Enantioselective, Stereodivergent Hydroazidation and Hydroamination of Allenes Catalyzed by Acyclic Diaminocarbene (ADC) Gold(I) Complexes

Article abstract of DOI:10.1002/anie.201601550

The gold-catalyzed enantioselective hydroazidation and hydroamination reactions of allenes are presented herein. ADC gold(I) catalysts derived from BINAM were critical for achieving high levels of enantioselectivity in both transformations. The sense of enantioinduction is reversed for the two different nucleophiles, allowing access to both enantiomers of the corresponding allylic amines using the same catalyst enantiomer. Chiral allylic azides and amines are obtained by enantioselective hydroazidation and hydroamination of allenes catalyzed by acyclic diaminocarbene gold(I) catalysts derived from BINAM. The sense of enantioinduction is reversed for the two different nucleophiles, allowing easy access to both enantiomers with a single catalyst enantiomer.

Full text of DOI:10.1002/anie.201601550

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International Edition: DOI: 10.1002/anie.201601550
German Edition: DOI: 10.1002/ange.201601550
Gold Catalysis
Enantioselective, Stereodivergent Hydroazidation and
Hydroamination of Allenes Catalyzed by Acyclic Diaminocarbene
(ADC) Gold(I) Complexes
Dimitri A. Khrakovsky+, Chuanzhou Tao+, Miles W. Johnson, Richard T. Thornbury,
Sophia L. Shevick, and F. Dean Toste*
Abstract: The gold-catalyzed enantioselective hydroazidation
and hydroamination reactions of allenes are presented herein.
ADC gold(I) catalysts derived from BINAM were critical for
achieving high levels of enantioselectivity in both transforma-
tions. The sense of enantioinduction is reversed for the two
different nucleophiles, allowing access to both enantiomers of
the corresponding allylic amines using the same catalyst
enantiomer.
A
llylic amines are an important functional motif in synthetic
organic chemistry and they have been utilized in the synthesis
of numerous biologically active compounds.[1] Closely related
allylic azides are valuable precursors for allylic amines, as well
as for amino acids[2] and amine-containing natural products.[3]
Allylic azides have typically been prepared via substitution
reactions from the corresponding allylic halides, (homo)-
allylic alcohols, and their derivatives.[4] More recently, Pd-
Scheme 1. Enantioselective conjugate azidations and hydroazidations.
Table 1: Assessment of chiral gold(I) catalysts.
catalyzed C H activation,[5] and Au-catalyzed hydroazidation
À
of allenes[6] have been employed.
While reports of the synthesis of allylic azides are
numerous, methods for asymmetric azidation are few.[7]
Fewer still are enantioselective hydroazidation reactions,
which have only been reported in a formal sense via conjugate
addition to activated double bonds (Scheme 1).[8–10] In light of
recent examples of transition-metal catalysed asymmetric
additions of nitrogen nucleophiles to allenes[11] and the
growing utility of organic azides, we sought to develop
Entry[a]
Precatalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
(R)-DM-SEGPHOS·(AuCl)2
(R)-DTBM-BINAP·(AuCl)2
P1·(AuCl)
N1·(AuCl)
N2·(AuCl)
50
49
35
21
51
12
37
20
10
2
5
3
a
gold(I)-catalyzed enantioselective hydroazidation of
N3·(AuCl)
A1·(AuCl)2
2
60
allenes. Cognizant of potential regioselectivity issues from
the Winstein rearrangement[12] of the product allylic azides,
we initiated our studies using aryl allene 3a (Table 1).[13]
[a] Conditions: 0.1 mmol 3a, 0.005 mmol precatalyst (0.0025 mmol for
dinuclear gold precatalysts), 0.06 mmol AgOTf, 0.3 mmol TMSN3,
0.2 mmol TFA, 1.0 mL THF (0.1m), 2 h at room temperature. [b] Deter-
mined by 1H NMR with 1,3,5-trimethoxybenzene as an internal standard.
[c] Determined by chiral HPLC.
