A new gold-catalysed azidation of allenes

Article abstract of DOI:10.1039/c3cc48017h

A new gold-catalysed azidation reaction of allenes is presented as a new highly modular approach for the synthesis of substituted allyl derivatives containing nitrogen from simple precursors. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc48017h

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A new gold-catalysed azidation of allenes†
Cesar Hurtado-Rodrigo, Stefanie Hoehne and Marıa Paz Munoz*
´
´
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Cite this: Chem. Commun., 2014,
50, 1494
Received 18th October 2013,
Accepted 30th November 2013
DOI: 10.1039/c3cc48017h
www.rsc.org/chemcomm
A new gold-catalysed azidation reaction of allenes is presented as a examples of this concept and our efforts to develop this new
new highly modular approach for the synthesis of substituted allyl methodology as a highly modular approach for the synthesis of allyl
derivatives containing nitrogen from simple precursors.
azides with extra functionalities that will enable a straightforward
increase in molecular complexity from simple allenes (Scheme 1b).
The challenge of this reaction is that, in contrast with
Organic azides are common building blocks for the synthesis of
natural products and nitrogen-containing heterocycles of pharmaco- alcohols or amines, the available nucleophilic azides, NaN3 or
logical relevance.1 As classic azides, allyl azides are useful precursors TMSN3, do not have the necessary proton to furnish the protonolysis
of many functional groups (e.g. amines, nitriles),2 and can be used in of the vinyl–gold complex intermediate and therefore, the catalytic
copper-catalysed 1,3-dipolar additions to alkynes for the synthesis of cycle cannot be completed.11 In order to close the catalytic cycle, the
allyl triazoles.3 The classic synthesis of allyl azides involves the volatile, toxic and explosive hydrazoic acid, HN3,12 has to be
substitution of primary or secondary allyl derivatives with nucleo- cautiously generated in situ.13 Nevertheless, protonolysis of vinyl–
philic azides, like NaN3 or TMSN3 (Scheme 1a).4 However these gold(I) complexes is only one way to close the catalytic cycle and
methods have limitations, and mixtures of regioisomers are often other electrophiles can be employed to break the C–Au bond
obtained. Pd- and Mo-catalysed allylic azidations have been also without the need for hazardous reagents.14
described with better results in the selectivity and scope.5
Using commercially available cyclohexylallene (1a) and
Allenes are versatile starting materials for developing Ph3PAuCl/AgOTf, we first investigated the optimal conditions
sequential reactions, affording new and efficient methods for the for the hydroazidation reaction. We found that TMSN3 was the
preparation of complex compounds of synthetic or biological impor- best source of the nucleophilic azide, and trifluoroacetic acid
tance. In this area, gold-catalysed intermolecular addition of nucleo- (TFA) in DCM was the best proton source to provide clean
philes to allenes is an important reaction that has been widely complete conversion to the expected allyl azide 2a, with its
developed in the last few years, especially for oxygen nucleophiles,6 regioisomer 2a0, together with allyl trifluoroacetate, 3a, plus
although the nitrogen7 and carbon-based nucleophile8 versions have acetamide 4a as an unexpected product (Scheme 2).15
also been described. We envisioned that nucleophilic azides could
be used in a similar gold-catalysed reaction9 with allenes,10 as a new
method for the synthesis of allyl azides. We report here the first
Scheme 2 Gold-catalysed hydroazidation of cyclohexylallene.
AgOTf seemed to be the most effective chloride abstractor in this
reaction, and was used for catalyst screening.16 NHC–Au complexes
Scheme 1 Different approaches for the synthesis of allyl azides.
did not favour the azidation reaction, and 3a was obtained as the
major component in low conversions. The best result was obtained
School of Chemistry, University of East Anglia, NR4 7TJ, Norwich, UK.
