Cyclizations of N-Stannylaminyl Radicals onto Nitriles

Article abstract of DOI:10.1021/ol036268n

(Matrix presented) Stannylaminyl radicals derived from radical reactions of Bu₃SnH with azidoalkylmalononitriles exhibit highly efficient 5- and 6-exo cyclization onto either nitrile group to give aminoiminyl radicals that in turn are reduced t

Full text of DOI:10.1021/ol036268n

ORGANIC
LETTERS
2004
Vol. 6, No. 3
417-420
Cyclizations of N-Stannylaminyl Radicals
onto Nitriles
,†
Luisa Benati,† Giorgio Bencivenni,† Rino Leardini,* Matteo Minozzi,†
,†
Daniele Nanni,† Rosanna Scialpi,† Piero Spagnolo,* Giuseppe Zanardi,† and
Corrado Rizzoli‡
Dipartimento di Chimica Organica “A. Mangini”, UniVersita` di Bologna,
Viale Risorgimento 4, I-40136 Bologna, Italy, and Dipartimento di Chimica
Generale ed Inorganica, Analitica e Chimica Fisica, UniVersita` di Parma,
Viale delle Scienze 78, I-43100 Parma, Italy
spagnolo@ms.fci.unibo.it
Received November 20, 2003
ABSTRACT
Stannylaminyl radicals derived from radical reactions of Bu3SnH with azidoalkylmalononitriles exhibit highly efficient 5- and 6-exo cyclization
onto either nitrile group to give aminoiminyl radicals that in turn are reduced to amidines or undergo successive 5-exo cyclization onto an
internal alkene.
Radical cyclization reactions have become a powerful tool
for the construction of carbocyclic and heterocyclic systems,
even those occurring in natural products.1 Radical cycliza-
tions most often involve carbon-carbon bond formation,
whereas those leading to carbon-nitrogen bonds are much
less documented. The reported methods rely on additions of
aminyl1e,2 and iminyl1e,3 radicals to CdC and CdO double
bonds or additions of carbon radicals to nitrogen atoms of
imines.1e,4 The synthetic potential of azide radical reactions
has so far been rather poorly investigated, though the reported
studies have revealed that the azido moiety can act as a
valuable radical acceptor toward carbon- and heteroatom-
centered species to yield an aminyl radical after loss of
molecular nitrogen by the initial triazenyl adduct.2e,f,5 Indeed,
intramolecular additions of aryl,6 thiocarbonyl,7 alkyl,8 vinyl,9
† Universita` di Bologna.
‡ Universita` di Parma.
(3) (a) Atmaran, S.; Forrester, A. E.; Gill, M.; Thomson, R. H. J. Chem.
Soc., Perkin Trans. 1 1981, 1721-1724. (b) Boivin, J.; Fouquet, E.; Zard,
S. Z. Tetrahedron 1994, 50, 1745-1756. (c) Kaim, L. E.; Meyer, C. J.
Org. Chem. 1996, 61, 1556-1557. (d) Zard, S. Z. Synlett 1996, 1148-
1154. (e) Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.;
Leach, D. C. J. Chem. Soc., Perkin Trans. 1 2002, 58-68.
(4) (a) Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1994, 37,
149-152. (b) Gioanola, M.; Leardini, R.; Nanni, D.; Pareschi, P.; Zanardi,
G. Tetrahedron 1995, 51, 2039-2054. (c) Tomaszewski, M. J.; Warkentin,
J.; Werstiuk, N. H. Aust. J. Chem. 1995, 48, 291-321. (d) Bowman, W.
R.; Stephenson, P. T.; Young, A. R. Tetrahedron 1996, 52, 11445-11462.
(e) Ryu, I.; Matsu, R. K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc.
1998, 120, 5838-5839 and refs therein.
(1) For leading reviews including radical cyclizations, see: (a). Moth-
erwell, W. B.; Crich, D. Free-Radical Chain Reactions in Organic Synthesis;
Academic: London, 1992. (b) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: New York, 1996. (c) Giese,
B.; Kopping, B.; Gobel, T.; Dickhaut; J.; Thoma, G.; Kulicke, K. J.; Trach,
F. Org. React. 1996, 48, 301-856. (d) Renaud, P.; Giraud, L. Synthesis
1996, 913-925. (e) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543-17594.