[*] D. A. Khrakovsky,[+] Prof. Dr. C. Tao,[+] M. W. Johnson, R. T. Thornbury,
S. L. Shevick, Prof. Dr. F. D. Toste
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
E-mail: fdtoste@berkeley.edu
Prof. Dr. C. Tao[+]
Current address: School of Chemical Engineering, Huaihai Institute
of Technology, Lianyungang 222005 (P.R. China)
M. W. Johnson
Current address: Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, CA 91125 (USA)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601550.
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Initial studies revealed that the use of ethereal solvents
was critical to obtaining reproducible data.[14] With the choice
of solvent established, the enantioinduction afforded by
a number of chiral gold(I) catalysts was evaluated under
conditions similar to those previously reported, with trifluoro-
acetic acid (TFA) and trimethylsilyl azide (TMSN3) used for
in situ generation of hydrazoic acid (Table 2).[6] Traditional
of chiral information was motivated by its commercial
availability, and the facile introduction of 3,3’-aryl substitu-
ents to tune the chiral environment around the metal center.
Preliminary results indicated that the ligands with both
unsaturated and saturated backbones performed with com-
parable efficiency; therefore, the latter were chosen due to
ease of synthesis[19] and superior crystallization properties.
A number of ADC catalysts were synthesized and
evaluated (Table 3). We explored the effect of various 3,3’-
Table 2: Optimization of hydroazidation with ADC gold(I) catalysts.
Table 3: Assessment of nitrogen nucleophiles.
Entry[a] Precatalyst Solvent
Acid
Yield [%][b] ee [%][c]
Entry[a]
HNuc
Time
Product
Major
ee
1
2
3
4
5
6
7
8
A1·(AuCl)2
A2·(AuCl)2
A3·(AuCl)2
A4·(AuCl)2
A5·(AuCl)2
A5·(AuCl)2
A5·(AuCl)2
A5·(AuCl)2
A5·(AuCl)2
A5·(AuCl)2
THF
THF
THF
THF
THF
THF
TFA
TFA
TFA
TFA
TFA
24
36
15
41
45
50
72
46
50
73
71
75
73
73
90
enantiomer[b]
[%][c]
[d]
1
2
3
4
HN3
60 min
24 h
14 days
14 days
4a
5a
6
R
S
S
S
35
27
65
30
H2NBoc
H2NNHBoc
H2NPh
7
AcOH 40
THF
H2O
H2O
H2O
H2O
77
91
[a] Conditions: 0.05 mmol 3a, 0.0025 mmol precatalyst, 0.006 mmol
AgOTf, 0.15 mmol nucleophile, 1.0 mL CDCl3 (0.05m). [b] Determined
by optical rotation and comparison to literature precedents (see
Supporting Information for details) [c] Determined by chiral HPLC.
[d] Generated in situ from TMSN3 (0.15 mmol) and TFA (0.10 mmol).
THF/PhMe[d]
[d]
9
THF/CHCl3
THF/CHCl3
91
10[e]
92[f]
[d]
[a] Conditions: 0.1 mmol 3a, 0.005 mmol precatalyst, 0.015 mmol
AgOTf, 0.3 mmol TMSN3, 0.2 mmol acid, 2.0 mL of appropriate solvent
(0.05m), 16 h at room temperature. [b] Determined by 1H NMR with 4-
chloroanisole as an internal standard. [c] Determined by chiral HPLC.
[d] 3:1 volumetric ratio. [e] Reaction run at À108C for 72 hours.
[f] Isolated yield.
aryl substituents on the BINAM scaffold, and found that
installation of 3,5-dimethyl (A2) or 3,5-bis(trifluoromethyl)
(A5) aryl groups at these positions gave improved ee values
(entries 2 and 5). Further studies were performed with
A5·(AuCl)2 as the optimal precatalyst, and a crystal structure
of the compound was obtained (See Supporting Information).
We hypothesized that the low yields could be the result of
catalyst decomposition, as a strong acid (TFA) could disrupt
the catalystꢀs stabilizing intramolecular hydrogen-bonding.
