Cobalt(lI)-catalyzed intramolecular C-H amination with phosphoryl azides: Formation of 6- and 7-membered cyclophosphoramidates

Article abstract of DOI:10.1021/ol100110z

"Chemical Equation Presented" A highly effective Co(II)-based system has been developed for catalytic intramolecular C-H amination with phosphoryl azides without the need of terminal oxidant or other additives, resulting in the high-yielding production of

Full text of DOI:10.1021/ol100110z

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1248-1251
Cobalt(II)-Catalyzed Intramolecular C-H
Amination with Phosphoryl Azides:
Formation of 6- and 7-Membered
Cyclophosphoramidates
Hongjian Lu, Jingran Tao, Jess E. Jones, Lukasz Wojtas, and X. Peter Zhang*
Department of Chemistry, UniVersity of South Florida, Tampa, Florida 33620-5250
pzhang@cas.usf.edu
Received January 15, 2010
ABSTRACT
A highly effective Co(II)-based system has been developed for catalytic intramolecular C-H amination with phosphoryl azides without the
need of terminal oxidant or other additives, resulting in the high-yielding production of cyclophosphoramidates with nitrogen gas as the
byproduct. Additional features of this new catalytic system include the amination of primary C-H bonds and formation of 7-membered-ring
structures.
Metal-catalyzed C-H amination via nitrene insertion con-
stitutes a general strategy for the direct functionalization of
C-H bonds with potential control of selectivities.1 The past
decade has witnessed enormous progress in intramolecular
C-H amination, as a direct result of the successful employ-
ment of dimeric Rh(II)2-based catalysts in combination of
various types of iminoiodane nitrene sources that can be
generated in situ with terminal oxidants.2 Notable examples
include Rh(II)2-catalyzed intramolecular oxidative C-H
amination of carbamates and sulfamates, generating syntheti-
cally valuable 5- and 6-membered heterocycles, respec-
tively.1-3 In addition to substrate design, the continued
success of this potentially far-reaching catalytic approach
demands further development of effective metal catalysts as
well as suitable nitrene sources.
As a broad class of compounds that can be readily accessed
via straightforward synthesis, azides have the potential to
serve as a general type of alternative nitrene source for metal-
catalyzed C-H amination.4 In addition to their wide avail-
ability, amination processes with azides can proceed under
neutral conditions without the need of a terminal oxidant or
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10.1021/ol100110z  2010 American Chemical Society
Published on Web 02/25/2010