(2) (a) Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1993, 115,
5,3328-3329 and refs therein. (b) Bowman, W. R.; Clark, D. N.; Marmon,
R. J. Tetrahedron 1994, 50, 1275-1294. (c) Maxwell, B. J.; Tsanaktsidis,
J. J. Am. Chem. Soc. 1996, 118, 4276-4283. (d) Bowman, W. R.;
Broadhurst, M. J.; Coghlan, D. R.; Lewis, K. A. Tetrahedron Lett. 1997,
38, 6301-6304. (e) Benati, L.; Nanni, D.; Sangiorgi, C.; Spagnolo, P. J.
Org. Chem. 1999, 64, 7836-7841. (f) Benati, L.; Leardini, R.; Minozzi,
M.; Nanni, D.; Spagnolo, P.; Strazzari, S.; Zanardi, G.; Calestani, G.
Tetrahedron 2002, 58, 3485-3492.
(5) Roberts, B. P.; Dang, H.-S. J. Chem. Soc., Perkin Trans. 1 1996,
1493-1497.
(6) Benati, L.; Montevecchi, P. C.; Spagnolo, P. Tetrahedron Lett. 1978,
19, 815-818.
(7) Benati, L.; Montevecchi, P. C. J. Org. Chem. 1981, 46, 4570-4573.
10.1021/ol036268n CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/10/2004

and acyl10 radicals have provided useful synthetic routes to
N-heterocycles.
through successive alkylations with ethyl or benzyl bromide
and then with 1,2-dibromoethane or 1,3-dibromopropane. The
known o-cyanobenzyl bromide was instead directly obtained
by bromination of o-tolunitrile.15
Moreover, intermolecular addition of stannyl radicals to
azides smoothly yields N-stannylaminyl radicals that act as
the key intermediates in several important synthetic pro-
cesses. In particular, these nitrogen intermediates, being
somewhat more nucleophilic than ordinary aminyl radicals,11
have been shown to perform three-,2e,f five-,2a and six-
membered2a cyclizations onto the carbonyl groups of cyclic
ketones and â-keto esters to give ring-expanded amides by
â-fragmentation of resulting alkoxyl radicals.
The reactions of azides 1a-c and 2 were performed by
adding a benzene solution of Bu3SnH (1.1 equiv) and AIBN
(0.1 equiv) with a syringe pump over 3 h to a refluxing ben-
zene solution of the appropriate substrate (0.05 M) under a
nitrogen atmosphere. The resulting mixtures were refluxed
for an additional 2-3 h until virtual disappearance of the
starting material and then subjected to column chromatog-
raphy. In all cases, complex mixtures were formed and prob-
lems were encountered in product separation from tin
residues.
Our long interest in the chemistry of azido and radical
species2e,f,6,7,9,12 prompted us to undertake a study of the
intramolecular reactivity of N-stannylaminyl radicals toward
a cyano group as a possible further entry to carbon-nitrogen
bond formation. In sharp contrast with various reports of
successful (and also unsuccessful) cyclizations of carbon-
centered radicals onto nitriles,1e,13 those involving aminyl
radicals remain to date virtually unknown. The sole example
appears to be that recently discovered by Kim and co-workers
in the course of their investigation of 1,5-hydrogen transfers
from carbon to stannylaminyl radicals.11 These authors found
that the radical reaction of 5-azidovaleronitrile with Bu3SnD/
AIBN afforded a modest yield (27%) of a pyridinimine
seemingly arising from 6-exo cyclization of the initial
stannylaminyl radical to the nitrile group. This finding is of
interest especially in view of the fact that carbon radical
cyclization onto nitriles normally occurs in a 5-exo fashion.1e,13
In this paper, we report our initial results of the radical
reactions of Bu3SnH with azidonitriles, showing that the
derived stannylaminyl radicals are actually highly capable
of performing cyclization onto the cyano moiety, giving
aminoiminyl radicals that can be reduced to amidines or
undergo efficient cyclization onto a suitable alkenyl group.