with (PhO)3PAuCl as the catalyst. In a final approach to get the
E-mail: m.munoz-herranz@uea.ac.uk; Fax: +44 (0) 1603592003
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc48017h optimum conditions, we found that the best ratio of products and
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Comparison of the reaction profile by analysis of the 31P NMR
spectra in experiments A and B, where the addition of the allene and
the azide were reversed, suggests that the azide coordinates to the
gold in both cases, even when the allene is present in the reaction,
and therefore an inner-sphere mechanism cannot be ruled out.23
Interestingly, after addition of TFA both reactions exhibited a broad
signal in 31P NMR around 100 ppm together with a sharp singlet at
127 ppm from the free (PhOꢀ)3P, which grew over the reaction time.24
This suggests the CF3CO2 is capable of displacing either the
(PhO)3P or the N3 from the gold to reach a complex equilibrium
where at least three allene–gold complexes might be involved with
Table 1 Scope of the gold-catalysed hydroazidation of allenes
Entrya
Allene
Yield (%), 2 : 20 (ratio)
1
2
3
4
5
6
7
8
R = Cy 1a
R = n-hexyl, 1b
R = n-octyl, 1c
R = Ph, 1d
59, 2a : 2a0 (3.7 : 1)b
48, 2b : 2b0 (1.9 : 1)c
47, 2c : 2c0 (1.8 : 1)d
62, 2d
R = (MeO2C)2CHCH2, 1e
R = CH2-N-phthalamide, 1f
R = (Boc)2NCH2, 1g
R = R0 = Me, 1h
43, 2e : 2e0 (3.8 : 1)c
c
48, 2f; 7, 2f0
38, 2g e
different ligands/counterions.25 The exchange of TfOꢀ by CF3CO2
ꢀ
2h : 2h0 (3.7 : 1) f
76, 2i
9
R = Ph, R00 = n-octyl, 1i
R = Bn, R00 = n-Pr, 1j
R = Bn, R00 = i-Pr, 1k
R = Ph(CH2)2, R00 = n-Pr, 1l
R = Ph(CH2)2, R00 = i-Pr, 1m
R = p-CF3Ph, 1n
and the displacement of (PhO)3P were also observed in experiment
C, where TFA was added first. Further shift of the 31P NMR signal
after addition of the TFA suggests the formation of the complex
(PhO)3PAu+ꢁꢀOCOCF3. The signal from free (PhO)3P was also
observed in this reaction when azide was added, suggesting an
equilibrium with the complex [(N3)Au(OCOCF3)]ꢀ. When the allene
was added to this mixture a similar reaction profile to the experi-
ments A and B was observed. Analysing the signals of the 1H NMR
spectra we could not observe the proposed vinyl–gold intermediate,
but clean conversion to the products, suggesting fast protonolysis. A
similar rate of formation of the different products was observed in all
experiments after all the components had been added, implying
similar catalytic species involved after addition of the aꢀcid and
suggesting that coordination with the allene and/or the N3 might
be the rate limiting step for the reaction. When we followed the
reaction using NMR under catalytic conditions, a broad signal
around 100 ppm, and free (PhO)3P (127 ppm) were observed in
31P NMR spectra, which suggests that the complicated equilibrium
between the complexes shown in Scheme 3 might be existing under
catalytic conditions.26
10
11
12
13
14g
15g
16
67, 2j : 2j0 (1.3 : 1)
55, 2k : 2k0 (1.67 : 1)
70, 2l : 2l0 (1 : 1.13)
80, 2m : 2m0 (1 : 1)
74, 2n
R = p-CF3Ph, R00 = n-Pr, 1o
R = p-ClPh, R00 = n-octyl, 1p
67, 2o
72, 2p
a
b
3 observed in traces (o5%) in the reaction mixture. 4a isolated as a
by-product (15%). c Methyl ketones isolated as by-products: 4b0 (R = n-hexyl,
16%), 4e0 (R = (MeO2C)2CHCH2, 17%), 4f0 (R = CH2-N-phthalamide, 32%).
d Run without water (0.08 M). e Deprotection of one Boc- was observed
f
under reaction conditions. 100% conversion; products not isolated due to
volatility issues. g Reactions carried out at 30 1C for 60 h.
yields was obtained changing the concentration, lowering the tem-
perature, adding up to 5 equivalents of water as additive,17,18 and
purifying the mixture over basic alumina. Under the best conditions,
we investigated the scope of the reaction with different substituted
allenes (Table 1).
