Overcoming product inhibition in catalysis of the intramolecular Schmidt reaction

Article abstract of DOI:10.1021/ja402848c

A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is reported. Following extensive screening, the use of the strong hydrogen-bond-donating solvent hexafluoro-2-propanol was found to be consistent with low catalyst loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are described.

Full text of DOI:10.1021/ja402848c

Article
pubs.acs.org/JACS
Overcoming Product Inhibition in Catalysis of the Intramolecular
Schmidt Reaction
Hashim F. Motiwala, Charlie Fehl, Sze-Wan Li, Erin Hirt, Patrick Porubsky, and Jeffrey Aube*
́
Department of Medicinal Chemistry, University of Kansas, Delbert M. Shankel Structural Biology Center, 2034 Becker Drive,
West Campus, Lawrence, Kansas 66047, United States
S
* Supporting Information
ABSTRACT: A method for carrying out the intramolecular Schmidt reaction of
alkyl azides and ketones using a substoichiometric amount of catalyst is reported.
Following extensive screening, the use of the strong hydrogen-bond-donating
solvent hexafluoro-2-propanol was found to be consistent with low catalyst
loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for
more difficult cases. Reaction optimization, broad substrate scope, and preliminary
mechanistic studies of this improved version of the reaction are described.
for these reactions have enabled the use of substoichiometric
amounts of Brønsted or Lewis acid, improving the efficiency and
expanding the scope of those processes.8,10 The use of ionic
liquids11 and extensive screening of catalysts and solvents led to
the realization of these catalytic reactions. We envisioned that
catalysis in the intramolecular Schmidt reaction might be more
efficient if conditions could be identified wherein a ligand,
solvent, or additive is capable of competing with the catalyst in
forming a complex with the Lewis basic lactam, thus allowing
catalyst turnover. Herein we disclose a first report of the catalytic
intramolecular Schmidt reaction that is superior in essentially
every way to the version that we and others have been exploring
since 1991.1,2d,4
INTRODUCTION
■
The intramolecular Schmidt reaction is a useful method for the
preparation of lactams from azidoalkyl ketones1,2 that has been
applied to alkaloid synthesis and natural-product-inspired
libraries.3 One limitation of the reaction has been the require-
ment of excess Lewis or Brønsted acid1a,4 in order to achieve
complete conversion, which often renders it unsuitable for
strongly acid-sensitive substrates and limits its scalability. In
addition, a version of this reaction that would employ vastly
smaller amounts of metal may well be cleaner and more efficient,
even as it minimizes the generation of metal waste.5 Two
representative examples are shown in Figure 1a,b. Indeed, we are
unaware of any examples that proceed to high conversion with
less than a full equivalent of promoter. This can be attributed to
strong product inhibition, which is intrinsic to any reaction that
converts a ketone to an amide. The first step in a hypothetical
catalytic cycle for the intramolecular Schmidt reaction is the
activation of a substrate S with a Lewis or Brønsted acid LA to
form the complex S−LA (Figure 1c).6 The tethered azide then
attacks the activated carbonyl, forming azidohydrin inter-
mediate A, which upon antiperiplanar bond migration and
nitrogen extrusion results in the formation of product P. The
lactam produced is strongly Lewis basic and sequesters the
catalyst in an unproductive manner. We propose that this
unfavorable catalyst−product interaction results in product
inhibition, deterring the progress of reaction and necessitating
the use of superstoichiometric amounts of catalyst.4a,7
RESULTS AND DISCUSSION
■
Screening. We sought to replace the stoichiometric Schmidt
reaction by identifying conditions that would (1) require low,
substoichiometric amounts of catalyst; (2) be mild and efficient,
allowing the reaction to proceed at room temperature; and (3)
result in a broad substrate scope. We initially focused on catalyst
and additive screening. Early on, we found that 10−25 mol %
scandium(III) triflate could efficiently promote the reaction of 1c
to 2c, but only at unacceptably high temperatures (Scheme 1; see
the Supporting Information for details of these and all other early
attempts). Moreover, these reaction conditions were plagued by
extremely limited substrate scope and low yields. For example,
higher catalyst loadings were generally necessary for cyclo-
pentanone 1a (we had in the interim found that MeCN was
a better solvent than H2O, either alone or with phase-transfer
catalysts), and the reaction of 1d under the same conditions
failed (<5% yield). Reactions of substrates such as 1a and 1d
required longer reaction times than 1c in the stoichiometric
reaction and were often poorer-yielding as well.1,12
A fundamental challenge in designing a catalytic variant for this
reaction lies in the inherent strength of the complex formed
between the catalyst and the product, which is a hard acid−hard
base interaction. Related reactions that generate amide or lactam
products, such as the Beckmann rearrangement and the Ritter
reaction, have also suffered in the past from the requirement of a
stoichiometric amount of strong acid and harsh reaction
conditions.8,10 The role of the lactam in product inhibition has
been demonstrated for the Beckmann rearrangement using a
microchemical system.9 However, recent catalytic developments
Received: March 20, 2013
© XXXX American Chemical Society
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Scheme 2
Finally, the phenyl chromophore in 1e allowed faster analyses and
quantification of reaction mixtures by ultraperformance liquid
chromatography (UPLC) (see the Supporting Information).
