Metal-Free Azidation of α-Hydroxy Esters and α-Hydroxy Ketones Using Azidotrimethylsilane

Article abstract of DOI:10.1002/adsc.201701345

We herein report a commercially available perchloric acid catalyst capable of catalyzing the azidation of α-hydroxy esters, α-hydroxy ketones and taddols using azidotrimethylsilane in dichloromethane at room temperature. Various substituted tertiary alcoh

Full text of DOI:10.1002/adsc.201701345

Title: Metal-Free Azidation of α-Hydroxy Esters and α-Hydroxy Ketones
Using Azidotrimethylsilane
Authors: Xiao-Ping Yin, Lei Zhu, and Jian Zhou
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10.1002/adsc.201701345
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.200((will be filled in by the editorial staff))
Metal-Free Azidation of α-Hydroxy Esters and α-Hydroxy
Ketones Using Azidotrimethylsilane
Xiao-Ping Yin,a Lei Zhu,b* and Jian Zhoua,c*
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062 (P. R. China)
Tel: (+86)-21-6223-4560; Fax: (+86)-21-6223-4560; E-mail: jzhou@chem.ecnu.edu.cn
College of Chemistry and Materials Science, Hubei Engineering University, Xiaogan, Hubei 432000 (P. R. China)
b
Tel: (+86)-71-0234-5464; Fax: (+86)-71-0234-5464; E-mail: zhuleio@mail.ustc.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
c
Sciences, Shanghai 200032 (P. R. China)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.200######.
and electrophilic amination of active methines and
perchloric acid catalyst capable of catalyzing the azidation their equivalents.[7] Despite ongoing progresses, it is
Abstract: We herein report a commercially available
of α-hydroxy esters, α-hydroxy ketones and taddols using
azidotrimethylsilane in dichloromethane at room
temperature. Various substituted tertiary alcohols are well
tolerated in this reaction. Cα-tetrasubstituted α-amino acid
derivatives were prepared by one-pot sequential azidation
and hydrogenation procedure. The advantage of this newly
developed method includes operational simplicity, ready
availability of catalyst, scale-up ability, and also good
functional group compatibility.
still necessary and important to exploit new synthetic
strategies.
Keywords: Azidation; α-Hydroxy esters; α-Hydroxy
ketones; Cα-tetrasubstituted α-amino acids; SN1 mechanism
Scheme 1. Representative bioactive compounds containing
Cα-tetrasubstituted α-amino acid scaffold.
Amino acids and their derivatives play an important
role in the improvement of life due to their wide
applications in medicine, pharmacology, nutrition and
so on.[1] In this scenario, non-proteinogenic Cα-
tetrasubstituted α-amino acids are in particular useful
in biochemical researches.[2] Such Cα-tetrasubstituted
α-amino acids represent a type of prominent structural
scaffolds widely present in drugs, pharmaceutically
and biochemically active compounds (Scheme 1). For
example, 2,2-diphenylglycine A[3a] has antibacterial
and antifungal properties, and its analogue B[3b] has
antagonist activity at group I metabotropic glutamate
receptors expressed in CHO cells. In addition,
compounds fused with Cα-tetrasubstituted α-amino
acid motifs also exhibit unique bioactivities and
Very recently, catalytic functionalization of α-
tertiary hydroxy esters emerges as a fruitful method
for the diverse synthesis of carbonyl compounds with
an α-fully substituted carbon.[8] The direct azidation
of such α-hydroxy esters provided a facile access to
α-tertiary azides featuring an ester group as precursors
to Cα-tetrasubstituted α-amino acid derivatives,[9] but
remained largely undeveloped.[10] In 2009, O’Donnell
& McCarthy reported an elegant Mitsunobu reaction
of α-tertiary hydroxy esters using HN3 as the azide
reagent (eq 1, Scheme 2).[11] However, it inevitably
produced stoichiometric amount of waste hydrazine-
1,2-dicarboxylates and tertiary phosphine oxides.
Recently, Matsugi & Shioiri reported a SN2 type
azidation using bis(p-nitrophenyl)phosphorazidate (p-
NO2DPPA) as the azide agent, but this method
required the use of three equivalents of DBU, leading
to the formation of significant amount of waste (eq
2).[12] In addition, because these protocols involved a
SN2 displacement at the tetrasubstituted carbon,
sterically congested α,α-diaryl α-tertiary hydroxy
esters are often difficult substrates. On the other hand,
the corresponding SN1 azidation would be more
sterically favourable, due to the formation of
carbocation intermediates, however, it remains
important
applications.
