The chemistry of amine-azide interconversion: Catalytic diazotransfer and regioselective azide reduction

Article abstract of DOI:10.1021/ja0264605

Azides have proven to be useful precursors to amines in organic syntheses. This report describes an improvement of the diazotransfer reaction and the first example of a regioselective azide reduction of compounds containing multiple azides. The use of a s

Full text of DOI:10.1021/ja0264605

Published on Web 08/15/2002
The Chemistry of Amine-Azide Interconversion: Catalytic
Diazotransfer and Regioselective Azide Reduction
Paul T. Nyffeler, Chang-Hsing Liang, Kathryn M. Koeller, and Chi-Huey Wong*
Contribution from the Department of Chemistry and the Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received April 8, 2002
Abstract: Azides have proven to be useful precursors to amines in organic syntheses. This report describes
an improvement of the diazotransfer reaction and the first example of a regioselective azide reduction of
compounds containing multiple azides. The use of a specific ratio of solvents and zinc chloride as a catalyst
resulted in a more efficient diazotransfer reaction capable of delivering >90% conversion per amine with
shorter reaction times than those previously reported. Azides can be reduced with good regioselectivity in
moderate yields by a modification of the Staudinger reaction using trimethylphosphine at low temperatures.
Electronic factors determine the selectivity for azide reduction, and the reaction is predictable by NMR
analysis of the starting material. Several examples for the diazotransfer and regioselective azide reduction
reactions are given, and a mechanistic hypothesis for both is proposed.
Introduction
Azides have several advantages as amino protecting groups over
carbamates and amides, including less steric hindrance, greater
The quest to overtake the rate of antibiotic resistance
development necessitates the search for new molecules that
possess antibiotic activity. One strategy to provide new antibiot-
ics is the modification of existing antibiotics to restore or
enhance their activity against resistant strains of bacteria.
Aminoglycoside antibiotics have found significant clinical use,
but the rapid proliferation of resistance to these compounds has
limited their applicability. Previously, synthetic chemists have
made modifications of known aminoglycoside antibiotics to fight
resistant bacteria.1,2 The presence of multiple amines, whose
high reactivity inhibits selective engagement, however, hampers
regioselective aminoglycoside modification. Several methods
for protecting unhindered amines have been presented,3-5 but
the search for other methods resulted in an interesting discovery.
The development of new aminoglycosides with antibiotic
activity has been an interest in our group for some time, and
we have had success using azides as amino protecting groups.6-10
solubility, and no rotamer formation or hydrogen or carbon
nuclei to complicate NMR spectra. Azides, which have proven
to be useful precursors for amines in chemical syntheses, can
be introduced by displacement of a suitable nucleofuge or direct
conversion of an existing amine by a diazotransfer reaction.
Furthermore, azides are resistant to many reaction conditions
and can be easily reduced to amines either generally (hydro-
genation, metal hydrides, etc.) or orthogonally (Staudinger
reaction).11 Azides are especially valuable in carbohydrate
chemistry, because azides at the 2 position of glycosyl donors
are nonparticipatory, allowing greater R selectivity for glyco-
sylation reactions. In an attempt to explore the possibility of
selective reductions of azides, a general and predictable
methodology, based on the Staudinger reaction,12,13 for the
reduction of one azide regioselectively in molecules containing
multiple azides was discovered. This report describes this new
methodology, as well as an improvement of the diazotransfer
reaction.
* To whom correspondence should be addressed. E-mail: wong@
scripps.edu.
(1) Kondo, S.; Hotta, K. J. Infect. Chemother. 1999, 5, 1-9.
(2) Ritter, T.; Wong, C.-H. Angew. Chem., Int. Ed. 2001, 40, 3508-3533.
(3) Grapsas, I.; Cho, Y. J.; Mobashery, S. J. Org. Chem. 1994, 59, 1918-
1922.
Improvements to the Diazotransfer Reaction
The diazotransfer reaction is ideal for protecting amines in
such natural products as aminoglycoside antibiotics, because
the transformation from an amine to an azide occurs with
retention of configuration.14-17 Recently, we reported that the
addition of a catalytic amount of a transition metal salt greatly
(4) Nunns, C. L.; Spence, L. A.; Slater, M. J.; Berrisford, D. J. Tetrahedron
Lett. 1999, 40, 9341-9345.