Figure 2 depicts the results of preliminary screening of reaction
conditions (see the Supporting Information for details).
Examination of 23 different solvents was first carried out using
20 mol % Sc(OTf)3 at 150 °C. Only five solvents [nitromethane,
benzonitrile, acetic acid, trifluoroethanol (TFE), and the ionic
liquid 1-butyl-3-methylimidazolium tetrafluoroborate] gave the
product in high yield. When the Sc(OTf)3 loading was reduced
to 10 mol %, only TFE resulted in complete conversion. We then
focused our attention on catalyst screening using 10 mol %
catalyst with TFE as the solvent at 80 °C. In total, 51 catalysts
were screened, including 44 Lewis acids representing 31 different
elements and seven Brønsted acids. Of these, a number of
transition-metal salts such as TiCl4, ZrCl4, and Fe(OTf)3, some
post-transition-metal salts such as In(OTf)3 and Bi(OTf)3, and
metalloid-containing compounds such as SiCl4 and SbCl5
gave results that were good enough for further screening.
Figure 1. (a, b) Examples of intramolecular Schmidt reactions requiring
>1 equiv of catalyst. (c) Hypothetical catalytic cycle displaying product
inhibition.
Scheme 1
On the basis of these preliminary results, we decided to expand
our search by focusing on three screening parameters: solvent,
catalyst, and temperature. trans-4-Phenyl-2-(3-azidopropyl)-
cyclohexanone (1e) was chosen as a test example to probe
several issues known to arise in intramolecular Schmidt reactions
(Scheme 2). The trans isomer was primarily chosen to probe for
epimerization (known to be a problem in some applications),13
which could lead to the thermodynamically more stable cis
ketone 1f; the readout for this process would be the detection of
lactam 2f following ring expansion. In addition, the trans ketone
1e is capable of generating either the fused lactam 2e or the
bridged isomer 3e by migration of one α-carbon or the other.1b
Figure 2. Screening flowchart (see the Supporting Information for
details). Transition metals are depicted in deep red, post-transition
metals in green, and metalloids in blue.
