Cyclizations of aminyl radicals generated from substoichiometric stannane

Article abstract of DOI:10.1055/s-0030-1259062

Substoichiometric amounts of tributyltin hydride were utilized in nitrogen-centered radical cyclizations onto silyl enol ethers for the formation of substituted cyclic imines

Full text of DOI:10.1055/s-0030-1259062

LETTER
3035
Cyclizations of Aminyl Radicals Generated from Substoichiometric Stannane
Cyclizations of
A
m
u
inyl
R
adica
i
ls min Zhai, Jason G. Wickenden, Glenn M. Sammis*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada
Fax +1(604)8220614; E-mail: gsammis@chem.ubc.ca
Received 16 September 2010
We hypothesized that the formation of imine 3 occurs
Abstract: Substoichiometric amounts of tributyltin hydride were
utilized in nitrogen-centered radical cyclizations onto silyl enol
ethers for the formation of substituted cyclic imines.
through the mechanism illustrated in Scheme 2. Treat-
ment of azide 1 with tributyltin radical results in the for-
mation of tin-bound aminyl radical 4, which rapidly
cyclizes to form pyrrolidine 5. Subsequent radical trap-
ping with hydrogen provides pyrrolidine 6. Protonolysis
of the nitrogen–tin bond readily occurs in workup to pro-
vide 2. The imine product may be formed through an in-
termolecular hydrogen transfer4,5 between pyrrolidines 5
and 6 to form pyrrolidines 6 and 7. Radical fragmentation
of pyrrolidine 76 results in the formation of the imine 3
and regeneration of tributyltin radical. This mechanism
suggests the possibility of cyclizing an azide to the corre-
sponding cyclic imine utilizing only a substoichiometric
amout of tributyltin hydride.
Key words: aminyl radical cyclization, substoichiometric tributyl-
tin hydride, silyl enol ethers, cyclic imines
Aminyl radical cyclizations1 are powerful synthetic meth-
ods for the construction of pyrrolidines and have been uti-
lized in the syntheses of numerous natural products. Of
the many methods that have been developed for the gen-
eration of nitrogen-centered radicals,1 the formation of
aminyl radicals from azides2 is synthetically attractive as
azides are readily incorporated into molecules and are sta-
ble under a variety of reaction conditions. Herein, we re-
port a new methodology for the formation of versatile
cyclic imines that utilizes aminyl radicals generated from
azides and only a substoichiometric amount of tributyltin
hydride.
We began our investigations into the selective formation
of cyclic imines using substoichiometric amounts of tribu-
tyltin hydride with a simple, unbiased cyclization precur-
sor (8, Scheme 3). Using our optimized conditions
developed for pyrrolidine formation, azide 8 cyclized to
form exclusively pyrrolidine 10 with no detectable
amounts of either cyclic imine 9 or starting material 8. De-
creasing the amount of tributyltin hydride to 50 mol% re-
sulted in the formation of pyrrolidine 10, unreacted azide
8, and two imine products (9 and 11). Imine 9 was the ex-
pected imine product based upon the mechanism pro-
posed in Scheme 2. Imine 11 is also likely formed through
an intermolcular hydrogen transfer at C2 followed by
elimination. Despite the large amount of unreacted azide,
the sum of all cyclized products is greater than the per-
centage of tin added to the reaction.
We recently reported a new route to polyhydroxylated
pyrrolidines using aminyl radical cyclizations onto silyl
enol ethers.3 These cyclizations required the addition of
1.2 equivalents of tributyltin hydride and 0.1 equivalents
of azobisisobutyronitrile (AIBN) to effect clean cycliza-
tions to the desired pyrrolidines. However, a sterically
bulky cyclization precursor, azide 1, cyclized to form both
the desired pyrrolidine 2 as well as a minor amount of cy-
clic imine 3 (Scheme 1).
TBSO
OTBS
OTBS
With the basic substoichiometric reactivity established,
we sought to optimize the ratio of imine products 9 and 11
to the pyrrolidine 10. Lowering the amount of tributyltin
hydride to 30 mol% led to an increase in total imine for-
mation relative to pyrrolidine and unreacted starting ma-
terial (Table 1, entries 1). Slowing the addition rate to 0.4
mL/h and 0.2 mL/h (entries 2 and 3) resulted in complete
conversion to cyclized products with no detectable
amounts of starting azide 8 (entry 2).7 Increasing the con-
centration provided a higher percentage of pyrrolidine 10
relative to imine products.
N
H
2
N3
OTBS
Bu3SnH (1.2 equiv)
AIBN (10 mol%)
major product
+
OTBS
benzene, 80 °C
TBSO
OTBS
OTBS
OTBS
1
N
3
minor product
(<30% conv.)
Scheme 1 Nitrogen-centered radical cyclization onto a silyl enol
Decreasing tributyltin hydride from 30 mol% to 15 mol%
using the new slow addition rate procedure (entry 4) af-
forded an increase in the ratio of imine products to pyrro-
lidine 10. However, decreasing the tin to 10 mol%
resulted in poor imine to pyrrolidine selectivities and a
large amount of unreacted azide 8. Changing the tin
ether
SYNLETT 2010, No. 20, pp 3035–3038
Advanced online publication: 24.11.2010
DOI: 10.1055/s-0030-1259062; Art ID: S06210ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