(5) Roestamadji, J.; Grapsas, I.; Mobashery, S. J. Am. Chem. Soc. 1995, 117,
11060-11069.
(6) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 37, 6029-
6032.
(7) Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C.-H. J. Am. Chem. Soc. 1998,
120, 1965-1978.
(11) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 351-368.
(12) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981,
37, 437-472.
(8) Greenberg, W. A.; Priestley, E. S.; Sears, P. S.; Alper, P. B.; Rosenbohm,
C.; Hendrix, M.; Hung, S.-C.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121,
6527-6541.
(13) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353-1406.
(14) Cavender, C. J.; Shiner, J., V. J. J. Org. Chem. 1972, 37, 3567-3569.
(15) Fischer, W.; Anselme, J.-P. J. Am. Chem. Soc. 1967, 89, 5284-5285.
(16) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV. Chim. Acta
1991, 74, 2073-2077.
(9) Sucheck, S. J.; Greenberg, W. A.; Tolbert, T. J.; Wong, C.-H. Angew.
Chem., Int. Ed. 2000, 39, 1080-1084.
(10) Sucheck, S. J.; Wong, A. L.; Koeller, K. M.; Boehr, D. D.; Draker, K.-A.;
Sears, P.; Wright, G. D.; Wong, C.-H. J. Am. Chem. Soc. 2000, 122, 5230-
5231.
(17) Zaloom, J.; Roberts, D. C. J. Org. Chem. 1981, 46, 5173-5176.
9
10.1021/ja0264605 CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 10773-10778
10773

A R T I C L E S
Nyffeler et al.
Table 1. Attempts To Optimize Triflyl Azide Formation
copper sulfate was reported to be the preferred catalyst for the
reaction, but other metal salts also demonstrated catalytic
activity.6 Experiments showed that, although some metals were
capable of rate enhancement, isolated yields and reaction times
were catalyst-dependent (see Table 2). Reactions using zinc
chloride as the catalyst would generally proceed no more than
2.5 h, whereas reactions employing copper sulfate would require
18 h to complete the reaction. The one exception found for zinc
chloride catalysis was with neomycin sulfate, 1a, where copper
sulfate proved to be the better catalyst. Reactions with 1a using
zinc chloride would become cloudy and were not reproducible
or efficient. One explanation could have been the in situ
formation of zinc sulfate, which has low solubility in alcohols,
but this hypothesis was discounted when the hydrochloride salt
of neomycin behaved identically to the sulfate salt. It was
concluded that this was probably a zinc-neomycin precipitate,
and precipitates of neomycin with divalent metal ions have been
documented in the literature.19 These findings suggest that either
copper sulfate or zinc chloride is an effective catalyst for the
diazotransfer reaction on various substrates, but optimization
for solubility may be necessary in some cases.
a
solvent
NaN equiv
temp
PTC
time
yield (%)
3
CH2Cl2/H2Ob
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl3/H2Ob
CH2Cl2
5
5
5
5
2
5
5
5
5
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
25 °C
25 °C
25 °C
no
no
no
no
no
no
no
yesc
yesd
0.5 h
1 h
2 h
18 h
2 h
2 h
18 h
18 h
15 h
62
68
72
42
63
68
<1
<1
81
CH2Cl2
CH2Cl2
a Phase-transfer catalyst. b 1:1 ratio. c Tetrabutylammonium hydrogen
sulfate, 5 mol %. d 18-Crown-6, 5 mol %.
increased the rate and efficiency of this reaction.6 However,
the procedure was still somewhat unreliable, with highly variable
reproducibility. Because of this irreproducibility, an optimization
of the diazotransfer reaction conditions was undertaken.
If the diazotransfer reaction was to be improved, the efficiency
of trifluoromethanesulfonyl (triflyl) azide formation needed to
be tested. However, its inherent explosiveness when dried has
made attempts to quantify its formation difficult.14 Previous
attempts to isolate pure triflyl azide by distillation have been
reported,18 but these practices are too dangerous to repeat.