B
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a b
,
Table 1. Optimization of Conditions for the Intramolecular Schmidt Reaction of 1e
c
d
entry
catalyst
TiCl4
catalyst loading (mol %)
solvent
CH2Cl2
additive
temp (°C) time (h) % yield (2e:2f)
% recovery (1e:1f)
1
2
10
10
10
10
−
10
10
5
−
−
−
−
−
25
37
37
25
37
25
25
25
25
25
25
25
25
25
25
25
25
25
25
18
18
18
18
18
18
12
38
38
38
38
38
38
38
38
38
38
38
38
6 (40:60)
trace
84 (10:90)
86 (3:97)
47 (1:99)
trace
TiCl4
TiCl4
TiCl4
none
TiCl4
TiCl4
TiCl4
i-PrOH
3
CH3CN
41 (15:85)
79 (82:18)
ND
d
4
CF3CH2OH
(CF3)2CHOH
CH3CN
5
93 (98:2)
61 (5:95)
ND
e
6
(CF3)2CHOH
34 (10:90)
f
7
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
(CF3)2CHOH
−
−
−
−
91 (98:2)
f
8
89 (99:1)
trace
g
9
TiCl4
TiCl4
TiCl4
TiCl4
SiCl4
5
86 (98:2)
89 (98:2)
52 (98:2)
21 (99:1)
trace
h
10
11
12
13
14
15
16
17
18
19
5
ND
i
5
DTBMP
19 (98:2)
j
c
5
DTBMP
50 (96:4)
f
5
−
−
−
−
−
−
−
86 (98:2)
ND
Sc(OTf)3
HCl
5
28 (97:3)
61 (98:2)
46 (98:2)
trace
f
10
20
10
5
40 (96:4)
f
HCl
78% (97:3)
62 (97:3)
CF3COOH
(S)-BNDHP
Ti(iOPr)4
34 (98:2)
62 (98:2)
93 (95:5)
k
32 (96:4)
10
trace
a
To a solution of substrate 1e (0.1 mmol) in solvent (0.5 mL) at room temperature was added a catalyst under a nitrogen or argon atmosphere,
unless otherwise mentioned (see the Supporting Information for the complete optimization table). For TiCl4 or SiCl4, a 1.0 M solution in CH2Cl2
b
was used, unless otherwise mentioned. A 2.0 M solution of HCl in diethyl ether was used. ND = Not detected. Concentration of substrate was ca.
c
1
0.2 M, unless otherwise mentioned. Isolated yields after preparative thin-layer chromatography (TLC) purification; ratios were determined by H
d
e
NMR analysis. Isolated yields after preparative TLC purification; ratios were determined by UPLC of the crude reaction mixtures. 1 equiv of
(CF3)2CHOH was added. Bridged lactam 3e was also isolated in 1−4% yield. Concentration of substrate was ca. 0.4 M. Concentration of
substrate was ca. 0.1 M. 10 mol % 2,6-di-tert-butyl-4-methylpyridine (DTBMP) was used as a Brønsted acid scavenger. 20 mol % DTBMP was used.
(S)-BNDHP = (S)-(+)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate. No kinetic resolution was observed.
f
g
h
i
j
k
Further evaluation of these selected catalysts at 10 mol % loading
in TFE at lower temperatures (50 and 25 °C) revealed TiCl4 and
SiCl4 to be the most effective. The identification of TiCl4 was
notable, as it has been a catalyst of choice for many stoichiometric
intramolecular Schmidt reactions.1b,4,14
results both in reaction rate enhancement15b,e,16,20 and as a helix-
inducing cosolvent.19a
Using HFIP as a substitute for TiCl4 in a control experiment
did not afford any product, and substrate 1e was recovered
almost quantitatively (Table 1, entry 5). Using 1 equiv of HFIP
as an additive with CH3CN as a solvent did not improve the
yield (entry 6). However, when HFIP was used as the solvent
in combination with 10 mol % TiCl4, complete conversion and
negligible epimerization was observed with increased catalyst
turnover compared with TFE (cf. entries 7 and 4). Lowering the
TiCl4 catalyst loading to 5 mol % produced similar results as with
10 mol % TiCl4 but at the expense of a longer reaction time
(entry 8). Changing the concentration of the reaction mixture
had minimal effect on the yield (entries 9 and 10).
We speculated that reaction of HFIP with TiCl4 might
generate HCl in situ along with Ti[OCH(CF3)2]4. If so, then
5 mol % TiCl4 should be capable of generating 20 mol % HCl in
situ. To test this hypothesis, we ran the reaction in the presence
of 10 and 20 mol % 2,6-di-tert-butyl-4-methylpyridine (DTBMP)
as a proton scavenger (Table 1, entries 11 and 12). Significant
catalyst inhibition resulting in lower yields was observed, but
reaction to some extent was still observed when 20 mol %
DTBMP was used. This could mean that the catalytically active
species is HCl generated in situ or that DTBMP, being a base, has
some other deleterious effect on the reaction.21 The reaction in
HFIP with SiCl4 provided the lactam in good yield (entry 13),
but Sc(OTf)3 provided the product in only 28% yield (entry 14).