4,5-Dihydro-1H-2,4-
benzodiazepine C[3c] has antiarrhythmic activity and
multi-functionalized compounds D[3d] could serve as
effective PTP-1B inhibitors. Therefore, it is very
much in demand to develop operationally simple and
efficient protocols for the catalytic synthesis of Cα-
tetrasubstituted α-amino acid derivatives.
During the past decades, several elegant methods
have been developed for the facile synthesis of Cα-
tetrasubstituted α-amino acid derivatives,[4] including
the Strecker reaction of ketimines,[5] the addition of
nucleophiles to ketimines derived from α-ketoesters,[6]
1
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10.1002/adsc.201701345
Advanced Synthesis & Catalysis
unexplored. This is possibly because the electron- (see the Supporting Information, Table S1).
withdrawing effect of the ester group makes it Furthermore, Brønsted acids such as HOTf and
difficult to generate the carbocation intermediates. HClO4 (70%, aq) were viable catalysts for this
With our continuation in catalytic functionalization of reaction (entries 7-8). Remarkably, HClO4 was an
tertiary alcohols bearing an α-electron-withdrawing extremely reactive catalyst, as it mediated the reaction
group,[13] we have developed a Friedel-Crafts reaction to finish within only 30 minutes to generate product
of α-tertiary hydroxy esters with electron-rich arenes 2a in 96% yield (entry 8). This is a very exciting
to furnish α-quaternary esters and ketones,[13a-c] along result, because the use of 70% aqueous solution of
with several SN1 type substitution reactions of 3-aryl- HClO4 as the catalyst is safe and operationally very
3-hydroxy oxindoles.[13d-f] On the basis of these work, simple. Different solvents such as n-hexane, Et2O,
we attempt to develop a catalytic azidation of α- toluene were investigated, and CH2Cl2 was found to
tertiary hydroxy esters and TMSN3. We speculate that be the optimal solvent (entries 8-11). Reducing the
this should be an attractive method for the synthesis amount of azide reagent TMSN3 caused an obvious
of α,α-diaryl Cα-tetrasubstituted α-amino esters, as the decrease in yield (entries 12-13). Comparable result
two aryl substituents are helpful in stabilizing the was observed when the reaction concentration was
carboncation intermediates. Such a SN1 azidation is increased (entry 14). Therefore, the optimized
not only complementary to the SN2 reaction, but has reaction conditions were determined to run the
an obvious advantage of improved atom-economy, reaction at room temperature in CH2Cl2 with 3.0
because of its much less waste generation. Herein, we equivs of TMSN3, using10 mol% HClO4 as catalyst.[14]
wish to report that cheap and easily available HClO4
Table 1. Optimization of reaction conditions.[a]
(70%, aq) is identified as a powerful metal-free
catalyst for the desired azidation reaction (eq 3).
Entry
Catalyst
Solvent
Time (h)
Yield (%)[b]
1
2
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
n-Hexane
Et2O
30
30
30
30
30
30
30
0.5
12
12
12
2
NR[c]
77
80
86
95
95
93
96
84
89
92
82
68
89
Ga(OTf)3
Bi(OTf)3
Sn(OTf)2
Cu(OTf)2
AgOTf
HOTf
3
4
5
6
7
8
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
9
Scheme 2. The azidation of α-hydroxy esters.
10
11
12[d]
13[e]
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
For initial investigation, we first conducted the
reaction of model substrate 1a with trimethylsilyl
azide (TMSN3) in dichloromethane by using various
metal triflates as catalysts. Without the existence of
catalyst, the reaction didn’t proceed at all (Table 1,
entry 1). Acid catalyst is essential for this reaction
because it plays an important role to activate the
tertiary alcohol substrate to produce the carbocation
intermediate.[8a] We had previously found that
Ga(OTf)3 could efficiently catalyze the substitution
reaction of 3-hydroxy oxindoles and TMSN3,[13f] so
we first tried it in the azidation of α-hydroxy ester 1a.
