A concomitant allylic azide rearrangement/intramolecular azide-alkyne cycloaddition sequence

Article abstract of DOI:10.1021/ol500011f

An intramolecular Huisgen cycloaddition of an interconverting set of isomeric allylic azides with alkynes affords substituted triazoles in high yield. The stereoisomeric vinyl-substituted triazoloxazines formed depend on the rate of cycloaddition of the d

Full text of DOI:10.1021/ol500011f

Letter
pubs.acs.org/OrgLett
A Concomitant Allylic Azide Rearrangement/Intramolecular Azide−
Alkyne Cycloaddition Sequence
Rakesh H. Vekariya, Ruzhang Liu, and Jeffrey Aube*
́
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: An intramolecular Huisgen cycloaddition of an
interconverting set of isomeric allylic azides with alkynes affords
substituted triazoles in high yield. The stereoisomeric vinyl-
substituted triazoloxazines formed depend on the rate of cyclo-
addition of the different allylic azide precursors when the reaction is
carried out under thermal conditions. In contrast, dimerized
macrocyclic products were obtained when the reaction was done
using copper(I)-catalyzed conditions, demonstrating the ability to
control the reaction products through changing conditions.
he 1,3-dipolar Huisgen azide−alkyne cycloaddition
would arise from i1 or i2, respectively. If one assumed rapid
T
(AAC) is one of the most commonly used modern
equilibrium of azides relative to cyclization (i.e., Curtin−
Hammet conditions; but see discussion below) and that the R
group in the tether would prefer an equatorial orientation in the
transition structure, the ratio of products x/y would reflect the
relative energies of transition states containing an equatorial or
axial vinyl group. In addition, terminal azide cis-t might form a
constitutional isomer z if the cis double bond could be
accommodated in the fused ring, although low yields of this
material would be expected given the low amounts of cis olefin
present in the equilibrium mixure of azides (usually <10%9).
Finally, for most ring sizes (and all of those investigated here),
azide trans-t containing a trans double bond would not be
expected to cyclize to any appreciable extent.
organic reactions.1−5 Allylic azides represent a particularly
interesting partner in AAC chemistry because such compounds
undergo facile 1,3-allylic azide rearrangements at room
temperature (known as Winstein rearrangements6), and the
resulting allyl triazoles can be converted into diverse products.7
The Winstein rearrangement typically provides access to
constitutionally isomeric (regiosiomeric) allylic azides, which
can be differentially reacted in a subsequent transformation; an
early example of this was the rearrangement/AAC sequence
reported by Sharpless and later investigated by Batra (Figure
1).7,8 Recently, we reported that equilibrating allylic azide
stereoisomers can selectively participate in a downstream azido-
Schmidt reaction sequence, affording diastereomerically
enriched lactam products a and b (Figure 1); this strategy
was used in the preparation of an intermediate useful in the
total synthesis of pinnaic acid.9 In this paper, we describe a
sequence in which a Winstein rearrangement is combined with
an intramolecular Huisgen cyclization, paying particular
attention to the effects of substrate structure and reaction
conditions on the product structure (Figure 1). A particularly
interesting outcome of these experiments is that the nature of
the final product is in some cases sensitive to reaction
conditions.
We prepared a series of alkynyl azides 1−10 linked by a
three-atom oxygen-containing tether (Scheme 2). In general,
alkylation of a propargylic alcohol with 1,4-dibromobutene
gives an allylic bromide that is then subjected to simple
substitution with NaN3. Each compound as drawn represents a
mixture of equilibrating azides with the thermodynamic ratio of
terminal and internal azides (pairs of enantiomers or
diastereomers) indicated in Table 1. The azides were initially
isolated as mixtures that were purified by chromatography to
1
yield the trans-t isomers. H NMR indicated that such samples
AAC reactions may be carried out thermally or using
transition-metal catalysts, notably Cu(I) and Ru(II).2,3 A high
measure of product control (regiocontrol) is possible through
transition-metal catalysis of the reaction, with 1,4-dialkyltria-
zoles predominantly formed using copper(I) promotion2 and
1,5-isomers using ruthenium(II) catalysts.3 In an intramolecular
context, the 1,5-isomer is formed under either thermal or
catalyzed versions.1c,5,10
An equilibrating mixture of terminal azides cis-t/trans-t with
internal i1/i2 isomers, containing an existing stereogenic center
elsewhere in the molecule, could in principle afford three
triazole products (Scheme 1). Thus, diastereomers x and y
generally reattained equilibrium in about a week at room
temperature (see the Supporting Information for the specific
case of compound 7; reported half-lives range from hours to
days6,7a).