Identification of TFE as nearly unique in permitting catalyst
turnover prompted us to examine more completely the effect of
the solvent using 1e as the substrate and 10 mol % TiCl4 as the
catalyst (Table 1). Again, TFE was observed to give the best
results with respect to both conversion and stereochemical
retention (cf. entry 4 with entries 1−3). The results with TFE
prompted us to consider other fluorinated alcohols, specifically
hexafluoro-2-propanol (HFIP). Compared with their non-
fluorinated alcohol analogues, TFE and HFIP have low
nucleophilicity, low pKa, high ionizing power, high polarity, the
ability to solvate anions, and strong hydrogen-bond donor
ability.15 Accordingly, they are often used as a solvent, cosolvent,
or Lewis acid substitute15e,16 in oxidations17 and in ring-opening
reactions of oxiranes, cycloadditions, and deprotection reac-
tions.15b,d,f Their utility has been attributed to the strong
hydrogen-bond donor ability of these solvents.15b,c,17b,18 More-
over, the use of these solvents to denature proteins and induce
α-helical secondary structures provided some ancillary expect-
ation that they might prove useful in modifying the ability of our
product lactams to coordinate with acid promoters.19 Because of
the stronger hydrogen-bond donor ability and higher ionizing
power of HFIP relative to TFE, HFIP often provides superior
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The reactions with Brønsted acids (5−20 mol %) delivered
comparatively lower yields of the product than the reaction with
5 mol % TiCl4 (entries 15−18). Interestingly, reaction with
20 mol % HCl in ether (entry 16) gave a lower yield that that with
5 mol % TiCl4 (entry 8). The use of a chiral phosphoric acid4b
neither provided good yield nor led to any degree of kinetic
resolution (entry 18). The reaction with Ti(iOPr)4 resulted in
only a trace amount of product with quantitative recovery of
substrate 1e (entry 19). Although this supported our supposition
that in situ-generated HCl could be the active catalyst, it was hard
to reconcile with the reduced yield obtained when HCl in ether
solution was added, possibly as a result of concentration errors in
the commercial product (see Table 4 and associated discussion
for more on this point).
Table 2. Initial Substrate Scope for the Catalytic
Intramolecular Schmidt Reaction of Cyclohexanone-Derived
Azido Ketones
a b
,
Scope. Having identified conditions that satisfied our goals,
we sought to determine the scope of this substoichiometric,
catalytic Schmidt reaction. We began with cyclohexanone-
derived azido ketones, as previous experience had taught us
that these are in general the most facile substrates (Table 2).1
Indeed, the results obtained were in general as good as or better
than those obtained using the stoichiometric reactions. Thus, the
transformations of 1c and cis ketone 1f required only 2.5 mol %
TiCl4 (entries 1 and 2), whereas trans ketone 1e required 5 mol %
TiCl4 and a longer reaction time to obtain a slightly lower yield
of the product (entry 3). The reaction of 1,3-diketone 1b
proceeded in higher yield than reported in the literature (entry 4;
cf. Figure 1b),4 while α-ester-substituted 1d, which failed in the
preliminary screening (Scheme 1), afforded an excellent yield of
2d using the optimized protocol (entry 5). Other functionalized
cyclohexanones such as β-tetralone 1g (entry 6) and allylic azide
1h (entry 7) also provided good yields of the corresponding
lactams 2g and 2h.
We next examined a broader range of ketone types, including
some that we have found to be challenging under previously
established reaction conditions (Table 3). Although the substrate
scope was broad, some recalcitrant substrates generally required
higher catalyst loadings compared with cyclohexanone-derived
azides. For example, cyclopentanone 1a with 20 mol % TiCl4
afforded a superior yield of indolizidinone 2a, a structural motif
found in many pharmacologically relevant alkaloids (entry 1).
The reaction of seven- and eight-membered cyclic azido ketones
afforded lactams with medium ring sizes in high yields (entries 2
and 3), and norcamphor-derived 1k provided a good yield of
tricyclic lactam 2k with 25 mol % TiCl4 (entry 4). N-substituted
pyrrolidinones were obtained in good yields from acyclic azido
ketones (entries 5 and 6), whereas benzylic azide 1n provided a
mixture of two regioisomers 2n and 3n in a 4:1 ratio in modest
yield with 15 mol % TiCl4 (entry 7).
