Phosphoryl azides as versatile new reaction partners in the Cu-catalyzed three-component couplings

Article abstract of DOI:10.1021/jo7016247

(Chemical Equation Presented) Phosphoryl azide was successfully employed as an efficient reacting partner in the Cu-catalyzed three-component reaction with 1-alkynes and amines to produce the corresponding phosphoryl amidines in high yields. A range of fr

Full text of DOI:10.1021/jo7016247

Phosphoryl Azides as Versatile New Reaction
Partners in the Cu-Catalyzed Three-Component
Couplings
The developed three-component coupling is believed to
proceed via three stages: copper-catalyzed cycloaddition be-
tween sulfonyl azides and alkynes to afford triazole species,
rearrangement of the cyclic compounds to form ketenimine
intermediates upon release of nitrogen, and then subsequent
addition of heteroatomic moieties leading to the N-sulfonimino
Seok Hwan Kim, Doo Young Jung, and Sukbok Chang*
9
products.
Center for Molecular Design and Synthesis (CMDS),
Department of Chemistry and School of Molecular Science
During the course of investigating the scope of azide
components, we were much interested in the utility of phos-
phoryl azides since the produced N-phosphorylated moiety is
(
BK21), Korea AdVanced Institute of Science and Technology
(
KAIST), Daejeon 305-701, Republic of Korea
10
more labile than the N-sulfonylated moiety. In addition, it was
envisioned that the prospective products, phosphoryl amidines,
were highly versatile because they were already known to have
sbchang@kaist.ac.kr
11
interesting bioactivities such as oncolytic activity. In addition,
a phosphoramidic acid has been used as a prodrug for inhibition
ReceiVed July 25, 2007
1
2
of D-alanine. Therefore, we envisaged that the N-phospho-
rylimino group would expand significantly the utility of amidine
chemistry.
Herein, we disclose the results of utilizing phosphoryl azides
in the Cu-catalyzed three-component reaction with terminal
alkynes and amines. Subsequent synthetic applications of the
obtained phosphoryl amidines also will be described.
We initially examined the feasibility of a range of phosphoryl
13
azides in the CuI-catalyzed reaction with phenylacetylene and
diisopropylamine (Table 1). Reactions with phosphoryl azides
derived from aliphatic alcohols were sluggish regardless of their
structural variations, thus leading to poor yields under ambient
conditions (entries 1 and 2). In sharp contrast, diphenylphos-
phoryl azide (DPPA) participated in the coupling reaction with
excellent efficiency to afford the corresponding N-phophoryl
amidine in 90% yield (entry 3). Electronic variation on the
phenoxy substituent turned out to affect significantly the reaction
efficiency as demonstrated in entry 4. Notably, an azide prepared
from BINOL readily underwent the coupling reaction in high
yield (entry 5). It should be mentioned that the low efficiency
encountered in the reaction with N-alkylphosphoryl azides could
be circumvented by an exchange reaction of N-arylphosphoryl
amidines with alkoxides (vide infra).
Phosphoryl azide was successfully employed as an efficient
reacting partner in the Cu-catalyzed three-component reaction
with 1-alkynes and amines to produce the corresponding
phosphoryl amidines in high yields. A range of fruitful
applicability of the produced amidines was also demonstrated
such as an alkoxide exchange and asymmetric R-alkylation
of optically active BINOL-derived amidines.
Under the optimized conditions, the reaction scope was
subsequently examined by using DPPA as a representative azide
1
Since the introduction of organic azides by Griess, extensive
investigation on those compounds has been carried out to
develop synthetically important transformations such as cy-
(7) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
(b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127,
cloaddition,2 nitrene transfer,3 Schmidt reactions, etc. In
4
5
16046. (c) Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S.
particular, the Cu-catalyzed cycloaddition of alkyl or aryl azides
with 1-alkynes has dramatically broadened the scope and utility
K. J. Am. Chem. Soc. 2006, 128, 12366. (d) Yoo, E. J.; Bae, I.; Cho, S. H.;
Han, H.; Chang, S. Org. Lett. 2006, 8, 1347. (e) Cho, S. H.; Chang, S.
Angew. Chem., Int. Ed. 2007, 46, 1897.
6
of azides. We have, in more recent years, explored the synthetic
(8) For some related reports from other groups, see: (a) Cassidy, M. P.;
utility of sulfonyl azides in the Cu-catalyzed three-component
reactions of 1-alkynes with amines, alcohols, or water
leading to N-sulfonyl amidines, imidates, and amides, respec-
Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3154. (b) Cui,
S.-L.; Lin, X.-F.; Wang, Y.-G. Org. Lett. 2006, 8, 4517. (c) Xu, X.; Cheng,
D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9, 1585. (d) Jin, Y.; Fu, H.;
Yin, Y.; Jiang, Y.; Zhao, Y. Synlett 2007, 901.
7
,8
tively.
(9) (a) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed.
2
006, 45, 3154. (b) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V.
(
(
(
1) Griess, P. Philos. Trans. R. Soc. London 1864, 154, 667.
2) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565.
3) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117,
V.; Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730.
(10) (a) Shioiri, T.; Kawai, N. J. Org. Chem. 1978, 14, 2936. (b) Gao,
G.-Y.; Jones, J. E.; Vyas, R.; Harden, J. D.; Zhang, X. P. J. Org. Chem.
2006, 71, 6655.
5
889.
(
(
4) Aub e´ , J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965.
5) Br a¨ se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
(11) Souza, M. C.; Macedo, W. P.; Silva, M. C. M.; Ramos, G. C.; Alt,
H. G. Phosphorus, Sulfur Silicon 2004, 179, 1047.
(12) Chakravarty, P. K.; Greenlee, W. J.; Parsons, W. H.; Patchett, A.
A.; Combs, P.; Roth, A.; Brusch, R. D.; Mellin, T. N. J. Med. Chem. 1989,
32, 1886.
Int. Ed. 2005, 44, 5188.
6) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
(
2
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) Kolb, H. C.; Sharpless,
K. B. Drug DiscoVery Today 2003, 8, 1128.
(13) For preparation: Lee, H. W.; Guha, A. K.; Kim, C. K.; Lee, I. C.
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1
0.1021/jo7016247 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/03/2007
J. Org. Chem. 2007, 72, 9769-9771
9769