Upon heating the unsubstituted azide 1, a 72% yield of 11
was obtained (Table 1, entry 1). The product exclusively
resulted from cycloaddition of the internal azide, which was
present in <20% of equilibrated 1. Thus, the rearrangement
Received: January 2, 2014
Published: March 17, 2014
© 2014 American Chemical Society
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Scheme 2. General Route to Allylic Azides
a
Table 1. Intramolecular AAC of Allylic Azides
b
c
entry azide (R1, R2, R3, R4) ter/int ratio triazole (yield, %) dr (a/b)
1
2
1 (H, H, H, H)
83:17
67:33
84:16
64:36
69:31
86:14
81:19
74:26
88:12
74:26
11 (72)
12 (85)
13 (83)
14 (76)
15 (93)
16 (88)
17 (84)
18 (84)
19 (79)
20 (82)
2 (Me, H, H, H)
3 (Ph, H, H, H)
4 (Ph, Me, H, H)12
5 (Me, H, Et, H)
6 (Et, H, Me, H)
7 (Me, H, Ph, H)
8 (iPr, H, Ph, H)
9 (H, H, H, Me)
10 (H, H, H, Ph)
1.7:1
1.4:1
1.3:1
1.9:1
1.5:1
2:1
3
e
4
5
6
7
d
e
8
1.5:1
1:1
9
Figure 1. Examples of selective reactions involving Winstein
rearrangements.
10
1:1
a
Conditions: toluene, reflux, 1−2 h (except for entry 1: CHCl3, reflux,
4 h). Equilibrium ratio as determined by NMR analysis of purified
a
b
Scheme 1
allylic azides; compounds attained equilibrium over 1 week at room
temperature.11 Ratio determined by NMR analysis of crude reaction
c
d
mixtures. The relative stereochemistry of triazoles 18a and 18b was
confirmed by X-ray crystallography (Supporting Information).
e
Inseparable mixture.
occurred at a sufficient rate to allow for successful cyclization
from the starting azide mixture.
We then subjected azides 2−10 to similar conditions.
Although good yields and separable compounds were generally
obtained, stereoselectivities were poor, topping out at only 2:1
for two cases (Table 1, entries 5 and 7). Compound 2 also
reacted slowly (ca. 20 days for similar conversion) at room
temperature to afford 12 with similar diastereoselectivity.
The poor stereoselectivities observed in these reactions were
not surprising. In both transition states A and B, the emerging
vinyl group has a 1,3-relationship with an oxygen atom, leading
to small energy differences between axial and equatorial
placement of the vinyl group (Figure 2; here, R1 and R4 are
presumed to both be equatorial). In examples where R3 is an
alkyl group, A1,3 strain would lead to alternatives where R3 is in
an axial position, but those cases were similarly nonselective
(Table 1, entries 5 and 6).
a
Note: R group assumed to be pseudoequatorial throughout.
We then prepared azido alkynes bearing all-carbon tethers in
which the stereocenter in the product would emerge in a 1,2 or
1,3 relationship to an existing atom (Table 2; see the
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effect of additional ring systems with mixed results. In most
cases, modest stereoselectivities were still observed, although a
6.2:1 ratio was obtained for the formation of 28a (Table 2,
entry 4). This can be understood by considering a transition
state that contains a 1,3-diaxial interaction both involving axial
alkyl groups across the resident cyclohexane ring and leads to
the minor product (Figure 3c). In contrast, the trans isomer
27a, which is formed with poorer selectivity, is hampered by an
analogous 1,3-transdiaxial interaction arising from the vinyl
group and a hydrogen atom (Figure 3b).
Figure 2. Equatorial vs axial orientation of vinyl group in transition
states arising from compounds 1−10, leading to isomers a and b,
respectively.
a
Table 2. Intramolecular AAC of Allylic Azides
1
As noted above, H NMR studies indicated that the allylic
rearrangement reaction occurred at room temperature to reach
equilibrium in about a week. In addition, we note that no 1,3-
dipole cycloaddition was apparent in these samples when
examples bearing terminal alkyne substitution, like 7, were
examined. On the other hand, alkynes without terminal
substitution (i.e., 1−10 where R3 = H) were observed to
undergo cyclization at a somewhat slower, but comparable, rate
(e.g., about 40% of product being observed at 6.5 days for
compound 1, when the terminal−internal azide equilibrium was
also reached9b). Assuming that the relative rates are similar at
higher temperatures, these data suggest that while terminally
substituted alkyne substrates are reacting under Curtin−
Hammett conditions, those with a terminal H atom are in a
mixed kinetic regime.14
An interesting result was obtained when we treated 2 with
CuSO4·5H2O (Scheme 3). Thus, a single new compound was
Scheme 3
a
b
Conditions: toluene, reflux, 2−8 h. Starting azides exist as mixtures
of terminal and internal azide stereoisomers; ratios noted indicate
specific examples used in the experiment noted (1H NMR).11 Ratio
c
d
determined by NMR analysis of crude reaction mixtures. The relative
stereochemistry of triazoles 27a, 28a, and 29a was determined by X-
e
ray crystallography (Supporting Information). Inseparable mixtures.
Supporting Information for routes to compounds 25−29).
Although some of these examples gave better ratios favoring all-
equatorial transition states, the overall results were still modest.