The reaction works for mono- and disubstituted allenes with
different functionalities, but functional groups sensitive to acid are
not well tolerated. Allyl azides 2 from the attack to the less
substituted carbon of the allene were obtained as the major or
only product in moderate to good yields. The regioselectivity of the
reaction seems to be dominated by electronic effects: allenes
directly substituted with a phenyl group gave only one regioisomer
(entries 4, 9, 14, 15 and 16, Table 1). However, when the phenyl
group was moved away from the allenic system (entries 10 to 13,
Table 1), both regioisomers were observed, even in the case of
bulkier substituents (R00 = i-Pr, entries 11 and 13).
It is known that allyl azides equilibrate in solution, even at
room temperature, by a [3,3] sigmatropic rearrangement.19
Monitoring the reaction of allene 1a by 1H NMR we observed that
although both allyl azides are formed in the gold-catalysed reaction,
the concentration of allyl azide 2a0 increases at the beginning and
then decreases (2a0 = 31% at 1 h, 2a0 = 17%, at 3 h), isomerising
into 2a during the reaction time.20 We postulate that amide 4a
comes from the gold-catalysed Schmidt reaction of the methyl
ketone,21 formed by protonation of the allene at the terminal
position and attack of H2O, with the in situ formed HN3.
Scheme 3 31P NMR-profile for stoichiometric experiments.
The important utility of this transformation is illustrated by the
straightforward synthesis of iodinated allyl azides. By using NIS as the
electrophile in the gold-catalysed azidation of allenes,14,27 an extra
functionality can be introduced in one step, making this method a
very useful tool for the orthogonal functionalization of simple mole-
cules into complex structures. The reaction of allene 1a with TMSN3, in
the presence of NIS using different gold complexes afforded the vinyl
iodide 5a as the only regioisomer (Scheme 4a). Vinyl iodide 5c was
obtained in moderate yield using the NHC–Au catalyst (Scheme 4b).28
To further demonstrate the potential of this method as a highly
modular approach, we carried out the synthesis of derivatives 6a and
To investigate the possible formation of LAuN3 complexes,22
we carried out a preliminary NMR study: three stoichiometric
experiments were performed at room temperature in which the
order of addition of the components was varied. 1H and 31P
NMR spectra were recorded after each addition (Scheme 3).
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9 For selected examples of the use of azides in gold-catalysis, see:
(a) D. J. Gorin, N. R. David and F. D. Toste, J. Am. Chem. Soc., 2005,
127, 11260–11261; (b) Y. Sawama, Y. Sawama and N. Krause, Org.
Lett., 2009, 11, 5034–5037; (c) Z. Huo, I. D. Gridnev and
Y. Yamamoto, J. Org. Chem., 2010, 75, 1266–1270; (d) Z. Y. Yan,
Y. Xiao and L. Zhang, Angew. Chem., Int. Ed., 2012, 51, 8624–8627.
10 For selected examples of reaction of allenes and nucleophilic azides,
see: (a) H.-M. Chang and C.-H. Cheng, J. Chem. Soc., Perkin Trans. 1,
2000, 3799–3807; (b) H.-M. Chang, X. Huang, R. Shen and T. Zhang,
J. Org. Chem., 2007, 72, 1534–1537.
11 For selected examples of hydroazidation of alkenes, see:
(a) I. Adamo, F. Benedetti, F. Berti and P. Campaner, Org. Lett.,
2006, 8, 51–54; (b) J. Waser, B. Gaspar, H. Nambu and E. M. Carreira,
J. Am. Chem. Soc., 2006, 128, 11693–11712.
Scheme 4 Orthogonal functionalization of allenes using the gold-
catalysed azidation methodology.
12 Ullmann’s Encyclopedia of Industrial Chemistry, VCH Verlag, Weinheim,
1989, vol. A13, pp. 193–197.