base, while generating nitrogen gas as the only byproduct.5
In spite of these potential advantages, only a few metal
complexes have been recognized as effective catalysts for
the decomposition of azides for C-H amination.6-9 They
include the recently reported intermolecular (Co/aryl6 and
carbonyl7a azides; Cu/adamantyl azide8) and intramolecular
(Co/arylsulfonyl azide;7b Rh2/vinyl9a and aryl9b azides)
systems.
Scheme 1. Co(II)-Catalyzed Intramolecular 1,6- and 1,7-C-H
Nitrene Insertion Processes with Phosphoryl Azides
Phosphoryl azides represent a common class of com-
pounds10 and have been previously employed by Breslow
and co-workers to generate phosphoryl nitrenes via photolysis
for studying photochemical reactions.11 It was shown that
the resulting phosphoryl nitrenes were so intriguingly
nonselective that they underwent intermolecular C-H ami-
nation with the solvents without the normal preference for
intramolecular reactions.11 While Rh2Piv4 was indicated to
catalyze the intramolecular C-H amination, the catalytic
thermolysis appeared to be ineffective (52% yield with 15%
catalyst at 120 °C for 87 h).11b We report herein that Co(II)
complexes of appropriate porphyrins [Co(Por)] are highly
effective catalysts for intramolecular C-H amination with
phosphoryl azides under mild conditions.12 Determined by
the nature of the azides, the Co(II)-based catalytic system
can undergo 1,6- or 1,7-C-H nitrene insertion processes,
forming O-P-N containing 6- or 7-membered benzohet-
erocyclic compounds in high yields (Scheme 1). Cyclophos-
phoramidates and related heterocycles have found a number
of applications, in particular in the fields of catalysis and
medicine.13 For example, the 1,3,2-oxazaphosphinane ring
system exists in anticancer drugs cyclophosphamide and
ifosfamide (Figure 1).13e,g In addition to secondary and
tertiary C-H bonds, the current catalytic system is featured
with effective amination of both benzylic and nonbenzylic
primary C-H bonds.
Figure 1. 1,3,2-Oxazaphosphinane ring-based anticancer drugs.
Using phosphoryl azide 1a as a model substrate, we
performed a systematic investigation of its potential catalytic
intramolecular C-H amination reactivity utilizing Co(II)
complexes of different porphyrins under various conditions
(Table 1 and Table S1 in the Supporting Information). As
summarized in Table 1, the commercially available [Co(T-
PP)] (TPP: tetraphenylporphyrin), which was demonstrated
previously to be effective in catalyzing both intermolecular
C-H amination of carbonyl azides7a and intramolecular
C-H amination of arylsulfonyl azides,7b was unproductive
for the amination of 1a (Table 1, entry 1), indicating
phosphoryl azides have lower reactivity than carbonyl and
sulfonyl azides. Encouraged by the hydrogen-bonding-
enhanced catalysis observed in the previous aziridination
system,14 [Co(P1)], in which the D2h-symmetric porphyrin
P1 has amide functionalities at the ortho-positions of the
meso-phenyl groups, was employed as a potential catalyst
and was indeed found to successfully catalyze formation of
the desired amination product 2a in 79% yield (Table 1, entry
2). This suggests possible hydrogen-bonding interaction
between the PdO and NsH units in the supposed nitrene
intermediate (Figure S1, Supporting Information).14 Con-
sistent with this depiction, the use of [Co(P2)] and [Co(P3)],
(4) (a) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297. (b)
Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed.
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T. G. J. Am. Chem. Soc. 2007, 129, 7500. (b) Shen, M.; Leslie, B. E.;
Driver, T. G. Angew. Chem., Int. Ed. 2008, 47, 5056
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(13) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008,
47, 1560. (b) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G.
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P. F.; Browne, P.; Knox, R. J.; Hu, L. J. Med. Chem. 2006, 49, 4333. (e)
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(10) For example, the commercially available, low cost diphenylphos-
phoryl azide (DPPA) is a stable and distillable liquid that has been widely
used in organic syntheses. For early examples, see: (a) Shioiri, T.; Ninomiya,
K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203. (b) Yamada, S.; Ikota,
N.; Shioiri, T.; Tachibana, S. J. Am. Chem. Soc. 1975, 97, 7174.
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71, 6655. (b) Jones, J. E.; Ruppel, J. V.; Gao, G.-Y.; Moore, T. M.; Zhang,
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Org. Lett., Vol. 12, No. 6, 2010
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Table 1. Intramolecular Nitrene C-H Bond Insertion of
Phosphoryl Azide 1a Catalyzed by Co(II) Complexes of
Different Porphyrinsa
Table 2. Co(II)-Catalyzed Intramolecular C-H Amination
To Form 6- and 7-Membered Cyclophosphoramidates from
Azidesa
a Performed with 2 mol % of [Co(Por)] for 12 h in PhCF3 at 80 °C
under N2 in the presence of 4 Å MS; [1a] ) 0.10 M. b Isolated yields.
c TPP ) tetraphenylporphyrin. d Trace amount product.
which have less steric amide functionalities, increased the
yields of 2a to 98% and 96%, respectively (Table 1, entries
3 and 4). Conversely, 2a was only produced in a trace amount
or not formed at all when [Co(P4)] or [Co(P5)] was used
(Table 1, entries 5 and 6), presumably due to the weakening
or prohibition of the hydrogen-bonding interaction resulting
from the steric hindrance of the bulky amides.
Under an optimized condition (1-2 mol % of [Co(P2)]
at 80 °C in PhCF3 for 24 h), the Co(II)-based catalytic system
was found to be effective for the intramolecular C-H
amination with a range of phosphoryl azides (Table 2).15
For example, the primary C-H bonds of both azides 1a and
1b could be intramolecularly aminated, producing the
6-membered cyclophosphoramides 2a and 2b, respectively,
in excellent yields (Table 2; entries 1 and 3). With a slightly
higher catalyst loading (2 mol %), it was noted that the
reactions could be catalyzed in equally high yields by
[Co(P1)] (Table 2; entries 2 and 4). As anticipated, tertiary
and secondary C-H bonds of various types were also
suitable substrates for the catalytic system, forming the
desired 6-membered heterocycles as a mixture of trans- and
cis-isomers (Table 2; entries 5-9). The selective formation
of 2e from 1e without amination of the primary CsH bonds
and aziridination of the CdC double bond (Table 2; entry
7) indicates that the catalytic system may allow for high
control of chemoselectivity. When azide 1h was used as the
substrate, it was a surprise to observe the formation of
a Performed with 1 mol % of [Co(P2)] for 24 h in PhCF3 at 80 °C
under N2 in the presence of 4 Å MS; [1] ) 0.10 M. b Isolated yields. c NMR
yields. d 2 mol % of [Co(P1)]. e 2 mol % of [Co(P2)]. f 60 °C. g dr: 65/35.
h dr: 55/45. i dr: 53/47. j dr: 91/9. k Partial decomposition during purification;
yield would be higher.
(15) DSC experiments indicated that these phosphoryl azides were stable
without decomposition up to at least 250 °C; see the Supporting Information
for details.
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Org. Lett., Vol. 12, No. 6, 2010

