 1. Functionalized Benzamidine Synthesis
The method takes advantage of boronic acids as readily
available, mild, stable and nontoxic reagents that are compat-
ible with a wide variety of functional groups. The cross-
coupling partner, amidination reagent 2, is easily prepared
from commercially available guanidylation reagent 15 in one
step by deprotonation with sodium hydride followed by
treatment with SEM chloride (Scheme 1). Preliminary
attempts to use guanidylation reagent 1 as a cross-coupling
partner under palladium-catalyzed, copper carboxylate-
mediated conditions gave unsatisfactory results.6 We, there-
fore, turned our attention to the SEM-protected reagent 2.
Boronic acids 3-10 reacted with amidination reagent 2
in THF or dioxane at 60-70 °C to give fully protected
functionalized benzamidines 11-18 in good to excellent
yields in a palladium-catalyzed (Pd(PPh3)4 or Pd2dba3 and
tri-2-furylphosphine (TFP), copper carboxylate (copper(I)
thiophenecarboxylate, CuTC)-mediated cross-coupling (Table
1). As described in earlier reports from the Liebeskind
laboratory,4 both the catalytic palladium and stoichiometric
copper carboxylate are required for cross-coupling. Of the
catalyst systems studied for the amidination cross-coupling,
the Pd2dba3/TFP system gave the best results.7 The ability
to generate the protected benzamidine products in the
presence of aldehyde, ketone, and ester functionality (entries
7, 8, and 9, respectively) is particularly noteworthy. The
reaction products are nonpolar materials due to the Boc- and
SEM-protecting groups and are easily purified by chroma-
tography on silica gel using hexanes/ethyl acetate mixtures.
Treatment of pyridine-3-boronic acid with amidination
reagent 2, 1.5 equiv of CuTC, and 5-10% Pd catalyst
afforded only trace amounts of the desired cross-coupling
product. The additive Zn(OAc)2 was shown earlier to have
a beneficial effect on these types of cross-coupling reactions
with heterocyclic boronic acids such as pyridine-3-boronic
acid (possibly by coordinating to Lewis basic sites of the
heterocycle).4a The addition of 1.2 equiv of Zn(OAc)2 to the
pyridine-3-boronic acid reaction mixture did increase the
overall conversion to the desired protected amidine product,
but in repeated runs, 40-50% starting material still remained
after the typical 12-16 h reaction time. We have now found
that for the amidination cross-coupling reaction with het-
a CuTC: Cu(I) thiophene-2-carboxylate. b Pd(PPh3)4/THF. c Pd2dba3 /TFP/
dioxane. d 90 °C.
erocyclic boronic acids, the use of 3 equiv of CuTC affords
much improved results. Table 2 illustrates representative
protected heterocyclic amidines that have been prepared by
this cross-coupling chemistry. In each case, little or no
product was observed under the standard coupling conditions
(1.5 equiv of CuTC), with starting amidination reagent 2
recovered unchanged. However, in the presence of 3 equiv
of CuTC, all of reagent 2 was consumed within 6-12 h. In
each of these heterocyclic cases, 2 equiv of the boronic acid
was used to optimize the cross-coupling yields. As is shown
for the three examples reported in Table 2, purified yields
ranged from 40 to 70%, slightly lower than the aryl cases
shown in Table 1. The fate of the mass balance of reagent
2, which is consumed but does not lead to coupling product,
is under investigation at this time.8
(4) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (b) Savarin,
C.; Srogl, J. Liebeskind, L. S. Org. Lett. 2001, 3, 91. (c) Liebeskind, L. S.;
Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(5) Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1987, 52, 1700.
(6) Low yields of cross-coupling products have been detected in the
palladium-catalyzed copper carboxylate-mediated reactions of reagent 1 with
3-methoxyphenylboronic acid, but the reaction mixtures have proven
difficult to optimize. â-Hydride elimination may divert the reaction manifold
away from the desired cross-coupling chemistry.
(7) Pd2dba3‚CHCl3 was purchased from Aldrich Chemical Co. and used
as received.
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Org. Lett., Vol. 4, No. 6, 2002

Table 2. Heterocyclic Amidine Synthesisa
Scheme 2. Synthesis of 4-Amidinophenylalanine
a 5% Pd2(dba)3 /TFP/THF/65 °C/3 equiv of CuTC.
Finally, we report the extension of this new methodology
to the preparation of the known 4-amidinophenylalanine
methyl ester 28. Again, this method provides an alternative
to the preparation of 4-cyanophenylalanine and subsequent
nitrile nucleophilic addition chemistry.9 As summarized in
Scheme 2, the commercially available 4-boronophenylalanine
25 was converted to the N-Boc methyl ester derivative 26
under standard conditions. Cross-coupling with amidination
reagent 2 under standard conditions proceeded smoothly to
afford the fully protected amidinophenylalanine derivative
27 in 54% yield. Deprotection of compound 27 to the free
amidine product 28 was accomplished in one step by
treatment with a 1:1 solution of TFA in methylene chloride.
In conclusion, the scope and limitations of this new
functionalized amidine synthesis via the Liebeskind-Srogl
copper carboxylate-mediated, palladium-catalyzed cross-
coupling chemisty have been studied. The methodology
allows the synthesis of fully protected aryl and heterocyclic
amidines in the presence of a range of sensitive functionality.
(8) It is possible that the solution aggregation hinders the transmetalation
of heterocyclic boronic acids to the oxidative addition product of the Pd
catalyst and thiomethyl reagent 2.
(9) Vieweg, H.; Wagner, G. Pharm. 1983, 38, 170. Kent, D. R.; Cody,
W. L.; Doherty, A. M. J. Pept. Res. 1998, 52, 201.
Acknowledgment. The authors thank Dr. Jiri Srogl of
Emory University and Dr. Samuel Tremont of Pharmacia
for helpful discussions. We also thank James Doom and
David Masters-Moore of the Pharmacia Mass Spectrometry
Group for high-resolution mass spectroscopy data.
(10) Typical experimental procedure: The boronic acid (1.2-1.5
equiv), Pd catalyst (5-10 mol %), and CuTC (1.5 equiv) were placed in a
50 mL flask and submitted to 3 vacuum/argon cycles. A sparged solution
of the amidination reagent 2 in dioxane was added via syringe. Additional
dry degassed dioxane was added as needed, and the mixture was heated at
60-70 °C for 16 h. Following the general procedure, a solution of
amidination reagent 2 (5.0 mL of a 45 mg/mL solution in dioxane) was
added to 3-nitrophenylboronic acid 5 (110 mg, 0.66 mmol), CuTC (151
mg, 0.80 mmol), Pd2dba3‚CHCl3 (27 mg, 5 mol %, 10 mol % Pd), and
TFP (43 mg, 7 × 5 mol %). Additional dioxane (10 mL) was added, and
the reaction was heated at 65 °C for 16 h; after radial chromatography (10/1
hexanes-ethyl acetate), 13 (200 mg, 80% yield) was obtained. Full details
are contained in the Supporting Information.
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025547S
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