On the basis of this hypothesis, we envisioned that a weaker
acid in combination with TMSN3 might afford our desired
product in greater yield. We tried acetic acid, which is roughly
as acidic as hydrazoic acid,[20] and found the results mostly
unchanged (compare entries 5 and 6). On the other hand,
when water[21] was employed, a substantial increase in the
yield was noted (entry 7). Gratifyingly, the formation of the
allylic alcohol from hydration of the allene was not
observed.[22] Finally, the yields were raised to the desired
levels by addition of toluene or chloroform as co-solvents
(entries 8 and 9), and the enantioselectivities were elevated
by decreasing the temperature and extending the reaction
times to compensate for the slower rate of conversion
(entry 10).
chiral phosphine gold(I) catalysts failed to afford high levels
of enantioinduction (entries 1 and 2) as did a previously
reported[15] phosphoramidite catalyst (entry 3). Chiral NHC
gold(I) catalysts[16] (entries 4–6) also were found to be
unsatisfactory. However, the use of a BINAM-derived ADC
gold(I) catalyst (entry 7) offered the first encouraging data,
and this scaffold established the basis for further exploration.
ADC frameworks are a relatively recent entry into the
library of ligands for gold(I) catalysis[17] and their modular,
convergent syntheses from amines and gold isocyanides
makes them an attractive platform for developing chiral
ligands. Applications of ADC gold(I) complexes to asym-
metric catalysis have been reported previously by the
Slaughter group, the Espinet group, and our own group.[18]
As in our previous work, our choice of BINAM as the source
Encouraged by the results of these optimization efforts,
we were eager to investigate whether ADC gold(I) catalysts
would be compatible with other nitrogen nucleophiles. We
surveyed tert-butyl carbamate, tert-butyl carbazate, and ani-
line (Table 3); in all cases, the opposite enantiomer of the
allylic amine analogue was produced as the major product
relative to the hydroazidation reaction. Enantiodivergence in
synthetic protocols has previously been reported,[23] and is
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Table 5: Substrate Scope of hydroazidation and hydroamination.
usually brought about by modification of various reaction
parameters, including catalyst identity (e.g. changes to metal
or ligand), temperature, solvent, and additives, among others.
However, the dependence of product stereochemistry on the
identity of nucleophile is relatively rare.[24,25]
On the basis of this discovery, we pursued efforts to
optimize the hydroamination reaction with the tert-butyl
carbamate nucleophile (Table 4).[26] In all cases, complete
Entry[a,b]
3
Ar
4, yield,[c] ee[d]
5, yield,[c] ee[d]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
Ph
4a, 92, 90
4b, 89, 84
4c, 67, 74
4d, 84, 84
4e, 86, 86
4 f, 88, 90
4g, 41, 74
4h, 89, 85
4i, 65, 84
4j, 92, 89
4k, 87, 88
4l, 81, 62
4m, 86, 75
5a, 89, 89
5b, 82, 80
5c, 56, 73
5d, 49, 64
5e, 75, 87
5 f, 84, 92
5g, 97, 92
5h, 63, 83
5i, 82, 78
5j, 74, 72
5k, 77, 85
5l, 74, 80
5m, 71, 77
4-MeC6H4
4-SiMe3C6H4
4-PhC6H4
4-FC6H4
4-BrC6H4
4-CF3C6H4
3-MeC6H4
3-OMeC6H4
3-PhC6H4
3-BrC6H4
2-MeC6H4
3-thienyl
Table 4: Optimization of hydroazidation with ADC gold(I) catalysts.