Because triflyl azide in solution has never caused a problem in
Regioselective Azide Reduction
our hands or been reported to be explosive in the literature, 19
F
In the literature, there are relatively few examples of a
regioselective azide reduction. Knouzi and co-workers reported
previously that steric hindrance could potentially allow a
selective azide reduction in the Staudinger reaction.20 They
found in competitive experiments that the selectivity for azides
when using triphenylphosphine was primary > secondary >
tertiary. An attempt to selectively reduce the primary azide of
5 led to the discovery of a new regioselective azide reduction
(Scheme 1). Compound 5 was prepared from per-azido-
per-benzyl neomycin, 4, by a copper chloride-catalyzed hy-
drolysis,21 which represented an improvement over the previ-
ously reported methodology.8 Subjection of 5 to a variant of
the Staudinger reaction using trimethylphosphine at low tem-
peratures was envisioned to reduce the more sterically accessible
6′-azide. Surprisingly, the major product of this reaction was
not the anticipated compound, but was in fact 6, the product of
reduction at the more hindered 2′-azide. With 5, triphenylphos-
phine did not react under similar conditions, and tri-N-
butylphosphine failed to go to completion.
NMR was recommended to study the progress and yield of its
formation. After workup, the trifluoromethyl group of triflyl
azide at δ 75.9 ppm could be clearly distinguished from 2,2,2-
trifluoromethylacetophenone (δ -71.9 ppm), which was used
as an internal standard for quantitation. As shown in Table 1,
variations in temperature, stoichiometry, solvent, and concentra-
tion had very little impact on the yield of the reaction. Moving
from a water/dichloromethane biphasic mixture to pure dichlo-
romethane solution also failed to improve the yields. The
presence or absence of tetrabutylammonium hydrogen sulfate
failed to induce significant conversion to triflyl azide. The only
productive catalyst was 18-crown-6, which at 5 mol % was
capable of complete conversion after 18 h. However, in all of
the cases, the isolated yield was 60-80%, regardless of the
conditions. The reactions reported herein used 2 equiv of sodium
azide, and a conservative yield of 50% was used to determine
the necessary conditions.
The ratio of solvent was found to have a dramatic influence
on the rate and reproducibility of the reaction. The diazotransfer
reaction reported previously used varying ratios of water,
methanol, and dichloromethane.6,8 These solvents become
monophasic at an approximate ratio of 1:2.5:1 H2O/MeOH/CH2-
Cl2, respectively, but a ratio of 3:10:3 minimized precipitation
of salts from the reaction. The total volume was determined by
the approximate volume of the triflyl azide solution needed for
the reaction. Using a standardized solvent system that maximized
the concentration decreased the yield variations and increased
rates for all of the catalysts. No further optimization of the
solvent ratio was attempted but might prove necessary for
substrates that exhibit poor solubility in the reaction conditions.
At first glance, the observed regioselectivity was thought to
involve some kind of hydrogen bonding between the Lewis base
trimethylphosphine22 and the unprotected hydroxyl on the
adjacent ring. The hydroxyl of 5 was protected as an acetyl
ester and methyl ether, but products of their attempted selective
azide reductions were too difficult to purify to determine yields
accurately. Nonetheless, phosphines are known to reduce azides
by nucleophilic attack on the terminal nitrogen of the azide,12,13
and it was difficult to envision an intermediate that would place
the end of the azide in proximity to the phosphine when
coordinated to the hydroxyl group.
(19) Abu-El-Wafa, S. M.; El-Ries, M. A.; Abou-Attia, F. M.; Issa, R. M. Anal.
Lett. 1989, 22, 2703-2716.
Another area of improvement for the diazotransfer reaction
was the choice of transition metal salt catalyst. Previously,
(20) Knouzi, N.; Vaultier, M.; Carrie´, R. Bull. Soc. Chim. Fr. 1985, 5, 815-
819.
(21) Saravanan, P.; Chandrasekhar, M.; Vijaya Anand, R.; Singh, V. K.
Tetrahedron Lett. 1998, 39, 3091.
(22) Allman, T.; Goel, R. G. Can. J. Chem. 1982, 60, 716-722.