We first examined the radical reactions of azidomalono-
nitriles 1a-c and azidobenzonitrile 2 (Figure 1). These new
Azides 1a,b and 2 led to isolation of the cyclized amidines
3a,b and 5 in varying yields (30-66%, Figure 1 and Table
1, entries 1-3), whereas azide 1c gave only a poor yield
Table 1. Cyclization Reactions of Azidomalononitriles 1a-c,
6a-d, and 7a-c and Azidobenzonitrile 2 with Bu3SnH/AIBN
entry
azide
product (%)a
entry
azide
product (%)a
1
2
3
4
5
6
7
1a
1b
1c
2
6a
6b
6c
3a (30)
3b (55)
4 (15)
8
9
6d
7a
7b
7c
8
6cb
6d b
10d (80)
11a (65)
11b (88)
11c (88)
16 (77)
10
11
12
13
14
5 (66)
9a (60)
10b (45)
10c (83)
9c (50)
9d (10)
a Yields isolated by column chromatography. b Reaction carried out in
the absence of AIBN.
(15%) of the pyridinone 4, which was evidently the hy-
drolytic product of pyridinimine 3c (Figure 1 and Table 1,
entry 4). The structures of all new compounds 3a,b, 4, and
5 were supported by analytical and spectral data.16 Our
present results with azides 1a,b and 2 appear to provide the
first chemical evidence of intramolecular 5-exo ring closure
of stannylaminyl radicals to nitriles; the process affords
cyclized aminoiminyl radicals and then amidines upon
subsequent reduction (Scheme 1). Moreover, the reaction of
Scheme 1a
Figure 1.
azides were generally prepared by treatment of the corre-
sponding bromides with sodium azide. The requisite bro-
momalononitriles were in turn available from malononitrile14
a Reagents: (i) Bu3SnH/AIBN; (ii) Bu3SnH, H2O.
azide 1c seemed to substantiate Kim’s original evidence11
that a stannylaminyl radical would be also entitled to add to
(8) (a) Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116,
5521-5522. (b) Kizil, M.; Patro, B.; Callaghan, O.; Murphy, J. A.;
Hursthouse, M. B.; Hibbs, D. J. Org. Chem. 1999, 64, 7856-7862. (c)
Lizos, D. E.; Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117-122 and
refs therein.
(9) (a) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. Tetrahedron
Lett. 1997, 38, 7913-7916. (b) Montevecchi, P. C.; Navacchia, M. L.;
Spagnolo, P. Eur. J. Org. Chem. 1998, 1219-1226.
(10) Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.;
Strazzari, S.; Zanardi, G. Org. Lett. 2002, 4, 3079-3081.
(11) Kim, S.; Yeon, K. M.; Yoon, K. S. Tetrahedron Lett. 1997, 38,
3919-3922.
418
Org. Lett., Vol. 6, No. 3, 2004

a nitrile in a 6-exo fashion, though possibly to a lesser extent
(Scheme 1).
Bowman and co-workers have revealed that iminyl radicals
generated by 5-exo cyclization of C-centered radicals onto
nitriles can undergo tandem cyclizations onto suitably placed
alkenes.13
However, at that stage we realized that the actual meaning
of the above azide reactions remained rather unclear, since
in principle the produced amidines 3a-c and 5 might
alternatively have formed through reduction of the stannyl-
aminyl radical by the hydride followed by nucleophilic
cyclization of the resulting amine onto the nitrile.17 Ad-
ditionally, since stannylaminyl radicals had been found to
undergo smooth 1,5-H transfer from carbon to nitrogen when
bearing a stabilizing substituent, including a phenyl group,
in the 5-position,11 the benzylated amidine 3b might also
have formed via 1,5-H transfer from the benzylic carbon to
the aminyl nitrogen and subsequent cyclization of the reduced
aminodinitrile.
To clarify the reactivity of aminyl radical cylization onto
nitriles as well as their utility in heterocyclic synthesis, we
were subsequently prompted to extend our study to analogous
reactions of a number of azidoethyl- and azidopropylmalo-
nonitriles, 6a-d,7a-c, and 8, each bearing a variously
substituted alkenyl moiety as shown in Figure 2. Our aim
The new azido precursors 6a-d, 7a-c, and 8 were gen-
erally produced from malononitrile by a methodology sim-
ilar to that employed for azides 1a-c. The usual reaction of
Bu3SnH/AIBN with the allylated azidoethylmalononitrile 6a
yielded the pyrrolidinimine 9a16 as the only identifiable
product (Figure 2 and Table 1, entry 5). However, the con-
geners 6b-d interestingly furnished tandem cyclization
products, the fused pyrroles 10b-d, respectively, in moderate
to good yields (Figure 2 and Table 1, entries 6-8). Similarly,
the azidopropylmalononitriles 7a-c also gave the respective
tandem cyclization products, the pyrrolopyridines 11a-c,
even in somewhat higher yields (Figure 2 and Table 1, entries
9-11). The azidoethylmalononitrile 8, instead, gave no traces
of any tandem product but, like azide 6a, only led to the
monocyclic pyrrolidinimine 1616 in fairly high yield (Figure
2 and Table 1, entry 12). No problems of separation from
tin residues were encountered in the reactions of azides
6a-d, 7a-c, and 8.