TABLE 1. Cu-Catalyzed Three-Component Coupling for the
Formation of Amidines Testing Various Phosphoryl Azidesa
TABLE 2. Scope of Amidine Reaction with DPPAa
a
A mixture of phenylacetylene (1.0 mmol), phosphoryl azide (0.5 mmol),
diisopropylamine (0.75 mmol), and CuI (0.05 mmol) in THF (1 mL) was
stirred at room temperature for 12 h. b Isolated yield. CuI (0.15 mmol)
was used.
c
(Table 2). A wide range of terminal alkynes were reacted all
smoothly, and the corresponding N-phosphoryl amidines were
obtained in good to excellent yields. Not only simple aliphatic
alkynes but also substrates bearing certain functional groups
readily participated in the reaction (entries 1-4). It should be
noted that steric bulk around the triple bond of alkyne has little
influence on the reaction efficiency as demonstrated in entry 4.
Conjugated enynes turned out to be another viable substrate
type for this transformation (entry 5). With aryl alkynes,
electronic variation on the aromatic moiety did not affect the
reaction efficacy (entries 6-8). Among heterocyclic alkynes
examined, while the 3-thienyl group was tolerant under the
conditions, the 2-pyridyl group displayed a deteriorating effect
(entries 9 and 10, respectively).
Functionalized alkynes such as methyl propargylate or
silylacetylene were smoothly reacted with DPPA and diisopro-
pylamine to afford the corresponding substituted amidines in
good yields (entries 11 and 12, respectively). In addition,
bisphosphoryl amidines could be produced by the reaction of
1,n-dialkynyl substrates (entry 13). The scope of the amine
counterpart also turned out to be broad, and various primary
and secondary amines were readily employed with high ef-
ficiency (entries 14 and 15).
a
A mixture of alkyne (1.0 mmol), DPPA (0.5 mmol), amine (0.75 mmol),
b
5
and CuI (0.05 mmol) in THF (1 mL) was stirred at 25 °C for 12 h. R :
(PhO)2P(O)-. c Isolated yield. d CuI (0.15 mmol) was used. Alkyne (0.5
mmol), DPPA (1.0 mmol), CuI (0.1 mmol), and amine (1.0 mmol) were
used. Alkyne (0.5 mmol), DPPA (0.6 mmol), and amine (0.53 mmol) were
reacted under 60 °C with triethylamine (0.75 mmol).
e
As mentioned above (Table 1), the scope of phosphoryl azides
was relatively limited, and only aryl derivatives were effectively
employed for satisfactory results. This limitation for the
formation of N-alkylphosphoryl amidines was circumvented by
an alkoxide exchange process (Table 3). With the use of
stoichiometric amounts of alkali metal alkoxides, the facile
exchange with the phosphoryl moiety could be easily achieved.
Treatment of N-diphenyl phosphoryl amidine with sodium
methoxide, lithium isopropoxide, or potassium tert-butoxide
resulted in a clean substitution of phenoxy with alkoxides
leading to N-dialkyl phosphoryl amidines in high yields (entries
f
We next turned our attention to optically active N-phosphoryl
amidines and their synthetic utilities. Considering that binaphthol
has been most widely used as an excellent chiral auxiliary,
chiral phosphoryl azide bearing the diol was prepared by the
14
a
reaction of (S)-1,1′-bi(2-naphthol) with phosphorus oxychloride
(14) For a recent review on the utility of BINOL, see: Brunel, J. M.
1
-3).
Chem. ReV. 2005, 105, 857.
9
770 J. Org. Chem., Vol. 72, No. 25, 2007