(18) Kamigata, N.; Yamamoto, K.; Kawakita, O.; Hikita, K.; Matsuyama, H.;
Yoshida, M.; Kobayashi, M. Bull. Chem. Soc. Jpn. 1984, 57, 3601-3602.
9
10774 J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002

The Chemistry of Amine−Azide Interconversion
Table 2. Diazotransfer Reactiona
A R T I C L E S
a Reagents and conditions: TfN3 (1.25-1.5 equiv), TEA (3 equiv), H2O/MeOH/CH2Cl2 3:10:3. b Reaction was very inconsistent, giving yields from 19
to 74%. c Substrate was HCl salt. d Product was acetylated: Ac2O, pyridine, DMAP.
Scheme 1. Synthesis of 5 and Subequent Regioselective Reduction to 6a
a Reagents and conditions: (a) CuCl2‚2H2O, CH3CN, 80 °C, 86%. (b) PMe3 [1.3 equiv], THF, aqueous NaOH, 0 °C, 46%.
Scheme 2. One-Pot Azide Conversion to Carbamates24,25
Further searching of the literature suggested that the observed
regioselectivity may have very little to do with steric hindrance.
Knowles and co-workers reported that azides reduced by
propane-1,3-dithiol exhibited different rates of reduction, con-
trolled not only by steric but also by electronic factors, with
electron-deficient azides being reduced more rapidly and
efficiently than electron-rich azides.23 The use of an electronic
argument to explain the observed regioselectivity in 5 seemed
valid, because the 2′-azide is adjacent to the anomeric center.
This would suggest that the 2′-azide would be more electron
deficient than any of the other azides, making it the most
electrophilic azide and, presumably, the most susceptible to
Several diazides were examined to probe the scope of the
phosphine reduction.
The direct conversion of the azide to carbamate, developed
by Ariza and co-workers,24,25 was predicted to be useful in this
reaction (Scheme 2). Ariza’s reaction never proceeds through
a free amine, easing purification and making the use of acyl
protecting groups in this reaction feasible. In all of the following
reactions, the reported products were the only isolated com-
pounds that were identifiable.
observed selectivity (see Table 3). In 7a,8 the minor difference
between the 4-OH and 6-OAc was sufficient to endow good
selectivity for 7b over 7c/d in modest yields. Identification of
products was rendered more difficult due to the formation of
7d, which presumably arises from a general-base-catalyzed acyl
migration of the 5-OAc of 7c to the adjacent 4-OH by the
iminophosphorane intermediate prior to benzyloxycarbonyl
(Cbz) capture. Protection of the 4-OH as a tert-butyldimethyl-
silyl (TBS) ether (8a) increased the selectivity to 47%/5% 8b:
(23) Bayley, H.; Standring, D. N.; Knowles, J. R. Tetrahedron Lett. 1978, 3633-
3634.
(24) Ariza, X.; Urp´ı, F.; Viladomat, C.; Vilarrasa, J. Tetrahedron Lett. 1998,
39, 9101-9102.
(25) Ariza, X.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40, 7515-
7517.
9
J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002 10775

A R T I C L E S
Nyffeler et al.
Table 3. Regioselective Azide Reductionsa
a Reagents and Conditions: (a) (i) PMe3 [1.1 equiv] THF, -78 °C f room temperature, 2 h; (ii) Cbz-Cl, -78 °C f room temperature, 30 min. (b)
Boc-ON, PMe3 [1.1 equiv], THF, -78 °C f room temperature, 18 h. (c) (i) PMe3 [1.3 equiv], THF, -78 °C f room temperature, 2 h; (ii) Cbz-Cl, -78
°C f room temperature, 30 min. b c/e R1 ) H, R2 ) Ac, 38:62; d/f R1 ) Ac, R2 ) H ratio undetermined.
