Copper-catalyzed synthesis of medium-and large-sized nitrogen heterocycles via N-arylation of phosphoramidates and carbamates

Article abstract of DOI:10.1021/ol052126c

(Chemical Equation Presented) We have developed an efficient method for the preparation of medium- and large-sized nitrogen heterocycles via copper-catalyzed intramolecular N-arylation of phosphoramidates and carbamates. Introduction of the phosphoryl gro

Full text of DOI:10.1021/ol052126c

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4781-4784
Copper-Catalyzed Synthesis of Medium-
and Large-Sized Nitrogen Heterocycles
via N-Arylation of Phosphoramidates
and Carbamates
Ting Yang,† Changxue Lin,† Hua Fu,*,† Yuyang Jiang,†,‡ and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology,
Ministry of Education, Department of Chemistry, Tsinghua UniVersity,
Beijing 100084, P. R. China, and Key Laboratory of Chemical Biology,
Guangdong ProVince, Graduate School of Shenzhen, Tsinghua UniVersity,
Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
Received September 3, 2005
ABSTRACT
We have developed an efficient method for the preparation of medium- and large-sized nitrogen heterocycles via copper-catalyzed intramolecular
N-arylation of phosphoramidates and carbamates. Introduction of the phosphoryl group or tert-butoxycarbonyl at N-termini can improve
intramolecular cyclization under copper catalysis, and the phosphoryl and tert-butoxycarbonyl can easily be removed under the mild conditions;
thus, the convenient and efficient method is suitable for the preparation of medium- and large-sized nitrogen heterocycles.
Medium-sized heterocycles are very important compounds
as biologically active natural products,1 as drug candidates,2
as materials3 and for catalysis.4 Direct cyclization methods
are often ineffective because of enthalpic (increasing strain
in the transition state) and entropic influences (probability
of the chain ends meeting) unless certain conformational
restraints are present in the acyclic precursor, so the
generation of medium-sized nitrogen heterocycles possessing
defined constitutions and configurations is still a challenge
in organic synthesis.1a Among the various available methods,
such as cycloaddition reactions, ring transformations, and
cyclization reactions, the latter are probably the most
commonly used because of a number of possible initiators
and terminators. For example, the Staudinger ligation reac-
tion, independently developed by the research groups of
Bertozzi5 and Raines,6 might also serve as a powerful method
for the facilitation of difficult lactamization reactions.
† Department of Chemistry.
‡ Graduate School of Shenzhen.
(1) Reviews: (a) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125.
(b) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073. (c) Evans, P. A.;
Holmes, B. Tetrahedron 1991, 47, 9131. Selected examples: (d) Lindstro¨m,
U. M.; Somfai, P. Chem. Eur. J. 2001, 7, 94. (e) Biera¨ugel, H.; Jansen, T.
P.; Schoemaker, H. E.; Hiemstra, H.; van Maarseveen, J. H. Org. Lett. 2002,
4, 2673. (f) Derrer, S.; Davies, J. E.; Holmes, A. B J. Chem. Soc., Perkin
Trans. 1 2000, 2957. (g) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.;
Baran, P. Angew. Chem., Int. Ed. 2000, 39, 44. (h) Maier, M. E. Angew.
Chem., Int. Ed. 2000, 39, 2073.
(2) (a) Taunton, J.; Collins, J. L.; Schreiber,S. L. J. Am. Chem. Soc.
1996, 118, 10412. (b) Murray, P. J.; Kranz, M.; Ladlow, M.; Taylor, S.;
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J. R.; Ghadiri, M. R. Angew. Chem., Int. Ed. 2001, 40, 988.
(4) Jarvo, E. R.; Miller,S. J. Tetrahedron 2002, 58, 2481.
On the other hand, palladium-catalyzed amination/amida-
tion of aryl halides and pseudohalides has attracted consider-
able attention during the past 10 years because of the
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pioneering contributions by the groups of Buchwald7 and
Hartwig.8 The copper-catalyzed Ullmann reaction (N-aryla-
tion of amines) and Goldberg reaction (N-arylation of
amides) have been the subject of recent studies.9-14 Copper-
catalyzed intramolecular N-arylation of amines leading to a
seven-membered ring has been reported from the groups of
Ma15a and Fukuyama,15b respectively. Banfi and co-workers
have elegantly demonstrated such a possibility for the
preparation of 7-membered heterocycles employing a ring
expansion of a R-lactam with a neighboring nitrogen
nucleophile.16 Both palladium- and copper-catalyzed in-
tramolecular N-arylations leading to 5-, 6-, and to a lesser
extent, 7-membered rings have been investigated, and various
efficient catalytic systems have been developed.15,17 However,
most of the attempts to access medium- and large-sized ring
systems by direct N-arylation were, to the best of our
