Regiochemical studies of the ring expansion reactions of hydroxy azides with cyclic ketones

Article abstract of DOI:10.1021/jo000056b

The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and 1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent methyl or ethyl group are generally unselective, but that bul

Full text of DOI:10.1021/jo000056b

J . Org. Chem. 2000, 65, 3771-3774
3771
Regioch em ica l Stu d ies of th e Rin g Exp a n sion Rea ction s of
Hyd r oxy Azid es w ith Cyclic Keton es
Brenton T. Smith, Vijaya Gracias, and J effrey Aube´*
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506
Received J anuary 13, 2000
The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and
1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent
methyl or ethyl group are generally unselective, but that bulkier substituents lead to preferential
migration of the more highly substituted carbon. In addition, it was found that ketones bearing
inductively electron-withdrawing substituents (OMe, Ph, Br) undergo selective migration of the
less highly substituted carbon. For some substrates, alternative reaction pathways were also
identified.
Sch em e 1
Nitrogen ring expansion reactions are capable of
converting an unsymmetrically substituted ketone to one
of two regioisomeric lactams (eq 1). In general, the
Schmidt and Beckmann reactions preferentially lead to
products of the type a (R2 ) H), in which the most highly
substituted carbon has undergone migration to an elec-
tron-deficient nitrogen atom.1 On the other hand, the only
ring-expansion technique that reliably affords products
of the type b (where R2 ) alkyl) utilizes the photochemi-
cal rearrangement of an intermediate oxaziridine.2
systematically varied to include increasingly bulky alkyl
(Me, Et, i-Pr, t-Bu) and inductively electron-withdrawing
substituents (Ph, OMe, Br). In addition, azido alcohols
containing two or three carbons were used. All starting
materials were purchased or synthesized according to
literature methods (see Experimental Section). Each of
the reactions was carried out according to the previously
reported standard protocol, in which 2 equiv of BF3‚OEt2
was added to a solution of 1.5 equiv of azido alcohol 1 or
2 and the ketone (1 equiv) in CH2Cl2 at -0 °C. The
reactions were allowed to come to room temperature and
then heated to reflux for 2 days. In both examples bearing
2-bromo substitution, the reactions were carried out at
room temperature. At the end of the reaction period, the
iminium ether products were hydrolyzed by treatment
with 15% aq KOH for ca. 1 h. The ratios of lactams thus
The direct synthesis of N-substituted lactams from
ketones can also be carried out using a hydroxy azide,
such as 1 or 2, as the nitrogen atom source.3 This process
involves the Lewis acid-promoted formation of an N-
diazonium intermediate, which undergoes rearrangement
to give an iminium ether intermediate that can be
hydrolyzed by base (Scheme 1). In this paper, the
regiochemistry of this process is examined using a series
of differentially 2-substituted cyclopentanones and cy-
clohexanones as prototypical examples.
Resu lts a n d Discu ssion
A series of 2-substituted cyclohexanones and cyclopen-
tanones was examined (Table 1). The R-substituent was
1
obtained were usually determined by H NMR examina-
tion of the crude reaction mixture, although in some cases
the ratios were obtained from the weights of the isolated
isomers. In general, the isomers were separable by
column chromatography. In most cases, the structures
* Corresponding author: Tel 785-864-4496, fax 785-864-5326,
e-mail: jaube@ukans.edu.
(1) (a) Gawley, R. E. Org. React. 1988, 35, 1-420. (b) Wolff, H. Org.
React. 1946, 3, 307-336. (c) Smith, P. A. S. In Molecular Rearrange-
ments; de Mayo, P., Ed.; J ohn Wiley & Sons: New York, 1963; Vol. 1,
pp 457-591. (d) Nitrogen ring-expansion reactions of bicyclic ketones
are known to depend strongly on substitution type: Krow, G. R.
Tetrahedron 1981, 37, 1283-1307.
(2) (a) Oliveros-Desherces, E.; Rivie`re, M.; Parello, J .; Lattes, A.