Table 4. 15N ∆δ for Azides
8c, or approximately 9:1. This result could be argued on the
R−N −N −N
γ
R
â
basis that the increased steric hindrance about the 3-azide caused
the increase in selectivity and overshadowed the electronic
effects. On the basis of the selectivity observed in the reaction
of 5, it seems that sterics play only a minor role in determining
the outcome of the reaction under these conditions. To simplify
the analysis, 9a was synthesized, which has its 4-OH uninhibited
for hydrogen bonding. This also exhibited regioselectivity that
was consistent with the electronic control hypothesis. The
regioselective azide reduction was not limited to aminoglyco-
sides, as the methyl ester of diazidolysine, 10a, was also
converted to the tert-butyl carbamate (BOC) with excellent
selectivity in modest yields.
compound
N
N
∆δN
R
1R
3R
3b
7a
8a
-300.0
-299.7
-299.4
-300.0
-299.4
-298.2
0.0
0.3
1.2
Table 5. Chemical Shifts of ipso-Protons of Azides in Substrates
δCHN , given in ppm (azide)
3
5
3.51 (2′) 3.38 (3) 3.49, 3.35 (6′), 3.18 (1)
3.6a (1) 3.48 (3)
3.58 (1) 3.36 (3)
3.51 (1) 3.33 (3)
3.87 (2) 3.30 (6)
3.78 (3′′) 3.6a (1) 3.27, 3.10 (6′) 3.4a (3) 3.00 (2′)
7a
8a
9a
10a
11a
On the basis of the examples of 7a-10a, the electron density
of the azide appeared to be the critical factor in determining
regioselectivity, but a qualitative model that would help predict
the outcome of a regioselective azide reduction for molecules
containing multiple azides would be useful. Examination of the
a Values are approximated.
density for individual azides and allow qualitative prediction
for the regioselectivity. 13C NMR was helpful but not always
accurate, because it predicted the wrong regioisomer in some
cases. 1H NMR proved to be very insightful for predicting this
reaction (see Table 5). In every example, the azide whose ipso-
proton resonance was the furthest downfield was the one
preferentially reduced, as shown in Chart 1, and the greater the
∆δ, the higher the selectivity. The accuracy of this qualitative
model should not be overestimated, because there were a limited
1
15N NMR resonances for 3b, 7a, and 8a by H-15N HMBC
2D correlation revealed that the difference between the various
NR and Nâ easily predicts the azide which will be reduced
selectively (Table 4). However, the low abundance and sensitiv-
ity of 15N renders this prediction method too cumbersome for
routine use. It was suggested that the degree of shielding of the
adjacent carbon or proton as determined by their respective
NMR chemical shifts might correlate to the relative electron
9
10776 J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002

The Chemistry of Amine−Azide Interconversion
Chart 1 1H ∆δ versus Regioselectivity
A R T I C L E S
Scheme 4. Mechanism of Staudinger Reduction of Azides to
Amines
and zinc-triflyl imido complex 14. This complex could be in
equilibrium with 16, which is supported by computational work
on similar structures by Brandt et al.27 From here, two possible
pathways could be operative. Amine complexation, followed
by the transfer of a proton, would provide 14, with one of the
ligands being triflamide. The other plausible mechanism is the
transimination of 15 to yield the transient zinc-imido complex
16. This explanation is similar to the azide metathesis reaction
reported by Bergman et al. with zirconium complexes.28 The
imido-metal complex could be engaged with triflyl azide in a
[3 + 2] dipolar cycloaddition to alternatively provide 13.
Investigation into the exact mechanism is ongoing in our
laboratory and will be the focus of later publications.
Scheme 3. Possible Mechanism for the Transition
Metal-Catalyzed Diazotransfer Reaction
The results of an electronically controlled regioselective azide
reduction could be rationalized by an examination of the
mechanism of the Staudinger reaction, generally accepted to
be that shown in Scheme 4. However, the formation of the
phosphazide in step 1 is not nearly as well researched as the
formation of the phosphinimine in the second step of the
reaction.12,13 The kinetics of the first step of the reaction (k1)
are completely dependent upon the donating properties of the
phosphine substituents and the electron deficiency of the azide;
steric hindrance about the phosphine or the azide plays no role
in determining the selectivity of the first step. The second step
is more complicated, because k3 is dependent upon both steric
and electronic factors. The kinetics of azide reduction with
trimethylphosphine have not been reported, but the importance
of steric screening in the second step (k3) would presumably
be lower for trimethylphosphine than for bulkier phosphines
such as triphenylphosphine.
number of available examples, and 1H chemical shifts are
dependent upon many factors.