knowledge, unsuccessful. Recently, domino copper-catalyzed
intermolecular N-arylation of R-lactam followed by ring
expansion has been developed for the synthesis of medium-
sized nitrogen heterocycles by Buchwald and co-workers.18
Zhu and co-workers have developed a novel catalytic domino
process to construct azaphenanthrenes fused to 8-, 10-, 11-,
and 13-membered lactam motifs, where the bisaryl diiodide
function plays the crucial role in the cyclization of amides.19
In this paper, our copper-catalyzed results are presented on
the development of novel and generally applicable methods
applying N-arylation of phosphoramidates and carbamates
to provide the closure of medium- and large-sized nitrogen
heterocycles.
N-Phosphorylation of various unnatural amino acids and
the peptide Ala-Pro was carried out via the Antherton-Todd
method (Scheme 1).20 Reaction of diisopropyl phosphite (1)
Scheme 1. Synthetic Route of Medium- and Large-Sized
Nitrogen Heterocycles
with amino acids (2a-f) or peptide Ala-Pro (2g) in water
and ethanol in the presence of carbon tetrachloride and
triethylamine provided N-diisopropylphosphoamino acids
(DIPP-AA) (3a-f) and peptide (DIPP-peptide) (3g) (Figure
1) in 85-89% yields. N-Boc-amino acids (N-tert-butoxy-
(5) (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007. (b) Saxon,
E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2, 2141. (c) Saxon,
E.; Luchansky, S. J.; Hang, H. C.; Yu, C.; Lee, S. C.; Bertozzi, C. R. J.
Am. Chem. Soc. 2002, 124, 14893.
(6) (a) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2,
1939. (b) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2001, 3,
9. (c) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Org. Chem. 2002,
67, 4993.
(7) (a) Wolfe, J. P.; Wagaw; S.; Marcoux, J. F.; Buchwald, S. F. Acc.
Chem. Res. 1998, 31, 805. (b) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125.
(8) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (b) Hartwig,
J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim,
2000; Chapter 7.
(9) Ley, S.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(10) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793 and
references therein.
(11) Klapars, A.; Antila, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727.
(12) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(13) Kang, S.-K.; Kim, D.-H.; Pak, J.-N. Synlett 2002, 427.
(14) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459. (b) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(15) Copper-catalyzed: (a) Ma, D.; Xia, C. Org. Lett. 2001, 2, 2583.
(b) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231.
(16) (a) Banfi, L.; Guanti, G.; Rasparini, M. Tetrahedron Lett. 1998,
39, 9539. (b) Banfi, L.; Guanti, G.; Rasparini, M. Eur. J. Org. Chem. 2003,
1319.
(17) Palladium-catalyzed: (a) Wolfe, J. P.; Rennels, R. A.; Buchwald,
S. L. Tetrahedron 1996, 52, 7525. (b) Wagaw, S.; Rennels, R. A.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 8451. (c) Yang, B. H.; Buchwald, S. L.
Org. Lett. 1999, 1, 35. (d) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519.
(e) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133. (f) Margolis, B. J.;
Swidorski, J. J.; Rogers, B. N. J. Org. Chem. 2003, 68, 644. (g) Nozaki,
K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang, H.-Z.; Fujiki, M.;
Yamaguchi, S.; Tamao, K. Angew. Chem., Int. Ed. 2003, 42, 2051. (h) Brain,
C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814.
Figure 1. Synthesized compounds 3a-i
carbonylamino acids) (3h and 3i) were also prepared
according to the general procedure.21 Coupling of N-
phosphoamino acids and peptide or N-Boc-amino acids with
2-bromoaniline in pyridine using 2 equiv of diphenyl
phosphite (DPP) as the coupling agent according to the
reported procedure22,23 gave phosphoramidates and N-Boc-
peptide analogues (4) in 65-95% yields.
The cyclization of phosphoramidates and carbamates via
N-arylation is the key step. We first attempted the cyclization
of compound 4b in toluene under catalysis of CuI using
proline as the ligand (Scheme 1). TLC showed that it
transferred into the eight-membered cyclic product 5b within
72 h, and isolation by silica gel column chromatography
(20) Ji, G. J.; Xue, C. B.; Zeng, J. N.; Li, L. P.; Chai, W. G.; Zhao, Y.
F. Synthesis 1988, 444.
(18) Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am.
Chem. Soc. 2004, 126, 3529.
(19) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004, 126,
14475.
(21) Ejim, L.; Mirza, I. A.; Capone, C.; Nazi, I.; Jenkins, S.; Chee, G.-
L.; Berghuisb, A. M.; Wrighta, G. D. Bioorg. Med. Chem. 2004, 12, 3825.
(22) Yamazaki, N.; Higashi, F. Tetrahedron Lett. 1972, 5047.
(23) Yamazaki, N.; Higashi, F. Tetrahedron 1974, 30, 1323.
4782
Org. Lett., Vol. 7, No. 21, 2005