9
10
11
12
13
3j
3k
3l
Entry[a]
Precatalyst
Solvent
Equivalents of
carbamate
Yield
[%][b]
ee
[%][c]
3m
1
2
3
4
5
6
7
8
A1·(AuCl)2
A2·(AuCl)2
A3·(AuCl)2
A4·(AuCl)2
A5·(AuCl)2
A4·(AuCl)2
A4·(AuCl)2
A4·(AuCl)2
A4·(AuCl)2
A5·(AuCl)2
A5·(AuCl)2
A5·(AuCl)2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DCM
PhMe
DMM
THF
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
3.0
3.0
33
32
28
53
46
54
73
48
30
62
64
89[e]
77
79
85
89
81
30
75
84
82
89
89
89
[a] Condition A: 0.1 mmol 3, 0.005 mmol A5·(AuCl)2, 0.015 mmol AgOTf,
0.3 mmol TMSN3, 0.2 mmol H2O, in 2.0 mL of THF:CHCl3 (3:1 v/v,
0.05m), 72 h at À108C. Condition B: 0.05 mmol 3, 0.0025 mmol
A4·(AuCl)2, 0.006 mmol AgOTf, 0.15 mmol tert-butyl carbamate, in
1.0 mL of 1,4-dioxane (0.05m), 24 h at rt. [b] Absolute stereochemistry
assigned by analogy to 4a and 5a. [c] Isolated yield. [d] Determined by
chiral HPLC.
9
10
11
12[d]
1,4-dioxane
1,4-dioxane
1,4-dioxane
Introduction of a larger terminal alkyl substituent (n-
propyl) proved challenging in the hydroazidation reaction
and resulted in only moderate yield and enantioselectivity
(Scheme 2a). However, in the case of hydroamination,
[a] Conditions: 0.05 mmol 3a, 0.0025 mmol precatalyst, 0.006 mmol
AgOTf, 0.15 mmol H2NBoc, 1.0 mL of appropriate solvent (0.05m), 16 h
at room temperature. [b] Determined by 1H NMR with 1,3,5-trimeth-
oxybenzene as an internal standard. The mass balance is unconsumed
starting material and traces of the hydration product. [c] Determined by
chiral HPLC. [d] Reaction run for 24 hours. [e] Isolated yield.
regio- and diastereoselectivity was observed. The same ADC
gold(I) catalysts were surveyed (entries 1–5), and the elec-
tron-rich 3,5-dimethoxy aryl substituted ligand A4 was found
to give the best enantioselectivity (entry 4). Chlorinated and
aromatic solvents were found to decrease the observed
enantioselectivity (entries 6 and 7). Other ethereal solvents
such as dimethoxymethane and tetrahydrofuran (entries 8
and 9) performed slightly worse than 1,4-dioxane, which was
ultimately the optimal choice. Finally, increasing the equiv-
alents of the carbamate afforded elevated yields (entries 10
and 11), which could be improved even more by extending the
reaction time to 24 hours (entry 12).
Scheme 2. Reactions of n-propyl substituted allene.
With these two sets of optimized conditions in hand, the
substrate scope was investigated for both reactions (Table 5).
Introduction of aromatic substituents revealed that both
electron-donating and withdrawing groups were well-toler-
excellent enantioselectivity was maintained with a small
decrease in yield (Scheme 2b), overcoming the requirement
for a methyl-substituted allene in the previously reported
allene hydroamination.[26]
In summary, we have demonstrated the first asymmetric
hydroazidation of unconjugated carbon–carbon p-bonds. The
use of ADC gold(I) catalysts derived from BINAM, 1,3-
disubstituted allenes, and hydrazoic acid generated in situ
allows for the enantioselective preparation of chiral allylic
azide products. Additionally, we have disclosed a related
protocol for hydroamination of allenes. Both classes of
ated at various positions on the ring (entries 1–12).[27]
A
heterocyclic substrate also gave good yields and moderate
enantioselectivities (entry 13). Notably, in some cases the
yield and enantioselectivity observed in the hydroazidation
reaction was markedly better than that of hydroamination
(entries 4 and 10) and vice versa (entries 7 and 12), further
illustrating the complementary of the two manifolds.
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[10] T. Bellavista, S. Meninno, A. Lattanzi, G. Della Salla, Adv.
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product compounds were synthesized with high levels of
regio- and diastereoselectivities, and with moderate to high
enantioselectivities (up to 92% ee). The two reaction mani-
folds are complementary and, therefore, allow access to
a range of enantioenriched allylic amine products using the
same catalyst family. Notably, a single enantiomer of the
catalysts can generate allylic amines with opposite chirality.[28]
Moreover, in cases where the hydroamination fails to provide
allylic amines with useful enantioselectivities, the hydroazi-
dation reaction can be used to address these deficiencies and
vice versa. Efforts to exploit to complementary reactivity of
the hydroazidation and hydroamination reactions, and to
explore the origin of the reversal in enantioinduction are
currently underway.