Per-azido per-benzyl tobramycin, 11a, was synthesized to
validate the model. Compound 11a is similar in structure to 5,
but it had one more azide and was deoxy at the 3′ position.
The proton NMR spectrum of 11a suggested that the 3′′-azide
was the azide predicted by the model to be selectively reduced,
unlike 5, which predicted the reduction of the 2′-azide. The
reduction produced many side products, but the only identifiable
product isolated from the reaction was 11b. This example not
only validated proton NMR as a qualitative model for predicting
selectivity, but also confirmed that electronics are the dominant
factor producing the observed products.
The regioselective azide reductions were conducted at dif-
ferent temperatures to probe the mechanism, but no detectable
dependence on temperature for regioselectivity was observed.29
One possible explanation is that the first step of the reaction is
reversible, allowing equilibrium to be established and one to
determine the regioselectivity on the basis of the electronic
differences between azides. The rate-determining step would
presumably be the E-to-Z isomerization of the phosphazide,
which is consistent with previous work studying the Staudinger
reaction.12,13 Prior to this step, regioselectivity is established,
but lower temperatures in the hope of further improving
selectivity should not affect the outcome of the reaction, because
k3 would proceed too slowly at low temperatures.
Mechanistic Hypothesis To Explain Observed Products
The mechanism of the diazotransfer reaction is currently
unknown. Fischer and Anselme proposed a dianionic tetrazene
intermediate stabilized by two sodium ions.15,26 Extending this
proposed mechanism to incorporate a divalent metal ion suggests
a mechanism as shown in Scheme 3. Amine complexation to
the zinc catalyst, under basic conditions, may provide 12. Owing
to the extreme electrophilicity of triflyl azide, nucleophilic attack
by the amine of 12 on the highly electrophilic triflyl azide,
followed by deprotonation, might form the zinc-stabilized mixed
tetrazene, 13. The breakdown of 13, possibly via a reverse [3
+ 2] dipolar cycloaddition, would produce the product azide
(27) Brandt, P.; So¨ergren, M. J.; Andersson, P. G.; Norrby, P.-O. J. Am. Chem.
Soc. 2000, 122, 8013-8020.
(28) Meyer, K. E.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1995, 117,
974-985.
(29) Reactions conducted at higher temperatures had a similar distribution of
products with more side products as determined by TLC.
(26) Anselme, J.-P.; Fischer, W. Tetrahedron 1969, 25, 855-859.
9
J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002 10777

A R T I C L E S
Nyffeler et al.
Conclusion
azide will be selectively reduced, and proton NMR analysis of
the starting material predicts the regioselectivity. Electronic
discrimination in the Staudinger reaction is attributed to the
trimethylphosphine’s smaller size relative to triphenylphosphine.
Taken together, the improvement of the diazotransfer reaction
and the possibility for the regioselective unmasking of protected
amines provide the opportunity for new synthetic strategies that
were not previously accessible. Applications centered on this
work are currently in progress.
This report describes an improvement of the diazotransfer
reaction and the first regioselective azide reduction for com-
pounds containing multiple azides. The improvements to the
diazotransfer reaction represent a careful optimization of the
previously reported methodology.6 The use of specific ratios
of solvents resulted in a general methodology that is capable
of reliably delivering >90% conversion per amine on a variety
of substrates. Zinc chloride was found to be as equally effective
as copper sulfate for catalyzing the conversion of amines to
azides, but catalyzed the transformation in significantly less time.
Azides can be reduced regioselectively with good selectivity
in moderate yields by a modification of the Staudinger reaction
using trimethylphosphine at low temperatures. Application of
Ariza’s one-pot methodology for the conversion of azides to
carbamates was useful for expanding the range of substrates
amenable to this reaction.24,25 Electronic factors determine which
Acknowledgment. This work was supported by the NIH
(GM58439) and NCI (CA 78045).
Supporting Information Available: Experimental details and
copies of spectral data for compounds 1b, 2b, 3b, 4, 5, 6, 7a-
f, 8a-d, 9a-d, 10a-d, 11a, and 11b (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0264605
9
10778 J. AM. CHEM. SOC. VOL. 124, NO. 36, 2002