Since alkyl azides also react with Bu3SnH under thermal
conditions, the reactions of azides 6c,d with the tin hydride
were repeated in the absence of the radical initiator in order
to fully exclude the possibility that our tandem cyclization
products might have arisen from some curious nonradical
mechanism. In the absence of AIBN, however, the corre-
sponding pyrrolidinimines 9c and 9d16 were obtained as the
only identifiable products (Figure 2 and Table 1, entries 13
and 14). Under these circumstances, compounds 9c,d con-
ceivably arose from intramolecular addition of the reduced
amine to either cyano group.17
As far as the newly observed fused pyrroles 10b-d and
pyridines 11a-c are concerned, their structures were pri-
1
marily suggested by analytical and H and 13C NMR data.
Spectral data, however, while being consistent in each case
with a single geometrical isomer, did not allow assignment
of a definite cis or trans stereochemistry. Moreover, spectral
data did not allow us to ascertain whether each compound
occurred as a single tautomeric form or as a mixture of the
two possible tautomers. Subsequent X-ray crystallographic
analysis of the benzylated cyanopyrrolopyrrole 10d and the
corresponding cyanopyrrolopyridine 11c established the
actual trans stereochemistry for both compounds.18 Crystal-
lographic analysis also proved that pyrrole 10d occurred as
a mixture of the two tautomers, whereas pyridine 11c was
present as a single form bearing the tautomeric hydrogen
on the pyridine nitrogen. On this basis, the trans stereo-
chemistry was generally assumed for all compounds 10 and
11; additionally, compounds 10 were assumed to occur as
Figure 2.
was to ascertain whether aminoiminyl radicals, possibly
generated by 5- and 6-exo stannylaminyl radical cyclization
onto either nitrile group, might be intercepted by the internal
alkene in 5-exo- (or 6-exo) mode. Very recent reports by
(12) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. J. Org. Chem.
1997, 62, 5846-5848.
(13) For very recent examples of carbon radical cyclizations onto nitriles
and their use in synthesis, see: (a) Bowman, W. R.; Bridge, C. F.; Brookes,
P. Tetrahedron Lett. 2000, 41, 8989-8994. (b) Bowman, W. R.; Bridge,
C. F.; Cloonan, M. O.; Leach, D. C. Synlett 2001, 765-768. (c) Bowman,
W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C J. Chem.
Soc., Perkin Trans. 1 2002, 58-68.
(16) Products 3, 5, 9, and 16 can exist as two tautomers. Calculations
suggest that the aminic form could be the preferred one (see Supporting
Information).
(17) Amidines are known to be formed by addition of amines to nitriles;
see: Smith, M. B.; March, J. In AdVanced Organic ChemistrysReactions,
Mechanisms and Structures, 5th ed.; Wiley-Interscience: New York, 2001;
pp 1191-1192.
(18) See Supporting Information for the X-ray analyses of 10d
and 11c.
(14) Diez-Barra, E.; De La Hoz, A.; Moreno, A.; Sanchez-Verdu`, P. J.
Chem. Soc., Perkin Trans. 1 1991, 2589-2592.
(15) Orita, A.; Hasegawa, D.; Nakamo, T.; Otera, J. Chem. Eur. J. 2002,
8, 2000-2004.
Org. Lett., Vol. 6, No. 3, 2004
419

tautomeric mixtures, while compounds 11 were assumed to
occur as single tautomers (Figure 2).
cyclization than 5-exo cyclization, which is usually the case
in radical chemistry.
The bulk of chemical evidence provided by the present
radical reactions of azidonitriles 6a-d, 7a-c, and 8 would
lead to the conclusion that the derived stannylaminyl radicals
could normally undergo highly efficient addition onto a
cyano group in both 5-exo and, even more interestingly,
6-exo fashion, yielding aminoiminyl radicals 12 and 13. The
5-exo cyclized iminyl radical 12a avoided subsequent
cyclization onto the allylic moiety and exhibited only
reduction to amidine 9a (Table 1, entry 5 and Scheme 2).