Tetrahedron Lett. 1975, 851-854. (b) Aube´, J .; Hammond, M.; Gher-
ardini, E.; Takusagawa, F. J . Org. Chem. 1991, 56, 499-508. Correc-
tion: Idem. Ibid. J . Org. Chem. 1991, 56, 4086.
(3) (a) Gracias, V.; Milligan, G. L.; Aube´, J . J . Am. Chem. Soc. 1995,
117, 8047-8048. (b) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube´,
J . Tetrahedron 1997, 53, 16241-16252. (c) Forsee, J . E.; Smith, B. T.;
Frank, K. E.; Aube´, J . Synlett 1998, 1258-1260. (d) Furness, K.; Aube´,
J . Org. Lett. 1999, 1, 495-497. (e) Forsee, J . E.; Aube´, J . J . Org. Chem.
1999, 64, 4381-4385.
1
of the regiosomers could be determined using H NMR,
recognizing that the products resulting from migration
of the less highly substituted carbon 3a -r are expected
to have one more downfield (>3.0 ppm) resonance when
compared to their counterparts 4a -r . In some cases, it
was thought prudent to more thoroughly analyze the
spectra through 2-D NMR techniques. Each regioisomeric
assignment is detailed in the Supporting Information.
In several examples, side products resulting from
idiosyncratic reaction pathways complicated the analysis
of regioselectivity (Scheme 2). In the reaction involving
10.1021/jo000056b CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/19/2000

3772 J . Org. Chem., Vol. 65, No. 12, 2000
Smith et al.
Ta ble 1. Regioselectivity in Lew is Acid -P r om oted
Rea ction s of Cyclic Keton es w ith Azid o Alcoh ols
Sch em e 3
entry compd
R
azide
m
n
yield (%) ratio 3:4:othera
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Me
Me
Me
Me
Et
Et
i-Pr
i-Pr
1
2
1
2
1
2
1
2
1
1
2
2
2
2
2
2
1
2
1
2
1
2
1
2
89
86
83
95
85
94
80
40
53:47
88:12
45:55
55:45
42:58
57:43
21:79
g
h
23:54:23b
(23:77)
13:87
9
10
11
12
13
i
j
k
l
m
t-Bu
t-Bu
Ph
Ph
OMe
1
2
1
2
1
2
2
2
2
1
1
2
1
2
1
11
NR
93
92
53
47:53
>95:5
47:36:17c
(47:53)
91:9
14
15
16
n
o
p
OMe
OMe
OMe
2
1
2
1
2
2
2
1
2
76
52
68
91:9
90:0:10d
(90:10)
76:0:24e
(>95:5)
83:0:17f
(>95:5)
shown in Scheme 2. Such products have been previously
observed to arise from iminium ethers derived from
macrocyclic lactones.3c,e Two products containing a mixed
aminal linkage, 4m and 4p , apparently undergo cycliza-
tion with the side chain hydroxyl group to afford bicyclic
products 6a and 6b, respectively. Finally, two R-bromo
lactams (3q and 3r ) underwent dehydrohalogenation to
afford the unsaturated lactams indicated. To focus at-
tention on the regiochemical issues, the overall regiose-
lectivity of each reaction that gave an additional side
product is indicated in parentheses in Table 1.
17
18
q
r
Br
Br
1
2
2
2
1
2
58
51
a
In cases where side products were isolated, the effective
regioselectivity (3:4) is indicated in parentheses. The identity of
each side product is indicated in Scheme 2. bLactone 5. Bicyclic
c
lactam 6a . dBicyclic lactam 6b. R,â-Unsaturated lactam 7a . R,â-
e
f
Unsaturated lactam 7b.
Sch em e 2
The combination of 2-bromocyclohexanone with a
single example of a substituted hydroxy azide yielded
interesting results (Scheme 3). Of the three products
isolated from this reaction, none resulted from a simple
ring-expansion pathway. The predominant course of the
reaction provided two epimeric spiro compounds contain-
ing a 4H-oxazoline unit, apparently the result of hydride
migration from the benzylic position of the N-diazonium
species initially formed. Alternatively, a concerted elimi-
nation of N2 and H+ cannot be ruled out. The structures
of both products were apparent from spectral analysis,
but the stereostructure of 8a was additionally secured
through X-ray crystallography (Supporting Information).