To our delight, the desired product 2a was isolated in
77% yield (entry 2). Encouraged by this result, a
series of metal triflates were then examined in order
to achieve a higher catalytic ability. Bi(OTf)3,
Sn(OTf)2, Cu(OTf)2 and AgOTf were found to be
effective to yield the corresponding product in better
yields (entries 3-6). However, no reaction took place
when Ba(OTf)2 and Hg(OTf)2 were used as catalyst
2
14[f]
0.2
[a]
Reaction were run with 1a (0.2 mmol), TMSN3 (3.0
equiv.), catalyst (10 mol%), solvent (1.0 mL), RT,
stirred for a specified time.
[b] Isolated yield.
[c] No reaction.
[d] TMSN3 (2.5 equiv.) was used.
[e] TMSN3 (2.0 equiv.) was used.
[f] CH2Cl2 (0.5 mL) was used.
With the optimal reaction conditions in hand, we
tested the substrate scope of α-hydroxy esters 1. This
reaction showed good functional group compatibility,
as demonstrated in Table 2. Different substituents on
the benzene ring such as methyl, methoxyl were well
tolerated, affording the corrsponding products (2a-2c,
2
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10.1002/adsc.201701345
Advanced Synthesis & Catalysis
2e-2g) in moderate to good yields. Substrates bearing version was still necessary, considering the
ortho or para substituent on the phenyl ring adjacent importance of the resulting α-azide ketones 4.[16] The
to the quaternary carbon were more reactive than the substrate scope is shown in Table 3. α-Tertiary
meta substituted one (entries 1 and 3 vs entry 2). hydroxy ketones 3a-c and 3d-f, with a methoxyl or a
Besides, the reaction of alcohol 1d showed decreased methyl substituent at ortho, meta or para position of
reactivity (entry 4). Electron donating groups seem to the phenyl ring were all viable substrates, furnishing
be effective to enhance the reaction rate, probably due the desirsed adducts in good to high yield (entries 1-
to their contribution for the stabilization of the 6). Those (3g-i) bearing an electron withdrawing
posssible carbocation intermediates. As expected, group (F, Cl, Br) also worked well to give the desired
alcohols 1h-j with electron withdrawing groups on products 4g-i (entries 7-9). Diphenyl and naphthyl
the phenyl ring showed lower activity, giving substituted tertiary alchols could be smoothly azidated
azidation products in moderate to excellent yield to give the desired poducts 4j and 4k in 77% and 80%
(entries 8-10). Almost no reaction occurred when yield, respectively (entries 10-11). Tertiary alchol 3l
trifluoromethyl substituted substrate 1k was used with a α-thiophenyl group worked inefficiently under
(entry 11). These results indicate that an SN1 reaction our condition, giving the product 4l in only 23% yield
might take place in the presence of strong Brønsted (entry 12). It’s remarkable that various aromatic
acid. It’s noteworthy that naphthyl and thiophenyl groups can be tolerated. Comparing with Singh's
substituted α-hydroxy esters 1l-n are also compatible work,[15] our method could succesfully achieve the
substrates (entries 12-14). Attempts to use methyl azidation of α-tertiary hydroxy ketones 3g-i bearing
substituted alcohol 1o failed under the optimized an electron withdrawing group (F, Cl, Br) and
reaction conditions (entry 15).
tertiary alchol 3l with a α-thiophenyl group rather
than previous report. Besides, the HClO4 (70%, aq)
catalyst used in our method was much more available
than InBr3. It's worth to note that the substrate 3m
bearing a methyl group could also be workable to
give the desired product 4m in 88% yield.