This may reflect the moderate penalty for placing a vinyl group
in an axial orientation (A values between 1.49 and 1.68,12,13
Figures 3a,b) or the intervention of flattened reactive
conformations (e.g., entry 2 in Table 2). We examined the
obtained in 78% yield (R = Me), which was assigned as 31. The
trans geometry of the double bonds in 31 was assigned based
on the vicinal J coupling constant (15.5 Hz); both vinyl protons
1
coincide in the H NMR spectrum of 32 so in this case trans
geometry is presumed by analogy. In each case, only a single set
1
of resonances was present in both H and 13C spectra, but it
was not possible to unambiguously assign relative stereo-
chemistry to either product (or, indeed, completely rule out the
possibility that mixtures of stereoisomers were obtained). The
formation of 1,4-disubstituted triazoles is in accord with
literature expectations for the Cu-catalyzed reaction leading
Figure 3. Steric interactions encountered en route to disfavored
isomers, specifically compounds (a) 25b, (b) 27b, and (c) 28b.
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preferentially to 1,4-disubstitued triazoles.15 In this case, the
cyclophane 30 could potentially arise from intramolecular
formation of the 1,4-disubstituted triazole, but is presumably
disfavored due to ring strain as well as the low population of cis-
t allylic azide. Accordingly, it is likely that intermolecular
reaction of the terminal azide occurs affording the intermediate
shown, which is then followed by equilibration to terminal
azide and subsequent cycloaddition/macrocyclization.
The oxazepine 34 and macrocylic triazole 35 were obtained
from the equilibrating mixture of homologous azides 33 in 81%
and 78% yields, respectively (Scheme 4). However, attempts to
obtain the ring systems containing an additional carbon
intervening between the reacting groups were not successful.
(d) Sletten, E. M.; Bertozzi, C. R. Acc. Chem. Res. 2011, 44, 666.
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Vemula, R. Chem.Eur. J. 2011, 17, 14727. (b) McNulty, J.; Keskar,
K. Eur. J. Org. Chem. 2012, 2012, 5462. (c) Kwok, S. W.; Fotsing, J. R.;
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Scheme 4
(7) (a) Feldman, A. K.; Colasson, B.; Sharpless, K. B.; Fokin, V. V. J.
Am. Chem. Soc. 2005, 127, 13444. (b) Mishra, A.; Hutait, S.; Bhowmik,
S.; Rastogi, N.; Roy, R.; Batra, S. Synthesis 2010, 2731.
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G.; Fabbroni, S.; Gentilucci, L.; Perciaccante, R.; Piccinelli, F.;
Tolomelli, A. Org. Lett. 2005, 7, 533. (b) Gagnon, D.; Lauzon, S.;
Godbout, C.; Spino, C. Org. Lett. 2005, 7, 4769. (c) Takasu, H.; Tsuji,
The triazoles obtained in this study represent interesting
classes of heterocyclic compounds that contain an alkene
moiety for further manipulation. Although the stereoselectiv-
ities obtained in this work were slight, the ability to separate
products and select between several equilibrating azides by
modification of reaction conditions is noteworthy and suggests
future applications for such azides in chemical synthesis.
́
Y.; Sajiki, H.; Hitota, K. Tetrahedron 2005, 61, 11027. (d) Sa, M. M.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
́
(9) (a) Liu, R.; Gutierrez, O.; Tantillo, D. J.; Aube, J. J. Am. Chem.
Soc. 2012, 134, 6528. (b) Liu, R. Ph.D. Dissertation, University of
Kansas, Lawrence, KS, 2012.
(10) Ellison, A.; Boyer, R.; Hoogestraat, P.; Bell, M. Tetrahedron lett.
2013, 54, 6005.
Experimental procedures, full spectroscopic data, and NMR
spectra for all new compounds; X-ray data for structures of
compounds 18a, 18b, 27a, 28a, and 29a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) We estimate the cis-t isomer to be formed in 0−5% yield,
AUTHOR INFORMATION
Corresponding Author
although it is generally hard to quantify due to overlapping signals in
■
1
the H NMR.
(12) For 1-methyl-1-phenylcyclohexane, the chair conformer with an
axial phenyl group is favored by 0.32 kcal/mol over the alternative
chair: Eliel, E. L.; Manoharan, M. J. Org. Chem. 1981, 46, 1959.
(13) Buchanan, G. W. Can. J. Chem. 1982, 60, 2908.
*E-mail: jaube@ku.edu.
Notes
The authors declare no competing financial interest.
(14) Seeman, J. I. Chem. Rev. 1983, 83, 83−134.
(15) (a) Angell, Y.; Burgess, K. J. Org. Chem. 2005, 70, 9595.
(b) Chandrasekhar, S.; Rao, C. L.; Nagesh, C.; Reddy, C. R.; Sridhar,
B. Tetrahedron Lett. 2007, 48, 5869.
ACKNOWLEDGMENTS
■
We are grateful to the National Institute of General Medical
Sciences P41 GM089164 for financial support. We thank
Patrick Porubsky for HRMS, Victor Day for X-ray crystallog-
raphy (the diffractometer and software used in this study were
purchased through NSF−MRI Grant No. CHE-0923449), and
Gurpreet Singh and Digamber Rane for helpful suggestions (all
at the University of Kansas).
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