Scheme 2. Preparation of Amino Alcohol and N-Protected
Amino Alcohol via Full and Partial Deprotection of Phosphoryl
Groups
Figure 2. X-ray crystal structures of 6-membered (2a) and
7-membered (2n) cyclophosphoramidates.
tection of the phosphoryl group also was found to be possible.
When 2n in THF was treated with a solution of NH3/MeOH
at room temperature, the N-protected 1,4-amino alcohol 4n
was isolated in 85% yield as a result of controlled double
methanolysis of the phosphoryl diester without affecting the
phosphoryl amide linkage.
In summary, a Co(II)-based catalytic system has been
established for the highly effective intramolecular C-H
amination of phosphoryl azides,15 producing a wide range
of cyclophosphoramidates in high yields with nitrogen gas
as the only byproduct. In addition to its neutral and
nonoxidative conditions, this new catalytic system is high-
lighted with features such as amination of primary C-H
bonds and formation of 7-membered-ring structures. Further
studies are underway to render the catalytic system stereo-
selective.
7-membered 2hb in addition to the major 6-membered 2ha
(Table 2; entries 10 and 11), suggesting the unusual capability
of the current catalytic system for the amination of both
benzylic and nonbenzylic primary C-H bonds as well as
for the construction of medium-sized ring structures. It was
shown subsequently that various 7-membered cyclophos-
phoramidates could be cleanly generated in high yields in
the absence of benzylic C-H bonds as exemplified with
azides 1i-p that contain different functional groups (Table
2; entries 12-22).
Besides various spectroscopic characterizations, both the
6-membered (2a) and 7-membered (2n) O-P-N containing
benzoheterocyclic structures were further confirmed by X-ray
crystallographic analysis (Figure 2).
In addition to their various applications shown in the
literature,13 these cyclophosphoramidates should also serve
as useful precursors for preparation of synthetically valuable
1,3- and 1,4-amino alcohols. As an example to demonstrate
this kind of synthetic utility, the phosphoryl group of
7-membered amination product 2n could be fully deprotected
upon treatment with LiAlH4 in THF at room temperature,
generating 1,4-amino alcohol 3n in 72% isolated yield
(Scheme 2). By changing reaction conditions, partial depro-
Acknowledgment. We are grateful to ACS-PRF (AC
Grant), NSF (CAREER Award), and NSF (CRIF: MU-
0443611, Mass Facility) for financial support.
Supporting Information Available: Experimental pro-
cedures and analytical data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL100110Z
Org. Lett., Vol. 12, No. 6, 2010
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