In addition, R-amino lactone 9 was obtained as a minor
product. Such materials have been previously noted to
occur in simpler systems, and are generally preferred
using the NaHCO3 conditions used in this specific experi-
ment (inferior yields of the same products were obtained
when KOH was used in the workup or if base was
omitted altogether).3c,e Interestingly, only a single dias-
tereomer of 9 (structure determined by X-ray; see Sup-
porting Information) was obtained in these reactions,
which used racemic ketone and hydroxy azide. However,
this point was not pursued, and the yields were suf-
ficiently low as to make stereochemical speculations
based on this evidence imprudent.
The overall yields of the reactions were generally high
throughout, although an understandable drop occurred
with the very sterically crowded 2-tert-butylcyclohex-
anone. In the present work, superior results were ob-
tained through the simple expedient of carrying out the
2-isopropylcyclohexanone, regioisomer 4h (migration of
the more highly substituted carbon) was accompanied by
lactone 5 (νCdO ) 1740 cm-1) resulting from the pathway

Ring Expansion of Cyclic Ketones with Hydroxy Azides
J . Org. Chem., Vol. 65, No. 12, 2000 3773
observed in the classical Schmidt or Beckmann reactions
(although a significant amount of methylene migration
has been reported for the Schmidt or Baeyer-Villiger
reactions of 2-halocyclohexanones4). It seems unlikely
that a strictly steric interpretation of these results will
suffice, inasmuch as there are no trends within this series
that reflect substituent size alone. One possible explana-
tion is that the electron-withdrawing substituent simply
slows down migration of that group. Besides leading to
the regiochemical results observed, this is also consistent
with the result shown in Scheme 3. In this case, the
simultaneous electronic deactivation of the more highly
substituted carbon by bromine combined with activation
of the benzylic position for hydride migration (which
would leave behind a stabilized cation) led to the high
proportion of compounds 8a ,b. This interpretation is
supported by the fact that such products were not
observed in reactions of 2-phenylazidoethanol with cy-
clohexanones lacking adjacent substitution.3a A similar
argument has been made to explain the nearly exclusive
methylene migrations observed in the acid-promoted
ring-expansion reactions of 2-bromocyclohexanone with
ethyl diazoacetate.5
F igu r e 1. Comparison of transition structures resulting from
equatorial addition of azide to the intermediate oxonium
species, with the migrating bond shown in bold. The structures
differ in the position of the diazonium moiety, which is (a) syn
or (b) anti to the more highly substituted carbon.
reactions at reflux in CH2Cl2 (as opposed to the room
temperature conditions previously reported3). The regio-
chemical outcomes seem to depend on two factors. First,
the reactions are poorly selective when smaller alkyl
groups (Me, Et) are used, although selectivity for migra-
tion of the more highly substituted carbon (i.e., products
of the type 4) was observed with increasing steric bulk
of the 2-substituent. Second, the use of substituents with
σ electron-withdrawing character (Ph, OMe, and Br)
significantly favored the opposite regioisomers 3, in which
the less highly substituted carbon becomes attached to
nitrogen. The results are complicated by differences in
ring size and hydroxy azide tether lengths (cf. entries 1
vs 2, 2 vs 4, 11 vs 12, and 13 vs 14). Clearly, changes in
structure, and presumably conformation, are able to
modify the overall trends in sometimes unpredictable
ways, but the above generalizations seem to be valid
nonetheless.
In summary, the regiochemistry of the reaction of cyclic
ketones with hydroxy azides under Lewis acids conditions
has been investigated. Although fairly small R-alkyl
substituents give essentially equal mixtures of regioiso-
mers, larger groups favor migration of the more heavily
substituted R-carbon and inductively electron-poor groups,
regardless of size, favor migration of the less-substituted
group.