It is noteworthy that the stannylaminyl radicals derived
from azides 6b-d and 7a-c provided diagnostic evidence
for neither H-abstraction from the tin hydride nor (6b-d)
1,5-H transfer from the allylic positions of their alkenylic
chains.
In conclusion, stannylaminyl radicals derived from azides
can perform highly efficient cyclization onto a cyano group
in both 5- and 6-exo fashion. The fair reactivity of stannyl-
aminyl radicals toward nitrile groups should be largely due
to both their nucleophilic nature, which would favor attack
to the electrophilic nitrile carbon,19 and, more importantly,
to the consequent production of aminoiminyl radicals, which
would be stabilized species as a result of resonance delo-
calization of the amino lone pair.20 In fact, these iminyls
did not bring about any 1,4- or 1,5-nitrile translocations, in
sharp contrast to the alkyl/aryl-substituted congeners.13a,21 The
cyclized aminoiminyl radicals can interestingly exhibit 5-exo
cyclization onto an internal alkene, thus offering a new
valuable entry to pyrrolopyrroles and pyrrolopyridines.
Studies are still in progress to further understand the
reactivity of stannylaminyl radical cyclization onto nitriles
as well as its potential in heterocyclic synthesis.
Scheme 2a
a Reagents: (i) Bu3SnH/AIBN; (ii) Bu3SnH.
Acknowledgment. The authors gratefully acknowledge
financial support from MIUR (2002-2003 Funds for “Radical
Processes in Chemistry and Biology: Fundamental Aspects
and Applications in Environment and Material Science”) and
the University of Bologna (2001-2003 Funds for Selected
Research Topics).
On the contrary, the other 5- and 6-exo cyclized iminyl
radicals 12b-d and 13a-c generally exhibited 5-exo cycli-
zation onto their alkenyl substituent yielding the eventual
products 10b-d and 11a-c. The tandem processes, however,
were found to occur to an extent increasing on passing from
12b to 12c,d and, similarly, from 13a to 13b,c (Table 1,
entries 5-8 and 9-11). It therefore appears that the
feasibility of the tandem cyclization is highly dependent on
the stability of the ensuing C-centered radicals 14 and 15
(Scheme 2).
It is worth noting that the stereochemistry of compounds
10b-d and 11a-c was also correctly predicted by using the
Beckwith-Houk models for the transition states of 5-exo
cyclizations (see Supporting Information).1b This result,
together with a very small calculated energy difference
between radicals cis-14b and trans-14b (-1.1 kcal/mol,
DFT, SnBu3 ) SnMe3) suggests that ring closure of amino-
iminyls could occur under kinetic control and could be
substantially irreversible.
Supporting Information Available: Experimental pro-
cedures for the synthesis of azidonitriles and their radical
reactions; spectral data for all new compounds; X-ray
diffraction details, as well as CIF files, for compounds 10d
and 11c; TS models for cyclization of 12d; and optimized
(DFT) structures of cis- and trans-14b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL036268N
(19) In malononitriles the concomitant presence of two CN groups on
the same carbon is expected to enhance the electrophilicity of both groups.
This might play a further role in favoring cyclization of the nucleophilic
stannylaminyl radical onto either nitrile group of our azidomalononitriles.
(20) Thermodynamic and structural data for 1-amino-substituted iminyl
radicals are not available in the literature.
(21) (a) Curran, D. P.; Seong, C. M. Tetrahedron 1992, 48, 2175-2190.
(b) Kim, S.; Jon, S. Y. J. Chem. Soc., Chem. Commun. 1998, 815-816. (c)
Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc.
1988, 110, 2565-2575. (d) Rychnovsky, S. D.; Swenson, S. S. Tetrahedron
1997, 53, 16489-16502. (e) Sulsky, R.; Gougoutas, J. Z.; DiMarco, J.;
Biller, S. A. J. Org. Chem. 1999, 64, 5504-5510.
As for the 5-exo cyclized iminyl radical derived from azide
8, the observed failure to undergo possible 6-exo cyclization
onto the alkenyl moiety to give a pyrrolopyridine in favor
of exclusive reduction to pyrrolidinimine 16 (Figure 2) was
likely a consequence of the lower feasibility of 6-exo
420
Org. Lett., Vol. 6, No. 3, 2004