Development of Bu3SnH-Catalyzed Processes: Efficient Reduction of Azides to Amines

Full text of DOI:10.1021/jo9721958

2796
J . Org. Chem. 1998, 63, 2796-2797
Develop m en t of Bu 3Sn H-Ca ta lyzed
P r ocesses: Efficien t Red u ction of Azid es to
Am in es
David S. Hays and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
F igu r e 1. Bu3SnH-catalyzed, silicon hydride-mediated reduction
of azides: an initial approach.
Received December 3, 1997
Taken together, the ever-increasing utility of tin chem-
istry1 and the growing concern about tin toxicity2 provide a
powerful incentive to discover processes in which tin com-
pounds are employed as catalysts, as opposed to stoichio-
metric reagents. We have initiated a program directed at
the development of reactions wherein Bu3SnH, one of the
most synthetically useful organotin compounds,3 is utilized
as a catalyst, and a silicon hydride fills the role of stoichio-
metric reductant. To date, we have focused our attention
largely on processes in which Bu3SnH reacts with a sub-
strate to produce an intermediate with a Sn-O bond, which
the silicon hydride then reduces to regenerate Bu3SnH.4 We
have now expanded the scope of our investigation to include
processes that furnish an intermediate with a Sn-N bond.
The radical-mediated reduction of azides to amines is an
example of a Sn-N bond-forming process that currently
requires stoichiometric Bu3SnH (eq 1).5,6 In this report, we
describe a strategy for effecting Bu3SnH-catalyzed reactions
that permits this reduction to be accomplished with only 5
mol % Bu3SnH (eq 2).
F igu r e 2. Bu3SnH-catalyzed, silicon hydride-mediated reduction
of azides: an alternate approach.
it might be possible to effect a Bu3SnH-catalyzed, silicon
hydride-mediated azide reduction process according to the
pathway outlined in Figure 1. Initially, as in eq 1, Bu3SnH
would reduce RN3 to RNHSnBu3; then, in the turnover step,
the stoichiometric reducing agent, HSiR3, would react with
RNHSnBu3 to regenerate the catalyst, Bu3SnH.
Unfortunately, this proposed catalytic process has not
proved to be viable. Thus, treatment of 1-azidoadamantane
with 10 mol % of Bu3SnH and 0.5 equiv of PhSiH3 (AIBN,
refluxing benzene) affords 1-aminoadamantane in low yield
(∼11%). Through NMR studies, we have determined that
RHNSnBu3 and RN(SnBu3)2, the major tin-containing prod-
ucts from the reaction of RN3 with Bu3SnH, are not readily
reduced by PhSiH3 to Bu3SnH.
Rather than depending upon the reduction of Sn-N to
Sn-H for our turnover step (Figure 1), we chose to pursue
an alternate strategy that relies upon the reduction of Sn-O
to Sn-H8 (Figure 2). Thus, we anticipated that if we added
an alcohol to the reaction, transfer of the SnBu3 group from
the nitrogen of the initially formed RNHSnBu3 to the oxygen
of the alcohol would occur (Figure 2, Sn exchange).9 The
resulting tin alkoxide could then be reduced by the silicon
hydride to regenerate the catalyst, Bu3SnH.
On the basis of our recent observation that PhSiH3 can
cleanly reduce Bu3SnNMe2 to Bu3SnH,7 we anticipated that
We chose a primary alcohol to be our additive, since the
reduction of Sn-O to Sn-H by silicon hydrides has been
shown to be sensitive to steric effects,8a and we found that
(1) (a) Pereyre, M.; Quintard, J .-P.; Rahm, A. Tin in Organic Synthesis;
Butterworths: Boston, 1987. (b) Davies, A. G. Organotin Chemistry; VCH:
New York, 1997.
(2) (a) Boyer, I. J . Toxicology 1989, 55, 253-298. (b) De Mora, S. J .
Tributyltin: Case Study of an Environmental Contaminant; Cambridge
University Press: Cambridge, UK, 1996.
(8) (a) Itoi, K. Fr. Patent 1,368,522, 1964. Itoi, K.; Kumano, S. Kogyo
Kagaku Zasshi 1967, 70, 82-86. (b) Hayashi, K.; Iyoda, J .; Shiihara, I. J .
Organomet. Chem. 1967, 10, 81-94. (c) Bellegarde, B.; Pereyre, M.; Valade,
J . Bull. Soc. Chim. Fr. 1967, 3082-3083.
(9) (a) Amberger, E.; Kula, M.-R.; Lorberth, J . Angew. Chem., Int. Ed.