Exp er im en ta l Section
Gen er a l m eth od s have been previously reported.3b All
ketones have been purchased or prepared via the following
reported procedures: 1 and 2,6 2-ethylcyclohexanone,7 2-iso-
propylcyclohexanone,8 2-methoxycyclopentanone,7 and 2-bro-
mocyclohexanone.9
The effect of substituent size probably reflects differ-
ences in nonbonded interactions in the spirocyclic N-
diazonium intermediates (Figure 1). In general, the
preferential migration of a bond antiperiplanar to the
leaving group has been presumed in the classical Schmidt
and Beckmann reactions.1 This supposition is also con-
sistent with high stereoselectivity observed in the asym-
metric ring-expansion reactions of hydroxy azides as
reported elsewhere.3a,d The hydroxy azide can attack the
intermediate oxonium ion from either an equatorial or
an axial direction; again, previous work has indicated
that the former is likely preferred3a,d although this point
has not been rigorously proven. One possible explanation
for the effect of increasing steric bulk of the 2-substituent
Gen er a l P r oced u r e for th e Syn th esis of N-Hyd r oxy-
a lk yl La cta m s Usin g BF 3‚OEt2. Rea ction of 2-Meth ylcy-
clop en ta n on e w ith Azid o Alcoh ol 2: N-Hyd r oxyeth yl-3-
m eth ylva ler ola cta m (3b) a n d N-Hyd r oxyeth yl-6-m eth yl-
va ler ola cta m (4b). A solution of ketone (0.263 g, 2.307 mmol)
and azido alcohol 2 (0.466 g, 4.614 mmol) in 8 mL of CH2Cl2
was cooled to 0 °C. BF3‚OEt2 (0.8 mL, 6.256 mmol) was added
dropwise over 5 min; gas evolution was observed. The reaction
was kept at 0 °C for 30 min, allowed to warm to room
temperature, and then heated to reflux for another 24-48 h.
The solution was concentrated, and 15% KOH was added to
the residual oil. The reaction mixture was stirred for 1 h at
room temperature. Additional CH2Cl2 was added, and the
organic layer was dried (anhydrous Na2SO4), filtered, and
concentrated to afford crude product, which was purified by
column chromatography.
+
on regiochemistry is that the alkyl group and the N2
N-Hyd r oxyp r op yl-3-m eth ylva ler ola cta m (3b): 1H NMR
(400 MHz, CDCl3) δ 1.23 (d, J ) 7.2 Hz, 3H), 1.54 (m, 1H),
1.72 (p, J ) 12.1, 5.9 Hz, 2H), 1.78 (m, 1H), 1.88-1.99 (m,
2H), 2.42 (s, J ) 14.2, 7.4 Hz, 1H), 3.30 (t, J ) 5.2 Hz, 2H),
3.42-3.54 (m, 4H); 13C NMR (400 MHz, CDCl3) δ 17.4, 20.8,
moieties experience various degrees of steric interaction
when they are in a syn orientation. This orientation leads
to migration of the less highly substituted carbon, af-
fording 3, as shown in Figure 1a. Conversely, the
alternative arrangement in which the leaving group and
the more highly substituted carbon are anti leads to
migration of the more highly substituted carbon and gives
compounds in series 4. Since the diazonium ion is a small,
cylindrical group, there is not much energy difference
between these forms for small alkyl groups, and a
preference only emerges for larger R groups.
(4) (a) Shechter, H.; Kirk, J . C. J . Am. Chem. Soc. 1951, 73, 3087-
3091. (b) Smissman, E. E.; Bergen, J . V. J . Org. Chem. 1962, 27, 2316-
2318. (c) Hirano, M.; Yakabe, S.; Satoh, A.; Clark, J . H.; Morimoto, T.
Synth. Commun. 1996, 26, 4591-4596.
(5) Dave, V.; Warnhoff, E. W. J . Org. Chem. 1983, 48, 2590-2598.
(6) Badiang, J . G.; Aube´, J . J . Org. Chem. 1996, 61, 2484-2487.
(7) Corey, E. J .; Suggs, W. Tetrahedron Lett. 1975, 31, 2647-2650.
(8) Stork, G.; Brizzolara, A.; Landesman, H.; J ., S.; Terrell, R. J .
Am. Chem. Soc. 1963, 85, 207-222.