3036
H. Zhai et al.
LETTER
OTBS
N2
N3
OTBS
OTBS
1
OTBS
TBSO
OTBS
OTBS
Bu3Sn
•
Bu3Sn
N
OTBS
•
OTBS
cyclization
OTBS
4
N
3
TBSO
OTBS
TBSO
4
3
4
3
2
2
5
5
OTBS
OTBS
TBSO
•
N
N
•
5
SnBu3
SnBu3
7
OTBS
OTBS
hydrogen transfer
N
SnBu3
6
Scheme 2 Proposed mechanism for the formation of imine 3
source to triphenyltin hydride did not significantly effect To test this hypothesis we examined substrates with vary-
the product distribution compared to tributyltin hydride ing steric bulk at C3 (Schemes 4 and 5). Using the previ-
(entries 6 and 7). Initiation using in situ generated dichloro- ously developed conditions (Scheme 4), cyclization of
indium hydride8 afforded poor yields of imine products.
azide 12 exclusively afforded pyrrolidine 13 in high yield.
Similarly, cyclization of phenyl-substituted substrate 14
provided pyrrolidine 15 in excellent yield and selectivity.
Using newly developed procedure with 30 mol% of tribu-
tyltin hydride (Scheme 5),9 azide 12 cyclized to afford
imines 16 and 17 in 67% yield as a 3.3:1 mixture. Cycliza-
tion of phenyl-substituted substrate 14 afforded only one
imine product (18).
Cyclization with 15 mol% tributyltin hydride favored the
formation of cyclic imine 9 to cyclic imine 11 in 2.1:1 ra-
tio. For this radical methodology to be synthetically use-
ful, it must provide higher selectivity for the formation of
one of the cyclic imines. Our original cyclization studies
(Scheme 1) indicated a possible solution as cyclization of
azide 1 resulted in the formation of only one imine prod-
uct. We postulated that the other cyclic imine does not Another method for increasing the selectivity of one of the
form because the steric bulk at C3 slows the rate of hydro- two cyclic imines is to stabilize the radical at C5 through
gen abstraction from C2.
substitition (Scheme 2, 7). Cyclization of alkyl-substitut-
Table 1 Optimization Studies for Total Imine Product 9 and 10
R3SnH (mol%)
AIBN (15 mol%)
OTBS
+
+
+ 8
benzene, 80 °C
N3
N
N
N
H
OTBS
OTBS
OTBS
8
9
11
10
Entrya
Addition rate (mL/h)
Metal hydride
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Ph3SnH
R3SnH (mol%)
Product ratiob (9 + 11)/10/8
1
2
3
4
5
6
7
1 portion
0.4
30
30
30
15
10
40
20
1.3:1.4:1
1.5:1:0
1.9:1:0
2.5:1:0
1.3:1:2.3
1.8:1:0
1.8:1:0
0.2
0.2
0.2
0.2
0.2
Ph3SnH
a Reactions were carried out on a 0.31 mmol scale and were 0.03 M in benzene.
b Product ratios were determined by 1H NMR spectroscopic analyses of crude reaction mixtures.
Synlett 2010, No. 20, 3035–3038 © Thieme Stuttgart · New York