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[14] In other solvents, cationic gold(I) complexes promoted racemi-
zation of the allylic azide products. See Supporting Information
for additional details.
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We gratefully acknowledge NIHGMS (RO1 GM073932) for
financial support. D.A.K. gratefully acknowledges the Novar-
tis Graduate Fellowship. C.T. thanks Huaihai Institute of
Technology and the Jiangsu Provincial Department of
Education for financial support. M.W.J. gratefully acknowl-
edges the NSF (GRFP No. DGE1106400) and UC Berkeley
for a Chancellorꢀs Fellowship. We thank William J. Wolf and
College of Chemistry CheXray (NIH Shared Instrumentation
Grant S10-RR027172) for X-ray crystallographic data. We
also thank Robert Bergman, David Nagib, Hosea Nelson,
Matthew Winston, and Weiwei Zi for helpful discussions.
Keywords: acyclic diaminocarbene · enantioselective synthesis ·
gold catalysis · hydroamination · hydroazidation
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6079–6083
Angew. Chem. 2016, 128, 6183–6187
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Communications
Chemie
[22] Z. Zhang, S. Du Lee, A. S. Fisher, R. A. Widenhoefer, Tetrahe-
observed when the putative catalytic intermediates associated
dron 2009, 65, 1794 – 1798.
with an inner-sphere mechanism were synthesized and reacted
with allene. See Supporting Information for details.
[26] For the enantioselective intermolecular hydroamination of
allenes with benzyl carbamate, see: K. L. Butler, M. Tragni,
R. A. Widenhoefer, Angew. Chem. Int. Ed. 2012, 51, 5175 – 5178;
Angew. Chem. 2012, 124, 5265 – 5268.
[23] Several reviews explore this phenomenon. See: a) G. Zanoni, F.
Castronovo, M. Franzini, G. Vidari, E. Giannini, Chem. Soc. Rev.
2003, 32, 115 – 129; b) T. Tanaka, M. Hayashi, Synthesis 2008,
3361 – 3376; c) M. Bartók, Chem. Rev. 2010, 110, 1663 – 1705;
d) J. Escorihuela, M. I. Burguete, S. V. Luis, Chem. Soc. Rev.
2013, 42, 5595 – 5617.
[27] For additional allene substrates that underwent hydroazidation,
see Supporting Information.
[24] M. Henrich, A. Delgado, E. Molins, A. Roig, A. Llebaria,
Tetrahedron Lett. 1999, 40, 4259 – 4262.
[28] Staudinger reduction and Boc-protection of 4a was carried out
in the same pot to furnish (R)-5a without loss of enantioselec-
tivity. Additionally, azide 4a was subjected to CuAAC with
phenylacetylene, affording the corresponding triazole product
with identical enantiomeric excess. See Supporting Information
for details.
[25] This inversion may result from a change from an outer-sphere
(a) Z. J. Wang, D. Benitez, E. Tkatchouk, W. A. Goddard III,
F. D. Toste, J. Am. Chem. Soc. 2010, 132, 13064 – 13071; b) A.
Zhdanko, M. E. Maier, Angew. Chem. Int. Ed. 2014, 53, 7760 –
7764; Angew. Chem. 2014, 126, 7894 – 7898) to an inner-sphere
(c) N. Nishina, Y. Yamamoto, Angew. Chem. Int. Ed. 2006, 45,
3314 – 3317; Angew. Chem. 2006, 118, 3392 – 3395; d) K. D. Hesp,
M. Stradiotto, J. Am. Chem. Soc. 2010, 132, 18026 – 18029)
mechanism; however, no hydroamination products were
Received: February 12, 2016
Published online: April 20, 2016
Angew. Chem. Int. Ed. 2016, 55, 6079 –6083
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