Substrate 1o containing a tertiary amine (a possible additional
source of catalyst inactivation) required 35 mol % TiCl4 to
provide pyrrolodiazepinone 2o (Table 3, entry 8).22 Typically,
for the intramolecular Schmidt reaction, nitrogen gas evolu-
tion is observed immediately upon addition of the catalyst.
However, when TiCl4 was added slowly to a solution of substrate
1o in HFIP, a yellow precipitate was initially observed, with
effervescence commencing only upon the addition of 25 mol %
TiCl4.23 This observation suggests that the initial 25 mol % TiCl4,
which was capable of generating 100 mol % HCl, formed a
salt with the basic amine, with the remaining 10 mol % TiCl4
being responsible for the desired transformation into lactam 2o.
Azido aldehyde 1p required only 5 mol % TiCl4 to provide
3-benzylpyrrolidinone (2p) in good yield (entry 9). Unfortu-
nately, extending the tether length between the carbonyl and the
a
To a solution of a substrate (0.4 mmol) in hexafluoro-2-propanol (2.0 mL)
at room temperature was added a 1.0 M solution of TiCl4 in CH2Cl2 under a
nitrogen atmosphere, and the reaction mixture was stirred at 25 °C for the
b
designated period, unless otherwise mentioned. Concentration of
substrate was ca. 0.2 M. Isolated yields. Bridged lactam 3e was also
isolated in ca. 2% yield.
c
d
azide moiety from the usual four to five carbons resulted in a
sluggish reaction that afforded only an 11% yield of lactam 2q,
even when 20 mol % TiCl4 was employed (entry 10). This is
consistent with the stringent dependence of the intramolecular
Schmidt reaction on tether length observed since the initial
discovery of the reaction.1,2d
Given the requirement of relatively high catalyst loading for
these less reactive substrates, we sought to optimize our reaction
conditions further using substrate 1a (Table 4). After evaluation
of a series of Lewis and Brønsted acids, TiCl4 was still found to be
the most effective catalyst for this substrate (entries 1−14).
However, the combination of TiCl4 with other Lewis or Brønsted
acids, while not initially promising (entries 15−20 and 28),
ultimately revealed acetyl chloride (CH3COCl, AcCl) as an
effective promoter of this reaction even in the absence of TiCl4
(entries 21−25). Thus, the reaction with 80 mol % AcCl (entry 25)
gave results comparable to those with 20 mol % TiCl4 (entry 1).
D
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ab
,
Table 3. Additional Evaluation of the Reaction Scope
a
To a solution of substrate (0.4 mmol) in hexafluoro-2-propanol (2.0 mL) at room temperature was added a 1.0 M solution of TiCl4 in CH2Cl2
b
under a nitrogen atmosphere, and the reaction mixture was stirred at 25 °C for the designated period, unless otherwise noted. Concentration of
substrate was ca. 0.2 M. Isolated yields. Yields in parentheses are based on recovered starting material. Bridged lactam 3i was also isolated in 2%
yield (see the Supporting Information). The product contained 7% 1-phenethylpiperidin-2-one (3l) (see the Supporting Information). The
product contained 3% N-methyl-2-piperidone (3m) (see the Supporting Information).
c
d
e
f
g
We realized that this would support the case that HCl is the active
catalytic species, provided that we could show HFIP to be capable
of generating HCl from AcCl (an ironic notion in view of the low
nucleophilicity of HFIP15b). To address this, we combined 1 equiv
of AcCl and 2 equiv of HFIP in CDCl3 and monitored the reaction
by 1H NMR spectroscopy (Figure 3; see the Supporting Information
for details). Within 6 min, ca. 50% conversion to HFIP acetate was
observed. The rate decreased after 20 min, and the reaction took 4 h
to reach >95% conversion. Conversely, we were not able to obtain any
evidence for the in situ generation of HCl from TiCl4.