LETTER
Cyclizations of Aminyl Radicals
3037
Bu3SnH (1.2 equiv)
AIBN (15 mol%)
Bu3SnH (30 mol%)
AIBN (15 mol%)
OTBS
+
OTBS
N3
N
N
N
benzene, 80 °C
(addition of Bu3SnH
in one portion)
benzene, 80 °C
(addition rate = 0.2 mL/h)
N3
N
H
OTBS
OTBS
OTBS
8
8
9
10
19
21
20
51% yield
only product
detected
Bu3SnH (30 mol%)
AIBN (15 mol%)
Bu3SnH (50 mol%)
AIBN (15 mol%)
OTBS
+
Ph
Ph
N3
N
N3
N
benzene, 80 °C
(addition rate = 0.2 mL/h)
benzene, 80 °C
(addition of Bu3SnH
in one portion)
OTBS
OTBS
OTBS
OTBS
22
65% yield
9
11
8
OTBS
+
Scheme 6 Cyclization of secondary azides 19 and 21
N
H
N3
OTBS
10
Bu3SnH (1.2 equiv)
AIBN (10 mol%)
ratio of (9 + 11)/10/8 = 3.6:4.4:1
Ph
Ph
N
N3
21
benzene, 80 °C
H
Scheme 3 Investigating substoichiometric generation of aminyl ra-
OTBS
OTBS
dicals
23
66% yield
>95:5 trans/cis
Bu3SnH (1.2 equiv)
AIBN (15 mol%)
71% yield
OTBS
OTBS
DIBAL-H
93:7 trans/cis
Ph
Ph
N3
N
H
N
H
N
benzene, 80 °C
CH2Cl2, –78 °C
OTBS
OTBS
OTBS
12
Ph
13
15
22
24
86% yield
>95:5 cis/trans
Ph
Bu3SnH (1.2 equiv)
AIBN (15 mol%)
68% yield
>95:5 trans/cis
Scheme 7 Synthesis of both trans- and cis-2,5-disubstituted pyrro-
N3
N
H
lidines
benzene, 80 °C
OTBS
14
azide 21 with stoichiometric tributyltin hydride provided
trans-pyrrolidine 23 in 66% yield.10 The corresponding
cis-isomer 24 can readily be accessed from DIBAL-H re-
duction of imine 22.11
Scheme 4 Cyclizations using stoichiometric tributyltin hydride
Bu3SnH (30 mol%)
AIBN (15 mol%)
OTBS
The addition of carbon nucleophiles to imines 20 and 22
can also readily provide fully substituted carbon centers.
Treatment of imine 20 with allyl magnesium bromide re-
sults in the formation of pyrrolidine 25 in excellent yield
as a 92:8 ratio of cis/trans isomers (Scheme 8).12
+
N3
N
N
benzene, 80 °C
(addition rate = 0.2 mL/h)
OTBS
OTBS
12
16
17
67% yield
(3.3:1 mixture of 16:17)
Ph
Ph
Bu3SnH (30 mol%)
AIBN (15 mol%)
MgBr
OTBS
66% yield
N3
N
benzene, 80 °C
(addition rate = 0.2 mL/h)
N
N
H
THF, 0 °C
OTBS
OTBS
OTBS
14
18
20
25
71% yield
92:8 cis/trans
Scheme 5 Cyclizations using substoichiometric tributyltin hydride
Scheme 8 Addition of allyl magnesium bromide to cyclic imines
ed azide (19, Scheme 6) provided cyclic imine 20 in good
yield, with the remainder of the mass balance correspond-
ing to the undesired cyclic imine (24%) and the corre-
sponding pyrrolidine (8% yield). While the methyl
provided some selectivity towards the formation of imine
20, phenyl substitution (21) provided only one of the two
imine products (22) along with 11% yield of the corre-
sponding pyrrolidine. The high selectivity for imine 22 is
presumably due to the enhanced stability of the benzylic
radical at C5. Changing the silyl enol ether geometry had
no effect on the product distribution.
In the proposed mechanism depicted in Scheme 2, the
only step which remained to be examined was the hydro-
gen transfer step (5 to 7). This transfer step may either oc-
cur through an intramolecular hydrogen transfer or
through an intermolecular pathway. To probe these two
possibilities, we explored whether a tin-bound pyrroli-
dine, such as 26, could serve as a hydrogen-transfer agent.
Indeed cyclization of azide 8 in the presence of a mixture
of imine 22 and pyrrolidine 26 led to the complete conver-
sion of tin-bound pyrrolidine to imine 22 along with cy-
clization products 9, 10, and 11 (Scheme 9). This result,
coupled with the geometrical constraints of an intramolec-
ular transfer within the ring system, strongly suggest that
Using both our previously developed nitrogen-centered
radical cyclizations and this new method, we can now ac-
cess both trans- and cis-2,5-disubstituted pyrrolidines
from a common intermediate (Scheme 7). Treatment of
Synlett 2010, No. 20, 3035–3038 © Thieme Stuttgart · New York