The observed selectivity for compounds 3 in the case
of ketones containing polar groups is very valuable
because this mode of migratory selectivity is rarely
(9) Kharasch, M. S.; Sosnovsky, G. J . Org. Chem. 1958, 23, 1322-
1326.

3774 J . Org. Chem., Vol. 65, No. 12, 2000
Smith et al.
28.7, 28.8, 35.7, 42.9, 47.6, 57.6, 173.8; IR (neat) 3420, 2960,
1625 cm-1; MS (FAB) m/e 172 (M+ + 1), 154; HRMS calcd for
C9H18NO2 (M+ + 1): 172.1331, found 172.1331.
CDCl3) δ 15.4, 25.6, 32.2, 50.9, 55.0, 61.5, 89.3, 171.6; IR (neat)
3400, 2960, 1635 cm-1; MS (CI) m/e 174 (M+ + 1), 142; HRMS
calcd for C8H16NO3 (M+ + 1): 174.1130, found 174.1125.
Com p ou n d 6a : 1H NMR (400 MHz, CDCl3) δ 1.47 (m, 1H),
1.68 (m, 1H), 1.92 (m, 2H), 2.29 (m, 2H), 2.46 (dd, J ) 11.9,
6.1 Hz, 1H), 3.39 (m, 1H), 3.87 (m, 2H), 4.15 (m, 1H), 4.70
(dd, J ) 9.28, 4.26 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 17.2,
28.1, 30.8, 42.5, 64.6, 87.4, 168.5; IR (neat) 3500, 2990, 1640
N-Hyd r oxyp r op yl-6-m eth ylva ler ola cta m (4b): 1H NMR
(400 MHz, CDCl3) δ 1.27 (d, J ) 6.5 Hz, 3H), 1.66-1.76 (m,
4H), 1.86-1.94 (m, 2H), 2.43 (m, 2H), 3.23 (dt, J ) 14.2, 5.4
Hz, 1H), 3.41-3.57 (m, 4H), 3.86 (m, 1H); 13C NMR (400 MHz,
CDCl3) δ 17.1, 19.8, 29.9, 30.5, 31.5, 40.7, 51.9, 58.2, 171.4; IR
(neat) 3410, 2960, 1620 cm-1; MS (FAB) m/e 172 (M+ + 1),
154; HRMS calcd for C9H18NO2 (M+ + 1): 172.1338, found
172.1330.
cm-1; MS (CI) m/e 142 (M+ + 1), 72; HRMS calcd for C7H12
NO2 (M+ + 1): 142.0856, found 142.0868.
-
Rea ction of 2-Meth oxycyclop en ta n on e w ith Azid o
Alcoh ol 1: N-Hydr oxyeth yl-3-m eth oxyvaler olactam (3m ),
N-Hyd r oxyeth yl-6-m eth oxyva ler ola cta m (4m ), a n d Bi-
cyclic Sid e P r od u ct (6a ). Com p ou n d 3m : 1H NMR (400
MHz, CDCl3) δ 1.73 (m, 1Η), 1.88-1.98 (m, 3H), 3.27-3.50
(m, 7H), 3.65-3.74 (m, 4H); 13C NMR (400 MHz, CDCl3) δ 19.1,
26.9, 49.0, 50.5, 58.5, 60.7, 76.6, 170.5; IR (neat) 3410, 2960,
1640 cm-1; MS (CI) m/e 174 (M+ + 1), 143; HRMS calcd for
C8H16NO3 (M+ + 1): 174.1130, found 174.1122. Com p ou n d
4m : 1H NMR (400 MHz, CDCl3) δ 1.66-1.78 (m, 2H), 1.98
(m, 1H), 2.10 (m, 1H), 2.32 (m, 1H), 2.49 (m, 1H), 3.36 (m,
4H), 3.76 (m, 4H), 4.51(t, J ) 2.7 Hz, 1H); 13C NMR (400 MHz,
Ack n ow led gm en t. This work was supported by the
National Institute of Health (GM-07775). The authors
thank Martha D. Morton for her assistance with NMR
studies, and Dr. Masao Hirano for his helpful comments.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental details, including characterization of new compounds,
summary of regioisomer assignments, and X-ray data for
compounds 8a and 9. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O000056B