Engl. 1964, 3, 138. (b) J ones, K.; Lappert, M. F. Proc. Chem. Soc. 1964,
22-23. (c) Lorberth, J .; Kula, M.-R. Chem. Ber. 1964, 97, 3444-3451.
(10) We use 2.5 mol % (Bu3Sn)2O as our precatalyst in these reductions.
Under the reaction conditions, it is converted to 5 mol % Bu3SnH (for a
discussion, see ref 4c). Relative to Bu3SnH, (Bu3Sn)2O has cost ($38 versus
$250 per mol of tin) and stability advantages.
(11) Typ ica l Exp er im en ta l P r oced u r e. (Bu3Sn)2O (29.8 mg, 0.0500
mmol), PhSiH3 (108-144 mg, 1.00-1.33 mmol), and n-PrOH (240 mg, 4.00
mmol) were added to a solution of the alkyl azide (2.00 mmol) and AIBN
(16 mg, 0.10 mmol) in benzene (2.0 mL). The reaction was heated to reflux
for 90-120 min in an oil bath maintained at 90 °C. After the mixture was
cooled to rt, pentane (10 mL) was added, followed by anhydrous HCl (5-7
mL of a 1.0 M solution in Et2O). The resulting white solid was collected by
filtration and then dissolved in MeOH. Removal of the solvent afforded the
product amine as a white hydrochloride salt. The 1H and 13C NMR spectra
of the hydrochloride salt were identical to spectra for material prepared by
protonation of the commercially available amine. Note: Reactions run on
a 20 mmol scale provide comparable results.
(3) For reviews of the chemistry of Bu3SnH, see: (a) Neumann, W. P.
Synthesis 1987, 665-683. (b) RajanBabu, T. V. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995.
(4) For Bu3SnH-catalyzed reactions. (a) Reductive cyclization: Hays, D.
S.; Fu, G. C. J . Org. Chem. 1996, 61, 4-5. (b) Conjugate reduction of R,â-
unsaturated ketones: Hays, D. S.; Scholl, M.; Fu, G. C. J . Org. Chem. 1996,
61, 6751-6752. (c) Barton-McCombie deoxygenation: Lopez, R. M.; Hays,
D. S.; Fu, G. C. J . Am. Chem. Soc. 1997, 119, 6949-6950.
(5) (a) For the reduction of benzoyl azide with Bu3SnH, see: Frankel,
M.; Wagner, D.; Gertner, D.; Zilkha, A. J . Organomet. Chem. 1967, 7, 518-
520. (b) For an application of Bu3SnH-mediated azide reduction in natural
product synthesis (O-methylorantine), see: Wasserman, H. H.; Brunner,
R. K.; Buynak, J . D.; Carter, C. G.; Oku, T.; Robinson, R. P. J . Am. Chem.
Soc. 1985, 107, 519-521. (c) Poopeiko, N. E.; Pricota, T. I.; Mikhailopulo,
I. A. Synlett 1991, 342. (d) Samano, M. C.; Robins, M. J . Tetrahedron Lett.
1991, 32, 6293-6296.
(6) (a) Larock, Richard C. Comprehensive Organic Transformations;
VCH: New York, 1989; pp 409-410. (b) Gilchrist, T. L. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 8,
Chapter 2.2. (c) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297-
368.
(7) Hays, D. S.; Fu, G. C. J . Org. Chem. 1997, 62, 7070-7071.
S0022-3263(97)02195-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/08/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2797
Ta ble 1. Bu 3Sn H-Ca ta lyzed Red u ction of Azid es to
Am in es
Sch em e 1
tions, but aldehydes, ketones, nitro groups, and alkyl
bromides are not.15 For the reaction of azido olefin 1, we
obtained the unsaturated amine in lower-than-usual yield
1
(eq 3; 72% yield by H NMR); interestingly, this appears to
be due to [3 + 2] cycloaddition of the substrate,16 not
cyclization of the intermediate nitrogen radical.17,18
this modified catalytic process is indeed extremely efficient.
Thus, treatment of a primary, secondary, tertiary, or aryl
azide with Bu3SnH (5 mol %)10 and PhSiH3 (0.6 equiv) in
the presence of n-PrOH (2 equiv) in refluxing benzene
provides the primary amine in excellent yield (92-99%;
To provide evidence for radical-mediated N-N bond
cleavage in these Bu3SnH-catalyzed reductions, we exam-
ined the reaction of azide 2 (Scheme 1); as demonstrated by
Kim, if the reduction of this substrate follows a radical
pathway, then a ring-opened product should be observed.19
We have established that under our Bu3SnH-catalyzed azide
reduction conditions ring opening does indeed occur to
generate an acyclic imino ester (eq 4).