Table 2. Substrate scope of α-hydroxy esters.[a]
Table 3. Substrate scope of α-hydroxy ketones.[a]
Entry 1: R
2
Time (h)
Yield (%)[b]
1
2
1a: 2-OMeC6H4
2a
2b
2c
2d
2e
2f
0.5
24
0.5
10
0.5
11
5
83
77
1b: 3-OMeC6H4
1c: 4-OMeC6H4
1d: Ph
3
89
Entry 3: Ar
4
Time (h)
Yield (%)[b]
4
76
1
2
3a: 2-OMeC6H4
4a
4b
4c
4d
4e
4f
42
1
87
69
64
76
65
75
90
77
77
77
80
23
5
1e: 2-MeC6H4
1f: 3-MeC6H4
1g: 4-MeC6H4
1h: 4-FC6H4
1i: 4-ClC6H4
1j: 4-BrC6H4
1k: 4-CF3C6H4
1l: 1-Naphthyl
1m: 2-Naphthyl
1n: 2-Thiophenyl
1o: Me
84
3b: 3-OMeC6H4
3c: 4-OMeC6H4
3d: 2-MeC6H4
3e: 3-MeC6H4
3f: 4-MeC6H4
3g: 4-FC6H4
6
79
3
1.5
18
5
7
2g
2h
2i
75
4
8
46
51
77
51
18
24
23
24
94
5
9
51
6
5
10
11
12
13
14
15
2j
58
7
4g
4h
4i
18
15
11
10
17
1
2k
2l
trace
81
8
3h: 4-ClC6H4
3i: 4-BrC6H4
9
2m
2n
2o
70
10
11
12
3j: 4-PhC6H4
3k: 2-Naphthyl
3l: 2-Thiophenyl
4j
53
4k
4l
mess
[a]
Reaction conditions: α-hydroxy esters 1 (0.5 mmol),
TMSN3 (3.0 equiv.), HClO4 (70%, aq, 10 mol%),
CH2Cl2 (2.5 mL), RT, stirred for a specified time.
[b] Isolated yield.
[a]
Reaction conditions: α-hydroxy ketones 3 (0.5 mmol),
TMSN3 (3.0 equiv.), HClO4 (70%, aq, 10 mol%),
CH2Cl2 (2.5 mL), RT, stirred for a specified time.
We were delighted to find that this reaction is
not only suitable for α-tertiary hydroxy esters, but
also workable to α-tertiary hydroxy ketones 3 (Table
3). It shoud be noted that the azidation of α-tertiary
hydroxy ketones were demonstrated as unsucessful
example in Matsugi & Shioiri's report.[12] Previously,
although Singh reported a InBr3-catalyzed version of
this reaction,[15] the development of a metal-free
[b] Isolated yield.
Tertiary alcohols bearing other electron
withdrawing groups, such as trifluoromethyl,
difluoromethyl and acetyl group, were also viable
substrates, if 100 mol% of HClO4 was used as the
3
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10.1002/adsc.201701345
Advanced Synthesis & Catalysis
catalyst, as shown in Table 4. The trifluoromethyl Han & Wang’s work,[18b] hydrazoic acid and sodium
substituted alcohols 5a-5c, with methoxyl azide were used, so the reaction must be conducted
a
substituent at ortho, meta or para position of the very carefully with strict protection. In contrast, only
phenyl ring afforded the desired products 6a-6c in 49- simple operation was adopted in our newly developed
54% yields (entries 1-3). The alcohol 5d bearing a method (Scheme 3).
chloro substituent on the phenyl ring showed lower
activity, furnishing product 6d in only 37% yield
(entry 4). The tertiary alcohol 5e with two methoxyl
substituents on the ortho and para position of the
phenyl ring showed higher activity, affording the
corrsponding product 6e in 50% yield (entry 5). The
difluoromethyl substituted alcohols 5f and 5g, with a
methoxyl substituent at ortho or para position of the
phenyl ring also worked well to give the
corresponding products 6f and 6g in 48% and 66%
yield, respectively (entries 6-7). The tertiary alcohol
5h bearing an acetyl group worked inefficiently under
this condition, giving product 6h in only 13% yield
(entry 8). We also found that O-TMS cyanohydrin 5i
could also give the desired azide 6i in 63% yield, if
using 100 mol% of HOTf as the catalyst (we tried the
removal of the TMS group of 5i using TBAF, but
only recovered the corresponding ketone).
Scheme 3. Modification of taddol derivatives.
This azidation method could be readily scaled up,
as evidenced by the gram scale synthesis of Cα-
tetrasubstituted α-amino acid derivatives 9a and 10a
in a one-pot manipulation. The azidation of 1a or 3a
were performed on a 6.0 mmol scale, followed by the
Pd-catalyzed hydrogenation of the crude mixtures to
give α-amino ester or ketone 9a and 10a in 85% and
81% isolated yield, respectively (Scheme 4).
Table 4. Substrate scope of other tertiary alcohols.[a]
Time
(h)
Yield
(%)[b]
Entry
5
R
Ar
6
1
2[c]
3
5a
5b
5c
5d
5e
5f
CF3
CF3
2-OMeC6H4
3-OMeC6H4
4-OMeC6H4
4-ClC6H4
6a
6b
6c
6d
6e
6f
72
72
72
72
24
72
36
0.5
49
49
54
37
50
48
66
13
CF3
4[c]
5
CF3
Scheme 4. Gram scale synthesis of amino acid derivatives.