TABLE 3. Exchange of Phenoxy Group with Aliphatic Alcoholsa
entry
alkoxide
yield (%)b
88
-
+
1
2
3
MeO Na
i
t
-
+
+
c
PrO Li
99
82
-
BuO K
FIGURE 1. ORTEP of an R-methylated amidine 3.
a
Alkoxide (3.0 mmol) and 1 (0.5 mmol) in THF (3 mL). b Isolated yield.
c
Run at 60 °C.
when the reaction was carried out at lower temperature (e.g.,
-
100 °C). On the other hand, allylation and benzylation of 2
SCHEME 1. Amidine Synthesis with Chiral Binaphthol
Azide and Subsequent Alkylation at the r-Position of the
Amidine
was less stereoselective compared to that of methylation under
otherwise identical conditions, resulting in the diastereomeric
ratio of 6:1 and 4:1, respectively (entries 2 and 3).
From the structural analysis of the obtained isomeric products,
we postulate that 6-membered transition states inducing steric
differentiation between the BINOL and diisopropyl amino group
are one of the possible reasons for the stereoselectivity shown
above.
In conclusion, phosphoryl azides have now been listed as new
and efficient reacting partners in the Cu-catalyzed three-
component coupling reactions with 1-alkynes and amines. The
fruitful utilization of phosphoryl azides has allowed us to
demonstrate the synthetic usefulness of those compounds, thus
expanding the scope of multicomponent chemistry, even includ-
ing an asymmetric version.
Experimental Section
General Procedure of Amidine Synthesis. To a stirred mixture
of azide (0.5 mmol), alkyne (1 mmol), and CuI (0.05 mmol) in
THF (1 mL) was slowly added an amine reactant (0.75 mmol) at
a
b
room temperature under N
completed, which was monitored with TLC, the reaction mixture
was diluted by adding CH Cl (3 mL) and aqueous NH Cl solution
(3 mL). The mixture was stirred for an additional 30 min and two
layers were separated. The aqueous layer was extracted with CH
Cl
(3 × 3 mL). The combined organic layers were dried over
MgSO , filtered, and concentrated in vacuo. The crude residue was
2
atmosphere. After the conversion was
For the isolated major isomer 3. 2 (0.1 mmol), KHMDS (0.12 mmol),
c
d
RX (0.8 mmol) in THF (1 mL). Isolated yield. Diastereomeric ratio was
determined by both H NMR and HPLC (see the Supporting Information).
Isolated yield of a mixture of two diastereomers.
1
2
2
4
e
2
-
and sodium azide.15 We were pleased to observe that the chiral
phosphoryl azide readily underwent the Cu-catalyzed three-
component reaction even in a gram scale with high yield
Scheme 1). Optical purity of the produced BINOL moiety was
observed to maintain completely without any racemization
during the three-component reaction.
2
4
purified by flash column chromatograph with an appropriate eluting
solvent system.
(
1
1
2
N ,N -Diisopropyl-N -(diphenylphosphoryl)-2-enylacetami-
1
dine (Table 1, entry 3): White solid; mp 95-96 °C; H NMR
400 MHz, CDCl ) δ 7.28-7.16 (m, 13H), 7.05 (t, J ) 6.9 Hz,
3
(
The synthetic utility of the chiral N-phosphoryl amidine 2
was subsequently investigated in the stereoselective R-alkylation
2H), 4.27 (s, 2H), 3.97-3.91 (m, 1H), 3.34 (br, 1H), 1.20 (d, J )
6.8 Hz, 6H), 0.84 (d, J ) 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl
δ 166.1, 166.0, 151.9, 151.8, 135.3, 129.2, 128.7, 127.8, 126.6,
3
)
1
6
reactions. As anticipated, the alkylation proceeded in a
diastereoselective manner, the extent of which turned out to be
varied depending on the type of electrophiles employed. For
example, R-methylation took place by the reaction of 2 with
iodomethane using KHMDS at -78 °C in good yield, and the
diastereoselectivity of the crude product mixture was determined
1
2
23.9, 120.5, 120.4, 50.7, 47.6, 41.6, 41.5, 19.8, 19.4; IR (NaCl) ν
-1
969, 2933, 1566, 1488, 1380, 1224, 1130, 1066, 916 cm ; HRMS
+
(EI) m/z calcd for C26
31 2 3
H N O P [M] 451.2072, found 451.2079.
Acknowledgment. This research was supported by a Korea
Research Foundation Grant (KRF-2005-C00248) and by the
CMDS at KAIST. We thank Dr. Junseung Lee (KAIST) for
the crystal structure determination. We also acknowledge the
Korea basic science institute (KBSI) for the mass analysis.
1
17
to be 9:1 by HPLC and H NMR.
The structure of R-methylated amidine 3 was determined
unambiguously by an X-ray diffraction analysis of a single
crystal. The diastereoselectivity was not further increased even
Supporting Information Available: Experimental details plus
1
13
spectral data and copies of H and C NMR spectra for new com-
pounds and crystallographic data of 3 in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
15) An, J.; Wilson, J. M.; An, Y. Z.; Wiemer, D. F. J. Org. Chem.
996, 12, 4040.
16) Asymmetric alkylation on N′-tert-butanesulfinyl amidines: Kochi,
T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.
17) See the Supporting Information for details.
1
(
(
JO7016247
J. Org. Chem, Vol. 72, No. 25, 2007 9771