Table 1, PhSiH3).11,12
A
119Sn NMR spectrum taken at the
end of the reduction of 2-azidododecane reveals that Bu3-
SnH is the only detectible tin-containing species, and GC
analysis shows that 96% of the original Bu3SnH still
remains.
We have established that inexpensive PMHS (TMSO-
(SiHMeO)n-TMS)13 can also be used as the stoichiometric
reductant in this Bu3SnH-catalyzed transformation. Reac-
tion of an organic azide with Bu3SnH (5 mol %), PMHS (3
equiv), and n-PrOH (2 equiv) at 80 °C affords the desired
amine in uniformly high yield (91-96%; Table 1, PMHS).14
With either set of reaction conditions (PMHS or PhSiH3),
little or no reduction of the azide (<10%) is observed in the
absence of Bu3SnH or of n-PrOH. Alkynes, esters, and alkyl
chlorides are compatible with both of the reduction condi-
In conclusion, we have developed a new Bu3SnH-catalyzed
process, the reduction of azides to amines. Although we
were not able to effect this transformation according to our
original plan (Figure 1), we have established the viability
of an alternate strategy for catalysis that is likely to be
general for reactions that involve the formation of Sn-N
bonds (Figure 2). The development of additional Bu3SnH-
catalyzed processes is underway.
(12) Under these reduction conditions, tertiary azides are slightly less
reactive than secondary azides, which are slightly less reactive than primary
azides.
(13) (a) Price per mole of hydride (Aldrich Chemical Co.): PMHS: $6;
Bu3SnH: $250. (b) Toxicity: LD50 of PMHS: 80 g/kg. Klyaschitskaya, A.
L.; Krasovskii, G. N.; Fridlyand, S. A. Gig. Sanit. 1970, 35, 28-31; Chem.
Abstr. 1970, 72, 124864r. (c) For a review of PMHS, see: Lipowitz, J .;
Bowman, S. A. Aldrichim. Acta 1973, 6, 1-6.
(14) Typ ica l Exp er im en ta l P r oced u r e. (Bu3Sn)2O (29.8 mg, 0.0500
mmol), PMHS (360 mg, 6.00 mmol), and n-PrOH (240 mg, 4.00 mmol) were
added to a mixture of the alkyl azide (2.00 mmol) and AIBN (16 mg, 0.10
mmol). The reaction was heated in an oil bath maintained at 80 °C. After
1-2 h, the residue was cooled to rt and treated with anhydrous HCl (5 mL
of a 1.0 M solution in Et2O). Hexane was added if needed to facilitate
precipitation. The resulting white solid was collected by filtration and then
dissolved in MeOH. If insoluble material appeared upon standing, the
solution was filtered prior to concentrating, which afforded the amine as a
white hydrochloride salt. The 1H and 13C NMR spectra of the hydrochloride
salt were identical to spectra for material prepared by protonation of the
commercially available amine. Note: Reactions run on a 20 mmol scale
provide comparable results; a rapid exotherm may accompany large-scale
reactions.
(15) The reductions were run individually in the presence of the following
compounds: 1-dodecyne, ethyl caprate, chlorocyclohexane, octyl aldehyde,
2-octanone, nitrocyclohexane, and bromocyclohexane. In the presence of
trans-2-heptene and cis-2-heptene, no isomerization was observed with
PhSiH3 as the stoichiometric reductant, but small amounts of olefin
isomerization were observed with PMHS.
Ack n ow led gm en t. Support has been provided by the
American Cancer Society, Eli Lilly, Firmenich, Glaxo
Wellcome, the National Science Foundation (predoctoral
fellowship to D.S.H.; Young Investigator Award to G.C.F.,
with funding from Procter & Gamble, Merck, Bristol-Myers
Squibb, DuPont, Pfizer, Rohm & Haas, Pharmacia &
Upjohn, and Bayer), and the Research Corporation. Ac-
knowledgment is made to the donors of the Petroleum
Research Fund, administered by the ACS, for partial
support of this research.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and compound characterization data (45 pages).
J O9721958
(18) For leading references to intramolecular additions of aminyl radicals
(16) Logothetis, A. L. J . Am. Chem. Soc. 1965, 87, 749-754.
(17) For the synthesis of 2-benzylpiperidine, see: Meyers, A. I.; Edwards,
P. D.; Bailey, T. R.; J agdmann, G. E., J r. J . Org. Chem. 1985, 50, 1019-
1026.
to olefins, see: Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543-
17594.
(19) Kim, S.; J oe, G. H.; Do, J . Y. J . Am. Chem. Soc. 1993, 115, 3328-
3329.