provided pure product 5b in 68% yield. Encouraged by these
results, we set out to test our proposal on the preparation of
7-, 9-, 10-, 12-, and 16-membered cyclic compounds.
Fortunately, these different-sized nitrogen heterocycles also
were obtained using a similar procedure in 53-64% yields
(see Table 1). All of these cyclic products (5) were
heterocycles. The phosphoryl group in 5 can be deprotected
in acetic acid saturated with gaseous HCl at room temper-
ature. For example, the P-N bond of compound 5e was
completely cleaved to give product 6e in 24 h under these
conditions.
Cyclization of N-Boc-protected peptide analogues 4h and
4i was also investigated under the similar cyclization
conditions, and the corresponding nitrogen heterocycles 5h
and 5i were obtained in good yields (60 and 62%, respec-
tively). It is well-known that Boc group can easily be
removed in TFA, so it is a good protecting reagent of
N-termini for the acyclic precursors.
Table 1. Yields of the Synthesized Medium- and Large-Sized
Nitrogen Heterocycles under Copper Catalysis
We are interested in mechanistic studies of the copper-
catalyzed intramolecular N-arylation. Deprotection of 4i in
TFA led to compound 4′i containing free amino group at
N-termini. We tried the CuI-catalyzed cyclization of 4′i under
similar conditions; interestingly, no 8-membered cycle
product was obtained. The result showed that introduction
of phosphoryl or Boc at the N-termini could conformationally
restrain the acyclic precursor, which could be favorable for
intramolecular cyclization. Thus, a simplified mechanistic
view for the formation of cyclic products (5) from 4 is
summarized in Scheme 2. First, cuprous ion reacted with
Scheme 2. Possible Copper-Catalyzed Cyclization Mechanism
proline salt to form the chelate I, the coordination of the
copper catalyst (I) with the two nitrogen atoms of the amide
and the DIPP-NH or Boc-NH led to the complex II, which
makes bromine and imine of DIPP-NH or Boc-NH near the
subsequent copper-catalyzed coupling produced III. The
other possible explanation is that the coordination of the
copper catalyst (I) with the phenylbromide ring and the
nitrogen of the DIPP-NH or Boc-NH provided the π-complex
II′. Next, intramolecular nucleophic substitution occurred at
the aromatic ring, and removal of HBr by the action of
potassium carbonate provided the desired nitrogen hetero-
cycle III′. The removal of copper catalyst system in III and
III′ yielded the target products 5.
In summary, we have developed an efficient method for
the preparation of medium- and large-sized nitrogen hetero-
cycles via copper-catalyzed intramolecular N-arylation of
phosphoramidates and carbamates. Introduction of the phos-
phoryl group or tert-butoxycarbonyl at N-termini can improve
intramolecular cyclization under copper catalysis, and the
1
determined by 31P, H, and 13C NMR and high-resolution
MS. To the best of our knowledge, this represents the first
examples wherein an intramolecular direct copper-catalyzed
N-arylation of phosphoramidates has been successfully
applied to the synthesis of medium- and large-sized nitrogen
Org. Lett., Vol. 7, No. 21, 2005
4783

phosphoryl and tert-butoxycarbonyl can easily be removed
under the mild conditions, so the convenient and efficient
method can be suitable for the preparation of medium and
large-sized nitrogen heterocycles.
Program of MOE, P. R. C., and the National Natural Science
Foundation of China (Grant No. 20472042).
Supporting Information Available: Experimental pro-
cedures, product characterization data, and 1H and 13C NMR
spectra of the synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
Excellent Dissertation Foundation of the Chinese Ministry
of Education (No. 200222), the Excellent Young Teacher
OL052126C
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Org. Lett., Vol. 7, No. 21, 2005