CF3
2,4-(OMe)2C6H3
2-OMeC6H4
4-OMeC6H4
2-OMeC6H4
6
CF2H
CF2H
Ac
In conclusion, we have developed a highly
efficient HClO4 catalyzed azidation reaction of α-
tertiary hydroxy esters and α-tertiary hydroxy ketones
using TMSN3 for the synthesis of Cα-tetrasubstituted
α-amino acid derivatives. Various substituted starting
materials could be applied under the optimized
conditions. Notably, the use of 70% aqueous solution
of HClO4 as the catalyst is safe and operationally very
simple, and importantly, free of the contamination of
transition metals with the final adducts that are
valuable targets in medicinal researches.
7
5g
5h
6g
6h
8
[a]
Reaction conditions: tertiary alcohols 5 (0.5 mmol),
TMSN3 (3.0 equiv.), HClO4 (70%, aq, 100 mol%),
CH2Cl2 (2.5 mL), 60 oC, stirred for a specified time.
[b] Isolated yield.
[c] TMSN3 (5.0 equiv.) was used.
Our method is also workable for the azidation of
tertiaryl alcohols without an α-electron-withdrawing
group, as shown by the facile synthesis of taddol
derived diazides 8. As shown in Scheme 3, under our
condition, taddols 7a and 7b readily provided the
desired diazides 8a and 8b in 72% and 86% yield,
respectively. Diazides 8 have wide applications in
asymmetric synthesis as chiral reagents or for the
Experimental Section
To a solution of α-hydroxy esters 1 or α-hydroxy
ketones 3 (0.5 mmol) in dry CH2Cl2 (2.5 mL) was
added HClO4 (70%, aq, 0.05 mmol) and TMSN3 (1.5
mmol) into 5.0 mL vial under air, and the reaction
mixture was stirred at room temperature until
complete consumption as monitored by TLC analysis.
The solvents were removed under reduced pressure,
design of new ligands and organocatalysts.[17]
[18a]
Comparing with Wang & Qu's work
as well as
4
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10.1002/adsc.201701345
Advanced Synthesis & Catalysis
and column chromatography was used to give the
N. Li, B. Tang, G. Zhao, Adv. Synth. Catal. 2017, 359,
1819; g) S. Mahajan, P. Chauhan, U. Kaya, K. Deckers,
K. Rissanen, D. Enders, Chem. Commun. 2017, 53,
6633.
desired product α-azide esters 2 or α-azide ketones 4.
Acknowledgements
[6] For some reviews, see: a) M. Shibasaki, M. Kanai,
Chem. Rev. 2008, 108, 2853; b) S. Kobayashi, Y. Mori,
J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626;
c) M. Yus, J. C. González-Gómez, F. Foubelo, Chem.
Rev. 2011, 111, 7774; d) A. Noble, J. C. Anderson,
Chem. Rev. 2013, 113, 2887; e) B. Eftekhari-Sis, M.
Zirak, Chem. Rev. 2017, 117, 8326; For selected recent
examples, see: f) P. Fu, M. L. Snapper, A. H. Hoveyda,
J. Am. Chem. Soc. 2008, 130, 5530; g) L. C. Wieland, E.
M. Vieira, M. L. Snapper, A. H. Hoveyda, J. Am. Chem.
Soc. 2009, 131, 570; h) Y. Yao, J.-L. Li, Q.-Q. Zhou, L.
Dong, Y.-C. Chen, Chem. Eur. J. 2013, 19, 9447; i) L.
Wu, R.-R. Liu, G. Zhang, D.-J. Wang, H. Wu, J. Gao,
Y.-X. Jia, Adv. Synth. Catal. 2015, 357, 709.
The financial support from 973 Program
(2015CB856600) and NSFC (21472049, 21672068，
21774029 and 21725203) is appreciated. Mr Xiao-
Ping Yin thanks the financial support of
“Outstanding doctoral dissertation cultivation plan
of action” from East China Normal University
(PY2015030).
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Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
COMMUNICATION
Metal-Free Azidation of α-Hydroxy Esters and α-
Hydroxy Ketones Using Azidotrimethylsilane
Adv. Synth. Catal. Year, Volume, Page-Page
Xiao-Ping Yin,a Lei Zhu,b* and Jian Zhoua,c*
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