E
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a b
,
Table 4. Further Optimization of the Reaction Conditions for 1a
c
entry
catalyst
TiCl4
catalyst loading (mol %)
additive
additive loading (mol %)
2a:1a
95:5
1
2
20
10
10
10
10
10
10
10
10
40
40
40
40
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
TiCl4
59:41
26:74
46:54
0:100
58:42
45:55
44:56
54:46
45:55
59:41
3
TiF4
4
TiBr4
Ti(iOPr)4
5
6
SiCl4
7
SbCl5
8
NbCl5
WCl6
9
d
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
HCl in ether
aqueous HCl
f
HCl in HFIP
57:43−75:25
76:24
49:51
42:58
49:51
56:44
50:50
47:53
95:5
H2SO4
−
−
CF3SO3H
CF3SO3H
ClSO3H
20
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
−
−
−
−
−
5
5
5
5
g
10
10
10
10
−
−
−
−
−
AgOTf
20
20
−
Al(iOPr)3
h
silica gel
i
CH3COCl
40
40
40
70
80
80
40
80
40
80
80
i
j
j
i
j
CH3COCl
CH3COCl
CH3COCl
CH3COCl
58:42
70:30
90:10
94:6
k
CH3COCl
97:3
l
−
−
TiCl4
−
−
10
CH3COBr
72:28
l
m
CH3COBr
98:2
(CH3)3SiCl
(CH3)3SiCl
(CH3)3SiI
89:11
92:8
−
−
−
−
n
13:87
a
To a solution of substrate 1a (0.1 mmol) in (CF3)2CHOH (0.5 mL) at room temperature was added a catalyst and/or an additive under a nitrogen
b
atmosphere, unless otherwise mentioned. For TiCl4, SiCl4, and SbCl5, a 1.0 M solution in CH2Cl2 was used. Concentration of substrate was ca.
c
d
0.2 M. 1H NMR ratios determined after a brief workup (see the Supporting Information for details). A 1.0 M solution of HCl in ether (commercial)
e
f
was used. Aqueous HCl (37%) was used. A 0.105−0.116 M solution of HCl in hexafluoro-2-propanol was prepared and used immediately.
g
h
i
TiCl2(OTf)2 was generated in situ from TiCl4 and AgOTf.24 Silica gel (50 mg) was added. An old container of acetyl chloride (>5 years since
j
k
l
initial opening) was used. A new container of acetyl chloride was used. The 2a:1a ratio did not change between 18 and 24 h. A new container of
acetyl bromide was used. The 2a:1a ratio did not change between 18 and 24 h. Several other unidentified byproducts/impurities were also
m
n
observed.
Additional experiments were carried out to gather further
detail about the effect of various sources of H+ on these Schmidt
reactions. In our initial survey, we had first tried adding HCl in
ether to the HFIP solvent (Table 1, entries 15 and 16, and Table
4, entry 10). Neither that method nor the addition of aqueous
HCl15f (Table 4, entry 11) gave good results in our hands. On the
other hand, when HCl gas was separately generated and infused
into the HFIP (Table 4, entry 12), a range of results were
obtained. The nonreproducibility of these experiments can be
blamed on the ease with which the HCl gas escaped the solution,
making it difficult to gauge accurately the amount of acid present
in a particular experiment. For example, markedly reduced
yields (on the low end noted in entry 12) were obtained when
HCl/HFIP solutions were aged for even a few minutes. We also
examined whether HBr generated by the addition of AcBr to
HFIP was a suitable substitute for HCl, and the initial evidence
suggested that it is (cf. entries 26 and 27 with 22 and 25). We still
prefer to use AcCl-generated HCl because AcCl is generally
easier to handle and more resistant to hydrolysis in air.
Moreover, we observed very little difference when different
sources of AcCl were used in the reaction (i.e., freshly opened
vs older bottles of reagent; cf. entries 25 and 24). Taking into
account both efficiency and practicality, we prefer using TiCl4
or AcCl as the HCl source among all of the methods tested to
date.
We decided to explore the substrate scope further under these
new reaction conditions utilizing AcCl as a procatalyst. The
substrate scope was comparable to that described for TiCl4,
and lactams were obtained in good to excellent yields (Table 5).