13 For selected examples of in situ generation of HN3 using TMSN3, see:
(a) G. W. Breton, K. A. Daus and P. J. Kropp, J. Org. Chem., 1992, 57,
7a by using a click29 and a Suzuki–Miyaura cross-coupling30 reaction
with product 5a (Scheme 4a).
¨
6646–6649; (b) H. Schafer, W. Saak and M. Weidenbruch,
In conclusion, we have found that the hydroazidation of allenes
to obtain allyl azides is possible by using (PhO)3PAuCl in the
presence of TMSN3 and TFA. The reaction works well for substituted
allenes, but functional groups sensitive to acid are not well tolerated.
Preliminary mechanistic studies point out to a complex mechanism
with equilibrium between several allene–gold–azide complexes, and
an unusual displacement of the phosphite ligand from the gold-
coordination sphere. Further investigation into this and a more
detailed mechanistic study is underway in our laboratories. Further
transformations involving the azide and diverse cross-couplings at
different stages of the process are envisioned31 and will be of general
interest to the synthetic chemistry community.
J. Organomet. Chem., 2000, 604, 211–213.
14 A. S. K. Hashmi, T. D. Ramamurthi, M. H. Todd, A. S.-K. Tsang and
K. Graft, Aust. J. Chem., 2010, 63, 1619–1626, and references therein.
15 All the control experiments gave negative results (see ESI† for details).
16 For silver effect in gold catalysis, see: D. Wang, R. Cai, S. Sharma,
J. Jirak, S. K. Thummanapelli, N. G. Akhmedow, H. Zhang, X. Liu,
J. L. Pettersen and X. Shi, J. Am. Chem. Soc., 2012, 134, 9012–9019.
17 Gold-catalysed reaction of allenes in the presence of water gives allyl
alcohols: Z. Zang, S. D. Lee, A. S. Fisher and R. A. Widenhoefer,
Tetrahedron, 2009, 65, 1794–1798. However, despite the high excess
of water, we do not observe significant amounts of hydration of the
allene in our reaction, and formation of 3 is minimised.
18 Different proton sources and additive to modulate the pH were
tested, being TFA (3 eq.) plus water (5 eq.) the best combination for
yield and selectivity. See Tables S2 and S3, in ESI†.
19 (a) A. Gagneux, S. Winstein and W. G. Young, J. Am. Chem. Soc.,
1960, 82, 5956–5957; (b) A. K. Feldman, B. Colasson, K. B. Sharpless
and V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 13444–13445.
20 This seems to be in agreement with reported examples using excess
of alcohol as nucleophile, where the kinetic product is the attack to
the more substituted carbon, and a gold-catalysed isomerisation
then occurs to give the thermodynamic less substituted allyl ethers.
(a) M. S. Hadfield and A.-L. Lee, Org. Lett., 2010, 12, 484–487;
(b) R. S. Paton and F. Maseras, Org. Lett., 2009, 11, 2237–2240.
21 K. F. Z. Schmidt, Angew. Chem., Int. Ed. Engl., 1923, 36, 511.
22 D. V. Partyka, T. J. Robilotto, M. Zeller, A. D. Hunter and T. G. Gray, Proc.
Natl. Acad. Sci. U. S. A., 2008, 105, 14293–14297, and references therein.
23 Independently synthesised (PhO)3PAuN3 has a 31P NMR signal at 105.80
ppm, and IR sharp band at 2060 cmꢀ1 (nas N3ꢀ). This complex resulted to
be very unstable and could not be tested as catalyst in the reaction.
The authors would like to thank Prof. Hashmi for his support and
the NHC–gold complexes. Funding by the University of East Anglia is
gratefully acknowledged. This work was supported by the A-I Chem
Channel program, selected by the European INTERREG IV A France
(Channel)
–
England Cross-border cooperation Programme,
co-financed by ERDF. The authors thank the EPSRC National Mass
Spectrometry Service Centre, Swansea, for the accurate HRMS analysis.
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,
mostly overlapped with the allyl azide 2, and would be difficult to
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˜
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1496 | Chem. Commun., 2014, 50, 1494--1496
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