3038
H. Zhai et al.
LETTER
References and Notes
+
Ph
N
(1) For reviews on nitrogen-centered radicals, see: (a) Neale,
R. S. Synthesis 1971, 1. (b) Mackiewicz, P.; Furstoss, R.
Tetrahedron 1978, 34, 3241. (c) Stella, L. Angew. Chem.,
Int. Ed. Engl. 1983, 22, 337. (d) Esker, J. L.; Newcomb, M.
Adv. Heterocycl. Chem. 1993, 58, 1. (e) Zard, S. Z. Synlett
1996, 1148. (f) Fallis, A. G.; Brinza, I. M. Tetrahedron
1997, 53, 17543. (g) Zard, S. Z. Chem. Soc. Rev. 2008, 37,
1603. (h) Curran, D. P. In Comprehensive Organic
Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, 811. (i) Stella, L. In Radicals in
Organic Synthesis, Vol. 2; Renaud, P.; Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001, 407.
(2) For initial studies, see: (a) Kim, S.; Joe, G. H.; Do, J. Y.
J. Am. Chem. Soc. 1993, 115, 3328. (b) Kim, S.; Joe, G. H.;
Do, J. Y. J. Am. Chem. Soc. 1994, 116, 5521. (c) Minozzi,
M.; Nanni, D.; Spagnolo, P. Chem. Eur. J. 2009, 15, 7830.
(3) Zhai, H.; Zlotorzynska, M.; Sammis, G. M. Chem. Commun.
2009, 5716.
Ph
N
OTBS
Bu3Sn
OTBS
22 (0.87 equiv)
Ph
26 (0.13 equiv)
OTBS
N
OTBS
N3
Bu3SnH (30 mol%)
AIBN (15 mol%)
(addition rate = 0.2 mL/h)
C6H6, 80 °C
22
8 (1 equiv)
+ 9 + 10 + 11
Scheme 9 Mechanistic investigations into radical transfer reaction
the hydrogen transfer most likely proceeds through an in-
termolecular pathway.
We have developed a new method for the synthesis of cy-
clic imines using substoichiometric amounts of tributyltin
hydride. The selectivity for formation of the desired cyclic
imine product can be influenced by either altering the ster-
ic bulk of the substituents at C3 or by increasing the sub-
stiution at C5. This new methodology is complementary to
our existing aminyl radical cyclizations onto silyl enol
ethers as we can now access both trans- and cis-1,5-disub-
stituted pyrrolidines. Addition of carbon nucleophiles to
the cyclic imines also provides the corresponding highly
substituted pyrrolidine in excellent yield. We are currently
exploring the efficacy of this cyclization in the context of
complex natural product synthesis.
(4) For a review of radical hydrogen transfer reactions, see:
Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001,
30, 94.
(5) For representative examples of hydrogen abstraction a to
amines, see: (a) Routaboul, L.; Vanthuyne, N.; Gastaldi, S.;
Gil, G.; Bertrand, M. J. Org. Chem. 2008, 73, 364.
(b) El Blidi, L.; Nechab, M.; Vanthuyne, N.; Gastildi, S.;
Bertrand, M.; Gil, G. J. Org. Chem. 2009, 74, 2901.
(6) For an example of an elimination of tributyltin radical from
a carbon-centered radical a to a tin-bound amine, see ref. 2b.
(7) We did not explore addition rates slower than 0.2 mL/h as
the reaction times became prohibitively long.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(8) Benati, L.; Bencivenni, G.; Leardini, R.; Nanni, D.; Minozzi,
M.; Spagnolo, P.; Scialpi, R.; Zanardi, G. Org. Lett. 2006, 8,
2499.
(9) While cyclization of azide 8 using 15 mol% of tributyltin
hydride provided good conversion to the cyclized products,
these conditions proved not to be robust for other substi-
tution patterns. Cyclizations using 30 mol% tributyltin
hydride proved to be general and reliable for all substrates
examined.
Acknowledgment
This work was supported by the University of British Columbia and
the Natural Sciences and Engineering Research Council of Canada
(NSERC).
(10) We were also able to isolate 12% of the cis-isomer.
(11) Marco, J. L. J. Heterocycl. Chem. 1986, 1059.
(12) Arai, T.; Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron
Lett. 2004, 45, 5921.
Synlett 2010, No. 20, 3035–3038 © Thieme Stuttgart · New York

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