Although higher amounts of AcCl than TiCl4 were required
to achieve complete conversion, the use of AcCl was con-
venient. In addition, both HFIP and its acetate ester byproduct
are volatile, easing the workup. Finally, no metal waste was
produced.
Mechanism. On the basis of precedent,15b−e,18 we propose
the involvement of HFIP as a strong hydrogen-bond donor to the
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Figure 3. Results of 1H NMR monitoring of the reaction of acetyl chloride with HFIP to generate HCl in situ.
HFIP has been shown to form aggregates, such as trimers,
having potential hydrogen bonds with strengths comparable to
those of covalent linkages.15c Such strong hydrogen bonding
could well explain the role of HFIP in the catalysis of the
intramolecular Schmidt reaction. Job’s method of continuous
variation was used to determine the stoichiometry of binding for
the HFIP−substrate and HFIP−product complexes (Figure 5).15c,26
The Job plots based on the 1H NMR data provide good evidence
that HFIP forms a 1:1 complex with both substrate 1a and
product 2a. Although the stoichiometries of binding were similar,
the complexation shift (Δδ) of the HFIP hydroxyl resonance
upon complexation of lactam 2a was significantly higher than for
azido ketone 1a, consistent with the expected stronger complex-
ation of HFIP with the lactam than with the ketone.
To gain more insight into the different behaviors of different
classes of azidoalkyl ketones, a competition experiment between
cyclohexanone-derived 1f and cyclopentanone-derived 1a was
performed (Figure 6 and Scheme 3a). Treating an equimolar
mixture of 1f and 1a in HFIP with 20 mol % AcCl resulted in
complete conversion of substrate 1f to lactam 2f within 3 h (also see
Table 5, entry 2). In sharp contrast, the conversion of 1a to lactam
2a was only 13% complete after 12 h (also see Table 5, entry 7).
These results could be explained by an innate kinetic difference
between the substrates, a difference in the degree of product
inhibition, or a combination of the two.
With respect to the latter point, we made note of the
requirement of different catalyst loadings for different substrate
classes. This could be attributed to the difference in basicity of
different lactam products, with a more basic lactam requiring a
higher catalyst loading.27 To demonstrate different degrees of
product inhibition with different lactams, 1H NMR experiments
were carried out to determine the effect of adding two different
product lactams at the outset of a single relatively fast reaction.
For this, we chose the product of the quicker reaction leading to
2f (and a case that succeeds with 10 mol % AcCl procatalyst) and
Figure 4. Proposed catalytic cycle for the intramolecular Schmidt
reaction employing HFIP as the solvent.
lactam carbonyl (Figure 4). As proposed above, we believe that
association of a Lewis or Brønsted acid with the Lewis basic
lactam product inhibits the catalytic reaction carried out in
CH2Cl2. Hexafluoro-2-propanol as the solvent can potentially
form complexes with the substrate, intermediates, and product.
Critically, hydrogen bonding of HFIP with the lactam carbonyl
by displacement of the Lewis or Brønsted acid allows for
regeneration of the catalyst (most likely a proton). In addition,
one cannot rule out coordination between HFIP and the
catalyst to produce a catalytically more reactive species such as
[HFIP·H]+.25 We note that a cursory measurement of the pH of
the reaction mixture using pH indicator strips (nonbleeding)
gave a reading of pH 4 for the present version, as opposed to pH
1 for an intramolecular Schmidt reaction carried out with TiCl4
in CH2Cl2 (the pH of pure HFIP was measured to be 5 by this
method), suggesting an overall buffering effect of the solvent.
G
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a b
,
Table 5. Scope under the Conditions Employing Acetyl Chloride
a
To a solution of a substrate (0.4 mmol) in HFIP (2.0 mL) at room temperature was added CH3COCl under a nitrogen atmosphere,
b
and the reaction mixture was stirred at 25 °C for the designated period, unless otherwise noted. Concentration of substrate was ca.
0.2 M. Isolated yields. Bridged lactam 3e was also isolated in ca. 3% yield. The reaction was run on a 0.1 mmol scale. Bridged lactam 3i was also
isolated in 3% yield (see the Supporting Information). The product contained 7% 1-phenethylpiperidin-2-one (3l) (see the Supporting
c
d
e
f
g
Information).
2a, the product of a much slower reaction (and one that requires
80 mol % AcCl to reach completion). In the first case, the facile
azido ketone substrate 1f was combined with an equimolar
amount of its lactam product 2f and then treated with 20 mol %
AcCl in HFIP (Figure 6 and Scheme 3b). The time needed for
quantitative conversion of 1f to 2f was ca. 6 h. In contrast, the
reaction of a 1:1 mixture of 1f and 2a with 20 mol % AcCl
in HFIP required >24 h to attain completion (Figure 6 and
Scheme 3c). These results suggested significantly more product
inhibition by lactam 2a than 2f, which is consistent with the
need for higher catalyst loadings with relatively recalcitrant
substrates.7c A more detailed series of kinetic studies is necessary
H
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Figure 5. Job plots for complexation of lactam 2a and azido ketone 1a with HFIP.
the presence of hexafluoro-2-propanol provided evidence that
HCl is an active catalytic species as well as providing a metal-free
catalytic reaction. Prior to this discovery, the primary metal-free
variations of the intramolecular Schmidt reaction used either
trifluoracetic acid as the solvent or TfOH or ClSO3H as a
stoichiometric reagent.
The most favorable examples utilized attractively low loadings
of catalyst, as low as 2.5% for the TiCl4-promoted version or
10 mol % AcCl. Although some of the least cooperative sub-
strates needed as much as 100 mol % “H+” catalyst added (via
either the addition of 25 mol % TiCl4 or the straight-ahead
addition of 100 mol % AcCl), we note that these conditions still
measure up very favorably to those previously reported for
analogous substrates. For example, the reaction of 1a in CH2Cl2
needed 4.5 equiv of TiCl4 to afford a 67% yield,1b while the same
reaction carried out with 20 mol % TiCl4 or 80 mol % AcCl gave a
product yield of 87% or 90%, respectively. Although we did not
quantitatively compare the purities of the products obtained in
these various reactions, we note informally that the presently
reported procedures tended to provide products requiring little
additional purification.
Figure 6. Relative reaction rates for 1f and 1a (see Scheme 3a), 1f with
1 equiv of 2f added at the outset of the reaction (Scheme 3b), and 1f
with 1 equiv of 2a added at the outset of the reaction (Scheme 3c).
Scheme 3
In addition, 1H NMR experiments were performed to exhibit
different degrees of product inhibition with different lactams.
That such structurally similar lactams have substantially different
effects on the rate of a given reaction is at minimum provocative
and might lead to increased understanding of the role of product
inhibition in this and other reactions that afford lactam or amide
products. Future efforts will be directed to extending the scope of
this reaction and elucidating further mechanistic details. In the
meantime, we consider the method reported herein as the best
means of preparatively carrying out this variation of the intra-
molecular Schmidt reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures for new compounds and mechanistic
experiments, list of known compounds, additional screening data
for reaction optimization experiments, and copies of 1H and 13C
NMR spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
to address fully the relative roles of kinetics versus product
inhibition and will be reported in due course.
CONCLUSIONS
■
We have demonstrated a catalytic intramolecular Schmidt
reaction with broad substrate scope and utility. Two versions
of the reaction, one using TiCl4 and the other with AcCl, have
been identified as having strong synthetic utility that is as good or
better than all previous versions of this process. In either case, the
strong hydrogen-bonding ability of hexafluoro-2-propanol was
critical to the development of these substoichiometric reactions.
The discovery of conditions employing AcCl as a procatalyst in
AUTHOR INFORMATION
■
Corresponding Author
jaube@ku.edu
Notes
The authors declare no competing financial interest.
I
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(14) Gu, P.; Zhao, Y.-M.; Tu, Y. Q.; Ma, Y.; Zhang, F. Org. Lett. 2006, 8,
5271−5273.
ACKNOWLEDGMENTS
■
We are grateful to the National Institute of General Medical
Sciences (GM-049093) and the University of Kansas for financial
support. We thank Sarah Neuenswander and Justin Douglas for
assistance with NMR analysis and Ryan Altman and an
anonymous reviewer of this manuscript for helpful suggestions.
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